DRUG INTERACTIONS-(summary)

 • Certain CYP3A substrates: Additional monitoring and dose adjustment of CYP3A substrate should be considered.

• Certain CYP1A2 substrates: Additional monitoring and dose adjustment of CYP1A2 substrate should be considered.

 • Certain CYP3A inducers: Coadministration with strong inducers of CYP3A is not recommended.

DRUG INTERACTIONS-(details)

.1 Effects of LITFULO on Other Drugs -

Table 3 includes clinically significant drug interactions affecting other drugs.

. Clinically Significant Interactions Affecting Other Drugs-

 CYP3A Substrates Where Small Concentration Changes May Lead to Serious Adverse Reactions Clinical Impact Ritlecitinib is a CYP3A inhibitor.

Concomitant use of ritlecitinib increases AUC and Cmax of CYP3A substrates , which may increase the risk of adverse reactions of these substrates.

Intervention -

Consider additional monitoring and dosage adjustment in accordance with approved product labeling of CYP3A substrates where small concentration changes may lead to serious adverse reactions when used with LITFULO. CYP1A2 Substrates Where Small Concentration Changes May Lead to Serious Adverse Reactions

Clinical Impact Ritlecitinib is a CYP1A2 inhibitor. Concomitant use of ritlecitinib increases AUC and Cmax of CYP1A2 substrates  which may increase the risk of adverse reactions of these substrates.

Intervention -Consider additional monitoring and dosage adjustment in accordance with the approved product labeling of CYP1A2 substrates where small concentration changes may lead to serious adverse reactions when used concomitantly with LITFULO.

2. Effects of Other Drugs on LITFULO- Table 4 includes clinically significant drug interactions affecting LITFULO. 

Clinically Significant Interactions Affecting LITFULO CYP3A Inducers Clinical Impact Concomitant use of strong CYP3A inducer (e.g., rifampin) may decrease AUC and Cmax of ritlecitinib , which may result in loss of or reduced clinical response. Intervention Coadministration with strong inducers of CYP3A is not recommended. 

BRIEF SUMMARY

RITLECITNIB- (June 2023)

Indication-  To treat  severely patchy hair loss 

Dosage-  Recommended dosage is 50 mg orally once daily. 

ADR- Most common adverse reactions (incidence =1%) are headache, diarrhea, acne, rash, urticaria, folliculitis, pyrexia, atopic dermatitis, dizziness, blood creatine phosphokinase

CI-  contraindicated in patients with known hypersensitivity to ritlecitinib or any of its excipients.

 WARNINGS-  Hypersensitivity: Discontinue LITFULO if a clinically significant hypersensitivity reaction occurs.

Pat inform- Advise patients not to crush, split or chew LITFULO capsules ].

Serious Infections- Inform patients that they may develop infections when taking LITFULO which in some cases can be serious. Instruct patients to tell their healthcare provider if they develop any signs or symptoms of an infection .

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U.S.  APPROVED DRUGS DURING 2023                                        

Serial No 24.

Name-                       LITFULO

Acive  Ingredient -  Ritlecitinib

Pharmacological clssificiation-        To treat  severely patchy hair loss                                                                                                                                                                                  

Date of Approval-         6/23/2023

HIGHLIGHTS OF PRESCRIBING INFORMATION -

These highlights do not include all the information needed to use LITFULO safely and effectively.

See full prescribing information for LITFULO. LITFULOTM (ritlecitinib) capsules, for oral use

Initial U.S. Approval: 2023

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 that may lead to hospitalization or death, including tuberculosis (TB).

Interrupt treatment if serious infection occurs until the infection is controlled. LITFULO should not be given to patients with active tuberculosis.

Test for latent TB before and during therapy; start treating latent TB prior to use. Monitor all patients for active TB during treatment, even patients with initial negative, latent TB test. 

Monitor all patients for signs and symptoms of infection during and after treatment with LITFULO. 

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

 • Malignancies were reported in patients treated with LITFULO

 Higher rate of lymphomas and lung cancers with another JAK inhibitor vs. TNF blockers in RA patients.

• 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 in patients treated with LITFULO. Increased incidence of pulmonary embolism, venous and arterial thrombosis with another JAK inhibitor vs. TNF blockers.

 INDICATIONS AND USAGE-

 LITFULO is a kinase inhibitor indicated for the treatment of severe alopecia areata in adults and adolescents 12 years and older.

 Limitations of Use: Not recommended for use in combination with other JAK inhibitors, biologic immunomodulators, cyclosporine or other potent immunosuppressants 

 ADVERSE REACTIONS-

 Most common adverse reactions (incidence =1%) are headache, diarrhea, acne, rash, urticaria, folliculitis, pyrexia, atopic dermatitis, dizziness, blood creatine phosphokinase increased, herpes zoster, red blood cell count decreased, and stomatitis.

 CONTRAINDICATIONS-

 LITFULO is contraindicated in patients with known hypersensitivity to ritlecitinib or any of its excipients.

 WARNINGS AND PRECAUTIONS-

 • Hypersensitivity: Discontinue LITFULO if a clinically significant hypersensitivity reaction occurs.

 • Laboratory Abnormalities: Perform ALC and platelet counts prior to LITFULO initiation. Treatment interruption or discontinuation are recommended based on ALC and platelet count abnormalities.

 • Vaccinations: Avoid use of live vaccines during or shortly prior to LITFULO treatment. 

DOSAGE AND ADMINISTRATION-

 • For recommended testing, evaluations and immunizations prior to LITFULO initiation, see Full Prescribing Information.

 • Recommended dosage is 50 mg orally once daily. (2.2

PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Administration-

Advise patients not to crush, split or chew LITFULO capsules ].

Serious Infections-

Inform patients that they may develop infections when taking LITFULO which in some cases can be serious.

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 LITFULO .

Malignancies-

Inform patients that LITFULO may increase their risk of certain cancers, including skin cancers.

Periodic skin examinations are recommended while using LITFULO .

Thromboembolic Events -

Advise patients that events of PE and retinal artery occlusion have been reported in clinical trials with LITFULO.

Instruct patients to seek immediate medical attention if they develop any signs or symptoms of a thrombosis.

Hypersensitivity Reactions-

Advise patients to discontinue LITFULO and seek immediate medical attention if they develop any signs and symptoms of serious allergic reaction.

Laboratory Abnormalities-

Inform patients that LITFULO may affect certain lab tests, and that blood tests are required before and during LITFULO treatment.

Vaccinations-

Advise patients that vaccination with live vaccines is not recommended during LITFULO treatment and shortly prior to LITFULO treatment.

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

Pregnancy-

Advise pregnant females and females of reproductive potential to inform their healthcare providers if they are pregnant or intend to becomes pregnant during treatment with LITFULO.

Instruct patients to report their pregnancy to Pfizer Inc. at 1-877-390-2940.

Lactation-

Advise women not to breastfeed during treatment with LITFULO and for 14 hours after the last dose.

For Medical Information about LITFULO, please visit www.pfizermedinfo.com or call 1-800-438-1985. LAB-1469-0.

 CLINICAL PHARMACOLOGY

1 Mechanism of Action

LITFULO is a kinase inhibitor. Ritlecitinib irreversibly inhibits Janus kinase 3 (JAK3) and the tyrosine kinase expressed in hepatocellular carcinoma (TEC) kinase family by blocking the adenosine triphosphate (ATP) binding site.

2. Pharmacodynamics Lymphocyte Subsets A dose-dependent early decrease in absolute lymphocyte levels, T lymphocytes (CD3) and T lymphocyte subsets (CD4 and CD8) was associated with LITFULO treatment in patients with alopecia areata.

Cardiac Electrophysiology At 12 times the mean maximum exposure of the 50 mg once daily dose in patients with alopecia areata, there was no clinically relevant effect on the QTc interval.

3. Pharmacokinetics Ritlecitinib AUC0-tau and Cmax increase in an approximately dose-proportional manner up to 200 mg. Steady state was reached approximately by Day 4.

Absorption The ritlecitinib absolute oral bioavailability is approximately 64%. Ritlecitinib peak plasma concentrations were reached within 1 hour following an oral dose.

Effect of Food

Food does not have a clinically significant impact on the systemic exposures of ritlecitinib.

The coadministration of a 100 mg ritlecitinib capsule with a high-fat meal reduced the ritlecitinib Cmax by ~32% and AUCinf was increased by 11%. In clinical trials, ritlecitinib was administered without regard to meals [see Dosage and Administration (2.2)].

Distribution Approximately 14% of circulating ritlecitinib is bound to plasma proteins.

Elimination The ritlecitinib mean terminal half-life ranges from 1.3 to 2.3 hours.

Metabolism The metabolism of ritlecitinib is mediated by multiple pathways with no single route contributing to more than 25% of the total metabolism. These pathways include:

• Glutathione S-transferase (GST): cytosolic GST A1/3, M1/3/5, P1, S1, T2, Z1 and microsomal GST 1/2/3

• CYP enzymes (CYP3A, CYP2C8, CYP1A2, and CYP2C9) Reference ID: 5196496 15 Excretion Approximately 66% of radiolabeled ritlecitinib dose is excreted in the urine and 20% in the feces. Approximately 4% of the ritlecitinib dose is excreted unchanged drug in urine

Specific Populations No clinically relevant differences in the pharmacokinetics of ritlecitinib were observed based on age (12-73 years), body weight, gender, GST genotype, and race

 Patients with Renal Impairment The AUC24 observed in patients with severe renal impairment (eGFR <30 mL/min) was 55.2% higher compared with the AUC24 in matched participants with normal renal functions.

These differences are not considered clinically significant. Ritlecitinib has not been studied in patients with mild (eGFR 60 to <90 mL/min) or moderate (eGFR 30 to <60 mL/min) renal impairment, as a clinically relevant increase in ritlecitinib exposure is not expected in these patients

 USE IN SPECIFIC POPULATIONS

1 Pregnancy-

Pregnancy Exposure Registry If a patient becomes pregnant while receiving LITFULO, healthcare providers should report LITFULO exposure by calling 1-877-390-2940.

Risk Summary Available data from clinical trials with LITFULO use in pregnant women are insufficient to identify a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes.

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 estimated 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 ritlecitinib in human milk, the effects on the breastfed infant, or the effects on milk production. 

Ritlecitinib is present in the milk of lactating rats (

. When a drug is present in animal milk, it is likely that it will be present in human milk.

3.Pediatric Use -

The safety and effectiveness of LITFULO for the treatment of alopecia areata have been established in pediatric patients ages 12 years and older. A total of 181 pediatric patients ages 12 to <18 years were enrolled in alopecia areata clinical trials, with 105 pediatric patients ages 12 to <18 years with alopecia areata randomized in a pivotal, double-blind, placebo-controlled trial (Trial AA-I).

4.Geriatric Use-

No dose adjustment is required for patients =65 years of age. A total of 28 patients enrolled in alopecia areata trials were 65 years of age and older, and none were 75 years of age and older.

Clinical trials of LITFULO did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients.

As there is a higher incidence of infections in the elderly population in general, caution should be used when treating the elderly.

5.Hepatic Impairment-

No dose adjustment is required in patients with mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment. LITFULO is not recommended in patients with severe (Child Pugh C) hepatic impairment .

 OVERDOSAGE-

LITFULO was administered in clinical trials up to a single oral dose of 800 mg. Adverse reactions were comparable to those seen at lower doses and no specific toxicities were identified. Pharmacokinetics (PK) data Reference ID: 5196496 13 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.

There is no specific antidote for overdose with LITFULO.

Treatment should be symptomatic and supportive, and monitor patients for signs and symptoms of adverse reactions.

In case of an overdose, call Poison Control Center at 1-800-222-1222 for latest recommendations.