Cibinqo

CIBINQO 50 mg film-coated tablets: Each film-coated tablet contains 50 mg abrocitinib.
Pink, oval tablet 11 mm long and 5 mm wide, debossed with "PFE" on one side and "ABR 50" on the other.
CIBINQO 100 mg film-coated tablets: Each film-coated tablet contains 100 mg abrocitinib.
Pink, round tablet 9 mm in diameter, debossed with "PFE" on one side and "ABR 100" on the other.
CIBINQO 200 mg film-coated tablets: Each film-coated tablet contains 200 mg abrocitinib.
Pink, oval tablet 18 mm long and 8 mm wide debossed with "PFE" on one side and "ABR 200" on the other.
Excipients/Inactive Ingredients: Microcrystalline cellulose, Anhydrous dibasic calcium phosphate, Sodium starch glycolate, Magnesium stearate.
Film coat: Hypromellose (E464), Titanium dioxide (E171), Lactose monohydrate, Macrogol, Triacetin (E1518), Iron red oxide (E172).

Pharmacology: Pharmacodynamics: Mechanism of action: CIBINQO is a Janus kinase (JAK) 1 inhibitor. JAKs are intracellular enzymes which transmit signals arising from cytokine or growth factor receptor interactions on the cellular membrane to influence cellular processes of hematopoiesis and immune cell function. JAKs phosphorylate and activate Signal Transducers and Activators of Transcription (STATs) which modulate intracellular activity including gene expression. Inhibition of JAK1 modulates the signaling pathway by preventing the phosphorylation and activation of STATs.
In biochemical assay, abrocitinib has selectivity for JAK1 over the other 3 JAK isoforms JAK2 (28-fold), JAK3 (>340-fold) and tyrosine kinase 2 (TYK 2, 43-fold). In cellular settings, it preferentially inhibits cytokine induced STAT phosphorylation by signaling pairs involving JAK1 and spares signaling by JAK2/JAK2 or JAK2/TYK2 pairs. The relevance of selective enzymatic inhibition of specific JAK enzymes to clinical effect is not currently known.
Pharmacodynamic effects: 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 4 weeks of drug discontinuation.
Mean absolute lymphocyte count increased by 2 weeks after starting treatment with abrocitinib and returned to baseline by Month 9 of treatment. Most patients maintained an ALC within the reference range. Treatment with abrocitinib was associated with a dose-related increase in B cell counts and a dose-related decrease in NK cell counts. The clinical significance of these changes in B cell and NK cell counts is unknown.
Clinical efficacy and safety: The efficacy and safety of CIBINQO as monotherapy and in combination with background medicated topical therapies over 12-16 weeks were evaluated in 1616 patients in 3 pivotal randomized, double-blind, placebo-controlled studies (MONO-1, MONO 2, and COMPARE). In addition, the efficacy and safety of Cibinqo in monotherapy over 52 weeks (with the option of rescue treatment in flaring patients) was evaluated in 1233 patients in a Phase 3 induction, randomized withdrawal, double-blind, placebo-controlled study (REGIMEN). The patients in these 4 studies were 12 years of age and older with moderate-to-severe atopic dermatitis as defined by Investigator's 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. Patients who had a prior inadequate response or for whom topical treatments were medically unadvisable, or who had received systemic therapies were eligible for inclusion.
All patients who completed the parent studies were eligible to enroll into the long-term extension study EXTEND.
Clinical response: Treatment with CIBINQO 100 mg or 200 mg once daily as monotherapy or in combination with background medicated topical therapy resulted in improvement in objective signs of atopic dermatitis and patient-reported pruritus.
Baseline characteristics: In the placebo-controlled studies (MONO-1, MONO-2, COMPARE) and the open label induction, randomized withdrawal study (REGIMEN) across all treatment groups 41.4% to 51.1% were female, 59.3% to 77.8% were Caucasian, 15.0% to 33.0% were Asian and 4.1% to 8.3% were Black, and the mean age was 32.1 to 37.7 years. In these studies, 32.2% to 40.8% had a baseline IGA of 4 (severe atopic dermatitis), and 41.4% to 59.5% of patients had received prior systemic treatment for atopic dermatitis. The baseline mean EASI score ranged from 28.5 to 30.9, the baseline PP-NRS ranged from 7.0 to 7.3 and the baseline Dermatology Life Quality Index (DLQI) ranged from 14.4 to 16.0.
Monotherapy studies: In both pivotal monotherapy studies (MONO-1, MONO-2), the proportion of patients who achieved IGA and/or EASI-75 response was significantly higher in patients who received CIBINQO 100 mg or 200 mg once daily compared with placebo at Week 12 (see Table 3).
A significantly higher proportion of patients who achieved PP-NRS4 (defined as an improvement of ≥4 points in the severity of PP-NRS) with CIBINQO 100 mg or 200 mg once daily compared with placebo was observed as soon as Week 2 and persisting through Week 12. Higher proportions of patients achieved PP-NRS4 with CIBINQO 100 mg or 200 mg once daily compared with placebo by Day 6 and Day 3 (2 days after the first dose), respectively (see Table 1). (See Table 1, Figures 1 and 2.)

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Treatment effects in subgroups (e.g., weight, age, sex, race and prior systemic immunosuppressant treatment) in MONO-1 and MONO-2 were consistent with the results in the overall study population.
Combination therapy study: In the pivotal combination therapy study (COMPARE), the proportion of patients who achieved IGA or EASI-75 response was significantly higher in patients who received CIBINQO 100 mg or 200 mg once daily compared with placebo at Week 12 (see Table 2). (See Table 2.)

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The proportion of patients who achieved EASI-90 or PP-NRS4 over time in COMPARE are shown in Figure 3. (See Figure 3.)

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Patients who received dupilumab and subsequently enrolled in EXTEND were randomized to either CIBINQO 100 mg or 200 mg once daily upon entering EXTEND. Among responders to dupilumab in COMPARE, the majority maintained response 12 weeks after switching to CIBINQO [77% and 86% for IGA (0 or 1) response, and 90% and 96% for EASI-75 with 100 mg once daily or 200 mg once daily, respectively]. Among non-responders to dupilumab in COMPARE, a substantial proportion of patients achieved response 12 weeks after switching to CIBINQO [34% and 47% for IGA (0 or 1) response, and 68% and 80% for EASI-75 with 100 mg once daily or 200 mg once daily, respectively].
Treatment effects in subgroups (e.g., weight, age, sex, race, and prior systemic immunosuppressant treatment) in COMPARE were consistent with the results in the overall study population.
Late-onset efficacy: Eligible patients who completed the full treatment period of a qualifying parent study (e.g., MONO-1, MONO-2, COMPARE) were considered for enrollment in the long-term extension study EXTEND, which allows patients to extend CIBINQO treatment for at least 92 weeks or until availability of commercial product in their country. In EXTEND, patients received CIBINQO with or without background medicated topical therapy. Patients who were previously randomized to CIBINQO 100 mg or 200 mg once daily in qualifying studies continued the same dose in EXTEND as in the parent study, and the blind was maintained. Patients not previously randomized to CIBINQO in a qualifying parent study were randomized to either CIBINQO 100 mg or 200 mg once daily upon entering EXTEND. Among patients who did not achieve IGA (0 or 1) response after 12 weeks of CIBINQO treatment and entered EXTEND, 14% and 22% of patients continuing CIBINQO 100 mg once daily in EXTEND achieved IGA (0 or 1) response by Week 16 and Week 24 (with 4 and 12 additional weeks of treatment), respectively, and 19% and 27% of patients continuing CIBINQO 200 mg once daily achieved IGA response by Week 16 and Week 24, respectively. Among patients who did not achieve EASI-75 after 12 weeks of CIBINQO treatment and entered EXTEND, 32% and 45% of patients continuing CIBINQO 100 mg once daily in EXTEND achieved EASI-75 by Week 16 and Week 24 (with 4 and 12 additional weeks of treatment), respectively, and 34% and 54% of patients continuing CIBINQO 200 mg once daily achieved EASI-75 response by Week 16 and Week 24, respectively.
Long-term efficacy: Among patients who achieved response at Week 12 of a qualifying parent study and entered EXTEND, the majority of patients maintained their response at Week 48 of cumulative CIBINQO treatment for both doses of CIBINQO [53% and 57% for IGA (0 or 1) response, 69% and 71% for EASI-75, and 52% and 69% for PP-NRS4 with 100 mg once daily and 200 mg once daily, respectively].
Health related outcomes: Treatment with either dose of CIBINQO as monotherapy resulted in significantly improved patient-reported outcomes at 12 weeks compared with placebo (see Table 5). A significantly larger proportion of the CIBINQO groups had clinically meaningful reductions in Dermatology Life Quality Index (DLQI) total scores (defined as a 4-point improvement) from baseline to Week 12 compared with placebo. CIBINQO groups also had a significantly larger proportion of patients who reported "no effect" of their disease on their quality of life (as measured by a DLQI score of 0 or 1).
Both groups significantly improved patient-reported atopic dermatitis symptoms and sleep disruption as measured by the Patient Oriented Eczema Measure (POEM), Night Time Itch Scale (NTIS), and SCORing Atopic Dermatitis (SCORAD) sleep loss subscale. In addition, anxiety and depression symptoms as measured by the Hospital Anxiety and Depression Scale (HADS) total score were significantly reduced in the CIBINQO groups compared with placebo at 12 weeks. (See Table 3.)

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In COMPARE, a significantly larger proportion of the CIBINQO groups had clinically meaningful reductions in DLQI total scores (defined as a 4-point improvement) from baseline to Week 12 compared with placebo (see Table 6). CIBINQO groups also had a significantly larger proportion of patients who reported "no effect" of their disease on their quality of life (as measured by a DLQI score of 0 or 1).
Both groups significantly improved patient-reported atopic dermatitis symptoms and sleep disruption as measured by the POEM and SCORAD sleep loss subscale, respectively. In addition, anxiety and depression symptoms as measured by the HADS total score were significantly reduced in the CIBINQO groups compared with placebo at 12 weeks. (See Table 4.)

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Open label induction, randomized withdrawal study (REGIMEN): A total of 1,233 patients received open label CIBINQO. Seven-hundred ninety-eight (798) induction responders were randomized to 200 mg or 100 mg of medicinal product or placebo.
Continuous treatment (200 mg continuous) and induction-maintenance treatment (200 mg for 12 weeks followed by 100 mg) prevented flare with 81.1% and 57.4% probability, respectively, versus 19.1% among patients who withdrew treatment (randomized to placebo) after 12 weeks of induction. Three hundred fifty-one (351) patients including 16.2% of 200 mg, 39.2% of 100 mg and 76.4% of placebo patients received rescue medication of 200 mg CIBINQO in combination with topical therapy. (See Table 5 and Figure 4.)

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A multivariate analysis was performed to identify predictors of successfully decreasing the dose from 200 mg to 100 mg and remaining flare-free for at least 12 weeks after the dose decrease. In that analysis, patients who had not received prior systemic agents (OR 1.8, 95% CI: 1.2, 2.6) and patients who had ≤50% BSA involvement before starting abrocitinib (OR 1.8, 95% CI: 1.2, 2.6) were almost twice as likely to remain protocol-defined flare-free than those who had received prior systemic agents and who had >50% BSA involvement.
Pediatric population: The efficacy and safety of CIBINQO as monotherapy was evaluated in 2 Phase 3 randomized, double blind, placebo-controlled studies (MONO-1, MONO 2) which included 124 patients who were 12 to less than 18 years of age. The efficacy and safety were also evaluated in open label induction, randomized withdrawal study (REGIMEN) which included 246 patients who were 12 to less than 18 years of age. In these studies, the results in the adolescent subgroup were consistent with the results in the overall study population.
The efficacy and safety of CIBINQO in combination with background medicated topical therapy was evaluated in the Phase 3 randomized, double-blind, placebo-controlled study TEEN. The study included 285 patients who were 12 to less than 18 years of age with moderate-to-severe atopic dermatitis as defined by IGA score ≥3, EASI score ≥16, BSA involvement ≥10%, and PP NRS ≥4 at the baseline visit prior to randomization. Patients who had a prior inadequate response or who had received systemic therapy, were eligible for inclusion.
Baseline characteristics: In TEEN, across all treatment groups 49.1% were female, 56.1% were Caucasian, 33.0% were Asian and 6.0% were Black patients. The median age was 15 years and the proportion of patients with severe atopic dermatitis (IGA of 4) was 38.6%. (See Table 6.)

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Pharmacokinetics: Absorption: Effect of Food: CIBINQO is well-absorbed with over 91% extent of oral absorption and absolute oral bioavailability of approximately 60%. The oral absorption of abrocitinib is rapid and peak plasma concentrations and reached within 1 hour. Steady-state plasma concentrations of abrocitinib are achieved within 48 hours after once daily administration. Both C_max and AUC of CIBINQO increased dose proportionally up to 400 mg. Coadministration of CIBINQO with a high-fat meal had no clinically relevant effect on CIBINQO exposures (AUC and C_max increased by approximately 26% and 29%, respectively, and T_max was prolonged by 2 hours). In clinical studies, CIBINQO was administered without regard to food (see Dosage & Administration).
Distribution: After intravenous administration, the volume of distribution of abrocitinibis about 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 distribute equally between red blood cells and plasma.
Metabolism: The metabolism of abrocitinib is mediated by multiple CYP enzymes, CYP2C19 (~53%), CYP2C9 (~30%), CYP3A4 (~11%) and CYP2B6 (~6%). In a human radiolabeled study, abrocitinib was the most prevalent circulating species, with 3 polar mono-hydroxylated metabolites identified as M1 (3-hydroxypropyl), M2 (2-hydroxypropyl), and M4 (pyrrolidinone pyrimidine). Of the 3 metabolites in circulation, M1 and M2 have similar JAK inhibitory profiles as CIBINQO, while M4 was pharmacologically inactive. The pharmacologic activity of abrocitinib is attributable to the unbound exposures of parent molecule (~60%) as well as M1 (~10%) and M2 (~30%) in systemic circulation. The sum of unbound exposures of CIBINQO, M1 and M2, each expressed in molar units and adjusted for relative potencies, is referred to as the CIBINQO active moiety.
In vitro, abrocitinib or its metabolites were not significant inhibitors or inducers of CYP enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) or of uridine diphosphate glucuronyltransferases (UGTs) (UGT1A1, UGT1A4, UGT1A6, UGT1A9, and UGT2B7). Abrocitinib or its metabolites at clinically meaningful concentrations are not inhibitors of organic anion transporter (OAT)3, organic cation transporter (OCT)1, multidrug and toxin compound extrusion protein (MATE)1/2K and breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1/1B3, bile salt export pump (BSEP), OAT1 or OCT2.
Elimination: The elimination half-life of abrocitinib is about 5 hours. Abrocitinib is eliminated primarily by metabolic clearance mechanisms, with less than 1% of the dose excreted in urine as unchanged drug. The metabolites of CIBINQO, M1, M2 and M4 are excreted predominantly in urine, and are substrates of OAT3 transporter.
Special populations: Body Weight, Gender, Genotype, Race, and Age: Body weight, gender, CYP2C19/2C9 genotype, race, and age did not have a clinically meaningful effect on abrocitinib exposure (see Dosage & Administration).
Adolescents (12 to less than 18 years of age): Based on population pharmacokinetic analysis, there was no clinically significant difference in mean abrocitinib steady-state exposure in adolescent patients compared to adults at their typical body weights.
Pediatric (under 12 years of age): The pharmacokinetics of abrocitinib in pediatric patients under 12 years of age have not yet been established (see Dosage & Administration).
Renal impairment: In a renal impairment study, patients with severe (eGFR <30 mL/min) and moderate (eGFR 30 to <60 mL/min) renal impairment had approximately 191% and 110% increase in active moiety AUC_inf, respectively, compared to patients with normal renal function (eGFR ≥90 mL/min; see Section 4.2). Pharmacokinetics of abrocitinib have not been determined in patients with mild renal impairment, however, based on the results observed in other groups, an increase of up to 70% in active moiety exposure is expected in patients with mild renal impairment (eGFR 60 to <90 mL/min). The increase of up to 70% is not clinically meaningful as the efficacy and safety of abrocitinib in atopic dermatitis patients with mild renal impairment (n=756) was comparable to the overall population in Phase 2 and 3 clinical studies. Based on these results, a clinically significant increase in CIBINQO active moiety is not expected in patients with mild renal impairment (creatinine clearance 60 to <90 mL/min). The eGFR in individual patients was estimated using Modification of Diet in Renal Disease (MDRD) formula.
CIBINQO has not been studied in patients with ESRD on renal replacement therapy (see Dosage & Administration). In Phase 3 clinical studies, CIBINQO was not evaluated in patients with atopic dermatitis with baseline creatinine clearance values less than 40 mL/min.
Hepatic impairment: Patients with mild (Child Pugh A) and moderate (Child Pugh B) hepatic impairment had approximately 4% decrease and 15% increase in active moiety AUCinf, respectively, compared to patients with normal hepatic function. These changes are not clinically significant, and no dose adjustment is required in patients with mild or moderate hepatic impairment (see Dosage & Administration). In clinical studies, CIBINQO was not evaluated in patients with severe (Child Pugh C) hepatic impairment, or in patients screened positive for active hepatitis B or hepatitis C.
Toxicology: Preclinical Safety Data: Genotoxicity: CIBINQO is not mutagenic in the bacterial mutagenicity assay (Ames assay). Although CIBINQO is aneugenic in the in vitro TK6 micronucleus assay, CIBINQO is not aneugenic or clastogenic based on the results of the in vivo rat bone marrow micronucleus assay.
Carcinogenicity: No evidence of tumorigenicity was observed in the 6 month Tg.rasH2 mice administered CIBINQO for at oral doses up to 75 mg/kg/day and 60 mg/kg/day in female and male mice, respectively. In the 2-year oral carcinogenicity study, CIBINQO resulted in a statistically higher incidence of benign thymomas in female rats at exposures greater than or equal to 2.8 times the unbound human AUC at the MRHD of 200 mg. No evidence of CIBINQO related tumorigenicity was observed following oral CIBINQO administration in female rats at exposures equal to 0.6 times the unbound human AUC at the MRHD of 200 mg or in male rats at exposures equal to 14 times the unbound human AUC at the MRHD of 200 mg.
Reproductive and developmental toxicity: CIBINQO had no effects on rat male fertility or spermatogenesis at doses up to 70 mg/kg/day at exposures equal to 26 times the unbound human AUC at the MRHD of 200 mg. CIBINQO resulted in effects on rat female fertility (lower fertility index, corpora lutea, and implantation sites) at exposures equal to 29 times the unbound human AUC at the MRHD of 200 mg and higher post implantation loss at exposures greater than or equal to 11 times the unbound human AUC at the MRHD of 200 mg. The effects on female fertility reversed 1 month after cessation of CIBINQO administration. No effects on female fertility were noted at exposures equal to 2 times the unbound human AUC at the MRHD of 200 mg.
No fetal malformations were observed in embryo-fetal development studies in rats or rabbits. In an embryo-fetal development study in pregnant rabbits, oral administration of CIBINQO during gestation days 7 to 19 had no effects on embryo-fetal survival or fetal morphological development at exposures equal to 4 times the unbound human AUC at the MRHD of 200 mg. CIBINQO resulted in increased incidence of delayed ossification of the forelimb phalanges at exposures equal to 4 times the unbound human AUC at the MRHD of 200 mg.
In an embryo-fetal development study in pregnant rats, oral administration of CIBINQO during gestation days 6 to 17 resulted in increased embryo-fetal lethality at exposures equal to 17 times the unbound human AUC at the MRHD of 200 mg. No embryo-fetal lethality was observed in pregnant rats orally dosed with CIBINQO during organogenesis at exposures equal to 11 times the unbound human AUC at the MRHD of 200 mg. CIBINQO resulted in increased incidences of skeletal variations of short 13^th ribs at exposures greater than or equal to 11 times the unbound human AUC at the MRHD of 200 mg and reduced ventral processes, thickened ribs, and unossified metatarsals at exposures equal to 17 times the unbound human AUC at the MRHD of 200 mg. No skeletal variations were noted in rats at exposures equal to 2.4 times the unbound human AUC at the MRHD of 200 mg.
In a pre- and postnatal development study in pregnant rats, oral administration of CIBINQO during gestation day 6 through lactation day 21 resulted in dystocia with prolonged parturition and lower offspring body weights at exposures greater than or equal to 11 times the unbound human AUC at the MRHD of 200 mg and lower postnatal survival at exposures equal to 17 times the unbound human AUC at the MRHD of 200 mg. No maternal or developmental toxicity was observed in either dams or offspring at exposures equal to 2.4 times the unbound human AUC at the MRHD of 200 mg.
Administration of abrocitinib to juvenile rats (comparable to a 3 month old human) resulted in macroscopic and microscopic bone findings. When dosing was initiated at postnatal Day 10 (at exposures greater than or equal to 0.8 times the unbound human AUC at the MRHD of 200 mg), macroscopic bone findings (malrotated and/or impaired use of forelimbs or hindlimbs or paws, fractures, and/or femoral head abnormalities) were noted. Only the microscopic bone dystrophy finding (similar to that observed in rat general toxicity studies of up to 1 month) was fully reversible after cessation of treatment.

CIBINQO is indicated for the treatment of patients 12 years of age and older with moderate to severe atopic dermatitis, including the relief of pruritus, who have had an inadequate response to prescribed topical therapy or for whom these treatments are not advisable. CIBINQO can be used with or without medicated topical therapies for atopic dermatitis.

Posology: The recommended dose of CIBINQO is either 100 mg or 200 mg once daily. For most patients, 200 mg is the recommended starting dose. A dose of 100 mg once daily is the recommended starting dose for patients aged ≥65 years, and for those who have risk factors for developing an adverse reaction to abrocitinib or those who are less likely to tolerate the adverse reactions (see Precautions and Adverse Reactions). During treatment, the dose may be decreased or increased based on tolerability and efficacy. The lowest effective dose for maintenance should be considered. The maximum daily dose is 200 mg.
CIBINQO can be used with or without medicated topical therapies for atopic dermatitis.
Treatment initiation: Treatment with CIBINQO should not be initiated in patients with a platelet count <150 × 10³/mm³, an absolute lymphocyte count (ALC) <0.5 × 10³/mm³, an absolute neutrophil count (ANC) <1 × 10³/mm³ or who have a hemoglobin value <8 g/dL (see Precautions).
Dose interruption: If a patient develops a serious infection, sepsis or opportunistic infection, consider interruption of CIBINQO until the infection is controlled should be considered (see Precautions).
Interruption of dosing may be needed for management of laboratory abnormalities as described in Table 7 (see Precautions).
Missed doses: If a dose is missed, patients should be advised to take the dose as soon as possible unless it is less than 12 hours before the next dose, in which case the patient should not take the missed dose. Thereafter, resume dosing at the regular scheduled time.
Drug-drug interactions: When recommended dose is 100 mg or 200 mg CIBINQO once daily, dose should be reduced by 50% to 50 mg or 100 mg once daily, respectively, in patients taking strong inhibitors of cytochrome P450 (CYP) 2C19 (e.g., fluvoxamine, fluconazole). The use of CIBINQO is not recommended concomitantly with strong inducers of CYP enzymes (e.g., rifampin) (see Interactions).
Special populations: Renal impairment: No dose adjustment is required in patients with mild renal impairment, i.e., estimated glomerular filtration rate (eGFR) of 60 to <90 mL/min.
In patients with moderate (eGFR 30 to <60 mL/min) renal impairment, the recommended dose of CIBINQO should be reduced by half to 100 mg or 50 mg once daily (see Pharmacology: Pharmacokinetics under Actions).
In patients with severe (eGFR <30 mL/min) renal impairment, 50 mg once daily is the recommended starting dose. The maximum daily dose is 100 mg (see Pharmacology: Pharmacokinetics under Actions).
Hepatic impairment: No dose adjustment is required in patients with mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment. CIBINQO has not been studied in patients with severe (Child Pugh C) hepatic impairment (see Pharmacology: Pharmacokinetics under Actions).
Elderly population: The recommended starting dose for patients ≥65 years of age is 100 mg once daily (see Precautions).
Pediatric population: The safety and efficacy of CIBINQO in pediatric patients under 12 years of age have not yet been established. No data are available.
Method of administration: CIBINQO is to be taken orally once daily with or without food at approximately the same time each day.
In patients who experience nausea while taking CIBINQO, taking with food may improve nausea.
Swallow CIBINQO tablets whole and intact with water. Do not crush, split, or chew CIBINQO tablets.

CIBINQO was administered in clinical studies up to a single oral dose of 800 mg. There is no experience with overdose of CIBINQO. There is no specific antidote for overdose with CIBINQO. In case of an overdose, it is recommended that the patient be monitored for signs and symptoms of adverse reactions. Treatment should be symptomatic and supportive.
Pharmacokinetic data up to and including a single oral dose of 800 mg in healthy adult volunteers indicate that more than 90% of the administered dose is expected to be eliminated within 48 hours.

None.

Serious infections: Serious infections have been reported in patients receiving CIBINQO. The most frequent serious infections in clinical studies were herpes simplex, herpes zoster, and pneumonia (see Adverse Reactions).
The risks and benefits of treatment with CIBINQO should be carefully considered for patients with chronic or recurrent infection; who have been exposed to TB; with a history of a serious or an opportunistic infection; who have resided or traveled in areas of endemic TB or endemic mycoses; or with underlying conditions that may predispose them to infection.
Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with CIBINQO. A patient who develops a new infection during treatment with CIBINQO should undergo prompt and complete diagnostic testing and appropriate antimicrobial therapy should be initiated. The patient should be closely monitored and CIBINQO therapy should be interrupted if the patient is not responding to standard therapy.
Tuberculosis: Tuberculosis was observed in clinical studies with abrocitinib. Patients should be screened for tuberculosis (TB) before starting CIBINQO therapy and consider yearly screening for patients in highly endemic areas for TB. CIBINQO should not be given to patients with active TB. For patients with a new diagnosis of latent TB or prior untreated latent TB, preventive therapy for latent TB should be started prior to initiation of CIBINQO.
Viral reactivation: Viral reactivation, including herpes virus reactivation (e.g., herpes zoster, herpes simplex), was reported in clinical studies (see Adverse Reactions). The rate of herpes zoster infections was higher in patients who were treated with 200 mg, 65 years of age and older, with a medical history of herpes zoster, with a confirmed ALC <1 × 103/mm3 prior to the event and patients with severe atopic dermatitis at baseline (see Adverse Reactions). If a patient develops herpes zoster, temporary interruption of treatment may be considered until the episode resolves.
Screening for viral hepatitis should be performed in accordance with clinical guidelines before starting therapy and during therapy with CIBINQO. Patients with evidence of active hepatitis B or hepatitis C (positive hepatitis C PCR) infection were excluded from clinical studies (see Pharmacology: Pharmacokinetics under Actions). Patients who were hepatitis B surface antigen negative, hepatitis B core antibody positive, and hepatitis B surface antibody positive had testing for hepatitis B virus (HBV) DNA. Patients who had HBV DNA above the lower limit of quantification (LLQ) were excluded. Patients who had HBV DNA negative or below LLQ could initiate treatment with CIBINQO; such patients had HBV DNA monitored. If HBV DNA is detected, a liver specialist should be consulted.
Vaccination: No data are available on the response to vaccination in patients receiving CIBINQO. Use of live, attenuated vaccines should be avoided during or immediately prior to treatment. Prior to initiating CIBINQO, it is recommended that patients be brought up to date with all immunizations, including prophylactic herpes zoster vaccinations, in agreement with current immunization guidelines.
Thrombotic events including pulmonary embolism: Events of deep venous thrombosis (DVT) and pulmonary embolism (PE) have been reported in patients receiving Janus kinase (JAK) inhibitors including abrocitinib (see Adverse Reactions). CIBINQO should be used with caution in patients at high risk for DVT/PE. Risk factors that should be considered in determining the patient's risk for DVT/PE include older age, obesity, a medical history of DVT/PE, prothrombotic disorder, use of combined hormonal contraceptives or hormone replacement therapy, patients undergoing major surgery, or prolonged immobilization. If clinical features of DVT/PE occur, CIBINQO treatment should be discontinued and patients should be evaluated promptly, followed by appropriate treatment.
Malignancy (including non-melanoma skin cancers): Malignancies, including non-melanoma skin cancer (NMSC), were observed in clinical studies with abrocitinib. Clinical data are insufficient to assess the potential relationship of exposure to abrocitinib and the development of malignancies. Long-term safety evaluations are ongoing.
The risks and benefits of CIBINQO treatment should be considered prior to initiating in patients with a known malignancy other than a successfully treated NMSC or cervical cancer in situ or when considering continuing CIBINQO therapy in patients who develop a malignancy. Periodic skin examination is recommended for patients who are at increased risk for skin cancer.
Hematologic abnormalities: Confirmed ALC <0.5 × 10³/mm³ and platelet count <50 × 10³/mm³ were observed in less than 0.5% of patients in clinical studies (see Adverse Reactions). Treatment with CIBINQO should not be initiated in patients with a platelet count <150 × 10³/mm³, an ALC <0.5 × 10³/mm³, an ANC <1 × 10³/mm³ or who have a hemoglobin value <8 g/dL (see Dosage & Administration). Complete blood count should be monitored 4 weeks after initiation of therapy with CIBINQO and thereafter according to routine patient management (see Table 7).
Lipids: In patients with a high burden of cardiovascular risk factors, including hyperlipidemia, the risks and benefits of abrocitinib compared to that of other available therapies for atopic dermatitis should be considered. Dose dependent increase in blood lipid parameters were reported in patients treated with CIBINQO (see Adverse Reactions). Lipid parameters should be assessed approximately 4 weeks following initiation of CIBINQO therapy and thereafter according to their risk for cardiovascular disease (see Table 7; The effect of these lipid parameter elevations on cardiovascular morbidity and mortality has not been determined. Patients with abnormal lipid parameters should be further monitored and managed according to clinical guidelines, due to the known cardiovascular risks associated with hyperlipidemia. If abrocitinib is chosen interventions to manage lipid concentrations should be implemented according to clinical guidelines.
Laboratory monitoring: (See Table 7.)

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Immunosuppressive conditions or medicinal products: Patients with immunodeficiency disorders or a first-degree relative with a hereditary immunodeficiency were excluded from clinical studies and no information on these patients is available.
Combination with biologic immunomodulators, potent immunosuppressants such as ciclosporin or other Janus kinase (JAK) inhibitors has not been studied. Their concomitant use with abrocitinib is not recommended as a risk of additive immunosuppression cannot be excluded.
Effects on Ability to Drive and Use Machines: CIBINQO has no or negligible sedating effect. However, patients who experience dizziness after the intake of abrocitinib should refrain from driving or using machines until the dizziness resolves.
Use in the Elderly: A total of 173 patients 65 years of age and older were enrolled in CIBINQO studies. The safety profile observed in elderly patients was similar to that of the adult population with the following exceptions: a higher proportion of patients 65 years of age and older discontinued from clinical studies and were more likely to have serious adverse events compared to younger patients; patients 65 years and older were more likely to develop low platelet and ALC values; the incidence rate of herpes zoster in patients 65 years of age and older was higher than that of younger patients (see Adverse Reactions). There are limited data in patients above 75 years of age.

Women of childbearing potential: Women of reproductive potential should be advised to use effective contraception during treatment and for 1 month following the final dose of CIBINQO. Consider pregnancy planning and prevention for females of reproductive potential.
Pregnancy: The limited human data on use of abrocitinib in pregnant women are not sufficient to evaluate a drug-associated risk for major birth defects or miscarriage. In embryo-fetal development studies, oral administration of abrocitinib to pregnant rats during organogenesis resulted in fetotoxicity at exposures equal to 17 times the unbound AUC at the maximum recommended human dose (MRHD) of 200 mg once daily. In embryo-fetal development studies, oral administration of abrocitinib to pregnant rabbits did not result in fetotoxicity at exposures equal to 4 times the unbound AUC at the MRHD of 200 mg. In a pre and postnatal development study in pregnant rats, abrocitinib oral administration during gestation and through lactation resulted in lower postnatal survival and lower offspring body weights at exposures greater than or equal to 11 times the unbound AUC at the MRHD of 200 mg once daily (see Pharmacology: Toxicology: Preclinical Safety Data: under Actions). Abrocitinib should not be used during pregnancy unless clearly necessary.
Breastfeeding: There are no data on the presence of abrocitinib in human milk, the effects on the breastfed infant, or the effects on milk production. Abrocitinib was secreted in milk of lactating rats. A risk to newborns/infants cannot be excluded and CIBINQO should not be used during breastfeeding.
Fertility: Based on the findings in rats, oral administration of CIBINQO may result in temporary reduced fertility in females of reproductive potential. These effects on female rat fertility were reversible 1 month after cessation of CIBINQO oral administration (see Pharmacology: Toxicology: Preclinical Safety Data: under Actions).

Summary of safety profile: The most commonly reported adverse reactions (ARs) occurring in ≥2% of patients treated with CIBINQO in placebo-controlled studies were nausea (15.1%), headache (7.9%), acne (4.8%), herpes simplex (4.2%), vomiting (3.5%), dizziness (3.4%), blood creatine phosphokinase increased (3.1%), and abdominal pain upper (2.2%). The most frequent serious adverse reactions in atopic dermatitis patients were infections (see Precautions).
Tabulated list of adverse reactions: A total of 3582 patients were treated with CIBINQO in clinical studies in atopic dermatitis; among them 2784 patients (representing 3006 patient-years of exposure) were integrated for safety analysis, 1451 patients with at least 48 weeks of exposure. The integrated safety analysis included 1761 patients receiving a constant dose of abrocitinib 200 mg and 1023 patients receiving 100 mg. Five placebo-controlled studies were integrated (703 patients on 100 mg once daily, 684 patients on 200 mg once daily and 438 patients on placebo) to evaluate the safety of CIBINQO in comparison to placebo for up to 16 weeks. (See Table 8.)

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Description of selected adverse reactions: Infections: In placebo-controlled studies, for up to 16 weeks, overall infections have been reported in 27.4% of patients treated with placebo and in 34.9% and 34.8% of patients treated with CIBINQO 100 mg and 200 mg, respectively. Most infections were mild or moderate.
The percentage of patients reporting infection related adverse reactions in the 200 mg and 100 mg groups compared to placebo were: herpes simplex (4.2% and 2.8% versus 1.4%), herpes zoster (1.2% and 0.6% versus 0%), pneumonia (0.1% and 0.1% versus 0%). Herpes simplex was more frequent in patients with a history of herpes simplex or eczema herpeticum. Most of the herpes zoster events involved a single dermatome and were non serious.
Among all patients treated with abrocitinib in the integrated safety analysis, including the long-term extension study, the incidence rate of herpes zoster in patients treated with abrocitinib 200 mg (4.83 per 100 patient-years) was higher than that of patients treated with 100 mg (2.39 per 100 patient-years). Incidence rates for herpes zoster were also higher for patients 65 years of age and older, patients with a medical history of herpes zoster, patients with severe atopic dermatitis at baseline, and a confirmed ALC <1.0 × 10³/mm³ prior to the event of herpes zoster.
In placebo-controlled studies, for up to 16 weeks, the rate of serious infections was 1.81 per 100 patient-years in patients treated with placebo, 3.32 per 100 patient-years in patients treated with 100 mg, and 1.12 per 100 patient-years in patients treated with 200 mg. Among all patients treated with Cibinqo in the integrated safety analysis, including the long term extension study, the rate of serious infections was 2.43 per 100 patient-years in the Cibinqo 100 mg group and 2.46 per 100 patient-years in the Cibinqo 200 mg group. The most commonly reported serious infections were herpes simplex, herpes zoster, and pneumonia (see Precautions).
Opportunistic infections: Most opportunistic infections were cases of multidermatomal cutaneous herpes zoster. Among all patients treated with CIBINQO in the integrated safety analysis, including the long-term extension study, the rate of opportunistic infections was (0.61 per 100 patient-years) in the CIBINQO 100 mg group and 1.23 per 100 patient-years) in the CIBINQO 200 mg. Most cases of opportunistic herpes zoster were mild or moderate.
Thrombotic events including pulmonary embolism: Among all patients treated with CIBINQO in the integrated safety analysis, including the long-term extension study, the rate of PE was 0.08 per 100 patient-years in the CIBINQO 100 mg group and 0.17 per 100 patient-years in the CIBINQO 200 mg group. The rate of DVT was 0 per 100 patient-years in the CIBINQO 100 mg group and 0.11 per 100 patient-years in the CIBINQO 200 mg group (see Precautions).
Thrombocytopenia: In placebo-controlled studies, for up to 16 weeks, treatment with CIBINQO was associated with a dose-related decrease in platelet count. Maximum effects on platelets were observed within 4 weeks, after which the platelet count returned towards baseline despite continued therapy. Confirmed platelet counts of <50 × 10³/mm³ were reported in 0.1% of patients exposed to CIBINQO 200 mg, 0 patients treated with CIBINQO 100 mg or placebo. Among all patients exposed to CIBINQO in the integrated safety analysis, including the long-term extension study, the rate of confirmed platelet counts of <50 × 10³/mm³ was 0.17 per 100 patient-years for 200 mg and 0 per 100 patient-years for 100 mg, most occurring at Week 4. Patients 65 years of age and older had a higher rate of platelet counts <75 × 10³/mm³ (see Precautions). There were no adolescent patients who developed platelet counts <75 × 10³/mm³.
Lymphopenia: In placebo-controlled studies, for up to 16 weeks, confirmed ALC <0.5 × 10³/mm³ occurred in 2 patients (0.3%) treated with CIBINQO 200 mg and 0 patients treated with CIBINQO 100 mg or placebo. Both cases occurred in the first 4 weeks of exposure. Among all patients exposed to CIBINQO in the integrated safety analysis, including the long term extension, the rate of confirmed ALC <0.5 × 10³/mm³ was 0.17 per 100 patient-years for 200 mg and 0 per 100 patient years for 100 mg, the highest rate was observed in patients 65 years of age and older (see Precautions). There were no adolescent patients who developed an ALC <0.5 × 10³/mm³.
Lipid elevations: In placebo controlled studies, for up to 16 weeks, there was a dose-related percent increase in low density lipoprotein cholesterol (LDL-c), total cholesterol, and high density lipoprotein cholesterol (HDL-c) relative to placebo at Week 4 which remained elevated through the final visit in the treatment period. The median % change in LDL-c at Week 4 was 9.1%, 4.9% and -2.8% in patients exposed to 200 mg, 100 mg and placebo, respectively. The median % change in HDL-c at Week 4 was 20.0%, 12.1%, and 0% in patients exposed to 200 mg, 100 mg and placebo, respectively. Events related to hyperlipidemia occurred in 0.4% of patients exposed to CIBINQO 100 mg, 0.6% of patients exposed to 200 mg, and 0% of patients exposed to placebo (see Precautions).
Creatine phosphokinase elevations (CPK): In placebo-controlled studies, for up to 16 weeks, events of blood CPK increased (>5 × ULN) were reported in 3.8% and 1.8% of patients treated with 200 mg and 100 mg of CIBINQO respectively. Most elevations were transient, and none led to discontinuation.
Nausea: Nausea was most frequent in the first week of CIBINQO therapy and generally resolved with continued therapy. The median duration of nausea was 15 days. Most of the cases were mild to moderate in severity.
Pediatric population: A total of 635 patients (12 to less than 18 years of age) were treated with abrocitinib in clinical studies in atopic dermatitis representing 851.5 patient-years of exposure. The safety profile observed in adolescents in atopic dermatitis clinical studies was similar to that of the adult population.

Potential for other medicines to affect pharmacokinetics of CIBINQO: Abrocitinib is metabolized predominantly by CYP2C19 and CYP2C9 enzymes and to a lesser extent by CYP3A4 and CYP2B6 enzymes, and its active metabolites are renally excreted and are substrates of the organic anion transporter 3 (OAT3). Therefore, exposures of abrocitinib and/or its active metabolites may be affected by medicinal products that strongly inhibit or induce CYP2C19 or CYP2C9 or inhibit the OAT3 transporter. Dose adjustments, as appropriate, based on these results are outlined in Dosage & Administration.
Coadministration with CYP2C19/CYP2C9 inhibitors: When CIBINQO 100 mg was administered concomitantly with fluvoxamine (a strong CYP2C19 and moderate CYP3A inhibitor) or fluconazole (a strong CYP2C19, moderate CYP2C9 and CYP3A inhibitor), the extent of exposure of abrocitinib active moiety increased by 91% and 155%, respectively, compared with administration alone.
Coadministration with CYP2C19/CYP2C9 inducers: Administration of CIBINQO 200 mg after multiple dosing with rifampin, a strong inducer of CYP enzymes, resulted in reduction of abrocitinib active moiety exposures by approximately 56%.
Coadministration with OAT3 inhibitors: When CIBINQO 200 mg was administered concomitantly with probenecid, an OAT3 inhibitor, abrocitinib active moiety exposures increased by approximately 66%. This is not clinically significant, and a dose adjustment is not needed.
Potential for CIBINQO to affect pharmacokinetics of other medicines: No clinically significant effects of CIBINQO were observed in drug interaction studies with oral contraceptives (e.g., ethinyl estradiol/levonorgestrel), or with substrates of BCRP and OAT3 (e.g., rosuvastatin), MATE1/2K (e.g., metformin) and CYP3A4 (e.g., midazolam). In vitro abrocitinib is an inhibitor of P-glycoprotein (P-gp). Coadministration of dabigatran etexilate (a P-gp substrate), with a single dose of CIBINQO 200 mg increased dabigatran AUC_inf and C_max by approximately 53% and 40%, respectively, compared with administration alone. Caution should be exercised for concomitant use of abrocitinib with dabigatran. The effect of abrocitinib on the pharmacokinetics of other P-gp substrates has not been evaluated. Caution should be exercised as the levels of P-gp substrates with a narrow therapeutic index, such as digoxin, may increase.

Incompatibilities: Not applicable.
Special Instructions for Use/Handling: Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Store below 30°C. Keep in Original Package.

Other Dermatologicals

D11AH08 - abrocitinib ; Belongs to the class of agents for atopic dermatitis, excluding corticosteroids. Used in the treatment of atopic dermatitis.

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