asciminib (Rx)

>10%

All grades

• Previously treated Ph+ CP-CML

  • Platelet count decreased (46%)
  • Triglycerides increased (44%)
  • Neutrophil count decreased (39%)
  • Hemoglobin decreased (35%)
  • Creatine kinase increased (27%)
  • Upper respiratory tract infection (26%)
  • ALT increased (23%)
  • Musculoskeletal pain (22%)
  • Headache (19%)
  • AST increased (19%)
  • Uric acid increased (19%)
  • Lymphocyte count decreased (18%)
  • Fatigue (17%)
  • Rash (17%)
  • Phosphate decreased (17%)
  • Lipase increased (14%)
  • Calcium corrected decreased (14%)
  • Creatinine increased (14%)
  • Hypertension (13%)
  • Arthralgia (12%)
  • Diarrhea (12%)
  • Nausea (12%)
  • Amylase increased (12%)
  • Bilirubin increased (12%)
  • Cholesterol increased (11%)

• Ph+ CP-CML with T3151 mutation

  • ALT increased (48%)
  • Potassium increased (48%)
  • Triglycerides increased (46%)
  • Lipase increased (46%)
  • Hemoglobin decreased (44%)
  • Neutrophil count decreased (44%)
  • Musculoskeletal pain (42%)
  • Lymphocyte count decreased (42%)
  • Phosphate decreased (40%)
  • Uric acid increased (40%)
  • AST increased (35%)
  • Calcium corrected decreased (33%)
  • Fatigue (31%)
  • Creatinine increased (31%)
  • Amylase increased (29%)
  • Nausea (27%)
  • Rash (27%)
  • Platelet count decreased (25%)
  • Bilirubin increased (23%)
  • Diarrhea (21%)
  • Vomiting (19%)
  • Headache (19%)
  • Arthralgia (17%)
  • Cough (15%)
  • Hemorrhage (15%)
  • Cholesterol increased (15%)
  • Pruritus (13%)
  • Hypertension (13%)
  • Upper respiratory tract infection (13%)
  • Alkaline phosphate increased (13%)

Grade 3 or 4

• Previously treated Ph+ CP-CML

  • Platelet count decreased (24%)
  • Neutrophil count decreased (17%)

• Ph+ CP-CML with T3151 mutation

  • Lipase increased (21%)
  • Neutrophil count decreased (15%)
  • Platelet count decreased (15%)

1-10%

• All grades

• Previously treated Ph+ CP-CML

  • Abdominal pain (10%)
  • Potassium decreased (10%)
  • Cough (<10%)
  • Dyspnea (<10%)
  • Pleural effusion (<10%)
  • Dizziness (<10%)
  • Peripheral neuropathy (<10%)
  • Edema (<10%)
  • Pyrexia (<10%)
  • Vomiting (<10%)
  • Constipation (<10%)
  • Dyslipidemia (<10%)
  • Decreased appetite (<10%)
  • Pruritus (<10%)
  • Urticaria (<10%)
  • Lower respiratory tract infection (<10%)
  • Influenza (<10%)
  • Urinary tract infection (<10%)
  • Pneumonia (<10%)
  • Hemorrhage (<10%)
  • Arrhythmia (including electrocardiogram QT prolonged) (<10%)
  • Palpitations (<10%)
  • Cardiac failure congestive (<10%)
  • Vision blurred (<10%)
  • Dry eye (<10%)
  • Hypothyroidism (<10%)
  • Febrile neutropenia (<10%)

• Ph+ CP-CML with T3151 mutation

  • Constipation (<10%)
  • Pancreatitis (<10%)
  • Pyrexia (<10%)
  • Dizziness (<10%)
  • Peripheral neuropathy (<10%)
  • Pneumonia (<10%)
  • Lower respiratory tract infection (<10%)
  • Dyspnea (<10%)
  • Pleural effusion (<10%)
  • Dry eye (<10%)
  • Vision blurred (<10%)
  • Arrhythmia (<10%)
  • Palpitations (<10%)
  • Cardiac failure congestive (<10%)
  • Decreased appetite (<10%)
  • Dyslipidemia (<10%)
  • Urticaria (<10%)

Grade 3 or 4

• Previously treated Ph+ CP-CML

  • Hypertension (6%)
  • Uric acid (6%)
  • Phosphate decreased (6%)
  • Triglycerides increased (5%)
  • Lipase increased (3.9%)
  • Musculoskeletal pain (2.6%)
  • Creatinine kinase increased (2.6%)
  • Hemoglobin decreased (2%)
  • Lymphocyte count decreased (2%)
  • AST increased (1.9%)
  • Headache (1.9%)
  • Amylase increased (1.3%)

• Ph+ CP-CML with T3151 mutation

  • Amylase increased (10%)
  • Abdominal pain (8%)
  • Hypertension (8%)
  • Vomiting (6%)
  • Phosphate decreased (6%)
  • ALT increased (6%)
  • Edema (4.2%)
  • Musculoskeletal pain (4.2%)
  • Uric acid increased (4.2%)
  • Hemoglobin decreased (4.2%)
  • Lymphocyte count decreased (4.2%)
  • Fatigue (2.1%)
  • Diarrhea (2.1%)
  • Hemorrhage (2.1%)
  • Headache (2.1%)
  • Potassium increased (2.1%)
  • Triglycerides increased (2.1%)
  • AST increased (2.1%)

<1%

Grade 3 or 4

• Previously treated Ph+ CP-CML

  • Upper respiratory tract infection (0.6%)
  • Fatigue (0.6%)
  • Rash (0.6%)
  • Nausea (0.6%)
  • ALT increase (0.6%)

Postmarketing Reports

Hypersensitivity

Contraindications

None

Cautions

Thrombocytopenia, neutropenia, and anemia occurred; perform complete blood cell counts every 2 weeks for the first 3 months of treatment and monthly thereafter or as clinically indicated; monitor for signs and symptoms of myelosuppression; advise patients to immediately report fever, any suggestion of infection, or signs or symptoms suggestive of bleeding or easy bruising

Hypertension occurred; monitor and manage hypertension using standard antihypertensive therapy during treatment as clinically indicated; advise patients to contact healthcare provider for elevated blood pressure or if symptoms of hypertension occur including confusion, headache, dizziness, chest pain, or shortness of breath

Hypersensitivity reactions (eg, rash, edema, bronchospasm) reported; monitor for signs and symptoms of hypersensitivity and initiate appropriate treatment as clinically indicated

Based on findings from animal studies and its mechanism of action, fetal harm may occur when administered to pregnant females

Pancreatitis

• Pancreatitis reported
• Assess serum lipase and amylase levels monthly during treatment or as clinically indicated; monitor for signs and symptoms of pancreatic toxicity
• Perform more frequent monitoring in patients with history of pancreatitis
• If lipase and amylase elevation are accompanied by abdominal symptoms, temporarily withhold therapy, and consider appropriate diagnostic tests to exclude pancreatitis
• Inform patients to report to healthcare professional symptoms of pancreatitis, including nausea, vomiting, severe abdominal pain, or abdominal discomfort

Cardiovascular toxicity

• Cardiovascular toxicity (including ischemic cardiac and CNS conditions, arterial thrombotic and embolic conditions) and cardiac failure occurred
• Cardiovascular toxicity occurred in patients with preexisting cardiovascular conditions or risk factors, and/or prior exposure to multiple TKIs
• Arrhythmia, including QTc prolongation, occurred
• Monitor patients with history of cardiovascular risk factors for cardiovascular signs and symptoms; initiate appropriate treatment as clinically indicated
• Cardiac electrophysiology testing showed asciminib does not cause a large mean increase in QTc interval (ie, >20 msec) at maximum dose (200 mg BID); based on available clinical data, small mean QTc increase (<10 msec) cannot be excluded

Drug interaction overview

• CYP3A4 substrate
• Inhibitor of CYP3A4, CYP2C9, and P-glycoprotein (P-gp)

• Strong CYP3A4 inhibitors

  • Closely monitor for adverse reactions, especially in patients treated at 200 mg q12hr
  • Strong CYP3A4 inhibitor increases both plasma concentrations and risk of toxicities of asciminib

• Itraconazole oral solution containing hydroxypropyl-β-cyclodextrin

  • Avoid coadministration
  • Itraconazole oral solution containing hydroxypropyl-β-cyclodextrin decreases asciminib plasma concentration and efficacy

• Sensitive CYP3A4 substrates

  • 80 mg/day dosing: Closely monitor for adverse reactions
  • 200 mg q12hr dosing: Avoid coadministration
  • Asciminib increases plasma levels of sensitive CYP3A4 substrates and risk of adverse reactions of these substrates

• Sensitive CYP2C9 substrates

  • Avoid coadministration
  • 80 mg/day-dosing: If coadministration unavoidable, consider reducing CYP2C9 substrate dosage as recommended in its prescribing information
  • 200 mg q12hr-dosing: If coadministration unavoidable, consider alternative therapy with non-CYP2C9 substrate
  • Asciminib increases plasma levels and risk of adverse reactions of sensitive CYP2C9 substrates

• Sensitive P-gp substrates

  • Closely monitor for adverse reactions of P-gp substrates
  • Asciminib increases the plasma concentrations and risk of adverse reactions of P-gp substrates

Pregnancy

Based on animal studies and the mechanism of action, embryofetal harm may occur when administered to pregnant females

There are no available data on use in pregnant females to evaluate any drug-associated risks

Verify pregnancy status of females of reproductive potential before initiating therapy

Contraception

• Females of reproductive potential: Use effective contraception during treatment and for 1 week after last dose

Infertility

• Based on animal studies, fertility may be impaired in females of reproductive potential; reversibility on the effect on fertility is unknown

Animal data

• Pregnant rats

  • Maternal toxicity occurred at 600 mg/kg/day, resulting in early termination of the dose group
  • Adverse embryofetal findings were observed at 25 and 150 mg/kg; no maternal toxicities occurred
  • Increases in fetal weights at 25 and 150 mg/kg/day were observed
  • Malformations were evident at 150 mg/kg and included cleft palate, anasarca (edema), and cardiac abnormalities

• Pregnant rabbits

  • Maternal toxicity occurred at 300 mg/kg/day, resulting in early termination of the dose group
  • Adverse embryofetal findings were observed at 50 mg/kg; no maternal toxicities occurred; findings include increases in early resorptions and postimplantation loss, decreases in number of live fetuses, and cardiac malformations

Lactation

There are no data on presence of asciminib or its metabolites in human milk, effects on breastfed infants, or effects on milk production

Advise females not to breastfeed during treatment and for 1 week after last dose

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

ABL/BCR-ABL1 tyrosine kinase inhibitor

Binds to ABL myristoyl pockets, which inhibits the ABL1 kinase activity of the BCR-ABL1 fusion protein

Absorption

Peak plasma time: 2.5 hr

Steady-state reached by 3 days

Peak plasma concentration

• 80 mg qDay: 1,781 ng/mL
• 40 mg q12hr: 793 ng/mL
• 200mg q12hr: 5,642 ng/mL

AUC

• 80 mg qDay: 15,112 ng⋅hr/mL
• 40 mg q12hr: 5,262 ng⋅hr/mL
• 200mg q12hr: 37,547 ng⋅hr/mL

Accumulation ratio

• 80 mg qDay: 1.3
• 40 mg q12hr: 1.65
• 200mg q12hr: 1.92

Effect of food

• High-fat meal (1000 calories, 50% fat): AUC and Cmax decreased by 62% and 68%
• Low-fat meal (400 calories, 25% fat): AUC and Cmax decreased by 30% and 35%

Distribution

• Vd (steady-state): 151 L
• Asciminib is the main circulating component in plasma (93% of administered dose)
• Protein bound: 97%

Metabolism

Metabolized by CYP3A4-mediated oxidation, UGT2B7- and UGT2B17-mediated glucuronidation

Elimination

Clearance: 6.7 L/hr (40 mg q12hr or 80 mg qDay); 4.1 L/hr (200 mg q12hr)

Half-life: 5.5 hr (40 mg q12hr or 80 mg qDay); 9 hr (200 mg q12hr)

Excretion: Feces (80% [57% unchanged]), urine (11% [2.5% unchanged])

Eliminated by biliary secretion via breast cancer–resistant protein

Oral Administration

Take without food

Avoid eating for at least 2 hr before and 1 hr after taking a dose

Once-daily dosing: Administer orally about the same time each day

Swallow tablets whole; do NOT break, crush, or chew

Missed dose

• Once-daily dosing regimen: If dose is missed by >12 hr, skip dose and take the next dose as scheduled
• Twice-daily dosing regimen: If dose is missed by >6 hr, skip dose and take the next dose as scheduled

Storage

Tablets: Store at 20-25ºC (68-77ºF); excursions permitted to 15-30ºC (59-86ºF)

Dispense and store in original container to protect from moisture