Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Bristol-Myers Squibb Pharma EEIG, Plaza 254, Blanchardstown Corporate Park 2, Dublin 15, D15 T867, Ireland
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
When nivolumab is administered in combination with ipilimumab, refer to the Summary of Product Characteristics for ipilimumab prior to initiation of treatment. Immune-related adverse reactions have occurred at higher frequencies when nivolumab was administered in combination with ipilimumab compared with nivolumab as monotherapy. Most immune-related adverse reactions improved or resolved with appropriate management, including initiation of corticosteroids and treatment modifications (see section 4.2).
Cardiac and pulmonary adverse events including pulmonary embolism have also been reported with combination therapy. Patients should be monitored for cardiac and pulmonary adverse reactions continuously, as well as for clinical signs, symptoms, and laboratory abnormalities indicative of electrolyte disturbances and dehydration prior to and periodically during treatment. Nivolumab in combination with ipilimumab should be discontinued for life-threatening or recurrent severe cardiac and pulmonary adverse reactions (see section 4.2).
Patients should be monitored continuously (at least up to 5 months after the last dose) as an adverse reaction with nivolumab or nivolumab in combination with ipilimumab may occur at any time during or after discontinuation of therapy.
For suspected immune-related adverse reactions, adequate evaluation should be performed to confirm aetiology or exclude other causes. Based on the severity of the adverse reaction, nivolumab or nivolumab in combination with ipilimumab should be withheld and corticosteroids administered. If immunosuppression with corticosteroids is used to treat an adverse reaction, a taper of at least 1 month duration should be initiated upon improvement. Rapid tapering may lead to worsening or recurrence of the adverse reaction. Non-corticosteroid immunosuppressive therapy should be added if there is worsening or no improvement despite corticosteroid use.
Nivolumab or nivolumab in combination with ipilimumab should not be resumed while the patient is receiving immunosuppressive doses of corticosteroids or other immunosuppressive therapy. Prophylactic antibiotics should be used to prevent opportunistic infections in patients receiving immunosuppressive therapy.
Nivolumab or nivolumab in combination with ipilimumab must be permanently discontinued for any severe immune-related adverse reaction that recurs and for any life-threatening immune-related adverse reaction.
Severe pneumonitis or interstitial lung disease, including fatal cases, has been observed with nivolumab monotherapy or nivolumab in combination with ipilimumab (see section 4.8). Patients should be monitored for signs and symptoms of pneumonitis such as radiographic changes (e.g. focal ground glass opacities, patchy filtrates), dyspnoea, and hypoxia. Infectious and disease-related aetiologies should be ruled out.
For Grade 3 or 4 pneumonitis, nivolumab or nivolumab in combination with ipilimumab must be permanently discontinued, and corticosteroids should be initiated at a dose of 2 to 4 mg/kg/day methylprednisolone equivalents.
For Grade 2 (symptomatic) pneumonitis, nivolumab or nivolumab in combination with ipilimumab should be withheld and corticosteroids initiated at a dose of 1 mg/kg/day methylprednisolone equivalents. Upon improvement, nivolumab or nivolumab in combination with ipilimumab may be resumed after corticosteroid taper. If worsening or no improvement occurs despite initiation of corticosteroids, corticosteroid dose should be increased to 2 to 4 mg/kg/day methylprednisolone equivalents and nivolumab or nivolumab in combination with ipilimumab must be permanently discontinued.
Severe diarrhoea or colitis has been observed with nivolumab monotherapy or nivolumab in combination with ipilimumab (see section 4.8). Patients should be monitored for diarrhoea and additional symptoms of colitis, such as abdominal pain and mucus or blood in stool. Infectious and disease-related aetiologies should be ruled out.
For Grade 4 diarrhoea or colitis, nivolumab or nivolumab in combination with ipilimumab must be permanently discontinued, and corticosteroids should be initiated at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents.
Nivolumab monotherapy should be withheld for Grade 3 diarrhoea or colitis, and corticosteroids initiated at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents. Upon improvement, nivolumab monotherapy may be resumed after corticosteroid taper. If worsening or no improvement occurs despite initiation of corticosteroids, nivolumab monotherapy must be permanently discontinued. Grade 3 diarrhoea or colitis observed with nivolumab in combination with ipilimumab requires permanent discontinuation of treatment and initiation of corticosteroids at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents.
For Grade 2 diarrhoea or colitis, nivolumab or nivolumab in combination with ipilimumab should be withheld. Persistent diarrhoea or colitis should be managed with corticosteroids at a dose of 0.5 to 1 mg/kg/day methylprednisolone equivalents. Upon improvement, nivolumab or nivolumab in combination with ipilimumab may be resumed after corticosteroid taper, if needed. If worsening or no improvement occurs despite initiation of corticosteroids, corticosteroid dose should be increased to 1 to 2 mg/kg/day methylprednisolone equivalents and nivolumab or nivolumab in combination with ipilimumab must be permanently discontinued.
Severe hepatitis has been observed with nivolumab monotherapy or nivolumab in combination with ipilimumab (see section 4.8). Patients should be monitored for signs and symptoms of hepatitis such as transaminase and total bilirubin elevations. Infectious and disease-related aetiologies should be ruled out.
For Grade 3 or 4 transaminase or total bilirubin elevation, nivolumab or nivolumab in combination with ipilimumab must be permanently discontinued, and corticosteroids should be initiated at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents.
For Grade 2 transaminase or total bilirubin elevation, nivolumab or nivolumab in combination with ipilimumab should be withheld. Persistent elevations in these laboratory values should be managed with corticosteroids at a dose of 0.5 to 1 mg/kg/day methylprednisolone equivalents. Upon improvement, nivolumab or nivolumab in combination with ipilimumab may be resumed after corticosteroid taper, if needed. If worsening or no improvement occurs despite initiation of corticosteroids, corticosteroid dose should be increased to 1 to 2 mg/kg/day methylprednisolone equivalents and nivolumab or nivolumab in combination with ipilimumab must be permanently discontinued.
Severe nephritis and renal dysfunction have been observed with monotherapy treatment or nivolumab in combination with ipilimumab (see section 4.8). Patients should be monitored for signs and symptoms of nephritis or renal dysfunction. Most patients present with asymptomatic increases in serum creatinine. Disease-related aetiologies should be ruled out.
For Grade 4 serum creatinine elevation, nivolumab or nivolumab in combination with ipilimumab must be permanently discontinued, and corticosteroids should be initiated at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents.
For Grade 2 or 3 serum creatinine elevation, nivolumab or nivolumab in combination with ipilimumab should be withheld, and corticosteroids should be initiated at a dose of 0.5 to 1 mg/kg/day methylprednisolone equivalents. Upon improvement, nivolumab or nivolumab in combination with ipilimumab may be resumed after corticosteroid taper. If worsening or no improvement occurs despite initiation of corticosteroids, corticosteroid dose should be increased to 1 to 2 mg/kg/day methylprednisolone equivalents, and nivolumab or nivolumab in combination with ipilimumab must be permanently discontinued.
Severe endocrinopathies, including hypothyroidism, hyperthyroidism, adrenal insufficiency (including secondary adrenocortical insufficiency), hypophysitis (including hypopituitarism), diabetes mellitus, and diabetic ketoacidosis have been observed with nivolumab monotherapy or nivolumab in combination with ipilimumab (see section 4.8).
Patients should be monitored for clinical signs and symptoms of endocrinopathies and for hyperglycaemia and changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation). Patients may present with fatigue, headache, mental status changes, abdominal pain, unusual bowel habits, and hypotension, or nonspecific symptoms which may resemble other causes such as brain metastasis or underlying disease. Unless an alternate aetiology has been identified, signs or symptoms of endocrinopathies should be considered immune-related.
For symptomatic hypothyroidism, nivolumab or nivolumab in combination with ipilimumab should be withheld, and thyroid hormone replacement should be initiated as needed. For symptomatic hyperthyroidism, nivolumab or nivolumab in combination with ipilimumab should be withheld and antithyroid medication should be initiated as needed. Corticosteroids at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents should also be considered if acute inflammation of the thyroid is suspected. Upon improvement, nivolumab or nivolumab in combination with ipilimumab may be resumed after corticosteroid taper, if needed. Monitoring of thyroid function should continue to ensure appropriate hormone replacement is utilised. Nivolumab or nivolumab in combination with ipilimumab must be permanently discontinued for life-threatening hyperthyroidism or hypothyroidism.
For symptomatic Grade 2 adrenal insufficiency, nivolumab or nivolumab in combination with ipilimumab should be withheld, and physiologic corticosteroid replacement should be initiated as needed. Nivolumab or nivolumab in combination with ipilimumab must be permanently discontinued for severe (Grade 3) or life-threatening (Grade 4) adrenal insufficiency. Monitoring of adrenal function and hormone levels should continue to ensure appropriate corticosteroid replacement is utilised.
For symptomatic Grade 2 or 3 hypophysitis, nivolumab or nivolumab in combination with ipilimumab should be withheld, and hormone replacement should be initiated as needed. Corticosteroids at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents should also be considered if acute inflammation of the pituitary gland is suspected. Upon improvement, nivolumab or nivolumab in combination with ipilimumab may be resumed after corticosteroid taper, if needed. Nivolumab or nivolumab in combination with ipilimumab must be permanently discontinued for life-threatening (Grade 4) hypophysitis. Monitoring of pituitary function and hormone levels should continue to ensure appropriate hormone replacement is utilised.
For symptomatic diabetes, nivolumab or nivolumab in combination with ipilimumab should be withheld, and insulin replacement should be initiated as needed. Monitoring of blood sugar should continue to ensure appropriate insulin replacement is utilised. Nivolumab or nivolumab in combination with ipilimumab must be permanently discontinued for life-threatening diabetes.
Severe rash has been observed with nivolumab in combination with ipilimumab and, less commonly, with nivolumab as monotherapy (see section 4.8). Nivolumab or nivolumab in combination with ipilimumab should be withheld for Grade 3 rash and discontinued for Grade 4 rash. Severe rash should be managed with high-dose corticosteroid at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents.
Rare cases of SJS and TEN some of them with fatal outcome have been observed. If symptoms or signs of SJS or TEN appear, treatment with nivolumab or nivolumab in combination with ipilimumab should be discontinued and the patient referred to a specialised unit for assessment and treatment. If the patient has developed SJS or TEN with the use of nivolumab or nivolumab in combination with ipilimumab, permanent discontinuation of treatment is recommended (see section 4.2).
Caution should be used when considering the use of nivolumab in a patient who has previously experienced a severe or life-threatening skin adverse reaction on prior treatment with other immune- stimulatory anticancer agents.
The following immune-related adverse reactions were reported in less than 1% of patients treated with nivolumab monotherapy or nivolumab in combination with ipilimumab in clinical trials across doses and tumour types: pancreatitis, uveitis, demyelination, autoimmune neuropathy (including facial and abducens nerve paresis), Guillain-Barré syndrome, myasthenia gravis, myasthenic syndrome, aseptic meningitis, encephalitis, gastritis, sarcoidosis, duodenitis, myositis, myocarditis, and rhabdomyolysis. Cases of Vogt-Koyanagi-Harada syndrome have been reported post-marketing (see section 4.8).
For suspected immune-related adverse reactions, adequate evaluation should be performed to confirm aetiology or exclude other causes. Based on the severity of the adverse reaction, nivolumab or nivolumab in combination with ipilimumab should be withheld and corticosteroids administered. Upon improvement, nivolumab or nivolumab in combination with ipilimumab may be resumed after corticosteroid taper. Nivolumab or nivolumab in combination with ipilimumab must be permanently discontinued for any severe immune-related adverse reaction that recurs and for any life-threatening immune-related adverse reaction.
Rare cases of myotoxicity (myositis, myocarditis, and rhabdomyolysis), some with fatal outcome, have been reported with nivolumab or nivolumab in combination with ipilimumab. If a patient develops signs and symptoms of myotoxicity, close monitoring should be implemented, and the patient referred to a specialist for assessment and treatment without delay. Based on the severity of myotoxicity, nivolumab or nivolumab in combination with ipilimumab should be withheld or discontinued (see section 4.2), and appropriate treatment instituted.
Solid organ transplant rejection has been reported in the post-marketing setting in patients treated with PD-1 inhibitors. Treatment with nivolumab may increase the risk of rejection in solid organ transplant recipients. The benefit of treatment with nivolumab versus the risk of possible organ rejection should be considered in these patients.
Severe infusion reactions have been reported in clinical trials of nivolumab or nivolumab in combination with ipilimumab (see section 4.8). In case of a severe or life-threatening infusion reaction, the nivolumab or nivolumab in combination with ipilimumab infusion must be discontinued and appropriate medical therapy administered. Patients with mild or moderate infusion reaction may receive nivolumab or nivolumab in combination with ipilimumab with close monitoring and use of premedication according to local treatment guidelines for prophylaxis of infusion reactions.
Patients with a baseline performance score ≥ 2, active brain metastases or leptomeningeal metastases, autoimmune disease, and patients who had been receiving systemic immunosuppressants prior to study entry were excluded from the pivotal clinical trials of nivolumab or nivolumab in combination with ipilimumab (see sections 4.5 and 5.1). Patients with ocular/uveal melanoma were excluded from pivotal clinical trials of melanoma. In addition, CA209037 excluded patients who have had a Grade 4 adverse reaction that was related to anti-CTLA-4 therapy (see section 5.1). Patients with baseline performance score of 2, treated leptomeningeal metastases, ocular/uveal melanoma, autoimmune disease and patients who have had a Grade 3-4 adverse reaction that was related to prior anti-CTLA-4 therapy were included in study CA209172 (see section 5.1). In the absence of data for patients who had been receiving systemic immunosuppressants prior to study entry, and for patients with active brain or leptomeningeal metastases, nivolumab should be used with caution in these populations after careful consideration of the potential benefit/risk on an individual basis.
Relative to nivolumab monotherapy, an increase in PFS for the combination of nivolumab with ipilimumab is established only in patients with low tumour PD-L1 expression. The improvement in OS was similar between nivolumab in combination with ipilimumab and nivolumab monotherapy in patients with high tumour PD-L1 expression (PD-L1 ≥1%). Before initiating treatment with the combination, physicians are advised to carefully evaluate the individual patient and tumour characteristics, taking into consideration the observed benefits and the toxicity of the combination relative to nivolumab monotherapy (see sections 4.8 and 5.1).
Physicians should consider the delayed onset of nivolumab effect before initiating treatment in patients with rapidly progressing disease (see section 5.1).
Adjuvant treatment of melanoma:
There are no data on adjuvant treatment in patients with melanoma with the following risk factors (see sections 4.5 and 5.1
In the absence of data, nivolumab should be used with caution in these populations after careful consideration of the potential benefit/risk on an individual basis.
Non-Small Cell Lung Cancer:
Patients with a baseline performance score ≥2, active brain metastases or autoimmune disease, symptomatic interstitial lung disease, and patients who had been receiving systemic immunosuppressants prior to study entry were excluded from the pivotal clinical trials of NSCLC (see sections 4.5 and 5.1). Patients with baseline performance score of 2 were included in study CA209171 (see section 5.1). In the absence of data for patients with autoimmune disease, symptomatic interstitial lung disease, active brain metastases and patients who had been receiving systemic immunosuppressants prior to study entry, nivolumab should be used with caution in these populations after careful consideration of the potential benefit/risk on an individual basis.
Physicians should consider the delayed onset of nivolumab effect before initiating treatment in patients with poorer prognostic features and/or aggressive disease. In non-squamous NSCLC, a higher number of deaths within 3 months was observed in nivolumab compared to docetaxel. Factors associated with early deaths were poorer prognostic factors and/or more aggressive disease combined with low or no tumour PD-L1 expression (see section 5.1).
Renal Cell Carcinoma:
Patients with any history of or concurrent brain metastases, active autoimmune disease, or medical conditions requiring systemic immunosuppression were excluded from the clinical trials of nivolumab or nivolumab in combination with ipilimumab (see sections 4.5 and 5.1). In the absence of data, nivolumab or nivolumab in combination with ipilimumab should be used with caution in these populations after careful consideration of the potential benefit/risk on an individual basis.
Classical Hodgkin Lymphoma:
Patients with active autoimmune disease and symptomatic interstitial lung disease were excluded from clinical trials of cHL (see section 5.1). In the absence of data, nivolumab should be used with caution in these populations after careful consideration of the potential benefit/risk on an individual basis.
Preliminary results from the follow-up of patients with cHL undergoing allogeneic HSCT after previous exposure to nivolumab showed a higher than expected number of cases of acute graft-versus-host disease (GVHD) and transplant related mortality (TRM). Until further data become available, careful consideration to the potential benefits of HSCT and the possible increased risk of transplant related complications should be made case-by-case (see section 4.8).
In patients treated with nivolumab after allogeneic HSCT, rapid-onset and severe GVHD, some with fatal outcome, have been reported in the post-marketing setting. Treatment with nivolumab may increase the risk of severe GVHD and death in patients who have had prior allogeneic HSCT, mainly in those with prior history of GVHD. The benefit of treatment with nivolumab versus the possible risk should be considered in these patients (see section 4.8).
Head and Neck Cancer:
Patients with a baseline performance score ≥2, active brain or leptomeningeal metastases, active autoimmune disease, medical conditions requiring systemic immunosuppression, or carcinoma of the nasopharynx or salivary gland as the primary tumour sites were excluded from the SCCHN clinical trial (see sections 4.5 and 5.1). In the absence of data, nivolumab should be used with caution in these populations after careful consideration of the potential benefit/risk on an individual basis.
Physicians should consider the delayed onset of nivolumab effect before initiating treatment in patients with poorer prognostic features and/or aggressive disease. In head and neck cancer, a higher number of deaths within 3 months was observed in nivolumab compared to docetaxel. Factors associated with early deaths were ECOG performance status, fast progressive disease on prior platinum therapy and high tumour burden.
Urothelial Carcinoma:
Patients with a baseline performance score 2, active brain metastases or leptomeningeal metastases, active autoimmune disease, or medical conditions requiring systemic immunosuppression were excluded from the clinical trials of urothelial carcinoma (see sections 4.5 and 5.1). In the absence of data, nivolumab should be used with caution in these populations after careful consideration of the potential benefit/risk on an individual basis.
Each mL of this medicinal product contains 0.1 mmol (or 2.5 mg) sodium. To be taken into consideration when treating patients on a controlled sodium diet.
All prescribers of OPDIVO must be familiar with the Physician Information and Management Guidelines. The prescriber must discuss the risks of OPDIVO therapy with the patient. The patient will be provided with the Patient Alert Card with each prescription.
Nivolumab is a human monoclonal antibody, as such pharmacokinetic interaction studies have not been conducted. As monoclonal antibodies are not metabolised by cytochrome P450 (CYP) enzymes or other drug metabolising enzymes, inhibition or induction of these enzymes by co-administered medicinal products is not anticipated to affect the pharmacokinetics of nivolumab.
The use of systemic corticosteroids and other immunosuppressants at baseline, before starting nivolumab, should be avoided because of their potential interference with the pharmacodynamic activity. However, systemic corticosteroids and other immunosuppressants can be used after starting nivolumab to treat immune-related adverse reactions. The preliminary results show that systemic immunosuppression after starting nivolumab treatment does not appear to preclude the response on nivolumab.
There are no data on the use of nivolumab in pregnant women. Studies in animals have shown embryofoetal toxicity (see section 5.3). Human IgG4 is known to cross the placental barrier and nivolumab is an IgG4; therefore, nivolumab has the potential to be transmitted from the mother to the developing foetus. Nivolumab is not recommended during pregnancy and in women of childbearing potential not using effective contraception unless the clinical benefit outweighs the potential risk. Effective contraception should be used for at least 5 months following the last dose of nivolumab.
It is unknown whether nivolumab is secreted in human milk. Because many medicinal products, including antibodies, can be secreted in human milk, a risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue from nivolumab therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Studies to evaluate the effect of nivolumab on fertility have not been performed. Thus, the effect of nivolumab on male and female fertility is unknown.
Based on its pharmacodynamic properties, nivolumab is unlikely to affect the ability to drive and use machines. Because of potential adverse reactions such as fatigue (see section 4.8), patients should be advised to use caution when driving or operating machinery until they are certain that nivolumab does not adversely affect them.
In the pooled dataset of nivolumab 3 mg/kg as monotherapy across tumour types (n=2578) with minimum follow-up ranging from 2.3 to 28 months, the most frequent adverse reactions (≥10%) were fatigue (30%), rash (17%), pruritus (13%), diarrhoea (13%), and nausea (12%). The majority of adverse reactions were mild to moderate (Grade 1 or 2). With a minimum of 24 months follow-up in NSCLC, no new safety signals were identified.
In the dataset of nivolumab 3 mg/kg as monotherapy for the adjuvant treatment of melanoma (n=452), the most frequent adverse reactions (≥10%) were fatigue (46%), rash (29%), diarrhoea (24%), pruritus (23%), nausea (15%), arthralgia (13%), musculoskeletal pain (11%), and hypothyroidism (11%). The majority of adverse reactions were mild to moderate (Grade 1 or 2).
Adverse reactions reported in the pooled dataset for patients treated with nivolumab monotherapy (n=2578) are presented in Table 5. These 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 post-marketing data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.
Table 5. Adverse reactions with nivolumab monotherapy:
Common: upper respiratory tract infection
Uncommon: pneumoniaa, bronchitis
Not known: aseptic meningitish
Rare: histiocytic necrotising lymphadenitis (Kikuchi lymphadenitis)
Very common: neutropaeniaa,b
Uncommon: eosinophilia
Common: infusion related reactionc, hypersensitivityc
Rare: anaphylactic reactionc
Not known: solid organ transplant rejectionh, sarcoidosish
Common: hypothyroidism, hyperthyroidism
Uncommon: adrenal insufficiency, hypopituitarism, hypophysitis, thyroiditis, diabetes mellitus
Rare: diabetic ketoacidosis
Common: decreased appetite
Uncommon: dehydration, metabolic acidosis
Not known: tumour lysis syndromei
Uncommon: hepatitisc
Rare: cholestasis
Common: peripheral neuropathy, headache, dizziness
Uncommon: polyneuropathy, autoimmune neuropathy (including facial and abducens nerve paresis)
Rare: Guillain-Barré syndrome, demyelination, myasthenic syndrome, encephalitisa,c
Uncommon: uveitis, blurred vision, dry eye
Not known: Vogt-Koyanagi-Harada syndromeh
Uncommon: tachycardia, pericardial disordersj
Rare: arrhythmia (including ventricular arrhythmia)d, atrial fibrillation, myocarditisa,f
Common: hypertension
Uncommon: vasculitis
Common: pneumonitisa,c, dyspnoeaa, cough
Uncommon: pleural effusion
Rare: lung infiltration
Very common: diarrhoea, nausea
Common: colitisa, stomatitis, vomiting, abdominal pain, constipation, dry mouth
Uncommon: pancreatitis, gastritis
Rare: duodenal ulcer
Very common: rashe, pruritus
Common: vitiligo, dry skin, erythema, alopecia
Uncommon: erythema multiforme, psoriasis, rosacea, urticaria
Rare: toxic epidermal necrolysisa,f, Stevens-Johnson syndromea,f
Common: musculoskeletal paing, arthralgia
Uncommon: polymyalgia rheumatica, arthritis
Rare: Sjogren’s syndrome, myopathy, myositis (including polymyositis)a,f, rhabdomyolysisa,f
Uncommon: tubulointerstitial nephritis, renal failure (including acute kidney injury)a,c
Very common: fatigue
Common: pyrexia, oedema (including peripheral oedema)
Uncommon: pain, chest pain
Very common: increased AST, increased ALT, increased alkaline phosphatase, increased lipase, increased amylase, hypocalcaemia, increased creatinine, hyperglycaemiac, lymphopaenia, leucopoenia, thrombocytopaenia, anaemiak, hypercalcaemia, hyperkalaemia, hypokalaemia, hypomagnesaemia, hyponatraemia
Common: increased total bilirubin, hypoglycaemia, hypermagnesaemia, hypernatraemia, weight decreased
a Fatal cases have been reported in completed or ongoing clinical studies
b Frequencies of laboratory terms reflect the proportion of patients who experienced a worsening from baseline in laboratory measurements. See “Description of selected adverse reactions; laboratory abnormalities” below.
c Life-threatening cases have been reported in completed or ongoing clinical studies.
d The frequency of adverse events in the cardiac disorders system organ class regardless of causality was higher in the nivolumab group than in the chemotherapy group in post-CTLA4/BRAF inhibitor metastatic melanoma population. Incidence rates per 100 person-years of exposure were 9.3 vs. 0; serious cardiac events were reported by 4.9% patients in the nivolumab group vs. 0 in the investigator ́s choice group. The frequency of cardiac adverse events was lower in the nivolumab group than in the dacarbazine group in the metastatic melanoma without prior treatment population. All were considered not related to nivolumab by investigators except arrhythmia (atrial fibrillation, tachycardia and ventricular arrhythmia).
e Rash is a composite term which includes maculopapular rash, rash erythematous, rash pruritic, rash follicular, rash macular, rash morbilliform, rash papular, rash pustular, rash papulosquamous, rash vesicular, rash generalised, exfoliative rash, dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis atopic, dermatitis bullous, dermatitis exfoliative, dermatitis psoriasiform, drug eruption and pemphigoid.
f Reported also in studies outside the pooled dataset. The frequency is based on the program-wide exposure.
g Musculoskeletal pain is a composite term which includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, and spinal pain.
h Post-marketing event (also see section 4.4).
i Reported in clinical studies and in the post-marketing setting.
j Pericardial disorders is a composite term which includes pericarditis, pericardial effusion, cardiac tamponade, and Dressler’s syndrome.
k Anaemia is a composite term which includes, among other causes, haemolytic anaemia and autoimmune anaemia.
The overall safety profile of nivolumab 3 mg/kg for the adjuvant treatment of melanoma (n=452) was consistent with that established across tumour types for nivolumab monotherapy.
When nivolumab is administered in combination with ipilimumab, refer to the Summary of Product Characteristics for ipilimumab prior to initiation of treatment. For additional information on the safety profile of ipilimumab monotherapy, please refer to the ipilimumab SmPC.
In the pooled dataset of nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg in melanoma (n=448) with minimum follow-up ranging from 6 to 28 months, the most frequent adverse reactions (≥10%) were rash (52%), fatigue (46%), diarrhoea (43%), pruritus (36%), nausea (26%), pyrexia (19%), decreased appetite (16%), hypothyroidism (16%), colitis (15%), vomiting (14%), arthralgia (13%), abdominal pain (13%), headache (11%), and dyspnoea (10%). The majority of adverse reactions were mild to moderate (Grade 1 or 2).
Among the patients treated with nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg in CA209067, 154/313 (49%) had the first onset of Grade 3 or 4 adverse reactions during the initial combination phase. Among the 147 patients in this group who continued treatment in the single-agent phase, 47 (32%) experienced at least one Grade 3 or 4 adverse reaction during the single-agent phase.
In the dataset of nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg in RCC (n=547), with a minimum follow-up of 17.5 months, the most frequent adverse reactions (≥10%) were fatigue (48%), rash (34%), pruritus (28%), diarrhoea (27%), nausea (20%), hypothyroidism (16%), musculoskeletal pain (15%), arthralgia (14%), decreased appetite (14%), pyrexia (14%), vomiting (11%), hyperthyroidism (11%). The majority of adverse reactions were mild to moderate (Grade 1 or 2).
Among the patients treated with nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg in CA209214, 169/547 (31%) had the first onset of Grade 3 or 4 adverse reactions during the initial combination phase. Among the 382 patients in this group who continued treatment in the single-agent phase, 144 (38%) experienced at least one Grade 3 or 4 adverse reaction during the single-agent phase.
Adverse reactions reported in the pooled dataset for patients treated with nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg (n=448) and for patients treated with nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg (n=547) are presented in Table 6. These 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 post-marketing data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.
Table 6. Adverse reactions with nivolumab in combination with ipilimumab:
Nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg*:
Common: pneumonia, upper respiratory tract infection
Uncommon: bronchitis
Not known: aseptic meningitish
Nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg**:
Common: pneumonia, upper respiratory tract infection, conjunctivitis
Uncommon: bronchitis, aseptic meningitis
Nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg*:
Common: eosinophilia
Nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg**:
Uncommon: eosinophilia
Nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg*:
Common: infusion related reaction, hypersensitivity
Uncommon: sarcoidosis
Not known: solid organ transplant rejectionh
Nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg**:
Common: infusion related reaction, hypersensitivity
Nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg*:
Very common: hypothyroidism
Common: adrenal insufficiency, hypopituitarism, hypophysitis, hyperthyroidism, thyroiditis
Uncommon: diabetic ketoacidosisc, diabetes mellitusc
Nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg**:
Very common: hypothyroidism, hyperthyroidism
Common: adrenal insufficiencyc, hypophysitisc, thyroiditis, diabetes mellitusc
Uncommon: diabetic ketoacidosisc, hypopituitarism
Nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg*:
Very common: decreased appetite
Common: dehydration
Not known: tumour lysis syndromei
Nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg**:
Very common: decreased appetite
Common: dehydration
Uncommon: metabolic acidosis
Nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg*:
Common: hepatitisc
Nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg**:
Common: hepatitisc
Nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg*:
Very common: headache
Common: peripheral neuropathy, dizziness
Uncommon: Guillain-Barré syndrome, polyneuropathy, neuritis, peroneal nerve palsy, autoimmune neuropathy (including facial and abducens nerve paresis), encephalitisc
Nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg**:
Common: headache, peripheral neuropathy, dizziness
Uncommon: polyneuropathy, autoimmune neuropathy (including facial and abducens nerve paresis), myasthenia gravisc
Nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg*:
Common: uveitis, blurred vision
Not known: Vogt-Koyanagi-Harada syndromeh
Nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg**:
Common: blurred vision
Uncommon: uveitis
Nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg*:
Common: tachycardia
Uncommon: arrhythmia (including ventricular arrhythmia)a,d, atrial fibrillation, myocarditisa,f
Not known: pericardial disordersj
Nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg**:
Common: tachycardia
Uncommon: arrhythmia (including ventricular arrhythmia), myocarditisc
Nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg*:
Common: hypertension
Nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg**:
Common: hypertension
Nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg*:
Very common: dyspnoea
Common: pneumonitisa,c, pulmonary embolisma, cough
Uncommon: pleural effusion
Nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg**:
Common: pneumonitis, dyspnoea, pleural effusion, cough
Nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg*:
Very common: colitisa, diarrhoea, vomiting, nausea, abdominal pain
Common: stomatitis, pancreatitis, constipation, dry mouth
Uncommon: intestinal perforationa, gastritis, duodenitis
Nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg**:
Very common: diarrhoea, vomiting, nausea
Common: colitis, stomatitis, pancreatitis, abdominal pain, constipation, dry mouth
Uncommon: gastritis
Nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg*:
Very common: rashe, pruritus
Common: vitiligo, dry skin, erythema, alopecia, urticaria
Uncommon: psoriasis
Σπάνιες: toxic epidermal necrolysisa,f, StevensJohnson syndromef
Nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg**:
Very common: rashe, pruritus
Common: dry skin, erythema, urticaria
Uncommon: Stevens-Johnson syndrome, vitiligo, erythema multiforme, alopecia, psoriasis
Nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg*:
Very common: arthralgia
Common: musculoskeletal paing
Uncommon: spondyloarthropathy, Sjogren’s syndrome, arthritis, myopathy, myositis (including polymyositis)a,e, rhabdomyolysisa,f
Nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg**:
Very common: musculoskeletal paing, arthralgia
Common: arthritis, muscle spasms, muscular weakness
Uncommon: polymyalgia rheumatica, myositis (including polymyositis), rhabdomyolysis
Nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg*:
Common: renal failure (including acute kidney injury)a,c
Uncommon: tubulointerstitial nephritis
Nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg**:
Common: renal failure (including acute kidney injury)c
Uncommon: tubulointerstitial nephritis
Nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg*:
Very common: fatigue, pyrexia
Common: oedema (including peripheral oedema), pain
Uncommon: chest pain
Nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg**:
Very common: fatigue, pyrexia
Common: oedema (including peripheral oedema), pain, chest pain, chills
Nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg*:
Very common: increased AST, increased ALT, increased total bilirubin, increased alkaline phosphatase, increased lipase, increased amylase, increased creatinine, hyperglycaemiac, hypoglycaemia, lymphopaenia, leucopoenia, neutropaenia, thrombocytopaenia, anaemiak, hypocalcaemia, hyperkalaemia, hypokalaemia, hypomagnesaemia, hyponatraemia
Common: hypercalcaemia, hypermagnesaemia, hypernatraemia, weight decreased
Nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg**:
Very common: increased AST, increased ALT, increased total bilirubin, increased alkaline phosphatase, increased lipase, increased amylase, increased creatinine, hyperglycaemiac, hypoglycaemia, lymphopaenia, leucopoenia, neutropaeniac, thrombocytopaenia, anaemiak, hypercalcaemia, hypocalcaemia, hyperkalaemia, hypokalaemia, hypomagnesaemia, hyponatraemia
Common: hypermagnesaemia, hypernatraemia, weight decreased
* nivolumab in combination with ipilimumab for the first 4 doses then followed by nivolumab monotherapy in melanoma.
** nivolumab in combination with ipilimumab for the first 4 doses then followed by nivolumab monotherapy in RCC.
a Fatal cases have been reported in completed or ongoing clinical studies
b Frequencies of laboratory terms reflect the proportion of patients who experienced a worsening from baseline in laboratory measurements. See “Description of selected adverse reactions; laboratory abnormalities” below.
c Life-threatening cases have been reported in completed or ongoing clinical studies.
d The frequency of adverse events in the cardiac disorders system organ class regardless of causality was higher in the nivolumab group than in the chemotherapy group in post-CTLA4/BRAF inhibitor metastatic melanoma population. Incidence rates per 100 person-years of exposure were 9.3 vs. 0; serious cardiac events were reported by 4.9% patients in the nivolumab group vs. 0 in the investigator´s choice group. The frequency of cardiac adverse events was lower in the nivolumab group than in the dacarbazine group in the metastatic melanoma without prior treatment population. All were considered not related to nivolumab by investigators except arrhythmia (atrial fibrillation, tachycardia and ventricular arrhythmia).
e Rash is a composite term which includes maculopapular rash, rash erythematous, rash pruritic, rash follicular, rash macular, rash morbilliform, rash papular, rash pustular, rash papulosquamous, rash vesicular, rash generalised, exfoliative rash, dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis atopic, dermatitis bullous, dermatitis exfoliative, dermatitis psoriasiform, drug eruption and pemphigoid.
f Reported also in studies outside the pooled dataset. The frequency is based on the program-wide exposure.
g Musculoskeletal pain is a composite term which includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, and spinal pain.
h Post-marketing event (also see section 4.4)
i Reported in clinical studies and in the post-marketing setting.
j Pericardial disorders is a composite term which includes pericarditis, pericardial effusion, cardiac tamponade, and Dressler’s syndrome.
k Anaemia is a composite term which includes, among other causes, haemolytic anaemia and autoimmune anaemia.
Nivolumab or nivolumab in combination with ipilimumab is associated with immune-related adverse reactions. With appropriate medical therapy, immune-related adverse reactions resolved in most cases. Permanent discontinuation of treatment was required in a greater proportion of patients receiving nivolumab in combination with ipilimumab than in those receiving nivolumab monotherapy. Table 7 presents the percentage for immune-related adverse reactions who were permanently discontinued from treatment by dosing regimen. Additionally, for patients who experienced an event, Table 7 presents the percentage of patients who required high-dose corticosteroids (at least 40 mg daily prednisone equivalents) by dosing regimen. The management guidelines for these adverse reactions are described in section 4.4.
Table 7. Immune-related adverse reactions leading to permanent discontinuation or requiring high-dose corticosteroids by dosing regimen:
| Nivolumab 3 mg/kg monotherapy % | Nivolumab 1 mg/kg in Combination with Ipilimumab 3 mg/kg % | Nivolumab 3 mg/kg in Combination with Ipilimumab 1 mg/kg % | |
|---|---|---|---|
| Immune-related adverse reaction leading to permanent discontinuation | |||
| Pneumonitis | 1.2 | 2.0 | 2.2 |
| Colitis | 0.8 | 16 | 4.0 |
| Hepatitis | 1.0 | 9 | 4.4 |
| Nephritis and Renal Dysfunction | 0.3 | 1.1 | 1.3 |
| Endocrinopathies | 0.1 | 2.7 | 2.9 |
| Skin | 0.3 | 0.9 | 1.5 |
| Hypersensitivity/Infusion Reaction | 0.2 | 0 | 0 |
| Immune-related adverse reaction requiring high-dose corticosteroidsa,b | |||
| Pneumonitis | 69 | 63 | 59 |
| Colitis | 15 | 46 | 26 |
| Hepatitis | 21 | 46 | 35 |
| Nephritis and Renal Dysfunction | 27 | 17 | 27 |
| Endocrinopathies | 7 | 27 | 25 |
| Skin | 4 | 7 | 7 |
| Hypersensitivity/Infusion Reaction | 20 | 6 | 9 |
a at least 40 mg daily prednisone equivalents
b frequency is based on the number of patients who experienced the immune-related adverse reaction
In patients treated with nivolumab monotherapy, the incidence of pneumonitis, including interstitial lung disease and lung infiltration, was 3.4% (87/2578). The majority of cases were Grade 1 or 2 in severity reported in 0.8% (21/2578) and 1.7% (44/2578) of patients respectively. Grade 3 and 4 cases were reported in 0.7% (19/2578) and <0.1% (1/2578) of patients respectively. Grade 5 cases were reported in <0.1% (2/2578) of patients in these studies. Median time to onset was 3.6 months (range: 0.2-19.6). Resolution occurred in 63 patients (72.4%) with a median time to resolution of 6.1 weeks (range: 0.1+ - 96.7+); + denotes a censored observation.
In patients treated with nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg in melanoma, the incidence of pneumonitis including interstitial lung disease, was 7.8% (35/448). Grade 2, Grade 3, and Grade 4 cases were reported in 4.7% (21/448), 1.1% (5/448), and 0.2% (1/448) of patients, respectively. One of the Grade 3 pneumonitis cases worsened over 11 days with a fatal outcome. Median time to onset was 2.6 months (range: 0.7-12.6). Resolution occurred in 33 patients (94.3%) with a median time to resolution of 6.1 weeks (range: 0.3-35.1).
In patients treated with nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg in RCC, the incidence of pneumonitis including interstitial lung disease was 6.2% (34/547). Grade 2 and Grade 3 cases were reported in 3.1% (17/547) and 1.1% (6/547), of patients, respectively. No Grade 4 or 5 cases were reported in this study. Median time to onset was 2.6 months (range: 0.25-20.6). Resolution occurred in 31 patients (91.2%) with a median time to resolution of 6.1 weeks (range: 0.7 – 85.9+).
In patients treated with nivolumab monotherapy, the incidence of diarrhoea, colitis, or frequent bowel movements was 13.1% (339/2578). The majority of cases were Grade 1 or 2 in severity reported in 8.5% (220/2578) and 3.0% (78/2578) of patients respectively. Grade 3 cases were reported in 1.6% (41/2578) of patients. No Grade 4 or 5 cases were reported in these studies. Median time to onset was 1.8 months (range: 0.0-26.6). Resolution occurred in 296 patients (88.1%) with a median time to resolution of 2.1 weeks (range: 0.1 – 124.4+).
In patients treated with nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg in melanoma, the incidence of diarrhoea or colitis was 46.7% (209/448). Grade 2, Grade 3, and Grade 4 cases were reported in 13.6% (61/448), 15.8% (71/448), and 0.4% (2/448) of patients, respectively. No Grade 5 cases were reported. Median time to onset was 1.2 months (range: 0.0-22.6). Resolution occurred in 186 patients (89.4%) with a median time to resolution of 3.0 weeks (range: 0.1 – 159.4+).
In patients treated with nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg in RCC, the incidence of diarrhoea or colitis was 28.2% (154/547). Grade 2 and Grade 3 cases were reported in 10.4% (57/547) and 4.9% (27/547) of patients, respectively. No Grade 4 or 5 cases were reported. Median time to onset was 1.2 months (range: 0.0-24.7). Resolution occurred in 140 patients (91.5%) with a median time to resolution of 2.4 weeks (range: 0.1 – 103.1+).
In patients treated with nivolumab monotherapy, the incidence of liver function test abnormalities was 6.7% (173/2578). The majority of cases were Grade 1 or 2 in severity reported in 3.5% (91/2578) and 1.2% (32/2578) of patients respectively. Grade 3 and 4 cases were reported in 1.6% (41/2578) and 0.3% (9/2578) of patients, respectively. No Grade 5 cases were reported in these studies. Median time to onset was 2.1 months (range: 0.0-27.6). Resolution occurred in 132 patients (76.7%) with a median time to resolution of 5.9 weeks (range: 0.1 – 82.6+).
In patients treated with nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg in melanoma, the incidence of liver function test abnormalities was 29.5% (132/448). Grade 2, Grade 3, and Grade 4 cases were reported in 6.7% (30/448), 15.4% (69/448), and 1.8% (8/448) of patients, respectively. No Grade 5 cases were reported. Median time to onset was 1.5 months (range: 0.0-30.1). Resolution occurred in 124 patients (93.9%) with a median time to resolution of 5.1 weeks (range: 0.1-106.9).
In patients treated with nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg in RCC, the incidence of liver function test abnormalities was 18.5% (101/547). Grade 2, Grade 3, and Grade 4 cases were reported in 4.8% (26/547), 6.6% (36/547), and 1.6% (9/547) of patients, respectively. No Grade 5 cases were reported. Median time to onset was 2.0 months (range: 0.4-26.8). Resolution occurred in 86 patients (85.1%) with a median time to resolution of 6.1 weeks (range: 0.1+ - 82.9+).
In patients treated with nivolumab monotherapy, the incidence of nephritis or renal dysfunction was 2.8% (71/2578). The majority of cases were Grade 1 or 2 in severity reported in 1.6% (41/2578) and 0.7% (18/2578) of patients respectively. Grade 3 and 4 cases were reported in 0.4% (11/2578) and <0.1% (1/2578) of patients, respectively. No Grade 5 nephritis or renal dysfunction was reported in these studies. Median time to onset was 2.3 months (range: 0.0-18.2). Resolution occurred in 42 patients (61.8%) with a median time to resolution of 12.1 weeks (range: 0.3 – 79.1+).
In patients treated with nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg in melanoma, the incidence of nephritis or renal dysfunction was 5.1% (23/448). Grade 2, Grade 3, and Grade 4 cases were reported in 1.6% (7/448), 0.9% (4/448), and 0.7% (3/448) of patients, respectively. No Grade 5 cases were reported. Median time to onset was 2.6 months (range: 0.5-21.8). Resolution occurred in 21 patients (91.3%) with a median time to resolution of 2.1 weeks (range: 0.1 – 125.1+).
In patients treated with nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg in RCC, the incidence of nephritis or renal dysfunction was 8.8% (48/547). Grade 2, Grade 3, and Grade 4 cases were reported in 4.4% (24/547), 0.7% (4/547), and 0.5% (3/547) of patients, respectively. No Grade 5 cases were reported. Median time to onset was 2.1 months (range: 0.0-16.1). Resolution occurred in 37 patients (77.1%) with a median time to resolution of 13.2 weeks (range: 0.1+ - 106.0+).
In patients treated with nivolumab monotherapy, the incidence of thyroid disorders, including hypothyroidism or hyperthyroidism, was 9.6% (248/2578). The majority of cases were Grade 1 or 2 in severity reported in 4.2% (107/2578) and 5.4% (139/2578) of patients, respectively. Grade 3 thyroid disorders were reported in <0.1% (2/2578) of patients. Hypophysitis (1 Grade 1, 2 Grade 2, 5 Grade 3, and 1 Grade 4), hypopituitarism (4 Grade 2 and 1 Grade 3), adrenal insufficiency (including secondary adrenocortical insufficiency) (1 Grade 1, 9 Grade 2, and 5 Grade 3), diabetes mellitus (including Type 1 diabetes mellitus) (3 Grade 2 and 1 Grade 3), and diabetic ketoacidosis (2 Grade 3) were reported. No Grade 5 cases were reported in these studies. Median time to onset of these endocrinopathies was 2.8 months (range: 0.3-29.1). Resolution occurred in 117 patients (42.9%). Time to resolution ranged from 0.4 to 144.1+ weeks.
In patients treated with nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg in melanoma, the incidence of thyroid disorders was 25.2% (113/448). Grade 2 and Grade 3 thyroid disorders were reported in 14.5% (65/448) and 1.3% (6/448) of patients, respectively. Grade 2 and Grade 3 hypophysitis (including lymphocytic hypophysitis) occurred in 5.8% (26/448) and 2.0% (9/448) of patients, respectively. Grade 2 and Grade 3 hypopituitarism occurred in 0.4% (2/448) and 0.7% (3/448) of patients, respectively. Grade 2, Grade 3, and Grade 4 adrenal insufficiency (including secondary adrenocortical insufficiency) occurred in 1.6% (7/448), 1.3% (6/448) and 0.2% (1/448) of patients, respectively. Grade 1, Grade 2, Grade 3, and Grade 4 diabetes mellitus and Grade 4 diabetic ketoacidosis were each reported in 0.2% (1/448) of patients. No Grade 5 endocrinopathy was reported. Median time to onset of these endocrinopathies was 1.9 months (range: 0.0-28.1). Resolution occurred in 64 patients (45.4%). Time to resolution ranged from 0.4 to 155.4+ weeks.
In patients treated with nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg in RCC, the incidence of thyroid disorders was 27.2% (149/547). Grade 2 and Grade 3 thyroid disorders were reported in 15.7% (86/547) and 1.3% (7/547) of patients, respectively. Hypophysitis occurred in 4.0% (22/547) of patients. Grade 2, Grade 3, and Grade 4 cases were reported in 0.5% (3/547), 2.4% (13/547), and 0.4% (2/547) of patients, respectively. Grade 2 hypopituitarism occurred in 0.4% (2/547) of patients. Grade 2, Grade 3, and Grade 4 adrenal insufficiency (including secondary adrenocortical insufficiency) occurred in 2.9% (16/547), 2.2% (12/547) and 0.4% (2/547) of patients, respectively. Diabetes mellitus including Type 1 diabetes mellitus (3 Grade 2, 2 Grade 3, and 3 Grade 4), and diabetic ketoacidosis (1 Grade 4) were reported. No Grade 5 endocrinopathy was reported. Median time to onset of these endocrinopathies was 1.9 months (range: 0.0-22.3). Resolution occurred in 76 patients (42.7%). Time to resolution ranged from 0.4 to 130.3+ weeks.
In patients treated with nivolumab monotherapy, the incidence of rash was 26.4% (680/2578). The majority of cases were Grade 1 in severity reported in 20.1% (518/2578) of patients. Grade 2 and Grade 3 cases were reported in 5.1% (131/2578) and 1.2% (31/2578) of patients respectively. No Grade 4 or 5 cases were reported in these studies. Median time to onset was 1.4 months (range: 0.0-27.9). Resolution occurred in 428 patients (63.8%) with a median time to resolution of 17.1 weeks (0.1 – 150.0+).
In patients treated with nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg in melanoma, the incidence of rash was 65.0% (291/448). Grade 2 and Grade 3 cases were reported in 20.3% (91/448) and 7.6% (34/448) of patients, respectively. No Grade 4 or 5 cases were reported. Median time to onset was 0.5 months (range: 0.0-19.4). Resolution occurred in 191 patients (65.9%) with a median time to resolution of 11.4 weeks (range: 0.1 – 150.1+).
In patients treated with nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg in RCC, the incidence of rash was 48.8% (267/547). Grade 2 and Grade 3 cases were reported in 13.7% (75/547) and 3.7% (20/547) of patients, respectively. No Grade 4 or 5 cases were reported. Median time to onset was 0.9 months (range: 0.0-17.9). Resolution occurred in 192 patients (72.2%) with a median time to resolution of 11.6 weeks (range: 0.1 – 126.7+).
Rare cases of SJS and TEN some of them with fatal outcome have been observed (see sections 4.2 and 4.4).
In patients treated with nivolumab monotherapy, the incidence of hypersensitivity/infusion reactions was 4.7% (121/2578), including 6 Grade 3 and 2 Grade 4 cases.
In patients treated with nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg, the incidence of hypersensitivity/infusion reactions was 3.8% (17/448); all were Grade 1 or 2 in severity. Grade 2 cases were reported in 2.2% (10/448) of patients. No Grade 3-5 cases were reported.
In patients treated with nivolumab 3 mg/kg in combination with ipilimumab 1 mg//kg, the incidence of hypersensitivity/infusion reactions was 4.0% (22/547); all were Grade 1 or 2 in severity. Grade 2 cases were reported in 2.4% (13/547) of patients. No Grade 3-5 cases were reported.
Rapid onset of GVHD has been reported with nivolumab use before and after allogeneic HSCT (see section 4.4). In 49 evaluated patients from two cHL studies who underwent allogeneic HSCT after discontinuing nivolumab monotherapy, Grade 3 or 4 acute GVHD was reported in 13/49 patients (26.5%). Hyperacute GVHD, defined as acute GVHD occurring within 14 days after stem cell infusion, was reported in three patients (6%). A steroid-requiring febrile syndrome, without an identified infectious cause, was reported in six patients (12%) within the first 6 weeks post-transplantation, with three patients responding to steroids. Hepatic veno-occlusive disease occurred in one patient, who died of GVHD and multi-organ failure. Nine of 49 patients (18.4%) died from complications of allogeneic HSCT after nivolumab. The 49 patients had a median follow-up from subsequent allogeneic HSCT of 5.6 months (range: 0-19 months).
In patients treated with nivolumab monotherapy, the proportion of patients who experienced a shift from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 5.2% for anaemia (all Grade 3), 1.0% for thrombocytopaenia, 1.0% for leucopoenia, 10.0% for lymphopaenia, 1.1% for neutropaenia, 2.1% for increased alkaline phosphatase, 2.7% for increased AST, 2.2% for increased ALT, 1.2% for increased total bilirubin, 0.9% for increased creatinine, 3.8% for hyperglycaemia, 1.0% for hypoglycaemia, 3.5% for increased amylase, 7.9% for increased lipase, 6.4% for hyponatraemia, 1.8% for hyperkalaemia, 1.5% for hypokalaemia, 1.2% for hypercalcaemia, 0.7% for hypermagnesaemia, 0.5% for hypomagnesaemia, 0.7% for hypocalcaemia, and 0.1% for hypernatraemia.
In patients treated with nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg in melanoma, the proportion of patients who experienced a worsening from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 2.8% for anaemia (all Grade 3), 1.2% for thrombocytopaenia, 0.5% for leucopoenia, 6.7% for lymphopaenia, 0.7% for neutropaenia, 4.3% for increased alkaline phosphatase, 12.4% for increased AST, 15.3% for increased ALT, 1.2% for increased total bilirubin, 2.4% for increased creatinine, 5.3% for hyperglycaemia, 8.7% for increased amylase, 19.5% for increased lipase, 1.2% for hypocalcaemia, 0.2% each for hypernatraemia and hypercalcaemia, 0.5% for hyperkalemia, 0.3% for hypermagnesaemia, 4.8% for hypokalaemia, and 9.5% for hyponatraemia.
In patients treated with nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg in RCC, the proportion of patients who experienced a worsening from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 3.0% for anaemia (all Grade 3), 0.7% for thrombocytopaenia, 0.6% for leucopoenia, 5.1% for lymphopaenia, 1.1% for neutropaenia, 2.0% for increased alkaline phosphatase, 4.8% for increased AST, 6.5% for increased ALT, 1.1% for increased total bilirubin, 2.1% for increased creatinine, 7.2% for hyperglycaemia, 1.8% for hypoglycemia, 12.2% for increased amylase, 20.1% for increased lipase, 0.4% for hypocalcaemia, 1.3% for hypercalcaemia, 2.4% for hyperkalemia, 1.1% for hypermagnesaemia, 0.4% for hypomagnesaemia 1.9% for hypokalaemia, and 9.9% for hyponatraemia.
Of the 2022 patients who were treated with nivolumab monotherapy 3 mg/kg every 2 weeks and evaluable for the presence of anti-product-antibodies, 231 patients (11.4%) tested positive for treatment-emergent anti-product-antibodies with fifteen patients (0.7%) testing positive for neutralising antibodies.
Of the patients who were treated with nivolumab in combination with ipilimumab and evaluable for the presence of anti-nivolumab antibodies, the incidence of anti-nivolumab antibodies was 26.0% with nivolumab 3 mg/kg and ipilimumab 1 mg/kg every 3 weeks and 37.8% with nivolumab 1 mg/kg and ipilimumab 3 mg/kg every 3 weeks. The incidence of neutralising antibodies against nivolumab was 0.5% with nivolumab 3 mg/kg and ipilimumab 1 mg/kg every 3 weeks and 4.6% with nivolumab 1 mg/kg and ipilimumab 3 mg/kg every 3 weeks. Of patients evaluable for the presence of anti-ipilimumab antibodies, the incidence of anti-ipilimumab antibodies ranged from 6.3 to 8.4% and neutralising antibodies against ipilimumab ranged from 0 to 0.3%.
Although the clearance of nivolumab was increased by 20% when anti-nivolumab-antibodies were present, there was no evidence of loss of efficacy or altered toxicity profile in the presence of nivolumab antibodies based on the pharmacokinetic and exposure-response analyses for both monotherapy and combination.
No overall differences in safety were reported between elderly (≥65 years) and younger patients (<65 years). Data from SCCHN and adjuvant melanoma patients 75 years of age or older are too limited to draw conclusions on this population (see section 5.1). Data from cHL patients 65 years of age or older are too limited to draw conclusions on this population (see section 5.1).
In the non-squamous NSCLC study (CA209057), the safety profile in patients with baseline renal or hepatic impairment was comparable to that in the overall population. These results should be interpreted with caution due to the small sample size within the subgroups.
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. OPDIVO should not be infused concomitantly in the same intravenous line with other medicinal products.
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