These Highlights Do Not Include All The Information Needed To Use Ustekinumab-aauz Safely And Effectively. See Full Prescribing Information For Ustekinumab-aauz.

Subcutaneous Pediatric Dosage Regimen

Administer Ustekinumab-aauz subcutaneously at Weeks 0 and 4, then every 12 weeks thereafter.

The recommended dose of Ustekinumab-aauz for pediatric patients (6-17 years old) with plaque psoriasis based on body weight is shown below (Table 1).

Dosage and Administration (2.1, 2.2, 2.4)                                                                                                  03/2025

INSTRUCTIONS FOR USE

Ustekinumab-aauz (u-ste-KIN-u-mab aauz)

injection, for subcutaneous use

This product is OTULFI (ustekinumab-aauz)

Read this Instructions for Use before you start using Ustekinumab-aauz. Your doctor or nurse should show you how to prepare and give your injection of Ustekinumab-aauz the right way.

If you cannot give yourself the injection:

• •
  ask your doctor or nurse to help you, or
• •
  ask someone who has been trained by a doctor or nurse to give your injections.

Do not try to inject Ustekinumab-aauz yourself until you have been shown how to inject Ustekinumab-aauz by your doctor, nurse or health professional.

Important information:

• •
  Before you start, check the carton to make sure that it is the right dose. You will have either 45 mg or 90 mg as prescribed by your doctor.
  • o
    If your dose is 45 mg, you will receive one 45 mg prefilled syringe.
  • o
    If your dose is 90 mg, you will receive either one 90 mg prefilled syringe or two 45 mg prefilled syringes. If you receive two 45 mg prefilled syringes for a 90 mg dose, you will need to give yourself two injections, one right after the other.
• •
  Children 12 years of age and older with psoriasis, who weigh 132 pounds (60 kg) or more may use a prefilled syringe.
• •
  Store Ustekinumab-aauz in a refrigerator between 36°F to 46°F (2°C to 8°C) in the original carton to protect from light.
• •
  If needed, individual Ustekinumab-aauz prefilled syringes may also be stored at room temperature up to 86°F (30°C) for a maximum single period of up to 30 days in the original carton to protect from light. Record the date when the prefilled syringe is first removed from the refrigerator on the carton in the space provided. If a syringe has been stored at room temperature, it should not be returned to the refrigerator.
• •
  Check the expiration date on the prefilled syringe and carton. If the expiration date has passed or if the prefilled syringe has been kept at room temperature up to 86°F (30°C) for longer than a maximum single period of 30 days or if the prefilled syringe has been stored above 86°F (30°C), do not use it. If the expiration date has passed or if the prefilled syringe has been stored above 86°F (30°C), call your doctor or pharmacist, or call or call manufacturer`s phone for help.
• •
  Make sure the syringe is not damaged.
• •
  Check your prefilled syringe for any particles or discoloration. Your prefilled syringe should look clear and colorless to slightly brown-yellow.
• •
  Do not use if it is frozen, discolored, cloudy or has particles. Get a new prefilled syringe.
• •
  Do not shake the prefilled syringe at any time. Shaking your prefilled syringe may damage your Ustekinumab-aauz medicine. If your prefilled syringe has been shaken, do not use it. Get a new prefilled syringe.
• •
  To reduce the risk of accidental needle sticks, each prefilled syringe has a needle guard that is automatically activated to cover the needle after you have given your injection. Do not pull back on the plunger at any time.

Gather the supplies you will need to prepare and to give your injection. (See Figure A)

You will need:

• •
  antiseptic wipes
• •
  cotton balls or gauze pads
• •
  adhesive bandage
• •
  your prescribed dose of Ustekinumab-aauz (See Figure B)
• •
  FDA-cleared sharps disposal container. See "Step 4: Dispose of the syringe."

Figure A

Figure B

To prevent early activation of the needle safety guard, do not touch the NEEDLE GUARD ACTIVATION CLIPS at any time during use.

Step 1: Prepare the injection.

• •
  Choose a well-lit, clean, flat work surface.
• •
  Wash your hands well with soap and warm water.
• •
  Hold the prefilled syringe with the covered needle pointing upward.

Step 2: Prepare your injection site

• •
  Choose an injection site around your stomach area (abdomen), buttocks, upper legs (thighs). If a caregiver is giving you the injection, the outer area of the upper arms may also be used. (See Figure C)
• •
  Use a different injection site for each injection. Do not give an injection in an area of the skin that is tender, bruised, red or hard.
• •
  Clean the skin with an antiseptic wipe where you plan to give your injection.
• •
  Do not touch this area again before giving the injection. Let your skin dry before injecting.
• •
  Do not fan or blow on the clean area.

Figure C

*Areas in gray are recommended injection sites.

Step 3: Inject Ustekinumab-aauz

• •
  Remove the needle cover when you are ready to inject your Ustekinumab-aauz.
• •
  Do not touch the plunger or plunger head while removing the needle cover.
• •
  Hold the body of the prefilled syringe with one hand and pull the needle cover straight off. (See Figure D)
• •
  Put the needle cover in the trash.
• •
  You may also see a drop of liquid at the end of the needle. This is normal.
• •
  Do not touch the needle or let it touch anything.
• •
  Do not use the prefilled syringe if it is dropped without the needle cover in place or if it is dropped onto a hard surface. Call your doctor, nurse or health professional for instructions.

Figure D

Figure E

• •
  Do not pull back on the plunger at any time.
• •
  Use the other hand to gently pinch the cleaned area of skin. Hold firmly.
• •
  Use a quick, dart-like motion to insert the needle into the pinched skin at about a 45-degree angle. (See Figure F)

Figure F

• •
  Inject all of the liquid by using your thumb to push in the plunger until the plunger head is completely between the needle guard wings. (See Figure G)

Figure G

• •
  When the plunger is pushed as far as it will go, keep pressure on the plunger head. Take the needle out of the skin and let go of the skin.
• •
  Slowly take your thumb off the plunger head. This will let the empty syringe move up until the entire needle is covered by the needle guard. (See Figure H)

Figure H

• •
  When the needle is pulled out of your skin, there may be a little bleeding at the injection site. This is normal. You can press a cotton ball or gauze pad to the injection site if needed. Do not rub the injection site. You may cover the injection site with a small adhesive bandage, if necessary.

If your dose is 90 mg, you will receive either one 90 mg prefilled syringe or two 45 mg prefilled syringes. If you receive two 45 mg prefilled syringes for a 90 mg dose, you will need to give yourself a second injection right after the first. Repeat Steps 1–3 for the second injection using a new syringe. Choose a different site for the second injection.

Step 4: Dispose of the syringe.

• •
  Put the syringe in an FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose syringes in your household trash.
• •
  If you do not have an FDA-cleared sharps disposal container, you may use a household container that is:
  • o
    made of heavy-duty plastic.
  • o
    can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out.
  • o
    upright and stable during use,
  • o
    leak-resistant,
  • o
    and properly labeled to warn of hazardous waste inside the container.
• •
  When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be local or state laws about how to throw away syringes and needles. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA's website at: http://www.fda.gov/safesharpsdisposal.
• •
  Do not dispose of your sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your sharps disposal container.
• •
  If you have any questions, talk to your doctor or pharmacist.

Keep Ustekinumab-aauz and all medicines out of the reach of children.

Manufactured by:

Fresenius Kabi USA, LLC, Lake Zurich, IL 60047, U.S.A, US License Number 2146

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

Issued: 04/2025

INSTRUCTIONS FOR USE

Ustekinumab-aauz (u-ste-KIN-u-mab aauz)

injection, for subcutaneous use

This product is OTULFI (ustekinumab-aauz)

Read this lnstructions for Use before you start using Ustekinumab-aauz. Your doctor or nurse should show you how to prepare, measure your dose, and give your injection of Ustekinumab-aauz the right way.

lf you cannot give yourself the injection:

• •
  ask your doctor or nurse to help you, or
• •
  ask someone who has been trained by a doctor or nurse to give your injections.

Do not try to inject Ustekinumab-aauz yourself until you have been shown how to inject Ustekinumab-aauz by your doctor, nurse or health professional.

lmportant information:

• •
  Before you start, check the carton to make sure that it is the right dose. You will have either 45 mg or 90 mg as prescribed by your doctor.
  • o
    lf your dose is 45 mg or less you will receive one 45 mg vial.
  • o
    lf your dose is 90 mg, you will receive two 45 mg vials and you will need to give yourself two injections, one right after the other.
• •
  Children 12 years of age and older weighing less than 132 pounds require a dose lower than 45 mg.
• •
  Check the expiration date on the vial and carton. lf the expiration date has passed, do not use it. lf the expiration date has passed, call your doctor or pharmacist, or call Fresenius Kabi USA, LLC at 1-800-551-7176 for help.
• •
  Check the vial for any particles or discoloration. Your vial should look clear and colorless to slightly brown-yellow.
• •
  Do not use if it is frozen, discolored, cloudy or has particles. Get a new vial.
• •
  Do not shake the vial at any time. Shaking your vial may damage your Ustekinumab-aauz medicine. lf your vial has been shaken, do not use it. Get a new vial.
• •
  Do not use a Ustekinumab-aauz vial more than one time, even if there is medicine left in the vial. After the rubber stopper is punctured, Ustekinumab-aauz can become contaminated by harmful bacteria which could cause an infection if re-used. Therefore, throw away any unused Ustekinumab-aauz after you give your injection.
• •
  Safely throw away (dispose of) Ustekinumab-aauz vials after use.
• •
  Do not re-use syringes or needles. See “Step 6: Dispose of needles and syringes."
• •
  To avoid needle-stick injuries, do not recap needles.

Storage Information

• •
  Store Ustekinumab-aauz vials in a refrigerator between 36°F to 46°F (2°C to 8°C).
• •
  Store Ustekinumab-aauz vials standing up straight.
• •
  Store Ustekinumab-aauz in the original carton to protect it from light until time to use it.
• •
  Do not freeze Ustekinumab-aauz.

Gather the supplies you will need to prepare Ustekinumab-aauz and to give your injection. (See Figure A)

You will need:

• •
  a syringe with the needle attached, you will need a prescription from your healthcare provider to get syringes with the needles attached from your pharmacy.
• •
  antiseptic wipes
• •
  cotton balls or gauze pads
• •
  adhesive bandage
• •
  your prescribed dose of Ustekinumab-aauz
• •
  FDA-cleared sharps disposal container. See "Step 6: Dispose of needles and syringes."

Figure A

Step 1: Prepare the injection.

• •
  Choose a well-lit, clean, flat work surface.
• •
  Wash your hands well with soap and warm water.

Step 2: Prepare your injection site

• •
  Choose an injection site around your stomach area (abdomen), buttocks, and upper legs (thighs). lf a caregiver is giving you the injection, the outer area of the upper arms may also be used. (See Figure B)
• •
  Use a different injection site for each injection. Do not give an injection in an area of the skin that is tender, bruised, red or hard.
• •
  Clean the skin with an antiseptic wipe where you plan to give your injection.
• •
  Do not touch this area again before giving the injection. Let your skin dry before injecting.
• •
  Do not fan or blow on the clean area.

Figure B

*Areas in gray are recommended injection sites.

Step 3: Prepare the vial.

• •
  Remove the cap from the top of the vial. Throw away the cap but do not remove the rubber stopper. (See Figure C)

Figure C

• •
  Clean the rubber stopper with an antiseptic swab. (See Figure D)

Figure D

Do not touch the rubber stopper after you clean it.

• •
  Put the vial on a flat surface.

Step 4: Prepare the needle

• •
  Pick up the syringe with the needle attached.
• •
  Remove the cap that covers the needle. (See Figure E)
• •
  Throw the needle cap away. Do not touch the needle or allow the needle to touch anything.

Figure E

• •
  Carefully pull back on the plunger to the line that matches the dose prescribed by your doctor.
• •
  Hold the vial between your thumb and index (pointer) finger.
• •
  Use your other hand to push the syringe needle through the center of the rubber stopper. (See Figure F)

Figure F

• •
  Push down on the plunger until all of the air has gone from the syringe into the vial.
• •
  Turn the vial and the syringe upside down. (See Figure G)
• •
  Hold the Ustekinumab-aauz vial with one hand.
• •
  lt is important that the needle is always in the liquid in order to prevent air bubbles forming in the syringe.
• •
  Pull back on the syringe plunger with your other hand.
• •
  Fill the syringe until the black tip of the plunger lines up with the mark that matches your prescribed dose.

Figure G

• •
  Do not remove the needle from the vial. Hold the syringe with the needle pointing up to see if it has any air bubbles inside.
• •
  lf there are air bubbles, gently tap the side of the syringe until the air bubbles rise to the top. (See Figure H)
• •
  Slowly press the plunger up until all of the air bubbles are out of the syringe {but none of the liquid is out).
• •
  Remove the syringe from the vial. Do not lay the syringe down or allow the needle to touch anything.

Figure H

Step 5: lnject Ustekinumab-aauz

• •
  Hold the barrel of the syringe in one hand, between the thumb and index fingers.
• •
  Do not pull back on the plunger at any time.
• •
  Use the other hand to gently pinch the cleaned area of skin. Hold firmly.
• •
  Use a quick, dart-like motion to insert the needle into the pinched skin at about a 45- degree angle. (See Figure I)

Figure I

• •
  Push the plunger with your thumb as far as it will go to inject all of the liquid. Push it slowly and evenly, keeping the skin gently pinched.
• •
  When the syringe is empty, pull the needle out of your skin and let go of the skin. (See Figure J)

Figure J

• •
  When the needle is pulled out of your skin, there may be a little bleeding at the injection site. This is normal. You can press a cotton ball or gauze pad to the injection site if needed. Do not rub the injection site. You may cover the injection site with a small adhesive bandage, if necessary.

lf your dose is 90 mg, you will receive two 45 mg vials and you will need to give yourself a second injection right after the first. Repeat Steps 1 to 5 using a new syringe. Choose a different site for the second injection.

Step 6: Dispose of the needles and syringes.

• •
  Do not re-use a syringe or needle.
• •
  To avoid needle-stick injuries, do not recap a needle.
• •
  Put your needles and syringes in an FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles and syringes in your household trash.
• •
  lf you do not have an FDA-cleared sharps disposal container, you may use a household container that is:
  • o
    made of heavy-duty plastic
  • o
    can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out
  • o
    upright and stable during use
  • o
    leak-resistant,
  • o
    and properly labeled to warn of hazardous waste inside the container.
• •
  When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be local or state laws about how to throw away syringes and needles. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA's website at: http://www.fda.gov/safesharpsdisposal.
• •
  Do not dispose of your sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your sharps disposal container.
• •
  Throw away the vial into the container where you put the syringes and needles.
• •
  lf you have any questions, talk to your doctor or pharmacist.

Keep Ustekinumab-aauz and all medicines out of the reach of children.

Vial Manufactured by: Fresenius Kabi USA, LLC, Lake Zurich, IL 60047, U.S.A, US License Number 2146

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

Issued: 04/2025

Single doses up to 6 mg/kg intravenously have been administered in clinical trials without dose-limiting toxicity. In case of overdosage, monitor the patient for any signs or symptoms of adverse reactions or effects and institute appropriate symptomatic treatment immediately. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.

• 1.
  Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov) SEER*Stat Database: Incidence - SEER 6.6.2 Regs Research Data, Nov 2009 Sub (1973- 2007) - Linked To County Attributes - Total U.S., 1969-2007 Counties, National Cancer Institute, DCCPS, Surveillance Research Program, Surveillance Systems Branch, released April 2010, based on the November 2009 submission.

Ustekinumab-aauz, a human IgG1κ monoclonal antibody, is a human interleukin-12 and -23 antagonist. Using DNA recombinant technology, ustekinumab-aauz is produced in a Chinese hamster ovary (CHO) cell line. The manufacturing process contains steps for the clearance of viruses. Ustekinumab-aauz is comprised of 1326 amino acids and has an estimated molecular mass that ranges from 148,079 to 149,690 Daltons.

Ustekinumab-aauz injection is a sterile, preservative-free, clear to slightly opalescent, and colorless to slightly brown-yellow solution with pH of 5.7- 6.3.

Ustekinumab products may increase the risk of infections and reactivation of latent infections. Serious bacterial, mycobacterial, fungal, and viral infections were observed in patients receiving ustekinumab products [see Adverse Reactions (6.1, 6.3)].

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

• •
  Plaque 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.

Avoid initiating treatment with Ustekinumab-aauz 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 Ustekinumab-aauz 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 Ustekinumab-aauz and discontinue Ustekinumab-aauz for serious or clinically significant infections until the infection resolves or is adequately treated.

Ustekinumab products are immunosuppressants and may increase the risk of malignancy. Malignancies were reported among subjects who received ustekinumab in clinical trials [see Adverse Reactions (6.1)]. In rodent models, inhibition of IL-12/IL-23p40 increased the risk of malignancy [see Nonclinical Toxicology (13)].

The safety of ustekinumab products has not been evaluated in patients who have a history of malignancy or who have a known malignancy.

There have been post-marketing reports of the rapid appearance of multiple cutaneous squamous cell carcinomas in patients receiving ustekinumab products who had pre-existing risk factors for developing non-melanoma skin cancer. Monitor all patients receiving Ustekinumab-aauz for the appearance of non-melanoma skin cancer. Closely follow patients greater than 60 years of age, those with a medical history of prolonged immunosuppressant therapy and those with a history of PUVA treatment [see Adverse Reactions (6.1)].

Prior to initiating therapy with Ustekinumab-aauz, patients should receive all age-appropriate immunizations as recommended by current immunization guidelines. Patients being treated with Ustekinumab-aauz should avoid receiving live vaccines. Avoid administering BCG vaccines during treatment with Ustekinumab-aauz or for one year prior to initiating treatment or one year following discontinuation of treatment. Caution is advised when administering live vaccines to household contacts of patients receiving Ustekinumab-aauz because of the potential risk for shedding from the household contact and transmission to patient.

Non-live vaccinations received during a course of Ustekinumab-aauz may not elicit an immune response sufficient to prevent disease.

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

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of ustekinumab or of other ustekinumab products.

Approximately 6 to 12.4% of subjects treated with ustekinumab 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.

In Crohn's disease and ulcerative colitis clinical trials, 2.9% and 4.6% of subjects, respectively, developed antibodies to ustekinumab 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 was seen.

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

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)]
• •
  Posterior Reversible Encephalopathy Syndrome (PRES) [see Warnings and Precautions (5.6)]
• •
  Noninfectious Pneumonia [see Warnings and Precautions (5.8)]

Ustekinumab was evaluated in three randomized, double-blind, placebo-controlled clinical trials in adult subjects 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 trials (CD-1 and CD-2) followed by a 44-week subcutaneous randomized withdrawal maintenance trial (CD-3) representing 52 weeks of therapy. Subjects in CD-1 had failed or were intolerant to treatment with one or more TNF blockers, while subjects in CD-2 had failed or were intolerant to treatment with immunomodulators or corticosteroids, but never failed treatment with a TNF blocker.

The formation of CYP450 enzymes can be suppressed by increased levels of certain cytokines (e.g., IL-1, IL-6, TNFα, IFN) during chronic inflammation. Thus, use of ustekinumab products, antagonists of IL-12 and IL-23, could normalize the formation of CYP450 enzymes. Upon initiation or discontinuation of Ustekinumab-aauz in patients who are receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index, consider monitoring for therapeutic effect or drug concentration and adjust the individual dosage of the CYP substrate as needed. See the prescribing information of specific CYP substrates.

A CYP-mediated drug interaction effect was not observed in subjects with Crohn’s disease [see Clinical Pharmacology (12.3)].

Ustekinumab-aauz is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis.

Ustekinumab-aauz is a human interleukin-12 and -23 antagonist indicated for the treatment of:

Adult patients with:

• •
  moderate to severe plaque psoriasis (PsO) who are candidates for phototherapy or systemic therapy. (1.1)
• •
  active psoriatic arthritis (PsA). (1.2)
• •
  moderately to severely active Crohn's disease (CD). (1.3)
• •
  moderately to severely active ulcerative colitis. (1.4)

Pediatric patients 6 years and older with:

• •
  moderate to severe plaque psoriasis, who are candidates for phototherapy or systemic therapy. (1.1)
• •
  active psoriatic arthritis (PsA). (1.2)

Ustekinumab was evaluated in two randomized, double-blind, placebo-controlled clinical trials [UC-1 and UC-2 (NCT02407236)] in adult subjects with moderately to severely active ulcerative colitis who had an inadequate response to or failed to tolerate a biologic (i.e., TNF blocker and/or vedolizumab), corticosteroids, and/or 6-MP or AZA therapy. The 8-week intravenous induction trial (UC-1) was followed by the 44-week subcutaneous randomized withdrawal maintenance trial (UC-2) for a total of 52 weeks of therapy.

Disease assessment was based on the Mayo score, which ranged from 0 to 12 and has four subscores that were each scored from 0 (normal) to 3 (most severe): stool frequency, rectal bleeding, findings on centrally reviewed endoscopy, and physician global assessment. Moderately to severely active ulcerative colitis was defined at baseline (Week 0) as Mayo score of 6 to 12, including a Mayo endoscopy subscore ≥2. An endoscopy score of 2 was defined by marked erythema, absent vascular pattern, friability, erosions; and a score of 3 was defined by spontaneous bleeding, ulceration. At baseline, subjects had a median Mayo score of 9, with 84% of subjects having moderate disease (Mayo score 6-10) and 15% having severe disease (Mayo score 11-12).

Subjects in these trials may have received other concomitant therapies including aminosalicylates, immunomodulatory agents (AZA, 6-MP, or MTX), and oral corticosteroids (prednisone).

Fetal/Neonatal Adverse Reactions

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

Data

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 MRHD 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.

Ustekinumab-aauz is indicated for the treatment of adult patients with moderately to severely active Crohn's disease.

Ustekinumab products are human IgG1қ monoclonal antibodies that bind with specificity to the p40 protein subunit used by both the IL-12 and IL-23 cytokines. 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 products were 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-12Rβ1. The cytokines IL-12 and IL-23 have been implicated as important contributors to the chronic inflammation that is a hallmark of Crohn's disease and ulcerative colitis. In animal models of colitis, genetic absence or antibody blockade of the p40 subunit of IL-12 and IL-23, the target of ustekinumab products was shown to be protective.

The safety and efficacy of ustekinumab was assessed in 927 subjects (PsA STUDY 1, n=615; PsA STUDY 2, n=312), in two randomized, double-blind, placebo-controlled trials in adult subjects 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. Subjects in these trials had a diagnosis of PsA for at least 6 months. Subjects 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 subjects, respectively, had enthesitis and dactylitis at baseline.

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

In PsA STUDY 1 and PsA STUDY 2, 80% and 86% of the subjects, 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 subjects 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.

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

Ustekinumab-aauz is indicated for the treatment of adults and pediatric patients 6 years of age and older with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy.

• •
  Infections: Serious infections have occurred. Avoid starting Ustekinumab-aauz during any clinically important active infection. If a serious infection or clinically significant infection develops, discontinue Ustekinumab-aauz until the infection resolves. (5.1)
• •
  Theoretical Risk for Particular Infections: Serious infections from mycobacteria, salmonella and Bacillus Calmette-Guerin (BCG) vaccinations have been reported in patients genetically deficient in IL- 12/IL-23. Consider diagnostic tests for these infections as dictated by clinical circumstances. (5.2)
• •
  Tuberculosis (TB): Evaluate patients for TB prior to initiating treatment with Ustekinumab-aauz. Initiate treatment of latent TB before administering Ustekinumab-aauz. (5.3)
• •
  Malignancies: Ustekinumab products may increase risk of malignancy. The safety of ustekinumab products in patients with a history of or a known malignancy has not been evaluated. (5.4)
• •
  Hypersensitivity Reactions: If an anaphylactic or other clinically significant hypersensitivity reaction occurs, institute appropriate therapy and discontinue Ustekinumab-aauz. (5.5)
• •
  Posterior Reversible Encephalopathy Syndrome (PRES): If PRES is suspected, treat promptly and discontinue Ustekinumab-aauz. (5.6)
• •
  Immunizations: Avoid use of live vaccines in patients during treatment with Ustekinumab-aauz. (5.7)
• •
  Noninfectious Pneumonia: Cases of interstitial pneumonia, eosinophilic pneumonia and cryptogenic organizing pneumonia have been reported during post-approval use of ustekinumab products. If diagnosis is confirmed, discontinue Ustekinumab-aauz and institute appropriate treatment. (5.8)

Ustekinumab products have not been evaluated in patients who have undergone allergy immunotherapy. Ustekinumab products 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.

Two multicenter, randomized, double-blind, placebo-controlled trials (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 trials.

Ps STUDY 1 enrolled 766 subjects and Ps STUDY 2 enrolled 1230 subjects. The trials had the same design through Week 28. In both trials, subjects were randomized in equal proportion to placebo, 45 mg or 90 mg of ustekinumab. Subjects randomized to ustekinumab 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 ustekinumab (either 45 mg or 90 mg) at Weeks 12 and 16.

In both trials, 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.

In both trials, 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.

Clinical Response

The results of Ps STUDY 1 and Ps STUDY 2 are presented in Table 8 below.

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

In subjects who weighed 100 kg or less, response rates were comparable 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 9 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 ustekinumab (ustekinumab at Week 40) or to withdrawal of therapy (placebo at Week 40). At Week 52, 89% (144/162) of subjects re- randomized to ustekinumab 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.

Psoriasis Adult Subcutaneous Recommended Dosage (2.1):

Psoriasis Pediatric Patients (6 to 17 years old) Subcutaneous Recommended Dosage (2.1): Weight-based dosing is recommended at the initial dose, 4 weeks later, then every 12 weeks thereafter.

Psoriatic Arthritis Adult Subcutaneous Recommended Dosage (2.2):

• •
  The recommended dosage is 45 mg administered subcutaneously initially and 4 weeks later, followed by 45 mg administered subcutaneously every 12 weeks.
• •
  For patients with co-existent moderate-to-severe plaque psoriasis weighing greater than 100 kg, the recommended dosage is 90 mg administered subcutaneously initially and 4 weeks later, followed by 90 mg administered subcutaneously every 12 weeks.

Psoriatic Arthritis Pediatric (6 to 17 years old) Subcutaneous Recommended Dosage (2.2): Weight-based dosing is recommended at the initial dose, 4 weeks later, then every 12 weeks thereafter.

Crohn's Disease and Ulcerative Colitis Initial Adult Intravenous Recommended Dosage (2.3): A single intravenous infusion using weight- based dosing:

Crohn's Disease and Ulcerative Colitis Maintenance Adult Subcutaneous Recommended Dosage (2.3): A subcutaneous 90 mg dose 8 weeks after the initial intravenous dose, then every 8 weeks thereafter.

Cases of interstitial pneumonia, eosinophilic pneumonia and cryptogenic organizing pneumonia have been reported during post-approval use of ustekinumab products. 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 Ustekinumab-aauz and institute appropriate treatment [see Postmarketing Experience (6.3)].

Ustekinumab-aauz is a clear to slightly opalescent and colorless to slightly brown-yellow solution.

Subcutaneous Injection

• •
  Injection: 45 mg/0.5 mL or 90 mg/mL solution in a single-dose prefilled syringe
• •
  Injection: 45 mg/0.5 mL solution in a single-dose vial

Intravenous Infusion

• •
  Injection: 130 mg/26 mL (5 mg/mL) solution in a single-dose vial

The following adverse reactions have been reported during post-approval use of ustekinumab products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to ustekinumab product exposure.

Immune system disorders: Serious hypersensitivity reactions (including anaphylaxis and angioedema), other hypersensitivity reactions (including rash and urticaria).

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

Neurological disorders: Posterior Reversible Encephalopathy Syndrome (PRES).

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

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

Ustekinumab-aauz is indicated for the treatment of adults and pediatric patients 6 years of age and older with active psoriatic arthritis.

Hypersensitivity reactions, including anaphylaxis and angioedema, have been reported with ustekinumab products [see Adverse Reactions (6.1, 6.3)]. If an anaphylactic or other clinically significant hypersensitivity reaction occurs, institute appropriate therapy and discontinue Ustekinumab-aauz.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

A multicenter, randomized, double blind, placebo-controlled trial (Ps STUDY 3) enrolled 110 pediatric subjects 12 to 17 years of age with a minimum BSA involvement of 10%, a PASI score greater than or equal to 12, and a PGA score greater than or equal to 3, who were candidates for phototherapy or systemic therapy and whose disease was inadequately controlled by topical therapy.

Subjects were randomized to receive placebo (n = 37), the recommended dose of ustekinumab (n = 36), or one-half the recommended dose of ustekinumab (n = 37) by subcutaneous injection at Weeks 0 and 4 followed by dosing every 12 weeks (q12w). The recommended dose of ustekinumab was 0.75 mg/kg for subjects weighing less than 60 kg, 45 mg for subjects weighing 60 kg to 100 kg, and 90 mg for subjects weighing greater than 100 kg. At Week 12, subjects who received placebo were crossed over to receive ustekinumab at the recommended dose or one-half the recommended dose.

Of the pediatric subjects, approximately 63% had prior exposure to phototherapy or conventional systemic therapy and approximately 11% had prior exposure to biologics.

The endpoints were the proportion of subjects who achieved a PGA score of cleared (0) or minimal (1), PASI 75, and PASI 90 at Week 12. Subjects were followed for up to 60 weeks following first administration of trial agent.

Advise the patient and/or caregiver to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).

Ustekinumab-aauz injection is a sterile, preservative-free, clear to slightly opalescent and colorless to slightly brown-yellow solution. It is supplied as individually packaged, single-dose prefilled syringes or single-dose vials.

In a 26-week toxicology study, one out of 10 monkeys subcutaneously administered 45 mg/kg ustekinumab twice weekly for 26 weeks had a bacterial infection.

Subcutaneous Adult Dosage Regimen

• •
  For patients weighing 100 kg or less, the recommended dosage is 45 mg initially and 4 weeks later, followed by 45 mg every 12 weeks.
• •
  For patients weighing more than 100 kg, the recommended dosage is 90 mg initially and 4 weeks later, followed by 90 mg every 12 weeks.

In subjects weighing more than 100 kg, 45 mg was also shown to be efficacious. However, 90 mg resulted in greater efficacy in these subjects [see Clinical Studies (14)].

• •
  Ustekinumab-aauz is intended for use under the guidance and supervision of a healthcare provider. Ustekinumab-aauz should only be administered to patients who will be closely monitored and have regular follow-up visits with a healthcare provider. The appropriate dose should be determined by a healthcare provider using the patient's current weight at the time of dosing. In pediatric patients, it is recommended that Ustekinumab-aauz be administered by a healthcare provider. If a healthcare provider determines that it is appropriate, a patient may self-inject or a caregiver may inject Ustekinumab-aauz after proper training in subcutaneous injection technique. Instruct patients to follow the directions provided in the Medication Guide [see Medication Guide].
• •
  The needle cover on the prefilled syringe is not made with natural rubber (a derivative of latex).
• •
  It is recommended that each injection be administered at a different anatomic location (such as upper arms, gluteal regions, thighs, or any quadrant of abdomen) than the previous injection, and not into areas where the skin is tender, bruised, erythematous, or indurated. When using the single-dose vial, a 1 mL syringe with a 29 gauge, ½ inch needle is recommended.
• •
  Prior to administration, visually inspect Ustekinumab-aauz for particulate matter and discoloration. Ustekinumab-aauz is a clear to slightly opalescent and colorless to slightly brown-yellow solution. Do not use Ustekinumab-aauz if it is discolored or cloudy, or if other particulate matter is present. Ustekinumab-aauz does not contain preservatives; therefore, discard any unused product remaining in the vial and/or syringe.

Evaluate patients for tuberculosis infection prior to initiating treatment with Ustekinumab-aauz.

Avoid administering Ustekinumab-aauz to patients with active tuberculosis infection. Initiate treatment of latent tuberculosis prior to administering Ustekinumab-aauz. Consider anti-tuberculosis therapy prior to initiation of Ustekinumab-aauz in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed. Closely monitor patients receiving Ustekinumab-aauz for signs and symptoms of active tuberculosis during and after treatment.

NDC 65219-862-01

RX only

Ustekinumab-aauz         45 mg / 0.5 mL

Injection

For subcutaneous use

1 Single-dose prefilled syringe. Discard unused portion.

Carton contains:

1 Single-dose prefilled syringe

1 Prescribing Information

1 Medication Guide

Manufactured by:

Fresenius Kabi USA, LLC

Lake Zurich, Illionis 60047

U.S. Licence No. 2146

NDC 65219-866-26

RX only

Ustekinumab-aauz          90mg / mL

Injection

For subcutaneous use

1 Single-dose prefilled syringe. Discard unused portion.

Carton contains:

1 Single-dose prefilled syringe

1 Prescribing Information

1 Medication Guide

Manufactured by:

Fresenius Kabi USA, LLC

Lake Zurich, Illionis 60047

U.S. Licence No. 2146

Single dose prefilled syringe

Discard unused portion

Ustekinumab-aauz

Injection

45 mg / 0.5 mL

For subcutaneous use

Mfg by: Fresenius Kabi USA, LLC

U.S. License No. 2146

NDC 65219-862-01

Rx only

Store at 36 °F to 46 °F

(2 °C to 8 °C). Protect

from light. Do not shake.

Do not freeze

Single dose prefilled syringe

Discard unused portion

Ustekinumab-aauz

Injection

90 mg / mL

For subcutaneous use

Mfg by: Fresenius Kabi USA, LLC

U.S. License No. 2146

NDC 65219-866-26

Rx only

Store at 36 °F to 46 °F

(2 °C to 8 °C). Protect

from light. Do not shake.

Do not freeze

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 product initiation. A few cases reported latency of a year or longer. Patients recovered with supportive care following withdrawal of ustekinumab products.

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

Animal studies have not been conducted to evaluate the carcinogenic or mutagenic potential of ustekinumab products. Published literature showed that administration of murine IL-12 caused an anti- tumor effect in mice that contained transplanted tumors and IL-12/IL-23p40 knockout mice or mice treated with anti-IL-12/IL-23p40 antibody had decreased host defense to tumors. Mice genetically manipulated to be deficient in both IL-12 and IL-23 or IL-12 alone developed UV- induced skin cancers earlier and more frequently compared to wild-type mice. The relevance of these experimental findings in mouse models for malignancy risk in humans is unknown.

No effects on fertility were observed in male cynomolgus monkeys that were administered ustekinumab at subcutaneous doses up to 45 mg/kg twice weekly (45 times the MRHD on a mg/kg basis) prior to and during the mating period. However, fertility and pregnancy outcomes were not evaluated in mated females.

No effects on fertility were observed in female mice that were administered an analogous IL-12/IL-23p40 antibody by subcutaneous administration at doses up to 50 mg/kg, twice weekly, prior to and during early pregnancy.

Individuals genetically deficient in IL-12/IL-23 are particularly vulnerable to disseminated infections from mycobacteria (including nontuberculous, environmental mycobacteria), salmonella (including nontyphi strains), and Bacillus Calmette-Guerin (BCG) vaccinations. Serious infections and fatal outcomes have been reported in such patients.

It is not known whether patients with pharmacologic blockade of IL-12/IL-23 from treatment with ustekinumab products may be susceptible to these types of infections. Consider appropriate diagnostic testing (e.g., tissue culture, stool culture, as dictated by clinical circumstances).

Refer to the diagram below for the provided instructions.

To prevent premature activation of the needle safety guard, do not touch the NEEDLE GUARD ACTIVATION CLIPS at any time during use.

• •
  Hold the BODY and remove the NEEDLE COVER. Do not hold the PLUNGER or PLUNGER HEAD while removing the NEEDLE COVER or the PLUNGER may move. Do not use the prefilled syringe if it is dropped without the NEEDLE COVER in place. Do not use the prefilled syringe if it is dropped or if it is dropped onto a hard surface.
• •
  Inject Ustekinumab-aauz subcutaneously as recommended [see Dosage and Administration (2.1, 2.2, 2.3)].
• •
  Inject all of the medication by pushing in the PLUNGER until the PLUNGER HEAD is completely between the needle guard wings. Injection of the entire prefilled syringe contents is necessary to activate the needle guard.
•  
• •
  After injection, maintain the pressure on the PLUNGER HEAD and remove the needle from the skin. Slowly take your thumb off the PLUNGER HEAD to allow the empty syringe to move up until the entire needle is covered by the needle guard, as shown by the illustration below:
•  
• •
  Used syringes should be placed in a puncture-resistant container.

Ustekinumab-aauz solution for intravenous infusion must be diluted, prepared and infused by a healthcare professional using aseptic technique.

• 1.
  Calculate the dose and the number of Ustekinumab-aauz vials needed based on patient weight (Table 4). Each 26 mL vial of Ustekinumab-aauz contains 130 mg of ustekinumab-aauz.
• 2.
  Withdraw, and then discard a volume of the 0.9% Sodium Chloride Injection, USP from the 250 mL infusion bag equal to the volume of Ustekinumab-aauz to be added (discard 26 mL sodium chloride for each vial of Ustekinumab-aauz needed, for 2 vials- discard 52 mL, for 3 vials- discard 78 mL, 4 vials- discard 104 mL). Alternatively, a 250 mL infusion bag containing 0.45% Sodium Chloride Injection, USP may be used.
• 3.
  Withdraw 26 mL of Ustekinumab-aauz from each vial needed and add it to the 250 mL infusion bag. The final volume in the infusion bag should be 250 mL. Gently mix.
• 4.
  Visually inspect the diluted solution before infusion. Do not use if visibly opaque particles, discoloration or foreign particles are observed.
• 5.
  Infuse the diluted solution over a period of at least one hour. Once diluted, the infusion should be completely administered within eight hours of the dilution in the infusion bag.
• 6.
  Use only polypropylene (PP) or polyvinylchloride (PVC) infusion sets with an in-line, sterile, non-pyrogenic, low protein-binding filter (pore size 0.2 micrometer).
• 7.
  Do not infuse Ustekinumab-aauz concomitantly in the same intravenous line with other agents.
• 8.
  Ustekinumab-aauz does not contain preservatives. Each vial is for one-time use in only one patient. Discard any remaining solution. Dispose any unused medicinal product in accordance with local requirements.

Subcutaneous Pediatric Dosage Regimen

Administer Ustekinumab-aauz subcutaneously at Weeks 0 and 4, then every 12 weeks thereafter.

The recommended dose of Ustekinumab-aauz for pediatric patients (6-17 years old) with plaque psoriasis based on body weight is shown below (Table 1).

Dosage and Administration (2.1, 2.2, 2.4)                                                                                                  03/2025

INSTRUCTIONS FOR USE

Ustekinumab-aauz (u-ste-KIN-u-mab aauz)

injection, for subcutaneous use

This product is OTULFI (ustekinumab-aauz)

Read this Instructions for Use before you start using Ustekinumab-aauz. Your doctor or nurse should show you how to prepare and give your injection of Ustekinumab-aauz the right way.

If you cannot give yourself the injection:

• •
  ask your doctor or nurse to help you, or
• •
  ask someone who has been trained by a doctor or nurse to give your injections.

Do not try to inject Ustekinumab-aauz yourself until you have been shown how to inject Ustekinumab-aauz by your doctor, nurse or health professional.

Important information:

• •
  Before you start, check the carton to make sure that it is the right dose. You will have either 45 mg or 90 mg as prescribed by your doctor.
  • o
    If your dose is 45 mg, you will receive one 45 mg prefilled syringe.
  • o
    If your dose is 90 mg, you will receive either one 90 mg prefilled syringe or two 45 mg prefilled syringes. If you receive two 45 mg prefilled syringes for a 90 mg dose, you will need to give yourself two injections, one right after the other.
• •
  Children 12 years of age and older with psoriasis, who weigh 132 pounds (60 kg) or more may use a prefilled syringe.
• •
  Store Ustekinumab-aauz in a refrigerator between 36°F to 46°F (2°C to 8°C) in the original carton to protect from light.
• •
  If needed, individual Ustekinumab-aauz prefilled syringes may also be stored at room temperature up to 86°F (30°C) for a maximum single period of up to 30 days in the original carton to protect from light. Record the date when the prefilled syringe is first removed from the refrigerator on the carton in the space provided. If a syringe has been stored at room temperature, it should not be returned to the refrigerator.
• •
  Check the expiration date on the prefilled syringe and carton. If the expiration date has passed or if the prefilled syringe has been kept at room temperature up to 86°F (30°C) for longer than a maximum single period of 30 days or if the prefilled syringe has been stored above 86°F (30°C), do not use it. If the expiration date has passed or if the prefilled syringe has been stored above 86°F (30°C), call your doctor or pharmacist, or call or call manufacturer`s phone for help.
• •
  Make sure the syringe is not damaged.
• •
  Check your prefilled syringe for any particles or discoloration. Your prefilled syringe should look clear and colorless to slightly brown-yellow.
• •
  Do not use if it is frozen, discolored, cloudy or has particles. Get a new prefilled syringe.
• •
  Do not shake the prefilled syringe at any time. Shaking your prefilled syringe may damage your Ustekinumab-aauz medicine. If your prefilled syringe has been shaken, do not use it. Get a new prefilled syringe.
• •
  To reduce the risk of accidental needle sticks, each prefilled syringe has a needle guard that is automatically activated to cover the needle after you have given your injection. Do not pull back on the plunger at any time.

Gather the supplies you will need to prepare and to give your injection. (See Figure A)

You will need:

• •
  antiseptic wipes
• •
  cotton balls or gauze pads
• •
  adhesive bandage
• •
  your prescribed dose of Ustekinumab-aauz (See Figure B)
• •
  FDA-cleared sharps disposal container. See "Step 4: Dispose of the syringe."

Figure A

Figure B

To prevent early activation of the needle safety guard, do not touch the NEEDLE GUARD ACTIVATION CLIPS at any time during use.

Step 1: Prepare the injection.

• •
  Choose a well-lit, clean, flat work surface.
• •
  Wash your hands well with soap and warm water.
• •
  Hold the prefilled syringe with the covered needle pointing upward.

Step 2: Prepare your injection site

• •
  Choose an injection site around your stomach area (abdomen), buttocks, upper legs (thighs). If a caregiver is giving you the injection, the outer area of the upper arms may also be used. (See Figure C)
• •
  Use a different injection site for each injection. Do not give an injection in an area of the skin that is tender, bruised, red or hard.
• •
  Clean the skin with an antiseptic wipe where you plan to give your injection.
• •
  Do not touch this area again before giving the injection. Let your skin dry before injecting.
• •
  Do not fan or blow on the clean area.

Figure C

*Areas in gray are recommended injection sites.

Step 3: Inject Ustekinumab-aauz

• •
  Remove the needle cover when you are ready to inject your Ustekinumab-aauz.
• •
  Do not touch the plunger or plunger head while removing the needle cover.
• •
  Hold the body of the prefilled syringe with one hand and pull the needle cover straight off. (See Figure D)
• •
  Put the needle cover in the trash.
• •
  You may also see a drop of liquid at the end of the needle. This is normal.
• •
  Do not touch the needle or let it touch anything.
• •
  Do not use the prefilled syringe if it is dropped without the needle cover in place or if it is dropped onto a hard surface. Call your doctor, nurse or health professional for instructions.

Figure D

Figure E

• •
  Do not pull back on the plunger at any time.
• •
  Use the other hand to gently pinch the cleaned area of skin. Hold firmly.
• •
  Use a quick, dart-like motion to insert the needle into the pinched skin at about a 45-degree angle. (See Figure F)

Figure F

• •
  Inject all of the liquid by using your thumb to push in the plunger until the plunger head is completely between the needle guard wings. (See Figure G)

Figure G

• •
  When the plunger is pushed as far as it will go, keep pressure on the plunger head. Take the needle out of the skin and let go of the skin.
• •
  Slowly take your thumb off the plunger head. This will let the empty syringe move up until the entire needle is covered by the needle guard. (See Figure H)

Figure H

• •
  When the needle is pulled out of your skin, there may be a little bleeding at the injection site. This is normal. You can press a cotton ball or gauze pad to the injection site if needed. Do not rub the injection site. You may cover the injection site with a small adhesive bandage, if necessary.

If your dose is 90 mg, you will receive either one 90 mg prefilled syringe or two 45 mg prefilled syringes. If you receive two 45 mg prefilled syringes for a 90 mg dose, you will need to give yourself a second injection right after the first. Repeat Steps 1–3 for the second injection using a new syringe. Choose a different site for the second injection.

Step 4: Dispose of the syringe.

• •
  Put the syringe in an FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose syringes in your household trash.
• •
  If you do not have an FDA-cleared sharps disposal container, you may use a household container that is:
  • o
    made of heavy-duty plastic.
  • o
    can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out.
  • o
    upright and stable during use,
  • o
    leak-resistant,
  • o
    and properly labeled to warn of hazardous waste inside the container.
• •
  When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be local or state laws about how to throw away syringes and needles. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA's website at: http://www.fda.gov/safesharpsdisposal.
• •
  Do not dispose of your sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your sharps disposal container.
• •
  If you have any questions, talk to your doctor or pharmacist.

Keep Ustekinumab-aauz and all medicines out of the reach of children.

Manufactured by:

Fresenius Kabi USA, LLC, Lake Zurich, IL 60047, U.S.A, US License Number 2146

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

Issued: 04/2025

INSTRUCTIONS FOR USE

Ustekinumab-aauz (u-ste-KIN-u-mab aauz)

injection, for subcutaneous use

This product is OTULFI (ustekinumab-aauz)

Read this lnstructions for Use before you start using Ustekinumab-aauz. Your doctor or nurse should show you how to prepare, measure your dose, and give your injection of Ustekinumab-aauz the right way.

lf you cannot give yourself the injection:

• •
  ask your doctor or nurse to help you, or
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  ask someone who has been trained by a doctor or nurse to give your injections.

Do not try to inject Ustekinumab-aauz yourself until you have been shown how to inject Ustekinumab-aauz by your doctor, nurse or health professional.

lmportant information:

• •
  Before you start, check the carton to make sure that it is the right dose. You will have either 45 mg or 90 mg as prescribed by your doctor.
  • o
    lf your dose is 45 mg or less you will receive one 45 mg vial.
  • o
    lf your dose is 90 mg, you will receive two 45 mg vials and you will need to give yourself two injections, one right after the other.
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  Children 12 years of age and older weighing less than 132 pounds require a dose lower than 45 mg.
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  Check the expiration date on the vial and carton. lf the expiration date has passed, do not use it. lf the expiration date has passed, call your doctor or pharmacist, or call Fresenius Kabi USA, LLC at 1-800-551-7176 for help.
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  Check the vial for any particles or discoloration. Your vial should look clear and colorless to slightly brown-yellow.
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  Do not use if it is frozen, discolored, cloudy or has particles. Get a new vial.
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  Do not shake the vial at any time. Shaking your vial may damage your Ustekinumab-aauz medicine. lf your vial has been shaken, do not use it. Get a new vial.
• •
  Do not use a Ustekinumab-aauz vial more than one time, even if there is medicine left in the vial. After the rubber stopper is punctured, Ustekinumab-aauz can become contaminated by harmful bacteria which could cause an infection if re-used. Therefore, throw away any unused Ustekinumab-aauz after you give your injection.
• •
  Safely throw away (dispose of) Ustekinumab-aauz vials after use.
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  Do not re-use syringes or needles. See “Step 6: Dispose of needles and syringes."
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  To avoid needle-stick injuries, do not recap needles.

Storage Information

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  Store Ustekinumab-aauz vials in a refrigerator between 36°F to 46°F (2°C to 8°C).
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  Store Ustekinumab-aauz vials standing up straight.
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  Store Ustekinumab-aauz in the original carton to protect it from light until time to use it.
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  Do not freeze Ustekinumab-aauz.

Gather the supplies you will need to prepare Ustekinumab-aauz and to give your injection. (See Figure A)

You will need:

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  a syringe with the needle attached, you will need a prescription from your healthcare provider to get syringes with the needles attached from your pharmacy.
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  antiseptic wipes
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  cotton balls or gauze pads
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  adhesive bandage
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  your prescribed dose of Ustekinumab-aauz
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  FDA-cleared sharps disposal container. See "Step 6: Dispose of needles and syringes."

Figure A

Step 1: Prepare the injection.

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  Choose a well-lit, clean, flat work surface.
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  Wash your hands well with soap and warm water.

Step 2: Prepare your injection site

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  Choose an injection site around your stomach area (abdomen), buttocks, and upper legs (thighs). lf a caregiver is giving you the injection, the outer area of the upper arms may also be used. (See Figure B)
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  Use a different injection site for each injection. Do not give an injection in an area of the skin that is tender, bruised, red or hard.
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  Clean the skin with an antiseptic wipe where you plan to give your injection.
• •
  Do not touch this area again before giving the injection. Let your skin dry before injecting.
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  Do not fan or blow on the clean area.

Figure B

*Areas in gray are recommended injection sites.

Step 3: Prepare the vial.

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  Remove the cap from the top of the vial. Throw away the cap but do not remove the rubber stopper. (See Figure C)

Figure C

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  Clean the rubber stopper with an antiseptic swab. (See Figure D)

Figure D

Do not touch the rubber stopper after you clean it.

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  Put the vial on a flat surface.

Step 4: Prepare the needle

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  Pick up the syringe with the needle attached.
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  Remove the cap that covers the needle. (See Figure E)
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  Throw the needle cap away. Do not touch the needle or allow the needle to touch anything.

Figure E

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  Carefully pull back on the plunger to the line that matches the dose prescribed by your doctor.
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  Hold the vial between your thumb and index (pointer) finger.
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  Use your other hand to push the syringe needle through the center of the rubber stopper. (See Figure F)

Figure F

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  Push down on the plunger until all of the air has gone from the syringe into the vial.
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  Turn the vial and the syringe upside down. (See Figure G)
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  Hold the Ustekinumab-aauz vial with one hand.
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  lt is important that the needle is always in the liquid in order to prevent air bubbles forming in the syringe.
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  Pull back on the syringe plunger with your other hand.
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  Fill the syringe until the black tip of the plunger lines up with the mark that matches your prescribed dose.

Figure G

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  Do not remove the needle from the vial. Hold the syringe with the needle pointing up to see if it has any air bubbles inside.
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  lf there are air bubbles, gently tap the side of the syringe until the air bubbles rise to the top. (See Figure H)
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  Slowly press the plunger up until all of the air bubbles are out of the syringe {but none of the liquid is out).
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  Remove the syringe from the vial. Do not lay the syringe down or allow the needle to touch anything.

Figure H

Step 5: lnject Ustekinumab-aauz

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  Hold the barrel of the syringe in one hand, between the thumb and index fingers.
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  Do not pull back on the plunger at any time.
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  Use the other hand to gently pinch the cleaned area of skin. Hold firmly.
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  Use a quick, dart-like motion to insert the needle into the pinched skin at about a 45- degree angle. (See Figure I)

Figure I

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  Push the plunger with your thumb as far as it will go to inject all of the liquid. Push it slowly and evenly, keeping the skin gently pinched.
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  When the syringe is empty, pull the needle out of your skin and let go of the skin. (See Figure J)

Figure J

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  When the needle is pulled out of your skin, there may be a little bleeding at the injection site. This is normal. You can press a cotton ball or gauze pad to the injection site if needed. Do not rub the injection site. You may cover the injection site with a small adhesive bandage, if necessary.

lf your dose is 90 mg, you will receive two 45 mg vials and you will need to give yourself a second injection right after the first. Repeat Steps 1 to 5 using a new syringe. Choose a different site for the second injection.

Step 6: Dispose of the needles and syringes.

• •
  Do not re-use a syringe or needle.
• •
  To avoid needle-stick injuries, do not recap a needle.
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  Put your needles and syringes in an FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles and syringes in your household trash.
• •
  lf you do not have an FDA-cleared sharps disposal container, you may use a household container that is:
  • o
    made of heavy-duty plastic
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    can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out
  • o
    upright and stable during use
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    leak-resistant,
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    and properly labeled to warn of hazardous waste inside the container.
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  When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be local or state laws about how to throw away syringes and needles. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA's website at: http://www.fda.gov/safesharpsdisposal.
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  Do not dispose of your sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your sharps disposal container.
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  Throw away the vial into the container where you put the syringes and needles.
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  lf you have any questions, talk to your doctor or pharmacist.

Keep Ustekinumab-aauz and all medicines out of the reach of children.

Vial Manufactured by: Fresenius Kabi USA, LLC, Lake Zurich, IL 60047, U.S.A, US License Number 2146

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

Issued: 04/2025

Single doses up to 6 mg/kg intravenously have been administered in clinical trials without dose-limiting toxicity. In case of overdosage, monitor the patient for any signs or symptoms of adverse reactions or effects and institute appropriate symptomatic treatment immediately. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.

• 1.
  Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov) SEER*Stat Database: Incidence - SEER 6.6.2 Regs Research Data, Nov 2009 Sub (1973- 2007) - Linked To County Attributes - Total U.S., 1969-2007 Counties, National Cancer Institute, DCCPS, Surveillance Research Program, Surveillance Systems Branch, released April 2010, based on the November 2009 submission.

Ustekinumab-aauz, a human IgG1κ monoclonal antibody, is a human interleukin-12 and -23 antagonist. Using DNA recombinant technology, ustekinumab-aauz is produced in a Chinese hamster ovary (CHO) cell line. The manufacturing process contains steps for the clearance of viruses. Ustekinumab-aauz is comprised of 1326 amino acids and has an estimated molecular mass that ranges from 148,079 to 149,690 Daltons.

Ustekinumab-aauz injection is a sterile, preservative-free, clear to slightly opalescent, and colorless to slightly brown-yellow solution with pH of 5.7- 6.3.

Ustekinumab products may increase the risk of infections and reactivation of latent infections. Serious bacterial, mycobacterial, fungal, and viral infections were observed in patients receiving ustekinumab products [see Adverse Reactions (6.1, 6.3)].

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

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  Plaque Psoriasis: diverticulitis, cellulitis, pneumonia, appendicitis, cholecystitis, sepsis, osteomyelitis, viral infections, gastroenteritis and urinary tract infections.
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  Psoriatic arthritis: cholecystitis.
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  Crohn's disease: anal abscess, gastroenteritis, ophthalmic herpes zoster, pneumonia, and listeria meningitis.
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  Ulcerative colitis: gastroenteritis, ophthalmic herpes zoster, pneumonia, and listeriosis.

Avoid initiating treatment with Ustekinumab-aauz 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 Ustekinumab-aauz 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 Ustekinumab-aauz and discontinue Ustekinumab-aauz for serious or clinically significant infections until the infection resolves or is adequately treated.

Ustekinumab products are immunosuppressants and may increase the risk of malignancy. Malignancies were reported among subjects who received ustekinumab in clinical trials [see Adverse Reactions (6.1)]. In rodent models, inhibition of IL-12/IL-23p40 increased the risk of malignancy [see Nonclinical Toxicology (13)].

The safety of ustekinumab products has not been evaluated in patients who have a history of malignancy or who have a known malignancy.

There have been post-marketing reports of the rapid appearance of multiple cutaneous squamous cell carcinomas in patients receiving ustekinumab products who had pre-existing risk factors for developing non-melanoma skin cancer. Monitor all patients receiving Ustekinumab-aauz for the appearance of non-melanoma skin cancer. Closely follow patients greater than 60 years of age, those with a medical history of prolonged immunosuppressant therapy and those with a history of PUVA treatment [see Adverse Reactions (6.1)].

Prior to initiating therapy with Ustekinumab-aauz, patients should receive all age-appropriate immunizations as recommended by current immunization guidelines. Patients being treated with Ustekinumab-aauz should avoid receiving live vaccines. Avoid administering BCG vaccines during treatment with Ustekinumab-aauz or for one year prior to initiating treatment or one year following discontinuation of treatment. Caution is advised when administering live vaccines to household contacts of patients receiving Ustekinumab-aauz because of the potential risk for shedding from the household contact and transmission to patient.

Non-live vaccinations received during a course of Ustekinumab-aauz may not elicit an immune response sufficient to prevent disease.

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

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of ustekinumab or of other ustekinumab products.

Approximately 6 to 12.4% of subjects treated with ustekinumab 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.

In Crohn's disease and ulcerative colitis clinical trials, 2.9% and 4.6% of subjects, respectively, developed antibodies to ustekinumab 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 was seen.

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

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

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  Infections [see Warnings and Precautions (5.1)]
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  Malignancies [see Warnings and Precautions (5.4)]
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  Hypersensitivity Reactions [see Warnings and Precautions (5.5)]
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  Posterior Reversible Encephalopathy Syndrome (PRES) [see Warnings and Precautions (5.6)]
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  Noninfectious Pneumonia [see Warnings and Precautions (5.8)]

Ustekinumab was evaluated in three randomized, double-blind, placebo-controlled clinical trials in adult subjects 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 trials (CD-1 and CD-2) followed by a 44-week subcutaneous randomized withdrawal maintenance trial (CD-3) representing 52 weeks of therapy. Subjects in CD-1 had failed or were intolerant to treatment with one or more TNF blockers, while subjects in CD-2 had failed or were intolerant to treatment with immunomodulators or corticosteroids, but never failed treatment with a TNF blocker.

The formation of CYP450 enzymes can be suppressed by increased levels of certain cytokines (e.g., IL-1, IL-6, TNFα, IFN) during chronic inflammation. Thus, use of ustekinumab products, antagonists of IL-12 and IL-23, could normalize the formation of CYP450 enzymes. Upon initiation or discontinuation of Ustekinumab-aauz in patients who are receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index, consider monitoring for therapeutic effect or drug concentration and adjust the individual dosage of the CYP substrate as needed. See the prescribing information of specific CYP substrates.

A CYP-mediated drug interaction effect was not observed in subjects with Crohn’s disease [see Clinical Pharmacology (12.3)].

Ustekinumab-aauz is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis.

Ustekinumab-aauz is a human interleukin-12 and -23 antagonist indicated for the treatment of:

Adult patients with:

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  moderate to severe plaque psoriasis (PsO) who are candidates for phototherapy or systemic therapy. (1.1)
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  active psoriatic arthritis (PsA). (1.2)
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  moderately to severely active Crohn's disease (CD). (1.3)
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  moderately to severely active ulcerative colitis. (1.4)

Pediatric patients 6 years and older with:

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  moderate to severe plaque psoriasis, who are candidates for phototherapy or systemic therapy. (1.1)
• •
  active psoriatic arthritis (PsA). (1.2)

Ustekinumab was evaluated in two randomized, double-blind, placebo-controlled clinical trials [UC-1 and UC-2 (NCT02407236)] in adult subjects with moderately to severely active ulcerative colitis who had an inadequate response to or failed to tolerate a biologic (i.e., TNF blocker and/or vedolizumab), corticosteroids, and/or 6-MP or AZA therapy. The 8-week intravenous induction trial (UC-1) was followed by the 44-week subcutaneous randomized withdrawal maintenance trial (UC-2) for a total of 52 weeks of therapy.

Disease assessment was based on the Mayo score, which ranged from 0 to 12 and has four subscores that were each scored from 0 (normal) to 3 (most severe): stool frequency, rectal bleeding, findings on centrally reviewed endoscopy, and physician global assessment. Moderately to severely active ulcerative colitis was defined at baseline (Week 0) as Mayo score of 6 to 12, including a Mayo endoscopy subscore ≥2. An endoscopy score of 2 was defined by marked erythema, absent vascular pattern, friability, erosions; and a score of 3 was defined by spontaneous bleeding, ulceration. At baseline, subjects had a median Mayo score of 9, with 84% of subjects having moderate disease (Mayo score 6-10) and 15% having severe disease (Mayo score 11-12).

Subjects in these trials may have received other concomitant therapies including aminosalicylates, immunomodulatory agents (AZA, 6-MP, or MTX), and oral corticosteroids (prednisone).

Fetal/Neonatal Adverse Reactions

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

Data

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 MRHD 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.

Ustekinumab-aauz is indicated for the treatment of adult patients with moderately to severely active Crohn's disease.

Ustekinumab products are human IgG1қ monoclonal antibodies that bind with specificity to the p40 protein subunit used by both the IL-12 and IL-23 cytokines. 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 products were 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-12Rβ1. The cytokines IL-12 and IL-23 have been implicated as important contributors to the chronic inflammation that is a hallmark of Crohn's disease and ulcerative colitis. In animal models of colitis, genetic absence or antibody blockade of the p40 subunit of IL-12 and IL-23, the target of ustekinumab products was shown to be protective.

The safety and efficacy of ustekinumab was assessed in 927 subjects (PsA STUDY 1, n=615; PsA STUDY 2, n=312), in two randomized, double-blind, placebo-controlled trials in adult subjects 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. Subjects in these trials had a diagnosis of PsA for at least 6 months. Subjects 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 subjects, respectively, had enthesitis and dactylitis at baseline.

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

In PsA STUDY 1 and PsA STUDY 2, 80% and 86% of the subjects, 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 subjects 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.

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

Ustekinumab-aauz is indicated for the treatment of adults and pediatric patients 6 years of age and older with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy.

• •
  Infections: Serious infections have occurred. Avoid starting Ustekinumab-aauz during any clinically important active infection. If a serious infection or clinically significant infection develops, discontinue Ustekinumab-aauz until the infection resolves. (5.1)
• •
  Theoretical Risk for Particular Infections: Serious infections from mycobacteria, salmonella and Bacillus Calmette-Guerin (BCG) vaccinations have been reported in patients genetically deficient in IL- 12/IL-23. Consider diagnostic tests for these infections as dictated by clinical circumstances. (5.2)
• •
  Tuberculosis (TB): Evaluate patients for TB prior to initiating treatment with Ustekinumab-aauz. Initiate treatment of latent TB before administering Ustekinumab-aauz. (5.3)
• •
  Malignancies: Ustekinumab products may increase risk of malignancy. The safety of ustekinumab products in patients with a history of or a known malignancy has not been evaluated. (5.4)
• •
  Hypersensitivity Reactions: If an anaphylactic or other clinically significant hypersensitivity reaction occurs, institute appropriate therapy and discontinue Ustekinumab-aauz. (5.5)
• •
  Posterior Reversible Encephalopathy Syndrome (PRES): If PRES is suspected, treat promptly and discontinue Ustekinumab-aauz. (5.6)
• •
  Immunizations: Avoid use of live vaccines in patients during treatment with Ustekinumab-aauz. (5.7)
• •
  Noninfectious Pneumonia: Cases of interstitial pneumonia, eosinophilic pneumonia and cryptogenic organizing pneumonia have been reported during post-approval use of ustekinumab products. If diagnosis is confirmed, discontinue Ustekinumab-aauz and institute appropriate treatment. (5.8)

Ustekinumab products have not been evaluated in patients who have undergone allergy immunotherapy. Ustekinumab products 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.

Two multicenter, randomized, double-blind, placebo-controlled trials (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 trials.

Ps STUDY 1 enrolled 766 subjects and Ps STUDY 2 enrolled 1230 subjects. The trials had the same design through Week 28. In both trials, subjects were randomized in equal proportion to placebo, 45 mg or 90 mg of ustekinumab. Subjects randomized to ustekinumab 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 ustekinumab (either 45 mg or 90 mg) at Weeks 12 and 16.

In both trials, 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.

In both trials, 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.

Clinical Response

The results of Ps STUDY 1 and Ps STUDY 2 are presented in Table 8 below.

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

In subjects who weighed 100 kg or less, response rates were comparable 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 9 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 ustekinumab (ustekinumab at Week 40) or to withdrawal of therapy (placebo at Week 40). At Week 52, 89% (144/162) of subjects re- randomized to ustekinumab 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.

Psoriasis Adult Subcutaneous Recommended Dosage (2.1):

Psoriasis Pediatric Patients (6 to 17 years old) Subcutaneous Recommended Dosage (2.1): Weight-based dosing is recommended at the initial dose, 4 weeks later, then every 12 weeks thereafter.

Psoriatic Arthritis Adult Subcutaneous Recommended Dosage (2.2):

• •
  The recommended dosage is 45 mg administered subcutaneously initially and 4 weeks later, followed by 45 mg administered subcutaneously every 12 weeks.
• •
  For patients with co-existent moderate-to-severe plaque psoriasis weighing greater than 100 kg, the recommended dosage is 90 mg administered subcutaneously initially and 4 weeks later, followed by 90 mg administered subcutaneously every 12 weeks.

Psoriatic Arthritis Pediatric (6 to 17 years old) Subcutaneous Recommended Dosage (2.2): Weight-based dosing is recommended at the initial dose, 4 weeks later, then every 12 weeks thereafter.

Crohn's Disease and Ulcerative Colitis Initial Adult Intravenous Recommended Dosage (2.3): A single intravenous infusion using weight- based dosing:

Crohn's Disease and Ulcerative Colitis Maintenance Adult Subcutaneous Recommended Dosage (2.3): A subcutaneous 90 mg dose 8 weeks after the initial intravenous dose, then every 8 weeks thereafter.

Cases of interstitial pneumonia, eosinophilic pneumonia and cryptogenic organizing pneumonia have been reported during post-approval use of ustekinumab products. 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 Ustekinumab-aauz and institute appropriate treatment [see Postmarketing Experience (6.3)].

Ustekinumab-aauz is a clear to slightly opalescent and colorless to slightly brown-yellow solution.

Subcutaneous Injection

• •
  Injection: 45 mg/0.5 mL or 90 mg/mL solution in a single-dose prefilled syringe
• •
  Injection: 45 mg/0.5 mL solution in a single-dose vial

Intravenous Infusion

• •
  Injection: 130 mg/26 mL (5 mg/mL) solution in a single-dose vial

The following adverse reactions have been reported during post-approval use of ustekinumab products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to ustekinumab product exposure.

Immune system disorders: Serious hypersensitivity reactions (including anaphylaxis and angioedema), other hypersensitivity reactions (including rash and urticaria).

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

Neurological disorders: Posterior Reversible Encephalopathy Syndrome (PRES).

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

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

Ustekinumab-aauz is indicated for the treatment of adults and pediatric patients 6 years of age and older with active psoriatic arthritis.

Hypersensitivity reactions, including anaphylaxis and angioedema, have been reported with ustekinumab products [see Adverse Reactions (6.1, 6.3)]. If an anaphylactic or other clinically significant hypersensitivity reaction occurs, institute appropriate therapy and discontinue Ustekinumab-aauz.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

A multicenter, randomized, double blind, placebo-controlled trial (Ps STUDY 3) enrolled 110 pediatric subjects 12 to 17 years of age with a minimum BSA involvement of 10%, a PASI score greater than or equal to 12, and a PGA score greater than or equal to 3, who were candidates for phototherapy or systemic therapy and whose disease was inadequately controlled by topical therapy.

Subjects were randomized to receive placebo (n = 37), the recommended dose of ustekinumab (n = 36), or one-half the recommended dose of ustekinumab (n = 37) by subcutaneous injection at Weeks 0 and 4 followed by dosing every 12 weeks (q12w). The recommended dose of ustekinumab was 0.75 mg/kg for subjects weighing less than 60 kg, 45 mg for subjects weighing 60 kg to 100 kg, and 90 mg for subjects weighing greater than 100 kg. At Week 12, subjects who received placebo were crossed over to receive ustekinumab at the recommended dose or one-half the recommended dose.

Of the pediatric subjects, approximately 63% had prior exposure to phototherapy or conventional systemic therapy and approximately 11% had prior exposure to biologics.

The endpoints were the proportion of subjects who achieved a PGA score of cleared (0) or minimal (1), PASI 75, and PASI 90 at Week 12. Subjects were followed for up to 60 weeks following first administration of trial agent.

Advise the patient and/or caregiver to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).

Ustekinumab-aauz injection is a sterile, preservative-free, clear to slightly opalescent and colorless to slightly brown-yellow solution. It is supplied as individually packaged, single-dose prefilled syringes or single-dose vials.

In a 26-week toxicology study, one out of 10 monkeys subcutaneously administered 45 mg/kg ustekinumab twice weekly for 26 weeks had a bacterial infection.

Subcutaneous Adult Dosage Regimen

• •
  For patients weighing 100 kg or less, the recommended dosage is 45 mg initially and 4 weeks later, followed by 45 mg every 12 weeks.
• •
  For patients weighing more than 100 kg, the recommended dosage is 90 mg initially and 4 weeks later, followed by 90 mg every 12 weeks.

In subjects weighing more than 100 kg, 45 mg was also shown to be efficacious. However, 90 mg resulted in greater efficacy in these subjects [see Clinical Studies (14)].

• •
  Ustekinumab-aauz is intended for use under the guidance and supervision of a healthcare provider. Ustekinumab-aauz should only be administered to patients who will be closely monitored and have regular follow-up visits with a healthcare provider. The appropriate dose should be determined by a healthcare provider using the patient's current weight at the time of dosing. In pediatric patients, it is recommended that Ustekinumab-aauz be administered by a healthcare provider. If a healthcare provider determines that it is appropriate, a patient may self-inject or a caregiver may inject Ustekinumab-aauz after proper training in subcutaneous injection technique. Instruct patients to follow the directions provided in the Medication Guide [see Medication Guide].
• •
  The needle cover on the prefilled syringe is not made with natural rubber (a derivative of latex).
• •
  It is recommended that each injection be administered at a different anatomic location (such as upper arms, gluteal regions, thighs, or any quadrant of abdomen) than the previous injection, and not into areas where the skin is tender, bruised, erythematous, or indurated. When using the single-dose vial, a 1 mL syringe with a 29 gauge, ½ inch needle is recommended.
• •
  Prior to administration, visually inspect Ustekinumab-aauz for particulate matter and discoloration. Ustekinumab-aauz is a clear to slightly opalescent and colorless to slightly brown-yellow solution. Do not use Ustekinumab-aauz if it is discolored or cloudy, or if other particulate matter is present. Ustekinumab-aauz does not contain preservatives; therefore, discard any unused product remaining in the vial and/or syringe.

Evaluate patients for tuberculosis infection prior to initiating treatment with Ustekinumab-aauz.

Avoid administering Ustekinumab-aauz to patients with active tuberculosis infection. Initiate treatment of latent tuberculosis prior to administering Ustekinumab-aauz. Consider anti-tuberculosis therapy prior to initiation of Ustekinumab-aauz in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed. Closely monitor patients receiving Ustekinumab-aauz for signs and symptoms of active tuberculosis during and after treatment.

NDC 65219-862-01

RX only

Ustekinumab-aauz         45 mg / 0.5 mL

Injection

For subcutaneous use

1 Single-dose prefilled syringe. Discard unused portion.

Carton contains:

1 Single-dose prefilled syringe

1 Prescribing Information

1 Medication Guide

Manufactured by:

Fresenius Kabi USA, LLC

Lake Zurich, Illionis 60047

U.S. Licence No. 2146

NDC 65219-866-26

RX only

Ustekinumab-aauz          90mg / mL

Injection

For subcutaneous use

1 Single-dose prefilled syringe. Discard unused portion.

Carton contains:

1 Single-dose prefilled syringe

1 Prescribing Information

1 Medication Guide

Manufactured by:

Fresenius Kabi USA, LLC

Lake Zurich, Illionis 60047

U.S. Licence No. 2146

Single dose prefilled syringe

Discard unused portion

Ustekinumab-aauz

Injection

45 mg / 0.5 mL

For subcutaneous use

Mfg by: Fresenius Kabi USA, LLC

U.S. License No. 2146

NDC 65219-862-01

Rx only

Store at 36 °F to 46 °F

(2 °C to 8 °C). Protect

from light. Do not shake.

Do not freeze

Single dose prefilled syringe

Discard unused portion

Ustekinumab-aauz

Injection

90 mg / mL

For subcutaneous use

Mfg by: Fresenius Kabi USA, LLC

U.S. License No. 2146

NDC 65219-866-26

Rx only

Store at 36 °F to 46 °F

(2 °C to 8 °C). Protect

from light. Do not shake.

Do not freeze

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 product initiation. A few cases reported latency of a year or longer. Patients recovered with supportive care following withdrawal of ustekinumab products.

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

Animal studies have not been conducted to evaluate the carcinogenic or mutagenic potential of ustekinumab products. Published literature showed that administration of murine IL-12 caused an anti- tumor effect in mice that contained transplanted tumors and IL-12/IL-23p40 knockout mice or mice treated with anti-IL-12/IL-23p40 antibody had decreased host defense to tumors. Mice genetically manipulated to be deficient in both IL-12 and IL-23 or IL-12 alone developed UV- induced skin cancers earlier and more frequently compared to wild-type mice. The relevance of these experimental findings in mouse models for malignancy risk in humans is unknown.

No effects on fertility were observed in male cynomolgus monkeys that were administered ustekinumab at subcutaneous doses up to 45 mg/kg twice weekly (45 times the MRHD on a mg/kg basis) prior to and during the mating period. However, fertility and pregnancy outcomes were not evaluated in mated females.

No effects on fertility were observed in female mice that were administered an analogous IL-12/IL-23p40 antibody by subcutaneous administration at doses up to 50 mg/kg, twice weekly, prior to and during early pregnancy.

Individuals genetically deficient in IL-12/IL-23 are particularly vulnerable to disseminated infections from mycobacteria (including nontuberculous, environmental mycobacteria), salmonella (including nontyphi strains), and Bacillus Calmette-Guerin (BCG) vaccinations. Serious infections and fatal outcomes have been reported in such patients.

It is not known whether patients with pharmacologic blockade of IL-12/IL-23 from treatment with ustekinumab products may be susceptible to these types of infections. Consider appropriate diagnostic testing (e.g., tissue culture, stool culture, as dictated by clinical circumstances).

Refer to the diagram below for the provided instructions.

To prevent premature activation of the needle safety guard, do not touch the NEEDLE GUARD ACTIVATION CLIPS at any time during use.

• •
  Hold the BODY and remove the NEEDLE COVER. Do not hold the PLUNGER or PLUNGER HEAD while removing the NEEDLE COVER or the PLUNGER may move. Do not use the prefilled syringe if it is dropped without the NEEDLE COVER in place. Do not use the prefilled syringe if it is dropped or if it is dropped onto a hard surface.
• •
  Inject Ustekinumab-aauz subcutaneously as recommended [see Dosage and Administration (2.1, 2.2, 2.3)].
• •
  Inject all of the medication by pushing in the PLUNGER until the PLUNGER HEAD is completely between the needle guard wings. Injection of the entire prefilled syringe contents is necessary to activate the needle guard.
•  
• •
  After injection, maintain the pressure on the PLUNGER HEAD and remove the needle from the skin. Slowly take your thumb off the PLUNGER HEAD to allow the empty syringe to move up until the entire needle is covered by the needle guard, as shown by the illustration below:
•  
• •
  Used syringes should be placed in a puncture-resistant container.

Ustekinumab-aauz solution for intravenous infusion must be diluted, prepared and infused by a healthcare professional using aseptic technique.

• 1.
  Calculate the dose and the number of Ustekinumab-aauz vials needed based on patient weight (Table 4). Each 26 mL vial of Ustekinumab-aauz contains 130 mg of ustekinumab-aauz.
• 2.
  Withdraw, and then discard a volume of the 0.9% Sodium Chloride Injection, USP from the 250 mL infusion bag equal to the volume of Ustekinumab-aauz to be added (discard 26 mL sodium chloride for each vial of Ustekinumab-aauz needed, for 2 vials- discard 52 mL, for 3 vials- discard 78 mL, 4 vials- discard 104 mL). Alternatively, a 250 mL infusion bag containing 0.45% Sodium Chloride Injection, USP may be used.
• 3.
  Withdraw 26 mL of Ustekinumab-aauz from each vial needed and add it to the 250 mL infusion bag. The final volume in the infusion bag should be 250 mL. Gently mix.
• 4.
  Visually inspect the diluted solution before infusion. Do not use if visibly opaque particles, discoloration or foreign particles are observed.
• 5.
  Infuse the diluted solution over a period of at least one hour. Once diluted, the infusion should be completely administered within eight hours of the dilution in the infusion bag.
• 6.
  Use only polypropylene (PP) or polyvinylchloride (PVC) infusion sets with an in-line, sterile, non-pyrogenic, low protein-binding filter (pore size 0.2 micrometer).
• 7.
  Do not infuse Ustekinumab-aauz concomitantly in the same intravenous line with other agents.
• 8.
  Ustekinumab-aauz does not contain preservatives. Each vial is for one-time use in only one patient. Discard any remaining solution. Dispose any unused medicinal product in accordance with local requirements.