1. Name Of The Medicinal Product
YERVOY
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 (IgG1ĸ) produced in Chinese hamster ovary cells by recombinant DNA technology.
Excipients
Each ml of concentrate contains 0.1 mmol sodium, which is 2.30 mg sodium.
For a 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 is indicated for the treatment of advanced (unresectable or metastatic) melanoma in adults who have received prior therapy.
4.2 Posology And Method Of Administration
Treatment must be initiated and supervised by specialist physicians experienced in the treatment of cancer.
Posology
Adults
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 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 1A, 1B, and section 4.4).
Permanent discontinuation of treatment or omission of doses
Management of immune-related adverse reactions may require omission of a dose or permanent discontinuation of YERVOY therapy and institution of systemic high-dose corticosteroid or, in some cases, the addition of other immunosuppressive therapy (see section 4.4).
Dose reduction is not recommended. Doses that are omitted due to an adverse reaction must not be replaced.
Guidelines for permanent discontinuation or omission of scheduled 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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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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a No dose reduction of YERVOY is recommended. Doses that are omitted due to an adverse reaction must not be replaced.
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 omit a scheduled dose should be based on severity.
ULN = upper limit of normal
Paediatric population
The safety and efficacy of YERVOY in children below 18 years of age have not been established. No data are available. YERVOY should not be used in children below 18 years of age.
Special populations
Elderly patients
No overall differences in safety or efficacy were reported between elderly (
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. YERVOY must be administered with caution in patients with transaminase levels
Method of administration
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.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients.
4.4 Special Warnings And Precautions For Use
YERVOY 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 YERVOY 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 YERVOY-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. YERVOY-specific management guidelines for immune-related adverse reactions are described below.
Immune-related gastrointestinal reactions
YERVOY 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 YERVOY 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 YERVOY 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 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 YERVOY. 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 YERVOY should be omitted 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, YERVOY may be resumed at the next scheduled dose. Doses omitted due to an adverse reaction must not be replaced (see section 4.2).
YERVOY must be permanently discontinued in patients with severe (Grade 3 or 4) diarrhoea or colitis (see section 4.2), and 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 hepatotoxicity
YERVOY is associated with serious immune-related hepatotoxicity. Fatal hepatic failure has been reported in clinical trials (see section 4.8).
In patients who received YERVOY 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 YERVOY 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, disease progression, or medicinal products 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 elevated AST or ALT in the range of > 5-
For patients with AST or ALT elevations > 8 x ULN that are suspected to be related to YERVOY, 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 LFT elevations are normalized, 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).
Immune-related skin adverse reactions
YERVOY is associated with serious skin adverse reactions that may be immune-related. Fatal toxic epidermal necrolysis has been reported in clinical trials (see section 4.8).
YERVOY-induced rash and pruritus were predominantly mild or moderate (Grade 1 or 2) and responsive to symptomatic therapy. In patients who received YERVOY 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).
YERVOY-induced rash and pruritus should be managed based on severity. Patients with a mild to moderate (Grade 1 or 2) skin adverse reaction may remain on YERVOY therapy with symptomatic treatment (e.g. antihistamines). For mild to moderate rash or 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) skin adverse reaction, the scheduled dose of YERVOY should be omitted. If initial symptoms improve to mild (Grade 1) or resolve, YERVOY therapy may be resumed at the next scheduled dose. Doses omitted due to an adverse reaction must not be replaced (see section 4.2).
YERVOY 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.
Immune-related neurological reactions
YERVOY is associated with serious immune-related neurological adverse reactions.Fatal Guillain-Barré syndrome has been reported in clinical trials (see section 4.8). Myasthenia gravis-like symptoms have also been reported. 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 medicinal products should be excluded. For patients with moderate (Grade 2) neuropathy (motor with or without sensory) likely related to YERVOY, the scheduled dose should be omitted. If neurologic symptoms resolve to baseline, the patient may resume YERVOY at the next scheduled dose. Doses omitted due to an adverse reaction must not be replaced (see section 4.2).
YERVOY must be permanently discontinued in patients with severe (Grade 3 or 4) sensory neuropathy suspected to be related to YERVOY (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. YERVOY must be permanently discontinued in patients with severe (Grade 3 or 4) motor neuropathy regardless of causality (see section 4.2).
Immune-related endocrinopathy
YERVOY can cause inflammation of the endocrine system organs, specifically hypophysitis, hypopituitarism, adrenal insufficiency, and hypothyroidism, 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 YERVOY-associated endocrinopathy is limited.
For patients who received YERVOY 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 immunosuppressant 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 YERVOY should be omitted (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 YERVOY 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.
Other immune-related adverse reactions
The following additional adverse reactions suspected to be immune-related have been reported in patients treated with YERVOY 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 YERVOY 3 mg/kg + gp100 peptide vaccine in MDX010-20 (see section 4.8).
If severe (Grade 3 or 4), these reactions may require immediate high-dose corticosteroid therapy and discontinuation of YERVOY (see section 4.2). For YERVOY-related uveitis, iritis, or episcleritis, topical corticosteroid eye drops should be considered as medically indicated.
Special populations
Patients with ocular melanoma, primary CNS melanoma and active brain metastases were not included in the pivotal clinical trial (see section 5.1).
Infusion reaction
There were isolated reports of severe infusion reactions in clinical trials. In case of a severe infusion reaction, YERVOY infusion must be discontinued and appropriate medical therapy administered. Patients with mild or moderate infusion reaction may receive YERVOY with close monitoring. Premedication with antipyretic and antihistamine may be considered.
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. YERVOY should be avoided in patients with severe active autoimmune disease where further immune activation is potentially imminently life threatening and used with caution in other patients with a history of autoimmune disease, 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.
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, and is not expected to have an effect on CYPs or other drug metabolizing enzymes in terms of inhibition or induction. Therefore, ipilimumab is not expected to have pharmacokinetic-based interactions.
Other forms of interaction
Corticosteroids
The use of systemic corticosteroids at baseline, before starting YERVOY, should be avoided because of their potential interference with the pharmacodynamic activity and efficacy of YERVOY. However, systemic corticosteroids or other immunosuppressants can be used after starting YERVOY to treat immune-related adverse reactions. The use of systemic corticosteroids after starting YERVOY treatment does not appear to impair the efficacy of YERVOY.
Anticoagulants
The use of anticoagulants is known to increase the risk of gastrointestinal haemorrhage. Since gastrointestinal haemorrhage is an adverse reaction with YERVOY (see section 4.8), patients who require concomitant anticoagulant therapy should be monitored closely.
4.6 Pregnancy And Lactation
Pregnancy
There are no data on the use of ipilimumab in pregnant women. Final results of animal reproduction studies have not yet been reported. 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
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 breastfed 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 YERVOY 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 YERVOY does not adversely affect them.
4.8 Undesirable Effects
Summary of safety profile
YERVOY has been administered to > 3,000 patients in a clinical program evaluating its use with various doses and tumour types. Unless otherwise specified, the data below reflect exposure to YERVOY 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).
YERVOY 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 YERVOY (see section 4.4 for management of immune-related adverse reactions).
In patients who received 3 mg/kg YERVOY monotherapy in MDX010-20, the most frequently reported adverse reactions (. The majority were mild to moderate (Grade 1 or 2). YERVOY therapy was discontinued for adverse reactions in 10% of patients.
Tabulated list of adverse reactions
Adverse reactions reported in patients with advanced melanoma who were treated with YERVOY 3 mg/kg in clinical trials (n= 767) are presented in Table 2.
These reactions are presented by system organ class and by frequency. Frequencies are defined as: very common (
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a Frequencies are based on pooled data from 9 clinical trials investigating the YERVOY 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 Reported in recent studies outside the completed clinical trials in melanoma.
Additional adverse reactions not listed in Table 2 have been reported in patients who received other doses (either < or > 3 mg/kg) of YERVOY in clinical trials of melanoma. These additional reactions all occurred at a frequency of < 1%: meningism, myocarditis, cardiomyopathy, autoimmune hepatitis, erythema multiforme, autoimmune nephritis, myasthenia gravis-like symptoms, autoimmune thyroiditis, hyperpituitarism, secondary adrenocortical insufficiency, hypoparathyroidism, thyroiditis, episcleritis, blepharitis, eye oedema, scleritis, temporal arteritis, Raynaud's phenomenon, proctitis, palmar-plantar erythrodysaesthesia syndrome, psoriasis, haematuria, proteinuria, decreased blood thyroid stimulating hormone, decreased blood gonadotrophin, decreased thyroxine, leukopenia, and polycythaemia.
Description of selected adverse reactions
Except where noted, data for the following selected adverse reactions are based on patients who received either YERVOY 3 mg/kg monotherapy (n= 131) or YERVOY 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). The management guidelines for these adverse reactions are described in section 4.4.
Immune-related gastrointestinal reactions
YERVOY is associated with serious immune-related gastrointestinal reactions. Fatalities due to gastrointestinal perforation have been reported in < 1% of patients
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