Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Regeneron Ireland Designated Activity Company (DAC), One Warrington Place, Dublin 2, D02 HH27, Ireland
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
Severe and fatal immune-mediated adverse reactions have been observed with cemiplimab (see section 4.2 and section 4.8). These immune-mediated reactions may involve any organ system. Immune-mediated reactions can manifest at any time during treatment with cemiplimab; however, immune-mediated adverse reactions can occur after discontinuation of cemiplimab.
The guidance for immune-mediated adverse reactions applies to cemiplimab whether administered as monotherapy or in combination with chemotherapy.
Immune-mediated adverse reactions affecting more than one body system can occur simultaneously, such as myositis and myocarditis or myasthenia gravis, in patients treated with cemiplimab or other PD-1/PD-L1 inhibitors.
Monitor patients for signs and symptoms of immune-mediated adverse reactions. Immune-mediated adverse reactions should be managed with cemiplimab treatment modifications, hormone replacement therapy (if clinically indicated), and corticosteroids. For suspected immune-mediated adverse reactions, patients should be evaluated to confirm an immune-mediated adverse reaction and to exclude other possible causes, including infection. Depending upon the severity of the adverse reaction, cemiplimab should be withheld or permanently discontinued (see section 4.2).
Immune-mediated pneumonitis, defined as requiring use of corticosteroids with no clear alternate aetiology, including fatal cases, has been observed in patients receiving cemiplimab (see section 4.8). Patients should be monitored for signs and symptoms of pneumonitis and causes other than immune-mediated pneumonitis should be ruled out. Patients with suspected pneumonitis should be evaluated with radiographic imaging as indicated based on clinical evaluation and managed with cemiplimab treatment modifications and corticosteroids (see section 4.2).
Immune-mediated diarrhoea or colitis, defined as requiring use of corticosteroids with no clear alternate aetiology, has been observed in patients receiving cemiplimab (see section 4.8). Patients should be monitored for signs and symptoms of diarrhoea or colitis and managed with cemiplimab treatment modifications, anti-diarrhoeal agents, and corticosteroids (see section 4.2).
Immune-mediated hepatitis, defined as requiring use of corticosteroids with no clear alternate aetiology, including fatal cases, has been observed in patients receiving cemiplimab (see section 4.8). Patients should be monitored for abnormal liver tests prior to and periodically during treatment as indicated based on clinical evaluation and managed with cemiplimab treatment modifications and corticosteroids (see section 4.2).
Immune-mediated endocrinopathies, defined as treatment-emergent endocrinopathies with no clear alternate aetiology, have been observed in patients receiving cemiplimab (see section 4.8).
Thyroid disorders (Hypothyroidism/Hyperthyroidism/Thyroiditis):
Immune-mediated thyroid disorders have been observed in patients receiving cemiplimab. Thyroiditis can present with or without an alteration in thyroid function tests. Hypothyroidism can follow hyperthyroidism. Thyroid disorders can occur at any time during the treatment. Patients should be monitored for changes in thyroid function at the start of treatment and periodically during the treatment as indicated based on clinical evaluation (see section 4.8). Patients should be managed with hormone replacement therapy (if indicated) and cemiplimab treatment modifications. Hyperthyroidism should be managed according to standard medical practice (see section 4.2).
Hypophysitis:
Immune-mediated hypophysitis has been observed in patients receiving cemiplimab (see section 4.8). Patients should be monitored for signs and symptoms of hypophysitis and managed with cemiplimab treatment modifications, corticosteroids and hormone replacement, as clinically indicated (see section 4.2).
Adrenal insufficiency:
Adrenal insufficiency has been observed in patients receiving cemiplimab (see section 4.8). Patients should be monitored for signs and symptoms of adrenal insufficiency during and after treatment and managed with cemiplimab treatment modifications, corticosteroids and hormone replacement, as clinically indicated (see section 4.2).
Type 1 Diabetes mellitus:
Immune-mediated type 1 diabetes mellitus, including diabetic ketoacidosis, has been observed in patients receiving cemiplimab (see section 4.8). Patients should be monitored for hyperglycaemia and signs and symptoms of diabetes as indicated based on clinical evaluation and managed with oral anti-hyperglycaemics or insulin and cemiplimab treatment modifications (see section 4.2).
Immune-mediated skin adverse reactions, defined as requiring use of systemic corticosteroids with no clear alternate aetiology, including severe cutaneous adverse reactions (SCARs), such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) (some cases with fatal outcome), and other skin reactions such as rash, erythema multiforme, pemphigoid, have been reported in association with cemiplimab treatment (see section 4.8).
Patients should be monitored for evidence of suspected severe skin reactions and exclude other causes. Patients should be managed with cemiplimab treatment modifications and corticosteroids (see section 4.2). For symptoms or signs of SJS or TEN, refer the patient for specialised care for assessment and treatment and manage patient with treatment modifications (see section 4.2).
Cases of SJS, fatal TEN and stomatitis occurred following 1 dose of cemiplimab in patients with prior exposure to idelalisib, who were participating in a clinical trial evaluating cemiplimab in Non-Hodgkin Lymphoma (NHL), and who had recent exposure to sulfa containing antibiotics (see section 4.8). Patients should be managed with cemiplimab treatment modifications and corticosteroids as described above (see section 4.2).
Immune-mediated nephritis, defined as requiring use of corticosteroids with no clear alternate aetiology, including a fatal case, has been observed in patients receiving cemiplimab (see section 4.8).
Monitor patients for changes in renal function. Patients should be managed with cemiplimab treatment modifications and corticosteroids (see section 4.2).
Other fatal and life-threatening immune-mediated adverse reactions have been observed in patients receiving cemiplimab including paraneoplastic encephalomyelitis, meningitis, myositis and myocarditis (see section 4.8 for other immune-mediated adverse reactions).
Noninfective cystitis has been reported with other PD-1/PD-L1 inhibitors.
Evaluate suspected immune-mediated adverse reactions to exclude other causes. Patients should be monitored for signs and symptoms of immune-mediated adverse reactions and managed with cemiplimab treatment modifications and corticosteroids as clinically indicated (see section 4.2 and section 4.8).
Solid organ transplant rejection has been reported in the post-marketing setting in patients treated with PD-1 inhibitors. Treatment with cemiplimab may increase the risk of rejection in solid organ transplant recipients. The benefit of treatment with cemiplimab versus the risk of possible organ rejection should be considered in these patients. Cases of graft-versus-host disease have been reported in the post-marketing setting in patients treated with other PD-1/PD-L1 inhibitors in association with allogeneic haematopoietic stem cell transplant.
Haemophagocytic lymphohistiocytosis (HLH) has been reported in patients receiving cemiplimab (see section 4.8). Patients should be monitored for clinical signs and symptoms of HLH. If HLH is confirmed, administration of cemiplimab should be discontinued and treatment for HLH initiated (see section 4.2).
Cemiplimab can cause severe or life-threatening infusion-related reactions (see section 4.8). Patients should be monitored for signs and symptoms of infusion-related reactions and managed with cemiplimab treatment modifications and corticosteroids. Cemiplimab should be interrupted or the rate of infusion slowed for mild or moderate infusion-related reactions. The infusion should be stopped and cemiplimab should be permanently discontinued for severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions (see section 4.2).
Patients that had active infections, were immunocompromised, had a history of autoimmune diseases, ECOG PS ≥ 2 or a history of interstitial lung disease were not included. For a full list of patients excluded from clinical studies, see section 5.1.
In the absence of data, cemiplimab should be used with caution in these populations after careful evaluation of the balance of benefits and risks for the patient.
No pharmacokinetic (PK) drug-drug interaction studies have been conducted with cemiplimab.
The use of systemic corticosteroids or immunosuppressants before starting cemiplimab, except for physiological doses of systemic corticosteroid (≤10 mg/day prednisone or equivalent), should be avoided because of their potential interference with the pharmacodynamic activity and efficacy of cemiplimab. However, systemic corticosteroids or other immunosuppressants can be used after starting cemiplimab to treat immune-mediated adverse reactions (see section 4.2).
Women of childbearing potential should use effective contraception during treatment with cemiplimab and for at least 4 months after the last dose of cemiplimab.
Animal reproduction studies have not been conducted with cemiplimab. There are no available data on the use of cemiplimab in pregnant women. Animal studies have demonstrated that inhibition of the PD-1/PD-L1 pathway can lead to increased risk of immune-mediated rejection of the developing foetus resulting in foetal death (see section 5.3).
Human IgG4 is known to cross the placental barrier and cemiplimab is an IgG4; therefore, cemiplimab has the potential to be transmitted from the mother to the developing foetus. Cemiplimab is not recommended during pregnancy and in women of childbearing potential not using effective contraception unless the clinical benefit outweighs the potential risk.
It is unknown whether cemiplimab is secreted in human milk. It is known that antibodies (including IgG4) are secreted in human milk; a risk to the breast-feeding newborn/infant cannot be excluded.
If a woman chooses to be treated with cemiplimab, she should be instructed not to breast-feed while being treated with cemiplimab and for at least 4 months after the last dose.
No clinical data are available on the possible effects of cemiplimab on fertility. No effects on fertility assessment parameters or in the male and female reproductive organs were observed in a 3-month repeat dose fertility assessment study with sexually mature cynomolgus monkeys.
Cemiplimab has no or negligible influence on the ability to drive and use machines. Fatigue has been reported following treatment with cemiplimab (see section 4.8).
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 as monotherapy 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).
The safety of cemiplimab in combination with platinum‐based chemotherapy has been evaluated in a clinical study of 465 patients with locally advanced or metastatic NSCLC. The median duration of exposure was 38.5 weeks (10 days to 102.6 weeks) in the cemiplimab and chemotherapy group, and 21.3 weeks (4 days to 95 weeks) in the chemotherapy group.
Immune-mediated adverse reactions occurred in 18.9% of patients including Grade 5 (0.3%), Grade 3 (2.6%), and Grade 2 (7.4%). Immune-mediated adverse reactions led to permanent discontinuation of cemiplimab in 1.0% of patients. The most common immune-mediated adverse reactions were hypothyroidism (7.7%), hyperthyroidism (5.1%), increased blood thyroid stimulating hormone (4.2%), immune-mediated skin reaction (1.9%), immune-mediated pneumonitis (1.9%), and decreased blood thyroid stimulating hormone (1.6%) (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 25.3% of patients.
Adverse events led to permanent discontinuation of cemiplimab in 5.1% of patients.
Table 2 lists the incidence of adverse reactions in the monotherapy safety dataset and in patients treated with cemiplimab in combination with chemotherapy. 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).
Adverse reactions known to occur with cemiplimab or combination therapy components given alone may occur during treatment with these medicinal products in combination.
Table 2. Tabulated list of adverse reactions in patients treated with cemiplimab monotherapy and cemiplimab in combination with chemotherapy:
| Cemiplimab Monotherapy | Cemiplimab in Combination with Chemotherapy | |||||
|---|---|---|---|---|---|---|
| System organ class Preferred term | Any Grade % | Grade 3-5 (%) | Any Grade % | Grade 3-5 (%) | ||
| 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 | Very common | 43.6 | 9.9 |
| Neutropaenia | Very common | 15.4 | 5.8 | |||
| Thrombocytopaenia | Very common | 13.1 | 2.6 | |||
| Haemophagocytic lymphohistiocytosisd | Not Known | -- | -- | |||
| Immune system disorders | ||||||
| Infusion-related reaction | Common | 3.3 | <0.1 | Uncommon | 0.3 | 0 |
| Thrombocytopaeniac | 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 | Common | 7.7 | 0.3 |
| Hyperthyroidism | Common | 3.0 | <0.1 | Common | 5.1 | 0 |
| Thyroiditisf | Uncommon | 0.6 | 0 | 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 | Uncommon | 0.3 | 0 |
| Nervous system disorders | ||||||
| Headache | Common | 8.0 | 0.3 | |||
| Peripheral neuropathyi | Common | 1.3 | <0.1 | Very common | 21.2 | 0 |
| Meningitisj | 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 polyradiculoneuropathy | Rare | <0.1 | 0 | |||
| Eye disorders | ||||||
| Keratitis | Rare | <0.1 | 0 | |||
| Uveitis | 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 | Very common | 17.0 | 1.0 |
| Hyperglycaemia | Very common | 17.6 | 1.9 | |||
| Hypoalbuminaemia | Very common | 10.3 | 0.6 | |||
| Respiratory, thoracic and mediastinal disorders | ||||||
| Coughn | Very common | 10.8 | 0.2 | |||
| Dyspnoea° | Common | 9.7 | 1.2 | Very common | 12.8 | 2.2 |
| Pneumonitisp | Common | 3.3 | 1.1 | Common | 4.2 | 0.6 |
| Gastrointestinal disorders | ||||||
| Nausea | Very common | 14.7 | 0.2 | Very common | 25.0 | 0 |
| Diarrhoea | Very common | 16.3 | 0.7 | Very common | 10.6 | 1.3 |
| Constipation | Very common | 12.3 | 0.2 | Very common | 13.8 | 0.3 |
| Abdominal painq | Very common | 11.5 | 0.7 | |||
| Vomiting | Common | 9.9 | 0.2 | Very common | 12.2 | 0 |
| Colitisr | Common | 2.0 | 0.8 | Common | 1.0 | 0.3 |
| Stomatitis | Common | 1.8 | <0.1 | |||
| Gastritiss | Uncommon | 0.2 | 0 | |||
| Hepatobiliary disorders | ||||||
| Hepatitist | Common | 2.7 | 1.8 | |||
| Psychiatric Disorders | ||||||
| Insomnia | Very common | 10.9 | 0 | |||
| Skin and subcutaneous skin disorders | ||||||
| Rashu | Very common | 21.4 | 1.6 | Very common | 12.5 | 1.3 |
| Pruritusv | Very common | 12.7 | 0.2 | Common | 3.5 | 0 |
| Actinic keratosis | Common | 3.7 | 0 | |||
| Alopecia | Very common | 36.9 | 0 | |||
| Musculoskeletal and connective tissue disorders | ||||||
| Musculoskeletal painw | Very common | 28.3 | 1.8 | Very common | 26.9 | 1.3 |
| Arthritisx | Uncommon | 0.9 | 0.2 | Common | 1.0 | 0 |
| 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 | Common | 2.6 | 0 |
| Noninfective cystitis | Not known | -- | -- | |||
| General disorders and administration site conditions | ||||||
| Fatigueaa | Very common | 29.9 | 2.6 | Very common | 23.4 | 3.8 |
| Pyrexiabb | Common | 8.7 | 0.2 | |||
| Oedemacc | Common | 7.9 | 0.4 | |||
| Investigations | ||||||
| Alanine aminotransferase increased | Common | 4.6 | 0.5 | Very common | 16.3 | 2.2 |
| Aspartate aminotransferase increased | Common | 4.4 | 0.7 | Very common | 14.7 | 0.3 |
| Blood alkaline phosphatase increased | Common | 1.9 | 0.2 | Common | 4.5 | 0 |
| Blood creatinine increased | Common | 1.6 | 0 | Common | 8.7 | 0 |
| Blood thyroid stimulating hormone increased | Uncommon | 0.8 | 0 | Common | 4.2 | 0 |
| Transaminases increased | Uncommon | 0.4 | <0.1 | |||
| Blood bilirubin increased | Uncommon | 0.4 | <0.1 | Common | 1.6 | 0.3 |
| Blood thyroid stimulating hormone decreased | Rare | <0.1 | 0 | Common | 1.6 | 0 |
| Weight decreased | Very common | 11.2 | 1.3 | |||
| Gamma-glutamyltransferase increased | Uncommon | 0.6 | 0.3 | |||
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.
° 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.
The selected adverse reactions described below are based on safety of cemiplimab in 1281 patients in clinical studies in monotherapy.
These selected adverse reactions were consistent when cemiplimab was administered in monotherapy or in combination with chemotherapy.
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 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 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.
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 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 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.
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: Pruritus
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.
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, pancreatic exocrine insufficiency.
Infusion-related reactions occurred in 94 (7.3%) of 1281 patients treated with cemiplimab monotherapy 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.
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 suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
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