Adverse reactions : תופעות לוואי

4.8     Undesirable effects

The most important serious adverse reactions were myocardial infarction/ischaemia, gastrointestinal perforation, drug induced hepatitis, haemorrhage, and hypertension/hypertensive crisis.

The most common adverse reactions were diarrhoea, fatigue, alopecia, infection, hand foot skin reaction (corresponds to palmar plantar erythrodysaesthesia syndrome in MedDRA) and rash.

Adverse reactions reported in multiple clinical trials or through post- marketing use are listed below in table 1, by system organ class (in MedDRA) and frequency. Frequencies are defined as: 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), not known (cannot be estimated from the available data).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.



Table 1: All adverse reactions reported in patients in multiple clinical trials or through post- marketing use
System organ       Very common         Common                Uncommon           Rare               Not known class infection           folliculitis
Infections and infestations
 lymphopenia           leucopenia
Blood and lymphatic                              neutropenia anaemia system disorders thrombocytopenia

Immune system                                                hypersensitivity   angioedema disorders                                                    reactions (including skin reactions and urticaria) anaphylactic reaction hypothyroidism         hyperthyroidism
Endocrine disorders

Metabolism and anorexia hypocalcaemia          dehydration                            tumour lysis nutrition      hypo-                  hypokalaemia                                                  syndrome disorders                             hyponatraemia phosphataemia hypoglycaemia

Psychiatric                            depression disorders

Nervous system                        peripheral sensory reversible                                 encephalopathy° neuropathy         posterior
System organ       Very common          Common               Uncommon            Rare               Not known class disorders                              dysgeusia            leukoencephalo- pathy*
Ear and                                 tinnitus labyrinth disorders

Cardiac                                 congestive heart                         QT prolongation disorders                               failure* myocardial ischaemia and infarction* haemorrhage          flushing             hypertensive                           aneurysms and Vascular
(inc.                                     crisis*                                artery disorders gastrointestinal,*                                                               dissections respiratory tract* and cerebral haemorrhage*) hypertension

Respiratory,                            rhinorrhoea          interstitial lung thoracic and                            dysphonia            disease-like mediastinal                                                  events* disorders                                                    (pneumonitis, radiation pneumonitis,
acute respiratory distress, etc.) diarrhoea            stomatitis           pancreatitis
Gastro intestinal         nausea               (including dry disorders          vomiting             mouth and            gastritis constipation         glossodynia) gastrointestinal dyspepsia            perforations*
 dysphagia
 gastro oesophageal reflux disease
Hepatobiliary                                                increase in         drug induced disorders                                                    bilirubin and       hepatitis* jaundice,
cholecystitis,
cholangitis dry skin             keratoacanthoma/     eczema              radiation recall Skin and squamous cell                            dermatitis subcutaneous       rash cancer of the skin   erythema tissue disorders alopecia             dermatitis           multiforme          Stevens-Johnson exfoliative                              syndrome hand foot skin leucocytoclastic reaction**           acne vasculitis erythema             skin desquamation
System organ        Very common        Common               Uncommon           Rare               Not known class toxic epidermal pruritus           hyperkeratosis                          necrolysis* 
Musculo-            arthralgia         myalgia                                  rhabdomyolysis skeletal and muscle spasms connective tissue disorders
 renal failure                           nephrotic
Renal and proteinuria                             syndrome urinary disorders
 erectile             gynaecomastia
Reproductive dysfunction system and breast disorders
General             fatigue            asthenia disorders and       pain (including administration                         influenza like mouth,             illness site conditions     abdominal, bone,
tumour pain and    mucosal headache)          inflammation fever weight decreased   transient increase   transient
Investigations in transaminases     increase in increased amylase                                 blood alkaline phosphatase increased lipase
INR abnormal,
prothrombin level abnormal

* The adverse reactions may have a life-threatening or fatal outcome. Such events are either uncommon or less frequent than uncommon.
** Hand foot skin reaction corresponds to palmar plantar erythrodysaesthesia syndrome in MedDRA.
° Cases have been reported in the post marketing setting.

Further information on selected adverse drug reactions

Congestive heart failure
In company sponsored clinical trials congestive heart failure was reported as an adverse event in 1.9% of patients treated with sorafenib (N= 2276). In study 11213 (RCC) adverse events consistent with congestive heart failure were reported in 1.7% of patients treated with sorafenib and 0.7% receiving placebo. In study 100554 (HCC), 0.99% of those treated with sorafenib and 1.1% receiving placebo were reported with these events.

Additional information on special populations
In clinical trials, certain adverse drug reactions such as hand foot skin reaction, diarrhoea, alopecia, weight decrease, hypertension, hypocalcaemia, and keratoacanthoma/squamous cell carcinoma of skin occurred at a substantially higher frequency in patients with differentiated thyroid compared to patients in the renal cell or hepatocellular carcinoma studies.

Laboratory test abnormalities in HCC (study 3) and RCC (study 1) patients Increased lipase and amylase were very commonly reported. CTCAE Grade 3 or 4 lipase elevations occurred in 11 % and 9 % of patients in the sorafenib group in study 1 (RCC) and study 3 (HCC), respectively, compared to 7 % and 9 % of patients in the placebo group. CTCAE Grade 3 or 4 amylase elevations were reported in 1 % and 2 % of patients in the sorafenib group in study 1 and study 3, respectively, compared to 3 % of patients in each placebo group. Clinical pancreatitis was reported in 2 of 451 sorafenib treated patients (CTCAE Grade 4) in study 1, 1 of 297 sorafenib treated patients in study 3 (CTCAE Grade 2), and 1 of 451 patients (CTCAE Grade 2) in the placebo group in study 1.

Hypophosphataemia was a very common laboratory finding, observed in 45 % and 35 % of sorafenib treated patients compared to 12 % and 11% of placebo patients in study 1 and study 3, respectively.
CTCAE Grade 3 hypophosphataemia (1 – 2 mg/dl) in study 1 occurred in 13% of sorafenib treated patients and 3% of patients in the placebo group, in study 3 in 11% of sorafenib treated patients and 2 % of patients in the placebo group. There were no cases of CTCAE Grade 4 hypophosphataemia (< 1 mg/dl) reported in either sorafenib or placebo patients in study 1, and 1 case in the placebo group in study 3. The aetiology of hypophosphataemia associated with sorafenib is not known.

CTCAE Grade 3 or 4 laboratory abnormalities occurring in ≥ 5 % of sorafenib treated patients included lymphopenia and neutropenia.

Hypocalcaemia was reported in 12% and 26.5% of sorafenib treated patients compared to 7.5% and 14.8% of placebo patients in study 1 and study 3, respectively. Most reports of hypocalcaemia were low grade (CTCAE Grade 1 and 2). CTCAE grade 3 hypocalcaemia (6.0 – 7.0 mg /dL) occurred in 1.1% and 1.8%of sorafenib treated patients and 0.2% and 1.1% of patients in the placebo group, and CTCAE grade 4 hypocalcaemia (< 6.0 mg/dL) occurred in 1.1% and 0.4% of sorafenib treated patients and 0.5% and 0% of patients in the placebo group in study 1 and 3, respectively. The aetiology of hypocalcaemia associated with sorafenib is not known.

In studies 1 and 3 decreased potassium was observed in 5.4% and 9.5% of sorafenib-treated patients compared to 0.7% and 5.9% of placebo patients, respectively. Most reports of hypokalaemia were low grade (CTCAE Grade 1). In these studies CTCAE Grade 3 hypokalaemia occurred in 1.1% and 0. 4% of sorafenib treated patients and 0.2% and 0.7% of patients in the placebo group. There were no reports of hypokalaemia CTCAE grade 4.

Laboratory test abnormalities in DTC patients (study 5)

Hypocalcaemia was reported in 35.7% of sorafenib treated patients compared to 11.0% of placebo patients. Most reports of hypocalcaemia were low grade. CTCAE grade 3 hypocalcaemia occurred in 6.8% of sorafenib treated patients and 1.9% of patients in the placebo group, and CTCAE grade 4 hypocalcaemia occurred in 3.4% of sorafenib treated patients and 1.0% of patients in the placebo group.

Other clinically relevant laboratory abnormalities observed in the study 5 are shown in table 2.

Table 2: Treatment-emergent laboratory test abnormalities reported in DTC patient (study 5) double blind period

Laboratory parameter,              Sorafenib N=207                     Placebo N=209 (in % of samples              All        Grade    Grade       All        Grade       Grade investigated)             Grades*       3*       4*       Grades*       3*          4* Blood and lymphatic system disorders
Anemia                          30.9           0.5        0        23.4         0.5         0 Thrombocytopenia                18.4            0         0        9.6           0          0 
Laboratory parameter,           Sorafenib N=207                     Placebo N=209 (in % of samples           All       Grade     Grade       All        Grade       Grade investigated)          Grades*      3*        4*       Grades*       3*          4* Neutropenia                        19.8        0.5       0.5        12           0          0 Lymphopenia                         42         9.7       0.5       25.8         5.3         0 Metabolism and nutrition disorders

Hypokalemia                        17.9        1.9        0          2.4         0         0 Hypophosphatemia**                19.3    12.6       0           2.4       1.4             0 Hepatobiliary disorders
Bilirubin increased               8.7       0        0           4.8         0              0 ALT increased                     58.9     3.4      1.0         24.4         0              0 AST increased                     53.6     1.0      1.0         14.8         0              0 Investigations
Amylase increased                 12.6     2.4      1.4          6.2         0             1.0 Lipase increased                  11.1     2.4       0           2.9       0.5              0 * Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 ** The aetiology of hypophosphatemia associated with sorafenib is not known.
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/