Risk Summary
ADCETRIS can cause fetal harm based on the findings from animal studies and the drug’s mechanism of action [see Clinical Pharmacology (12.1)]. In animal reproduction studies, administration of brentuximab vedotin to pregnant rats during organogenesis at doses similar to the clinical dose of 1.8 mg/kg every three weeks caused embryo-fetal toxicities, including congenital malformations (see Data). The available data from case reports on ADCETRIS use in pregnant women are insufficient to inform a drug-associated risk of adverse developmental outcomes. Advise a pregnant woman of the potential risk to a fetus.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.
Animal Data
In an embryo-fetal developmental study, pregnant rats received 2 intravenous doses of 0.3, 1, 3, or 10 mg/kg brentuximab vedotin during the period of organogenesis (once each on Pregnancy Days 6 and 13). Drug-induced embryo-fetal toxicities were seen mainly in animals treated with 3 and 10 mg/kg of the drug and included increased early resorption (≥99%), post-implantation loss (≥99%), decreased numbers of live fetuses, and external malformations (i.e., umbilical hernias and malrotated hindlimbs). Systemic exposure in animals at the brentuximab vedotin dose of 3 mg/kg is approximately the same exposure in patients with cHL or sALCL who received the recommended dose of 1.8 mg/kg every three weeks.
Risk Summary
There is no information regarding the presence of brentuximab vedotin in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child from ADCETRIS, including cytopenias and neurologic or gastrointestinal toxicities, advise patients that breastfeeding is not recommended during ADCETRIS treatment.
ADCETRIS can cause fetal harm based on the findings from animal studies and the drug’s mechanism of action [see Use in Specific Populations (8.1)].
Pregnancy Testing
Verify the pregnancy status of females of reproductive potential prior to initiating ADCETRIS therapy.
Contraception
Females
Advise females of reproductive potential to use effective contraception during ADCETRIS treatment and for 2 months after the last dose of ADCETRIS. Advise females to immediately report pregnancy [see Use in Specific Populations (8.1)].
Males
ADCETRIS may damage spermatozoa and testicular tissue, resulting in possible genetic abnormalities. Males with female sexual partners of reproductive potential should use effective contraception during ADCETRIS treatment and for 4 months after the last dose of ADCETRIS [see Nonclinical Toxicology (13.1)].
Infertility
Females
Based on findings in animal studies with MMAE-containing antibody-drug conjugates (ADCs), ADCETRIS may impair female fertility. The effect on fertility is reversible [see Nonclinical Toxicology (13.1)].
Males
Based on findings in rats, male fertility may be compromised by treatment with ADCETRIS [see Nonclinical Toxicology (13.1)].
The safety and effectiveness of ADCETRIS have been established in pediatric patients age 2 years and older with previously untreated high risk classical Hodgkin lymphoma in combination with doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide. The safety and effectiveness of ADCETRIS have not been established for all other indications [see Indications and Usage (1)].
Previously Untreated, High Risk Classical Hodgkin Lymphoma (cHL) in Combination with Doxorubicin, Vincristine, Etoposide, Prednisone, and Cyclophosphamide
The safety and effectiveness of ADCETRIS have been established in pediatric patients 2 years and older with previously untreated high risk cHL in combination with doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide chemotherapy.
Use of ADCETRIS for this indication is supported by evidence from Study 7: AHOD1331, a randomized study which included pediatric patients with previously untreated high risk cHL, including patients in the following age groups: 9 patients 3 to less than 6 years of age, 81 patients 6 to less than 12 years of age, and 345 patients 12 to less than 17 years of age [see Adverse Reactions (6.1) and Clinical Studies (14.1)].
The safety and efficacy of ADCETRIS have not been established for this indication in patients younger than 2 years.
Previously Untreated High Risk Classical Hodgkin Lymphoma (cHL) in Combination with Etoposide, Prednisone, Doxorubicin, Cyclophosphamide, Prednisone, and Dacarbazine
The safety and effectiveness of ADCETRIS in combination with etoposide (E), prednisone (P), and doxorubicin (A)/cyclophosphamide (C), prednisone (P), and dacarbazine (Dac) (AEPA/CAPDac) were assessed but have not been established based on a single arm, open-label trial (NCT01920932) in 77 patients, which included 48 pediatric patients age 6 to less than 17 with previously untreated high risk (IIB, IIIB, IVA, or IVB) cHL. No new safety signals were identified in this study.
Relapsed or Refractory Classical HL (cHL)
ADCETRIS in Combination with Gemcitabine
The safety and effectiveness of ADCETRIS in combination with gemcitabine were assessed but have not been established based on a study (NCT01780662) in 45 patients, which included 18 pediatric patients age 5 to less than 17 with relapsed or refractory cHL. No new safety signals were identified in this study.
ADCETRIS Monotherapy
The safety and effectiveness of ADCETRIS monotherapy was assessed but have not been established based on a study (NCT01492088) in 36 patients, which included 15 pediatric patients age 8 to less than 17 with relapsed or refractory cHL. No new safety signals were identified in this study.
Relapsed or Refractory Systemic ALCL (sALCL)
ADCETRIS monotherapy
The safety and effectiveness of ADCETRIS monotherapy was assessed but have not been established based on a study (NCT01492088) in 36 patients, which included 16 pediatric patients age 7 to less than 17 with sALCL. No new safety signals were identified in this study.
Newly Diagnosed ALK+ ALCL
The safety and effectiveness of ADCETRIS in combination with alternating chemotherapy Courses A (dexamethasone, ifosfamide, methotrexate, etoposide, cytarabine) and B (dexamethasone, methotrexate, cyclophosphamide, doxorubicin) administered every 21 days for a total of 6 cycles was assessed but have not been established based on a study (NCT01979536) in 67 patients, which included 61 pediatric patients age 2 to less than 17 years with newly diagnosed ALK+ ALCL. No new safety signals were identified in this study.
In the clinical trial of ADCETRIS in combination with AVD for patients with previously untreated Stage III or IV cHL (Study 5: ECHELON-1), 9% of ADCETRIS + AVD-treated patients were age 65 or older. Older age was a risk factor for febrile neutropenia, occurring in 39% of patients who were age 65 or older versus 17% of patients less than age 65, who received ADCETRIS + AVD [see Dosage and Administration (2.3)]. The ECHELON-1 trial did not contain sufficient information on patients age 65 and older to determine whether they respond differently from younger patients [see Clinical Studies (14.1)].
In the clinical trial of ADCETRIS in combination with CHP for patients with previously untreated, CD30-expressing PTCL (Study 6: ECHELON-2), 31% of ADCETRIS + CHP-treated patients were age 65 or older. Among older patients, 74% had adverse reactions ≥ Grade 3 and 49% had serious adverse reactions. Among patients younger than age 65, 62% had adverse reactions ≥ Grade 3 and 33% had serious adverse reactions. Older age was a risk factor for febrile neutropenia, occurring in 29% of patients who were age 65 or older versus 14% of patients less than age 65.
Other clinical trials of ADCETRIS in cHL (Study 1; Study 3: AETHERA) and sALCL (Study 2) did not include sufficient numbers of patients who were age 65 and older to determine whether they respond differently from younger patients.
In the clinical trial of ADCETRIS in pcALCL or CD30-expressing MF (Study 4: ALCANZA), 42% of ADCETRIS-treated patients were age 65 or older. No meaningful differences in safety or efficacy were observed between these patients and younger patients.
Avoid the use of ADCETRIS in patients with severe renal impairment (CrCL <30 mL/min) [see Warnings and Precautions (5.6) and Clinical Pharmacology (12.3)]. No dosage adjustment is required for mild (CrCL >50–80 mL/min) or moderate (CrCL 30–50 mL/min) renal impairment.
Avoid the use of ADCETRIS in patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment [see Warnings and Precautions (5.7) and Clinical Pharmacology (12.3)]. Dosage reduction is required in patients with mild (Child-Pugh A) hepatic impairment [see Dosage and Administration (2.1)].
Risk Summary
ADCETRIS can cause fetal harm based on the findings from animal studies and the drug’s mechanism of action [see Clinical Pharmacology (12.1)]. In animal reproduction studies, administration of brentuximab vedotin to pregnant rats during organogenesis at doses similar to the clinical dose of 1.8 mg/kg every three weeks caused embryo-fetal toxicities, including congenital malformations (see Data). The available data from case reports on ADCETRIS use in pregnant women are insufficient to inform a drug-associated risk of adverse developmental outcomes. Advise a pregnant woman of the potential risk to a fetus.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.
Animal Data
In an embryo-fetal developmental study, pregnant rats received 2 intravenous doses of 0.3, 1, 3, or 10 mg/kg brentuximab vedotin during the period of organogenesis (once each on Pregnancy Days 6 and 13). Drug-induced embryo-fetal toxicities were seen mainly in animals treated with 3 and 10 mg/kg of the drug and included increased early resorption (≥99%), post-implantation loss (≥99%), decreased numbers of live fetuses, and external malformations (i.e., umbilical hernias and malrotated hindlimbs). Systemic exposure in animals at the brentuximab vedotin dose of 3 mg/kg is approximately the same exposure in patients with cHL or sALCL who received the recommended dose of 1.8 mg/kg every three weeks.
Risk Summary
There is no information regarding the presence of brentuximab vedotin in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child from ADCETRIS, including cytopenias and neurologic or gastrointestinal toxicities, advise patients that breastfeeding is not recommended during ADCETRIS treatment.
ADCETRIS can cause fetal harm based on the findings from animal studies and the drug’s mechanism of action [see Use in Specific Populations (8.1)].
Pregnancy Testing
Verify the pregnancy status of females of reproductive potential prior to initiating ADCETRIS therapy.
Contraception
Females
Advise females of reproductive potential to use effective contraception during ADCETRIS treatment and for 2 months after the last dose of ADCETRIS. Advise females to immediately report pregnancy [see Use in Specific Populations (8.1)].
Males
ADCETRIS may damage spermatozoa and testicular tissue, resulting in possible genetic abnormalities. Males with female sexual partners of reproductive potential should use effective contraception during ADCETRIS treatment and for 4 months after the last dose of ADCETRIS [see Nonclinical Toxicology (13.1)].
Infertility
Females
Based on findings in animal studies with MMAE-containing antibody-drug conjugates (ADCs), ADCETRIS may impair female fertility. The effect on fertility is reversible [see Nonclinical Toxicology (13.1)].
Males
Based on findings in rats, male fertility may be compromised by treatment with ADCETRIS [see Nonclinical Toxicology (13.1)].
The safety and effectiveness of ADCETRIS have been established in pediatric patients age 2 years and older with previously untreated high risk classical Hodgkin lymphoma in combination with doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide. The safety and effectiveness of ADCETRIS have not been established for all other indications [see Indications and Usage (1)].
Previously Untreated, High Risk Classical Hodgkin Lymphoma (cHL) in Combination with Doxorubicin, Vincristine, Etoposide, Prednisone, and Cyclophosphamide
The safety and effectiveness of ADCETRIS have been established in pediatric patients 2 years and older with previously untreated high risk cHL in combination with doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide chemotherapy.
Use of ADCETRIS for this indication is supported by evidence from Study 7: AHOD1331, a randomized study which included pediatric patients with previously untreated high risk cHL, including patients in the following age groups: 9 patients 3 to less than 6 years of age, 81 patients 6 to less than 12 years of age, and 345 patients 12 to less than 17 years of age [see Adverse Reactions (6.1) and Clinical Studies (14.1)].
The safety and efficacy of ADCETRIS have not been established for this indication in patients younger than 2 years.
Previously Untreated High Risk Classical Hodgkin Lymphoma (cHL) in Combination with Etoposide, Prednisone, Doxorubicin, Cyclophosphamide, Prednisone, and Dacarbazine
The safety and effectiveness of ADCETRIS in combination with etoposide (E), prednisone (P), and doxorubicin (A)/cyclophosphamide (C), prednisone (P), and dacarbazine (Dac) (AEPA/CAPDac) were assessed but have not been established based on a single arm, open-label trial (NCT01920932) in 77 patients, which included 48 pediatric patients age 6 to less than 17 with previously untreated high risk (IIB, IIIB, IVA, or IVB) cHL. No new safety signals were identified in this study.
Relapsed or Refractory Classical HL (cHL)
ADCETRIS in Combination with Gemcitabine
The safety and effectiveness of ADCETRIS in combination with gemcitabine were assessed but have not been established based on a study (NCT01780662) in 45 patients, which included 18 pediatric patients age 5 to less than 17 with relapsed or refractory cHL. No new safety signals were identified in this study.
ADCETRIS Monotherapy
The safety and effectiveness of ADCETRIS monotherapy was assessed but have not been established based on a study (NCT01492088) in 36 patients, which included 15 pediatric patients age 8 to less than 17 with relapsed or refractory cHL. No new safety signals were identified in this study.
Relapsed or Refractory Systemic ALCL (sALCL)
ADCETRIS monotherapy
The safety and effectiveness of ADCETRIS monotherapy was assessed but have not been established based on a study (NCT01492088) in 36 patients, which included 16 pediatric patients age 7 to less than 17 with sALCL. No new safety signals were identified in this study.
Newly Diagnosed ALK+ ALCL
The safety and effectiveness of ADCETRIS in combination with alternating chemotherapy Courses A (dexamethasone, ifosfamide, methotrexate, etoposide, cytarabine) and B (dexamethasone, methotrexate, cyclophosphamide, doxorubicin) administered every 21 days for a total of 6 cycles was assessed but have not been established based on a study (NCT01979536) in 67 patients, which included 61 pediatric patients age 2 to less than 17 years with newly diagnosed ALK+ ALCL. No new safety signals were identified in this study.
In the clinical trial of ADCETRIS in combination with AVD for patients with previously untreated Stage III or IV cHL (Study 5: ECHELON-1), 9% of ADCETRIS + AVD-treated patients were age 65 or older. Older age was a risk factor for febrile neutropenia, occurring in 39% of patients who were age 65 or older versus 17% of patients less than age 65, who received ADCETRIS + AVD [see Dosage and Administration (2.3)]. The ECHELON-1 trial did not contain sufficient information on patients age 65 and older to determine whether they respond differently from younger patients [see Clinical Studies (14.1)].
In the clinical trial of ADCETRIS in combination with CHP for patients with previously untreated, CD30-expressing PTCL (Study 6: ECHELON-2), 31% of ADCETRIS + CHP-treated patients were age 65 or older. Among older patients, 74% had adverse reactions ≥ Grade 3 and 49% had serious adverse reactions. Among patients younger than age 65, 62% had adverse reactions ≥ Grade 3 and 33% had serious adverse reactions. Older age was a risk factor for febrile neutropenia, occurring in 29% of patients who were age 65 or older versus 14% of patients less than age 65.
Other clinical trials of ADCETRIS in cHL (Study 1; Study 3: AETHERA) and sALCL (Study 2) did not include sufficient numbers of patients who were age 65 and older to determine whether they respond differently from younger patients.
In the clinical trial of ADCETRIS in pcALCL or CD30-expressing MF (Study 4: ALCANZA), 42% of ADCETRIS-treated patients were age 65 or older. No meaningful differences in safety or efficacy were observed between these patients and younger patients.
Avoid the use of ADCETRIS in patients with severe renal impairment (CrCL <30 mL/min) [see Warnings and Precautions (5.6) and Clinical Pharmacology (12.3)]. No dosage adjustment is required for mild (CrCL >50–80 mL/min) or moderate (CrCL 30–50 mL/min) renal impairment.
Avoid the use of ADCETRIS in patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment [see Warnings and Precautions (5.7) and Clinical Pharmacology (12.3)]. Dosage reduction is required in patients with mild (Child-Pugh A) hepatic impairment [see Dosage and Administration (2.1)].
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