TAZVERIK

TAZVERIK- tazemetostat hydrobromide tablet, film coated
Epizyme, Inc.

1 INDICATIONS AND USAGE

1.1 Epithelioid Sarcoma

TAZVERIK is indicated for the treatment of adults and pediatric patients aged 16 years and older with metastatic or locally advanced epithelioid sarcoma not eligible for complete resection.

This indication is approved under accelerated approval based on overall response rate and duration of response [see Clinical Studies (14.1)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

1.2 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 as detected by an FDA-approved test and who have received at least 2 prior systemic therapies.
• TAZVERIK is indicated for the treatment of adult patients with R/R FL who have no satisfactory alternative treatment options.

These indications are approved under accelerated approval based on overall response rate and duration of response [see Clinical Studies (14.2)]. Continued approval for these indications may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

2 DOSAGE AND ADMINISTRATION

2.1 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 Clinical Studies (14.2)]. Information on FDA-approved tests for the detection of EZH2 mutation in relapsed or refractory follicular lymphoma is available at: http://www.fda.gov/CompanionDiagnostics.

2.2 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.

2.3 Dosage Modifications for Adverse Reactions

Table 1 summarizes the recommended dose reductions, and Table 2 summarizes the recommended dosage modifications of TAZVERIK for adverse reactions.

Table 1. Recommended Dose Reductions of TAZVERIK for Adverse Reactions

*Permanently discontinue TAZVERIK in patients who are unable to tolerate 400 mg orally twice daily.
Dose Reduction	Dosage
First	600 mg orally twice daily
Second	400 mg orally twice daily*

Table 2. Recommended Dosage Modifications of TAZVERIK for Adverse Reactions

Adverse Reaction	Severity	Dosage Modification
Neutropenia[see Adverse Reactions (6.1)]	Neutrophil count less than 1 × 109 /L	Withhold until neutrophil count is greater than or equal to 1 × 109 /L or baseline. For first occurrence, resume at same dose. For second and third occurrence, resume at reduced dose. Permanently discontinue after fourth occurrence.
Thrombocytopenia[see Adverse Reactions (6.1)]	Platelet count less than 50 × 109 /L	Withhold until platelet count is greater than or equal to 75 × 109 /L or baseline. For first and second occurrence, resume at reduced dose. Permanently discontinue after third occurrence.
Anemia[see Adverse Reactions (6.1)]	Hemoglobin less than 8 g/dL	Withhold until improvement to at least Grade 1 or baseline, then resume at same or reduced dose.
Other adverse reactions[see Adverse Reactions (6.1)]	Grade 3	Withhold until improvement to at least Grade 1 or baseline. For first and second occurrence, resume at reduced dose. Permanently discontinue after third occurrence.
	Grade 4	Withhold until improvement to at least Grade 1 or baseline. For first occurrence, resume at reduced dose. Permanently discontinue after second occurrence.

2.4 Dosage Modifications for Drug Interactions

Strong and Moderate CYP3A Inhibitors

Avoid coadministration of TAZVERIK with strong or moderate CYP3A inhibitors. If coadministration with a moderate CYP3A inhibitor cannot be avoided, reduce the TAZVERIK dose as shown in Table 3 below. 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 Drug Interactions (7.1), Clinical Pharmacology (12.3)].

Table 3. Recommended Dose Reductions of TAZVERIK for Moderate CYP3A Inhibitors

Current Dosage	Adjusted Dosage
800 mg orally twice daily	400 mg orally twice daily
600 mg orally twice daily	400 mg for first dose and 200 mg for second dose
400 mg orally twice daily	200 mg orally twice daily

3 DOSAGE FORMS AND STRENGTHS

Tablets: 200 mg film-coated, red, round, biconvex shape and debossed with “EZM 200” on one side and plain on the other.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Secondary Malignancies

The risk of developing secondary malignancies is increased following treatment with TAZVERIK. Across clinical trials of 729 adults who received TAZVERIK 800 mg twice daily, myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) occurred in 0.7% of patients. One pediatric patient developed T-cell lymphoblastic lymphoma (T-LBL). Monitor patients long-term for the development of secondary malignancies.

5.2 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 Use in Specific Populations (8.1, 8.3)].