Tazverik

TAZVERIK 200 mg film-coated tablets are red, round, biconvex shape and debossed with "EZM 200" on one side and plain on the other.
Each tablet contains 200 mg tazemetostat equivalent to 228.3 mg tazemetostat hydrobromide.
Tazemetostat is a methyltransferase inhibitor. Tazemetostat hydrobromide has the following chemical name: [1,1'-Biphenyl]-3-carboxamide, N-[(1,2-dihydro-4,6-dimethyl-2-oxo-3-pyridinyl)methyl]-5-[ethyl(tetrahydro-2H-pyran-4-yl)amino]-4-methyl-4'-(4-morpholinylmethyl)-, hydrobromide (1:1). The molecular formula of tazemetostat hydrobromide is C₃₄H₄₄N₄O₄·HBr. Tazemetostat hydrobromide has a molecular weight of 653.66 g/mol.
Tazemetostat hydrobromide is a white to off-white solid that is slightly soluble in water and has pKa values of 5.26, 6.88, and 12.62. A saturated aqueous solution of tazemetostat hydrobromide has a pH of approximately 5 at ambient conditions.
Excipients/Inactive Ingredients: Each tablet contains the following inactive ingredients in the tablet core: hydroxypropyl cellulose, lactose monohydrate, low-substituted hydroxypropyl cellulose, magnesium stearate, and sodium starch glycolate. The film-coat contains hypromellose, polyethylene glycol, red iron oxide, talc, and titanium dioxide.

Pharmacology: Mechanism of Action: Tazemetostat is an inhibitor of the methyltransferase, EZH2, and some EZH2 gain-of-function mutations including Y646X, A682G, and A692V. 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.
The most well-characterized function of EZH2 is as the catalytic subunit of the polycomb repressive complex 2 (PRC2), catalyzing mono-, di-, and trimethylation of lysine 27 of histone H3. Trimethylation of histone H3 leads to transcriptional repression.
Tazemetostat suppressed proliferation of B-cell lymphoma cell lines in vitro and demonstrated antitumor activity in a mouse xenograft model of B-cell lymphoma with or without EZH2 gain-of-function mutations. Tazemetostat demonstrated greater effects on the inhibition of proliferation of lymphoma cell lines with mutant EZH2.
Pharmacodynamics: Tazemetostat 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.
Clinical Studies: Relapsed or Refractory Follicular Lymphoma: The efficacy of TAZVERIK was evaluated in two open-label, single-arm cohorts (Cohorts 4 and 5) of a multi-center study (Study E7438-G000-101, NCT01897571) in patients with histologically confirmed follicular lymphoma after at least 2 prior systemic therapies. Patients were required to have ECOG PS of 0-2 and were enrolled based on EZH2 mutation status. EZH2 mutations were identified prospectively using formalin-fixed, paraffin-embedded tumor samples, which were centrally tested using the cobas EZH2 Mutation Test; the cobas EZH2 Mutation test is designed to detect the following mutations: Y646X [S,H,C], Y646F, Y646N, A682G, and A692V. Patients received TAZVERIK 800 mg orally twice daily until confirmed disease progression or unacceptable toxicity. Tumor response assessments were performed every 8 weeks through Week 24 and then every 12 weeks. The major efficacy outcome measures were ORR and DOR according to the International Working Group Non-Hodgkin Lymphoma (IWG-NHL) criteria as assessed by Independent Review Committee. Median duration of follow-up was 22 months (range 3 months to 44 months) for patients with EZH2 MT positive tumors and 36 months (range 32 months to 39 months) for patients whose tumors did not have an EZH2 mutation detected.
A total of 99 patients were enrolled, including 45 patients whose tumors had one of these EZH2 mutations (mutant) and 54 patients whose tumors did not have one of these mutations (wild-type).
Among the 45 patients with EZH2 mutant follicular lymphoma, median age was 62 years (range 38 to 80), 58% were female, 42% had early progression following front-line therapy (POD24), and all had an ECOG PS of 0 or 1. Race was reported in 84% of patients; of these patients, 82% were White. Based on the cobas EZH2 Mutation test, 36%, 29%, 27%, 11% and 2% of patients had the following mutations: Y646X [S,H,C], Y646F, Y646N, A682G, and A692V, respectively. The median number of lines of prior systemic therapy was 2 (range 1 to 11), with 49% refractory to rituximab, 49% refractory to their last therapy, and 9% had received prior stem cell transplant.
Among the 54 patients with EZH2 wild-type follicular lymphoma, median age was 61 years (range 36 to 87), 63% were male, 59% had POD24, and 91% had an ECOG PS of 0 or 1. Race was reported in 57% of patients; of these patients, 48% were White and 3% were Asian. The median number of lines of prior systemic therapy was 3 (range 1 to 8), with 59% refractory to rituximab, 41% refractory to their last therapy, and 39% had received prior stem cell transplant.
The approval of TAZVERIK was based upon the efficacy in 95 patients (42 EZH2 Mutant, 53 EZH2 Wild-Type) who had received at least 2 prior systemic therapies and is presented in Table 1. (See Table 1.)

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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 (C_max) was 829 (56%) ng/mL and AUC_0-12h 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 (V_ss/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 (CL_ss/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: Co-administration of fluconazole (a moderate CYP3A inhibitor) with TAZVERIK 400 mg twice daily in patients increased tazemetostat steady-state AUC_0-8h by 3.1-fold and C_max by 2.3-fold.
Effect of Gastric Acid Reducing Agents on Tazemetostat: Co-administration of omeprazole (a proton pump inhibitor) with TAZVERIK 800 mg twice daily in patients increased tazemetostat steady-state AUC_0-8h by 26% and C_max by 25%, which is not expected to have clinically relevant impact.
Effect of Tazemetostat on CYP3A Substrate: Co-administration of TAZVERIK 800 mg twice daily with oral midazolam (a sensitive CYP3A substrate) in patients decreased midazolam AUC_0-12h by 40% and C_max by 21%.
Effect of Tazemetostat on CYP2C8 and CYP2C19 Substrates: Co-administration of TAZVERIK 800 mg twice daily with repaglinide (a sensitive CYP2C8 substrate) and omeprazole (a sensitive CYP2C19 substrate) in patients increased repaglinide AUC_0-8h by 80% and C_max 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.
Toxicology: Nonclinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: Dedicated carcinogenicity studies were not conducted with tazemetostat, but T-LBL, MDS, AML, and B-ALL have been reported clinically and T-LBL occurred in juvenile and adult rats after ~9 or more weeks of tazemetostat administration during 13-week toxicity studies. Based on nonclinical studies in rats, the risk of T-LBL appears to be greater with longer duration dosing.
Tazemetostat did not cause genetic damage in a standard battery of studies including a screening and pivotal bacterial reverse mutation (Ames) assay, an in vitro micronucleus assessment in human peripheral blood lymphocytes, and an in vivo micronucleus assessment in rats after oral administration.
Fertility and early embryonic development studies have not been conducted with tazemetostat; however, an assessment of male and female reproductive organs were included in 4- and 13-week repeat-dose toxicity studies in rats and Cynomolgus monkeys. Oral daily administration of tazemetostat did not result in any notable effects in the adult male and female reproductive organs [see Females and Males of Reproductive Potential under Use in Pregnancy & Lactation].

Relapsed or Refractory Follicular Lymphoma: TAZVERIK is indicated for the treatment of adult patients with relapsed or refractory (R/R) follicular lymphoma (FL) whose tumors are positive for an EZH2 mutation and who have received at least 2 prior systemic therapies.

Patient Selection: Select patients with R/R FL for treatment with TAZVERIK based on the presence of EZH2 mutation of codons Y646, A682, or A692 in tumor specimens [see Pharmacology: Pharmacodynamics: Clinical Studies under Actions].
Recommended Dosage: The recommended dosage of TAZVERIK is 800 mg orally twice daily with or without food until disease progression or unacceptable toxicity.
Swallow tablets whole. Do not cut, crush, or chew tablets.
Do not take an additional dose if a dose is missed or vomiting occurs after TAZVERIK, but continue with the next scheduled dose.
Dosage Modifications for Adverse Reactions: Table 2 summarizes the recommended dose reductions, and Table 3 summarizes the recommended dosage modifications of TAZVERIK for adverse reactions. (See Tables 2 and 3.)

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Dosage Modifications for Drug Interactions: Strong and Moderate CYP3A Inhibitors: Avoid co-administration of TAZVERIK with strong or moderate CYP3A inhibitors. If co-administration with a moderate CYP3A inhibitor cannot be avoided, reduce the TAZVERIK dose as shown in Table 4 as follows. After discontinuation of the moderate CYP3A inhibitor for 3 elimination half-lives, resume the TAZVERIK dose that was taken prior to initiating the inhibitor [see Effect of Other Drugs on TAZVERIK under Interactions; Pharmacology: Pharmacokinetics under Actions]. (See Table 4.)

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None.

Secondary Malignancies: The risk of developing secondary malignancies is increased following treatment with TAZVERIK. Across clinical trials of 758 adults who received TAZVERIK 800 mg twice daily as monotherapy, myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), or B-cell acute lymphoblastic leukemia (B-ALL) occurred in 1.7% of patients. One pediatric patient developed T-cell lymphoblastic lymphoma (T-LBL). Monitor patients long-term for the development of secondary malignancies.
Embryo-Fetal Toxicity: 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. Administration of tazemetostat to pregnant rats and rabbits during organogenesis resulted in dose-dependent increases in skeletal developmental abnormalities in both species beginning at maternal exposures approximately 1.5 times the adult human exposure (area under the plasma concentration time curve [AUC_0-45h]) at the 800 mg twice daily dose.
Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective 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 [see Pregnancy and Females and Males of Reproductive Potential under Use in Pregnancy & Lactation].
Renal Impairment: No dose adjustment of TAZVERIK is recommended for patients with mild to severe renal impairment or end stage renal disease [see Pharmacology: Pharmacokinetics under Actions].
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 [see Pharmacology: Pharmacokinetics under Actions].
Use in Children: The safety and effectiveness of TAZVERIK in pediatric patients aged less than 16 years have not been established.
Juvenile Animal Toxicity Data: In a 13-week juvenile rat toxicology study, animals were dosed daily from post-natal day 7 to day 97 (approximately equivalent to neonate to adulthood). Tazemetostat resulted in: T-LBL at doses ≥50 mg/kg (approximately 2.8 times the adult human exposure at the 800 mg twice daily dose); Increased trabecular bone at doses ≥100 mg/kg (approximately 10 times the adult human exposure at the 800 mg twice daily dose); Increased body weight at doses ≥50 mg/kg (approximately equal to the adult human exposure at the 800 mg twice daily dose); Distended testicles in males at doses ≥50 mg/kg (approximately equal to the adult human exposure at the 800 mg twice daily dose).
Use in the Elderly: Clinical studies of TAZVERIK did not include sufficient numbers of patients with relapsed or refractory follicular lymphoma aged 65 and over to determine whether they respond differently from younger subjects.

Pregnancy: Risk Summary: Based on findings from animal studies and its mechanism of action [see Pharmacology: Mechanism of Action under Actions], 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. Administration of tazemetostat to pregnant rats and rabbits during organogenesis resulted in dose-dependent increases in skeletal developmental abnormalities in both species beginning at maternal exposures approximately 1.5 times the adult human exposure [AUC_0-45h] at the 800 mg twice daily dose (see Data as follows). 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.
Data: Animal Data: In pregnant rats, once daily oral administration of tazemetostat during the period of organogenesis from gestation day (GD) 7 through 17 resulted in no maternal adverse effects at doses up to 100 mg/kg/day (approximately 6 times the adult human exposure at 800 mg twice daily). Skeletal malformations and variations occurred in fetuses at doses of ≥50 mg/kg (approximately 2 times the adult human exposure at the 800 mg twice daily dose). At 200 mg/kg (approximately 14 times the adult human exposure at the 800 mg twice daily dose), major findings included increased post implantation loss, missing digits, fused vertebrae, domed heads and fused bones of the skull, and reduced fetal body weights.
In pregnant rabbits, no adverse maternal effects were observed after once daily oral administration of 400 mg/kg/day tazemetostat (approximately 7 times the adult human exposure at the 800 mg twice daily dose) from GD 7 through 19. Skeletal variations were present at doses ≥100 mg/kg/day (approximately 1.5 times the adult human exposure at the 800 mg twice daily dose), with skeletal malformations at ≥200 mg/kg/day (approximately 5.6 times the adult human exposure at the 800 mg twice daily dose). At 400 mg/kg (approximately 7 times the adult human exposure at the 800 mg twice daily dose), major findings included increased post implantation loss and cleft palate and snout.
Lactation: Risk Summary: There are no animal or human data on the presence of tazemetostat in human milk or on its effects on the breastfed child or milk production. 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.
Females and Males of Reproductive Potential: Pregnancy Testing: Verify the pregnancy status of females of reproductive potential prior to initiating TAZVERIK [see Pregnancy as previously mentioned].
Risk Summary: TAZVERIK can cause fetal harm when administered to pregnant women [see Pregnancy as previously mentioned].
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 [see Effect of TAZVERIK on Other Drugs under Interactions].
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.

The following clinically significant adverse reactions are described in Precautions: Secondary Malignancies.
Clinical Trial Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Relapsed or Refractory Follicular Lymphoma: The safety of TAZVERIK was evaluated in two cohorts (Cohorts 4 and 5) of Study E7438-G000-101 that enrolled patients with relapsed or refractory follicular lymphoma [see Pharmacology: Pharmacodynamics: Clinical Studies under Actions]. Patients received TAZVERIK 800 mg orally twice daily (n=99). Among patients who received TAZVERIK, 68% were exposed for 6 months or longer, 39% were exposed for 12 months or longer, and 21% were exposed for 18 months or longer.
The median age was 62 years (range 36 to 87 years), 54% were male, and 95% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. The median number of prior therapies was 3 (range 1 to 11). Patients were required to have a creatinine clearance ≥40 mL/min per the Cockcroft and Gault formula.
Serious adverse reactions occurred in 30% of patients who received TAZVERIK. Serious adverse reactions in ≥2% of patients who received TAZVERIK were general physical health deterioration, abdominal pain, pneumonia, sepsis, and anemia.
Permanent discontinuation due to an adverse reaction occurred in 8% of patients who received TAZVERIK. Adverse reaction resulting in permanent discontinuation in ≥2% of patients was second primary malignancy.
Dosage interruptions due to an adverse reaction occurred in 28% of patients who received TAZVERIK. Adverse reactions requiring dosage interruptions in ≥3% of patients were thrombocytopenia and fatigue.
Dose reduction due to an adverse reaction occurred in 9% of patients who received TAZVERIK.
The most common adverse reactions (≥20%) were fatigue, upper respiratory tract infection, musculoskeletal pain, nausea, and abdominal pain.
Table 5 presents adverse reactions in patients with relapsed or refractory follicular lymphoma in Cohorts 4 and 5 of Study E7438-G000-101. (See Table 5.)

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Clinically relevant adverse reactions occurring in <10% of patients who received TAZVERIK included: Infection: sepsis (2%), pneumonia (2%), and herpes zoster (2%).
Table 6 summarizes select laboratory abnormalities in patients with follicular lymphoma in Cohorts 4 and 5 of Study E7438-G000-101. (See Table 6.)

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Effect of Other Drugs on TAZVERIK: Strong and Moderate CYP3A Inhibitors: Co-administration of TAZVERIK with a strong or moderate CYP3A inhibitor increases tazemetostat plasma concentrations [see Pharmacology: Pharmacokinetics under Actions], which may increase the frequency or severity of adverse reactions. Avoid co-administration of strong or moderate CYP3A inhibitors with TAZVERIK. If co-administration of moderate CYP3A inhibitors cannot be avoided, reduce TAZVERIK dose [see Dosage Modifications for Drug Interactions under Dosage & Administration].
Strong and Moderate CYP3A Inducers: Co-administration of TAZVERIK with a strong or moderate CYP3A inducer may decrease tazemetostat plasma concentrations [see Pharmacology: Pharmacokinetics under Actions], which may decrease the efficacy of TAZVERIK. Avoid co-administration of moderate and strong CYP3A inducers with TAZVERIK.
Effect of TAZVERIK on Other Drugs: CYP3A Substrates: Co-administration of TAZVERIK with CYP3A substrates, including hormonal contraceptives, can result in decreased concentrations and reduced efficacy of CYP3A substrates [see Females and Males of Reproductive Potential under Use in Pregnancy & Lactation; Pharmacology: Pharmacokinetics under Actions].

Do not store above 30°C (86°F).

Secondary Malignancies: Advise patients of the increased risk of secondary malignancies. Advise patients to inform their healthcare provider if they experience fatigue, easy bruising, fever, bone pain, or paleness [see Secondary Malignancies under Precautions].
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 [see Pregnancy under Use in Pregnancy & Lactation].
Advise females of reproductive potential to use effective non-hormonal contraception during treatment with TAZVERIK and for 6 months after the final dose [see Females and Males of Reproductive Potential under Use in Pregnancy & Lactation].
Advise males with female partners of reproductive potential to use effective contraception during treatment with TAZVERIK and for 3 months after the final dose [see Females and Males of Reproductive Potential under Use in Pregnancy & Lactation; Pharmacology: Toxicology: Nonclinical Toxicology under Actions].
Lactation: Advise women not to breastfeed during treatment with TAZVERIK and for 1 week after the final dose [see Lactation under Use in Pregnancy & Lactation].
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 [see Effect of Other Drugs on TAZVERIK under Interactions].

Targeted Cancer Therapy

L01XX72 - tazemetostat ; Belongs to the class of other antineoplastic agents. Used in the treatment of cancer.

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