2.1 Recommended Evaluations and Immunizations Prior to Treatment Initiation

Evaluate patients for active and latent tuberculosis (TB) infection prior to initiating treatment with SOTYKTU. If positive, start treatment for TB prior to SOTYKTU use [see Warnings and Precautions (5.3)].

Update immunizations according to current immunization guidelines [see Warnings and Precautions (5.7)].

2.2 Recommended Dosage

The recommended dosage of SOTYKTU is 6 mg taken orally once daily, with or without food.

Do not crush, cut, or chew the tablets.

2.3 Recommended Dosage in Patients with Hepatic Impairment

SOTYKTU is not recommended in patients with severe hepatic impairment (Child-Pugh C) [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

No dosage adjustment is needed for patients with mild to moderate hepatic impairment.

5.1 Hypersensitivity

Hypersensitivity reactions such as angioedema have been reported in subjects receiving SOTYKTU. If a clinically significant hypersensitivity reaction occurs, institute appropriate therapy and discontinue SOTYKTU [see Adverse Reactions (6.1)].

5.2 Infections

SOTYKTU may increase the risk of infections.

Serious infections have been reported in subjects with psoriasis who received SOTYKTU. The most common serious infections reported with SOTYKTU included pneumonia and COVID-19 [see Adverse Reactions (6.1)].

Avoid use of SOTYKTU in patients with an active or serious infection.

Consider the risks and benefits of treatment prior to initiating SOTYKTU in patients:

•

with chronic or recurrent infection

•

who have been exposed to tuberculosis

•

with a history of a serious or an opportunistic infection

•

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 SOTYKTU. A patient who develops a new infection during treatment with SOTYKTU should undergo prompt and complete diagnostic testing; appropriate antimicrobial therapy should be initiated; and the patient should be closely monitored. Interrupt SOTYKTU if a patient develops a serious infection. Do not resume SOTYKTU until the infection resolves or is adequately treated.

Viral Reactivation

Herpes virus reactivation (e.g., herpes zoster, herpes simplex), was reported in clinical trials with SOTYKTU. In the 16‑week placebo-controlled period, herpes simplex infections were reported in 17 subjects (6.8 per 100 patient‑years) treated with SOTYKTU, and 1 subject (0.8 per 100 patient-years) treated with placebo.

Multidermatomal herpes zoster was reported in an immunocompetent subject who received SOTYKTU.

During PSO-1, PSO-2, and the open-label extension trial in which subjects who completed the controlled trials could enroll, the majority of subjects who reported events of herpes zoster while receiving SOTYKTU were under 50 years of age.

The impact of SOTYKTU on chronic viral hepatitis reactivation is unknown. Subjects with positive screening tests for hepatitis B or C, or chronic hepatitis B, or untreated hepatitis C were excluded from clinical trials. Consider viral hepatitis screening and monitoring for reactivation in accordance with clinical guidelines before starting therapy and during therapy with SOTYKTU. If signs of reactivation occur, consult a hepatitis specialist. SOTYKTU is not recommended for use in patients with active hepatitis B or hepatitis C.

5.3 Tuberculosis

In clinical trials, of 4 subjects with latent tuberculosis (TB) who were treated with SOTYKTU and received appropriate TB prophylaxis, no subjects developed active TB (during the mean follow-up of 34 weeks). One subject, who did not have latent TB, developed active TB after receiving 54 weeks of SOTYKTU.

Evaluate patients for latent and active TB infection prior to initiating treatment with SOTYKTU. Do not administer SOTYKTU to patients with active TB. Initiate treatment of latent TB prior to administering SOTYKTU.

Consider anti-TB therapy prior to initiation of SOTYKTU in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed. Monitor patients receiving SOTYKTU for signs and symptoms of active TB during treatment.

5.4 Malignancy including Lymphomas

Malignancies, including lymphomas, were observed in clinical trials with SOTYKTU [see Adverse Reactions (6.1)].

Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with SOTYKTU, particularly in patients with a known malignancy (other than a successfully treated non-melanoma skin cancer) and patients who develop a malignancy when on treatment with SOTYKTU.

5.5 Rhabdomyolysis and Elevated CPK

Cases of rhabdomyolysis were reported in subjects treated with SOTYKTU resulting in interruption or discontinuation of SOTYKTU dosing.

Treatment with SOTYKTU was associated with an increased incidence of asymptomatic creatine phosphokinase (CPK) elevation and rhabdomyolysis compared to treatment with placebo. Discontinue SOTYKTU if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever [see Adverse Reactions (6.1)].

5.6 Laboratory Abnormalities

Triglyceride Elevations - Treatment with SOTYKTU was associated with increases in triglyceride levels. The effect of this elevated parameter on cardiovascular morbidity and mortality has not been determined. Periodically evaluate serum triglycerides according to the clinical guidelines for hyperlipidemia while patients are receiving treatment with SOTYKTU. Manage patients according to clinical guidelines for the management of hyperlipidemia [see Adverse Reactions (6.1)].

Liver Enzyme Elevations - Treatment with SOTYKTU was associated with an increase in the incidence of liver enzyme elevation compared to treatment with placebo. Liver serum transaminase elevations ≥ 3 times the ULN were reported in subjects treated with SOTYKTU. Evaluate liver enzymes at baseline and thereafter in patients with known or suspected liver disease according to routine patient management. If treatment-related increases in liver enzymes occur and drug-induced liver injury is suspected, interrupt SOTYKTU until a diagnosis of liver injury is excluded [see Adverse Reactions (6.1)].

5.7 Immunizations

Prior to initiating therapy with SOTYKTU, consider completion of all age-appropriate immunizations according to current immunization guidelines including prophylactic herpes zoster vaccination. Avoid use of live vaccines in patients treated with SOTYKTU. The response to live or non-live vaccines has not been evaluated.

5.8 Potential Risks Related to JAK Inhibition

It is not known whether TYK2 inhibition may be associated with the observed or potential adverse reactions of Janus Kinase (JAK) inhibition. In a large, randomized, postmarketing safety trial of a JAK inhibitor in rheumatoid arthritis (RA), patients 50 years of age and older with at least one cardiovascular risk factor, higher rates of all-cause mortality, including sudden cardiovascular death, major adverse cardiovascular events, overall thrombosis, deep venous thrombosis, pulmonary embolism, and malignancies (excluding non-melanoma skin cancer) were observed in patients treated with the JAK inhibitor compared to those treated with TNF blockers. SOTYKTU is not approved for use in RA.

6.1 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 SOTYKTU was evaluated in two placebo- and active-controlled trials (PSO-1 and PSO-2) and an open-label extension trial in which subjects who completed PSO-1 or PSO-2 could enroll [see Clinical Studies (14)]. In these clinical trials, a total of 1,519 subjects with moderate-to-severe plaque psoriasis who were candidates for systemic therapy or phototherapy received SOTYKTU 6 mg orally once daily. Of these, 1,141 subjects were exposed to SOTYKTU for at least one year.

In trials PSO-1 and PSO-2, 1,681 subjects were randomized to receive SOTYKTU 6 mg (840 subjects), placebo (419 subjects), or apremilast 30 mg twice daily (422 subjects). All subjects randomized to placebo switched to SOTYKTU at Week 16. All other subjects remained in their original treatment group until Week 24, at which point subjects could have continued on the same treatment or be switched to SOTYKTU or placebo. The mean age of subjects was 47 years. The majority of subjects were White (87%) and male (67%).

In the 16-week placebo-controlled period of the pooled clinical trials (PSO-1 and PSO-2), discontinuation of therapy due to adverse reactions in subjects who received SOTYKTU was 2.4%, compared to 3.8% for placebo.

Table 1 summarizes the adverse reactions that occurred in at least 1% of subjects in the SOTYKTU group and at a higher rate than the placebo group during the 16-week controlled period.

Adverse reactions that occurred in < 1% of subjects in the SOTYKTU group were herpes zoster.

Specific Adverse Reactions

Exposure adjusted incidence rates are reported for all the adverse reactions presented below.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and effectiveness of SOTYKTU in pediatric patients have not been established.

8.5 Geriatric Use

Of the 1,519 subjects with plaque psoriasis treated with SOTYKTU, 152 (10%) subjects were 65 years or older and 21 (1.4%) subjects were 75 years or older.

During the Week 0-16 period, for those subjects (80 subjects ≥ 65 years old, including 12 subjects ≥ 75 years old) who received SOTYKTU without switching treatment arms, there was a higher rate of overall serious adverse reactions, including serious infections, and discontinuations due to adverse reactions compared with younger adults.

No overall differences in effectiveness of SOTYKTU have been observed between patients 65 years of age and older and younger adult patients.

8.6 Renal Impairment

No dose adjustment of SOTYKTU is recommended in patients with mild, moderate, or severe renal impairment or in patients with end stage renal disease (ESRD) on dialysis [see Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

No dose adjustment of SOTYKTU is recommended in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment. SOTYKTU is not recommended for use in patients with severe hepatic impairment (Child-Pugh C) [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)].

12.1 Mechanism of Action

Deucravacitinib is an inhibitor of tyrosine kinase 2 (TYK2). TYK2 is a member of the Janus kinase (JAK) family. Deucravacitinib binds to the regulatory domain of TYK2, stabilizing an inhibitory interaction between the regulatory and the catalytic domains of the enzyme. This results in allosteric inhibition of receptor-mediated activation of TYK2 and its downstream activation of Signal Transducers and Activators of Transcription (STATs) as shown in cell-based assays. JAK kinases, including TYK2, function as pairs of homo- or heterodimers in the JAK-STAT pathways. TYK2 pairs with JAK1 to mediate multiple cytokine pathways and also pairs with JAK2 to transmit signals as shown in cell-based assays. The precise mechanism linking inhibition of TYK2 enzyme to therapeutic effectiveness in the treatment of adults with moderate-to-severe plaque psoriasis is not currently known.

12.2 Pharmacodynamics

In patients with psoriasis, deucravacitinib reduced psoriasis-associated gene expression in psoriatic skin in a dose dependent manner, including reductions in IL-23-pathway and type I IFN pathway regulated genes. Deucravacitinib reduced IL-17A, IL-19 and beta-defensin by 47 to 50%, 72%, and 81 to 84% respectively following 16 weeks of once daily treatment. The relationship between these pharmacodynamic markers and the mechanism(s) by which deucravacitinib exerts its clinical effects is unknown.

12.3 Pharmacokinetics

Following oral administration, deucravacitinib plasma Cmax and AUC increased proportionally over a dose range from 3 mg to 36 mg (0.5 to 6 times the approved recommended dosage) in healthy subjects. The accumulation of deucravacitinib was <1.4-fold following once daily dosing in healthy subjects. The PK of deucravacitinib and its active metabolite, BMT‑153261, were comparable between healthy subjects and subjects with psoriasis. The steady state Cmax and AUC24 of deucravacitinib following administration of 6 mg once daily were 45 ng/mL and 473 ng·hr/mL, respectively. The steady state Cmax and AUC24 of the active deucravacitinib metabolite, BMT-153261, following administration of 6 mg once daily were 5 ng/mL and 95 ng·hr/mL, respectively.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

The carcinogenic potential of deucravacitinib was assessed in 2-year rat and 6-month rasH2 transgenic mouse studies. No evidence of tumorigenicity was observed in male or female rats that received deucravacitinib at oral doses up to 15 mg/kg/day (51 times the MRHD based on AUC comparison). No evidence of tumorigenicity was observed in male or female Tg.rasH2 mice that received deucravacitinib at oral doses up to 60 mg/kg/day.

Deucravacitinib was not mutagenic in a bacterial mutagenicity assay (Ames test) or clastogenic in an in vitro chromosomal aberration assay (cultured Chinese hamster ovary cells) or in an in vivo rat peripheral blood micronucleus assay.

In male rats, deucravacitinib had no effects on reproductive parameters (mating, fertility, and sperm morphology) or early embryonic development of their offspring at oral doses up to 50 mg/kg/day (224 times the MRHD based on AUC comparison).

In female rats, deucravacitinib had no effects on mating, fertility, or early embryonic parameters at oral doses up to 50 mg/kg/day (171 times the MRHD based on AUC comparison).

14.1 Plaque Psoriasis

The efficacy and safety of SOTYKTU 6 mg once daily were assessed in two multicenter, randomized, double-blind, placebo- and active-controlled clinical trials, PSO-1 (NCT03624127) and PSO-2 (NCT03611751) which enrolled subjects 18 years of age and older with moderate-to-severe plaque psoriasis who were eligible for systemic therapy or phototherapy. Subjects had a body surface area (BSA) involvement of ≥ 10%, a Psoriasis Area and Severity Index (PASI) score ≥ 12, and a static Physician’s Global Assessment (sPGA) ≥ 3 (moderate or severe).

In PSO-1 and PSO-2, efficacy was assessed in 1,684 subjects randomized to either SOTYKTU (6 mg orally once daily), placebo, or apremilast (30 mg orally twice daily).

16.1 How Supplied

SOTYKTU™ (deucravacitinib) tablets are available as listed in the table below:

16.2 Storage and Handling

Store SOTYKTU tablets at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F) [see USP Controlled Room Temperature].