YERVOY 5 mg/ml concentrate for solution for infusion
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.
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.
YERVOY is indicated for the treatment of advanced (unresectable or metastatic) melanoma in adults.
Treatment must be initiated and supervised by specialist physicians experienced in the treatment of cancer.
Posology
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.
Liver function tests (LFTs) and thyroid function tests should be eva luated 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 1A, 1B, and section 4.4).
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 reduction is not recommended.
Guidelines for permanent discontinuation or withholding of doses are described in Tables 1A and 1B. Detailed guidelines for the management of immune-related adverse reactions are described in section 4.4.
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Table 1A When to permanently discontinue YERVOY
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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).
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Severe or life-threatening adverse reactions
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NCI-CTCAE v3 Gradea
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Gastrointestinal:
Severe symptoms (abdominal pain, severe diarrhoea or significant change in the number of stools, blood in stool, gastrointestinal haemorrhage, gastrointestinal perforation)
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▪ Grade 3 or 4 diarrhoea or colitis
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Hepatic:
Severe elevations in aspartate aminotransferase (AST), alanine aminotransferase (ALT), or total bilirubin or symptoms of hepatotoxicity
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▪ AST or ALT > 8 x ULN or
▪ Total bilirubin > 5 x ULN
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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
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▪ Grade 4 rash or Grade 3 pruritus
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Neurologic:
New onset or worsening severe motor or sensory neuropathy
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▪ Grade 3 or 4 motor or sensory neuropathy
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Other organ systemsb:
(e.g. nephritis, pneumonitis, pancreatitis, non-infectious myocarditis)
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▪ ≥ Grade 3 immune-related reactionsc
▪ ≥ Grade 2 for immune-related eye disorders NOT responding to topical immunosuppressive therapy
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a Toxicity grades are in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events. Version 3.0 (NCI-CTCAE v3).
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.
ULN = upper limit of normal
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Table 1B When to withhold dose of YERVOY
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Withhold YERVOY dosea in patients with the following immune-related adverse reactions. See section 4.4 for detailed management guidelines.
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Mild to moderate adverse reactions
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Action
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Gastrointestinal:
Moderate diarrhoea or colitis that either is not controlled with medical management or that persists (5-7 days) or recurs
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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.
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Hepatic:
Moderate elevations in transaminase (AST or ALT > 5 to ≤ 8 x ULN) or total bilirubin (> 3 to ≤ 5 x ULN) levels
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Skin:
Moderate to severe (Grade 3)b skin rash or widespread/intense pruritus regardless of etiology
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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
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Neurological:
Moderate (Grade 2)b unexplained motor neuropathy, muscle weakness, or sensory neuropathy (lasting more than 4 days)
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Other moderate adverse reactionsc
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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 3.0 (NCI-CTCAE v3).
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.
ULN = upper limit of normal
Special populations
Paediatric population
The safety and efficacy of YERVOY in children and adolescents below 18 years of age have not been established. No data are available. YERVOY should not be used in children and adolescents below 18 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.
For instructions on the handling of the medicinal product before administration, see section 6.6.
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
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.
Immune-related gastrointestinal reactions
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 eva luated 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 v3 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 eva luated for evidence of gastrointestinal perforation or peritonitis.
The experience from clinical trials on the management of corticosteroid-refractory diarrhoea or colitis is limited. However,
