Cibinqo

Abrocitinib.

CIBINQO 50 mg film-coated tablets: Pink, oval tablet 10.50 mm long and 4.75 mm wide, debossed with "PFE" on one side and "ABR 50" on the other.
Each film-coated tablet contains 50 mg abrocitinib.
CIBINQO 100 mg film-coated tablets: Pink, round tablet 9.00 mm in diameter, debossed with "PFE" on one side and "ABR 100" on the other.
Each film-coated tablet contains 100 mg abrocitinib.
CIBINQO 200 mg film-coated tablets: Pink, oval tablet 18.42 mm long and 8.00 mm wide, debossed with "PFE" on one side and "ABR 200" on the other.
Each film-coated tablet contains 200 mg abrocitinib.
Excipient with known effect: Each CIBINQO 50 mg film-coated tablet contains 1.365 mg of lactose monohydrate.
Each CIBINQO 100 mg film-coated tablet contains 2.73 mg of lactose monohydrate.
Each CIBINQO 200 mg film-coated tablet contains 5.46 mg of lactose monohydrate.
Excipients/Inactive Ingredients: Tablet core: Microcrystalline cellulose, Dibasic calcium phosphate anhydrous, Sodium starch glycolate, Magnesium stearate.
Film-coat: Hypromellose (E464), Titanium dioxide (E171), Lactose monohydrate, Macrogol/PEG, 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 haematopoiesis 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 signalling 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 signalling pairs involving JAK1, and spares signalling 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: Clinical biomarkers: 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.
Blood counts: Mean ALC 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.
Cardiac electrophysiology: The effect of CIBINQO on the QTc interval was examined in subjects who received single doses of abrocitinib 600 mg in a placebo- and positive-controlled thorough QT study. In a concentration-QTc analysis, abrocitinib at therapeutic and supratherapeutic plasma concentrations did not lead to a prolongation of the QTc intervals.
Clinical efficacy and safety: The efficacy and safety of CIBINQO as monotherapy and in combination with background medicated topical therapies over 12 to 16 weeks were evaluated in 1,616 patients in 3 pivotal Phase 3 randomised, 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 subjects) was evaluated in 1,233 subjects in a Phase 3 induction, randomised 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 baseline visit prior to randomisation. 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 enrol into the long-term extension study EXTEND.
Baseline characteristics: In the placebo-controlled studies (MONO-1, MONO-2, COMPARE) and the open-label induction, randomised 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.
Clinical response: 12-week monotherapy (MONO-1, MONO-2) and 16-week TCS combination (COMPARE) studies: A significantly larger proportion of patients achieved both primary endpoints IGA 0 or 1 and/or EASI-75 with 100 mg or 200 mg once daily CIBINQO compared with placebo at Week 12 or Week 16 (see Table 1).
A significantly greater proportion of patients achieved at least a PP-NRS 4-point improvement with CIBINQO 100 mg or 200 mg once daily compared with placebo. This improvement was observed as early as Week 2 and persisting through Week 12 (see Figure 1).
In the COMPARE study, superiority of CIBINQO 200 mg compared with dupilumab at Week 2 was demonstrated for the proportion of patients achieving PP-NRS 4-point improvement with significantly higher itch responses seen as early as Day 4 after the first dose.
Treatment effects in subgroups (e.g., weight, age, sex, race and prior systemic immunosuppressant treatment) in MONO-1, MONO-2 and COMPARE were consistent with the results in the overall study population. (See Tables 1 and 2.)

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The proportion of patients who achieved PP-NRS4 over time in studies MONO-1, MONO-2 and COMPARE are shown in Figure 1. (See Figure 1.)

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Health-related outcomes: Both the 100 mg and 200 mg doses of CIBINQO, whether as monotherapy or combination therapy, led to a higher proportion of patients with reductions in DLQI than placebo at 12 weeks. Patients also had improved symptoms of atopic dermatitis, sleep disturbances, and anxiety and depression symptoms, from the patient's perspective, as measured by the Patient Oriented Eczema Measure (POEM) after 12 weeks, the sleep loss subscale of the SCORing Atopic Dermatitis (SCORAD) and the Hospital Anxiety and Depression Scale (HADS) scores.
Dose reduction: Open-label induction, randomised withdrawal study (REGIMEN): A total of 1,233 patients received open-label abrocitinib 200 mg once daily in the 12-week run-in phase. Among these patients, 798 patients (64.7%) met responder criteria (defined as achieving IGA [0 or 1] response and EASI-75) and were randomised to placebo (267 patients), abrocitinib 100 mg once daily (265 patients) or abrocitinib 200 mg once daily (266 patients).
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 (randomised 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 abrocitinib in combination with topical therapy. (See Table 3 and Figure 2.)

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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.
Long-term efficacy: Eligible patients who completed the full treatment period of a qualifying parent study (e.g., MONO-1, MONO-2, COMPARE, REGIMEN) were considered for enrollment in the long-term extension study EXTEND. In EXTEND, patients received CIBINQO with or without background medicated topical therapy. Patients who were previously randomised to CIBINQO 100 mg or 200 mg once daily in parent studies continued the same dose in EXTEND as in the parent study, and the blind was maintained.
Among patients who achieved response after 12 weeks of treatment 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].
Among patients who did not achieve response after 12 weeks of CIBINQO treatment and entered EXTEND, a proportion of patients achieved late-onset response by Week 24 (from baseline) of continued treatment with CIBINQO [22% and 27% for IGA (0 or 1) response, and 45% and 54% for EASI-75 with 100 mg once daily and 200 mg once daily, respectively].
Patients who received dupilumab in the COMPARE study and subsequently entered EXTEND were randomised to either 100 mg or 200 mg of CIBINQO once daily upon entering EXTEND. Among non-responders to dupilumab, 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].
Adolescent population: The efficacy and safety of CIBINQO as monotherapy was evaluated in 2 Phase 3 randomised, 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, randomised 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.
Efficacy results in adolescents in MONO-1 and MONO-2 are shown in Table 4. (See Table 4.)

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The efficacy and safety of CIBINQO in combination with background medicated topical therapy was evaluated in the Phase 3 randomised, 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 randomisation. 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%.
Efficacy results in TEEN are shown in Table 5. (See Table 5.)

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Pharmacokinetics: Absorption: Abrocitinib 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 are 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 abrocitinib increased dose proportionally from 30 to 400 mg. Co-administration of 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, CIBINQO was administered without regard to food (see Dosage & Administration).
Distribution: After intravenous administration, the volume of distribution of abrocitinib 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.
Biotransformation: The in vitro 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). At steady state, M2 (11%) and M4 (24%) are major metabolites and M1 (9.6%) is a minor metabolite. 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 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.
In vitro, abrocitinib or its metabolites were not significant inhibitors or inducers of CYP enzymes (CYP2C8, CYP2C9, and CYP2D6) 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 total body clearance of abrocitinib is 22 L/hr. The elimination half-life of abrocitinib is about 5 hours. Steady-state plasma concentrations of abrocitinib are achieved within 48 hours after once daily administration. Abrocitinib is eliminated primarily by metabolic clearance mechanisms, with less than 1% of the dose excreted in urine as unchanged drug. The urinary excretion of the metabolites of abrocitinib is 16%, 14% and 15% of the administered abrocitinib dose for M1, M2 and M4, respectively, and the metabolites are substrates of OAT3 transporter. As a percent of total clearance, the renal elimination for M1 is 74% and >90% for M2 and M4, while the faecal elimination of M1, M2, and M4 are 8%, 4%, and 2% respectively.
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 <18 years): Based on population pharmacokinetic analysis, there was no clinically significant difference in mean abrocitinib steady-state exposures in adolescent patients compared to adults at their typical body weights.
Paediatric: The pharmacokinetics of CIBINQO in paediatric patients under 12 years of age or body weight <25 kg 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). 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. 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 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, CIBINQO was not evaluated in patients with severe (Child Pugh C) hepatic impairment (see Contraindications), or in patients screened positive for active hepatitis B or hepatitis C (see Precautions).
Toxicology: Preclinical safety data: General toxicity: In toxicity studies of up to 1 month of CIBINQO dosing in rats initiated at 6-8 weeks and 9-weeks of age, a bone dystrophy finding was noted, at exposure of greater than or equal to 22 times the human AUC at the maximum recommended human dose (MRHD) of 200 mg. No bone findings were observed in rats at any dose in the 6-month toxicity study (up to 25 times the human AUC at the MRHD of 200 mg) or in any of the toxicity studies in cynomolgus monkeys (up to 30 times the human AUC at the MRHD of 200 mg).
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 26 weeks at exposures equal to 0.6 and 0.2 times the human AUC at the MRHD of 200 mg 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 2.7 times the 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 human AUC at the MRHD of 200 mg or in male rats at exposures equal to 13 times the 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 25 times the 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 28 times the human AUC at the MRHD of 200 mg and higher postimplantation loss at exposures greater than or equal to 10 times the 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 1.9 times the human AUC at the MRHD of 200 mg.
No foetal malformations were observed in embryo-foetal development studies in rats or rabbits. In an embryo-foetal development study in pregnant rabbits, oral administration of CIBINQO during Gestation Days 7 to 19 had no effects on embryo-foetal survival or foetal morphological development at exposures equal to 7.6 times the human AUC at the MRHD of 200 mg. CIBINQO resulted in increased incidence of unossified forelimb phalanges at exposures equal to 7.6 times the human AUC at the MRHD of 200 mg.
In an embryo-foetal development study in pregnant rats, oral administration of CIBINQO during Gestation Days 6 to 17 resulted in increased embryo-foetal lethality at exposures equal to 16 times the human AUC at the MRHD of 200 mg. No embryo-foetal lethality was observed in pregnant rats orally dosed with CIBINQO during organogenesis at exposures equal to 10 times the 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 10 times the human AUC at the MRHD of 200 mg and reduced ventral processes, thickened ribs, and unossified metatarsals were observed at exposures equal to 16 times the human AUC at the MRHD of 200 mg. No skeletal variations were noted in rats at exposures equal to 2.3 times the 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 10 times the human AUC at the MRHD of 200 mg and lower postnatal survival at exposures equal to 16 times the human AUC at the MRHD of 200 mg. No maternal or developmental toxicity was observed in either dams or offspring at exposures equal to 2.3 times the human AUC at the MRHD of 200 mg.
Administration of abrocitinib to juvenile rats beginning on Postnatal Day 21 and older (comparable to a 2-year-old human and older) was not associated with microscopic or macroscopic bone findings. Administration of abrocitinib to juvenile rats beginning on Postnatal Day 10 (comparable to a 3-month old human infant) resulted in adverse microscopic and macroscopic bone findings, including malrotated paws, fractures, and/or femoral head abnormalities.
Juvenile animal toxicity: In the juvenile rat study, oral administration of CIBINQO to rats initiated at Postnatal Day 10 resulted in bone findings (malrotated and/or impaired use of the forelimbs, hindlimbs, or paws, fractures and/or abnormalities of the femoral head, and bony dystrophy), at exposures ≥0.8 times the human AUC at the MRHD of 200 mg. Irreversible low femur length and width were observed at exposures 26 times the human AUC at the MRHD of 200 mg.

CIBINQO is indicated for the treatment of moderate-to-severe atopic dermatitis in adults and adolescents (age 12 years and above) who are candidates for systemic therapy and whose disease is not adequately controlled with topical medications or for whom topical treatments are otherwise medically inadvisable.

Treatment should be initiated and supervised by a healthcare professional experienced in the diagnosis and treatment of conditions for which CIBINQO is indicated (see Indications/Uses).
Posology: The recommended starting dose of CIBINQO is 100 mg or 200 mg once daily based on individual patient characteristics: A starting dose of 100 mg once daily is recommended for patients at higher risk of venous thromboembolism (VTE), major adverse cardiovascular event (MACE) and malignancy (see Precautions). If the patient does not respond adequately to 100 mg once daily, the dose can be increased to 200 mg once daily (see as follows).
A dose of 200 mg once daily may be appropriate for patients who are not at higher risk of VTE, MACE and malignancy or for patients with an inadequate response to 100 mg once daily. Upon disease control, dose should be decreased to 100 mg once daily. If disease control is not maintained after dose reduction, re-treatment with 200 mg once daily can be considered.
The lowest effective dose for maintenance should be used (see Pharmacology: Pharmacodynamics under Actions). Discontinuation of treatment should be considered in patients who show no evidence of therapeutic benefit after 24 weeks.
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 haemoglobin 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 (see Precautions).
Interruption of dosing may be needed for management of laboratory abnormalities as described in Table 6 (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.
Special dosage instructions: In patients receiving strong inhibitors of cytochrome P450 (CYP) 2C19 (e.g., fluvoxamine, fluconazole, fluoxetine and ticlopidine), the recommended dose of CIBINQO should be reduced by half to 100 mg or 50 mg once daily. The use of CIBINQO is not recommended concomitantly with moderate or strong inducers of CYP2C19/CYP2C9 enzymes (e.g., rifampin, apalutamide, efavirenz, enzalutamide, phenytoin) (see Interactions).
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 renal impairment (eGFR 30 to <60 mL/min), 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 renal impairment (eGFR <30 mL/min), the recommended starting dose of CIBINQO should be 50 mg once daily. The maximum daily dose is 100 mg. The dosing of CIBINQO in severe renal impairment patients is based on modelling and simulation which demonstrated comparability of active moiety exposures to patients with normal renal function administered doses of 100 mg and 200 mg once daily.
CIBINQO has not been studied in patients with end-stage renal disease (ESRD) on renal replacement therapy.
Hepatic impairment: No dose adjustment is required in patients with mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment (see Pharmacology: Pharmacokinetics under Actions). CIBINQO must not be used in patients with severe (Child Pugh C) hepatic impairment (see Contraindications).
Elderly population: The recommended starting dose for patients ≥65 years of age is 100 mg once daily (see Precautions). The risks and benefits of the recommended dose for patients ≥65 years of age should be considered (see Precautions). There are no conclusive data in patients 75 years of age and older.
Paediatric population: Use in paediatric patients under 12 years of age is not recommended.
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, taking CIBINQO with food may improve nausea.
CIBINQO tablets should be swallowed whole with water and should not be split, crushed, or chewed.

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.
Pharmacokinetics 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.

Hypersensitivity to the active substance or to any of the excipients listed in Description.
Active serious systemic infections, including tuberculosis (TB) (see Precautions).
Severe hepatic impairment (see Dosage & Administration).
Pregnancy and breast-feeding (see Use in Pregnancy & Lactation).

Infections/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).
Treatment must not be initiated in patients with an active, serious systemic infection (see Contraindications).
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 travelled 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. Discontinuation of CIBINQO should also be considered until the infection has resolved.
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 must not be given to patients with active TB (see Contraindications). 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 should be considered until the episode resolves.
Eczema herpeticum (disseminated viral infection mostly due to herpes simplex virus) was also reported in clinical studies with CIBINQO. The condition is characterised by rapid spread of vesicular and erosive lesions, fever and malaise in patients with atopic dermatitis and requires prompt treatment with antiviral agents. Discontinuation or interruption of CIBINQO therapy until the resolution of an eczema herpeticum infection should be considered, depending on the seriousness of the event.
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 immunisations, including prophylactic herpes zoster vaccinations, in agreement with current immunisation guidelines.
Mortality: In a large, randomised, active-controlled study of tofacitinib (another Janus kinase [JAK] inhibitor) in rheumatoid arthritis (RA) patients 50 years and older with at least one additional cardiovascular risk factor, a higher rate of all-cause mortality, including sudden cardiovascular death, was observed in patients treated with the tofacitinib compared with TNF inhibitors.
Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with CIBINQO.
Major adverse cardiovascular events (MACE): Events of MACE have been observed in patients taking abrocitinib.
In a large, randomised, active-controlled study of tofacitinib (another JAK inhibitor) in RA patients 50 years and older with at least one additional cardiovascular risk factor, a higher rate of major adverse cardiovascular events (MACE), defined as cardiovascular death, non-fatal myocardial infarction (MI) and non-fatal stroke, was observed with tofacitinib compared to TNF inhibitors.
Therefore, in patients 65 years of age and older, patients who are long-term current or long-term past smokers, and patients with a history of atherosclerotic cardiovascular disease or other cardiovascular risk factors, abrocitinib should be used with caution.
Venous thromboembolism (VTE): Events of deep venous thrombosis (DVT) and pulmonary embolism (PE) have been reported in patients receiving JAK inhibitors including abrocitinib (see Adverse Reactions).
In a large, randomised, active-controlled study of tofacitinib (another JAK inhibitor) in RA patients 50 years and older with at least one additional cardiovascular risk factor, a dose-dependent higher rate of VTE including DVT and PE was observed with tofacitinib compared to TNF inhibitors.
CIBINQO should be used with caution in patients at risk for DVT/PE. Risk factors that should be considered in determining the patient's risk for DVT/PE include age ≥65 years, long-term smoking, current malignancy (excluding non-melanoma skin cancer [NMSC]), a medical history of DVT/PE, prothrombotic disorder, use of combined hormonal contraceptives or hormone replacement therapy, patients undergoing major surgery, or prolonged immobilisation. Patients should be re-evaluated periodically during abrocitinib treatment to assess for changes in VTE risk.
Promptly evaluate patients with signs and symptoms of VTE and discontinue abrocitinib in patients with suspected VTE, regardless of dose.
Malignancy (excluding non-melanoma skin cancer [NMSC]): Lymphoma and other malignancies have been reported in patients receiving JAK inhibitors, including abrocitinib.
In a large, randomised, active-controlled study of tofacitinib (another JAK inhibitor) in RA patients 50 years and older with at least one additional cardiovascular risk factor, a higher rate of malignancies, particularly lung cancer, lymphoma and non-melanoma skin cancer (NMSC) was observed with tofacitinib compared to TNF inhibitors.
In patients 65 years of age and older, patients who are long-term current or long-term past smokers, or with other malignancy risk factors (e.g., current malignancy or history of malignancy), abrocitinib should be used with caution.
Non-melanoma skin cancer: NMSCs have been reported in patients receiving abrocitinib. Periodic skin examination is recommended for all patients, particularly those who are at increased risk for skin cancer.
Haematologic 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. 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 haemoglobin 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 6).
Lipids: 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 6). 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 hyperlipidaemia. If abrocitinib is chosen, interventions to manage lipid concentrations should be implemented according to clinical guidelines.
Laboratory monitoring: (See Table 6.)

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Excipients: Lactose: Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Sodium content: This medicinal product contains less than 1 mmol sodium (23 mg) per tablet. Patients on low sodium diets can be informed that this medicinal product is essentially 'sodium-free'.
Effects on ability to drive and use machines: No studies have been conducted on the effect of CIBINQO on driving ability or ability to operate machinery. CIBINQO has no or negligible sedating effect. Patients should be informed that dizziness has been reported during treatment with CIBINQO (see Adverse Reactions). 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 176 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 no conclusive data in patients above 75 years of age.
Use in patients 65 years of age and older: Considering the increased risk of MACE, malignancies, serious infections, and all-cause mortality in patients 65 years of age and older, as observed in a large, randomised study of tofacitinib (another JAK inhibitor), abrocitinib should be used with caution in these patients.

Pregnancy: There are no or limited amount of data on the use of CIBINQO in pregnant women. Studies in animals have shown reproductive toxicity (see Pharmacology: Toxicology: Preclinical safety data under Actions). CIBINQO is contraindicated during pregnancy (see Contraindications).
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. Pregnancy planning and prevention for females of reproductive potential is encouraged.
Breast-feeding: There are no data on the presence of abrocitinib in human milk, the effects on the breast-fed infant, or the effects on milk production. Abrocitinib was secreted in milk of lactating rats. A risk to newborns/infants cannot be excluded and CIBINQO is contraindicated during breast-feeding.
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 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 were infections (0.3%) (see Precautions).
Tabulated list of adverse reactions: A total of 3,802 patients were treated with CIBINQO in clinical studies in atopic dermatitis; among them 3,004 patients (representing 3,680 patient-years of exposure) were integrated for safety analysis, 1,549 patients with at least 48 weeks of exposure. The integrated safety analysis included 1,981 patients receiving a constant dose of abrocitinib 200 mg and 1,023 patients receiving a constant dose of 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.
Listed in Table 7 are adverse reactions observed in atopic dermatitis clinical studies presented by system organ class and frequency, using the following categories: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. (See Table 7.)

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Description of selected adverse reactions: Infections: In placebo-controlled studies, for up to 16 weeks, 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 drug reactions in the 200 mg and 100 mg groups compared to placebo were: herpes simplex (4.2% and 2.8% vs 1.4%), herpes zoster (1.2% and 0.6% vs 0%), pneumonia (0.1% and 0.1% vs 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 in clinical studies with consistent dosing regimens of either CIBINQO 100 mg or 200 mg, including the long-term extension study, the incidence rate of herpes zoster in patients treated with abrocitinib 200 mg (4.70 per 100 patient-years) was higher than that of patients treated with 100 mg (2.11 per 100 patient-years). Incidence rates of herpes zoster were also higher for patients 65 years of age and older (HR 3.83), patients with a medical history of herpes zoster (HR 3.53), patients with severe atopic dermatitis at baseline (HR 1.16), and a confirmed ALC <1.0 × 10³/mm³ prior to the event of herpes zoster (HR 2.04) (see Precautions).
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 CIBINQO 100 mg, and 1.12 per 100 patient-years in patients treated with CIBINQO 200 mg. Among all patients treated in clinical studies with consistent dosing regimens of either CIBINQO 100 mg or 200 mg, including the long-term extension study, the rate of serious infections was 2.20 per 100 patient-years in the CIBINQO 100 mg group and 2.69 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 non-serious cases of multidermatomal cutaneous herpes zoster. Among all patients treated in clinical studies with consistent dosing regimens of either CIBINQO 100 mg or 200 mg, including the long-term extension study, the rate of opportunistic infections was 0.58 per 100 patient-years in the CIBINQO 100 mg group and 1.17 per 100 patient-years in the CIBINQO 200 mg group. Most cases of opportunistic herpes zoster were mild or moderate.
Venous thromboembolism: Among all patients treated in clinical studies with consistent dosing regimen of either CIBINQO 100 mg or 200 mg, including the long-term extension study, the rate of PE was 0.13 per 100 patient-years in the CIBINQO 200 mg group and 0.06 per 100 patient-years in the CIBINQO 100 mg group. The rate of DVT was 0.09 per 100 patient-years in the CIBINQO 200 mg group and 0.13 per 100 patient-years in the CIBINQO 100 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, and 0 patients treated with CIBINQO 100 mg or placebo. Among all patients treated in clinical studies with consistent dosing regimens of either CIBINQO 100 mg or 200 mg, including the long-term extension study, the rate of confirmed platelet counts of <50 × 10³/mm³ was 0.22 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 0.3% of patients treated with CIBINQO 200 mg and 0% of patients treated with CIBINQO 100 mg or placebo. Both cases occurred in the first 4 weeks of exposure. Among all patients treated in clinical studies with consistent dosing regimens of either CIBINQO 100 mg or 200 mg, including the long-term extension, the rate of confirmed ALC <0.5 × 10³/mm³ was 0.40 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 hyperlipidaemia 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% of patients treated with 200 mg of CIBINQO, 1.8% of patients treated with 100 mg of CIBINQO and 1.8% of patients treated with placebo. Most elevations were transient, and none led to discontinuation.
Nausea: In placebo-controlled studies, for up to 16 weeks, nausea was reported in 1.8% of patients treated with placebo and in 6.3% and 15.1% of patients treated with 100 mg and 200 mg, respectively. Discontinuation due to nausea occurred in 0.4% of patients treated with CIBINQO. Among patients with nausea, 63.5% of patients had onset of nausea in the first week of CIBINQO therapy. The median duration of nausea was 15 days. Most of the cases were mild to moderate in severity.
Psychiatric disorders: Patients who showed suicidal ideation(s)/behaviour(s) in relevant preliminary investigations were excluded from the clinical trials.
Adolescent population: A total of 635 adolescents (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 (see Dosage & Administration).
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions.

Potential for other medicines to affect pharmacokinetics of CIBINQO: Abrocitinib is metabolised 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.
Co-administration 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 (see Pharmacology: Pharmacokinetics under Actions) increased by 91% and 155%, respectively, compared with administration alone (see Dosage & Administration).
Co-administration with CYP2C19/CYP2C9 inducers: Administration of CIBINQO 200 mg after multiple doses with rifampin, a strong inducer of CYP enzymes, resulted in reduction of abrocitinib active moiety exposures by approximately 56% (see Dosage & Administration). Based on the results of PBPK analysis, moderate induction of CYP enzymes reduces the exposure of abrocitinib active moiety by 44%.
Co-administration 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.
Co-administration with products which increase gastric pH: The effect of elevating gastric pH on abrocitinib active moiety exposures is not clinically significant and dose adjustment is not needed.
When abrocitinib 200 mg was administered concomitantly with famotidine 40 mg, a H2-receptor antagonist, the peak (C_max) and extent (AUC_inf) of abrocitinib active moiety exposures decreased by approximately 82% and 20% respectively. The effect of elevating gastric pH with antacids, or proton pump inhibitors (omeprazole) on the pharmacokinetics of abrocitinib has not been studied and may reduce the absorption of abrocitinib in a manner similar to that seen with famotidine.
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 oestradiol/levonorgestrel), or with substrates of BCRP and OAT3 (e.g., rosuvastatin), MATE1/2K (e.g., metformin), CYP3A4 (e.g., midazolam), CYP1A2 (e.g., caffeine) and CYP2B6 (e.g., efavirenz). In vitro, abrocitinib is an inhibitor of P-glycoprotein (P-gp). Co-administration 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 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.
In vitro, abrocitinib is an inhibitor of CYP2C19 enzyme. Co-administration of abrocitinib 200 mg once daily with omeprazole 10 mg single dose increased the AUC_inf and C_max of omeprazole by approximately 189% and 134%, respectively, indicating that abrocitinib is a moderate inhibitor of CYP2C19 enzyme. Caution should be exercised when using abrocitinib concomitantly with narrow therapeutic index medicines that are primarily metabolized by CYP2C19 enzyme (e.g., S-mephenytoin, clopidogrel).

Incompatibilities: Not applicable.
Special precautions for disposal and other handling: Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

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.

POM