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
Brands: Stelara

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: 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 Ustekinumab

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

Psoriatic Arthritis

Used alone or in conjunction with methotrexate for the management of active psoriatic arthritis in adults.1 11 12 13

Ustekinumab Dosage and Administration

General

  • REMS for ustekinumab includes a voluntary, disease-specific patient registry (Psoriasis Longitudinal Assessment and Registry [PSOLAR]); for additional information, including instructions for patient enrollment, call 888-PSOLAR5 (888-776-5275) or access and search for PSOLAR.5 (See REMS.)

Concomitant Therapy

  • Used with or without methotrexate for management of psoriatic arthritis; corticosteroids and/or NSAIAs also may be continued.1 11 12

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, 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 after appropriate training.1

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

Psoriatic Arthritis
Sub-Q

45 mg at 0 and 4 weeks, then every 12 weeks.1

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

Contraindications

  • History of clinically important hypersensitivity to ustekinumab or any ingredient in the formulation.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, appendicitis, cholecystitis, sepsis) 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 (e.g., nonmelanoma skin cancer, prostate cancer, melanoma, colorectal cancer, breast cancer) reported in clinical studies.1 Incidence of malignancies other than nonmelanoma skin cancer similar to expected incidence in general US population.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

Rapid appearance of multiple cutaneous squamous cell carcinomas reported in patients with preexisting risk factors for nonmelanoma skin cancer.1 Monitor all patients receiving ustekinumab for nonmelanoma skin cancer.1 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.1

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

Sensitivity Reactions

Hypersensitivity Reactions

Hypersensitivity reactions (e.g., anaphylaxis, angioedema, rash, urticaria) reported.1

If anaphylactic or other clinically important hypersensitivity 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 patient who 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.)

Immunogenicity

Antibodies to ustekinumab detected, generally in low titers, in approximately 6% of patients; majority of these patients had neutralizing antibodies.1 No apparent association between antibody development and injection site reactions.1 No serious hypersensitivity reactions observed in these studies.1

Specific Populations

Pregnancy

Category B.1 Pregnancy registry at 877-311-8972.1

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

Patients with psoriasis: 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

Patients with psoriatic arthritis: Arthralgia,1 nausea,1 dental infections.1

Interactions for Ustekinumab

No formal drug interaction studies to date.1

Administered concomitantly with methotrexate, corticosteroids, and/or NSAIAs in clinical studies in psoriatic arthritis.1 11 12

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 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.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

Allergy immunotherapy

Possible decreased protective effect of allergy immunotherapy; possible increased risk of allergic reaction to dose of allergen immunotherapy1

Not evaluated; use with caution in patients who are receiving or have received allergy immunotherapy, particularly for anaphylaxis1

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

Corticosteroids, oral

Concomitant use does not appear to alter ustekinumab clearance1

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 in psoriasis patients not established1

Methotrexate

Concomitant use does not appear to alter ustekinumab clearance or safety or efficacy for psoriatic arthritis 1

NSAIAs

Concomitant use does not appear to alter ustekinumab clearance1

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

TNF blocking agents

Prior TNF blocker use does not appear to alter ustekinumab clearance1

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

Ustekinumab 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

90-mg dose in patients weighing >100 kg results in median trough serum concentrations comparable to those achieved following 45-mg dose in patients 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

  • 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.1

  • 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.1

  • 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 Encourage women who have been exposed to ustekinumab during pregnancy to enroll in pregnancy registry at 877-311-8972.1

  • 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

90 mg/mL

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

Janssen Biotech

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions May 22, 2014. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Janssen Biotech Inc. Stelara (ustekinumab) injection prescribing information. Horsham, PA; 2014 Mar.

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 2014 Mar 26.

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.

10. Smolen JS, Kay J, Doyle MK et al. Golimumab in patients with active rheumatoid arthritis after treatment with tumour necrosis factor alpha inhibitors (GO-AFTER study): a multicentre, randomised, double-blind, placebo-controlled, phase III trial. Lancet. 2009; 374:210-21. [PubMed 19560810]

11. McInnes IB, Kavanaugh A, Gottlieb AB et al. Efficacy and safety of ustekinumab in patients with active psoriatic arthritis: 1 year results of the phase 3, multicentre, double-blind, placebo-controlled PSUMMIT 1 trial. Lancet. 2013; 382:780-9. [PubMed 23769296]

12. Ritchlin C, Rahman P, Kavanaugh A et al. Efficacy and safety of the anti-IL-12/23 p40 monoclonal antibody, ustekinumab, in patients with active psoriatic arthritis despite conventional non-biological and biological anti-tumour necrosis factor therapy: 6-month and 1-year results of the phase 3, multicentre, double-blind, placebo-controlled, randomised PSUMMIT 2 trial. Ann Rheum Dis. 2014; :. [PubMed 24482301]

13. Kavanaugh A, Ritchlin C, Rahman P et al. Ustekinumab, an anti-IL-12/23 p40 monoclonal antibody, inhibits radiographic progression in patients with active psoriatic arthritis: results of an integrated analysis of radiographic data from the phase 3, multicentre, randomised, double-blind, placebo-controlled PSUMMIT-1 and PSUMMIT-2 trials. Ann Rheum Dis. 2014; :. [PubMed 24553909]

Hide
(web1)