Fluoxetine Hydrochloride

Approved Indications:

• Major Depressive Disorder (MDD):
  Treatment of acute and maintenance phases in adults and children aged 8 years and older.
• Obsessive-Compulsive Disorder (OCD):
  Indicated for adults and pediatric patients ≥7 years.
• Bulimia Nervosa:
  Management of moderate to severe binge-eating and purging behavior.
• Panic Disorder:
  With or without agoraphobia.
• Premenstrual Dysphoric Disorder (PMDD):
  Management of severe premenstrual symptoms in adult women.
• Depressive Episodes in Bipolar I Disorder (with olanzapine):
  Approved in adults for acute depressive episodes.
• Treatment-Resistant Depression (TRD):
  In combination with olanzapine after inadequate response to at least two antidepressants.

Clinically Accepted Off-label Uses:

• Generalized Anxiety Disorder (GAD)
• Social Anxiety Disorder (SAD)
• Post-Traumatic Stress Disorder (PTSD)
• Body Dysmorphic Disorder (BDD)
• Premature Ejaculation
• Fibromyalgia-related depression
• Autism-related irritability and mood dysregulation (in select pediatric cases)

Route of Administration: Oral
Dosage Forms: Tablets, capsules, oral solution, delayed-release capsules

Adults:

• MDD:
  Start with 20 mg once daily in the morning; may increase after several weeks if needed.
  Maximum dose: 80 mg/day.
• OCD:
  Initial: 20 mg/day.
  Titrate in 20 mg/week increments.
  Max: 80 mg/day.
• Bulimia Nervosa:
  60 mg once daily (target dose).
• Panic Disorder:
  Start with 10 mg/day for 1 week, then increase to 20 mg/day.
  Max: 60 mg/day.
• PMDD:
  Continuous: 20 mg/day throughout the menstrual cycle.
  Intermittent: 20 mg/day starting 14 days before menstruation and stopping at onset of menses.
• Bipolar I Depression (with Olanzapine):
  Start: Olanzapine 5 mg + Fluoxetine 20 mg once daily.
  Adjust based on response; max fluoxetine: 50 mg/day.

Pediatrics:

• MDD (≥8 years):
  Initial: 10 mg/day for 1 week, then increase to 20 mg/day.
  Max: 60 mg/day.
• OCD (≥7 years):
  Start: 10 mg/day.
  Titrate up to 20–60 mg/day as tolerated.

Elderly:

• Start at 10–20 mg/day; use with caution.
• Monitor for hyponatremia and reduced clearance.

Hepatic Impairment:

• Consider reducing dose or increasing dosing interval due to prolonged half-life.

Renal Impairment:

• Generally, no adjustment required, but caution advised in severe impairment.

Fluoxetine Hydrochloride is a selective serotonin reuptake inhibitor (SSRI). It increases synaptic concentrations of serotonin (5-HT) by selectively inhibiting its reuptake at the presynaptic neuron. This action enhances serotonergic neurotransmission in the central nervous system. Elevated serotonin levels improve mood, reduce anxiety, control obsessive behaviors, and suppress appetite-related urges. Fluoxetine has minimal or no effect on norepinephrine and dopamine reuptake at therapeutic doses, contributing to its tolerability and safety profile.

• Absorption:
  Rapid and complete after oral administration.
  Peak plasma levels in 6–8 hours.
• Bioavailability:
  Approximately 72% (not affected by food).
• Distribution:
  Extensive distribution (volume of distribution: 20–40 L/kg).

95% plasma protein binding.

• Metabolism:
  Hepatic metabolism primarily via CYP2D6.
  Major active metabolite: Norfluoxetine.
• Elimination Half-life:
  Fluoxetine: ~2–4 days
  Norfluoxetine: ~7–15 days
• Excretion:
  Renal (~60%) as metabolites
  Fecal (~15%)
• Steady-State:
  Reached in 3–4 weeks; persists post-discontinuation due to long half-life.

Pregnancy:

• Former FDA Category C
• Use only if benefits outweigh risks.
• Late-pregnancy exposure may lead to neonatal complications such as persistent pulmonary hypertension of the newborn (PPHN), feeding issues, or withdrawal symptoms.

Lactation:

• Excreted in breast milk in low concentrations.
• Monitor infants for sedation, irritability, or feeding problems.
• Consider alternative SSRI with a shorter half-life if needed.

• Primary Class: Antidepressant
• Subclass: Selective Serotonin Reuptake Inhibitor (SSRI)

• Hypersensitivity to fluoxetine or formulation components
• Use with MAO inhibitors or within 14 days of discontinuing MAOIs
• Use with pimozide or thioridazine (risk of QT prolongation)
• Concomitant use with linezolid or IV methylene blue
• Severe hepatic impairment without dosage adjustment

• Suicidality: Higher risk in patients ≤24 years old, especially in early treatment.
• Serotonin Syndrome: Risk with serotonergic drugs or MAOIs—monitor closely.
• QT Prolongation: Caution in patients with cardiac risk factors or electrolyte imbalance.
• Hyponatremia/SIADH: Especially in elderly or volume-depleted patients.
• Seizures: Use with caution in seizure-prone individuals.
• Bipolar Disorder: May precipitate mania/hypomania—screen before use.
• Bleeding Risk: Enhanced with NSAIDs, anticoagulants, antiplatelets.
• Discontinuation Symptoms: Gradual tapering is recommended despite long half-life.

Common (≥1%):

• CNS: Insomnia, nervousness, headache, anxiety, tremor
• GI: Nausea, diarrhea, anorexia, dry mouth, dyspepsia
• Sexual: Decreased libido, delayed ejaculation, anorgasmia
• Dermatologic: Sweating, rash

Serious (Rare):

• Serotonin syndrome
• Suicidal thoughts/behavior
• Seizures
• QT interval prolongation
• Hepatic injury
• Stevens-Johnson Syndrome
• Hyponatremia/SIADH

Timing & Severity:
Most adverse effects begin within the first 1–2 weeks. Sexual dysfunction and sleep disturbances may persist longer. Side effects may be dose-dependent.

Major Interactions:

• MAO Inhibitors, Linezolid, Methylene Blue: Risk of serotonin syndrome; contraindicated.
• Tramadol, SNRIs, TCAs, Lithium: Increase serotonergic toxicity.
• Pimozide, Thioridazine: Risk of life-threatening arrhythmias.
• NSAIDs, Aspirin, Warfarin: Increased bleeding risk.
• CYP2D6 Substrates (e.g., TCAs, tamoxifen): Fluoxetine inhibits CYP2D6, reducing metabolism.
• Alcohol: May worsen CNS side effects—avoid use.

Enzyme System Involved:
Strong CYP2D6 inhibitor
Moderate interaction with CYP3A4 substrates at high doses

• FDA Black Box Warning (Reaffirmed): Suicide risk in children, adolescents, and young adults.
• Pharmacogenomic Advisory: Consider CYP2D6 genotyping for dose adjustment in poor metabolizers.
• NICE & APA Guidelines: Recommend fluoxetine as first-line therapy for MDD, OCD, PMDD.
• New Clinical Use Exploration: Investigated in COVID-19 for potential anti-inflammatory properties (not approved for this use).

• Tablets and Capsules:
  Store at 20°C to 25°C (68°F to 77°F); excursions between 15°C and 30°C are acceptable.
  Protect from light and moisture. Keep tightly sealed.
• Oral Solution:
  Store between 2°C and 30°C
  Do not freeze.
  Shake well before use.
  Discard after 30 days from opening if not used.