Jane S. Ricciuti, RPh, MS

Disclosures

October 23, 2002

In This Article

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.
Abstract

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.
Abstract

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.
Abstract

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.

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