Leitlinien & Arzneimittelsicherheit

HOS-096404 · has-adverse-reaction-information · PDF-Seite 13

Summary of the safety profile The most serious adverse reactions during treatment were liver aminotransferase abnormalities (see section 4.4). The most common adverse reactions in adults are gastrointestinal effects (93%) i.e. diarrhoea (79%), nausea (65%), dyspepsia (38%), and vomiting (34%). Other reactions reported by at least 20% of patients include abdominal pain, abdominal discomfort, abdominal distension, constipation, and flatulence. Gastrointestinal adverse reactions occurred more frequently during the dose escalation phase of the study and decreased once patients established the maximum tolerated dose of lomitapide. The most commonly reported adverse reactions of severe intensity were diarrhoea (14%), vomiting (10%), abdominal distension (7%) and ALT increased (7%). Tabulated list of adverse reactions The adverse reactions are listed below by MedDRA SOC (System Organ Class) and by frequency, most frequent reactions first. Frequency of the adverse reactions is defined as: 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). 13 Table 4 lists all adverse reactions reported across the adult and paediatric HoFH patients treated in clinical studies and post marketing experience. Table 4: Frequency of adverse reactions in HoFH patients System organ class Frequency Adverse reaction Infections and infestations Common Gastroenteritis Metabolism and nutrition Very common Decreased appetite* disorders Not known Dehydration Nervous system disorders Common Dizziness Headache Migraine Gastrointestinal disorders Very common Diarrhoea* Nausea* Vomiting* Abdominal discomfort Dyspepsia Abdominal pain* Abdominal pain upper*

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HOS-096400 · has-contraindication-information · PDF-Seite 5

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. • Patients with moderate or severe hepatic impairment and those with unexplained persistent abnormal liver function tests (see section 4.2). • Patients with a known significant or chronic bowel disease such as inflammatory bowel disease or malabsorption. • Concomitant administration of > 40 mg simvastatin (see section 4.5). 5 • Concomitant use of Lojuxta with strong or moderate CYP3A4 inhibitors (e.g. antifungal azoles such as itraconazole, fluconazole,ketoconazole, voriconazole, posaconazole; macrolide antibiotics such as erythromycin or clarithromycin; ketolide antibiotics such as telithromycin; human immunodeficiency virus (HIV) protease inhibitors; the calcium channel blockers diltiazem and verapamil, and the anti-arrhythmic dronedarone [see section 4.5]). • Pregnancy (see section 4.6).

HOS-096399 · has-indication-information · PDF-Seite 3

Lojuxta is indicated as an adjunct to a low-fat diet and other lipid-lowering medicinal products with or without low density lipoprotein (LDL) apheresis for the treatment of adult and paediatric patients aged 5 years and older with homozygous familial hypercholesterolaemia (HoFH). Genetic confirmation of HoFH should be obtained whenever possible. Other forms of primary hyperlipoproteinemia and secondary causes of hypercholesterolaemia (e.g. nephrotic syndrome, hypothyroidism) must be excluded.

HOS-096402 · has-interaction-information · PDF-Seite 10

Effects of other medicinal products on lomitapide and other forms of interaction Table 3: Interactions between lomitapide and other medicinal products and other forms of interaction Medicinal Effects on lomitapide levels Recommendation concerning products co-administration with lomitapide Inhibitors of Strong and moderate inhibitors Strong and moderate inhibitors CYP3A4 When lomitapide 60 mg was Use of strong or moderate inhibitors of co-administered with ketoconazole CYP3A4 is contraindicated with Lojuxta. If 200 mg twice daily, a strong treatment with antifungal azoles (e.g. inhibitor of CYP3A4, lomitapide itraconazole, ketoconazole, fluconazole, area under the curve (AUC) voriconazole, posaconazole); the increased approximately 27-fold and antiarrhythmic dronedarone; macrolide maximum plasma concentration antibiotics (e.g. erythromycin, (Cmax) increased approximately clarithromycin); ketolide antibiotics (e.g. 15-fold. telithromycin); HIV protease inhibitors; the calcium channel blockers diltiazem and Interactions between moderate verapamil is unavoidable, therapy with CYP3A4 inhibitors and lomitapide Lojuxta should be suspended during the have not been studied. course of treatment (see sections 4.3 and 4.4). Moderate CYP3A4 inhibitors are predicted to have a substantial Grapefruit juice is a moderate inhibitor of impact on lomitapide CYP3A4 and is expected to substantially pharmacokinetics. Concomitant use increase exposure to lomitapide. Patients of moderate CYP3A4 inhibitors are taking Lojuxta should avoid consumption of expected to increase lomitapide grapefruit juice. exposure by 4-10 fold based on the results of the study with the strong CYP3A4 inhibitor ketoconazole and on historical data for the mod

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HOS-096403 · has-pregnancy-information · PDF-Seite 13

Use in women and adolescents of child-bearing potential Before initiating treatment in women and adolescents of child-bearing potential, the absence of pregnancy should be confirmed, appropriate advice on effective methods of contraception provided, and effective contraception initiated. Patients taking oestrogen-based oral contraceptives should be advised about possible loss of effectiveness due to diarrhoea and/or vomiting. Additional contraceptive measures should be used until resolution of symptoms (see section 4.5). Pregnancy Lojuxta is contraindicated during pregnancy. There are no reliable data on its use in pregnant women. Animal studies have shown developmental toxicity (teratogenicity, embryotoxicity, see section 5.3). The potential risk for humans is unknown. Breast-feeding It is not known whether lomitapide is excreted into human milk. Because of the potential for adverse effects based on findings in animal studies with lomitapide (see section 5.3), a decision should be made whether to discontinue breast-feeding or discontinue the medicinal product, taking into account the importance of the medicinal product to the mother. Fertility No adverse effects on fertility were observed in male and female rats administered lomitapide at systemic exposures (AUC) estimated to be 4 to 5 times higher than in humans at the maximum recommended human dose (see section 5.3).

HOS-096401 · has-warning-information · PDF-Seite 6

Liver enzyme abnormalities Lomitapide can cause elevations in the liver enzymes alanine aminotransferase [ALT] and aspartate aminotransferase [AST] and hepatic steatosis (see section 5.1). There have been no concomitant or subsequent clinically meaningful elevations in serum bilirubin, International Normalised Ratio (INR), or alkaline phosphatase. The extent to which lomitapide-associated hepatic steatosis promotes the elevations in aminotransferase is unknown. The liver enzyme changes can occur at any time during therapy. Although cases of hepatic dysfunction (elevated aminotransferase with increase in bilirubin or INR) or hepatic failure have not been reported, there is concern that lomitapide could induce steatohepatitis, which can progress to cirrhosis over several years. The clinical studies supporting the safety and efficacy of lomitapide in HoFH would have been unlikely to detect this adverse outcome given their size and duration. Monitoring of liver function tests Measure ALT, AST, alkaline phosphatase, total bilirubin, gamma-glutamyl transferase (gamma-GT) and serum albumin before initiation of treatment with Lojuxta. The medicinal product is contraindicated in patients with moderate or severe hepatic impairment and those with unexplained persistent abnormal liver function tests. If the baseline liver-related tests are abnormal, consider initiating the medicinal product after appropriate investigation by a hepatologist and the baseline abnormalities are explained or resolved. During the first year, measure liver-related tests (ALT and AST, at a minimum) prior to each increase in dose or monthly, whichever occurs first. After the first year, do these tests at least every 3 months and before any increase in dose. Decrease the dose of lomitapide if elevations of aminotransferase are observed and discontinue treatment for persistent or clinically significant elevations (see Table 2). Dose modification based on elevated hepatic aminotransferases Table 2 summarises recommendations for dose adjustment and monitoring for patients who develop elevated aminotransferase during therapy with Lojuxta. 6 Table 2: Dose adjustment and monitoring for patients with elevated aminotransferases ALT or AST Treatment and monitoring recommendations* ≥ 3 x and < 5 x Upper • Confirm elevation with a repeat measurement within one week. Limit of Normal (ULN) •

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