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Tazemetostat

Medically reviewed by Drugs.com. Last updated on July 2, 2020.

Pronunciation

(TAZ e MET oh stat)

Index Terms

  • CAS 1403254-99-8
  • E7438
  • EPZ-6438
  • EPZ6438
  • Histone methyl transferase EZH2 inhibitor E7438
  • Tazemetostat hydrobromide

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Tazverik: 200 mg

Brand Names: U.S.

  • Tazverik

Pharmacologic Category

  • Antineoplastic Agent, EZH2-Inhibitor
  • Antineoplastic Agent, Histone Methyltransferase (HMT) Inhibitor

Pharmacology

Tazemetostat is a potent and selective inhibitor of histone methyltransferase EZH2 (enhancer of zeste homolog 2); it also inhibits some EZH2 gain-of-function mutations (including Y646X and A687V), as well as EZH1. EZH2 is overexpressed or mutated in many cancer types and plays a role in tumor proliferation. SWItch/Sucrose Non-Fermentable (SWI/SNF) complex aids in facilitating gene expression and terminal differentiation; altered EZH2 upregulation and loss-of-function mutations in SWI/SNF are oncogenic in many human cancers; tazemetostat has antitumor activity in EZH2-mutant cell lines (Italiano 2018). Tazemetostat suppressed B-cell lymphoma cell lines proliferation in vitro, and showed antitumor activity in an animal model of B-cell lymphoma with or without EZH2 gain-of-function mutations; tazemetostat demonstrated increased inhibition of lymphoma cell line proliferation with mutant EZH2.

Distribution

Vss/F: 1,230 L.

Metabolism

Via CYP3A to form the inactive major metabolites M5 (EPZ-6930) and M3 (EPZ006931); M5 is further metabolized by CYP3A.

Excretion

Feces: 79%; urine: 15%.

Clearance: 274 L/hour.

Time to Peak

1 to 2 hours.

Half-Life Elimination

3.1 hours.

Protein Binding

88%.

Use: Labeled Indications

Epithelioid sarcoma, metastatic or locally advanced: Treatment of metastatic or locally advanced epithelioid sarcoma not eligible for complete resection in adults and adolescents ≥16 years of age.

Follicular lymphoma, relapsed/refractory:

Treatment of relapsed or refractory follicular lymphoma in adults whose tumors are positive for an EZH2 mutation (as detected by an approved test) and who have received at least 2 prior systemic therapies.

Treatment of relapsed or refractory follicular lymphoma in adults who have no satisfactory alternative treatment options.

Contraindications

There are no contraindications listed in the manufacturer's labeling.

Dosing: Adult

Epithelioid sarcoma, metastatic or locally advanced: Oral: 800 mg twice daily until disease progression or unacceptable toxicity (Stacchiotti 2019).

Follicular lymphoma, relapsed/refractory, EZH2 mutation-positive: Oral: 800 mg twice daily until disease progression or unacceptable toxicity.

Follicular lymphoma, relapsed/refractory, salvage therapy: Oral: 800 mg twice daily until disease progression or unacceptable toxicity.

Missed dose: If a dose is missed or vomited, do not take an additional dose; continue with the next scheduled dose.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Epithelioid sarcoma, metastatic or locally advanced: Adolescents ≥16 years: Oral: 800 mg twice daily until disease progression or unacceptable toxicity.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosage adjustment for toxicity:

Dose reductions:

First dose reduction: Oral: Tazemetostat 600 mg twice daily.

Second dose reduction: Oral: Tazemetostat 400 mg twice daily.

Note: Discontinue permanently if unable to tolerate tazemetostat 400 mg twice daily.

Dosage adjustment for neutropenia (neutrophil count <1 x 109/L): Hold tazemetostat until neutrophil count ≥1 x 109/L or baseline, then resume as follows:

If first occurrence: Resume tazemetostat at same dose.

For second or third occurrence: Resume tazemetostat at reduced dose.

After fourth occurrence: Permanently discontinue tazemetostat.

Dosage adjustment for thrombocytopenia (platelet count <50 x 109/L): Hold tazemetostat until platelet count ≥75 x 109/L or baseline, then resume as follows:

For first and second occurrence: Resume tazemetostat at reduced dose.

After third occurrence: Permanently discontinue tazemetostat.

Dosage adjustment for anemia (hemoglobin <8 g/dL): Hold tazemetostat until improved to least grade 1 or baseline, then resume at the same or reduced dose.

Dosage adjustment for other grade 3 adverse reactions: Hold tazemetostat until improved to at least grade 1 or baseline, then resume as follows:

For first and second occurrence: Resume tazemetostat at reduced dose.

After third occurrence: Permanently discontinue tazemetostat.

Dosage adjustment for other grade 4 adverse reactions: Hold tazemetostat until improved to at least grade 1 or baseline, then resume as follows:

For first occurrence: Resume tazemetostat at reduced dose.

After second occurrence: Permanently discontinue tazemetostat.

Dosing: Adjustment for Toxicity

Recommended Tazemetostat Dosage Reduction Levels

Initial (usual) dose

800 mg twice daily

First dose reduction level

600 mg twice daily

Second dose reduction level

400 mg twice daily

Unable to tolerate 400 mg twice daily

Permanently discontinue tazemetostat

Tazemetostat Dosage Adjustment for Toxicities

Toxicity

Severity

Tazemetostat Dose Modification

Neutropenia

Neutrophil count <1,000/mm3

Withhold tazemetostat until neutrophils ≥1,000/mm3 or baseline. If first occurrence, resume at the same dose. For second and third occurrence, resume at a reduced dose. Permanently discontinue after fourth occurrence.

Thrombocytopenia

Platelet count <50,000/mm3

Withhold tazemetostat until platelets ≥75,000/mm3 or baseline. If first or second occurrence, resume at a reduced dose. Permanently discontinue after third occurrence.

Anemia

Hemoglobin <8 g/dL

Withhold tazemetostat until improvement to at least grade 1 or baseline, then resume at the same or a reduced dose.

Other adverse reactions

Grade 3

Withhold tazemetostat until improvement to at least grade 1 or baseline. If first or second occurrence, resume at a reduced dose. Permanently discontinue after third occurrence.

Grade 4

Withhold tazemetostat until improvement to at least grade 1 or baseline. If first occurrence, resume at a reduced dose. Permanently discontinue after second occurrence.

Administration

Oral: May administer with or without food. Swallow tablets whole; do not cut, crush, or chew.

Storage

Do not store above 30°C (86°F).

Drug Interactions

Abametapir: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Baricitinib: Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted. Consider therapy modification

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. Avoid combination

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

CloZAPine: CYP3A4 Inducers (Weak) may decrease the serum concentration of CloZAPine. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of Tazemetostat. Avoid combination

CYP3A4 Inducers (Strong): May decrease the serum concentration of Tazemetostat. Avoid combination

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Tazemetostat. Management: Avoid when possible. If combined, reduce tazemetostat dose from 800 mg twice daily to 400 mg twice daily, from 600 mg twice daily to 400 mg in AM and 200 mg in PM, or from 400 mg twice daily to 200 mg twice daily. Consider therapy modification

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Tazemetostat. Avoid combination

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Management: Consider avoiding Echinacea in patients receiving therapeutic immunosuppressants. If coadministered, monitor for reduced efficacy of the immunosuppressant during concomitant use. Consider therapy modification

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Hormonal Contraceptives: Tazemetostat may decrease the serum concentration of Hormonal Contraceptives. Management: Women of reproductive potential should use a non-hormonal contraceptive method during treatment with tazemetostat and for 6 months after. Men with female partners should use contraception during treatment and for 3 months after. Consider therapy modification

Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Inebilizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Larotrectinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

NiMODipine: CYP3A4 Inducers (Weak) may decrease the serum concentration of NiMODipine. Monitor therapy

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Management: Avoid use of immunosuppressants (including systemic corticosteroids) prior to initiation of nivolumab. Use of immunosuppressants after administration of nivolumab (eg, for immune-related toxicity) is unlikely to affect nivolumab efficacy. Consider therapy modification

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Ozanimod: Immunosuppressants may enhance the immunosuppressive effect of Ozanimod. Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Repaglinide: CYP2C8 Inhibitors (Weak) may increase the serum concentration of Repaglinide. Monitor therapy

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Management: Consider avoiding concomitant use of roflumilast and immunosuppressants as recommended by the Canadian product monograph. Inhaled or short-term corticosteroids are unlikely to be problematic. Consider therapy modification

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Selpercatinib: CYP3A4 Inducers (Weak) may decrease the serum concentration of Selpercatinib. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy. Consider therapy modification

Smallpox and Monkeypox Vaccine (Live): Immunosuppressants may diminish the therapeutic effect of Smallpox and Monkeypox Vaccine (Live). Monitor therapy

Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Tacrolimus (Systemic): CYP3A4 Inducers (Weak) may decrease the serum concentration of Tacrolimus (Systemic). Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Talimogene Laherparepvec: Immunosuppressants may enhance the adverse/toxic effect of Talimogene Laherparepvec. Specifically, the risk for disseminated herpetic infection may be increased. Avoid combination

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Consider therapy modification

Ubrogepant: CYP3A4 Inducers (Weak) may decrease the serum concentration of Ubrogepant. Management: Use an initial ubrogepant dose of 100 mg and second dose (if needed) of 100 mg when used with a weak CYP3A4 inducer. Consider therapy modification

Upadacitinib: Immunosuppressants may enhance the immunosuppressive effect of Upadacitinib. Management: Concomitant use of upadacitinib with potent immunosuppressants is not recommended. Avoid combination

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated less than 2 weeks before starting or during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.

>10%:

Dermatologic: Alopecia, skin rash

Endocrine & metabolic: Decreased serum albumin, decreased serum calcium, decreased serum glucose, decreased serum phosphate, decreased serum potassium, decreased serum sodium, increased serum glucose, increased serum potassium, increased serum triglycerides, weight loss

Gastrointestinal: Abdominal pain, constipation, decreased appetite, diarrhea, nausea, vomiting

Genitourinary: Urinary tract infection

Hematologic & oncologic: Decreased hemoglobin (including anemia), decreased neutrophils, decreased platelet count, decreased white blood cell count, hemorrhage (including cerebral hemorrhage, hemoptysis, pulmonary hemorrhage, rectal hemorrhage, wound hemorrhage), lymphocytopenia, prolonged partial thromboplastin time

Hepatic: Increased serum alanine aminotransferase, increased serum alkaline phosphatase, increased serum aspartate aminotransferase

Nervous system: Fatigue (includes asthenia), headache, pain

Neuromuscular & skeletal: Musculoskeletal pain

Renal: Increased serum creatinine

Respiratory: Cough, dyspnea, lower respiratory tract infection, upper respiratory tract infection

1% to 10%:

Dermatologic: Skin infection

Infection: Herpes zoster infection, sepsis

Respiratory: Pleural effusion, pneumonia, respiratory distress

Miscellaneous: Fever

<1%: Hematologic & oncologic: Myelodysplastic syndrome, myeloid leukemia, T-cell lymphoma

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: Anemia, lymphocytopenia, and leukopenia have been observed, including grade 3 and 4 events. Hematologic toxicity may require treatment interruption, dose reduction, and/or discontinuation.

• GI toxicity: Mild nausea and vomiting have occurred with tazemetostat.

• Secondary malignancies: Tazemetostat may increase the risk of developing secondary malignancies. Myelodysplastic syndromes and acute myeloid leukemia have been reported in adults; T-cell lymphoblastic lymphoma was observed (case report) in pediatrics. Monitor (long term) for signs/symptoms of secondary malignancies.

Other warnings/precautions:

• Appropriate use: Select patients for tazemetostat treatment of relapsed/refractory follicular lymphoma (excluding salvage therapy) based on the presence of EZH2 mutation of codons Y646, A682, or A692 in tumor specimens. Information on approved tests is available at http://www.fda.gov/CompanionDiagnostics.

Monitoring Parameters

CBC with differential. Evaluate pregnancy status prior to use in females of reproductive potential. Monitor (long term) for development of secondary malignancies. Monitor adherence.

Reproductive Considerations

Evaluate pregnancy status prior to use in females of reproductive potential. Females of reproductive potential should use effective nonhormonal contraception during therapy and for 6 months after the last tazemetostat dose. Males with female partners of reproductive potential should use effective contraception during therapy and for at least 3 months after the last dose of tazemetostat.

Pregnancy Considerations

Based on the mechanism of action, and data from animal reproduction studies, in utero exposure to tazemetostat may cause fetal harm.

Patient Education

What is this drug used for?

• It is used to treat soft tissue sarcoma.

• It is used to treat a type of lymphoma.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Feeling tired or weak

• Constipation, diarrhea, stomach pain, upset stomach, throwing up, or feeling less hungry

• Signs of a common cold

• Hair loss

• Neck pain

• Muscle pain

• Back pain

• Headache

• Weight loss

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Bleeding like throwing up or coughing up blood; vomit that looks like coffee grounds; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a cause or that get bigger; or bleeding you cannot stop

• Electrolyte problems like mood changes, confusion, muscle pain or weakness, a heartbeat that does not feel normal, seizures, not hungry, or very bad upset stomach or throwing up

• Infection like fever, chills, very bad sore throat, ear or sinus pain, cough, more sputum or change in color of sputum, pain with passing urine, mouth sores, or wound that will not heal

• Skin infection like oozing, heat, swelling, redness, or pain

• Chest pain

• Shortness of breath

• Bone pain

• Pale skin

• Weakness on 1 side of the body, trouble speaking or thinking, change in balance, drooping on one side of the face, or blurred eyesight

• High or low blood sugar like breath that smells like fruit, dizziness, fast breathing, fast heartbeat, feeling confused, feeling sleepy, feeling weak, flushing, headache, more thirsty or hungry, passing urine more often, shaking, or sweating

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a limited summary of general information about the medicine's uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.