The use of systemic corticosteroids at baseline, before starting ipilimumab, should be avoided because of their potential interference with the pharmacodynamic activity and efficacy of ipilimumab. However, systemic corticosteroids or other immunosuppressants can be used after starting ipilimumab to treat immune-related adverse reactions. The use of systemic corticosteroids after starting ipilimumab treatment does not appear to impair the efficacy of ipilimumab.

The use of anticoagulants is known to increase the risk of gastrointestinal haemorrhage. Since gastrointestinal haemorrhage is an adverse reaction with ipilimumab, patients who require concomitant anticoagulant therapy should be monitored closely.

Severe endocrinopathies, including hypothyroidism, hyperthyroidism, adrenal insufficiency (including secondary adrenocortical insufficiency), hypophysitis (including hypopituitarism), diabetes mellitus, and diabetic ketoacidosis have been observed with ipilimumab in combination with nivolumab.

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, ipilimumab in combination with nivolumab should be withheld, and thyroid hormone replacement should be initiated as needed. For symptomatic hyperthyroidism, ipilimumab in combination with nivolumab 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, ipilimumab in combination with nivolumab may be resumed after corticosteroid taper, if needed. Monitoring of thyroid function should continue to ensure appropriate hormone replacement is utilised. Ipilimumab in combination with nivolumab must be permanently discontinued for life-threatening hyperthyroidism or hypothyroidism.

For symptomatic Grade 2 adrenal insufficiency, ipilimumab in combination with nivolumab should be withheld, and physiologic corticosteroid replacement should be initiated as needed. ipilimumab in combination with nivolumab 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, ipilimumab in combination with nivolumab 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, ipilimumab in combination with nivolumab may be resumed after corticosteroid taper, if needed. Ipilimumab in combination with nivolumab 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, ipilimumab in combination with nivolumab should be withheld, and insulin replacement should be initiated as needed. Monitoring of blood sugar should continue to ensure appropriate insulin replacement is utilised. Ipilimumab in combination with nivolumab must be permanently discontinued for life-threatening diabetes.

The following immune-related adverse reactions were reported in less than 1% of patients treated with ipilimumab in combination with nivolumab 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 and serous retinal detachment have been reported post-marketing. Transient vision loss has been reported in patients with ipilimumab-related ocular inflammations.

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, ipilimumab in combination with nivolumab should be withheld and corticosteroids administered. Upon improvement, ipilimumab in combination with nivolumab may be resumed after corticosteroid taper. Ipilimumab in combination with nivolumab 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 ipilimumab in combination with nivolumab. 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, ipilimumab in combination with nivolumab should be withheld or discontinued, and appropriate treatment instituted.

Concurrent administration with vemurafenib

In a Phase 1 trial, asymptomatic grade 3 increases in transaminases (ALT/AST >5 × ULN) and bilirubin (total bilirubin >3 × ULN) were reported with concurrent administration of ipilimumab (3 mg/kg) and vemurafenib (960 mg BID or 720 mg BID). Based on these preliminary data, the concurrent administration of ipilimumab and vemurafenib is not recommended.

Sequential administration with vemurafenib

In a Phase 2 trial, the sequential treatment with vemurafenib followed by 10 mg/kg ipilimumab in patients with BRAF-mutated metastatic melanoma showed a higher incidence of Grade 3+ skin adverse reactions than with ipilimumab alone. Caution should be used when ipilimumab is administered following prior vemurafenib.

Patients with a history of autoimmune disease (other than vitiligo and adequately controlled endocrine deficiencies such as hypothyroidism), including those who require systemic immunosuppressive therapy for pre-existing active autoimmune disease or for organ transplantation graft maintenance, were not evaluated in clinical trials. Ipilimumab is a T-cell potentiator that enables the immune response and may interfere with immunosuppressive therapy, resulting in an exacerbation of the underlying disease or increased risk of graft rejection. Ipilimumab should be avoided in patients with severe active autoimmune disease where further immune activation is potentially imminently life threatening. In other patients with a history of autoimmune disease, ipilimumab should be used with caution after careful consideration of the potential risk-benefit on an individual basis.

There are no data on the use of ipilimumab in pregnant women. Animal reproduction studies have shown reproductive toxicity. Human IgG1 crosses the placental barrier. The potential risk of treatment to the developing foetus is unknown. Ipilimumab is not recommended during pregnancy or in women of childbearing potential not using effective contraception, unless the clinical benefit outweighs the potential risk.

Ipilimumab has been shown to be present at very low levels in milk from cynomolgus monkeys treated during pregnancy. It is unknown whether ipilimumab is secreted in human milk. Secretion of IgGs in human milk is generally limited and IgGs have a low oral bioavailability. Significant systemic exposure of the infant is not expected and no effects on the breast-fed newborn/infant are anticipated. However, because of the potential for adverse reactions in nursing infants, a decision must be made whether to discontinue breast-feeding or to discontinue from ipilimumab therapy taking into account the benefit of breast-feeding for the child and the benefit of ipilimumab therapy for the woman.

Fertility

Studies to evaluate the effect of ipilimumab on fertility have not been performed. Thus, the effect of ipilimumab on male and female fertility is unknown.

Ipilimumab has minor influence on the ability to drive and use machines.

Because of potential adverse reactions such as fatigue, patients should be advised to use caution when driving or operating machinery until they are certain that ipilimumab does not adversely affect them.

Ipilimumab as monotherapy

a. Summary of safety profile

Ipilimumab has been administered to approximately 10,000 patients in a clinical program evaluating its use with various doses and tumour types. Unless otherwise specified, the data below reflect exposure to ipilimumab at 3 mg/kg in clinical trials of melanoma. In the Phase 3 study MDX010-20, patients received a median of 4 doses (range 1-4).

Ipilimumab is most commonly associated with adverse reactions resulting from increased or excessive immune activity. Most of these, including severe reactions, resolved following initiation of appropriate medical therapy or withdrawal of ipilimumab.

In patients who received 3 mg/kg ipilimumab monotherapy in MDX010-20, the most frequently reported adverse reactions (≥10% of patients) were diarrhoea, rash, pruritus, fatigue, nausea, vomiting, decreased appetite, and abdominal pain. The majority were mild to moderate (Grade 1 or 2). Ipilimumab therapy was discontinued for adverse reactions in 10% of patients.

b. List of adverse reactions

Adverse reactions reported in patients with advanced melanoma who were treated with ipilimumab 3 mg/kg in clinical trials (n=767) and from post-marketing surveillance are presented in the following list.

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. Rates of immune-related adverse reactions in HLA-A2*0201 positive patients who received ipilimumab in MDX010-20 were similar to those observed in the overall clinical program.

The safety profile of ipilimumab 3 mg/kg in chemotherapy-naive patients pooled across Phase 2 and 3 clinical trials (N=75; treated), in treatment-naive patients in two retrospective observational studies (N=273 and N=157), and in CA184-169 (N=362) was similar to that in previously-treated advanced melanoma.

The safety data for patients with unresectable or metastatic melanoma, treated with ipilimumab (3 mg/kg, with a minimum of 3 year follow-up) and enrolled in multi-national, prospective, observational study CA184143 (N=1151) were similar to what has been reported in ipilimumab clinical trials for advanced melanoma.

Adverse reactions in patients with advanced melanoma treated with ipilimumab 3 mg/kg (n=767)^a:

Infections and infestations

Uncommon: sepsis^b, septic shock^b, urinary tract infection, respiratory tract infection

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Common: tumour pain

Uncommon: paraneoplastic syndrome

Blood and lymphatic system disorders

Common: anaemia, lymphopenia

Uncommon: haemolytic anaemia^b, thrombocytopenia, eosinophilia, neutropenia

Not known: histiocytosis haematophagice

Immune system disorders

Uncommon: hypersensitivity

Very rare: anaphylactic reaction

Endocrine disorders

Common: hypopituitarism (including hypophysitis)^c, hypothyroidismc

Uncommon: adrenal insufficiency^c, secondary adrenocortical insufficiency^d, hyperthyroidism^c, hypogonadism

Rare: autoimmune thyroiditis^d, thyroiditis^d

Metabolism and nutrition disorders

Very common: decreased appetite

Common: dehydration, hypokalemia

Uncommon: hyponatremia, alkalosis, hypophosphatemia, tumour lysis syndrome, hypocalcaemiad

Psychiatric disorders

Common: confusional state

Uncommon: mental status changes, depression, decreased libido

Nervous system disorders

Common: peripheral sensory neuropathy, dizziness, headache, lethargy

Uncommon: Guillain-Barré syndrome^b,c, meningitis (aseptic), autoimmune central neuropathy (encephalitis)^d, syncope, cranial neuropathy, brain oedema, peripheral neuropathy, ataxia, tremor, myoclonus, dysarthria

Rare: myasthenia gravis^d

Eye disorders

Common: blurred vision, eye pain

Uncommon: uveitis^c, vitreous haemorrhage, iritis^c, eye oedema^d, blepharitis^d, reduced visual acuity, foreign body sensation in eyes, conjunctivitis

Rare: Vogt-Koyanagi-Harada syndrome^e, serous retinal detachment

Cardiac disorders

Uncommon: arrhythmia, atrial fibrillation

Vascular disorders

Common: hypotension, flushing, hot flush

Uncommon: vasculitis, angiopathy^b, peripheral ischaemia, orthostatic hypotension

Rare: temporal arteritis^d

Respiratory, thoracic and mediastinal disorders

Common: dyspnea, cough

Uncommon: respiratory failure, acute respiratory distress syndrome^b, lung infiltration, pulmonary oedema, pneumonitis, allergic rhinitis

Gastrointestinal disorders

Very common: diarrhoea^c, vomiting, nausea

Common: gastrointestinal haemorrhage, colitis^b,c, constipation, gastroesophageal reflux disease, abdominal pain, mucosal inflammation^d

Uncommon: gastrointestinal perforation^b,c, large intestine perforation^b,c, intestinal perforation^b,c, peritonitis^b, gastroenteritis, diverticulitis, pancreatitis, enterocolitis, gastric ulcer, large intestinal ulcer, stomatitis, oesophagitis, ileus^d

Rare: proctitis^d

Hepatobiliary disorders

Common: abnormal hepatic function

Uncommon: hepatic failure^b,c, hepatitis, hepatomegaly, jaundice

Skin and subcutaneous tissue disorders

Very common: rash^c, pruritus^c

Common: dermatitis, erythema, vitiligo, urticaria, eczema^d, alopecia, night sweats, dry skin

Uncommon: toxic epidermal necrolysis^b,c, leukocytoclastic vasculitis, skin exfoliation, hair colour changes^d

Rare: erythema multiforme^d, psoriasis^d, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)^d

Not known: pemphigoid

Musculoskeletal and connective tissue disorders

Common: arthralgia, myalgia, musculoskeletal pain^f, muscle spasms

Uncommon: polymyalgia rheumatica, myositis^d, arthritis, muscular weakness^d

Rare: polymyositis^d

Renal and urinary disorders

Uncommon: renal failure^b, glomerulonephritis^c, autoimmune nephritis^d, renal tubular acidosis, haematuria^d

Rare: proteinuria^d

Reproductive system and breast disorders

Uncommon: amenorrhea

General disorders and administration site conditions

Very common: fatigue, injection site reaction, pyrexia

Common: chills, asthenia, oedema, pain, influenza-like illness^d

Uncommon: multi-organ failure^b,c, systemic inflammatory response syndrome^d, infusion related reaction

Investigations

Common: increased alanine aminotransferase^c, increased aspartate aminotransferase^c, increased lood alkaline phosphatase^d, increased blood bilirubin, weight decreased

Uncommon: increased gamma-glutamyltransferase^d, increased blood creatinine, increased blood thyroid stimulating hormone, decreased blood cortisol, decreased blood corticotrophin, increased lipase^c, increased blood amylase^c, positive antinuclear antibody^d, decreased blood testosterone

Rare: decreased blood thyroid stimulating hormone^d, decreased thyroxine^d, abnormal blood prolactin^d

^a Frequencies are based on pooled data from 9 clinical trials investigating the ipilimumab 3 mg/kg dose in melanoma.
^b Including fatal outcome.
^c Additional information about these potentially inflammatory adverse reactions is provided in “Description of selected adverse reactions”. Data presented in those sections primarily reflect experience from a Phase 3 study, MDX010-20.
^d Data outside the 9 completed clinical trials in melanoma were included in frequency determinations.
^e Post-marketing event.
^f 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.

Additional adverse reactions not listed above have been reported in patients who received other doses (either < or > 3 mg/kg) of ipilimumab in clinical trials of melanoma. These additional reactions occurred at a frequency of <1% unless otherwise noted: meningism, myocarditis, pericardial effusion, cardiomyopathy, autoimmune hepatitis, erythema nodosum, autoimmune pancreatitis, hyperpituitarism, hypoparathyroidism, infectious peritonitis, episcleritis, scleritis, Raynaud’s phenomenon, palmar-plantar erythrodysaesthesia syndrome, cytokine release syndrome, sarcoidosis, decreased blood gonadotrophin, leukopenia, polycythaemia, lymphocytosis, ocular myositis, and neurosensory hypoacusis.

The overall safety profile of ipilimumab 3 mg/kg in clinical trial CA184-169 (N=362) was consistent with that established for ipilimumb in patients treated for advanced melanoma.

Ipilimumab in combination with nivolumab

a. Summary of the safety profile

When ipilimumab is administered in combination with nivolumab, refer to the Summary of Product Characteristics for nivolumab prior to initiation of treatment. For additional information on warnings and precautions associated with nivolumab treatment, please refer to the nivolumab SmPC.

Melanoma

In the pooled dataset of ipilimumab 3 mg/kg in combination with nivolumab 1 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 ipilimumab 3 mg/kg in combination with nivolumab 1 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.

RCC

In the dataset of ipilimumab 1 mg/kg in combination with nivolumab 3 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 ipilimumab 1 mg/kg in combination with nivolumab 3 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.

b. Summary of adverse reactions

Adverse reactions reported in the pooled dataset for patients treated with ipilimumab 3 mg/kg in combination with nivolumab 1 mg/kg (n=448) are presented in the following list. 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.

Adverse reactions with ipilimumab in combination with nivolumab:

Ipilimumab 3 mg/kg in combination with nivolumab 1 mg/kg:

Infections and infestations

Common: pneumonia, upper respiratory tract infection

Uncommon: bronchitis

Blood and lymphatic system disorders

Common: eosinophilia

Immune system disorders

Common: infusion related reaction, hypersensitivity

Uncommon: sarcoidosis

Not known: solid organ transplant rejection^h

Endocrine disorders

Very common: hypothyroidism

Common: adrenal insufficiency, hypopituitarism, hypophysitis, hyperthyroidism, thyroiditis

Uncommon: diabetic ketoacidosis^c, diabetes mellitus^c

Metabolism and nutrition disorders

Very common: decreased appetite

Common: dehydration

Not known: tumour lysis syndromeⁱ

Hepatobiliary disorders

Common: hepatitis^c

Nervous system disorders

Very common: headache

Common: peripheral neuropathy, dizziness

Uncommon: Guillain-Barré syndrome, polyneuropathy, neuritis, peroneal nerve palsy, autoimmune neuropathy (including facial and abducens nerve paresis), encephalitis^c

Eye disorders

Common: uveitis, blurred vision

Not known: Vogt-Koyanagi-Harada syndrome^h

Rare: serous retinal detachment

Cardiac disorders

Common: tachycardia

Uncommon: arrhythmia (including ventricular arrhythmia)^a,d, atrial fibrillation, myocarditis^a,f

Not known: pericardial disorders^j

Vascular disorders

Common: hypertension

Respiratory, thoracic and mediastinal disorders

Very common: dyspnoea

Common: pneumonitis^a,c, pulmonary embolism^a, cough

Uncommon: pleural effusion

Gastrointestinal disorders

Very common: colitis^a, diarrhoea, vomiting, nausea, abdominal pain

Common: stomatitis, pancreatitis, constipation, dry mouth

Uncommon: intestinal perforation^a, gastritis, duodenitis

Skin and subcutaneous tissue disorders

Very common: rash^e , pruritus

Common: vitiligo, dry skin, erythema, alopecia, urticaria

Uncommon: psoriasis

Rare: toxic epidermal necrolysis^a,f, Stevens-Johnson syndrome^f

Musculoskeletal and connective tissue disorders

Very common: arthralgia

Common: musculoskeletal pain^g

Uncommon: spondyloarthropathy, Sjogren’s syndrome, arthritis, myopathy, myositis (including polymyositis)^a,e, rhabdomyolysis^a,f

Renal and urinary disorders

Common: renal failure (including acute kidney injury)^a,c

Uncommon: tubulointerstitial nephritis

General disorders and administration site conditions

Very common: fatigue, pyrexia

Common: oedema (including peripheral oedema), pain

Uncommon: chest pain

Investigations^b

Very common: increased AST, increased ALT, increased total bilirubin, increased alkaline phosphatase, increased lipase, increased amylase, increased creatinine, hyperglycaemia^c, hypoglycaemia, lymphopaenia, leucopoenia, neutropaenia, thrombocytopaenia, anaemia, hypocalcaemia, hyperkalaemia, hypokalaemia, hypomagnesaemia, hyponatraemia

Common: hypercalcaemia, hypermagnesaemia, hypernatraemia, weight decreased

Ipilimumab 1 mg/kg in combination with nivolumab 3 mg/kg*:

Infections and infestations

Common: pneumonia, upper respiratory tract infection, conjunctivitis

Uncommon: bronchitis, aseptic meningitis

Blood and lymphatic system disorders

Uncommon: eosinophilia

Immune system disorders

Common: infusion related reaction, hypersensitivity

Endocrine disorders

Very common: hypothyroidism, hyperthyroidism

Common: adrenal insufficiency^c, hypophysitis^c, thyroiditis, diabetes mellitus^c

Uncommon: diabetic ketoacidosis^c, hypopituitarism

Metabolism and nutrition disorders

Very common: decreased appetite

Common: dehydration

Uncommon: metabolic acidosis

Hepatobiliary disorders

Common: hepatitis^c

Nervous system disorders

Common: headache, peripheral neuropathy, dizziness

Uncommon: polyneuropathy, autoimmune neuropathy (including facial and abducens nerve paresis), myasthenia gravis^c

Eye disorders

Common: blurred vision

Uncommon: uveitis

Rare: serous retinal detachment

Cardiac disorders

Common: tachycardia

Uncommon: arrhythmia (including ventricular arrhythmia), myocarditis^c

Vascular disorders

Common: hypertension

Respiratory, thoracic and mediastinal disorders

Common: pneumonitis, dyspnoea, pleural effusion, cough

Gastrointestinal disorders

Very common: diarrhoea, vomiting, nausea

Common: colitis, stomatitis, pancreatitis, abdominal pain, constipation, dry mouth

Uncommon: gastritis

Skin and subcutaneous tissue disorders

Very common: rash^e, pruritus

Common: dry skin, erythema, urticaria

Uncommon: Stevens-Johnson syndrome, vitiligo, erythema multiforme, alopecia, psoriasis

Musculoskeletal and connective tissue disorders

Very common: musculoskeletal pain^g, arthralgia

Common: arthritis, muscle spasms, muscular weakness

Uncommon: polymyalgia rheumatica, myositis (including polymyositis), rhabdomyolysis

Renal and urinary disorders

Common: renal failure (including acute kidney injury)^c

Uncommon: tubulointerstitial nephritis

General disorders and administration site conditions

Very common: fatigue, pyrexia

Common: oedema (including peripheral oedema), pain, chest pain, chills

Investigations^b

Very common: increased AST, increased ALT, increased total bilirubin, increased alkaline phosphatase, increased lipase, increased amylase, increased creatinine, hyperglycaemia^c, hypoglycaemia, lymphopaenia, leucopoenia, neutropaenia^c, thrombocytopaenia, anaemia, hypercalcaemia, hypocalcaemia, hyperkalaemia, hypokalaemia, hypomagnesaemia, hyponatraemia

Common: hypermagnesaemia, hypernatraemia, weight decreased

* ipilimumab in combination with nivolumab for the first 4 doses then followed by nivolumab monotherapy in melanoma.
** ipilimumab in combination with nivolumab 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
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.

c. Description of selected adverse reactions

Except where noted, data relating to ipilimumab monotherapy are based on patients who received either ipilimumab 3 mg/kg monotherapy (n=131) or ipilimumab 3 mg/kg in combination with gp100 (n=380) in a Phase 3 study of advanced (unresectable or metastatic) melanoma (MDX010-20).

Ipilimumab in combination with nivolumab 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 ipilimumab in combination with nivolumab than in those receiving nivolumab monotherapy. Table 1 presents the percentage of patients with immune-related adverse reactions who were permanently discontinued from treatment with ipilimumab in combination with nivolumab. Additionally, for patients who experienced an event, Table 1 presents the percentage of patients who required high-dose corticosteroids (at least 40 mg daily prednisone equivalents).

Table 1. Immune-related adverse reactions leading to permanent discontinuation or requiring high-dose corticosteroids by dosing regimen:

^a at least 40 mg daily prednisone equivalents
^b frequency is based on the number of patients who experienced the immune-related adverse reaction

Immune-related gastrointestinal reactions

Ipilimumab is associated with serious immune-related gastrointestinal reactions. Fatalities due to gastrointestinal perforation have been reported in <1% of patients who received ipilimumab 3 mg/kg in combination with gp100.

In the ipilimumab 3 mg/kg monotherapy group, diarrhoea and colitis of any severity were reported in 27% and 8%, respectively. The frequency of severe (Grade 3 or 4) diarrhoea and severe (Grade 3 or 4) colitis was 5% each. The median time to onset of severe or fatal (Grade 3 to 5) immune-related gastrointestinal reactions was 8 weeks (range 5 to 13 weeks) from the start of treatment. With protocol-specified management guidelines, resolution (defined as improvement to mild [Grade 1] or less or to the severity at baseline) occurred in most cases (90%), with a median time from onset to resolution of 4 weeks (range 0.6 to 22 weeks). In clinical trials, immune-related colitis was associated with evidence of mucosal inflammation, with or without ulcerations, and lymphocytic and neutrophilic infiltration.

Immune-related colitis

In patients treated with ipilimumab 3 mg/kg in combination with nivolumab 1 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 ipilimumab 1 mg/kg in combination with nivolumab 3 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+).

Immune-related pneumonitis

In patients treated with ipilimumab 3 mg/kg in combination with nivolumab 1 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 ipilimumab 1 mg/kg in combination with nivolumab 3 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+).

Immune-related hepatotoxicity

Ipilimumab is associated with serious immune-related hepatotoxicity. Fatal hepatic failure has been reported in <1% of patients who received ipilimumab 3 mg/kg monotherapy.

Increases in AST and ALT of any severity were reported in 1% and 2% of patients, respectively. There were no reports of severe (Grade 3 or 4) AST or ALT elevation. Time to onset of moderate to severe or fatal (Grade 2 to 5) immune-related hepatotoxicity ranged from 3 to 9 weeks from the start of treatment. With protocol-specified management guidelines, time to resolution ranged from 0.7 to 2 weeks. In clinical trials, liver biopsies from patients who had immune-related hepatotoxicity showed evidence of acute inflammation (neutrophils, lymphocytes, and macrophages).

In patients receiving ipilimumab at a higher than recommended dose in combination with dacarbazine, immune-related hepatotoxicity occurred more frequently than in patients receiving ipilimumab 3 mg/kg monotherapy.

In patients treated with ipilimumab 3 mg/kg in combination with nivolumab 1 mg/kg, 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 ipilimumab 1 mg/kg in combination with nivolumab 3 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+).

Immune-related skin adverse reactions

Ipilimumab is associated with serious skin adverse reactions that may be immune-related. Fatal toxic epidermal necrolysis (including SJS) has been reported in <1% of patients who received ipilimumab in combination with gp100. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been rarely reported with Ipilimumab in clinical studies and during post-marketing use. Incidental cases of pemphigoid have been reported during post-marketing use.

In the ipilimumab 3 mg/kg monotherapy group, rash and pruritus of any severity were each reported in 26% of patients. Ipilimumab-induced rash and pruritus were predominantly mild (Grade 1) or moderate (Grade 2) and responsive to symptomatic therapy. The median time to onset of moderate to severe or fatal (Grade 2 to 5) skin adverse reactions was 3 weeks from start of treatment (range 0.9 to 16 weeks). With protocol-specified management guidelines, resolution occurred in most cases (87%), with a median time from onset to resolution of 5 weeks (range 0.6 to 29 weeks).

In patients treated with ipilimumab 3 mg/kg in combination with nivolumab 1 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+). Rare cases of SJS and TEN some of them with fatal outcome have been observed.

In patients treated with ipilimumab 1 mg/kg in combination with nivolumab 3 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+).

Immune-related neurological reactions

Ipilimumab is associated with serious immune-related neurological reactions. Fatal Guillain-Barré syndrome has been reported in <1% of patients who received ipilimumab 3 mg/kg in combination with gp100. Myasthenia gravis-like symptoms have also been reported in <1% of patients who received higher doses of ipilimumab in clinical trials.

Immune-related nephritis and renal dysfunction

In patients treated with ipilimumab 3 mg/kg in combination with nivolumab 1 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 ipilimumab 1 mg/kg in combination with nivolumab 3 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+).

Immune-related endocrinopathy

In the ipilimumab 3 mg/kg monotherapy group, hypopituitarism of any severity was reported in 4% of patients. Adrenal insufficiency, hyperthyroidism, and hypothyroidism of any severity were each reported in 2% of patients. The frequency of severe (Grade 3 or 4) hypopituitarism was reported in 3% of patients. There were no reports of severe or very severe (Grade 3 or 4) adrenal insufficiency, hyperthyroidism, or hypothyroidism. Time to onset of moderate to very severe (Grade 2 to 4) immune-related endocrinopathy ranged from 7 to nearly 20 weeks from the start of treatment. Immune-related endocrinopathy observed in clinical trials was generally controlled with hormone replacement therapy.

In patients treated with ipilimumab 3 mg/kg in combination with nivolumab 1 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 ipilimumab 1 mg/kg in combination with nivolumab 3 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.

Infusion reactions

In patients treated with ipilimumab 3 mg/kg in combination with nivolumab 1 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 ipilimumab 1 mg/kg in combination with nivolumab 3 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.

Immunogenicity

Less than 2% of patients with advanced melanoma who received ipilimumab in Phase 2 and 3 clinical trials developed antibodies against ipilimumab. None had any infusion-related or peri-infusional hypersensitivity or anaphylactic reactions. Neutralising antibodies against ipilimumab were not detected. Overall, no apparent association was observed between antibody development and adverse reactions.

Of the patients who were treated with ipilimumab in combination with nivolumab and evaluable for the presence of anti-ipilimumab antibodies, the incidence of anti-ipilimumab antibodies ranged from 6.3 to 8.4%%. Neutralising antibodies against ipilimumab ranged from 0 to 0.3%. Of patients evaluable for the presence of anti-nivolumab antibodies, the incidence of anti-nivolumab antibodies was 26% 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.

When administered in combination with nivolumab, the CL of ipilimumab was unchanged in the presence of anti-ipilimumab antibodies and there was no evidence of altered toxicity profile.

Laboratory abnormalities with ipilimumab in combination with nivolumab

In patients treated with ipilimumab 3 mg/kg in combination with nivolumab 1 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 ipilimumab 1 mg/kg in combination with nivolumab 3 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.

d. Paediatric population

No new adverse drug reactions were reported in adolescents 12 years of age and older.

In study CA184070, no immune-related adverse reactions (irAR) Grade 3 were reported for the single patient 12 years of age and older who was treated with ipilimumab 3 mg/kg. Two (25.0%) of 8 patients treated with 5 mg/kg and 1 (11.1%) of 9 patients treated with 10 mg/kg reported Grade 3–4 events. None of the events were fatal. The types of irARs were consistent with the adult experience, with the most commonly reported irARs across all groups in the categories of gastrointestinal (0 [3 mg/kg], 62.5% [5 mg/kg], and 44.4% [10 mg/kg]), hepatic function (0 [3 mg/kg], 75.0% [5 mg/kg], 33.3% [10 mg/kg]), and skin (0 [3 mg/kg], 25.0% [5 mg/kg], 33.3% [10 mg/kg]) events. No new or unexpected irARs were observed in this study. No differences in the spectrum of irARs reported in adults and the paediatric population were evident.

In study CA184178, no new or unexpected irARs were observed, and the observed irARs were similar in frequency, intensity and organ site to what has been reported in adult studies. Two patients in the 10 mg/kg group experienced a Grade 1 and Grade 3 on-study endocrine irAR of hyperglycemia. No other endocrine abnormalities were reported.

A summary of adverse events in adolescents 12 years of age and older, as well as adults, is presented in Table 2.

Table 2. Summary of Adverse Events after up to Four Doses of 3, 5 and 10 mg/kg, All Treated Patients:

MedDRA v.17.0 for CA184070, v.19.0 for CA184178, and V.12.1 for Adult Safety Pool. NA = not assessed
For adults, deaths reported in this table are within 70 days of the last dose, regardless of relationship. Deaths for pediatric patients are those with on-study events within 30 days of the last dose, except for “All Deaths,” which were >30 days after the last dose. In CA184178, deaths were reported at least 90 days of the last dose.
Attribution to ipilimumab reported as Possible, Probable, Definite, or Missing for CA184178 and Adult Safety Pool, and Related or Missing for CA184070.
Abbreviations: SAEs = serious adverse events; AEs = adverse events; irAEs = immune-related adverse events