Bosulif (Tablets) Instructions for Use

ATC Code

L01EA04 (Bosutinib)

Active Substance

Bosutinib

Clinical-Pharmacological Group

Antitumor drug. Protein kinase inhibitor

Pharmacotherapeutic Group

Antineoplastic agents; protein kinase inhibitors; BCR-ABL tyrosine kinase inhibitors

Pharmacological Action

Antitumor agent, kinase inhibitor. Bosutinib inhibits the pathological Ber-Abl kinase, which is responsible for the development of chronic myeloid leukemia (CML). It has been shown that Bosutinib binds to the kinase domain of Ber-Abl. Bosutinib is also an inhibitor of Src family kinases, including Src, Lyn, and Hck. Furthermore, Bosutinib has minimal inhibitory activity against PDGF and c-Kit receptors.

Pharmacokinetics

After a single oral dose of 500 mg bosutinib taken with food, absorption was relatively slow; the median time to reach C_max was 6 hours. The mean plasma C_max and AUC values were 112 ng/mL and 2740 ng×h/mL, respectively. The increase in bosutinib AUC and C_max over the dose range of 200 mg to 800 mg was dose-proportional. Food increased bosutinib C_max by 1.8-fold and bosutinib AUC by 1.7-fold compared to administration under fasting conditions. After 15 days of daily oral administration of 500 mg bosutinib with food in patients with CML, the mean C_max values were 200 ng/mL, and the mean AUC values were 3650 ng×h/mL.

After a single oral dose of 500 mg bosutinib taken with food, the mean apparent V_d was 7700 µL (2940 L), indicating extensive distribution of bosutinib into extravascular tissues. In vitro protein binding to human plasma proteins is 94%, independent of the active substance concentration.

In vitro and in vivo studies have shown that bosutinib is primarily metabolized in the liver in humans. After single and multiple doses of 400 mg or 500 mg bosutinib in humans, the main circulating metabolites in the bloodstream were oxydechlorinated (M2) and N-demethylated (M5) Bosutinib; bosutinib N-oxide (M6) was present in smaller amounts. The systemic exposure of the N-demethylated metabolite was 25% of the parent substance, and the oxydechlorinated metabolite was 19% of the parent substance. All three metabolites accounted for <5% of bosutinib activity when assessing free proliferation of Src-transformed fibroblasts. In feces, Bosutinib and N-demethylbosutinib were the main active substance-related components. In vitro studies using human liver microsomes have shown that the primary cytochrome P450 isoenzyme involved in the metabolism of bosutinib is CYP3A4. Flavin-containing monooxygenases (FMO1, FMO3, and FMO5) are capable of metabolizing Bosutinib to form its N-oxide.

After a single oral dose of 500 mg bosutinib taken with food, the mean terminal phase T_1/2 was 33.8 hours; the mean clearance (Cl/F) was 197 L/h. In patients who received a single oral dose of radioactively labeled [¹⁴C] Bosutinib, an average of 94.6% of the total administered dose of labeled unchanged substance was excreted over 9 days. The main route of excretion is via the intestine (91.3% of the administered dose); 3.29% of the administered dose is excreted by the kidneys. 75% of the administered dose was excreted within 96 hours. Renal excretion of unchanged bosutinib is low – approximately 1% of the administered dose.

Indications

Treatment of Philadelphia chromosome-positive chronic myeloid leukemia (Ph⁺ CML) in the chronic phase, accelerated phase, or blast crisis in cases of intolerance or resistance to prior therapy with imatinib, nilotinib, and dasatinib.

ICD codes

Dosage Regimen

Take a 500 mg dose orally once daily with food.

Continue therapy until disease progression or unacceptable toxicity occurs.

Administer the tablets with a meal to enhance absorption and minimize gastrointestinal upset.

For patients with mild, moderate, or severe hepatic impairment at baseline, use a lower starting dose.

For patients with severe renal impairment at baseline, use a lower starting dose.

If a dose is missed, take it if remembered on the same day. Skip the missed dose if it is not remembered until the next day; then resume the usual daily schedule.

Manage adverse reactions like diarrhea, nausea, or vomiting with standard supportive care, including antidiarrheal or antiemetic medications.

For persistent or severe adverse reactions, implement dose interruption, dose reduction, or therapy discontinuation.

Monitor liver function tests monthly for the first three months and as clinically indicated thereafter.

Perform complete blood counts weekly during the first month of therapy, then monthly or as clinically indicated.

Monitor for fluid retention, including pericardial and pleural effusion.

Assess electrolytes and correct hypokalemia and hypomagnesemia before initiating treatment.

Obtain an ECG at baseline and monitor periodically for QTc interval prolongation.

Avoid concomitant use with potent or moderate CYP3A inhibitors or inducers; if co-administration is unavoidable, consider a bosutinib dose reduction.

Use caution with proton pump inhibitors; consider short-acting antacids taken at a different time of day.

Adverse Reactions

Cardiovascular system Common – pericardial effusion.

Hearing organ Common – tinnitus.

Digestive system Very common – diarrhea, vomiting, abdominal pain (including upper and lower abdominal pain, abdominal discomfort, abdominal tenderness, GI pain), nausea; Common – gastritis, gastrointestinal bleeding (including gastric hemorrhage, upper gastrointestinal hemorrhage); Uncommon – acute pancreatitis.

Hepatobiliary system Common – hepatotoxicity (including toxic hepatitis, cytolytic hepatitis), impaired liver function; Uncommon – hepatic cell damage.

Laboratory parameters Very common – increased ALT, AST; Common – increased blood lipase, increased blood amylase, increased gamma-glutamyltransferase (GGT), increased plasma creatine phosphokinase, increased plasma bilirubin concentration, prolonged QT interval on electrocardiogram (ECG), increased plasma creatinine concentration.

Hematopoietic organs Very common – thrombocytopenia, anemia, neutropenia; Common – leukopenia; Uncommon – febrile neutropenia, granulocytopenia.

Immune system Common – drug hypersensitivity; Uncommon – anaphylactic shock.

Infectious and parasitic diseases Very common – infections (including upper and lower respiratory tract infections, viral respiratory infections); Common – pneumonia (including bronchopneumonia, primary atypical pneumonia), influenza, bronchitis, nasopharyngitis.

Metabolism Very common – decreased appetite; Common – hyperkalemia, hypophosphatemia, dehydration.

Nervous system Very common – headache; Common – dizziness, dysgeusia.

Respiratory system Very common – dyspnea, cough; Common – pleural effusion; Uncommon – acute pulmonary edema, respiratory failure, pulmonary hypertension.

Skin Very common – rash (including maculopapular rash, pruritic rash, generalized rash, papular rash); Common – urticaria, pruritus, acne; Uncommon – erythema multiforme, exfoliative rash, drug dermatitis.

Urinary system Common – renal failure (including acute).

Musculoskeletal system Very common – arthralgia; Common – back pain, myalgia.

Other Very common – fatigue (including malaise), pyrexia, edema (including facial edema, localized edema, peripheral edema); Common – asthenia, chest pain (including chest discomfort), pain.

Contraindications

Hypersensitivity to bosutinib; concomitant use with potent or moderate inhibitors or inducers of the CYP3A isoenzyme should be avoided; pregnancy, breastfeeding; children under 18 years of age.

Use with caution

Concomitant use with weak inhibitors or inducers of the CYP3A isoenzyme, P-glycoprotein substrates, proton pump inhibitors; in patients with a history of arrhythmias or factors predisposing to QTc interval prolongation, with uncontrolled or severe cardiovascular diseases, including recent myocardial infarction, congestive heart failure, unstable angina, or clinically significant bradycardia, and in patients taking medications that may cause QT interval prolongation (e.g., antiarrhythmic drugs and other substances that may cause QT interval prolongation), patients with gastrointestinal dysfunction (recent conditions or acute).

Use in Pregnancy and Lactation

Contraindicated during pregnancy and breastfeeding.

Pediatric Use

Contraindicated in children and adolescents under 18 years of age.

Geriatric Use

Use with caution in elderly patients to avoid the risk of exacerbation of chronic diseases.

Special Precautions

In patients receiving Bosutinib, liver function should be monitored monthly during the first 3 months of therapy and as clinically indicated. In case of increased AST and ALT activity, temporary discontinuation of bosutinib therapy, dose reduction, and/or complete withdrawal may be necessary.

Diarrhea, nausea, vomiting, and abdominal pain may develop during bosutinib therapy. Standard therapy, including antidiarrheal, antiemetic medications, and/or infusion therapy, is used for these adverse reactions. Additionally, temporary discontinuation of bosutinib therapy, dose reduction, and/or complete withdrawal of bosutinib may also be necessary.

The antiemetic drug domperidone may lead to QT interval prolongation and induce torsades de pointes ventricular tachycardia. Therefore, concomitant use of bosutinib and domperidone should be avoided. It may be used only if other drugs are ineffective. In this situation, the benefit-risk ratio for the patient should be assessed, and ECG monitoring for QT interval prolongation should be performed.

Patients with Ph⁺ CML who have received prior anticancer therapy should have a complete blood count performed once weekly during the first month of bosutinib therapy and then once monthly (or as clinically indicated).

In case of myelosuppression, temporary discontinuation of bosutinib therapy, dose reduction, and/or complete withdrawal may be necessary.

Therapy with bosutinib may be associated with fluid retention, including pericardial effusion, pleural effusion, pulmonary edema, and/or peripheral edema. Appropriate patient monitoring and, if necessary, standard therapy should be conducted. Additionally, for these adverse events, temporary discontinuation of bosutinib therapy, dose reduction, and/or complete withdrawal may be necessary.

In case of elevated plasma lipase accompanied by clinical symptoms, bosutinib should be discontinued and a diagnostic workup should be performed to rule out pancreatitis.

The use of bosutinib may predispose to the development of bacterial, fungal, viral, or protozoal infections.

Cases of QTc interval prolongation, recorded on ECG, without signs of arrhythmia have been reported. It is recommended to perform an ECG before starting therapy and periodically during therapy to monitor for QTc interval prolongation. Hypokalemia and hypomagnesemia must be corrected before starting therapy, and plasma potassium and magnesium levels should be monitored periodically during therapy.

Increased bosutinib exposure was observed in patients with impaired liver function. In patients with mild to severe hepatic impairment (at baseline), it is recommended to use bosutinib at a lower starting dose.

Increased bosutinib exposure was observed in patients with impaired renal function. In patients with severe renal impairment (at baseline), it is recommended to use bosutinib at a lower starting dose.

Effect on ability to drive and operate machinery

Patients who experience dizziness, fatigue, visual disturbances, or other adverse effects with a potential impact on the ability to drive a car or operate machinery while taking bosutinib should refrain from these activities for the entire duration of these adverse effects.

Drug Interactions

Concomitant use of bosutinib with potent inhibitors of the CYP3A isoenzyme (e.g., ritonavir, indinavir, nelfinavir, saquinavir, ketoconazole, itraconazole, voriconazole, posaconazole, troleandomycin, clarithromycin, telithromycin, mibefradil, nefazodone, conivaptan) or moderate inhibitors (e.g., fluconazole, darunavir, erythromycin, diltiazem, dronedarone, atazanavir, aprepitant, amprenavir, imatinib, verapamil, grapefruit products, tofisopam, ciprofloxacin, cimetidine) should be avoided, as this may lead to increased plasma concentrations of bosutinib.

Bosutinib should be used with caution concomitantly with weak inhibitors of the CYP3A isoenzyme.

If concomitant use of bosutinib with potent or moderate inhibitors of the CYP3A isoenzyme is necessary, a dose reduction of bosutinib should be considered.

When ketoconazole at a dose of 400 mg/day was co-administered with a single 100 mg dose of bosutinib, bosutinib C_max increased 5.2-fold and bosutinib AUC increased 8.6-fold compared to the corresponding values when bosutinib was administered as monotherapy (fasting).

Concomitant use of bosutinib with potent (e.g., rifampicin, phenytoin, carbamazepine, St. John’s wort preparations, rifabutin, phenobarbital) or moderate (e.g., bosentan, nafcillin, efavirenz, modafinil, etravirine) inducers of the CYP3A isoenzyme should be avoided.

Due to the sharp decrease in bosutinib exposure observed with its concomitant use with rifampicin, increasing the bosutinib dose when co-administered with potent or moderate inducers of the CYP3A isoenzyme is unlikely to adequately compensate for the decrease in exposure.

Bosutinib should be used with caution concomitantly with weak inducers of the CYP3A isoenzyme.

When a single 500 mg dose of bosutinib was co-administered with multiple doses of rifampicin at a daily dose of 600 mg, bosutinib exposure (plasma C_max and AUC) decreased by 14% and 6%, respectively, compared to the corresponding values when bosutinib was administered as a 500 mg monotherapy, after a meal.

Bosutinib should be used with caution during concomitant use of proton pump inhibitors. Short-acting antacids should be considered as an alternative to proton pump inhibitors; however, whenever possible, Bosutinib and antacids should be taken at different times (i.e., take Bosutinib in the morning and antacids in the evening). When a single 400 mg oral dose of bosutinib was co-administered with multiple 60 mg oral doses of lansoprazole (both medications taken on an empty stomach), bosutinib C_max and AUC decreased to 54% and 74%, respectively, relative to the values observed with bosutinib monotherapy at a dose of 400 mg.

Caution should be exercised when bosutinib is used concomitantly with P-glycoprotein substrates. An in vitro study suggested that bosutinib administration may lead to increased plasma concentrations of P-glycoprotein substrates (e.g., digoxin).

Caution should be exercised when using bosutinib in patients with or at risk of QT interval prolongation, including patients receiving antiarrhythmic drugs such as amiodarone, disopyramide, procainamide, quinidine, and sotalol, or other medications that may cause QT interval prolongation (e.g., chloroquine, halofantrine, clarithromycin, domperidone, haloperidol, methadone, and moxifloxacin).

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.