Cymbalta 30 mg, 60 mg hard gastro-resistant capsules
*Company:
Eli Lilly and Company (Ireland) LimitedStatus:
No Recent UpdateLegal Category:
Product subject to medical prescription which may not be renewed (A)Active Ingredient(s):
*Additional information is available within the SPC or upon request to the company
Updated on 05 July 2024
File name
Cymbalta_SmPC_Jun24_CYM036_IE-NI-MT.pdf
Reasons for updating
- Change to section 4.4 - Special warnings and precautions for use
- 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)
Updated on 05 July 2024
File name
Cymbalta_PIL_CYM037_Jun24_IE-NI-MT.pdf
Reasons for updating
- Change to section 2 - what you need to know - warnings and precautions
- Change to section 4 - possible side effects
- Change to section 6 - date of revision
- Correction of spelling/typing errors
Updated on 20 January 2023
File name
Cymbalta_SmPC_Jun20_CYM30M_UK-IE.pdf
Reasons for updating
- Document format updated
Legal category:Product subject to medical prescription which may not be renewed (A)
Updated on 24 December 2021
File name
Cymbalta_PIL_CYM031_Dec21_IE-NI-MT.pdf
Reasons for updating
- Change to section 4 - how to report a side effect
- Change to section 6 - marketing authorisation holder
- Change to section 6 - date of revision
Free text change information supplied by the pharmaceutical company
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
Updated on 30 July 2020
File name
Cymbalta_SmPC_Jun20_CYM30M_UK-IE.pdf
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 8 - Marketing authorisation number(s)
- 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
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
Updated on 30 July 2020
File name
Cymbalta_PIL_UK-IE-MT_Jun20.pdf
Reasons for updating
- Change to section 2 - what you need to know - warnings and precautions
- Change to section 6 - date of revision
Free text change information supplied by the pharmaceutical company
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
June 2020July 2019
Updated on 23 August 2019
File name
Cymbalta PIL Jul19.pdf
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
File name
Cymbalta SmPC Jul19 CYM29M UK-IE.pdf
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.
- 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
File name
Cymbalta SmPC Jul19 CYM28M UK-IE.pdf
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
File name
Cymbalta PIL Jun19.pdf
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
File name
Cymbalta SmPC Jun19 CYM27M UK-IE.pdf
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
File name
Cymbalta PIL Nov18.pdf
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
File name
CYMBALTA SmPC UK-IE Nov18 CYM26M.pdf
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 SPC
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 08 February 2017
Reasons for updating
- New SPC for new product
Legal category:Product subject to medical prescription which may not be renewed (A)
Updated on 08 February 2017
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 07 February 2017
File name
PIL_9321_225.pdf
Reasons for updating
- New PIL for new product
Updated on 07 February 2017
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
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
Reasons for updating
- Change to date of revision
- Change to MA holder contact details
Updated on 03 September 2015
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
Reasons for updating
- Change to side-effects
- Change to further information section
- Change to date of revision
Updated on 16 June 2015
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
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 09 May 2014
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
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 05 November 2013
Reasons for updating
- Change to warnings or special precautions for use
- Change to date of revision
Updated on 15 July 2013
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 Somnolence |
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 Dry mouth |
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
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
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 02 August 2011
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
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
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
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 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
Updated on 28 October 2010
Reasons for updating
- Change to information about pregnancy or lactation
- Change to further information section
- Change to date of revision
Updated on 05 October 2010
Reasons for updating
- Change to side-effects
- Change to information about pregnancy or lactation
- Change to further information section
Updated on 12 August 2010
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
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 07 August 2009
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
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 |
|||||||||
|
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Anaphylactic reaction Hyper-sensitivity disorder |
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Endocrine disorders |
|||||||||
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|
|
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 |
|
|
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Ear and Labyrinth Disorders |
|||||||||
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Tinnitus1 |
Vertigo Ear pain |
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|
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Cardiac Disorders |
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|
Palpitations |
Tachycardia Supra-ventricular arrhythmia, mainly atrial fibrillation |
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Vascular Disorders |
|||||||||
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|
Blood pressure increase Peripheral coldness Orthostatic hypotension2 Syncope2 |
|
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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 |
|||||||||
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|
Urinary Retention Dysuria Urinary hesitation Nocturia Polyuria Urine flow decreased |
Urine odour abnormal |
|
|
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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 03 August 2009
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
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 08 April 2009
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 |
|
|
|
Nervous System Disorders |
|||||
Headache ( Somnolence (10. Dizziness (10. |
Tremor Paraesthesia
|
Myoclonus NervousnessDisturbance in attention Lethargy Dysgeusia Dyskinesia Restless legs syndrome Poor quality sleep |
Convulsion |
|
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 ( Dry mouth (
|
Constipation Diarrhoea Vomiting Dyspepsia Flatulence |
Gastroenteritis Eructation Gastritis
|
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 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
Hyponatremia |
|
SIADH |
Infections and infestations |
|||||
|
|
Laryngitis |
|
|
|
Vascular Disorders |
|||||
|
|
Blood pressure increase Peripheral coldness Orthostatic hypotension2 Syncope2 |
|
|
Hypertension Hypertensive crisis |
General Disorders and Administration Site Conditions |
|||||
|
Fatigue Abdominal pain
|
Feeling abnormal Feeling cold Thirst Chills Malaise Feeling hot Gait disturbance |
|
|
Chest pain |
Immune system disorders |
|||||
|
|
|
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 Agitation Libido decreased Anxiety Orgasm abnormal Abnormal dreams
|
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
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
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 08 August 2008
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
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 08 May 2008
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 08 May 2008
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
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
Added (bold):
Store in the original package in order to protect from moisture. Do not store above 30 C.
10. DATE OF REVISION OF THE TEXT
New date of revision:
21 April 2008
Updated on 23 April 2008
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
21 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
Added (bold):
Store in the original package in order to protect from moisture. Do not store above 30 C.
10. DATE OF REVISION OF THE TEXT
New date of revision:
21 April 2008
Updated on 19 September 2007
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 4.9 - Overdose
- Change to section 6.5 - Nature and contents of container
- Change to section 8 - MA number
- 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
Changes in bold text
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 drugs in psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo in patients less than 25 years old. Cases of suicidal thoughts and suicidal behaviours have been reported during duloxetine therapy or early after treatment discontinuation (see section 4.8). Close supervision of patients and in particular those at high risk should accompany drug therapy, especially in early treatment and following dose changes. Patients (and caregivers of patients) should be alerted about the need to monitor for any clinical worsening, suicidal /behaviour or thoughts and unusual changes in behaviour and to seek medical advice immediately if these symptoms present.
Diabetic peripheral neuropathic pain: As with other medicinal products with similar pharmacological action (antidepressants), isolated cases of suicidal ideation and suicidal behaviours have been reported during duloxetine therapy or early after treatment discontinuation. Concerning risk factors risk factors for suicidality in depression, see above. Physicians should encourage patients to report any distressing thoughts or feelings at any time.
4.8 Undesirable effects
Added new adverse reactions in Table 1:
Uncommon - Hyperglycemia (reported especially in diabetic patients)
Uncommon – Epistaxis
Rare – Haematochezia
Frequency not known - Gastro-intestinal haemorrhage
Uncommon - Increased tendency to bruise
Common - Muscle spasm
Uncommon - Gynaecological haemorrhage
New text in bold:
Discontinuation of duloxetine (particularly when abrupt) commonly leads to withdrawal symptoms. Dizziness, sensory disturbances (including paraesthesia), sleep disturbances (including insomnia and intense dreams), agitation or anxiety, nausea and/or vomiting, tremor, headache, irritability, diarrhoea, hyperhydrosis and vertigo are the most commonly reported reactions.
4.9 Overdose
Changes in bold text
Cases of overdoses, alone or in combination with other drugs, with duloxetine doses of 4800mg were reported.
6. PHARMACEUTICAL PARTICULARS
6.5 Nature and contents of container
30mg: Added a new pack size of 98 capsules.
60mg: Added 2 new pack sizes of 100 and 500 capsules.
8. MARKETING AUTHORISATION NUMBERS
Added new marketing authorisation numbers due to new pack sizes
60mg, 100 capsules: EU/1/04/296/008
60mg, 500 capsules: EU/1/04/296/007
30mg, 98 capsules: EU/1/04/296/009
10. DATE OF REVISION OF THE TEXT
New date of revision:
28 August 2007
Updated on 19 September 2007
Reasons for updating
- Change to warnings or special precautions for use
- Change to side-effects
- Change to instructions about overdose
- Change due to harmonisation of patient information leaflet
- Change to date of revision
Updated on 22 December 2006
Reasons for updating
- Change to warnings or special precautions for use
- Change of contraindications
- Change to side-effects
- Change to date of revision
Updated on 14 December 2006
Reasons for updating
- Change to section 4.3 - Contraindications
- 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 4.8 - 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
4.3 Contra-indications
Added:
The initiation of treatment with Cymbalta is contra-indicated in patients with uncontrolled hypertension that could expose patients to a potential risk of hypertensive crisis (see sections 4.4 and 4.8).
4.4 Special warnings and precautions for use
Added (new text in bold):
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 drugs 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).
Deleted (text removed crossed through):
Akathisia/Psychomotor Restlessness
The use of duloxetine has been associated with the development of akathisia, characterised by a subjectively unpleasant or distressing restlessness and need to move, often accompanied by an inability to sit or stand still. This is most likely to occur within the first few weeks of treatment. In patients who develop these symptoms, increasing the dose may be detrimental and it may be necessary to review the use of duloxetine.
4.5 Interaction with other medicinal products and other forms of interaction
Re-worded - added new text in bold, deleted text removed crossed through:
Effect of Duloxetine on Other Drugs
Medicinal products metabolised by CYP1A2: In a clinical study, the pharmacokinetics of theophylline, a CYP1A2 substrate, were not significantly affected by co-administration with duloxetine (60mg twice daily). The study was performed in males and it cannot be excluded that females having a lower CYP1A2 activity and higher plasma concentrations of duloxetine may experience an interaction with a CYP1A2 substrate.
Medicinal products metabolised by CYP2D6: Duloxetine is a moderate inhibitor of CYP2D6. When duloxetine was administered at a dose of 60mg twice daily with a single dose of desipramine, a CYP2D6 substrate, the AUC of desipramine increased 3-fold. The co-administration of duloxetine (40mg twice daily) increases steady-state AUC of tolterodine (2mg twice daily) by 71%, but does not affect the pharmacokinetics of its active 5-hydroxyl metabolite and no dosage adjustment is recommended. Caution is advised if Cymbalta is co-administered with medicinal products that are predominantly metabolised by CYP2D6 (risperidone, tricyclic antidepressants [TCAs], such as nortriptyline, amitriptyline, and imipramine), particularly if they have a narrow therapeutic index (such as flecainide, propafenone, and metoprolol).
Anticoagulants and antiplatelet agents: Caution should be exercised when duloxetine is combined with oral anticoagulants or antiplatelet agents due to a potential increased risk of bleeding. Furthermore, increases in INR values have been reported when duloxetine was co-administered with warfarin.
Deleted:
Warfarin and INR: Increases in INR have been reported when duloxetine was co-administered with warfarin.
4.6 Pregnancy and lactation
Added (new text in bold):
Duloxetine is very weakly excreted into human milk, based on a study of 6 lactating patients who did not breast-feed their children.
4.8 Undesirable effects
Added (new text in bold):
Table 1 gives the adverse reactions observed from spontaneous reporting and in placebo-controlled clinical trials (comprising a total of 4,926 patients, 3,127 on duloxetine and 1,799 on placebo) in depression and diabetic neuropathic pain.
The most commonly reported adverse reactions in patients with depression treated with Cymbalta were nausea, dry mouth, headache, and constipation diarrhoea.
Added to Table 1 or moved:
Very Common
Somnolence (moved from common)
Common
Orgasm abnormal
Agitation (moved from uncommon)
Abnormal dreams
Paraesthesia
Constipation
Flatulence
Rash
Musculoskeletal pain
Muscle tightness
Abdominal pain
Uncommon
Laryngitis
Hypersensitivity disorder
Apathy
Disturbance in attention
Myoclonus
Dyskinesia
Ear pain
Orthostatic hypotension
Syncope (moved from frequency unknown)
Throat tightness
Gastritis
Elevated liver enzymes (ALT, AST, alkaline phosphatase) (moved from common)
Cold sweat
Dysuria
Ejaculation disorder (moved from common)
Ejaculation delayed
Feeling cold
Chills
Rare
Hypothyroidism
Dehydration (moved from uncommon)
Mania
Glaucoma (moved from frequency unknown)
Halitosis
Trismus
Menopausal symptoms
Blood cholesterol increased
Frequency Not Known
Supraventricular arrhythmia, mainly atrial fibrillation
Hypertensive crisis
Hepatic failure
Urine odour abnormal
4.9 Overdose
Fatalities have been very rarely reported, primarily with mixed overdoses, but also with duloxetine alone at a dose of approximately 1000mg.
Replaced by:
Some fatalities have occurred, primarily with mixed overdoses but also with duloxetine alone, at a dose of approximately 1000mg.
10. DATE OF REVISION OF THE TEXT
New date of revision:
24 November 2006
Updated on 14 July 2006
Reasons for updating
- Change to section 2 - Qualitative and quantitative composition
- Change to section 4.2 - Posology and method of administration
- Change to section 4.4 - Special warnings and precautions for use
- Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
- Change to section 4.6 - Pregnancy and lactation
- Change to section 4.8 - Undesirable effects
- Change to section 4.9 - Overdose
- 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
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Added:
Excipients: Sucrose.
4. CLINICAL PARTICULARS
4.2 Posology and method of administration
Deleted:
When discontinuing Cymbalta after more than 1 week of therapy, it is generally recommended that the dose be tapered over no less than 2 weeks before discontinuation in an effort to decrease the risk of discontinuation symptoms. As a general recommendation, the dose should be reduced by half or administered on alternate days during this period. The precise regimen followed should, however, take into account the individual circumstances of the patient, such as duration of treatment, dose at discontinuation, etc.
Replaced by:
Discontinuation of Treatment
Abrupt discontinuation should be avoided. When stopping treatment with Cymbalta the dose should be gradually reduced over a period of at least one to two weeks in order to reduce the risk of withdrawal reactions (see sections 4.4 and 4.8). If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose, but at a more gradual rate.
4.4 Special warnings and precautions for use
Added (new text in bold):
Blood Pressure and Heart Rate
Duloxetine is associated with an increase in blood pressure in some patients. This may be due to the noradrenergic effect of duloxetine. In patients with known hypertension and/or other cardiac disease, blood pressure monitoring is recommended as appropriate, especially at the beginning 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.
Deleted:
Discontinuation of Treatment
Some patients may experience symptoms on discontinuation of Cymbalta, particularly if treatment is stopped abruptly (see sections 4.2 and 4.8).
Replaced by:
Discontinuation of Treatment
Withdrawal symptoms when treatment is discontinued are common, particularly if discontinuation is abrupt (see section 4.8). In clinical trials, adverse events seen on abrupt treatment discontinuation occurred in approximately 45% of patients treated with Cymbalta and 23% of patients taking placebo.
The risk of withdrawal symptoms seen with SSRIs and SNRIs may be dependent on several factors, including the duration and dose of therapy and the rate of dose reduction. The most commonly reported reactions are listed in section 4.8. Generally, these symptoms are mild to moderate, however, in some patients they may be severe in intensity. They usually occur within the first few days of discontinuing treatment, but there have been very rare reports of such symptoms in patients who have inadvertently missed a dose. Generally, these symptoms are self-limiting and usually resolve within 2 weeks, though in some individuals they may be prolonged (2-3 months or more). It is therefore advised that duloxetine should be gradually tapered when discontinuing treatment over a period of no less than 2 weeks, according to the patient’s needs (see section 4.2).
Added:
Akathisia/Psychomotor Restlessness
The use of duloxetine has been associated with the development of akathisia, characterised by a subjectively unpleasant or distressing restlessness and need to move, often accompanied by an inability to sit or stand still. This is most likely to occur within the first few weeks of treatment. In patients who develop these symptoms, increasing the dose may be detrimental and it may be necessary to review the use of duloxetine.
4.5 Interactions with other medicinal products and other forms of interaction
Added (new text in bold):
Medicinal products metabolised by CYP2D6: The co-administration of duloxetine (40mg twice daily) increases steady-state AUC of tolterodine (2mg twice daily) by 71%, but does not affect the pharmacokinetics of its active 5-hydroxyl metabolite and no dosage adjustment is recommended. Caution is advised if Cymbalta is co-administered with medicinal products that are predominantly metabolised by CYP2D6 if they have a narrow therapeutic index (such as flecainide, propafenone, and metoprolol).
Added:
Warfarin and INR: Increases in INR have been reported when duloxetine was co-administered with warfarin.
4.6 Pregnancy and lactation
Added (new text in bold):
Breast-Feeding
Duloxetine is excreted into the milk of lactating women. The estimated daily infant dose on a mg/kg basis is approximately 0.14% of the maternal dose (see section 5.2). Adverse behavioural effects were seen in offspring in a perinatal/postnatal toxicity study in rats (see section 5.3). As the safety of duloxetine in infants is not known, the use of Cymbalta while breast-feeding is not recommended.
4.8 Undesirable effects
Added (Nervous system disorders, frequency not known):
Akathisia
Psychomotor restlessness
Added (Psychiatric disorders, frequency not known):
Hallucinations
Added (Vascular disorders, frequency not known):
Hypertension
Added (General disorders and administration site conditions, frequency not known):
Chest pain
Deleted:
Discontinuation symptoms have been reported when stopping Cymbalta. Common symptoms, particularly on abrupt discontinuation, include dizziness, nausea, insomnia, headache, and anxiety (see sections 4.2 and 4.4).
Replaced by:
Discontinuation of duloxetine (particularly when abrupt) commonly leads to withdrawal symptoms. Dizziness, sensory disturbances (including paraesthesia), sleep disturbances (including insomnia and intense dreams), agitation or anxiety, nausea and/or vomiting, tremor, and headache are the most commonly reported reactions.
Generally, for SSRIs and SNRIs, these events are mild to moderate and self-limiting, however, in some patients they may be severe and/or prolonged. It is therefore advised that when duloxetine treatment is no longer required, gradual discontinuation by dose tapering should be carried out (see sections 4.2 and 4.4).
Deleted:
In clinical trials of duloxetine in patients with diabetic neuropathic pain, small but statistically significant increases in fasting blood glucose were observed in duloxetine-treated patients compared to placebo at 12 weeks and routine care at 52 weeks. The increase was similar at both time points and was not considered clinically relevant. Relative to placebo or routine care, mean HbA1c values were stable, there was no mean weight gain, mean lipid concentrations (cholesterol, LDL, HDL, triglycerides) were stable, and there were no differences in incidence of serious and non-serious diabetes-related adverse reactions.
Replaced by:
In the 12-week acute phase of three clinical trials of duloxetine in patients with diabetic neuropathic pain, small but statistically significant increases in fasting blood glucose were observed in duloxetine-treated patients. HbA1c was stable in both duloxetine-treated and placebo-treated patients. In the extension phase of these studies, which lasted up to 52 weeks, there was an increase in HbA1c in both the duloxetine and routine care groups, but the mean increase was 0.3% greater in the duloxetine-treated group. There was also a small increase in fasting blood glucose and in total cholesterol in duloxetine-treated patients, while those laboratory tests showed a slight decrease in the routine care group.
4.9 Overdose
Deleted:
There is limited clinical experience with duloxetine overdose in humans. In pre-marketing clinical trials, no cases of fatal overdose of duloxetine have been reported. Cases of acute ingestions up to 1400mg, alone or in combination with other medicinal products, have been reported.
No specific antidote is known for duloxetine.
Replaced by:
There is limited clinical experience with duloxetine overdose in humans. Cases of overdoses, alone or in combination with other drugs, with duloxetine doses of almost 2000mg were reported. Fatalities have been very rarely reported, primarily with mixed overdoses, but also with duloxetine alone at a dose of approximately 1000mg. Signs and symptoms of overdose (mostly with mixed drugs) included serotonin syndrome, somnolence, vomiting, and seizures.
No specific antidote is known for duloxetine but if serotonin syndrome ensues, specific treatment (such as with cyproheptadine and/or temperature control) may be considered.
5. PHARMACOLOGICAL PROPERTIES
5.2 Pharmacokinetic properties
Added:
Nursing mothers: The disposition of duloxetine was studied in 6 lactating women who were at least 12 weeks postpartum. Duloxetine is detected in breast milk, and steady-state concentrations in breast milk are about one-fourth those in plasma. The amount of duloxetine in breast milk is approximately 7µg/day while on 40mg twice daily dosing. Lactation did not influence duloxetine pharmacokinetics.
10. DATE OF REVISION OF THE TEXT
New date of revision:
31 May 2006
Updated on 22 June 2006
Reasons for updating
- Change to warnings or special precautions for use
- Change to side-effects
- Change to date of revision
Updated on 04 May 2006
Reasons for updating
- Change to section 4.4 - Special warnings and precautions for use
- Change to section 4.7 - Effects on ability to drive and use machines
- 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)
Updated on 15 November 2005
Reasons for updating
- Change to, or new use for medicine
- Change to warnings or special precautions for use
- Change to side-effects
Updated on 08 November 2005
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)
Updated on 11 August 2005
Reasons for updating
- Change to section 4.1 - Therapeutic indications
- Change to section 4.2 - Posology and method of administration
- Change to section 4.4 - Special warnings and precautions for use
- Change to section 4.8 - Undesirable effects
- Change to section 5.1 - Pharmacodynamic properties
- Change to section 6.5 - Nature and contents of container
- Change to section 8 - MA number
- 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 03 February 2005
Reasons for updating
- New PIL for new product
Updated on 14 January 2005
Reasons for updating
- New SPC for new product
Legal category:Product subject to medical prescription which may not be renewed (A)