Ritlecitinib (Monograph)

Brand name: Litfulo
Drug class: Skin and Mucous Membrane Agents, Miscellaneous

Warning

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. Ritlecitinib 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 ritlecitinib.
Higher rate of all-cause mortality, including sudden cardiovascular death with another Janus kinase inhibitor (JAK) versus TNF blockers in rheumatoid arthritis (RA) patients. Ritlecitinib is not approved for use in RA patients.
Malignancies were reported in patients treated with ritlecitinib. 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 ritlecitinib. Increased incidence of pulmonary embolism, venous and arterial thrombosis with another JAK inhibitor vs. TNF blockers.

Introduction

Ritlecitinib tosylate is a janus kinase 3 (JAK3) inhibitor and also an inhibitor of the tyrosine kinase expressed in hepatocellular carcinoma (TEC) family.

Uses for Ritlecitinib

Ritlecitinib tosylate has the following uses:

Ritlecitinib is indicated for the treatment of severe alopecia areata in adults and adolescents 12 years of age and older.

Not recommended for use in combination with other JAK inhibitors, biologic immunomodulators, cyclosporine, or other potent immunosuppressants.

Ritlecitinib Dosage and Administration

General

Ritlecitinib tosylate is available in the following dosage form(s) and strength(s):

Capsules: 50 mg of ritlecitinib.

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Pediatric Patients

Dosage and Administration

For recommended testing, evaluations and immunizations prior to ritlecitinib initiation, see Full Prescribing Information.
Recommended dosage of ritlecitinib in adolescents 12 years of age and older is 50 mg orally once daily.
For dosage interruption for certain adverse reactions, see Full Prescribing Information.

Adults

Dosage and Administration

For recommended testing, evaluations and immunizations prior to ritlecitinib initiation, see Full Prescribing Information.
Recommended dosage of ritlecitinib in adults is 50 mg orally once daily.
For dosage interruption for certain adverse reactions, see Full Prescribing Information.

Cautions for Ritlecitinib

Contraindications

Patients with known hypersensitivity to ritlecitinib or any of its excipients.

Warnings/Precautions

Serious Infections

Serious infections have been reported in patients receiving ritlecitinib. The most frequent serious infections have been appendicitis, COVID-19 infection (including pneumonia), and sepsis. Among opportunistic infections, multi-dermatomal herpes zoster was reported with ritlecitinib.

Avoid use of ritlecitinib in patients with an active, serious infection. Consider the risks and benefits of treatment prior to initiating ritlecitinib in patients with chronic or recurrent infection, patients who have been exposed to tuberculosis (TB), patients with a history of serious infection or an opportunistic infection, patients who have resided or traveled in areas of endemic TB or mycosis, or patients with underlying conditions that may predispose them to infection.

Closely monitor patients for the development of signs and symptoms of infection during and after treatment with ritlecitinib. Interrupt therapy if a patient develops a serious or opportunistic infection. A patient who develops a new infection during treatment with ritlecitinib should undergo prompt and complete diagnostic testing appropriate for an immunocompromised patient, appropriate antimicrobial therapy should be initiated, and the patient should be closely monitored. Ritlecitinib may be resumed once the infection is controlled.

Tuberculosis

Screen patients for TB before starting therapy. Ritlecitinib should not be given to patients with active TB. Anti-TB therapy should be started prior to initiating therapy with ritlecitinib in patients with a new diagnosis of latent TB or previously untreated latent TB. In patients with a negative latent TB test, consider anti-TB therapy before initiating treatment with ritlecitinib in those at high risk and consider screening patients at high risk for TB during treatment with the drug.

Viral Reactivation

Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster), was reported in clinical trials. If a patient develops herpes zoster, consider interrupting treatment until the episode resolves.

Screening for viral hepatitis should be performed in accordance with clinical guidelines before starting therapy with ritlecitinib. Patients with evidence of HIV infection or hepatitis B or C infection were excluded from clinical trials.

Mortality

In a large, randomized, postmarketing safety study of another JAK inhibitor in rheumatoid arthritis patients 50 years of age and older with at least one cardiovascular risk factor, a higher rate of all-cause mortality, including sudden cardiovascular death, was observed in patients treated with the JAK inhibitor compared with TNF blockers. Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with ritlecitinib.

Malignancy and Lymphoproliferative Disorders

Malignancies, including non-melanoma skin cancer (NMSC), were observed in clinical trials of ritlecitinib.

In a large, randomized, postmarketing safety study of another JAK inhibitor in rheumatoid arthritis 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. 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 ritlecitinib treatment should be considered prior to initiating or continuing therapy in patients with a known malignancy other than a successfully treated NMSC or cervical cancer.

Periodic skin examination is recommended for patients who are at increased risk for skin cancer.

Major Adverse Cardiovascular Events (MACE)

In a large, randomized, postmarketing safety study of another JAK inhibitor in rheumatoid arthritis patients 50 years of age and older with at least one cardiovascular risk factor, a higher rate of major adverse cardiovascular events (MACE) defined as cardiovascular death, non-fatal myocardial infarction (MI), and non-fatal stroke was observed with the JAK inhibitor compared to those treated with TNF blockers. 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 ritlecitinib, 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 ritlecitinib in patients that have experienced a MI or stroke.

Thromboembolic Events

Pulmonary embolism (PE) was reported in a patient receiving ritlecitinib. In a higher dosing group, one patient reported an event of retinal artery occlusion.

Avoid ritlecitinib in patients who may be at increased risk of thrombosis. If symptoms of thrombosis or embolism occur, patients should interrupt therapy and be evaluated promptly and treated appropriately.

Hypersensitivity

Serious reactions including anaphylactic reactions, urticaria, and rash have been observed in patients receiving ritlecitinib in clinical trials. If a clinically significant hypersensitivity reaction occurs, discontinue the drug and institute appropriate therapy.

Laboratory Abnormalities

Treatment with ritlecitinib was associated with decreases in lymphocytes and platelets.

Prior to ritlecitinib initiation, perform absolute lymphocyte count (ALC) and platelet counts. After initiating treatment, treatment interruption or discontinuation are recommended based on ALC and platelet count abnormalities.

Liver Enzyme Elevations – Treatment with ritlecitinib was associated with increased incidence of liver enzyme elevation compared to placebo. Increases of ALT ≥5 times the upper limit of normal (ULN) and increases of AST ≥5 times the ULN were observed in patients receiving ritlecitinib clinical trials. Evaluate at baseline and thereafter according to routine patient management. Prompt investigation of the cause of liver enzyme elevation is recommended to identify potential cases of drug-induced liver injury. If increases in ALT or AST are observed and drug-induced liver injury is suspected, interrupt ritlecitinib until this diagnosis is excluded.

Creatine Phosphokinase (CPK) Elevations – Treatment with ritlecitinib was associated with increased incidence of CPK elevation compared to placebo.

Vaccinations

No data are available on the response to vaccination in patients receiving ritlecitinib. Use of live attenuated vaccines should be avoided during or shortly prior to initiating treatment. Prior to initiating ritlecitinib, it is recommended that patients be brought up to date with all immunizations, including prophylactic herpes zoster vaccinations, in agreement with current immunization guidelines.

Specific Populations

Pregnancy

If a patient becomes pregnant while receiving ritlecitinib, healthcare providers should report the exposure by calling 1-877-390-2940.

Available data from clinical trials with ritlecitinib use in pregnant women are insufficient to identify a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. In animal reproduction studies, oral administration of ritlecitinib to pregnant rats and rabbits during organogenesis caused fetotoxicity and fetal malformations at exposures 49 and 55 times the maximum recommended human dose (MRHD) based on AUC comparison, respectively.

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.

Lactation

There are no data on the presence 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. Because of serious adverse effects in adults, including risks of serious infection and malignancy, advise women not to breastfeed during treatment with ritlecitinib and for approximately 14 hours after the last dose (approximately 6 elimination half-lives).

Pediatric Use

The safety and effectiveness of ritlecitinib for the treatment of alopecia areata have been established in pediatric patients 12 years of age and older. A total of 181 pediatric patients 12 to <18 years of age were enrolled in alopecia areata clinical trials, with 105 pediatric patients 12 to <18 years of age with alopecia areata randomized in a pivotal, double-blind, placebo-controlled trial (Trial AA-I). Efficacy was consistent between pediatric patients and adults. The adverse reaction profile in pediatric patients was similar to adults.

The safety and efficacy of ritlecitinib have not been established in pediatric patients younger than 12 years of age.

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 ritlecitinib 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.

Hepatic Impairment

No dose adjustment is required in patients with mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment.

Ritlecitinib is not recommended in patients with severe (Child Pugh C) hepatic impairment.

Common Adverse Effects

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

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

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.

Actions

Mechanism of Action

Ritlecitinib tosylate 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. In cellular settings, ritlecitinib inhibits cytokine induced STAT phosphorylation mediated by JAK3-dependent receptors. Additionally, ritlecitinib inhibits signaling of immune receptors dependent on TEC kinase family members. The relevance of inhibition of specific JAK or TEC family enzymes to therapeutic effectiveness is not currently known.

Advice to Patients

Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Advise patients not to crush, split or chew ritlecitinib tosylate capsules.
Inform patients that they may develop infections when taking ritlecitinib 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 ritlecitinib.
Inform patients that ritlecitinib may increase their risk of certain cancers, including skin cancers. Periodic skin examinations are recommended while taking the drug.
Advise patients that pulmonary embolism (PE) and retinal artery occlusion have been reported in clinical trials with ritlecitinib. Instruct patients to seek immediate medical attention if they develop any signs or symptoms of thrombosis.
Advise patients to discontinue ritlecitinib and seek immediate medical attention if they develop any signs and symptoms of serious allergic reaction.
Inform patients that ritlecitinib may affect certain lab tests, and that blood tests are required before and during treatment.
Advise patients that vaccination with live vaccines is not recommended during ritlecitinib treatment and shortly prior to treatment. Instruct patients to inform the healthcare practitioner that they are taking ritlecitinib prior to a potential vaccination.
Advise pregnant females and females of reproductive potential to inform their healthcare providers if they are pregnant or intend to become pregnant during treatment with ritlecitinib. Instruct patients to report their pregnancy to Pfizer Inc. at 1-877-390-2940.
Advise women not to breastfeed during treatment with ritlecitinib and for 14 hours after the last dose.

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.