Serious Warnings and Precautions
CIBINQO (abrocitinib) is indicated for the treatment of patients 12 years and older with refractory moderate to severe atopic dermatitis, including the relief of pruritus, who have had an inadequate response to other systemic drugs (e.g. steroid or biologic), or for whom these treatments are not advisable.
CIBINQO can be used with or without medicated topical therapies for atopic dermatitis.
Limitations of Use: Use of CIBINQO in combination with other JAK inhibitors, biologic immunomodulators, or potent immunosuppressants such as methotrexate and cyclosporine has not been studied and is not recommended (see 7 WARNINGS AND PRECAUTIONS, Immune).
Pediatrics (12-17 years of age): Based on the data submitted and reviewed by Health Canada, the safety and efficacy of CIBINQO in pediatric patients 12-17 years of age has been established for treatment of moderate to severe atopic dermatitis.
Pediatrics under 12 years of age: The safety and efficacy of CIBINQO in pediatric patients under 12 years of age have not yet been established. Therefore, Health Canada has not authorized an indication for pediatric use in pediatric patients under 12 years of age.
Geriatrics ≥65 years of age: Caution should be used when treating geriatric patients with CIBINQO. There are limited data in patients 75 years of age and older. Clinical study results indicated that elderly patients were at increased risk for specific serious adverse events. (see 4.2 Recommended Dose and Dosage Adjustment, and 7.1.4 Geriatrics).
CIBINQO is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 Dosage Forms, Strengths, Composition and Packaging.
Serious Warnings and Precautions
CIBINQO should be taken orally once daily with or without food at approximately the same time each day.
In patients who experience nausea while taking CIBINQO, taking with food may improve nausea.
Treatment with CIBINQO should not be initiated in patients with a platelet count less than 150 × 103/mm3, an absolute lymphocyte count (ALC) less than 0.5 × 103/mm3, an absolute neutrophil count (ANC) less than 1 × 103/mm3 or who have a hemoglobin value less than 8 g/dL.
The recommended dose of CIBINQO is 100 mg or 200 mg orally once daily for adolescents and adults under 65 years of age, based on individual goal of therapy and potential risk for adverse reactions. For patients using the 200 mg once daily dosage, after symptom control is achieved by week 12, consider dose reduction to 100 mg once daily. Relative to patients who maintained the 200 mg dose, the risk of occurrence of serious adverse reactions decreased in patients who reduced their dose to 100 mg beyond 12 weeks in clinical studies. If symptom control is lost after dose reduction, the dose can be increased to 200 mg. Exceeding a daily dosage of 200 mg is not recommended.
CIBINQO can be used with or without medicated topical therapies for atopic dermatitis.
Elderly population
The recommended starting dose for patients ≥65 years of age is 100 mg. Some side effects that were more common in elderly patients in clinical trials, including herpes zoster, lymphopenia, and thrombocytopenia, occurred more frequently at the 200 mg daily dosage (see 8.2 Clinical Trial Adverse Reactions).
Pediatric population
For pediatric patients 12 to < 18 years of age, the starting recommended dose of CIBINQO is 100 mg or 200 mg once daily. Dosage adjustment should be considered based on individual goal of therapy and potential risk for adverse reactions.
The safety and efficacy of CIBINQO in pediatric patients under 12 years of age have not yet been established. No data are available.
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) or severe (eGFR <30 mL/min) renal impairment, the recommended dose of CIBINQO is to be reduced by 50% as shown in Table 1.
The use of CIBINQO has not been studied in patients with end-stage renal disease (ESRD) on renal replacement therapy.
| Renal Impairment Stage | Estimated Glomerular Filtration rate (eGFR) | Dose Adjustment | |
|---|---|---|---|
Indicated Dose 100 mg Once Daily | Indicated Dose 200 mg Once Daily | ||
Mild | 60 to <90 mL/min | None | None |
Moderate | 30 to <60 mL/min | CIBINQO 50 mg once daily | CIBINQO 100 mg once daily |
Severe | <30 mL/min | CIBINQO 50 mg once daily | CIBINQO 100 mg once daily |
Hepatic Impairment
No dose adjustment is required in patients with mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment. The safety of CIBINQO following daily dosing has not been studied in patients with hepatic impairment.
CIBINQO has not been studied in patients with severe hepatic impairment (Child Pugh C).
Concomitant use of CYP2C19 and CYP2C9 inhibitors
The dosage of CIBINQO should be reduced in half when co-administered with strong CYP2C19 and moderate CYP2C9 inhibitors (see 9.4 Drug-Drug Interactions).
Concomitant use of CYP2C19 and CYP2C9 inducers
Co-administration of CIBINQO with CYP2C19/2C9 inducers is not recommended (see 9.4 Drug-Drug Interactions).
Not applicable
CIBINQO should be taken orally once daily with or without food at approximately the same time each day.
Swallow CIBINQO tablets whole and intact with water. Do not crush, split, or chew CIBINQO tablets.
In patients who experience nausea while taking CIBINQO, taking with food may improve nausea.
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, resume dosing at the regular scheduled time.
Dose interruption
If a patient develops a serious infection, sepsis or opportunistic infection, interruption of treatment with CIBINQO until the infection is controlled should be considered (see Section 7 WARNINGS AND PRECAUTIONS).
Interruption of dosing may be needed for management of laboratory abnormalities as described in Table 3.
There is no experience with overdose of CIBINQO. There is no specific antidote for overdose with CIBINQO. 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.
Pharmacokinetic data up to and including a single dose of 800 mg in healthy volunteers indicate that more than 90% of the administered dose is expected to be eliminated within 48 hours.
| For management of a suspected drug overdose, contact your regional poison control centre. |
| Route of Administration | Dosage Form / Strength/Composition | Non-medicinal Ingredients |
|---|---|---|
| Oral | Tablet 50 mg, 100 mg, 200 mg / abrocitinib | Dibasic calcium phosphate anhydrous, Hypromellose, Iron oxide, Lactose monohydrate, Magnesium stearate, Microcrystalline cellulose, Sodium starch glycolate, Macrogol/PEG, Titanium dioxide and Triacetin |
CIBINQO is packaged in bottles or in blisters. Each blister pack contains (7 tablets x 4 blisters) 28 tablets and each bottle contains 30 tablets.
Please see the 3 SERIOUS WARNINGS AND PRECAUTIONS BOX at the beginning of Part I: Health Professional Information.
Malignancies, including non-melanoma skin cancer (NMSC), were observed in clinical studies with CIBINQO. Clinical data are insufficient to assess the potential relationship of exposure to CIBINQO and the development of malignancies. Long-term safety evaluations are ongoing.
Malignancies, including lymphomas, have occurred in patients receiving JAK inhibitors used to treat other inflammatory conditions. In a large, randomized, post-marketing safety study of another JAK inhibitor in RA patients, a higher rate of malignancies (excluding non-melanoma skin cancer (NMSC)) was observed in patients treated with the JAK inhibitor compared to those treated with TNF blockers. CIBINQO is not approved for use in RA. A higher rate of lymphomas was observed in patients treated with the JAK inhibitor compared to those treated with TNF blockers. A higher rate of lung cancers was observed in current or past smokers treated with the JAK inhibitor compared to those treated with TNF blockers. In this study, current or past smokers had an additional increased risk of overall malignancies.
The risks and benefits of CIBINQO treatment should be considered prior to initiating in patients with a known malignancy other than a successfully treated NMSC or cervical cancer in situ or when considering continuing CIBINQO therapy in patients who develop a malignancy. Periodic skin examination is recommended for patients who are at increased risk for skin cancer.
Venous thromboembolism
Events of deep venous thrombosis (DVT) and pulmonary embolism (PE) have been reported in patients receiving Janus kinase (JAK) inhibitors, including CIBINQO. In a large, randomized, postmarketing safety study of another JAK inhibitor in RA patients 50 years of age and older with at least one cardiovascular risk factor, higher rates of overall thrombosis, DVT, and PE were observed compared to those treated with TNF blockers. CIBINQO 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 include older age, obesity, a medical history of DVT/PE, prothrombotic disorder, use of combined hormonal contraceptives or hormone replacement therapy, patients undergoing major surgery, or prolonged immobilization. If clinical features of DVT/PE occur, CIBINQO treatment should be discontinued and patients should be evaluated promptly, followed by appropriate treatment.
Major Adverse Cardiovascular Events
Major adverse cardiovascular events were reported in clinical studies of CIBINQO for atopic dermatitis. In a large, randomized, post-marketing safety study of another JAK inhibitor in RA patients 50 years of age and older with at least one cardiovascular risk factor, a higher rate of MACE (defined as cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke) was observed with the JAK inhibitor compared to those treated with TNF blockers. CIBINQO is not approved for use in RA. Patients who are current or past smokers are at additional increased risk.
Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with CIBINQO, particularly in patients who are current or past smokers and patients with other cardiovascular risk factors. Patients should be informed about the symptoms of serious cardiovascular events and the steps to take if they occur. Discontinue CIBINQO in patients that have experienced a myocardial infarction or stroke.
Dizziness has been reported in patients receiving CIBINQO, which could influence the ability to drive or operate machines [see 8 ADVERSE REACTIONS]. Due caution should be exercised when driving or operating a vehicle or potentially dangerous machinery. Patients experiencing dizziness should be advised not to drive or operate machines until symptoms abate.
Lipids
Dose‑dependent increase in blood lipid parameters were reported in patients treated with CIBINQO. Lipid parameters should be assessed approximately 4 weeks following initiation of CIBINQO therapy and thereafter patients should be managed according to clinical guidelines for hyperlipidemia. The effect of these lipid parameter elevations on cardiovascular morbidity and mortality has not been determined.
Hematologic 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 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 hemoglobin value <8 g/dL. Platelet count and ALC should be monitored 4 weeks after initiation of therapy with CIBINQO and thereafter according to routine patient management.
CIBINQO is not recommended for use in patients with severe hepatic impairment (see 4.2 Recommended Dose and Dosage Adjustment, and 10.3 Pharmacokinetics, Special Populations and Conditions).
CIBINQO should not be used concomitantly with other potent immunosuppressants. Concomitant use of CIBINQO with other potent immunosuppressants (such as methotrexate and cyclosporine) or other JAK inhibitors has not been evaluated in clinical studies. There is a risk of additive immunosuppression when CIBINQO is co-administered with potent immunosuppressant drugs.
Vaccination
Avoid use of live, attenuated vaccines during or immediately prior to CIBINQO therapy. Prior to initiating CIBINQO, it is recommended that patients be brought up to date with all immunizations, including prophylactic herpes zoster vaccinations, in agreement with current immunization guidelines.
Serious infections have been reported in patients receiving CIBINQO. The most frequent serious infections in clinical studies were herpes simplex, herpes zoster, and pneumonia. The risks and benefits of treatment with CIBINQO should be carefully considered prior to initiating in patients with active, chronic, or recurrent infections.
Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with CIBINQO. A patient who develops a new infection during treatment with CIBINQO 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 interrupted if the patient is not responding to standard therapy.
Tuberculosis
Patients should be screened for tuberculosis (TB) before starting CIBINQO therapy and consider yearly screening for patients in highly endemic areas for TB. CIBINQO should 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 CIBINQO.
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 65 years of age and older.
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. 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 with CIBINQO; such patients had HBV DNA monitored. If HBV DNA is detected, a liver specialist should be consulted.
| Laboratory measure | Monitoring guidance | Action |
|---|---|---|
Complete blood count including Platelet Count, Absolute Lymphocyte Count (ALC), Absolute Neutrophil Count (ANC), and Hemoglobin (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 hyperlipidemia. | Patients should be monitored according to clinical guidelines for hyperlipidemia. |
Based on findings in rats, oral administration of CIBINQO may impair female fertility. Impaired fertility in female rats was reversible 1 month after cessation of abrocitinib oral administration (see 16 NON-CLINICAL TOXICOLOGY, Reproductive and developmental toxicity).
Women of childbearing potential:
Women of reproductive potential should be advised to use effective contraception during treatment with CIBINQO and for at least 1 month after the last dose. Consider pregnancy planning and prevention for females of reproductive potential.
Pregnancy:
The limited human data on use of CIBINQO in pregnant women are not sufficient to evaluate a drug-associated risk for major birth defects or miscarriage. In animal embryo-fetal development studies, oral administration of CIBINQO to pregnant rats during organogenesis resulted in fetotoxicity at exposures equal to approximately 17 times the unbound human AUC at the maximum recommended clinical dose of 200 mg once daily. No fetal malformations were observed. CIBINQO increased the incidence of skeletal variations at equal to or greater than 11 times the unbound human AUC at the maximum recommended clinical dose of 200 mg once daily (see 16 NON-CLINICAL TOXICOLOGY, Reproductive and developmental toxicity).
In a pre- and postnatal development study in pregnant rats, CIBINQO oral administration during gestation and through lactation resulted in lower postnatal survival, lower offspring body weights and/or dystocia with prolonged parturition at exposures equal to or greater than approximately 11 times the unbound human AUC at the maximum recommended clinical dose of 200 mg once daily (see 16 NON-CLINICAL TOXICOLOGY, Reproductive and developmental toxicity). CIBINQO should not be used during pregnancy unless clearly necessary.
There are no data on the presence of CIBINQO in human milk, the effects on the breast‑fed infant, or the effects on milk production. CIBINQO was secreted in milk of lactating rats. Women should not breast‑feed while treated with CIBINQO. A risk to newborns and infants cannot be excluded and CIBINQO should not be used during breast‑feeding.
Pediatrics (12-17 years of age):
Based on the data submitted and reviewed by Health Canada, the safety and efficacy of CIBINQO in pediatric patients 12-17 years of age has been established for treatment of moderate to severe atopic dermatitis.
Of the 2856 patients with atopic dermatitis exposed to CIBINQO, a total of 364 adolescents (12 to less than 18 years of age) were enrolled in CIBINQO studies. The safety profile observed in adolescents in atopic dermatitis clinical studies was similar to that of the adult population. There were no adolescent patients who developed platelet counts <75 × 103/mm3 or ALC <0.5 × 103/mm3.
Pediatrics under 12 years of age:
The safety and efficacy of CIBINQO in pediatric patients under 12 years of age have not yet been established. Therefore, Health Canada has not authorized an indication for pediatric use in pediatric patients under 12 years of age.
A total of 145 patients 65 years of age and older were enrolled in CIBINQO studies. The safety profile observed in elderly patients was generally similar to that of the adult population overall. A higher proportion of patients 65 years of age and older discontinued from clinical studies compared to younger patients. Among all patients exposed to CIBINQO, including the long‑term extension study, confirmed ALC <0.5 × 103/mm3 occurred only in patients 65 years of age and older. A higher proportion of patients 65 years of age and older had platelet counts <75 × 103/mm3. The incidence rate of herpes zoster in patients 65 years of age and older treated with CIBINQO (7.40 per 100 patient-years) was higher than that of patients 18 to less than 65 years of age (3.44 per 100 patient‑years) and less than that of patients younger than 18 years of age (2.12 per 100 patient‑years). There are limited data in patients above 75 years of age. (see 10 ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions).
For more information on the CIBINQO Education Program (Prescriber Brochure and Patient Card), please visit the CIBINQO website www.pfizer.ca.
The most commonly reported dose-related adverse reactions (ARs) occurring in ≥2% of patients treated with CIBINQO in placebo-controlled studies were nausea (10.3%), headache (6.8%), herpes simplex (3.8%), acne (3.2%), blood creatine phosphokinase increased (2.6%), dizziness (2.3%), and vomiting (2.3%). The most frequent serious adverse reactions were infections.
Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
A total of 2856 patients were treated with CIBINQO in Phase 2 and Phase 3 clinical studies in atopic dermatitis representing 1614 patient-years of exposure. There were 606 patients with more than 1 year of exposure to CIBINQO. The median age was 31.0 years, 12.7% were adolescents, and 5.1% were 65 years of age or older. Nearly half of the subjects (45.6%) were female. The majority of the subjects were White (72.2%); however, a substantial proportion were Asian (19.4%) and Black or African American (6%).
Four placebo‑controlled studies were integrated (608 patients on 100 mg once daily, 590 patients on 200 mg once daily and 342 patients on placebo) to evaluate the safety of CIBINQO in comparison to placebo for up to 16 weeks. Table 4 presents dose-related ADRs from these studies by Preferred term (PT) for CIBINQO listed by decreasing medical seriousness.
| ||||
| Number (%) of Patients | ||||
|---|---|---|---|---|
| Placebo N = 342 | CIBINQO 100 mg N = 608 | CIBINQO 200 mg N = 590 | ||
| Nausea, n (%) | 7 (2.0) | 37 (6.1) | 86 (14.6) | |
| Vomiting, n (%) | 3 (0.9) | 9 (1.5) | 19 (3.2) | |
| Abdominal pain upper (%) | 0 | 4 (0.7) | 11 (1.9%) | |
| Herpes simplex* | 6 (1.8) | 20 (3.3) | 25 (4.2) | |
| Headache | 12 (3.5) | 36 (5.9) | 46 (7.8) | |
| Dizziness | 3 (0.9) | 11 (1.8) | 17 (2.9) | |
| Acne | 0 | 10 (1.6) | 28 (4.7) | |
| Blood CPK increased | 5 (1.5) | 14 (2.3) | 17 (2.9) | |
Other adverse reactions reported in less than 2% of patients treated with CIBINQO in placebo-controlled studies for up to 12 or 16 weeks included pneumonia, and herpes zoster.
Overall Infections:
In placebo‑controlled studies, for up to 16 weeks, overall infections have been reported in 26.3% of patients treated with placebo and in 35.2% and 34.6% of patients treated with CIBINQO 100 mg and 200 mg, respectively. Most infections were mild or moderate.
Serious Infections:
In placebo‑controlled studies, for up to 16 weeks, serious infections have been reported in 2 patients (2.31 per 100 patient‑years) treated with placebo, 6 patients (3.80 per 100 patient-years) treated with CIBINQO 100 mg, and 2 patients (1.28 per 100 patient-years) treated with CIBINQO 200 mg. Among all patients treated with CIBINQO, including the long-term extension study, serious infections were reported in 17 patients (2.65 per 100 patient-years) treated with CIBINQO 100 mg and 24 patients (2.33 per 100 patient-years) treated with CIBINQO 200 mg. The most commonly reported serious infections were herpes simplex, herpes zoster and pneumonia.
Opportunistic Infections:
All observed opportunistic infections were cases of multidermatomal cutaneous herpes zoster. Among all patients treated with CIBINQO, including the long-term extension study, opportunistic infections were reported in 1 patient (0.16 per 100 patient-years) treated with CIBINQO 100 mg and 9 patients (0.87 per 100 patient-years) treated with CIBINQO 200 mg. Most cases of opportunistic herpes zoster were mild or moderate.
Venous Thromboembolism:
Among all patients treated with CIBINQO, including the long-term extension study, PE was reported in 3 patients (0.18 per 100 patient-years), all treated with CIBINQO 200 mg. Events of DVT were reported in 2 patients (0.09 per 100 patient-years) treated with CIBINQO 200 mg
Thrombocytopenia:
In placebo‑controlled studies, for up to 16 weeks, treatment with CIBINQO 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 1 patient (0.1%) exposed to CIBINQO 200 mg, 0 patients treated with CIBINQO 100 mg or placebo. Among all patients exposed to CIBINQO, including the long‑term extension study, confirmed platelet counts of <50 × 103/mm3 were reported in 2 patients (0.1%), both treated with CIBINQO 200 mg.
Lymphopenia:
In placebo‑controlled studies, for up to 16 weeks, confirmed ALC <0.5 × 103/mm3 occurred in 2 patients (0.3%) treated with CIBINQO 200 mg and 0 patients treated with CIBINQO 100 mg or placebo. Both cases occurred in the first 4 weeks of exposure. Among all patients exposed to CIBINQO, including the long-term extension study, confirmed ALC <0.5 × 103/mm3 were reported in 4 patients (0.1%) treated with 200 mg of CIBINQO and 0 patients treated with CIBINQO 100 mg.
Nausea:
Nausea was most frequent in the first week of CIBINQO therapy and generally resolved with continued therapy. The median duration of nausea was 15 days. Most of the cases were mild to moderate in severity.
Pediatric population:
Of the 2,856 patients with atopic dermatitis exposed to CIBINQO, a total of 364 adolescents (12 to less than 18 years of age) were enrolled in CIBINQO studies. The safety profile observed in adolescents in atopic dermatitis clinical studies was similar to that of the adult population. There were no adolescent patients who developed platelet counts < 75 x 103/mm3 or ALC < 0.5 x 103/mm3.
Elderly:
A total of 145 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 overall. A higher proportion of patients 65 years of age and older discontinued from clinical studies compared to younger patients. Among all patients exposed to CIBINQO, including the long‑term extension study, confirmed ALC <0.5 × 103/mm3 occurred only in patients 65 years of age and older. A higher proportion of patients 65 years of age and older had platelet counts <75 × 103/mm3. The incidence rate of herpes zoster in patients 65 years of age and older treated with CIBINQO (7.40 per 100 patient-years) was higher than that of patients 18 to less than 65 years of age (3.44 per 100 patient‑years) and less than 18 years of age (2.12 per 100 patient‑years). There are limited data in patients above 75 years of age.
In the All Exposure Pool (which included subjects from 5 clinical studies plus a long-term extension study), adolescent subjects were more likely to have any Adverse Event (AE) relative to the 18 - <65-year-old subgroup. The results of an additional study conducted in adolescents using a combination therapy of CIBINQO with medicated topical treatments were consistent with this finding. There was no clustering of AEs driving the difference and, as such, the overall AE profile was similar.
In the All Exposure Pool, there were no meaningful differences in the proportions of adolescent subjects having serious infection relative to the other age groups. The IR for all herpes zoster infections was lowest in the adolescent subgroup relative to the other age groups. No adolescent subject had hematology laboratory values meeting pre-specified discontinuation criteria. In the Primary Pool, a similar proportion of adolescent subjects in the placebo and abrocitinib groups had shifts above 130 mg/dL in LDL.
Blood and lymphatic system disorders: Thrombocytopenia, Lymphopenia
Metabolism and nutrition disorders: Hyperlipidemia (dyslipidemia and hypercholesterolemia)
Vascular disorders: Venous thromboembolism (includes pulmonary embolism and deep vein thrombosis)
Lipid Elevations:
In placebo‑controlled studies, for up to 16 weeks, there was a dose-related percent 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 change in the LDL/HDL ratio or triglycerides. Events related to hyperlipidemia occurred in 1 patient (0.2%) exposed to CIBINQO 100 mg, 7 patients (1.2%) exposed to CIBINQO 200 mg and 0 patients exposed to placebo.
Creatine Phosphokinase Elevations (CPK):
In placebo‑controlled studies, for up to 16 weeks, events of blood CPK increased were reported in 1.5% of patients treated with placebo, 2.3% and 2.9% of patients treated with 100 mg and 200 mg of CIBINQO, respectively. Most elevations were transient, and none led to discontinuation. In the clinical studies, there were no reported events of rhabdomyolysis.
Not applicable.
When indicated dose is 100 mg or 200 mg CIBINQO dose should be reduced by half to 50 mg or 100 mg once daily respectively in patients receiving strong inhibitors of cytochrome P450 (CYP) 2C19 (e.g., fluconazole, fluvoxamine, fluoxetine) and in patients receiving one or more concomitant medicinal products that result in both moderate inhibition of CYP2C9 (e.g., amiodarone, fluconazole) as well as strong inhibition of CYP2C19. The use of CIBINQO is not recommended concomitantly with strong inducers of CYP enzymes (e.g., rifampin).
The drugs listed in table 5 are based on either drug interaction case reports or studies, or potential interactions due to the expected magnitude and seriousness of the interaction (i.e., those identified as contraindicated).
Potential for Other Drugs to Affect Pharmacokinetics of Abrocitinib:
Abrocitinib is metabolized predominantly by CYP2C19 and CYP2C9 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 below.
| |||
| Proper/Common name | Source of Evidence | Effect | Clinical comment |
|---|---|---|---|
Fluvoxamine Fluconazole
| CT | When CIBINQO 100 mg 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. | Caution should be exercised when administering CIBINQO with dual strong CYP2C19/ and moderate CYP2C9 inhibitors, or strong CYP2C19 inhibitors alone.
Dosage reduction of CIBINQO is recommended [see 4.2 Recommended Dose and Dosage Adjustment, 10 ACTION AND CLINICAL PHARMACOLOGY] |
Rifampin | CT | Administration of CIBINQO 200 mg after multiple dosing with rifampin, a strong inducer of CYP enzymes, resulted in reduction of abrocitinib active moiety exposures by approximately 56%. | Coadministration of CIBINQO with strong or moderate CYP2C19/CYP2C9 inducers is not recommended [see 10 ACTION AND CLINICAL PHARMACOLOGY] |
Probenecid | CT | 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.
|
Potential for Abrocitinib to Affect Pharmacokinetics of Other Drugs:
In vitro, abrocitinib or its metabolites were not significant inhibitors or inducers of CYPs (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) or of uridine diphosphate-glucuronyltransferases (UGTs) (UGT1A1, UGT1A4, UGT1A6, UGT1A9, and UGT2B7). In vitro, abrocitinib is an inhibitor of P-glycoprotein (P-gp), organic anion transporter (OAT)3, organic cation transporter (OCT)1, multidrug and toxin compound extrusion protein (MATE)1/2K and breast cancer resistance protein (BCRP) but is not an inhibitor of organic anion transporting polypeptide (OATP)1B1/1B3, bile salt export pump (BSEP), OAT1 or OCT2 at clinically meaningful concentrations. The metabolites do not change the transporter inhibition risk compared to abrocitinib.
No clinically significant effects of CIBINQO were observed in drug interaction studies with oral contraceptives (e.g., ethinyl estradiol/levonorgestrel), or with substrates of BCRP and OAT3 (e.g., rosuvastatin), MATE1/2K (e.g., metformin) and CYP3A4 (e.g., midazolam).
Coadministration 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.
CIBINQO was administered without regard to food.
Interactions with herbal products have not been evaluated.
Interactions with laboratory tests have not been evaluated.
Abrocitinib is a highly selective Janus kinase (JAK)1 inhibitor. JAKs are intracellular enzymes which transmit signals arising from cytokine or growth factor‑receptor interactions on the cellular membrane to influence cellular processes of hematopoiesis and immune cell function. Within signaling pathways, JAKs phosphorylate and activate Signal Transducers and Activators of Transcription (STATs) which modulate intracellular activity including gene expression. Abrocitinib modulates the signaling pathway at the point of JAK1, preventing the phosphorylation and activation of STATs.
Abrocitinib reversibly and selectively inhibits JAK1 by blocking the adenosine triphosphate (ATP) binding site. In a cell-free isolated enzyme assay, abrocitinib has biochemical selectivity for JAK1 over the other 3 JAK isoforms JAK2 (28-fold), JAK3 (>340-fold) and tyrosine kinase (TYK) 2 (43-fold), and even higher selectivity over the broader kinome. In cellular settings, where JAK enzymes transmit signals in pairs (i.e., JAK1/JAK2, JAK1/JAK3, JAK1/TYK2, JAK2/JAK2, JAK2/TYK2), abrocitinib preferentially inhibits cytokine‑induced STAT phosphorylation mediated by receptors utilizing JAK1 relative to receptors utilizing JAK2 only or JAK2/TYK2 pairs. The relevance of inhibition of specific JAK enzymes to therapeutic effectiveness is not currently known. Both the parent compound and the active metabolites (M1 and M2) inhibit cytokine signaling with similar levels of selectivity.
Treatment with CIBINQO was associated with dose-dependent reduction in serum markers of inflammation, including high sensitivity C-reactive protein (hsCRP), interleukin-31 (IL-31) and thymus and activation-regulated chemokine (TARC). These changes returned to near baseline within 4 weeks of drug discontinuation.
|
| Cmax (ng/mL)a | Tmax (h)b | t½ (h)c | AUC0-∞ (ng·h/mL)a | CL/F (L/h)a | Vz/F (L)a |
|---|---|---|---|---|---|---|
| 100 mg | ||||||
| Abrocitinib | 420.2 | 1 | 4.3 | 1578 | 63.41 | 323.3 |
| M1 | 49.0 | 1 | 4.3 | 565.6 | N/A | N/A |
| M2 | 95.8 | 1 | 2.9 | 532.9 | N/A | N/A |
| 200 mg | ||||||
| Abrocitinib | 756.5 | 1 | 5.9 | 3902 | 51.24 | 375.2 |
| M1 | 210.2 | 1 | 4.2 | 998.5 | N/A | N/A |
| M2 | 162.1 | 2 | 3.9 | 1197 | N/A | N/A |
| ||||||
Abrocitinib is well-absorbed with over 91% extent of oral absorption and absolute oral bioavailability of approximately 60%. Both Cmax and AUC of abrocitinib increased dose proportionally over the recommended daily dosage range. Coadministration of CIBINQO with a high-fat meal had no clinically relevant effect on abrocitinib exposures (AUC and Cmax increased by approximately 26% and 29%, respectively, and Tmax was prolonged by 2 hours). In clinical studies, CIBINQO was administered without regard to food.
After intravenous administration, the volume of distribution of CIBINQO 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 bind predominantly to albumin. Abrocitinib and its active metabolites distribute equally between red blood cells and plasma.
The metabolism of abrocitinib is mediated by multiple CYP enzymes, CYP2C19 (~53%), CYP2C9 (~30%), CYP3A4 (~11%) and CYP2B6 (~6%). In a human radiolabeled study, abrocitinib was the most prevalent circulating species, with 3 polar mono-hydroxylated metabolites identified as M1 (3-hydroxypropyl), M2 (2-hydroxypropyl), and M4 (pyrrolidinone pyrimidine). Of the 3 metabolites in circulation, M1 and M2 have similar JAK inhibitory profiles as abrocitinib, while M4 was pharmacologically inactive. The pharmacologic activity of CIBINQO is attributable to the unbound exposures 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 adjusted for relative potencies, is referred to as the abrocitinib active moiety.
CIBINQO is eliminated primarily by metabolic clearance mechanisms, with less than 1% of the dose excreted in urine as unchanged drug. The metabolites of abrocitinib, M1, M2 and M4 are excreted predominantly in urine, and are substrates of OAT3 transporter.
Pediatric (under 12 years of age):
The pharmacokinetics of CIBINQO in pediatric patients under 12 years of age have not yet been established.
In a pre- and postnatal development study in pregnant rats, CIBINQO oral administration during gestation and through lactation resulted in lower postnatal survival and lower offspring body weights at exposures equal to or greater than approximately 11 times the unbound human AUC the maximum recommended clinical dose of 200 mg once. CIBINQO should not be used during pregnancy unless clearly necessary.
CIBINQO has not been studied in patients with ESRD on renal replacement therapy. In Phase 3 clinical studies, CIBINQO was not evaluated in patients with atopic dermatitis with baseline creatinine clearance values less than 40 mL/min.
Store CIBINQO at room temperature, 15°C - 30°C in original package.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Control #: 271439
June 30, 2023
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