TAZVERIK Film coated tablet Ref.[10219] Active ingredients:

5.1 Secondary Malignancies

The risk of developing secondary malignancies is increased following treatment with TAZVERIK. Across clinical trials of 729 adults who received TAZVERIK 800 mg twice daily, myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) occurred in 0.7% of patients. One pediatric patient developed T-cell lymphoblastic lymphoma (T-LBL). Monitor patients long-term for the development of secondary malignancies.

5.2 Embryo-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)].

The following clinically significant adverse reactions are described elsewhere in labeling:

• Secondary Malignancies [see Warnings and Precautions (5.1)].

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:

^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

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.

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 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:

^a Includes fatigue and asthenia
^b Includes laryngitis, nasopharyngitis, pharyngitis, rhinitis, sinusitis, upper repiratory 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

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.

Table 7. Select Laboratory Abnormalities (≥10%) Worsening from Baseline in Patients with Relapsed or Refractory Follicular Lymphoma Who Received TAZVERIK in Cohorts 4 and 5 of Study E7438-G000-101:

* The denominator used to calculate the rate varied from 88 to 96 based on the number of patients with a baseline value and at least one post-treatment value.

7.1 Effect of Other Drugs on TAZVERIK

Strong and 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 moderate CYP3A inhibitors cannot be avoided, reduce TAZVERIK dose [see Dosage and Administration (2.3)].

Strong and Moderate CYP3A Inducers

Coadministration of TAZVERIK with a strong or moderate CYP3A inducer may decrease tazemetostat plasma concentrations [see Clinical Pharmacology (12.3)], which may decrease the efficacy of TAZVERIK. Avoid coadministration of moderate and strong CYP3A inducers with TAZVERIK.

7.2 Effect 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)].

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.

Risk Summary

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. Because of the potential risk for serious adverse reactions from TAZVERIK in the breastfed child, advise women not to breastfeed during treatment with TAZVERIK and for one week after the final dose.

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating TAZVERIK [see Use in Specific Populations (8.1)].

Risk Summary

TAZVERIK can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)].

Contraception

Females

Advise females of reproductive potential to use effective non-hormonal contraception during treatment with TAZVERIK and for 6 months after the final dose. TAZVERIK can render some hormonal contraceptives ineffective [see Drug Interactions (7.2)].

Males

Advise males with female partners of reproductive potential to use effective contraception during treatment with TAZVERIK and for at least 3 months after the final dose.

The safety and effectiveness of TAZVERIK have been established in pediatric patients aged 16 years and older (adolescents) with metastatic or locally advanced epithelioid sarcoma. Use of TAZVERIK for this indication is supported by evidence from adequate and well-controlled studies in adults (including 3 adolescent patients aged 16 years) [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.1)].

The safety and effectiveness of TAZVERIK in pediatric patients aged less than 16 years have not been established.

Juvenile Animal Toxicity Data

In a 13-week juvenile rat toxicology study, animals were dosed daily from post-natal day 7 to day 97 (approximately equivalent to neonate to adulthood). Tazemetostat resulted in:

• T-LBL at doses ≥50 mg/kg (approximately 2.8 times the adult human exposure at the 800 mg twice daily dose)
• Increased trabecular bone at doses ≥100 mg/kg (approximately 10 times the adult human exposure at the 800 mg twice daily dose)
• Increased body weight at doses ≥50 mg/kg (approximately equal to the adult human exposure at the 800 mg twice daily dose)
• Distended testicles in males at doses ≥50 mg/kg (approximately equal to the adult human exposure at the 800 mg twice daily dose)

Clinical studies of TAZVERIK did not include sufficient numbers of patients with epithelioid sarcoma or relapsed or refactory follicular lymphoma aged 65 and over to determine whether they respond differently from younger subjects.

No dose adjustment of TAZVERIK is recommended for patients with mild to severe renal impairment or end stage renal disease [see Clinical Pharmacology (12.3)].

No dose adjustment of TAZVERIK is recommended for patients with mild hepatic impairment (total bilirubin >1 to 1.5 times upper limit of normal [ULN] or AST > ULN). TAZVERIK has not been studied in patients with moderate (total bilirubin >1.5 to 3 times ULN) or severe (total bilirubin >3 times ULN) hepatic impairment [see Clinical Pharmacology (12.3)].