Active ingredients: Ustekinumab
STELARA 45 mg solution for injection
Stelara package inserts are available for pack sizes:- STELARA 45 mg solution for injection
- STELARA 90 mg solution for injection
Indications Why is Stelara used? What is it for?
What is Stelara
Stelara contains the active substance "ustekinumab", a monoclonal antibody.
Monoclonal antibodies are proteins that recognize and bind certain specific proteins in the body. Stelara belongs to a group of medicines called 'immunosuppressants'. These medicines reduce the activity of the immune system to some extent.
What is Stelara for
Stelara is used to treat the following inflammatory diseases:
- plaque psoriasis (in adults and children from 12 years of age)
- psoriatic arthritis (in adults)
Plaque psoriasis
Plaque psoriasis is a skin condition that causes inflammation of the skin and nails. Stelara will reduce inflammation and other signs of the disease.
Stelara is used in adults with moderate to severe plaque psoriasis, who cannot use cyclosporine, methotrexate or phototherapy, or for whom these treatments do not work.
Stelara is used in children from 12 years of age with moderate to severe plaque psoriasis who cannot tolerate phototherapy or other systemic therapies, or when these treatments have not worked.
Psoriatic arthritis
Psoriatic arthritis is an inflammatory joint disease, usually accompanied by psoriasis. If you have active psoriatic arthritis you will first be treated with other medicines. If you do not respond adequately to these medicines, you can take Stelara to:
- reduce the signs and symptoms of the disease.
- improve physical function.
- slow down the damage to the joints.
Contraindications When Stelara should not be used
Do not use Stelara
- If you are allergic to ustekinumab or any of the other ingredients of this medicine (listed in section 6 below)
- If you have an 'active infection which your doctor thinks is important.
If you are not sure if any of the above applies to you, talk to your doctor or pharmacist before using Stelara.
Precautions for use What you need to know before taking Stelara
Talk to your doctor or pharmacist before using Stelara. Your doctor will check your health before each treatment. Be sure to inform your doctor before any treatment about the diseases you are suffering from. Also, tell your doctor even if you have recently been in contact with people who may have had tuberculosis. Your doctor will examine you and carry out tests for tuberculosis before giving you Stelara. If your doctor thinks you are at risk for tuberculosis, he may give you medicines to treat tuberculosis.
Beware of serious side effects
Stelara can cause serious side effects, including allergic reactions and infections. You must pay attention to certain signs of the disease while taking Stelara. See "Serious side effects" in section 4 for a full list of these side effects.
Before using Stelara contact your doctor:
- If you have ever had an allergic reaction to Stelara. Ask your doctor if you are not sure.
- If you have ever had any type of cancer - this is because immunosuppressants like Stelara partially weaken the immune system. This can increase the risk of cancer.
- If you have or have had a recent infection.
- If you have ever had any new or changed lesions within the psoriasis area or on normal skin.
- If you are taking any other type of treatment for psoriasis and / or psoriatic arthritis - such as another immunosuppressant or phototherapy (when the body is treated with a type of ultraviolet (UV) light). These treatments may also reduce the activity of the immune system in part. The concomitant use of these therapies with Stelara has not been studied. However, it is possible that it may increase the possibility of diseases related to a weakening of the immune system.
- If you are using or have ever used injections to treat allergies - it is not known if Stelara can affect them.
- If you are 65 or older - you may be more likely to get infections
If you are not sure if any of the above conditions apply to you, talk to your doctor or pharmacist before having treatment with Stelara.
Children and adolescents
Stelara is not recommended for the treatment of children (under 12 years of age) because it has not been studied in this age group.
Interactions Which drugs or foods can change the effect of Stelara
Tell your doctor or pharmacist:
- If you are taking, have recently taken or might take any other medicines.
- If you have recently been vaccinated or are about to be vaccinated. Some types of vaccines (live vaccines) should not be given while you are using Stelara.
Warnings It is important to know that:
Pregnancy and breastfeeding
- It is preferable to avoid the use of Stelara during pregnancy. The effects of Stelara on pregnant women are not known. If you are of childbearing age, it is advisable to avoid becoming pregnant; you must use adequate contraception while using Stelara and for at least 15 weeks after stopping treatment with Stelara. If you are pregnant, think you may be pregnant or are planning to become pregnant, please ask your doctor for advice.
- If you are breast-feeding or planning to breast-feed ask your doctor for advice. You and your doctor will decide whether you should breastfeed or use Stelara. It cannot do both.
Driving and using machines
Stelara has no or negligible influence on the ability to drive or use machines.
Dose, Method and Time of Administration How to use Stelara: Posology
Stelara is intended for use under the guidance and supervision of a physician experienced in the diagnosis and treatment of psoriasis or psoriatic arthritis. Always use this medicine exactly as your doctor has told you. If in doubt, consult your doctor. Discuss with your doctor when you will need to have the injections and follow-up visits.
How much Stelara is given
Your doctor will decide how much Stelara you need and for how long.
Adults from 18 years old
- The recommended starting dose is 45 mg of Stelara. Patients weighing more than 100 kilograms (kg) can start with a dose of 90 mg instead of 45 mg.
- After the initial dose, you will take the next dose 4 weeks later, and then every 12 weeks. Subsequent doses are usually the same as the starting dose.
Children and adolescents from 12 years of age
- Your doctor will calculate the right dose, including the amount (volume) of Stelara that needs to be injected to ensure that the correct dose is delivered. The correct dose will depend on the child's body weight at the time of each dose.
- If your body weight is less than 60 kg, the recommended dose is 0.75 mg of Stelara per kg of body weight.
- If the body weight is between 60 kg and 100 kg, the recommended dose is 45 mg of Stelara.
- If the weight exceeds 100 kg, the recommended dose is 90 mg of Stelara.
- After the initial dose, you will need to receive the next dose after 4 weeks, and every 12 weeks thereafter.
How Stelara is given
- Stelara is given as an 'injection under the skin (' subcutaneously '). At the start of treatment, your doctor or nurse may inject Stelara.
- However, you and your doctor can decide whether you can inject Stelara yourself. In this case, you will be taught how to inject Stelara yourself.
- For instructions on how to inject Stelara, see 'Instructions for administration' at the end of this leaflet.
Tell your doctor if you have any questions about injecting yourself.
If you forget to use Stelara
If you miss a dose, contact your doctor or pharmacist. Do not take a double dose to make up for a forgotten dose.
If you stop taking Stelara
It is not dangerous to stop using Stelara. However, if you stop the treatment your psoriasis can come back.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Overdose What to do if you have taken too much Stelara
If you have used or received too much Stelara, tell your doctor or pharmacist immediately. Always take the outer carton of your medicine with you, even if it is empty.
Side Effects What are the side effects of Stelara
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Serious side effects
Some patients may experience serious side effects that may need urgent treatment.
Allergic reactions - these may need urgent treatment, so contact your doctor or seek emergency medical help if you notice any of the following signs.
- Serious allergic reactions ("anaphylaxis") are rare in patients taking Stelara (affecting up to 1 in 1,000 patients). The signs include:
- difficulty in breathing or swallowing
- low blood pressure, which can cause dizziness
- feeling light-headed or swollen in the face, lips, mouth or throat.
- Common signs of an allergic reaction include skin rash and hives (affecting up to 1 in 100 people).
If you have a severe allergic reaction, your doctor may decide that you should not use Stelara again.
Infections - these may need urgent treatment, so contact your doctor right away if you notice any of the following signs.
- Nose and throat infections and the common cold are common (affecting up to 1 in 10 people).
- "Inflammation of the subcutaneous tissue ('cellulitis") is uncommon (affects up to 1 in 100 patients).
- Herpes zooster (a type of blistered rash) is uncommon (affects up to 1 in 100 patients).
Stelara can decrease the ability to fight infections, and some infections could become serious.
You must pay attention to the signs of infection while you are using Stelara. These include:
- fever, flu-like symptoms, night sweats
- feeling tired or short of breath, persistent cough
- hot, red, sore skin, or a painful, blistered rash
- burning when urinating
- diarrhea
Tell your doctor right away if you notice any of these signs of infection. Talk to your doctor if you have any type of infection that persists or keeps coming back. Your doctor may decide to stop Stelara until the infection clears up. Also tell your doctor if you have any open cuts or wounds that can become infected.
Skin peeling - increased redness and peeling of the skin over a large area of the body may be symptoms of erythrodermal psoriasis or exfoliative dermatitis, which are serious skin conditions. If you notice any of these signs you should tell your doctor immediately.
Other side effects
Common side effects (affects up to 1 in 10 patients):
- Diarrhea
- Nausea
- Feeling tired
- Feeling dizzy
- Headache
- Itching
- Back, muscle or joint pain
- Sore throat
- Dental infection
- Redness and pain at the injection site
Uncommon side effects (affects up to 1 in 100 patients):
- Depression
- Runny or stuffy nose
- Bleeding, bruising, stiffness, swelling and itching where the injection is given
- Drooping eyelid and muscle relaxation on one side of the face ("facial palsy" or "Bell's palsy"), which is usually temporary
- A change in psoriasis with redness and new small, yellow or white skin blisters, sometimes accompanied by fever (pustular psoriasis)
- Peeling of the skin (skin exfoliation)
Rare side effects (affects up to 1 in 1,000 patients)
- Redness and peeling of the skin over a large surface area of the body, which can be itchy or painful (exfoliative dermatitis). Similar symptoms sometimes develop as a natural progression in the type of psoriasis symptoms (erythrodermal psoriasis).
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
- Keep this medicine out of the sight and reach of children.
- Store in a refrigerator (2 ° C - 8 ° C). Do not freeze.
- Keep the vial in the outer carton to protect the medicine from light.
- Do not shake the vials of Stelara. Prolonged vigorous shaking can damage the medicine.
Do not use this medicine
- After the expiry date which is stated on the label and carton after "EXP". The expiry date refers to the last day of the month.
- If the liquid is discolored, opaque or if you see floating foreign particles (see section 6 "Description of what Stelara looks like and contents of the pack").
- If you know or believe that the medicine has been exposed to extreme temperatures (for example, accidentally frozen or heated).
- If the product has been shaken vigorously.
- If the seal is broken.
Stelara is for single use only. Any unused product remaining in the vial and syringe should be discarded.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Deadline "> Other information
What Stelara contains
- The active ingredient is ustekinumab. Each vial contains 45 mg of ustekinumab in 0.5 ml
- The other ingredients are: L-histidine, L-histidine monohydrochloride monohydrate, polysorbate 80, sucrose, water for injections.
What Stelara looks like and contents of the pack
Stelara is a clear to slightly opalescent (pearl-like appearance), colorless to pale yellow solution for injection.
The solution may contain a few small translucent or white particles of protein. It is supplied in a carton pack containing 1 single dose, in a 2 ml glass vial.
Each vial contains 45 mg ustekinumab dose in 0.5 ml solution for injection.
Expiry "> Instructions for administration
At the start of treatment, your doctor will assist you during the first injection. However, you and your doctor can decide whether you can inject Stelara yourself. In this case, you will be taught how to inject Stelara yourself. Tell your doctor in case if you have any questions about injecting yourself.
- Do not mix Stelara with other injection fluids
- Do not shake the vials of Stelara, as shaking them vigorously can damage the medicine. Do not use the medicine if it has been shaken vigorously.
Check the number of vials and prepare the materials:
Take the vial or several vials out of the refrigerator. Leave the vial out of the refrigerator for about half an hour. This will allow the liquid to reach a comfortable temperature for injection (room temperature).
Check that:
- the number of vials and the dose are correct
- if your dose is 45 mg or less you will take a 45 mg vial of Stelara
- if your dose is 90 mg you will take two 45 mg vials of Stelara and you will need to give two injections. Choose two different body sites for these injections (for example, one injection on the right thigh and the other injection on the left thigh), and proceed with the injections one after the other. Use a new needle and a new syringe for each injection.
- the medicine is right
- the medicine has not expired
- the vial is not damaged and the stopper is broken
- the solution in the vial is clear or slightly opalescent (pearl-like appearance) and colorless or pale yellow
- the liquid does not have an altered or opaque color and does not contain foreign particles
- is not frozen.
Children with a body weight of less than 60 kg need a dose of less than 45 mg. You need to be sure of the appropriate amount (volume) to remove from the vial and the type of syringe needed for dosing. If you do not know the amount of medicine or the type of syringe to use, contact your doctor for further instructions.
Take everything you need and place it on a clean surface. There should be a syringe, needle, antiseptic swabs, a cotton ball or gauze pad, and a sharps container.
Choose the injection site and prepare it:
Choose an injection site.
- Stelara is given by injection under the skin (subcutaneously).
- A good place to inject is the top of the thigh or around the belly (abdomen) at least 5cm away from the navel.
- If possible, do not choose areas of the skin with signs of psoriasis.
- If someone is assisting you during the injection, they may also choose the upper arms as the injection site.
Prepare the injection site
- Wash your hands very well with soap and warm water
- Rub the injection site into the skin with an antiseptic swab
- Do not touch this area again before injecting.
Prepare the dose:
- Remove the cap from the top of the vial.
- Do not remove the cap
- Clean the cap with an antiseptic swab
- Place the vial on a flat surface.
- Take the syringe and remove the protective cap from the needle.
- Do not touch the needle or let the needle touch anything.
- Push the needle through the rubber stopper.
- Turn the vial and syringe upside down.
- Pull the syringe plunger to fill the syringe with the amount of liquid as prescribed by your doctor.
- It is important that the needle is always inside the liquid so that no air bubbles form in the syringe.
- Remove the needle from the vial.
- Hold the syringe with the needle pointing up to see if there are any bubbles inside.
- If there are air bubbles, gently tap the side of the syringe until the air bubbles reach the top of the syringe.
- Then press the plunger until all the air (but not the liquid) has been removed. Do not rest the syringe and avoid the needle touching anything.
Inject the dose:
- Gently squeeze the portion of clean skin by holding it between your thumb and forefinger. Do not squeeze too vigorously.
- Push the needle into the pinched skin.
- Push the plunger with your thumb until you finish injecting all the liquid. Press slowly and steadily, keeping the skin gently tight.
- When the plunger reaches the end of the syringe, pull out the needle and release the skin.
After the injection:
- Press an antiseptic pad over the injection site for a few seconds after the injection.
- There may be a small amount of blood or fluid at the injection site. It's normal.
- You can press a cotton ball or gauze onto the injection site and hold it for 10 seconds.
- Do not rub the skin at the injection site - you can cover the injection site with a small patch if necessary.
Disposal:
- Used syringes and needles should be placed in a puncture-resistant container, such as a sharps container. For your health and safety and the safety of others, never reuse needles or syringes. Dispose of the sharps container in accordance with local regulations.
- Empty vials, antiseptic wipes and other devices can be disposed of in the waste.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT -
STELARA SOLUTION FOR INJECTION
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION -
STELARA 45 mg solution for injection
Each vial contains 45 mg of ustekinumab in 0.5 mL.
STELARA 90 mg solution for injection
Each vial contains 90 mg of ustekinumab in 1 mL.
STELARA 45 mg solution for injection in pre-filled syringe
Each pre-filled syringe contains 45 mg of ustekinumab in 0.5 mL.
STELARA 90 mg solution for injection in pre-filled syringe
Each pre-filled syringe contains 90 mg of ustekinumab in 1 mL.
Ustekinumab is a fully human, interleukin (IL) -12/23 binding IgG1κ monoclonal antibody produced in a mouse myeloma cell line using recombinant DNA technology.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM -
STELARA 45 mg solution for injection
Injectable solution.
STELARA 90 mg solution for injection
Injectable solution.
STELARA 45 mg solution for injection in pre-filled syringe
Injectable solution.
STELARA 90 mg solution for injection in pre-filled syringe
Injectable solution.
The solution is clear to slightly opalescent, colorless to pale yellow.
04.0 CLINICAL INFORMATION -
04.1 Therapeutic indications -
Plaque psoriasis
STELARA is indicated for the treatment of moderate to severe plaque psoriasis in adult patients who have not responded, or who have contraindications or who are intolerant to other systemic therapies, including cyclosporine, methotrexate (MTX) or PUVA (psoralen and ultraviolet rays A) (see section 5.1).
Plaque psoriasis in pediatric patients
STELARA is indicated for the treatment of moderate to severe plaque psoriasis in adolescent patients from 12 years of age who are inadequately controlled by or are intolerant of other systemic therapies or phototherapy (see section 5.1).
Psoriatic arthritis (PsA)
STELARA, alone or in combination with MTX, is indicated for the treatment of active psoriatic arthritis in adult patients when the response to previous therapy with non-biological disease-modifying antirheumatic drugs (DMARDs) has been inadequate (see section 5.1).
Crohn's disease
STELARA is indicated for the treatment of adult patients with moderate to severe active Crohn's disease who have had an inadequate response, lost response or were found to be intolerant to conventional therapy or a TNFα antagonist or who have contraindications. for such therapies.
04.2 Posology and method of administration -
STELARA should be used under the guidance and supervision of medical specialists with experience in the diagnosis and treatment of the conditions for which STELARA is indicated.
Dosage
Plaque psoriasis
The recommended posology of STELARA is an initial dose of 45 mg administered subcutaneously, followed by a dose of 45 mg after 4 weeks and every 12 weeks thereafter.
Treatment discontinuation should be considered in patients who have shown no response to 28 weeks of treatment.
Patients with body weight> 100 kg
In patients weighing more than 100 kg the initial dose to be administered subcutaneously is 90 mg, followed by a dose of 90 mg after 4 weeks and every 12 weeks thereafter. The 45 mg dose has also been shown to be effective in these patients. However, the 90 mg dose showed greater efficacy (see section 5.1, Table 4).
Psoriatic arthritis (PsA)
The recommended posology of STELARA is an initial dose of 45 mg administered subcutaneously, followed by a dose of 45 mg after 4 weeks and every 12 weeks thereafter. Alternatively, 90 mg can be used in patients with a body weight> 100 kg. Treatment discontinuation should be considered in patients who have shown no response to 28 weeks of treatment.
Elderly (≥ 65 years old)
No dose adjustment is necessary for elderly patients (see section 4.4).
Renal and hepatic insufficiency
STELARA has not been studied in this patient population. No recommendation on the dose to be given can be made.
Pediatric population
The safety and efficacy of STELARA in children with psoriasis under 12 years of age or in children with psoriatic arthritis under 18 years of age have not yet been established.
Plaque psoriasis in pediatric patients (from 12 years of age)
The recommended dose of STELARA based on body weight is shown in the tables below (Tables 1 and 2). STELARA should be given at Weeks 0 and 4, and every 12 weeks thereafter.
Table 1: Recommended dose of STELARA for pediatric patients with psoriasis
a To calculate injection volume (mL) for patients body weight (kg) x 0,0083 (mL / kg) or see Table 2. The calculated volume should be rounded to the nearest 0.01 mL and administered using a 1 mL graduated syringe. A 45 mg vial is available for pediatric patients who need to receive less than the full 45 mg dose.
Table 2: STELARA injection volumes for pediatric patients
Treatment discontinuation should be considered in patients who do not show a response for up to 28 weeks of treatment.
Crohn's disease
In the treatment regimen, the first dose of STELARA is administered intravenously. For the posology of the intravenous dosing regimen, see section 4.2 of the SmPC of STELARA 130 mg concentrate for solution for infusion.
The first subcutaneous administration of 90 mg of STELARA should occur at week 8 following the intravenous dose. After this, dosing every 12 weeks is recommended.
Patients who have not shown adequate response 8 weeks after the first subcutaneous dose may then receive a second subcutaneous dose (see section 5.1).
Patients who have failed to dose every 12 weeks may benefit from an increase in dosing frequency every 8 weeks (see section 5.1).
Patients may receive the dose every 8 weeks or every 12 weeks thereafter based on clinical judgment (see section 5.1).
Treatment discontinuation should be considered in patients who show no evidence of therapeutic benefit at week 16 or week 16 after switching to the every 8 week dosing.
Immunomodulators and / or corticosteroids can be continued during treatment with STELARA. In patients who have responded to treatment with STELARA, corticosteroids may be reduced or discontinued according to standard of care.
If therapy is interrupted, resuming treatment with subcutaneous administration every 8 weeks is safe and effective.
Elderly (≥ 65 years old)
No dose adjustment is necessary for elderly patients (see section 4.4).
Renal and hepatic insufficiency
STELARA has not been studied in this patient population. No recommendation on the dose to be given can be made.
Pediatric population
The safety and efficacy of STELARA in the treatment of Crohn's disease in children under 18 years of age have not yet been established. There are no data available.
Method of administration
STELARA 45 mg and 90 mg in vials or pre-filled syringes is formulated for subcutaneous injection only. If possible, avoid injection into areas affected by psoriasis.
After receiving adequate instructions on the subcutaneous injection technique, patients or their carers may administer STELARA if the physician deems it appropriate. However, the physician must ensure appropriate periodic monitoring of patients. Patients or caregivers should be instructed to administer the prescribed amount of STELARA as directed in the package leaflet. Full instructions for administration are given in the package leaflet.
For further information on preparation and special handling precautions, see section 6.6.
04.3 Contraindications -
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Active, clinically relevant infection (e.g. active tuberculosis; see section 4.4).
04.4 Special warnings and appropriate precautions for use -
Infections
Ustekinumab can increase the risk of getting infections and reactivating latent ones.
In some clinical studies, serious bacterial, fungal and viral infections have been observed in patients receiving STELARA (see section 4.8).
Caution should be exercised when considering the use of STELARA in patients with a chronic infection or with a history of recurrent infection (see section 4.3).
Before starting treatment with STELARA, all patients should be evaluated for the presence of tuberculosis infection. STELARA must not be administered to patients with active tuberculosis (see section 4.3). Treatment of latent tuberculosis infection should be initiated prior to administering STELARA. Anti-tuberculosis therapy should be considered prior to initiating STELARA in patients with a history of latent or active tuberculosis who are not Adequate therapeutic pathway can be confirmed Patients on STELARA therapy should be carefully monitored for signs and symptoms of active tuberculosis, during and after treatment.
Patients should be advised to seek medical advice if they observe signs and symptoms that may indicate an "ongoing infection. If a patient develops a severe" infection, they should be monitored closely and STELARA should not be administered until "infection does not clear up.
Neoplasms
Immunosuppressants such as ustekinumab may increase the risk of developing cancer.
Some patients who received STELARA in clinical trials developed cutaneous and non-cutaneous malignancies (see section 4.8).
No clinical studies have been conducted that included patients with a history of malignancy or in whom treatment with STELARA continued despite the onset of ongoing malignancies. Therefore, caution should be used when considering treatment with STELARA in these patients.
All patients, particularly those over 60 years of age, patients with a history of prolonged immunosuppressive therapy or with a history of PUVA treatment, should be monitored for non-melanoma skin cancer (see section 4.8).
Hypersensitivity reactions
Serious hypersensitivity reactions have been reported in post-marketing experience, in some cases even several days after treatment. Anaphylaxis and angioedema have occurred. adequate therapy and administration of STELARA should be discontinued (see section 4.8).
Sensitivity to latex
The needle cap of the STELARA pre-filled syringe is made from dry natural rubber (a derivative of latex) which may cause allergic reactions in latex sensitive individuals.
Vaccinations
It is recommended not to administer live viral or bacterial vaccines (such as Calmette and Guérin bacillus, BCG) concurrently with treatment with STELARA. No specific clinical studies have been conducted in patients who have recently been given live viral or bacterial vaccines. There are no data on secondary transmission of live vaccine infections in patients receiving STELARA. Before administering a live viral or bacterial vaccine, treatment with STELARA should be stopped for at least 15 weeks after the last administration and can be resumed no earlier than 2 weeks after vaccination. The prescribing physician is required to consult the Summary of Product Characteristics of the vaccine, to benefit from additional data and guidance on the concomitant use of post-vaccination immunosuppressive agents.
Patients on STELARA therapy can be treated concurrently with inactivated or non-live vaccines.
Long-term treatment with STELARA does not suppress the humoral immune response to the pneumococcal polysaccharide or the tetanus vaccine (see section 5.1).
Concomitant immunosuppressive therapy
The safety and efficacy of STELARA in combination with other immunosuppressants, including biological agents or phototherapy, have not been evaluated in psoriasis studies. In psoriatic arthritis clinical studies, concomitant use of MTX has not been shown to affect safety. ol "efficacy of STELARA. In Crohn's disease studies, concomitant use of immunosuppressants or corticosteroids did not appear to affect the safety or efficacy of STELARA.
Caution should be exercised when considering concomitant use of other immunosuppressants and STELARA, or when resulting from treatment with other biological immunosuppressants (see section 4.5).
Immunotherapy
STELARA has not been evaluated in patients who have undergone allergy immunotherapy.
It is not known whether STELARA can affect allergy immunotherapy.
Severe skin conditions
In patients with psoriasis, exfoliative dermatitis has been reported following treatment with ustekinumab (see section 4.8). Patients with plaque psoriasis may develop erythrodermal psoriasis, with symptoms that may be clinically indistinguishable from exfoliative dermatitis, as a natural course of the disease. As part of monitoring patients with psoriasis, physicians should pay attention to symptoms of erythrodermal psoriasis or exfoliative dermatitis. If these symptoms occur, appropriate therapy should be instituted. STELARA should be discontinued if a drug reaction is suspected.
Special populations
Elderly (≥ 65 years old)
Overall, no differences were observed in the efficacy or safety of STELARA in patients aged 65 or over compared to younger patients, however the number of patients aged 65 or over is not sufficient to determine whether they respond. differently than in younger patients Due to the higher incidence of infections in the elderly population in general, caution should be used when treating elderly patients.
04.5 Interactions with other medicinal products and other forms of interaction -
Live vaccines should not be administered concomitantly with STELARA (see section 4.4).
No interaction studies have been performed in humans. In the population pharmacokinetic analyzes of the Phase III studies, the effect of the most commonly used concomitant medications in psoriasis patients (including paracetamol, ibuprofen, acetylsalicylic acid) was examined. , metformin, atorvastatin, levothyroxine) on the pharmacokinetic profile of ustekinumab. No interaction was found with these concomitantly administered medicinal products. The basis for this analysis was the presence of at least 100 patients (> 5% of the study population) treated concomitantly with these medicinal products for at least 90% of the study period. In patients with psoriatic arthritis or Crohn's disease, the pharmacokinetics of ustekinumab were not affected by concomitant use of MTX, NSAIDs, 6-mercaptopurine, azathioprine and oral corticosteroids, or by previous exposure to anti-TNFα agents. of a study in vitro do not indicate the need for dose adjustment in patients concomitantly taking CYP450 substrates (see section 5.2).
In psoriasis studies, the safety and efficacy profiles of STELARA, administered in combination with immunosuppressants, including biological agents or phototherapy, have not been evaluated. In psoriatic arthritis studies, concomitant use of MTX did not appear to affect the safety and efficacy of STELARA. In Crohn's disease studies, concomitant use of immunosuppressants or corticosteroids did not appear to affect the safety or efficacy of STELARA. (see section 4.4).
04.6 Pregnancy and breastfeeding -
Women of childbearing potential
Women of childbearing potential must use effective contraceptive methods during treatment and for at least 15 weeks after stopping treatment.
Pregnancy
There are insufficient data on the use of ustekinumab during pregnancy. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal / fetal development, parturition or postnatal development (see section 5.3). As a precautionary measure, it is it is preferable to avoid the use of STELARA during pregnancy.
Feeding time
It is unknown whether ustekinumab is excreted in human milk. Some clinical studies in animals have shown the excretion of low levels of ustekinumab in breast milk. It is not known whether ustekinumab is absorbed systemically after ingestion. Given the ability of ustekinumab to trigger adverse reactions in infants, the decision whether to discontinue breastfeeding during treatment and up to 15 weeks after discontinuation, or administration of STELARA therapy must be made taking into account the benefit of the treatment. "breastfeeding for the baby and the benefit of STELARA treatment for the mother.
Fertility
The effects of ustekinumab on human fertility have not been evaluated (see section 5.3).
04.7 Effects on ability to drive and use machines -
STELARA has no or negligible influence on the ability to drive or use machines.
04.8 Undesirable effects -
Summary of the safety profile
The most common adverse reactions with ustekinumab (> 5%) in the controlled phases of psoriasis, psoriatic arthritis and Crohn's disease clinical trials in adults were nasopharyngitis and headache. Most were considered mild and were not Study therapy had to be discontinued. The most serious adverse reactions that have been reported with STELARA are severe hypersensitivity reactions including anaphylaxis (see section 4.4). The overall safety profile was similar for patients with psoriasis, psoriatic arthritis and Crohn's disease.
Summary table of adverse reactions
The safety data reported below reflect ustekinumab exposure in adults in 12 phase II and phase III clinical trials involving 5,884 patients (4,135 with psoriasis and / or psoriatic arthritis and 1,749 with Crohn's disease). This includes exposure to STELARA in the controlled and uncontrolled phases of clinical trials for at least 6 months or 1 year (4,105 and 2,846 patients with psoriasis, psoriatic arthritis or Crohn's disease respectively) with exposure for at least 4 or 5 years (1,482 and 838 respectively patients with psoriasis).
Table 3 provides a list of adverse reactions from clinical trials in psoriasis, psoriatic arthritis and Crohn's disease in adults, as well as adverse reactions reported from post-marketing experience. Adverse drug reactions have been listed by system organ class and frequency, using the following convention: Very common (≥ 1/10), Common (≥ 1/100 to
Within each frequency class, adverse reactions are reported in order of decreasing severity.
Table 3 - List of adverse reactions
Description of selected adverse reactions
Infections
In some placebo-controlled studies in patients with psoriasis, psoriatic arthritis and Crohn's disease, the frequency of infection or severe infection was similar between patients treated with ustekinumab and those treated with placebo. In the placebo treatment phase in clinical trials in patients with psoriasis, patients with psoriatic arthritis and patients with Crohn's disease, the frequency of infection was 1.38 per patient-year of follow up in patients receiving ustekinumab and 1.35 in those receiving placebo. Cases of severe infections occurred to the extent of 0.03 per patient-year follow up in ustekinumab-treated patients (27 serious infections in 829 patient-years of follow up) and 0.03 in placebo-treated patients (11 severe infections in 385 patient-years of follow up) (see section 4.4).
In the controlled and uncontrolled phases of clinical trials in psoriasis, psoriatic arthritis and Crohn's disease, representing 10,953 patient-years of exposure in 5,884 patients, the follow up median was 0.99 years; 3.2 years for psoriasis studies, 1.0 year for psoriatic arthritis studies and 0.6 years for Crohn's disease studies. The frequency of infection was 0.91 per patient-year of follow up in ustekinumab-treated patients and the frequency of serious infections was 0.02 per patient-year of follow up in patients receiving ustekinumab (178 serious infections in 10,953 patient-years of follow up) and serious infections reported included anal abscess, cellulitis, pneumonia, diverticulitis, gastroenteritis, and viral infections.
In clinical trials, patients with latent tuberculosis who were concomitantly treated with isoniazid did not develop tuberculosis.
Neoplasms
In the placebo-controlled phases of clinical trials in psoriasis, psoriatic arthritis and Crohn's disease, the incidence of malignancies, excluding non-melanoma skin cancer, was 0.12 per 100 patient-years of follow up for patients treated with ustekinumab (1 patient out of 829 patient-years of follow up) compared with 0.26 for placebo-treated patients (1 patient out of 385 patient-years of follow up). The incidence of non-melanoma skin cancer was 0.48 per 100 patient-years follow up for patients on ustekinumab therapy (4 patients out of 829 patient-years of follow up) compared with 0.52 for placebo-treated patients (2 patients out of 385 patient-years of follow up).
In the controlled and uncontrolled phases of clinical trials in psoriasis, psoriatic arthritis and Crohn's disease, representing 10,935 patient-years of exposure in 5,884 patients, the follow up median was 1.0 year; 3.2 years for the psoriasis studies, 1.0 years for the psoriatic arthritis studies and 0.6 years for the Crohn's disease studies. Neoplasms, excluding non-melanoma skin cancer, were reported in 58 patients on 10,935 patient-years of follow up (incidence of 0.53 per 100 patient-years of follow up for patients treated with ustekinumab). The incidence of malignancies reported in patients treated with ustekinumab is comparable to the expected incidence in the general population (standardized incidence rate = 0.87 [95% confidence interval: 0.66, 1.14], corrected for age, gender and race). The most frequently observed malignancies, other than non-melanoma skin cancer, were prostate cancer, melanoma, colorectal cancer and breast cancer. The incidence of non-melanoma skin cancer was 0.49 per 100 patient-years of follow up for patients treated with ustekinumab (53 patients out of 10,919 patient-years of follow up). The ratio of patients with basal cell to squamous cell skin cancers (4: 1) is comparable to the expected ratio in the general population (see section 4.4).
Hypersensitivity reactions
During the controlled phases of the psoriasis and psoriatic arthritis clinical trials of ustekinumab, rash and urticaria were observed in
Immunogenicity
In clinical trials in psoriasis and psoriatic arthritis less than 8% of patients taking ustekinumab developed antibodies to ustekinumab. In clinical trials in Crohn's disease, less than 3% of ustekinumab-treated patients developed antibodies to ustekinumab. No apparent association was observed between the development of antibodies to ustekinumab and the development of injection site reactions. Most patients positive for antiustekinumab antibodies had neutralizing antibodies. Treatment efficacy tended to be less in positive patients. to anti-ustekinumab antibodies; however, antibody positivity did not preclude a clinical response.
Pediatric population
Undesirable effects in pediatric patients from 12 years of age with plaque psoriasis
The safety of ustekinumab was studied in a Phase 3 study involving 110 patients aged 12-17 years for up to 60 weeks. Adverse events reported in this study were similar to those seen in previous studies in adults with plaque psoriasis.
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.
04.9 Overdose -
Single doses of the medicinal product up to 6 mg / kg have been administered intravenously in clinical studies, without observing the occurrence of dose limiting toxicity. In the event of an overdose, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions and appropriate symptomatic therapy instituted immediately.
05.0 PHARMACOLOGICAL PROPERTIES -
05.1 "Pharmacodynamic properties -
Pharmacotherapeutic group: Immunosuppressants, interleukin inhibitors, ATC code: L04AC05.
Mechanism of action
Ustekinumab is an entirely human IgG1κ monoclonal antibody that specifically binds the p40 protein, shared subunit of interlukin (IL) -12 and IL-23, human cytokines. Ustekinumab inhibits the biological activity of human IL-12 and IL-23 by preventing the binding of p40 to the IL-12Rb1 receptor protein expressed on the surface of immune cells. Ustekinumab cannot bind to IL-12 or IL-23 which are already bound to IL-12Rb1 receptors present on the cell surface. Thus, ustekinumab is unlikely to contribute to complement-mediated or antibody-mediated cytotoxicity of cells with IL-12 and / or IL-23 receptors. IL-12 and IL- 23 are heterodimer cytokines secreted by activated antigen-presenting cells, such as macrophages and dendritic cells, and both cytokines participate in immune activity; IL-12 stimulates cells natural killer (NK) and leads the differentiation of CD4 + T cells towards the T phenotype helper 1 (Th1), IL-23 induces the pathway of T helper 17 (Th17). However, abnormal regulation of IL-12 and IL-23 has been associated with immune-mediated diseases, such as psoriasis, psoriatic arthritis and Crohn's disease.
By binding to the shared p40 subunit of IL-12 and IL-23, ustekinumab can exert its clinical effects in psoriasis, psoriatic arthritis and Crohn's disease by disrupting the Th1 and Th17 cytokine pathways, which are crucial for the disease. of these diseases. In patients with Crohn's disease, treatment with ustekinumab resulted in a decrease in inflammatory indices including C-reactive protein (CRP) and fecal calprotectin during the induction phase; this induction was then maintained throughout the maintenance phase.
Immunization
During the long-term extension of Psoriasis Study 2 (PHOENIX 2), adult patients treated with STELARA for at least 3.5 years showed similar antibody responses to both pneumococcal polysaccharide and tetanus vaccine as a group of control of psoriatic patients treated with non-systemic drugs.A similar proportion of adult patients developed protective levels of anti-pneumococcal and anti-tetanus antibodies and antibody titers were similar between patients treated with STELARA and patients in the control group.
Clinical efficacy and safety
Plaque psoriasis (Adults)
The efficacy and safety profiles of ustekinumab were evaluated in 1,996 patients in two randomized, double-blind, placebo-controlled clinical trials conducted in patients with moderate to severe plaque psoriasis who were candidates for phototherapy or to systemic therapy. In addition, an active treatment-controlled, randomized, evaluator-blinded clinical trial compared ustekinumab and etanercept in patients with moderate to severe plaque psoriasis who responded inadequately or who were intolerant or who had contraindications to cyclosporine, MTX or PUVA.
Psoriasis Study 1 (PHOENIX 1) evaluated 766 patients. Of these, 53% had not responded, were intolerant or had contraindications to another systemic therapy. Patients randomly assigned to ustekinumab were treated with doses of 45 mg or 90 mg at weeks 0 and 4 and subsequently with the same. dose every 12 weeks. Patients, who were randomized to the placebo treatment group at weeks 0 and 4, switched to ustekinumab (45 mg or 90 mg) at weeks 12 and 16, followed by one dose every 12 weeks. Patients originally randomized to ustekinumab, who achieved a response of 75 on the index Psoriasis Area and Severity Index (PASI) (improvement in PASI of at least 75% from baseline) at weeks 28 and 40, were re-randomized and assigned to the ustekinumab treatment group, given every 12 weeks, or to the placebo group (i.e., suspension of therapy). Patients re-randomized to the placebo group at week 40 restarted ustekinumab with their original dosing schedule if they experienced a loss of at least 50% of the PASI improvement achieved at week 40. All patients were followed up. for a total of 76 weeks after the first study drug administration.
Psoriasis Study 2 (PHOENIX 2) evaluated 1,230 patients. Of these, 61% were unresponsive, intolerant, or had contraindications to "other systemic therapy. Patients randomly assigned to ustekinumab were treated with 45 mg or 90 mg doses at weeks 0 and 4 and then with a dose additional at week 16. Patients who were randomized to the placebo treatment group at weeks 0 and 4 were switched to ustekinumab (45 mg or 90 mg) at weeks 12 and 16. All patients were followed up for a total of 52 weeks after the first administration of study treatment.
Psoriasis Study 3 (ACCEPT) evaluated 903 patients with moderate to severe psoriasis who responded inadequately or who were intolerant or who had contraindications to other systemic therapies, comparing the efficacy of ustekinumab versus etanercept and evaluating the safety of the two biologics in patients. During the 12-week active control period of the study, patients were randomized to receive etanercept (50 mg twice weekly), ustekinumab 45 mg at weeks 0 and 4, or ustekinumab 90 mg at weeks 0 and 4.
In psoriasis clinical trials 1 and 2, baseline disease characteristics were generally overlapping across all treatment groups with a median baseline PASI score ranging from 17 to 18, a "psoriatic area of the body surface (Body Surface Area, BSA) median ≥ 20 and a median dermatological quality of life index score (Dermatology Life Quality Index, DLQI) between 10 and 12. About one third (Psoriasis Study 1) and a quarter (Psoriasis Study 2) of the patients had psoriatic arthritis (PsA). Similar disease severity was also seen in Psoriasis Study 3.
L"endpoint Primary in these studies was the proportion of patients who achieved a PASI 75 response from baseline at week 12 (see Tables 4 and 5).
Table 4 - Summary of clinical response in Psoriasis Study 1 (PHOENIX 1) and Study 2 (PHOENIX 2)
on p
b PGA = (Physician Global Assessment) global evaluation of the physician
Table 5 - Summary of clinical response at week 12 in Psoriasis Study 3 (ACCEPT)
on p
b p = 0.012 for ustekinumab 45 mg versus etanercept.
In Psoriasis Study 1, maintenance of a PASI 75 score was significantly higher with continued treatment than with treatment discontinuation (p
In patients re-randomized to placebo who restarted ustekinumab at their original dosing schedule after a ≥ 50% loss of PASI improvement, 85% regained a PASI 75 response within 12 weeks of reintroduction of therapy. In Psoriasis Study 1, at week 2 and week 12, significant improvements in baseline DLQI were observed in each ustekinumab treatment group compared to the placebo group. The improvement was maintained through Week 28. Similarly, significant improvements were seen in Psoriasis Study 2 at Weeks 4 and 12, which were maintained through Week 24. In Psoriasis Study 1, improvements in psoriasis were also significant. nail psoriasis (NAPSI index, Nail Psoriasis Severity Index), the overall scores of the mental and physical component of the SF-36 and the visual analog scale (Visual Analogue Scale, VAS) for pruritus, in each ustekinumab treatment group compared to placebo. In Psoriasis Study 2, the HADS scale (Hospital Anxiety and Depression Scale) and the WLQ questionnaire (Work Limitations Questionnaire) in each ustekinumab treatment group versus placebo.
Psoriatic Arthritis (PsA) (Adults)
Ustekinumab has been shown to improve signs and symptoms, physical function and health-related quality of life and reduce the rate of progression of peripheral joint damage in adult patients with active PsA.
The safety and efficacy of ustekinumab were evaluated in 927 patients in two randomized, double-blind, placebo-controlled clinical trials in patients with active PsA (≥ 5 swollen and ≥ 5 painful joints) despite non-steroidal anti-inflammatory therapy. (NSAID) or disease-modifying antirheumatic drug therapy (DMARD). Patients in these studies had been diagnosed with PsA for at least 6 months. Patients with any subtype of PsA were enrolled, including polyarticular arthritis without evidence of nodules remautoids (39%), spondylitis with peripheral arthritis (28%), asymmetric peripheral arthritis (21%), involvement of the distal interphalangeal joints (12%) and mutilating arthritis (0.5%). Over 70% and 40% of patients in both studies had enthesitis and dactylitis at baseline, respectively. Patients were randomized to receive ustekinumab 45 mg, 90 mg or placebo subcutaneously at weeks 0 and 4 followed by a
administration every 12 weeks (q12w). Approximately 50% of patients continued on stable doses of MTX (≤ 25 mg / week).
In PsA Study 1 (PSUMMIT I) and PsA Study 2 (PSUMMIT II), 80% and 86% of patients, respectively, had previously been treated with DMARDs. Previous treatment with anti-tumor necrosis factor (TNF) α agents was not allowed in Study 1. In Study 2, the majority of patients (58%, n = 180) had previously received one or more treatments with an anti-TNFα agent, of which more than 70% had stopped anti-TNFα treatment at any time for loss of efficacy or intolerance.
Signs and symptoms
Ustekinumab treatment resulted in significant improvements in the assessment of disease activity compared to placebo at week 24. The primary endpoint was the percentage of patients achieving American College of Rheumatology (ACR) 20 response at Week 24. I Key efficacy results are shown in Table 6 below. Table 6 - Number of patients achieving clinical response in Psoriatic Arthritis Study 1 (PSUMMIT I) and Study 2 (PSUMMIT II) at week 24
on p
b p
c p = NS
d Number of patients with skin psoriasis involvement at baseline BSA ≥ 3%
ACR 20, 50, and 70 responses continuously improved or remained constant through Week 52 (PsA Study 1 and 2) and Week 100 (PsA Study 1). In PsA Study 1, ACR 20 responses at Week 100 were achieved by 57% and 64%, for 45 mg and 90 mg, respectively. In PsA Study 2, ACR 20 responses at Week 52 were achieved by 47% and 48%, for 45 mg and 90 mg, respectively.
The percentage of patients achieving a response under the Modified Psoriatic Arthritis Response Criteria (PsARC) was also significantly higher in the ustekinumab group compared to placebo at week 24. PsARC responses were maintained through Weeks 52 and 100. A "high" Percentage of ustekinumab-treated patients who had spondylitis with peripheral arthritis as their primary presentation, showed a 50 and 70 percent improvement in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score compared to placebo at week 24. treatment with ustekinumab were similar between patients receiving concomitant MTX and those not receiving MTX and were maintained through Weeks 52 and 100. Patients previously treated with anti-TNFα agents who received ustekinumab achieved a greater response at Week 24 compared to patients who received the placeb or (ACR 20 response at Week 24 for 45 mg and 90 mg was 37% and 34%, respectively, compared with placebo 15%; p
For patients with enthesitis and / or dactylitis at baseline, a significant improvement in enthesitis and dactylitis score was observed in the ustekinumab group compared to the placebo group in Week 24 in PsA Study 2. Significant improvement in enthesitis score and numerical (non-statistically significant) improvement in dactylitis score in the ustekinumab 90 mg group (p = NS) compared to placebo at Week 24. The improvements in enthesitis and dactylitis score were maintained through Weeks 52 and 100.
Radiographic response
Structural damage in both hands and feet was expressed as the change in van der Heijde-Sharp total score (vdH-S score), modified for PsA by adding distal interphalangeal joints of the hand, from baseline. A pre-specific integrated analysis was performed combining data from 927 subjects from both PsA Study 1 and Study 2.
Ustekinumab demonstrated a statistically significant decrease in the rate of progression of structural damage compared to placebo, as measured by the change from baseline to Week 24 in the modified total vdH-S score (mean ± SD score was 0.97 ± 3.85 in the placebo group versus 0.40 ± 2.11 and 0.39 ± 2.40 in the ustekinumab 45 mg groups (p
Physical function and health-related quality of life
Patients treated with ustekinumab showed significant improvement in physical function as assessed by the Disability Index of the Health Assessment Questionnaire (HAQ-DI) at Week 24. Also the percentage of patients who achieved a clinically significant improvement ≥ 0.3 in score HAQ-DI from baseline was significantly greater in the ustekinumab group than in the placebo group. The improvement in HAQ-DI score from baseline was maintained through Weeks 52 and 100.
C "was a significant improvement in the DLQI score in the ustekinumab group compared to placebo at Week 24 which was maintained through Weeks 52 and 100. In PsA Study 2 c" was a significant improvement in the Functional Assessment of Chronic score Illness Therapy - Fatigue (FACIT-F) in the ustekinumab group when compared to the placebo group at Week 24. The percentage of patients who achieved significant improvement in fatigue (4 points in FACIT-F) was also significantly greater in the ustekinumab group compared to placebo. Improvements in FACIT score were maintained through Week 52.
Pediatric population
The European Medicines Agency has deferred the obligation to submit the results of studies with ustekinumab in one or more subsets of the pediatric population aged 6-11 years for moderate to severe plaque psoriasis and juvenile idiopathic arthritis (see section 4.2 for information on pediatric use).
Plaque psoriasis in pediatric patients
Ustekinumab has been shown to improve health-related signs and symptoms and quality of life in pediatric patients aged 12 years and older with plaque psoriasis.
The efficacy of ustekinumab was studied in 110 pediatric patients aged 12 to 17 years with moderate to severe plaque psoriasis in a Phase 3, multicentre, randomized, double-blind, placebo-controlled study (CADMUS). patients were randomized to take placebo (n = 37), either the recommended ustekinumab dose (see section 4.2; n = 36) or half the recommended ustekinumab dose (n = 37) by subcutaneous injection at Weeks 0 and 4 and thereafter every 12 weeks (q12w) At Week 12, placebo-treated patients were switched to ustekinumab treatment.
Patients with PASI ≥ 12, PGA ≥ 3, and BSA involvement of at least 10% who were candidates for systemic therapy or phototherapy were eligible for the study. Approximately 60% of patients had previous exposure to conventional systemic therapy or phototherapy. Approximately 11% of patients had previous exposure to biologics.
The primary endpoint was the proportion of patients achieving a PGA index at Week 12 cleared or minimal . Secondary endpoints included PASI 75, PASI 90, change from baseline in Children "s Dermatology Life Quality Index (CDLQI), change from baseline in PedsQL total score (Pediatric Quality of Life Inventory) at Week 12. At Week 12, subjects treated with ustekinumab showed significantly greater improvement in their psoriasis and health-related quality of life than subjects treated with placebo (Table 7).
All patients were followed up for efficacy up to 52 weeks after the first administration of the study agent. The percentage of patients with a PGA score cleared or minimal and the proportion of patients who achieved PASI 75 showed a gap between the ustekinumab and placebo groups at the first post-baseline visit at Week 4, peaking at Week 12. The improvements in PGA, PASI, CDLQI and PedsQL were maintained at Week 52 (Table 7).
Table 7: Summary of primary and secondary endpoints at Week 12 and Week 52
on p
b CDLQI: CDLQI is a dermatological tool to assess the effect of a skin problem on health-related quality of life in the pediatric population. CDLQI of 0 or 1 indicate no effect on the child's quality of life.
c p = 0.002
d PedsQL: PedsQL is a general measure of health-related quality of life developed for use in children and adolescents.
and p = 0.028
During the placebo-controlled period up to Week 12, efficacy in both groups at the recommended dose and half the recommended dose was generally comparable with respect to the primary endpoint (69.4% and 67.6%, respectively. ) although there was evidence of a dose-related response for higher level efficacy criteria (eg PGA cleared , PASI 90). Beyond Week 12, efficacy was generally higher and better sustained in the treatment group receiving the full recommended dose than in the group receiving half, in which modest loss of efficacy observed at the end of treatment was more frequent. each dose interval of 12 weeks. The safety profile of the recommended dose and half of the recommended dose was comparable.
Crohn's disease
The safety and efficacy of ustekinumab were evaluated in three multicentre, randomized, double-blind, placebo-controlled studies in adult patients with moderate to severe active Crohn's disease (Crohn's Disease Activity Index [CDAI] = Crohn's disease activity index ≥ 220 and ≤ 450). The clinical development program consisted of two 8-week intravenous induction studies (UNITED-1 and UNITED-2) followed by a 44-week randomized subcutaneous maintenance study (IM-UNITED) consisting of 52 weeks of therapy. The induction studies involved 1,409 patients (UNITED-1, n = 769; UNITED-2 n = 640). The primary endpoint of both induction studies was the proportion of subjects in clinical response (defined as a reduction in CDAI by ≥ 100 points) at week 6. Efficacy data were collected and analyzed up to week 8 for both studies. Concomitant doses of oral corticosteroids, immunomodulators, aminosalicylates and antibiotics were allowed and 75% of patients continued to receive at least one of these drugs. In both studies, patients were randomized to receive a single intravenous dose of a weight-varying recommended dose of approximately 6 mg / kg (see section 4.2 of the SmPC of STELARA 130 mg concentrate for solution for infusion), or a fixed dose of 130 mg ustekinumab, or placebo at week 0.
Patients on UNITED-1 did not respond or were intolerant to previous anti-TNFα therapy. Approximately 48% of patients did not respond to previous therapy with one anti-TNFα and 52% did not respond to previous therapies with 2 or 3 anti-TNF-α. In this study, 29.1% of patients had an inadequate initial response (primary non-responders), 69.4% responded but "lost response" (secondary non-responders), and 36, 4% were intolerant to anti-TNFα therapies.
Patients on UNITED-2 have failed at least one conventional therapy, including corticosteroids or immunomodulators, and were either anti-TNF-α naive (68.6%) or had previously received, but not failed, anti-TNFα therapy. (31.4%).
In both UNITED-1 and UNITED-2, a significantly higher proportion of patients were in clinical response and in remission in the ustekinumab group compared to placebo (Table 8). Clinical responses and remissions were significant as early as week 3 in ustekinumab-treated patients and continued to improve through week 8. In these induction studies, efficacy was greater and better maintained in the dose-variable group than the group with the 130 mg dose and variable dosage is therefore recommended for intravenous induction.
Table 8: Induction of clinical response and remission in UNITED-1 and UNITED-2
Clinical remission is defined as the CDAI index
Response 70 points is defined as a reduction of the CDAI index by at least 70 points
* anti-TNFα failures
** failures of conventional therapy
on p
b p
The maintenance study (IM-UNITED) evaluated 388 patients who achieved a clinical response of 100 points at week 8 of ustekinumab induction in the UNITED-1 and UNITED-2 studies. Patients were randomized to a subcutaneous maintenance regimen of 90 mg ustekinumab every 8 weeks or 90 mg ustekinumab every 12 weeks or placebo for 44 weeks (for recommended maintenance dose, see section 4.2). A higher percentage of patients maintained clinical remission and clinical response in the ustekinumab groups compared to the placebo group at week 44 (see Table 9).
Table 9: Maintenance of clinical response and remission in IM-Uniti (Week 44; 52 weeks from initiation of induction dose)
Clinical remission is defined as the CDAI index
* The placebo group consisted of patients who were in response to ustekinumab and were randomized to receive placebo at the start of maintenance therapy.
† Patients who were in clinical response of 100 points of ustekinumab at the start of maintenance therapy
‡ Patients who have failed conventional therapy but not anti-TNF α therapy
§ Patients who are refractory / intolerant to anti-TNF α
on p
b p
c nominally significant (p
In the IM-UNITED, 29 of 129 patients did not maintain response to ustekinumab when treated every 12 weeks and were allowed to adjust the dose to receive ustekinumab every 8 weeks.
Loss of response was defined as a CDAI index ≥ 220 points and a ≥ 100 point increase in CDAI from baseline. In these patients, clinical remission was achieved in 41.4% of patients 16 weeks after surgery. dose adjustment.
Patients who had no clinical response after ustekinumab induction at week 8 in the UNITED-1 and UNITED-2 induction studies (476 patients) entered the non-randomized portion of the maintenance study (IM-UNITED) and then received a subcutaneous injection of 90 mg of ustekinumab. Eight weeks later, 50.5% of patients achieved a clinical response and continued to receive the maintenance dose every 8 weeks; among these patients on continued maintenance dose, the majority maintained response (68.1%) and achieved remission (50.2%) at week 44, in rates that were similar to patients who initially responded to induction with ustekinumab.
Of the 131 patients who responded to ustekinumab in the induction phase, and who were randomized to the placebo group at the start of the maintenance study, 51 subsequently did not respond and received ustekinumab 90 mg subcutaneously every 8 weeks. Some of the patients who lost response and restarted ustekinumab did so within 24 weeks of the induction infusion. Of these 51 patients, 70.6% achieved clinical response and 39.2% achieved clinical remission 16 weeks after receiving the first subcutaneous dose of ustekinumab.
Endoscopy
The endoscopic appearance of the mucosa was evaluated in a substudy in 252 eligible patients with baseline endoscopic disease activity. The primary endpoint was the change from baseline on the Simplified Endoscopic Disease Severity Score for Crohn's disease (SES-CD). , a composite index of the 5 ileo-colic segments of presence / size of ulcers, percentage of mucosal surface covered by ulcers, percentage of mucosal surface affected by any other lesions and presence / type of narrowing / stenosis. At week 8, following a single intravenous induction dose, the change in SES-CD index was greater in the ustekinumab group (n = 155, mean change = -2.8) than in the placebo group (n = 97, mean change = -0.7, p = 0.012).
Response in fistulising disease
In a subset of patients with draining fistulas at baseline (8.8%; n = 26), 12/15 (80%) of ustekinumab-treated patients achieved a response after 44 weeks (defined as ≥ 50% reduction from baseline in the induction study in the number of draining fistulas) compared with 5/11 (45.5%) exposed to placebo.
Health-related quality of life
Health-related quality of life was assessed using IBDQ and SF-36 questionnaires. At week 8, patients treated with ustekinumab showed statistically significant greater clinical improvements in the IBDQ Total Index and SF-36 Mental Component Summary Score in both the US-1 and UNITED-2, and SF-36 Physical Component Summary Score in the UNITED STATES -2, compared to placebo These improvements were generally better maintained in ustekinumab-treated patients in the IM-Uniti study through week 44 compared to placebo.
Pediatric population
The European Medicines Agency has deferred the obligation to submit the results of studies with ustekinumab in one or more subsets of the pediatric population in Crohn's disease (see section 4.2 for information on pediatric use).
05.2 "Pharmacokinetic properties -
Absorption
In healthy subjects, the median time to reach maximum serum concentration (Tmax) was 8.5 days after a single 90 mg subcutaneous administration. The median T values of ustekinumab following a single subcutaneous administration of 45 mg or 90 mg in patients with psoriasis are comparable to those seen in healthy subjects.
The absolute bioavailability of ustekinumab in patients with psoriasis after a single subcutaneous administration was estimated to be 57.2%.
Distribution
The median volume of distribution during the terminal phase (Vz) following a single intravenous administration in patients with psoriasis ranged from 57 to 83 mL / kg.
Biotransformation
The exact metabolic process of ustekinumab is unknown.
Elimination
There clearance Median systemic (CL) in patients with psoriasis after a single intravenous administration ranged from 1.99 to 2.34 mL /die/ kg.
The median half-life (t1 / 2) of ustekinumab was approximately 3 weeks in patients with psoriasis, psoriatic arthritis or Crohn's disease, ranging from 15 to 32 days in all psoriasis and psoriatic arthritis studies.
In a "population pharmacokinetic profile analysis in patients with psoriasis, the clearance apparent (CL / F) and apparent volume of distribution (V / F) were 0.465 L / day and 15.7 L, respectively. The CL / F of ustekinumab was not affected by gender. Population pharmacokinetic analysis showed a trend towards increasing ustekinumab clearance in anti-ustekinumab antibody positive patients.
Linearity of the dose
The systemic exposure of ustekinumab (Cmax and AUC) increased fairly dose proportionally after a single intravenous administration of doses ranging from 0.09 mg / kg to 4.5 mg / kg or after a single administration subcutaneously in doses ranging from about 24 mg to 240 mg in patients with psoriasis.
Single dose versus multiple doses
Ustekinumab serum concentration-time profiles were broadly predictable after single or multiple subcutaneous doses. In patients with psoriasis, steady-state serum concentrations (steady-state) of ustekinumab were achieved starting at week 28 following subcutaneous dosing at weeks 0 and 4, followed by dosing every 12 weeks. The minimum median steady-state concentration (steadystate) was between 0.21 mcg / mL and 0.26 mcg / mL (45 mg) and between 0.47 mcg / mL and 0.49 mcg / mL (90 mg).
Following subcutaneous administration every 12 weeks, no apparent accumulation of ustekinumab serum concentration over time was observed. In patients with Crohn's disease, after an intravenous dose of ~ 6 mg / kg, a maintenance dose of 90 mg of ustekinumab was administered subcutaneously every 8 or 12 weeks starting at week 8. The steady-state concentration (steady-state) of ustekinumab was reached by the start of the second maintenance dose. The median trough concentration at steady state (steady-state) of ustekinumab ranged from 1.97 mg / mL to 2.24 mg / mL and from 0.61 mg / mL to 0.76 mg / mL for 90 mg of ustekinumab every 8 weeks or every 12 weeks, respectively. Steady-state trough ustekinumab levels (steady-state) results from ustekinumab 90 mg every 8 weeks were associated with higher clinical remission rates than steady-state trough levels of 90 mg every 12 weeks.
Impact of weight on the pharmacokinetic profile
In a "PK analysis of the patient population using data from patients with psoriasis, it was found that body weight was the covariate that most significantly influenced clearance by ustekinumab. The median CL / F of patients weighing> 100 kg was approximately 55% higher than that of patients weighing ≤ 100 kg. The median V / F of patients weighing> 100 kg was approximately 37% higher than that of patients weighing ≤ 100 kg. The lower median serum concentrations of ustekinumab in the heavier weight patients (> 100 kg) in the 90 mg dose group were comparable to those in the lower weight patients (≤ 100 kg) in the treated group. with the dose of 45 mg. Similar results were obtained from a confirmatory population pharmacokinetic analysis using data from patients with psoriatic arthritis.
Special populations
No pharmacokinetic data are available in patients with renal or hepatic dysfunction.
No specific clinical studies have been conducted in elderly patients.
The pharmacokinetic profile of ustekinumab was generally comparable between Asian and non-Asian patients with psoriasis.
In patients with Crohn's disease, ustekinumab CL variability was affected by body weight, serum albumin level, CRP, previous TNF antagonist failure, gender, race (Asian versus non-Asian), and presence of antibodies to ustekinumab, while body weight was the major covariate affecting volume of distribution. Concomitant use of immunomodulators did not have a significant impact on ustekinumab disposition. The impact of these statistically significant covariates on their respective pharmacokinetic parameters was within ± 20% when evaluated in a representative data range of covariates or categories that is within the overall observed variability in ustekinumab PK. In the patient population pharmacokinetic analysis, no indications of an effect of tobacco or alcohol on the pharmacokinetic profile of ustekinumab were observed.
The serum concentrations of ustekinumab in pediatric patients 12 to 17 years of age with psoriasis treated with the recommended dose based on body weight were generally comparable to those in the adult psoriasis population treated with the recommended adult dose, while concentrations serum tests of ustekinumab in pediatric patients with psoriasis treated with half the recommended dose based on body weight were generally lower than in adults.
Regulation of CYP450 enzymes
The effects of IL-12 or IL-23 on the regulation of CYP450 enzymes were evaluated in one study in vitro using human hepatocytes, this study demonstrated that IL-12 and / or IL-23 at levels of 10 ng / mL do not alter the enzymatic activity of human CYP450 (CYP1A2, 2B6, 2C9, 2C19, 2D6, or 3A4; see section 4.5).
05.3 Preclinical safety data -
Non-clinical data reveal no special hazard for humans (eg organ toxicity) based on repeated dose toxicity and developmental and reproductive toxicity studies, including assessments of safety pharmacology. In reproductive and developmental toxicity studies conducted in cynomolgus monkeys, no adverse effects on male fertility indices, birth defects or developmental toxicity were observed. No adverse effects on female fertility indices were observed with the use of an antibody analogous to IL-12/23 in mice.
Dose levels in animal studies were up to approximately 45 times higher than the highest equivalent dose intended to be given to patients with psoriasis. In monkeys, these levels translated into peak serum concentrations that were 100 times or more higher than those observed in humans.
Carcinogenicity studies of ustekinumab have not been conducted due to the absence of appropriate antibody models free from cross-reacting IL-12/23 p40 in rodents.
06.0 PHARMACEUTICAL INFORMATION -
06.1 Excipients -
L-histidine
L-histidine monohydrochloride monohydrate
Polysorbate 80
Sucrose
Water for injections
06.2 Incompatibility "-
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
06.3 Period of validity "-
2 years
06.4 Special precautions for storage -
Store in a refrigerator (2 ° C - 8 ° C). Do not freeze.
Keep the vial or pre-filled syringe in the outer carton in order to protect the medicine from light.
06.5 Nature of the immediate packaging and contents of the package -
STELARA 45 mg solution for injection
0.5 mL of solution in a 2 mL vial made of type I glass, closed with a butyl rubber stopper.
STELARA 90 mg solution for injection
1 mL of solution in a 2 mL vial made of type I glass, closed with a butyl rubber stopper.
STELARA 45 mg solution for injection in pre-filled syringe
0.5 mL of solution in a 1 mL type I glass syringe, with a non-removable steel needle protected by a cap containing dried natural rubber (a derivative of latex). The syringe is equipped with a passive safety device.
STELARA 90 mg solution for injection in pre-filled syringe
1 mL of solution in a 1 mL type I glass syringe with a non-removable steel needle protected by a cap containing dried natural rubber (a derivative of latex). The syringe is equipped with a passive safety device.
STELARA is available in packs of 1 vial or 1 pre-filled syringe.
06.6 Instructions for use and handling -
The solution contained in the STELARA vial or pre-filled syringe must not be shaken. The solution should be visually inspected for any particulate matter or discoloration prior to subcutaneous administration. The solution is clear to slightly opalescent, colorless to pale yellow and may contain some small translucent or white protein particles. it is not unusual for protein solutions. The medicinal product should not be used if the solution is discolored or opaque, or if foreign particulate matter is present. Before administration, STELARA should be allowed to reach room temperature (approximately half an hour) . Detailed instructions for use are provided in the package leaflet.
STELARA contains no preservatives, so any unused medicine remaining in the vial and syringe should not be used. STELARA is supplied as a sterile single-use vial or single-use pre-filled syringe. The syringe, needle and vial must never be reused. Unused medicine and waste from this medicine should be disposed of in accordance with local requirements.
07.0 HOLDER OF THE "MARKETING AUTHORIZATION" -
Janssen-Cilag International NV
Turnhoutseweg 30
2340 Beerse
Belgium
08.0 MARKETING AUTHORIZATION NUMBER -
STELARA 45 mg solution for injection
EU / 1/08/494/001
STELARA 90 mg solution for injection
EU / 1/08/494/002
STELARA 45 mg solution for injection in pre-filled syringe
EU / 1/08/494/003
STELARA 90 mg solution for injection in pre-filled syringe
EU / 1/08/494/004
038936035
038936047
038936011
038936023
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION -
Date of first authorization: January 16, 2009
Date of most recent renewal: 19 September 2013
