Drug Class Description

Generic Name

Drug Description

Presentation

Indications

Adult Dosage

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. 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 Insufficiency

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

Renal insufficiency

No dosage adjustment is necessary for patients with mild or moderate renal dysfunction (creatinine clearance 30 to 80ml/min).

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.

Child Dosage

Elderly Dosage

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 enoxacine, since the combination results in elevated plasma concentrations of duloxetine.

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

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.

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

Undesirable effects 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 gastro-intestinal haemorrhage, with selective serotonin reuptake inhibitors (SSRIs) and serotonin/noradrenalin reuptake inhibitors (SNRIs). Caution is advised in patients taking anticoagulants and/or medicinal products known to affect platelet function, 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 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.

Hyponatraemia

Hyponatraemia has been reported rarely, predominantly in the elderly, when administering YENTREVE. 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).

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 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 episodes, as well as 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, YENTREVE 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.

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.

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 (benzodiazepines, morphinomimetics, antipsychotics, phenobarbital, sedative antihistamines).

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 medicinal product 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. Furthermore, increases in INR values have been reported when duloxetine was co-administered with 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.

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.

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

Adverse Reactions

Table 1 gives the adverse reactions observed from spontaneous reporting and in placebo-controlled clinical trials (comprising a total of 7976 patients, 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, 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).

Frequency is defined as: Very common (1/10), common (1/100 to <1/10), uncommon (1/1,000 to <1/100), rare (1/10,000 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

Investigations
Uncommon:  Weight decrease, Weight increase, Blood cholesterol increased
Rare: Creatine phosphokinase increased

Cardiac Disorders
Common: Palpitations
Uncommon: Tachycardia
Frequency not known: Supra-ventricular arrhythmia, mainly atrial fibrillation

Nervous System Disorders
Common: Headache, Dizziness, Tremor, Lethargy, Somnolence, Paraesthesia
Uncommon: Poor quality sleep, Disturbance in attention, Nervousness, Dysgeusia
Rare: Dyskinesia, Myoclonus
Frequency not known: Serotonin syndrome, Psychomotor restlessness, Convulsions, Akathisia, Extrapyramidal symptoms

Eye Disorders
Common: Blurred vision
Uncommon: Visual disturbance, Mydriasis
Rare: Glaucoma

Ear and Labyrinth Disorders
Common: Vertigo
Uncommon:  Tinnitus^1, Ear pain

Respiratory, Thoracic and Mediastinal Disorders
Uncommon: Yawning
Rare: Epistaxis, Throat tightness

Gastrointestinal Disorders
Very common: Nausea (23.3%), Dry mouth (11.9%), Constipation (10.3%)
Common: Diarrhoea, Vomiting, Dyspepsia
Uncommon:  Gastroenteritis, Stomatitis, Gastritis, Flatulence, Eructation, Breath odour
Rare: Haematochezia
Frequency not known: Gastrointestinal haemorrhage

Renal and Urinary Disorders
Uncommon: Urinary hesitation, Dysuria, Nocturia, Urine odour abnormal
Rare: Urine flow decreased, Polyuria
Frequency not known: Urinary retention

Skin and Subcutaneous Tissue Disorders
Common: Sweating increased
Uncommon: Rash, Increased tendency to bruise, Night sweats, Cold sweat
Rare: Potosensitivity reactions, Dermatitis contact, Urticaria
Frequency not known: Stevens-Johnson Syndrome, Angioneurotic oedema

Muscoskeletal and Connective Tissue Disorders
Uncommon: Muscle spasm, Muscle tightness, Musculoskeletal pain, Trismus
Rare: Muscle twitching

Endocrine Disorders
Uncommon: Hypothyroidism

Metabolism and Nutrition Disorders
Common: Appetite decreased
Uncommon: Dehydration
Rare: Hyperglycaemia (reported especially in diabetic patients), SIADH, Hyponatraemia

Infections and Infestations
Uncommon: Laryngitis

Vascular Disorders
Common: Flushing
Uncommon: Syncope^2, Blood pressure increase
Rare: Hypertensive crisis, Orthostatic hypotension^{2 ,} Peripheral coldness
Frequency not known: Hypertension

General Disorders and Administration Site Conditions
Very common: Fatigue (10.9%)
Common: Abdominal pain, Pruritus, Weakness, Chills
Uncommon: Malaise, Feeling abnormal, Feeling hot, Thirst
Rare: Gait disturbance, Feeling cold
Frequency not known: chest pain

Immune System Disorders
Uncommon: Hypersensitivity disorder
Rare: Anaphylactic reaction

Hepato-biliary Disorders
Uncommon: Hepatitis^3, Elevated liver enzymes (ALT, AST, alkaline phosphatase),Acute liver injury
Frequency not known: Hepatic failure , Jaundice

 Reproductive System and Breast Disorders
Uncommon: Menopausal symptoms, Gynaecological haemorrhage, Psychiatric Disorders

Psychiatric Disorders
Common: Insomnia, Anxiety , Sleep disorder, Agitation, Libido decreased
Uncommon: Disorientation, Abnormal dreams, Apathy, Bruxism Orgasm abnormal
Rare: Hallucinations
Frequency not known:  Suicidal behaviour, Suicidal ideation³, Mania, Aggression and anger⁴

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

³Cases of suicidal ideation and suicidal behaviours have been reported during duloxetine therapy or early after treatment discontinuation

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

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.

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.

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.

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.

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