Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to CIBINQO during pregnancy. Pregnant women exposed to CIBINQO and health care providers are encouraged to call 1-877-311-3770.
Risk Summary
Available data from pregnancies reported in clinical trials with CIBINQO are not sufficient to establish a drug‑associated risk for major birth defects, miscarriage, or other adverse maternal or fetal outcomes. In animal reproduction studies, oral administration of abrocitinib to pregnant rats and rabbits during organogenesis at exposure 11 or 4 times the maximum recommended human dose (MRHD) based on AUC comparison, respectively, resulted in maternal dystocia and skeletal variations in rats and no adverse effects in rabbits (see Data).
The background risks of major birth defects and miscarriage for the indicated population are unknown. All pregnancies carry some risk of birth defects, loss, or other adverse outcomes. The background risks in the U.S. general population of major birth defects and miscarriages are 2–4% and 15–20% of clinically recognized pregnancies, respectively.
Animal Data
In an embryofetal development study, abrocitinib was administered orally to pregnant rats at doses of 10, 30, or 60 mg/kg/day during the period of organogenesis. No fetal malformations were observed. Abrocitinib increased the incidence of skeletal variations of short 13th ribs at 30 mg/kg/day (11 times the MRHD based on AUC comparison). Increased embryofetal lethality and additional skeletal variations (cervical arches with reduced ventral processes, thickened ribs, and unossified metatarsals) were noted at 60 mg/kg/day (17 times the MRHD based on AUC comparison).
In an embryofetal development study, abrocitinib was administered orally to pregnant rabbits at doses of 10, 30, or 75 mg/kg/day during the period of organogenesis. No abrocitinib-related maternal or developmental toxicity was noted at doses up to 75 mg/kg/day (4 times the MRHD based on AUC comparison).
In a prenatal and postnatal development study, abrocitinib was administered orally to pregnant rats at doses of 10, 30, and 60 mg/kg/day beginning on gestation day 6 and continuing through lactation day 20. Dystocia with prolonged parturition and reduced offspring body weights were noted at 30 mg/kg/day (11 times the MRHD based on AUC comparison). Postnatal survival was markedly decreased at 60 mg/kg/day (17 times the MRHD based on AUC comparison). No maternal toxicity was observed at 10 mg/kg/day (2.4 times the MRHD based on AUC comparison). No abrocitinib-related effects on postnatal developmental, neurobehavioral, or reproductive performance of offspring was noted at doses up to 30 mg/kg/day (11 times the MRHD based on AUC comparison).
Risk Summary
There are no data on the presence of abrocitinib in human milk, the effects on the breast-fed infant, or the effects on milk production. Abrocitinib was secreted in milk of lactating rats (see Data). When a drug is present in animal milk, it is likely that the drug will be present in human milk. Because of the serious adverse findings in adults, including risks of serious infections, malignancy, and thrombosis, advise women not to breastfeed during treatment with CIBINQO and for one day after the last dose (approximately 5–6 elimination half-lives).
Infertility
Females
Based on the findings in rats, oral administration of CIBINQO may impair female fertility. Impaired fertility in female rats was reversible 1 month after cessation of abrocitinib oral administration [see Nonclinical Toxicology (13.1)].
The safety and effectiveness of CIBINQO in pediatric patients 12 years of age and older with atopic dermatitis have been established.
In trials Trial-AD-1 and Trial-AD-2, 124 pediatric subjects 12 to less than 18 years old weighing 25 kg or more with moderate-to-severe atopic dermatitis were enrolled and randomized to receive either CIBINQO 100 mg (N=51), 200 mg (N=48), or matching placebo (N=25) in monotherapy. Additional 284 pediatric subjects 12 to less than 18 years of age weighing 25 kg or more with moderate-to-severe atopic dermatitis, were enrolled and randomized to receive either CIBINQO 100 mg (N=95) or 200 mg (N=94) or matching placebo (N=95) in combination with topical corticosteroids in Trial-AD-4. Efficacy and adverse reaction profile were comparable between the pediatric patients and adults [see Clinical Studies (14) and Adverse Reactions (6.1)].
The safety and effectiveness of CIBINQO have not been established in pediatric patients below 12 years of age.
Juvenile Animal Toxicity Data
In a juvenile animal toxicity study, abrocitinib was administered orally to juvenile rats at doses of 5, 25, and 75 mg/kg/day from postnatal day 10 (approximately equivalent to a human infant) through postnatal day 63 (approximately equivalent to an adolescent). Abrocitinib caused a reversible, dose‑related decrease in the primary spongiosa in the metaphysis of the proximal tibia and distal femur and adverse effects on bone development at all dose levels. Abrocitinib caused irreversible dose-related small or misshapen femoral heads at doses ≥5 mg/kg/day (0.8 times the MRHD based on AUC comparison); irreversibly decreased femur size and caused paw malrotation and limb impairment at doses ≥25 mg/kg/day (7.2 times the MRHD based on AUC comparison); and fractures at 75 mg/kg/day (27 times the MRHD based on AUC comparison).
In a follow-up study, abrocitinib (25 mg/kg/day, at least 4.5 times the MRHD based on AUC comparison) was orally administered to juvenile rats from postnatal day (PND) 10, 15, 21, or 30 through PND day 63. Administration beginning PND 10 caused adverse macroscopic and microscopic bone findings consistent with the previous juvenile animal study. However, administration beginning PND 15 (approximately equivalent to a 6- to 12-month old infant) caused non-adverse reversible microscopic bone findings. No bone findings were noted when administration began on PND 21 or 30 (approximately equivalent to 2- and 6-year old children, respectively).
A total of 145 (4.6%) subjects 65 years of age and older, while 25 (0.8%) were 75 years of age and older, were enrolled in CIBINQO clinical trials. Clinical trials of CIBINQO did not include sufficient numbers of subjects 65 years of age and older to determine whether they respond differently from younger adult subjects.
A higher proportion of subjects 65 years of age and older discontinued from clinical trials compared to younger subjects. Among all subjects exposed to CIBINQO, including the long-term extension trial, confirmed ALC <500/mm3 occurred only in subjects 65 years of age and older. A higher proportion of subjects 65 years of age and older had platelet counts <75,000/mm3. The incidence rate of herpes zoster in subjects 65 years of age and older treated with CIBINQO (7.40 per 100 patient-years) was higher than that of subjects 18 to less than 65 years of age (3.44 per 100 patient-years).
In patients with severe (eGFR <30 mL/min) and moderate (eGFR 30–59 mL/min) renal impairment, the combined exposure (AUCinf,u) of abrocitinib and its two active metabolites, M1 and M2, is increased compared to patients with normal renal function (eGFR ≥90 mL/min) [see Clinical Pharmacology (12.3)]. This may increase the risk of adverse reactions such as infections.
CIBINQO is not recommended for use in patients with severe renal impairment and ESRD including those on renal replacement therapy [see Dosage and Administration (2.3)].
A dosage reduction in patients with moderate renal impairment is recommended. No dosage adjustment is required in patients with mild renal impairment (eGFR 60–89 mL/min) [see Dosage and Administration (2.3)].
CIBINQO has not been studied in subjects on renal replacement therapy. In Phase 3 clinical trials, CIBINQO was not evaluated in subjects with atopic dermatitis with baseline creatinine clearance values less than 40 mL/min.
Avoid use of CIBINQO in patients with severe (Child Pugh C) hepatic impairment. In clinical trials, CIBINQO was not evaluated in subjects with severe (Child Pugh C) hepatic impairment.
Dosage adjustment is not required in patients with mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment based on similar combined exposure (AUCinf,u) of abrocitinib and its two active metabolites, M1 and M2 compared to patients with normal hepatic function [see Clinical Pharmacology (12.3)].
In patients who are CYP2C19 poor metabolizers, the AUC of abrocitinib is increased compared to CYP2C19 normal metabolizers due to reduced metabolic clearance. Dosage reduction of CIBINQO is recommended in patients who are known or suspected to be CYP2C19 poor metabolizers based on genotype or previous history/experience with other CYP2C19 substrates [see Dosage and Administration (2.4) and Clinical Pharmacology (12.5)].
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to CIBINQO during pregnancy. Pregnant women exposed to CIBINQO and health care providers are encouraged to call 1-877-311-3770.
Risk Summary
Available data from pregnancies reported in clinical trials with CIBINQO are not sufficient to establish a drug‑associated risk for major birth defects, miscarriage, or other adverse maternal or fetal outcomes. In animal reproduction studies, oral administration of abrocitinib to pregnant rats and rabbits during organogenesis at exposure 11 or 4 times the maximum recommended human dose (MRHD) based on AUC comparison, respectively, resulted in maternal dystocia and skeletal variations in rats and no adverse effects in rabbits (see Data).
The background risks of major birth defects and miscarriage for the indicated population are unknown. All pregnancies carry some risk of birth defects, loss, or other adverse outcomes. The background risks in the U.S. general population of major birth defects and miscarriages are 2–4% and 15–20% of clinically recognized pregnancies, respectively.
Animal Data
In an embryofetal development study, abrocitinib was administered orally to pregnant rats at doses of 10, 30, or 60 mg/kg/day during the period of organogenesis. No fetal malformations were observed. Abrocitinib increased the incidence of skeletal variations of short 13th ribs at 30 mg/kg/day (11 times the MRHD based on AUC comparison). Increased embryofetal lethality and additional skeletal variations (cervical arches with reduced ventral processes, thickened ribs, and unossified metatarsals) were noted at 60 mg/kg/day (17 times the MRHD based on AUC comparison).
In an embryofetal development study, abrocitinib was administered orally to pregnant rabbits at doses of 10, 30, or 75 mg/kg/day during the period of organogenesis. No abrocitinib-related maternal or developmental toxicity was noted at doses up to 75 mg/kg/day (4 times the MRHD based on AUC comparison).
In a prenatal and postnatal development study, abrocitinib was administered orally to pregnant rats at doses of 10, 30, and 60 mg/kg/day beginning on gestation day 6 and continuing through lactation day 20. Dystocia with prolonged parturition and reduced offspring body weights were noted at 30 mg/kg/day (11 times the MRHD based on AUC comparison). Postnatal survival was markedly decreased at 60 mg/kg/day (17 times the MRHD based on AUC comparison). No maternal toxicity was observed at 10 mg/kg/day (2.4 times the MRHD based on AUC comparison). No abrocitinib-related effects on postnatal developmental, neurobehavioral, or reproductive performance of offspring was noted at doses up to 30 mg/kg/day (11 times the MRHD based on AUC comparison).
Risk Summary
There are no data on the presence of abrocitinib in human milk, the effects on the breast-fed infant, or the effects on milk production. Abrocitinib was secreted in milk of lactating rats (see Data). When a drug is present in animal milk, it is likely that the drug will be present in human milk. Because of the serious adverse findings in adults, including risks of serious infections, malignancy, and thrombosis, advise women not to breastfeed during treatment with CIBINQO and for one day after the last dose (approximately 5–6 elimination half-lives).
Infertility
Females
Based on the findings in rats, oral administration of CIBINQO may impair female fertility. Impaired fertility in female rats was reversible 1 month after cessation of abrocitinib oral administration [see Nonclinical Toxicology (13.1)].
The safety and effectiveness of CIBINQO in pediatric patients 12 years of age and older with atopic dermatitis have been established.
In trials Trial-AD-1 and Trial-AD-2, 124 pediatric subjects 12 to less than 18 years old weighing 25 kg or more with moderate-to-severe atopic dermatitis were enrolled and randomized to receive either CIBINQO 100 mg (N=51), 200 mg (N=48), or matching placebo (N=25) in monotherapy. Additional 284 pediatric subjects 12 to less than 18 years of age weighing 25 kg or more with moderate-to-severe atopic dermatitis, were enrolled and randomized to receive either CIBINQO 100 mg (N=95) or 200 mg (N=94) or matching placebo (N=95) in combination with topical corticosteroids in Trial-AD-4. Efficacy and adverse reaction profile were comparable between the pediatric patients and adults [see Clinical Studies (14) and Adverse Reactions (6.1)].
The safety and effectiveness of CIBINQO have not been established in pediatric patients below 12 years of age.
Juvenile Animal Toxicity Data
In a juvenile animal toxicity study, abrocitinib was administered orally to juvenile rats at doses of 5, 25, and 75 mg/kg/day from postnatal day 10 (approximately equivalent to a human infant) through postnatal day 63 (approximately equivalent to an adolescent). Abrocitinib caused a reversible, dose‑related decrease in the primary spongiosa in the metaphysis of the proximal tibia and distal femur and adverse effects on bone development at all dose levels. Abrocitinib caused irreversible dose-related small or misshapen femoral heads at doses ≥5 mg/kg/day (0.8 times the MRHD based on AUC comparison); irreversibly decreased femur size and caused paw malrotation and limb impairment at doses ≥25 mg/kg/day (7.2 times the MRHD based on AUC comparison); and fractures at 75 mg/kg/day (27 times the MRHD based on AUC comparison).
In a follow-up study, abrocitinib (25 mg/kg/day, at least 4.5 times the MRHD based on AUC comparison) was orally administered to juvenile rats from postnatal day (PND) 10, 15, 21, or 30 through PND day 63. Administration beginning PND 10 caused adverse macroscopic and microscopic bone findings consistent with the previous juvenile animal study. However, administration beginning PND 15 (approximately equivalent to a 6- to 12-month old infant) caused non-adverse reversible microscopic bone findings. No bone findings were noted when administration began on PND 21 or 30 (approximately equivalent to 2- and 6-year old children, respectively).
A total of 145 (4.6%) subjects 65 years of age and older, while 25 (0.8%) were 75 years of age and older, were enrolled in CIBINQO clinical trials. Clinical trials of CIBINQO did not include sufficient numbers of subjects 65 years of age and older to determine whether they respond differently from younger adult subjects.
A higher proportion of subjects 65 years of age and older discontinued from clinical trials compared to younger subjects. Among all subjects exposed to CIBINQO, including the long-term extension trial, confirmed ALC <500/mm3 occurred only in subjects 65 years of age and older. A higher proportion of subjects 65 years of age and older had platelet counts <75,000/mm3. The incidence rate of herpes zoster in subjects 65 years of age and older treated with CIBINQO (7.40 per 100 patient-years) was higher than that of subjects 18 to less than 65 years of age (3.44 per 100 patient-years).
In patients with severe (eGFR <30 mL/min) and moderate (eGFR 30–59 mL/min) renal impairment, the combined exposure (AUCinf,u) of abrocitinib and its two active metabolites, M1 and M2, is increased compared to patients with normal renal function (eGFR ≥90 mL/min) [see Clinical Pharmacology (12.3)]. This may increase the risk of adverse reactions such as infections.
CIBINQO is not recommended for use in patients with severe renal impairment and ESRD including those on renal replacement therapy [see Dosage and Administration (2.3)].
A dosage reduction in patients with moderate renal impairment is recommended. No dosage adjustment is required in patients with mild renal impairment (eGFR 60–89 mL/min) [see Dosage and Administration (2.3)].
CIBINQO has not been studied in subjects on renal replacement therapy. In Phase 3 clinical trials, CIBINQO was not evaluated in subjects with atopic dermatitis with baseline creatinine clearance values less than 40 mL/min.
Avoid use of CIBINQO in patients with severe (Child Pugh C) hepatic impairment. In clinical trials, CIBINQO was not evaluated in subjects with severe (Child Pugh C) hepatic impairment.
Dosage adjustment is not required in patients with mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment based on similar combined exposure (AUCinf,u) of abrocitinib and its two active metabolites, M1 and M2 compared to patients with normal hepatic function [see Clinical Pharmacology (12.3)].
In patients who are CYP2C19 poor metabolizers, the AUC of abrocitinib is increased compared to CYP2C19 normal metabolizers due to reduced metabolic clearance. Dosage reduction of CIBINQO is recommended in patients who are known or suspected to be CYP2C19 poor metabolizers based on genotype or previous history/experience with other CYP2C19 substrates [see Dosage and Administration (2.4) and Clinical Pharmacology (12.5)].
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