ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following clinically significant adverse reactions are described elsewhere in the labeling:Serious Infections [see Warnings and Precautions (5.1)] Mortality [see Warnings and Precautions (5.2)] Malignancy and Lymphoproliferative Disorders [see Warnings and Precautions (5.3)] Major Adverse Cardiovascular Events [see Warnings and Precautions (5.4)] Thrombosis [see Warnings and Precautions (5.5)] Laboratory Abnormalities [see Warnings and Precautions (5.6)] Serious Infections [see Warnings and Precautions (5.1)] Mortality [see Warnings and Precautions (5.2)] Malignancy and Lymphoproliferative Disorders [see Warnings and Precautions (5.3)] Major Adverse Cardiovascular Events [see Warnings and Precautions (5.4)] Thrombosis [see Warnings and Precautions (5.5)] Laboratory Abnormalities [see Warnings and Precautions (5.6)] Most common adverse reactions (>=1%) in subjects receiving 100 mg and 200 mg include: nasopharyngitis, nausea, headache, herpes simplex, increased blood creatinine phosphokinase, dizziness, urinary tract infection, fatigue, acne, vomiting, oropharyngeal pain, influenza, gastroenteritis.Most common adverse reactions (>=1%) in subjects receiving either 100 mg or 200 mg also include: impetigo, hypertension, contact dermatitis, upper abdominal pain, abdominal discomfort, 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.. 6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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, combination therapy with topical corticosteroid, and dose-ranging) and one long-term extension trial in subjects with moderate to severe atopic dermatitis (AD). 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 year of exposure to CIBINQO.In the placebo-controlled clinical trials, 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%). While subjects aged 12 to 17 years were included in these trials, CIBINQO is not approved for use in pediatric subjects [see Use in Specific Populations (8.4)]. Adverse reactions occurring at >=1% in any of the treated groups and at higher rate than in the placebo group are presented in Table 3. 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 WeeksWeeks 0-16CIBINQO200 mgN=590n (%Study size adjusted percentages)CIBINQO100 mgN=608n (%)PlaceboN=342n (%)Nasopharyngitis51 (8.7)75 (12.4)27 (7.9)Nausea86 (14.5)37 (6.0)7 (2.1)Headache46 (7.8)36 (6.0)12 (3.5)Herpes simplexHerpes simplex also includes oral herpes, ophthalmic herpes, herpes dermatitis, genital herpes. 25 (4.2)20 (3.3)6 (1.8)Increased blood creatinine phosphokinase17 (2.9)14 (2.3)5 (1.5)Dizziness17 (2.9)11 (1.8)3 (0.9)Urinary tract infection13 (2.2)10 (1.7)4 (1.2)Fatigue8 (1.3)10 (1.6)2 (0.5)Acne28 (4.7)10 (1.6)0 (0.0)Vomiting19 (3.2)9 (1.5)3 (0.9)Impetigo3 (0.5)9 (1.5)1 (0.3)Oropharyngeal pain6 (1.0)8 (1.4)2 (0.6)Hypertension5 (0.8)7 (1.2)2 (0.7)Influenza6 (1.1)7 (1.2)0 (0.0)Gastroenteritis8 (1.3)7 (1.1)2 (0.6)Dermatitis contact3 (0.5)6 (1.1)1 (0.3)Abdominal pain upper11 (1.9)4 (0.6)0 (0.0)Abdominal discomfort7 (1.2)3 (0.5)1 (0.3)Herpes zoster7 (1.2)2 (0.3)0 (0.0)Thrombocytopenia9 (1.5)0 (0.0)0 (0.0). Specific Adverse ReactionsExposure adjusted incidence rates were adjusted by trial size for all the adverse reactions reported in this section.. Overall InfectionsIn 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 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 InfectionsIn the placebo-controlled trials, for up to 16 weeks, serious infections were reported in subjects (2.6 per 100 patient-years) treated with placebo, subjects (3.9 per 100 patient-years) treated with CIBINQO 100 mg, and subjects (1.3 per 100 patient-years) treated with CIBINQO 200 mg. In all 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 ZosterIn the placebo-controlled trials, for up to 16 weeks, opportunistic infections were generally cases of multidermatomal cutaneous herpes zoster. Herpes zoster was reported in subjects treated with placebo, subjects (1.9 per 100 patient-years) treated with CIBINQO 100 mg and subjects (5.1 per 100 patient-years) treated with CIBINQO 200 mg. In all 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.. MalignancyIn the placebo-controlled trials, for up to 16 weeks, no malignancy was reported in subjects treated with placebo or CIBINQO 100 mg and in patient (0.65 per 100 patient-years) treated with CIBINQO 200 mg. In all clinical trials, including the long-term extension trial, malignancy was reported in subjects (0.5 per 100 patient-years) treated with CIBINQO 100 mg and subjects (0.3 per 100 patient-years) treated with CIBINQO 200 mg.. ThrombosisIn all clinical trials, including the long-term extension trial, pulmonary embolism was reported in subjects (0.4 per 100 patient-years), who were treated with CIBINQO 200 mg. Deep vein thrombosis was reported in 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 EventsIn the placebo-controlled trials, for up to 16 weeks, major adverse cardiovascular event (MACE) was reported in subject (0.6 per 100 patient-years) treated with CIBINQO 100 mg. In all clinical trials, including the long-term extension trial, MACE was reported in patient (0.1 per 100 patient-years) treated with CIBINQO 100 mg and subjects (0.3 per 100 patient-years) treated with CIBINQO 200 mg.. ThrombocytopeniaIn the placebo-controlled trials, for up to 16 weeks, treatment with CIBINQO was associated with dose-related decrease in platelet count. Maximum effects on platelets were observed within weeks, after which the platelet count returned towards baseline despite continued therapy. In all clinical trials, including the long-term extension trial 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.. LymphopeniaIn the placebo-controlled trials, for up to 16 weeks, confirmed ALC <500/mm3 occurred in subjects (1.2 per 100 patient-years) treated with CIBINQO 200 mg and subjects treated with CIBINQO 100 mg or placebo. Both cases occurred in the first weeks of exposure.. Lipid ElevationsIn the placebo-controlled trials, for up to 16 weeks, there was 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 which remained elevated through the final visit in the treatment period. Adverse reactions related to hyperlipidemia occurred in subject (0.6 per 100 patient-years) exposed to CIBINQO 100 mg, subjects (2.0 per 100 patient-years) exposed to CIBINQO 200 mg.. Retinal DetachmentIn the placebo-controlled trials, for up to 16 weeks, retinal detachment occurred in subject (0.6 per 100 patient-years) treated with CIBINQO 100 mg. In all clinical trials, including the long-term extension trial, retinal detachment occurred in 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 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.

BOXED WARNING SECTION.

WARNING: SERIOUS INFECTIONS, MORTALITY, MALIGNANCY, MAJOR ADVERSE CARDIOVASCULAR EVENTS, and THROMBOSIS. WARNING: SERIOUS INFECTIONS, MORTALITY, MALIGNANCY, MAJOR ADVERSE CARDIOVASCULAR EVENTS (MACE), and THROMBOSISSee full prescribing information for complete boxed warning.Increased risk of serious bacterial, fungal, viral and opportunistic infections leading to hospitalization or death, including tuberculosis (TB). Discontinue treatment with CIBINQO if serious or opportunistic infection occurs. Test for latent TB before and during therapy; treat latent TB prior to use. Monitor all patients for active TB during treatment, even patients with initial negative latent TB test. (5.1)Higher rate of all-cause mortality, including sudden cardiovascular death, with another JAK inhibitor vs. TNF blockers in rheumatoid arthritis (RA) patients. CIBINQO is not approved for use in RA patients. (5.2)Malignancies have occurred with CIBINQO. Higher rate of lymphomas and lung cancers with another JAK inhibitor vs. TNF blockers in RA patients. (5.3)MACE has occurred with CIBINQO. Higher rate of MACE (defined as cardiovascular death, myocardial infarction, and stroke) with another JAK inhibitor vs. TNF blockers in RA patients. (5.4)Thrombosis has occurred with CIBINQO. Increased incidence of pulmonary embolism, venous and arterial thrombosis with another JAK inhibitor vs. TNF blockers. (5.5). Increased risk of serious bacterial, fungal, viral and opportunistic infections leading to hospitalization or death, including tuberculosis (TB). Discontinue treatment with CIBINQO if serious or opportunistic infection occurs. Test for latent TB before and during therapy; treat latent TB prior to use. Monitor all patients for active TB during treatment, even patients with initial negative latent TB test. (5.1). Higher rate of all-cause mortality, including sudden cardiovascular death, with another JAK inhibitor vs. TNF blockers in rheumatoid arthritis (RA) patients. CIBINQO is not approved for use in RA patients. (5.2). Malignancies have occurred with CIBINQO. Higher rate of lymphomas and lung cancers with another JAK inhibitor vs. TNF blockers in RA patients. (5.3). MACE has occurred with CIBINQO. Higher rate of MACE (defined as cardiovascular death, myocardial infarction, and stroke) with another JAK inhibitor vs. TNF blockers in RA patients. (5.4). Thrombosis has occurred with CIBINQO. Increased incidence of pulmonary embolism, venous and arterial thrombosis with another JAK inhibitor vs. TNF blockers. (5.5). Serious InfectionsPatients treated with CIBINQO may be at increased risk for developing serious infections that may lead to hospitalization or death; The most frequent serious infections reported with CIBINQO were herpes simplex, herpes zoster, and pneumonia [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)].If serious or opportunistic infection develops, discontinue CIBINQO and control the infection.Reported infections from Janus kinase (JAK) inhibitors used to treat inflammatory conditions:Active tuberculosis, which may present with pulmonary or extrapulmonary disease. Test for latent TB before and during therapy; treat latent TB prior to use. Monitor all patients for active TB during treatment, even patients with initial negative, latent TB test.Invasive fungal infections, including cryptococcosis and pneumocystosis. Patients with invasive fungal infections may present with disseminated, rather than localized, disease.Bacterial, viral, including herpes zoster, and other infections due to opportunistic pathogens.Avoid use of CIBINQO in patients with an active, serious infection including localized infections. The risks and benefits of treatment with CIBINQO should be carefully considered prior to initiating therapy in patients with chronic or recurrent infections. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with CIBINQO, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy [see Warnings and Precautions (5.1)].. Active tuberculosis, which may present with pulmonary or extrapulmonary disease. Test for latent TB before and during therapy; treat latent TB prior to use. Monitor all patients for active TB during treatment, even patients with initial negative, latent TB test.. Invasive fungal infections, including cryptococcosis and pneumocystosis. Patients with invasive fungal infections may present with disseminated, rather than localized, disease.. Bacterial, viral, including herpes zoster, and other infections due to opportunistic pathogens.. MortalityIn large, randomized, postmarketing safety study in rheumatoid arthritis (RA) patients 50 years of age and older with at least one cardiovascular risk factor comparing another JAK inhibitor to TNF blocker treatment, higher rate of all-cause mortality, including sudden cardiovascular death, was observed with the JAK inhibitor. CIBINQO is not approved for use in RA patients [see Warnings and Precautions (5.2)].. MalignanciesMalignancies were reported in patients treated with CIBINQO. Lymphoma and other malignancies have been observed in patients receiving JAK inhibitors used to treat inflammatory conditions. In RA patients treated with another JAK inhibitor, higher rate of malignancies (excluding non-melanoma skin cancer (NMSC)) was observed when compared with TNF blockers. Patients who are current or past smokers are at additional increased risk [see Warnings and Precautions (5.3)].. Major Adverse Cardiovascular EventsMajor adverse cardiovascular events were reported in patients treated with CIBINQO. In RA patients 50 years of age and older with at least one cardiovascular risk factor treated with another JAK inhibitor, higher rate of major adverse cardiovascular events (MACE) (defined as cardiovascular death, myocardial infarction, and stroke), was observed when compared with TNF blockers. Patients who are current or past smokers are at additional increased risk. Discontinue CIBINQO in patients that have experienced myocardial infarction or stroke [see Warnings and Precautions (5.4)].. ThrombosisDeep venous thrombosis (DVT) and pulmonary embolism (PE) have been reported in patients treated with CIBINQO. Thrombosis, including PE, DVT, 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 RA patients 50 years of age and older with at least one cardiovascular risk factor treated with another JAK inhibitor, higher rate of thrombosis was observed when compared with TNF blockers. Avoid CIBINQO in patients at risk. If symptoms of thrombosis occur, discontinue CIBINQO and treat appropriately [see Warnings and Precautions (5.5)].

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. CIBINQO is Janus kinase (JAK) inhibitor.Abrocitinib reversibly inhibits JAK1 by blocking the adenosine triphosphate (ATP) binding site. In cell-free isolated enzyme assay, abrocitinib was selective for JAK1 over JAK2 (28-fold), JAK3 (>340-fold), and tyrosine kinase (TYK) (43-fold), as well as the broader kinome. The relevance of inhibition of specific JAK enzymes to therapeutic effectiveness is not currently known. Both the parent compound and the active metabolites inhibit JAK1 activity in vitro with similar levels of selectivity.. 12.2 Pharmacodynamics. Treatment with CIBINQO was associated with dose-dependent reduction in serum markers of inflammation, including high sensitivity C-reactive protein (hsCRP), interleukin-31 (IL-31) and thymus and activation regulated chemokine (TARC). These changes returned to near baseline within weeks of drug discontinuation.. Effect on Platelet CountTreatment with CIBINQO was also associated with transient, dose-dependent decrease in platelet count with the nadir occurring at 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 270x 103/mm3, respectively). Recovery of platelet count (~40% recovery by 12 weeks) occurred without discontinuation of the treatment. Cardiac ElectrophysiologyAt dose times the maximum approved recommended dose, abrocitinib does not prolong the QT interval to any clinically relevant extent. 12.3 Pharmacokinetics. Abrocitinib plasma Cmax and AUC increased dose proportionally up to 200 mg. Steady-state plasma concentrations of abrocitinib are achieved within 48 hours after once daily administration.. AbsorptionAbrocitinib 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 hour.. Effect of FoodCoadministration of CIBINQO with 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 Cmax of abrocitinib increased by approximately 26% and 29%, respectively, and Tmax was prolonged by hours) [see Dosage and Administration (2.7)].. DistributionAfter 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.. EliminationAbrocitinib is eliminated primarily by metabolic clearance mechanisms. The mean elimination half-lives of abrocitinib and its two active metabolites, M1 and M2, range to hours.. MetabolismThe metabolism of abrocitinib is mediated by multiple CYP enzymes, CYP2C19 (~53%), CYP2C9 (~30%), CYP3A4 (~11%) and CYP2B6 (~6%). In 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.. ExcretionAfter 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 PopulationsBody weight, sex, race, and age did not have clinically meaningful effect on CIBINQO exposure.. Patients with Renal ImpairmentIn 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 (AUCinf,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, 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 clinical studies, CIBINQO was not evaluated in subjects with atopic dermatitis with baseline creatinine clearance values less than 40 mL/min.. Patients with Hepatic ImpairmentSubjects with mild hepatic impairment (Child Pugh A) had approximately 4% decrease in the combined exposure (AUCinf,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 (AUCinf,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 or hepatitis [see Use in Specific Populations (8.7) and Warnings and Precautions (5.1)].. Drug Interaction Studies. Clinical StudiesThe 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 DrugsCoadministered DrugsRegimen of Coadministered DrugDose of AbrocitinibRatioRatios for Cmax,u and AUCinf,u compare coadministration of the drug with abrocitinib versus administration of abrocitinib alone. (90% Confidence Interval)Cmax,u AUCinf,u Strong CYP2C19 and moderate CYP3A inhibitor:Fluvoxamine [see Drug Interactions (7.1)] 50 mg once daily 9 days100 mg1.33 (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 and 200 mg on Days 2-7100 mg1.23 (1.08-1.42)2.55When 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 days200 mg0.69 (0.50-0.94)0.44 (0.41-0.47)OAT3 inhibitor:ProbenecidDrug interaction with OAT3 inhibitor is not clinically significant. 1,000 mg twice daily 3 days200 mg1.30 (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 AbrocitinibCoadministered Drugs or In Vivo Markers of CYP ActivityDose Regimen of AbrocitinibRatioRatios for Cmax and AUCinf compare coadministration of abrocitinib with the drug versus administration of the drug alone. (90% Confidence Interval)Cmax AUCinf Oral contraceptive:Ethinyl estradiol (EE) and levonorgestrel (LN)200 mg once daily 9 daysEE: 1.07 (0.99, 1.15)LN: 0.86 (0.75, 0.97)EE: 1.19 (1.12, 1.26)LNAUClast of levonorgestrel was reported in lieu of AUCinf because the terminal phase of levonorgestrel was not well characterized.: 0.98 (0.87, 1.10)Sensitive CYP3A Substrate:Midazolam200 mg once daily 7 days0.93 (0.84, 1.04)0.92 (0.86, 0.99)Sensitive P-gp substrate:Dabigatran200 mg single dose1.40 (0.92, 2.13)1.53 (1.09, 2.15)Sensitive BCRP and OAT3 substrate:Rosuvastatin200 mg once daily 3 days0.99 (0.86, 1.14)1.02 (0.93, 1.12)Sensitive MATE1/2K substrate:Metformin200 mg once daily 2 days0.88 (0.81, 0.96)0.93 (0.85, 1.03)Coadministration of dabigatran etexilate (a P-gp substrate), with single dose of CIBINQO 200 mg increased dabigatran AUCinf and Cmax 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)].

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. The efficacy of CIBINQO as monotherapy and in combination with background topical corticosteroids were evaluated in randomized, double-blind, placebo-controlled trials [Trial-AD-1 (NCT03349060), Trial-AD-2 (NCT03575871), and Trial-AD-3 (NCT03720470)] in 1615 subjects 12 years of age and older (CIBINQO is not approved for use in pediatric patients) with moderate-to-severe atopic dermatitis as defined by Investigators Global Assessment (IGA) score >=3, Eczema Area and Severity Index (EASI) score >=16, body surface area (BSA) involvement >=10%, and Peak Pruritus Numerical Rating Scale (PP-NRS) >=4 at the baseline visit prior to randomization.Overall, 53% of subjects were male, 69% of subjects were white, 64% of subjects had baseline IGA score of (moderate AD), and 36% of subjects had baseline IGA score of (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.Trial-AD-1, Trial-AD-2, and Trial-AD-3 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 DesignsStudy Name (regimen type)Treatment DurationPopulation(number of randomized and dosed subjects)Treatment ArmsCo-Primary EndpointsAbbreviations: EASI=Eczema Area and Severity Index; IGA=Investigators Global Assessment; QD=once daily; Q2W=once every weeks. Trial-AD-1 (monotherapy)12 weeksPediatric subjects 12 years of age and older were included in the trial population; however, CIBINQO is not approved for use in pediatric patients.Subjects 12 years of age or older (387)Oral administration of:CIBINQO 200 mg QDCIBINQO 100 mg QDPlacebo IGA responseIGA response was based on IGA score of clear (0) or almost clear (1) (on 5-point scale) and reduction from baseline of >=2 points. at Week 12EASI-75EASI-75 was based on >=75% improvement in EASI from baseline. at Week 12Trial-AD-2 (monotherapy)12 weeksSubjects 12 years of age or older (391)Oral administration of:CIBINQO 200 mg QDCIBINQO 100 mg QDPlacebo Trial-AD-3 (combination therapy)16 weeksSubjects 18 years of age or older (837)Oral administration of: CIBINQO 200 mg QDCIBINQO 100 mg QDPlaceboSubcutaneous administration of:Dupilumab 300 mg Q2W SCDupilumab 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. CIBINQO 200 mg QD. CIBINQO 100 mg QD. Placebo. IGA responseIGA response was based on IGA score of clear (0) or almost clear (1) (on 5-point scale) and reduction from baseline of >=2 points. at Week 12. EASI-75EASI-75 was based on >=75% improvement in EASI from baseline. at Week 12. CIBINQO 200 mg QD. CIBINQO 100 mg QD. Placebo. CIBINQO 200 mg QD. CIBINQO 100 mg QD. Placebo. Dupilumab 300 mg Q2W SCDupilumab treatment in Trial-AD-3: An initial dose of 600 mg on day 1, followed by 300 mg Q2W. Clinical Response Monotherapy TrialsThe 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)Trial-AD-1Trial-AD-2CIBINQOPlaceboN=77CIBINQOPlaceboN=78200 mg QDN=154100 mg QD N=156200 mg QDN=155100 mg QDN=158Abbreviations: CI=confidence interval; EASI=Eczema Area and Severity Index; IGA=Investigator Global Assessment; QD=once daily.IGA or 1IGA responders were subjects with IGA score of clear (0) or almost clear (1) (on 5-point scale) and 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-75EASI -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 (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 TrialThe 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)% RespondersCIBINQOPlaceboN=131200 mg QDN=226100 mg QDN=238Abbreviations: CI=confidence interval; EASI=Eczema Area and Severity Index; IGA=Investigator Global Assessment; QD=once daily.IGA or 1IGA responders were subjects with IGA score of clear (0) or almost clear (1) (on 5-point scale) and reduction from baseline of >=2 points.at Week 1247%36%14% Difference from Placebo(95% CI)34%(25%, 42%)23%(15%, 31%)-EASI-75EASI-75 responders were subjects with >=75% improvement in EASI, from baseline. at Week 1268%58%27% Difference from Placebo(95% CI)41%(32%, 51%)32%(22%, 41%)-The proportions of subjects achieving PP-NRS4 at Week 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.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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, combination therapy with topical corticosteroid, and dose-ranging) and one long-term extension trial in subjects with moderate to severe atopic dermatitis (AD). 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 year of exposure to CIBINQO.In the placebo-controlled clinical trials, 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%). While subjects aged 12 to 17 years were included in these trials, CIBINQO is not approved for use in pediatric subjects [see Use in Specific Populations (8.4)]. Adverse reactions occurring at >=1% in any of the treated groups and at higher rate than in the placebo group are presented in Table 3. 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 WeeksWeeks 0-16CIBINQO200 mgN=590n (%Study size adjusted percentages)CIBINQO100 mgN=608n (%)PlaceboN=342n (%)Nasopharyngitis51 (8.7)75 (12.4)27 (7.9)Nausea86 (14.5)37 (6.0)7 (2.1)Headache46 (7.8)36 (6.0)12 (3.5)Herpes simplexHerpes simplex also includes oral herpes, ophthalmic herpes, herpes dermatitis, genital herpes. 25 (4.2)20 (3.3)6 (1.8)Increased blood creatinine phosphokinase17 (2.9)14 (2.3)5 (1.5)Dizziness17 (2.9)11 (1.8)3 (0.9)Urinary tract infection13 (2.2)10 (1.7)4 (1.2)Fatigue8 (1.3)10 (1.6)2 (0.5)Acne28 (4.7)10 (1.6)0 (0.0)Vomiting19 (3.2)9 (1.5)3 (0.9)Impetigo3 (0.5)9 (1.5)1 (0.3)Oropharyngeal pain6 (1.0)8 (1.4)2 (0.6)Hypertension5 (0.8)7 (1.2)2 (0.7)Influenza6 (1.1)7 (1.2)0 (0.0)Gastroenteritis8 (1.3)7 (1.1)2 (0.6)Dermatitis contact3 (0.5)6 (1.1)1 (0.3)Abdominal pain upper11 (1.9)4 (0.6)0 (0.0)Abdominal discomfort7 (1.2)3 (0.5)1 (0.3)Herpes zoster7 (1.2)2 (0.3)0 (0.0)Thrombocytopenia9 (1.5)0 (0.0)0 (0.0). Specific Adverse ReactionsExposure adjusted incidence rates were adjusted by trial size for all the adverse reactions reported in this section.. Overall InfectionsIn 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 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 InfectionsIn the placebo-controlled trials, for up to 16 weeks, serious infections were reported in subjects (2.6 per 100 patient-years) treated with placebo, subjects (3.9 per 100 patient-years) treated with CIBINQO 100 mg, and subjects (1.3 per 100 patient-years) treated with CIBINQO 200 mg. In all 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 ZosterIn the placebo-controlled trials, for up to 16 weeks, opportunistic infections were generally cases of multidermatomal cutaneous herpes zoster. Herpes zoster was reported in subjects treated with placebo, subjects (1.9 per 100 patient-years) treated with CIBINQO 100 mg and subjects (5.1 per 100 patient-years) treated with CIBINQO 200 mg. In all 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.. MalignancyIn the placebo-controlled trials, for up to 16 weeks, no malignancy was reported in subjects treated with placebo or CIBINQO 100 mg and in patient (0.65 per 100 patient-years) treated with CIBINQO 200 mg. In all clinical trials, including the long-term extension trial, malignancy was reported in subjects (0.5 per 100 patient-years) treated with CIBINQO 100 mg and subjects (0.3 per 100 patient-years) treated with CIBINQO 200 mg.. ThrombosisIn all clinical trials, including the long-term extension trial, pulmonary embolism was reported in subjects (0.4 per 100 patient-years), who were treated with CIBINQO 200 mg. Deep vein thrombosis was reported in 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 EventsIn the placebo-controlled trials, for up to 16 weeks, major adverse cardiovascular event (MACE) was reported in subject (0.6 per 100 patient-years) treated with CIBINQO 100 mg. In all clinical trials, including the long-term extension trial, MACE was reported in patient (0.1 per 100 patient-years) treated with CIBINQO 100 mg and subjects (0.3 per 100 patient-years) treated with CIBINQO 200 mg.. ThrombocytopeniaIn the placebo-controlled trials, for up to 16 weeks, treatment with CIBINQO was associated with dose-related decrease in platelet count. Maximum effects on platelets were observed within weeks, after which the platelet count returned towards baseline despite continued therapy. In all clinical trials, including the long-term extension trial 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.. LymphopeniaIn the placebo-controlled trials, for up to 16 weeks, confirmed ALC <500/mm3 occurred in subjects (1.2 per 100 patient-years) treated with CIBINQO 200 mg and subjects treated with CIBINQO 100 mg or placebo. Both cases occurred in the first weeks of exposure.. Lipid ElevationsIn the placebo-controlled trials, for up to 16 weeks, there was 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 which remained elevated through the final visit in the treatment period. Adverse reactions related to hyperlipidemia occurred in subject (0.6 per 100 patient-years) exposed to CIBINQO 100 mg, subjects (2.0 per 100 patient-years) exposed to CIBINQO 200 mg.. Retinal DetachmentIn the placebo-controlled trials, for up to 16 weeks, retinal detachment occurred in subject (0.6 per 100 patient-years) treated with CIBINQO 100 mg. In all clinical trials, including the long-term extension trial, retinal detachment occurred in 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 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.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. For recommended testing, evaluations and procedures prior to CIBINQO initiation, see Full Prescribing Information. (2.1)Recommended dosage is 100 mg orally once daily. (2.2)200 mg orally once daily is recommended for those patients who are not responding to 100 mg once daily. (2.2)Moderate renal impairment: 50 mg once daily or 100 mg once daily for those patients who are not responding to 50 mg once daily. (2.3)CYP2C19 poor metabolizer: 50 mg once daily or 100 mg once daily for those patients who are not responding to 50 mg once daily. (2.4)For dosage modifications for certain adverse reactions, see Full Prescribing Information. (2.6). For recommended testing, evaluations and procedures prior to CIBINQO initiation, see Full Prescribing Information. (2.1). Recommended dosage is 100 mg orally once daily. (2.2). 200 mg orally once daily is recommended for those patients who are not responding to 100 mg once daily. (2.2). Moderate renal impairment: 50 mg once daily or 100 mg once daily for those patients who are not responding to 50 mg once daily. (2.3). CYP2C19 poor metabolizer: 50 mg once daily or 100 mg once daily for those patients who are not responding to 50 mg once daily. (2.4). For dosage modifications for certain adverse reactions, see Full Prescribing Information. (2.6). 2.1 Recommended Testing, Evaluations, and Procedures Prior to Treatment Initiation. Perform the following tests and evaluations prior to CIBINQO initiation:Tuberculosis (TB) infection evaluation CIBINQO initiation is not recommended in patients with active TB. For patients with latent TB or those with 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 or hepatitis [see Warnings and Precautions (5.1)].A complete blood count (CBC) CIBINQO initiation is not recommended in patients with platelet count <150,000/mm3, an absolute lymphocyte count <500/mm3, an absolute neutrophil count <1,000/mm3, or 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)].. Tuberculosis (TB) infection evaluation CIBINQO initiation is not recommended in patients with active TB. For patients with latent TB or those with 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 or hepatitis [see Warnings and Precautions (5.1)].. complete blood count (CBC) CIBINQO initiation is not recommended in patients with platelet count <150,000/mm3, an absolute lymphocyte count <500/mm3, an absolute neutrophil count <1,000/mm3, or hemoglobin value <8 g/dL [see Warnings and Precautions (5.6)].. 2.2Recommended 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 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.. 2.3Recommended Dosage in Patients with Renal Impairment or Hepatic Impairment. Renal ImpairmentCIBINQO dosage recommendations for patients with renal impairment are provided in Table [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 ImpairmentRenal Impairment StageEstimated Glomerular Filtration (eGFR)Glomerular filtration rate was estimated by the Modification of Diet in Renal Disease (MDRD) formula. DosageMild60 89 mL/minuteCIBINQO 100 mg once dailyModerate30 59 mL/minuteCIBINQO 50 mg once dailySevereSevere Renal Impairment and End-Stage Renal Disease include patients on renal replacement therapy. 15 29 mL/minuteNot recommended for useEnd-Stage Renal Disease (ESRD)<15 mL/minute. Hepatic ImpairmentCIBINQO is not recommended for use in patients with severe hepatic impairment [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)]. 2.4Recommended 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. 2.5Dosage 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.. 2.6Treatment Discontinuation due to Serious Infections or Hematologic Adverse Reactions. Serious or Opportunistic InfectionsIf patient develops 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 AbnormalitiesRecommendations for CIBINQO discontinuation for laboratory abnormalities are summarized in Table 2.Table 2. Recommendations for CIBINQO Discontinuation for Hematologic AbnormalitiesLaboratory MeasureRecommendationAbbreviations: ALC=absolute lymphocyte count; ANC=absolute neutrophil count; CBC=complete blood count; Hb=hemoglobinPlatelet Count <50,000/mm3 Discontinue CIBINQO and follow with CBC until >100,000/mm3 ALC <500/mm3 Treatment should be temporarily discontinued if ALC is less than 500 cells/mm3 and may be restarted once ALC return above this valueANC <1,000/mm3 Treatment should be temporarily discontinued if ANC is less than 1,000 cells/mm3 and may be restarted once ANC return above this valueHb value <8 g/dLTreatment should be temporarily discontinued if Hb is less than g/dL and may be restarted once Hb return above this valueCBC evaluations are recommended at baseline, weeks after treatment initiation and 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)].. 2.7Administration 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.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Strong inhibitors of CYP2C19: The recommended dose is 50 mg daily or 100 mg once daily for those patients who are not responding to 50 mg once daily. (2.5, 7.1)Moderate to strong inhibitors of both CYP2C19 and CYP2C9, or strong CYP2C19 or CYP2C9 inducers: Avoid concomitant use. (7.1)P-gp substrate where small concentration changes may lead to serious or life-threatening toxicities: Monitor or titrate dosage of P-gp substrate. (7.2). Strong inhibitors of CYP2C19: The recommended dose is 50 mg daily or 100 mg once daily for those patients who are not responding to 50 mg once daily. (2.5, 7.1). Moderate to strong inhibitors of both CYP2C19 and CYP2C9, or strong CYP2C19 or CYP2C9 inducers: Avoid concomitant use. (7.1). P-gp substrate where small concentration changes may lead to serious or life-threatening toxicities: Monitor or titrate dosage of P-gp substrate. (7.2). 7.1Effects of Other Drugs on CIBINQO. Table includes drugs with clinically significant drug interactions affecting CIBINQO.Table 4. Clinically Significant Drug Interactions Affecting CIBINQO Strong CYP2C19 Inhibitors Clinical ImpactCoadministration of CIBINQO with strong CYP2C19 inhibitors increases the combined exposure of abrocitinib and its two active metabolites, M1 and M2 which may increase the adverse reactions of CIBINQO [see Clinical Pharmacology (12.3)]. InterventionDosage reduction of CIBINQO is recommended when coadministered with strong CYP2C19 inhibitors [see Dosage and Administration (2.5)]. Moderate to Strong Inhibitors of both CYP2C19 and CYP2C9Clinical ImpactCoadministration 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)]. InterventionAvoid concomitant use of CIBINQO with drugs that are moderate to strong inhibitors of both CYP2C19 and CYP2C9. Strong CYP2C19 or CYP2C9 Inducers Clinical ImpactCoadministration 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)].InterventionAvoid concomitant use of CIBINQO with strong CYP2C19 or CYP2C9 inducers.. 7.2Effects of CIBINQO on Other Drugs. Table 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 ToxicitiesClinical ImpactCoadministration 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)].InterventionMonitor 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 DrugsClinical ImpactCoadministration 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)]. InterventionAntiplatelet drugs, except for low-dose aspirin (<=81 mg daily), during the first months of treatment are contraindicated with CIBINQO [see Contraindications (4)].

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Abrocitinib plasma Cmax and AUC increased dose proportionally up to 200 mg. Steady-state plasma concentrations of abrocitinib are achieved within 48 hours after once daily administration.. AbsorptionAbrocitinib 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 hour.. Effect of FoodCoadministration of CIBINQO with 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 Cmax of abrocitinib increased by approximately 26% and 29%, respectively, and Tmax was prolonged by hours) [see Dosage and Administration (2.7)].. DistributionAfter 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.. EliminationAbrocitinib is eliminated primarily by metabolic clearance mechanisms. The mean elimination half-lives of abrocitinib and its two active metabolites, M1 and M2, range to hours.. MetabolismThe metabolism of abrocitinib is mediated by multiple CYP enzymes, CYP2C19 (~53%), CYP2C9 (~30%), CYP3A4 (~11%) and CYP2B6 (~6%). In 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.. ExcretionAfter 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 PopulationsBody weight, sex, race, and age did not have clinically meaningful effect on CIBINQO exposure.. Patients with Renal ImpairmentIn 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 (AUCinf,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, 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 clinical studies, CIBINQO was not evaluated in subjects with atopic dermatitis with baseline creatinine clearance values less than 40 mL/min.. Patients with Hepatic ImpairmentSubjects with mild hepatic impairment (Child Pugh A) had approximately 4% decrease in the combined exposure (AUCinf,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 (AUCinf,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 or hepatitis [see Use in Specific Populations (8.7) and Warnings and Precautions (5.1)].. Drug Interaction Studies. Clinical StudiesThe 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 DrugsCoadministered DrugsRegimen of Coadministered DrugDose of AbrocitinibRatioRatios for Cmax,u and AUCinf,u compare coadministration of the drug with abrocitinib versus administration of abrocitinib alone. (90% Confidence Interval)Cmax,u AUCinf,u Strong CYP2C19 and moderate CYP3A inhibitor:Fluvoxamine [see Drug Interactions (7.1)] 50 mg once daily 9 days100 mg1.33 (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 and 200 mg on Days 2-7100 mg1.23 (1.08-1.42)2.55When 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 days200 mg0.69 (0.50-0.94)0.44 (0.41-0.47)OAT3 inhibitor:ProbenecidDrug interaction with OAT3 inhibitor is not clinically significant. 1,000 mg twice daily 3 days200 mg1.30 (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 AbrocitinibCoadministered Drugs or In Vivo Markers of CYP ActivityDose Regimen of AbrocitinibRatioRatios for Cmax and AUCinf compare coadministration of abrocitinib with the drug versus administration of the drug alone. (90% Confidence Interval)Cmax AUCinf Oral contraceptive:Ethinyl estradiol (EE) and levonorgestrel (LN)200 mg once daily 9 daysEE: 1.07 (0.99, 1.15)LN: 0.86 (0.75, 0.97)EE: 1.19 (1.12, 1.26)LNAUClast of levonorgestrel was reported in lieu of AUCinf because the terminal phase of levonorgestrel was not well characterized.: 0.98 (0.87, 1.10)Sensitive CYP3A Substrate:Midazolam200 mg once daily 7 days0.93 (0.84, 1.04)0.92 (0.86, 0.99)Sensitive P-gp substrate:Dabigatran200 mg single dose1.40 (0.92, 2.13)1.53 (1.09, 2.15)Sensitive BCRP and OAT3 substrate:Rosuvastatin200 mg once daily 3 days0.99 (0.86, 1.14)1.02 (0.93, 1.12)Sensitive MATE1/2K substrate:Metformin200 mg once daily 2 days0.88 (0.81, 0.96)0.93 (0.85, 1.03)Coadministration of dabigatran etexilate (a P-gp substrate), with single dose of CIBINQO 200 mg increased dabigatran AUCinf and Cmax 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.

SPL MEDGUIDE SECTION.

Medication Guide CIBINQO (Si BINK oh) (abrocitinib) tablets, for oral useThis Medication Guide has been approved by the U.S. Food and Drug Administration.Issued: 1/2022What is the most important information should know about CIBINQOCIBINQO may cause serious side effects, including: 1. Serious infectionsCIBINQO is medicine that affects your immune system. CIBINQO can lower the ability of your immune system to fight infections. Some people have had serious infections while taking CIBINQO or other similar medicines, including tuberculosis (TB), and infections caused by bacteria, fungi, or viruses that can spread throughout the body. Some people have died from these infections. Your healthcare provider should test you for TB before starting treatment with CIBINQO.Your healthcare provider should watch you closely for signs and symptoms of TB during treatment with CIBINQO.You should not start taking CIBINQO if you have any kind of infection unless your healthcare provider tells you it is okay. You may be at higher risk of developing shingles (herpes zoster).Before starting CIBINQO, tell your healthcare provider if you:are being treated for an infection.have had an infection that does not go away or that keeps coming back.have diabetes, chronic lung disease, HIV, or weak immune system.have TB or have been in close contact with someone with TB.have had shingles (herpes zoster).have had hepatitis or hepatitis C.live or have lived or have traveled to certain parts of the country (such as the Ohio and Mississippi River valleys and the Southwest) where there is an increased chance for getting certain kinds of fungal infections. These infections may happen or become more severe if you use CIBINQO. Ask your healthcare provider if you do not know if you have lived in an area where these infections are common.think you have an infection or have symptoms of an infection such as: fever, sweating, or chillsmuscle achescough or shortness of breathblood in your phlegmweight losswarm, red, or painful skin or sores on your bodydiarrhea or stomach painburning when you urinate or urinating more often than usualfeeling very tiredAfter starting CIBINQO, call your healthcare provider right away if you have any symptoms of an infection. CIBINQO can make you more likely to get infections or make any infections that you have worse. 2. Increased risk of death in people 50 years of age and older who have at least heart disease (cardiovascular) risk factor and are taking medicine in the class of medicines called Janus kinase (JAK) inhibitors. CIBINQO is JAK inhibitor medicine.3. Cancer and immune system problems CIBINQO may increase your risk of certain cancers by changing the way your immune system works. Lymphoma and other cancers, including skin cancers, can happen in people taking CIBINQO. People taking medicine in the class of medicines called Janus kinase (JAK) inhibitors have higher risk of certain cancers including lymphoma and lung cancer, especially if you are current or past smoker. Follow your healthcare providers advice about having your skin checked for skin cancer during treatment with CIBINQO. Limit the amount of time you spend in sunlight. Avoid using tanning beds or sunlamps. Wear protective clothing when you are in the sun and use sunscreen with high protection factor (SPF 30 and above). This is especially important if your skin is very fair or of you have family history of skin cancer.Tell your healthcare provider if you have ever had any type of cancer. 4. Increased risk of major cardiovascular events such as heart attack, stroke or death in people 50 years of age and older who have at least heart disease (cardiovascular) risk factor and taking medicine in the class of medicines called JAK inhibitors, especially if you are current or past smoker. Some people taking CIBINQO have had major cardiovascular events.Get emergency help right away if you develop any symptoms of heart attack or stroke during treatment with CIBINQO, including:discomfort in the center of your chest that lasts for more than few minutes, or that goes away and comes backsevere tightness, pain, pressure, or heaviness in your chest, throat, neck, or jawpain or discomfort in your arms, back, neck, jaw, or stomachweakness in one part or on one side of your bodyslurred speechshortness of breath with or without chest discomfortbreaking out in cold sweatnausea or vomitingfeeling lightheaded 5. Blood clots Blood clots in the veins of your legs (deep vein thrombosis, DVT) or lungs (pulmonary embolism, PE) can happen in some people taking CIBINQO. This may be life-threatening. Blood clots in the veins of the legs (deep vein thrombosis, DVT) and lungs (pulmonary embolism, PE) have happened more often in people who are 50 years of age and older and with at least heart disease (cardiovascular) risk factor taking medicine in the class of medicines called Janus kinase (JAK) inhibitors.Tell your healthcare provider if you have had blood clots in the veins of your legs or lungs in the past.Get medical help right away if you have any signs and symptoms of blood clots during treatment with CIBINQO, including: swelling, pain or tenderness in one or both legssudden, unexplained chest or upper back pain shortness of breath or difficulty breathing 6. Changes in certain laboratory test results Your healthcare provider should do blood tests before you start taking CIBINQO and during treatment with CIBINQO to check for the following:low lymphocyte count. Lymphocytes are white blood cells that help the body fight off infections.low neutrophil count. Neutrophils are white blood cells that help the body fight off infections.low red blood cell count. This may mean that you have anemia, which may make you feel weak and tired. low platelet count. Platelets help form clots and stop or prevent bleeding.You should not take CIBINQO if your lymphocyte counts, neutrophil counts, red blood cell counts, or platelet counts are too low. Your healthcare provider may stop your CIBINQO treatment for period of time if needed because of changes in these blood test results. You may also have changes in other laboratory tests, such as your blood cholesterol levels. Your healthcare provider should do blood tests about weeks after you start taking CIBINQO, and weeks after any increase in your dose of CIBINQO to check your blood cell counts, and as often as needed for your other laboratory tests.See What are the possible side effects of CIBINQO for more information about side effects.What is CIBINQOCIBINQO is prescription medicine that is Janus Kinase (JAK) inhibitor. CIBINQO is used to treat adults with moderate-to-severe atopic dermatitis (eczema) that did not respond to other treatment and is not well controlled with prescription therapies, including biologic medicines or in adults who cannot tolerate these therapies. It is not known if CIBINQO is safe and effective in children.During the first months of treatment with CIBINQO, do not take CIBINQO with other medicines that prevent blood clots. You can take low-dose aspirin up to dose of 81 mg each day during this time if prescribed by your healthcare provider.Before taking CIBINQO, tell your healthcare provider about all of your medical conditions, including if you:See What is the most important information should know about CIBINQOhave an infection. are current or past smokerhave had heart attack, other heart problems, or strokehave kidney problems or liver problems.have low platelet counts or white blood cell counts.have any eye problems, including cataracts or retinal detachment.have recently received or are scheduled to receive an immunization (vaccine). People who take CIBINQO should not receive live vaccines.are pregnant or plan to become pregnant. It is not known if CIBINQO will harm your unborn baby.Pregnancy Exposure Registry. Pfizer has registry for women who take CIBINQO during pregnancy. The purpose of this registry is to check the health of you and your baby. If you are pregnant or become pregnant during treatment with CIBINQO, talk to your healthcare provider about how you can join this pregnancy registry, or you may contact the registry at 1-877-311-3770 or www.cibinqopregnancyregistry.com. are breastfeeding or plan to breastfeed. It is not known if CIBINQO passes into your breast milk. You and your healthcare provider should decide if you will take CIBINQO or breastfeed. You should not do both.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. CIBINQO and other medicines may affect each other causing side effects.Especially tell your healthcare provider if you take aspirin or any antiplatelet therapies. See Do not take CIBINQO if you. Ask your healthcare provider if you are unsure. Know the medicines you take. Keep list of them to show your healthcare provider and pharmacist whenever you get new medicine.How should take CIBINQOTake CIBINQO exactly as your healthcare provider tells you to take it. Take CIBINQO time each day, at about the same time each day. Swallow CIBINQO tablets whole with water. Do not split, crush, or chew the tablets.You can take CIBINQO with or without food. CIBINQO can be used with or without prescribed topical medicines for atopic dermatitis. Prescribed topical medicine are lotions, creams, or ointments applied to your skin.If you miss dose, take the dose as soon as possible. If it is less than 12 hours before the next dose, skip the dose. Take the next dose at your usually scheduled time.If you take too much CIBINQO, call the Poison Control Center at 1-800-222-1222 right away.What are the possible side effects of CIBINQO CIBINQO may cause serious side effects, including:See What is the most important information should know about CIBINQO The most common side effects of CIBINQO include:See What is the most important information should know about CIBINQO.common coldnauseaheadacheherpes simplex including cold soresincreased blood level of creatinine phosphokinasedizzinessurinary tract infectiontirednessacnevomitingmouth and throat painflustomach flubacterial skin infection (impetigo)high blood pressureallergic skin rash to something you came into contact withstomach-area painshingleslow platelet countCIBINQO may cause fertility problems in females, which may affect your ability to get pregnant. Talk to your healthcare provider if you have concerns about fertility.Separation or tear to the lining of the back part of the eye (retinal detachment) has happened in people with atopic dermatitis treated with CIBINQO. Call your healthcare provider right away if you have any sudden changes in your vision during treatment with CIBINQO.These are not all the possible side effects of CIBINQO. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.You may also report side effects to Pfizer at 1-800-438-1985. How should store CIBINQO Store CIBINQO at room temperature between 68F to 77F (20C to 25C).Store CIBINQO in the original package.The container has child resistant closure.Keep CIBINQO and all medicines out of the reach of children.General information about the safe and effective use of CIBINQO.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use CIBINQO for condition for which it was not prescribed. Do not give CIBINQO to other people, even if they have the same symptoms you have. It may harm them.You can ask your pharmacist or healthcare provider for information about CIBINQO that is written for health professionals.What are the ingredients in CIBINQOActive ingredient: abrocitinib Inactive ingredients: dibasic calcium phosphate anhydrous, hypromellose, iron oxide red, lactose monohydrate, Macrogol, magnesium stearate, microcrystalline cellulose, sodium starch glycolate, titanium dioxide, and triacetin.LAB-1424-1.0. Your healthcare provider should test you for TB before starting treatment with CIBINQO.. Your healthcare provider should watch you closely for signs and symptoms of TB during treatment with CIBINQO.. are being treated for an infection.. have had an infection that does not go away or that keeps coming back.. have diabetes, chronic lung disease, HIV, or weak immune system.. have TB or have been in close contact with someone with TB.. have had shingles (herpes zoster).. have had hepatitis or hepatitis C.. live or have lived or have traveled to certain parts of the country (such as the Ohio and Mississippi River valleys and the Southwest) where there is an increased chance for getting certain kinds of fungal infections. These infections may happen or become more severe if you use CIBINQO. Ask your healthcare provider if you do not know if you have lived in an area where these infections are common.. think you have an infection or have symptoms of an infection such as: fever, sweating, or chills. muscle aches. cough or shortness of breath. blood in your phlegm. weight loss. warm, red, or painful skin or sores on your body. diarrhea or stomach pain. burning when you urinate or urinating more often than usual. feeling very tired. Lymphoma and other cancers, including skin cancers, can happen in people taking CIBINQO. People taking medicine in the class of medicines called Janus kinase (JAK) inhibitors have higher risk of certain cancers including lymphoma and lung cancer, especially if you are current or past smoker. Follow your healthcare providers advice about having your skin checked for skin cancer during treatment with CIBINQO. Limit the amount of time you spend in sunlight. Avoid using tanning beds or sunlamps. Wear protective clothing when you are in the sun and use sunscreen with high protection factor (SPF 30 and above). This is especially important if your skin is very fair or of you have family history of skin cancer.. discomfort in the center of your chest that lasts for more than few minutes, or that goes away and comes back. severe tightness, pain, pressure, or heaviness in your chest, throat, neck, or jaw. pain or discomfort in your arms, back, neck, jaw, or stomach. weakness in one part or on one side of your body. slurred speech. shortness of breath with or without chest discomfort. breaking out in cold sweat. nausea or vomiting. feeling lightheaded. Tell your healthcare provider if you have had blood clots in the veins of your legs or lungs in the past.. Get medical help right away if you have any signs and symptoms of blood clots during treatment with CIBINQO, including: swelling, pain or tenderness in one or both legssudden, unexplained chest or upper back pain shortness of breath or difficulty breathing swelling, pain or tenderness in one or both legs. sudden, unexplained chest or upper back pain shortness of breath or difficulty breathing. low lymphocyte count. Lymphocytes are white blood cells that help the body fight off infections.. low neutrophil count. Neutrophils are white blood cells that help the body fight off infections.. low red blood cell count. This may mean that you have anemia, which may make you feel weak and tired. low platelet count. Platelets help form clots and stop or prevent bleeding.. See What is the most important information should know about CIBINQO. have an infection. are current or past smoker. have had heart attack, other heart problems, or stroke. have kidney problems or liver problems.. have low platelet counts or white blood cell counts.. have any eye problems, including cataracts or retinal detachment.. have recently received or are scheduled to receive an immunization (vaccine). People who take CIBINQO should not receive live vaccines.. are pregnant or plan to become pregnant. It is not known if CIBINQO will harm your unborn baby.Pregnancy Exposure Registry. Pfizer has registry for women who take CIBINQO during pregnancy. The purpose of this registry is to check the health of you and your baby. If you are pregnant or become pregnant during treatment with CIBINQO, talk to your healthcare provider about how you can join this pregnancy registry, or you may contact the registry at 1-877-311-3770 or www.cibinqopregnancyregistry.com. Pregnancy Exposure Registry. Pfizer has registry for women who take CIBINQO during pregnancy. The purpose of this registry is to check the health of you and your baby. If you are pregnant or become pregnant during treatment with CIBINQO, talk to your healthcare provider about how you can join this pregnancy registry, or you may contact the registry at 1-877-311-3770 or www.cibinqopregnancyregistry.com. are breastfeeding or plan to breastfeed. It is not known if CIBINQO passes into your breast milk. You and your healthcare provider should decide if you will take CIBINQO or breastfeed. You should not do both.. Take CIBINQO exactly as your healthcare provider tells you to take it. Take CIBINQO time each day, at about the same time each day. Swallow CIBINQO tablets whole with water. Do not split, crush, or chew the tablets.. You can take CIBINQO with or without food. CIBINQO can be used with or without prescribed topical medicines for atopic dermatitis. Prescribed topical medicine are lotions, creams, or ointments applied to your skin.. If you miss dose, take the dose as soon as possible. If it is less than 12 hours before the next dose, skip the dose. Take the next dose at your usually scheduled time.. If you take too much CIBINQO, call the Poison Control Center at 1-800-222-1222 right away.. See What is the most important information should know about CIBINQO common cold. nausea. headache. herpes simplex including cold sores. increased blood level of creatinine phosphokinase. dizziness. urinary tract infection. tiredness. acne. vomiting. mouth and throat pain. flu. stomach flu. bacterial skin infection (impetigo). high blood pressure. allergic skin rash to something you came into contact with. stomach-area pain. shingles. low platelet count. Store CIBINQO at room temperature between 68F to 77F (20C to 25C).. Store CIBINQO in the original package.. The container has child resistant closure.. Logo.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Breastfeeding not recommended. (8.2)Renal Impairment: Avoid use in patients with severe renal impairment or end-stage renal disease. (8.6)Hepatic Impairment: Avoid use in patients with severe hepatic impairment. (8.7). Lactation: Breastfeeding not recommended. (8.2). Renal Impairment: Avoid use in patients with severe renal impairment or end-stage renal disease. (8.6). Hepatic Impairment: Avoid use in patients with severe hepatic impairment. (8.7). 8.1 Pregnancy. Pregnancy Exposure RegistryThere is 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 SummaryAvailable data from pregnancies reported in clinical trials with CIBINQO are not sufficient to establish 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 14 or 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.. 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 13th ribs at 30 mg/kg/day (14 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 (22 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 (5 times the MRHD based on AUC comparison).In 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 and continuing through lactation day 20. Dystocia with prolonged parturition and reduced offspring body weights were noted at 30 mg/kg/day (14 times the MRHD based on AUC comparison). Postnatal survival was markedly decreased at 60 mg/kg/day (22 times the MRHD based on AUC comparison). No maternal toxicity was observed at 10 mg/kg/day (3 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 (14 times the MRHD based on AUC comparison).. 8.2 Lactation. Risk SummaryThere 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 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 DataLactating female rats were orally administered single dose of 10 mg/kg abrocitinib on lactation day 12. Abrocitinib AUC was approximately times greater in milk than in plasma.. 8.3 Females and Males of Reproductive Potential. Infertility. FemalesBased on the findings in rats, oral administration of CIBINQO may impair female fertility. Impaired fertility in female rats was reversible month after cessation of abrocitinib oral administration [see Nonclinical Toxicology (13.1)].. 8.4 Pediatric Use. The safety and effectiveness of CIBINQO have not been established in pediatric patients.. Juvenile Animal Toxicity DataIn 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 human infant) and continuing through postnatal day 63 (approximately equivalent to an adolescent). Abrocitinib caused 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 (1.1 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 (10 times the MRHD based on AUC comparison). At 75 mg/kg/day (36 times the MRHD based on AUC comparison), paw fractures generally corresponded to limb impairment, fractured tibia was noted in single female, and effects noted at lower doses were increased in frequency and severity. Irreversible bone findings have not been observed in older animals.. 8.5 Geriatric Use. 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/mm3 occurred only in patients 65 years of age and older. higher proportion of patients 65 years of age and older had platelet counts <75,000/mm3. 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 (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 [see Dosage and Administration (2.3)]. dosage reduction in patient 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 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 (AUCinf,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)].. 8.8CYP2C19 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)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Laboratory Abnormalities: Laboratory monitoring is recommended due to potential changes in platelets, lymphocytes, and lipids. (5.6)Immunizations: Avoid use of live vaccines prior to, during, and immediately after CIBINQO treatment. (5.7). Laboratory Abnormalities: Laboratory monitoring is recommended due to potential changes in platelets, lymphocytes, and lipids. (5.6). Immunizations: Avoid use of live vaccines prior to, during, and immediately after CIBINQO treatment. (5.7). 5.1Serious Infections The most frequent serious infections reported in clinical studies with CIBINQO for atopic dermatitis were herpes simplex, herpes zoster, and pneumonia [see Adverse Reactions (6.1)]. Serious infections leading to hospitalization or death, including tuberculosis and bacterial, invasive fungal, viral, and other opportunistic infections, have occurred in patients receiving JAK inhibitors used to treat inflammatory conditions. Avoid use of CIBINQO in patients with active, serious infection including localized infections. Consider the risks and benefits of treatment prior to initiating CIBINQO in patients:with chronic or recurrent infectionwho have been exposed to tuberculosiswith history of serious or an opportunistic infectionwho have resided or traveled in areas of endemic tuberculosis or endemic mycoseswith underlying conditions that may predispose them to infectionClosely monitor patients for the development of signs and symptoms of infection during and after treatment with CIBINQO. If patient develops 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.. with chronic or recurrent infection. who have been exposed to tuberculosis. with history of 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. TuberculosisEvaluate 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 new diagnosis of latent TB or prior untreated latent TB, or for patients with 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 ReactivationViral reactivation, including herpes virus reactivation (e.g., herpes zoster, herpes simplex), was reported in clinical studies with CIBINQO [see Adverse Reactions (6.1)]. If patient develops herpes zoster, consider interrupting CIBINQO until the episode resolves.Hepatitis 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 or hepatitis [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 liver specialist.. 5.2Mortality. In 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, 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.. 5.3Malignancy 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 large, randomized, postmarketing safety study of another JAK inhibitor in RA patients, 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. higher rate of lymphomas was observed in patients treated with the JAK inhibitor compared to those treated with TNF blockers. 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 known malignancy (other than successfully treated NMSC), patients who develop malignancy when on treatment, and patients who are current or past smokers.. 5.4Major Adverse Cardiovascular Events. Major adverse cardiovascular events were reported in clinical studies of CIBINQO for atopic dermatitis [see Adverse Reactions (6.1)]. In 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 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 myocardial infarction or stroke.. 5.5Thrombosis. 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 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.. 5.6Laboratory Abnormalities. Hematologic AbnormalitiesTreatment with CIBINQO was associated with an increased incidence of thrombocytopenia and lymphopenia [see Adverse Reactions (6.1)]. Prior to CIBINQO initiation, perform CBC [see Dosage and Administration (2.1)]. CBC evaluations are recommended at weeks after initiation and weeks after dose increase of CIBINQO. Discontinuation of CIBINQO therapy is required for certain laboratory abnormalities [see Dosage and Administration (2.6)]. Lipid ElevationsDose-dependent increase in blood lipid parameters were reported in patients treated with CIBINQO [see Adverse Reactions (6.1)]. Lipid parameters should be assessed approximately 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.. 5.7Immunizations. 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.