Tazemetostat has been discontinued in the US. Because this drug is no longer available in the US market, the material in this monograph is no longer updated by AHFS DI. If this drug is used in countries other than the US, it is essential that the manufacturers' labeling be consulted for more recently available information. |
Tazemetostat hydrobromide, a potent and selective inhibitor of the histone methyltransferase enhancer of zeste homolog 2 (EZH2), is an antineoplastic agent.1, 2, 4, 5, 6
Tazemetostat hydrobromide is used for the treatment of metastatic or locally advanced epithelioid sarcoma in patients who are not candidates for complete resection.1 The accelerated approval of tazemetostat for this indication is based on overall response rate and duration of response; continued approval may be contingent on verification and description of clinical benefit of the drug in confirmatory studies.1 Tazemetostat has been designated an orphan drug by FDA for the treatment of soft tissue sarcoma.8
The current indication for tazemetostat for the treatment of epithelioid sarcoma is based principally on the results for a cohort of 62 patients with metastatic or locally advanced epithelioid sarcoma with loss of integrase interactor-1 (INI-1) expression in a multicenter, open-label, noncomparative study (Study EZH-202).1, 2 In this study, patients received tazemetostat 800 mg orally twice daily until disease progression or unacceptable toxicity occurred.1 The primary efficacy end points were overall response rate (as evaluated by a blinded independent review committee) according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) and duration of response.1 The median age of patients included in the INI-1-negative epithelioid sarcoma cohort was 34 years; 92% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, 63% were male, 76% were White, 11% were Asian, and 44% had proximal disease.1 Most patients (77%) had undergone surgery and 61% had received prior systemic chemotherapy.1
At a median follow-up of 14 months, the overall response rate for patients receiving tazemetostat for the treatment of INI-1-negative epithelioid sarcoma was 15% (9 of 62 patients); complete response was achieved in 1 patient (1.6%).1, 2, 15 The time to complete or partial response was 1.4-18.4 months following initiation of tazemetostat.1 At the time of analysis, 67% of responders (6 of 9 patients) had a durable response of at least 6 months.1, 2
Tazemetostat hydrobromide is used for the treatment of relapsed or refractory follicular lymphoma harboring EZH2 mutation in patients who have received at least 2 prior systemic therapies; the drug also is used for the treatment of relapsed or refractory follicular lymphoma regardless of EZH2 mutation status in patients who are not candidates for other treatment options.1, 13 The accelerated approval of tazemetostat for this indication is based on overall response rate and duration of response; continued approval may be contingent on verification and description of clinical benefit of the drug in confirmatory studies.1 Tazemetostat has been designated an orphan drug by FDA for the treatment of follicular lymphoma.8
The current indication for tazemetostat in the treatment of relapsed or refractory follicular lymphoma is based principally on the results for a cohort of 42 patients with EZH2 mutation-positive follicular lymphoma in a multicenter, open-label, noncomparative, phase 2 study (Study E7438-G000-10113 ).1 In this study, patients with follicular lymphoma were enrolled in 2 cohorts: those with disease harboring EZH2 mutation and those with wild-type EZH2 .9 EZH2 mutations were determined using a cobas® EZH2 Mutation Test designed to detect mutations at codon Y646S, Y646H, Y646C, Y646F, Y646N, A682G, and A692V.1 In this study, 99 patients with follicular lymphoma received tazemetostat 800 mg orally twice daily until disease progression or unacceptable toxicity occurred.1 The major efficacy end points were overall response rate (as evaluated by an independent review committee) according to the International Working Group Non-Hodgkin Lymphoma (IWG-NHL) criteria and duration of response.1 In the EZH2 mutation cohort, the median age of patients was 62 years; 100% of patients had an ECOG performance status of 0 or 1, 58% were female, and 42% had early progression of disease (POD24) following first-line therapy.1 EZH2 mutations at codon Y646X [S, H, C], Y646F, Y646N, A682G, or A692V were detected in 36, 29, 27, 11, or 2% of patients, respectively.1 The median number of prior systemic therapies was 2 (range: 1-11) in the EZH2 mutation cohort; 49% of these patients were refractory to rituximab, 49% were refractory to their most recent therapy, and 9% had undergone prior stem cell transplantation.1 In the wild-type EZH2 cohort, the median age of patients was 61 years; 63% were male, 59% had POD24, and 91% had an ECOG performance status of 0 or 1.1 The median number of prior systemic therapies was 3 (range: 1-8) in the wild-type EZH2 cohort; 59% of these patients were refractory to rituximab, 41% were refractory to their most recent therapy, and 39% had undergone prior stem cell transplantation.1 The primary efficacy population included 95 patients who had received at least 2 prior systemic therapies.1
At a median follow-up of 22 or 36 months in the EZH2 mutation or wild-type EZH2 cohort, respectively, a higher overall response rate was observed in the EZH2 mutation cohort compared with the wild-type EZH2 cohort (69 versus 35%); complete response was achieved in 12 or 4% of patients, respectively.1, 14 In the EZH2 mutation or wild-type EZH2 cohort, the time to response was 3.7 months (range: 1.6-10.9 months) or 3.9 months (range: 1.6-16.3 months), respectively, following initiation of tazemetostat.1 At the time of analysis, the median duration of response in the EZH2 mutation or wild-type EZH2 cohort was 10.9 or 13 months, respectively.1, 14
Tazemetostat is administered orally twice daily without regard to meals.1 The tablets should be swallowed whole; they should not be cut, chewed, or crushed.1
If a dose of tazemetostat is missed or vomited after administration, an additional dose should not be administered to replace the missed or vomited dose.1 The next dose should be administered at the next scheduled time.1
Tazemetostat tablets should not be stored above 30°C.1
Dosage of tazemetostat hydrobromide is expressed in terms of tazemetostat.1
For the treatment of metastatic or locally advanced epithelioid sarcoma in adults and adolescents 16 years of age or older who are not candidates for complete resection, the recommended dosage of tazemetostat is 800 mg twice daily.1 Treatment should be continued until disease progression or unacceptable toxicity occurs.1
For the treatment of relapsed or refractory follicular lymphoma harboring EZH2 mutation in adults who have received at least 2 prior systemic therapies or for the treatment of relapsed or refractory follicular lymphoma regardless of EZH2 mutation status in adults who are not candidates for other treatment options, the recommended dosage of tazemetostat is 800 mg twice daily.1 Treatment should be continued until disease progression or unacceptable toxicity occurs.1
Dosage Modification for Toxicity
If adverse reactions occur during tazemetostat therapy, temporary interruption of therapy, dosage reduction, and/or discontinuance of the drug may be necessary.1 If dosage reduction is required, the dosage of tazemetostat should be reduced as described in Table 1.1
Dose Reduction Level | Dosage Reduction after Recovery from Toxicity (Initial Dosage = 800 mg twice daily) |
|---|---|
First | Resume at 600 mg twice daily |
Second | Resume at 400 mg twice daily |
Third | Permanently discontinue drug |
The following Recommended Dosage Modification for Tazemetostat Toxicity table indicates the recommended dosage modification (i.e., temporary interruption of therapy, dosage reduction, discontinuance of therapy) for adverse effects according to severity.1
Adverse Reaction and Severity | Toxicity Occurrence | Dosage Modification |
|---|---|---|
Neutropenia | ||
Absolute neutrophil count (ANC) <1000/mm3 | First | Withhold therapy; when ANC improves to baseline or ≥1000/mm3, resume therapy at same dosage |
Second or third | Withhold therapy; when ANC improves to baseline or ≥1000/mm3, resume therapy at a reduced dosage | |
Fourth | Permanently discontinue therapy | |
Thrombocytopenia | ||
Platelet count <50,000/mm3 | First or second | Withhold therapy; when platelet count improves to baseline or ≥75,000/mm3, resume therapy at a reduced dosage |
Third | Permanently discontinue therapy | |
Anemia | ||
Hemoglobin concentration <8 g/dL | Any | Withhold therapy; when anemia improves to grade 1 or less or to baseline, resume therapy at same or reduced dosage |
Other Toxicity | ||
Grade 3 | First or second | Withhold therapy; when toxicity improves to grade 1 or less or to baseline, resume therapy at a reduced dosage |
Third | Permanently discontinue therapy | |
Grade 4 | First | Withhold therapy; when toxicity improves to grade 1 or less or to baseline, resume therapy at a reduced dosage |
Second | Permanently discontinue therapy |
Dosage Modification for Concomitant Use with Drugs Affecting Hepatic Microsomal Enzymes
Concomitant use of tazemetostat with strong or moderate cytochrome P-450 (CYP) isoenzyme 3A inhibitors should be avoided.1 If concomitant use of a strong or moderate CYP3A inhibitor cannot be avoided, the manufacturer recommends reducing the daily dosage of tazemetostat as described in Table 3.1 When concomitant use of the strong or moderate CYP3A inhibitor is discontinued, the tazemetostat dosage should be returned (after 3 elimination half-lives of the CYP3A inhibitor) to the dosage used prior to initiation of the strong or moderate CYP3A inhibitor.1
Current Dosage | Dosage Reduction for Concomitant Use with a Strong or Moderate CYP3A Inhibitor |
|---|---|
800 mg twice daily | 400 mg twice daily |
600 mg twice daily | 600 mg daily in 2 divided doses (e.g., 400 mg in the morning followed by 200 mg in the evening for a total daily dosage of 600 mg) |
400 mg twice daily | 200 mg twice daily |
No dosage adjustment is necessary in patients with mild hepatic impairment (total bilirubin concentration exceeding the upper limit of normal [ULN], but no more than 1.5 times the ULN, or AST concentration exceeding the ULN).1
No dose adjustment is necessary in patients with renal impairment or end-stage renal disease.1
The manufacturer makes no specific dosage recommendations for geriatric patients.1
Development of Secondary Malignancies
Development of secondary malignancies may occur following treatment with tazemetostat.1 In clinical trials involving 758 adults who were administered tazemetostat 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.1 A single pediatric patient developed T-cell lymphoblastic lymphoma (T-LBL).1
Patients should be monitored long term for the development of secondary malignancies.1
Fetal/Neonatal Morbidity and Mortality
There are no adequate and well-controlled studies of tazemetostat in pregnant women; however, based on its mechanism of action and animal findings, tazemetostat may cause fetal harm.1 Skeletal abnormalities have been observed in animals receiving tazemetostat at exposure levels as low as approximately 1.5 times the adult human exposure at the recommended dosage.1
Pregnancy should be avoided during tazemetostat therapy.1 The manufacturer states that a pregnancy test should be performed prior to initiation of tazemetostat therapy in women of reproductive potential and that such women should be advised to use effective nonhormonal methods of contraception while receiving the drug and for 6 months after the last dose.1 In addition, men who are partners of such women should use effective contraceptive methods while receiving the drug and for at least 3 months after the last dose.1 Concomitant use of tazemetostat and hormonal contraceptives may result in decreased systemic exposure to the hormonal contraceptive and reduced efficacy of the hormonal contraceptive.1 If tazemetostat is used during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential fetal hazard.
Tazemetostat may cause fetal harm if administered to pregnant women based on animal findings.1
It is not known whether tazemetostat is distributed into human milk or if the drug has any effect on milk production or the nursing infant.1 Because of the potential for serious adverse reactions to tazemetostat in nursing infants, women should be advised to discontinue nursing during tazemetostat therapy and for 1 week after the last dose.1
Safety and efficacy of tazemetostat have not been established in adolescents younger than 16 years of age.1
Safety and efficacy of tazemetostat for the treatment of metastatic or locally advanced epithelioid sarcoma in adolescents 16 years of age or older have been established in clinical studies evaluating tazemetostat in adults and 3 adolescent patients 16 years of age.1
T-LBL, weight gain, and distended testicles have been observed in immature rats receiving tazemetostat from postnatal day 7-97 at exposure levels approximately equal to the adult human exposure at the recommended dosage, and increased trabecular bone was observed at exposure levels approximately 10 times the adult human exposure at the recommended dosage.1
Experience with tazemetostat in patients 65 years of age or older with epithelioid sarcoma or follicular lymphoma is insufficient to determine whether geriatric patients respond differently than younger individuals.1
Population pharmacokinetic analysis suggests that the pharmacokinetics of tazemetostat are not substantially altered in patients with mild hepatic impairment (total bilirubin concentration exceeding the upper limit of normal [ULN], but no more than 1.5 times the ULN, or AST concentration exceeding the ULN).1
The effect of moderate to severe hepatic impairment (total bilirubin concentration exceeding 1.5 times the ULN) on the pharmacokinetics of tazemetostat has not been established.1
Population pharmacokinetic analysis suggests that the pharmacokinetics of tazemetostat are not substantially altered in patients with renal impairment, including those with end-stage renal disease.1
Adverse effects reported in 20% or more of patients receiving tazemetostat for the treatment of epithelioid sarcoma include pain, fatigue, nausea, decreased appetite, vomiting, and constipation.1 Grade 3 or 4 laboratory abnormalities reported in 10% or more of patients receiving tazemetostat include anemia and lymphocytopenia.1
Adverse effects reported in 20% or more of patients receiving tazemetostat for the treatment of follicular lymphoma include fatigue, upper respiratory tract infection, musculoskeletal pain, nausea, and abdominal pain.1 Grade 3 or 4 laboratory abnormalities reported in 5% or more of patients receiving tazemetostat include lymphocytopenia, hyperglycemia, leukopenia, neutropenia, thrombocytopenia, and anemia.1
Tazemetostat is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A.1
In vitro, tazemetostat does not inhibit CYP isoenzymes 1A2, 2B6, 2C9, or 2D6 at clinically relevant concentrations.1
In vitro studies also suggest that tazemetostat is a substrate of P-glycoprotein (P-gp), but is not a substrate of breast cancer resistance protein (BCRP), organic cation transporter (OCT) 2, organic anion transporter (OAT) 3, multidrug and toxin extrusion (MATE) transporter 1, organic anion transporting polypeptide (OATP) 1B1, and OATP1B3.1
In vitro, tazemetostat inhibits MATE1 and MATE2K, but does not inhibit P-gp, BCRP, OATP1B1, OATP1B3, OCT1, OCT2, OAT1, OAT3, or bile salt export pump (BSEP) at clinically relevant concentrations.1
Drugs and Foods Affecting Hepatic Microsomal Enzymes
Concomitant use of tazemetostat with strong or moderate inhibitors of CYP3A may result in increased systemic exposure to tazemetostat and possible toxicity.1 When the moderate CYP3A inhibitor fluconazole was administered concomitantly with tazemetostat (400 mg twice daily), peak plasma concentration and area under the concentration-time curve (AUC) of tazemetostat increased 2.3- and 3.1-fold, respectively.1 When coadministered with itraconazole, a strong CYP3A inhibitor, the peak plasma concentration and AUC of tazemetostat (400 mg twice daily) increased 1.9- and 2.5-fold, respectively.1
Concomitant use of tazemetostat with strong or moderate CYP3A inhibitors (e.g., fluconazole, grapefruit, grapefruit juice) should be avoided.1 If concomitant use of a strong or moderate CYP3A inhibitor cannot be avoided, the manufacturer recommends reducing the dosage of tazemetostat as described in Table 3.1 When concomitant use of the strong or moderate CYP3A inhibitor is discontinued, the tazemetostat dosage should be returned (after 3 elimination half-lives of the CYP3A inhibitor) to the dosage used prior to initiation of the strong or moderate CYP3A inhibitor.1
Concomitant use of tazemetostat with strong or moderate inducers of CYP3A (e.g., rifampin, St. John's wort [ Hypericum perforatum ]) may result in decreased systemic exposure to tazemetostat and reduced tazemetostat efficacy; concomitant use should be avoided.1 The coadministration of rifampin, a strong CYP3A inducer, with tazemetostat (800 mg twice daily) resulted in a reduction in peak plasma concentration and AUC of tazemetostat of 84% for both pharmacokinetic variables.1
Drugs Metabolized by Hepatic Microsomal Enzymes
Concomitant use of tazemetostat and substrates of CYP3A (e.g., midazolam, hormonal contraceptives) may result in decreased systemic exposure to the CYP3A substrate and reduced efficacy of the substrate drug.1 When the sensitive CYP3A substrate midazolam was administered concomitantly with tazemetostat (800 mg twice daily) in patients, peak plasma concentration and AUC of midazolam decreased by 21 and 40%, respectively.1
Substrates of Other CYP Isoenzymes
When the sensitive CYP2C8 substrate repaglinide and sensitive CYP2C19 substrate omeprazole were administered concomitantly with tazemetostat, peak plasma concentration and AUC of repaglinide increased by 51 and 80%, respectively, and systemic exposure to omeprazole was unaffected.1
Drugs Affecting Gastric Acidity
When the proton-pump inhibitor omeprazole was administered concomitantly with tazemetostat (800 mg twice daily), steady-state AUC and peak plasma concentration of tazemetostat increased by 26 and 25%, respectively; however, this effect is not expected to be clinically relevant.1
Tazemetostat hydrobromide, a potent and selective inhibitor of the histone methyltransferase enhancer of zeste homolog 2 (EZH2), including EZH2 with Y646X, A682G, or A692V activating mutations, is an antineoplastic agent.1, 2, 4, 5, 6 EZH2 is the catalytic subunit of the polycomb repressive complex 2 (PRC2), a complex that methylates lysine 27 of histone H3 to promote transcriptional silencing of target genes.1, 6, 11 In vitro and in vivo, loss or dysfunction of the chromatin remodeling complex switch/sucrose nonfermentable (SWI/SNF) results in aberrant EZH2 activity and oncogenic dependency on EZH2 enzymatic activity.1, 11 In vivo, tazemetostat has demonstrated antitumor activity in xenograft models of B-cell lymphoma with or without EZH2 activating mutations; however, the drug has demonstrated greater effects on inhibition of proliferation of lymphoma cell lines with mutant EZH2.1 Tazemetostat also has demonstrated inhibition of EZH1 with a half-maximal inhibitory concentration approximately 36 times higher than the half-maximal inhibitory concentration for EZH2.1
The mean absolute bioavailability of tazemetostat following oral administration is approximately 33%.1 Following oral administration, peak plasma concentrations of tazemetostat are achieved in approximately 1-2 hours.1 Following administration of tazemetostat, systemic exposure to tazemetostat increases in an approximately dose-proportional manner over a dosage range of 200-1600 mg twice daily.1 Following repeated twice-daily dosing, steady-state concentrations of the drug are attained in 15 days, with a mean accumulation ratio of 0.58.1 Administration of a high-fat, high-calorie meal (approximately 800-1000 calories) with tazemetostat did not affect systemic exposure to the drug.1 Tazemetostat is 88% bound to plasma proteins in vitro.1 Tazemetostat is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A to form the major inactive metabolites M5 and M3.1 M5 is further metabolized by CYP3A.1 Most (94%) of an orally administered dose is recovered over 12 days; 79% of the dose is eliminated in feces and 15% is eliminated in urine.1 The elimination half-life of tazemetostat is 3.1 hours.1 The pharmacokinetics of tazemetostat are not affected by age (16-91 years of age), sex, body weight (37-173 kg), or race.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].
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.
Distribution of tazemetostat is restricted.3 Contact manufacturer for additional information.3
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, film-coated | 200 mg (of tazemetostat) | Epizyme |
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions April 10, 2026. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Epizyme, Inc. Tazverik® (tazemetostat) tablets prescribing information. Cambridge, MA; 2024 Aug.
2. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 211723Orig1s000: Multi-discipline review. From FDA website. [Web]
3. Epizyme, Inc. From Tazveri® (tazemetostat hydrobromide) for healthcare professionals website. Accessed 21 Jul 2020. [Web]
4. Knutson SK, Kawano S, Minoshima Y et al. Selective inhibition of EZH2 by EPZ-6438 leads to potent antitumor activity in EZH2-mutant non-Hodgkin lymphoma. Mol Cancer Ther . 2014; 13:842-54. [PubMed 24563539]
5. Kurmasheva RT, Sammons M, Favours E et al. Initial testing (stage 1) of tazemetostat (EPZ-6438), a novel EZH2 inhibitor, by the Pediatric Preclinical Testing Program. Pediatr Blood Cancer . 2017; 64 [PubMed 27555605]
6. Gulati N, Béguelin W, Giulino-Roth L. Enhancer of zeste homolog 2 (EZH2) inhibitors. Leuk Lymphoma . 2018; 59:1574-1585. [PubMed 29473431]
7. Mittal P, Roberts CWM. The SWI/SNF complex in cancer - biology, biomarkers and therapy. Nat Rev Clin Oncol . 2020; 17:435-448. [PubMed 32303701]
8. Food and Drug Administration. FDA Application: Search orphan drug designations and approvals. Silver Spring, MD. From FDA web site. [Web]
9. Open-label, multicenter, phase 1/2 Study of tazemetostat (EZH2 histone methyl transferase [HMT] inhibitor) as a single agent in subjects with adv. solid tumors or with B-cell lymphomas and tazemetostat in combination with prednisolone in subjects with DLBCL. From ClinicalTrials.gov registry. Accessed 2020 Jul 20. [Web]
11. Kim KH, Roberts CW. Targeting EZH2 in cancer. Nat Med . 2016; 22:128-34. [PubMed 26845405]
13. Italiano A, Soria JC, Toulmonde M et al. Tazemetostat, an EZH2 inhibitor, in relapsed or refractory B-cell non-Hodgkin lymphoma and advanced solid tumours: a first-in-human, open-label, phase 1 study. Lancet Oncol . 2018; 19:649-659. [PubMed 29650362]
14. Morschhauer F, Tilly H, Chaidos A, et al. Tazemetostat for patients with relapsed or refractory follicular lymphoma: an open-label, single-arm, multicenter, phase 2 trial. Lancet Oncol . 2020;21:1433-42.
15. Gounder M, Schoffski P, Jones RL, et al. Tazemetostat in advanced epithelial sarcoma with loss of INI1/SMARCB1: a n international, open-label, phase 2 basket study. Lancet Oncol . 2020;21:1423-32.