inqo is recommended when coadministered with strong cyp2c19 inhibitors [see dosage and administration (2.5) ]. moderate to strong inhibitors of both cyp2c19 and cyp2c9 clinical impact coadministration of cibinqo with drugs that are moderate to strong inhibitors of both cyp2c19 and cyp2c9 increases the exposure of abrocitinib and its two active metabolites, m1 and m2 which may increase the adverse reactions of cibinqo [ clinical pharmacology (12.3) ]. intervention avoid concomitant use of cibinqo with drugs that are moderate to strong inhibitors of both cyp2c19 and cyp2c9 . strong cyp2c19 or cyp2c9 inducers clinical impact coadministration of cibinqo with strong cyp2c19 or cyp2c9 inducers decreases the combined exposure of abrocitinib and its two active metabolites, m1 and m2, which may result in loss of or reduced clinical response [see clinical pharmacology (12.3) ] . intervention avoid concomitant use of cibinqo with strong cyp2c19 or cyp2c9 inducers. 7.2 effects of cibinqo on other drugs table 5 includes clinically significant drug interactions affecting other drugs. table 5. clinically significant interactions affecting other drugs p-gp substrate where small concentration changes may lead to serious or life-threatening toxicities clinical impact coadministration of cibinqo with p-gp substrate increases plasma concentrations of p-gp substrates and may result in potential adverse reactions of the p-gp substrate where small concentration changes may lead to serious or life-threatening toxicities (e.g., digoxin) [see clinical pharmacology (12.3) ] . intervention monitor appropriately or dose titrate p-gp substrate where small concentration changes may lead to serious or life-threatening toxicities when coadministered with cibinqo . antiplatelet therapy drugs clinical impact coadministration of cibinqo with antiplatelet therapy drugs may increase the risk of bleeding with thrombocytopenia [see warnings and precautions (5.5) and clinical pharmacology (12.2) ]. intervention antiplatelet drugs, except for low-dose aspirin (≤81 mg daily), during the first 3 months of treatment are contraindicated with cibinqo [see contraindications (4) ] .

culosis • with a history of a serious or an opportunistic infection • who have resided or traveled in areas of endemic tuberculosis or endemic mycoses • with underlying conditions that may predispose them to infection closely monitor patients for the development of signs and symptoms of infection during and after treatment with cibinqo. if a patient develops a serious or opportunistic infection, discontinue cibinqo. initiate complete diagnostic testing and appropriate antimicrobial therapy. the risks and benefits of treatment with cibinqo should be carefully considered prior to reinitiating therapy with cibinqo. tuberculosis evaluate and test patients for tb before starting cibinqo therapy and consider yearly screening for patients in highly endemic areas for tb. cibinqo is not recommended for use in patients with active tb. for patients with a new diagnosis of latent tb or prior untreated latent tb, or for patients with a negative test for latent tb but who are at high risk for tb infection, start preventive therapy for latent tb prior to initiation of cibinqo. monitor patients for the development of signs and symptoms of tb, including patients who were tested negative for latent tb infection prior to initiating therapy. viral reactivation viral reactivation, including herpes virus reactivation (e.g., herpes zoster, herpes simplex), was reported in clinical studies with cibinqo [see adverse reactions (6.1) ] . if a patient develops herpes zoster, consider interrupting cibinqo until the episode resolves. hepatitis b virus (hbv) reactivation has been reported in patients receiving jak inhibitors. perform viral hepatitis screening and monitoring for reactivation in accordance with clinical guidelines before starting therapy and during therapy with cibinqo. cibinqo is not recommended for use in patients with active hepatitis b or hepatitis c [see clinical pharmacology (12.3) ] . monitor patients with inactive hbv for expression of hbv dna during therapy with cibinqo. if hbv dna is detected during therapy with cibinqo, consult a liver specialist. 5.2 mortality in a large, randomized, postmarketing safety study of another jak inhibitor in rheumatoid arthritis (ra) patients 50 years of age and older with at least one cardiovascular risk factor, a higher rate of all-cause mortality, including sudden cardiovascular death, was observed in patients treated with the jak inhibitor compared with tnf blockers. cibinqo is not approved for use in ra. consider the benefits and risks for the individual patient prior to initiating or continuing therapy with cibinqo. 5.3 malignancy and lymphoproliferative disorders malignancies, including non-melanoma skin cancer (nmsc), were observed in clinical studies with cibinqo for atopic dermatitis [see adverse reactions (6.1) ] . perform periodic skin examination for patients who are at increased risk for skin cancer. exposure to sunlight and uv light should be limited by wearing protective clothing and using broad-spectrum sunscreen. malignancies, including lymphomas, have occurred in patients receiving jak inhibitors used to treat inflammatory conditions. in a large, randomized, postmarketing safety study of another jak inhibitor in ra patients, a higher rate of malignancies (excluding non-melanoma skin cancer (nmsc)) was observed in patients treated with the jak inhibitor compared to those treated with tnf blockers. cibinqo is not approved for use in ra. a higher rate of lymphomas was observed in patients treated with the jak inhibitor compared to those treated with tnf blockers. a higher rate of lung cancers was observed in current or past smokers treated with the jak inhibitor compared to those treated with tnf blockers. in this study, current or past smokers had an additional increased risk of overall malignancies. consider the benefits and risks for the individual patient prior to initiating or continuing therapy with cibinqo, particularly in patients with a known malignancy (other than a successfully treated nmsc), patients who develop a malignancy when on treatment, and patients who are current or past smokers. 5.4 major adverse cardiovascular events major adverse cardiovascular events were reported in clinical studies of cibinqo for atopic dermatitis [see adverse reactions (6.1) ]. in a large, randomized, postmarketing safety study of another jak inhibitor in ra patients 50 years of age and older with at least one cardiovascular risk factor, a higher rate of major adverse cardiovascular events (mace) defined as cardiovascular death, non-fatal myocardial infarction (mi), and non-fatal stroke was observed with the jak inhibitor compared to those treated with tnf blockers. cibinqo is not approved for use in ra. patients who are current or past smokers are at additional increased risk. consider the benefits and risks for the individual patient prior to initiating or continuing therapy with cibinqo, particularly in patients who are current or past smokers and patients with other cardiovascular risk factors. patients should be informed about the symptoms of serious cardiovascular events and the steps to take if they occur. discontinue cibinqo in patients that have experienced a myocardial infarction or stroke. 5.5 thrombosis deep venous thrombosis (dvt) and pulmonary embolism (pe) were observed in patients receiving cibinqo in the clinical studies for atopic dermatitis [see adverse reactions (6.1) ] . thrombosis, including dvt, pe, and arterial thrombosis have been reported in patients receiving jak inhibitors used to treat inflammatory conditions. many of these adverse reactions were serious and some resulted in death. in a large, randomized, postmarketing safety study of another jak inhibitor in ra patients 50 years of age and older with at least one cardiovascular risk factor, higher rates of overall thrombosis, dvt, and pe were observed compared to those treated with tnf blockers. cibinqo is not approved for use in ra. avoid cibinqo in patients that may be at increased risk of thrombosis. if symptoms of thrombosis occur, discontinue cibinqo and evaluate and treat patients appropriately. 5.6 laboratory abnormalities hematologic abnormalities treatment with cibinqo was associated with an increased incidence of thrombocytopenia and lymphopenia [see adverse reactions (6.1) ] . prior to cibinqo initiation, perform a cbc [see dosage and administration (2.1) ] . cbc evaluations are recommended at 4 weeks after initiation and 4 weeks after dose increase of cibinqo. discontinuation of cibinqo therapy is required for certain laboratory abnormalities [see dosage and administration (2.6) ]. lipid elevations dose-dependent increase in blood lipid parameters were reported in patients treated with cibinqo [see adverse reactions (6.1) ] . lipid parameters should be assessed approximately 4 weeks following initiation of cibinqo therapy and thereafter patients should be managed according to clinical guidelines for hyperlipidemia. the effect of these lipid parameter elevations on cardiovascular morbidity and mortality has not been determined. 5.7 immunizations prior to initiating cibinqo, complete all age-appropriate vaccinations as recommended by current immunization guidelines including prophylactic herpes zoster vaccinations. avoid vaccination with live vaccines immediately prior to, during, and immediately after cibinqo therapy.

tb. for patients with latent tb or those with a negative latent tb test who are at high risk for tb, start preventive therapy for latent tb prior to initiation of cibinqo [see warnings and precautions (5.1) ] . • viral hepatitis screening in accordance with clinical guidelines – cibinqo initiation is not recommended in patients with active hepatitis b or hepatitis c [see warnings and precautions (5.1) ] . • a complete blood count (cbc) – cibinqo initiation is not recommended in patients with a platelet count <150,000/mm 3 , an absolute lymphocyte count <500/mm 3 , an absolute neutrophil count <1,000/mm 3 , or a hemoglobin value <8 g/dl [see warnings and precautions (5.6) ] . complete any necessary immunizations, including herpes zoster vaccinations, in agreement with current immunization guidelines prior to cibinqo initiation [see warnings and precautions (5.7) ] . 2.2 recommended dosage the recommended dosage of cibinqo is 100 mg orally once daily. if an adequate response is not achieved with cibinqo 100 mg orally daily after 12 weeks, consider increasing dosage to 200 mg orally once daily. discontinue therapy if inadequate response is seen after dosage increase to 200 mg once daily. cibinqo can be used with or without topical corticosteroids. if a dose is missed, administer the dose as soon as possible unless it is less than 12 hours before the next dose, in which case skip the missed dose. thereafter, resume dosing at the regular scheduled time. 2.3 recommended dosage in patients with renal impairment or hepatic impairment renal impairment cibinqo dosage recommendations for patients with renal impairment are provided in table 1 [see use in specific populations (8.6) and clinical pharmacology (12.3) ] . in subjects with mild and moderate renal impairment, if an adequate response is not achieved after 12 weeks, dose of cibinqo can be doubled [see dosage and administration (2.2) ] . table 1. dosage recommendations in patients with renal impairment renal impairment stage estimated glomerular filtration (egfr) glomerular filtration rate was estimated by the modification of diet in renal disease (mdrd) formula. dosage mild 60 – 89 ml/minute cibinqo 100 mg once daily moderate 30 – 59 ml/minute cibinqo 50 mg once daily severe severe renal impairment and end-stage renal disease include patients on renal replacement therapy. 15 – 29 ml/minute not recommended for use end-stage renal disease (esrd) <15 ml/minute hepatic impairment cibinqo is not recommended for use in patients with severe hepatic impairment [see use in specific populations (8.7) and clinical pharmacology (12.3) ]. 2.4 recommended dosage in cyp2c19 poor metabolizers in patients who are known or suspected to be cyp2c19 poor metabolizers, the recommended dosage of cibinqo is 50 mg once daily [see use in specific populations (8.8) and clinical pharmacology (12.5) ]. if an adequate response is not achieved with cibinqo 50 mg orally daily after 12 weeks, consider increasing dosage to 100 mg orally once daily. discontinue therapy if inadequate response is seen after dosage increase to 100 mg once daily . 2.5 dosage modifications due to strong inhibitors in patients taking strong inhibitors of cytochrome p450 (cyp) 2c19 reduce the dosage to 50 mg once daily [see drug interactions (7.1) and clinical pharmacology (12.3) ] . if an adequate response is not achieved with cibinqo 50 mg orally daily after 12 weeks, consider increasing dosage to 100 mg orally once daily. discontinue therapy if inadequate response is seen after dosage increase to 100 mg once daily. 2.6 treatment discontinuation due to serious infections or hematologic adverse reactions serious or opportunistic infections if a patient develops a serious or opportunistic infection, discontinue cibinqo and control the infection. the risks and benefits of treatment with cibinqo should be carefully considered prior to reinitiating therapy with cibinqo [see warnings and precautions (5.1) ] . hematologic abnormalities recommendations for cibinqo discontinuation for laboratory abnormalities are summarized in table 2. table 2. recommendations for cibinqo discontinuation for hematologic abnormalities abbreviations: alc=absolute lymphocyte count; anc=absolute neutrophil count; cbc=complete blood count; hb=hemoglobin laboratory measure recommendation platelet count <50,000/mm 3 discontinue cibinqo and follow with cbc until >100,000/mm 3 alc <500/mm 3 treatment should be temporarily discontinued if alc is less than 500 cells/mm 3 and may be restarted once alc return above this value anc <1,000/mm 3 treatment should be temporarily discontinued if anc is less than 1,000 cells/mm 3 and may be restarted once anc return above this value hb value <8 g/dl treatment should be temporarily discontinued if hb is less than 8 g/dl and may be restarted once hb return above this value cbc evaluations are recommended at baseline, 4 weeks after treatment initiation and 4 weeks after dosing increase of cibinqo. laboratory evaluations may be extended for patients on chronic cibinqo therapy who develop hematologic abnormalities [see warnings and precautions (5.6) ] . 2.7 administration instructions administer cibinqo with or without food at approximately the same time each day. swallow cibinqo tablets whole with water. do not crush, split, or chew cibinqo tablets.

iscomfort, herpes zoster, and thrombocytopenia. ( 6.1 ) to report suspected adverse reactions, contact pfizer inc. at 1-800-438-1985 or fda at 1-800-fda-1088 or www.fda.gov/medwatch . 6.1 clinical trials 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 to rates in the clinical trials of another drug and may not reflect the rates observed in practice. the safety of cibinqo was evaluated in four randomized, placebo-controlled clinical trials (2 monotherapy, 1 combination therapy with topical corticosteroid, and 1 dose-ranging) and one long-term extension trial in subjects with moderate to severe atopic dermatitis (ad). a total of 1623 subjects with moderate to severe atopic dermatitis were treated with cibinqo in these clinical trials representing 1428 patient-years of exposure. there were 634 subjects with at least 1 year of exposure to cibinqo. in the placebo-controlled clinical trials, a total of 1198 subjects were exposed to cibinqo with 608 subjects receiving cibinqo 100 mg once daily and 590 subjects receiving cibinqo 200 mg once daily for up to 16 weeks. the median age of subjects was 33.0 years, 124 subjects (8.1%) were 12 to less than 18 years old and 94 subjects (6.1%) were 65 years of age or older. the majority of subjects were white (68.7%) and male (53.9%). adverse reactions occurring at ≥1% in any of the treated groups and at a higher rate than in the placebo group are presented in table 3. a total of 61 (5.1%) subjects treated with cibinqo were discontinued from the trials due to adverse reactions. the safety profile of cibinqo in the monotherapy and the combination trial(s) were similar. table 3. adverse reactions from placebo-controlled trials reported in ≥1% of cibinqo treated subjects with moderate to severe atopic dermatitis and at higher rate than placebo for up to 16 weeks weeks 0–16 cibinqo 200 mg n=590 n (% study size adjusted percentages ) cibinqo 100 mg n=608 n (% ) placebo n=342 n (% ) nasopharyngitis 51 (8.7) 75 (12.4) 27 (7.9) nausea 86 (14.5) 37 (6.0) 7 (2.1) headache 46 (7.8) 36 (6.0) 12 (3.5) herpes simplex herpes simplex also includes oral herpes, ophthalmic herpes, herpes dermatitis, genital herpes. 25 (4.2) 20 (3.3) 6 (1.8) increased blood creatine phosphokinase 17 (2.9) 14 (2.3) 5 (1.5) dizziness 17 (2.9) 11 (1.8) 3 (0.9) urinary tract infection 13 (2.2) 10 (1.7) 4 (1.2) fatigue 8 (1.3) 10 (1.6) 2 (0.5) acne 28 (4.7) 10 (1.6) 0 (0.0) vomiting 19 (3.2) 9 (1.5) 3 (0.9) impetigo 3 (0.5) 9 (1.5) 1 (0.3) oropharyngeal pain 6 (1.0) 8 (1.4) 2 (0.6) hypertension 5 (0.8) 7 (1.2) 2 (0.7) influenza 6 (1.1) 7 (1.2) 0 (0.0) gastroenteritis 8 (1.3) 7 (1.1) 2 (0.6) dermatitis contact 3 (0.5) 6 (1.1) 1 (0.3) abdominal pain upper 11 (1.9) 4 (0.6) 0 (0.0) abdominal discomfort 7 (1.2) 3 (0.5) 1 (0.3) herpes zoster 7 (1.2) 2 (0.3) 0 (0.0) thrombocytopenia 9 (1.5) 0 (0.0) 0 (0.0) specific adverse reactions exposure adjusted incidence rates were adjusted by trial size for all the adverse reactions reported in this section. overall infections in the placebo-controlled trials, for up to 16 weeks, overall infections were reported in 90 subjects (126.8 per 100 patient-years) treated with placebo, 211 subjects (168.8 per 100 patient-years) treated with cibinqo 100 mg and 204 subjects (159.5 per 100 patient-years) treated with cibinqo 200 mg. in all 5 clinical trials, including the long-term extension trial, overall infections were reported in 427 subjects (91.8 per 100 patient-years) treated with cibinqo 100 mg and 394 subjects (103.2 per 100 patient-years) treated with cibinqo 200 mg. serious infections in the placebo-controlled trials, for up to 16 weeks, serious infections were reported in 2 subjects (2.6 per 100 patient-years) treated with placebo, 6 subjects (3.9 per 100 patient-years) treated with cibinqo 100 mg, and 2 subjects (1.3 per 100 patient-years) treated with cibinqo 200 mg. in all 5 clinical trials, including the long-term extension trial, serious infections were reported in 18 subjects (2.3 per 100 patient-years) treated with cibinqo 100 mg and 16 subjects (2.3 per 100 patient-years) treated with cibinqo 200 mg. the most commonly reported serious infections were herpes simplex, herpes zoster, and pneumonia. herpes zoster in the placebo-controlled trials, for up to 16 weeks, opportunistic infections were generally cases of multidermatomal cutaneous herpes zoster. herpes zoster was reported in 0 subjects treated with placebo, 3 subjects (1.9 per 100 patient-years) treated with cibinqo 100 mg and 8 subjects (5.1 per 100 patient-years) treated with cibinqo 200 mg. in all 5 clinical trials, including the long-term extension trial, herpes zoster was reported in 16 subjects (2.0 per 100 patient-years) treated with cibinqo 100 mg and 35 subjects (5.2 per 100 patient-years) treated with cibinqo 200 mg. malignancy in the placebo-controlled trials, for up to 16 weeks, no malignancy was reported in subjects treated with placebo or cibinqo 100 mg and in 1 patient (0.65 per 100 patient-years) treated with cibinqo 200 mg. in all 5 clinical trials, including the long-term extension trial, malignancy was reported in 4 subjects (0.5 per 100 patient-years) treated with cibinqo 100 mg and 2 subjects (0.3 per 100 patient-years) treated with cibinqo 200 mg. thrombosis in all clinical trials, including the long-term extension trial, pulmonary embolism was reported in 3 subjects (0.4 per 100 patient-years), who were treated with cibinqo 200 mg. deep vein thrombosis was reported in 2 subjects (0.3 per 100 patient-years) who were treated with cibinqo 200 mg. no thrombosis occurred in subjects treated with cibinqo 100 mg. major adverse cardiovascular events in the placebo-controlled trials, for up to 16 weeks, major adverse cardiovascular event (mace) was reported in 1 subject (0.6 per 100 patient-years) treated with cibinqo 100 mg. in all 5 clinical trials, including the long-term extension trial, mace was reported in 1 patient (0.1 per 100 patient-years) treated with cibinqo 100 mg and 2 subjects (0.3 per 100 patient-years) treated with cibinqo 200 mg. thrombocytopenia in the placebo-controlled trials, for up to 16 weeks, treatment with cibinqo was associated with a dose-related decrease in platelet count. maximum effects on platelets were observed within 4 weeks, after which the platelet count returned towards baseline despite continued therapy. in all 5 clinical trials, including the long-term extension trial 6 subjects (0.9 per 100 patient-years) treated with cibinqo 200 mg had adverse reactions of thrombocytopenia, no subjects treated with cibinqo 100 mg had an adverse reaction of thrombocytopenia. lymphopenia in the placebo-controlled trials, for up to 16 weeks, confirmed alc <500/mm 3 occurred in 2 subjects (1.2 per 100 patient-years) treated with cibinqo 200 mg and 0 subjects treated with cibinqo 100 mg or placebo. both cases occurred in the first 4 weeks of exposure. lipid elevations in the placebo-controlled trials, for up to 16 weeks, there was a dose-related percent increase in low-density lipoprotein cholesterol (ldl-c), total cholesterol, and high-density lipoprotein cholesterol (hdl-c) relative to placebo at week 4 which remained elevated through the final visit in the treatment period. adverse reactions related to hyperlipidemia occurred in 1 subject (0.6 per 100 patient-years) exposed to cibinqo 100 mg, 3 subjects (2.0 per 100 patient-years) exposed to cibinqo 200 mg. retinal detachment in the placebo-controlled trials, for up to 16 weeks, retinal detachment occurred in 1 subject (0.6 per 100 patient-years) treated with cibinqo 100 mg. in all 5 clinical trials, including the long-term extension trial, retinal detachment occurred in 2 subjects (0.3 per 100 patient-years) treated with cibinqo 100 mg. creatine phosphokinase elevations (cpk) in the placebo-controlled trials, for up to 16 weeks, events of blood cpk increased were reported in 6 subjects (7.5 per 100 patient-years) treated with placebo, 11 subjects (6.9 per 100 patient-years) treated with 100 mg of cibinqo and 19 subjects (12.3 per 100 patient-years) treated with 200 mg of cibinqo. most elevations were transient, there were no reported adverse reactions of rhabdomyolysis. adolescent subjects (12 to less than 18 years of age) the safety of cibinqo was assessed in a trial of 284 subjects 12 to less than 18 years of age with moderate-to-severe atopic dermatitis (trial-ad-4). the safety profile of cibinqo in these subjects, assessed through the initial treatment period of 12 weeks and the long-term period (213 with at least 52 weeks of abrocitinib exposure), was similar to the safety profile from trials in adults with atopic dermatitis.

inqo is recommended when coadministered with strong cyp2c19 inhibitors [see dosage and administration (2.5) ]. moderate to strong inhibitors of both cyp2c19 and cyp2c9 clinical impact coadministration of cibinqo with drugs that are moderate to strong inhibitors of both cyp2c19 and cyp2c9 increases the exposure of abrocitinib and its two active metabolites, m1 and m2 which may increase the adverse reactions of cibinqo [ clinical pharmacology (12.3) ]. intervention avoid concomitant use of cibinqo with drugs that are moderate to strong inhibitors of both cyp2c19 and cyp2c9 . strong cyp2c19 or cyp2c9 inducers clinical impact coadministration of cibinqo with strong cyp2c19 or cyp2c9 inducers decreases the combined exposure of abrocitinib and its two active metabolites, m1 and m2, which may result in loss of or reduced clinical response [see clinical pharmacology (12.3) ] . intervention avoid concomitant use of cibinqo with strong cyp2c19 or cyp2c9 inducers. 7.2 effects of cibinqo on other drugs table 5 includes clinically significant drug interactions affecting other drugs. table 5. clinically significant interactions affecting other drugs p-gp substrate where small concentration changes may lead to serious or life-threatening toxicities clinical impact coadministration of cibinqo with p-gp substrate increases plasma concentrations of p-gp substrates and may result in potential adverse reactions of the p-gp substrate where small concentration changes may lead to serious or life-threatening toxicities (e.g., digoxin) [see clinical pharmacology (12.3) ] . intervention monitor appropriately or dose titrate p-gp substrate where small concentration changes may lead to serious or life-threatening toxicities when coadministered with cibinqo . antiplatelet therapy drugs clinical impact coadministration of cibinqo with antiplatelet therapy drugs may increase the risk of bleeding with thrombocytopenia [see warnings and precautions (5.5) and clinical pharmacology (12.2) ]. intervention antiplatelet drugs, except for low-dose aspirin (≤81 mg daily), during the first 3 months of treatment are contraindicated with cibinqo [see contraindications (4) ] .

y, 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. data 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 13 th 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). 8.2 lactation 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). data animal data lactating female rats were orally administered a single dose of 10 mg/kg abrocitinib on lactation day 12. abrocitinib auc was approximately 5 times greater in milk than in plasma. 8.3 females and males of reproductive potential 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) ] . 8.4 pediatric use the safety and effectiveness of cibinqo in pediatric patients 12 years of age and older weighing 25 kg or more with atopic dermatitis has been established. in trials trial-ad-1 and trial-ad-2, 124 adolescent subjects 12 to less than 18 years old 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 adolescent subjects 12 to less than 18 years of age 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 consistent 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 beginning on postnatal day 10 (approximately equivalent to a human infant) and continuing 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. abrocitinib produced 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). abrocitinib also 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). at 75 mg/kg/day (27 times the mrhd based on auc comparison), paw fractures generally corresponded to limb impairment, a fractured tibia was noted in a single female. irreversible bone findings have not been observed in older animals. 8.5 geriatric use a total of 145 (4.6%) patients 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 patients 65 years of age and older to determine whether they respond differently from younger adult patients. a higher proportion of patients 65 years of age and older discontinued from clinical trials compared to younger patients. among all patients exposed to cibinqo, including the long-term extension trial, confirmed alc <500/mm 3 occurred only in patients 65 years of age and older. a higher proportion of patients 65 years of age and older had platelet counts <75,000/mm 3 . the incidence rate of herpes zoster in patients 65 years of age and older treated with cibinqo (7.40 per 100 patient-years) was higher than that of patients 18 to less than 65 years of age (3.44 per 100 patient-years). 8.6 renal impairment in patients with severe (egfr <30 ml/min) and moderate (egfr 30–59 ml/min) renal impairment, the combined exposure (auc inf,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 patients on renal replacement therapy. in phase 3 clinical trials, cibinqo was not evaluated in patients with atopic dermatitis with baseline creatinine clearance values less than 40 ml/min. 8.7 hepatic impairment avoid use of cibinqo in patients 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 (auc inf,u ) of abrocitinib and its two active metabolites, m1 and m2 compared to patients with normal hepatic function. in clinical trials, cibinqo was not evaluated in patients with severe (child pugh c) hepatic impairment [see clinical pharmacology (12.3) ] . 8.8 cyp2c19 poor metabolizers 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) ] .

comes. 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. data 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 13 th 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).

xicity data in a juvenile animal toxicity study, abrocitinib was administered orally to juvenile rats at doses of 5, 25, and 75 mg/kg/day beginning on postnatal day 10 (approximately equivalent to a human infant) and continuing 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. abrocitinib produced 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). abrocitinib also 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). at 75 mg/kg/day (27 times the mrhd based on auc comparison), paw fractures generally corresponded to limb impairment, a fractured tibia was noted in a single female. irreversible bone findings have not been observed in older animals.

ith a transient, dose-dependent decrease in platelet count with the nadir occurring at a median of 24 days after continuous administration of abrocitinib 200 mg once daily. the percent change from baseline of the nadir increases with decreasing baseline platelet counts (-41.2%, -33.4%, and -26.5% for baseline platelet counts of 170, 220, and 270 × 10 3 /mm 3 , respectively). recovery of platelet count (~40% recovery by 12 weeks) occurred without discontinuation of the treatment. cardiac electrophysiology at a dose 3 times the maximum approved recommended dose, abrocitinib does not prolong the qt interval to any clinically relevant extent. 12.3 pharmacokinetics abrocitinib plasma c max and auc increased dose proportionally up to 200 mg. steady-state plasma concentrations of abrocitinib are achieved within 48 hours after once daily administration. absorption abrocitinib is absorbed with over 91% extent of oral absorption and absolute oral bioavailability of approximately 60%. the peak plasma concentrations of abrocitinib are reached within 1 hour. effect of food coadministration of cibinqo with a high-fat, high-calorie meal (total 916 calories, with approximate distribution of 55% fat, 29% carbohydrates, and 16% protein) had no clinically relevant effect on abrocitinib exposures (auc and c max of abrocitinib increased by approximately 26% and 29%, respectively, and t max was prolonged by 2 hours) [see dosage and administration (2.7) ] . distribution after intravenous administration, the volume of distribution of abrocitinib is approximately 100 l. approximately 64%, 37% and 29% of circulating abrocitinib and its active metabolites m1 and m2, respectively, are bound to plasma proteins. abrocitinib and its active metabolites m1 and m2 bind predominantly to albumin and distribute equally between red blood cells and plasma. elimination abrocitinib is eliminated primarily by metabolic clearance mechanisms. the mean elimination half-lives of abrocitinib and its two active metabolites, m1 and m2, range 3 to 5 hours. metabolism the metabolism of abrocitinib is mediated by multiple cyp enzymes, cyp2c19 (~53%), cyp2c9 (~30%), cyp3a4 (~11%) and cyp2b6 (~6%). in a human radiolabeled study, abrocitinib was the most prevalent circulating species, with two active polar mono-hydroxylated metabolites identified as m1 (3-hydroxypropyl), and m2 (2-hydroxypropyl). metabolite m1 is less active than abrocitinib while metabolite m2 is as active as the parent. the pharmacologic activity of abrocitinib is attributable to the unbound exposure of parent molecule (~60%) as well as m1 (~10%) and m2 (~30%) in systemic circulation. the sum of unbound exposures of abrocitinib, m1 and m2, each expressed in molar units and adjusted for relative potencies, is referred to as the combined exposure of abrocitinib and its two active metabolites, m1 and m2. excretion after a single radiolabeled abrocitinib dose, less than 1% of the dose was excreted in urine as unchanged drug. the metabolites of abrocitinib, m1 and m2 are excreted predominantly in urine, and are substrates of oat3 transporter. specific populations body weight, sex, race, and age did not have a clinically meaningful effect on cibinqo exposure. patients with renal impairment in a renal impairment study, subjects with severe (egfr <30 ml/min as estimated by mdrd equation) and moderate (egfr 30–59 ml/min, mdrd) renal impairment had approximately 191% and 110% increase in the combined exposure (auc inf,u ) of abrocitinib and its active metabolites, m1 and m2, respectively, compared to subjects with normal renal function (egfr ≥90 ml/min, mdrd) . based on these results, a clinically significant increase in the combined exposure of abrocitinib and its active metabolites, m1 and m2, is not expected in subjects with mild renal impairment (egfr 60 –89 ml/min, mdrd) [see dosage and administration (2.3) and use in specific population (8.6) ] . cibinqo has not been studied in subjects on renal replacement therapy [see dosage and administration (2.3) and use in specific population (8.6) ] . in phase 3 clinical studies, cibinqo was not evaluated in subjects with atopic dermatitis with baseline creatinine clearance values less than 40 ml/min. patients with hepatic impairment subjects with mild hepatic impairment (child pugh a) had approximately 4% decrease in the combined exposure (auc inf,u ) of abrocitinib and its two active metabolites, m1 and m2, compared to subjects with normal hepatic function. subjects with moderate hepatic impairment (child pugh b) had approximately 15% increase in the combined exposure (auc inf,u ) of abrocitinib and its two active metabolites, m1 and m2, compared to subjects with normal hepatic function. these changes are not clinically significant. in clinical studies, cibinqo has not been studied in subjects with severe (child pugh c) hepatic impairment, or in subjects screened positive for active hepatitis b or hepatitis c [see use in specific populations (8.7) and warnings and precautions (5.1) ] . drug interaction studies clinical studies the effect of coadministered drugs on the pharmacokinetics of abrocitinib is presented in table 6. table 6. change in pharmacokinetics of the combined exposure of abrocitinib and its two active metabolites (m1 and m2) in the presence of coadministered drugs coadministered drugs regimen of coadministered drug dose of abrocitinib ratio ratios for c max,u and auc inf,u compare coadministration of the drug with abrocitinib versus administration of abrocitinib alone. (90% confidence interval) c max,u auc inf,u strong cyp2c19 and moderate cyp3a inhibitor: fluvoxamine [see drug interactions (7.1) ] 50 mg once daily × 9 days 100 mg 1.33 (1.00–1.78) 1.91 (1.74–2.10) strong cyp2c19, moderate cyp2c9 and cyp3a inhibitor: fluconazole [see drug interactions (7.1) ] 400 mg on day 1 and 200 mg on days 2–7 100 mg 1.23 (1.08–1.42) 2.55 when coadministered with fluconazole, the systemic exposure of abrocitinib was approximately 4.8-fold higher compared to when abrocitinib is administered alone. (2.42–2.69) strong cyp enzymes inducers: rifampin [see drug interactions (7.1) ] 600 mg once daily × 8 days 200 mg 0.69 (0.50–0.94) 0.44 (0.41–0.47) oat3 inhibitor: probenecid drug interaction with oat3 inhibitor is not clinically significant. 1,000 mg twice daily × 3 days 200 mg 1.30 (1.04–1.63) 1.66 (1.52–1.80) the effect of abrocitinib on the pharmacokinetics of coadministered drugs is presented in table 7. table 7. change in pharmacokinetics of coadministered drugs in the presence of abrocitinib coadministered drugs or in vivo markers of cyp activity dose regimen of abrocitinib ratio ratios for c max and auc inf compare coadministration of abrocitinib with the drug versus administration of the drug alone. (90% confidence interval) c max auc inf oral contraceptive: ethinyl estradiol (ee) and levonorgestrel (ln) 200 mg once daily × 9 days ee: 1.07 (0.99, 1.15) ln: 0.86 (0.75, 0.97) ee: 1.19 (1.12, 1.26) ln auc last of levonorgestrel was reported in lieu of auc inf because the terminal phase of levonorgestrel was not well characterized. : 0.98 (0.87, 1.10) sensitive cyp3a substrate: midazolam 200 mg once daily × 7 days 0.93 (0.84, 1.04) 0.92 (0.86, 0.99) sensitive p-gp substrate: dabigatran 200 mg single dose 1.40 (0.92, 2.13) 1.53 (1.09, 2.15) sensitive bcrp and oat3 substrate: rosuvastatin 200 mg once daily × 3 days 0.99 (0.86, 1.14) 1.02 (0.93, 1.12) sensitive mate1/2k substrate: metformin 200 mg once daily × 2 days 0.88 (0.81, 0.96) 0.93 (0.85, 1.03) coadministration of dabigatran etexilate (a p-gp substrate), with a single dose of cibinqo 200 mg increased dabigatran auc inf and c max by approximately 53% and 40%, respectively, compared with administration alone. these increases in dabigatran exposure are not considered clinically significant change. however, appropriate dose titration of p-gp substrate where small concentration changes may lead to serious or life-threatening toxicities (e.g., digoxin) when coadministered with the cibinqo would be needed. in vitro studies cytochrome p450 (cyp) enzymes: abrocitinib and its metabolites m1 and m2 are not inhibitors or inducers of cyp1a2, cyp2b6, cyp2c8, cyp2c9, cyp2c19, cyp2d6, or cyp3a4. uridine diphosphate (udp)-glucuronosyl transferase (ugt) enzymes: abrocitinib and its metabolites m1 and m2 are not inhibitors or inducers of ugt1a1, ugt1a4, ugt1a6, ugt1a9, or ugt2b7. transporter systems: abrocitinib is an inhibitor of organic cation transporter (oct)1 but is not an inhibitor of organic anion transporting polypeptide (oatp)1b1/1b3, bile salt export pump (bsep), oat1 or oct2. 12.5 pharmacogenomics patients who are cyp2c19 poor metabolizers have little to no cyp2c19 enzyme function compared to cyp2c19 normal metabolizers that have fully functional cyp2c19 enzymes. after single doses of abrocitinib, cyp2c19 poor metabolizers demonstrated dose-normalized auc of abrocitinib values that were 2.3-fold higher when compared to cyp2c19 normal metabolizers. approximately 3–5% of caucasians and blacks and 15 to 20% of asians are cyp2c19 poor metabolizers [see dosage and administration (2.4) and use in specific populations (8.8) ] .

tabolites m1 and m2, respectively, are bound to plasma proteins. abrocitinib and its active metabolites m1 and m2 bind predominantly to albumin and distribute equally between red blood cells and plasma. elimination abrocitinib is eliminated primarily by metabolic clearance mechanisms. the mean elimination half-lives of abrocitinib and its two active metabolites, m1 and m2, range 3 to 5 hours. metabolism the metabolism of abrocitinib is mediated by multiple cyp enzymes, cyp2c19 (~53%), cyp2c9 (~30%), cyp3a4 (~11%) and cyp2b6 (~6%). in a human radiolabeled study, abrocitinib was the most prevalent circulating species, with two active polar mono-hydroxylated metabolites identified as m1 (3-hydroxypropyl), and m2 (2-hydroxypropyl). metabolite m1 is less active than abrocitinib while metabolite m2 is as active as the parent. the pharmacologic activity of abrocitinib is attributable to the unbound exposure of parent molecule (~60%) as well as m1 (~10%) and m2 (~30%) in systemic circulation. the sum of unbound exposures of abrocitinib, m1 and m2, each expressed in molar units and adjusted for relative potencies, is referred to as the combined exposure of abrocitinib and its two active metabolites, m1 and m2. excretion after a single radiolabeled abrocitinib dose, less than 1% of the dose was excreted in urine as unchanged drug. the metabolites of abrocitinib, m1 and m2 are excreted predominantly in urine, and are substrates of oat3 transporter. specific populations body weight, sex, race, and age did not have a clinically meaningful effect on cibinqo exposure. patients with renal impairment in a renal impairment study, subjects with severe (egfr <30 ml/min as estimated by mdrd equation) and moderate (egfr 30–59 ml/min, mdrd) renal impairment had approximately 191% and 110% increase in the combined exposure (auc inf,u ) of abrocitinib and its active metabolites, m1 and m2, respectively, compared to subjects with normal renal function (egfr ≥90 ml/min, mdrd) . based on these results, a clinically significant increase in the combined exposure of abrocitinib and its active metabolites, m1 and m2, is not expected in subjects with mild renal impairment (egfr 60 –89 ml/min, mdrd) [see dosage and administration (2.3) and use in specific population (8.6) ] . cibinqo has not been studied in subjects on renal replacement therapy [see dosage and administration (2.3) and use in specific population (8.6) ] . in phase 3 clinical studies, cibinqo was not evaluated in subjects with atopic dermatitis with baseline creatinine clearance values less than 40 ml/min. patients with hepatic impairment subjects with mild hepatic impairment (child pugh a) had approximately 4% decrease in the combined exposure (auc inf,u ) of abrocitinib and its two active metabolites, m1 and m2, compared to subjects with normal hepatic function. subjects with moderate hepatic impairment (child pugh b) had approximately 15% increase in the combined exposure (auc inf,u ) of abrocitinib and its two active metabolites, m1 and m2, compared to subjects with normal hepatic function. these changes are not clinically significant. in clinical studies, cibinqo has not been studied in subjects with severe (child pugh c) hepatic impairment, or in subjects screened positive for active hepatitis b or hepatitis c [see use in specific populations (8.7) and warnings and precautions (5.1) ] . drug interaction studies clinical studies the effect of coadministered drugs on the pharmacokinetics of abrocitinib is presented in table 6. table 6. change in pharmacokinetics of the combined exposure of abrocitinib and its two active metabolites (m1 and m2) in the presence of coadministered drugs coadministered drugs regimen of coadministered drug dose of abrocitinib ratio ratios for c max,u and auc inf,u compare coadministration of the drug with abrocitinib versus administration of abrocitinib alone. (90% confidence interval) c max,u auc inf,u strong cyp2c19 and moderate cyp3a inhibitor: fluvoxamine [see drug interactions (7.1) ] 50 mg once daily × 9 days 100 mg 1.33 (1.00–1.78) 1.91 (1.74–2.10) strong cyp2c19, moderate cyp2c9 and cyp3a inhibitor: fluconazole [see drug interactions (7.1) ] 400 mg on day 1 and 200 mg on days 2–7 100 mg 1.23 (1.08–1.42) 2.55 when coadministered with fluconazole, the systemic exposure of abrocitinib was approximately 4.8-fold higher compared to when abrocitinib is administered alone. (2.42–2.69) strong cyp enzymes inducers: rifampin [see drug interactions (7.1) ] 600 mg once daily × 8 days 200 mg 0.69 (0.50–0.94) 0.44 (0.41–0.47) oat3 inhibitor: probenecid drug interaction with oat3 inhibitor is not clinically significant. 1,000 mg twice daily × 3 days 200 mg 1.30 (1.04–1.63) 1.66 (1.52–1.80) the effect of abrocitinib on the pharmacokinetics of coadministered drugs is presented in table 7. table 7. change in pharmacokinetics of coadministered drugs in the presence of abrocitinib coadministered drugs or in vivo markers of cyp activity dose regimen of abrocitinib ratio ratios for c max and auc inf compare coadministration of abrocitinib with the drug versus administration of the drug alone. (90% confidence interval) c max auc inf oral contraceptive: ethinyl estradiol (ee) and levonorgestrel (ln) 200 mg once daily × 9 days ee: 1.07 (0.99, 1.15) ln: 0.86 (0.75, 0.97) ee: 1.19 (1.12, 1.26) ln auc last of levonorgestrel was reported in lieu of auc inf because the terminal phase of levonorgestrel was not well characterized. : 0.98 (0.87, 1.10) sensitive cyp3a substrate: midazolam 200 mg once daily × 7 days 0.93 (0.84, 1.04) 0.92 (0.86, 0.99) sensitive p-gp substrate: dabigatran 200 mg single dose 1.40 (0.92, 2.13) 1.53 (1.09, 2.15) sensitive bcrp and oat3 substrate: rosuvastatin 200 mg once daily × 3 days 0.99 (0.86, 1.14) 1.02 (0.93, 1.12) sensitive mate1/2k substrate: metformin 200 mg once daily × 2 days 0.88 (0.81, 0.96) 0.93 (0.85, 1.03) coadministration of dabigatran etexilate (a p-gp substrate), with a single dose of cibinqo 200 mg increased dabigatran auc inf and c max by approximately 53% and 40%, respectively, compared with administration alone. these increases in dabigatran exposure are not considered clinically significant change. however, appropriate dose titration of p-gp substrate where small concentration changes may lead to serious or life-threatening toxicities (e.g., digoxin) when coadministered with the cibinqo would be needed. in vitro studies cytochrome p450 (cyp) enzymes: abrocitinib and its metabolites m1 and m2 are not inhibitors or inducers of cyp1a2, cyp2b6, cyp2c8, cyp2c9, cyp2c19, cyp2d6, or cyp3a4. uridine diphosphate (udp)-glucuronosyl transferase (ugt) enzymes: abrocitinib and its metabolites m1 and m2 are not inhibitors or inducers of ugt1a1, ugt1a4, ugt1a6, ugt1a9, or ugt2b7. transporter systems: abrocitinib is an inhibitor of organic cation transporter (oct)1 but is not an inhibitor of organic anion transporting polypeptide (oatp)1b1/1b3, bile salt export pump (bsep), oat1 or oct2.

at 10 mg/kg/day (2 times the mrhd based on auc comparison). abrocitinib impaired female fertility (reducing fertility index, corpora lutea, and implantation sites) at 70 mg/kg/day (29 times the mrhd based on auc comparison). impaired fertility in female rats reversed 1 month after cessation of abrocitinib administration.

the mrhd based on auc comparison). abrocitinib impaired female fertility (reducing fertility index, corpora lutea, and implantation sites) at 70 mg/kg/day (29 times the mrhd based on auc comparison). impaired fertility in female rats reversed 1 month after cessation of abrocitinib administration.

si score ≥16, bsa involvement ≥10%, and pp-nrs ≥4 at the baseline visit prior to randomization. baseline characteristics in trials trial-ad-1, trial-ad-2, trial-ad-3, 53% of subjects were male, 69% of subjects were white, 64% of subjects had a baseline iga score of 3 (moderate ad), and 36% of subjects had a baseline iga score of 4 (severe ad). the baseline mean easi score was 30. the baseline mean age was 36 years old with 8% of subjects 12 to less than 18 years old and 92% of subjects 18 years of age or older. subjects in these trials were those who had inadequate response to previous topical therapy, or were subjects for whom topical treatments were medically inadvisable, or who had received systemic therapies including dupilumab. in each of the trials, over 40% of subjects had prior exposure to systemic therapy. in trial-ad-1 and trial-ad-2, 6% of the subjects had received dupilumab, whereas prior use of dupilumab was not allowed in trial-ad-3. in trial-ad-4, 49% of subjects were female, 56% of subjects were white, 33% of subjects were asian and 6% of subjects were black. the median age was 15 years and the proportion of subjects with severe atopic dermatitis (iga of 4) was 38%. trial-ad-1, trial-ad-2, trial-ad-3, and trial-ad-4 assessed the co-primary endpoints of iga and easi-75 responses at week 12. the designs of the trials are summarized in table 8. table 8. summary of clinical study designs abbreviations: easi=eczema area and severity index; iga=investigator’s global assessment; qd=once daily; q2w=once every 2 weeks. study name (regimen type) treatment duration population (number of randomized and dosed subjects) treatment arms co-primary endpoints trial-ad-1 (monotherapy) 12 weeks subjects 12 years of age or older (387) oral administration of: • cibinqo 200 mg qd • cibinqo 100 mg qd • placebo • iga response iga response was based on iga score of clear (0) or almost clear (1) (on a 5-point scale) and a reduction from baseline of ≥2 points. at week 12 • easi-75 easi-75 was based on ≥75% improvement in easi from baseline. at week 12 trial-ad-2 (monotherapy) 12 weeks subjects 12 years of age or older (391) oral administration of: • cibinqo 200 mg qd • cibinqo 100 mg qd • placebo trial-ad-3 (combination therapy) 16 weeks subjects 18 years of age or older (837) oral administration of: • cibinqo 200 mg qd • cibinqo 100 mg qd • placebo subcutaneous administration of: • dupilumab 300 mg q2w sc dupilumab treatment in trial-ad-3: an initial dose of 600 mg on day 1, followed by 300 mg q2w. all subjects received background topical corticosteroids trial-ad-4 (combination therapy) 12 weeks subjects 12 to less than 18 years of age (285) oral administration of: • cibinqo 200 mg qd • cibinqo 100 mg qd • placebo all subjects received background topical corticosteroids clinical response monotherapy trials the results of the cibinqo monotherapy trials (trial-ad-1 and trial-ad-2) are presented in table 9. table 9. efficacy results of cibinqo monotherapy at week 12 in subjects with moderate-to-severe ad (trial-ad-1 and trial-ad-2) abbreviations: ci=confidence interval; easi=eczema area and severity index; iga=investigator global assessment; qd=once daily. trial-ad-1 trial-ad-2 cibinqo placebo n=77 cibinqo placebo n=78 200 mg qd n=154 100 mg qd n=156 200 mg qd n=155 100 mg qd n=158 iga 0 or 1 iga responders were subjects with iga score of clear (0) or almost clear (1) (on a 5-point scale) and a reduction from baseline of ≥2 points. 44% 24% 8% 38% 28% 9% difference from placebo (95% ci) 36% (26%, 46%) 16% (7%, 25%) - 29% (19%, 39%) 19% (9%, 29%) - easi-75 easi -75 responders were patients with ≥75% improvement in easi from baseline. 62% 40% 12% 61 % 44 % 10% difference from placebo (95% ci) 51% (40%, 61%) 28% (18%, 39%) - 50% (40%, 61%) 33% (23%, 44%) - the proportion of subjects achieving pp-nrs4 at week 2 (defined as an improvement of ≥4 points from baseline in pp-nrs) was higher in subjects treated with cibinqo monotherapy 200 mg once daily (28% in trial-ad-1 and 24% in trial-ad-2) and 100 mg once daily (11% in both trials) compared to placebo (2% in both trials). a higher proportion of subjects in the cibinqo monotherapy 100 mg or 200 mg once daily arm compared to placebo achieved improvement in itching at week 12. combination therapy trial the results of cibinqo in combination with background topical corticosteroids (trial-ad-3) are presented in table 10. table 10. efficacy results of cibinqo with concomitant topical corticosteroids at week 12 in subjects with moderate-to-severe ad (trial-ad-3) abbreviations: ci=confidence interval; easi=eczema area and severity index; iga=investigator global assessment; qd=once daily. % responders cibinqo placebo n=131 200 mg qd n=226 100 mg qd n=238 iga 0 or 1 iga responders were subjects with iga score of clear (0) or almost clear (1) (on a 5-point scale) and a reduction from baseline of ≥2 points. at week 12 47% 36% 14% difference from placebo (95% ci) 34% (25%, 42%) 23% (15%, 31%) - easi-75 easi-75 responders were subjects with ≥75% improvement in easi, from baseline. at week 12 68% 58% 27% difference from placebo (95% ci) 41% (32%, 51%) 32% (22%, 41%) - the proportions of subjects achieving pp-nrs4 at week 2 was higher in subjects treated with cibinqo 200 mg once daily (30%) and 100 mg once daily (14%) in combination with background medicated topical therapies compared to placebo (8%). examination of age, gender, race, weight and previous systemic ad therapy treatment did not identify differences in response to cibinqo 100 mg or 200 mg once daily among these subgroups in trial-ad-1, trial-ad-2, and trial-ad-3. the results of cibinqo in combination with background topical corticosteroids for adolescent subjects (trial-ad-4) are presented in table 11. table 11. efficacy results of cibinqo with concomitant topical corticosteroids at week 12 in adolescent subjects with moderate-to-severe ad (trial-ad-4) abbreviations: ci=confidence interval; easi=eczema area and severity index; iga=investigator global assessment; n=number of patients treated; qd=once daily. % responders cibinqo placebo n=95 200 mg qd n=94 100 mg qd n=95 iga 0 or 1 iga responders were patients with iga score of clear (0) or almost clear (1) (on a 5-point scale) and a reduction from baseline of ≥2 points. 46% 39% 24% difference from placebo (95% ci) 21% (8%, 34%) 15% (2%, 28%) - easi-75 easi-75 responders were patients with ≥75% improvement in easi from baseline. 71% 64% 41% difference from placebo (95% ci) 29% (16%, 43%) 23% (10%, 36%) - the proportion of adolescents achieving pp-nrs4 at week 2 in trial-ad-4 was higher with cibinqo 200 mg once daily (25%) and 100 mg once daily (13%) compared to placebo (8%). a higher proportion of subjects in the cibinqo 200 mg once daily arm compared to placebo achieved improvement in itching at week 12.

rse cardiovascular events inform patients that cibinqo may increase their risk of major adverse cardiovascular events (mace) including myocardial infarction, stroke, and cardiovascular death. instruct all patients, especially current or past smokers or patients with other cardiovascular risk factors, to be alert for the development of signs and symptoms of cardiovascular events [see warnings and precautions (5.4) ] . thrombosis advise patients that events of dvt and pe have been reported in clinical trials with cibinqo. instruct patients to seek immediate medical attention if they develop any signs or symptoms of a dvt or pe [see warnings and precautions (5.5) ] . laboratory abnormalities inform patients that cibinqo may affect certain lab tests, and that blood tests are required before and during cibinqo treatment [see dosage and administration (2.1) and warnings and precautions (5.6) ] . immunizations advise patients that vaccination with live vaccines is not recommended during cibinqo treatment and immediately prior to or after cibinqo treatment. instruct patients to inform the healthcare practitioner that they are taking cibinqo prior to a potential vaccination [see warnings and precautions (5.7) ] . retinal detachment inform patients that retinal detachment has been reported in clinical trials for atopic dermatitis in patients who received cibinqo. advise patients to immediately inform their healthcare provider if they develop any sudden changes in vision while receiving cibinqo [see adverse reactions (6.1) ] . infertility advise females of reproductive potential that cibinqo may impair fertility [see use in specific populations (8.3) ] . lactation advise a woman not to breastfeed during treatment with cibinqo [see use in specific populations (8.2) ] . administration advise patients not to chew, crush, or split cibinqo tablets [see dosage and administration (2.7) ].