Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Pfizer Europe MA EEIG, Boulevard de la Plaine 17, 1050 Bruxelles, Belgium
Abrocitinib should only be used if no suitable treatment alternatives are available in patients:
Serious infections have been reported in patients receiving abrocitinib. 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 abrocitinib should be considered for patients:
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 therapy should be temporarily interrupted if the patient is not responding to standard therapy.
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 treatment.
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.
Screening for viral hepatitis should be performed in accordance with clinical guidelines before starting therapy and during therapy. 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.
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 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.
Events of deep venous thrombosis (DVT) and pulmonary embolism (PE) have been reported in patients receiving abrocitinib (see section 4.8).
In a large randomized 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.
Events of MACE have been observed in patients taking abrocitinib.
In a large randomized 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 history of atherosclerotic cardiovascular disease or other cardiovascular risk factors, abrocitinib should only be used if no suitable treatment alternatives are available.
Lymphoma and other malignancies have been reported in patients receiving JAK inhibitors, including abrocitinib.
In a large randomized 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 history of malignancy), abrocitinib should only be used if no suitable treatment alternatives are available.
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.
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 in patients with a platelet count <150 × 103/mm³, an ALC <0.5 × 103/mm³, an ANC <1.2 × 103/mm³ or who have a haemoglobin value <10 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).
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 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 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.
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 reactions 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.
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.
Patients with immunodeficiency disorders or a first-degree relative with a hereditary immunodeficiency were excluded from clinical studies and no information on these patients is available.
Combination with biologic immunomodulators, potent immunosuppressants such as ciclosporin or other Janus kinase (JAK) inhibitors has not been studied. Their concomitant use with abrocitinib is not recommended as a risk of additive immunosuppression cannot be excluded.
Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-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’.
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 inhibit or induce these enzymes and transporter. Dose adjustments, as appropriate, are outlined in section 4.2.
When 100 mg abrocitinib 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).
Administration of 200 mg abrocitinib 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).
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.
When abrocitinib 200 mg was administered concomitantly with famotidine 40 mg, an H2-receptor antagonist, abrocitinib active moiety exposures decreased by approximately 35%. The effect of elevating gastric pH with antacids, or proton pump inhibitors (omeprazole) on the pharmacokinetics of abrocitinib has not been studied and may be similar to that seen with famotidine. The higher 200 mg daily dose should be considered for patients treated concomitantly with products which increase gastric pH, as they may reduce the efficacy of abrocitinib.
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 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 the pharmacokinetics of other P-gp substrates has not been evaluated. Caution should be exercised as the levels of P-gp substrates with a narrow therapeutic index, such as digoxin, may increase.
In vitro, abrocitinib is an inhibitor of CYP2C19 enzyme. Co-administration of abrocitinib 200 mg once daily with omeprazole 10 mg single dose increased the 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 and 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 treatment and for 1 month following the final dose of Cibinqo. Pregnancy planning and prevention for females of reproductive potential should be encouraged.
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 embryo-foetal lethality 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 is contraindicated 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, 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).
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).
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. Among them 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 mg and 1 053 patients receiving a constant dose of 100 mg. There were 2 013 patients with at least 48 weeks of exposure. 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 abrocitinib 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 | ||
| Metabolism and nutrition disorders | Hyperlipidaemiac | ||
| Nervous system disorders | Headache Dizziness | ||
| Vascular disorders | Venous thromboembolismd | ||
| Gastrointestinal disorders | Nausea | Vomiting Abdominal pain upper | |
| Skin and subcutaneous tissue disorders | Acne | ||
| Investigations | Creatine phosphokinase increased ˃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 patients treated 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 reporting infection-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 herpes simplex or eczema herpeticum. Most of the herpes zoster events involved a single dermatome and were non-serious. Most opportunistic infections 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), most of which were non-serious multidermatomal cutaneous infections. 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 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 abrocitinib 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 2.46 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).
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 rate of PE was 0.21 per 100 patient-years for 200 mg and 0.05 per 100 patient-years for 100 mg. The rate of DVT was 0.06 per 100 patient-years in the 200 mg group and 0.05 per 100 patient-years in the 100 mg group (see section 4.4).
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 exposed to 200 mg, and in 0 patients treated with 100 mg or placebo. Among all patients treated with clinical studies with consistent dosing regimens of either abrocitinib 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 patients-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).
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 abrocitinib 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 per 100 patient-years for 100 mg, the highest rate was observed in patients 65 years of age and older (see section 4.4).
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. There was no meaningful change in the LDL/HDL ratio in patients treated with abrocitinib relative to patients treated with placebo. Events related to hyperlipidaemia occurred in 0.4% of patients exposed to abrocitinib 100 mg, 0.6% of patients exposed to 200 mg and 0% of patients exposed to placebo (see section 4.4).
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 abrocitinib, respectively. Most elevations were transient and none led to discontinuation.
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 abrocitinib. 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.
A total of 635 adolescent patients (12 to less than 18 years of age) were treated with abrocitinib in clinical studies in atopic dermatitis representing 1 326.1 patient-years of exposure. The safety profile observed 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. 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 national reporting system listed in Appendix Ⅴ.
Not applicable.
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