Schedule H

Oral

Formulation Strengths Available

Capsules 1.5 mg, 3 mg, 4.5 mg, 6 mg

INDICATIONS + DOSING — FOR CLINICIAN USE ONLY

Primary Indications (Approved / Standard in India):

1. Schizophrenia (Adults)

Parameter Recommendation

Starting dose 1.5 mg once daily

Titration May increase to 3 mg once daily on Day 2; further increments of 1.5–3 mg at intervals of ≥2 weeks based on response and tolerability

Usual maintenance dose 1.5–6 mg once daily

Maximum dose 6 mg/day

Clinical Notes:

• May be taken with or without food

• Akathisia is dose-related; slower titration reduces risk

• Due to long half-life of active metabolites (1–3 weeks), dose changes may take several weeks to show full effect

• Dose reduction required with concomitant strong CYP3A4 inhibitors

1. Bipolar I Disorder — Manic or Mixed Episodes (Adults)

Parameter Recommendation

Starting dose 1.5 mg once daily on Day 1

Titration Increase to 3 mg once daily on Day 2; may increase to 6 mg/day based on response

Usual maintenance dose 3–6 mg once daily

Maximum dose 6 mg/day

Clinical Notes:

• Effective for acute manic and mixed episodes

• Monitor for extrapyramidal symptoms during titration

• Not established as monotherapy for maintenance prevention of bipolar episodes

• Consider slower titration if sedation is problematic

Secondary Indications – Adults (Off-label):

Indication Dose Duration Notes

Bipolar Depression Starting: 1.5 mg once daily; Usual: 1.5–3 mg once daily; Maximum: 3 mg/day Acute phase: 6–8 weeks; reassess for continuation OFF-LABEL in India; US FDA-approved; Specialist psychiatrist only; Evidence: RCTs (Durgam et al., Earley et al.)

Adjunctive therapy in Major Depressive Disorder (treatment-resistant) 1.5–3 mg once daily as augmentation 6–8 weeks trial OFF-LABEL; Specialist only; Limited evidence; extrapolated from bipolar depression data

PAEDIATRIC DOSING (Specialist Only)

Primary Indications:

NOT APPROVED for paediatric use in India. No approved indications for patients below 18 years of age.

Secondary Indications – Paediatrics (Off-label):

Not applicable. Insufficient safety and efficacy data in paediatric population.

Age Restrictions:

• Not recommended in individuals <18 years

• If use is unavoidable in exceptional circumstances, only under child and adolescent psychiatry specialist supervision

• No established paediatric dosing available

• Known hypersensitivity to cariprazine or any excipient

• Severe hepatic impairment (Child-Pugh C)

• Concurrent use with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin) without appropriate dose reduction

• Concurrent use with strong CYP3A4 inducers (e.g., rifampicin, carbamazepine, phenytoin) — results in loss of efficacy

• History of neuroleptic malignant syndrome (NMS) with any antipsychotic

• Parkinson's disease or Lewy body dementia — may exacerbate motor symptoms

• History of seizures or conditions lowering seizure threshold

• Cardiovascular disease — risk of orthostatic hypotension, especially during initial titration

• Cerebrovascular disease — increased stroke risk in elderly with dementia

• Diabetes mellitus or metabolic syndrome risk factors — may worsen glycaemic control

• Dyslipidaemia — monitor lipid profile

• Elderly patients with dementia-related psychosis — NOT approved; increased mortality risk (boxed warning equivalent)

• History of leukopenia/neutropenia

• Risk of akathisia — dose-dependent; most common in first few weeks

• Suicidal ideation — monitor closely, especially in younger adults

• Swallowing difficulties — risk of aspiration

• CYP2D6 poor metabolisers — may have higher drug exposure (use caution)

• Long half-life of active metabolites — effects persist for weeks after discontinuation; consider when switching agents

Parameter Recommendation

Overall safety Limited human data; animal studies show developmental toxicity at high doses

Risk category Not formally assigned; avoid unless clearly necessary

When may be used Only if potential benefit justifies risk to fetus; specialist psychiatry input essential

Preferred alternatives Haloperidol (most safety data for acute use), Olanzapine or Quetiapine (reasonable safety profile in Indian obstetric psychiatry practice)

Maternal monitoring Mental status, metabolic parameters, extrapyramidal symptoms

Fetal/neonatal monitoring Third trimester use: monitor neonate for extrapyramidal symptoms, sedation, feeding difficulties, respiratory distress (withdrawal/toxicity symptoms reported with antipsychotics)

Parameter Recommendation

Compatibility Not recommended during breastfeeding

Milk excretion Unknown; likely excreted based on lipophilicity and molecular properties

Preferred alternatives Quetiapine, Olanzapine (more lactation data; relatively low milk transfer)

Infant monitoring If breastfeeding unavoidable: monitor for sedation, poor feeding, irritability, excessive weight gain or poor weight gain, developmental milestones

Parameter Recommendation

Starting dose 1.5 mg once daily

Titration Slower than younger adults; increase at 2-week intervals

Maximum dose 6 mg/day (same as adults, but lower effective doses often sufficient)

Key risks Orthostatic hypotension (falls risk), sedation, confusion, extrapyramidal symptoms, impaired renal reserve

Special warning NOT approved for dementia-related behavioural symptoms — increased risk of cerebrovascular events and mortality in this population

Monitoring Blood pressure (lying and standing), renal function, cognitive status, falls assessment

Interacting Drug/Class Mechanism Effect & Recommendation

Strong CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin, ritonavir, nelfinavir) Decreased metabolism of cariprazine and active metabolites Markedly increased plasma levels → Reduce cariprazine dose by 50% (e.g., if on 4.5 mg, reduce to 1.5–3 mg)

Strong CYP3A4 inducers (rifampicin, carbamazepine, phenytoin, phenobarbital, St. John's Wort) Increased metabolism Significantly reduced efficacy → Avoid concomitant use; if essential, effect of cariprazine will be substantially diminished

Other CNS depressants (alcohol, opioids, benzodiazepines, sedating antihistamines) Additive CNS depression Enhanced sedation, respiratory depression → Avoid alcohol; use CNS depressants with caution

Dopamine agonists (levodopa, pramipexole, ropinirole, bromocriptine) Pharmacodynamic antagonism Reduced efficacy of dopamine agonists → Avoid combination; if essential, monitor for worsening parkinsonian symptoms

QT-prolonging drugs (Class Ia/III antiarrhythmics, haloperidol, methadone, certain fluoroquinolones) Additive QT prolongation Risk of torsades de pointes → Avoid combination if possible; ECG monitoring if unavoidable

Interacting Drug/Class Effect & Recommendation

Moderate CYP3A4 inhibitors (erythromycin, diltiazem, verapamil, fluconazole, grapefruit juice) May modestly increase cariprazine levels → monitor for adverse effects; consider dose reduction if toxicity emerges

SSRIs/SNRIs Potential for increased serotonergic effects; some SSRIs (fluoxetine, paroxetine) are CYP2D6 inhibitors → monitor for EPS, akathisia

Antihypertensives (all classes) Additive hypotensive effect → monitor BP, especially during titration

Anticholinergic drugs Additive anticholinergic burden → monitor for confusion, constipation, urinary retention, especially in elderly

Antidiabetic agents Cariprazine may affect glycaemic control → monitor blood glucose closely

Valproate May increase valproate levels in some patients → monitor valproate levels if clinically indicated

• Akathisia (restlessness) — most frequent; dose-related

• Extrapyramidal symptoms (parkinsonism, dystonia)

• Insomnia

• Headache

• Nausea and vomiting

• Dizziness

• Constipation

• Somnolence/sedation

• Weight gain (generally less than olanzapine)

• Anxiety/restlessness

• Dyspepsia

• Fatigue

• Blurred vision

Adverse Effect Clinical Action

Neuroleptic malignant syndrome (NMS) Hyperthermia, severe rigidity, autonomic instability, altered consciousness → Immediate discontinuation; ICU care

Tardive dyskinesia Involuntary movements, especially orofacial → consider dose reduction or discontinuation; may be irreversible

Suicidal ideation/behaviour Especially in younger adults and early treatment → close monitoring; consider discontinuation

Seizures Rare → discontinue if seizures occur

Severe orthostatic hypotension Falls, syncope, especially in elderly → manage supportively; consider dose reduction

Leukopenia / Neutropenia / Agranulocytosis Rare → discontinue if ANC <1000/mm³; monitor for infection

Cerebrovascular events (in elderly with dementia) Increased stroke risk → Do not use in dementia-related psychosis

Severe hyperglycaemia / Diabetic ketoacidosis Rare → monitor glucose; discontinue if DKA

Dysphagia / Aspiration pneumonia Risk in elderly or those with swallowing difficulties

Rhabdomyolysis Rare; associated with NMS or severe dystonia

Week 1–4 Akathisia and EPS assessment (weekly during titration); suicidality monitoring; blood pressure; weight

Month 3 Weight, BMI; fasting glucose; lipid profile; blood pressure; EPS/tardive dyskinesia screening; mental status

Every 6–12 months (long-term) Weight/BMI; fasting glucose and HbA1c; fasting lipid profile; blood pressure; EPS/tardive dyskinesia assessment; mental status; renal/hepatic function if comorbidities

As clinically indicated ECG (if QT concerns or cardiac symptoms); prolactin (if symptoms of hyperprolactinaemia); CBC (if infection signs)

Caripra Torrent Pharmaceuticals 1.5 mg, 3 mg, 4.5 mg, 6 mg

Carzine Sun Pharma 1.5 mg, 3 mg, 6 mg

Cariz Intas Pharmaceuticals 1.5 mg, 3 mg, 4.5 mg, 6 mg

Vraylar Allergan/AbbVie (limited import) 1.5 mg, 3 mg, 4.5 mg, 6 mg

Note: Brand availability may vary by region. No fixed-dose combinations currently available in India.

Strength Approximate Price per Capsule

1.5 mg ₹25–₹45

4.5 mg ₹55–₹80

• Not included in NLEM 2022

• Not under NPPA price control

• Primarily available in private retail; limited government supply

• D3-preferring pharmacology — cariprazine has highest D3:D2 binding ratio among available antipsychotics; theoretically beneficial for negative symptoms and cognitive deficits in schizophrenia, though clinical significance is still being evaluated

• Very long half-life — cariprazine and its active metabolites have half-lives of 2–4 days (parent) and 1–3 weeks (metabolites); steady state takes 4–8 weeks; dose changes require patience; effects persist weeks after discontinuation

• Akathisia is the most common limiting adverse effect — occurs in up to 20% of patients; dose-related; slower titration (2-week intervals) reduces incidence; may require propranolol or benzodiazepine short-term

• Lower metabolic burden compared to olanzapine and clozapine — may be preferred in patients with pre-existing obesity, diabetes, or metabolic syndrome, though monitoring still required

• CYP3A4 awareness is critical — avoid strong inducers (including rifampicin used in TB treatment, common in India); reduce dose by 50% with strong inhibitors

• Not for dementia-related psychosis — increased mortality and cerebrovascular events; avoid in elderly patients with dementia regardless of indication

• Useful alternative to aripiprazole — similar mechanism (partial agonist) but different receptor preference; may be tried in patients who did not respond to or tolerate aripiprazole

cariprazine; schizophrenia; bipolar disorder; bipolar mania; atypical antipsychotic; D3 partial agonist; akathisia; CYP3A4 substrate; long half-life; NLEM-excluded; psychiatry

RxIndia v1.0 — 21 May 2025

• CDSCO approved product information

• Indian Pharmacopoeia 2022

• National Formulary of India (NFI)

• Indian Psychiatric Society clinical practice guidelines

• AIIMS Psychiatry Department treatment protocols

• API Textbook of Medicine, 12th Edition

• Goodman & Gilman's The Pharmacological Basis of Therapeutics, 14th Edition

• Harrison's Principles of Internal Medicine, 21st Edition

• Durgam S et al. Cariprazine in bipolar depression (RCT) — for off-label indication only

• Earley W et al. Cariprazine in bipolar I depression (RCT) — for off-label indication only

• US FDA prescribing information (Vraylar) — supportive reference