FDA

Litfulo

Approved 23 Jun 2023OralCapsule

Indications

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 ).

Contraindications

LITFULO is contraindicated in patients with known hypersensitivity to ritlecitinib or any of its excipients [see Warnings and Precautions (5.6) ] . LITFULO is contraindicated in patients with known hypersensitivity to ritlecitinib or any of its excipients. ( 4 )

Warnings and precautions

Hypersensitivity: Discontinue LITFULO if a clinically significant hypersensitivity reaction occurs. ( 5.6 )
Laboratory Abnormalities: Perform ALC and platelet counts prior to LITFULO initiation. Treatment interruption or discontinuation are recommended based on ALC and platelet count abnormalities. ( 5.7 )
Vaccinations: Avoid use of live vaccines during or shortly prior to LITFULO treatment. ( 5.8 )

5.1Serious Infections

Serious infections have been reported in patients receiving LITFULO. The most frequent serious infections have been appendicitis, COVID-19 infection (including pneumonia), and sepsis [see Adverse Reactions (6.1) ] . Among opportunistic infections, multi-dermatomal herpes zoster was reported with LITFULO. Avoid use of LITFULO in patients with an active, serious infection. Consider the risks and benefits of treatment prior to initiating LITFULO in patients:

with chronic or recurrent infection
who have been exposed to TB
with a history of serious infection 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 Closely monitor patients for the development of signs and symptoms of infection during and after treatment with LITFULO. Interrupt LITFULO if a patient develops a serious or opportunistic infection. A patient who develops a new infection during treatment with LITFULO 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. LITFULO may be resumed once the infection is controlled. Tuberculosis Screen patients 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 and consider screening patients at high risk for TB during treatment with LITFULO. Viral Reactivation Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster), was reported in clinical trials [see Adverse Reactions (6.1) ] . If a patient develops herpes zoster, consider interrupting treatment until the episode resolves. Screening for viral hepatitis should be performed in accordance with clinical guidelines before starting therapy with LITFULO. Patients with evidence of HIV infection or hepatitis B or C infection were excluded from clinical trials.

At a glance

Brand name: Litfulo
Active substance: ritlecitinib tosylate
Route: Oral
Dosage form: Capsule
Applicant: Pfizer
Status: Prescription
FDA approval: 23 Jun 2023
Application: NDA215830-001

Indications

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

Warnings and precautions

Hypersensitivity: Discontinue LITFULO if a clinically significant hypersensitivity reaction occurs. ( 5.6 )
Laboratory Abnormalities: Perform ALC and platelet counts prior to LITFULO initiation. Treatment interruption or discontinuation are recommended based on ALC and platelet count abnormalities. ( 5.7 )
Vaccinations: Avoid use of live vaccines during or shortly prior to LITFULO treatment. ( 5.8 )

5.1Serious Infections

with chronic or recurrent infection
who have been exposed to TB
with a history of serious infection 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 Closely monitor patients for the development of signs and symptoms of infection during and after treatment with LITFULO. Interrupt LITFULO if a patient develops a serious or opportunistic infection. A patient who develops a new infection during treatment with LITFULO 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. LITFULO may be resumed once the infection is controlled. Tuberculosis Screen patients 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 and consider screening patients at high risk for TB during treatment with LITFULO. Viral Reactivation Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster), was reported in clinical trials [see Adverse Reactions (6.1) ] . If a patient develops herpes zoster, consider interrupting treatment until the episode resolves. Screening for viral hepatitis should be performed in accordance with clinical guidelines before starting therapy with LITFULO. Patients with evidence of HIV infection or hepatitis B or C infection were excluded from clinical trials.

Interactions

Certain CYP3A substrates: Additional monitoring and dose adjustment of CYP3A substrate should be considered. ( 7.1 )
Certain CYP1A2 substrates: Additional monitoring and dose adjustment of CYP1A2 substrate should be considered. ( 7.1 )
Certain CYP3A inducers: Coadministration with strong inducers of CYP3A is not recommended. ( 7.2 )

7.1Effects of

LITFULO on Other Drugs Table 3 includes clinically significant drug interactions affecting other drugs. Table 3. Clinically Significant Interactions Affecting Other Drugs CYP3A Substrates Where Small Concentration Changes May Lead to Serious Adverse Reactions Clinical Impact Ritlecitinib is a CYP3A inhibitor. Concomitant use of ritlecitinib increases AUC and C max of CYP3A substrates [see Clinical Pharmacology (12.3 )] , which may increase the risk of adverse reactions of these substrates.

Intervention Consider additional monitoring and dosage adjustment in accordance with approved product labeling of CYP3A substrates where small concentration changes may lead to serious adverse reactions when used with LITFULO. CYP1A2 Substrates Where Small Concentration Changes May Lead to Serious Adverse Reactions Clinical Impact Ritlecitinib is a CYP1A2 inhibitor. Concomitant use of ritlecitinib increases AUC and C max of CYP1A2 substrates [see Clinical Pharmacology (12.3) ] , which may increase the risk of adverse reactions of these substrates.

Intervention Consider additional monitoring and dosage adjustment in accordance with the approved product labeling of CYP1A2 substrates where small concentration changes may lead to serious adverse reactions when used concomitantly with LITFULO.

7.2Effects of Other Drugs on

LITFULO Table 4 includes clinically significant drug interactions affecting LITFULO. Table 4. Clinically Significant Interactions Affecting LITFULO CYP3A Inducers Clinical Impact Concomitant use of strong CYP3A inducer (e.g., rifampin) may decrease AUC and C max of ritlecitinib [see Clinical Pharmacology (12.3) ] , which may result in loss of or reduced clinical response. Intervention Coadministration with strong inducers of CYP3A is not recommended.

Pregnancy and breastfeeding

8.1Pregnancy Pregnancy Exposure Registry If

a patient becomes pregnant while receiving LITFULO, healthcare providers should report LITFULO exposure by calling 1-877-390-2940. Risk Summary Available data from clinical trials with LITFULO use in pregnant women are insufficient to identify a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. In animal reproduction studies, oral administration of ritlecitinib to pregnant rats and rabbits during organogenesis caused fetotoxicity and fetal malformations at exposures 49 and 55 times the maximum recommended human dose (MRHD) based on area under the curve (AUC) comparison, respectively (see Animal Data ) .

The background risks of major birth defects and miscarriage for the indicated population are unknown. All pregnancies carry some risk of birth defects, loss, or other adverse outcomes. The estimated background risks in the U.S. general population of major birth defects and miscarriages are 2-4% and 15-20% of clinically recognized pregnancies, respectively. Data Animal Data In an embryo-fetal development study in pregnant rats, oral administration of ritlecitinib from gestation days 6 to 17 decreased fetal body weights and caused fetal skeletal malformations (malformed vertebrae and ribs) and variations (delayed ossification) at doses ≥175 mg/kg/day (49 times the MRHD based on AUC comparison).

Maternal toxicity (lower body weights) was noted at 325 mg/kg/day (102 times the MRHD based on AUC comparison). There was no developmental toxicity at 75 mg/kg/day (16 times the MRHD based on AUC comparison). In an embryo-fetal development study in pregnant rabbits, oral administration of ritlecitinib from gestation days 7 to 19 decreased mean fetal body weights and increased visceral malformations (malpositioned kidneys), skeletal malformations (supernumerary sternebrae, absent thoracic arch, and/or fused thoracic centra), and skeletal variations (delayed ossification) at 75 mg/kg/day (55 times the MRHD based on AUC comparison).

There was no developmental toxicity at doses up to 25 mg/kg/day (12 times the MRHD based on AUC comparison). In a pre- and postnatal development study in rats, oral administration of ritlecitinib from gestation day 6 through lactation day 20 had no effects on pre- and postnatal development at doses up to 75 mg/kg/day (14 times the MRHD based on AUC comparison). At 175 mg/kg/day (41 times the MRHD based on AUC comparison), ritlecitinib caused adverse lower postnatal survival and lower offspring body weights, which correlated with delayed sexual maturation in both sexes.

Bred females in the F 1 generation also exhibited lower mean numbers of corpora lutea at 175 mg/kg/day.

Adverse reactions

The following clinically significant adverse reactions are described elsewhere in the labeling:

Serious Infections [see Warnings and Precautions (5.1) ]
Malignancy and Lymphoproliferative Disorders [see Warnings and Precautions (5.3) ]
Thromboembolic Events [see Warnings and Precautions (5.5) ]
Hypersensitivity [see Warnings and Precautions (5.6) ]
Laboratory Abnormalities [see Warnings and Precautions (5.7) ] 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. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1Clinical 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. The median age of subjects was 33 years, 105 (11.9%) subjects were 12 to <18 years old and 22 (2.5%) subjects were 65 years of age or older.

The majority of subjects were White (70.7%) and female (63.6%). Adverse reactions occurring at ≥1% in the treated groups and at a higher rate than placebo are presented in Table 2. A total of 2 (1.5%) 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. 14 (10.8) 18 (8.5) Diarrhea Diarrhea includes diarrhea and frequent bowel movements. 13 (10.0) 8 (3.8) Acne Acne includes acne and acne pustular. 8 (6.2) 10 (4.7) Rash Rash includes rash and dermatitis allergic. 7 (5.4) 2 (0.9) Urticaria 6 (4.6) 3 (1.4) Folliculitis 4 (3.1) 4 (1.9) Pyrexia 4 (3.1) 0 Dermatitis atopic 3 (2.3) 1 (0.5) Dizziness 3 (2.3) 3 (1.4) Blood creatine phosphokinase increased 2 (1.5) 0 Herpes zoster 2 (1.5) 0 Red blood cell count decreased 2 (1.5) 0 Stomatitis 2 (1.5) 0 Specific Adverse Reactions Exposure adjusted incidence rates were adjusted by clinical trial size for all adverse reactions reported in this section.

Overall Infections In the placebo-controlled trials, for up to 24 weeks, overall infections were reported in 66 subjects (80.35 per 100 subject-years) treated with placebo and 43 subjects (74.53 per 100 subject-years) treated with LITFULO 50 mg. Across clinical trials, including the long-term trial, overall infections were reported in 645 subjects (50.71 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.

Across clinical trials, including the long-term trial, serious infections were reported in 12 subjects (0.66 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.

Across clinical trials, including the long-term trial, herpes zoster was reported in 21 subjects (1.17 per 100 subject-years) treated with LITFULO 50 mg or higher. Opportunistic infections of multi-dermatomal herpes zoster were reported in 1 subject (0.50 per 100 subject-years) treated with the ritlecitinib higher dose in the placebo-controlled trials and 2 subjects (0.1 per 100 subject-years) treated with LITFULO 50 mg or higher in all clinical trials.

Malignancy In the placebo-controlled trials, for up to 24 weeks, 1 malignancy (breast cancer) was reported in 1 subject (1.33 per 100 subject-years) treated with ritlecitinib higher dose and no malignancy was reported in subjects treated with placebo. Across clinical trials, including the long-term trial, malignancies excluding NMSC were reported in 7 subjects (0.37 per 100 subject-years) treated with LITFULO 50 mg or higher.

Thromboembolic Events Across clinical trials, including the long-term trial, pulmonary embolism (PE) was reported in 1 subject (0.06 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.

The rate of urticaria was 8.23 per 100 subject-years in subjects treated with ritlecitinib 50 mg and 4.03 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. Among all subjects treated with ritlecitinib 50 mg or higher in the integrated safety analysis, the rate of urticaria was 4.10 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. Decreased Lymphocyte Counts Across clinical trials, including the long-term trial confirmed ALC <500/mm 3 occurred in 1 subject (<0.1%) 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. Across clinical trials, including the long-term trial, 1 subject (<0.1%) had a confirmed platelet count <100,000/mm 3 . No subject had a confirmed platelet count <75,000/mm 3 . Creatine Phosphokinase (CPK) Elevations In the placebo-controlled trials, for up to 24 weeks, events of blood CPK increased were reported in 2 (1.5%) subjects treated with LITFULO 50 mg and 0 subjects treated with placebo.

Liver Enzyme Elevations In the placebo-controlled trials, for up to 24 weeks, events of increases in liver enzymes ≥3 times the upper limit of normal (ULN) were observed in subjects treated with LITFULO [see Warnings and Precautions (5.7) ] .

Litfulo

Indications

Contraindications

Warnings and precautions

5.1Serious Infections

At a glance

Two medicines in one question?

Litfulo

Indications

Contraindications

Warnings and precautions

5.1Serious Infections

At a glance

Two medicines in one question?

5.3Malignancy and Lymphoproliferative Disorders

5.5Thromboembolic Events

5.6Hypersensitivity

5.7Laboratory Abnormalities Treatment with

5.8Vaccinations

Interactions

7.1Effects of

7.2Effects of Other Drugs on

Pregnancy and breastfeeding

8.1Pregnancy Pregnancy Exposure Registry If

Adverse reactions

6.1Clinical Trials Experience

Composition

Official product information