Data Sheet

PROZAC^® 20

Fluoxetine hydrochloride. Lilly

Presentation

PROZAC 20 capsules are presented as size 3, green/cream capsules bearing the identicode "Lilly 3105" printed in black ink on both the capsule cap and base. Each capsule contains fluoxetine hydrochloride equivalent to 20 mg fluoxetine.

Uses

Actions

PROZAC 20 is an antidepressant intended for oral administration.
Fluoxetine is a selective inhibitor of serotonin reuptake, its presumed mechanism of action. Fluoxetine has practically no affinity to other receptors such as α1-, α2- and β-adrenergic; serotonergic; dopaminergic; histaminergic; muscarinic; and GABA receptors.

Pharmacokinetics

Absorption and distribution

Fluoxetine is well absorbed after oral administration. Peak plasma concentration is reached in six to eight hours. Fluoxetine is extensively bound to plasma proteins. Fluoxetine is widely distributed. Steady-state plasma concentrations are achieved after dosing for several weeks. Steady-state concentrations after prolonged dosing are similar to concentrations seen at four to five weeks.

Metabolism and excretion

Fluoxetine is extensively metabolised in the liver to norfluoxetine and a number of other, unidentified metabolites which are excreted in urine. The elimination half-life of fluoxetine is four to six days and that of its active metabolite is four to 16 days.

Pharmacological Properties

Pharmacodynamic properties - The aetiology of premenstrual dysphoric disorder is unknown, but endogenous steroids (neuro and/or ovarian) involved in the menstrual cycle may interrelate with neuronal serotonergic activity.

Clinical data premenstrual dysphoric disorder (PMDD): In clinical trials fluoxetine was shown to be effective in relieving both the cyclical mood changes and physical symptoms (tension, irrritability and dysphoria, bloating and breast tenderness) associated with PMDD.

Indications

Depression and it's associated anxiety,

Bulimia nervosa,

Obsessive-Compulsive disorder and

Premenstrual dysphoric disorder - a severe form of PMS.
Diagnosis of PMDD: The essential features of PMDD are clear and established cyclicity of symptoms (occurring during the last week of the luteal phase in most menstrual cycles) such as depressed mood, anxiety, affective lability, and physical symptoms such as breast tenderness or swelling, headaches, joint or muscle pain, bloating, and weight gain. PMDD is a severe clinical entity and is distinguished from the broader premenstrual syndrome by the intensity of its symptoms (particularly mood symptoms) and the extent to which it interferes with social and/or occupational function.

Dosage and Administration

Depression

20 mg per day is the recommended initial dose.

Bulimia Nervosa

60 mg per day is the recommended dose.

Obsessive-Compulsive Disorder

20 mg to 60 mg per day is the recommended dose.

Premenstrual Dysphoric Disorder

20 mg per day is recommended continuously throughout the menstrual cycle. Initial treatment should be limited to six months, after which patients should be reassessed regarding the benefit of continued therapy.

All Indications

The recommended dose may be increased or decreased. Doses above 80 mg/day have not been systematically evaluated.

Age

There are no data to suggest that alternate dosing is required on the basis of age alone.

Use in Children and Adolescents (<18 years)

The safety and efficacy of fluoxetine for the treatment of children and adolescents less than 18 years of age has not been established.

Administration with Food

PROZAC 20 may be administered with or without food.

Concurrent Disease and/or Concomitant Medication

A lower or less frequent dose should be considered in patients with hepatic impairment, with concurrent diseases, or who are taking multiple medications.

Contraindications

Hypersensitivity

PROZAC 20 is contraindicated in patients known to be hypersensitive to fluoxetine.

MAOIs

PROZAC 20 should not be used in combination with a monoamine oxidase inhibitor (MAOI) or within a minimum of 14 days of discontinuing treatment with a MAOI. At least five weeks should elapse between discontinuation of PROZAC 20 and initiation of therapy with a MAOI. If PROZAC 20 has been prescribed chronically and/or at a high dose, a longer interval should be considered. Serious and fatal cases of serotonin syndrome (which may resemble and be diagnosed as neuroleptic malignant syndrome) have been reported in patients treated with fluoxetine and a MAOI in close temporal proximity.

Warnings and Precautions

Warnings

Clinical Worsening and Suicide Risk

The risk of suicide attempt is inherent in depression and other psychiatric disorders and may persist until significant remission occurs. As with other drugs with similar pharmacological action (antidepressants), isolated cases of suicidal ideation and suicidal behaviours have been reported during fluoxetine therapy or early after treatment discontinuation. This risk must be considered in all depressed patients.

Although a causal role for PROZAC in inducing such events has not yet been established, some analyses from pooled studies of antidepressants in psychiatric disorders found an increased risk for suicidal ideation and/or suicidal behaviours in paediatric and young adult (<25 years of age) patients compared to placebo. Patients with depression may experience worsening of their depressive symptoms and/or the emergence of suicidal ideation and behaviours (suicidality) whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored for clinical worsening and suicidality, especially at the beginning of a course of treatment, or at the time of dose changes, either increases or decreases. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse or whose emergent suicidality is severe, abrupt in onset, or was not part of the patient's presenting symptoms. Patients (and caregivers of patients) should be alerted about the need to closely monitor for any worsening of their condition and/or the emergence of suicidal ideation/behaviour or thoughts of harming themselves and to seek medical advice immediately if these symptoms present. Physicians should encourage patients of all ages to report any distressing thoughts or feelings at any time. Patients with co-morbid depression associated with other psychiatric disorders being treated with antidepressants should be similarly observed for clinical worsening and suicidality.

Pooled analyses of 24 short-term (4 to 16 weeks), placebo-controlled trials of nine antidepressant medicines [selective serotonin reuptake inhibitors (SSRIs) and others] in 4400 children and adolescents with major depressive disorder (16 trials), obsessive compulsive disorder (4 trials), or other psychiatric disorders (4 trials) have revealed a greater risk of adverse events representing suicidal behaviour or thinking (suicidality) during the first few months of treatment in those receiving antidepressants. The average risk of such events in patients treated with an antidepressant was 4%, compared with 2% of patients given placebo. There was considerable variation in risk among the antidepressants, but there was a tendency towards an increase for almost all antidepressants studied. The risk of suicidality was most consistently observed in the major depressive disorder trials, but there were signals of risk arising from trials in other psychiatric indications (obsessive compulsive disorder and social anxiety disorder) as well. No suicides occurred in these trials. It is unknown whether the suicidality risk in children and adolescent patients extends to use beyond several months. The nine antidepressant medicines in the pooled analyses included five SSRIs (citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) and four non-SSRIs (bupropion, mirtazapine, nefazodone, venlafaxine).

Symptoms of anxiety, agitation, panic attacks, insomnia, irritability, hostility (aggressiveness), impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adults, adolescents and children being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either worsening of depression and/or emergence of suicidal impulses has not been established, there is concern that such symptoms may be precursors of emerging suicidality.

Families and caregivers of children and adolescents being treated with antidepressants for major depressive disorder or for any other condition (psychiatric or nonpsychiatric) should be informed about the need to monitor these patients for the emergence of agitation, irritability, unusual changes in behaviour, and other symptoms described above, as well as the emergence of suicidality, and to report such symptoms to health care providers immediately. It is particularly important that monitoring be undertaken during the initial few months of antidepressant treatment or at times of dose increase or decrease.

Prescriptions for PROZAC should be written for the smallest quantity of medicine consistent with good patient management, in order to reduce the risk of overdose.

Rash

Rash, anaphylactoid events, and progressive systemic events, sometimes serious and involving skin, kidney, liver or lung have been reported in patients taking PROZAC 20. Upon the appearance of rash, or of other possible allergic phenomena for which an alternative aetiology cannot be identified PROZAC 20 should be discontinued.

Mania and Bipolar Disorder

A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with any antidepressant alone may increase the likelihood of a mixed/manic episode in patients at risk for bipolar disorder. Prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder. It should be noted that fluoxetine is not approved for use in treating bipolar depression.

Precautions

Seizures

As with other antidepressants, PROZAC 20 should be introduced cautiously in patients who have a history of seizures.

Hyponatraemia

Cases of hyponatraemia (some with serum sodium lower than 110 mmol/L) have been reported. The majority of these cases occurred in elderly patients and in patients treated with diuretics or otherwise volume-depleted.

Glycaemic Control

In patients with diabetes, hypoglycaemia has occurred during therapy with PROZAC 20 and hyperglycaemia has developed following discontinuation. Insulin and/or oral hypoglycaemic dosage may need to be adjusted when PROZAC 20 therapy is initiated or discontinued.

Withdrawal Reactions

Discontinuation symptoms have been reported in association with selective serotonin reuptake inhibitors (SSRIs). Because of the long elimination half-life of fluoxetine, and its active metabolite norfluoxetine, plasma fluoxetine and norfluoxetine concentrations decrease gradually at the conclusion of therapy, which reduces greatly the likelihood of developing discontinuation symptoms and makes dosage tapering unnecessary in most patients. Common symptoms associated with withdrawal of SSRIs include dizziness, paraesthesia, headache, anxiety and nausea. Onset of symptoms can occur within a day of discontinuation but may be delayed, particularly in the case of fluoxetine, due to its long half-life. The majority of symptoms experienced on withdrawal of SSRIs are non serious, self-limiting and have varying durations. Fluoxetine has been only rarely associated with such symptoms.

Haemorrhage

There have been reports of cutaneous bleeding abnormalities such as ecchymosis and purpura with SSRI's. Ecchymosis has been reported as an infrequent event during treatment with fluoxetine. Other haemorrhagic manifestations (e.g., gynaecological haemorrhages, gastrointestinal bleedings and other cutaneous or mucous bleedings) have been reported rarely.  Caution is advised in patients with a history of bleeding disorders as well as in patients taking SSRI's particularly in concomitant use with oral anticoagulants, drugs known to affect platelet function (e.g. atypical antipsychotics such as clozapine, phenothiazines, most TCA's, aspirin, NSAID's) or other drugs that may increase risk of bleeding.

Carcinogenesis, Mutagenesis, Impairment of Fertility

There is no evidence of carcinogenicity or mutagenicity from in vitro or animal studies. Impairment of fertility in adult animals at doses up to 12.5 mg/kg/day (approximately 1.5 times the MRHD on a mg/m2 basis) was not observed.

In a juvenile toxicology study in CD rats, administration of 30 mg/kg of fluoxetine hydrochloride on postnatal days 21 through 90 resulted in increased serum activities of creatine kinase (CK) and aspartate aminotransferase (AST), which were accompanied microscopically by skeletal muscle degeneration, necrosis and regeneration. Other findings in rats administered 30 mg/kg included degeneration and necrosis of seminiferous tubules of the testis, epididymal epithelial vacuolation, and immaturity and inactivity of the female reproductive tract. Plasma levels achieved in these animals at 30 mg/kg were approximately 5 to 8 fold (fluoxetine) and 18 to 20 fold (norfluoxetine), and at 10 mg/kg approximately 2 fold (fluoxetine) and 8 fold (norfluoxetine) higher compared to plasma concentrations usually achieved in paediatric patients. Following an approximate 11-week recovery period, sperm assessments in the 30 mg/kg males only, indicated an approximately 30% decrease in sperm concentrations without affecting sperm morphology or motility. Microscopic evaluation of testes and epididymides of these 30 mg/kg males indicated that testicular degeneration was irreversible. Delays in sexual maturation occurred in the 10 mg/kg males and in the 30 mg/kg males and females. The significance of these findings in humans is unknown. Femur length at 30 mg/kg increased to a lesser extent compared with control rats.

Pregnancy

Experimental animal studies do not indicate direct or indirect harmful effects, with respect to the development of the embryo or foetus or the course of gestation. Because animal reproduction studies are not always predictive of human response, this medicine should be used during pregnancy only if clearly needed.

This drug crosses the placenta. Transitory withdrawal symptoms have been reported rarely in the neonate after maternal use near term.

Neonates exposed to fluoxetine and other SSRIs or serotonin and noradrenaline reuptake inhibitors (SNRIs), late in the third trimester have been uncommonly reported to have clinical findings of respiratory distress, cyanosis, apnoea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycaemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability and constant crying. Such events can arise immediately upon delivery and are usually transient. These features could be consistent with either a direct effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. When treating a pregnant woman with fluoxetine during the third trimester, the physician should carefully consider the potential risks and benefits of treatment.

Lactation

Fluoxetine is excreted in human milk; therefore, caution should be exercised when PROZAC 20 is administered to nursing women.

Labour and Delivery

The effect of PROZAC 20 on labour and delivery in humans is unknown.

Effects on Ability to Drive and Use Machines

Psychoactive medicines may impair judgement, thinking, or motor skills. Patients should be advised to avoid driving a car or operating machinery until they are reasonably certain that their performance is not affected.

Information for Patients and Families

Physicians are advised to discuss the following issues with patients for whom they prescribe fluoxetine:
Because PROZAC 20 may impair judgement, thinking, or motor skills, patients should be advised to avoid driving a car or operating hazardous machinery until they are reasonably certain that their performance is not affected.
Patients should be advised to inform their physician if they are taking or plan to take any prescription or over-the-counter medicines, or alcohol.
Patients should be advised to inform their physician if they become pregnant or intend to become pregnant during therapy.
Patients should be advised to notify their physician if they are breast feeding an infant.
Patients should be advised to notify their physician if they develop a rash or hives.
The patient has the right to treatment meeting appropriate ethical and professional standards, and the patient needs to be fully informed with frank discussion of risk/benefit issues relating to the medicine's efficacy and safety when used in the treatment regimen proposed.

Adverse Effects

Table 1
Clinical Trial Incidence Rates of Fluoxetine Undesirable Effects
All US IND Placebo-Controlled Clinical Trials
Fluoxetine N = 4,397; Placebo N = 2,918

The prescriber should be aware that the information presented in Table 1 cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of medicine and non-medicine factors to the side effect incidence rate in the population studied.

Post-Marketing Experience

The following events have not been reported in clinical trials of fluoxetine, but have been reported in clinical practice and are associated with fluoxetine therapy. These events are classified as either very rare (occurring in less than 1/10000 patients) or uncommon (occurring in 1/100 to 1/1000 patients).

Body as a Whole: (Very rare) angioedema; serotonin syndrome, erythema multiforme.

Digestive System: (Very rare) idiosyncratic hepatitis.

Endocrine System: (Very rare) inappropriate secretion of antidiuretic hormone.

Blood and Lymphatic System: (Rare) haemorrhagic manifestations (e.g. gynacological haemorrhages, gastrointestinal bleedings and other cutaneous or mucous bleedings) (see PRECAUTIONS, Haemorrhage).

Nervous System: (Uncommon) seizures.

Special Populations:

Children: (Very rare) headache

(Very rare) Weight loss and decreased height gain: As with other SSRIs, decreased weight gain has been observed in association with the use of fluoxetine in children and adolescent patients. After 19 weeks of treatment in a clinical trial, paediatric subjects treated with fluoxetine gained an average of 1.1 cm less in height (p=0.004) and 1.1 kg less in weight (p=0.008) than subjects treated with placebo. In addition, fluoxetine treatment was associated with a decrease in alkaline phosphate levels. The safety of fluoxetine treatment for paediatric patients has not been systematically assessed for chronic treatment longer than several months in duration. There are no studies that directly evaluate the longer-term effects of fluoxetine on the growth, development and maturation of children and adolescent patients. Therefore, height and weight should be monitored periodically in paediatric patients receiving fluoxetine.

Interactions

Monoamine Oxidase Inhibitors

See CONTRAINDICATIONS.

Medicines Metabolised by Cytochrome P450IID6 Isoenzyme

Because fluoxetine has the potential to inhibit the cytochrome P450IID6 isoenzyme, therapy with medications that are predominantly metabolised by the P450IID6 system and that have a relatively narrow therapeutic index should be initiated at the low end of the dose range if a patient is receiving PROZAC 20 concurrently or has taken it in the previous five weeks. If PROZAC 20 is added to the treatment range of a patient already receiving such a medicine, the need for decreased dose of the original medication should be considered.

CNS active medicines

Changes in the blood levels of phenytoin, carbamazepine, haloperidol, clozapine, diazepam, alprazolam, lithium, imipramine and desipramine, and in some cases, clinical manifestations of toxicity have been observed. Consideration should be given to using conservative titration schedules of the concomitant medicine and monitoring of clinical status. Concomitant use of other drugs with serotonergic activity (e.g. SNRIs, SSRIs, triptans or tramadol) may result in serotonin syndrome.

Protein binding

Because fluoxetine is tightly bound to plasma protein, the administration of PROZAC 20 to a patient taking another medicine that is tightly bound to protein may cause a shift in plasma concentrations of either medicine.

Drugs that interfere with haemostasis

Caution is advised in patients with a history of bleeding disorders as well as in patients taking SSRI's, particularly in concomitant use with oral anticoagulants, medicines known to affect platelet function (e.g. atypical antipsychotics such as clozapine, phenothiazines, most TCA's, aspirin, NSAID's) or other drugs that may increase risk of bleeding.

Warfarin

Altered anti-coagulant effects (laboratory values and/or clinical signs and symptoms), with no consistent pattern, but increased bleeding, have been reported uncommonly when PROZAC 20 is co-administered with warfarin. As is prudent in concomitant use of warfarin with many other medicines, patients receiving warfarin therapy should receive careful monitoring when PROZAC 20 is initiated or stopped.

Electroconvulsive therapy (ECT)

There have been rare reports of prolonged seizures in patients on PROZAC 20 receiving ECT treatment.

Elimination half-life

The long elimination half-lives of fluoxetine and its principal metabolite, norfluoxetine, are of potential consequence when medicines are prescribed which might interact with either substance following the discontinuation of PROZAC 20.

Overdosage

Symptoms

Cases of overdose of fluoxetine alone usually have a mild course. Symptoms of overdose have included nausea, vomiting, seizures, cardiovascular dysfunction ranging from asymptomatic arrhythmias to cardiac arrest, pulmonary dysfunction, and signs of altered CNS status ranging from excitation to coma. Fatality attributed to overdose of fluoxetine alone has been extremely rare.

Management

Cardiac and vital signs monitoring is recommended, along with general symptomatic and supportive measures. No specific antidote is known. Forced diuresis, dialysis, haemoperfusion, and exchange transfusion are unlikely to be of benefit. In managing overdosage, consider the possibility of multiple medicine involvement. The physician should consider contacting the Poisons Information Centre on 0800 764 766 or 0800 POISON for advice on the treatment and management of any overdose.

Pharmaceutical Precautions

Shelf Life and Special Precautions for Storage

20 mg capsules: Three years < 30°C

Instructions for use

Capsules: none

Major Incompatibilities

None known.

Medicine Classification

Prescription Medicine.

Package Quantities

Capsules: Each pack contains 30 capsules in 3 platforms of 10 capsules each.

Further Information

List of Excipients

Capsules: starch, silicone fluid, gelatin.

Name and Address

Eli Lilly and Company (NZ) Limited
Level 3, Axon House,
414-422 Khyber Pass Road
Newmarket

P.O. Box 109 197
Newmarket, Auckland
NEW ZEALAND.
Phone: (09) 523 9300

Date of Preparation

8 March 2007