Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Sun Pharmaceutical Industries Europe B.V., Polarisavenue 87, 2132JH Hoofddorp, Netherlands
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).
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 events, 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.
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.
A woman of childbearing potential is defined in the Odomzo Pregnancy Prevention Programme as a sexually mature female who
Odomzo is contraindicated in women of childbearing potential who do not comply with the Odomzo Pregnancy Prevention Programme. A woman of childbearing potential must understand that:
h4.For men
Sonidegib may pass into the semen. To avoid potential foetal exposure during pregnancy, a male patient must understand that:
Healthcare professionals must educate patients so they understand and acknowledge all the conditions of the Odomzo Pregnancy Prevention Programme.
Women of child-bearing potential must use two methods of recommended contraception, including one highly effective method and a barrier method, while taking Odomzo and for 20 months after ending treatment (see section 4.6).
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 ending treatment (see sections 4.6 and 5.3).
The pregnancy status of women of child-bearing potential must be established within 7 days prior to the initiation of Odomzo treatment and monthly during treatment by means of a test performed by a healthcare professional. Pregnancy tests should have a minimum sensitivity of 25 mIU/ml as per local availability. In the event of pregnancy, treatment must not be initiated. In case of pregnancy occurring during treatment, Odomzo must be stopped immediately (see section 5.3). Patients who present with amenorrhoea during treatment with Odomzo should continue monthly pregnancy testing while on treatment.
The initial prescription and dispensing of Odomzo should occur within 7 days of a negative pregnancy test. Prescriptions of Odomzo should be limited to 30 days of treatment, with continuation of treatment requiring a new prescription.
In order to help healthcare providers and patients avoid embryonic and foetal exposure to Odomzo, the Marketing Authorisation Holder will provide educational materials (Odomzo Pregnancy Prevention Programme) to reinforce the potential risks associated with use of the medicinal product.
Patients should be instructed not to donate blood while taking Odomzo and for at least 20 months after ending treatment.
Male patients should not donate semen while taking Odomzo and for at least 6 months after ending treatment.
Concomitant treatment with strong CYP inducers (e.g. rifampicin, carbamazepine or phenytoin) should be avoided, as a risk for decreased plasma concentrations and decreased efficacy of sonidegib cannot be excluded (see also section 4.5).
Patients with advanced BCC have an increased risk of developing cuSCC. Cases of cuSCC have been reported in advanced BCC patients treated with Odomzo. It has not been determined whether cuSCC is related to Odomzo treatment. Therefore, all patients should be monitored routinely while taking Odomzo, and cuSCC should be treated according to the standard of care.
Patients should be instructed never to give this medicinal product to another person. Any capsules that remain unused at the end of treatment should immediately be disposed of by the patient in accordance with local requirements (e.g. by returning the capsules to their pharmacist or physician).
Odomzo capsules contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Sonidegib undergoes metabolism primarily by CYP3A4, and concomitant administration of strong inhibitors or inducers of CYP3A4 can increase or decrease sonidegib concentrations significantly.
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.
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 Odomzo 200 mg with esomeprazole (a proton pump inhibitor) at 40 mg daily for 6 days in healthy subjects. This interaction is not expected to be clinically significant.
Sonidegib is a competitive inhibitor of CYP2B6 and CYP2C9 in vitro. However, results of a drug-drug interaction study in cancer patients demonstrate that the systemic exposure of bupropion (a CYP2B6 substrate) and warfarin (a CYP2C9 substrate) is not altered when co-administered with sonidegib. Sonidegib is also a breast cancer resistance protein (BCRP) inhibitor (IC50 ~1.5µM). Patients concomitantly using substrates of BCRP transporters should be carefully monitored for adverse drug reactions. Substances that are BCRP substrates with narrow therapeutic range (e.g. methotrexate, mitoxantrone, irinotecan, topotecan) should be avoided.
Due to overlapping toxicities, patients taking Odomzo who are also taking medicinal products known to increase the risk of muscle-related toxicity may be at increased risk of developing muscle-related adverse events. Patients should be closely monitored and dose adjustments should be considered if muscle symptoms develop.
In the phase II pivotal trial, 12 (15.2%) patients treated with Odomzo 200 mg took concomitant HMG-CoA reductase inhibitors (9 took pravastatin, 3 took non-pravastatin HMG-CoA reductase inhibitors including rosuvastatin and simvastatin). Of these patients, 7 (58.3%) had up to grade 1 muscle symptoms while 43 (64.1%) patients not taking HMG-CoA reductase inhibitors experienced up to grade 3 symptoms. No patient taking HMG-CoA reductase inhibitors experienced grade ¾ CK elevations, as opposed to 6 (9.0%) patients not taking HMG-CoA reductase inhibitors.
The bioavailability of sonidegib is increased in the presence of food (see section 5.2). Odomzo must be taken at least two hours after a meal and at least one hour before the following meal.
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).
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.
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.
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.
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.
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 ending treatment (see section 5.3).
Data from studies in rats and dogs indicate that male and female fertility may be irreversibly compromised by treatment with Odomzo (see section 5.3). Additionally, amenorrhoea has been observed in clinical trials in women of childbearing potential (see section 4.8). Fertility preservation strategies should be discussed with women of childbearing potential prior to starting treatment with Odomzo.
Odomzo has no or negligible influence on the ability to drive and use machines.
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 ¾ 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 ¾ adverse reactions, except fatigue.
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 Preferred term | Frequency all grades 200 mg |
|---|---|
| Metabolism and nutrition disorders | |
| Decreased appetite | Very common |
| Dehydration | Common |
| Nervous system disorders | |
| Dysgeusia | Very common |
| Headache | Very common |
| Gastrointestinal disorders | |
| Nausea | Very common |
| Diarrhoea | Very common |
| Abdominal pain | Very common |
| Vomiting | Very common |
| Dyspepsia | Common |
| Constipation | Common |
| Gastro-oesophageal reflux disorder | Common |
| Skin and subcutaneous tissue disorders | |
| Alopecia | Very common |
| Pruritus | Very common |
| Rash | Common |
| Abnormal hair growth | Common |
| Musculoskeletal and connective tissue disorders | |
| Muscle spasms | Very common |
| Musculoskeletal pain | Very common |
| Myalgia | Very common |
| Myopathy [muscular fatigue and muscular weakness] | Common |
| Reproductive system and breast disorders | |
| Amenorrhoea* | |
| General disorders and administration site conditions | |
| Fatigue | Very common |
| Pain | Very common |
| Investigations | |
| Weight decreased | Very common |
* Of the 79 patients receiving Odomzo 200 mg, 5 were women of childbearing age. Among these women, amenorrhoea was observed in 1 patient (20%).
The most commonly reported grade ¾ laboratory abnormalities with an incidence of ≥5% occurring in patients treated with Odomzo 200 mg were lipase increase and blood CK increase (Table 3).
Table 3. Laboratory abnormalities*:
| Laboratory test | Frequency all grades 200 mg |
|---|---|
| Haematological parameters | |
| Haemoglobin decreased | Very common |
| Lymphocyte count decreased | Very common |
| Biochemistry parameters | |
| Serum creatinine increased | Very common |
| Serum creatine phosphokinase (CK) increased | Very common |
| Blood glucose increased | Very common |
| Lipase increased | Very common |
| Alanine amino transaminase (ALT) increased | Very common |
| Aspartate amino transaminase (AST) increased | Very common |
| Amylase increased | Very common |
* Based on worst laboratory value post-treatment regardless of baseline, grading by CTCAE version 4.03
Muscle toxicity is the most clinically relevant side effect reported in patients receiving sonidegib therapy and is believed to be a class effect of inhibitors of the Hedgehog (Hh) signalling pathway. In the phase II pivotal study muscle spasms were the most common “muscle-related” adverse events, and were reported in fewer patients in the Odomzo 200 mg group (54%) than in the Odomzo 800 mg group (69%).
Grade ¾ increase in blood CK was reported in 8% of patients taking Odomzo 200 mg. The majority of patients who had grade 2 or higher CK elevations developed muscle symptoms prior to the CK elevations. In these patients, increases in laboratory values of CK to grade 2 and higher severity had a median time to onset of 12.9 weeks (range 2 to 39 weeks) after initiating Odomzo therapy and a median time to resolution (to normalisation or grade 1) of 12 days (95% CI 8 to 14 days).
One patient receiving Odomzo 200 mg experienced muscle symptoms and CK elevations above 10x ULN and required intravenous fluids, compared to 6 patients receiving Odomzo 800 mg.
In the phase II pivotal study, no reported cases of rhabdomyolysis were confirmed (defined as CK levels >10-fold above the pre-treatment or baseline level or >10x ULN if no baseline level reported plus a 1.5-fold increase in serum creatinine from the pre-treatment or baseline level). However, one reported case in a patient treated with Odomzo 800 mg in a non-pivotal study was confirmed.
In the phase II pivotal study, 2 (14.3%) out of 14 women of either child-bearing potential or of child-bearing age sterilised by tubal ligation developed amenorrhoea while on treatment with Odomzo 200 mg or 800 mg once daily.
The evaluation of safety in the paediatric population is based on data from 16 adult and 60 paediatric patients from Study CLDE225X2104 and 16 adult and 2 paediatric patients from Study CLDE225C2301. The median duration of exposure to sonidegib during Study X2104 was 97 days (range 34 to 511 days) for adult patients and 55 days (range 2 to 289 days) for paediatric patients. The median duration of exposure to sonidegib during Study C2301 was 2.8 months (range 0.4 to 33.2 months) for adult patients and 3.5 months (range 1.3 to 5.7 months) for paediatric patients.
The toxicity of sonidegib as observed in studies C2301 and X2104 in adults was in line with the already known treatment related toxicity reported in adult patients with basal cell carcinoma. The sonidegib-related toxicity reported in paediatric patients was similar to the results reported in adults, with the exceptions of a reduced incidence of muscle toxicity (e.g. CK elevations observed in 16.7% of paediatric patients compared with 50% of adults in study X2104) and the observation of post-natal development effect particularly with prolonged exposure (reported as cases of epiphyseal plate of phalanx disorder, knee subchondral condensation of area of growth plate, physeal distal femur disorder, chondropathy, and chipped tooth).
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
Not applicable.
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