Prozac liquid 20 mg per 5 mL oral solution *

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

 

Each 5 mL of oral solution contains 20 mg of fluoxetine (as fluoxetine hydrochloride).

 

Excipients with known effect:

Ccontains 3 g of sucrose, per 5 mL dose and 2.5 mg benzoic acid(E 210), 9.56 mg of ethanol and traces of benzyl alcohol in each 5 mL dose. Also contains small amounts of ethanol (alcohol), less than 100 mg per 5 mL dose.

 

For the full list of excipients, see section 6.1.

 

4.4       Special warnings and precautions for use

[…]

Benzoic acid

 

This medicine contains 2.5 mg benzoic acid in each 5 mL dose.

 

Ethanol

Oral solution: The flavouring for this medicinal product contains small amounts of ethanol (alcohol), less than 100 mg per dose.

This medicine contains 9.56 mg of alcohol in each 5 mL dose. The amount in 5 mL dose of this medicine is equivalent to less than 1 mL beer or 1 mL wine. The small amount of alcohol in this medicine will not have any noticeable effects.

 

Benzyl alcohol

 

This medicine contains traces of 0.00006 mg benzyl alcohol in each 5 mL dose. Benzyl alcohol may cause allergic reactions. High volumes should be used with caution and only if necessary, especially in subjects with liver or kidney impairment as well as in pregnant women or while breast-feeding, because of the risk of accumulation and toxicity (metabolic acidosis).

 

5.         PHARMACOLOGICAL PROPERTIES

 

5.1       Pharmacodynamic properties

[…]

Effects on growth see sections 4.4 and 4.8:

[…]

 

5.2       Pharmacokinetic properties

 

[…]

Special populations

 

Elderly:

[…]

 

Paediatric population:

[…]

 

 

Hepatic insufficiency:

[…]

 

Renal insufficiency:

[…]

 

6.         PHARMACEUTICAL PARTICULARS

 

6.1       List of excipients

 

Benzoic acid  (E 210)

Sucrose

Glycerine

Mint flavour (containing small amounts of 0.23% ethanol (alcohol) and benzyl alcohol)

Purified water

 

 

10.       DATE OF REVISION OF THE TEXT

 

            10 Nov 201918 January 2021

 

            Detailed information on this medicinal product is available on the website of Ireland/HPRA.

 

                                                                                                                                                                                                      PZ865M

2.             What you need to know before you take Prozac oral solution

 

Do not take Prozac if you are:

[…]

Warnings and precautions

[…]

Prozac oral solution contains sucrose

Prozac oral solution contains 3 g of sucrose per 5 mL dose. This should be taken into account in patients with diabetes mellitus. May be harmful to the teeth. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.

 

Prozac oral solution contains ethanol

This medicine contains 9.56 mg of alcohol in each 5 mL dose (see section 6). The amount in 5 mL dose of this medicine is equivalent to less than 1 mL beer or 1 mL wine. The small amount of alcohol in this medicine will not have any noticeable effects.The flavouring for this medicinal product contains small amounts of ethanol (alcohol), less than 100 mg per dose (see Section 6).

 

Prozac oral solution contains benzoic acid

This medicine contains 2.5 mg benzoic acid in each 5 mL dose.

 

Prozac oral solution contains benzyl alcohol

This medicine contains traces of benzyl alcohol in each 5 mL dose. Benzyl alcohol may cause allergic reactions. Ask your doctor or pharmacist for advice if you have a liver or kidney disease, and if you are pregnant or breast-feeding. This is because large amounts of benzyl alcohol can build-up in your body and may cause side effects (called “metabolic acidosis”).

 

[…]

 

6.         Content of the pack and other information

 

What Prozac oral solution contains

[…]

The other ingredients are: benzoic acid (E 210), sucrose, glycerine, mint flavour (containing small amounts of 0.23% ethanol (alcohol) and benzyl alcohol) and purified Water.

 

[…]

 

This leaflet was last revised in December 2020January 2021.

Changes

Added (underline) deleted (strikethrough)

Formatting changes thoughout the document 

4.4          Special warnings and precautions for use

[…]

Haemorrhage

There have been reports of cutaneous bleeding abnormalities such as ecchymosis and purpura with SSRI’s. Ecchymosis has been reported as an infrequent event during treatment with fluoxetine. SSRIs/SNRIs may increase the risk of postpartum haemorrhage (see sections 4.6, 4.8). […]

 

4.6       Fertility, pregnancy and lactation

[…]

Observational data indicate an increased risk (less than 2-fold) of postpartum haemorrhage following SSRI/SNRI exposure within the month prior to birth (see sections 4.4, 4.8).

[…]

 

4.8       Undesirable effects

[…]

Frequency estimate: Very common (³1/10), common (³1/100 to <1/10), uncommon (³1/1,000 to <1/100), rare (³1/10,000 to <1/1,000), not known (cannot be estimated from the available data).

 

Very Common	Common	Uncommon	Rare	Not known
Blood and lymphatic system disorders
			Thrombocytopenia Neutropenia Leucopenia
Immune system disorders
			Anaphylactic reaction Serum sickness
Endocrine disorders
			Inappropriate antidiuretic hormone secretion
Metabolism and nutrition disorders
	Decreased appetite1		Hyponatraemia
Psychiatric disorders
Insomnia2	Anxiety Nervousness Restlessness Tension Libido decreased3 Sleep disorder Abnormal dreams4	Depersonalisation Elevated mood Euphoric mood Thinking abnormal Orgasm abnormal5 Bruxism Suicidal thoughts and behaviour 6	Hypomania Mania Hallucinations Agitation Panic attacks Confusion Dysphemia Aggression
Nervous system disorders
Headache	Disturbance in attention Dizziness Dysgeusia Lethargy Somnolence7 Tremor	Psychomotor hyperactivity Dyskinesia Ataxia Balance disorder Myoclonus Memory impairment	Convulsion Akathisia Buccoglossal syndrome Serotonin syndrome
Eye disorders
	Vision blurred	Mydriasis
Ear and labyrinth disorders
		Tinnitus
Cardiac disorders
	Palpitations Electrocardiogram QT prolonged (QTcF ≥450 msec)8		Ventricular arrhythmia including torsades de pointes
Vascular disorders
	Flushing9	Hypotension	Vasculitis Vasodilatation
Respiratory, thoracic and mediastinal disorders
	Yawning	Dyspnoea Epistaxis	Pharyngitis Pulmonary events (inflammatory processes of varying histopathology and/or fibrosis)10
Gastrointestinal disorders
Diarrhoea Nausea	Vomiting Dyspepsia Dry mouth	Dysphagia Gastrointestinal haemorrhage11	Oesophageal pain
Hepato-biliary disorders
			Idiosyncratic hepatitis
Skin and subcutaneous tissue disorders
	Rash12 Urticaria Pruritus Hyperhidrosis	Alopecia Increased tendency to bruise Cold sweat	Angioedema Ecchymosis Photosensitivity reaction Purpura Erythema multiforme Stevens-Johnson syndrome Toxic Epidermal Necrolysis (Lyell Syndrome)
Musculoskeletal and connective tissue disorders
	Arthralgia	Muscle twitching	Myalgia
Renal and urinary disorders
	Frequent urination13	Dysuria	Urinary retention Micturition disorder
Reproductive system and breast disorders
	Gynaecological bleeding14 Erectile dysfunction Ejaculation disorder15	Sexual dysfunction16	Galactorrhoea Hyperprolactinaemia Priapism	Postpartum haemorrhage17
General disorders and administration site conditions
Fatigue187	Feeling jittery Chills	Malaise Feeling abnormal Feeling cold Feeling hot	Mucosal haemorrhage
Investigations
	Weight decreased	Transaminases increased Gamma-glutamyltransferase increased

[…]

¹⁷ This event has been reported for the therapeutic class of SSRIs/SNRIs (see sections 4.4, 4.6).

¹⁸ Includes asthenia

 

10.          DATE OF REVISION OF THE TEXT

 

10 Nov 201922 December 2020

 

PZ853M

 

2.             What you need to know before you take Prozac oral solution

[…]

Warnings and precautions

 

Talk to your doctor or pharmacist before taking Prozac if any of the following applies to you:

[…]

• history of bleeding disorders or appearance of bruises or unusual bleeding, or if you are pregnant (see ‘Pregnancy’;

[…]

Pregnancy, breast-feeding and fertility

[…]

If you take Prozac near the end of your pregnancy there may be an increased risk of heavy vaginal bleeding shortly after birth, especially if you have a history of bleeding disorders. Your doctor or midwife should be aware that you are taking Prozac so they can advise you.

[…]

 

4.             Possible side effects

[…]

Not known (cannot be estimated from the available data)

• Heavy vaginal bleeding shortly after birth (postpartum haemorrhage), see “Pregnancy” in section 2 for more information

[…]

 

 

6.         Content of the pack and other information

[…]

United Kingdom: Prozac

[…]

 

This leaflet was last revised in November 2019December 2020.

2.           QUALITATIVE AND QUANTITATIVE COMPOSITION

 

Oral solution excipients with known effect: contains 3 g of sucrose per 5 mlmL dose and 2.5 mg benzoic acid in each 5 mL dose. Also contains small amounts of ethanol (alcohol), less than 100 mg per 5 mlmL dose.

 

 

4.           CLINICAL PARTICULARS

 

4.4         Special warnings and precautions for use

 

Sexual dysfunction

Selective serotonin reuptake inhibitors (SSRI) may cause symptoms of sexual dysfunction (see section 4.8). There have been reports of long-lasting sexual dysfunction where the symptoms have continued despite discontinuation of SSRIs.

 

PROZAC oral solution contains sSucrose

Prozac oral solution contains sucrose: Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

 

Ethanol

Oral solution: The flavouring for this medicinal product contains small amounts of ethanol (alcohol), less than 100 mg per dose.

 

1. 8. Undesirable effects

 

Reproductive system and breast disorders
	Gynaecological bleeding14 Erectile dysfunction Ejaculation disorder15	Sexual dysfunction16	Galactorrhoea Hyperprolactinaemia Priapism
General disorders and administration site conditions
Fatigue176	Feeling jittery Chills	Malaise Feeling abnormal Feeling cold Feeling hot	Mucosal haemorrhage

 

¹⁶ Occasionally persisting after treatment discontinuation

¹⁷⁶ Includes asthenia

 

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2, Tel: +353 1 6764971, Fax: +353 1 6762517,  Website: www.hpra.ie , e-mail: medsafety@hpra.ie

 

 

10.         DATE OF REVISION OF THE TEXT

 

              22 June 2018 10 Nov 2019

 

PZ81MPZ83M

 

Update to IE ADR details

 

Throughout changed

• ml to mL
• PROZAC to Prozac

7.         MARKETING AUTHORISATION HOLDER

Eli Lilly Nederland B.V.,

Papendorpseweg 83

3528 BJ Utrecht

The Netherlands

Eli Lilly and Company Limited

Lilly House

Priestley Road

Basingstoke

Hampshire

RG24 9NL

United Kingdom

8.         MARKETING AUTHORISATION NUMBERS

20mg capsules:  PA 2276/004/002PA 0047/077/002

Oral solution:    PA 2276/004/001PA 0047/077/001

10.          DATE OF REVISION OF THE TEXT

2208 JuneMarch 2018

PZ7981M

 

PROZAC^®

 

(fluoxetine)

1. NAME OF THE MEDICINAL PRODUCT

PROZAC

 

* 20 mg hard capsules

 

LEGAL CATEGORY

S.1.A.

PROZAC is marketed in the Republic of Ireland by:

Eli Lilly and Company (Ireland) Limited

Hyde House, 65 Adelaide Road

Dublin 2, Republic of Ireland

Telephone: Dublin (01) 661 4377

*PROZAC (fluoxetine hydrochloride) is a trademark of Eli Lilly and Company.

New text bold.  Text struck-through removed.

 

4.6           Fertility, pregnancy and lactation

 

Pregnancy

Some epidemiological studies suggest an increased risk of cardiovascular defects associated with the use of fluoxetine during the first trimester. The mechanism is unknown. Overall the data suggest that the risk of having an infant with a cardiovascular defect following maternal fluoxetine exposure is in the region of 2/100 compared with an expected rate for such defects of approximately 1/100 in the general population.

 

Epidemiological data have suggested that the use of SSRIs in pregnancy, particularly in late pregnancy, may increase the risk of persistent pulmonary hypertension in the newborn (PPHN). The observed risk was approximately 5 cases per 1000 pregnancies. In the general population 1 to 2 cases of PPHN per 1000 pregnancies occur.

 

Furthermore, although fluoxetine can be used during pregnancy, Fluoxetine should not be used during pregnancy unless the clinical condition of the woman requires treatment with fluoxetine and justifies the potential risk to the foetus. Abrupt discontinuation of therapy should be avoided during pregnancy (see section 4.2 “Posology and method of administration”). If fluoxetine is used during pregnancy, caution should be exercised, especially during late pregnancy or just prior to the onset of labour since some other effects have been reported in neonates: irritability, tremor, hypotonia, persistent crying, difficulty in sucking or in sleeping.  These symptoms may indicate either serotonergic effects or a withdrawal syndrome.  The time to occur and the duration of these symptoms may be related to the long half-life of fluoxetine (4-6 days) and its active metabolite, norfluoxetine (4-16 days).

 

10.           DATE OF REVISION OF THE TEXT

 

30 October 201523 February 2016

 

 

PROZAC (fluoxetine hydrochloride) is a trademark of Eli Lilly and Company.    PZ768M

New text bold.  Text struck-through removed.

 

 

4.3           Contraindications

 

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Fluoxetine is contra-indicated in combination with irreversible, non-selective monoamine oxidase inhibitors (e.g. iproniazid) (see sections 4.4 and 4.5).

Fluoxetine is contra-indicated in combination with metoprolol used in cardiac failure (see section 4.5).

 

Monoamine Oxidase Inhibitors:  Cases of serious and sometimes fatal reactions have been reported in patients receiving an SSRI in combination with a monoamine oxidase inhibitor (MAOI), and in patients who have recently discontinued an SSRI and have been started on a MAOI.  Treatment of fluoxetine should only be started 2 weeks after discontinuation of an irreversible MAOI and the following day after discontinuation of a reversible MAOI-A.

 

Some cases presented with features resembling serotonin syndrome (which may resemble and be diagnosed as neuroleptic malignant syndrome). Cyproheptadine or dantrolene may benefit patients experiencing such reactions.  Symptoms of a drug interaction with a MAOI include: hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes that include confusion, irritability and extreme agitation progressing to delirium and coma.

 

Therefore, fluoxetine is contra-indicated in combination with a non-selective MAOI.  Similarly, at least 5 weeks should elapse after discontinuing fluoxetine treatment before starting a MAOI.  If fluoxetine has been prescribed chronically and/or at a high dose, a longer interval should be considered.

 

The combination of fluoxetine with a reversible MAOI (e.g. moclobemide, linezolid, methylthioninium chloride (also called methylene blue; a reversible non-selective MAOI indicated for <indication(s) authorised in member state>)) is not recommended.  Treatment with fluoxetine can be initiated the following day after discontinuation of a reversible MAOI.

 

In exceptional circumstances, linezolid (an antibiotic which is a reversible non‑selective MAOI) can be given in combination with fluoxetine provided that there are facilities for close observation of symptoms of serotonin syndrome and monitoring of blood pressure.

 

 

4.4           Special warnings and precautions for use

 

Paediatric population - Children and adolescents under 18 years of age

Suicide-related behaviours (suicide attempt and suicidal thoughts), and hostility (predominantly aggression, oppositional behaviour and anger) were more frequently observed in clinical trials among children and adolescents treated with antidepressants compared to those treated with placebo. Prozac should only be used in children and adolescents aged 8 to 18 years for the treatment of moderate to severe major depressive episodes and it should not be used in other indications. If, based on clinical need, a decision to treat is nevertheless taken, the patient should be carefully monitored for the appearance of suicidal symptoms. In addition, only limited evidence is available concerning long-term effect on safety in children and adolescents, including effects on growth, sexual maturation and cognitive, emotional and behavioural developments (see section 5.3).

 

In a 19-week clinical trial decreased height and weight gain was observed in children and adolescents treated with fluoxetine (see section 5.1). It has not been established whether there is an effect on achieving normal adult height. The possibility of a delay in puberty cannot be ruled out (see sections 5.3 and 4.8). Growth and pubertal development (height, weight and TANNER staging) should therefore be monitored during and after treatment with fluoxetine. If either is slowed, referral to a paediatrician should be considered.

 

In paediatric trials, mania and hypomania were commonly reported (see section 4.8). Therefore, regular monitoring for the occurrence of mania/hypomania is recommended. Fluoxetine should be discontinued in any patient entering a manic phase.

 

It is important that the prescriber discusses carefully the risks and benefits of treatment with the child/young person and/or their parents.

 

Suicide/suicidal thoughts or clinical worsening

Depression is associated with an increased risk of suicidal thoughts, self-harm and suicide (suicide-related events). This risk persists until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs. It is general clinical experience that the risk of suicide may increase in the early stages of recovery.

Other psychiatric conditions for which Prozac is prescribed can also be associated with an increased risk of suicide-related events. In addition, these conditions may be co-morbid with major depressive disorder. The same precautions observed when treating patients with major depressive disorder should therefore be observed when treating patients with other psychiatric disorders.

Patients with a history of suicide-related events, those exhibiting a significant degree of suicidal ideation prior to commencement of treatment are known to be at greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment. A meta-analysis of placebo-controlled clinical trials of antidepressants drugs in adult patients with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo in patients less than 25 years old.

Close supervision of patients and in particular those at high risk should accompany drug therapy especially in early treatment and following dose changes. Patients (and caregivers of patients) should be alerted about the need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual changes in behaviour and to seek medical advice immediately if these symptoms present.

 

Cardiovascular Effects

Cases of QT interval prolongation and ventricular arrhythmia including torsade de pointes have been reported during the post-marketing period (see sections 4.5, 4.8 and 4.9).

Fluoxetine should be used with caution in patients with conditions such as congenital long QT syndrome, a family history of QT prolongation or other clinical conditions that predispose to arrhythmias (e.g., hypokalemia and hypomagnesemia, bradycardia, acute myocardial infarction or uncompensated heart failure) or increased exposure to fluoxetine (e.g., hepatic impairment) or concomitant use with medicinal products known to induce QT prolongation and/or torsade de pointes (see section 4.5).

If patients with stable cardiac disease are treated, an ECG review should be considered before treatment is started.

If signs of cardiac arrhythmia occur during treatment with fluoxetine, the treatment should be withdrawn and an ECG should be performed.

 

Serotonin syndrome or neuroleptic malignant syndrome-like events

On rare occasions development of a serotonin syndrome or neuroleptic malignant syndrome-like events have been reported in association with treatment of fluoxetine, particularly when given in combination with other serotonergic (among others L-tryptophan) and/or neuroleptic drugs. As these syndromes may result in potentially life-threatening conditions, treatment with fluoxetine should be discontinued if such events (characterised by clusters of symptoms such as hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes including confusion, irritability, extreme agitation progressing to delirium and coma) occur and supportive symptomatic treatment should be initiated.

 

Mania

Antidepressants should be used with caution in patients with a history of mania/hypomania. As with all antidepressants, fluoxetine should be discontinued in any patient entering a manic phase.

 

Haemorrhage

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

 

Seizures

Seizures are a potential risk with antidepressant drugs. Therefore, as with other antidepressants, fluoxetine should be introduced cautiously in patients who have a history of seizures. Treatment should be discontinued in any patient who develops seizures or where there is an increase in seizure frequency. Fluoxetine should be avoided in patients with unstable seizure disorders/epilepsy and patients with controlled epilepsy should be carefully monitored.

 

Electroconvulsive Therapy (ECT)

There have been rare reports of prolonged seizures in patients on fluoxetine receiving ECT treatment, therefore caution is advisable.

 

Tamoxifen

Fluoxetine, a potent inhibitor of CYP2D6, may lead to reduced concentrations of endoxifen, one of the most important active metabolites of tamoxifen. Therefore, fluoxetine should whenever possible be avoided during tamoxifen treatment (see section 4.5).

 

Akathisia/psychomotor restlessness

The use of fluoxetine has been associated with the development of akathisia, characterised by a subjectively unpleasant or distressing restlessness and need to move often accompanied by an inability to sit or stand still. This is most likely to occur within the first few weeks of treatment. In patients who develop these symptoms, increasing the dose may be detrimental.

 

Diabetes

In patients with diabetes, treatment with an SSRI may alter glycaemic control. Hypoglycaemia has occurred during therapy with fluoxetine and hyperglycaemia has developed following discontinuation. Insulin and/or oral hypoglycaemic dosage may need to be adjusted.

 

Hepatic/Renal Function

Fluoxetine is extensively metabolised by the liver and excreted by the kidneys. A lower dose, e.g., alternate day dosing, is recommended in patients with significant hepatic dysfunction. When given fluoxetine 20 mg/day for 2 months, patients with severe renal failure (GFR <10 ml/min) requiring dialysis showed no difference in plasma levels of fluoxetine or norfluoxetine compared to controls with normal renal function.

 

Rash and allergic reactions

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

 

Seizures

Seizures are a potential risk with antidepressant drugs. Therefore, as with other antidepressants, fluoxetine should be introduced cautiously in patients who have a history of seizures.  Treatment should be discontinued in any patient who develops seizures or where there is an increase in seizure frequency. Fluoxetine should be avoided in patients with unstable seizure disorders/epilepsy and patients with controlled epilepsy should be carefully monitored (see section 4.5).

 

Electroconvulsive Therapy (ECT)

There have been rare reports of prolonged seizures in patients on fluoxetine receiving ECT treatment, therefore caution is advisable.

 

Mania

Antidepressants should be used with caution in patients with a history of mania/hypomania.  As with all antidepressants, fluoxetine should be discontinued in any patient entering a manic phase.

 

Hepatic/Renal Function

Fluoxetine is extensively metabolised by the liver and excreted by the kidneys.  A lower dose, e.g., alternate day dosing, is recommended in patients with significant hepatic dysfunction.  When given fluoxetine 20 mg/day for 2 months, patients with severe renal failure (GFR <10 ml/min) requiring dialysis showed no difference in plasma levels of fluoxetine or norfluoxetine compared to controls with normal renal function.

 

Tamoxifen

Fluoxetine, a potent inhibitor of CYP2D6, may lead to reduced concentrations of endoxifen, one of the most important active metabolites of tamoxifen. Therefore, fluoxetine should whenever possible be avoided during tamoxifen treatment (see section 4.5).

 

Cardiovascular Effects

Cases of QT interval prolongation and ventricular arrhythmia including torsades de pointes have been reported during the post-marketing period (see sections 4.5, 4.8 and 4.9).

Fluoxetine should be used with caution in patients with conditions such as congenital long QT syndrome, a family history of QT prolongation or other clinical conditions that predispose to arrhythmias (e.g., hypokalemia,  hypomagnesemia, bradycardia, acute myocardial infarction or uncompensated heart failure) or increased exposure to fluoxetine (e.g., hepatic impairment).

If patients with stable cardiac disease are treated, an ECG review should be considered before treatment is started.

If signs of cardiac arrhythmia occur during treatment with fluoxetine, the treatment should be withdrawn and an ECG should be performed.

 

Weight Loss

Weight loss may occur in patients taking fluoxetine but it is usually proportional to baseline body weight.

 

Diabetes

In patients with diabetes, treatment with an SSRI may alter glycaemic control.  Hypoglycaemia has occurred during therapy with fluoxetine and hyperglycaemia has developed following discontinuation.  Insulin and/or oral hypoglycaemic dosage may need to be adjusted.

 

Suicide/suicidal thoughts or clinical worsening

Depression is associated with an increased risk of suicidal thoughts, self harm and suicide (suicide-related events). This risk persists until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs. It is general clinical experience that the risk of suicide may increase in the early stages of recovery.

Other psychiatric conditions for which Prozac is prescribed can also be associated with an increased risk of suicide-related events. In addition, these conditions may be co-morbid with major depressive disorder. The same precautions observed when treating patients with major depressive disorder should therefore be observed when treating patients with other psychiatric disorders.

Patients with a history of suicide-related events, those exhibiting a significant degree of suicidal ideation prior to commencement of treatment are known to be at greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment.  A meta-analysis of placebo-controlled clinical trials of antidepressants drugs in adult patients with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo in patients less than 25 years old.

Close supervision of patients and in particular those at high risk should accompany drug therapy especially in early treatment and following dose changes. Patients (and caregivers of patients) should be alerted about the need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual changes in behaviour and to seek medical advice immediately if these symptoms present.

 

Akathisia/psychomotor restlessness

The use of fluoxetine has been associated with the development of akathisia, characterised by a subjectively unpleasant or distressing restlessness and need to move often accompanied by an inability to sit or stand still. This is most likely to occur within the first few weeks of treatment. In patients who develop these symptoms, increasing the dose may be detrimental.

 

 

Withdrawal symptoms seen on discontinuation of SSRI treatment

Withdrawal symptoms when treatment is discontinued are common, particularly if discontinuation is abrupt (see section 4.8). In clinical trials adverse events seen on treatment discontinuation occurred in approximately 60% of patients in both the fluoxetine and placebo groups. Of these adverse events, 17% in the fluoxetine group and 12% in the placebo group were severe in nature.

The risk of withdrawal symptoms may be dependent on several factors including the duration and dose of therapy and the rate of dose reduction. Dizziness, sensory disturbances (including paraesthesia), sleep disturbances (including insomnia and intense dreams), asthenia, agitation or anxiety, nausea and/or vomiting, tremor and headache are the most commonly reported reactions. Generally these symptoms are mild to moderate however, in some patients they may be severe in intensity. They usually occur within the first few days of discontinuing treatment. Generally these symptoms are self-limiting and usually resolve within 2 weeks, though in some individuals they may be prolonged (2-3 months or more). It is therefore advised that Prozac should be gradually tapered when discontinuing treatment over a period of at least one to two weeks, according to the patient’s needs (see Withdrawal symptoms seen on discontinuation of Prozac, section 4.2).

 

Haemorrhage

There have been reports of cutaneous bleeding abnormalities such as ecchymosis and purpura with SSRI’s.  Ecchymosis has been reported as an infrequent event during treatment with fluoxetine. Other haemorrhagic manifestations (e.g., gynaecological haemorrhages, gastrointestinal bleedings and other cutaneous or mucous bleedings) have been reported rarely. Caution is advised in patients taking SSRI’s, particularly in concomitant use with oral anticoagulants, drugs known to affect platelet function (e.g. atypical antipsychotics such as clozapine, phenothiazines, most TCA’s, aspirin, NSAID’s) or other drugs that may increase risk of bleeding as well as in patients with a history of bleeding disorders (see section 4.5).

 

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.

 

St John’s Wort

An increase in serotonergic effects, such as serotonin syndrome, may occur when selective serotonin reuptake inhibitors and herbal preparations containing St John’s Wort (Hypericum perforatum) are used together.

 

Serotonin syndrome or neuroleptic malignant syndrome-like events

On rare occasions development of a serotonin syndrome or neuroleptic malignant syndrome-like events have been reported in association with treatment of fluoxetine, particularly when given in combination with other serotonergic (among others L-tryptophan) and/or neuroleptic drugs (see section 4.5).  As these syndromes may result in potentially life-threatening conditions, treatment with fluoxetine should be discontinued if such events (characterised by clusters of symptoms such as hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes including confusion, irritability, extreme agitation progressing to delirium and coma) occur and supportive symptomatic treatment should be initiated.

 

Irreversible, non-selective monoamine oxidase inhibitors (e.g. iproniazid)

Some cases of serious and sometimes fatal reactions have been reported in patients receiving an SSRI in combination with an irreversible, non-selective monoamine oxidase inhibitor (MAOI).

These cases presented with features resembling serotonin syndrome (which may be confounded with (or diagnosed as) neuroleptic malignant syndrome). Cyproheptadine or dantrolene may benefit patients experiencing such reactions. Symptoms of a drug interaction with a MAOI include: hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes that include confusion, irritability and extreme agitation progressing to delirium and coma.

Therefore, fluoxetine is contra-indicated in combination with an irreversible, non-selective MAOI (see section 4.3). Because of the two weeks-lasting effect of the latter, treatment of fluoxetine should only be started 2 weeks after discontinuation of an irreversible, non-selective MAOI. Similarly, at least 5 weeks should elapse after discontinuing fluoxetine treatment before starting an irreversible, non-selective MAOI.

 

PROZAC oral solution contains sucrose

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

 

4.5           Interaction with other medicinal products and other forms of interaction

 

Half-life: The long elimination half-lives of both fluoxetine and norfluoxetine should be borne in mind (see section 5.2) when considering pharmacodynamic or pharmacokinetic drug interactions (e.g., when switching from fluoxetine to other antidepressants).

 

Contra-indicated combinations

Monoamine oxidase inhibitors: See section 4.3.

 

Not recommended combinations: MAOI-A (see section 4.3).

Irreversible, non-selective monoamine oxidase inhibitors (e.g. iproniazid): Some cases of serious and sometimes fatal reactions have been reported in patients receiving an SSRI in combination with an irreversible, non-selective monoamine oxidase inhibitor (MAOI).

These cases presented with features resembling serotonin syndrome (which may be confounded with [or diagnosed as] neuroleptic malignant syndrome). Cyproheptadine or dantrolene may benefit patients experiencing such reactions. Symptoms of a drug interaction with a MAOI include: hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes that include confusion, irritability and extreme agitation progressing to delirium and coma.

Therefore, fluoxetine is contra-indicated in combination with an irreversible, non-selective MAOI (see section 4.3). Because of the two weeks-lasting effect of the latter, treatment of fluoxetine should only be started 2 weeks after discontinuation of an irreversible, non-selective MAOI. Similarly, at least 5 weeks should elapse after discontinuing fluoxetine treatment before starting an irreversible, non-selective MAOI.

 

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 (see section 4.3).

 

Combinations requiring precautions for use: MAOI-B (selegeline): Risk of serotonin syndrome.  Clinical monitoring is recommended.

Not recommended combinations

 

Tamoxifen: Pharmacokinetic interaction between CYP2D6 inhibitors and tamoxifen, showing a 65-75 % reduction in plasma levels of one of the more active forms of the tamoxifen, i.e. endoxifen, has been reported in the literature. Reduced efficacy of tamoxifen has been reported with concomitant usage of some SSRI antidepressants in some studies. As a reduced effect of tamoxifen cannot be excluded, co-administration with potent CYP2D6 inhibitors (including fluoxetine) should whenever possible be avoided (see section 4.4).

 

Alcohol: In formal testing, fluoxetine did not raise blood alcohol levels or enhance the effects of alcohol. However, the combination of SSRI treatment and alcohol is not advisable.

 

MAOI-A including linezolid and methylthioninium chloride (methylene blue): Risk of serotonin syndrome including diarrhoea, tachycardia, sweating, tremor, confusion or coma. If concomitant use of these active substances with fluoxetine cannot be avoided, close clinical monitoring should be undertaken and the concomitant agents should be initiated at the lower recommended doses (see section 4.4).

 

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

 

Combinations requiring caution

 

Phenytoin: Changes in blood levels have been observed when combined with fluoxetine.  In some cases manifestations of toxicity have occurred.  Consideration should be given to using conservative titration schedules of the concomitant drug and to monitoring clinical status.

 

Serotoninergic drugs (lithium, tramadol, triptans, tryptophan, selegiline (MAOI-B), St. John’s Wort (Hypericum perforatum)): There have been reports of mild serotonin syndrome when SSRIs were given with drugs also having a serotoninergic effect. Therefore, the concomitant use of fluoxetine with these drugs should be undertaken with caution, with closer and more frequent clinical monitoring (see section 4.4).

Serotonergic drugs: Co-administration with serotonergic drugs (e.g., tramadol, triptans) may increase the risk of serotonin syndrome.  Use with triptans carries the additional risk of coronary vasoconstriction and hypertension.

 

Lithium and tryptophan: There have been reports of serotonin syndrome when SSRIs have been given with lithium or tryptophan and, therefore, the concomitant use of fluoxetine with these drugs should be undertaken with caution.  When fluoxetine is used in combination with lithium, closer and more frequent clinical monitoring is required.

 

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, such as Class IA and III antiarrhythmics, antipsychotics (e.g. phenothiazine derivatives, pimozide, haloperidol), tricyclic antidepressants, certain antimicrobial agents (e.g. sparfloxacin, moxifloxacin, erythromycin IV, pentamidine), anti-malaria treatment particularly halofantrine, certain antihistamines (astemizole, mizolastine), should be used with caution (see sections 4.4, 4.8 and 4.9).

 

Drugs affecting haemostasis (oral anticoagulants, whatever their mechanism, platelets antiaggregants including aspirin and NSAIDs): risk of increased bleeding. Clinical monitoring, and more frequent monitoring of INR with oral anticoagulants, should be made. A dose adjustment during the fluoxetine treatment and after its discontinuation may be suitable (see sections 4.4 and 4.8).

 

Cyproheptadine: There are individual case reports of reduced antidepressant activity of fluoxetine when used in combination with cyproheptadine.

 

Drugs inducing hyponatremia: Hyponatremia is an undesirable effect of fluoxetine. Use in combination with other agents associated with hyponatremia (e.g. diuretics, desmopressin, carbamazepine and oxcarbazepine) may lead to an increased risk (see section 4.8).

 

Drugs lowering the epileptogenic threshold: Seizures are an undesirable effect of fluoxetine. Use in combination with other agents which may lower the seizure threshold (for example, TCAs, other SSRIs, phenothiazines, butyrophenones, mefloquine, chloroquine, bupropion, tramadol) may lead to an increased risk.

 

Other drugs metabolised by CYP2D6: Fluoxetine is a strong inhibitor of CYP2D6 enzyme, therefore concomitant therapy with drugs also metabolised by this enzyme system may lead to drug interactions, notably those having a narrow therapeutic index (such as flecainide, propafenone and nebivolol) and those that are titrated, but also with atomoxetine, carbamazepine, tricyclic antidepressants and risperidone. They should be initiated at or adjusted to the low end of their dose range. This may also apply if fluoxetine has been taken in the previous 5 weeks.

 

CYP2D6 isoenzyme: Because fluoxetine’s metabolism (like tricyclic antidepressants and other selective serotonin antidepressants) involves the hepatic cytochrome CYP2D6 isoenzyme system, concomitant therapy with drugs also metabolised by this enzyme system may lead to drug interactions.  Concomitant therapy with drugs predominantly metabolised by this isoenzyme, and which have a narrow therapeutic index (such as flecainide, encainide, carbamazepine and tricyclic antidepressants), should be initiated at or adjusted to the low end of their dose range.  This will also apply if fluoxetine has been taken in the previous 5 weeks.

 

Pharmacokinetic interaction between CYP2D6 inhibitors and tamoxifen, showing a 65-75% reduction in plasma levels of one of the more active forms of the tamoxifen, i.e., endoxifen, has been reported in the literature. Reduced efficacy of tamoxifen has been reported with concomitant usage of some SSRI antidepressants in some studies. As a reduced effect of tamoxifen cannot be excluded, co-administration with potent CYP2D6 inhibitors (including fluoxetine) should whenever possible be avoided (see section 4.4).

 

Oral anticoagulants: 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 co-administered with oral anticoagulants.  Patients receiving warfarin therapy should receive careful coagulation monitoring when fluoxetine is initiated or stopped (see section 4.4, ‘Haemorrhage’).

 

Electroconvulsive therapy (ECT): There have been rare reports of prolonged seizures in patients on fluoxetine receiving ECT treatment; therefore, caution is advisable.

 

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, such as Class IA and III antiarrhythmics, antipsychotic (e.g., phenothiazine derivatives, pimozide, haloperidol), tricyclic antidepressants, certain antimicrobial agents (e.g., sparfloxacin, moxifloxacin, erythromycin IV, pentamidine), anti-malaria treatment particularly halofantrine, certain antihistamines (astemizole, mizolastine), should be used with caution.

 

Alcohol: In formal testing, fluoxetine did not raise blood alcohol levels or enhance the effects of alcohol.  However, the combination of SSRI treatment and alcohol is not advisable.

 

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.

 

Paediatric population: Interaction studies have only been performed in adults.

 

 

4.8           Undesirable effects

 

Very Common	Common	Uncommon	Rare
Blood and lymphatic system disorders
			Thrombocytopenia Neutropenia Leucopenia
Immune system disorders
			Anaphylactic reaction Serum sickness
Endocrine disorders
			Inappropriate antidiuretic hormone secretion
Metabolism and nutrition disorders
	Decreased appetite1		Hyponatraemia
Psychiatric disorders
Insomnia2	Anxiety Nervousness Restlessness Tension Libido decreased3 Sleep disorder Abnormal dreams4	Depersonalisation Elevated mood Euphoric mood Thinking abnormal Orgasm abnormal5 Bruxism Suicidal thoughts and behaviour 6	Hypomania Mania Hallucinations Agitation Panic attacks Confusion Dysphemia Aggression
Nervous system disorders
Headache	Disturbance in attention Dizziness Dysgeusia Lethargy Somnolence7 Tremor	Psychomotor hyperactivity Dyskinesia Ataxia Balance disorder Myoclonus Memory impairment	Convulsion Akathisia Buccoglossal syndrome Serotonin syndrome
Eye disorders
	Vision blurred	Mydriasis
Ear and labyrinth disorders
		Tinnitus
Cardiac disorders
	Palpitations Electrocardiogram QT prolonged (QTcF ≥450 msec)8		Ventricular arrhythmia including torsades de pointes Electrocardiogram QT prolonged
Vascular disorders
	Flushing89	Hypotension	Vasculitis Vasodilatation
Respiratory, thoracic and mediastinal disorders
	Yawning	Dyspnoea Epistaxis	Pharyngitis Pulmonary events (inflammatory processes of varying histopathology and/or fibrosis) 910
Gastrointestinal disorders
Diarrhoea Nausea	Vomiting Dyspepsia Dry mouth	Dysphagia Gastrointestinal haemorrhage1110	Oesophageal pain
Hepato-biliary disorders
			Idiosyncratic hepatitis
Skin and subcutaneous tissue disorders
	Rash1211 Urticaria Pruritus Hyperhidrosis	Alopecia Increased tendency to bruise Cold sweat	Angioedema Ecchymosis Photosensitivity reaction Purpura Erythema multiforme12 Stevens-Johnson syndrome Toxic Epidermal Necrolysis (Lyell Syndrome)
Musculoskeletal and connective tissue disorders
	Arthralgia	Muscle twitching	Myalgia
Renal and urinary disorders
	Frequent urination1312	Dysuria	Urinary retention Micturition disorder
Reproductive system and breast disorders
	Gynaecological bleeding1413 Erectile dysfunction Ejaculation disorder1514	Sexual dysfunction	Galactorrhoea Hyperprolactinemia Priapism
General disorders and administration site conditions
Fatigue1615	Feeling jittery Chills	Malaise Feeling abnormal Feeling cold Feeling hot	Mucosal haemorrhage
Investigations
	Weight decreased	Transaminases increased Gamma-glutamyltransferase increased

¹ Includes anorexia

² Includes early morning awakening, initial insomnia, middle insomnia

³ Includes loss of libido

⁴ Includes nightmares

⁵ Includes anorgasmia

⁶ Includes completed suicide, depression suicidal, intentional self-injury, self-injurious ideation, suicidal behavior, suicidal ideation, suicide attempt, morbid thoughts, self injurious behaviour. These symptoms may be due to underlying disease

⁷ Includes hypersomnia, sedation

⁸ Based on ECG measurements from clinical trials

⁸⁹ Includes hot flush

⁹¹⁰ Includes atelectasis, interstitial lung disease, pneumonitis

¹⁰¹¹ Includes most frequently gingival bleeding, haematemesis, haematochezia, rectal haemorrhage, diarrhoea haemorrhagic, melaena, and gastric ulcerhaemorrhage

¹² Could progress to Stevens-Johnson syndrome or Toxic Epidermal Necrolysis (Lyell Syndrome)

¹¹¹² Includes erythema, exfoliative rash, heat rash, rash, rash erythematous, rash follicular, rash generalized, rash macular, rash macular-papular, rash morbilliform, rash papular, rash pruritic, rash vesicular, umbilical erythema rash

¹²¹³ Includes pollakiuria

¹³¹⁴ Includes cervix haemorrhage, uterine dysfunction, uterine bleeding, genital haemorrhage, menometrorhagia, menorrhagia, metrorrhagia, polymenorrhea, postmenopausal haemorrhage, uterine haemorrhage, vaginal haemorrhage

¹⁴¹⁵ Includes ejaculation failure, ejaculation dysfunction, premature ejaculation, ejaculation delayed, retrograde ejaculation

¹⁵¹⁶ Includes asthenia

 

4.9           Overdose

 

Symptoms

Cases of overdose of fluoxetine alone usually have a mild course. Symptoms of overdose have included nausea, vomiting, seizures, cardiovascular dysfunction ranging from asymptomatic arrhythmias (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. Fatality attributed to overdose of fluoxetine alone has been extremely rare.

 

 

                10.          DATE OF REVISION OF THE TEXT

 

                09 October 201416 November 2015

Formatting changes made throughout the SPC

 

1.         NAME OF THE MEDICINAL PRODUCT

 

Added (underlined) deleted (strikethrough):

 

PROZAC* 20 mg hard capsules

 

PROZAC 20 mg per 5 ml oral liquid solution

 

 

 

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

 

Added (underlined) deleted (strikethrough):

 

Each capsule contains 20 mg of fluoxetine (as fluoxetine hydrochloride) equivalent to 20mg of fluoxetine.

 

Each 5 ml of oral liquid solution contains 20 mg of fluoxetine (as fluoxetine hydrochloride) fluoxetine hydrochloride equivalent to 20mg of fluoxetine.

 

Oral liquid solution excipients with known effect: contains 3 g of sucrose per 5 ml dose. This should be taken into account in patients with diabetes mellitus. Also contains small amounts of ethanol (alcohol), less than 100 mg per 5 ml dose.

 

For a  the full list of excipients, see section 6.1.

 

 

3.         PHARMACEUTICAL FORM

 

Added (underlined) deleted (strikethrough):

 

Hard capsules

The capsules are green and yellow, printed ‘Lilly 3105’.

 

Oral liquid solution (

The solution is clear, colourless, mint odoured).

 

 

 

 

 

4.2       Posology and method of administration

 

Added (bold) deleted (strikethrough):

 

For oral administration. Posology

Adults

 

Major depressive episodes

Adults and the elderly: The recommended dose is 20 mg daily.  Dosage should be reviewed and adjusted if necessary, within 3 to 4 weeks of initiation of therapy and thereafter as judged clinically appropriate.  Although there may be an increased potential for undesirable effects at higher doses, in some patients, with insufficient response to 20 mg, the dose may be increased gradually up to a maximum of 60 mg (see section 5.1).  Dosage adjustments should be made carefully on an individual patient basis, to maintain the patients at the lowest effective dose.

 

….

 

All indications: Adults:

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

 

Fluoxetine may be administered as a single or divided dose, during or between meals.

 

When dosing is stopped, active drug substances will persist in the body for weeks.  This should be borne in mind when starting or stopping treatment.

 

The capsule and liquid dosage forms are bioequivalent.

Paediatric population - Children and adolescents aged 8 years and above (moderate to severe major depressive episode)

 

Treatment should be initiated and monitored under specialist supervision.  The starting dose is 10 mg/day given as 2.5 ml of the PROZAC liquid formulation oral solution. Dose adjustments should be made carefully, on an individual basis, to maintain the patient at the lowest effective dose.

 

After one to two weeks, the dose may be increased to 20 mg/day.  Clinical trial experience with daily doses greater than 20 mg is minimal.  There is only limited data on treatment beyond 9 weeks.

 

Lower-weight children:

Due to higher plasma levels in lower-weight children, the therapeutic effect may be achieved with lower doses (see section 5.2).

 

For paediatric patients who respond to treatment, the need for continued treatment after 6 months should be reviewed.  If no clinical benefit is achieved within 9 weeks, treatment should be reconsidered.

 

Elderly patients

Caution is recommended when increasing the dose, and the daily dose should generally not exceed 40mg.  Maximum recommended dose is 60 mg/day.

 

Patients with hepatic impairment

A lower or less frequent dose (e.g., 20 mg every second day) should be considered in patients with hepatic impairment (see section 5.2), or in patients where concomitant medication has the potential for interaction with PROZAC (see section 4.5).

 

Withdrawal symptoms seen on discontinuation of PROZAC: Abrupt discontinuation should be avoided.  When stopping treatment with PROZAC the dose should be gradually reduced over a period of at least one to two weeks in order to reduce the risk of withdrawal reactions (see section 4.4 and section 4.8).  If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered.  Subsequently, the physician may continue decreasing the dose, but at a more gradual rate.

 

Method of administration

 

For oral administration.

Fluoxetine may be administered as a single or divided dose, during or between meals.

 

When dosing is stopped, active drug substances will persist in the body for weeks.  This should be borne in mind when starting or stopping treatment. 

 

The capsule and oral solution forms are bioequivalent.

 

4.3       Contraindications

 

Added (underlined) deleted (strikethrough):

 

Hypersensitivity to fluoxetine the active substance or to any of its the excipients listed in section 6.1.

 

Monoamine oxidase inhibitors: Cases of serious and sometimes fatal reactions have been reported in patients receiving an SSRI in combination with a monoamine oxidase inhibitor (MAOI), and in patients who have recently discontinued an SSRI and have been started on a MAOI.  Treatment of fluoxetine should only be started 2 weeks after discontinuation of an irreversible MAOI and the following day after discontinuation of a reversible MAOI-A.

 

Some cases presented with features resembling serotonin syndrome (which may resemble and be diagnosed as neuroleptic malignant syndrome).  Cyproheptadine or dantrolene may benefit patients experiencing such reactions.  Symptoms of a drug interaction with a MAOI include: hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes that include confusion, irritability and extreme agitation, progressing to delirium and coma.

 

Therefore, fluoxetine is contraindicated in combination with a non-selective MAOI.  Similarly, at least 5 weeks should elapse after discontinuing fluoxetine treatment before starting a MAOI.  If fluoxetine has been prescribed chronically and/or at a high dose, a longer interval should be considered.

 

The combination of fluoxetine with a reversible MAOI (e.g. moclobemide, linezolid, methylthioninium chloride (also called methylene blue; a reversible non-selective MAOI indicated for

medicinal or chemical induced methaemogobinaemiathe treatment of methaemoglobinaemia)) is not recommended.  Treatment with fluoxetine can be initiated the following day after discontinuation of a reversible MAOI.

 

In exceptional circumstances, linezolid (an antibiotic which is a reversible non‑selective MAOI) can be given in combination with fluoxetine provided that there are facilities for close observation of symptoms of serotonin syndrome and monitoring of blood pressure.

 

4.4       Special warnings and precautions for use

 

Added (bold) deleted (strikethrough):

 

Paediatric population - Use in cChildren and adolescents under 18 years of age

 

….

 

Fluoxetine should be used with caution in patients with conditions such as congenital long QT syndrome, a family history of QT prolongation or other clinical conditions that predispose to arrhythmias (e.g., hypokalemia and hypomagnesemia, bradycardia, acute myocardial infarction or uncompensated heart failure) or increased exposure to fluoxetine (e.g., hepatic impairment).

 

….

 

Serotonin syndrome or neuroleptic malignant syndrome-like events

On rare occasions, development of a serotonin syndrome or neuroleptic malignant syndrome-like events have been reported in association with treatment of fluoxetine, particularly when given in combination with other serotonergic (among others, L-tryptophan) and/or neuroleptic drugs.  As these syndromes may result in potentially life-threatening conditions, treatment with fluoxetine should be discontinued if such events (characterised by clusters of symptoms, such as hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes, including confusion, irritability, extreme agitation, progressing to delirium and coma) occur and supportive symptomatic treatment should be initiated.

 

PROZAC oral liquid solution contains sucrose: Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

 

4.5       Interaction with other medicinal products and other forms of interaction

 

Added (bold) deleted (strikethrough):

 

Interaction studies have only been performed in adults.

Half-life: The long elimination half-lives of both fluoxetine and norfluoxetine should be borne in mind (see section 5.2) when considering pharmacodynamic or pharmacokinetic drug interactions (e.g., when switching from fluoxetine to other antidepressants).

 

…

 

 

Paediatric population

Interaction studies have only been performed in adults.

 

4.6       Fertility, pregnancy and lactation

 

Added (bold) deleted (strikethrough):

 

…

 

Lactation: Breast-feeding

Fluoxetine and its metabolite, norfluoxetine, are known to be excreted in human breast milk.  Adverse events have been reported in breast-feeding infants.  If treatment with fluoxetine is considered necessary, discontinuation of breast-feeding should be considered; however, if breast-feeding is continued, the lowest effective dose of fluoxetine should be prescribed.

 

4.7       Effects on ability to drive and use machines

 

Added (underlined) deleted (strikethrough):

 

Prozac has no or negligible influence on the ability to drive and use machines. Although fluoxetine has been shown not to affect psychomotor performance in healthy volunteers, any psychoactive drug may impair judgement or 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.

 

4.8  Undesirable effects

 

Added (bold) deleted (strikethrough):

 

a. Summary of the safety profile

 

The most commonly reported adverse reactions in patients treated with fluoxetine were headache, nausea, insomnia, fatigue and diarrhoea.  Undesirable effects may decrease in intensity and frequency with continued treatment and do not generally lead to cessation of therapy.

 

b. Tabulated list of adverse reactions

 

The table below gives the adverse reactions observed with fluoxetine treatment in adult and paediatric populations.in clinical trials (n = 9297) and from spontaneous reporting.  Some of these adverse reactions are in common with other SSRIs.

 

The following frequencies have been calculated from clinical trials in adults (n = 9297) and from spontaneous reporting. 

 

Frequency estimate: Very common (³1/10), common (³1/100 to <1/10), uncommon (³1/1,000 to <1/100), rare (³1/10,000 to <1/1,000). very rare (<1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

 

 

 

Very Common	Common	Uncommon	Rare	Very Rare	Frequency Not Known
Blood and lymphatic system disorders
			Thrombocytopenia	Thrombocytopenia
Immune system disorders
			Anaphylactic reaction Serum sickness
Endocrine disorders
			Inappropriate antidiuretic hormone secretion		Inappropriate antidiuretic hormone secretion
Metabolism and nutrition disorders
	Decreased appetite1		Hyponatraemia
Psychiatric disorders
Insomnia2	Anxiety Nervousness Restlessness Tension Libido decreased34 Sleep disorder Abnormal dreams43	Depersonalisation Elevated mood Euphoric mood Thinking abnormal Orgasm abnormal5 Bruxism Suicidal thoughts and behaviour 6	Hypomania Mania Hallucinations Agitation Panic attacks Confusion Dysphemia		Suicidal thoughts and behaviour 14 Confusion Dysphemia
Nervous system disorders
Headache	Disturbance in attention Dizziness Dysgeusia Lethargy Somnolence76 Tremor	Psychomotor hyperactivity Dyskinesia Ataxia Balance disorder Myoclonus Memory impairment	Convulsion Akathisia Buccoglossal syndrome Serotonin syndrome		Serotonin syndrome Memory impairment
Eye disorders
	Vision blurred	Mydriasis
Ear and labyrinth disorders
		Tinnitus			Tinnitus
Cardiac disorders
	Palpitations		Ventricular arrhythmia including torsade de pointes Electrocardio-gram QT prolonged
Vascular disorders
	Flushing87	Hypotension	Vasculitis Vasodilatation
Respiratory, thoracic and mediastinal disorders
	Yawning	Dyspnoea Epistaxis	Pharyngitis Pulmonary events (inflammatory processes of varying histopathology and/or fibrosis)9		Pulmonary events (inflammatory processes of varying histopathology and/or fibrosis) Epistaxis
Gastrointestinal disorders
Diarrhoea Nausea	Vomiting Dyspepsia Dry mouth	Dysphagia Gastrointestinal haemorrhage10	Oesophageal pain		Gastrointestinal haemorrhage15
Hepato-biliary disorders
			idiosyncratic hepatitis		Very rare idiosyncratic hepatitis
Skin and subcutaneous tissue disorders
	Rash118 Urticaria Pruritus Hyperhidrosis	Alopecia Increased tendency to bruise Cold sweat	Angioedema Ecchymosis Photosensitivity reaction Purpura Erythema multiforme12		Erythema multiforme13
Musculoskeletal and connective tissue and bone disorders
	Arthralgia	Muscle twitching	Myalgia		Myalgia
Renal and urinary disorders
	Frequent urination913	Dysuria	Urinary retention Micturition disorder		Micturition disorder
Reproductive system and breast disorders
	Gynaecological bleeding1114 Erectile dysfunction Ejaculation disorder150	Sexual dysfunction	Galactorrhoea, Hyperprolactinaemia Priapism		Priapism
General disorders and administration site conditions
Fatigue162	Feeling jittery Chills	Malaise Feeling abnormal Feeling cold Feeling hot	Mucosal haemorrhage		Mucosal haemorrhage
Investigations
	Weight decrease	Abnormal liver function tests			Abnormal liver function tests

 

¹ Includes anorexia

² Includes early morning awakening, initial insomnia, middle insomnia

³ Includes loss of libido Includes nightmares⁴ Includes nightmares

Includes loss of libido

⁵ Includes anorgasmia

⁶ Includes completed suicide, depression suicidal, intentional self-injury, self-injurious ideation, suicidal behavior, suicidal ideation, suicide attempt, morbid thoughts, self injurious behaviour. These symptoms may be due to underlying disease

⁶⁷ Includes hypersomnia, sedation

⁷⁸ Includes hot flush

⁹ Includes atelectasis, interstitial lung disease, pneumonitis

⁸ Includes erythema, exfoliative rash, heat rash, rash, rash erythematous, rash follicular, rash generalized, rash macular, rash macular-papular, rash morbilliform, rash papular, rash pruritic, rash vesicular, umbilical erythema rash

⁹ Includes pollakiuria

¹⁰ Includes most frequently gingival bleeding, haematemesis, haematochezia, rectal haemorrhage, diarrhoea haemorrhagic, melaena, and gastric ulcerhaemorrhage

¹¹ Includes erythema, exfoliative rash, heat rash, rash, rash erythematous, rash follicular, rash generalized, rash macular, rash macular-papular, rash morbilliform, rash papular, rash pruritic, rash vesicular, umbilical erythema rash

¹² Could progress to Stevens-Johnson syndrome or Toxic Epidermal Necrolysis (Lyell Syndrome)

¹³ Includes pollakiuria

¹⁴ Includes cervix haemorrhage, uterine dysfunction, uterine bleeding, genital haemorrhage, menometrorhagia, menorrhagia, metrorrhagia, polymenorrhea, postmenopausal haemorrhage, uterine haemorrhage, vaginal haemorrhage

¹⁵⁰ Includes ejaculation failure, ejaculation dysfunction, premature ejaculation, ejaculation delayed, retrograde ejaculation

¹¹ Includes cervix haemorrhage, uterine dysfunction, uterine bleeding, genital haemorrhage, menometrorhagia, menorrhagia, metrorrhagia, polymenorrhea, postmenopausal haemorrhage, uterine haemorrhage, vaginal haemorrhage

¹⁶² Includes asthenia

¹³ Could progress to Stevens-Johnson syndrome or Toxic Epidermal Necrolysis (Lyell Syndrome)

¹⁴ These symptoms may be due to underlying disease.

¹⁵ Includes most frequently gingival bleeding, haematemesis, haematochezia, rectal haemorrhage, diarrhoea haemorrhagic, melaena, and gastric ulcer haemorrhage.

 

 

 

 

c. Description of selected adverse reactions

Suicide/suicidal thoughts or clinical worsening: Cases of suicidal ideation and suicidal behaviour have been reported during fluoxetine therapy or early after treatment discontinuation (see section 4.4).

 

Bone fractures: Epidemiological studies, mainly conducted in patients 50 years of age and older, show an increased risk of bone fractures in patients receiving SSRIs and TCAs. The mechanism leading to the risk is unknown.

 

Withdrawal symptoms seen on discontinuation of fluoxetine treatments: Discontinuation of fluoxetine commonly leads to withdrawal symptoms. Dizziness, sensory disturbances (including paraesthesia), sleep disturbances (including insomnia and intense dreams), asthenia, agitation or anxiety, nausea and/or vomiting, tremor and headache are the most commonly reported reactions. Generally these events are mild to moderate and are self-limiting; however, in some patients they may be severe and/or prolonged (see section 4.4). It is therefore advised that when PROZAC treatment is no longer required, gradual discontinuation by dose tapering should be carried out (see sections 4.2 and 4.4).

 

d. Paediatric population (see sections 4.4 and 5.1)

 

Children and adolescents (see sections 4.4 and 5.1):

 

Additional aAdverse reactions that have been observed specifically or with a different frequency in this population and are described below. Frequencies for these events are based on paediatric clinical trial exposures (n = 610). 

 

In paediatric clinical trials, suicide-related behaviours (suicide attempt and suicidal thoughts), and hostility (the events reported were: anger, irritability, aggression, agitation, activation syndrome), manic reactions, including mania and hypomania (no prior episodes reported in these patients) and epistaxis, were commonly reported and were more frequently observed among children and adolescents treated with antidepressants compared to those treated with placebo.  Manic reactions, including mania and hypomania, were reported (2.6% of fluoxetine-treated patients vs. 0% in placebo-controls), leading to discontinuation in the majority of cases.  These patients had no prior episodes of hypomania/mania. 

 

Isolated cases of growth retardation have been reported from clinical use. (See also section 5.1.)

 

In paediatric clinical trials, epistaxis was commonly reported, and fluoxetine treatment was also associated with a decrease in alkaline phosphatase levels.

 

Isolated cases of adverse events potentially indicating delayed sexual maturation or sexual dysfunction have been reported from paediatric clinical use.  (See also section 5.3.)

 

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via IMB Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2. Tel: +353 1 6764971, Fax: +353 1 6762517, Website: www.imb.ie, e-mail: imbpharmacovigilance@imb.ie.

 

4.9       Overdose

 

Added (bold):

 

Symptoms

Cases of overdose of fluoxetine alone usually have a mild course.  Symptoms of overdose have included nausea, vomiting, seizures, cardiovascular dysfunction ranging from asymptomatic arrhythmias  (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.  Fatality attributed to overdose of fluoxetine alone has been extremely rare. 

 

Management

Cardiac and vital signs monitoring are recommended, along with general symptomatic and supportive measures.  No specific antidote is known.

 

Forced diuresis, dialysis, haemoperfusion, and exchange transfusion are unlikely to be of benefit.  Activated charcoal, which may be used with sorbitol, may be as or more effective than emesis or lavage.  In managing overdosage, consider the possibility of multiple drug involvement.  An extended time for close medical observation may be needed in patients who have taken excessive quantities of a tricyclic antidepressant if they are also taking, or have recently taken, fluoxetine.

 

 

 

5.         PHARMACOLOGICAL PROPERTIES

 

5.1       Pharmacodynamic properties

 

Added (bold) deleted (strikethrough):

 

Pharmacotherapeutic group: Selective serotonin reuptake inhibitors.  ATC code: N06A B03.

 

Mechanism of action

 

Fluoxetine is a selective inhibitor of serotonin reuptake, and this probably accounts for the mechanism of action.  Fluoxetine has practically no affinity to other receptors such as α₁-, α₂-, and β-adrenergic; serotonergic; dopaminergic; histaminergic₁; muscarinic; and GABA receptors.

 

Clinical efficacy and safety

 

Major depressive episodes: Clinical trials in patients with major depressive episodes have been conducted versus placebo and active controls.  PROZAC has been shown to be significantly more effective than placebo, as measured by the Hamilton Depression Rating Scale (HAM-D).  In these studies, PROZAC produced a significantly higher rate of response (defined by a 50 % decrease in the HAM-D score) and remission compared to placebo.

 

Dose response: In the fixed dose studies of patients with major depression there is a flat dose response curve, providing no suggestion of advantage in terms of efficacy for using higher than the recommended doses.  However, it is clinical experience that uptitrating might be beneficial for some patients.

 

Obsessive-compulsive disorder: In short-term trials (under 24 weeks), fluoxetine was shown to be significantly more effective than placebo.  There was a therapeutic effect at 20 mg/day, but higher doses (40 or 60 mg/day) showed a higher response rate.  In long-term studies (three short-term studies extension phase and a relapse prevention study), efficacy has not been shown.

 

Bulimia nervosa: In short-term trials (under 16 weeks), in out-patients fulfilling DSM-III-R-criteria for bulimia nervosa, fluoxetine 60 mg/day was shown to be significantly more effective than placebo for the reduction of bingeing, vomiting and purging activities.  However, for long-term efficacy no conclusion can be drawn.

 

Pre-Menstrual Dysphoric Disorder: Two placebo-controlled studies were conducted in patients meeting pre-menstrual dysphoric disorder (PMDD) diagnostic criteria according to DSM-IV.  Patients were included if they had symptoms of sufficient severity to impair social and occupational function and relationships with others.  Patients using oral contraceptives were excluded.  In the first study of continuous 20 mg daily dosing for 6 cycles, improvement was observed in the primary efficacy parameter (irritability, anxiety and dysphoria).  In the second study, with intermittent luteal phase dosing (20 mg daily for 14 days) for 3 cycles, improvement was observed in the primary efficacy parameter (Daily Record of Severity of Problems score).  However, definitive conclusions on efficacy and duration of treatment cannot be drawn from these studies.

 

Paediatric population

 

Major depressive episodes (children and adolescents): Clinical trials in children and adolescents aged 8 years and above have been conducted versus placebo.  PROZAC, at a dose of 20 mg, has been shown to be significantly more effective than placebo in two short-term pivotal studies, as measured by the reduction of Childhood Depression Rating Scale-Revised (CDRS-R) total scores and Clinical Global Impression of Improvement (CGI-I) scores.  In both studies, patients met criteria for moderate to severe MDD (DSM-III or DSM-IV) at three different evaluations by practising child psychiatrists.  Efficacy in the fluoxetine trials may depend on the inclusion of a selective patient population (one that has not spontaneously recovered within a period of 3-5 weeks and whose depression persisted in the face of considerable attention).  There is only limited data on safety and efficacy beyond 9 weeks.  In general, efficacy of fluoxetine was modest.  Response rates (the primary endpoint, defined as a 30 % decrease in the CDRS-R score) demonstrated a statistically significant difference in one of the two pivotal studies (58 % for fluoxetine versus 32 % for placebo, P = 0.013; and 65 % for fluoxetine versus 54 % for placebo, P = 0.093).  In these two studies, the mean absolute changes in CDRS-R from baseline to endpoint were 20 for fluoxetine versus 11 for placebo, P = 0.002; and 22 for fluoxetine versus 15 for placebo, P <0.001.

 

Effects on growth (children and adolescents), see sections 4.4 and 4.8:

After 19 weeks of treatment, paediatric subjects treated with fluoxetine in a clinical trial 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 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 adjusted for expected growth in height from their matched, untreated controls (0.0 cm, p=0.9673).

 

5.2       Pharmacokinetic properties

 

Added (bold) deleted (strikethrough):

 

…

 

Distribution

Fluoxetine is extensively bound to plasma proteins (about 95 %) and it is widely distributed (volume of distribution: 20-40 lL/kg).  Steady-state plasma concentrations are achieved after dosing for several weeks.  Steady-state concentrations after prolonged dosing are similar to concentrations seen at 4 to 5 weeks.

 

BiotransformationMetabolism:

Fluoxetine has a non-linear pharmacokinetic profile with first pass liver effect.  Maximum plasma concentration is generally achieved 6 to 8 hours after administration.  Fluoxetine is extensively metabolised by the polymorphic enzyme CYP2D6.  Fluoxetine is primarily metabolised by the liver to the active metabolite norfluoxetine (desmethylfluoxetine), by desmethylation.

 

…

 

At-RiskSpecial Ppopulations

 

Elderly: Kinetic parameters are not altered in healthy elderly when compared to younger subjects.

 

Paediatric populationChildren and adolescents: The mean fluoxetine concentration in children is approximately 2-fold higher than that observed in adolescents and the mean norfluoxetine concentration 1.5-fold higher.  Steady-state plasma concentrations are dependent on body weight and are higher in lower weight children (see section 4.2).  As in adults, fluoxetine and norfluoxetine accumulated extensively following multiple oral dosing; steady-state concentrations were achieved within 3 to 4 weeks of daily dosing.

 

 

6.         PHARMACEUTICAL PARTICULARS

 

Added (underlined) deleted (strikethrough):

 

6.1       List of excipients

 

The liquid oral solution contains:

Benzoic acid

Sucrose

Glycerine

Mint flavour (containing 0.23 % ethanol (alcohol))

Purified water

 

 

 

 

6.3       Shelf-life

 

Added (underlined) deleted (strikethrough):

 

20mg capsules: 3 years.

 

Liquid Oral solution: 2 years.

 

6.4       Special precautions for storage

 

Added (underlined) deleted (strikethrough):

 

Do not store above 30°C.

 

Liquid Oral solution: Store in the original bottle to protect from light.

 

6.5       Nature and contents of container

 

Added (underlined) deleted (strikethrough):

 

20mg capsules: PVC/aluminium blister packs of 2, 7, 12, 14, 20, 28, 30, 50, 56, 70, 98, 100 and 500 capsules.

 

Liquid Oral solution: Brown glass bottles containing 60 ml, or 70 ml with dosing syringe or 140 ml oral liquidsolution. The pack may include a measuring cup or syringeone of the following measuring and dosing devices:

-            a measuring cup, with a 5 ml graduation,

-            a 5 ml capacity syringe with graduations to measure 1.25, 2.5, 3.75 and 5 ml,

-            a 5 ml capacity syringe with graduations to measure 5, 10, 15 and 20 mg,

-            a double ended spoon with the smaller spoon marked with a fill level equivalent to 2.5 ml and the larger spoon marked with a fill level equivalent to 5 ml.

 

Not all pack/bottle sizes may be marketed.

 

Deleted (strikethrough):

 

6.6       Special precautions for disposal of a used medicinal product or waste material derived from such medicinal product and other handling of the product

 

No special requirements.

 

 

8.         MARKETING AUTHORISATION NUMBERS

 

Added (underlined) deleted (strikethrough):

 

 

20mg capsules:            PA 0047/077/002

Liquid Oral solution:   PA 0047/077/001

 

 

9.         DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

 

Added (underlined) deleted (strikethrough):

 

Capsules:

 

Date of first authorisation:            9 February 1989

Date of last renewal:                     02 April 20081 April 2013

 

Liquid Oral solution:

 

Date of first authorisation:            23 February 1994

Date of last renewal:                     01 April 20081 April 2013

 

 

 

10.       DATE OF REVISION OF THE TEXT

 

Added (underlined) deleted (strikethrough):

 

01 March 201323 May 2014

 

 

Detailed information on this medicinal product is available on the website of Ireland/IMB

 

4.             CLINICAL PARTICULARS

4.3          Contraindications

 

Added (bold):

 

The combination of fluoxetine with a reversible MAOI (e.g. moclobemide, linezolid, methylthioninium chloride (also called methylene blue; a reversible non-selective MAOI indicated for the treatment of methaemoglobinaemia)) is not recommended.  Treatment with fluoxetine can be initiated the following day after discontinuation of a reversible MAOI.

 

In exceptional circumstances, linezolid (an antibiotic which is a reversible non‑selective MAOI) can be given in combination with fluoxetine provided that there are facilities for close observation of symptoms of serotonin syndrome and monitoring of blood pressure.

 

4.4.         Special warnings and precautions for use

 

Added (bold) deleted (strikethrough):

 

Cardiovascular Effects: Cases of QT interval prolongation and ventricular arrhythmia including torsade de pointes have been reported during the post-marketing period (see sections 4.5, 4.8 and 4.9).

 

Fluoxetine should be used with caution in patients with conditions such as congenital long QT syndrome, a family history of QT prolongation or other clinical conditions that predispose to arrhythmias (e.g., hypokalemia and  hypomagnesemia, bradycardia, acute myocardial infarction or uncompensated heart failure) or increased exposure to fluoxetine (e.g., hepatic impairment). No conduction abnormalities that resulted in heart block were observed in the ECG of 312 patients who received fluoxetine in double blind clinical trials.  However, clinical experience in acute cardiac disease is limited, therefore caution is advisable.

 

If patients with stable cardiac disease are treated, an ECG review should be considered before treatment is started.If signs of cardiac arrhythmia occur during treatment with fluoxetine, the treatment should be withdrawn and an ECG should be performed.

 

4.5.         Interaction with other medicinal products and other forms of interaction

 

Added:

 

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, such as Class IA and III antiarrhythmics, antipsychotic (e.g. phenothiazine derivatives, pimozide, haloperidol), tricyclic antidepressants, certain antimicrobial agents (e.g.sparfloxacin, moxifloxacin, erythromycin IV, pentamidine), anti-malaria treatment particularly halofantrine, certain antihistamines (astemizole, mizolastine), should be used with caution.

 

4.8.         Undesirable effects

 

Added (bold):

 

Very Common	Common	Uncommon	Rare	Very Rare	Frequency Not Known
Cardiac disorders
	Palpitations		Ventricular arrhythmia including torsade de pointes Electrocardio-gram QT prolonged
Reproductive system and breast disorders
	Gynaecological bleeding11 Erectile dysfunction Ejaculation disorder10	Sexual dysfunction	Galactorrhoea Hyperprolactinaemia		Priapism

 

 

4.9.         Overdose

 

Added (bold):

 

Cases of overdose of fluoxetine alone usually have a mild course. Symptoms of overdose have included nausea, vomiting, seizures, cardiovascular dysfunction ranging from asymptomatic arrhythmias (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. Fatality attributed to overdose of fluoxetine alone has been extremely rare.  Cardiac and vital signs monitoring are recommended, along with general symptomatic and supportive measures. No specific antidote is known.

 

 

10.          DATE OF REVISION OF THE TEXT

 

New date:

                01 March 2013

6.             Pharmaceutical Particulars

 

 

6.1.         List of excipients

 

Capsule components:

 

Added (Bold):

containing shellac, hydrated ferric oxide (black) E172, propylene glycol and may contain ammonium hydroxide and potassium hydroxide.

 

 

 

10.          DATE OF REVISION OF THE TEXT

 

New date:

                28 January 2013

4.             CLINICAL PARTICULARS

 

4.6.         Fertility, pregnancy and lactation

 

Added:

 

Fertility

Animal data have shown that fluoxetine may affect sperm quality (see section 5.3).

Human case reports with some SSRI’s have shown that an effect on sperm quality is reversible.

Impact on human fertility has not been observed so far.

 

5.             PHARMACOLOGICAL PROPERTIES

5.3.         Preclinical safety data

 

Added:

 

Adult animal studies

In a 2-generation rat reproduction study, fluoxetine did not produce adverse effects on the mating or fertility of rats, was not teratogenic, and did not affect growth, development, or reproductive parameters of the offspring.

The concentrations in the diet provided doses approximately equivalent to 1.5, 3.9, and 9.7 mg fluoxetine/kg body weight.

Male mice treated daily for 3 months with fluoxetine in the diet at a dose approximately equivalent to 31 mg/kg showed a decrease in testis weight and hypospermatogenesis. However, this dose level exceeded the maximum-tolerated dose (MTD) as significant signs of toxicity were seen.

 

Added:

 

Juvenile animal studies

 

 

10.          DATE OF REVISION OF THE TEXT

 

New date:

                25 September 2012

4.             CLINICAL PARTICULARS

 

4.8.         Undesirable effects

 

Added (bold)

 

Very Common	Common	Uncommon	Rare	Very Rare	Frequency Not Known
Gastrointestinal disorders
Diarrhoea Nausea	Vomiting Dyspepsia Dry mouth	Dysphagia	Oesophageal pain		Gastrointestinal haemorrhage15

 

Added:

 

¹⁵ Includes most frequently gingival bleeding, haematemesis, haematochezia, rectal haemorrhage, diarrhoea haemorrhagic, melaena, and gastric ulcerhaemorrhage.

 

 

 

10.          DATE OF REVISION OF THE TEXT

 

New date:

27 March 2012

4.             CLINICAL PARTICULARS

 

4.4          Special warnings and precautions for use

 

Added:

 

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.

 

4.8          Undesirable effects

 

Added (Bold):

 

Nervous system disorders
Headache	Disturbance in attention Dizziness Dysgeusia Lethargy Somnolence6 Tremor	Psychomotor hyperactivity Dyskinesia Ataxia Balance disorder Myoclonus	Convulsion Akathisia Buccoglossal syndrome		Serotonin syndrome Memory impairment

 

Deleted:

After 19 weeks of treatment, paediatric subjects treated with fluoxetine in a clinical trial 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. 

 

Deleted:

The safety of fluoxetine has not been assessed in this population for chronic treatment longer than 19 weeks. 

 

 

 

5.             PHARMACOLOGICAL PROPERTIES

 

5.1.         Pharmacodynamic properties

 

Added:

 

Effects on growth (children and adolescents), see sections 4.4 and 4.8:

 

After 19 weeks of treatment, paediatric subjects treated with fluoxetine in a clinical trial 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 a retrospective matched control observational study with a mean of 1.8 years of exposure to fluoxetine, pediatric subjects treated with fluoxetine had no difference in growth adjusted for expected growth in height from their matched, untreated controls (0.0 cm, p=0.9673).

 

 

10.          DATE OF REVISION OF THE TEXT

 

New date:

 

31 January 2012

4.             CLINICAL PARTICULARS

 

4.8.         Undesirable effects

 

Table – Added:

 

Very Common	Common		Uncommon		Rare		Very Rare		Frequency Not Known
Blood and lymphatic system disorders
								Thrombocytopenia

 

Added (bold):

 

Psychiatric disorders
Insomnia2	Anxiety Nervousness Restlessness Tension Libido decreased4 Sleep disorder Abnormal dreams3	Depersonalisation Elevated mood Euphoric mood Thinking abnormal Orgasm abnormal5 Bruxism	Hypomania Mania Hallucinations Agitation Panic attacks		Suicidal thoughts and behaviour 14 Confusion Dysphemia

 

Added:

 

Ear and labyrinth disorders
					Tinnitus

 

 

 

10.          DATE OF REVISION OF THE TEXT

 

New date:

 

23 September 2011