CIBINQO® (abrocitinib) 12 CLINICAL PHARMACOLOGY

(abrocitinib)

Prescribing Information

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

CIBINQO is a Janus kinase (JAK) inhibitor.

Abrocitinib reversibly inhibits JAK1 by blocking the adenosine triphosphate (ATP) binding site. In a cell-free isolated enzyme assay, abrocitinib was selective for JAK1 over JAK2 (28-fold), JAK3 (>340-fold), and tyrosine kinase (TYK) 2 (43-fold), as well as the broader kinome. The relevance of inhibition of specific JAK enzymes to therapeutic effectiveness is not currently known. Both the parent compound and the active metabolites inhibit JAK1 activity in vitro with similar levels of selectivity.

12.2 Pharmacodynamics

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.

Effect on Platelet Count

Treatment with CIBINQO was also associated with a transient, dose-dependent decrease in platelet count with the nadir occurring at a median of 24 days after continuous administration of abrocitinib 200 mg once daily. The percent change from baseline of the nadir increases with decreasing baseline platelet counts (-41.2%, -33.4%, and -26.5% for baseline platelet counts of 170, 220, and 270 × 103/mm3, respectively). Partial recovery of platelet count (~40% recovery in platelet count by 12 weeks) occurred without discontinuation of the treatment.

Cardiac Electrophysiology

At a dose 3 times the maximum approved recommended dose, abrocitinib does not prolong the QT interval to any clinically relevant extent.

12.3 Pharmacokinetics

Abrocitinib plasma Cmax and AUC increased dose proportionally up to 200 mg. Steady-state plasma concentrations of abrocitinib are achieved within 48 hours after once daily administration.

Absorption

Abrocitinib is absorbed with over 91% extent of oral absorption and absolute oral bioavailability of approximately 60%. The peak plasma concentrations of abrocitinib are reached within 1 hour.

Effect of Food

Coadministration of CIBINQO with a high-fat, high-calorie meal (total 916 calories, with approximate distribution of 55% fat, 29% carbohydrates, and 16% protein) had no clinically relevant effect on abrocitinib exposures (AUC and Cmax of abrocitinib increased by approximately 26% and 29%, respectively, and Tmax was prolonged by 2 hours) [see Dosage and Administration (2.7)].

Distribution

After intravenous administration, the volume of distribution of abrocitinib is approximately 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 M1 and M2 bind predominantly to albumin and distribute equally between red blood cells and plasma.

Elimination

Abrocitinib is eliminated primarily by metabolic clearance mechanisms. The mean elimination half-lives of abrocitinib and its two active metabolites, M1 and M2, range 3 to 5 hours.

Metabolism

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 two active polar mono-hydroxylated metabolites identified as M1 (3-hydroxypropyl), and M2 (2-hydroxypropyl). Metabolite M1 is less active than abrocitinib while metabolite M2 is as active as the parent. The pharmacologic activity of abrocitinib is attributable to the unbound exposure 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 combined exposure of abrocitinib and its two active metabolites, M1 and M2.

Excretion

After a single radiolabeled abrocitinib dose, less than 1% of the dose was excreted in urine as unchanged drug. The metabolites of abrocitinib, M1 and M2 are excreted predominantly in urine, and are substrates of OAT3 transporter.

Specific Populations

Body weight, sex, race, and age did not have a clinically meaningful effect on CIBINQO exposure.

Patients with Renal Impairment

In a renal impairment study, subjects with severe (eGFR <30 mL/min as estimated by MDRD equation) and moderate (eGFR 30–59 mL/min, MDRD) renal impairment had approximately 191% and 110% increase in the combined exposure (AUCinf,u) of abrocitinib and its active metabolites, M1 and M2, respectively, compared to subjects with normal renal function (eGFR ≥90 mL/min, MDRD). Based on these results, a clinically significant increase in the combined exposure of abrocitinib and its active metabolites, M1 and M2, is not expected in patients with mild renal impairment (eGFR 60 –89 mL/min, MDRD) [see Dosage and Administration (2.3) and Use in Specific Population (8.6)].

CIBINQO has not been studied in subjects on renal replacement therapy [see Dosage and Administration (2.3) and Use in Specific Population (8.6)]. In Phase 3 clinical trials, CIBINQO was not evaluated in subjects with atopic dermatitis with baseline creatinine clearance values less than 40 mL/min.

Patients with Hepatic Impairment

Subjects with mild hepatic impairment (Child Pugh A) had approximately 4% decrease in the combined exposure (AUCinf,u) of abrocitinib and its two active metabolites, M1 and M2, compared to subjects with normal hepatic function. Subjects with moderate hepatic impairment (Child Pugh B) had approximately 15% increase in the combined exposure (AUCinf,u) of abrocitinib and its two active metabolites, M1 and M2, compared to subjects with normal hepatic function. These changes are not clinically significant. In clinical trials, CIBINQO has not been studied in subjects with severe (Child Pugh C) hepatic impairment, or in subjects screened positive for active hepatitis B or hepatitis C [see Use in Specific Populations (8.7) and Warnings and Precautions (5.1)].

Drug Interaction Studies

Clinical Studies

The effect of coadministered drugs on the pharmacokinetics of abrocitinib is presented in Table 6.

Table 6. Change in Pharmacokinetics of the Combined Exposure of Abrocitinib and its Two Active Metabolites (M1 and M2) in the Presence of Coadministered Drugs
* Ratios for Cmax,u and AUCinf,u compare coadministration of the drug with abrocitinib versus administration of abrocitinib alone. † When coadministered with Fluconazole, the systemic exposure of abrocitinib was approximately 4.8-fold higher compared to when abrocitinib is administered alone. ‡ Drug interaction with OAT3 inhibitor is not clinically significant.
Coadministered Drugs	Regimen of Coadministered Drug	Dose of Abrocitinib	Ratio* (90% Confidence Interval)
Coadministered Drugs	Regimen of Coadministered Drug	Dose of Abrocitinib	Cmax,u	AUCinf,u
Strong CYP2C19 and moderate CYP3A inhibitor: Fluvoxamine [see Drug Interactions (7.1)]	50 mg once daily × 9 days	100 mg	1.33 (1.00–1.78)	1.91 (1.74–2.10)
Strong CYP2C19, moderate CYP2C9 and CYP3A inhibitor: Fluconazole [see Drug Interactions (7.1)]	400 mg on Day 1 and 200 mg on Days 2–7	100 mg	1.23 (1.08–1.42)	2.55† (2.42–2.69)
Strong CYP Enzymes Inducers: Rifampin [see Drug Interactions (7.1)]	600 mg once daily × 8 days	200 mg	0.69 (0.50–0.94)	0.44 (0.41–0.47)
OAT3 inhibitor: Probenecid‡	1,000 mg twice daily × 3 days	200 mg	1.30 (1.04–1.63)	1.66 (1.52–1.80)

The effect of abrocitinib on the pharmacokinetics of coadministered drugs is presented in Table 7.

Table 7. Change in Pharmacokinetics of Coadministered Drugs in the Presence of Abrocitinib
* Ratios for Cmax and AUCinf compare coadministration of abrocitinib with the drug versus administration of the drug alone. † AUClast of levonorgestrel was reported in lieu of AUCinf because the terminal phase of levonorgestrel was not well characterized.
Coadministered Drugs or In Vivo Markers of CYP Activity	Dose Regimen of Abrocitinib	Ratio* (90% Confidence Interval)
Coadministered Drugs or In Vivo Markers of CYP Activity	Dose Regimen of Abrocitinib	Cmax	AUCinf
Oral contraceptive: Ethinyl estradiol (EE) and levonorgestrel (LN)	200 mg once daily × 9 days	EE: 1.07 (0.99, 1.15) LN: 0.86 (0.75, 0.97)	EE: 1.19 (1.12, 1.26) LN†: 0.98 (0.87, 1.10)
Sensitive CYP3A Substrate: Midazolam	200 mg once daily × 7 days	0.93 (0.84, 1.04)	0.92 (0.86, 0.99)
Sensitive P-gp substrate: Dabigatran	200 mg single dose	1.40 (0.92, 2.13)	1.53 (1.09, 2.15)
Sensitive BCRP and OAT3 substrate: Rosuvastatin	200 mg once daily × 3 days	0.99 (0.86, 1.14)	1.02 (0.93, 1.12)
Sensitive MATE1/2K substrate: Metformin	200 mg once daily × 2 days	0.88 (0.81, 0.96)	0.93 (0.85, 1.03)

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. These increases in dabigatran exposure are not considered clinically significant change. However, appropriate dose titration of P-gp substrate where small concentration changes may lead to serious or life-threatening toxicities (e.g., digoxin) when coadministered with the CIBINQO would be needed.

In Vitro Studies

Cytochrome P450 (CYP) Enzymes: Abrocitinib and its metabolites M1 and M2 are not inhibitors or inducers of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4.

Uridine diphosphate (UDP)-glucuronosyl transferase (UGT) Enzymes: Abrocitinib and its metabolites M1 and M2 are not inhibitors or inducers of UGT1A1, UGT1A4, UGT1A6, UGT1A9, or UGT2B7.

Transporter Systems: Abrocitinib is an inhibitor of organic cation transporter (OCT)1 but is not an inhibitor of organic anion transporting polypeptide (OATP)1B1/1B3, bile salt export pump (BSEP), OAT1 or OCT2.

12.5 Pharmacogenomics

Patients who are CYP2C19 poor metabolizers have little to no CYP2C19 enzyme function compared to CYP2C19 normal metabolizers that have fully functional CYP2C19 enzymes.

After single doses of abrocitinib, CYP2C19 poor metabolizers demonstrated dose-normalized AUC of abrocitinib values that were 2.3-fold higher when compared to CYP2C19 normal metabolizers. Approximately 3–5% of Whites and Blacks and 15 to 20% of Asians are CYP2C19 poor metabolizers [see Dosage and Administration (2.4) and Use in Specific Populations (8.8)].

Medication Guide

MEDICATION GUIDE

Medication Guide CIBINQO (Si BINK oh) (abrocitinib) tablets, for oral use
What is the most important information I should know about CIBINQO? CIBINQO may cause serious side effects, including: 1. Serious infections CIBINQO is a medicine that affects your immune system. CIBINQO can lower the ability of your immune system to fight infections. Some people have had serious infections while taking CIBINQO or other similar medicines, including tuberculosis (TB), and infections caused by bacteria, fungi, or viruses that can spread throughout the body. Some people have been hospitalized or died from these infections. • Your healthcare provider should test you for TB before starting treatment with CIBINQO. • Your healthcare provider should watch you closely for signs and symptoms of TB during treatment with CIBINQO. You should not start taking CIBINQO if you have any kind of infection unless your healthcare provider tells you it is okay. You may be at a higher risk of developing shingles (herpes zoster). Before starting CIBINQO, tell your healthcare provider if you: • are being treated for an infection • have had an infection that does not go away or that keeps coming back • have diabetes, chronic lung disease, HIV, or a weak immune system • have TB or have been in close contact with someone with TB • have had shingles (herpes zoster) • have had hepatitis B or hepatitis C • live or have lived or have traveled to certain parts of the country (such as the Ohio and Mississippi River valleys and the Southwest) where there is an increased chance for getting certain kinds of fungal infections. These infections may happen or become more severe if you use CIBINQO. Ask your healthcare provider if you do not know if you have lived in an area where these infections are common. • think you have an infection or have symptoms of an infection such as:
	o fever, sweating, or chills o muscle aches o cough or shortness of breath	o blood in your phlegm o weight loss o warm, red, or painful skin or sores on your body o diarrhea or stomach pain o burning when you urinate or urinating more often than usual o feeling very tired
After starting CIBINQO, call your healthcare provider right away if you have any symptoms of an infection. CIBINQO can make you more likely to get infections or make any infections that you have worse. If you get a serious infection, your healthcare provider may stop treatment with CIBINQO until your infection is controlled. 2. Increased risk of death in people 50 years of age and older who have at least 1 heart disease (cardiovascular) risk factor and are taking a medicine in the class of medicines called Janus kinase (JAK) inhibitors. CIBINQO is a JAK inhibitor medicine. 3. Cancer and immune system problems CIBINQO may increase your risk of certain cancers by changing the way your immune system works. • Lymphoma and other cancers, including skin cancers, can happen in people taking CIBINQO. • People taking a medicine in the class of medicines called Janus kinase (JAK) inhibitors have a higher risk of certain cancers including lymphoma and lung cancer, especially if you are a current or past smoker. • Follow your healthcare provider's advice about having your skin checked for skin cancer during treatment with CIBINQO. Limit the amount of time you spend in sunlight. Avoid using tanning beds or sunlamps. Wear protective clothing when you are in the sun and use a sunscreen with a high protection factor (SPF 30 and above). This is especially important if your skin is very fair or of you have a family history of skin cancer. Tell your healthcare provider if you have ever had any type of cancer. 4. Increased risk of major cardiovascular events such as heart attack, stroke or death in people 50 years of age and older who have at least 1 heart disease (cardiovascular) risk factor and taking a medicine in the class of medicines called JAK inhibitors, especially if you are a current or past smoker. Some people taking CIBINQO have had major cardiovascular events. Get emergency help right away if you develop any symptoms of a heart attack or stroke during treatment with CIBINQO, including: • discomfort in the center of your chest that lasts for more than a few minutes, or that goes away and comes back • severe tightness, pain, pressure, or heaviness in your chest, throat, neck, or jaw • pain or discomfort in your arms, back, neck, jaw, or stomach • weakness in one part or on one side of your body • slurred speech • shortness of breath with or without chest discomfort • breaking out in a cold sweat • nausea or vomiting • feeling lightheaded 5. Blood clots Blood clots in the veins of your legs (deep vein thrombosis, DVT) or lungs (pulmonary embolism, PE) can happen in some people taking CIBINQO. This may be life-threatening. Blood clots in the veins of the legs (deep vein thrombosis, DVT) and lungs (pulmonary embolism, PE) have happened more often in people who are 50 years of age and older and with at least 1 heart disease (cardiovascular) risk factor taking a medicine in the class of medicines called Janus kinase (JAK) inhibitors. • Tell your healthcare provider if you have had blood clots in the veins of your legs or lungs in the past. • Stop taking CIBINQO and get medical help right away if you have any signs and symptoms of blood clots during treatment with CIBINQO, including: o swelling, pain or tenderness in one or both legs o sudden, unexplained chest or upper back pain o shortness of breath or difficulty breathing 6. Changes in certain laboratory test results Your healthcare provider should do blood tests before you start taking CIBINQO and during treatment with CIBINQO to check for the following: • low lymphocyte count. Lymphocytes are white blood cells that help the body fight off infections. • low neutrophil count. Neutrophils are white blood cells that help the body fight off infections. • low red blood cell count. This may mean that you have anemia, which may make you feel weak and tired. • low platelet count. Platelets help form clots and stop or prevent bleeding. You should not take CIBINQO if your lymphocyte counts, neutrophil counts, red blood cell counts, or platelet counts are too low. Your healthcare provider may stop your CIBINQO treatment for a period of time if needed because of changes in these blood test results. Increased cholesterol levels. You may also have increases in the amount of fat found in your blood. Your healthcare provider should check your cholesterol about 4 weeks after you start CIBINQO, and then as needed. See "What are the possible side effects of CIBINQO?" for more information about side effects.
What is CIBINQO? CIBINQO is a prescription medicine that is a Janus Kinase (JAK) inhibitor. CIBINQO is used to treat adults and children 12 years of age and older with moderate-to-severe atopic dermatitis (eczema) that did not respond to other treatment and is not well controlled with prescription therapies, including biologic medicines or when these medicines cannot be tolerated. It is not known if CIBINQO is safe and effective in children under 12 years of age.
Who should not take CIBINQO? Do not take CIBINQO if you take medicines that prevent blood clots (antiplatelet medicines), except for low-dose aspirin up to a dose of 81 mg each day during the first 3 months of CIBINQO treatment.
Before taking CIBINQO, tell your healthcare provider about all of your medical conditions, including if you: • See "What is the most important information I should know about CIBINQO?" • have an infection • are a current or past smoker • have had a heart attack, other heart problems, or stroke • have kidney problems or liver problems • have low platelet counts or white blood cell counts • have high levels of fat in your blood (high cholesterol) • have any eye problems, including cataracts or retinal detachment. • have recently received or are scheduled to receive an immunization (vaccine). People who take CIBINQO should not receive live vaccines. • are pregnant or plan to become pregnant. It is not known if CIBINQO will harm your unborn baby. o Pregnancy Exposure Registry. Pfizer has a registry for women who take CIBINQO during pregnancy. The purpose of this registry is to check the health of you and your baby. If you are pregnant or become pregnant during treatment with CIBINQO, talk to your healthcare provider about how you can join this pregnancy registry, or you may contact the registry at 1-877-311-3770 or www.cibinqopregnancyregistry.com. • are breastfeeding or plan to breastfeed. It is not known if CIBINQO passes into your breast milk. You and your healthcare provider should decide if you will take CIBINQO or breastfeed. You should not do both. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. CIBINQO and other medicines may affect each other causing side effects. Especially tell your healthcare provider if you take aspirin or any antiplatelet therapies (See the "Who should not take CIBINQO?" section). Ask your healthcare provider if you are unsure. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist whenever you get a new medicine.
How should I take CIBINQO? • Take CIBINQO exactly as your healthcare provider tells you to take it. • Take CIBINQO 1 time each day, at about the same time each day. • Swallow CIBINQO tablets whole with water. Do not split, crush, or chew the tablets. • You can take CIBINQO with or without food. • CIBINQO can be used with or without prescribed topical steroid medicines for atopic dermatitis. Prescribed topical medicine are lotions, creams, or ointments applied to your skin. • If you miss a dose, take the dose as soon as possible. If it is less than 12 hours before the next dose, skip the dose. Take the next dose at your usually scheduled time. • In case of overdose, get medical help or contact a Poison Center expert right away at 1-800-222-1222. Advice is also available online at poisonhelp.org.
What are the possible side effects of CIBINQO? CIBINQO may cause serious side effects. See "What is the most important information I should know about CIBINQO?" The most common side effects of CIBINQO include: • See "What is the most important information I should know about CIBINQO."
• common cold • nausea • headache • herpes simplex including cold sores • increased blood level of creatine phosphokinase • dizziness • urinary tract infection • tiredness • acne • vomiting			• mouth and throat pain • flu • stomach flu • bacterial skin infection (impetigo) • high blood pressure • allergic skin rash to something you came into contact with • stomach-area pain • shingles • low platelet count
Separation or tear to the lining of the back part of the eye (retinal detachment) has happened in people with atopic dermatitis treated with CIBINQO. Call your healthcare provider right away if you have any sudden changes in your vision during treatment with CIBINQO. CIBINQO may cause fertility problems in females, which may affect your ability to get pregnant. Talk to your healthcare provider if you have concerns about fertility. These are not all the possible side effects of CIBINQO. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Pfizer at 1-800-438-1985.
How should I store CIBINQO? • Store CIBINQO at room temperature between 68°F to 77°F (20°C to 25°C). • Store CIBINQO in the original package. • The container has a child resistant closure. Keep CIBINQO and all medicines out of the reach of children.
General information about the safe and effective use of CIBINQO. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use CIBINQO for a condition for which it was not prescribed. Do not give CIBINQO to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about CIBINQO that is written for health professionals.

What are the ingredients in CIBINQO? Active ingredient: abrocitinib Inactive ingredients: dibasic calcium phosphate anhydrous, hypromellose, iron oxide red, lactose monohydrate, Macrogol, magnesium stearate, microcrystalline cellulose, sodium starch glycolate, titanium dioxide, and triacetin. LAB-1424-3.0

This Medication Guide has been approved by the U.S. Food and Drug Administration. Approved: 12/2023

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