Fluoxetine Practical Guide: Pharmacology, Indications, Dosing Guidelines and Adverse Effects

In a nutshell

• Pharmacodynamics:
  • Fluoxetine potently inhibits the serotonin transporter (SERT).
  • At higher doses, it also acts as an antagonist at 5HT2C receptors, which may contribute to its activating properties.
• Clinical uses:
  • Fluoxetine is FDA-approved to treat major depressive disorder, obsessive-compulsive disorder, panic disorder, and bulimia nervosa.
  • It is also used off-label to treat repetitive behaviors in autism spectrum disorder.
• Unique features:
  • Fluoxetine has a long half-life of 2-4 days (norfluoxetine metabolite has a half-life of 7-14 days).

Pharmacodynamics

• Animal studies reveal that:
  • Fluoxetine inhibits the serotonin transporter protein (SERT).
    • Fluoxetine is a potent serotonin uptake inhibitor.
  • At higher concentrations, fluoxetine inhibits 5HT2C receptors. ¹
    • This may mediate increased synaptic norepinephrine and dopamine in the prefrontal cortex. ²
• Potential clinical implications:
  • The 5HT2C antagonism is thought to contribute to fluoxetine’s activating properties.

Pharmacokinetics

Half-life

• Fluoxetine half-life: 2-4 days
  • Norfluoxetine (active metabolite) half-life: 7-14 days
• Benefits of a long half-life:
  • Patients are less likely to experience serotonin discontinuation symptoms after a missed dose or when discontinuing treatment. ³
• Prescribing considerations related to long-half life:
  • The effects of dose changes will not be fully reflected for several weeks.
  • If you need to switch a patient from fluoxetine to an MAOI, you must wait a longer washout period before initiating the MAOI. It is generally recommended to wait 5 weeks.⁴
  • Weekly delayed-release fluoxetine 90mg yields similar plasma levels to 10-20mg daily. ⁵

Effects on CYP2D6

• Fluoxetine inhibits the activity of CYP2D6.
  • This may cause individuals with regular CYP2D6 metabolic activity to resemble poor metabolizers.
  • Fluoxetine can increase the levels of pimozide and thioridazine.

Dosage forms and available strengths

• Prozac and generic fluoxetine ⁶
  • Pulvules (Lilly’s brand of gelatin capsules):
    • 10 mg
    • 20 mg
    • 40 mg
  • Capsules (generic):
    • 10 mg
    • 20 mg
    • 40 mg
  • Tablets (generic):
    • 10 mg
    • 20 mg
    • 60 mg.
  • Delayed-release capsules (generic):
    • 90 mg
  • Oral solution (generic):
    • 20mg/5mL
• Symbyax [^Symbyax]
  • Capsules:
    • 25mg/3mg (fluoxetine/olanzapine)
    • 25mg/6mg (fluoxetine/olanzapine)

Indications

FDA-approved indications and dosing

Overview

• Mood disorders:
  • Major depressive disorder
  • Bipolar depression (as olanzapine/fluoxetine combination, Symbyax)
  • Treatment-resistant depression(as olanzapine/fluoxetine combination, Symbyax)
• Anxiety disorders:
  • Panic disorder
  • OCD
• Fluoxetine is the only antidepressant approved for the treatment of bulimia.

Major depressive disorder

• Adults
  • Starting dose:
    • Initiate 20 mg/day orally in the morning.
  • Dose increases:
    • Consider a dose increase after several weeks if insufficient clinical improvement is observed.
      • Administer doses above 20 mg/day once daily in the morning or twice daily (i.e., morning and noon).
    • Maximum dose: 80 mg/day.
• Pediatric (children and adolescents):
  • Fluoxetine is the recommended first-line medication for depression in children and adolescents. ⁷
  • Initiate 10 or 20 mg/day.
  • After 1 week at 10 mg/day, increase the dose to 20 mg/day.
    • However, due to higher plasma levels in lower-weight children, the starting and target dose in this group may be 10 mg/day.
    • Consider a dose increase to 20 mg/day after several weeks if insufficient clinical improvement is observed.

Obsessive-compulsive disorder

• Adults
  • Starting dose:
    • Initiate 20 mg/day orally in the morning.
  • Dose increases:
    • It may take at least 5 weeks of treatment for the complete therapeutic effect to be achieved.
    • If there is not enough clinical improvement after several weeks, consider a dose increase.
    • Administer doses above 20 mg/day once daily in the morning or twice daily (i.e., morning and noon).
  • Dose range:
    • A dose range of 20 to 60 mg/day is recommended.
    • Maximum dose:
      • The maximum dose should not exceed 80 mg/day.
  • Pediatric (children and adolescents)
    • In adolescents and higher-weight children:
      • Initiate treatment with a dose of 10 mg/day.
      • After 2 weeks, increase the dose to 20 mg/day.
      • Dose range: 20 to 60 mg/day.
    • In lower-weight children:
      • Initiate treatment with a dose of 10 mg/day.
      • Dose range: 20 to 30 mg/day.

Panic disorder

• Starting dose:
  • Initiate 10 mg/day.
• Dose increases:
  • After one week, increase the dose to 20 mg/day.
• Dose range: 10 to 60 mg/day.
• Maximum dose: 60 mg/day
  • The most frequently administered dose in the 2 flexible-dose clinical trials was 20 mg/day.

Bulimia nervosa

• Early response (at 3 weeks) is a strong predictor of response overall.⁸
• Starting dose:
  • 60 mg/day in the morning.
  • For some patients, it may be advisable to titrate up to this target dose over several days.
• Dose range:
  • 60 mg/day
• Maximum dose:
  • Fluoxetine doses above 60 mg/day have not been systematically studied in patients with bulimia.

Bipolar depression (as Symbyax)

• The olanzapine/fluoxetine combination is recommended by NICE guidelines, along with quetiapine, as the first-line treatment for bipolar depression in youth as in adults. ⁹
  • The well-known adverse effect profile of olanzapine constrains its use.
• In markets where Symbyax is not available, combining olanzapine and fluoxetine (e.g. 5/20mg or 10/40mg) can achieve the same effects. ¹⁰
• Adults
  • Timing: Once daily in the evening.
  • Starting dose:
    • Start with the olanzapine 6 mg/ fluoxetine 25 mg capsule.
  • Maximum dose: olanzapine 12 mg/ fluoxetine 50 mg once daily.
• Children and adolescents (10 -17 years of age)
  • Timing: Once daily in the evening.
  • Starting dose:
    • Olanzapine 3 mg/ fluoxetine 25 mg
  • Maximum dose:
    • Olanzapine 12 mg/ fluoxetine 50 mg

Treatment-resistant depression (as Symbyax)

• Adults
  • Timing: Once daily in the evening.
  • Starting dose:
    • Start with the olanzapine 6 mg/ fluoxetine 25 mg capsule.
  • Maximum dose: olanzapine 12 mg/ fluoxetine 50 mg once daily.

Off-label uses

Repetitive behaviors in ASD

• Normally, much lower doses of fluoxetine are required to treat repetitive behaviors in ASD patients than those used to treat depression. ¹¹
• Use a liquid preparation and begin at the lowest possible dose, monitoring for adverse effects.
• Dosing:
  • 2.5mg/day a day for 1 week
    • 2.5mg = 0.625mL, which is difficult to measure accurately.
  • Follow with a flexible titration schedule of 0.8mg/kg/day.
    • Week 2: 0.3mg/kg
    • Week 3: 0.5mg/kg/day
    • 0.8mg/kg/ day subsequently

PTSD

• The overall evidence is inconclusive regarding the efficacy of fluoxetine for PTSD, especially in veterans. The results from placebo-controlled trials are mixed. ¹²

Social anxiety disorder

• All SSRIs are probably effective for social anxiety disorder, but some have stronger supporting evidence. ¹³
• Fluoxetine may have some efficacy in treating SAD, but the results appear less robust than those of other SSRIs. ¹⁴

Adverse effects

Most common side effects

• Nausea, diarrhea
• Activation symptoms
  • Nervousness
  • Insomnia
• Sleep symptoms:
  • Insomnia
  • Abnormal dreams
• Anorexia
  • Monitor for significant weight loss, especially if the patient is underweight or has a bulimia nervosa diagnosis.
• Antidepressant-induced excessive sweating (ADIES): ^{15 16}
  • Dose-related side effect
  • If antidepressant dose reduction is clinically feasible, it should be tried.
  • Switching to another antidepressant might be effective.
  • Adding another medication (an “antidote”):
    • When antidepressant dose reduction or switching is not an option.
    • Evidence of fair quality supports the use of terazosin (an alpha-1 adrenergic blocker).
• Tremor
• Sexual dysfunction: ¹⁷
  • Decreased libido: up to 4% incidence
  • There are no specific incidence reports for impotence, erectile dysfunction, delayed ejaculation, or anorgasmia.
  • “Drug holidays” are not effective for fluoxetine. ¹⁸
• Headache
• Rash

Serious, but rare side effects

• Hyponatremia, mainly in the elderly.
• Gastrointestinal bleeding, especially when combined with NSAIDs such as ibuprofen.

Use in special populations

Breastfeeding

• The average amount of drug in breastmilk is higher with fluoxetine than with most other SSRIs
• Agents that are less excreted in breast milk may be a better option, especially when nursing a newborn or preterm infant. ¹⁹
• Should breastfeeding be stopped?
  • If fluoxetine is required by the mother, it is not a reason to discontinue breastfeeding.
• Should fluoxetine be switched during breastfeeding?
  • If a mother was taking fluoxetine during pregnancy or if other antidepressants proved ineffective, most experts advise against switching medications while breastfeeding.

Hepatic impairment

• Liver impairment can increase the half-lives of fluoxetine and norfluoxetine. ²⁰
  • It can take many weeks to reach steady-state serum levels.
  • Fluoxetine is complex to use in this population.
• If fluoxetine is administered to patients with liver disease: ²¹
  • consider a dose reduction of at least 50%, or
  • consider alternate-day dosing.

Renal impairment

• GFR 20–50mL/min: dose as normal renal function.
• GFR <20mL/min:
  • use a low dose or,
  • use alternate day dosing, and increase according to response

Brand names

• Other brand names (some may be discontinued): Prozac Weekly (discontinued), Sarafem (discontinued), Rapiflux (discontinued), Selfemra (discontinued), Fluctin, Fluctine, Fluoxétine Lilly, Fluoxétine RPG Prozac, Fontex, Ladose.

References

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