Odomzo · 4.5 Interaction with other medicinal products and other forms of interaction · 1

HOS-216647 · has-adverse-reaction-information · PDF-Seite 10

Summary of the safety profile The phase II pivotal study evaluated the safety of Odomzo in a total of 229 adult patients with locally advanced or metastatic BCC. Patients were treated with Odomzo 200 mg daily (n=79) or with Odomzo 800 mg daily (n=150). The median duration of treatment was 11.0 months for patients treated with Odomzo at the recommended dose of 200 mg (range 1.3 to 41.3 months). One death occurred while on treatment or within 30 days of the last dose taken in either metastatic BCC or locally advanced BCC patients taking Odomzo 200 mg. The most common adverse drug reactions occurring in ≥10% of patients treated with Odomzo 200 mg were muscle spasms, alopecia, dysgeusia, fatigue, nausea, musculoskeletal pain, diarrhoea, weight decreased, decreased appetite, myalgia, abdominal pain, headache, pain, vomiting and pruritus. The most common grade 3/4 adverse drug reactions occurring in ≥2% of patients treated with Odomzo 200 mg were fatigue, weight decreased and muscle spasms. Among adverse drug reactions reported (Table 2), the frequency was greater in patients taking Odomzo 800 mg than in patients taking Odomzo 200 mg except for musculoskeletal pain, diarrhoea, abdominal pain, headache and pruritus. This was also true for grade 3/4 adverse reactions, except fatigue. 10 Tabulated list of adverse drug reactions Adverse drug reactions for the recommended dose from the phase II pivotal clinical study (Table 2) are listed by Medical Dictionary for Regulatory Activities (MedDRA) version 18 system organ class. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): 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 2 Adverse drug reactions observed in the phase II pivotal study Primary system organ class Frequency all grades Preferred term 200 mg Metabolism and nutrition disorders Decreased appetite Very common De

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HOS-216643 · has-contraindication-information · PDF-Seite 5

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Pregnancy and breast-feeding (see sections 4.4 and 4.6). Women of childbearing potential who do not comply with the Odomzo Pregnancy Prevention Programme (see sections 4.4 and 4.6).

HOS-216642 · has-indication-information · PDF-Seite 2

Odomzo is indicated for the treatment of adult patients with locally advanced basal cell carcinoma (BCC) who are not amenable to curative surgery or radiation therapy.

HOS-216645 · has-interaction-information · PDF-Seite 8

Sonidegib undergoes metabolism primarily by CYP3A4, and concomitant administration of strong inhibitors or inducers of CYP3A4 can increase or decrease sonidegib concentrations significantly. Agents that may increase sonidegib plasma concentration In healthy subjects, co-administration of a single 800 mg dose of sonidegib with ketoconazole (200 mg twice daily for 14 days), a strong CYP3A inhibitor, resulted in a 2.25-fold and a 1.49-fold increase in sonidegib AUC and Cmax, respectively, compared with sonidegib alone. Longer duration of concomitant use of CYP3A4 strong inhibitors (e.g. more than 14 days) will lead to a larger fold change in sonidegib exposure based on simulation. If concomitant use of a strong CYP3A inhibitor is required, the sonidegib dose should be reduced to 200 mg every other day. Strong CYP3A inhibitors include, but are not limited to, ritonavir, saquinavir, telithromycin, ketoconazole, itraconazole, voriconazole, posaconazole and nefazodone. Patients should be carefully monitored for adverse events if one of these agents is used together with sonidegib. Agents that may decrease sonidegib plasma concentration In healthy subjects, co-administration of a single dose of 800 mg sonidegib with rifampicin (600 mg daily for 14 days), a strong CYP3A inducer, resulted in 72% and 54% decreases in sonidegib AUC and Cmax respectively, compared with when sonidegib was given alone. Co-administration of sonidegib with strong CYP3A inducers decreases sonidegib plasma concentration. Concomitant use of strong CYP3A inducers should be avoided; this includes, but is not limited to, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampicin and St John’s Wort (Hypericum perforatum). If a strong CYP3A4 inducer must be used concomitantly with sonidegib, consideration should be given to increasing the daily dose of sonidegib to 400-800 mg. This dose of sonidegib is predicted to adjust the AUC to the range observed without inducers based on pharmacokinetic data when the concomitant treatment with the inducer is no longer than 14 days. Longer concomitant treatment with inducer is not recommended because sonidegib exposure will be decreased and this may compromise efficacy. The dose of sonidegib used prior to initiation of the strong inducer should be resumed if the strong inducer is discontinued. Results from a clinical study demonstrated a change in sonidegib exposure (32% and 38% decrease in AUC and Cmax) after co-administration of a single dose of Od

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HOS-216646 · has-pregnancy-information · PDF-Seite 9

Women of childbearing potential Due to the risk of embryofoetal death or severe birth defects caused by sonidegib, women taking Odomzo must not be pregnant or become pregnant during treatment and for 20 months after ending treatment (see section 4.4). Odomzo is contraindicated in woman of childbearing potential who do not comply with the Odomzo Pregnancy Prevention Programme (see section 4.3). In case of pregnancy or missed menstrual periods If the patient does become pregnant, misses a menstrual period, or suspects for any reason that she may be pregnant, she must notify her treating physician immediately. Persistent lack of menses during treatment with Odomzo should be assumed to indicate pregnancy until medical evaluation and confirmation. Contraception in males and females Women of childbearing potential Women of childbearing potential must be able to comply with effective contraceptive measures. They must use two methods of recommended contraception, including one highly effective method and a barrier method, during Odomzo therapy and for 20 months after the final dose. Women of childbearing potential whose periods are irregular or have stopped must follow all the advice on effective contraception. Men It is unknown whether sonidegib is contained in semen. Men should not father a child or donate semen while taking Odomzo and for at least 6 months after ending treatment. To avoid potential foetal exposure during pregnancy, male patients, even those who have had a vasectomy, must always use a condom (with spermicide, if available) when having sex with a female partner while taking Odomzo and for 6 months after the final dose. 9 The following are recommended forms of highly effective methods • Tubal sterilisation • Vasectomy • Intrauterine device (IUD) The following are recommended barrier methods • Any male condom (with spermicide, if available) • Diaphragm (with spermicide, if available) Pregnancy There are no data on the use of sonidegib in pregnant women. Studies in animals have shown teratogenicity and foetotoxicity (see section 5.3). Odomzo is contraindicated during pregnancy. Breast-feeding It is unknown whether sonidegib is excreted in human milk. Because of the potential for serious adverse drug reactions, such as serious developmental defects in breast-fed newborns/infants from sonidegib, women must not breast-feed while taking Odomzo or for 20 months after

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HOS-216644 · has-warning-information · PDF-Seite 5

Muscle-related adverse reactions In the phase II pivotal study, muscle spasms, myalgia, myopathy and cases of CK elevations were observed. The majority of patients treated with Odomzo 200 mg daily who had grade 2 or higher CK elevations developed muscle symptoms prior to the CK elevations. For most patients, muscle symptoms and CK elevations resolved with appropriate management. All patients starting therapy with Odomzo must be informed of the risk of muscle-related adverse reactions, including the possibility of rhabdomyolysis. They must be instructed to report promptly any unexplained muscle pain, tenderness or weakness occurring during treatment with Odomzo or if symptoms persist after discontinuing treatment. CK levels should be checked prior to starting treatment and as clinically indicated thereafter, e.g. if muscle-related symptoms are reported. If clinically notable elevation of CK is detected, renal function should be assessed (see section 4.2). Dose modification or interruption guidelines should be followed (see section 4.2). Management of high-grade CK elevation using supportive therapy, including proper hydration, should be considered according to local standards of medical practice and treatment guidelines. Patients should be closely monitored for muscle-related symptoms if Odomzo is used in combination with certain medicinal products that may increase the potential risk of developing muscle toxicity (e.g. CYP3A4 inhibitors, chloroquine, hydroxychloroquine, fibric acid derivatives, penicillamine, zidovudine, niacin and HMG-CoA reductase inhibitors) (see section 4.5). Patients with neuromuscular disorders (e.g. inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy) must be closely monitored due to an increased risk of muscle toxicity. 5 Embryofoetal death or severe birth defects Odomzo may cause embryo-foetal death or severe birth defects when administered to pregnant women. Based on the mechanism of action, in animal studies, sonidegib has been shown to be teratogenic and foetotoxic. Women taking Odomzo must not be pregnant or become pregnant during treatment and for 20 months after ending treatment. Criteria defining a woman of childbearing potential A woman of childbearing potential is defined in the Odomzo Pregnancy Prevention Programme as a sexually mature female who • has menstruated at any time during the previous 12 conse

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