Asciminib Hydrochloride (Monograph)
Brand name: Scemblix
Drug class: Antineoplastic Agents
Introduction
Antineoplastic agent; a kinase inhibitor.1
Uses for Asciminib Hydrochloride
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).1
Currently available TKIs recommended for first-line treatment of chronic phase CML include dasatinib, imatinib, and nilotinib.36 Asciminib may provide an additional option in the resistant and intolerant setting.4
Philadelphia Chromosome-Positive Chronic Myeloid Leukemia with T315I Mutation
Treatment of chronic phase Ph+ CML in adults with the T315I mutation.1
Ponatinib is generally considered the drug of choice in patients with CML and the T315I mutation.36 It is not clear due to its recent approval where asciminib will be positioned among other available TKIs.4
Asciminib Hydrochloride Dosage and Administration
General
Pretreatment Screening
-
Verify pregnancy status of females of reproductive potential prior to starting treatment.1
Patient Monitoring
-
Perform CBC every 2 weeks for the first 3 months of treatment and monthly thereafter or as clinically indicated.1
-
Assess serum lipase and amylase levels monthly during treatment, or as clinically indicated.1 Monitor patients for signs and symptoms of pancreatic toxicity.1 Perform more frequent monitoring in patients with a history of pancreatitis.1
-
Monitor and manage hypertension using standard antihypertensive therapy during treatment as clinically indicated.1
-
Monitor patients for signs and symptoms of hypersensitivity reactions and initiate appropriate treatment as clinically indicated. 1
-
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).1
Administration
Oral Administration
Administer orally without food.1 Avoid food for at least 2 hours before and 1 hour after taking asciminib.1
Swallow tablets whole.1 Do not break, crush, or chew the tablets.1
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.1 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.1
Dosage
Dosage of asciminib hydrochloride is expressed in terms of asciminib.1
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.1 Continue treatment as long as clinical benefit is observed or until unacceptable toxicity occurs.1
Chronic Phase Ph+ CML in Patients with the T315I Mutation
Oral
200 mg orally twice daily without food at approximately 12-hour intervals.1
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.1 For recommended dosage reductions for adverse events, see Table 1, and for recommended interventions for specific adverse events see Table 2.1
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.
Adverse Reaction |
Dosage Modification |
---|---|
Thrombocytopenia and/or neutropenia |
|
Absolute neutrophil count (ANC) <1,000/mm3 and/or platelet count <50,000/mm3 |
Withhold drug until ANC resolves to ≥1,000/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 ≥1,000/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.1
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.1
Geriatric Patients
No specific dosage recommendation.1
Related/similar drugs
cyclophosphamide, hydroxyurea, Gleevec, Sprycel, Tasigna, Bosulif
Cautions for Asciminib Hydrochloride
Contraindications
-
None.1
Warnings/Precautions
Myelosuppression
Thrombocytopenia, neutropenia, and anemia can occur.1
Perform CBC every 2 weeks for the first 3 months of treatment and monthly thereafter or as clinically indicated.1 Monitor patients for signs and symptoms of myelosuppression.1
Based on the severity of thrombocytopenia and/or neutropenia, reduce dose, temporarily withhold, or permanently discontinue asciminib.1
Pancreatic Toxicity
Pancreatitis reported.1 Asymptomatic elevation of serum lipase and amylase also have occurred.1
Assess serum lipase and amylase levels monthly during treatment with asciminib, or as clinically indicated.1 Monitor patients for signs and symptoms of pancreatic toxicity.1 Perform more frequent monitoring in patients with a history of pancreatitis.1 If lipase and amylase elevations are accompanied by abdominal symptoms, temporarily withhold asciminib and consider appropriate diagnostic tests to exclude pancreatitis.1
Based on the severity of lipase and amylase elevation, reduce dose, temporarily withhold, or permanently discontinue asciminib.1
Hypertension
Hypertension reported.1
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.1
Hypersensitivity
Hypersensitivity, including rash, edema, and bronchospasm, reported.1
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.1
Cardiovascular Toxicity
Cardiovascular toxicity (including ischemic cardiac and CNS conditions, arterial thrombotic and embolic conditions) and cardiac failure reported.1 Cardiovascular toxicity occurred in patients with pre-existing cardiovascular conditions or risk factors, and/or prior exposure to multiple TKIs.1
Arrhythmia, including QTc prolongation, also have occurred.1
Monitor patients with a history of cardiovascular risk factors for cardiovascular signs and symptoms.1 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.1
Fetal/Neonatal Morbidity and Mortality
Based on findings from animal studies and its mechanism of action, asciminib can cause fetal harm.1
Verify pregnancy status of females of reproductive potential prior to starting treatment.1
Specific Populations
Pregnancy
Based on findings from animal studies and the mechanism of action, asciminib can cause embryo-fetal harm.1 No available data on asciminib use in pregnant women.1 Animal reproduction studies demonstrated structural abnormalities, embryo-fetal mortality, and alterations in growth.1
Advise patients of potential risk to fetus.1
Lactation
No data on the presence of asciminib or its metabolites in human milk, the effects on the breastfed child, or milk production.1
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.1
Females and Males of Reproductive Potential.
Verify pregnancy status prior to starting treatment.1
Females of reproductive potential should use effective contraception during treatment and for 1 week after the last dose.1
Based on findings in animals, asciminib may impair fertility in females of reproductive potential.1 The reversibility of the effect on fertility is unknown.1
Pediatric Use
Safety and efficacy in pediatric patients not established.1
Geriatric Use
Overall, no differences in safety or efficacy observed between patients ≥65 years of age compared to younger patients.1 Insufficient experience in patients ≥75 years of age to assess whether there are differences in safety or efficacy.1
Hepatic Impairment
Changes in exposure not clinically important; no dosage adjustment required.1
Renal Impairment
Changes in exposure not clinically important; no dosage adjustment required.1
Common Adverse Effects
Most common adverse reactions (≥ 20%) are upper respiratory tract infections, musculoskeletal pain, headache, fatigue, nausea, rash, diarrhea.1
Most common laboratory abnormalities (≥ 20%) are decreased platelet count, increased triglycerides, decreased neutrophil count, decreased hemoglobin, increased creatine kinase, increased alanine aminotransferase, increased lipase, increased amylase, increased aspartate aminotransferase, increased uric acid, and decreased lymphocyte count.1
Drug Interactions
Metabolized principally by CYP isoenzyme 3A4 (CYP3A4) and UDP-glucuronosyltransferase (UGT) isoenzymes 2B7 (UGT2B7), and UGT2B17.1 Eliminated by biliary secretion via breast-cancer resistance protein (BCRP).1
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)1.1
Drugs Affecting Hepatic Microsomal Enzymes
Strong inhibitors of CYP3A4: Increased Cmax and AUC of asciminib.1 Closely monitor for adverse reactions during concomitant use of asciminib at 200 mg twice daily.1
Strong inducers of CYP3A: Effects of concomitant use not fully characterized.1
Drugs Metabolized by Hepatic Microsomal Enzymes
Substrates of CYP3A4: Increased Cmax and AUC of the CYP3A4 substrate, which may increase the risk of adverse reactions of the substrate.1 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.1 Avoid use of asciminib at 200 mg twice daily with certain CYP3A4 substrates where minimal concentration changes may lead to serious adverse reactions.1
Substrates of CYP2C9: Increased Cmax and AUC of the CYP2C9 substrate, which may increase the risk of adverse reactions of the substrate.1 Avoid concomitant use of asciminib at all recommended dosages with CYP2C9 substrates where minimal concentration changes may lead to serious adverse reactions.1 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.1 If concomitant use is unavoidable with asciminib 200 mg twice daily, consider alternative therapy with a non-CYP2C9 substrate.1
Specific Drugs
Drug |
Interaction |
Comments |
---|---|---|
Atorvastatin |
Concomitant use may increase the risk of adverse effects1 |
Avoid coadministration1 |
Clarithromycin |
Increase Cmax and AUC of asciminib1 |
Closely monitor for adverse reactions with concomitant use of asciminib 200 mg twice daily1 |
Imatinib |
Increased Cmax and AUC of asciminib administered at a dose of 40 mg; change in exposure not considered clinically meaningful1 Concomitant use of imatinib with asciminib 200 mg twice daily not fully characterized1 |
|
Itraconazole |
Concomitant use with itraconazole oral solution containing hydroxypropyl-β-cyclodextrin decreased Cmax 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 1 |
Avoid concomitant use at all recommended asciminib dosages1 |
Midazolam |
Increased Cmax and AUC of midazolam by 17% and 24%, respectively, following a dose of asciminib 80 mg daily1 Increased peak Cmax and AUC of midazolam by 58% and 88%, respectively, following asciminib 200 mg twice daily1 |
Closely monitor for adverse reactions during concomitant use of asciminib at 80 mg total daily dose1 Avoid use with asciminib 200 mg twice daily1 |
Quinidine |
No clinically significant differences in pharmacokinetics of asciminib observed1 |
|
Rabeprazole |
No clinically significant differences in pharmacokinetics of asciminib observed1 |
|
Rosuvastatin |
Concomitant use may increase the risk of adverse effects1 |
Avoid coadministration1 |
Warfarin |
Increased Cmax and AUC of S-warfarin by 8% and 41%, respectively, with asciminib 40 mg twice daily1 Increased Cmax and AUC of S-warfarin by 4% and 52%, respectively, with asciminib 80 mg once daily1 Increased Cmax and AUC of S-warfarin by 7% and 314%, respectively, following asciminib 200 mg twice daily1 |
Avoid concomitant use 1 If concomitant use of asciminib 80 mg daily dose is unavoidable, reduce warfarin dosage as clinically indicated1 If concomitant use of asciminib 200 mg twice daily is unavoidable, consider alternative therapy with a non-CYP2C9 substrate1 |
Asciminib Hydrochloride Pharmacokinetics
Absorption
Peak plasma concentrations attained at median of 2.5 hours (range 2–3 hours).1
Exhibits slightly greater than dose-proportional pharmacokinetics at steady state across the dose range of 10–200 mg administered once or twice daily.1
Food
High-fat meal decreased the Cmax and AUC of asciminib by 68% and 62%, respectively; low-fat meal decreased Cmax and AUC by 35% and 30%, respectively.1
Distribution
Extent
Not known if excreted into human milk.1
Plasma Protein Binding
Approximately 97%.1
Elimination
Metabolism
Metabolized principally by CYP3A4-mediated oxidation, UGT2B7 and UGT2B17-mediated glucuronidation.1
Elimination Route
Approximately 80% (57% unchanged drug) and 11% (2.5% unchanged) of radiolabeled dose recovered in feces and urine, respectively.1
Eliminated by biliary secretion via BCRP.1
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.1
Special Populations
No clinically significant differences in pharmacokinetics based on sex, age (range 20–88 years), race, or body weight (range 42–184 kg).1
Stability
Storage
Oral
Tablets
Store at 20–25°C (excursions permitted between 15–30°C).1
Actions
-
Asciminib is an ABL/BCR-ABL1 tyrosine kinase inhibitor.1 Asciminib inhibits the ABL1 kinase activity of the BCR-ABL1 fusion protein, by binding to the ABL myristoyl pocket.1 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.1
Advice to Patients
-
Advise the patient to read the FDA-approved patient labeling (Patient Information).1
-
Inform patients of the possibility of developing low blood cell counts.1 Advise patients to immediately report fever, any suggestion of infection, or signs or symptoms suggestive of bleeding or easy bruising.1
-
Inform patients of the possibility of developing pancreatitis that may accompany nausea, vomiting, severe abdominal pain, or abdominal discomfort, and promptly report these symptoms.1
-
Inform patients of the possibility of developing hypertension.1 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.1
-
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.1
-
Inform patients of the possibility of the occurrence of cardiovascular toxicity, especially those with a history of cardiovascular risk factors.1 Advise patients to immediately contact their healthcare provider or get medical help if they develop cardiovascular signs and symptoms.1
-
Advise females to inform their healthcare provider if they are pregnant or become pregnant.1 Inform female patients of the potential risk to a fetus.1
-
Advise females of reproductive potential to use effective contraception during treatment and for 1 week after receiving the last dose of asciminib.1
-
Advise women not to breastfeed during treatment with asciminib and for 1 week after the last dose.1
-
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.1
-
Advise patients to take asciminib orally without food.1 Advise patients to avoid food for at least 2 hours before and 1 hour after taking asciminib.1 Asciminib tablets should be swallowed whole.1 Patients should not break, crush, or chew the tablets.1
-
Advise patients that if they take asciminib once daily and miss a dose by more than 12 hours to skip the missed dose.1 Advise patients that if they take asciminib twice daily and miss a dose by more than 6 hours to skip the missed dose.1 Advise patients to take the next dose as scheduled.1
-
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.1
-
Inform patients of other important precautionary information.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
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.
Routes |
Dosage Forms |
Strengths |
Brand Names |
Manufacturer |
---|---|---|---|---|
Oral |
Tablets, film-coated |
20 mg (of asciminib) |
Scemblix |
Novartis |
40 mg (of asciminib) |
Scemblix |
Novartis |
||
100 mg (of asciminib) |
Scemblix |
AHFS DI Essentials™. © Copyright 2024, Selected Revisions August 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
References
1. Novartis Pharmaceuticals Corporation. SCEMBLIX (asciminib) tablets prescribing information. East Hanover, NJ; 2024 Apr. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e33001e7-3650-42b1-ae56-cddb5c43aa2b
2. Réa D, Mauro MJ, Boquimpani C, et al. A phase 3, open-label, randomized study of asciminib, a STAMP inhibitor, vs bosutinib in CML after 2 or more prior TKIs. Blood. 2021;138(21):2031-2041. http://www.ncbi.nlm.nih.gov/pubmed/34407542?dopt=AbstractPlus
3. Hughes TP, Mauro MJ, Cortes JE, et al. Asciminib in Chronic Myeloid Leukemia after ABL Kinase Inhibitor Failure. N Engl J Med. 2019;381(24):2315-2326. http://www.ncbi.nlm.nih.gov/pubmed/31826340?dopt=AbstractPlus
4. Shanmuganathan N, Hughes TP. Asciminib for chronic myeloid leukaemia: Next questions [published online ahead of print, 2022 Jun 21]. Br J Haematol. 2022;10.1111/bjh.18323. http://www.ncbi.nlm.nih.gov/pubmed/35729850?dopt=AbstractPlus
5. Hochhaus A, Rea D, Boquimpani C, et al. Asciminib vs bosutinib in chronic-phase chronic myeloid leukemia previously treated with at least two tyrosine kinase inhibitors: longer-term follow-up of ASCEMBL. Leukemia. 2023;37:617-26.
36. Hochhaus A, Saussele S, Rosti G, et al. Chronic myeloid leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018;29(Suppl 4):iv261. http://www.ncbi.nlm.nih.gov/pubmed/30285223?dopt=AbstractPlus
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