ZIPRASIDONE MESYLATE
Clinical safety rating: safe
Other drugs that prolong the QT interval are contraindicated Can cause QT prolongation and rash.
Ziprasidone mesylate is an atypical antipsychotic with high affinity for serotonin 5-HT2A and dopamine D2 receptors. It also antagonizes 5-HT1D, 5-HT2C, and alpha1-adrenergic receptors, and inhibits serotonin and norepinephrine reuptake.
| Metabolism | Primarily metabolized via aldehyde oxidase (AO); minor pathways include CYP3A4 and CYP1A2. Less than 1/3 of metabolism is mediated by cytochrome P450 enzymes. |
| Excretion | Approximately 20% renal, 80% fecal/biliary. Unchanged drug accounts for <1% of renal excretion. |
| Half-life | Terminal elimination half-life is approximately 2.2 hours (range 1.4–3.6 h) for the mesylate salt; clinical context: requires twice-daily dosing. |
| Protein binding | >99% bound to albumin and alpha1-acid glycoprotein. |
| Volume of Distribution | Approximately 1.5 L/kg (range 1.0–2.0 L/kg); reflects extensive tissue distribution. |
| Bioavailability | Oral: approximately 60% (with food increases absorption); intramuscular: 100%. |
| Onset of Action | Intramuscular: 15–30 minutes; oral: 1–3 hours. |
| Duration of Action | Intramuscular: 2–4 hours; oral: 12 hours (supports twice-daily dosing for maintenance). |
| Molecular Weight | 412.94 |
20 mg intramuscularly (IM) as needed, not to exceed 40 mg/day; oral: 20 mg twice daily with food, titrated up to 80 mg twice daily. Maximum: 160 mg/day oral.
| Dosage form | POWDER |
| Renal impairment | No adjustment required for mild to moderate renal impairment (CrCl >10 mL/min). Not studied in severe impairment (CrCl <10 mL/min); use caution. |
| Liver impairment | No adjustment required for mild to moderate hepatic impairment (Child-Pugh A or B). Not recommended in severe impairment (Child-Pugh C) due to lack of data. |
| Pediatric use | Not FDA-approved for patients <18 years. Off-label for bipolar disorder: initial 20 mg twice daily, titrate to 40-80 mg twice daily. Weight-based: 0.2-0.8 mg/kg/day in divided doses; maximum 160 mg/day. |
| Geriatric use | Initiate at 20 mg twice daily orally; titrate slowly. Monitor for orthostatic hypotension, sedation, and QT prolongation. Lower initial doses and slower titration recommended. |
| 1st trimester | Limited human data; animal studies show fetal toxicity at high doses. Use only if potential benefit justifies risk. |
| 2nd trimester | Limited human data; may cause extrapyramidal symptoms and/or withdrawal in neonates. Consider risk-benefit. |
| 3rd trimester | Neonates exposed during third trimester are at risk for extrapyramidal symptoms and/or withdrawal after delivery. Use only if clearly needed. |
Clinical note
Other drugs that prolong the QT interval are contraindicated Can cause QT prolongation and rash.
| FDA category | Animal |
| Placental transfer | Ziprasidone crosses the placenta in animal studies; human data limited but expected to cross due to molecular weight and lipophilicity. |
| Breastfeeding |
■ FDA Black Box Warning
Increased mortality in elderly patients with dementia-related psychosis. Ziprasidone is not approved for the treatment of dementia-related psychosis.
| Common Effects | bipolar disorder |
| Serious Effects |
QT prolongation (QTc >450 msec)Recent myocardial infarctionUncompensated heart failureConcurrent use with drugs that prolong QT intervalKnown hypersensitivity to ziprasidone
| Precautions | QT prolongation: Avoid in patients with risk factors (e.g., electrolyte disturbances, concurrent QT-prolonging drugs, bradycardia, congenital long QT syndrome)., Neuroleptic malignant syndrome (NMS): Discontinue if signs/symptoms appear., Tardive dyskinesia: Discontinue if clinically appropriate., Hyperglycemia: Monitor blood glucose in patients with diabetes or risk factors., Orthostatic hypotension: Use cautiously in patients with cardiovascular disease., Seizures: Use cautiously in patients with history of seizures., Priapism: Rarely reported; seek medical attention if prolonged erection occurs., Suicide risk: Monitor for worsening depression or suicidal ideation. |
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| Ziprasidone is excreted into human breast milk in small amounts. Monitor infant for sedation, feeding difficulties, and weight gain. Consider risks versus benefits. |
| Lactation Rating | L3 (Moderately Safe) |
| Teratogenic Risk | First trimester: Limited human data; animal studies show no teratogenicity at clinically relevant doses. Second and third trimesters: Risk of extrapyramidal symptoms and/or withdrawal in neonates following exposure. Atypical antipsychotics may cause abnormal muscle movements and agitation in newborns. |
| Fetal Monitoring | Maternal: Monitor weight, blood glucose, lipid profile, and blood pressure; assess for extrapyramidal symptoms and QTc prolongation. Fetal/neonatal: Monitor for extrapyramidal symptoms, sedation, and withdrawal after delivery. |
| Fertility Effects | Ziprasidone may increase prolactin levels, potentially causing menstrual irregularities, galactorrhea, and reduced fertility. Return to baseline after discontinuation. |
| Food/Dietary | Take with a meal of at least 500 kcal; grapefruit juice may reduce absorption; avoid alcohol. |
| Clinical Pearls | Administer with food (≥500 kcal) to increase absorption by ~100%. QT prolongation risk is dose-related; avoid in patients with QTc >450 msec or with drugs that prolong QTc. Monitor for tardive dyskinesia, neuroleptic malignant syndrome, and metabolic changes (weight, lipids, glucose). IM formulation for acute agitation. |
| Patient Advice | Take this medication exactly as prescribed with a meal of at least 500 calories (e.g., a sandwich and milk) to ensure proper absorption. · Avoid alcohol and grapefruit juice while taking this medication. · Do not drive or operate heavy machinery until you know how this medication affects you; it may cause drowsiness or dizziness. · Report any irregular heartbeat, fainting, or severe dizziness immediately to your doctor. · Seek emergency help if you experience muscle stiffness, fever, confusion, or unusual movements of the face or tongue. · Do not stop taking this medication abruptly without consulting your doctor; sudden discontinuation can cause withdrawal symptoms. |