Ritlecitinib

DAE Class; Rx

Common Brand Names; Litfulo

• Dermatologics, JAK Inhibitors; 
• Dermatologics, Tyrosine Kinase Inhibitors

Irreversibly inhibits Janus kinase 3 (JAK3) and the tyrosine kinase expressed in hepatocellular carcinoma (TEC) kinase family by blocking 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; relevance of inhibition of specific JAK or TEC family enzymes to therapeutic effectiveness is not currently known

Indicated for severe alopecia areata

Known hypersensitivity to ritlecitinib or any of its excipients

Headache (10.8%)

Diarrhea (10%)

Acne (6.2%)

Rash (5.4%)

Urticaria (4.6%)

Folliculitis (3.1%)

Pyrexia (3.1%)

Atopic dermatitis (2.3%)

Dizziness (2.3%)

Increased CPK (1.5%)

Herpes zoster (1.5%)

Decreased RBCs (1.5%)

Stomatitis (1.5%)

Black Box Warnings

Serious infections

• Increased risk of serious bacterial, fungal, viral and opportunistic infections leading to hospitalization or death, including tuberculosis (TB)
• Interrupt treatment if serious infection occurs until the infection is controlled
• Do not prescribe to patients with active TB; 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

Increased mortality

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

Malignancies

• Malignancies have occurred
• Higher rate of lymphomas and lung cancers with another JAK inhibitor compared with TNF blockers patients with RA

MACE

• Higher rate of major adverse cardiovascular events (MACE), defined as CV death, myocardial infarction, and stroke, with another JAK inhibitor compared with TNF blockers in patients with RA

Thrombosis

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

Cautions

In a large, randomized, postmarketing safety study of another JAK inhibitor in patients with RA aged ≥50 years with at least 1 CV risk factor, a higher rate of all-cause mortality, including sudden CV death, was observed in patients treated with the JAK inhibitor compared TNF blockers

Similarly, increased risk for MACE and thromboembolic events were observed with another JAK inhibitor in patients with RA aged ≥50 years; avoid 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

Malignancies, including non-melanoma skin cancer (NMSC), were observed in clinical trial; consider risks and benefits of treatment before initiating or continuing therapy in patients with known malignancy other than a successfully treated NMSC or cervical cancer; perform periodic skin examination for patients who are at increased risk for skin cancer

Consider benefits and risks for individual patient prior to initiating or continuing therapy with, particularly in patients who are current or past smokers and patients with other cardiovascular risk factors; patients should be informed about symptoms of serious cardiovascular events and steps to take if they occur; discontinue in patients that have experienced myocardial infarction or stroke

Serious reactions including anaphylactic reactions, urticaria and rash observed in clinical trials; discontinue and institute appropriate therapy if clinically significant rash occurs

Pregnancy

Data from clinical trials are insufficient regarding use in pregnant females to identify drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes

Lactation

Data are unavailable on presence  in human milk, effects on breastfed infants, or effects on milk production

Ritlecitinib is present in milk of lactating rats; when a drug is present in animal milk, it is likely that it will be present in human milk

Owing to the serious adverse effects in adults, including risks of serious infection and malignancy, advise females not to breastfeed during treatment and for ~14 hr after last dose (~6 elimination half-lives)

Alopecia Areata

Indicated for severe alopecia areata

50 mg PO qDay

Dosage Modifications

Treatment interruption or discontinuation

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

Hematologic abnormalities

• Platelet count <50,000/mm³: Discontinue treatment
• Absolute lymphocyte count (ALC) <500/mm³: Interrupt treatment; may restart once ALC returns above this value

Renal impairment

• Mild-to-moderate (eGFR 30-89 mL/min): Not studied as a clinically relevant increase in exposure is not expected
• Severe (eGFR <30 mL/min): AUC₂₄ was 55.2% higher compared with participants with normal renal functions; these differences were not considered clinically significant
• ESRD or in renal transplant recipients: Not studied

Hepatic impairment

• Mild-to-moderate (Child-Pugh A or B): No dosage adjustment required
• Severe (Child-Pugh C): Not recommended

Dosing Considerations

Limitations of use

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

Ritlecitinib