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Yervoy is a brand name for Ipilimumab. The medicine, its uses, side effects and dosage are the same regardless of brand.
Used for: Melanoma YERVOY as monotherapy or in combination with nivolumab 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). Relative to nivolumab monotherapy, an increase in progression-free survival (PFS) and overall survival…
Verbatim from this product's EMA label. Tap a section to expand.
Treatment must be initiated and supervised by specialist physicians experienced in the treatment of cancer. 1). MSI/MMR testing If specified in the indication, patient selection for treatment with YERVOY based on MSI-H/dMMR tumour status should be assessed by a CE-marked IVD with the corresponding intended purpose.
1). Posology YERVOY as monotherapy Melanoma Adults and adolescents 12 years of age and older The recommended induction regimen of YERVOY is 3 mg/kg administered intravenously over a 30-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 Melanoma In adults and adolescents 12 years of age and older and weighing at least 50 kg, the recommended dose is 3 mg/kg ipilimumab in combination with 1 mg/kg nivolumab administered intravenously every 4 3 weeks for the first 4 doses.
2), 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.
In adolescents 12 years of age and older and weighing less than 50 kg, 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. 2), 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 3 mg/kg every 2 weeks; or ▪ 6 weeks after the last dose of the combination of nivolumab and ipilimumab if using 6 mg/kg 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 Adults and adolescents 12 years of age and older: 1 mg/kg over 30 minutes Adults and adolescents (12 years of age and older weighing at least 50 kg): 240 mg every 2 weeks over 30 minutes or 480 mg every 4 weeks over 60 minutes Adolescents (12 years of age and older and weighing less than 50 kg): 3 mg/kg every 2 weeks over 30 minutes or 6 mg/kg every 4 weeks over 60 minutes Ipilimumab Adults and adolescents 12 years of age and older: 3 mg/kg over 30 minutes - Renal cell carcinoma The recommended dose is 1 mg/kg ipilimumab in combination with 3 mg/kg nivolumab administered intravenously every 3 weeks for the first 4 doses.
2) a. Summary of safety profile Ipilimumab has been administered to approximately 10 000 patients in a clinical programme 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.
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. 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) and from post-marketing surveillance are presented in Table 6.
These reactions are presented by system organ class and by frequency. Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1 000 to < 1/100); rare (≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000), not known (cannot be estimated from available post-marketing data).
Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness. 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 programme.
23 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.
Traceability In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. Assessment of PD-L1 status When assessing the PD-L1 status of the tumour, it is important that a well-validated and robust methodology is used.
Assessment of MSI/MMR status When assessing the MSI-H and dMMR status of the tumour, it is important that a well-validated and robust methodology is used. 11 Ipilimumab in combination with nivolumab When ipilimumab is administered in combination, refer to the Summary of Product Characteristics of the other combination therapy components prior to initiation of treatment.
For additional information on warnings and precautions associated with nivolumab treatment, please refer to the nivolumab SmPC. 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.
2). 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.
1.
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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 2. For the monotherapy phase, the first dose of nivolumab should be administered; ▪ 3 weeks after the last dose of the combination of ipilimumab and nivolumab if using 240 mg every 2 weeks; or ▪ 6 weeks after the last dose of the combination of ipilimumab and nivolumab if using 480 mg every 4 weeks.
Table 2:
Recommended doses and infusion times for intravenous administration of ipilimumab in combination with nivolumab for RCC Combination phase, every 3 weeks for 4 dosing cycles Monotherapy phase Nivolumab 3 mg/kg over 30 minutes 240 mg every 2 weeks over 30 minutes or 480 mg every 4 weeks over 60 minutes Ipilimumab 1 mg/kg over 30 minutes - 5 dMMR or MSI-H colorectal cancer The recommended dose for first-line treatment of dMMR or MSI-H CRC is 1 mg/kg ipilimumab in combination with 240 mg of nivolumab administered intravenously every 3 weeks for a maximum of 4 doses, followed by nivolumab monotherapy is administered intravenously at either 240 mg every 2 weeks or at 480 mg every 4 weeks, as presented in Table 3.
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. Treatment with nivolumab is recommended until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.
The recommended dose in patients who received prior fluoropyrimidine-based combination chemotherapy for dMMR or MSI-H CRC is 1 mg/kg ipilimumab in combination with 3 mg/kg nivolumab administered intravenously every 3 weeks for the first 4 doses, followed by nivolumab monotherapy administered intravenously 240 mg every 2 weeks, as presented in Table 3.
For the monotherapy phase, the first dose of nivolumab should be administered 3 weeks after the last dose of the combination of ipilimumab and nivolumab.
Table 3:
Recommended doses and infusion times for intravenous administration of ipilimumab in combination with nivolumab for dMMR or MSI-H CRC Combination phase, every 3 weeks for 4 dosing cycles Monotherapy phase Nivolumab First-line 240 mg over 30 minutes 240 mg every 2 weeks over 30 minutes or 480 mg every 4 weeks over 30 minutes After prior fluoropyrimidine-based combination chemotherapy 3 mg/kg over 30 minutes 240 mg every 2 weeks over 30 minutes Ipilimumab 1 mg/kg over 30 minutes - Malignant pleural […]
The safety data for patients with unresectable or metastatic melanoma, treated with ipilimumab (3 mg/kg, with a minimum of 3 year follow-up) and enrolled in multi-national, prospective, observational study CA184143 (N = 1151) were similar to what has been reported in ipilimumab clinical trials for advanced melanoma.
Table 6:
Adverse reactions in patients with advanced melanoma treated with ipilimumab 3 mg/kga Infections and infestations Common sepsisb, urinary tract infection, respiratory tract infection Uncommon septic shockb, pneumonia Neoplasms benign, malignant and unspecified (including cysts and polyps) Common tumour pain Uncommon paraneoplastic syndrome Blood and lymphatic system disorders Common anaemia, lymphopaenia, thrombocytopaenia, neutropaenia Uncommon haemolytic anaemiab, eosinophilia Not known haemophagocytic lymphohistiocytosise Immune system disorders Uncommon hypersensitivity Very rare anaphylactic reaction Not known solid organ transplant rejectione 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, hypokalaemia, weight decreased, hyponatremia Uncommon alkalosis, hypophosphatemia, tumour lysis syndrome, hypocalcaemiad Rare type 1 diabetes mellitus (including diabetic ketoacidosis)h Psychiatric disorders Common confusional state, depression Uncommon mental status changes, decreased libido Nervous system disorders Common peripheral sensory neuropathy, dizziness, headache, lethargy, cranial neuropathy, brain oedema, peripheral neuropathy Uncommon Guillain-Barré syndromeb,c, meningitis (aseptic), autoimmune central neuropathy (encephalitis)d, syncope, ataxia, tremor, myoclonus, dysarthria Rare myasthenia gravisd Not known myelitis 24 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, serous retinal detachment Cardiac disorders Common 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 dyspnoea, cough, allergic rhinitis Uncommon respiratory failure, acute respiratory distress syndromeb, lung infiltration, pulmonary oedema, pneumonitis Gastrointestinal disorders Very common diarrhoeac, vomiting, nausea, constipation, abdominal pain Common gastrointestinal haemorrhage, colitisb,c, gastroesophageal reflux disease, mucosal inflammationd, gastroenteritis, stomatitis Uncommon gastrointestinal perforationb,c, large intestine perforationb,c, intestinal perforationb,c, peritonitisb, diverticulitis, pancreatitis, enterocolitis, gastric ulcer, large intestinal ulcer, oesophagitis, ileusd, proctitisd Rare pancreatic exocrine insufficiency; coeliac disease 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 Very common musculoskeletal […]
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, or 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.
12 Immune-related gastrointestinal reactions Ipilimumab as monotherapy Ipilimumab is associated with serious immune-related gastrointestinal reactions. 8). 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.
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.
In clinical trials, immune-related colitis was associated with evidence of mucosal inflammation, with or without ulcerations, and lymphocytic and neutrophilic infiltration. Post-marketing cases of cytomegalovirus (CMV) infection/reactivation have been reported in patients with corticosteroid-refractory immune-related colitis.
Stool infections work-up should be performed upon presentation of diarrhoea or colitis to exclude infectious or other alternate etiologies. Management recommendations for diarrhoea or colitis are based on severity of symptoms (per NCI-CTCAE v4 severity grading classification).
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