Adverse reactions : תופעות לוואי

4.8    Undesirable effects

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.

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
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                                      Common
[muscular fatigue and muscular weakness]
Reproductive system and breast disorders
Amenorrhoea*                                  Very common
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%).

Clinically relevant laboratory abnormalities

The most commonly reported grade 3/4 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

Description of selected adverse drug reactions

Muscle-related adverse reactions including CK elevation
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 reactions, and were reported in fewer patients in the Odomzo 200 mg group (54%) than in the Odomzo 800 mg group (69%).

Grade 3/4 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.

Amenorrhoea
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.


Paediatric population
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).

Premature fusion of the epiphyses
Three cases (one case of cartilage injury, one case of epiphyseal disorder and one case of epiphyseal fracture) of epiphyseal growth plate disorders were reported in paediatric patients treated with sonidegib during clinical studies but causal association with sonidegib cannot be ascertained conclusively. Premature fusion of the epiphyses has been reported in paediatric patients exposed to Hh (Hedgehog) pathway inhibitors. Odomzo should not be used in paediatric patients as safety and effectiveness is not established in this population.

Reporting of suspected adverse reactions
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.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il