Risk Summary
Based on its mechanism of action and findings from animal studies [see Clinical Pharmacology (12.1), Nonclinical Toxicology (13.1)], BESPONSA can cause embryo-fetal harm when administered to a pregnant woman. There are no available data on BESPONSA use in pregnant women to inform a drug-associated risk. In rat embryo-fetal development studies, inotuzumab ozogamicin caused embryo-fetal toxicity at maternal systemic exposures that were ≥ 0.4 times the exposure in patients at the maximum recommended dose, based on AUC [see Data]. Advise patients 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 are 2–4% and 15–20%, respectively.
Animal Data
In embryo-fetal development studies in rats, pregnant animals received daily intravenous doses of inotuzumab ozogamicin up to 0.36 mg/m2 during the period of organogenesis. Embryo-fetal toxicities including increased resorptions and fetal growth retardation as evidenced by decreased live fetal weights and delayed skeletal ossification were observed at ≥ 0.11 mg/m2 (approximately 2 times the exposure in patients at the maximum recommended dose, based on AUC). Fetal growth retardation also occurred at 0.04 mg/m2 (approximately 0.4 times the exposure in patients at the maximum recommended dose, based on AUC).
In an embryo-fetal development study in rabbits, pregnant animals received daily intravenous doses up to 0.15 mg/m2 (approximately 3 times the exposure in patients at the maximum recommended dose, based on AUC) during the period of organogenesis. At a dose of 0.15 mg/m2, slight maternal toxicity was observed in the absence of any effects on embryo‑fetal development.
Risk Summary
There are no data on the presence of inotuzumab ozogamicin or its metabolites 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, advise women not to breastfeed during treatment with BESPONSA and for 2 months after the last dose.
Based on its mechanism of action and findings from animal studies, BESPONSA can cause embryo-fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].
Pregnancy Testing
Verify the pregnancy status of females of reproductive potential prior to initiating BESPONSA.
Contraception
Females
Advise females of reproductive potential to use effective contraception during treatment with BESPONSA and for 8 months after the last dose [see Nonclinical Toxicology (13.1)].
Males
Advise males with female partners of reproductive potential to use effective contraception during treatment with BESPONSA and for 5 months after the last dose [see Nonclinical Toxicology (13.1)].
Infertility
Females
Based on findings in animals, BESPONSA may impair fertility in females of reproductive potential [see Nonclinical Toxicology (13.1)].
Males
Based on findings in animals, BESPONSA may impair fertility in males of reproductive potential [see Nonclinical Toxicology (13.1)].
The safety and effectiveness of BESPONSA in pediatric patients 1 year and older with relapsed or refractory CD22-positive B-cell precursor ALL have been established. The use of BESPONSA for this indication is supported by evidence of safety and effectiveness in Study WI203581 (ITCC-059) [see Adverse Reactions (6.1), Clinical Studies (14.1)]. The study included patients in the following age groups: 2 patients 1 year to < 2 years old, 10 patients 2 years to < 6 years old, 20 patients 6 years to < 12 years old, and 20 patients 12 years to < 17 years old. Compared to adults, pediatric patients had a higher incidence of liver test abnormalities; with grade 3-4 increases in AST, ALT, and total bilirubin in 21%, 21%, and 9%, respectively, in pediatric patients treated with BESPONSA compared to 4%, 4%, and 5% in adults.
The safety and effectiveness of BESPONSA in patients < 1 year of age with relapsed or refractory CD22-positive B-cell precursor ALL have not been established.
In the INO-VATE ALL trial, 30/164 patients (18%) treated with BESPONSA were ≥ 65 years of age. No differences in responses were identified between older and younger patients.
Based on a population pharmacokinetic analysis in 765 patients, no adjustment to the starting dose is required based on age [see Clinical Pharmacology (12.3)].
Based on a population pharmacokinetic analysis, the clearance of inotuzumab ozogamicin in patients with mild hepatic impairment (total bilirubin less than or equal to ULN and AST greater than ULN, or total bilirubin greater than 1.0–1.5 × ULN and AST any level; n=150) was similar to patients with normal hepatic function (total bilirubin/AST less than or equal to ULN; n=611). In patients with moderate (total bilirubin greater than 1.5–3 × ULN and AST any level; n=3) and severe hepatic impairment (total bilirubin greater than 3 × ULN and AST any level; n=1), inotuzumab ozogamicin clearance did not appear to be reduced [see Clinical Pharmacology (12.3)].
No adjustment to the starting dose is required when administering BESPONSA to patients with total bilirubin less than or equal to 1.5 × ULN and AST/ALT less than or equal to 2.5 × ULN [see Dosage and Administration (2.3)]. There is limited safety information available in patients with total bilirubin greater than 1.5 × ULN and/or AST/ALT greater than 2.5 × ULN prior to dosing. Interrupt dosing until recovery of total bilirubin to less than or equal to 1.5 × ULN and AST/ALT to less than or equal to 2.5 × ULN prior to each dose unless due to Gilbert's syndrome or hemolysis. Permanently discontinue treatment if total bilirubin does not recover to less than or equal to 1.5 × ULN or AST/ALT does not recover to less than or equal to 2.5 × ULN [see Dosage and Administration (2.3), Warnings and Precautions (5.1)].
Risk Summary
Based on its mechanism of action and findings from animal studies [see Clinical Pharmacology (12.1), Nonclinical Toxicology (13.1)], BESPONSA can cause embryo-fetal harm when administered to a pregnant woman. There are no available data on BESPONSA use in pregnant women to inform a drug-associated risk. In rat embryo-fetal development studies, inotuzumab ozogamicin caused embryo-fetal toxicity at maternal systemic exposures that were ≥ 0.4 times the exposure in patients at the maximum recommended dose, based on AUC [see Data]. Advise patients 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 are 2–4% and 15–20%, respectively.
Animal Data
In embryo-fetal development studies in rats, pregnant animals received daily intravenous doses of inotuzumab ozogamicin up to 0.36 mg/m2 during the period of organogenesis. Embryo-fetal toxicities including increased resorptions and fetal growth retardation as evidenced by decreased live fetal weights and delayed skeletal ossification were observed at ≥ 0.11 mg/m2 (approximately 2 times the exposure in patients at the maximum recommended dose, based on AUC). Fetal growth retardation also occurred at 0.04 mg/m2 (approximately 0.4 times the exposure in patients at the maximum recommended dose, based on AUC).
In an embryo-fetal development study in rabbits, pregnant animals received daily intravenous doses up to 0.15 mg/m2 (approximately 3 times the exposure in patients at the maximum recommended dose, based on AUC) during the period of organogenesis. At a dose of 0.15 mg/m2, slight maternal toxicity was observed in the absence of any effects on embryo‑fetal development.
Risk Summary
There are no data on the presence of inotuzumab ozogamicin or its metabolites 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, advise women not to breastfeed during treatment with BESPONSA and for 2 months after the last dose.
Based on its mechanism of action and findings from animal studies, BESPONSA can cause embryo-fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].
Pregnancy Testing
Verify the pregnancy status of females of reproductive potential prior to initiating BESPONSA.
Contraception
Females
Advise females of reproductive potential to use effective contraception during treatment with BESPONSA and for 8 months after the last dose [see Nonclinical Toxicology (13.1)].
Males
Advise males with female partners of reproductive potential to use effective contraception during treatment with BESPONSA and for 5 months after the last dose [see Nonclinical Toxicology (13.1)].
Infertility
Females
Based on findings in animals, BESPONSA may impair fertility in females of reproductive potential [see Nonclinical Toxicology (13.1)].
Males
Based on findings in animals, BESPONSA may impair fertility in males of reproductive potential [see Nonclinical Toxicology (13.1)].
The safety and effectiveness of BESPONSA in pediatric patients 1 year and older with relapsed or refractory CD22-positive B-cell precursor ALL have been established. The use of BESPONSA for this indication is supported by evidence of safety and effectiveness in Study WI203581 (ITCC-059) [see Adverse Reactions (6.1), Clinical Studies (14.1)]. The study included patients in the following age groups: 2 patients 1 year to < 2 years old, 10 patients 2 years to < 6 years old, 20 patients 6 years to < 12 years old, and 20 patients 12 years to < 17 years old. Compared to adults, pediatric patients had a higher incidence of liver test abnormalities; with grade 3-4 increases in AST, ALT, and total bilirubin in 21%, 21%, and 9%, respectively, in pediatric patients treated with BESPONSA compared to 4%, 4%, and 5% in adults.
The safety and effectiveness of BESPONSA in patients < 1 year of age with relapsed or refractory CD22-positive B-cell precursor ALL have not been established.
In the INO-VATE ALL trial, 30/164 patients (18%) treated with BESPONSA were ≥ 65 years of age. No differences in responses were identified between older and younger patients.
Based on a population pharmacokinetic analysis in 765 patients, no adjustment to the starting dose is required based on age [see Clinical Pharmacology (12.3)].
Based on a population pharmacokinetic analysis, the clearance of inotuzumab ozogamicin in patients with mild hepatic impairment (total bilirubin less than or equal to ULN and AST greater than ULN, or total bilirubin greater than 1.0–1.5 × ULN and AST any level; n=150) was similar to patients with normal hepatic function (total bilirubin/AST less than or equal to ULN; n=611). In patients with moderate (total bilirubin greater than 1.5–3 × ULN and AST any level; n=3) and severe hepatic impairment (total bilirubin greater than 3 × ULN and AST any level; n=1), inotuzumab ozogamicin clearance did not appear to be reduced [see Clinical Pharmacology (12.3)].
No adjustment to the starting dose is required when administering BESPONSA to patients with total bilirubin less than or equal to 1.5 × ULN and AST/ALT less than or equal to 2.5 × ULN [see Dosage and Administration (2.3)]. There is limited safety information available in patients with total bilirubin greater than 1.5 × ULN and/or AST/ALT greater than 2.5 × ULN prior to dosing. Interrupt dosing until recovery of total bilirubin to less than or equal to 1.5 × ULN and AST/ALT to less than or equal to 2.5 × ULN prior to each dose unless due to Gilbert's syndrome or hemolysis. Permanently discontinue treatment if total bilirubin does not recover to less than or equal to 1.5 × ULN or AST/ALT does not recover to less than or equal to 2.5 × ULN [see Dosage and Administration (2.3), Warnings and Precautions (5.1)].
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