Bosutinib oral
- Drugs List
- Therapeutic Indications
- Dosage
- Contraindications
- Precautions and Warnings
- Pregnancy and Lactation
- Side Effects
- Monograph
Presentation
Oral formulations of bosutinib.
Drugs List
Therapeutic Indications
Uses
Ph+ CML accelerated, chronic & blast phase: patient resistant/intolerant
Ph+ CML in chronic phase: treatment naive patient
Newly-diagnosed chronic phase (CP) Philadelphia chromosome-positive chronic myelogenous leukaemia (Ph+ CML).
Chronic phase, accelerated phase (AP), and blast phase (BP) Philadelphia chromosome-positive chronic myelogenous leukaemia previously treated with one or more tyrosine kinase inhibitors and for whom imatinib, nilotinib and dasatinib are not considered appropriate treatment options.
Dosage
Whilst the doses stated below are those recommended by the manufacturer, local cancer network protocols for the relevant indication should be consulted.
When using this agent, specialist literature, national guidelines, cancer networks protocols and Trust chemotherapy protocols should be consulted.
Adults
Newly-diagnosed CP Ph+ CML
400mg once daily.
CP, AP or BP Ph+ CML with resistance or intolerance to prior therapy
500mg once daily.
Patients with Renal Impairment
Newly-diagnosed CP Ph+ CML
Moderate renal impairment (creatinine clearance 30 to 50 ml/minute, as estimated by the Cockcroft-Gault formula): 300mg once daily with food. Dose escalation to 400mg once daily with food may be considered if the patient does not achieve an adequate haematological, cytogenetic or molecular response, and does not experience severe or persistent moderate adverse reactions.
Severe renal impairment (creatinine clearance less than 30 ml/minute, as estimated by the Cockcroft-Gault formula): 200mg once daily with food. Dose escalation to 300mg once daily with food may be considered if the patient does not achieve an adequate haematological, cytogenetic or molecular response, and does not experience severe or persistent moderate adverse reactions.
CP, AP or BP Ph+ CML with resistance or intolerance to prior therapy
Moderate renal impairment (creatinine clearance 30 to 50 ml/minute, as estimated by the Cockcroft-Gault formula): 400mg once daily with food. Dose escalation to 500mg once daily with food may be considered if the patient does not achieve an adequate haematological, cytogenetic or molecular response, and does not experience severe or persistent moderate adverse reactions.
Severe renal impairment (creatinine clearance less than 30 ml/minute, as estimated by the Cockcroft-Gault formula): 300mg once daily with food. Dose escalation to 400mg once daily with food may be considered if the patient does not achieve an adequate haematological, cytogenetic or molecular response, and does not experience severe or persistent moderate adverse reactions.
Additional Dosage Information
Dose adjustments
CP, AP or BP Ph+ CML with resistance or intolerance to prior therapy
Dose may be increased to a maximum of 600mg once daily with food if patient fails to achieve complete haematologic response by week 8, or complete cytogenetic response by week 12 and did not have grade 3 or higher adverse events.
Newly-diagnosed CP Ph+ CML
Dose may be increased in 100mg increments, up to a maximum of 600mg once daily with food, if the patient fails to demonstrate breakpoint cluster region-Abelson transcripts less than or equal to 10% at month 3, did not have grade 3 or 4 adverse reaction at the time of escalation, and all grade 2 non-haematological toxicities were resolved to at least grade 1.
Dose adjustments for adverse reactions
Moderate to severe non-haematological toxicity
Treatment should be interrupted and, when toxicity has resolved, resumed with a 100mg dose reduction. Re-escalation to previous dosage may be considered if clinically appropriate.
NCI CTCAE Grade 3 or 4 diarrhoea
Interrupt treatment until recovery to grade 1 or below then resume treatment at 400mg once daily.
Elevated liver enzymes
Hepatic transaminases greater than 5 times upper limit of normal (ULN): Interrupt treatment until transaminases equal to or less than 2.5 times ULN and reduce dose to 400mg once daily. If recovery takes more than 4 weeks discontinuation should be considered.
Transaminase elevations equal to or greater than 3 times ULN concurrently with bilirubin elevations greater than 2 times ULN and alkaline phosphatase less than 2 times ULN: Discontinue treatment.
Severe or persistent neutropenia and thrombocytopenia
Neutrophil (ANC) count below 1 x 10 to the power of 9 per litre and/or platelet count below 50 x 10 to the power of 9 per litre: Suspend treatment until ANC equal to or greater than 1 x 10 to the power of 9 per litre and/or platelet count equal to or greater than 50 x 10 to the power of 9 per litre. If recovery occurs within 2 weeks, restart at the previous dose. If recovery takes longer than 2 weeks, resume treatment with a 100mg dose reduction upon recovery. If cytopenia recurs, reduce dose by 100mg.
Missed dose
If a dose is missed by more than 12 hours, the patient should wait until the next usual prescribed dose.
Contraindications
Children under 18 years
Breastfeeding
Hepatic impairment
Long QT syndrome
Pregnancy
Torsade de pointes
Precautions and Warnings
Asian ancestry
Family history of long QT syndrome
Females of childbearing potential
Patients over 65 years
Cardiovascular disorder
Dehydration
Electrolyte imbalance
History of hepatitis B
History of pancreatitis
History of torsade de pointes
Moderate renal impairment
Severe gastrointestinal disorder
Correct electrolyte disorders before treatment
Reduce dose in patients with moderate renal impairment
Advise ability to drive/operate machinery may be affected by side effects
Anti-diarrhoeals may be required during treatment
Anti-emetics may be required during therapy
Before initiating screen all patients for hepatitis B infection
Consider premedication with hypouricaemic agent
Give pre-treatment counselling and consideration of sperm cryopreservation
Hepatitis B: Refer prior to initiation to liver disease specialist
Maintain adequate hydration of patient prior / during treatment
Treatment to be initiated and supervised by a specialist
Consult local policy on the safe use of oral anti-cancer drugs
Staff: Not to be handled by pregnant staff
Monitor renal function before treatment and regularly during treatment
Perform liver function tests before commencing therapy
Perform liver function tests monthly for first 3 months of treatment
Consider monitoring ECG in patients at risk of QT prolongation
Discontinue if AST/ALT > 3x ULN & bilirubin > 2x ULN & ALKP < 2x ULN
Monitor blood counts weekly for 1 month, then monthly thereafter
Monitor for active hepatitis B during therapy and for several months after
Monitor for signs of fluid retention
Monitor patients for signs of tumour lysis syndrome
Monitor serum electrolytes
Consider dose reduction for subsequent doses if severe diarrhoea occurs
Reactivation of hepatitis B may occur in chronic carriers
Consider dose interruption & reduction in non-haematological toxicity
Consider treatment interruption & dose reduction in haematological toxicity
Discontinue if severe skin reaction occurs
Interrupt therapy if hepatic transaminases > 5 times upper limit of normal
Interrupt therapy if neutrophil count <1.0x10 to the power 9/L
Suspend or modify therapy if platelet count less than 50,000 per cubic mm
Suspend treatment if elevated serum lipase plus abdominal pain
Suspend treatment if grade 3 or greater diarrhoea occurs
Advise patient not to take St John's wort concurrently
Advise patient grapefruit products may increase plasma level
Advise patient Seville (sour) orange products may increase plasma level
Advise patient that blueberry products may increase plasma level
Advise patient that cranberry products may increase plasma level
May cause impaired fertility
Female: Contraception required during and for 1 month after treatment
Advise patient on appropriate sun protection methods
Advise patient to avoid exposure to sunlight and UV rays during treatment
Advise patient to use SPF 50+ sunscreen and lip balm during treatment
Patients should be monitored and treated for fluid retention using standard of care treatment. Fluid retention may also be managed by suspending, discontinuing or reducing the dose of bosutinib.
Treatment with bosutinib may predispose patients to bacterial, fungal, viral or protozoan infections.
Asian patients have a lower clearance of bosutinib resulting in increased exposure. Monitor patients with Asian ancestry closely for adverse reactions, especially in case of dose escalation.
Pregnancy and Lactation
Pregnancy
Bosutinib is contraindicated during pregnancy.
The manufacturer recommends that bosutinib should be avoided in pregnancy, due to the risk of foetal harm. Animal studies have indicated reproductive toxicity. At the time of writing there is limited published information regarding the use of bosutinib during pregnancy.
Lactation
Bosutinib is contraindicated during breastfeeding.
The manufacturer recommends that breastfeeding should be discontinued during treatment with bosutinib. It is unknown if bosutinib or its metabolites are excreted in human breast milk. High plasma protein binding may limit the amount of bosutinib present in breast milk, but the long half-life of the drug may result in accumulation in the breastfed infant. Animal studies have indicated the excretion of bosutinib in milk. At the time of writing there is limited published information regarding the use of bosutinib during breastfeeding.
Side Effects
Abdominal pain
Acne
Acute kidney injury
Anaemia
Arthralgia
Asthenia
Back pain
Bronchitis
Chest pain
Cough
Creatine phosphokinase increased
Decreased appetite
Dehydration
Diarrhoea
Dizziness
Dysgeusia
Dyspnoea
Elevated amylase levels
Elevated serum lipase
Erythema multiforme
Exfoliative rash
Fatigue
Febrile neutropenia
Fixed drug eruption
Gamma glutamyl transferase (GGT) increased
Gastritis
Gastro-intestinal haemorrhage
Granulocytopenia
Headache
Hepatic impairment
Hepatotoxicity
Hyperkalaemia
Hypersensitivity reactions including anaphylaxis
Hypertension
Hypophosphataemia
Increase in serum ALT/AST
Increased susceptibility to infection
Influenza
Leukopenia
Liver damage
Myalgia
Nasopharyngitis
Nausea
Neutropenia
Oedema
Pain
Pancreatitis
Pericardial effusion
Pericarditis
Photosensitivity
Pleural effusion
Pneumonia
Prolongation of QT interval
Pruritus
Pulmonary hypertension
Pulmonary oedema
Pyrexia
Rash
Reactivation of hepatitis B
Renal failure
Renal impairment
Respiratory failure
Respiratory tract infection
Serum bilirubin increased
Serum creatinine increased
Stevens-Johnson syndrome
Thrombocytopenia
Tinnitus
Toxic epidermal necrolysis
Tumour lysis syndrome
Urticaria
Vomiting
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: August 2019.
Reference Sources
Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 10th edition (2015) ed. Briggs, G., Freeman, R. Wolters Kluwer Health, Philadelphia.
Summary of Product Characteristics: Bosulif 100mg, 400mg and 500mg tablets. Pfizer Limited. Revised December 2020.
US National Library of Medicine. Toxicology Data Network. Drugs and Lactation Database (LactMed).
Available at: https://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT
Bosutinib. Last revised: 03 December 2018
Last accessed: 27 August 2019
Medscape UK | Univadis prescription drug monographs & interactions are based on FDB Multilex Content
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