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Ustekinumab

Pronunciation

(yoo stek in YOO mab)

Index Terms

  • CNTO 1275

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Prefilled Syringe, Subcutaneous [preservative free]:

Stelara: 45 mg/0.5 mL (0.5 mL); 90 mg/mL (1 mL) [contains polysorbate 80]

Brand Names: U.S.

  • Stelara

Pharmacologic Category

  • Antipsoriatic Agent
  • Interleukin-12 Inhibitor
  • Interleukin-23 Inhibitor
  • Monoclonal Antibody

Pharmacology

Ustekinumab is a human monoclonal antibody that binds to and interferes with the proinflammatory cytokines, interleukin (IL)-12 and IL-23. Biological effects of IL-12 and IL-23 include natural killer (NK) cell activation, CD4+ T-cell differentiation and activation. Ustekinumab also interferes with the expression of monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-α), interferon-inducible protein-10 (IP-10), and interleukin-8 (IL-8). Significant clinical improvement in psoriasis and psoriatic arthritis patients is seen in association with reduction of these proinflammatory signalers.

Distribution

Vd (terminal elimination phase): 45 mg: 0.161 ± 0.065 L/kg; 90 mg: 0.179 ± 0.085 L/kg

Time to Peak

Plasma: 45 mg: 13.5 days; 90 mg: 7 days

Half-Life Elimination

10-126 days

Special Populations Note

Weight

When given the same dose, subjects weighing >100 kg had lower median serum concentrations compared with those subjects weighing ≤100 kg. The median trough serum concentrations of ustekinumab in subjects >100 kg in the 90 mg group were comparable with those in subjects ≤100 kg in the 45 mg group.

Use: Labeled Indications

Plaque psoriasis:

US labeling: Treatment of moderate to severe plaque psoriasis in adults who are candidates for phototherapy or systemic therapy

Canadian labeling:

Treatment of chronic moderate to severe plaque psoriasis in pediatric patients 12 to 17 years of age, who are inadequately controlled by, or are intolerant to, other systemic therapy or phototherapy

Treatment of chronic moderate to severe plaque psoriasis in adults who are candidates for phototherapy or systemic therapy

Psoriatic arthritis: Treatment of active psoriatic arthritis (as monotherapy or in combination with methotrexate) in adults

Contraindications

Clinically significant hypersensitivity to ustekinumab or any component of the formulation

Canadian labeling: Additional contraindications (not in U.S. labeling): Severe infections such as sepsis, tuberculosis, and opportunistic infections

Dosing: Adult

Plaque psoriasis: SubQ:

Initial and maintenance: Note: Following an interruption in therapy, re-treatment may be initiated at the initial dosing interval. Consider therapy discontinuation in any patient failing to demonstrate a response after 12 weeks of therapy. The Canadian labeling suggests that if the response is inadequate on every-12-week therapy, may consider increasing frequency to every 8 weeks.

≤100 kg: 45 mg at 0 and 4 weeks, and then every 12 weeks thereafter

>100 kg: 90 mg at 0 and 4 weeks, and then every 12 weeks thereafter. Note: Doses of 45 mg given to patients >100 kg were also efficacious; however, 90 mg is the recommended dose in these patients due to greater efficacy.

Psoriatic arthritis: SubQ: Note: When used for psoriatic arthritis, may be administered alone or in combination with methotrexate.

U.S. labeling:

Initial and maintenance: 45 mg at 0 and 4 weeks, and then every 12 weeks thereafter.

Coexistent psoriatic arthritis and moderate to severe plaque psoriasis in patients >100 kg: Initial and maintenance: 90 mg at 0 and 4 weeks, and then every 12 weeks thereafter.

Canadian labeling: Initial and maintenance:

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

>100 kg: 90 mg at 0 and 4 weeks, and then every 12 weeks thereafter.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Canadian labeling: Plaque psoriasis: Children ≥12 years and Adolescents: SubQ:

<60 kg: 0.75 mg/kg at 0 and 4 weeks, and then every 12 weeks thereafter (manufacturer recommends obtaining dose from vial). Dose may be calculated as follows: body weight (kg) x 0.0083 mL/kg

≥60 kg to ≤100 kg: 45 mg at 0 and 4 weeks, and then every 12 weeks thereafter

>100 kg: 90 mg at 0 and 4 weeks, and then every 12 weeks thereafter

Note: Consider therapy discontinuation in any patient failing to demonstrate a response after 12 weeks of therapy

Dosing: Renal Impairment

There are no dosage adjustment provided in the manufacturer’s labeling (has not been studied).

Dosing: Hepatic Impairment

There are no dosage adjustment provided in the manufacturer’s labeling (has not been studied).

Administration

Administer by subcutaneous injection into the top of the thigh, abdomen, upper arms, or buttocks. Rotate sites. Do not inject into tender, bruised, erythematous, or indurated skin. Avoid areas of skin where psoriasis is present. Discard any unused portion. Intended for use under supervision of physician; self-injection may occur after proper training.

Storage

Refrigerate at 2°C to 8°C (36°F to 46°F); do not freeze. Store vials upright. Keep the product in the original carton to protect from light until the time of use. Do not shake. Discard any unused portion.

Drug Interactions

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Belimumab: Monoclonal Antibodies may enhance the adverse/toxic effect of Belimumab. Avoid combination

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

InFLIXimab: Ustekinumab may enhance the immunosuppressive effect of InFLIXimab. Avoid combination

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Avoid combination

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination

Adverse Reactions

>10%: Infection: Infection (27% to 70%; severe infection: ≤3%)

1% to 10%:

Central nervous system: Headache (5%), fatigue (3%), dizziness (2%), depression (1%)

Dermatologic: Pruritus (2%)

Gastrointestinal: Nausea (3%)

Immunologic: Antibody development (3% to 6%)

Local: Erythema at injection site (1% to 2%)

Neuromuscular & skeletal: Arthralgia (3%), back pain (2%)

Respiratory: Pharyngolaryngeal pain (2%)

<1%, postmarketing, and/or case reports (Limited to important or life-threatening): Anaphylaxis, angina pectoris, angioedema, appendicitis, bacterial infection, bleeding at injection site, bruising at injection site, cellulitis, cerebrovascular accident, cholecystitis, dactylitis, diverticulitis, erythrodermic psoriasis, exfoliative dermatitis, fungal infection, gastroenteritis, herpes zoster, hypersensitivity reaction, hypertension, induration at injection site, irritation at injection site, itching at injection site, malignant melanoma (in situ), malignant neoplasm (breast, colon, head and neck, kidney, prostate, thyroid), myocardial infarction, nephrolithiasis, osteomyelitis, pain at injection site, pneumonia, pustular psoriasis, reversible posterior leukoencephalopathy syndrome, sepsis, squamous cell carcinoma of skin, swelling at injection site, urinary tract infection, viral infection

Warnings/Precautions

Concerns related to adverse effects:

• Antibody formation: Antibody formation to ustekinumab has been observed with therapy and has been associated with decreased serum levels and therapeutic response in some patients.

• Hypersensitivity reactions: Hypersensitivity, including anaphylaxis and angioedema, has been reported. Discontinue immediately with signs/symptoms of hypersensitivity reaction and treat appropriately as indicated.

• Infections: May increase the risk for infections or reactivation of latent infections. Serious bacterial, fungal, and viral infections have been observed with use. Avoid use in patients with clinically important active infection. Exercise caution when considering use in patients with a history of new/recurrent infections, with conditions that predispose them to infections (eg, diabetes or residence/travel from areas of endemic mycoses), with chronic, latent, or localized infections, or who are genetically deficient in IL-12/IL-23 (IL-12/IL-23 genetic deficiency may predispose patients to disseminated infection). Patients who develop a new infection while undergoing treatment should be monitored closely. If a patient develops a serious infection, therapy should be discontinued or withheld until successful resolution of infection.

• Malignancy: May increase the risk for malignancy although the impact on the development and course of malignancies is not fully defined. Rapidly appearing cutaneous squamous cell carcinomas (multiple) have been reported in patients receiving ustekinumab who were at risk for developing nonmelanoma skin cancer. Monitor all patients closely for the development of nonmelanoma skin cancer; closely follow patients >60 years of age, with a history of prolonged immunosuppression, and in patients with a history of PUVA treatment. Use with caution in patients with prior malignancy (use not studied in this population).

• Neurotoxicity: Reversible posterior leukoencephalopathy syndrome (RPLS) has been observed (rare). RPLS symptoms include headache, seizures, confusion, and visual disturbances; may be fatal. Monitor; discontinue ustekinumab if symptoms occur and administer appropriate therapy.

• Tuberculosis: Do not use in patients with active tuberculosis (TB). Patients should be evaluated for latent tuberculosis infection with a tuberculin skin test prior to starting therapy. Treatment of latent TB should be initiated before ustekinumab therapy is used. Consider antituberculosis treatment in patients with a history of latent or active tuberculosis if an adequate prior treatment course cannot be confirmed. During and following treatment, monitor for signs/symptoms of active TB.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

• Immunosuppressive therapy: Use in combination with other immunosuppressive drugs during psoriasis studies has not been evaluated; use caution. Use in combination with methotrexate during psoriatic arthritis studies did not appear to affect safety or efficacy.

Special populations:

• Patients >100 kg: May require higher dose to achieve adequate serum levels.

Dosage form specific issues:

• Latex: Packaging may contain natural latex rubber.

• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson, 2002; Lucente 2000; Shelley, 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade, 1986; CDC, 1984). See manufacturer’s labeling.

Other warnings/precautions:

• Immunizations: Patients should be brought up to date with all immunizations before initiating therapy. Live vaccines should not be given concurrently; inactivated or nonlive vaccines may be given concurrently, but may not elicit a proper immune response. BCG vaccines should not be given 1 year prior to, during, or 1 year following treatment.

• Phototherapy: Use in combination with phototherapy has not been studied; use caution.

Monitoring Parameters

Tuberculosis screening (prior to initiating and periodically during therapy); CBC; ustekinumab-antibody formation; monitor for signs/symptoms of infection, reversible posterior leukoencephalopathy syndrome (RPLS), and squamous cell skin carcinoma

Pregnancy Risk Factor

B

Pregnancy Considerations

Adverse events were not observed in animal reproduction studies. There is limited information related to the use of ustekinumab in pregnancy (Andrulonis, 2012). In general, other agents are preferred for the treatment of plaque psoriasis in pregnant women (Hsu, 2012). Patients exposed to ustekinumab during pregnancy are encouraged to enroll in the pregnancy registry by calling 877-311-8972.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience rhinitis, rhinorrhea, pharyngitis, or sternutation. Have patient report immediately to prescriber signs of infection, significant headache, illogical thinking, severe dizziness, syncope, considerable asthenia, vision changes, mole changes, skin growths, or injection site pain or irritation (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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