Ipilimumab

Ipilimumab is a fully human anti-CTLA-4 monoclonal antibody (IgG1 kappa), produced in Chinese hamster ovary cells by recombinant DNA technology. CTLA-4 (cytotoxic T-lymphocyte antigen 4) is a key brake on T-cell activity; blocking it releases that brake so that T cells can attack tumour cells.

Mechanism of Action

• Competition with CD28: CTLA-4 competes with the stimulatory molecule CD28 for binding to B7 on antigen-presenting cells. Both are found on T cells.
• Checkpoint blockade: ipilimumab blocks the inhibitory signals induced by CTLA-4, which increases the number of reactive T-effector cells that mobilise to mount a direct T-cell attack on tumour cells.
• Regulatory T cells: CTLA-4 blockade can also reduce the function of regulatory T cells. Ipilimumab may selectively deplete regulatory T cells at the tumour site, which raises the ratio of T-effector to regulatory T cells inside the tumour and drives tumour cell death.
• Immune markers: in melanoma patients, absolute lymphocyte counts rose during the induction doses (dose-dependent in phase 2 studies), together with more activated HLA-DR-positive CD4 and CD8 T cells and more central memory and effector memory T cells.
• With nivolumab: dual blockade of CTLA-4 and PD-1 gave synergistic anti-tumour activity in mouse tumour models and improved anti-tumour responses in metastatic melanoma.

Pharmacokinetics

• Exposure: studied in 785 melanoma patients given 0.3 to 10 mg/kg every 3 weeks for 4 doses. Cmax, Cmin and AUC were proportional to the dose, clearance did not change with time, accumulation was 1.5-fold or less, and steady state was reached by the third dose. The mean Cmin at steady state with 3 mg/kg was 19.4 µg/mL.
• Distribution: volume of distribution at steady state about 7.47 L.
• Metabolism and elimination: not metabolised by cytochrome P450 enzymes; as a protein it is expected to be broken down to small peptides and amino acids. Systemic clearance about 16.8 mL/h and terminal half-life about 15.4 days.
• Special populations: clearance rose with body weight and baseline LDH, but no dose adjustment is needed for either when dosing per kg. Age (23–88 years), sex, concomitant budesonide or dacarbazine, performance status, HLA-A2*0201 status, mild hepatic impairment, renal impairment, immunogenicity and prior anticancer therapy had no effect on clearance. The effect of race was not examined. No controlled studies were done in children or in hepatic or renal impairment.
• With nivolumab: clearance changes of both antibodies in combination were not considered clinically relevant.

• Melanoma: as monotherapy or in combination with nivolumab for advanced (unresectable or metastatic) melanoma in adults and adolescents 12 years of age and older. Compared with nivolumab alone, the combination has been shown to improve progression-free and overall survival only in patients with low tumour PD-L1 expression.
• Renal cell carcinoma (RCC): in combination with nivolumab, first-line treatment of adults with intermediate/poor-risk advanced RCC.
• Non-small cell lung cancer (NSCLC): in combination with nivolumab and 2 cycles of platinum-based chemotherapy, first-line treatment of metastatic NSCLC in adults whose tumours have no sensitising EGFR mutation or ALK translocation.
• Malignant pleural mesothelioma (MPM): in combination with nivolumab, first-line treatment of adults with unresectable disease.
• Colorectal cancer (CRC): in combination with nivolumab, for adults with mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) disease, as first-line treatment of unresectable or metastatic CRC, or for metastatic CRC after prior fluoropyrimidine-based combination chemotherapy.
• Oesophageal squamous cell carcinoma (OSCC): in combination with nivolumab, first-line treatment of adults with unresectable advanced, recurrent or metastatic disease with tumour cell PD-L1 expression of 1% or more.
• Hepatocellular carcinoma (HCC): in combination with nivolumab, first-line treatment of adults with unresectable or advanced HCC.

• Hypersensitivity to ipilimumab or to any of the excipients.

Ipilimumab is most often associated with reactions caused by increased or excessive immune activity. Most of them, including severe ones, resolved after appropriate medical treatment or withdrawal of ipilimumab. Reactions of this kind can start during treatment or months after the last dose.

As monotherapy (3 mg/kg in advanced melanoma; the frequency groups below come from 767 patients): in the main phase 3 study the most frequent reactions (10% or more) were diarrhoea, rash, pruritus, fatigue, nausea, vomiting, decreased appetite and abdominal pain, mostly mild or moderate. Treatment was stopped for adverse reactions in 10% of patients.

With nivolumab, with or without chemotherapy (2,626 patients across tumour types): the most frequent reactions were fatigue (47%), rash (37%), diarrhoea (35%), pruritus (29%), nausea (27%), musculoskeletal pain (26%), pyrexia (23%), decreased appetite (22%) and cough (21%). Grade 3 to 5 reactions occurred in 66% and fatal reactions in 1.0%. In melanoma patients given nivolumab 1 mg/kg with ipilimumab 3 mg/kg, fatigue (62%), rash (57%), diarrhoea (52%), nausea (42%), pruritus (40%), pyrexia (36%) and headache (26%) were at least 10 percentage points more frequent than in the pooled data. In lung cancer with chemotherapy, anaemia (32%) and neutropenia (15%) were similarly more frequent.

Combination with nivolumab: very common (≥1/10): upper respiratory tract infection, anaemia, thrombocytopenia, leucopenia, lymphopenia, neutropenia, hypothyroidism, decreased appetite, hyperglycaemia, hypoglycaemia, headache, cough, dyspnoea, diarrhoea, vomiting, nausea, abdominal pain, constipation, rash, pruritus, musculoskeletal pain, arthralgia, fatigue, pyrexia, oedema, and laboratory increases in alkaline phosphatase, AST, ALT, bilirubin, creatinine, amylase and lipase with changes in sodium, potassium and calcium.

Combination: common (≥1/100 to <1/10): pneumonia, bronchitis, conjunctivitis, eosinophilia, infusion-related reaction (including cytokine release syndrome), hypersensitivity, hyperthyroidism, thyroiditis, adrenal insufficiency, hypophysitis, hypopituitarism, diabetes mellitus, dehydration, weight decrease, dizziness, peripheral neuropathy, blurred vision, dry eye, tachycardia, atrial fibrillation, hypertension, pneumonitis, pulmonary embolism, pleural effusion, colitis, pancreatitis, stomatitis, gastritis, dry mouth, hepatitis, alopecia, vitiligo, urticaria, dry skin, erythema, muscle spasms, muscular weakness, arthritis, renal failure (including acute kidney injury), chest pain, pain, chills.

Combination: uncommon (≥1/1,000 to <1/100): febrile neutropenia, diabetic ketoacidosis, metabolic acidosis, polyneuropathy, peroneal nerve palsy, autoimmune neuropathy, encephalitis, myasthenia gravis, myocarditis-myositis-myasthenia gravis overlap syndrome, uveitis, episcleritis, myocarditis, arrhythmia, bradycardia, duodenitis, Stevens-Johnson syndrome, erythema multiforme, psoriasis, polymyalgia rheumatica, myopathy, myositis, nephritis.

Combination: rare (≥1/10,000 to <1/1,000): aseptic meningitis, sarcoidosis, hypoparathyroidism, Guillain-Barré syndrome, neuritis, myelitis, Vogt-Koyanagi-Harada syndrome, serous retinal detachment, intestinal perforation, exocrine pancreatic insufficiency, coeliac disease, toxic epidermal necrolysis, lichen sclerosus, spondyloarthropathy, Sjögren’s syndrome, rhabdomyolysis, non-infective cystitis.

Combination: not known: haemophagocytic lymphohistiocytosis, solid organ transplant rejection, tumour lysis syndrome, pericardial disorders.

Monotherapy: very common (≥1/10): decreased appetite, diarrhoea, vomiting, nausea, constipation, abdominal pain, rash, pruritus, musculoskeletal pain, fatigue, injection-site reaction, pyrexia, oedema, pain.

Monotherapy: common (≥1/100 to <1/10): sepsis, urinary and respiratory tract infection, tumour pain, anaemia, lymphopenia, thrombocytopenia, neutropenia, hypopituitarism (including hypophysitis), hypothyroidism, dehydration, hypokalaemia, hyponatraemia, weight decrease, confusional state, depression, peripheral neuropathy, dizziness, headache, lethargy, cranial neuropathy, cerebral oedema, blurred vision, eye pain, arrhythmia, atrial fibrillation, hypotension, flushing, dyspnoea, cough, gastrointestinal haemorrhage, colitis, mucosal inflammation, stomatitis, abnormal liver function, dermatitis, erythema, vitiligo, urticaria, alopecia, arthralgia, myalgia, arthritis, renal failure, chills, asthenia, increases in ALT, AST, alkaline phosphatase, bilirubin and lipase.

Monotherapy: uncommon (≥1/1,000 to <1/100): septic shock, pneumonia, haemolytic anaemia, hypersensitivity, adrenal insufficiency, hyperthyroidism, hypogonadism, tumour lysis syndrome, Guillain-Barré syndrome, aseptic meningitis, encephalitis, uveitis, vasculitis, pneumonitis, respiratory distress syndrome, gastrointestinal perforation, peritonitis, pancreatitis, hepatic failure, hepatitis, toxic epidermal necrolysis, myositis, glomerulonephritis, autoimmune nephritis, multi-organ failure, infusion-related reaction.

Monotherapy: rare (≥1/10,000 to <1/1,000): type 1 diabetes mellitus (including diabetic ketoacidosis), thyroiditis, myasthenia gravis, Vogt-Koyanagi-Harada syndrome, temporal arteritis, exocrine pancreatic insufficiency, coeliac disease, erythema multiforme, psoriasis, drug reaction with eosinophilia and systemic symptoms (DRESS), polymyositis. Very rare (<1/10,000): anaphylactic reaction. Not known: haemophagocytic lymphohistiocytosis, solid organ transplant rejection, myelitis, pemphigoid.

• Metabolism: ipilimumab is a monoclonal antibody and is not metabolised by cytochrome P450 or other drug-metabolising enzymes. In a study with dacarbazine or paclitaxel/carboplatin, no clinically relevant pharmacokinetic interaction was seen.
• Corticosteroids: systemic corticosteroids before starting ipilimumab should be avoided because they may interfere with its activity and efficacy. After treatment has started, corticosteroids or other immunosuppressants can be used to treat immune-related reactions without apparently reducing efficacy.
• Immunosuppressive therapy: ipilimumab strengthens the immune response and may interfere with immunosuppressive therapy, causing a flare of the underlying disease or graft rejection.
• Anticoagulants: they raise the risk of gastrointestinal bleeding, which is a reaction to ipilimumab, so patients needing them should be monitored closely.
• Vemurafenib: given together with ipilimumab 3 mg/kg, vemurafenib was associated with asymptomatic grade 3 rises in transaminases and bilirubin, so concurrent use is not recommended. After prior vemurafenib, grade 3 or higher skin reactions were more frequent with ipilimumab 10 mg/kg, so caution is advised.

Treatment must be started and supervised by specialist physicians experienced in cancer treatment. Where the indication requires it, PD-L1 expression must be confirmed by a validated test and MSI-H/dMMR status assessed with a CE-marked test. Ipilimumab is given as an intravenous infusion over 30 minutes, undiluted or diluted with sodium chloride 9 mg/mL (0.9%) or glucose 50 mg/mL (5%) to 1–4 mg/mL, and never as a push or bolus injection. With nivolumab, nivolumab is given first, then ipilimumab, then chemotherapy if used, on the same day, each in a separate bag with its own filter. Liver and thyroid function tests are checked at baseline and before each dose.

Recommended Dose by Indication

• Melanoma, monotherapy (adults and adolescents 12 years and older): 3 mg/kg every 3 weeks for 4 doses. The whole induction course should be given as tolerated, even if new lesions appear or existing ones grow; response is assessed only after induction.
• Melanoma with nivolumab: ipilimumab 3 mg/kg with nivolumab 1 mg/kg every 3 weeks for 4 doses, then nivolumab alone (240 mg every 2 weeks or 480 mg every 4 weeks; in adolescents under 50 kg, 3 mg/kg every 2 weeks or 6 mg/kg every 4 weeks). The first nivolumab dose after the combination is given 3 weeks later for the 2-weekly schedule and 6 weeks later for the 4-weekly schedule.
• Renal cell carcinoma: ipilimumab 1 mg/kg with nivolumab 3 mg/kg every 3 weeks for 4 doses, then nivolumab 240 mg every 2 weeks or 480 mg every 4 weeks.
• dMMR or MSI-H colorectal cancer, first line: ipilimumab 1 mg/kg with nivolumab 240 mg every 3 weeks for up to 4 doses, then nivolumab 240 mg every 2 weeks or 480 mg every 4 weeks. After prior fluoropyrimidine-based chemotherapy: ipilimumab 1 mg/kg with nivolumab 3 mg/kg every 3 weeks for 4 doses, then nivolumab 240 mg every 2 weeks. Nivolumab continues until progression, unacceptable toxicity or up to 24 months without progression.
• Malignant pleural mesothelioma: ipilimumab 1 mg/kg every 6 weeks with nivolumab 360 mg every 3 weeks, for up to 24 months in patients without progression.
• Oesophageal squamous cell carcinoma: ipilimumab 1 mg/kg every 6 weeks with nivolumab 3 mg/kg every 2 weeks or 360 mg every 3 weeks, until progression, unacceptable toxicity or up to 24 months without progression.
• Hepatocellular carcinoma: ipilimumab 3 mg/kg with nivolumab 1 mg/kg every 3 weeks for up to 4 doses, then nivolumab 240 mg every 2 weeks or 480 mg every 4 weeks, until progression, unacceptable toxicity or up to 24 months.
• NSCLC: ipilimumab 1 mg/kg every 6 weeks with nivolumab 360 mg every 3 weeks and platinum-based chemotherapy every 3 weeks; after 2 chemotherapy cycles, ipilimumab 1 mg/kg every 6 weeks with nivolumab 360 mg every 3 weeks, until progression, unacceptable toxicity or up to 24 months without progression.
• Duration: while clinical benefit continues or until the treatment is no longer tolerated, within any maximum above. Atypical responses (an early transient increase in tumour size or small new lesions followed by shrinkage) occur, so clinically stable patients with early signs of progression can continue until progression is confirmed.

Withholding and Stopping Treatment

Doses are never escalated or reduced. A dose is withheld or treatment stopped according to the reaction.

• Monotherapy, permanent discontinuation: grade 3 or 4 diarrhoea or colitis (severe abdominal pain, bloody stool, gastrointestinal haemorrhage or perforation); grade 3 or 4 rise in AST, ALT or bilirubin; grade 4 rash (including Stevens-Johnson syndrome or toxic epidermal necrolysis) or grade 3 pruritus; grade 3 or 4 motor or sensory neuropathy; grade 3 or higher immune-related reaction in other organs (for example nephritis, pneumonitis, pancreatitis, non-infectious myocarditis, diabetes) and grade 2 or higher eye disorders not responding to topical therapy. Patients with a severe endocrine disorder controlled with hormone replacement may continue.
• Monotherapy, withhold the dose: moderate diarrhoea or colitis not controlled or lasting 5–7 days or recurring; grade 2 rise in AST, ALT or bilirubin; grade 3 rash or grade 2 widespread pruritus; severe endocrine disorders not controlled with hormone replacement; grade 3 diabetes; grade 2 unexplained neuropathy or muscle weakness lasting more than 4 days. Resume when the reaction falls to grade 1 or less or to baseline; if that does not happen, discontinue. Withheld doses can be resumed until all 4 doses are given or 16 weeks from the first dose, whichever is earlier.
• With nivolumab: withhold for grade 2 pneumonitis, colitis, or rise in AST, ALT or bilirubin, grade 2 or 3 creatinine rise, symptomatic grade 2 or 3 thyroid disorders or hypophysitis, grade 2 adrenal insufficiency, grade 3 diabetes, grade 3 rash, grade 2 myocarditis and grade 2 myocarditis-myositis-myasthenia gravis overlap syndrome. Discontinue permanently for grade 3 or 4 pneumonitis, colitis, liver test rise, myocarditis and overlap syndrome; grade 4 rash and grade 4 creatinine rise; grade 3 or 4 adrenal insufficiency; life-threatening endocrine disorders; and Stevens-Johnson syndrome or toxic epidermal necrolysis. In hepatocellular carcinoma the liver thresholds depend on baseline values (see the SmPC).
• Combination in general: discontinue for any grade 4 or recurrent grade 3 reaction, for grade 2 or 3 reactions that persist despite treatment, or if the corticosteroid dose cannot be reduced to 10 mg prednisone or equivalent per day. If one of the two antibodies is withheld, the other is withheld too; after a delay, either the combination or nivolumab alone can be resumed.

Special Populations

• Elderly (65 years and over): no overall difference in safety or efficacy and no dose adjustment. Data from first-line RCC patients aged 75 or over are too limited to draw conclusions.
• Renal impairment: not studied; no adjustment for mild to moderate impairment based on population pharmacokinetics.
• Hepatic impairment: not studied; no adjustment for mild impairment. Use with caution if transaminases are 5 times the upper limit of normal or more, or bilirubin is more than 3 times the upper limit, at baseline.
• Children and adolescents: monotherapy is not established in children under 12 years and should not be used; the combination with nivolumab has not been established below 18 years except in adolescents 12 years and older with melanoma.

Immune-Related Reactions

Ipilimumab causes inflammatory reactions from increased immune activity that can be severe or life-threatening and can involve the gastrointestinal tract, liver, skin, nervous system, endocrine glands and other organs. Most appear during the induction period, but onset months after the last dose is possible. Unless another cause is found, diarrhoea, more frequent stools, bloody stool, raised liver tests, rash and endocrine disorders are treated as immune-related. When ipilimumab is combined with nivolumab, patients should be monitored for at least 5 months after the last dose. For suspected reactions the cause should be confirmed or other causes excluded, the next dose withheld, and corticosteroids started; once the reaction improves, the corticosteroid is tapered over at least 1 month, because rapid tapering can bring the reaction back. Other immunosuppressants are added if there is no improvement. The combination should not be resumed while the patient needs immunosuppressive doses of corticosteroids, and prophylactic antibiotics should be given to prevent opportunistic infections during immunosuppression.

Gastrointestinal Reactions

Severe colitis and gastrointestinal perforation, including fatal cases, have occurred. Diarrhoea, more frequent stools, abdominal pain or blood in the stool call for a stool infection work-up and symptomatic care. Mild to moderate diarrhoea may continue treatment; if it lasts 5–7 days or recurs, the dose is withheld and corticosteroids (for example prednisone 1 mg/kg) started. Severe diarrhoea or colitis needs permanent discontinuation and high-dose intravenous corticosteroids at once, and the patient should be checked for perforation or peritonitis. Cytomegalovirus infection or reactivation has been reported after marketing in steroid-refractory colitis. In steroid-refractory colitis, another immunosuppressant such as infliximab can be added if other causes are excluded, but infliximab must not be used if perforation or sepsis is suspected.

Hepatotoxicity

Serious hepatitis, including fatal liver failure, has occurred. Transaminases and bilirubin must be checked before each dose, because early changes can precede symptoms. Other causes (infection, tumour progression, other medicines) should be excluded. Grade 2 rises mean the dose is withheld; grade 3 or 4 rises mean permanent discontinuation and high-dose corticosteroids (for example methylprednisolone 2 mg/kg daily), tapered over at least 1 month. Mycophenolate mofetil can be considered if there is no response to corticosteroids.

Skin Reactions

Rash and pruritus are mostly mild or moderate. Rare cases of toxic epidermal necrolysis and Stevens-Johnson syndrome, some fatal, and of drug reaction with eosinophilia and systemic symptoms (DRESS) have occurred, DRESS sometimes after a latency of two to eight weeks. Caution is needed in patients who had a severe skin reaction on earlier immune-stimulating cancer therapy. If signs of Stevens-Johnson syndrome or toxic epidermal necrolysis appear, treatment is stopped and the patient referred to a specialised unit.

Neurological Reactions

Fatal Guillain-Barré syndrome and myasthenia gravis-like symptoms have been reported. Unexplained motor neuropathy, muscle weakness or sensory neuropathy lasting more than 4 days should be evaluated and other causes excluded. Grade 3 or 4 neuropathy requires permanent discontinuation and intravenous corticosteroids.

Nephritis and Renal Dysfunction

With nivolumab, severe nephritis and renal dysfunction have occurred, usually first seen as a symptomless rise in serum creatinine. Renal function should be monitored.

Endocrine Reactions

Hypophysitis, hypopituitarism, adrenal insufficiency, hypothyroidism, hyperthyroidism, type 1 diabetes mellitus and diabetic ketoacidosis can occur. Symptoms are often non-specific (headache, fatigue, visual field defects, behavioural changes, electrolyte disturbances, low blood pressure) and can mimic brain metastases. Adrenal crisis must be excluded, and signs of it (severe dehydration, hypotension, shock) call for immediate intravenous corticosteroids. Patients are monitored for hyperglycaemia and thyroid changes; hormone replacement may be needed long term.

Pneumonitis, Myocarditis and Myotoxicity (Combination with Nivolumab)

Severe pneumonitis or interstitial lung disease, including fatal cases, has occurred; patients are watched for radiographic changes, dyspnoea and hypoxia. Cardiac and pulmonary events including pulmonary embolism have also been reported, and the combination should be stopped for life-threatening or recurrent severe cardiac or pulmonary reactions. Myositis, myocarditis and rhabdomyolysis, some fatal, and the overlap syndrome of myocarditis, myositis and myasthenia gravis have occurred; suspected myocarditis needs prompt high-dose steroids (prednisone or methylprednisolone 1 to 2 mg/kg/day) and cardiology review.

Infusion Reactions

Severe infusion reactions have been reported. Severe or life-threatening ones need the infusion stopped; patients with mild or moderate reactions may continue with close monitoring and premedication.

Other Immune-Related Reactions

Uveitis, eosinophilia, raised lipase, glomerulonephritis, iritis, haemolytic anaemia, raised amylase, pneumonitis, multi-organ failure, and after marketing Vogt-Koyanagi-Harada syndrome, serous retinal detachment and non-infective cystitis have been reported. Transient vision loss has occurred with ocular inflammation, and corticosteroid eye drops can be considered. Solid organ transplant rejection has been reported, and ipilimumab may raise the risk in transplant recipients. Haemophagocytic lymphohistiocytosis has been seen with ipilimumab alone or with a PD-1 or PD-L1 inhibitor; if it is confirmed, treatment is stopped.

Disease-Specific Precautions

• Melanoma: patients with ocular melanoma, primary central nervous system melanoma and active brain metastases were not in the main trial. The combination with nivolumab improves progression-free survival over nivolumab alone only in patients with low tumour PD-L1 expression, and its onset of effect is delayed, which matters in rapidly progressing disease.
• Oesophageal squamous cell carcinoma and hepatocellular carcinoma: more deaths occurred within 4 months (oesophageal) and 6 months (liver) with the combination than with the comparator, so the delayed onset of effect and poor prognostic features should be weighed.
• Patients excluded from the combination studies: baseline performance score of 2 or more, active brain metastases, active autoimmune disease, need for systemic immunosuppression and, depending on the indication, several disease-specific conditions. Use with caution in these groups after weighing benefit and risk. Data in NSCLC patients aged 75 or over are limited.

Autoimmune Disease

Patients with a history of autoimmune disease were not evaluated. Ipilimumab should be avoided where further immune activation could be imminently life-threatening, and used with caution after weighing benefit and risk in other patients with such a history.

Sodium

Each 10 mL vial contains 23 mg of sodium and each 40 mL vial 92 mg, which should be considered in patients on a controlled sodium diet.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: there are no data in pregnant women, and animal studies showed reproductive toxicity. Human IgG1 crosses the placenta. Ipilimumab is not recommended in pregnancy or in women of childbearing potential not using effective contraception, unless the benefit outweighs the risk.
• Breastfeeding: ipilimumab was present at very low levels in the milk of monkeys; it is not known whether it passes into human milk. A decision must be made between stopping breastfeeding and stopping treatment.
• Fertility: not studied.

Traceability

To improve traceability of biological medicines, the name and batch number of the administered product should be clearly recorded.

Effect on Driving

Ipilimumab has a minor influence on the ability to drive and use machines. Because of reactions such as fatigue, patients should take care until they are sure that it does not affect them.

Store vials in a refrigerator at 2–8 °C. Do not freeze. Keep in the original package to protect from light. Keep the cold chain unbroken during transport and handling. For storage after opening or dilution, see Shelf Life.

• Unopened vial: 3 years.
• After opening or dilution: from a microbiological point of view, once opened the medicine should be infused, or diluted and infused, immediately. Chemical and physical in-use stability of the undiluted or diluted concentrate (1 to 4 mg/mL) has been shown for 24 hours at 25 °C and at 2–8 °C. If not used immediately, the infusion solution may be stored for up to 24 hours in a refrigerator (2–8 °C) or at room temperature (20–25 °C).

Prescription only (Rx); treatment is started and supervised by specialist physicians experienced in cancer treatment. Ipilimumab is given as an intravenous infusion in hospital or clinic, so it is supplied to the hospital or clinic that administers it, under cold-chain conditions at 2–8 °C.