Consumer medicine information

Noumed Fluoxetine

Fluoxetine

BRAND INFORMATION

Brand name

Noumed Fluoxetine

Active ingredient

Fluoxetine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

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

SUMMARY CMI

Noumed Fluoxetine

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using Noumed Fluoxetine?

Noumed Fluoxetine contains the active ingredient fluoxetine hydrochloride. Noumed Fluoxetine is used to treat depression and obsessive compulsive disorder (OCD). For more information, see Section 1. Why am I using Noumed Fluoxetine? in the full CMI.

2. What should I know before I use Noumed Fluoxetine?

Do not use if you have ever had an allergic reaction to fluoxetine hydrochloride or any of the ingredients listed at the end of the CMI. Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use Noumed Fluoxetine? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Noumed Fluoxetine and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use Noumed Fluoxetine?

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

More instructions can be found in Section 4. How do I use Noumed Fluoxetine? in the full CMI.

5. What should I know while using Noumed Fluoxetine?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are taking Noumed Fluoxetine.
  • Tell your doctor if you become pregnant while taking Noumed Fluoxetine
  • Keep all of your doctor's appointments so that your progress can be checked.
  • 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 should not do
  • Do not stop using this medicine suddenly or lower the dosage without checking with your doctor.
  • Do not take Noumed Fluoxetine 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 Noumed Fluoxetine.
  • Do not let yourself run out of Noumed Fluoxetine over the weekend or on holidays.
Driving or using machines
  • Do not drive or operate machinery until you know how Noumed Fluoxetine affects you.
  • Noumed Fluoxetine may cause drowsiness in some people. If you experience drowsiness, do not drive, operate machinery or do anything else that could be dangerous.
Drinking alcohol
  • Tell your doctor if you drink alcohol.
  • Although drinking alcohol is unlikely to affect your response to Noumed Fluoxetine, your doctor may suggest avoiding alcohol while you are being treated for depression.
Looking after your medicine
  • Store your medicine in a cool dry place where the temperature stays below 25°C.
  • Keep it where children cannot reach it.

For more information, see Section 5. What should I know while using Noumed Fluoxetine? in the full CMI.

6. Are there any side effects?

Common side effects include: 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 and changes in vision. Serious side effects include: 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 and overactive reflexes. For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

Noumed Fluoxetine

Active ingredient(s): [fluoxetine (as hydrochloride)]

Consumer Medicine Information (CMI)

This leaflet provides important information about using Noumed Fluoxetine. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Noumed Fluoxetine.

Where to find information in this leaflet:

1. Why am I using Noumed Fluoxetine?
2. What should I know before I use Noumed Fluoxetine?
3. What if I am taking other medicines?
4. How do I use Noumed Fluoxetine?
5. What should I know while using Noumed Fluoxetine?
6. Are there any side effects?
7. Product details

1. Why am I using Noumed Fluoxetine?

Noumed Fluoxetine contains the active ingredient fluoxetine hydrochloride. Noumed Fluoxetine is a selective serotonin reuptake inhibitor (SSRI). 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.

Noumed Fluoxetine is used to treat depression and obsessive compulsive disorder (OCD).

2. What should I know before I use Noumed Fluoxetine?

Warnings

Do not use Noumed Fluoxetine if:

  • you are allergic to fluoxetine hydrochloride, or any of the ingredients listed at the end of this leaflet.
  • Always check the ingredients to make sure you can use this medicine.
  • you are allergic to any other similar medicines.
  • 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 Noumed Fluoxetine 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 used to treat disturbances in thinking, feelings and behaviour. Taking pimozide together with Noumed Fluoxetine may alter the rhythm of your heart.
  • you are taking metoprolol, a medicine used to treat cardiac failure.

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.

Check with your doctor if you:

  • have any other medical conditions such as:
    - kidney problems
    - liver problems
    - diabetes
    - fits
    - a bleeding disorder or a tendency to bleed more than usual.
  • take any medicines for any other condition

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Your doctor will discuss the risks and benefits of taking this medicine during pregnancy. If Noumed Fluoxetine 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.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy 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 may interfere with Noumed Fluoxetine and affect how 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 Noumed Fluoxetine
  • 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.

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

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

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect Noumed Fluoxetine.

4. How do I use Noumed Fluoxetine?

How much to take / use

Your doctor will tell you how much Noumed Fluoxetine 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.

Swallow the capsules whole with a glass of water.

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, Noumed Fluoxetine may not work as well and your problem may not improve.

When to take / use Noumed Fluoxetine

Noumed Fluoxetine 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 Noumed Fluoxetine

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, Noumed Fluoxetine 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 use Noumed Fluoxetine

Noumed Fluoxetine should be used regularly at the same time each day. If you miss your dose at the usual time, 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 use too much Noumed Fluoxetine

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

If you think that you have used too much Noumed Fluoxetine, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using Noumed Fluoxetine?

Things you should do

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

Remind any doctor, dentist or pharmacist you visit that you are using Noumed Fluoxetine.

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 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 should not do

  • Do not stop using this medicine suddenly or lower the dosage without checking with your doctor. Suddenly stopping Noumed Fluoxetine 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 Noumed Fluoxetine you are taking before stopping completely.
  • Do not take Noumed Fluoxetine 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 Noumed Fluoxetine. 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 let yourself run out of Noumed Fluoxetine over the weekend or on holidays.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how Noumed Fluoxetine affects you.

Noumed Fluoxetine may cause drowsiness in some people. If you experience drowsiness, do not drive, operate machinery or do anything else that could be dangerous.

Drinking alcohol

Tell your doctor if you drink alcohol.

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

Looking after your medicine

  • Keep your medicine in the original container
  • If you take it out of its original container, it may not keep well
  • Store your medicine in a cool dry place where the temperature stays below 25°C.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
Adults
  • 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.
Children & Adolescents
  • Headaches
  • Weight loss
  • Decreased height gain
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
  • 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.
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What Noumed Fluoxetine contains

Active ingredient
(main ingredient)
  • Fluoxetine hydrochloride
Other ingredients
(inactive ingredients)
  • pregelatinised maize starch
  • dimeticone 350
  • gelatin
  • titanium dioxide
  • iron oxide yellow CI 77492
  • patent blue V CI42051

Do not take this medicine if you are allergic to any of these ingredients.

What Noumed Fluoxetine looks like

Noumed Fluoxetine is a green, size 3, hard‐shell gelatin capsule filled with a homogeneous white powder. (Aust R 308455).

It is available in PVC/PVDC/Al blister packs of 28 capsules.

Who distributes Noumed Fluoxetine

Sponsor

Avallon Pharmaceuticals Pty Ltd
Level 5, 7 Eden Park Drive
Macquarie Park NSW 2113
Tel: 1800 930 999
www.avallon-pharma.com.au

This leaflet was prepared in December 2022.

Published by MIMS February 2023

BRAND INFORMATION

Brand name

Noumed Fluoxetine

Active ingredient

Fluoxetine

Schedule

S4

 

1 Name of Medicine

Fluoxetine hydrochloride.

2 Qualitative and Quantitative Composition

Noumed Fluoxetine 20 mg capsule contains fluoxetine hydrochloride equivalent to fluoxetine 20 mg.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Capsule.
Green, hard-shell gelatin capsules, size 3, filled with a homogeneous white powder.

4 Clinical Particulars

4.1 Therapeutic Indications

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

4.2 Dose and Method of Administration

Dosage.

Depression. 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.

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).

Maintenance/continuation treatment.

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

Method of administration.

For oral administration. The capsule should be swallowed whole.

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 Noumed Fluoxetine in patients with hepatic disease must be approached with caution. If Noumed Fluoxetine 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, Use in hepatic 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).

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

4.3 Contraindications

Known hypersensitivity 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 a selective serotonin reuptake inhibitors (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

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 six-fold that seen in placebo controls. A weight loss of greater than 5% of bodyweight occurred in 13% of fluoxetine hydrochloride treated patients compared to 4% of placebo and 3% of tricyclic antidepressant treated patients. However, 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.

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 patient's 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 non-psychiatric. 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 non-psychiatric) 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 capsules 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).

Long elimination half-lives of fluoxetine and its metabolites.

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.

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)) and postpartum haemorrhage (see Section 4.6 Fertility, Pregnancy and Lactation). Other haemorrhagic manifestations (e.g. gynaecological haemorrhages and other cutaneous or mucous bleedings) have been reported rarely. 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.

Laboratory tests.

No specific laboratory tests are recommended.

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.

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 co-administration. When tamoxifen is used for the treatment or prevention of breast cancer, prescribers should consider using an alternative anti-depressant with little or no CYP2D6 inhibition.

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.

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 pre-marketing 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 4.4 Special Warnings and Precautions for Use, Hyponatraemia; Section 4.2 Dose and Method of Administration).

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 4.4 Special Warnings and Precautions for Use, 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) is a possibility (see Section 5.2 Pharmacokinetic Properties, Accumulation and slow elimination).

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 co-administration of fluoxetine with single doses of terfenadine (a cytochrome P4503 A4 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.

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 (CYP 2D6). Such individuals have been referred to as poor metabolisers of drugs such as dextromethorphan and tricyclic antidepressants. Many drugs, such as antipsychotics (e.g. phenothiazines and some atypical) and most antidepressants including fluoxetine and other selective uptake inhibitors of serotonin, are metabolised by this isoenzyme, thus both the pharmacokinetic properties and relative proportion of metabolites are altered in poor metabolisers.
Fluoxetine, like other agents that are metabolised by P450 2D6 (CYP 2D6), inhibits the activity of this isoenzyme and thus may make normal metabolisers resemble poor metabolisers. Therapy with medications that are predominantly metabolised by P450 2D6 (CYP 2D6) 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).

Potential effects of co-administration of drugs highly bound to plasma proteins.

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 effects, including agitation, restlessness and gastrointestinal distress.

Warfarin.

Altered anticoagulant effects (laboratory values and/or clinical signs and symptoms), with no consistent pattern, but including increase bleeding, have been reported uncommonly when fluoxetine is co-administered 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 co-administration 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.

Co-administration 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 co-administered 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, co-administration 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 C1)
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 fetus, 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.
1 Australian Pregnancy Category C: Drugs, which, owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects on the human fetus or neonate without causing malformations. These effects may be reversible. Accompanying texts should be consulted for further details.

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 fetus 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 Noumed 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 breast fed 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.

4.7 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 Noumed Fluoxetine does not affect them adversely.

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.

Events observed during therapy with fluoxetine - clinical trials.

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

Body as a whole.

Very common: fatigue (includes asthenia).
Common: allergic 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.

Investigations.

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

Children and adolescents.

Very common: headache.
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 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 bleeding2.

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.
The following events have been reported for the therapeutic class of SSRIs/SNRIs (see Section 4.4 Special Warnings and Precautions for Use; Section 4.6 Fertility, Pregnancy and Lactation).
Frequency "not known": Postpartum haemorrhage.

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.
2 Includes: esophageal varices hemorrhage, gingival and mouth bleeding, hematemesis, hematochezia, hematomas [intraabdominal, 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.

4.9 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).

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 multi-centre 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.
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 non-saturable 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 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.

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. 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.

6 Pharmaceutical Particulars

6.1 List of Excipients

Noumed Fluoxetine 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

Noumed Fluoxetine 20 mg capsules - available in PVC/PVDC/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.

6.7 Physicochemical Properties

Fluoxetine hydrochloride is a white to off-white crystalline solid with a solubility of 14 mg/mL in water.

Chemical structure.

The chemical name of fluoxetine hydrochloride is (R,S)-N-methyl-3-phenyl-3-[α,α,α,-trifluoro-p-tolyl) oxy]-propylamine hydrochloride.
C17H18F3NO.HCl (MW: 345.79).

CAS number.

59333-67-4.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes