Cibinqo

/ Pfizer

* The recommended starting dose is 100 mg or 200 mg once daily based on individual patient characteristics:
• A starting dose of 100 mg once daily is recommended for patients at higher risk  of venous thromboembolism (VTE), major adverse cardiovascular event (MACE) and malignancy. If the patient does not respond adequately to 100 mg once daily, the dose can be increased 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 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.
See prescribing information for full details.

Treatment of moderate-to-severe atopic dermatitis in adults who are candidates for systemic therapy.

• Hypersensitivity to the active substance or to any of the excipients.
• Active serious systemic infections, including tuberculosis (TB).
• Severe hepatic impairment.
• Pregnancy and breast-feeding.

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)
Serious infections
Serious infections have been reported in patients receiving abrocitinib. The most frequent serious infections in clinical studies were herpes simplex, herpes zoster and pneumonia.
Treatment must not be initiated in patients with an active, serious systemic infection.
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 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
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. 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
Viral reactivation, including herpes virus reactivation (e.g. herpes zoster, herpes simplex), was reported in clinical studies. 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. 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. 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 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.
Venous thromboembolism (VTE)
Events of deep venous thrombosis (DVT) and pulmonary embolism (PE) have been reported in patients receiving abrocitinib. Abrocitinib should be used with caution in patients at high risk for DVT/PE. Risk factors that should be considered in determining the patient’s risk for DVT/PE: dependent dose, a medical history of DVT/PE, prothrombotic disorder, use of combined hormonal contraceptives or hormone replacement therapy, patients undergoing major surgery or prolonged immobilization, inherited coagulation disorder. Patients should be re-evaluated periodically during abrocitinib treatment to assess for changes in VTE risk. If clinical features of DVT/PE occur, treatment should be discontinued and patients should be evaluated promptly, followed by appropriate treatment.
Major adverse cardiovascular events (MACE)
Events of MACE have been observed in patients taking abrocitinib
Malignancy (excluding non-melanoma skin cancers)
Lymphoma and other malignancies have been reported in patients receiving JAK inhibitors, including abrocitinib.
A higher rate of malignancies (excluding non-melanoma skin cancer, NMSC) was observed with abrocitinib 200 mg compared to abrocitinib 100 mg.
Non-melanoma skin cancer
NMSCs have been reported in patients receiving abrocitinib. Periodic skin examination is recommended for all patients, particularly those who are at increased risk for skin cancer.
Haematologic abnormalities
Confirmed ALC < 0.5 × 103/mm3 and platelet count < 50 × 103/mm3 were observed in less than 0.5% of patients in clinical studies. Treatment with 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. Complete blood count should be monitored 4 weeks after initiation of therapy and thereafter according to routine patient management.
Lipids
Dose-dependent increases in blood lipid parameters were reported in patients treated with abrocitinib compared to placebo. Lipid parameters should be assessed approximately 4 weeks following initiation of therapy and thereafter according to the patient’s 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. In patients with a high burden of cardiovascular risk factors, the risks and benefits of abrocitinib compared to that of other available therapies for atopic dermatitis should be considered. If abrocitinib is chosen, interventions to manage lipid concentrations should be implemented according to clinical guidelines.
Elderly
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. There are limited data in patients above 75 years of age.
Immunosuppressive conditions or medicinal products
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.
See prescribing information for full details.

Very common: Nausea.
Common: Herpes simplex, herpes zoster, headache, dizziness, vomiting
abdominal pain upper, acne, creatine phosphokinase increased ˃ 5 × ULN.
See prescribing information for full details.

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 inhibit or induce these enzymes and transporter.
Co-administration with CYP2C19/CYP2C9 inhibitors
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 increased by 91% and 155%, respectively, compared with administration alone.
Co-administration with CYP2C19/CYP2C9 inducers
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% .
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-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.
Potential for abrocitinib to affect pharmacokinetics of other medicinal products
No clinically significant effects of abrocitinib were observed in interaction studies with oral contraceptives (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 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.

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 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. This medicinal product is contraindicated during pregnancy.
Lactation
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. This medicinal product is contraindicated during breast-feeding.

This medicinal product 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. 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 volunteers indicate that more than 90% of the administered dose is expected to be eliminated within 48 hours.

Shelf life after first opening:
HDPE bottle: 45 days.