Drug class: Janus Kinase Inhibitors

Medically reviewed by Drugs.com on Aug 10, 2024. Written by ASHP.

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Introduction

Janus kinase 3 (JAK3) inhibitor; also inhibits tyrosine kinase expressed in hepatocellular carcinoma (TEC) family.

Uses for Ritlecitinib Tosylate

Alopecia Areata

Used orally for treatment of severe alopecia areata in adults and adolescents ≥12 years of age. Not recommended for use in combination with other Janus kinase inhibitors, biologic immunomodulators, cyclosporine, or other potent immunosuppressants.

Specific place in therapy not addressed in guidelines; typical treatments of alopecia areata include intralesional, topical, and systemic corticosteroids; minoxidil; and other immunomodulators.

Ritlecitinib Tosylate Dosage and Administration

General

Pretreatment Screening

• Evaluate for active or latent tuberculosis (TB) infection; initiate preventative antimycobacterial therapy for latent TB prior to initiation of therapy.

• Screen for viral hepatitis infection in accordance with clinical guidelines.

• Measure absolute lymphocyte count (ALC) and platelet count; do not initiate therapy in patients with an ALC <500/mm³or a platelet count <100,000/mm³.

• Evaluate liver enzymes.

• Update immunizations, including herpes zoster vaccinations, according to current guidelines.

• Weigh benefits of therapy against risks in patients with chronic or recurrent infection, or with a history of serious infection or an opportunistic infection, patients who have been exposed to TB or who have resided or traveled in areas of endemic TB or mycoses, or patients with underlying conditions that may predispose them to infection.

• Weigh benefits of therapy against risks of all-cause mortality.

• Weigh benefits of therapy against risks of developing malignancies, particularly in patients with a known malignancy (other than successfully treated nonmelanoma skin cancer or cervical cancer).

• Weigh benefits of therapy against risks for major cardiovascular events (MACE), particularly in patients who are current or past smokers and those with other cardiovascular risk factors.

• Evaluate for risk of thrombosis; avoid therapy in patients at increased risk.

Patient Monitoring

• Monitor all patients for signs or symptoms of infection during and after treatment.

• Monitor all patients for development of active TB during treatment, even patients with an initial negative, latent TB test.

• Monitor ALC and platelet counts at 4 weeks after treatment initiation, and therafter according to routine patient management.

• Weigh benefits of therapy against risks of all-cause mortality when continuing therapy with ritlecitinib.

• Weigh benefits of therapy against risks of developing malignancies when continuing therapy with ritlecitinib, particularly in patients with a known malignancy (other than successfully treated nonmelanoma skin cancer or cervical cancer).

• Evaluate for risk of MACE during therapy. Weigh benefits of contuining therapy against risks for MACE, particularly in patients who are current or past smokers and those with other cardiovascular risk factors.

• Monitor liver enzymes during therapy according to routine patient management.

• Perform dermatologic examinations periodically during therapy in patients at increased risk for skin cancers.

• Monitor for signs and symptoms of thrombosis.

• Monitor for hypersensitivity reactions such as anaphylaxis, urticaria, and rash.

Other General Considerations

• Avoid use of live vaccines during or shortly prior to ritlecitinib treatment.

• Do not use ritlecitinib concomitantly with other Janus kinase inhibitors, biologic immunomodulators, or potent immunosuppressants.

Administration

Oral Administration

Administer orally without regard to food.

Swallow capsules whole; do not crush, split, or chew.

If a dose is missed, administer as soon as possible unless <8 hours before the next dose, in which case, skip missed dose. Thereafter, resume dosing at regularly scheduled time.

Dosage

Dosage of ritlecitinib tosylate expressed in terms of ritlecitinib.

Pediatric Patients

<D> Alopecia Areata

<E> Oral

Adolescents ≥12 years of age: 50 mg once daily.

Adults

Alopecia Areata

Oral

50 mg once daily.

<C> Treatment Interruption for Toxicity

Temporary treatment interruption <6 weeks not expected to result in significant loss of regrown scalp hair.

Refer to Table 1 for recommendations for treatment interruption for hematological laboratory abnormalities.

Special Populations

Hepatic Impairment

Dosage adjustment not required in mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment.

Not recommended in severe hepatic impairment (Child-Pugh class C).

Renal Impairment

No specific dosage recommendations at this time.

Geriatric Patients

Dosage adjustment not required in geriatric patients (≥65 years of age).

Cautions for Ritlecitinib Tosylate

Contraindications

• Known hypersensitivity to ritlecitinib or any of its excipients.

Warnings/Precautions

Warnings

Serious Infections

Serious (and sometimes fatal) infections, including bacterial, fungal, viral, and opportunistic infections, reported (see Boxed Warning). Most common serious infections reported include appendicitis, COVID-19 infection (including pneumonia), and sepsis. Among opportunistic infections, multidermatomal herpes zoster reported. Viral reactivation, including herpes virus reactivation (e.g., herpes zoster), reported; patients with evidence of HIV, HBV, or HCV excluded from clinical trials.

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

Closely monitor for development of signs and symptoms of infection during and after treatment. Interrupt therapy if patients develop serious or opportunistic infection. If new infection occurs during therapy, perform prompt and complete diagnostic testing appropriate for an immunocompromised patient, initiate appropriate antimicrobial therapy, and closely monitor patient. May resume ritlecitinib once infection controlled.

Screen for TB before starting therapy. Do not use in patients with active TB. Start anti-TB therapy prior to initiating ritlecitinib in patients with new diagnosis of latent TB or previously untreated latent TB. In patients with negative latent TB test, consider anti-TB therapy before initiating ritlecitinib in those at high risk. Consider screening patients at high risk for TB during treatment with ritlecitinib.

If herpes zoster reactivation occurs, consider interrupting ritlecitinib treatment until episode resolves.

Screen for viral hepatitis according to clinical guidelines before starting ritlecitinib.

Mortality

Higher rate of all-cause mortality, including sudden cardiovascular death, reported in postmarketing safety study in patients with rheumatoid arthritis (RA) receiving another Janus kinase (JAK) inhibitor compared with those who received a tumor necrosis factor (TNF) blocking agent; all patients were ≥50 years of age and had ≥1 cardiovascular risk factor (see Boxed Warning).

Consider risks and benefits of ritlecitinib prior to initiating or continuing therapy.

Malignancies and Lymphoproliferative Disorders

Malignancies, including lymphoma and nonmelanoma skin cancer (NMSC), observed (see Boxed Warning).

In postmarketing safety study of another JAK inhibitor in patients with RA, a higher rate of malignancies (excluding NMSC) observed in patients treated with another JAK inhibitor compared to those treated with a TNF blocking agent. Current or past smokers were at additional risk.

Consider risks and benefits of ritlecitinib prior to initiating or continuing therapy in patients with known malignancy (other than successfully treated NMSC or cervical cancer).

Periodic dermatologic examinations recommended for patients at increased risk for skin cancer.

Major Adverse Cardiovascular Events (MACE)

In postmarketing safety study of another JAK inhibitor in patients with RA, higher risk of MACE (i.e., cardiovascular death, nonfatal MI, and nonfatal stroke) observed in patients treated with another JAK inhibitor compared to those treated with a TNF blocking agent; all patients were ≥50 years of age with ≥1 cardiovascular risk factor (see Boxed Warning). Current or past smokers are at additional risk.

Consider risks and benefits of ritlecitinib prior to initiating or continuing therapy, particularly in patients who are current or past smokers and in those with other cardiovascular risk factors.

Inform patients of symptoms of serious cardiovascular events. Discontinue ritlecitinib if a patient experiences an MI or stroke.

Thromboembolic Events

Retinal artery occlusion and PE reported (see Boxed Warning).

Increased risk of thrombosis, DVT, and PE observed in postmarketing safety study of another JAK inhibitor in patients with RA compared to those treated with TNF blockers; all patients ≥50 years of age with ≥1 cardiovascular risk factor.

Avoid in patients at increased risk of thrombosis. Promptly interrupt ritlecitinib and evaluate all patients with signs or symptoms suggestive of thrombosis or embolism; initiate treatment as appropriate.

Other Warnings and Precautions

Hypersensitivity Reactions

Hypersensitivity reactions (i.e., anaphylactic reactions, urticaria, rash), sometimes serious, reported.

If serious hypersensitivity reaction occurs, discontinue ritlecitinib and institute appropriate therapy.

Laboratory Abnormalities

Decreases in lymphocytes and platelets observed during treatment; may require interruption or discontinuation of ritlecitinib therapy (refer to Table 1). Elevated hepatic enzyme concentrations (ALT and AST ≥5 times ULN) observed; increased incidence of CPK elevation also observed.

Perform absolute lymphocyte count (ALC) and platelet counts prior to therapy initiation; do not initiate ritlecitinib in patients with ALC <500/mm³or platelet count <100,000/mm³.

Monitor liver function tests at baseline and and thereafter according to routine patient management. In case of elevations, promptly evaluate for drug-induced hepatotoxicity. If ALT/AST elevated and drug-induced hepatic injury suspected, interrupt ritlecitinib until diagnosis excluded.

Immunization

Avoid live vaccines during or shortly before initiating ritlecitinib.

Update immunizations, including prophylactic herpes zoster vaccinations, according to current administration guidelines prior to initiating ritlecitinib.

Specific Populations

Pregnancy

No adequate data in pregnant women to identify a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes.

Pregnancy exposure registry available; if patient becomes pregnant while receiving ritlecitinib, call pregnancy exposure registry at 1-877-390-2940.

Lactation

Distributed into milk in rats; not known whether ritlecitinib distributes into human milk, affects nursing infants, or affects milk production.

Do not breast-feed during treatment with ritlecitinib and for 14 hours after last dose.

Pediatric Use

Safety and effectiveness established in pediatric patients ≥12 years of age with alopecia areata. Efficacy and adverse reaction profiles similar between pediatric patients and adults.

Safety and efficacy not established in pediatric patients <12 years of age.

Geriatric Use

Insufficient number of patients ≥65 years of age included in clinical trials to determine whether they respond differently from younger adults.

Use caution due to higher risk of infections in geriatric population in general.

Hepatic Impairment

Increased drug exposure observed in patients with moderate (Child-Pugh class B) hepatic impairment. Not studied in patients with mild (Child-Pugh class A) hepatic impairment; clinically important increase in exposure not expected. Dosage adjustment not necessary for mild or moderate hepatic impairment.

Not studied in patients with severe (Child-Pugh class C) hepatic impairment; use not recommended.

Renal Impairment

Higher drug exposure observed in patients with severe renal impairment (eGFR <30 mL/minute); not considered clinically important.

Not studied in patients with mild (eGFR 60–<90 mL/minute) or moderate (eGFR 30–<60 mL/minute) renal impairment; clinically important increase in exposure not expected.

Not studied in patients with end-stage renal disease or in renal transplant recipients.

Common Adverse Effects

Most common adverse effects (incidence ≥1%): headache, diarrhea, acne, rash, urticaria, folliculitis, pyrexia, atopic dermatitis, dizziness, increased blood CPK, herpes zoster, decreased RBC count, stomatitis.

Drug Interactions

Metabolism mediated by CYP isoenzymes (CYP3A, CYP2C8, CYP1A2, CYP2C9) and glutathione S-transferases (GSTs) (cytosolic GST A1/3, M1/3/5, P1, S1, T2, Z1 and microsomal GST 1/2/3).

Inhibits CYP3A4 and CYP1A2. Does not inhibit CYP2D6.

Does not inhibit uridine 5’ diphospho glucuronosyltransferases (UGTs) (UGT1A1, UGT1A4, UGT1A6, UGT1A9, and UGT2B7), GSTs, or sulfotransferases; also does not inhibit P-glycoprotein or bile salt export pump.

Drugs Affecting or Affecting or Metabolized by Hepatic Microsomal Enzymes

CYP3A Substrates

Concomitant use increases AUC and peak plasma concentration of CYP3A substrates; small concentration changes may increase risk of adverse reactions (including serious reactions) of the substrates.

Consider additional monitoring and dosage adjustment in accordance with prescribing information of CYP3A substrates where small concentration changes may lead to serious adverse reactions when used with ritlecitinib.

CYP1A2 Substrates

Concomitant use increases AUC and peak plasma concentration of CYP1A2 substrates; small concentration changes may increase risk of adverse reactions (including serious reactions) of the substrates.

Consider additional monitoring and dosage adjustment in accordance with prescribing information of CYP1A2 substrates where small concentration changes may lead to serious adverse reactions when used with ritlecitinib.

CYP3A Inducers

Concomitant use with strong CYP3A inducers (e.g., rifampin) may decrease AUC and peak plasma concentration of ritlecitinib; may result in loss of or reduced clinical response.

Concomitant use not recommended.

Janus Kinase (JAK) Inhibitors

Concomitant use with other JAK inhibitors not recommended.

Biologic Immunomodulators

Concomitant use with biologic immunomodulators not recommended.

Immunosuppressive Agents

Concomitant use with potent immunosuppressive agents (e.g., cyclosporine) not recommended.

Vaccines

Avoid live vaccines during or shortly prior to treatment.

Specific Drugs

Ritlecitinib Tosylate Pharmacokinetics

Absorption

Bioavailability

Absolute oral bioavailability approximately 64%.

AUC and peak plasma concentration increase in approximately dose-proportional manner up to 200 mg.

Steady-state concentrations attained in approximately 4 days following once daily dosing.

Peak plasma concentrations attained approximately 1 hour following oral administration.

Food

High-fat meal reduced peak drug plasma concentration by approximately 32% and increased AUC by 11%; not considered clinically important.

Special Populations

Renal impairment: AUC 55.2% higher in severe renal impairment (eGFR <30 mL/minute); not considered clinically important. Not studied in mild (eGFR 60–<90 mL/minute) or moderate (eGFR 30–<60 mL/minute) renal impairment; clinically relevant increase in exposure not expected.

Hepatic impairment: AUC increased by 18.5% in moderate (Child-Pugh class B) hepatic impairment. Not studied in mild (Child-Pugh class A) hepatic impairment; clinically relevant increase in exposure not expected.

Distribution

Extent

Distributed into milk in rats; not known whether distributed into human milk.

Plasma Protein Binding

Approximately 14% bound to plasma proteins.

Elimination

Metabolism

Mediated by multiple pathways with no single route contributing to >25% of total metabolism: glutathione S-transferases (GSTs) (cytosolic GST A1/3, M1/3/5, P1, S1, T2, Z1 and microsomal GST 1/2/3) and CYP isoenzymes (CYP3A, CYP2C8, CYP1A2, and CYP2C9).

Elimination Route

Approximately 66% excreted in urine and 20% in feces; 4% excreted as unchanged drug in urine.

Half–Life

1.3–2.3 hours.

Special Populations

Age, body weight, gender, or race: no clinically important differences in ritlecitinib pharmacokinetics.

Stability

Storage

Oral

Capsules

20–25°C in original package (excursions permitted between 15–30°C).

Actions

• Irreversibly inhibits Janus kinase 3 (JAK3) and tyrosine kinase expressed in hepatocellular carcinoma (TEC) kinase family by blocking adenosine triphosphate (ATP) binding site; relevance of inhibition of specific JAK or TEC family enzymes to therapeutic effectiveness currently unknown.

• Inhibits cytokine-induced STAT phosphorylation mediated by JAK3-dependent receptors in cellular settings.

• Inhibits signaling of immune receptors dependent on TEC kinase family members.

• Causes dose-dependent early decrease in absolute lymphocyte levels, T lymphocytes (CD3), T lymphocyte subsets (CD4 and CD8), and NK cells (CD16/56); no changes observed in B lymphocytes (CD19).

Advice to Patients

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

• Advise patients not to crush, split, or chew ritlecitinib capsules.

• Inform patients that they may develop infections when taking ritlecitinib, which can be serious in some cases. Instruct patients to inform their clinician if they develop any signs or symptoms of an infection (e.g., fever, sweating, chills, myalgia, cough, dyspnea, fatigue, diarrhea, dysuria, erythema).

• 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, and that periodic skin examinations are recommended while taking the drug.

• Advise patients that pulmonary embolism and retinal artery occlusion have been reported in studies with ritlecitinib. Instruct patients to seek immediate medical attention if they develop any signs or symptoms of thrombosis (e.g., shortness of breath; chest pain; swelling, pain, or tenderness in the leg).

• Inform patients of the increased risk of major adverse cardiovascular events, including heart attack, stroke, and cardiovascular death, with ritlecitinib. Instruct patients, especially current or past smokers and those with other cardiovascular risk factors, to monitor for the development of signs and symptoms of cardiovascular events.

• Advise patients to discontinue ritlecitinib and seek immediate medical attention if they develop any signs and symptoms of a 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 the use of live vaccines is not recommended during ritlecitinib treatment and shortly prior to treatment. Instruct patients to inform clinicians that they are taking ritlecitinib prior to a potential vaccination.

• Advise pregnant females and females of reproductive potential to inform their clinician if they are pregnant or intend to become pregnant during treatment with ritlecitinib. Instruct patients to report their pregnancy to the manufacturer at 1-877-390-2940.

• Advise women not to breast-feed during treatment with ritlecitinib and for 14 hours after the last dose.

• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

• Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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.

Ritlecitinib is obtained through designated specialty pharmacies. Contact the manufacturer or consult the Litfulo website ([Web]) for specific availability information.

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