Sibinquo film-coated tablets 100 mg blister No. 28

Instructions for use: Sibinquo film-coated tablets 100 mg blister No. 28

Composition

active ingredient: abrocitinib;

1 film-coated tablet contains 50 mg or 100 mg or 200 mg of abrocitinib.

excipients: microcrystalline cellulose, calcium phosphate dibasic anhydrous, sodium starch glycolate, magnesium stearate; film coating Opadry® II Pink (33G150000): hypromellose, titanium dioxide; lactose monohydrate; macrogol, triacetin, iron oxide red.

Dosage form

Film-coated tablets.

Main physicochemical properties:

50 mg tablets - oval pink film-coated tablets, approximately 11 mm long and 5 mm wide, embossed with “ABR 50” on one side and “PFE” on the other side;

100 mg tablets - round pink film-coated tablets, approximately 9 mm in diameter, embossed with “ABR 100” on one side and “PFE” on the other side;

200 mg tablets are oval pink film-coated tablets, approximately 18 mm long and 8 mm wide, embossed with “ABR 200” on one side and “PFE” on the other side.

Pharmacotherapeutic group

Other dermatological preparations, anti-dermatitis preparations, except corticosteroids. ATX code D11AN08.

Pharmacological properties

Mechanism of action

Abrocitinib is a Janus kinase 1 inhibitor. Janus kinases are intracellular enzymes that transduce signals generated by cytokine or growth factor receptor interactions and the cell membrane to influence cellular processes of hematopoiesis and the function of cells of the immune system. Janus kinases phosphorylate and activate signal transducers and activators of transcription, which modulate intracellular activity, including gene expression. Inhibition of Janus kinase 1 modulates signaling pathways by preventing phosphorylation and activation of signal transducers and activators of transcription. In biochemical assays, abrocitinib demonstrates selectivity for Janus kinase 1 (JAK1) compared to the other three JAK isoforms: JAK2 (28-fold), JAK3 (> 340-fold), and tyrosine kinase 2 (TYK2, 43-fold). In the cellular context, it preferentially inhibits cytokine-induced phosphorylation of signal transducers and activators of transcription by signaling pairs containing JAK1, and does not interfere with signaling by JAK2/JAK2 or JAK2/TYK2 pairs. The significance of selective enzymatic inhibition of specific JAK enzymes on the therapeutic efficacy of the drug is currently unknown.

Pharmacodynamic action

Clinical biomarkers

Treatment with abrocitinib was associated with dose-dependent reductions in serum biomarkers of inflammation in atopic dermatitis (interleukin-31 (IL-31), interleukin-22 (IL-22), eosinophil count, thymus-activated and -regulated chemokine (TARC)), inhibition of JAK1 signaling pathways (decreased natural killer cells and interferon gamma-induced protein 10 (IP-10)), or both (high-sensitivity C-reactive protein). These changes were reversible after discontinuation of therapy. The mean absolute lymphocyte count increased at 2 weeks after initiation of abrocitinib therapy and returned to baseline by month 9 of therapy. In most patients, absolute lymphocyte counts remained within the normal range. Treatment with abrocitinib was associated with a dose-dependent increase in B-lymphocyte counts and a dose-dependent decrease in natural killer cells. The clinical significance of these changes in B-lymphocyte and natural killer cell counts is unknown.

Cardioelectrophysiology

The effect of abrocitinib on the adjusted QTc interval was studied in subjects receiving a single supratherapeutic dose of 600 mg abrocitinib in a placebo- and active-controlled study with a focus on QT interval assessment. A concentration-dependent prolongation of the QTc interval by abrocitinib was observed; the mean (90% confidence interval) increase in QTc interval was 6.0 (4.52, 7.49) ms, indicating no clinically meaningful effect of abrocitinib on the QTc interval at the dose studied.

The efficacy and safety of abrocitinib as monotherapy and in combination with background topical medication for 12–16 weeks were evaluated in 1,616 patients in 3 pivotal, randomized, double-blind, placebo-controlled phase 3 studies (MONO-1, MONO 2, and COMPARE). In addition, the efficacy and safety of abrocitinib as monotherapy for 52 weeks (with the option of rescue therapy for patients with flare-ups) were evaluated in 1,233 patients in a double-blind, placebo-controlled phase 3 induction therapy study with randomised withdrawal (REGIMEN). The 4 studies enrolled patients 12 years of age and older with moderate to severe atopic dermatitis, defined as ≥ 3 on the Investigator's Global Assessment (IGA), ≥ 16 on the Eczema Area and Severity Index (EASI), ≥ 10% body surface area involvement, and ≥ 4 on the Maximum Pruritus Numeric Rating Scale (PP-NRS) at baseline prior to randomization. Patients who had not responded adequately to prior therapy, or for whom topical therapy was medically inappropriate, or who were receiving systemic therapy were eligible to participate in these studies. All patients who completed the study end-of-study were eligible to participate in the long-term extension study, EXTEND.

Baseline characteristics

In the placebo-controlled trials (MONO-1, MONO-2, COMPARE) and the open-label induction trial with randomised withdrawal (REGIMEN), across all treatment groups, 41.4% to 51.1% of participants were female, 59.3% to 77.8% were Caucasian, 15.0% to 33.0% were Asian, and 4.1% to 8.3% were Black; the mean age of participants ranged from 32.1 to 37.7 years. A total of 134 patients aged 65 years and older were enrolled in these trials. In these trials, 32.2% to 40.8% of participants had an IGA score of 4 (severe atopic dermatitis) at baseline, and 41.4% to 59.5% of patients had received prior systemic therapy for atopic dermatitis. The baseline mean EASI score ranged from 28.5 to 30.9, the baseline PP-NRS score ranged from 7.0 to 7.3, and the baseline Disease-related Life Quality Index (DLQI) ranged from 14.4 to 16.0.

Clinical response

A 12-week monotherapy study (MONO-1, MONO-2) and a 16-week combination therapy study (COMPARE).

A statistically significantly greater proportion of patients achieved both primary endpoints of 0 or 1 on IGA and/or EASI 75 with abrocitinib 100 mg or 200 mg once daily compared to placebo at week 12 or week 16 (see Table 1 and Table 2). A statistically significantly greater proportion of patients achieved at least a 4-point improvement on PP-NRS with abrocitinib 100 mg or 200 mg once daily compared to placebo. This improvement was observed as early as week 2 and was maintained through week 12. In the COMPARE study, abrocitinib 200 mg was superior to dupilumab in the proportion of patients achieving at least a 4-point improvement in the PP-NRS at week 2, with a statistically significant higher rate of achieving a reduction in itching as early as day 4 after the first dose. The treatment effects in different patient subgroups (e.g., by body weight, age, gender, race, and history of systemic immunosuppressant therapy) in MONO-1, MONO-2, and COMPARE were consistent with these effects in the overall study population.

Table 1.

Results of the efficacy evaluation of abrocitinib as monotherapy at week 12

Abbreviations: CI - confidence interval; EASI (Eczema Area and Severity Index) - Eczema Area and Severity Index; IGA (Investigator Global Assessment) - Investigator's Global Assessment; N - number of randomized patients; PP-NRS (Peak Pruritus Numerical RatingScale) - Peak Pruritus Numerical Rating Scale.

b. Patients with an improvement in EASI score of ≥ 75% from baseline were considered to be an EASI-75 responder.

c. Patients who achieved a PP-NRS4 response were considered to have an improvement of ≥ 4 points on this scale from baseline.

d. Abrocitinib was used as monotherapy.

d. Statistically significant result adjusted for multiplicity compared to placebo.

Table 2.

Results of the evaluation of the efficacy of abrocitinib in combination with topical therapy at 12 weeks and 16 weeks

Abbreviations: CI – confidence interval; DUP – dupilumab; EASI – Eczema Area and Severity Index; IGA – Investigator’s Global Assessment; N – number of patients randomized; PBO – placebo; PP-NRS – Maximum Pruritus Numeric Rating Scale.

a. Patients who achieved an IGA response were considered to be patients with a score of “clear” (0 points) or “almost clear” (1 point) (on a 5-point scale) and a decrease in score from baseline of ≥ 2 points.

b. Patients who achieved an EASI-75 response were considered to have an improvement in EASI score of ≥ 75% from baseline.

c. Patients who achieved a PP-NRS4 response were considered to have an improvement of ≥ 4 points on this scale from baseline.

d. Abrocitinib was used in combination with topical therapy.

d. Statistically significant result adjusted for multiplicity compared to placebo.

Health-related outcomes

In both the monotherapy studies (MONO-1 and MONO-2) and the combination therapy study (COMPARE), abrocitinib statistically significantly improved patient-reported outcomes after 12 weeks of treatment, including reduction in itching, improvement in sleep (SCORAD Sleep VAS), reduction in atopic dermatitis symptoms (POEM), improvement in quality of life (DLQI), and reduction in anxiety and depression symptoms (HADS)), which were not adjusted for multiplicity, compared to placebo (see Table 3).

Table 3.

Patient-reported outcomes after abrocitinib monotherapy and in combination with topical therapy (at week 12)

-3.6

(-5.3;

-1.9)

CI — confidence interval; DLQI (Dermatology Life Quality Index) — Dermatology Life Quality Index; HADS (Hospital Anxiety and Depression Scale) — Hospital Anxiety and Depression Scale; N — number of randomized patients; PBO — placebo; POEM (Patient-Oriented Eczema Measure) — Patient-Oriented Eczema Measure; SCORAD (SCORing for AD) — Scoring of Atopic Dermatitis in the Sleep Assessment Section; VAS — Visual Analogue Pain Scale.

* Statistically significant result without correction for multiplicity.

Open-label study of induction therapy with randomised withdrawal (REGIMEN)

A total of 1,233 patients received abrocitinib 200 mg once daily in an open-label study during a 12-week run-in phase. Of these patients, 798 participants (64.7%) met response criteria (defined as achieving an IGA response of 0 or 1 and EASI-75) and were randomized to placebo (267 patients), abrocitinib 100 mg once daily (265 patients), or abrocitinib 200 mg once daily (266 patients).

Continuous therapy (200 mg continuously) and induction-maintenance therapy (200 mg for 12 weeks followed by 100 mg) prevented exacerbations with 81.1% and 57.4%, respectively, compared with 19.1% in patients (randomized to placebo) who withdrew from the study after the 12-week induction period. 351 patients, including 16.2% in the 200 mg dose group, 39.2% in the 100 mg dose group, and 76.4% in the placebo group, required rescue therapy with abrocitinib 200 mg in combination with topical therapy.

Long-term effectiveness

Eligible patients who completed a full course of therapy in the pivotal baseline study (e.g., MONO-1, MONO 2, COMPARE, REGIMEN) were offered the option to enter the long-term extension study EXTEND. In EXTEND, patients received abrocitinib with or without background topical medication. Patients who had previously been randomized to receive abrocitinib 100 mg or 200 mg once daily in the baseline studies continued on the same dose in EXTEND. In EXTEND, patients who had received double-blind therapy prior to completion of the baseline study received single-blind therapy (the group to which the participant was randomized was disclosed to the investigators but not to the patients). Among patients who achieved a response after 12 weeks of therapy and entered the EXTEND study, the majority of patients maintained their response through 48 weeks of total therapy for both doses of abrocitinib (60% and 70% for IGA response (0 or 1 score), 79% and 187% for EASI-75, and 62% and 83% for PP-NRS4 at 100 mg once daily and 200 mg once daily, respectively). Among patients who did not respond after 12 weeks of therapy and who entered the EXTEND study, a proportion of patients achieved a late response by week 24 (from baseline) with continued abrocitinib therapy (25% and 29% for IGA response (0 or 1 score) and 50% and 59% for EASI-75 response at 100 mg once daily and 200 mg once daily, respectively). The likelihood of benefit from therapy at week 24 was higher in patients who achieved a partial response at week 12 compared with patients who did not respond at week 12. Patients who received dupilumab in the COMPARE study and subsequently entered the EXTEND study were randomized to receive abrocitinib at doses of 100 mg or 200 mg once daily after enrollment in the EXTEND study. Among patients who did not respond to dupilumab therapy, a significant proportion of patients achieved a response 12 weeks after switching to abrocitinib (34% and 47% for IGA response (0 or 1 score) and 68% and 80% for EASI 75 response at 100 mg once daily or 200 mg once daily, respectively).

The efficacy and safety of abrocitinib as monotherapy were evaluated in 2 randomized, double-blind, placebo-controlled phase 3 studies (MONO 1, MONO 2) that enrolled 124 patients aged 12 to <18 years. Efficacy and safety were also evaluated in an open-label, randomized, randomised withdrawal study (REGIMEN) that enrolled 246 patients aged 12 to <18 years. In these studies, the results in the adolescent subgroup were consistent with the results in the overall study population. The efficacy and safety of abrocitinib in combination with background topical medical therapy were evaluated in the randomized, double-blind, placebo-controlled phase 3 study TEEN. The study enrolled 287 patients aged 12 to <18 years with moderate to severe atopic dermatitis with an IGA score of ≥3, EASI score of ≥16, involvement of ≥10% of body surface area, and PP-NRS score of ≥4 at the pre-randomization baseline assessment visit. Patients who had not previously responded to therapy or who were receiving systemic therapy were eligible.

Baseline characteristics

In the TEEN study, across all treatment groups, 49.1% of participants were female, 56.1% were Caucasian, 33.0% were Asian, and 6.0% were Black. The median age of participants was 15 years, and the proportion of patients with severe atopic dermatitis (IGA score 4) was 38.6%.

Table 4.

Results of the TEEN study on adolescent efficacy

Abbreviations: CI – confidence interval; EASI (Eczema Area and Severity Index) – Eczema Area and Severity Index; IGA (Investigator Global Assessment) – Investigator’s Global Assessment; N – number of patients randomized; PP-NRS (Peak Pruritus Numerical Rating Scale) – Peak Pruritus Numerical Rating Scale.

a. Patients who achieved an IGA response were considered to be patients with a score of “clear” (0 points) or “almost clear” (1 point) (on a 5-point scale), and a decrease in score from baseline of ≥ 2 points.

b. Patients with an improvement in EASI score of ≥ 75% from baseline were considered to be an EASI-75 responder.

c. Patients who achieved a PP-NRS4 response were considered to have an improvement of ≥ 4 points on this scale from baseline.

d. Abrocitinib was used in combination with topical drug therapy.

d. Statistically significant result adjusted for multiplicity compared to placebo.

Pharmacokinetics.

Absorption

Abrocitinib is well absorbed, with greater than 91% of the dose absorbed after oral administration, and the absolute oral bioavailability is approximately 60%. Absorption of abrocitinib is rapid following oral administration, with peak plasma concentrations occurring within 1 hour. Steady-state plasma concentrations of abrocitinib are reached within 48 hours after a single dose. Abrocitinib Cmax and AUC increased in a dose-proportional manner after doses up to 200 mg. Co-administration of abrocitinib with a high-fat meal had no clinically relevant effect on abrocitinib exposure (AUC and Cmax increased by approximately 26% and 29%, respectively, and Tmax was delayed by 2 hours). In clinical studies, abrocitinib was administered without regard to food intake (see section 4.2).

Distribution

Following intravenous administration, the volume of distribution of abrocitinib is approximately 100 L. Approximately 64%, 37%, and 29% of circulating abrocitinib and its active metabolites MI and M2, respectively, are bound to plasma proteins. Abrocitinib and its active metabolites are equally distributed between erythrocytes and plasma.

The in vitro metabolism of abrocitinib is mediated by several cytochrome P450 (CYP) isoenzymes: CYP2C19 (53%), CYP2C9 (30%), CYP3A4 (11%), and CYP2B6 (6%). In a human study using radiolabeled abrocitinib, abrocitinib was the most abundant circulating species; 3 polar monohydroxylated metabolites identified as MI (3-hydroxypropyl), M2 (2-hydroxypropyl), and M4 (pyrrolidinone pyrimidine) were also detected. At steady state, M2 and M4 are the major metabolites, and MI is a minor one. Of the 3 circulating metabolites, MI and M2 have JAK inhibition profiles similar to abrocitinib, while M4 was a pharmacologically inactive metabolite. The pharmacological activity of abrocitinib is attributed to exposure of the unbound parent molecule (60%), as well as the metabolites MI (10%) and M2 (30%) in the systemic circulation. The sum of exposures of unbound abrocitinib, MI, and M2, each expressed in molar units and corrected for relative activity, is referred to as the active component of abrocitinib.

No clinically significant effects were observed in interaction studies of abrocitinib with substrates of BCRP and OATP (e.g. rosuvastatin), MATE1/2K (e.g. metformin), CYP3A4 (e.g. midazolam), and CYP2B6 (e.g. efavirenz).

Breeding

The elimination half-life of abrocitinib is approximately 5 hours. Abrocitinib is eliminated primarily by metabolic clearance, with less than 1% of the dose excreted unchanged in the urine. The metabolites of abrocitinib—MI, M2, and M4—are excreted primarily in the urine and are substrates for organic anion transporter 3.

Special patient groups.

Body weight, gender, genotype, race and age

Body weight, gender, CYP2C19/2C9 genotype, race, and age had no clinically meaningful effect on abrocitinib exposure (see Dosage and Administration).

Adolescents (ages 12 to 18)

Based on population pharmacokinetic analysis, there is no clinically meaningful difference in mean steady-state exposure levels of abrocitinib in adolescent patients compared to adults of normal weight for their age.

Pediatric patients (up to 12 years of age)

Drug interaction studies have only been conducted in adult patients. The pharmacokinetics of abrocitinib in children under 12 years of age have not been evaluated (see Dosage and Administration).

Kidney dysfunction

In a study involving patients with renal impairment, patients with severe (estimated glomerular filtration rate (eGFR) <30 mL/min) and moderate (eGFR 30 to <60 mL/min) renal impairment had an increase in AUCinf of the active component of abrocitinib of approximately 191% and 110%, respectively, compared to patients with normal renal function (eGFR ≥90 mL/min) (see section 4.2). The pharmacokinetics of abrocitinib have not been evaluated in patients with mild renal impairment; however, based on results observed in other subgroups, exposure to the active component of abrocitinib is expected to increase by up to 70% in patients with mild renal impairment (eGFR 60 to <90 mL/min). The 70% increase in exposure is not clinically relevant as the efficacy and safety of abrocitinib in atopic dermatitis patients with mild renal impairment (n = 756) was comparable to that in the general population in Phase 2 and Phase 3 clinical studies. The eGFR in individual patients was estimated using the recommended Modification of Diet in Renal Disease (MDRD) formula. Abrocitinib has not been studied in patients with end-stage renal disease receiving renal replacement therapy (see Dosage and Administration). Abrocitinib has not been studied in patients with atopic dermatitis with baseline creatinine clearance less than 40 mL/min in Phase 3 clinical studies.

Effects on liver function

In patients with mild (Child-Pugh Class A) and moderate (Child-Pugh Class B) hepatic impairment, AUCinf values of the active component are reduced by approximately 4% and increased by 15%, respectively, compared with these values in patients with normal hepatic function. These changes are not clinically significant, therefore, no dose adjustment is required in patients with mild or moderate hepatic impairment (see section 4.2). This parameter of abrocitinib has not been evaluated in clinical studies in patients with severe (Child-Pugh Class C) hepatic impairment (see section 4.3) or in patients with a positive test result for active hepatitis B or hepatitis C at screening (see section 4.4).

Indication

Sibinquo is indicated for the treatment of moderate to severe atopic dermatitis in adults who are candidates for systemic therapy.

Contraindication

Hypersensitivity to the active substance or to any of the excipients of the drug listed in the "Composition" section.

Active severe systemic infections, including tuberculosis (see section "Special warnings and precautions for use").

Severe hepatic impairment (see section "Method of administration and dosage").

Pregnancy and breast-feeding (see section “Use during pregnancy or breast-feeding”).

Interaction with other medicinal products and other types of interactions

Potential for other medicinal products to affect the pharmacokinetics of abrocitinib.

Abrocitinib is metabolized primarily by CYP2C19 and CYP2C9 isoenzymes and, to a lesser extent, CYP3A4 and CYP2B6 isoenzymes, and its active metabolites are excreted renally and are substrates of organic anion transporter 3 (OAT3). Therefore, the exposure of abrocitinib and/or its active metabolites may be affected by medicinal products that inhibit or induce these isoenzymes and transporters. Recommendations for dose adjustment, if necessary, are provided in the “Method of administration and dosage” section.

Concomitant use with CYP2C19/CYP2C9 inhibitors.

When abrocitinib 100 mg was co-administered with fluvoxamine (a potent CYP2C19 inhibitor and a moderate CYP3A inhibitor) or fluconazole (a potent CYP2C19 inhibitor, a moderate CYP2C9 and CYP3A inhibitor), the exposure to the active component of abrocitinib (see section 5.2) was increased by 91% and 155%, respectively, compared to abrocitinib administered alone (see section 4.2).

Concomitant use with CYP2C19/CYP2C9 inducers.

Administration of abrocitinib 200 mg after multiple administration of rifampicin, a potent inducer of cytochrome CYP isoenzymes, resulted in a decrease in exposure to the active component of abrocitinib by approximately 56% (see section 4.2).

Concomitant use with organic anion transporter inhibitors 3.

When abrocitinib 200 mg was co-administered with probenecid, an inhibitor of organic anion transporter 3, exposure to the active component of abrocitinib increased by approximately 66%. This effect is not clinically relevant and no dose adjustment is required.

Simultaneous use with agents that increase gastric pH.

When abrocitinib 200 mg was co-administered with famotidine 40 mg, an H2-receptor antagonist, exposure to the active moiety of abrocitinib was reduced by approximately 35%. The effect of increased gastric pH caused by antacids or proton pump inhibitors (omeprazole) on the pharmacokinetics of abrocitinib has not been studied and may be similar to the effect of famotidine. A higher daily dose of 200 mg should be considered for patients taking concomitant products that increase gastric pH, as these may reduce the efficacy of abrocitinib.

The potential for abrocitinib to affect the pharmacokinetics of other medicinal products.

In interaction studies with oral contraceptives (such as ethinyl estradiol/levonorgestrel), no clinically significant effects of abrocitinib were observed.

In vitro studies have shown that abrocitinib is an inhibitor of P-glycoprotein (P-gp). When dabigatran etexilate (a P-gp substrate) was co-administered with a single 200 mg dose of abrocitinib, the AUCinf and Cmax of dabigatran were increased by approximately 53% and 40%, respectively, compared to dabigatran etexilate alone. Caution should be exercised when co-administering abrocitinib with dabigatran. The effect of abrocitinib on the pharmacokinetics of other P-gp substrates has not been studied. Such combinations should be used with caution as levels of P-gp substrates with a narrow therapeutic window, such as digoxin, may be increased.

In vitro studies have shown that abrocitinib is an inhibitor of the CYP2C19 enzyme. Co-administration of abrocitinib 200 mg once daily with a single dose of omeprazole 10 mg increased the AUCinf and Cmax of omeprazole by approximately 189% and 134%, respectively, indicating that abrocitinib is a moderate inhibitor of the CYP2C19 enzyme. Caution should be exercised when abrocitinib is co-administered with medicinal products with a narrow therapeutic window that are primarily metabolised by the CYP2C19 enzyme (e.g. S-mephenytoin and clopidogrel). Dose adjustments may be required for other medicinal products that are primarily metabolised by the CYP2C19 enzyme, as indicated in the prescribing information (e.g. citalopram, clobazam, escitalopram and selumetinib).

Co-administration of abrocitinib 200 mg once daily with a single dose of caffeine 100 mg increased caffeine AUCinf by 40% without affecting Cmax, indicating that abrocitinib is a moderate inhibitor of CYP1A2. No general dose adjustment is recommended.

Application features

In the following patient groups, abrocitinib should only be used in the absence of appropriate alternative treatments:

- patients aged 65 and over;
- patients with a history of atherosclerotic cardiovascular disease or other risk factors for cardiovascular disease (e.g. current smoking or a history of long-term smoking);

- patients with risk factors for the development of malignant neoplasms (for example, the presence of a malignant neoplasm at present or in history).

Infections/severe infections.

Because the elderly and the diabetic population in general have a higher incidence of infections, this drug should be used with caution in the treatment of the elderly and patients with diabetes. In patients aged 65 years and older, abrocitinib should only be used in the absence of appropriate alternative treatments (see section 4.2).

The drug should not be initiated in patients with an active severe systemic infection (see section 4.3). Before initiating abrocitinib therapy, a