Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Cabozantinib as monotherapy
Summary of safety profile
The most common serious adverse drug reactions in the RCC population (≥1% incidence) are pneumonia abdominal pain, diarrhoea, nausea, hypertension, embolism, hyponatraemia, pulmonary embolism, vomiting, dehydration, fatigue, asthenia, decreased appetite, deep vein thrombosis, dizziness, hypomagnesaemia and palmar-plantar erythrodysaesthesia syndrome (PPES).

The most frequent adverse reactions of any grade (experienced by at least 25% of patients) in the RCC population included diarrhoea, fatigue, nausea, decreased appetite, PPES, hypertension, weight decreased, vomiting, dysgeusia, constipation, and AST increased. Hypertension was observed more frequently in the treatment naïve RCC population (67%) compared to RCC patients following prior VEGF-targeted therapy (37%).

The most common serious adverse drug reactions in the HCC population (≥1% incidence) are hepatic encephalopathy, asthenia, fatigue, PPES, diarrhoea, hyponatraemia, vomiting, abdominal pain and thrombocytopenia.
The most frequent adverse reactions of any grade (experienced by at least 25% of patients) in the HCC population included diarrhoea, decreased appetite, PPES, fatigue, nausea, hypertension and vomiting.

The most common serious adverse drug reactions in the DTC population (≥1% incidence) are diarrhoea, pleural effusion, pneumonia, pulmonary embolism, hypertension, anaemia, deep vein thrombosis, hypocalcemia, osteonecrosis of jaw, pain, palmar-plantar erythrodysaesthesia syndrome, vomiting and renal impairment.

The most frequent adverse reactions of any grade (experienced by at least 25% of patients) in the DTC population included diarrhoea, PPES, hypertension, fatigue, decreased appetite, nausea, alanine aminotransferase increased, aspartate aminotransferase increased and hypocalcaemia.

Tabulated list of adverse reactions
Adverse reactions reported in the pooled dataset for patients treated with cabozantinib monotherapy in RCC, HCC and DTC (n=1128) or reported after post-marketing use of cabozantinib are listed in Table 2. The adverse reactions are listed by MedDRA system organ class and frequency categories. Frequencies are based on all grades and defined as: very common (≥1/10), common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 2: Adverse drug reactions (ADRs) reported in clinical trials or after post-marketing use in patients treated with cabozantinib in monotherapy
Infections and infestations
Common                 Abscess, pneumonia
Blood and lymphatic disorders
Very common            anaemia, thrombocytopenia
Common                 neutropenia, lymphopenia
Endocrine disorders
Very common            hypothyroidism*
Metabolism and nutrition disorders
Very common            decreased appetite, hypomagnesaemia, hypokalaemia, hypoalbuminaemia Common                 dehydration, hypophosphataemia, hyponatraemia, hypocalcaemia, hyperkalaemia, hyperbilirubinemia, hyperglycaemia, hypoglycaemia
Nervous system disorders
Very common            dysgeusia, headache, dizziness
Common                 peripheral neuropathy a
Uncommon               convulsion, cerebrovascular accident, posterior reversible encephalopathy syndrome
Ear and labyrinth disorders
Common                 tinnitus
Cardiac disorders
Uncommon               acute myocardial infarction
Vascular disorders
Very common            hypertension, haemorrhageb*
Common                 venous thrombosisc,
Uncommon               hypertensive crisis, arterial thrombosis, embolism arterial Not known              aneurysms and artery dissections
Respiratory, thoracic, and mediastinal disorders
Very common            dysphonia, dyspnoea, cough
Common                 pulmonary embolism
Uncommon               pneumothorax
Gastrointestinal disorders
Very common            diarrhoea*, nausea, vomiting, stomatitis, constipation, abdominal pain, dyspepsia Common                 gastrointestinal perforation*, pancreatitis, fistula*, gastroesophageal reflux disease, haemorrhoids, oral pain, dry mouth, dysphagia,
Uncommon              glossodynia
Hepatobiliary disorders
Common                hepatic encephalopathy*
Uncommon              hepatitis cholestatic
Skin and subcutaneous tissue disorders
Very common           palmar-plantar erythrodysaesthesia syndrome, rash Common                pruritus, alopecia, dry skin, dermatitis acneiform, hair colour change, hyperkeratosis, erythema
Not known             cutaneous vasculitis
Musculoskeletal and connective tissue disorders
Very common           pain in extremity
Common                muscle spasms, arthralgia
Uncommon              osteonecrosis of the jaw
Renal and urinary disorders
Common                proteinuria
General disorders and administration site conditions
Very common           fatigue, mucosal inflammation, asthenia, peripheral oedema d
Investigations
Very common           weight decreased, serum ALT increased, AST increased Common                blood ALP increased, GGT increased, blood creatinine increased, amylase increased, lipase increased, blood cholesterol increased, blood triglycerides increased
Injury, poisoning and procedural complications
Uncommon              wound complicationse
*
See section 4.8 Description of selected adverse reactions for further characterisation.
a including polyneuropathy; peripheral neuropathy is mainly sensory b
Including epistaxis as the most commonly reported adverse reaction c
All venous thrombosis including deep vein thrombosis d
Based on reported adverse reactions e
Impaired healing, incision site complication and wound dehiscence

Cabozantinib in combination with nivolumab in first-line advanced RCC Summary of safety profile
When cabozantinib is administered in combination with nivolumab, refer to the SmPC for nivolumab prior to initiation of treatment. For additional information on the safety profile of nivolumab monotherapy, please refer to the nivolumab SmPC.

In a dataset of cabozantinib 40 mg once daily in combination with nivolumab 240 mg every two weeks in RCC (n =320), with a minimum follow‑up of 16 months, the most common serious adverse drug reactions (≥1% incidence) are diarrhoea, pneumonitis, pulmonary embolism, pneumonia, hyponatremia, pyrexia, adrenal insufficiency, vomiting, dehydration.

The most frequent adverse reactions (≥25%) were diarrhoea, fatigue, palmar-plantar erythrodysaesthesia syndrome, stomatitis, musculoskeletal pain, hypertension, rash, hypothyroidism, decrease appetite, nausea, abdominal pain. The majority of adverse reactions were mild to moderate (Grade 1 or 2).

Tabulated list of adverse reactions
Adverse reactions identified in the clinical study of cabozantinib in combination with nivolumab are listed in Table 3, according to MedDRA System Organ Class and frequency categories. Frequencies are based on all grades and defined as: very common (≥1/10), common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.


Table 3: Adverse reactions with cabozantinib in combination with nivolumab Infections and infestations
Very Common               upper respiratory tract infection
Common                    pneumonia
Blood and lymphatic system disorders
Common                    eosinophilia
Immune system disorders
Common                    hypersensitivity (including anaphylactic reaction) Uncommon                  infusion related hypersensitivity reaction
Endocrine disorders
Very common               hypothyroidism, hyperthyroidism
Common                    adrenal insufficiency
Uncommon                  hypophysitis, thyroiditis
Metabolism and nutrition disorders
Very common               decreased appetite
Common                    dehydration
Nervous system disorders
Very common               dysgeusia, dizziness, headache
Common                    peripheral neuropathy
Uncommon                  encephalitis autoimmune, Guillain-Barré syndrome, myasthenic syndrome Ear and labyrinth disorders
Common                    tinnitus
Eye disorders
Common                    dry eye, blurred vision
Uncommon                  uveitis
Cardiac disorders
Common                    atrial fibrillation, tachycardia
Uncommon                  myocarditis
Vascular disorders
Very common               hypertension
Common                    thrombosisa
Uncommon                  embolism arterial
Respiratory, thoracic and mediastinal disorders
Very common               dysphonia, dyspnoea, cough
Common                    pneumonitis, pulmonary embolism, epistaxis, pleural effusion Uncommon                  pneumothorax
Gastrointestinal disorders diarrhoea, vomiting, nausea, constipation, stomatitis, abdominal pain, Very common dyspepsia
Common                    colitis, gastritis, oral pain, dry mouth, haemorrhoids Uncommon                  pancreatitis, small intestine perforation b, glossodynia Hepatobiliary disorders
Common                    hepatitis
Not known                 vanishing bile duct syndromec
Skin and subcutaneous tissue disorders
Very common               palmar-plantar erythrodysaesthesia syndrome, rashd, pruritus Common                    alopecia, dry skin, erythema, hair colour change Uncommon                  psoriasis, urticaria
Not known                 cutaneous vasculitis
Musculoskeletal and connective tissue disorders
Very common               musculoskeletal paine, arthralgia, muscle spasm, Common                    arthritis
Uncommon                myopathy, osteonecrosis of the jaw, fistula
Renal and urinary disorders
Very common             proteinuria
Common                  renal failure, acute kidney injury
Uncommon                nephritis
General disorders and administration site conditions
Very common             fatigue, pyrexia, oedema
Common                  pain, chest pain
Investigationsf increased ALT, increased AST, hypophosphataemia, hypocalcaemia,
hypomagnesaemia, hyponatraemia, hyperglycaemia, lymphopenia,
increased alkaline phosphatase, increased lipase, increased amylase,
Very common                   thrombocytopaenia, increased creatinine, anaemia, leucopenia, hyperkalaemia, neutropenia, hypercalcaemia, hypoglycaemia,
hypokalaemia, increased total bilirubin, hypermagnesaemia,
hypernatraemia, weight decreased
Common                        blood cholesterol increased, hypertriglyceridaemia Adverse reaction frequencies presented in Table 3 may not be fully attributable to cabozantinib alone but may contain contributions from the underlying disease or from nivolumab used in a combination.
a
Thrombosis is a composite term which includes portal vein thrombosis, pulmonary vein thrombosis, pulmonary thrombosis, aortic thrombosis, arterial thrombosis, deep vein thrombosis, pelvic vein thrombosis, vena cava thrombosis, venous thrombosis, venous thrombosis limb b
Fatal cases have been reported c
With prior or concomitant immune checkpoint inhibitor exposure d
Rash is a composite term which includes dermatitis, dermatitis acneiform, dermatitis bullous, exfoliative rash, rash erythematous, rash follicular, rash macular, rash maculo-papular, rash papular, rash pruritic and drug eruption e
Musculoskeletal pain is a composite term which includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, spinal pain f
Frequencies of laboratory terms reflect the proportion of patients who experienced a worsening from baseline in laboratory measurements with the exception of weight decreased, blood cholesterol increased and hypertriglyceridaemia

Description of selected adverse reactions
Data for the following reactions are based on patients who received CABOMETYX 60 mg orally once daily as monotherapy in the pivotal studies in RCC following prior VEGF-targeted therapy and in treatment-naïve RCC, in HCC following prior systemic therapy and in DTC in patient refractory or not eligible to radioactive iodine (RAI) who have progressed during or after prior systemic therapy or in patients who received CABOMETYX 40 mg orally once daily in combination with nivolumab in first-line advanced RCC (section 5.1).

Gastrointestinal (GI) perforation (see section 4.4)
In the study in RCC following prior VEGF-targeted therapy (METEOR), GI perforations were reported in 0.9% (3/331) of cabozantinib-treated RCC patients. Events were Grade 2 or 3. Median time to onset was 10.0 weeks.
In the treatment-naïve RCC study (CABOSUN), GI perforations were reported in 2.6% (2/78) of cabozantinib-treated patients. Events were Grade 4 and 5.
In the HCC study (CELESTIAL), GI perforations were reported in 0.9% of cabozantinib-treated patients (4/467). All events were Grade 3 or 4. Median time to onset was 5.9 weeks.
In the DTC study (COSMIC-311), GI perforation grade 4 was reported in one patient (0.6%) of cabozantinib-treated patients and occurred after 14 weeks of treatment.
In combination with nivolumab in advanced RCC in first-line treatment (CA2099ER) the incidence of GI perforations was 1.3% (4/320) treated patients. One event was grade 3, two events were grade 4 and one event was grade 5 (fatal).
Fatal perforations have occurred in the cabozantinib clinical program.
Hepatic encephalopathy (see section 4.4)
In the HCC study (CELESTIAL), hepatic encephalopathy (hepatic encephalopathy, encephalopathy, hyperammonaemic encephalopathy) was reported in 5.6% of cabozantinib-treated patients (26/467); Grade 3-4 events in 2.8%, and one (0.2%) Grade 5 event. Median time to onset was 5.9 weeks.
No cases of hepatic encephalopathy were reported in the RCC studies (METEOR, CABOSUN and CA2099ER) and in the DTC study (COSMIC-311).

Diarrhoea (see section 4.4)
In the study in RCC following prior VEGF-targeted therapy (METEOR), diarrhoea was reported in 74% of cabozantinib-treated RCC patients (245/331); Grade 3-4 events in 11%. Median time to onset was 4.9 weeks.
In the treatment-naïve RCC study (CABOSUN), diarrhoea was reported in 73% of cabozantinib-treated patients (57/78); Grade 3-4 events in 10%.
In the HCC study (CELESTIAL), diarrhoea was reported in 54% of cabozantinib-treated patients (251/467); Grade 3- 4 events in 9.9%. Median time to onset of all events was 4.1 weeks. Diarrhoea led to dose modifications, interruptions and discontinuations in 84/467 (18%), 69/467 (15%) and 5/467 (1%) of subjects, respectively.
In the DTC study (COSMIC-311), diarrhoea was reported in 62% of cabozantinib treated patients (105/170); Grade 3-4 events in 7.6%. Diarrhoea led to dose reduction and interruption in 24/170 (14%) and 36/170 (21%) of subjects respectively.
In combination with nivolumab in advanced RCC in first-line treatment (CA2099ER), the incidence of diarrhoea was reported in 64.7% (207/320) of treated patients; Grade 3-4 events in 8.4% (27/320). Median time to onset of all events was 12.9 weeks. Dose delay or reduction occurred in 26.3% (84/320) and discontinuation in 2.2% (7/320) of patients with diarrhoea, respectively.

Fistulas (see section 4.4)
In the study in RCC following prior VEGF-targeted therapy (METEOR), fistulas were reported in 1.2% (4/331) of cabozantinib-treated patients and included anal fistulas in 0.6% (2/331) cabozantinib-treated patients. One event was Grade 3; the remainder were Grade 2. Median time to onset was 30.3 weeks.
In the treatment-naïve RCC study (CABOSUN), no cases of fistulas were reported.
In the HCC study (CELESTIAL), fistulas were reported in 1.5% (7/467) of the HCC patients. Median time to onset was 14 weeks.
In the DTC study (COSMIC-311), fistulas (two anal and one pharyngeal fistula) were reported in 1.8 % (3/170) of the cabozantinib treated patients.
In combination with nivolumab in advanced RCC in first-line treatment (CA2099ER) the incidence of fistula was reported in 0.9% (3/320) of treated patients and the severity was Grade 1.
Fatal fistulas have occurred in the cabozantinib clinical program

Haemorrhage (see section 4.4)
In the study in RCC following prior VEGF-targeted therapy (METEOR), the incidence of severe haemorrhagic events (Grade ≥ 3) was 2.1% (7/331) in cabozantinib-treated RCC patients. Median time to onset was 20.9 weeks.
In the treatment-naïve RCC study (CABOSUN), the incidence of severe haemorrhagic events (Grade ≥ 3) was 5.1% (4/78) in cabozantinib-treated RCC patients.
In the HCC study (CELESTIAL), the incidence of severe haemorrhagic events (Grade ≥ 3) was 7.3% in cabozantinib-treated patients (34/467). Median time to onset was 9.1 weeks.
In combination with nivolumab in advanced RCC in first-line treatment (CA2099ER) the incidence of ≥ Grade 3 haemorrhage was in 1.9% (6/320) of treated patients.
In the DTC study (COSMIC-311), the incidence of severe haemorrhagic events (grade ≥ 3) was 2.4% in cabozantinib-treated patients (4/170). Median time to onset was 80.5 days.
Fatal haemorrhages have occurred in the cabozantinib clinical program.

Posterior reversible encephalopathy syndrome (PRES) (see section 4.4) No case of PRES was reported in the METEOR,CABOSUN, CA2099ER or CELESTIAL studies, but PRES has been reported in one patient in the DTC study (COSMIC-311) and rarely in other clinical trials (in 2/4872 subjects; 0.04%).
Elevated liver enzymes when cabozantinib is combined with nivolumab in RCC In a clinical study of previously untreated patients with RCC receiving cabozantinib in combination with nivolumab, a higher incidence of Grades 3 and 4 ALT increased (10.1%) and AST increased (8.2%) were observed relative to cabozantinib monotherapy in patients with advanced RCC (ALT increased of 3.6% and AST increased of 3.3% in METEOR study). The median time to onset of grade > 2 increased ALT or AST was 10.1 weeks (range: 2 to 106.6 weeks; n=85). In patients with grade ≥ 2 increased ALT or AST, the elevations resolved to Grades 0-1in 91% with median time to resolution of 2.29 weeks (range: 0.4 to 108.1 weeks).
Among the 45 patients with Grade ≥2 increased ALT or AST who were rechallenged with either cabozantinib (n=10) or nivolumab (n=10) administered as a single agent or with both (n=25), recurrence of Grade ≥2 increased ALT or AST was observed in 4 patients receiving cabozantinib, in 3 patients receiving nivolumab and 8 patients receiving both cabozantinib and nivolumab.

Hypothyroidism
In the study in RCC following prior VEGF-targeted therapy (METEOR), the incidence of hypothyroidism was 21% (68/331).
In the treatment-naïve RCC study (CABOSUN), the incidence of hypothyroidism was 23% (18/78) in cabozantinib-treated RCC patients.
In the HCC study (CELESTIAL), the incidence of hypothyroidism was 8.1% (38/467) in cabozantinib- treated patients and Grade 3 events in 0.4% (2/467).
In the DTC study (COSMIC-311), the incidence of hypothyroidism was 2.4% (4/170), all grade 1-2, none requiring modification of treatment.
In combination with nivolumab in advanced RCC in first-line treatment (CA2099ER) the incidence of hypothyroidism was 35.6% (114/320) of treated patients.

Paediatric population (see section 5.1)

In study ADVL1211, a limited dose-escalation study of cabozantinib in paediatric and adolescent patients with recurrent or refractory solid tumors including CNS tumors, the following events: aspartate aminotransferase (AST) increased (very common, 76.9%), alanine aminotransferase (ALT) increased (very common, 71.8%), lymphocyte count decreased (very common, 48.7%), neutrophil count decreased (very common, 35.9%), and lipase increased (very common, 33.3%) were observed at a higher frequency in all subjects across all dose groups included in the safety population (N=39), compared to adults. The increased rates for these Preferred Terms (PTs) concern any grade as well as grade 3/4 of these ADRs. The adverse events reported are in line qualitatively with the recognised safety profile for cabozantinib in adult populations. However, the small numbers of subjects preclude a conclusive assessment of trends and frequencies and further comparison with the recognised safety profile of cabozantinib.

In study ADVL1622 of cabozantinib in children and young adults with the following solid tumor strata: Ewing sarcoma, rhabdomyosarcoma, non-rhabdomyosarcoma soft tissue sarcomas (NRSTS), osteosarcoma, Wilms tumor and other rare solid tumors (nonstatistical cohort), the safety profile of cabozantinib treated children and young adults in all strata was comparable with that observed in adults treated with cabozantinib.

Physeal widening has been observed in children with open growth plates when treated with cabozantinib.


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/