Cymbalta

  • Name:

    Cymbalta

  • Company:
    info
  • Active Ingredients:

    duloxetine hydrochloride

  • Legal Category:

    Product subject to medical prescription which may not be renewed (A)

Patient Information Leaflet Patient Information Leaflet last updated on medicines.ie: 23/08/19

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Summary of Product Characteristics last updated on medicines.ie: 23/8/2019

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Eli Lilly and Company (Ireland) Limited

Eli Lilly and Company (Ireland) Limited

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1 - 0 of 41 items.Total: Infinity pages

When a pharmaceutical company changes any document, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.

Updated on 23 August 2019 PIL

Reasons for updating

  • Change to section 2 - what you need to know - warnings and precautions
  • Change to section 2 - pregnancy, breast feeding and fertility
  • Change to section 4 - possible side effects
  • Change to section 4 - how to report a side effect
  • Change to section 6 - date of revision

Updated on 23 August 2019 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

[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.

 

  1. 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

 

 

Updated on 24 July 2019 SmPC

Reasons for updating

  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

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

 

 

Updated on 28 June 2019 PIL

Reasons for updating

  • Change to section 2 - what you need to know - warnings and precautions
  • Change to section 6 - date of revision

Updated on 28 June 2019 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

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

Updated on 29 November 2018 PIL

Reasons for updating

  • Change to section 4 - possible side effects
  • Change to section 4 - how to report a side effect
  • Change to section 6 - date of revision

Updated on 28 November 2018 SmPC

Reasons for updating

  • Change to section 4.8 - Undesirable effects
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 10 - Date of revision of the text
  • Improved presentation of SmPC

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

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

Updated on 8 February 2017 SmPC

Reasons for updating

  • New SmPC for new product

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 8 February 2017 SmPC

Reasons for updating

  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 6.5 - Nature and contents of container
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

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

 

Updated on 7 February 2017 PIL

Reasons for updating

  • New PIL for new product

Updated on 7 February 2017 PIL

Reasons for updating

  • Change to section 6 - what the product looks like and pack contents
  • Change to section 6 - date of revision

Updated on 15 January 2016 SmPC

Reasons for updating

  • Change to section 7 - Marketing authorisation holder
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

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

Updated on 11 January 2016 PIL

Reasons for updating

  • Change to date of revision
  • Change to MA holder contact details

Updated on 3 September 2015 SmPC

Reasons for updating

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

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

Updated on 27 August 2015 PIL

Reasons for updating

  • Change to side-effects
  • Change to further information section
  • Change to date of revision

Updated on 16 June 2015 SmPC

Reasons for updating

  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

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

Updated on 30 July 2014 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.8 - Undesirable effects
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

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

Updated on 9 May 2014 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

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

Updated on 12 November 2013 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

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.

Updated on 5 November 2013 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change to date of revision

Updated on 15 July 2013 SmPC

Reasons for updating

  • Change to section 5.3 - Preclinical safety data
  • Change to section 10 - Date of revision of the text
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 2 - Qualitative and quantitative composition

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

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

Updated on 11 July 2013 PIL

Reasons for updating

  • Change to side-effects
  • Change to information about pregnancy or lactation
  • Change to how the medicine works
  • Change to date of revision

Updated on 2 August 2011 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

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

Updated on 29 July 2011 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change to side-effects
  • Change to further information section
  • Change to date of revision

Updated on 14 February 2011 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change to side-effects
  • Change to drug interactions
  • Change to further information section
  • Change to date of revision

Updated on 11 February 2011 SmPC

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

*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 CymbaltaHyponatraemia 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

Updated on 28 October 2010 PIL

Reasons for updating

  • Change to information about pregnancy or lactation
  • Change to further information section
  • Change to date of revision

Updated on 5 October 2010 PIL

Reasons for updating

  • Change to side-effects
  • Change to information about pregnancy or lactation
  • Change to further information section

Updated on 12 August 2010 SmPC

Reasons for updating

  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

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

Updated on 11 December 2009 SmPC

Reasons for updating

  • Change to section 4 - Clinical particulars
  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 5 - Pharmacological properties
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

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 on 7 August 2009 SmPC

Reasons for updating

  • Change to section 9 - Date of renewal of authorisation
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.8 - Undesirable effects
  • Change to section 4.9 - Overdose
  • Change to section 10 - Date of revision of the text
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 3 - Pharmaceutical form
  • Change to section 4.2 - Posology and method of administration

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

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 Cmax 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

Updated on 3 August 2009 PIL

Reasons for updating

  • Change to instructions about overdose
  • Change to storage instructions
  • Change to side-effects
  • Change to date of revision

Updated on 24 April 2009 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change to side-effects
  • Change to further information section
  • Change to date of revision

Updated on 8 April 2009 SmPC

Reasons for updating

  • Change to section 4.8 - Undesirable effects
  • Change to section 4.9 - Overdose
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

 

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

Updated on 16 March 2009 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 6.1 - List of excipients
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

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

Updated on 11 March 2009 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 6.1 - List of excipients
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 8 August 2008 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change to side-effects
  • Change to information about pregnancy or lactation
  • Change to date of revision
  • Changes to therapeutic indications
  • Change to dosage and administration

Updated on 31 July 2008 SmPC

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

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

Updated on 8 May 2008 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change to side-effects
  • Change to storage instructions
  • Change to further information section
  • Change to date of revision

Updated on 8 May 2008 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change to storage instructions
  • Change to side-effects
  • Change to further information section
  • Change to date of revision

Updated on 25 April 2008 SmPC

Reasons for updating

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.7 - Effects on ability to drive and use machines
  • Change to section 4.8 - Undesirable effects
  • Change to section 4.9 - Overdose
  • Change to section 6.1 - List of excipients
  • Change to section 6.4 - Special precautions for storage
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

 

Deleted:

 

The active ingredient in CYMBALTA is duloxetine.

 

Added:

 

Each capsule contains 30 mg of duloxetine (as hydrochloride)

 

Excipients: sucrose 8.6 mg.

 

 

 

4.         CLINICAL PARTICULARS

 

4.4           Special warnings and precautions for use


Changed (bold text):

 

Blood pressure and heart rate

Duloxetine has been associated with an increase in blood pressure and clinically significant hypertension in some patients. This may be due to the noradrenergic effect of duloxetine. Cases of hypertensive crisis have been reported with duloxetine, especially in patients with pre-existing hypertension. Therefore,in patients with known hypertension and/or other cardiac disease, blood pressure monitoring is recommended, especially during the first month of treatment. Duloxetine should be used with caution in patients whose conditions could be compromised by an increased heart rate or by an increase in blood pressure. Caution should also be exercised when duloxetine is used with medicinal products that may impair its metabolism (see section 4.5). For patients who experience a sustained increase in blood pressure while receiving duloxetine either dose reduction or gradual discontinuation should be considered (see section 4.8). In patients with uncontrolled hypertension duloxetine should not be initiated (see section 4.3).

 

Suicide

Major Depressive Episodes

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

 

Hepatitis/increased liver enzymes

Cases of liver injury, including severe elevations of liver enzymes (>10 times upper limit of normal), hepatitis and jaundice have been reported with duloxetine (see section 4.8). Most of them occurred during the first months of treatment. The pattern of liver damage was predominantly hepatocellular. Duloxetine should be used with caution in patients treated with other medicinal products associated with hepatic injury.

 

 

Moved (end of section 4.4):

 

Sucrose

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

4.5       Interaction with other medicinal products and other forms of interaction

 

Subheadings changed (bold):

 

Effect of duloxetine on other medicinal products

 

Effects of other medicinal products on duloxetine

 

4.6       Pregnancy and lactation

 

The potential risk for humans is unknown. As with other serotoninergic medicinal products, discontinuation symptoms may occur in the neonate after maternal duloxetine use near term. CYMBALTA should be used in pregnancy only if the potential benefit justifies the potential risk to the foetus. Women should be advised to notify their physician if they become pregnant, or intend to become pregnant, during therapy.

 

4.7       Effects on ability to drive and use machines

 

Added:

 

No studies on the effects on the ability to drive and use machines have been performed. CYMBALTA may be associated with sedation and dizziness. Patients should be instructed that if they experience sedation or dizziness they should avoid potentially hazardous tasks such as driving or operating machinery.

 

Deleted:

 

Although in controlled studies duloxetine has not been shown to impair psychomotor performance, cognitive function, or memory, it may be associated with sedation and dizziness. Patients should be cautioned about their ability to drive a car or operate hazardous machinery.

 

4.8       Undesirable effects

 

Changed (bold - strikethrough deleted):

 

Table 1 gives the adverse reactions observed from spontaneous reporting and in placebo-controlled clinical trials (comprising a total of 5253 4926 patients, 3289 3127 on duloxetine and 1964 1799 on placebo) in depression and diabetic neuropathic pain.

 

The most commonly reported adverse reactions in patients with depression treated with CYMBALTA were nausea, headache, dry mouth, somnolence headache and diarrhoea. 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 1: Adverse reactions

Frequency estimate: Very common (³1/10), common (³1/100 to <1/10), uncommon (³1/1,000 to <1/100), rare (³1/10,000 and <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.

 

 

NEW TABLE

 

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

2Cases of orthostatic hypotension and syncope have been reported especially at the initiation of treatment.

3See section 4.4

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

 

 

 

4.9       Overdose

 

Changed:

 

There is limited clinical experience with duloxetine overdose in humans. Cases of overdoses, alone or in combination with other medicinal products, with duloxetine doses of 4800mg were reported. Some fatalities have occurred, primarily with mixed overdoses, but also with duloxetine alone at a dose of approximately 1000 mg. Signs and symptoms of overdose (duloxetine alone or  with mixed medicinal products) included somnolence, coma, serotonin syndrome, seizures, , vomiting andtachycardia. 

 

 

 

6.         PHARMACEUTICAL PARTICULARS

 

6.1       List of excipients

 

Deleted:

 

Capsule Shell Cap colour:

30 mg: Opaque Blue

 

Capsule Shell Body colour:

30 mg: Opaque White

 

6.4       Special precautions for storage