Instructions for Tazemetostat

1. Name: Tazemetostat, Tazemetostat, Tazemetostat,Tazverik, EPZ-6438

2. Indications:

1. Epithelioid sarcoma (ES): Tazemetostat (Tazemetostat) is suitable for the treatment of adult and pediatric patients 16 years of age and older who have metastatic or locally advanced epithelioid sarcoma and are not suitable for complete resection.

2. Relapsed or refractory (R/R) follicular lymphoma (FL): Tazerestat is indicated for the treatment of adult patients with relapsed or refractory follicular lymphoma whose tumors have tested positive for EZH2 mutations and who have received at least 2 previous systemic therapies; it is also indicated for the treatment of adult patients with relapsed or refractory follicular lymphoma who have no satisfactory alternative treatment options.

3. Usage and dosage:

1. Before treatment: Doctors will select patients with relapsed or refractory (R/R) follicular lymphoma (FL) to receive tazerestat based on whether there is an EZH2 mutation of codon Y646, A682 or A692 in the tumor specimen.

2. Recommended dose: The recommended dose of tazerestat is 800 mg twice daily, with or without food, until disease progression or unacceptable toxicity occurs.

3. Dose adjustment: If the patient experiences adverse reactions after use, the use of tazerestat should be interrupted, reduced or stopped under the guidance of a doctor. The first dose of tazerestat can be reduced to 600 mg orally twice daily; the second dose can be reduced to 400 mg orally twice daily. For patients who cannot tolerate 400 mg orally twice daily, tazetostat should be permanently discontinued.

(1) Drug interactions: Avoid coadministration with strong or moderate CYP3A inhibitorstazerestat , if this cannot be avoided, adjust the drug dose. After discontinuing a moderate CYP3A inhibitor for 3 elimination half-lives, resume the dose of tazerestat that was taken before initiating the inhibitor. For patients taking 800 mg tazerestat orally twice daily, adjust the dose to 400 mg tazerestat orally twice daily; for patients taking tazerestat 600 mg orally twice daily Patients will adjust their dosage to 400 mg for the first dose and 200 mg for the second dose; patients who take tazerestat 400 mg orally twice a day will have their dose adjusted to 200 mg orally twice a day.

4. Adverse reactions:

在使用他泽司他治疗上皮样肉瘤的临床研究中，最常见的（≥20%) adverse reactions include pain, fatigue, nausea, decreased appetite, vomiting, constipation, anemia, and lymphopenia. In clinical studies for the treatment of follicular lymphoma, the most common (≥20%) adverse reactions include fatigue, upper respiratory tract infection, musculoskeletal pain, nausea, abdominal pain, lymphopenia, hyperglycemia, leukopenia, neutropenia, thrombocytopenia, and anemia.

5. Storage:

Tazerestat should not be stored above 30°C (86°F).

6. Special groups:

1. Women: Due to the potential risk of serious adverse reactions of tazerestat in breastfed children, it is recommended that women not breastfeed during treatment with tazerestat and within one week after the last dose; tazerestat can render some hormonal contraceptives ineffective. It is recommended that women of reproductive potential use effective non-hormonal contraceptive methods during treatment and within 6 months after the last dose.

2. Men: It is recommended that men with female partners of potential reproductive potential use effective contraceptive measures during treatment with tazerestat and for at least 3 months after the last dose.

7. Mechanism of action:

Tazerestat is an inhibitor of the methyltransferase EZH2 and some EZH2 gain-of-function mutations (including Y646X, A682G and A692V). Tazerestat also inhibited EZH1 with a half-maximal inhibitory concentration (IC50) of 392 nM, approximately 36 times the inhibitory IC50 of EZH2. The most characteristic function of EZH2 is as the catalytic subunit of polycomb repressive complex 2 (PRC2), catalyzing the mono-, di- and trimethylation of lysine 27 of histone H3. Trimethylation of histone H3 results in transcriptional repression.

Tazerestat inhibits the proliferation of B-cell lymphoma cell lines in vitro and shows anti-tumor activity in a B-cell lymphoma mouse xenograft model with or without EZH2 gain-of-function mutations. Tazetostat had a greater inhibitory effect on the proliferation of lymphoma cell lines with mutated EZH2.

The original drug of tazerestat is not yet available in the domestic market and is therefore not included in medical insurance. Tazerestat US version of the original drug, specification200mg*240 tablets, which is marketed overseas, may cost around 200,000 yuan per bottle (the price may fluctuate due to exchange rates), which is very expensive. At present, there are no generic drugs of tazerestat produced and launched. For more drug information and specific prices, please consult the medical consultant of the drug.