Consumer medicine information

Prozac

Fluoxetine

BRAND INFORMATION

Brand name

Prozac

Active ingredient

Fluoxetine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Prozac.

What is in this leaflet

This leaflet answers some common questions about PROZAC. It does not contain all the available information. It does not take the place of talking with your doctor or pharmacist.

All medicines have risks and benefits.

Your doctor has weighed the risks of you taking PROZAC against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, talk to your doctor or pharmacist.

Keep this leaflet with this medicine. You may need to read it again.

What PROZAC is used for

PROZAC is used to treat:

  • depression
  • obsessive compulsive disorder (OCD)
  • premenstrual dysphoric disorder (PMDD)

Ask your doctor if you have any questions about why PROZAC has been prescribed for you. Your doctor may have prescribed PROZAC for another reason.

PROZAC belongs to a group of medicines called selective serotonin reuptake inhibitors (SSRIs). SSRIs are thought to work by their action on brain chemicals called amines which are involved in controlling mood.

PROZAC is available only with a doctor's prescription.

PROZAC is not recommended for use in children and adolescents under 18 years of age.

Before you take PROZAC

When you must not take it

Do not take PROZAC if you are allergic to

  • any medicines containing fluoxetine
  • any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue or other parts of the body; rash, itching or hives on the skin.

Do not take PROZAC if you are taking another medicine for depression called a monoamine oxidase inhibitor (MAOI) or have been taking a MAOI within the last 14 days. Check with your doctor or pharmacist if you are unsure as to whether or not you are taking a MAOI.

If you do take PROZAC while you are taking a MAOI, you may experience shaking (tremor), shivering, muscle stiffness, fever, rapid pulse, rapid breathing or confusion.

Do not take PROZAC if you are taking another medicine called pimozide to treat disturbances in thinking, feelings and behaviour. Taking pimozide together with PROZAC may alter the rhythm of your heart.

Do not take PROZAC if the packaging is torn or shows signs of tampering or the capsules or tablets do not look quite right.

Do not take PROZAC if the expiry date on the pack has passed. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking PROZAC, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you are pregnant or plan to become pregnant. Your doctor will discuss the risks and benefits of taking PROZAC during pregnancy. If PROZAC is taken during pregnancy, you should be careful, particularly at the end of pregnancy. Transitory withdrawal symptoms have been reported rarely in the newborn after maternal use in the last 3 months of pregnancy.

Tell your doctor if you are breastfeeding or wish to breastfeed.

Tell your doctor if you have, or have had, any medical conditions, especially the following:

  • liver problems
  • kidney problems
  • fits
  • diabetes
  • a bleeding disorder or a tendency to bleed more than usual

Tell your doctor if you drink alcohol. Although drinking alcohol is unlikely to affect your response to PROZAC, your doctor may suggest avoiding alcohol while you are being treated for depression.

If you have not told your doctor about any of the above, tell them before you start taking PROZAC.

Taking other medicines

Tell your doctor if you are taking any other medicines, including any that you buy without a prescription from a pharmacy, supermarket or health food shop.

Some combinations of medicines may increase the risk of serious side effects and are potentially life threatening.

Some medicines may be affected by PROZAC, or may affect how well it works. These include:

  • monoamine oxidase inhibitors (MAOIs), medicines used to treat some types of depression.
    You should stop taking MAOIs at least two weeks before starting PROZAC
  • lithium, a medicine used to treat mood swings and some types of depression
  • SNRIs, SSRIs and other medicines for depression, obsessive compulsive disorder or premenstrual dysphoric disorder (PMDD)
  • sleeping tablets or sedatives
  • medicines used to relieve anxiety
  • medicines used to treat certain mental and emotional conditions, also called antipsychotics
  • medicine used to treat disturbances in thinking, feelings and behaviour, such as pimozide
  • medicines used to control fits
  • medicines used to prevent blood clots, such as warfarin
  • flecainide, a medicine used to treat some heart conditions
  • tryptophan
  • St John's Wort
  • medicines used to relieve pain, such as tramadol
  • sumitriptan, a medicine used to treat migraine.

Your doctor can tell you what to do if you are taking any other medicines.

If you are not sure whether you are taking any of these medicines, check with your doctor or pharmacist.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking PROZAC.

Do not start taking other medicines for depression without checking with your doctor. Do this even if you have already stopped taking PROZAC.

Monoamine oxidase inhibitors (MAOIs), which are other medicines used for depression, may interfere with PROZAC. You should not start a MAOI for at least 5 weeks after stopping PROZAC.

How to take PROZAC

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions on the box, ask your doctor or pharmacist for help.

How much to take

Your doctor will tell you how much PROZAC you need to take each day.

The usual dose for PROZAC is one capsule or one tablet taken once a day. Your doctor may increase or decrease your dose depending on your condition.

For premenstrual dysphoric disorder (PMDD), PROZAC may be prescribed to be taken every day or only during a certain part of the month. Your doctor will prescribe the dosing schedule that is right for you.

How to take it

Swallow the capsules whole with a glass of water.

If you cannot swallow the tablets, disperse them in water.

Swirl the tablet in half a glass of water until it falls apart, then drink it immediately.

When to take it

PROZAC is usually taken as a single morning dose.

If your doctor tells you to take PROZAC twice a day, take a dose in the morning and at noon.

Take your medicine at about the same time each day. Taking it at the same time each day will help you remember when to take it.

It does not matter if you take this medicine before or after food.

How long to take it

Continue taking PROZAC for as long as your doctor recommends.

The length of treatment with PROZAC will depend on how quickly your symptoms improve.

Most medicines of this type take time to work so don't be discouraged if you do not feel better right away. While some symptoms will be relieved sooner than others, PROZAC commonly takes two to four weeks before improvement is really apparent.

If you do not start to feel better in about four weeks, check with your doctor.

If you forget to take it

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Otherwise, take it as soon as you remember, and then go back to taking your medicine as you would normally.

Do not take a double dose to make up for the dose that you missed.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or Poisons Information Centre (13 11 26) for advice or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much PROZAC. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

If you have taken too much PROZAC, you may feel sick in the stomach, vomit, feel restless, agitated or excited.

While you are taking PROZAC

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking PROZAC.

Tell all doctors, dentists and pharmacists who are treating you that you are taking PROZAC.

Tell your doctor if you become pregnant while taking PROZAC. Your doctor will discuss the risks and benefits of taking PROZAC during pregnancy. If PROZAC is used during pregnancy, you should be careful, particularly at the end of pregnancy. Transitory withdrawal symptoms have been reported rarely in the newborn after maternal use in the last 3 months of pregnancy.

Keep all of your doctor's appointments so that your progress can be checked.

The symptoms of depression or other psychiatric conditions may include thoughts of harming yourself or suicide. These symptoms may continue or get worse during the first one or two months of treatment until the full antidepressant effect of PROZAC becomes apparent. This is more likely to occur in young adults under 25 years of age.

If you or someone you know is demonstrating any of the following warning signs, contact your doctor or a mental health professional right away or go to the nearest hospital for treatment:

  • worsening of your depression
  • thoughts or talk of death or suicide
  • thoughts or talk of self-harm or harm to others
  • any recent attempts at self-harm
  • increase in aggressive behaviour, irritability or any other unusual changes in behaviour or mood

All mentions of suicide or violence must be taken seriously.

Things to be careful of

If you experience drowsiness, do not drive, operate machinery or do anything else that could be dangerous.

Things you must NOT do

Do not stop taking your medicine or lower the dosage without checking with your doctor. Suddenly stopping PROZAC may cause symptoms such as dizziness, anxiety, headache, feeling sick, or tingling or numbness of the hands or feet. Your doctor may want you to gradually reduce the amount of PROZAC you are taking before stopping completely.

Do not take the herbal remedy St. John's Wort while you are being treated with PROZAC. If you are already taking the herbal remedy, stop taking St. John's Wort and mention it to your doctor at your next visit.

Do not drive or operate machinery until you know how PROZAC affects you.

PROZAC may cause drowsiness in some people.

Do not give PROZAC to anyone else, even if they have the same condition as you.

Do not let yourself run out of PROZAC over the weekend or on holidays.

Do not use PROZAC to treat any other complaints unless your doctor tells you to.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking PROZAC.

PROZAC may have unwanted side effects in some people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Side effects vary from patient to patient and often lessen with continued use.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

  • nausea, vomiting
  • upset stomach, diarrhoea
  • loss of appetite, weight loss, changes in taste, dry mouth
  • trouble sleeping, unusual dreams
  • nervousness, anxiety
  • drowsiness, weakness
  • dizziness
  • excessive sweating, flushing, chills
  • lesions of skin and mucous membrane
  • fever and joint aches
  • sexual problems
  • more frequent urination
  • changes in vision.

If any of the following happen, tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

  • itching, skin rash or hives
  • shortness of breath, wheezing or trouble breathing
  • swelling of the face, lips, tongue or other parts of the body
  • muscle spasms
  • tremors
  • twitches
  • convulsions or fits
  • fast, irregular heart beat
  • abnormal bleeding or bruising
  • sudden switches of mood to one of overactivity and uninhibited behaviour.
  • sudden fever
  • hallucinations
  • loss of coordination
  • confusion
  • overactive reflexes

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation.

Children and Adolescents

Headaches are very common side effects.

Weight loss and decreased height gain have been observed in association with the use of PROZAC in children and adolescent patients. This is similar to other medicines that belong to the group of medicines called selective serotonin reuptake inhibitors (SSRIs).

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people.

After taking PROZAC

Storage

Keep your capsules or tablets in the blister pack until it is time to take them. If you take your capsules or tablets out of the blister pack they may not keep as well.

Keep your capsules in a cool dry place where the temperature stays below 30 degrees C.

Keep your tablets in a cool dry place where the temperature stays below 25 degrees C.

Do not store PROZAC or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking PROZAC or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What it looks like

PROZAC capsules and tablets are available in packs of 28.

The capsules are coloured green and off-white and are marked with "Lilly" and "3105".

The tablets are white and scored and marked with 4400.

Ingredients

Capsules
PROZAC capsules contain 20 mg of fluoxetine as the active ingredient. They also contain:

  • pre-gelatinized maize starch
  • dimeticone 350
  • gelatin
  • iron oxide yellow CI77492
  • patent blue V CI42051
  • titanium dioxide
  • edible black ink.

Tablets
PROZAC tablets contain 20 mg of fluoxetine as the active ingredient. They also contain:

  • microcrystalline cellulose
  • saccharin sodium
  • mannitol
  • sorbitol
  • colloidal anhydrous silica
  • maize starch
  • sodium stearylfumarate
  • crospovidone
  • peppermint flavouring
  • aniseed flavouring.

PROZAC capsules and tablets are gluten free.

Supplier

PROZAC is a product of:

Eli Lilly Australia Pty Limited
112 Wharf Road
WEST RYDE NSW 2114

Eli Lilly and Company (NZ) Limited
PO Box 109 197, Newmarket
Auckland
Telephone (09) 523 9300

Australian Registration Number:

PROZAC Capsules 20mg:
AUST R 14653

PROZAC Tablets 20mg:
AUST R 61081

This leaflet was revised in December 2019

Published by MIMS February 2020

BRAND INFORMATION

Brand name

Prozac

Active ingredient

Fluoxetine

Schedule

S4

 

1 Name of Medicine

Fluoxetine hydrochloride.

6.7 Physicochemical Properties

Chemical structure.

Fluoxetine hydrochloride is an antidepressant for oral administration. It is designated (±)-N-methyl-3-phenyl-3-[(α,α,α-trifluoro-p-tolyl)-oxy]-propylamine hydrochloride, and has the empirical formula of C17H18F3NO.HCl. Its molecular weight is 345.79.
Fluoxetine hydrochloride is a white to off-white crystalline solid with a solubility of 14 mg/mL in water.
The structural formula is as follows:

CAS number.

The CAS number for fluoxetine hydrochloride is 59333-67-4.

2 Qualitative and Quantitative Composition

Prozac tablets.

Fluoxetine 20 mg (present as the hydrochloride).
Excipients with known effect: Prozac tablets contain saccharin.

Prozac capsules.

Fluoxetine 20 mg fluoxetine (present as the hydrochloride).

Prozac liquid (not available in Australia).

Fluoxetine 20 mg/5 mL (present as the hydrochloride).
Excipients with known effect: Prozac liquid contains sugars (as sucrose) and benzoate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Tablets.

Prozac 20 mg tablets are white, elongated, scored dispersible tablets embossed with "4400".

Capsules.

Prozac 20 mg capsules have an opaque green cap and opaque yellow body. Imprinted with "Lilly 3105".

Liquid (not available in Australia).

Prozac Liquid is a clear, colourless, mint flavoured oral solution (M-5120).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

The antidepressant and antiobsessional action of fluoxetine is presumed to be linked to its inhibition of CNS neuronal uptake of serotonin. Studies at clinically relevant doses in man have demonstrated that fluoxetine blocks the uptake of serotonin, but not of noradrenaline, into human platelets. Studies in animals also suggest that fluoxetine is a much more potent uptake inhibitor of serotonin than of noradrenaline.
Antagonism of muscarinic, histaminergic, and α1-adrenergic receptors has been hypothesised to be associated with various anticholinergic, sedative and cardiovascular effects of classical tricyclic antidepressant drugs. Fluoxetine binds to these and other membrane receptors from brain tissue much less potently in vitro than do the tricyclic drugs.

Clinical trials.

Anxiety associated with major depression.

A meta-analysis of randomised clinical trials provided acceptable evidence that (i) fluoxetine shows an efficacy at least equal to that of tricyclic antidepressants and statistically significantly superior to placebo in the treatment of patients who have anxiety symptoms associated with a depressive illness, and (ii) the effect of fluoxetine is similar in depressed patients regardless of the presence or absence of associated anxiety.

Elderly.

Fluoxetine has been studied in four clinical trials in elderly depressed patients (> 60 years of age). The efficacy shown by fluoxetine in these elderly patients was similar to its effects in younger adults. Fluoxetine was well tolerated by elderly depressed patients.

Maintenance of remission of depression.

In a multicentre randomised double blind continuation of those who were in remission after 12 weeks of open label fluoxetine 20 mg/day, after 50 weeks (total duration) of fluoxetine 20 mg/day, the fluoxetine treated patients had a statistically significant lower rate of re-emergence of depressive symptoms than those on placebo. Although the numbers treated for 62 weeks were too few for efficacy evaluation, treatment with fluoxetine was safe and well tolerated for this time.

Premenstrual dysphoric disorder (PMDD).

The effectiveness of fluoxetine for the treatment of PMDD has been studied in four placebo controlled trials (one intermittent and three continuous) in a total of 628 patients (415 exposed to fluoxetine).
In an intermittent dosing double blind, parallel group study of 3 months duration, patients (N = 260 randomised) were treated with fluoxetine 10 mg/day, fluoxetine 20 mg/day, or placebo. Fluoxetine or placebo was started 14 days prior to the anticipated onset of menstruation and was continued through the first full day of menses. Fluoxetine 20 mg/day was shown to be significantly more effective than placebo as measured by the Daily Record of Severity of Problem (DRSP) total score (including mood and physical symptoms) and the DRSP social and functional impairment symptom cluster score. The DRSP is a patient rated instrument that mirrors the diagnostic criteria for PMDD as identified in the DSM-IV. Fluoxetine 10 mg/day was shown to be significantly more effective than placebo as measured by the DRSP social and functional impairment symptom cluster score, but did not show a significant difference to placebo for DRSP total score. The average DRSP total score decreased 38% on fluoxetine 20 mg/day, 35% on fluoxetine 10 mg/day and 30% on placebo. The average DRSP social and functional impairment symptom cluster score decreased 42% on fluoxetine 20 mg/day, 40% on fluoxetine 10 mg/day and 33% on placebo. Both fluoxetine 20 mg/day and 10 mg/day were well tolerated in this study.
In the first continuous dosing double blind, parallel study of 6 months duration, fixed doses of fluoxetine 20 mg (n = 95) and 60 mg (n = 85) per day were shown to be significantly more effective than placebo (n = 94) in improving the cyclical mood disturbance characteristic of PMDD as measured by visual analogue scales (VAS) evaluating dysphoria, irritability and tension. The average score calculated from these three VAS items decreased 6% on placebo treatment compared to 37% on 20 mg (p < 0.001 vs placebo) and 42% on 60 mg fluoxetine (p < 0.001 vs placebo). Fluoxetine was also shown to be significantly more effective than placebo in improving physical symptoms of PMDD as measured by the VAS evaluating bloating, breast tenderness and headache. The average score calculated from these 3 VAS items decreased 8% on placebo, 33% on 20 mg (p = 0.005 vs placebo) and 31% on 60 mg fluoxetine (p = 0.012 vs placebo). Fluoxetine 20 mg and 60 mg per day were also significantly more effective than placebo on a number of secondary measures of mood, physical symptoms and social impairment. The other two continuous dosing clinical studies were supportive of the differences seen between fluoxetine and placebo.

5.2 Pharmacokinetic Properties

Absorption.

In man, following a single oral 40 mg dose, peak plasma concentrations of fluoxetine from 15 to 55 nanogram/mL are observed after 6 to 8 hours. Fluoxetine is 80 to 95% absorbed following oral administration. There is a linear dose proportionality for the absorption of fluoxetine over the therapeutic dose range.
Prozac 20 capsules (20 mg fluoxetine) and Prozac liquid (20 mg/5 mL fluoxetine) are bioequivalent. Prozac 20 capsules (20 mg fluoxetine) and Prozac tab (20 mg fluoxetine tablets) are bioequivalent. (Prozac Liquid is not available in Australia.)
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.

Distribution.

The volume of distribution for fluoxetine is estimated at 30-40 L/kg.

Protein binding.

Over the concentration range from 200 to 1,000 nanogram/mL, approximately 94.5% of fluoxetine is bound in vitro to human serum proteins, including albumin and α1-glycoprotein. The interaction between fluoxetine and other highly protein bound drugs has not been fully evaluated, but may be important (see Section 4.4 Special Warnings and Precautions for Use).

Metabolism.

Fluoxetine is extensively metabolised in the liver to norfluoxetine and a number of other, unidentified metabolites. The only identified active metabolite, norfluoxetine, is formed by demethylation of fluoxetine. In animal models, norfluoxetine's potency and selectivity as a serotonin uptake blocker are essentially equivalent to fluoxetine's.
Multiple cytochrome P450 isoenzymes, including CYP2D6, are responsible for the conversion of fluoxetine to norfluoxetine; thus other nonsaturable oxidative pathways (i.e. non-2D6 pathways) contribute considerably to norfluoxetine formation (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Excretion.

The primary route of elimination appears to be hepatic metabolism to inactive metabolites excreted by the kidney.

Clinical issues related to metabolism/elimination.

The complexity of the metabolism of fluoxetine has several consequences which may potentially affect fluoxetine's clinical use.

Accumulation and slow elimination.

The relatively slow elimination of fluoxetine (elimination half-life of 1 to 3 days after acute administration and 4 to 6 days after chronic administration) and its active metabolite, norfluoxetine (elimination half-life of 4 to 16 days after acute and chronic administration), leads to significant accumulation of these active species in chronic use. After 30 days of dosing at 40 mg/day, plasma concentrations of fluoxetine in the range of 91 to 302 nanogram/mL and norfluoxetine in the range of 72 to 258 nanogram/mL have been observed. Plasma concentrations of fluoxetine were higher than those predicted by single dose studies, presumably because fluoxetine's metabolism is not proportional to dose. Norfluoxetine, however, appears to have linear pharmacokinetics. Its mean terminal half-life after a single dose was 8.6 days and after multiple dosing was 9.3 days.
Thus, even if patients are given a fixed dose, steady-state plasma concentrations are only achieved after continuous dosing for weeks. Nevertheless, plasma concentrations do not appear to increase without limit. Specifically, 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 or 5 weeks.

Clinical issues related to accumulation and slow elimination.

1. The long elimination half-lives of fluoxetine and norfluoxetine assure that, even when dosing is stopped, active drug substance will persist in the body for weeks (primarily depending on individual patient characteristics, previous dosing regimen and length of previous therapy at discontinuation). This is of potential consequence when drug withdrawal is required or when drugs are prescribed that might interact with fluoxetine and norfluoxetine following the discontinuation of fluoxetine hydrochloride.
2. See Section 4.4 Special Warnings and Precautions for Use, The long elimination half-lives of fluoxetine and its metabolites.

5.3 Preclinical Safety Data

Genotoxicity.

Fluoxetine and norfluoxetine have been shown to have no genotoxic effects based on the following assays: bacterial mutation assay, DNA repair assay in cultured rat hepatocytes, and in vivo sister chromatid exchange assay in Chinese hamster bone marrow cells.

Carcinogenicity.

There is no evidence of carcinogenicity with fluoxetine hydrochloride from animal studies. The dietary administration of fluoxetine to rats for two years at dose levels of 8-11 mg/kg/day produced no evidence of carcinogenicity.

4 Clinical Particulars

4.1 Therapeutic Indications

Prozac is indicated for the treatment of major depression, obsessive compulsive disorder, premenstrual dysphoric disorder (PMDD) as defined by DSM-IV criteria.
The essential features of PMDD, according to the Diagnostic and Statistical Manual-4th edition (DSM-IV) include markedly depressed mood, anxiety or tension, affective lability and persistent anger or irritability. Other features include decreased interest in usual activities, difficulty concentrating, lack of energy, change in appetite or sleep and feeling out of control. Physical symptoms associated with PMDD include breast tenderness, headache, joint and muscle pain, bloating and weight gain. These symptoms occur regularly during the luteal phase and remit within a few days following onset of menses; the disturbance markedly interferes with work or school or with usual social activities and relationships with others.

4.3 Contraindications

Prozac is contraindicated in patients known to be hypersensitive to fluoxetine hydrochloride or any of the other ingredients in the formulation.

Monoamine oxidase inhibitors.

The combined administration of fluoxetine and a monoamine oxidase inhibitor (MAOI) has been associated with the development of serotonin syndrome, a serious, sometimes fatal, reaction in patients receiving an SSRI in combination with a MAOI and in patients treated with fluoxetine and a MAOI in close temporal proximity. Some cases presented with features resembling neuroleptic malignant syndrome. Symptoms and signs of serotonin syndrome include: clonus, myoclonus, tremor, shivering, hyper-reflexia, hyperthermia, rigidity, autonomic instability with possible rapid fluctuations of vital signs and mental status changes that include extreme agitation progressing to delirium and coma.
Therefore, Prozac should not be used in combination with a MAOI (selective, reversible or irreversible), 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 (perhaps longer, especially if fluoxetine has been prescribed chronically and/or at higher doses (see Section 5.2 Pharmacokinetic Properties, Accumulation and slow elimination)) should be allowed after stopping fluoxetine hydrochloride before starting a MAOI. Limited reports suggest that orally administered cyproheptadine (Periactin) or intravenously administered dantrolene (Dantrium) may benefit patients experiencing such reactions. Animal studies also suggest that cyproheptadine may be beneficial.

Pimozide.

Concomitant use in patients taking pimozide is contraindicated (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.4 Special Warnings and Precautions for Use

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 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 comorbid 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 4,400 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.

Serotonin syndrome.

Development of serotonin syndrome may occur in association with treatment with SSRls and SNRls, particularly when given in combination with MAOls or other serotonergic agents. Symptoms and signs of serotonin syndrome include rapid onset of neuromuscular excitation (hyper-reflexia, incoordination, myoclonus, tremor), altered mental status (confusion, agitation, hypomania) and autonomic dysfunction (diaphoresis, diarrhoea, fever, shivering and rapidly fluctuating vital signs). Treatment with Prozac should be discontinued if such events occur and supportive symptomatic treatment initiated.

Cardiovascular effects.

QT prolongation can occur with fluoxetine treatment. Fluoxetine should be used with caution in patients with conditions such as congenital long QT syndrome; acquired long QT syndrome (e.g. due to concomitant use of a drug that prolongs the QT); a family history of QT prolongation; or other clinical conditions that predispose to arrhythmias (e.g. hypokalaemia or hypomagnesaemia) or increased exposure to fluoxetine (e.g. hepatic impairment).

Rash and possibly allergic events.

During premarketing testing of more than 5,600 U.S. 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 rash include fever, leucocytosis, arthralgias, oedema, 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.
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 leucocytoclastic vasculitis and the other, a severe desquamating syndrome that was considered variously to be a vasculitis or erythema multiforme. Several other patients have had systemic syndromes suggestive of serum sickness.
Since the introduction of fluoxetine hydrochloride, 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 dyspnoea as the only preceding symptom.
Whether these systemic events and rash have a common underlying cause or are due to different aetiologies or pathogenic processes is not known. Upon the appearance of rash or of other possibly allergic phenomena for which an alternative aetiology cannot be identified, Prozac should be discontinued.

Anxiety and insomnia.

Anxiety, nervousness and insomnia were reported by 10% to 15% of patients treated with fluoxetine hydrochloride. These symptoms led to drug discontinuation in 5% of patients treated with fluoxetine hydrochloride.

Altered appetite and weight.

Significant weight loss, especially in underweight depressed patients, may be an undesirable result of treatment with fluoxetine hydrochloride. In controlled clinical trials, approximately 9% of patients treated with fluoxetine hydrochloride experienced anorexia. This incidence is approximately 6-fold that seen in placebo controls. A weight loss of greater than 5% of bodyweight occurred in 13% of fluoxetine hydrochloride treated patients compared to 4% of placebo and 3% of tricyclic antidepressant treated patients. However, only rarely have fluoxetine hydrochloride patients been discontinued for weight loss.

Screening for bipolar disorder.

A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk of bipolar disorder. Prior to initiating treatment with an antidepressant, patients should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression.

Activation of mania/hypomania.

During premarketing testing, hypomania or mania occurred in approximately 1% of fluoxetine treated patients. Activation of mania/hypomania has also been reported in a small proportion of patients with major affective disorder treated with other marketed antidepressants.

Seizures.

Twelve patients among more than 6,000 evaluated worldwide in the course of premarketing development of fluoxetine experienced convulsions (or events described as possibly having been seizures), a rate of 0.2% that appears to be similar to that associated with other marketed antidepressants. Prozac should be introduced with care in patients with a history of seizures.

The long elimination half-lives of fluoxetine and its metabolites.

Because of the long elimination half-lives of the parent drug (1 to 3 days) and its major active metabolite (4 to 16 days), 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 Section 5 Pharmacological Properties; Section 4.2 Dose and Method of Administration).

Withdrawal reactions.

Discontinuation symptoms have been reported in association with 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 nonserious, self limiting and have varying durations. Fluoxetine has been only rarely associated with such symptoms.

Tamoxifen.

Some studies have shown that the efficacy of tamoxifen, as measured by the risk of breast cancer relapse, may be reduced when coprescribed with fluoxetine as a result of inhibition of CYP2D6 (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). This risk may increase with longer duration of coadministration. When tamoxifen is used for the treatment or prevention of breast cancer, prescribers should consider using an alternative antidepressant with little or no CYP2D6 inhibition.

Use in patients with concomitant illness.

Clinical trial experience with fluoxetine hydrochloride in patients with concomitant systemic illness is limited. Caution is advisable in using Prozac in patients with diseases or conditions that could affect metabolism or haemodynamic responses.
Prozac 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 clinical studies during the product's premarket testing. However, the electrocardiograms of 312 patients who received fluoxetine hydrochloride in double blind trials were retrospectively evaluated; no conduction abnormalities that resulted in heart block were observed. The mean heart rate was reduced by approximately 3 beats/min.
In subjects with cirrhosis of the liver, the clearances of fluoxetine and its active metabolite, norfluoxetine, were decreased, thus increasing the elimination half-lives of these substances. A lower or less frequent dose should be used in patients with cirrhosis.
Since fluoxetine is extensively metabolised, excretion of unchanged drug in urine is a minor route of elimination. However, until adequate numbers of patients with severe renal impairment have been evaluated during chronic treatment with fluoxetine, it should be used with caution in such patients.
In patients with diabetes, fluoxetine hydrochloride may alter glycaemic control. Hypoglycaemia has occurred during therapy with fluoxetine hydrochloride and hyperglycaemia 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 hypoglycaemic dosage may need to be adjusted when therapy with Prozac is instituted or discontinued.
Mydriasis has been reported in association with fluoxetine; therefore, caution should be used when prescribing Prozac in patients with raised intraocular pressure or those at risk of acute narrow angle glaucoma.

Abnormal bleeding.

SSRIs and SNRIs, including fluoxetine, may increase the risk of bleeding events, including gastrointestinal bleeding (see Section 4.8 Adverse Effects (Undesirable Effects)). Therefore, caution is advised in patients taking fluoxetine concomitantly with anticoagulants and/or medicinal products known to affect platelet function (e.g. NSAIDs, aspirin) and in patients with known bleeding tendencies.

Drug abuse and dependence.

Physical and psychological dependence.

Fluoxetine hydrochloride has not been systematically studied, in animals or humans, for its potential for abuse, tolerance, or physical dependence. While the premarketing clinical experience with fluoxetine hydrochloride did not reveal any tendency for a withdrawal syndrome or any drug seeking behaviour, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of Prozac misuse or abuse (e.g. development of tolerance, incrementation of dose, drug seeking behaviour).

Hyponatraemia.

Several cases of hyponatraemia (some with serum sodium lower than 110 mmol/L) have been reported. The hyponatraemia appeared to be reversible when Prozac was discontinued. Although these cases were complex with varying possible aetiologies, 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, 10 of 313 fluoxetine patients and 6 of 320 placebo recipients had a lowering of serum sodium below the reference range; this difference was not statistically significant. The lowest observed concentration was 129 mmol/L. The observed decreases were not clinically significant in this trial.

Hyponatraemia in the elderly.

There have been seven reports (total 5628) of hyponatraemia (serum sodium 114-128 mmol/L) in elderly patients taking fluoxetine 20 mg daily. In five, hyponatraemia occurred within 19 days of commencement of fluoxetine, however fluoxetine withdrawal was associated with recovery in all cases. Hence, it may be advisable to monitor electrolytes in geriatric patients during the first weeks of therapy.

Platelet function.

There have been 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.

Electroconvulsive therapy.

There are no clinical studies establishing the benefit of the combined use of ECT and Prozac. There have been some reports of prolonged seizures in patients on Prozac receiving ECT treatment.

Animal toxicology.

Phospholipids are increased in some tissues of mice, rats, and dogs given fluoxetine chronically. This effect is reversible after cessation of fluoxetine treatment. Phospholipid accumulation in animals has been observed with many cationic amphiphilic drugs, including fenfluramine, imipramine, and ranitidine. The significance of this effect in humans is unknown.
Administration of fluoxetine to juvenile rats from weaning to young adulthood was associated with growth retardation, skeletal muscle degeneration and adverse effects on male and female reproductive systems (see Section 4.6, Effects on fertility). Post-treatment assessment revealed impaired nervous system function and adverse effects in reproductive parameters (see Section 4.6, Effects on fertility). These effects were observed at systemic exposures (plasma AUC) to fluoxetine and norfluoxetine of 5- to 20-fold higher than clinical paediatric exposure at a dose of 20 mg/day and a 2- to 7-fold higher than clinical paediatric exposure of 60 mg/day. At the no effect level for these changes, exposure to fluoxetine and norfluoxetine was less than clinical exposure to 8-fold higher than clinical exposure. The significance of these findings for human risk is unknown.

Use in hepatic impairment.

See Section 4.2 Dose and Method of Administration.

Use in renal impairment.

See Section 4.2 Dose and Method of Administration.

Use in the elderly.

Evaluation of patients over the age of 60 who receive fluoxetine 20 mg daily revealed no unusual pattern of adverse events relative to the clinical experience in younger patients. However, these data are 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 (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use, Hyponatraemia).

Paediatric use.

While clinical studies have been conducted in children and adolescents, the use of Prozac is not recommended in this population (see Section 4.4 Special Warnings and Precautions for Use, Clinical worsening and suicide risk; Section 4.6, Effects on fertility; Section 4.8 Adverse Effects (Undesirable Effects)).

Effects on laboratory tests.

No specific drug laboratory interactions involving cross-reactivity of fluoxetine with assays for other substances (i.e. producing a false positive or false negative result) have been identified.

Information for patients.

Physicians are advised to discuss the following issues with patients for whom they prescribe fluoxetine.
Because fluoxetine hydrochloride may impair judgment, 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 drugs or alcohol.
Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy.
Patients should be advised to notify their physician if they are breastfeeding an infant.
Patients should be advised to notify their physician if they develop a rash or hives.

4.5 Interactions with Other Medicines and Other Forms of Interactions

As with all drugs, the potential for interaction by a variety of mechanisms (i.e. pharmacodynamic, pharmacokinetic drug inhibition or enhancement, etc.) is a possibility (see Section 5.2 Pharmacokinetic Properties, Accumulation and slow elimination).

Drugs metabolised by P450 2D6 (CYP2D6).

Approximately 3% to 10% of the normal population has a genetic defect that leads to reduced levels of activity of cytochrome P450 2D6 (CYP2D6). Such individuals have been referred to as poor metabolisers of drugs such as dextromethorphan and tricyclic antidepressants. Many drugs, such as antipsychotics (e.g. phenothiazines and some atypical) and most antidepressants including fluoxetine and other selective uptake inhibitors of serotonin, are metabolised by this isoenzyme, thus both the pharmacokinetic properties and relative proportion of metabolites are altered in poor metabolisers.
Fluoxetine, like other agents that are metabolised by P450 2D6 (CYP2D6), inhibits the activity of this isoenzyme and thus may make normal metabolisers resemble poor metabolisers. Therapy with medications that are predominantly metabolised by P450 2D6 (CYP2D6) and that have a relatively narrow therapeutic index (e.g. flecainide, carbamazepine and tricyclic antidepressants) should be initiated at the low end of the dose range if a patient is taking fluoxetine concurrently or have taken it in the previous 5 weeks.
Tamoxifen has an important active metabolite, endoxifen, which is produced by CYP2D6 and contributes significantly to the efficacy of tamoxifen. Inhibition of CYP2D6 by fluoxetine leads to reduced plasma concentration of endoxifen (see Section 4.4 Special Warnings and Precautions for Use).

Drugs metabolised by P450 3A4.

In vitro studies have shown ketoconazole, a potent inhibitor of P450 3A4 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. In an in vivo interaction study involving coadministration of fluoxetine with single doses of terfenadine (a cytochrome P450 3A4 substrate), no increase in plasma terfenadine concentrations occurred with concomitant fluoxetine. No change in the pharmacokinetic profile or cognitive effect of midazolam 10 mg orally was observed, following a course of fluoxetine administration intended to produce steady-state conditions, when compared with baseline determinations. These data indicate that fluoxetine's extent of inhibition of P450 3A4 activity is not likely to be of clinical significance.

Potential effects of coadministration of drugs highly bound to plasma proteins.

Because Prozac is tightly bound to plasma protein, the administration of fluoxetine to a patient taking another drug which is tightly bound to protein (e.g. warfarin) 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 (see Section 5.2 Pharmacokinetic Properties, Accumulation and slow elimination).

Tryptophan.

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

Warfarin.

Altered anticoagulant effects (laboratory values and/or clinical signs and symptoms), with no consistent pattern, but including increased bleeding, have been reported uncommonly when fluoxetine is coadministered with warfarin. As is prudent in the concomitant use of warfarin with many other drugs, patients receiving warfarin therapy should receive careful coagulation monitoring when fluoxetine is initiated or stopped.

CNS active drugs.

The risk of using Prozac in combination with other CNS active drugs has not been systematically evaluated. Data have been derived from circumstances which do not directly reflect the clinical setting. The clinical significance of in vitro and individual case report data is unknown. Nonetheless, caution is advised if the concomitant administration of Prozac and such drugs is required. In evaluating individual cases, consideration should be given to using lower initial doses of the concomitantly administered drugs, using conservative titration schedules and monitoring of clinical status (see Section 5.2 Pharmacokinetic Properties, Accumulation and slow elimination).

Anticonvulsants.

Patients on stable doses of phenytoin and carbamazepine have developed elevated plasma anticonvulsant concentrations and clinical anticonvulsant toxicity following initiation of concomitant fluoxetine treatment.

Antipsychotics.

Some evidence suggests a possible pharmacodynamic and/or pharmacokinetic interaction between some serotonin specific reuptake inhibitors (SSRIs) and some antipsychotics, including possible elevation of blood levels of haloperidol and clozapine. Clinical studies of pimozide with other antidepressants demonstrate an increase in drug interaction or QTc prolongation. While a specific study with pimozide and fluoxetine has not been conducted, the potential for drug interactions or QTc prolongation warrants restricting the concurrent use of pimozide and Prozac. Concomitant use of Prozac and pimozide is contraindicated (see Section 4.3 Contraindications).

Benzodiazepines.

The half-life of concurrently administered diazepam may be prolonged in some patients and coadministration of alprazolam may result in increased plasma alprazolam concentrations.

Lithium.

There have been reports of both increased and decreased lithium levels when lithium was used concomitantly with fluoxetine. Cases of lithium toxicity and increased serotonergic effects have been reported. Lithium levels should be monitored when these drugs are administered concomitantly.

Serotonergic drugs.

Coadministration with serotonergic drugs (e.g. SNRIs, SSRIs, tramadol or triptans such as sumatriptan) may result in serotonin syndrome.

Monoamine oxidase inhibitors.

See Section 4.3 Contraindications.

Other 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 Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Drugs metabolised by P450 2D6 (CYP2D6)).

St John's wort.

In common with other SSRIs, pharmacodynamic interactions between fluoxetine and the herbal remedy St John's wort (Hypericum perforatum) may occur, which may result in an increase of undesirable effects.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Two fertility studies conducted in rats at dose levels of up to 9-12.5 mg/kg/day indicated that fluoxetine had no adverse effects on fertility. A slight decrease in neonatal survival was noted but this was probably associated with depressed maternal food consumption and suppressed weight gain.
Administration of fluoxetine to juvenile rats from weaning to young adulthood was associated with delayed sexual maturation, degenerative testicular and epididymal changes, and immaturity and inactivity of the female reproductive tract. Post-treatment assessment revealed reduced sperm concentrations and fertility, prolonged pairing coitus interval, and histopathological changes indicative of irreversible seminiferous tubular degeneration and reversible epididymal vacuolation. These effects were observed at systemic exposures (plasma AUC) to fluoxetine and norfluoxetine of 5- to 20-fold higher than clinical paediatric exposure at a dose of 20 mg/day, and 2- to 7-fold higher than clinical paediatric exposure at 60 mg/day. At the no-effect level for these changes, exposure to fluoxetine and norfluoxetine was from less than clinical exposure to 8-fold higher than clinical exposure. The significance of these findings for human risk is unknown.
(Category C)
This drug crosses the placenta.
Results of a number of epidemiological studies assessing the risk of fluoxetine exposure in early pregnancy have been inconsistent and have not provided conclusive evidence of an increased risk of congenital malformations. However, one meta-analysis suggests a potential risk of cardiovascular defects in infants of women exposed to fluoxetine during the first trimester of pregnancy compared to infants of women who were not exposed to Prozac.
Fluoxetine use should be considered during pregnancy only if the potential benefit justifies the potential risk to the foetus, taking into account the risks of untreated depression.
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, hyper-reflexia, 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.
Epidemiological data have suggested that the use of SSRIs in pregnancy, particularly in late pregnancy, may increase the risk of persistent pulmonary hypertension in the newborn (PPHN). The observed risk was approximately 5 cases per 1000 pregnancies. In the general population 1 to 2 cases of PPHN per 1000 pregnancies occur.

Teratogenic effects.

Reproduction studies have been performed in rats and rabbits at doses of up to 12.5 and 15 mg/kg/day and have revealed no evidence of harm to the foetus due to fluoxetine hydrochloride. There are, however, no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Labour and delivery.

The effect of Prozac on labour and delivery in humans is unknown.
Because fluoxetine is excreted in human milk, breastfeeding while on Prozac is not recommended. In one breast milk sample, the concentration of fluoxetine plus norfluoxetine was 70.4 nanogram/mL. The concentration in the mother's plasma was 295.0 nanogram/mL. No adverse effects on the infant were reported. In another case, an infant breastfed by a mother on Prozac developed crying, sleep disturbance, vomiting and watery stools. The infant's plasma drug levels were 340 nanogram/mL of fluoxetine and 208 nanogram/mL of norfluoxetine on the second day of feeding.

4.8 Adverse Effects (Undesirable Effects)

Adverse effects are dose dependent and more common at higher doses than 20 mg per day.

Associated with discontinuation of treatment.

Fifteen percent of approximately 4,000 patients who received fluoxetine hydrochloride in US premarketing clinical trials discontinued treatment due to an adverse event. The more common events causing discontinuation included psychiatric (5.3%), primarily nervousness, anxiety and insomnia; digestive (3.0%), primarily nausea; nervous system (1.6%), primarily dizziness; body as a whole (1.5%), primarily asthenia and headache; and skin (1.4%), 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.

Events observed during therapy with fluoxetine - clinical trials.

The following events listed by body system have been observed. Very common adverse events are defined as those occurring in 1 or more occasions in at least 1/10 patients; common adverse events are defined as those occurring in 1 or more occasions in at least 1/100 patients; uncommon adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in less than 1/1000 patients; very rare events are those occurring in less than 1/10,000 patients. It is important to emphasise that, although the events reported did occur during treatment with fluoxetine, they were not necessarily caused by it.

Body as a whole.

Very common: fatigue (includes asthenia). Common: allergic reaction, chills. Uncommon: feeling abnormal. Rare: photosensitivity reaction, serum sickness. Very rare: anaphylactoid reaction, serotonin syndrome (neuroleptic malignant syndrome-like effects), mild intensity headache.

Cardiovascular system.

Common: palpitations, vasodilatation. Uncommon: hypotension. Very rare: orthostatic hypotension.

Digestive system.

Very common: diarrhoea, nausea. Common: anorexia, dyspepsia, gastrointestinal disorder, mouth dryness, vomiting. Uncommon: dysphagia. Rare: oesophageal pain.

Haemic and lymphatic systems.

Uncommon: ecchymosis.

Metabolic and nutritional disorders.

Common: weight loss.

Musculoskeletal system.

Common: twitching.

Nervous system.

Very common: anxiety, dizziness, headache, insomnia, nervousness, somnolence, tremor. Common: abnormal dreams, libido decreased, sleep disorder, thinking abnormal. Uncommon: akathisia, ataxia, balance disorder, bruxism, buccoglossal syndrome, depersonalisation, dyskinesia, manic reaction, myoclonus, seizures.

Respiratory system.

Common: yawn.

Skin and appendages.

Common: pruritus, rash, sweating, urticaria. Uncommon: alopecia.

Special senses.

Common: abnormal vision, taste perversion. Uncommon: mydriasis.

Urogenital system.

Common: abnormal ejaculation, gynaecological bleeding, impotence, urinary frequency. Uncommon: anorgasmia, breast pain, sexual dysfunction (occasionally persisting after treatment discontinuation), urination impaired. Rare: priapism.

Investigations.

Common: electrocardiogram data: QT interval prolongation (QTcF ≥ 450 msec).

Children and adolescents.

Common: epistaxis.

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. Fluoxetine treatment was also associated with a decrease in serum alkaline phosphatase levels in this study. In a retrospective matched control observational study with a mean of 1.8 years of exposure to fluoxetine, paediatric subjects treated with fluoxetine had no difference in growth (0.0 cm) adjusted for expected growth in height from their matched, untreated controls (95% CI: -0.6 to 0.6, p = 0.9673). The subjects grew more than their controls in observed-minus-expected BMI by 0.5 kg/m2 (95% CI: 0.0 to 1.0, p = 0.0328). The mean additional change associated with fluoxetine treatment would amount to an extra 1.2 kg in a 152 cm tall person weighing 45 kg. Limited evidence is available concerning the longer-term effects of fluoxetine on the development and maturation of children and adolescent patients. Height and weight should be monitored periodically in paediatric patients receiving fluoxetine (see Section 4.4 Special Warnings and Precautions for Use).

Spontaneous events.

The following events have not been reported in clinical trials of fluoxetine, but have been reported in clinical practice and are possibly related to fluoxetine therapy. All these events are classified as very rare (occurring in less than 1/10,000 patients).

Body as a whole.

Malignant hyperthermia, Stevens-Johnson syndrome, erythema multiforme.

Cardiovascular.

Angioedema.

Digestive system.

Abnormal hepatic function, aggravation of hepatic damage, hepatic failure/necrosis, idiosyncratic hepatitis, gastrointestinal bleeding1.

Endocrine system.

Inappropriate secretion of antidiuretic hormone.

Haemic and lymphatic systems.

Eosinophilia, thrombocytopenic purpura.

Nervous system.

Oculogyric crisis, tardive dyskinesia, memory impairment, confusion.

Skin and appendages.

Epidermal necrolysis.

Urogenital system.

Enlarged clitoris.

Reproduction system and breast disorders.

Gynaecomastia, galactorrhea, hyperprolactinemia.
1 Includes: esophageal varices hemorrhage, gingival and mouth bleeding, hematemesis, hematochezia, hematomas [intra-abdominal, peritoneal], hemorrhage [anal, esophageal, gastric, gastrointestinal (upper and lower), haemorrhoidal, peritoneal, rectal], hemorrhagic diarrhoea and enterocolitis, hemorrhagic diverticulitis, hemorrhagic gastritis, melaena, and ulcer hemorrhage [esophageal, gastric, duodenal].

Discontinuation symptoms.

Discontinuation symptoms have been reported when fluoxetine treatment is stopped. The most commonly reported symptoms include dizziness, sleep disorders, sensory disturbances/paraesthesia, anxiety, agitation, asthenia, confusion, headache, and irritability.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at http://www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

Prozac capsules should be swallowed whole.
Prozac tablets may be swallowed whole, broken in half for a 10 mg dose or dispersed in approximately 100 mL of water.

Depression.

A dose of 20 mg/day, administered in the morning, is the usual recommended initial dose.
If no clinical improvement is observed, a dose increase may be considered after several weeks. Doses above 20 mg/day should be administered on a b.i.d. schedule (i.e. morning and noon) and should not exceed a maximum dose of 80 mg/day (see Section 5.2 Pharmacokinetic Properties, Clinical issues related to accumulation and slow elimination).
As with other antidepressants, the full antidepressant effect may be delayed until 4 weeks of treatment or longer (see Section 5.2 Pharmacokinetic Properties, Clinical issues related to accumulation and slow elimination).
As with many other medications, a lower or less frequent dosage should be used in patients with hepatic impairment. A lower or less frequent dosage should also be considered for patients, such as the elderly, with concurrent disease or on multiple medications.

Obsessive compulsive disorder.

Initial treatment.

A dose of 20 mg/day administered in the morning is recommended as the initial dose. If insufficient clinical improvement is observed, a dose increase may be considered after several weeks. The full therapeutic effect may be delayed until 5 weeks of treatment or longer.
Doses above 20 mg/day may be administered on a once a day (i.e. morning) or b.i.d. schedule (i.e. morning and noon). A dose range of 20 to 60 mg/day is recommended, however doses of up to 80 mg/day have been well tolerated in open studies of OCD. The maximum fluoxetine dose should not exceed 80 mg/day.
A lower or less frequent dosage should be used in patients with hepatic impairment. A lower or less frequent dosage should also be considered for patients, such as the elderly (see Section 4.4 Special Warnings and Precautions for Use, Use in the elderly) with concurrent disease or on multiple medications.

Maintenance/continuation treatment.

While there are no systematic studies that answer the question of how long to continue Prozac, OCD is a chronic condition and it is reasonable to consider continuation for a responding patient.
However, dosage adjustments should be made to maintain the patient on the lowest effective dosage and patients should be periodically reassessed to determine the need for treatment.

Premenstrual dysphoric disorder (PMDD).

The recommended dose of fluoxetine for the treatment of PMDD is 20 mg/day given continuously (every day of the menstrual cycle) or intermittently (defined as starting a daily dose 14 days prior to the anticipated onset of menstruation through the first full day of menses and repeating with each new cycle).

General.

Liver disease.

As might be predicted from its primary site of metabolism, liver impairment can affect the elimination of fluoxetine. The elimination half-life of fluoxetine was prolonged in a study of cirrhotic patients, with a mean of 7.6 days compared to the range of 2 to 3 days seen in subjects without liver disease; norfluoxetine elimination was also delayed, with a mean duration of 12 days for cirrhotic patients compared to the range of 7 to 9 days in normal subjects. This suggests that the use of Prozac in patients with liver disease must be approached with caution. If Prozac is administered to patients with liver disease, a lower or less frequent dose should be used (see Section 4.4 Special Warnings and Precautions for Use).

Renal disease.

In depressed patients on dialysis (N = 12), fluoxetine administered as 20 mg once daily for two months produced steady-state fluoxetine and norfluoxetine plasma concentrations comparable to those seen in patients with normal renal function. While the possibility exists that renally excreted metabolites of fluoxetine may accumulate to higher levels in patients with severe renal dysfunction, use of a lower or less frequent dose is not routinely necessary in renally impaired patients.

Age.

Adjustment of dosage should not be required on the basis of age alone (see Section 4.4 Special Warnings and Precautions for Use, Use in hepatic impairment, Use in renal impairment, Use in patients with concomitant illness; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Children and adolescents (< 18 years).

While clinical studies have been conducted in children and adolescents, the use of Prozac is not recommended in this population.

4.7 Effects on Ability to Drive and Use Machines

Interference with cognitive and motor performance.

Patients should be cautioned about operating hazardous machinery, or driving a car, until they are reasonably certain that treatment with Prozac does not affect them adversely.

4.9 Overdose

Symptoms.

Cases of overdose of fluoxetine alone usually have an uncomplicated course and resolve without residual effects. Symptoms of overdose have included nausea, vomiting, seizures, cardiovascular dysfunction ranging from asymptomatic arrhythmias (including nodal rhythm and ventricular arrhythmias) or ECG changes indicative of QTc prolongation to cardiac arrest (including very rare cases of torsades de pointes), pulmonary dysfunction and signs of altered CNS status ranging from excitation to coma. During a 13 year period, there were 34 fatal reports of overdose where fluoxetine was the only reported ingestant although many of the case reports were incomplete.

Management of overdose.

Establish and maintain an airway; ensure adequate oxygenation and ventilation. Activated charcoal, which may be used with sorbitol, should be considered in treating overdose. Activated charcoal may reduce absorption of the medicine if given within one or two hours after ingestion. In patients who are not fully conscious or have impaired gag reflex, consideration should be given to administering activated charcoal via a nasogastric tube, once the airway is protected.
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 hydrochloride.
Due to the large volume of distribution of fluoxetine hydrochloride, forced diuresis, dialysis, haemoperfusion, and exchange transfusion are unlikely to be of benefit.
In managing overdosage, consider the possibility of multiple drug involvement. For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

7 Medicine Schedule (Poisons Standard)

S4 - Prescription only Medicine.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each Prozac capsule contains fluoxetine hydrochloride equivalent to 20 mg (64.7 micromoles) of fluoxetine. It also contains Patent Blue V CI42051, gelatin, iron oxide yellow CI77492, dimeticone 350, pregelatinized maize starch, titanium dioxide and edible black ink (PI 1445).
Each Prozac tab contains fluoxetine hydrochloride equivalent to 20 mg (64.7 micromoles) of fluoxetine. It also contains microcrystalline cellulose, saccharin sodium, mannitol, sorbitol, aniseed flavouring (ANIS 501007 BP0551 (PI 2889)), peppermint flavouring (NAEFCO P0551 957685 (PI 2890)), colloidal anhydrous silica, maize starch, sodium stearylfumarate and crospovidone.
Prozac liquid contains fluoxetine hydrochloride equivalent to 20 mg/5 mL (64.7 micromoles) of fluoxetine. It also contains benzoic acid, sucrose, glycerol and a mint flavouring agent (Mint 587207 SE (PI 1278)). (Not available in Australia).

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Capsules.

Store below 30°C.

Tablets.

Store below 25°C in a dry place.

Liquid (not available in Australia).

Store below 30°C. Protect from light.

6.5 Nature and Contents of Container

Capsules.

Prozac capsules are available in PVC/Al blister packs of 7 and 28 capsules per carton.

Tablets.

Prozac tablets are available in PVC/Al blister packs of 7 and 28 tablets per carton.

Liquid (not available in Australia).

Prozac Liquid is available in amounts of 35, 70 and 140 mL in bottles.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

Summary Table of Changes