PRODUCT MONOGRAPH

APO-FLUOXETINE

Fluoxetine Hydrochloride Capsules USP 10 mg and 20 mg

APO-FLUOXETINE

Fluoxetine Hydrochloride Oral Solution USP 20 mg/5 mL

Antidepressant/Antiobsessional/ Antibulimic Agent

APOTEX INC. DATE OF PREPARATION:

150 Signet Drive March 19, 1996

Weston, Ontario DATE OF REVISION:

M9L 1T9 May 9, 2005

Control Number # 096160

PRODUCT MONOGRAPH

APO-FLUOXETINE Fluoxetine Hydrochloride Capsules USP 10 mg and 20 mg Fluoxetine Hydrochloride Oral Solution USP 20 mg/5 mL

ACTIONS AND CLINICAL PHARMACOLOGY

The antidepressant, antiobsessional and antibulimic actions of fluoxetine are presumed to be linked to its ability to selectively inhibit the neuronal reuptake of serotonin. At clinically relevant doses fluoxetine blocks the uptake of serotonin into human platelets. Antagonism of muscarinic, histaminergic and a1-adrenergic receptors has been hypothesized to be associated with various anticholinergic, sedative and cardiovascular effects of classical tricyclic antidepressant drugs. In vitro receptor binding studies have demonstrated that fluoxetine binds to these and other membrane receptors [opiate, serotonergic (5-HT1, 5-HT2), adrenergic (a1, a2, b) and dopaminergic] much less potently than do the tricyclic drugs.

Pharmacokinetics: Fluoxetine is well absorbed after oral administration. In man, following a single 40 mg dose, peak plasma concentrations of fluoxetine from 15 to 55 ng/mL are observed after 6 to 8 hours. The capsule and oral solution dosage forms of Apo-fluoxetine are bioequivalent. Food does not appear to affect the systemic bioavailability of fluoxetine, although it may delay its absorption inconsequentially. Thus, fluoxetine may be administered with or without food. Fluoxetine is extensively metabolized in the liver to norfluoxetine, and other unidentified metabolites. The pharmacological activity of norfluoxetine, which is formed by demethylation of fluoxetine appears to be similar to that of the parent drug. Norfluoxetine contributes to the long duration of action of fluoxetine. The primary route of elimination appears to be hepatic meta- bolism to inactive metabolites excreted by the kidney. The elimination half-life of fluoxetine is 4 to 6 days and that of its active metabolite is 4 to 16 days.

Comparative Bioavailability

A two-way, single-dose, randomized, crossover bioavailability study using 18 normal male volun- teers was conducted to evaluate the relative bioavailability of APO-FLUOXETINE 20 mg Capsules and Prozac(r) 20 mg Capsules (manufactured by Eli Lilly Inc.). The mean pharmacokinetic parameters obtained are listed below.

• For raw data; for Tmax these are medians.

* *Based on the geometric means for AUC0-72, AUCT AUCI and Cmax and arithmetic

means for Tmax, l and t1/2.

For raw data; for Tmax these are medians.

* *Based on the geometric means for AUC0-72, AUCT AUCI and Cmax and arithmetic

means for Tmax, l and t1/2.

Clinical Issues Related To Metabolism/Elimination

Variability in Metabolism

The metabolism of fluoxetine, like that of a number of other compounds, including tricyclic antidepressants and some selective serotonin reuptake inhibitors, involves the P450IID6 system. Concomitant therapy with fluoxetine and the aforementioned drugs may lead to clinically significant drug interactions (see Drug Interactions under PRECAUTIONS).

Accumulation and Slow Elimination

The relatively slow elimination of fluoxetine and its active metabolite, norfluoxetine, results in significant accumulation of these active moieties in chronic use. Therefore, it may take up to 1 to 2 months for the active drug substance(s) to disappear from the body. This persistence of active moieties is important to keep in mind when APO-FLUOXETINE is discontinued, or when drugs that are predicted to interact with APO-FLUOXETINE are to be administered soon after its discontinuation (see Implications of the Long Elimination Half-Life of Fluoxetine under WARNINGS and Drug Interactions under PRECAUTIONS).

Kinetic Data

After 30 days of dosing at 20 mg/day, mean plasma concentrations of fluoxetine 79.1 +- 33.4 ng/mL and of norfluoxetine 129 +- 42.0 ng/mL have been observed. Plasma concentrations of fluoxetine (elimination half-life of 1 to 3 days after acute administration and 4 to 6 days after chronic administration) were higher than those predicted by single dose studies. Norfluoxetine appears to have linear pharmacokinetics. Its mean terminal half-lives after a single dose and multiple doses were 8.6 days and 9.3 days, respectively. Steady state plasma levels are attained after 4 to 5 weeks of continuous drug administration. Patients receiving fluoxetine at doses of 40 to 80 mg/day over periods as long as 3 years exhibited, on average, plasma concentrations similar to those seen among patients treated for 4 to 5 weeks at the same dose.

Age

The effects of age upon the metabolism of fluoxetine have been investigated in a subset of 260 elderly, but otherwise healthy, depressed patients (mean age: 67.4 years, range 60 to 85 years) who received 20 mg fluoxetine for 6 weeks. The mean plasma concentrations were found to be +- 53.6 ng/mL for fluoxetine and 119 +- 51.3 ng/mL for norfluoxetine. However, the effects of concomitant illness and/or concomitant drugs have not been evaluated.

Protein Binding

Approximately 94% of fluoxetine is protein bound. The interaction between fluoxetine and other highly protein bound drugs has not been fully evaluated, but may be important (see PRECAUTIONS).

Liver Disease

In patients with cirrhosis, the elimination half-life of fluoxetine was prolonged, with a mean of 7.6 days compared to the range of 2 to 3 days seen in healthy subjects; norfluoxetine half-life was also prolonged, with a mean of 12 days compared to a range of 7 to 9 days in healthy subjects. Fluoxetine should therefore be used with caution in patients with liver disease (see PRE- CAUTIONS and DOSAGE AND ADMINISTRATION).

Renal Disease

In single dose studies, the pharmacokinetics of fluoxetine and norfluoxetine were similar among subjects with all levels of impaired renal function including anephric patients on chronic hemo- dialysis. However, with chronic administration, additional accumulation of fluoxetine or its meta- bolites (possibly including some not yet identified) may occur in patients with severely impaired renal function and use of a lower or less frequent dose is advised (see PRECAUTIONS).

Clinical Trials

The efficacy of fluoxetine was established in 5 and 6-week placebo-controlled clinical trials in depressed outpatients ($18 years of age), who met the DSM-III-R criteria for major depressive disorder. Two, 6-week placebo-controlled clinical trials in depressed elderly patients, who met the DSM-III- R criteria for major depressive disorder (mean age 67.4 years, range 60 to 85 years) have shown fluoxetine, 20 mg/day, to be effective. A study was conducted involving depressed outpatients who had responded (modified HAMD-17 score of 7 during each of the last 3 weeks of open-label treatment and absence of major depression by DSM-III-R criteria) by the end of an initial 12-week open treatment phase on fluoxetine 20 mg/day. These patients (N=298) were randomized to continuation on double-blind fluoxetine 20 mg/day or placebo. At 38 weeks (50 weeks total), a statistically significantly lower relapse rate (defined as symptoms sufficient to meet a diagnosis of major depression for 2 weeks or a modified HAMD-17 score of $14 for 3 weeks) was observed for patients taking fluoxetine compared to those on placebo.

CONTRAINDICATIONS

APO-FLUOXETINE (fluoxetine hydrochloride) is contraindicated in patients with known hypersensitivity to the drug.

Monoamine Oxidase Inhibitors

There have been reports of serious, sometimes fatal, reactions (including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma) in patients receiving fluoxetine in combination with a monoamine oxidase inhibitor (MAOI), and in patients who have recently discontinued fluoxetine and then started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Therefore, APO-FLUOXETINE should

not be used in combination with an MAOI, or within 14 days of discontinuing therapy with an MAOI.

Since fluoxetine and its major metabolite have very long elimination half-lives, at least 5 weeks should be allowed after stopping APO-FLUOXETINE before starting an MAOI. Limited reports suggest that intravenously administered dantrolene (Dantrium(r)) or orally administered cyproheptadine (Periactin(r)) may benefit patients experiencing such reactions.

Thioridazine - Thioridazine should not be ad ministered with fluoxetine or within a minimum of 5 weeks after fluoxetine has been discontinued (see WARNINGS)

WARNINGS

POTENTIAL ASSOCIATION WITH BEHAVIOURAL AND EMOTIONAL CHANGES, INCLUDING SELF-HARM

Pediatrics: Placebo-Controlled Clinical Trial Data

Recent analyses of placebo-controlled clinical trial safety databases from SSRIs and other newer anti-depressants suggests that use of these drugs in patients under the age of 18 may be associated with behavioural and emotional changes, including an increased risk of suicidal ideation and behaviour over that of placebo.

The small denominators in the clinical trial database, as well as the variability in placebo rates, preclude reliable conclusions on the relative safety profiles among these drugs.

Adults and Pediatrics: Additional data

there are clinical trial and post-marketing reports with SSRIs and other newer anti- depressants, in both pediatrics and adults, of severe agitation-type adverse events coupled with self-harm or harm to others. The agitation-type events include:

akathisia, agitation, disinhibition, emotional lability, hostility, aggression, depersonalization. In some cases, the events occurred within several weeks of starting treatment.

Rigorous clinical monitoring for suicidal ideation or other indicators of potential for suicidal behaviour is advised in patients of all ages. This includes monitoring for agitation-type emotional and behavioural changes.

Discontinuation Symptoms

Patients currently taking SSRIs or a newer anti-depressant should NOT be discontinued abruptly, due to risk of discontinuation symptoms. At the time that a medical decision is made to discontinue an SSRI or other newer anti-depressant drug, a gradual reduction in the dose rather than an abrupt cessation, except for fluoxetine, is recommended. Plasma fluoxetine and norfluoxetine concentrations decrease gradually at the conclusion of therapy which makes dose tapering unnecessary in most patients taking this drug (see PRECAUTIONS: DISCONTINUATION OF TREATMENT WITH FLUOXETINE (POST- MARKETING AND CLINICAL TRIALS); ADVERSE REACTIONS: Discontinuation of

Treatment with Fluoxetine (Post-Marketing and Clinical Trials); DOSAGE AND ADMINISTRATION: DISCONTINUATION OF TREATMENT WITH FLUOXETINE).

Allergic Reactions (Rash and Accompanying Events)

During premarketing testing, 7% of 10,782 patients developed various types of a rash and/or urticaria. Among these cases, almost a third were withdrawn from the treatment because of the rash and/or systemic signs or symptoms associated with the rash. Clinical findings reported in association with these allergic reactions include rash, fever, leukocytosis, arthralgias, edema, carpal tunnel syndrome, respiratory distress, lymphadenopathy, proteinuria, and mild transaminase elevation. Most patients improved promptly with discontinuation of fluoxetine and/or adjunctive treatment with antihistamines or steroids, and all patients experiencing these events were reported to recover completely. In premarketing clinical trials, two patients are known to have developed a serious cutaneous systemic illness. In neither patient was there an unequivocal diagnosis, but one was considered to have a leukocytoclastic vasculitis, and the other severe desquamation that was considered variously to be a vasculitis or erythema multiforme. Other patients have had systemic manifestations suggestive of serum sickness. Since the introduction of fluoxetine, systemic events, possibly related to vasculitis, and including lupus-like syndrome, have developed in patients with rash. Although these events are rare, they may be serious, involving the lung, kidney, or liver. Death has been reported to occur in association with these systemic events. Anaphylactoid events, including bronchospasm, angioedema, laryngospasm and urticaria alone and in combination, have been reported. Pulmonary events, including inflammatory processes of varying histopathology and/or fibrosis, have been reported rarely. These events have occurred with dyspnea as the only preceding symptom. Whether these systemic events and rash have a common underlying cause or are due to different etiologies or pathogenic processes is not known. Furthermore, a specific underlying immunologic basis for these events has not been identified. Upon the appearance of rash or of other possibly allergic phenomena for which an alternative etiology cannot be identified, APO-FLUOXETINE (fluoxetine hydrochloride) should be discontinued. Particular caution should be exercised in patients with a history of allergic reactions.

Potential Interaction with Thioridazine

In a study of 19 healthy male subjects, which included 6 slow and 13 rapid hydroxylators of debrisoquin, a single 25 mg oral dose of thioridazine produced a 2.4-fold higher Cmax and a 4.5- fold higher AUC for thioridazine in the slow hydroxylators compared to the rapid hydroxylators. The rate of debrisoquin hydroxylation is felt to depend on the level of cytochrome P4502D6 isozyme activity. Thus, this study suggests that drugs which inhibit P4502D6, such as certain SSRIs, including fluoxetine, will produce elevated plasma levels of thioridazine (see PRECAUTIONS). Thioridazine administration produces a dose-related prolongation of the QTc interval which is associated with serious ventricular arrhythmias, such as torsades de pointes-type arrhythmias, and sudden death. This risk is expected to increase with fluoxetine-induced inhibition of thioridazine metabolism (see CONTRAINDICATIONS).

Implications of the Long Elimination Half-Life of Fluoxetine

Because of the long elimination half-lives of fluoxetine and its major active metabolite norfluoxetine, changes in dose will not be fully reflected in plasma for several weeks, affecting both strategies for titration to final dose and withdrawal from treatment (see ACTIONS AND CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). Even when dosing is stopped, active drug substance will persist in the body for weeks due to the long elimination half- lives of fluoxetine and norfluoxetine. This is of potential consequence when drug discontinuation is required or when drugs are prescribed that might interact with fluoxetine and norfluoxetine following discontinuation of APO-FLUOXETINE.

PRECAUTIONS

Anxiety and Insomnia

During premarketing clinical trials anxiety, nervousness and insomnia were reported by 10 to 15% of patients treated with fluoxetine. These symptoms led to discontinuation of the drug in 5% of the patients.

Weight Change

Significant weight loss, especially in underweight depressed patients and the elderly, may be an undesirable result of treatment with APO-FLUOXETINE (fluoxetine hydrochloride).

Mania/Hypomania

During pre-marketing clinical trials in a patient population comprised primarily of unipolar depres- sives, hypomania or mania occurred in approximately 1% of fluoxetine treated patients. The incidence in a general patient population which might also include bipolar depressives is unknown. The likelihood of hypomanic or manic episodes may be increased at the higher dosage levels. Such reactions require a reduction in dosage or discontinuation of the drug.

Seizures

APO-FLUOXETINE should be used with caution in patients with a history of convulsive disorders. The incidence of seizures associated with fluoxetine during clinical trials did not appear to differ from that reported with other marketed antidepressants; however, patients with a history of convulsive disorders were excluded from these trials. Concurrent administration with electroshock therapy should be avoided because of the absence of experience in this area. There have been rare reports of prolonged seizures in patients on fluoxetine receiving ECT treatment. DISCONTINUATION OF TREATMENT WITH FLUOXETINE (POST-MARKETING AND CLINICAL TRIALS): When discontinuing treatment, patients should be monitored for symptoms which may be associated with discontinuation (e.g. headache, insomnia, paresthesias, nervousness, anxiety, nausea, sweating, numbness, dizziness, jitteriness, asthenia or other symptoms which may be of clinical significance). Fluoxetine has been only rarely associated with such symptoms. Plasma fluoxetine and norfluoxetine concentrations decrease gradually at the conclusion of therapy, which makes dose tapering unnecessary in most patients (See ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION).

Hypokalemia

Self-induced vomiting often leads to hypokalemia which may lower seizure threshold and/or may lead to cardiac conduction abnormalities. Electrolyte levels of bulimic patients should be assessed prior to initiation of treatment.

Suicide

The possibility of a suicide attempt is inherent in depression and may persist until significant remission occurs. Therefore, high risk patients should be closely supervised throughout therapy and consideration should be given to the possible need for hospitalization. In order to minimize the opportunity for over-dosage, prescriptions for fluoxetine should be written for the smallest quantity of drug consistent with good patient management (see WARNINGS: POTENTIAL ASSOCIATION WITH BEHAVIOURAL AND EMOTIONAL CHANGES, INCLUDING SELF- HARM).

Concomitant Illness

Clinical experience with fluoxetine in patients with concomitant systemic illness is limited and it should be used cautiously in such patients, especially those with diseases or conditions that could affect metabolism or hemodynamic responses. Fluoxetine hydrochloride has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were systematically excluded from premarketing clinical studies. Retrospective evaluation of EKG's in some of these studies showed no conduction abnormalities that resulted in heart block. The mean heart rate was reduced by approximately 3 beats/minute. APO-FLUOXETINE should be given with caution to patients suffering from anorexia nervosa and only if the expected benefits (e.g. co-morbid depression) markedly outweigh the potential weight reducing effect of the drug. In patients with diabetes, fluoxetine may alter glycemic control. Hypoglycemia has occurred during therapy with fluoxetine, and hyperglycemia has developed following discontinuation of the drug. As is true with many other types of medication when taken concurrently by patients with diabetes, insulin and/or oral hypoglycemic dosage may need to be adjusted when therapy with fluoxetine is instituted or discontinued. Since fluoxetine is extensively metabolized, excretion of unchanged drug in urine is a minor route of elimination. However, until an adequate number of patients with severe renal impairment have been evaluated in the course of chronic treatment, fluoxetine should be used with caution in such patients. Since clearances of fluoxetine and norfluoxetine may be decreased in patients with impaired liver function including cirrhosis, a lower or less frequent dose should be used in such patients.

Hyponatremia

Several cases of hyponatremia (some with serum sodium lower than 110 mmol/L) have been reported. The hyponatremia appeared to be reversible when fluoxetine was discontinued. Although these cases were complex with varying possible etiologies, some were possibly due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH). The majority of these occurrences have been in older patients and in patients taking diuretics or who were otherwise volume depleted. In two 6-week controlled studies in patients $60 years of age, 10 of 323 fluoxetine patients and 6 of 327 placebo recipients had a lowering of serum sodium below the reference range; this difference was not statistically significant. The lowest observed concentration of sodium in a fluoxetine treated patient was 129 mmol/L. The observed decreases were not clinically significant.

Platelet Function

There have been rare reports of altered platelet function and/or abnormal results from laboratory studies in patients taking fluoxetine. While there have been reports of abnormal bleeding in several patients taking fluoxetine, it is unclear whether fluoxetine had a causative role.

Cognitive and Motor Performance

Patients should be cautioned against driving an automobile or performing hazardous tasks until they are reasonably certain that treatment with APO-FLUOXETINE does not affect them adversely.

Electroconvulsive Therapy (ECT)

There are no clinical studies to support the safety and efficacy of combined use of ECT and fluoxetine. There have been rare reports of prolonged seizures in patients on fluoxetine receiving ECT treatment.

Use in Pregnancy

Safe use of fluoxetine during pregnancy has not been established. Therefore it should not be administered to women of childbearing potential unless, in the opinion of the treating physician, the expected benefits to the patient markedly outweigh the possible hazards to the fetus or the child. Post-marketing reports indicate that some neonates exposed to FLUOXETINE, other SSRIs (Selective Serotonin Reuptake Inhibitors), or other newer anti-depressants late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and other newer anti-depressants, or possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see CONTRAINDICATIONS, Monoamine Oxidase Inhibitors). When treating a pregnant woman with FLUOXETINE during the third trimester, the physician should carefully consider the potential risks and benefits of treatment (see DOSAGE AND ADMINISTRATION).

Use in Lactation

Fluoxetine and its metabolites are excreted in breast milk and have been observed to reach high plasma levels in nursing infants. Women who are taking APO-FLUOXETINE should not breast feed unless in the opinion of the treating physician, breast feeding is necessary, in which case the infant should be closely monitored. In one breast milk sample, the concentration of fluoxetine plus norfluoxetine was 70.4 ng/mL. The concentration in the mother's plasma was 295.0 ng/mL. No adverse effects on the infant were reported. In another case, a 6-week infant, nursed by a mother on fluoxetine, developed crying, decreased sleep, vomiting and watery stools. The breast milk showed concentrations of 69 ng/mL for fluoxetine and 90 ng/mL for norfluoxetine. In the infant's plasma, the concentrations of fluoxetine and norfluoxetine on the second day of feeding were 340 and 208 ng/mL, respectively. Safety and effectiveness in patients below the age of 18 have not been established.

Use in the Elderly

Evaluation of patients over the age of 60 who received fluoxetine 20 mg daily revealed no unusual pattern of adverse events relative to the clinical experience in younger patients. These data are, however, insufficient to rule out possible age-related differences during chronic use, particularly in elderly patients who have concomitant systemic illnesses or who are receiving concomitant drugs.

DRUG INTERACTIONS

Monoamine Oxidase Inhibitors

Combined use of fluoxetine and MAO inhibitors is contraindicated (see CONTRAINDICATIONS).

Tricyclic Antidepressants

In two studies, previously stable plasma levels of imipramine and desipramine have increased greater than 2 to 10 fold when fluoxetine has been administered in combination. This influence may persist for three weeks or longer after fluoxetine is discontinued. Thus, the dose of tricyclic antidepressant (TCA) may need to be reduced and plasma TCA concentrations may need to be monitored temporarily when fluoxetine is coadministered or has been recently discontinued (see Accumulation and Slow Elimination under ACTIONS AND CLINICAL PHARMACOLOGY and P450 Isoenzyme [IID6] under PRECAUTIONS). There have been reports of both increased and decreased lithium levels when lithium was used concomitantly with fluoxetine. Cases of lithium toxicity have been reported. Lithium levels should be monitored when these drugs are administered concomitantly.

Tryptophan

Five patients receiving fluoxetine in combination with tryptophan experienced adverse reactions, including agitation, restlessness and gastrointestinal distress.

Benzodiazepines

The half-life of concurrently administered diazepam may be prolonged in some patients. Coadministration of alprazolam and fluoxetine has resulted in increased alprazolam plasma concentrations and in further psychomotor performance decrement due to increased alprazolam levels. Consideration should be given to monitoring of clinical status. Experience with the use of fluoxetine in combination with other CNS-active drugs is limited and caution is advised if such concomitant medication is required (see WARNINGS).

Phenytoin

In patients on stable, maintenance doses of phenytoin, plasma phenytoin concentrations increased substantially and symptoms of phenytoin toxicity appeared (nystagmus, diplopia, ataxia and CNS depression) following initiation of concomitant fluoxetine treatment. Patients on stable doses of phenytoin and carbamazepine have developed elevated plasma anticonvulsant concentrations and clinical anticonvulsant toxicity following initiation of concomitant fluoxetine treatment. Consideration should be given to monitoring of clinical status when fluoxetine treatment is initiated in these patients.

Antipsychotics

Elevation of blood levels of haloperidol and clozapine and in some cases, clinical manifestations of toxicity have been observed with coadministration of fluoxetine. Consideration should be given to monitoring of clinical status.

Sumatriptan

There have been rare postmarketing reports describing patients with weakness, hyperreflexia, and incoordination following the use of an SSRI and sumatriptan. If concomitant treatment with sumatriptan and an SSRI (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline, or citalopram) is clinically warranted, appropriate observation of the patient is advised.

Alcohol

The concomitant use of fluoxetine and alcohol on cognitive and psychomotor effects in depressed, panic disorder or OCD patients is not known and is not recommended. In common with other SSRI's, pharmacodynamic interactions between fluoxetine and the herbal remedy St. John's Wort may occur and may result in an increase in undesirable effects.

Drugs Tightly Bound to Plasma Protein

Because fluoxetine is highly bound to plasma protein, the administration of fluoxetine to a patient taking another drug which is tightly bound to protein (e.g. warfarin, digitoxin) may cause a shift in plasma concentrations potentially resulting in an adverse effect. Conversely, adverse effects may result from displacement of protein bound fluoxetine by other tightly bound drugs.

Warfarin

Altered anti-coagulant effects, including increased bleeding, have been reported when fluoxetine is co-administered with warfarin. Serious bleeding events have been reported including five with outcome of death. However, a causal relationship to the bleeding events cannot be established. Therefore, patients receiving warfarin therapy should receive careful coagulation monitoring when fluoxetine is initiated or stopped.

Drugs Metabolized by P450 Isoenzyme (IID6)

Approximately 3 to 10% of the normal population has a genetic defect that leads to reduced levels of activity of the cytochrome P450 isoenzyme P450IID6. Such individuals have been referred to as "poor metabolizers" of drugs such as debrisoquine, dextromethorphan, sparteine, tricyclic antidepressants (e.g. nortriptyline, amitriptyline, imipramine and desipramine), pheno- thiazine neuroleptics (e.g. perphenazine and thioridazine) and Type 1C antiarrhythmics (e.g. propafenone and flecainide). Conversely, approximately 90 to 97% of the normal population do not have this genetic defect, and are known as "extensive metabolizers". Fluoxetine, like other agents that are metabolized by the P450IID6 system, inhibits the activity of this isoenzyme, and thus may make normal "extensive" metabolizers resemble "poor metabolizers". Therapy with medications that are predominantly metabolized by the P450IID6 system and that have a relatively narrow therapeutic index (e.g. flecainide, encainide, vinblastine, carbamazepine and tricyclic antidepressants) should be initiated at the low end of the dose range if a patient is receiving fluoxetine concurrently, or has taken it in the previous 5 weeks. If fluoxetine is added to the treatment regimen of a patient already receiving a drug metabolized by P450IID6 the need for decreased dose of the original medication should be considered. The aforementioned drugs with a narrow therapeutic index represent the greatest concern. Due to the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, thioridazine should not be administered with fluoxetine or within a minimum of 5 weeks after fluoxetine has been discontinued (see CONTRAINDICATIONS and WARNINGS).

Drugs Metabolized by Cytochrome P4503A4

In an in vivo interaction study involving co-administration of fluoxetine with single doses of terfenadine (a cytochrome P4503A4 substrate), no increase in plasma terfenadine concentrations occurred with concomitant fluoxetine. In addition, in vitro studies have shown ketoconazole, a potent inhibitor of P4503A4 activity, to be at least 100 times more potent than fluoxetine or norfluoxetine as an inhibitor of the metabolism of several substrates for this enzyme, including astemizole, cisapride, and midazolam. These data indicate that fluoxetine's extent of inhibition of cytochrome P4503A4 activity is not likely to be of clinical significance.

Dependence Liability

Fluoxetine has not been systematically studied, in animals or humans, for its potential for abuse, tolerance or physical dependence. Physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of fluoxetine.

PHARMACOLOGY

In vitro and in vivo studies have shown fluoxetine and norfluoxetine (the major metabolite) to be potent and selective inhibitors of neuronal presynaptic reuptake of serotonin. Serotonin released into the synaptic cleft by a nerve impulse is inactivated principally by reuptake into the pre- synaptic nerve ending where it is metabolized or retained in storage granules. Fluoxetine specifi- cally inhibits the reuptake process, thereby allowing serotonin to remain longer in the synaptic cleft and enhancing the action of the neurotransmitter on synaptic receptors. Fluoxetine has only weak affinity for various receptor systems in receptor binding studies. A number of behavioral, neuroendocrinologic, and other pharmacologic effects of fluoxetine in experimental animals have been attributed to its enhancement of serotonergic function by inhibition of serotonin uptake. Fluoxetine restored the capacity for acquisition of passive avoidance task in olfactory bulbectomized rats, potentiated 5-hydroxytryptophan-induced head twitch in mice, potentiated 5-hydroxytryptophan-induced depression of operant behavior in pigeons, and potentiated the behavioral effect of 5-hydroxytryptophan in rats working on a milk reinforcement schedule. Fluoxetine suppressed REM sleep in rats and cats, and reduced the amount or altered the composition of dietary intake in rats. It also selectively reduced non-protein caloric intake in rats. Few pharmacologic actions of fluoxetine other than inhibition of serotonin uptake and consequences of that inhibition have been found. For instance, fluoxetine does not antagonize reserpine or apomorphine-induced hypothermia in mice, and does not reduce immobility in the forced swimming test in rats.

Pharmacokinetics: Fluoxetine was well absorbed orally and the oral bioavailability of fluoxetine in dogs was 72%. In dogs given oral doses of 1 to 10 mg/kg fluoxetine for one year, dose dependent increases in fluoxetine and norfluoxetine concentrations were observed in liver, adrenal, and lung. Norfluoxetine concentrations exceeded fluoxetine concentrations in the tissues, and persisted for a longer period in plasma. In rats, after a single i.p. dose of 10 mg/kg, the plasma half-life of fluoxetine was 26 hours and that of norfluoxetine, 40 hours. The plasma half-life in dogs dosed orally at 5 to 10 mg/kg for 15 days, was 1 day for fluoxetine and 2.1 to 5.4 days for norfluoxetine.

In vitro, fluoxetine was N-demethylated to norfluoxetine by rat, guinea pig, and rabbit liver micro- somes. In vivo, fluoxetine was metabolized mainly by N-demethylation in mice, rats, guinea pigs, rabbits, and dogs. The other major metabolite was p-trifluoromethylphenol, formed by O-dealkylation, which was excreted as a sulphate or glucuronide conjugate by rats, guinea pigs, and dogs. Fluoxetine and norfluoxetine were also excreted in the urine unchanged in guinea pigs, rabbits, and dogs. In rats, fluoxetine and norfluoxetine were both further metabolized, so that neither fluoxetine nor its N-demethylated metabolite was found in the urine. Rats eliminated 16 to 42 percent of the dose in urine as p-trifluoromethylphenol and 8 percent of the dose as hippuric acid in 24 hours.

TOXICOLOGY

Acute Toxicity

Signs of toxicity included vomiting, anorexia, mydriasis, salivation, tremors, clonic convulsions, hyperirritability and cachexia.

Subchronic Toxicity

Mice (5/sex/dose) were maintained on diets containing ca. 25, 59 and 204 mg/kg/day fluoxetine for 15 days. Thirty and 100% mortality were observed at the middle and high dose, respectively. Significant effects at the two highest doses included: hyperactivity and body weight loss, decrease in spleen weights and phospholipidosis. Mice were maintained for three months on diets equivalent to ca. 2, 7 or 31 mg/kg/day. Significant effects were essentially limited to high dose mice and included 15% mortality; persistent hyperac- tivity and decreased body weight gain; slight and reversible increases in alkaline phosphatase and alanine transaminase; decreases in testes, heart, and spleen weights; hypospermatogenesis; reversible pulmonary phospholipidosis. Pulmonary histiocytosis (phospholipidosis) was the major pathological finding in rats maintained on diets providing average doses of approximately 9, 25 or 74 mg/kg/day for three months. All animals at ca. 74 mg/kg/day died by week 8. Decreased food consumption, weight loss, and hyperirritability were observed at ca. 25 and 74 mg/kg/day. Dogs given 5 to 50 mg/kg/day orally for two weeks experienced anorexia, mydriasis and vomiting. Dogs receiving 50 mg/kg/day exhibited ataxia, tremors and a convulsion in one dog. Dogs survived oral doses up to 20 mg/kg/day for three months with significant anorexia as the major treatment related effect. Significant accumulation of both fluoxetine and norfluoxetine occurred in the plasma and tissues. Mydriasis and tremors were observed during the first month. Monkeys given 10 or 25 mg/kg/day p.o. for two weeks exhibited anorexia and weight loss. One monkey at 25 mg/kg/day exhibited clonic convulsions after six doses. Accumulation of fluoxetine and norfluoxetine was observed after multiple dosing and decreased erythrocyte and white blood cell counts were observed.

Chronic Toxicology

Fluoxetine was given daily to rats (25/sex/dose) for one year at dietary levels of ca. 0.5, 2.3 and 10.7 mg/kg/day. Physical signs of toxicity were limited to females at the high dose level and consisted of anorexia, chromodacryorrhea and an unusual behaviour first noted during the eighth month of treatment in which the animals walked on their toes with feet extended and backs arched after they had been handled. Evidence of phospholipidosis was obtained in the lung, liver and adrenal cortex of 24/40 animals at the high dose level and in one rat at the mid dose level. Phospholipidosis was reversible after two months' withdrawal from treatment. Minimal to slight fat deposition in the liver was prevalent at the mid- and high-dose levels. Reversible, minimal reticuloendothelial cell hyperplasia was present in the lymph nodes of the high dose level animals. Dogs (5/sex/dose) received daily oral doses of 1, 4.5, or 20 mg/kg (decreased to 10 mg/kg after 6 months as three females died) of fluoxetine for one year. The toxic effects observed in this study were similar to those of the subchronic study except that phospholipidosis was seen after chronic administration in the lung, liver, adrenals, the inner plexiform layer of the retina, lymph nodes, spleen, and peripheral leukocytes in the animals receiving the high dose. They also showed moderate bradycardia and a moderate decrease in adrenal weight. Phospholipidosis was only observed in the lung and leukocytes in a few of the dogs at the lowest dose level of 1.0 mg/kg/day. No cardiovascular effects were seen apart from a slight decrease in basal heart rate. All treatment related effects were reversible during the recovery period in surviving animals.

Carcinogenicity

Rats were maintained for two years at dietary levels equivalent to a time weighted average dose of ca. 0.45, 2 and 9 mg/kg/day. Age related observations such as chromodacryorrhea, alopecia, and poor grooming increased at the high dose, especially in females. Weight gain and food consumption were depressed at the high dose and a handling-induced behaviour involving arching of the back and walking on toes was observed primarily in females in this group. Increased tissue levels of fluoxetine and norfluoxetine were observed at all doses, and phospholipidosis was observed primarily at the high dose. There were no significant increases in tumor incidence or animal mortality. Mice were fed dietary levels of fluoxetine equivalent to ca. 1.2, 4.8 and 12.1 mg/kg/day. The dietary levels were based on the results of the three month subchronic study. Unexpectedly, high mortality occurred in females receiving the high dose early in the two-year study, necessitating lowering the dose after 30 days. The survival rate of females receiving the high dose was reduced at two years. No major toxicological effects were seen in mice other than a moderate increase in alanine transaminase in males receiving the high dose and slight changes in organ weights. Hepatocellular degeneration, fat deposition in liver, and centrilobular hepatocellular degeneration were observed microscopically at the median and high dose. There was no evi- dence of phospholipid accumulation in the lung and no oncogenic response was observed. A second two-year mouse study using similar doses gave similar results. Survival at two years was reduced in females receiving the high dose. Handling-induced clonic convulsions occurred at all levels in males, and in females, at the high-dose level it was accompanied by a slight increase in liver weight. Minimal-to-moderate fatty change in the liver and hepatocellular cytomegaly were seen in mice from the median- and high-dose levels. There was a dose- dependent increase in concentrations of fluoxetine and norfluoxetine in lung tissue. There was no evidence of phospholipid accumulation in the lung, and no oncogenic response was observed.

Mutagenicity

The mutagenicity of fluoxetine and its metabolite norfluoxetine was evaluated in a battery of in vitro and in vivo tests including Ames test, modified Ames test, DNA repair in rat hepatocytes, sister chromatid exchange in Chinese hamster bone marrow assays, and mouse lymphoma assay. Fluoxetine and norfluoxetine were negative in all 5 systems.

Teratology Studies

Virgin female Fischer 344 rats (25/dose) were bred with untreated control males and were given daily oral (gavage) doses of 2, 5, or 12.5 mg/kg/day fluoxetine on gestation days 6-15; animals were evaluated on gestation day 20. Body weight gains and food consumption were depressed at 12.5 mg/kg/day. Fluoxetine produced no teratogenic effects and no changes in reproductive parameters. Virgin female Dutch Belted rabbits (15/dose) were artificially inseminated with semen from untreated control males and were given daily oral (gavage) doses of 2.5, 7.5, or 15 mg/kg/day fluoxetine on gestation days 6-18; animals were evaluated on gestation day 28. Maternal toxicity was demonstrated by depressed body weight gains and food consumption at all dose levels in a dose-dependent manner. At the 15 mg/kg/day dose, two rabbits died and three aborted. Resorptions were also increased in this group. There was no evidence of a teratogenic effect.

Reproductive Studies

Female Wistar rats (30/dose) were given daily oral doses of 2, 5, or 12.5 mg/kg from two weeks prior to mating through gestation or lactation. In a second study, male Wistar rats (40/dose) were maintained on diets approximately equivalent to 1.5, 3.9, or 9.7 mg/kg for 10 weeks prior to mating and through the breeding trial. These treated males were mated with female Wistar rats (40/dose) maintained at the same dietary levels for three weeks prior to mating and throughout lactation. In both studies, a depression in neonatal survival was obtained at the high dose level. No teratogenic effects or adverse effects on fertility or post-natal development were associated with fluoxetine administration.

Discussion of Phospholipidosis

Systemic phospholipidosis was associated with the subchronic and/or chronic administration of fluoxetine to mice, rats and dogs. This effect was associated with the accumulation of norfluoxe- tine, and to a lesser extent, fluoxetine, in affected tissues. Systemic phospholipidosis was not associated with any adverse effects and was shown to be reversible after the chronic admini- stration of fluoxetine for one year in rats and dogs. This effect has been demonstrated in animals with a number of other clinically useful cationic amphiphilic drugs including anti-depressants - imipramine, clomipramine, iprindole and other drugs - chlorphentermine, fenfluramine, clozapine, chloroquine, mepacocine, chlorcyclizine, tamoxifen, 4,4Ndiethylaminoethoxyhexestrol, amiodarone and perhexiline. The significance of this finding for man is not fully understood. It is anticipated that in the clinical use of fluoxetine, the properties of the drug which are associated with phospholipidosis will not result in any untoward effect.

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