LITFULO 50mg capsules medication leaflet

Litfulo 50 mg hard capsules

Each hard capsule contains ritlecitinib tosylate equivalent to 50 mg ritlecitinib.

Each hard capsule contains 21.27 mg of lactose monohydrate.

For the full list of excipients, see section 6.1.

Hard capsule (capsule)

Opaque hard capsules, yellow body and blue cap approximately 16 mm long and 6 mm wide, of whichthe body is printed with “RCB 50” and the cap is printed with “Pfizer” in black.

Litfulo is indicated for the treatment of severe alopecia areata in adults and adolescents 12 years of ageand older (see section 5.1).

Treatment should be initiated and supervised by a healthcare professional experienced in the diagnosisand treatment of alopecia areata.

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 benefitafter 36 weeks.

Laboratory monitoring

Table 1. Laboratory measures and monitoring guidance

Laboratory Monitoring guidance Actionmeasures

Platelet count Treatment should be

Before treatment initiation, 4 weeks after discontinued if platelet count isinitiation, and thereafter according to < 50 × 103/mm3.

Lymphocytes routine patient management. Treatment should be interruptedif ALC is < 0.5 × 103/mm3 andmay be restarted once ALCreturn above this value.

Abbreviation: ALC = absolute lymphocyte count

Treatment initiation

Treatment with ritlecitinib should not be initiated in patients with an absolute lymphocyte count(ALC) < 0.5 × 103/mm3 or a platelet count < 100 × 103/mm3 (see section 4.4).

Treatment interruption or discontinuation

If a patient develops a serious infection or opportunistic infection, ritlecitinib should be interrupteduntil the infection is controlled (see section 4.4).

Interruption or discontinuation of treatment may be needed for management of haematologicabnormalities as described in Table 1.

If treatment interruption is needed, the risk of significant loss of regrown scalp hair after a temporarytreatment interruption for less than 6 weeks is low.

If a dose is missed, patients should be advised to take the dose as soon as possible unless it is less than8 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.

No dose adjustment is required in patients with mild, moderate, or severe renal impairment (seesection 5.2).

Ritlecitinib has not been studied in patients with end-stage renal disease (ESRD) or in patients withrenal transplants and is therefore not recommended for use in these patients.

No dose adjustment is required in patients with mild (Child Pugh A) or moderate (Child Pugh B)hepatic impairment (see section 5.2). Ritlecitinib is contraindicated in patients with severe (Child Pugh

C) hepatic impairment (see section 4.3).

No dose adjustment is required for patients ≥ 65 years of age. There are limited data in patients≥ 65 years of age.

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. Nodata are available.

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 thesemethods of administration have not been studied in clinical trials.

- Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1.

- Active serious infections, including tuberculosis (TB) (see section 4.4).

- Severe hepatic impairment (see section 4.2).

- Pregnancy and breast-feeding (see section 4.6).

Serious infections have been reported in patients receiving ritlecitinib. The most frequent seriousinfections have been appendicitis, COVID-19 infection (including pneumonia), and sepsis. Treatmentwith ritlecitinib must not be initiated in patients with an active, serious infection (see section 4.3).

The risks and benefits of treatment should be considered in patients:

- with chronic or recurrent infection

- who have been exposed to tuberculosis (TB)

- with a history of serious or an opportunistic infection

- who have resided or traveled in areas of endemic TB or mycoses, or

- with underlying conditions that may predispose them to infection

Patients should be closely monitored for the development of signs and symptoms of infection duringand after treatment with ritlecitinib. Treatment should be interrupted if a patient develops a serious oropportunistic infection. A patient who develops a new infection during treatment with ritlecitinibshould undergo prompt and complete diagnostic testing appropriate for an immunocompromisedpatient, appropriate antimicrobial therapy should be initiated, and the patient should be closelymonitored. If interrupted, ritlecitinib may be resumed once the infection is controlled.

As there is a higher incidence of infections in elderly and in the diabetic population in general, cautionshould be exercised when treating the elderly and patients with diabetes, and particular attention paidwith respect to occurrence of infections.

Patients should be screened for TB before starting therapy with ritlecitinib. Ritlecitinib must not begiven to patients with active TB (see section 4.3). Anti-TB therapy should be started prior to initiatingtherapy with ritlecitinib in patients with a new diagnosis of latent TB or previously untreated latent

TB. In patients with a negative latent TB test, anti-TB therapy should still be considered beforeinitiating treatment with ritlecitinib in those at high risk and screening for patients at high risk for TBduring treatment with ritlecitinib should be considered.

Viral reactivations, including cases of herpes virus reactivation (e.g., herpes zoster), have beenreported (see section 4.8). If a patient develops herpes zoster, temporary interruption of treatment maybe considered until the episode resolves.

Screening for viral hepatitis should be performed in accordance with clinical guidelines before startingtherapy with ritlecitinib. Patients with evidence of hepatitis B or C infection were excluded fromstudies with ritlecitinib. Monitoring for reactivation of viral hepatitis according to clinical guidelines isrecommended during ritlecitinib treatment. If there is evidence of reactivation, a liver specialist shouldbe consulted.

Malignancy (including non-melanoma skin cancer)

Malignancies, including non-melanoma skin cancer (NMSC) have been reported in patients receivingritlecitinib.

It is not known whether selective JAK3 inhibition may be associated with adverse reactions of Janus

Kinase (JAK) inhibition predominantly involving JAK1 and JAK2. In a large randomisedactive-controlled study of tofacitinib (another JAK inhibitor) in rheumatoid arthritis (RA) patients 50years and older with at least one additional cardiovascular risk factor, a higher rate of malignancies,particularly lung cancer, lymphoma and NMSC, was observed with tofacitinib compared to tumournecrosis factor (TNF) inhibitors.

Limited clinical data are available to assess the potential relationship of exposure to ritlecitinib and thedevelopment of malignancies. Long-term safety evaluations are ongoing. The risks and benefits ofritlecitinib treatment should be considered prior to initiating or continuing therapy in patients with aknown malignancy other than a successfully treated NMSC or cervical cancer.

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

Major adverse cardiovascular events (MACE), deep venous thrombosis (DVT) and pulmonaryembolism (PE)

Events of venous and arterial thromboembolism, including MACE, have been reported in patientsreceiving ritlecitinib.

It is not known whether selective JAK3 inhibition may be associated with adverse reactions of JAKinhibition predominantly involving JAK1 and JAK2. In a large randomised active-controlled study oftofacitinib (another JAK inhibitor) in RA patients 50 years and older with at least one additionalcardiovascular risk factor, a higher rate of MACE, defined as cardiovascular death, non-fatalmyocardial infarction and non-fatal stroke, and a dose-dependent higher rate of venousthromboembolism including DVT and PE were observed with tofacitinib compared to TNF inhibitors.

Long-term safety evaluations for ritlecitinib are ongoing. Ritlecitinib should be used with caution inpatients with known risk factors for thromboembolism. In patients with a suspected thromboembolicevent, discontinuation of ritlecitinib and prompt re-evaluation is recommended. The risks and benefitsof ritlecitinib treatment should be considered prior to initiating therapy in patients.

Ritlecitinib-related axonal dystrophy has been observed in chronic Beagle dog toxicity studies(see section 5.3). Treatment with ritlecitinib should be discontinued in case unexplained neurologicalsymptoms occur.

Haematologic abnormalities

Treatment with ritlecitinib was associated with decreases in lymphocytes and platelets (see section4.8). Prior to initiating treatment with ritlecitinib, ALC and platelet counts should be performed.

Treatment with ritlecitinib should not be initiated in patients with an ALC < 0.5 × 103/mm3 or aplatelet count < 100 × 103/mm3. After initiating treatment with ritlecitinib, treatment interruption ordiscontinuation are recommended based on ALC and platelet count abnormalities (see section 4.2).

ALC and platelet counts are recommended at 4 weeks after initiation of therapy with ritlecitinib, andthereafter according to routine patient management.

No data are available on the response to vaccination in patients receiving ritlecitinib. Use of liveattenuated vaccines should be avoided during or immediately prior to ritlecitinib treatment. Prior toinitiating ritlecitinib, it is recommended that patients are brought up to date with all immunisations,including prophylactic herpes zoster vaccinations, in agreement with current immunisation guidelines.

There are limited data in patients ≥ 65 years of age. Age appeared to be a risk factor for lower ALC inpatients ≥ 65 years of age.

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency orglucose-galactose malabsorption should not take this medicinal product.

Potential for other medicinal products to affect the pharmacokinetics of ritlecitinib

The coadministration of multiple 200 mg doses of itraconazole, a strong CYP3A inhibitor, increasedthe area under curve (AUC)inf of ritlecitinib by approximately 15%. This is not considered clinicallysignificant and, therefore dose adjustment is not required when ritlecitinib is coadministered with

The coadministration of multiple 600 mg doses of rifampicin, a strong inducer of CYP enzymes,decreased the AUCinf of ritlecitinib by approximately 44%. This is not considered clinically significantand, therefore dose adjustment is not required when ritlecitinib is coadministered with inducers of

CYP enzymes.

Potential for ritlecitinib to affect the pharmacokinetics of other medicinal products

Multiple doses of 200 mg once daily ritlecitinib increased the AUCinf and Cmax of midazolam a

CYP3A4 substrate, by approximately 2.7-fold and 1.8-fold, respectively. Ritlecitinib is a moderateinhibitor of CYP3A; caution should be exercised with concomitant use of ritlecitinib with CYP3Asubstrates (e.g., quinidine, cyclosporine, dihydroergotamine, ergotamine, pimozide) where moderateconcentration changes may lead to serious adverse reactions. Dose adjustment recommendations forthe CYP3A substrate (e.g., colchicine, everolimus, tacrolimus, sirolimus) should be considered.

Multiple doses of 200 mg once daily ritlecitinib increased the AUCinf and Cmax of caffeine, a CYP1A2substrate, by approximately 2.7-fold and 1.1-fold, respectively. Ritlecitinib is a moderate inhibitor of

CYP1A2; caution should be exercised with concomitant use of ritlecitinib with other CYP1A2substrates (e.g., tizanidine) where moderate concentration changes may lead to serious adversereactions. Dose adjustment recommendations for the CYP1A2 substrate (e.g., theophylline,pirfenidone) should be considered.

The coadministration of a single 400 mg dose of ritlecitinib increased the AUCinf of sumatriptan (anorganic cation transporter [OCT]1 substrate) by approximately 1.3 to 1.5-fold relative to sumatriptandose given alone. The increase in sumatriptan exposure is not considered clinically relevant. Cautionshould be exercised with concomitant use of ritlecitinib with OCT1 substrates where smallconcentration changes may lead to serious adverse reactions.

Ritlecitinib did not produce clinically significant changes in the exposures of oral contraceptives (e.g.,ethinyl oestradiol or levonorgestrel), CYP2B6 substrates (e.g., efavirenz), CYP2C substrates (e.g.,tolbutamide), or substrates of organic anion transporter (OAT)P1B1, breast cancer resistant protein(BCRP), and OAT3 (e.g., rosuvastatin).

Interaction studies have only been performed in adults.

Ritlecitinib is not recommended in women of childbearing potential not using contraception. Womenof childbearing potential have to use effective contraception during treatment and for 1 monthfollowing the final dose of Litfulo.

There are no or limited data from the use of ritlecitinib in pregnant women. Studies in animals haveshown reproductive toxicity (see section 5.3). Ritlecitinib was teratogenic in rats and rabbits at highdoses (see section 5.3). Litfulo is contraindicated during pregnancy (see section 4.3).

Available pharmacodynamic/toxicological data in animals have shown excretion of ritlecitinib in milk(see section 5.3). A risk to newborns/infants cannot be excluded. Litfulo is contraindicated duringbreast-feeding (see section 4.3).

The effect of ritlecitinib on human fertility has not been evaluated. There were no effects on fertility inrats at clinically relevant exposures (see section 5.3).

Litfulo has no or negligible influence on the ability to drive and use machines.

The most frequently reported adverse reactions are diarrhoea (9.2%), acne (6.2%), upper respiratorytract infections (6.2%), urticaria (4.6%), rash (3.8%), folliculitis (3.1%), and dizziness (2.3%).

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 participantson placebo) to evaluate the safety of ritlecitinib in comparison to placebo for up to 24 weeks aftertreatment initiation.

Table 2 lists all adverse reactions observed in alopecia areata placebo-controlled studies presented bysystem 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 decreasingseriousness.

Table 2. Adverse reactions

System organ class Common Uncommon

Infections and infestations Herpes zoster

Folliculitis

Upper respiratory tractinfections

Nervous system disorders Dizziness

Gastrointestinal disorders Diarrhoea

Skin and subcutaneous tissue Acnedisorders Urticaria

Investigations Blood creatine phosphokinase Platelet count decreasedincreased Lymphocyte count decreased

Alanine aminotransferaseincreased ˃ 3 × ULNa

Aspartate aminotransferaseincreased ˃ 3 × ULNa

a. Includes changes detected during laboratory monitoring

In the placebo-controlled studies, for up to 24 weeks, overall infections have been reported in 31% ofpatients (80.35 per 100 patient-years) treated with placebo and 33% of patients (74.53 per100 patient-years) treated with ritlecitinib 50 mg. In study AA-I, for up to 48 weeks, overall infectionswere reported in 51% of patients (89.32 per 100 patient-years) treated with ritlecitinib 50 mg orhigher.

Among all patients treated with ritlecitinib in the integrated safety analysis, including the long-termstudy and a study in vitiligo, overall infections were reported in 56.3% of patients (45.3 per100 patient-years) treated with ritlecitinib 50 mg or higher. Most infections were mild or moderate inseverity.

In the placebo-controlled studies the percentage of patients reporting infection-related adverse reactionof herpes zoster were 1.5% in the ritlecitinib 50 mg group compared to 0 in placebo. All herpes zosterevents were non-serious; 1 patient receiving ritlecitinib 200/50 mg (200 mg once daily for 4 weeksfollowed by 50 mg once daily) experienced an event of varicella zoster virus infection that met criteriaas an opportunistic infection (multi-dermatomal herpes zoster). In study AA-I, for up to 48 weeks,2.3% of patients (2.61 per 100 patient-years) treated with ritlecitinib 50 mg or higher reported herpeszoster Among all patients treated with ritlecitinib in the integrated safety analysis, including thelong-term study and a study in vitiligo, the rate of herpes zoster was 1.05 per 100 patient-years inpatients treated with ritlecitinib 50 mg or higher.

In the placebo-controlled studies, for up to 24 weeks, no serious infections were reported in patientstreated with placebo or ritlecitinib 50 mg. The proportion and rate of serious infections in patientstreated with ritlecitinib 200/50 mg was 0.9% (2.66 per 100 patient-years). In study AA-I, for up to48 weeks, serious infections were reported in 0.8% of patients (0.86 per 100 patient-years) treated withritlecitinib 50 mg or higher. Among all patients treated with ritlecitinib in the integrated safetyanalysis, including the long-term study and a study in vitiligo, the proportion and rate of seriousinfection in ritlecitinib 50 mg or higher was 1.3% (0.57 per 100 patient-years).

Opportunistic infections of multi-dermatomal herpes zoster were reported in 1 patient (0.50 per100 patient-years) treated with ritlecitinib 200/50 mg in the placebo-controlled studies, no patients instudy AA-I, for up to 48 weeks, and 4 patients (0.12 per 100 patient-years) treated with ritlecitinib 50 mgor higher in the integrated safety analysis, including the long-term study and a study in vitiligo. Casesof 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, treatmentwith ritlecitinib was associated with a decrease in lymphocyte count. Maximum effects onlymphocytes were observed within 4 weeks, after which lymphocyte count remained stable at a lowerlevel with continued therapy. Among all patients treated with ritlecitinib in the integrated safetyanalysis, including the long-term study and a study in vitiligo, confirmed ALC < 0.5 × 103/mm3occurred in 3 participants (0.2%) 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, treatmentwith ritlecitinib was associated with a decrease in platelet count. Maximum effects on platelets wereobserved within 4 weeks, after which platelet count remained stable at a lower level with continuedtherapy. Among all patients treated with ritlecitinib in the integrated safety analysis, including thelong-term study and a study in vitiligo, 2 patients (0.1%) treated with ritlecitinib 50 mg or higher had aconfirmed platelet count < 100 × 103/mm3.

Creatine phosphokinase (CPK) elevations

In the placebo-controlled studies, for up to 24 weeks, events of blood CPK increased were reported in2 patients (1.5%) treated with ritlecitinib 50 mg. In study AA-I, for up to 48 weeks, events of blood

CPK increased were reported in 3.8% of patients treated with ritlecitinib 50 mg or higher. CPKelevations >5x upper limit of normal (ULN) were reported in 2 (0.9%) of patients treated with placeboand 5 (3.9%) of patients treated with ritlecitinib 50 mg. In study AA-I, for up to 48 weeks, CPKelevations >5x ULN were reported in 6.6% of patients treated with ritlecitinib 50 mg or higher. Mostelevations were transient and none led to discontinuation.

Increased transaminases

In the placebo-controlled studies, for up to 24 weeks, events of increases in ALT and AST values(>3 × ULN) were reported in 3 patients (0.9%) and 2 patients (0.6%) treated with ritlecitinib 50 mg orhigher, respectively. Most elevations were transient, and none led to discontinuation.

A total of 181 adolescents (12 to < 18 years of age) were enrolled in ritlecitinib alopecia areata studies.

The safety profile observed in adolescents was similar to that of the adult population.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Ritlecitinib was administered in placebo-controlled studies up to a single oral dose of 800 mg andmultiple oral doses of 400 mg daily for 14 days. No specific toxicities were identified. In case ofoverdose, it is recommended that the patient be monitored for signs and symptoms of adversereactions (see section 4.8). There is no specific antidote for overdose with ritlecitinib. Treatmentshould be symptomatic and supportive.

Pharmacokinetics (PK) data up to and including a single oral dose of 800 mg in healthy adultvolunteers indicate that more than 90% of the administered dose is expected to be eliminated within48 hours.

Pharmacotherapeutic group: Immunosuppressants, Janus-associated kinase (JAK) inhibitors, ATCcode: L04AF08

Ritlecitinib irreversibly and selectively inhibits Janus kinase (JAK) 3 and the tyrosine kinaseexpressed in hepatocellular carcinoma (TEC) family by blocking the adenosine triphosphate (ATP)binding site. In cellular settings, ritlecitinib specifically inhibits γ-common cytokines (IL-2, IL-4, IL-7,

IL-15 and IL-21) signalling through JAK3-dependent common-γ chain receptors. Additionally,ritlecitinib inhibits TEC family of kinases, resulting in reduced cytolytic activity of NK cells and

CD8+ T cells.

JAK3 and TEC family mediated signalling pathways are both involved in alopecia areatapathogenesis, although complete pathophysiology is still not understood.

Lymphocyte subsets

In patients with alopecia areata, treatment with ritlecitinib was associated with dose-dependent earlydecreases in absolute lymphocyte levels, T lymphocytes (CD3) and T lymphocyte subsets (CD4 and

CD8). After the initial decrease, the levels partially recovered and remained stable up to 48 weeks.

There was no change observed in B lymphocytes (CD19) in any treatment group. There was adose-dependent early decrease in NK cells (CD16/56) which remained stable at the lower level up to

Week 48.

Immunoglobulins

In patients with alopecia areata, treatment with ritlecitinib was not associated with clinicallymeaningful changes in Immunoglobulin (Ig)G, IgM or IgA up to Week 48, indicating a lack ofsystemic humoral immunosuppression.

The efficacy and safety of ritlecitinib was evaluated in a pivotal, randomised, double-blind,placebo-controlled study (study AA-I) in alopecia areata patients 12 years of age and older with ≥ 50%scalp hair loss, including alopecia totalis and alopecia universalis. The dose-response of ritlecitinibwas also evaluated in this study. The study treatment period consisted of a placebo-controlled 24-weekperiod and a 24-week extension period. Study AA-I evaluated a total of 718 patients who wererandomised to one of the following treatment regimens for 48 weeks: 1) 200 mg once daily for 4weeks followed by 50 mg once daily for 44 weeks; 2) 200 mg once daily for 4 weeks followed by30 mg once daily for 44 weeks; 3) 50 mg once daily for 48 weeks; 4) 30 mg once daily for 48 weeks;5) 10 mg once daily for 48 weeks; 6) placebo for 24 weeks followed by 200 mg once daily for 4 weeksand 50 mg once daily for 20 weeks; or 7) placebo for 24 weeks followed by 50 mg for 24 weeks.

This study assessed as primary outcome the proportion of subjects who achieved a SALT (Severity of

Alopecia Tool) score of ≤ 10 (90% or more scalp hair coverage) at Week 24. Additionally, this studyassessed as key secondary outcome the Patient’s Global Impression of Change (PGI-C) response at

Week 24 and also assessed as secondary outcomes SALT score of ≤ 20 (80% or more scalp haircoverage) at Week 24 and improvements in regrowth of eyebrows and/or eyelashes at Week 24.

Baseline characteristics

Male or female patients 12 years of age and older, were assessed in study AA-I. All patients hadalopecia areata with ≥ 50% scalp hair loss (SALT [Severity of Alopecia Tool] score ≥ 50) withoutevidence of terminal hair regrowth within the previous 6 months and with the current episode of scalphair loss ≤ 10 years and no other known cause of hair loss (e.g., androgenetic alopecia).

Across all treatment groups 62.1% were female, 68.0% were White, 25.9% were Asian, and 3.8%were Black or African American. The mean age of patients was 33.7 years and the majority (85.4%)were adults (≥ 18 years of age). A total of 105 (14.6%) patients 12 to < 18 years of age and 20 (2.8%)patients 65 years of age and older were enrolled. The mean (SD) baseline absolute SALT score rangedfrom 88.3 (16.87) to 93.0 (11.50) across treatment groups; among patients without alopeciatotalis/alopecia universalis at baseline, the mean SALT score ranged from 78.3 to 87.0. The majorityof patients had abnormal eyebrows (83.0%) and eyelashes (74.7%) at baseline across treatmentgroups. The median duration since alopecia areata diagnosis was 6.9 years and the median duration ofthe current alopecia areata episode was 2.5 years. Randomisation was stratified by alopeciatotalis/alopecia universalis status with 46% of patients classified as alopecia totalis/alopeciauniversalis based upon a baseline SALT score of 100.

A significantly greater proportion of patients achieved SALT ≤ 10 response with ritlecitinib 50 mgcompared to placebo at Week 24 (Table 3). The SALT ≤ 10 response rate for ritlecitinib 50 mgincreased further at Week 48 (Figure 1).

A significantly greater proportion of patients achieved Patient’s Global Impression of Change (PGI-C)response with ritlecitinib 50 mg compared to placebo at Week 24 (Table 3) with response ratescontinuing to increase through Week 48 (Figure 1).

A significantly greater proportion of patients achieved a SALT ≤ 20 response with ritlecitinib 50 mgcompared to placebo at Week 24 (Table 3). The SALT ≤ 20 response rate increased further at

Week 48.

Improvements in regrowth of eyebrows and/or eyelashes were seen at Week 24 (Table 3) withritlecitinib 50 mg among patients with abnormal eyebrows and/or eyelashes at baseline with furtherincreases seen at Week 48.

Treatment effects at Week 24 in subgroups (age, gender, race, region, weight, duration of disease sincediagnosis, duration of current episode, prior pharmacologic treatment) were consistent with the resultsin the overall study population. Treatment effects at Week 24 in the alopecia totalis/alopeciauniversalis subgroup were lower compared to the non-alopecia totalis/non-alopecia universalissubgroup. Treatment effects at Week 24 in adolescents 12 to less than 18 years of age were consistentwith the results in the overall study population.

Table 3. Efficacy results of ritlecitinib at week 24

Endpoint Ritlecitinib 50 mg once Placebo Difference fromdaily (N = 131) placebo(N = 130) % Responders (95% CI)% Responders

SALT ≤ 10 responsea,b 13.4 1.5 11.9(5.4, 18.3)

PGI-C responseb,c 49.2 9.2 40.0(28.9, 51.1)

SALT ≤ 20 responsed,e 23.0 1.6 21.4(13.4, 29.5)

EBA responsef 29.0 4.7 24.3(14.8, 34.5)

ELA responseg 28.9 5.2 23.7(13.6, 34.5)

Abbreviations: EBA = eyebrow assessment; ELA = eyelash assessment; CI = confidence interval; N = totalnumber of patients; PGI-C = Patient’s Global Impression of Change; SALT = Severity of Alopecia Tool

a. SALT ≤ 10 responders were patients with scalp hair loss of ≤ 10%. SALT scores range from 0 to 100 with0 = no scalp hair loss and 100 = total scalp hair loss.

b. Statistically significant with adjustment for multiplicity.

c. PGI-C responders were patients with a score of “moderately improved” or “greatly improved” based upon a7-point scale from “greatly improved” to “greatly worsened”.

d. SALT ≤ 20 responders were patients with scalp hair loss of ≤ 20%. SALT scores range from 0 to 100 with0 = no scalp hair loss and 100 = total scalp hair loss.

e. Statistically significant.

f. EBA response is defined as at least a 2-grade improvement from baseline or normal EBA score on a 4-pointscale in patients with abnormal eyebrows at baseline.g. ELA response is defined as at least a 2-grade improvement from baseline or normal ELA score on a 4-pointscale in patients with abnormal eyelashes at baseline.

Figure 1. SALT ≤ 10 and PGI-C response through Week 48

Abbreviations: CI = confidence interval; N = total number of patients; PGI-C = Patient Global Impression of

Change; QD = once daily; SALT = Severity of Alopecia Tool

The European Medicines Agency has deferred the obligation to submit the results of studies withritlecitinib in one or more subsets of the paediatric population in the treatment of alopecia areata (seesection 4.2 for information on paediatric use).

The absolute oral bioavailability of ritlecitinib is about 64%. Based on oral and intravenousadministration of the labelled active substance, the relative urinary recovery (oral/intravenous) oflabelled compounds was about 89%, indicating a high fraction absorbed (fa). Peak plasmaconcentrations are reached within 1 hour following multiple oral doses. Food does not have aclinically significant impact on the extent of ritlecitinib absorption, as a high-fat meal decreased theritlecitinib Cmax by ~ 32% and increased AUCinf by ~11%. In placebo-controlled studies, ritlecitinibwas administered without regard to meals (see section 4.2).

In vitro, ritlecitinib is a substrate of P-glycoprotein (P-gp) and BCRP. However, as ritlecitinib has ahigh fraction absorbed (fa) with both Cmax and AUC increases in a dose proportional manner (20 -200 mg single dose range), P-gp and BCRP are not expected to have a meaningful impact on theabsorption of ritlecitinib.

After intravenous administration, the volume of distribution of ritlecitinib is about 74 L.

Approximately 14% of circulating ritlecitinib is bound to plasma proteins, primarily albumin. Theblood/plasma distribution ratio of ritlecitinib is 1.62. Ritlecitinib is a covalent inhibitor that has beenshown to bind to off-target proteins such as MAP2K7, DOCK10, albumin, CYP1A2, CYP3A,

UGT1A1, and UGT1A4, some of which may have clinical relevance in drug interactions (seesection 4.5).

The metabolism of ritlecitinib is mediated by multiple isoforms of Glutathione S-transferase (GST:cytosolic GST A1/3, M1/3/5, P1, S1, T2, Z1, and microsomal Membrane Associated Proteins involvedin Eicosanoid and Glutathione metabolism [MAPEG]1/2/3) and CYP enzymes (CYP3A, CYP2C8,

CYP1A2, and CYP2C9), with no single clearance route contributing more than 25%. Hence,medicinal products inhibiting a selective metabolic pathway are unlikely to impact the systemicexposures of ritlecitinib. Specific inhibitors of transporters are unlikely to result in clinically relevantchanges in the bioavailability of ritlecitinib.

In a human radiolabeled study, ritlecitinib was the most prevalent circulating species (30.4% ofcirculating radioactivity) after oral administration, with a major cysteine conjugate metabolite M2(16.5%), which is pharmacologically inactive.

Ritlecitinib is eliminated primarily by metabolic clearance mechanisms, with approximately 4% of thedose excreted as unchanged active substance in urine. Approximately 66% of radiolabeled ritlecitinibdose is excreted in the urine and 20% in the faeces. Following multiple oral doses, steady state wasreached approximately by Day 4 due to non-stationary PK. The steady state PK parameters of AUCtauand Cmax appeared to increase in an approximately dose-proportional manner up to 200 mg with themean terminal half-life ranging from 1.3 to 2.3 hours.

Body weight, gender, genotype, race and age

Body weight, gender, GST P1, M1, and T1 genotype, race and age did not have a clinicallymeaningful effect on ritlecitinib exposure.

Adolescents (≥ 12 to < 18 years)

Based on population PK analysis, there was no clinically relevant difference in ritlecitinib exposures inadolescent patients compared to adults.

Paediatric (< 12 years)

The PK of ritlecitinib in children under 12 years of age have not yet been established.

The AUC24 and Cmax in patients with severe renal impairment (estimated glomerular filtration rate[eGFR] < 30 mL/min) was about 55% and 44% higher, respectively, compared with matchedparticipants with normal renal functions. This was confirmed by popPK analysis. These differences arenot considered clinically significant. Ritlecitinib was not studied in patients with mild (eGFR 60 to< 90 mL/min) or moderate (eGFR 30 to < 60 mL/min) renal impairment. However, based on theresults obtained in patients with severe renal impairment, a clinically significant increase in ritlecitinibexposure is not expected in these patients. The eGFR and classification of renal function status ofparticipants was done using the Modification of Diet in Renal Disease (MDRD) formula.

Based on the above considerations, no dose adjustment is required in patients with mild, moderate orsevere renal impairment. Ritlecitinib has not been studied in patients with ESRD or in renal transplantrecipients (see section 4.2).

Patients with moderate (Child Pugh B) hepatic impairment had an 18.5% increase in ritlecitinib AUC24compared to participants with normal hepatic function. Ritlecitinib was not studied in patients withmild (Child Pugh A) hepatic impairment. However, based on the results obtained in patients withmoderate hepatic impairment, a clinically significant increase in ritlecitinib exposure is not expected inthese patients. No dose adjustment is required in patients with mild or moderate hepatic impairment(see section 4.2). Ritlecitinib has not been studied in patients with severe (Child Pugh C) hepaticimpairment (see section 4.3).

Decreased lymphocyte counts and decreased lymphoid cellularity of organs and tissues of the immuneand haematolymphopoietic systems were observed in nonclinical toxicity studies and were attributedto the pharmacological properties (JAK3/TEC inhibition) of ritlecitinib.

Chronic administration of ritlecitinib to Beagle dogs led to the occurrence of axonal dystrophy atsystemic exposures of at least 7.4-times the expected exposure in patients treated with 50 mg per day(based on unbound AUC24). Axonal dystrophy is presumably related to binding to off-target neuronalproteins. It is not known if axonal dystrophy occurred in dogs at lower systemic exposures. At asystemic exposure that was 33-times above the expected exposure in patients treated with 50 mg perday (based on unbound AUC24), axonal dystrophy was associated with neurological hearing loss.

While these findings proved to reverse after dosing cessation of ritlecitinib in dogs, a risk to patients ata chronic dosing regimen cannot be fully excluded (see section 4.4).

Ritlecitinib was not mutagenic in the bacterial mutagenicity assay (Ames assay). Ritlecitinib is notaneugenic or clastogenic at exposures equal to 130 times the MRHD on an unbound AUC basis basedon the results of the in vivo rat bone marrow micronucleus assay.

No evidence of tumorigenicity was observed in the 6-month Tg.ras H2 mice administered ritlecitinibat exposures equal to 11 times the MRHD on an unbound AUC basis. In a 2-year rat carcinogenicitystudy, a higher incidence of benign thymomas in female rats and benign thyroid follicular adenomas inmale rats was noted following ritlecitinib administration at exposures equal to 29 times the MRHD onan unbound AUC basis. At this ritlecitinib exposure, a higher incidence of malignant thymomas infemale rats cannot be excluded. No ritlecitinib-related thymomas or thyroid follicular adenomas wereobserved at exposures equal to 6.3 times the MRHD on an unbound AUC basis.

Ritlecitinib had no effects on female rat fertility at exposures equal to 55 times the MRHD on anunbound AUC basis. Effects on male rat fertility were noted (higher preimplantation loss resulting inlower number of implantation sites and corresponding lower litter size in naïve females mated withritlecitinib dosed males) at exposure equal to 55 times the MRHD on an unbound AUC basis. Noeffects on male fertility were noted at exposures equal to 14 times the MRHD on an unbound AUCbasis. No effects on spermatogenesis (sperm counts, sperm production rate, motility, and morphology)were noted at any dose in the rat fertility study.

In an embryo-foetal development study in pregnant rats, oral administration of ritlecitinib fromgestation days 6 to 17 resulted in foetal skeletal malformations and variations and lower foetal bodyweights at exposures greater than or equal to 49 times the unbound AUC at the MRHD (see section4.3). There were no effects on embryo-foetal development at exposures equal to 16 times the unbound

AUC at the MRHD.

In an embryo-foetal development study in pregnant rabbits, oral administration of ritlecitinib fromgestation days 7 to 19 resulted in lower mean foetal body weights and higher incidences of visceralmalformations, skeletal malformations, and skeletal variations at exposures equal to 55 times theunbound AUC at the MRHD (see section 4.3). There were no effects on embryo-foetal development atexposures equal to 12 times the unbound AUC at the MRHD.

In a rat pre- and postnatal development study, oral administration of ritlecitinib from gestation day 6through lactation day 20 resulted in developmental toxicity that included lower postnatal survival,lower offspring body weights, and secondary developmental delays at exposure equal to 41 times theunbound AUC at the MRHD (see section 4.3). Bred females in the F1 generation exhibited lowermean numbers of corpora lutea at exposures equal to 41 times the unbound AUC at the MRHD. Therewere no effects on pre- and postnatal development at exposures equal to 14 times the unbound AUC atthe MRHD.

In a juvenile rat toxicity study, oral administration of ritlecitinib from postnatal day 10 to 60(comparable to infant through adolescence human age) was not associated with effects on the nervousor skeletal systems.

Following administration of ritlecitinib to lactating rats, concentrations of ritlecitinib in milk over timewere higher than those in plasma, where the mean milk to plasma AUC ratio was determined to be 2.2(see section 4.3).

Hard capsule content

Cellulose microcrystalline

Lactose monohydrate

Crospovidone

Glycerol dibehenate

Hard capsule shell

Hypromellose (E464)

Titanium dioxide (E171)

Yellow iron oxide (E172)

Brilliant Blue FCF (E133)

Shellac

Ammonia solution concentrated

Black iron oxide (E172)

Potassium hydroxide

Not applicable.

3 years.

This medicinal product does not require any special temperature storage conditions. Store in theoriginal package in order to protect from light.

High-density polyethylene (HDPE) bottle with a silica gel desiccant and polypropylene closurecontaining 28 hard capsules.

OPA/Al/PVC/Al blisters containing 10 hard capsules. Each pack contains 30 or 90 hard capsules.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Pfizer Europe MA EEIG

Boulevard de la Plaine 171050 Bruxelles

Belgium

EU/1/23/1755/001

EU/1/23/1755/002

EU/1/23/1755/003

Date of first authorisation: 15 September 2023

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.