CIBINQO 50mg tablets medication leaflet

Cibinqo 50 mg film-coated tablets

Cibinqo 100 mg film-coated tablets

Cibinqo 200 mg film-coated tablets

Cibinqo 50 mg film-coated tablets

Each film-coated tablet contains 50 mg of abrocitinib.

Each film-coated tablet contains 1.37 mg of lactose monohydrate.

Cibinqo 100 mg film-coated tablets

Each film-coated tablet contains 100 mg of abrocitinib.

Each film-coated tablet contains 2.73 mg of lactose monohydrate.

Cibinqo 200 mg film-coated tablets

Each film-coated tablet contains 200 mg of abrocitinib.

Each film-coated tablet contains 5.46 mg of lactose monohydrate.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet)

Cibinqo 50 mg film-coated tablets

Pink, approximately 11 mm long and 5 mm wide oval tablet debossed with “PFE” on one side and“ABR 50” on the other.

Cibinqo 100 mg film-coated tablets

Pink, approximately 9 mm in diameter round tablet debossed with “PFE” on one side and “ABR 100”on the other.

Cibinqo 200 mg film-coated tablets

Pink, approximately 18 mm long and 8 mm wide oval tablet debossed with “PFE” on one side and“ABR 200” on the other.

Cibinqo is indicated for the treatment of moderate-to-severe atopic dermatitis in adults and adolescents12 years and older who are candidates for systemic therapy.

Treatment should be initiated and supervised by a healthcare professional experienced in the diagnosisand treatment of atopic dermatitis.

The recommended starting dose is 100 mg or 200 mg once daily based on individual patientcharacteristics:

- A starting dose of 100 mg once daily is recommended for patients at higher risk of venousthromboembolism (VTE), major adverse cardiovascular event (MACE) and malignancy (seesection 4.4). If the patient does not respond adequately to 100 mg once daily, the dose can beincreased to 200 mg once daily.

- A dose of 200 mg once daily may be appropriate for patients who are not at higher risk of VTE,

MACE and malignancy with high disease burden or for patients with an inadequate response to100 mg once daily. Upon disease control, dose should be decreased to 100 mg once daily. Ifdisease control is not maintained after dose reduction, re-treatment with 200 mg once daily canbe considered. In adolescents (12 years to 17 years of age), weighing 25 kg to < 59 kg, a startingdose of 100 mg once a day is recommended. If the patient does not respond adequately to100 mg once daily, the dose can be increased to 200 mg once daily. In adolescents weighing atleast 59 kg, a starting dose of 100 mg or 200 mg once daily may be appropriate.

The lowest effective dose for maintenance should be considered.

Discontinuation of treatment should be considered in patients who show no evidence of therapeuticbenefit after 24 weeks.

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

Laboratory monitoring

Table 1. Laboratory measures and monitoring guidance

Laboratory measures Monitoring guidance Action

Platelets: Treatment should bediscontinued if platelet counts are< 50 × 103/mm3.

ALC: Treatment should be

Complete blood count interrupted if ALC isincluding Platelet < 0.5 × 103/mm3 and may be restarted

Count, Absolute Before treatment initiation, 4 weeks once ALC returns above this value.

Lymphocyte Count after initiation and thereafter Treatment should be discontinued if(ALC), Absolute according to routine patient confirmed.

Neutrophil Count management. ANC: Treatment should be(ANC) and interrupted if ANC is < 1 × 103/mm3

Haemoglobin (Hb) and may be restarted once ANCreturns above this value.

Hb: Treatment should be interruptedif Hb is < 8 g/dL and may berestarted once Hb returns above thisvalue.

Before treatment initiation, 4 weeksafter initiation and thereafter Patients should be monitored

Lipid parameters according to the patient’s risk for according to clinical guidelines forcardiovascular disease and clinical hyperlipidaemia.guidelines for hyperlipidaemia.

Treatment initiation

Treatment should not be initiated in patients with a platelet count < 150 × 103/mm3, an absolutelymphocyte count (ALC) < 0.5 × 103/mm3, an absolute neutrophil count (ANC) < 1.2 × 103/mm3 orwho have a haemoglobin value < 10 g/dL (see section 4.4).

If a patient develops a serious infection, sepsis or opportunistic infection, dose interruption should beconsidered until the infection is controlled (see section 4.4).

Interruption of dosing may be needed for management of laboratory abnormalities as described in

Table 1.

If a dose is missed, patients should be advised to take the dose as soon as possible unless it is less than12 hours before the next dose, in which case the patient should not take the missed dose. Thereafter,dosing should be resumed at the regular scheduled time.

In patients receiving dual strong inhibitors of CYP2C19 and moderate inhibitors of CYP2C9, or stronginhibitors of CYP2C19 alone (e.g. fluvoxamine, fluconazole, fluoxetine and ticlopidine), therecommended dose should be reduced by half to 100 mg or 50 mg once daily (see section 4.5).

Treatment is not recommended concomitantly with moderate or strong inducers of

CYP2C19/CYP2C9 enzymes (e.g. rifampicin, apalutamide, efavirenz, enzalutamide, phenytoin) (seesection 4.5).

In patients receiving acid reducing agents (e.g. antacids, proton pump inhibitors and H2 receptorantagonists), 200 mg once daily dose of abrocitinib should be considered (see section 4.5).

No dose adjustment is required in patients with mild renal impairment, i.e. estimated glomerularfiltration rate (eGFR) of 60 to < 90 mL/min.

In patients with moderate (eGFR 30 to < 60 mL/min) renal impairment, the recommended dose ofabrocitinib should be reduced by half to 100 mg or 50 mg once daily (see section 5.2).

In patients with severe (eGFR < 30 mL/min) renal impairment, 50 mg once daily is the recommendedstarting dose. The maximum daily dose is 100 mg (see section 5.2).

Abrocitinib has not been studied in patients with end-stage renal disease (ESRD) on renal replacementtherapy.

No dose adjustment is required in patients with mild (Child Pugh A) or moderate (Child Pugh B)hepatic impairment. Abrocitinib is contraindicated to patients with severe (Child Pugh C) hepaticimpairment (see section 4.3).

For patients 65 years of age and older, the recommended dose is 100 mg once daily (see section 4.4).

The safety and efficacy of Cibinqo in children under 12 years of age have not yet been established. Nodata are available.

This medicinal product is to be taken orally once daily with or without food at approximately the sametime each day.

In patients who experience nausea, taking tablets with food may improve nausea.

Tablets should be swallowed whole with water and should not be split, crushed or chewed becausethese methods have not been studied in clinical trials.

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

- Active serious systemic infections, including tuberculosis (TB) (see section 4.4).

- Severe hepatic impairment (see section 4.2).

- Pregnancy and breast-feeding (see section 4.6).

Abrocitinib should only be used if no suitable treatment alternatives are available in patients:

- 65 years of age and older;

- patients with history of atherosclerotic cardiovascular disease or other cardiovascular risk factors(such as current or past long-time smokers);

- patients with malignancy risk factors (e.g. current malignancy or history of malignancy)

Infections/serious infections

Serious infections have been reported in patients receiving abrocitinib. The most frequent seriousinfections in clinical studies were herpes simplex, herpes zoster and pneumonia (see section 4.8).

As there is a higher incidence of infections in the elderly and in the diabetic populations in general,caution should be used when treating the elderly and patients with diabetes. In patients 65 years of ageand older abrocitinib should only be used if no suitable treatment alternatives are available (see section4.2).

Treatment must not be initiated in patients with an active, serious systemic infection (see section 4.3).

Risks and benefits of treatment prior to initiating abrocitinib should be 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 duringand after treatment with abrocitinib. A patient who develops a new infection during treatment shouldundergo prompt and complete diagnostic testing and appropriate antimicrobial therapy should beinitiated. The patient should be closely monitored and therapy should be temporarily interrupted if thepatient is not responding to standard therapy.

Tuberculosis was observed in clinical studies with abrocitinib. Patients should be screened for TBbefore starting treatment and yearly screening for patients in highly endemic areas for TB should beconsidered. Abrocitinib must not be given to patients with active TB (see section 4.3). For patientswith a new diagnosis of latent TB or prior untreated latent TB, preventive therapy for latent TB shouldbe started prior to initiation of treatment.

Viral reactivation, including herpes virus reactivation (e.g. herpes zoster, herpes simplex), wasreported in clinical studies (see section 4.8). The rate of herpes zoster infections was higher in patientswho were treated with 200 mg, 65 years of age and older, with a medical history of herpes zoster, witha confirmed ALC < 1 × 103/mm3 prior to the event and patients with severe atopic dermatitis atbaseline (see section 4.8). If a patient develops herpes zoster, temporary interruption of treatmentshould be considered until the episode resolves.

Screening for viral hepatitis should be performed in accordance with clinical guidelines before startingtherapy and during therapy. Patients with evidence of active hepatitis B or hepatitis C (positivehepatitis C PCR) infection were excluded from clinical studies (see section 5.2). Patients who werehepatitis B surface antigen negative, hepatitis B core antibody positive, and hepatitis B surfaceantibody positive had testing for hepatitis B virus (HBV) DNA. Patients who had HBV DNA abovethe lower limit of quantification (LLQ) were excluded. Patients who had HBV DNA negative or below

LLQ could initiate treatment; such patients had HBV DNA monitored. If HBV DNA is detected, aliver specialist should be consulted.

No data are available on the response to vaccination in patients receiving abrocitinib. Use of live,attenuated vaccines should be avoided during or immediately prior to treatment. Prior to initiatingtreatment with this medicinal product, it is recommended that patients be brought up to date with allimmunisations, including prophylactic herpes zoster vaccinations, in agreement with currentimmunisation guidelines.

Events of deep venous thrombosis (DVT) and pulmonary embolism (PE) have been reported inpatients receiving abrocitinib (see section 4.8).

In a large randomized active-controlled study of tofacitinib (another JAK inhibitor) in rheumatoidarthritis patients 50 years and older with at least one additional cardiovascular risk factor, a dosedependent higher rate of VTE including deep venous thrombosis (DVT) and pulmonary embolism(PE) was observed with tofacitinib compared to TNF inhibitors.

A higher rate of VTE was observed with abrocitinib 200 mg compared to abrocitinib 100 mg.

In patients with cardiovascular or malignancy risk factors (see also section 4.4 “Major adversecardiovascular events (MACE)” and “Malignancy”) abrocitinib should only be used if no suitabletreatment alternatives are available.

In patients with known VTE risk factors other than cardiovascular or malignancy risk factors,abrocitinib should be used with caution. VTE risk factors other than cardiovascular or malignancy riskfactors include previous VTE, patients undergoing major surgery, immobilisation, use of combinedhormonal contraceptives or hormone replacement therapy, inherited coagulation disorder.

Patients should be re-evaluated periodically during abrocitinib treatment to assess for changes in VTErisk.

Promptly evaluate patients with signs and symptoms of VTE and discontinue abrocitinib in patientswith suspected VTE, regardless of dose.

Major adverse cardiovascular events (MACE)

Events of MACE have been observed in patients taking abrocitinib.

In a large randomized active-controlled study of tofacitinib (another JAK inhibitor) in rheumatoidarthritis patients 50 years and older with at least one additional cardiovascular risk factor, a higher rateof major adverse cardiovascular events (MACE), defined as cardiovascular death, non-fatalmyocardial infarction (MI) and non-fatal stroke, was observed with tofacitinib compared to TNFinhibitors.

Therefore, in patients 65 years of age and older, patients who are current or past long-time smokers,and patients with history of atherosclerotic cardiovascular disease or other cardiovascular risk factors,abrocitinib should only be used if no suitable treatment alternatives are available.

Malignancy (excluding non-melanoma skin cancer [NMSC])

Lymphoma and other malignancies have been reported in patients receiving JAK inhibitors, includingabrocitinib.

In a large randomized active controlled study of tofacitinib (another JAK inhibitor) in rheumatoidarthritis patients 50 years and older with at least one additional cardiovascular risk factor, a higher rateof malignancies, particularly lung cancer, lymphoma and non-melanoma skin cancer (NMSC) wasobserved with tofacitinib compared to TNF inhibitors.

A higher rate of malignancies (excluding non-melanoma skin cancer, NMSC) was observed withabrocitinib 200 mg compared to abrocitinib 100 mg.

In patients 65 years of age and older, patients who are current or past long-time smokers, or with othermalignancy risk factors (e.g. current malignancy or history of malignancy), abrocitinib should only beused if no suitable treatment alternatives are available.

NMSCs have been reported in patients receiving abrocitinib. Periodic skin examination isrecommended 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 (see section 4.8). Treatment with abrocitinib should not be initiated inpatients with a platelet count < 150 × 103/mm3, an ALC < 0.5 × 103/mm3, an ANC < 1.2 × 103/mm3 orwho have a haemoglobin value < 10 g/dL (see section 4.2). Complete blood count should bemonitored 4 weeks after initiation of therapy and thereafter according to routine patient management(see Table 1).

Dose-dependent increases in blood lipid parameters were reported in patients treated with abrocitinibcompared to placebo (see section 4.8). Lipid parameters should be assessed approximately 4 weeksfollowing initiation of therapy and thereafter according to the patient’s risk for cardiovascular disease(see Table 1). The effect of these lipid parameter elevations on cardiovascular morbidity and mortalityhas not been determined. Patients with abnormal lipid parameters should be further monitored andmanaged according to clinical guidelines, due to the known cardiovascular risks associated withhyperlipidaemia.

The safety profile observed in elderly patients was similar to that of the adult population with thefollowing exceptions: a higher proportion of patients 65 years of age and older discontinued fromclinical studies and were more likely to have serious adverse reactions compared to younger patients;patients 65 years and older were more likely to develop low platelet and ALC values; the incidencerate of herpes zoster in patients 65 years of age and older was higher than that of younger patients (seesection 4.8). There are limited 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 inpatients 65 years of age and older, as observed in a large randomised study of tofacitinib (another JAKinhibitor), abrocitinib should only be used in these patients if no suitable treatment alternatives areavailable.

Immunosuppressive conditions or medicinal products

Patients with immunodeficiency disorders or a first-degree relative with a hereditaryimmunodeficiency were excluded from clinical studies and no information on these patients isavailable.

Combination with biologic immunomodulators, potent immunosuppressants such as ciclosporin orother Janus kinase (JAK) inhibitors has not been studied. Their concomitant use with abrocitinib is notrecommended as a risk of additive immunosuppression cannot be excluded.

Lactose monohydrate

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency orglucose-galactose malabsorption should not take this medicinal product.

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially‘sodium-free’.

Potential for other medicines to affect pharmacokinetics of abrocitinib

Abrocitinib is metabolised predominantly by CYP2C19 and CYP2C9 enzymes, and to a lesser extentby CYP3A4 and CYP2B6 enzymes, and its active metabolites are renally excreted and are substratesof the organic anion transporter 3 (OAT3). Therefore, exposures of abrocitinib and/or its activemetabolites may be affected by medicinal products that inhibit or induce these enzymes andtransporter. Dose adjustments, as appropriate, are outlined in section 4.2.

Co-administration with CYP2C19/CYP2C9 inhibitors

When 100 mg abrocitinib was administered concomitantly with fluvoxamine (a strong CYP2C19 andmoderate CYP3A inhibitor) or fluconazole (a strong CYP2C19, moderate CYP2C9 and CYP3Ainhibitor), the extent of exposure of abrocitinib active moiety (see section 5.2) increased by 91% and155%, respectively, compared with administration alone (see section 4.2).

Co-administration with CYP2C19/CYP2C9 inducers

Administration of 200 mg abrocitinib after multiple doses with rifampicin, a strong inducer of CYPenzymes, resulted in reduction of abrocitinib active moiety exposures by approximately 56% (seesection 4.2).

Co-administration with OAT3 inhibitors

When abrocitinib 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

When abrocitinib 200 mg was administered concomitantly with famotidine 40 mg, an H2-receptorantagonist, abrocitinib active moiety exposures decreased by approximately 35%. The effect ofelevating gastric pH with antacids, or proton pump inhibitors (omeprazole) on the pharmacokinetics ofabrocitinib has not been studied and may be similar to that seen with famotidine. The higher 200 mgdaily dose should be considered for patients treated concomitantly with products which increasegastric pH, as they may reduce the efficacy of abrocitinib.

Potential for abrocitinib to affect pharmacokinetics of other medicinal products

No clinically significant effects of abrocitinib were observed in interaction studies with oralcontraceptives (e.g. ethinyl oestradiol/levonorgestrel).

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 abrocitinib 200 mg increased dabigatran AUCinf and Cmax byapproximately 53% and 40%, respectively, compared with administration alone. Caution should beexercised for concomitant use of abrocitinib with dabigatran. The effect of abrocitinib on thepharmacokinetics of other P-gp substrates has not been evaluated. Caution should be exercised as thelevels 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 mgonce daily with omeprazole 10 mg single dose increased the AUCinf and Cmax of omeprazole byapproximately 189% and 134%, respectively, indicating that abrocitinib is a moderate inhibitor of

CYP2C19 enzyme. Caution should be exercised when using abrocitinib concomitantly with narrowtherapeutic index medicines that are primarily metabolised by CYP2C19 enzyme (e.g. S-mephenytoinand clopidogrel). Dose adjustment may be required for other medicines primarily metabolised by

CYP2C19 enzyme in accordance with their product information (e.g. citalopram, clobazam,escitalopram and selumetinib).

Co-administration of abrocitinib 200 mg once daily with caffeine 100 mg single dose increased the

AUCinf of caffeine by 40% with lack of effect on Cmax, suggesting that abrocitinib is a mild inhibitor of

CYP1A2 enzyme. No general dose adjustment can be recommended.

Women of reproductive potential should be advised to use effective contraception during treatmentand for 1 month following the final dose of Cibinqo. Pregnancy planning and prevention for femalesof reproductive potential should be encouraged.

There are no or limited amount of data on the use of abrocitinib in pregnant women. Studies inanimals have shown reproductive toxicity. Abrocitinib has been shown to cause embryo-foetallethality in pregnant rats and rabbits, skeletal variations in the foetuses of pregnant rats and rabbits,and to affect parturition and peri/postnatal development in rats (see section 5.3). Cibinqo iscontraindicated during pregnancy (see section 4.3).

There are no data on the presence of abrocitinib in human milk, the effects on the breast-fed infant, orthe effects on milk production. Abrocitinib was secreted in milk of lactating rats. A risk tonewborns/infants cannot be excluded and Cibinqo is contraindicated during breast-feeding (seesection 4.3).

Based on the findings in rats, oral administration of Cibinqo may result in temporary reduced fertilityin females of reproductive potential. The effects on female rat fertility were reversible 1 month aftercessation of abrocitinib oral administration (see section 5.3).

Cibinqo has no or negligible influence on the ability to drive and use machines.

The most commonly reported adverse reactions are nausea (15.1%), headache (7.9%), acne (4.8%),herpes simplex (4.2%), blood creatine phosphokinase increased (3.8%), vomiting (3.5%), dizziness(3.4%) and abdominal pain upper (2.2%). The most frequent serious adverse reactions are infections(0.3%) (see section 4.4).

A total of 3 848 patients were treated with abrocitinib in clinical studies in atopic dermatitis. Amongthem 3 050 patients (representing 5 166 patient-years of exposure) were integrated for safety analysis.

The integrated safety analysis included 1 997 patients receiving a constant dose of abrocitinib 200 mgand 1 053 patients receiving a constant dose of 100 mg. There were 2 013 patients with at least 48weeks of exposure. Five placebo-controlled studies were integrated (703 patients on 100 mg oncedaily, 684 patients on 200 mg once daily and 438 patients on placebo) to evaluate the safety ofabrocitinib in comparison to placebo for up to 16 weeks.

Listed in Table 2 are adverse reactions observed in atopic dermatitis clinical studies presented bysystem 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 decreasingseriousness.

Table 2. Adverse reactions

System organ class Very common Common Uncommon

Infections and infestations Herpes simplexa Pneumonia

Herpes zosterb

Blood and lymphatic system Thrombocytopeniadisorders Lymphopenia

Metabolism and nutrition Hyperlipidaemiacdisorders

Nervous system disorders Headache

Dizziness

Vascular disorders Venousthromboembolismd

Gastrointestinal disorders Nausea Vomiting

Abdominal pain upper

Skin and subcutaneous tissue Acnedisorders

Investigations Creatinephosphokinaseincreased ˃ 5 × ULNe

a. Herpes simplex includes oral herpes, ophthalmic herpes simplex, genital herpes, and herpes dermatitis.

b. Herpes zoster includes ophthalmic herpes zoster.

c. Hyperlipidaemia includes dyslipidaemia and hypercholesterolaemia.

d. Venous thromboembolism includes pulmonary embolism and deep vein thrombosis.

e. Includes changes detected during laboratory monitoring (see text below).

In placebo-controlled studies, for up to 16 weeks, infections have been reported in 27.4% of patientstreated with placebo and in 34.9% and 34.8% of patients treated with abrocitinib 100 mg and 200 mg,respectively. Most infections were mild or moderate. The percentage of patients reportinginfection-related adverse reactions in the 200 mg and 100 mg groups compared to placebo were:herpes simplex (4.2% and 2.8% versus 1.4%), herpes zoster (1.2% and 0.6% versus 0%), pneumonia(0.1% and 0.1% versus 0%). Herpes simplex was more frequent in patients with a history of herpessimplex or eczema herpeticum. Most of the herpes zoster events involved a single dermatome andwere non-serious. Most opportunistic infections were cases of herpes zoster (0.70 per100 patient-years in the abrocitinib 100 mg group and 0.96 per 100 patient-years in the abrocitinib200 mg group), most of which were non-serious multidermatomal cutaneous infections. Among allpatients treated in clinical studies with consistent dosing regimens of either abrocitinib 100 mg or200 mg, including the long-term extension study, the incidence rate of herpes zoster in patients treatedwith abrocitinib 200 mg (4.36 per 100 patient-years) was higher than that of patients treated with100 mg (2.61 per 100 patient-years). Incidence rates for herpes zoster were also higher for patients65 years of age and older (HR 1.76), patients with a medical history of herpes zoster (HR 3.41),patients with severe atopic dermatitis at baseline (HR 1.17), and a confirmed ALC < 1.0 × 103/mm3prior to the event of herpes zoster (HR 2.18) (see section 4.4).

In placebo-controlled studies, for up to 16 weeks, the rate of serious infections was 1.81 per100 patient-years in patients treated with placebo, 3.32 per 100 patient-years in patients treated with100 mg, and 1.12 per 100 patient-years in patients treated with 200 mg. Among all patients treated inclinical studies with consistent dosing regimens of either abrocitinib 100 mg or 200 mg, including thelong-term extension study, the rate of serious infections was 2.20 per 100 patient-years treated with100 mg and 2.48 per 100 patient-years treated with 200 mg. The most commonly reported seriousinfections were herpes simplex, herpes zoster, and pneumonia (see section 4.4).

Among all patients treated in clinical studies with consistent dosing regimens of either abrocitinib100 mg or 200 mg, including the long-term extension study, the rate of PE was 0.21 per100 patient-years for 200 mg and 0.05 per 100 patient-years for 100 mg. The rate of DVT was 0.06 per100 patient-years in the 200 mg group and 0.05 per 100 patient-years in the 100 mg group (seesection 4.4).

In placebo-controlled studies, for up to 16 weeks, treatment was associated with a dose-relateddecrease in platelet count. Maximum effects on platelets were observed within 4 weeks, after whichthe platelet count returned towards baseline despite continued therapy. Confirmed platelet counts of< 50 × 103/mm3 were reported in 0.1% of patients exposed to 200 mg, and in 0 patients treated with100 mg or placebo. Among all patients treated with clinical studies with consistent dosing regimens ofeither abrocitinib 100 mg or 200 mg, including the long-term extension study, the rate of confirmedplatelet counts of < 50 × 103/mm3 was 0.15 per 100 patients-years for 200 mg and 0 per100 patient-years for 100 mg, most occurring at Week 4. Patients 65 years of age and older had ahigher rate of platelet counts < 75 × 103/mm3 (see section 4.4).

Lymphopenia

In placebo-controlled studies, for up to 16 weeks, confirmed ALC < 0.5 × 103/mm3 occurred in0.3% of patients treated with 200 mg and 0% of patients treated with 100 mg or placebo. Both casesoccurred in the first 4 weeks of exposure. Among all patients treated in clinical studies with consistentdosing regimens of either abrocitinib 100 mg or 200 mg, including the long-term extension, the rate ofconfirmed ALC < 0.5 × 103/mm3 was 0.34 per 100 patient-years for 200 mg and 0.05 per100 patient-years for 100 mg, the highest rate was observed in patients 65 years of age and older (seesection 4.4).

Lipid elevations

In placebo-controlled studies, for up to 16 weeks, there was a dose-related increase in low-densitylipoprotein 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 meaningful change in the LDL/HDL ratio in patients treated with abrocitinib relative topatients treated with placebo. Events related to hyperlipidaemia occurred in 0.4% of patients exposedto abrocitinib 100 mg, 0.6% of patients exposed to 200 mg and 0% of patients exposed to placebo (seesection 4.4).

Creatine phosphokinase elevations (CPK)

In placebo-controlled studies, for up to 16 weeks, significant increases in CPK values (> 5 × ULN)occurred in 1.8% of patients treated with placebo, 1.8% of patients treated with 100 mg and 3.8% ofpatients treated with 200 mg of abrocitinib, respectively. Most elevations were transient and none ledto discontinuation.

Nausea

In placebo-controlled studies, for up to 16 weeks, nausea was reported in 1.8% of patients treated withplacebo 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 abrocitinib. Among patientswith nausea, 63.5% of patients had onset of nausea in the first week of therapy. The median durationof nausea was 15 days. Most of the cases were mild to moderate in severity.

A total of 635 adolescent patients (12 to less than 18 years of age) were treated with abrocitinib inclinical studies in atopic dermatitis representing 1 326.1 patient-years of exposure. The safety profileobserved in adolescents in atopic dermatitis clinical studies was similar to that of the adult population.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix Ⅴ.

Cibinqo was administered in clinical studies up to a single oral dose of 800 mg and 400 mg daily for28 days. Adverse reactions were comparable to those seen at lower doses and no specific toxicitieswere identified. In case of an overdose, it is recommended that the patient be monitored for signs andsymptoms of adverse reactions (see section 4.8). Treatment should be symptomatic and supportive.

There is no specific antidote for overdose with this medicinal product.

Pharmacokinetics data up to and including a single oral dose of 800 mg in healthy adult volunteersindicate that more than 90% of the administered dose is expected to be eliminated within 48 hours.

Pharmacotherapeutic group: Other dermatological preparations, agents for dermatitis, excludingcorticosteroids; ATC code: D11AH08

Abrocitinib is a Janus kinase (JAK)1 inhibitor. JAKs are intracellular enzymes which transmit signalsarising from cytokine or growth factor-receptor interactions on the cellular membrane to influencecellular processes of haematopoiesis and immune cell function. JAKs phosphorylate and activate

Signal Transducers and Activators of Transcription (STATs) which modulate intracellular activityincluding gene expression. Inhibition of JAK1 modulates the signalling pathways by preventing thephosphorylation and activation of STATs.

In biochemical assays, abrocitinib has selectivity for JAK1 over the other 3 JAK isoforms JAK2(28-fold), JAK3 (> 340-fold) and tyrosine kinase 2 (TYK2, 43-fold). In cellular settings, itpreferentially inhibits cytokine-induced STAT phosphorylation by signalling pairs involving JAK1,and spares signalling by JAK2/JAK2, or JAK2/TYK2 pairs. The relevance of selective enzymaticinhibition of specific JAK enzymes to clinical effect is not currently known.

Clinical biomarkers

Treatment with abrocitinib was associated with dose-dependent reduction in serum biomarkers ofinflammation in atopic dermatitis [interleukin-31 (IL-31), interleukin-22 (IL-22), eosinophil count,and thymus and activation-regulated chemokine (TARC)], JAK1 signalling [natural killer (NK) cellcount and interferon gamma-induced protein 10 (IP-10)] or both [high sensitivity C-reactive protein(hsCRP)]. These changes were reversible after treatment discontinuation.

Mean absolute lymphocyte count increased by 2 weeks after starting treatment with abrocitinib andreturned to baseline by Month 9 of treatment. Most patients maintained an ALC within the referencerange. Treatment with abrocitinib was associated with a dose-related increase in B cell counts and adose-related decrease in NK cell counts. The clinical significance of these changes in B cell and NKcell counts is unknown.

The effect of abrocitinib on the QTc interval was examined in subjects who received a singlesupratherapeutic dose of abrocitinib 600 mg in a placebo- and positive-controlled thorough QT study.

A concentration-dependent QTc prolonging effect of abrocitinib was seen; the mean (90% confidenceinterval) for the increase in QTc interval was 6.0 (4.52, 7.49) msec, indicating the lack of a clinicallyrelevant effect of abrocitinib on QTc interval at the dose tested.

The efficacy and safety of abrocitinib as monotherapy and in combination with background medicatedtopical therapies over 12-16 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, theefficacy and safety of abrocitinib in monotherapy over 52 weeks (with the option of rescue treatmentin flaring patients) was evaluated in 1 233 patients in a Phase 3 induction, randomised withdrawal,double-blind, placebo-controlled study (REGIMEN). The patients in these 4 studies were 12 years ofage 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, BSA involvement≥ 10%, and Peak Pruritus Numerical Rating Scale (PP-NRS) ≥ 4 at baseline prior to randomisation.

Patients who had a prior inadequate response or for whom topical treatments were medicallyunadvisable, or who had received systemic therapies were eligible for inclusion. All patients whocompleted 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 themean age was 32.1 to 37.7 years. A total of 134 patients 65 years of age and older were enrolled inthese studies. In these studies, 32.2% to 40.8% had a baseline IGA of 4 (severe atopic dermatitis), and41.4% to 59.5% of patients had received prior systemic treatment for atopic dermatitis. The baselinemean EASI score ranged from 28.5 to 30.9, the baseline PP-NRS ranged from 7.0 to 7.3 and thebaseline Dermatology Life Quality Index (DLQI) ranged from 14.4 to 16.0.

Clinical response12-week monotherapy (MONO-1, MONO-2) and 16-week combination therapy (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 abrocitinib compared with placebo at Week 12 or

Week 16 (see Table 3 and Table 4).

A significantly greater proportion of patients achieved at least a PP-NRS 4-point improvement with100 mg or 200 mg once daily abrocitinib compared with placebo. This improvement was observed asearly as Week 2 and persisted through Week 12 (Figure 1).

In the COMPARE study, superiority of abrocitinib 200 mg compared with dupilumab at Week 2 wasdemonstrated for the proportion of patients achieving at least a PP-NRS 4-point improvement withsignificantly 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 immunosuppressanttreatment) in MONO-1, MONO-2 and COMPARE were consistent with the results in the overall studypopulation.

Table 3. Efficacy results of abrocitinib in monotherapy at Week 12

MONO-1d MONO-2d

Week 12 Week 12

Abrocitinib monotherapy Abrocitinib monotherapy200 mg QD 100 mg QD PBO 200 mg QD 100 mg QD PBO

N=154 N=156 N=77 N=155 N=158 N=78% Responders (95% CI)43.8e 23.7e 7.9 38.1e 28.4e 9.1

IGA 0 or 1a (35.9, 51.7) (17.0, 30.4) (1.8, 14.0) (30.4, 45.7) (21.3, 35.5) (2.7, 15.5)62.7e 39.7e 11.8 61.0e 44.5e 10.4

EASI-75b (55.1, 70.4) (32.1, 47.4) (4.6, 19.1) (53.3, 68.7) (36.7, 52.3) (3.6, 17.2)57.2e 37.7e 15.3 55.3e 45.2e 11.5

PP-NRS4c (48.8, 65.6) (29.2, 46.3) (6.6, 24.0) (47.2, 63.5) (37.1, 53.3) (4.1, 19.0)

Abbreviations: CI=confidence interval; EASI=Eczema Area and Severity Index; IGA=Investigator Global Assessment;

N=number of patients randomised; PBO=placebo; PP-NRS=Peak Pruritus Numerical Rating Scale; QD=once daily.

a. IGA responders were patients with IGA score of clear (0) or almost clear (1) (on a 5-point scale) and a reduction frombaseline of  2 points.

b. EASI-75 responders were patients with ≥ 75% improvement in EASI from baseline.

c. PP-NRS4 responders were patients with ≥ 4-point improvement in PP-NRS from baseline.

d. Abrocitinib used as monotherapy.

e. Statistically significant with adjustment for multiplicity versus placebo.

Table 4. Efficacy results of abrocitinib in combination with topical therapy at Week 12 and

Week 16

COMPAREd

Week 12 Week 16

Abrocitinib + topicals PBO + DUP + Abrocitinib + topicals PBO + DUP +topicals topicals topicals topicals200 mg 100 mg N=131 N=243 200 mg 100 mg N=131 N=243

QD QD QD QD

N=226 N=238 N=226 N=238% Responders (95% CI)48.4e 36.6e 14.0 36.5 47.5e 34.8e 12.9 38.8

IGA 0 or 1a (41.8, 55.0) (30.4, 42.8) (8.0, 19.9) (30.4, 42.6) (40.9, 54.1) (28.6, 40.9) (7.0, 18.8) (32.5, 45.1)70.3e 58.7e 27.1 58.1 71.0e 60.3e 30.6 65.5

EASI-75b (64.3, 76.4) (52.4, 65.0) (19.5, 34.8) (51.9, 64.3) (65.1, 77.0) (53.9, 66.6) (22.5, 38.8) (59.4, 71.6)63.1 47.5 28.9 54.5 62.8 47.0 28.7 57.1

PP-NRS4c (56.7, 69.6) (40.9, 54.1) (20.8, 37.0) (47.9, 61.0) (55.6, 70.0) (39.5, 54.6) (19.6, 37.9) (50.1, 64.2)

Abbreviations: CI=confidence interval; DUP=Dupilumab; EASI=Eczema Area and Severity Index; IGA=Investigator

Global Assessment; N=number of patients randomised; PBO=placebo; PP-NRS=Peak Pruritus Numerical Rating Scale;

QD=once daily.

a. IGA responders were patients with IGA score of clear (0) or almost clear (1) (on a 5-point scale) and a reduction frombaseline of  2 points.

b. EASI-75 responders were patients with ≥ 75% improvement in EASI from baseline.

c. PP-NRS4 responders were patients with ≥ 4-point improvement in PP-NRS from baseline.

d. Abrocitinib used in combination with topical therapy.

e. Statistically significant with adjustment for multiplicity versus placebo.

The proportion of patients who achieved PP-NRS4 over time in studies MONO-1, MONO-2 and

COMPARE are shown in Figure 1.

Figure 1. Proportion of patients who achieved PP-NRS4 over time in MONO-1, MONO-2and COMPARE

Abbreviations: PP-NRS=Peak Pruritus Numerical Rating Scale; QD=once daily; Q2W=every 2 weeks.

PP-NRS4 responders were patients with ≥ 4-point improvement in PP-NRS from baseline.

a. Abrocitinib used as monotherapy.

b. Abrocitinib used in combination with medicated topical therapy.

* Statistically significant with adjustment for multiplicity versus placebo.

** Statistically significant with adjustment for multiplicity versus dupilumab.

Health-related outcomes

In both monotherapy studies (MONO-1 and MONO-2) and in the combination therapy study(COMPARE), abrocitinib significantly improved patient-reported outcomes, including itch, sleep(SCORAD Sleep VAS), AD symptoms (POEM), quality of life (DLQI) and symptoms of anxiety anddepression (HADS) that were uncorrected for multiplicity, at 12 weeks compared to placebo (see

Table 5).

Table 5. Patient-reported outcomes results of abrocitinib monotherapy and in combinationwith topical therapy at Week 12

Monotherapy Combination therapy

MONO-1 MONO-2 COMPARE200 mg 100 mg PBO 200 mg 100 mg PBO 200 mg QD 100 mg QD PBO +

QD QD QD QD + topicals + topicals topicals

N 154 156 77 155 158 78 226 238 131

SCORAD Sleep

VAS, change -3.7* -2.9* -1.6 -3.8* -3.0* -2.1 -4.6* -3.7* -2.4from baseline (-4.2, -3.3) (-3.4, -2.5) (-2.2, -1.0) (-4.2, -3.4) (-3.4, -2.6) (-2.7, -1.5) (-4.9, -4.3) (-4.0, -3.4) (-2.8, -2.0)(95% CI)

DLQI ≥ 4-pointimprovement, % 72.6%* 67.2%* 43.6% 78.1%* 73.3%* 32.3% 86.4%* 74.7%* 56.5%responders

POEM, change

- 10.6* -6.8* -3.7 -11.0* -8.7* -3.6 -12.6* -9.6* -5.1from baseline(-11.8, -9.4) (-8.0, -5.6) (-5.5, -1.9) (-12.1, -9.8) (-9.9, -7.5) (-5.3, -1.9) (-13.6, -11.7) (-10.5, -8.6) (-6.3, -3.9)(95% CI)

HADS Anxiety,change from -2.1* -1.6 -1.0 -1.7* -1.6* -0.6 -1.6* -1.2* -0.4baseline (-2.5, -1.6) (-2.0, -1.1) (-1.7, -0.4) (-2.2, -1.2) (-2.1, -1.1) (-1.3, 0.2) (-2.0, -1.2) (-1.5, -0.8) (-0.9, 0.1)(95% CI)

HADS

Depression,

- 1.8* -1.4* -0.2 -1.4* -1.0* 0.3 -1.6* -1.3* -0.3change from(-2.2, -1.4) (-1.8, -0.9) (-0.8, 0.4) (-1.8, -1.0) (-1.5, -0.6) (-0.3, 0.9) (-1.9, -1.2) (-1.6, -0.9) (-0.7, 0.2)baseline(95% CI)

CI=confidence interval; DLQI=Dermatology Life Quality Index; HADS=Hospital Anxiety and Depression Scale; N=numberof patients randomised; PBO=placebo; POEM=Patient-Oriented Eczema Measure; QD=once daily; SCORAD=SCORing for

AD; VAS=visual analog scale.

*Statistically significant without adjusting for multiplicity

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-inphase. 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 mgonce daily (265 patients) or abrocitinib 200 mg once daily (266 patients).

Continuous treatment (200 mg continuous) and induction-maintenance treatment (200 mg for12 weeks followed by 100 mg) prevented flare with 81.1% and 57.4% probability, respectively, versus19.1% 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% ofplacebo patients received rescue medication of 200 mg abrocitinib in combination with topicaltherapy.

Figure 2. Time to protocol-defined flare

Abrocitinib used as monotherapy.

Protocol-defined flare=A loss of at least 50% of the EASI response at Week 12 and an IGA score of 2 or higher.

Multiplicity-controlled p < 0.0001 200 mg versus placebo; 100 mg versus placebo; 200 mg versus 100 mg.

Eligible patients who completed the full treatment period of a qualifying parent study (e.g. MONO-1,

MONO-2, COMPARE, REGIMEN) were considered for enrolment in the long-term extension study

EXTEND. In EXTEND, patients received abrocitinib with or without background medicated topicaltherapy. Patients who were previously randomised to medicinal product 100 mg or 200 mg once dailyin parent studies continued the same dose in EXTEND as in the parent study. In EXTEND, patientsreceived double-blind treatment until the parent study was completed, after which patients receivedsingle-blind treatment (treatment assignment disclosed to the investigators but not to the patients).

Among patients who achieved response after 12 weeks of treatment and entered EXTEND, themajority of patients maintained their response at Week 96 of cumulative treatment for both doses ofabrocitinib [64% and 72% for IGA (0 or 1) response, 87% and 90% for EASI-75, and 75% and 80%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 treatment and entered EXTEND, aproportion of patients achieved late-onset response by Week 24 (from baseline) of continued treatmentwith abrocitinib [25% and 29% for IGA (0 or 1) response, and 50% and 57% for EASI-75 with100 mg once daily and 200 mg once daily, respectively]. Patients who achieved partial response at

Week 12 were more likely than those with no response at Week 12 to achieve treatment benefit at

Week 24.

Patients who received dupilumab in the COMPARE study and subsequently entered EXTEND wererandomised to either 100 mg or 200 mg of abrocitinib once daily upon entering EXTEND. Amongnon-responders to dupilumab, a substantial proportion of patients achieved response 12 weeks afterswitching to abrocitinib [34% and 47% for IGA (0 or 1) response, and 68% and 80% for EASI-75 with100 mg once daily or 200 mg once daily, respectively].

The European Medicines Agency has deferred the obligation to submit the results of studies withabrocitinib in one or more subsets of the paediatric population in the treatment of atopic dermatitis(see section 4.2 for information on paediatric use).

The efficacy and safety of 12 weeks of abrocitinib monotherapy were evaluated in 2 Phase3 randomised, double-blind, placebo-controlled studies (MONO-1, MONO-2) which included124 patients who were 12 to less than 18 years of age. The efficacy and safety of abrocitinibmonotherapy over 52 weeks (with the option of rescue treatment for flaring patients) were alsoevaluated in an open-label induction, randomised withdrawal study (REGIMEN), which included246 patients who were 12 to less than 18 years of age. In these studies, the results in the adolescentsubgroup were consistent with the results in the overall study population.

The efficacy and safety of 12 weeks of abrocitinib in combination with background medicated topicaltherapy were evaluated in the Phase 3 randomised, double-blind, placebo-controlled study TEEN. Thestudy included 287 patients who were 12 to less than 18 years of age with moderate-to-severe atopicdermatitis as defined by IGA score ≥ 3, EASI score ≥ 16, BSA involvement ≥ 10%, and PP-NRS  4at the baseline visit prior to randomisation. Patients who had a prior inadequate response or who hadreceived 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 Asianand 6.0% were Black patients. The median age was 15 years and the proportion of patients with severeatopic dermatitis (IGA of 4) was 38.6%.

Results of 12-week abrocitinib treatment in adolescents in pooled MONO-1 and MONO-2, and the

TEEN study are shown in Table 6.

Table 6. Adolescent efficacy results at Week 12 in pooled MONO-1 and MONO-2, and in

TEEN

Pooled MONO-1 and MONO-2 TEENd

Abrocitinib Abrocitinib Placebo Abrocitinib Abrocitinib Placebo200 mg QD 100 mg QD 200 mg QD 100 mg QD

IGA 0 or 1a

N 48 50 23 93 89 94% 31.3 22.0 8.7 46.2e 41.6e 24.595% CI (18.1, 44.4) (10.5, 33.5) (0.0, 20.2) (36.1, 56.4) (31.3, 51.8) (15.8, 33.2)

EASI-75b

N 48 50 23 93 89 94% 56.3 44.0 8.7 72.0e 68.5e 41.595% CI (42.2, 70.3) (30.2, 57.8) (0.0, 20.2) (62.9, 81.2) (58.9, 78.2) (31.5, 51.4)

PP-NRS4c

N 36 42 22 74 76 84% 61.1 28.6 9.1 55.4e 52.6 29.895% CI (45.2, 77.0) (14.9, 42.2) (0.0, 21.1) (44.1, 66.7) (41.4, 63.9) (20.0, 39.5)

Abbreviations: CI=confidence interval; EASI=Eczema Area and Severity Index; IGA=Investigator Global Assessment;

N=number of evaluable patients; PP-NRS=Peak Pruritus Numerical Rating Scale; QD=once daily.

a. IGA responders were patients with IGA score of clear (0) or almost clear (1) (on a 5-point scale) and a reductionfrom baseline of  2 points.

b. EASI-75 responders were patients with ≥ 75% improvement in EASI from baseline.

c. PP-NRS4 responders were patients with ≥ 4-point improvement in PP-NRS from baseline.

d. Abrocitinib used in combination with medicated topical therapy.

e. Statistically significant with adjustment for multiplicity versus placebo.

Among adolescent patients who achieved response after 12 weeks of treatment and entered long-termextension study EXTEND, the majority of patients maintained their response at Week 96 ofcumulative treatment for both doses of abrocitinib [62% and 78% for IGA (0 or 1) response, 89% and93% for EASI-75, and 77% and 76% for PP-NRS4 with 100 mg and 200 mg once daily, respectively].

Among adolescent patients who did not achieve response after 12 weeks of treatment and entered

EXTEND, a proportion of patients achieved late-onset response by Week 24 (from baseline) ofcontinued treatment with both doses of abrocitinib [34% and 28% for IGA (0 or 1) response, and 41%and 55% for EASI-75 with 100 mg and 200 mg once daily, respectively].

Abrocitinib is well-absorbed with over 91% extent of oral absorption and absolute oral bioavailabilityof approximately 60%. The oral absorption of abrocitinib is rapid and peak plasma concentrations arereached within 1 hour. Steady-state plasma concentrations of abrocitinib are achieved within 48 hoursafter once daily administration. Both Cmax and AUC of abrocitinib increased dose proportionally up to200 mg. Co-administration of abrocitinib with a high-fat meal had no clinically relevant effect onabrocitinib exposures (AUC and Cmax increased by approximately 26% and 29%, respectively, and

Tmax was prolonged by 2 hours). In clinical studies, abrocitinib was administered without regard tofood (see section 4.2).

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 equallybetween red blood cells and plasma.

The in vitro metabolism of abrocitinib is mediated by multiple CYP enzymes, CYP2C19 (~53%),

CYP2C9 (~30%), CYP3A4 (~11%) and CYP2B6 (~6%). In a human radiolabelled study, abrocitinibwas the most prevalent circulating species, with mainly 3 polar mono-hydroxylated metabolitesidentified as M1 (3-hydroxypropyl), M2 (2-hydroxypropyl) and M4 (pyrrolidinone pyrimidine). Atsteady state, M2 and M4 are major metabolites and M1 is a minor metabolite. Of the 3 metabolites incirculation, M1 and M2 have similar JAK inhibitory profiles as abrocitinib, while M4 waspharmacologically inactive. The pharmacologic activity of abrocitinib is attributable to the unboundexposures 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 adjustedfor relative potencies, is referred to as the abrocitinib active moiety.

No clinically significant effects of abrocitinib were observed in interaction studies with substrates of

BCRP and OAT3 (e.g. rosuvastatin), MATE1/2K (e.g. metformin), CYP3A4 (e.g. midazolam), and

CYP2B6 (e.g. efavirenz).

The elimination half-life of abrocitinib is about 5 hours. Abrocitinib is eliminated primarily bymetabolic clearance mechanisms, with less than 1% of the dose excreted in urine as unchanged activesubstance. The metabolites of abrocitinib, M1, M2 and M4 are excreted predominantly in urine, andare substrates of OAT3 transporter.

Body weight, gender, genotype, race and age

Body weight, gender, CYP2C19/2C9 genotype, race and age did not have a clinically meaningfuleffect on abrocitinib exposure (see section 4.2).

Adolescents (≥ 12 to <18 years)

Based on population pharmacokinetic analysis, there was no clinically relevant difference in meanabrocitinib steady-state exposures in adolescent patients compared to adults at their typical bodyweights.

Paediatric (< 12 years)

Interaction studies have been performed in adults only. The pharmacokinetics of abrocitinib inchildren under 12 years of age have not yet been established (see section 4.2).

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 activemoiety AUCinf, respectively, compared to patients with normal renal function (eGFR ≥ 90 mL/min)(see section 4.2). Pharmacokinetics of abrocitinib have not been determined in patients with mild renalimpairment, however, based on the results observed in other groups, an increase of up to 70% in activemoiety exposure is expected in patients with mild renal impairment (eGFR 60 to< 90 mL/min). Theincrease of up to 70% is not clinically meaningful as the efficacy and safety of abrocitinib in atopicdermatitis 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.

Abrocitinib has not been studied in patients with ESRD on renal replacement therapy (see section 4.2).

In Phase 3 clinical studies, abrocitinib was not evaluated in patients with atopic dermatitis withbaseline creatinine clearance values less than 40 mL/min.

Patients with mild (Child Pugh A) and moderate (Child Pugh B) hepatic impairment hadapproximately 4% decrease and 15% increase in active moiety AUCinf, respectively, compared topatients with normal hepatic function. These changes are not clinically significant, and no doseadjustment is required in patients with mild or moderate hepatic impairment (see section 4.2). Inclinical studies, abrocitinib was not evaluated in patients with severe (Child Pugh C) hepaticimpairment (see section 4.3), or in patients screened positive for active hepatitis B or hepatitis C (seesection 4.4).

Decreased lymphocyte counts and decreased size and/or lymphoid cellularity of organs/tissues of theimmune and haematopoietic systems were observed in nonclinical studies and were attributed to thepharmacological properties (JAK inhibition) of abrocitinib.

In toxicity studies of up to 1 month of abrocitinib dosing in rats at an age comparable to adolescenthuman age of ≥ 12 years, a microscopic bone dystrophy finding, considered transient and reversible,was noted, and exposure margins at which no bone finding was noted were 5.7 to 6.1 times the human

AUC at the maximum recommended human dose (MRHD) of 200 mg. No bone findings wereobserved 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 (comparable to humanage of ≥ 8 years; up to 30 times the human AUC at the MRHD of 200 mg).

Abrocitinib was not mutagenic in the bacterial mutagenicity assay (Ames assay). It was not aneugenicor clastogenic based on the results of the in vivo rat bone marrow micronucleus assay.

No evidence of tumorigenicity was observed in the 6-month Tg.rasH2 mice administered abrocitinib atoral doses up to 75 mg/kg/day and 60 mg/kg/day in female and male mice, respectively. In the 2-yearcarcinogenicity study, higher incidence of benign thymoma was noted in female rats at the lowest dosetested. Thus, a lowest observed adverse effect level (LOAEL) is set in females at exposures equal to0.6 times the human AUC at the MRHD of 200 mg. In males the no observed adverse effect level(NOAEL) was set at exposures equal to 13 times the human AUC at the MRHD of 200 mg. Thehuman relevance of benign thymoma is unknown.

Abrocitinib had no effects on male fertility or spermatogenesis. Abrocitinib resulted in effects onfemale fertility (lower fertility index, corpora lutea, implantation sites and post-implantation loss), butno fertility effects were noted at exposures equal to 1.9 times the human AUC at the MRHD of200 mg. The effects reversed 1 month after cessation of treatment.

No foetal malformations were observed in embryo-foetal development studies in rats or rabbits. In anembryo-foetal development study in pregnant rabbits, effects on embryo-foetal survival were noted atthe lowest dose tested with exposures equal to 0.14 times the unbound human AUC at the MRHD of200 mg. Increased litter incidences of unossified hindlimb phalanges and tarsals and forelimbphalanges were observed with effects on forelimb phalanges noted at exposures equal to 0.14 times theunbound human AUC at the MRHD of 200 mg.

In an embryo-foetal development study in pregnant rats, while increased embryo-foetal lethality wasnoted, none was observed at exposures equal to 10 times the human AUC at the MRHD of 200 mg.

Increased incidence of skeletal variations of short 13th ribs, reduced ventral processes, thickened ribs,and unossified metatarsals were noted in the foetuses, but none were observed at exposures equal to2.3 times the human AUC at the MRHD of 200 mg.

In a pre- and postnatal development study in pregnant rats, dams had dystocia with prolongedparturition, offspring had lower body weights and lower postnatal survival. No maternal ordevelopmental toxicity was observed in either dams or offspring at exposures equal to 2.3 times thehuman AUC at the MRHD of 200 mg.

Administration of abrocitinib to juvenile rats beginning on postnatal Day 10 (comparable to a3-month-old human infant) resulted in adverse microscopic and macroscopic bone findings, includingmalrotated paws, fractures, and/or femoral head abnormalities at exposures ≥ 0.8 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 microscopicor macroscopic bone finding.

Microcrystalline cellulose (E460i)

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Triacetin (E1518)

Iron red oxide (E172)

Not applicable.

4 years.

This medicinal product does not require any special storage conditions.

Cibinqo 50 mg film-coated tablets

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Cibinqo 50 mg film-coated tablets

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Date of first authorisation: 09 December 2021

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