Yentreve 20 mg, 40 mg hard gastro-resistant capsules

4.       Possible side effects

…

If you get any side effects, talk to your doctor of pharmacist. This includes any possible side effects not listed in this leaflet.  You can also report side effects directly via Ireland: HPRA Pharmacovigilance; website: www.hpra.ie, 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

 

 

This leaflet was last revised in June 2020December 2021.

YEN024

 

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)

 

20mg, 28 capsules:                             EU/1/04/280/007

20mg, 56 capsules:                             EU/1/04/280/001

20mg, 98 capsules:                             EU/1/04/280/008

40mg, 28 capsules:                             EU/1/04/280/002

40mg, 56 capsules:                             EU/1/04/280/003

40mg, 98 capsules:                             EU/1/04/280/004

40mg, 140 capsules:                           EU/1/04/280/005

40mg, 98 x 2 capsules:                      EU/1/04/280/006

 

EU/1/04/280/001

EU/1/04/280/002

EU/1/04/280/003

EU/1/04/280/004

EU/1/04/280/005

EU/1/04/280/006

EU/1/04/280/007

EU/1/04/280/008

 

 

10.          DATE OF REVISION OF THE TEXT

 

25 July 201911 June 2020

 

2.       What you need to know before you take YENTREVE

 

Pregnancy and breast-feeding

 

• Available data from the use of YENTREVE during the first three months of pregnancy do not show an increased risk of overall birth defects in general in the child. If YENTREVE 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 YENTREVE in the second half of pregnancy), mostly between weeks 35 and 36 of pregnancy.
   
   
   

YENTREVE 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

 

This leaflet was last revised in July 2019June 2020.

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

 

4.4      Special warnings and precautions for use

 

Haemorrhage

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

 

Sucrose

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

 

4.6          Fertility, pregnancy and lactation

 

Pregnancy

 

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

 

4. Undesirable effects

 

Table 1: Adverse reactions

 

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

 

 

 

10.          DATE OF REVISION OF THE TEXT

 

24 June25 July 2019

 

 

YEN212M

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

 

YENTREVE^®                                             

duloxetine (as hydrochloride)

1.             NAME OF THE MEDICINAL PRODUCT

YENTREVE* 20 mg and 40 mg hard gastro-resistant capsules.

4.2          Posology and method of administration

Posology

Some patients may benefit from starting treatment at a dose of 20 mg twice daily for two weeks before increasing to the recommended dose of 40mg twice daily. Dose escalation may decrease, though not eliminate, the risk of nausea and dizziness.

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.

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

*YENTREVE (duloxetine) is a trademark of Eli Lilly and Company

Changes

Added (bold), Deleted (strikethrough):

 

 

 

7.       MARKETING AUTHORISATION HOLDER

 
Eli Lilly Nederland B.V., Grootslag 1‑5 NL‑3991 RA, HoutenPapendorpseweg 83, 3528 BJ Utrecht, The Netherlands

 

 

10.     DATE OF REVISION OF THE TEXT

 

09 July 201501 January 2016

Changes

Added (bold), Deleted (strikethrough):

 

2.       QUALITATIVE AND QUANTITATIVE COMPOSITION

 

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

 

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

 

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

 

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

 

For the full list of excipients, see section 6.1.

 

4.       CLINICAL PARTICULARS

 

4.8     Undesirable effects

b. Tabulated summary of adverse reactions

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

 

Added (bold):

 

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

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

⁹ Estimated frequency based on all clinical trial data.

5.         PHARMACOLOGICAL PROPERTIES

 

5.2     Pharmacokinetic properties

 

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

 

10.       DATE OF REVISION OF THE TEXT

 

New date of revision:

 

09 July 2015

4.       CLINICAL PARTICULARS

4.8     Undesirable effects

 

b. Tabulated summary of adverse reactions

 

Added (bold), Deleted (strikethrough):

 

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

 

Added (bold):

 

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

 

 

 

10.       DATE OF REVISION OF THE TEXT

 

New date of revision:

 

27 May 2015

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 concomitant use of YENTREVE with selective, reversible MAOIs, like moclobemide, is not recommended (see section 4.4). The antibiotic linezolid is a reversible non-selective MAOI and should not be given to patients treated with YENTREVE (see section 4.4).'
And the section on Serotinergic agents has been updated.

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

Changes made throughout SPC due to QRD template changes.

 

 

2.       QUALITATIVE AND QUANTITATIVE COMPOSITION

 

Added (bold):

 

Excipient(s) with known effect 20mg: Each capsule contains 5.7mg 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

 

Added :

Paediatric population

 

The safety and efficacy of duloxetine for the treatment of stress urinary incontinence has not been studied. No data are available.

 

Special populations

 

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. YENTREVE 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.  In addition, long-term safety data in children and adolescents concerning growth, maturation and cognitive and behavioural development are lacking.

 

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):

 

Gastrointestinal disorders
Nausea (22.8%) Dry mouth (12.1%) Constipation (10.3%)	Diarrhoea Abdominal pain Vomiting Dyspepsia	Gastrointestinal haemorrhage7 Gastroenteritis Stomatitis Eructation Gastritis Dysphagia Flatulence Breath odour	Haematochezia

 

Added (bold):

 

Renal and urinary disorders
		Urinary hesitation Dysuria Nocturia Pollakiuia Urine odour abnormal	Urinary retention6 Polyuria Urine flow decreased

 

Deleted (strikethrough):

 

General disorders and administration site conditions
Fatigue (10.9%)	Asthenia Chills	Chest pain7 Falls8 Feeling abnormal Feeling cold Thirst 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:

 

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.

 

5.3     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:

 

 

01 July 2013

4.         CLINICAL PARTICULARS

 

4.4       Special warnings and precautions for use

 

Haemorrhage

 

Added (bold):

 

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

 

Medicinal products containing duloxetine

 

Added (bold)Deleted (strikethrough):

 

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

 

4.8              Undesirable effects

 

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:

 

27 July 2011

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

 

 

 

4.             Clinical particulars

 

4.1          Therapeutic indications

 

Added:

 

Yentreve 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 Yentreve, including cases with serum sodium lower than 110 mmol/lbeen reported rarely, predominantly in the elderly, when administering Yentreve.  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 Yentreve 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:

 

21 January 2011

 

Updated:

 

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

4.         CLINICAL PARTICULARS

4.6       Pregnancy and lactation

 

Added (bold):

 

Pregnancy

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

 

Epidemiological data have suggested that the use of SSRIs in pregnancy, particularly in late pregnancy, may increase the risk of persistent pulmonary hypertension in the newborn (PPHN). Although no studies have investigated the association of PPHN to SNRI treatment, this potential risk cannot be ruled out with duloxetine taking into account the related mechanism of action (inhibition of the re-uptake of serotonin).

 

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

 

4.8       Undesirable effects

 

Added (bold):

 

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

 

 

 

10.          DATE OF REVISION OF THE TEXT

 

New date of revision:

 

22 July 2010

Note: SPC updated in entirety for Renewal.

 

 

 

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

 

Added (bold) deleted (strikethrough):

 

Excipients: each capsule contains 11.5 mg sucrose11.5 mg.

 

 

 

3.         PHARMACEUTICAL form

 

Added (bold) deleted (strikethrough):

 

The capsule has an oOpaque orange body, imprinted with ’40mg’ and an opaque blue cap, imprinted with ‘9545’.

 

 

 

4.         Clinical particulars

4.2           Posology and method of administration

 

Added (bold) deleted (strikethrough):

 

Hepatic insufficiencyimpairment:

YENTREVE should must not be used in women with liver disease resulting in hepatic impairment (see section 4.3).

 

Added (bold) deleted (strikethrough):

 

Renal insufficiencyimpairment:

 

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

 

Added:

 

Method of administration

For oral use.

 

 

 

Children and adolescents:

 

Added (bold) deleted (strikethrough):

 

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

The safety and efficacy of duloxetine in patients in these age groups have not been studied. Therefore, administration of YENTREVE to children and adolescents is not recommended.

 

4.4       Special warnings and precautions for use

 

St John’s wort

 

Added (bold) deleted (strikethrough):

 

Undesirable effectsAdverse reactions may be more common during concomitant use of YENTREVE and herbal preparations containing St John’s wort (Hypericum perforatum).

 

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).

 

4.5       Interaction with other medicinal products and other forms of interaction

 

Anticoagulants and antiplatelet agents:

 

Added (bold):

 

Caution should be exercised when duloxetine is combined with oral anticoagulants or antiplatelet agents due to a potential increased risk of bleeding attributable to a pharmacodynamic interaction. Furthermore, increases in INR values have been reported when duloxetine was co-administered to patients treated with warfarin. However, concomitant administration of duloxetine with warfarin under steady state conditions, in healthy volunteers, as part of a clinical pharmacology study, did not result in a clinically significant change in INR from baseline or in the pharmacokinetics of R- or S-warfarin.

 

4.8           Undesirable effects

 

Table 1: Adverse reactions

 

Table revised in entirety

 

Very common	Common	Uncommon	Rare	Very Rare	Frequency not known
Infections and infestations
		Laryngitis
Immune system disorders
		Hyper-sensitivity disorder	Anaphylactic reaction
Endocrine disorders
		Hypo-thyroidism
Metabolism and Nutrition Disorders
	Appetite decreased	Dehydration	Hyperglycaemia (reported especially in diabetic patients) Hyponatraemia		SIADH
Psychiatric Disorders
	Insomnia Anxiety Sleep disorder Agitation Libido decreased	Disorientation Abnormal dreams Apathy Bruxism Orgasm abnormal	Hallucinations		Suicidal behaviour Suicidal ideation4 Mania Aggression and anger5
Nervous System Disorders
	Headache Dizziness Tremor Lethargy Somnolence Paraesthesia	Poor quality sleep Disturbance in attention Nervousness Dysgeusia	Dyskinesia Myoclonus Restless legs syndrome		Serotonin syndrome Psychomotor  restlessness Convulsions1 Akathisia Extrapyramidal symptoms
Eye Disorders
	Blurred vision	Visual disturbance Mydriasis	Glaucoma
Ear and Labyrinth Disorders
	Vertigo	Tinnitus1 Ear pain
Cardiac Disorders
		Palpitations Tachycardia			Supra-ventricular arrhythmia, mainly atrial fibrillation
Vascular Disorders
	Flushing	Syncope2 Blood pressure increase	Hypertensive crisis Orthostatic hypotension2 Peripheral coldness		Hypertension
Respiratory, thoracic and mediastinal disorders
		Yawning	Epistaxis Throat tightness
Gastrointestinal Disorders
Nausea (22.8%) Dry mouth (12.1%) Constipation (10.3%)	Diarrhoea Vomiting Dyspepsia	Gastroenteritis Stomatitis Gastritis Flatulence Eructation Breath odour	Haematochezia		Gastrointestinal haemorrhage
Hepato-biliary disorders
		Hepatitis3 Elevated liver enzymes (ALT, AST, alkaline phosphatase) Acute liver injury			Hepatic failure Jaundice
Skin and Subcutaneous Tissue Disorders
	Sweating increased	Rash Increased tendency to bruise Night sweats Cold sweat Dermatitis contact Urticaria	Photo-sensitivity reactions		Stevens-Johnson Syndrome Angioneurotic oedema
Musculoskeletal and connective tissue disorders
		Muscle spasm Muscle tightness Musculo-skeletal pain Trismus	Muscle twitching
Renal and Urinary Disorders
		Urinary hesitation Dysuria Nocturia Urine odour abnormal	Urine flow decreased Polyuria		Urinary retention
Reproductive System and Breast Disorders
		Menopausal symptoms Gynaecological haemorrhage
General Disorders and Administration Site Conditions
Fatigue (10.9%)	Abdominal pain Asthenia Chills	Malaise Feeling abnormal Feeling cold Feeling hot Thirst	Gait disturbance		Chest pain
Investigations
		Weight decrease Weight increase Blood cholesterol increased Creatine phosphokinase increased

 

Added (bold) deleted (strikethrough):

 

The heart rate-corrected QT interval in duloxetine-­treated patients did not differ from that seen in placebo-treated patients. No clinically significant differences were observed for QT, PR, QRS, or QTcB measurements between duloxetine-treated and placebo-treated patients. Electrocardiograms were obtained from 755 duloxetine-treated patients with SUI and 779 placebo-treated patients in 12-week clinical trials. The heart rate-corrected QT interval in duloxetine-treated patients did not differ from that seen in placebo-treated patients.

 

4.9           Overdose

 

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

 

 

 

5.         PHARMACOLOGICAL PROPERTIES

5.2       Pharmacokinetic properties

 

Sub-headings added throughout section:

 

Absorption: 

 

Distribution:

 

Biotransformation:

 

Elimination:

 

Added (bold) deleted (strikethrough):

 

Breast-feeding Nursing mothers:

 

 

 

9.       DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

 

Date of first authorisation: 11 August 2004

Date of latest renewal: 24 June 2009

 

 

10.       DATE OF REVISION OF THE TEXT

 

New date of revision:

 

07 July 2009

 

 

Added:

 

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



4.              Clinical particulars

4.8           Undesirable effects

 

Added (bold) deleted (strikethrough):

 

Table 1 gives the adverse reactions observed from spontaneous reporting and in placebo-controlled clinical trials (comprising a total of 79768241 patients, 43704504 on duloxetine and 36063737 on placebo) in SUI and other lower urinary tract disorders.

 

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

 

Very common	Common	Uncommon	Rare	Very Rare	Frequency not known
Investigations
		Weight decrease Weight increase Blood cholesterol increased Creatine phosphokinase increased	Creatine phosphokinase increased
Cardiac Disorders
	Palpitations	Palpitations Tachycardia			Supra-ventricular arrhythmia, mainly atrial fibrillation
Nervous System Disorders
	Headache Dizziness Tremor Lethargy Somnolence Paraesthesia	Poor quality sleep Disturbance in attention Nervousness Dysgeusia	Dyskinesia Myoclonus Restless legs syndrome		Serotonin syndrome Psychomotor  restlessness Convulsions1 Akathisia Extrapyramidal symptoms
Eye Disorders
	Blurred vision	Visual disturbance Mydriasis	Glaucoma
Ear and Labyrinth Disorders
	Vertigo	Tinnitus1 Ear pain
Respiratory, thoracic and mediastinal disorders
		Yawning	Epistaxis Throat tightness
Gastrointestinal Disorders
Nausea (23.322.8%) Dry mouth (11.912.1%) Constipation (10.3%)	Diarrhoea Vomiting Dyspepsia	Gastroenteritis Stomatitis Gastritis Flatulence Eructation Breath odour	Haematochezia		Gastrointestinal haemorrhage
Renal and Urinary Disorders
		Urinary hesitation Dysuria Nocturia Urine odour abnormal	Urine flow decreased Polyuria		Urinary retention
Skin and Subcutaneous Tissue Disorders
	Sweating increased	Rash Increased tendency to bruise Night sweats Cold sweat Dermatitis contact Urticaria	Photo-sensitivity reactions Dermatitis contact Urticaria		Stevens-Johnson Syndrome Angioneurotic oedema
Musculoskeletal and connective tissue disorders
		Muscle spasm Muscle tightness Musculo-skeletal pain Trismus	Muscle twitching
Endocrine disorders
		Hypo-thyroidism
Metabolism and Nutrition Disorders
	Appetite decreased	Dehydration	Hyperglycemia (reported especially in diabetic patients) SIADH Hyponatremia		SIADH
Infections and infestations
		Laryngitis
Vascular Disorders
	Flushing	Syncope2 Blood pressure increase	Hypertensive crisis Orthostatic hypotension2Peripheral coldness		Hypertension
General Disorders and Administration Site Conditions
Fatigue (10.9%)	Abdominal pain Pruritus Weakness Asthenia Chills	Malaise Feeling abnormal Feeling cold Feeling hot Thirst Pruritus	Gait disturbance Feeling cold		Chest pain
Immune system disorders
		Hyper-sensitivity disorder	Anaphylactic reaction
Hepato-biliary disorders
		Hepatitis3 Elevated liver enzymes (ALT, AST, alkaline phosphatase) Acute liver injury			Hepatic failure Jaundice
Reproductive System and Breast Disorders
		Menopausal symptoms Gynaecologica-l haemorrhage
Psychiatric Disorders
	Insomnia Anxiety Sleep disorder Agitation Libido decreased	Disorientation Abnormal dreams Apathy Bruxism Orgasm abnormal	Hallucinations		Suicidal behaviour Suicidal ideation4 Mania Aggression and anger5

 

Added (bold):

 

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

 

4.9       Overdose

 

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:

 

03 April 2009

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

 

Deleted:

 

The active ingredient in YENTREVE is duloxetine.

 

Each capsule contains 40 mg of duloxetine (as duloxetine hydrochloride).

 

 

 

 

4.         Clinical particulars

 

4.3       Contraindications

 

Deleted:

 

Pregnancy and lactation (see section 4.6).

 

4.4       Special warnings and precautions for use

 

Added:

 

St John’s wort

Undesirable effects may be more common during concomitant use of YENTREVE and herbal preparations containing St John’s wort (Hypericum perforatum).

 

Added (bold) deleted (strikethrough):

 

Blood pressure and heart rate

………..Caution should also be exercised when duloxetine is used with drugs medicinal products that may impair its metabolism (see section 4.5).

 

Depression, suicidal ideation and behaviour

………. A meta-analysis of placebo-controlled clinical trials of antidepressants drugs 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

……… The pattern of liver damage was predominantly hepatocellular. Duloxetine should be used with caution in patients treated with other drugs medicinal products associated with hepatic injury.

 

Moved to end of section 4.4:

 

Sucrose

YENTREVE 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

 

Added (bold) deleted (strikethrough):

 

CNS drugsmedicinal products: caution is advised when YENTREVE is taken in combination with other centrally acting drugs medicinal product or substances, including alcohol and sedative drugs medicinal product (benzodiazepines, morphinomimetics, antipsychotics, phenobarbital, sedative antihistamines).

 

Effect of duloxetine on other drugs medicinal products

 

Oral contraceptives and other steroidal agents: …….Specific in vivo drug medicinal product interaction studies have not been performed.

 

Effects of other drugs medicinal products on duloxetine

 

4.6       Pregnancy and lactation

 

Pregnancy

There are no 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. Withdrawal symptoms may occur in the neonate after maternal duloxetine use near term. YENTREVE is contraindicated during pregnancy (see section 4.3). As with other serotoninergic medicinal products, discontinuation symptoms may occur in the neonate after maternal duloxetine use near term. YENTREVE 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. YENTREVE 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. Therefore, patients should be cautioned about their ability to drive a car or operate hazardous machinery.

 

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 7977 7976 patients, 4371 4370 on duloxetine and 3606 on placebo) in SUI and other lower urinary tract disorders.

The most commonly reported adverse events in patients treated with YENTREVE in clinical trials in SUI and other lower urinary tract disorders were nausea, dry mouth and fatigue and constipation.

 

Added/changed:

 

Table 1: Adverse reactions

Frequency are defined as: 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

⁴Cases 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

 

Added (bold) deleted (strikethrough):

 

There is limited clinical experience with duloxetine overdose in humans. Cases of overdoses, alone or in combination with other drugsmedicinal 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 ormostly with mixed drugsmedicinal products) included somnolence, coma, serotonin syndrome, seizures, somnolence, vomiting and tachycardia seizures.  

 

 

 

6.         PHARMACEUTICAL PARTICULARS

 

6.1       List of excipients

 

Deleted:

 

Capsule Shell Cap colour:

Opaque Blue

 

Capsule Shell Body colour:

Opaque Orange

 

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

4.             CLINICAL PARTICULARS

 

4.4                Special warnings and precautions for use

 

Changes in bold text

 

Depression, suicidal ideation and behaviour: Although Yentreve is not indicated for the treatment of depression, its active ingredient (duloxetine) also exists as an antidepressant medication.  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 a greater risk of suicidal thoughts or suicidal behaviour, and should receive careful monitoring during treatment. A meta-analysis of placebo-controlled clinical trials of antidepressants 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).

 

4.8          Undesirable effects

 

Added new adverse reactions in Table 1:

 

Rare - Hyperglycemia (reported especially in diabetic patients)

Rare – Epistaxis

Rare – Haematochezia

Frequency not known - Gastro-intestinal haemorrhage

Uncommon - Increased tendency to bruise

Uncommon - 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

 

Added a new pack size of 98 capsules

 

 

 

8.             MARKETING AUTHORISATION NUMBERS

 

Added new marketing authorisation number due to new pack size

 

20mg, 98 capsules:             EU/1/04/280/008

 

 

 

10.          DATE OF REVISION OF THE TEXT

 

New date of revision:

 

28 August 2007

4.             CLINICAL PARTICULARS

 

4.3          Contra-indications

 

Added:

 

Severe renal impairment (creatinine clearance <30ml/min) (see section 4.4).

 

The initiation of treatment with Yentreve 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).

 

Renal impairment: Increased plasma concentrations of duloxetine occur in patients with severe renal impairment on haemodialysis (creatinine clearance <30ml/min).  For patients with severe renal impairment, see section 4.3.  See section 4.2 for information on patients with mild or moderate renal dysfunction.

 

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          Interactions with other medicinal products and other forms of interaction

 

Revised (new text in bold, text removed crossed through)

 

Medicinal products metabolised by CYP1A2: In a clinical study, the 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.

 

Added:

 

Inducers of CYP1A2: Population pharmacokinetic studies analyses have shown that smokers have almost 50% lower plasma concentrations of duloxetine compared with non-smokers

 

4.6                Pregnancy and lactation

 

Revised (new text in bold, text removed crossed through)

 

Duloxetine is very weakly excreted into human milk based on a study of 6 lactating patients who did not breast-feed their children. 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, Yentreve is contra-indicated while breast-feeding (see section 4.3). As the safety of duloxetine in infants is not known, the use of Yentreve while breast-feeding is not recommended. 

 

4.8          Undesirable effects

 

Deleted (text removed crossed through):

 

The most commonly reported adverse events in patients treated with Yentreve in clinical trials in SUI and other lower urinary tract disorders were nausea, dry mouth, and fatigue. insomnia, dizziness, headache and constipation.

 

Added to ‘Common’

Insomnia (moved from ‘Very common’)

Agitation (moved from ‘Uncommon’)

Headache (moved from ‘Very common’)

Dizziness

Paraesthesia

Constipation (moved from ‘Very common’)

Abdominal pain

Chills

 

Added to ‘Uncommon’

Laryngitis

Hypersensitivity disorder

Hypothyroidism

Orgasm abnormal

Apathy

Abnormal dreams

Disturbance in attention

Ear pain

Syncope

Halitosis

Gastritis

Flatulence

Elevated liver enzymes (ALT, AST, alkaline phosphatase) (moved from ‘Common’)

Cold sweat

Rash

Musculoskeletal pain

Trismus

Urine odour abnormal

Dysuria

Menopausal symptoms

Feeling abnormal (moved from ‘Common’)

Blood cholesterol increased

 

Added to ‘Rare’:

Myoclonus

Dyskinesia

Glaucoma (moved from ‘Frequency not known’)

Peripheral coldness (moved from ‘Frequency not known’)

Orthostatic hypotension (moved from ‘Frequency not known’)

Hypertensive crisis

Throat tightness

Photosensitivity reactions (moved from ‘Uncommon’)

Muscle twitching (moved from ‘Uncommon’)

Feeling cold

 

Added to ‘Frequency not known’

Mania

Supraventricular arrhythmia, mainly atrial fibrillation

Hepatic failure

 

10.          DATE OF REVISION OF THE TEXT

 

New date of revision:

 

24 November 2006

2.             QUALITATIVE AND QUANTITATIVE COMPOSITION

 

Added:

 

Excipients: Sucrose.

 

4.             CLINICAL PARTICULARS

 

4.2          Posology and method of administration

 

Deleted:

 

When discontinuing Yentreve 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 Yentreve 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 Yentreve, 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 a clinical trial, adverse events seen on abrupt treatment discontinuation occurred in approximately 44% of patients treated with Yentreve and 24% 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, the 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):

 

Drugs 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 duloxetine 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, Yentreve is contra-indicated while breast-feeding (see section 4.3).

 

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 Yentreve.  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 HbA_1c 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.  HbA_1c 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 HbA_1c 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