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.

Fluoxetine is well absorbed after oral administration. In man, following a single oral 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 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 metabolism to inactive metabolites excreted by the kidney.

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).

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 fluoxetine is discontinued, or when drugs that are predicted to interact with 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).

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.

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. Mean plasma concentrations were found to be 89.5 +- 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.

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).

In patients with cirrhosis, the elimination half-life of fluoxetine was prolonged, with a mean of 7.6 days compared to a 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 PRECAUTIONS and DOSAGE AND ADMINISTRATION).

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 hemodialysis. However, with chronic administration, additional accumulation of fluoxetine or its metabolites (possibly including some not yet identified) may occur in patients with severely impaired renal function and the use of a lower or less frequent dose is advised (see PRECAUTIONS).

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.

BIOAVAILABILITY

In two recently conducted studies, the bioavailability of ratio *-FLUOXETINE (fluoxetine hydrochloride) 10 and 20 mg capsules (ratiopharm inc.), was compared with respect to the Canadian reference product, Prozac(r), 10 and 20 mg capsules (Eli Lilly Canada, Inc.) under single dose, fasting conditions.

Fluoxetine 10 mg capsule comparative bioavailability study: Of the 26 healthy male volunteers enrolled in this study, one did not complete the crossover. Pharmacokinetic and statistical analyses were conducted on data from 24 subjects (Subject Nos. 1-11, 13-24 and 26). The relative bioavailability of ratio *- FLUOXETINE (mfr by ratiopharm inc.) and Prozac(r) (mfr by Eli Lilly Canada, Inc.) 10 mg flu oxetine hydrochloride capsules is shown in Table 1 below.

) and Eli Lilly (Prozac(r)) fluoxetine hydrochloride 10 mg capsules under fasting conditions following administration of a single 40 mg dose.

Fluoxetine 20 mg capsule comparative bioavailability study: Of the 26 healthy male volunteers enrolled in this study, one did not complete the crossover. Pharmacokinetic and statistical analyses were conducted on data from 24 subjects (Subject Nos. 1, 3-24 and 26). The relative bioavailability of ratio *-FLUOXETINE (mfr by ratiopharm inc.) and Prozac(r) (Mfr by Eli Lilly).

) and Eli Lilly (Prozac(r)) fluoxetine hydrochloride 20 mg capsules under fasting conditions following administration of a single 40 mg dose.

The Tmax parameter is expressed as the arithmetic means. Conclusion: The 90% confidence intervals for the ln-transformed parameters AUC0-72 and Cmax for fluoxetine were within the 80-125% TPD acceptance range both before and after correction for measured content. Based on these results, the ratiopharm inc. (ratio *-FLUOXETINE) and Eli Lilly (Prozac(r)) 10 and 20 mg fluoxetine HCL capsules are bioequivalent under single dose, fasting conditions.

(fluoxetine hydrochloride) is indicated for the symptomatic relief of depressive illness.

has been shown to significantly decrease binge-eating and purging activity when compared with placebo treatment.

has been shown to significantly reduce the symptoms of obsessive- compulsive disorder in double-blind, placebo-controlled clinical trials.

The obsessions or compulsions must be experienced as intrusive, markedly distressing, time consuming, or interfering significantly with the person's social or occupational functioning. The efficacy of fluoxetine in hospitalized patients has not been adequately studied. The effectiveness of fluoxetine in long-term use (i.e., for more than 5 to 6 weeks in depression, for more than 16 weeks in bulimia nervosa, or for more than 13 weeks in obsessive compulsive disorder), has not been systematically evaluated in controlled trials. Therefore, the physician who elects to use ratio *-FLUOXETINE for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

CONTRAINDICATIONS

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

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 a MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Therefore, ratio *-FLUOXETINE should not be used in combination with a MAOI or within a minimum of 14 days of discontinuing therapy with a MAOI. Since fluoxetine and its major metabolite have very long elimination half-lives, at least 5 weeks should be allowed after stopping ratio *-FLUOXETINE before starting a MAOI. Limited reports suggest that intravenously administered dantrolene (Dantrium(r)) or orally administered cyproheptadine (Periactin(r)) may benefit patients experiencing such reactions.

WARNINGS

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

Recent analyses of placebo-controlled clinical trial safety databases from SSRIs and other newer anti-depressants suggest 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.

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.

Patients currently taking 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 treatment, a gradual reduction in the dose rather than an abrupt cessation, except for fluoxetine, is recommended. (See WARNINGS: IMPLICATIONS OF THE LONG ELIMINATION HALF-LIFE OF FLUOXETINE).

During premarketing testing of more than 5 600 patients given fluoxetine, approximately 4% developed a rash and/or urticaria. Among these cases, almost a third were withdrawn from 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 2 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, 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, 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, ratio *-FLUOXETINE should be discontinued. Particular caution should be exercised in patients with a history of allergic reactions.

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

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 ratio *-

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.

Significant weight loss, especially in underweight depressed patients and the elderly, may be an undesirable result of treatment with fluoxetine.

During premarketing clinical trials in a patient population comprised primarily of unipolar depressives, 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.

(fluoxetine hydrochloride) 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.

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.

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 overdosage, prescriptions for ratio *-FLUOXETINE (fluoxetine hydrochloride) 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).

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 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 ECGs 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.

(fluoxetine hydrochloride) 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.

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 a placebo-controlled, double-blind trial in elderly patients, 10 of 313 fluoxetine treated patients and 6 of 320 placebo-treated patients had a lowering of serum sodium below the reference range. The lowest observed concentration of sodium in a fluoxetine treated patient was 129 mmol/L.

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.

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

Safe use of fluoxetine during pregnancy has not been established. Therefore, ratio *- FLUOXETINE (fluoxetine hydrochloride) 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 child.

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 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.

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.

Monoamine oxidase inhibitors: Combined use of ratio *-FLUOXETINE (fluoxetine hydrochloride) and MAOIs 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 3 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 co-administered or has been recently discontinued. (See Accumulation and Slow elimination under ACTIONS AND CLINICAL PHARMACOLOGY and Drugs metabolized by 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.

The half-life of concurrently administered diazepam may be prolonged in some patients. 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).

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.

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.

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), phenothiazine 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, encainida, 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.

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.

ADVERSE REACTIONS

Commonly observed:

In clinical trials, the most commonly observed adverse events associated with the use of fluoxetine and not seen at an equivalent incidence among placebo treated patients were: CNS complaints, including headache, nervousness, insomnia, drowsiness, fatigue or asthenia, anxiety, tremor, and dizziness or lightheadedness; gastrointestinal complaints, including nausea, diarrhea, dry mouth and anorexia; and excessive sweating.

Adverse events leading to discontinuation of treatment:

Fifteen percent of approximately 4 000 patients who received fluoxetine in North American clinical trials discontinued treatment due to an adverse event. The more common events causing discontinuation from depression trials in adults and elderly, included: psychiatric, primarily nervousness, anxiety, and insomnia; digestive, primarily nausea; nervous system, primarily dizziness, asthenia and headaches; skin, primarily rash and pruritus. In obsessive-compulsive disorder studies, 12.1% of fluoxetine treated patients discontinued treatment early because of adverse events. Anxiety, and rash, at incidences of less than 2%, were the most frequently reported events. In bulimia nervosa studies, 10.2% of fluoxetine treated patients discontinued treatment early because of adverse events. Insomnia, anxiety and rash, at incidences of less than 2%, were the most frequently reported events.

Serious adverse reactions:

Suicidal thoughts and acts are far more common among depressed patients than in the general population. It is estimated that suicide is 22 to 36 times more prevalent in depressed persons than in the general population. A comprehensive meta-analysis of pooled data from 17 double-blind clinical trials in patients with major depressive disorder compared fluoxetine (n=1 765) with a tricyclic antidepressant (n=731) or placebo (n=569), or both. The pooled incidence of emergence of substantial suicidal ideation was 1.2% for fluoxetine, 2.6% for placebo, and 3.6% for tricyclic antidepressants. In countries where the drug has already been marketed, the following potentially serious adverse reactions have been reported: interactions with MAOIs and possibly other drugs, allergic reactions, cardiovascular reactions, syndrome of inappropriate ADH secretion, and grand mal seizure. Death and life-threatening events have been associated with some of these reactions, although causal relationship to fluoxetine has not been necessarily established. Postmarketing experience also confirms the profile of adverse reactions commonly reported during clinical trials with fluoxetine including allergic skin reactions.

Adverse experience reports:

The pattern of treatment-emergent adverse experience incidence (>=5%) for both fluoxetine and placebo was somewhat different in bulimia and obsessive-compulsive disorder (OCD) trials than in the adult and elderly depression studies, and is summarized overleaf in Table I. Table 1

Percentage of patients reporting event

DEPRESSION

(Elderly)

OCD BULIMIA
Body system/ Adverse event	Fluoxetine (N=1 730)	Placebo (N= 799)	Fluoxetine (N=335)	Placebo (N= 336)	Fluoxetine (N=264)	Placebo (N= 89)	Fluoxetine (N=418)	Placebo (N=210)
N ERVOUS
Headache	20.3	15.5	27.5	23.8	32.6	23.6	30.1	26.9
Nervousness	14.9	8.5	12.2	7.4	14.4	14.6	10.8	5.2
Isomnia	13.8	7.1	18.2	12.5	29.6	22.5	33.1	15.0
Somnolence	11.6	6.3	9.3	5.7	17.1	6.7	12.7	7.1
Anxiety	9.4	5.5	13.1	8.0	13.6	6.7	16.3	11.1
Tremor	7.9	2.4	7.8	3.9	9.1	1.1	13.7	2.0
Dizziness	5.7	3.3	11.0	10.1	13.3	11.2	11.4	5.4
Libido, decreased	1.6	-	-	-	11.4	2.3	5.9	0.9
Depression	-	-	-	-	8.0	14.6	10.1	16.4
Emotional lability	-	-	-	-	-	-	2.7	7.8
DIGESTI VE
Nausea	21.1	10.1	16.7	7.4	26.5	13.5	29.7	13.5
Diarrhea	12.3	7.0	14.3	8.9	18.2	13.5	7.5	6.7
Dry mouth	9.5	6.0	6.6	4.8	12.1	3.4	9.9	8.6
Anorexia	8.7	1.5	10.7	1.8	16.7	10.1	8.8	4.4
Dyspepsia	6.4	4.3	11.0	5.1	9.9	4.5	10.7	6.7
Gastrointestinal disorder	-	-	-	-	5.7	1.1	5.7	5.9
Constipation	-	-	6.9	6.3	4.2	6.7	4.8	4.6
Flatulence	-	-	7.2	2.4	3.4	5.6	-	-

Percentage of patients reporting event

NERVOUS

DIGESTIVE

DEPRESSION

(Elderly)

OCD BULIMIA
Body system/ Adverse event	Fluoxetine (N=1 730)	Placebo (N= 799)	Fluoxetine (N=335)	Placebo (N= 336)	Fluoxetine (N=264)	Placebo (N= 89)	Fluoxetine (N=418)	Placebo (N=210)
SKIN & APPENDAGES
Sweating , excessive	8.4	3.8	7.2	3.3	7.2	-	8.9	1.6
Rash	-	-	-	-	6.4	3.4	5.1	4.9
BODY AS A WHOLE
Asthenia	4.4	1.9	12.8	10.1	15.2	10.1	21.7	9.6
Flu syndrome	-	-	-	-	9.9	6.7	10.1	5.9
Back pain	-	-	6.9	8.6	2.7	5.6	3.9	7.0
Infection	-	-	-	-	-	-	6.2	6.2
Abdominal pain	-	-	6.0	5.7	4.9	11.2	9.6	6.5
Myalgia	-	-	3.3	5.4	-	-	4.7	9.4
RESPIRATO RY
Upper respiratory infection	7.6	6.0	-	-	-	-	-	-
Rhinitis	-	-	9.0	14.3	22.7	23.6	23.0	29.1
Pharyngitis	-	-	-	-	10.6	9.0	11.1	5.5
Sinusitis	-	-	3.3	6.8	-	-	5.7	6.9
Yawn	-	-	-	-	7.2	-	11.1	0.8
CARDIOVASCULAR
Vasodilatation	-	-	-	-	5.3	-	-	-
UROGENITAL
Menstrual disorder	-	-	-	-	3.4	5.6	8.3	4.8
Dysmenorrhea	-	-	-	-	3.4	5.6	6.1	7.8
Urinary frequency	-	-	-	-	-	-	6.2	1.6
Urinary tract infection	-	-	-	-	-	-	5.1	2.0

The following adverse reactions, were reported on at least one occasion by patients during treatment with fluoxetine either during clinical trials or after marketing. All reported events are included except those where a drug cause was remote or the event term so general as to be unhelpful. Multiple events may have been reported by a single patient and related to a single condition, which may have preexisted. Therefore, while the following events occurred during treatment with fluoxetine, they were not necessarily caused by it. Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring on 1 or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in less than 1/100 but at least 1/1 000 patients; rare events are those occurring in less than 1/1 000 patients.

Allergic or toxic:

Frequent:

rash, pruritus.

Infrequent:

chills and fever, urticaria, maculopapular rash.

Rare

: allergic reaction, erythema multiforme, vesiculobullous rash, serum sickness, contact dermatitis, erythema nodosum, purpuric rash, leukocytoclastic vasculitis, leukopenia, thrombocytopenia, arthralgia, angioedema, bronchospasm, lung fibrosis, allergic alveolitis, larynx edema, respiratory distress.

Neurologic:

Frequent:

headache, tremor, dizziness or lightheadedness, asthenia.

Infrequent:

abnormal gait, ataxia, akathisia, buccoglossal syndrome, hyperkinesia, hypertonia, incoordination, neck rigidity, extrapyramidal syndrome, convulsions, photophobia, myoclonus, vertigo, migraine, tinnitus, hyposthesia, neuralgia, neuropathy, acute brain syndrome.

Rare:

dysarthria, dystonia, torticollis, decreased reflexes, nystagmus, paralysis, paresthesia, carpal tunnel syndrome, stupor, coma, abnormal EEG, chronic brain syndrome, dyskinesia and other movement disorders (including worsening of preexisting conditions or appearance in patients with risk factors [e.g., Parkinson's disease, treatment with neuroleptics or other drugs known to be associated with movement disorders]), neuroleptic malignant syndrome-like events.

Behavioural:

Frequent:

insomnia, anxiety, nervousness, agitation, abnormal dreams, drowsiness and fatigue.

Infrequent:

confusion, delusions, hallucinations, manic reaction, paranoid reaction, psychosis, depersonalization, apathy, emotional lability, euphoria, hostility, amnesia, increased libido.

Rare:

antisocial reaction, hysteria, suicidal ideation, violent behaviours.

Autonomic:

Frequent:

excessive sweating.

Infrequent:

dry mouth, constipation, urinary retention, vision disturbance, diplopia, mydriasis, hot flushes.

Cardiovascular:

Infrequent:

chest pain, hypertension, syncope, hypotension (including postural hypotension), angina pectoris, arrhythmia, tachycardia.

Rare:

bradycardia, ventricular arrhythmia, first degree AV block, bundle branch block, myocardial infarct, cerebral ischemia, cerebral vascular accident, thrombophlebitis.

Gastrointestinal:

Frequent:

nausea, disturbances of appetite, diarrhea.

Infrequent

: vomiting, stomatitis, dysphagia, eructation, esophagitis, gastritis, gingivitis, glossitis, melena, thirst, abnormal liver function tests.

Rare:

bloody diarrhea, hematemesis, gastrointestinal hemorrhage, duodenal ulcer, stomach ulcer, mouth ulceration, hyperchlorhydria, colitis, enteritis, cholecystitis, cholelithiasis, hepatitis, hepatomegaly, liver tenderness, jaundice, increased salivation, salivary gland enlargement, tongue discolouration, fecal incontinence, pancreatitis.

Respiratory:

Frequent:

bronchitis, rhinitis, yawn.

Infrequent:

asthma, dyspnea, hyperventilation, pneumonia, hiccups, epistaxis.

Rare:

apnea, lung edema, hypoxia, pleural effusion, hemoptysis.

Endocrine:

Frequent:

weight loss.

Infrequent:

generalized edema, peripheral edema, face edema, tongue edema, hypoglycemia, hypothyroidism, weight gain.

Rare:

dehydration, gout, goitre, hyperthyroidism, hypercholesteremia, hyperglycemia, hyperlipemia, hyperprolactinemia, hypokalemia, hyponatremia, iron deficiency anemia, syndrome of inappropriate ADH secretion.

Hematologic:

Infrequent

: anemia, lymphadenopathy, hemorrhage.

Rare:

bleeding time increased, leukocytosis, lymphocytosis, thrombocytopenia, thrombocytopenic purpura, thrombocythemia, retinal hemorrhage, petechia, purpura, sedimentation rate increased, aplastic anemia, pancytopenia, immune-related hemolytic anemia.

Dermatologic:

Infrequent:

acne, alopecia, dry skin, herpes simplex.

Rare:

eczema, psoriasis, seborrhea, skin hypertrophy, skin discolouration, herpes zoster, fungal dermatitis, hirsutism, ecchymoses.

Musculoskeletal:

Frequent

: muscle pain, back pain, joint pain.

Infrequent:

arthritis, bone pain, bursitis, tenosynovitis, twitching.

Rare:

bone necrosis, osteoporosis, pathological fracture, chondrodystrophy, myositis, rheumatoid arthritis, muscle hemorrhage.

Urogenital:

Frequent:

painful menstruation, impotence, sexual dysfunction, urinary tract infection, frequent micturition.

Infrequent:

abnormal ejaculation, menopause, amenorrhea, menorrhagia, ovarian disorder, vaginitis, leukorrhea, fibrocystic breast, breast pain, cystitis, dysuria, urinary urgency, urinary incontinence.

Rare

: breast enlargement, galactorrhea, abortion, dyspareunia, uterine spasm, vaginal hemorrhage, metrorrhagia, hematuria, albuminuria, polyuria, pyuria, epididymitis, orchitis, pyelonephritis, salpingitis, urethritis, kidney calculus, urethral pain, urolithiasis.

Miscellaneous:

Frequent:

chills, abnormal vision.

Infrequent:

amblyopia, conjunctivitis, cyst, ear pain, eye pain, jaw pain, neck pain, pelvic pain, hangover effect, malaise.

Rare:

abdomen enlarged, blepharitis, cataract, corneal lesion, glaucoma, iritis, ptosis, strabismus, deafness, taste loss, moniliasis, hydrocephalus, LE syndrome.

SYMPTOMS AND TREATMENT OF OVERDOSAGE

During clinical trials, there were 2 deaths among approximately 38 reports of acute overdose with fluoxetine, either alone or in combination with other drugs and/or alcohol. One death involved a combined overdose with approximately 1 800 mg of fluoxetine and an undetermined amount of maprotiline. Plasma concentrations of fluoxetine and maprotiline were 4.57 mg/L and 4.18 mg/L, respectively. A second death involved 3 drugs yielding plasma concentrations as follows: fluoxetine, 1.93 mg/L; norfluoxetine, 1.10 mg/L; codeine, 1.80 mg/L; temazepam, 3.80 mg/L. One other patient who reportedly took up to 3 000 mg of fluoxetine experienced 2 grand mal seizures that remitted spontaneously without specific treatment. Since vomiting occurred, the amount of drug absorbed may have been less than that ingested. In the postmarketing phase, there have been 16 confirmed reports of overdose of fluoxetine taken alone. The amount of drug ingested has varied from 80 mg to 2 000 mg and the patients have ranged in age from 13 to 51 years. There have been no deaths in this group of patients, some of whom were treated vigorously with activated charcoal in the acute phase. Furthermore, patient recoveries were remarkable in the absence of serious adverse events with the exception of a 13 year old male who ingested 1 880 mg and experienced 2 brief seizures but thereafter had an uneventful recovery. Since introduction, reports of death attributed to overdosage of fluoxetine alone have been rare.

Symptoms:

Nausea and vomiting were prominent in overdoses involving higher fluoxetine doses. Other prominent symptoms of overdose included agitation, restlessness, hypomania, and other signs of CNS excitation, including seizures.

Treatment:

Establish and maintain an airway; ensure adequate oxygenation and ventilation. Activated charcoal, which may be used with sorbitol, may be as or more effective than emesis or lavage, and should be considered in treating overdose. Cardiac and vital signs monitoring is recommended, along with general symptomatic and supportive measures. Based on experience in animals, which may not be relevant to humans, fluoxetine-induced seizures which fail to remit spontaneously may respond to diazepam. There are no specific antidotes for fluoxetine. Due to the large volume of distribution of fluoxetine, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a Poison Control Centre on the treatment of any overdosage.

DOSAGE AND ADMINISTRATION

ratio *-SERTRALINE (sertraline) is not indicated for use in children under 18 years of age (see WARNINGS: POTENTIAL ASSOCIATION WITH BEHAVIOURAL AND EMOTIONAL CHANGES, INCLUDING SELF-HARM).

Since it may take up to 4 or 5 weeks to reach steady-state plasma levels of fluoxetine, sufficient time should be allowed to elapse before dosage is gradually increased. Higher dosages are usually associated with an increased incidence of adverse reactions.

Depression:

Initial adult dosage: The usual initial dosage is 20 mg administered once daily in the morning. A gradual dose increase should be considered only after a trial period of several weeks if the expected clinical improvement does not occur. Dosage should not exceed a maximum of 80 mg per day since clinical experience with doses above 80 mg per day is very limited.

Use in the elderly: Fluoxetine was in depressed elderly patients evaluated only at a dosage of 20 mg/day. A lower or less frequent dosage may be effective and should be considered in elderly patients with concurrent disease or on multiple medications.

Use in children: The safety and effectiveness of fluoxetine in patients below the age of 18 years have not been established. (see WARNINGS: POTENTIAL ASSOCIATION WITH BEHAVIOURAL AND EMOTIONAL CHANGES, INCLUDING SELF-HARM).

Bulimia nervosa:

Adult dosage: The recommended dosage is 60 mg per day, although studies show that lower doses may also be efficacious. Electrolyte levels should be assessed prior to initiation of treatment.

Obsessive-compulsive disorder:

A dose range of 20 mg per day to 60 mg per day is recommended for the treatment of obsessive-compulsive disorder. For any indication, the total fluoxetine dosage should not exceed a maximum of 80 mg per day since clinical experience with doses above 80 mg per day is very limited. During maintenance therapy, the dosage should be kept at the lowest effective level.

A lower or less frequent dosage should be used in patients with renal and/or hepatic impairment and in those on multiple medications.

Switching patients to a tricyclic antidepressant (TCA):

Dosage of a TCA may need to be reduced, and plasma TCA concentrations may need to be monitored temporarily when fluoxetine is co-administered or has been recently discontinued (see tricyclic antidepressants under Drug interactions).

Switching patients to or from a monoamine oxidase inhibitor (MAOI):

At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with ratio *-FLUOXETINE (fluoxetine hydrochloride). In addition, at least 5 weeks, perhaps longer, should be allowed after stopping ratio *-FLUOXETINE (fluoxetine hydrochloride) before starting an MAOI (see CONTRAINDICATIONS).

Drugs substance

PHARMACEUTICAL INFORMATION

Trade name: ratio *-FLUOXETINE Proper name: fluoxetine hydrochloride Chemical name: (+)-N-methyl-3-phenyl-3-[4-(trifluoromethyl)-phenoxy]- propylamine hydrochloride Structural formula: Molecular formula: C17H18F3NO.HCl Molecular weight: 345.79 Physical form: White to almost white, crystalline powder. Solubility : Sparingly soluble in water and in dichloromethane; freely soluble in alcohol and in methanol; practically insoluble in ether.

Composition: ratio *-FLUOXETINE

10 mg capsules contain: 11.18 mg

fluoxetine hydrochloride equivalent to 10 mg of fluoxetine base. Non-medicinal ingredients in alphabetical order: Black ink, black iron oxide, D&C yellow #10, FD&C blue # 1, FD&C yellow # 6, gelatin, pregelatinized corn starch, silicone dioxide, sodium lauryl sulfate and titanium dioxide.

ratio *-FLUOXETINE

20 mg capsules contain: 22.36 mg fluoxetine hydrochloride equivalent to 20 mg of fluoxetine base. Non-medicinal ingredients in alphabetical order: Black ink, D&C yellow #10, FD&C blue #1, FD&C yellow #6, gelatin, pregelatinized corn starch, silicone dioxide, sodium lauryl sulfate and titanium dioxide.

AVAILABILITY OF DOSAGE FORMS

ratio *-FLUOXETINE

(fluoxetine hydrochloride) 10 mg capsules are grey and light green, imprinted with TEC 137A, packaged in white HDPE bottles of 100.

ratio *-FLUOXETINE

(fluoxetine hydrochloride) 20 mg capsules are ivory and light green, imprinted with TEC 137B, packaged in white HDPE bottles of 100 and 500.

Storage: Store at 15 - 30oC. Keep tightly closed. Protect from light.

PHARMACOLOGY

In vitro and in vivo studies have shown fluoxetine and norfluoxetine (the major metabolite) to be potent and selective inhibitors of neuronal pre-synaptic reuptake of serotonin. Serotonin released into the synaptic cleft by a nerve impulse is inactivated principally by reuptake into the presynaptic nerve ending where it is metabolized or retained in storage granules. Fluoxetine specifically 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 behavioural 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- hydroxy-tryptophan-induced head twitch in mice, potentiated 5-hydroxytryptophan- induced depression of operant behaviour in pigeons, and potentiated the behavioural 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 microsomes. In vivo, fluoxetine was metabolized mainly by N-demethylation in mice, rats, guinea pigs, rabbits, and dogs. The other major metabolite was trifluoro- methylphenol, formed by O-dealkylation, which was excreted as a sulfate 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.

Acute toxicity:

TOXICOLOGY

Species	Route	Sex	Fluoxetine LD 5 0 (mg/kg)	Norfluoxetine LD 5 0 (mg/kg)
Mouse	Oral	F	248 +- 14	361 +- 14
	I.V.	F	45 +- 1.5	42 +- 3
Rat	Oral	M	467 +- 33
		F	437 +- 40
Rat	I.V.	M	35 +- 1
		F	35 +- 1	37 +- 2
Guinea Pig	Oral	M	>250
Cat	Oral	M/F	> 50
Dog	Oral	M/F	>100
Monkey	Oral	M/F	>50

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 hyperactivity 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 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 toxicity:

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. .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 evidence 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 norfluoxetine, 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 administration 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 antidepressants - imipramine, clomipramine, iprindole and other drugs - chlorphentermine, fenfluramine, clozapine, chloroquine, mepacocine, chlorcyclizine, tamoxifen, 4,4'diethylaminoethoxyhexestrol, 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.

THERAPEUTIC CLASSIFICATION

ACTIONS AND CLINICAL PHARMACOLOGY

BIOAVAILABILITY

CONTRAINDICATIONS

WARNINGS

ADVERSE REACTIONS

DEPRESSION

NERVOUS

DIGESTIVE

DEPRESSION

BODY AS A WHOLE

RESPIRATORY

CARDIOVASCULAR

UROGENITAL

REFERENCES