Rejoy

Approved Indications:

• Major Depressive Disorder (MDD) in adults: Used for the treatment of moderate to severe episodes of major depressive disorder, particularly where sedation and weight gain are desired.

Clinically Accepted Off-label Uses:

• Generalized Anxiety Disorder (GAD): Utilized in patients unresponsive to first-line agents.
• Post-Traumatic Stress Disorder (PTSD): For its anxiolytic and sedative properties.
• Obsessive-Compulsive Disorder (OCD): As adjunctive therapy where SSRIs alone are insufficient.
• Insomnia (low-dose): Common off-label use due to strong sedative effects.
• Appetite Stimulation/Cachexia: Especially in cancer or elderly patients with severe weight loss.
• Social Anxiety Disorder: Alternative when SSRIs or SNRIs are ineffective or poorly tolerated.

Adults:

• Initial dose: 15 mg orally once daily, preferably at bedtime.
• Maintenance dose: May be increased every 1–2 weeks in increments of 15 mg/day based on clinical response.
• Usual therapeutic dose range: 15 mg to 45 mg once daily at bedtime.
• Maximum dose: 45 mg/day.

Geriatric:

• Initial dose: 7.5–15 mg once daily at bedtime.
• Titrate cautiously due to increased sensitivity to sedation and hypotension.

Pediatric:

• Not FDA-approved for use in children. Safety and efficacy not established.

Renal Impairment:

• Mild to moderate (CrCl ≥30 mL/min): No dosage adjustment usually necessary.
• Severe impairment (CrCl <30 mL/min): Use with caution; consider lower starting dose and slow titration.

Hepatic Impairment:

• Mild to moderate: Initiate with lower doses and titrate cautiously.
• Severe hepatic impairment: Use with extreme caution or avoid.

Route of Administration:

• Oral tablets (swallow whole) or orally disintegrating tablets (ODT) — allow to dissolve on the tongue.

Duration of Therapy:

• Continue for several months after symptom remission.
• Reevaluate periodically for long-term need.

Mirtazapine is a noradrenergic and specific serotonergic antidepressant (NaSSA). It enhances central noradrenergic and serotonergic activity by antagonizing central presynaptic α2-adrenergic autoreceptors and heteroreceptors, resulting in increased norepinephrine and serotonin release. Additionally, it selectively antagonizes 5-HT2 and 5-HT3 receptors, enhancing 5-HT1-mediated neurotransmission which contributes to its antidepressant effects with fewer gastrointestinal side effects. Its strong histamine H1 receptor antagonism is responsible for its sedative properties.

• Absorption: Rapidly and well absorbed after oral administration; bioavailability ~50% due to first-pass metabolism.
• Onset of action: Clinical effects may begin within 1–2 weeks; full effect seen in 4–6 weeks.
• Peak plasma concentration: 2 hours post-dose (tablet); 1 hour (ODT).
• Protein binding: ~85%
• Metabolism: Extensively hepatic via CYP1A2, CYP2D6, and CYP3A4 isoenzymes.
• Active metabolites: Desmethylmirtazapine (minor activity).
• Elimination half-life: 20–40 hours (average ~30 hours); prolonged in elderly or hepatic/renal impairment.
• Excretion: Primarily via urine (~75%) and feces (~15%) as metabolites.

• Pregnancy: No longer categorized under the old FDA system; however, based on human data, no clear teratogenic effects have been reported. Use only if potential benefit justifies the potential risk.
• Lactation: Mirtazapine is excreted in small amounts in breast milk. Although considered relatively low-risk, caution is advised due to limited data. Monitor infants for sedation or feeding difficulties.
• Recommendation: Use with caution in pregnancy and breastfeeding; consult specialist if needed.

• Primary Class: Antidepressant
• Subclass: Noradrenergic and Specific Serotonergic Antidepressant (NaSSA)
• Generation: Atypical antidepressant

• Known hypersensitivity to mirtazapine or any component of the formulation
• Concomitant use with MAO inhibitors (including linezolid or IV methylene blue) or within 14 days of MAOI discontinuation
• Use in children and adolescents under 18 for depression (due to increased suicide risk)

• Suicidality: Increased risk in children, adolescents, and young adults. Close monitoring required during early treatment.
• Serotonin Syndrome: Risk when combined with other serotonergic agents (SSRIs, SNRIs, triptans, etc.).
• Agranulocytosis: Rare but potentially life-threatening; monitor for signs of infection or sore throat.
• Seizure Risk: Caution in patients with history of seizures.
• Mania/Hypomania Activation: Use cautiously in bipolar disorder.
• Hyponatremia/SIADH: Especially in elderly or those on diuretics.
• Weight Gain and Sedation: Common, dose-related; monitor weight and activity levels.
• Hepatic or Renal Impairment: Requires dose adjustment and close monitoring.

Common (≥1%):

• CNS: Drowsiness, sedation, dizziness, confusion (especially elderly)
• GI: Increased appetite, weight gain, dry mouth, constipation
• Metabolic: Elevated cholesterol or triglycerides

Less Common (<1%):

• Abnormal dreams, irritability, restlessness, tremor, anxiety, orthostatic hypotension

Serious/Rare:

• Agranulocytosis
• Seizures
• Mania
• Hyponatremia
• Serotonin syndrome

Timing & Severity:

• Sedation and appetite increase often occur within days. Mood improvement typically within 2–4 weeks. Most side effects are dose-dependent and reversible upon dose reduction or discontinuation.

Major Interactions:

• MAO Inhibitors: Risk of serotonin syndrome or hypertensive crisis; contraindicated within 14 days.
• CNS Depressants (e.g., benzodiazepines, alcohol): Enhanced sedation and CNS depression.
• SSRIs/SNRIs, Triptans, Linezolid: Additive serotonergic effects.
• CYP Inhibitors (e.g., ketoconazole, fluvoxamine): May increase mirtazapine levels.
• CYP Inducers (e.g., carbamazepine, phenytoin): May reduce efficacy.

CYP450 Involvement:

• Substrate of CYP1A2, CYP2D6, and CYP3A4

Food & Alcohol:

• Food does not significantly affect absorption.
• Alcohol potentiates sedation — avoid concurrent use.

• 2023–2024: EMA and NICE re-emphasized use of low-dose mirtazapine for sleep and appetite stimulation as off-label options in palliative care and elderly.
• FDA Warning Updated (2022): Reinforced caution on suicide risk, especially in younger patients.
• Guidelines: Still included as a second-line antidepressant in multiple international guidelines when SSRIs are not tolerated or effective.

• Temperature: Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C.
• Humidity: Protect from excessive moisture.
• Light Protection: Store in a well-closed container away from light.
• Orally Disintegrating Tablets (ODT): Use immediately after removal from blister; do not store once removed.
• Handling: Do not split or crush tablets unless specified. Avoid freezing.