LEQSELVI

Posology The recommended dosage of Leqselvi for the treatment of severe alopecia areata is 8 mg orally twice daily, with or without food. If a dose is missed, skip the missed dose and resume dosing at the next scheduled dose. Serious or opportunistic infections If a patient develops a serious or opportunistic infection, interrupt Leqselvi treatment until the infection is controlled.

Haematologic abnormalities Recommendations for Leqselvi treatment interruption for haematologic abnormalities are described in Table 1.

Table 1:

Recommendations for Leqselvi Treatment Interruption for Haematologic Abnormalities and Resumption Laboratory Measure Interruption Criterion Resumption Criterion Absolute Lymphocyte Count (ALC) <500 cells/mm3 ≥500 cells/mm3 Absolute Neutrophil Count (ANC) <1000 cells/mm3 ≥1000 cells/mm3 Haemoglobin <8 g/dL ≥8 g/dL Renal impairment Leqselvi is not recommended for use in patients with severe renal impairment or end- stage renal disease (eGFR < 30 mL/min).

No adjustment of dosage is required in patients with mild or moderate renal impairment. The effect of severe renal impairment on deuruxolitinib pharmacokinetics is unknown. Hepatic Impairment Leqselvi is not recommended for use in patients with severe hepatic impairment (Child Pugh C).

No adjustment of dosage is required in patients with mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment. The effect of severe hepatic impairment on deuruxolitinib pharmacokinetics is unknown. CYP2C9 Poor Metabolizers Based on PBPK modelling, higher exposure of deuruxolitinib in patients who are CYP2C9 poor metabolizers is expected with concomitant use of Leqselvi, which may increase the risk of Leqselvi -associated serious adverse reactions.

Before initiation of treatment with Leqselvi, test patients to determine CYP2C9 genotype. Elderly There are limited data in patients ≥ 65 years of age. Paediatric population The safety and efficacy of Leqselvi in children less than 18 years of age has not been established.

No data are available. Method of administration Oral use Leqselvi should be swallowed with water, with or without food. Precautions to be taken before handling or administering the medicinal product. Perform the following prior to treatment with Leqselvi: • CYP2C9 genotype determination: Test patients for CYP2C9 variants to determine CYP2C9 genotype.

Leqselvi is contraindicated in patients who are CYP2C9 poor metabolizers (patients with decreased cytochrome P450 (CYP) 2C9 function). 5). • Active and latent tuberculosis (TB) evaluation: Leqselvi treatment is not recommended in patients with active TB.

For patients with latent TB or those with a negative latent TB test who are at high risk of TB, start preventive therapy for TB prior to Leqselvi treatment. • Viral hepatitis screening in accordance with clinical guidelines: Leqselvi treatment is not recommended in patients with active hepatitis B or hepatitis C.

• Hepatitis B infection screening: If hepatitis B infection is discovered, follow hepatitis B clinical guidelines, or refer to a liver specialist. Monitor patients for reactivation in accordance with clinical guidelines during treatment.

• Complete blood count (CBC): Leqselvi treatment is not recommended in patients with an absolute lymphocyte count (ALC) <500 cells/mm3 absolute neutrophil count (ANC) <1000 cells/mm3, or haemoglobin level <8 g/dL. Monitor complete blood counts periodically during treatment and modify dosage as recommended.

• Complete any necessary immunizations, including herpes zoster vaccinations, according to current immunization guidelines prior to Leqselvi treatment. Pharmacogenomics Deuruxolitinib is primarily metabolized by CYP2C9 (76%) and CYP3A4 (21%).

CYP2C9 activity is reduced in patients with genetic variants in CYP2C9, such as the CYP2C9*2 and CYP2C9*3 alleles. The impact of CYP2C9 genetic variants on the pharmacokinetics of deuruxolitinib has not been directly evaluated. , *2/*3, *3/*3) may have up to 2-fold higher concentrations of deuruxolitinib, when compared to normal metabolizers.

, individuals with *1/*3 genotype). 5 to 4% in Asian populations, and <1% in Black or African American populations. , *5, *6, *8, *11) are more prevalent in Black or African American populations.

Summary of the safety profile The safety of Leqselvi was evaluated in three randomized, placebo-controlled clinical trials (including a dose-ranging trial), two open-label trials, and two long-term extension trials in adult subjects with severe alopecia areata.

These subjects had at least 50% scalp hair loss as measured by the Severity of Alopecia Tool (SALT) for more than six months. The most frequently (>1%) reported adverse reactions are headache, nasopharyngitis, acne, nasopharyngitis, blood creatine phosphokinase increased, hyperlipidemia, fatigue, weight increased, lymphopenia, thrombocytosis, anemia, skin and soft tissue infections, neutropenia, and herpes.

9 patient-years of exposure. There were 974 subjects who were exposed to either Leqselvi 8 mg (326 subjects) or deuruxolitinib 12 mg (454 subjects) for at least 1 year and 104 subjects who were exposed for at least 3 years. Table 2 lists all adverse reactions observed in alopecia areata placebo-controlled studies presented by system organ class and frequency, using the following categories: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1 000 to < 1/100); rare (≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. 1% - 1%[ Infection and infestations Nasopharyngitis –Skin and soft tissue infections 1 Herpes 2 Blood and lymphatic system disorders Anemia 3 Neutropenia 4 Lymphopenia Thrombocytosis 5 Metabolism and nutrition disorders Hyperlipidemia 6 Nervous system disorders Headache Skin and subcutaneous tissue disorders Acne 7 General Disorders and Administration Site Conditions Fatigue 8 Investigations Blood creatine phosphokinase increased Weight increased 1.

Skin and soft issue infections includes: folliculitis, impetigo, skin infection, subcutaneous abscess, furuncle, paronychia, and pustule. 2 Herpes includes: oral herpes, herpes simplex, genital herpes simplex, and nasal herpes. 3 Anemia includes: anemia, hematocrit decreased, hemoglobin decreased, iron deficiency anemia, and red blood cell count decreased.

4. Neutropenia includes: neutropenia and neutrophil count decreased.

g. 8). Avoid use of Leqselvi in patients with an active, serious infection including localized infections. Prior to Leqselvi treatment, consider the risks and benefits in patients: • with chronic or recurrent infection • who have been exposed to tuberculosis • with a history of a serious or opportunistic infection • who have resided or travelled in areas of endemic tuberculosis or endemic mycoses; or • 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 Leqselvi.

If the patient develops a serious infection, interrupt treatment with Leqselvi until the infection resolves or is adequately treated. If a patient develops a new infection during treatment with Leqselvi, initiate complete diagnostic testing appropriate for an immunocompromised patient and appropriate antimicrobial therapy.

Tuberculosis Evaluate patients for latent and active tuberculosis (TB) infection prior to Leqselvi treatment. Leqselvi is not recommended for use in patients with active TB. Treat patients with latent TB before Leqselvi treatment. Consider anti-TB therapy prior to Leqselvi treatment in patients with previously untreated latent TB or active TB in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent TB but who have risk factors for TB infection.

Consultation with a physician with expertise in the treatment of TB is recommended to aid in the decision about whether initiating anti-TB therapy is appropriate for an individual patient. Monitor patients receiving Leqselvi for signs and symptoms of active TB during treatment, including patients who tested negative for latent TB infection prior to treatment.

, herpes zoster) were reported in clinical trials with Leqselvi. If a patient develops herpes zoster, consider interrupting Leqselvi treatment until the episode resolves. The impact of Leqselvi on chronic viral hepatitis reactivation is unknown.

Subjects with positive results for hepatitis B surface antigens (HBsAg), antibodies to hepatitis B core antigens (anti-HBc), or hepatitis C virus (HCV) with detectable HCV RNA at screening were excluded from Leqselvi clinical trials.

Perform screening for viral hepatitis before treatment with Leqselvi. Leqselvi is not recommended for use in patients with active hepatitis B or hepatitis C (HCV RNA detected). If non-active hepatitis B infection is discovered, monitoring for reactivation or prophylactic treatment is recommended.

Follow hepatitis B clinical guidelines or refer to a liver specialist. Hepatitis B viral load (HBV-DNA titer) increase, with or without associated elevations in alanine aminotransferase and aspartate aminotransferase, has been reported in subjects with chronic HBV infections receiving JAK inhibitors used to treat inflammatory conditions.

The effect of Leqselvi on viral replication in patients with chronic HBV infection is unknown. Mortality In a large, randomized, post-marketing safety trial of another JAK inhibitor in rheumatoid arthritis (RA) subjects 50 years and older with at least one cardiovascular risk factor, a higher rate of all-cause mortality, including sudden cardiovascular death, was observed in subjects treated with the JAK inhibitor compared with TNF blockers.

Consider the benefits and risks for the individual patient prior to and during treatment with Leqselvi. Malignancy and Lymphoproliferative Disorders Malignancies were observed in clinical trials of Leqselvi. In a large, randomized, post-marketing safety trial of another JAK inhibitor in subjects with RA, a higher rate of malignancies (excluding non-melanoma skin cancer (NMSC)) was observed in subjects treated with the JAK inhibitor compared to those treated with TNF blockers.

A higher rate of lymphomas was observed in subjects 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 trial, current or past smokers had an additional increased risk of overall malignancies. Consider the benefits and risks for the individual patient prior to and during treatment with Leqselvi, particularly in patients with a known malignancy (other than successfully treated NMSC), patients who develop a malignancy, and patients who are current or past smokers.

Non-melanoma skin cancers Non-melanoma skin cancers (NMSCs) have been reported in patients treated with Leqselvi. Periodic skin examination is recommended for patients who are at increased risk for skin cancer. Major Adverse Cardiovascular Events (MACE) In a large, randomized, post-marketing safety trial of another JAK inhibitor in subjects with RA 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 and during treatment with Leqselvi, particularly in patients who are current or past smokers and patients with other cardiovascular risk factors.

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4). 4). 1 Limitations of Use Leqselvi is not recommended for use in combination with other Janus-associated kinase (JAK) inhibitors, biologic immunomodulators, cyclosporine, or other potent immunosuppressants.