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Tazemetostat

Class: Antineoplastic Agents
- Enhancer of Zeste Homolog 2 Inhibitor
- EZH2 Inhibitor
Chemical Name: N-[(4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-5-[ethyl (oxan-4-yl)amino]-4-methyl-4¢-[(morpholin-4-yl)methyl][1,1¢-biphenyl]-3-carboxamide monohydrobromide
Molecular Formula: C34H44N4O4•HBr
CAS Number: 1467052-75-0
Brands: Tazverik

Medically reviewed by Drugs.com. Last updated on Oct 12, 2020.

Introduction

Antineoplastic agent; potent and selective inhibitor of the histone methyltransferase enhancer of zeste homolog 2 (EZH2).1 2 4 5 6

Uses for Tazemetostat

Soft Tissue Sarcoma

Treatment of metastatic or locally advanced epithelioid sarcoma in patients who are not candidates for complete resection;1 designated an orphan drug by FDA for the treatment of soft tissue sarcoma.8

Accelerated approval based on overall response rate and duration of response; continued approval may be contingent on verification and description of clinical benefit in confirmatory studies.1

Non-Hodgkin Lymphoma

Treatment of relapsed or refractory follicular lymphoma harboring EZH2 mutation in patients who have received at least 2 prior systemic therapies; also used in patients with relapsed or refractory follicular lymphoma who are not candidates for other treatment options regardless of EZH2 mutation status.1 13

Designated an orphan drug by FDA for the treatment of this cancer.8

Accelerated approval based on overall response rate and duration of response; continued approval may be contingent on verification and description of clinical benefit in confirmatory studies.1

Tazemetostat Dosage and Administration

General

  • Confirm presence of EZH2 mutation in codon Y646, A682, or A692 in tumor specimens of certain patients with relapsed or refractory follicular lymphoma prior to initiation of therapy.1 (See Non-Hodgkin Lymphoma under Uses.)

Restricted Distribution

  • Obtain tazemetostat through designated specialty distributors.3

Administration

Oral Administration

Administer orally twice daily without regard to meals.1

Swallow tablets whole; do not cut, chew, or crush.1

Dosage

Available as tazemetostat hydrobromide; dosage expressed in terms of tazemetostat.1

Pediatric Patients

Epithelioid Sarcoma
Oral

Adolescents ≥16 years of age: 800 mg twice daily.1

Continue therapy until disease progression or unacceptable toxicity occurs.1

If concomitant use with moderate CYP3A inhibitors cannot be avoided, adjust dosage of tazemetostat.1 (See Interactions.)

Dosage Modification for Toxicity
Oral

Temporary interruption of therapy, dosage reduction, and/or permanent discontinuance of drug may be necessary.1 Recommendations for dosage modification for toxicity in adults also apply to adolescents (see Table 2).1 When dosage reduction is required in adolescents, reduce dosage of tazemetostat as described in Table 1.1

Table 1: Recommended Dosage Reduction for Tazemetostat Toxicity1

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

If an adverse reaction occurs, modify treatment accordingly (see Table 2).1

Table 2. Recommended Dosage Modification for Tazemetostat Toxicity1

Adverse Reaction and Severity

Toxicity Occurrence

Dosage Modification

Neutropenia

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

Adults

Epithelioid Sarcoma
Oral

800 mg twice daily.1

Continue therapy until disease progression or unacceptable toxicity occurs.1

If concomitant use with moderate CYP3A inhibitors cannot be avoided, adjust dosage of tazemetostat.1 (See Interactions.)

Follicular Lymphoma
Oral

800 mg twice daily.1

Continue therapy until disease progression or unacceptable toxicity occurs.1

If concomitant use with moderate CYP3A inhibitors cannot be avoided, adjust dosage of tazemetostat.1 (See Interactions.)

Dosage Modification for Toxicity
Oral

Temporary interruption of therapy, dosage reduction, and/or permanent discontinuance of drug may be necessary.1 When dosage modification is required, reduce dosage of tazemetostat as described in Table 1.1

Prescribing Limits

Pediatric Patients

Epithelioid Sarcoma
Oral

Dosage <400 mg twice daily not recommended.1

Adults

Epithelioid Sarcoma
Oral

Dosage <400 mg twice daily not recommended.1

Follicular Lymphoma
Oral

Dosage <400 mg twice daily not recommended.1

Special Populations

Hepatic Impairment

Mild hepatic impairment (total bilirubin concentration exceeding the ULN, but not >1.5 times the ULN, or AST concentration exceeding the ULN): No dosage adjustment required.1

Moderate to severe hepatic impairment (total bilirubin concentration >1.5 times the ULN): No specific dosage recommendations at this time.1

Renal Impairment

Renal impairment, including end-stage renal disease: No dose adjustment required.1

Geriatric Patients

No specific dosage recommendations at this time.1 (See Geriatric Uses under Cautions.)

Cautions for Tazemetostat

Contraindications

  • Manufacturer states none known.1

Warnings/Precautions

Development of Secondary Malignancies

Development of secondary malignancies (i.e., myelodysplastic syndrome [MDS], acute myeloid leukemia [AML], T-cell lymphoblastic lymphoma [T-LBL]) reported 14 months to over 4 years following initiation of tazemetostat therapy.1 2

Monitor patients long term for development of secondary malignancies.1

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm.1 Teratogenicity (i.e., skeletal abnormalities) demonstrated in animals.1

Avoid pregnancy during therapy.1 Perform pregnancy test prior to initiation of tazemetostat in women of reproductive potential.1 Women of reproductive potential should use effective nonhormonal methods of contraception while receiving the drug and for 6 months after the last dose.1 (See Interactions.) Men who are partners of such women should use effective methods of contraception while receiving the drug and for at least 3 months after the last dose.1 If used during pregnancy or if patient becomes pregnant, apprise patient of potential fetal hazard.1

Specific Populations

Pregnancy

May cause fetal harm.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether tazemetostat is distributed into human milk or affects nursing infants or milk production.1 Discontinue nursing during therapy and for 1 week after the last dose.1

Pediatric Use

Safety and efficacy not established in pediatric patients <16 years of age.1

Safety and efficacy of tazemetostat for metastatic or locally advanced epithelioid sarcoma in adolescents ≥16 years of age have been established in clinical studies evaluating tazemetostat in adults and 3 adolescent patients 16 years of age.1

T-LBL, weight gain, distended testicles, and increased trabecular bone observed in immature rats.1

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether efficacy and safety are similar to those in younger adults.1

Hepatic Impairment

Pharmacokinetics not altered in patients with mild hepatic impairment (total bilirubin concentration exceeding the ULN, but not >1.5 times the ULN, or AST concentration exceeding the ULN).1

Effect of moderate to severe hepatic impairment (total bilirubin concentration >1.5 times the ULN) on pharmacokinetics not established.1

Renal Impairment

Pharmacokinetics not altered in patients with renal impairment, including those with end-stage renal disease.1

Common Adverse Effects

Epithelioid sarcoma: Pain, fatigue, nausea, decreased appetite, vomiting, constipation, anemia, lymphocytopenia.1

Follicular lymphoma: Fatigue, upper respiratory tract infection, musculoskeletal pain, nausea, abdominal pain, lymphocytopenia, hyperglycemia, leukopenia, neutropenia, thrombocytopenia, anemia.1

Interactions for Tazemetostat

Metabolized principally by CYP3A.1

Does not inhibit CYP isoenzymes 1A2, 2B6, 2C9, or 2D6 at clinically relevant concentrations.1

Substrate of P-glycoprotein (P-gp), but 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 polypepetide (OATP) 1B1, and OATP1B3.1

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

Potent or moderate CYP3A inhibitors: Possible increased systemic exposure to, and increased toxicity of, tazemetostat.1 Avoid concomitant use.1 If concomitant use of a moderate CYP3A inhibitor cannot be avoided, reduce daily dosage of tazemetostat by 50% as described in Table 3.1 If moderate CYP3A inhibitor is discontinued, return tazemetostat dosage (after 3 elimination half-lives of CYP3A inhibitor) to dosage used prior to initiation of the moderate CYP3A inhibitor.1 (See Specific Drugs and Foods under Interactions.)

Table 3: Recommended Dosage Reduction for Concomitant Use with a Moderate CYP3A Inhibitor1

Current Dosage

Dosage Reduction for Concomitant Use with a 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 and 200 mg in the evening)

400 mg twice daily

200 mg twice daily

Potent or moderate CYP3A inducers: Possible decreased systemic exposure to, and reduced efficacy of, tazemetostat.1 Avoid concomitant use.1 (See Specific Drugs and Foods under Interactions.)

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP3A: Possible decreased systemic exposure to, and reduced efficacy of, the CYP3A substrate.1 (See Specific Drugs and Foods under Interactions.)

Specific Drugs and Foods

Drug or Food

Interaction

Comments

Fluconazole

Increased tazemetostat peak plasma concentration and AUC (2.3- and 3.1-fold, respectively)1

Avoid concomitant use; if concomitant use cannot be avoided, reduce tazemetostat daily dosage by 50% as described in Table 3 (see Drugs and Foods Affecting Hepatic Microsomal Enzymes under Interactions)

When fluconazole is discontinued, return tazemetostat dosage (after 3 elimination half-lives of fluconazole) to prior dosage1

Grapefruit or grapefruit juice

Possible increased systemic exposure to tazemetostat and increased risk of toxicity1

Avoid concomitant use1

Hormonal contraceptives

Possible decreased systemic exposure to hormonal contraceptive and reduced efficacy1

Manufacturer states that women of reproductive potential should use an effective nonhormonal method of contraception1

Midazolam

Decreased midazolam peak plasma concentration and AUC by 21 and 40%, respectively1

Omeprazole

Increased tazemetostat AUC and peak plasma concentration at steady state by 26 or 25%, respectively; not expected to be clinically relevant1

Repaglinide

Increased repaglinide peak plasma concentration and AUC by 51 and 80%, respectively1

St. John’s wort (Hypericum perforatum)

Possible decreased systemic exposure to tazemetostat and reduced efficacy1

Avoid concomitant use1

Tazemetostat Pharmacokinetics

Absorption

Bioavailability

Following oral administration, mean absolute bioavailability is approximately 33%.1

Systemic exposure increases in approximately dose-proportional manner over a dosage range of 200–1600 mg twice daily.1

Peak plasma concentrations achieved in approximately 1–2 hours.1

Steady-state concentrations achieved in 15 days.1 Mean accumulation ratio is 0.58.1

Food

Systemic exposure not affected by administration with a high-fat, high-calorie meal (approximately 800–1000 calories).1

Special Populations

Mild hepatic impairment (total bilirubin concentration exceeding the ULN, but not >1.5 times the ULN, or AST concentration exceeding the ULN): No effect on pharmacokinetics of tazemetostat.1

Moderate to severe hepatic impairment (total bilirubin concentration >1.5 times the ULN): Pharmacokinetics not studied.1

Renal impairment, including end-stage renal disease: No effect on pharmacokinetics of tazemetostat.1

Age (16–91 years of age), sex, body weight (37–173 kg), or race: No substantial effect on pharmacokinetics.1

Distribution

Extent

Not known whether tazemetostat is distributed into human milk.1

Plasma Protein Binding

88%.1

Elimination

Metabolism

Metabolized principally by CYP3A to form major inactive metabolites (M5 and M3); M5 is further metabolized by CYP3A.1

Elimination Route

Most (94%) of an orally administered dose is recovered over 12 days.1

Eliminated primarily in feces (79%) and to a lesser extent in urine (15%).1

Half-life

3.1 hours.1

Stability

Storage

Oral

Tablets

≤30°C.1

Actions

  • Potent and selective inhibitor of EZH2, including EZH2 with Y646X, A682G, or A692V activating mutations.1 2 4 5 6

  • EZH2 is the catalytic subunit of the polycomb repressive complex 2 (PRC2), a complex responsible for promoting transcriptional silencing of target genes.1 6 11

  • In vitro and in vivo, loss or dysfunction of chromatin remodeling complex switch/sucrose nonfermentable (SWI/SNF) resulted in aberrant EZH2 activity and oncogenic dependency on EZH2 enzymatic activity.1 11

  • In vivo, demonstrated antitumor activity in xenograft models of B-cell lymphoma with or without EZH2 activating mutations; greater inhibitory effects on lymphoma cell lines harboring mutant EZH2.1

  • Inhibits EZH1 with a half-maximal inhibitory concentration approximately 36 times higher than half-maximal inhibitory concentration for EZH2.1

Advice to Patients

  • Importance of advising patients to read the manufacturer's patient information (medication guide).1

  • Importance of advising patients that if they miss or vomit a dose of tazemetostat, they should take their prescribed dose at the next scheduled time; an additional dose should not be administered to replace the missed or vomited dose.1

  • Risk of secondary malignancies.1 Importance of informing clinicians if fatigue, easy bruising, fever, bone pain, or paleness occurs.1

  • Risk of fetal harm.1 Necessity of advising women of reproductive potential that they should use effective nonhormonal methods of contraception while receiving tazemetostat and for 6 months after the last dose.1 Importance of advising men who are partners of such women that they should use effective methods of contraception while receiving the drug and for 3 months after the last dose.1 Importance of women informing clinicians if they are or plan to become pregnant.1 Apprise patient of potential hazard to the fetus if used during pregnancy.1

  • Importance of advising women to avoid breast-feeding while receiving tazemetostat and for one week after the last dose.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements (e.g., St. John's wort [Hypericum perforatum]), as well as any concomitant illnesses.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

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 (See Restricted Distribution under Dosage and Administration.)

Tazemetostat Hydrobromide

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

200 mg (of tazemetostat)

Tazverik

Epizyme

AHFS DI Essentials™. © Copyright 2021, Selected Revisions October 12, 2020. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Epizyme, Inc. Tazverik (tazemetostat) tablets prescribing information. Cambridge, MA; 2020 Jun.

2. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 211723Orig1s000: Multi-discipline review. From FDA website. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/211723Orig1s000MultidisciplineR.pdf

3. Epizyme, Inc. From Tazveri (tazemetostat hydrobromide) for healthcare professionals website. Accessed 21 Jul 2020. https://www.tazverik.com/hcp/follicular-lymphoma

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. http://www.ncbi.nlm.nih.gov/pubmed/24563539?dopt=AbstractPlus

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 http://www.ncbi.nlm.nih.gov/pubmed/27555605?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=PMC5584632&blobtype=pdf

6. Gulati N, Béguelin W, Giulino-Roth L. Enhancer of zeste homolog 2 (EZH2) inhibitors. Leuk Lymphoma. 2018; 59:1574-1585. http://www.ncbi.nlm.nih.gov/pubmed/29473431?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=PMC6659997&blobtype=pdf

7. Mittal P, Roberts CWM. The SWI/SNF complex in cancer - biology, biomarkers and therapy. Nat Rev Clin Oncol. 2020; 17:435-448. http://www.ncbi.nlm.nih.gov/pubmed/32303701?dopt=AbstractPlus

8. Food and Drug Administration. FDA Application: Search orphan drug designations and approvals. Silver Spring, MD. From FDA web site. https://www.accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm

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. https://clinicaltrials.gov/ct2/show/NCT01897571

11. Kim KH, Roberts CW. Targeting EZH2 in cancer. Nat Med. 2016; 22:128-34. http://www.ncbi.nlm.nih.gov/pubmed/26845405?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=PMC4918227&blobtype=pdf

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. http://www.ncbi.nlm.nih.gov/pubmed/29650362?dopt=AbstractPlus