Stelara

Stelara is the brand-name form of the generic drug ustekinumab, used to treat severe plaque psoriasis, a condition in which red, scaly patches form on the skin, and psoriatic arthritis, a form of arthritis that affects some people who have psoriasis.

The drug is typically prescribed only when topical medications alone aren't successful in treating these conditions.

It's also used to treat Crohn's disease, a chronic digestive disorder.

Stelara belongs to a class of drugs called monoclonal antibodies. It works by reducing the action of certain substances in the body that can cause inflammation.

The Food and Drug Administration (FDA) approved Stelara in 2009. It's manufactured by Janssen Biotech Inc.

Stelara Warnings

Stelara may limit your body's ability to fight infections, and raise your risk of developing a serious or life-threatening infection.

Tell your doctor if you have any type of infection or are prone to getting infections.

Try to avoid being around people who are sick or have infections while taking this medicine.

Let your doctor know right away if you experience any of the following symptoms while taking Stelara:

• Fever, chills, or night sweats
• Sore throat
• Muscle aches
• Shortness of breath
• Diarrhea or stomach pain
• Painful, burning, or difficult urination
• Weakness
• Painful skin sores
• Skin redness or warmth
• Other signs of infection

Stelara may raise your risk of developing tuberculosis (TB).

Tell your doctor if you have ever had TB, been in a country where TB is prevalent, or have been in contact with someone having active TB.

Your doctor will perform a skin or blood test to check for TB before starting you on Stelara.

Call your doctor immediately if you develop any of the following symptoms:

• Chest pain
• Cough or coughing up blood or mucus
• Extreme weakness or tiredness
• Loss of appetite or weight loss

Tell your healthcare provider you're taking Stelara before having any type of surgery, including a dental procedure.

Be sure to let your doctor know about all vaccinations you've had. Don't receive any vaccines while taking this medicine without first talking to your doctor.

In particular, you shouldn't receive the BCG vaccine for one year prior to starting on Stelara, during your treatment, or for one year after your treatment with Stelara ends.

Stelara may reduce the activity of your immune system and raise your risk of developing certain cancers.

Some people who have taken Stelara have developed skin cancer (non-melanoma varieties), but these people may have already been at high risk for skin cancer. Talk to your doctor about this possibility.

Before receiving Stelara, tell your doctor if you have, or have ever had:

• Any type of cancer
• Hepatitis
• Phototherapy (an ultraviolet light treatment)
• A history of infections
• Allergies to medications, or a latex allergy
• Allergy shots
• New or changing skin lesions

Your doctor will order frequent tests to monitor your body's response to Stelara. Keep all appointments with your doctor's office and laboratory while taking this drug.

Pregnancy and Stelara

Stelara isn't believed to harm an unborn baby.

Still, talk to your doctor if you're pregnant or might become pregnant during your treatment.

The medicine passes into breast milk and may hurt a breastfeeding baby. Don't breastfeed while taking Stelara.

Stelara is a prescription medication used to treat adults with:

• moderate or severe psoriasis that involves large areas of the body and may benefit from using injections, pills, or phototherapy
• psoriatic arthritis (Stelara may be used alone or with methotrexate)
• moderate to severe active Crohn’s disease in those who have tried taking other medications but did not work or was not tolerated

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

The dosing for the treatment of psoriasis:

• For patients weighing ≤100 kg (220 lbs), the recommended dose is 45 mg initially and 4 weeks later, followed by 45 mg every 12 weeks.
• For patients weighing >100 kg (220 lbs), the recommended dose is 90 mg initially and 4 weeks later, followed by 90 mg every 12 weeks.

The dosing for the treatment of psoriatic arthritis:

• The recommended dose is 45 mg initially and 4 weeks later, followed by 45 mg every 12 weeks. 
• For patients with co-existent moderate-to-severe plaque psoriasis weighing >100 kg (220 lbs), the recommended dose is 90 mg initially and 4 weeks later, followed by 90 mg every 12 weeks.

The dosing for the treatment of Crohn’s disease is a one-time infusion and is as follows:

• Up to 55 kg (up to 121 lbs): 260 mg 
• Greater than 55 kg (121 lbs) but less than 85 kg (187lbs): 390 mg
• Greater than 85 kg (187lbs): 520 mg

You should not use this medicine if you have received a BCG (Bacillus Calmette and Guérin) vaccine within the past 12 months.

Serious infections may occur during treatment with ustekinumab. Call your doctor right away if you have signs of infection such as: fever, chills, muscle pain, shortness of breath, weight loss, diarrhea or stomach pain, burning when you urinate, feeling very tired, skin warmth or redness, painful skin sores, or coughing up blood.

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Serious infections may occur during treatment with ustekinumab. Call your doctor right away if you have signs of infection such as: fever, chills, muscle pain, shortness of breath, weight loss, diarrhea or stomach pain, burning when you urinate, feeling very tired, skin warmth or redness, painful skin sores, or coughing up blood.

Also call your doctor at once if you have:

• a mole that has changed in size or color;

• swelling, pain, warmth, or redness anywhere on your body;

• stomach pain that is sudden and severe or comes on slowly, changes in bowel habits (diarrhea or constipation);

• pain or burning when you urinate;

• stabbing chest pain, wheezing, cough with yellow or green mucus; or

• severe headache, confusion, change in mental status, vision problems, and/or seizure (convulsions).

Common side effects may include:

• cold symptoms such as stuffy nose, sneezing, cough, sore throat;

• itching;

• vomiting;

• headache;

• vaginal itching or discharge;

• mild tiredness; or

• redness where ustekinumab was injected.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Other drugs may interact with ustekinumab, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.

Stelara® is contraindicated in patients with clinically significant hypersensitivity to ustekinumab or to any of the excipients [see Warnings and Precautions (5.5)].

Single doses up to 6 mg/kg intravenously have been administered in clinical studies without dose-limiting toxicity. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment be instituted immediately.

Ustekinumab is a human IgG1κ monoclonal antibody against the p40 subunit of the IL-12 and IL-23 cytokines. Using DNA recombinant technology, ustekinumab is produced in a well characterized recombinant cell line and is purified using standard bio-processing technology. The manufacturing process contains steps for the clearance of viruses. Ustekinumab is comprised of 1326 amino acids and has an estimated molecular mass that ranges from 148,079 to 149,690 Daltons.

Stelara® (ustekinumab) Injection is a sterile, preservative-free, colorless to slightly yellow solution that may contain a few small translucent or white particles with pH of 5.7– 6.3.

Stelara® for Subcutaneous Use

Available as 45 mg of ustekinumab in 0.5 mL and 90 mg of ustekinumab in 1 mL, supplied as a sterile solution in a single-dose prefilled syringe with a 27 gauge fixed ½ inch needle and as 45 mg of ustekinumab in 0.5 mL in a single-dose 2 mL Type I glass vial with a coated stopper. The syringe is fitted with a passive needle guard and a needle cover that contains dry natural rubber (a derivative of latex).

Each 0.5 mL prefilled syringe or vial delivers 45 mg ustekinumab, L-histidine and L-histidine monohydrochloride monohydrate (0.5 mg), Polysorbate 80 (0.02 mg), and sucrose (38 mg).

Each 1 mL prefilled syringe delivers 90 mg ustekinumab, L-histidine and L-histidine monohydrochloride monohydrate (1 mg), Polysorbate 80 (0.04 mg), and sucrose (76 mg).

Stelara® for Intravenous Infusion

Available as 130 mg of ustekinumab in 26 mL, supplied as a single-dose 30 mL Type I glass vial with a coated stopper.

Each 26 mL vial delivers 130 mg ustekinumab, EDTA disodium salt dihydrate (0.52 mg), L-histidine (20 mg), L-histidine hydrochloride monohydrate (27 mg), L-methionine (10.4 mg), Polysorbate 80 (10.4 mg) and sucrose (2210 mg).

Psoriasis

Two multicenter, randomized, double-blind, placebo-controlled studies (Ps STUDY 1 and Ps STUDY 2) enrolled a total of 1996 subjects 18 years of age and older with plaque psoriasis who had a minimum body surface area involvement of 10%, and Psoriasis Area and Severity Index (PASI) score ≥12, and who were candidates for phototherapy or systemic therapy. Subjects with guttate, erythrodermic, or pustular psoriasis were excluded from the studies.

Ps STUDY 1 enrolled 766 subjects and Ps STUDY 2 enrolled 1230 subjects. The studies had the same design through Week 28. In both studies, subjects were randomized in equal proportion to placebo, 45 mg or 90 mg of Stelara®. Subjects randomized to Stelara® received 45 mg or 90 mg doses, regardless of weight, at Weeks 0, 4, and 16. Subjects randomized to receive placebo at Weeks 0 and 4 crossed over to receive Stelara® (either 45 mg or 90 mg) at Weeks 12 and 16.

In both studies, the endpoints were the proportion of subjects who achieved at least a 75% reduction in PASI score (PASI 75) from baseline to Week 12 and treatment success (cleared or minimal) on the Physician's Global Assessment (PGA). The PGA is a 6-category scale ranging from 0 (cleared) to 5 (severe) that indicates the physician's overall assessment of psoriasis focusing on plaque thickness/induration, erythema, and scaling.

In both studies, subjects in all treatment groups had a median baseline PASI score ranging from approximately 17 to 18. Baseline PGA score was marked or severe in 44% of subjects in Ps STUDY 1 and 40% of subjects in Ps STUDY 2. Approximately two-thirds of all subjects had received prior phototherapy, 69% had received either prior conventional systemic or biologic therapy for the treatment of psoriasis, with 56% receiving prior conventional systemic therapy and 43% receiving prior biologic therapy. A total of 28% of subjects had a history of psoriatic arthritis.

Clinical Response

The results of Ps STUDY 1 and Ps STUDY 2 are presented in Table 5 below.

Examination of age, gender, and race subgroups did not identify differences in response to Stelara® among these subgroups.

In subjects who weighed 100 kg or less, response rates were similar with both the 45 mg and 90 mg doses; however, in subjects who weighed greater than 100 kg, higher response rates were seen with 90 mg dosing compared with 45 mg dosing (Table 6 below).

Subjects in Ps STUDY 1 who were PASI 75 responders at both Weeks 28 and 40 were re-randomized at Week 40 to either continued dosing of Stelara® (Stelara® at Week 40) or to withdrawal of therapy (placebo at Week 40). At Week 52, 89% (144/162) of subjects re-randomized to Stelara® treatment were PASI 75 responders compared with 63% (100/159) of subjects re-randomized to placebo (treatment withdrawal after Week 28 dose). The median time to loss of PASI 75 response among the subjects randomized to treatment withdrawal was 16 weeks.

Psoriatic Arthritis

The safety and efficacy of Stelara® was assessed in 927 patients (PsA STUDY 1, n=615; PsA STUDY 2, n=312), in two randomized, double-blind, placebo-controlled studies in adult patients 18 years of age and older with active PsA (≥5 swollen joints and ≥5 tender joints) despite non-steroidal anti-inflammatory (NSAID) or disease modifying antirheumatic (DMARD) therapy. Patients in these studies had a diagnosis of PsA for at least 6 months. Patients with each subtype of PsA were enrolled, including polyarticular arthritis with the absence of rheumatoid nodules (39%), spondylitis with peripheral arthritis (28%), asymmetric peripheral arthritis (21%), distal interphalangeal involvement (12%) and arthritis mutilans (0.5%). Over 70% and 40% of the patients, respectively, had enthesitis and dactylitis at baseline.

Patients were randomized to receive treatment with Stelara® 45 mg, 90 mg, or placebo subcutaneously at Weeks 0 and 4 followed by every 12 weeks (q12w) dosing. Approximately 50% of patients continued on stable doses of MTX (≤25 mg/week). The primary endpoint was the percentage of patients achieving ACR 20 response at Week 24.

In PsA STUDY 1 and PsA STUDY 2, 80% and 86% of the patients, respectively, had been previously treated with DMARDs. In PsA STUDY 1, previous treatment with anti-tumor necrosis factor (TNF)-α agent was not allowed. In PsA STUDY 2, 58% (n=180) of the patients had been previously treated with TNF blocker, of whom over 70% had discontinued their TNF blocker treatment for lack of efficacy or intolerance at any time.

Clinical Response

In both studies, a greater proportion of patients achieved ACR 20, ACR 50 and PASI 75 response in the Stelara® 45 mg and 90 mg groups compared to placebo at Week 24 (see Table 7). ACR 70 responses were also higher in the Stelara® 45 mg and 90 mg groups, although the difference was only numerical (p=NS) in STUDY 2. Responses were similar in patients regardless of prior TNFα exposure.

The percent of patients achieving ACR 20 responses by visit is shown in Figure 1.

Figure 1: Percent of patients achieving ACR 20 response through Week 24

The results of the components of the ACR response criteria are shown in Table 8.

An improvement in enthesitis and dactylitis scores was observed in each Stelara® group compared with placebo at Week 24.

Physical Function

Stelara® treated patients showed improvement in physical function compared to patients treated with placebo as assessed by HAQ-DI at Week 24. In both studies, the proportion of HAQ-DI responders (≥0.3 improvement in HAQ-DI score) was greater in the Stelara® 45 mg and 90 mg groups compared to placebo at Week 24.

Crohn's Disease

Stelara® was evaluated in three randomized, double-blind, placebo-controlled clinical studies in adult patients with moderately to severely active Crohn's disease (Crohn's Disease Activity Index [CDAI] score of 220 to 450). There were two 8-week intravenous induction studies (CD-1 and CD-2) followed by a 44-week subcutaneous randomized withdrawal maintenance study (CD-3) representing 52 weeks of therapy.

Studies CD-1 and CD-2

In studies CD-1 and CD-2, 1409 patients were randomized, of whom 1368 (CD-1, n=741; CD-2, n=627) were included in the final efficacy analysis. Induction of clinical response (defined as a reduction in CDAI score of greater than or equal to 100 points or CDAI score of less than 150) at Week 6 and clinical remission (defined as a CDAI score of less than 150) at Week 8 were evaluated. In both studies, patients were randomized to receive a single intravenous administration of Stelara® at either approximately 6 mg/kg, placebo (see Table 1), or 130 mg (a lower dose than recommended).

In Study CD-1, patients had failed or were intolerant to prior treatment with a TNF blocker: 29% patients had an inadequate initial response (primary non-responders), 69% responded but subsequently lost response (secondary non-responders) and 36% were intolerant to a TNF blocker. Of these patients, 48% failed or were intolerant to one TNF blocker and 52% had failed 2 or 3 prior TNF blockers. At baseline and throughout the study, approximately 46% of the patients were receiving corticosteroids and 31% of the patients were receiving immunomodulators (azathioprine, 6-mercaptopurine, methotrexate). The median baseline CDAI score was 319 in the Stelara® approximately 6 mg/kg group and 313 in the placebo group.

In Study CD-2, patients had failed or were intolerant to prior treatment with corticosteroids (81% of patients), at least one immunomodulator (6-mercaptopurine, azathioprine, methotrexate; 68% of patients), or both (49% of patients). Additionally, 69% never received a TNF blocker and 31% previously received but had not failed a TNF blocker. At baseline, and throughout the study, approximately 39% of the patients were receiving corticosteroids and 35% of the patients were receiving immunomodulators (azathioprine, 6-mercaptopurine, methotrexate). The median baseline CDAI score was 286 in the Stelara® and 290 in the placebo group.

In these induction studies, a greater proportion of patients treated with Stelara® achieved clinical response at Week 6 and clinical remission at Week 8 compared to placebo (see Table 9 for clinical response and remission rates). Clinical response and remission were significant as early as Week 3 in Stelara®-treated patients and continued to improve through Week 8.

Study CD-3

The maintenance study (CD-3), evaluated 388 patients who achieved clinical response (≥100 point reduction in CDAI score) at Week 8 of induction with Stelara® in studies CD-1 or CD-2. Patients were randomized to receive a subcutaneous maintenance regimen of either 90 mg Stelara® every 8 weeks or placebo for 44 weeks (see Table 10).

At Week 44, 47% of patients who received Stelara® were corticosteroid-free and in clinical remission, compared to 30% of patients in the placebo group.

At Week 0 of Study CD-3, 34/56 (61%) Stelara® treated patients who previously failed or were intolerant to TNF blocker therapies were in clinical remission and 23/56 (41%) of these patients were in clinical remission at Week 44. In the placebo arm, 27/61 (44%) patients were in clinical remission at Week 0 while 16/61 (26%) of these patients were in remission at Week 44.

At Week 0 of Study CD-3, 46/72 (64%) Stelara® treated patients who had previously failed immunomodulator therapy or corticosteroids (but not TNF blockers) were in clinical remission and 45/72 (63%) of these patients were in clinical remission at Week 44. In the placebo arm, 50/70 (71%) of these patients were in clinical remission at Week 0 while 31/70 (44%) were in remission at Week 44. In the subset of these patients who were also naïve to TNF blockers, 34/52 (65%) of Stelara® treated patients were in clinical remission at Week 44 as compared to 25/51 (49%) in the placebo arm.

Patients who were not in clinical response 8 weeks after Stelara® induction were not included in the primary efficacy analyses for Study CD-3; however, these patients were eligible to receive a 90 mg subcutaneous injection of Stelara® upon entry into Study CD-3. Of these patients, 102/219 (47%) achieved clinical response eight weeks later and were followed for the duration of the study.

Applies to ustekinumab: intravenous solution, subcutaneous solution

Respiratory

Common (1% to 10%): Nasopharyngitis, upper respiratory tract infection, oropharyngeal pain
Uncommon (0.1% to 1%): Nasal congestion[Ref]

Nervous system

Common (1% to 10%): Headache, dizziness
Uncommon (0.1% to 1%): Facial palsy[Ref]

Other

Common (1% to 10%): Fatigue[Ref]

Gastrointestinal

Common (1% to 10%): Diarrhea, nausea[Ref]

Musculoskeletal

Common (1% to 10%): Back pain, myalgia, arthralgia[Ref]

Local

Common (1% to 10%): Injection site erythema, pain, bruising, irritation
Uncommon (0.1% to 1%): Injection site reactions (including hemorrhage, hematoma, induration, swelling, and pruritus)[Ref]

Dermatologic

Common (1% to 10%): Pruritus
Uncommon (0.1% to 1%): Pustular psoriasis, skin exfoliation
Rare (less than 0.1%): Exfoliative dermatitis
Postmarketing reports: Erythrodermic psoriasis[Ref]

Psychiatric

Common (1% to 10%): Depression[Ref]

Oncologic

Common (1% to 10%): Malignancies (1.7%)
Postmarketing reports: Rapidly appearing, multiple cutaneous squamous cell carcinomas[Ref]

Hypersensitivity

Uncommon (0.1% to 1%): Hypersensitivity reactions (including rash, urticaria)
Rare (less than 0.1%): Serious hypersensitivity reactions (including anaphylaxis and angioedema)[Ref]

Immunologic

Very common (10% or more): Infections (up to 27%)
Common (1% to 10%): About 6% of patients developed antibodies to this drug, dental infections
Uncommon (0.1% to 1%): Cellulitis, herpes zoster, viral upper respiratory tract infection[Ref]

Some side effects of Stelara may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.