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Wellcome), was withdrawn from the market before the end of the year because of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 QTc > 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 QTc. 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 QTc
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 evenin
