When a pharmaceutical company changes an SPC or PIL, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.
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
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
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
Discontinuation of duloxetine (particularly when abrupt) commonly leads to withdrawal symptoms. Dizziness, sensory disturbances (including paraesthesia), sleep disturbances (including insomnia and intense dreams), fatigue, somnolence, agitation or anxiety, nausea and/or vomiting, tremor, headache, irritability, diarrhoea, hyperhydrosis and vertigo are the most commonly reported reactions.
10. DATE OF REVISION OF THE TEXT
New date of revision:
26 July 2011
*Note: Updated in entirety for QRD template formatting, sections re-ordered & new subheadings introduced throughout SPC
4. Clinical particulars
4.1 Therapeutic indications
Deleted (strikethrough):
Treatment of diabetic peripheral neuropathic pain in adults.
Cymbalta is indicated in adults.
For further information see section 5.1.
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).
Note: Table updated in entirety
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
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.
27 January 2011
Updated:
Detailed information on this medicine is available on the European Medicines Agency (EMA) web site: http://www.ema.europa.eu
4.6 Pregnancy and lactation
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.
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
22 July 2010
Changes
Major depressive episodes changed to major depressive disorder throughout SPC text.
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.
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).
20 November 2009
Updated in entirety for Renewal.
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
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
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’.
Deleted:
For oral use.
Adults
Major depressive episodes:
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.
Method of administration
Elderly
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
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
CYMBALTA should must
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).
St John’s wort
Undesirable effectsAdverse reactions
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.
Monoamine Oxidase Inhibitors (MAOIs):
due to the risk of serotonin syndrome, CYMBALTA duloxetine should
Table 1: Adverse reactions
Frequency estimate: rare (³1/10,000 and to <1/1,000)
Table revised in entirety
Infections and infestations
Laryngitis
Immune system disorders
Anaphylactic reaction Hyper-sensitivity disorder
Endocrine disorders
Hypo-thyroidism
Metabolism and Nutrition Disorders
Decreased Appetite
Hyperglycemia (reported especially in diabetic patients)
Dehydration
Hyponatremia
SIADH
Psychiatric Disorders
Insomnia Agitation
Libido decreased
Anxiety
Orgasm abnormal
Abnormal dreams
Sleep disorder
Bruxism
Disorientation
Apathy
Mania
Hallucinations
Aggression and anger4
Suicidal ideation 5
Suicidal5
behaviour
Nervous System Disorders
Headache (14.3%)
Somnolence (10.7%)
Dizziness (10.2%)
Tremor
Paraesthesia
Myoclonus
Nervousness
Disturbance in attention
Lethargy Dysgeusia
Dyskinesia
Restless legs syndrome
Poor quality sleep
Convulsions
Serotonin syndrome
Extra-pyramidal symptoms
Akathisia
Psychomotor restlessness
Eye Disorders
Blurred vision
Mydriasis Visual disturbance
Glaucoma
Ear and Labyrinth Disorders
Tinnitus1
Vertigo
Ear pain
Cardiac Disorders
Palpitations
Tachycardia
Supra-ventricular arrhythmia, mainly atrial fibrillation
Vascular Disorders
Flushing
Blood pressure increase
Peripheral coldness
Orthostatic hypotension2
Syncope2
Hypertension Hypertensive crisis
Respiratory, thoracic and mediastinal disorders
Yawning
Throat tightness
Epistaxis
Gastrointestinal Disorders
Nausea (24.3%)
Dry mouth (12.8%)
Constipation Diarrhoea
Vomiting
Dyspepsia
Flatulence
Gastroenteritis
Eructation
Gastritis
Stomatitis
Breath odour
Haematochezia
Gastrointestinal haemorrhage
Hepato-biliary disorders
Elevated liver enzymes (ALT, AST, alkaline phosphatase)
Hepatitis3
Acute liver injury
Jaundice
Hepatic failure
Skin and Subcutaneous Tissue Disorders
Sweating increased
Rash
Night sweats Urticaria
Dermatitis contact
Cold sweat
Photo-sensitivity reactions
Increased tendency to bruise
Angio-neurotic oedema
Stevens-Johnson Syndrome
Muscoloskeletal and connective tissue disorders
Musculo-skeletal pain
Muscle tightness
Muscle spasm
Muscle twitching
Trismus
Renals and Urinary Disorders
Urinary Retention
Dysuria
Urinary hesitation
Nocturia
Polyuria
Urine flow decreased
Urine odour abnormal
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
Signs and symptoms of overdose (duloxetine alone or in combination with mixedother medicinal products)
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:
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
Date of latest renewal: 24 June 2009
06 July 2009
Detailed information on this medicine is available on the European Medicines Agency (EMEA) web site: http://www.emea.europa.eu
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):
Headache (1514.3%)
Somnolence (10.97%)
Dizziness (10.32%)
Dysgeusia
Lethargy
Myoclonus NervousnessDisturbance in attention
Convulsions1
Nausea (25.224.23%)
Dry mouth (1312.8%)
Constipation (10.3%)
Constipation
Diarrhoea
Renal and Urinary Disorders
Night sweats
Musculoskeletal and connective tissue disorders
Hyperglycemi-a (reported especially in diabetic patients)
Fatigue (10.8%)
Hyper-sensitivity disorder
Hyper-sensitivity disorder Anaphylactic reaction
Insomnia (10.4%)
1 Cases of convulsion and cases of tinnitus have also been reported after treatment discontinuation.
Cases of overdoses, alone or in combination with other medicinal products, with duloxetine doses of 4800mg5400mg were reported.
25 March 2009
Diabetic Peripheral Neuropathic Pain:
The medicinal product response should be evaluated after 2 months of treatment. Additional response after this time is unlikely (see 5.1).
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).
nor epinephrine adrenaline
As with other serotoninergic medicinal products,
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.
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:
Hydroxypropyl methylcellulose Hypromellose acetate succinate
02 March 2009
Treatment of generalised anxiety disorder.
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.
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).
Suicide
Major Depressive Episodes and Generalised Anxiety Disorder
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.
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).
There are no adequate data on the use of duloxetine in pregnant women.
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 – 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)
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.
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.
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.
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.
28 July 2008
The active ingredient in CYMBALTA is duloxetine.
Each capsule contains 30 mg of duloxetine (as hydrochloride)
Excipients: sucrose 8.6 mg.
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).
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.
Subheadings changed (bold):
Effect of duloxetine on other medicinal products
Effects of other medicinal products on duloxetine
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
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.
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.
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.
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.
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.
Capsule Shell Cap colour:
30 mg: Opaque Blue
Capsule Shell Body colour:
30 mg: Opaque White
6.4 Special precautions for storage
Store in the original package in order to protect from moisture. Do not store above 30 C.
21 April 2008
21 Cases of tinnitus have also been reported after treatment discontinuation.
Changes in bold text
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.
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.
Cases of overdoses, alone or in combination with other drugs, with duloxetine doses of 4800mg were reported.
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
28 August 2007
4.3 Contra-indications
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).
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.
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.
Warfarin and INR: Increases in INR have been reported when duloxetine was co-administered with warfarin.
Duloxetine is very weakly excreted into human milk, based on a study of 6 lactating patients who did not breast-feed their children.
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)
Agitation (moved from uncommon)
Musculoskeletal pain
Abdominal pain
Hypersensitivity disorder
Orthostatic hypotension
Syncope (moved from frequency unknown)
Elevated liver enzymes (ALT, AST, alkaline phosphatase) (moved from common)
Ejaculation disorder (moved from common)
Hypothyroidism
Dehydration (moved from uncommon)
Glaucoma (moved from frequency unknown)
Halitosis
Frequency Not Known
Supraventricular arrhythmia, mainly atrial fibrillation
Hypertensive crisis
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.
24 November 2006
Excipients: Sucrose.
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.
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.
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.
Some patients may experience symptoms on discontinuation of Cymbalta, particularly if treatment is stopped abruptly (see sections 4.2 and 4.8).
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).
4.5 Interactions with other medicinal products and other forms of interaction
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).
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.
Added (Nervous system disorders, frequency not known):
Added (Psychiatric disorders, frequency not known):
Added (Vascular disorders, frequency not known):
Hypertension
Added (General disorders and administration site conditions, frequency not known):
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).
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).
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.
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.
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.
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.
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.
31 May 2006