Pharmacy Division Ramathibodi Hospital


Food and Drug Administration New Drug Approvals of 2002

The following are selected from the FDA's list of recently approved products. Complete, updated information on FDA approvals and notifications is available on the FDA Web site (

October 2002


FDA new product approvals and labeling changes for these products as well as the following:

Antifungal Agents Antihypertensive Agents Anti-Infective Agents Antilipemic Agents Antiviral Agents Dermatologic Agents Gastrointestinal Agents Nonsteroidal Antiestrogens Vaccines

Antifungal Agents

Cancidas (caspofungin acetate) for Injection

Manufacturer: Merck Research Laboratories

Drug Approval Classification: Supplemental New Drug Application (Approval Date: 9/20/02)

New Indication: This supplemental new drug application provides for the use of Cancidas (caspofungin acetate) for Injection for the treatment of esophageal candidiasis.

Cancidas previously was only indicated for the treatment of invasive aspergillosis in patients intolerant to other therapies.

Dosing: For the treatment of esophageal candidiasis, Cancidas 50 mg daily should be administered by slow intravenous infusion over approximately 1 hour. Because of the risk of relapse of oropharyngeal candidiasis in patients with HIV infections, suppressive oral therapy could be considered. A 70-mg loading dose has not been studied with this indication.

Clinical Summary:Cancidas was studied in 166 patients with culture-confirmed esophageal candidiasis in a randomized, double-blind, controlled, noninferiority clinical trial. Patients were treated for a period of 7-21 days (average 9 days) with Cancidas 50 mg/day vs fluconazole 200 mg/day. The primary end point was a favorable overall response at 5-7 days following discontinuation of study therapy. The overall response for the primary end point was comparable for Cancidas (81.5%) and fluconazole (85.1%)

Pharmacokinetics: A drug-interaction study with rifampin has shown a 30% decrease on caspofungin trough concentrations. It is recommended that patients on rifampin receive 70 mg of Cancidas daily.

Patient pharmacokinetic data suggest that coadministration of other inducers of drug clearance (carbamazepine, dexamethasone, efavirenz, nevirapine, phenytoin) with Cancidas may result in clinically meaningful reductions in caspofungin concentrations. It is recommended that a 70-mg daily dose be administered in patients receiving carbamazepine, dexamethasone, efavirenz, nevirapine, or phenytoin.


Cancidas (caspofungin acetate) for injection labeling.

Antihypertensive Agents

Atacand (candesartan cilexetil) Tablets

Manufacturer: AstraZeneca

Drug Approval Classification: Supplemental New Drug Application (Approval Date: 9/13/02)

Indication:Atacand (candesartan cilexetil) is indicated for the treatment of hypertension.

Clinical Summary: This supplemental new drug application provides superiority data on the comparison of the antihypertensive effects of Atacand (candesartan cilexetil) tablets and Cozaar (losartan potassium) tablets.

Atacand's superiority over Cozaar was demonstrated in two 8-week, multicenter, double-blind, randomized, parallel-group, forced-titration studies in a total of 1268 hypertensive patients (CLAIM studies). Candesartan cilexetil 32 mg lowered systolic and diastolic blood pressure by 2-3 mm Hg on average -- which was a greater reduction that that seen with losartan potassium 100 mg, when measured at the time of either peak or trough effect. Once-daily dosing of candesartan was the only dosing regimen studied.


Atacand (candesartan cilexetil) labeling.

Bakris G, Gradman A, Reif M, et al. Antihypertensive efficacy of candesartan in comparison to losartan: the CLAIM study. J Clin Hypertens. 2001;3:16-21.

Vidt DG, White WB, Ridley E, et al. A forced titration study of antihypertensive efficacy of candesartan cilexetil in comparison to losartan: CLAIM Study II. J Hum Hypertens. 2001;15:475-480.

Atacand (candesartan cilexetil)

Avapro (irbesartan) Tablets

Manufacturer: Bristol-Myers Squibb

Drug Approval Classification: Supplemental New Drug Application (Approval Date: 9/17/02)

New Indication:Avapro (irbesartan) is indicated for the treatment of diabetic nephropathy with an elevated serum creatinine and proteinuria (> 300 mg/day) in patients with type 2 diabetes and hypertension. In this population, Avapro reduces the rate of progression of nephropathy as measured by the occurrence of doubling of serum creatinine or end-stage renal disease (need for dialysis or renal transplantation).

The FDA approved Cozaar (losartan potassium) for the supplemental indication for the treatment of patients with type 2 diabetic nephropathy (see Cozaar below).

Dosing: The recommended target maintenance dose for the treatment of diabetic nephropathy in patients with type 2 diabetes is 300 mg once daily. There are no data on the clinical effects of lower doses of Avapro on diabetic nephropathy.

Clinical Summary: Previously to this new supplemental indication, Avapro was indicated for the treatment of hypertension.

The FDA approval is based on results from the Irbesartan Diabetic Nephropathy Trial (IDNT). IDNT studied 1715 patients with high blood pressure, type 2 diabetes, and evidence of kidney disease. Patients were randomized to irbesartan 300 mg daily or amlodipine 10 mg daily or placebo. Patients in the irbesartan group had a 20% lower risk of progression of their nephropathy or death than that of the placebo (control) group (P = .02) and a 23% lower risk than the group treated with amlodipine (P = .006).

Adverse Effects: No new adverse events were reported in the Avapro-treated patients in IDNT. Patients on Avapro experienced more orthostatic symptoms and increases in serum potassium vs the control group.


Avapro (Irbesartan) labeling.

Lewis EJ, Hunsicker LG, Clarke WR, et al, for the Collaborative Study Group. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345:851-860.

Avapro (irbesartan)

Cozaar (losartan potassium) Tablets

Manufacturer: Merck & Co, Inc

Drug Approval Classification: Supplemental New Drug Application (Approval Date: 9/17/02)

New Indication:Cozaar (losartan potassium) is indicated for the treatment of diabetic nephropathy with an elevated serum creatinine and proteinuria (urinary albumin to creatinine ratio >/= 300 mg/g) in patients with type 2 diabetes and a history of hypertension. In this population, Cozaar reduces the rate of progression of nephropathy as measured by the occurrence of doubling of serum creatinine or end-stage renal disease (need for dialysis or renal transplantation)

The FDA approved Avapro (irbesartan) for the supplemental indication for the treatment of patients with type 2 diabetic nephropathy (see Avapro above)

Dosing: For the treatment of type 2 diabetic nephropathy, the usual starting dose is 50 mg once daily. The dose could be increased to 100 mg once daily based on blood pressure response. Cozaar may be administered with insulin and other commonly used hypoglycemic agents (eg, sulfonylureas, glitazones, and glucosidase inhibitors).

Clinical Summary: Prior to this new supplemental indication, Cozaar was indicated for the treatment of hypertension.

The basis for approval of Cozaar for the treatment of nephropathy in patients with type 2 diabetes is the Reduction of Endpoints in NIDDM with the Angiotensin II Receptor Antagonist Losartan (RENAAL) study. RENAAL was a randomized, placebo-controlled, double-blind, multicenter study in 1513 patients with type 2 diabetes with nephropathy. Patients were randomized to Cozaar 50 mg daily or placebo. Patients were followed for 3 1/2 years. Patients treated with Cozaar had a 16% risk reduction in the primary end point, defined as the time to first occurrence of any 1 of the following events: doubling of serum creatinine, end-stage renal disease (need for dialysis or transplantation), or death. Cozaar reduced the occurrence of sustained doubling of serum creatinine by 25% and end-stage renal disease by 29%. No effect on mortality was seen in the RENAAL study.

Adverse Effects: No new adverse effects were seen with Cozaar in the RENAAL study. The discontinuation rate due to adverse events was 19% for Cozaar-treated patients vs 24% in placebo patients.


Cozaar (losartan potassium) labeling.

Cozaar (losartan potassium)

Inspra (eplerenone) Tablets

Manufacturer: Pharmacia

Drug Approval Classification: Original New Drug Application (Approval Date: 9/27/02)

Indication:Inspra (eplerenone) is indicated for the treatment of hypertension. Inspra may be used alone or in combination with other antihypertensive agents.

Dosing: The recommended starting dose of Inspra is 50 mg once daily. The full therapeutic effect of Inspra is apparent within 4 weeks. Patients may be increased to 50 mg twice daily if blood pressure response is inadequate. Doses higher than 100 mg daily are associated with increased risk of hyperkalemia and no greater efficacy in blood pressure lowering.

For patients receiving weak CYP3A4 inhibitors, such as erythromycin, fluconazole, saquinavir, and verapamil, the recommended starting dose of Inspra is 25 mg once daily.

Clinical Summary:Inspra (eplerenone) is a blocker of aldosterone binding at the mineralocorticoid receptor.

Inspra has been studied in 3091 hypertensive patients as monotherapy and in combination therapy. Efficacy was demonstrated as a decrease in systolic blood pressure at trough with differences from placebo of 6-13 mm Hg and diastolic differences of 3-7 mm Hg.

Warnings: Serious hyperkalemia is associated with Inspra. Patients who have impaired renal function should not use potassium supplements, salt substitutes containing potassium, or contraindicated drugs.

Adverse Effects:Inspra clinical trials have reported adverse events in 47% of Inspra-treated patients compared with 45% of those receiving placebo. The most common adverse events noted for discontinuation of therapy were headache, dizziness, angina pectoris/myocardial infarction, and increased GGT. Gynecomastia and abnormal vaginal bleeding were reported with Inspra but not with placebo.

Pharmacokinetics: Eplerenone is cleared predominantly by CYP450 3A4 metabolism, with an elimination half-life of 4-6 hours. Steady state is reached within 2 days. Absorption is not affected by food. Mean peak plasma concentrations of eplerenone are reached approximately 1.5 hours following oral administration.

Eplerenone is metabolized primarily by CYP3A4. A pharmacokinetic study with ketoconazole showed a 1.7-fold increase in Cmax of eplerenone and a 5.4-fold increase in AUC of eplerenone. Inspra should not be used with strong inhibitors of CYP450 3A4 (eg, erythromycin, fluconazole, itraconazole, ketoconazole, saquinavir, and verapamil).

Inspra used in combination with angiotensin-converting enzyme inhibitors and angiontensin II receptor antagonists increased mean serum potassium slightly; caution should be used in administering Inspra.

No pharmacokinetic studies have been performed with other drugs that are metabolized via CYP450 3A4 or renally eliminated, such as lithium or nonsteroidal anti-inflammatory drugs.


Inspra (eplerenone) labeling.

Anti-infective Agents

Augmentin XR (Amoxicillin/Clavulanate Potassium) Extended-release Tablets, 1000 mg/62.5 mg

Manufacturer: GlaxoSmithKline

Drug Approval Classification: Original New Drug Application (Approval Date: 9/25/02)

Indication:Augmentin XR extended-release tablets are indicated for the treatment of patients with community-acquired pneumonia (CAP) or acute bacterial sinusitis due to confirmed or suspected beta-lactamase-producing pathogens (ie, H influenzae, M catarrhalis, H parainfluenzae, K pneumoniae, or methicillin-susceptible S aureus) and S pneumoniae with reduced susceptibility to penicillin.

Dosing: Augmentin XR should be taken at the start of a meal to enhance the absorption of amoxicillin and to minimize the potential for gastrointestinal intolerance.

The recommended dose of Augmentin XR is 4000 mg/250 mg daily. Augmentin tablets (250 mg or 500 mg) CANNOT be used to provide the same dosages as Augmentin XR extended-release tablets.

Clinical Summary:Augmentin XR is contraindicated in patients with a history of allergic reactions to any penicillin. It is also contraindicated in patients with a previous history of cholestatic jaundice/hepatic dysfunction associated with treatment with amoxicillin/clavulanate.

Augmentin XR is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min) and in hemodialysis patients.

For the indication of CAP, 3 randomized, controlled, double-blind clinical studies in adults with CAP were conducted. Patients received Augmentin XR at a dosage of 2000/125 mg orally every 12 hours for 7 or 10 days. The clinical success rate at test of cure ranged from 86.3% to 94.7% in clinically evaluable patients in the Augmentin XR group.

Three clinical studies were conducted in adults with a diagnosis of acute bacterial sinusitis. In a double-blind, multicenter prospective trial, patients received either Augmentin XR 2000/125 mg orally q12h or levofloxacin 500 mg orally daily for 10 days. The combined clinical and radiologic responses were 83.7% for Augmentin XR and 84.3% for levofloxacin at the test-of-cure visit in clinically evaluable patients.

Adverse Effects: The safety database contains more than 4100 patients treated with Augmentin XR in clinical trials. The most common adverse effects suspected or probably drug-related were diarrhea (15.6%), nausea (2.2%), genital moniliasis (2.1%), and abdominal pain (1.6%).

Pharmacokinetics:Augmentin XR is an extended-release formulation that provides sustained plasma concentrations of amoxicillin. Absorption of amoxicillin is decreased in the fasted state. Augmentin XR is not recommended to be taken with a high-fat meal, because clavulanate absorption is decreased.

The half-life of amoxicillin after oral administration of Augmentin XR is approximately 1.3 hours, and that of clavulanate is approximately 1.0 hour.

Clearance of amoxicillin is predominantly renal, with approximately 60% to 80% of the dose being excreted unchanged in urine, whereas clearance of clavulanate has both a renal (30% to 50%) and a nonrenal component.

Drug interactions include:


Augmentin XR (Amoxicillin/Clavulanate Potassium) extended-release tablets Labeling


Antilipemic Agents

Mevacor (lovastatin) Tablets

Manufacturer: Merck & Co, Inc

Drug Approval Classification: Supplemental New Drug Application (Approval Date: 9/20/02)

Revised Warnings: This supplemental new drug application changes wording on the approved labeling. The changes strengthen the warnings for the potential of Mevacor to cause myopathy/rhabdomyolysis.

The label sections affected include "Clinical Pharmacology," "Warnings," "Precautions," and "Dosage and Administration."

Inhibitors of CYP3A4 can raise the plasma levels of HMG-CoA reductase inhibitor activity and increase the risk of myopathy.

The risk of myopathy/rhabdomyolysis is increased by concomitant use of lovastatin with the following agents: Dosing: There is a dose-response relationship to myopathy/rhabdomyolysis. Dosing adjustments should be made for patients who are concomitantly taking Mevacor with cyclosporine, gemfibrozil, other fibrates, or lipid-lowering doses of amiodarone, niacin, or verapamil.


Mevacor (lovastatin) Labeling

Mevacor (lovastatin) Letter

Mevacor (lovastatin)

Dermatologic Agents

Aldara (imiquimod) Topical Cream

Manufacturer: 3M Pharmaceuticals

Drug Approval Classification: Supplemental New Drug Application (Approval Date: 9/03/02)

New Indication: Two supplemental indications were approved for Aldara topical cream, Dosing: Aldara cream is applied 3 times per week, prior to normal sleeping hours, and left on the skin for 6-10 hours. Following the treatment period, the cream should be removed by washing the treated area with mild soap and water. Aldara treatment should continue until there is total clearance of the genital/perianal warts or for a maximum of 16 weeks.


Aldara (imiquimod) Topical Cream Labeling

Aldara (imiquimod) Topical Cream

Antiviral Agents

Hepsera (adefovir dipivoxil) Tablets

Manufacturer: Gilead Sciences, Inc

Drug Approval Classification: Original New Drug Application (Approval Date: 9/20/02)

Indication:Hepsera (adefovir dipivoxil) is indicated for the treatment of chronic hepatitis B in adults with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease.

This indication is based on histologic, virologic, biochemical, and serologic responses in adult patients with HBeAg+ and HBeAg- chronic hepatitis B with compensated liver function, and in adult patients with clinical evidence of lamivudine-resistant hepatitis B virus with either compensated or decompensated liver function.

Dosing:Hepsera in chronic hepatitis B patients with normal renal function is dosed at 10 mg once daily. The optimal duration of therapy is unknown.

Dose adjustment is necessary for patients with renal impairment (see Table).

Table. Dosing Interval Adjustment of Hepsera in Patients With Renal Impairment

Creatinine Clearance (mL/min)

>/= 50 mL/min 20-49 mL/min 10-19 mL/min Hemodialysis Patients
Recommended Dose and Dosing Interval 10 mg every 24 hours 10 mg every 48 hours 10 mg every 72 hours 10 mg every 7 days following dialysis

Clinical Summary: Adefovir dipivoxil is a diester prodrug of adefovir. Adefovir is an acyclic nucleotide analogue with activity against human hepatitis B virus (HBV). Adefovir diphosphate inhibits HBV DNA polymerase (reverse transcriptase) by competing with the natural substrate deoxyadenosine triphosphate and by causing DNA chain termination after its incorporation into viral DNA.

Hepsera 10 mg was studied in HBeAg-positive chronic hepatitis B patients in a randomized, double-blind, placebo-controlled, 3-arm study. Hepsera was associated with a 53% histologic improvement, defined as a 2-point decrease in the Knodell necro-inflammatory score with no worsening of the Knodell fibrosis score. Placebo-controlled patients showed an improvement of 25%. No improvement was seen in 37% of Hepsera-treated patients vs in 67% of placebo patients.

In patients with HBeAg-negative (anti-HBe positive/HBV DNA positive) chronic hepatitis B, Hepsera demonstrated a 64% histologic improvement vs a 35% improvement in the placebo group in a randomized, double-blind, placebo-controlled study. No improvement was seen in 29% and 63% of Hepsera vs placebo patients, respectively.

In both HBeAg-positive and HBeAg-negative chronic hepatitis B patients, treatment was continued to 72 weeks with continued maintenance of mean reductions in HBV DNA observed at week 48.

The FDA is requiring Gilead Sciences, Inc. to conduct postmarketing studies. Some of the postmarketing commitments include obtaining 5-year long-term follow-up information from the submitted pivotal clinical trials to address the following factors: maintenance of virologic suppression; durability of HBeAg and HBsAg seroconversion and the rate of new events; risk of drug-related adverse effects, particularly nephrotoxicity; and risk for development of HBV resistance to adefovir. Other required studies are being conducted to determine the optimal dosing in renally impaired patients and pharmacokinetic data in nonwhite patients.

Warnings: Hepsera labeling contains significant warnings for acute exacerbations of hepatitis upon discontinuation, potential for nephrotoxicity in chronic administration, HIV resistance, and lactic acidosis and severe hepatomegaly.

Adverse Effects: The incidence of treatment-related adverse events observed in the pivotal trials include asthenia (13%), headache (9%), abdominal pain (9%), nausea (5%), flatulence (4%), diarrhea (3%), and dyspepsia (3%).

Pharmacokinetics: The peak adefovir plasma concentration (Cmax) was 18.4 ng/mL and occurred between 0.58 and 4.00 hours. The adefovir area under the plasma concentration-time curve (AUC) was 220 ng*h/mL. Food does not affect adefovir exposure. Adefovir is eliminated by the kidney.

In patients with moderately or severely impaired renal function or with end-stage renal disease requiring hemodialysis, Cmax, AUC, and half-life (T1/2) were increased compared with subjects with normal renal function. It is recommended that the dosing interval of Hepsera be modified in these patients (see Dosing).

Adefovir does not inhibit any of the common human CYP450 enzymes, CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. The potential for adefovir to induce CYP450 enzymes is unknown.


Hepsera (adefovir dipivoxil) labeling.

Valtrex (valacyclovir)

Manufacturer: GlaxoSmithKline

Drug Approval Classification: Supplemental New Drug Application (Approval Date: 9/9/02)

New Indication:Valtrex (valacyclovir) is indicated for the treatment of cold sores (herpes labialis) in adult and adolescent patients 12 years of age and older.

Prior to this supplemental indication, Valtrex was indicated for the treatment of herpes zoster and the treatment or suppression of genital herpes.

Dose: For the treatment of cold sores (herpes labialis), the recommended dose is 2 g twice daily for 1 day initiated at the earliest symptoms of a cold sore (eg, tingling, itching, or burning).

Clinical Summary:Valtrex was evaluated in 2 double-blind, placebo-controlled studies in 1856 subjects with a history of recurrent cold sores. Valtrex 2 g twice daily for 1 day was compared with placebo. The mean duration of the cold sore was about 1 day shorter with Valtrex than with placebo.

Adverse Effects: No new adverse effects have been reported. The most common side effects are headache, nausea, and abdominal pain.


Valtrex (valacyclovir) Letter

Valtrex (valacyclovir)

Gastrointestinal Agents

Prevacid SoluTab (lansoprazole), Delayed-Release Orally Disintegrating Tablets

Manufacturer: TAP Pharmaceutical Products, Inc

Drug Approval Classification: Supplemental New Drug Application (Approval Date: 8/30/02)

New Dosage Form: This supplement includes the addition of Prevacid SoluTab (lansoprazole), a new formulation. This new dosage form is formulated to disintegrate in the mouth without chewing.

Prevacid SoluTab delayed-release orally disintegrating tablets are available in 15-mg and 30-mg strengths. Prevacid SoluTabs are not designed to be swallowed intact or chewed. The tablet typically disintegrates in less than 1 minute. Place the tablet on the tongue and allow it to disintegrate with or without water until the particles can be swallowed.


PrevacidSoluTab (lansoprazole) Labeling

Prevacid (lansoprazole)

Nonsteroidal Antiestrogens

Nolvadex (tamoxifen) Tablets

Manufacturer: AstraZeneca Pharmaceuticals

Drug Approval Classification: Supplemental New Drug Application (Approval Date: 8/30/02)

Clinical Summary: This supplemental new drug application provides for the labeling to include the results of tamoxifen 20-mg tablets studied in girls with McCune-Albright syndrome. Twenty-eight female patients, aged 2 to 10 years, were treated for up to 12 months. There was a 50% reduction in the frequency of vaginal bleeding episodes. The linear growth rate was reduced during tamoxifen therapy in the majority of patients. Long-term effects beyond 12 months and use below 2 years of age have not been studied

In adult patients treated with tamoxifen, there is an increased incidence of endometrial adenocarcinoma and uterine sarcoma. It is recommended that patients treated with tamoxifen be monitored for long-term uterine effects.


Nolvadex (tamoxifen) labeling.

Nolvadex (tamoxifen)


Fluzone (Preservative-Free Influenza Virus Vaccine) Intramuscular Injection

Manufacturer: Aventis

Drug Approval Classification: Biological License Application Supplement Approval (Approval Date: 9/4/02)

New Indication: The FDA approved Fluzone preservative-free influenza virus vaccine formulation in a single-dose product in 0.25-mL syringes for pediatric use (infants aged 6-35 months).


Fluzone (Preservative-Free Influenza Virus Vaccine) Labeling

Fluzone (Preservative-Free Influenza Virus Vaccine)

November 2002

Colorectal Cancer Drug Approved

The FDA has approved a new drug for the treatment of recurrent or worsening colorectal cancer in combination with infusional 5-fluorouracil (5-FU) and leucovorin.

Generic Name:   Oxaliplatin

Brand Name:   Eloxatin

Manufacturer:   Sanofi-Synthelabo

Function:   Oxaliplatin is for use in patients who have experienced a recurrence of colorectal cancer or in patients in whom the cancer worsens after initial treatment with a combination of irinotecan with a bolus of fluorouracil and leucovorin. A black-box warning lists the anaphylactic-like reactions associated with the drug. Side effects include numbness or tingling in the hands or feet or around the mouth, vomiting, diarrhea, and anemia. Women should not become pregnant while on this drug, as it may harm the fetus.


FDA approves Eloxatin for colorectal cancer (P02-25). FDA Talk Paper, U.S. Food and Drug Administration, August 12, 2002 (

New Drug for Constipation-Predominant Irritable Bowel Syndrome

The FDA has approved a new drug for the treatment of constipation-predominant irritable bowel syndrome in women. The efficacy of this drug has not been demonstrated in men.

Generic Name:   Tegaserod maleate

Brand Name:   Zelnorm

Manufacturer:   Novartis Pharmaceuticals Corp.

Function:   Tegaserod maleate increases movement of fecal matter through the bowels, reducing abdominal pain and discomfort, bloating, and constipation. The drug was studied only for 3 months; efficacy appears to be greatest in the first month after initiation of treatment and lessens thereafter. Diarrhea is the most common side effect. Studies showed that use of tegaserod maleate is associated with an increased risk of abdominal surgeries (mostly for gallbladder removal).


FDA approves first treatment for women with constipation-predominant irritable bowel syndrome (T02-33). FDA Talk Paper, U.S. Food and Drug Administration, July 24, 2002 (

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