Consumer medicine information

Fluoxetine Sandoz

Fluoxetine

BRAND INFORMATION

Brand name

Fluoxetine Sandoz

Active ingredient

Fluoxetine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Fluoxetine Sandoz.

What is in this leaflet

This leaflet answers some common questions about Fluoxetine Sandoz.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking this medicine against the benefits it is expected to have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist. Keep this leaflet with the medicine. You may need to read it again.

What Fluoxetine Sandoz is used for

This medicine is used to treat:

  • depression
  • obsessive compulsive disorder (OCD).

It contains the active ingredient fluoxetine hydrochloride.

Fluoxetine hydrochloride belongs to a group of medicines called selective serotonin reuptake inhibitors (SSRIs). It works by inhibiting the neuronal uptake of serotonin in the central nervous system. Serotonin is one of several brain chemicals called amines which are involved in controlling mood.

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

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

Before you take Fluoxetine Sandoz

When you must not take it

Do not take this medicine if you have an allergy to:

  • fluoxetine hydrochloride, or to any of the other ingredients listed at the end of this leaflet under Product Description
  • any other similar medicines.

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 this medicine if:

  • you are taking another medicine for depression called monoamine oxidase inhibitor (MAOI), or have been taking a MAOI within the last 14 days.
    Examples of MAOIs are phenelzine and tranylcypromine. There may be others so please check with your doctor. If you do take Fluoxetine Sandoz while you are taking a MAOI, you may experience shaking (tremor), shivering, muscle stiffness, fever, rapid pulse, rapid breathing or confusion.
  • you are taking pimozide, a medicine to treat disturbances in thinking, feelings and behaviour.
    Taking pimozide together with Fluoxetine Sandoz may alter the rhythm of your heart.
  • you are taking metoprolol, a medicine to treat cardiac failure

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering or the capsules do not look quite right. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, 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 this medicine during pregnancy. If Fluoxetine Sandoz 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 while you are using Fluoxetine Sandoz.

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

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

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

If you have not told your doctor about any of the above, tell him/her before you start taking Fluoxetine Sandoz.

Taking other medicines

Tell your doctor if you are taking any other medicines, including any that you get without a prescription from your 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 and Fluoxetine Sandoz may interfere with each other. 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 Fluoxetine Sandoz
  • 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)
  • metoprolol, used to treat cardiac failure
  • mequitazine, used to treat allergies and rhinitis
  • sleeping tablets or sedatives
  • medicines used to relieve anxiety
  • medicines used to treat certain mental and emotional conditions, also called antipsychotics
  • medicines 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
  • sumatriptan, a medicine used to treat migraine
  • tamoxifen, a medicine used to treat or prevent breast cancer.

These medicines may be affected by Fluoxetine Sandoz or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

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 this medicine.

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

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

How to take Fluoxetine Sandoz

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, ask your doctor or pharmacist for help.

How much to take

Your doctor will tell you how much Fluoxetine Sandoz you need to take each day. The usual dose is one capsule taken once a day. Your doctor may increase or decrease your dose depending on your condition.

Ask your doctor or pharmacist if you are unsure of the correct dose for you. They will tell you exactly how much to take.

Follow the instructions they give you. If you take the wrong dose, Fluoxetine Sandoz may not work as well and your problem may not improve.

How to take it

Swallow the capsules whole with a glass of water.

When to take Fluoxetine Sandoz

Fluoxetine Sandoz is usually taken as a single morning dose. If your doctor tells you to take it 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 Fluoxetine Sandoz

Continue taking your medicine for as long as your doctor tells you.

The length of treatment 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, Fluoxetine Sandoz 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

Take your dose as soon as you remember, and continue to take it as you would normally.

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

Do not take a double dose to make up for the dose you missed. This may increase the chance of you getting an unwanted side effect.

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

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

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26 or New Zealand 0800 POISON or 0800 764766) for advice, or go to Accident and Emergency at the nearest hospital, if you think you or anyone else may have taken too much Fluoxetine Sandoz. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

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

While you are taking Fluoxetine Sandoz

Things you must do

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

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

Tell your doctor if you become pregnant while taking Fluoxetine Sandoz. Your doctor will discuss the risks and benefits of taking Fluoxetine Sandoz during pregnancy. If Fluoxetine Sandoz 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 anti-depressant effect of your medicine 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 you must not do

Do not stop taking Fluoxetine Sandoz or lower the dosage without checking with your doctor. Suddenly stopping Fluoxetine Sandoz 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 Fluoxetine Sandoz you are taking before stopping completely.

Do not take Fluoxetine Sandoz to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if their symptoms seem similar to yours.

Do not take the herbal remedy St John's Wort while you are being treated with Fluoxetine Sandoz. 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 Fluoxetine Sandoz affects you.

Fluoxetine Sandoz may cause drowsiness in some people.

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

Things to be careful of

Be careful driving or operating machinery until you know how Fluoxetine Sandoz affects you. This medicine may cause drowsiness in some people. If you experience drowsiness, do not drive, operate machinery or do anything else that could be dangerous.

Side effects

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

Fluoxetine Sandoz 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 attention 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.

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.

Children and Adolescents

Headaches are very common side effects.

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

After taking Fluoxetine Sandoz

Storage

Keep your medicine in the original container.

If you take it out of its original container it may not keep well.

Keep your medicine in a cool dry place where the temperature stays below 25°C.

Do not store Fluoxetine Sandoz 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 this medicine 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

Fluoxetine Sandoz comes in capsules:

Fluoxetine Sandoz 20mg - green capsule.

Available in blister packs of 28 capsules.

Ingredients

Active ingredient:
Fluoxetine Sandoz 20mg - 20mg fluoxetine (as hydrochloride)

Inactive ingredients:

  • pregelatinised maize starch
  • dimeticone-350.

Hard-shell capsule:

  • gelatin
  • titanium dioxide
  • iron oxide yellow CI 77492
  • patent blue V CI42051

This medicine does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

Supplier

Sandoz Pty Ltd
ABN 60 075 449 553
54 Waterloo Road
Macquarie Park, NSW 2113
Australia
Tel: 1800 726 369

Novartis New Zealand Ltd
Private Bag 65904 Mairangi Bay
Auckland 0754
New Zealand
Tel: 0800 354 335

This leaflet was revised in April 2019.

Australian Register Number
20 mg capsules: AUST R 64564 (blisters)

Published by MIMS June 2019

BRAND INFORMATION

Brand name

Fluoxetine Sandoz

Active ingredient

Fluoxetine

Schedule

S4

 

1 Name of Medicine

Fluoxetine hydrochloride.

6.7 Physicochemical Properties

Fluoxetine hydrochloride is a white to off-white crystalline solid with a solubility of 14 mg/mL in water.
Chemical name: (3RS)-N-methyl -3-phenyl-3-[4-(trifluoromethyl) phenoxy] propan-1-amine hydrochloride.
Chemical formula: C17H18F3NO.HCl.
Molecular weight: 345.79.

Chemical structure.


CAS number.

59333-67-4.

2 Qualitative and Quantitative Composition

Each Fluoxetine Sandoz Capsule contains fluoxetine hydrochloride 22.4 mg equivalent to fluoxetine 20 mg.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Fluoxetine Sandoz 20 mg capsules are green hard-shell gelatin capsules, size 3, filled with a homogeneous white powder.

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 humans 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-adrenegic receptors has been hypothesised to be associated with various anticholinergic, sedative and cardiovascular effects of classic 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 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 depressive illness, and that 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 the elderly depressed patients (> 60 years of age). The efficacy shown by fluoxetine in these elderly patients was similar to 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 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.

5.2 Pharmacokinetic Properties

Absorption.

In humans, 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. 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 1000 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, the potency and selectivity of norfluoxetine as a serotonin uptake blocker are essentially equivalent to those of fluoxetine.
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 its 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 its 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 a 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 ensure 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. For the clinical significance of the long elimination half lives of fluoxetine and its metabolites, see Section 4.4 Special Warnings and Precautions for Use.

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 of dose levels of 8-11 mg/kg/day produced no evidence of carcinogenicity.

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 Fertility, Pregnancy and Lactation, Effects on fertility). Post treatment assessment revealed impaired nervous system function and adverse effects in reproductive parameters (see Section 4.6 Fertility, Pregnancy and Lactation, Effects on fertility). These effects were observed at systemic exposures (plasma AUC) to fluoxetine and norfluoxetine of 5-20 fold higher than clinical paediatric exposure of 20 mg/day and 2-7 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.

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of major depression.
Treatment of obsessive compulsive disorder (OCD).

4.3 Contraindications

Fluoxetine Sandoz 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, hyperreflexia, hyperthermia, rigidity, autonomic instability with possible rapid fluctuation of vital signs and mental status changes that include extreme agitation progressing to delirium and coma.
Therefore, fluoxetine hydrochloride 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 five 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 4.4 Special Warnings and Precautions for Use).
Fluoxetine is contraindicated in combination with metoprolol used in cardiac failure.

4.4 Special Warnings and Precautions for Use

Clinical worsening and suicide risk.

The risk of suicide attempts 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 fluoxetine 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 dosage 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 patients presenting symptoms. Patients (and caregivers of patients) should be alerted about the need to 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 analysis of 24 short-term (4 to 16 weeks) placebo controlled trials of nine antidepressant medicines (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 almost 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 analysis 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 immediately to health care providers. 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 fluoxetine should be written for the smallest quantity of tablets 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 SSRIs and SNRIs, particularly when given in combination with MAOIs or other serotonergic agents. Symptoms and signs of serotonin syndrome include rapid onset of neuromuscular excitation (hyperreflexia, incoordination, myoclonus, tremor), altered mental status (confusion, agitation, hypomania) and autonomic dysfunction (diaphoresis, diarrhoea, fever, shivering and rapidly fluctuating vital signs). Treatment with fluoxetine 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. hypokalemia or hypomagnesemia) or increased exposure to fluoxetine (e.g. Hepatic impairment).

Rash and possibly allergic events.

During premarketing testing of more than 5,600 US 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 which 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 aetiology cannot be identified, fluoxetine 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 sixfold 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, fluoxetine hydrochloride has only rarely been discontinued because of 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 a 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%, which appears to be similar to that associated with other marketed antidepressants. Fluoxetine hydrochloride should be introduced with care in patients with a history of seizures.

Long elimination half-lives.

Because of the long elimination half-lives of the parent drug fluoxetine (1 to 3 days) and its major active metabolite norfluoxetine (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 5.2 Pharmacokinetic 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 non serious, self limiting and have varying durations. Fluoxetine has been only rarely associated with such symptoms.

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 fluoxetine hydrochloride in patients with diseases or conditions that could affect metabolism or haemodynamic responses.
Fluoxetine has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with those diagnoses were systematically excluded from clinical studies during 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/minute.
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 fluoxetine hydrochloride is instituted or discontinued.
Mydriasis has been reported in association with fluoxetine; therefore, caution should be used when prescribing fluoxetine 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.

Hyponatraemia.

Several cases of hyponatraemia (some with serum sodium lower than 110 mmol/L) have been reported. The hyponatraemia appeared to be reversible when fluoxetine hydrochloride 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, ten of 313 fluoxetine patients and six 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 5,628) of hyponatraemia (serum sodium 114 to 128 mmol/L) in elderly patients taking fluoxetine 20 mg daily. In five patients, 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 fluoxetine. There have been some reports of prolonged seizures in patients on fluoxetine receiving ECT treatment.

Tamoxifen.

Some studies have shown that the efficacy of tamoxifen, as measured by the risk of breast cancer relapse, may be reduced when co-prescribed 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.

Drug abuse and 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 fluoxetine hydrochloride misuse or abuse (e.g. development of tolerance, incrementation of dose, drug seeking behaviour).

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, if they are breastfeeding an infant or if they develop a rash or hives.

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 years who receive fluoxetine 20 mg daily revealed no unusual pattern of adverse events relative to 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 fluoxetine is not recommended in this population (see Section 4.4 Special Warnings and Precautions for Use, Clinical worsening and suicide risk; Section 4.6 Fertility, Pregnancy and Lactation, Effects on fertility; Section 4.8 Adverse Effects (Undesirable Effects); Section 5.3 Preclinical Safety Data, Animal toxicology).

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.

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) is a possibility (see Section 5.2 Pharmacokinetic Properties, Accumulation and slow elimination).

Drugs metabolised by cytochrome P450 2D6.

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 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 CYP2D6, inhibits the activity of this isoenzyme and thus may make normal metabolisers resemble poor metabolisers. Therapy with medications that are predominantly metabolised by CYP2D6 and that have a relatively narrow therapeutic index (e.g. flecainide, carbamazepine, vinblastine, tricyclic antidepressants) should be initiated at the low end of the dose range if a patient is taking fluoxetine concurrently or has taken it in the previous five 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 concentrations of endoxifen (see Section 4.4 Special Warnings and Precautions for Use).

Drugs metabolised by cytochrome 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.

Highly protein bound drugs.

Because fluoxetine is tightly bound to plasma protein, the administration of fluoxetine to a patient taking another drug that 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 reactions, including agitation, restlessness and gastrointestinal distress.

Warfarin.

Altered anticoagulant effects (laboratory values and or clinical signs and symptoms), with no consistent pattern, but including increase 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.

Central nervous system active drugs.

The risk of using fluoxetine 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 fluoxetine 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 Pharmacological Properties).

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 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 fluoxetine. Concomitant use of fluoxetine 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 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 two to ten times when fluoxetine has been administered in combination. This influence may persist for three weeks or longer after fluoxetine has been discontinued. Thus, the dose of tricyclic antidepressant may need to be reduced and plasma tricyclic antidepressant concentrations may need to be monitored temporarily when fluoxetine is coadministered or has been recently discontinued (see Drugs metabolised by cytochrome P450 2D6, above).

Metoprolol used in cardiac failure.

Risk of metoprolol adverse events including excessive bradycardia, may be increased because of an inhibition of its metabolism by fluoxetine.

Mequitazine.

Risk of mequitazine adverse events (such as QT prolongation) may be increased because of an inhibition of its metabolism by fluoxetine.

Drugs that cause QT interval prolongation.

Pharmacokinetic and pharmacodynamic studies between fluoxetine and other medicinal products that prolong the QT interval have not been performed. An additive effect of fluoxetine and these medicinal products cannot be excluded. Therefore, coadministration of fluoxetine with medicinal products that prolong the QT interval, should be used with caution.

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 5-20 fold higher than clinical paediatric exposure at a dose of 20 mg/day, and 2-7 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 fluoxetine.
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, 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.
Epidemiological studies have shown that the use of SSRIs (including fluoxetine) in pregnancy, particularly use in late pregnancy, was associated with an increased risk of persistent pulmonary hypertension of the newborn (PPHN). The risk of PPHN among infants born to women who used SSRIs late in pregnancy was estimated to be 4 to 5 times higher than the rate of 1 to 2 per 1000 pregnancies observed in the general population.
This potential risk should be weighed against the need for treatment during pregnancy.

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

4.8 Adverse Effects (Undesirable Effects)

Adverse reactions are dose dependent and more common at doses higher than 20 mg/day.

Associated with treatment discontinuation.

15% 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 patients treated with fluoxetine discontinued treatment early because of adverse events. Anxiety and rash at incidences of less than 2% were the most frequently reported events.

Incidence in clinical trials.

The following events listed by body system have been observed. Very common adverse events are defined as those occurring on one or more occasions in at least 10% of patients; common adverse events are defined as those occurring on one or more occasions in at least 1% of patients; uncommon adverse events are those occurring in 0.1 to 1% of patients; rare events are those occurring in less than 0.1% of patients; very rare events are those occurring in less than 0.01% of 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 reactions, 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/nutritional disorders.

Common: weight loss.

Musculoskeletal system.

Common: twitching.

Nervous system.

Very common: anxiety, dizziness, headache, insomnia, nervousness, somnolence, tremor. Common: abnormal dreams, decreased libido, sleep disorder, abnormal thinking. 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 (occasional persistence after treatment discontinuation), impaired urination. Rare: priapism.

Children and adolescents.

Very common: headache. Common: epistaxis.

Investigations.

Common: electrocardiogram data: QT interval prolongation (QTcF ≥ 450 msec).
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 serum alkaline phosphatase levels. 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 = 0.328). 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 0.01% of patients).

Body as a whole.

Malignant hyperthermia, Stevens-Johnson syndrome, erythema multiforme.

Cardiovascular.

Angioedema.

Digestive system.

Aggravation of hepatic damage, abnormal hepatic function, 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.

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.
1Includes: 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]).

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 www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

Dosage.

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, Accumulation and slow elimination.) As with other antidepressants, the full antidepressant effect may be delayed until four weeks of treatment or longer. (See Section 5.2 Pharmacokinetic Properties, Accumulation and slow elimination.)
As with many other medications, a lower or less frequent dosage should be used in patients with hepatic impairment (see Section 4.4 Special Warnings and Precautions for Use). A lower or less frequent dosage should also be considered for patients, such as the elderly, with concurrent disease or on multiple medications (see Section 4.4 Special Warnings and Precautions for Use).

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 five 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) schedule. 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 obsessive compulsive disorder (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, with concurrent disease or on multiple medications (see Section 4.4 Special Warnings and Precautions for Use, Use in the elderly).

Maintenance/continuation treatment.

While there are no systematic studies that answer the question of how long to continue Fluoxetine Sandoz therapy, 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.

Dosage adjustment in renal impairment.

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.

Dosage adjustment in hepatic impairment.

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

Age.

Adjustment of dosage should not be required on the basis of age alone (see Section 4.4 Special Warnings and Precautions for Use for information on 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 fluoxetine is not recommended in this population.

4.7 Effects on Ability to Drive and Use Machines

Patients should be cautioned about operating hazardous machinery or driving a car until they are reasonably certain that treatment with fluoxetine 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 Torsade 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.

In case of overdose treatment should be supportive and symptomatic.
Establish and maintain an airway; ensure adequate oxygenation and ventilation. Activated charcoal, which may be used with sorbitol, should be considered in treating overdose. Cardiac and vital sign 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 that fail to remit spontaneously may respond to diazepam.
There are no specific antidotes for fluoxetine hydrochloride.
Because of 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 Poison Information Centre on 131126 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Fluoxetine Sandoz capsules also contain pregelatinised maize starch, dimeticone 350, gelatin, titanium dioxide, iron oxide yellow CI 77492, and patent blue V CI42051.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.
For information on interactions with other medicines and other forms of interactions, see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

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

Store below 25°C.

6.5 Nature and Contents of Container

Fluoxetine Sandoz are available in PP/Al blister packs of 28 capsules.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

Summary Table of Changes