Emcitate · 4.1 Therapeutic indications · 1

HOS-099351 · has-adverse-reaction-information · PDF-Seite 8

Summary of the safety profile The most commonly reported adverse reactions associated with the use of tiratricol treatment were hyperhidrosis (7%), diarrhoea (6%), irritability (2%), anxiety (2%), and nightmares (2%). These reactions usually occurred at the start of treatment and/or when the dose was increased, and generally resolved within a few days. Tabulated list of of adverse reactions The safety assessment of tiratricol is based on data from clinical trials. Adverse reactions are listed by MedDRA system organ class and frequency convention as follows: 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). Table 3. Adverse reactions System organ class Adverse reaction Frequency category Psychiatric disorders Irritability Common Anxiety Common Nightmares Common Insomnia Not known 8  Cardiac disorders Tachycardia Not known Gastrointestinal disorders Diarrhoea Common Skin and subcutaneous tissue disorders Hyperhidrosis Common General disorders and administration site Hyperthermia Not known conditions Description of selected adverse reactions Hypermetabolic signs and symptoms In clinical trials in patients with MCT8 deficiency, the onset of the observed adverse reactions hyperhidrosis, irritability, anxiety, and nightmares coincided with treatment initiation or dose modification. In all cases, these reactions were mild and resolved spontaneously. At initiation of tiratricol treatment and/or during dose titration, new onset or worsening of hypermetabolic signs and symptoms, such as hyperhidrosis, irritability, anxiety, insomnia, nightmares, hyperthermia, tachycardia, transient elevations in systolic blood pressure (SBP), or diarrhoea, may occur (see section 4.4). Paediatric population Safety data were evaluated in 63 patients between 0 and 17 years of age, in Triac Trial I and Triac Trial II combined. Thirty (30) patients were below 2 year

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HOS-099347 · has-contraindication-information · PDF-Seite 5

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Hyperthyroidism for other reasons than MCT8 deficiency (e.g. Grave’s Disease). Pregnancy (see section 4.6).

HOS-099346 · has-indication-information · PDF-Seite 2

Emcitate is indicated for the treatment of peripheral thyrotoxicosis in patients with monocarboxylate transporter 8 (MCT8) deficiency (Allan-Herndon-Dudley Syndrome), from birth.

HOS-099349 · has-interaction-information · PDF-Seite 6

Effect of other medicinal products on the pharmacokinetics of tiratricol No clinical interaction studies have been performed evaluating the effect of other medicinal products on tiratricol. The potential interactions described below are based on the in vitro characterisation of tiratricol and on known pharmacokinetic or pharmacodynamic interactions of thyromimetic agents with other medicinal products and not specifically studied with tiratricol. Concomitant use with precaution Medicinal products that may affect the absorption of tiratricol Antacids, charcoal, calcium, cationic resins (e.g. cholestyramine), iron, sucralphate, and other gastrointestinal agents may interfere with the gastrointestinal absorption of tiratricol. These treatments should be taken before or after tiratricol (more than 2 hours before or after if possible). In the case of cholestyramine, tiratricol should be taken 1 hour before or 4 hours after the resin dose. Adjustment of the tiratricol dose may be required to obtain the desired effect. Proton pump inhibitors (PPIs) Co-administration with PPIs may cause a decrease in the absorption of the thyroid hormones, due to the increase of the intragastric pH caused by PPIs such as omeprazole, esomeprazole, pantoprazole, rabeprazole and lansoprazole. Serum concentrations of T3 should be monitored and dose adjustment of tiratricol considered when initiating, changing or discontinuing PPI treatment. Sevelamer Sevelamer may decrease the concentration of thyroid hormones and result in reduced efficacy of tiratricol. Sevelamer should be taken more than 2 hours before or after administration of tiratricol. Medicinal products with enzyme-inducing effect including anti-epileptics Medicinal products that can induce the enzyme system in the liver, such as barbiturates, phenytoin carbamazepine, rifabutin, rifampicin or products containing St. John’s wort (Hypericum perforatum) may increase the hepatic clearance of tiratricol. Serum concentrations of T3 should be monitored and dose adjustment of tiratricol considered when initiating, changing or discontinuing an antiepileptic treatment regimen or other enzyme inducing agents. Antimalarial medicinal products 6 Concomitant use of tiratricol and antimalarial medicinal products (chloroquine, proguanil) may cause clinical hypothyroidism. Monitoring of serum concentrations of T3 and dose adjustment of tiratricol may be necessary during and after trea

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HOS-099350 · has-pregnancy-information · PDF-Seite 8

MCT8 deficiency is an X-linked disease that almost exclusively affects males. Pregnancy Tiratricol crosses the placenta. There are no or limited amount of data from the use of tiratricol in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Emcitate is contraindicated during pregnancy (see section 4.3). Women of childbearing potential Women of childbearing potential have to use effective contraception during treatment. Breast-feeding It is unknown whether tiratricol/metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Emcitate therapy considering the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility A study in rats showed no impact on fertility and mating ability (see section 5.3).

HOS-099348 · has-warning-information · PDF-Seite 5

Hypermetabolic signs and symptoms At initiation of Emcitate treatment and/or during dose titration, new onset or worsening of hypermetabolic signs and symptoms, such as hyperhidrosis, irritability, anxiety, insomnia, nightmares, hyperthermia, tachycardia, transient elevations in systolic blood pressure (SBP), or diarrhoea, may occur (see section 4.8). These signs and symptoms are usually transient and resolve spontaneously within a few days. If hypermetabolic signs and symptoms do not resolve within 2 weeks, the dose should be reduced according to the steps in the dose titration regimen (see section 4.2). Following the resolution of hypermetabolic signs and symptoms, dose titration may be resumed, as clinically appropriate. Cardiac disease Caution should be used during dose titration in patients with cardiac disease, as they may be at increased risk of adverse reactions associated with a hypermetabolic state (see section 4.8). Interference with laboratory tests Tiratricol cross-reacts with T3 if assessed by immunoassay, which may cause unreliable test results. It is recommended to use an LC/MS/MS method to measure T3 levels. Care should be taken if an immunoassay method is used. Specific guidelines should be followed for interpreting T3 test results when determining or adjusting the dose of tiratricol (see section 4.2). Diabetes Caution should be used in patients with diabetes (see section 4.5). 5 Hepatic impairment The safety and efficacy of Emcitate in patients with hepatic impairment have not been studied. Special care is required in these patients (see section 4.2). Renal impairment The safety and efficacy of Emcitate in patients with renal impairment have not been studied. Special care is required in these patients (see section 4.2). Misuse for weight reduction Tiratricol should not be taken for weight reduction. It may cause serious or life-threatening undesirable effects, particularly in combination with orlistat (see section 4.5 under “Orlistat”). Lactose Emcitate tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.