New Drugs of 2000

NEW DRUGS OF 2000

Daniel A. Hussar
[J Am Pharm Assoc 41(2):229-272, 2001. © 2001 American Pharmaceutical Association, Inc.]

Abstract

Objective: To provide information regarding the most important properties of the new therapeutic agents marketed in 2000.
Data Sources: Published studies, drug information reference sources, and product labeling.
Data Synthesis: In 2000, 33 new therapeutic agents were marketed. The indications and information on dosage and administration for the new agents are reviewed, as are the most important pharmacokinetic properties, adverse events, drug interactions, and other precautions. Practical considerations for the use of the new agents are also discussed. Where possible, the properties of the new drugs are compared with those of older drugs marketed for the same indications.
Conclusion: A number of the new therapeutic agents marketed in 2000 have important advantages over older medications. An understanding of the properties of these agents is important if the pharmacist is to effectively counsel patients about their use and to serve as a valuable source of information for other health care professionals regarding these drugs.

Introduction

In 2000 the Food and Drug Administration (FDA) approved 27 new molecular entities (NMEs) for therapeutic use. Twenty of these NMEs, as well as one new biological intended for therapeutic use, were approved and marketed in the United States in 2000. In addition, 12 other NMEs that FDA approved before 2000 were marketed during the year. Thus, a total of 33 therapeutic agents reached the U. S. market for the first time in 2000 (see Table 1). Some of the eight therapeutic agents approved in 2000 but not marketed before the end of the year (Table 2) have become available in early 2001.
The 33 new therapeutic agents marketed in 2000 is higher than the 28 new drugs marketed in 1999, but lower than the record-setting numbers of the 1996 to 1998 period when 41, 45, and 44 new agents were marketed, respectively. One of the new drugs that was marketed in 2000, alosetron hydrochloride (Lotronex -- Glaxo Wellcome), was withdrawn from the market before the end of the year because of concerns about the occurrence of serious adverse events and, therefore, is not considered in this review. Indicated for the treatment of women with diarrhea-predominant irritable bowel syndrome, alosetron infrequently caused serious complications of constipation (e.g., obstruction, perforation, impaction) that, in some cases, required intestinal surgery, as well as ischemic colitis in a small number of patients.
This review of the therapeutic agents first marketed in 2000 considers their most important properties and, when possible, compares them with other available agents that have similar properties. This discussion of new drugs is not intended to be all-inclusive; when additional information is needed, more comprehensive references and the product literature should be consulted.

Antibacterial Agents

Gram-positive cocci such as staphylococci, streptococci, and enterococci are the most common causes of nosocomial, or hospital-acquired, infections. For many years these bacteria were almost always susceptible to vancomycin (e.g., Vancocin), and this agent has been effective as a "last-resort" treatment for serious infections in many patients in whom the usual "first-line" antibiotics were either ineffective or contraindicated. Recently, however, there have been frequent reports of infections caused by vancomycin-resistant enterococci (VRE), as well as occurrences of infections caused by vancomycin-resistant staphylococci, and the development of new antibacterial agents that are active against these organisms has become more urgent. The marketing of quinupristin/dalfopristin (Synercid) in 1999 was a significant first step in the treatment of patients with serious infections associated with vancomycin-resistant Enterococcus faecium (VREF) bacteremia.

In 2000 linezolid (Zyvox -- Pharmacia), a synthetic antibacterial agent that is the first of a new class of oxazolidinone derivatives, was approved, representing an important advance in the treatment of infections caused by some enterococci that are resistant to vancomycin and staphylococci that are resistant to methicillin. The infections for which the clinical efficacy of linezolid has been demonstrated are caused by aerobic gram-positive bacteria. However, its in vitro spectrum of activity also includes certain gram-negative bacteria and anaerobic bacteria. Linezolid inhibits bacterial protein synthesis by binding to a site on the bacterial 23S ribosomal RNA of the 50S subunit and preventing the formation of a functional 70S initiation complex, which is an essential component of the bacterial translation process. Its action is bacteriostatic against enterococci and staphylococci, and bactericidal for most strains of streptococci.
Linezolid has several advantages over quinupristin/dalfopristin, including a broader range of labeled indications, a lower risk of adverse events and drug interactions, and effectiveness following both oral and intravenous administration (quinupristin/dalfopristin is only administered intravenously).
In addition to infections caused by VREF, quinupristin/dalfopristin is also indicated for the treatment of complicated skin and skin structure infections. The labeled indications for linezolid are identified in Table 3. Linezolid and quinupristin/dalfopristin are both active against VREF and this is a labeled indication for both products. However, linezolid has been shown in in vitro studies to also be active against Enterococcus faecalis, whereas the quinupristin/dalfopristin combination is not. The VREF infections in which the effectiveness of linezolid was demonstrated included complicated intra-abdominal infections, complicated skin and skin structure infections, urinary tract infections, and bacteremia of unknown origin.
Other important indications for linezolid include nosocomial pneumonia and complicated skin and skin structure infections, including cases caused by methicillin-resistant Staphylococcus aureus (MRSA). If the documented or presumptive pathogens in these infections include gram-negative bacteria, the use of linezolid in combination with an agent like aztreonam (Azactam) or an aminoglycoside (e.g., gentamicin [e.g., Garamycin]) may be indicated.
Limited data suggest that linezolid may be active against penicillin-resistant strains of Streptococcus pneumoniae. However, this is not a labeled indication at the present time.
The use of linezolid is of greatest benefit in the treatment of infections caused by certain bacteria that are resistant to other antibacterial agents. Because the excessive or otherwise inappropriate use of an antimicrobial agent is likely to increase the rate at which strains of microorganisms develop resistance, the use of a standard antibacterial regimen should be carefully considered before treatment with linezolid is initiated, particularly in the outpatient setting. In the clinical studies, the development of resistance to linezolid was observed in a small number of patients. Cross-resistance between linezolid and other antibacterial agents is unlikely because the mechanism of action of the new agent is different from that of other agents.
Linezolid is well tolerated by most patients and the adverse events experienced most frequently include diarrhea (8%), headache (7%), nausea (6%), and vomiting (4%). Vaginal moniliasis, oral moniliasis, taste alteration, and tongue discoloration (e.g., brown) are among the less commonly reported effects.
Some patients treated with linezolid have experienced thrombocytopenia and it is recommended that platelet counts be monitored in patients who are at increased risk of bleeding, who have pre-existing thrombocytopenia, who receive concomitant medications that may decrease platelet count or function, or who may require linezolid therapy for longer than 2 weeks. Increases in alanine transaminase (ALT) and aspartate transaminase (AST) values have also been reported (10% and 5%, respectively), as have alterations in hemoglobin concentrations (7%).
Like nearly all antibacterial agents, linezolid has been infrequently associated with the occurrence of pseudomembranous colitis ("antibiotic-associated colitis") that may be severe. This possibility should be considered in patients who experience diarrhea subsequent to the administration of the new drug.
Linezolid is classified in Pregnancy Category C. It is not known whether it is excreted in human milk and caution should be exercised when it is administered to a nursing woman. Its effectiveness and safety have not been established in pediatric patients, although the available data indicate that the clearance of the drug is increased in children, resulting in a shorter half-life.
Linezolid is a reversible, nonselective inhibitor of monoamine oxidase (MAO) and may interact with adrenergic and serotonergic agents. Patients treated with the new drug may experience a reversible increase in the pressor response to adrenergic agents, such as indirect-acting sympathomimetic agents, vasopressor agents, or dopaminergic agents, and this response has been reported in specific studies with pseudoephedrine and phenylpropanolamine. When it is necessary to use linezolid concurrently with agents such as dopamine and epinephrine, the initial dosage of the latter agents should be reduced and titrated to achieve the desired response.
Patients treated with linezolid should avoid consuming large quantities of food or beverages having a high tyramine content (e.g., aged cheeses, fermented or air-dried meats, sauerkraut, soy sauce, tap beers, red wines). The quantity of tyramine consumed should be less than 100 mg per meal. The usual tyramine content of some of these foods and beverages is included in the product labeling for linezolid although the tyramine content of any protein-rich food may increase if stored for long periods or improperly refrigerated.
Experience with the concomitant use of linezolid and serotonergic agents such as the selective serotonin reuptake inhibitors (e.g., fluoxetine [Prozac]) is limited. If the concurrent use of a serotonergic agent is necessary, patients should be monitored for the possibility of signs and symptoms of serotonin syndrome (e.g., hyperpyrexia, cognitive dysfunction).
Following oral administration linezolid is rapidly and extensively absorbed, and it may be administered without regard to the timing of meals. Its absolute bioavailability is approximately 100% and dosage adjustment is not necessary when switching from intravenous to oral administration. Linezolid is primarily metabolized to two inactive derivatives, but it is not a substrate for the cytochrome P450 metabolic pathways, nor does it inhibit or induce these enzyme systems. The parent drug and its metabolites are primarily eliminated via the kidneys. Dosage adjustment is not considered necessary in patients with renal insufficiency because the pharmacokinetics of linezolid are not altered. However, the metabolites may accumulate and caution should be exercised, particularly in patients with severe renal dysfunction. When linezolid is to be used in patients on hemodialysis, it should be administered after hemodialysis.
Dosage adjustment of linezolid is not necessary in patients with mild-to-moderate hepatic insufficiency. The use of the drug has not been evaluated in patients with severe hepatic dysfunction.
The usual adult dosage of linezolid is 600 mg every 12 hours, and the dosage regimens for the specific infections for which it is indicated are identified in Table 3. When administered intravenously, linezolid should be administered by intravenous infusion over a period of 30 to 120 minutes. Although data regarding the use of linezolid in children is limited and it is not yet indicated for use in this patient population, there has been some experience with the intravenous use of a 10 mg/kg dose. This provided a similar peak serum concentration but a higher average clearance than was indicated by the studies in adults.
Tablet formulations containing 400 mg and 600 mg of linezolid have been approved, although only the 600 mg potency is marketed at this time. It is also supplied in a formulation for oral suspension (100 mg/5 mL when constituted as directed) and as an intravenous injection in single-use, ready-to-use flexible plastic infusion bags (latex-free and in a foil laminate overwrap) that contain 200 mg (in 100 mL) and 600 mg (in 300 mL) of the drug.
Linezolid is incompatible with numerous other medications and additives should not be introduced into the solution. The intravenous infusion bags should not be used in series connections. If the same intravenous line is used for sequential infusion of several drugs, the line should be flushed before and after infusion of linezolid injection with an infusion solution that is compatible with linezolid (e.g., 5% Dextrose Injection, 0.9% Sodium Chloride Injection) and with any other drug(s) administered via this common line. The infusion bags should be stored at room temperature and kept in the overwrap until ready to use. The injection may exhibit a yellow color that may intensify over time without adversely affecting potency.
Linezolid for oral suspension is supplied as a powder for constitution. The bottle should be tapped gently to loosen the powder, and a total of 123 mL of distilled water is added in two portions. After the first half of the water is added, the bottle should be vigorously shaken to wet all of the powder. The second half of the water is then added and the bottle vigorously shaken to obtain a uniform suspension. When the suspension is to be administered, the bottle should not be shaken but rather should be inverted three to five times to permit gentle mixing. The constituted suspension should be stored at room temperature and used within 21 days.
Linezolid for oral suspension contains aspartame, which, following administration, is metabolized to phenylalanine (20 mg/5 mL of suspension). Patients with phenylketonuria who must restrict their intake of phenylalanine should be warned that this formulation (but not the other formulations) is a source of this agent.

Gatifloxacin (Tequin -- Bristol-Myers Squibb) and moxifloxacin hydrochloride (Avelox -- Bayer) are the newest fluoroquinolone antibacterial agents, increasing the number of agents in this class to 10. They exhibit a bactericidal action by inhibiting DNA gyrase (topoisomerase II) and topoisomerase IV, which are required for bacterial DNA replication, transcription, repair, and recombination. Both of the new drugs contain a methoxy substituent at position 8 of the molecule, and this is thought to provide enhanced activity and lower selection of resistant mutants of gram-positive bacteria.
Gatifloxacin and moxifloxacin are active against a wide range of gram-positive and gram-negative bacteria, and also against Chlamydia pneumoniae and Mycoplasma pneumoniae. They are more active than the early fluoroquinolones (e.g., ciprofloxacin [Cipro] and norfloxacin [Noroxin]) against gram-positive bacteria such as Streptococcus pneumoniae, and gram-positive bacteria that are resistant to other fluoroquinolones may be susceptible to the new agents. Both agents have been shown in in vitro studies to have activity against penicillin-resistant Streptococcus pneumoniae (PRSP strains). However, data from patients with infections caused by PRSP are limited, and this is not a labeled indication at the present time. Another fluoroquinolone, levofloxacin (Levaquin), was recently approved for the treatment of community-acquired pneumonia (CAP) caused by PRSP. Gatifloxacin and moxifloxacin are less active against Pseudomonas aeruginosa than agents such as ciprofloxacin, and are not indicated for the treatment of infections caused by this organism.
Respiratory infections are the primary indications for gatifloxacin and moxifloxacin, although gatifloxacin is also indicated for urinary tract infections, pyelonephritis, and gonorrhea. The specific labeled indications are noted in Tables 4 and 5 and are considered later in the discussions of the individual agents.
Serious hypersensitivity reactions, some following the first dose, have infrequently occurred with the use of the fluoroquinolones, and the new agents are contraindicated in patients with a history of hypersensitivity to any of the drugs in this class, including the quinolones, cinoxacin (Cinobac), and nalidixic acid (NegGram). If a rash or other sign of hypersensitivity develops, treatment should be immediately discontinued.
An important concern with the use of both gatifloxacin and moxifloxacin is the possibility of their prolonging the QT interval of the electrocardiogram and the associated increased risk of ventricular arrhythmias including torsade de pointes. This has also been a particular concern with grepafloxacin (Raxar), which has been withdrawn from the market because of infrequent reports of cardiovascular adverse events, and sparfloxacin (Zagam). It has been suggested that such increased risk may be associated with the use of all of the fluoroquinolones.
Moxifloxacin has been shown to prolong the QT interval, whereas the labeling for gatifloxacin notes that it "may have the potential to prolong the QT interval...." Based on currently available information, gatifloxacin appears less likely than moxifloxacin to prolong the QT interval. However, the pertinent warnings should be observed for the use of both agents. Both drugs should be avoided in patients with known prolongation of the QT interval, uncorrected hypokalemia, or who are receiving Class IA (e.g., quinidine, procainamide [Pronestyl]) or Class III (e.g., amiodarone [e.g., Cordarone], sotalol [e.g., Betapace]) antiarrhythmic agents. Caution should be exercised when the new agents are used concurrently with other medications that prolong the QT interval, such as cisapride (Propulsid, available only in a restricted program), erythromycin (e.g., E-Mycin), antipsychotic agents, and tricyclic antidepressants, as well as in patients with ongoing proarrhythmic conditions (e.g., clinically significant bradycardia, acute myocardial ischemia).
Like the other fluoroquinolones, gatifloxacin and moxifloxacin may cause dizziness, nervousness, central nervous system (CNS) stimulation, and other CNS effects, and patients should know how they react to the new medication before they engage in activities requiring alertness and coordination (e.g., operating vehicles or machinery). The new drugs must also be used with caution in patients with known or suspected CNS disorders such as epilepsy.
The labeling for all the fluoroquinolones includes a warning about the potential for pain, inflammation, or rupture of a tendon (e.g., Achilles tendon) that may require surgical repair or result in prolonged disability. Although these problems were not observed in the clinical trials with gatifloxacin and moxifloxacin, any patient treated with these agents who experiences such symptoms should discontinue the medication, and rest and avoid exercise until the possibility of tendonitis or tendon rupture can be excluded.
Phototoxicity has been associated with the use of the fluoroquinolones, particularly lomefloxacin (Maxaquin) and sparfloxacin. Phototoxic reactions have not been observed with gatifloxacin and moxifloxacin when they are used in the recommended dosages, but patients should be advised to avoid excessive sunlight or artificial ultraviolet light (e.g., tanning beds) while being treated with these drugs.
The fluoroquinolones, including gatifloxacin and moxifloxacin, have caused erosion of cartilage in weight-bearing joints and other signs of arthropathy in immature animals of several species. For this reason, the use of a fluoroquinolone is best avoided in patients younger than 18 years of age, in women who are nursing, and in pregnant women. Both of the new agents are classified in Pregnancy Category C.
Pseudomembranous colitis has occurred with nearly all antibacterial agents, and this diagnosis should be considered in patients who develop diarrhea subsequent to the use of gatifloxacin or moxifloxacin.
As with the other fluoroquinolones, the absorption and activity of gatifloxacin and moxifloxacin may be markedly reduced by metal-containing products such as aluminum- and/or magnesium-containing antacids; sucralfate (Carafate); ferrous sulfate; dietary supplements including multivitamins/minerals that contain iron, magnesium, or zinc; and buffered formulations of didanosine (Videx). An appropriate interval of time must separate the administration of a fluoroquinolone and a metal-containing product.
The cytochrome P450 system is not involved in the metabolism of gatifloxacin or moxifloxacin, nor is this system induced or inhibited by the new agents. Therefore, unlike ciprofloxacin and enoxacin (Penetrex), which inhibit certain CYP450 pathways, the two new fluoroquinolones are not likely to interact with medications, such as theophylline, that are extensively metabolized via these pathways. In studies in which gatifloxacin or moxifloxacin was used in individuals receiving warfarin (e.g., Coumadin), no significant change in anticoagulant activity was noted. Nevertheless, concurrent therapy should be closely monitored.
The concurrent use of a nonsteroidal anti-inflammatory drug (NSAID) and a fluoroquinolone has been suggested to increase the risk of CNS stimulation and convulsions. However, this response was not noted in the studies of gatifloxacin and moxifloxacin.
Some patients with diabetes treated with insulin or an oral antidiabetic agent have experienced alterations in blood glucose concentrations (hypoglycemia or hyperglycemia) while being treated with a fluoroquinolone. Although interactions appear unlikely, gatifloxacin and moxifloxacin should be considered to have a potential for changing glucose concentrations.
Both gatifloxacin and moxifloxacin have a long enough duration of action to be administered just once every 24 hours. They are administered orally and gatifloxacin is also available in formulations intended for intravenous infusion. In the following discussions, gatifloxacin and moxifloxacin are considered on an individual basis.

Gatifloxacin is a racemic mixture, with the antibacterial activity and disposition of the R- and S-enantiomers being virtually identical. It is indicated for the treatment of acute sinusitis, acute bacterial exacerbation of chronic bronchitis (ABECB), CAP, uncomplicated and complicated urinary tract infections, pyelonephritis, and gonorrhea caused by susceptible strains of the microorganisms identified in Table 4.
In comparative studies in patients with CAP, gatifloxacin was as effective as levofloxacin and clarithromycin (Biaxin, administered twice a day), and in hospitalized patients with severe CAP, was as effective as ceftriaxone (Rocephin), with or without intravenous erythromycin and followed by clarithromycin. In patients with ABECB, gatifloxacin was more effective than cefuroxime axetil (Ceftin, administered twice a day) and as effective as levofloxacin, and in the treatment of sinusitis, the new agent was as effective as clarithromycin (administered twice a day).
In the treatment of urinary tract infections, including pyelonephritis, gatifloxacin was as effective as ciprofloxacin (administered twice a day), and it was as effective as ofloxacin (Floxin) in the treatment of gonorrhea. Gatifloxacin has also been evaluated in the treatment of skin and skin-structure infections, but this is not a labeled indication at the present time.
The adverse events experienced most often with the use of gatifloxacin include nausea (8%), diarrhea (4%), vaginitis (6%), headache (3%), dizziness (3%), and, with intravenous use, local injection-site reactions (5%). In the clinical trials treatment was discontinued because of adverse events in 3% of patients.
The administration of aluminum- and/or magnesium-containing antacids, ferrous sulfate, or other metal-containing products at the same time as a dose of gatifloxacin may reduce the bioavailability of the antibacterial agent by more than 50%. To avoid this interaction, gatifloxacin should not be administered within 4 hours before or after administration of the metal-containing product. No significant interactions have been observed when milk or calcium carbonate has been administered at the same time as gatifloxacin, and the new agent may be administered without regard to food, including milk and dietary supplements containing calcium.
The bioavailability and half-life of gatifloxacin are markedly increased by the concurrent administration of probenecid (e.g., Benemid), presumably because the latter agent inhibits the tubular secretion of the fluoroquinolone. In a study in which 11 healthy volunteers received gatifloxacin and digoxin concurrently, 8 of the 11 experienced modest increases in digoxin concentrations and, in 3 of the 11, there were significant increases in concentration. Patients taking both gatifloxacin and digoxin should be monitored closely for signs and/or symptoms of digoxin toxicity.
Following oral administration, gatifloxacin is well absorbed and its absorption is not affected by food. Its absolute bioavailability is 96%, and it is not necessary to adjust the dosage when switching from the intravenous to oral route of administration. It is metabolized to only a very limited extent and it is excreted, primarily as unchanged drug, via the kidneys. The clearance of the drug is substantially reduced in patients with impaired renal function, and the dosage should be reduced. Dosage adjustment of gatifloxacin is not necessary in patients with moderate hepatic impairment, but the effect of severe hepatic impairment on the action of the drug is not known.
The usual dosage of gatifloxacin for most infections is 400 mg once a day; the specific recommendations are provided in Table 4. In patients with creatinine clearance < 40 mL/minute, including patients requiring hemodialysis or continuous ambulatory peritoneal dialysis (CAPD), an initial dose of 400 mg is given on the first day and the dosage is reduced to 200 mg once a day on subsequent days. For patients on hemodialysis, gatifloxacin should be administered after a dialysis session.
In the treatment of gonorrhea, gatifloxacin is administered as a single 400 mg dose treatment, and in the treatment of uncomplicated urinary tract infections, it is used as a single 400 mg dose or in a dosage of 200 mg once a day for 3 days. Adjustment of these dosage regimens is not necessary in patients with impaired renal function.
Gatifloxacin tablets are supplied in 200 and 400 mg potencies. The formulations for intravenous use include single-use vials containing a concentrated solution of 200 mg (10 mg/mL, 20 mL) and 400 mg (10 mg/mL, 40 mL) of gatifloxacin in 5% Dextrose Injection, and ready-to-use flexible bags containing a dilute solution of 200 mg or 400 mg of gatifloxacin in 5% Dextrose Injection.
Gatifloxacin injection should be administered by intravenous infusion over a period of 60 minutes. It should not be administered by rapid or bolus intravenous infusion. The single-use vials must be further diluted to a concentration of 2 mg/mL with a compatible solution (e.g., 5% Dextrose Injection, 0.9% Sodium Chloride Injection) prior to administration. It is not necessary to further dilute the premixed gatifloxacin solution provided in the flexible bags.
Additives or other medications should not be added to gatifloxacin solutions or infused simultaneously through the same intravenous line. If the same intravenous line is used for sequential infusion of several different drugs, the line should be flushed before and after infusion of gatifloxacin injection with an infusion solution compatible with gatifloxacin injection and with any other drug(s) administered via this common line.

Moxifloxacin hydrochloride has been approved for the treatment of acute bacterial sinusitis, ABECB, and CAP of mild-to-moderate severity caused by susceptible strains of the microorganisms identified in Table 5. In comparative studies in patients with sinusitis, moxifloxacin was as effective as cefuroxime axetil (administered twice a day), and in patients with CAP, it was as effective as clarithromycin (administered twice a day). In patients with ABECB, a 5-day regimen of moxifloxacin was as effective as a 10-day regimen of clarithromycin (administered twice a day). It is the first fluoroquinolone to be demonstrated to be effective in a 5-day regimen for the treatment of this infection, although azithromycin (Zithromax) and cefdinir (Omnicef) are also approved for use in 5-day regimens for the treatment of ABECB.
Moxifloxacin has also been evaluated for the treatment of skin and skin structure infections, but this is not a labeled indication at the present time.
The adverse events reported most often in the studies of moxifloxacin include nausea (8%), diarrhea (6%), and dizziness (3%). Treatment was discontinued in 4% of patients because of adverse events.
If administered at the same time, metal-containing products can reduce the bioavailability of moxifloxacin by more than 50%, and it is recommended that this fluoroquinolone be administered at least 4 hours before or 8 hours after the administration of metal-containing products.
Following oral administration moxifloxacin is well absorbed and its absolute bioavailability is approximately 90%. Its absorption is not affected by food and it may be administered without regard to meals.
Moxifloxacin is metabolized via glucuronide and sulfate conjugation. The cytochrome P450 system is not involved in its metabolism, nor is this system inhibited or induced by the new agent. Approximately 45% of a dose of moxifloxacin is excreted as unchanged drug, with approximately one-half being eliminated in the urine and one-half in the feces. It is not necessary to adjust the dosage in patients with renal impairment or in patients with mild hepatic insufficiency. The actions of moxifloxacin have not been evaluated in patients with moderate and severe hepatic insufficiency, and use of the drug in these patients is not recommended.
The recommended dosage of moxifloxacin is 400 mg every 24 hours for 10 days in the treatment of sinusitis and CAP, and for 5 days in the treatment of ABECB. Tablets are supplied that contain the equivalent of 400 mg of moxifloxacin. A parenteral formulation is being developed but has not yet been approved.

Antiviral Agent

A combination of a new HIV protease inhibitor, lopinavir, with a previously available HIV protease inhibitor, ritonavir (Norvir), has been marketed under the trade name Kaletra (Abbott). Ritonavir is included in the combination because it is a potent inhibitor of the CYP3A-mediated metabolism of lopinavir, thereby providing significantly increased plasma concentrations of lopinavir. The increased concentration of lopinavir is accomplished with the use of a dose of ritonavir (100 mg) that is only one-sixth of the usual therapeutic dose of ritonavir (i.e., 600 mg). The use of the recommended dosage of the combination formulation (400 mg of lopinavir and 100 mg of ritonavir) provides plasma concentrations of lopinavir that are 15- to 20-fold higher than those of ritonavir, and the concentrations of ritonavir are less than 7% of those obtained when it is used in its therapeutic dosage of 600 mg. Therefore, the antiviral activity of the combination formulation is attributed to lopinavir.
Lopinavir is the sixth HIV protease inhibitor to be marketed, joining amprenavir (Agenerase), indinavir (Crixivan), nelfinavir (Viracept), ritonavir, and saquinavir (Fortovase, Invirase). Lopinavir/ritonavir is indicated in combination with other antiretroviral agents for the treatment of HIV infection, and was approved under the provisions of the accelerated approval process based on surrogate marker changes (i.e., decreased plasma HIV RNA concentrations, increased CD4 cell counts).
In the largest clinical study of lopinavir/ritonavir, either the new agent or nelfinavir was used in conjunction with lamivudine (Epivir) and stavudine (Zerit) in patients who had not received prior antiretroviral therapy. The lopinavir regimen was determined to be at least as effective as the nelfinavir regimen in reducing HIV RNA concentrations and increasing CD4 cell counts. Although the clinical effectiveness (e.g., prolongation of survival, reduced occurrence of opportunistic infections) of lopinavir has not yet been demonstrated, it is expected that continuing studies will provide such documentation.
Varying degrees of cross-resistance have been observed among protease inhibitors, but little is known regarding the cross-resistance of viruses that developed decreased susceptibility to lopinavir in the clinical studies. The presence of ritonavir does not appear to influence the selection of lopinavir-resistant viruses in vitro.
The most commonly reported adverse events of moderate-to-severe intensity in adult patients treated with lopinavir/ritonavir include diarrhea (14%), nausea (6%), abdominal pain (3%), asthenia (3%), and headache (3%). In the comparative study, the rates of discontinuation of therapy (3%) because of adverse events were similar for the lopinavir/ritonavir regimen and the nelfinavir regimen. The adverse event profile in children is generally similar to that for adults, with rash (2%) being the only drug-related adverse event of moderate or severe intensity reported in 2% or more of pediatric patients.
Treatment with lopinavir/ritonavir has resulted in large increases in the concentrations of total cholesterol (7%) and triglycerides (5%). Cholesterol and triglyceride concentrations should be determined prior to initiating therapy and periodically during therapy. If necessary, lipid-lowering drug therapy should be employed, but the selection of such therapy should be done with caution because of the potential for lopinavir/ritonavir to interact with certain of these medications. There have been infrequent reports of pancreatitis in patients treated with lopinavir/ritonavir, including some who developed marked elevations in triglyceride concentrations. Pancreatitis should be considered if symptoms (nausea, vomiting, abdominal pain) or abnormalities in laboratory values (e.g., increased serum lipase or amylase values) suggestive of this complication should occur.
The postmarketing experience with earlier protease inhibitors has identified concerns that warrant caution when using any of the agents in this class, including lopinavir. There have been reports of hyperglycemia, exacerbation of pre-existing diabetes mellitus, and new-onset diabetes during therapy. Redistribution/ accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, breast enlargement, and "cushingoid appearance" have also been observed. There have been reports of spontaneous bleeding in patients with hemophilia, and patients with this disorder should be monitored for this potential problem. Although a causal relationship between the use of protease inhibitors and the occurrence of these events has not been established, the labeling for these agents now includes precautions regarding the potential for such effects.
Lopinavir/ritonavir is classified in Pregnancy Category C. An Antiretroviral Pregnancy Registry has been established to monitor maternal-fetal outcomes, and women who are pregnant and receiving lopinavir/ritonavir can be registered by calling 800-258-4263. The Centers for Disease Control and Prevention (CDC) recommends that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of the virus. The use of lopinavir/ritonavir has been studied in pediatric patients who were 6 months of age or older. However, its effectiveness and safety in children less than 6 months of age have not been established.
The action of ritonavir to inhibit the CYP3A-mediated metabolism (and CYP2D6 to a lesser extent) and markedly increase the concentrations and activity of numerous other therapeutic agents is well recognized. Indeed, it is for this reason that it is used in combination with lopinavir, an agent that otherwise would have to be administered in larger doses and more frequently in a patient population for whom the "pill burden" often results in noncompliance. Although the interaction with lopinavir provides an advantageous result, the interaction of ritonavir with many other medications can have serious consequences. The use of lopinavir/ritonavir is contraindicated with flecainide (Tambocor), propafenone (Rythmol), cisapride (Propulsid; available only on a restricted basis), and pimozide (Orap) because of the risk of cardiac arrhythmias; with midazolam (Versed) and triazolam (e.g., Halcion) because of the potential for prolonged or increased sedation or respiratory depression, and with ergot derivatives such as dihydroergotamine (e.g., DHE-45, Migranal), ergotamine (e.g., Ergomar), ergonovine (e.g., Ergotrate), and methylergonovine (e.g., Methergine) because of the risk of acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues. In addition, the new product should not be used concomitantly with lovastatin (Mevacor) or simvastatin (Zocor) because of a greater risk of myopathy, including rhabdomyolysis. A similar risk may exist with atorvastatin (Lipitor) and cerivastatin (Baycol) that are also metabolized via the CYP3A pathway, but fluvastatin (Lescol) and pravastatin (Pravachol) are less likely to interact.
Lopinavir/ritonavir may also markedly increase the concentration and activity of sildenafil (Viagra). The dosage of the latter agent should be reduced to no more than 25 mg every 48 hours, and patients should be advised to promptly report the occurrence of sildenafil-associated adverse events such as hypotension, visual changes, and sustained erections. Other agents whose activity may be increased by lopinavir/ritonavir, and for which concurrent therapy warrants caution, include itraconazole (Sporanox) and ketoconazole (e.g., Nizoral), with which doses higher than 200 mg a day are not recommended; rifabutin (Mycobutin), the dosage of which should be reduced by at least 75%; antiarrhythmic agents (e.g., amiodarone [e.g., Cordarone], bepridil [Vascor], lidocaine, quinidine); clarithromycin (Biaxin); dihydropyridine calcium channel blocking agents (e.g., felodipine [Plendil]); immunosuppressants (cyclosporine [e.g., Neoral]; tacrolimus [Prograf]; sirolimus [Rapamune]); and other HIV protease inhibitors (amprenavir, indinavir, saquinavir).
Lopinavir/ritonavir may induce its own metabolism and increase the biotransformation of some drugs that are metabolized by CYP450 enzymes and by glucuronidation. Medications whose activity may be reduced by the new product include atovaquone (Mepron), methadone, and estrogens such as ethinyl estradiol. When lopinavir/ritonavir treatment is to be initiated in a woman who is using an estrogen-based oral contraceptive, alternative or additional contraceptive measures should be used.
Lopinavir itself undergoes extensive hepatic metabolism via the CYP3A pathway, and its action may be altered by other agents that induce or inhibit this system. Rifampin (e.g., Rifadin) may substantially reduce the plasma concentration of and virologic response to lopinavir, and the two agents should not be used concurrently. Other agents that may increase the metabolism and reduce the activity of lopinavir include carbamazepine (e.g., Tegretol), phenobarbital, phenytoin (e.g., Dilantin), corticosteroids (e.g., dexamethasone [e.g., Decadron]), and St. John's wort, and concurrent use should be closely monitored. Plasma concentrations of lopinavir may be reduced by the concurrent use of the non-nucleoside reverse transcriptase inhibitors efavirenz (Sustiva) and nevirapine (Viramune) and increased by delavirdine (Rescriptor).
The oral solution formulation of lopinavir/ritonavir contains 42.4% alcohol, and a risk of a disulfiram-like reaction exists in patients treated with disulfiram (e.g., Antabuse) or agents like metronidazole (e.g., Flagyl).
The plasma concentration and bioavailability of lopinavir are increased when the product is administered with a meal, and it is recommended that doses be taken with food to enhance bioavailability and minimize pharmacokinetic variability. The drug is extensively metabolized and eliminated by the liver, and caution should be exercised when it is administered to patients with hepatic impairment, in whom concentrations are likely to be increased. Less than 3% of a dose of lopinavir is excreted unchanged in the urine and clearance of the drug is not expected to be reduced in patients with impaired renal function.
Lopinavir/ritonavir capsules each contain 133.3 mg of lopinavir and 33.3 mg of ritonavir, and the oral solution contains 400 mg/100 mg per 5 mL. The recommended adult dosage is 400 mg/100 mg (three capsules or 5 mL) twice a day with food. In patients also treated with efavirenz or nevirapine, an increase in dosage to 533 mg/133 mg twice a day should be considered in treatment-experienced patients where reduced susceptibility to lopinavir is clinically suspected (by treatment history or laboratory evidence).
In children 6 months to 12 years of age, the recommended dosage of the oral solution is 12 mg/3 mg/kg for those 7 to < 15 kg, and 10 mg/2.5 mg/kg for those 15 to 40 kg twice a day with food, up to a maximum dose of 400 mg/100 mg in children > 40 kg. An increased dosage should be considered in children also treated with efavirenz or nevirapine.
Lopinavir/ritonavir capsules and oral solution should be stored in a refrigerator until dispensed. Following dispensing, the formulations remain stable until the expiration date printed on the label if they are stored in the refrigerator. If stored at room temperature up to 77°F, the formulation should be used within 2 months.

Agent for Cold Sores

Cold sores (herpes labialis) are most often caused by herpes simplex virus type 1 (HSV-1), and are experienced by approximately one in five Americans each year. Most of these individuals have one to three episodes a year, and some may suffer as many as 10 outbreaks a year. If not treated, cold sores often last for 7 to 10 days.
Most individuals who experience cold sores use nonprescription lip balms and other topical preparations. Although these products may help to relieve symptoms such as pain, burning, and itching, they have not been shown to reduce the healing time or duration of symptoms. The topically applied antiviral agent penciclovir (Denavir) has been demonstrated to shorten the duration of cold sore lesions and lesion pain, but this agent is available only on prescription.
Docosanol (Abreva -- SmithKline Beecham Consumer) is a saturated 22-carbon, straight-chain alcohol that has been approved for nonprescription use in a cream formulation for the treatment of cold sores/fever blisters. Cold sores worsen when the viral infection spreads from infected cells to healthy ones. Docosanol does not have antiviral activity but is thought to enter healthy cells and modify the cell membrane in a manner that prevents the virus from entering the cell and spreading the infection.
In studies involving more than 700 patients, Docosanol was shown to shorten healing time as well as the duration of symptoms such as tingling, pain, burning, and itching. Although the new drug has not been directly compared with penciclovir, study results with the two agents are generally similar, and docosanol has the advantage of being available without a prescription. Both drugs are more effective when treatment is initiated as soon as possible after the first sign of the tingle, redness, bump, or itch that can signal the onset of a cold sore, and the greater accessibility of docosanol because of its nonprescription status facilitates rapid initiation of treatment.
Docosanol is well tolerated and the frequency of adverse events in the clinical studies was similar to that experienced by those receiving placebo. It is indicated for use in adults and children 12 years of age or older.
Docosanol cream is applied to the affected area on the face or lips at the first sign of a cold sore. It should be rubbed in gently but completely, and applied 5 times a day until the lesion is healed. The cream should not be applied directly inside the mouth, or in or near the eyes. If the cold sore gets worse or is not healed within 10 days after initiating docosanol treatment, the patient should contact his physician.
Cosmetics, such as lipstick, may be applied over docosanol; however, use of a separate applicator like a cotton swab, to apply cosmetics over an unhealed cold sore is recommended to avoid spreading the infection.
Docosanol cream contains the drug in a 10% concentration. The cream has no medicinal smell or taste, and dries clear following application.

Antihyperlipidemic Agent

Colesevelam hydrochloride (WelChol -- Sankyo) is a nonabsorbed, polymeric, lipid-lowering agent that binds with bile acids in the intestine and significantly reduces their reabsorption. As the bile acid pool becomes depleted, there is an increased conversion of cholesterol to bile acids, thereby reducing cholesterol concentrations. The mechanism of action of colesevelam is similar to that of cholestyramine (e.g., Questran) and colestipol (Colestid). However, the new drug has a greater binding affinity for bile acids, permitting the use of a lower dosage, and appears to have a lower incidence of gastrointestinal (GI) adverse events and a lower potential for drug interactions.
Colesevelam is indicated for use, alone or in combination with a hydroxymethyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitor (a "statin"), as adjunctive therapy to diet and exercise for the reduction of elevated low-density lipoprotein cholesterol (LDL-C) in patients with primary hypercholesterolemia (Fredrickson Type IIa). In the clinical studies, colesevelam reduced LDL-C concentrations by 15% to 18%, and increased high-density lipoprotein cholesterol (HDL-C) concentrations by 3%. There were small increases in triglyceride concentrations, but these were not statistically different from the results in those receiving placebo. Although comparative studies with cholestyramine and colestipol have not been conducted, the type and extent of the action of colesevelam on lipid concentrations appear to be similar to those of the previously available agents.
The action of the bile acid sequestrants, including colesevelam, on lipid concentrations is weaker than that of statins such as atorvastatin (Lipitor). Although the target cholesterol concentrations can be attained in some patients with colesevelam monotherapy, in many patients it will be necessary to use a statin alone, or a bile acid sequestrant with a statin, to achieve the treatment goal. Studies in which colesevelam was used in conjunction with atorvastatin, lovastatin (Mevacor), or simvastatin (Zocor) demonstrated an additive reduction of LDL-C, resulting in up to an additional 16% reduction in LDL-C above that seen when the statin was used alone. The LDL-C reduction with atorvastatin in a dosage of 80 mg a day did not differ to a statistically significant extent from the combination of atorvastatin in a dosage of 10 mg a day and colesevelam in a dosage of 3.8 grams a day. Both atorvastatin and simvastatin produced significant reductions in triglyceride concentrations in the studies, even when used in a low dosage of 10 mg a day. The concurrent use of colesevelam almost completely eliminated the triglyceride reduction provided by atorvastatin, but had little effect on the triglyceride reduction produced by simvastatin.
The most commonly experienced adverse events with the use of colesevelam include flatulence (12%), constipation (11%), dyspepsia (8%), infection (10%), and headache (6%), although only constipation and dyspepsia occurred at greater frequencies than in those in the placebo group. GI effects, most notably constipation, appear to occur considerably less frequently with the new agent than with cholestyramine and colestipol. All three of the bile acid sequestrants are more likely than the statins to cause GI adverse events but, because they are not absorbed, they are less likely to cause systemic adverse events that some patients experience with the statins. Colesevelam is contraindicated in patients with bowel obstruction, and caution must be exercised if it is used in patients with dysphagia, swallowing disorders, or severe GI motility disorders or patients who have had major GI tract surgery.
Colesevelam is classified in Pregnancy Category B and should be used during pregnancy only if clearly needed. Its effectiveness and safety have not been evaluated in pediatric patients.
The use of cholestyramine and colestipol has been associated with a reduction in the absorption of the fat-soluble vitamins A, D, E, and K. During the clinical studies of up to 1 year's duration, colesevelam did not cause any clinically significant reduction in the absorption of these vitamins. Nevertheless, therapy in patients who are susceptible to deficiencies of vitamin K or other fat-soluble vitamins should be closely monitored.
Cholestyramine and colestipol have been reported to bind not only with bile acids in the intestine but also with numerous medications, with a resultant reduction in their absorption and activity. Therefore, it is generally recommended that other medications be administered at least 1 hour before or 4 hours after these agents. In drug interaction studies in which colesevelam was administered at the same time as various other medications, it was determined to have no significant effect on the bioavailability of digoxin, lovastatin, metoprolol (e.g., Lopressor), quinidine, valproic acid (e.g., Depakene), or warfarin (e.g., Coumadin). Although there was a decrease in the peak plasma concentration and the bioavailability of sustained-release verapamil (Calan SR), the clinical importance of this observation is not clear because of the high degree of variability in the bioavailability of verapamil.
Colesevelam hydrochloride is supplied in tablets in an amount equivalent to 625 mg of colesevelam. The drug should be administered with a liquid and a meal, and the recommended initial dosage is 6 tablets once a day or 3 tablets twice a day (i.e., with the morning and evening meals). The maximum therapeutic response is usually achieved within 2 weeks and, depending on the desired therapeutic effect, the dosage can be increased to 7 tablets a day. When used in conjunction with a statin, the two drugs may be administered at the same time, unlike the recommendations for cholestyramine and colestipol, which advise that an interval of time separate the administration of the drugs to avoid interactions that might reduce the absorption and action of the statin. The dosage of colesevelam when used with a statin is the same as when it is used as monotherapy.

Antiarrhythmic Agent

Dofetilide (Tikosyn -- Pfizer) is an antiarrhythmic agent with Class III (i.e., prolong duration of cardiac action potential) properties. It joins amiodarone (e.g., Cordarone), bretylium, ibutilide (Corvert), and sotalol (e.g., Betapace), that are similarly classified based on their electrophysiologic properties. However, dofetilide has a more selective action than most of the Class III agents, such as sotalol, which also exhibits b-adrenergic-blocking activity, and the new drug is actually a derivative of the non-b-blocking moiety of sotalol.
Dofetilide is indicated for the conversion of atrial fibrillation and atrial flutter to normal sinus rhythm. It is also indicated for the maintenance of normal sinus rhythm (delay in time to recurrence of atrial fibrillation/atrial flutter) in patients with atrial fibrillation/atrial flutter of greater than 1 week duration who have been converted to normal sinus rhythm. The use of the drug should be reserved for patients in whom atrial fibrillation/atrial flutter is highly symptomatic because it may cause life-threatening ventricular arrhythmias.
The effectiveness of dofetilide is dose-related and, in the clinical studies, about 30% of the patients receiving a dosage of 500 mcg twice a day converted to normal sinus rhythm, most within 24 to 36 hours, compared with about 1% of those receiving placebo. Patients who did not convert to normal sinus rhythm within 48 to 72 hours had electrical cardioversion. Those patients remaining in normal sinus rhythm after conversion in the hospital were continued on maintenance therapy as outpatients for up to 1 year unless they experienced a recurrence of the arrhythmia or withdrew for other reasons (e.g., adverse events). The number of patients still in normal sinus rhythm with the 500 mcg twice-a-day dosage of dofetilide was 52% to 57% at 6 months and 46% to 49% at 12 months, compared with 22% to 32% and 16% to 22%, respectively, in the placebo groups.
The most important concern with the use of dofetilide is its ability to cause serious ventricular arrhythmias, primarily torsade de pointes-type ventricular tachycardia, a problem that is associated with QT interval prolongation. QT interval prolongation is directly related to the plasma concentration of dofetilide, and precautions must be taken with respect to the factors that will increase concentrations of the drug, such as reduced creatinine clearance and certain drug interactions.
Dofetilide is contraindicated in patients with congenital or acquired long QT syndromes, and in patients with a baseline QT interval or QT_c > 440 msec (500 msec in patients with ventricular conduction abnormalities). It is also contraindicated in patients with severe renal impairment (calculated creatinine clearance < 20 mL/minute). The concurrent use of cimetidine (e.g., Tagamet), ketoconazole (e.g., Nizoral), or verapamil (e.g., Calan) with dofetilide is contraindicated because they cause a marked increase in the plasma concentrations of the antiarrhythmic agent. The concomitant use of dofetilide with other drugs that prolong the QT interval (e.g., phenothiazines, tricyclic antidepressants, bepridil [Vascor], cisapride [Propulsid]) has not been studied and is not recommended. Class I or Class III antiarrhythmic agents should be withheld for at least three half-lives prior to initiating treatment with dofetilide. The potential for torsade de pointes is increased with hypokalemia or hypomagnesemia, which may occur with the use of potassium-depleting diuretics (e.g., hydrochlorothiazide [e.g., HydroDIURIL]). Potassium concentrations should be in the normal range prior to initiating treatment with dofetilide and maintained in the normal range during treatment.
Most episodes of torsade de pointes that were reported in the clinical studies of dofetilide occurred in the first 3 days of treatment. To minimize the risk of drug-induced arrhythmia, the product labeling includes a black box warning stating that patients for whom treatment with the drug is to be initiated or re-initiated should be placed for a minimum of 3 days in a facility that can provide calculations of creatinine clearance, continuous electrocardiographic monitoring, and cardiac resuscitation. Calculation of the creatinine clearance must precede the administration of the first dose of the drug, and the dosage can be subsequently adjusted as necessary according to creatinine clearance and by monitoring the electrocardiograms for excessive increases in the QT interval. The incidence of torsade de pointes in patients in the clinical trials who were treated with dofetilide according to the recommended dosing regimen was 0.8%.
Because of the potential for drug-induced arrhythmias, the distribution of dofetilide has been restricted to just those hospitals and prescribers who have received dosing and treatment initiation education regarding the drug. As part of this process, prescriptions for dofetilide are dispensed by one central pharmacy (Stadtlanders) and the medication may only be obtained from this source. Some have been critical of this restricted distribution system for several reasons including the possibility that a patient's other physicians or local pharmacist may not be aware of the use of dofetilide, and that other medications having a potential to interact with the antiarrhythmic drug may be inadvertently prescribed and dispensed.
Other adverse events experienced in the clinical studies of dofetilide include headache (11%), chest pain (10%), and dizziness (8%). Treatment was discontinued because of adverse events in 9% of the patients treated with dofetilide and in 8% of patients in the placebo groups. Although dofetilide has not been demonstrated to reduce mortality, it also did not increase mortality in patients with structural heart disease. This finding is important because certain other antiarrhythmic agents that were studied in the Cardiac Arrhythmia Suppression Trial (CAST) were found to increase mortality in post-infarction patients.
Dofetilide is classified in Pregnancy Category C and should be used during pregnancy only if the anticipated benefit justifies the risk to the fetus. Women treated with dofetilide should not breast feed an infant. These precautions assume even greater importance because the experience in the clinical development program of dofetilide has identified that the risk of torsade de pointes in females was approximately three times the risk in males. The effectiveness and safety of dofetilide in patients less than 18 years of age have not been established.
Approximately 80% of a dose of dofetilide is excreted in the urine, of which approximately 80% is excreted as unchanged drug, with the remaining 20% consisting of essentially inactive metabolites. Renal elimination involves both glomerular filtration and active tubular secretion (via the cation transport system). Because cimetidine and ketoconazole inhibit the cationic secretion and substantially increase the plasma concentrations of dofetilide, their concurrent use is contraindicated. Caution must be exercised when other inhibitors of renal cationic secretion (e.g., trimethoprim [e.g., Proloprim], prochlorperazine [e.g., Compazine], megestrol [e.g., Megace]) are used concomitantly with dofetilide. When other drugs that are actively secreted via this route (e.g., triamterene [e.g., Dyrenium], metformin [Glucophage], amiloride [Midamor]) are used concurrently with dofetilide, therapy must also be closely monitored because of the potential for dofetilide concentrations to be increased.
Although dofetilide is metabolized to only a limited extent, the metabolism that does occur is primarily via the CYP3A4 pathway, and inhibition of this system could result in increased plasma concentrations and risk of toxicity of the drug. Therefore, the concurrent use of other agents that are known to inhibit this metabolic pathway (e.g., certain azole antifungal agents, macrolide antibiotics, or selective serotonin reuptake inhibitors, HIV protease inhibitors, grapefruit juice) must be closely monitored. Dofetilide does not affect the pharmacokinetics of digoxin; however, the concomitant use of the two agents has been associated with a higher incidence of torsade de pointes.
Following oral administration, the bioavailability of dofetilide is greater than 90% and maximal plasma concentrations occur at about 2 to 3 hours in the fasted state. The bioavailability of the drug is not affected by administration with food or antacids. The clearance of the drug is reduced in patients with renal impairment and it is very important that dosage determinations be based on calculated creatinine clearance. The pharmacokinetics of dofetilide are not significantly altered in patients with mild-to- moderate hepatic impairment, but its use in patients with severe hepatic impairment has not been studied.
Treatment with dofetilide must be initiated in a setting that provides continuous electrocardiographic monitoring, and patients should continue to be monitored in this manner for at least 3 days. Patients should not be discharged within 12 hours of pharmacological or electrical conversion to normal sinus rhythm. The usual recommended dosage of dofetilide is 500 mcg twice a day, but must be individualized according to calculated creatinine clearance and QT_c. The product labeling should be consulted for the specific treatment and dosage guidelines. Patients must be advised that, if they miss a dose, they should not double the next dose and they should take the next dose at the usual time. Renal function and QT_c should be re-evaluated every 3 months or as medically warranted.
Before initiating dofetilide treatment, any previous antiarrhythmic therapy should be withdrawn under careful monitoring for a minimum of three plasma half-lives. Because of the unpredictable pharmacokinetics of amiodarone, dofetilide should not be initiated following amiodarone therapy until amiodarone plasma concentrations are below 0.3 mcg/mL or until amiodarone has been withdrawn for at least 3 months. If dofetilide needs to be discontinued to permit the use of other potentially interacting drugs, a washout period of at least 2 days should elapse before starting treatment with the other drug(s). Dofetilide capsules are supplied in 125 mcg, 250 mcg, and 500 mcg potencies.

Thrombolytic Agent

Tenecteplase recombinant (TNKase -- Genentech) is a modified form of human tissue plasminogen activator (tPA) that is produced by recombinant DNA technology. It is a 527 amino acid glycoprotein that differs from natural human tPA, the recombinant version of which is available as alteplase (Activase), only by the substitution of different amino acids at three locations in the molecule. These structural modifications result in tenecteplase having a greater specificity for fibrin and a longer plasma half-life.
Tenecteplase exhibits thrombolytic activity that is generally similar to that of alteplase, anistreplase (Eminase), reteplase (Retavase), and streptokinase (e.g., Streptase). These agents catalyze the conversion of plasminogen to plasmin, leading to a breakdown of fibrin in the thrombus, producing thrombolysis. In the presence of fibrin, in vitro studies show that the tenecteplase conversion of plasminogen to plasmin is increased relative to its conversion in the absence of fibrin. This fibrin specificity decreases systemic activation of plasminogen and the resulting degradation of circulating fibrinogen and, therefore, may reduce the risk of bleeding complications. However, the clinical significance of fibrin specificity on safety or efficacy has not been established.
Tenecteplase is indicated for intravenous use in the reduction of mortality associated with acute myocardial infarction (AMI). As with the other thrombolytic agents, treatment should be initiated as soon as possible after the onset of symptoms.
The approval of tenecteplase was primarily based on the results of a clinical study in almost 17,000 patients (ASSENT 2), in which the new agent, administered as a single intravenous bolus dose, was compared with alteplase administered as an accelerated (over 90 minutes) intravenous infusion. Patients also received heparin and aspirin as part of the study regimen. The 30-day mortality rate was the same (6.2%) in both groups, and the rates of in-hospital procedures (e.g., percutaneous transluminal coronary angioplasty, stent placement, coronary artery bypass graft surgery) were similar. The results of another study, in which coronary arteriograms were reviewed, showed that tenecteplase was similar to alteplase in restoring patency.
Other studies of tenecteplase that have been initiated or planned involve use with a GP IIb/IIIa inhibitor -- abciximab (ReoPro), eptifibatide (Integrilin), or tirofiban (Aggrastat) -- and with heparin or enoxaparin (Lovenox).
In addition to their use in the treatment of AMI, alteplase is indicated for the treatment of patients with pulmonary embolism or acute ischemic stroke, and the indications for streptokinase also include pulmonary embolism, deep-vein thrombosis, arterial thrombosis or embolism, and occlusion of arteriovenous cannulae. However, these are not labeled indications for tenecteplase.
The most important adverse event associated with the use of tenecteplase, as well as other thrombolytic agents, is bleeding, and the concomitant use of heparin may contribute to this complication. The incidence of major bleeding (defined as bleeding requiring blood transfusion or leading to hemodynamic compromise) in the ASSENT 2 study was 5% in the patients receiving tenecteplase and 6% in those receiving alteplase, and the incidence of minor bleeding was 22% and 23%, respectively. The incidence of intracranial hemorrhage was 0.9% with both agents but the occurrence of nonintracranial bleeding and the need for blood transfusion was lower in patients treated with tenecteplase.
Bleeding sites were both internal (e.g., intracranial, retroperitoneal, gastrointestinal, genitourinary, respiratory) and superficial (e.g., venous cutdowns, arterial punctures, sites of recent surgical interventions). Potential bleeding sites should receive close attention, and intramuscular injections and nonessential handling of the patient should be avoided for the first few hours following treatment with tenecteplase. The use of anticoagulants or drugs that alter platelet function (e.g., aspirin, dipyridamole [e.g., Persantine], GP IIb/IIIa inhibitors) may increase the risk of bleeding if administered prior to, during, or after tenecteplase therapy. If serious bleeding occurs, heparin and antiplatelet agents should be immediately discontinued.
The use of tenecteplase is contraindicated in patients with active internal bleeding, known bleeding diathesis, severe uncontrolled hypertension, a history of cerebrovascular accident, intracranial neoplasm, arteriovenous malformation, or aneurysm, or who have had intracranial or intraspinal surgery or trauma within the past 2 months. Numerous other situations are also associated with an increased risk of bleeding (e.g., recent major surgery or trauma, recent gastrointestinal or genitourinary bleeding, cerebrovascular disease), and the anticipated benefits of tenecteplase therapy must be weighed against the risks.
Some patients treated with thrombolytic agents have experienced arrhythmias associated with reperfusion, and it is recommended that antiarrhythmic therapy for bradycardia and/or ventricular irritability be available when tenecteplase is administered. There have also been rare reports of cholesterol embolism following treatment with thrombolytic agents.
Allergic-type reactions (e.g., anaphylaxis, angioedema, rash, urticaria) were reported in less than 1% of the patients treated with tenecteplase. Anaphylaxis was reported in less than 0.1% of patients, although causality was not established. Of 487 patients who were tested for antibody formation to tenecteplase, 3 had a positive antibody titer at 30 days. The readministration of plasminogen activators, including tenecteplase, to patients who have received prior plasminogen activator therapy has not been systematically studied.
Tenecteplase is classified in Pregnancy Category C and should be administered to a pregnant woman only if the anticipated benefit justifies the risk to the fetus. It is not known if the drug is excreted in human milk, and caution should be exercised when it is administered to a nursing woman.
The intravenous administration of tenecteplase is simpler and more convenient than the administration of the other thrombolytic agents, and this represents an important advantage for the new agent. Tenecteplase is administered as a single intravenous bolus dose over 5 seconds, whereas alteplase is usually administered as an initial bolus dose followed by an intravenous infusion over 90 minutes, and reteplase is administered as a double-bolus injection with the two injections administered about 30 minutes apart and each injection administered over 2 minutes.
The recommended dosage of tenecteplase is based upon patient weight and should not exceed 50 mg. Patients weighing less than 60 kg should receive a dose of 30 mg, and patients weighing 90 kg or more should receive a dose of 50 mg. Patients weighing between 60 and < 70 kg, 70 and < 80 kg, or 80 and < 90 kg should receive doses of 35 mg, 40 mg, or 45 mg, respectively.
Tenecteplase is supplied as a sterile, lyophilized powder in vials that contain 52.5 mg of the drug (a 5% overfill) but deliver 50 mg. It is constituted with 10 mL of Sterile Water for Injection from the vial of diluent that is supplied with the medication, and the vial should be gently swirled, but not shaken, until the contents are completely dissolved. The constituted solution contains the drug in a concentration of 5 mg/mL and, based on the dose that has been determined, the appropriate amount of solution should be withdrawn from the vial and administered as a single bolus over 5 seconds. Any unused solution should be discarded. If tenecteplase is administered in an intravenous line containing dextrose, precipitation may occur, and dextrose-containing lines should be flushed with a saline-containing solution prior to and following single-bolus administration of the drug.
Because the formulation of tenecteplase contains no antibacterial preservatives, it should be constituted immediately before use. If the constituted solution is not used immediately, the vial should be refrigerated and the solution used within 8 hours.

Anticoagulants

Tinzaparin sodium (Innohep -- DuPont) is the fourth low molecular weight heparin (LMWH) to be approved in the United States, joining enoxaparin (Lovenox), dalteparin (Fragmin), and ardeparin (Normiflo), although the marketing of ardeparin has been discontinued. The LMWHs exhibit antithrombotic activity and are considered to be as effective as heparin, and to have a similar or lesser risk of bleeding adverse events. The LMWHs have the advantage of convenience of use because they have a longer duration of action and are administered subcutaneously, whereas heparin is typically administered intravenously in the conditions in which the LMWHs are indicated.
Tinzaparin is produced by enzymatic depolymerization of heparin from porcine intestinal mucosa using heparinase. It inhibits reactions that lead to the clotting of blood and the formation of fibrin clots, primarily by inhibiting coagulation factors Xa and IIa (thrombin). Although the LMWHs have different ratios of antifactor Xa to antifactor IIa activity, the clinical importance of these differences has not been determined. The LMWHs do not dissolve clots but prevent the extension of clots while the body's natural mechanisms slowly resolve the thrombus.
Tinzaparin is indicated for the treatment of acute symptomatic deep vein thrombosis (DVT) with or without pulmonary embolism (PE) when administered in conjunction with warfarin (e.g., Coumadin). In studies in which tinzaparin or heparin was administered for 6 days, and followed with warfarin to day 90, the 90-day cumulative thromboembolic rate (recurrent DVT or PE) for the two agents was not significantly different. The mortality rate was 4.6% with tinzaparin and 9.6% with heparin.
The indications for tinzaparin are more limited than those for enoxaparin, which is also indicated for the outpatient treatment of acute DVT without PE, the prevention of DVT in patients undergoing abdominal surgery or hip or knee replacement surgery, the prevention of ischemic complications of unstable angina and non-Q-wave myocardial infarction, and the prevention of DVT in patients at risk of thromboembolic complications due to severely restricted mobility during acute illnesses. Although preliminary studies suggest that tinzaparin is also effective in these situations, they are not labeled indications for the new agent at the present time.
As with the other LMWHs and heparin, the primary concern with the use of tinzaparin is the risk of hemorrhage, which can occur at virtually any site. Bleeding is the most common adverse event, although the incidence of major bleeding is low (0.8%). The new agent is contraindicated in patients with active major bleeding and should not be used in patients with a history of heparin-induced thrombocytopenia (HIT). Tinzaparin should be used only with extreme caution in patients with conditions in which there is an increased risk of hemorrhage (e.g., severe uncontrolled hypertension, congenital or acquired bleeding disorders, bacterial endocarditis, active ulcerative gastrointestinal disease). It is recommended that periodic complete blood counts, including platelet count and hematocrit or hemoglobin, and stool tests for occult blood be monitored during treatment. Caution must also be exercised in patients who are also receiving oral anticoagulants, platelet inhibitors (e.g., aspirin, nonsteroidal anti-inflammatory drugs [NSAIDs]), or thrombolytic agents, which may induce or increase bleeding.
Spinal or epidural hematomas have been infrequently reported with the associated use of LMWHs or heparinoids (danaparoid [Orgaran]) and spinal/epidural anesthesia or spinal puncture. This may result in long-term or permanent paralysis and is the subject of a black box warning in the labeling for these drugs. The risk of these events is higher with the use of postoperative indwelling epidural catheters or with the concomitant use of additional drugs affecting hemostasis such as NSAIDs.
The most commonly reported adverse events associated with the use of tinzaparin in the clinical studies include injection-site hematoma (16%), urinary tract infection (4%), pulmonary embolism (2%), chest pain (2%), and epistaxis (2%), as well as elevations of alanine (ALT) and aspartate (AST) aminotransferase concentrations greater than three times the upper limit of normal in 13% and 8% of patients, respectively. Thrombocytopenia occurred in 1% of patients, and there have been rare reports of priapism.
The use of tinzaparin is contraindicated in patients with known hypersensitivity to heparin, pork products, sulfites, or benzyl alcohol. The formulation of the new drug contains sodium metabisulfite that may cause allergic-type reactions including life-threatening anaphylactic symptoms in susceptible individuals. The incidence of sulfite hypersensitivity is low, but is more frequent in asthmatic than in nonasthmatic patients.
Like dalteparin and enoxaparin, tinzaparin is classified in Pregnancy Category B. The multiple-dose vial formulations of tinzaparin and dalteparin contain benzyl alcohol as a preservative. There have been infrequent reports of premature infants experiencing a "gasping syndrome" following the administration of formulations of medications that contain benzyl alcohol as a preservative. Because benzyl alcohol may cross the placenta, tinzaparin should be used in pregnant women only if clearly needed. Enoxaparin formulations are for single-dose use and do not contain a preservative, and there is a preservative-free, single-dose formulation of dalteparin. However, there is not a single-dose, preservative-free formulation of tinzaparin available at this time.
It is not known if tinzaparin is excreted in human milk, and caution should be exercised if it is used in a nursing woman. Its effectiveness and safety in pediatric patients have not been established.
Tinzaparin is administered by deep subcutaneous injection, and must not be administered by intramuscular or intravenous injection. Patients should be lying down or sitting when the drug is administered. Administration should be alternated between the left and right anterolateral and left and right posterolateral abdominal wall. The injection site should be varied daily. The whole length of the needle should be introduced into a skin fold held between the thumb and forefinger, and the skin fold should be held throughout the injection. To minimize bruising, the injection site should not be rubbed after completion of the injection.
Plasma concentrations of LMWHs cannot be measured directly, and the activity of tinzaparin is determined based on its anti-Xa activity. Its absolute bioavailability is 87% following subcutaneous administration. It is primarily eliminated via the kidneys and the use of the drug in patients with severe renal impairment should be closely monitored. The hepatic route is not a major route of elimination for the LMWHs including tinzaparin.
The recommended dosage of tinzaparin is 175 anti-Xa international units (IUs) per kg of body weight once a day for at least 6 days and until the patient is adequately anticoagulated with warfarin (international normalized ratio [INR] of at least 2 for two consecutive days). Warfarin treatment is usually initiated within 1 to 3 days after starting tinzaparin therapy.
Because coagulation parameters such as prothrombin time (PT) and activated partial thromboplastin time (aPTT) are not suitable for monitoring tinzaparin activity, routine monitoring of coagulation parameters is not required. However, tinzaparin may prolong PT and aPTT and patients receiving both tinzaparin and warfarin should have blood for PT/INR determinations drawn just prior to the next scheduled dose of tinzaparin.
Tinzaparin sodium is supplied in multiple-dose 2 mL vials containing 20,000 anti-Xa IUs/mL (i.e., 40,000 anti-Xa IUs per vial). Information that facilitates the determination of the volume of the formulation to be administered based on patient weight is provided in the product labeling.
An excessive dosage of tinzaparin may lead to hemorrhagic complications, and its action may be neutralized by the slow intravenous infusion of a 1% solution of protamine sulfate at a dose of 1 mg of protamine for every 100 anti-Xa IUs of tinzaparin administered.
Each year, nearly 12 million Americans are treated with heparin to prevent the development of blood clots or the further extension of clots that have already formed. As many as 360,000 of these individuals will develop heparin-induced thrombocytopenia (HIT), an immune, allergy-like adverse event that is characterized by a drop in the platelet count below 100,000/mL or a 50% or greater reduction in platelet count compared with the baseline count. It typically occurs 5 to 10 days following the initiation of heparin treatment, and it may not be quickly diagnosed because the reaction may paradoxically result in the development of blood clots when it is expected that the use of heparin would prevent them. If misdiagnosed or untreated, patients who experience HIT may develop thromboembolic complications such as deep vein thrombosis, pulmonary embolism, myocardial infarction, ischemic stroke, and occlusion of limb arteries, which may eventually result in necroses requiring amputation. Of the approximately 360,000 patients who develop HIT each year, an estimated 120,000 develop thromboembolic complications and up to 36,000 die.
Until recently there have not been suitable alternatives to heparin in patients with HIT in whom anticoagulant therapy is needed. LMWHs are also associated with a risk of HIT and would not be appropriate for use in these patients. The heparinoid danaparoid (Orgaran) was marketed in 1997 and is sufficiently different from heparin in its properties that it may be useful in some patients with HIT although it is not a labeled indication for its use. In 1998 the hirudin analog lepirudin (Refludan), a biosynthetic agent prepared using recombinant DNA technology, was marketed for intravenous use for anticoagulation in patients with HIT and associated thromboembolic disease in order to prevent further thromboembolic complications.
Argatroban (SmithKline Beecham) has the distinction of having been marketed without a trade name. The trade name initially proposed (Novastan) was considered to be too similar to Novantrone (the trade name for mitoxantrone), and the name subsequently considered (Acova) had a potential trademark conflict. Rather than experiencing a delay in marketing the new drug while a satisfactory trade name was being identified, the company decided to market it without one.
Heparin, the LMWHs, danaparoid, and warfarin are indirect thrombin inhibitors that either inhibit the formation or the activity of coagulation factors involved in the production of thrombin, or exert their inhibitory effects by using an endogenous cofactor. Lepirudin and argatroban are direct thrombin inhibitors and act on thrombin itself by interacting specifically with one or more of the functional domains of the molecule. Argatroban is a low molecular weight synthetic arginine derivative that is a competitive, reversible inhibitor of thrombin and acts by directly blocking the active catalytic site. It is highly selective for thrombin and is capable of inhibiting the action of both free and clot-associated thrombin. It does not interact with heparin-induced antibodies.
Argatroban is indicated for intravenous use as an anticoagulant for prophylaxis or treatment of thrombosis in patients with HIT, an indication that is broader than that for lepirudin. The new agent was evaluated in historically controlled studies and its effectiveness demonstrated in patients with HIT and heparin-induced thrombocytopenia and thrombosis syndrome (HITTS). In the clinical trials in which outcomes were monitored over 37 days, the composite of death, amputation, or new thrombosis occurred in 34% of the argatroban-treated patients compared with 43% of the historical controls. Argatroban and lepirudin have not been directly compared in clinical studies.
The use of argatroban is also being evaluated in patients who have experienced a stroke or disseminated intravascular coagulation, and as an adjunct to thrombolytic agents in the treatment of acute myocardial infarction. However, these are not labeled indications at the present time.
As with the other anticoagulants, the primary concern with the use of argatroban is the risk of hemorrhage, which can occur at any site in the body. Hemorrhagic events were designated as "major" or "minor" and are most commonly experienced at gastrointestinal (2% major and 14% minor) and genitourinary (1% major and 12% minor) sites. Intracranial bleeding was not observed in patients with HIT/HITTS but has occurred in some patients with acute myocardial infarction who were initially treated with both argatroban and streptokinase. The new agent is contraindicated in patients with overt major bleeding and should be used only with extreme caution in patients with conditions in which there is an increased risk of hemorrhage (e.g., severe hypertension, congenital or acquired bleeding disorders, ulcerative gastrointestinal disease). Caution must also be exercised in patients who are receiving antiplatelet agents (e.g., aspirin, NSAIDs), thrombolytic agents, or other anticoagulants.
Other commonly experienced adverse events with the use of argatroban include dyspnea (8%), hypotension (7%), fever (7%), diarrhea (6%), sepsis (6%), and cardiac arrest (6%). Allergic reactions (e.g., dyspnea, cough, rash, and/or vasodilation) or suspected allergic reactions occurred in more than 10% of the patients receiving argatroban in the clinical pharmacology studies or for other indications. About 95% of these reactions were reported in patients who also were treated with a thrombolytic agent (e.g., streptokinase) for acute myocardial infarction and/or contrast media for coronary angiography.
Argatroban is classified in Pregnancy Category B and should be used during pregnancy only if clearly needed. It is not known whether it is excreted in human milk, and a decision should be made whether to discontinue nursing or not use the drug. The effectiveness and safety of argatroban in patients under 18 years of age have not been established.
The use of argatroban was not associated with the development of neutralizing antibodies in the clinical studies, and there was no loss of anticoagulant activity in patients in whom argatroban therapy was repeated. The formation of antihirudin antibodies has been observed in about 40% of the patients treated with lepirudin, which may increase the anticoagulant effect and require closer monitoring of therapy.
Argatroban increases in a dose-dependent manner aPTT, the activated clotting time (ACT), PT and INR, and the thrombin time (TT). The concurrent use of argatroban and warfarin results in prolongation of the PT and INR beyond that produced by warfarin alone. However, concurrent therapy, compared with warfarin monotherapy, exerts no additional effect on vitamin K-dependent factor Xa activity. The product labeling should be consulted for guidelines to determine the INR for warfarin alone, based on the INR for concurrent therapy of warfarin and argatroban.
Because heparin is contraindicated in patients with HIT, its concurrent use with argatroban would not be appropriate for this indication. However, if argatroban is to be initiated after heparin therapy is discontinued, sufficient time should be allowed for the effect of heparin on aPTT to decrease prior to starting argatroban treatment.
Argatroban is extensively metabolized in the liver, in part by CYP3A4/5, and its primary metabolite exerts 3- to 5-fold weaker anticoagulant effects than the parent compound. Erythromycin, a known inhibitor of CYP3A4/5, does not alter the pharmacokinetics of argatroban, suggesting that CYP3A4/5-mediated metabolism is not an important elimination pathway. The drug is excreted primarily in the feces, presumably via biliary secretion. Hepatic impairment is associated with decreased clearance of argatroban and the dosage should be reduced in these patients. Dosage adjustment is not necessary in patients with renal dysfunction. With the use of lepirudin, the dosage should be reduced in patients with renal dysfunction, but a change in dosage would not likely be necessary in patients with hepatic impairment.
Argatroban injection is supplied in single-use vials containing 2.5 mL of solution with the drug in a concentration of 100 mg/mL (i.e., 250 mg/vial). This solution is concentrated and must be diluted 100-fold prior to infusion. The contents of each vial of argatroban injection should be diluted with 250 mL of 0.9% Sodium Chloride Injection, 5% Dextrose Injection, or Lactated Ringer's Injection to a final concentration of 1 mg/mL. The constituted solution must be mixed by repeated inversion of the diluent bag for 1 minute. Argatroban is administered as a continuous intravenous infusion and the recommended initial dosage is 2 mcg/kg/minute. Guidelines for determining the infusion rate based on body weight are provided in the product labeling. In patients with HIT with hepatic impairment, the recommended initial dosage is 0.5 mcg/kg/minute based on the approximate fourfold decrease in argatroban clearance compared with those with normal hepatic function. Immediately upon the initiation of argatroban infusion, anticoagulant effects are produced as concentrations of the drug begin to rise. Steady-state concentrations of both the drug and anticoagulant effects are typically attained within 1 to 3 hours and are maintained until the infusion is discontinued or the dosage adjusted.
Treatment with argatroban is generally monitored using aPTT, which should be determined at baseline, and at 2 hours after initiation of therapy to confirm that aPTT is within the desired therapeutic range. After the initial dose of argatroban, the dosage can be adjusted as clinically indicated, but not to exceed 10 mcg/kg/minute, until the steady state aPTT is 1.5 to 3 times the initial baseline value (not to exceed 100 seconds).
When it is appropriate to initiate oral anticoagulant therapy, warfarin should be initiated in a dosage corresponding to the expected daily dose. A loading dose should not be used. The INR should be determined daily when warfarin and argatroban are administered concurrently. In general, when argatroban is used in a dosage up to 2 mcg/kg/minute, it can be discontinued when the INR is higher than 4 on combined therapy. After argatroban is discontinued, the INR measurement should be repeated in 4 to 6 hours. If the repeat INR is below the desired therapeutic range, the infusion of argatroban should be resumed and the procedure repeated daily until the desired therapeutic range on warfarin alone is reached.
No specific antidote to argatroban is available, and excessive anticoagulation, with or without bleeding, may be controlled by discontinuing the drug or reducing the dosage.
Vials of argatroban injection should be kept in the original carton to protect them from light. Prepared solutions of the drug are stable in ambient indoor light for 24 hours. However, the vials should not be exposed to direct sunlight.
On December 15, 2000, the FDA approved bivalirudin (Angiomax -- The Medicines Company) for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty. This agent did not reach the market before the end of the year and was marketed in early 2001.

Sedative

After individuals undergo major surgery or trauma, various medications, or combinations of medications, are used in intensive care units (ICUs) to control stress, anxiety, and pain, and to facilitate mechanical ventilation of the patient. The agents most commonly used, typically in combination, include opioid analgesics (e.g., morphine), and general anesthetics (e.g., propofol [e.g., Diprivan]) and benzodiazepines (e.g., midazolam [Versed]) for sedation. However, some patients experience respiratory depression and hemodynamic instability with the use of these agents.
Dexmedetomidine hydrochloride (Precedex -- Abbott) is a relatively selective a₂-adrenoceptor agonist with sedative properties. The activation of these receptors in the central nervous system (CNS) can inhibit stress response, moderate blood pressure and heart rate, reduce anxiety, and induce sedation. The pharmacologic properties of dexmedetomidine are generally similar to those of clonidine (e.g., Catapres), but its blood pressure-lowering action is less pronounced than with the latter agent.
Dexmedetomidine is administered by continuous intravenous infusion and is indicated for sedation of initially intubated and mechanically ventilated patients during treatment in an intensive care setting. In the two placebo-controlled clinical trials in which its effectiveness was demonstrated, dexmedetomidine treatment was initiated as a single agent in patients being treated in a surgical ICU and used for up to 24 hours. The addition of "rescue" medications was permitted as required to achieve a specified level of sedation (i.e., midazolam in one study and propofol in the second) and for pain (morphine). In both studies, approximately 60% of dexmedetomidine-treated patients remained adequately sedated without the addition of other medications, compared with approximately 24% of the patients in the placebo group. Approximately 41% to 44% of dexmedetomidine-treated patients needed no opioids for pain, compared with approximately 15% to 19% of those receiving placebo. Those patients who did require opioid analgesia achieved adequate pain relief with lower doses of the opioid than were required by those in the placebo group.
When dexmedetomidine can be used as a single agent, it represents a less complex and safer regimen than the use of a traditional sedative plus an analgesic. However, for patients who require an additional sedative plus an analgesic, the need to monitor the use of three potent drugs instead of two results in a more complex regimen, which may also be associated with a greater risk of problems than with a two-drug regimen. In addition, dexmedetomidine should not be administered for more than a 24-hour period because its safety has not been established for use over longer periods of time, and many patients in an ICU need to be mechanically ventilated for more than 24 hours.
The adverse events most frequently experienced with the use of dexmedetomidine include hypotension (30%), bradycardia (8%), atrial fibrillation (7%), nausea (11%), and hypoxia (6%). In patients who experience hypotension and/or bradycardia, intervention may be required and treatment may include decreasing or stopping the infusion of dexmedetomidine, increasing the rate of intravenous fluid administration, elevation of the lower extremities, and the use of pressor agents. Dexmedetomidine has the potential to augment bradycardia induced by vagal stimuli, and the intravenous administration of anticholinergic agents (e.g., atropine, glycopyrrolate [Robinul]) has been effective in most situations in which bradycardia required specific treatment. Caution should be exercised when administering dexmedetomidine to patients with advanced heart block.
Transient hypertension has occurred during the administration of the loading dose in association with the initial peripheral vasoconstrictive effects of dexmedetomidine. Treatment of the hypertension is not usually necessary, although reduction of the loading infusion rate may be beneficial.
Some patients receiving dexmedetomidine have been arousable and alert when stimulated. However, this response alone should not be considered as evidence of lack of efficacy in the absence of other signs and symptoms.
Dexmedetomidine is classified in Pregnancy Category C. Its safety has not been established, and its use is not recommended, during labor and delivery, including cesarean section deliveries. The effectiveness and safety of dexmedetomidine in patients less than 18 years of age have not been established.
The concurrent use of dexmedetomidine with anesthetics, sedatives, hypnotics, and/or opioids is likely to result in an increased CNS depressant action, and a reduction in dosage of one or more agents may be required. This interaction represents an additive pharmacodynamic response, and interactions developing through pharmacokinetic mechanisms (e.g., CYP450-mediated) have not been reported.
Dexmedetomidine undergoes almost complete biotransformation involving direct glucuronidation and CYP450-mediated metabolism, primarily by CYP2A6. Approximately 95% of a dose is excreted in the urine in the form of metabolites. The terminal elimination half-life of the drug is approximately 2 hours.
The pharmacokinetics of dexmedetomidine are not significantly different in patients with severe renal impairment (creatinine clearance < 30 mL/minute) when compared with healthy subjects. However, the pharmacokinetics of its metabolites have not been evaluated in patients with impaired renal function. The clearance of dexmedetomidine is lower in patients with hepatic impairment than in healthy subjects, and it may be necessary to reduce the dosage in these patients.
Dexmedetomidine is administered by intravenous infusion using a controlled infusion device. Its dosage should be individualized and titrated to the desired clinical effect. In adult patients, treatment is generally initiated with a loading infusion of 1 mcg/kg over 10 minutes, followed by a maintenance infusion of 0.2 to 0.7 mcg/kg/hour. The rate of the maintenance infusion should be adjusted to achieve the desired level of sedation. The drug is not indicated for infusions lasting longer than 24 hours. If dexmedetomidine is administered chronically and discontinued abruptly, withdrawal symptoms similar to those reported for clonidine (e.g., nervousness, agitation, headache, rapid rise in blood pressure) may result.
Dexmedetomidine hydrochloride injection is supplied in 2 mL vials and ampules containing the equivalent of 100 mcg of dexmedetomidine base per mL. To prepare the infusion, 2 mL of the solution are withdrawn and added to 48 mL of 0.9% Sodium Chloride Injection. The preparation of solutions is the same, whether for the loading dose or maintenance infusion.
The product labeling should be consulted for information regarding intravenous fluids and medications that are compatible with dexmedetomidine injection. Compatibility of the drug with blood, serum, or plasma has not been established. Studies have demonstrated the potential for adsorption of dexmedetomidine to some types of natural rubber, and it is advisable to use administration components made with synthetic or coated natural rubber gaskets.

Antiepileptic Drugs

Seizure disorders affect more than two million Americans, with approximately 180,000 new cases diagnosed annually. Partial seizures, that begin in a localized area of the brain, account for up to 70% of seizure disorders, and the pharmaceutical companies that develop new antiepileptic drugs (AEDs) usually evaluate them first in patients with this seizure type.
Although the seizure disorders experienced by some patients can be effectively managed with just one AED, the use of two or more AEDs is necessary in many patients, and this increases the occurrence of adverse events and drug interactions, as well as the potential for noncompliance. Even with the use of multiple-AED regimens, the seizure disorders of many patients are not optimally controlled, and it is estimated that 30% to 50% of people with epilepsy continue to experience seizures despite treatment with the medications now available.
Following a 15-year period from 1978 to 1992 in which there were no new AEDs marketed, eight new AEDs have been marketed since 1993, including three in the first 6 months of 2000 -- levetiracetam (Keppra -- UCB Pharma), oxcarbazepine (Trileptal -- Novartis), and zonisamide (Zonegran -- Elan). These three agents have been approved for use in conjunction with other AEDs in the treatment of partial seizures, and oxcarbazepine also for use as monotherapy in adults. All of the new AEDs represent a very useful addition to this class of agents because they provide alternatives that may be of value in the development of an AED regimen that is more effective and/or better tolerated than the regimens now being used by many patients.
Levetiracetam and zonisamide are structurally unrelated to previously marketed AEDs (or to each other), whereas oxcarbazepine is related to carbamazepine (e.g., Tegretol). The precise mechanism(s) by which the new drugs exert their antiseizure activity is not known, but various actions that help explain the clinical benefits and certain adverse events associated with their use have been attributed to the individual agents.
Although the properties of the three new AEDs are very different in many respects, they are similar in some others. As with other AEDs, central nervous system (CNS) reactions are the most frequently experienced adverse events with the use of each of the new agents. Somnolence, fatigue, and dizziness are the most common adverse events, and patients should be advised not to engage in activities such as driving, operating machinery, or performing other potentially hazardous tasks until they have determined whether the medication adversely affects their mental and/or motor performance. Caution must also be exercised if other medications with CNS depressant activity, as well as alcoholic beverages, are used concurrently. Other CNS adverse events that patients may experience with the new AEDs (and their predecessors) include cognitive symptoms (e.g., difficulty with concentration, speech or language problems, psychomotor slowing), coordination abnormalities (e.g., ataxia, gait disturbances), and psychiatric symptoms (e.g., psychosis, depression).
Levetiracetam, oxcarbazepine, and zonisamide are classified in Pregnancy Category C and may cause fetal abnormalities if used during pregnancy. These agents should be used during pregnancy only if the anticipated benefit justifies the risk to the fetus. To facilitate monitoring fetal outcomes of pregnant women exposed to AEDs, physicians are encouraged to register patients, before fetal outcome is known, in the Antiepileptic Drug Pregnancy Registry by calling 888-233-2334.
Oxcarbazepine and its active metabolite are excreted in human milk, but it is not known whether levetiracetam and zonisamide are. If one of these agents is being considered for use in a nursing woman, a decision should be made whether to discontinue nursing or not use the drug. The effectiveness and safety of levetiracetam and zonisamide in patients under 16 years of age have not been established; however, oxcarbazepine has been approved for use as adjunctive therapy in children as young as 4 years of age.
As with other AEDs, the abrupt withdrawal of therapy with the new agents may precipitate increased seizure frequency or status epilepticus. When treatment is to be discontinued, the drugs should be withdrawn gradually.
In the following discussions, levetiracetam, zonisamide, and oxcarbazepine are considered on an individual basis.
Levetiracetam is a pyrrolidine derivative that is indicated as adjunctive therapy in the treatment of partial seizures in adults with epilepsy. The effectiveness of levetiracetam was demonstrated in three placebo-controlled clinical studies in patients who had refractory partial seizures. The addition of levetiracetam to the regimen resulted in a 50% or greater reduction in the frequency of seizures in up to 40% of the patients receiving the new drug, a significantly better response than in the group for whom placebo was added to the regimen. There have been limited studies of levetiracetam in pediatric patients, in patients with generalized seizure disorders, and as monotherapy in patients with partial or generalized seizures. However, these are not labeled indications at the present time.
The adverse events most frequently reported in the well-controlled clinical studies of levetiracetam include somnolence (15%), asthenia (15%), infection (13%), and dizziness (9%). Somnolence, asthenia, and coordination difficulties (3%, reported either as ataxia, abnormal gait, or incoordination) occurred most often within the first 4 weeks of treatment. A small number of patients (approximately 0.5%) experienced psychotic symptoms or depression that resulted in attempted suicide. Fifteen percent of the patients treated with levetiracetam either discontinued treatment or had a dose reduction as a result of an adverse event, compared with 12% of those receiving placebo.
Headache was experienced by 14% of patients but the incidence of this effect was about the same in the individuals receiving placebo. Hematologic abnormalities, such as small decreases in hemoglobin, hematocrit, and red and white blood cell counts, have been observed in some patients, but have not required discontinuation of therapy.
Like gabapentin (Neurontin), levetiracetam has an advantage over most AEDs because it does not appear to interact via pharmacokinetic machanisms with other medications. One of the challenges in developing combination regimens for the treatment of epilepsy is that so many of the AEDs interact with each other, thereby making it more difficult to predict the response to concurrent therapy and to determine the optimum dosage for the individual agents.
Following oral administration, levetiracetam is rapidly and almost completely absorbed, and its bioavailability is 100%. Food does not affect the extent of absorption, and it may be administered without regard to meals. The drug is not extensively metabolized, and only approximately 25% of a dose is converted to metabolites that are inactive, via enzymatic hydrolysis that is not CYP450 dependent. Most of the drug is excreted in unchanged form via the kidneys and clearance is reduced in patients with impaired renal function, necessitating a reduction in dosage. Dosage adjustment is not needed in patients with impaired hepatic function.
The recommended initial dosage of levetiracetam is 500 mg twice a day. The dosage may be increased, after a period of at least 2 weeks, to 1,000 mg twice a day and, following a period of at least 2 more weeks, to the maximum recommended dosage of 1,500 mg twice a day. The product labeling should be consulted for the dosage recommendations for patients with impaired renal function. Patients undergoing hemodialysis experience a significantly increased clearance of levetiracetam, and a supplemental dose of 250 mg or 500 mg is recommended following dialysis. Levetiracetam tablets are supplied in 250 mg, 500 mg, and 750 mg potencies.
Zonisamide is chemically classified as a sulfonamide and shares certain of the properties of the antibacterial sulfonamides. It has been marketed in Japan since 1989 where considerable experience has been acquired with its use. The antiseizure activity of zonisamide is probably due to several mechanisms, including its apparent ability to block sodium channels and reduce voltage-dependent, transient inward currents. It also exhibits weak carbonic anhydrase inhibiting activity, but this effect is not thought to be a major contributing factor to its antiseizure activity.
Zonisamide is indicated as adjunctive therapy in the treatment of partial seizures in adults with epilepsy. Its effectiveness was demonstrated in three placebo-controlled clinical studies in patients who had refractory partial seizures. The addition of zonisamide to the regimen resulted in a 50% or greater reduction in the frequency of seizures in up to 42% of the patients receiving the new drug, a response that was approximately twice as high as in the group for whom placebo was added to the regimen. The new drug has also been reported to be effective in the treatment of generalized tonic-clonic, tonic, myoclonic, and atypical absence seizures; however, these are not labeled indications at the present time.
The adverse events most frequently reported in the controlled clinical studies of zonisamide include somnolence (17%), dizziness (13%), agitation/irritability (9%), fatigue (8%), headache (10%), anorexia (13%), and nausea (9%). Somnolence and fatigue tended to occur within the first month of treatment and, in most cases, were of mild-to-moderate severity. Approximately 2% of patients discontinued treatment or were hospitalized for depression, and approximately 1% of patients attempted suicide. Twelve percent of patients discontinued therapy because of an adverse event, compared with 6% of those receiving placebo.
Because of its sulfonamide structure, the use of zonisamide is contraindicated in patients who have experienced hypersensitivity reactions when using an antibacterial sulfonamide such as sulfamethoxazole (e.g., used in combination with trimethoprim in Bactrim and Septra). As with the antibacterial sulfonamides, the use of zonisamide has been associated with rare occurrences of severe, and even fatal, reactions such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), aplastic anemia, and agranulocytosis. If signs of hypersensitivity or other serious reactions occur during zonisamide treatment, the drug should be immediately discontinued. If patients develop an unexplained rash, discontinuation of therapy should be considered because of the potential for a serious reaction such as SJS or TEN. If treatment is continued, patients should be observed frequently.
Approximately 4% of patients treated with zonisamide have developed kidney stones, a reaction that may be related to the carbonic anhydrase inhibitory action of the drug. Increasing fluid intake and urine output may help reduce the risk of stone formation, and patients should be advised to drink 6 to 8 glasses of water a day. Patients should contact their physician promptly if they develop signs or symptoms, such as sudden back pain, abdominal pain, and/or blood in the urine, that could indicate a kidney stone.
In some clinical studies, zonisamide was associated with an 8% mean increase from baseline of serum creatinine and blood urea nitrogen compared with essentially no change in patients receiving placebo. This has been interpreted as an effect on glomerular filtration rate (GFR), although there have been no occurrences of unexplained acute renal failure. The drug should not be used in patients with renal failure (estimated GFR < 50 mL/minute) because there has been insufficient experience in identifying a dosage regimen that would avoid toxicity.
Approximately 1% of the patients treated with zonisamide in the controlled studies experienced status epilepticus, compared with none of the patients receiving placebo.
Because of the possibility for teratogenic effects if used during pregnancy, women of childbearing potential should be advised to use effective contraception. In the experience with zonisamide in Japan, there have been rare occurrences of oligohydrosis and hyperthermia in patients less than 18 years of age. Although zonisamide is not indicated for use in patients under 16 years of age in the United States, it might be used "off-label" in some children and, if decreased sweating and/or fever occur, the patient's physician should be contacted immediately.
Approximately 50% of a dose of zonisamide is metabolized via the CYP3A4 pathway. Drugs that induce CYP3A4, including other AEDs such as carbamazepine, phenobarbital, and phenytoin (e.g., Dilantin), increase the rate of metabolism and decrease the half-life and activity of zonisamide. Conversely, drugs that inhibit CYP3A4 would be expected to increase its half-life and activity as well as the risk of adverse events. Zonisamide does not alter the activity of CYP450 enzymes and does not appreciably alter the concentrations of carbamazepine, phenytoin, or valproate (Depakene, Depakote), the agents with which it is most likely to be used in combination in AED regimens.
Zonisamide is rapidly absorbed following oral administration, and its bioavailability is not affected by the presence of food. It is excreted primarily in the urine as parent drug (approximately 35% of a dose) and metabolites. Its elimination half-life in plasma is about 63 hours, and it has a long duration of action. An increased AUC of zonisamide of approximately 35% has been observed in patients with marked renal impairment (creatinine clearance < 20 mL/minute). The pharmacokinetics of the drug in patients with impaired hepatic function have not been studied.
The recommended initial dosage of zonisamide is 100 mg once a day. After 2 weeks, the dosage may be increased to 200 mg/day for at least 2 weeks. Dosages above 100 mg/day can be administered once a day or divided and administered twice a day. The dosage may be subsequently increased to 300 mg/day and 400 mg/day, with the dosage stable for at least 2 weeks to achieve steady state at each level. Although dosages as high as 600 mg/day have been used in some studies, there is no evidence of an increasing response above a dosage of 400 mg/day, but the risk of adverse events increases.
Caution should be exercised in patients with impaired renal or hepatic function, and slower dosage titration and more frequent monitoring may be necessary.
Zonisamide capsules are supplied in a 100 mg potency. The capsules should be swallowed whole and may be administered without regard to meals.
Oxcarbazepine is structurally related to carbamazepine and shares certain of its pharmacologic actions. Its antiseizure activity appears to be similar to that of carbamazepine, although most of the action of the new agent is attributed to its 10-monohydroxy metabolite (MHD), to which it is rapidly and extensively converted following administration. Oxcarbazepine and MHD are thought to act primarily by producing blockade of voltage-sensitive sodium channels.
Oxcarbazepine is indicated for use as monotherapy or adjunctive therapy in the treatment of partial seizures in adults with epilepsy, and as adjunctive therapy in the treatment of partial seizures in children ages 4 to 16 with epilepsy. The efficacy of oxcarbazepine has been demonstrated in a number of studies, and it was effective as monotherapy in some patients whose partial seizures were not adequately controlled with carbamazepine monotherapy. There have been limited studies of oxcarbazepine in patients with generalized tonic-clonic seizures and other seizure disorders, as well as trigeminal neuralgia and bipolar disorder. However, these are not labeled indications at the present time.
The adverse events most frequently reported in the controlled clinical studies of oxcarbazepine monotherapy in adults previously treated with other AEDs (and the incidence with the use of a dosage of 2,400 mg/day) include dizziness (28%), fatigue (21%), somnolence (19%), headache (31%), nausea (22%), vomiting (21%), abnormal vision (14%), and diplopia (12%). These reactions were also among those most commonly experienced in other studies of oxcarbazepine, although their incidence and the rate of discontinuation of therapy vary with the dosage used, whether the drug is used as monotherapy or adjunctive therapy, and whether the patients are adults or children.
Although hypersensitivity reactions to carbamazepine are seldom experienced, it would be expected that these patients would experience a similar problem with the use of oxcarbazepine. However, data suggest that only about 25% to 30% of the patients with a history of this hypersensitivity experience such a problem with the new drug. Nevertheless, it is best to avoid the use of oxcarbazepine in patients who have had hypersensitivity reactions to carbamazepine. If oxcarbazepine is used and symptoms of hypersensitivity develop, the drug should be discontinued immediately.
In the controlled studies of oxcarbazepine, 2.5% of the patients receiving the new agent developed clinically significant hyponatremia (sodium < 125 mmol/L), whereas no patients assigned to placebo or an active control (e.g., carbamazepine, phenobarbital, phenytoin, valproate) experienced this response. Hyponatremia generally occurred during the first 3 months of treatment and most patients were asymptomatic. However, the close monitoring of the patients in the clinical studies facilitated interventions (e.g., reduction in dosage, restricted fluid intake), preventing more serious events, and cases of symptomatic hyponatremia (e.g., nausea, headache, malaise, lethargy) have been reported during postmarketing use. The monitoring of serum sodium concentrations should be considered for patients receiving maintenance treatment with oxcarbazepine, particularly if the patient is being treated with other medications known to decrease serum sodium concentrations (e.g., drugs associated with inappropriate antidiuretic hormone secretion) or if symptoms suggestive of hyponatremia develop.
The use of carbamazepine has been associated with rare reports of serious hematologic reactions (e.g., agranulocytosis, aplastic anemia) that are the subject of a black box warning in its labeling, as well as serious dermatologic reactions (e.g., SJS), cardiovascular adverse events (e.g., congestive heart failure, edema), and hepatic effects. Hematologic and liver function tests should be performed at baseline, and liver function tests should be periodically monitored. These reactions have not been associated with the use of oxcarbazepine and, although there has been considerably less experience with its use, the new drug appears to be better tolerated than carbamazepine.
Studies of the use of oxcarbazepine during pregnancy are limited but, because of its structural relationship to carbamazepine, which is considered to be teratogenic in humans, the new agent is also likely to be teratogenic. Although oxcarbazepine is classified in Pregnancy Category C, compared with Category D for carbamazepine, it should be used during pregnancy only if the anticipated benefit justifies the risk to the fetus.
Oxcarbazepine and MHD can inhibit CYP2C19 and induce CYP3A4/5; however, its action on CYP450 enzymes appears to be less pronounced than that of carbamazepine. The new agent has been reported to reduce the plasma concentrations of the hormonal components of oral contraceptives, and women using hormonal contraceptives should be advised to use alternative or additional nonhormonal forms of contraception. The concurrent use of oxcarbazepine and felodipine (Plendil) has resulted in a reduction of the AUC of the latter agent by almost 30%.
When used in higher dosages (greater than 1,200 mg/day), oxcarbazepine and MHD may inhibit CYP3A4/5, and concurrent use with phenytoin resulted in a 40% increase in phenytoin concentrations. However, lower dosages of oxcarbazepine caused little or no change in phenytoin concentrations.
Strong inducers of CYP450 enzymes (e.g., carbamazepine, phenobarbital, phenytoin) have been reported to reduce the plasma concentrations of MHD, usually by 30% to 40%. However, unlike the experience with carbamazepine, drugs that inhibit CYP450 enzymes (e.g., cimetidine [e.g., Tagamet], erythromycin) do not significantly affect the pharmacokinetics of oxcarbazepine.
Following oral administration, oxcarbazepine is completely absorbed and is extensively metabolized in the liver to MHD, most of which is metabolized further by conjugation with glucuronic acid. More than 95% of a dose is excreted in the urine, with less than 1% as unchanged oxcarbazepine. The elimination half-life of MHD is prolonged in patients with impaired renal function (creatinine clearance < 30 mL/minute), and an adjustment of dosage is recommended for these patients. It is not necessary to adjust the dosage in patients with mild-to-moderate hepatic impairment. Oxcarbazepine has not been studied in patients with severe hepatic impairment.
Oxcarbazepine is administered twice a day without regard to meals. When used as adjunctive therapy, treatment of adult patients should be initiated with a dosage of 300 mg twice a day and increased, as clinically indicated, by a maximum of 600 mg/day at approximately weekly intervals, to the recommended daily dosage of 600 mg twice a day. Although dosages above 1,200 mg/day were more effective in the clinical trials, most patients were not able to tolerate a 2,400 mg/day dosage, primarily because of CNS effects. It is recommended that plasma concentrations of the AEDs used concurrently be monitored during the period of oxcarbazepine titration.
When adult patients treated with other AEDs are to be converted to monotherapy with oxcarbazepine, treatment with the new drug should be initiated at a dosage of 300 mg twice a day, simultaneously initiating the reduction of the dosage of the other AEDs. The concomitant AEDs should be completely withdrawn over a period of 3 to 6 weeks, whereas the maximum dosage of oxcarbazepine should be reached in about 2 to 4 weeks. The dosage of oxcarbazepine should be increased, as indicated, by a maximum increment of 600 mg/day at approximately weekly intervals to the recommended dosage of 1,200 mg twice a day.
Adult patients not being treated with other AEDs may have monotherapy initiated with oxcarbazepine in a dosage of 300 mg twice a day. The dosage should be increased by 300 mg/day every third day to a dosage of 600 mg twice a day. Although this was the maintenance dosage evaluated in the clinical studies in these patients, a dosage of 1,200 mg twice a day has been shown to be effective in patients being converted from other AEDs to oxcarbazepine monotherapy.
The pharmacokinetics of oxcarbazepine are similar in older children (more than 8 years old) and adults. However, younger children have an increased clearance (by about 30% to 40%) compared with older children and adults. When used as adjunctive therapy in pediatric patients (ages 4 to 16), treatment with oxcarbazepine should be initiated at a daily dosage of 8 to 10 mg/kg, divided into two doses and generally not to exceed 300 mg twice a day. The target maintenance dosage of oxcarbazepine should be achieved over 2 weeks, and is dependent on patient weight according to the following guidelines:

20 to 29 kg -- 450 mg twice a day
29.1 to 39 kg -- 600 mg twice a day
> 39 kg -- 900 mg twice a day

In patients with impaired renal function (creatinine clearance < 30 mL/minute), oxcarbazepine therapy should be initiated in a dosage of 150 mg twice a day (one-half the usual starting dosage) and increased slowly to achieve the desired clinical response.
Oxcarbazepine film-coated tablets are supplied in 150 mg, 300 mg, and 600 mg potencies.

Agent for Alzheimer's Disease

Rivastigmine tartrate (Exelon -- Novartis) is the third drug to be approved for the treatment of Alzheimer's disease, joining tacrine (Cognex) and donepezil (Aricept). Tacrine, however, is rarely used in current therapy because it is more likely than the newer agents to cause adverse events and drug interactions, must be administered more frequently (four times a day), and liver function tests must be monitored during its use. Therefore, rivastigmine can best be compared with donepezil, although studies that directly compare the two agents have not been conducted. The two drugs differ structurally because rivastigmine is a carbamate derivative and donepezil a piperidine derivative.
The symptoms of Alzheimer's disease have been suggested to be caused, in part, by a deficiency of acetylcholine in the brain. Like its predecessors, rivastigmine is a reversible cholinesterase inhibitor, and its use results in increased concentrations of acetylcholine and enhanced cholinergic function. Some data suggest that rivastigmine and donepezil exhibit a greater action on acetylcholinesterase in the central nervous system (CNS), thereby reducing the likelihood of adverse events associated with inhibition of this enzyme in peripheral tissues. These agents may also inhibit butyrylcholinesterase, the other major cholinesterase enzyme. Although this enzyme is abundant in peripheral tissues, rivastigmine and donepezil may preferentially inhibit it in the CNS.
The specific indication for rivastigmine, donepezil, and tacrine is the treatment of mild-to-moderate dementia of the Alzheimer's type. In the clinical studies, the effectiveness of rivastigmine was assessed based on a comprehensive evaluation of patient cognition, behavior, and functioning, including assessment of activities of daily living. The use of the drug in a dosage of 6 to 12 mg/day was determined to provide clinical benefits that, to a statistically significant degree, were superior to placebo. None of the three agents is a cure for Alzheimer's disease, and there is no evidence that these agents alter the course of the underlying dementing process.
The adverse events most often reported with the use of rivastigmine in controlled clinical trials are primarily gastrointestinal (GI) effects related to its cholinergic activity and include nausea (47%), vomiting (31%), diarrhea (19%), anorexia (17%), and abdominal pain (13%). Dizziness (21%) and headache (17%) have also been commonly experienced. Data that directly compare rivastigmine and donepezil are not available; however, the incidence of adverse events reported with the use of the recommended dosage of donepezil is considerably lower than that reported with the use of the recommended dosage of rivastigmine.
Because cholinesterase inhibitors are likely to increase gastric acid secretion, patients should be monitored for symptoms of GI bleeding, particularly those who are at increased risk for developing ulcers.
Rivastigmine should also be used with caution in patients with asthma, obstructive pulmonary disease, or seizure disorders because of the potential for its cholinergic activity to exacerbate these disorders. Cholinesterase inhibitors may cause bradycardia, and this action may increase the risk of complications in patients with sick sinus syndrome or other supraventricular cardiac conduction conditions. Rivastigmine is contraindicated in patients with known hypersensitivity to the drug or to other carbamate derivatives.
The use of succinylcholine (e.g., Anectine) or a related neuromuscular blocking agent in a patient treated with rivastigmine is likely to cause exaggerated muscle relaxation during anesthesia. The concurrent use of rivastigmine with a cholinergic agonist such as bethanechol (e.g., Urecholine) would also be expected to produce a synergistic action. Conversely, rivastigmine would be expected to antagonize the activity of anticholinergic medications.
Following oral administration, rivastigmine is rapidly and completely absorbed. However, it undergoes extensive first-pass metabolism and its absolute bioavailability is about 35%. Although administration of the drug with food delays absorption and decreases peak plasma concentration, bioavailability is increased by approximately 30%, and it is recommended that doses of the drug be administered with food.
Rivastigmine is extensively metabolized, primarily by cholinesterase-mediated hydrolysis to the decarbamylated metabolite. The major pathway of elimination is via the kidneys, with more than 95% of a dose of the drug being eliminated as metabolites via this route. Dosage adjustment is not necessary in patients with hepatic impairment because the dose of the drug is individually titrated to tolerability. Variable changes in clearance of rivastigmine have been reported in patients with impaired renal function, but dosage adjustments may not be necessary because dosage is titrated in patients based on their tolerance of the drug.
Rivastigmine is metabolized to only a minimal extent by cytochrome P450 enzymes, and its activity is not likely to be altered by the concurrent use of other agents that inhibit or induce these enzymes. This provides an advantage over donepezil, which is metabolized, in part, via CYP450 pathways, resulting in a potential to interact with other medications that inhibit, induce, or act as a substrate for these enzymes.
Rivastigmine is administered twice a day with food in the morning and evening. This regimen is less convenient than that for donepezil, which is administered once a day without regard to food and with easier dosage titration. The recommended starting dosage is 1.5 mg twice a day. If this dosage is well tolerated, after a minimum of 2 weeks of treatment, the dosage may be increased to 3 mg twice a day. Subsequent increases to 4.5 mg twice a day and 6 mg twice a day should be attempted after a minimum of 2 weeks at the previous dosage. If adverse events (e.g., nausea, vomiting, abdominal pain) cause intolerance during treatment, the patient should be instructed to discontinue treatment for several doses and then start therapy again at the same or next lower dosage level. The maximum recommended dosage is 6 mg twice a day.
Rivastigmine tartrate is supplied in capsules in an amount equivalent to 1.5 mg, 3 mg, 4.5 mg, and 6 mg of rivastigmine base. An oral solution formulation has also been approved by the Food and Drug Administration (FDA) but has not yet been marketed.

Antiarthritic Agent

Meloxicam (Mobic -- Boehringer Ingelheim; Abbott) is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic, and antipyretic actions. The NSAIDs are thought to exhibit their anti-inflammatory action by inhibiting cyclooxygenase (COX) enzymes that are required for prostaglandin synthesis. Two COX enzymes, COX-1 and COX-2, have been identified, but it is thought that the inhibition of COX-1 is not necessary for the NSAIDs to provide anti-inflammatory activity. However, the inhibition of this enzyme is a factor in the occurrence of gastrointestinal (GI) adverse events that many patients experience with the use of the NSAIDs.
The older NSAIDs (e.g., ibuprofen [e.g., Motrin], naproxen [e.g., Naprosyn]) inhibit the action of both COX-1 and COX-2, whereas the recently marketed celecoxib (Celebrex) and rofecoxib (Vioxx) are selective inhibitors of COX-2 and do not inhibit COX-1 when used in therapeutic doses. This selective action appears to result in a lower risk of serious GI adverse events with celecoxib and rofecoxib than with the older NSAIDs. Meloxicam inhibits COX-2 more than COX-1 and has been described as COX-2 preferential to distinguish its action from the COX-2 selective agents, as well as the older NSAIDs.
Meloxicam is indicated for the relief of the signs and symptoms of osteoarthritis and, in comparative studies, it was considered to be as effective as controlled-release diclofenac (e.g., Voltaren-XR) and piroxicam (e.g., Feldene). The use of the new agent has also been studied in patients with rheumatoid arthritis and ankylosing spondylitis, but these are not labeled indications at the present time.
The risks and precautions associated with the use of meloxicam are generally similar to those for other NSAIDs. Its use is contraindicated in patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs, because of the potential for severe, and even fatal anaphylactic-like reactions. Such experiences are most likely to occur in patients with asthma; however, caution must be exercised in all patients because fatal reactions have resulted when an NSAID was taken by a patient with a history of a hypersensitivity reaction to aspirin that was either unknown to, or ignored by, the health professionals prescribing and dispensing the NSAID.
As with the other NSAIDs, GI effects are the adverse events most often associated with the use of meloxicam, with diarrhea, dyspepsia, nausea, flatulence, or abdominal pain occurring in up to 20% of the patients in the clinical trials. However, the incidence of GI effects was lower with meloxicam than with diclofenac or piroxicam in the comparative studies. Caution must be exercised in patients with a prior history of ulcer disease or GI bleeding. Other factors that increase the risk of GI bleeding include older age, treatment with anticoagulants or oral corticosteroids, smoking, alcoholism, and longer duration of NSAID therapy.
Other commonly experienced adverse events (and the incidence with the use of a dosage of 15 mg daily) with the use of meloxicam in the placebo-controlled trials include headache (8%), dizziness (4%), influenza-like symptoms (6%), and edema (5%). As with other NSAIDs, it should be used with caution in patients with fluid retention, hypertension, or heart failure. Caution also should be exercised in patients with considerable dehydration, and it is recommended that patients be rehydrated prior to starting treatment with an NSAID.
Some patients treated with NSAIDs have experienced renal adverse events, such as renal papillary necrosis and a reduction in renal blood flow, that may precipitate overt renal decompensation. Although these reactions are infrequent, the risk is greater when the NSAID is used on a long-term basis (e.g., for the treatment of arthritic disorders) or in elderly patients, those with impaired renal or hepatic function or heart failure, or those taking a diuretic and/or angiotensin-converting enzyme inhibitor (ACEI). The use of meloxicam in patients with mild-to-moderate renal failure (i.e., creatinine clearance > 15 mL/minute) does not require an adjustment in dosage. However, its use has not been adequately studied in patients with severe renal impairment and, therefore, is not recommended in these patients.
In the experience with the use of NSAIDs, borderline elevations of one or more liver function tests have occurred in up to 15% of patients, and notable elevations of alanine or aspartate transaminases (to three or more times the upper limit of normal) in approximately 1% of patients. Rare cases of severe hepatic reactions (e.g., jaundice, hepatitis, hepatic failure) have been reported and, indeed, one NSAID (bromfenac [Duract]) has been withdrawn from the market because of concerns about its hepatotoxicity. Although the risk of hepatic reactions with the use of meloxicam appears to be very low, patients with signs, symptoms, or abnormal laboratory tests that suggest liver dysfunction should be carefully monitored.
The older NSAIDs inhibit platelet aggregation but, unlike aspirin, their effect on platelet function is reversible and of short duration. Like celecoxib and rofecoxib, meloxicam does not interfere with platelet aggregation and does not generally affect prothrombin time or partial thromboplastin time. In a study of the effect of meloxicam on the anticoagulant action of warfarin (e.g., Coumadin), the new drug did not alter warfarin pharmacokinetics or the average anticoagulant effect as determined by prothrombin time. However, one patient did experience a significantly increased International Normalized Ratio (INR) and, if meloxicam must be used by a patient treated with warfarin, therapy should be closely monitored.
Meloxicam, as well as the other NSAIDs, should not be used in late pregnancy because it may cause premature closure of the ductus arteriosus. The new agent is classified in Pregnancy Category C. Although it is not known whether meloxicam is excreted in human milk, a decision should be made whether to discontinue nursing or not take the drug. The effectiveness and safety of meloxicam in patients under 18 years of age have not been established.
The use of cholestyramine (e.g., Questran) has been reported to increase the clearance of meloxicam by approximately 50%, presumably by binding with and preventing the reabsorption of the fraction of the dose that is excreted into the GI tract via biliary elimination.
The use of other NSAIDs has been reported to decrease the antihypertensive effect of ACEIs (e.g., lisinopril [Prinivil, Zestril]) and the natriuretic effect of thiazide diuretics and furosemide (e.g., Lasix), and increase the serum concentrations of lithium. Similar interactions should be anticipated with meloxicam and the new drug has been reported to increase the concentrations and AUC of lithium by about 20%.
Following oral administration the absolute bioavailability of meloxicam is 89%. Neither food nor antacids are likely to alter its activity and it may be administered without regard to the timing of meals and antacids. Meloxicam is almost completely metabolized, primarily by CYP2C9 and, to a lesser extent, by CYP3A4, and the metabolites are eliminated to equal extents in the urine and feces. Dosage adjustment is not necessary in patients with mild-to-moderate hepatic insufficiency, but the drug has not been adequately studied in patients with severe hepatic impairment.
The recommended starting and maintenance dosage of meloxicam is 7.5 mg once daily. Some patients may experience additional benefit by increasing the dosage to 15 mg once a day. Meloxicam tablets are supplied in a 7.5 mg potency.

Antisecretory Agent

Pantoprazole sodium (Protonix -- Wyeth-Ayerst) is the fourth proton pump inhibitor to be marketed in the United States, joining omeprazole (Prilosec), lansoprazole (Prevacid), and rabeprazole (Aciphex). Designated chemically as substituted benzimidazole derivatives, these agents inhibit the gastric hydrogen, potassium-adenosine triphosphatase (H⁺, K⁺-ATPase) enzyme system, also known as the acid or proton pump, at the secretory surface of the gastric parietal cell, thereby blocking the final step of acid production.
Pantoprazole is indicated for the short-term treatment (up to 8 weeks) in the healing and symptomatic relief of erosive esophagitis associated with gastroesophageal reflux disease (GERD). For those patients who have not healed after 8 weeks of treatment, an additional 8-week course of pantoprazole may be considered. In comparative studies, the new agent was as effective as omeprazole, and more effective than nizatidine (Axid) and ranitidine (e.g., Zantac).
The three previously marketed proton pump inhibitors are also indicated for maintaining healing and reduction in relapse of heartburn symptoms in patients with erosive or ulcerative GERD, the treatment of duodenal ulcers, and the treatment of pathological hypersecretory conditions (e.g., Zollinger-Ellison syndrome). In addition, lansoprazole and omeprazole are indicated for the treatment of symptomatic GERD, active benign gastric ulcers, in combination with antibacterial agents for the treatment of Helicobacter pylori infection and active duodenal ulcer, and, for lansoprazole, the maintenance of healed duodenal ulcers. Although these are not labeled indications for pantoprazole at the present time and comparative data are limited, it is likely that the four agents are similar in effectiveness, and expanded indications for the new agent can be expected as additional studies are completed and evaluated.
An intravenously administered formulation of pantoprazole has been developed, but has not yet been approved by the Food and Drug Administration (FDA). None of the other proton pump inhibitors is available in a parenteral formulation and, when approved, this formulation of pantoprazole will extend the usefulness of this class of agents to include seriously ill patients who are unable to take medications orally, and for treating stress-related mucosal damage occurring in patients in intensive care units.
Like the other proton pump inhibitors, pantoprazole is well tolerated. The adverse events reported most often in the short-term placebo-controlled trial conducted in the United States were headache (6%), diarrhea (4%), and flatulence (2%), although headache and flatulence occurred at the same incidence in those receiving placebo as in those treated with pantoprazole. In rodents, pantoprazole is carcinogenic and has caused rare types of gastrointestinal tumors. The relevance of these animal findings to humans is not known; however, the long-term human experience with omeprazole, with which there were similar observations and cautions when it was first marketed, suggests that these agents do not cause tumors in humans. Indeed, the safety of omeprazole, demonstrated in both short-term and long-term use, has prompted an initiative to switch this agent from prescription-only to over-the-counter status.
Pantoprazole, rabeprazole, and lansoprazole are classified in Pregnancy Category B, whereas omeprazole is in Category C. Although it is not known whether pantoprazole is excreted in human milk, a decision should be made whether to discontinue nursing or not use the drug. The effectiveness and safety of pantoprazole in pediatric patients have not been established.
Because the proton pump inhibitors are such potent inhibitors of gastric acid secretion, they may alter the activity of agents such as ketoconazole (e.g., Nizoral) for which gastric acidity is an important determinant of their bioavailability. Therefore, therapy with these agents should be closely monitored when pantoprazole is used concurrently.
Pantoprazole is extensively metabolized by the cytochrome P450 system, primarily by CYP2C19 and CYP3A4. Based on studies in which it was used concurrently with numerous other medications, it appears that pantoprazole is not likely to interact with other medications that are metabolized via these pathways, such as diazepam (e.g., Valium), phenytoin (e.g., Dilantin), theophylline, and warfarin (e.g., Coumadin). Omeprazole has been shown to decrease the rate of elimination and increase the plasma concentration of diazepam, phenytoin, and warfarin, and there have also been interactions reported with other agents, such as cyclosporine (e.g., Neoral), that are metabolized by the CYP450 system. In vitro studies of rabeprazole have also suggested a potential to inhibit the metabolism of cyclosporine. Lansoprazole has not been implicated in these interactions, but has been reported to cause a small increase in theophylline clearance that is unlikely to be clinically important.
Following oral administration, pantoprazole is rapidly absorbed and its absolute bioavailability is approximately 77%. Neither antacids nor food appreciably alter its activity, and it may be administered without regard to meals. Approximately 71% of a dose is excreted in the urine in the form of metabolites, and 18% excreted in the feces through biliary excretion. Because pantoprazole is extensively metabolized in the liver, caution should be exercised if it is used in patients with severe hepatic impairment. Dosage adjustment is not considered necessary in patients with mild-to-moderate hepatic impairment or in patients with renal impairment.
The recommended dosage of pantoprazole is 40 mg once a day for up to 8 weeks. If there is not sufficient healing after 8 weeks of treatment, therapy can be continued for an additional 8 weeks.
Like the other proton pump inhibitors, pantoprazole is rapidly degraded in acidic media, and the drugs are provided in formulations that are designed to protect them from degradation by gastric acid. Pantoprazole sodium sesquihydrate is supplied in delayed-release, enteric-coated tablets in an amount (45.1 mg) equivalent to 40 mg of pantoprazole. Patients should be advised to swallow the tablets whole, and that they should not be chewed, crushed, or split.

Cholinergic Agonist

Sjogren's syndrome is a chronic autoimmune rheumatic disease that may occur as the primary disorder or concomitantly with another autoimmune disease, such as rheumatoid arthritis or systemic lupus erythematosus. It occurs in about nine times as many women as men, and is characterized by xerostomia and xerophthalmia that result from inflammation of the salivary and lacrimal glands. Although the symptoms are minor in many patients, persistent dryness of the mouth can cause pain, be associated with an increased likelihood of oral infections and dental caries, and cause difficulty in chewing, swallowing, talking, wearing dentures, and sleeping. Some patients benefit from taking frequent sips of water, chewing sugar-free gum, sucking hard candy, or using a saliva substitute. However, these approaches do not provide adequate relief of symptoms in some patients, and pilocarpine (Salagen) has been administered orally to increase the secretion of saliva.
Cevimeline hydrochloride (Evoxac -- Daiichi) is, like pilocarpine, a cholinergic agonist that is indicated for the treatment of symptoms of dry mouth in patients with Sjogren's syndrome. It binds to muscarinic receptors and increases the secretion of exocrine glands such as salivary and sweat glands, and also increases the tone of the smooth muscle in the gastrointestinal tract and urinary tract. In two placebo-controlled clinical studies, cevimeline provided significant improvement in the symptoms of dry mouth when compared with placebo, although, in a third study, no statistically significant differences were noted between the cevimeline and placebo groups. The properties of cevimeline and pilocarpine are generally similar, but data are not available to permit a direct comparison.
Pilocarpine tablets are also indicated for the treatment of symptoms of dry mouth from salivary gland hypofunction caused by radiation therapy for cancer of the head and neck. It is likely that cevimeline is also effective in this situation, but this is not a labeled indication for the new agent at the present time.
The most frequently experienced adverse events that result from the muscarinic- agonist action of cevimeline include excessive sweating (19%), nausea (14%), diarrhea (10%), and rhinitis (11%). Dehydration may occur in patients who sweat excessively and they should be advised to drink more water. Other commonly reported reactions include headache (14%), sinusitis (12%), upper respiratory tract infection (11%), dyspepsia (8%), and abdominal pain (8%), although the incidence of these events was similar, or in some cases even higher, in the individuals receiving placebo. Fifteen percent of the patients treated with cevimeline discontinued therapy because of adverse events.
Both cevimeline and pilocarpine are contraindicated in patients with uncontrolled asthma and when miosis is undesirable (e.g., acute iritis, narrow-angle glaucoma). Because these agents may increase airway resistance, bronchial smooth muscle tone, and bronchial secretions, they must be used with caution in patients with controlled asthma, chronic bronchitis, or chronic obstructive pulmonary disease.
Cholinergic agonists may alter cardiac conduction and/or heart rate, and caution must be exercised in patients with a history of cardiovascular disease evidenced by angina pectoris or myocardial infarction. The concurrent use of a b-adrenergic blocking agent may increase the risk of conduction disturbances. These agents must also be used cautiously in patients with a history of nephrolithiasis or cholelithiasis because contractions of the gall bladder or biliary smooth muscle may result in complications such as cholecystitis or biliary obstruction.
Cevimeline and pilocarpine may cause visual disturbances, especially at night, and patients should be warned about the possible impairment of driving ability and the risk of performing other potentially hazardous activities.
Cevimeline is classified in Pregnancy Category C and should be used during pregnancy only if the anticipated benefit justifies the risk to the fetus. It is not known whether the drug is excreted in human milk and a decision should be made whether to discontinue nursing or not use the drug. The effectiveness and safety of cevimeline in pediatric patients have not been established.
The concurrent use of cevimeline and another agent with parasympathomimetic activity would be expected to result in additive effects. If an antimuscarinic agent is used concurrently for another condition, cevimeline will probably reduce the desired action(s) of that drug.
Following oral administration, cevimeline is rapidly absorbed. It is extensively metabolized, primarily by CYP2D6 and CYP3A3/4, and drugs that inhibit or induce these isozymes may alter its activity. The new agent should be used with caution in patients who are known or suspected to be deficient in CYP2D6 activity. Cevimeline has been shown to not inhibit the common CYP450 isozymes on which its action has been studied.
Almost all of a dose of cevimeline is excreted in the urine, primarily in the form of metabolites. The effects of renal or hepatic impairment on the pharmacokinetics and activity of cevimeline have not been studied.
The recommended dosage of cevimeline is 30 mg three times a day, which is slightly more convenient than the use of pilocarpine (administered four times a day). There is insufficient evidence that a higher dosage of cevimeline is more effective than the 30 mg three-times-a-day regimen.
Cevimeline hydrochloride is supplied in capsules in an amount equivalent to 30 mg of cevimeline.

Agent for Respiratory Distress Syndrome

Respiratory distress syndrome (RDS) is a life-threatening illness that occurs in approximately 100,000 premature infants each year in the United States. RDS is caused by a deficiency in lung surfactant, a complex mixture of phospholipids and proteins produced by alveolar cells. Surfactant stabilizes the alveoli during ventilation by reducing alveolar surface tension, decreases the negative pressures needed to open airways, and reduces the work of breathing (i.e., increases lung compliance). In the absence of sufficient amounts of endogenous surfactant at birth, progressive collapse of alveoli (atelectasis) occurs, which limits lung ventilation. Thus, infants who develop RDS often require supplemental oxygen, mechanical ventilation, and/or other supportive measures until their lungs are able to synthesize adequate amounts of surfactant. These interventions are lifesaving, but also are associated with significant risk.
In 1990 a synthetic product (Exosurf Neonatal) containing colfosceril palmitate, cetyl alcohol, and tyloxapol was marketed as the first surfactant formulation to be approved for the treatment of RDS. A year later, beractant (Survanta) was marketed and this product represents a natural bovine lung extract to which di-palmitoyl phosphatidylcholine (DPPC), palmitic acid, and tripalmitin are added to standardize the composition. Administered intratracheally, these lung surfactants have been the standard of treatment for infants with RDS and are generally credited for a 30% decrease in mortality in infants of very low birth weight. In 1999 calfactant (Infasurf) was marketed, and this product is an extract of natural surfactant from calf lungs that includes phospholipids, neutral lipids, and hydrophobic surfactant-associated proteins B and C (SP-B and SP-C).
Poractant alfa (Curosurf -- Dey) is the fourth lung surfactant product to be marketed, and is an extract of natural porcine lung surfactant consisting of 99% polar lipids (mainly phospholipids) and 1% hydrophobic low-molecular weight proteins (SP-B and SP-C). Available as a suspension in 0.9% sodium chloride solution for intratracheal administration, each mL contains 80 mg of total phospholipids (including 54 mg of phosphatidylcholine, of which 30.5 mg is DPPC) and 1 mg of protein, including 0.3 mg of SP-B. Following administration, poractant alfa adsorbs to the surface of the air-liquid interface and reduces surface tension, similar to the action of natural lung surfactant.
Poractant alfa is indicated for the treatment ("rescue") of RDS in premature infants, and it reduces mortality, pneumothoraces, and pulmonary interstitial emphysema associated with RDS. Its effectiveness has been demonstrated in two studies in infants having a birth weight of 700 to 2,000 grams, in which it was administered after RDS developed and before 15 hours of age. The use of a multiple-dose regimen (two or three doses) was more effective than a single-dose treatment in reducing mortality and pneumothoraces. The three natural surfactant products appear to be similar in their effectiveness, and some comparative studies suggest that they are slightly more effective than the synthetic product (i.e., Exosurf Neonatal).
The three previously marketed lung surfactant products are indicated for prophylaxis of RDS in premature infants, as well as for the treatment of RDS after it occurs. Although prophylaxis of RDS is not a labeled indication for poractant alfa at the present time, its use for this purpose is currently being studied.
The most common adverse events associated with the use of poractant alfa include bradycardia, hypotension, endotracheal tube blockage, and oxygen desaturation. These events were generally transient and not associated with serious complications; however, administration of the drug should be interrupted and the infant's condition should be stabilized using appropriate interventions before administration is resumed. Common complications of prematurity and RDS (e.g., patent ductus arteriosus, intracranial hemorrhage, bronchopulmonary dysplasia, acquired pneumonia) were experienced at a similar incidence in the infants receiving poractant alfa as in the control group. When an infant who is a candidate for poractant alfa treatment is experiencing acidosis, anemia, hypotension, hypoglycemia, and/or hypothermia, it is recommended that these problems be corrected before the drug is administered.
The administration of exogenous surfactants, including poractant alfa, often rapidly improves oxygenation and lung compliance. Patients should be closely monitored so that oxygen therapy and ventilatory support can be modified in response to changes in respiratory status.
The initial recommended dose of poractant alfa is 2.5 mL/kg birth weight, which represents the lowest dosing volume of the four surfactant products. Immediately before administering the drug, the infant's ventilator settings should be changed to a rate of 40 to 60 breaths/minute, inspiratory time 0.5 second, and supplemental oxygen sufficient to maintain arterial oxygen percent saturation (SaO₂) > 92%. The drug is administered intratracheally by instillation through a 5 French end-hole catheter (cut to a standard length of 8 cm) inserted into the infant's endotracheal tube, with the tip positioned distally in the endotracheal tube. Each dose should be administered as two aliquots, with each aliquot administered into one of the two main bronchi by positioning the infant with either the right- or left-side dependent. The airways should not be suctioned for 1 hour after surfactant instillation unless signs of significant airway obstruction occur.
Up to two repeat doses of 1.25 mL/kg birth weight each may be administered, at approximately 12-hour intervals, in infants who remain intubated and in whom RDS is considered responsible for their persistent or deteriorating respiratory status. The maximum recommended total dosage is 5 mL/kg, representing the sum of the initial dose and two repeat doses.
Poractant alfa intratracheal suspension is supplied in ready-to-use vials containing 1.5 mL (120 mg phospholipids) and 3 mL (240 mg phospholipids) of suspension. The vials should be stored in a refrigerator. Before use, the vial should be warmed to room temperature and gently turned upside down, but not shaken, to obtain a uniform suspension. Unopened, unused vials of poractant alfa that have been warmed to room temperature can be returned to refrigerated storage within 24 hours for future use. However, vials should not be warmed to room temperature and returned to refrigerated storage more than once. After a vial is opened, any unused portion of the drug should be discarded.

Pulmonary Vasodilator

Persistent pulmonary hypertension of the newborn occurs as a primary developmental effect or as a condition secondary to other diseases, such as meconium aspiration syndrome, pneumonia, sepsis, hyaline membrane disease, congenital diaphragmatic hernia, and pulmonary hypoplasia. It is common in neonates with respiratory failure and is characterized by high pulmonary vascular resistance, which results in hypoxemia secondary to right-to-left shunting of blood through the patent ductus arteriosus and foramen ovale.
It is estimated that approximately 24,000 newborn infants in the United States experience hypoxic respiratory failure each year. In many cases, the disease progressively worsens and, when other therapies are not successful, infants are treated with extracorporeal membrane oxygenation (ECMO). Although this therapy improves survival, its use is labor intensive and costly. The mortality rate in infants treated with ECMO is 15% to 20%, and 10% to 20% of the infants who survive experience significant developmental delay.
Nitric oxide is produced by many cells in the body and, by relaxing vascular smooth muscle, it plays an important role in increasing blood flow to the lungs after birth. Nitric oxide (INOmax -- INO Therapeutics) has been approved in the form of a gaseous blend of nitric oxide (0.8%) and nitrogen (99.2%) for administration by inhalation. When inhaled, it produces pulmonary vasodilation and appears to increase the partial pressure of arterial oxygen (PaO₂).
Nitric oxide, in conjunction with ventilatory support and other appropriate agents, is indicated for the treatment of term and near-term (> 34 weeks) neonates with hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension, where it improves oxygenation and reduces the need for extracorporeal membrane oxygenation. Its effectiveness and safety have been demonstrated in placebo-controlled trials in infants who were also receiving other therapies for hypoxic respiratory failure, including vasodilators, intravenous fluids, bicarbonate therapy, and mechanical ventilation. Although the incidence of death was similar in both the nitric oxide and control groups, significantly fewer infants in the nitric oxide group required ECMO compared with the control group.
The incidence of adverse events in the nitric oxide and placebo groups was generally similar. The adverse events most often experienced by infants receiving nitric oxide include hypotension (13%), withdrawal syndrome (12%), atelectasis (9%), hematuria (8%), hyperglycemia (8%), sepsis (7%), and infection (6%). The use of nitric oxide is contraindicated in neonates known to be dependent on right-to-left shunting of blood.
Nitric oxide is absorbed systemically after inhalation, and most of it combines with hemoglobin that is 60% to 100% oxygen-saturated, resulting in the production of methemoglobin and nitrate. Methemoglobinemia increases with the dose of nitric oxide, and maximum methemoglobin concentrations usually are reached approximately 8 hours after initiation of inhalation. In the clinical trials, methemoglobin concentrations > 7% were treated by reducing the dosage or by discontinuing administration of nitric oxide. Although the potential for drug interactions has not been studied, a possibility exists that the concurrent use of nitric oxide donor compounds, such as sodium nitroprusside and nitroglycerin, may have an additive effect on the risk of developing methemoglobinemia.
Nitrate is the predominant nitric oxide metabolite excreted in the urine, accounting for more than 70% of the nitric oxide dose inhaled.
The recommended dosage of nitric oxide is 20 ppm. Treatment should be continued for up to 14 days or until the underlying oxygen desaturation has resolved and the infant is ready to be weaned from nitric oxide therapy. Although doses as high as 80 ppm were used in some patients in the clinical studies, the higher doses were not found to provide significant improvement, but did increase the risk of methemoglobinemia. Therefore, doses above 20 ppm ordinarily should not be used. Additional therapies should be used to maximize oxygen delivery and, in infants with collapsed alveoli, such therapies might include surfactant and high-frequency oscillatory ventilation.
Nitric oxide must be delivered through a system that does not cause generation of excessive inhaled nitrogen dioxide. A delivery device, INOvent, has also been approved for use in the administration of nitric oxide. Administration of the drug should not be abruptly discontinued because it may lead to worsening oxygenation and increasing pulmonary artery pressure.
Nitric oxide is supplied in aluminum cylinders as a compressed gas under high pressure, in 100 ppm and 800 ppm concentrations in nitrogen.

Local Anesthetic

A combination of a new local anesthetic, articaine hydrochloride, with an old vasoconstrictor, epinephrine bitartrate, has been marketed under the trade name Septocaine (Septodont). Articaine is a member of the amide class of local anesthetics that also includes agents such as lidocaine (e.g., Xylocaine), bupivacaine (e.g., Marcaine), mepivacaine (e.g., Carbocaine), and prilocaine (Citanest). Epinephrine is included to slow absorption of articaine into the general circulation, thereby prolonging active tissue concentrations of the anesthetic in the area in which it was injected.
Articaine is administered by submucosal infiltration and/or nerve block to provide anesthesia for dental procedures. It is specifically indicated for local, infiltrative, or conductive anesthesia in both simple and complex dental and periodontal procedures. In clinical studies in which it was compared with lidocaine, articaine provided effective pain relief during most dental procedures, and had a time to onset and duration of anesthesia comparable to those observed for other local anesthetics.
Articaine is well tolerated and adverse reactions experienced with its use are characteristic of those associated with other amide-type local anesthetics. Pain (13%) and headache (4%) were the most commonly experienced adverse events in the clinical studies. Adverse reactions may also result from excessive plasma concentrations, which may be due to overdosage, unintentional intravascular injection, or slow metabolic degradation. Although plasma concentrations associated with the administration of therapeutic doses of articaine are not likely to cause cardiovascular or neurologic reactions, accidental intravascular injection may result in convulsions, followed by central nervous system or cardiorespiratory depression and coma. To avoid intravascular injection, aspiration should be performed before articaine is injected. The needle must be repositioned until no return of blood can be elicited by aspiration. The use of articaine is contraindicated in patients with a history of hypersensitivity to any of the local anesthetics of the amide type.
Articaine is classified in Pregnancy Category C and should be used during pregnancy only if the anticipated benefit justifies the risk to the fetus. It is not known whether the drug is excreted in human milk and caution should be exercised if it is administered to a nursing woman. The effectiveness and safety of articaine in children less than 4 years of age have not been established.
The inclusion of epinephrine in the formulation as a vasoconstrictor also warrants certain precautions. Patients with peripheral vascular disease and those with hypertensive vascular disease may exhibit an exaggerated vasoconstrictor response, and ischemic injury or necrosis may result. The use of epinephrine in patients treated with a monoamine oxidase inhibitor (e.g., tranylcypromine [Parnate]) or tricyclic antidepressant (e.g., amitriptyline [e.g., Elavil]) may cause severe, prolonged hypertension, and phenothiazines (e.g., chlorpromazine [e.g., Thorazine]) and butyrophenones (e.g., haloperidol [e.g., Haldol]) may reduce or reverse the pressor effect of epinephrine. The concurrent use of epinephrine and one of these agents should generally be avoided.
The articaine/epinephrine formulation contains sodium metabisulfite, a sulfite that may cause allergic-type reactions, including anaphylactic symptoms in susceptible individuals. Sulfite sensitivity is experienced more frequently in asthmatic than in nonasthmatic people.
Following dental injection by the submucosal route of a solution that also contains epinephrine, peak blood concentrations of articaine are reached about 25 minutes after a single-dose injection. The drug is rapidly metabolized, primarily by plasma carboxyesterase and to a low extent via CYP450 enzymes, to articainic acid, which is inactive. The drug is excreted primarily in the urine.
The onset of anesthesia following administration of articaine/epinephrine is usually within 1 to 6 minutes of injection, and complete anesthesia lasts approximately 1 hour. The onset and duration of anesthesia are proportional to the volume and concentration (i.e., total dose) of local anesthetic used.
Articaine hydrochloride/epinephrine bitartrate injection contains the local anesthetic in a 4% concentration and the vasoconstrictor in an amount equivalent to a 1:100,000 concentration of epinephrine base. The product is formulated with a 15% overage of epinephrine and supplied in 1.7 mL glass cartridges. The recommended dosages are 0.5 to 2.5 mL for infiltration, 0.5 to 3.4 mL for nerve block, and 1 to 5.1 mL for oral surgery. The smallest dose that will provide the desired level of anesthesia should be used. The dosage should be reduced for children, geriatric patients, and patients with cardiac and/or liver disease. The maximum dose of articaine administered by submucosal infiltration and/or nerve block should not exceed 7 mg/kg.

Agent for Infertility

Infertility affects more than six million couples in the United States, or approximately 10% of the reproductive age population. The approaches that have been used to address the problem of infertility, such as in vitro fertilization, often involve a complex regimen of medications and procedures. The development of ganirelix acetate (Antagon -- Organon) to suppress ovulation represents an important step in reducing the complexity of fertility drug therapy.
Ganirelix is a synthetic decapeptide that acts as an antagonist against naturally occurring gonadotropin-releasing hormone (GnRH), the hormone that stimulates the synthesis and secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). By competitively blocking the GnRH receptors on the pituitary gonadotroph and subsequent transduction pathway, ganirelix induces a rapid, reversible suppression of gonadotropin secretion. The suppression of pituitary LH secretion by ganirelix is more pronounced than that of FSH.
GnRH is released from the pituitary in a pulsatile manner and, in normal ovulatory cycles, a large pulse of LH is released (LH surge) about midcycle that initiates egg ripening and release. Although it is not a labeled indication, leuprolide (Lupron) has been used in in vitro fertilization treatment cycles to suppress the premature release of LH for the purpose of inhibiting ovulation so that the eggs remain available for retrieval by a fertility specialist. However, leuprolide must be administered daily for an average of 22 days in these procedures, whereas ganirelix is administered daily for an average of just 5 days.
Ganirelix is administered subcutaneously and is indicated for the inhibition of premature LH surges in women undergoing controlled ovarian hyperstimulation. It is included as a component of an infertility regimen that also includes FSH to initially stimulate the development of follicles containing eggs, and human chorionic gonadotropin (hCG) for ovulation induction when a sufficient number of follicles of adequate size are present. Retrieval of the eggs, followed by in vitro fertilization or intracytoplasmatic sperm injection, are subsequently performed. In a multicenter study in which ganirelix was evaluated in 463 patients, a premature LH surge prior to hCG administration occurred in less than 1% of the patients.
The adverse events most often associated with the use of ganirelix include abdominal pain (gynecological, 5%), fetal death (4%), headache (3%), ovarian hyperstimulation syndrome (2%), and vaginal bleeding (2%). Headaches and hot flashes occur less frequently than with leuprolide. Increased neutrophil counts were reported in 12% of patients, and reductions in hematocrit and total bilirubin were also observed; however, the clinical significance of these findings was not determined. In follow-up studies of 283 newborns of women administered ganirelix, it was determined that 3 of the neonates had major congenital anomalies and 18 neonates had minor congenital anomalies. Whether there is a causal relationship between the use of the drug and the occurrence of the anomalies is not known.
Ganirelix is contraindicated in patients with known hypersensitivity to the drug, GnRH, or any other GnRH analogue. There were no reports of anaphylactic reactions or ganirelix antibody formation in the clinical studies. Ganirelix is classified in Pregnancy Category X and its use is contraindicated during pregnancy, and pregnancy must be excluded before initiating treatment. It is not known whether the drug is excreted in human milk and should not be used in lactating women.
Drug interaction studies have not been conducted with ganirelix. However, because it suppresses the secretion of pituitary gonadotropins, dosage adjustments of exogenous gonadotropins may be necessary when used during controlled ovarian hyperstimulation.
Following subcutaneous administration ganirelix is rapidly absorbed, and maximum serum concentrations are reached approximately 1 hour after administration. Approximately 75% of a dose of the drug is excreted in the feces in the form of metabolites, with the remainder eliminated via the urine.
The use of the infertility regimen is begun by initiating FSH therapy on day 2 or 3 of a natural menstrual cycle. Ganirelix is usually initiated on day 7 or 8 (day 6 of FSH administration) in a dosage of 250 mcg administered subcutaneously (usually in the abdomen around the navel or upper thigh) once a day during the early to mid-follicular phase. Because of the endogenous pituitary FSH secretion, the requirement for exogenously administered FSH may be reduced. Treatment with ganirelix and FSH should be continued until the day of hCG administration, and the average duration of treatment with ganirelix in the clinical studies was 5 days, with a range of 2 to 14 days. When a sufficient number of follicles of adequate size are present (e.g., at least three follicles 17 mm or greater in diameter), as assessed by ultrasound, the final maturation of follicles is induced by administering hCG. The administration of hCG should be withheld in patients in whom the ovaries are abnormally enlarged on the last day of FSH therapy to reduce the risk of the occurrence of ovarian hyperstimulation syndrome.
Ganirelix acetate is supplied in prefilled 1 mL glass syringes containing the drug in a concentration of 250 mcg/0.5 mL. The packaging of the product contains natural rubber latex, which may cause allergic reactions.

Abortifacient

Long before its approval by FDA on September 28, 2000, the use of mifepristone (Mifeprex -- Danco), formerly known as RU-486, to produce abortion was surrounded by controversy. Now that it has been approved and is available on a restricted basis from physicians who agree to comply with conditions regarding the use of the drug, the number of issues being debated have increased even further. In addition to the religious, ethical, women's rights, and other issues that pertain to the subject of abortion, questions regarding the safety of mifepristone; FDA's role and the appropriateness of its decision; the recommended concurrent use of misoprostol (Cytotec), the labeling for which notes that it is contraindicated in women who are pregnant; the advocacy by some for use in a manner that does not comply with very specific labeling information; the restricted distribution system; the rights of health care professionals who decline to be associated with the use of the drug; and other issues add to the complexity and intensity of the debate. Although these issues are very important and deserving of additional consideration, the primary focus of the following discussion will be on the properties and use of mifepristone.
Mifepristone is a synthetic steroid with antiprogestational effects. It competitively inhibits the binding of progesterone to its receptor sites, thereby antagonizing its hormonal activity. Progesterone is needed to maintain a pregnancy, and the use of mifepristone results in termination of the pregnancy. Mifepristone also sensitizes the myometrium to the contraction-inducing activity of prostaglandins (e.g., misoprostol), and misoprostol is used in conjunction with mifepristone to induce contractions that facilitate the expulsion of the fetus.
Mifepristone is indicated for the medical termination of intrauterine pregnancy through 49 days' pregnancy. For purposes of this treatment, pregnancy is dated from the first day of the last menstrual period in a presumed 28-day cycle with ovulation occurring at mid-cycle. The duration of pregnancy may be determined from menstrual history and by clinical examination. Ultrasonographic scan should be used if the duration of pregnancy is uncertain, or if ectopic pregnancy is suspected. If the woman is using an intrauterine device (IUD), it should be removed prior to the administration of mifepristone.
Mifepristone is administered in a single oral dose of 600 mg that should be followed 2 days later with a single oral dose of 400 mcg of misoprostol unless a complete abortion has already been confirmed before that time. In situations in which mifepristone and misoprostol fail to cause termination of intrauterine pregnancy, surgical termination of the pregnancy is recommended.
In the clinical studies conducted in the United States, 92% of the women had a complete medical abortion, including 6% in whom expulsion of the fetus occurred within 2 days, resulting from the action of mifepristone alone without the addition of misoprostol. The other women in the study also received misoprostol and expulsion of the fetus occurred in 44% and 63% within 4 hours and 24 hours, respectively, following misoprostol administration. Eight percent of the women received surgical interventions, most because of incomplete abortions at the end of the study protocol.
In addition to its antiprogestational action, mifepristone exhibits antiglucocorticoid and weak antiandrogenic activity. Limited studies suggest that it may be of value in a number of disorders including fibroids, endometriosis, ovarian cancer, breast cancer, brain tumors, Cushing's syndrome, and psychotic depression. However, these are not labeled indications at the present time.
The use of mifepristone and misoprostol will not terminate an ectopic pregnancy, and their use is contraindicated in women with confirmed or suspected ectopic pregnancy or undiagnosed adnexal mass. The new drug is also contraindicated in women with an IUD in place, a history of allergy to mifepristone, misoprostol, or other prostaglandins, chronic adrenal failure, inherited porphyrias, hemorrhagic disorders or concurrent anticoagulant therapy, or who are on long-term corticosteroid therapy. In addition, treatment is contraindicated in women who may not understand or be able to comply with the regimen, or if a woman does not have adequate access to medical facilities equipped to provide emergency treatment of incomplete abortion, blood transfusions, and emergency resuscitation. There are no data regarding the safety of mifepristone in women with chronic medical conditions such as hepatic, renal, or respiratory disease, hypertension, diabetes, or anemia. The drug must be used with caution in women who are more than 35 years of age and who also smoke 10 or more cigarettes a day because these individuals were generally excluded from clinical trials.
Treatment with mifepristone and misoprostol is expected to induce the vaginal bleeding and uterine cramping necessary to produce an abortion, and almost all women experience these responses. Bleeding or spotting occurs for an average of 9 to 16 days, and 8% of the women in the clinical studies experienced some type of bleeding for 30 days or longer. In some cases, excessive bleeding may require treatment with vasoconstrictor drugs, curettage, administration of saline infusions, and/or blood transfusions. Heavy bleeding requiring curettage occurs in approximately 1% of patients, and caution must be exercised in patients with hemostatic disorders, hypocoagulability, or severe anemia.
Other adverse events frequently experienced with the use of mifepristone and misoprostol include nausea (61%), vomiting (26%), diarrhea (20%), headache (31%), dizziness (12%), and fatigue (10%). In the event that mifepristone and misoprostol do not produce abortion, and the woman declines to have a surgical abortion at that time, the potential exists for drug-induced harm to the fetus.
Mifepristone is extensively metabolized, primarily via the CYP3A4 pathway, and it is possible that other drugs that inhibit or induce this metabolic pathway may alter the serum concentrations and activity of mifepristone. However, the clinical importance of these potential interactions is not known. Mifepristone may cause increases in concentrations of other drugs that are CYP3A4 substrates and, because mifepristone is slowly eliminated from the body, an interaction may be observed over a prolonged period after its administration. Caution should be exercised when it is used during the same general time period with drugs that are CYP3A4 substrates and also have a narrow therapeutic range, such as some of the agents used during general anesthesia.
Following oral administration mifepristone is rapidly absorbed and has an absolute bioavailability of approximately 70%. Most of the drug is eliminated in the feces in the form of metabolites.
Mifepristone is not supplied through pharmacies but is only provided to physicians who sign and return a Prescriber's Agreement. Participating physicians must have the ability to assess the duration of pregnancy accurately, diagnose ectopic pregnancies, and provide surgical intervention in cases of incomplete abortion or severe bleeding, or have made plans to provide such care through others, and are able to ensure patient access to medical facilities equipped to provide blood transfusions and resuscitation, if necessary. Physicians must also provide a Medication Guide and explain the treatment to a woman to whom the drug will be administered, have the woman read and sign a Patient Agreement (which is also signed by the physician), agree to follow the guidelines for using the drug, and report the occurrence of any serious adverse event.
Although mifepristone is not supplied through pharmacies, pharmacists may receive prescriptions for the misoprostol component of this regimen or physician requests to purchase this agent.
Treatment with mifepristone and misoprostol requires three office visits. On the first visit the woman must read the Medication Guide and read and sign the Patient Agreement, prior to the administration of 600 mg of mifepristone (three 200 mg tablets) as a single oral dose. The second visit occurs 2 days later and, unless abortion has already occurred and has been confirmed, the woman takes a single oral dose of 400 mcg of misoprostol (two 200 mcg tablets). Approximately 14 days after the administration of mifepristone, the woman should return for a follow-up visit to confirm by clinical examination or ultrasonographic scan that a complete termination of pregnancy has occurred. Vaginal bleeding should not be viewed as evidence of the termination of pregnancy.
Although these "conditions" for using mifepristone in the United States are less restrictive than those in certain other countries in which its use is approved (e.g., France), some have contended that they are too restrictive. Some studies have suggested that mifepristone can be used for longer periods than the first 49 days of pregnancy, that women can visit the health care provider's office less than three times, that different doses of both mifepristone and misoprostol would be equally effective, and that misoprostol could be administered vaginally instead of orally. If the alternative dosage regimens and number of physician visits were used instead of those noted in the product labeling and agreements, a question exists as to whether the agreement through which a participating physician obtains mifepristone continues to be valid.

Antineoplastic Agents

Many cancers of the breast have estrogen receptors, and estrogens can stimulate the growth of these tumors. In postmenopausal women, the primary source of circulating estrogen is the conversion of adrenal androgens (primarily androstenedione and testosterone) to estrogen (primarily estrone and estradiol) in peripheral tissues, which is catalyzed by the enzyme aromatase.
Many of these patients are treated with an antiestrogen (e.g., tamoxifen [e.g., Nolvadex]) as first-line treatment. Progestins such as megestrol acetate (e.g., Megace) have often been used as second-line therapy, but the recent marketing of selective aromatase inhibitors, anastrozole (Arimidex) and letrozole (Femara), has provided effective alternatives. Additional studies and postmarketing experience with these two agents have resulted in their even more recent approval as first-line therapy in the treatment of breast cancer in postmenopausal women.
Exemestane (Aromasin -- Pharmacia) is an irreversible, steroidal aromatase inactivator that is derived from androstenedione. It acts as a false substrate for aromatase, and is converted to an intermediate that binds irreversibly to the active site of the enzyme causing its inactivation, an effect also known as "suicide inhibition." In contrast, anastrozole and letrozole are not steroids and reversibly inhibit aromatase. However, whether the difference in the manner in which these agents reduce the action of aromatase is of clinical importance is not known. Treatment with exemestane reduces plasma estrogen concentrations by 85% to 95%, without significantly affecting adrenal corticoid synthesis or plasma concentrations of androgens.
Exemestane is indicated for the treatment of advanced breast cancer in postmenopausal women whose disease has progressed following tamoxifen therapy. In a clinical study in which the new agent (administered once a day) was compared with megestrol acetate (administered four times a day), the objective response rate (complete and partial responses) was 15% with exemestane and 12% with megestrol acetate. The median duration of response was 76 weeks for the patients treated with exemestane and 71 weeks for those receiving megestrol acetate. Exemestane has been effective in some patients who failed to respond to megestrol acetate, or to anastrozole or letrozole, but data are not available to permit a direct comparison of exemestane with anastrozole or letrozole.
Treatment with exemestane was better tolerated than treatment with megestrol acetate, as evidenced by discontinuation rates of 2% and 5%, respectively, because of adverse events. The most frequently reported adverse events with the use of exemestane that were considered drug related or of indeterminate cause included hot flashes (13%), nausea (9%), fatigue (8%), increased sweating (4%), increased appetite (3%), and excessive weight gain (8%). Approximately 20% of the patients treated with exemestane in the clinical studies experienced grade 3 or 4 lymphocytopenia; however, approximately 90% of these patients had a pre-existing lower grade lymphopenia, and 40% of patients either recovered or improved to a lesser severity while on treatment. Elevations in liver function tests were experienced by some patients, but most were attributed to the underlying presence of liver metastases. Approximately 3% of patients had elevations of liver function tests without evidence of liver metastasis.
Exemestane may cause fetal harm and is classified in Pregnancy Category D. It is indicated for use in postmenopausal women but, if there is exposure to the drug during pregnancy, the patient should be apprised of the potential harm to the fetus.
The goal of exemestane treatment is to reduce estrogen concentrations, and patients should not be using estrogen-containing products. However, the use of such a product may be inadvertently overlooked, and caution should be exercised to be certain that patients avoid the use of these products.
Following oral administration, exemestane is rapidly, but incompletely, absorbed. Plasma concentrations are increased by approximately 40% when the drug is administered after a high-fat breakfast. It is extensively metabolized, primarily via the CYP3A4 pathway, to derivatives with no or little activity. Similar amounts of the drug are excreted in the urine and feces, and the amount of drug excreted in unchanged form in the urine is less than 1% of the dose. Dosage adjustment does not appear to be necessary in patients with moderate or severe hepatic or renal impairment.
Although exemestane is metabolized to a significant extent by CYP3A4, a study of the concurrent use of ketoconazole (e.g., Nizoral), that is known to be a potent inhibitor of this metabolic pathway, did not cause any significant change in the pharmacokinetics of the new agent. A potential exists, however, for drugs that are known to increase the activity of CYP3A4 to reduce the plasma concentrations and activity of exemestane.
The recommended dosage of exemestane is 25 mg once a day after a meal. Treatment should be continued until worsening of the tumor is evident. Exemestane tablets are supplied in a 25 mg potency.
Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. Almost 10,000 new cases occur in the United States each year, more than three-fourths of which are in patients over the age of 60. The disorder is characterized by a rapid accumulation of abnormal white blood cells in the blood and bone marrow, resulting in severe anemia, infection, and hemorrhage during the course of the disease.
If untreated, AML is rapidly fatal and, even with treatment, only about 20% of patients with AML survive more than 5 years. The conventional treatment has been a combination regimen that includes cytarabine (e.g., Cytosar-U) and an anthracycline (e.g., daunorubicin [e.g., Cerubidine]). Although more than 60% of patients will have a complete remission with this chemotherapy, most relapse and subsequent therapy is less effective. The prognosis is least favorable for older patients, and these individuals are also less tolerant of the conventional treatment regimens.
The CD33 antigen is a glycoprotein that is expressed on the surface of leukemic blasts in more than 80% of patients with AML. It is also found on other bone marrow hematopoietic cells, but not on pluripotent hematopoietic stem cells. These observations have provided the basis for research initiatives designed to develop therapeutic agents with activity that is targeted against specific cells.
Gemtuzumab ozogamicin (Mylotarg -- Wyeth-Ayerst) is the first "antibody-targeted chemotherapy." Designated as an orphan drug and approved by FDA under its accelerated approval regulations, it combines the specific targeting of a humanized recombinant monoclonal antibody with the cytotoxic activity of the antitumor antibiotic, calicheamicin. The antibody portion binds specifically to the CD33 antigen, resulting in the formation of a complex that is internalized, the release of calicheamicin inside the lysosomes of the myeloid cells, and the binding of this agent with DNA in a manner that causes cell death. Gemtuzumab ozogamicin has approximately 50% of the antibody loaded with 4 to 6 moles of calicheamicin per mole of antibody. The remaining 50% of the antibody is not linked to calicheamicin.
Gemtuzumab ozogamicin is administered by intravenous infusion and is indicated for the treatment of patients with CD33-positive AML in first relapse who are 60 years of age and older and who are not considered candidates for cytotoxic chemotherapy. In the clinical studies that included 142 patients, the overall response rate in the 80 patients meeting these criteria was 26%, a remission rate that is similar to that attained with conventional chemotherapy. The median duration of overall survival for the 142 patients was 5.9 months. Data are not available that would permit a direct comparison of gemtuzumab ozogamicin with other regimens. However, the new agent provides an effective alternative to the limited number of medications that are effective in the treatment of AML, and it can be used advantageously in certain patients.
The indication for the use of gemtuzumab ozogamicin is limited because there are no data to demonstrate that it is as effective as conventional regimens for a broader range of patients with relapsed AML (i.e., patients under 60 years and/or those who would be considered candidates for cytotoxic chemotherapy). Studies in such patients, as well as comparative studies with a cytarabine/daunorubicin regimen and its use with the other agents in a three-drug regimen, are currently being conducted.
The most important toxicity associated with the use of gemtuzumab ozogamicin is severe myelosuppression, with essentially all patients treated with the recommended dosage experiencing neutropenia and thrombocytopenia of grade 3 or 4 severity and approximately one-half of patients experiencing grade 3 or 4 anemia. In the clinical studies, 28% of patients experienced grade 3 or 4 infections (e.g., sepsis [16%], pneumonia [7%]), including opportunistic infections. Herpes simplex infection was reported in 22% of the patients. Fifteen percent of patients experienced Grade 3 or 4 bleeding. Careful hematologic monitoring is required, and monitoring of hepatic function tests and electrolyte concentrations should also be performed during treatment.
Other frequently reported adverse events with the use of gemtuzumab ozogamicin include fever (85%), chills (73%), asthenia (44%), headache (35%), nausea (70%), vomiting (63%), diarrhea (38%), constipation (25%), abdominal pain (37%), stomatitis (32%), anorexia (29%), hypokalemia (31%), dyspnea (32%), epistaxis (31%), and hypotension (20%). Some patients experience a postinfusion symptom complex of fever and chills, and less commonly hypotension and dyspnea, which may occur during the first 24 hours after administration. These symptoms generally occur at the end of the 2-hour intravenous infusion, and usually resolve within 2 to 4 hours with treatment with diphenhydramine (e.g., Benadryl), acetaminophen (e.g., Tylenol), and, if needed, intravenous fluids. To reduce the frequency and/or severity of these effects, patients should be pretreated 1 hour before the administration of gemtuzumab ozogamicin with 50 mg of diphenhydramine (by mouth) and 650 to 1,000 mg of acetaminophen. Two additional doses of acetaminophen can be administered as needed, at 4-hour intervals between doses.
In the clinical studies, 23% of the patients experienced Grade 3 or 4 hyperbilirubinemia, and 9% and 17% experienced grade 3 or 4 abnormalities in ALT and AST values, respectively. Gemtuzumab ozogamicin has not been studied in patients with bilirubin concentrations greater than 2 mg/dL, and caution must be exercised if it is used in patients with hepatic impairment.
Local reactions (25%) and rash (22%) have been commonly reported adverse events but, unlike the experience with many antineoplastic agents, alopecia has not occurred with its use. Tumor lysis syndrome may be a consequence of leukemia treatment, and appropriate measures such as hydration and the use of allopurinol (e.g., Zyloprim) should be taken to prevent hyperuricemia.
Gemtuzumab ozogamicin may cause fetal harm if used during pregnancy and it is classified in Pregnancy Category D. Although it is indicated at the present time for use in patients who are 60 years of age or older, this precaution should be observed in situations in which it is used "off-label" in women of childbearing potential.
Gemtuzumab ozogamicin appears to be converted to a number of metabolites. However, studies have not been conducted to identify the specific enzymes involved in its metabolism.
The recommended dose of gemtuzumab ozogamicin is 9 mg/m², administered as a 2-hour intravenous infusion in patients who have received prophylactic medications 1 hour prior to starting the infusion. Vital signs should be monitored during the infusion and for 4 hours following the infusion. The course of treatment includes two doses with a 14-day interval separating the first and second doses. Full recovery from hematologic toxicity is not a requirement for administration of the second dose. The drug may be administered in an outpatient setting, and this represents an advantage over some of the other regimens for the treatment of AML for which administration and monitoring requirements necessitate hospitalization of the patient.
Gemtuzumab ozogamicin is supplied in amber glass vials containing 5 mg of the drug in lyophilized form, and it should be stored in a refrigerator and protected from light. The product is light sensitive and must be protected from direct and indirect sunlight and unshielded fluorescent light during the preparation and administration of the infusion. The preparation of the infusion solution should be done in a biologic safety hood with the fluorescent light off. The contents of the vial should be constituted with 5 mL of Sterile Water for Injection to provide a 1 mg/mL concentration of the drug. The volume of solution needed to provide the dose that has been determined should be withdrawn from each vial and injected into a bag of 100 mL of 0.9% Sodium Chloride Injection. This bag should be placed in an ultraviolet protectant bag, and the solution should be used immediately and infused over a 2-hour period. The solution should not be administered as an intravenous push or bolus.
Acute promyelocytic leukemia (APL) is characterized by a rapid accumulation of abnormal white blood cells in the bone marrow and blood resulting in anemia, susceptibility to infections, and bleeding. The leukemia cells carry a specific genetic abnormality, a translocation called t(15;17). Approximately 1,500 new cases of APL are diagnosed each year, of which an estimated 400 patients will not respond to, or will relapse from, the use of all-trans retinoic acid (Vesanoid) and anthracycline (e.g., daunorubicin [e.g., Cerubidine])-based chemotherapy, which is considered first-line therapy for APL.
Arsenic compounds have been used for many centuries for the treatment of a number of diseases, including use in the early part of the last century for infections (e.g., syphilis) and certain leukemias. There has been a recent reactivation of the interest in arsenic-based therapy because of reports of antileukemic activity of some traditional Chinese preparations that contain arsenic, which lead to specific studies of arsenic trioxide. The development and evaluation of this agent was rapid, and it was approved for marketing only 3 years after study of the drug was started in the United States.
Arsenic trioxide (Trisenox -- Cell Therapeutics) is an inorganic arsenic compound that apparently causes cells to die by a process of intracellular breakdown and cell fragmentation known as apoptosis or "programmed cell death." It also damages or degrades the PML protein, thus disrupting the aberrant fusion protein PML/RAR-alpha, which is the abnormal protein that is present in the cells of patients with APL.
Arsenic trioxide is indicated for intravenous use for induction of remission and consolidation in patients with acute promyelocytic leukemia who are refractory, or have relapsed from, retinoid and anthracycline chemotherapy, and whose APL is characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression. It is a designated orphan drug that represents a highly effective and important alternative for the treatment of APL. In a study of 40 relapsed or refractory patients with APL, treatment with arsenic trioxide resulted in a complete response (absence of visible leukemic cells in bone marrow and peripheral recovery of platelets and white blood cells 30 or more days later) in 28 (70%) of these previously treated patients. Among the 22 patients who had relapsed less than 1 year after treatment with all-trans retinoic acid, there were 18 complete responders (82%). The median time to bone marrow remission was 44 days and to onset of a complete response was 53 days. Many patients experienced molecular eradication of the genetic abnormality associated with APL and relapse-free survival.
The use of arsenic trioxide is also being evaluated in numerous other types of cancer, including multiple myeloma, renal cell carcinoma, prostate cancer, cervical cancer, acute and chronic leukemia, and aggressive lymphoma. However, these are not labeled indications at the present time.
Serious adverse events have occurred with the use of arsenic trioxide, and APL differentiation syndrome (23%) and electrocardiographic abnormalities (40%) are the subject of black box warnings in the product labeling. The APL differentiation syndrome is characterized by fever, dyspnea, weight gain, pulmonary infiltrates and pleural or pericardial effusions, with or without leukocytosis, and can be fatal. At the first signs of this syndrome, treatment with high-dose steroids (e.g., dexamethasone [e.g., Decadron] 10 mg intravenously twice a day) should be immediately initiated and continued for at least 3 days until signs and symptoms have abated. Most patients do not require termination of arsenic trioxide therapy during treatment of the APL differentiation syndrome.
Many patients treated with arsenic trioxide experienced prolongation of the QT interval of the electrocardiogram (ECG), which can lead to a torsade de pointes-type ventricular arrhythmia. The drug has also been reported to cause complete atrioventricular block. Prior to initiating therapy, a 12-lead ECG should be performed and serum electrolytes (potassium, calcium, and magnesium) and creatinine should be assessed. Pre-existing electrolyte abnormalities should be corrected and, during therapy, potassium concentrations should be kept above 4 mEq/dL and magnesium concentrations should be kept above 1.8 mg/dL. If possible, other drugs that are known to prolong the QT interval (e.g., antiarrhythmic agents) should be discontinued. When the QT_c is greater than 500 msec, corrective measures should be completed and the QT_c reassessed with serial ECGs prior to initiating therapy with arsenic trioxide. If the absolute QT interval value exceeds 500 msec during therapy, patients should be reassessed and action taken to address any risk factors, while consideration is given to whether therapy should be continued or suspended. If syncope, or rapid or irregular heartbeat develops, the patient should be hospitalized for monitoring, serum electrolytes should be assessed, and arsenic trioxide should be temporarily discontinued until the QT_c interval regresses to below 460 msec, electrolyte abnormalities are corrected, and symptoms cease.
Hyperleukocytosis was reported in 50% of the patients in the clinical study, but it was not considered necessary to initiate chemotherapy or to suspend therapy with arsenic trioxide.
Other frequently reported adverse events associated with the use of arsenic trioxide include gastrointestinal effects (e.g., nausea [75%], vomiting [58%], abdominal pain [58%], diarrhea [53%]), fatigue (63%), fever (63%), edema (40%), headache (60%), insomnia (43%), cough (65%), dyspnea (53%), tachycardia (55%), dermatitis (43%), hypokalemia (50%), hypomagnesemia (45%), and hyperglycemia (45%). Unlike many antineoplastic agents, arsenic trioxide does not commonly cause hair loss and mucositis. Although arsenic trioxide provides effective therapy for patients with APL with no or limited alternatives, the drug itself is known to be a human carcinogen.
Arsenic trioxide may cause fetal harm if administered to a pregnant woman and is classified in Pregnancy Category D. Women of childbearing potential should be advised to avoid becoming pregnant. The drug is excreted in human milk and a decision should be made whether to discontinue nursing or not use the drug. The effectiveness and safety of arsenic trioxide in children less than 5 years of age have not been established.
The potential for arsenic trioxide to interact with other drugs has not been studied. However, because of the increased risk of prolongation of the QT interval and subsequent complications, the concurrent use of other medications that prolong the QT interval or cause electrolyte abnormalities (e.g., diuretics) should be avoided, if possible.
Arsenic trioxide is primarily metabolized in the liver but not via the CYP450 system. Renal excretion is the main route of elimination and caution should be exercised when the drug is used in patients with renal failure.
Arsenic trioxide is administered intravenously over a period of 1 to 2 hours. The duration of the infusion may be extended to 4 hours if acute vasomotor reactions are observed. The recommended dosage for induction treatment is 0.15 mg/kg daily until bone marrow remission, but not to exceed 60 doses. Consolidation treatment should begin 3 to 6 weeks after completion of induction therapy at a dosage of 0.15 mg/kg daily for 25 doses over a period of up to 5 weeks.
Arsenic trioxide injection is supplied in a concentration of 1 mg/mL in single-use ampules containing 10 mL of solution (10 mg per ampule). The quantity of solution needed to provide the dose needed should be diluted with 100 to 250 mL of 5% Dextrose Injection or 0.9% Sodium Chloride Injection. Unused portions of each ampule should be discarded and should not be saved for later administration. Arsenic trioxide should not be mixed with other medications. Electrolyte, hematologic, and coagulation profiles should be monitored at least twice weekly, and more frequently for unstable patients, during the induction phase and at least weekly during the consolidation phase. ECGs should be obtained weekly, and more frequently for clinically unstable patients, during induction and consolidation.
Cutaneous T-cell lymphoma (CTCL) is a general term for a group of low-grade non-Hodgkin's lymphomas in which malignant T cells typically manifest initially in the skin. There are an estimated 16,000 to 20,000 patients with CTCL in the United States, and the most common forms are mycosis fungoides and its erythrodermic, leukemic variant, Sezary syndrome.
Although CTCL initially involves the skin, systemic involvement of the lymph nodes, the spleen, liver, or other viscera can occur with time, often early in the course of the disease before it is diagnosed. Skin lesions typically progress through three phases -- patch, plaque, and tumor -- but may occur simultaneously at any time during the course of the disease. Lesions are often pruritic, sometimes intensely so, and can be painful. Some patients are incapacitated because of the symptomatology involving the skin. The lesions may become ulcerative and necrotic, and patients with later-stage CTCL are highly susceptible to infection because their skin barrier is compromised.
For many patients, CTCL is a persistent, disfiguring, and debilitating disease that requires multiple treatments over time. In the earliest stages of the disease, emollients, antipruritics, and topical corticosteroids are used to control symptoms. As the disease worsens, topical and systemic (e.g., denileukin diftitox [Ontak]) chemotherapies, skin irradiation, and photophoresis (oral psoralen plus extracorporeal long-wave radiation of white blood cells) have been employed. Although some patients respond to these therapies, long-term remissions are rare in patients with more advanced disease.
Bexarotene (Targretin -- Ligand) is a member of a subclass of retinoids that selectively binds and activates retinoid X receptors (RXRs). These retinoid receptors have biologic activity that is distinct from that of retinoic acid receptors (RARs). When activated, the RXRs function as transcription factors to regulate the expression of genes that control cellular differentiation and proliferation. The new drug was initially approved in a capsule formulation for oral administration, and subsequently in a gel formulation for topical use.
Bexarotene capsules are indicated for the treatment of cutaneous manifestations of CTCL in patients who are refractory to at least one prior systemic therapy, and the gel formulation is indicated for the treatment of cutaneous lesions in patients with CTCL (stages IA and IB) who have refractory or persistent disease after other therapies or who have not tolerated other therapies. In the clinical studies in which bexarotene capsules were used in the recommended initial dosage of 300 mg/m²/day, the drug produced an overall (complete and partial) tumor response in 32% of the patients, with responses seen as early as 4 weeks. The rate of relapse in patients who had experienced a response was 30% over a median duration of observation of 21 weeks. The overall response rate with bexarotene gel was 26%, and the rate of relapse in responding patients was 23% over a median observation period of approximately 21 weeks.
The most important concern with the use of bexarotene is its potential to cause harm to a fetus if it is administered during pregnancy. It is classified in Pregnancy Category X, and its use is contraindicated in women who are pregnant. Women of childbearing potential should be advised to avoid becoming pregnant when bexarotene is used. A negative pregnancy test with a sensitivity of at least 50 mIU/L should be obtained within 1 week prior to initiating bexarotene, and the pregnancy test must be repeated at monthly intervals while the patient remains on the drug. Effective contraception must be used for 1 month prior to the initiation of therapy, during therapy, and for at least 1 month following discontinuation of therapy. It is recommended that two reliable forms of contraception be used simultaneously unless abstinence is the chosen method. Male patients treated with bexarotene who have sexual partners who are pregnant, possibly pregnant, or who could become pregnant must use condoms during sexual intercourse while using the drug, and for at least 1 month after the last dose of the drug. Bexarotene therapy should be initiated on the second or third day of a normal menstrual period. No more than a 1-month supply of bexarotene should be given to the patient so that the results of pregnancy testing can be assessed and counseling regarding avoidance of pregnancy and birth defects can be reinforced.
As would be expected, the incidence of systemic adverse events is much higher when bexarotene is administered orally, and the following discussion pertains to the experience and precautions associated with oral therapy. Major lipid abnormalities (e.g., hyperlipemia [79%], hypercholesterolemia [32%]) are experienced by most patients, and some patients have experienced pancreatitis associated with marked elevations of serum triglycerides. Bexarotene should generally not be used in patients who have risk factors for pancreatitis (e.g., prior pancreatitis, uncontrolled hyperlipidemia, uncontrolled diabetes). Fasting blood lipid determinations should be performed before bexarotene therapy is initiated, weekly until the lipid response to the drug is established (usually within 2 to 4 weeks), and at 8-week intervals thereafter. Attempts should be made to maintain triglyceride concentrations below 400 mg/dL to reduce the risk of complications such as pancreatitis. If fasting triglycerides are elevated, or become elevated during treatment, antilipemic therapy should be initiated and, if necessary, the dosage of bexarotene should be reduced or its use should be suspended. In the studies in which the use of bexarotene was initiated at a dosage of 300 mg/m²/day, 60% of the patients were given lipid-lowering drugs, usually atorvastatin (Lipitor). Because the concurrent use of gemfibrozil (e.g., Lopid) may markedly increase the plasma concentrations of bexarotene, its use is best avoided in patients treated with the new agent.
Hypothyroidism (29%) has been commonly experienced by patients treated with bexarotene and treatment with thyroid hormone should be considered for these individuals. Baseline thyroid function tests should be obtained and patients should be monitored during treatment. Leukopenia was reported in 17% of patients and the white blood cell count with differential should be determined at baseline and periodically during treatment.
Some patients experience elevations in liver function tests (e.g., ALT, AST) and these tests should be performed at baseline, after 1, 2, and 4 weeks following initiation of treatment, and, if stable, at least every 8 weeks thereafter during treatment. If test results reach greater than three times the upper limit of normal values for ALT, AST, or bilirubin, the suspension or discontinuation of bexarotene treatment should be considered.
Other adverse events commonly reported with the oral use of bexarotene include headache (30%), asthenia (20%), nausea (16%), abdominal pain (11%), infection (13%), peripheral edema (13%), rash (17%), and dry skin (11%). Caution should be exercised in patients with diabetes being treated with insulin, an agent that increases insulin secretion (e.g., sulfonylureas, repaglinide [Prandin]), or a thiazolidinedione (pioglitazone [Actos], rosiglitazone [Avandia]), because bexarotene may increase the action of these agents, possibly resulting in hypoglycemia.
Bexarotene is extensively metabolized via the CYP3A4 pathway, and its plasma concentrations and activity are likely to be increased by other agents that inhibit this enzyme system (e.g., ketoconazole [e.g., Nizoral], erythromycin, gemfibrozil, grapefruit juice) and decreased by drugs that are inducers of this pathway (e.g., rifampin [e.g., Rifadin], phenytoin [e.g., Dilantin]).
Following oral administration, peak plasma concentrations of bexarotene are attained in approximately 2 hours. Both the peak concentration and AUC are significantly higher when the drug is administered after a fat-containing meal than after a glucose solution, and it is recommended that the single daily dose be administered with a meal. The drug is highly bound (> 99%) to plasma proteins.
Bexarotene is metabolized to at least four metabolites, and excretion occurs primarily through the hepatobiliary system. Although the use of the drug has not been studied in patients with hepatic insufficiency, hepatic impairment would be expected to greatly reduce its clearance. Only small amounts of bexarotene and its metabolites are eliminated in the urine. However, because bexarotene is so highly bound to plasma proteins and renal insufficiency can result in significant protein binding changes, the pharmacokinetics may be altered in patients with impaired renal function.
Some precautions apply to both the oral and topical use of bexarotene. The new drug must be used with caution, if at all, in patients with a known hypersensitivity to any of the retinoids. As a class, the retinoids have been associated with photosensitivity, and patients should be advised to minimize their exposure to sunlight and artificial ultraviolet light while using the medication. Because of the relationship of bexarotene to vitamin A, patients should be cautioned to limit their use of vitamin A supplements to avoid potential additive toxic effects. In the clinical studies, patients were advised to limit vitamin A intake to no more than 15,000 IU/day.
Dermatologic adverse events, often at the application site, are the reactions most often experienced with the topical use of bexarotene and include rash (72%), pruritus (36%), skin disorders such as erythema and irritation (26%), and contact dermatitis (14%). Other commonly reported reactions include pain (30%), headache (14%), infection (18%), hyperlipemia (10%), and edema (10%). Patients who are using bexarotene gel should not concurrently use a product that contains DEET, a common component of insect repellent products, because of the increased possibility of DEET toxicity.
Bexarotene capsules are supplied in a 75 mg potency. The recommended initial dosage is 300 mg/m² once a day with a meal. If the occurrence of adverse events necessitates dosage adjustment, the dosage may be reduced to 200 mg/m²/day, then to 100 mg/m²/day, or the use of the drug may be temporarily suspended. When toxicity is controlled, the dosage may be carefully readjusted upward. If there is no tumor response after 8 weeks of treatment and if the initial dosage is well tolerated, the dosage may be increased to 400 mg/m²/day with close monitoring. Treatment may be continued as long as the patient is deriving benefit.
Bexarotene gel contains the drug in a 1% concentration. The gel should be initially applied once every other day for the first week. The application frequency should be increased at weekly intervals to once daily, then twice daily, then three times daily, and finally four times daily according to individual lesion tolerance. Most responses were seen at dosing frequencies of two or more times a day, and most patients were able to maintain this dosing frequency. If application-site toxicity occurs, the dosing frequency can be reduced.
Sufficient gel should be applied to cover the lesions with a generous coating. The gel should be allowed to dry before covering the area with clothing. Application of the gel to normal skin surrounding the lesions should be avoided because of the likelihood of irritation. In addition, the gel should not be applied near mucosal surfaces. Occlusive dressings should not be used with bexarotene gel.

Agent for Macular Degeneration

In the Western world, age-related macular degeneration (AMD) is a major cause of deteriorating vision and blindness in individuals older than 60 years. The macula is in the center of the retina and is the area of the eye that is responsible for central vision, which is essential for visual activities such as reading, driving, and recognizing faces. Approximately 90% of individuals with AMD have the "dry" (atrophic), nonneovascular form of the disorder in which the deterioration of central vision may occur slowly or not at all. "Wet" (neovascular or exudative) AMD, although much less common, is more likely to result in severe and irreversible impairment of central vision.
Wet AMD is caused by the growth of abnormal blood vessels that leak blood and fluid into the back of the eye. This results in the formation of a blister on the retina that leads to scarring and the impairment of central vision, although peripheral vision is retained. Approximately 200,000 individuals in North America are diagnosed with wet AMD annually and, if untreated, most of the affected eyes will become functionally blind within 2 years.
The only effective treatment for wet AMD has been laser photocoagulation using a hot thermal laser that burns or cauterizes the leaky blood vessels. However, this treatment can be used in only about 20% of patients (those in whom the area of leakage is small, well-defined, and outside the central area), and some patients may experience some permanent vision loss immediately following treatment because of damage to the overlying retina.
Verteporfin (Visudyne -- Ciba Vision) is a benzoporphyrin derivative that is used in a two-stage photodynamic treatment in which the drug is administered intravenously and then activated by shining nonthermal red laser light into the patient's eye. When verteporfin is activated by light in the presence of oxygen, highly reactive, short-lived singlet oxygen and reactive oxygen radicals are generated, causing local damage to neovascular endothelium, which result in occlusion of the abnormal vessels. Neither the drug nor the light exert any effect until combined.
Following intravenous administration, verteporfin is thought to accumulate in higher concentrations in the more rapidly proliferating abnormal cells, including choroidal neovasculature. Because the light is shone directly at the targeted tissue, the treatment is highly selective, which reduces the risk of damage to normal surrounding tissue.
Verteporfin is indicated for the treatment of AMD in patients with predominantly classic subfoveal choroidal neovascularization (CNV). In the placebo-controlled clinical trials in which analyses were conducted at 1 year, and in which retreatment was permitted if there was recurrence or persistence of leakage, vision was stabilized in 67% of the patients with predominantly classic CNV lesions who were treated with verteporfin, compared with 39% of those receiving placebo. Severe vision loss was experienced by 12% of those receiving the medication and 33% of those receiving placebo. Although verteporfin slows retinal damage, it does not restore vision in eyes that have been damaged by AMD. The studies showed that patients older than 75 years, patients with dark irides, patients with occult lesions, or patients with less than 50% classic CNV are less likely to benefit from verteporfin therapy.
The adverse events most often attributed to verteporfin include headache, injection- site reactions (including extravasation and rashes), and visual disturbances (including blurred vision, decreased visual acuity, and visual field defects), each of which occurred in 10% to 20% of patients. Up to 10% of patients have experienced back pain, primarily during infusion of the drug. Severe vision decrease, occurring within 7 days after treatment, has been reported in 1% to 4% of patients, although partial recovery of vision was observed in many patients. These patients should not be retreated, at least until their vision completely recovers to pretreatment levels and the potential benefits and risks can be carefully evaluated. The use of verteporfin is contraindicated in patients with porphyria.
Some patients in the clinical studies experienced photosensitivity reactions. Because verteporfin exhibits a photosensitizing action, patients should be warned to avoid exposure of unprotected skin, eyes, or other body organs to direct sunlight or bright indoor light (e.g., tanning salons, bright halogen lighting, high-power lighting used in surgical operating rooms or dental offices) for 5 days after treatment. The occurrence and severity of such reactions may be increased in patients who are also being treated with other photosensitizing medications (e.g., tetracyclines, sulfonamides). If emergency surgery is necessary within 48 hours after treatment, steps should be taken to protect as much of the internal tissue as possible from intense light.
If treated patients must go outdoors in daylight during the first 5 days after treatment, they should wear appropriate clothing and sunglasses to protect all areas of skin as well as their eyes. Ultraviolet sunscreens are not effective in protecting against photosensitivity reactions because photoactivation of the residual drug in the skin can be caused by visible light. Patients should not stay in the dark but should be encouraged to expose their skin to ambient indoor light because this will help inactivate the drug in the skin.
Verteporfin is metabolized to a small extent by liver and plasma esterases, but the CYP450 isozymes do not appear to play a role in its metabolism. Excretion of the drug occurs almost entirely by the fecal route. The half-life of verteporfin has been reported to be increased by approximately 20% in patients with mild hepatic insufficiency. There has not been any clinical experience in patients with moderate-to-severe hepatic impairment, and the drug must be used very carefully, if at all, in these patients.
The preparation for using verteporfin includes an estimation of the greatest linear dimension of the lesion and determination of the treatment spot size, and the product labeling should be consulted for the specific guidelines for these determinations.
Verteporfin is supplied in single-use vials containing a lyophilized cake with 15 mg of the drug. The contents of the vial are constituted with 7 mL of Sterile Water for Injection to provide 7.5 mL of solution containing the drug in a concentration of 2 mg/mL. The constituted solution is dark green and must be protected from light and used within 4 hours. The recommended dosage is 6 mg/m²body surface area, and the amount of solution needed to provide the desired amount of the drug is withdrawn from the vial and diluted with 5% Dextrose for Injection to a total infusion volume of 30 mL. The full infusion volume is administered intravenously over 10 minutes at a rate of 3 mL/minute, using an appropriate syringe pump and in-line filter.
A free-flowing intravenous line should be established before starting the infusion of verteporfin, and it is recommended that the largest arm vein possible, preferably antecubital, be used for injection. If extravasation occurs, the infusion should be stopped immediately and cold compresses applied, and the site should be protected from light.
The laser systems that have been tested for compatibility with verteporfin are Coherent Opal Photoactivator Laser Console and LaserLink Adapter and Zeiss VISULAS 690s laser and VISULINK PDT adapter, and these systems deliver light to the retina as a single circular spot via a fiber optic and a slit lamp. The delivery of 689 nm wavelength laser light should be initiated 15 minutes after the start of the 10-minute infusion of verteporfin. The photoactivation of verteporfin is controlled by the total light dose delivered. In the treatment of choroidal neovascularization, the recommended light dose is 50 J/cm² of neovascular lesion at an intensity of 600 mW/cm². The dose is administered over 83 seconds.
Patients should be reevaluated every 3 months and, if choroidal neovascular leakage is detected, therapy should be repeated. Some patients have treatable lesions in both eyes and concurrent bilateral treatment can be considered. If the patient has already received previous verteporfin therapy in one eye and has tolerated it satisfactorily, both eyes can be treated concurrently after a single administration of the drug. The more aggressive lesion should be treated first, at 15 minutes after the start of the infusion. Immediately at the end of light application to the first eye, the laser settings should be adjusted to introduce the treatment parameters for the second eye, with the same light dose and intensity as for the first eye, starting no later than 20 minutes from the start of the infusion.

Agent for Allergic Conjunctivitis

Allergic conjunctivitis is the most common type of ocular allergy and is estimated to affect approximately 50 million Americans. The condition is usually characterized by signs and symptoms such as itching, redness, burning, tearing, and lid edema. The drugs that have been used in ophthalmic formulations for the treatment of allergic conjunctivitis include antihistamines (emedastine [Emadine], levocabastine [Livostin]), mast cell stabilizers (cromolyn [e.g., Crolom], lodoxamide [Alomide], and a new formulation of nedocromil [Alocril]), the dual-acting antihistamine/mast cell stabilizers (olopatadine [Patanol], ketotifen [Zaditor], and a new formulation of azelastine [Optivar] marketed in 2000), the nonsteroidal anti-inflammatory drug ketorolac (Acular), and corticosteroids.
Pemirolast potassium (Alamast -- Santen) is a mast cell stabilizer that inhibits the release of inflammatory mediators from human mast cells. It is indicated for ophthalmic use for the prevention of itching of the eye due to allergic conjunctivitis. The new agent has been shown to be significantly more effective than placebo; however, data are not available to compare its efficacy with other mast cell stabilizers or the dual-acting drugs.
The most commonly experienced adverse events with the use of pemirolast are headache, rhinitis, and cold/flu symptoms, which occurred in 10% to 25% of patients and were usually mild in severity. Other adverse events that were reported at an incidence of less than 5% include dry eye, ocular burning, foreign body sensation, and/or discomfort, allergy, back pain, bronchitis, cough, dysmenorrhea, fever, sinusitis, and sneezing/nasal congestion.
Unlike the other ophthalmic mast cell stabilizers that are classified in Pregnancy Category B, pemirolast is classified in Category C and should be used during pregnancy only if the anticipated benefit outweighs the risk. It is not known whether the new agent is excreted in human milk and caution should be exercised when used by a nursing woman. The effectiveness and safety of pemirolast in children younger than 3 years of age have not been established.
The recommended dosage of pemirolast is one to two drops in each affected eye four times daily. Cromolyn and lodoxamide are also administered four times daily, whereas nedocromil and the dual-acting agents olopatadine and ketotifen are administered twice a day. A symptomatic response to therapy (i.e. decreased itching) may occur within a few days, but often requires a longer period of treatment (up to 4 weeks).
Pemirolast potassium ophthalmic solution contains the drug in a concentration of 1 mg/mL (0.1%). The solution contains lauralkonium chloride as a preservative and may be absorbed by soft contact lenses. It should not be administered while soft contact lenses are being worn, and patients should be instructed to wait at least 10 minutes after instilling pemirolast solution before inserting contact lenses. Patients should not wear a contact lens if their eye is red, and pemirolast should not be used to treat contact lens-related irritation.

Agent for Glaucoma

Unoprostone isopropyl (Rescula -- Ciba Vision) is a prostaglandin analogue that is designated as a docosanoid. Docosanoids are omega-3 polyunsaturated fatty acids that are endogenous to the central nervous system including the retina. They are structurally similar to eicosanoids such as prostaglandins and leukotrienes; however, eicosanoids are derived from arachidonic acid, whereas docosanoids are derived from docosahexaenoic acid. Following ophthalmic administration, unoprostone isopropyl is rapidly absorbed through the cornea and conjunctival epithelium where it is hydrolyzed by esterases to a biologically active metabolite, unoprostone free acid. The properties of the new drug are generally similar to those of latanoprost (Xalatan).
Unoprostone is indicated for the lowering of intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension who are intolerant of other IOP-lowering medications or insufficiently responsive (failed to achieve target IOP determined after multiple measurements over time) to another IOP-lowering medication. Whereas certain medications (e.g., timolol [e.g., Timoptic]) that are used in the treatment of open-angle glaucoma lower IOP by reducing the production of aqueous humor, unoprostone and latanoprost appear to lower IOP by increasing the outflow of aqueous humor. In comparative studies unoprostone was as effective as timolol in lowering IOP. The new drug has not been directly compared with latanoprost, but the latter agent has been shown to be as effective or more effective than timolol.
Unoprostone may cause changes to pigmented tissue. The incidence observed in clinical trials was 0.12%, and the changes may be permanent. The drug may gradually change eye color by increasing the amount of brown pigment in the iris, and patients should be advised of this effect. The change in iris color occurs slowly and may not be noticeable for months to several years.
The most frequently experienced adverse events with the use of unoprostone (each reported in 10% to 25% of patients) include burning/stinging, burning/stinging upon drug instillation, dry eyes, itching, and increased length of eyelashes. Approximately 10% to 14% of patients were observed to have an increase in the length of their eyelashes of 1 mm or more at 12 months, while 7% of patients were observed to have a decrease in the length of their eyelashes. Based on the studies of the individual agents, latanoprost appears to cause a change in eye color more often than unoprostone, and unoprostone appears more likely to increase the length of eyelashes. However, the extent to which there is a significant difference between the two agents in the incidence of these effects must be determined in studies in which the two agents are directly compared.
The most common systemic adverse event associated with the use of unoprostone is flu syndrome that occurred in approximately 6% of patients. The drug is classified in Pregnancy Category C and should be used during pregnancy only if the anticipated benefit justifies the risk to the fetus. It is not known whether unoprostone is excreted in human milk, and caution should be exercised when the drug is administered to a nursing mother.
Unoprostone isopropyl ophthalmic solution contains the drug in a concentration of 0.15%. The recommended dosage is one drop in the affected eye(s) twice a day, a dosing frequency that represents a disadvantage in comparison with latanoprost, which is administered just once a day. Some patients with glaucoma are being treated with more than one drug by using the ophthalmic route of administration. In these situations, the drugs should be administered at least 5 minutes apart.
Like many ophthalmic solutions, the formulation of unoprostone contains benzalkonium chloride, and this preservative may be absorbed by contact lenses. Patients should be advised to remove contact lenses before instilling the solution and that the lenses may be reinserted 15 minutes after administration.

Agent for Actinic Keratoses

Actinic (solar) keratoses are potentially precancerous skin lesions that are caused by chronic sun exposure and are characterized by rough, scaly, red or brown patches that begin on the surface of the skin. Of the estimated five million cases of skin cancer in the United States, almost one-half began as actinic keratoses. Various approaches have been used in treating these lesions, including cryotherapy, curettage, dermabrasion, excision, laser treatment, and topically applied agents such as fluorouracil (e.g., Efudex).
Aminolevulinic acid hydrochloride (Levulan Kerastick for Topical Solution -- Dusa; Berlex) has been approved for use in conjunction with photodynamic therapy (blue light illumination using the BLU-U Blue Light Photodynamic Therapy Illuminator) for the treatment of nonhyperkeratotic actinic keratoses of the face or scalp.
Aminolevulinic acid (ALA) is present in the body, and its metabolism is the first step in the biochemical pathway that results in the synthesis of heme. ALA is not a photosensitizer, but rather a metabolic precursor of protoporphyrin IX (PpIX), which is a photosensitizer. It is thought that photosensitization following application of ALA topical solution occurs through the metabolic conversion of ALA to PpIX, which accumulates in the skin to which ALA topical solution has been applied. When exposed to light of appropriate wavelength and energy, the accumulated PpIX produces a photodynamic reaction, a cytotoxic process dependent upon the simultaneous presence of light and oxygen. The absorption of light results in an excited state of the porphyrin molecule, and the subsequent generation of singlet oxygen, which can further react to form superoxide and hydroxyl radicals.
In the clinical studies approximately 77% of the patients treated with ALA and blue light experienced clearing of 75% or more of the actinic keratosis lesions within 8 weeks, and approximately 66% experienced a complete response. Those patients who were not complete responders at week 8 had retreatment of the persistent lesions at week 8, and this increased the overall response rates at week 12 to 88% (75% or more lesions cleared) and 72% (complete responders). The response rates at both weeks 8 and 12 were much higher than in the group of patients who were treated with vehicle and blue light. Lesions on the face or scalp, but not in both locations in the same patient, were treated in the clinical studies, and the therapy is not currently indicated for the treatment of actinic keratoses of the back and arms.
The actinic keratosis lesions are exposed to blue light 14 to 18 hours after the ALA topical solution is applied, and the treatment sites become photosensitive during this time period. Patients should avoid exposure of the photosensitive treatment sites to sunlight or bright indoor light (e.g., examination lamps, operating room lamps, tanning beds, or lights at close proximity) during the period prior to blue light treatment. Such exposure may result in a stinging and/or burning sensation and may cause erythema and/or edema of the lesions. Before exposure to sunlight, patients should, therefore, protect treated lesions from the sun by wearing a wide-brimmed hat or similar head covering. Sunscreens will not protect against photosensitivity reactions caused by visible light. Although drug interactions were not observed in the clinical studies, a potential exists for other known photosensitizing agents (e.g., tetracyclines, sulfonamides, phenothiazines) to increase the photosensitivity reaction of actinic keratoses treated with ALA topical solution.
If for any reason the patient cannot return for blue light treatment in the 14 to 18 hour period following application of ALA topical solution, the patient should contact the physician and also continue to avoid exposure of the photosensitized lesions to sunlight or prolonged or intense light for at least 40 hours.
The majority of patients in the clinical studies reported that all lesions treated exhibited at least slight stinging and/or burning, and severe stinging and/or burning at one or more lesions being treated was reported by at least 50% of patients at some time during treatment. Stinging and/or burning subsided between 1 minute and 24 hours after the blue light was turned off. Some or all lesions were erythematous in 99% of patients and edematous in 35%. Other adverse events that were commonly experienced include scaling/crusting, itching, hypo/hyperpigmentation, and erosion.
ALA is classified in Pregnancy Category C and should be used during pregnancy only if clearly needed. Caution should be exercised if this treatment is used in a nursing woman.
Each Levulan Kerastick for topical solution applicator consists of a plastic tube containing two sealed glass ampules and an applicator tip. One ampule contains 354 mg of ALA and the other ampule contains 1.5 mL of solution vehicle. The applicator is covered with a protective cardboard sleeve and cap. A 20% topical solution is prepared just prior to the time of use by breaking the ampules by applying finger pressure at the designated positions on the cardboard sleeve, and shaking the contents gently for at least 3 minutes to completely dissolve the drug powder in the solution vehicle. The solution should be used immediately following preparation because of the instability of the activated product. If the solution is not applied within 2 hours of activation, it should be discarded. Application should involve either scalp or face lesions, but not both simultaneously.
Following solution admixture, the cap should be removed from the applicator and the dry applicator tip should be dabbed on a gauze pad until uniformly wet with solution. The solution should be applied directly to the target lesions by dabbing gently with the wet applicator tip. Enough solution should be applied to uniformly wet the lesion surface, but should not be allowed to contact ocular or mucosal surfaces. Once the initial application has dried, the solution should be applied again in the same manner.
Photosensitization of the treated lesions takes place over the 14 to 18 hour period following application of the solution, and the actinic keratoses should not be washed during this time. At the visit for light illumination 14 to 18 hours after application of the solution, the treated actinic keratoses should be gently rinsed with water and patted dry. Photoactivation of the treated lesions is accomplished with blue light illumination from the BLU-U Blue Light Photodynamic Therapy Illuminator. A 1,000 second (16 minutes 40 seconds) exposure is required to provide a 10 J/cm² light dose. During light treatment, both patients and medical personnel should use blue-blocking protective eyewear to minimize ocular exposure. The operating instructions and product labeling should be consulted for the specific guidelines for providing the blue light illumination.
The recommended treatment frequency is one application of the ALA topical solution and one dose of illumination per treatment site per 8-week treatment session.
Because of the potential for the skin to be photosensitized, ALA topical solution should be applied only to the actinic keratoses, and not to adjacent skin, by a qualified health care professional. The use of ALA topical solution plus light illumination is contraindicated in patients with cutaneous photosensitivity at wavelengths of 400 to 450 nm, or with porphyria or known allergies to porphyrins.

Protective Agent

A viscous white paste containing a 50:50 mixture of a perfluoroalkylpolyether and a polytetrafluoroethylene (PTFE) (Skin Exposure Reduction Paste Against Chemical Warfare Agents [SERPACWA] -- U.S. Army Medical Research and Material Command) has been approved for use in situations in which there is a threat of an imminent attack with chemical warfare agents (CWA). It is indicated for use only in conjunction with Mission-Oriented Protective Posture (MOPP) gear to reduce or delay the absorption of CWA through the skin when SERPACWA is applied prior to exposure.
SERPACWA serves as a physical barrier and is not absorbed through intact skin in detectable amounts. In studies in animals, it has been shown to reduce or delay skin exposure to a variety of CWA, including sulfur mustard, a blistering agent; the nerve agents soman and VX; T-2 mycotoxin, a skin necrosis agent; and CS, a lacrimating riot control gas. In human trials, the protective action of SERPACWA was evaluated against chemicals used as surrogates (e.g., urushiol, a resin contained in plants like poison ivy) for CWA. Not all SERPACWA-treated subjects were completely protected from a urushiol reaction, but SERPACWA-treated sites exhibited dermatitis scores lower than the SERPACWA-untreated matched sites.
The use of SERPACWA has not been associated with acute skin irritation or with allergic sensitization. Application of the paste to 20% of body surface area did not impair normal heat exchange for personnel who were exposed to an environment that simulated the effects of wearing MOPP gear.
The handling of smoking products, such as cigarettes, by personnel who have even small amounts of SERPACWA on their hands may result in contamination of these products. Smoking of products contaminated with the PTFE component of SERPACWA generates harmful fumes. A flu-like syndrome called polymer fume fever has been reported in individuals who have been exposed to fumes generated by the burning of PTFE. The severity of this syndrome depends upon the amount of exposure and the number of exposures, but the risk associated with smoking products contaminated with SERPACWA has not been characterized. Personnel should not touch smoking products after they have applied SERPACWA to their skin surface, and should wash their hands thoroughly to remove all visible traces of SERPACWA prior to handling smoking products. Some individuals with polymer fume fever reported that the tobacco smoke had an unusual or unpleasant taste. In these situations, individuals should cease smoking and discard the potentially contaminated products. Even in the absence of an unusual or unpleasant taste, the smoking product may still be contaminated, so smoking should be avoided after use of SERPACWA. Clothing or other materials exposed to SERPACWA, including the packaging, should not be destroyed by burning, because of the release of toxic fumes.
In animal studies, the presence of insect repellent products that contain DEET has been demonstrated to significantly reduce the barrier effects of SERPACWA. The use of water to remove products containing DEET reduces the barrier effect of SERPACWA, while removal of insect repellent with dry gauze partially restores a barrier effect. Therefore, DEET products should be removed with a dry towel or cloth, but not with water or a moist towelette, before SERPACWA is applied. Some camouflage paints (loam and sand), as well as permethrin (e.g., Nix), may also reduce the protective effects of SERPACWA.
Prior to putting on the chemical protective overgarment, a dry towel should be used to wipe off sweat, insect repellent, camouflage paint, sand, or dirt from the skin in the areas to which SERPACWA is to be applied.
SERPACWA is supplied in a packet that contains 84 grams of the paste, an amount sufficient for one application per individual. Approximately one-third of the contents of the packet should be placed in the palm of the hand and rubbed in evenly around the wrists, neck, and boot tops of the lower legs until it forms a white film that is barely noticeable. The remaining amount of paste should be rubbed evenly onto the armpits, groin area, and waistline. The protective action of SERPACWA has been demonstrated for up to 5 hours, but its effectiveness beyond this time is not known.
To remove SERPACWA in the absence of exposure to CWA, the sites should be scrubbed with a dry towel or, if possible, with a cloth using both soap and water. If exposure to CWA is either confirmed or suspected, the appropriate protocol for decontamination should be followed.

New Indications and Dosage Forms

In addition to the new therapeutic agents marketed for the first time in 2000, a number of previously available agents now have expanded indications for use or are marketed in new dosage forms. Selected examples are noted in Table 6.
Daniel A. Hussar, PhD, is Remington professor of pharmacy, Philadelphia College of Pharmacy, University of the Sciences in Philadelphia.

Table 1. New Therapeutic Agents Marketed in 2000

Generic Name (Page No.) Trade Name Manufacturer Therapeutic
Classification Route of
Administration FDA
Classification^a

Alosetron hydrochloride (229) Lotronex Glaxo Wellcome Agent for irritable
bowel syndrome Oral 1-P

Aminolevulinic acid
hydrochloride^b (267) Levulan
Kerastick Berlex; Dusa Agent for
actinic keratoses Topical 1-S

Argatroban (244) -- SmithKline Beecham Anticoagulant Intravenous 1-S

Arsenic trioxide (262) Trisenox Cell Therapeutics Antineoplastic agent Intravenous 1-P, V

Articaine hydrochloride/
epinephrine bitartrate
(256) Septocaine Septodont Local anesthetic Local injection 1, 4-S

Bexarotene^b (263) Targretin Ligand Antineoplastic agent Oral; topical 1-P, V

Cevimeline hydrochloride Evoxac Daiichi Cholinergic agonist Oral 1-S
(253)

Colesevelam hydrochloride
(238) WelChol Sankyo Antihyperlipidemic
agent Oral 1-S

Dexmedetomidine
hydrochloride^b (245) Precedex Abbott Sedative Intravenous 1-S

Docosanol (238) Abreva SmithKline
Beecham Consumer Agent for cold sores Topical 1-S

Dofetilide^b (239) Tikosyn Pfizer Antiarrhythmic agent Oral 1-S

Exemestane^b (259) Aromasin Pharmacia Antineoplastic agent Oral 1-S, V

Ganirelix acetate^b (257) Antagon Organon Agent for infertility Subcutaneous 1-P

Gatifloxacin^b (233) Tequin Bristol-Myers Squibb Antibacterial agent Oral; intravenous 1-S

Gemtuzumab ozogamicin (260) Mylotarg Wyeth-Ayerst Antineoplastic agent Intravenous 1-P, H, V

Levetiracetam^b (246) Keppra UCB Pharma Antiepileptic drug Oral 1-S

Linezolid (229) Zyvox Pharmacia Antibacterial agent Oral; intravenous 1-P

Lopinavir/ritonavir (236) Kaletra Abbott Antiviral agent Oral 1, 4-P, AA, H

Meloxicam (251) Mobic Boehringer Ingelheim;
Abbott Antiarthritic agent Oral 1-S

Mifepristone (258) Mifeprex Danco Abortifacient Oral 1-S, H

Moxifloxacin hydrochloride^b
(233) Avelox Bayer Antibacterial agent Oral 1-S

Nitric oxide^b (255) INOmax INO Therapeutics Pulmonary vasodilator Inhalation 1-P, V

Oxcarbazepine (246) Trileptal Novartis Antiepileptic drug Oral 1-S

Pantoprazole sodium (252) Protonix Wyeth-Ayerst Antisecretory agent Oral 1-S

Pemirolast potassium^b (266) Alamast Santen Agent for allergic
conjunctivitis Ophthalmic 1-P

Perfluoroalkylpolyether/
polytetrafluoroethylene (268) SERPACWA U.S. Army Protective agent Topical 1-P

Poractant alfa^b (254) Curosurf Dey Agent for respiratory
distress syndrome Intratracheal 1-S, V

Rivastigmine tartrate (250) Exelon Novartis Agent for Alzheimer's
disease Oral 1-S

Tenecteplase recombinant
(241) TNKase Genentech Thrombolytic agent Intravenous S^c

Tinzaparin sodium (242) Innohep DuPont Anticoagulant Subcutaneous 1-S

Unoprostone isopropyl (266) Rescula Ciba Vision Agent for glaucoma Ophthalmic 1-P

Verteporfin (265) Visudyne Ciba Vision Agent for macular
degeneration Intravenous 1-P

Zonisamide (246) Zonegran Elan Antiepileptic drug Oral 1-S

^aFDA classification of new drugs: 1 = new molecular entity; 4 = combination porduct; P = priority review; S = standard review; AA = treatment for AIDS and/or its complications; H = accelerated approval; V = designated orphan drug.
^bApproved by FDA before 2000 but not marketed until 2000.
^cA biological approved through an FDA procedure that does not assign a numerical classification.

Table 2. Other Therapeutic Agents Approved by FDA in 2000^a

Generic Name Trade Name Manufacturer Therapeutic Classification FDA Classification^b

Balsalazide Colazal Salix Agent for ulcerative colitis 1-S

Bivalirudin Angiomax The Medicines
Company Anticoagulant 1-S

Botulinum toxin type B Myobloc Elan Agent for cervical dystonia S^c

Cetrorelix acetate Cetrotide Serono Agent for infertility 1-S

Insulin aspart, rDNA origin NovoLog Novo Nordisk Antidiabetic agent 1-S

Insulin glargine, rDNA origin Lantus Aventis Antidiabetic agent 1-S

Nateglinide Starlix Novartis Antidiabetic agent 1-S

Triptorelin pamoate Trelstar Depot Pharmacia Antineoplastic agent 1-S

^aThese therapeutic agents were approved by the FDA during 2000 but did not appear on the market before the end of the year. Therefore, they are not considered in this review.
^bFDA classification of new drugs: 1 = new molecular entity; S = standard review.
^cA biological approved through an FDA procedure that does not assign a numerical classification.

Table 3. Labeled Indications and Dosage Recommendations for Linezolid

Indication Recommended Dosage

Vancomycin-resistant Enterococcus faecium infections, including cases with 600 mg IV or oral every 12 hours for 14 to 28 days
concurrent bacteremia

Nosocomial pneumonia caused by Staphylococcus aureus (methicillin-susceptible
and -resistant strains) or Streptococcus pneumoniae (penicillin-susceptible
strains only) 600 mg IV or oral every 12 hours for 10 to 14 days

Community-acquired pneumonia caused by Streptococcus pneumoniae
(penicillin-susceptible strains only), including cases with concurrent
bacteremia, or S. aureus (methicillin-susceptible strains only) 600 mg IV or oral every 12 hours for 10 to 14 days

Complicated skin and skin structure infections caused by S. aureus
(methicillin-susceptible and -resistant strains), Streptococcus pyogenes,
or Streptococcus agalactiae 600 mg IV or oral every 12 hours for 10 to 14 days

Uncomplicated skin and skin structure infections caused by 400 mg oral every 12 hours for 10 to 14 days
S. aureus (methicillin-susceptible strains only) or S. pyogenes

Table 4. Labeled Indications and Dosage Recommendations for Gatifloxacin

Indication Recommended Dosage

Acute sinusitis caused by Streptococcus pneumoniae or Haemophilus influenzae 400 mg once a day for 10 days

Acute bacterial exacerbation of chronic bronchitis caused by S. pneumoniae,
S. aureus, H. influenzae, H. parainfluenzae, or Moraxella catarrhalis 400 mg once a day for 7 to 10 days

Community-acquired pneumonia, caused by S. pneumoniae, Staphylococcus aureus,
H. influenzae, H. parainfluenzae, M. catarrhalis, Legionella pneumophila,
Chlamydia pneumoniae, or Mycoplasma pneumoniae 400 mg once a day for 7 to 14 days

Uncomplicated urinary tract infections (cystitis) caused by Escherichia coli,
Klebsiella pneumoniae, or Proteus mirabilis 400 mg as a single dose,
or 200 mg once a day for 3 days

Complicated urinary tract infections caused by E. coli, K. pneumoniae, or P. mirabilis 400 mg once a day for 7 to 10 days

Pyelonephritis caused by E. coli 400 mg once a day for 7 to 10 days

Uncomplicated urethral and cervical gonorrhea caused by Neisseria gonorrhoeae;
acute, uncomplicated rectal infections in women caused by N. gonorrhoeae 400 mg as a single dose

Table 5. Labeled Indications and Dosage Recommendations for Moxifloxacin

Indication Recommended Dosage

Acute bacterial sinusitis caused by Streptococcus pneumoniae, Haemophilus influenzae, or
Moraxella catarrhalis 400 mg once a day for 10 days

Acute bacterial exacerbation of chronic bronchitis caused by S. pneumoniae, Staphylococcus
aureus, H. influenzae, H. parainfluenzae, Klebsiella pneumoniae, or M. catarrhalis 400 mg once a day for 5 days

Community-acquired pneumonia (of mild-to-moderate severity) caused by S. pneumoniae,
H. influenzae, M. catarrhalis, Chlamydia pneumoniae, or Mycoplasma pneumoniae 400 mg once a day for 10 days

Table 6. Selected New Indications and Dosage Forms

Generic Name Trade Name -- Manufacturer New Indication New Dosage Form

Adapalene Differin -- Galderma -- Cream

Alendronate sodium Fosamax -- Merck To increase bone mass in men with osteoporosis --

Amphotericin B
liposomal AmBisome -- Fujisawa Cryptococcal meningitis in HIV-infected patients --

Anastrozole Arimidex -- AstraZeneca First-line treatment of postmenopausal women
with hormone receptor-positive or unknown
locally advanced or metastatic breast cancer --

Atovaquone/proguanil Malarone -- Glaxo Wellcome Treatment and prevention of Plasmodium
falciparum malaria Tablet

Azelastine
hydrochloride Astelin -- Wallace Nonallergic vasomotor rhinitis --

Optivar -- Muro Treatment of itching of the eye associated with
allergic conjunctivitis Ophthalmic solution

Budesonide Pulmicort respules --
AstraZeneca -- Inhalation suspension
for nebulization

Caffeine citrate Cafcit -- Roxane -- Oral solution

Cerivastatin sodium Baycol -- Bayer Increase HDL-C in patients with primary
hypercholesterolemia and mixed dyslipidemia --

Ciclopirox Penlac -- Dermik Mild-to-moderate onychomycosis of fingernails
and toenails due to Trichophyton rubrum Topical solution

Ciprofloxacin Cipro -- Bayer Post-exposure prophylaxis of clinical disease
from Bacillus anthracis --

Clarithromycin Biaxin XL -- Abbott -- Extended-release tablet

Diclofenac Solaraze -- SkyePharma Actinic keratoses Gel

Didanosine Videx EC -- Bristol-Myers
Squibb -- Enteric-coated capsule

Divalproex sodium Depakote ER -- Abbott -- Extended-release tablet

Docetaxel Taxotere -- Aventis Locally advanced or metastatic non-small-cell
lung cancer in patients who have failed prior
platinum-based chemotherapy --

Doxercalciferol Hectorol -- Bone Care
International -- Parenteral

Eflornithine
hydrochloride Vaniqa -- Bristol-Myers
Squibb Reduction of unwanted facial hair in women Cream

Enoxaparin sodium Lovenox -- Aventis Prevention of deep vein thrombosis in patients
at risk for thromboembolic complications due to
severely restricted mobility during acute illnesses --

Epoprostenol sodium Flolan -- Glaxo Wellcome Pulmonary hypertension associated with the
scleroderma in NYHA Class III and IV patients
who do not respond to conventional therapy --

Etanercept Enbrel -- Immunex;
Wyeth-Ayerst First-line treatment of patients with moderately to
severely active rheumatoid arthritis and for
delaying structural damage --

Etodolac Lodine XL -- Wyeth-Ayerst Juvenile rheumatoid arthritis --

Fenofibrate micronized Tricor -- Abbott Adjunctive therapy to diet for reduction of LDL-C,
total cholesterol, triglycerides, and apolipoprotein B
in patients with primary hypercholesterolemia or
mixed dyslipidemia --

Fexofenadine
hydrochloride Allegra -- Aventis Uncomplicated manifestations of chronic
idiopathic urticaria --

Fluoxetine
hydrochloride Sarafem -- Lilly Premenstrual dysphoric disorder --

Fluvastatin sodium Lescol XL -- Novartis Increase HDL-C in patients with primary
hypercholesterolemia and mixed dyslipidemia Extended-release tablet

Follitropin alfa Gonal-F -- Serono Induction of spermatogenesis in men with primary
and secondary hypogonadotropic hypogonadism
in whom the cause of infertility is not due to
primary testicular failure --

Gabapentin Neurontin -- Pfizer -- Oral solution

Ibuprofen Advil Migraine -- Whitehall
Motrin Migraine Pain --
McNeil Consumer Migraine headache pain --

Insulin lispro Humalog -- Lilly In combination with a sulfonylurea in patients
with Type 2 diabetes --

Interferon gamma-1b Actimmune -- InterMune Delay time to disease progression in patients
with severe, malignant osteopetrosis --

Irinotecan
hydrochloride Camptosar -- Pharmacia First-line use in combination with fluorouracil
and leucovorin in patients with metastatic
carcinoma of the colon or rectum --

Levobetaxolol
hydrochloride Betaxon -- Alcon Chronic open-angle glaucoma and ocular
hypertension Ophthalmic suspension

Levocarnitine Carnitor -- Sigma-Tau
Pharmaceuticals Prevention and treatment of carnitine deficiency in
patients with end-stage renal disease who are
undergoing dialysis --

Levofloxacin Levaquin -- Ortho-McNeil Treatment of community-acquired pneumonia
caused by penicillin-resistant Streptococcus
pneumoniae; complicated skin and skin
structure infections --

Quixin -- Santen Bacterial conjunctivitis Ophthalmic solution

Lidocaine/prilocaine EMLA -- AstraZeneca Topical analgesic for superficial minor surgery
of genital mucous membranes and for adjunctive
use with local infiltration anesthesia in genital
mucous membranes --

Medroxyprogesterone
acetate/estradiol
cypionate Lunelle -- Pharmacia -- Parenteral (for once-a-
month administration
for contraception)

Metformin
hydrochloride Glucophage XR --
Bristol-Myers Squibb -- Extended-release tablet

Mitoxantrone
hydrochloride Novantrone -- Immunex Reduce neurologic disability and/or the frequency
of relapses in patients with chronic progressive,
progressive relapsing, or worsening relapsing-
remitting multiple sclerosis --

Mycophenolate mofetil CellCept -- Roche Prophylaxis of organ rejection in patients
receiving allogeneic hepatic transplants --

Olanzapine Zyprexa -- Lilly Short-term treatment of acute manic episodes
associated with bipolar disorder; long-term
treatment and maintenance of schizophrenia --

-- Orally-disintegrating tablet

Oseltamivir phosphate Tamiflu -- Roche Prevention of influenza A and B virus infection --

Pravastatin Pravachol -- Bristol-Myers
Squibb Treatment of Frederickson Types III and IV
hyperlipidemias; increase HDL-C in patients with
primary hypercholesterolemia and mixed
dyslipidemia; reduce risk of total mortality by
reducing coronary death in patients with evident
coronary heart disease --

Ramipril Altace -- Monarch;
Wyeth-Ayerst Reduce the risk of stroke, myocardial infarction,
and death from cardiovascular causes in patients
55 and over with a history of coronary artery
disease, stroke, peripheral vascular disease, or
diabetes and at least one other cardiovascular
risk factor --

Risedronate sodium Actonel -- Aventis;
Procter & Gamble Prevention and treatment of postmenopausal
osteoporosis and corticosteroid-induced
osteoporosis --

Rosiglitazone maleate Avandia -- SmithKline
Beecham In combination with a sulfonylurea in patients
with Type 2 diabetes --

Sertraline hydrochloride Zoloft -- Pfizer -- Liquid oral concentrate

Sirolimus Rapamune -- Wyeth-Ayerst -- Tablet

Somatropin Genotropin -- Pharmacia Treatment of pediatric patients who have
growth failure due to Prader-Willi syndrome --

Sotalol hydrochloride Betapace AF -- Berlex Maintenance of normal sinus rhythm in patients
with symptomatic atrial fibrillation/atrial flutter
who are currently in sinus rhythm --

Sulfasalazine Azulfidine EN -- Pharmacia Treatment of pediatric patients with polyarticular
course juvenile rheumatoid arthritis who have
responded inadequately to salicylates or other
nonsteroidal anti-inflammatory drugs --

Tacrolimus Protopic -- Fujisawa Treatment of patients with moderate-to-severe
eczema, for whom standard therapies are
inadvisable because of potential risks, or who are
not adequately treated by or who are intolerant
of standard eczema therapies Ointment

Tamoxifen citrate Nolvadex -- AstraZeneca Adjuvant treatment of ductal carcinoma in situ
following breast surgery and radiation to reduce
risk of invasive breast cancer --

Tazarotene Tazorac -- Allergan -- Cream

Trimethoprim
hydrochloride Primsol -- Ascent Pediatrics Otitis media Oral solution

HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol

Generic Name (Page No.)	Trade Name	Manufacturer	Therapeutic Classification	Route of Administration	FDA Classification^a
Alosetron hydrochloride (229)	Lotronex	Glaxo Wellcome	Agent for irritable bowel syndrome	Oral	1-P
Aminolevulinic acid hydrochloride^b (267)	Levulan Kerastick	Berlex; Dusa	Agent for actinic keratoses	Topical	1-S
Argatroban (244)	--	SmithKline Beecham	Anticoagulant	Intravenous	1-S
Arsenic trioxide (262)	Trisenox	Cell Therapeutics	Antineoplastic agent	Intravenous	1-P, V
Articaine hydrochloride/ epinephrine bitartrate (256)	Septocaine	Septodont	Local anesthetic	Local injection	1, 4-S
Bexarotene^b (263)	Targretin	Ligand	Antineoplastic agent	Oral; topical	1-P, V
Cevimeline hydrochloride	Evoxac	Daiichi	Cholinergic agonist	Oral	1-S (253)
Colesevelam hydrochloride (238)	WelChol	Sankyo	Antihyperlipidemic agent	Oral	1-S
Dexmedetomidine hydrochloride^b (245)	Precedex	Abbott	Sedative	Intravenous	1-S
Docosanol (238)	Abreva	SmithKline Beecham Consumer	Agent for cold sores	Topical	1-S
Dofetilide^b (239)	Tikosyn	Pfizer	Antiarrhythmic agent	Oral	1-S
Exemestane^b (259)	Aromasin	Pharmacia	Antineoplastic agent	Oral	1-S, V
Ganirelix acetate^b (257)	Antagon	Organon	Agent for infertility	Subcutaneous	1-P
Gatifloxacin^b (233)	Tequin	Bristol-Myers Squibb	Antibacterial agent	Oral; intravenous	1-S
Gemtuzumab ozogamicin (260)	Mylotarg	Wyeth-Ayerst	Antineoplastic agent	Intravenous	1-P, H, V
Levetiracetam^b (246)	Keppra	UCB Pharma	Antiepileptic drug	Oral	1-S
Linezolid (229)	Zyvox	Pharmacia	Antibacterial agent	Oral; intravenous	1-P
Lopinavir/ritonavir (236)	Kaletra	Abbott	Antiviral agent	Oral	1, 4-P, AA, H
Meloxicam (251)	Mobic	Boehringer Ingelheim; Abbott	Antiarthritic agent	Oral	1-S
Mifepristone (258)	Mifeprex	Danco	Abortifacient	Oral	1-S, H
Moxifloxacin hydrochloride^b (233)	Avelox	Bayer	Antibacterial agent	Oral	1-S
Nitric oxide^b (255)	INOmax	INO Therapeutics	Pulmonary vasodilator	Inhalation	1-P, V
Oxcarbazepine (246)	Trileptal	Novartis	Antiepileptic drug	Oral	1-S
Pantoprazole sodium (252)	Protonix	Wyeth-Ayerst	Antisecretory agent	Oral	1-S
Pemirolast potassium^b (266)	Alamast	Santen	Agent for allergic conjunctivitis	Ophthalmic	1-P
Perfluoroalkylpolyether/ polytetrafluoroethylene (268)	SERPACWA	U.S. Army	Protective agent	Topical	1-P
Poractant alfa^b (254)	Curosurf	Dey	Agent for respiratory distress syndrome	Intratracheal	1-S, V
Rivastigmine tartrate (250)	Exelon	Novartis	Agent for Alzheimer's disease	Oral	1-S
Tenecteplase recombinant (241)	TNKase	Genentech	Thrombolytic agent	Intravenous	S^c
Tinzaparin sodium (242)	Innohep	DuPont	Anticoagulant	Subcutaneous	1-S
Unoprostone isopropyl (266)	Rescula	Ciba Vision	Agent for glaucoma	Ophthalmic	1-P
Verteporfin (265)	Visudyne	Ciba Vision	Agent for macular degeneration	Intravenous	1-P
Zonisamide (246)	Zonegran	Elan	Antiepileptic drug	Oral	1-S

Generic Name	Trade Name	Manufacturer	Therapeutic Classification	FDA Classification^b
Balsalazide	Colazal	Salix	Agent for ulcerative colitis	1-S
Bivalirudin	Angiomax	The Medicines Company	Anticoagulant	1-S
Botulinum toxin type B	Myobloc	Elan	Agent for cervical dystonia	S^c
Cetrorelix acetate	Cetrotide	Serono	Agent for infertility	1-S
Insulin aspart, rDNA origin	NovoLog	Novo Nordisk	Antidiabetic agent	1-S
Insulin glargine, rDNA origin	Lantus	Aventis	Antidiabetic agent	1-S
Nateglinide	Starlix	Novartis	Antidiabetic agent	1-S
Triptorelin pamoate	Trelstar Depot	Pharmacia	Antineoplastic agent	1-S

Indication	Recommended Dosage
Vancomycin-resistant Enterococcus faecium infections, including cases with	600 mg IV or oral every 12 hours for 14 to 28 days concurrent bacteremia
Nosocomial pneumonia caused by Staphylococcus aureus (methicillin-susceptible and -resistant strains) or Streptococcus pneumoniae (penicillin-susceptible strains only)	600 mg IV or oral every 12 hours for 10 to 14 days
Community-acquired pneumonia caused by Streptococcus pneumoniae (penicillin-susceptible strains only), including cases with concurrent bacteremia, or S. aureus (methicillin-susceptible strains only)	600 mg IV or oral every 12 hours for 10 to 14 days
Complicated skin and skin structure infections caused by S. aureus (methicillin-susceptible and -resistant strains), Streptococcus pyogenes, or Streptococcus agalactiae	600 mg IV or oral every 12 hours for 10 to 14 days
Uncomplicated skin and skin structure infections caused by	400 mg oral every 12 hours for 10 to 14 days S. aureus (methicillin-susceptible strains only) or S. pyogenes

Indication	Recommended Dosage
Acute sinusitis caused by Streptococcus pneumoniae or Haemophilus influenzae	400 mg once a day for 10 days
Acute bacterial exacerbation of chronic bronchitis caused by S. pneumoniae, S. aureus, H. influenzae, H. parainfluenzae, or Moraxella catarrhalis	400 mg once a day for 7 to 10 days
Community-acquired pneumonia, caused by S. pneumoniae, Staphylococcus aureus, H. influenzae, H. parainfluenzae, M. catarrhalis, Legionella pneumophila, Chlamydia pneumoniae, or Mycoplasma pneumoniae	400 mg once a day for 7 to 14 days
Uncomplicated urinary tract infections (cystitis) caused by Escherichia coli, Klebsiella pneumoniae, or Proteus mirabilis	400 mg as a single dose, or 200 mg once a day for 3 days
Complicated urinary tract infections caused by E. coli, K. pneumoniae, or P. mirabilis	400 mg once a day for 7 to 10 days
Pyelonephritis caused by E. coli	400 mg once a day for 7 to 10 days
Uncomplicated urethral and cervical gonorrhea caused by Neisseria gonorrhoeae; acute, uncomplicated rectal infections in women caused by N. gonorrhoeae	400 mg as a single dose

Indication	Recommended Dosage
Acute bacterial sinusitis caused by Streptococcus pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis	400 mg once a day for 10 days
Acute bacterial exacerbation of chronic bronchitis caused by S. pneumoniae, Staphylococcus aureus, H. influenzae, H. parainfluenzae, Klebsiella pneumoniae, or M. catarrhalis	400 mg once a day for 5 days
Community-acquired pneumonia (of mild-to-moderate severity) caused by S. pneumoniae, H. influenzae, M. catarrhalis, Chlamydia pneumoniae, or Mycoplasma pneumoniae	400 mg once a day for 10 days

Generic Name	Trade Name -- Manufacturer	New Indication	New Dosage Form
Adapalene	Differin -- Galderma	--	Cream
Alendronate sodium	Fosamax -- Merck	To increase bone mass in men with osteoporosis	--
Amphotericin B liposomal	AmBisome -- Fujisawa	Cryptococcal meningitis in HIV-infected patients	--
Anastrozole	Arimidex -- AstraZeneca	First-line treatment of postmenopausal women with hormone receptor-positive or unknown locally advanced or metastatic breast cancer	--
Atovaquone/proguanil	Malarone -- Glaxo Wellcome	Treatment and prevention of Plasmodium falciparum malaria	Tablet
Azelastine hydrochloride	Astelin -- Wallace	Nonallergic vasomotor rhinitis	--
Azelastine hydrochloride	Optivar -- Muro	Treatment of itching of the eye associated with allergic conjunctivitis	Ophthalmic solution
Budesonide	Pulmicort respules -- AstraZeneca	--	Inhalation suspension for nebulization
Caffeine citrate	Cafcit -- Roxane	--	Oral solution
Cerivastatin sodium	Baycol -- Bayer	Increase HDL-C in patients with primary hypercholesterolemia and mixed dyslipidemia	--
Ciclopirox	Penlac -- Dermik	Mild-to-moderate onychomycosis of fingernails and toenails due to Trichophyton rubrum	Topical solution
Ciprofloxacin	Cipro -- Bayer	Post-exposure prophylaxis of clinical disease from Bacillus anthracis	--
Clarithromycin	Biaxin XL -- Abbott	--	Extended-release tablet
Diclofenac	Solaraze -- SkyePharma	Actinic keratoses	Gel
Didanosine	Videx EC -- Bristol-Myers Squibb	--	Enteric-coated capsule
Divalproex sodium	Depakote ER -- Abbott	--	Extended-release tablet
Docetaxel	Taxotere -- Aventis	Locally advanced or metastatic non-small-cell lung cancer in patients who have failed prior platinum-based chemotherapy	--
Doxercalciferol	Hectorol -- Bone Care International	--	Parenteral
Eflornithine hydrochloride	Vaniqa -- Bristol-Myers Squibb	Reduction of unwanted facial hair in women	Cream
Enoxaparin sodium	Lovenox -- Aventis	Prevention of deep vein thrombosis in patients at risk for thromboembolic complications due to severely restricted mobility during acute illnesses	--
Epoprostenol sodium	Flolan -- Glaxo Wellcome	Pulmonary hypertension associated with the scleroderma in NYHA Class III and IV patients who do not respond to conventional therapy	--
Etanercept	Enbrel -- Immunex; Wyeth-Ayerst	First-line treatment of patients with moderately to severely active rheumatoid arthritis and for delaying structural damage	--
Etodolac	Lodine XL -- Wyeth-Ayerst	Juvenile rheumatoid arthritis	--
Fenofibrate micronized	Tricor -- Abbott	Adjunctive therapy to diet for reduction of LDL-C, total cholesterol, triglycerides, and apolipoprotein B in patients with primary hypercholesterolemia or mixed dyslipidemia	--
Fexofenadine hydrochloride	Allegra -- Aventis	Uncomplicated manifestations of chronic idiopathic urticaria	--
Fluoxetine hydrochloride	Sarafem -- Lilly	Premenstrual dysphoric disorder	--
Fluvastatin sodium	Lescol XL -- Novartis	Increase HDL-C in patients with primary hypercholesterolemia and mixed dyslipidemia	Extended-release tablet
Follitropin alfa	Gonal-F -- Serono	Induction of spermatogenesis in men with primary and secondary hypogonadotropic hypogonadism in whom the cause of infertility is not due to primary testicular failure	--
Gabapentin	Neurontin -- Pfizer	--	Oral solution
Ibuprofen	Advil Migraine -- Whitehall Motrin Migraine Pain -- McNeil Consumer	Migraine headache pain	--
Insulin lispro	Humalog -- Lilly	In combination with a sulfonylurea in patients with Type 2 diabetes	--
Interferon gamma-1b	Actimmune -- InterMune	Delay time to disease progression in patients with severe, malignant osteopetrosis	--
Irinotecan hydrochloride	Camptosar -- Pharmacia	First-line use in combination with fluorouracil and leucovorin in patients with metastatic carcinoma of the colon or rectum	--
Levobetaxolol hydrochloride	Betaxon -- Alcon	Chronic open-angle glaucoma and ocular hypertension	Ophthalmic suspension
Levocarnitine	Carnitor -- Sigma-Tau Pharmaceuticals	Prevention and treatment of carnitine deficiency in patients with end-stage renal disease who are undergoing dialysis	--
Levofloxacin	Levaquin -- Ortho-McNeil	Treatment of community-acquired pneumonia caused by penicillin-resistant Streptococcus pneumoniae; complicated skin and skin structure infections	--
Levofloxacin	Quixin -- Santen	Bacterial conjunctivitis	Ophthalmic solution
Lidocaine/prilocaine	EMLA -- AstraZeneca	Topical analgesic for superficial minor surgery of genital mucous membranes and for adjunctive use with local infiltration anesthesia in genital mucous membranes	--
Medroxyprogesterone acetate/estradiol cypionate	Lunelle -- Pharmacia	--	Parenteral (for once-a- month administration for contraception)
Metformin hydrochloride	Glucophage XR -- Bristol-Myers Squibb	--	Extended-release tablet
Mitoxantrone hydrochloride	Novantrone -- Immunex	Reduce neurologic disability and/or the frequency of relapses in patients with chronic progressive, progressive relapsing, or worsening relapsing- remitting multiple sclerosis	--
Mycophenolate mofetil	CellCept -- Roche	Prophylaxis of organ rejection in patients receiving allogeneic hepatic transplants	--
Olanzapine	Zyprexa -- Lilly	Short-term treatment of acute manic episodes associated with bipolar disorder; long-term treatment and maintenance of schizophrenia	--
Olanzapine	Zyprexa -- Lilly	--	Orally-disintegrating tablet
Oseltamivir phosphate	Tamiflu -- Roche	Prevention of influenza A and B virus infection	--
Pravastatin	Pravachol -- Bristol-Myers Squibb	Treatment of Frederickson Types III and IV hyperlipidemias; increase HDL-C in patients with primary hypercholesterolemia and mixed dyslipidemia; reduce risk of total mortality by reducing coronary death in patients with evident coronary heart disease	--
Ramipril	Altace -- Monarch; Wyeth-Ayerst	Reduce the risk of stroke, myocardial infarction, and death from cardiovascular causes in patients 55 and over with a history of coronary artery disease, stroke, peripheral vascular disease, or diabetes and at least one other cardiovascular risk factor	--
Risedronate sodium	Actonel -- Aventis; Procter & Gamble	Prevention and treatment of postmenopausal osteoporosis and corticosteroid-induced osteoporosis	--
Rosiglitazone maleate	Avandia -- SmithKline Beecham	In combination with a sulfonylurea in patients with Type 2 diabetes	--
Sertraline hydrochloride	Zoloft -- Pfizer	--	Liquid oral concentrate
Sirolimus	Rapamune -- Wyeth-Ayerst	--	Tablet
Somatropin	Genotropin -- Pharmacia	Treatment of pediatric patients who have growth failure due to Prader-Willi syndrome	--
Sotalol hydrochloride	Betapace AF -- Berlex	Maintenance of normal sinus rhythm in patients with symptomatic atrial fibrillation/atrial flutter who are currently in sinus rhythm	--
Sulfasalazine	Azulfidine EN -- Pharmacia	Treatment of pediatric patients with polyarticular course juvenile rheumatoid arthritis who have responded inadequately to salicylates or other nonsteroidal anti-inflammatory drugs	--
Tacrolimus	Protopic -- Fujisawa	Treatment of patients with moderate-to-severe eczema, for whom standard therapies are inadvisable because of potential risks, or who are not adequately treated by or who are intolerant of standard eczema therapies	Ointment
Tamoxifen citrate	Nolvadex -- AstraZeneca	Adjuvant treatment of ductal carcinoma in situ following breast surgery and radiation to reduce risk of invasive breast cancer	--
Tazarotene	Tazorac -- Allergan	--	Cream
Trimethoprim hydrochloride	Primsol -- Ascent Pediatrics	Otitis media	Oral solution