Ustekinumab - Drug Monograph

Introduction

Ustekinumab is a human monoclonal antibody that represents a significant advancement in the treatment of immune-mediated inflammatory diseases. As a biologic therapy targeting specific interleukin pathways, it has revolutionized the management of moderate to severe plaque psoriasis, psoriatic arthritis, and Crohn's disease. Approved by the FDA in 2009, ustekinumab offers a targeted mechanism of action with durable clinical responses.

Mechanism of Action

Ustekinumab exerts its therapeutic effects through selective inhibition of interleukin-12 (IL-12) and interleukin-23 (IL-23), which are naturally occurring cytokines involved in inflammatory and immune responses. The drug binds with high specificity to the p40 protein subunit shared by both IL-12 and IL-23, preventing these cytokines from interacting with their cell surface receptors. This inhibition disrupts the downstream inflammatory cascade, including Th1 and Th17 cell differentiation and activation, thereby reducing the production of inflammatory cytokines such as TNF-α, IL-17, and IL-22.

Indications

• Plaque Psoriasis: Moderate to severe disease in adults and pediatric patients (6 years and older) who are candidates for systemic therapy or phototherapy
• Psoriatic Arthritis: Active disease in adults, alone or in combination with methotrexate
• Crohn's Disease: Moderately to severely active disease in adults who have failed or were intolerant to conventional therapy or TNF blockers
• Ulcerative Colitis: Moderately to severely active disease in adults

Dosage and Administration

• Psoriasis: 45 mg for patients ≤100 kg; 90 mg for patients >100 kg at weeks 0, 4, and every 12 weeks thereafter
• Psoriatic Arthritis: 45 mg at weeks 0, 4, and every 12 weeks (90 mg if >100 kg)
• Crohn's Disease: Weight-based IV induction (approximately 6 mg/kg), followed by 90 mg SC every 8 weeks
• Pediatric Psoriasis: 0.75 mg/kg (≤60 kg), 45 mg (60-100 kg), or 90 mg (>100 kg) at weeks 0, 4, and every 12 weeks

• Subcutaneous injection in abdomen, thighs, or upper arms
• Rotate injection sites
• Allow prefilled syringe or vial to reach room temperature (30 minutes) before administration

Pharmacokinetics

• Absorption: Bioavailability approximately 57% following subcutaneous administration
• Distribution: Volume of distribution ~5.1-6.1 L; does not readily cross blood-brain barrier
• Metabolism: Degraded via proteolytic enzymes throughout the body; no hepatic cytochrome P450 involvement
• Elimination: Half-life approximately 21 days (range 15-45 days); clearance influenced by body weight and presence of anti-drug antibodies
• Steady State: Achieved by week 28 with every-12-week dosing

Contraindications

• History of serious hypersensitivity reaction to ustekinumab or any component of the formulation
• Clinically significant active infection (e.g., tuberculosis)
• Severe immunocompromised states

Warnings and Precautions

Drug Interactions

• Live Vaccines: Avoid concurrent administration
• CYP450 Substrates: Potential for altered metabolism of drugs with narrow therapeutic index
• Other Biologics: Increased risk of infections; avoid concurrent use with other immunosuppressants
• TNF Blockers: Limited data on combination therapy

Adverse Effects

• Upper respiratory infections (16%)
• Headache (5%)
• Fatigue (4%)
• Injection site reactions (erythema, itching, pain, swelling)
• Nausea (3%)
• Arthralgia (3%)

• Serious infections (1.5%)
• Malignancies (0.3%)
• Hypersensitivity reactions
• Reversible posterior leukoencephalopathy syndrome
• Cardiovascular events

Monitoring Parameters

• CBC with differential
• Liver function tests
• Renal function
• Tuberculosis screening (quantiferon Gold or PPD)
• Hepatitis B and C screening
• Pregnancy test if applicable

• Signs and symptoms of infection at each visit
• Skin examination for new malignancies (especially in psoriasis patients)
• Clinical response assessment
• Injection site reactions
• Patient-reported outcomes

• Routine laboratory monitoring every 3-6 months
• Vaccination status review annually
• Cancer screening per guidelines

Patient Education

• Administration: Proper injection technique and site rotation
• Storage: Refrigerate at 2-8°C; do not freeze
• Infection Recognition: Report fever, cough, flu-like symptoms, or unusual infections promptly
• Missed Dose: Administer as soon as remembered, then resume regular schedule
• Concomitant Therapies: Inform providers of all medications, including OTC products
• Pregnancy/Lactation: Discuss family planning; registry available for pregnant patients
• Follow-up: Maintain regular appointments for monitoring
• Travel: Plan for medication access during travel

References

1. Benson JM, et al. Therapeutic targeting of the IL-12/23 pathways: from discovery to clinical practice. Ann N Y Acad Sci. 2007;1110:17-27. 2. FDA Prescribing Information: Stelara® (ustekinumab) 3. Papp KA, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis. Lancet. 2008;371(9625):1665-1674. 4. Sandborn WJ, et al. Ustekinumab induction and maintenance therapy in refractory Crohn's disease. N Engl J Med. 2012;367(16):1519-1528. 5. McInnes IB, et al. Efficacy and safety of ustekinumab in patients with active psoriatic arthritis. Lancet. 2013;382(9894):780-789. 6. American Academy of Dermatology Guidelines of Care for the Management of Psoriasis with Biologics. J Am Acad Dermatol. 2019;80(4):1029-1072.