Ziprasidone: uses, appearance and warnings

Ziprasidone capsules are indicated for the treatment of schizophrenia, as monotherapy for the acute treatment of bipolar manic or mixed episodes, and as an adjunct to lithium or valproate for the maintenance treatment of bipolar disorder. 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 ( 5.3 ) ]. 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 ( 5.3 ) ]. Schizophrenia Ziprasidone capsules are indicated for the treatment of schizophrenia in adults [see Clinical Studies ( 14.1 )]. Bipolar I Disorder (Acute Mixed or Manic Episodes and Maintenance Treatment as an Adjunct to Lithium or Valproate) Ziprasidone capsules are indicated as monotherapy for the acute treatment of adults with manic or mixed episodes associated with bipolar I disorder [see Clinical Studies ( 14.2 )]. Ziprasidone capsules are indicated as an adjunct to lithium or valproate for the maintenance treatment of bipolar I disorder in adults [see Clinical Studies ( 14.2 )]. Ziprasidone capsules are an atypical antipsychotic. In choosing among treatments, prescribers should be aware of the capacity of ziprasidone capsules to prolong the QT interval and may consider the use of other drugs first. ( 1 ) Ziprasidone capsules are indicated for the: treatment of schizophrenia in adults. ( 1 ) acute treatment of adults as monotherapy of manic or mixed episodes associated with bipolar I disorder. ( 1 ) maintenance treatment of bipolar I disorder as an adjunct to lithium or valproate in adults. ( 1 )

Ziprasidone capsules, USP are differentiated by capsule color/size and are imprinted in black ink with “APO ZIP” and a unique number. Ziprasidone capsules, USP are supplied for oral administration in 20 mg (purple/white), 40 mg (purple/purple), 60 mg (white/white), and 80 mg (purple/white) capsules. They are supplied in the following strengths and package configurations: Ziprasidone Capsules, USP Capsule Strength (mg) Imprint 20 APO ZIP 20 40 APO ZIP 40 60 APO ZIP 60 80 APO ZIP 80 Capsules: 20 mg, 40 mg, 60 mg, and 80 mg ( 3 )

Ziprasidone capsules, USP are differentiated by capsule color/size and are imprinted in black ink with “APO ZIP” and a unique number. Ziprasidone capsules, USP are supplied for oral administration in 20 mg (purple/white), 40 mg (purple/purple), 60 mg (white/white), and 80 mg (purple/white) capsules. They are supplied in the following strengths and package configurations: Ziprasidone Capsules Package Configuration Capsule Strength (mg) NDC (National Drug Code) Imprint Bottles of 60 20 NDC-60505-2528-6 APO ZIP 20 Bottles of 60 40 NDC-60505-2529-6 APO ZIP 40 Bottles of 60 60 NDC-60505-2530-6 APO ZIP 60 Bottles of 60 80 NDC-60505-2531-6 APO ZIP 80 Store at 20°C to 25°C (68°F to 77°F); excursions permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Dispense in a tight, light-resistant container [see USP].

Do not use in patients with a known history of QT prolongation ( 4.1 ) Do not use in patients with recent acute myocardial infarction ( 4.1 ) Do not use in patients with uncompensated heart failure ( 4.1 ) Do not use in combination with other drugs that have demonstrated QT prolongation ( 4.1 ) Do not use in patients with known hypersensitivity to ziprasidone ( 4.2 ) Concomitant use of monoamine oxidase inhibitors (MAOIs), or use within 14 days of stopping MAOIs. ( 4.3 ) 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 (5.3) ] . 4.2 Hypersensitivity Ziprasidone is contraindicated in individuals with a known hypersensitivity to the product. …

Cerebrovascular Adverse Reactions in Elderly Patients with Dementia- Related Psychosis: Increased incidence of cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack). ( 5.2 ) QT Interval Prolongation : Ziprasidone capsules use should be avoided in patients with bradycardia, hypokalemia or hypomagnesemia, congenital prolongation of the QT interval, or in combination with other drugs that have demonstrated QT prolongation. ( 5.3 ) Serotonin Syndrome: Increased risk when co-administered with other serotonergic agents, but also when taken alone. If it occurs, discontinue ziprasidone and serotonergic agents and initiate supportive treatment. ( 5.4 ) Neuroleptic Malignant Syndrome (NMS): Potentially fatal symptom complex has been reported with antipsychotic drugs. Manage with immediate discontinuation of drug and close monitoring. ( 5.5 ) Severe Cutaneous Adverse Reactions, such as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) and Stevens-Johnson syndrome has been reported with ziprasidone exposure. DRESS and other Severe Cutaneous Adverse Reactions (SCAR) are sometimes fatal. Discontinue ziprasidone capsules if DRESS or SCAR are suspected. ( 5.6 ) Tardive Dyskinesia : May develop acutely or chronically. ( 5.7 ) Metabolic Changes : Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/ cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and weight gain. ( 5.8 ) Hyperglycemia and Diabetes Mellitus (DM): Monitor all patients for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients with DM risk factors should undergo blood glucose testing before and during treatment. ( 5.8 ) Dyslipidemia : Undesirable alterations have been observed in patients treated with atypical antipsychotics. ( 5.8 ) Weight Gain : Weight gain has been reported. Monitor weight gain. ( 5.8 ) Rash : Discontinue in patients who develop a rash without an identified cause. ( 5.9 ) Orthostatic Hypotension : Use with caution in patients with known cardiovascular or cerebrovascular disease. ( 5.10 ) Leukopenia, Neutropenia, and Agranulocytosis has been reported with antipsychotics. Patients with a pre-existing low white blood cell count (WBC) or a history of leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and should discontinue ziprasidone capsules at the first sign of a decline in WBC in the absence of other causative factors. ( 5.12 ) Seizures : Use cautiously in patients with a history of seizures or with conditions that lower seizure threshold. ( 5.13 ) Potential for Cognitive and Motor Impairment: Patients should use caution when operating machinery. ( 5.16 ) Suicide: Closely supervise high-risk patients. ( 5.19 ) 5.1 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. Ziprasidone capsules are not approved for the treatment of patients with dementia-related psychosis. [see Boxed Warning , Warnings and Precautions ( 5.2 )]. 5.2 Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis In placebo-controlled trials in elderly subjects with dementia, patients randomized to risperidone, aripiprazole, and olanzapine had a higher incidence of stroke and transient ischemic attack, including fatal stroke. Ziprasidone capsules are not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions ( 5.1 )]. 5.3 QT Prolongation and Risk of Sudden Death Ziprasidone use should be avoided in combination with other drugs that are known to prolong the QTc interval [see Contraindications (4.1) and Drug Interactions (7.4) ] . Additionally, clinicians should be alert to the identification of other drugs that have been consistently observed to prolong the QTc interval. Such drugs should not be prescribed with ziprasidone. Ziprasidone should also be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias [see Contraindications (4) ]. A study directly comparing the QT/QTc prolonging effect of oral ziprasidone with several other drugs effective in the treatment of schizophrenia was conducted in patient volunteers. In the first phase of the trial, ECGs were obtained at the time of maximum plasma concentration when the drug was administered alone. In the second phase of the trial, ECGs were obtained at the time of maximum plasma concentration while the drug was co-administered with an inhibitor of the CYP4503A4 metabolism of the drug. In the first phase of the study, the mean change in QTc from baseline was calculated for each drug, using a sample-based correction that removes the effect of heart rate on the QT interval. The mean increase in QTc from baseline for ziprasidone ranged from approximately 9 to 14 msec greater than for four of the comparator drugs (risperidone, olanzapine, quetiapine, and haloperidol), but was approximately 14 msec less than the prolongation observed for thioridazine. …

The following adverse reactions are described in more detail in other sections of the prescribing information: Increased Mortality in Elderly Patients with Dementia-Related Psychosis [see Boxed Warning and Warnings and Precautions ( 5.1 )] Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis [see Warnings and Precautions ( 5.2 )] QT Prolongation and Risk of Sudden Death [see Contraindications ( 4.2 ), Warnings and Precautions ( 5.3 )] Serotonin Syndrome [see Contraindications ( 4.3 ), Warnings and Precautions ( 5.4 ), Drug Interactions ( 7.1 )] Neuroleptic Malignant Syndrome (NMS) [see Warnings and Precautions ( 5.5 )] Severe Cutaneous Adverse Reactions [see Warnings and Precautions ( 5.6 )] Tardive Dyskinesia [see Warnings and Precautions ( 5.7 )] Metabolic Changes [see Warnings and Precautions ( 5.8 )] Rash [see Warnings and Precautio …

Drug-drug interactions can be pharmacodynamic (combined pharmacologic effects) or pharmacokinetic (alteration of plasma levels). The risks of using ziprasidone in combination with other drugs have been evaluated as described below. All interactions studies have been conducted with oral ziprasidone. Based upon the pharmacodynamic and pharmacokinetic profile of ziprasidone, possible interactions could be anticipated: Ziprasidone should not be used in combination with other drugs that have demonstrated QT prolongation. ( 4.1 , 7.3 ) The absorption of ziprasidone is increased up to two-fold in the presence of food. ( 7.10 ) The full prescribing information contains additional drug interactions. ( 7 ). 7.1 Metabolic Pathway Approximately two-thirds of ziprasidone is metabolized via a combination of chemical reduction by glutathione and enzymatic reduction by aldehyde oxidase. …