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SCEMBLIX is a brand name for Asciminib, supplied as a tablet. The medicine, its uses, side effects and dosage are the same regardless of brand.
Verbatim from this product's HC label. Tap a section to expand.
). Hepatic/Biliary/Pancreatic Pancreatic toxicity Pancreatitis occurred in 11 of 556 (2%) patients receiving SCEMBLIX, with grade 3 reactions occurring in 6 (1%) patients. 5%) patients, while it was temporarily withheld in 6 (1%) patients due to pancreatitis.
Asymptomatic elevation of serum lipase and amylase occurred in 107 of 556 (19%) patients receiving SCEMBLIX, with grade 3 and 4 reactions occurring in 41 (7%) and 11 (2%) patients, respectively. SCEMBLIX was permanently discontinued in 11 (2%) patients due to the asymptomatic elevation of serum lipase and amylase (see Monitoring and Laboratory Tests).
If serum lipase and amylase elevation are accompanied by abdominal symptoms, treatment should be temporarily withheld and appropriate diagnostic tests should be considered to exclude pancreatitis (see 4 DOSAGE AND ADMINISTRATION). Based on the severity of serum lipase and amylase elevation, the SCEMBLIX dose should be reduced, temporarily withheld or permanently discontinued as described in Table 2 (see 4 DOSAGE AND ADMINISTRATION).
Immune Hepatitis B reactivation Reactivation of hepatitis B virus (HBV) has occurred in patients who are chronic carriers of this virus following administration of other BCR::ABL1 tyrosine kinase inhibitors (TKIs). Patients should be tested for HBV infection before the start of treatment with SCEMBLIX (see Monitoring and Laboratory Tests).
Hypersensitivity Hypersensitivity events occurred in 169 of 556 (30%) patients receiving SCEMBLIX, with ≥grade 3 events reported in 8 (1%) patients (see Monitoring and Laboratory Tests). Monitoring and Laboratory Tests It is recommended that an electrocardiogram is performed prior to the start of treatment with SCEMBLIX and monitored during treatment as clinically indicated.
Hypokalemia and SCEMBLIX (asciminib) Page 10 of 40 hypomagnesemia should be corrected prior to SCEMBLIX administration and monitored during treatment as clinically indicated. Hypertension should be monitored and managed using standard antihypertensive therapy during treatment with SCEMBLIX as clinically indicated.
The pregnancy status of females of reproductive potential should be verified prior to starting treatment with SCEMBLIX. Complete blood counts should be performed every two weeks for the first 3 months of treatment and monthly thereafter, or as clinically indicated.
Patients should be monitored for signs and symptoms of myelosuppression. Serum lipase and amylase levels should be assessed monthly during treatment with SCEMBLIX, or as clinically indicated. Patients should be monitored for signs and symptoms of pancreatic toxicity.
More frequent monitoring should be performed in patients with a history of pancreatitis. HBV carriers who require treatment with SCEMBLIX should be closely monitored for signs and symptoms of active HBV infection throughout therapy and for several months following termination of therapy.
and Monitoring and Laboratory Tests). In the ASCEMBL clinical study, one patient had a prolonged QTcF greater than 500 ms together with more than 60 ms QTcF increase from baseline and one patient had prolonged QTcF with more than 60 ms QTcF increase from baseline.
Caution should be exercised when administering SCEMBLIX concomitantly with medicinal products with a known risk of torsades de pointes (see
and 10 CLINICAL PHARMACOLOGY). Caution should be exercised during concomitant administration of SCEMBLIX and medicinal products known to cause torsades de pointes. , digoxin, dabigatran and colchicine) T PBPK models predict that co-administration of asciminib 80 mg total daily dose with a P-gp substrate (digoxin) would increase digoxin AUCinf by 4%- 34% and Cmax by 6%- 38%.
Caution should be exercised during concomitant administration of SCEMBLIX with P-gp substrates known to have a narrow therapeutic index. , sulfasalazine, methotrexate, rosuvastatin) T Based upon a mechanistic understanding of the elimination of asciminib and its in vitro inhibitory potential, concomitant use of SCEMBLIX with BCRP substrates may increase Cmax and AUC of the substrates, increasing the risk of adverse reactions.
Caution should be exercised during concomitant administration of SCEMBLIX with BCRP substrates and the dosage of the substrates should be reduced as recommended in their product monographs. Avoid coadministration of SCEMBLIX with rosuvastatin.
SCEMBLIX (asciminib) Page 22 of 40 Legend:
C = Case Study; CT = Clinical Trial; T = Theoretical Clinical studies Effect of CYP3A4 inhibitors on asciminib: Co-administration of a strong CYP3A4 inhibitor, clarithromycin, with a single SCEMBLIX dose of 40 mg increased asciminib AUC by 36% and Cmax by 20%.
The exposure changes are not considered clinically meaningful.
Effect of acid-reducing agents on asciminib:
Co-administration of a proton pump inhibitor, rabeprazole, had no effect on the AUC and Cmax of asciminib.
Effect of P-gp inhibitors on asciminib:
Co-administration of a P-gp inhibitor, quinidine, had no effect on the AUC and Cmax of asciminib.
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Patients should be monitored for signs and symptoms of hypersensitivity and appropriate treatment should be initiated as clinically indicated. Reproductive Health Fertility Based on findings in animals, SCEMBLIX may impair fertility.
There are no data on the effect of SCEMBLIX on human fertility (see 16 NON-CLINICAL TOXICOLOGY). 1. 1 Pregnancy Based on findings from animal studies, SCEMBLIX can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies in pregnant women to inform a product-associated risk.
There have been reports of spontaneous abortion and fetal or infant anomalies from women who have taken asciminib during pregnancy. The causal relationship to asciminib has not been yet established. Animal reproduction studies in pregnant rats and rabbits demonstrated that oral administration of asciminib during organogenesis induced embryotoxicity, fetotoxicity and teratogenicity.
Pregnant women and females of reproductive potential should be advised of the potential risk to a fetus if SCEMBLIX is used during pregnancy or if the patient becomes pregnant while taking SCEMBLIX (see Reproductive Health) and 16 NON-CLINICAL TOXICOLOGY).
The pregnancy status of females of reproductive potential should be verified prior to starting treatment with SCEMBLIX. Sexually-active females and males of reproductive potential should use effective contraception (in addition to a barrier method) during treatment with SCEMBLIX and for at least 7 days after the last dose (see Pregnancy and Monitoring and Laboratory Tests).
2 Breastfeeding It is unknown whether SCEMBLIX is excreted in human milk. Because of the potential for serious adverse reactions in the breastfed child, breast-feeding is not recommended during treatment with SCEMBLIX and for at least 7 days after the last dose.
3 Pediatrics Pediatrics (< 18 years): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for SCEMBLIX for pediatric use. 4 Geriatrics Geriatrics (≥ 65 years): Among the 556 patients receiving SCEMBLIX in the ASC4FIRST, ASCEMBL and X2101 studies, 130 (23%) were 65 years of age or older and 31 (6%) were 75 years of age or older.
No overall differences in the safety or efficacy of SCEMBLIX were observed between patients of 65 years of age or above and younger patients. 8. 1. Adverse Reaction Overview The overall safety profile of SCEMBLIX has been evaluated in 556 patients with Ph+ CML in chronic (CP) and accelerated (AP) phases receiving SCEMBLIX as monotherapy.
It is based on the safety pool of the pivotal phase III study J12301 (ASC4FIRST) (N=200 newly diagnosed Ph+ CML-CP patients), the pivotal phase III study A2301 (ASCEMBL) (N=156 Ph+ CML-CP patients previously treated with two or more TKIs) and the phase I study X2101, including patients with: - Ph+ CML-CP (N=115), - Ph+ CML-CP harboring the T315I mutation (N=70), - Ph+ CML-AP (N=15).
The […]
Effect of combined inhibitors of BCRP, CYP3A4, and UGT2B17 on asciminib:
Co-administration of imatinib, an inhibitor of BCRP, CYP3A4, and UGT2B17, increased asciminib AUC by 108% and Cmax by 59%. The exposure changes are not considered clinically meaningful.
Effect of asciminib on CYP2C8 substrates:
Co-administration of asciminib with a CYP2C8 substrate, repaglinide, had no effect on the AUC and Cmax of repaglinide. g. atorvastatin): Co-administration of asciminib at 80 mg once daily with an OATP1B, CYP3A4 and P-gp substrate (atorvastatin) increased atorvastatin AUCinf and Cmax by 14% and 24%, respectively, in healthy subjects.
Clinically relevant interactions between SCEMBLIX and OATP1B substrates are unlikely to occur.
In vitro studies Asciminib and CYP/UGT enzymes:
At plasma concentrations reached at a total daily dose of 80 mg, asciminib is a reversible inhibitor of CYP3A4, CYP2C9, UGT1A1 and a weak inducer of CYP1A2. Asciminib is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C19, CYP2D6, CYP2E1, or UGT2B7 at clinically relevant plasma concentrations.
Asciminib and transporters:
Asciminib is a substrate of BCRP and P-gp. Asciminib is an inhibitor of BCRP, P-gp, OATP1B1, and OATP1B3 (see Table 8). Asciminib is not an inhibitor of BSEP, OCT1, OCT2, OAT1, OAT3, MATE1, or MATE2-K at clinically relevant plasma concentrations.
5. Drug-Food Interactions The bioavailability of asciminib decreases on consumption of food (see 4 DOSAGE AND ADMINISTRATION and 10 CLINICAL PHARMACOLOGY). 6. Drug-Herb Interactions St. John’s wort (Hypericum perforatum) is an inducer of CYP3A4 that may increase the metabolism of asciminib and hence decrease asciminib blood levels and caution should be exercised during concomitant administration of SCEMBLIX with strong CYP3A4 inducers.
SCEMBLIX (asciminib) Page 23 of 40 10. 1. Mechanism of Action Asciminib is an oral inhibitor of ABL/BCR::ABL1 tyrosine kinase. Asciminib inhibits the ABL1 kinase activity of the BCR::ABL1 fusion protein, by specifically targeting the ABL myristoyl pocket (STAMP).
2. Pharmacodynamics In vitro, asciminib inhibits the tyrosine kinase activity of ABL1 at mean IC50 values below 3 nanomolar. In patient-derived cancer cells, asciminib specifically inhibits the proliferation of cells harboring BCR::ABL1 with IC50 values between 1 and 25 nanomolar.
21 nanomolar. 5 mg/kg twice daily. Cardiac electrophysiology SCEMBLIX treatment is associated with an exposure-related prolongation of the QT interval. The correlation between asciminib concentration and the estimated maximum mean change from baseline of the QT interval with Fridericia’s correction (ΔQTcF) was evaluated in 239 patients with Ph+ CML or Ph+ acute lymphoblastic leukemia (ALL).
, >20 msec) following a total daily dose of 80 mg. 3. 25 to 5 times the recommended 80 mg total daily dose) administered once or twice daily. Steady-state conditions are achieved within 3 days. Table 9 summarizes the steady state asciminib exposures and accumulation ratios in patients at the recommended dosages under fasting condition.
7 Cmax = maximum (peak) concentration; AUCtau = AUC0-12h for twice daily dosing and AUC0-24h for once daily dosing Absorption Asciminib is rapidly absorbed, with median maximum plasma levels (Tmax) reached 2 to 3 hours after oral administration.
SCEMBLIX (asciminib) Page 24 of 40 Food effect Food […]