Tazemetostat Hydrobromide (Monograph)

Brand name: Tazverik
Drug class: Antineoplastic Agents

Medically reviewed by Drugs.com on Mar 10, 2024. Written by ASHP.

Introduction

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

Uses for Tazemetostat Hydrobromide

Soft Tissue Sarcoma

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

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.

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.

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

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.

Tazemetostat Hydrobromide Dosage and Administration

General

Pretreatment Screening

Presence of EZH2 mutation in codon Y646, A682, or A692 in tumor specimens of patients with relapsed or refractory follicular lymphoma who have received ≥2 prior systemic therapies.
Verify pregnancy status in females of reproductive potential.

Patient Monitoring

Monitor long term for development of secondary malignancies.

Administration

Oral Administration

Administer orally twice daily without regard to meals.

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

Dosage

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

Pediatric Patients

Epithelioid Sarcoma

Oral

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

Continue therapy until disease progression or unacceptable toxicity occurs.

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

Dosage Modification for Toxicity

Oral

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

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.

Continue therapy until disease progression or unacceptable toxicity occurs.

If concomitant use with moderate CYP3A inhibitors cannot be avoided, adjust dosage of tazemetostat.

Follicular Lymphoma

Oral

800 mg twice daily.

Continue therapy until disease progression or unacceptable toxicity occurs.

If concomitant use with moderate CYP3A inhibitors cannot be avoided, adjust dosage of tazemetostat.

Dosage Modification for Toxicity

Oral

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

Prescribing Limits

Pediatric Patients

Epithelioid Sarcoma

Oral

Dosage <400 mg twice daily not recommended.

Adults

Epithelioid Sarcoma

Oral

Dosage <400 mg twice daily not recommended.

Follicular Lymphoma

Oral

Dosage <400 mg twice daily not recommended.

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.

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

Renal Impairment

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

Geriatric Patients

No specific dosage recommendations at this time.

Cautions for Tazemetostat Hydrobromide

Contraindications

Manufacturer states none known.

Warnings/Precautions

Development of Secondary Malignancies

Development of secondary malignancies (i.e., myelodysplastic syndrome [MDS], acute myeloid leukemia [AML], B-cell acute lymphoblastic leukemia [B-ALL], T-cell lymphoblastic lymphoma [T-LBL]) reported following initiation of tazemetostat therapy.

Monitor patients long term for development of secondary malignancies.

Fetal/Neonatal Morbidity and Mortality

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

Avoid pregnancy during therapy. Perform pregnancy test prior to initiation of tazemetostat in women of reproductive potential. Women of reproductive potential should use effective nonhormonal methods of contraception while receiving the drug and for 6 months after the last dose. (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. If used during pregnancy or if patient becomes pregnant, apprise patient of potential fetal hazard.

Specific Populations

Pregnancy

May cause fetal harm.

Lactation

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

Pediatric Use

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

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.

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

Geriatric Use

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

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).

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

Renal Impairment

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

Common Adverse Effects

Epithelioid sarcoma (≥20%): Pain, fatigue, nausea, decreased appetite, vomiting, constipation, anemia, lymphocytopenia.

Follicular lymphoma(≥20%): Fatigue, upper respiratory tract infection, musculoskeletal pain, nausea, abdominal pain, lymphocytopenia, hyperglycemia, leukopenia, neutropenia, thrombocytopenia, anemia.

Drug Interactions

Metabolized principally by CYP3A.

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

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.

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.

Drugs and Foods Affecting Hepatic Microsomal Enzymes

Potent or moderate CYP3A inhibitors: Possible increased systemic exposure to, and increased toxicity of, tazemetostat. Avoid concomitant use. If concomitant use of a moderate CYP3A inhibitor cannot be avoided, reduce daily dosage of tazemetostat by 50% as described in Table 3. 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.

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. Avoid concomitant use.

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP3A: Possible decreased systemic exposure to, and reduced efficacy of, the CYP3A substrate.

Specific Drugs and Foods

Drug or Food	Interaction	Comments
Fluconazole	Increased tazemetostat peak plasma concentration and AUC (2.3- and 3.1-fold, respectively)	Avoid concomitant use; if concomitant use cannot be avoided, reduce tazemetostat daily dosage by 50% as described in Table 3 When fluconazole is discontinued, return tazemetostat dosage (after 3 elimination half-lives of fluconazole) to prior dosage
Grapefruit or grapefruit juice	Possible increased systemic exposure to tazemetostat and increased risk of toxicity	Avoid concomitant use
Hormonal contraceptives	Possible decreased systemic exposure to hormonal contraceptive and reduced efficacy	Manufacturer states that women of reproductive potential should use an effective nonhormonal method of contraception
Midazolam	Decreased midazolam peak plasma concentration and AUC by 21 and 40%, respectively
Omeprazole	Increased tazemetostat AUC and peak plasma concentration at steady state by 26 or 25%, respectively; not expected to be clinically relevant
Repaglinide	Increased repaglinide peak plasma concentration and AUC by 51 and 80%, respectively
St. John’s wort (Hypericum perforatum)	Possible decreased systemic exposure to tazemetostat and reduced efficacy	Avoid concomitant use

Tazemetostat Hydrobromide Pharmacokinetics

Absorption

Bioavailability

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

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

Peak plasma concentrations achieved in approximately 1–2 hours.

Steady-state concentrations achieved in 15 days. Mean accumulation ratio is 0.58.

Food

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

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.

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

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

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

Distribution

Extent

Not known whether tazemetostat is distributed into human milk.

Plasma Protein Binding

88%.

Elimination

Metabolism

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

Elimination Route

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

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

Half-life

3.1 hours.

Stability

Storage

Oral

Tablets

≤30°C.

Actions

Potent and selective inhibitor of EZH2, including EZH2 with Y646X, A682G, or A692V activating mutations.
EZH2 is the catalytic subunit of the polycomb repressive complex 2 (PRC2), a complex responsible for promoting transcriptional silencing of target genes.
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.
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.
Inhibits EZH1 with a half-maximal inhibitory concentration approximately 36 times higher than half-maximal inhibitory concentration for EZH2.

Advice to Patients

Advise patients to read the manufacturer's patient information (medication guide).
Advise 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.
Risk of secondary malignancies. Inform clinicians if fatigue, easy bruising, fever, bone pain, or paleness occurs.
Risk of fetal harm. Advise women of reproductive potential that they should use effective nonhormonal methods of contraception while receiving tazemetostat and for 6 months after the last dose. Advise 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. Importance of women informing clinicians if they are or plan to become pregnant. Apprise patient of potential hazard to the fetus if used during pregnancy.
Advise women to avoid breast-feeding while receiving tazemetostat and for one week after the last dose.
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.
Inform patients of other important precautionary information.

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 https://www.ahfsdruginformation.com.

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.