Bosutinib

Bosutinib is a kinase inhibitor. Chronic myeloid leukaemia (CML) is driven by the abnormal BCR-ABL kinase formed by the Philadelphia chromosome, and bosutinib blocks this kinase. It also inhibits kinases of the Src family.

Mechanism of Action

• BCR-ABL inhibition: modelling studies indicate that bosutinib binds the kinase domain of BCR-ABL, the abnormal enzyme that promotes CML.
• Src-family kinases: it also inhibits Src, Lyn and Hck, while inhibiting the platelet-derived growth factor (PDGF) receptor and c-Kit only minimally.
• Laboratory activity: bosutinib inhibited the proliferation and survival of established CML cell lines, Ph+ acute lymphoblastic leukaemia cell lines and patient-derived primitive CML cells. It inhibited 16 of 18 imatinib-resistant forms of BCR-ABL expressed in mouse myeloid cell lines, but did not inhibit the T315I and V299L mutants.
• Other kinases: in vitro it also inhibits c-Fms, EphA and EphB receptors, Trk, Axl and Tec family kinases, some members of the ErbB family, the non-receptor kinase Csk, Ste20-family serine/threonine kinases and two calmodulin-dependent protein kinases.
• Exposure and response: both the likelihood of response and the likelihood of safety events were greater with higher exposure.
• Cardiac electrophysiology: in a study in healthy subjects, 500 mg with food did not prolong the QTc interval, even at supratherapeutic concentrations. QTc prolongation without arrhythmia has nevertheless been observed in patients (see Special Instructions).

Pharmacokinetics

• Absorption: absolute bioavailability 34% in healthy subjects (single 500 mg dose with food). Absorption is relatively slow, with a median time to peak of about 6 hours, and exposure rises in proportion to dose from 100 to 600 mg. At steady state on 400 mg the peak concentration was 127 ng/mL, the trough 68 ng/mL and the AUC 2,370 ng·h/mL; on 500 mg they were 171 ng/mL, 91 ng/mL and 3,150 ng·h/mL. Tablets and intact capsules give no clinically significant difference in the fed state, and capsule contents mixed with apple sauce or yoghurt give comparable exposure. Solubility depends on pH, and absorption falls when gastric pH is raised.
• Food effect: a high-fat meal raised the peak 1.8-fold and the AUC 1.7-fold for tablets compared with fasting; for capsules, exposure with food was about 1.5 to 1.6-fold higher. This is why bosutinib is taken with food.
• Distribution: volume of distribution 2,331 L after an intravenous dose, indicating extensive distribution to tissues outside the blood. Protein binding is 94% in vitro and 96% ex vivo, independent of concentration.
• Metabolism: mainly hepatic, through CYP3A4. The main circulating metabolites, oxydechlorinated (M2) and N-desmethylated (M5) bosutinib, reach about 19% and 25% of the parent exposure; all metabolites are inactive.
• Elimination: terminal half-life about 22.5 hours. After an oral radiolabelled dose, about 91% was recovered in faeces and about 3% in urine.
• Special populations: exposure rose in moderate and severe renal impairment (see Administration and Dosage). Hepatic impairment is a contraindication. Population analysis showed lower clearance, and so higher exposure, in Asian patients.

Bosutinib is indicated for Philadelphia chromosome-positive chronic myelogenous (myeloid) leukaemia (Ph+ CML):

• Newly diagnosed chronic phase (CP) Ph+ CML: adults and paediatric patients aged 6 years and older.
• Chronic phase Ph+ CML previously treated with one or more tyrosine kinase inhibitors: adults and paediatric patients aged 6 years and older, for whom imatinib, nilotinib and dasatinib are not considered appropriate treatment options.
• Accelerated phase (AP) and blast phase (BP) Ph+ CML previously treated with one or more tyrosine kinase inhibitors: adults, for whom imatinib, nilotinib and dasatinib are not considered appropriate treatment options.

• Hypersensitivity to bosutinib or to any of the excipients.
• Hepatic impairment.

In 1,372 adult leukaemia patients who received at least one dose of single-agent bosutinib (median treatment duration 26.3 months), 98.3% had at least one adverse reaction of any grade and 68.7% had at least one of grade 3 or 4. Reactions in at least 20% of patients were diarrhoea (80.4%), nausea (41.5%), abdominal pain (35.6%), thrombocytopenia (34.4%), vomiting (33.7%), rash (32.8%), fatigue (32.0%), increased ALT (28.0%), anaemia (27.2%), pyrexia (23.4%), increased AST (22.5%) and headache (20.3%). Grade 3 or 4 reactions in at least 5% were thrombocytopenia (19.7%), increased ALT (14.6%), neutropenia (10.6%), diarrhoea (10.6%), anaemia (10.3%), increased lipase (10.1%), increased AST (6.7%) and rash (5.0%).

Very common (≥1/10): nasopharyngitis, respiratory tract infection, thrombocytopenia, anaemia, neutropenia, decreased appetite, headache, dizziness, cough, dyspnoea, pleural effusion, diarrhoea, nausea, abdominal pain, vomiting, rash, arthralgia, back pain, fatigue, pyrexia, oedema, increased ALT, AST, lipase and blood creatinine.

Common (≥1/100 to <1/10): influenza, pneumonia, bronchitis, leukopenia, drug hypersensitivity, low blood phosphate, dehydration, raised potassium, altered taste, tinnitus, pericardial effusion, cardiac failure, cardiac ischaemia, hypertension, pulmonary hypertension, gastritis, gastrointestinal haemorrhage, acute pancreatitis, abnormal liver function, hepatotoxicity, pruritus, acne, urticaria, photosensitivity reaction, myalgia, acute kidney injury, renal failure, renal impairment, chest pain, pain, increased amylase, creatine phosphokinase, bilirubin and gamma-glutamyltransferase, QT prolongation on the electrocardiogram.

Uncommon (≥1/1,000 to <1/100): tumour lysis syndrome, febrile neutropenia, granulocytopenia, anaphylactic shock, pericarditis, respiratory failure, acute pulmonary oedema, liver injury, drug eruption, exfoliative rash, erythema multiforme, cutaneous vasculitis.

Not known: interstitial lung disease, Stevens–Johnson syndrome, toxic epidermal necrolysis.

Important serious reactions are liver toxicity, severe diarrhoea, myelosuppression, fluid retention, cardiovascular toxicity, decline in kidney function and severe skin reactions. They are described under Special Instructions.

• Strong CYP3A inhibitors (itraconazole, ketoconazole, posaconazole, voriconazole, clarithromycin, telithromycin, nefazodone, mibefradil, indinavir, lopinavir/ritonavir, nelfinavir, ritonavir, saquinavir, boceprevir, telaprevir, and grapefruit products including grapefruit juice): avoid. Ketoconazole raised the peak concentration of a single 100 mg dose of bosutinib 5.2-fold and the AUC 8.6-fold.
• Moderate CYP3A inhibitors (fluconazole, ciprofloxacin, erythromycin, diltiazem, verapamil, amprenavir, atazanavir, darunavir/ritonavir, fosamprenavir, aprepitant, crizotinib, imatinib): avoid. Aprepitant raised the peak 1.5-fold and the AUC 2.0-fold. If a strong or moderate inhibitor must be given, interrupting bosutinib or reducing its dose should be considered.
• Mild CYP3A inhibitors: use with caution, and choose an alternative with no or minimal CYP3A inhibition if possible.
• CYP3A inducers: strong inducers (for example carbamazepine, phenytoin, rifampicin, St John’s wort) and moderate inducers should be avoided, because they lower bosutinib concentrations.
• Domperidone and other QT-prolonging medicines: domperidone can prolong the QT interval and cause torsade de pointes, so it should be avoided with bosutinib and used only if other medicines are not effective, with an individual benefit–risk assessment and QTc monitoring. Caution is also needed with anti-arrhythmic medicines and other substances that may prolong the QTc.
• Medicines that raise gastric pH (such as proton pump inhibitors): because bosutinib’s solubility depends on pH and absorption falls when gastric pH rises, they may lower exposure. The SmPC (section 4.5) gives advice on such combinations.
• Medicines that can harm the kidneys (diuretics, ACE inhibitors, angiotensin receptor blockers, NSAIDs): increase the risk of renal dysfunction, so kidney function needs close monitoring.
• Oral contraceptives: vomiting or diarrhoea can stop them being fully absorbed and reduce their effect.
• Food and herbal products: avoid grapefruit and other foods that inhibit CYP3A, and avoid St John’s wort. Take bosutinib with food.

Bosutinib is taken by mouth once daily with food, at the doses below. Treatment in the clinical studies continued until disease progression or intolerance.

Recommended Dose

• Adults, newly diagnosed chronic phase Ph+ CML: 400 mg once daily.
• Adults, chronic, accelerated or blast phase Ph+ CML with resistance or intolerance to prior therapy: 500 mg once daily.
• Paediatric patients (6 years and older): 300 mg/m² body surface area once daily if newly diagnosed, and 400 mg/m² once daily if resistant or intolerant to prior therapy, by body surface area as follows. The dose can be made up by combining tablet and capsule strengths.
• Newly diagnosed: 0.55 to under 0.63 m², 200 mg; 0.63 to under 0.75 m², 200 mg; 0.75 to under 0.9 m², 250 mg; 0.9 to under 1.1 m², 300 mg; 1.1 m² or more, 400 mg (the maximum starting dose).
• Resistant or intolerant: 0.55 to under 0.63 m², 250 mg; 0.63 to under 0.75 m², 300 mg; 0.75 to under 0.9 m², 350 mg; 0.9 to under 1.1 m², 400 mg; 1.1 m² or more, 500 mg (the maximum starting dose).

Dose Escalation

• Adults resistant or intolerant to prior therapy: the dose can be raised to 600 mg once daily if the response is unsatisfactory or there are signs of progression, and there has been no grade 3 or 4 or persistent grade 2 adverse event.
• Adults with newly diagnosed chronic phase CML: the dose can be raised in 100 mg steps to a maximum of 600 mg once daily if BCR-ABL transcripts are not 10% or lower at month 3, there is no grade 3 or 4 adverse reaction at the time, and all grade 2 non-haematological toxicities have resolved to at least grade 1.
• Paediatric patients: with a body surface area under 1.1 m² and an insufficient response after 3 months, consider raising the dose in 50 mg steps up to 100 mg above the recommended dose; with 1.1 m² or more, in 100 mg steps as in adults. If the response is inadequate and the dose cannot be raised further, treatment is stopped. The maximum is 600 mg once daily in previously treated CML and 500 mg once daily in newly diagnosed CML.
• Doses above 600 mg/day have not been studied and should not be given.

Dose Adjustments for Side Effects

• Moderate or severe non-haematological toxicity: interrupt bosutinib and restart, once resolved, at a dose 100 mg lower once daily. Re-escalation to the previous dose can be considered. Doses below 300 mg/day have been used, but efficacy has not been established.
• Raised liver transaminases: if above 5 times the upper limit of normal (ULN), interrupt until they fall to 2.5 times ULN or lower, then resume at 400 mg once daily. If recovery takes longer than 4 weeks, consider stopping. If transaminases of 3 times ULN or more occur together with bilirubin above 2 times ULN and alkaline phosphatase below 2 times ULN, stop bosutinib.
• Diarrhoea of grade 3 or 4: interrupt, and resume at 400 mg once daily once it has fallen to grade 1 or lower.
• Neutropenia and thrombocytopenia: if the absolute neutrophil count falls below 1.0 × 10⁹/L and/or platelets below 50 × 10⁹/L, hold bosutinib until the count is at least 1.0 × 10⁹/L and platelets at least 50 × 10⁹/L. Resume at the same dose if recovery takes up to 2 weeks. If counts stay low for more than 2 weeks, reduce the dose by 100 mg on recovery (50 mg in children under 1.1 m²), and reduce by a further 100 mg (or 50 mg) if the cytopenia recurs.
• Children: non-haematological toxicity is managed as in adults, but with dose reductions of 50 mg for those under 1.1 m².

Special Populations

• Elderly (65 years and over): no specific dose recommendation; caution, because information is limited.
• Renal impairment: patients with serum creatinine above 1.5 times ULN were excluded from CML studies, and exposure rose in moderate and severe impairment. For newly diagnosed chronic phase CML in adults, the dose with food is 300 mg daily in moderate impairment (creatinine clearance 30 to 50 mL/min) and 200 mg daily in severe impairment (below 30 mL/min), and escalation to 400 mg or 300 mg daily respectively can be considered. For resistant or intolerant disease, it is 400 mg daily in moderate and 300 mg daily in severe impairment, with escalation to 500 mg or 400 mg respectively if the response is inadequate and there have been no severe or persistent moderate reactions.
• Hepatic impairment: contraindicated.
• Cardiac and gastrointestinal disorders: patients with uncontrolled or significant cardiac disease, or recent or ongoing clinically significant gastrointestinal disorders, were excluded from studies, so caution is needed.
• Children: safety and efficacy under 1 year are not established. Data under 6 years are too limited for dose recommendations.

Method of Administration and Missed Dose

• Film-coated tablets: swallow whole. Do not cut, crush, break or chew.
• Hard capsules: may be swallowed whole. For patients who cannot swallow a whole capsule, each capsule can be opened and the contents mixed with apple sauce or yoghurt. This is no substitute for a proper meal, so the dose must still be taken with food. The whole mixture is eaten at once without chewing and must not be stored. If it is not all swallowed, no extra dose is given and dosing resumes the next day. Recommended volumes: 200 mg, 20 mL; 250 mg, 25 mL; 300 mg and 350 mg, 30 mL; 400 mg, 35 mL; 500 mg, 45 mL.
• Missed dose: if a dose is missed by more than 12 hours, do not take an extra dose. Take the usual dose the next day.

Liver Function

Raised ALT and AST are associated with bosutinib in adults and children; more than 80% of first events came within the first 3 months. Liver function tests are done before treatment, monthly for the first 3 months and as clinically indicated. Raised transaminases with raised bilirubin may be an early sign of drug-induced liver injury. Management is by temporary withholding, dose reduction or discontinuation.

Diarrhoea and Vomiting

Diarrhoea and vomiting are very common and are treated with standard care, including an antidiarrhoeal or antiemetic medicine and fluid replacement, and if needed temporary withholding, dose reduction or discontinuation. Caution is needed in patients with a recent or ongoing clinically significant gastrointestinal disorder. Domperidone should be avoided (see Drug Interactions).

Myelosuppression

Anaemia, neutropenia and thrombocytopenia occur. Complete blood counts are done weekly for the first month and then monthly, or as clinically indicated.

Fluid Retention and Serum Lipase

• Fluid retention: pericardial effusion, pleural effusion, pulmonary oedema and peripheral oedema can occur in adults, and low-grade pericardial effusion and peripheral oedema in children. Patients are monitored and treated with standard care.
• Lipase: raised serum lipase has been seen. Caution is advised in patients with a history of pancreatitis; if raised lipase comes with abdominal symptoms, bosutinib is interrupted and pancreatitis excluded.
• Infections: bosutinib may predispose to bacterial, fungal, viral or protozoan infections.

Cardiovascular Toxicity and QT Interval

Cardiac failure and cardiac ischaemic events can occur. Failure was more frequent in previously treated patients, older patients and those with risk factors such as previous cardiac failure; ischaemic events were more common with coronary risk factors (diabetes, body mass index above 30, hypertension, vascular disorders). Patients are monitored for signs of cardiac failure and ischaemia.

QTc prolongation without arrhythmia has been seen. Bosutinib is used with caution in patients with a history or predisposition to QTc prolongation, uncontrolled or significant cardiac disease (recent myocardial infarction, congestive heart failure, unstable angina, clinically significant bradycardia) or taking QT-prolonging medicines. A baseline electrocardiogram is recommended, and low potassium or magnesium must be corrected before starting and monitored during treatment.

Kidney Function

Bosutinib can cause a clinically significant decline in kidney function in adults and children, with a fall in estimated glomerular filtration rate over time. Kidney function is assessed before treatment and monitored closely, particularly in patients with existing kidney problems or risk factors, including diuretics, ACE inhibitors, angiotensin receptor blockers and NSAIDs.

Asian Patients

Asian patients had lower clearance and higher exposure, so they should be monitored closely for adverse reactions, especially if the dose is raised.

Severe Skin Reactions and Photosensitivity

Bosutinib can cause severe skin reactions such as Stevens–Johnson syndrome and toxic epidermal necrolysis; it is stopped permanently if one occurs. Direct sunlight and ultraviolet radiation should be avoided or minimised because of photosensitivity, using protective clothing and a high-factor sunscreen.

Tumour Lysis Syndrome and Hepatitis B Reactivation

• Tumour lysis syndrome: clinically significant dehydration should be corrected and high uric acid treated before starting.
• Hepatitis B: reactivation has occurred in chronic carriers after BCR-ABL tyrosine kinase inhibitors, sometimes causing acute liver failure, liver transplantation or death. Patients are tested for hepatitis B infection before treatment; liver and hepatitis B specialists are consulted if serology is positive, and carriers are monitored during treatment and for several months afterwards.

Pregnancy, Contraception, Breastfeeding and Fertility

• Contraception: women of childbearing potential should use effective contraception during treatment and for at least 1 month after the last dose, and avoid becoming pregnant. Vomiting or diarrhoea may stop oral contraceptives being fully absorbed.
• Pregnancy: data are limited and animal studies showed reproductive toxicity. Bosutinib is not recommended in pregnancy or in women of childbearing potential not using contraception. A patient who becomes pregnant must be told of the potential hazard to the foetus.
• Breastfeeding: it is unknown whether bosutinib passes into human milk, though radioactivity from labelled bosutinib appeared in the milk of rats. A risk to the infant cannot be excluded, so breastfeeding should be stopped during treatment.
• Fertility: non-clinical findings suggest bosutinib may impair reproductive function and fertility. Men are advised to seek advice on sperm conservation before treatment.

Sodium

Each tablet or capsule contains less than 1 mmol (23 mg) of sodium, so the medicine is essentially sodium-free.

Effect on Driving

Bosutinib has no or negligible influence on the ability to drive and use machines. A patient who has dizziness, fatigue, visual impairment or another effect that could affect safe driving or machine use should refrain from these activities while it lasts.

• Film-coated tablets: no special storage conditions.
• Hard capsules: do not store above 30 °C. Keep in the original package to protect from light.

Keep out of the sight and reach of children.

• Film-coated tablets: 4 years.
• Hard capsules: 3 years.

Do not use after the expiry date on the pack.

Prescription only (Rx), subject to restricted medical prescription (Annex II B), on the prescription of a specialist experienced in treating leukaemia. Bosutinib is taken at home, so it is supplied to the patient or to the treating clinic on prescription.