Ritlecitinib

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

( 1 ) Limitations of Use : Not recommended for use in combination with other JAK inhibitors, biologic immunomodulators, cyclosporine or other potent immunosuppressants ( 1 ).

2 DOSAGE AND ADMINISTRATION • For recommended testing, evaluations and immunizations prior to LITFULO initiation, see Full Prescribing Information. 1 ) • Recommended dosage is 50 mg orally once daily. 2 ) • For dosage interruption for certain adverse reactions, see Full Prescribing Information.

1 Recommended Evaluations and Immunizations Prior to Treatment Initiation Perform the following evaluations prior to LITFULO initiation: • Tuberculosis (TB) infection evaluation: LITFULO initiation is not recommended in patients with active TB.

1) ] . 1) ] . 7) ] . 8) ] . 3) ] . Swallow capsules whole. Do not crush, split, or chew LITFULO capsules. If a dose is missed, administer the dose as soon as possible unless it is less than 8 hours before the next dose, in which case, skip the missed dose.

Thereafter, resume dosing at the regular scheduled time. 3) ] . 4 Treatment Interruption or Discontinuation If treatment interruption is indicated, a temporary treatment interruption for less than 6 weeks is not expected to result in significant loss of regrown scalp hair.

Hematologic Abnormalities Recommendations for LITFULO treatment interruption or discontinuation for hematologic abnormalities are summarized in Table 1. Table 1. Laboratory Monitoring Guidance Laboratory Measure Recommendation ALC = absolute lymphocyte count.

Platelet Count Treatment should be discontinued if platelet count is <50,000/mm 3 Lymphocytes Treatment should be interrupted if ALC is <500/mm 3 and may be restarted once ALC return above this value. 7) ] .

7) ] 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.

1 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. gov/medwatch . 1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of LITFULO was evaluated in three randomized, placebo-controlled clinical trials and one long-term trial in subjects with alopecia areata, including alopecia totalis and alopecia universalis, who were 12 years of age and older.

A total of 1628 subjects were treated with LITFULO representing 2085 subject-years of exposure. There were 1011 subjects with at least 1 year of exposure to LITFULO. In the placebo-controlled period of clinical trials in alopecia areata, a total of 668 subjects were exposed to LITFULO with 130 receiving 50 mg once daily for up to 24 weeks.

5%) subjects were 65 years of age or older. 6%). Adverse reactions occurring at ≥1% in the treated groups and at a higher rate than placebo are presented in Table 2. 5%) subjects treated with LITFULO 50 mg were discontinued from the trials due to adverse reactions.

Table 2. Adverse Reactions in Clinical Trials of LITFULO for the Treatment of Alopecia Areata Reported in ≥1% of subjects and at a higher rate than placebo for up to 24 weeks. LITFULO 50 mg N=130 n (%) Placebo N=213 n (%) Headache Headache includes headache and migraine.

5) Diarrhea Diarrhea includes diarrhea and frequent bowel movements. 8) Acne Acne includes acne and acne pustular. 7) Rash Rash includes rash and dermatitis allergic. 5) 0 Specific Adverse Reactions Exposure adjusted incidence rates were adjusted by clinical trial size for all adverse reactions reported in this section.

53 per 100 subject-years) treated with LITFULO 50 mg. 71 per 100 subject-years) treated with LITFULO 50 mg or higher. Serious Infections In the placebo-controlled trials, for up to 24 weeks, 3 subjects reported serious infections across all ritlecitinib doses studied.

66 per 100 subject-years) treated with LITFULO 50 mg or higher. The most common serious infections were related to appendicitis, COVID-19 infection (including pneumonia), and sepsis. Herpes Zoster In the placebo-controlled trials, for up to 24 weeks, herpes zoster was reported in 4 subjects across all ritlecitinib doses studied and 0 subjects treated with placebo.

17 per 100 subject-years) treated with LITFULO 50 mg or higher. 1 per 100 subject-years) treated with LITFULO 50 mg or higher in all clinical trials. 33 per 100 subject-years) treated with ritlecitinib higher dose and no malignancy was reported in subjects treated with placebo.

37 per 100 subject-years) treated with LITFULO 50 mg or higher. 06 per 100 subject-years) treated with LITFULO. There was 1 report of retinal artery occlusion and 1 report of acute myocardial infarction. Urticaria In the placebo-controlled trials, for up to 24 weeks, urticaria was reported in 28 subjects treated in all ritlecitinib doses studied and 3 subjects treated with placebo.

03 per 100 subject-years in subjects treated with placebo. Across clinical trials, including the long-term trial, urticaria was reported in 76 subjects treated with LITFULO 50 mg or higher. 10 per 100 subject-years. The median time to onset of an initial event was 8 weeks; median duration of urticaria was 7 days.

Most of the cases were mild to moderate in severity. 1%) treated with LITFULO 50 mg. Age appeared to be a risk factor for lower ALC in subjects ≥65 years of age. Decreased Platelet Count In the placebo-controlled trials, for up to 24 weeks, treatment with LITFULO was associated with a decrease in platelet count.

Maximum effects on platelets were observed within 4 weeks, after which platelet count remained stable at a lower level with continued therapy. 1%) had a confirmed platelet count <100,000/mm 3 . No subject had a confirmed platelet count <75,000/mm 3 .

5%) subjects treated with LITFULO 50 mg and 0 subjects treated with placebo. 7) ] .

6) ] . LITFULO is contraindicated in patients with known hypersensitivity to ritlecitinib or any of its excipients. ( 4 )

LITFULO (ritlecitinib) is indicated for: • the treatment of adults and adolescents 12 years and older with severe alopecia areata.

Limitations of Use:

Not recommended for use in combination with JAK inhibitors, biologic immunomodulators, cyclosporine or other potent immunosuppressants. 1 Pediatrics 12-17 years of age: Based on the data submitted and reviewed by Health Canada, the safety and efficacy of LITFULO in pediatric patients 12-17 years of age has been established for severe alopecia areata.

Under 12 years of age:

No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use in patients under 12 years of age. 2 Geriatrics There are limited data in patients ≥ 65 years of age. 4 Geriatrics.

1 Dosing Considerations Treatment should be initiated and supervised by a healthcare professional experienced in the diagnosis and treatment of alopecia areata. The benefit-risk of treatment should be re-assessed at regular intervals on an individual basis.

Consideration should be given to discontinuing patients who show no evidence of therapeutic benefit after 36 weeks of treatment. Recommended Evaluations and Immunizations Prior to Treatment Initiation Perform the following evaluations prior to LITFULO initiation: • Patients should be screened for tuberculosis (TB) before starting therapy.

LITFULO should not be given to patients with active TB. Anti-TB therapy should be started prior to initiating therapy with LITFULO 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 LITFULO in those at high risk [see 7 WARNINGS AND PRECAUTIONS].

• Viral hepatitis screening in accordance with clinical guidelines: LITFULO initiation is not recommended in patients with hepatitis B or hepatitis C [see 7 WARNINGS AND PRECAUTIONS]. • Treatment with LITFULO should not be initiated in patients with an absolute lymphocyte count (ALC) <500/mm3 or a platelet count <100,000/mm3 [see 7 WARNINGS AND PRECAUTIONS].

• Blood work for liver enzymes should be drawn 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 LITFULO [see 8 ADVERSE REACTIONS]. • Update immunizations according to current immunization guidelines [see 7 WARNINGS AND PRECAUTIONS]. • Skin examination for malignancy is recommended before treatment initiation and periodically thereafter, especially for patients who are at increased risk for skin cancer [see 7 WARNINGS AND PRECAUTIONS].

2 Recommended Dose and Dosage Adjustment • The recommended dosage of LITFULO is 50 mg orally once daily. 3 Pharmacokinetics, Special Populations and Conditions]. 3 Pharmacokinetics, Special Populations and Conditions].

Under 12 years of age:

No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use. 3 Pharmacokinetics, Special Populations and Conditions]. LITFULO is contraindicated in patients with severe hepatic impairment (Child Pugh C) [see 2 CONTRAINDICATIONS].

3 Pharmacokinetics, Special Populations and Conditions]. LITFULO has not been studied in patients with end-stage renal disease (ESRD) or in patients with renal transplants and is therefore not recommended for use in these patients. Treatment Interruption or Discontinuation There is variability in time to response to treatment.

Consideration should be given to discontinuing patients who show no evidence of therapeutic benefit after 36 weeks of treatment. The benefit-risk of treatment should be re-assessed at regular intervals on an individual basis. If treatment interruption is indicated, a temporary treatment interruption for less than 6 weeks is not expected to result in significant loss of regrown scalp hair.

Infections If a patient develops serious infection or an opportunistic infection, LITFULO should be interrupted until the infection is controlled [see 7 WARNINGS AND PRECAUTIONS]. Hematologic abnormalities Recommendations for LITFULO treatment interruption or discontinuation for hematologic abnormalities are summarized in Table 1.

Monitoring during Treatment Consider screening patients at high risk for TB during treatment with LITFULO.

LITFULO (ritlecitinib) Page 7 of 31 Table 1:

Laboratory Measures and Monitoring Guidance Laboratory Measure Monitoring guidance Recommendation Platelet Count Before treatment initiation and 4 weeks after initiation, and thereafter according to routine patient management. [see 7 WARNINGS AND PRECAUTIONS] Treatment should be discontinued if platelet count is <50,000/mm3 Lymphocytes Treatment should be interrupted if ALC is <500/mm3 and may be restarted once ALC returns above this value.

3 Pharmacokinetics]. 3 Pharmacokinetics]. 3 Pharmacokinetics]. Capsules should be swallowed whole and should not be crushed, split, or chewed. 5 Missed Dose If a dose is missed, patients should be advised to take the dose as soon as possible unless it is less than 8 hours before the next dose, in which case the patient should not take the missed dose.

Thereafter, dosing should be resumed at the regular scheduled time.

]. Reported infections from Janus kinase (JAK) inhibitors used to treat inflammatory conditions: • Active tuberculosis (TB), which may present with pulmonary or extrapulmonary disease. Test for latent TB before and during therapy; start treatment of latent TB prior to use.

Monitor all patients for active TB during treatment, even patients with initial negative latent TB test. • Invasive fungal infections, including cryptococcosis and pneumocystosis. Patients with invasive fungal infections may present with disseminated, rather than localized, disease.

• Bacterial, viral, including herpes zoster, and other infections due to opportunistic pathogens. LITFULO (ritlecitinib) Page 5 of 31 Treatment with LITFULO should be avoided in patients with an active, serious infection. If a serious or opportunistic infection develops during treatment, interrupt LITFULO until the infection is controlled.

The risks and benefits of treatment with LITFULO should be carefully considered prior to initiating therapy in patients with chronic or recurrent infections. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with LITFULO [see 7 WARNINGS AND PRECAUTIONS].

Malignancies Malignancies were reported in patients treated with LITFULO [see 7 WARNINGS AND PRECAUTIONS]. 1 Dosing Considerations Treatment should be initiated and supervised by a healthcare professional experienced in the diagnosis and treatment of alopecia areata.

The benefit-risk of treatment should be re-assessed at regular intervals on an individual basis. Consideration should be given to discontinuing patients who show no evidence of therapeutic benefit after 36 weeks of treatment. Recommended Evaluations and Immunizations Prior to Treatment Initiation Perform the following evaluations prior to LITFULO initiation: • Patients should be screened for tuberculosis (TB) before starting therapy.

LITFULO should not be given to patients with active TB. Anti-TB therapy should be started prior to initiating therapy with LITFULO 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 LITFULO in those at high risk [see 7 WARNINGS AND PRECAUTIONS].

• Viral hepatitis screening in accordance with clinical guidelines: LITFULO initiation is not recommended in patients with hepatitis B or hepatitis C [see 7 WARNINGS AND PRECAUTIONS]. • Treatment with LITFULO should not be initiated in patients with an absolute lymphocyte count (ALC) <500/mm3 or a platelet count <100,000/mm3 [see 7 WARNINGS AND PRECAUTIONS].

• Blood work for liver enzymes should be drawn 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 LITFULO [see 8 ADVERSE REACTIONS]. • Update immunizations according to current immunization guidelines [see 7 WARNINGS AND PRECAUTIONS]. • Skin examination for malignancy is recommended before treatment initiation and periodically thereafter, especially for patients who are at increased risk for skin cancer [see 7 WARNINGS AND PRECAUTIONS].

2 Recommended Dose and Dosage Adjustment • The recommended dosage of LITFULO is 50 mg orally once daily. 3 Pharmacokinetics, Special Populations and Conditions]. 3 Pharmacokinetics, Special Populations and Conditions].

Under 12 years of age:

No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use. 3 Pharmacokinetics, Special Populations and Conditions]. LITFULO is contraindicated in patients with severe hepatic impairment (Child Pugh C) [see 2 CONTRAINDICATIONS].

3 Pharmacokinetics, Special Populations and Conditions]. LITFULO has not been studied in patients with end-stage renal disease (ESRD) or in patients with renal transplants and is therefore not recommended for use in these patients. Treatment Interruption or Discontinuation There is variability in time to response to treatment.

Consideration should be given to discontinuing patients who show no evidence of therapeutic benefit after 36 weeks of treatment. The benefit-risk of treatment should be re-assessed at regular intervals on an individual basis. If treatment interruption is indicated, a temporary treatment interruption for less than 6 weeks is not expected to result in significant loss of regrown scalp hair.

Infections If a patient develops serious infection or an opportunistic infection, LITFULO should be interrupted until the infection is controlled [see 7 WARNINGS AND PRECAUTIONS]. Hematologic abnormalities Recommendations for LITFULO treatment interruption or discontinuation for hematologic abnormalities are summarized in Table 1.

Monitoring during Treatment Consider screening patients at high risk for TB during treatment with LITFULO.

LITFULO (ritlecitinib) Page 7 of 31 Table 1:

Laboratory Measures and Monitoring Guidance Laboratory Measure Monitoring guidance Recommendation Platelet Count Before treatment initiation and 4 weeks after initiation, and thereafter according to routine patient management. [see 7 WARNINGS AND PRECAUTIONS] Treatment should be discontinued if platelet count is <50,000/mm3 Lymphocytes Treatment should be interrupted if ALC is <500/mm3 and may be […]

• LITFULO is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient or component of the container. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.

2 Breast-feeding]. 3 Pharmacokinetics, Special Populations and Conditions].

1).

Treatment should be initiated and supervised by a healthcare professional experienced in the diagnosis and treatment of alopecia areata. Posology The recommended dose is 50 mg once daily. The benefit-risk of treatment should be re-assessed at regular intervals on an individual basis.

Consideration should be given to discontinuing patients who show no evidence of therapeutic benefit after 36 weeks. 3 Laboratory monitoring Table 1. Laboratory measures and monitoring guidance Laboratory measures Monitoring guidance Action Platelet count Before treatment initiation, 4 weeks after initiation, and thereafter according to routine patient management.

Treatment should be discontinued if platelet count is < 50 × 103/mm3. 5 × 103/mm3 and may be restarted once ALC return above this value. 4). 4). Interruption or discontinuation of treatment may be needed for management of haematologic abnormalities as described in Table 1.

If treatment interruption is needed, the risk of significant loss of regrown scalp hair after a temporary treatment interruption for less than 6 weeks is low. Missed doses If a dose is missed, patients should be advised to take the dose as soon as possible unless it is less than 8 hours before the next dose, in which case the patient should not take the missed dose.

Thereafter, dosing should be resumed at the regular scheduled time. 2). Ritlecitinib has not been studied in patients with end-stage renal disease (ESRD) or in patients with renal transplants and is therefore not recommended for use in these patients.

2). 3). Elderly No dose adjustment is required for patients ≥ 65 years of age. There are limited data in patients ≥ 65 years of age. Paediatric population No dose adjustment is required for adolescents 12 to < 18 years of age. The safety and efficacy of Litfulo in children under 12 years of age have not yet been established.

No data are available. 4 Method of administration Oral use. Litfulo is to be taken once daily with or without food. Capsules should be swallowed whole and should not be crushed, split or chewed, because these methods of administration have not been studied in clinical trials.

3%). Tabulated list of adverse reactions A total of 1630 patients were treated with ritlecitinib representing 3751 patient-years of exposure. Three placebo-controlled studies were integrated (130 participants on 50 mg daily and 213 participants on placebo) to evaluate the safety of ritlecitinib in comparison to placebo for up to 24 weeks after treatment initiation.

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. 8 Table 2. Adverse reactions System organ class Common Uncommon Infections and infestations Herpes zoster Folliculitis Upper respiratory tract infections Nervous system disorders Dizziness Gastrointestinal disorders Diarrhoea Skin and subcutaneous tissue disorders Acne Urticaria Rash Investigations Blood creatine phosphokinase increased Platelet count decreased Lymphocyte count decreased Alanine aminotransferase increased ˃ 3 × ULNa Aspartate aminotransferase increased ˃ 3 × ULNa a.

53 per 100 patient-years) treated with ritlecitinib 50 mg. 32 per 100 patient-years) treated with ritlecitinib 50 mg or higher. 3 per 100 patient-years) treated with ritlecitinib 50 mg or higher. Most infections were mild or moderate in severity.

5% in the ritlecitinib 50 mg group compared to 0 in placebo. All herpes zoster events were non-serious; 1 patient receiving ritlecitinib 200/50 mg (200 mg once daily for 4 weeks followed by 50 mg once daily) experienced an event of varicella zoster virus infection that met criteria as an opportunistic infection (multi-dermatomal herpes zoster).

05 per 100 patient-years in patients treated with ritlecitinib 50 mg or higher. In the placebo-controlled studies, for up to 24 weeks, no serious infections were reported in patients treated with placebo or ritlecitinib 50 mg. 66 per 100 patient-years).

86 per 100 patient-years) treated with ritlecitinib 50 mg or higher. 57 per 100 patient-years). 12 per 100 patient-years) treated with ritlecitinib 50 mg 9 or higher in the integrated safety analysis, including the long-term study and a study in vitiligo.

Cases of opportunistic herpes zoster were mild or moderate in severity. Decreased lymphocyte count In the placebo-controlled studies, for up to 24 weeks, and study AA-I, for up to 48 weeks, treatment with ritlecitinib was associated with a decrease in lymphocyte count.

Maximum effects on lymphocytes were observed within 4 weeks, after which lymphocyte count remained stable at a lower level with continued therapy. 2%) treated with ritlecitinib 50 mg. Decreased platelet count In the placebo-controlled studies, for up to 24 weeks, and study AA-I, for up to 48 weeks, treatment with ritlecitinib was associated with a decrease in platelet count.

Maximum effects on platelets were observed within 4 weeks, after which platelet count remained stable at a lower level with continued therapy. 1%) treated with ritlecitinib 50 mg or higher had a confirmed platelet count < 100 × 103/mm3.

5%) treated with ritlecitinib 50 mg. 8% of patients treated with ritlecitinib 50 mg or higher. 9%) of […]

1. 4). 2). 6).