TAZVERIK is a methyltransferase inhibitor indicated for the treatment of: Adults and pediatric patients aged 16 years and older with metastatic or locally advanced epithelioid sarcoma not eligible for complete resection. ( 1.1 ) Adult patients with relapsed or refractory follicular lymphoma whose tumors are positive for an EZH2 mutation as detected by an FDA-approved test and who have received at least 2 prior systemic therapies.
( 1.2 ) Adult patients with relapsed or refractory follicular lymphoma who have no satisfactory alternative treatment options. ( 1.2 ) These indications are approved under accelerated approval based on overall response rate and duration of response. Continued approval for these indications may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).
1.1Epithelioid Sarcoma
TAZVERIK is indicated for the treatment of adults and pediatric patients aged 16 years and older with metastatic or locally advanced epithelioid sarcoma not eligible for complete resection. This indication is approved under accelerated approval based on overall response rate and duration of response [see Clinical Studies ( 14.1 )]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).
1.2Relapsed or Refractory Follicular Lymphoma
TAZVERIK is indicated for the treatment of adult patients with relapsed or refractory (R/R) follicular lymphoma (FL) whose tumors are positive for an EZH2 mutation as detected by an FDA-approved test and who have received at least 2 prior systemic therapies. TAZVERIK is indicated for the treatment of adult patients with R/R FL who have no satisfactory alternative treatment options. These indications are approved under accelerated approval based on overall response rate and duration of response [see Clinical Studies ( 14.2 )].
Continued approval for these indications may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).
Contraindications
None. None. ( 4 )
Warnings and precautions
Secondary Malignancies : TAZVERIK increases the risk of developing secondary malignancies, including T-cell lymphoblastic lymphoma, myelodysplastic syndrome, acute myeloid leukemia, and B-cell acute lymphoblastic leukemia. Monitor patients long-term for the development of secondary malignancies. ( 5.1 ) Embryo-Fetal Toxicity : Can cause fetal harm. Advise patients of potential risk to a fetus and to use effective non-hormonal contraception.
The risk of developing secondary malignancies is increased following treatment with TAZVERIK. Across clinical trials of 758 adults who received TAZVERIK 800 mg twice daily as monotherapy, myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), or B-cell acute lymphoblastic leukemia (B-ALL) occurred in 1.7% of patients. One pediatric patient developed T-cell lymphoblastic lymphoma (T-LBL). Monitor patients long-term for the development of secondary malignancies.
5.2Embryo-Fetal Toxicity Based
on findings from animal studies and its mechanism of action, TAZVERIK can cause fetal harm when administered to pregnant women. There are no available data on TAZVERIK use in pregnant women to inform the drug-associated risk. 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 approximately 1.5 times the adult human exposure (area under the plasma concentration time curve [AUC 0-45h ]) at the 800 mg twice daily dose.
Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TAZVERIK and for 6 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with TAZVERIK and for 3 months after the final dose [see Use in Specific Populations ( 8.1 , 8.3 )] .
Interactions
Strong or Moderate Cytochrome P450 (CYP)3A Inhibitors : Avoid coadministration of strong or moderate CYP3A inhibitors with TAZVERIK. Reduce the dose of TAZVERIK if coadministration of strong or moderate CYP3A inhibitors cannot be avoided. ( 2.3 , 7.1 ) Strong or Moderate CYP3A Inducers : Avoid coadministration with TAZVERIK. ( 7.1 )
7.1Effect of Other Drugs on
TAZVERIK Strong or Moderate CYP3A Inhibitors Coadministration of TAZVERIK with a strong or moderate CYP3A inhibitor increases tazemetostat plasma concentrations [see Clinical Pharmacology ( 12.3 )], which may increase the frequency or severity of adverse reactions. Avoid coadministration of strong or moderate CYP3A inhibitors with TAZVERIK. If coadministration of strong or moderate CYP3A inhibitors cannot be avoided, reduce TAZVERIK dose [see Dosage and Administration ( 2.4 )].
Strong or Moderate CYP3A Inducers Coadministration of TAZVERIK with a strong CYP3A inducer decreases tazemetostat plasma concentrations [see Clinical Pharmacology ( 12.3 )] , and coadministration of TAZVERIK with a moderate CYP3A inducer may also decrease tazemetostat plasma concentrations. The decrease in tazemetostat plasma concentration may decrease the efficacy of TAZVERIK. Avoid coadministration of moderate or strong CYP3A inducers with TAZVERIK.
7.2Effect of
TAZVERIK on Other Drugs CYP3A Substrates Coadministration of TAZVERIK with CYP3A substrates, including hormonal contraceptives, can result in decreased concentrations and reduced efficacy of CYP3A substrates [see Use in Specific Populations ( 8.3 ), Clinical Pharmacology ( 12.3 )] .
Pregnancy and breastfeeding
8.1Pregnancy Risk Summary Based
on findings from animal studies and its mechanism of action [see Clinical Pharmacology ( 12.1 )] , TAZVERIK can cause fetal harm when administered to pregnant women. There are no available data on TAZVERIK use in pregnant women to inform the drug-associated risk. 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 approximately 1.5 times the adult human exposure [AUC 0-45h ] at the 800 mg twice daily dose (see Data ) .
Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In pregnant rats, once daily oral administration of tazemetostat during the period of organogenesis from gestation day (GD) 7 through 17 resulted in no maternal adverse effects at doses up to 100 mg/kg/day (approximately 6 times the adult human exposure at 800 mg twice daily).
Skeletal malformations and variations occurred in fetuses at doses of ≥50 mg/kg (approximately 2 times the adult human exposure at the 800 mg twice daily dose). At 200 mg/kg (approximately 14 times the adult human exposure at the 800 mg twice daily dose), major findings included increased post implantation loss, missing digits, fused vertebrae, domed heads and fused bones of the skull, and reduced fetal body weights.
In pregnant rabbits, no adverse maternal effects were observed after once daily oral administration of 400 mg/kg/day tazemetostat (approximately 7 times the adult human exposure at the 800 mg twice daily dose) from GD 7 through 19. Skeletal variations were present at doses ≥100 mg/kg/day (approximately 1.5 times the adult human exposure at the 800 mg twice daily dose), with skeletal malformations at ≥200 mg/kg/day (approximately 5.6 times the adult human exposure at the 800 mg twice daily dose).
At 400 mg/kg (approximately 7 times the adult human exposure at the 800 mg twice daily dose), major findings included increased post implantation loss and cleft palate and snout.
Adverse reactions
The following clinically significant adverse reactions are described elsewhere in labeling: Secondary Malignancies [see Warnings and Precautions ( 5.1 )]. The most common (≥20%) adverse reactions in patients with epithelioid sarcoma are pain, fatigue, nausea, decreased appetite, vomiting, and constipation. ( 6.1 ) The most common (≥20%) adverse reactions in patients with follicular lymphoma are fatigue, upper respiratory tract infection, musculoskeletal pain, nausea, and abdominal pain.
( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Epizyme at 855-463-5127 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
6.1Clinical Trial Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Epithelioid Sarcoma The safety of TAZVERIK was evaluated in a cohort (Cohort 5) of Study EZH-202 that enrolled patients with epithelioid sarcoma [see Clinical Studies ( 14.1 )].
Patients received TAZVERIK 800 mg orally twice daily (n=62). Among patients who received TAZVERIK, 44% were exposed for 6 months or longer and 24% were exposed for greater than one year. Serious adverse reactions occurred in 37% of patients who received TAZVERIK. Serious adverse reactions in ≥3% of patients who received TAZVERIK were hemorrhage, pleural effusion, skin infection, dyspnea, pain, and respiratory distress.
One patient (2%) permanently discontinued TAZVERIK due to an adverse reaction of altered mood. Dosage interruptions due to an adverse reaction occurred in 34% of patients who received TAZVERIK. The most frequent adverse reactions requiring dosage interruptions in ≥3% were hemorrhage, increased alanine aminotransferase (ALT), and increased aspartate aminotransferase (AST). Dose reduction due to an adverse reaction occurred in one (2%) patient who received TAZVERIK; the dose was reduced in this patient for decreased appetite.
The most common adverse reactions (≥20%) were pain, fatigue, nausea, decreased appetite, vomiting, and constipation. Table 4 presents adverse reactions in patients with epithelioid sarcoma in Cohort 5 of Study EZH-202. Table 4. Adverse Reactions (≥10%) in Patients with Epithelioid Sarcoma Who Received TAZVERIK in Cohort 5 of Study EZH-202 Adverse Reaction TAZVERIK N=62 All Grades (%) Grade 3 or 4 (%) a Includes tumor pain, pain in extremity, non-cardiac chest pain, flank pain, back pain, arthralgia, bone pain, cancer pain, musculoskeletal pain, myalgia, neck pain b Includes fatigue and asthenia c Includes abdominal pain, gastrointestinal pain, abdominal pain lower d Includes dyspnea and dyspnea exertional e Includes wound hemorrhage, rectal hemorrhage, pulmonary hemorrhage, hemorrhage intracranial, cerebral hemorrhage, hemoptysis General Pain a 52 7 Fatigue b 47
4.8 Respiratory, thoracic and mediastinal Cough 18 0 Dyspnea d 16
4.8Vascular
Hemorrhage e 18
4.8 Nervous system Headache 18 0 Investigations Weight decreased 16 7 Table 5 summarizes select laboratory abnormalities in patients with epithelioid sarcoma in Cohort 5 of Study EZH-202. Table 5. Select Laboratory Abnormalities (≥ 10%) Worsening from Baseline in Patients with Epithelioid Sarcoma Who Received TAZVERIK in Cohort 5 of Study EZH-202 *The denominator used to calculate the rate varied from 39 to 61 based on the number of patients with a baseline value and at least one post-treatment value.
3.4 Increased creatinine 12 0 Increased potassium 12 0 Relapsed or Refractory Follicular Lymphoma The safety of TAZVERIK was evaluated in two cohorts (Cohorts 4 and 5) of Study E7438-G000-101 that enrolled patients with relapsed or refractory follicular lymphoma [see Clinical Studies ( 14.2 )]. Patients received TAZVERIK 800 mg orally twice daily (n=99). Among patients who received TAZVERIK, 68% were exposed for 6 months or longer, 39% were exposed for 12 months or longer, and 21% were exposed for 18 months or longer.
The median age was 62 years (range 36 to 87 years), 54% were male, and 95% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. The median number of prior therapies was 3 (range 1 to 11). Patients were required to have a creatinine clearance ≥40 mL/min per the Cockcroft and Gault formula. Serious adverse reactions occurred in 30% of patients who received TAZVERIK. Serious adverse reactions in ≥2% of patients who received TAZVERIK were general physical health deterioration, abdominal pain, pneumonia, sepsis, and anemia.
Permanent discontinuation due to an adverse reaction occurred in 8% of patients who received TAZVERIK. Adverse reaction resulting in permanent discontinuation in ≥2% of patients was second primary malignancy. Dosage interruptions due to an adverse reaction occurred in 28% of patients who received TAZVERIK. Adverse reactions requiring dosage interruptions in ≥3% of patients were thrombocytopenia and fatigue. Dose reduction due to an adverse reaction occurred in 9% of patients who received TAZVERIK.
The most common adverse reactions (≥20%) were fatigue, upper respiratory tract infection, musculoskeletal pain, nausea, and abdominal pain. Table 6 presents adverse reactions in patients with relapsed or refractory follicular lymphoma in Cohorts 4 and 5 of Study E7438-G000-101. Table 6. Adverse Reactions (≥10%) in Patients with Relapsed or Refractory Follicular Lymphoma Who Received TAZVERIK in Cohorts 4 and 5 of Study E7438-G000-101 Adverse Reaction TAZVERIK N=99 All Grades (%) Grade 3 or 4 (%) a Includes fatigue and asthenia b Includes laryngitis, nasopharyngitis, pharyngitis, rhinitis, sinusitis, upper respiratory tract infection, viral upper respiratory tract infection c Includes bronchitis, lower respiratory tract infection, tracheobronchitis d Includes cystitis, urinary tract infection, urinary tract infection staphylococcal e Includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper f Includes back pain, limb discomfort, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, myalgia, neck pain, non-cardiac chest pain, pain in extremity, pain in jaw, spinal pain g Includes erythema, rash, rash erythematous, rash generalized, rash maculo-papular, rash pruritic, rash pustular, skin exfoliation h Includes cough and productive cough i Includes headache, migraine, sinus headache General Fatigue a 36 5 Pyrexia 10 0 Infections Upper respiratory tract infection b 30 0 Lower respiratory tract infection c 17 0 Urinary tract infection d 11 2 Gastrointestinal Nausea 24 1 Abdominal pain e 20 3 Diarrhea 18 0 Vomiting 12 1 Musculoskeletal and connective tissue Musculoskeletal pain f 22 1 Skin and subcutaneous tissue Alopecia 17 0 Rash g 15 0 Respiratory and mediastinal system Cough h 17 0 Nervous system Headache i 13 0 Clinically relevant adverse reactions occurring in <10% of patients who received TAZVERIK included: Infection: sepsis (2%), pneumonia (2%), and herpes zoster (2%) Table 7 summarizes select laboratory abnormalities in patients with follicular lymphoma in Cohorts 4 and 5 of Study E7438-G000-101.
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Composition
Active ingredients
TAZEMETOSTAT HYDROBROMIDE EQ 200MG BASE
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
Prognia shows this product information for reference and learning. It is not treatment advice and can lag behind the official text. Always check the current product information and local protocols before prescribing.
Table 7. Select Laboratory Abnormalities (≥10%) Worsening from Baseline in Patients with Relap
