Ipilimumab

Registered South African indications:

• Unresectable or metastatic melanoma (previously treated)

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients

Cautions

• Pregnancy
• Breastfeeding
• Renal impairment
• Hepatic impairment
• Children
• Combination therapy with nivolumab
• Patient who has previously experienced a severe or life-threatening skin adverse reaction on a prior cancer immune stimulatory therapy
• Ocular melanoma
• Primary central nervous system melanoma
• History of or active brain metastases
• Rapidly progressing disease
• History of or active autoimmune disease
• Patients requiring systemic immunosuppressive therapy for pre-existing autoimmune disease
• Patients requiring systemic immunosuppressive therapy for organ transplantation graft maintenance
• Sodium controlled diet
• May impair ability to drive or operate machinery

Forms avail. in SA and covered in this monograph: inj

Used for the treatment of

• Melanoma
  - As monotherapy or in combination with nivolumab in advanced (unresectable or metastatic) melanoma
• Renal cell carcinoma
  - First-line treatment in combination with nivolumab in patients with intermediate/poor-risk advanced renal cell carcinoma

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Consult specialist for dosages and regimens

Not established for use in children in South Africa

Used for the treatment of 

• Melanoma
  - As monotherapy for advanced (unresectable or metastatic) melanoma in adolescents 12 years and older

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Consult specialist for dosages and regimens

Pregnancy

• Caution
• There is no data on the use of ipilimumab in pregnant women. Animal reproduction studies have shown reproductive toxicity
• Human IgG1 crosses the placental barrier. The potential risk to the developing foetus is unknown
• Ipilimumab is not recommended during pregnancy or in women of childbearing potential not using effective contraception, unless the clinical benefit outweighs the potential risk

Breastfeeding

• Caution; not recommended
• Ipilimumab has been shown to be present at very low levels in milk from cynomolgus monkeys treated during pregnancy. 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 breastfeeding infants, a decision must be made whether to discontinue breastfeeding or discontinue ipilimumab therapy taking into account the benefit of breastfeeding for the child and the benefit of ipilimumab therapy for the woman

Fertility

• Studies to evaluate the effect of ipilimumab on fertility have not been performed. Thus the effect of ipilimumab on male and female fertility is unknown

Renal Impairment

• Caution; no information available
  Ipilimumab has not been studied in patients with renal impairment. Based on population pharmacokinetic results, no specific dose adjustment is necessary in mild to moderate renal impairment

Hepatic Impairment

• Caution; no information available
  Ipilimumab has not been studied in patients with hepatic impairment. Based on population pharmacokinetic results, no specific dose adjustment is necessary in mild hepatic impairment
  Caution is required if transaminase levels >5 x ULN or bilirubin levels >3 x ULN at baseline

Elderly

• No dose adjustment recommended

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Confusional state
• Mental status changes
• Depression
• Decreased libido
• Peripheral sensory neuropathy
• Dizziness
• Headache
• Lethargy
• Guillain-Barré syndrome (including fatal outcome)
• Meningitis (aseptic)
• Autoimmune central neuropathy (including facial and abducens nerve paresis in combination with nivolumab)
• Encephalitis
• Syncope
• Cranial neuropathy
• Brain oedema
• Peripheral neuropathy
• Ataxia
• Tremor
• Myoclonus
• Dysarthria
• Myasthenia gravis
• Fatigue

Cardiovascular Disorders

• Arrhythmia
• Atrial fibrillation
• Hypotension
• Flushing
• Hot flush
• Vasculitis
• Angiopathy
• Peripheral ischaemia
• Orthostatic hypotension
• Temporal arteritis
• Tachycardia (in combination with nivolumab)
• Ventricular arrhythmia (including fatal outcome in combination with nivolumab)
• Myocarditis (including fatal outcome in combination with nivolumab)
• Pericardial disorders (in combination with nivolumab)
  - Pericarditis
  - Pericardial effusion
  - Cardiac tamponade
  - Dressler's syndrome
• Hypertension (in combination with nivolumab)

Respiratory Disorders

• Dyspnoea
• Cough
• Respiratory failure
• Acute respiratory distress syndrome (including fatal outcome)
• Lung infiltration
• Pulmonary oedema
• Pneumonitis (including fatal outcome in combination with nivolumab)
• Allergic rhinitis
• Pleural effusion (in combination with nivolumab)

Gastrointestinal Disorders

• Diarrhoea
• Nausea and vomiting
• Gastrointestinal haemorrhage
• Colitis (including fatal outcome)
• Constipation
• Gastroesophageal reflux disease
• Abdominal pain
• Mucosal inflammation
• Gastrointestinal perforation (including fatal outcome)
• Peritonitis
• Gastroenteritis
• Diverticulitis
• Pancreatitis
• Enterocolitis
• Gastric ulcer
• Large intestinal ulcer
• Stomatitis
• Oesophagitis
• Ileus
• Proctitis
• Gastritis (in combination with nivolumab)
• Duodenitis (in combination with nivolumab)
• Colitis (including fatal outcome in combination with nivolumab)

Hepatobiliary Disorders

• Abnormal hepatic function
• Hepatic failure (including fatal outcome)
• Hepatitis
• Hepatomegaly
• Jaundice
• Increased alanine aminotransferase
• Increased aspartate aminotransferase
• Increased blood alkaline phosphatase
• Increased blood bilirubin
• Increased gamma-glutamyltransferase
• Increased lipase
• Increased blood amylase

Genitourinary Disorders

• Renal failure (including fatal outcome)
• Glomerulonephritis
• Autoimmune nephritis
• Renal tubular acidosis
• Haematuria
• Proteinuria
• Amenorrhea
• Increased blood creatinine
• Acute kidney injury (including fatal outcome in combination with nivolumab)
• Tubulointerstitial nephritis (in combination with nivolumab)

Endocrine and Metabolic Disorders

• Hypopituitarism
• Hypophysitis
• Hypothyroidism
• Adrenal insufficiency
• Secondary adrenocortical insufficiency
• Hyperthyroidism
• Hypogonadism
• Autoimmune thyroiditis
• Thyroiditis
• Decreased appetite
• Dehydration
• Hypokalemia
• Hyponatremia
• Alkalosis
• Hypophosphatemia
• Tumour lysis syndrome
• Hypocalcaemia
• Decreased weight
• Increased blood thyroid stimulating hormone
• Decreased blood thyroid stimulating hormone
• Decreased blood cortisol
• Decreased blood corticotrophin
• Decreased blood testosterone
• Decreased thyroxine
• Abnormal blood prolactin
• Increased blood creatinine
• Diabetes mellitus (in combination with nivolumab)
• Diabetic ketoacidosis (in combination with nivolumab)
• Hyperglycaemia (in combination with nivolumab)
• Hypoglycaemia (in combination with nivolumab)
• Hypomagnesaemia (in combination with nivolumab)
• Hypermagnesaemia (in combination with nivolumab)
• Hyponatraemia (in combination with nivolumab)
• Hypernatraemia (in combination with nivolumab)

Musculoskeletal Disorders

• Arthralgia
• Myalgia
• Musculoskeletal pain
  - Back pain
  - Bone pain
  - Musculoskeletal chest pain
  - Musculoskeletal discomfort
  - Neck pain
  - Pain in extremities
  - Spinal pain
• Muscle spasms
• Polymyalgia rheumatica
• Myositis
• Arthritis
• Muscular weakness
• Spondylarthropathy (in combination with nivolumab)
• Sjogren's syndrome (in combination with nivolumab)
• Polymyositis (in combination with nivolumab)
• Rhabdomyolysis (including fatal outcomes in combination with nivolumab)

Skin and Subcutaneous Tissue Disorders

• Rash
  - Maculopapular rash
  - Erythematous rash
  - Pruritic rash
  - Follicular rash
  - Macular rash
  - Morbilliform rash
  - Papular rash
  - Pustular rash
  - Papulosquamous rash
  - Vesicular rash
  - Generalised rash
  - Exfoliative rash
  - Dermatitis
  - Acneiform dermatitis
  - Allergic dermatitis
  - Atopic dermatitis
  - Bullous dermatitis
  - Exfoliative dermatitis
  - Psoirasiform dermatitis
  - Drug Eruption
• Pruritus
• Dermatitis
• Erythema
• Vitiligo
• Urticaria
• Eczema
• Alopecia
• Night sweats
• Dry skin
• Toxic epidermal necrolysis (including fatal outcome)
• Leukocytoclastic vasculitis
• Skin exfoliation
• Hair colour changes
• Erythema multiforme
• Psoriasis
• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)
• Pemphigoid
• Oedema
• Injection site reaction
• Stevens-Johnson syndrome (in combination with nivolumab)

Immune, Blood and Lymphatic System Disorders

• Sepsis (including fatal outcome)
• Septic shock (including fatal outcome)
• Urinary tract infection
• Respiratory tract infection
• Tumour pain
• Paraneoplastic syndrome
• Anaemia
• Lymphopenia
• Haemolytic anaemia (including fatal outcome)
• Thrombocytopenia
• Eosinophilia
• Neutropenia
• Haematophagic histiocytosis
• Hypersensitivity
• Anaphylactic reaction
• Fever
• Influenza-like illness
• Chills
• Multi-organ failure (including fatal outcome)
• Systemic inflammatory response syndrome
• Infusion related reaction
• Positive antinuclear antibody
• Pneumonia (in combination with nivolumab)
• Bronchitis (in combination with nivolumab)
• Sarcoidosis (in combination with nivolumab)
• Solid organ transplant rejection (in combination with nivolumab)
• Tumour lysis syndrome (in combination with nivolumab)

Sensory Disorders

• Blurred vision
• Eye pain
• Uveitis
• Vitreous haemorrhage
• Iritis
• Eye oedema
• Blepharitis
• Reduced visual acuity
• Foreign body sensation in eyes
• Conjunctivitis
• Vogt-Koyanagi-Harada syndrome
• Serous retinal detachment

• Systemic corticosteroids
• Anticoagulants
• Systemic immunosuppressive agents
• Vemurafenib 

• Hepatic function
• Adrenocorticotropic hormone (ACTH)
• Serum creatinine
• Thyroid function
• Cortisol levels

None routine. Specific cases may require

• Pregnancy test 

Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is a key regulator of T-cell activity. Ipilimumab is a CTLA-4 immune checkpoint inhibitor that blocks T-cell inhibitory signals induced by the CTLA-4 pathway, increasing the number of reactive T-effector cells which mobilize to mount a direct T-cell immune attack against tumour cells. CTLA-4 blockade can also reduce T-regulatory cell function, which may contribute to an anti-tumour immune response. Ipilimumab may selectively deplete T-regulatory cells at the tumour site, leading to an increase in the intratumoral T-effector/ T-regulatory cell ratio which drives tumour cell death.

Injection (per ml) 5mg

• Yervoy (Bristol Myers Squibb) originator