Cibinqo

Abrocitinib.

Abrocitinib (Cibinqo) 100 mg film-coated tablets: Each film-coated tablet contains 100 mg abrocitinib.
Abrocitinib (Cibinqo) 200 mg film-coated tablets: Each film-coated tablet contains 200 mg abrocitinib.
Excipients/Inactive Ingredients: Excipients with known effects: Each Abrocitinib (Cibinqo) 100 mg film-coated tablet contains 2.73 mg of lactose monohydrate.
Each Abrocitinib (Cibinqo) 200 mg film-coated tablet contains 5.46 mg of lactose monohydrate.

Pharmacologic Category: Agent for Dermatitis (Janus Kinase Inhibitor).
Pharmacology: Pharmacodynamics: Mechanism of action: Abrocitinib (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. Within signaling pathways, JAKs phosphorylate and activate Signal Transducers and Activators of Transcription (STATs) which modulate intracellular activity including gene expression. Abrocitinib (Cibinqo) modulates the signaling pathway at the point of JAK1, preventing the phosphorylation and activation of STATs.
Abrocitinib (Cibinqo) reversibly and selectively inhibits JAK1 by blocking the adenosine triphosphate (ATP) binding site. In a cell-free isolated enzyme assay, Abrocitinib (Cibinqo) has biochemical selectivity for JAK1 over the other 3 JAK isoforms JAK2 (28-fold), JAK3 (>340-fold) and tyrosine kinase (TYK) 2 (43-fold), and even higher selectivity over the broader kinome. In cellular settings, where JAK enzymes transmit signals in pairs (i.e., JAK1/JAK2, JAK1/JAK3, JAK1/TYK2, JAK2/JAK2, JAK2/TYK2), Abrocitinib (Cibinqo) preferentially inhibits cytokine induced STAT phosphorylation mediated by receptors utilizing JAK1 relative to receptors utilizing JAK2 only or JAK2/TYK2 pairs. The relevance of inhibition of specific JAK enzymes to therapeutic effectiveness is not currently known. Both the parent compound and the active metabolites inhibit cytokine signaling with similar levels of selectivity.
Pharmacodynamic effects: Treatment with Abrocitinib (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.
Clinical efficacy and safety: The efficacy and safety of Abrocitinib (Cibinqo) as monotherapy and in combination with background medicated topical therapies were evaluated in 3 pivotal randomized, double-blind, placebo controlled studies (MONO-1, MONO 2, and COMPARE) in 1616 patients 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 in these studies were those who had inadequate response to previous topical medication, or were patients for whom topical treatments were medically inadvisable, or who had received systemic therapies including dupilumab. In each of the pivotal studies, over 40% of patients had prior exposure to systemic therapy. In MONO-1 and MONO-2, 6% of the patients had received dupilumab, whereas prior use of dupilumab was not allowed in COMPARE.
Eligible patients from qualifying parent studies were able to enroll in the long-term extension study EXTEND, e.g., if they completed the full treatment period of the any of the pivotal qualifying parent studies.
MONO-1, MONO-2, and COMPARE assessed the co-primary endpoints of IGA and EASI- 75 responses at Week 12. Key secondary endpoints in MONO-1 and MONO-2 included improvement of ≥4 points in the severity of PP-NRS (PP-NRS4) at Week 12 and change from baseline to Week 12 for the Pruritus and Symptoms Assessment for Atopic Dermatitis (PSAAD). The PSAAD is an 11-item, self-reported instrument using a 24-hour recall period, designed to assess the severity of key symptoms and signs of atopic dermatitis including itching, pain, dryness, flaking, cracking, bumps, redness, discoloration, bleeding, fluid, and swelling. Key secondary endpoints in COMPARE were PP-NRS4 at Week 2 in addition to IGA response and EASI-75 at Week 16. The designs of the pivotal and long-term extension studies are summarized in Table 1. (See Table 1.)

Click on icon to see table/diagram/image

Clinical response: Treatment with Abrocitinib (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.
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 Abrocitinib (Cibinqo) 100 mg or 200 mg once daily compared with placebo at Week 12 (see Table 2).
A significantly higher proportion of patients who achieved PP-NRS4 (defined as an improvement of ≥4 points in the severity of PP-NRS) with Abrocitinib (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 Abrocitinib (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 2).

Click on icon to see table/diagram/image

The proportion of patients who achieved EASI-90 or PP-NRS4 over time in studies MONO-1 and MONO-2 are shown in Figures 1 and 2. (See Figures 1 and 2.)

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

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 Abrocitinib (Cibinqo) 100 mg or 200 mg once daily compared with placebo at Week 12 (see Table 3).
The proportions of patients achieving PP-NRS4 with Abrocitinib (Cibinqo) 100 mg and 200 mg once daily were significantly higher than placebo by Day 9 and Day 4, respectively, and remained significantly higher than placebo with both Abrocitinib (Cibinqo) doses at Week 2 and Week 16.
The proportion of patients achieving PP-NRS4 with Abrocitinib (Cibinqo) 200 mg once daily was significantly higher than dupilumab as early as Day 4 and remained significantly higher than dupilumab at Week 2. The proportion of patients achieving PP-NRS4 was similar between abrocitinib (Cibinqo) 100 mg once daily and dupilumab at Week 2.

Click on icon to see table/diagram/image

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

Click on icon to see table/diagram/image

Patients who received dupilumab and subsequently enrolled in EXTEND were randomized to either Abrocitinib (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 Abrocitinib (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 Abrocitinib (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 Abrocitinib (Cibinqo) treatment for at least 92 weeks or until availability of commercial product in their country. In EXTEND, patients received Abrocitinib (Cibinqo) with or without background medicated topical therapy. Patients who were previously randomized to Abrocitinib (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 Abrocitinib (Cibinqo) in a qualifying parent study were randomized to either Abrocitinib (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 Abrocitinib (Cibinqo) treatment and entered EXTEND, 14% and 22% of patients continuing Abrocitinib (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 Abrocitinib (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 Abrocitinib (Cibinqo) treatment and entered EXTEND, 32% and 45% of patients continuing Abrocitinib (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 Abrocitinib (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 Abrocitinib (Cibinqo) treatment for both doses of Abrocitinib (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 Abrocitinib (Cibinqo) as monotherapy resulted in significantly improved patient-reported outcomes at 12 weeks compared with placebo (see Table 4). A significantly larger proportion of the Abrocitinib (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. Abrocitinib (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 Abrocitinib (Cibinqo) groups compared with placebo at 12 weeks.

Click on icon to see table/diagram/image

In COMPARE, a significantly larger proportion of the Abrocitinib (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 5). Abrocitinib (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 Abrocitinib (Cibinqo) groups compared with placebo at 12 weeks.

Click on icon to see table/diagram/image

Pharmacokinetics: The pharmacokinetic profile of abrocitinib is characterized by rapid absorption (peak plasma concentrations are reached within 1 hour), and an elimination half-life of about 5 hours. Steady state plasma concentrations of abrocitinib are achieved within 48 hours after once daily administration.
Absorption: Effect of Food: Abrocitinib is well-absorbed with over 91% extent of oral absorption and absolute oral bioavailability of approximately 60%. Both C_max and AUC of Abrocitinib increased dose proportionally up to 400 mg. Coadministration of Abrocitinib (Cibinqo) with a high-fat meal had no clinically relevant effect on abrocitinib exposures (AUC and C_max increased by approximately 26% and 29%, respectively, and T_max was prolonged by 2 hours). In clinical studies, Abrocitinib (Cibinqo) was administered without regard to food (see Dosage & Administration).
Distribution: After intravenous administration, the volume of distribution of Abrocitinib (Cibinqo) is 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 abrocitinib, while M4 was pharmacologically inactive. The pharmacologic activity of Abrocitinib (Cibinqo) 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 abrocitinib, M1 and M2, each expressed in molar units and adjusted for relative potencies, is referred to as the abrocitinib active moiety.
Elimination: Abrocitinib (Cibinqo) is eliminated primarily by metabolic clearance mechanisms, with less than 1% of the dose excreted in urine as unchanged drug. The metabolites of abrocitinib, 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 (Cibinqo) exposure (see Dosage & Administration).
Adolescents (12 to less than 18 years of age): Based on population pharmacokinetic analysis, mean Abrocitinib (Cibinqo) steady-state exposure in adolescent patients is estimated to be approximately 30% lower compared to adults of the same weight, with similar range of exposures in adult and adolescent patients. These differences in mean exposures were not considered clinically significant.
Pediatric (under 12 years of age): The pharmacokinetics of Abrocitinib (Cibinqo) 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 Dosage & Administration). Based on these results, a clinically significant increase in abrocitinib 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.
Abrocitinib (Cibinqo) has not been studied in patients with ESRD on renal replacement therapy (see Dosage & Administration). In Phase 3 clinical studies, Abrocitinib (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 AUC_inf, 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, Abrocitinib (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: Abrocitinib (Cibinqo) is not mutagenic in the bacterial mutagenicity assay (Ames assay). Although Abrocitinib (Cibinqo) is aneugenic in the in vitro TK6 micronucleus assay, Abrocitinib (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 Tg.rasH2 mice administered Abrocitinib (Cibinqo) for 26 weeks at oral doses up to 75 mg/kg/day and 60 mg/kg/day in female and male mice, respectively. In the 104-week oral carcinogenicity study, Abrocitinib (Cibinqo) resulted in 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 Abrocitinib (Cibinqo) related tumorigenicity was observed following oral Abrocitinib (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: Abrocitinib (Cibinqo) had no effects on 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. Abrocitinib (Cibinqo) resulted in effects on 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 postimplantation loss in rats at exposures greater than or equal to 11 times the unbound human AUC at the MRHD of 200 mg. The effects on female fertility in rats reversed 1 month after cessation of Abrocitinib (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 Abrocitinib (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. Abrocitinib (Cibinqo) resulted in an increase 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 Abrocitinib (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 Abrocitinib (Cibinqo) during organogenesis at exposures equal to 11 times the unbound human AUC at the MRHD of 200 mg. Abrocitinib (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 rat pre- and postnatal development study in pregnant rats, oral administration of Abrocitinib (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.

Abrocitinib (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. Abrocitinib (Cibinqo) can be used with or without medicated topical therapies for atopic dermatitis.

Posology: The recommended dose of Abrocitinib (Cibinqo) is 100 mg or 200 mg once daily, based on individual goal of therapy and potential risk for adverse reactions.
Abrocitinib (Cibinqo) can be used with or without medicated topical therapies for atopic dermatitis.
Abrocitinib (Cibinqo) should be taken orally once daily with or without food at approximately the same time each day.
Treatment with Abrocitinib (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).
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.
Dose interruption: If a patient develops a serious infection, sepsis or opportunistic infection, consider interruption of Abrocitinib (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).
Drug-drug interactions: When indicated dose is 100 mg or 200 mg Abrocitinib (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 Abrocitinib (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) or severe (eGFR <30 mL/min) renal impairment, the recommended dose of Abrocitinib (Cibinqo) is to be reduced by 50% as shown in Table 6 (see Pharmacology: Pharmacokinetics under Actions). The use of Abrocitinib (Cibinqo) has not been studied in patients with end-stage renal disease (ESRD) on renal replacement therapy. (See Table 6.)

Click on icon to see table/diagram/image

Hepatic impairment: No dose adjustment is required in patients with mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment. Abrocitinib (Cibinqo) has not been studied in patients with severe (Child Pugh C) hepatic impairment (see Pharmacology: Pharmacokinetics under Actions).
Elderly population: No dose adjustment is recommended for patients ≥65 years of age.
Pediatric population: The safety and efficacy of Abrocitinib (Cibinqo) in pediatric patients under 12 years of age have not yet been established. No data are available.
Method of administration: Abrocitinib (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 Abrocitinib (Cibinqo), taking with food may improve nausea.
Swallow Abrocitinib (Cibinqo) tablets whole and intact with water. Do not crush, split, or chew Abrocitinib (Cibinqo) tablets.

Abrocitinib (Cibinqo) was administered in clinical studies up to a single oral dose of 800 mg. There is no experience with overdose of Abrocitinib (Cibinqo). There is no specific antidote for overdose with Abrocitinib (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 Abrocitinib (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 Abrocitinib (Cibinqo) should be carefully considered prior to initiating in patients with active, chronic, or recurrent infections.
Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with Abrocitinib (Cibinqo). A patient who develops a new infection during treatment with Abrocitinib (Cibinqo) should undergo prompt and complete diagnostic testing and appropriate antimicrobial therapy should be initiated. The patient should be closely monitored and Abrocitinib (Cibinqo) therapy should be interrupted if the patient is not responding to standard therapy.
Tuberculosis: Patients should be screened for tuberculosis (TB) before starting Abrocitinib (Cibinqo) therapy and consider yearly screening for patients in highly endemic areas for TB. Abrocitinib (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 Abrocitinib (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 65 years of age and older (see Adverse Reactions).
Screening for viral hepatitis should be performed in accordance with clinical guidelines before starting therapy and during therapy with Abrocitinib (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 Abrocitinib (Cibinqo); such patients had HBV DNA monitored. If HBV DNA is detected, a liver specialist should be consulted.
Vaccination: Avoid use of live, attenuated vaccines during or immediately prior to Abrocitinib (Cibinqo) therapy. Prior to initiating Abrocitinib (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.
Venous thromboembolism: Events of deep venous thrombosis (DVT) and pulmonary embolism (PE) have been reported in patients receiving Janus kinase (JAK) inhibitors including Abrocitinib (Cibinqo) (see Adverse Reactions). Abrocitinib (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, Abrocitinib (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 (Cibinqo). Clinical data are insufficient to assess the potential relationship of exposure to Abrocitinib (Cibinqo) and the development of malignancies. Long-term safety evaluations are ongoing.
The risks and benefits of Abrocitinib (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 Abrocitinib (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 Abrocitinib (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). Platelet count and ALC should be monitored 4 weeks after initiation of therapy with Abrocitinib (Cibinqo) and thereafter according to routine patient management.
Lipids: Dose dependent increase in blood lipid parameters were reported in patients treated with Abrocitinib (Cibinqo) (see Adverse Reactions). Lipid parameters should be assessed approximately 4 weeks following initiation of Abrocitinib (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.
Laboratory monitoring: See Table 7.

Click on icon to see table/diagram/image

Effects on Ability to Drive and Use Machines: Abrocitinib (Cibinqo) has no or negligible influence on the ability to drive and use machines.

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 Abrocitinib (Cibinqo). Consider pregnancy planning and prevention for females of reproductive potential.
Pregnancy: The limited human data on use of Abrocitinib (Cibinqo) 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 (Cibinqo) 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 (Cibinqo) 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 (Cibinqo) 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 (Cibinqo) should not be used during pregnancy unless clearly necessary.
Breastfeeding: There are no data on the presence of Abrocitinib (Cibinqo) in human milk, the effects on the breastfed infant, or the effects on milk production. Abrocitinib (Cibinqo) was secreted in milk of lactating rats. A risk to newborns/infants cannot be excluded and Abrocitinib (Cibinqo) should not be used during breastfeeding.
Fertility: Based on the findings in rats, oral administration of Abrocitinib (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 Abrocitinib (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 Abrocitinib (Cibinqo) in placebo-controlled studies were nausea (10.3%), headache (6.8%), herpes simplex (3.8%), acne (3.2%), blood creatine phosphokinase increased (2.6%), dizziness (2.3%), and vomiting (2.3%). The most frequent serious adverse reactions in atopic dermatitis patients were infections (see Precautions).
Tabulated list of adverse reactions: A total of 2856 patients were treated with Abrocitinib (Cibinqo) in clinical studies in atopic dermatitis representing 1614 patient-years of exposure. There were 606 patients with more than 1 year of exposure to Abrocitinib (Cibinqo). Four placebo- controlled studies were integrated (608 patients on 100 mg once daily, 590 patients on 200 mg once daily and 342 patients on placebo) to evaluate the safety of Abrocitinib (Cibinqo) in comparison to placebo for up to 16 weeks. (See Table 8.)

Click on icon to see table/diagram/image

Description of selected adverse reactions: Overall infections: In placebo-controlled studies, for up to 16 weeks, overall infections have been reported in 26.3% of patients treated with placebo and in 35.2% and 34.6% of patients treated with Abrocitinib (Cibinqo) 100 mg and 200 mg, respectively. Most infections were mild or moderate.
Serious infections: In placebo-controlled studies, for up to 16 weeks, serious infections have been reported in 2 patients (2.31 per 100 patient-years) treated with placebo, 6 patients (3.80 per 100 patient-years) treated with Abrocitinib (Cibinqo) 100 mg, and 2 patients (1.28 per 100 patient years) treated with Abrocitinib (Cibinqo) 200 mg. Among all patients treated with Abrocitinib (Cibinqo), including the long term extension study, serious infections were reported in 17 patients (2.65 per 100 patient- years) treated with Abrocitinib (Cibinqo) 100 mg and 24 patients (2.33 per 100 patient- years) treated with Abrocitinib (Cibinqo) 200 mg. The most commonly reported serious infections were herpes simplex, herpes zoster, and pneumonia (see Precautions).
Opportunistic infections: All observed opportunistic infections were cases of multidermatomal cutaneous herpes zoster. Among all patients treated with Abrocitinib (Cibinqo), including the long-term extension study, opportunistic infections were reported in 3 patients (0.47 per 100 patient-years) treated with Abrocitinib (Cibinqo) 100 mg and 10 patients (0.97 per 100 patient-years) treated with Abrocitinib (Cibinqo) 200 mg. Most cases of opportunistic herpes zoster were mild or moderate.
Venous thromboembolism: Among all patients treated with Abrocitinib (Cibinqo), including the long term extension study, PE was reported in 3 patients (0.18 per 100 patient-years), all treated with Abrocitinib (Cibinqo) 200 mg. Events of DVT were reported in 2 patients (0.09 per 100 patient-years) treated with Abrocitinib (Cibinqo) 200 mg (see Precautions).
Thrombocytopenia: In placebo-controlled studies, for up to 16 weeks, treatment with Abrocitinib (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 1 patient (0.1%) exposed to Abrocitinib (Cibinqo) 200 mg, 0 patients treated with Abrocitinib (Cibinqo) 100 mg or placebo. Among all patients exposed to Abrocitinib (Cibinqo), including the long term extension study, confirmed platelet counts of <50 × 103/mm3 were reported in 2 patients (0.1%), both treated with Abrocitinib (Cibinqo) 200 mg (see Precautions).
Lymphopenia: In placebo-controlled studies, for up to 16 weeks, confirmed ALC <0.5 × 10³/mm³ occurred in 2 patients (0.3%) treated with Abrocitinib (Cibinqo) 200 mg and 0 patients treated with Abrocitinib (Cibinqo) 100 mg or placebo. Both cases occurred in the first 4 weeks of exposure. Among all patients exposed to Abrocitinib (Cibinqo), including the long term extension, confirmed ALC <0.5 × 10³/mm³ were reported in 4 patients (0.1%) treated with 200 mg of Abrocitinib (Cibinqo) and 0 patients treated with Abrocitinib (Cibinqo) 100 mg (see Precautions).
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. There was no change in the LDL/HDL ratio or triglycerides. Events related to hyperlipidemia occurred in 1 patient (0.2%) exposed to Abrocitinib (Cibinqo) 100 mg, 7 patients (1.2%) exposed to Abrocitinib (Cibinqo) 200 mg and 0 patients exposed to placebo (see Precautions).
Creatine phosphokinase elevations (CPK): In placebo-controlled studies, for up to 16 weeks, events of blood CPK increased were reported in 1.5% of patients treated with placebo, 2.3% and 2.9% of patients treated with 100 mg and 200 mg of Abrocitinib (Cibinqo), respectively. Most elevations were transient, and none led to discontinuation. In the clinical studies, there were no reported events of rhabdomyolysis.
Nausea: Nausea was most frequent in the first week of Abrocitinib (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: The pharmacokinetics, safety and efficacy of Abrocitinib (Cibinqo) in pediatric patients under 12 years of age have not yet been established.
Of the 2856 patients with atopic dermatitis exposed to Abrocitinib (Cibinqo), a total of 364 adolescents (12 to less than 18 years of age) were enrolled in Abrocitinib (Cibinqo) studies. The safety profile observed in adolescents in atopic dermatitis clinical studies was similar to that of the adult population. There were no adolescent patients who developed platelet counts <75 × 10³/mm³ or absolute lymphocyte count <0.5× 10³/mm³.
Elderly population: A total of 145 patients 65 years of age and older were enrolled in Abrocitinib (Cibinqo) studies. The safety profile observed in elderly patients was similar to that of the adult population overall. A higher proportion of patients 65 years of age and older discontinued from clinical studies compared to younger patients. Among all patients exposed to Abrocitinib (Cibinqo) including the long-term extension study, confirmed ALC <0.5 × 10³/mm³ occurred only in patients 65 years of age and older. A higher proportion of patients 65 years of age and older had platelet counts <75 × 10³/mm³. The incidence rate of herpes zoster in patients 65 years of age and older treated with Abrocitinib (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) and less than 18 years of age (2.12 per 100 patient years). There is limited data in patients above 75 years of age.

Potential for other medicines to affect pharmacokinetics of Abrocitinib (Cibinqo): Abrocitinib is metabolized predominantly by CYP2C19 and CYP2C9 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 Abrocitinib (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 Abrocitinib (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 Abrocitinib (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 abrocitinib (Cibinqo) to affect pharmacokinetics of other medicines: In vitro, abrocitinib or its metabolites were not significant inhibitors or inducers of CYPs (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) or of uridine diphosphate-glucuronyltransferases (UGTs) (UGT1A1, UGT1A4, UGT1A6, UGT1A9, and UGT2B7). In vitro, abrocitinib is an inhibitor of P-glycoprotein (P-gp), 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) but is not an inhibitor of organic anion transporting polypeptide (OATP)1B1/1B3, bile salt export pump (BSEP), OAT1 or OCT2 at clinically meaningful concentrations. The metabolites do not change the transporter inhibition risk compared to abrocitinib.
No clinically significant effects of Abrocitinib (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). Coadministration of dabigatran etexilate (a P-gp substrate), with a single dose of Abrocitinib (Cibinqo) 200 mg increased dabigatran AUC_inf and C_max by approximately 53% and 40%, respectively, compared with administration alone.

Incompatibilities: Not applicable.

Store at temperatures not exceeding 30°C.

Other Dermatologicals

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

Rx