Pyzchiva Drug Information

Plaque Psoriasis (PsO) PYZCHIVA is indicated for the treatment of adults and pediatric patients 6 years of age and older with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy.

Psoriatic Arthritis (PsA) PYZCHIVA is indicated for the treatment of adults and pediatric patients 6 years of age and older with active psoriatic arthritis.

Crohn's Disease (CD) PYZCHIVA is indicated for the treatment of adult patients with moderately to severely active Crohn's disease.

Ulcerative Colitis PYZCHIVA is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis.

Recommended Dosage in Plaque Psoriasis Subcutaneous Adult Dosage Regimen For patients weighing 100 kg or less, the recommended dosage is 45 mg initially and 4 weeks later, followed by 45 mg every 12 weeks. In subjects weighing more than 100 kg, 45 mg was also shown to be efficacious. However, 90 mg resulted in greater efficacy in these subjects.

Subcutaneous Pediatric Dosage Regimen Administer PYZCHIVA subcutaneously at Weeks 0 and 4, then every 12 weeks thereafter. The recommended dose of PYZCHIVA for pediatric patients 6 years of age and older with plaque psoriasis based on body weight is shown below (Table 1). Table 1: Recommended Dose of PYZCHIVA for Subcutaneous Injection in Pediatric Patients 6 Years of Age and Older with Plaque Psoriasis, the administration volume for the recommended dose (0.75 mg/kg) is shown in Table 2; withdraw the appropriate volume from the vial.

The recommended dose of PYZCHIVA for pediatric patients 6 years of age and older with psoriatic arthritis, based on body weight, is shown below (Table 3).

Recommended Dosage in Crohn's Disease and Ulcerative Colitis Intravenous Induction Adult Dosage Regimen A single intravenous infusion dose of PYZCHIVA using the weight-based dosage regimen specified in Table 4. Table 4: Initial Intravenous Regimen The recommended maintenance dosage is a subcutaneous 90 mg dose administered 8 weeks after the initial intravenous dose, then every 8 weeks thereafter.

General Considerations for Administration PYZCHIVA is intended for use under the guidance and supervision of a healthcare provider. PYZCHIVA should only be administered to patients who will be closely monitored and have regular follow-up visits with a healthcare provider. The appropriate dose should be determined by a healthcare provider using the patient's current weight at the time of dosing.

In pediatric patients, it is recommended that PYZCHIVA be administered by a healthcare provider. If a healthcare provider determines that it is appropriate, a patient may self-inject or a caregiver may inject PYZCHIVA after proper training in subcutaneous injection technique. Instruct patients to follow the directions provided in the Instructions for Use.

It is recommended that each injection be administered at a different anatomic location (such as upper arms, gluteal regions, thighs, or any quadrant of abdomen) than the previous injection, and not into areas where the skin is tender, bruised, erythematous, or indurated. When using the vial, a 1 mL syringe with a 27 gauge, ½ inch needle is recommended. Prior to administration, visually inspect PYZCHIVA for particulate matter and discoloration.

PYZCHIVA is a clear, colorless to light yellow, sterile and preservative-free solution. Do not use PYZCHIVA if it is discolored or cloudy, or if other particulate matter is present. PYZCHIVA does not contain preservatives; therefore, discard any unused product remaining in the vial, syringe and/or PYZCHIVA AUTOINJECTOR.

Preparation and Administration of PYZCHIVA 130 mg/26 mL (5 mg/mL) Vial for Intravenous Infusion (Crohn's Disease and Ulcerative Colitis) PYZCHIVA solution for intravenous infusion must be diluted, prepared and infused by a healthcare professional using aseptic technique. Calculate the dose and the number of PYZCHIVA vials needed based on patient weight (Table 4). Each 26 mL vial of PYZCHIVA contains 130 mg of ustekinumab-ttwe.

Alternatively, a 250 mL infusion bag containing 0.45% Sodium Chloride Injection, USP may be used. Withdraw 26 mL of PYZCHIVA from each vial needed and add it to the 250 mL infusion bag. The final volume in the infusion bag should be 250 mL.

Gently mix. Protect from light. Visually inspect the diluted solution before infusion.

Do not use if visibly opaque particles, discoloration or foreign particles are observed. Infuse the diluted solution over a period of at least one hour. Once diluted in the infusion bag, the infusion should be completely administered within 36 hours at room temperature up to 30°C (86°F).

Use only an infusion set with an in-line, sterile, non-pyrogenic, low protein-binding filter (pore size 0.2 micrometer). Do not infuse PYZCHIVA concomitantly in the same intravenous line with other agents. PYZCHIVA does not contain preservatives.

Each vial is for one-time use in only one patient. Discard any remaining solution. Dispose any unused medicinal product in accordance with local requirements.

Storage The diluted infusion solution may be kept at room temperature up to 30°C (86°F) for up to 36 hours including infusion period. If necessary, the diluted infusion solution may be stored refrigerated at 2ºC to 8ºC (36ºF to 46ºF) for up to 15 days. After removal from refrigeration, the diluted solution may be stored at room temperature at up to 30°C (86°F) for an additional 24 hours including infusion period.

Storage time at refrigerated or room temperature begins once the diluted solution has been prepared. Do not freeze. Protect from light.

Discard any unused portion of the infusion solution.

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. Table 5 summarizes the adverse reactions that occurred at a rate of at least 1% with higher rates in the ustekinumab groups during the placebo-controlled period of Ps STUDY 1 and Ps STUDY 2. One case of PRES occurred during clinical trials in adult subjects with plaque psoriasis.

Infections In the placebo-controlled period of clinical trials of subjects with plaque psoriasis (average follow-up of 12.6 weeks for subjects receiving placebo and 13.4 weeks for ustekinumab-treated subjects), 27% of ustekinumab-treated subjects reported infections (1.39 per patient-years of follow-up) compared with 24% of subjects receiving placebo (1.21 per patient-years of follow-up). In the controlled and non-controlled portions of clinical trials in subjects with plaque psoriasis (median follow-up of 3.2 years), representing 8998 patient-years of exposure, 72.3% of ustekinumab-treated subjects reported infections (0.87 per patient-years of follow-up). Serious infections were reported in 2.8% of subjects (0.01 per patient-years of follow-up).

Non-melanoma skin cancer was reported in 1.5% of ustekinumab-treated subjects (0.52 per hundred patient-years of follow-up). The most frequently observed malignancies other than non-melanoma skin cancer during the clinical trials were: prostate, melanoma, colorectal and breast. Malignancies other than non-melanoma skin cancer in ustekinumab-treated subjects during the controlled and uncontrolled portions of trials were similar in type and number to what would be expected in the general U.S. population according to the SEER database (adjusted for age, gender and race). 1 Pediatric Subjects with Plaque Psoriasis The safety of ustekinumab was assessed in two trials of pediatric subjects with moderate to severe plaque psoriasis.

The safety profile in pediatric subjects was similar to the safety profile from trials in adults with plaque psoriasis. Psoriatic Arthritis The safety of ustekinumab was assessed in 927 subjects in two randomized, double-blind, placebo-controlled trials in adults with active psoriatic arthritis (PsA). The overall safety profile of ustekinumab in subjects with PsA was consistent with the safety profile seen in clinical trials in adult subjects with plaque psoriasis.

Crohn's Disease The safety of ustekinumab was assessed in 1407 subjects with moderately to severely active Crohn's disease (Crohn's Disease Activity Index greater than or equal to 220 and less than or equal to 450) in three randomized, double-blind, placebo-controlled, parallel-group, multicenter trials. These 1407 subjects included 40 subjects who received a prior investigational intravenous ustekinumab formulation but were not included in the efficacy analyses. In trials CD-1 and CD-2 there were 470 subjects who received ustekinumab 6 mg/kg as a weight-based single intravenous induction dose and 466 who received placebo.

Subjects who were responders in either trial CD-1 or CD-2 were randomized to receive a subcutaneous maintenance regimen of either 90 mg ustekinumab every 8 weeks, or placebo for 44 weeks in trial CD-3. Subjects in these 3 trials may have received other concomitant therapies including aminosalicylates, immunomodulatory agents, oral corticosteroids (prednisone or budesonide), and/or antibiotics for their Crohn's disease. Common adverse reactions in trials CD-1 and CD-2 and in trial CD-3 are listed in Table 6 and Table 7, respectively.

Table 7: Common Adverse Reactions Through Week 44 in Trial CD-3 Occurring in ≥3% of Ustekinumab-Treated Subjects and Higher Than Subjects Receiving Infections In subjects with Crohn's disease, serious or other clinically significant infections included anal abscess, gastroenteritis, and pneumonia. In addition, listeria meningitis and ophthalmic herpes zoster were reported in one subject each. Malignancies With up to one year of treatment in the Crohn's disease clinical trials, 0.2% of ustekinumab-treated subjects (0.36 events per hundred patient-years) and 0.2% of placebo-treated subjects (0.58 events per hundred patient-years) developed non- melanoma skin cancer.

Malignancies other than non-melanoma skin cancers occurred in 0.2% of ustekinumab-treated subjects (0.27 events per hundred patient-years) and in none of the placebo-treated subjects. Hypersensitivity Reactions Including Anaphylaxis In CD trials, two subjects reported hypersensitivity reactions following ustekinumab administration. One subject experienced signs and symptoms consistent with anaphylaxis (tightness of the throat, shortness of breath, and flushing) after a single subcutaneous administration (0.1% of subjects receiving subcutaneous ustekinumab).

In addition, one subject experienced signs and symptoms consistent with or related to a hypersensitivity reaction (chest discomfort, flushing, urticaria, and increased body temperature) after the initial intravenous ustekinumab dose (0.08% of subjects receiving intravenous ustekinumab). These subjects were treated with oral antihistamines or corticosteroids and in both cases symptoms resolved within an hour. Ulcerative Colitis The safety of ustekinumab was evaluated in two randomized, double-blind, placebo- controlled clinical trials (UC-1 and UC-2 ) in 960 adult subjects with moderately to severely active ulcerative colitis.

The overall safety profile of ustekinumab in subjects with ulcerative colitis was consistent with the safety profile seen across all approved indications. Adverse reactions reported in at least 3% of ustekinumab-treated subjects and at a higher rate than placebo were: Induction (UC-1): nasopharyngitis (7% vs 4%). Maintenance (UC-2): nasopharyngitis (2 ).

Infections In subjects with ulcerative colitis, serious or other clinically significant infections included gastroenteritis and pneumonia. Malignancies With up to one year of treatment in the ulcerative colitis clinical trials, 0.4% of ustekinumab-treated subjects (0.48 events per hundred patient-years) and 0.0% of subjects receiving placebo (0.00 events per hundred patient-years) developed non- melanoma skin cancer. Malignancies other than non-melanoma skin cancers occurred in 0.5% of ustekinumab-treated subjects (0.64 events per hundred patient-years) and 0.2% of subjects receiving placebo (0.40 events per hundred patient-years).

Immunogenicity

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of ustekinumab or of other ustekinumab products. Approximately 6 to 12.4% of subjects treated with ustekinumab in clinical trials in subjects with plaque psoriasis and psoriatic arthritis developed antibodies to ustekinumab, which were generally low-titer.

In clinical trials in subjects with plaque psoriasis, antibodies to ustekinumab were associated with reduced or undetectable serum ustekinumab concentrations and reduced efficacy. In trials in subjects with plaque psoriasis, the majority of subjects who were positive for antibodies to ustekinumab had neutralizing antibodies. In clinical trials in subjects with Crohn's disease and ulcerative colitis, 2.9% and 4.6% of subjects, respectively, developed antibodies to ustekinumab when treated with ustekinumab for approximately one year.

No apparent association between the development of antibodies to ustekinumab and the development of injection site reactions was seen.

Postmarketing Experience

The following adverse reactions have been reported during post-approval use of ustekinumab products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to ustekinumab product exposure. Immune system disorders: Hypersensitivity reactions (e.g., anaphylaxis, angioedema, dyspnea, rash, urticaria), including a fatal case that presented with chest tightness and dyspnea during infusion of the first dose.

Infections and infestations: Lower respiratory tract infection (including opportunistic fungal infections and tuberculosis). Neurological disorders: Posterior Reversible Encephalopathy Syndrome (PRES). Respiratory, thoracic and mediastinal disorders: Interstitial pneumonia, eosinophilic pneumonia and cryptogenic organizing pneumonia.

Skin reactions: Pustular psoriasis, erythrodermic psoriasis, hypersensitivity vasculitis.

Concomitant Therapies

In trials in subjects with plaque psoriasis the safety of ustekinumab products in combination with immunosuppressive agents or phototherapy has not been evaluated. In trials in subjects with psoriatic arthritis, concomitant MTX use did not appear to influence the safety or efficacy of ustekinumab. In trials in subjects with Crohn's disease (CD-1 and CD-2) and ulcerative colitis (UC-1), immunomodulators (6-MP, AZA, MTX) were used concomitantly in approximately 30% of subjects and corticosteroids were used concomitantly in approximately 40% and 50% of Crohn's disease and ulcerative colitis subjects, respectively.

Use of these concomitant therapies did not appear to influence the overall safety or efficacy of ustekinumab.

CYP450 Substrates

The formation of CYP450 enzymes can be suppressed by increased levels of certain cytokines (e.g., IL-1, IL-6, TNFα, IFN) during chronic inflammation. Thus, use of ustekinumab products, antagonists of IL-12 and IL-23, could normalize the formation of CYP450 enzymes. Upon initiation or discontinuation of PYZCHIVA in patients who are receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index, consider monitoring for therapeutic effect or drug concentration and adjust the individual dosage of the CYP substrate as needed.

See the prescribing information of specific CYP substrates. A CYP-mediated drug interaction effect was not observed in subjects with Crohn's disease.

Allergen Immunotherapy

Ustekinumab products have not been evaluated in patients who have undergone allergy immunotherapy. Ustekinumab products may decrease the protective effect of allergen immunotherapy (decrease tolerance) which may increase the risk of an allergic reaction to a dose of allergen immunotherapy. Therefore, caution should be exercised in patients receiving or who have received allergen immunotherapy, particularly for anaphylaxis.

Pregnancy Risk Summary Available data from the Organization of Teratology Information Specialists (OTIS)/MotherToBaby Pregnancy Registry, published literature and pharmacovigilance in pregnant women have not identified a ustekinumab-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes (see Data ). There are risks to the mother and the fetus associated with inflammatory bowel disease (IBD) in pregnancy. In animal reproductive and developmental toxicity studies, no adverse developmental effects were observed in offspring after administration of ustekinumab to pregnant monkeys at exposures greater than 100 times the maximum recommended human dose (MRHD).

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage of clinically recognized pregnancies is respectively. Clinical Considerations Disease-associated Maternal and Embryo/Fetal Risk Published data suggest that the risk of adverse pregnancy outcomes in women with IBD is associated with increased disease activity.

Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth. Fetal/Neonatal Adverse Reactions Transport of endogenous IgG antibodies across the placenta increases as pregnancy progresses, and peaks during the third trimester. Therefore, ustekinumab products may be present in infants exposed in utero.

The potential clinical impact of ustekinumab product exposure in infants exposed in utero should be considered. Data Human Data An observational pregnancy registry conducted by (OTIS)/MotherToBaby in the U.S. and Canada (enrollment between 2013 and 2019) assessed the risk of major birth defects, pattern of major and minor anomalies in live-born infants, miscarriage, and adverse infant outcomes in women with ustekinumab exposure. Most participants had a primary indication of CD (65.4%) or psoriasis (30.8%).

The pregnancy registry did not identify a ustekinumab-associated risk of major birth defects, pattern of major or minor anomalies, increased risk of miscarriage or adverse infant outcomes. Methodological limitations of the registry include small sample size, lack of an internal comparison group, a mix of prospective and retrospective reports, and unmeasured confounders. The conclusions from the pregnancy registry were consistent with the published literature and pharmacovigilance.

Animal Data Ustekinumab was tested in two embryo-fetal development toxicity studies in cynomolgus monkeys. No teratogenic or other adverse developmental effects were observed in fetuses from pregnant monkeys that were administered ustekinumab subcutaneously twice weekly or intravenously weekly during the period of organogenesis. Serum concentrations of ustekinumab in pregnant monkeys were greater than 100 times the serum concentration in patients treated subcutaneously with 90 mg of ustekinumab weekly for 4 weeks.

In a combined embryo-fetal development and pre- and post-natal development toxicity study, pregnant cynomolgus monkeys were administered subcutaneous doses of ustekinumab twice weekly at exposures greater than 100 times the MRHD from the beginning of organogenesis to Day 33 after delivery. Neonatal deaths occurred in the offspring of one monkey administered ustekinumab at 22.5 mg/kg and one monkey dosed at 45 mg/kg. No ustekinumab-related effects on functional, morphological, or immunological development were observed in the neonates from birth through six months of age.

Pediatric Use Plaque Psoriasis The safety and effectiveness of PYZCHIVA have been established for the treatment of moderate to severe plaque psoriasis in pediatric patients 6 years of age and older who are candidates for phototherapy or systemic therapy. Use of PYZCHIVA in pediatric patients 6 to 11 years of age is supported by evidence from an open- label, single-arm, efficacy, safety and pharmacokinetics trial (Ps STUDY 4) of ustekinumab in 44 subjects. The safety and effectiveness of PYZCHIVA have not been established in pediatric patients less than 6 years of age with plaque psoriasis.

Use of PYZCHIVA in these age groups is supported by evidence from adequate and well controlled trials of ustekinumab in adult subjects with psoriasis and PsA, pharmacokinetic data from adult subjects with psoriasis, adult subjects with PsA and pediatric subjects with psoriasis, and safety data of ustekinumab from two clinical trials in 44 pediatric subjects 6 to 11 years old with psoriasis and 110 pediatric subjects 12 years of age and older with psoriasis. The observed pre-dose (trough) concentrations are generally comparable between adult subjects with psoriasis, adult subjects with PsA and pediatric subjects with psoriasis, and the PK exposure is expected to be comparable between adult and pediatric subjects with PsA. The safety and effectiveness of PYZCHIVA have not been established in pediatric patients less than 6 years old with psoriatic arthritis.

Crohn's Disease and Ulcerative Colitis The safety and effectiveness of PYZCHIVA have not been established in pediatric patients with Crohn's disease or ulcerative colitis.

PYZCHIVA is contraindicated in patients with clinically significant hypersensitivity to ustekinumab products or to any of the excipients in PYZCHIVA.

Single doses up to 6 mg/kg intravenously have been administered in clinical trials without dose-limiting toxicity. In case of overdosage, monitor the patient for any signs or symptoms of adverse reactions or effects and institute appropriate symptomatic treatment immediately. Consider contacting the Poison Help line 1-800-222-1222 or a medical toxicologist for additional overdose management recommendations.