Dosing and uses of Prozac, Sarafem (fluoxetine)
Adult dosage forms and strengths
capsule
- 10mg
- 20mg
- 40mg
tablet
- 10mg
- 20mg
- 60mg
capsule, delayed-release
- 90mg
oral solution
- 20mg/5mL
Major Depressive Disorder
Prozac
- Initial: 20 mg PO qDay
- May consider gradually increasing dose after several weeks by 20 mg/day; not to exceed 80 mg qDay
Prozac Weekly
- 90 mg PO qWeek
Obsessive-Compulsive Disorder
Prozac
- Initial: 20 mg PO qDay
- May consider gradually increasing dose after several weeks by 20 mg/day (20-60 mg/day recommended range); not to exceed 80 mg qDay
Prozac Weekly
- 90 mg PO qWeek
Bulimia Nervosa
Initial or maintenance: May titrate dose to 60 mg PO qDay over several days
Panic Disorder
Initial: 10 mg PO qDay for first week, THEN 20 mg PO qDay
May consider gradually increasing dose after several weeks; not to exceed 60 mg qDay; doses > 60 mg/day not evaluated
Premenstrual Dysphoric Disorder
Continuous (Sarafem): 20 mg PO qDay initially; may gradually increase dose; not to exceed 80 mg/day, Or
Intermittent (Sarafem): 20 mg PO qDay starting 14 days before menstruation and through first full day of menses (repeat each cycle)
Fibromyalgia (Off-label)
20-80 mg PO qDay
Dosing considerations
- Efficacy may increase with concomitant amitriptyline
Migraine (Off-label)
Prophylaxis
20-40 mg PO qDay
Hot Flashes Caused by Hormonal Chemotherapy (Off-label)
20 mg/day PO x 4 weeks
Raynaud Phenomenon (Off-label)
20-60 mg/day PO
Dosing Modifications
Upon therapy discontinuation, taper gradually over 4-6 months to minimize incidence of withdrawal symptoms and allow for detection of re-emerging symptoms; if withdrawal symptoms intolerable, following a dose reduction, resume previously prescribed dose and/or decrease dose at more gradual rate
Renal impairment: Use caution; drug accumulation may occur with severe renal impairment
Hepatic impairment (cirrhosis): Decreased clearance of parent drug and active metabolite (norfluoxetine); lower or less frequent dose recommended
Pediatric dosage forms and strengths
capsule
- 10mg
- 20mg
- 40mg
tablet
- 10mg
- 20mg
- 60mg
oral solution
- 20mg/5mL
Major Depressive Disorder
>8 years: 10-20 mg PO qDay, initially
Start at 10 mg/day in lower weight children
May gradually increase dose after 1 week; not to exceed 20 mg qDay
Obsessive-Compulsive Disorder
>7 years: 10 mg PO qDay, initially; may gradually increase dose after 2 weeks to 20 mg qDay; further increases may be considered after several weeks
Adolescents and higher-weight children: Typical dosage range 20-60 mg qDay
Lower-weight children: Typical dosage range 20-30 mg qDay
Body Dysmorphic Disorder (Orphan)
Treatment of body dysmorphic disorder in children and adolescents
Orphan indication sponsor
- Hollander, Eric MD; The Mount Sinai School of Medicine, One Gustave L. Levy Place; New York, NY 10029-6574
Autism (Orphan)
Orphan indication sponsor
- Neuropharm, Ltd; Felcham Park House, Lower Road, Leatherhead; UK
Geriatric dosage forms and strengths
Major Depressive Disorder
Initial: 10 mg PO qDay
May gradually increase dose by 10-20 mg after several weeks as tolerated
Do not take at night unless sedation occurs
Dosing Considerations
Preferred drug of choice in elderly over tricyclic antidepressants because of fewer side effects
Prozac, Sarafem (fluoxetine) adverse (side) effects
>10%
Headache (20-25%)
Nausea (12-29%)
Insomnia (10-33%)
Anorexia (4-17%)
Anxiety (6-15%)
Asthenia (10-15%)
Diarrhea (8-18%)
Nervousness (8-14%)
Somnolence (5-17%)
Tremor (3-13%)
Weakness (7-21%)
1-10%
Dizziness (9%)
Dry mouth (6-10%)
Dyspepsia (6-10%)
Sweating (5-10%)
Decreased libido (2-5%)
Abnormal taste (>1%)
Agitation (>1%)
Chest pain (>1%)
Chills (>1%)
Confusion (>1%)
Ear pain (>1%)
Hypertension (>1%)
Increased appetite (>1%)
Palpitation (>1%)
Sleep disorder (>1%)
Tinnitus (>1%)
Urinary frequency (>1%)
Vomiting (>1%)
Weight gain (>1%)
Frequency not defined
Dysglycemia in patients with Dm
Risk of seizure with concomitant electroconvulsive therapy (rare)
Warnings
Black box warnings
In short-term studies, antidepressants increased the risk of suicidal thinking and behavior in children, adolescents, and young adults (<24 years) taking antidepressants for major depressive disorders and other psychiatric illnesses
This increase was not seen in patients >24 years; a slight decrease in suicidal thinking was seen in adults >65 years
In children and young adults, the risks must be weighed against the benefits of taking antidepressants
Patients should be monitored closely for changes in behavior, clinical worsening, and suicidal tendencies; this should be done during the initial 1-2 months of therapy and dosage adjustments
The patient’s family should communicate any abrupt changes in behavior to the health-care provider
Worsening behavior and suicidal tendencies that are not part of the presenting symptoms may require discontinuation of therapy
Not FDA approved for treatment of bipolar depression
Contraindications
Hypersensitivity
Concomitant pimozide or thioridazine
Breastfeeding
Coadministration with MAOIs
- Coadministration may cause serotonin syndrome
- Coadministration of MAOIs with fluoxetine or within 5 weeks of discontinuing fluoxetine
- Initiating fluoxetine within 14 days of stopping an MAOI
- Starting fluoxetine in a patient who is being treated with linezolid or IV methylene blue is contraindicated because of an increased risk of serotonin syndrome
- If linezolid or IV methylene blue must be administered, discontinue fluoxetine immediately and monitor for CNS toxicity; may resume fluoxetine 24 hr after last linezolid or methylene blue dose or after 5 weeks of monitoring, whichever comes first
Cautions
Clinical worsening and suicidal ideation may occur despite medication in adolescents and young adults (aged 18-24 years)
Risk of serotonin syndrome when used with other strong serotonergic drugs (see Contraindications and Drug Interactions)
Risk of bleeding (GI and other) when used in combination with NSAIDs, aspirin, or drugs affecting coagulation; may impair platelet aggregation
Activation of mania/hypomania (screen for bipolar disorder)
Fluoxetine therapy has been associated with occurrence of rash and allergic reaction, including vasclitis; discontinue if they occur
Bone fractures have been associated with antidepressant therapy; consider possibility of bone fracture when patient presents with bone pain
May cause or exacerbate sexual dysfunction
Use caution in patients with risk for QT prolongation, including congenital long QT syndrome, history of prolonged QT, or history of prolonged QT; QT prolongation and ventricular arrhythmia, iincluding torsade de pointes
Hyponatremia reported with use; consider discontinuation if symptomatic hyponatremia occurs
Use caution in patients with history of seizure disorders
May prolong QT interval and cause ventricular arrhythmia, including torsade de pointes
May cause nervousness, anxiety, insomnia, or anorexia
Risk of mydriasis; may trigger angle closure attack in patients with angle closure glaucoma with anatomically narrow angles without a patent iridectomy
Hypoglycemia reported; may alter glycemic control in patients with diabetes
Pregnancy: Conflicting evidence regarding use of SSRIs during pregnancy and increased risk of persistent pulmonary hypertension of the newborn, or PPHN (see Pregnancy)
Risk of complications in neonates exposed to SNRIs/SSRIs late in third trimester (eg, feeding difficulties, irritability, and respiratory problems)
Wait 1 week after discontinuation of Prozac before starting Prozac Weekly
Gradually decrease dose when discontinuing
Has long half-life, decrease in dose will not be fully reflected in plasma for several weeks
Pregnancy and lactation
Pregnancy
Pregnancy category: C
Treatment of pregnant women during the first trimester: There are no adequate and well-controlled clinical studies on the use of fluoxetine in pregnant women, but 1 prospective cohort study conducted by the European Network of Teratology Information Services reported an increased risk of cardiovascular malformations in infants born to women (N = 253) exposed to fluoxetine during the first trimester of pregnancy, compared with infants of women (N = 1359) who were not exposed to fluoxetine
Use late in the third trimester associated with complications in newborns and may require prolonged hospitalization, respiratory support, and tube feeding
A study of nearly 28,000 women taking SSRIs confirmed 2 previously reported birth defercts associated with fluoxetine - heart wall defects and craniosynostosis (BMJ 2015; 351:h3190)
Persistent pulmonary hypertension of the newborn
- Potential risk of PPHN when used during pregnancy
- Initial public health advisory, in 2006, was based on a single published study; since then, there have been conflicting findings from new studies, making it unclear whether the use of SSRIs during pregnancy can cause PPHN
- The FDA has reviewed the new study results and has concluded that, given the conflicting results from different studies, it is premature to reach any conclusion about a possible link between SSRI use in pregnancy and PPHN
- FDA recommendation: The FDA advises health-care professionals not to alter their current clinical practice of treating depression during pregnancy and to report any adverse events to the FDA MedWatch program
- A meta-analysis of 7 observational studies, found exposure to SSRIs in late pregnancy (ie, >20 weeks' gestation) more than doubled the risk of PPHN that could not be explained by other etiologies (eg, congenital malformations, meconium aspiration) (BMJ 2014;348:f6932)
Lactation
Excreted in milk; avoid (AAP states effect on nursing infants is unknown but may be of concern)
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Prozac, Sarafem (fluoxetine)
Mechanism of action
Selective serotonin reuptake inhibitor; little or no affinity for alpha-adrenergic histamine or cholinergic receptor
Absorption
Peak plasma time: 6-8 hr
Peak plasma concentration: 15-55 ng/mL
Steady-state plasma concentration: 91-302 ng/mL (parent drug), 72-258 ng/mL (metabolite)
Time to peak: 6-8 hr (serum)
Distribution
Protein bound: 95%
Vd: 12-43 L/kg
Metabolism
Hepatic P450 enzyme CYP2D6 substrate
Enzymes induced: CYP2C9
Enzymes inhibited: CYP2C19, CYP2D6, CYP3A4
Metabolites: Norfluoxetine
Elimination
Half-life: 4-6 days (chronic administration); 1-3 days (acute); 7-6 days (cirrhosis)
Dialyzable: No
Excretion: Urine (15%)
Pharmacogenomics
Several SSRIs (eg, fluoxetine, fluvoxamine, paroxetine, sertraline) are metabolized by CYP2D6
CYP2D6 is involved in the metabolism of approximately 20% of drugs in clinical use and displays large individual-to-individual variability in activity due to genetic polymorphisms
More than 80 CYP2D6 variant alleles have been identified; however, 4 of the most prevalent alleles, CYP2D6*3, *4, *5, and *6, account for 93-97% of CYP2D6 poor metabolizers (PMs)
CYP2D6*4, the most common variant (~25% frequency in whites), causes a splicing defect, CYP2D6*3 (2.7% frequency) causes a frameshift mutation, and CYP3D6*5 (2.6%) is an entire deletion of the CYP2D6 gene; individuals homozygous for these alleles have no CYP2D6 activity
The impact of CYP2D6 activity is further complicated by some SSRIs (eg, fluoxetine, fluvoxamine, paroxetine, sertraline) that, in addition to being substrates for CYP2D6, are also known to moderately inhibit CYP2D6 activity
Genetic testing laboratories
- Genotyping tests for CYP2D6 variants are commercially available through the following companies
- Applied Biosystems (https://www.appliedbiosystems.com/)
- GenPath Diagnostics (https://www.genpathdiagnostics.com/)
