Cymbalta 30 mg, 60 mg hard gastro-resistant capsules

4.       Possible side effects

…

If you get any side effects, talk to your doctor of pharmacist. This includes any possible side effects not listed in this leaflet.  You can also report side effects directly via Ireland: HPRA Pharmacovigilance; website: www.hpra.ie, Malta: ADR Reporting, Website: www.medicinesauthority.gov.mt/adrportal or United Kingdom (Northern Ireland): Yellow Card Scheme; website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.  By reporting side effects you can help provide more information on the safety of this medicine.

 

 

6.       Contents of the pack and other information

 

Marketing Authorisation Holder and Manufacturer

 

United Kingdom

Eli Lilly and Company Limited
Tel: + 44-(0) 1256 315000

Ireland and United Kingdom (Northern Ireland)

Eli Lilly and Company (Ireland) Limited

Tel: +353-(0) 1 661 4377

Malta

Charles de Giorgio Ltd.

Tel: + 356 25600 500

 

 

This leaflet was last revised in June 2020December 2021.

CYM031

4.4          Special warnings and precautions for use

 Sodium

This medicine contains less than 1 mmol sodium (23 mg) per capsule, that is to say essentially ‘sodium-free’.

 

4.6          Fertility, pregnancy and lactation

 Fertility:

In animal studies, Dduloxetine had no effect on male fertility, and effects in females were only evident at doses that caused maternal toxicity.

 Pregnancy

There are no adequate data on the use of duloxetine in pregnant women

 Studies in animals have shown reproductive toxicity at systemic exposure levels (AUC) of duloxetine lower than the maximum clinical exposure (see section 5.3).

 The potential risk for humans is unknown.

Two large observational studies do not suggest an overall increased risk of major congenital malformation (one from the US including 2,500 exposed to duloxetine during the first trimester and one from the EU including 1,500 exposed to duloxetine during the first trimester). The analysis on specific malformations such as cardiac malformations shows inconclusive results.

In the EU study, maternal exposure to duloxetine during late pregnancy (at any time from 20 weeks gestational age to delivery) was associated with an increased risk for preterm birth (less than 2-fold, corresponding to approximately 6 additional premature births per 100 women treated with duloxetine late in pregnancy). The majority occurred between 35 and 36 weeks of gestation. This association was not seen in the US study.

The US Oobservational data have provided evidence of an increased risk (less than 2 -fold) of postpartum haemorrhage following duloxetine exposure within the month prior to birth…]

 Observational data have provided evidence of an increased risk (less than 2 -fold) of postpartum haemorrhage following duloxetine exposure within the month prior to birth.

8.             MARKETING AUTHORISATION NUMBER(S)

 30 mg, 7 capsules:                       EU/1/04/296/006

30 mg, 28 capsules:                     EU/1/04/296/001

30 mg, 98 capsules:                     EU/1/04/296/009

60 mg, 28 capsules:                     EU/1/04/296/002

60 mg, 56 capsules:                     EU/1/04/296/005

60 mg, 84 capsules:                     EU/1/04/296/003

60 mg, 98 capsules:                     EU/1/04/296/004

60 mg, 100 capsules:                  EU/1/04/296/008

60 mg, 500 capsules:                  EU/1/04/296/007

EU/1/04/296/001

EU/1/04/296/002

EU/1/04/296/003

EU/1/04/296/004

EU/1/04/296/005

EU/1/04/296/006

EU/1/04/296/007

EU/1/04/296/008

EU/1/04/296/009

10.          DATE OF REVISION OF THE TEXT

25 July 201911 June 2020

2.       What you need to know before you take Cymbalta

[…]

 Available data from the use of Cymbalta during the first three months of pregnancy do not show an increased risk of overall birth defects in general in the child. If Cymbalta is taken during the second half of pregnancy, there may be an increased risk that the infant will be born early (6 additional premature infants for every 100 women who take Cymbalta in the second half of pregnancy), mostly between weeks 35 and 36 of pregnancy.

 […]

Cymbalta contains sodium

This medicine contains less than 1 mmol sodium (23 mg) per capsule, that is to say essentially ‘sodium-free’. […]

  6.             DATE OF REVISION OF THE TEXT

 July 2019June 2020

[Throughout document – minor format changes for improvement and also heading formats]

 

4.4      Special warnings and precautions for use

 

Haemorrhage

There have been reports of bleeding abnormalities, such as ecchymoses, purpura, and gastrointestinal haemorrhage, with selective serotonin reuptake inhibitors (SSRIs) and serotonin/noradrenaline reuptake inhibitors (SNRIs), including duloxetine. Duloxetine may increase the risk of postpartum haemorrhage (see section 4.6). Caution is advised in patients taking anticoagulants and/or medicinal products known to affect platelet function (e.g., NSAIDs or acetylsalicylic acid (ASA)), and in patients with known bleeding tendencies.

 

Sucrose

Cymbalta hard gastro-resistant capsules contain sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucraose-isomaltase insufficiency should not take this medicine.

 

4.6          Fertility, pregnancy and lactation

 

Pregnancy

 

Observational data have provided evidence of an increased risk (less than 2-fold) of postpartum haemorrhage following duloxetine exposure within the month prior to birth.

 

4. Undesirable effects

 

Table 1: Adverse reactions

 

Reproductive system and breast disorders [Rare] Menopausal symptoms Galactorrhoea, Hyper-prolactinaemia, Postpartum haemorrhage⁶

 

 

 

10.          DATE OF REVISION OF THE TEXT

 

06 201925 July 2019

 

 

CYM289M

 

 

4.8     Undesirable effects

 

Healthcare professionals are asked to report any suspected adverse reactions via Ireland: HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2, Tel: +353 1 6764971, Fax: +353 1 6762517; website: www.hpra.ie; e-mail: medsafety@hpra.ie,

 

 

5.1     Pharmacodynamic properties

 

A single study has been performed in paediatric patients with juvenile primary fibromyalgia syndrome (JPFS) in which the duloxetine-treated group did not separate from placebo group for the primary efficacy measure. Therefore, there is no evidence of efficacy in this paediatric patient population. The randomised, double-blind, placebo-controlled, parallel study of duloxetine was conducted in 184 adolescents aged 13 to 18 years (mean age 15.53 years) with JPFS. The study included a 13-weekdouble-blind period where patients were randomised to duloxetine 30 mg/60 mg, or placebo daily. Duloxetine did not show efficacy in reducing pain as measured by primary outcome measure of Brief Pain Inventory (BPI) average pain score endpoint: least squares (LS) mean change from baseline in BPI average pain score at 13 weeks was -0.97 in the placebo group, compared with -1.62 in the duloxetine 30/60 mg group (p = 0.052). The safety results from this study were consistent with the known safety profile of duloxetine.

 

 

 

10.          DATE OF REVISION OF THE TEXT

 

24 June 201906 2019

 

 

CYM278M

 

 

4.4          Special warnings and precautions for use

Sexual dysfunction

Selective serotonin reuptake inhibitors (SSRIs)/serotonin norepinephrine reuptake inhibitors (SNRIs) 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/SNRI.

 

10.          DATE OF REVISION OF THE TEXT

 

09 November 2018 24 June 2019

CYMBALTA^®                                              

duloxetine (as hydrochloride)

1.             NAME OF THE MEDICINAL PRODUCT

Cymbalta * 30 mg hard gastro-resistant capsules.

4.8          Undesirable effects

Respiratory, thoracic and mediastinal disorders
	Yawning	Throat tightness Epistaxis	Interstitial lung disease10 Eosinophilic pneumonia6

¹⁰ Estimated frequency based on placebo-controlled clinical trials.

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 Ireland: HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2, Tel: +353 1 6764971, Fax: +353 1 6762517; website: www.hpra.ie; e-mail: medsafety@hpra.ie, or United Kingdom: Yellow Card Scheme; website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store. By reporting side effects you can help provide more information on the safety of this medicine.

UK: www.mhra.gov.uk/yellowcard or Ireland: 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

09 November 2018 01 January 2016

Changes

Added (bold), Deleted (strikethrough):

 

 

4.6       Fertility, pregnancy and lactation

 

Fertility

 

In animal studies, Dduloxetine had no effect on male fertility, and effects in females were only evident at doses that caused maternal toxicity.

 

6.             PHARMACEUTICAL PARTICULARS

 

6.5       Nature and contents of container

 

Polyvinylchloride (PVC), polyethylene (PE), and polychlorotrifluoroethylene (PCTFE) blister sealed with an aluminium foil.

 

Cymbalta 30 mg

Cymbalta 30 mg is available in packs of 7, 28 and 98 hard gastro-resistant capsules.

 

Cymbalta 60 mg

Cymbalta 60 mg is available in packs of 28, 56, 84, and 98, 100 (Each pack contains 5 cartons of 20 capsules) and 500 capsules (Each pack contains 25 cartons of 20 capsules). hard gastro-resistant capsules and in multipacks containing 100 (5 packs of 20) and 500 (25 packs of 20) hard gastro-resistant capsules.

 

Not all pack sizes may be marketed.

 

 

10.     DATE OF REVISION OF THE TEXT

 

01 January 201626 January 2017

 

Changes

Added (bold), Deleted (strikethrough):

 

 

 

10      MARKETING AUTHORISATION HOLDER

 

Eli Lilly Nederland B.V.

Grootslag 1‑5

NL‑3991 RA, Houten

Papendorpseweg 83

3528 BJ Utrecht

The Netherlands

 

 

10.     DATE OF REVISION OF THE TEXT

 

09 July 201501 January 2016

Changes

Added (bold), Deleted (strikethrough):

 

2.       QUALITATIVE AND QUANTITATIVE COMPOSITION

 

Each capsule contains 30 mg of duloxetine (as hydrochloride).

 

Excipient(s) with known effect 30 mg: each capsule may contains 8 up to 56 mg sucrose.

 

Each capsule contains 60 mg of duloxetine (as hydrochloride).

 

Excipient(s) with known effect 60 mg: each capsule may contains 17.2 up to 111 mg sucrose.

 

For the full list of excipients, see section 6.1.

 

4.       CLINICAL PARTICULARS

 

4.8     Undesirable effects

b. Tabulated summary of adverse reactions

Table 1 gives the adverse reactions observed from spontaneous reporting and in placebo-controlled clinical trials.

 

Added (bold):

 

Very common	Common	Uncommon	Rare	Very Rare
Gastrointestinal disorders
Nausea Dry mouth	Constipation Diarrhoea Abdominal pain Vomiting Dyspepsia Flatulence	Gastrointestinal haemorrhage7 Gastroenteritis Eructation Gastritis Dysphagia	Stomatitis Haematochezia Breath odour Microscopic colitis9

⁸ Falls were more common in the elderly (≥65 years old).

⁹ Estimated frequency based on all clinical trial data.

5.         PHARMACOLOGICAL PROPERTIES

 

5.2     Pharmacokinetic properties

 

Biotransformation: Duloxetine is extensively metabolised and the metabolites are excreted principally in urine. Both cytochromes P450-2D6 and 1A2 catalyse the formation of the two major metabolites glucuronide conjugate of 4-hydroxy duloxetine and sulfphate conjugate of 5-hydroxy 6-methoxy duloxetine. Based upon in vitro studies, the circulating metabolites of duloxetine are considered pharmacologically inactive. The pharmacokinetics of duloxetine in patients who are poor metabolisers with respect to CYP2D6 has not been specifically investigated. Limited data suggest that the plasma levels of duloxetine are higher in these patients.

 

10.       DATE OF REVISION OF THE TEXT

 

New date of revision:

 

09 July 2015

4.       CLINICAL PARTICULARS

4.8     Undesirable effects

 

b. Tabulated summary of adverse reactions

 

Added (bold), Deleted (strikethrough):

 

Table 1 gives the adverse reactions observed from spontaneous reporting and in placebo-controlled clinical trials (comprising a total of 9454 patients, 5703 on duloxetine and 3751 on placebo) in depression, generalised anxiety disorder and diabetic neuropathic pain.

 

Added (bold):

 

Very common	Common	Uncommon	Rare	Very Rare
Skin and subcutaneous tissue disorders
	Sweating increased Rash	Night sweats Urticaria Dermatitis contact Cold sweat Photo-sensitivity reactions Increased tendency to bruise	Stevens-Johnson Syndrome6 Angio-neurotic oedema6	Cutaneous vasculitis

 

 

 

10.       DATE OF REVISION OF THE TEXT

 

New date of revision:

 

27 May 2015

4.             Clinical particulars

4.2          Posology and method of administration

 

Paediatric population

 

Added:

 

The safety and efficacy of duloxetine for the treatment of generalised anxiety disorder in paediatric patients aged 7-17 years have not been established. Current available data are described in sections 4.8, 5.1 and 5.2.

 

Deleted (strikethrough):

 

The safety and efficacy of duloxetine for the treatment of diabetic peripheral neuropathic pain or generalised anxiety disorder has not been studied. No data are available.

 

4.8     Undesirable effects

 

d. Paediatric population

Added (bold) Deleted (strikethrough):

 

A total of 509 paediatric patients aged 7 to 17 years with MDD major depressive disorder and 241 paediatric patients aged 7 to 17 years with generalised anxiety disorder were treated with duloxetine in clinical trials. In general, the adverse reaction profile of duloxetine in children and adolescents was similar to that seen for adults.

 

Three hundred and thirty two A total of 467 paediatric patients initially randomized to duloxetine in clinical trials experienced a 0.2 0.1 kg mean decrease in weight at 10-weeks compared with a 0.9 kg mean increase in 353 placebo-treated patients. Subsequently, over the four- to six-month extension period, most of thesepatients on average trended toward recovery to their expected baseline weight percentile expected based on population data from age- and gender-matched peers (see section 4.4).

 

Added:

 

In studies of up to 9 months an overall mean decrease of 1% in height percentile (decrease of 2% in children (7-11 years) and increase of 0.3% in adolescents (12-17 years)) was observed in duloxetine-treated paediatric patients (see section 4.4).

 

 

 

5.             PHARMACOLOGICAL PROPERTIES

5.1       Pharmacodynamic properties

 

Added:

A randomised, double-blind, placebo-controlled study was performed in 272 patients aged 7-17 years with generalised anxiety disorder.  The study included a 10 week placebo-controlled acute phase, followed by an 18 week extension treatment period.  A flexible dose regimen was used in this study, to allow for slow dose escalation from 30 mg once daily to higher doses (maximum 120 mg once daily).  Treatment with duloxetine showed a statistically significantly greater improvement in GAD symptoms, as measured by PARS severity score for GAD (mean difference between duloxetine and placebo of 2.7 points [95% CI 1.3-4.0]), after 10 weeks of treatment. The maintenance of the effect has not been evaluated. There was no statistically significant difference in discontinuation due to adverse events between duloxetine and placebo groups during the 10 week acute treatment phase. Two patients who transitioned from placebo to duloxetine after the acute phase experienced suicidal behaviours while taking duloxetine during the extension phase. A conclusion on the overall benefit/risk in this age group has not been established (see also sections 4.2 and 4.8).

 

Removed:

 

A randomized, double-blind, placebo-controlled study was performed in 272 patients aged 7-17 years

with generalised anxiety disorder. The study included a 10 week placebo-controlled acute phase,

followed by an 18 week extension treatment period. A flexible dose regimen was used in this study, to

allow for slow dose escalation from 30 mg once daily (QD) to higher doses (maximum 120 mg QD).

Treatment with duloxetine showed a statistically significantly greater improvement in GAD symptoms,

as measured by PARS severity score for GAD, from 2 weeks of treatment, continuing to the primary

endpoint at 10 weeks. There was no statistically significant difference in discontinuation due to

adverse events between duloxetine and placebo groups during the 10 week acute treatment phase. Two

patients who transitioned from placebo to duloxetine after the acute phase experienced suicidal

behaviours while taking duloxetine during the extension phase.

 

 

 

10.       DATE OF REVISION OF THE TEXT

 

New date of revision:

 

26 June 2014

4.             Clinical particulars

4.2          Posology and method of administration

Elderly

 

Added (bold):

No dosage adjustment is recommended for elderly patients solely on the basis of age. However, as with any medicine, caution should be exercised when treating the elderly, especially with Cymbalta 120 mg per day for major depressive disorder or generalised anxiety disorder, for which data are limited (see sections 4.4 and 5.2).

 

4.4       Special warnings and precautions for use

Elderly

 

Added (bold), Deleted (strikethrough):

Data on the use of Cymbalta 120 mg in elderly patients with major depressive disorder and generalised anxiety disorder are limited. Therefore, caution should be exercised when treating the elderly with the maximum dosage (see sections 4.2 and 5.2). Data on the use of Cymbalta in elderly patients with generalised anxiety disorder are limited.

 

 

 

5.             PHARMACOLOGICAL PROPERTIES

5.1       Pharmacodynamic properties

 

Added:

The efficacy of Cymbalta 30-120 mg (flexible dosing) once a day in elderly patients (>65 years) with generalised anxiety disorder was evaluated in a study that demonstrated statistically significant improvement in the HAM-A total score for duloxetine treated patients compared to placebo treated patients.  The efficacy and safety of Cymbalta 30-120 mg once daily in elderly patients with generalised anxiety disorder was similar to that seen in studies of younger adult patients.  However, data on elderly patients exposed to the maximum dose (120 mg per day) are limited and, thus, caution is recommended when using this dose with the elderly population.

 

 

 

10.       DATE OF REVISION OF THE TEXT

 

New date of revision:

  

20 March 2014

In Section 4.4, Special warnings and precautions for use, the section 'Use with Antidepressants' is replaced with information on serotonin syndrome.

In Section 4.5, Interation with other medicinal products and other forms of interaction, the followings statements are added - 'The antibiotic linezolid is a reversible non-selective MAOI and should not be given to patients treated with Cymbalta (see section 4.4).'
And the section on Serotinergic agents has been updated.

In Section 10, Date of revision of text, the date of revision is updated.

Changes made throughout SPC due to QRD template changes.

 

 

 

2.       QUALITATIVE AND QUANTITATIVE COMPOSITION

 

Added (bold):

 

Excipient(s) with known effect 30 mg: each capsule contains 8.6 mg sucrose.

 

Excipient(s) with known effect 60 mg: each capsule contains 17.2 mg sucrose.

 

 

4.       CLINICAL PARTICULARS

4.2     Posology and method of administration

 

Paediatric population

Moved:

Duloxetine should not be used in children and adolescents under the age of 18 years for the treatment of major depressive disorder because of safety and efficacy concerns (see sections 4.4, 4.8 and 5.1).

 

Added :

The safety and efficacy of duloxetine for the treatment of diabetic peripheral neuropathic pain or generalized anxiety disorder have not been studied. No data are available.

 

Deleted :

 

Children and adolescents

Duloxetine is not recommended for use in children and adolescents due to insufficient data on safety and efficacy (see section 4.4).

 

 

4.3     Contraindications

 

Added (bold):

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

 

Added (bold), Deleted (strikethrough):

 

Use in children and adolescents under 18 years of age

No clinical trials have been conducted with duloxetine in paediatric populations. Cymbalta should not be used in the treatment of children and adolescents under the age of 18 years. Suicide-related behaviours (suicide attempts 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. If, based on clinical need, a decision to treat is nevertheless taken, the patient should be carefully monitored for the appearance of suicidal symptoms (see section 5.1). In addition, long-term safety data in children and adolescents concerning growth, maturation and cognitive and behavioural development are lacking (see section 4.8).

 

4.6     Fertility, pregnancy and lactation

 

Added :

 

Fertility

Duloxetine had no effect on male fertility, and effects in females were only evident at doses that caused maternal toxicity.

 

4.8     Undesirable effects

 

Added (bold), Deleted (strikethrough):

 

b. Tabulated summary of adverse reactions

Table 1 gives the adverse reactions observed from spontaneous reporting and in placebo-controlled clinical trials (comprising a total of 78199454 patients, 48235703 on duloxetine and 29963751 on placebo) in depression, generalised anxiety disorder and diabetic neuropathic pain.

 

Nervous system disorders
Headache (14.4%) Somnolence (10.4%)	Dizziness Lethargy Tremor Paraesthesia	Myoclonus Akathisia7 Nervousness Disturbance in attention Dysgeusia Dyskinesia Restless legs syndrome Poor quality sleep	Serotonin syndrome6 Convulsion1 Psychomotor restlessness6 Extra-pyramidal symptoms6

 

Added (bold), Deleted (strikethrough):

 

Gastrointestinal disorders
Nausea (24.1%) Dry mouth (13.1%)	Constipation Diarrhoea Abdominal pain Vomiting Dyspepsia Flatulence	Gastrointestinal haemorrhage7 Gastroenteritis Eructation Gastritis Dysphagia	Stomatitis Haematochezia Breath odour

 

Added (bold):

 

Reproductive system and breast disorders
	Erectile dysfunction Ejaculation disorder Ejaculation delayed	Gynaecological haemorrhage Menstrual disorder Sexual dysfunction Testicular pain	Menopausal symptoms Galactorrhoea Hyperprolactinaemia

 

Added (bold), Deleted (strikethrough):

 

General disorders and administration site conditions
	Falls8 Fatigue	Chest pain7 Falls8 Feeling abnormal Feeling cold Thirst Chills Malaise Feeling hot Gait disturbance

 

Added (bold):

 

c. Description of selected adverse reactions

Discontinuation of duloxetine (particularly when abrupt) commonly leads to withdrawal symptoms. Dizziness, sensory disturbances (including paraesthesia or electric shock-like sensations, particularly in the head), sleep disturbances (including insomnia and intense dreams), fatigue, somnolence, agitation or anxiety, nausea and/or vomiting, tremor, headache, myalgia, irritability, diarrhoea, hyperhydrosis and vertigo are the most commonly reported reactions.

 

Added:

 

d. Paediatric population

A total of 509 paediatric patients aged 7 to 17 years with MDD were treated with duloxetine in clinical trials. In general, the adverse reaction profile of duloxetine in children and adolescents was similar to that seen for adults.

 

Three hundred and thirty two paediatric patients initially randomized to duloxetine in clinical trials, experienced a 0.2 kg mean decrease in weight at 10-weeks. Subsequently, over a six-month extension period, most of these patients trended toward recovery to their baseline weight percentile expected based on population data from age- and gender-matched peers (see section 4.4)”.

 

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 UK: www.mhra.gov.uk/yellowcard or Ireland: Pharmacovigilance Section, Irish Medicines Board, Kevin O’Malley House, Earlsfort Centre, Earlsfort Terrace, IRL - Dublin 2, Tel: +353 1 6764971, Fax: +353 1 6762517, www.imb.ie, imbpharmacovigilance@imb.ie.

 

5.       PHARMACOLOGICAL PROPERTIES

 

5.1     Pharmacodynamic properties

 

Added:

 

Duloxetine has not been studied in patients under the age of 7. 

 

Two randomized, double-blind, parallel clinical trials were performed in 800 paediatric patients aged 7 to 17 years with major depressive disorder (see section 4.2). These two studies included a 10 week placebo and active (fluoxetine) controlled acute phase followed by six months period of active controlled extension treatment. Neither duloxetine (30-120 mg) nor the active control arm (fluoxetine 20-40 mg) statistically separated from placebo on change from baseline to endpoint in the Children´s Depression Rating Scale-Revised (CDRS-R) total score. Discontinuation due to adverse events was higher in patients taking duloxetine compared with those treated with fluoxetine, mostly due to nausea. There were no statistically significant differences in suicidal behaviour between duloxetine, fluoxetine, and placebo during the 10-week acute treatment period (duloxetine 0/333 [0%], fluoxetine 2/225 [0.9%], placebo 1/220 [0.5%]). Over the entire 36-week course of the study, for patients initially randomized to active treatment, the exposure adjusted incidence of suicidal behaviours was 0.039 events per patient year [6 out of 333 patients] for duloxetine, and 0.026 events per patient year [3  out of 225 patients] for fluoxetine. In addition, one patient who transitioned from placebo to duloxetine experienced a suicidal behaviour while taking duloxetine.

 

5.2     Pharmacokinetic properties

 

Added:

 

Paediatric population: Pharmacokinetics of duloxetine in paediatric patients aged 7 to 17 years with major depressive disorder following oral administration of 20 to 120 mg once daily dosing regimen was characterized using population modelling analyses based on data from 3 studies. The model-predicted duloxetine steady state plasma concentrations in paediatric patients were mostly within the concentration range observed in adult patients.

 

5.3     Preclinical safety data

 

Added:

 

Studies in juvenile rats reveal transient effects on neurobehaviour, as well as significantly decreased body weight and food consumption; hepatic enzyme induction; and hepatocellular vacuolation at 45 mg/kg/day. The general toxicity profile of duloxetine in juvenile rats was similar to that in adult rats. The no-adverse effect level was determined to be 20 mg/kg/day.

 

 

10.          DATE OF REVISION OF THE TEXT

 

New date of revision:

 

04 July 2013

4.         CLINICAL PARTICULARS

 

4.4       Special warnings and precautions for use

 

Haemorrhage

 

Added (bold):

 

There have been reports of bleeding abnormalities, such as ecchymoses, purpura and gastrointestinal haemorrhage with selective serotonin reuptake inhibitors (SSRIs) and serotonin/noradrenaline reuptake inhibitors (SNRIs), including duloxetine. Caution is advised in patients taking anticoagulants and/or medicinal products known to affect platelet function (e.g. NSAIDs or acetylsalicylic acid (ASA)), and in patients with known bleeding tendencies.

 

Medicinal products containing duloxetine

 

Added (bold)Deleted (strikethrough):

 

Duloxetine is used under different trademarks in several indications (treatment of diabetic neuropathic pain, major depressive disorder, generalised anxiety disorder as well as and stress urinary incontinence).

 

4.5              Interaction with other medicinal products and other forms of interaction

 

Added (bold)Deleted (strikethrough):

 

CNS medicinal products: The risk of using duloxetine in combination with other CNS-active medicinal products has not been systematically evaluated, except in the cases described in this section. Consequently, caution is advised when Cymbalta is taken in combination with other centrally acting medicinal products orand substances, including alcohol and sedative medicinal products (e.g. benzodiazepines, morphinomimetics, antipsychotics, phenobarbital, sedative antihistamines).

 

4.8              Undesirable effects

 

Added (bold)Deleted (strikethrough):

 

b. Tabulated summary of adverse reactions

Table 1 gives the adverse reactions observed from spontaneous reporting and in placebo-controlled clinical trials (comprising a total of 78196828 patients, 48234199 on duloxetine and 29962629 on placebo) in depression, generalised anxiety disorder and diabetic neuropathic pain.

 

Note: table updated in entirety.

 

Added:

 

⁸ Falls were more common in the elderly (≥65 years old)

 

c. Description of selected adverse reactions

 

Added (bold):

 

Discontinuation of duloxetine (particularly when abrupt) commonly leads to withdrawal symptoms. Dizziness, sensory disturbances (including paraesthesia), sleep disturbances (including insomnia and intense dreams), fatigue, somnolence, agitation or anxiety, nausea and/or vomiting, tremor, headache, irritability, diarrhoea, hyperhydrosis and vertigo are the most commonly reported reactions.

 

 

 

10.          DATE OF REVISION OF THE TEXT

 

New date of revision:

 

26 July 2011

*Note: Updated in entirety for QRD template formatting, sections re-ordered & new subheadings introduced throughout SPC

 

 

 

4.             Clinical particulars

 

4.1          Therapeutic indications

 

Deleted (strikethrough):

 

Treatment of diabetic peripheral neuropathic pain in adults.

 

Added:

 

Cymbalta is indicated in adults.

 

For further information see section 5.1.

 

4.4           Special warnings and precautions for use

 

Added (bold) Deleted (strikethrough):

 

Hyponatraemia has been reported when administering Cymbalta, including cases with serum sodium lower than 110 mmol/lbeen reported rarely, predominantly in the elderly, when administering Cymbalta.  Hyponatraemia may be due to a syndrome of inappropriate anti-diuretic hormone secretion (SIADH). The majority of cases of hyponatraemia were reported in the elderly, especially when coupled with a recent history of, or condition pre-disposing to, altered fluid balance. Caution is required in patients at increased risk for hyponatraemia, such as elderly, cirrhotic, or dehydrated patients or patients treated with diuretics. Hyponatraemia may be due to a syndrome of inappropriate anti-diuretic hormone secretion (SIADH).

 

4.8       Undesirable effects

 

Note: Table updated in entirety

 

Added:

 

⁶  Estimated frequency of post-marketing surveillance reported adverse reactions; not observed in placebo-controlled clinical trials.

⁷  Not statistically significantly different from placebo.

 

 

 

5.             PHARMACOLOGICAL PROPERTIES

 

5.1          Pharmacodynamic properties

 

Added:

 

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Cymbalta in all subsets of the paediatric population in the treatment of major depressive disorder, diabetic neuropathic pain and generalised anxiety disorder. See section 4.2 for information on paediatric use.

 

 

 

10.          DATE OF REVISION OF THE TEXT

 

New date of revision:

 

27 January 2011

 

Updated:

 

Detailed information on this medicine is available on the European Medicines Agency (EMA) web site: http://www.ema.europa.eu

4.         CLINICAL PARTICULARS

4.6       Pregnancy and lactation

 

Added (bold):

 

Pregnancy

There are no adequate data on the use of duloxetine in pregnant women. Studies in animals have shown reproductive toxicity at systemic exposure levels (AUC) of duloxetine lower than the maximum clinical exposure (see section 5.3). The potential risk for humans is unknown.

 

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). Although no studies have investigated the association of PPHN to SNRI treatment, this potential risk cannot be ruled out with duloxetine taking into account the related mechanism of action (inhibition of the re-uptake of serotonin).

 

As with other serotonergic medicinal products, discontinuation symptoms may occur in the neonate after maternal duloxetine use near term. Discontinuation symptoms seen with duloxetine may include hypotonia, tremor, jitteriness, feeding difficulty, respiratory distress and seizures.  The majority of cases have occurred either at birth or within a few days of birth.

 

4.8       Undesirable effects

 

Added (bold):

 

Very common	Common	Uncommon	Rare	Very Rare	Frequency not known
Reproductive System and Breast Disorders
	Erectile dysfunction	Ejaculation disorder Ejaculation delayed Sexual dysfunction Gynaecological haemorrhage	Menopausal symptoms Galactorrhoea Hyper-prolactinaemia

 

 

 

10.          DATE OF REVISION OF THE TEXT

 

New date of revision:

 

22 July 2010

Changes

 

Major depressive episodes changed to major depressive disorder throughout SPC text.

 

 

4.         CLINICAL PARTICULARS

 

4.1       Therapeutic indications

 

   Added (bold) deleted (strikethrough):

 

            Treatment of major depressive episodes disorder.

 

 

4.2       Posology and method of administration

           

            Added (bold)

 

            Therapeutic response is usually seen after 2-4 weeks of treatment.

 

After consolidation of the antidepressive response, it is recommended to continue treatment for several months, in order to avoid relapse. In patients responding to duloxetine, and with a history of repeated episodes of major depression, further long-term treatment at a dose of 60 to 120 mg/day could be considered.

 

 

5.         PHARMACOLOGICAL PROPERTIES

 

5.1       Pharmacodynamic properties

 

            Added

         

          During 52 weeks of placebo-controlled double blind treatment, duloxetine-treated patients with recurrent MDD had a significantly longer symptom free period (p<.001) compared with patients randomised to placebo. All patients had previously responded to duloxetine during open-label duloxetine treatment (28 to 34 weeks) at a dose of 60 to 120 mg/day. During the 52-week placebo-controlled double-blind treatment phase, 14.4% of the duloxetine-treated patients and 33.1% of the placebo-treated patients experience a return of their depressive symptoms (p<.001).

 

 

 

10.        DATE OF REVISION OF THE TEXT

 

New date of revision:

 

20 November 2009

Updated in entirety for Renewal.

 

 

 

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

 

Added (bold) deleted (strikethrough):

 

Excipients 30mg: each capsule contains 8.6 mg sucrose 8.6 mg.

 

Excipients 60mg: each capsule contains 17.2 mg sucrose 17.2 mg.

 

 

3.         PHARMACEUTICAL FORM

 

Deleted (strikethrough):

 

The CYMBALTA 30 mg capsule has an o Opaque white body, imprinted with ‘30 mg’ and an opaque blue cap, imprinted with ‘9543’.

 

The CYMBALTA 60 mg capsule has an o Opaque green body, imprinted with ’60 mg’ and an opaque blue cap, imprinted with ‘9542’.

 

 

 

4.         Clinical particulars

 

4.2              Posology and method of administration

 

Deleted:

 

For oral use.

 

Adults

Major depressive episodes:

 

Deleted (strikethrough):

 

Dosages above 60 mg once daily, up to a maximum dose of 120 mg per day administered in evenly divided doses, have been evaluated from a safety perspective in clinical trials.

 

Added:

 

Method of administration

For oral use.

 

Elderly

 

Added (bold) deleted (strikethrough):

 

Major Depressive Episodes: No dosage adjustment is recommended for elderly patients solely on the basis of age. However, as with any medicine, caution should be exercised when treating the elderly, especially with CYMBALTA 120 mg per day for major depressive episodes, for which data are limited (see sections 4.4 and 5.2).

Other Indications: No dosage adjustment is recommended for elderly patients solely on the basis of age. However, caution should be exercised when treating the elderly (see section 5.2).

 

Children and adolescents

 

Added (bold) deleted (strikethrough):

 

Duloxetine is not recommended for use in children and adolescents due to insufficient data on safety and efficacy (see section 4.4)The safety and efficacy of duloxetine in these age groups have not been studied. Therefore, administration of CYMBALTA to children and adolescents is not recommended (see section 4.4).

 

Hepatic impairment

 

Added (bold) deleted (strikethrough):

 

CYMBALTA should must

 

Added (bold) deleted (strikethrough):

 

Renal impairment insufficiency

 

No dosage adjustment is necessary for patients with mild or moderate renal dysfunction (creatinine clearance 30 to 80 ml/min). CYMBALTA must not be used in patients with See section 4.3 for severe renal impairment (creatinine clearance <30 ml/min; see section 4.3).

 

4.4              Special warnings and precautions for use

 

St John’s wort

 

Added (bold) deleted (strikethrough):

 

Undesirable effectsAdverse reactions

 

Elderly

 

Added (bold) deleted (strikethrough):

 

Major Depressive Episodes: Data on the use of CYMBALTA 120mg in elderly patients with major depressive disorders are limited. Therefore, caution should be exercised when treating the elderly with the maximum dosage (see sections 4.2 and 5.2). Data on the use of CYMBALTA in elderly patients with generalised anxiety disorder are limited.

Generalised Anxiety Disorder: Data on the use of CYMBALTA in elderly patients with generalised anxiety disorder are limited.

 

4.5              Interaction with other medicinal products and other forms of interaction

 

Monoamine Oxidase Inhibitors (MAOIs):

 

Added (bold) deleted (strikethrough):

 

due to the risk of serotonin syndrome, CYMBALTA duloxetine should

 

4.8              Undesirable effects

 

Table 1: Adverse reactions

 

Added (bold) deleted (strikethrough):

 

Frequency estimate: rare (³1/10,000 and to <1/1,000)

 

Table revised in entirety

 

Very common		Common		Uncommon	Rare	Very Rare		Frequency not known
Infections and infestations
				Laryngitis
Immune system disorders
					Anaphylactic reaction Hyper-sensitivity disorder
Endocrine disorders
					Hypo-thyroidism
Metabolism and Nutrition Disorders
		Decreased Appetite		Hyperglycemia (reported especially in diabetic patients)	Dehydration Hyponatremia			SIADH
Psychiatric Disorders
	Insomnia Agitation Libido decreased Anxiety Orgasm abnormal Abnormal dreams		Sleep disorder Bruxism Disorientation Apathy		Mania Hallucinations Aggression and anger4				Suicidal ideation 5 Suicidal5 behaviour
Nervous System Disorders
Headache (14.3%) Somnolence (10.7%) Dizziness (10.2%)		Tremor Paraesthesia		Myoclonus Nervousness Disturbance in attention Lethargy Dysgeusia Dyskinesia Restless legs syndrome Poor quality sleep	Convulsions			Serotonin syndrome Extra-pyramidal symptoms Akathisia Psychomotor restlessness
Eye Disorders
		Blurred vision		Mydriasis Visual disturbance	Glaucoma
Ear and Labyrinth Disorders
		Tinnitus1		Vertigo Ear pain
Cardiac Disorders
		Palpitations		Tachycardia Supra-ventricular arrhythmia, mainly atrial fibrillation
Vascular Disorders
		Flushing		Blood pressure increase Peripheral coldness Orthostatic hypotension2 Syncope2				Hypertension Hypertensive crisis
Respiratory, thoracic and mediastinal disorders
		Yawning		Throat tightness Epistaxis
Gastrointestinal Disorders
Nausea (24.3%) Dry mouth (12.8%)		Constipation Diarrhoea Vomiting Dyspepsia Flatulence		Gastroenteritis Eructation Gastritis	Stomatitis Breath odour Haematochezia			Gastrointestinal haemorrhage
Hepato-biliary disorders
				Elevated liver enzymes (ALT, AST, alkaline phosphatase) Hepatitis3 Acute liver injury				Jaundice Hepatic failure
Skin and Subcutaneous Tissue Disorders
		Sweating increased Rash		Night sweats Urticaria Dermatitis contact Cold sweat Photo-sensitivity reactions Increased tendency to bruise				Angio-neurotic oedema Stevens-Johnson Syndrome
Muscoloskeletal and connective tissue disorders
		Musculo-skeletal pain Muscle tightness Muscle spasm		Muscle twitching	Trismus
Renals and Urinary Disorders
				Urinary Retention Dysuria Urinary hesitation Nocturia Polyuria Urine flow decreased	Urine odour abnormal
Reproductive System and Breast Disorders
		Erectile dysfunction		Ejaculation disorder Ejaculation delayed Sexual dysfunction Gynaecological haemorrhage	Menopausal symptoms
General Disorders and Administration Site Conditions
		Fatigue Abdominal pain		Feeling abnormal Feeling cold Thirst Chills Malaise Feeling hot Gait disturbance				Chest pain
Investigations
		Weight decrease		Weight increase Creatine phosphokinase increased	Blood cholesterol increased

4.9              Overdose

 

Added (bold) deleted (strikethrough):

 

Signs and symptoms of overdose (duloxetine alone or in combination with mixedother medicinal products)

 

5.         PHARMACOLOGICAL PROPERTIES

 

5.2                     Pharmacokinetic properties

 

Sub-headings added to each paragraph (bold):

 

Absorption: Duloxetine is well absorbed after oral administration with a C_max occurring 6 hours post dose.

 

Distribution: Duloxetine is approximately 96% bound to human plasma proteins.

 

Biotransformation: Duloxetine is extensively metabolised and the metabolites are excreted principally in urine.

 

Elimination: The elimination half-life of duloxetine ranges from 8 to 17 hours (mean of 12 hours).

 

Special populations:

 

Added (bold) deleted (strikethrough):

 

Nursing Breast-feeding mothers: The disposition of duloxetine was studied in 6 lactating women who were at least 12‑weeks postpartum.

 

 

 

9.         DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

 

Added:

 

Date of latest renewal: 24 June 2009

 

 

 

10.       DATE OF REVISION OF THE TEXT

 

New date of revision:

 

06 July 2009

 

Added:

 

Detailed information on this medicine is available on the European Medicines Agency (EMEA) web site: http://www.emea.europa.eu

 

4.              Clinical particulars

4.8           Undesirable effects

 

Added (bold) deleted (strikethrough):

 

Table 1 gives the adverse reactions observed from spontaneous reporting and in placebo-controlled clinical trials (comprising a total of 8239 6828 patients, 5075 4199 on duloxetine and 3164 2629 on placebo) in depression, generalized anxiety disorder and diabetic neuropathic pain and fibromyalgia.

 

The most commonly reported adverse reactions in patients treated with CYMBALTA were nausea, headache, dry mouth, somnolence, fatigue, insomnia,and dizziness and constipation. However, the majority of common adverse reactions were mild to moderate, they usually started early in therapy, and most tended to subside even as therapy was continued.

 

Table change in entirety - Added (bold) deleted (strikethrough):

 

Very common	Common	Uncommon	Rare	Very Rare	Frequency not known
Investigations
	Weight decrease	Weight increase Creatine phosphokinase increased	Blood cholesterol increased
Cardiac Disorders
	Palpitations	Tachycardia Supra-ventricular arrhythmia, mainly atrial fibrillation	Supra-ventricular arrhythmia, mainly atrial fibrillation
Nervous System Disorders
Headache (1514.3%) Somnolence (10.97%) Dizziness (10.32%)	Tremor Paraesthesia Dysgeusia Lethargy	Myoclonus NervousnessDisturbance in attention Lethargy Dysgeusia Dyskinesia Restless legs syndrome Poor quality sleep	Myoclonus Convulsions1		Serotonin syndrome Extra-pyramidal symptoms Akathisia Psychomotor restlessness
Eye Disorders
	Blurred vision	Mydriasis Visual disturbance	Glaucoma
Ear and Labyrinth Disorders
	Tinnitus1	Vertigo Ear pain
Respiratory, thoracic and mediastinal disorders
	Yawning	Throat tightness Epistaxis
Gastrointestinal Disorders
Nausea (25.224.23%) Dry mouth (1312.8%) Constipation (10.3%)	Constipation Diarrhoea Vomiting Dyspepsia Flatulence	Gastroenteritis Eructation Gastritis Stomatitis	Stomatitis Breath odour Haematochezia		Gastrointestinal haemorrhage
Renal and Urinary Disorders
		Urinary Retention Dysuria Urinary hesitation Nocturia Polyuria Urine flow decreased	Urine odour abnormal
Skin and Subcutaneous Tissue Disorders
	Sweating increased Rash Night sweats	Night sweats Urticaria Dermatitis contact Cold sweat Photo-sensitivity reactions Increased tendency to bruise			Angio-neurotic oedema Stevens-Johnson Syndrome
Musculoskeletal and connective tissue disorders
	Musculo-skeletal pain Muscle tightness Muscle spasm	Muscle twitching	Trismus
Endocrine disorders
			Hypo-thyroidism
Metabolism and Nutrition Disorders
	Decreased Appetite	Hyperglycemi-a (reported especially in diabetic patients)	Dehydration SIADH Hyponatremia		SIADH
Infections and infestations
		Laryngitis
Vascular Disorders
	Flushing	Blood pressure increase Peripheral coldness Orthostatic hypotension2 Syncope2			Hypertension Hypertensive crisis
General Disorders and Administration Site Conditions
Fatigue (10.8%)	Fatigue Abdominal pain Chills	Feeling abnormal Feeling cold Thirst Chills Malaise Feeling hot Gait disturbance			Chest pain
Immune system disorders
		Hyper-sensitivity disorder	Hyper-sensitivity disorder Anaphylactic reaction
Hepato-biliary disorders
		Elevated liver enzymes (ALT, AST, alkaline phosphatase) Hepatitis3 Acute liver injury			Jaundice Hepatic failure
Reproductive System and Breast Disorders
	Erectile dysfunction	Ejaculation disorder Ejaculation delayed Sexual dysfunction Gynaecological haemorrhage	Menopausal symptoms
Psychiatric Disorders
Insomnia (10.4%)	Insomnia Agitation Libido decreased Anxiety Orgasm abnormal Abnormal dreams Sleep disorder	Sleep disorder Bruxism Disorientation Apathy	Mania Hallucinations Aggression and anger4		Suicidal ideation 5 Suicidal5 behaviour

 

Added (bold):

 

¹ Cases of convulsion and cases of tinnitus have also been reported after treatment discontinuation.

 

4.9       Overdose

 

Added (bold) deleted (strikethrough):

 

Cases of overdoses, alone or in combination with other medicinal products, with duloxetine doses of 4800mg5400mg were reported.

 

 

 

10.          DATE OF REVISION OF THE TEXT

 

New date of revision:

 

25 March 2009

4.         Clinical particulars

4.2       Posology and method of administration

 

Diabetic Peripheral Neuropathic Pain:

 

Deleted:

 

The medicinal product response should be evaluated after 2 months of treatment. Additional response after this time is unlikely (see 5.1).

 

Added:

 

Response to treatment should be evaluated after 2 months. In patients with inadequate initial response, additional response after this time is unlikely.

 

Deleted (strikethrough) Added (bold):

 

The therapeutic benefit should be reassessed regularly (at least every three months) be reassessed(see Section 5.1).

 

4.4       Special warnings and precautions for use

 

Haemorrhage

 

Deleted (strikethrough) Added (bold):

 

nor epinephrine adrenaline

 

4.6       Pregnancy and lactation

 

Pregnancy

 

Deleted (strikethrough):

 

As with other serotoninergic medicinal products,

 

 

 

5.         PHARMACOLOGICAL PROPERTIES

 

5.1       Pharmacodynamic properties

 

Deleted:

 

Although data from a one-year open label study offer some evidence for longer-term efficacy, no conclusive efficacy data for treatments longer than 12 weeks duration are available from placebo-controlled studies.

 

Added:

 

In an open label long-term uncontrolled study, the pain reduction in patients responding to 8-weeks of acute treatment of CYMBALTA 60 mg once daily was maintained for a further 6-months as measured by change on the Brief Pain Inventory(BPI) 24-hour average pain item.

 

 

 

6.         PHARMACEUTICAL PARTICULARS

 

6.1       List of excipients

 

Capsule content:

 

Deleted (strikethrough) Added (bold):

 

Hydroxypropyl methylcellulose Hypromellose acetate succinate

 

 

 

10.          DATE OF REVISION OF THE TEXT

 

New date of revision:

 

02 March 2009

4.             Clinical particulars

 

4.1          Therapeutic indications

 

Added:

 

Treatment of generalised anxiety disorder.

 

4.2                Posology and method of administration

 

Added:

 

Generalised Anxiety Disorder:

The recommended starting dose in patients with Generalised Anxiety Disorder is 30 mg once daily

with or without food. In patients with insufficient response the dose should be increased to 60 mg,

which is the usual maintenance dose in most patients.

 

In patients with co-morbid Major Depressive Episodes, the starting and maintenance dose is 60 mg

once daily (please see also dosing recommendation above).

 

Doses up to 120 mg per day have been shown to be efficacious and have been evaluated from a safety

perspective in clinical trials. In patients with insufficient response to 60 mg, escalation up to 90 mg or

120 mg may therefore be considered. Dose escalation should be based upon clinical response and

tolerability.

 

After consolidation of the response, it is recommended to continue treatment for several months, in

order to avoid relapse.

 

Elderly

 

Deleted (strikethrough) Added (bold):

 

Other IndicationsDiabetic Peripheral Neuropathic Pain: No dosage adjustment is recommended for elderly patients solely on the basis of age. However, caution should be exercised when treating the elderly (see section 5.2).

 

4.4                Special warnings and precautions for use

 

Suicide

 

Added:

 

Major Depressive Episodes and Generalised Anxiety Disorder

 

Added:

 

Other psychiatric conditions for which CYMBALTA 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.

 

Elderly

 

Added:

 

Generalised Anxiety Disorder: Data on the use of CYMBALTA in elderly patients with generalised anxiety disorder are limited.

 

Medicinal products containing duloxetine

 

Added (bold):

 

Duloxetine is used under different trademarks in several indications (treatment of diabetic neuropathic pain, major depressive episodes, generalised anxiety disorder as well as stress urinary incontinence).

 

4.6           Pregnancy and lactation

 

Pregnancy

 

Added (bold):

 

There are no adequate data on the use of duloxetine in pregnant women.

 

4.8       Undesirable effects

 

Added (bold):

 

Table 1 gives the adverse reactions observed from spontaneous reporting and in placebo-controlled clinical trials (comprising a total of 8239 patients, 5075 on duloxetine and 3164 on placebo) in depression, generalized anxiety disorder and diabetic neuropathic pain and fibromyalgia.

 

The most commonly reported adverse reactions in patients treated with CYMBALTA were nausea, headache, dry mouth, somnolence, fatigue, insomnia, dizziness and constipation.

 

Table 1: Adverse reactions

 

Table – corrections/re-formatted throughout

 

Changed:

 

⁴Cases of aggression and anger have been reported particularly early in treatment of after treatment discontinuation.

⁵Cases of suicidal ideation and suicidal behaviours have been reported during duloxetine therapy or early after treatment discontinuation (see section 4.4)

 

Added (bold):

 

Discontinuation of duloxetine (particularly when abrupt) commonly leads to withdrawal symptoms. Dizziness, sensory disturbances (including paraesthesia), sleep disturbances (including insomnia and intense dreams), fatigue, agitation or anxiety, nausea and/or vomiting, tremor ,headache, irritability, diarrhoea, hyperhydrosis and vertigo are the most commonly reported reactions.

 

Deleted:

 

Electrocardiograms were obtained from 1139 duloxetine treated patients and 777 placebo-­treated patients in 8-week clinical trials in major depressive disorder, and from 528 duloxetine-treated and 205 placebo-treated patients with diabetic neuropathic pain in clinical trials lasting up to 13-weeks.

 

 

5.         PHARMACOLOGICAL PROPERTIES

 

5.1       Pharmacodynamic properties

Added:

 

Generalised Anxiety Disorder

CYMBALTA demonstrated statistically significant superiority over placebo in five out of five studies including four randomized, double-blind, placebo-controlled acute studies and a relapse prevention study in adult patients with generalised anxiety disorder.

 

CYMBALTA demonstrated statistically significant superiority over placebo as measured by improvement in the Hamilton Anxiety Scale (HAM-A) total score and by the Sheehan Disability Scale (SDS) global functional impairment score. Response and remission rates were also higher with CYMBALTA compared to placebo. CYMBALTA showed comparable efficacy results to venlafaxine in terms of improvements on the HAM-A total score.

 

In a relapse prevention study, patients responding to 6 months of acute treatment with open-­label CYMBALTA were randomised to either CYMBALTA or placebo for further 6-months. CYMBALTA 60 mg to 120 mg once daily demonstrated statistically significant superiority compared to placebo (p<0.001) on the prevention of relapse, as measured by time to relapse. The incidence of relapse during the 6-months double-blind follow-up period was 14% for CYMBALTA and 42% for placebo.

 

Diabetic Peripheral Neuropathic Pain:

 

Changed (bold):

 

The efficacy of CYMBALTA as a treatment for diabetic neuropathic pain was established in 2 randomised, 12-week, double-blind, placebo-controlled, fixed dose studies in adults (22 to 88 years) having diabetic neuropathic pain for at least 6 months. 

 

In both studies, CYMBALTA 60 mg once daily and 60 mg twice daily significantly reduced pain compared with placebo.

 

 

 

10.          DATE OF REVISION OF THE TEXT

 

New date of revision:

 

28 July 2008