Yentreve · 4.3 Contraindications · 1

HOS-093784 · has-adverse-reaction-information · PDF-Seite 8

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. 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), not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. 8  Very Common Uncommon Rare Very rare Not known common Infections and infestations Laryngitis Immune system disorders Hyper- Anaphylactic sensitivity reaction disorder Endocrine disorders Hypo- thyroidism Metabolism and nutrition disorders Appetite Dehydration Hyperglycaemi decreased a (reported especially in diabetic patients) Hyponatraemia SIADH6 Psychiatric disorders Insomnia Bruxism Suicidal Agitation Disorientation behaviour5,6 Libido Apathy Suicidal decreased Orgasm ideation5,7 Anxiety abnormal Mania6 Sleep Abnormal Hallucinations disorder dreams Aggression and

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HOS-093780 · has-contraindication-information · PDF-Seite 3

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). 3

HOS-093779 · has-indication-information · PDF-Seite 2

YENTREVE is indicated for women for the treatment of moderate to severe Stress Urinary Incontinence (SUI). YENTREVE is indicated in adults. For further information see section 5.1.

HOS-093782 · has-interaction-information · PDF-Seite 6

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 (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). 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 (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). 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). 6 Serotonergic agents: 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). 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 (60 mg twice daily). Medicinal products metabolised by CYP2D6: 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 stead

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HOS-093783 · has-pregnancy-information · PDF-Seite 7

Fertility In animal studies, duloxetine had no effect on male fertility, and effects in females were only evident at doses that caused maternal toxicity. Pregnancy Studies in animals have shown reproductive toxicity at systemic exposure levels (AUC) of duloxetine lower than the maximum clinical exposure (see section 5.3). Two large observational studies do not suggest an overall increased risk of major congenital malformation (one from the US including 2,500 exposed to duloxetine during the first trimester and one from the EU including 1,500 exposed to duloxetine during the first trimester). The analysis on specific malformations such as cardiac malformations shows inconclusive results. 7 In the EU study, maternal exposure to duloxetine during late pregnancy (at any time from 20 weeks gestational age to delivery) was associated with an increased risk for preterm birth (less than 2-fold, corresponding to approximately 6 additional premature births per 100 women treated with duloxetine late in pregnancy). The majority occurred between 35 and 36 weeks of gestation. This association was not seen in the US study. The US observational data have provided evidence of an increased risk (less than 2-fold) of postpartum haemorrhage following duloxetine exposure within the month prior to birth. 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. Breast feeding Duloxetine is very weakly excreted into human milk based on a study of 6 lactating patients, who did

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HOS-093781 · has-warning-information · PDF-Seite 4

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. Serotonin syndrome/ Neuroleptic malignant syndrome As with other serotonergic agents, serotonin syndrome or neuroleptic malignant syndrome (NMS), 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). Serotonin syndrome in its most severe form can resemble NMS, which includes hyperthermia, muscle rigidity, elevated serum creatine kinase levels, autonomic instability with possible rapid fluctuation of vital signs and mental status changes. If concomitant treatment with duloxetine and other serotonergic/neuroleptic 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. 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 intraocular 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

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