Consumer medicine information

Zactin Tabs

Fluoxetine

BRAND INFORMATION

Brand name

Zactin Tabs

Active ingredient

Fluoxetine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Zactin Tabs.

What is in this leaflet

This leaflet answers some common questions about Zactin Tabs.

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

All medicines have benefits and risks. Your doctor has weighed the risks of you taking Zactin Tabs 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 your medicine. You may need to read it again.

What Zactin Tabs is used for

Zactin Tabs is used to treat:

  • Depression
  • Obsessive compulsive disorder (OCD)
  • Premenstrual dysphoric disorder (PMDD).

Your doctor may have prescribed Zactin Tabs for another reason.

Ask your doctor if you have any questions about why Zactin Tabs has been prescribed for you.

Zactin belongs to a group of medicines called selective serotonin reuptake inhibitors (SSRIs). They are thought to work by acting on chemicals in your brain called amines. These amines are involved in controlling mood.

Zactin Tabs is not recommended for use in children, as the safety and effectiveness of fluoxetine in children have not been established.

Zactin Tabs is available only with a doctor's prescription.

Before you take Zactin Tabs

When you must not take it

Do not take Zactin Tabs if you have an allergy to:

  • 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 Zactin Tabs 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. Taking Zactin Tabs with a MAOI may cause a serious reaction with a sudden increase in body temperature, shivering, rapid breathing, muscle stiffness and severe convulsions. Check with your doctor or pharmacist if you are unsure as to whether or not you have been taking a MAOI.

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

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to our 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 are allergic to any other medicines, foods, dyes or preservatives.

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

Tell your doctor if you are breastfeeding or wish to breastfeed. Zactin Tabs passes into breast milk and may affect your baby. Your doctor will discuss the risks and benefits of taking Zactin Tabs when breastfeeding.

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

  • Liver problems
  • Kidney problems
  • Seizures (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 Zactin Tabs, 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 him/her before you start taking Zactin Tabs.

Taking other medicines

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

Some medicines may be affected by Zactin Tabs, 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 Zactin Tabs.
  • 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 such as diazepam and alprazolam
  • Medicines used to treat certain mental and emotional conditions, also called antipsychotics such as haloperidol, clozapine and pimozide
  • Medicines used to control fits including phenytoin and carbamazepine
  • Medicines used to prevent blood clots, such as warfarin
  • Flecainide, a medicine used to treat some heart conditions
  • Tryptophan, an amino acid found in certain supplements
  • Other serotonergic drugs e.g., tramadol, sumatriptan
  • St John's Wort (Hypericum perforatum), a herbal remedy.

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

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

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

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

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

How to take Zactin Tabs

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

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

How much to take

The usual starting dose is one tablet (20 mg) each morning. Your doctor may change this dose depending on how you respond to this medicine.

Patients with kidney or liver problems, are elderly, or are on multiple medications may be given a lower or less frequent dose.

How to take it

Swallow the tablets whole with a glass of water or disperse the tablets in half a glass of water before swallowing. To disperse Zactin Tabs, remove the tablet from its foil packaging and drop it into about half a glass of water. Swirl the tablet in the water until it disperses (falls apart), then drink it immediately.

Zactin Tabs may be halved along the scoreline if your doctor has prescribed half a tablet.

When to take it

Zactin Tabs can be taken with or without food.

Zactin Tabs is usually taken as a single morning dose.

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

Take Zactin Tabs at about the same time each day. This will help you remember when to take it.

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 the missed dose as soon as you remember, and then go back to taking your tablets as you would normally.

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

If you have any questions about this, check with your doctor or pharmacist.

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.

How long to take it for

The length of treatment with Zactin Tabs will depend on how quickly your symptoms improve. Most medicines of this type take time to work, so do not be discouraged if you do not feel better right away. While some symptoms will be relieved sooner than others, it can take up to 4 weeks or longer to feel the full benefits of Zactin Tabs.

Keep taking Zactin Tabs for as long as your doctor recommends.

If you do not start to feel better in about 4 weeks, check with your doctor.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 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 Zactin Tabs. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

If you take too much Zactin Tabs, you may feel sick in the stomach, vomit, feel restless, agitated or excited.

While you are taking Zactin Tabs

Things you must do

Before starting any new medicine, tell your doctor or pharmacist that you are taking Zactin Tabs.

Tell all the doctors, dentists and pharmacists who are treating you that you are taking Zactin Tabs.

Tell your doctor if you feel that Zactin Tabs is not helping your condition, or if, for any reason, you have not taken it exactly as prescribed.

Tell your doctor immediately if you have any suicidal thoughts or other mental/mood changes.

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

Contact your doctor or a mental health professional immediately or go to the nearest hospital for treatment if you or someone you know is demonstrating any of the following warning signs:

  • Worsening of your depression
  • Thoughts or talk about 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 mood or behaviour.

All mentions of suicide or violence must be taken seriously.

If you become pregnant while taking Zactin Tabs, tell your doctor immediately. Your doctor will discuss the risks and benefits of taking Zactin Tabs during pregnancy. If Zactin Tabs is taken during pregnancy, you should be careful, particularly at the end of your pregnancy. Temporary withdrawal symptoms have been reported rarely in the newborn baby after maternal use during the last 3 months of pregnancy.

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

Things you must not do

Do not stop taking Zactin Tabs, or lower the dose, without checking with your doctor. Stopping Zactin Tabs suddenly may cause nausea, headache, dizziness or anxiety. Your doctor may want you to gradually reduce the amount of Zactin Tabs you are taking before stopping completely.

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

Do not use Zactin Tabs to treat any other conditions unless your doctor tells you to.

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

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

Things to be careful of

Be careful driving or operating machinery until you know how Zactin Tabs affects you.

Zactin Tabs may cause drowsiness, dizziness or sleepiness in some people and affect alertness. Make sure you know how you react to Zactin Tabs before you drive or operate machinery. If any of the above mentioned symptoms occur, 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 Zactin Tabs.

Like all other medicines, Zactin Tabs may have unwanted side effects in some people. 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 list of possible side effects. You may not experience any of them.

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

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

  • Nausea, vomiting
  • Stomach upset, diarrhoea
  • Loss of appetite, weight loss, changes in taste, dry mouth
  • Trouble sleeping, unusual dreams
  • Anxiety, nervousness
  • Drowsiness, weakness
  • Dizziness
  • Headache
  • Excessive sweating, flushing, chills
  • Lesions of skin and mucous membrane
  • Fever and joint aches
  • Sexual problems
  • More frequent urination
  • Changes in vision

Tell your doctor immediately or go to Accident and Emergency at the nearest hospital if you notice any of the following:

  • Itching, skin rash or hives
  • Shortness of breath, wheezing or trouble breathing
  • Swelling of the face, lips, tongue or other parts of the body
  • Sudden switches of moods to one of excitement, overactivity and uninhibited behaviours
  • Sudden fever
  • Hallucinations
  • Muscle spasms, tremors, twitches
  • Convulsions or fits
  • Fast, irregular heart beat
  • Bleeding or bruising more easily than normal
  • Loss of coordination, including uncontrolled movements of the eye, arms or legs
  • Confusion
  • Overactive reflexes

The above lists uncommon yet serious side effects. If any of these occur you may need urgent medical attention.

Children and Adolescents

Headaches are very common side effects. Weight loss and decreased height gain have been observed in association with the use of Zactin Tabs 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 Zactin Tabs

Storage

Keep Zactin Tabs 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.

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

Keep your tablets in a cool dry place where the temperature stays below 30°C.

Do not store Zactin Tabs or any other medicine in the bathroom or near a sink.

Do not leave Zactin Tabs in the car or on window sills. Heat and dampness can destroy some medicines.

Disposal

If your doctor tells you to stop taking Zactin Tabs, or your tablets have passed their expiry date, ask your pharmacist what to do with any that are left over.

Product description

What it looks like

Zactin Tabs is an oval, convex, white tablet debossed "FL|20" on one side and "G" on the other.

Each blister pack contains 28 dispersible tablets.

Ingredients

The active ingredient in Zactin Tabs is 20 mg fluoxetine (as hydrochloride).

The tablets also contain:

  • Microcrystalline cellulose
  • Colloidal anhydrous silica
  • Maize starch
  • Crospovidone
  • Saccharin sodium
  • Magnesium stearate
  • Nat. Peppermint Micron TIM-11812
  • The tablets are gluten free.

Manufacturer

Zactin Tabs is made in Australia by:

Alphapharm Pty Limited
Level 1, 30 The Bond
30-34 Hickson Road
Millers Point NSW 2000
www.mylan.com.au

Australian registration numbers:
Blister pack - AUST R 90913

This leaflet was prepared in
June 2019.

ZactinTabs_cmi\Jun19/00

Published by MIMS August 2019

BRAND INFORMATION

Brand name

Zactin Tabs

Active ingredient

Fluoxetine

Schedule

S4

 

1 Name of Medicine

Fluoxetine (as fluoxetine hydrochloride).

2 Qualitative and Quantitative Composition

Each Zactin Tabs dispersible tablet contains fluoxetine hydrochloride equivalent to fluoxetine 20 mg.
Zactin Tabs also contains sulfites.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Zactin Tabs dispersible tablet.

20 mg fluoxetine (as hydrochloride); oval, normal convex, white tablet, debossed "FL / 20" on one side and "G" on the other.

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of major depression, obsessive compulsive disorder (OCD), premenstrual dysphoric disorder (PMDD) as defined by the Diagnostic and Statistical Manual fourth edition (DSM-IV) criteria.
The essential features of PMDD, according to the 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.

4.2 Dose and Method of Administration

Zactin Tabs dispersible tablet may be swallowed whole or broken in half for a 10 mg dose. For patients with swallowing difficulties, the tablets may be dispersed in approximately 100 mL of water.

Depression.

The usual recommended initial dose of fluoxetine in the treatment of depression is 20 mg/day, taken in the morning.
A dose increase may be considered after several weeks if no clinical improvement is observed. Doses above 20 mg/day should be administered twice daily (morning and noon) and should not exceed a maximum daily dose of 80 mg (see Section 5.2 Pharmacokinetic Properties, Clinical issues related to accumulation and slow elimination).
As with other antidepressant agents, the full antidepressant effect may be delayed until 4 or more weeks of therapy (see Section 5.2 Pharmacokinetic Properties, Clinical issues related to accumulation and slow elimination).
As with many other medications, patients with renal and/or hepatic impairment should be given a lower or less frequent dosage. A lower or less frequent dosage should also be considered for patients who are elderly, with concurrent disease or are on multiple medications.

Obsessive compulsive disorder (OCD).

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 twice a day 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 renal and/or hepatic impairment.
A lower or less frequent dosage should also be considered for elderly patients (see Section 4.4 Special Warnings and Precautions for Use, Use in the elderly), and those 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 fluoxetine, 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).

A dose of 20 mg per day is recommended.

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 fluoxetine in patients with liver disease must be approached with caution. If fluoxetine 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 patients with renal impairment (see Section 4.4 Special Warnings and Precautions for Use, Use in renal impairment).

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).

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

4.3 Contraindications

Known hypersensitivity to fluoxetine or any of the other ingredients in Zactin Tabs.

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, Zactin Tabs should not be administered concomitantly with MAOIs (selective, reversible or irreversible), or within 14 days of discontinuing therapy with a MAOI. Since fluoxetine and its major metabolite have very long elimination half-lives, at least 5 weeks wash out (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 ceasing Zactin Tabs 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).

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 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 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 4400 children and adolescents with major depressive disorder (16 trials), obsessive compulsive disorder (4 trials), or other psychiatric disorders (4 trials) have revealed a greater risk of adverse events representing suicidal behaviour or thinking (suicidality) during the first few months of treatment in those receiving antidepressants. The average risk of such events in patients treated with an antidepressant was 4%, compared with 2% of patients given placebo. There was considerable variation in risk among the antidepressants, but there was a tendency towards an increase for almost all antidepressants studied. The risk of suicidality was most consistently observed in the major depressive disorder trials, but there were signals of risk arising from trials in other psychiatric indications (obsessive compulsive disorder and social anxiety disorder) as well. No suicides occurred in these trials. It is unknown whether the suicidality risk in children and adolescent patients extends to use beyond several months. The nine antidepressant medicines in the pooled analyses included five SSRIs (citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) and four non-SSRIs (bupropion, mirtazapine, nefazodone, venlafaxine).
Symptoms of anxiety, agitation, panic attacks, insomnia, irritability, hostility (aggressiveness), impulsivity, akathisia (psychomotor restlessness), hypomania, and mania have been reported in adults, adolescents and children being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either worsening of depression and/or emergence of suicidal impulses has not been established, there is concern that such symptoms may be precursors of emerging suicidality.
Families and caregivers of children and adolescents being treated with antidepressants for major depressive disorder or for any other condition (psychiatric or nonpsychiatric) should be informed about the need to monitor these patients for the emergence of agitation, irritability, unusual changes in behaviour, and other symptoms described above, as well as the emergence of suicidality, and to report such symptoms to health care providers immediately. It is particularly important that monitoring be undertaken during the initial few months of antidepressant treatment or at times of dose increase or decrease.
Prescriptions for Zactin Tabs should be written for the smallest quantity consistent with good patient management, in order to lower 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 (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 fluoxetine hydrochloride 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 premarket testing of more than 5,600 US patients treated with fluoxetine, approximately 4% developed a rash and/or urticaria. Almost a third of these cases 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, arthralgias, leucocytosis, carpal tunnel syndrome, oedema, respiratory distress, proteinuria, lymphadenopathy, 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 reported to have developed a serious cutaneous systemic illness. 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, although in neither patient was there an unequivocal diagnosis. Several other patients have had systemic syndromes suggestive of serum sickness.
Since the introduction of fluoxetine, systemic events possibly related to vasculitis have developed in patients with rash. Although these events are rare, they may be serious, involving the lung, kidney or liver. Death has been reported to occur in association with these systemic events.
Anaphylactoid events, including urticaria, bronchospasm, and angioedema, alone and in combination, have been reported.
Pulmonary events, including inflammatory processes of varying histopathology and/or fibrosis, have been rarely reported. These events have occurred with dyspnoea as the only preceding symptom.
It is not known whether these systemic events and rash have a common underlying cause or are due to different aetiologies or pathogenic processes. Zactin Tabs should be discontinued upon the appearance of rash or of other possibly allergic phenomena for which an alternative cause cannot be identified.

Anxiety and insomnia.

10 to 15% of patients receiving fluoxetine reported anxiety, nervousness and insomnia. These symptoms led to drug discontinuation in 5% of patients treated with fluoxetine.

Altered appetite and weight.

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

Hypomania or mania occurred in about 1% of patients who received fluoxetine during premarket testing. Activation of mania/ hypomania has also been reported in a small percentage of patients with major affective disorder treated with other marketed antidepressants.

Seizures.

Among more than 6,000 patients evaluated worldwide during premarket development of fluoxetine, 12 patients experienced convulsions (or events described as possibly having been seizures). Convulsions/ seizures associated with other marketed antidepressants appear to occur at a similar rate (0.2%). Therefore, Zactin Tabs 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 fluoxetine (1 to 3 days after acute dosing and 4 to 6 days after chronic dosing) and its major active metabolite, norfluoxetine (4 to 16 days on acute and chronic dosing), dose changes will not be fully reflected in plasma concentrations 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.

Withdrawal reactions have been reported with selective serotonin reuptake inhibitor (SSRI) antidepressants. Due to 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 in patients with concomitant systemic illness is limited. In patients with diseases or conditions which could affect metabolism or haemodynamic responses, fluoxetine should be used with caution. Fluoxetine has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were systematically excluded from clinical studies during the product's premarket testing. However, the electrocardiograms of 312 patients who received fluoxetine in double blind trials were retrospectively evaluated and no conduction abnormalities resulting in heart block were observed. The mean heart rate was decreased by approximately 3 beats/minute.
In subjects with liver cirrhosis, the clearances of fluoxetine and norfluoxetine, were reduced, thus increasing the elimination half-lives of these substances. A lower or less frequent dose should be used in these patients.
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.
Fluoxetine may alter the glycaemic control of patients with diabetes. Hypoglycaemia has occurred during therapy with fluoxetine and hyperglycaemia has developed following cessation of the drug. Thus, in diabetic patients, the dosage of insulin and/or oral hypoglycaemics may need to be adjusted when therapy with fluoxetine is commenced or discontinued.

Mydriasis.

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.

Interference with cognitive and motor performance.

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

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.
Patients should be advised to notify their physician if they develop a rash or hives.

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 was discontinued. Although these cases were complex with varying possible aetiologies, some were possibly due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Most of these occurrences have been in older patients and in patients taking diuretics or who were otherwise volume depleted. Ten of 313 fluoxetine patients and 6 of 320 placebo recipients in a placebo controlled, double blind trial, had a reduction in 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 receiving fluoxetine 20 mg daily. In five patients hyponatraemia occurred within 19 days of starting fluoxetine, however in all cases, the patients recovered after fluoxetine was withdrawn. Hence, in elderly patients, it may be advisable to monitor electrolyte levels during the initial 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 (ECT).

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.

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

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 received fluoxetine 20 mg daily revealed no unusual pattern of adverse events relative to the clinical experience in younger patients. These data are insufficient, however, to dismiss the possibility of 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 (< 18 years).

The safety and efficacy of fluoxetine for the treatment of children and adolescents less than 18 years of age has not been established (see Section 4.6 Fertility, Pregnancy and Lactation, Effects on fertility, Animal toxicology; 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.

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 cytochrome P450 2D6 (CYP2D6).

Approximately 3 to 10% of the normal population has reduced levels of activity of cytochrome P450 2D6 (CYP2D6) as a result of a genetic defect. Such individuals have been referred to as poor metabolisers of drugs such as dextromethorphan and tricyclic antidepressants. Many drugs, such as antipsychotic (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.
Like other agents that are metabolised by CYP2D6, fluoxetine inhibits the activity of this isoenzyme and thus may make normal metabolisers resemble poor metabolisers. Treatment with medications that are predominantly metabolised by 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 in patients currently taking fluoxetine or who have taken it in the preceding 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 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 cytochrome 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 cytochrome P450 3A4 activity is not likely to be of clinical significance.

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

Since fluoxetine is tightly bound to plasma protein, the concomitant use of fluoxetine with another highly protein bound drug (e.g. warfarin) may cause a shift in plasma concentrations of either drug, thus 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 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 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 5.2 Pharmacokinetic Properties, Accumulation and slow elimination).

Anticonvulsants.

Patients receiving stable doses of phenytoin and carbamazepine have developed raised plasma anticonvulsant levels 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 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 plasma alprazolam concentrations.

Lithium.

There have been reports of both increased and decreased lithium levels during combined therapy with fluoxetine and lithium. 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 other 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 cytochrome P450 2D6 (CYP2D6)).

St John's wort (Hypericum perforatum).

In common with other SSRIs, pharmacodynamic interactions between fluoxetine and the herbal remedy St John's wort 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.

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 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)
Fluoxetine 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, 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 studies have shown that the use of SSRIs in pregnancy, particularly use in late pregnancy, was associated with an increased risk of persistent pulmonary hypertension of 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 oral doses of up to 12.5 and 15 mg/kg/day respectively, and have revealed no evidence of harm to the fetus due to fluoxetine. However, there are no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, fluoxetine should only be used during pregnancy if clearly required.

Labour and delivery.

The effect of fluoxetine on labour and delivery in humans is not known.
Fluoxetine and norfluoxetine are excreted in breast milk. Therefore, breastfeeding is not recommended during treatment with Zactin Tabs. The concentration of fluoxetine plus norfluoxetine was 70.4 nanogram/mL in one breast milk sample, while the mother's plasma concentration was 295.0 nanogram/mL. No adverse effects on the baby were reported. In another case, an infant breastfed by a mother on fluoxetine developed crying, sleep disturbance, vomiting and watery stools. The infant's plasma concentrations of fluoxetine and norfluoxetine on the second day of feeding were 340 nanogram/mL and 208 nanogram/mL, respectively.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

Adverse reactions 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 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 1/1,000 patients; rare events are those occurring in less than 1/1,000 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 (including 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, 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 (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. In addition, fluoxetine treatment was 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, galactorrhoea, hyperprolactinaemia.

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.
1 Includes: oesophageal varices haemorrhage, gingival and mouth bleeding, haematemesis, haematochezia, haematomas [intra-abdominal, peritoneal], haemorrhage [anal, oesophageal, gastric, gastrointestinal (upper and lower), haemorrhoidal, peritoneal, rectal], haemorrhagic diarrhoea and enterocolitis, haemorrhagic diverticulitis, haemorrhagic gastritis, melaena, and ulcer haemorrhage [oesophageal, 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.

4.9 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 no 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. The physician should consider contacting the Poisons Information Centre on 13 11 26 for advice on the treatment of any overdosage.

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. Animal studies 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. In vitro, fluoxetine binds to these and other membrane receptors from brain tissue much less potently than do the tricyclic antidepressants.

Clinical trials.

1. 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 is 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.

2. 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.

3. 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 significantly 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.

4. 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 six 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 versus placebo) and 42% on fluoxetine 60 mg (p < 0.001 versus 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 three VAS items decreased 8% on placebo, 33% on 20 mg (p = 0.005 versus placebo) and 31% on fluoxetine 60 mg (p = 0.012 versus 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 clinical studies were supportive of the differences seen between fluoxetine and placebo.

5.2 Pharmacokinetic Properties

Absorption.

In humans, following a single oral 40 mg dose of fluoxetine, peak plasma concentrations 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.
The systemic bioavailability of fluoxetine does not appear to be affected by food, although the absorption of fluoxetine may be slightly delayed. Thus, fluoxetine may be taken with or without food.

Distribution.

The volume of distribution for fluoxetine is estimated at 30 to 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. Norfluoxetine is the only identified active metabolite and is formed by demethylation of fluoxetine. In animal models, norfluoxetine's potency and selectivity as a serotonin uptake inhibitor 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 which are excreted by the kidney.

Clinical issues related to metabolism/ elimination.

The complexity of the metabolism of fluoxetine has several consequences that may potentially affect its clinical use.

Accumulation and slow elimination.

The relatively low 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 the 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. The 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 weeks of continuous dosing. Nevertheless, the increase in plasma concentrations does not appear to be limitless. Specifically, patients taking 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, the active drug substance will persist in the body for weeks even after treatment is ceased (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.

6 Pharmaceutical Particulars

6.1 List of Excipients

Microcrystalline cellulose, colloidal anhydrous silica, maize starch, crospovidone, saccharin sodium, magnesium stearate, Nat. Peppermint Micron TIM-11812.

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

Store below 30°C.
This medicinal product does not require any special storage conditions.

6.5 Nature and Contents of Container

Container type.

HDPE bottle* or PVC/PVDC/Al blister packs.

Pack sizes.

28's.
* Not marketed in Australia.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Chemical name: (±)-N-methyl- 3-phenyl-3-[(α,α,α-trifluoro- p-tolyl)-oxy]- propylamine hydrochloride.
Molecular formula: C17H18F3NO.HCl.
Molecular weight: 345.79.
Fluoxetine hydrochloride is a white to off white crystalline solid with a solubility of 14 mg/mL in water.

Chemical structure.


CAS number.

59333-67-4.

7 Medicine Schedule (Poisons Standard)

S4 (Prescription Only Medicine).

Summary Table of Changes