DRUG INTERACTIONS- (summary)

­ • Strong inhibitors of CYP2C19: The recommended dose is 50 mg daily or 100 mg once daily for those patients who are not responding to 50 mg once daily

• Moderate to strong inhibitors of both CYP2C19 and CYP2C9, or strong CYP2C19 or CYP2C9 inducers: Avoid concomitant use.

• P-gp substrate where small concentration changes may lead to serious or life-threatening toxicities: Monitor or titrate dosage of P-gp substrate.

DRUG INTERACTIONS- (details)

 Clinically Significant Interactions Affecting Other Drugs P-gp Substrate Where Small Concentration Changes May Lead to Serious or Life-threatening Toxicities Clinical Impact Coadministration of CIBINQO with P-gp substrate increases plasma concentrations of P-gp substrates and may result in potential adverse reactions of the P-gp substrate where small concentration changes may lead to serious or life-threatening toxicities (e.g., digoxin) 

 Intervention- Monitor appropriately or dose titrate P-gp substrate where small concentration changes may lead to serious or life-threatening toxicities when coadministered with CIBINQO.

Antiplatelet Therapy Drugs-                                                                                   Clinical Impact Coadministration of CIBINQO with antiplatelet therapy drugs may increase the risk of bleeding with thrombocytopenia.

Intervention Antiplatelet drugs, except for low-dose aspirin (=81 mg daily), during the first 3 months of treatment are contraindicated with CIBINQO 

 BRIEF SUMMARY

ABROCITINIB-( Jan 2022)

Indicn- To treat Refractory ,Moderate to Severe Atopic  Decimatitis

Dosage- Tablets: 50 mg, 100 mg, and 200 mg.  Recommended dosage is 100 mg orally once daily.  200 mg orally once daily is recommended for those patients who are not responding to 100 mg once daily.   

ADR- Most common adverse reactions (=1%) in subjects receiving 100 mg and 200 mg include:: nasopharyngitis, nausea, headache, herpes simplex, increased blood creatinine phosphokinase, dizziness, urinary tract infection, fatigue, acne, vomiting, oropharyngeal pain, influenza, gastroenteritis.

CI-  Antiplatelet therapies except for low-dose aspirin (=81 mg daily), during the first 3 months of treatment.

 WARNINGS-                                                                                                     ­• Laboratory Abnormalities: Laboratory monitoring is recommended due to potential changes in platelets, lymphocytes, and lipids.

Pat Inform-

Serious Infections-                                                                                                    Inform patients that they may develop infections when taking the drug

 Instruct patients to tell their healthcare provider if they develop any signs or symptoms of an infection 

Advise patients that the risk of herpes zoster is increased in patients treated with the drug and some cases can be serious 

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U.S. FDA APPROVED DRUGS SURING 2022                                        

Serial No 2

Name of the Drug-    CIBINQO

Active Ingredient -   Abrocitinib

Pharmacological Classification- To treat Refractory ,Moderate to Severe Atopic                                                              Decimatitis                                                                                                                                                                                                           Date of Approval-          1/14//22                                                    

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use                       CIBINQO safely and effectively.                                                                                    See full prescribing information for CIBINQO. CIBINQOTM (abrocitinib) tablets, for oral use

Initial U.S. Approval: 2022

WARNING: SERIOUS INFECTIONS, MORTALITY, MALIGNANCY, MAJOR ADVERSE CARDIOVASCULAR EVENTS (MACE), and THROMBOSIS                                     

See full prescribing information for complete boxed warning

 • Increased risk of serious bacterial, fungal, viral and opportunistic infections leading to hospitalization or death, including tuberculosis (TB).                               

Discontinue treatment with CIBINQO if serious or opportunistic infection occurs.          Test for latent TB before and during therapy; treat latent TB prior to use. Monitor all patients for active TB during treatment, even patients with initial negative latent TB test.

 • Higher rate of all-cause mortality, including sudden cardiovascular death, with another JAK inhibitor vs. TNF blockers in rheumatoid arthritis (RA) patients. CIBINQO is not approved for use in RA patients.

 • Malignancies have occurred with CIBINQO. Higher rate of lymphomas and lung cancers with another JAK inhibitor vs. TNF blockers in RA patients.

 • MACE has occurred with CIBINQO. Higher rate of MACE (defined as cardiovascular death, myocardial infarction, and stroke) with another JAK inhibitor vs. TNF blockers in RA patients.

 • Thrombosis has occurred with CIBINQO. Increased incidence of pulmonary embolism, venous and arterial thrombosis with another JAK inhibitor vs. TNF blockers.

INDICATIONS AND USAGE

­ CIBINQO is a Janus kinase (JAK) inhibitor indicated for the treatment of adults with refractory, moderate-to-severe atopic dermatitis whose disease is not adequately controlled with other systemic drug products, including biologics, or when use of those therapies is inadvisable.

 Limitation of Use: CIBINQO is not recommended for use in combination with other JAK inhibitors, biologic immunomodulators, or with other immunosuppressants.

ADVERSE REACTIONS

­ Most common adverse reactions (=1%) in subjects receiving 100 mg and 200 mg include:: nasopharyngitis, nausea, headache, herpes simplex, increased blood creatinine phosphokinase, dizziness, urinary tract infection, fatigue, acne, vomiting, oropharyngeal pain, influenza, gastroenteritis.

Most common adverse reactions (=1%) in subjects receiving either 100 mg or 200 mg also include: impetigo, hypertension, contact dermatitis, upper abdominal pain, abdominal discomfort, herpes zoster, and thrombocytopenia.

 CONTRAINDICATIONS-                                                                                               Antiplatelet therapies except for low-dose aspirin (=81 mg daily), during the first 3 months of treatment.

 WARNINGS AND PRECAUTIONS-                                                                                  ­ • Laboratory Abnormalities: Laboratory monitoring is recommended due to potential changes in platelets, lymphocytes, and lipids.

 • Immunizations: Avoid use of live vaccines prior to, during, and immediately after CIBINQO treatment.

DOSAGE AND ADMINISTRATION

­ • For recommended testing, evaluations and procedures prior to CIBINQO initiation, see Full Prescribing Information.

 • Recommended dosage is 100 mg orally once daily.                                                        • 200 mg orally once daily is recommended for those patients who are not responding to 100 mg once daily.                                                                                                              • Moderate renal impairment: 50 mg once daily or 100 mg once daily for those patients who are not responding to 50 mg once daily.                                                                        • CYP2C19 poor metabolizer: 50 mg once daily or 100 mg once daily for those patients who are not responding to 50 mg once daily.                                                                      • For dosage modifications for certain adverse reactions, see Full Prescribing Information. 

DOSAGE FORMS AND STRENGTHS-                                                                 ­ CIBINQO Tablets: 50 mg, 100 mg, and 200 mg

PATIENT COUNSELING INFORMATION -

Advise the patient to read the FDA-approved patient labeling (Medication Guide). Pregnancy Registry Advise patients to report their pregnancy to 1-877-311-3770 [see Use in Specific Populations (8.1)].

Serious Infections-                                                                                                    Inform patients that they may develop infections when taking CIBINQO

 Instruct patients to tell their healthcare provider if they develop any signs or symptoms of an infection 

Advise patients that the risk of herpes zoster is increased in patients treated with CIBINQO and some cases can be serious 

Malignancies-                                                                                                            Inform patients that CIBINQO may increase their risk of certain cancers, including skin cancers.

Periodic skin examinations are recommended while using CIBINQO.

Advise patients that exposure to sunlight and UV 23 light should be limited by wearing protective clothing and using a broad-spectrum sunscreen].

Major Adverse Cardiovascular Events-                                                                           Inform patients that CIBINQO may increase their risk of major adverse cardiovascular events (MACE) including myocardial infarction, stroke, and cardiovascular death.

Instruct all patients, especially current or past smokers or patients with other cardiovascular risk factors, to be alert for the development of signs and symptoms of cardiovascular events

 Thrombosis-                                                                                                                Advise patients that events of DVT and PE have been reported in clinical trials with CIBINQO. Instruct patients to seek immediate medical attention if they develop any signs or symptoms of a DVT or PE.

Laboratory Abnormalities-                                                                                             Inform patients that CIBINQO may affect certain lab tests, and that blood tests are required before and during CIBINQO treatment

 Immunizations -                                                                                                                Advise patients that vaccination with live vaccines is not recommended during CIBINQO treatment and immediately prior to or after CIBINQO treatment.

Instruct patients to inform the healthcare practitioner that they are taking CIBINQO prior to a potential vaccination

 Retinal Detachment -                                                                                                  Inform patients that retinal detachment has been reported in clinical trials for atopic dermatitis in patients who received CIBINQO.

Advise patients to immediately inform their healthcare provider if they develop any sudden changes in vision while receiving CIBINQO].

Infertility-                                                                                                                       Advise females of reproductive potential that CIBINQO may impair fertility

Lactation-                                                                                                                  Advise a woman not to breastfeed during treatment with CIBINQO

 Administration-                                                                                                                Advise patients not to chew, crush, or split CIBINQO tablets.].

This product’s labeling may have been updated. For the most recent prescribing information, please visit www.pfizer.com. For Medical Information about CIBINQO, please visit www.pfizermedinfo.com or call 1-800-438-1985. 24 Reference ID: 4920574 LAB-1423-0.4

 CLINICAL PHARMACOLOGY

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 N N N H N N S O  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.

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). Recovery of platelet count (~40% recovery 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.

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)

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.

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).

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 studies, 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

 USE IN SPECIFIC POPULATIONS

1. Pregnancy -                                                                                                          Pregnancy Exposure Registry- There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to CIBINQO during pregnancy.

Pregnant women exposed to CIBINQO and health care providers are encouraged to call 1­ 877-311-3770.

Risk Summary -                                                                                                        Available data from pregnancies reported in clinical trials with CIBINQO are not sufficient to establish a drugassociated risk for major birth defects, miscarriage, or other adverse maternal or fetal outcomes. In animal reproduction studies, oral administration of abrocitinib to pregnant rats and rabbits during organogenesis at exposure 14 or 5 times the maximum recommended human dose (MRHD) based on AUC comparison, respectively, resulted in maternal dystocia and skeletal variations in rats and no adverse effects in rabbits

 The background risks of major birth defects and miscarriage for the indicated population are unknown.

All pregnancies carry some risk of birth defects, loss, or other adverse outcomes.

The background risks in the U.S. general population of major birth defects and miscarriages are 2-4% and 15-20% of clinically recognized pregnancies, respectively.

2. Lactation Risk Summary-                                                                                       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.

When a drug is present in animal milk, it is likely that the drug will be present in human milk. Because of the serious adverse findings in adults, including risks of serious infections, malignancy, and thrombosis, advise women not to breastfeed during treatment with CIBINQO and for one day after the last dose (approximately 5-6 elimination half-lives).

8.3 Females and Males of Reproductive Potential-                                                  Infertility Females-                                                                                                     Based on the 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 Nonclinical Toxicology (13.1)].

4. Pediatric Use-                                                                                                           The safety and effectiveness of CIBINQO have not been established in pediatric patients.

5. Geriatric Use-                                                                                                                A total of 145 (4.6%) patients 65 years of age and older, while 25 (0.8%) were 75 years of age and older, were enrolled in CIBINQO clinical trials. Clinical trials of CIBINQO did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients.

A higher proportion of patients 65 years of age and older discontinued from clinical trials compared to younger patients. Among all patients exposed to CIBINQO, including the long-term extension trial, confirmed ALC <500/mm3 occurred only in patients 65 years of age and older.

6. Renal Impairment-                                                                                                       In patients with severe (eGFR <30 mL/min) and moderate (eGFR 30-59 mL/min) renal impairment, the combined exposure (AUCinf,u) of abrocitinib and its two active metabolites, M1 and M2, is increased compared to patients with normal renal function (eGFR =90 mL/min).

This may increase the risk of adverse reactions such as infections. CIBINQO is not recommended for use in patients with severe renal impairment and ESRD including those on renal replacement

7. Hepatic Impairment -                                                                                                      Avoid use of CIBINQO in patients with severe (Child Pugh C) hepatic impairment. Dosage adjustment is not required in patients with mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment based on similar combined exposure (AUCinf,u) of abrocitinib and its two active metabolites, M1 and M2 compared to patients with normal hepatic function.

OVERDOSAGE-                                                                                                                There is no experience regarding human overdosage with CIBINQO. There is no specific antidote for overdose with CIBINQO. In case of an overdose, call Poison Control Center at 1-800-222-1222 for latest recommendations.