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Drug Details

Yentreve 20mg and 40mg hard gastro-resistant capsules

• Drug Class Description
  Other antidepressants - ATC code: N06AX21
• Generic Name
  duloxetine hydrochloride
• Presentation
  Hard gastro-resistant capsule. The 20mg capsule has an opaque blue body, imprinted with '20mg', and an opaque blue cap, imprinted with '9544'. The 40mg capsule has an opaque orange body, imprinted with '40mg', and an opaque blue cap, imprinted with '9545'.
• Description
  Each 20mg capsule contains 20mg of duloxetine (as hydrochloride). Excipients 20mg: Each capsule contains 5.7mg sucrose. Each 40mg capsule contains 40mg of duloxetine (as hydrochloride). Excipients 40mg: Each capsule contains 11.5mg sucrose.
• Indications
  

  YENTREVE is indicated for women for the treatment of moderate to severe stress urinary incontinence (SUI).

• Adult Dosage
  

  Posology

  The recommended dose of YENTREVE is 40mg twice daily, without regard to meals. After 2-4 weeks of treatment, patients should be re-assessed in order to evaluate the benefit and tolerability of the therapy. Some patients may benefit from starting treatment at a dose of 20mg 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.

  A 20 mg capsule is also available. However, limited data are available to support the efficacy of YENTREVE 20mg twice daily.

  The efficacy of YENTREVE has not been evaluated for longer than 3 months in placebo-controlled studies. The benefit of treatment should be re-assessed at regular intervals.

  Combining YENTREVE with a pelvic floor muscle training (PFMT) programme may be more effective than either treatment alone. It is recommended that consideration be given to concomitant PFMT.

  Hepatic impairment

  YENTREVE must not be used in women with liver disease resulting in hepatic impairment.

  Renal impairment

  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.

  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. 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.

  Method of Administration

  For oral use.

• Child Dosage
  

  Children and Adolescents

  Duloxetine is not recommended for use in children and adolescents due to insufficient data on safety and efficacy.

• Elderly Dosage
  

  Caution should be exercised when treating the elderly.

• Contra Indications
  

  Hypersensitivity to the active substance or to any of the excipients.

  Liver disease resulting in hepatic impairment.

  YENTREVE should not be used in combination with non selective, irreversible monoamine oxidase inhibitors (MAOIs).

  YENTREVE should not be used in combination with CYP1A2 inhibitors, like fluvoxamine, ciprofloxacin, or enoxacin, since the combination results in elevated plasma concentrations of duloxetine.

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

  The initiation of treatment with YENTREVE is contraindicated in patients with uncontrolled hypertension that could expose patients to a potential risk of hypertensive crisis

• Special Precautions
  

  Mania and Seizures

  YENTREVE should be used with caution in patients with a history of mania or a diagnosis of bipolar disorder, and/or seizures.

  Use with Antidepressants

  The use of YENTREVE in combination with antidepressants (especially with SSRI, SNRI, and reversible MAOIs) is not recommended.

  St John's Wort

  Adverse reactions may be more common during concomitant use of YENTREVE and herbal preparations containing St John's Wort (Hypericum perforatum).

  Mydriasis

  Mydriasis has been reported in association with duloxetine; therefore, caution should be used when prescribing duloxetine in patients with increased intra ocular pressure, or those at risk of acute narrow-angle glaucoma.

  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. For patients who experience a sustained increase in blood pressure while receiving duloxetine, either dose reduction or gradual discontinuation should be considered. In patients with uncontrolled hypertension, duloxetine should not be initiated.

  Renal Impairment

  Increased plasma concentrations of duloxetine occur in patients with severe renal impairment on haemodialysis (creatinine clearance <30ml/min).

  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. Caution is advised in patients taking anticoagulants and/or medicinal products known to affect platelet function (e.g. NSAIDs or acetylsalicyclic acid (ASA)), and in patients with known bleeding tendencies.

  Discontinuation of Treatment

  Withdrawal symptoms when treatment is discontinued are common, particularly if discontinuation is abrupt. 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 Adverse Reactions. 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.

  Hyponatraemia

  Hyponatraemia has been reported when administering YENTREVE, including cases with serum sodium lower than 110 mmol/l. 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.

  Depression, Suicidal Ideation and Behaviour

  Although YENTREVE is not indicated for the treatment of depression, its active ingredient (duloxetine) also exists as an antidepressant medicinal product. 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 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. Cases of suicidal thoughts and suicidal behaviours have been reported during duloxetine therapy or early after treatment discontinuation. Physicians should encourage patients to report any distressing thoughts or feelings or depressive symptoms at any time. If, while on YENTREVE therapy, the patient develops agitation or depressive symptoms, specialised medical advice should be sought, as depression is a serious medical condition. If a decision to initiate antidepressant pharmacological therapy is taken, the gradual discontinuation of YENTREVE is recommended.

  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. Long-term safety data in children and adolescents concerning growth, maturation, and cognitive and behavioural development are lacking.

  Medicinal Products Containing Duloxetine

  Duloxetine is used under different trademarks in several indications (treatment of diabetic neuropathic pain, major depressive disorder, generalised anxiety disorder and stress urinary incontinence). The use of more than one of these products concomitantly should be avoided.

  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. 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.

  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.

  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.

• Interactions
  

  Monoamine oxidase inhibitors (MAOIs): Due to the risk of serotonin syndrome, duloxetine should not be used in combination with non selective, irreversible monoamine oxidase inhibitors (MAOIs), or within at least 14 days of discontinuing treatment with an MAOI. Based on the half-life of duloxetine, at least 5 days should be allowed after stopping YENTREVE before starting an MAOI.

  Inhibitors of CYP1A2: Because CYP1A2 is involved in duloxetine metabolism, concomitant use of YENTREVE with potent inhibitors of CYP1A2 is likely to result in higher concentrations of duloxetine. Fluvoxamine (100mg once daily), a potent inhibitor of CYP1A2, decreased the apparent plasma clearance of duloxetine by about 77% and increased AUC_0-t 6-fold. Therefore, YENTREVE should not be administered in combination with potent inhibitors of CYP1A2 like fluvoxamine.

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

  Serotonin syndrome: In rare cases, serotonin syndrome has been reported in patients using SSRIs concomitantly with serotonergic medicinal products. The use of YENTREVE in combination with serotonergic antidepressants like SSRIs, tricyclics like clomipramine or amitriptyline, venlafaxine, or triptans, tramadol and tryptophan is not recommended.

  Effect of Duloxetine on Other Medicinal Products

  Medicinal products metabolised by CYP1A2: The pharmacokinetics of theophylline, a CYP1A2 substrate, were not significantly affected by co-administration with duloxetine (60mg twice daily).

  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 YENTREVE 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).

  Oral contraceptives and other steroidal agents: Results of in vitro studies demonstrate that duloxetine does not induce the catalytic activity of CYP3A. Specific in vivo drug interaction studies have not been performed.

  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.

  Effects of Other Medicinal Products on Duloxetine

  Antacids and H₂-antagonists: Co-administration of YENTREVE with aluminium- and magnesium-containing antacids or with famotidine had no significant effect on the rate or extent of duloxetine absorption after administration of a 40mg oral dose.

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

• Adverse Drug Reactions
  

  a. Summary of the safety profile

  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, fatigue and constipation. The data analysis of four 12-week, placebo-controlled clinical trials in patients with SUI, including 958 duloxetine-treated and 955 placebo-treated patients, showed that the onset of the reported adverse events typically occurred in the first week of therapy. However, the majority of the most frequent adverse events were mild to moderate and resolved within 30 days of occurrence (e.g., nausea).

  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 8241 patients, 4504 on duloxetine and 3737 on placebo) in SUI and other lower urinary tract disorders.

  Table 1: Adverse reactions

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

  Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

  Very common	Common	Uncommon	Rare	Very Rare
  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 SIADH6
  Psychiatric Disorders
  	Insomnia Agitation Libido decreased Anxiety Sleep disorder	Bruxism Disorientation Apathy Orgasm abnormal Abnormal dreams	Suicidal behaviour5,6 Suicidal ideation5,7 Mania6 Hallucinations Aggression and anger4,6
  Nervous System Disorders
  	Headache Dizziness Lethargy Somnolence Tremor Paraesthesia	Nervousness Disturbance in attention Dysgeusia Poor quality sleep	Serotonin syndrome6 Convulsions1,6 Myoclonus Akathisia6 Psychomotor restlessness6 Extra-pyramidal symptoms6 Dyskinesia Restless legs syndrome
  Eye Disorders
  	Blurred vision	Mydriasis Visual impairment Dry eye	Glaucoma
  Ear and Labyrinth Disorders
  	Vertigo	Tinnitus1 Ear pain
  Cardiac Disorders
  		Palpitations Tachycardia	Supra-ventricular arrhythmia, mainly atrial fibrillation6
  Vascular Disorders
  	Hypertension3,7 Flushing	Syncope2 Blood pressure increase3	Hypertensive crisis3 Orthostatic hypotension2 Peripheral coldness
  Respiratory, Thoracic and Mediastinal Disorders
  		Yawning	Throat tightness Epistaxis
  Gastrointestinal Disorders
  Nausea (22.8%) Dry mouth (12.1%) Constipation (10.3%)	Diarrhoea Abdominal pain Vomiting Dyspepsia	Gastrointestinal haemorrhage7 Gastroenteritis Stomatitis Eructation Gastritis Flatulence Breath odour	Haematochezia
  Hepato-biliary Disorders
  		Hepatitis3 Elevated liver enzymes (ALT, AST, alkaline phosphatase) Acute liver injury	Hepatic failure6 Jaundice6
  Skin and Subcutaneous Tissue Disorders
  	Sweating increased	Rash Night sweats Urticaria Dermatitis contact Cold sweat Increased tendency to bruise	Stevens-Johnson Syndrome6 Angio-neurotic oedema6 Photo-sensitivity reactions
  Musculoskeletal and Connective Tissue Disorders
  		Musculo-skeletal pain Muscle tightness Muscle spasm Trismus	Muscle twitching
  Renal and Urinary Disorders
  		Urinary hesitation Dysuria Nocturia Urine odour abnormal	Urinary retention6 Polyuria Urine flow decreased
  Reproductive System and Breast Disorders
  		Gynaecological haemorrhage Menopausal symptoms	Menstrual disorder Galactorrhoea Hyperprolactinaemia
  General Disorders and Administration Site Conditions
  Fatigue (10.9%)	Asthenia Chills	Chest pain7 Falls8 Feeling abnormal Feeling cold Thirst Malaise Feeling hot	Gait disturbance
  Investigations
  		Weight decrease Weight increase Blood cholesterol increased Blood creatine phosphokinase increased	Blood potassium increased

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

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

  ³ See Precautions

  ⁴ Cases of aggression and anger have been reported particularly early in treatment or after treatment discontinuation.

  ⁵ Cases of suicidal ideation and suicidal behaviours have been reported during duloxetine therapy or early after treatment discontinuation

  ⁶ Estimated frequency of post-marketing surveillance reported adverse reactions; not observed in placebo-controlled clinical trials.

  ⁷ Not statistically significantly different from placebo.

  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.

  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.

  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.

  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.