DRUG INTERACTIONS-(summary)

­ • Strong CYP3A4 Inhibitors: Closely monitor for adverse reactions during concomitant use of SCEMBLIX at 200 mg twice daily.

• Itraconazole Oral Solution Containing Hydroxypropyl-ß-cyclodextrin: Avoid concomitant use of SCEMBLIX at all recommended doses.

• Certain Substrates of CYP3A4: Closely monitor for adverse reactions during concomitant use of SCEMBLIX at 80 mg total daily dose. Avoid use of SCEMBLIX at 200 mg twice daily.

 • Substrates of CYP2C9: Avoid concomitant use of SCEMBLIX at all recommended doses. o 80 mg total daily dose: If unavoidable, reduce the CYP2C9 substrate dosage as necessary. (7.2) o 200 mg twice daily: If unavoidable, consider alternative therapy with non-CYP2C9 substrate.

 • Certain P-gp Substrates: Closely monitor for adverse reactions during concomitant use of SCEMBLIX at all recommended doses.

DRUG INTERACTIONS-details

1.Effect of Other Drugs on SCEMBLIX -                                                                        Strong CYP3A4 Inhibitors- Asciminib is a CYP3A4 substrate. Concomitant use of SCEMBLIX with a strong CYP3A4 inhibitor increases both the asciminib Cmax and AUC, which may increase the risk of adverse reactions 

Closely monitor for adverse reactions in patients treated with SCEMBLIX at 200 mg twice daily with concomitant use of strong CYP3A4 inhibitors.

Itraconazole Oral Solution Containing Hydroxypropyl-ß-cyclodextrin-                Concomitant use of SCEMBLIX with itraconazole oral solution containing hydroxypropyl-ß-cyclodextrin decreases asciminib Cmax and AUC, which may reduce SCEMBLIX efficacy .                                                                                                           

  Avoid coadministration of SCEMBLIX at all recommended doses with itraconazole oral solution containing hydroxypropyl-ßcyclodextrin.

2. Effect of SCEMBLIX on Other Drugs Certain CYP3A4 Substrates-              Asciminib is a CYP3A4 inhibitor. Concomitant use of SCEMBLIX increases the Cmax and AUC of CYP3A4 substrates, which may increase the risk of adverse reactions of these substrates.                  

Closely monitor for adverse reactions in patients treated with SCEMBLIX at 80 mg total daily dose with concomitant use of certain CYP3A4 substrates, where minimal concentration changes may lead to serious adverse reactions.

Avoid coadministration of SCEMBLIX at 200 mg twice daily with certain CYP3A4 substrates, where minimal concentration changes may lead to serious adverse reactions.

CYP2C9 Substrates- Asciminib is a CYP2C9 inhibitor. Concomitant use of SCEMBLIX increases the Cmax and AUC of CYP2C9 substrates, which may increase the risk of adverse reactions of these substrates

 Avoid coadministration of SCEMBLIX at 80 mg total daily dose with certain CYP2C9 substrates, where minimal concentration changes may lead to serious adverse reactions.

If coadministration is unavoidable, reduce the CYP2C9 substrate dosage as recommended in its prescribing information.

Avoid coadministration of SCEMBLIX at 200 mg twice daily with sensitive CYP2C9 substrates and certain CYP2C9 substrates, where minimal concentration changes may lead to serious adverse reactions.

If coadministration is unavoidable, consider alternative therapy with non-CYP2C9 substrate.

Certain P-gp Substrates- Asciminib is a P-gp inhibitor. Concomitant use of SCEMBLIX increases the plasma concentrations of P-gp substrates, which may increase the risk of adverse reactions of these substrates 

Closely monitor for adverse reactions in patients treated with SCEMBLIX at all recommended doses with concomitant use of P-gp substrates, where minimal concentration changes may lead to serious toxicities.

BRIEF SUMMARY

ASCIMINIB- (Oct 2021)

Indn-   - To treat Philadelphia Chromosome-positive  chronic   Myeloid Leukemia with disease that meet certain criteria      

Comp-    • Film-coated tablets: 20 mg and 40 mg   Recommended Dosage in Ph+ CML in CP: 80 mg orally once daily or 40 mg twice daily.                                                             • Recommended Dosage in Ph+ CML in CP with the T315I Mutation: 200 mg orally twice daily.

• Avoid food for at least 2 hours before and 1 hour after taking.

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

CI-    ­ None. 

WARNINGS -

­ • Myelosuppression: Severe thrombocytopenia and neutropenia events may occur. Monitor complete blood counts regularly during therapy and manage by treatment interruption or dose reduction.

 • Pancreatic Toxicity: Monitor serum lipase and amylase. Interrupt, then resume at reduced dose or discontinue  based on severity. Evaluate for pancreatitis when lipase elevation is accompanied by abdominal symptoms.

Pat Inform-

Myelosuppression-                                                                                                    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 

Pancreatic Toxicity-                                                                                                             Inform patients of the possibility of developing pancreatitis that may be accompanied by nausea, vomiting, severe abdominal pain, or abdominal discomfort, and to promptly report these symptoms

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U.S. FDA APPROVED DRUGS SURING 2021                                        

Serial No 43

Name of the Drug-    SCEMBIX

Active Ingredient -   Asciminib

Pharmacological Classification- To treat Philadelphia Chromosome-positive                                                                        chronic   Myeloid Leukemia with disease that                                                                     meet certain criteria                                                                                                                                                                                                          Date of Approval-          10/29/21 

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use                            SCEMBLIX® safely and effectively.

See full prescribing information for SCEMBLIX. SCEMBLIX (asciminib) tablets, for oral use

Initial U.S. Approval: 2021

INDICATIONS AND USAGE-

 SCEMBLIX is a kinase inhibitor indicated for the treatment of adult patients with:

• Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase (CP), previously treated with two or more tyrosine kinase inhibitors (TKIs).

 This indication is approved under accelerated approval based on major molecular response (MMR). Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

• Ph+ CML in CP with the T315I mutation.

ADVERSE REACTIONS

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

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

CONTRAINDICATIONS-                                                                                                     ­ None. 

WARNINGS AND PRECAUTIONS-

­ • Myelosuppression: Severe thrombocytopenia and neutropenia events may occur. Monitor complete blood counts regularly during therapy and manage by treatment interruption or dose reduction.

 • Pancreatic Toxicity: Monitor serum lipase and amylase. Interrupt, then resume at reduced dose or discontinue SCEMBLIX based on severity. Evaluate for pancreatitis when lipase elevation is accompanied by abdominal symptoms.

 • Hypertension: Monitor blood pressure and manage hypertension as clinically indicated. Interrupt, dose reduce, or stop SCEMBLIX if hypertension is not medically controlled. 

Hypersensitivity: May cause hypersensitivity reactions. Monitor patients for signs and symptoms and initiate appropriate treatment as clinically indicated.

 • Cardiovascular Toxicity: Cardiovascular toxicity may occur. Monitor patients with history of cardiovascular risk factors for cardiovascular signs and symptoms. Initiate appropriate treatment as clinically indicated.

 • Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception.

DOSAGE AND ADMINISTRATION-

­ • Recommended Dosage in Ph+ CML in CP: 80 mg orally once daily or 40 mg twice daily.                                                                                                                                     • Recommended Dosage in Ph+ CML in CP with the T315I Mutation: 200 mg orally twice daily.

• Avoid food for at least 2 hours before and 1 hour after taking SCEMBLIX.

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

DOSAGE FORMS AND STRENGTHS-                                                                                     ­ • Film-coated tablets: 20 mg and 40 mg

PATIENT COUNSELING INFORMATION-                                                                           Advise the patient to read the FDA-approved patient labeling (Patient Information).

Myelosuppression-                                                                                                    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 

Pancreatic Toxicity-                                                                                                             Inform patients of the possibility of developing pancreatitis that may be accompanied by nausea, vomiting, severe abdominal pain, or abdominal discomfort, and to promptly report these symptoms

Hypertension- 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

 Hypersensitivity-                                                                                                            Advise the patient to discontinue SCEMBLIX and seek immediate medical attention if any signs or symptoms of a hypersensitivity reaction, such as rash, edema, or bronchospasm occur

 Cardiovascular Toxicity-                                                                                                   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

 Embryo-Fetal Toxicity-                                                                                                    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 SCEMBLIX

 Lactation-                                                                                                                           Advise women not to breastfeed during treatment with SCEMBLIX and for 1 week after the last dose

 Drug Interactions -                                                                                                             Advise patients that SCEMBLIX and certain other medicines, including over the counter medications or herbal supplements, can interact with each other and may alter the effects of SCEMBLIX 

Instructions for Taking SCEMBLIX-                                                                               Advise patients to take SCEMBLIX exactly as prescribed and not to change their dose or schedule or to stop taking SCEMBLIX unless they are told to do so by their healthcare provider

Advise patients to take SCEMBLIX orally without food.

Advise patients to avoid food for at least 2 hours before and 1 hour after taking SCEMBLIX. SCEMBLIX tablets should be swallowed whole.

Patients should not break, crush, or chew the tablets

Advise patients that if they take SCEMBLIX once daily and miss a dose by more than 12 hours to skip the missed dose.

Advise patients that if they take SCEMBLIX 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

Distributed by: Novartis Pharmaceuticals Corporation One Health Plaza East Hanover, New Jersey 07936 © Novartis

CLINICAL PHARMACOLOGY-

1. Mechanism of Action-                                                                                                Asciminib is an ABL/BCR-ABL1 tyrosine kinase inhibitor. Asciminib inhibits the ABL1 kinase activity of the BCRABL1 fusion protein, by binding to the ABL myristoyl pocket.

2. Pharmacodynamics-                                                                                                     Exposure-Response Relationships Over asciminib dosages of 10 mg to 200 mg twice daily (0.25 to 5 times the recommended 80 mg daily dosage), a lower exposure was associated with a smaller decrease in BCR-ABL1 level and a lower MMR rate at Week 24

Cardiac Electrophysiology-                                                                                       Asciminib does not cause a large mean increase in QTc interval (i.e., >20 msec) at the maximum recommended clinical dosage (200 mg twice daily). Based on available clinical data, small mean QTc increase (<10 msec) cannot be excluded.

3. Pharmacokinetics-                                                                                                   Asciminib steady-state exposure (AUC and Cmax) increase slightly more than dose proportional across the dose range of 10 to 200 mg (0.25 to 5 times the recommended 80 mg daily dosage) administered once or twice daily.

Steady State- Asciminib Exposure at Recommended Dosages Asciminib Dosage Cmax (ng/mL) AUCtau b (ng*h/mL) Accumulation Ratio 80 mg once daily 1781 (23%) 15112 (28%) 1.30 40 mg twice daily 793 (49%) 5262 (48%) 1.65 200 mg twice daily 5642 (40%) 37547 (41%) 1.92 a Steady state is achieved within 3 days. b AUCtau represents AUC0-12h for twice daily dosing and AUC0-24h for once daily dosing.

Absorption- The median (range) Tmax of asciminib is 2.5 hours (2 to 3 hours).

Effect of Food-                                                                                                               The AUC and Cmax of asciminib decreased by 62% and 68%, respectively, with a high-fat meal (1000 calories, 50% fat) and by 30% and 35%, respectively, with a low-fat meal (400 calories, 25% fat) compared to the fasted state following administration of SCEMBLIX.

Distribution-                                                                                                                   The apparent volume of distribution of asciminib at steady state is 151 L (135%). Asciminib is the main circulating component in plasma (93% of the administered dose). Asciminib is 97% bound to human plasma proteins in vitro.

Elimination-                                                                                                                       The total apparent clearance of asciminib is 6.7 L/hour (48%) at 40 mg twice daily and 80 mg once daily, and 4.1 L/hour (38%) at 200 mg twice daily. The terminal elimination half-life of asciminib is 5.5 hours (38%) at 40 mg twice daily and 80 mg once daily, and 9.0 hours (33%) at 200 mg twice daily.

Metabolism -                                                                                                               Asciminib is metabolized by CYP3A4-mediated oxidation, UGT2B7- and UGT2B17-mediated glucuronidation.

Excretion- Eighty percent (57% as unchanged) and 11% (2.5% as unchanged) of the asciminib dose were recovered in the feces and in the urine of healthy subjects, respectively, following oral administration of a single 80 mg dose of radio-labeled asciminib. Asciminib is eliminated by biliary secretion via breast cancer-resistant protein (BCRP). Reference ID: 4880647

Specific Populations-                                                                                                        No clinically significant differences in the pharmacokinetics of asciminib were observed based on sex, age (20 to 88 years), race (Asian 20%, White 70%, Black/African American 4%), or body weight (42 - 184 kg), mild to moderate renal impairment (eGFR 30 to 89 mL/min/1.73 m2 ), or mild (total bilirubin = ULN and AST > ULN or total bilirubin > 1 to 1.5 times ULN and any AST) to moderate (total bilirubin > 1.5 to 3 times ULN and any AST) hepatic impairment.

Patients with Renal Impairment-                                                                                 Asciminib AUCinf and Cmax are increased by 57% and 6%, respectively, in subjects with eGFR between 13 to < 30 mL/min/1.73 m2 and not requiring dialysis compared to subjects with normal renal function (eGFR = 90 mL/min/1.73 m2 ) following oral administration of a single 40 mg dose of SCEMBLIX. The exposure changes in patients with severe renal impairment are not considered clinically meaningful.

Patients with Hepatic Impairment-                                                                              Asciminib AUCinf and Cmax are increased by 33% and 4%, respectively, in subjects with severe hepatic impairment (total bilirubin > 3 times ULN and any AST), compared to subjects with normal hepatic function (total bilirubin = ULN and AST = ULN) following oral administration of a single 40 mg dose of SCEMBLIX. The exposure changes are not considered clinically meaningful.

Drug Interaction Studies-                                                                                                 Clinical Studies and Model-Informed Approaches                                                             Drugs That Affect Asciminib Plasma Concentration Strong CYP3A Inhibitors: The asciminib AUCinf and Cmax increased by 36% and 19%, respectively, following coadministration of a single SCEMBLIX dose of 40 mg with a strong CYP3A4 inhibitor (clarithromycin).

No clinically significant differences in the pharmacokinetics of asciminib were observed when coadministered with itraconazole, which is also a strong CYP3A4 inhibitor.

Strong CYP3A Inducers: Concomitant use of strong CYP3A inducers with SCEMBLIX has not been fully characterized.

Itraconazole Oral Solution: Coadministration of multiple doses of itraconazole oral solution containing hydroxypropyl-ßcyclodextrin with a single SCEMBLIX dose of 40 mg decreased asciminib AUCinf and Cmax by 40% and 50%, respectively.

Concomitant use of oral products containing hydroxypropyl-ß-cyclodextrin with SCEMBLIX other than itraconazole oral solution has not been fully characterized.

Imatinib: The asciminib AUCinf and Cmax increase by 108% and 59%, respectively following coadministration of a single SCEMBLIX dose of 40 mg with imatinib (an inhibitor of BCRP, CYP3A4, UGT2B17 and UGT1A3/4). The exposure changes are not considered clinically meaningful. Concomitant use of imatinib with SCEMBLIX at 200 mg twice daily has not been fully characterized.

USE IN SPECIFIC POPULATIONS-

1. Pregnancy Risk Summary-                                                                                         Based on findings from animal studies and the mechanism of action, SCEMBLIX can cause embryo-fetal harm when administered to a pregnant woman.

There are no available data on SCEMBLIX use in pregnant women to evaluate a drug associated risk.

Advise pregnant women and females of reproductive potential of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively

2. Lactation Risk Summary-                                                                                           There are 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 SCEMBLIX and for 1 week after the last dose.

3. Females and Males of Reproductive Potential-                                                  Based on findings from animal studies, SCEMBLIX can cause embryo-fetal harm when administered to a pregnant woman

 Pregnancy Testing- Verify the pregnancy status of females of reproductive potential prior to starting treatment with SCEMBLIX.

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

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

4. Pediatric Use- The safety and efficacy of SCEMBLIX in pediatric patients have not been established.

5. Geriatric Use-                                                                                                                In the ASCEMBL study, 44 of the 233 (19%) patients were 65 years of age or older and 6 (2.6%) were 75 years of age or older. In the X2101 study, 16 of the 48 (33%) patients with the T315I mutation were 65 years of age or older and 4 (8%) were 75 years of age or older.

Overall, no differences in safety or efficacy of SCEMBLIX were observed between patients 65 years of age or older compared to younger patients. There is an insufficient number of patients 75 years of age or older to assess whether there are differences in safety or efficacy.

6. Renal Impairment-                                                                                                       No dose adjustment is required for patients with mild to severe renal impairment (estimated glomerular filtration rate [eGFR] 15 to 89 mL/min/1.73 m2 ) and not requiring dialysis receiving SCEMBLIX .

7. Hepatic Impairment -No dose adjustment is required for patients with mild [total bilirubin = upper limit of normal (ULN) and aspartate aminotransferase (AST) > ULN or total bilirubin > 1 to 1.5 times ULN and any AST] to severe hepatic impairment (total bilirubin > 3 times ULN and any AST) receiving SCEMBLIX.