Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile
The most common adverse drug reactions (ADR) of any grade (> 30%) reported with vemurafenib include arthralgia, fatigue, rash, photosensitivity reaction, alopecia, nausea diarrhea, headache, pruritus, vomiting, skin papilloma and hyperkeratosis. The most common (≥ 5%) Grade 3 ADRs were cuSCC, keratoacanthoma, rash, arthralgia and gamma-glutamyltransferase (GGT) increased. CuSCC was most commonly treated by local excision.

Tabulated summary of adverse reactions
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

In this section, ADRs are based on results in 468 patients from a phase III randomised open label study in adult patients with BRAF V600 mutation-positive unresectable or stage IV melanoma, as well as a phase II single-arm study in patients with BRAF V600 mutation-positive stage IV melanoma who had previously failed at least one prior systemic therapy (see section 5.1). In addition ADRs originating from safety reports across all clinical trials and post-marketing sources are reported. All terms included are based on the highest percentage observed among phase II and phase III clinical trials. Within each frequency grouping, ADRs are presented in order of decreasing severity and were reported using NCI-CTCAE v 4.0 (common toxicity criteria) for assessment of toxicity.


Table 3: ADRs occurring in patients treated with vemurafenib in the phase II or phase III study and events originating from safety reports across all trials(1) and post-marketing sources(2).

System organ class         Very Common                Common                Uncommon                     Rare 

Infections and                                  Folliculitis infestations
Neoplasms benign,       SCC of the skin (d),   Basal cell carcinoma, Non-cuSCC(1)(3)             Chronic malignant and           keratoacanthoma,       new primary                                       myelomonocytic unspecified             seborrhoeic keratosis, melanoma(3)                                       leukaemia(2)(4), (including cysts and    skin papilloma                                                           pancreatic polyps)                                                                                          adenocarcinoma(5) Blood and lymphatic                             Neutropenia system disorders                                thrombocytopenia(6)
Immune System                                                                                    Sarcoidosis (1)(2)(j) Disorders
Metabolism and          Decreased appetite nutrition disorders
Nervous system          Headache, dysgeusia, 7th nerve paralysis,
disorders               dizziness            neuropathy peripheral
Eye disorders                                Uveitis,                 Retinal vein occlusion, iridocyclitis
Vascular disorders                              Vasculitis
Respiratory, thoracic   Cough and mediastinal disorders
Gastrointestinal        Diarrhoea, vomiting,    Stomatitis            Pancreatitis(2) disorders               nausea, constipation
Hepatobiliary                                                         Liver injury(1)(2) (g) disorders
Skin and                Photosensitivity        Rash papular,         Toxic epidermal          Drug reaction with subcutaneous tissue     reaction, actinic       panniculitis          necrolysis (e), Stevens- eosinophilia and disorders               keratosis, rash, rash   (including erythema   Johnson syndrome (f)     systemic maculo-papular,         nodosum), keratosis                            symptoms(1)(2) pruritus,               pilaris hyperkeratosis,
erythema, palmar- plantar erythrodysaesthesia syndrome, alopecia,
dry skin, sunburn
Musculoskeletal and     Arthralgia, myalgia,    Arthritis,            Plantar fascial connective tissue       pain in extremity,                            fibromatosis(1)(2) disorders               musculoskeletal pain,                         Dupuytren’s back pain                                     contracture(1)(2)


System organ class            Very Common                      Common                 Uncommon                      Rare 

Renal and urinary                                                                                           Acute interstitial disorders                                                                                                   nephritis(1)(2) (h), acute tubular necrosis(1)(2) (h)
General disorders         Fatigue, pyrexia,
and administration        oedema peripheral,
site conditions           asthenia
Investigations                                       ALT increased (c), alkaline phosphatase increased (c), AST increased (c),bilirubin increased (c) GGT increased (c, weight decreased,
electrocardiogram
QT prolonged, blood creatinine increased(1)(2) (h)
Injury, Poisoning,                                   Potentiation of and Procedural                                       Radiation toxicity (1) (2) (i)
Complications
(1) Events originating from safety reports across all trials
(2) Events originating from post-marketing sources.
(3) A causal relationship between the medicinal product and the adverse event is at least a reasonable possibility.
(4) Progression of pre-existing chronic myelomonocytic leukaemia with NRAS mutation.
(5) Progression of pre-existing pancreatic adenocarcinoma with KRAS mutation.
(6)
Calculated based on phase II and phase III studies.


Description of selected adverse reactions
Hepatic enzyme increase (c)
Liver enzyme abnormalities reported in the phase III clinical study are expressed below as the proportion of patients who experienced a shift from baseline to a grade 3 or 4 liver enzyme abnormalities:
• Very common: GGT
• Common: ALT, alkaline phosphatase, bilirubin
• Uncommon: AST

There were no increases to Grade 4 ALT, alkaline phosphatase or bilirubin.

Liver injury (g)
Based on the criteria for drug induced liver injury developed by an international expert working group of clinicians and scientists, liver injury was defined as any one of the following laboratory abnormalities:
•    ≥ 5x ULN ALT
•    ≥ 2x ULN ALP (without other cause for ALP elevation)
•    ≥ 3x ULN ALT with simultaneous elevation of bilirubin concentration > 2x ULN 
Cutaneous squamous cell carcinoma (d) (cuSCC)
Cases of cuSCC have been reported in patients treated with vemurafenib. The incidence of cuSCC in vemurafenib-treated patients across studies was approximately 20%. The majority of the excised lesions reviewed by an independent central dermatopathology laboratory were classified as SCC- keratoacanthoma subtype or with mixed-keratoacanthoma features (52%). Most lesions classified as “other” (43%) were benign skin lesions (e.g. verruca vulgaris, actinic keratosis, benign keratosis, cyst/benign cyst). CuSCC usually occurred early in the course of treatment with a median time to the first appearance of 7 to 8 weeks. Of the patients who experienced cuSCC, approximately 33% experienced > 1 occurrence with median time between occurrences of 6 weeks. Cases of cuSCC were typically managed with simple excision, and patients generally continued on treatment without dose modification (see sections 4.2 and 4.4).

Non-cutaneous squamous cell carcinoma (non-cuSCC)
Cases of non-cuSCC have been reported in patients receiving vemurafenib while enrolled in clinical trials. Surveillance for non-cuSCC should occur as outlined in section 4.4.

New primary melanoma
New primary melanomas have been reported in clinical trials. These cases were managed with excision, and patients continued treatment without dose adjustment. Monitoring for skin lesions should occur as outlined in section 4.4.

Potentiation of radiation toxicity(i)
Cases reported include recall phenomenon, radiation skin injury, radiation pneumonitis, radiation esophagitis, radiation proctitis, radiation hepatitis, cystitis radiation, and radiation necrosis.

In a phase III clinical trial (MO25515, N= 3219), a higher incidence of potentiation of radiation toxicity was reported when vemurafenib patients received radiation prior to and during vemurafenib therapy (9.1%) compared to those patients who received radiation and vemurafenib concomitantly (5.2 %) or to those whose radiation treatment was prior to vemurafenib (1.5%).

Hypersensitivity reactions (e)
Serious hypersensitivity reactions, including anaphylaxis have been reported in association with vemurafenib. Severe hypersensitivity reactions may include Stevens-Johnson syndrome, generalised rash, erythema or hypotension. In patients who experience severe hypersensitivity reactions, vemurafenib treatment should be permanently discontinued (see section 4.4).

Dermatologic reactions (f)
Severe dermatologic reactions have been reported in patients receiving vemurafenib, including rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis in the pivotal clinical trial. In patients who experience a severe dermatologic reaction, vemurafenib treatment should be permanently discontinued.

QT prolongation
Analysis of centralised ECG data from an open-label uncontrolled phase II QT sub-study in 132 patients dosed with vemurafenib 960 mg twice daily (NP22657) showed an exposure-dependent QTc prolongation. The mean QTc effect remained stable between 12-15 ms beyond the first month of treatment, with the largest mean QTc prolongation (15.1 ms; upper 95% CI: 17.7 ms) observed within the first 6 months (n=90 patients). Two patients (1.5%) developed treatment-emergent absolute QTc values >500 ms (CTC Grade 3), and only one patient (0.8%) exhibited a QTc change from baseline of >60 ms (see section 4.4).

Acute kidney injury (h)
Cases of renal toxicity have been reported with vemurafenib ranging from creatinine elevations to acute interstitial nephritis and acute tubular necrosis, some observed in the setting of dehydration events. Serum creatinine elevations were mostly mild (>1-1.5x ULN) to moderate (>1.5-3x ULN) and observed to be reversible in nature (see table 4).

Table 4: Creatinine changes from baseline in the phase III study

Vemurafenib (%)      Dacarbazine (%)
Change  1 grade from baseline to any grade                   27.9                  6.1 Change  1 grade from baseline to grade 3 or higher            1.2                  1.1 •   To grade 3                                                  0.3                   0.4 •   To grade 4                                                  0.9                   0.8 
Table 5: Acute kidney injury cases in the phase III study

Vemurafenib (%)        Dacarbazine (%)
Acute kidney injury cases*                                      10.0                    1.4 Acute kidney injury cases associated with
5.5                   1.0 dehydration events
Dose modified for acute kidney injury                              2.1                    0 All percentages are expressed as cases out of total patients exposed to each medicinal product.
* Includes acute kidney injury, renal impairment, and laboratory changes consistent with acute kidney injury.

Sarcoidosis (j)
Cases of sarcoidosis have been reported in patients treated with vemurafenib, mostly involving the skin, lung and eye. In majority of the cases, vemurafenib was maintained and the event of sarcoidosis either resolved or persisted.

Special populations

Elderly
In the phase III study, ninety-four (28%) of 336 patients with unresectable or metastatic melanoma treated with vemurafenib were ≥ 65 years. Older patients (≥ 65 years) may be more likely to experience adverse reactions, including cuSCC, decreased appetite, and cardiac disorders.

Gender
During clinical trials with vemurafenib, grade 3 adverse reactions reported more frequently in females than males were rash, arthralgia and photosensitivity.

Paediatric population
The safety of vemurafenib in children and adolescents has not been established. No new safety signals were observed in a clinical study with six adolescent patients.

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