What are the side effects of fluoxetine (Prozac) 90 mg extended release taken weekly?

Side Effects of Fluoxetine 90 mg Extended Release Weekly

Fluoxetine 90 mg weekly is generally well tolerated with a safety profile similar to daily 20 mg dosing, though patients should expect common gastrointestinal and neuropsychiatric effects, and require monitoring for serious but rare adverse events including suicidal ideation in younger patients. 1, 2

Common Side Effects

The most frequently reported adverse effects with fluoxetine 90 mg weekly include:

• Gastrointestinal effects: Nausea, diarrhea, dry mouth, and anorexia occur commonly, with diarrhea reported in 10% of weekly formulation users versus 5% with daily dosing 1, 3
• Neuropsychiatric symptoms: Insomnia, nervousness, anxiety, headache, and dizziness are frequent early in treatment 4, 1, 3
• Other common effects: Sweating/diaphoresis, tremor, fatigue, vivid dreams, and changes in appetite or weight 4

These adverse effects typically emerge within the first few weeks and are generally manageable without discontinuation 4.

Serious Adverse Effects Requiring Monitoring

Suicidal Ideation and Behavior

• All patients under age 24 require close monitoring for suicidal thinking, particularly during the first months of treatment, with a risk of 1% versus 0.2% for placebo (number needed to harm = 143) 4
• Monitoring should intensify after any dose adjustments 4

Behavioral Activation and Agitation

• Motor or mental restlessness, insomnia, impulsiveness, disinhibited behavior, and aggression may occur, especially in younger patients and those with anxiety disorders 4, 5
• This typically appears early in treatment or with dose increases and may require dose reduction 4

Mania/Hypomania

• Rare but serious, typically appearing later in treatment than behavioral activation and may persist after discontinuation, requiring active psychiatric management 4

Other Serious Risks

• Sexual dysfunction: Ejaculatory delay, erectile dysfunction, and anorgasmia are common with long-term use 4
• Seizures: Rare but documented risk 4
• Abnormal bleeding: Due to effects on platelet function 4
• Serotonin syndrome: Particularly when combined with other serotonergic medications, MAOIs (contraindicated), or drugs affecting serotonin pathways 4

Pharmacokinetic Considerations Specific to Weekly Dosing

• Increased fluctuation in drug levels: The 90 mg weekly formulation produces 164% fluctuation in fluoxetine levels (versus 24% with daily dosing) and 43% fluctuation in norfluoxetine levels (versus 17% daily) 1
• Peak concentrations: The 90 mg dose produces peak fluoxetine levels approximately 1.7-fold higher than daily 20 mg dosing 1
• Trough concentrations: Average trough levels are 76% lower for fluoxetine and 47% lower for norfluoxetine compared to daily dosing 1
• Long elimination half-life: Fluoxetine (4-6 days) and norfluoxetine (9-16 days) persist for weeks after discontinuation 1

Drug Interaction Risks

• CYP2D6 inhibition: Fluoxetine strongly inhibits CYP2D6, increasing levels of co-administered drugs metabolized by this pathway (tricyclics, certain antipsychotics, beta-blockers) 4, 5, 1
• CYP2D6 poor metabolizers: Approximately 7% of the population may experience dramatically elevated drug levels (up to 11.5-fold higher) with increased risk of QT prolongation and arrhythmias 5, 1
• Contraindicated combinations: Never combine with MAOIs due to serotonin syndrome risk 4
• Caution with serotonergic drugs: Exercise caution when combining with other SSRIs, SNRIs, tramadol, triptans, or St. John's wort 4

Special Population Considerations

• Liver disease: Elimination half-life extends to 7.6 days (versus 2-3 days normally), requiring dose reduction or less frequent dosing 1
• Renal disease: No routine dose adjustment needed, though metabolites may accumulate in severe dysfunction 1
• Elderly patients: Pharmacokinetics similar to younger adults, though maximum recommended dose is 20 mg daily in Alzheimer's populations 4, 1

Discontinuation Syndrome

• Gradual tapering recommended when stopping therapy, though fluoxetine's long half-life makes discontinuation syndrome less likely than with shorter-acting SSRIs like paroxetine or sertraline 4, 6
• Active drug persists for weeks after stopping due to prolonged elimination 1

Clinical Monitoring Recommendations

• Monitor for suicidal ideation at every visit, especially in the first 3 months and after dose changes in patients under age 24 4
• Assess for behavioral activation in the first 24-48 hours after initiating treatment, particularly in younger children 4, 5
• Screen for serotonin syndrome symptoms if any concomitant serotonergic medications are used 5
• Consider CYP2D6 genotyping in patients with suspected poor metabolizer status or those requiring concomitant CYP2D6-metabolized medications 5