An aldosterone blocker for treating hypertension, used alone or in combination with other antihypertensives. The first drug in this class to be approved.
Recommended Dosage: Starting dose of 50 mg once a day, increasing to 50 mg twice a day if necessary.
Special Considerations: The most common side effects reported in trials included dizziness (3%), and fatigue, flulike symptoms, diarrhea, and cough (all occurring at a rate of 2%). Contraindicated in patients with serum potassium above 5.5 mEq/L; type 2 diabetes with microalbuminuria; serum creatinine above 2 mg/dL in men or 1.8 mg/dL in women; or a creatinine clearance below 50 mL/min. Also contraindicated in people on potassium supplements, potassium-sparing diuretics (amiloride, spironolactone, or triamterene), and drugs that are strong inhibitors of CYP450 3A4, such as ketoconazole or itraconazole.
Comment: Inspra blocks the binding of aldosterone, part of the renin-angiotensin-aldosterone system. In studies of more than 3,000 patients, Inspra lowered systolic and diastolic blood pressure, as monotherapy and when used with other antihypertensives. In a 16-week trial of about 500 black and white patients with mild to moderate hypertension, use of Inspra (50-200 mg) was associated with greater reductions in blood pressure in black patients than use of the angiotensin receptor blocker Cozaar (losartan). In white patients, blood pressure reductions were comparable with both.
Inspra is expected to become available sometime in 2003, a company spokesman said. The company plans to file an application this year with the Food and Drug Administration for approval of the drug for treating post-MI heart failure, based on the results of an international study of more than 6,000 patients.
An atypical antipsychotic for reducing the risk of recurrent suicidal behavior in people with schizophrenia or schizoaffective disorder. This is the first time the FDA has approved a suicidality claim for any medication. Approved in 1990 for severely ill schizophrenic patients who fail to respond adequately to standard drug therapy.
Recommended Dosage: Target dose of 300-450 mg/day.
Special Considerations: Treatment recommended for at least 2 years to reduce the risk of recurrent suicidal behavior, the FDA said in a statement. Weekly white blood cell counts and weekly drug dispensing mandatory because of the risk of agranulocytosis, which can be reversed if detected at an early stage. Postmarketing data suggest that Clozaril is "associated with an increased risk of fatal myocarditis," especially during the first month of therapy. The seizure risk ranges from 1% to 2% of patients on low doses (under 300 mg/day) to 5% of those on high doses (300-600 mg/day).
Comment: Approval was based on results of the International Suicide Prevention Trial (InterSePT), data from a national clozapine registry, and other data. In InterSePT, a prospective open-label trial of 980 patients with schizophrenia or schizoaffective disorder at high risk for suicide, the risk of suicide attempts or hospitalizations to prevent suicide over 2 years was reduced by 26% among those on Clozaril, vs. those treated with another atypical antipsychotic, Zyprexa (olanzapine). The reduction in risk did not appear to be attributable to a greater effect on psychotic or depressive symptoms, or to greater use of concomitant psychotropic medications, according to Novartis. No difference was seen in the number of completed suicides, which was similar in both groups. Data from clozapine treatment registries in the United Kingdom and Texas also showed a reduced suicide rate associated with Clozaril.
The FDA advised health care professionals that most of the patients on Clozaril and Zyprexa were receiving other treatments aimed at reducing their risk of suicide, including antidepressants, psychotherapy, and hospitalization. "The contributions of these additional measures are unknown," the FDA said in a statement. The approval does not apply to generic clozapine because Novartis has been granted exclusive rights to market Clozaril for this indication for 36 months.
An estimated 3,600 suicides associated with schizophrenia occur each year in the United States.
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