Firdapse (previously Zenas) · 4.6 Fertility, pregnancy and lactation · 1

HOS-154484 · has-adverse-reaction-information · PDF-Seite 5

Summary of the safety profile 5 The most commonly reported adverse reactions are paraesthesias (such as peripheral and peribucal paraesthesias) and gastro-intestinal disorders (such as epigastralgia, diarrhoea, nausea and abdominal pain). The intensity and incidence of most adverse reactions is dose-dependent. Table 1 below lists the adverse reactions reported with amifampridine. Tabulated list of adverse reactions Frequencies are defined as: Very common (≥ 1/10), Common (≥ 1/100 to < 1/10), Uncommon (≥ 1/1000 to < 1/100), Rare (≥ 1/10,000 to < 1/1,000), Very rare (< 1/10,000) and Unknown (cannot be estimated from available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Frequencies were estimated based on a clinical study to evaluate the effects of amifampridine on cardiac repolarization at a single dose of 30 mg or 60 mg in healthy volunteers. Table 1: Adverse Reactions Reported with FIRDAPSE MedDRA MedDRA Frequency System organ class Preferred term Psychiatric disorders Sleep disorders, anxiety Unknown Nervous system Convulsions, chorea, myoclonia drowsiness, Unknown disorders weakness, fatigue, headache Dizziness1, hypoaesthesia1, paraesthesia1 Very common Eye disorders Blurred vision Unknown Cardiac disorders Cardiac rhythm disorders, palpitations Unknown Vascular disorders Raynaud's syndrome Unknown 1 Cold extremities Common Respiratory, thoracic Bronchial hypersecretion, asthma attack in asthmatic Unknown and mediastinal patients or patients with a history of asthma, cough disorders Gastrointestinal Hypoaesthasia oral1, paraesthesia oral1, peripheral and Very common disorders peribucal paraesthesias, nausea1 Abdominal pain Common Diarrhoea, epigastralgia Unknown Hepatobiliary Elevated liver enzyme levels (transaminases) Unknown disorders Skin and Hyperhidrosis1, cold sweat1

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HOS-154480 · has-contraindication-information · PDF-Seite 3

Hypersensitivity to the active substance, or to any of the excipients listed in section 6.1 Epilepsy Uncontrolled asthma Concomitant use with sultopride (see sections 4.5 and 5.1) Concomitant use with medicinal products with a narrow therapeutic window (see section 4.5) Concomitant use with medicinal products with a known potential to cause QTc prolongation In patients with congenital QT syndromes (see section 4.4)

HOS-154479 · has-indication-information · PDF-Seite 2

Symptomatic treatment of Lambert-Eaton myasthenic syndrome (LEMS) in adults.

HOS-154482 · has-interaction-information · PDF-Seite 4

Pharmacokinetic interactions Medicinal products eliminated through metabolism or active secretion There are no data on the effects of amifampridine on the metabolism or active secretion of other medicinal products. Thus, special care should be taken in patients undergoing concomitant treatment with medicinal products eliminated through metabolism or active secretion. Monitoring is advised when possible. The dose of the concomitantly given medicinal product should be adjusted if necessary. Concomitant use of medicinal products with a narrow therapeutic window is contraindicated (see section 4.3). Substances which are potent inhibitors of enzymes that metabolise medicinal products (see section 5.2) Potent cytochrome P450 (CYP450) enzyme inhibitors e.g. cimetidine, ketoconazole are not likely to inhibit the metabolism of amifampridine by human N-acetyl-transferase enzymes (NATs) giving rise to increased amifampridine exposure. The results from the in vitro CYP450 inhibition study indicate amifampridine is unlikely to play a role in metabolic-based clinical drug-drug interactions related to inhibition of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 metabolism of co-administered medicinal products. Regardless, patients should be closely monitored for adverse reactions when initiating treatment with a potent enzyme or renal transporter inhibitor. If treatment with a potent inhibitor is discontinued, patients should be monitored for efficacy as an increase of amifampridine dose may be necessary. Substances which are potent inducers of enzymes that metabolise medicinal products (see section 5.2) The results from in vitro studies suggest there is low potential for drug-drug interactions due to enzyme induction of CYP1A2, CYP2B6, and CYP3A4 enzymes by amifampridine. Pharmacodynamic interactions Based on the pharmacodynamic properties of amifampridine, the concomitant use with sultopride or other medicinal products known to cause QT prolongation (e.g., disopyramide, cisapride, domperidone, rifampicin and ketoconazole) is contraindicated as this combination may lead to an enhanced risk of ventricular tachycardia, notably torsade de pointes (see sections 4.3 and 5.1). Combinations requiring precautions for use Medicinal products known to lower the epileptic threshold The concomitant use of amifampridine and substances known to lower the epileptic threshold may lead to an increased risk of seizures. The decision to administer procon

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HOS-154483 · has-pregnancy-information · PDF-Seite 5

Pregnancy FIRDAPSE should not be used during pregnancy. Women of childbearing potential must use effective contraception during FIRDAPSE treatment. No adequate clinical data on exposed pregnancies are available for amifampridine. Amifampridine has shown no effect on embryo-foetal viability and development in rabbits; however, in rats, an increase in the number of mothers delivering still-born offspring was observed (see section 5.3). Breast-feeding It is unknown whether amifampridine is excreted in human breast milk. Available reproductive data in animals have shown presence of amifampridine in milk of breast-feeding mothers. Assessment of breast-feeding neo-natal animals showed no indication of adverse reactions when exposed to amifampridine through breast-milk. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from FIRDAPSE therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman. Fertility Non-clinical safety data are available regarding the effects of amifampridine on reproductive function. No impairment of fertility has been observed in non-clinical studies with amifampridine (see section 5.3).

HOS-154481 · has-warning-information · PDF-Seite 3

Renal and hepatic impairment The pharmacokinetics of amifampridine has been assessed in a single dose Phase I study in patients with renal impairment (see section 5.2). No studies have been conducted in patients with hepatic impairment. In view of the risk of markedly increased exposure to medicinal product, patients with renal or hepatic impairment must be carefully monitored. The dose of amifampridine should be titrated more slowly in patients with renal and hepatic impairment than those with normal renal and hepatic function. Upward dose titration should be discontinued if any adverse reaction occurs (see section 4.2). Seizures Exposure to amifampridine is associated with an increased risk for epileptic seizures. The risk of seizures is dose-dependent and is increased in patients with risk factors which lower the epileptic threshold; including use in combination with other medicinal products known to lower the epileptic threshold (see section 4.5). In the event of a seizure, treatment should be discontinued. Carcinogenicity risk In a 2-year dietary carcinogenicity study, benign and malignant Schwannomas have been observed in rats treated with amifampridine (see section 5.3). Amifampridine was not genotoxic in a standard battery of in vitro and in vivo tests. The correlation between the use of amifampridine and the development of tumours in humans is unknown at this time. Most Schwannomas are benign and asymptomatic. They can present in many locations, therefore the clinical presentation can be varied. A diagnosis of Schwannoma should be considered for patients who present with symptoms such as a mass that is painful on palpation or symptoms similar to a compressive neuropathy. Schwannomas are generally slow-growing and can exist for months to years without producing symptoms. The benefit of continuing treatment with amifampridine should be reviewed for any patient who develops a Schwannoma. Amifampridine should be used with caution in patients with an increased risk of Schwannomas, such as patients with past medical history of such tumours, neurofibromatosis Type 2 or schwannomatosis. Cardiac effects 3 Clinical and electrocardiogram (ECG) monitoring are indicated at the initiation of the treatment and yearly thereafter. In case of signs and symptoms indicative of cardiac arrhythmias, ECG should be performed immediately. Concomitant diseases Patients must be told to inform any physician they

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