DRUG INTERACTIONS

Summary

1. Effect of Other Drugs on TAZVERIK Strong and Moderate CYP3A Inhibitors-   Coadministration of TAZVERIK with a strong or moderate CYP3A inhibitor increases tazemetostat plasma concentrations which may increase the frequency or severity of adverse reactions.

Avoid coadministration of strong or moderate CYP3A inhibitors with TAZVERIK.

If coadministration of moderate CYP3A inhibitors cannot be avoided, reduce TAZVERIK dose 

Strong and Moderate CYP3A Inducers Coadministration of TAZVERIK with a strong or moderate CYP3A inducer may decrease tazemetostat plasma concentrations which may decrease the efficacy of TAZVERIK.

Avoid coadministration of moderate and strong CYP3A inducers with TAZVERIK. 

2. Effect of TAZVERIK on Other Drugs CYP3A Substrates-               Coadministration of TAZVERIK with CYP3A substrates, including hormonal contraceptives, can result in decreased concentrations and reduced efficacy of CYP3A substrates

Details

Drug Interaction Studies -                                                                                      Clinical Studies Effect of CYP3A Inhibitors on Tazemetostat: Coadministration of fluconazole (a moderate CYP3A inhibitor) with TAZVERIK 400 mg twice daily in patients increased tazemetostat steady-state AUC0-8h by 3.1-fold and Cmax by 2.3-fold.

Effect of Gastric Acid Reducing Agents on Tazemetostat:                       Coadministration of omeprazole (a proton pump inhibitor) with TAZVERIK 800 mg twice daily in patients increased tazemetostat steady-state AUC0-8h by 26% and Cmax by 25%, which is not expected to have clinically relevant impact.

Effect of Tazemetostat on CYP3A Substrate:                                          Coadministration of TAZVERIK 800 mg twice daily with oral midazolam (a sensitive CYP3A substrate) in patients decreased midazolam AUC0-12h by 40% and Cmax by 21%. 

Effect of Tazemetostat on CYP2C8 and CYP2C19 Substrates:              Coadministration of TAZVERIK 800 mg twice daily with repaglinide (a sensitive CYP2C8 substrate) and omeprazole (a sensitive CYP2C19 substrate) in patients increased repaglinide AUC0-8h by 80% and Cmax by 51%; and had no effect on the exposure of omeprazole.

In Vitro Studies Metabolic Enzymes:                                                         Tazemetostat does not inhibit CYP1A2, CYP2B6, CYP2C9, and CYP2D6 at clinically relevant concentrations.

Drug Transporters: Tazemetostat is a substrate of p-glycoprotein (P-gp). Tazemetostat is not a substrate of breast cancer resistance protein (BCRP); renal transporters organic cation transporter 2 (OCT2), organic anion transporter 3 (OAT3), and multidrug and toxin extrusion transporter 1 (MATE1); or hepatic transporters organic anion transporting polypeptide 1B1 (OATP1B1) and organic anion transporting polypeptide 1B3 (OATP1B3). 

Tazemetostat is an inhibitor of MATE1 and multidrug and toxin extrusion transporter 2-K (MATE2-K). 

Tazemetostat does not inhibit P-gp, BCRP, OATP1B1, OATP1B3, organic cation transporter 1 (OCT1), OCT2, organic anion transporter 1 (OAT1), OAT3, or bile salt export pump (BSEP) at clinically relevant concentrations. 

U.S. FDA APPROVED  DRUGS DURING 2020

Sr.No-  3

 ADVERSE REACTIONS

 The most common (=20%) adverse reactions are pain, fatigue, nausea, decreased appetite, vomiting, and constipation. 

 CONTRAINDICATIONS                                                                                                    None. 

 WARNINGS AND PRECAUTIONS

­ • Secondary Malignancies: TAZVERIK increases the risk of developing secondary malignancies, including T-cell lymphoblastic lymphoma, myelodysplastic syndrome, and acute myeloid leukemia. 

Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of potential risk to a fetus and to use effective non-hormonal contraception. 

 PATIENT COUNSELING INFORMATION

Instruct the patient to read the FDA-approved patient labeling (Medication Guide).

Secondary Malignancies                                                                                      Advise patients of the increased risk of secondary malignancies, including AML, MDS, and T-LBL.

Advise patients to inform their healthcare provider if they experience fatigue, easy bruising, fever, bone pain, or paleness 

Embryo-Fetal Toxicity                                                                                           Advise pregnant women and females of reproductive potential of the potential risk to a fetus.

Advise females to inform their healthcare provider of a known or suspected pregnancy 

Advise females of reproductive potential to use effective non-hormonal contraception during treatment with TAZVERIK and for 6 months after the final dose 

Advise males with female partners of reproductive potential to use effective contraception during treatment with TAZVERIK and for 3 months after the final dose 

Lactation                                                                                                               Advise women not to breastfeed during treatment with TAZVERIK and for 1 week after the final dose 

Drug Interactions

Advise patients and caregivers to inform their healthcare provider of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products. Inform patients to avoid St. John’s wort, grapefruit, and grapefruit juice while taking TAZVERIK 

Manufactured for: Epizyme, Inc. 400 Technology Square Cambridge, MA 02139 ©2020 Epizyme, Inc.

 CLINICAL PHARMACOLOGY

1. Mechanism of Action                                                                             Tazemetostat is an inhibitor of the methyltransferase, EZH2, and some EZH2 gain-of-function mutations including Y646X and A687V. Tazemetostat also inhibited EZH1 with a half-maximal inhibitory concentration (IC50) of 392 nM, approximately 36 times higher than the IC50 for inhibition of EZH2.

2. Pharmacodynamics                                                                                        Tzemetostat exposure-response relationships and the time course of pharmacodynamic responses are unknown.

Cardiac Electrophysiology                                                                                        The effect of orally administered TAZVERIK, at doses ranging from 100 mg to 1600 mg twice daily (0.125 to 2 times the approved recommended dosage) for 15 days, on the heart-rate corrected QT (QTc) interval was evaluated in a dose-finding study in 38 patients with advanced malignancies.

Tazemetostat and its metabolite EPZ-6930 did not cause a large mean increase (i.e. >20 ms) on the QTc interval at the 800 mg twice daily dose. The largest mean increase (upper bound of 90% confidence interval) in QTc were 6.1 ms (8.5 ms) and 9.3 ms (12.5 ms) at a dose of 800 mg twice daily and 1600 mg twice daily, respectively. 

3. Pharmacokinetics                                                                                                   The systemic exposure of tazemetostat is approximately dose proportional over the dose range of 200 mg to 1600 mg twice daily of TAZVERIK (0.25 to 2 times the approved recommended dosage).

Following TAZVERIK 800 mg orally twice daily, steady-state was reached by Day 15. The mean (coefficient of variation [CV]%) steady-state peak plasma concentration (Cmax) was 829 (56%) ng/mL and AUC0-12h was 3340 (49%) ng•h/mL.   

Tazemetostat exhibited time-dependent pharmacokinetics (PK). The mean accumulation ratio (measured by AUC) was 0.58. Absorption The mean absolute oral bioavailability of tazemetostat is approximately 33%. The median time to reach the peak plasma concentration of tazemetostat is 1 to 2 hours.

Effect of Food                                                                                                               A high-fat, high-calorie (approximately 800 to 1000 calories) meal does not have a significant effect on tazemetostat exposure.

Distribution                                                                                                                  The mean (CV%) apparent volume of distribution at steady-state (Vss/F) is 1230 L (46%). Tazemetostat is 88% bound to human plasma proteins in vitro. The blood-to-plasma ratio is 0.73.

Elimination                                                                                                                        At steady-state, the estimated mean (CV%) terminal elimination half-life of tazemetostat is 3.1 hours (14%) and the apparent total clearance (CLss/F) is 274 L/h (49%).

Metabolism                                                                                                                   In vitro, tazemetostat is metabolized by CYP3A to form the inactive major metabolites M5 (EPZ-6930) and M3 (EPZ006931). M5 undergoes further metabolism by CYP3A.

Excretion                                                                                                           Following a single oral dose of radiolabeled tazemetostat, 94% of the total radioactivity was recovered over 12 days, with 15% excreted into urine and 79% into feces.

Specific Populations                                                                                                 Age (16 to 91 years), sex, race (White, Black, Asian), body weight (37.3 to 173 kg), mild hepatic impairment (total bilirubin > 1 to 1.5 times ULN or AST > ULN) and renal impairment, including end stage renal disease, have no clinically meaningful effect on the pharmacokinetics of tazemetostat.

The effect of moderate to severe hepatic impairment has not been studied.

Drug Interaction Studies                                                                                         Clinical Studies Effect of CYP3A Inhibitors on Tazemetostat: Coadministration of fluconazole (a moderate CYP3A inhibitor) with TAZVERIK 400 mg twice daily in patients increased tazemetostat steady-state AUC0-8h by 3.1-fold and Cmax by 2.3-fold.

Effect of Gastric Acid Reducing Agents on Tazemetostat:                       Coadministration of omeprazole (a proton pump inhibitor) with TAZVERIK 800 mg twice daily in patients increased tazemetostat steady-state AUC0-8h by 26% and Cmax by 25%, which is not expected to have clinically relevant impact.

Effect of Tazemetostat on CYP3A Substrate:                                          Coadministration of TAZVERIK 800 mg twice daily with oral midazolam (a sensitive CYP3A substrate) in patients decreased midazolam AUC0-12h by 40% and Cmax by 21%. 

Effect of Tazemetostat on CYP2C8 and CYP2C19 Substrates:              Coadministration of TAZVERIK 800 mg twice daily with repaglinide (a sensitive CYP2C8 substrate) and omeprazole (a sensitive CYP2C19 substrate) in patients increased repaglinide AUC0-8h by 80% and Cmax by 51%; and had no effect on the exposure of omeprazole.

In Vitro Studies Metabolic Enzymes:                                                         Tazemetostat does not inhibit CYP1A2, CYP2B6, CYP2C9, and CYP2D6 at clinically relevant concentrations.

Drug Transporters: Tazemetostat is a substrate of p-glycoprotein (P-gp). Tazemetostat is not a substrate of breast cancer resistance protein (BCRP); renal transporters organic cation transporter 2 (OCT2), organic anion transporter 3 (OAT3), and multidrug and toxin extrusion transporter 1 (MATE1); or hepatic transporters organic anion transporting polypeptide 1B1 (OATP1B1) and organic anion transporting polypeptide 1B3 (OATP1B3).

Tazemetostat is an inhibitor of MATE1 and multidrug and toxin extrusion transporter 2-K (MATE2-K).

Tazemetostat does not inhibit P-gp, BCRP, OATP1B1, OATP1B3, organic cation transporter 1 (OCT1), OCT2, organic anion transporter 1 (OAT1), OAT3, or bile salt export pump (BSEP) at clinically relevant concentrations.

USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary                                                                                Based on findings from animal studies and its mechanism of action 

TAZVERIK can cause fetal harm when administered to pregnant women.

There are no available data on TAZVERIK use in pregnant women to inform the drug-associated risk.

Advise pregnant women 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.

Because of the potential risk for serious adverse reactions from TAZVERIK in the breastfed child, advise women not to breastfeed during treatment with TAZVERIK and for one week after the final dose.

3. Females and Males of Reproductive Potential Pregnancy Testing                      Verify the pregnancy status of females of reproductive potential prior to initiating TAZVERIK 

TAZVERIK can cause fetal harm when administered to pregnant women 

Contraception Females                                                                                        Advise females of reproductive potential to use effective non-hormonal contraception during treatment with TAZVERIK and for 6 months after the final dose. TAZVERIK can render some hormonal contraceptives ineffective 

Males                                                                                                                        Advise males with female partners of reproductive potential to use effective contraception during treatment with TAZVERIK and for at least 3 months after the final dose.

4 Pediatric Use                                                                                                          The safety and effectiveness of TAZVERIK have been established in pediatric patients aged 16 years and older (adolescents) with metastatic or locally advanced epithelioid sarcoma.

Use of TAZVERIK for this indication is supported by evidence from adequate and well-controlled studies in adults (including 3 adolescent patients aged 16 years) 

The safety and effectiveness of TAZVERIK in pediatric patients aged less than 16 years have not been established.

5. Geriatric Use                                                                                                        Clinical studies of TAZVERIK did not include sufficient numbers of patients with epithelioid sarcoma aged 65 and over to determine whether they respond differently from younger subjects.

6. Renal Impairment                                                                                                    No dose adjustment of TAZVERIK is recommended for patients with mild to severe renal impairment or end stage renal disease [see Clinical Pharmacology (12.3)].

7. Hepatic Impairment                                                                                                 No dose adjustment of TAZVERIK is recommended for patients with mild hepatic impairment (total bilirubin > 1 to 1.5 times upper limit of normal [ULN] or AST > ULN). TAZVERIK has not been studied in patients with moderate (total bilirubin > 1.5 to 3 times ULN) or severe (total bilirubin > 3 times ULN) hepatic impairment.