ZIPRASIDONE HYDROCHLORIDE
Clinical safety rating: safe
Animal studies have demonstrated safety
Ziprasidone is an atypical antipsychotic with high affinity for serotonin 5-HT2A and dopamine D2 receptors. It also antagonizes 5-HT2C, 5-HT1D, and alpha1-adrenergic receptors, and has moderate affinity for histamine H1 and alpha2-adrenergic receptors. It exhibits partial agonism at 5-HT1A receptors.
| Metabolism | Primarily metabolized by aldehyde oxidase, with minor contributions from CYP3A4 and CYP1A2. Two major metabolites: ziprasidone sulfoxide and ziprasidone sulfone. |
| Excretion | Primarily hepatic metabolism via aldehyde oxidase and CYP3A4; <1% excreted unchanged in urine, approximately 20% in feces as metabolites. |
| Half-life | Terminal elimination half-life is approximately 7 hours (range 6–10 hours) for oral administration; clinically, steady state is achieved within 1–3 days. |
| Protein binding | >99% bound, primarily to albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | Approximately 1.5 L/kg (range 0.7–2.5 L/kg), indicating extensive tissue distribution. |
| Bioavailability | Oral: approximately 60% (with food increases absorption by up to 100%); intramuscular: 100%. |
| Onset of Action | Oral: 1–3 hours for antipsychotic effect; intramuscular: 15–30 minutes for acute agitation. |
| Duration of Action | Oral: 12 hours for antipsychotic effect, supporting twice-daily dosing; intramuscular: up to 4 hours for agitation. |
| Molecular Weight | 412.94 |
20 mg PO BID with food, titrated up to max 80 mg PO BID; IM: 10-20 mg q2h or q4h, max 40 mg/day
| Dosage form | CAPSULE |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment; no data for severe renal impairment (CrCl <10 mL/min); use caution |
| Liver impairment | Child-Pugh Class A or B: no adjustment; Child-Pugh Class C: not recommended due to limited data |
| Pediatric use | Children ≥10 years: 20 mg PO BID with food, titrate in 20 mg increments weekly up to 60 mg BID; weight-based: 0.5 mg/kg/day in 2 divided doses, max 160 mg/day |
| Geriatric use | Initiate at 20 mg PO BID with food; titrate slowly; monitor for orthostatic hypotension, sedation, and QTc prolongation; lower effective doses may be sufficient |
| 1st trimester | Limited human data; animal studies show adverse effects. Use only if benefit outweighs risk. |
| 2nd trimester | Limited human data; animal studies show adverse effects. Use only if benefit outweighs risk. |
| 3rd trimester | Risk of extrapyramidal symptoms and withdrawal in neonate. use only if benefit outweighs risk. |
Clinical note
Other drugs that prolong the QT interval are contraindicated Can cause QT prolongation and rash.
| Placental transfer | Ziprasidone crosses the placenta; fetal plasma levels approximately 50% of maternal levels. |
| Breastfeeding | Ziprasidone is excreted into human breast milk in low amounts; limited data. Monitor infant for sedation, irritability, and feeding problems. Use with caution. |
| Lactation Rating |
■ 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 |
Known hypersensitivity to ziprasidoneHistory of QT prolongationRecent myocardial infarctionUncompensated heart failureConcomitant use with drugs that prolong QT interval
| Precautions | QT interval prolongation, especially in patients with hypokalemia, hypomagnesemia, or concomitant use of other QT-prolonging drugs; neuroleptic malignant syndrome; tardive dyskinesia; hyperglycemia and diabetes mellitus; orthostatic hypotension; seizures; priapism; body temperature dysregulation; dysphagia; suicide risk. |
| Food/Dietary | Ziprasidone must be administered with a meal containing at least 500 calories to achieve adequate and consistent absorption. Grapefruit and grapefruit juice should be avoided due to potential CYP3A4 inhibition leading to increased ziprasidone levels. High-fat meals significantly increase absorption; advise consistent intake with a similar meal to maintain stable drug levels. Avoid excessive caffeine or stimulants as they may exacerbate side effects. |
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| L3 |
| Teratogenic Risk | Ziprasidone is classified as Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. In animal studies, ziprasidone caused developmental toxicity (reduced fetal weight, delayed ossification, increased fetal mortality) at doses approximately 0.5 to 2 times the maximum recommended human dose (MRHD) based on mg/m². Risk to fetus cannot be ruled out; use during pregnancy only if potential benefit justifies potential risk. |
| Fetal Monitoring | Monitor for extrapyramidal symptoms (EPS), sedation, and cardiovascular effects (QT prolongation) in the mother. For the neonate, monitor for signs of extrapyramidal syndrome, withdrawal, or hypertonicity if exposure occurred in the third trimester. Consider baseline ECG and periodic monitoring of electrolytes (potassium, magnesium) in the mother due to QT prolongation risk. |
| Fertility Effects | Ziprasidone may cause hyperprolactinemia, which can suppress gonadotropin-releasing hormone (GnRH) and lead to decreased libido, erectile dysfunction, anorgasmia, amenorrhea, and galactorrhea. These effects are reversible upon dose reduction or discontinuation. In animal studies, no adverse effects on fertility were observed at doses up to 2 times MRHD. |
| Clinical Pearls | Ziprasidone hydrochloride is associated with a low risk of weight gain and metabolic changes, making it favorable for patients concerned with metabolic side effects. However, it can significantly prolong the QTc interval; avoid in patients with baseline QTc >450 ms, electrolyte disturbances, or concurrent use of other QTc-prolonging drugs. Must be taken with food (≥500 kcal) to enhance absorption by up to twofold and ensure consistent bioavailability. Titrate slowly to minimize orthostatic hypotension and somnolence. Monitor for extrapyramidal symptoms, especially akathisia, which is dose-related. |
| Patient Advice | Take this medication exactly as prescribed, with a meal containing at least 500 calories (e.g., a sandwich and milk) to ensure proper absorption. · Do not consume grapefruit or grapefruit juice while taking this medicine, as it may increase side effects. · Avoid alcohol and other central nervous system depressants (e.g., benzodiazepines, opioids) as they can worsen drowsiness and dizziness. · Rise slowly from sitting or lying positions to prevent dizziness or fainting, especially when starting treatment or increasing dose. · Contact your doctor immediately if you experience fast or irregular heartbeat, fainting, or seizures. · May cause drowsiness; do not drive or operate heavy machinery until you know how this medication affects you. · Report any involuntary muscle movements, restlessness, or stiffness to your doctor. · Do not stop taking this medication abruptly; discontinuation should be supervised by your doctor to avoid withdrawal symptoms. |