Jane S. Ricciuti, RPh, MS

Disclosures

January 23, 2004

In This Article

Antipsychotics

Clozaril
(clozapine) Tablets

Manufacturer: Novartis Pharmaceuticals Corporation

Drug Approval Classification: Supplemental New Drug Application (Approval Date: 12/23/03)

New Warnings: This supplemental approval is for the addition of information to the Warnings section regarding diabetes mellitus and hyperglycemia associated with Clozaril (clozapine).

  • Hyperglycemia and Diabetes Mellitus

    • Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics including clozapine. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiologic studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not available.

    • Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (eg, obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia, including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of antidiabetic treatment despite discontinuation of the suspect drug.

Clozaril (clozapine) Tablets Letter

Clozaril (clozapine) Tablets

Risperdal (risperidone) Tablets, Oral Solution & Disintegrating Tablets

Manufacturer: Johnson & Johnson

Drug Approval Classification: Supplemental New Drug Application (Approval Date: 12/4/03)

New Indication: Risperdal (risperidone) is approved as monotherapy for the short-term treatment of acute manic or mixed episodes associated with bipolar I disorder. Risperidone is approved for combination therapy with lithium or valproate for the short-term treatment of acute manic or mixed episodes associated with bipolar I disorder.

Dosing: Risperidone 2-3 mg once daily. Dosage adjustments, if indicated, should occur at intervals of not less than 24 hours and in dosage increments/decrements of 1 mg per day.

There are no data to support the use of risperidone in acute response mania for longer than 3 weeks.

Clinical Summary: Risperidone monotherapy was tested in two 3-week placebo-controlled trials with patients meeting DSM-IV criteria for bipolar I disorder who currently displayed an acute manic or mixed episode with or without psychotic features

  • In the first 3-week placebo-controlled trial (n = 246), which was limited to patients with manic episodes and involved a dose range of risperidone 1-6 mg/day, once daily, starting at 3 mg/day (mean modal dose was 4.1 mg/day), risperidone was superior to placebo in the reduction of Y-MRS total score.

  • In the second 3-week placebo-controlled trial (n = 286), which involved a dose range of 1-6 mg/day, once daily, starting at 3 mg/day (mean modal dose was 5.6 mg/day), risperidone was superior to placebo in the reduction of Y-MRS total score.

Risperidone used as part of combination therapy with lithium or valproate was tested in two 3-week, placebo-controlled trials:

  • In the first trial, 148 in- or outpatients on lithium or valproate therapy with inadequately controlled manic or mixed symptoms were randomized to receive risperidone, placebo, or an active comparator, in combination with their original therapy. Risperidone, in a dose range of 1-6 mg/day, once daily, starting at 2 mg/day (mean modal dose of 3.8 mg/day), combined with lithium or valproate (in a therapeutic range of 0.6-1.4 mEq/L or 50-125 mcg/mL, respectively) was superior to lithium or valproate alone in the reduction of Y-MRS total score.

  • In the second trial, 142 in- or outpatients on lithium, valproate, or carbamazepine therapy with inadequately controlled manic or mixed symptoms were randomized to receive risperidone or placebo, in combination with their original therapy. Risperidone, in a dose range of 1-6 mg/day, once daily, starting at 2 mg/day (mean modal dose of 3.7 mg/day), combined with lithium, valproate, or carbamazepine (in therapeutic ranges of 0.6-1.4 mEq/L for lithium, 50-125 mcg/mL for valproate, or 4-12 mcg/mL for carbamazepine, respectively), was not superior to lithium, valproate, or carbamazepine alone in the reduction of Y-MRS total score. A possible explanation for the failure of this trial was induction of risperidone and 9-hydroxy risperidone clearance by carbamazepine, leading to subtherapeutic levels of risperidone and 9-hydroxy risperidone.

Risperdal (risperidone) Labeling

Risperdal (risperidone)

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