Ustekinumab

Introduction Overview

Generic Name

ustekinumab

Brand Name

Stelara

Dosage Form

Subcutaneous injection (prefilled syringe, vial), Intravenous infusion (vial)

Drug Class

Interleukin inhibitors

Pharmacokinetics

Absorption:
Ustekinumab is administered via subcutaneous injection or intravenous infusion. Following subcutaneous administration, ustekinumab exhibits slow absorption with a median time to maximum serum concentration of approximately 7 to 14 days. The bioavailability after subcutaneous injection is estimated to be approximately 57-68%. Clinical studies indicate that absorption is consistent and predictable across patients, with minimal variability. The intravenous formulation provides immediate bioavailability, used primarily for induction dosing in Crohn's disease and ulcerative colitis to rapidly achieve therapeutic levels.

Distribution:
Ustekinumab is a monoclonal antibody antibody that distributes primarily within the vascular and interstitial spaces due to its large molecular size. The estimated volume of distribution is relatively low, approximately 6.1 to 7.3 liters, reflecting limited tissue penetration outside of plasma and extracellular fluids. Binding to the target interleukins (IL-12 and IL-23) may influence distribution dynamics in inflamed tissues. Distribution is not significantly altered by age, gender, or weight, although dosing is weight-adjusted in some indications.

Metabolism:
As a monoclonal antibody, ustekinumab is metabolized via proteolytic catabolism into small peptides and amino acids through nonspecific pathways involving the reticuloendothelial system. It is not metabolized by cytochrome P450 enzymes and does not undergo hepatic metabolism typical of small molecule drugs. Therefore, it has a minimal risk for hepatic drug interactions. This catabolic degradation results in no active metabolites, and its elimination pathway is consistent with other IgG1 kappa monoclonal antibodies.

Elimination:
The elimination half-life of ustekinumab averages around 3 weeks (approximately 15 to 32 days), supporting dosing intervals of every 8 to 12 weeks depending on the indication. The prolonged half-life is consistent with IgG1 monoclonal antibodies, primarily eliminated via cellular catabolism rather than renal or hepatic excretion. Clearance may be influenced by immunogenicity or anti-drug antibody formation, although clinically relevant neutralizing antibodies are uncommon. No significant accumulation occurs with repeated dosing owing to its elimination kinetics.

Dosage Forms

Available Dosage Forms:
- Subcutaneous injection: single-dose prefilled syringe 45 mg/0.5 mL
- Subcutaneous injection: single-dose prefilled syringe 90 mg/mL
- Subcutaneous injection: single-dose vial 45 mg/0.5 mL
- Intravenous infusion: single-dose vial 130 mg/26 mL (5 mg/mL)

Dosages for Adults and Adolescents:
- For plaque psoriasis and psoriatic arthritis (patients 6 years and older): initial subcutaneous injection, followed by a second dose 4 weeks later, then maintenance doses every 12 weeks.
- For Crohn’s disease and ulcerative colitis (adults): induction dose as intravenous infusion based on weight, followed by subcutaneous injections every 8 weeks.
- Dose adjustments are weight-based for Crohn’s disease and ulcerative colitis, with heavier patients receiving higher induction doses.

Specific Patient Populations:
- Pediatric patients 6 years and older can receive Stelara for plaque psoriasis and psoriatic arthritis; administration is recommended to be performed by healthcare professionals.
- In Crohn’s disease and ulcerative colitis, dosing is carefully weight adjusted in adults; current data for pediatric use in these indications is limited.
- Patients with history of allergies to the formulation components or latex should be cautious as the needle cover contains latex.
- No significant dosage adjustment is required for patients with renal or hepatic impairment due to monoclonal antibody metabolism.
- Injection sites include upper arms, thighs, buttocks, or abdomen, avoiding areas of skin irritation or damage.
- Special instructions recommend rotating injection sites to minimize localized skin reactions.

Mechanism Of Action

Ustekinumab, marketed as Stelara, exerts its therapeutic effects by specifically targeting and inhibiting the activity of two key pro-inflammatory cytokines, interleukin-12 (IL-12) and interleukin-23 (IL-23). These cytokines play pivotal roles in the pathogenesis of autoimmune inflammatory disorders including plaque psoriasis, psoriatic arthritis, Crohn’s disease, and ulcerative colitis. The drug is a fully human IgG1 kappa monoclonal antibody that binds with high affinity to the p40 protein subunit shared by IL-12 and IL-23, thereby blocking their interaction with the IL-12Rβ1 receptor on the surface of immune cells.

By neutralizing IL-12 and IL-23, ustekinumab effectively inhibits the downstream signaling pathways that lead to the differentiation and activation of T-helper 1 (Th1) and T-helper 17 (Th17) cells. These T cell subsets contribute to the chronic inflammatory response characteristic of the aforementioned diseases by producing various pro-inflammatory cytokines such as interferon-gamma, IL-17, and tumor necrosis factor-alpha (TNF-α). The blockade results in attenuation of inflammation, immune cell recruitment, and tissue damage.

Clinically, this targeted immunomodulation leads to a reduction in the signs and symptoms of inflammation including erythema, scaling, joint pain, bowel inflammation, and mucosal lesions. Compared with other biologics like TNF inhibitors (e.g., adalimumab), ustekinumab offers a distinct mechanism focusing on upstream cytokines involved specifically in Th1/Th17 pathways. Clinical trials have demonstrated sustained efficacy and safety, affirming the significance of IL-12 and IL-23 in autoimmune etiologies and validating this approach.

Emerging research highlights the role of IL-23 in the differentiation of pathogenic Th17 cells, suggesting that dual inhibition of IL-12 and IL-23 via the shared p40 subunit confers broader immunoregulatory effects than targeting one cytokine alone. This mechanism also differentiates ustekinumab from monoclonal antibodies that selectively block only IL-23 (e.g., risankizumab). Overall, ustekinumab’s mechanism reflects a sophisticated blockade of key inflammatory drivers, providing an effective and targeted therapeutic modality to manage complex autoimmune diseases.

Pharmacological Actions

Selective inhibition of interleukin-12 and interleukin-23 to reduce immune-mediated inflammation.
Suppression of Th1 and Th17 cell-mediated immune responses.
Reduction of pro-inflammatory cytokines, including interferon-gamma, IL-17, and TNF-alpha.
Mitigation of skin inflammation and joint damage in psoriasis and psoriatic arthritis.
Attenuation of intestinal inflammation in Crohn’s disease and ulcerative colitis.
Immune modulation without broad immunosuppression, preserving some immune function.
Prolonged duration of action allowing infrequent dosing regimens.
Decreases clinical symptoms such as skin plaques, joint pain, and gastrointestinal manifestations.
Demonstrated efficacy in pediatric populations with psoriasis and psoriatic arthritis.
Minimal hepatic metabolism reducing risk of drug interactions.
Inhibition of inflammatory pathways implicated in autoimmunity and chronic inflammatory disorders.
Potential reduction in disease progression by modulating pathogenic immune responses.
Amelioration of systemic and local inflammation through targeted cytokine blockade.
Improvement in quality of life and functional status in treated patients.

Therapeutic Or Clinical Uses

Treatment of moderate to severe plaque psoriasis in adults and pediatric patients aged 6 years and older.
Management of active psoriatic arthritis in patients 6 years and older.
Induction and maintenance therapy for moderately to severely active Crohn’s disease in adults.
Induction and maintenance treatment of moderately to severely active ulcerative colitis in adults.
Reduction of skin symptoms including erythema, scaling, and thickness in plaque psoriasis.
Alleviation of joint pain, swelling, and stiffness in psoriatic arthritis.
Improvement in gastrointestinal symptoms such as abdominal pain and diarrhea in Crohn’s disease and ulcerative colitis.
Used in patients who are candidates for phototherapy or systemic therapy for psoriasis.
Alternative treatment option for patients with inadequate response or intolerance to other biologics or systemic therapies.
Treatment option reducing inflammation through selective immunomodulation rather than broad immunosuppression.
Considered in pediatric populations for management of chronic autoimmune skin and joint diseases.
Utilized in maintenance therapy to sustain remission in inflammatory bowel diseases.
Monotherapy or in combination with other immunosuppressants per clinical judgment.
Applicable for long-term management to improve disease control and patient quality of life.
Off-label use may be considered in related autoimmune inflammatory conditions based on emerging evidence.

Side Or Adverse Effects

Nasopharyngitis (flu or cold-like symptoms), occurring in up to 24% of patients depending on indication.
Injection site reactions such as redness, pain, or swelling in approximately 1-5% of patients.
Headache reported in 5-10% of treated patients.
Fatigue or tiredness affecting around 3-4% of patients.
Muscle pain (myalgia) and back pain in 1-2% of patients.
Upper respiratory tract infections including bronchitis in 3-5% of patients.
Dizziness reported in about 1% of patients.
Pharyngolaryngeal pain and sinusitis occurring in 3-4% of cases.
Urinary tract infections observed in 3-4% of Crohn’s disease patients.
Vaginal yeast infections reported in approximately 5% of female patients with Crohn’s disease.
Stomach pain, diarrhea, nausea, and fever in patients treated for ulcerative colitis.
Rare but serious allergic reactions including anaphylaxis requiring immediate medical attention.
Increased risk of serious infections including tuberculosis and opportunistic infections.
Potential increased risk of malignancies, including non-melanoma skin cancer.
Rare cases of posterior reversible encephalopathy syndrome (PRES) manifesting as neurological symptoms.

Precautions

Screen patients for latent or active tuberculosis prior to initiation and during treatment.
Avoid administration in patients with active infections or chronic infections until resolved.
Monitor patients regularly for signs and symptoms of infection during therapy.
Patients with history of malignancy should be evaluated carefully before use due to potential increased risk of cancer.
Avoid live vaccines during treatment and for at least 1 year after the last dose due to immunosuppression.
Be cautious in patients with latex allergy, as the needle cover contains natural rubber latex.
Advise patients to report any new or worsening skin lesions promptly for evaluation.
Use caution in patients receiving other immunosuppressive therapies; monitor closely.
Pregnant patients should be counseled on unknown risks; use only if benefits justify potential risks.
Advise breastfeeding patients regarding the potential excretion of ustekinumab in human milk.
Adjust dosing in pediatric patients carefully with healthcare provider oversight.
Patients should avoid exposure to individuals who have received live vaccines during treatment course.
Maintain scheduled follow-up appointments to monitor efficacy and adverse effects.
Instruct patients not to inject themselves unless adequately trained.
Review all concurrent medications for potential interactions or additive immunosuppression.

Warnings

Do not use in patients who have received BCG vaccine within 1 year before, during, or 1 year after treatment.
Risk of serious infections including bacterial, viral, fungal, and mycobacterial infections.
Can cause a rare but serious neurological condition known as posterior reversible encephalopathy syndrome (PRES).
Increased risk of malignancies including lymphoma and non-melanoma skin cancer; monitor skin regularly.
Potential for hypersensitivity reactions including anaphylaxis.
Live vaccines are contraindicated in patients receiving ustekinumab.
Use with caution in patients with a history of chronic infections or immune compromise.
Patients should be observed for new or worsening signs of tuberculosis during and after therapy.
Immunosuppressive effects may reduce response to vaccines.
Sudden discontinuation may exacerbate underlying autoimmune disease; follow prescribed dosing schedule.
Seek immediate medical attention for signs of infection such as fever, cough, or skin lesions.
Symptoms such as confusion, severe headache, seizures, or vision changes warrant urgent evaluation.
Use not recommended in combination with other biologics targeting the immune system due to infection risk.
Monitor closely for infusion reactions during intravenous administration.
Pregnancy and lactation safety not established; use only if benefit outweighs risk.

Contraindication

Known hypersensitivity to ustekinumab or any component of the formulation.
Active tuberculosis or other serious infections at the time of initiation.
Receipt of Bacillus Calmette-Guerin (BCG) vaccine within the past 12 months.
Use of live vaccines concurrently with ustekinumab treatment.
Patients with a history of hypersensitivity reactions to monoclonal antibodies.
Severe infections requiring hospitalization or intravenous antibiotics.
Any condition where immunosuppression significantly increases risk of harm.
Known latex allergy for patients expected to use prefilled syringes containing latex in needle covers.
Known active malignancy unless otherwise advised by oncology specialist.
Children under 6 years of age due to lack of established safety and efficacy data.
Patients with prior serious neurological disorders related to biologic therapies.
Individuals for whom regular monitoring or follow-up is not feasible.
Patients who cannot comply with vaccination recommendations or infection prevention measures.
Concurrent administration with other immunomodulatory biologics is contraindicated.
Pregnancy unless potential benefits outweigh risks and close monitoring is ensured.

Drug Interactions

Concomitant use with other immunosuppressive agents such as azathioprine, cyclosporine, methotrexate, sirolimus, or tacrolimus may increase risk of infections.
Potential interaction with oral corticosteroids including prednisone or methylprednisolone, requiring close monitoring for immunosuppressive effects.
No significant cytochrome P450-mediated drug interactions due to monoclonal antibody metabolism.
Caution advised with anticoagulants like warfarin; monitor for bleeding complications.
Live vaccines should be avoided during and for at least one year after ustekinumab therapy due to risk of infection.
Non-live vaccines may have reduced efficacy when administered during treatment.
No known interactions with common over-the-counter medications and vitamins, but always report all agents to healthcare provider.
Concurrent use with other biologic agents, including tumor necrosis factor (TNF) inhibitors, is generally discouraged due to additive risk.
Potential alteration of immune response may affect efficacy of immunizations and response to infections.
Herbal supplements with immunomodulating properties should be used cautiously and under medical advice.
No data suggests interaction with cytochrome P450 substrates, inducers, or inhibitors.
Combination with potent immunosuppressants requires dose adjustments and enhanced infection surveillance.
Monitor chemotherapy or other cancer treatment regimens closely when used concomitantly.
Drug interactions have not been fully characterized in pediatric populations; use caution.
Renal or hepatic impairment is unlikely to alter ustekinumab metabolism but monitor concomitant medications processed by these organs.

Preparations Of The Drug

Single-dose prefilled syringe for subcutaneous use containing 45 mg/0.5 mL or 90 mg/mL ustekinumab.
Single-dose vial for subcutaneous injection containing 45 mg/0.5 mL ustekinumab.
Single-dose vial for intravenous infusion containing 130 mg/26 mL (5 mg/mL) ustekinumab.
Prefilled syringes include excipients such as L-histidine, L-histidine monohydrochloride monohydrate, Polysorbate 80, and sucrose.
Vial formulations for IV infusion additionally contain EDTA disodium salt dihydrate and L-methionine alongside other stabilizers.
Packaging protects from light and requires refrigeration at 2°C to 8°C to maintain stability.
Prefilled syringes provided with needle covers containing natural rubber latex; alternative preparations may be required for latex-allergic patients.
Diluted infusion solutions should be used within 8 hours after preparation.
Unused portions of infusion solutions are to be discarded and not reused.
Storage guidance allows prefilled syringes to be kept at room temperature (up to 30°C) for a single period of up to 30 days in original carton.
Prefilled syringes must not be frozen or shaken, as this can compromise drug stability.
Instructions recommend removing the vial from storage shortly before use and allowing to warm to room temperature before administration.
Injection instructions include rotating injection sites and avoiding damaged or irritated skin.
Disposal of needles and syringes should be in puncture-proof sharps containers as per local regulations.
The manufacturing company is Janssen Biotech, Inc., Horsham, PA, USA.