Duloxetine Zentiva · 4.6 Fertility, pregnancy and lactation · 1

HOS-097357 · has-adverse-reaction-information · PDF-Seite 10

Summary of the safety profile The most commonly reported adverse reactions in patients treated with duloxetine were nausea, headache, dry mouth, somnolence, and dizziness. However, the majority of common adverse reactions were mild to moderate, they usually started early in therapy, and most tended to subside even as therapy was continued. 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 esWLPDWH9HU\FRPPRQ •  FRPPRQ • 1/100 to <  XQFRPPRQ • 1/1,000 to <  UDUH • 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. Very common Common Uncommon Rare Very Not known rare Infections and infestations Laryngitis Immune system disorders Anaphylactic reaction Hyper- sensitivity disorder Endocrine disorders Hypo- thyroidism 10 Very common Common Uncommon Rare Very Not known rare Metabolism and nutrition disorders Decreased Hyperglycaemi Dehydration appetite a (reported Hyponatraemi especially in a diabetic SIADH6 patients) Psychiatric disorders Insomnia Suicidal Suicidal Agitation ideation5,7 behaviour5,7 Libido Sleep disorder Mania decreased Bruxism Hallucinations Anxiety Disorientation Aggression

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HOS-097353 · has-contraindication-information · PDF-Seite 4

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Concomitant use of Duloxetine Zentiva with nonselective, irreversible monoamine oxidase inhibitors (MAOIs) is contraindicated (see section 4.5). Liver disease resulting in hepatic impairment (see section 5.2). Duloxetine Zentiva should not be used in combination with fluvoxamine, ciprofloxacin or enoxacin (i.e. potent CYP1A2 inhibitors) 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 Duloxetine Zentiva 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).

HOS-097352 · has-indication-information · PDF-Seite 2

Treatment of major depressive disorder. Treatment of diabetic peripheral neuropathic pain. Treatment of generalised anxiety disorder. Duloxetine Zentiva is indicated in adults. For further information see section 5.1. 2

HOS-097355 · has-interaction-information · PDF-Seite 8

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 Duloxetine Zentiva before starting an MAOI (see section 4.3). The concomitant use of Duloxetine Zentiva 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 duloxetine (see section 4.4). Inhibitors of CYP1A2 Because CYP1A2 is involved in duloxetine metabolism, concomitant use of duloxetine 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 AUCo-t 6-fold. Therefore Duloxetine Zentiva should not be administered in combination with potent inhibitors of CYP1A2 like fluvoxamine (see section 4.3). CNS medicinal products The risk of using duloxetine in combination with other CNS-active medicinal products has not been systematically evaluated, except in the cases described in this section. Consequently, caution is advised when duloxetine 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). Serotonergic agents In rare cases, serotonin syndrome has been reported in patients using SSRIs/SNRIs concomitantly with serotonergic agents. Caution is advisable if duloxetine 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, buprenorphine, 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

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HOS-097356 · has-pregnancy-information · PDF-Seite 9

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. 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). 9 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. Duloxetine 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 d

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HOS-097354 · has-warning-information · PDF-Seite 4

Mania and seizures Duloxetine should be used with caution in patients with a history of mania or a diagnosis of bipolar disorder, and/or seizures. 4 Mydriasis Mydriasis has been reported in association with duloxetine, therefore, caution should be used when prescribing Duloxetine Zentiva to 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 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). Renal impairment 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. 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, with antipsychotics or other dopamine antagonists or with opioids such as buprenorphine (with or without naloxone), tramadol and pethidine that may affect the serotonergic neurotransmitter systems (see sections 4.3 and 4.5). Serotonin syndrome symptoms may incl

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