Adverse reactions : תופעות לוואי

4.8     Undesirable effects

Unresectable or Metastatic Melanoma
Summary of the safety profile
The safety of Cotellic in combination with vemurafenib has been evaluated in 247 patients with advanced BRAF V600 mutated melanoma in Study GO28141.The median time to onset for the first Grade ≥3 adverse events was 0.6 months in the Cotellic plus vemurafenib arm vs 0.8 months in the placebo plus vemurafenib arm.

The safety of Cotellic in combination with vemurafenib has also been evaluated in 129 patients with advanced BRAF V600 mutated melanoma in Study NO25395. The safety profile of Study NO25395 was consistent with that observed in Study GO28141.

In Study GO28141, the most common adverse reactions (>20%) observed with a higher frequency in the Cotellic plus vemurafenib arm were diarrhoea, rash, nausea, pyrexia, photosensitivity reaction, increased alanine aminotransferase, increased aspartate aminotransferase, increased blood creatine phosphokinase, and vomiting. The most common adverse reactions (>20%) observed with a higher frequency in the placebo plus vemurafenib arm were arthralgia, alopecia, and hyperkeratosis. Fatigue was observed at similar frequencies in both arms.

Please refer to the vemurafenib Prescribing Information for complete descriptions of all undesirable effects associated with vemurafenib treatment.

Tabulated list of adverse reactions
Adverse drug reactions (ADRs) are based on results from a multi-centre, randomised, double-blind, placebo-controlled, Phase III Study (GO28141) that evaluated the safety and efficacy of Cotellic in combination with vemurafenib as compared to vemurafenib alone in previously untreated BRAF V600 mutation-positive patients with unresectable locally advanced (Stage IIIc) or metastatic melanoma (Stage IV).

ADR frequencies are based upon the safety analysis of patients treated with cobimetinib plus vemurafenib with a median follow up of 11.2 months (data cut-off date of 19 September 2014).

ADRs which were reported in melanoma patients are listed below by MedDRA body system organ class, frequency and grade of severity. The following convention has been used for the classification of frequency:
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

Table 3 lists adverse reactions considered associated with the use of Cotellic. Within each frequency grouping, ADRs are presented in order of decreasing severity and were reported according to NCI- CTCAE v 4.0 (common toxicity criteria) for assessment of toxicity in Study GO28141.


Table 3 Adverse drug reactions (ADRs) in patients treated with Cotellic in combination with vemurafenib in Study GO28141^

System organ class             Very Common                   Common                     Uncommon 

Neoplasms benign,                                            Basal cell carcinoma, malignant and                                                Cutaneous squamous unspecified (incl. cysts                                     cell carcinoma**, and polyps)                                                  Keratoacanthoma** Blood and lymphatic            Anaemia system disorders
Metabolism and                                               Dehydration, nutrition disorders                                          Hypophosphataemia, Hyponatremia,
Hyperglycaemia

Eye disorders                  Serous retinopathya,          Visual impairment Blurred vision

Vascular disorders             Hypertension,
Haemorrhage*

Respiratory, thoracic                                        Pneumonitis and mediastinal disorders
Gastrointestinal               Diarrhoea, Nausea,
disorders                      Vomiting, Stomatitis

Skin and subcutaneous          Photosensitivityb, Rash,
tissue disorders               Rash maculo-papular,
Dermatitis acneiform,
Hyperkeratosis**,
Pruritus c, Dry skin c

Musculoskeletal and                                                                     Rhabdomyolysis*** connective tissue disorders
General disorders and          Pyrexia, Chills, Oedema administration site            peripheralc conditions
Investigations                 Blood CPK increased,   Ejection fraction ALT increased, AST     decreased, Blood increased, Gamma-      bilirubin increased
Glutamyltransferase
(GGT) increased, Blood
ALP increased
^ Data cut-off date of 19 September 2014
* Please refer to the paragraph Haemorrhage in the “Description of selected adverse reactions” section ** Please refer to the paragraph Cutaneous squamous cell carcinoma, keratoacanthoma and hyperkeratosis in the “Description of selected adverse reactions” section.
*** Please refer to the paragraph Rhabdomyolysis in the “Description of selected adverse reactions” section.
a
Includes both chorioretinopathy and retinal detachment events indicative of serous retinopathy (see section 4.4) b
Combined figure includes reports of photosensitivity reaction, sunburn, solar dermatitis, actinic elastosis c
ADRs identified in a cobimetinib monotherapy study (ML29733; US study). However, these were also reported ADRs for cobimetinib plus vemurafenib combination in clinical trials conducted in patients with unresectable or metastatic melanoma.

Histiocytic Neoplasms

The safety of Cotellic was evaluated in Study ML29733, a single-center single-arm trial in patients with histiocytic neoplasms (see section 5.1). In Study ML29733, 26 patients with histiocytic neoplasms received Cotellic 60 mg once daily for 21 days on, then 7 days off, in a 28-day treatment cycle. The median treatment duration was 10.7 months. Table 4 presents adverse reactions in at least 15% of patients reported with histiocytic neoplasms treated with Cotellic. Table 5 presents laboratory abnormalities of grades ≥3 reported in patients with histiocytic neoplasms treated Cotellic.

In Study ML29733, 4 patients (15%) receiving Cotellic experienced an adverse reaction that resulted in permanent discontinuation of Cotellic. One patient discontinued due to worsening of underlying dyspnea and hypoxia; one patient discontinued due to retinal vascular disorder; one patient discontinued due to hyponatremia; and the other patient discontinued due to pneumonia.

Table 4       Incidence of Adverse Reactions Reported Occurring in ≥15% (All Grades) or Any Percentage (Grade ≥3) in Patients with Histiocytic Neoplasms Treated with Cotellic in Study ML29733

All Grades* (%)      Grades ≥3* (%)
Body Systems                                                   (n=26)               (n=26) Adverse reactions

GASTROINTESTINAL DISORDERS
Diarrhea                                                       62                   8 Nausea                                                         46                   0 Dyspepsia1                                                     27                   0 Vomiting                                                       27                   0 Dry Mouth                                                      15                   0 Oral pain2                                                     15                   0 GENERAL DISORDERS AND ADMINISTRATION SITE
CONDITIONS
Fatigue3                                                   42                   0 Edema4                                                         42                   4 Pain                                                           15                   0 INFECTIONS AND INFESTATIONS
Infections5                                                 62                   23 Urinary tract infection                                        23                   8 Pulmonary infections6                                          19                   12 INJURY, POISONING AND PROCEDURAL
COMPLICATIONS
Fall                                                           15                   4 INVESTIGATIONS
Decreased Ejection Fraction                                    19                   12 RENAL AND URINARY
Acute kidney injury                                            15                   12 RESPIRATORY, THORACIC AND MEDIASTINAL
DISORDERS
Dyspnea                                                        27                   15 Cough                                                          15                   0 SKIN AND SUBCUTANEOUS TISSUE DISORDERS
Acneiform dermatitis                                           65                   0 Dry skin                                                       31                   0 Maculo-papular rash                                            31                   0 Pruritus                                                       31                   4 
VASCULAR DISORDERS
Hemorrhage7                                                         19                  0 Hypertension                                                           15                  4 * NCI CTCAE v4.0.
1 Gastritis, and gastroesophageal reflux disease.
2 Oral dysesthesia and oropharyngeal pain.
3 Malaise
4 Facial edema, edema genital, edema peripheral, periorbital edema, and lymphoedema.
5 Influenza like illness, mucosal infection, paronychia, pharyngitis, pneumonia, bronchitis, sepsis, sinusitis, skin infection, tooth infection, upper respiratory tract infection., and urinary tract infection.
6 Pneumonia and bronchitis.
7 Epistaxis, contusion, purpura, hematoma, and rectal hemorrhage.

The following clinically relevant adverse reactions (all grades) of Cotellic were reported with <15% incidence in Study ML29733:
Eye disorders: Vision blurred (12%), retinal vascular disorder (4%) and retinopathy (4%).
Gastrointestinal disorders: Stomatitis (12%)
Nervous system disorders: Headache (12%)
Respiratory, thoracic, and mediastinal disorders: Hypoxia (12%), pulmonary edema (4%), and respiratory failure (8%).

Table 5 Incidence of Grade ≥3 Laboratory Abnormalities Occurring in Patients with Histiocytic Neoplasms Treated with Cotellic in Study ML29733*

Grades 3–4a
%
Chemistry
Increased blood creatine                27 phosphokinase
Hyponatremia                            18
Hypokalemia                             12
Increased blood creatinine              9
Increased AST                           9
Hypocalcemia                            9
Increased ALT                           5
Hematology
Lymphopenia                            27
Leukopenia                           9
Anemia                                  8
Neutropenia                             5
AST - aspartate aminotransferase, ALT - alanine aminotransferase
*All the percentages are based on the number of patients who had a baseline result and at least one on-study laboratory test.
a
NCI CTCAE v4.0

Description of selected adverse reactions

Haemorrhage
Bleeding events have been reported more frequently in the Cotellic plus vemurafenib arm than in the placebo plus vemurafenib arm (all types and Grades: 13% vs 7%). The median time to first onset was 6.1 months in the Cotellic plus vemurafenib arm.

The majority of events were Grade 1 or 2 and non-serious. Most events resolved with no change in Cotellic dose. Major haemorrhagic events (including intracranial and gastrointestinal tract haemorrhage) were reported in the post-marketing setting. The risk of haemorrhage may be increased with concomitant use of antiplatelet or anticoagulant therapy. If haemorrhage occurs, treat as clinically indicated (see section 4.2 and 4.4).
In Study ML29733, in patients with histiocytic neoplasms, 19% of patients experienced haemorrhage events (all were of grade 1 severity).


Rhabdomyolysis
Rhabdomyolysis has been reported in the post-marketing setting. Signs or symptoms of rhabdomyolysis warrant an appropriate clinical evaluation and treatment as indicated, along with Cotellic dose modification or discontinuation according to the severity of the adverse reaction (see section 4.2 and 4.4).

Photosensitivity

Photosensitivity has been observed with a higher frequency in the Cotellic plus vemurafenib arm vs placebo plus vemurafenib arm (47% vs 35%). The majority of events were Grades 1 or 2, with Grade ≥3 events occurring in 4% of patients in the Cotellic plus vemurafenib arm vs 0% in the placebo plus vemurafenib arm.

There were no apparent trends in the time of onset of Grade ≥3 events. Grade ≥3 photosensitivity events in the Cotellic plus vemurafenib arm were treated with primary topical medicinal products in conjunction with dose interruptions of both cobimetinib and vemurafenib (see section 4.2).

No evidence of phototoxicity was observed with Cotellic as a single agent.

Cutaneous squamous cell carcinoma, keratoacanthoma and hyperkeratosis 
Cutaneous squamous cell carcinoma has been reported with a lower frequency in the Cotellic plus vemurafenib arm vs placebo plus vemurafenib arm (all Grade: 3% vs 13%). Keratoacanthoma has been reported with a lower frequency in the Cotellic plus vemurafenib arm vs placebo plus vemurafenib arm (all Grade: 2% vs 9%). Hyperkeratosis has been reported with a lower frequency in the Cotellic plus vemurafenib vs placebo plus vemurafenib arm (all Grade: 11% vs 30%).

Serous retinopathy

Cases of serous retinopathy have been reported in patients treated with Cotellic (see section 4.4.) For patients reporting new or worsening visual disturbances, an ophthalmologic examination is recommended. Serous retinopathy can be managed with treatment interruption, dose reduction or with treatment discontinuation (see Table 1 in section 4.2).

Left ventricular dysfunction

Decrease in LVEF from baseline has been reported in patients receiving Cotellic (see section 4.4).
LVEF should be evaluated before initiation of treatment to establish baseline values, then after the first month of treatment and at least every 3 months or as clinically indicated until treatment discontinuation. Decrease in LVEF from baseline can be managed using treatment interruption, dose reduction or with treatment discontinuation (see section 4.2).
Laboratory abnormalities

Liver laboratory abnormalities
Liver laboratory abnormalities, specifically ALT, AST, and ALP have been observed in patients treated with Cotellic in combination with vemurafenib (see section 4.4).
Liver laboratory tests should be monitored before initiation of combination treatment and monthly during treatment, or more frequently if clinically indicated (see section 4.2).


Blood creatine phosphokinase increase
Asymptomatic increases in blood CPK levels were observed with a higher frequency in the Cotellic plus vemurafenib arm vs placebo plus vemurafenib arm in Study GO28141 (see section 4.2 and 4.4).
One event of rhabdomyolysis was observed in each treatment arm of the study with concurrent increases in blood CPK.

Table 6 provides the frequency of measured liver laboratory abnormalities and elevated creatine phosphokinase for all Grades and Grades 3-4.

Table 6 Liver function and other laboratory tests observed in the Phase III Study GO28141 
Changes in reported              Cobimetinib plus          Placebo plus vemurafenib laboratory data                 vemurafenib                      (n = 246) (n = 247)                         (%)
(%)
All Grades Grades 3-4         All Grades      Grades 3-4
Liver function test
Increased ALP                       69                  7          55              3 Increased ALT                       67                 11          54              5 Increased AST                       71                  7          43              2 Increased GGT                       62                 20          59              17 Increased blood bilirubin           33                  2          43              1 Other laboratory abnormalities
Increased blood CPK                 70                 12          14             <1 
In Study ML29733, in patients with histiocytic neoplasms, 27% of patients experienced grade 2 CPK elevation and 27% of patients experienced grade 3-4 CPK elevation.

Special populations

Elderly patients
In the Phase III study with Cotellic in combination with vemurafenib in patients with unresectable or metastatic melanoma (n=247), 183 patients (74%) were <65 years of age, and 44 patients (18%) were 65-74 years of age, 16 (6%) were 75-84 years of age, and 4 patients (2%) were aged 85 years. The proportion of patients experiencing adverse events (AE) was similar in the patients aged 65 years and those aged 65 years. Patients ≥65 years were more likely to experience serious adverse events (SAEs) and experience AEs leading to discontinuation of cobimetinib than those 65 years.

Paediatric population

The safety of Cotellic in children and adolescents has not been fully established. The safety of Cotellic was assessed in a multi-centre, open-label, dose-escalation study in 55 paediatric patients aged 2 to 17 years with solid tumours. The safety profile of Cotellic in these patients was consistent with that in the adult population (see section 5.2).
Renal impairment

No pharmacokinetic trial in subjects with renal impairment has been conducted. Dose adjustment is not recommended for mild to moderate renal impairment based on the results of the population pharmacokinetic analysis. There are minimal data for Cotellic in patients with severe renal impairment. Cotellic should be used with caution in patients with severe renal impairment.

Hepatic impairment

No dose adjustment is recommended in patients with hepatic impairment (see section 5.2).
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