Tazedx Tazemetostat

I. Drug Name

Generic Name: Tazemetostat Tablets

English Name: Tazemetostat

Brand Names: Tazverik, Tazedx

Dosage Form: Oral Film-Coated Tablets

Specification: 200 mg per tablet; 80 tablets per box

Manufacturer: Laos Daxiong Pharmaceutical Co., Ltd.

Regulatory Approval Number: 07 L1139/24

II. Pharmacological Actions

Pharmacological Classification: Enhancer of Zeste Homolog 2 (EZH2) Inhibitor

Mechanism of Action:

EZH2 is a histone methyltransferase that inhibits the transcription of genes associated with cellular differentiation and proliferation by catalyzing the trimethylation of lysine 27 on histone H3 (H3K27me3).

In certain cancers, the EZH2 gene undergoes gain-of-function mutations, or associated proteins (such as INI-1/SMARCB1) are lost; this leads to abnormally elevated EZH2 activity, thereby suppressing the expression of tumor suppressor genes and driving tumor growth.

Tazemetostat is a potent, selective EZH2 inhibitor that acts by inhibiting EZH2 activity, reducing H3K27me3 levels, relieving the suppression of tumor suppressor genes, and consequently blocking the proliferation of tumor cells.

III. Indications

Tazemetostat is indicated for the treatment of the following tumors in adult and adolescent patients aged ≥16 years:

1. Epithelioid Sarcoma (ES):

Locally advanced or metastatic epithelioid sarcoma that is not eligible for complete resection. 

Prerequisite: The tumor must harbor an INI-1 (SMARCB1) loss.

2. Follicular Lymphoma (FL):

Relapsed or refractory follicular lymphoma. 

Prerequisite: The tumor must be confirmed to harbor an EZH2 activating mutation via an FDA-approved diagnostic test, and the patient must have received at least two prior lines of systemic therapy. 

OR: For relapsed or refractory follicular lymphoma with wild-type EZH2 (no EZH2 mutation) for which there are no satisfactory alternative treatment options. IV. Dosage and Administration

Recommended Dosage:

800 mg, twice daily (approximately every 12 hours), taken orally.

May be taken with or without food.

Method of Administration:

Swallow the tablets whole; do not chew, crush, or split the tablets.

If a dose is missed or if vomiting occurs after administration, do not take a replacement dose; instead, wait until the next scheduled time to take the regular dose.

V. Contraindications

Patients with a history of severe hypersensitivity to Tazemetostat or to any of the excipients.

VI. Warnings and Precautions

1.  Secondary Malignancies:

Treatment with Tazemetostat may increase the risk of secondary malignancies, including treatment-related myeloid neoplasms (t-MNs) and lymphomas.

Monitor complete blood cell counts prior to initiating treatment and at least every 6 months during treatment.

Weigh the benefits of treatment against the potential risk of secondary malignancies.

2.  Embryo-Fetal Toxicity:

Based on its mechanism of action, Tazemetostat may cause fetal harm when administered to a pregnant woman. 

Verify the pregnancy status of females of reproductive potential prior to initiating treatment.

Females of reproductive potential should use effective contraception during treatment and for 6 months after the last dose.

Male patients with female partners who are pregnant or of reproductive potential should use effective contraception (condoms) during treatment and for 3 months after the last dose.

VII. Adverse Reactions

Very Common (>10%) Serious and/or Major Adverse Reactions:

General: Fatigue, Asthenia. 

Musculoskeletal: Musculoskeletal pain. 

Gastrointestinal: Nausea, Abdominal pain, Vomiting, Constipation, Diarrhea. 

Respiratory: Upper respiratory tract infection, Dyspnea, Cough. 

Laboratory Abnormalities: Lymphopenia, Decreased hemoglobin, Thrombocytopenia, Neutropenia, Elevated AST/ALT, Elevated total cholesterol.

Common Adverse Reactions of Concern:

Tumor Lysis Syndrome (TLS), Decreased appetite, Headache, Rash. VIII. Drug Interactions

CYP3A Inhibitors:

Strong CYP3A Inhibitors (e.g., clarithromycin, itraconazole, ritonavir):

Co-administration significantly increases tazemetostat plasma concentrations, thereby increasing the risk of adverse reactions. 

Avoid co-administration. If short-term co-administration is unavoidable, reduce the tazemetostat dosage to 400 mg twice daily. 

Moderate CYP3A Inhibitors (e.g., fluconazole, diltiazem, verapamil):

Co-administration increases tazemetostat plasma concentrations. 

Consider reducing the tazemetostat dosage to 400 mg twice daily.

CYP3A Inducers:

Strong CYP3A Inducers (e.g., rifampin, carbamazepine, St. John’s wort):

Co-administration significantly decreases tazemetostat plasma concentrations, potentially compromising efficacy. 

Avoid co-administration.

P-gp, BCRP, and OATP1B1 Substrates:

Tazemetostat may inhibit these transporters, thereby increasing the plasma concentrations of their respective substrate drugs (e.g., digoxin, methotrexate, statins).

When co-administering, closely monitor for adverse reactions associated with these substrate drugs and consider reducing their dosages.

IX. Use in Specific Populations

Pregnant Women: May cause fetal harm. Advise pregnant women of the potential risk to the fetus.

Lactating Women: It is recommended to discontinue breastfeeding during treatment and for 1 week following the last dose.

Pediatric Patients: The safety and efficacy of tazemetostat have not been established in patients under 16 years of age.

Geriatric Patients: In patients aged 65 years and older, no overall significant differences in safety were observed compared to younger patients.

Patients with Hepatic/Renal Impairment:

Hepatic Impairment:

For patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment, the recommended dosage is 600 mg twice daily. 

For patients with severe (Child-Pugh C) hepatic impairment, the recommended dosage is 400 mg twice daily. Renal Impairment: No dose adjustment is required for patients with mild to moderate renal impairment (eGFR 30–89 mL/min/1.73 m²). For patients with severe renal impairment (eGFR 15–29 mL/min/1.73 m²), the recommended dose is 600 mg taken twice daily. Data are limited for patients with end-stage renal disease; therefore, caution is advised.

X. Overdosage

Symptoms: Expected symptoms consist of an exacerbation of known adverse reactions.

Management: There is no specific antidote. General supportive measures should be instituted, and symptomatic treatment should be provided.

XI. Clinical Pharmacology

Pharmacokinetics: Tazemetostat is rapidly absorbed following oral administration, reaching peak plasma concentrations approximately 1 to 2 hours after dosing. High-fat meals result in a slight increase in exposure. *In vivo*, the drug is primarily metabolized via CYP3A4. Fecal excretion is the primary route of elimination.

XII. Patient Counseling Information

1.  Genetic Testing: Patients must understand that testing for EZH2 mutations or INI-1 deletions is mandatory prior to initiating treatment.

2.  Risk of Secondary Malignancies: Patients should be informed of the potential risks and agree to undergo regular blood monitoring.

3.  Contraception Requirements: Patients of reproductive potential must understand and strictly adhere to the prescribed contraception requirements.

4.  Adherence to Prescribing Instructions: Do not arbitrarily adjust the dosage or discontinue the medication without consulting a healthcare professional.

5.  Disclosure of Medication History: Inform your physician of all other medications you are currently taking, including over-the-counter drugs and herbal supplements.

6.  Reporting Signs of Infection: Report any signs of infection—such as fever, chills, or a persistent cough—which may be associated with cytopenias (low blood cell counts).

Final Reminder: Please strictly follow the specific instructions provided by your treating physician and pharmacist. If you have any questions or experience any discomfort during the course of treatment, please contact your healthcare team immediately.