Eli Lilly and Company Limited

4.             CLINICAL PARTICULARS

4.8.         Undesirable effects

Added (bold)

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:

                26 April 2012

4.             CLINICAL PARTICULARS

4.4.         Special warnings and precautions for use

Added:

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).

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

Added:

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).

4.8.         Undesirable effects

Note: This section has had major additions and deletions and as such has been re-formatted in entirety:

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.

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

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.

¹ Includes anorexia

² Includes early morning awakening, initial insomnia, middle insomnia

³ Includes nightmares

⁴ Includes loss of libido

⁵ Includes anorgasmia

⁶ Includes hypersomnia, sedation

⁷ Includes hot flush

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 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

¹² Includes asthenia

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

¹⁴ These symptoms may be due to underlying disease.

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).

Children and adolescents (see section 4.4 ):

Additional adverse reactions have been observed specifically in this population and are described below.  

In paediatric clinical trials, suicide-related behaviours (suicide attempt and suicidal thoughts), and hostility 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. 

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.  Isolated cases of growth retardation have also been reported from clinical use. 

In paediatric clinical trials, epistaxis was commonly reported, and fluoxetine treatment was 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)

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

10.          DATE OF REVISION OF THE TEXT

New date:

10 March 2011

4.             CLINICAL PARTICULARS

4.6.         Pregnancy and lactation

                Added:

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.

10.          DATE OF REVISION OF THE TEXT

New date:

14 October 2010

4.          CLINICAL PARTICULARS

4.6.        Pregnancy and lactation

             Added text in bold. Deletions shown in strikethrough

Pregnancy: Epidemiological data have suggested that the use of SSRIs in pregnancy, particular 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.

 Data on a large number of exposed pregnancies do not indicate a teratogenic effect of fluoxetine. Furthermore, although Ffluoxetine can be used during pregnancy, but caution should be exercised, especially during late pregnancy or just prior to the onset of labour since the following 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).

4.8.       Undesirable effects

             Added:

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.

6.         Pharmaceutical Particulars

6.1.       List of excipients

Added text in bold:

The capsules contain:

Maize starch flowable

10.        DATE OF REVISION OF THE TEXT

New date:

1 July 2010

2.             QUALITATIVE AND QUANTITATIVE COMPOSITION

Added:

Oral liquid xcipients: contains 3g of sucrose per 5ml dose. This should be taken into account in patients with diabetes mellitus.

4.             CLINICAL PARTICULARS

4.4.         Special warnings and precautions for use

Added:

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

6.             Pharmaceutical Particulars

6.1.         List of excipients

Added:

…containing shellac and hydrated ferric oxide (black) E172.

Deleted:

Formulation 1:

Shellac

Propylene Glycol

Ammonium Hydroxide

Black Iron Oxide E172

Formulation 2:

Shellac

Soya Lecithin

Antifoam DC 1510

Black Iron Oxide E172

6.4.         Special precautions for storage

Added:

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

9.             DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Added:

Date of latest renewal:  02 April 2008

10.          DATE OF REVISION OF THE TEXT

New date:

18 February 2009

4.             CLINICAL PARTICULARS

4.4.         Special warnings and precautions for use

Use in children and adolescents under 18 years of age

Added (bold):

Suicide/suicidal thoughts or clinical worsening:

Amended:

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.

4.8.         Undesirable effects

Body as a whole:

Amended:

Hypersensitivity (e.g. pruritis, rash, urticaria, anaphylactoid reaction, vasculitis, serum sickness-like reaction, angioedema) (see sections 4.3 and 4.4), chills, serotonin syndrome, photosensitivity, and very rarely Erythema Multiforme that could progress to Stevens-Johnson syndrome or Toxic Epidermal Necrolysis (Lyell syndrome).

Nervous system:

Amended:

Headache, sleep abnormalities (e.g. abnormal dreams, insomnia), dizziness, anorexia, fatigue (e.g. somnolence, drowsiness), euphoria, transient abnormal movement (e.g., twitching, ataxia, tremor, myoclonus), seizures and rarely psychomotor restlessness/akathisia (see section 4.4).  Hallucinations, manic reaction, confusion, agitation, anxiety and associated symptoms (e.g. nervousness), impaired concentration and thought process (e.g. depersonalisation), panic attacks, very rarely serotonin syndrome, suicidal thoughts and behaviour (these symptoms may be due to the underlying disease). Cases of suicidal ideation and suicidal behaviour have been reported during fluoxetine therapy or early after treatment discontinuation (see Section 4.4)

6.             Pharmaceutical Particulars

6.5.         Nature and contents of container

Amended:

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

6.6.              Special precautions for disposal

Sub-Title changed

Added:

No special requirements.

9.             DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Re-formatted Sub-Heading:

Date of latest renewal:

10.          DATE OF REVISION OF THE TEXT

New date:

20 June 2008

4.             CLINICAL PARTICULARS

4.4          Special warnings and precautions for use

Added

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

4.8                Undesirable effects

Addition in bold text

Body as a whole: Hypersensitivity (eg, pruritus, rash, urticaria, anaphylactoid reaction, vasculitis, serum sickness-like reaction, angioedema) (see sections 4.3 and 4.4), chills, serotonin syndrome, photosensitivity and very rarely, erythema multiforme that could progress to Stevens-Johnson syndrome or toxic epidermal necrolysis (Lyell syndrome).

10.          DATE OF REVISION OF THE TEXT

New date:

March 2007

Removal of 60mg capsule.

3.             PHARMACEUTICAL FORM

The 20mg capsules are green and yellow, printed ‘Prozac 20mg’.

Changed to:

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

4.             CLINICAL PARTICULARS

4.1          Therapeutic indications

Added:

Children and Adolescents Aged 8 Years and Above

Moderate to severe major depressive episode, if depression is unresponsive to psychological therapy after 4-6 sessions.  Antidepressant medication should be offered to a child or young person with moderate to severe depression only in combination with a concurrent psychological therapy.

4.2          Posology and method of administration

Removed:

Children: The use of fluoxetine in children and adolescents (under the age of 18) is not recommended, as safety and efficacy have not been established.

Replaced by:

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 10mg/day given as 2.5ml of the Prozac liquid formulation.  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 20mg/day.  Clinical trial experience with daily doses greater than 20mg 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.

4.4          Special warnings and precautions for use

Added:

Use in 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 4.8).  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.

4.5          Interaction with other medicinal products and other forms of interaction

Added:

Interaction studies have only been performed in adults.

4.8          Undesirable effects

Added:

Children and adolescent (see section 4.4): In paediatric clinical trials, suicide-related behaviours (suicide attempt and suicidal thoughts) and hostility were more frequently observed among children and adolescents treated with antidepressants compared to those treated with placebo.

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

In paediatric clinical trials, manic reactions, including mania and hypomania, were reported (2.6% of fluoxetine-treated patients versus 0% in placebo-controls), leading to discontinuation in the majority of cases.  These patients had no prior episodes of hypomania/mania.

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.  Isolated cases of growth retardation have also been reported from clinical use.

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).

In paediatric clinical trials, fluoxetine treatment was associated with a decrease in alkaline phosphatase levels.

5.             PHARMACOLOGICAL PROPERTIES

5.1          Pharmacodynamic properties

Added:

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

Added:

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 20mg, 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.

5.2          Pharmacokinetic properties

Added:

Children 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.

5.3          Preclinical safety data

There is no evidence of carcinogenicity, mutagenicity, or impairment of fertility from in vitro or animal studies.

Changed to:

There is no evidence of carcinogenicity or mutagenicity from in vitro or animal studies.

Added:

In a juvenile toxicology study in CD rats, administration of 30mg/kg/day of fluoxetine hydrochloride on postnatal days 21 to 90 resulted in irreversible testicular degeneration and necrosis, epididymal epithelial vacuolation, immaturity and inactivity of the female reproductive tract, and decreased fertility.  Delays in sexual maturation occurred in males (10 and 30mg/kg/day) and females (30mg/kg/day).  The significance of these findings in humans is unknown.  Rats administered 30mg/kg also had decreased femur lengths compared with controls and skeletal muscle degeneration, necrosis, and regeneration.  At 10mg/kg/day, plasma levels achieved in animals were approximately 0.8 to 8.8-fold (fluoxetine) and 3.6 to 23.2-fold (norfluoxetine) those usually observed in paediatric patients.  At 3mg/kg/day, plasma levels achieved in animals were approximately 0.04 to 0.5-fold (fluoxetine) and 0.3 to 2.1-fold (norfluoxetine) those usually achieved in paediatric patients.

A study in juvenile mice has indicated that inhibition of the serotonin transporter prevents the accrual of bone formation.  This finding would appear to be supported by clinical findings.  The reversibility of this effect has not been established.

Another study in juvenile mice (treated on postnatal days 4 to 21) has demonstrated that inhibition of the serotonin transporter had long lasting effects on the behaviour of the mice.  There is no information on whether the effect was reversible.  The clinical relevance of this finding has not been established.

6.             PHARMACEUTICAL PARTICULARS

6.4          Special precautions for storage

Do not store above 25°C.

Changed to:

Do not store above 30°C.

10.          DATE OF REVISION OF THE TEXT

New date:

September 2006