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Ustekinumab

Class: Disease-modifying Antirheumatic Drugs
Chemical Name: Anti-(human interleukin 12 p40 subunit) (human monoclonal CNTO 1275 γ1-chain)-immunoglobulin G1 disulfide with human monoclonal CNTO 1275 κ-chain dimer
Molecular Formula: C6482H10004N1712O2016S46
CAS Number: 815610-63-0
Brands: Stelara

Medically reviewed by Drugs.com on Aug 17, 2020. Written by ASHP.

Introduction

Immunosuppressive agent; a human IgG1 kappa monoclonal antibody directed against the p40 subunit of interleukin-12 (IL-12) and interleukin-23 (IL-23).

Uses for Ustekinumab

Plaque Psoriasis

Management of moderate to severe plaque psoriasis in adults and adolescents ≥12 years of age who are candidates for systemic therapy or phototherapy.

Psoriatic Arthritis

Used alone or in conjunction with methotrexate for the management of active psoriatic arthritis in adults.

Crohn's Disease

Treatment of moderately to severely active Crohn's disease in adults.

Ulcerative Colitis

Treatment of moderately to severely active ulcerative colitis in adults.

Ustekinumab Dosage and Administration

Administration

Administer by sub-Q injection or IV infusion.

Administer only to patients who will be closely monitored and have regular follow-up visits with a clinician.

Sub-Q Administration

For sub-Q administration, available as 90-mg/mL solution in 0.5- or 1-mL prefilled syringes and 0.5-mL single-dose vials.

Administer by sub-Q injection at a different anatomic site (e.g., upper arms, gluteal regions, thighs, any quadrant of the abdomen) than the previous injection. Do not make injections into areas where the skin is tender, bruised, erythematous, or indurated.

When using ustekinumab in single-dose vial, use a 1-mL syringe with a 27-gauge, ½-inch needle to administer the drug.

Do not shake the injection.

Injection contains no preservative; discard any unused portion.

Intended for use under the supervision of a clinician, but may be self-administered if the clinician determines that the patient and/or their caregiver is competent to prepare and safely administer the drug by sub-Q injection after appropriate training. When used in adolescents, manufacturer recommends administration by a clinician.

IV Administration

For solution compatibility information, see Compatibility under Stability.

For IV infusion, available as 5-mg/mL injection concentrate in 26-mL (130-mg) single-dose vials.

Administer using an inline, nonpyrogenic, low-protein-binding 0.2-µm filter.

Do not infuse simultaneously through the same IV line with any other drug.

Dilution

Dilute in 0.9% sodium chloride injection to provide a total volume of 250 mL (i.e., remove a volume of diluent equal to the total required volume of ustekinumab injection concentrate from a 250-mL infusion bag prior to adding the drug concentrate). Mix gently.

Do not use diluted solution if visibly opaque particles, discoloration, or foreign particles are observed.

Injection contains no preservative; discard any unused portion.

Rate of Administration

Administer over at least 1 hour.

Dosage

Use patient's current weight at the time of dosing to determine weight-based doses.

Pediatric Patients

Plaque Psoriasis
Sub-Q

Adolescents 12–17 years of age weighing <60 kg: 0.75 mg/kg at 0 and 4 weeks, then every 12 weeks.

Adolescents 12–17 years of age weighing 60–100 kg: 45 mg at 0 and 4 weeks, then every 12 weeks.

Adolescents 12–17 years of age weighing >100 kg: 90 mg at 0 and 4 weeks, then every 12 weeks.

Adults

Plaque Psoriasis
Sub-Q

Adults weighing ≤100 kg: 45 mg at 0 and 4 weeks, then every 12 weeks.

Adults weighing >100 kg: 90 mg at 0 and 4 weeks, then every 12 weeks. Although 45-mg doses were effective in these patients in clinical studies, 90-mg doses were more effective.

Psoriatic Arthritis
Sub-Q

45 mg at 0 and 4 weeks, then every 12 weeks.

Adults weighing >100 kg with coexisting moderate to severe plaque psoriasis: 90 mg at 0 and 4 weeks, then every 12 weeks.

Crohn's Disease or Ulcerative Colitis
IV, then Sub-Q

IV induction: Single dose of 260 mg in patients weighing ≤55 kg, 390 mg in those weighing >55 to 85 kg, and 520 mg in those weighing >85 kg.

Sub-Q maintenance: 90 mg every 8 weeks; initiate 8 weeks after the IV induction dose.

Special Populations

Hepatic Impairment

Manufacturer makes no specific dosage recommendations.

Renal Impairment

Manufacturer makes no specific dosage recommendations.

Geriatric Patients

Manufacturer makes no specific dosage recommendations.

Cautions for Ustekinumab

Contraindications

  • History of clinically important hypersensitivity to ustekinumab or any ingredient in the formulation.

Warnings/Precautions

Infectious Complications

May increase risk of infection, including reactivation of latent infections. Serious bacterial, fungal, and viral infections observed. Serious or clinically important infections (e.g., requiring hospitalization) including cellulitis, diverticulitis, osteomyelitis, viral infections, gastroenteritis, pneumonia, urinary tract infections, appendicitis, cholecystitis, sepsis, anal abscess, ophthalmic herpes zoster, listeriosis, and listeria meningitis reported.

Individuals genetically deficient in IL-12/IL-23 are particularly vulnerable to disseminated infections caused by mycobacteria (including nontuberculous, environmental mycobacteria), salmonella (including nontyphi strains), and BCG vaccine; serious, sometimes fatal, infections reported in such individuals. Not known whether patients with ustekinumab-induced blockade of IL-12/IL-23 are susceptible to these infections. Consider appropriate diagnostic testing for these infections (e.g., tissue culture, stool culture) as dictated by clinical circumstances.

Do not initiate ustekinumab in patients with any clinically important active infection and do not administer until the infection resolves or is adequately treated. If a serious or clinically important infection develops, consider discontinuing ustekinumab until infection resolves or is adequately treated. Consider potential risks and benefits of the drug prior to initiating therapy in patients with chronic infection or history of recurrent infection.

Evaluate patients for active or latent tuberculosis prior to initiation of ustekinumab. Do not administer to patients with active tuberculosis. When indicated, initiate appropriate antimycobacterial regimen for treatment of latent tuberculosis prior to ustekinumab therapy. Also consider antimycobacterial therapy prior to ustekinumab therapy in individuals with a history of latent or active tuberculosis in whom an adequate course of antimycobacterial treatment cannot be confirmed. Closely monitor patients for active tuberculosis during and after treatment.

Malignancies

May increase risk of malignancy.

Malignancies (e.g., nonmelanoma skin cancer, prostate cancer, melanoma, colorectal cancer, breast cancer) reported in clinical studies. Incidence of malignancies other than nonmelanoma skin cancer in ustekinumab-treated psoriasis patients similar to expected incidence in general US population.

Inhibition of the p40 subunit of IL-12/IL-23 increased the risk of malignancy in animals. Ultraviolet (UV) radiation-induced skin cancers developed earlier and more frequently in mice genetically manipulated to be deficient in both IL-12 and IL-23 or IL-12 alone. Relevance of these data to risk of malignancy in humans unknown.

Rapid appearance of multiple cutaneous squamous cell carcinomas reported in patients with preexisting risk factors for nonmelanoma skin cancer. Monitor all patients receiving ustekinumab for nonmelanoma skin cancer. Closely monitor patients >60 years of age, those with a history of prolonged immunosuppressive therapy, and those with a history of psoralen and UVA radiation (PUVA) treatment.

Safety of ustekinumab not evaluated in patients with history of malignancy or with known malignancy.

Sensitivity Reactions

Hypersensitivity Reactions

Hypersensitivity reactions (e.g., anaphylaxis, angioedema, rash, urticaria) reported.

If anaphylactic or other clinically important hypersensitivity reaction occurs, discontinue ustekinumab and institute appropriate therapy.

Latex Sensitivity

The needle cover of the prefilled syringe contains dry natural rubber and should not be handled by individuals sensitive to latex.

Reversible Posterior Leukoencephalopathy Syndrome

Reversible posterior leukoencephalopathy syndrome (RPLS), a neurologic syndrome characterized by reversible vasogenic subcortical edema, observed in 1 patient who received 12 doses of ustekinumab over approximately 2 years and presented with headache, seizures, and confusion. Drug was discontinued and patient fully recovered with appropriate treatment.

RPLS reported in association with conditions such as preeclampsia, eclampsia, and acute hypertension and with cytotoxic or immunosuppressive therapy; not caused by demyelination or known infectious agent. Manifestations include visual and neurologic disturbances (e.g., headache, seizures, confusion, encephalopathy, blindness). Magnetic resonance imaging (MRI) is used to confirm diagnosis of RPLS.

If RPLS suspected, discontinue ustekinumab and institute appropriate treatment.

Immunization

Administer all age-appropriate vaccines prior to initiation of ustekinumab therapy.

Avoid live vaccines. Do not administer BCG vaccine during, for 1 year before, or for 1 year after ustekinumab therapy. (See Interactions.)

Noninfectious Pneumonia

Interstitial pneumonia, eosinophilic pneumonia, and cryptogenic organizing pneumonia reported. Manifestations included cough, dyspnea, and interstitial infiltrates following 1–3 doses of ustekinumab; serious outcomes (e.g., respiratory failure, prolonged hospitalization) also reported. Improvement has occurred following discontinuance of ustekinumab and, in some cases, administration of corticosteroids.

If a diagnosis of interstitial pneumonia, eosinophilic pneumonia, or cryptogenic organizing pneumonia is confirmed, discontinue ustekinumab and institute appropriate treatment,

Immunogenicity

Antibodies to ustekinumab detected, generally in low titers, in 6–12.4% of patients with psoriasis or psoriatic arthritis. In psoriasis patients, anti-ustekinumab antibodies were associated with reduced or undetectable serum ustekinumab concentrations and reduced efficacy; majority of psoriasis patients with anti-ustekinumab antibodies had neutralizing antibodies.

Antibodies to ustekinumab also detected in 2.9 or 4.6% of patients with Crohn's disease or ulcerative colitis, respectively.

No apparent association between antibody development and injection site reactions.

Specific Populations

Pregnancy

Reproductive and developmental toxicity studies in monkeys revealed no evidence of adverse developmental effects on fetuses or neonatal offspring. Data regarding ustekinumab use in pregnant women are insufficient to inform a drug-associated risk.

Pregnancy registry at 877-311-8972.

Lactation

Not known whether ustekinumab distributes into human milk or affects breast-fed infants or milk production. Ustekinumab distributes into milk in monkeys, and maternal IgG distributes into human milk. Systemic exposure to ustekinumab in breast-fed infants is expected to be low since the drug is a large molecule and is degraded in the GI tract. Any effects of local exposure to ustekinumab in the GI tract are unknown.

Consider developmental and health benefits of breast-feeding along with the mother's clinical need for ustekinumab and any potential adverse effects on the breast-fed infant from either the drug or underlying maternal condition.

Pediatric Use

Safety and efficacy established in pediatric patients 12–17 years of age with moderate to severe plaque psoriasis based on evidence from a randomized clinical trial in this age group; safety profile similar to that in adults with psoriasis.

Safety and efficacy not established in pediatric patients with psoriatic arthritis, Crohn's disease, or ulcerative colitis or in pediatric patients <12 years of age with psoriasis.

Geriatric Use

No apparent differences in safety and efficacy relative to younger adults; however, insufficient experience in patients ≥65 years of age to determine whether they respond differently than younger adults.

Common Adverse Effects

Patients with psoriasis: Nasopharyngitis, upper respiratory tract infection, headache, fatigue.

Patients with psoriatic arthritis: Adverse effects similar to those in patients with psoriasis.

Patients with Crohn's disease: Vomiting during induction therapy; nasopharyngitis, injection site erythema, vulvovaginal candidiasis/mycotic infection, bronchitis, pruritus, urinary tract infection, sinusitis during maintenance therapy.

Patients with ulcerative colitis: Nasopharyngitis during induction therapy; nasopharyngitis, headache, abdominal pain, influenza, fever, diarrhea, sinusitis, fatigue, nausea during maintenance therapy.

Interactions for Ustekinumab

No formal drug interaction studies to date.

Administered concomitantly with methotrexate, corticosteroids, and/or NSAIAs in clinical studies in psoriatic arthritis.

Drugs Metabolized by Hepatic Microsomal Enzymes

Because increased levels of cytokines (e.g., interleukin-1 [IL-1], interleukin-6 [IL-6], interleukin-10 [IL-10], tumor necrosis factor [TNF; TNF-α], interferon [IFN]) during chronic inflammation may suppress formation of CYP isoenzymes, ustekinumab may normalize formation of CYP enzymes. IL-12 and/or IL-23 did not alter activity of CYP isoenzymes 1A2, 2B6, 2C9, 2C19, 2D6, or 3A4 in vitro; however, clinical relevance not established.

Drugs metabolized by CYP isoenzymes, particularly those with a low therapeutic index: Consider monitoring therapeutic effect and serum drug concentrations following initiation of ustekinumab; adjust dosage as needed.

Vaccines

Avoid live vaccines.

Use caution when administering live vaccines to household contacts of patients receiving ustekinumab because of potential risk for shedding vaccine organism from household contact and transmission to patient.

Inactive vaccines administered during ustekinumab therapy may not elicit an immune response sufficient to prevent disease.

Specific Drugs and Therapies

Drug or Therapy

Interaction

Comments

Allergy immunotherapy

Possible decreased protective effect of allergy immunotherapy; possible increased risk of allergic reaction to dose of allergen immunotherapy

Not evaluated; use with caution in patients who are receiving or have received allergy immunotherapy, particularly for anaphylaxis

Azathioprine

Concomitant use does not appear to alter ustekinumab clearance or serum concentrations or affect safety or efficacy for Crohn's disease or ulcerative colitis

BCG vaccine

Individuals with genetic IL-12/IL-23 deficiency are vulnerable to disseminated infections caused by BCG vaccine

Do not administer BCG vaccine during, for 1 year before, or for 1 year after ustekinumab therapy

Corticosteroids, oral

Concomitant use does not appear to alter ustekinumab clearance in patients with psoriatic arthritis

Concomitant use does not appear to alter ustekinumab clearance or serum concentrations or affect safety or efficacy for Crohn's disease or ulcerative colitis

Cyclosporine

Possible effect on cyclosporine metabolism; because increased levels of cytokines during chronic inflammation may suppress formation of CYP isoenzymes, ustekinumab may normalize formation of CYP enzymes

Consider monitoring cyclosporine concentrations following initiation of ustekinumab; adjust dosage as needed

Immunosuppressive agents

Safety of concomitant therapy in psoriasis patients not established

Mercaptopurine

Concomitant use does not appear to alter ustekinumab clearance or serum concentrations or affect safety or efficacy for Crohn's disease or ulcerative colitis

Methotrexate

Concomitant use does not appear to alter ustekinumab clearance or affect safety or efficacy for psoriatic arthritis

Concomitant use does not appear to alter ustekinumab clearance or serum concentrations or affect safety or efficacy for Crohn's disease or ulcerative colitis

NSAIAs

Concomitant use does not appear to alter ustekinumab clearance

Phototherapy

Increased risk of UV radiation-induced skin cancers in mice with IL-12/IL-23 or IL-12 deficiency; relevance to humans unknown

Safety of concomitant therapy not established

TNF blocking agents

Prior TNF blocker use does not appear to alter ustekinumab clearance

Warfarin

Possible effect on warfarin metabolism; because increased levels of cytokines during chronic inflammation may suppress formation of CYP isoenzymes, ustekinumab may normalize formation of CYP enzymes

Consider monitoring therapeutic effect of warfarin following initiation of ustekinumab; adjust dosage as needed

Ustekinumab Pharmacokinetics

Absorption

Bioavailability

In psoriasis patients, peak serum concentrations achieved in a median of 13.5 or 7 days following a single sub-Q dose of 45 or 90 mg, respectively. Steady-state concentrations achieved within 28 weeks with multiple-dose sub-Q administration. No apparent accumulation in serum over time when administered sub-Q every 12 weeks.

In patients with Crohn's disease or ulcerative colitis receiving recommended induction and maintenance dosages, steady-state concentrations achieved by start of second maintenance dose. No apparent accumulation in serum over time when maintenance doses administered sub-Q every 8 weeks.

Special Populations

Body weight: 90-mg dose in patients with psoriasis or psoriatic arthritis who weigh >100 kg results in median trough serum concentrations comparable to those achieved following 45-mg dose in patients weighing ≤100 kg. (See Dosage under Dosage and Administration.)

Distribution

Extent

Distributed into milk in lactating monkeys.

Special Populations

Geriatric patients: No apparent change in volume of distribution in psoriasis patients >65 years of age.

Elimination

Metabolism

Metabolic pathway not characterized.

Expected to be degraded into small peptides and amino acids via catabolic pathways in same manner as endogenous IgG.

Half-life

Psoriasis patients: Mean half-life of 14.9–45.6 days following sub-Q administration.

Patients with Crohn's disease or ulcerative colitis: Estimated median terminal half-life of approximately 19 days.

Special Populations

Geriatric patients: No apparent change in clearance in individuals >65 years of age.

Stability

Storage

Parenteral

Injection

2–8°C; do not freeze. Store in original carton to protect from light until administration. Store vials upright.

Injection Concentrate

2–8°C; do not freeze. Store in original carton to protect from light until administration. Store vials upright.

Diluted solution: ≤4 hours at room temperature (≤25°C) prior to administration.

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility

Compatible

Sodium chloride 0.9%

Actions

  • Binds with high affinity and specificity to the p40 subunit of both IL-12 and IL-23.

  • IL-12 and IL-23 are naturally occurring cytokines involved in inflammatory and immune responses, such as natural killer cell activation and CD4+ T-cell differentiation and activation.

  • IL-12 and IL-23 contribute to chronic inflammation associated with Crohn's disease and ulcerative colitis; in animal models of colitis, genetic absence or antibody blockade of the p40 subunit of IL-12 and IL-23 was protective.

  • Disrupts IL-12- and IL-23-mediated signaling and cytokine cascades by disrupting the interaction of these cytokines with a shared cell-surface receptor chain, IL-12 β1.

  • Produced using recombinant DNA technology and purified using standard bioprocessing technology.

Advice to Patients

  • Importance of instructing patients to read the manufacturer’s patient information (medication guide) prior to initiation of therapy and each time the prescription is refilled.

  • Importance of instructing patient and/or caregiver regarding proper dosage and administration of ustekinumab, including the use of aseptic technique, and proper disposal of needles and syringes if it is determined that the patient and/or caregiver is competent to safely administer the drug.

  • Importance of informing patients that ustekinumab may lower the ability of their immune system to fight infections. Importance of contacting clinicians if any signs or symptoms of infection develop.

  • Risk of malignancies while receiving ustekinumab.

  • Importance of advising patients to discontinue use of ustekinumab and seek immediate medical attention if they experience any symptoms of serious allergic reactions.

  • Importance of advising patients that the needle cover of the prefilled syringe contains dry natural rubber, which may cause allergic reactions in individuals sensitive to latex.

  • Importance of advising patients that ustekinumab can interfere with the usual response to immunizations and that they should avoid receiving live vaccines during ustekinumab therapy.

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses or any history of infection.

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed. Encourage women who have been exposed to ustekinumab during pregnancy to enroll in pregnancy registry at 877-311-8972.

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Ustekinumab

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Concentrate, for injection, for IV infusion

5 mg/mL

Stelara

Janssen Biotech

Injection, for subcutaneous use

45 mg/0.5 mL

Stelara (available as single-use prefilled syringes and single-use vials)

Janssen Biotech

90 mg/mL

Stelara (available as single-use prefilled syringes)

Janssen Biotech

AHFS DI Essentials™. © Copyright 2021, Selected Revisions August 17, 2020. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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