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  • CLASSES

    Antipsoriatic Monoclonal Antibodies and Others
    Interleukin-23 (IL-23) Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    Interleukin (IL)-12 and IL-23 antagonist; given intravenously and subcutaneously
    Used for moderate to severe plaque psoriasis in adult and pediatric patients 6 years and older, and for active psoriatic arthritis (PsA) in adults, and for adults with moderate to severely active Crohn's disease or ulcerative colitis
    As with other interleukin inhibitors, may increase risk of infection

    COMMON BRAND NAMES

    Stelara

    HOW SUPPLIED

    Stelara Intravenous Inj Sol: 1mL, 5mg
    Stelara Subcutaneous Inj Sol: 0.5mL, 1mL, 45mg, 90mg

    DOSAGE & INDICATIONS

    For the treatment of moderate to severe plaque psoriasis in those patients who are candidates for phototherapy or systemic therapy.
    Subcutaneous dosage
    Adults weighing more than 100 kg

    90 mg subcutaneously; repeat dose 4 weeks later. Then, give 90 mg subcutaneously every 12 weeks starting at week 16. A lower dose of 45 mg may be considered; however, greater efficacy is seen with a 90 mg dose. The British Association of Dermatologist guidelines suggest a maintenance dose of 90 mg subcutaneously every 8 weeks when an inadequate primary response may be due to insufficient drug exposure (e.g., known subtherapeutic drug concentrations, obese patients, relapse during treatment); however, the guidelines warn that consideration should be given to an increased risk for infection and adverse reactions.

    Adults weighing 100 kg or less

    45 mg subcutaneously; repeat dose 4 weeks later. Then, give 45 mg subcutaneously every 12 weeks starting at week 16. The British Association of Dermatologist guidelines suggest a maintenance dose of 90 mg subcutaneously every 8 to 12 weeks when an inadequate primary response may be due to insufficient drug exposure (e.g., known subtherapeutic drug concentrations, relapse during treatment); however, the guidelines warn that consideration should be given to an increased risk for infection and adverse reactions.

    Children and Adolescents 6 to 17 years weighing more than 100 kg

    90 mg subcutaneously; repeat dose 4 weeks later. Then, give 90 mg subcutaneously every 12 weeks starting at week 16.

    Children and Adolescents 6 to 17 years weighing 60 to 100 kg

    45 mg subcutaneously; repeat dose 4 weeks later. Then, give 45 mg subcutaneously every 12 weeks starting at week 16.

    Children and Adolescents 6 to 17 years weighing less than 60 kg

    0.75 mg/kg/dose subcutaneously; repeat dose 4 weeks later. Then, give 0.75 mg/kg/dose subcutaneously every 12 weeks starting at week 16.

    For the treatment of active psoriatic arthritis with or without methotrexate.
    Subcutaneous dosage
    Adults

    The recommended dose for most patients is 45 mg subcutaneously initially and a repeat dose 4 weeks later, followed by 45 mg subcutaneously every 12 weeks.

    Adults weighing more than 100 kg who have co-existent moderate-to-severe plaque psoriasis

    90 mg subcutaneously initially; repeat dose 4 weeks later, then follow with 90 mg subcutaneously every 12 weeks.

    For the treatment of moderately to severely active Crohn's disease.
    For the induction treatment of Crohn's disease.
    Intravenous dosage
    Adults weighing more than 85 kg

    520 mg IV infusion as a single dose. Begin the subcutaneous maintenance regimen 8 weeks after this initial intravenous dose. The American College of Gastroenterology strongly recommends ustekinumab be given for moderate-to-severe Crohn's disease patients who failed previous treatment with corticosteroids, thiopurines, methotrexate, or TNF-blockers or in those patients who have had no prior exposure to TNF-blockers.

    Adults weighing 56 kg to 85 kg

    390 mg IV infusion as a single dose. Begin the subcutaneous maintenance regimen 8 weeks after this initial intravenous dose. The American College of Gastroenterology strongly recommends ustekinumab be given for moderate-to-severe Crohn's disease patients who failed previous treatment with corticosteroids, thiopurines, methotrexate, or TNF-blockers or in those patients who have had no prior exposure to TNF-blockers.

    Adults weighing 55 kg or less

    260 mg IV infusion as a single dose. Begin the subcutaneous maintenance regimen 8 weeks after this initial intravenous dose. The American College of Gastroenterology strongly recommends ustekinumab be given for moderate-to-severe Crohn's disease patients who failed previous treatment with corticosteroids, thiopurines, methotrexate, or TNF-blockers or in those patients who have had no prior exposure to TNF-blockers.

    For the maintenance treatment of Crohn's disease.
    Subcutaneous dosage
    Adults

    90 mg subcutaneously starting 8 weeks after the initial intravenous induction dose, followed by 90 mg subcutaneously every 8 weeks thereafter. Guidelines support the use of ustekinumab for maintenance of remission in patients with a ustekinumab-induced induction response.

    For the treatment of moderately to severely active ulcerative colitis.
    For the induction treatment of ulcerative colitis.
    Intravenous dosage
    Adults weighing more than 85 kg

    520 mg IV infusion as a single dose. Begin the subcutaneous maintenance regimen 8 weeks after this initial intravenous dose. Guidelines strongly recommend the use of ustekinumab for the induction of remission in patients with moderately to severely active UC.[64393]

    Adults weighing 56 kg to 85 kg

    390 mg IV infusion as a single dose. Begin the subcutaneous maintenance regimen 8 weeks after this initial intravenous dose. Guidelines strongly recommend the use of ustekinumab for the induction of remission in patients with moderately to severely active UC.[64393]

    Adults weighing 55 kg or less

    260 mg IV infusion as a single dose. Begin the subcutaneous maintenance regimen 8 weeks after this initial intravenous dose. Guidelines strongly recommend the use of ustekinumab for the induction of remission in patients with moderately to severely active UC.[64393] 

    For the maintenance treatment of ulcerative colitis.
    Subcutaneous dosage
    Adults

    90 mg subcutaneously starting 8 weeks after the initial intravenous induction dose, followed by 90 mg subcutaneously every 8 weeks thereafter. Guidelines strongly recommend the use of ustekinumab for the maintenance of remission in patients with moderately to severely active UC who responded to induction.[64393]

    MAXIMUM DOSAGE

    Adults

    Psoriasis and Psoriatic Arthritis
    Weighing more than 100 kg: 90 mg/dose subcutaneously for plaque psoriasis +/- psoriatic arthritis and 45 mg/dose subcutaneously for psoriatic arthritis alone; maintenance therapy every 12 weeks.
    Weighing 100 kg or less: 45 mg/dose subcutaneously; maintenance therapy every 12 weeks.
     
    Crohn's Disease and Ulcerative Colitis
    Weighing more than 85 kg: 520 mg single dose IV and 90 mg/dose subcutaneously every 8 weeks.
    Weighing 56 to 85 kg: 390 mg single dose IV and 90 mg/dose subcutaneously every 8 weeks.
    Weighing 55 kg or less: 260 mg single dose IV and 90 mg/dose subcutaneously every 8 weeks.

    Geriatric

    Psoriasis and Psoriatic Arthritis
    Weighing more than 100 kg: 90 mg/dose subcutaneously for plaque psoriasis +/- psoriatic arthritis and 45 mg/dose subcutaneously for psoriatic arthritis alone; maintenance therapy every 12 weeks.
    Weighing 100 kg or less: 45 mg/dose subcutaneously; maintenance therapy every 12 weeks.
     
    Crohn's Disease and Ulcerative Colitis
    Weighing more than 85 kg: 520 mg single dose IV and 90 mg/dose subcutaneously every 8 weeks.
    Weighing 56 to 85 kg: 390 mg single dose IV and 90 mg/dose subcutaneously every 8 weeks.
    Weighing 55 kg or less: 260 mg single dose IV and 90 mg/dose subcutaneously every 8 weeks.

    Adolescents

    Weighing more than 100 kg: 90 mg/dose subcutaneously for plaque psoriasis; maintenance therapy every 12 weeks.
    Weighing 60 to 100 kg: 45 mg/dose subcutaneously for plaque psoriasis; maintenance therapy every 12 weeks.
    Weighing less than 60 kg: 0.75 mg/kg/dose subcutaneously for plaque psoriasis; maintenance therapy every 12 weeks.

    Children

    6 to 12 years weighing more than 100 kg: 90 mg/dose subcutaneously for plaque psoriasis; maintenance therapy every 12 weeks.
    6 to 12 years weighing 60 to 100 kg: 45 mg/dose subcutaneously for plaque psoriasis; maintenance therapy every 12 weeks.
    6 to 12 years weighing less than 60 kg: 0.75 mg/kg/dose subcutaneously for plaque psoriasis; maintenance therapy every 12 weeks.
    1 to 5 years: Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Injectable Administration

    Do not shake the prefilled syringe or vial, as irreparable damage to ustekinumab may occur.
    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. The solution should be colorless to slightly yellow and may contain a few small translucent or white particles. Do not use if discolored, cloudy, or if foreign particulate matter is present.

    Intravenous Administration

    Intravenous infusion preparation
    Ustekinumab is administered as an IV infusion only for the induction treatment of Crohn's disease or ulcerative colitis.
    Each vial is for single use only.
    Calculate the dose and the number of ustekinumab vials needed based on patient weight; each 26 mL vial contains 130 mg of ustekinumab.
    The ustekinumab solution must be further diluted prior to infusion.
    Withdraw and discard a volume of the 0.9% Sodium Chloride Injection from a 250 mL infusion bag equal to the volume of ustekinumab to be added (e.g., discard 26 mL sodium chloride solution from the bag for each vial of ustekinumab needed, for 2 vials- discard 52 mL, for 3 vials- discard 78 mL, 4 vials- discard 104 mL). Alternatively, a 250 mL infusion bag containing 0.45% Sodium Chloride Injection, USP may be used.
    Withdraw 26 mL of ustekinumab from each vial needed and add it to the 250 mL infusion bag. The final volume in the infusion bag should be 250 mL.
    Gently mix. Do not shake.
    Storage: If necessary, the diluted infusion solution may be kept at room temperature up to 25 degrees C (77 degrees F) for up to 7 hours. Storage time at room temperature begins once the diluted solution has been prepared. The infusion should be completed within 8 hours after the dilution in the infusion bag (cumulative time after preparation including the storage and the infusion period). Do not freeze. Discard any unused portion of the infusion solution.
     
    Intravenous Infusion administration
    Infuse the diluted usetkinumab infusion solution over a period of at least 1 hour. Once diluted, the infusion should be completely administered within 8 hours of the dilution in the infusion bag.
    Use only an infusion set with an in-line, sterile, non-pyrogenic, low protein-binding filter (pore size 0.2 micron).
    Do not infuse concomitantly in the same intravenous line with other agents.

    Subcutaneous Administration

    Only an individual trained in subcutaneous drug delivery should administer the injection.
    An adult who is properly trained in injection technique may self-inject using the prefilled syringe or vial, if the prescriber deems the action appropriate. However, the first injection needs to be under the supervision of a qualified healthcare professional.
    For pediatric patients, it is recommended that doses be administered by a health care professional.
    Injection sites include the front part of the middle thigh, the gluteal or abdominal region, and the outer area of the upper arm. Do not administer where skin is tender, bruised, red, or indurated.
    Rotate injection sites. If a second injection is needed because two 45 mg vials or prefilled syringes are used for a 90 mg dose, repeat the injection process with new materials, and use a different injection site.
    For the vial, use a 1 mL syringe with a 27-gauge, 0.5-inch needle to withdraw the dose.
    Gently pinch the cleaned area of skin and insert the needle at about a 45-degree angle subcutaneously using a quick, dart-like motion. Push the plunger slowly and evenly to deliver the dose, remove the needle, and release the pinched skin. Do not rub the injection site; slight bleeding may occur.
    For the prefilled syringe, hold the syringe body and pull off the needle cover. The needle cover of the prefilled syringe contains latex. Persons allergic to natural rubber or latex should not handle the cover of the prefilled syringe.
    Gently pinch the cleaned area of skin and insert the needle at about a 45-degree angle subcutaneously using a quick, dart-like motion. Push the plunger in as far as it can go to deliver the dose, remove the needle while maintaining pressure on the plunger head, and release the pinched skin.
    Do not rub the injection site; slight bleeding may occur. The needle safety guard will be activated once the pressure on the plunger head is released; do not touch the needle guard activation clips to prevent premature activation of the needle safety guard.
    Each single-use vial or single-use prefilled syringe contains 45 mg/0.5 mL or 90 mg/mL of ustekinumab. No preservatives are present; discard any unused portion.
    Storage: Store unopened vials and prefilled syringes in the refrigerator between 2 to 8 degrees C (36 to 46 degrees F). Do not freeze or shake. If needed, individual prefilled syringes may be stored at room temperature up to 30 degrees C (86 degrees F) for a maximum single period of up to 30 days; keep in the original carton to protect from light. Once a syringe is stored at room temperature, do not return to the refrigerator. Discard the syringe if not used within 30 days at room temperature storage.

    STORAGE

    Stelara :
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Do not freeze
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)
    - Store in original package until time of use
    - Store upright

    CONTRAINDICATIONS / PRECAUTIONS

    History of angioedema, latex hypersensitivity, serious hypersensitivity reactions or anaphylaxis

    Ustekinumab is contraindicated for use by patients with a clinically significant hypersensitivity to ustekinumab or to any of its excipients, including a history of angioedema to the drug. Serious hypersensitivity reactions or anaphylaxis have been reported. Patients with a latex hypersensitivity should not handle the needle cover of the prefilled syringe since it contains latex. If an anaphylactic or other clinically significant hypersensitivity reaction occurs, institute appropriate therapy and discontinue usetkinumab treatment.

    Desensitization procedures

    Ustekinumab has not been evaluated in patients who have undergone allergy immunotherapy as part of desensitization procedures. Ustekinumab may decrease the protective effect of allergen immunotherapy (decrease tolerance) which may increase the risk of an allergic reaction to a dose of allergen immunotherapy. Therefore, caution should be exercised in patients receiving or who have received allergen immunotherapy, particularly for anaphylaxis.

    Diabetes mellitus, fungal infection, immunosuppression, infection, influenza, mycobacterial infection, sepsis, tuberculosis, viral infection

    Ustekinumab may increase the risk of infections and reactivation of latent infections. In clinical trials, serious bacterial infection, fungal infection, and viral infection were noted; some patients required hospitalization. Do not start ustekinumab in a patient who has any clinically important active infection including chronic, localized, or systemic infections such as sepsis, influenza, or tuberculosis. Do not start ustekinumab until the infection resolves or is adequately treated. Also, if a serious infection develops, consider the discontinuation of ustekinumab until the infection resolves. Instruct patients to seek medical advice if signs or symptoms suggestive of an infection occur while on treatment with ustekinumab. Serious disseminated infections from mycobacterial infection (including nontuberculous, environmental mycobacteria), salmonella infection (including nontyphi strains), and Bacillus Calmette-Guerin vaccine receipt have been reported in patients who are genetically deficient in IL-12/IL-23. Serious infections and fatal outcomes have been reported in such patients. It is not known whether patients with pharmacologic blockade of IL-12/IL-23 from treatment with ustekinumab may be susceptible to these types of infections. Appropriate diagnostic testing should be considered (e.g., tissue culture, stool culture, etc.), as dictated by clinical circumstances. Evaluate all patients for tuberculosis before ustekinumab initiation. If a patient has latent tuberculosis, start treatment for the latent infection before starting ustekinumab. Consider antituberculosis therapy before ustekinumab receipt in patients with a history of latent or active tuberculosis without a confirmed adequate treatment course. Monitor all patients, even those with an initial negative latent tuberculosis test, for active tuberculosis and other infections during and after ustekinumab receipt. Patients with a chronic infection or a history of recurrent infections or with underlying conditions that may predispose them to infections (e.g., patients with advanced or uncontrolled diabetes mellitus or immunosuppression), or those who have lived in tuberculosis or histoplasmosis endemic areas may not be appropriate candidates for ustekinumab therapy. Carefully consider the benefits and risks of ustekinumab therapy before drug initiation, especially in patients with chronic or recurrent infection.

    Eosinophilic pneumonia, idiopathic interstitial pneumonia

    Cases of non-infectious idiopathic interstitial pneumonia, eosinophilic pneumonia, and cryptogenic organizing pneumonia have been reported during postmarketing use of ustekinumab. Clinical presentations included cough, dyspnea, and interstitial infiltrates following 1 to 3 doses. Serious outcomes have included respiratory failure and prolonged hospitalization. Patients improved with discontinuation of therapy and in certain cases administration of corticosteroids. If diagnosis is confirmed, discontinue ustekinumab and institute appropriate treatment.

    Neoplastic disease, new primary malignancy, skin cancer, sunlight (UV) exposure

    The safety of ustekinumab has not been evaluated in patients who have a history of malignancy or who have a known neoplastic disease. Ustekinumab is an immunosuppressant and may increase the risk of a new primary malignancy. Malignancies were reported among human subjects who received ustekinumab in clinical studies. In rodent models, inhibition of IL-12/IL-23p40 increased the risk of malignancy. There have been postmarketing reports of the rapid appearance of multiple cutaneous squamous cell carcinomas in patients receiving ustekinumab who had pre-existing risk factors for developing non-melanoma skin cancer. All patients receiving ustekinumab should be monitored for the appearance of non-melanoma skin cancer. Patients greater than 60 years of age, those with a medical history of prolonged immunosuppressant therapy and those with a history of PUVA (phototherapy) treatment should be followed closely. It is advisable for patients to limit sunlight (UV) exposure; the safety of ustekinumab in combination with phototherapy has not been established. In mice deficient in IL-12 or in IL-12 and IL-23, UV-induced skin cancers developed earlier and more frequently. The most frequently observed malignancies other than non-melanoma skin cancer during the clinical studies were: prostate, melanoma, colorectal and breast; these were similar in type and number to what would be expected in the general U.S. population according to the SEER database (adjusted for age, gender and race).

    Encephalopathy

    Ustekinumab has been associated with cases of posterior reversible encephalopathy syndrome (PRES), also known as reversible posterior leukoencephalopathy syndrome (RPLS), a potentially fatal neurological disorder of unknown cause. Clinical presentation of PRES include headache, seizures, confusion, visual disturbances, and imaging changes within a few days to several months after starting ustekinumab; a few cases reported latency of a year or longer. Patients who developed PRES recovered with supportive care and discontinuation of ustekinumab. Monitor all recipients of ustekinumab for signs and symptoms of PRES. Discontinue ustekinumab if PRES is suspected, and administer appropriate treatment.

    Vaccination

    Prior to initiating therapy with ustekinumab, patients should receive all age-appropriate immunizations as recommended by current immunization guidelines. Patients being treated with ustekinumab should not receive live virus vaccination. Bacillus Calmette-Guerin (BCG) vaccines should not be given during ustekinumab treatment or for 1 year prior to initiating treatment or 1 year following discontinuation of treatment. Caution is advised when administering live vaccines to household contacts of patients receiving ustekinumab because of the potential risk for shedding from the household contact and transmission to patient. Non-live vaccinations received during a course of treatment may not elicit an immune response sufficient to prevent disease.

    Infants, neonates, pregnancy

    Data on the use of ustekinumab during human pregnancy from observational studies, published case reports, and postmarketing surveillance are limited and are insufficient to inform a drug-associated risk. In developmental and reproductive studies involving cynomolgus monkeys, no teratogenic or other adverse developmental effects were observed following administration of ustekinumab resulting in exposures greater than 100 times the human exposure at the maximum recommended human subcutaneous dose (MRHD). In a combined embryo-fetal and pre- and post-natal development toxicity study in which pregnant cynomolgus monkeys received subcutaneous doses of ustekinumab at exposures greater than 100 time the MRHD, neonatal deaths occurred in the offspring of 1 monkey administered ustekinumab at 22.5 mg/kg and in 1 monkey dosed at 45 mg/kg. No effects on functional, morphological, or immunological development were observed in offspring from birth to 6 months of age. Guidelines recommend that ustekinumab be replaced before conception and during pregnancy by other medication until more data regarding the drug's use during pregnancy are available; use ustekinumab during pregnancy only when no other pregnancy-compatible drug can effectively control maternal disease. Current evidence does not indicate an increased rate of congenital malformations; because of limited evidence, however, alternative medications should be considered for treatment throughout pregnancy. If the drug must be used during pregnancy, experts recommend that ustekinumab use be discontinued 8 to 10 weeks before delivery, as transplacental drug transfer is expected later in pregnancy and during delivery. Pediatricians should be informed of any in utero exposure of an infant. Experts recommend avoidance of live vaccines in exposed neonates or infants for at least 9 months following birth or until infant drug levels become undetectable. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to ustekinumab; information about the registry can be obtained at mothertobaby.org/ongoing-study/stelara or by calling 1-877-311-8972.

    Breast-feeding

    There are no data on the presence of ustekinumab in human milk, the effects on the breast-fed infant, or the effects on milk production. Ustekinumab was present in the milk of lactating monkeys; however, animal data may not reliably predict drug concentrations in human milk. Maternal IgG is known to be present in human milk. Published data suggest that the systemic exposure to a breastfed infant during breast-feeding is expected to be low because ustekinumab is a large molecule and is degraded in the gastrointestinal tract. If excreted into breast milk, the effects of local ustekinumab exposure on the gastrointestinal tract are unknown. The development and health benefits of breast-feeding should be considered along with the mother's clinical need for ustekinumab and any potential adverse effects on the breast-fed infantfrom ustekinumab or from the underlying maternal condition. Avoid during lactation if alternative therapy is available to control the disease for which there are more data available regarding lactation; however, the indication for use and patient specific factors should be assessed before choosing an alternative agent.

    Geriatric

    Cautious ustekinumab use may be advisable in geriatric patients, as elderly may be more predisposed to infections. In clinical trials for various indications, no differences in safety or efficacy were observed between older and younger subjects; however, limited data are available. Closely monitor patients greater than 60 years of age for the appearance of non-melanoma skin cancer, as older patients in general have higher risk for skin cancers.

    Hepatitis, hepatitis C infection, HIV serum status

    Before starting ustekinumab, test potential drug recipients for hepatitis B (surface antigen and core antibody), hepatitis C (IgG), and HIV serum status (HIV-1 and HIV-2 antibodies and HIV-1 antigen). Consider ongoing screening (e.g., annually) in people who are at increased risk for HIV, hepatitis B, or hepatitis C infection. Retest for HIV infection in any person who displays symptoms or other conditions that may suggest HIV seroconversion or infection. In patients found to be infected with HIV, consider involving relevant specialists to ensure HIV viral load is suppressed on antiretroviral therapy. Similarily, retest for viral hepatitis in any person who develops unexplained elevations in hepatic enzymes. It is recommended to consult a hepatologist when using a biological therapy in patients who are infected with hepatitis B or C, whether newly diagnosed or chronically infected.

    Surgery

    Patients who undergo surgery while taking a biologic therapy, such as ustekinumab, may be at greater risk for postoperative infections. In patients undergoing elective surgery, balance the risk of postoperative infection against the risk of developing a severe or unstable disease by stopping the biologic therapy. When possible, it is advised to stop the biologic therapy 3- to 5-times the half-live or the length of the treatment cycle (whichever is longer) between the last dose and the planned surgery. Restart the biologic therapy postoperatively if there is no evidence of infection and wound healing is satisfactory.

    ADVERSE REACTIONS

    Severe

    new primary malignancy / Delayed / 0.2-1.7
    skin cancer / Delayed / 0.2-1.3
    leukoencephalopathy / Delayed / 0-1.0
    angioedema / Rapid / Incidence not known
    anaphylactic shock / Rapid / Incidence not known
    eosinophilic pneumonia / Delayed / Incidence not known

    Moderate

    antibody formation / Delayed / 0-12.4
    erythema / Early / 1.0-5.0
    candidiasis / Delayed / 3.0
    ocular infection / Delayed / Incidence not known
    meningitis / Delayed / Incidence not known
    depression / Delayed / Incidence not known
    dyspnea / Early / Incidence not known
    pneumonitis / Delayed / Incidence not known
    encephalopathy / Delayed / Incidence not known
    psoriasis / Delayed / Incidence not known

    Mild

    infection / Delayed / 3.0-27.0
    headache / Early / 5.0-10.0
    pharyngitis / Delayed / 3.0-8.0
    abdominal pain / Early / 7.0-7.0
    influenza / Delayed / 6.0-6.0
    fever / Early / 5.0-5.0
    injection site reaction / Rapid / 0-5.0
    sinusitis / Delayed / 3.0-4.0
    fatigue / Early / 3.0-4.0
    vomiting / Early / 4.0-4.0
    diarrhea / Early / 2.0-4.0
    arthralgia / Delayed / 0-3.0
    nausea / Early / 3.0-3.0
    back pain / Delayed / 1.0-2.0
    dizziness / Early / 1.0-2.0
    pruritus / Rapid / 1.0-2.0
    asthenia / Delayed / 1.0-1.0
    myalgia / Early / 0-1.0
    ecchymosis / Delayed / 0-1.0
    skin irritation / Early / 0-1.0
    acne vulgaris / Delayed / 0-1.0
    dental caries / Delayed / Incidence not known
    urticaria / Rapid / Incidence not known
    rash / Early / Incidence not known

    DRUG INTERACTIONS

    Abatacept: (Major) Concomitant use of abatacept with biological DMARDs, such as ustekinumab, is not recommended because of the possibility of additive immunosuppression and increased risk of infection. There is insufficient experience to assess the safety and efficacy of abatacept administered concurrently with ustekinumab.
    Bacillus Calmette-Guerin Vaccine, BCG: (Contraindicated) If possible, administer all recommended vaccines before ustekinumab initiation. Ustekinumab recipients may receive inactive vaccines, but the elicited immune response may be insufficient to prevent disease. Do not administer live vaccines to a ustekinumab recipient. Furthermore, do not administer BCG live vaccines for either 1 year before or 1 year after ustekinumab receipt, due to the infectious risk for Mycobacteria. No data are available on the response to live vaccination or on the risk of infection or infection transmission after the administration of other live vaccines to ustekinumab recipients. Cautious administration of ustekinumab to household contacts of ustekinumab recipients may be warranted due to the potential risk for shedding from the household contact and transmission to the patient. Practitioners should also refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Baricitinib: (Major) Concomitant use of baricitinib with biologic DMARDs, such as ustekinumab, is not recommended because of the possibility of additive immunosuppression and increased infection risk. Baricitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs.
    Canakinumab: (Major) Avoid the concomitant use of canakinumab with other interleukin inhibitors, such as ustekinumab; coadministration has not been studied and may result in additive immunosuppression and increased risk of infection.
    Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
    Cyclosporine: (Moderate) Upon initiation of usetkinumab in patients who are receiving cyclosporine, consider monitoring cyclosporine drug concentrations and adjusting the cyclosporine dose if clinically indicated, due to potential changes in CYP450 activity as inflammation is treated. The formation of CYP450 enzymes can be altered by increased levels of certain cytokines (e.g., IL-1, IL-6, IL-10, TNF, IFN) during chronic inflammation. Thus, ustekinumab, an antagonist of IL-12 and IL-23, could normalize the formation of CYP450 enzymes, which might affect CYP450 substrates with a narrow therapeutic index.
    Intranasal Influenza Vaccine: (Contraindicated) If possible, administer all recommended vaccines before ustekinumab initiation. Ustekinumab recipients may receive inactive vaccines, but the elicited immune response may be insufficient to prevent disease. Do not administer live vaccines to a ustekinumab recipient. Furthermore, do not administer BCG live vaccines for either 1 year before or 1 year after ustekinumab receipt, due to the infectious risk for Mycobacteria. No data are available on the response to live vaccination or on the risk of infection or infection transmission after the administration of other live vaccines to ustekinumab recipients. Cautious administration of ustekinumab to household contacts of ustekinumab recipients may be warranted due to the potential risk for shedding from the household contact and transmission to the patient. Practitioners should also refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Live Vaccines: (Contraindicated) If possible, administer all recommended vaccines before ustekinumab initiation. Ustekinumab recipients may receive inactive vaccines, but the elicited immune response may be insufficient to prevent disease. Do not administer live vaccines to a ustekinumab recipient. Furthermore, do not administer BCG live vaccines for either 1 year before or 1 year after ustekinumab receipt, due to the infectious risk for Mycobacteria. No data are available on the response to live vaccination or on the risk of infection or infection transmission after the administration of other live vaccines to ustekinumab recipients. Cautious administration of ustekinumab to household contacts of ustekinumab recipients may be warranted due to the potential risk for shedding from the household contact and transmission to the patient. Practitioners should also refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Contraindicated) If possible, administer all recommended vaccines before ustekinumab initiation. Ustekinumab recipients may receive inactive vaccines, but the elicited immune response may be insufficient to prevent disease. Do not administer live vaccines to a ustekinumab recipient. Furthermore, do not administer BCG live vaccines for either 1 year before or 1 year after ustekinumab receipt, due to the infectious risk for Mycobacteria. No data are available on the response to live vaccination or on the risk of infection or infection transmission after the administration of other live vaccines to ustekinumab recipients. Cautious administration of ustekinumab to household contacts of ustekinumab recipients may be warranted due to the potential risk for shedding from the household contact and transmission to the patient. Practitioners should also refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Measles/Mumps/Rubella Vaccines, MMR: (Contraindicated) If possible, administer all recommended vaccines before ustekinumab initiation. Ustekinumab recipients may receive inactive vaccines, but the elicited immune response may be insufficient to prevent disease. Do not administer live vaccines to a ustekinumab recipient. Furthermore, do not administer BCG live vaccines for either 1 year before or 1 year after ustekinumab receipt, due to the infectious risk for Mycobacteria. No data are available on the response to live vaccination or on the risk of infection or infection transmission after the administration of other live vaccines to ustekinumab recipients. Cautious administration of ustekinumab to household contacts of ustekinumab recipients may be warranted due to the potential risk for shedding from the household contact and transmission to the patient. Practitioners should also refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Rotavirus Vaccine: (Contraindicated) If possible, administer all recommended vaccines before ustekinumab initiation. Ustekinumab recipients may receive inactive vaccines, but the elicited immune response may be insufficient to prevent disease. Do not administer live vaccines to a ustekinumab recipient. Furthermore, do not administer BCG live vaccines for either 1 year before or 1 year after ustekinumab receipt, due to the infectious risk for Mycobacteria. No data are available on the response to live vaccination or on the risk of infection or infection transmission after the administration of other live vaccines to ustekinumab recipients. Cautious administration of ustekinumab to household contacts of ustekinumab recipients may be warranted due to the potential risk for shedding from the household contact and transmission to the patient. Practitioners should also refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Rubella Virus Vaccine Live: (Contraindicated) If possible, administer all recommended vaccines before ustekinumab initiation. Ustekinumab recipients may receive inactive vaccines, but the elicited immune response may be insufficient to prevent disease. Do not administer live vaccines to a ustekinumab recipient. Furthermore, do not administer BCG live vaccines for either 1 year before or 1 year after ustekinumab receipt, due to the infectious risk for Mycobacteria. No data are available on the response to live vaccination or on the risk of infection or infection transmission after the administration of other live vaccines to ustekinumab recipients. Cautious administration of ustekinumab to household contacts of ustekinumab recipients may be warranted due to the potential risk for shedding from the household contact and transmission to the patient. Practitioners should also refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Sarilumab: (Major) Avoid the concomitant use of sarilumab with other biological DMARDs such as ustekinumab; coadministration has not been studied and may result in additive immunosuppression and increased risk of infection.
    SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
    Smallpox and Monkeypox Vaccine, Live, Nonreplicating: (Contraindicated) If possible, administer all recommended vaccines before ustekinumab initiation. Ustekinumab recipients may receive inactive vaccines, but the elicited immune response may be insufficient to prevent disease. Do not administer live vaccines to a ustekinumab recipient. Furthermore, do not administer BCG live vaccines for either 1 year before or 1 year after ustekinumab receipt, due to the infectious risk for Mycobacteria. No data are available on the response to live vaccination or on the risk of infection or infection transmission after the administration of other live vaccines to ustekinumab recipients. Cautious administration of ustekinumab to household contacts of ustekinumab recipients may be warranted due to the potential risk for shedding from the household contact and transmission to the patient. Practitioners should also refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Smallpox Vaccine, Vaccinia Vaccine: (Contraindicated) If possible, administer all recommended vaccines before ustekinumab initiation. Ustekinumab recipients may receive inactive vaccines, but the elicited immune response may be insufficient to prevent disease. Do not administer live vaccines to a ustekinumab recipient. Furthermore, do not administer BCG live vaccines for either 1 year before or 1 year after ustekinumab receipt, due to the infectious risk for Mycobacteria. No data are available on the response to live vaccination or on the risk of infection or infection transmission after the administration of other live vaccines to ustekinumab recipients. Cautious administration of ustekinumab to household contacts of ustekinumab recipients may be warranted due to the potential risk for shedding from the household contact and transmission to the patient. Practitioners should also refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Tocilizumab: (Major) Avoid the concomitant use of tocilizumab with other biological DMARDs such as ustekinumab; coadministration has not been studied and may result in additive immunosuppression and increased risk of infection.
    Tofacitinib: (Major) Concomitant use of tofacitinib with biologic DMARDs, such as ustekinumab, is not recommended because of the possibility of additive immunosuppression and increased infection risk. Tofacitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs.
    Typhoid Vaccine: (Contraindicated) If possible, administer all recommended vaccines before ustekinumab initiation. Ustekinumab recipients may receive inactive vaccines, but the elicited immune response may be insufficient to prevent disease. Do not administer live vaccines to a ustekinumab recipient. Furthermore, do not administer BCG live vaccines for either 1 year before or 1 year after ustekinumab receipt, due to the infectious risk for Mycobacteria. No data are available on the response to live vaccination or on the risk of infection or infection transmission after the administration of other live vaccines to ustekinumab recipients. Cautious administration of ustekinumab to household contacts of ustekinumab recipients may be warranted due to the potential risk for shedding from the household contact and transmission to the patient. Practitioners should also refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Upadacitinib: (Major) Concomitant use of upadacitinib with biologic DMARDs, such as ustekinumab, is not recommended because of the possibility of increased immunosuppression and increased infection risk. Upadacitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs.
    Varicella-Zoster Virus Vaccine, Live: (Contraindicated) If possible, administer all recommended vaccines before ustekinumab initiation. Ustekinumab recipients may receive inactive vaccines, but the elicited immune response may be insufficient to prevent disease. Do not administer live vaccines to a ustekinumab recipient. Furthermore, do not administer BCG live vaccines for either 1 year before or 1 year after ustekinumab receipt, due to the infectious risk for Mycobacteria. No data are available on the response to live vaccination or on the risk of infection or infection transmission after the administration of other live vaccines to ustekinumab recipients. Cautious administration of ustekinumab to household contacts of ustekinumab recipients may be warranted due to the potential risk for shedding from the household contact and transmission to the patient. Practitioners should also refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Warfarin: (Moderate) The formation of CYP450 enzymes may be altered during chronic inflammation; the formation of CYP450 enzymes could be normalized during ustekinumab receipt. For CYP450 substrates that have a narrow therapeutic index such as warfarin, consider monitoring the warfarin concentration if ustekinumab is initiated or discontinued; warfarin dose adjustment may be needed.
    Yellow Fever Vaccine, Live: (Contraindicated) If possible, administer all recommended vaccines before ustekinumab initiation. Ustekinumab recipients may receive inactive vaccines, but the elicited immune response may be insufficient to prevent disease. Do not administer live vaccines to a ustekinumab recipient. Furthermore, do not administer BCG live vaccines for either 1 year before or 1 year after ustekinumab receipt, due to the infectious risk for Mycobacteria. No data are available on the response to live vaccination or on the risk of infection or infection transmission after the administration of other live vaccines to ustekinumab recipients. Cautious administration of ustekinumab to household contacts of ustekinumab recipients may be warranted due to the potential risk for shedding from the household contact and transmission to the patient. Practitioners should also refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.

    PREGNANCY AND LACTATION

    Pregnancy

    Data on the use of ustekinumab during human pregnancy from observational studies, published case reports, and postmarketing surveillance are limited and are insufficient to inform a drug-associated risk. In developmental and reproductive studies involving cynomolgus monkeys, no teratogenic or other adverse developmental effects were observed following administration of ustekinumab resulting in exposures greater than 100 times the human exposure at the maximum recommended human subcutaneous dose (MRHD). In a combined embryo-fetal and pre- and post-natal development toxicity study in which pregnant cynomolgus monkeys received subcutaneous doses of ustekinumab at exposures greater than 100 time the MRHD, neonatal deaths occurred in the offspring of 1 monkey administered ustekinumab at 22.5 mg/kg and in 1 monkey dosed at 45 mg/kg. No effects on functional, morphological, or immunological development were observed in offspring from birth to 6 months of age. Guidelines recommend that ustekinumab be replaced before conception and during pregnancy by other medication until more data regarding the drug's use during pregnancy are available; use ustekinumab during pregnancy only when no other pregnancy-compatible drug can effectively control maternal disease. Current evidence does not indicate an increased rate of congenital malformations; because of limited evidence, however, alternative medications should be considered for treatment throughout pregnancy. If the drug must be used during pregnancy, experts recommend that ustekinumab use be discontinued 8 to 10 weeks before delivery, as transplacental drug transfer is expected later in pregnancy and during delivery. Pediatricians should be informed of any in utero exposure of an infant. Experts recommend avoidance of live vaccines in exposed neonates or infants for at least 9 months following birth or until infant drug levels become undetectable. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to ustekinumab; information about the registry can be obtained at mothertobaby.org/ongoing-study/stelara or by calling 1-877-311-8972.

    MECHANISM OF ACTION

    Ustekinumab is a human IgG monoclonal antibody that binds with high affinity and specificity to the p40 protein subunit, which is part of both interleukin (IL)-12 and IL-23. Both IL-12 and IL-23 are naturally occurring cytokines that are involved in inflammatory and immune responses, such as natural killer cell activation and CD4+ T-cell differentiation and activation. In in vitro models, ustekinumab was shown to disrupt 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-12R,beta-1. The cytokines IL-12 and IL-23 have also been implicated as important contributors to the chronic inflammation that is a hallmark of Crohn's disease and ulcerative colitis. In animal models of colitis, genetic absence or antibody blockade of IL-12 p40 and IL-23 p40 was shown to be protective. In a small exploratory study, a decrease was observed in the expression of mRNA of its molecular targets IL-12 and IL-23 in lesional skin biopsies in patients with psoriasis.
     
    Normally, CD4+ T cells develop into T helper-1 (Th1) cells under the influence of IL-12. Th1 cells produce interferon gamma and mediate cellular immunity. In addition, IL-12 induces cutaneous lymphocyte antigen (CLA), resulting in T cell homing to the skin. Under the influence of IL-23, CD4+ T cells develop into IL-17 producing T cells (Th17). Th17 cells produce IL-17, IL-17F, IL-6, and TNF-alpha to mediate cellular immunity. Ustekinumab, by disrupting IL-12 and IL-23 signal transduction, suppresses the formation of the proinflammatory Th1 and Th17 cells. In vitro, ustekinumab inhibited IL-12 and IL-23-induced interferon-gamma, IL-17A, TNF-alpha, IL-2, and IL-10 secretion.
     
    In rodent models, inhibition of IL-12/IL-23p40 increased the risk of malignancy. In mice deficient in IL-12 or in IL-12 and IL-23, ultraviolet-induced skin cancers developed earlier and more frequently; the relevance of these findings to humans is not known.

    PHARMACOKINETICS

    Ustekinumab is administered subcutaneously and intravenously. Ustekinumab metabolism has not been characterized, but the drug is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG. The volume of distribution (Vd) of ustekinumab in the central compartment is 2.7 L in patients with Crohn's disease and 3 L in patients with ulcerative colitis. The total Vd at steady-state is 4.6 L in patients with Crohn's disease and 4.4 L in patients with ulcerative colitis. After subcutaneous administration in psoriasis patients, the mean half-life ranged from 14.9 +/- 4.6 days to 45.6 +/- 80.2 days. In a population pharmacokinetic analysis of ustekinumab, the clearance was 0.19 L/day with an estimated median terminal half-life of approximately 19 days in patients with Crohn's disease and ulcerative colitis.[36889]
     
    Affected cytochrome P450 enzymes and drug transporters: unknown
    The effects of interleukins IL-12 or IL-23 on the regulation of CYP450 enzymes were evaluated in an in vitro study using human hepatocytes, which showed that IL-12 and/or IL-23 (at concentrations of 10 ng/mL) did not alter human CYP450 enzyme activities (CYP1A2, 2B6, 2C9, 2C19, 2D6, or 3A4). However, the clinical relevance has not been established. No in vivo drug interaction studies have been conducted with ustekinumab. The formation of CYP450 enzymes can be altered by increased concentrations of certain cytokines (e.g., IL-1, IL-6, IL-10, TNF-alpha, IFN) during chronic inflammation. Thus, ustekinumab, an antagonist of IL-12 and IL-23, could normalize the formation of CYP450 enzymes. Monitor the therapeutic effect of any concomitant CYP450 substrates, particularly those with a narrow therapeutic index, when ustekinumab is initiated.[36889]

    Intravenous Route

    After the recommended intravenous induction dose, the mean peak serum ustekinumab concentration was 125.2 +/- 33.6 mcg/mL in patients with Crohn's disease and 129.1 +/- 27.6 mcg/mL in patients with ulcerative colitis.

    Subcutaneous Route

    The median time to reach the maximum serum concentration was 13.5 days after a single 45-mg subcutaneous dose and 7 days after a single 90-mg subcutaneous dose to patients with psoriasis. Steady-state serum concentrations were achieved by week 28. After the same dose, lower median ustekinumab concentrations were noted among people who weighed more than 100 kg as compared with concentrations from people who weighed 100 kg or less. For psoriasis patients receiving different doses according to weight, the mean (+/- SD) steady-state trough serum ustekinumab concentrations were 0.69 +/- 0.69 mcg/mL for patients weighing 100 kg or less receiving a 45-mg dose and 0.74 +/- 0.78 mcg/mL for patients weighing more than 100 kg receiving a 90-mg dose. In patients with Crohn's disease receiving subcutaneous maintenance doses of ustekinumab 90 mg starting at week 8 and continuing every 8 weeks thereafter, steady-state was achieved by the start of the second maintenance dose. There was no apparent accumulation in ustekinumab concentration over time when given subcutaneously every 8 weeks. Mean steady-state trough concentration for ustekinumab 90-mg administered every 8 weeks was 2.51 +/- 2.06 mcg/mL in Crohn's patients and 3.3 +/- 2.3 mcg/mL in patients with ulcerative colitis. No apparent accumulation of ustekinumab was noted.[36889]