Ustekinumab is an intravenously and subcutaneously administered interleukin (IL)-12 and IL-23 antagonist. IL-12 and IL-23 are involved in normal inflammatory and immune responses. Elevated concentrations of these interleukins are found in several inflammatory conditions. Use of ustekinumab in plaque psoriasis results in significant improvement in psoriatic skin lesions and a reduction of itching and inflammation. The drug improves moderate to severe plaque psoriasis in adult and pediatric patients 6 years and older who are candidates for phototherapy or systemic therapy. In patients 6 years and older with psoriatic arthritis (PsA), ustekinumab improves clinical signs and symptoms, inhibits the radiographic progression of structural joint damage, and improves physical function. The ideal combination of therapy for individual patients with plaque psoriasis or PsA is determined by treat to target strategies and severity of disease. While TNF-blockers are often first-line biologic treatments, the IL-inhibiting biologics may be considered when the patient has severe disease and either has contraindications or adverse reactions to TNF-blocking biologics or inadequate response. Ustekinumab is also approved for the treatment of adults with moderate to severely active Crohn's disease (CD) or ulcerative colitis (UC); the drug helps induce and maintain remission in these patients. Treatment guidelines recommend the use of the drug in selected adult patients with moderate to severely active CD and for the induction and maintenance of remission in patients with moderately to severely active UC. As with other interleukin inhibitors, ustekinumab can increase the risk of infection.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific 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.
-Stelara solution should be colorless to light yellow and may contain a few small translucent or white particles. Wezlana is clear to opalescent and colorless to light yellow solution. Do not use if discolored, cloudy, or if foreign particulate matter is present.
Intravenous Administration
Intravenous infusion preparation
-Calculate the dose and the number of ustekinumab vials needed based on patient weight; each 26 mL vial contains 130 mg of ustekinumab.
-Ustekinumab can be mixed with 0.9% Sodium Chloride Injection or 0.45% Sodium Chloride Injection.
-Withdraw and discard the volume of medication to be added to 250 mL infusion bag (e.g., discard 26 mL sodium chloride solution from the bag for each vial of ustekinumab needed). Add the appropriate dose of medication to the infusion bag. Final volume should be 250 mL.
-Gently mix. Do not shake.
-Storage: The diluted infusion solution may be kept at room temperature up to 25 degrees C (77 degrees F) for up to 7 hours. The infusion must be completed within 8 hours after the dilution (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 over at least 1 hour.
-Use only an infusion set with an in-line, sterile, non-pyrogenic, low protein-binding filter (pore size 0.2 micron).
-Do not infuse other agents concomitantly through the same line.
Subcutaneous Administration
-Only an individual trained in subcutaneous drug delivery should administer the injection. For pediatric patients, it is recommended that doses be administered by a health care professional.
-Injection sites include the upper arms, buttocks, thighs, or any quadrant of the abdomen. Do not administer where skin is tender, bruised, red, or hard.
-Rotate injection sites. If the dose requires 2 injections, use a different site for the second injection.
-When using a single-dose 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.
-Storage: Vials and prefilled syringes are single-use; discard any unused portion. Store unopened vials and prefilled syringes in the refrigerator between 2 and 8 degrees C (36 and 46 degrees F). 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.
Ustekinumab may increase the risk of infection and reactivation of latent infection. Serious bacterial, mycobacterial, fungal, and viral infections have been observed in patients receiving ustekinumab. Consider interruption of ustekinumab treatment for serious or clinically significant infections until the infection resolves or is adequately treated. In adult trials for psoriatic indications, infections were reported in 27% of patients treated with ustekinumab compared to 24% of those receiving placebo. In controlled and non-controlled portions of the trials, 72.3% of ustekinumab-treated patients reported infections; 2.8% of patients reported serious infections. Serious infections requiring hospitalization, or otherwise clinically significant infections, reported in adults treated for psoriasis include cellulitis, diverticulitis, osteomyelitis, viral infection, gastroenteritis, pneumonia, appendicitis, cholecystitis, sepsis, and urinary tract infections. Naso-pharyngitis (7% to 24%), upper respiratory tract infection (4% to 5%), dental infections/dental caries (1%), vulvovaginal candidiasis or mycotic infection (5%), bronchitis (5%), urinary tract infection (4%), sinusitis (3% to 4%), and influenza (6%) were reported in adult trials. Cellulitis, herpes zoster, and diverticulitis occurred in less than 1% of ustekinumab-treated patients with psoriasis. Anal abscess, gastroenteritis, pneumonia, listeriosis, listeria meningitis, and herpes zoster ocular infection were reported in adults with Crohn's disease or ulcerative colitis. Lower respiratory tract infections, including opportunistic fungal infections and tuberculosis, have been reported with postmarketing use. Evaluate patients for tuberculosis (TB) prior to initiation. Monitor all patients regardless of TB status result for signs and symptoms of active TB during and after ustekinumab receipt. Instruct patients to seek medical advice if signs or symptoms of an infection occur.
Headache (5% to 10%), fatigue (3% to 4%), asthenia (1%), fever (5%) have been reported in adult patients treated with ustekinumab during clinical trials. Dizziness, back pain, and pharyngolaryngeal pain were each reported in 1% to 2% of treated patients, while myalgia and depression were each reported in 1% of treated patients. A higher incidence of arthralgia (3% vs. 1%) was observed in adults treated with ustekinumab compared to those receiving placebo during clinical trials for psoriatic arthritis.
Vomiting occurred in 4% of patients receiving ustekinumab for Crohn's disease during clinical trials. Nausea was reported in 3% of adults treated for psoriatic arthritis or ulcerative colitis. Diarrhea occurred in 4% of ustekinumab-treated adult patients with ulcerative colitis. Abdominal pain was reported in 7% of adults during trials for ulcerative colitis.
Injection site reaction, including localized pain, swelling, itching, induration, bleeding, bruising (ecchymosis), or skin irritation may occur. Injection site erythema was reported in 1% to 5% of adult patients receiving ustekinumab during clinical trials.
Hypersensitivity reactions, including anaphylactoid reactions and angioedema have been reported with ustekinumab use. Pruritus was reported in 1% to 4% of adult patients receiving ustekinumab during clinical trials. Hypersensitivity vasculitis, rash, and urticaria have been reported with postmarketing use. Instruct patients to seek immediate medical attention if they develop signs or symptoms of a serious allergic reaction. Discontinue ustekinumab and institute appropriate therapy if anaphylactoid reactions or other serious allergic reactions occur.
Interstitial pneumonitis or pneumonia, eosinophilic pneumonia, and cryptogenic organizing pneumonia have been reported with postmarketing use of ustekinumab. Patients presented with cough, dyspnea, and interstitial infiltrates after 1 to 3 doses of ustekinumab. Serious outcomes have included respiratory failure and prolonged hospitalization. Patients improved with discontinuation of therapy and, in certain cases, administration of corticosteroids. If the diagnosis is confirmed, discontinue the drug and institute appropriate treatment.
Two cases of posterior reversible encephalopathy syndrome (PRES), also known as reversible posterior leukoencephalopathy syndrome (RPLS), a potentially fatal neurological disorder of unknown cause, were observed during ustekinumab clinical studies. Additionally, cases have been reported during postmarketing use of the drug for psoriasis, psoriatic arthritis, and Crohn's disease. Clinical presentation included headache, seizures, confusion, visual disturbances, and imaging changes consistent with PRES a few days to several months after starting ustekinumab. A few cases reported latency of a year or longer. Patients recovered with supportive care following discontinuation of ustekinumab. If PRES is suspected, promptly stop ustekinumab and administer appropriate treatment.
Ustekinumab is an immunosuppressant and may increase the risk of a new primary malignancy. The rapid appearance of multiple cutaneous squamous cell carcinomas in patients with pre-existing risk factors for non-melanoma skin cancer have been reported with postmarketing use of ustekinumab. Monitor patients for the appearance of non-melanoma skin cancer. Closely follow those with a medical history of prolonged immunosuppressant therapy or a history of PUVA phototherapy treatment. In adult clinical trials, 1.7% of patients with psoriasis, 0.2% of patients with Crohn's disease, and 0.5% of patients with ulcerative colitis, all of whom received ustekinumab, reported malignancies other than non-melanoma skin cancers. Non-melanoma skin cancer was reported in 1.5%, 0.2%, and 0.4% of treated patients. The most frequently observed malignancies other than non-melanoma skin cancer during adult clinical trials for psoriasis were prostate, colorectal, melanoma, and breast. Malignancies other than non-melanoma skin cancer among ustekinumab recipients were similar in type and number to what would be expected in the general US population when adjusted for age, gender, and race.
Acne vulgaris was reported in 1% of patients treated with ustekinumab during clinical trials, compared to 0.4% of adults receiving placebo.
Pustular and erythrodermic psoriasis have been reported with postmarketing use of ustekinumab. In one case, a patient with plaque psoriasis and persistent plaque lesions with occasional flares with a pustular component had pustular psoriasis diagnosed by biopsy 4 days after initial ustekinumab receipt. Similar pustular exacerbations of 7 to 10 days duration occurred after the second and third ustekinumab injections. No recurrence of pustular lesions occurred after ustekinumab discontinuation. In another case, a woman with plaque psoriasis developed generalized pustular psoriasis 2 days after initial ustekinumab administration. Ustekinumab was discontinued, and complete remission was observed. The mechanism of ustekinumab-induced pustular psoriasis is unknown, but a triggering event in predisposed individuals may cause a possible disruption in a sensitive cytokine balance (increased interferon-alpha concentrations). Of note, ustekinumab has been used with positive response for both pustular and erythrodermic psoriasis.
Antibody formation may occur with ustekinumab use. In adult clinical trials, antibody formation was reported in 6% to 12.4% of those treated with ustekinumab for psoriasis or psoriatic arthritis. These antibodies were generally low-titer. In the psoriasis studies, the majority of patients who were positive for antibodies had neutralizing antibodies. Antibodies to ustekinumab were associated with reduced or undetectable serum drug concentrations and reduced efficacy. In trials for Crohn's disease and ulcerative colitis, 2.9% and 4.6% of treated patients, respectively, developed antibodies when treated with ustekinumab for approximately one year. No apparent association between the development of antibodies to ustekinumab and the development of injection site reactions or hypersensitivity reactions was seen. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. The observed incidence of antibody positivity in an assay may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to ustekinumab with the incidence of antibodies to other products may be misleading. Ustekinumab appears to be associated with less immunogenicity than the tumor necrosis factor (TNF) blockers in patients with inflammatory bowel disease.
Ustekinumab may increase the risk of infections and reactivation of latent infections. Serious bacterial infection, fungal infection, mycobacterial infection, and viral infection have been observed in patients receiving ustekinumab. Do not start ustekinumab in patients who have a clinically important active infection until the infection resolves or is adequately treated. Consider the risks and benefits of treatment in patients with a chronic infection or a history of recurrent infections. Instruct patients to seek medical advice if signs or symptoms suggestive of an infection occur while receiving ustekinumab. Discontinue treatment for serious or clinically significant infections until the infection resolves or is adequately treated. People genetically deficient in IL-12/IL-23 are vulnerable to disseminated infections from mycobacterial infections (including infection from nontuberculous or environmental mycobacteria), salmonella infection (including infection from nontyphi strains), and Bacillus Calmette-Guerin vaccinations. 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. Consider appropriate diagnostic testing (e.g., tissue culture, stool culture, etc.), as dictated by clinical circumstances. Evaluate all patients for tuberculosis before ustekinumab initiation. Do not administer ustekinumab to patients with active tuberculosis infection. Initiate treatment for the latent tuberculosis before starting ustekinumab. Consider antituberculosis therapy before treatment initiation 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.
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. These patients had pre-existing risk factors for developing non-melanoma skin cancer. Monitor all patients receiving ustekinumab for the appearance of non-melanoma skin cancer. Follow older adults greater than 60 years of age, those with a medical history of prolonged immunosuppressant therapy, and those with a history of PUVA (phototherapy) treatment 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 psoriasis 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).
Two cases of posterior reversible encephalopathy syndrome (PRES), also known as reversible posterior leukoencephalopathy syndrome (RPLS), a potentially fatal neurological disorder of unknown cause, were observed during ustekinumab clinical studies. Additionally, cases have been reported during postmarketing use of the drug for psoriasis, psoriatic arthritis, and Crohn's disease. Clinical presentation included headache, seizures, confusion, visual disturbances, and imaging changes consistent with PRES a few days to several months after starting ustekinumab. A few cases reported latency of a year or longer. Monitor all drug recipients for signs and symptoms of PRES. Discontinue ustekinumab if PRES is suspected, and administer appropriate treatment.
Cases of interstitial pneumonia (drug-induced interstitial lung disease), eosinophilic pneumonia and cryptogenic organizing pneumonia have been reported during post-approval 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.
Prior to initiating therapy with ustekinumab, patients should receive all age-appropriate immunizations as recommended by current immunization guidelines. Patients treated with ustekinumab should not receive live virus vaccines. Patients should not receive Bacillus Calmette-Guerin (BCG) vaccines 1 year before, during, and for 1 year after ustekinumab therapy. Use caution when administering live virus vaccines to household contacts because of the potential risk for viral 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.
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 of major birth defects, miscarriages, or other adverse maternal or fetal outcomes. Transport of human IgG antibody across the placenta increases as pregnancy progresses and peaks during the third trimester; therefore, ustekinumab may be transferred to the developing fetus. 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 increases as pregnancy progresses and peaks during the third trimester. Inform pediatricians of any in utero exposure, as ustekinumab may theoretically interfere with immune response to infections. Consider the risks and benefits of administering live vaccines to neonates or infants exposed to ustekinumab in utero. Although a specific timeframe to delay administration of live attenuated vaccines in infants exposed in utero is unknown, consider the risks and benefits of delaying a minimum of 6 months after birth because of the clearance of the product. Some experts recommend avoidance of live vaccines in exposed infants for at least 9 months following birth or until infant drug levels become undetectable. There are insufficient data regarding exposed infant serum drug concentrations at birth and the duration of persistence of ustekinumab in infant serum after birth.
Limited data from published literature suggest that ustekinumab is present in human breast milk. There are no data available regarding the effects of the drug on milk production. It is unknown how local gastrointestinal exposure and limited systemic exposure to ustekinumab effects a breastfed infant. No adverse effects on the breastfed infant causally related to ustekinumab have been identified in the published literature or postmarketing experience. Consider the development and health benefits of breast-feeding along with the patient's clinical need for ustekinumab and any potential adverse effects on the breastfed child from ustekinumab or from the underlying condition.
Ustekinumab products have not been evaluated in patients who have undergone allergy immunotherapy or 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. 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.
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. Similarly, 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.
Inform patients with a latex hypersensitivity that the needle cover of the Stelara prefilled syringe contains natural rubber, a derivative of latex. This may cause allergic reactions in sensitive patients. However, the Wezlana prefilled syringe is latex free.
For the treatment of moderate to severe plaque psoriasis in patients who are candidates for phototherapy or systemic therapy:
Subcutaneous dosage:
Adults weighing more than 100 kg: 90 mg subcutaneously at Weeks 0 and 4, then 90 mg subcutaneously every 12 weeks. May consider a lower dose of 45 mg; however, greater efficacy is seen with 90 mg per dose. Per guidelines, may increase the dose to 90 mg subcutaneously every 8 weeks if an inadequate primary response may be due to insufficient drug exposure (e.g., known subtherapeutic drug concentrations, obesity, relapse during treatment); however, consider the increased risk for infection and adverse reactions.
Adults weighing 100 kg or less: 45 mg subcutaneously at Weeks 0 and 4, then 45 mg subcutaneously every 12 weeks. Per guidelines, may increase the dose to 90 mg subcutaneously every 8 to 12 weeks if an inadequate primary response may be due to insufficient drug exposure (e.g., known subtherapeutic drug concentrations, relapse during treatment); however, consider the increased risk for infection and adverse reactions.
Children and Adolescents 6 to 17 years weighing more than 100 kg: 90 mg subcutaneously at Weeks 0 and 4, then 90 mg subcutaneously every 12 weeks.
Children and Adolescents 6 to 17 years weighing 60 to 100 kg: 45 mg subcutaneously at Weeks 0 and 4, then 45 mg subcutaneously every 12 weeks.
Children and Adolescents 6 to 17 years weighing less than 60 kg: 0.75 mg/kg/dose subcutaneously at Weeks 0 and 4, then 0.75 mg/kg/dose subcutaneously every 12 weeks. Obtain the dose from a single-dose vial.
For the treatment of active psoriatic arthritis:
-for the treatment of active psoriatic arthritis without coexistent plaque psoriasis:
Subcutaneous dosage:
Adults: 45 mg subcutaneously at Weeks 0 and 4, then 45 mg subcutaneously every 12 weeks.
Children and Adolescents 6 to 17 years weighing 60 kg or more: 45 mg subcutaneously at Weeks 0 and 4, then 45 mg subcutaneously every 12 weeks.
Children and Adolescents 6 to 17 years weighing less than 60 kg: 0.75 mg/kg/dose subcutaneously at Weeks 0 and 4, then 0.75 mg/kg/dose subcutaneously every 12 weeks. Obtain the dose from a single-dose vial.
-for the treatment of active psoriatic arthritis with coexistent moderate to severe plaque psoriasis:
Subcutaneous dosage:
Adults weighing more than 100 kg: 90 mg subcutaneously at Weeks 0 and 4, then 90 mg subcutaneously every 12 weeks.
Adults weighing 100 kg or less: 45 mg subcutaneously at Weeks 0 and 4, then 45 mg subcutaneously every 12 weeks.
Children and Adolescents 6 to 17 years weighing more than 100 kg: 90 mg subcutaneously at Weeks 0 and 4, then 90 mg subcutaneously every 12 weeks.
Children and Adolescents 6 to 17 years weighing 60 to 100 kg: 45 mg subcutaneously at Weeks 0 and 4, then 45 mg subcutaneously every 12 weeks.
Children and Adolescents 6 to 17 years weighing less than 60 kg: 0.75 mg/kg/dose subcutaneously at Weeks 0 and 4, then 0.75 mg/kg/dose subcutaneously every 12 weeks. Obtain the dose from a single-dose vial.
For the treatment of moderate to severe active Crohn's disease:
Intravenous dosage (induction):
Adults weighing more than 85 kg: 520 mg IV as a single dose. Begin the subcutaneous maintenance regimen 8 weeks after the initial IV dose. Guidelines strongly recommend ustekinumab for moderate-to-severe Crohn's disease patients who failed previous treatment with corticosteroids, thiopurines, methotrexate, or TNF-blockers or in those persons who have had no prior exposure to TNF-blockers.
Adults weighing 56 kg to 85 kg: 390 mg IV as a single dose. Begin the subcutaneous maintenance regimen 8 weeks after the initial IV dose. Guidelines strongly recommend ustekinumab for moderate-to-severe Crohn's disease patients who failed previous treatment with corticosteroids, thiopurines, methotrexate, or TNF-blockers or in those persons who have had no prior exposure to TNF-blockers.
Adults weighing 55 kg or less: 260 mg IV as a single dose. Begin the subcutaneous maintenance regimen 8 weeks after the initial IV dose. Guidelines strongly recommend ustekinumab for moderate-to-severe Crohn's disease patients who failed previous treatment with corticosteroids, thiopurines, methotrexate, or TNF-blockers or in those persons who have had no prior exposure to TNF-blockers.
Adolescents*: 6 mg/kg IV as a single dose rounded to the nearest 130 mg (Max: 520 mg). Begin the subcutaneous maintenance regimen 8 weeks after the initial IV dose. Consider ustekinumab in patients who fail to achieve or maintain clinical remission on TNF-blockers.
Children* 2 to 12 years weighing 40 kg or more: 6 mg/kg IV as a single dose rounded to the nearest 130 mg (Max: 520 mg). Alternatively, 130 mg and 390 mg IV as a single dose have been studied. Begin the subcutaneous maintenance regimen 8 weeks after the initial IV dose. In a phase 1 induction dose range study, 44 patients (age range: 2 to 17 years, median 13 years, weighing less than 40 kg [n = 18] or 40 kg or more [n = 26]) received either low or high dose ustekinumab as IV induction followed by subcutaneous maintenance doses. Low dose was defined as 130 mg (n = 13) and high dose was defined as 390 (n = 13). Both groups had similar clinical response at week 8, but the high dose induction group had a higher percentage of clinical remission at 16 weeks (22% for low dose vs. 29% for high dose). Consider ustekinumab in patients who fail to achieve or maintain clinical remission on TNF-blockers.
Children* 2 to 12 years weighing 10 to 39 kg: 6 mg/kg IV as a single dose rounded to the nearest 130 mg. Alternatively, 3 mg/kg and 9 mg/kg IV as a single dose have been studied. Begin the subcutaneous maintenance regimen 8 weeks after the initial IV dose. In a phase 1 induction dose range study, 44 patients (age range: 2 to 17 years, median 13 years, weighing less than 40 kg [n = 18] or 40 kg or more [n = 26]) received either low or high dose ustekinumab as IV induction followed by subcutaneous maintenance doses. Low dose was defined as 3 mg/kg/dose (n = 10) and high dose was defined as 9 mg/kg/dose (n = 8). Both groups had similar clinical response at week 8, but the high dose induction group had a higher percentage of clinical remission at 16 weeks (22% for low dose vs. 29% for high dose). Consider ustekinumab in patients who fail to achieve or maintain clinical remission on TNF-blockers.
Subcutaneous dosage (maintenance):
Adults: 90 mg subcutaneously every 8 weeks, starting 8 weeks after the initial IV induction dose. Guidelines support the use of ustekinumab for maintenance of remission in persons with an ustekinumab-induced induction response.
Children* and Adolescents* 2 to 17 years weighing 40 kg or more: 90 mg subcutaneously every 8 weeks, starting 8 weeks after the initial IV induction dose; dose escalation after a median of 6 months via a shorter dosing interval of 4 to 6 weeks was shown to increase response in patients with loss of or insufficient response. Consider ustekinumab in patients who fail to achieve or maintain clinical remission on TNF-blockers.
Children* 2 to 12 years weighing 10 kg to 39 kg: 2 mg/kg/dose (Max: 90 mg) subcutaneously every 8 weeks, starting 8 weeks after the initial IV induction dose; dose escalation after a median of 6 months via a shorter dosing interval of 4 to 6 weeks was shown to increase response in patients with loss of or insufficient response. In a phase 1 induction dose range study, 44 patients (age range: 2 to 17 years, median 13 years, weighing less than 40 kg [n = 18] or 40 kg or more [n = 26]) received ustekinumab as IV induction followed by subcutaneous maintenance doses of 2 mg/kg in patients less than 40 kg and 90 mg in patients 40 kg or more every 8 weeks. Clinical remission was achieved in 22% to 29% of patients at week 16. Consider ustekinumab in patients who fail to achieve or maintain clinical remission on TNF-blockers.
For the treatment of moderately to severely active ulcerative colitis:
Intravenous dosage:
Adults weighing more than 85 kg: 520 mg IV as a single dose. Begin subcutaneous maintenance dose 8 weeks after the initial intravenous dose. Guidelines strongly recommend ustekinumab for induction of remission in persons with moderately to severely active ulcerative colitis.
Adults weighing 56 kg to 85 kg: 390 mg IV as a single dose. Begin subcutaneous maintenance dose 8 weeks after the initial intravenous dose. Guidelines strongly recommend ustekinumab for induction of remission in persons with moderately to severely active ulcerative colitis.
Adults weighing 55 kg or less: 260 mg IV as a single dose. Begin subcutaneous maintenance dose 8 weeks after the initial intravenous dose. Guidelines strongly recommend ustekinumab for induction of remission in persons with moderately to severely active ulcerative colitis.
Subcutaneous dosage:
Adults: 90 mg subcutaneously every 8 weeks starting 8 weeks after the initial intravenous induction dose. Guidelines strongly recommend ustekinumab for maintenance of remission in persons with moderately to severely active ulcerative colitis who responded to ustekinumab induction.
Therapeutic Drug Monitoring:
Target concentrations of ustekinumab in patients with Inflammatory Bowel Disease per guidelines
-Week 8: at least 3 to 7 mcg/mL
-Maintenance therapy: at least 1 to 3 mcg/mL
Maximum Dosage Limits:
-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 or psoriatic arthritis; safety and efficacy have not been established for Crohn's disease or ulcerative colitis.
weighing 60 kg to 100 kg: 45 mg/dose subcutaneously for plaque psoriasis or psoriatic arthritis; safety and efficacy have not been established for Crohn's disease or ulcerative colitis.
weighing less than 60 kg: 0.75 mg/kg/dose subcutaneously for plaque psoriasis or psoriatic arthritis; safety and efficacy have not been established for Crohn's disease or ulcerative colitis.
-Children
6 to 12 years weighing more than 100 kg: 90 mg/dose subcutaneously for plaque psoriasis or psoriatic arthritis; safety and efficacy have not been established for Crohn's disease or ulcerative colitis.
6 to 12 years weighing 60 kg to 100 kg: 45 mg/dose subcutaneously for plaque psoriasis or psoriatic arthritis; safety and efficacy have not been established for Crohn's disease or ulcerative colitis.
6 to 12 years weighing less than 60 kg: 0.75 mg/kg/dose subcutaneously for plaque psoriasis or psoriatic arthritis; safety and efficacy have not been established for Crohn's disease or ulcerative colitis.
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.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
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.
Chikungunya 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.
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.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
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.
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.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (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.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (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.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (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.
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 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.
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 Vd of ustekinumab in the central compartment was 2.7 to 3 L in patients with Crohn's disease or ulcerative colitis. The total Vd at steady-state was 4.4 to 4.6 L. Mean half-life ranged from 14.9 +/- 4.6 days to 45.6 +/- 80.2 days across all psoriasis studies following subcutaneous administration. Clearance was 0.19 L/day with an estimated median terminal half-life of approximately 19 days in patients with Crohn's disease or ulcerative colitis.
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.
-Route-Specific Pharmacokinetics
Intravenous Route
The mean peak serum ustekinumab concentration was 125.2 +/- 33.6 mcg/mL in adults with Crohn's disease and 129.1 +/- 27.6 mcg/mL in adults with ulcerative colitis after the recommended intravenous induction dose.
Subcutaneous Route
The median Tmax 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 those patients who weighed more than 100 kg as compared with concentrations from those 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 adult patients with Crohn's disease and ulcerative colitis 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 adults with Crohn's disease and 3.3 +/- 2.3 mcg/mL in adults with ulcerative colitis. No apparent accumulation of ustekinumab was noted.
-Special Populations
Pediatrics
Children and Adolescents 6 to 17 years
Steady-state serum concentrations are achieved by week 28 of treatment. At week 28, trough serum concentrations were 0.36 +/- 0.26 mcg/mL and 0.54 +/- 0.43 mcg/mL in pediatric patients 6 to 11 years and 12 to 17 years, respectively.
Geriatric
There were no apparent changes in pharmacokinetic parameters (clearance and Vd) in geriatric subjects compared to younger adult patients.
Obesity
Lower median ustekinumab concentrations were noted among patients weighing more than 100 kg compared to those weighing 100 kg or less. The median trough serum concentrations in patients weighing more than 100 kg with the 90 mg dose were comparable to those weighing 100 kg or less with the 45 mg dose.