ziprasidone (as ziprasidone hydrochloride monohydrate) 40 MG Oral Capsule

Generic Name: ZIPRASIDONE HYDROCHLORIDE
Brand Name: Ziprasidone Hydrochloride
  • Substance Name(s):
  • ZIPRASIDONE HYDROCHLORIDE

DRUG INTERACTIONS

7 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 (7.9) •The full prescribing information contains additional drug interactions (7).

7.1 Metabolic Pathway Approximately two-thirds of ziprasidone is metabolized via reduction by aldehyde oxidase.

There are no known clinically relevant inhibitors or inducers of aldehyde oxidase.

Less than one-third of ziprasidone metabolic clearance is mediated by cytochrome P450 catalyzed oxidation.

7.2 In Vitro Studies An in vitro enzyme inhibition study utilizing human liver microsomes showed that ziprasidone had little inhibitory effect on CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4, and thus would not likely interfere with the metabolism of drugs primarily metabolized by these enzymes.

There is little potential for drug interactions with ziprasidone due to displacement [See Clinical Pharmacology (12.3)].

7.3 Pharmacodynamic Interactions Ziprasidone should not be used with any drug that prolongs the QT interval [See Contraindications (4.1)].

Given the primary CNS effects of ziprasidone, caution should be used when it is taken in combination with other centrally acting drugs.

Because of its potential for inducing hypotension, ziprasidone may enhance the effects of certain antihypertensive agents.

Ziprasidone may antagonize the effects of levodopa and dopamine agonists.

7.4 Pharmacokinetic Interactions • Carbamazepine Carbamazepine is an inducer of CYP3A4; administration of 200 mg twice daily for 21 days resulted in a decrease of approximately 35% in the AUC of ziprasidone.

This effect may be greater when higher doses of carbamazepine are administered.

Ketoconazole Ketoconazole, a potent inhibitor of CYP3A4, at a dose of 400 mg QD for 5 days, increased the AUC and Cmax of ziprasidone by about 35–40%.

Other inhibitors of CYP3A4 would be expected to have similar effects.

• Cimetidine Cimetidine at a dose of 800 mg QD for 2 days did not affect ziprasidone pharmacokinetics.

• Antacid The co-administration of 30 mL of Maalox® with ziprasidone did not affect the pharmacokinetics of ziprasidone.

7.5 Lithium Ziprasidone at a dose of 40 mg twice daily administered concomitantly with lithium at a dose of 450 mg twice daily for 7 days did not affect the steady-state level or renal clearance of lithium.

7.6 Oral Contraceptives In vivo studies have revealed no effect of ziprasidone on the pharmacokinetics of estrogen or progesterone components.

Ziprasidone at a dose of 20 mg twice daily did not affect the pharmacokinetics of concomitantly administered oral contraceptives, ethinyl estradiol (0.03 mg) and levonorgestrel (0.15 mg).

7.7 Dextromethorphan Consistent with in vitro results, a study in normal healthy volunteers showed that ziprasidone did not alter the metabolism of dextromethorphan, a CYP2D6 model substrate, to its major metabolite, dextrorphan.

There was no statistically significant change in the urinary dextromethorphan/dextrorphan ratio.

7.8 Valproate A pharmacokinetic interaction of ziprasidone with valproate is unlikely due to the lack of common metabolic pathways for the two drugs.

7.9 Other Concomitant Drug Therapy Population pharmacokinetic analysis of schizophrenic patients enrolled in controlled clinical trials has not revealed evidence of any clinically significant pharmacokinetic interactions with benztropine, propranolol, or lorazepam.

7.10 Food Interaction The absolute bioavailability of a 20 mg dose under fed conditions is approximately 60%.

The absorption of ziprasidone is increased up to two-fold in the presence of food [see Clinical Pharmacology (12.3)].

OVERDOSAGE

10 10.1 Human Experience In premarketing trials involving more than 5400 patients and/or normal subjects, accidental or intentional overdosage of oral ziprasidone was documented in 10 patients.

All of these patients survived without sequelae.

In the patient taking the largest confirmed amount, 3,240 mg, the only symptoms reported were minimal sedation, slurring of speech, and transitory hypertension (200/95).

Adverse reactions reported with ziprasidone overdose included extrapyramidal symptoms, somnolence, tremor, and anxiety.

[see Adverse Reactions (6.2)] 10.2 Management of Overdosage In case of acute overdosage, establish and maintain an airway and ensure adequate oxygenation and ventilation.

Intravenous access should be established, and gastric lavage (after intubation, if patient is unconscious) and administration of activated charcoal together with a laxative should be considered.

The possibility of obtundation, seizure, or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis.

Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias.

If antiarrhythmic therapy is administered, disopyramide, procainamide, and quinidine carry a theoretical hazard of additive QT-prolonging effects that might be additive to those of ziprasidone.

Hypotension and circulatory collapse should be treated with appropriate measures such as intravenous fluids.

If sympathomimetic agents are used for vascular support, epinephrine and dopamine should not be used, since beta stimulation combined with α1 antagonism associated with ziprasidone may worsen hypotension.

Similarly, it is reasonable to expect that the alpha-adrenergic-blocking properties of bretylium might be additive to those of ziprasidone, resulting in problematic hypotension.

In cases of severe extrapyramidal symptoms, anticholinergic medication should be administered.

There is no specific antidote to ziprasidone, and it is not dialyzable.

The possibility of multiple drug involvement should be considered.

Close medical supervision and monitoring should continue until the patient recovers.

DESCRIPTION

11 Ziprasidone hydrochloride is available as capsules for oral administration.

Ziprasidone is a psychotropic agent that is chemically unrelated to phenothiazine or butyrophenone antipsychotic agents.

It has a molecular weight of 412.94 (free base), with the following chemical name: 5-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one.

The molecular formula of C21H21ClN4OS (free base of ziprasidone) represents the following structural formula: Ziprasidone capsules contain a hydrochloride salt of ziprasidone.

Chemically, ziprasidone hydrochloride monohydrate is 5-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one, hydrochloride.

The molecular formula is C21H21ClN4OS • HCl and its molecular weight is 449.40.

Ziprasidone hydrochloride is a light pink to pink colored powder.

Ziprasidone capsules are supplied for oral administration in 20 mg, 40 mg, 60 mg, and 80 mg capsules.

Ziprasidone hydrochloride capsules contain ziprasidone hydrochloride anhydrous lactose, magnesium stearate, polysorbate 80, povidone (PVK-3), pregelatinized starch and silicon dioxide.

The components of the capsule shell are FD&C Blue #1, FD&C Red #3, gelatin, red iron oxide and titanium dioxide.

The capsule shells are imprinted with black ink.

The components of Black Ink (Black SW-9008/SW-9009) are black iron oxide, butyl alcohol, dehydrated alcohol, isopropyl alcohol, potassium hydroxide, propylene glycol, shellac and strong ammonia solution.

Chemical Structure

CLINICAL STUDIES

14 14.1 Schizophrenia The efficacy of oral ziprasidone in the treatment of schizophrenia was evaluated in 5 placebo-controlled studies, 4 short-term (4- and 6-week) trials and one maintenance trial.

All trials were in adult inpatients, most of whom met DSM III-R criteria for schizophrenia.

Each study included 2 to 3 fixed doses of ziprasidone as well as placebo.

Four of the 5 trials were able to distinguish ziprasidone from placebo; one short-term study did not.

Although a single fixed-dose haloperidol arm was included as a comparative treatment in one of the three short-term trials, this single study was inadequate to provide a reliable and valid comparison of ziprasidone and haloperidol.

Several instruments were used for assessing psychiatric signs and symptoms in these studies.

The Brief Psychiatric Rating Scale (BPRS) and the Positive and Negative Syndrome Scale (PANSS) are both multi-item inventories of general psychopathology usually used to evaluate the effects of drug treatment in schizophrenia.

The BPRS psychosis cluster (conceptual disorganization, hallucinatory behavior, suspiciousness, and unusual thought content) is considered a particularly useful subset for assessing actively psychotic schizophrenic patients.

A second widely used assessment, the Clinical Global Impression (CGI), reflects the impression of a skilled observer, fully familiar with the manifestations of schizophrenia, about the overall clinical state of the patient.

In addition, the Scale for Assessing Negative Symptoms (SANS) was employed for assessing negative symptoms in one trial.

The results of the oral ziprasidone trials in schizophrenia follow: •In a 4-week, placebo-controlled trial (n=139) comparing 2 fixed doses of ziprasidone (20 and 60 mg twice daily) with placebo, only the 60 mg dose was superior to placebo on the BPRS total score and the CGI severity score.

This higher dose group was not superior to placebo on the BPRS psychosis cluster or on the SANS.

•In a 6-week, placebo-controlled trial (n=302) comparing 2 fixed doses of ziprasidone (40 and 80 mg twice daily) with placebo, both dose groups were superior to placebo on the BPRS total score, the BPRS psychosis cluster, the CGI severity score and the PANSS total and negative subscale scores.

Although 80 mg twice daily had a numerically greater effect than 40 mg twice daily, the difference was not statistically significant.

•In a 6-week, placebo-controlled trial (n=419) comparing 3 fixed doses of ziprasidone (20, 60, and 100 mg twice daily) with placebo, all three dose groups were superior to placebo on the PANSS total score, the BPRS total score, the BPRS psychosis cluster, and the CGI severity score.

Only the 100 mg twice daily dose group was superior to placebo on the PANSS negative subscale score.

There was no clear evidence for a dose-response relationship within the 20 mg twice daily to 100 mg twice daily dose range.

•In a 4-week, placebo-controlled trial (n=200) comparing 3 fixed doses of ziprasidone (5, 20, and 40 mg twice daily), none of the dose groups was statistically superior to placebo on any outcome of interest.

•A study was conducted in stable chronic or subchronic (CGI-S ≤5 at baseline) schizophrenic inpatients (n=294) who had been hospitalized for not less than two months.

After a 3-day single-blind placebo run-in, subjects were randomized to one of 3 fixed doses of ziprasidone (20 mg, 40 mg, or 80 mg twice daily) or placebo and observed for relapse.

Patients were observed for “impending psychotic relapse,” defined as CGI-improvement score of ≥6 (much worse or very much worse) and/or scores ≥6 (moderately severe) on the hostility or uncooperativeness items of the PANSS on two consecutive days.

Ziprasidone was significantly superior to placebo in time to relapse, with no significant difference between the different dose groups.

There were insufficient data to examine population subsets based on age and race.

Examination of population subsets based on gender did not reveal any differential responsiveness.

HOW SUPPLIED

16 /STORAGE AND HANDLING Ziprasidone hydrochloride capsules, 20 mg (ziprasidone), are light pink to brown granular powder filled in size “4” hard gelatin capsules having Lavender opaque cap and Flesh opaque body, imprinted “RDY” on cap and “256” on body with black ink, and are supplied in unit dose package of 40 (4×10).

Unit dose package of 40 (4 x 10) NDC 0904-6269-08 Ziprasidone hydrochloride capsules, 40 mg (ziprasidone), are light pink to brown granular filled in size “4” hard gelatin capsules having Lavender opaque cap and LT Turquoise blue opaque body, imprinted “RDY” on cap and “257” on body with black ink, and are supplied in unit dose package of 40 (4×10).

Unit dose package of 40 (4 x 10) NDC 0904-6270-08 Ziprasidone hydrochloride capsules, 60 mg (ziprasidone), are light pink to brown granular powder filled in size “3” hard gelatin capsules having Flesh opaque cap and Flesh opaque body, imprinted “RDY” on cap and “258” on body with black ink, and are supplied in unit dose package of 40 (4×10).

Unit dose package of 40 (4 x 10) NDC 0904-6271-08 Ziprasidone hydrochloride capsules, 80 mg (ziprasidone), are light pink to brown filled in size “2” hard gelatin capsules having LT Turquoise blue opaque cap and Flesh opaque body, imprinted “RDY” on cap and “259” on body with black ink, are supplied in unit dose package of 40 (4×10).

Unit dose package of 40 (4 x 10) NDC 0904-6272-08 Ziprasidone hydrochloride capsules should be stored at 20 – 25°C (68 – 77°F); excursions permitted to 15–30°C (59–86°F) [See USP Controlled Room Temperature].

GERIATRIC USE

8.5 Geriatric Use Of the total number of subjects in clinical studies of ziprasidone, 2.4 percent were 65 and over.

No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Nevertheless, the presence of multiple factors that might increase the pharmacodynamic response to ziprasidone, or cause poorer tolerance or orthostasis, should lead to consideration of a lower starting dose, slower titration, and careful monitoring during the initial dosing period for some elderly patients.

DOSAGE FORMS AND STRENGTHS

3 Ziprasidone hydrochloride capsules, 20 mg (ziprasidone), are light pink to brown granular powder filled in size “4” hard gelatin capsules having Lavender opaque cap and Flesh opaque body, Imprinted “RDY” on cap and “256” on body with black ink.

Ziprasidone hydrochloride capsules, 40 mg (ziprasidone), are light pink to brown granular powder filled in size “4” hard gelatin capsules having Lavender opaque cap and LT Turquoise blue opaque body, Imprinted “RDY” on cap and “257” on body with black ink.

Ziprasidone hydrochloride capsules, 60 mg (ziprasidone), are light pink to brown granular powder filled in size “3” hard gelatin capsules having Flesh opaque cap and Flesh opaque body, Imprinted “RDY” on cap and “258” on body with black ink.

Ziprasidone hydrochloride capsules, 80 mg (ziprasidone), are light pink to brown granular powder filled in size “2” hard gelatin capsules having LT Turquoise blue opaque cap and Flesh opaque body, Imprinted “RDY” on cap and “259” on body with black ink.

•Capsules: 20 mg, 40 mg, 60 mg, and 80 mg (3)

MECHANISM OF ACTION

12.1 Mechanism of Action The mechanism of action of ziprasidone, as with other drugs having efficacy in schizophrenia, is unknown.

However, it has been proposed that this drug’s efficacy in schizophrenia is mediated through a combination of dopamine type 2 (D2) and serotonin type 2 (5HT2) antagonism.

INDICATIONS AND USAGE

1 Ziprasidone hydrochloride capsule is an atypical antipsychotic.

In choosing among treatments, prescribers should be aware of the capacity of ziprasidone hydrochloride capsule to prolong the QT interval and may consider the use of other drugs first (5.2) Ziprasidone is an atypical antipsychotic.

In choosing among treatments, prescribers should be aware of the capacity of ziprasidone to prolong the QT interval and may consider the use of other drugs first (5.2) Ziprasidone is indicated as an oral formulation for the: Treatment of schizophrenia.

(1.1) •Adults: Efficacy was established in four 4–6 week trials and one maintenance trial in adult patients with schizophrenia (14.1) Acute treatment as monotherapy of manic or mixed episodes associated with bipolar I disorder (1.2) •Adults: Efficacy was established in two 3-week trials in adult patients with manic or mixed episodes.

(14.2) Maintenance treatment of bipolar I disorder as an adjunct to lithium or valproate.

(1.2) •Adults: Efficacy was established in one maintenance trial in adult patients.

(14.2) 1.1 Schizophrenia Ziprasidone hydrochloride capsule is indicated as an oral formulation for the treatment of schizophrenia.

(1.1) Adults: Efficacy was established in 4 to 6 week trials and one maintenance trial in adult patients with schizophrenia (14.1)

PEDIATRIC USE

8.4 Pediatric Use The safety and effectiveness of ziprasidone in pediatric patients have not been established.

PREGNANCY

8.1 Pregnancy Pregnancy Category C In animal studies ziprasidone demonstrated developmental toxicity, including possible teratogenic effects at doses similar to human therapeutic doses.

When ziprasidone was administered to pregnant rabbits during the period of organogenesis, an increased incidence of fetal structural abnormalities (ventricular septal defects and other cardiovascular malformations and kidney alterations) was observed at a dose of 30 mg/kg/day (3 times the MRHD of 200 mg/day on a mg/m2 basis).

There was no evidence to suggest that these developmental effects were secondary to maternal toxicity.

The developmental no-effect dose was 10 mg/kg/day (equivalent to the MRHD on a mg/m2 basis).

In rats, embryofetal toxicity (decreased fetal weights, delayed skeletal ossification) was observed following administration of 10 to 160 mg/kg/day (0.5 to 8 times the MRHD on a mg/m2 basis) during organogenesis or throughout gestation, but there was no evidence of teratogenicity.

Doses of 40 and 160 mg/kg/day (2 and 8 times the MRHD on a mg/m2 basis) were associated with maternal toxicity.

The developmental no-effect dose was 5 mg/kg/day (0.2 times the MRHD on a mg/m2 basis).

There was an increase in the number of pups born dead and a decrease in postnatal survival through the first 4 days of lactation among the offspring of female rats treated during gestation and lactation with doses of 10 mg/kg/day (0.5 times the MRHD on a mg/m2 basis) or greater.

Offspring developmental delays and neurobehavioral functional impairment were observed at doses of 5 mg/kg/day (0.2 times the MRHD on a mg/m2 basis) or greater.

A no-effect level was not established for these effects.

There are no adequate and well-controlled studies in pregnant women.

Ziprasidone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Non-teratogenic Effects Neonates exposed to antipsychotic drugs, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery.

There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates.

These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization.

Ziprasidone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

NUSRING MOTHERS

8.3 Nursing Mothers It is not known whether ziprasidone or its metabolites are excreted in human milk.

It is recommended that women receiving ziprasidone should not breastfeed.

BOXED WARNING

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS See full prescribing information for complete boxed warning Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death compared to placebo treatment (5.1).

Ziprasidone is not approved for elderly patients with Dementia-Related Psychosis (5.1) WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS See full prescribing information for complete boxed warning • Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death compared to placebo treatment (5.1) • Ziprasidone is not approved for elderly patients with dementia-related psychosis (5.1)

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS • QT Interval Prolongation: Ziprasidone 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 (5.2) • Neuroleptic Malignant Syndrome (NMS): Potentially fatal symptom complex has been reported with antipsychotic drugs.

Manage with immediate discontinuation of drug and close monitoring.

(5.3) • Tardive Dyskinesia: May develop acutely or chronically (5.4) • Hyperglycemia and Diabetes Mellitus (DM): Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness.

When starting treatment, patients with DM risk factors should undergo blood glucose testing before and during treatment (5.5) • Rash: Discontinue in patients who develop a rash without an identified cause (5.6) • Orthostatic Hypotension: Use with caution in patients with known cardiovascular or cerebrovascular disease (5.7) • 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 at the first sign of a decline in WBC in the absence of other causative factors.(5.8) • Seizures: Use cautiously in patients with a history of seizures or with conditions that lower seizure threshold (5.9) • Potential for Cognitive and Motor impairment: Patients should use caution when operating machinery (5.12) • Suicide: Closely supervise high-risk patients (5.15) 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.

Ziprasidone is not approved for the treatment of dementia-related psychosis.

[see Boxed Warning] 5.2 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), 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.

In the second phase of the study, the effect of ziprasidone on QTc length was not augmented by the presence of a metabolic inhibitor (ketoconazole 200 mg twice daily).

In placebo-controlled trials, oral ziprasidone increased the QTc interval compared to placebo by approximately 10 msec at the highest recommended daily dose of 160 mg.

In clinical trials with oral ziprasidone, the electrocardiograms of 2/2988 (0.06%) patients who received ziprasidone and 1/440 (0.23%) patients who received placebo revealed QTc intervals exceeding the potentially clinically relevant threshold of 500 msec.

In the ziprasidone-treated patients, neither case suggested a role of ziprasidone.

One patient had a history of prolonged QTc and a screening measurement of 489 msec; QTc was 503 msec during ziprasidone treatment.

The other patient had a QTc of 391 msec at the end of treatment with ziprasidone and upon switching to thioridazine experienced QTc measurements of 518 and 593 msec.

Some drugs that prolong the QT/QTc interval have been associated with the occurrence of torsade de pointes and with sudden unexplained death.

The relationship of QT prolongation to torsade de pointes is clearest for larger increases (20 msec and greater) but it is possible that smaller QT/QTc prolongations may also increase risk, or increase it in susceptible individuals.

Although torsade de pointes has not been observed in association with the use of ziprasidone in premarketing studies and experience is too limited to rule out an increased risk, there have been rare post-marketing reports (in the presence of multiple confounding factors) [see Adverse Reactions (6.2)].

As with other antipsychotic drugs and placebo, sudden unexplained deaths have been reported in patients taking ziprasidone at recommended doses.

The premarketing experience for ziprasidone did not reveal an excess risk of mortality for ziprasidone compared to other antipsychotic drugs or placebo, but the extent of exposure was limited, especially for the drugs used as active controls and placebo.

Nevertheless, ziprasidone’s larger prolongation of QTc length compared to several other antipsychotic drugs raises the possibility that the risk of sudden death may be greater for ziprasidone than for other available drugs for treating schizophrenia.

This possibility needs to be considered in deciding among alternative drug products [see Indications and Usage (1)].

Certain circumstances may increase the risk of the occurrence of torsade de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval, including (1) bradycardia; (2) hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that prolong the QTc interval; and (4) presence of congenital prolongation of the QT interval.

It is recommended that patients being considered for ziprasidone treatment who are at risk for significant electrolyte disturbances, hypokalemia in particular, have baseline serum potassium and magnesium measurements.

Hypokalemia (and/or hypomagnesemia) may increase the risk of QT prolongation and arrhythmia.

Hypokalemia may result from diuretic therapy, diarrhea, and other causes.

Patients with low serum potassium and/or magnesium should be repleted with those electrolytes before proceeding with treatment.

It is essential to periodically monitor serum electrolytes in patients for whom diuretic therapy is introduced during ziprasidone treatment.

Persistently prolonged QTc intervals may also increase the risk of further prolongation and arrhythmia, but it is not clear that routine screening ECG measures are effective in detecting such patients.

Rather, ziprasidone should be avoided in patients with histories of significant cardiovascular illness, e.g., QT prolongation, recent acute myocardial infarction, uncompensated heart failure, or cardiac arrhythmia.

Ziprasidone should be discontinued in patients who are found to have persistent QTc measurements >500 msec.

For patients taking ziprasidone who experience symptoms that could indicate the occurrence of torsade de pointes, e.g., dizziness, palpitations, or syncope, the prescriber should initiate further evaluation, e.g., Holter monitoring may be useful.

5.3 Neuroleptic Malignant Syndrome (NMS) A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs.

Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia).

Additional signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

The diagnostic evaluation of patients with this syndrome is complicated.

In arriving at a diagnosis, it is important to exclude cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS).

Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system (CNS) pathology.

The management of NMS should include: (1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; (2) intensive symptomatic treatment and medical monitoring; and (3) treatment of any concomitant serious medical problems for which specific treatments are available.

There is no general agreement about specific pharmacological treatment regimens for NMS.

If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered.

The patient should be carefully monitored, since recurrences of NMS have been reported.

5.4 Tardive Dyskinesia A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients undergoing treatment with antipsychotic drugs.

Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome.

Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.

The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase.

However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses.

There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn.

Antipsychotic treatment itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome, and thereby may possibly mask the underlying process.

The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

Given these considerations, ziprasidone should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia.

Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that (1) is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate.

In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought.

The need for continued treatment should be reassessed periodically.

If signs and symptoms of tardive dyskinesia appear in a patient on ziprasidone, drug discontinuation should be considered.

However, some patients may require treatment with ziprasidone despite the presence of the syndrome.

5.5 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.

There have been few reports of hyperglycemia or diabetes in patients treated with ziprasidone.

Although fewer patients have been treated with ziprasidone, it is not known if this more limited experience is the sole reason for the paucity of such reports.

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 reactions is not completely understood.

However, epidemiological studies, which did not include ziprasidone, suggest an increased risk of treatment-emergent hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics included in these studies.

Because ziprasidone was not marketed at the time these studies were performed, it is not known if ziprasidone is associated with this increased risk.

Precise risk estimates for hyperglycemia-related adverse reactions 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 (e.g., 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.

5.6 Rash In premarketing trials with ziprasidone, about 5% of patients developed rash and/or urticaria, with discontinuation of treatment in about one-sixth of these cases.

The occurrence of rash was related to dose of ziprasidone, although the finding might also be explained by the longer exposure time in the higher dose patients.

Several patients with rash had signs and symptoms of associated systemic illness, e.g., elevated WBCs.

Most patients improved promptly with adjunctive treatment with antihistamines or steroids and/or upon discontinuation of ziprasidone, and all patients experiencing these reactions were reported to recover completely.

Upon appearance of rash for which an alternative etiology cannot be identified, ziprasidone should be discontinued.

5.7 Orthostatic Hypotension Ziprasidone may induce orthostatic hypotension associated with dizziness, tachycardia, and, in some patients, syncope, especially during the initial dose-titration period, probably reflecting its α1-adrenergic antagonist properties.

Syncope was reported in 0.6% of the patients treated with ziprasidone.

Ziprasidone should be used with particular caution in patients with known cardiovascular disease (history of myocardial infarction or ischemic heart disease, heart failure or conduction abnormalities), cerebrovascular disease, or conditions which would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medications).

5.8 Leukopenia, Neutropenia, and Agranulocytosis In clinical trial and postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic age-nts.

Agranulocytosis (including fatal cases) has also been reported.

Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug induced leukopenia/neutropenia.

Patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and should discontinue ziprasidone at the first sign of decline in WBC in the absence of other causative factors.

Patients with neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur.

Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue ziprasidone and have their WBC followed until recovery.

5.9 Seizures During clinical trials, seizures occurred in 0.4% of patients treated with ziprasidone.

There were confounding factors that may have contributed to the occurrence of seizures in many of these cases.

As with other antipsychotic drugs, ziprasidone should be used cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold, e.g., Alzheimer’s dementia.

Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older.

5.10 Dysphagia Esophageal dysmotility and aspiration have been associated with antipsychotic drug use.

Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with advanced Alzheimer’s dementia.

Ziprasidone and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia [see Boxed Warning].

5.11 Hyperprolactinemia As with other drugs that antagonize dopamine D2 receptors, ziprasidone elevates prolactin levels in humans.

Increased prolactin levels were also observed in animal studies with this compound, and were associated with an increase in mammary gland neoplasia in mice; a similar effect was not observed in rats [see Nonclinical Toxicology (13.1)].

Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin-dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with previously detected breast cancer.

Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported with prolactin-elevating compounds, the clinical significance of elevated serum prolactin levels is unknown for most patients.

Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans; the available evidence is considered too limited to be conclusive at this time.

5.12 Potential for Cognitive and Motor Impairment Somnolence was a commonly reported adverse reaction in patients treated with ziprasidone.

In the 4- and 6-week placebo-controlled trials, somnolence was reported in 14% of patients on ziprasidone compared to 7% of placebo patients.

Somnolence led to discontinuation in 0.3% of patients in short-term clinical trials.

Since ziprasidone has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about performing activities requiring mental alertness, such as operating a motor vehicle (including automobiles) or operating hazardous machinery until they are reasonably certain that ziprasidone therapy does not affect them adversely.

5.13 Priapism One case of priapism was reported in the premarketing database.

While the relationship of the reaction to ziprasidone use has not been established, other drugs with alpha-adrenergic blocking effects have been reported to induce priapism, and it is possible that ziprasidone may share this capacity.

Severe priapism may require surgical intervention.

5.14 Body Temperature Regulation Although not reported with ziprasidone in premarketing trials, disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic agents.

Appropriate care is advised when prescribing ziprasidone for patients who will be experiencing conditions which may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration.

5.15 Suicide The possibility of a suicide attempt is inherent in psychotic illness or bipolar disorder, and close supervision of high-risk patients should accompany drug therapy.

Prescriptions for ziprasidone should be written for the smallest quantity of capsules consistent with good patient management in order to reduce the risk of overdose.

5.16 Patients with concomitant illnesses Clinical experience with ziprasidone in patients with certain concomitant systemic illnesses is limited [see Use in Specific Populations (8.6),( 8.7)] Ziprasidone has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease.

Patients with these diagnoses were excluded from premarketing clinical studies.

Because of the risk of QTc prolongation and orthostatic hypotension with ziprasidone, caution should be observed in cardiac patients [see Warnings and Precautions (5.2), (5.7)] 5.17 Laboratory Tests Patients being considered for ziprasidone treatment that are at risk of significant electrolyte disturbances should have baseline serum potassium and magnesium measurements.

Low serum potassium and magnesium should be replaced before proceeding with treatment.

Patients who are started on diuretics during ziprasidone therapy need periodic monitoring of serum potassium and magnesium.

Ziprasidone should be discontinued in patients who are found to have persistent QTc measurements >500 msec.

[see Warnings and Precautions (5.2)]

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling (17.3) .

Please refer to the patient package insert.

To assure safe and effective use of ziprasidone, the information and instructions provided in the patient information should be discussed with patients.

17.1 Administration with Food Patients should be instructed to take ziprasidone hydrochloride capsules with food for optimal absorption.

The absorption of ziprasidone is increased up to two-fold in the presence of food [see Drug Interactions (7.8) and Clinical Pharmacology (12.3)].

17.2 QTc Prolongation Patients should be advised to inform their health care providers of the following: History of QT prolongation; recent acute myocardial infarction; uncompensated heart failure; prescription of other drugs that have demonstrated QT prolongation; risk for significant electrolyte abnormalities; and history of cardiac arrhythmia [see Contraindications (4.1) and Warnings and Precautions (5.2)].

Patients should be instructed to report the onset of any conditions that put them at risk for significant electrolyte disturbances, hypokalemia in particular, including but not limited to the initiation of diuretic therapy or prolonged diarrhea.

In addition, patients should be instructed to report symptoms such as dizziness, palpitations, or syncope to the prescriber [see Warnings and Precautions (5.2)].

17.3 FDA-Approved Patient Labeling

DOSAGE AND ADMINISTRATION

2 Give oral doses with food.

•Schizophrenia: Initiate at 20 mg twice daily.

Daily dosage may be adjusted up to 80 mg twice daily.

Dose adjustments should occur at intervals of not less than 2 days.

Safety and efficacy has been demonstrated in doses up to 100 mg twice daily.

The lowest effective dose should be used.

(2.1) •Acute treatment of manic/mixed episodes of bipolar I disorder: Initiate at 40 mg twice daily.

Increase to 60 mg or 80 mg twice daily on day 2 of treatment.

Subsequent dose adjustments should be based on tolerability and efficacy within the range of 40–80 mg twice daily.

(2.2) •Maintenance treatment of bipolar I disorder as an adjunct to lithium or valproate: Continue treatment at the same dose on which the patient was initially stabilized, within the range of 40–80 mg twice daily.

(2.2) 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.

[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.

2.3 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.