Active ingredients: Golimumab
Simponi 50 mg solution for injection in pre-filled pen
Simponi package inserts are available for pack sizes:- Simponi 50 mg solution for injection in pre-filled pen
- Simponi 100 mg solution for injection in pre-filled pen
Why is Simponi used? What is it for?
Simponi contains an active substance called golimumab.
Simponi belongs to a group of medicines called 'TNF blockers'. It is used in adults for the treatment of the following inflammatory diseases:
- Rheumatoid arthritis
- Psoriatic arthritis
- Axial spondyloarthritis, including ankylosing spondylitis and non-radiographic axial spondyloarthritis
- Ulcerative colitis
In children weighing at least 40 kg, Simponi is used for the treatment of polyarticular juvenile idiopathic arthritis.
Simponi works by blocking the action of a protein called "tumor necrosis factor alpha" (TNF-α). This protein is involved in the body's inflammatory processes and by blocking it, it is possible to reduce inflammation in the body.
Rheumatoid arthritis
Rheumatoid arthritis is an inflammatory joint disease. If you have active rheumatoid arthritis, you will initially be treated with other medicines. If you do not respond adequately to these medicines, you will be treated with Simponi in combination with another medicine called methotrexate for:
- Reduce the signs and symptoms of the disease.
- Slow down the damage to bones and joints.
- Improve physical function.
Psoriatic arthritis
Psoriatic arthritis is an inflammatory joint disease, usually accompanied by psoriasis, an inflammatory skin disease. If you have active psoriatic arthritis, you will be treated with other medicines first. If you do not respond adequately to these medicines, you will be treated with Simponi for :
- Reduce the signs and symptoms of the disease.
- Slow down the damage to bones and joints.
- Improve physical function.
Ankylosing spondylitis and non-radiographic axial spondyloarthritis
Ankylosing spondylitis and non-radiographic axial spondyloarthritis are inflammatory diseases of the spine. If you have ankylosing spondylitis or non-radiographic axial spondyloarthritis, you will be treated with other medicines first. If you do not respond adequately to these medicines, you will be treated with Simponi to:
- Reduce the signs and symptoms of the disease.
- Improve physical function.
Ulcerative colitis
Ulcerative colitis is an inflammatory bowel disease. If you have ulcerative colitis you will be given other medicines first. If you do not respond adequately to these medicines, you will be given Simponi to treat your disease.
Polyarticular juvenile idiopathic arthritis
Polyarticular juvenile idiopathic arthritis is an inflammatory disease that causes pain and swelling in the joints in children. If your child has polyarticular juvenile idiopathic arthritis, your child will be given other medicines first. If your child does not respond adequately to these medicines, your child will be given Simponi in combination with methotrexate to treat the disease.
Contraindications When Simponi should not be used
Do not use Simponi:
- If you are allergic (hypersensitive) to golimumab or any of the other ingredients of this medicine (listed in section 6).
- If you have tuberculosis (TB) or any other serious infection.
- If you have heart failure that is moderate or severe.
If you are not sure if any of the above conditions apply to you, talk to your doctor, pharmacist or nurse before using Simponi.
Precautions for use What you need to know before you take Simponi
Talk to your doctor, pharmacist or nurse before using Simponi.
Infections
Tell your doctor straight away if you have already had or have symptoms of infection during or after treatment with Simponi. Symptoms of the infection include fever, cough, shortness of breath, flu-like symptoms, diarrhea, wounds, dental problems or a burning sensation when urinating.
- You can get infections more easily when using Simponi.
- Infections can progress more rapidly and be more severe. Also, infections from the past can come back.
Tuberculosis (TB)
Tell your doctor right away if you notice symptoms of TB during treatment. Symptoms of TB include persistent cough, weight loss, feeling tired, fever, or night sweats.
- A few cases of TB have been reported in patients treated with Simponi, on rare occasions even in patients who have been treated with medicines for TB. Your doctor will do tests to see if you have TB. The doctor will record these tests on the Patient Alert Card.
- It is very important that you tell your doctor if you have had TB in the past, or if you have come into close contact with someone who has or has had TB.
- If your doctor thinks you are at risk for TB, you may be treated with medicines for TB before you are given Simponi.
Hepatitis B virus (HBV)
- Tell your doctor if you are a carrier or have or have had hepatitis B before you are given Simponi
- Tell your doctor if you think you may be at risk of contracting hepatitis B
- Your doctor should evaluate if you have hepatitis B
- Treatment with TNF blockers such as Simponi can cause hepatitis B virus to become reactivated in patients carrying this virus, which in some cases can cause death.
Invasive fungal infections
Tell your doctor immediately if you have lived in or traveled to an "area where infections caused by specific types of fungi that can affect the lungs or other parts of the body (called histoplasmosis, coccidioidomycosis, or blastomycosis) are common. Ask your doctor if you don't know. whether these fungal infections are common in the area where you lived or traveled.
Cancer and lymphoma
Tell your doctor if you have or have ever had lymphoma (a type of blood cancer) or other types of cancer before you are given Simponi.
- If you use Simponi or other TNF blockers you may increase the risk of developing lymphoma or another type of cancer.
- Patients with severe rheumatoid arthritis or other inflammatory conditions who have suffered from this disease for a long time may have a higher than average risk of developing lymphoma.
- Cancer, including unusual, sometimes fatal cancers, have been reported in children and adolescent patients taking TNF-blocking medicinal products.
- On rare occasions, a specific and severe type of lymphoma called hepatosplenic T-cell lymphoma has been observed in patients taking other TNF blockers. Most of these patients were adolescents or young male adults. This form of cancer has usually resulted in death. Almost all of these patients also received medicines known as azathioprine or 6-mercaptopurine. Tell your doctor if you are taking azathioprine or 6-mercaptopurine with Simponi.
- Patients with severe persistent asthma, chronic obstructive pulmonary disease (COPD), or heavy smokers may have an increased risk of cancer with Simponi treatment. If you have severe persistent asthma, COPD or are a heavy smoker, you should discuss with your doctor whether treatment with a TNF blocker is appropriate.
- Some golimumab-treated patients have developed certain types of skin cancer. If you experience any kind of change in skin appearance or growths on the skin during or after therapy, please tell your doctor.
Heart failure
Tell your doctor right away if you notice new or worsening symptoms of heart failure. Symptoms of heart failure include shortness of breath or swelling of the feet.
- Cases of new onset or worsening congestive heart failure have been reported with TNF blockers, including Simponi. Some of these patients died.
- If you have mild heart failure and are treated with Simponi, your doctor will keep you closely monitored.
Nervous system disease
Tell your doctor right away if you have ever been diagnosed with or develop symptoms of a demyelinating disease, such as multiple sclerosis. Symptoms may include changes in vision, weakness in the arms and legs, numbness or tingling in any part of the body. Your doctor will decide if you should take Simponi.
Dental operations or procedures
- Tell your doctor if you are going to have any dental operations or procedures.
- Tell the surgeon or dentist performing the procedure that you are being treated with Simponi by showing the Patient Alert Card.
Autoimmune diseases
Tell your doctor if you develop symptoms of a disease called lupus. Symptoms include persistent rash, fever, joint pain, and fatigue.
- On rare occasions, people treated with TNF blockers have developed lupus.
Diseases of the blood
In some patients, the body may not produce enough blood cells that help the body fight infections or help stop bleeding. If you have persistent fever that you do not understand, you bruise or bleed easily or look pale, call your doctor immediately. Your doctor may decide to stop your treatment.
If you are not sure if any of the above conditions apply to you, talk to your doctor or pharmacist before using Simponi.
Vaccinations
Tell your doctor if you have recently been vaccinated or are planning to be vaccinated.
- You must not receive certain (live) vaccines while being treated with Simponi.
- Some vaccinations can cause infections. If you received Simponi while you were pregnant, your baby may have an increased risk of getting this infection for approximately six months after the last dose received during pregnancy. It is important to tell your pediatrician and other healthcare professionals about using Simponi. so that they can decide when the child should receive any vaccines.
Talk to your child's doctor regarding vaccinations for your child. If possible, your child should be up to date with all vaccinations before using Simponi.
Infectious therapeutic agents
Talk to your doctor if you have recently taken or are planning to take treatment with an infectious therapeutic agent (such as BCG instillation used to treat cancer).
Allergic reactions
Tell your doctor immediately if you develop symptoms of an allergic reaction after treatment with Simponi. Symptoms of an allergic reaction may include swelling of the face, lips, mouth or throat which may cause difficulty in swallowing or breathing, skin rash, hives, swelling of the hands, feet and ankles.
- Some of these reactions can be severe or, rarely, life-threatening.
- Some of these reactions occur after the first administration of Simponi.
Children and adolescents
Simponi is not recommended for children weighing less than 40 kg with polyarticular juvenile idiopathic arthritis or in children and adolescents under the age of 18 for any other condition.
Interactions Which drugs or foods can modify the effect of Simponi
- Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including any other medicines to treat rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, axial spondyloarthritis non-radiographic or ulcerative colitis.
- You should not take Simponi with medicines containing the active substance anakinra or abatacept. These medicines are used for the treatment of rheumatic diseases.
- Tell your doctor or pharmacist if you are taking any other medicines that affect the immune system.
- It cannot be treated with certain (live) vaccines while using Simponi.
If you are not sure if any of the above conditions apply to you, talk to your doctor or pharmacist before using Simponi.
Warnings It is important to know that:
Pregnancy and breastfeeding
Talk to your doctor before using Simponi if:
- You are pregnant or planning to become pregnant while using Simponi. The effects of this medicine in pregnant women are not known. The use of Simponi in pregnant women is not recommended. If you are to be treated with Simponi, you should avoid becoming pregnant by using adequate contraception during treatment and for at least 6 months after your last Simponi injection.
- Before breastfeeding, the last Simponi treatment must be at least 6 months earlier. You must stop breastfeeding if Simponi is to be given to you.
- If you received Simponi during your pregnancy, your baby may have an increased risk of getting an infection. It is important to tell your pediatrician and other healthcare professionals about your use of Simponi before your baby receives any vaccines (for more information see the paragraph on vaccinations).
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.
Driving and using machines
Simponi may slightly impair your ability to drive and use tools or machines. You may feel dizzy after using Simponi. In this case, do not drive or use any tools or machines.
Simponi contains latex and sorbitol
Sensitivity to latex
Latex sensitivity One part of the pre-filled pen, the cap that covers the needle, contains latex. Since latex can cause severe allergic reactions, tell your doctor before using Simponi, if you or your caregiver are allergic to latex.
Sorbitol intolerance
Simponi contains sorbitol (E420). If you have been told by your doctor that you have an "intolerance to some sugars, contact your doctor before taking this medicine.
Dosage and method of use How to use Simponi: Dosage
Always use this medicine exactly as your doctor or pharmacist has told you. If in doubt, you should consult your doctor or pharmacist.
How much Simponi is given
Rheumatoid arthritis, psoriatic arthritis and axial spondyloarthritis, including ankylosing spondylitis and non-radiographic axial spondyloarthritis:
- The recommended dose is 50 mg (the content of 1 pre-filled pen) administered once a month, on the same day each month.
- Talk to your doctor before taking the fourth dose. Your doctor will decide whether you should continue your Simponi treatment.
- If you weigh more than 100 kg, the dose can be increased to 100 mg (the content of 2 pre-filled pens), given once a month, always on the same day each month.
Polyarticular Juvenile Idiopathic Arthritis:
- The recommended dose is 50 mg given once a month, on the same day each month.
- Talk to your child's doctor before your child takes the fourth dose. Your child's doctor will decide whether you should continue Simponi treatment.
Ulcerative colitis
- The table below shows how you will generally use this medicine.
- In patients weighing less than 80 kg, 50 mg (the content of 1 pre-filled pen) 4 weeks after your last treatment, then every 4 weeks thereafter.
- In patients weighing 80 kg or more, 100 mg (the contents of 2 pre-filled pens) 4 weeks after your last treatment, then every 4 weeks thereafter.
How Simponi is given
- Simponi is given by injection under the skin (subcutaneously).
- At first, your doctor or nursing staff will inject Simponi. However, you and your doctor may decide that you can inject Simponi yourself. In this case, you will be instructed on how to inject Simponi yourself.
Talk to your doctor if you have any questions about self-administering an injection. At the end of this leaflet, you will find detailed "Instructions for administration".
If you forget to use Simponi
If you forget to use Simponi on your scheduled day, inject the missed dose as soon as you remember.
Do not use a double dose to make up for a forgotten dose.
When to inject the next dose:
- If you are less than 2 weeks late, inject the missed dose as soon as you remember and continue to follow your original schedule.
- If you are more than 2 weeks late, inject the forgotten dose as soon as you remember and tell your doctor or pharmacist and ask when you should take your next dose.
If you are not sure what to do, ask your doctor, pharmacist or nurse.
If you stop using Simponi
If you are considering stopping Simponi, talk to your doctor or pharmacist first.
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 Simponi
If you have used or given too much Simponi (injecting too much in a single dose, or using it too often), tell your doctor or pharmacist immediately. Always take the outer carton and this leaflet with you, even if it is empty.
Side Effects What are the side effects of Simponi
Like all medicines, this medicine can cause side effects, although not everybody gets them. Some patients may experience severe side effects which may require medical treatment. The risk of some side effects is higher with the 100 mg dose compared to the 50 mg dose. Undesirable effects may also occur several months after the last injection.
Tell your doctor immediately if you notice any of the following serious side effects of Simponi which include:
- allergic reactions which can be severe, or rarely, life-threatening (rare).Symptoms of an allergic reaction may include swelling of the face, lips, mouth or throat which may cause difficulty in swallowing or breathing, skin rash, hives, swelling of the hands, feet or ankles. Some of these reactions occurred after the first administration of Simponi.
- severe infections (including TB, bacterial infections including severe blood infections and pneumonia, severe fungal infections and other opportunistic infections) (common). Symptoms of an infection may include fever, fatigue, (persistent) cough, shortness of breath, flu-like symptoms, weight loss, night sweats, diarrhea, wounds, dental problems and a burning sensation when urinating.
- reactivation of the hepatitis B virus if you are a carrier or have previously had hepatitis B (rare). Symptoms may include yellowing of the skin and eyes, dark brown urine, pain in the right side of the abdomen, fever, feeling unwell, malaise and feeling very tired.
- nervous system disease such as multiple sclerosis (rare). Symptoms of nervous system disease may include changes in vision, weakness in the arms or legs, numbness or tingling in any part of the body.
- cancer of the lymph nodes (lymphoma) (rare). Symptoms of lymphoma can include swollen lymph nodes, weight loss, or fever.
- heart failure (rare). Symptoms of heart failure can include shortness of breath or swelling of the feet.
- signs of immune system disorders called: - lupus (rare). Symptoms may include joint pain or a rash on the cheeks or arms that is sensitive to the sun. - sarcoidosis (rare). Symptoms may include a persistent cough, shortness of breath, chest pain, fever, swollen lymph nodes, weight loss, rash and blurred vision.
- swelling of small blood vessels (vasculitis) (rare). Symptoms may include fever, headache, weight loss, night sweats, rash, and nerve problems such as numbness and tingling.
- skin cancer (uncommon). Skin cancer symptoms may include changes in the appearance of the skin or growths on the skin.
- blood disease (common). Symptoms of blood disease may include a fever that does not go away, a strong tendency to bruise or bleed, or a very pale appearance.
- blood cancer (leukemia) (rare). Symptoms of leukemia can include fever, feeling tired, frequent infections, bruising and night sweats.
Tell your doctor immediately if you notice any of the symptoms listed above.
The following additional side effects have been observed with Simponi:
Very common side effects (may affect more than 1 in 10 people):
- Upper respiratory tract infections, sore throat or hoarseness, cold
Common side effects (may affect up to 1 in 10 people):
- Abnormal liver tests (increased liver enzymes), found during blood tests done by your doctor
- Feeling dizzy
- Headache
- Feeling numb or tingling
- Superficial fungal infections
- Abscess
- Bacterial infections (such as cellulitis)
- Reduction of red blood cells
- Positive blood test for lupus
- Allergic reactions
- Indigestion
- Stomach pain
- Feeling sick (nausea)
- Influence
- Bronchitis
- Sinus infection
- Facial herpes
- High blood pressure
- Fever
- Asthma, shortness of breath, wheezing
- Disorders of the stomach and intestines which include inflammation of the interior of the stomach and colon which can cause fever
- Pain and ulcers in the mouth
- Reactions at the injection site (including redness, hardness, pain, bruising, itching, tingling and irritation)
- Hair loss
- Rash and itchy skin
- Difficulty sleeping
- Depression
- Feeling of weakness
- Fractures of the bones
- Chest pain
Uncommon side effects (may affect up to 1 in 100 people):
- Kidney infection
- Cancer, including skin cancer and non-cancerous lumps or small masses, including moles
- Skin blisters
- Psoriasis (including that of the palms of the hands and / or soles of the feet and / or in the form of skin pustules)
- Reduction of platelets
- Reduction of white blood cells
- Combined reduction of platelets, red blood cells and white blood cells
- Thyroid disorders
- Increase in blood sugar levels
- Increase in blood cholesterol levels
- Balance disorders
- Visual disturbances
- Feeling of irregular heartbeat
- Narrowing of blood vessels in the heart
- Blood clots
- Redness
- Constipation
- Chronic inflammation of the lungs
- Acid reflux
- Stones in the bile
- Liver problems
- Breast Disorders
- Menstrual disturbances
Rare side effects (may affect up to 1 in 1,000 people):
- Inability of the bone marrow to produce blood cells
- Infection of the joints or surrounding tissues
- Difficult healing
- Inflammation of the blood vessels of the internal organs
- Leukemia
- Melanoma (a type of skin cancer)
- Peeling skin
- Immunological disorders that can affect the lungs, skin and lymph nodes (very commonly present as sarcoidosis)
- Pain and discoloration in the fingers or toes
- Taste disturbances
- Bladder Disorders
- Kidney problems
- Inflammation of the blood vessels in the skin causing a rash
Side effects with frequency not known:
- Merkel cell carcinoma (a type of skin cancer)
- A rare blood cancer that mainly affects young people (hepatosplenic T-cell lymphoma)
Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. 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. 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.
- 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 that month.
- Store in a refrigerator (2 ° C-8 ° C). Do not freeze.
- Keep the pre-filled pen in the outer carton to protect the medicine from light.
- Do not use this medicine if you notice that the liquid is not light to light yellow in color, is cloudy, or contains foreign particles.
- Do not throw away any medicines via wastewater or household waste. Ask your doctor or pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Other information
What Simponi contains
The active ingredient is golimumab. One 0.5 ml pre-filled pen contains 50 mg of golimumab.
The other ingredients are sorbitol (E420), L-histidine, L-histidine monohydrochloride monohydrate, polysorbate 80 and water for injections.
Simponi looks like and contents of the pack
Simponi is supplied as a solution for injection in a single-use pre-filled pen. Simponi is available in packs containing 1 pre-filled pen and multipacks containing 3 (3 packs of 1) pre-filled pens. Not all pack sizes may be marketed.
The solution is clear to slightly opalescent (shiny like a pearl), colorless to light yellow and may contain some small translucent or white protein particles. Do not use Simponi if the solution has changed color, is cloudy or if it contains visible foreign particles.
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
SIMPONI 50 MG INJECTABLE SOLUTION
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Simponi 50 mg solution for injection in pre-filled pen
One 0.5 mL pre-filled pen contains 50 mg of golimumab *.
Simponi 50 mg solution for injection in pre-filled syringe
One 0.5 mL pre-filled syringe contains 50 mg of golimumab *.
* IgG1 human monoclonal antibody? produced from a murine hybridoma cell line with recombinant DNA technology.
Excipient with known effect:
Each pre-filled pen contains: 20.5 mg of sorbitol for a 50 mg dose.
Each pre-filled syringe contains: 20.5 mg of sorbitol for a 50 mg dose.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Solution for injection in pre-filled pen (injection), SmartJect
Solution for injection in pre-filled syringe (injection)
The solution is clear to slightly opalescent, colorless to pale yellow.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Rheumatoid arthritis (RA)
Simponi, in combination with methotrexate (MTX), is indicated for:
• the treatment of moderate to severe active rheumatoid arthritis in adult patients when the response to disease-modifying anti-rheumatic drugs (DMARDs), including MTX, has been inadequate .
• the treatment of severe, active and progressive rheumatoid arthritis in adults not previously treated with MTX.
Simponi, in combination with MTX, has been shown to reduce the rate of progression of joint damage as measured by X-rays and to improve physical function.
Juvenile idiopathic arthritis
Polyarticular Juvenile Idiopathic Arthritis (PIA)
Simponi in combination with MTX is indicated for the treatment of polyarticular juvenile idiopathic arthritis in children weighing at least 40 kg who have responded inadequately to prior MTX therapy.
Psoriatic arthritis (AP)
Simponi, alone or in combination with methotrexate (MTX), is indicated for the treatment of active and progressive psoriatic arthritis in adults when the response to previous DMARD treatments has been inadequate. Simponi has been shown to reduce the rate of progression of the drug. peripheral joint damage, as measured by X-rays in patients with symmetrical polyarticular disease subtypes (see section 5.1) and to improve physical function.
Axial spondyloarthritis
Ankylosing spondylitis (AS)
Simponi is indicated for the treatment of severe, active ankylosing spondylitis in adults who have not responded adequately to conventional therapies.
Non-radiographic axial spondyloarthritis (axial SpA nr)
Simponi is indicated for the treatment of adult patients with severe active non-radiographic axial spondyloarthritis with objective signs of inflammation as indicated by elevated C-reactive protein (CRP) and / or magnetic resonance imaging (MRI) evidence. who have had an inadequate response or are intolerant to non-steroidal anti-inflammatory drugs (NSAIDs).
Ulcerative colitis (CU)
Simponi is indicated for the treatment of moderate to severe active ulcerative colitis in adult patients who have not responded adequately to conventional therapy including corticosteroids and 6-mercaptopurine (6-MP) or azathioprine (AZA), or who are intolerant or for which there is a medical contraindication to these therapies.
04.2 Posology and method of administration
Simponi treatment should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis or ulcerative colitis. Patients treated with Simponi should be given the Patient Alert Card.
Dosage
Rheumatoid arthritis
Simponi 50 mg given once a month, on the same day each month.
Simponi must be administered concomitantly with MTX.
Psoriatic arthritis, ankylosing spondylitis or non-radiographic axial spondyloarthritis
Simponi 50 mg given once a month, on the same day each month.
For all of the above indications, available data suggest that clinical response is usually achieved within 12-14 weeks of initiation of treatment (after 3-4 doses). Consideration should be given to continuing therapy in patients who do not show evidence of therapeutic benefit within this time frame.
Patients with a body weight greater than 100 kg
For all of the above indications, in patients with RA, AP, SA or axial SpA nr weighing more than 100 kg, who do not achieve an adequate clinical response after 3 or 4 doses, an increase in the dose of golimumab up to 100 mg once monthly, considering the increased risk of some serious adverse drug reactions with the 100 mg dose compared with the 50 mg dose (see section 4.8). Consideration should be given to continuing therapy in patients who show no evidence of therapeutic benefit after receiving 3-4 supplemental doses of 100 mg.
Ulcerative colitis
Patients with a body weight of less than 80 kg
Simponi given as a starting dose of 200 mg, followed by 100 mg at week 2, then 50 mg every 4 weeks thereafter (see section 5.1).
Patients with a body weight greater than or equal to 80 kg
Simponi given as a starting dose of 200 mg, followed by 100 mg at week 2, then 100 mg every 4 weeks thereafter (see section 5.1).
During maintenance treatment, corticosteroids can be gradually reduced in accordance with clinical practice guidelines.
Available data suggest that clinical response is generally achieved within 12-14 weeks of treatment (after 4 doses). Consideration should be given to continuing therapy in patients who do not show evidence of therapeutic benefit within this time period.
Missed dose
If a patient forgets to inject Simponi on the scheduled day, the missed dose should be injected as soon as the patient remembers. Patients should be instructed not to inject a double dose to make up for a forgotten dose.
The next dose should be administered according to the following guide:
• If the delayed dose is less than 2 weeks, the patient should inject the missed dose and continue to follow their original schedule.
• If the delay in dosing is more than 2 weeks, the patient should inject the missed dose and a new dosing schedule will need to be defined from the date of this injection.
Special populations
Elderly (≥ 65 years old)
No dose adjustment is required in the elderly.
Renal and hepatic impairment
Simponi has not been studied in these patient populations. No dose recommendations can be made.
Pediatric population
The safety and efficacy of Simponi in patients under the age of 18 for indications other than pIA have not been established.
Polyarticular juvenile idiopathic arthritis
Simponi 50 mg given once a month, on the same day of each month, for children with a body weight of at least 40 kg.
Available data suggest that clinical response is usually achieved within 12-14 weeks of treatment (after 3-4 doses). Continuation of therapy should be reconsidered in children who show no evidence of therapeutic benefit within this time period.
Method of administration
Simponi is for subcutaneous use. After adequate training in the subcutaneous injection technique, patients will be able to self-inject Simponi if their physician determines that they are able, with appropriate medical supervision if necessary. Patients should be instructed to inject the full amount of Simponi in accordance with the complete administration instructions provided in the package leaflet. If multiple injections are required, the injections should be administered at different body sites.
For instructions on administration, see section 6.6.
04.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Active tuberculosis (TB) or other serious infections such as sepsis and opportunistic infections (see section 4.4).
Patients with moderate to severe heart failure (NYHA Class III / IV - New York Heart Association) (see section 4.4).
04.4 Special warnings and appropriate precautions for use
Infections
Before, during and after Simponi treatment, patients should be monitored closely for infections including tuberculosis. Since elimination of golimumab may take up to 5 months, monitoring should continue during this period. Further treatment with Simponi should not be given if a patient develops severe infections or sepsis (see section 4.3).
Simponi must not be used in patients with clinically significant, active infection. Caution is required when considering the use of Simponi in patients with chronic infection or a history of recurrent infections. Patients should be appropriately informed of the need to avoid exposure to potential risk factors for infections.
Patients taking TNF-blocking medicines are more prone to severe infections.
In patients treated with Simponi, bacterial infections (including sepsis and pneumonia), mycobacterial (including TB), invasive fungal infections and opportunistic infections, including those with fatal outcome, have been reported. Some of these serious infections have developed in patients on concomitant immunosuppressive therapy which, in addition to their underlying disease, may predispose them to infections. Patients who develop a new infection while on Simponi treatment should be carefully monitored and undergo a "careful diagnostic evaluation. Simponi administration should be discontinued if a patient develops a new severe infection or sepsis and appropriate" initiation. antimicrobial or antifungal therapy until the infection is resolved. For patients who have lived in or traveled to regions where invasive fungal infections such as histoplasmosis, coccidioidomycosis or blastomycosis are endemic, the benefits and risks of Simponi treatment should be carefully considered. before starting Simponi therapy. In high-risk patients treated with Simponi, an invasive fungal infection should be suspected if they develop severe systemic disease. If possible, the diagnosis and administration of empiric antifungal therapy in these patients should be made in consultation with a physician experienced in the care of patients with invasive fungal infections.
Tuberculosis
Cases of tuberculosis have been reported in patients treated with Simponi. It should be noted that in the majority of these cases, it was extrapulmonary tuberculosis, both localized and diffuse.
Before starting Simponi treatment, all patients should be evaluated for both active and inactive ("latent") tuberculosis. This evaluation should include a detailed medical history including a personal history of tuberculosis or possible previous contact with a source of TB infection and previous and / or concomitant immunosuppressive therapy. Appropriate diagnostic tests such as tuberculin skin or blood tests and chest x-rays should be performed in all patients (local guidelines may apply). It is recommended that these tests be reported on the Patient Alert Card. Prescribers are reminded of the risk of false negative tuberculin skin test results, particularly in severely ill or immunocompromised patients.
If active tuberculosis is diagnosed, Simponi therapy must not be initiated (see section 4.3).
If latent tuberculosis is suspected, a physician experienced in the treatment of tuberculosis should be consulted. In all situations described below, the benefit / risk balance of Simponi therapy must be carefully considered.
If inactive ("latent") tuberculosis is diagnosed, antituberculosis therapy for latent tuberculosis should be started prior to initiating Simponi therapy, according to local guidelines.
In patients who have many or significant risk factors for tuberculosis and have a negative test for latent tuberculosis, anti-tuberculosis therapy should be considered prior to initiation of Simponi. Use of anti-tuberculosis therapy should also be considered prior to initiation of Simponi therapy in patients with a previous history of latent or active tuberculosis for whom an adequate course of treatment cannot be confirmed.
Cases of active tuberculosis have occurred in patients treated with Simponi during and after treatment for latent tuberculosis. Patients treated with Simponi should be closely monitored for signs and symptoms of active tuberculosis, including patients who have tested negative for latent tuberculosis, patients who are being treated for latent tuberculosis, or patients who have previously been treated for latent tuberculosis. "tuberculosis infection.
All patients should be advised to seek medical advice if signs / symptoms suggestive of tuberculosis (e.g. persistent cough, wasting / weight loss, low-grade fever) appear during or after Simponi treatment.
Reactivation of the hepatitis B virus
Reactivation of hepatitis B has been observed in patients treated with a TNF-antagonist, including Simponi, who were chronic carriers of this virus (ie, positive for surface antigen). In some cases, fatal outcomes have occurred.
Patients should be evaluated for HBV infection before starting Simponi treatment. For patients who test positive for HBV infection, consultation with a physician experienced in the treatment of hepatitis B is recommended.
Carriers of hepatitis B virus requiring Simponi treatment should be closely monitored for signs and symptoms of active hepatitis B virus infection for the duration of therapy and for many months following the end of therapy. Sufficient data are available on patients with hepatitis B virus treated with antiviral therapy in combination with TNF-antagonist therapy to prevent reactivation of the hepatitis B virus. In patients who develop hepatitis B virus reactivation, treatment with Simponi should be discontinued and effective antiviral therapy with appropriate supportive treatment initiated.
Malignant neoplasms and lymphoproliferative diseases
The potential role of TNF inhibitor therapy in the development of malignancies is unknown. Based on current knowledge, the possible risk of developing lymphoma, leukemia or other malignancies in patients treated with a TNF antagonist cannot be excluded. Care should be taken when considering TNF inhibitor therapy in patients with a history of malignancy or when considering continuing treatment in patients who develop malignancy.
Pediatric malignancies
In post-marketing experience, malignancies, some fatal, have been reported among children, adolescents and young adults (up to 22 years of age) treated with TNF-blocking agents (initiation of therapy ≤ 18 years of age Approximately half of the cases were lymphomas. The other cases were represented by a variety of different malignancies and included rare malignancies usually associated with immunosuppression. A risk for the development of malignant neoplasms in children and adolescents treated with TNF inhibitors cannot be excluded.
Lymphoma and leukemia
In controlled phases of clinical trials with all TNF inhibitor medicines, including Simponi, more cases of lymphoma were observed among patients receiving anti-TNF treatment than in control patients. During the Phase IIb and III clinical trials of Simoni in RA, AP and SA, the incidence of lymphoma in Simponi-treated patients was higher than expected in the general population. Cases of leukemia have been reported in Simponi-treated patients. There is an increased background risk for lymphoma and leukemia in rheumatoid arthritis patients with longstanding, highly active inflammatory disease, which complicates risk estimation.
Rare cases of hepatosplenic T-cell lymphoma (HSTCL) have been reported post-marketing in patients treated with other TNF-blocking agents (see section 4.8). This rare form of T-cell lymphoma has an extremely aggressive course and a usually fatal outcome. Most cases have occurred in adolescent and young adult males almost all receiving concomitant treatment with azathioprine (AZA) or 6-mercaptopurine (6-MP) for inflammatory bowel disease. The potential risk of the combination of AZA or 6-MP and Simponi must be carefully considered. A risk of developing hepatosplenic T-cell lymphoma in patients treated with TNF-blocking agents cannot be excluded.
Malignant neoplasms other than lymphoma
In the controlled phases of Phase IIb and III clinical trials conducted with Simponi in RA, AP, SA and CU, the incidence of malignancies other than lymphoma (excluding non-melanoma skin cancer) was similar between the treatment group with Simponi and the control one.
Colon dysplasia / carcinoma
It is not known whether golimumab treatment affects the risk of developing dysplasia or colon cancer. All patients with ulcerative colitis who have an increased risk of developing colon dysplasia or carcinoma (for example, patients with long-term ulcerative colitis or primary sclerosing cholangitis) or who have a medical history of dysplasia or colon cancer should be investigated for this dysplasia at regular intervals before starting therapy and during the course of the disease. This evaluation should include a colonoscopy and biopsies in accordance with local recommendations. In patients with newly diagnosed dysplasia being treated with Simponi, the benefit / risk ratio in the individual patient should be carefully considered and whether therapy should be continued.
In an exploratory clinical study evaluating the use of Simponi in patients with severe persistent asthma, more cases of malignancies were reported in Simponi-treated patients than in control patients (see section 4.8). The significance of these findings is not known.
In an exploratory clinical study evaluating the use of another anti-TNF agent, infliximab, in patients with moderate to severe chronic obstructive pulmonary disease (COPD), more cases of malignancies were reported. in patients treated with infliximab compared to patients in the control group. All patients were heavy smokers for a long time. Therefore, care should be taken in evaluating the use of a TNF antagonist in COPD patients, as well as in patients with a greater risk of malignancy as heavy smokers.
Skin tumors
Melanoma and Merkel cell carcinoma have been reported in patients treated with TNF-inhibiting agents, including Simponi (see section 4.8). Periodic skin examination is recommended, particularly for patients with risk factors for skin cancer.
Congestive heart failure (CHF)
There have been reports of worsening of congestive heart failure (CHF) and new cases of CHF with TNF antagonists, including Simponi. Some cases have had a fatal outcome. In a clinical study with another TNF antagonist, worsening of congestive heart failure and increased mortality due to CHF were observed. Simponi has not been studied in patients with CHF. Simponi should be used with caution in patients with insufficiency. cardiac mild (NYHA class I / II) Patients should be closely monitored and Simponi treatment discontinued in patients presenting with new or worsening symptoms of heart failure (see section 4.3).
Effects on the nervous system
The use of TNF-blocking medicinal products, including Simponi, has been associated with new onset or exacerbated cases of clinical symptoms and / or radiographic evidence of central nervous system demyelinating disorders, including multiple sclerosis and peripheral demyelinating disorders. pre-existing or recent demyelinating disorders, the benefits and risks of anti-TNF treatment should be carefully considered before initiating Simponi therapy.
Discontinuation of Simponi therapy should be considered if these conditions develop (see section 4.8).
Surgical interventions
Experience with the safety of Simponi treatment in patients who have undergone surgery, including arthroplasty, is limited. The long elimination half-life should be considered when planning surgery. A patient requiring surgery during Simponi treatment should be closely monitored for an increased risk of infections and appropriate measures should be considered.
Immunosuppression
The possibility exists that anti-TNF drugs, including Simponi, affect the host's defenses against infections and malignancies, as TNF mediates inflammation and modulates cellular immune responses.
Autoimmune reactions
The relative deficiency of TNF? caused by anti-TNF therapy, may lead to the initiation of an autoimmune process. If a patient exhibits symptoms predictive of a lupus-like syndrome following treatment with Simponi and is positive for double-stranded DNA antibodies, treatment with Simponi must be discontinued (see section 4.8).
Hematological reactions
Post-marketing cases of pancytopenia, leukopenia, neutropenia, aplastic anemia and thrombocytopenia have been reported in patients treated with anti-TNF drugs. Cytopenias, including pancytopenia, have not been reported frequently in clinical trials with Simponi. All patients should be advised to seek immediate medical attention if they develop compatible signs or symptoms of blood dyscrasias (e.g. persistent fever, bruising, bleeding, and paleness). Discontinuation of Simponi therapy should be considered in patients with confirmed significant haematological abnormalities.
Concomitant administration of TNF antagonists and anakinra
Serious infections and neutropenia have occurred in combination clinical trials of anakinra and another TNF inhibitor, etanercept, without additional clinical benefit. Given the nature of the adverse events observed with this combination therapy, similar toxicities may occur with the combination of anakinra and other TNF inhibitors. The combination of Simponi and anakinra is not recommended.
Concomitant administration of TNF antagonists and abatacept
In clinical studies, the combined use of TNF-antagonists and abatacept was associated with an increased risk of infections, including serious infections, compared with TNF-antagonists used alone, without an increase in clinical benefit. Simponi and abatacept is not recommended.
Concomitant administration with other biological therapies
There is insufficient information regarding the concomitant use of Simponi with other biological therapies used to treat the same conditions as Simponi. The concomitant use of Simponi with these biologics is not recommended due to the possibility of an increased risk of infection, and other potential drug interactions.
Substitution between biological DMARDs
Caution should be exercised and patients should continue to be monitored when changing from one biologic to another, as overlapping biological activity may further increase the risk of adverse events, including infection.
Vaccinations / infectious therapeutic agents
Patients treated with Simponi may receive concomitant vaccinations, excluding live vaccines (see sections 4.5 and 4.6). In patients treated with anti-TNF therapy, limited data are available on the response to vaccination, with live vaccines or on the secondary transmission of infection with the administration of live vaccines. The use of live vaccines could lead to clinical infections, including infections disseminated.
Other uses of infectious therapeutic agents such as live attenuated bacteria (for example, intravesical instillations with BCG for cancer treatment) could result in clinical infections, including disseminated infections. It is recommended that therapeutic infectious agents not be given concomitantly with Simponi.
Allergic reactions
In post-marketing experience, serious systemic hypersensitivity reactions (including anaphylactic reaction) have been reported following administration of Simponi. Some of these reactions occurred after the first administration of Simponi. In case of anaphylactic or other reactions allergic, Simponi should be discontinued immediately and appropriate therapy initiated.
Sensitivity to latex
The needle cap on the pre-filled pen or pre-filled syringe is made from latex containing dried natural rubber and may cause allergic reactions in latex sensitive individuals.
Special populations
Elderly (≥ 65 years old)
In the Phase III RA, AP, SA, and CU studies, no overall differences in adverse events (AEs), serious adverse events (EAGs) and serious infections were observed in patients 65 years of age or older receiving therapy. with Simponi, compared to younger patients. However, caution should be exercised in the treatment of the elderly and particular attention should be paid to the occurrence of infections. There were no patients aged 45 years or older in the axial SpA study no.
Renal and hepatic impairment
No specific studies have been conducted with Simponi in patients with renal or hepatic impairment. Simponi should be used with caution in subjects with impaired hepatic function (see section 4.2).
Pediatric population
Vaccinations
If possible, it is recommended that pediatric patients be in good standing with all immunizations in accordance with current immunization guidelines prior to initiating Simponi therapy.
Excipients
Simponi contains sorbitol (E420). Patients with rare hereditary problems of fructose intolerance should not take Simponi.
Potential for treatment errors
Simponi is registered in strengths of 50 mg and 100 mg for subcutaneous administration. It is important that the correct dosage is used to administer the correct dose as indicated in the posology (see section 4.2). Care should be taken in providing the right dosage to ensure that patients are not underdosed or overdosed.
04.5 Interactions with other medicinal products and other forms of interaction
No interaction studies have been performed.
Concomitant use with other biological therapies
The combination of Simponi with other biological therapies used to treat the same conditions as Simponi, including anakinra and abatacept is not recommended (see section 4.4).
Live vaccines / infectious therapeutic agents
Live vaccines should not be administered concomitantly with Simponi (see sections 4.4 and 4.6).
Infectious therapeutic agents should not be administered concomitantly with Simponi (see section 4.4).
Methotrexate
Although concomitant use of methotrexate (MTX) results in increased steady-state simponi trough concentrations in patients with RA, AP or AS, the data do not suggest the need to adjust either Simponi dose or MTX (see section 5.2).
04.6 Pregnancy and breastfeeding
Women of childbearing potential
Women of childbearing potential must use adequate contraception to prevent pregnancy and continue its use for at least 6 months after the last golimumab administration.
Pregnancy
There are no adequate data from the use of golimumab in pregnant women. Due to its inhibition of TNF, administration of golimumab during pregnancy may affect the normal immune responses of the newborn. Animal studies do not indicate direct or harmful effects. indirect effects on pregnancy, embryonic / fetal development, parturition or postnatal development (see section 5.3). The use of golimumab is not recommended in pregnant women; golimumab should only be given to pregnant women when clearly needed.
Golimumab crosses the placenta. Following treatment with a TNF-inhibiting monoclonal antibody during pregnancy, the antibody was found for up to 6 months in the serum of infants born to treated women. Consequently, these infants may have an increased risk of infection.
Administration of live vaccines in exposed infants in utero a golimumab is not recommended for 6 months following the mother's last golimumab injection during pregnancy (see sections 4.4 and 4.5).
Breastfeeding
It is not known whether golimumab is excreted in human milk or absorbed systemically after ingestion. Golimumab has been shown to pass into the milk of monkeys and, because human immunoglobulins are excreted in milk, women should not breastfeed during treatment and for at least 6 months after golimumab treatment.
Fertility
Fertility studies with golimumab have not been conducted in animals. A fertility study in mice using a similar antibody that selectively inhibits the functional activity of murine TNF showed no relevant effects on fertility (see section 5.3).
04.7 Effects on ability to drive and use machines
Simponi may slightly impair the ability to drive and use machines. Dizziness may occur following administration of Simponi (see section 4.8).
04.8 Undesirable effects
Summary of the safety profile
In the control period of the pivotal RA, AP, SA, Axial SpA nr, and CU studies, upper respiratory tract infection was the most common adverse drug reaction (ADR) reported in 12.6% of golimumab-treated patients. compared to 11.0% of control patients. The most serious ADRs reported for golimumab include severe infections (including sepsis, pneumonia, TB, invasive fungal infections and opportunistic infections), demyelinating diseases, HBV reactivation, CHF, autoimmune processes (lupus-like syndrome), haematological reactions, severe hypersensitivity systemic (including anaphylactic reaction), vasculitis, lymphoma and leukemia (see section 4.4).
Table with list of adverse reactions
ADRs observed in clinical trials and reported following worldwide post-marketing use of golimumab are listed in Table 1. Within the System Organ Class, adverse drug reactions are listed by frequency using the following categories : very common (≥ 1/10); common (≥ 1/100,
Table 1
Table with list of ADRs
*: Observed with other TNF blocking agents.
In this section, the median duration of follow-up (approximately 4 years) is generally presented for all golimumab uses. Where golimumab use is described by dose, the median duration of follow-up varies (approximately 2 years for a 50 mg dose, approximately 3 years for a 100 mg dose) as patients could be switched between doses.
Description of selected adverse drug reactions
Infections
In the control period of the pivotal studies, upper respiratory tract infection was the most common adverse reaction reported in 12.6% of golimumab-treated patients (incidence per 100 subject-years: 60.8; 95% CI: 55.0, 67.1) compared to 11.0% of control patients (incidence per 100 subjects / year: 54.5; 95% CI: 46.1, 64.0). In the controlled and uncontrolled phases of the studies with a median follow-up of approximately 4 years, the incidence per 100 subject-years of upper respiratory tract infections was 34.9 events; 95% CI: 33.8, 36.0 for golimumab-treated patients.
In the control period of the pivotal studies, infections were observed in 23.0% of golimumab-treated patients (incidence per 100 subject-years: 132.0; 95% CI: 123.3, 141.1) compared with 20 , 2% of control patients (incidence per 100 subject-years: 122.3; 95% CI: 109.5, 136.2). In the controlled and uncontrolled phases of the studies with a median follow-up of approximately 4 years, the per 100 subject-year incidence of infections was 81.1 events; 95% CI: 79.5, 82.8 per golimumab-treated patients.
In the control period of the RA, AP, SA, and Axial SpA nr studies, serious infections were observed in 1.2% of golimumab-treated patients and 1.2% of control patients. The incidence of serious infections per 100 subject-years during the follow-up in the control period of the RA, AP, SA and nr-Axial SpA studies was 7.3; 95% CI: 4.6, 11 , 1 for the golimumab 100 mg group, of 2.9; 95% CI: 1.2, 6.0 for the golimumab 50 mg group and 3.6; 95% CI: 1 , 5, 7.0 for the placebo group. In the control period of the golimumab induction UC studies, serious infections were seen in 0.8% of golimumab-treated patients versus 1.5% of control patients . Serious infections seen in golimumab-treated patients included tuberculosis, bacterial infections including sepsis and pneumonia, invasive fungal infections, and other opportunistic infections. Some of these infections have been fatal. In the controlled and uncontrolled portions of the pivotal studies with a median follow-up of up to 3 years, there was a higher incidence of serious infections, including opportunistic infections and TB in patients treated with golimumab 100 mg compared to treated patients. with golimumab 50 mg. The incidence per 100 subject-years of all serious infections was 4.1; 95% CI: 3.6, 4.5, for patients treated with golimumab 100 mg and 2.5; 95% CI: 2.0, 3.1, for patients treated with golimumab 50 mg.
Malignant neoplasms
Lymphoma
The incidence of lymphoma in golimumab-treated patients during the pivotal studies was higher than expected in the general population. In the controlled and uncontrolled portions of these studies with a median follow-up of up to 3 years, a higher incidence of lymphoma was observed in patients treated with golimumab 100 mg compared to patients treated with golimumab 50 mg. Lymphoma was diagnosed in 11 subjects (1 in the golimumab 50 mg treatment groups and 10 in the golimumab 100 mg treatment groups) with an incidence (95% CI) per 100 subject-years of follow-up of 0.03 and 0.13 events for golimumab 50 mg and golimumab 100 mg, respectively, and 0.00 events for placebo. The majority of lymphomas occurred in the GO-AFTER study in which patients previously exposed to anti-TNF drugs and with a longer and more refractory duration of disease were enrolled (see section 4.4).
Malignant neoplasms other than lymphoma
In the control periods of the pivotal studies and for approximately 4 years of follow-up, the incidence of malignancies other than lymphoma (excluding non-melanoma skin cancer) was similar between the golimumab and control groups. approximately 4 years of follow-up, the incidence of non-lymphoma malignancies (excluding non-melanoma skin cancer) was similar to that in the general population.
In the controlled and uncontrolled periods of the pivotal studies with a median follow-up of up to 3 years, non-melanoma skin cancer was diagnosed in 5 subjects treated with placebo, 10 treated with golimumab 50 mg and 31 treated with golimumab 100 mg with an incidence (95% CI) per 100 subject-years of follow-up of 0.36 for combined golimumab and 0.87 for placebo.
In the controlled and uncontrolled periods of the pivotal studies with a median follow-up of up to 3 years, malignancies in addition to melanoma, non-melanoma skin cancer and lymphoma were diagnosed in 5 subjects treated with placebo, in 21 treated with golimumab 50 mg and in 34 treated with golimumab 100 mg with an incidence (95% CI) per 100 subject-years of follow-up of 0.48 for combined golimumab and 0.87 for placebo (see section 4.4).
Cases reported in clinical trials in the presence of asthma
In an exploratory clinical study, patients with severe persistent asthma received a golimumab loading dose (150% of the assigned treatment dose) subcutaneously at week 0, followed by golimumab 200 mg, golimumab 100 mg, or golimumab 50 mg each. 4 weeks subcutaneously through week 52. Eight malignancies in the golimumab combination treatment group (n = 230) and none in the placebo treatment group (n = 79) were reported. Lymphoma was reported in 1 patient, non-melanoma skin cancer in 2 patients and other malignancies in 5 patients. There was no specific amalgamation of any type of malignancy.
In the placebo-controlled phase of the study, the incidence (95% CI) of all malignancies per 100 subject-years of follow-up was 3.19 in the golimumab treatment group. In this study, the " incidence (95% CI) per 100 subject-years of follow-up in golimumab-treated patients was 0.40 for lymphoma, 0.79 for non-melanoma skin cancer, and 1.99 for other malignancies. For subjects treated with placebo, the incidence (95% CI) of these malignancies per 100 subjects / year of follow-up was 0.00. The significance of these findings is unknown.
Neurological events
In the controlled and uncontrolled periods of the pivotal studies with a median follow-up of up to 3 years, a higher incidence of demyelination was observed in patients treated with golimumab 100 mg compared to patients treated with golimumab 50 mg (see section 4.4). .
Increases in liver enzymes
In the control periods of the pivotal RA and AP studies, slight elevations in ALT (> 1 and 1 and
In the control period of the pivotal RA and AS studies, ALT elevations ≥ 5 times ULN were uncommon and were observed in a greater number of golimumab-treated patients (0.4% to 0, 9%) compared to control patients (0.0%). This trend was not observed in the AP population. In the controlled and uncontrolled periods of the pivotal RA, AP, and SA studies with a median follow-up of 5 years, the incidence of ALT elevations ≥ 5 times ULN was similar for both golimumab-treated and control patients. In general, these elevations were asymptomatic and the abnormalities decreased or resolved with continuation or discontinuation of golimumab or modification of concomitant medications. No cases were reported in the controlled and uncontrolled periods of the Axial SpA study. (up to 1 year) In the control periods of the pivotal CU induction studies with golimumab, elevations in ALT ≥ 5 x ULN were observed in similar rates in golimumab-treated and placebo-treated patients (0 , 3% to 1.0%).In the controlled and uncontrolled periods of the pivotal UC studies with a median follow-up of approximately 2 years, the proportion of patients with ALT elevations ≥ 5 x ULN was 0.8% in patients receiving golimumab during the maintenance of the UC study.
In the pivotal RA, AP, SA, and axial SpA studies, a patient in a RA study with pre-existing liver abnormalities and confounding factor drugs treated with golimumab developed lethal non-infectious hepatitis with jaundice. The role of golimumab as a contributing or aggravating factor cannot be excluded.
Injection site reactions
In the control periods of the pivotal studies, injection site reactions were observed in 5.4% of golimumab-treated patients, compared with 2.0% of control patients. The presence of antibodies to golimumab may increase the risk of injection site reactions. Most injection site reactions were mild and moderate and most frequent manifestations were injection site erythema. Injection site reactions generally do not require discontinuation of treatment with the medicine.
In the controlled Phase IIb and / or III studies in RA, AP, SA, Axial nr SpA, severe persistent asthma and in the Phase II / III UC studies, no golimumab-treated patients developed anaphylactic reactions.
Autoimmune antibodies
In the controlled and uncontrolled periods of the pivotal studies with 1 year of follow-up, 3.5% of golimumab-treated patients and 2.3% of control patients had recent positive ANA (titrations of 1: 160 or higher). The frequency of anti-dsDNA antibodies at 1 year of follow-up in anti-dsDNA negative patients at baseline was 1.1%.
Pediatric population
Polyarticular juvenile idiopathic arthritis
The safety of golimumab was studied in a Phase III study of 173 patients with pJIA from 2 to 17 years of age. The mean follow-up was approximately two years. In this study, the type and frequency of adverse events reported were generally similar to those seen in studies in adults with RA.
Reporting of suspected adverse reactions
The reporting of suspected adverse reactions that occur after the authorization of the medicine is important, as it allows continuous monitoring of the benefit / risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions via the Italian Medicines Agency, website: http://www.agenziafarmaco.gov.it/it/responsabili.
04.9 Overdose
Single doses up to 10 mg / kg intravenously were administered in a clinical study, without any dose-limiting toxicity. In the event of an overdose, it is recommended that the patient be monitored for signs and symptoms of adverse events and appropriate symptomatic treatment instituted immediately.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: immunosuppressants, tumor necrosis factor alpha (TNF-?) Inhibitors, ATC code: L04AB06
Mechanism of action
Golimumab is a human monoclonal antibody that forms stable complexes with high affinity for both the soluble and bioactive transmembrane forms of TNF-? human, preventing the binding of TNF-? to its receptors.
Pharmacodynamic effects
Golimumab binding to human TNF has been shown to inhibit TNF-? Induced cell surface expression of adhesion molecules, selectin E, vascular cell adhesion molecule type 1 (VCAM) and intracellular adhesion molecule of type 1 (ICAM) by human endothelial cells. In vitro, TNF-induced secretion by interleukin (IL) -6, IL-8 and granulocyte and macrophage colony-stimulating factor (GM-CSF) by human endothelial cells was also inhibited by golimumab.
An improvement in C-reactive protein (CRP) levels was observed compared to the placebo groups, and Simponi treatment resulted in significant reductions in serum levels from baseline of IL-6, ICAM-1, matrix metalloproteinase. 3 (MMP) and vascular endothelial growth factor (VEGF), compared to the control treatment. Furthermore, in RA and AS patients, the levels of TNF-? decreased and IL-8 levels decreased in patients with AP. These changes were observed in the first evaluation (week 4) after the initial Simponi administration and generally lasted through week 24.
Clinical efficacy
Rheumatoid arthritis
The efficacy of Simponi has been demonstrated in three multicentre, randomized, double-blind, placebo-controlled clinical trials conducted in more than 1500 patients ≥ 18 years of age with moderate to severe active RA diagnosed according to the criteria American College of Rheumatology (ACR) for at least a 3-month period prior to screening. Patients had to have at least 4 swollen and 4 painful joints. Simponi or placebo was administered subcutaneously every 4 weeks.
GO-FORWARD evaluated 444 patients with active RA despite a stable dose of at least 15 mg / week of MTX and who had not previously been treated with any anti-TNF medicines. Patients were randomized to placebo + MTX, Simponi 50 mg + MTX, Simponi 100 mg + MTX, or Simponi 100 mg + placebo. Patients receiving placebo + MTX were, after week 24, assigned to Simponi 50 mg + MTX. At week 52, patients entered an open-label long-term extension study.
GO-AFTER evaluated 445 patients previously treated with one or more anti-TNF medicines, adalimumab, etanercept, or infliximab. Patients were randomized to placebo, Simponi 50 mg, or Simponi 100 mg. During the study, patients were able to continue concomitant DMARD therapy with MTX, sulfasalazine (SSZ), and / or hydroxychloroquine (HCQ). The reasons given for the discontinuation of previous anti-TNF therapies were lack of efficacy (58%), intolerance (13%), and / or reasons other than safety or efficacy (29%, mostly for financial reasons).
GO-BEFORE evaluated 637 patients with active RA, MTX-naïve and not previously treated with an anti-TNF medicine. Patients were randomized to receive placebo + MTX, Simponi 50 mg + MTX, Simponi 100 mg + MTX, or Simponi 100 mg + placebo. At week 52, patients entered an open-label long-term extension study in which patients who received placebo + MTX and had at least 1 tender or swollen joint were moved to Simponi 50 mg + MTX treatment.
In GO-FORWARD the (co) primary endpoints were the proportion of patients achieving an ACR 20 response at week 14 and improvement in Health Assessment Questionnaire (HAQ) at week 24 from baseline. was the proportion of patients who achieved an ACR 20 response at week 14. In GO-BEFORE, the co-primary endpoints were the proportion of patients who achieved an ACR 50 response at week 24 and a change from baseline in modified Sharp score by van der Heijde (vdH-S) at week 52. In addition to the primary endpoints, additional assessments of the impact of Simponi treatment on signs and symptoms of arthritis, radiographic response, physical function and status-related quality of life were performed. of health.
In general, no clinically significant differences in efficacy assessments were observed between Simponi 50 mg and 100 mg in combination with MTX dosing regimens up to week 104 in GO-FORWARD and GO-BEFORE and up to week 24. in the GO-AFTER In each of the RA studies according to the study design, patients in the long-term extension could be switched between Simponi 50 mg and 100 mg doses at the discretion of the study physician.
Signs and symptoms
The key ACR criteria results for Simponi 50 mg dose at weeks 14, 24 and 52 for GO-FORWARD, GO-AFTER and GO-BEFORE are shown in Table 2 and are described below. Responses were seen in the first evaluation (week 4) after the initial administration of Simponi.
In the GO-FORWARD study, of the 89 subjects randomized to Simponi 50 mg + MTX, 48 were still on treatment at week 104. Among these, 40, 33 and 24 patients had an ACR 20/50/70 response at week 104, respectively. Among patients who remained in the study and treated with Simponi, similar ACR 20/50/70 response rates were observed from week 104 through week 256.
In the GO-AFTER study, the percentage of patients who achieved an ACR 20 response was higher among Simponi-treated patients compared with placebo-treated patients, regardless of the reported reason for discontinuing one or more anti-inflammatory therapies. -TNF.
Table 2
Key efficacy results from the controlled parts of the GO-FORWARD, GO-AFTER and GO-BEFORE studies
a n corresponds to randomized patients; the actual number of patients evaluable for each endpoint may vary by timepoint.
* p ≤ 0.001
NA: Not Applicable
In the GO-BEFORE study, the primary analysis in patients with moderate to severe rheumatoid arthritis (Simponi 50 and 100 mg + MTX combination groups versus MTX alone for ACR 50) was not statistically significant at week 24 (p = 0.053 At week 52 across the population, the proportion of patients in the Simponi 50 mg + MTX group who achieved an ACR response was generally higher but not significantly different when compared to MTX alone (see Table 2). Additional subgroup analyzes representative of the indicated population of patients with severe, active and progressive RA.A generally superior effect was demonstrated with Simponi 50 mg + MTX versus MTX alone in the indicated population compared to the total population.
In the GO-FORWARD and GO-AFTER studies, statistically and clinically significant responses on the Disease Activity Scale (DAS28) were observed at each pre-specified stage at week 14 and week 24 (p ≤ 0.001). Among patients who remained on Simponi treatment, randomized at study initiation, DAS28 responses were maintained through week 104. Among patients who remained on the study and treated with Simponi, DAS28 responses were similar from week 104 through week 256.
In the GO-BEFORE study, major clinical response was assessed, defined as maintaining an ACR 70 response over a continuous 6-month period. At week 52, 15% of patients in the Simponi 50 mg + MTX group achieved a superior clinical response compared with 7% of patients in the placebo + MTX group (p = 0.018). Of the 159 subjects randomized to Simponi 50 mg + MTX, 96 were still on treatment at week 104. Among these 85, 66 and 53 patients had an ACR 20/50/70 response at week 104, respectively. and treated with Simponi, similar ACR 20/50/70 response rates were observed from week 104 through week 256.
Radiographic response:
In the GO-BEFORE study, changes from baseline in vdH-S score, a composite structural damage score that radiographically measures the number and size of joint erosions and the degree of joint space reduction in the hands / wrists and feet, was used to assess the degree of structural damage. Key results for Simponi at 50 mg at week 52 are presented in Table 3.
The number of patients with no new erosion or change from baseline in total vdH-S score ≤ 0 was significantly higher in the Simponi group than in the control group (p = 0.003). Radiographic effects observed at week 52 were maintained through week 104. Among patients who remained in the study and treated with Simponi, radiographic effects were similar from week 104 through week 256.
Table 3
Mean (SD) of radiographic changes from baseline to week 52 in total vdH-S score across the GO-BEFORE study population
a n corresponds to randomized patients
* p = 0.015
** p = 0.044
Physical function and health-related quality of life
Physical function and disability were assessed as separate endpoints in the GO-FORWARD and GO-AFTER studies, using the HAQ DI disability index. In these studies, at week 24, Simponi showed a clinically and statistically significant improvement in HAQ DI from baseline when compared to the control group. Among patients who remained on Simponi treatment, randomized at study initiation, improvement in HAQ DI was maintained through week 104. Among patients who remained in the study and treated with Simponi, improvement in HAQ DI was similar from week 104 through week 256.
The GO-FORWARD study showed clinically and statistically significant improvements in health-related quality of life as measured by the physical component score of SF-36 in patients treated with Simponi versus placebo at week 24. Among patients who remained on Simponi treatment, randomized at study initiation, the improvement in SF-36 was maintained through week 104. Among patients who remained on the study and treated with Simponi, the improvement in the physical component of SF-36 was similar status from week 104 through week 256. In the GO-FORWARD and GO-AFTER studies, statistically significant improvements in fatigue were observed, according to the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scale.
Psoriatic arthritis
The efficacy and safety of Simponi were evaluated in a multicentre, randomized, double-blind, placebo-controlled clinical study (GO-REVEAL) conducted in 405 adult patients with active PA (≥ 3 swollen joints and ≥ 3 joints painful), despite therapy with non-steroidal anti-inflammatory drugs (NSAIDs) or DMARDs. Patients in this study had a diagnosis of AP for at least 6 months and at least mild psoriasis. Patients with each subtype of psoriatic arthritis, including arthritis, were enrolled polyarticular without rheumatoid nodules (43%), asymmetric peripheral arthritis (30%), distal interphalangeal joint arthritis (DIP) (15%), spondylitis with peripheral arthritis (11%) and mutilating arthritis (1%). no previous treatment with an anti-TNF drug. Simponi or placebo were administered subcutaneously every 4 weeks. Patients were randomized to placebo, Simponi 50 mg, or to S impose 100 mg. Patients receiving placebo were, after week 24, assigned to Simponi 50 mg. At week 52, patients entered a long-term open-label extension study.
Approximately 48% of patients continued on stable doses of methotrexate (≤ 25 mg / week). The co-primary endpoints were the proportion of patients who achieved an ACR 20 response at week 14 and the change from baseline in modified AP vdH-S total score at week 24.
In general, no clinically significant differences in efficacy measures were observed between the Simponi 50 mg and 100 mg dosing regimens through week 104. According to the study design, patients in the long-term extension could undergo a switch between Simponi 50 mg and 100 mg doses at the discretion of the study physician.
Signs and symptoms
Key results for the 50 mg dose at weeks 14 and 24 are shown in Table 4 and are described below.
Table 4
Key efficacy results from the GO-REVEAL study
* p
a n corresponds to randomized patients; the actual number of patients evaluable for each endpoint may vary by timepoint
b Psoriasis Area and Severity Index
c Based on the subgroup of patients with body surface area (BSA) involvement ≥ 3% at baseline, 79 patients (69.9%) in the placebo treatment group and 109 (74.3%) in the Simponi 50 mg.
Responses were observed at the first evaluation (week 4) after the initial administration of Simponi. Similar ACR 20 responses were seen at week 14 in patients with polyarticular arthritis in the absence of rheumatoid nodules and AP subtypes, asymmetric peripheral arthritis. The number of patients with other PA subtypes was too small to allow for a meaningful assessment.The responses observed in the Simponi treatment groups were similar in patients treated or not treated with concomitant MTX. Of the 146 patients randomized to Simponi 50 mg, 70 were still on treatment at week 104. Among these 70 patients, 64, 46 and 31 patients had an ACR 20/50/70 response, respectively. Among patients who remained in the study and treated with Simponi, similar ACR 20/50/70 response rates were observed from week 104 through week 256.
Statistically significant responses were also observed in DAS28 at weeks 14 and 24 (p
At week 24, improvements in peripheral activity parameters typical of psoriatic arthritis (eg, number of swollen joints, number of tender joints, dactylitis and enthesitis) were observed in patients treated with Simponi. Treatment with Simponi resulted in significant improvement in physical function as assessed by HAQ DI and significant improvements in health-related quality of life based on summary scores of the physical and mental components of the SF-36. on Simponi treatment, to which they were randomized at study initiation, DAS28 and HAQ DI responses were maintained through week 104. Among patients who remained in the study and treated with Simponi, DAS28 and HAQ DI responses were similar. week 104 through week 256.
Radiographic response:
Structural damage to the hands and feet was radiologically assessed by the change from baseline in the vdH-S score, modified for the AP with the addition of the distal interphalangeal joints (DIP) of the hand.
Simponi 50 mg treatment reduces the rate of progression of peripheral joint damage compared to placebo treatment at week 24 measured as change from baseline in modified total vdH-S score (mean ± SD score was 0.27 ± 1, 3 in the placebo group compared with -0.16 ± 1.3 in the Simponi group; p = 0.011). Of the 146 patients who were randomized to Simponi 50 mg, X-ray data at week 52 were available for 126 patients, of whom 77% showed no progression from baseline. At week 104, X-ray data were available for 114 patients and 77% showed no progression from baseline. Among patients who remained in the study and treated with Simponi, similar proportions of patients showed no progression from baseline from week 104 through week 256.
Axial spondyloarthritis
Ankylosing spondylitis
The efficacy and safety of Simponi were evaluated in a multicenter, double-blind, randomized, placebo-controlled clinical study (GO-RAISE) conducted in 356 adult patients with active ankylosing spondylitis (defined as the Bath Index pathological activity of ankylosing spondylitis (BASDAI) ≥ 4 and a VAS for total back pain ≥ 4 on a scale of 0 to 10 cm). Patients enrolled in this study had the disease in active phase, despite current or previous therapy with NSAIDs or DMARDs and had not previously been treated with any anti-TNF drugs. Simponi or placebo was administered subcutaneously every 4 weeks. Patients were randomized to placebo, Simponi 50 mg, or Simponi 100 mg and were able to continue concomitant DMARD therapy (MTX, SSZ, and / or HCQ). The primary endpoint was the percentage of patients with ankylosing spondylitis assessment study group (ASAS 20) response at week 14. Placebo-controlled efficacy data were collected and analyzed through week 24.
The key results for the 50 mg dose are shown in Table 5 and are described below. In general, no clinically significant differences in efficacy measures were observed between Simponi 50 mg and 100 mg dosing regimens up to week 24. According to the study design, patients in the long-term extension could undergo a switch between Simponi 50 mg and 100 mg doses at the discretion of the study physician.
Table 5
Key efficacy results from the GO-RAISE study
* p ≤ 0.001 for all comparisons
a n corresponds to randomized patients; the actual number of patients evaluable for each endpoint may vary by timepoint
Among patients who remained in the study and treated with Simponi, the proportion of patients with ASAS 20 and ASAS 40 response was similar from week 24 through week 256.
Statistically significant responses were also observed in BASDAI 50, 70 and 90 (p ≤ 0.017) at weeks 14 and 24. Improvements in key disease activity measurements were found at the first assessment (week 4) after the initial Simponi administration which were maintained through week 24. Among patients who remained in the study and treated with Simponi, similar rates of change from baseline were observed in BASDAI from week 24 through week 256. Consistent efficacy was observed in patients at regardless of the use of DMARDs (MTX, sulfasalazine and / or hydroxychloroquine), presence of the HLA-B27 antigen or baseline CRP levels based on the assessment of ASAS 20 responses at week 14.
Simponi treatment resulted in significant improvements in physical function as assessed by changes from baseline in Bath Ankylosing Spondylitis Functional Index (BASFI) at weeks 14 and 24. Health-related quality of life, as measured by the component score. SF-36, was significantly improved at weeks 14 and 24. Among patients who remained in the study and treated with Simponi, improvements in physical function and health-related quality of life were similar from week 24 through week 256.
Non-radiographic axial spondyloarthritis
The safety and efficacy of Simponi were evaluated in a multicentre, randomized, double-blind, placebo-controlled study (GO-AHEAD) conducted in 197 adult patients with severe axial SpA nr in active phase (defined as those patients who met the ASAS classification criteria for the diagnosis of axial spondyloarthritis but did not meet the modified New York criteria for the diagnosis of AS.) Patients enrolled in this study had active disease (defined by a BASDAI ≥ 4 and a Visual Analogue Scale (VAS) for overall back pain ≥ 4, each on a scale of 0 to 10 cm) despite ongoing or previous NSAID therapy and had not previously been treated with any biological agent including anti TNF. Patients were randomized to placebo or Simponi 50 mg administered subcutaneously every 4 weeks. At week 16, patients entered an open-label treatment period in which all received Simponi 50 mg administered subcutaneously every 4 weeks through week 48 with efficacy assessments performed through week 52 and safety follow-up through week 60. Approximately 93% of patients who had received Simponi at the start of the open label extension (week 16) remained on treatment until the end of the study (week 52). Analyzes were performed both on the entire population treated (AT, N = 197) and on the population with objective signs of inflammation (OSI, N = 158, as indicated by high levels of CRP and / or by "evidence of sacroiliitis in the MRI performed. at baseline). Placebo-controlled efficacy data were collected and analyzed through week 16. The primary endpoint was the proportion of patients who achieved an ASAS 20 response at week 16. Key results are shown in Table 6 and are described below.
Table 6
Key efficacy results from the GO-AHEAD study at week 16
a n corresponds to randomized and treated patients
b Ankylosing spondylitis C-reactive protein disease activity score (AT-Placebo, N = 90; AT-Simponi 50 mg, N = 88; OSI-Placebo, N = 71; OSI-Simponi 50 mg, N = 71)
c n corresponds to the number of patients with baseline and week 16 MRI data
d SPARCC (Spondyloarthritis Research Consortium of Canada)
** p vs placebo
* p vs placebo
Statistically significant improvements in signs and symptoms of severe active phase nr axial SpA were demonstrated in patients treated with Simponi 50 mg compared to placebo at week 16 (Table 6). Improvements were seen at the first evaluation (week 4) after the initial administration of Simponi. The SPARCC MRI score showed statistically significant reductions in inflammation in the SI joint at week 16 in patients treated with Simponi 50 mg compared to placebo (Table 6). Pain as assessed by VAS overall back pain and nocturnal back pain and disease activity as measured by ASDAS-C also showed statistically significant improvement from baseline to week 16 in patients treated with Simponi 50 mg compared to placebo (p
Statistically significant improvements in spinal mobility as assessed by BASMI (Bath Ankylosing Spondylitis Metrology Index) and in physical function as assessed by BASFI were demonstrated in patients treated with Simponi 50 mg compared to patients treated with placebo (p
For all the endpoints described above, statistically significant results were also demonstrated in the OSI population at week 16.
In both the AT and OSI populations, the improvements in signs and symptoms, spinal mobility, physical function, quality of life and productivity observed at week 16 among patients treated with Simponi 50 mg persisted in those patients remaining in the study. at week 52.
Ulcerative colitis
The efficacy of Simponi was evaluated in two randomized, double-blind, placebo-controlled clinical trials in adult patients.
The induction study (PURSUIT-Induction) evaluated patients with moderate to severe active ulcerative colitis (Mayo score 6 to 12; endoscopic sub-score ≥ 2) who had an inadequate response or who had not tolerated conventional therapies or that they were corticosteroid dependent. In the dose-confirmation portion of the study, 761 patients were randomized to receive Simponi SC 400 mg at week 0 and 200 mg at week 2, Simponi SC 200 mg at week 0 and 100 mg at week 2 or placebo SC at weeks 0 and 2. Concomitant administration of stable doses of oral aminosalicylates, corticosteroids and / or immunomodulatory agents was allowed. The efficacy of Simponi up to week 6 was evaluated in this study.
The results of the maintenance study (PURSUIT-Maintenance) were based on the evaluation of 456 patients who had achieved a clinical response in the previous Simponi induction. Patients were randomized to receive Simponi 50 mg, Simponi 100 mg or placebo administered subcutaneously every 4 weeks. Concomitant administration of stable doses of oral aminosalicylates and / or immunomodulatory agents was allowed. Corticosteroids were to be gradually reduced at the start of the maintenance study. The efficacy of Simponi was evaluated up to week 54 in this study. Patients who had completed the maintenance study up to week 54 continued treatment in one study. extension, with efficacy assessed up to week 216. Evaluation of efficacy in the extension study was based on changes in corticosteroid use, physician's global assessment (PGA) of disease activity, and improvement in quality of life as measured by the Inflammatory Bowel Disease Questionnaire (IBDQ).
Table 7
Key efficacy results from the PURSUIT - Induction and PURSUIT - Maintenance studies
N = number of patients
** p ≤ 0.001
* p ≤ 0.01
a Defined as a decrease from baseline in Mayo score of ≥ 30% and ≥ 3 points, accompanied by a decrease in rectal bleeding subscore ≥ 1 or a rectal bleeding subscore of 0 or 1.
b Defined as Mayo score ≤ 2 points, with no individual sub-scores> 1
c Defined as 0 or 1 in the endoscopic sub-score of the Mayo score.
d Induction with Simponi only.
e Patients were evaluated for CU activity with Mayo partial score every 4 weeks (loss of response was confirmed with endoscopy). Therefore, one patient who maintained response was in a continuous clinical response state at each clinical evaluation through week 54.
f A patient had to be in remission at weeks 30 and 54 (showing no loss of response at any point in time up to week 54) to achieve sustained remission.
g In patients weighing less than 80 kg, a greater proportion of patients receiving 50 mg maintenance therapy exhibited sustained clinical remission than those receiving placebo.
More Simponi-treated patients showed sustained mucosal healing (patients with mucosal healing at weeks 30 and 54) in the 50 mg group (42%, nominal p
Among the 54% of patients (247/456) who received concomitant corticosteroid therapy at the start of PURSUIT-Maintenance, the proportion of patients who maintained a clinical response through week 54 and did not receive concomitant corticosteroid therapy at the start of PURSUIT-Maintenance. week 54 was greater in the 50 mg group (38%, 30/78) and in the 100 mg group (30%, 25/82) compared to the placebo group (21%, 18/87). The proportion of patients who had eliminated corticosteroids by week 54 were greater in the 50 mg group (41%, 32/78) and in the 100 mg group (33%, 27/82) compared to the placebo group (22%, 19/87). had entered the extension study, the proportion of subjects who remained corticosteroid-free was generally maintained through week 216.
At week 6, Simponi significantly improved quality of life as measured by change from baseline in a disease-specific measure, IBDQ (Inflammatory Bowel Disease Questionnaire). Among patients who received maintenance therapy with Simponi, the improvement in quality of life as measured by IBDQ was maintained through week 54.
Approximately 63% of patients who received Simponi at the start of the extension study (week 56) remained on treatment until the end of the study (last golimumab administration at week 212).
Immunogenicity
In the Phase III RA, AP and SA studies through week 52, antibodies to golimumab were detected with the enzyme immunoassay (EIA) in 5% (105/2062) of golimumab-treated patients and where tested, nearly all were antibodies neutralizing in vitro. Similar percentages have been highlighted in the rheumatological indications. Co-administration of MTX resulted in a lower percentage of patients with antibodies to golimumab than patients who received golimumab without MTX (approximately 3% [41/1235] versus 8% [64/827], respectively).
In axial SpA nr, antibodies to golimumab were detected in 7% (14/193) of golimumab-treated patients through week 52 with the EIA assay.
In the Phase II and III UC studies through Week 54, antibodies to golimumab were detected with the EIA assay in 3% (26/946) of golimumab-treated patients. Sixty-eight percent (21/31) of the antibody-positive patients had neutralizing antibodies in vitro. Concomitant treatment with immunomodulators (azathioprine, 6-mercaptopurine and MTX) resulted in a lower percentage of patients with antibodies to golimumab than in patients who received golimumab without immunomodulators (1% (4/308) versus 3% (22), respectively. / 638)). Among patients who continued the extension study and who had evaluable samples up to week 228, antibodies to golimumab were detected in 4% (23/604) of golimumab-treated patients. Eighty-two percent (18/22) of the antibody-positive patients had neutralizing antibodies in vitro.
A drug-tolerant EIA assay was used in the pJIA study for the detection of antibodies against golimumab.Given the increased sensitivity and improved drug tolerance, a higher incidence of antibodies against golimumab was expected to be detected with the drug-tolerant EIA assay compared with the EIA assay. In the Phase III pIA trial through week 48, antibodies to golimumab were detected with the drug-tolerant EIA assay in 40% (69/172) of the golimumab-treated children, of which the majority had a titer less than 1: 1,000 . An effect on golimumab serum concentrations was seen at titers> 1: 100, while no effect on efficacy was seen up to titers> 1: 1,000, although the numbers of children with titers> 1: 1,000 were low ( N = 8). Among children who tested positive for antibodies against golimumab, 39% (25/65) had neutralizing antibodies. The higher incidence of antibodies with the drug-tolerant EIA assay, considering they were mainly antibodies to low titer, had no obvious impact on drug levels, efficacy and safety and therefore does not represent any new safety signals.
The presence of antibodies to golimumab may increase the risk of injection site reactions (see section 4.4). The small number of golimumab antibody positive patients limits the ability to draw firm conclusions regarding the relationship between anti-golimumab antibodies and clinical efficacy or safety measures.
Since immunogenicity assays are product and assay specific, comparison of antibody percentages with those of other products is not appropriate.
Pediatric population
Polyarticular juvenile idiopathic arthritis
The safety and efficacy of Simponi were evaluated in a randomized, double-blind, placebo-controlled suspension study (GO-KIDS) in 173 children (2 to 17 years of age) with active pJIA with at least 5 active joints. and an inadequate response to MTX. Children with polyarticular course JIA (rheumatoid factor positive or negative polyarthritis, extensive oligoarthritis, juvenile psoriatic arthritis, or systemic JIA with no ongoing systemic symptoms) were included in the study. The median number of active joints at baseline it was 12 and the median CRP was 0.17 mg / dL.
Part 1 of the study involved an open-label 16-week phase in which the 173 enrolled children received Simponi 30 mg / m2 (maximum 50 mg) subcutaneously every 4 weeks and MTX. The 154 children who achieved an ACR Ped 30 response at week 16 entered part 2 of the study, the randomized withdrawal phase, and received Simponi 30 mg / m2 (maximum 50 mg) + MTX or placebo + MTX each. 4 weeks. After disease flare, children received Simponi 30 mg / m2 (maximum 50 mg) + MTX. At week 48, the babies entered a long-term extension phase.
The children in this study showed ACR Ped 30, 50, 70, and 90 responses as early as week 4.
At week 16, 87% of the children were ACR Ped 30 responders and 79%, 66%, and 36% of the children were ACR Ped 50, ACR Ped 70, and ACR Ped 90 responders, respectively. At week 16, the 34% of children had inactive disease defined by the presence of all of the following: absence of joints with active arthritis; absence of fever, rash, serositis, splenomegaly, hepatomegaly or generalized lymphadenopathy attributable to JIA; absence of active uveitis ; Normal ESR (
At week 16, all ACR Ped components showed clinically relevant improvement from baseline (see Table 8).
Table 8
Improvements from baseline in ACR Ped components at week 16
at baseline = week 0
b "n" reflects enrolled patients
c VAS: Visual Analog Scale
d CHAQ: Child Health Assessment Questionaire
and ESR (mm / h): erythrocyte sedimentation rate (millimeters per hour)
The primary endpoint of the study, the percentage of children who were ACR Ped 30 responders at week 16 and who did not experience an exacerbation between week 16 and week 48, was not met. Most of the children did not have an exacerbation. exacerbation between week 16 and week 48 (59% in the Simponi + MTX group and 53% in the placebo + MTX group, respectively; p = 0.41).
A pre-specified subgroup analysis of the primary endpoint based on baseline CRP values (≥ 1 mg / dL vs
At week 48, 53% and 55% of children in the Simponi + MTX group and the placebo + MTX group, respectively, were ACR Ped 30 responders, and 40% and 28% of children in the Simponi + MTX group and the placebo + MTX, respectively, achieved inactive disease.
The European Medicines Agency has deferred the obligation to submit the results of studies with Simponi in the pediatric population in ulcerative colitis (see section 4.2 for information on pediatric use).
05.2 Pharmacokinetic properties
Absorption
After a single "subcutaneous golimumab administration to healthy subjects or RA patients, the mean time to reach maximum serum concentrations (Tmax) ranged from 2 to 6 days. A" 50 mg subcutaneous golimumab injection in healthy subjects resulted in produced a mean maximum serum concentration (Cmax) ± standard deviation of 3.1 ± 1.4 mcg / mL.
After a single 100 mg subcutaneous injection, golimumab absorption was similar in the arm, abdomen and thigh, with a mean absolute bioavailability of 51%. subcutaneously, the absolute bioavailability of a 50 mg or 200 mg golimumab dose is expected to be similar.
Distribution
After a single IV administration, the mean volume of distribution was 115 ± 19 mL / kg.
Elimination
Systemic clearance of golimumab was estimated to be 6.9 ± 2.0 mL / day / kg. The terminal half-life was estimated to be about 12 ± 3 days in healthy subjects and had similar values in patients with RA, AP, SA or CU.
When a 50 mg dose of golimumab was administered subcutaneously to patients with RA, AP, or AS every 4 weeks, serum concentrations reached steady state by week 12. With concomitant use of MTX, treatment with golimumab 50 mg subcutaneously every 4 weeks produced a mean (± standard deviation) trough serum concentration at steady state of approximately 0.6 ± 0.4 μg / mL in patients with active RA despite MTX therapy , approximately 0.5 ± 0.4 μg / mL in patients with active AP, and approximately 0.8 ± 0.4 μg / mL in patients with AS. Golimumab mean steady state trough serum concentrations in patients with Axial SpA nr were similar to those observed in AS patients following subcutaneous administration of golimumab 50 mg every 4 weeks.
Patients with RA, AP, or SA who did not receive MTX co-administered had approximately 30% lower steady-state golimumab trough concentrations than those of patients who received golimumab with MTX. In a limited number of RA patients treated with golimumab subcutaneously for longer than 6 months, co-administration of MTX reduced the apparent clearance of golimumab by approximately 36%. However, population pharmacokinetic analyzes indicate that concomitant use of NSAIDs, oral corticosteroids, or sulfasalazine did not affect the apparent clearance of golimumab.
Following induction doses of 200 mg and 100 mg of golimumab at Week 0 and 2, respectively, and subsequently maintenance doses of 50 mg or 100 mg of golimumab subcutaneously every 4 weeks in UC patients, golimumab serum concentrations reached steady state approximately 14 weeks after initiation of therapy. Treatment with golimumab 50 mg or 100 mg subcutaneously every 4 weeks during maintenance resulted in a mean steady state trough serum concentration of approximately 0. , 9 ± 0.5 mcg / mL and 1.8 ± 1.1 mcg / mL, respectively.
In UC patients treated with golimumab 50 mg or 100 mg subcutaneously every 4 weeks, concomitant use of immunomodulators had no substantial effect on steady state golimumab trough levels.
Patients who developed anti-golimumab antibodies had broadly low steady state serum trough concentrations of golimumab (see section 5.1).
Linearity
Golimumab, in RA patients, exhibited approximately dose proportional pharmacokinetic parameters over the dose range of 0.1 - 10.0 mg / kg after a single intravenous dose. Following a single SC dose in healthy subjects Approximately dose proportional pharmacokinetic parameters were also observed over the dose range of 50 mg to 400 mg.
Effect of weight on pharmacokinetics
There is a trend towards higher golimumab apparent clearance with weight gain (see section 4.2).
Pediatric population
Golimumab pharmacokinetics were determined in 173 children with pJIA between the ages of 2 and 17 years. In the pJIA study, children treated with golimumab 30 mg / m2 (maximum 50 mg) subcutaneously every 4 weeks had median steady-state golimumab trough concentrations that were similar across age groups and were also similar or slightly higher than those seen in adult RA patients treated with golimumab 50 mg every 4 weeks.
Population pharmacokinetic / pharmacodynamic models and simulations in children with pJIA confirmed the relationship between golimumab serum exposures and clinical efficacy and support that golimumab 50 mg every 4 weeks dosing regimen in children with pJIA weighing at least 40 kg it allows to achieve exposures similar to those which have been shown to be effective in adults.
05.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, reproductive and developmental toxicity.
Mutagenicity, animal fertility, or long-term carcinogenicity studies have not been conducted with golimumab.
In a mouse fertility and general reproductive function study using a similar antibody that selectively inhibits the functional activity of murine TNF ?, the number of pregnant mice was reduced. It is not known whether these results were due to the effects. in males and / or females. In an evolutionary toxicity study conducted in mice after administration of the same analog antibody and in cynomolgus monkeys using golimumab, there was no indication of maternal toxicity, embryotoxicity or teratogenicity.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Sorbitol (E420)
L-histidine
L-histidine monohydrochloride monohydrate
Polysorbate 80
Water for injections.
06.2 Incompatibility
In the absence of compatibility studies, this medicinal product must not be mixed with other products.
06.3 Period of validity
22 months
06.4 Special precautions for storage
Store in a refrigerator (2 ° C - 8 ° C).
Do not freeze.
Keep the pre-filled pen or pre-filled syringe in the outer carton to protect from light.
06.5 Nature of the immediate packaging and contents of the package
Simponi 50 mg solution for injection in pre-filled pen
0.5 mL of solution in a pre-filled syringe (type 1 glass) with a fixed needle (stainless steel) and a needle cap (rubber containing latex), in a pre-filled pen. Simponi is available in packs containing 1 pre-filled pen and multipacks containing 3 (3 packs of 1) pre-filled pens.
Simponi 50 mg solution for injection in pre-filled syringe
0.5 mL of solution in a pre-filled syringe (type 1 glass) with a fixed needle (stainless steel) and a needle cap (rubber containing latex). Simponi is available in packs containing 1 pre-filled syringe and multipacks containing 3 (3 packs of 1) pre-filled syringes.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
Simponi is supplied in a single-use pre-filled pen called SmartJect or in a single-use pre-filled syringe. Each Simponi pack comes with instructions for use that fully describe how to use the pen or syringe. Once the pre-filled pen or pre-filled syringe has been removed from the refrigerator, it should be allowed to reach room temperature by waiting for 30 minutes before injecting Simponi. The pen or syringe should not be shaken.
The solution is clear to slightly opalescent, colorless to pale yellow and may contain some small translucent or white protein particles. This aspect is not unusual for solutions containing proteins.
Simponi must not be used if the solution has changed color, is cloudy or contains visible foreign particles.
Full instructions for preparing and administering Simponi in a pre-filled pen or pre-filled syringe are provided in the package leaflet.
Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
Janssen Biologics B.V.
Einsteinweg 101
2333 CB Leiden
Netherlands
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/09/546/001 1 pre-filled pen
EU / 1/09/546/002 3 pre-filled pens
EU / 1/09/546/003 1 pre-filled syringe
EU / 1/09/546/004 3 pre-filled syringes
039541014
039541026
039541038
039541040
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 1 October 2009
Date of most recent renewal: June 19, 2014
10.0 DATE OF REVISION OF THE TEXT
02 February 2017
11.0 FOR RADIO DRUGS, COMPLETE DATA ON THE INTERNAL RADIATION DOSIMETRY
12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON EXEMPORARY PREPARATION AND QUALITY CONTROL
