Permival

Approved Indications:

• Depressive Disorders with Psychotic Features: Treatment of major depressive episodes accompanied by psychotic symptoms such as hallucinations or delusions.
• Schizoaffective Disorder (Depressive Type): Used in the management of psychosis with co-existing depressive symptoms.
• Chronic Psychotic Depression: Particularly effective in patients with coexisting anxiety and agitation.
• Mixed Anxiety-Depression with Agitation: Where both antipsychotic and antidepressant effects are required.

Off-label (Clinically Accepted) Uses:

• Refractory Depression with Somatic Symptoms: In patients unresponsive to SSRIs or SNRIs.
• Obsessive-Compulsive Disorder with Comorbid Psychotic Features: When conventional therapy fails.
• Behavioral Disorders in Elderly or Dementia-related Depression (with extreme caution): Where depression coexists with delusional thinking.

General Principles:

• This combination is administered orally, usually once or twice daily.
• Dosing should be individualized based on response and tolerability.

Adults:

• Starting dose: 1 tablet (typically containing Nortriptyline 10–25 mg + Fluphenazine 0.5–1 mg) once or twice daily.
• Maintenance dose: 2–4 tablets per day, depending on severity.
• Maximum total daily dose: Nortriptyline 100 mg, Fluphenazine 4 mg.

Elderly:

• Initial dose: ½ tablet once daily.
• Titration: Slow and cautious; monitor for orthostatic hypotension and extrapyramidal symptoms.

Pediatrics:

• Not recommended due to lack of safety and efficacy data.

Renal Impairment:

• Use with caution; no specific adjustment, but start at the lowest dose.

Hepatic Impairment:

• Avoid in severe impairment. In mild-to-moderate cases, use lower doses and monitor closely.

Duration:

• Short- to medium-term use; periodic reassessment needed.
• Discontinue slowly to avoid withdrawal or symptom recurrence.

This combination provides dual pharmacological action:
Fluphenazine is a first-generation (typical) antipsychotic that works by blocking dopamine D2 receptors in the mesolimbic pathway, reducing hallucinations, delusions, and agitation. Nortriptyline is a tricyclic antidepressant that inhibits the reuptake of norepinephrine and serotonin, increasing their synaptic availability. The combined effect targets both mood stabilization and psychotic symptoms, making it effective in complex depressive illnesses with psychosis or agitation.

Fluphenazine:

• Absorption: Moderate oral bioavailability (20–40%) due to first-pass metabolism.
• Onset: 2–3 days (antipsychotic effect).
• Distribution: Highly protein-bound.
• Metabolism: Hepatic, primarily via CYP2D6.
• Half-life: 15–30 hours (oral).
• Elimination: Renal and biliary excretion.

Nortriptyline:

• Absorption: Well absorbed orally; bioavailability ~45–70%.
• Onset: 2–4 weeks for antidepressant effect.
• Distribution: Widely distributed; protein binding ~92%.
• Metabolism: Hepatic via CYP2D6.
• Half-life: 18–44 hours (may increase in elderly).
• Elimination: Renal (major), partly as metabolites.

Pregnancy:

• FDA Category C (both components): Risk cannot be ruled out. Use only if the potential benefit justifies the risk to the fetus.
• Risks include extrapyramidal symptoms and withdrawal in neonates if used in the third trimester.

Lactation:

• Both drugs are excreted into breast milk.
• Use not recommended during breastfeeding due to possible sedation, irritability, or feeding difficulties in infants.

Caution: Limited human data; decision should be based on clinical judgment.

• Fluphenazine: Typical Antipsychotic (Phenothiazine class)
• Nortriptyline: Tricyclic Antidepressant (Secondary Amine TCA)
• Combined Therapeutic Class: Antidepressant + Antipsychotic Combination

• Hypersensitivity to Fluphenazine, Nortriptyline, phenothiazines, or any excipients
• Concomitant use with MAO inhibitors or within 14 days of MAOI discontinuation
• Severe liver disease
• History of bone marrow suppression
• Recent myocardial infarction or severe arrhythmias
• Glaucoma (narrow-angle)
• Urinary retention
• Pheochromocytoma

• Suicidality: Increased risk in adolescents and young adults with depression.
• Extrapyramidal Symptoms (EPS): Risk of dystonia, akathisia, or Parkinsonism.
• Neuroleptic Malignant Syndrome (NMS): Rare but life-threatening; discontinue immediately if suspected.
• QT Prolongation: Avoid in patients with known cardiac conduction issues.
• Orthostatic Hypotension: Especially in elderly.
• Seizure Risk: Dose-dependent, especially with Nortriptyline.
• Hepatic Impairment: Use with caution and monitor LFTs.
• Withdrawal Effects: Taper gradually.

Common Side Effects:

• Central Nervous System:
• Drowsiness, dizziness, fatigue
• Anxiety, agitation, confusion (especially elderly)
• Extrapyramidal:
• Tremor, rigidity, restlessness (Fluphenazine-related)
• Cardiovascular:
• Palpitations, orthostatic hypotension, tachycardia
• Anticholinergic Effects:
• Dry mouth, constipation, blurred vision, urinary retention
• Gastrointestinal:
• Nausea, vomiting, appetite changes

Serious or Rare Side Effects:

• Tardive dyskinesia
• Neuroleptic Malignant Syndrome
• Seizures
• Agranulocytosis
• Hepatotoxicity
• Arrhythmias (including Torsades de Pointes)

Major Interactions:

• MAO Inhibitors: Risk of serotonin syndrome or hypertensive crisis.
• CYP2D6 Inhibitors (e.g., Fluoxetine, Paroxetine): May increase Nortriptyline levels.
• QT-prolonging agents (e.g., Amiodarone, Haloperidol): Additive risk.
• Alcohol/CNS depressants: Enhanced sedative and respiratory depressant effects.
• Anticholinergic drugs: Increased anticholinergic toxicity.

Food Interactions:

• Avoid alcohol.
• No significant food-drug interactions reported.

Enzyme System Involvement:

• Primarily CYP2D6 for both components.

• EMA & FDA continue to advise caution regarding antipsychotic use in elderly patients with dementia-related psychosis due to increased risk of death.
• Updated warnings regarding suicide risk in younger populations when initiating tricyclic antidepressants.
• No new major label changes or approvals as of the most recent international updates.

• Storage Temperature: Store below 25°C.
• Humidity Protection: Store in a dry place, away from moisture.
• Light Protection: Keep in the original packaging to protect from light.
• Handling: Keep out of reach of children. Do not crush or split tablets unless specified.
• Shelf Life: Refer to packaging; typically 24–36 months unopened.