TAZVERIK
Clinical safety rating: caution
Comprehensive clinical and safety monograph for TAZVERIK (TAZVERIK).
TAZVERIK is a histone methyltransferase EZH2 inhibitor. It selectively inhibits the enzymatic activity of EZH2, leading to decreased trimethylation of lysine 27 on histone H3 (H3K27me3), which results in reactivation of silenced genes and inhibition of proliferation in EZH2-mutant or wild-type cells.
| Metabolism | Primarily metabolized by CYP3A4 and to a lesser extent by CYP2C8 and CYP3A5. |
| Excretion | Primarily hepatobiliary excretion: approximately 70% of the dose recovered in feces as unchanged drug and metabolites, with <1% excreted renally as unchanged tazemetostat. |
| Half-life | Terminal elimination half-life is approximately 3.6 hours (range 1.6–7.1 hours) in patients with epithelioid sarcoma at steady state. Short half-life supports twice-daily dosing. Consider accumulation with renal or hepatic impairment. |
| Protein binding | Approximately 88% bound to human plasma proteins (mainly albumin and α1-acid glycoprotein), independent of concentration. |
| Volume of Distribution | Volume of distribution (Vd) is 112 L (approximately 1.6 L/kg for a 70 kg adult). Indicates extensive extravascular distribution, likely due to binding to EZH2 in tissues. |
| Bioavailability | Absolute bioavailability not determined. Relative bioavailability of oral tablet is high based on exposure data; administration with high-fat meal increases Cmax by 2-fold and AUC by 1.6-fold compared to fasting. |
| Onset of Action | Oral tablet: Time to peak plasma concentration (Tmax) is 1–2 hours. Clinical response assessed after several weeks of continuous therapy; no immediate effect. |
| Duration of Action | Duration of action is 12 hours corresponding to twice-daily dosing interval. Clinical effect persists as long as drug is administered; no formal duration defined after discontinuation. |
600 mg orally twice daily, with or without food, for advanced epithelioid sarcoma. Continue until disease progression or unacceptable toxicity.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment (CrCl ≥30 mL/min). Not studied in severe renal impairment (CrCl <30 mL/min) or dialysis. |
| Liver impairment | No dose adjustment for mild hepatic impairment (Child-Pugh A). For moderate (Child-Pugh B) or severe (Child-Pugh C), reduce dose to 400 mg orally twice daily. |
| Pediatric use | Safety and efficacy not established in pediatric patients; no recommended dose. |
| Geriatric use | No specific dose adjustment recommended. Elderly patients may be more sensitive to renal function and concomitant medications; monitor accordingly. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for TAZVERIK (TAZVERIK).
| Breastfeeding | No data on presence in human milk, effects on breastfed child, or milk production. Due to potential for serious adverse reactions, advise women not to breastfeed during treatment and for 1 week after the last dose. |
| Teratogenic Risk | TAZVERIK (tazemetostat) is an EZH2 inhibitor. Based on its mechanism of action and animal studies, it can cause fetal harm. There are no adequate human data. Advise females of reproductive potential to use effective contraception during treatment and for 6 months after the last dose. |
■ FDA Black Box Warning
WARNING: SECONDARY MALIGNANCIES. TAZVERIK increases the risk of developing secondary malignancies, such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Monitor patients for signs and symptoms of MDS/AML and discontinue if confirmed.
| Serious Effects |
["None known"]
| Precautions | ["Secondary malignancies (MDS/AML) - monitor complete blood counts","Fetal toxicity - can cause fetal harm; advise females of reproductive potential of effective contraception","Embryo-fetal toxicity - animal studies show adverse developmental effects"] |
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| Fetal Monitoring |
| No specific monitoring recommendations for pregnancy. For all patients, monitor complete blood counts prior to initiation and periodically, as myelosuppression may occur. Monitor for secondary malignancies, including myelodysplastic syndrome and acute myeloid leukemia. |
| Fertility Effects | May impair fertility in females of reproductive potential based on animal studies. Reversibility of effect is unknown. No data on male fertility. |