Asciminib (Monograph)

Brand name: Scemblix
Drug class: Antineoplastic Agents
Chemical name: N-[4-[chloro(difluoro)methoxy]phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamide
Molecular formula: C₂₀H₁₈ClF₂N₅O₃
CAS number: 1492952-76-7

Medically reviewed by Drugs.com on Nov 30, 2022. Written by ASHP.

Introduction

Antineoplastic agent; a kinase inhibitor.

Uses for Asciminib

Philadelphia Chromosome-Positive Chronic Myeloid Leukemia

Treatment of Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in adults in the chronic phase of the disease who were previously treated with ≥2 tyrosine kinase inhibitors (TKIs). The accelerated approval of asciminib for this indication is based on major molecular response (MMR); continued approval may be contingent upon verification of clinical benefit in a confirmatory trial(s).

Currently available TKIs recommended for first-line treatment of chronic phase CML include dasatinib, imatinib, and nilotinib. Asciminib may provide an additional option in the resistant and intolerant setting.

Philadelphia Chromosome-Positive Chronic Myeloid Leukemia with T315I Mutation

Treatment of chronic phase Ph+ CML in adults with the T315I mutation.

Ponatinib is generally considered the drug of choice in patients with CML and the T315I mutation. It is not clear due to its recent approval where asciminib will be positioned among other available TKIs.

Asciminib Dosage and Administration

General

Pretreatment Screening

Verify pregnancy status of females of reproductive potential prior to starting treatment.

Patient Monitoring

Perform CBC every 2 weeks for the first 3 months of treatment and monthly thereafter or as clinically indicated.
Assess serum lipase and amylase levels monthly during treatment, or as clinically indicated. Monitor patients for signs and symptoms of pancreatic toxicity. Perform more frequent monitoring in patients with a history of pancreatitis.
Monitor and manage hypertension using standard antihypertensive therapy during treatment as clinically indicated.
Monitor patients for signs and symptoms of hypersensitivity reactions and initiate appropriate treatment as clinically indicated.
Monitor patients with a history of cardiovascular risk factors for signs and symptoms of cardiovascular toxicity (e.g., ischemic cardiac and CNS conditions, arterial thromboembolic conditions, cardiac failure).

Administration

Oral Administration

Administer orally without food. Avoid food for at least 2 hours before and 1 hour after taking asciminib.

Swallow tablets whole. Do not break, crush, or chew the tablets.

For once daily regimens, if a dose of asciminib is missed by more than 12 hours, skip the dose and take the next dose as scheduled. For twice daily regimens, if a dose is missed by more than 6 hours, skip the missed dose and take the next dose as scheduled.

Dosage

Dosage of asciminib hydrochloride is expressed in terms of asciminib.

Adults

Chronic Phase Ph+ CML in Patients Previously Treated with 2 or more TKIs

Oral

80 mg orally once daily without food at approximately the same time each day or 40 mg twice daily at approximately 12-hour intervals. Continue treatment as long as clinical benefit is observed or until unacceptable toxicity occurs.

Chronic Phase Ph+ CML in Patients with the T315I Mutation

Oral

200 mg orally twice daily without food at approximately 12-hour intervals.

Dosage Modification for Adverse Reactions

If adverse reactions occur during asciminib therapy, dosage reduction, interruption, and/or permanent discontinuance of the drug may be necessary. For recommended dosage reductions for adverse events, see Table 1, and for recommended interventions for specific adverse events see Table 2.

Table 1: Recommended Dosage Reductions for Asciminib for Adverse Reactions1
Dosage Reduction	Dosage for Chronic Phase CML in Patients Previously Treated with ≥2 TKIs	Dosage for Chronic Phase CML in Patients with T315I mutation
First	40 mg once daily OR 20 mg twice daily	160 mg twice daily
Subsequent	Permanently discontinue asciminib in patients unable to tolerate 40 mg once daily OR 20 mg twice daily	Permanently discontinue asciminib in patients unable to tolerate 160 mg twice daily

Based on Common Terminology Criteria for Adverse Events (CTCAE) v 4.03.

Table 2: Recommended Asciminib Dosage Modifications for the Management of Adverse Reactions1
Adverse Reaction	Dosage Modification
Thrombocytopenia and/or neutropenia
Absolute neutrophil count (ANC) <100,000/mm³ and/or platelet count <50,000/mm³	Withhold drug until ANC resolves to ≥100,000/mm³ and/or platelet count ≥50,000/mm³ If resolved within 2 weeks, resume asciminib at starting dosage If resolved after more than 2 weeks, resume asciminib at reduced dosage For severe, recurrent thrombocytopenia and/or neutropenia, withhold asciminib until ANC recovers to ≥100,000/mm³ and platelet count ≥50,000/mm³, then resume at reduced dosage
Asymptomatic amylase and/or lipase elevation
Elevation >2 × upper limit of normal (ULN)	Withhold drug until resolves to <1.5 × ULN If resolved, resume asciminib at a reduced dosage; if events reoccur at the reduced dosage, permanently discontinue therapy If not resolved, permanently discontinue asciminib; perform diagnostic workup to exclude pancreatitis
Nonhematologic adverse reactions
Grade 3 or higher	Withhold drug until recovery to grade ≤1 If resolved, resume asciminib at reduced dosage If not resolved, permanently discontinue asciminib

Special Populations

Hepatic Impairment

No dosage adjustment required for patients with mild (total bilirubin ≤ ULN and AST > ULN or total bilirubin >1–1.5 times ULN and any AST) to severe (total bilirubin >3 times ULN and any AST) hepatic impairment.

Renal Impairment

No dosage adjustment required for patients with mild to severe renal impairment (eGFR 15–89 mL/min/1.73 m²) and not requiring dialysis.

Geriatric Patients

No specific dosage recommendation.

Cautions for Asciminib

Contraindications

None.

Warnings/Precautions

Myelosuppression

Thrombocytopenia, neutropenia, and anemia can occur.

Perform CBC every 2 weeks for the first 3 months of treatment and monthly thereafter or as clinically indicated. Monitor patients for signs and symptoms of myelosuppression.

Based on the severity of thrombocytopenia and/or neutropenia, reduce dose, temporarily withhold, or permanently discontinue asciminib.

Pancreatic Toxicity

Pancreatitis reported. Asymptomatic elevation of serum lipase and amylase also have occurred.

Assess serum lipase and amylase levels monthly during treatment with asciminib, or as clinically indicated. Monitor patients for signs and symptoms of pancreatic toxicity. Perform more frequent monitoring in patients with a history of pancreatitis. If lipase and amylase elevations are accompanied by abdominal symptoms, temporarily withhold asciminib and consider appropriate diagnostic tests to exclude pancreatitis.

Based on the severity of lipase and amylase elevation, reduce dose, temporarily withhold, or permanently discontinue asciminib.

Hypertension

Hypertension reported.

Monitor and manage hypertension using standard antihypertensive therapy during treatment with asciminib as clinically indicated; for grade 3 or higher hypertension, temporarily withhold, reduce dose, or permanently discontinue asciminib depending on persistence of hypertension.

Hypersensitivity

Hypersensitivity, including rash, edema, and bronchospasm, reported.

Monitor patients for signs and symptoms of hypersensitivity and initiate appropriate treatment as clinically indicated; for grade 3 or higher hypersensitivity reactions, temporarily withhold, reduce dose, or permanently discontinue asciminib depending on hypersensitivity persistence.

Cardiovascular Toxicity

Cardiovascular toxicity (including ischemic cardiac and CNS conditions, arterial thrombotic and embolic conditions) and cardiac failure reported. Cardiovascular toxicity occurred in patients with pre-existing cardiovascular conditions or risk factors, and/or prior exposure to multiple TKIs.

Arrhythmia, including QT_c prolongation, also have occurred.

Monitor patients with a history of cardiovascular risk factors for cardiovascular signs and symptoms. Initiate appropriate treatment as clinically indicated; for grade 3 or higher cardiovascular toxicity, temporarily withhold, reduce dose, or permanently discontinue asciminib depending on cardiovascular toxicity persistence.

Fetal/Neonatal Morbidity and Mortality

Based on findings from animal studies and its mechanism of action, asciminib can cause fetal harm.

Verify pregnancy status of females of reproductive potential prior to starting treatment. (See Pregnancy under Cautions.)

Specific Populations

Pregnancy

Based on findings from animal studies and the mechanism of action, asciminib can cause embryo-fetal harm. No available data on asciminib use in pregnant women. Animal reproduction studies demonstrated structural abnormalities, embryo-fetal mortality, and alterations in growth.

Advise patients of potential risk to fetus. (See Females and Males of Reproductive Potential under Cautions.)

Lactation

No data on the presence of asciminib or its metabolites in human milk, the effects on the breastfed child, or milk production.

Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with asciminib and for 1 week after the last dose.

Females and Males of Reproductive Potential.

Verify pregnancy status prior to starting treatment. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Females of reproductive potential should use effective contraception during treatment and for 1 week after the last dose.

Based on findings in animals, asciminib may impair fertility in females of reproductive potential. The reversibility of the effect on fertility is unknown.

Pediatric Use

Safety and efficacy in pediatric patients not established.

Geriatric Use

Overall, no differences in safety or efficacy observed between patients ≥65 years of age compared to younger patients. Insufficient experience in patients ≥75 years of age to assess whether there are differences in safety or efficacy.

Hepatic Impairment

Changes in exposure not clinically important; no dosage adjustment required.

Renal Impairment

Changes in exposure not clinically important; no dosage adjustment required.

Common Adverse Effects

Most common adverse reactions (≥ 20%) are upper respiratory tract infections, musculoskeletal pain, fatigue, nausea, rash, and diarrhea.

Most common laboratory abnormalities (≥ 20%) are decreased platelet count, increased triglycerides, decreased neutrophil count, decreased hemoglobin, increased creatine kinase, increased alanine aminotransferase, increased lipase, and increased amylase.

Drug Interactions

Metabolized principally by CYP isoenzyme 3A4 (CYP3A4) and UDP-glucuronosyltransferase (UGT) isoenzymes 2B7 (UGT2B7), and UGT2B17. Eliminated by biliary secretion via breast-cancer resistance protein (BCRP).

Asciminib is a substrate of CYP3A4, BCRP, and P-glycoprotein (P-gp), and is an inhibitor of CYP3A4, CYP2C9, P-gp, BCRP, organic anion transporter polypeptide (OATP)1B1, OATP1B3, and organic cation transporter (OCT)1.

Drugs Affecting Hepatic Microsomal Enzymes

Strong inhibitors of CYP3A4: Increased C_max and AUC of asciminib. Closely monitor for adverse reactions during concomitant use of asciminib at 200 mg twice daily.

Strong inducers of CYP3A: Effects of concomitant use not fully characterized.

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP3A4: Increased C_max and AUC of the CYP3A4 substrate, which may increase the risk of adverse reactions of the substrate. Closely monitor for adverse reactions during concomitant use of asciminib at 80 mg total daily dose with certain CYP3A4 substrates where minimal concentration changes may lead to serious adverse reactions. Avoid use of asciminib at 200 mg twice daily with certain CYP3A4 substrates where minimal concentration changes may lead to serious adverse reactions.

Substrates of CYP2C9: Increased C_max and AUC of the CYP2C9 substrate, which may increase the risk of adverse reactions of the substrate. Avoid concomitant use of asciminib at all recommended dosages with CYP2C9 substrates where minimal concentration changes may lead to serious adverse reactions. If concomitant use is unavoidable with asciminib at a total daily dose of 80 mg, reduce the CYP2C9 substrate dosage as recommended in its prescribing information. If concomitant use is unavoidable with asciminib 200 mg twice daily, consider alternative therapy with a non-CYP2C9 substrate.

Specific Drugs

Drug	Interaction	Comments
Clarithromycin	Increase C_max and AUC of asciminib	Closely monitor for adverse reactions with concomitant use of asciminib 200 mg twice daily
Imatinib	Increased C_max and AUC of asciminib administered at a dose of 40 mg; change in exposure not considered clinically meaningful Concomitant use of imatinib with asciminib 200 mg twice daily not fully characterized
Itraconazole	Concomitant use with itraconazole oral solution containing hydroxypropyl-β-cyclodextrin decreased C_max and AUC of asciminib; concomitant use of oral products containing hydroxypropyl-β-cyclodextrin with asciminib other than itraconazole oral solution has not been fully characterized	Avoid concomitant use at all recommended asciminib dosages
Midazolam	Increased C_max and AUC of midazolam by 17% and 24%, respectively, following a dose of asciminib 80 mg daily Increased peak C_max and AUC of midazolam by 58% and 88%, respectively, following asciminib 200 mg twice daily	Closely monitor for adverse reactions during concomitant use of asciminib at 80 mg total daily dose Avoid use with asciminib 200 mg twice daily
Quinidine	No clinically significant differences in pharmacokinetics of asciminib observed
Rabeprazole	No clinically significant differences in pharmacokinetics of asciminib observed
Warfarin	Increased C_max and AUC of S-warfarin by 8% and 41%, respectively, with asciminib 40 mg twice daily Increased C_max and AUC of S-warfarin by 4% and 52%, respectively, with asciminib 80 mg once daily Increased C_max and AUC of S-warfarin by 7% and 314%, respectively, following asciminib 200 mg twice daily	Avoid concomitant use If concomitant use of asciminib 80 mg daily dose is unavoidable, reduce warfarin dosage as clinically indicated If concomitant use of asciminib 200 mg twice daily is unavoidable, consider alternative therapy with a non-CYP2C9 substrate

Asciminib Pharmacokinetics

Absorption

Peak plasma concentrations attained at median of 2.5 hours (range 2–3 hours).

Exhibits slightly greater than dose-proportional pharmacokinetics at steady state across the dose range of 10–200 mg administered once or twice daily.

Food

High-fat meal decreased the C_max and AUC of asciminib by 68% and 62%, respectively; low-fat meal decreased C_max and AUC by 35% and 30%, respectively.

Distribution

Extent

Not known if excreted into human milk.

Plasma Protein Binding

Approximately 97%.

Elimination

Metabolism

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

Elimination Route

Approximately 80% (57% unchanged drug) and 11% (2.5% unchanged) of radiolabeled dose recovered in feces and urine, respectively.

Eliminated by biliary secretion via BCRP.

Half-life

5.5 hours with dosage of 40 mg twice daily or 80 mg once daily; 9 hours with dosage of 200 mg twice daily.

Special Populations

No clinically significant differences in pharmacokinetics based on sex, age (range 20–88 years), race, or body weight (range 42–184 kg).

Stability

Storage

Oral

Tablets

Store at 20–25°C (excursions permitted between 15–30°C).

Actions

Asciminib is an ABL/BCR-ABL1 tyrosine kinase inhibitor. Asciminib inhibits the ABL1 kinase activity of the BCR-ABL1 fusion protein, by binding to the ABL myristoyl pocket. In studies conducted in vitro or in animal models of CML, asciminib showed activity against wild-type BCR-ABL1 and several mutant forms of the kinase, including the T315I mutation.

Advice to Patients

Advise the patient to read the FDA-approved patient labeling (Patient Information).
Inform patients of the possibility of developing low blood cell counts. Advise patients to immediately report fever, any suggestion of infection, or signs or symptoms suggestive of bleeding or easy bruising.
Inform patients of the possibility of developing pancreatitis that may accompany nausea, vomiting, severe abdominal pain, or abdominal discomfort, and promptly report these symptoms.
Inform patients of the possibility of developing hypertension. Advise patients to contact their healthcare provider for elevated blood pressure or if symptoms of hypertension occur including confusion, headache, dizziness, chest pain, or shortness of breath.
Advise the patient to discontinue asciminib and seek immediate medical attention if any signs or symptoms of a hypersensitivity reaction, such as rash, edema, or bronchospasm occur.
Inform patients of the possibility of the occurrence of cardiovascular toxicity, especially those with a history of cardiovascular risk factors. Advise patients to immediately contact their healthcare provider or get medical help if they develop cardiovascular signs and symptoms.
Advise females to inform their healthcare provider if they are pregnant or become pregnant. Inform female patients of the potential risk to a fetus.
Advise females of reproductive potential to use effective contraception during treatment and for 1 week after receiving the last dose of asciminib.
Advise women not to breastfeed during treatment with asciminib and for 1 week after the last dose.
Advise patients that asciminib and certain other medicines, including OTC or herbal supplements, can interact with each other and may alter the effects of asciminib.
Advise patients to take asciminib exactly as prescribed and not to change their dose or schedule or to stop taking asciminib unless they are told to do so by their healthcare provider.
Advise patients to take asciminib orally without food. Advise patients to avoid food for at least 2 hours before and 1 hour after taking asciminib. Asciminib tablets should be swallowed whole. Patients should not break, crush, or chew the tablets.
Advise patients that if they take asciminib once daily and miss a dose by more than 12 hours to skip the missed dose. Advise patients that if they take asciminib twice daily and miss a dose by more than 6 hours to skip the missed dose. Advise patients to take the next dose as scheduled.
Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.
Importance of informing patients of other important precautionary information.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.