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).
4.8 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
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
Yentreve is indicated in adults.
For further information see section 5.1.
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).
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 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.
21 January 2011
Updated:
Detailed information on this medicine is available on the European Medicines Agency (EMA) web site: http://www.ema.europa.eu
4.6 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
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
The capsule has an oOpaque orange body, imprinted with ’40mg’ and an opaque blue cap, imprinted with ‘9545’.
4.2 Posology and method of administration
Hepatic insufficiencyimpairment:
YENTREVE should must not be used in women with liver disease resulting in hepatic impairment (see section 4.3).
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)..
Method of administration
For oral use.
Children and adolescents:
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.
St John’s wort
Undesirable effectsAdverse reactions may be more common during concomitant use of YENTREVE and herbal preparations containing St John’s wort (Hypericum perforatum).
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:
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.
Table 1: Adverse reactions
Table revised in entirety
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
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
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)
5.2 Pharmacokinetic properties
Sub-headings added throughout section:
Absorption:
Distribution:
Biotransformation:
Elimination:
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
07 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 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):
Palpitations
Epistaxis Throat tightness
Nausea (23.322.8%)
Dry mouth (11.912.1%)
Hyperglycemia (reported especially in diabetic patients)
Hyponatremia
Orthostatic hypotension2Peripheral coldness
Pruritus
Weakness
Feeling cold
Gynaecologica-l haemorrhage
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.
03 April 2009
Deleted:
The active ingredient in YENTREVE is duloxetine.
Each capsule contains 40 mg of duloxetine (as duloxetine hydrochloride).
4.3 Contraindications
Pregnancy and lactation (see section 4.6).
Undesirable effects may be more common during concomitant use of YENTREVE and herbal preparations containing St John’s wort (Hypericum perforatum).
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.
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
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
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.
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.
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:
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.
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
Capsule Shell Cap colour:
Opaque Blue
Capsule Shell Body colour:
Opaque Orange
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
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).
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.
Cases of overdoses, alone or in combination with other drugs, with duloxetine doses of 4800mg were reported.
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
28 August 2007
4.3 Contra-indications
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).
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.
Warfarin and INR: Increases in INR have been reported when duloxetine was co-administered with warfarin.
Inducers of CYP1A2: Population pharmacokinetic studies analyses have shown that smokers have almost 50% lower plasma concentrations of duloxetine compared with non-smokers
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.
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’)
Constipation (moved from ‘Very common’)
Added to ‘Uncommon’
Hypersensitivity disorder
Hypothyroidism
Syncope
Halitosis
Flatulence
Elevated liver enzymes (ALT, AST, alkaline phosphatase) (moved from ‘Common’)
Musculoskeletal pain
Feeling abnormal (moved from ‘Common’)
Added to ‘Rare’:
Glaucoma (moved from ‘Frequency not known’)
Peripheral coldness (moved from ‘Frequency not known’)
Orthostatic hypotension (moved from ‘Frequency not known’)
Photosensitivity reactions (moved from ‘Uncommon’)
Muscle twitching (moved from ‘Uncommon’)
Added to ‘Frequency not known’
Supraventricular arrhythmia, mainly atrial fibrillation
24 November 2006
Excipients: Sucrose.
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.
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.
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).
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).
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).
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).
Added (Nervous system disorders, frequency not known):
Added (Psychiatric disorders, frequency not known):
Added (Vascular disorders, frequency not known):
Added (General disorders and administration site conditions, frequency not known):
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).
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