Fluoxetine Hydrochloride

Pronunciation: (floo-OX-e-teen HYE-droe-KLOR-ide)Class: SSRI

Trade Names:Prozac- Capsules 10 mg- Capsules 20 mg- Capsules 40 mg- Solution, oral 20 mg per 5 mL

Trade Names:Prozac Weekly- Capsules, delayed-release 90 mg

Trade Names:Sarafem- Tablets 10 mg- Tablets 15 mg- Tablets 20 mg

Trade Names:Selfemra- Capsules 10 mg- Capsules 20 mg

Apo-Fluoxetine (Canada)CO Fluoxetine (Canada)FXT (Canada)Gen-Fluoxetine (Canada)Novo-Fluoxetine (Canada)Nu-Fluoxetine (Canada)PMS-Fluoxetine (Canada)ratio-Fluoxetine (Canada)Sandoz Fluoxetine (Canada)

Pharmacology

Presumed to be linked to inhibition of CNS neuronal reuptake of serotonin.

Pharmacokinetics

Absorption

T _max is 6 to 8 h. C _max is 15 to 55 ng/mL (40 mg dose). Food does not affect systemic bioavailability, but may delay absorption 1 to 2 h.

Distribution

Protein binding is approximately 94.5%.

Metabolism

Major metabolite is norfluoxetine (active) formed by demethylation. Primary route is hepatic (CYP2D6).

Elimination

The half-life is 1 to 16 days, including active metabolite. Primary route is renal excretion of inactive metabolites.

Special Populations

Renal Function Impairment

Routine dosage adjustment is not needed.

Hepatic Function Impairment

The half-life for fluoxetine and norfluoxetine is prolonged.

Elderly

In healthy subjects, the disposition of fluoxetine did not differ in patients older than 65 yr of age compared with younger patients.

Indications and Usage

Prozac

Major depressive disorder; depressive episodes associated with bipolar I disorder (only in combination with olanzapine); obsessive-compulsive disorder (OCD); bulimia nervosa; panic disorder; treatment-resistant depression (only in combination with olanzapine).

Sarafem , Selfemra

Premenstrual dysphoric disorder.

Unlabeled Uses

Alcoholism; borderline personality disorder; diabetic neuropathy; fibromyalgia; hot flashes; nocturnal enuresis; postherpetic neuralgia; posttraumatic stress disorder; Raynaud phenomenon; second-line prophylaxis of migraines.

Contraindications

Concurrent thioridazine use or within a minimum of 5 wk after discontinuing fluoxetine; concurrent use with or within a minimum of 14 days of discontinuing an MAOI (allow at least 5 wk after stopping fluoxetine before starting an MAOI); concurrent pimozide use; hypersensitivity to any component of the product.

Dosage and Administration

Bulimia NervosaAdults

PO Initial: 60 mg daily in the morning; for some patients it may be advisable to titrate up to this target dose over several days.

Depressive Episodes Associated With Bipolar I DisorderAdults

PO Initial: fluoxetine 20 mg/day with olanzapine 5 mg once daily in the evening. Adjust dose as needed according to efficacy and tolerability (max, fluoxetine 75 mg/day, olanzapine 18 mg/day).

Major Depressive DisorderAdults

PO Initial: 20 mg/day; increase after several weeks if insufficient clinical improvement noted (max, 80 mg/day). Weekly dosing (90 mg delayed-release capsule) may be started 7 days after last 20 mg/day dosage. If response is not satisfactory, consider reestablishing daily dosage regimen.

Children 8 yr of age and older

PO Initial: 10 mg/day; increase after 1 wk (several weeks in lower-weight children) if insufficient clinical improvement noted (max, 20 mg/day).

Obsessive-Compulsive DisorderAdults

PO Initial: 20 mg once daily in the morning; increase after several weeks if insufficient clinical improvement noted (max, 80 mg/day).

Children 7 yr of age and older

PO Initial: 10 mg/day; increase after 2 wk (several weeks in lower-weight children) if insufficient clinical improvement noted (max, 60 mg/day).

Panic DisorderAdults

PO Initial: 10 mg/day; increase to 20 mg/day after 1 wk. Further dose increases may be considered after several weeks if no clinical improvement noted (max, 60 mg/day).

Premenstrual Dysphoric Disorder ( Sarafem and Selfemra only)Adults

PO Initial: 20 mg/day continuously (every day of menstrual cycle) or intermittently (starting 14 days prior to anticipated onset of menstruation through first full day of menses and repeating with each new cycle); dose may be increased if no clinical improvement noted (max, 80 mg/day).

Treatment-Resistant DepressionAdults

PO Initial: fluoxetine 20 mg/day with olanzapine 5 mg once daily in the evening. Adjust dose as needed according to efficacy and tolerability (max, fluoxetine 75 mg/day, olanzapine 18 mg/day).

General Advice

• Capsule, tablet, oral solution, and delayed-release capsules are bioequivalent.
• Administer without regard to meals. Administer with food if GI upset occurs.
• Dosages above 20 mg/day may be administered on a once-daily (morning) or twice-daily schedule (eg, morning and noon).
• When used in combination with olanzapine, administer once-daily in the evening.
• Measure and administer prescribed dose of oral solution using dosing syringe, dosing spoon, or dosing cup.

Storage/Stability

Prozac , Sarafem

Store at 59° to 86°F. Protect from light.

Selfemra

Store at 68° to 77°F. Protect from light.

Drug Interactions

Alcohol

Potentiation of impairment of cognitive and motor skills. Concurrent use is not recommended.

Antipsychotics (eg, aripiprazole, clozapine, haloperidol, risperidone)

Serum levels may be increased. Elevated serum clozapine levels have occurred; closely monitor patients.

Benzodiazepines

Coadministration of alprazolam and fluoxetine has resulted in increased alprazolam levels and decreased psychomotor performance. Halve the initial alprazolam dose and titrate to lowest effective dose. Diazepam half-life may be prolonged.

Beta-blockers (eg, carvedilol, metoprolol, propranolol)

Elevated plasma concentrations of certain beta-blockers may occur, resulting in excessive beta-blockade.

Buspirone

Effects of buspirone may be decreased.

Carbamazepine

Increased carbamazepine levels, causing toxicity.

CNS active drugs

Use with caution, titrating the dose and monitoring the clinical status of the patient.

Cyclosporine

Concentrations of cyclosporine may be elevated, increasing the risk of toxicity.

Cyproheptadine

Decreased or reversed effects of fluoxetine.

Digoxin

The pharmacologic effects of digoxin may be increased, possibly because of displaced protein binding.

Drugs metabolized by CYP2D6

Because fluoxetine inhibits CYP2D6, fluoxetine may cause patients with normal CYP2D6 metabolic activity to resemble poor metabolizers. Coadminister fluoxetine with caution to patients receiving drugs that are CYP2D6 substrates, especially drugs with a narrow therapeutic index (eg, flecainide, propafenone, vinblastine).

5-HT ₁ agonists (eg, sumatriptan)

Increased risk of serotonin syndrome (eg, hyperreflexia, incoordination, weakness) has been reported rarely.

Hydantoins (eg, phenytoin)

Increased hydantoin levels, causing toxicity.

Linezolid, metoclopramide, narcotic analgesics (eg, oxycodone), sibutramine, sympathomimetics (eg, amphetamine), tramadol

Risk of serotonin syndrome may be increased.

Lithium

Lithium levels may be increased or decreased by fluoxetine, with possible neurotoxicity and increased serotonergic effects.

MAOIs

Combination may lead to serious, possibly fatal, reactions. Discontinue MAOI at least 14 days before starting fluoxetine; discontinue fluoxetine at least 5 wk before starting MAOIs.

Mirtazapine, olanzapine, propafenone, risperidone, valproic acid

Inhibition of metabolism by fluoxetine, resulting in elevated plasma concentrations and increasing the pharmacologic effects and risk of adverse reactions.

NSAIDs (eg, aspirin, ibuprofen)

The risk of GI bleeding may be increased.

Phosphodiesterase type 5 inhibitors (PDE5) (eg, sildenafil)

Metabolism inhibited by fluoxetine. Coadminister with caution; reduce initial dose of PDE5 inhibitor.

Pimozide

A case of life-threatening sinus bradycardia has been reported. Coadministration is contraindicated.

Protease inhibitors (eg, ritonavir)

Plasma concentrations of ritonavir and fluoxetine may be elevated, increasing the pharmacologic effects and adverse reactions of both agents. Risk of serotonin syndrome may be increased.

Protein-bound drugs

Because fluoxetine is tightly bound to plasma protein, the risk of adverse reactions may be increased if fluoxetine is displaced from protein-binding sites by other tightly bound drugs.

Serotonergic drugs

Because of the potential for serotonin syndrome, caution is advised when fluoxetine is administered with other drugs that may affect serotonergic neurotransmission (eg, lithium, St. John's wort, tramadol).

Tamoxifen

Plasma levels may be decreased by fluoxetine. Coadminister with caution.

Thioridazine

Concurrent use is contraindicated because of risk of prolongation of QTc interval and development of serious ventricular arrhythmias (eg, torsades de pointes) and sudden death.

Trazodone

Plasma levels may be increased by fluoxetine; serotonin syndrome may occur.

Tricyclic antidepressants

Increased toxic effects of tricyclic antidepressant. Dosage of tricyclic antidepressants may need to be reduced and plasma concentrations may need to be monitored when fluoxetine is coadministered or has been recently discontinued.

Tryptophan

The risk of CNS symptoms and peripheral toxicity may be increased.

Warfarin

The anticoagulant effects of warfarin may be increased, possibly because of displaced protein binding.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Vasodilation (5%); palpitations (3%); hemorrhage, hypertension (at least 1%); atrial fibrillation, heart arrest, QT prolongation, ventricular tachycardia including torsades de pointes–type arrhythmia (postmarketing).

CNS

Insomnia (33%); headache (24%); asthenia (21%); somnolence (17%); anxiety (15%); nervousness (14%); tremor (13%); decreased libido, dizziness (11%); abnormal thinking (6%); abnormal dreams (5%); agitation, hyperkinesia, personality disorder, thirst (at least 2%); amnesia, confusion, emotional lability, paresthesia, sleep disorder, suicidal ideation (at least 1%); cerebrovascular accident, dyskinesia, movement disorders, violent behaviors (postmarketing).

Dermatologic

Sweating (8%); rash (6%); pruritus (3%); epidermal necrolysis, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, thrombocytopenic purpura (postmarketing).

EENT

Rhinitis (23%); pharyngitis (11%); abnormal vision (3%); epistaxis (at least 2%); ear pain, taste perversion, tinnitus (at least 1%); cataract (postmarketing).

GI

Nausea (29%); diarrhea (18%); anorexia (17%); dry mouth (12%); dyspepsia (10%); abdominal pain (6%); constipation (5%); flatulence, vomiting (3%); increased appetite (at least 1%); pancreatitis (postmarketing).

Genitourinary

Abnormal ejaculation, impotence (7%); menorrhagia, urinary frequency (at least 2%); gynecomastia, kidney failure, vaginal bleeding (postmarketing).

Hematologic-Lymphatic

Aplastic anemia, immune-related hemolytic anemia, pancytopenia, thrombocytopenia (postmarketing).

Hepatic

Cholestatic jaundice, hepatic failure/necrosis (postmarketing).

Metabolic-Nutritional

Weight loss (3%); weight gain (at least 1%); hyperprolactinemia, hypoglycemia (postmarketing).

Respiratory

Yawn (11%); sinusitis (6%); eosinophilic pneumonia, pulmonary embolism, pulmonary hypertension (postmarketing).

Miscellaneous

Flu syndrome (12%); pain (9%); accidental injury (8%); infection (7%); fever (3%); chest pain, chills (at least 1%).

Precautions

Warnings Suicidality Compared with placebo, antidepressants increased the risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants for major depressive disorders and other psychiatric disorders. Appropriately monitor and closely observe patients of all ages who are started on antidepressant therapy for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber.

Monitor Monitor all patients for clinical worsening, suicidality, and unusual changes in behavior, especially during the first few months of therapy, or at times of dose changes, either increases or decreases. Frequently assess patient for response to treatment. Periodically review therapy to determine if therapy needs to be continued without change or if a dose change (eg, increase, decrease, discontinuation) is indicated. Monitor for signs and symptoms of hyponatremia, changes in weight, and for discontinuation symptoms if treatment is stopped.

Pregnancy

Category C . Neonates exposed to fluoxetine late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Consider potential risks and benefits of treatment when treating women during the third trimester.

Lactation

Excreted in breast milk.

Children

Safety and efficacy have not been established in children younger than 8 yr of age with depression, or younger than 7 yr of age with OCD. Safety and efficacy not established ( Sarafem and Selfemra ).

Elderly

No overall differences in safety and efficacy in patients 65 yr of age and older compared with younger subjects, but greater sensitivity cannot be ruled out.

Hypersensitivity

Anaphylactoid reactions, including angioedema, bronchospasm, laryngospasm, and urticaria, alone and in combination, have been reported.

Hepatic Function

Use lower dose or less frequent dosing in patients with cirrhosis.

Special Risk Patients

Use with caution in patients with diseases or conditions that could affect metabolism or hemodynamic response.

Hazardous Tasks

May impair judgment, thinking, or motor skills. Caution patients about operating potentially hazardous machinery (eg, driving) until they know whether the drug impairs their ability. Advise patients to avoid use of alcohol.

Abnormal bleeding

Bleeding episodes have occurred in patients treated with psychotropic drugs that interfere with serotonin reuptake.

Activation of mania/hypomania

Has been reported. Use cautiously in patients with history of mania.

Anxiety and insomnia

Treatment-emergent anxiety, nervousness, or insomnia have been reported.

Discontinuation of treatment

Withdrawal symptoms have been reported following rapid discontinuation of therapy. If treatment is to be discontinued, or the dose reduced, gradually taper the dose and monitor patient for withdrawal symptoms (eg, abnormal skin sensations, agitation, anxiety, confusion, dizziness, dysphoric mood, emotional lability, headaches, hypomania, insomnia, irritability, lethargy). If significant withdrawal symptoms develop, reinstitute previous dosing schedule and attempt a less rapid tapering regimen after patient has stabilized.

Dose changes

Because of the long elimination half-life of fluoxetine and norfluoxetine, changes in dose will not be fully reflected in plasma for several weeks, affecting titration to final dose and withdrawal from treatment.

Electroconvulsive therapy

Prolonged seizures have been reported in patients receiving concurrent electroconvulsive therapy treatment and fluoxetine.

Glycemic control

Hypoglycemia has occurred during treatment with fluoxetine, and hyperglycemia has developed following discontinuation of fluoxetine. Dosage adjustment of insulin and/or oral hypoglycemic drugs may be necessary.

Hyponatremia

Hyponatremia and/or SIADH may occur. Use with caution in patients who are elderly or volume-depleted, or taking diuretics.

NMS

Has occurred and is potentially fatal. Signs and symptoms include altered mental status, diaphoresis, hyperpyrexia, irregular BP, irregular pulse, muscle rigidity, and tachycardia.

Rash/Allergic events

Various types of rashes and/or urticaria have been reported, some with systemic signs and symptoms (eg, arthralgia, edema, fever, lymphadenopathy, respiratory distress, vasculitis). Discontinue fluoxetine upon appearance of rash or other possibly allergic phenomena.

Screening for bipolar disorder

A major depressive episode may be the initial presentation of bipolar disorder. Treating such an episode with an antidepressant alone may increase the likelihood of precipitating a mixed/manic episode in patients at risk for bipolar disorder. Screen patients with depression for risk of bipolar disorder prior to initiating therapy with an antidepressant.

Seizures

May occur; use with caution in patients with a history of seizures or with conditions that potentially lower the seizure threshold.

Serotonin syndrome

Development of a potentially life-threatening serotonin syndrome may occur with SSRIs, including fluoxetine, particularly with coadministration of serotonergic drugs (eg, 5-HT ₁ agonists [eg, sumatriptan]) and with drugs that impair metabolism of serotonin (eg, MAOIs).

Weight changes

Weight gain, as well as decreased appetite and weight loss, may occur in adult patients. Decreased weight gain has been reported in children. Document patient weight prior to and periodically during prolonged treatment.

Overdosage

Symptoms

Events reported with overdose of fluoxetine, alone or coadministered with other drugs, include abnormal accommodation, abnormal gait, coma, confusion, death in children, delirium, ECG abnormalities (eg, QT interval prolongation), elevated BP, hypomania, hypotension, impotence, mania, movement disorder, nausea, nervousness, NMS-like reaction, pulmonary dysfunction, pyrexia, seizures, somnolence, stupor, syncope, tachycardia, tremor, unresponsiveness, vertigo, vomiting.

Patient Information

• Advise patient, family, or caregiver to read the Medication Guide before starting therapy and with each refill, especially if the patient is a child or adolescent.
• Advise patient that dose will usually be started low and then increased until max benefit is obtained.
• Instruct patient to take prescribed dose without regard to meals, but to take with food if stomach upset occurs.
• Advise patient or caregiver using oral solution to measure and administer prescribed dose using dosing syringe, dosing spoon, or dosing cup.
• Instruct patient not to stop taking the medication when they feel better.
• Advise patients to inform their health care providers if they are taking or plan to take any prescription or OTC drugs or use alcohol. Also advise patients to inform their health care provider if they plan to discontinue any medications they are taking while on fluoxetine.
• Caution patient not to take aspirin or aspirin-containing products, NSAIDs, ginkgo biloba, or any other medication or herbal product that can affect coagulation because of increased risk of serious bleeding.
• Instruct patient to contact health care provider if symptoms do not appear to be getting better or are getting worse, or if bothersome adverse reactions (eg, excessive drowsiness, diarrhea, tremors, nausea, diarrhea, nervousness, changes in sexual function) occur.
• Advise patients of symptoms of serotonin syndrome or NMS-like reactions, including agitation, coma, diarrhea, hallucinations, hyperthermia, incoordination, muscle rigidity, nausea, tachycardia, and vomiting. Instruct patient to seek immediate medical care if these occur.
• Advise patients to report symptoms of hyponatremia, including confusion, difficulty concentrating, headache, memory impairment, unsteadiness that may lead to falls, and weakness. More severe symptoms include coma, hallucinations, respiratory arrest, seizure, and syncope.
• Advise patient to take frequent sips of water, suck on ice chips or sugarless hard candy, or chew sugarless gum if dry mouth occurs.
• Instruct diabetic patient to monitor blood glucose more frequently when drug is started or dose is changed and to inform health care provider of significant changes in readings.
• Advise patient being treated for depression, and family or caregiver of patient, to be alert for abnormal changes in mood or thinking and to immediately report any of the following to health care provider: change in personality, change in mood, anxiety, agitation, panic attacks, insomnia, irritability, hostility or aggressiveness, impulsivity, akathisia (psychomotor restlessness), suicidal thoughts or behavior. Advise families and caregivers of patients to observe for emergence on a day-to-day basis, because changes may be abrupt.
• Instruct patient or caregiver to immediately report rash, hives, or itching to health care provider.
• Advise patient that if medication needs to be discontinued, it will be slowly withdrawn unless safety concerns (eg, rash) require a more rapid withdrawal.
• Advise patient that drug may impair judgment, thinking, or motor skills, or cause drowsiness, and to use caution while driving or performing other tasks requiring mental alertness or coordination until tolerance is determined.

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