Fluoxetine

1. Drug Name

• Generic Name: Fluoxetine

• Brand Names: Prozac, Sarafem, Rapiflux, Selfemra, Fontex.

2. Drug Classification

• Class: Antidepressant

• Subclass: Selective Serotonin Reuptake Inhibitor (SSRI)

3. Mechanism of Action

• Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) that works by inhibiting the reuptake of serotonin (5-HT) into the presynaptic neuron. By preventing the reuptake, fluoxetine increases the serotonin levels in the synaptic cleft, enhancing serotonergic neurotransmission.

• Receptor Interaction: Fluoxetine primarily affects the serotonin transporter (SERT). It has little effect on other neurotransmitter systems, which contributes to its relatively favorable side-effect profile compared to older antidepressants.

• Pharmacological Effects: It has minimal to no affinity for dopamine, norepinephrine, and histamine receptors, leading to a lower risk of sedation, hypotension, or anticholinergic effects.

4. Pharmacokinetics

• Absorption:

  • Bioavailability: Fluoxetine has approximately 60-80% bioavailability following oral administration. However, it has a long half-life, which results in steady-state concentrations being reached after several weeks.

  • Food: The presence of food does not significantly alter its absorption.

• Distribution:

  • Volume of Distribution (Vd): Approximately 20–40 L/kg, indicating extensive distribution, including to the central nervous system.

  • Protein Binding: Fluoxetine is about 94-95% protein-bound, primarily to albumin.

• Metabolism:

  • Hepatic: Fluoxetine is extensively metabolized in the liver via CYP2D6 and CYP3A4 enzymes. Its major active metabolite, norfluoxetine, has a longer half-life and also contributes to the drug’s clinical effects.

  • Fluoxetine’s metabolism can be affected by inhibitors or inducers of these enzymes (e.g., paroxetine, quinidine, rifampin).

• Excretion:

  • Half-life (t½): Fluoxetine has a half-life of 4 to 6 days. The active metabolite norfluoxetine has a half-life of about 4–16 days, which contributes to the prolonged clinical effect.

  • Excretion: Fluoxetine is primarily excreted in the urine (mainly as metabolites).

• Special Considerations:

  • Fluoxetine’s long half-life means it may take several weeks to reach steady-state concentrations and several weeks for complete clearance, which is significant for dose adjustments and discontinuation.

5. Indications

• Primary Indications:

  • Major Depressive Disorder (MDD): First-line treatment for depression in adults and adolescents (aged 8 years and above).

  • Obsessive-Compulsive Disorder (OCD): Approved for the treatment of OCD in adults and children.

  • Panic Disorder: First-line treatment for panic disorder, including with and without agoraphobia.

  • Bulimia Nervosa: Approved for use in the treatment of bulimia nervosa in adults.

  • Premenstrual Dysphoric Disorder (PMDD): FDA-approved for PMDD in women.

• Off-label Uses:

  • Post-traumatic Stress Disorder (PTSD): Some use for treating PTSD.

  • Social Anxiety Disorder: Fluoxetine may be prescribed off-label for social anxiety, though sertraline is often preferred.

  • Generalized Anxiety Disorder (GAD): Used off-label for GAD when other treatments fail.

• Special Populations:

  • Pediatrics: Approved for depression and OCD in children aged 8 years and older.

  • Elderly: Fluoxetine should be used cautiously in the elderly, as they may be more susceptible to side effects like hyponatremia and sedation.

6. Dosage and Administration

• Adult Dosing:

  • Major Depressive Disorder (MDD): Initial dose of 20 mg/day, which may be increased to 40 mg/day after 1–2 weeks. The typical dose range is 20–60 mg/day. Maximum dose is 80 mg/day.

  • Obsessive-Compulsive Disorder (OCD): Initial dose is 20 mg/day, with a typical dose range of 20–60 mg/day.

  • Panic Disorder: Start with 10 mg/day and increase after 1 week to 20 mg/day, with a maximum dose of 60 mg/day.

  • Bulimia Nervosa: Start with 60 mg/day, with a maximum dose of 80 mg/day.

  • Premenstrual Dysphoric Disorder (PMDD): Dosing is similar to depression, typically starting at 20 mg/day.

• Pediatric Dosing:

  • Major Depressive Disorder (MDD): Children aged 8–18 years, the initial dose is 10 mg/day, with a maximum dose of 40 mg/day.

  • OCD: Similar dosing as MDD in children aged 8 years and older.

• Renal or Hepatic Impairment:

  • Dose adjustment may be required in hepatic dysfunction due to fluoxetine's metabolism in the liver.

  • In severe renal impairment, dose adjustments are generally not necessary.

• Route of Administration: Oral (tablet, capsule, or oral solution).

• Max Safe Dose: 80 mg/day for most indications.

7. Contraindications

• Absolute Contraindications:

  • Known hypersensitivity to fluoxetine or any of its components.

  • Concurrent use with monoamine oxidase inhibitors (MAOIs), or within 14 days of stopping an MAOI due to the risk of serotonin syndrome.

  • Pimozide, due to potential QT prolongation and arrhythmia.

• Relative Contraindications:

  • Seizure disorders: Caution is advised as fluoxetine may lower the seizure threshold.

  • History of bipolar disorder: SSRIs can induce mania or hypomania in patients with bipolar disorder.

8. Warnings and Precautions

• Black Box Warning:

  • Suicidality: Like other antidepressants, fluoxetine carries a black box warning regarding the increased risk of suicidality in children, adolescents, and young adults, particularly during the initial treatment phase.

• Other Warnings:

  • Serotonin Syndrome: Fluoxetine, like all SSRIs, can cause serotonin syndrome, a potentially life-threatening condition when combined with other serotonergic agents (e.g., MAOIs, triptans, linezolid).

  • QT Prolongation: High doses of fluoxetine may cause QT prolongation, particularly in patients with pre-existing heart conditions.

  • Hyponatremia: Caution in elderly patients, as fluoxetine may lead to low sodium levels (especially in those on diuretics).

  • Bleeding Risk: SSRIs increase the risk of bleeding, particularly when used with anticoagulants, NSAIDs, or antiplatelet agents.

9. Adverse Effects

• Common Adverse Effects:

  • Gastrointestinal: Nausea, diarrhea, dry mouth, anorexia.

  • Central Nervous System: Insomnia, headache, dizziness, sexual dysfunction (including decreased libido, erectile dysfunction).

• Less Common but Clinically Significant:

  • Serotonin Syndrome: Symptoms may include agitation, hyperreflexia, tremor, fever, confusion, muscle rigidity.

  • QT prolongation: Rare but can increase the risk of arrhythmias.

  • Hyponatremia: Can be significant in elderly patients or those on diuretics.

• Rare/Serious:

  • Seizures: Though uncommon, fluoxetine may lower the seizure threshold.

  • Suicidal Thoughts: Increased risk of suicidal ideation, particularly in younger patients.

10. Drug Interactions

• Major Drug Interactions:

  • MAOIs: Severe interaction leading to serotonin syndrome.

  • Triptans (e.g., sumatriptan): Increased risk of serotonin syndrome when used with fluoxetine.

  • CYP2D6 inhibitors (e.g., paroxetine, fluvoxamine) can increase fluoxetine levels.

  • CYP2C9 inhibitors (e.g., fluconazole) may also increase fluoxetine levels.

• Food-Drug Interactions: No significant food interactions.

• Lab Test Interactions: Fluoxetine may interfere with serum glucose tests in diabetic patients and LFTs (liver function tests) due to its hepatic metabolism.

11. Clinical Pharmacology

• Pharmacodynamics: Fluoxetine selectively inhibits the serotonin transporter (SERT), leading to increased serotonergic neurotransmission. It has minimal effect on norepinephrine or dopamine.

• Additional Effects: Fluoxetine has a relatively high receptor affinity for serotonin and a prolonged half-life due to the active metabolite, norfluoxetine.

12. Special Populations

• Pregnancy: Category C (US FDA). Use only if the potential benefit outweighs the risk, particularly in the third trimester, due to the risk of neonatal withdrawal symptoms or pulmonary hypertension.

• Lactation: Fluoxetine is excreted in breast milk. Caution is advised, and monitoring of the infant is necessary for signs of sedation or poor feeding.

• Pediatrics: Approved for the treatment of depression and OCD in children over 8 years. Close monitoring for suicidal thoughts is critical.

• Geriatrics: Elderly patients may experience more side effects, including hyponatremia, sedation, and GI upset.

13. Therapeutic Uses

• First-line treatments for MDD, OCD, panic disorder, bulimia nervosa, and PMDD.

• Clinical evidence supports fluoxetine's use in adolescents and adults with depression and OCD.

14. Monitoring and Follow-Up

• Before Treatment: Monitor weight, serum sodium, liver enzymes, and ECG.

• During Treatment: Regular monitoring of serum sodium, weight, lipid profile, and glucose levels.

• Therapeutic Levels: No routine blood tests are required for monitoring fluoxetine levels, but clinical efficacy and side effects guide therapy.

15. Overdose Management

• Symptoms of Overdose: Drowsiness, tremors, seizures, serotonin syndrome (hyperreflexia, fever, confusion), and QT prolongation.

• Treatment Protocol:

  • Administer activated charcoal if within 1 hour of ingestion.

  • Symptomatic treatment, including IV fluids, respiratory support, and cardiovascular monitoring.

• Antidote: No specific antidote for fluoxetine overdose.

16. Patient Counseling Information

• Key Points:

  • Take fluoxetine once daily, in the morning.

  • It may take 1–4 weeks to see the full effects of treatment.

  • Avoid alcohol and CNS depressants while on fluoxetine.

• Signs for Immediate Medical Attention:

  • Symptoms of serotonin syndrome (e.g., tremors, fever, confusion).

  • Increased suicidal thoughts or worsening of depression.