Drugs List

Therapeutic Indications

Uses

Advanced (unresectable/metastatic) malignant melanoma
Advanced, metastatic or recurrent non-small cell lung cancer
Malignant pleural mesothelioma
Mismatch repair-deficient/microsatellite instability-high colorectal cancer
Oesophageal squamous cell carcinoma
Renal cell carcinoma

As monotherapy for advanced (unresectable or metastatic) melanoma in adults, and adolescents 12 years of age or older.

In combination with nivolumab for advanced (unresectable or metastatic) melanoma in adults only.

In combination with nivolumab for the first-line treatment of adult patients with intermediate/poor-risk advanced renal cell carcinoma

In combination with nivolumab and 2 cycles of platinum-based chemotherapy is indicated for the first-line treatment of metastatic non-small cell lung cancer in adults whose tumours have no sensitising EGFR mutation or ALK translocation. In combination with nivolumab is indicated for the first-line treatment of adult patients with unresectable malignant pleural mesothelioma. In combination with nivolumab is indicated for the treatment of adult patients with mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) metastatic colorectal cancer after prior fluoropyrimidine-based combination chemotherapy. In combination with nivolumab is indicated for the first-line treatment of adult patients with unresectable advanced, recurrent or metastatic oesophageal squamous cell carcinoma with tumour cell PD-L1 expression = 1%.

Administration

For intravenous infusion.

Contraindications

Children under 12 years
Breastfeeding
Pregnancy
Severe active autoimmune disorder

Precautions and Warnings

Autoimmune disease
Children aged 12 to 18 years
Elevated serum transaminases - greater than 5 times upper limit of normal
History of autoimmune disorder
Restricted sodium intake
Solid organ transplant recipients
Cerebral metastases
Serum bilirubin above 3 times upper limit of normal
Severe renal impairment

Sodium content of formulation may be significant
Advise ability to drive/operate machinery may be affected by side effects
Consider pre-medication with antihistamines and/or antipyretics
May increase risk of solid organ graft rejection
Treatment to be initiated and supervised by a specialist
Consult local policy on the safe use of anti-cancer drugs
Staff: Not to be handled by pregnant staff
Monitor liver function tests at baseline and before each dose
Monitor thyroid function at baseline and before each dose
Monitor for gastrointestinal toxicity
Perform stool infection workup & screen for CMV if diarrhoea/colitis occurs
Advise patient to report gastrointestinal signs or symptoms
Advise patient to report signs of neuropathy
Advise patient to report skin reaction, pain, erythema, pruritus
Discontinue if AST or ALT level exceeds 8 x ULN
Discontinue if grade 2 or higher unresponsive immune related eye disorders
Discontinue if grade 3 or higher diarrhoea or colitis occurs
Discontinue if grade 3 or higher immune related reactions occur
Discontinue if grade 3 or higher neuropathy occurs
Discontinue if grade 3 pruritus occurs
Discontinue if grade 4 skin reaction occurs
Discontinue if total bilirubin >5 x ULN
Interrupt therapy if elevations in bilirubin of > 3 x ULN occur
Interrupt treatment if ALT or AST > 5 x ULN
Suspend if grade 2 neuropathy or muscle weakness occurs
Suspend if moderate diarrhoea/colitis that cannot be controlled occurs
Suspend if moderate diarrhoea/colitis that recurs or persists (>5 days)
Suspend if severe reactions of endocrine system that cannot be controlled
Suspend treatment if up to grade 3 rash or intense/ widespread pruritus
Not licensed for all indications in all age groups
Female: Ensure adequate contraception during treatment

Ipilimumab is associated with inflammatory adverse reactions resulting from increased or excessive immune activity. Unless an alternate aetiology has been identified diarrhoea, increased stool frequency, bloody stools, LFT elevations, rash and endocrinopathy must be considered inflammatory and ipilimumab related.

Management of immune related adverse reactions may require omission of doses, permanent discontinuation of therapy and the initiation of systemic high dose corticosteroid with or without the addition of further immunosuppressive therapy.

Toxicity grades are based on severity of symptoms using the NCI-CTCAE v3 severity grading classification.

Permanent discontinuation
If ipilimumab requires discontinuation systemic high dose intravenous corticosteroid therapy should be initiated immediately. Once symptoms are under control, the initiation of corticosteroid taper should be based on clinical judgement. Tapering should occur over a period of at least 1 month.

Withholding Doses
Withhold doses until the adverse reaction resolves to Grade 1 or 0 (or returns to baseline). If resolution occurs, resume therapy until administration of all 4 doses or 16 weeks from first dose, whichever occurs earlier. Discontinue if resolution to Grade 1 or 0 (or returns to baseline) does not occur.

Immune related gastrointestinal toxicity
Diarrhoea or colitis occurring after initiation of ipilimumab must be promptly evaluated to exclude infectious or other alternate aetiologies. Patients with mild to moderate diarrhoea or suspected mild to moderate diarrhoea may remain on treatment. Symptomatic treatment and close monitoring are advised.
Cases of cytomegalovirus (CMV) infection/reactivation have been reported in patients with corticosteroid-refractory immune-related colitis, consideration should only be given to additional immunosuppressive agents if other causes are excluded (including CMV infection or reactivation evaluated using PCR on biopsy, as well as other viral, parasitic or bacterial causes).

Immune related hepatotoxicity
Hepatic transaminases and bilirubin must be evaluated before each dose of ipilimumab; early laboratory changes may be indicative of emerging immune related hepatitis. Elevations in liver function tests 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 such as infections, disease progression, or medicinal products and monitored until resolution.

For patients refractory to corticosteroid therapy with significant liver function test elevations, addition of an alternative immunosuppressive agent to the corticosteroid regimen may be considered.

Immune related neurological reactions
Unexplained motor neuropathy, muscle weakness, or sensory neuropathy lasting longer than 4 days must be evaluated and non-inflammatory causes such as disease progression, infections, metabolic syndromes and medicinal products should be excluded.

Immune related skin reactions
Cases of toxic epidermal necrolysis and Drug Reaction with Eosinophila and systemic symptoms (DRESS) have been reported in patients. DRESS may be characterised by a long latency (2 to 8 weeks) between exposure and disease onset.

Caution should be used when considering the use of ipilimumab in patients who have previously experienced a severe or life threatening skin reaction with a prior immune stimulatory cancer therapy.

Immune related endocrinopathy
Ipilimumab can cause inflammation of the endocrine system organs, specifically hypophysitis, hypopituitarism, adrenal insufficiency, and hypothyroidism, and patients may present with non specific 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.

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 and endocrine function should be assessed prior to corticosteroid administration. If pituitary imaging or laboratory tests of endocrine function are abnormal, a short course of high dose corticosteroid therapy is recommended and the scheduled dose of ipilimumab should be omitted. Appropriate hormone replacement should also be initiated, long term therapy may be necessary.

Pregnancy and Lactation

Pregnancy

Ipilimumab is contraindicated in pregnancy.

Human IgG1 crosses the placenta.

The manufacturer states that ipilimumab should not be used during pregnancy unless the clinical benefit outweighs the potential risk.

The effect of concurrent therapies must also be considered.

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14 to 17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Lactation

Ipilimumab is contraindicated in breastfeeding.

It is unknown if ipilimumab is secreted in human breast milk. A risk to neonates cannot be excluded.

Secretion of IgGs in human milk is generally limited and IgGs have a low oral bioavailability. Neonate or infant consumption of breast milk is not thought to result in substantial absorption of maternal antibodies into the circulation.

The effect of concurrent therapies must also be considered.

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Side Effects

Abnormal liver function
Acute respiratory distress
Adrenal suppression
Alkalosis
Alopecia
Amenorrhoea
Anaemia
Arrhythmias
Arthritis
Aseptic meningitis
Asthenia
Ataxia
Atrial fibrillation
Autoimmune disorders
Cardiovascular disturbances
Chills
Colitis
Cough
Decreased appetite
Dehydration
Depression
Dizziness
Drug rash with eosinophilia and systemic symptoms (DRESS)
Dysarthria
Dyspnoea
Electrolyte disturbances
Elevated amylase levels
Elevated serum lipase
Elevated TSH
Enterocolitis
Eosinophilia
Eye disorder
Fatigue
Flushing
Gastro-intestinal haemorrhage
Gastro-intestinal perforation
Gastro-intestinal symptoms
Gastro-intestinal ulceration
Glomerulonephritis
Guillain-Barre syndrome
Haematuria
Haemolytic anaemia
Headache
Hepatic failure
Hepatitis
Hepatomegaly
Histiocytosis haematophagic
Hypersensitivity reactions
Hypogonadism
Hypophysitis
Hypotension
Increase in serum ALT/AST
Infections
Infusion-related symptoms
Iritis
Jaundice
Leukocytoclastic vasculitis
Lymphopenia
Multiorgan failure
Muscle spasm
Myasthenia gravis-like syndrome
Myoclonus
Neuropathy
Neutropenia
Night sweats
Oedema
Pain
Palmar-Plantar Erythrodysaesthesia syndrome
Pancreatitis
Paraneoplastic syndromes
Pemphigoid reaction
Peripheral ischaemia
Peritonitis
Pituitary disorder
Pneumonitis
Polymyalgia rheumatica
Pulmonary infiltration
Pulmonary oedema
Pyrexia
Reduced libido
Reduction in serum cortisol levels
Renal failure
Renal tubular acidosis
Respiratory failure
Rhinitis
Serum bilirubin increased
Skin disorder
Solid organ graft rejection
Stevens-Johnson syndrome
Syncope
Thrombocytopenia
Thyroid abnormalities
Toxic epidermal necrolysis
Tremor
Tumour lysis syndrome
Uveitis
Vasculitis
Vitreous haemorrhage
Vogt-Koyanagi- Harada (VKH) syndrome
Weight loss

Presentation

Infusions of ipilimumab.

Drugs List

Therapeutic Indications

Uses

Advanced (unresectable/metastatic) malignant melanoma
Advanced, metastatic or recurrent non-small cell lung cancer
Malignant pleural mesothelioma
Mismatch repair-deficient/microsatellite instability-high colorectal cancer
Oesophageal squamous cell carcinoma
Renal cell carcinoma

As monotherapy for advanced (unresectable or metastatic) melanoma in adults, and adolescents 12 years of age or older.

In combination with nivolumab for advanced (unresectable or metastatic) melanoma in adults only.

In combination with nivolumab for the first-line treatment of adult patients with intermediate/poor-risk advanced renal cell carcinoma

In combination with nivolumab and 2 cycles of platinum-based chemotherapy is indicated for the first-line treatment of metastatic non-small cell lung cancer in adults whose tumours have no sensitising EGFR mutation or ALK translocation. In combination with nivolumab is indicated for the first-line treatment of adult patients with unresectable malignant pleural mesothelioma. In combination with nivolumab is indicated for the treatment of adult patients with mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) metastatic colorectal cancer after prior fluoropyrimidine-based combination chemotherapy. In combination with nivolumab is indicated for the first-line treatment of adult patients with unresectable advanced, recurrent or metastatic oesophageal squamous cell carcinoma with tumour cell PD-L1 expression = 1%.

Dosage

Whilst the doses stated below are those recommended by the manufacturer, local cancer network protocols for the relevant indication should be consulted.

Adults

Children

Administration

For intravenous infusion.

Contraindications

Children under 12 years
Breastfeeding
Pregnancy
Severe active autoimmune disorder

Precautions and Warnings

Autoimmune disease
Children aged 12 to 18 years
Elevated serum transaminases - greater than 5 times upper limit of normal
History of autoimmune disorder
Restricted sodium intake
Solid organ transplant recipients
Cerebral metastases
Serum bilirubin above 3 times upper limit of normal
Severe renal impairment

Sodium content of formulation may be significant
Advise ability to drive/operate machinery may be affected by side effects
Consider pre-medication with antihistamines and/or antipyretics
May increase risk of solid organ graft rejection
Treatment to be initiated and supervised by a specialist
Consult local policy on the safe use of anti-cancer drugs
Staff: Not to be handled by pregnant staff
Monitor liver function tests at baseline and before each dose
Monitor thyroid function at baseline and before each dose
Monitor for gastrointestinal toxicity
Perform stool infection workup & screen for CMV if diarrhoea/colitis occurs
Advise patient to report gastrointestinal signs or symptoms
Advise patient to report signs of neuropathy
Advise patient to report skin reaction, pain, erythema, pruritus
Discontinue if AST or ALT level exceeds 8 x ULN
Discontinue if grade 2 or higher unresponsive immune related eye disorders
Discontinue if grade 3 or higher diarrhoea or colitis occurs
Discontinue if grade 3 or higher immune related reactions occur
Discontinue if grade 3 or higher neuropathy occurs
Discontinue if grade 3 pruritus occurs
Discontinue if grade 4 skin reaction occurs
Discontinue if total bilirubin >5 x ULN
Interrupt therapy if elevations in bilirubin of > 3 x ULN occur
Interrupt treatment if ALT or AST > 5 x ULN
Suspend if grade 2 neuropathy or muscle weakness occurs
Suspend if moderate diarrhoea/colitis that cannot be controlled occurs
Suspend if moderate diarrhoea/colitis that recurs or persists (>5 days)
Suspend if severe reactions of endocrine system that cannot be controlled
Suspend treatment if up to grade 3 rash or intense/ widespread pruritus
Not licensed for all indications in all age groups
Female: Ensure adequate contraception during treatment

Ipilimumab is associated with inflammatory adverse reactions resulting from increased or excessive immune activity. Unless an alternate aetiology has been identified diarrhoea, increased stool frequency, bloody stools, LFT elevations, rash and endocrinopathy must be considered inflammatory and ipilimumab related.

Management of immune related adverse reactions may require omission of doses, permanent discontinuation of therapy and the initiation of systemic high dose corticosteroid with or without the addition of further immunosuppressive therapy.

Toxicity grades are based on severity of symptoms using the NCI-CTCAE v3 severity grading classification.

Permanent discontinuation
If ipilimumab requires discontinuation systemic high dose intravenous corticosteroid therapy should be initiated immediately. Once symptoms are under control, the initiation of corticosteroid taper should be based on clinical judgement. Tapering should occur over a period of at least 1 month.

Withholding Doses
Withhold doses until the adverse reaction resolves to Grade 1 or 0 (or returns to baseline). If resolution occurs, resume therapy until administration of all 4 doses or 16 weeks from first dose, whichever occurs earlier. Discontinue if resolution to Grade 1 or 0 (or returns to baseline) does not occur.

Immune related gastrointestinal toxicity
Diarrhoea or colitis occurring after initiation of ipilimumab must be promptly evaluated to exclude infectious or other alternate aetiologies. Patients with mild to moderate diarrhoea or suspected mild to moderate diarrhoea may remain on treatment. Symptomatic treatment and close monitoring are advised.
Cases of cytomegalovirus (CMV) infection/reactivation have been reported in patients with corticosteroid-refractory immune-related colitis, consideration should only be given to additional immunosuppressive agents if other causes are excluded (including CMV infection or reactivation evaluated using PCR on biopsy, as well as other viral, parasitic or bacterial causes).

Immune related hepatotoxicity
Hepatic transaminases and bilirubin must be evaluated before each dose of ipilimumab; early laboratory changes may be indicative of emerging immune related hepatitis. Elevations in liver function tests 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 such as infections, disease progression, or medicinal products and monitored until resolution.

For patients refractory to corticosteroid therapy with significant liver function test elevations, addition of an alternative immunosuppressive agent to the corticosteroid regimen may be considered.

Immune related neurological reactions
Unexplained motor neuropathy, muscle weakness, or sensory neuropathy lasting longer than 4 days must be evaluated and non-inflammatory causes such as disease progression, infections, metabolic syndromes and medicinal products should be excluded.

Immune related skin reactions
Cases of toxic epidermal necrolysis and Drug Reaction with Eosinophila and systemic symptoms (DRESS) have been reported in patients. DRESS may be characterised by a long latency (2 to 8 weeks) between exposure and disease onset.

Caution should be used when considering the use of ipilimumab in patients who have previously experienced a severe or life threatening skin reaction with a prior immune stimulatory cancer therapy.

Immune related endocrinopathy
Ipilimumab can cause inflammation of the endocrine system organs, specifically hypophysitis, hypopituitarism, adrenal insufficiency, and hypothyroidism, and patients may present with non specific 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.

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 and endocrine function should be assessed prior to corticosteroid administration. If pituitary imaging or laboratory tests of endocrine function are abnormal, a short course of high dose corticosteroid therapy is recommended and the scheduled dose of ipilimumab should be omitted. Appropriate hormone replacement should also be initiated, long term therapy may be necessary.

Pregnancy and Lactation

Pregnancy

Ipilimumab is contraindicated in pregnancy.

Human IgG1 crosses the placenta.

The manufacturer states that ipilimumab should not be used during pregnancy unless the clinical benefit outweighs the potential risk.

The effect of concurrent therapies must also be considered.

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14 to 17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Lactation

Ipilimumab is contraindicated in breastfeeding.

It is unknown if ipilimumab is secreted in human breast milk. A risk to neonates cannot be excluded.

Secretion of IgGs in human milk is generally limited and IgGs have a low oral bioavailability. Neonate or infant consumption of breast milk is not thought to result in substantial absorption of maternal antibodies into the circulation.

The effect of concurrent therapies must also be considered.

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Side Effects

Abnormal liver function
Acute respiratory distress
Adrenal suppression
Alkalosis
Alopecia
Amenorrhoea
Anaemia
Arrhythmias
Arthritis
Aseptic meningitis
Asthenia
Ataxia
Atrial fibrillation
Autoimmune disorders
Cardiovascular disturbances
Chills
Colitis
Cough
Decreased appetite
Dehydration
Depression
Dizziness
Drug rash with eosinophilia and systemic symptoms (DRESS)
Dysarthria
Dyspnoea
Electrolyte disturbances
Elevated amylase levels
Elevated serum lipase
Elevated TSH
Enterocolitis
Eosinophilia
Eye disorder
Fatigue
Flushing
Gastro-intestinal haemorrhage
Gastro-intestinal perforation
Gastro-intestinal symptoms
Gastro-intestinal ulceration
Glomerulonephritis
Guillain-Barre syndrome
Haematuria
Haemolytic anaemia
Headache
Hepatic failure
Hepatitis
Hepatomegaly
Histiocytosis haematophagic
Hypersensitivity reactions
Hypogonadism
Hypophysitis
Hypotension
Increase in serum ALT/AST
Infections
Infusion-related symptoms
Iritis
Jaundice
Leukocytoclastic vasculitis
Lymphopenia
Multiorgan failure
Muscle spasm
Myasthenia gravis-like syndrome
Myoclonus
Neuropathy
Neutropenia
Night sweats
Oedema
Pain
Palmar-Plantar Erythrodysaesthesia syndrome
Pancreatitis
Paraneoplastic syndromes
Pemphigoid reaction
Peripheral ischaemia
Peritonitis
Pituitary disorder
Pneumonitis
Polymyalgia rheumatica
Pulmonary infiltration
Pulmonary oedema
Pyrexia
Reduced libido
Reduction in serum cortisol levels
Renal failure
Renal tubular acidosis
Respiratory failure
Rhinitis
Serum bilirubin increased
Skin disorder
Solid organ graft rejection
Stevens-Johnson syndrome
Syncope
Thrombocytopenia
Thyroid abnormalities
Toxic epidermal necrolysis
Tremor
Tumour lysis syndrome
Uveitis
Vasculitis
Vitreous haemorrhage
Vogt-Koyanagi- Harada (VKH) syndrome
Weight loss

Overdosage

It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.

The following number will direct the caller to the relevant local centre (0844) 892 0111

Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Further Information

Last Full Review Date: January 2016

Reference Sources

Summary of Product Characteristics: Yervoy 5mg/ml concentrate for solution for infusion. Bristol-Myers Squibb Pharmaceutical Ltd. Revised August 2022.

MHRA Drug Safety Update January 2019
Available at: https://www.mhra.gov.uk
Last accessed: 16 May 2019

NICE Evidence Services Available at: www.nice.org.uk Last accessed: 26 July 2017