BOSUTINIB PFIZER 400 MG FILM-COATED TABLETS

Indications

• Chronic phase Philadelphia chromosome-positive chronic myeloid leukaemia
• Imatinib-resistant CML

Dosage

Adults: 400 mg once daily; consult product literature for specific dosing adjustments based on side effects or treatment response.

Mechanism of action

Bosutinib inhibits the BCR-ABL kinase, which promotes the development of chronic myeloid leukaemia (CML). It effectively inhibits 16 of 18 imatinib-resistant forms of BCR-ABL kinase expressed in murine myeloid cell lines. Additionally, it acts as an inhibitor of Src-family kinases including Src, Lyn, and Hck.

Pharmacodynamics

Clinical studies indicate that higher exposure to bosutinib correlates with a greater likelihood of therapeutic response, although the time course of this pharmacodynamic effect is not fully characterized. Importantly, bosutinib does not significantly prolong the QT interval when administered with ketoconazole, a strong CYP3A inhibitor.

Pharmacokinetics

Bosutinib has a molecular formula of C26H29Cl2N5O3. It undergoes hepatic metabolism and is primarily eliminated via the liver. Dosage adjustments may be necessary in patients with hepatic impairment due to increased drug exposure.

Contra-indications

• Severe hepatic impairment
• History of pancreatitis
• History of QT prolongation

Adverse effects

• Anaemia
• Decreased appetite
• Arthralgia
• Asthenia
• Chest discomfort
• Cough
• Dehydration
• Diarrhea
• Dizziness
• Dyspnea
• Electrolyte imbalance
• Fever
• Gastritis
• Gastrointestinal discomfort
• Hemorrhage
• Headache
• Hepatic disorders
• Skin reactions
• Taste altered
• Vomiting
• Facial paralysis
• Pancreatitis
• Respiratory disorders
• Vision disorders
• Retinal occlusion

Interactions

• Grapefruit juice (severe - increases exposure)
• NNRTIs (severe - decreases exposure)
• St John's Wort (severe - decreases exposure)
• Dronedarone (moderate - increases exposure)
• Belzutifan (moderate - decreases exposure)
• Cenobamate (moderate - decreases exposure)
• Cobicistat (moderate - increases exposure)
• Crizotinib (moderate - increases exposure)
• Idelalisib (moderate - increases exposure)
• Imatinib (moderate - increases exposure)

Precautions

• Monitor liver function before and during treatment
• Assess left ventricular ejection fraction before treatment
• Monitor for visual disturbances
• Monitor blood pressure before and during treatment
• Monitor creatine kinase and creatinine levels monthly during the first 6 months of treatment
• Patients with a history of cardiac disease or hepatitis B infection should be closely monitored

Pregnancy

Manufacturer advises to avoid use due to potential toxicity in animal studies.

Breast-feeding

Manufacturer advises to avoid due to lack of information on safety.

Storage

Store at room temperature, protected from moisture and light.

Formulations

• Tablets: 100 mg
• Tablets: 400 mg

Mechanism of action

Bosutinib is a tyrosine kinase inhibitor. Bosutinib inhibits the BCR-ABL kinase that promotes CML; it is also an inhibitor of Src-family kinases including Src, Lyn, and Hck. Bosutinib inhibited 16 of 18 imatinib-resistant forms of BCR-ABL kinase expressed in murine myeloid cell lines. Bosutinib did not inhibit the T315I and V299L mutant cells.

Pharmacodynamics

A greater likelihood of response and a greater likelihood of safety events were observed with higher bosutinib exposure in clinical studies. The time course of bosutinib pharmacodynamic response has not been fully characterized. At a single oral dose of 500 mg bosutinib with ketoconazole (a strong CYP3A inhibitor), bosutinib does not prolong the QT interval to any clinically relevant extent.