fenfluramine hydrochloride

HOS-097349 · has-adverse-reaction-information · PDF-Seite 10

Summary of the safety profile The most commonly reported adverse reactions are decreased appetite (31.9%), fatigue (17.6%), diarrhoea (16.7%), and somnolence (15%). Tabulated list of adverse reactions Adverse reactions reported with fenfluramine in placebo-controlled clinical studies and from post- marketing surveillance are listed in the tables below by System Organ Class and frequency. Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10) or not known (cannot be estimated from the available data). Table 3: Adverse reactions MedDRA System Organ Class Very common Common Not known Infections and infestations Bronchitis Metabolism and nutrition Decreased appetite disorders Psychiatric disorders Abnormal behaviour Irritability Aggression Agitation Insomnia Mood swings Nervous system disorders Somnolence Ataxia Serotonin syndrome Hypotonia Lethargy Seizure Status epilepticus Tremor Cardiac disorders Valvular heart disease Respiratory, thoracic and Pulmonary arterial mediastinal disorders hypertension Gastrointestinal disorders Diarrhoea Constipation Salivary Hypersecretion Vomiting 10 Skin and subcutaneous tissue Rash disorders General disorders and Fatigue administration site conditions Investigations Weight decreased

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HOS-097345 · has-contraindication-information · PDF-Seite 5

Hypersensitivity to the active substance or any of the excipients listed in section 6.1. Aortic or mitral valvular heart disease. Pulmonary arterial hypertension. Within 14 days of the administration of monoamine oxidase inhibitors due to an increased risk of serotonin syndrome.

HOS-097344 · has-indication-information · PDF-Seite 2

Fintepla is indicated for the treatment of seizures associated with Dravet syndrome and Lennox- Gastaut syndrome as an add-on therapy to other anti-epileptic medicines for patients 2 years of age and older.

HOS-097347 · has-interaction-information · PDF-Seite 8

Pharmacodynamic interactions Pharmacodynamic interactions with other central nervous system depressants increase the risk of aggravated central nervous system depression. Examples of such depressants are other serotonergic medicinal products (including SSRIs, SNRIs, tricyclic antidepressants, or triptans); medicinal products that impair metabolism of serotonin such as MAOIs; or antipsychotics that may affect the serotonergic neurotransmitter systems (see sections 4.3 and 4.4). Pharmacokinetic interactions Clinical studies Effect of steady state stiripentol plus clobazam and/or valproate on fenfluramine At steady state in the Phase 3 studies, the co-administration of 0.2 mg/kg twice daily (0.4 mg/kg/day), maximum 17 mg/day, fenfluramine with a standard anti-epileptic medicine regimen of stiripentol plus clobazam and/or valproate, resulted in a 130% increase in fenfluramine AUC 0-24 and a 60% decrease in norfenfluramine AUC 0-24 , as compared to 0.35 mg/kg twice daily (0.7 mg/kg/day), maximum 26 mg/day, fenfluramine without stiripentol (see section 4.2). Effect of steady state cannabidiol on fenfluramine Co-administration of a single 0.35 mg/kg dose of fenfluramine with repeated doses of cannabidiol increased the AUC 0-INF of fenfluramine by 59% and the C max by 10%, and decreased the AUC 0-INF of norfenfluramine by 22% and the C max by 33%, as compared to fenfluramine administered alone. Co-administration of a single 0.35 mg/kg dose of fenfluramine, with repeated doses of cannabidiol, did not affect the pharmacokinetics of cannabidiol, as compared to cannabidiol alone. No dose adjustment is necessary when fenfluramine is co-administered with cannabidiol. Effect of rifampicin (a strong inducer of CYP3A and 2C19 and a moderate inducer of CYP1A2, 2B6, 2C8 and 2C9), or strong CYP1A2 or CYP2B6 inducers Rifampicin induces multiple CYP enzymes which metabolize fenfluramine and norfenfluramine. Coadministration of a single 0.35 mg/kg dose of fenfluramine with rifampicin at steady state (600 mg once daily) in healthy volunteers decreased the AUC 0-t of fenfluramine by 58% and the C max by 40%, and decreased the AUC 0-t of norfenfluramine by 50%, and increased the C max of norfenfluramine by 13%, as compared to fenfluramine administered alone. An increase in fenfluramine dose may be necessary when coadministered with rifampicin or a strong CYP1A2 or CYP2B6 inducer (see section 4.4). 8 Effect of CYP1A2 or CYP2D

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HOS-097348 · has-pregnancy-information · PDF-Seite 9

Pregnancy There are limited data (less than 300 pregnancy outcomes) from the use of fenfluramine in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity in the absence of paternal or maternal toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of Fintepla during pregnancy. Breast-feeding It is unknown whether fenfluramine/metabolites are excreted in human milk. Available pharmacokinetic data in animals have shown excretion of fenfluramine/metabolites in milk (see section 5.3). 9 A risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Fintepla therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility No effects of fenfluramine on human fertility up to clinical doses of 104 mg/day were noted. However, animal studies suggest that fenfluramine may possibly affect female fertility (see section 5.3).

HOS-097346 · has-warning-information · PDF-Seite 5

Aortic or mitral valvular heart disease and pulmonary arterial hypertension Fenfluramine can cause valvular heart disease and pulmonary arterial hypertension in patients treated for Dravet syndrome or Lennox-Gastaut syndrome (see section 4.8). Therefore, echocardiographic monitoring must be performed. Prior to starting treatment, patients must undergo an echocardiogram to establish a baseline prior to initiating treatment (see section 4.3) and exclude any pre-existing valvular heart disease or pulmonary hypertension. Echocardiogram monitoring should be conducted every 6 months for the first 2 years and annually thereafter. Once treatment is discontinued for any reasons, a final echocardiogram should be conducted 3-6 months after the last dose of treatment with fenfluramine. If an echocardiogram indicates pathological valvular changes, a follow-up echocardiogram should be considered at an earlier timeframe to evaluate whether the abnormality is persistent. If pathological abnormalities on the echocardiogram are observed, it is recommended to evaluate the benefit versus risk of continuing fenfluramine treatment with the prescriber, caregiver, and cardiologist. 5 If treatment is stopped because of aortic or mitral valvular heart disease, appropriate monitoring and follow-up should be provided in accordance with local guidelines for the treatment of aortic or mitral valvular heart disease. If echocardiogram findings are suggestive of pulmonary arterial hypertension, a repeat echocardiogram should be performed as soon as possible and within 3 months to confirm these findings. If the echocardiogram finding is confirmed suggestive of an increased probability of pulmonary arterial hypertension defined as “intermediate probability” by the European Society of Cardiology (ESC) and the European Respiratory Society (ERS) guidelines, it should lead to a benefit- risk evaluation of continuation of Fintepla by the prescriber, carer, and cardiologist. If the echocardiogram finding, after confirmation, suggests of a high probability of pulmonary arterial hypertension, as defined by the ESC and ERS guidelines, it is recommended fenfluramine treatment should be stopped. Decreased appetite and weight loss Fenfluramine can cause decreased appetite and weight loss (see section 4.8). An additive effect on decreased appetite can occur when fenfluramine is combined with other anti-epileptic medicines, for example stirip

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