Adverse reactions : תופעות לוואי

4.8 Undesirable effects

Summary of the safety profile
Immune-mediated adverse reactions can occur with cemiplimab. Most of these, including severe reactions, resolved following initiation of appropriate medical therapy or withdrawal of cemiplimab (see “Description of selected adverse reactions” below).

The safety of cemiplimab has been evaluated in 1281 patients with advanced solid malignancies who received cemiplimab monotherapy in 5 clinical studies. The median duration of exposure to cemiplimab was 28 weeks (range: 2 days to 144 weeks).

Immune-mediated adverse reactions occurred in 21% of patients treated with cemiplimab in clinical trials including Grade 5 (0.3%), Grade 4 (0.6%), Grade 3 (5.7%), and Grade 2 (11.2%). Immune-mediated adverse reactions led to permanent discontinuation of cemiplimab in 4.6% of patients. The most common immune-mediated adverse reactions were hypothyroidism (6.8%), hyperthyroidism (3.0%), immune- mediated pneumonitis (2.6%), immune-mediated hepatitis (2.4%), immune-mediated colitis (2.0%), and immune-mediated skin adverse reactions (1.9%) (see “Description of selected adverse reactions” below, Special warnings and precautions for use in section 4.4 and Recommended treatment modifications in section 4.2).

Adverse events were serious in 32.4% of patients. Adverse events led to permanent discontinuation of cemiplimab in 9.4% of patients.

Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in association with cemiplimab treatment (see section 4.4).

Tabulated list of adverse reactions
Adverse reactions observed in clinical studies of cemiplimab as monotherapy (N=1281) or reported from post-marketing use of cemiplimab are listed in Table 2. Adverse reactions are presented by system organ class and by 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); very rare (< 1/10,000); not known (cannot be estimated from available data).
Table 2: Tabulated list of adverse reactions in patients treated with cemiplimab monotherapy (N=1281)
System organ class Preferred                         Any Grade %                  Grades 3-5 % term

Infections and infestations
Upper respiratory tract infectiona     Very Common                  10.9             0.4 Urinary tract infectionb               Common                         8.4            2.3 Blood and lymphatic system disorders
Anaemia                                Very Common                  15.0             5.2 Haemophagocytic lymphohistiocytosisd   Not Known                       --             -- Immune system disorders
Infusion-related reaction              Common                         3.3            < 0.1 Thrombocytopaenia   c
Uncommon                       0.9             0
Sjogren’s syndrome                     Uncommon                       0.2             0 Solid organ transplant rejectiond      Not known                      --              -- Endocrine disorders
Hypothyroidisme                        Common                        6.8             < 0.1 Hyperthyroidism                        Common                        3.0             < 0.1 Thyroiditisf                           Uncommon                      0.6              0 Hypophysitisg                          Uncommon                      0.5             0.2 Adrenal insufficiency                  Uncommon                      0.5             0.5 Type 1 diabetes mellitush             Rare                        < 0.1             < 0.1 Nervous system disorders
Headache                               Common                        8.0            0.3 Peripheral neuropathyi                 Common                        1.3          < 0.1 Meningitis  j
Rare                          < 0.1        < 0.1
Encephalitis                           Rare                          < 0.1        < 0.1 Myasthenia Gravis                      Rare                          < 0.1           0 Paraneoplastic encephalomyelitis       Rare                          < 0.1        < 0.1 Chronic inflammatory demyelinating      Rare                          < 0.1           0 polyradiculoneuropathy
Eye disorders
Keratitis                              Rare                          < 0.1           0 Uvetis                                 Rare                          <0.1           <0.1 Cardiac disorders
Myocarditisk                           Uncommon                      0.5            0.3 Pericarditisl                          Uncommon                      0.3            0.2 Vascular disorders
Hypertensionm                          Common                        5.7            2.6 

Metabolism and nutrition disorders
Decreased appetite                      Very common   13.0    0.6
Respiratory, thoracic and mediastinal disorders
Coughn                                  Very common   10.8    0.2
Dyspnoeao                               Common        9.7     1.2
Pneumonitis    p
Common        3.3     1.1
Gastrointestinal disorders
Diarrhoea                               Very common   16.3    0.7
Nausea                                 Very common   14.7    0.2
Constipation                            Very common   12.3    0.2
Abdominal pain     q
Very common   11.5    0.7
Vomiting                                Common        9.9     0.2
Colitisr                                Common        2.0     0.8
Stomatitis                             Common        1.8    < 0.1
Gastritiss                              Uncommon      0.2     0
Hepatobiliary disorders
Hepatitist                              Common        2.7     1.8
Skin and subcutaneous skin disorders
Rashu                                   Very common   21.4    1.6
Pruritusv                               Very common   12.7    0.2
Actinic keratosis                       Common        3.7     0
Musculoskeletal and connective tissue disorders
Musculoskeletal painw                   Very common   28.3    1.8
Arthritis  x
Uncommon      0.9     0.2
Myositisy                               Uncommon      0.3    < 0.1
Muscular weakness                       Uncommon      0.2     0
Polymyalgia rheumatica                  Uncommon      0.2     0
Renal and urinary disorders
Nephritisz                              Common        1.2     0.2
Noninfective cystitis                   Not known      --     --
General disorders and administration site conditions
Fatigueaa                               Very common   29.9    2.6
Pyrexiabb                               Common        8.7     0.2
Oedemacc                                Common        7.9     0.4
Investigations
Alanine aminotransferase increased      Common        4.6     0.5
Aspartate aminotransferase              Common        4.4     0.7 increased
Blood alkaline phosphatase increased    Common        1.9     0.2

Blood creatinine increased                   Common                                    1.6                    0 Blood thyroid stimulating hormone            Uncommon                                  0.8                    0 increased
Transaminases increased                      Uncommon                                  0.4                  <0.1 Blood bilirubin increased                    Uncommon                                  0.4                  <0.1 Blood thyroid stimulating hormone               Rare                                     < 0.1                  0 decreased
Version 4.03 of NCI CTCAE was used to grade toxicity.
a.
Upper respiratory tract infection includes upper respiratory tract infection, nasopharyngitis, sinusitis, respiratory tract infection, rhinitis, viral upper respiratory tract infection, viral respiratory tract infection, pharyngitis, laryngitis, viral rhinitis, acute sinusitis, tonsillitis, and tracheitis.
b.
Urinary tract infection includes urinary tract infection, cystitis, pyelonephritis, kidney infection, pyelonephritis acute, urosepsis, bacterial cystitis, escherichia urinary tract infection, pyelocystitis, bacterial urinary tract infection, and urinary tract infection pseudomonal.
c.
Thrombocytopaenia includes thrombocytopaenia and immune thrombocytopaenia.
d.
Post marketing event.
e.
Hypothyroidism includes hypothyroidism and immune-mediated hypothyroidism.
f.
Thyroiditis includes thyroiditis, autoimmune thyroiditis, and immune-mediated thyroiditis.
g.
Hypophysitis includes hypophysitis and lymphocytic hypophysitis.
h.
Type 1 diabetes mellitus includes diabetic ketoacidosis and Type 1 diabetes mellitus.
i.
Peripheral neuropathy includes peripheral sensory neuropathy, peripheral neuropathy, paraesthesia, polyneuropathy, neuritis, and peripheral motor neuropathy.
j.
Meningitis includes aseptic meningitis.
k.
Myocarditis includes myocarditis, autoimmune myocarditis, and immune-mediated myocarditis.
l.
Pericarditis includes autoimmune pericarditis and pericarditis.
m.
Hypertension includes hypertension and hypertensive crisis.
n.
Cough includes cough, productive cough, and upper-airway cough syndrome.
o.
Dyspnea includes dyspnea and dyspnea exertional.
p.
Pneumonitis includes pneumonitis, immune-mediated lung disease, interstitial lung disease, and pulmonary fibrosis.
q.
Abdominal pain includes abdominal pain, abdominal pain upper, abdominal distension, abdominal pain lower, abdominal discomfort, and gastrointestinal pain.
r.
Colitis includes colitis, autoimmune colitis, enterocolitis, and immune-mediated enterocolitis.
s.
Gastritis includes gastritis and immune-mediated gastritis.
t.
Hepatitis includes autoimmune hepatitis, immune-mediated hepatitis, hepatitis, hepatotoxicity, hyperbilirubinemia, hepatocellular injury, hepatic failure, and abnormal hepatic function.
u.
Rash includes rash, rash maculo-papular, dermatitis, erythema, rash pruritic, urticaria, rash erythematous, dermatitis bullous, dermatitis acneiform, rash macular, psoriasis, rash papular, dyshidrotic eczema, pemphigoid, autoimmune dermatitis, dermatitis allergic, atopic dermatitis, drug eruption, erythema nodosum, skin reaction, skin toxicity, dermatitis exfoliative, dermatitis exfoliative generalised, dermatitis psoriasiform, erythema multiforme, exfoliative rash, immune-mediated dermatitis, lichen planus, and parapsoriasis.
v.
Pruritus includes pruritus and allergic pruritus.
w.
Musculoskeletal pain includes arthralgia, back pain, pain in extremity, myalgia, neck pain, musculoskeletal chest pain, bone pain, musculoskeletal pain, spinal pain, musculoskeletal stiffness, and musculoskeletal discomfort.
x.
Arthritis includes arthritis, polyarthritis, autoimmune arthritis, and immune-mediated arthritis.
y.
Myositis includes myositis and dermatomyositis.
z.
Nephritis includes acute kidney injury, renal impairment, immune-mediated nephritis, nephritis, renal failure, tubulointerstitial nephritis, and nephropathy toxic.
aa.
Fatigue includes fatigue, asthenia, and malaise.
bb.
Pyrexia includes pyrexia, hyperthermia, and hyperpyrexia.
cc.
Edema includes peripheral edema, face edema, peripheral swelling, face swelling, localised edema, generalised edema, and swelling.

Description of selected adverse reactions
The selected adverse reactions described below are based on safety of cemiplimab in 1281 patients in clinical studies in monotherapy.

Immune-mediated adverse reactions (see section 4.2 and section 4.4)
Immune-mediated pneumonitis
Immune-mediated pneumonitis occurred in 33 (2.6%) of 1281 patients receiving cemiplimab, including 4(0.3%) patients with Grade 4, and 8 (0.6%) patients with Grade 3 immune-mediated pneumonitis.
Immune-mediated pneumonitis led to permanent discontinuation of cemiplimab in 17 (1.3%) of 1281 patients. Among the 33 patients with immune-mediated pneumonitis, the median time to onset was 2.7 months (range: 7 days to 22.2 months) and the median duration of pneumonitis was 1.1 months (range: 5 days to 16.9 months). Twenty-seven of the 33 patients (81.8%) received high-dose corticosteroids for a median of 15 days (range: 1 day to 5.9 months). Resolution of pneumonitis had occurred in 20 (60.6%) of the 33 patients at the time of data cutoff.

Immune-mediated colitis
Immune-mediated diarrhoea or colitis occurred in 25 (2.0%) of 1281 patients receiving cemiplimab, including 10 (0.8%) with Grade 3 immune-mediated diarrhoea or colitis. Immune-mediated diarrhoea or colitis led to permanent discontinuation of cemiplimab in 5 (0.4%) of 1281 patients. Among the 25 patients with immune-mediated diarrhoea or colitis, the median time to onset was 3.8 months
(range: 1 day to 16.6 months) and the median duration of immune-mediated diarrhoea or colitis was 2.1 months (range: 4 days to 26.8 months). Nineteen of the 25 patients (76.0%) with immune-mediated diarrhoea or colitis received high-dose corticosteroids for a median of 22 days (range: 2 days to 5.2 months). Resolution of immune-mediated diarrhoea or colitis had occurred in 14 (56.0%) of the 25 patients at the time of data cutoff.

Immune-mediated hepatitis
Immune-mediated hepatitis occurred in 31 (2.4%) of 1281 patients receiving cemiplimab, including 1 (< 0.1%) patient with Grade 5, 4 (0.3%) patients with Grade 4, and 21 (1.6%) patients with Grade 3 immune-mediated hepatitis. Immune-mediated hepatitis led to permanent discontinuation of cemiplimab in 18 (1.4%) of 1281 patients. Among the 31 patients with immune-mediated hepatitis, the median time to onset was 2.8 months (range: 7 days to 22.5 months) and the median duration of hepatitis was 2.3 months (range: 5 days to 8.7 months). Twenty-seven of the 31 patients (87.1%) with immune-mediated hepatitis received high-dose corticosteroids for a median of 24 days (range: 2 days to 3.8 months).
Resolution of hepatitis had occurred in 12 (38.7%) of the 31 patients at the time of data cutoff.

Immune-mediated endocrinopathies
Hypothyroidism occurred in 87 (6.8%) of 1281 patients receiving cemiplimab, including 1 (< 0.1%) patient with Grade 3 hypothyroidism. Three (0.2%) of 1281 patients discontinued cemiplimab due to hypothyroidism. Among the 87 patients with hypothyroidism, the median time to onset was 4.0 months (range: 15 days to 18.9 months) with a median duration of 9.2 months (range: 1 day to 37.1 months). Resolution of hypothyroidism had occurred in 5 (5.7%) of the 87 patients at the time of data cutoff.
Hyperthyroidism occurred in 39 (3.0%) of 1281 patients receiving cemiplimab, including 1 (< 0.1%) patient with Grade 3 and 11 (0.9%) patients with Grade 2 hyperthyroidism. No patient discontinued cemiplimab due to hyperthyroidism. Among the 39 patients with hyperthyroidism, the median time to onset was 1.9 months (range: 20 days to 23.8 months) and the median duration was 1.9 months (range: 9 days to 32.7 months). Resolution of hyperthyroidism had occurred in 22 (56.4%) of the 39 patients at the time of data cutoff.

Thyroiditis occurred in 8 (0.6%) of 1281 patients receiving cemiplimab, including 4 (0.3%) patients with Grade 2 thyroiditis. No patient discontinued cemiplimab due to thyroiditis. Resolution of thyroiditis had occurred in 1 (12.5%) of the 8 patients at the time of data cutoff.

Adrenal insufficiency occurred in 6 (0.5%) of 1281 patients receiving cemiplimab, including 6 (0.5%) patients with Grade 3 adrenal insufficiency. One (< 0.1%) of 1281 patients discontinued cemiplimab due to adrenal insufficiency. Among the 6 patients with adrenal insufficiency, the median time to onset was 7.5 months (range: 4.2 months to 18.3 months) and the median duration was 2.9 months (range: 22 days to 6.1 months). Two of the 6 patients (33.3%) received high-dose corticosteroids. Resolution of adrenal insufficiency had occurred in 1 (16.7%) of 6 patients at the time of data cutoff.

Immune-mediated hypophysitis occurred in 7 (0.5%) of 1281 patients receiving cemiplimab, including 3 (0.2%) patients with Grade 3 immune-mediated hypophysitis. One (< 0.1%) of 1281 patients discontinued cemiplimab due to hypophysitis. Among the 7 patients with hypophysitis, the median time to onset was 7.4 months (range: 2.5 months to 10.4 months) with a median duration of 2.7 months (range: 9 days to 34.9 months). Three of the 7 patients (42.9%) received high-dose corticosteroids. Resolution of hypophysitis had occurred in 1 (14.3%) of 7 patients at the time of data cutoff.

Type 1 diabetes mellitus without an alternative aetiology occurred in 1 ( < 0.1%) of 1281 patients (Grade 4).

Immune-mediated skin adverse reactions
Immune-mediated skin adverse reactions occurred in 24 (1.9%) of 1281 patients receiving cemiplimab, including 11 (0.9%) patients with Grade 3 immune-mediated skin adverse reactions. Immune-mediated skin adverse reactions led to permanent discontinuation of cemiplimab in 3 (0.2%) of 1281 patients.
Among the 24 patients with immune-mediated skin adverse reactions, the median time to onset was 2.0 months (range: 2 days to 17.0 months) and the median duration was 2.9 months (range: 8 days to
38.8 months). Seventeen of the 24 patients (70.8%) with immune-mediated skin adverse reactions received high-dose corticosteroids for a median of 10 days (range: 1 day to 2.9 months). Resolution of skin reaction had occurred in 17 (70.8%) of 24 patients at the time of data cutoff.

Immune-mediated nephritis
Immune-mediated nephritis occurred in 9 (0.7%) of 1281 patients receiving cemiplimab, including 1 (< 0.1%) patient with Grade 5, and 1 (< 0.1%) patient with Grade 3 immune-mediated nephritis.
Immune-mediated nephritis led to permanent discontinuation of cemiplimab in 2 (0.2%) of 1281 patients. Among the 9 patients with immune-mediated nephritis, the median time to onset was 2.1 months (range: 14 days to 12.5 months) and the median duration of nephritis was 1.5 months (range: 9 days to 5.5 months). Six of the 9 patients (66.7%) with immune-mediated nephritis received high-dose corticosteroids for a median of 18 days (range: 3 days to 1.3 months). Resolution of nephritis had occurred in 7 (77.8%) of the 9 patients at the time of data cutoff.

Other immune-mediated adverse reactions
The following clinically significant, immune-mediated adverse reactions occurred at an incidence of less than 1% (unless otherwise noted) of 1281 patients treated with cemiplimab monotherapy. The events were Grade 3 or less unless stated otherwise:

Nervous system disorders: Aseptic meningitis, paraneoplastic encephalomyelitis (Grade 5), chronic inflammatory demyelinating polyradiculoneuropathy, encephalitis, myasthenia gravis, peripheral neuropathya
Cardiac Disorders: Myocarditisb (Grade 5), pericarditisc
Immune system disorders: Immune thrombocytopaenia
Musculoskeletal and connective tissue disorders: Arthralgia (1.2%), arthritisd, muscular weakness, myalgia, myositise (Grade 4), polymyalgia rheumatica, Sjogren’s syndrome Skin and Subcutaneous Tissue Disorders: Pruritis
Eye disorders: Keratitis, Uveitisf (Grade 4)
Gastrointestinal disorders: Stomatitis, immune-mediated gastritis a.
includes neuritis, peripheral neuropathy, peripheral sensory neuropathy, and polyneuropathy b.
includes autoimmune myocarditis, immune-mediated myocarditis, and myocarditis c.
includes autoimmune pericarditis and pericarditis d.
includes arthritis, immune-mediated arthritis, and polyarthritis e includes myositis and dermatomyositis f.
reported in clinical studies outside the pooled dataset


The following additional immune-mediated adverse reactions were observed in patients receiving combination therapy in clinical trials: vasculitis, Guillain-Barre syndrome, central nervous system inflammation, and meningitis (Grade 4), each with the frequency of rare.

Immune checkpoint inhibitor class effects
There have been cases of the following adverse reactions reported during treatment with other immune checkpoint inhibitors, which might also occur during treatment with cemiplimab: coeliac disease and pancreatic exocrine insufficiency.

Infusion-related reactions
Infusion-related reactions occurred in 94 (7.3%) of 1281 patients treated with cemiplimab including 2 (0.2%) patients with Grade 3 or 4 infusion-related reactions. Infusion-related reaction led to permanent discontinuation of cemiplimab in 1 (< 0.1%) patient. Common symptoms of infusion-related reaction include nausea, pyrexia, and vomiting. Ninety-three of 94 (98.9%) patients recovered from the infusion-related reaction at the time of data cutoff.

Immunogenicity
As with all therapeutic proteins, there is a potential for immunogenicity with cemiplimab. In clinical studies with 1029 patients treated with cemiplimab, 2.1% of patients developed treatment-emergent antibodies, with approximately 0.3% exhibiting persistent antibody responses. No neutralising antibodies have been observed. There was no evidence of an altered pharmacokinetic or safety profile with anti- cemiplimab antibody development.

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/