Amlodipine
Launched in the United States in 1996, amlodipine besylate (Pfizer’s Norvasc/Amlor/Amlodin) is the top-selling agent in the antihyperten-sive marketplace. The compound is marketed by Sumitomo in Japan, Almirall in Spain, and Pfizer in the rest of the world. Amlodipine is a long-acting dihydropyridine.
Pfizer reports that 15 double-blind, placebo-controlled studies involving more than 1,300 patients with mild-to-moderate hypertension have investigated amlodipine’s antihypertensive efficacy. Once-daily administration of amlodipine (5-10 mg) resulted in statistically significant reductions in supine blood pressure (mean reductions equal =13 [systolic blood pressure]/7 [diastolic blood pressure] mm Hg) and standing blood pressure (mean reductions = 12/6 mm Hg) at 24 hours postdose. There were no significant gender or race differences with respect to the response observed. Improvements in forearm blood flow corresponding to improved vascular function have been observed in hypertensive patients being treated with amlodipine. Positive effects on vascular structure, such as a reduction in intimamedia thickness in the carotid artery, have also been demonstrated.
Despite these observations, recent comparative trials have been somewhat disappointing. For example, the Valsartan and Amlodipine in Isolated Systolic Hypertension in the Elderly (Val-Syst) study, which involved 421 patients from 35 outpatient centers in Italy, demonstrated that although valsartan and amlodipine were similarly efficacious, the AURA was better tolerated. In the ALLHAT study, the amlodipine besylate treatment group achieved a significantly lower diastolic blood pressure ( — 0.8 mm Hg) but a significantly higher systolic blood pressure ( + 0.8 mm Hg) compared with the diuretic chlorthalidone. Amlodipine besylate is not superior in preventing combined fatal coronary heart disease or nonfatal myocardial infarction (MI), and although a nonsignificant trend toward protection from stroke was identified, this trend was countered by a significantly raised rate of chronic heart failure.
Under the Hatch-Waxman Act, Pfizer’s U.S. patent on amlodipine was extended until 2007, but legal proceedings have challenged the application of this extension to a second amlodipine salt: amlodipine maleate. In November 2002, generics manufacturer Dr. Reddy’s Laboratories received an approvable letter for amlodipine maleate from the FDA despite the lack of clinical trial data comparing the efficacy of amlodipine besylate with the maleate salt in the treatment of hypertension. The U.S. district courts decreed that Dr. Reddy’s had not infringed upon Pfizer’s patent for amlodipine, but in February 2004, the U.S. Court of Appeals overturned this decision, thus protecting Pfizer from potentially large financial losses. Dr. Reddy’s has since filed an abbreviated new drug application (ANDA) with the FDA for the besylate version of the salt.
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