4.1. Therapeutic indications

Cibinqo is indicated for the treatment of moderate-to-severe atopic dermatitis in adults and adolescents 12 years and older who are candidates for systemic therapy.

4.2. Posology and method of administration

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

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 adolescents (12 to 17 years old), and for patients at higher risk of venous thromboembolism (VTE), major adverse cardiovascular event (MACE) and malignancy (see section 4.4). If the patient does not respond adequately to 100 mg once daily, the dose can be increased to 200 mg once daily (see below).

• 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 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 considered. 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 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 section 4.4).

Dose interruption

If a patient develops a serious infection, sepsis or opportunistic infection, dose interruption should be considered 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 (see section 4.4).

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, dosing should be resumed at the regular scheduled time.

Interactions

In patients receiving strong inhibitors of cytochrome P450 (CYP) 2C19 (e.g. fluvoxamine, fluconazole, fluoxetine and ticlopidine), the recommended starting 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. rifampicin, apalutamide, efavirenz, enzalutamide, phenytoin) (see section 4.5).

Special populations

Renal impairment

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

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

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

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. Cibinqo must not be used in patients with severe (Child Pugh C) hepatic impairment (see section 4.3).

Elderly

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

Paediatric population

The recommended starting dose for adolescents (12 to 17 years old) is 100 mg once daily.

The safety and efficacy of Cibinqo in children under 12 years of age have not yet been established. No data are available.

Method of administration

This medicinal product 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.

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

4.3. Contraindications

• 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).

4.4. Special warnings and precautions for use

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

-65 years of age and older;

-patients with a 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 a history of malignancy)

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 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 age and older abrocitinib should only be used if no suitable treatment alternatives are available (see section 4.2).

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 Cibinqo 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 during and after treatment with abrocitinib. A patient who develops a new infection during treatment should undergo prompt and complete diagnostic testing and appropriate antimicrobial therapy should be initiated. The patient should be closely monitored and Cibinqo therapy should be temporarily interrupted if the patient is not responding to standard therapy.

Tuberculosis

Tuberculosis was observed in clinical studies with abrocitinib. Patients should be screened for TB before starting treatment and yearly screening for patients in highly endemic areas for TB should be considered. Abrocitinib must not be given to patients with active TB (see section 4.3). 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 section 4.8). 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 section 4.8). 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 abrocitinib. 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 abrocitinib 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 section 5.2). 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; 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 treatment with this medicinal product, it is recommended that patients be brought up to date with all immunisations, including prophylactic herpes zoster vaccinations, in agreement with current immunisation guidelines.

Venous thromboembolism (VTE)

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

In a large randomised active-controlled study of tofacitinib (another JAK inhibitor) in rheumatoid arthritis patients 50 years and older with at least one additional cardiovascular risk factor, a dose dependent 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 adverse cardiovascular events (MACE)” and “Malignancy”) abrocitinib should only be used if no suitable treatment 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 risk factors include previous VTE, patients undergoing major surgery, immobilisation, use of combined hormonal contraceptives or hormone replacement therapy, inherited coagulation disorder.

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.

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 rheumatoid arthritis 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 current or past long-time smokers, and patients with a 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, including abrocitinib.

In a large randomised active controlled study of tofacitinib (another JAK inhibitor) in rheumatoid arthritis 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.

A higher rate of malignancies (excluding non-melanoma skin cancer, NMSC) was observed with abrocitinib 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 other malignancy risk factors (e.g. current malignancy or a history of malignancy), abrocitinib should only be used if no suitable treatment alternatives are available.

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 (see section 4.8). 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 section 4.2). Complete blood count should be monitored 4 weeks after initiation of therapy and thereafter according to routine patient management (see Table 1).

Lipids

Dose-dependent increases in blood lipid parameters were reported in patients treated with abrocitinib compared to placebo (see section 4.8). Lipid parameters should be assessed approximately 4 weeks following initiation of Cibinqo therapy and thereafter according to their risk for cardiovascular disease. 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.

Laboratory monitoring

Table 1. Laboratory measure and monitoring guidance

Laboratory measure

Monitoring guidance

Action

Complete blood count including Platelet Count,

Absolute Lymphocyte Count (ALC),

Absolute Neutrophil Count (ANC), and

Haemoglobin (Hb)

Before treatment initiation, 4 weeks after initiation and thereafter according to routine patient management.

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

ALC: Treatment should be interrupted if ALC is < 0.5 × 103/mm3 and may be restarted once ALC returns above this value. Treatment should be discontinued if confirmed.

ANC: Treatment should be interrupted if ANC is < 1 × 103/mm3 and may be restarted once ANC returns above this value.

Hb: Treatment should be interrupted if Hb < 8 g/dL and may be restarted once Hb returns above this value.

Lipid parameters

Before treatment initiation, 4 weeks after initiation and thereafter according to clinical guidelines for hyperlipidaemia.

Patients should be monitored according to clinical guidelines for hyperlipidaemia.

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 section 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 in patients 65 years of age and older, as observed in a large randomised study of tofacitinib (another JAK inhibitor), abrocitinib should only be used in these patients if no suitable treatment alternatives are available.

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, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

Potential for other medicines to affect pharmacokinetics of abrocitinib

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 section 4.2.

Co-administration with CYP2C19/CYP2C9 inhibitors

When 100 mg Cibinqo 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 section 5.2) increased by 91% and 155%, respectively, compared with administration alone (see section 4.2).

Co-administration with CYP2C19/CYP2C9 inducers

Administration of 200 mg Cibinqo after multiple doses with rifampicin, a strong inducer of CYP enzymes, resulted in reduction of abrocitinib active moiety exposures by approximately 56% (see section 4.2). 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 MAO inhibitors

In-vitro, abrocitinib showed reversible inhibition of MAO-A. Co administration of Cibinqo with MAO inhibitors such as selegiline or isocarboxazid, has not been studied in humans. Caution should be exercised for concomitant use of abrocitinib with MAO inhibitors.

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, an H2-receptor antagonist, the peak and extent 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 medicinal products

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 AUCinf and Cmax 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 and ciclosporin, 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 AUCinf and Cmax 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 metabolised by CYP2C19 enzyme (e.g. S-mephenytoin, clopidogrel).

4.6. Fertility, pregnancy and lactation

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 should be encouraged.

Pregnancy

There are no or limited amount of data on the use of abrocitinib in pregnant women. Studies in animals have shown reproductive toxicity. Abrocitinib has been shown to cause 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 is contraindicated during pregnancy (see section 4.3).

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 (see section 4.3).

Fertility

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

4.7. Effects on ability to drive and use machines

Cibinqo has no or negligible sedating effect. However, patients who experience dizziness after the intake of abrocitinib should refrain from driving or using machines until the dizziness resolves.

4.8. Undesirable effects

Summary of the safety profile

The most commonly reported adverse reactions occurring in ≥ 2% of patients treated with Cibinqo 200 mg in placebo-controlled studies 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).

Tabulated list of adverse reactions

A total of 3848 patients were treated with Cibinqo in clinical studies in atopic dermatitis, among them 3050 patients (representing 5166 patient-years of exposure) were integrated for safety analysis, 2013 with at least 48 weeks of exposure. The integrated safety analysis included 1997 patients receiving a constant dose of abrocitinib 200 mg and 1053 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 2 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.

Table 2. Adverse reactions

System organ class

Very common

Common

Uncommon

Infections and infestations

Herpes simplexa

Herpes zosterb

Pneumonia

Blood and lymphatic system disorders

Thrombocytopenia

Lymphopenia

Neutropeniac

Metabolism and nutrition disorders

Hyperlipidaemiad

Nervous system disorders

Headache

Dizziness

Vascular disorders

Venous thromboembolisme

Gastrointestinal disorders

Nausea

Vomiting

Abdominal pain upper

Skin and subcutaneous tissue disorders

Acne

Investigations

Creatine phosphokinase increased ˃ 5 × ULNf

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

b. Herpes zoster includes ophthalmic herpes zoster.

c. Neutropenia includes neutrophil count decreased and granulocytopenia.

d. Hyperlipidaemia includes dyslipidaemia and hypercholesterolaemia.

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

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

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% versus 1.4%), herpes zoster (1.2% and 0.6% versus 0%), pneumonia (0.1% and 0.1% versus 0%). Herpes simplex was more frequent in patients with a history of herpes simplex or eczema herpeticum. Most of the herpes zoster events involved a single dermatome and were non-serious.

Among all patients treated 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 (4.36 per 100 patient-years) was higher than that of patients treated with 100 mg (2.61 per 100 patient-years). Incidence rates for herpes zoster were also higher for patients 65 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/mm3 prior 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 per 100 patient-years in patients treated with placebo, 3.32 per 100 patient-years in patients treated with 100 mg, and 1.12 per 100 patient-years in patients treated with 200 mg.

Among all patients treated 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 treated with 100 mg and 2.48 per 100 patient-years treated with 200 mg. The most commonly reported serious infections were herpes simplex, herpes zoster, and pneumonia (see section 4.4). Opportunistic infections were observed. Most of these were cases of herpes zoster (0.70 per 100 patient-years in the abrocitinib 100 mg group and 0.96 per 100 patient-years in the abrocitinib 200 mg group) and were non-serious multidermatomal cutaneous infections. Tuberculosis was observed in the abrocitinib 200 mg group (0.06 per 100 patient-years).

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 0.05 per 100 patient-years for 100 mg group and 0.21 per 100 patient-years for 200 mg group. The rate of DVT was 0.05 per 100 patient-years in the Cibinqo 100 mg group and 0.06 per 100 patient‑years in the Cibinqo 200 mg group (see section 4.4).

Thrombocytopenia

In placebo‑controlled studies, for up to 16 weeks, treatment 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 treated with 200 mg, and in 0 patients treated with 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 0.15 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 section 4.4).

Lymphopenia

In placebo‑controlled studies, for up to 16 weeks, confirmed ALC < 0.5 × 103/mm3 occurred in 0.3% of patients treated with 200 mg and 0% of patients treated with 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 0.34 per 100 patient-years for 200 mg and 0.05 per 100 patient-years for 100 mg, the highest rate was observed in patients 65 years of age and older (see section 4.4). There were no adolescent patients who developed an ALC < 0.5 × 103/mm3.

Neutropenia

Among all patients treated in clinical studies with consistent dosing regimens of either abrocitinib 100 mg or 200 mg, including the long‑term extension study, the incidence rate of confirmed ANC < 1 × 103/mm3 was 0.03 per 100 patient-years for 200 mg and 0 per 100 patient-years for 100 mg.

Lipid elevations

In placebo‑controlled studies, for up to 16 weeks, there was a dose-related 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; at Month 12 the median % change was 22.8% and 13.7% in the 200 mg and 100 mg groups, 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; at Month 12 the median % change was 17.1% and 8.9% in the 200 mg and 100 mg groups, 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 section 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% of patients treated with 200 mg of Cibinqo. 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 therapy. The median duration of nausea was 15 days. Most of the cases were mild to moderate in severity.

Acne

In placebo-controlled studies, for up to 16 weeks, acne was reported in 0.2% of patients treated with placebo and in 1.8% and 4.8% of patients treated with 100 mg and 200 mg, respectively. No subjects discontinued due to an event of acne. All events were mild to moderate in severity.

Paediatric population

A total of 635 adolescents (12 to less than 18 years of age) were enrolled in Cibinqo atopic dermatitis studies representing 1326.1 patient-years of exposure. The safety profile observed in adolescents in atopic dermatitis clinical studies was similar to that of the adult population (see section 4.2).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization 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 via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Cibinqo was administered in clinical studies up to a single oral dose of 800 mg and 400 mg daily for 28 days. Adverse reactions were comparable to those seen at lower doses and no specific toxicities were identified. In case of an overdose, it is recommended that the patient be monitored for signs and symptoms of adverse reactions (see section 4.8). 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.