tazemetostat (Rx)

Brand and Other Names:Tazverik
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

tablet

  • 200mg

Epithelial Sarcoma

Indicated for metastatic or locally advanced epithelioid sarcoma not eligible for complete resection

800 mg PO BID; continue until disease progression or unacceptable toxicity

Dosage Modifications

Dose reduction schedule

  • First reduction: 600 mg PO BID
  • Second reduction: 400 mg PO BID
  • Permanently discontinue if unable to tolerate 400 mg BID

Neutropenia

  • Neutrophil count <1 x 109/L: Withhold until neutrophil count ≥1 x 109/L or baseline
  • First occurrence: Resume at same dose
  • Second and third occurrences: Resume at reduced dose
  • Permanently discontinue after fourth occurrence

Thrombocytopenia

  • Platelet count <50 x 109/L: Withhold until platelet count ≥75 x 109/L or baseline
  • First and second occurrences: Resume at reduced dose
  • Permanently discontinue after third occurrence

Anemia

  • Hemoglobin <8 g/dL: Withhold until improvement to at least Grade 1 or baseline, then resume at same or reduced dose

Other adverse reactions

  • Grade 3
    • Withhold until improvement to at least Grade 1 or baseline
    • First and second occurrences: Resume at reduced dose
    • Permanently discontinue after third occurrence
  • Grade 4
    • Withhold until improvement to at least Grade 1 or baseline
    • First and second occurrences: Resume at reduced dose
    • Permanently discontinue after second occurrence

Coadministration with CYP3A inhibitors

  • Strong CYP3A inhibitors: Avoid use
  • Moderate CYP3A inhibitors
    • Avoid use; if coadministration with a moderate CYP3A inhibitor cannot be avoided, reduce dose
    • Current dose 800 mg BID: Reduce to 400 mg BID
    • Current dose 600 mg BID: Reduce to 400 mg for first dose and 200 mg for second dose
    • Current dose 400 mg BID: Reduce to 200 mg BID
    • After discontinuation of the moderate CYP3A inhibitor for 3 elimination half-lives, resume tazemetostat dose that was taken before initiating the inhibitor

Renal impairment

  • Mild-to-severe or end-stage renal disease: No dosage adjustment necessary

Hepatic impairment

  • Mild (total bilirubin >1-1.5 times ULN or AST > ULN): No dosage adjustment necessary
  • Moderate-to-severe (total bilirubin >1.5 times ULN): Not studied

Orphan Designations

Follicular lymphoma (FL)

Malignant rhabdoid tumors (MRTs)

Mesothelioma

Soft tissue sarcoma

Orphan Sponsor

  • Epizyme, Inc; 400 Technology Square,4th Floor Cambridge, Massachusetts 02139

Dosage Forms & Strengths

tablet

  • 200mg

Epithelioid Sarcoma

Indicated for metastatic or locally advanced epithelioid sarcoma not eligible for complete resection in adults and adolescents aged ≥16 years

<16 years: Safety and efficacy not established

≥16 years: 800 mg PO BID; continue until disease progression or unacceptable toxicity

Dosage Modifications

Dose reduction schedule

  • First reduction: 600 mg PO BID
  • Second reduction: 400 mg PO BID
  • Permanently discontinue if unable to tolerate 400 mg BID

Neutropenia

  • Neutrophil count <1 x 109/L: Withhold until neutrophil count ≥1 x 109/L or baseline
  • First occurrence: Resume at same dose
  • Second and third occurrences: Resume at reduced dose
  • Permanently discontinue after fourth occurrence

Thrombocytopenia

  • Platelet count <50 x 109/L: Withhold until platelet count ≥75 x 109/L or baseline
  • First and second occurrences: Resume at reduced dose
  • Permanently discontinue after third occurrence

Anemia

  • Hemoglobin <8 g/dL: Withhold until improvement to at least Grade 1 or baseline, then resume at same or reduced dose

Other adverse reactions

  • Grade 3
    • Withhold until improvement to at least Grade 1 or baseline
    • First and second occurrences: Resume at reduced dose
    • Permanently discontinue after third occurrence
  • Grade 4
    • Withhold until improvement to at least Grade 1 or baseline
    • First and second occurrences: Resume at reduced dose
    • Permanently discontinue after second occurrence

Coadministration with CYP3A inhibitors

  • Strong CYP3A inhibitors: Avoid use
  • Moderate CYP3A inhibitors
    • Avoid use; if coadministration with a moderate CYP3A inhibitor cannot be avoided, reduce dose
    • Current dose 800 mg BID: Reduce to 400 mg BID
    • Current dose 600 mg BID: Reduce to 400 mg for first dose and 200 mg for second dose
    • Current dose 400 mg BID: Reduce to 200 mg BID
    • After discontinuation of the moderate CYP3A inhibitor for 3 elimination half-lives, resume tazemetostat dose that was taken before initiating the inhibitor

Renal impairment

  • Mild-to-severe or end-stage renal disease: No dosage adjustment necessary

Hepatic impairment

  • Mild (total bilirubin >1-1.5 times ULN or AST > ULN): No dosage adjustment necessary
  • Moderate-to-severe (total bilirubin >1.5 times ULN): Not studied
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Interactions

Interaction Checker

and tazemetostat

No Results

     activity indicator 
    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

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            Adverse Effects

            >10%

            All grades

            • Pain (52%)
            • Decreased hemoglobin (49%)
            • Fatigue (47%)
            • Decreased lymphocytes (36%)
            • Increased triglycerides (36%)
            • Nausea (36%)
            • Increased glucose (33%)
            • Decreased sodium (30%)
            • Decreased phosphate (28%)
            • Decreased appetite (26%)
            • Vomiting (24%)
            • Decreased albumin (23%)
            • Increased alkaline phosphatase (23%)
            • Increased AST (18%)
            • Decreased potassium (20%)
            • Constipation (21%)
            • Decreased WBC count (19%)
            • Cough (18%)
            • Hemorrhage (18%)
            • Headache (18%)
            • Decreased calcium (16%)
            • Anemia (16%)
            • Decreased weight (16%)
            • Decreased glucose (16%)
            • Dyspnea (16%)
            • Diarrhea (16%)
            • Increased partial thromboplastin time (15%)
            • Increased ALT (14%)
            • Abdominal pain (13%)
            • Increased creatinine (12%)
            • Increased potassium (12%)

            Grade 3-4

            • Anemia (13%)

            1-10%

            Grade 3-4

            • Pain (7%)
            • Decreased weight (7%)
            • Increased partial thromboplastin time (5%)
            • Dyspnea (4.8%)
            • Hemorrhage (4.8%)
            • Decreased appetite (4.8%)
            • Increased AST (3.5%)
            • Increased ALT (3.4%)
            • Increased triglycerides (3.3%)
            • Increased alkaline phosphatase (1.7%)
            • Decreased potassium (1.7%)
            • Decreased sodium (1.7%)
            • Decreased phosphate (1.7%)
            • Fatigue (1.6%)
            • Abdominal pain (1.6%)
            • Increased glucose (1.6%)
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            Warnings

            Contraindications

            None

            Cautions

            May increase the risk of developing secondary malignancies, including T-cell lymphoblastic lymphoma, myelodysplastic syndrome, and acute myeloid leukemia

            Can cause fetal harm; advise patients of potential risk to a fetus and to use effective nonhormonal contraception

            Drug interaction overview

            Tazemetostat is a CYP3A4 substrate and CYP3A4 inducer

            • Strong and moderate CYP3A inhibitors
              • Avoid coadministration
              • Coadministration increases tazemetostat plasma concentrations, which may increase the frequency or severity of adverse reactions
              • If unable to avoid coadministration with moderate CYP3A inhibitors, modify tazemetostat dose
            • Strong and moderate CYP3A inducers
              • Avoid coadministration
              • Coadministration with a strong or moderate CYP3A inducer may decrease tazemetostat plasma concentrations, which may decrease the efficacy of tazemetostat
            • CYP3A substrates
              • Coadministration with CYP3A substrates, including hormonal contraceptives, can result in decreased concentrations and reduced efficacy of CYP3A substrates
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            Pregnancy & Lactation

            Pregnancy

            Based on findings from animal studies and its mechanism of action, fetal harm may occur when administered to pregnant women

            No data available on use in pregnant women to inform a drug-associated risk

            Advise pregnant women of the potential risk to a fetus

            Verify pregnancy status of females of reproductive potential before use

            Animal data

            • 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 ~1.5 times the adult human dose at 800 mg BID

            Contraception

            • Females of reproductive potential: Use effective nonhormonal contraception during treatment and for 6 months after the final dose; may render some hormonal contraceptives ineffective
            • Males with female partners of reproductive potential: Use effective contraception during treatment and for at least 3 months after the final dose

            Lactation

            There are no animal or human data on the presence of tazemetostat in human milk or on its effects on the breastfed child or milk production

            Owing to the potential risk for serious adverse reactions from tazemetostat in the breastfed child, advise women not to breastfeed during treatment and for 1 week after the final dose

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Enhancer of zeste homolog 2 (EZH2) inhibitor

            Misregulated EZH2 enzyme activity results in poorly regulated genes that control cell proliferation

            Absorption

            Peak plasma concentration (steady-state): 829 ng/mL

            Peak plasma time: 1-2 hr

            Oral bioavailability: ~33%

            Steady-state is reached by Day 15

            AUC: 3340 ng⋅hr/mL

            Effect of food

            • A high-fat, high-calorie (~800 to 1000 calories) meal does not have a significant effect on tazemetostat exposure

            Distribution

            Vd (steady-state): 1230 L

            Protein bound: 88%

            Metabolism

            Metabolized by CYP3A to form the inactive major metabolites M5 (EPZ-6930) and M3 (EPZ006931)

            M5 undergoes further metabolism by CYP3A

            Elimination

            Half-life: 3.1 hr

            Total clearance (steady-state): 274 L/hr

            Excretion: Urine (15%); feces (79%)

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            Administration

            Oral Administration

            Take with or without food

            Swallow tablets whole

            Missed dose

            • Do not take an additional dose if a dose is missed or vomiting occurs after dose, but continue with the next scheduled dose

            Storage

            Tablets: Do not store above 30ºC (86ºF)

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            Formulary

            FormularyPatient Discounts

            Adding plans allows you to compare formulary status to other drugs in the same class.

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            • View the formulary and any restrictions for each plan.
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            • Compare formulary status to other drugs in the same class.
            • Access your plan list on any device – mobile or desktop.

            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
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            Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
            ST Step Therapy
            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
            OR Other Restrictions
            Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.