Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Eli Lilly Nederland B.V., Papendorpseweg 83, 3528 BJ Utrecht, The Netherlands
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Liver disease resulting in hepatic impairment (see section 5.2).
YENTREVE should not be used in combination with nonselective, irreversible monoamine oxidase inhibitors – MAOIs (see section 4.5).
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 (see section 4.5).
Severe renal impairment (creatinine clearance <30 ml/min) (see section 4.4).
The initiation of treatment with YENTREVE is contraindicated in patients with uncontrolled hypertension that could expose patients to a potential risk of hypertensive crisis (see sections 4.4 and 4.8).
YENTREVE should be used with caution in patients with a history of mania or a diagnosis of bipolar disorder, and/or seizures.
As with other serotonergic agents, serotonin syndrome, a potentially life-threatening condition, may occur with duloxetine treatment, particularly with concomitant use of other serotonergic agents (including SSRIs, SNRIs tricyclic antidepressants or triptans), with agents that impair metabolism of serotonin such as MAOIs, or with antipsychotics or other dopamine antagonists that may affect the serotonergic neurotransmitter systems (see sections 4.3 and 4.5).
Serotonin syndrome symptoms may include mental status changes (e.g. agitation, hallucinations, coma), autonomic instability (e.g. tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g. hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g. nausea, vomiting, diarrhoea).
If concomitant treatment with duloxetine and other serotonergic agents that may affect the serotonergic and/or dopaminergic neurotransmitter systems in clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.
Adverse reactions may be more common during concomitant use of YENTREVE and herbal preparations containing St John’s wort (Hypericum perforatum).
Mydriasis has been reported in association with duloxetine, therefore, caution should be used when prescribing duloxetine in patients with increased intraocular pressure, or those at risk of acute narrow-angle glaucoma.
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).
Increased plasma concentrations of duloxetine occur in patients with severe renal impairment on haemodialysis (creatinine clearance <30 ml/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.
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.
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 SSRI’s and SNRI’s 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).
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.
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 (see section 4.8). 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 (see section 4.2).
YENTREVE should not be used in the treatment of children and adolescents under the age of 18 years. Suicide-related behaviours (suicide attempts and suicidal thoughts), and hostility (predominantly aggression, oppositional behaviour and anger), were more frequently observed in clinical trials among children and adolescents treated with antidepressants compared to those treated with placebo. If, based on clinical need, a decision to treat is nevertheless taken, the patient should be carefully monitored for the appearance of suicidal symptoms. In addition, long-term safety data in children and adolescents concerning growth, maturation and cognitive and behavioural development are lacking.
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.
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.
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.
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.
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 (see section 4.3).
The concomitant use of YENTREVE with selective, reversible MAOIs, like moclobemide, is not recommended (see section 4.4). The antibiotic linezolid is a reversible non-selective MAOI and should not be given to patients treated with YENTREVE (see section 4.4).
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 (100 mg once daily), a potent inhibitor of CYP1A2, decreased the apparent plasma clearance of duloxetine by about 77% and increased AUC0-t 6-fold. Therefore YENTREVE should not be administered in combination with potent inhibitors of CYP1A2 like fluvoxamine (see section 4.3).
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).
In rare cases, serotonin syndrome has been reported in patients using SSRIs/SNRIs concomitantly with serotonergic agents. Caution is advisable if YENTREVE is used concomitantly with serotonergic agents like SSRIs, SNRIs, tricyclic antidepressants like clomipramine or amitriptyline, MAOIs like moclobemide or linezolid, St John’s wort (Hypericum perforatum) or triptans, tramadol pethidine and tryptophan (see section 4.4).
The pharmacokinetics of theophylline, a CYP1A2 substrate, were not significantly affected by co-administration with duloxetine (60 mg twice daily).
Duloxetine is a moderate inhibitor of CYP2D6. When duloxetine was administered at a dose of 60 mg twice daily with a single dose of desipramine, a CYP2D6 substrate, the AUC of desipramine increased 3-fold. The co-administration of duloxetine (40 mg twice daily) increases steady state AUC of tolterodine (2 mg 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).
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.
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.
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 40 mg oral dose.
Population pharmacokinetic studies analyses have shown that smokers have almost 50% lower plasma concentrations of duloxetine compared with non-smokers.
Duloxetine had no effect on male fertility, and effects in females were only evident at doses that caused maternal toxicity.
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.
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.
Duloxetine is very weakly excreted into human milk based on a study of 6 lactating patients, who did not breast feed their children. The estimated daily infant dose on a mg/kg basis is approximately 0.14% of the maternal dose (see section 5.2). As the safety of duloxetine in infants is not known, the use of YENTREVE while breast-feeding is not recommended.
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.
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).
Table 1 gives the adverse reactions observed from spontaneous reporting and in placebo-controlled clinical trials.
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.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Uncommon: Laryngitis
Uncommon: Hyper-sensitivity disorder
Rare: Anaphylactic reaction
Uncommon: Hypo-thyroidism
Common: Appetite decreased
Uncommon: Dehydration
Rare: Hyperglycaemia (reported especially in diabetic patients) Hyponatraemia SIADH6
Common: Insomnia, Agitation, Libido decreased, Anxiety, Sleep disorder
Uncommon: Bruxism, Disorientation, Apathy, Orgasm abnormal, Abnormal dreams
Rare: Suicidal behaviour5,6, Suicidal ideation5,7, Mania6, Hallucinations, Aggression and anger4,6
Common: Headache, Dizziness, Lethargy, Somnolence, Tremor, Paraesthesia
Uncommon: Nervousness, Disturbance in attention, Dysgeusia, Poor quality sleep
Rare: Serotonin syndrome6, Convulsions1,6, Myoclonus, Akathisia6, Psychomotor restlessness6, Extra-pyramidal symptoms6, Dyskinesia, Restless legs syndrome
Common: Blurred vision
Uncommon: Mydriasis, Visual impairment, Dry eye
Rare: Glaucoma
Common: Vertigo
Uncommon: Tinnitus1, Ear pain
Uncommon: Palpitations, Tachycardia
Rare: Supra-ventricular arrhythmia, mainly atrial fibrillation6
Common: Hypertension3,7, Flushing
Uncommon: Syncope2, Blood pressure increase3
Rare: Hypertensive crisis3, Orthostatic hypotension2, Peripheral coldness
Uncommon: Yawning
Rare: Throat tightness, Epistaxis, Interstitial lung disease10, Eosinophilic pneumonia6
Very common: Nausea, Dry mouth, Constipation
Common: Diarrhoea, Abdominal pain, Vomiting, Dyspepsia
Uncommon: Gastrointestinal haemorrhage7, Gastroenteritis, Stomatitis, Eructation, Gastritis, Dysphagia, Flatulence, Breath odour
Rare: Haematochezia, Microscopic colitis9
Uncommon: Hepatitis3, Elevated liver enzymes (ALT, AST, alkaline phosphatase), Acute liver injury
Rare: Hepatic failure6, Jaundice6
Common: Sweating increased
Uncommon: Rash, Night sweats, Urticaria, Dermatitis contact, Cold sweat, Increased tendency to bruise
Rare: Stevens-Johnson Syndrome6, Angio-neurotic oedema6, Photo-sensitivity reactions
Very Rare: Cutaneous vasculitis
Uncommon: Musculo-skeletal pain, Muscle tightness, Muscle spasm, Trismus
Rare: Muscle twitching
Uncommon: Urinary hesitation, Dysuria, Nocturia, Pollakiuria, Urine odour abnormal
Rare: Urinary retention6, Polyuria, Urine flow decreased
Uncommon: Gynaecological haemorrhage, Menopausal symptoms
Rare: Menstrual disorder, Galactorrhoea, Hyperprolactinae mia
Very common: Fatigue
Common: Asthenia Chills
Uncommon: Chest pain7, Falls8, Feeling abnormal, Feeling cold, Thirst, Malaise, Feeling hot
Rare: Gait disturbance
Uncommon: Weight decrease, Weight increase, Blood cholesterol increased, Blood creatine phosphokinase increased
Rare: 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 section 4.4.
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 (see section 4.4).
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).
9 Estimated frequency based on all clinical trial data.
10 Estimated frequency based on placebo-controlled clinical trials.
Discontinuation of duloxetine (particularly when abrupt) commonly leads to withdrawal symptoms. Dizziness, sensory disturbances (including paraesthesia or electric shock-like sensations, particularly in the head), sleep disturbances (including insomnia and intense dreams), fatigue, somnolence, agitation or anxiety, nausea and/or vomiting, tremor, headache, myalgia, irritability, diarrhoea, hyperhydrosis and vertigo are the most commonly reported reactions.
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).
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.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
Not applicable.
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