Drug Safety-related Labeling Changes (SrLC)

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Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

STELARA (BLA-125261)

(USTEKINUMAB)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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03/18/2024 (SUPPL-163)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Infections

Additions and/or revisions underlined:

…

Plaque Psoriasis: diverticulitis, cellulitis, pneumonia, appendicitis, cholecystitis, sepsis, osteomyelitis, viral infections, gastroenteritis, and urinary tract infections.

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

Table 5 title revision; see label for complete information

Adult Subjects with Plaque Psoriasis

The safety data reflect exposure to STELARA® in 3117 adult subjects with plaque psoriasis, including 2414 exposed for at least 6 months, 1855 exposed for at least one year, 1653 exposed for at least two years, 1569 exposed for at least three years, 1482 exposed for at least four years and 838 exposed for at least five years.

…

Infections

In the placebo-controlled period of clinical trials of subjects with plaque psoriasis (average follow- up of 12.6 weeks for placebo-treated subjects and 13.4 weeks for STELARA®-treated subjects)…

… In the controlled and non-controlled portions of plaque psoriasis clinical trials (median follow--up of 3.2 years), representing 8998 subject-years of exposure, 72.3% of STELARA®-treated subjects reported infections (0.87 per subject-years of follow-up). Serious infections were reported in 2.8% of subjects (0.01 per subject-years of follow-up).

Malignancies

In the controlled and non-controlled portions of plaque psoriasis clinical trials (median follow-up of 3.2 years, representing 8998 subject-years of exposure)…

…

Pediatric Subjects with Plaque Psoriasis

The safety of STELARA® was assessed in two trials of pediatric subjects with moderate to severe plaque psoriasis. Ps STUDY 3 evaluated safety for up to 60 weeks in 110 pediatric subjects 12 to 17 years old. Ps STUDY 4 evaluated safety for up to 56 weeks in 44 pediatric subjects 6 to 11 years old. The safety profile in pediatric subjects was similar to the safety profile from trials in adults with plaque psoriasis.

6.2 Immunogenicity

Additions and/or revisions underlined:

…

Approximately 6 to 12.4% of subjects treated with STELARA® in plaque psoriasis and psoriatic arthritis clinical trials developed antibodies to ustekinumab, which were generally low-titer. In plaque psoriasis clinical trials, antibodies to ustekinumab were associated with reduced or undetectable serum ustekinumab concentrations and reduced efficacy. In plaque psoriasis trials, the majority of subjects who were positive for antibodies to ustekinumab had neutralizing antibodies.

7 Drug Interactions

7.1 Concomitant Therapies

Additions and/or revisions underlined:

In plaque psoriasis trials the safety of STELARA® in combination with immunosuppressive agents or phototherapy has not been evaluated.

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

Risk Summary

Limited data from observational studies, published case reports, and postmarketing surveillance on the use of STELARA® during pregnancy are insufficient to inform a drug associated risk of major birth defects, miscarriage, and 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, STELARA® may be transferred to the developing fetus (see Clinical Considerations). In animal reproductive and developmental toxicity studies, no adverse developmental effects were observed in offspring after administration of ustekinumab to pregnant monkeys at exposures greater than 100 times the maximum recommended human dose (MRHD).

…

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Because ustekinumab may theoretically interfere with immune response to infections, consider risks and benefits prior to administering live vaccines to infants exposed to STELARA® in utero. There are insufficient data regarding exposed infant serum levels of ustekinumab at birth and the duration of persistence of ustekinumab in infant serum after birth. 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.

…

Animal Data

…

8.2 Lactation

Additions and/or revisions underlined:

Limited data from published literature suggests that ustekinumab is present in human breast milk. There are no available data on the effects of ustekinumab on milk production. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed infant to ustekinumab are unknown. No adverse effects on the breastfed infant causally related to ustekinumab have been identified in the published literature or postmarketing experience.

8.4 Pediatric Use

Additions and/or revisions underlined:

The safety and effectiveness of STELARA® have been established for the treatment of moderate to severe plaque psoriasis in pediatric patients 6 to 17 years of age who are candidates for phototherapy or systemic therapy.

…

The safety and effectiveness of STELARA® have not been established in pediatric patients less than 6 years of age with plaque psoriasis.

8.5 Geriatric Use

Additions and/or revisions underlined:

Of the 6709 patients exposed to STELARA®, a total of 340 were 65 years of age or older (183 patients with plaque psoriasis, 65 patients with psoriatic arthritis, 58 patients with Crohn’s disease, and 34 patients with ulcerative colitis), and 40 patients were 75 years of age or older. Clinical trials of STELARA® did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined:

Before you receive STELARA, tell your doctor about all of your medical conditions, including if you:

are pregnant or plan to become pregnant. It is not known if STELARA can harm your unborn baby. You and your doctor should decide if you will receive STELARA. See “What should I avoid while using STELARA?”
received STELARA while you were pregnant. It is important that you tell your baby’s healthcare provider before any vaccinations are given to your baby.
are breastfeeding or plan to breastfeed. STELARA can pass into your breast milk.

03/06/2023 (SUPPL-158)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.6 Reversible Posterior Leukoencephalopathy Syndrome

Subsection title revised; Additions and/or revisions underlined:

One case of reversible posterior leukoencephalopathy syndrome (RPLS) was observed in clinical studies of psoriasis and psoriatic arthritis. The subject, who had received 12 doses of STELARA® over approximately two years, presented with headache, seizures and confusion. No additional STELARA® injections were administered and the subject fully recovered with appropriate treatment. No cases of RPLS were observed in clinical studies of Crohn’s disease or ulcerative colitis.

RPLS is a neurological disorder, which is not caused by demyelination or a known infectious agent. RPLS can present with headache, seizures, confusion and visual disturbances. Conditions with which it has been associated include preeclampsia, eclampsia, acute hypertension, cytotoxic agents and immunosuppressive therapy. Fatal outcomes have been reported.

If RPLS is suspected, administer appropriate treatment and discontinue STELARA.

6 Adverse Reactions

Additions and/or revisions underlined:

The following serious adverse reactions are discussed elsewhere in the label:

· Infections [see Warnings and Precautions (5.1)]
· Malignancies [see Warnings and Precautions (5.4)]
· Hypersensitivity Reactions [see Warnings and Precautions (5.5)]
· Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions (5.6)]

6.1 Clinical Trials Experience

Table numbers revised

6.3 Postmarketing Experience

Additions and/or revisions underlined:

…

Skin reactions: Pustular psoriasis, erythrodermic psoriasis, hypersensitivity vasculitis.

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

The safety and effectiveness of STELARA® have been established in pediatric patients 6 to 17 years old with moderate to severe plaque psoriasis. Use of STELARA® in adolescents is supported by evidence from a multicenter, randomized, 60-week trial (Ps STUDY 3) that included a 12-week, double-blind, placebo-controlled, parallel-group portion, in 110 pediatric subjects 12 years and older [see Adverse Reactions (6.1), Clinical Studies (14.2)].

Use of STELARA® in children 6 to 11 years with moderate to severe plaque psoriasis is supported by evidence from an open-label, single-arm, efficacy, safety and pharmacokinetics study (Ps STUDY 4) in 44 subjects [see Adverse Reactions (6.1), Pharmacokinetics (12.3)].

The safety and effectiveness of STELARA® for pediatric patients less than 6 years of age with psoriasis have not been established.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined:

…

Reversible Posterior Leukoencephalopathy Syndrome (RPLS). RPLS is a rare condition that affects the brain and can cause death. The cause of RPLS is not known. If RPLS is found early and treated, most people recover. Tell your doctor right away if you have any new or worsening medical problems including:

…

07/29/2022 (SUPPL-161)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined

Plaque Psoriasis

The safety and effectiveness of STELARA® have been established for the treatment of moderate to severe plaque psoriasis in pediatric patients 6 to 17 years old. Use of STELARA® in patients 12 to less than 17 years old is supported by evidence from a multicenter, randomized, 60-week trial (Ps STUDY 3) that included a 12-week, double-blind, placebo-controlled, parallel-group portion, in 110 pediatric subjects 12 years and older [see Adverse Reactions (6.1), Clinical Studies (14.2)].

…

The safety and effectiveness of STELARA® have not been established in pediatric patients less than 6 years of age with psoriasis.

Psoriatic Arthritis

The safety and effectiveness of STELARA® have been established for treatment of psoriatic arthritis in pediatric patients 6 to 17 years old.

Use of STELARA® in these age groups is supported by evidence from adequate and well controlled studies of STELARA® in adults with psoriasis and PsA, pharmacokinetic data from adult patients with psoriasis, adult patients with PsA and pediatric patients with psoriasis, and safety data from two clinical studies in 44 pediatric patients 6 to 11 years old with psoriasis and 110 pediatric patients 12 to 17 years old with psoriasis. The observed pre-dose (trough) concentrations are generally comparable between adult patients with psoriasis, adult patients with PsA and pediatric patients with psoriasis, and the PK exposure is expected to be comparable between adult and pediatric patients with PsA [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.1, 14.2, 14.3)].

The safety and effectiveness of STELARA® have not been established in pediatric patients less than 6 years old with psoriatic arthritis.

Crohn’s Disease and Ulcerative Colitis

The safety and effectiveness of STELARA® have not been established in pediatric patients with Crohn’s disease or ulcerative colitis.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

STELARA is a prescription medicine used to treat:

adults and children 6 years and older with moderate or severe psoriasis who may benefit from taking injections or pills (systemic therapy) or phototherapy (treatment using ultraviolet light alone or with pills).
adults and children 6 years and older with active psoriatic arthritis.
…
How should I use STELARA?
…

Adults with psoriasis or psoriatic arthritis, and children 6 years and older with psoriasis or psoriatic arthritis will receive STELARA as an injection under the skin (subcutaneous injection) as described below.
…

12/11/2020 (SUPPL-157)

5 Warnings and Precautions

Additions and/or revisions underlined:

5.6 Posterior Reversible Encephalopathy Syndrome (PRES)

Two cases of posterior reversible encephalopathy syndrome (PRES), also known as Reversible Posterior Leukoencephalopathy Syndrome (RPLS), were reported in clinical trials. Cases have also been reported in postmarketing experience in patients with psoriasis, psoriatic arthritis and Crohn’s disease. Clinical presentation included headaches, seizures, confusion, visual disturbances, and imaging changes consistent with PRES a few days to several months after ustekinumab initiation. A few cases reported latency of a year or longer. Patients recovered with supportive care following withdrawal of ustekinumab.

Monitor all patients treated with STELARA® for signs and symptoms of PRES. If PRES is suspected, promptly administer appropriate treatment and discontinue STELARA®.

6 Adverse Reactions

Additions and/or revisions underlined in bulleted line listing:

Posterior Reversible Encephalopathy Syndrome (PRES) [see Warnings and Precautions (5.6)]

6.1 Clinical Trials Experience

Adult Subjects with Plaque Psoriasis

Additions and/or revisions underlined following Table 4:

One case of PRES occurred during adult plaque psoriasis clinical studies [see Warnings and Precautions (5.6)].

6.3 Postmarketing Experience

Newly added information:

Neurological disorders: Posterior Reversible Encephalopathy Syndrome (PRES) [see Warnings and Precautions (5.6)].

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined:

What is the most important information I should know about STELARA?

Posterior Reversible Encephalopathy Syndrome (PRES). PRES is a rare condition that affects the brain and can cause death. The cause of PRES is not known. If PRES is found early and treated, most people recover. Tell your doctor right away if you have any new or worsening medical problems including ….

PATIENT COUNSELING INFORMATION

Newly added information following ‘Hypersensitivity Reactions’:

Posterior Reversible Encephalopathy Syndrome (PRES)

Inform patients to immediately contact their healthcare provider if they experience signs and symptoms of PRES (which may include headache, seizures, confusion, or visual disturbances) [see Warnings and Precautions (5.6)].

07/29/2020 (SUPPL-150)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.8 Concomitant Therapies

(Additions and/or revisions underlined)

In clinical studies of psoriasis the safety of STELARA® in combination with other biologic immunosuppressive agents or phototherapy was not evaluated. Ultraviolet-induced skin cancers developed earlier and more frequently in mice genetically manipulated to be deficient in both IL- 12 and IL-23 or IL-12 alone [see Concomitant Therapies (7.1), Nonclinical Toxicology (13.1)].

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions underlined)

…

Pediatric Subjects with Plaque Psoriasis

The safety of STELARA® was assessed in two studies of pediatric subjects with moderate to severe plaque psoriasis. Ps STUDY 3 evaluated safety for up to 60 weeks in 110 adolescents (12 to 17 years old). Ps STUDY 4 evaluated safety for up to 56 weeks in 44 children (6 to 11 years old). The safety profile in pediatric subjects was similar to the safety profile from studies in adults with plaque psoriasis.

…

8 Use in Specific Populations

8.4 Pediatric Use

(Additions and/or revisions underlined)

The safety and effectiveness of STELARA® for pediatric patients less than 6 years of age with psoriasis have not been established.

The safety and effectiveness of STELARA® have not been established in pediatric patients with psoriatic arthritis, Crohn’s disease or ulcerative colitis.

11/07/2019 (SUPPL-142)

Approved Drug Label (PDF)

5 Warnings and Precautions

Additions and/or revisions underlined:

5.1 Infections

STELARA® may increase the risk of infections and reactivation of latent infections. Serious bacterial, mycobacterial, fungal, and viral infections were observed in patients receiving STELARA®.

Serious infections requiring hospitalization, or otherwise clinically significant infections, reported in clinical studies included the following:

Psoriasis: diverticulitis, cellulitis …
Psoriatic arthritis: cholecystitis.
Crohn’s disease: anal abscess, gastroenteritis, ophthalmic herpes zoster, pneumonia, and listeria meningitis.

Ulcerative colitis: gastroenteritis, ophthalmic herpes zoster, pneumonia, and listeriosis.

5.6 Reversible Posterior Leukoencephalopathy Syndrome

… No cases of RPLS were observed in clinical studies of Crohn’s disease or ulcerative colitis.

6 Adverse Reactions

6.1 Clinical Trials Experience

Following Table 6, additions and/or revisions underlined:

Infections

In patients with Crohn’s disease, serious or other clinically significant infections included anal abscess, gastroenteritis, and pneumonia. In addition, listeria meningitis and ophthalmic herpes zoster were reported in one patient each.

Newly added information:

Ulcerative Colitis

The safety of STELARA® was evaluated in two randomized, double-blind, placebo-controlled clinical studies (UC-1 [IV induction] and UC-2 [SC maintenance]) in 960 adult patients with moderately to severely active ulcerative colitis. The overall safety profile of STELARA® in patients with ulcerative colitis was consistent with the safety profile seen across all approved indications. Adverse reactions reported in at least 3% of STELARA®-treated patients and at a higher rate than placebo were: Induction (UC-1): nasopharyngitis (7% vs 4%).

Maintenance (UC-2): nasopharyngitis (24% vs 20%), headache (10% vs 4%), abdominal pain (7% vs 3%), influenza (6% vs 5%), fever (5% vs. 4%), diarrhea (4% vs 1%), sinusitis (4% vs 1%), fatigue (4% vs 2%), and nausea (3% vs 2%).

Infections

In patients with ulcerative colitis, serious or other clinically significant infections included gastroenteritis and pneumonia. In addition, listeriosis and ophthalmic herpes zoster were reported in one patient each.

Malignancies

With up to one year of treatment in the ulcerative colitis clinical studies, 0.4% of STELARA®- treated patients (0.48 events per hundred patient-years) and 0.0% of placebo-treated patients (0.00 events per hundred patient-years) developed non-melanoma skin cancer. Malignancies other than non-melanoma skin cancers occurred in 0.5% of STELARA®-treated patients (0.64 events per hundred patient-years) and 0.2% of placebo-treated patients (0.40 events per hundred patient- years).

6.2 Immunogenicity

Additions and/or revisions underlined:

… In psoriasis clinical studies, antibodies to ustekinumab were associated with reduced or undetectable serum ustekinumab concentrations and reduced efficacy. In psoriasis studies, the majority of patients who were positive for antibodies to ustekinumab had neutralizing antibodies.

In Crohn’s disease and ulcerative colitis clinical studies, 2.9% and 4.6% of patients, respectively, developed antibodies to ustekinumab when treated with STELARA® for approximately one year. No apparent association between the development of antibodies.

6.3 Postmarketing Experience

Newly added information:

Infections and infestations: Lower respiratory tract infection (including opportunistic fungal infections and tuberculosis).

7 Drug Interactions

7.2 Concomitant Therapies

Additions and/or revisions underlined:

… In Crohn’s disease and ulcerative colitis induction studies, immunomodulators (6-MP, AZA, MTX) were used concomitantly in approximately 30% of patients and corticosteroids were used concomitantly in approximately 40% and 50% of Crohn’s disease and ulcerative colitis patients, respectively. Use of these concomitant therapies did not appear to influence the overall safety or efficacy of STELARA®.

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

… The safety and effectiveness of STELARA® for pediatric patients less than 12 years of age with psoriasis have not been established.

The safety and effectiveness of STELARA® have not been established in pediatric patients with psoriatic arthritis, Crohn’s disease or ulcerative colitis.

10/18/2019 (SUPPL-152)

5 Warnings and Precautions

Infections

Additions and/or revisions underlined:

STELARA® may increase the risk of infections and reactivation of latent infections. Serious bacterial, fungal, and viral infections were observed in subjects receiving STELARA®.

Serious infections requiring hospitalization, or otherwise clinically significant infections, reported in clinical studies included the following:

· Psoriasis: diverticulitis, cellulitis, pneumonia, appendicitis, cholecystitis, sepsis, osteomyelitis, viral infections, gastroenteritis and urinary tract infections.

· Psoriatic arthritis: cholecystitis.

· Crohn’s disease: anal abscess, gastroenteritis, ophthalmic herpes zoster, pneumonia, and listeria meningitis.

· Ulcerative colitis: gastroenteritis, ophthalmic herpes zoster, pneumonia, and listeriosis.

Reversible Posterior Leukoencephalopathy Syndrome

Additions and/or revisions underlined:

appropriate treatment.

6 Adverse Reactions

Clinical Trials Experience

Adult Subjects with Plaque Psoriasis

Additions and/or revisions underlined:

The safety data reflect exposure to STELARA® in 3117 adult psoriasis subjects, including 2414 exposed for at least 6 months, 1855 exposed for at least one year, 1653 exposed for at least two years, 1569 exposed for at least three years, 1482 exposed for at least four years and 838 exposed for at least five years.

Adolescent Subjects with Plaque Psoriasis

Newly added subsection:

The safety of STELARA® was assessed in a study of 110 subjects 12 to 17 years of age with moderate to severe plaque psoriasis. The safety profile in these subjects through Week 60 was similar to the safety profile from studies in adults with plaque psoriasis.

Crohn’s Disease

Additions and/or revisions underlined:

. . . Patients in these 3 studies may have received other concomitant therapies including aminosalicylates, immunomodulatory agents [azathioprine (AZA), 6-mercaptopurine (6-MP), MTX], oral corticosteroids (prednisone or budesonide), and/or antibiotics for their Crohn’s disease.

Ulcerative Colitis

Newly added subsection:

The safety of STELARA® was evaluated in two randomized, double-blind, placebo-controlled clinical studies (UC-1 [IV induction] and UC-2 [SC maintenance]) in 960 adult patients with moderately to severely active ulcerative colitis [see Clinical Studies (14.5)]. The overall safety profile of STELARA® in patients with ulcerative colitis was consistent with the safety profile seen across all approved indications. Adverse reactions reported in at least 3% of STELARA®-treated patients and at a higher rate than placebo were:

· Induction (UC-1): nasopharyngitis (7% vs 4%).

· Maintenance (UC-2): nasopharyngitis (24% vs 20%), headache (10% vs 4%), abdominal pain (7% vs 3%), influenza (6% vs 5%), fever (5% vs. 4%), diarrhea (4% vs 1%), sinusitis (4% vs 1%), fatigue (4% vs 2%), and nausea (3% vs 2%).

Infections

Newly added subsection:

Malignancies

Newly added subsection:

Immunogenicity

Additions and/or revisions underlined:

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications and underlying disease. For these reasons, comparison of the incidence of antibodies to ustekinumab in the studies described below with the incidence of antibodies to other products may be misleading.

Approximately 6 to 12.4% of subjects treated with STELARA® in psoriasis and psoriatic arthritis clinical studies developed antibodies to ustekinumab, which were generally low-titer. In psoriasis clinical studies, antibodies to ustekinumab were associated with reduced or undetectable serum ustekinumab concentrations and reduced efficacy. In psoriasis studies, the majority of patients who were positive for antibodies to ustekinumab had neutralizing antibodies.

Postmarketing Experience

Additions and/or revisions underlined:

The following adverse reactions have been reported during post-approval of STELARA®. . .

Respiratory, thoracic and mediastinal disorders: Interstitial pneumonia, eosinophilic pneumonia and cryptogenic organizing pneumonia

7 Drug Interactions

Concomitant Therapies

Additions and/or revisions underlined:

In psoriasis studies the safety of STELARA® in combination with immunosuppressive agents or phototherapy has not been evaluated. In psoriatic arthritis studies, concomitant MTX use did not appear to influence the safety or efficacy of STELARA®. In Crohn’s disease and ulcerative colitis induction studies, immunomodulators (6-MP, AZA, MTX) were used concomitantly in approximately 30% of patients and corticosteroids were used concomitantly in approximately 40% and 50% of Crohn’s disease and ulcerative colitis patients, respectively. Use of these concomitant therapies did not appear to influence the overall safety or efficacy of STELARA®.

8 Use in Specific Populations

Geriatric Use

Of the 6709 patients exposed to STELARA®, a total of 340 were 65 years or older (183 patients with psoriasis, 65 patients with psoriatic arthritis, 58 patients with Crohn’s disease and 34 patients with ulcerative colitis), and 40 patients were 75 years or older. Although no overall differences in safety or efficacy were observed between older and younger patients, the number of patients aged 65 and over is not sufficient to determine whether they respond differently from younger patients.

Pediatric Use

Additions and/or revisions underlined:

The safety and effectiveness of STELARA® have been established in pediatric patients 12 to 17 years old with moderate to severe plaque psoriasis. Use of STELARA® in this age group is supported by evidence from a multicenter, randomized, 60-week trial that included a 12-week, double-blind, placebo-controlled, parallel-group portion, in 110 pediatric subjects 12 years and older. The safety and effectiveness of STELARA® for pediatric patients less than 12 years of age with psoriasis have not been established.

The safety and effectiveness of STELARA® have not been established in pediatric patients with psoriatic arthritis, Crohn’s disease or ulcerative colitis.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Medication Guide

Additions and/or revisions underlined:

What is STELARA?

STELARA is a prescription medicine used to treat:

• adults and children 12 years and older with moderate or severe psoriasis who may benefit from taking injections or pills (systemic therapy) or phototherapy (treatment using ultraviolet light alone or with pills).

• adults 18 years and older with active psoriatic arthritis. STELARA can be used alone or with the medicine methotrexate.

• adults 18 years and older with moderately to severely active Crohn’s disease.

• adults 18 years and older with moderately to severely active ulcerative colitis. It is not known if STELARA is safe and effective in children less than 12 years of age.

How should I use STELARA?

Adults with Crohn’s disease and ulcerative colitis will receive the first dose of STELARA through a vein in the arm (intravenous infusion) in a healthcare facility by a healthcare provider. It takes at least 1 hour to receive the full dose of medicine. You will then receive STELARA as an injection under the skin (subcutaneous injection) 8 weeks after the first dose of STELARA, as described below.

• Adults with psoriasis or psoriatic arthritis and children 12 years and older with psoriasis will receive STELARA as an injection under the skin (subcutaneous injection) as described below.

• Injecting STELARA under your skin

o STELARA is intended for use under the guidance and supervision of your doctor. In children 12 years and older, it is recommended that STELARA be administered by a healthcare provider. If your doctor decides that you or a caregiver may give your injections of STELARA at home, you should receive training on the right way to prepare and inject STELARA. Your doctor will determine the right dose of STELARA for you, the amount for each injection, and how often you should receive it.

Read the detailed Instructions for Use at the end of this Medication Guide for instructions about how to prepare and inject a dose of STELARA, and how to properly throw away (dispose of) used needles and syringes. The syringe, needle and vial must never be re-used. After the cap is punctured, STELARA can become contaminated by harmful bacteria which could cause an infection if re-used. Therefore, throw away any unused portion of STELARA.

STELARA may cause serious side effects, including:

Lung inflammation. Cases of lung inflammation have happened in some people who receive STELARA, and may be serious. These lung problems may need to be treated in a hospital. Tell your doctor right away if you develop shortness of breath or a cough that doesn’t go away during treatment with STELARA.

Common side effects of STELARA include:

• nasal congestion, sore throat, and runny nose • redness at the injection site

• upper respiratory infections • vaginal yeast infections

• fever • urinary tract infections

• headache • sinus infection

• tiredness • stomach pain

• itching • diarrhea

• nausea and vomiting

How should I store STELARA?

• Store STELARA vials standing up straight.

06/08/2018 (SUPPL-147)

Approved Drug Label (PDF)

5 Warnings and Precautions

Newly created subsection:

5.9 Noninfectious Pneumonia

Cases of interstitial pneumonia, eosinophilic pneumonia and cryptogenic organizing pneumonia have been reported during post-approval use of STELARA®. Clinical presentations included cough, dyspnea, and interstitial infiltrates following one to three 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 STELARA® and institute appropriate treatment.

6 Adverse Reactions

6.3 Postmarketing Experience

Addition of the following:

Respiratory, thoracic and mediastinal disorders: Interstitial pneumonia, eosinophilic pneumonia and cryptogenic organizing pneumonia

02/16/2018 (SUPPL-141)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Immunogenicity

(additions underlined)

…

Approximately 6-12.4% of subjects treated with STELARA® in psoriasis and psoriatic arthritis clinical studies developed antibodies to ustekinumab, which were generally low-titer. In Crohn’s disease clinical studies, less than 3% of patients treated with STELARA® developed antibodies to ustekinumab. In psoriasis clinical studies, antibodies to ustekinumab were associated with reduced or undetectable serum ustekinumab concentrations and reduced efficacy. No apparent association between the development of antibodies to ustekinumab and the development of injection site reactions was seen. In psoriasis studies, the majority of patients who were positive for antibodies to ustekinumab had neutralizing antibodies.

10/13/2017 (SUPPL-138)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Infections

(additions underlined)

STELARA® may increase the risk of infections and reactivation of latent infections. Serious bacterial, fungal, and viral infections were observed in subjects receiving STELARA®

Serious infections requiring hospitalization occurred in patients with psoriasis, psoriatic arthritis and Crohn’s disease in clinical studies. In patients with psoriasis, serious infections included diverticulitis, cellulitis, pneumonia, appendicitis, cholecystitis, sepsis, osteomyelitis, viral infections, gastroenteritis and urinary tract infections. In patients with psoriatic arthritis, serious infections included cholecystitis. In patients with Crohn’s disease, serious or other clinically significant infections included anal abscess, gastroenteritis, ophthalmic herpes, pneumonia, and listeria meningitis.

Treatment with STELARA® should not be initiated in patients with any clinically important active infection until the infection resolves or is adequately treated. Consider the risks and benefits of treatment prior to initiating use of STELARA® in patients with a chronic infection or a history of recurrent infection.

Instruct patients to seek medical advice if signs or symptoms suggestive of an infection occur while on treatment with STELARA® and consider discontinuing STELARA® for serious or clinically significant infections until the infection resolves or is adequately treated.

5.6 Reversible Posterior Leukoencephalopathy Syndrome

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6 Adverse Reactions

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Infections
Malignancies
Hypersensitivity Reactions
Reversible Posterior Leukoencephalopathy Syndrome

6.1 Clinical Trials Experience

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6.2 Immunogenicity

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Approximately 6% of subjects treated with STELARA® in psoriasis and psoriatic arthritis clinical studies developed antibodies to ustekinumab, which were generally low-titer. In Crohn’s disease clinical studies, less than 3% of patients treated with STELARA® developed antibodies to ustekinumab. In psoriasis clinical studies, antibodies to ustekinumab were associated with reduced serum ustekinumab concentrations and reduced efficacy. No apparent association between the development of antibodies to ustekinumab and the development of injection site reactions was seen. No ustekinumab-related serious hypersensitivity reactions were observed in psoriasis, psoriatic arthritis and Crohn’s disease clinical studies. In psoriasis studies, the majority of patients who were positive for antibodies to ustekinumab had neutralizing antibodies.

7 Drug Interactions

7.2 Concomitant Therapies

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In psoriasis studies the safety of STELARA® in combination with immunosuppressive agents or phototherapy has not been evaluated. In psoriatic arthritis studies, concomitant methotrexate use did not appear to influence the safety or efficacy of STELARA. In Crohn’s disease studies, immunomodulators (6-mercaptopurine, azathioprine, methotrexate) were used concomitantly in approximately 30% of patients and corticosteroids were used concomitantly in approximately 40% of patients. Use of these concomitant therapies did not appear to influence the overall safety or efficacy of STELARA®.

8 Use in Specific Populations

8.1 Pregnancy

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Risk Summary

Limited data on the use of STELARA® in pregnant women are insufficient to inform a drug associated risk [see Data]. In animal reproductive and developmental toxicity studies, no adverse developmental effects were observed after administration of ustekinumab to pregnant monkeys at exposures greater than 100 times the human exposure at the maximum recommended human subcutaneous dose (MRHD).

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated population(s) are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage of clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Human Data

Limited data on use of STELARA® in pregnant women from observational studies, published case reports, and postmarketing surveillance are insufficient to inform a drug associated risk.

Animal Data

Ustekinumab was tested in two embryo-fetal development toxicity studies in cynomolgus monkeys. No teratogenic or other adverse developmental effects were observed in fetuses from pregnant monkeys that were administered ustekinumab subcutaneously twice weekly or intravenously weekly during the period of organogenesis. Serum concentrations of ustekinumab in pregnant monkeys were greater than 100 times the serum concentration in patients treated subcutaneously with 90 mg of ustekinumab weekly for 4 weeks.

In a combined embryo-fetal development and pre- and post-natal development toxicity study, pregnant cynomolgus monkeys were administered subcutaneous doses of ustekinumab twice weekly at exposures greater than 100 times the human subcutaneous exposure from the beginning of organogenesis to Day 33 after delivery. Neonatal deaths occurred in the offspring of one monkey administered ustekinumab at 22.5 mg/kg and one monkey dosed at 45 mg/kg. No ustekinumab-related effects on functional, morphological, or immunological development were observed in the neonates from birth through six months of age.

8.2 Lactation

(PLLR conversion, additions underlined)

Risk Summary

There are no data on the presence of ustekinumab in human milk, the effects on the breastfed infant, or the effects on milk production. Ustekinumab was present in the milk of lactating monkeys administered ustekinumab. Due to species-specific differences in lactation physiology, animal data may not reliably predict drug levels in human milk. Maternal IgG is known to be present in human milk. Published data suggest that the systemic exposure to a breastfed infant is expected to be low because ustekinumab is a large molecule and is degraded in the gastrointestinal tract. However, if ustekinumab is transferred into human milk the effects of local exposure in the gastrointestinal tract are unknown.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for STELARA® and any potential adverse effects on the breastfed child from STELARA® or from the underlying maternal condition.

8.4 Pediatric Use

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The safety and effectiveness of STELARA® have been established in pediatric subjects 12 to 17 years old with moderate to severe plaque psoriasis. Use of STELARA® in this age group is supported by evidence from a multicenter, randomized, 60-week trial that included a 12-week, double-blind, placebo-controlled, parallel-group portion, in 110 pediatric subjects 12 years and older. The safety and effectiveness of STELARA® for pediatric patients less than 12 years of age have not been established.

8.5 Geriatric Use

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Of the 5884 subjects exposed to STELARA®, a total of 306 were 65 years or older (183 patients with psoriasis, 65 patients with psoriatic arthritis and 58 with Crohn’s disease), and 34 subjects were 75 years or older. Although no differences in safety or efficacy were observed between older and younger subjects, the number of subjects aged 65 and over is not sufficient to determine whether they respond differently from younger subjects.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

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Immunizations

Inform patients that STELARA® can interfere with the usual response to immunizations and that they should avoid live vaccines

Pregnancy Registry

Inform patients that there is a pregnancy registry to monitor fetal outcomes of pregnant women exposed to STELARA®

Administration

Instruct patients to follow sharps disposal recommendations, as described in the Instructions for Use.

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