4.1. Therapeutic indications

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

4.2. Posology and method of administration

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.

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.

Lymphocytes

Treatment should be interrupted if ALC is < 0.5 × 103/mm3 and may be restarted once ALC return 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 interrupted until the infection is controlled (see section 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. If the duration of treatment interruption is more than 6 weeks, the risk of significant hair loss increases and is greater the longer the duration of treatment interruption (see section 5.1).

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.

Special populations

Renal impairment

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

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.

Hepatic impairment

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).

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.

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.

4.3. Contraindications

• 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).

4.4. Special warnings and precautions for use

Serious infections

Serious infections have been reported in patients receiving ritlecitinib. The most frequent serious infections have been appendicitis, COVID-19 infection (including pneumonia), and sepsis. Treatment with 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 travelled 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 during and after treatment with ritlecitinib. Treatment should be interrupted if a patient develops a serious or opportunistic infection. A patient who develops a new infection during treatment with ritlecitinib should undergo prompt and complete diagnostic testing appropriate for an immunocompromised patient, appropriate antimicrobial therapy should be initiated, and the patient should be closely monitored. 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, caution should be exercised when treating the elderly and patients with diabetes, and particular attention paid with respect to occurrence of infections.

Tuberculosis

Patients should be screened for TB before starting therapy with ritlecitinib. Ritlecitinib must not be given to patients with active TB (see section 4.3). Anti-TB therapy should be started prior to initiating therapy 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 before initiating treatment with ritlecitinib in those at high risk and screening for patients at high risk for TB during treatment with ritlecitinib should be considered.

Viral reactivation

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

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

Malignancy (including non-melanoma skin cancer)

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

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 randomised active-controlled study of tofacitinib (another JAK inhibitor) in rheumatoid arthritis (RA) patients 50 years 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 tumour necrosis factor (TNF) inhibitors.

Limited clinical data are available to assess the potential relationship of exposure to ritlecitinib and the development of malignancies. Long-term safety evaluations are ongoing. The risks and benefits of ritlecitinib treatment should be considered prior to initiating or continuing therapy in patients with a known 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 pulmonary embolism (PE)

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

It is not known whether selective JAK3 inhibition may be associated with adverse reactions of JAK inhibition predominantly involving JAK1 and JAK2. In a large randomised active-controlled study of tofacitinib (another JAK inhibitor) in RA patients 50 years and older with at least one additional cardiovascular risk factor, a higher rate of MACE, defined as cardiovascular death, non-fatal myocardial infarction and non-fatal stroke, and a dose-dependent higher rate of venous thromboembolism 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 in patients with known risk factors for thromboembolism such as previous VTE, patients undergoing major surgery, immobilisation, use of combined hormonal contraceptives or hormone replacement therapy, and inherited coagulation disorder. In patients with a suspected thromboembolic event, discontinuation of ritlecitinib and prompt re-evaluation is recommended. The risks and benefits of ritlecitinib treatment should be considered prior to initiating therapy in patients.

Neurological events

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 neurological symptoms occur.

Haematologic abnormalities

Treatment with ritlecitinib was associated with decreases in lymphocytes and platelets (see section 4.8). 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 a platelet count < 100 × 103/mm3. After initiating treatment with ritlecitinib, treatment interruption or discontinuation 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, and thereafter according to routine patient management.

Vaccinations

No data are available on the response to vaccination in patients receiving ritlecitinib. Use of live attenuated vaccines should be avoided during or immediately prior to ritlecitinib treatment. Prior to initiating 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.

Immunosuppressive medicinal products

Combination with systemic immunosuppressive medicinal products has not been studied. Their concomitant use with ritlecitinib is not recommended as a risk of additive immunosuppression cannot be excluded.

Elderly

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

Excipients with known effect

Lactose

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

4.5. Interaction with other medicinal products and other forms of interaction

Potential for other medicinal products to affect the pharmacokinetics of ritlecitinib

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

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 significant and, 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 moderate inhibitor of CYP3A; caution should be exercised with concomitant use of ritlecitinib with CYP3A substrates (e.g., quinidine, ciclosporin, dihydroergotamine, ergotamine, pimozide) where moderate concentration changes may lead to serious adverse reactions. Dose adjustment recommendations for the 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 CYP1A2 substrate, 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 CYP1A2 substrates (e.g., tizanidine) where moderate concentration changes may lead to serious adverse reactions. 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 (an organic cation transporter [OCT]1 substrate) by approximately 1.3 to 1.5-fold relative to sumatriptan dose given alone. The increase in sumatriptan exposure is not considered clinically relevant. Caution should be exercised with concomitant use of ritlecitinib with OCT1 substrates where small concentration 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).

Paediatric population

Interaction studies have only been performed in adults.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential

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

Pregnancy

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

Breast-feeding

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 during breast-feeding (see section 4.3).

Fertility

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

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of the safety profile

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

Tabulated list of adverse reactions

A total of 1 630 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.

Table 2. Adverse reactions

System organ class

Common

Uncommon

Infections and infestations

Herpes zoster

Folliculitis

Nervous system disorders

Dizziness

Headache

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. Includes changes detected during laboratory monitoring

Description of selected adverse reactions

Infections

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

Among all patients treated with ritlecitinib in the integrated safety analysis, including the long-term study and a study in vitiligo, overall infections were reported in 56.3% of patients (45.3 per 100 patient-years) treated with ritlecitinib 50 mg or higher. Most infections were mild or moderate in severity.

In the placebo-controlled studies the percentage of patients reporting infection-related adverse reaction of herpes zoster were 1.5% 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). 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 herpes zoster. Among all patients treated with ritlecitinib in the integrated safety analysis, including the long-term study and a study in vitiligo, the rate of herpes zoster was 1.05 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. The proportion and rate of serious infections in patients treated with ritlecitinib 200/50 mg was 0.9% (2.66 per 100 patient-years). In study AA-I, for up to 48 weeks, serious infections were reported in 0.8% of patients (0.86 per 100 patient-years) treated with ritlecitinib 50 mg or higher. Among all patients treated with ritlecitinib in the integrated safety analysis, including the long-term study and a study in vitiligo, the proportion and rate of serious infection in ritlecitinib 50 mg or higher was 1.3% (0.57 per 100 patient-years).

Opportunistic infections

Opportunistic infections of multi-dermatomal herpes zoster were reported in 1 patient (0.50 per 100 patient-years) treated with ritlecitinib 200/50 mg in the placebo-controlled studies, no patients in study AA-I, for up to 48 weeks, and 4 patients (0.12 per 100 patient-years) treated with ritlecitinib 50 mg 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. Among all patients treated with ritlecitinib in the integrated safety analysis, including the long-term study and a study in vitiligo, confirmed ALC < 0.5 × 103/mm3 occurred 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, 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. Among all patients treated with ritlecitinib in the integrated safety analysis, including the long-term study and a study in vitiligo, 2 patients (0.1%) treated with ritlecitinib 50 mg or higher had a confirmed 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 in 2 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. CPK elevations >5x upper limit of normal (ULN) were reported in 2 (0.9%) of patients treated with placebo and 5 (3.9%) of patients treated with ritlecitinib 50 mg. In study AA-I, for up to 48 weeks, CPK elevations >5x ULN were reported in 6.6% of patients treated with ritlecitinib 50 mg or higher. Most elevations 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 or higher, respectively. Most elevations were transient, and none led to discontinuation.

Paediatric population

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 of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Ritlecitinib was administered in placebo-controlled studies up to a single oral dose of 800 mg and multiple oral doses of 400 mg daily for 14 days. No specific toxicities were identified.

In case of overdose, it is recommended that the patient be monitored for signs and symptoms of adverse reactions (see section 4.8). There is no specific antidote for overdose with ritlecitinib. Treatment should be symptomatic and supportive.

Pharmacokinetics (PK) data up to and including a single oral dose of 800 mg in healthy adult volunteers indicate that more than 90% of the administered dose is expected to be eliminated within 48 hours.