This information is intended for use by health professionals

1. Name of the medicinal product

YERVOY 5 mg/ml concentrate for solution for infusion

2. Qualitative and quantitative composition

Each ml of concentrate contains 5 mg ipilimumab.

One 10 ml vial contains 50 mg of ipilimumab.

One 40 ml vial contains 200 mg of ipilimumab.

Ipilimumab is a fully human anti-CTLA-4 monoclonal antibody (IgG1κ) produced in Chinese hamster ovary cells by recombinant DNA technology.

Excipients with known effect:

Each ml of concentrate contains 0.1 mmol sodium, which is 2.30 mg sodium.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Concentrate for solution for infusion (sterile concentrate).

Clear to slightly opalescent, colourless to pale yellow liquid that may contain light (few) particulates and has a pH of 7.0 and an osmolarity of 260-300 mOsm/kg.

4. Clinical particulars
4.1 Therapeutic indications

YERVOY as monotherapy is indicated for the treatment of advanced (unresectable or metastatic) melanoma in adults, and adolescents 12 years of age and older (see section 4.4).

YERVOY in combination with nivolumab is indicated for the treatment of advanced (unresectable or metastatic) melanoma in adults.

Relative to nivolumab monotherapy, an increase in progression-free survival (PFS) and overall survival (OS) for the combination of nivolumab with ipilimumab is established only in patients with low tumour PD-L1 expression (see sections 4.4 and 5.1).

4.2 Posology and method of administration

Treatment must be initiated and supervised by specialist physicians experienced in the treatment of cancer.

Posology

YERVOY as monotherapy

Adults and adolescents 12 years of age and older

The recommended induction regimen of YERVOY is 3 mg/kg administered intravenously over a 90-minute period every 3 weeks for a total of 4 doses. Patients should receive the entire induction regimen (4 doses) as tolerated, regardless of the appearance of new lesions or growth of existing lesions. Assessments of tumour response should be conducted only after completion of induction therapy.

YERVOY in combination with nivolumab

The recommended dose is 3 mg/kg ipilimumab in combination with 1 mg/kg nivolumab administered intravenously every 3 weeks for the first 4 doses. This is then followed by a second phase in which nivolumab monotherapy is administered intravenously at either 240 mg every 2 weeks-or at 480 mg every 4 weeks, as presented in Table 1. For the monotherapy phase, the first dose of nivolumab should be administered;

▪ 3 weeks after the last dose of the combination of nivolumab and ipilimumab if using 240 mg every 2 weeks; or

▪ 6 weeks after the last dose of the combination of nivolumab and ipilimumab if using 480 mg every 4 weeks.

Table 1: Recommended doses and infusion times for intravenous administration of ipilimumab in combination with nivolumab

Combination phase, every 3 weeks for 4 dosing cycles

Monotherapy phase

Nivolumab

1 mg/kg over 30 minutes

240 mg every 2 weeks over 30 minutes or 480 mg every 4 weeks over 60 minutes

Ipilimumab

3 mg/kg over 90 minutes

-

Treatment with YERVOY in combination with nivolumab, should be continued as long as clinical benefit is observed or until treatment is no longer tolerated by the patient. Atypical responses (i.e., an initial transient increase in tumour size or small new lesions within the first few months followed by tumour shrinkage) have been observed. It is recommended to continue treatment with YERVOY in combination with nivolumab for clinically stable patients with initial evidence of disease progression until disease progression is confirmed.

Liver function tests (LFTs) and thyroid function tests should be evaluated at baseline and before each dose of YERVOY. In addition, any signs or symptoms of immune-related adverse reactions, including diarrhoea and colitis, must be assessed during treatment with YERVOY (see Tables 2A, 2B, and section 4.4).

Children younger than 12 years of age

The safety and efficacy of ipilimumab in children younger than 12 years of age has not been established.

Permanent discontinuation of treatment or withholding of doses

Management of immune-related adverse reactions may require withholding of a dose or permanent discontinuation of YERVOY therapy and institution of systemic high-dose corticosteroid. In some cases, addition of other immunosuppressive therapy may be considered (see section 4.4).

Dose escalation or reduction is not recommended. Dosing delay or discontinuation may be required based on individual safety and tolerability.

Guidelines for permanent discontinuation or withholding of doses are described in Tables 2A and 2B for YERVOY as monotherapy, and in Table 2C for YERVOY in combination with nivolumab or administration of the second phase of treatment (nivolumab monotherapy) following combination treatment. Detailed guidelines for the management of immune-related adverse reactions are described in section 4.4.

Table 2A When to permanently discontinue YERVOY as monotherapy

Permanently discontinue YERVOY in patients with the following adverse reactions. Management of these adverse reactions may also require systemic high-dose corticosteroid therapy if demonstrated or suspected to be immune-related (see section 4.4 for detailed management guidelines).

Severe or life-threatening adverse reactions

NCI-CTCAE v4 Gradea

Gastrointestinal:

Severe symptoms (abdominal pain, severe diarrhoea or significant change in the number of stools, blood in stool, gastrointestinal haemorrhage, gastrointestinal perforation)

▪ Grade 3 or 4 diarrhoea or colitis

Hepatic:

Severe elevations in aspartate aminotransferase (AST), alanine aminotransferase (ALT), or total bilirubin or symptoms of hepatotoxicity

▪ Grade 3 or 4 elevation in AST, ALT, or total bilirubin

Skin:

Life threatening skin rash (including Stevens-Johnson syndrome or toxic epidermal necrolysis) or severe widespread pruritus interfering with activities of daily living or requiring medical intervention

▪ Grade 4 rash or Grade 3 pruritus

Neurologic:

New onset or worsening severe motor or sensory neuropathy

▪ Grade 3 or 4 motor or sensory neuropathy

Other organ systemsb:

(e.g. nephritis, pneumonitis, pancreatitis, non-infectious myocarditis)

▪ ≥ Grade 3 immune-related reactionsc

▪ ≥ Grade 2 for immune-related eye disorders NOT responding to topical immunosuppressive therapy

a Toxicity grades are in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events. Version 4.0 (NCI-CTCAE v4).

b Any other adverse reactions that are demonstrated or suspected to be immune-related should be graded according to CTCAE. Decision whether to discontinue YERVOY should be based on severity.

c Patients with severe (Grade 3 or 4) endocrinopathy controlled with hormone replacement therapy may remain on therapy.

Table 2B When to withhold dose of YERVOY as monotherapy

Withhold YERVOY dosea in patients with the following immune-related adverse reactions. See section 4.4 for detailed management guidelines.

Mild to moderate Immune-related adverse reactions

Action

Gastrointestinal:

Moderate diarrhoea or colitis that either is not controlled with medical management or that persists (5-7 days) or recurs

1. Withhold dose until an adverse reaction resolves to Grade 1 or Grade 0 (or returns to baseline).

2. If resolution occurs, resume therapy.d

3. If resolution has not occurred, continue to withhold doses until resolution then resume treatment.d

4. Discontinue YERVOY if resolution to Grade 1 or Grade 0 or return to baseline does not occur.

Hepatic:

Grade 2 elevation in AST, ALT, or total bilirubin

Skin:

Moderate to severe (Grade 3)b skin rash or (Grade 2) widespread/intense pruritus regardless of etiology

Endocrine:

Severe adverse reactions in the endocrine glands, such as hypophysitis and thyroiditis that are not adequately controlled with hormone replacement therapy or high-dose immunosuppressive therapy

Neurological:

Moderate (Grade 2)b unexplained motor neuropathy, muscle weakness, or sensory neuropathy (lasting more than 4 days)

Other moderate adverse reactionsc

a No dose reduction of YERVOY is recommended.

b Toxicity grades are in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events. Version 4.0 (NCI-CTCAE v4).

c Any other organ system adverse reactions that are considered immune-related should be graded according to CTCAE. Decision whether to withhold a dose should be based on severity.

d Until administration of all 4 doses or 16 weeks from first dose, whichever occurs earlier.

Table 2C: Recommended treatment modifications for YERVOY in combination with nivolumab or administration of the second phase of treatment (nivolumab monotherapy) following combination treatment

Immune-related adverse reaction

Severity

Treatment modification

Immune-related pneumonitis

Grade 2 pneumonitis

Withhold dose(s) until symptoms resolve, radiographic abnormalities improve, and management with corticosteroids is complete

Grade 3 or 4 pneumonitis

Permanently discontinue treatment

Immune-related colitis

Grade 2 diarrhoea or colitis

Withhold dose(s) until symptoms resolve and management with corticosteroids, if needed, is complete

Grade 3 or 4 diarrhoea or colitis

Permanently discontinue treatment

Immune-related hepatitis

Grade 2 elevation in aspartate aminotransferase (AST), alanine aminotransferase (ALT), or total bilirubin

Withhold dose(s) until laboratory values return to baseline and management with corticosteroids, if needed, is complete

Grade 3 or 4 elevation in AST, ALT, or total bilirubin

Permanently discontinue treatment

Immune-related nephritis and renal dysfunction

Grade 2 or 3 creatinine elevation

Withhold dose(s) until creatinine returns to baseline and management with corticosteroids is complete

Grade 4 creatinine elevation

Permanently discontinue treatment

Immune-related endocrinopathies

Symptomatic Grade 2 or 3 hypothyroidism, hyperthyroidism, hypophysitis,

Grade 2 adrenal insufficiency

Grade 3 diabetes

Withhold dose(s) until symptoms resolve and management with corticosteroids (if needed for symptoms of acute inflammation) is complete. Treatment should be continued in the presence of hormone replacement therapya as long as no symptoms are present

Grade 4 hypothyroidism

Grade 4 hyperthyroidism

Grade 4 hypophysitis

Grade 3 or 4 adrenal insufficiency

Grade 4 diabetes

Permanently discontinue treatment

Immune-related skin adverse reactions

Grade 3 rash

Withhold dose(s) until symptoms resolve and management with corticosteroids is complete

Grade 4 rash

Permanently discontinue treatment

Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN)

Permanently discontinue treatment (see section 4.4)

Other immune-related adverse reactions

Grade 3 (first occurrence)

Withhold dose(s)

Grade 3 myocarditis

Permanently discontinue treatment

Grade 4 or recurrent Grade 3 ; persistent Grade 2 or 3 despite treatment modification ; inability to reduce corticosteroid dose to 10 mg prednisone or equivalent per day

Permanently discontinue treatment

Note: Toxicity grades are in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4).

a Recommendation for the use of hormone replacement therapy is provided in section 4.4.

YERVOY in combination with nivolumab should be permanently discontinued for:

• Grade 4 or recurrent Grade 3 adverse reactions;

• Persistent Grade 2 or 3 adverse reactions despite management.

When YERVOY is administered in combination with nivolumab, if either agent is withheld, the other agent should also be withheld. If dosing is resumed after a delay, either the combination treatment or nivolumab monotherapy could be resumed based on the evaluation of the individual patient.

Special populations

Paediatric population

The safety and efficacy of YERVOY in children younger than 12 years of age have not been established. Very limited data are available. YERVOY should not be used in children younger than 12 years of age.

Elderly

No overall differences in safety or efficacy were reported between elderly (≥ 65 years) and younger patients (< 65 years). No specific dose adjustment is necessary in this population.

Renal impairment

The safety and efficacy of YERVOY have not been studied in patients with renal impairment. Based on population pharmacokinetic results, no specific dose adjustment is necessary in patients with mild to moderate renal dysfunction (see section 5.2).

Hepatic impairment

The safety and efficacy of YERVOY have not been studied in patients with hepatic impairment. Based on the population pharmacokinetic results, no specific dose adjustment is necessary in patients with mild hepatic impairment (see section 5.2). YERVOY must be administered with caution in patients with transaminase levels ≥ 5 x ULN or bilirubin levels > 3 x ULN at baseline (see section 5.1).

Method of administration

YERVOY is for intravenous use. The recommended infusion period is 90 minutes.

YERVOY can be used for intravenous administration without dilution or may be diluted in sodium chloride 9 mg/ml (0.9%) solution for injection or glucose 50 mg/ml (5%) solution for injection to concentrations between 1 and 4 mg/ml.

YERVOY must not be administered as an intravenous push or bolus injection.

When administered in combination with nivolumab, nivolumab should be given first followed by YERVOY on the same day. Use separate infusion bags and filters for each infusion.

For instructions on the handling of the medicinal product before administration, see section 6.6.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

Ipilimumab in combination with nivolumab

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. Most immune-related adverse reactions improved or resolved with appropriate management, including initiation of corticosteroids and treatment modifications (see section 4.2). Immune-related adverse reactions have occurred at higher frequencies when nivolumab was administered in combination with ipilimumab compared with nivolumab as monotherapy.

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. Ipilimumab in combination with nivolumab should be discontinued for life-threatening or recurrent severe cardiac and pulmonary adverse reactions.

Patients should be monitored continuously (at least up to 5 months after the last dose) as an adverse reaction with ipilimumab in combination with nivolumab may occur at any time during or after discontinuation of therapy.

Immune-related reactions

Ipilimumab is associated with inflammatory adverse reactions resulting from increased or excessive immune activity (immune-related adverse reactions), likely to be related to its mechanism of action. Immune-related adverse reactions, which can be severe or life-threatening, may involve the gastrointestinal, liver, skin, nervous, endocrine, or other organ systems. While most immune-related adverse reactions occurred during the induction period, onset months after the last dose of ipilimumab has also been reported. Unless an alternate etiology has been identified, diarrhoea, increased stool frequency, bloody stool, LFT elevations, rash and endocrinopathy must be considered inflammatory and ipilimumab-related. Early diagnosis and appropriate management are essential to minimise life-threatening complications.

Systemic high-dose corticosteroid with or without additional immunosuppressive therapy may be required for management of severe immune-related adverse reactions.

Ipilimumab specific management guidelines for immune-related adverse reactions are described below for use as monotherapy and in combination with nivolumab.

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. If immunosuppression with corticosteroids is used to treat an adverse reaction that occurs as a consequence of combination therapy, 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.

Ipilimumab in combination with nivolumab 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.

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.

Immune-related gastrointestinal reactions

Ipilimumab as monotherapy

Ipilimumab is associated with serious immune-related gastrointestinal reactions. Fatalities due to gastrointestinal perforation have been reported in clinical trials (see section 4.8).

In patients who received ipilimumab 3 mg/kg monotherapy in a Phase 3 study of advanced (unresectable or metastatic) melanoma (MDX010-20, see section 5.1), the median time to onset of severe or fatal (Grade 3-5) 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).

Patients must be monitored for gastrointestinal signs and symptoms that may be indicative of immune-related colitis or gastrointestinal perforation. Clinical presentation may include diarrhoea, increased frequency of bowel movements, abdominal pain, or haematochezia, with or without fever. Diarrhoea or colitis occurring after initiation of ipilimumab must be promptly evaluated to exclude infectious or other alternate etiologies. In clinical trials, immune-related colitis was associated with evidence of mucosal inflammation, with or without ulcerations, and lymphocytic and neutrophilic infiltration.

Management recommendations for diarrhoea or colitis are based on severity of symptoms (per NCI-CTCAE v4 severity grading classification). Patients with mild to moderate (Grade 1 or 2) diarrhoea (an increase of up to 6 stools per day) or suspected mild to moderate colitis (e.g. abdominal pain or blood in stools) may remain on ipilimumab. Symptomatic treatment (e.g. loperamide, fluid replacement) and close monitoring are advised. If mild to moderate symptoms recur or persist for 5-7 days, the scheduled dose of ipilimumab should be withheld and corticosteroid therapy (e.g. prednisone 1 mg/kg orally once daily or equivalent) should be initiated. If resolution to Grades 0-1 or return to baseline occurs, ipilimumab may be resumed (see section 4.2).

Ipilimumab must be permanently discontinued in patients with severe (Grade 3 or 4) diarrhoea or colitis (see section 4.2), and systemic high-dose intravenous corticosteroid therapy should be initiated immediately. (In clinical trials, methylprednisolone 2 mg/kg/day has been used). Once diarrhoea and other symptoms are controlled, the initiation of corticosteroid taper should be based on clinical judgment. In clinical trials, rapid tapering (over periods < 1 month) resulted in recurrence of diarrhoea or colitis in some patients. Patients must be evaluated for evidence of gastrointestinal perforation or peritonitis.

The experience from clinical trials on the management of corticosteroid-refractory diarrhoea or colitis is limited. However, addition of an alternative immunosuppressive agent to the corticosteroid regimen may be considered. In clinical trials, a single dose of infliximab 5 mg/kg was added unless contraindicated. Infliximab must not be used if gastrointestinal perforation or sepsis is suspected (see the Summary of Product Characteristics for infliximab).

Immune-related colitis

Ipilimumab in combination with nivolumab

Severe diarrhoea or colitis has been observed with ipilimumab in combination with nivolumab with (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, ipilimumab in combination with nivolumab must be permanently discontinued, and corticosteroids should be initiated at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents.

Grade 3 diarrhoea or colitis observed with ipilimumab in combination with nivolumab 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, ipilimumab in combination with nivolumab 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, ipilimumab in combination with nivolumab 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 ipilimumab in combination with nivolumab must be permanently discontinued.

Immune-related pneumonitis

Ipilimumab in combination with nivolumab

Severe pneumonitis or interstitial lung disease, including fatal cases, has been observed with ipilimumab in combination with nivolumab (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, ipilimumab in combination with nivolumab 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, ipilimumab in combination with nivolumab should be withheld and corticosteroids initiated at a dose of 1 mg/kg/day methylprednisolone equivalents. Upon improvement, ipilimumab in combination with nivolumab 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 ipilimumab in combination with nivolumab must be permanently discontinued.

Immune-related hepatotoxicity

Ipilimumab as monotherapy

Ipilimumab is associated with serious immune-related hepatotoxicity. Fatal hepatic failure has been reported in clinical trials (see section 4.8).

In patients who received ipilimumab 3 mg/kg monotherapy in MDX010-20, time to onset of moderate to severe or fatal (Grade 2-5) 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.

Hepatic transaminase and bilirubin must be evaluated before each dose of ipilimumab, as early laboratory changes may be indicative of emerging immune-related hepatitis (see section 4.2). Elevations in LFTs may develop in the absence of clinical symptoms. Increases in AST and ALT or total bilirubin should be evaluated to exclude other causes of hepatic injury, including infections, tumour progression, or concomitant medication and monitored until resolution. Liver biopsies from patients who had immune-related hepatotoxicity showed evidence of acute inflammation (neutrophils, lymphocytes, and macrophages).

For patients with Grade 2 transaminase or total bilirubin elevation, the scheduled dose of ipilimumab should be withheld, and LFTs must be monitored until resolution. Upon improvement, ipilimumab may be resumed (see section 4.2).

For patients with Grade 3 or 4 transaminase or total bilirubin elevation, treatment must be permanently discontinued (see section 4.2), and systemic high-dose intravenous corticosteroid therapy (e.g. methylprednisolone 2 mg/kg daily or equivalent) should be initiated immediately. In such patients, LFTs must be monitored until normalization. Once symptoms have resolved and LFTs show sustained improvement or return to baseline, the initiation of corticosteroid taper should be based on clinical judgment. Tapering should occur over a period of at least 1 month. Elevations in LFTs during taper may be managed with an increase in the dose of corticosteroid and a slower taper.

For patients with significant LFT elevations that are refractory to corticosteroid therapy, addition of an alternative immunosuppressive agent to the corticosteroid regimen may be considered. In clinical trials, mycophenolate mofetil was used in patients without response to corticosteroid therapy, or who had an LFT elevation during corticosteroid tapering that was not responsive to an increase in the dose of corticosteroids (see the Summary of Product Characteristics for mycophenolate mofetil).

Ipilimumab in combination with nivolumab

Severe hepatitis has been observed with ipilimumab in combination with nivolumab (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, ipilimumab in combination with nivolumab 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, ipilimumab in combination with nivolumab 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, ipilimumab in combination with nivolumab 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 ipilimumab in combination with nivolumab must be permanently discontinued.

Immune-related skin adverse reactions

Caution should be used when considering the use of ipilimumab or ipilimumab in combination with nivolumab in a patient who has previously experienced a severe or life-threatening skin adverse reaction on a prior cancer immune stimulatory therapy).

Ipilimumab as monotherapy

Ipilimumab is associated with serious skin adverse reactions that may be immune-related. Rare cases of toxic epidermal necrolysis (TEN) (including Steven Johnson Syndrome) have been observed, some with fatal outcome. Rare cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) have also been reported in clinical trials and during post-marketing use (see section 4.8).

DRESS presents as a rash with eosinophilia associated with one or more of the following features: fever, lymphadenopathy, facial oedema, and internal organ involvement (hepatic, renal, pulmonary). DRESS may be characterized by a long latency (two to eight weeks) between medicinal product exposure and disease onset.

Ipilimumab-induced rash and pruritus were predominantly mild or moderate (Grade 1 or 2) and responsive to symptomatic therapy. In patients who received ipilimumab 3 mg/kg monotherapy in MDX010-20, the median time to onset of moderate to severe or fatal (Grade 2-5) skin adverse reactions was 3 weeks (range 0.9-16 weeks) from start of treatment. 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).

Ipilimumab-induced rash and pruritus should be managed based on severity. Patients with a mild to moderate (Grade 1 or 2) rash may remain on ipilimumab therapy with symptomatic treatment (e.g. antihistamines). For mild to moderate rash or mild pruritus that persists for 1 to 2 weeks and does not improve with topical corticosteroids, oral corticosteroid therapy should be initiated (e.g. prednisone 1 mg/kg once daily or equivalent).

For patients with a severe (Grade 3) rash, the scheduled dose of ipilimumab should be withheld. If initial symptoms improve to mild (Grade 1) or resolve, ipilimumab therapy may be resumed (see section 4.2).

Ipilimumab must be permanently discontinued in patients with a very severe (Grade 4) rash or severe (Grade 3) pruritus (see section 4.2), and systemic high-dose intravenous corticosteroid therapy (e.g. methylprednisolone 2 mg/kg/day) should be initiated immediately. Once rash or pruritus is controlled, initiation of corticosteroid taper should be based on clinical judgment. Tapering should occur over a period of at least 1 month.

Ipilimumab in combination with nivolumab

Severe rash has been observed with ipilimumab in combination with nivolumab (see section 4.8). Ipilimumab in combination with nivolumab 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 ipilimumab in combination with nivolumab 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 ipilimumab in combination with nivolumab, permanent discontinuation of treatment is recommended (see section 4.2).

Immune-related neurological reactions

Ipilimumab as monotherapy

Ipilimumab is associated with serious immune-related neurological adverse reactions. Fatal Guillain-Barré syndrome has been reported in clinical trials. Myasthenia gravis-like symptoms have also been reported (see section 4.8). Patients may present with muscle weakness. Sensory neuropathy may also occur.

Unexplained motor neuropathy, muscle weakness, or sensory neuropathy lasting > 4 days must be evaluated, and non-inflammatory causes such as disease progression, infections, metabolic syndromes and concomitant medication should be excluded. For patients with moderate (Grade 2) neuropathy (motor with or without sensory) likely related to ipilimumab, the scheduled dose should be withheld. If neurologic symptoms resolve to baseline, the patient may resume ipilimumab (see section 4.2).

Ipilimumab must be permanently discontinued in patients with severe (Grade 3 or 4) sensory neuropathy suspected to be related to ipilimumab (see section 4.2). Patients must be treated according to institutional guidelines for management of sensory neuropathy, and intravenous corticosteroids (e.g. methylprednisolone 2 mg/kg/day) should be initiated immediately.

Progressive signs of motor neuropathy must be considered immune-related and managed accordingly. Ipilimumab must be permanently discontinued in patients with severe (Grade 3 or 4) motor neuropathy regardless of causality (see section 4.2).

Immune-related nephritis and renal dysfunction

Ipilimumab in combination with nivolumab

Severe nephritis and renal dysfunction have been observed with ipilimumab in combination with nivolumab (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, ipilimumab in combination with nivolumab 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, ipilimumab in combination with nivolumab should be withheld, and corticosteroids should be initiated at a dose of 0.5 to 1 mg/kg/day methylprednisolone equivalents. Upon improvement, ipilimumab in combination with nivolumab 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 ipilimumab in combination with nivolumab must be permanently discontinued.

Immune-related endocrinopathy

Ipilimumab as monotherapy

Ipilimumab can cause inflammation of the endocrine system organs, manifesting as hypophysitis, hypopituitarism, adrenal insufficiency, and hypothyroidism (see section 4.8), and patients may present with nonspecific symptoms, which may resemble other causes such as brain metastasis or underlying disease. The most common clinical presentation includes headache and fatigue. Symptoms may also include visual field defects, behavioural changes, electrolyte disturbances, and hypotension. Adrenal crisis as a cause of the patient's symptoms must be excluded. Clinical experience with ipilimumab-associated endocrinopathy is limited.

For patients who received ipilimumab 3 mg/kg monotherapy in MDX010-20, time to onset of moderate to very severe (Grade 2-4) 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 immunosuppressive therapy and hormone replacement therapy.

If there are any signs of adrenal crisis such as severe dehydration, hypotension, or shock, immediate administration of intravenous corticosteroids with mineralocorticoid activity is recommended, and the patient must be evaluated for presence of sepsis or infections. If there are signs of adrenal insufficiency but the patient is not in adrenal crisis, further investigations should be considered including laboratory and imaging assessment. Evaluation of laboratory results to assess endocrine function may be performed before corticosteroid therapy is initiated. If pituitary imaging or laboratory tests of endocrine function are abnormal, a short course of high-dose corticosteroid therapy (e.g. dexamethasone 4 mg every 6 hrs or equivalent) is recommended to treat the inflammation of the affected gland, and the scheduled dose of ipilimumab should be withheld (see section 4.2). It is currently unknown if the corticosteroid treatment reverses the gland dysfunction. Appropriate hormone replacement should also be initiated. Long-term hormone replacement therapy may be necessary.

Once symptoms or laboratory abnormalities are controlled and overall patient improvement is evident, treatment with ipilimumab may be resumed and initiation of corticosteroid taper should be based on clinical judgment. Tapering should occur over a period of at least 1 month.

Ipilimumab in combination with nivolumab

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 (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, 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.

Infusion reaction

Ipilimumab as monotherapy or in combination with nivolumab

Severe infusion reactions have been reported in clinical trials of ipilimumab or ipilimumab in combination with nivolumab (see section 4.8). In case of a severe or life-threatening infusion reaction, the ipilimumab or ipilimumab in combination with nivolumab infusion must be discontinued and appropriate medical therapy administered. Patients with mild or moderate infusion reaction may receive ipilimumab or ipilimumab in combination with nivolumab with close monitoring and use of premedication according to local treatment guidelines for prophylaxis of infusion reactions.

Other immune-related adverse reactions

Ipilimumab as monotherapy

The following adverse reactions suspected to be immune-related have been reported in patients treated with ipilimumab 3 mg/kg monotherapy in MDX010-20: uveitis, eosinophilia, lipase elevation, and glomerulonephritis. In addition, iritis, haemolytic anaemia, amylase elevations, multi-organ failure, and pneumonitis have been reported in patients treated with ipilimumab 3 mg/kg + gp100 peptide vaccine in MDX010-20. Cases of Vogt-Koyanagi-Harada syndrome have been reported post-marketing (see section 4.8).

If severe (Grade 3 or 4), these reactions may require immediate systemic high-dose corticosteroid therapy and discontinuation of ipilimumab (see section 4.2). For ipilimumab-related uveitis, iritis, or episcleritis, topical corticosteroid eye drops should be considered as medically indicated.

Histiocytosis haematophagic

Histiocytosis haematophagic has been reported in relation to ipilimumab therapy. The adverse reaction mostly responded well to treatment with corticosteroids. In most reported cases prior or concurrent therapy with a PD-1 or PD-L1 inhibitor has occurred. Caution should be taken when ipilimumab is given following or in combination with a PD-1 or PD-L1 inhibitor.

Ipilimumab in combination with nivolumab

The following immune-related adverse reactions were reported in less than 1% of patients treated with ipilimumab in combination with nivolumab in clinical trials: pancreatitis, uveitis, demyelination, autoimmune neuropathy (including facial and abducens nerve paresis), Guillain-Barré syndrome, myasthenic syndrome, 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, 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 (see section 4.2), and appropriate treatment instituted.

Disease specific precautions

Melanoma

Patients with ocular melanoma, primary CNS melanoma and active brain metastases were not included in the MDX010-20 trial (see section 5.1).

Patients with ocular melanoma were not included in the CA184-169 clinical trial. However, patients with brain metastases were included in this study, if they were free of neurologic symptoms related to metastatic brain lesions and if they did not require or receive systemic corticosteroid therapy in the 10 days prior to beginning ipilimumab therapy (see section 5.1).

Patients with ocular melanoma, active brain metastases and prior therapy with ipilimumab were not included in the paediatric trial CA184070 (see section 5.1).

Patients with ocular melanoma, active brain metastases and prior therapy with CTLA-4, PD-1, PD-L1, or CD137 targeted agents were not included in the paediatric trial CA184178 (see section 5.1).

Patients with a baseline performance score ≥ 2, active brain metastases or autoimmune disease, and patients who had been receiving systemic immunosuppressants prior to study entry were excluded from the clinical trials of ipilimumab in combination with nivolumab. Patients with ocular/uveal melanoma were excluded from clinical trials of melanoma. 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.

Relative to nivolumab monotherapy, an increase in PFS for the combination of ipilimumab with nivolumab is established only in patients with low tumour PD-L1 expression. The improvement in OS was similar between ipilimumab with nivolumab 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).

Use of ipilimumab in combination with nivolumab in melanoma patients with rapidly progressing disease.

Physicians should consider the delayed onset of ipilimumab in combination with nivolumab effect before initiating treatment in patients with rapidly progressing disease (see section 5.1).

Patients with autoimmune disease

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 (see section 5.1) 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.

Patients on controlled sodium diet

Each ml of this medicinal product contains 0.1 mmol (or 2.30 mg) sodium. To be taken into consideration when treating patients on a controlled sodium diet.

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.

Paediatric population

Limited, but no long-term, safety data is available on the use of ipilimumab in adolescents 12 years of age and older.

Only very limited data are available in children younger than 12 years of age. Therefore, ipilimumab should not be used in children younger than 12 years of age.

Before initiating treatment with ipilimumab monotherapy in adolescents of 12 years and older, physicians are advised to carefully evaluate the individual patient, taking into consideration the limited available data, the observed benefits and the toxicity of ipilimumab monotherapy in the paediatric population (see sections 4.8 and 5.1).

4.5 Interaction with other medicinal products and other forms of interaction

Ipilimumab is a human monoclonal antibody that is not metabolized by cytochrome P450 enzymes (CYPs) or other drug metabolizing enzymes.

A drug-interaction study in adults of ipilimumab administered alone and in combination with chemotherapy (dacarbazine or paclitaxel/carboplatin) was conducted evaluating interaction with CYP isozymes (particularly CYP1A2, CYP2E1, CYP2C8, and CYP3A4) in patients with treatment-naive advanced melanoma. No clinically relevant pharmacokinetic drug-drug interaction was observed between ipilimumab and paclitaxel/carboplatin, dacarbazine or its metabolite, 5-aminoimidazole-4-carboxamide (AIC).

Other forms of interaction

Corticosteroids

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.

Anticoagulants

The use of anticoagulants is known to increase the risk of gastrointestinal haemorrhage. Since gastrointestinal haemorrhage is an adverse reaction with ipilimumab (see section 4.8), patients who require concomitant anticoagulant therapy should be monitored closely.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no data on the use of ipilimumab in pregnant women. Animal reproduction studies have shown reproductive toxicity (see section 5.3). Human IgG1 crosses the placental barrier. The potential risk of treatment to the developing foetus is unknown. YERVOY is not recommended during pregnancy or in women of childbearing potential not using effective contraception, unless the clinical benefit outweighs the potential risk.

Breast-feeding

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 YERVOY therapy taking into account the benefit of breast-feeding for the child and the benefit of YERVOY 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.

4.7 Effects on ability to drive and use machines

YERVOY has minor influence on 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 ipilimumab does not adversely affect them.

4.8 Undesirable effects

Ipilimumab as monotherapy (see section 4.2)

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, (see section 5.1), 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 (see section 4.4 for management of immune-related adverse reactions).

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. Tabulated 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) are presented in Table 3.

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.

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

Infections and infestations

Uncommon

sepsisb, septic shockb, 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 anaemiab, 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 insufficiencyc, secondary adrenocortical insufficiencyd, hyperthyroidismc, hypogonadism

Rare

autoimmune thyroiditisd, thyroiditisd

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 syndromeb,c, meningitis (aseptic), autoimmune central neuropathy (encephalitis)d, syncope, cranial neuropathy, brain oedema, peripheral neuropathy, ataxia, tremor, myoclonus, dysarthria

Rare

myasthenia gravisd

Eye disorders

Common

blurred vision, eye pain

Uncommon

uveitisc, vitreous haemorrhage, iritisc, eye oedemad, blepharitisd, reduced visual acuity, foreign body sensation in eyes, conjunctivitis

Rare

Vogt-Koyanagi-Harada syndromee

Cardiac disorders

Uncommon

arrhythmia, atrial fibrillation

Vascular disorders

Common

hypotension, flushing, hot flush

Uncommon

vasculitis, angiopathyb, peripheral ischaemia, orthostatic hypotension

Rare

temporal arteritisd

Respiratory, thoracic and mediastinal disorders

Common

dyspnea, cough

Uncommon

respiratory failure, acute respiratory distress syndromeb, lung infiltration, pulmonary oedema, pneumonitis, allergic rhinitis

Gastrointestinal disorders

Very common

diarrhoeac, vomiting, nausea

Common

gastrointestinal haemorrhage, colitisb,c, constipation, gastroesophageal reflux disease, abdominal pain, mucosal inflammationd

Uncommon

gastrointestinal perforationb,c, large intestine perforationb,c, intestinal perforationb,c, peritonitisb, gastroenteritis, diverticulitis, pancreatitis, enterocolitis, gastric ulcer, large intestinal ulcer, oesophagitis, ileusd

Rare

proctitisd

Hepatobiliary disorders

Common

abnormal hepatic function

Uncommon

hepatic failureb,c, hepatitis, hepatomegaly, jaundice

Skin and subcutaneous tissue disorders

Very common

rashc, pruritusc

Common

dermatitis, erythema, vitiligo, urticaria, eczemad, alopecia, night sweats, dry skin

Uncommon

toxic epidermal necrolysisb,c, leukocytoclastic vasculitis, skin exfoliation, hair colour changesd

Rare

erythema multiformed, psoriasisd, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)d

Not known

pemphigoid

Musculoskeletal and connective tissue disorders

Common

arthralgia, myalgia, musculoskeletal pain, muscle spasms

Uncommon

polymyalgia rheumatica, myositisd, arthritis, muscular weaknessd

Rare

polymyositisd

Renal and urinary disorders

Uncommon

renal failureb, glomerulonephritisc, autoimmune nephritisd, renal tubular acidosis, haematuriad

Rare

proteinuriad

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 illnessd

Uncommon

multi-organ failureb,c, systemic inflammatory response syndromed, infusion related reaction

Investigations

Common

increased alanine aminotransferasec, increased aspartate aminotransferasec, increased blood alkaline phosphatased, increased blood bilirubin, weight decreased

Uncommon

increased gamma-glutamyltransferased, increased blood creatinine, increased blood thyroid stimulating hormone, decreased blood cortisol, decreased blood corticotrophin, increased lipasec, increased blood amylasec, positive antinuclear antibodyd, decreased blood testosterone

Rare

decreased blood thyroid stimulating hormoned, decreased thyroxined, abnormal blood prolactind

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” and section 4.4. 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 (also see section 4.4).

Additional adverse reactions not listed in Table 3 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 (see section 4.2)

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.

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.

b. Tabulated 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 Table 4. 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 4: Adverse reactions in patients with advanced melanoma treated with 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

Endocrine disorders

Very common

hypothyroidism

Common

adrenal insufficiency, hypopituitarism, hypophysitis, hyperthyroidism, thyroiditis

Uncommon

diabetic ketoacidosisc, diabetes mellitusc

Metabolism and nutrition disorders

Very common

decreased appetite

Common

dehydration

Hepatobiliary disorders

Common

hepatitisc

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), encephalitisc

Eye disorders

Common

uveitis, blurred vision

Not known

Vogt-Koyanagi-Harada syndromeh

Cardiac disorders

Common

tachycardia

Uncommon

arrhythmia (including ventricular arrhythmia)a,d, atrial fibrillation, myocarditisa,f

Vascular disorders

Common

hypertension

Respiratory, thoracic and mediastinal disorders

Very common

dyspnoea

Common

pneumonitisa,c, pulmonary embolisma, cough

Uncommon

pleural effusion

Gastrointestinal disorders

Very common

colitisa, diarrhoea, vomiting, nausea, abdominal pain

Common

stomatitis, pancreatitis, constipation, dry mouth

Uncommon

intestinal perforationa, gastritis, duodenitis

Skin and subcutaneous tissue disorders

Very common

rashe, pruritus

Common

vitiligo, dry skin, erythema, alopecia, urticaria

Uncommon

psoriasis

Rare

toxic epidermal necrolysisa,f, Stevens-Johnson syndromef

Musculoskeletal and connective tissue disorders

Very common

arthralgia

Common

musculoskeletal paing

Uncommon

spondyloarthropathy, Sjogren's syndrome, arthritis, myopathy, myositis (including polymyositis)a,f, rhabdomyolysisa,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

Investigationsb

Very common

increased AST, increased ALT, increased total bilirubin, increased alkaline phosphatase, increased lipase, increased amylase, increased creatinine, hyperglycaemiac, hypoglycaemia, lymphopaenia, leucopoenia, neutropaenia, thrombocytopaenia, anaemia, hypocalcaemia, hyperkalaemia, hypokalaemia, hypomagnesaemia, hyponatraemia

Common

hypercalcaemia, hypermagnesaemia, hypernatraemia, weight decreased

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

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)

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, see section 5.1).

Ipilimumab in combination with nivolumab is associated with immune-related adverse reactions. With appropriate medical therapy, immune-related adverse reactions resolved in most cases. Table 5 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 5 presents the percentage of patients who required high-dose corticosteroids (at least 40 mg daily prednisone equivalents).The management guidelines for these adverse reactions are described in section 4.4.

Table 5: Immune-related adverse reactions leading to permanent discontinuation or requiring high-dose corticosteroids by dosing regimen

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

%

Immune-related adverse reaction leading to permanent discontinuation

Pneumonitis

2.0

Colitis

16

Hepatitis

9

Nephritis and Renal Dysfunction

1.1

Endocrinopathies

2.7

Skin

0.9

Hypersensitivity/Infusion Reaction

0

Immune-related adverse reaction requiring high-dose corticosteroidsa,b

Pneumonitis

63

Colitis

46

Hepatitis

46

Nephritis and Renal Dysfunction

17

Endocrinopathies

27

Skin

7

Hypersensitivity/Infusion Reaction

6

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+).

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).

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).

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 (see section 5.1). 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 (see sections 4.2 and 4.4).

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+).

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.

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.

Immunogenicity

Less than 3% 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, 8.4% tested positive for treatment-emergent anti-ipilimumab antibodies with 0.3% testing positive for neutralising antibodies.

The clearance of ipilimumab was unchanged when anti-ipilimumab antibodies were present following monotherapy or in combination with nivolumab. There was no evidence of loss of efficacy or altered toxicity profile in the presence of ipilimumab antibodies with the combination.

Laboratory abnormalities with ipilimumab in combination with nivolumab

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.

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 6.

Table 6: Summary of Adverse Events after up to Four Doses of 3, 5 and 10 mg/kg, All Treated Patients

Number of Patients (%)

Age ≥ 12 to 21 years

Age 12 to < 18 years

Adults

Advanced Melanoma and Non-Melanoma Solid Tumors

Advanced Melanoma

Advanced Melanoma

CA184070

CA184178

CA184004/ 022Pooled

CA184004/007 /008/022 Pooled

3 mg/kg

n = 1

5 mg/kg

n = 8

10 mg/kg

n = 9

3 mg/kg

n = 4

10 mg/kg

n = 8

3 mg/kg

n = 111

10 mg/kg

n = 325

All Deaths, n (%)

1 (100.0)

4 (50.0)

2 ( 22.2)

2 (50.0)

3 (37.5)

26 (23.4)

71 (21.8)

Treatment-Related Deaths, n (%)

0

0

0

0

0

2 (1.8)

6 (1.8)

SAEs, n (%)

1 (100.0)

7 ( 87.5)

4 ( 44.4)

1 (25.0)

6 (75.0)

50 (45.0)

168 (51.7)

SAEs, drug-related, n (%)

1 (100.0)

5 ( 62.5)

4 ( 44.4)

1 (25.0)

5 (62.5)

19 (17.1)

95 (29.2)

AEs leading to study drug discontinuation, n (%)

0

3 ( 37.5)

2 ( 22.2)

1 (25.0)

5 (62.5)

12 (10.8)

88 (27.1)

Drug-related AEs leading to study drug discontinuation, n (%)

0

3 ( 37.5)

2 ( 22.2)

1 (25.0)

5 (62.5)

9 (8.1)

61 (18.8)

irAEs, n (%)

1 (100.0)

7 ( 87.5)

7 ( 77.8)

2 (50.0)

4 (50.0)

68 (61.3)

234 (72.0)

AE, n (%)

1 (100.0)

8 (100.0)

9 (100.0)

4 (100.0)

8 (100.0)

108 (97.3)

315 (96.9)

Drug-related AEs, n (%)

1 (100.0)

7 ( 87.5)

9 (100.0)

2 (50.0)

7 (87.5)

88 (79.3)

274 (84.3)

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via :

Ireland

HPRA Pharmacovigilance,

Earlsfort Terrace,

IRL - Dublin 2;

Tel: +353 1 6764971; Fax: +353 1 6762517.

Website: www.hpra.ie;

E-mail: medsafety@hpra.ie.

United Kingdom

Yellow Card Scheme at: www.mhra.gov.uk/yellowcard

Or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

The maximum tolerated dose of ipilimumab has not been determined. In clinical trials, patients received up to 20 mg/kg without apparent toxic effects.

In case of overdose, patients must be closely monitored for signs or symptoms of adverse reactions, and appropriate symptomatic treatment instituted.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies, ATC code: L01XC11.

Mechanism of action

Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is a key regulator of T-cell activity. Ipilimumab is a CTLA-4 immune checkpoint inhibitor that blocks T-cell inhibitory signals induced by the CTLA-4 pathway, increasing the number of reactive T-effector cells which mobilize to mount a direct T-cell immune attack against tumour cells. CTLA-4 blockade can also reduce T-regulatory cell function, which may contribute to an anti-tumour immune response. Ipilimumab may selectively deplete T-regulatory cells at the tumour site, leading to an increase in the intratumoral T-effector/ T-regulatory cell ratio which drives tumour cell death.

Pharmacodynamic effects

In patients with melanoma who received ipilimumab, the mean peripheral blood absolute lymphocyte counts (ALC) increased throughout the induction dosing period. In Phase 2 studies, this increase was dose-dependent. In MDX010-20 (see section 5.1), ipilimumab at 3 mg/kg with or without gp100 increased ALC throughout the induction dosing period, but no meaningful change in ALC was observed in the control group of patients who received an investigational gp100 peptide vaccine alone.

In peripheral blood of patients with melanoma, a mean increase in the percent of activated HLA-DR+ CD4+ and CD8+ T cells was observed after treatment with ipilimumab, consistent with its mechanism of action. A mean increase in the percent of central memory (CCR7+ CD45RA-) CD4+ and CD8+ T cells and a smaller, but significant, mean increase in the percent of effector memory (CCR7- CD45RA-) CD8+ T cells also was observed after treatment with ipilimumab.

Clinical efficacy and safety

Ipilimumab in combination with nivolumab

For additional information on clinical efficacy and safety associated with the dosing recommendations of nivolumab when administered as monotherapy following combination therapy with ipilimumab, please refer to the nivolumab SmPC.

Clinical trials

Overall survival (OS) advantage of ipilimumab at the recommended dose of 3 mg/kg in patients with previously-treated advanced (unresectable or metastatic) melanoma was demonstrated in a Phase 3 study (MDX010-20). Patients with ocular melanoma, primary CNS melanoma, active brain metastases, human immunodeficiency virus (HIV), hepatitis B, and hepatitis C were not included in the MDX010-20 clinical trial. Clinical trials excluded patients with ECOG performance status > 1 and mucosal melanoma. Patients without liver metastasis who had a baseline AST > 2.5 x ULN, patients with liver metastasis who had a baseline AST > 5 x ULN, and patients with a baseline total bilirubin ≥ 3 x ULN were also excluded.

For patients with a history of autoimmune disease, see also section 4.4.

MDX010-20

A Phase 3, double-blind study enrolled patients with advanced (unresectable or metastatic) melanoma who had previously been treated with regimens containing one or more of the following: IL-2, dacarbazine, temozolomide, fotemustine, or carboplatin. Patients were randomized in a 3:1:1 ratio to receive ipilimumab 3 mg/kg + an investigational gp100 peptide vaccine (gp100), ipilimumab 3 mg/kg monotherapy, or gp100 alone. All patients were HLA-A2*0201 type; this HLA type supports the immune presentation of gp100. Patients were enrolled regardless of their baseline BRAF mutation status. Patients received ipilimumab every 3 weeks for 4 doses as tolerated (induction therapy). Patients with apparent tumour burden increase before completion of the induction period were continued on induction therapy as tolerated if they had adequate performance status. Assessment of tumour response to ipilimumab was conducted at approximately Week 12, after completion of induction therapy.

Additional treatment with ipilimumab (re-treatment) was offered to those who developed PD after initial clinical response (PR or CR) or after SD (per the modified WHO criteria) > 3 months from the first tumour assessment. The primary endpoint was OS in the ipilimumab+ gp100 group vs. the gp100 group. Key secondary endpoints were OS in the ipilimumab+ gp100 group vs. the ipilimumab monotherapy group and in the ipilimumab monotherapy group vs. the gp100 group.

A total of 676 patients were randomized: 137 to the ipilimumab monotherapy group, 403 to the ipilimumab + gp100 group, and 136 to the gp100 alone group. The majority had received all 4 doses during induction. Thirty-two patients received re-treatment: 8 in the ipilimumab monotherapy group, 23 in the ipilimumab + gp100 group, and 1 in the gp100 group. Duration of follow-up ranged up to 55 months. Baseline characteristics were well balanced across groups. The median age was 57 years. The majority (71-73%) of patients had M1c stage disease and 37-40% of patients had an elevated lactate dehydrogenase (LDH) at baseline. A total of 77 patients had a history of previously treated brain metastases.

The ipilimumab-containing regimens demonstrated a statistically significant advantage over the gp100 control group in OS. The hazard ratio (HR) for comparison of OS between ipilimumab monotherapy and gp100 was 0.66 (95% CI: 0.51, 0.87; p = 0.0026).

By subgroup analysis, the observed OS benefit was consistent within most of the subgroups of patients (M [metastases]-stage, prior interleukin-2, baseline LDH, age, sex, and the type and number of prior therapy). However, for women above 50 years of age, the data supporting an OS benefit of ipilimumab treatment were limited. As the subgroups analysis includes only small numbers of patients, no definitive conclusions can be drawn from these data.

Median and estimated rates of OS at 1 year and 2 years are presented in Table 7.

Table 7: Overall survival in MDX010-20

Ipilimumab 3 mg/kg

n= 137

gp100 a

n= 136

Median Months (95% CI)

10 months

(8.0, 13.8)

6 months

(5.5, 8.7)

OS at 1 year % (95% CI)

46% (37.0, 54.1)

25% (18.1, 32.9)

OS at 2 years % (95% CI)

24% (16.0, 31.5)

14% (8.0, 20.0)

a gp100 peptide vaccine is an experimental control.

In the ipilimumab 3 mg/kg monotherapy group, median OS was 22 months and 8 months for patients with SD and those with PD, respectively. At the time of this analysis, medians were not reached for patients with CR or PR.

For patients who required re-treatment, the BORR was 38% (3/8 patients) in the ipilimumab monotherapy group, and 0% in the gp100 group. The disease control rate (DCR) (defined as CR+PR+SD) was 75% (6/8 patients) and 0%, respectively. Because of the limited number of patients in these analyses, no definitive conclusion regarding the efficacy of ipilimumab re-treatment can be drawn.

The development or maintenance of clinical activity following ipilimumab treatment was similar with or without the use of systemic corticosteroids.

CA184-169

A Phase 3, double-blind study enrolled patients with previously treated or untreated unresectable Stage III or Stage IV melanoma. A total of 727 patients were randomized, 362 to receive ipilimumab 3 mg/kg and 365 to receive ipilimumab 10 mg/kg every 3 weeks for 4 doses. In the ipilimumab 10 mg/kg group, the median OS (95% CI) was 16 months (11.63, 17.84) and in the ipilimumab 3 mg/kg group the median OS (95% CI) was 12 months (9.86, 13.27). Overall survival compared between Ipilimumab 10 mg/kg and 3 mg/kg groups showed HR = 0.84 (95% CI: 0.70, 0.99; P-value = 0.04). No statistically significant difference in progression free survival (PFS) was observed between the 10 mg/kg and the 3 mg/kg groups. (HR 0.89 with a 95% CI of 0.76, 1.04 and log-rank test P-value = 0.1548). BORR was similar in the 10 mg/kg and 3 mg/kg groups. BORR in the 10 mg/kg group was 15.3% (95% CI: 11.8, 19.5) and in the 3 mg/kg group was 12.2% (95% CI: 9.0, 16.0). Ipilimumab 10 mg/kg was associated with higher rates of adverse events compared with the 3 mg/kg dose. The frequencies of serious adverse reactions in the 10 mg/kg and 3 mg/kg groups were 37% and 18%, with the 3 most common serious adverse reactions being diarrhea (10.7% vs 5.5%), colitis (8.0% vs 3.0%), and hypophysitis (4.4% vs 1.9%). Adverse events leading to discontinuation in the 10 mg/kg and 3 mg/kg groups occurred in 31% and 19% of patients, with AEs leading to death in 4 and 2 patients, respectively.

At the recommended dose of 3 mg/kg median OS was similar in the subgroup of females ≥ 50 years of age compared to the overall population: (11.40 vs 11.53 months). Median OS in the subgroup with brain metastases at baseline was 5.67 months at the recommended dose of 3 mg/kg.

Other studies

OS of ipilimumab 3 mg/kg monotherapy in chemotherapy-naive patients pooled across Phase 2 and 3 clinical trials (N= 78; randomised) and in treatment-naive patients in two retrospective observational studies (N= 273 and N= 157) were generally consistent. In the two observational studies, 12.1% and 33.1% of the patients had brain metastases at the time of advanced melanoma diagnosis. Median OS and estimated 1-year, 2-year, 3-year and 4-year survival rates are presented in Table 8. The estimated 1-year, 2-year and 3-year survival rates for chemotherapy-naive patients (N= 78) pooled across Phase 2 and 3 clinical trials were 54.1% (95% CI: 42.5 - 65.6), 31.6% (95% CI: 20.7 - 42.9) and 23.7% (95% CI: 14.3 - 34.4) respectively.

Table 8: Overall survival in observational studies

CA184338

n= 273

CA184332

n= 157

Median OS (95% CI)

14 months

(12.8, 18.7)

10 months

(7.0, 12.8)

OS at 1 year % (95% CI)

59% (52.5, 64.3)

44% (35.5, 51.4)

OS at 2 years % (95% CI)

39% (33.1, 44.8)

26% (18.9, 33.3)

OS at 3 years % (95% CI)

31% (25.5-36.7)

22% (15.5-29.2)

OS at 4 years % (95% CI)

26% (20.4-31.3)

22% (15.5-29.2)

Patients with brain metastases in study CA184332 had a median OS of 7 months (95% CI: 5.06 - 12.81) and patients without brain metastases had a median OS of 14.1 months (95% CI: 9.96-Not estimated).

Patients with brain metastases in study CA184338 had a median OS of 6.3 months (95% CI: 3.2 - 12.0) and patients without brain metastases had a median OS of 17.7 months (95% CI: 13.6 - 12.1).

Long term survival benefit of treatment with ipilimumab (at 3mg/kg) is demonstrated through a pooled analysis of OS data from clinical trials in patients with previously treated and treatment naive advanced melanoma (N = 965). The Kaplan-Meier OS curve revealed a plateau beginning around year 3 (OS rate = 21% [95% CI: 17-24]) that extended up to 10 years in some patients (see Figure 1).

Figure 1: Overall Survival with ipilimumab 3 mg/kg in pooled analysis

No. at Risk

3.0 mg/kg

965

429

127

73

41

29

28

12

8

4

0

Randomised phase 3 study of receive ipilimumab in combination with nivolumab or nivolumab as monotherapy vs. ipilimumab as monotherapy (CA209067)

The safety and efficacy of ipilimumab 3 mg/kg in combination with nivolumab 1 mg/kg nivolumab 3 mg/kg vs. ipilimumab 3 mg/kg monotherapy for the treatment of advanced (unresectable or metastatic) melanoma were evaluated in a phase 3, randomised, double-blind study (CA209067). The differences between the two nivolumab-containing groups were evaluated descriptively. The study included adult patients with confirmed unresectable Stage III or Stage IV melanoma. Patients were to have ECOG performance status score of 0 or 1. Patients who had not received prior systemic anticancer therapy for unresectable or metastatic melanoma were enrolled. Prior adjuvant or neoadjuvant therapy was allowed if it was completed at least 6 weeks prior to randomisation. Patients with active autoimmune disease, ocular/uveal melanoma, or active brain or leptomeningeal metastases were excluded from the study.

A total of 945 patients were randomised to receive ipilimumab in combination with nivolumab (n = 314), nivolumab monotherapy (n = 316), or ipilimumab monotherapy (n = 315). Patients in the combination arm received nivolumab 1 mg/kg over 60 minutes and ipilimumab 3 mg/kg over 90 minutes administered intravenously every 3 weeks for the first 4 doses, followed by nivolumab 3 mg/kg as monotherapy every 2 weeks. Patients in the nivolumab monotherapy arm received nivolumab 3 mg/kg every 2 weeks. Patients in the comparator arm received ipilimumab 3 mg/kg and nivolumab-matched placebo intravenously every 3 weeks for 4 doses followed by placebo every 2 weeks. Randomisation was stratified by PD-L1 expression (≥ 5% vs. < 5% tumour cell membrane expression), BRAF status, and M stage per the American Joint Committee on Cancer (AJCC) staging system. Treatment was continued as long as clinical benefit was observed or until treatment was no longer tolerated. Tumour assessments were conducted 12 weeks after randomisation then every 6 weeks for the first year, and every 12 weeks thereafter. The co-primary outcome measures were progression-free survival and OS. ORR and the duration of response were also assessed.

Baseline characteristics were balanced across the three treatment groups. The median age was 61 years (range: 18 to 90 years), 65% of patients were men, and 97% were white. ECOG performance status score was 0 (73%) or 1 (27%). The majority of the patients had AJCC Stage IV disease (93%); 58% had M1c disease at study entry. Twenty-two percent of patients had received prior adjuvant therapy. Thirty-two percent of patients had BRAF mutation-positive melanoma; 26.5% of patients had PD-L1 ≥ 5% tumour cell membrane expression. Four percent of patients had a history of brain metastasis, and 36% of patients had a baseline LDH level greater than ULN at study entry. Among patients with quantifiable tumour PD-L1 expression, the distribution of patients was balanced across the three treatment groups. Tumour PD-L1 expression was determined using the PD-L1 IHC 28-8 pharmDx assay.

PFS results (with minimum follow up of 18 months) are shown in Figure 2 (all randomised population), Figure 3 (at the tumour PD-L1 5% cut off), and Figure 4 (at the tumour PD-L1 1% cut off).

Figure 2: Progression-free survival (CA209067)

Nivolumab+ipilimumab vs. ipilimumab (primary analysis) - HR (99.5% CI): 0.42 (0.32, 0.56); p-value: < 0.0001

Nivolumab vs. ipilimumab (primary analysis) - HR (99.5% CI): 0.55 (0.42, 0.73); p-value: < 0.0001

Nivolumab+ipilimumab vs. nivolumab (descriptive analysis) - HR (95% CI): 0.76 (0.62, 0.95)

Figure 3: Progression-free survival by PD-L1 expression: 5% cut off (CA209067)

Figure 4: Progression-free survival by PD-L1 expression: 1% cut off (CA209067)

The final OS analysis occurred when all patients had a minimum follow-up of 28 months. OS results at an additional analysis undertaken at a minimum follow-up of 36 months show outcomes consistent with the original analysis. OS results from this follow-up analysis are shown in Figure 5 (all randomised), Figure 6 (at the tumour PD-L1 1% cut off), and Table 9 (at the tumour PD-L1 5% cut off).

The OS analysis was not adjusted to account for subsequent therapies received. Subsequent systemic therapy was received by 31.8%, 44.3%, and 62.2% of patients in the combination, nivolumab monotherapy, and ipilimumab arms, respectively. Subsequent immunotherapy (including anti-PD1 therapy, anti-CTLA-4 antibody, or other immunotherapy) was received by 14.6%, 29.1%, and 44.1% of patients in the combination, nivolumab monotherapy, and ipilimumab arms, respectively.

Figure 5 Overall survival (CA209067) - Minimum follow-up of 36 months

Figure 6: Overall survival by PD-L1 expression: 1% cut off (CA209067) - Minimum follow-up of 36 months

Table 9: Summary of overall survival by PD-L1 expression: 5% cut off - CA209067 - Minimum follow-up of 36 months

Tumour

PD-L1 expression

n

nivolumab + ipilimumab

Median OS (95% CI)

n

ipilimumab

Median OS (95% CI)

Hazard Ratio (95% CI)

<5%

210

NR (32.72, NR)

202

18.40 (13.70, 22.51)

0.56 (0.43, 0.72)

≥5%

68

NR (39.06, NR)

75

28.88 (18.10, NR)

0.59 (0.36, 0.97)

nivolumab

Median OS (95% CI)

ipilimumab

Median OS (95% CI)

Hazard Ratio (95% CI)

<5%

208

35.94 (23.06, NR)

202

18.40 (13.70, 22.51)

0.68 (0.53, 0.87)

≥5%

80

NR (35.75, NR)

75

28.88 (18.10, NR)

0.60 (0.38, 0.95)

nivolumab + ipilimumab

Median OS (95% CI)

nivolumab

Median OS (95% CI)

Hazard Ratio (95% CI)

<5%

210

NR (32.72, NR)

208

35.94 (23.06, NR)

0.82 (0.62, 1.08)

≥5%

68

NR (39.06, NR)

80

NR (35.75, NR)

0.99 (0.59, 1.67)

NR = not reached

Minimum follow-up for the analysis of ORR was 28 months. Responses are summarised in Table 10.

Table 10: Objective response (CA209067)

nivolumab + ipilimumab

(n=314)

nivolumab

(n=316)

ipilimumab

(n=315)

Objective response

185 (59%)

141 (45%)

60 (19%)

(95% CI)

(53.3, 64.4)

(39.1, 50.3)

(14.9, 23.8)

Odds ratio (vs. ipilimumab)

6.50

3.54

(99.5% CI)

(3.81, 11.08.)

(2.10, 5.95)

Complete response (CR)

54 (17%)

47 (15%)

14 (4%)

Partial response (PR)

131 (42%)

94 (30%)

46 (15%)

Stable disease (SD)

36 (12%)

31 (10%)

67 (21%)

Duration of response

Median (range), months

Not reached

(0+ - 33.3+)

31.1 (0+ - 32.3+)

18.2 (0+ - 31.5+)

Proportion ≥12 months in duration

64%

70%

53%

Proportion ≥24 months in duration

50%

49%

32%

ORR (95% CI) by tumour PD-L1 expression

<5%

56% (49.2, 63.0)

n=210

42% (35.5, 49.3)

n=208

18% (12.8, 23.8)

n=202

≥5%

74% (61.4, 83.5)

n=68

59% (47.2, 69.6)

n=80

21% (12.7, 32.3)

n=75

<1%

55% (45.2, 63.5)

n=123

35% (26.5, 44.4)

n=117

19% (11.9, 27.0)

n=113

≥1%

65% (57.1, 72.6)

n=155

55% (47.2, 62.6)

n=171

19% (13.2, 25.7)

n=164

+” denotes a censored observation.

Both nivolumab-containing arms demonstrated a significant PFS and OS benefit and greater ORR compared with ipilimumab alone. The observed PFS results at 18 months of follow-up and ORR and OS results at 28 months of follow-up were consistently demonstrated across subgroups of patients including baseline ECOG performance status, BRAF status, M stage, age, history of brain metastases, and baseline LDH level. This observation was maintained with the OS results with a minimum follow-up of 36 months.

Among 128 patients who discontinued ipilimumab in combination with nivolumab due to adverse reaction after 18 months of follow-up, median PFS was 16.7 months (95% CI: 10.2, NA). Among 131 patients who discontinued the combination due to adverse reaction after 28 months of follow-up, the ORR was 71% (93/131) with 20% (26/131) achieving a complete response and median OS was not reached.

Both nivolumab-containing arms demonstrated greater objective response rates than ipilimumab regardless of PD-L1 expression levels. ORRs were higher for the combination of nivolumab and ipilimumab relative to nivolumab monotherapy across tumour PD-L1 expression levels (Table 9) after 28 months of follow-up, with a best overall response of complete response correlating to an improved survival rate.

After 28 months of follow-up, median durations of response for patients with tumour PD-L1 expression level ≥5% were not reached (range: 0+-31.6+) in the combination arm, not reached (range: 2.8-30.6+) in the nivolumab monotherapy arm and not reached (range: 1.4-30.6+) in the ipilimumab arm. At tumour PD-L1 expression <5%, median durations of response were not reached (range: 0+-33.3+) in the combination arm, not reached (range: 0+-32.3+) in the nivolumab monotherapy arm and 18.2 months (range: 0.0+-31.5+) in the ipilimumab monotherapy arm.

No clear cut off for PD-L1 expression can reliably be established when considering the relevant endpoints of tumour response and PFS and OS. Results from exploratory multivariate analyses identified patient and tumour characteristics (ECOG performance status, M stage, baseline LDH, BRAF mutation status, PD-L1 status, and gender) which might contribute to the survival outcome.

Efficacy by BRAF status: After18 months of follow-up, BRAF[V600] mutation-positive and BRAF wild-type patients randomised to ipilimumab in combination with nivolumab had a median PFS of 15.5 months (95% CI: 8.0, NA) and 11.3 months (95% CI: 8.3, 22.2), while those in the nivolumab monotherapy arm had a median PFS of 5.6 months (95% CI: 2.8, 9.3) and 7.1 months (95% CI: 4.9, 14.3), respectively. After 28 months of follow-up, BRAF[V600] mutation-positive and BRAF wild-type patients randomised to ipilimumab in combination with nivolumab had an ORR of 67.6% (95% CI: 57.7, 76.6; n = 102) and 54.7% (95% CI: 47.8, 61.5; n = 212), while those in the nivolumab monotherapy arm had an ORR of 36.7% (95% CI: 27.2, 47.1; n = 98) and 48.2% (95% CI: 41.4, 55.0; n = 218), respectively. After 28 months of follow-up, median OS was not reached in either of the nivolumab containing arms regardless of BRAF status. The OS HRs for ipilimumab in combination with nivolumab vs. nivolumab monotherapy were 0.71 (95% CI: 0.45, 1.13) for BRAF[V600] mutation-positive patients and 0.97 (95% CI: 0.74, 1.28) for BRAF wild-type patients.

Randomised phase 2 study of ipilimumab in combination with nivolumab and ipilimumab (CA209069)

Study CA209069 was a randomised, Phase 2, double-blind study comparing the combination of nivolumab and ipilimumab with ipilimumab alone in 142 patients with advanced (unresectable or metastatic) melanoma with similar inclusion criteria to study CA209067 and the primary analysis in patients with BRAF wild-type melanoma (77% of patients). Investigator assessed ORR was 61% (95% CI: 48.9, 72.4) in the combination arm (n = 72) versus 11% (95% CI: 3.0, 25.4) for the ipilimumab arm (n = 37). The estimated 2 and 3 year OS rates were 68% (95% CI: 56, 78) and 61% (95% CI: 49, 71), respectively, for the combination (n = 73) and 53% (95% CI: 36, 68) and 44% (95% CI: 28, 60), respectively, for ipilimumab (n = 37).

Paediatric population

Study CA184070 was a multi-center, Phase 1, open-label, dose-escalation study of ipilimumab in paediatric patients ≥1 year to ≤ 21 years of age with measurable/evaluable, untreatable, relapsed or refractory solid malignant tumors without a curative option with standard therapy. The study enrolled 13 patients < 12 of age and 20 patients ≥ 12 years of age. Ipilimumab was administered every 3 weeks for 4 doses and then every 12 weeks thereafter in the absence of dose limiting toxicity (DLT) and disease progression. The primary endpoints were safety and pharmacokinetics (PK). Of patients 12 years of age and older with advanced melanoma, ipilimumab 5 mg/kg was administered to three patients and ipilimumab 10 mg/kg was administered to two patients. Stable disease was achieved in two patients at the ipilimumab 5mg/kg dose, one with a duration of > 22 months.

Study CA184178 was a non-randomized, multicenter, open-label Phase 2 study, in adolescent patients 12 to < 18 years of age with previously treated or untreated, unresectable Stage III or Stage IV malignant melanoma. Ipilimumab was administered every 3 weeks for 4 doses. The primary efficacy endpoint was 1-year survival rate. Secondary efficacy endpoints of best overall response rate (BORR), stable disease (SD), disease control rate (DCR), and progression free survival (PFS) were based on mWHO criteria and determined by the investigator's assessment. Overall survival (OS) was also evaluated. Tumor assessment was performed at Week 12. All patients were followed for at least 1 year. Ipilimumab 3 mg/kg was administered to four patients and ipilimumab 10 mg/kg was administered to eight patients. Most patients were male (58%) and white (92%). Median age was 15 years. Stable disease was achieved for 260 days in one patient on ipilimumab 3 mg/kg and approximately 14 months in one patient on ipilimumab 10 mg/kg. Two patients treated with ipilimumab 10 mg/kg experienced a partial response, one of which was a durable response for more than 1 year. Additional efficacy results are presented in Table 11.

Table 11: Efficacy Results in CA184178

Ipilimumab 3 mg/kg

N= 4

Ipilimumab 10 mg/kg

N= 8

1-year OS (%) (95% CI)

75% (12.8, 96.1)

62.5% (22.9, 86.1)

BORR (%) (95% CI)

0% (0, 60.2)

25% (3.2, 65.1)

SD (n/N)a

1/4

1/8

DCR (%) (95% CI)

25% (0.6, 80.6)

37.5% (8.5, 75.5)

Median PFS (months) (95% CI)

2.6 (2.3, 8.5)

2.9 (0.7,NEa)

Median OS (months) (95% CI)

18.2 (8.9, 18.2)

Not reached (5.2, NE)

a NE= not estimable

5.2 Pharmacokinetic properties

The pharmacokinetics of ipilimumab was studied in 785 patients with advanced melanoma who received induction doses ranging from 0.3 to 10 mg/kg administered once every 3 weeks for 4 doses. Cmax, Cmin and AUC of ipilimumab were found to be dose proportional within the dose range examined. Upon repeated dosing of ipilimumab administered every 3 weeks, clearance was found to be time-invariant, and minimal systemic accumulation was observed as evident by an accumulation index 1.5 fold or less. Ipilimumab steady-state was reached by the third dose. Based on population pharmacokinetic analysis, the following mean (percent coefficient of variation) parameters of ipilimumab were obtained: terminal half-life of 15.4 days (34.4%); systemic clearance of 16.8 ml/h (38.1%); and volume of distribution at steady-state of 7.47 l (10.1%). The mean (percent coefficient of variation) ipilimumab Cmin achieved at steady-state with a 3 mg/kg induction regimen was 19.4 µg/ml (74.6%).

Ipilimumab clearance increased with increasing body weight and with increasing LDH at baseline; however, no dose adjustment is required for elevated LDH or body weight after administration on a mg/kg basis. Clearance was not affected by age (range 23-88 years), gender, concomitant use of budesonide or dacarbazine, performance status, HLA-A2*0201 status, mild hepatic impairment, renal impairment, immunogenicity, and previous anticancer therapy. The effect of race was not examined as there was insufficient data in non-Caucasian ethnic groups. No controlled studies have been conducted to evaluate the pharmacokinetics of ipilimumab in the paediatric population or in patients with hepatic or renal impairment.

Based on an exposure-response analysis in 497 patients with advanced melanoma, OS was independent of prior systemic anti-cancer therapy and increased with higher ipilimumab Cminss plasma concentrations.

Yervoy in combination with nivolumab: When ipilimumab 3 mg/kg was administered in combination with nivolumab 1 mg/kg, there was no effect of nivolumab on the CL of ipilimumab.

When administered in combination, there was no effect of anti-ipilimumab antibodies on the CL of ipilimumab.

Renal impairment

In the population pharmacokinetic analysis of data from clinical studies in patients with metastatic melanoma, pre-existing mild and moderate renal impairment did not influence the clearance of ipilimumab. Clinical and pharmacokinetic data with pre-existing severe renal impairment are limited; the potential need for dose adjustment cannot be determined.

Hepatic impairment

In the population pharmacokinetic analysis of data from clinical studies in patients with metastatic melanoma, pre-existing mild hepatic impairment did not influence the clearance of ipilimumab. Clinical and pharmacokinetic data with pre-existing moderate hepatic impairment are limited; the potential need for dose adjustment cannot be determined. No patients with pre-existing severe hepatic impairment were identified in clinical studies.

Paediatric Population

Based on a population PK analysis using available pooled data from 565 patients from 4 phase 2 adult studies (N=521) and 2 paediatric studies (N=44), clearance of ipilimumab increased with increasing baseline body weight. Age (2-87 years) had no clinically important effect on the clearance of ipilimumab. The estimated geometric mean clearance (CL) is 8.72 mL/h in adolescent patients aged ≥12 to <18 years. Exposures in adolescents are comparable with those in adults receiving the same mg/kg dose. Based on the simulation in adults and paediatrics, comparable exposure is achieved in adults and paediatrics at the recommended dose of 3 mg/kg every 3 weeks.

5.3 Preclinical safety data

In intravenous repeat-dose toxicology studies in monkeys, ipilimumab was generally well tolerated. Immune-mediated adverse reactions were observed infrequently (~3%) and included colitis (which resulted in a single fatality), dermatitis, and infusion reaction (possibly due to acute cytokine release resulting from a rapid injection rate). A decrease in the weight of the thyroid and testes was seen in one study without accompanying histopathologic findings; the clinical relevance of this finding is unknown.

The effects of ipilimumab on prenatal and postnatal development were investigated in a study in cynomolgus monkeys. Pregnant monkeys received ipilimumab every 3 weeks from the onset of organogenesis in the first trimester through delivery, at exposure (AUC) levels either similar to or higher than those associated with the clinical dose of 3 mg/kg of ipilimumab. No treatment-related adverse effects on reproduction were detected during the first two trimesters of pregnancy. Beginning in the third trimester, both ipilimumab groups experienced higher incidences of abortion, stillbirth, premature delivery (with corresponding lower birth weight), and infant mortality relative to control animals; these findings were dose-dependent. Additionally, developmental external or visceral abnormalities were identified in the urogenital system of 2 infants exposed in utero to ipilimumab. One female infant had unilateral renal agenesis of the left kidney and ureter, and one male infant had an imperforate urethra with associated urinary obstruction and subcutaneous scrotal edema. The relationship of these malformations to treatment is unclear.

Studies to evaluate the mutagenic and carcinogenic potential of ipilimumab have not been performed. Fertility studies have not been performed.

6. Pharmaceutical particulars
6.1 List of excipients

Tris hydrochloride (2-amino-2-hydroxymethyl-1,3-propanediol hydrochloride)

Sodium chloride

Mannitol (E421)

Pentetic acid (diethylenetriaminepentaacetic acid)

Polysorbate 80

Sodium hydroxide (for pH-adjustment)

Hydrochloric acid (for pH-adjustment)

Water for injections

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf life

Unopened vial

3 years

After opening

From a microbiological point of view, once opened, the medicinal product should be infused or diluted and infused immediately. The chemical and physical in-use stability of the undiluted or diluted concentrate (between 1 and 4 mg/ml) has been demonstrated for 24 hrs at 25°C and 2°C to 8°C. If not used immediately, the infusion solution (undiluted or diluted) may be stored for up to 24 hours in a refrigerator (2°C to 8°C) or at room temperature (20°C to 25°C).

6.4 Special precautions for storage

Store in a refrigerator (2°C-8°C).

Do not freeze.

Store in the original package in order to protect from light.

For storage conditions after first opening or dilution of the medicinal product, see section 6.3.

6.5 Nature and contents of container

10 ml of concentrate in a vial (Type I glass) with a stopper (coated butyl rubber) and a flip-off seal (aluminium). Pack size of 1.

40 ml of concentrate in a vial (Type I glass) with a stopper (coated butyl rubber) and a flip-off seal (aluminium). Pack size of 1.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Preparation should be performed by trained personnel in accordance with good practices rules, especially with respect to asepsis.

Calculating the dose:

The prescribed dose for the patient is given in mg/kg. Based on this prescribed dose, calculate the total dose to be given. More than one vial of YERVOY concentrate may be needed to give the total dose for the patient.

▪ Each 10 ml vial of YERVOY concentrate provides 50 mg of ipilimumab; each 40 ml vial provides 200 mg of ipilimumab.

▪ The total ipilimumab dose in mg = the patient's weight in kg × the prescribed dose in mg/kg.

▪ The volume of YERVOY concentrate to prepare the dose (ml) = the total dose in mg, divided by 5 (the YERVOY concentrate strength is 5 mg/ml).

Preparing the infusion:

Take care to ensure aseptic handling when you prepare the infusion.

YERVOY can be used for intravenous administration either:

▪ without dilution, after transfer to an infusion container using an appropriate sterile syringe;

or

▪ after diluting to up to 5 times the original volume of concentrate (up to 4 parts of diluent to 1 part of concentrate). The final concentration should range from 1 to 4 mg/ml. To dilute the YERVOY concentrate, you can use either:

▪ sodium chloride 9 mg/ml (0.9%) solution for injection; or

▪ 50 mg/ml (5%) glucose solution for injection

STEP 1

▪ Allow the appropriate number of vials of YERVOY to stand at room temperature for approximately 5 minutes.

▪ Inspect the YERVOY concentrate for particulate matter or discoloration. YERVOY concentrate is a clear to slightly opalescent, colourless to pale yellow liquid that may contain light (few) particulates. Do not use if unusual amount of particles and signs of discoloration are present.

▪ Withdraw the required volume of YERVOY concentrate using an appropriate sterile syringe.

STEP 2

▪ Transfer the concentrate into a sterile, evacuated glass bottle or intravenous bag (PVC or non-PVC).

▪ If applicable, dilute with the required volume of sodium chloride 9 mg/ml (0.9%) solution for injection or 50 mg/ml (5%) glucose solution for injection. For ease of preparation, the concentrate can also be transferred directly into a pre-filled bag containing the appropriate volume of sodium chloride 9 mg/mL (0.9%) solution for injection or 50 mg/mL (5%) glucose solution for injection. Gently mix the infusion by manual rotation.

Administration:

The YERVOY infusion must not be administered as an intravenous push or bolus injection.

Administer the YERVOY infusion intravenously over a period of 90 minutes.

The YERVOY infusion should not be infused at the same time in the same intravenous line with other agents. Use a separate infusion line for the infusion.

Use an infusion set and an in-line, sterile, non-pyrogenic, low protein binding filter (pore size of 0.2 μm to 1.2 μm).

The YERVOY infusion is compatible with:

▪ PVC infusion sets

▪ Polyethersulfone (0.2 μm to 1.2 μm) and nylon (0.2 μm) in-line filters

Flush the line with sodium chloride 9 mg/ml (0.9%) solution for injection or 50 mg/ml (5%) glucose solution for injection at the end of the infusion.

Any unused medicinal product or waste material should be discarded in accordance with local requirements.

7. Marketing authorisation holder

Bristol-Myers Squibb Pharma EEIG

Uxbridge Business Park

Sanderson Road

Uxbridge UB8 1DH

United Kingdom

8. Marketing authorisation number(s)

EU/1/11/698/001-002

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 13 July 2011

Date of latest renewal: 21 April 2016

10. Date of revision of the text

14 June 2018

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu