Generic Name: Ustekinumab
Class: Skin and Mucous Membrane Agents, Miscellaneous
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

Warning(s)

REMS:

FDA approved a REMS for ustekinumab to ensure that the benefits of a drug outweigh the risks. The REMS may apply to one or more preparations of ustekinumab and consists of the following: medication guide and communication plan. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

Immunosuppressive agent; 1 a human IgG1 kappa monoclonal antibody directed against the p40 subunit of interleukin-12 (IL-12) and interleukin-23 (IL-23).1 2 3 4

Uses for Stelara

Plaque Psoriasis

Management of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy.1 2 3 4

Slideshow: Psoriasis: Treatment Options to Manage Your Symptoms

Stelara Dosage and Administration

General

REMS Program

  • FDA has approved a Risk Evaluation and Mitigation Strategy (REMS) for ustekinumab.5

  • The program consists of a medication guide that must be provided to patients and a communication plan that includes initial and/or periodic communications targeting selected groups of clinicians.5

  • The goals are to evaluate and mitigate potential risks of serious infections, malignancy, and reversible posterior leukoencephalopathy syndrome (RPLS) by warning patients and health care providers about these risks and informing health care providers about the Psoriasis Longitudinal Assessment and Registry (PSOLAR), a voluntary, disease-specific patient registry (see Warnings/Precautions under Cautions).5

  • For additional information on PSOLAR, including instructions for patient enrollment, call 888-PSOLAR5 (888-776-5275) or access and search for PSOLAR.5

Administration

Sub-Q Administration

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.1 Do not make injections into areas where the skin is tender, bruised, erythematous, or indurated.1 Use a 27-gauge, ½-inch needle to administer the drug.1

Do not shake the injection.1

Injection contains no preservative; discard any unused portion.1

Intended for use under the supervision of a clinician; should only be administered by a health care provider (i.e., self-administration is not recommended).1 9 Administer only to patients who will be closely monitored and have regular follow-up visits with a clinician.1

Dosage

Adults

Plaque Psoriasis
Sub-Q

Adults weighing ≤100 kg: 45 mg at 0 and 4 weeks, then every 12 weeks.1

Adults weighing >100 kg: 90 mg at 0 and 4 weeks, then every 12 weeks.1 Although 45-mg doses were effective in these patients in clinical studies, 90-mg doses were more effective.1

Prescribing Limits

Adults

Psoriasis
Sub-Q

Safety and efficacy not evaluated beyond 2 years.1

Special Populations

Hepatic Impairment

Manufacturer makes no specific dosage recommendations.1

Renal Impairment

Manufacturer makes no specific dosage recommendations.1

Geriatric Patients

Manufacturer makes no specific dosage recommendations.1

Cautions for Stelara

Contraindications

  • Manufacturer states none known.1

Warnings/Precautions

Infectious Complications

May increase risk of infection, including reactivation of latent infections.1 Serious bacterial, fungal, and viral infections observed.1 Serious infections requiring hospitalization (e.g., cellulitis, diverticulitis, osteomyelitis, viral infections, gastroenteritis, pneumonia, urinary tract infections) reported.1

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.1 Not known whether patients with ustekinumab-induced blockade of IL-12/IL-23 are susceptible to these infections.1 Consider appropriate diagnostic testing for these infections (e.g., tissue culture, stool culture) as dictated by clinical circumstances.1

Do not use ustekinumab in patients with any clinically important active infection and do not administer until the infection resolves or is adequately treated.1 If a serious infection develops, discontinue ustekinumab until infection resolves.1 Exercise caution when considering use of ustekinumab in patients with chronic infection or history of recurrent infection.1

Evaluate patients for active or latent tuberculosis prior to initiation of ustekinumab.1 Do not administer to patients with active tuberculosis.1 When indicated, initiate appropriate antimycobacterial regimen for treatment of latent tuberculosis prior to ustekinumab therapy.1 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.1 Closely monitor patients for active tuberculosis during and after treatment.1

Malignancies

May increase risk of malignancy.1

Malignancies reported in clinical studies;1 serious malignancies included breast, colon, head and neck, kidney, prostate, and thyroid cancers.1

Inhibition of the p40 subunit of IL-12/IL-23 increased the risk of malignancy in animals.1 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.1 Relevance of these data to risk of malignancy in humans unknown.1

Safety of ustekinumab not evaluated in patients with history of malignancy or with known malignancy.1

Sensitivity Reactions

Hypersensitivity Reactions

Serious allergic reactions (e.g., angioedema, dyspnea, hypotension, possible anaphylaxis) and hypersensitivity reactions (e.g., rash, urticaria) reported.1

If anaphylactic or other serious allergic reaction occurs, discontinue ustekinumab and institute appropriate therapy.1

Latex Sensitivity

The needle cover of the prefilled syringe contains dry natural rubber and should not be handled by individuals sensitive to latex.1

Reversible Posterior Leukoencephalopathy Syndrome

Reversible posterior leukoencephalopathy syndrome (RPLS), a neurologic syndrome characterized by reversible vasogenic subcortical edema,7 observed in 1 of 3523 ustekinumab-treated patients during premarketing studies.1 Patient received 12 doses of ustekinumab over approximately 2 years and presented with headache, seizures, and confusion.1 Drug was discontinued and patient fully recovered with appropriate treatment.1

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.1 7 Manifestations include visual and neurologic disturbances (e.g., headache, seizures, confusion, encephalopathy, blindness).1 7 Magnetic resonance imaging (MRI) is used to confirm diagnosis of RPLS.7

If RPLS suspected, discontinue ustekinumab and institute appropriate treatment.1

Immunization

Administer all age-appropriate vaccines prior to initiation of ustekinumab therapy.1

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

Theoretical Risk of Immunotherapy

Ustekinumab not evaluated in patients who have undergone allergy immunotherapy.1

Ustekinumab may decrease protective effect of allergy immunotherapy and may increase risk of an allergic reaction to a dose of allergen immunotherapy.1

Exercise caution in patients who are receiving or who have received allergy immunotherapy, particularly for anaphylaxis.1

Immunogenicity

Testing for antibodies to ustekinumab was positive in 3–5%, negative in 8–47%, and inconclusive in 48–90% of patients in clinical studies.1 Presence of ustekinumab in serum may interfere with assay and produce inconclusive results; ustekinumab may have been present in serum when testing was performed.1

Specific Populations

Pregnancy

Category B.1

Lactation

Distributed into milk in lactating monkeys.1 Since IgG distributes into human milk, ustekinumab is expected to distribute into human milk.1 Not known whether ustekinumab is absorbed systemically following ingestion; however, published data suggest that antibodies in breast milk do not enter the neonatal and infant circulation in substantial amounts.1

Caution if used in nursing women.1 Weigh unknown risks to infant (from GI or systemic exposure to ustekinumab) against known benefits of breast-feeding.1

Pediatric Use

Safety and efficacy not established in children <18 years of age.1

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.1

Common Adverse Effects

Nasopharyngitis,1 upper respiratory tract infection,1 headache,1 fatigue,1 diarrhea,1 back pain,1 dizziness,1 pharyngolaryngeal pain,1 pruritus,1 injection site erythema,1 myalgia,1 depression.1

Interactions for Stelara

No formal drug interaction studies to date.1

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.1 6 A role for IL-12 or IL-23 in regulation of CYP enzymes not reported.1

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.1

Vaccines

Avoid live vaccines.1

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.1

Inactive vaccines administered during ustekinumab therapy may not elicit an immune response sufficient to prevent disease.1

Specific Drugs and Therapies

Drug or Therapy

Interaction

Comments

BCG vaccine

Individuals with genetic IL-12/IL-23 deficiency are vulnerable to disseminated infections caused by BCG vaccine1

Do not administer BCG vaccine during, for 1 year before, or for 1 year after ustekinumab therapy1

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 enzymes1 6

Consider monitoring cyclosporine concentrations following initiation of ustekinumab; adjust dosage as needed1

Immunosuppressive agents

Safety of concomitant therapy not established1

Phototherapy

Increased risk of UV radiation-induced skin cancers in mice with IL-12/IL-23 or IL-12 deficiency; relevance to humans unknown1

Safety of concomitant therapy not established1

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 enzymes1 6

Consider monitoring therapeutic effect of warfarin following initiation of ustekinumab; adjust dosage as needed1

Stelara Pharmacokinetics

Absorption

Bioavailability

Peak serum concentrations achieved in a median of 13.5 or 7 days following sub-Q administration of a single 45- or 90-mg dose, respectively, in patients with psoriasis.1

Steady-state concentrations achieved within 28 weeks with multiple-dose sub-Q administration.1

No apparent accumulation in serum over time when administered sub-Q every 12 weeks.1

Special Populations

When the same dose was administered regardless of body weight, patients weighing >100 kg had lower median serum ustekinumab concentrations compared with those weighing ≤100 kg.1 (See Dosage under Dosage and Administration.)

Distribution

Extent

Distributed into milk in lactating monkeys.1 Because IgG distributes into human milk, ustekinumab is expected to distribute into human milk.1

Special Populations

No apparent change in volume of distribution in individuals >65 years of age.1

Elimination

Metabolism

Metabolic pathway not characterized.1

Expected to be degraded into small peptides and amino acids via catabolic pathways in same manner as endogenous IgG.1

Half-life

Mean half-life: 14.9–45.6 days following IV and sub-Q administration in patients with psoriasis.1

Special Populations

No apparent change in clearance in individuals >65 years of age.1

Pharmacokinetic data in patients with renal or hepatic impairment not available.1

Stability

Storage

Parenteral

Injection

2–8°C; do not freeze.1 Store in original carton to protect from light until administration.1 Store vials upright.1 Discard any unused portion.1

Actions

  • Binds with high affinity and specificity to the p40 subunit of both IL-12 and IL-23.1 2 3

  • 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.1 2 4

  • 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 β1.1 2

  • Produced using recombinant DNA technology and purified using standard bioprocessing technology.1

Advice to Patients

  • A copy of the manufacturer’s patient information (medication guide) for ustekinumab must be provided to all patients with each prescription of the drug.5 Importance of instructing patients to read the medication guide prior to initiation of therapy and each time the prescription is refilled.1 (See REMS Program under Dosage and Administration.)

  • Importance of informing patients that ustekinumab may lower the ability of their immune system to fight infections.1 Importance of contacting clinicians if any signs or symptoms of infection develop.1

  • Risk of malignancies while receiving ustekinumab.1

  • Importance of advising patients to seek immediate medical attention if they experience any symptoms of serious allergic reactions.1

  • Importance of alerting clinician if allergy to latex exists.1

  • 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.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

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

Ustekinumab

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, for subcutaneous use

45 mg/0.5 mL

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

Janssen Biotech, (formerly Centocor Ortho Biotech)

90 mg/mL

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

Janssen Biotech, (formerly Centocor Ortho Biotech)

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions October 27, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Centocor Ortho Biotech Inc. Stelara (ustekinumab) injection prescribing information. Horsham, PA; 2010 Oct.

2. Leonardi CL, Kimball AB, Papp KA et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet. 2008; 371:1665-74. [PubMed 18486739]

3. Papp KA, Langley RG, Lebwohl M et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2). Lancet. 2008; 371:1675-84. [PubMed 18486740]

4. Griffiths CE, Strober BE, van de Kerkhof P et al. Comparison of ustekinumab and etanercept for moderate-to-severe psoriasis. N Engl J Med. 2010; 362:118-28. [PubMed 20071701]

5. Stelara (ustekinumab) risk evaluation and mitigation strategy (REMS). From FDA website (). Accessed 2011 Feb 14.

6. Centocor Ortho Biotech Inc. Simponi (golimumab) injection prescribing information. Horsham, PA; 2011 Mar.

7. Lee VH, Wijdicks EF, Manno EM et al. Clinical spectrum of reversible posterior leukoencephalopathy syndrome. Arch Neurol. 2008; 65:205-10. [PubMed 18268188]

8. Lebwohl M, Yeilding N, Szapary P et al. Impact of weight on the efficacy and safety of ustekinumab in patients with moderate to severe psoriasis: rationale for dosing recommendations. J Am Acad Dermatol. 2010; 63:571-9. [PubMed 20599293]

9. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number: 12561: Medical review(s) for ustekinumab. From FDA website (). Accessed 2011 Mar 31.

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