Ziprasidone Hydrochloride

ZIPRASIDONE HYDROCHLORIDE- ziprasidone hydrochloride capsule
Mylan Institutional Inc.

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. Ziprasidone is not approved for the treatment of patients with Dementia-Related Psychosis [see Warnings and Precautions (5.1)] .

1 INDICATIONS AND USAGE

Ziprasidone hydrochloride capsules are indicated for the treatment of schizophrenia. When deciding among the alternative treatments available for the condition needing treatment, the prescriber should consider the finding of ziprasidone’s greater capacity to prolong the QT/QTc interval compared to several other antipsychotic drugs [see Warnings and Precautions (5.2)]. Prolongation of the QTc interval is associated in some other drugs with the ability to cause torsade de pointes type arrhythmia, a potentially fatal polymorphic ventricular tachycardia, and sudden death. In many cases this would lead to the conclusion that other drugs should be tried first. Whether ziprasidone will cause torsade de pointes or increase the rate of sudden death is not yet known [see Warnings and Precautions (5.2)].

1.1 Schizophrenia

Ziprasidone hydrochloride capsules are indicated for the treatment of schizophrenia. The efficacy of oral ziprasidone was established in four short-term (4- and 6-week) controlled trials of adult schizophrenic inpatients and in one maintenance trial of stable adult schizophrenic inpatients [see Clinical Studies (14.1)].

2 DOSAGE AND ADMINISTRATION

2.1 Schizophrenia

Dose Selection

Ziprasidone hydrochloride capsules should be administered at an initial daily dose of 20 mg twice daily with food. In some patients, daily dosage may subsequently be adjusted on the basis of individual clinical status up to 80 mg twice daily. Dosage adjustments, if indicated, should generally occur at intervals of not less than 2 days, as steady-state is achieved within 1 to 3 days. In order to ensure use of the lowest effective dose, patients should ordinarily be observed for improvement for several weeks before upward dosage adjustment.

Efficacy in schizophrenia was demonstrated in a dose range of 20 mg to 100 mg twice daily in short-term, placebo-controlled clinical trials. There were trends toward dose response within the range of 20 mg to 80 mg twice daily, but results were not consistent. An increase to a dose greater than 80 mg twice daily is not generally recommended. The safety of doses above 100 mg twice daily has not been systematically evaluated in clinical trials [see Clinical Studies (14.1)].

Maintenance Treatment

While there is no body of evidence available to answer the question of how long a patient treated with ziprasidone should remain on it, a maintenance study in patients who had been symptomatically stable and then randomized to continue ziprasidone or switch to placebo demonstrated a delay in time to relapse for patients receiving ziprasidone hydrochloride capsules [see Clinical Studies (14.1)]. No additional benefit was demonstrated for doses above 20 mg twice daily. Patients should be periodically reassessed to determine the need for maintenance treatment.

2.4 Dosing in Special Populations

Oral

Dosage adjustments are generally not required on the basis of age, gender, race, or renal or hepatic impairment. Ziprasidone hydrochloride capsules are not approved for use in children or adolescents.

3 DOSAGE FORMS AND STRENGTHS

Ziprasidone Hydrochloride Capsules are available containing ziprasidone hydrochloride monohydrate equivalent to 20 mg, 40 mg, 60 mg or 80 mg of ziprasidone.

The 20 mg capsule is a hard-shell gelatin capsule with a blue opaque cap and white opaque body axially printed with MYLAN over ZE 20 in black ink on both the cap and the body. It is filled with slightly pink colored powder.

The 40 mg capsule is a hard-shell gelatin capsule with a blue opaque cap and blue opaque body axially printed with MYLAN over ZE 40 in black ink on both the cap and the body. It is filled with slightly pink colored powder.

The 60 mg capsule is a hard-shell gelatin capsule with a white opaque cap and white opaque body axially printed with MYLAN over ZE 60 in black ink on both the cap and the body. It is filled with slightly pink colored powder.

The 80 mg capsule is a hard-shell gelatin capsule with a blue opaque cap and white opaque body axially printed with MYLAN over ZE 80 in black ink on both the cap and the body. It is filled with slightly pink colored powder.

4 CONTRAINDICATIONS

4.1 QT Prolongation

Because of ziprasidone’s dose-related prolongation of the QT interval and the known association of fatal arrhythmias with QT prolongation by some other drugs, ziprasidone is contraindicated:

  • in patients with a known history of QT prolongation (including congenital long QT syndrome)
  • in patients with recent acute myocardial infarction
  • in patients with uncompensated heart failure

Pharmacokinetic/pharmacodynamic studies between ziprasidone and other drugs that prolong the QT interval have not been performed. An additive effect of ziprasidone and other drugs that prolong the QT interval cannot be excluded. Therefore, ziprasidone should not be given with:

  • dofetilide, sotalol, quinidine, other Class Ia and III anti-arrhythmics, mesoridazine, thioridazine, chlorpromazine, droperidol, pimozide, sparfloxacin, gatifloxacin, moxifloxacin, halofantrine, mefloquine, pentamidine, arsenic trioxide, levomethadyl acetate, dolasetron mesylate, probucol or tacrolimus.
  • other drugs that have demonstrated QT prolongation as one of their pharmacodynamic effects and have this effect described in the full prescribing information as a contraindication or a boxed or bolded warning [see Warnings and Precautions (5.2)].

4.2 Hypersensitivity

Ziprasidone is contraindicated in individuals with a known hypersensitivity to the product.

5 WARNINGS AND PRECAUTIONS

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