Adverse reactions : תופעות לוואי

         4.8        Undesirable effects

Summary of the safety profile
The overall safety profile of Stivarga is based on data from more than 4,800 treated patients in clinical trials including placebo-controlled phase III data for 636 patients with metastatic colorectal cancer (CRC), 132 patients with gastrointestinal stromal tumours (GIST) and 374 patients with hepatocellular carcinoma (HCC).

The safety profile of regorafenib in these studies was consistent with the safety results of a phase III B study conducted in 2872 patients with metastatic colorectal cancer whose disease had progressed after treatment with standard therapies.

The most serious adverse drug reactions in patients receiving Stivarga are severe liver injury, haemorrhage ,gastrointestinal perforation and infection.

The most frequently observed adverse drug reactions (≥30%) in patients receiving Stivarga are pain, hand foot skin reaction asthenia/fatigue, diarrhoea, decreased appetite and food intake, hypertension and infection.

Tabulated list of adverse reactions
The adverse drug reactions reported in clinical trials in patients treated with Stivarga are shown in Table 3. They are classified according to System Organ Class and the most appropriate MedDRA term is used to describe a certain reaction and its synonyms and related conditions.
Adverse drug reactions are grouped according to their frequencies. Frequency groups are defined by the following convention: 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) and not known (cannot be estimated from the available data).
.
Within each frequency group, undesirable effects are presented in order of decreasing seriousness.

Table 3: Adverse drug reactions (ADRs) reported in clinical trials in patients treated with Stivarga

System Organ
Class               Very common               Common               Uncommon                 Rare              Not known (MedDRA)
Infections and        Infection* infestations
Neoplasms                                                                                 Keratoacanthoma/ benign, malignant                                                                         Squamous cell and unspecified                                                                           carcinoma of the (including cysts                                                                          skin and polyps)
Blood and             Thrombocytopenia       Leucopenia                                      Thrombotic lymphatic system      Anaemia                                                              microangiopathy disorders
Immune system                                                         Hypersensitivity disorders                                                             reaction Endocrine                                    Hypothyroidism disorders


System Organ
Class             Very common             Common            Uncommon               Rare          Not known (MedDRA)
Metabolism and      Decreased appetite    Hypokalaemia nutrition disorders and food intake       Hypophosphataemia
Hypocalcaemia
Hyponatraemia
Hypomagnesaemia
Hyperuricaemia
Dehydration
Nervous system                            Headache                                 Posterior disorders                                 Tremor                                   reversible Peripheral                               encephalopathy neuropathy                               syndrome
(PRES)
Cardiac disorders                                              Myocardial infarction
Myocardial ischaemia
Vascular            Haemorrhage*                               Hypertensive                            Aneurysms disorders           Hypertension                               crisis                                   and artery dissections
Respiratory,        Dysphonia thoracic and mediastinal disorders
Gastrointestinal    Diarrhoea             Taste disorders      Gastrointestinal disorders           Stomatitis            Dry mouth            perforation* Vomiting              Gastro-oesophageal   Gastrointestinal
Nausea                reflux               fistula
Constipation          Gastroenteritis      Pancreatitis
Hepatobiliary       Hyperbilirubinaemia                        Severe liver disorders           Increase in                                injury(including transaminases                              hepatic failure )
*#
Skin and            Hand-foot skin        Alopecia             Nail disorder       Stevens-Johnson subcutaneous        reaction**            Dry skin             Erythema            syndrome tissue disorders    Rash                  Exfoliative rash     multiforme          Toxic epidermal necrolysis
Musculoskeletal and connective                            Muscle spasms tissue disorders
Renal and urinary                         Proteinuria disorders
General disorders   Asthenia/fatigue and                 Pain*** administration      Fever site conditions     Mucosal inflammation


System Organ
Class              Very common                 Common               Uncommon                Rare             Not known (MedDRA)
Investigations       Weight loss              Increase in amylase
Increase in lipase
Abnormal
International normalised ratio
* fatal cases have been reported
** palmar-plantar erythrodysesthesia syndrome in MedDRA terminology
***Most frequently reported types of pain (≥10%) are abdominal pain and back pain # according to drug-induced liver injury (DILI) criteria of the international DILI expert working group

Description of selected adverse reactions
In most cases of severe liver injury, liver dysfunction had an onset within the first 2 months of therapy, and was characterized by a hepatocellular pattern of injury with transaminase elevations >20xULN, followed by bilirubin increase. In clinical trials, a higher incidence of severe liver injury with fatal outcome was observed in Japanese patients (~1.5%) treated with Stivarga compared, with non- Japanese patients (<0.1%).
In the placebo-controlled phase III trials, the overall incidence of hemorrhage was 18.2% in patients treated with Stivarga and 9.5% in patients receiving placebo. Most cases of bleeding events in patients treated with Stivarga were mild to moderate in severity (Grades 1 and 2: 15.2%), most notably epistaxis (6.1 %). Fatal outcome in patients treated with Stivarga was uncommon (0.7 %), and included cerebral ,respiratory, gastrointestinal and genitourinary events.
In the placebo-controlled phase III trials, infections were more often observed in patients treated with Stivarga compared to patients receiving placebo (all grades: 31.6% vs. 17.2%). Most infections in patients treated with Stivarga were mild to moderate in severity (Grades 1 and 2: 23.0%), and included urinary tract infections (5.7%), nasopharyngitis (4.0%), mucocutaneous and systemic fungal infections (3.3%) as well as pneumonia (2.6%). Fatal outcomes associated with infection were observed more often in patients treated with Stivarga (1.0%), compared to patients receiving placebo (0.3%), and were mainly respiratory events.

In the placebo-controlled phase III trials, the overall incidence of hand-foot skin reaction was higher in patients treated with Stivarga compared to patients receiving placebo (all grades: 51.4% vs. 6.5% CRC, 66.7% vs. 15.2% GIST and 51.6% vs.7.3% HCC) . Most cases of hand-foot skin reaction in patients treated with Stivarga appeared during the first cycle of treatment and were mild to moderate in severity (Grades 1 and 2: 34.3%, CRC ,44.7%, GIST and 39.3%, HCC). The incidence of Grade 3 hand-foot skin reaction was 17.1%, (CRC) 22.0% (GIST) and 12.3% (HCC). The overall incidence of hand-foot skin reaction (74.8%, CRC, 88.2%, GIST and 67.1%, HCC) was higher in Stivarga-treated Asian patients compared to other ethnicities. The incidence of Grade 3 hand-foot skin reaction in Asians was 20.5% (CRC) ,23.5% (GIST) and 13.5% (HCC) (see sections 4.2 and 4.4).

In the placebo-controlled phase III trials, the overall incidence of hypertension was higher in patients treated with Stivarga, compared to patients receiving placebo (29.6% vs. 7.5% CRC, 60.6% vs. 25.8% GIST and 31.0% vs. 6.2% HCC). Most cases of hypertension in patients treated with Stivarga appeared during the first cycle of treatment and were mild to moderate in severity (Grades 1 and 2:           20.9%, CRC , 31.8%, GIST and 15.8% HCC). The incidence of Grade 3 hypertension was 8.7%
(CRC) , 28% (GIST) and 15.2% (HCC). One case of Grade 4 hypertension was reported in the GIST trial.


In the placebo-controlled phase III trials, the overall incidence of treatment emergent proteinuria was 9.1% in patients treated with Stivarga, compared to 1.9% in patients receiving placebo. Of these events, 35.6% in the Stivarga arm and 54.5% in the placebo arm have been reported as not recovered/not resolved

Across all clinical trials, cardiac disorder events (all grades) have been more often (13.7% vs. 6.5%) reported in Stivarga-treated patients aged 75 years or older (N=410) , compared to Stivarga-treated patients below 75 years (N=4108).

Laboratory test abnormalities
Treatment-emergent laboratory abnormalities observed in the placebo-controlled phase III trials are shown in Table 4 and, Table 4a (see also section 4.4).


Table 4: Treatment-emergent laboratory test abnormalities reported in placebo-controlled phase III trials in patients with metastatic CRC (CORRECT), GIST (GRID) and HCC (RESORCE)
 mCRC (CORRECT)                                         GIST (GRID)                                  HCC (RESORCE) Stivarga    Placebo Stivarga        Placebo   Stivarga plus     Placebo   Stivarga       Placebo   Stivarga    Placebo  Stivarga        Placebo plus     plus BSC plus BSC       plus BSC       BSC          plus BSC plus BSC        plus BSC   plus BSC   plus BSC plus BSC        plus BSC Laboratory Parameter           BSC       (n=253) (n= 500)        (n=253)     (n= 132)        (n= 66)  (n=132)         (n= 66)   (n= 374)    (n=193) (n= 374)         (n=193) (in % of samples           (n= 500) investigated)
Grade a                                             Grade b                                        Grade b All Grades %              Grade 3/4 %           All Grades %                   Grade 3/4 %         All Grades %               Grade 3/4 % Blood and lymphatic system disorders
Hemoglobin decreased              78.5        66.3          5.3       2.8         75.0             72.7         3.0        1.5       72.5       71.3            6.0       4.8 Thrombocytopenia                  40.5        16.8          2.8       0.4         12.9              1.5         0.8        1.5       63.1       50.0            5.4        0 Neutropenia                        2.8         0            0.6        0          15.9             12.1         3.1        3.0       13.6       14.9            3.0      1.0 Lymphopenia                       54.1        34.8          9.3       4.0         29.9             24.2         7.6        3.0       67.8       58.5           17.4      11.7 Metabolism and nutrition disorders
Hypocalcemia                      59.3        18.3           1.2      1.2         16.7             4.5           1.5        0        23.4       10.1            0.3        0 Hypokalemia                       25.7         8.3           4.3      0.4         20.5             3.0           3.0        0        30.7        9.0            4.3       2.1 Hypophosphatemia                  57.4        11.1          31.1      3.6         54.5             3.1          21.2       1.5       70.4       31.4           33.9       6.9 Hepatobiliary disorders
Hyperbilirubinemia
Increased AST                     44.6        17.1          12.2      8.4         33.3             12.1         3.8        1.5       78.2       54.5           15.9      15.7 Increased ALT                     65.0        45.6           5.9      5.2         58.3             47.0         3.8        3.0       92.7       84.3           17.8      19.9 45.2        29.8           5.5      3.2         39.4             39.4         4.6        1.5       70.4       58.6            6.2       4.7 Renal and urinary disorders
Proteinuria                       83.6        61.0          1.8       0.8         59.2             52.5         3.1        3.4       51.0       36.5           16.7       3.1 Investigations
Increased INR*                       23.7      16.6        4.2      1.6            9.3             12.5         1.6        4.7       44.4       35.4            0.7       2.1 Increased Lipase                     46.0      18.7       11.4      4.4           14.4              4.6         0.8         0        40.5       27.0           14.2       8.7 Increased Amylase                    25.5      16.7        2.6      2.4             -                -           -          -        23.0       19.0            2.8       2.7 a
Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0 b
Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0
* International normalized ratio
BSC = Best Supportive Care


Compared to the global phase III CRC trial (CORRECT) with predominantly (~80%) Caucasian patients enrolled, a higher incidence of liver enzyme increases was observed in Stivarga-treated patients in the Asian phase III CRC trial (CONCUR) with predominantly (> 90%) East Asian patients enrolled.
Table 4a: Treatment emergent liver enzyme test abnormalities reported in placebo-controlled phase III trial in Asian patients with metastatic CRC (CONCUR)
Stivarga plus BSC§                  Placebo plus BSC§
(N=136)                             (N=68)
Laboratory parameter,
(in % of samples
All        Grade        Grade       All        Grade       Grade investigated)
Grades*       3*           4*       Grades*       3*          4*

Bilirubin increased         66.7         7.4        4.4      32.8                4.5         0.0 AST increased               69.6        10.4        0.7      47.8                3.0         0.0 ALT increased               54.1         8.9        0.0      29.9                1.5         0.0 §
Best Supportive Care
* Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0 
In the placebo-controlled phase III trials, tests on thyroid stimulating hormone (TSH) showed post baseline >ULN in 34.6% of patients treated with Stivarga and in 17.2% of patients receiving placebo.
TSH post baseline >4 times ULN was reported in 6.5% of patients treated with Stivarga and in 1.3% of patients receiving placebo. Concentration of free triiodothyronine (FT3) post baseline below lower limit of normal (