The Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) has recommended updating the product information for Litfulo (ritlecitinib tosylate, Pfizer) to strengthen its side effect warnings. The drug, a JAK inhibitor, is indicated for the treatment of severe alopecia areata in adults and adolescents 12 years of age and older. 

The revised warnings bring Litfulo in line with other JAK inhibitors, which are known to have an increased risk for serious side effects, including cardiovascular issues, blood clots, cancer, and serious infections. PRAC said these risks are also considered to apply to Litfulo.

Alopecia areata is a chronic and unpredictable form of hair loss due to an autoimmune attack on hair follicles. It classically presents with patchy loss of scalp hair, with women older than 45 most often affected. Hair loss can also occur on any hair-bearing body area. The condition has a profound psychological impact, with those affected frequently experiencing anxiety, depression, and lowered self-esteem. The public stigma associated with visible hair loss can lead to social isolation and severely impact overall quality of life. 

Lifetime prevalence of alopecia areata is estimated at around 2%. Cases are increasing in Europe, believed to be due to rising autoimmune triggers such as stress, environmental pollution, dietary changes, and genetic predisposition, along with heightened awareness and improved diagnosis.

Immunomodulatory Action 

Ritlecitinib has an immunomodulatory action on the immune system pathway that is overactive in alopecia areata. The drug works by irreversibly and selectively inhibiting the action of JAK3 and tyrosine-protein (TEC) kinases, signaling pathways involved in disease pathogenesis. 

In clinical trials, around 1 in 4 patients on ritlecitinib experienced significant hair regrowth covering 80% or more of their scalp area in just under 6 months (compared with 1.6% on placebo), while 1 in 7 had 90% or more scalp hair coverage (vs 1.5% on placebo).

PRAC said that following a review of available data from clinical trials, medical literature, and spontaneous post ‑ marketing reports of suspected side effects, and considering that the drug works by JAK enzyme inhibition, the committee concluded that the product information and educational material for Litfulo should be amended with the addition of a boxed warning to include the same information as for other JAK inhibitors.

The boxed warning will state that the drug should be used in certain patients only if suitable treatment alternatives are not available. This includes patients aged 65 years or older, those at increased risk for major cardiovascular problems such as heart attack or stroke, those who currently smoke or have done so for a long time in the past, and those at increased risk for cancer. In addition, Litfulo should be used with caution in patients with risk factors for pulmonary embolism or deep vein thromboembolism.

Risk for Serious Infections and Malignancies 

The most frequently reported adverse reactions from ritlecitinib are diarrhea (9.2%), headache (9.2%), acne (6.2%), urticaria (4.6%), rash (3.8%), folliculitis (3.1%), and dizziness (2.3%). Serious infections including tuberculosis represent a major risk. Patients also have an increased risk for shingles; malignancies including skin cancers, lymphomas, and lung cancer; major cardiovascular events; and thrombosis.

Treatment with ritlecitinib should be initiated and supervised by a healthcare professional experienced in the diagnosis and treatment of alopecia areata. Platelet and lymphocyte counts should be established before treatment initiation, again 4 weeks later, and thereafter monitored during the course of treatment. The benefit-risk for treatment should be re-assessed at regular intervals, with consideration given to discontinuation in patients who show no evidence of therapeutic benefit after 36 weeks.

Ritlecitinib is subject to additional monitoring to allow rapid identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions.

The PRAC recommendation for Litfulo will be forwarded to the EMA’s Committee for Medicinal Products for Human Use, which will adopt the agency’s position. Once adopted, it will be disseminated to healthcare professionals by the marketing authorization holder according to an agreed communication plan and published on the Direct Healthcare Professional Communications page and in national registers in EU Member States.