Active ingredients: Infliximab
Remicade 100 mg powder for concentrate for solution for infusion
Why is Remicade used? What is it for?
Remicade contains an active substance called infliximab. Infliximab is a protein of human and animal (from the mouse) origin.
Remicade 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
- Ankylosing spondylitis (Bechterew's disease)
- Psoriasis.
Remicade is also used in adults and children 6 years of age and older for:
- Crohn's disease
- Ulcerative colitis.
Remicade works by blocking the action of a protein called 'tumor necrosis factor alpha' (TNFα). 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 rheumatoid arthritis, you will initially be treated with other medicines. If you do not respond adequately to these medicines, you will be treated with Remicade in combination with another medicine called methotrexate for:
- Reduce the signs and symptoms of the disease,
- Slow down the progression of damage to the joints,
- Improve physical function.
Psoriatic arthritis
Psoriatic arthritis is an inflammatory joint disease, usually accompanied by psoriasis. If you have psoriatic arthritis, you will be treated with other medicines first. If you do not respond adequately to these medicines, you will be treated with Remicade to:
- Reduce the signs and symptoms of the disease,
- Slow down the progression of damage to the joints,
- Improve physical function.
Ankylosing spondylitis (Bechterew's disease)
Ankylosing spondylitis is an inflammatory disease of the spine. If you have ankylosing spondylitis, you will be treated with other medicines first. If you do not respond adequately to these medicines, you will be treated with Remicade to:
- Reduce the signs and symptoms of the disease,
- Improve physical function.
Psoriasis
Psoriasis is an inflammatory skin disease. If you have moderate to severe plaque psoriasis, you will be treated first with other medicines or other treatments, such as phototherapy. If you do not respond adequately to these medicines or treatments, you will be treated with Remicade to reduce the signs and symptoms of your disease.
Ulcerative colitis
Ulcerative colitis is an inflammatory bowel disease. If you have ulcerative colitis, you will be treated with other medicines first. If you do not respond adequately to these medicines, you will be given Remicade to treat the disease.
Crohn's disease
Crohn's disease is an inflammatory bowel disease. If you have Crohn's disease, you will be treated with other medicines first. If you do not respond adequately to these medicines, you will be treated with Remicade to: • Treat active Crohn's disease • Reduce the number of abnormal openings (fistulas) between the intestine and the skin, for which other medications or surgery have proved inadequate.
Contraindications When Remicade should not be used
You should not be given Remicade if:
- you are allergic to infliximab (active substance in Remicade) or any of the other ingredients of this medicine (listed in section 6)
- you are allergic (hypersensitive) to mouse proteins
- have tuberculosis (TB) or an "other serious infection such as pneumonia or sepsis
- have "heart failure that is moderate or severe.
Do not take Remicade if any of the above conditions apply to you. If you are not sure, talk to your doctor before you are given Remicade
Precautions for use What you need to know before taking Remicade
Talk to your doctor before you are given Remicade if you have:
Previously received Remicade
- Tell your doctor if you have had treatment with Remicade in the past and if you are restarting treatment with Remicade.
If you have stopped taking Remicade for more than 16 weeks, there is an increased risk of allergic reactions when you restart Remicade.
Infections
Tell your doctor if you have an "infection, even a very minor one, before you are given Remicade
- Tell your doctor before you are given Remicade if you have lived in or traveled to an "area where infections called histoplasmosis, coccidioidomycosis, or blastomycosis are common. These infections are caused by specific types of fungi that can affect the lungs or other parts of the body. body
- You can be more prone to infections when treated with Remicade. If you are 65 or older, you have a higher risk
- These infections can be serious and include tuberculosis, infections caused by viruses, fungi or bacteria, or other opportunistic infections and sepsis which can, in rare cases, be life-threatening.
Tell your doctor right away if you get any symptoms of infection while being treated with Remicade. Symptoms include, fever, cough, flu-like symptoms, feeling unwell, red or very hot skin, wounds or dental problems. Your doctor may recommend a temporary stop of Remicade.
Tuberculosis (TB)
- It is very important that you tell your doctor if you have ever had TB or if you have been in close contact with people who have had or have TB
- Your doctor will do tests to see if you have tuberculosis. A few cases of tuberculosis have been reported in patients treated with Remicade, on rare occasions even in patients who had been treated with medicines for TB. The doctor will record these tests on the Patient Alert Card
- If your doctor thinks you are at risk for tuberculosis, you may be treated with medicines for tuberculosis before you are given Remicade.
Tell your doctor right away if you notice any signs of tuberculosis while taking Remicade. The signs include persistent cough, weight loss, tired feeling, fever, night sweats.
Hepatitis B virus (HBV)
- Tell your doctor if you are a carrier or have or have had hepatitis B before you are given Remicade
- Tell your doctor if you think you may be at risk of contracting hepatitis B
- Should the doctor evaluate if you have hepatitis B? Treatment with TNF blockers such as Remicade can cause hepatitis B virus to reactivate in patients with this virus, which in some cases can cause death.
Heart problems
- Tell your doctor if you have any heart problems, such as mild heart failure
- Your doctor will monitor your heart function closely.
Tell your doctor immediately if you notice new or worsening signs of heart failure during treatment with Remicade. The signs include shortness of breath or swelling of the feet.
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 Remicade
- Patients with severe rheumatoid arthritis who have suffered from this disease for a long time may have a higher than average risk of developing lymphoma.
- Children and adults taking Remicade may have an increased risk of developing lymphoma or another type of cancer.
- Some patients who have been treated with TNF blockers, including Remicade have developed a rare type of cancer called Hepatosplenic T-Cell Lymphoma. Most of these patients were adolescents or young adult males and most had Crohn's or ulcerative colitis. This type of cancer is usually lethal. Almost all patients were also treated with medicines called azathioprine or 6-mercaptopurine in addition to TNF blockers.
- Some patients treated with infliximab 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.
Lung disease or heavy smoking
- Tell your doctor if you have a lung disease called chronic obstructive pulmonary disease (COPD) or if you are a heavy smoker before you are given Remicade
- Patients with COPD and who are heavy smokers may be at increased risk of cancer when treated with Remicade.
Nervous system disease
- Tell your doctor if you have or have ever had a nervous system problem before you are given Remicade. This includes multiple sclerosis, Guillain-Barré syndrome, attacks or a diagnosis of "optic neuritis".
Tell your doctor right away if you notice symptoms of a nerve disease while taking Remicade. The signs include changes in vision, weakness in the arms and legs, numbness or tingling in any part of the body.
Abnormal skin openings
- Tell your doctor if you have any abnormal skin openings (fistulas) before you are given Remicade.
Vaccinations
- Tell your doctor if you have recently been vaccinated or are planning to be vaccinated
- You must not receive any vaccines while being treated with Remicade
- Some vaccinations can cause infections. If you received Remicade 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 Remicade so that can decide when your child should receive any vaccines.
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).
Dental operations or procedures
- Tell your doctor if you are going to have any dental procedures or treatments
- Tell the surgeon or dentist performing the procedure that you are being treated with Remicade by showing the Patient Alert Card.
Children and adolescents
The above information also applies to children and adolescents. Furthermore:
- some children and adolescent patients who have taken TNF-blocking medicines, such as Remicade, have developed cancers, including unusual types, which have sometimes been fatal.
- Compared to adults, more children taking Remicade developed infections
- Children should receive recommended vaccinations before starting Remicade treatment.
If you are not sure if any of the above conditions apply to you, contact your doctor before you are given Remicade.
Interactions Which drugs or foods may change the effect of Remicade
Patients with inflammatory diseases are already taking medicines to treat the disease. These medicines can cause side effects. Your doctor will advise you which other medicines you should continue to take while you are being treated with Remicade.
Tell your doctor if you are taking or have recently taken any other medicines, including any other medicines to treat Crohn's disease, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis or psoriasis or medicines you get without a prescription, such as vitamins and herbal medicines.
In particular, tell your doctor if you are using any of these medicines:
- Medicines that affect the immune system
- Kineret (anakinra). Remicade and Kineret must not be administered together
- Orencia (abatacept). Remicade and Orencia must not be given together.
If you are not sure if any of the above conditions apply to you, contact your doctor before you are given Remicade.
Warnings It is important to know that:
Pregnancy, breastfeeding, and fertility
- If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine. Remicade is not recommended during pregnancy
- You must avoid becoming pregnant while being treated with Remicade and for at least 6 months after stopping treatment. Make sure you are using adequate contraception during this time.
- Do not breast-feed while being treated with Remicade or for 6 months after the last Remicade treatment
- If you received Remicade 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 Remicade before your baby receives any vaccines (for more information see section on vaccinations).
Driving and using machines
Remicade is unlikely to affect your ability to drive or use machines. If you feel tired or unwell after Remicade treatment, you should not drive or use any tools or machines.
Dose, Method and Time of Administration How to use Remicade: Posology
How Remicade is given
- Remicade will be given to you by your doctor or nurse
- Your doctor or nurse will prepare the Remicade solution for injection
- The Remicade solution will be injected slowly (over a 2 hour period) into a vein, usually in the arm. This procedure is called an "intravenous infusion" or drip. After the third treatment, your doctor may decide to give you Remicade over a 1 hour period
- You will be monitored during the administration of Remicade and for 1-2 hours thereafter.
How much Remicade is given
- Your doctor will work out the dose (in mg) and the interval between doses of Remicade. This will depend on your disease, weight and response to treatment.
- The table below shows the frequency of administration of this medicine.
Rheumatoid arthritis
The usual dose is 3 mg for every kg of body weight
Psoriatic arthritis, ankylosing spondylitis (Bechterew's disease), psoriasis, ulcerative colitis and Crohn's disease
The usual dose is 5 mg for every kg of body weight.
Use in children and adolescents
Remicade is only to be used in children for Crohn's disease or ulcerative colitis. These children must be 6 years of age or older.
Overdose What to do if you have taken too much Remicade
If you are given more Remicade than you need
As this medicine is given to you by your doctor or nurse, it is unlikely that you will get too much. There are no known side effects of overdosing Remicade.
If you forget or miss a "Remicade" infusion
If you forget or miss an appointment to administer Remicade, make another appointment as soon as possible.
If you have any further questions on the use of this medicine, ask your doctor
Side Effects What are the side effects of Remicade
Like all medicines, this medicine can cause side effects, although not everybody gets them. Most of these effects are mild to moderate. However, some patients may experience severe side effects and require medical treatment. Side effects may also occur after Remicade treatment has finished.
Tell your doctor right away if you notice any of the following side effects:
- Signs of an allergic reaction, such as swelling of the face, lips, mouth or throat which may cause difficulty in swallowing or breathing, rash, hives, swelling of the hands, feet or ankles. The allergic reaction may occur within 2 hours of the injection or later. Other signs of an allergic reaction that may occur up to 12 days after the injection include muscle aches, fever, joint or jaw pain, sore throat or sore throat. head
- Signs of a heart problem, such as shortness of breath, swelling of the feet or changes in heartbeat
- Signs of an infection (including tuberculosis), such as fever, feeling tired, cough (persistent), shortness of breath, flu-like symptoms, weight loss, night sweats, diarrhea, wounds, dental problems or burning while urinating
- Signs of a lung problem, such as cough, difficulty in breathing or tightness in the chest
- Signs of neurological problems (including eye problems), such as seizures, tingling or numbness in any part of the body, weakness in the arms or legs, changes in vision, such as double vision or other eye problems
- Signs of a liver problem, such as yellowing of the skin or eyes, dark brown urine or pain in the upper right side of the stomach, fever
- Signs of an immune system disorder, called lupus, such as joint pain or rash on cheeks or arms, sun-sensitive areas
- Signs of a decrease in the number of blood cells, such as persistent fever, bleeding or bruising more frequently or looking pale.
If you notice any of the symptoms described above, tell your doctor right away.
Very common side effects (affects more than 1 in 10 patients)
- Stomach pain, malaise
- Viral infections such as herpes or flu
- Upper respiratory tract infections such as sinusitis
- Headache
- Undesirable effect due to the infusion
- Ache.
Common side effects (affects 1 to 10 users in 100)
- Changes in liver function, increase in liver enzymes (seen in blood tests)
- Infections of the lungs or chest, such as bronchitis or pneumonia
- Breathing difficulties or pain when breathing, chest pain
- Bleeding in the stomach or intestines, diarrhea, indigestion, heartburn, constipation
- Urticaria-like rash, itchy rash or dry skin
- Problems with balance or feeling dizzy
- Fever, increased sweating
- Circulation problems, such as low or high blood pressure
- Bruising, flushing or nosebleed, hot, red skin (redness)
- Feeling tired or weak
- Bacterial infections such as generalized infection, abscess or infection of the deep layers of the skin (cellulitis)
- Blood problems such as anemia or low white blood cell count
- Enlarged lymph nodes
- Depression, sleep disturbances
- Eye problems, including red eyes and infections
- Rapid heartbeat (tachycardia) or palpitations
- Pain in joints, muscles or back
- Urinary tract infection
- Psoriasis, skin problems such as eczema and hair loss
- Reactions at the injection site such as pain, swelling, redness or itching
- Chills, accumulation of fluid under the skin causing swelling
- Numbness or tingling sensation.
Uncommon side effects (affects 1 to 10 users in 1,000)
- Poor blood supply, swelling of a vein
- Skin problems such as blistering, warts, abnormal discoloration or pigmentation of the skin or swollen lips
- Severe allergic reactions (e.g., anaphylaxis), immune system disorder called lupus, allergic reactions to foreign proteins
- Wounds that are slow to heal
- Swelling of the liver (hepatitis) or gallbladder (gallbladder), liver damage
- Distraction, irritability, confusion, nervousness
- Eye problems including blurred or reduced vision, swollen eyes or styes
- New or worsened heart failure, slow heart rate
- Fainting
- Convulsions, nervous disorders
- Bowel perforation or intestinal blockage, stomach pain or cramps
- Swelling of the pancreas (pancreatitis)
- Fungal infections such as yeast infection
- Lung problems (such as edema)
- Excessive fluid around the lungs (pleural effusion)
- Kidney infections
- Low platelet count, excessive number of white blood cells
- Infections of the vagina.
Rare side effects (affects 1 to 10 users in 10,000)
- A type of blood cancer (lymphoma)
- Poor supply of oxygen to organs through the blood, circulation problems such as narrowing of a blood vessel
- Inflammation of the membrane that lines the brain (meningitis)
- Infections due to a weakened immune system
- Hepatitis B infection, if you have had hepatitis B in the past? Swelling or growth of abnormal tissues
- Swelling of the small blood vessels (vasculitis)? Immunological disorders that can affect the lungs, skin and lymph nodes (such as sarcoidosis)
- Lack of interest or emotion
- Serious skin problems such as toxic epidermal necrolysis, Steven-Johnson syndrome or erythema multiforme, skin problems such as boils
- Serious nervous system disorders, such as transverse myelitis, multiple sclerosis-like disease, optic neuritis, and Guillain-Barré syndrome
- Fluid in the membrane that lines the heart (pericardial effusion)
- Severe lung problems (such as interstitial pneumonia)
- Melanoma (a type of skin cancer).
Other side effects (frequency is unknown)
- Cancer in children and adults
- A rare blood cancer that mainly affects young people (hepatosplenic T-cell lymphoma)
- Hepatic insufficiency
- Merkel cell carcinoma (a type of skin cancer)
- Worsening of a condition called dermatomyositis (looks like a "rash that accompanies muscle weakness).
Additional side effects in children and adolescents
Children who took Remicade for Crohn's disease showed some differences in side effects compared to adults who took Remicade for Crohn's disease.
The most common side effects in children were: low red blood cell count (anemia), blood in stool, low white blood cell count (leukopenia), flushing or redness (hot flashes), viral infections, low number of neutrophils (neutropenia) which are white blood cells that fight infection, bone fracture, bacterial infection, and respiratory tract allergic reactions.
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
Remicade will generally be stored by healthcare professionals. Should you need it, the retention details are as follows:
- 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).
- This medicine can also be stored in the original carton outside the refrigerator up to a maximum of 25 ° C for a single period of up to six months. In this situation, it should not be stored in the refrigerator again. Write the new expiration date on the box including day / month / year. Discard this medicine if not used by the new expiration date or by the expiration date printed on the carton, whichever comes first.
- When Remicade is prepared for infusion, it is recommended to use it as soon as possible (within 3 hours). However, if the solution is prepared under completely germ-free conditions, it can be stored in the refrigerator for 24 hours at between 2 ° C and 8 ° C.
- Do not use this medicine if it is discolored or has particles.
What Remicade contains
- The active ingredient is infliximab. Each vial contains 100 mg of infliximab. After preparation each ml contains 10 mg of infliximab.
- The other ingredients are sucrose, polysorbate 80, monobasic sodium phosphate and dibasic sodium phosphate.
What Remicade looks like and contents of the pack
Remicade is supplied in a glass vial containing the powder for concentrate for solution for infusion. The powder consists of freeze-dried white granules.
Remicade is available in packs of 1, 2, 3, 4 or 5 vials. Not all pack sizes can be marketed
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
REMICADE 100 MG POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each vial contains 100 mg of infliximab. Infliximab is a chimeric human-murine IgG1 monoclonal antibody produced in murine hybridoma cells by recombinant DNA technology. After reconstitution, each ml contains 10 mg of infliximab.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Powder for concentrate for solution for infusion.
The powder consists of freeze-dried white granules.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Rheumatoid arthritis
Remicade, in combination with methotrexate, is indicated for the reduction of signs and symptoms and the improvement of physical function in:
• adult patients with active disease when the response to disease-modifying anti-rheumatic drugs (DMARDs), including methotrexate, has been inadequate.
• adult patients with severe, active and progressive disease not previously treated with methotrexate or other DMARDs.
A reduction in the rate of progression of joint damage has been demonstrated by radiographic evaluation in this patient population (see section 5.1).
Crohn's disease in adults
Remicade is indicated for:
• the treatment of moderate to severe active Crohn's disease in adult patients who have failed to respond despite complete and adequate treatment with corticosteroids and / or immunosuppressants; or in patients who do not tolerate or have medical contraindications for the aforementioned therapies.
• the treatment of active fistulising Crohn's disease in adult patients who have not responded despite a complete and adequate course of therapy with conventional treatment (including antibiotics, drainage and immunosuppressive therapy).
Crohn's disease in children
Remicade is indicated for the treatment of severe active Crohn's disease, in children and adolescents aged 6-17 years who have failed to respond to conventional therapy with a corticosteroid, an immunomodulator and primary nutritional therapy, or in patients who do not tolerate or have contraindications for the aforementioned therapies. Remicade has only been studied in combination with conventional immunosuppressive therapy.
Ulcerative colitis
Remicade 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.
Pediatric ulcerative colitis
Remicade is indicated for the treatment of severe, active ulcerative colitis in children and adolescents 6 to 17 years of age who have not responded adequately to conventional therapy including corticosteroids and 6-MP or AZA, or who have intolerant or for which there is a medical contraindication to these therapies.
Ankylosing spondylitis
Remicade is indicated for the treatment of severe, active ankylosing spondylitis in adult patients who have not responded adequately to conventional therapies.
Psoriatic arthritis
Remicade is indicated for the treatment of active and progressive psoriatic arthritis in adult patients when the response to previous DMARD treatments has been inadequate.
Remicade should be given:
• in association with methotrexate
• or individually in patients who are intolerant to methotrexate or for whom it is contraindicated
Remicade has been shown to improve physical function in patients with psoriatic arthritis and to reduce the rate of progression of peripheral joint damage as measured by X-rays in patients with symmetrical polyarticular subtypes of the disease (see section 5.1).
Psoriasis
Remicade is indicated for the treatment of moderate to severe plaque psoriasis in adult patients who have failed or are contraindicated or who have been intolerant to other systemic treatments including cyclosporine, methotrexate or PUVA (see section 5.1 ).
04.2 Posology and method of administration
Remicade treatment should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of rheumatoid arthritis, inflammatory bowel disease, ankylosing spondylitis, psoriatic arthritis or psoriasis. Remicade must be administered intravenously. Remicade infusions should be administered by qualified healthcare professionals trained in recognizing any infusion-related issues. Patients treated with Remicade should be given the package leaflet and the Patient Alert Card.
During treatment with Remicade, the use of other concomitant therapies such as corticosteroids and immunosuppressants should be optimized.
Dosage
Adults (≥ 18 years old)
Rheumatoid arthritis
A 3 mg / kg intravenous infusion followed by additional 3 mg / kg infusions at weeks 2 and 6 after the first infusion, then every 8 weeks.
Remicade must be administered concomitantly with methotrexate.
Available data suggest that clinical response is usually achieved within 12 weeks of initiation of treatment. If a patient has an inadequate response or loses response after this period, a gradual increase in dosage of 1.5 mg may be considered. / kg, up to a maximum of 7.5 mg / kg, every 8 weeks. Alternatively, administration of 3 mg / kg every 4 weeks could be considered. If adequate response is achieved, treatment should continue. patients with the chosen dosage or frequency.Careful consideration should be given to whether to continue therapy in patients who show no evidence of therapeutic benefit within the first 12 weeks of treatment or after dose adjustment.
Moderate to severe active Crohn's disease
5 mg / kg administered as an intravenous infusion followed by an additional 5 mg / kg infusion 2 weeks after the first infusion. If a patient fails to respond to therapy after 2 doses, no further treatment with infliximab should be given. The available data do not support further treatment with infliximab in non-patients responders within 6 weeks of the first infusion.
In responding patients, alternative solutions for continued treatment are:
• Maintenance: supplemental infusion of 5 mg / kg at week 6 after the first dose, followed by repeated infusions every 8 weeks or
• Re-administration: an infusion of 5 mg / kg if signs and symptoms of the disease persist (see under “Re-administration” and section 4.4).
Although comparative data are lacking, limited data in patients who initially responded to 5 mg / kg therapy but lost response indicate that some patients may recover response by increasing the dose (see section 5.1). Continued therapy should be carefully reconsidered in patients who show no evidence of therapeutic benefit after dose adjustment.
Active fistulising Crohn's disease
5 mg / kg given as an intravenous infusion followed by additional 5 mg / kg infusions at week 2 and week 6 after the first infusion. If a patient fails to respond after 3 doses, no further treatment with infliximab should be given.
In responding patients, alternative solutions for continued treatment are:
• Maintenance: additional infusions of 5 mg / kg every 8 weeks or
• Re-administration: an infusion of 5 mg / kg if signs and symptoms of disease persist, followed by infusions of 5 mg / kg every 8 weeks (see under "Re-administration" and section 4.4).
Although comparative data are lacking, limited data in patients who initially responded to 5 mg / kg therapy but lost response indicate that some patients may recover response by increasing the dose (see section 5.1). Continued therapy should be carefully reconsidered in patients who show no evidence of therapeutic benefit after dose adjustment.
In Crohn's disease, the experience of re-administration, if signs and symptoms of disease persist, is limited and no comparative risk / benefit data of alternative solutions for continued treatment are available.
Ulcerative colitis
A 5 mg / kg intravenous infusion followed by additional 5 mg / kg infusions at weeks 2 and 6 after the first infusion, then repeated every 8 weeks.
Available data suggest that clinical response is usually achieved within 14 weeks of initiation of treatment, ie after three administrations. Careful consideration should be given to continuing therapy in patients who do not respond within this time period.
Ankylosing spondylitis
A 5 mg / kg intravenous infusion followed by additional 5 mg / kg infusions at weeks 2 and 6 after the first infusion, then repeated after 6 to 8 weeks. If a patient does not respond within 6 weeks (i.e. after 2 doses) they should not receive any further treatment with infliximab.
Psoriatic arthritis
A 5 mg / kg intravenous infusion followed by additional 5 mg / kg infusions at weeks 2 and 6 after the first infusion, then repeated every 8 weeks.
Psoriasis
A 5 mg / kg intravenous infusion followed by additional 5 mg / kg infusions at weeks 2 and 6 after the first infusion, then repeated every 8 weeks. If a patient does not respond within 14 weeks (i.e. after 4 doses), no further treatment of infliximab should be given.
Re-administration for Crohn's disease and rheumatoid arthritis
If signs and symptoms of the disease recur, Remicade can be re-administered within 16 weeks of the last infusion. In clinical studies, delayed hypersensitivity reactions were "uncommon" and occurred after intervals without Remicade administration. less than 1 year (see sections 4.4 and 4.8). The safety and efficacy of re-administration has not been established after more than 16 weeks without Remicade administration. This applies to both Crohn's disease patients and rheumatoid arthritis patients.
Re-administration for ulcerative colitis
The safety and efficacy of re-administrations at intervals other than 8 weeks have not been established (see sections 4.4 and 4.8).
Re-administration for ankylosing spondylitis
The safety and efficacy of re-administrations other than those given with an interval of 6 to 8 weeks have not been established (see sections 4.4 and 4.8).
Re-administration for psoriatic arthritis
The safety and efficacy of re-administrations at intervals other than 8 weeks have not been established (see sections 4.4 and 4.8).
Re-administration for psoriasis
A "limited experience in psoriasis resulting from re-treatment with a single dose of Remicade after an interval of 20 weeks suggests a" reduced efficacy and a "higher incidence of mild to moderate infusion reactions" when compared to the initial induction regimen. (see section 5.1).
A "limited experience from retreatment following disease worsening via a re-induction regimen suggests a" high incidence of infusion reactions, including severe ones, when compared to those at 8 weeks of maintenance treatment (see paragraph 4.8).
Re-administration in the different indications
In the event that maintenance therapy is discontinued and there is a need to restart treatment, the use of a re-induction regimen is not recommended (see section 4.8). In this situation, treatment with Remicade should be restarted as single dose followed by the maintenance dose as per the recommendations described above.
Elderly patients (≥ 65 years old)
No specific studies have been conducted with Remicade in elderly patients. No substantial age-related differences in clearance or volume of distribution were observed in clinical studies.
No dose adjustment is required (see section 5.2). For more information on the safety of Remicade in elderly patients see sections 4.4 and 4.8.
Impaired renal and / or hepatic function
Remicade has not been studied in these patient populations. No dose recommendation can be made (see section 5.2).
Pediatric population
Crohn's disease (6 - 17 years)
A 5 mg / kg dose administered by intravenous infusion followed by subsequent infusions of 5 mg / kg doses at 2 and 6 weeks after the first infusion and every 8 weeks thereafter. Available data do not support further treatment with infliximab in children and adolescents who are unresponsive within the first 10 weeks of treatment (see section 5.1).
Some patients may require a shorter dose interval to maintain clinical benefit, while for others a longer dose interval may be sufficient. Patients who have had the time interval between doses reduced to less than 8 weeks may be at increased risk of adverse reactions. Continued therapy with a shortened interval should be carefully considered in those patients who show no evidence of therapeutic benefit. after a change in the time interval between doses.
The safety and efficacy of Remicade in children with Crohn's disease under 6 years of age have not been studied. Currently available pharmacokinetic data are described in section 5.2 but no recommendation on a posology can be made in children less than 6 years of age.
Ulcerative colitis (6 - 17 years)
A 5 mg / kg dose administered by intravenous infusion followed by subsequent infusions of 5 mg / kg doses at 2 and 6 weeks after the first infusion and every 8 weeks thereafter. Available data do not support further treatment with infliximab in pediatric patients who are unresponsive within the first 8 weeks of treatment (see section 5.1).
The safety and efficacy of Remicade in children with ulcerative colitis below 6 years of age have not been studied. Currently available pharmacokinetic data are described in section 5.2 but no recommendation on a posology can be made in children less than 6 years of age.
Psoriasis
The safety and efficacy of Remicade in children and adolescents under 18 years of age in the indication psoriasis have not been established. Currently available data are described in section 5.2 but no recommendation on a posology can be made. .
Juvenile idiopathic arthritis, psoriatic arthritis and ankylosing spondylitis
The safety and efficacy of Remicade in children and adolescents under 18 years of age in the indications juvenile idiopathic arthritis, psoriatic arthritis and ankylosing spondylitis have not been established. Currently available data are described in section 5.2 but no recommendation on a posology can be made.
Juvenile rheumatoid arthritis
The safety and efficacy of Remicade in children and adolescents under 18 years of age in the juvenile rheumatoid arthritis indication have not been established. Currently available data are described in sections 4.8 and 5.2 but no can be done. recommendation on posology.
Impaired renal and / or hepatic function
Remicade has not been studied in these patient populations. No dose recommendation can be made (see section 5.2).
Method of administration
Remicade should be administered intravenously over a 2 hour period. All patients treated with Remicade should be observed for at least 1-2 hours after the infusion for acute infusion-related reactions. Emergency equipment such as adrenaline, antihistamines, corticosteroids and an artificial respirator should be kept available. Patients can be pretreated with, for example, an antihistamine, hydrocortisone and / or paracetamol and the infusion rate can be slowed to reduce the risk of infusion-related reactions, especially if infusion-related reactions have occurred previously (see section 4.4).
Infusions abbreviated in adult indications
In carefully selected adult patients who have tolerated at least 3 initial 2-hour Remicade infusions (induction phase) and who are receiving maintenance therapy, administration of subsequent infusions over a period of no less than 1 hour If an infusion reaction associated with the shortened infusion occurs, a slower infusion rate may be considered for future infusions, should treatment continue. Abbreviated infusions at doses> 6 mg / kg have not been studied (see section 4.8).
For instructions on preparation and administration, see section 6.6.
04.3 Contraindications
Patients with a history of hypersensitivity to infliximab (see section 4.8), to other murine proteins, or to any of the excipients listed in section 6.1.
Patients with tuberculosis or other serious infections such as sepsis, abscesses, and opportunistic infections (see section 4.4).
Patients with moderate to severe heart failure (NYHA - New York Heart Association - Class III / IV) (see sections 4.4 and 4.8).
04.4 Special warnings and appropriate precautions for use
In order to improve the traceability of biological medicinal products, the trademark and batch number of the administered product should be clearly recorded (or marked) in the patient record.
Infusion reactions and hypersensitivity
Infliximab has been associated with acute infusion-related reactions including anaphylactic shock and delayed hypersensitivity reactions (see section 4.8).
Acute infusion reactions including anaphylactic reactions may occur during (within seconds) or within hours following the infusion. If acute reactions to the infusion occur, the infusion must be stopped immediately. Emergency equipment such as adrenaline, antihistamines, corticosteroids and an artificial ventilator should be kept available. Patients can be pretreated, eg, with an antihistamine, hydrocortisone and / or paracetamol to prevent mild and transient effects.
Antibodies to infliximab may develop and have been associated with an increased frequency of infusion reactions. A low rate of infusion reactions were severe allergic reactions. An association was also observed between the development of antibodies to infliximab and a decreased response. Concomitant administration of immunomodulators was associated with a lower incidence of antibodies to infliximab and a reduction in the frequency of infusion reactions. The effect of concomitant immunomodulatory therapy was more intense in episodically treated patients than in patients receiving maintenance therapy. . Patients who have discontinued immunosuppressant therapy before or during treatment with Remicade have an increased risk of developing these antibodies. Antibodies to infliximab cannot always be detected in serum samples. If severe reactions occur, symptomatic treatment should be given and further Remicade infusions should not be given (see section 4.8.).
Delayed hypersensitivity reactions have been reported in clinical studies. Available data suggest an increased risk of delayed hypersensitivity to increasing the length of time intervals without Remicade administration. Patients should be advised to contact their physician immediately in the event of a delayed adverse event (see section 4.8). If patients are retreated after a prolonged period, they should be closely monitored for signs and symptoms of delayed hypersensitivity.
Infections
Patients should be monitored closely for infections including tuberculosis before, during and after Remicade treatment. As the elimination of infliximab may take up to six months, monitoring should continue during this period. Further treatment with Remicade should not be given if a patient develops severe infections or sepsis.
Caution is required when using Remicade in patients with chronic infection or a history of recurrent infections, including concomitant therapy with immunosuppressants. Patients should be appropriately advised of the need to avoid exposure to potential risk factors for infections.
Tumor necrosis factor alpha (TNFα) mediates inflammation and modulates cellular immune responses. Experimental data demonstrate that TNFα is essential for the resolution of intracellular infections. Clinical experience shows that host immune defenses are compromised in some patients treated with infliximab.
It should be noted that TNFα suppression may mask the symptoms of an infection such as fever. Early recognition of atypical clinical manifestations of severe infections and clinical manifestations typical of rare and unusual infections is critical to minimize delays in diagnosis and treatment.
Patients taking TNF-blocking drugs are more prone to serious infections.
Tuberculosis, bacterial infections, including sepsis and pneumonia, invasive fungal, viral and other opportunistic infections have been observed in patients treated with infliximab. Some of these infections have been fatal; the most frequently reported opportunistic infections with a mortality rate> 5% include penumocystosis, candidiasis, listeriosis and aspergillosis.
Patients who develop a new infection while being treated with Remicade should be carefully monitored and undergo a thorough diagnostic evaluation. Administration of Remicade should be discontinued if a patient develops a new serious infection or sepsis and appropriate antimicrobial or antifungal therapy initiated until the infection is resolved.
Tuberculosis
Cases of active tuberculosis have been reported in patients treated with Remicade. It should be noted that in the majority of these cases, it was extrapulmonary tuberculosis, both localized and diffuse.
Before starting treatment with Remicade, 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 test and chest radiography 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, Remicade 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 Remicade therapy must be carefully considered.
If inactive ("latent") tuberculosis is diagnosed, anti-tuberculosis therapy for latent tuberculosis should be started before initiating therapy with Remicade 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 Remicade.
The use of anti-tuberculosis therapy should also be considered prior to initiation of Remicade therapy in patients with a previous history of latent or active tuberculosis for whom an adequate course of treatment cannot be confirmed.
Some cases of active tuberculosis have been reported in patients treated with Remicade during and after treatment for latent tuberculosis.
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 Remicade treatment.
Invasive fungal infections
An invasive fungal infection such as aspergillosis, candidiasis, pneumocystosis, histoplasmosis, coccidioidomycosis or blastomycosis, should be suspected in patients treated with Remicade if they develop severe systemic disease and a physician competent in diagnosing and treating invasive fungal infections should be consulted at an early stage when visiting these patients. Invasive fungal infections may present as disseminated rather than localized disease, and antigen and antibody tests may be negative in some patients with active infection. Appropriate empirical antifungal therapy should be considered in the diagnostic process, taking into account both the risk of a severe fungal infection and the risks of antifungal therapy.
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 Remicade treatment should be carefully considered before initiating Remicade therapy.
Fistulising Crohn's disease
Patients with fistulising Crohn's disease with acute suppurative fistulas should not initiate therapy with Remicade until a source of possible infection, particularly abscesses, has been excluded (see section 4.3).
Reactivation of hepatitis B (HBV)
Reactivation of hepatitis B has been observed in patients treated with a TNF-antagonist, including infliximab and who were chronic carriers of this virus. In some cases, fatal outcomes have occurred.
Patients should be evaluated for HBV infection before starting treatment with Remicade. For patients who test positive for HBV infection, consultation with a physician experienced in the treatment of hepatitis B is recommended.
HBV carriers requiring Remicade treatment should be closely monitored for signs and symptoms of active HBV infection throughout the duration of therapy and for several months after the end of therapy. Insufficient data are available on HBV patients. treated with antiviral therapy in combination with TNF-antagonist therapy to prevent HBV reactivation In patients who develop HBV reactivation, Remicade treatment should be discontinued and effective antiviral therapy with appropriate supportive treatment initiated.
Hepatobiliary events
During the marketing period of Remicade, very rare cases of jaundice and non-infectious hepatitis, some with features of autoimmune hepatitis, have been observed. There have been isolated cases of liver failure resulting in liver transplantation or death. In patients with signs and symptoms of hepatic dysfunction, the level of liver damage should be assessed. If jaundice and / or ALT elevations ≥ 5 times the upper limit of normal develop, Remicade treatment should be discontinued and a thorough examination of the abnormal conditions undertaken.
Association of a TNF-alpha inhibitor and anakinra
Serious infections and neutropenia occurred in combination clinical trials of anakinra and another TNFα inhibitor, with no additional clinical benefit over the use of etanercept alone. Given the nature of the adverse events observed with the combination of etanercept and anakinra, Similar toxicities may occur with the combination of anakinra and other TNFα inhibitors. Therefore, the combination of Remicade and anakinra is not recommended.
Association of a TNF-alpha inhibitor and abatacept
In clinical trials, 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. Remicade and abatacept is not recommended.
Association with other biological therapies
There is insufficient information regarding the concomitant use of infliximab with other biological therapies used to treat the same conditions as infliximab. Concomitant use of infliximab 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 switching from one biologic to another, as overlapping biologic activity may further increase the risk of adverse events, including infection.
Live vaccines / infectious therapeutic agents
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 can lead to clinical infections, including disseminated infections. . Co-administration of live vaccines with Remicade is not recommended.
In infants exposed in utero to infliximab, a fatal outcome due to disseminated Calmette-Guérin bacillus (BCG) infection has been reported following administration of BCG vaccine after birth. Before administering live vaccines to exposed infants in utero a waiting period of at least six months after birth is recommended for infliximab (see section 4.6).
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 Remicade.
Autoimmune reactions
The relative deficiency of TNFα caused by anti-TNF therapy can lead to the initiation of an autoimmune process. If a patient has symptoms predictive of a lupus-like syndrome following treatment with Remicade and is positive for anti-DNA antibodies to double helix, further treatment with Remicade should not be given (see section 4.8).
Effects on the nervous system
The use of TNF-blocking agents, including infliximab, has been associated with onset or exacerbation of clinical symptoms and / or radiographic evidence of central nervous system demyelinating disorders, including multiple sclerosis, and peripheral demyelinating disorders, including Guillain-Barré syndrome In patients with pre-existing or recent demyelinating disorders, the benefits and risks of anti-TNF treatment should be carefully considered before initiating therapy with Remicade.
Discontinuation of Remicade therapy should be considered if these conditions develop.
Malignant neoplasms and lymphoproliferative diseases
In controlled phases of clinical trials with TNF inhibitors, more cases of malignancies including lymphoma were observed among patients who received a TNF inhibitor than in control patients. During clinical trials with Remicade, in all approved indications, the incidence of lymphoma in patients treated with Remicade was higher than expected in the general population, but the frequency of lymphoma was rare. In post-marketing experience, Cases of leukemia have been reported in patients treated with a TNF antagonist. There is an increased background risk of developing lymphoma and leukemia in rheumatoid arthritis patients with a very active and longstanding inflammatory disease that complicates risk assessment.
In an exploratory clinical trial evaluating the use of Remicade in patients with moderate to severe chronic obstructive pulmonary disease (Chronic Obstructive Pulmonary Disease, COPD), more cases of malignancies were reported in patients treated with Remicade than in control patients. All patients were heavy smokers. Care should be taken in evaluating the treatment of patients at increased risk of malignancy as heavy smokers.
Based on current knowledge, the risk of developing lymphoma or malignancy in patients treated with a TNF inhibitor cannot be excluded (see section 4.8). Care should be taken when considering TNF inhibitor therapy in patients with a history of malignancy or when considering prolonged treatment in patients who develop malignancy.
Caution should also be exercised in patients with psoriasis who have been treated extensively previously with immunosuppressants or for prolonged periods with PUVA.
In post-marketing experience, malignancies, some fatal, have been reported among children, adolescents and young adults (up to 22 years) treated with TNF-blocking drugs (initiation of therapy ≤ 18 years of age), including Remicade. Approximately half of the cases were lymphomas. The other cases were a variety of different malignancies and included rare malignancies usually associated with immunosuppression. A risk for the development of malignancies in patients treated with TNF inhibitors cannot be excluded.
Post-marketing rare cases of hepatosplenic T-cell lymphoma (HSTCL) have been reported in patients treated with TNF-blocking agents, including infliximab. This rare form of T-cell lymphoma has an extremely aggressive course and outcome. usually fatal. Almost all patients had received treatment with AZA or 6-MP concurrently with or immediately prior to a TNF blocker. The vast majority of cases with Remicade occurred in patients with Crohn's disease or ulcerative colitis and Most cases have been reported in adolescents or young male adults. The potential risk of the combination of AZA or 6-MP and Remicade must be carefully considered. A risk of developing hepatosplenic T-cell lymphoma in patients treated with Remicade cannot be excluded (see section 4.8).
Melanoma and Merkel cell carcinoma have been reported in patients receiving therapy with a TNF blocker, including Remicade (see section 4.8). Periodic skin examination is recommended, particularly for patients with risk factors for skin cancer.
A retrospective cohort study based on data from Swedish national health registers found an increased incidence of cervical cancer in women with rheumatoid arthritis treated with infliximab compared to biologically untreated patients or the general population, including those over 60 years of age Periodic screening should continue in women treated with Remicade, including those over 60 years of age.
All patients with ulcerative colitis who have an increased risk of developing colon dysplasia or carcinoma (for example, patients with long-standing ulcerative colitis or primary sclerosing cholangitis) or who have a medical history of dysplasia or colon cancer should be investigated. in relation to this dysplasia at regular intervals, before starting therapy and during the course of the disease. This evaluation should include a colonoscopy and biopsies according to local guidelines. In light of current data it is not known whether infliximab treatment affects the risk of developing dysplasia or colon cancer (see section 4.8).
Since the possibility of an increased risk of developing cancer in patients treated with Remicade with newly diagnosed dysplasia has not been established, it is necessary to evaluate the benefit / risk ratio in the individual patients and consider discontinuing therapy.
Heart failure
Remicade should be used with caution in patients with mild heart failure (NYHA class I / II). Patients should be closely monitored and treatment with Remicade should be discontinued in patients with new or worsening symptoms of heart failure (see sections 4.3 and 4.8).
Hematological reactions
Cases of pancytopenia, leukopenia, neutropenia and thrombocytopenia have been reported in patients receiving anti-TNF drugs, including Remicade. 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 Remicade therapy should be considered in patients with confirmed significant haematological abnormalities.
Others
There is limited experience with the safety of Remicade treatment in patients who have undergone surgery, including arthroplasty. The long elimination half-life of infliximab should be considered when planning surgery. A patient requiring surgery while on Remicade treatment should be closely monitored for an increased risk of infections and appropriate measures should be considered.
Failure to respond to treatment for Crohn's disease may indicate the presence of rigid fibrotic strictures that may require surgical treatment. There is no clinical evidence to suggest that infliximab worsens or causes fibrotic strictures.
Special populations
Elderly patients (≥ 65 years old)
The incidence of serious infections in patients aged 65 and over treated with Remicade was higher than in patients under the age of 65. Some of these were fatal. Particular attention should be paid to the risk of infection when treating the elderly (see section 4.8).
Pediatric population
Infections
In clinical studies, infections were reported more frequently in pediatric than in adult populations (see section 4.8).
Vaccinations
It is recommended that pediatric patients, if possible, have all vaccinations in accordance with the latest guidelines prior to initiating Remicade therapy.
Malignant neoplasms and lymphoproliferative disorders
In post-marketing experience, malignancies, some fatal, have been reported among children, adolescents and young adults (up to 22 years) treated with TNF-blocking drugs (initiation of therapy ≤ 18 years of age), including Remicade. Approximately half of the cases were lymphomas. The other cases were 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.
Rare cases of hepatosplenic T-cell lymphoma have been reported post-marketing in patients treated with TNF-blocking agents, including infliximab. This rare form of T-cell lymphoma has an extremely aggressive course and usually fatal outcome. Almost all patients had received treatment with AZA or 6-MP concurrently with or immediately prior to a TNF blocker. The vast majority of cases with Remicade occurred in patients with Crohn's disease or ulcerative colitis and most cases have been reported in adolescents or young male adults. The potential risk of the combination of AZA or 6-MP and Remicade must be carefully considered. A risk of developing hepatosplenic T-cell lymphoma in patients treated with Remicade cannot be excluded (see section 4.8).
04.5 Interactions with other medicinal products and other forms of interaction
No interaction studies have been performed.
There are indications that concomitant use of methotrexate and other immunomodulators in patients with rheumatoid arthritis, psoriatic arthritis and Crohn's disease reduces the formation of antibodies against infliximab and increases plasma concentrations of infliximab. However, the results are uncertain due to the limitations of the methods used for the assay of infliximab and the antibodies to infliximab in serum.
Corticosteroids do not appear to alter the pharmacokinetics of infliximab in a clinically relevant way.
The combination of Remicade with other biological therapies used to treat the same conditions as Remicade, including anakinra and abatacept, is not recommended (see section 4.4).
It is recommended that live vaccines not be given at the same time as Remicade. It is also recommended that live vaccines are not given to infants after exposure in utero to infliximab for at least 6 months after birth (see section 4.4).
Infectious therapeutic agents should not be administered concomitantly with Remicade (see section 4.4).
04.6 Pregnancy and lactation
Women of childbearing age
Women of childbearing potential should use adequate contraception during treatment with Remicade and continue its use for at least 6 months after the last dose.
Pregnancy
A moderate number of prospectively collected data on pregnant patients (approximately 450) treated with infliximab with known outcomes, including a limited number (approximately 230) of pregnancies treated during the first trimester, showed no unexpected effects on outcome. Due to inhibition of TNFα, infliximab administered during pregnancy may alter the normal immune responses of the newborn. Neither maternal toxicity, embryotoxicity, nor teratogenicity was found in a mouse developmental toxicity study using a similar antibody that selectively inhibits TNFα functionality (see section 5.3).
The available clinical experience is too limited to exclude risks and the administration of infliximab is therefore not recommended during pregnancy.
Infliximab passes through the placenta and has been detected in the serum of infants for up to 6 months after birth. After the exposure in utero to infliximab, infants may have a higher risk of infection, including a "severe disseminated infection that can have a fatal outcome. The administration of live vaccines (eg BCG vaccine) to exposed infants in utero infliximab is not recommended for at least 6 months after birth (see sections 4.4 and 4.5). Cases of agranulocytosis have also been reported (see section 4.8).
Feeding time
It is not known whether infliximab is excreted in breast milk or absorbed systemically after ingestion. Since human immunoglobulins are excreted in breast milk, women should not breastfeed for at least 6 months after treatment with Remicade.
Fertility
Insufficient preclinical data are available to draw conclusions on the effects of infliximab on fertility and overall reproductive function (see section 5.3).
04.7 Effects on ability to drive and use machines
Remicade has minor effects on the ability to drive or use machines. Dizziness may occur following administration of Remicade (see section 4.8).
04.8 Undesirable effects
Summary of the safety profile
Upper respiratory tract infection was the most common adverse reaction (ADR) reported in clinical trials, occurring in 25.3% of infliximab-treated patients versus 16.5% of control patients. "Use of TNF inhibitors reported for Remicade include HBV reactivation, congestive heart failure (CHF), severe infections (including sepsis, opportunistic infections and TB), serum sickness (delayed hypersensitivity reactions), haematological reactions, lupus systemic erythematosus / lupus-like syndrome, demyelinating disease, hepatobiliary events, lymphoma, HSTCL, leukemia, Merkel cell carcinoma, melanoma, pediatric malignancy, sarcoidosis / sarcoid-type reaction, intestinal or perianal abscess (in Crohn's disease) and severe infusion reactions (see section 4.4).
Table of adverse reactions
Table 1 lists ADRs reported in clinical trials, as well as adverse reactions, some with fatal outcome, reported post-marketing. Within the System Organ Class, adverse reactions are listed by frequency using the following categories: very common (≥ 1/10); common (≥ 1/100 to
Table 1
Undesirable effects in clinical trials and after marketing
* including bovine tuberculosis (disseminated BCG infection), see section 4.4
Infusion related reactions
In clinical studies, an infusion-related reaction was defined as any adverse event occurring during an infusion or within 1 hour after the infusion. In phase III clinical studies, 18% of patients treated with infliximab compared to 5% of patients treated with placebo had an infusion-related reaction. Overall, a higher proportion of patients who received infliximab monotherapy experienced an infusion-related reaction than patients who received concomitant infliximab with immunomodulators. Approximately 3% of patients discontinued treatment at due to infusion-related reactions and all patients recovered with or without medical therapy.
Of the infliximab-treated patients who had an infusion reaction during the induction period through week 6, 27% experienced an infusion reaction during the maintenance period between week 7 and week 54. Of patients who did not have an infusion reaction during the induction period, 9% experienced an infusion reaction during the maintenance period.
In a clinical study in patients with rheumatoid arthritis (ASPIRE), infusions were administered over 2 hours for the first 3 infusions. The duration of subsequent infusions could be shortened to no less than 40 minutes in patients who did not experience any reactions. severe to the infusion. In this study, sixty-six percent of patients (686 out of 1040) received at least one shortened infusion lasting 90 minutes or less and 44% of patients (454 out of 1040) received at least one shortened infusion lasting 60 minutes or less. In infliximab-treated patients who received at least one shortened infusion, infusion-related reactions occurred in 15% of patients and severe infusion reactions occurred in 0.4% of patients.
In a clinical study in patients with Crohn's disease (SONIC), infusion-related reactions were seen in 16.6% (27/163) of patients receiving infliximab monotherapy, in 5% (9/179) of patients receiving infliximab monotherapy. patients receiving infliximab in combination with AZA and in 5.6% (9/161) of patients receiving AZA monotherapy. A severe infusion reaction (
In the post-marketing period, cases of anaphylactoid reactions, including laryngeal / pharyngeal edema, severe bronchospasm and seizures, have been associated with Remicade administration.
In addition, there have also been rare reports of transient loss of vision and myocardial ischaemia / myocardial infarction occurring during or within two hours of the Remicade infusion (see section 4.4).
Infusion reactions following re-administration of Remicade
A clinical study was designed in patients with moderate to severe psoriasis to evaluate the efficacy and safety of long-term maintenance therapy, compared with retreatment with a Remicade induction regimen (maximum of four infusions at 0, 2, 6 and 14 weeks) following disease worsening. Patients received no concomitant immunosuppressive therapy. In the retreatment arm, 4% (8/219) of patients experienced severe infusion reactions towards facial edema and hypotension. In all cases, Remicade treatment was stopped and / or another treatment was adopted with complete resolution of signs and symptoms.
Delayed hypersensitivity
In clinical studies, delayed hypersensitivity reactions were uncommon and occurred after Remicade-free time intervals of less than 1 year. In psoriasis studies, delayed hypersensitivity reactions occurred early during treatment. Signs and symptoms included myalgia and / or arthralgia with fever and / or rash, with some patients presenting with itching, facial, hand or lip edema, dysphagia, hives, sore throat and headache.
Insufficient data are available on the incidence of delayed hypersensitivity reactions after Remicade-free time intervals of more than 1 year, but limited data from clinical trials suggest an increased risk of delayed hypersensitivity to the increase. the duration of the time intervals without administration of Remicade (see section 4.4).
In a 1-year clinical study with repeated infusions in patients with Crohn's disease (ACCENT I study), the incidence of reactions resulting from the development of serum sickness-like reactions was 2.4%.
Immunogenicity
Patients who developed antibodies to infliximab were more likely to experience infusion-related reactions (approximately 2 to 3 times higher). Concomitant use of immunosuppressive agents appeared to reduce the frequency of infusion-related reactions.
In clinical trials in which single and multiple doses of infliximab were administered ranging from 1 to 20 mg / kg, antibodies to infliximab were found in 14% of patients receiving any immunosuppressive therapy, and in 24% of patients without immunosuppressive therapy. . 8% of rheumatoid arthritis patients treated repeatedly with the recommended dosage and methotrexate developed antibodies to infliximab. In psoriatic arthritis patients treated at 5 mg / kg with or without methotrexate, antibodies developed in 15% overall. patients (in 4% of patients receiving methotrexate and 26% of patients not receiving methotrexate at baseline). In patients with Crohn's disease receiving maintenance treatment, on average 3.3% of patients receiving immunosuppressants and 13.3% of patients not receiving immunosuppressants developed antibodies against infliximab. The incidence of antibodies was 2-3 times higher for patients treated episodically. Due to methodological limitations, a negative test did not rule out the presence of antibodies to infliximab. Some patients who developed high titers of antibodies to infliximab had reduced efficacy. In psoriasis patients treated with infliximab maintenance regimen, in the absence of concomitant treatment with immunomodulators, approximately 28% developed antibodies to infliximab (see section 4.4: "Infusion reactions and hypersensitivity").
Infections
Tuberculosis, bacterial infections, including sepsis and pneumonia, invasive fungal, viral and other opportunistic infections have been observed in patients receiving Remicade. Some of these have been fatal. The most frequently reported opportunistic infections with a mortality rate> 5% include pneumocystosis, candidiasis, listeriosis and aspergillosis (see section 4.4).
In clinical trials, 36% of infliximab-treated patients were treated for infections, compared with 25% of placebo-treated patients.
In rheumatoid arthritis clinical trials, the incidence of serious infections including pneumonia was higher in patients treated with infliximab and methotrexate than in those treated with methotrexate alone, especially at doses of 6 mg / kg or higher (see section 4.4). .
Among the spontaneous reports reported in the post-marketing period, infections are the most common serious adverse event. Some of the cases had a fatal outcome. Almost 50% of the reported deaths were associated with infection. Cases of tuberculosis have been reported. , sometimes fatal, including cases of miliary tuberculosis and extrapulmonary localization tuberculosis (see section 4.4).
Malignant neoplasms and lymphoproliferative diseases
In clinical trials performed with infliximab in which 5,780 patients, representing 5,494 patient-years, were treated, 5 cases of lymphomas and 26 cases of non-lymphoma malignancies were detected, compared with no cases of lymphoma and 1 case of non-lymphoma malignancy. observed in 1,600 placebo-treated patients representing 941 patient-years.
In long-term safety clinical studies of up to 5 years with infliximab, representing 6,234 patient-years (3,210 patients), 5 cases of lymphoma and 38 cases of non-lymphoma malignancies have been reported.
Cases of malignancies, including lymphoma, have also been reported during the post-marketing period (see section 4.4).
In an exploratory clinical study involving patients with moderate to severe COPD who were either smokers or former smokers, 157 adult patients were treated with Remicade at similar doses to those used in rheumatoid arthritis and Crohn's disease. Nine of these patients developed malignancies, including 1 lymphoma. The median duration of a follow-up was 0.8 years (incidence 5.7% [95% CI 2.65% - 10.6%]. One case of malignancy was reported among the 77 patients in the control (median duration of follow-up 0.8 years; incidence 1.3% [95% CI 0.03% - 7.0%]). The majority of these malignancies involved lung, head or neck.
A population-based retrospective cohort study found an increased incidence of cervical cancer in infliximab-treated women with rheumatoid arthritis compared with biologically untreated patients or the general population, including those over 60 years of age ( see section 4.4).
In addition, rare cases of hepatosplenic T-cell lymphoma have been reported post-marketing in patients treated with Remicade, the vast majority of cases occurred in patients with Crohn's disease and ulcerative colitis, most patients were adolescents or young male adults (see section 4.4).
Heart failure
In a phase II study aiming to evaluate Remicade in Congestive Heart Failure (CHF), a higher incidence of mortality due to worsening of heart failure was found in patients treated with Remicade, particularly in those treated. with the highest dose of 10 mg / kg (i.e. double the maximum approved dose). In this study, 150 patients with NYHA class III and IV CHF (left ventricular ejection fraction ≤ 35%), were treated with 3 infusions of Remicade 5 mg / kg, 10 mg / kg, or placebo over a period of 6 weeks. At 38 weeks, 9 of the 101 patients treated with Remicade (2 to 5 mg / kg and 7 to 10 mg / kg) died while there was one death among the 49 patients treated with placebo.
Cases of worsening heart failure, with and without identifiable triggers, have been reported during the post-marketing period in patients treated with Remicade. New onset heart failure, including heart failure, has also been reported during the post-marketing period. in patients with no known pre-existing cardiovascular disease Some of these patients were under the age of 50.
Hepatobiliary events
In clinical studies, mild or moderate elevations in ALT and AST have been observed in patients receiving Remicade without progressing to severe hepatic injury. Elevations of ALT ≥ 5 x Above Normal Limits (ULN) were observed (see Table 2). Aminotransferase elevations (more common in ALT than AST) were observed in a greater proportion of patients receiving Remicade than in control groups, both when Remicade was given alone and when given in combination with other immunosuppressive drugs. Most of the aminotransferase abnormalities were transient; however, prolonged increases occurred in a small number of patients. In general, patients who developed elevations in ALT and AST were asymptomatic and the abnormalities decreased or resolved either by continuing or discontinuing Remicade treatment or by changing concomitant therapy. Very rare cases of jaundice and hepatitis, some with features of autoimmune hepatitis, have been reported in patients receiving Remicade during the post-marketing surveillance period (see section 4.4).
Table 2
Number of patients with increased ALT activity in clinical trials
1 Patients in the placebo group received methotrexate while patients in the infliximab group received both infliximab and methotrexate.
2 Patients in the placebo group in the 2 Phase III Crohn's disease studies, ACCENT I and ACCENT II, received a starting dose of 5 mg / kg infliximab at study initiation and placebo in the maintenance phase. were randomized to the placebo maintenance group and subsequently switched to infliximab, they were included in the infliximab group in the ALT analysis. In the Phase IIIb study in Crohn's disease, SONIC, patients in the placebo arm received AZA 2.5 mg / kg / day as an active control, in addition to infliximab placebo infusions.
3 Number of patients evaluated for ALT.
4 Mean follow-up is based on treated patients.
Antinuclear antibodies (ANA) / double-stranded DNA antibodies (dsDNA)
About half of infliximab-treated patients in clinical trials who were ANA negative at baseline became ANA positive during the study, compared with about one-fifth of placebo-treated patients. Anti-dsDNA antibodies were recently detected in approximately 17% of infliximab-treated patients compared with 0% of placebo-treated patients. In the latest evaluation, 57% of patients treated with infliximab remained positive for anti-dsDNA antibodies. However, reports of similar lupus and lupus syndromes remain infrequent (see section 4.4).
Pediatric population
Juvenile rheumatoid arthritis patients
Remicade was studied in a clinical study involving 120 patients (age range: 4-17 years) with active juvenile rheumatoid arthritis regardless of methotrexate use. Patients were treated with infliximab 3 or 6 mg / kg as a 3-dose induction regimen (week 0, 2, 6 or week 14,16, 20 respectively) followed by maintenance therapy every 8 weeks, in combination with methotrexate.
Infusion reactions
Infusion reactions occurred in 35% of juvenile rheumatoid arthritis patients receiving 3 mg / kg compared with 17.5% of patients receiving 6 mg / kg. In the Remicade 3 mg / kg group, 4 of 60 patients experienced a severe infusion reaction and 3 patients reported a possible anaphylactic reaction (2 of which were included in severe infusion reactions). In the 6 mg / kg group, 2 of 57 patients experienced a severe infusion reaction. "infusion, one of which had a possible anaphylactic reaction (see section 4.4).
Immunogenicity
38% of patients receiving 3 mg / kg developed antibodies to infliximab compared with 12% of patients receiving 6 mg / kg. Antibody titers were significantly higher in the group receiving 3 mg / kg than in the group receiving 6 mg / kg.
Infections
Infections occurred in 68% (41/60) of children who received 3 mg / kg for 52 weeks, in 65% (37/57) of children who received 6 mg / kg of infliximab for 38 weeks, and in 47% ( 28/60) of children receiving placebo for 14 weeks (see section 4.4).
Pediatric patients with Crohn's disease
The following undesirable effects were reported more commonly in pediatric Crohn's disease patients included in the REACH study (see section 5.1) than in adult Crohn's disease patients: anemia (10.7%), blood in stool (9.7 %), leukopenia (8.7%), flushing with skin redness (8.7%), viral infections (7.8%), neutropenia (6.8%), bone fractures (6.8%), bacterial infections (5.8%) and allergic reactions involving the respiratory tract (5.8%). Other special considerations are outlined below.
Infusion related reactions
17.5% of randomized patients in the REACH study experienced 1 or more infusion reactions. No serious cases of infusion reactions were reported and 2 subjects in the REACH study developed non-serious anaphylactic reactions.
Immunogenicity
Antibodies to infliximab were detected in 3 (2.9%) of pediatric patients.
Infections
In the REACH study, infections were reported in 56.3% of randomized subjects treated with infliximab. Infections were reported more frequently in subjects who received infusions every 8 weeks than in those treated every 12 weeks (73.6% and 38.0% respectively), while serious infections were reported in 3 subjects in the group maintenance treatment every 8 weeks and in 4 subjects in the treated group every 12 weeks. The most commonly reported infections were upper respiratory tract infection and pharyngitis. Abscess was the most common of serious infections. 3 cases of pneumonia (1 severe) and 2 cases of herpes zoster (both non-serious) have been reported.
Pediatric patients with ulcerative colitis
Overall, adverse reactions reported in the study in pediatric patients with ulcerative colitis (C0168T72) were generally consistent with those reported in studies in adult patients with ulcerative colitis (ACT 1 and ACT 2). In study C0168T72, the most common adverse reactions were upper respiratory tract infection, pharyngitis, abdominal pain, fever, and headache. The most common adverse event was a worsening of ulcerative colitis, the incidence of which was higher in patients treated every 12 weeks than in those treated every 8 weeks.
Infusion related reactions
Overall, 8 (13.3%) of 60 treated patients reported one or more infusion reactions, with 4 of 22 patients (18.2%) in the every 8 week maintenance group and 3 of 23 patients (13, 0%) in the maintenance group treated every 12 weeks No serious infusion reactions were reported. All infusion reactions were mild or moderate in intensity.
Immunogenicity
Antibodies to infliximab were detected in 4 (7.7%) of patients through week 54.
Infections
Infections were reported in 31 (51.7%) of the 60 patients treated in study C0168T72 and 22 (36.7%) required oral or parenteral antimicrobial treatment. The proportion of patients with infections in study C0168T72 was similar to that in the pediatric Crohn's disease study (REACH) but higher than the proportion in the adult ulcerative colitis studies (ACT 1 and ACT 2). The overall incidence of infections in study C0168T72 was 13/22 (59%) in the maintenance group treated every 8 weeks and 14/23 (60.9%) in the maintenance group treated every 12 weeks. upper respiratory tract (7/60 [12%]) and pharyngitis (5/60 [8%]) were the most frequently reported respiratory system infections. Serious infections were reported in 12% (7/60) of all treated patients.
In this study, there were more patients in the 12 to 17 year age group than in the 6 to 11 year age group (45/60 [75.0%]) vs. 15/60 [25.0%] ). Although the number of patients in each subgroup was too small to make any firm conclusions regarding the "effect of age on safety related events," there was a higher proportion of patients with serious adverse events and treatment discontinuation caused by events. adverse in the younger age group compared to the older age group. Although the proportion of patients with infections was also higher in the younger age group, for severe infections, the proportions in the two groups were similar. The overall proportion of the adverse events and infusion reactions were similar between the 6 to 11 year and 12 to 17 year age groups.
Post-marketing experience
Spontaneous post-marketing reporting of serious adverse events in pediatric patients included malignancies including hepatosplenic T-cell lymphoma, transient liver enzyme abnormalities, lupus-like syndromes and autoantibody positive (see sections 4.4 and 4.8). .
Additional information on special populations
Elderly patients (≥ 65 years old)
In rheumatoid arthritis clinical trials, the incidence of serious infections was higher in patients treated with infliximab plus methotrexate aged 65 and over (11.3%) than in patients under 65 years of age (4, 6%). In patients treated with methotrexate alone, the incidence of serious infections was 5.2% in patients aged 65 and over compared to 2.7% in patients under 65 (see section 4.4).
Reporting of suspected adverse reactions
The reporting of suspected adverse reactions that occur after the authorization of the medicinal product is important, as it allows continuous monitoring of the benefit / risk ratio of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions to the Italian Medicines Agency. , website: www.agenziafarmaco.gov.it/it/responsabili.
04.9 Overdose
No cases of overdose have been reported. Single doses up to a maximum of 20 mg / kg were administered without toxic effects.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: tumor necrosis factor alpha (TNF-alpha) inhibitors.
ATC code: L04AB02.
Mechanism of action
Infliximab is a chimeric, human-murine, monoclonal antibody that binds with high affinity to both the soluble and transmembrane forms of TNFα, but not to lymphotoxin α (TNFβ).
Pharmacodynamic effects
Infliximab inhibits in vitro TNFα activity over a wide range of biological dosages. Infliximab prevented disease in transgenic mice that develop polyarthritis as a consequence of essential human TNFα expression, and when administered after disease onset, it allowed joint erosions to regress. In vivo, infliximab rapidly forms stable complexes with human TNFα, a process that leads to the loss of biological activity of TNFα.
High concentrations of TNFα were detected in the joints of patients with rheumatoid arthritis and related to the high activity of the disease. Treatment with infliximab resulted in a reduction in the infiltration of inflammatory cells in the inflamed areas of the joints and in the reduction of expression in rheumatoid arthritis. molecules mediating cell adhesion, chemotaxis and tissue degradation. After infliximab treatment, patients experienced reduced serum interleukin 6 (IL-6) and C-reactive protein (CRP) levels and elevated hemoglobin levels in RA patients with reduced hemoglobin levels compared to pre-treatment values. . In addition, peripheral blood lymphocytes did not show a significant decrease in the number and proliferative response to the test in vitro of mitogenic stimulation compared to the cells of untreated patients. In patients with psoriasis, treatment with infliximab resulted in decreased epidermal inflammation and normalization of keratinocyte differentiation into psoriatic plaques. In psoriatic arthritis, short-term treatment with Remicade reduced the number of T cells and blood vessels. in the synovium and psoriatic skin.
A histological evaluation of colon biopsies performed before and 4 weeks after infliximab administration revealed a substantial reduction in detectable TNFα. Infliximab treatment of patients with Crohn's disease was also associated with a substantial
decrease in serum concentration of CRP, a commonly elevated inflammatory marker. Total peripheral leukocyte counts were minimally affected in patients treated with infliximab, although changes in lymphocytes, monocytes and neutrophils reflected changes from normal values. Peripheral blood mononuclear cells (PBMCs) of patients treated with infliximab showed an unaffected proliferative response capacity to stimuli, compared to untreated patients; furthermore, following treatment with infliximab, no substantial changes were observed in the production of cytokines by the stimulated PBMC cells. Analysis of lamina propria mononuclear cells obtained following intestinal mucosal biopsy showed that infliximab treatment resulted in a reduction in the number of cells capable of expressing TNFα and interferon γ. Further histological studies have provided evidence that infliximab treatment reduces the infiltration of inflammatory cells into the involved areas of the intestine and the presence of markerEndoscopic studies of the intestinal mucosa have shown mucosal healing in patients treated with infliximab.
Clinical efficacy and safety
Arthritis rheumatoid in adults
The efficacy of infliximab was evaluated in two multicenter, randomized, double-blind pilot clinical trials: ATTRACT and ASPIRE. In both studies, concomitant use of stable doses of folic acid, oral corticosteroids (≤ 10 mg / die) and / or non-steroidal anti-inflammatory drugs (NSAIDs).
Primary endpoints were reduction of signs and symptoms as defined by the American College of Rheumatology criteria (ACR20 for ATTRACT, ACR-N indicator for ASPIRE), prevention of structural joint damage, and improvement in physical function.A reduction in signs and symptoms was defined as an improvement of at least 20% (ACR20) in the number of painful and swollen joints and in 3 of the following 5 criteria: Physician's Global Assessment, Patient Global Assessment, Functional Assessment / disability, pain visual analog scale, erythrocyte sedimentation rate or C-reactive protein. ACR-N uses the same criteria as ACR20, calculated considering the lowest percentage of improvement in the count of swollen joints, painful joints and the median of the remaining 5 components of the ACR response. joint) in both hands and feet, was measured by evaluating the change from baseline in van der Heijde's modified total Sharp score (0-440). The Health Assessment Questionnaire (HAQ; scale 0 to 3 ), was used to evaluate the mean change in physical function over time from baseline.
The ATTRACT study evaluated responses at weeks 30, 54 and 102 in a placebo-controlled study in 428 patients with active rheumatoid arthritis despite treatment with methotrexate. Approximately 50% of the patients were in functional class III. Patients were treated with placebo, 3 mg / kg or 10 mg / kg of infliximab at weeks 0, 2 and 6 and every 4 or 8 weeks thereafter. All patients took a stable dose of methotrexate (median of 15 mg / week) for 6 months prior to enrollment and remained on stable doses throughout the study.
Results at week 54 (ACR20, van der Heijde-modified total Sharp score and HAQ), are shown in Table 3. A higher incidence of clinical response (ACR50 and ACR70) was observed in all groups treated with infliximab at weeks 30 and 54 compared with methotrexate alone.
A reduction in the rate of progression of structural joint damage (erosion and joint gap reduction) was observed in all infliximab treated groups at 54 weeks (Table 3).
Effects observed at week 54 were maintained through week 102 of treatment. Due to the number of treatment interruptions, the extent of the difference in effect between the infliximab and methotrexate monotherapy groups could not be defined.
Table 3
Effects on ACR20, structural joint damage and physical function at week 54, ATTRACT
controlled = All patients had active RA despite treatment with stable doses of methotrexate for 6 months prior to enrollment and had to remain at stable doses during the study. Concomitant use of stable doses of oral corticosteroids (≤ 10 mg / day ) and / or a non-steroidal anti-inflammatory drug (NSAID) was permitted; a folate supplement was given.
b All doses of infliximab were administered concomitantly with methotrexate and folate and in some cases with corticosteroids and / or non-steroidal anti-inflammatory drugs (NSAIDs)
c p
d higher values indicate greater joint damage.
and HAQ = Health Assessment Questionnaire; higher values indicate a "lesser disability.
The ASPIRE study evaluated responses at week 54 in 1004 previously methotrexate-naive patients with active rheumatoid arthritis (median count of swollen and tender joints: 19 and 31, respectively) of recent onset (disease duration ≤ 3 years, median of 0.6 years). All patients received methotrexate (optimized to 20 mg / week by week 8) in combination with placebo or infliximab 3 mg / kg or 6 mg / kg at weeks 0, 2 and 6 and every 8 weeks thereafter. The results at week 54 are shown in Table 4.
After 54 weeks of treatment, both doses of infliximab + methotrexate gave statistically significant improvement in signs and symptoms greater than methotrexate alone, as measured by the proportion of patients achieving ACR 20, 50 and 70 responses.
In ASPIRE, more than 90% of patients had at least two evaluable radiographs. Reduction in the rate of progression of structural damage was observed at weeks 30 and 54 in the infliximab + methotrexate groups compared with methotrexate alone.
Table 4
Effects on ACRn, structural joint damage and physical function at week 54, ASPIRE
on p
b higher values indicate greater joint damage.
c health assessment questionnaire; higher values indicate a "lesser disability.
d p = 0.030 e
Data to support dose titration in rheumatoid arthritis come from the studies
ATTRACT, ASPIRE and START. START was a randomized, multicenter, double-blind, 3-arm, parallel group, safety study. In one of the study arms (group 2, n = 329), patients with an inadequate response were allowed dose titration in 1.5 mg / kg increments from 3 to 9 mg / kg. The majority (67%) of these patients did not require dose titration. Of the patients who required it, 80% achieved clinical response and the majority (64%) of these required only an increase of 1.5 mg / kg.
Crohn's disease in adults
Induction treatment in active, moderate to severe Crohn's disease The efficacy of a single dose of infliximab was evaluated in 108 patients with active Crohn's disease, which ranged in severity from moderate to severe (Crohn's disease activity index (CDAI) ≥ 220 ≤ 400) in a study randomized, double-blind, placebo-controlled dose response. Of the 108 patients, 27 were treated with the recommended dose of infliximab (5 mg / kg). All patients had inadequate response to previous conventional therapies Concomitant use of unchanged doses of conventional therapies was allowed and 92% of patients then continued to receive such therapies.
The primary endpoint was the calculation of the number of patients experiencing a clinical response, defined as a decrease in CDAI of ≥ 70 points from baseline, at week 4 and with no increase in the use of drugs or surgery for the disease. Crohn. Patients who responded at week 4 were followed up until week 12. Secondary endpoints included the number of patients in clinical remission at week 4 (CDAI
At week 4, following single dose administration, 22/27 (81%) patients treated with infliximab at a dose of 5 mg / kg had a clinical response compared with 4/25 (16%) patients treated with placebo (p
Maintenance treatment in active, moderate to severe Crohn's disease in adults
The efficacy of repeated infusions with infliximab was evaluated in a 1-year clinical study (ACCENT I). A total of 573 patients with moderate to severe active Crohn's disease (CDAI ≥ 220 ≤ 400) received a single infusion of 5 mg / kg at week 0. 178 of the 580 enrolled patients (30.7%) had severe disease (CDAI score> 300 and concomitant therapy with corticosteroids and / or immunosuppressants) corresponding to the population defined in the indications ( see section 4.1) At week 2, all patients were evaluated for clinical response and randomized into one of 3 treatment groups; a placebo maintenance group, a 5 mg / kg maintenance group and a maintenance with 10 mg / kg Then, all 3 groups received repeated infusions at week 2, 6 and every 8 weeks thereafter.
Of the 573 randomized patients, 335 (58%) achieved clinical response at week 2. These patients were classified as week 2 responders and included in the primary analysis (see Table 5). week 2, 32% (26/81) in the placebo maintenance group and 42% (68/163) in the infliximab maintenance group achieved clinical response at week 6. After that, there was no no difference between groups in the number of patients who subsequently responded to therapy.
The co-primary end points were the percentage of patients in clinical remission (CDAI
Table 5
Effects on speed of response and remission, data from ACCENT I (patients achieving response at week 2)
a Reduction in CDAI ≥ 25% and ≥ 70 points.
b CDAI
At the beginning of week 14, patients who had responded to treatment but subsequently lost their clinical benefit were switched to a dose of infliximab 5 mg / kg higher than the dose to which they were originally randomized. L "Eighty-nine percent (50/56) of patients who lost clinical response on infliximab 5 mg / kg maintenance therapy after week 14 responded to 10 mg / kg infliximab treatment.
At weeks 30 and 54, improvements in quality of life assessments, a reduction in disease-related hospitalizations, and corticosteroid use were observed in the infliximab maintenance groups compared to the placebo maintenance group.
Infliximab, with or without AZA, was evaluated in a randomized, double-blind, active comparator (SONIC) study of 508 adult patients with moderate to severe Crohn's disease (CDAI ≥ 220 ≤ 450) who had never been treated before. with biologics and immunosuppressants and with a median disease duration of 2.3 years. At baseline, 27.4% of patients were on systemic corticosteroids, 14.2% of patients on budesonide, and 54.3% of patients on 5-ASA compounds. Patients were randomized to receive AZA monotherapy, infliximab monotherapy, or infliximab plus AZA combination therapy. Infliximab was administered at a dose of 5 mg / kg at weeks 0, 2, 6 and every 8 weeks thereafter. AZA was administered at a daily dose of 2.5 mg / kg.
The primary endpoint of the study was corticosteroid-free clinical remission at week 26, defined as patients in clinical remission (CDAI prednisone or equivalent) or budesonide at dose> 6 mg / day. For results see Table 6. Proportions of patients with mucosal healing at Week 26 were significantly greater in the infliximab plus AZA combination groups (43.9%, p
Table 6
Percentage of patients achieving corticosteroid-free clinical remission at Week 26, SONIC
* P-values represent each infliximab treatment group versus AZA monotherapy
Similar patterns in the achievement of corticosteroid-free clinical remission were observed at Week 50. In addition, an improvement in quality of life was observed with infliximab as reported by the IBDQ questionnaire.
Induction treatment in active fistulising Crohn's disease
Efficacy was evaluated in a randomized, double-blind, placebo-controlled study in 94 patients with Crohn's disease who had had fistulas for at least 3 months. Thirty-one of these patients were treated with 5 mg / kg of infliximab. About 93% of patients had previously undergone antibiotic or immunosuppressive therapy.
Concomitant, unchanged dose use of conventional therapies was allowed and 83% of patients continued to receive at least one of these therapies. Patients received three doses of placebo or infliximab at weeks 0, 2 and 6. Follow-up of patients patients was 26 weeks. The primary endpoint was the number of patients experiencing a clinical response, defined as a ≥ 50% reduction from baseline in the number of purging fistulas after mild compression in at least two consecutive controls ( 4 weeks later), with no increase in drug use or surgery for Crohn's disease.
68% (21/31) of patients given infliximab at a dose of 5 mg / kg experienced a clinical response compared with 26% (8/31) of patients treated with placebo (p = 0.002). The mean time to response in the infliximab group was 2 weeks. The mean duration of response was 12 weeks. In addition, closure of all fistulas was seen in 55% of patients receiving infliximab, compared with 13% of patients receiving placebo (p = 0.001).
Maintenance treatment in active fistulising Crohn's disease
The efficacy of repeated infusions of infliximab in patients with fistulising Crohn's disease was evaluated in a 1-year study (ACCENT II). A total of 306 patients received 3 doses of 5 mg / kg infliximab at weeks 0, 2 and 6. At baseline, 87% of patients had perianal fistulas, 14% had abdominal fistulas, 9% had rectovaginal fistulas. The median CDAI score was 180. At week 14, 282 patients were evaluated for clinical response and randomized to be treated with placebo or infliximab 5 mg / kg every 8 weeks through week 46.
Patients who responded at week 14 (195/282) were analyzed for the primary endpoint, which was the time between randomization and loss of response (see table 7). Decreased corticosteroids were allowed after week 6.
Table 7
Effects on speed of response, data from ACCENT II study (patients achieving response at week 14)
a ≥ 50% reduction from baseline in the number of draining fistulas over a period of ≥ 4 weeks
b Absence of draining fistulas
At the beginning of week 22, patients who initially responded to treatment and who subsequently lost response were switched to active retreatment every 8 weeks at a dose of infliximab 5 mg / kg higher than the dose at which they had been initially randomized. Among patients in the 5 mg / kg infliximab maintenance group who switched to active retreatment because they had lost fistula reduction response after week 22, 57% (12/21) responded to infliximab retreatment 10 mg / kg every 8 weeks.
There was no significant difference between placebo and infliximab in the proportion of patients with sustained closure of all fistulas up to week 54, in symptoms of proctalgia, abscess and urinary tract infections, or in the number of new fistulas developed during treatment.
Maintenance therapy with infliximab every 8 weeks significantly reduced disease-related hospitalizations and surgery when compared with placebo. In addition, a reduction in the use of corticosteroids and an improvement in the quality of life were observed.
Ulcerative colitis in adults
The safety and efficacy of Remicade were evaluated in two randomized, double-blind, placebo-controlled clinical trials (ACT 1 and ACT 2) in adult patients with moderate to severe active ulcerative colitis (Mayo score 6 to 12; endoscopic subscore ≥ 2) with inadequate response to conventional therapies [oral corticosteroids, aminosalicylates and / or immunomodulators (6 MP, AZA)]. Concomitant administration of fixed doses of oral aminosalicylates, corticosteroids and / or immunolodulatory drugs was allowed. studies patients were randomized to receive placebo or Remicade 5 mg / kg or Remicade 10 mg / kg at weeks 0, 2, 6, 14 and 22 and in ACT 1 at weeks 30, 38 and 46. Corticosteroid reduction was allowed after 8 weeks.
Table 8
Effects on clinical response, clinical remission and mucosal healing at weeks 8 and 30.
Combined data from ACT 1 & 2
on p
The efficacy of Remicade at week 54 was evaluated in ACT 1 study.
At week 54, 44.9% of patients in the infliximab combination group had a clinical response compared with 19.8% in the placebo group (p
A greater proportion of patients in the infliximab combination group were able to discontinue corticosteroid treatment and remain in clinical remission compared to the placebo group at both week 30 (22.3% vs 7.2%, p
Combined data from the ACT 1 and ACT 2 studies and their extensions, analyzed from baseline through week 54, demonstrated a reduction in ulcerative colitis-related hospitalizations and surgical interventions following infliximab treatment. The number of ulcerative colitis-related hospitalizations was significantly lower in the infliximab 5 and 10 mg / kg treatment groups compared to the placebo group (mean number of hospitalizations per 100 subjects per year: 21 and 19 versus 40 in the placebo group; p = 0.019 and p = 0.007, respectively).
The number of ulcerative colitis-related surgeries was also lower in the infliximab 5 and 10 mg / kg treatment groups compared to the placebo group (mean number of surgeries per 100 subjects per year: 22 and 19 versus 34; p = 0.145 and p = 0.022, respectively).
The number of subjects who underwent colectomy at any time during the 54 weeks following the first infusion of the study agent was collected and combined with data from the ACT 1 and ACT 2 studies and their extensions. Fewer subjects were underwent colectomy in the infliximab 5 mg / kg group (28/242 or 11.6% [NS]) and in the infliximab 10 mg / kg group (18/242 or 7.4% [p = 0.011 ]) compared to the placebo group (36/244; 14.8%).
The reduction in the incidence of colectomies was also examined in another randomized, double-blind study (C0168Y06) in hospitalized patients (n = 45) with moderate to severe active ulcerative colitis who had failed to respond to intravenous corticosteroids. and who were therefore at high risk for colectomy. There were significantly fewer colectomies within 3 months of infusion in patients who received a single 5 mg / kg infliximab dose compared to patients who received placebo (29.2 % versus 66.7% respectively, p = 0.017).
In the ACT 1 and ACT 2 studies, infliximab improved the quality of life, confirmed by a statistically significant improvement in both the measure of a specific disease parameter, IBDQ, and in the improvement of the 36 generic questions that make up SF-36.
Ankylosing spondylitis in adults
The efficacy and safety of infliximab were studied in two double-blind, placebo-controlled multicenter studies in patients with active ankylosing spondylitis (Bath Index of Ankylosing Spondylitis Disease Activity [BASDAI] score ≥ 4 and pain spinal ≥ 4 on a scale of 1 to 10).
In the first study (P01522), which included a 3-month double-blind phase, 70 patients were treated with either infliximab 5 mg / kg or placebo at weeks 0, 2, 6 (35 patients per group). Beginning at week 12, patients treated so far with placebo began receiving infliximab at a dose of 5 mg / kg every 6 weeks through week 54. After the first year, 53 patients were placed in a open-label protocol through week 102.
In a second clinical study (ASSERT), 279 patients were randomized to treatment with placebo (group 1, n = 78) or infliximab 5 mg / kg (group 2, n = 201) at weeks 0, 2, 6 and each 6 weeks through week 24. Thereafter, all study subjects continued on infliximab every 6 weeks through week 96. Group 1 received a 5 mg / kg dose of infliximab. In group 2, starting at week 36, patients who had a BASDAI ≥ 3 for 2 consecutive visits were treated with an infliximab dose of 7.5 mg / kg every 6 weeks through week 96.
In the ASSERT study, improvement in signs and symptoms was seen from week 2. At week 24, the number of patients who had an ASAS 20 response was 15/78 (19%) in the placebo group and equal to 123/201 (61%) in the infliximab 5 mg / kg group (p
In study P01522, improvement in signs and symptoms was observed from week 2. At week 12, patients who had a BASDAI 50 response were 3/35 (9%) in the placebo group and 20/35 (57 %) in the infliximab 5 mg / kg group (p
In both studies, physical function and quality of life, as measured by the BASFI and the physical component score on the SF-36 scale, improved significantly.
Psoriatic arthritis in adults
Efficacy and safety were evaluated in two double-blind, placebo-controlled, multicenter studies in patients with active psoriatic arthritis.
In the first clinical study (IMPACT), the efficacy and safety of infliximab were studied in 104 patients with polyarticular active psoriatic arthritis. During the 16-week double-blind phase, patients received either 5 mg / kg of infliximab or palcebo. at weeks 0, 2, 6, and 14 (52 patients in each group). Starting at week 16, patients in the placebo group were switched to infliximab and then all patients received infliximab at a dose of 5 mg / kg each. 8 weeks through week 46. After the first year of the study, 78 patients continued with an open label extension through week 98.
In the second clinical study (IMPACT 2), the efficacy and safety of infliximab were studied in 200 patients with active psoriatic arthritis (swollen joints ≥ 5 and painful joints ≥ 5). Forty-six percent of patients continued on fixed doses of methotrexate (≤ 25 mg / week) During the 24-week double-blind phase, patients received either 5 mg / kg of infliximab or placebo at weeks 0, 2, 6, 14 and 22 (100 patients in each group). At week 16, 47 patients were receiving placebo with improvement
The key efficacy results for IMPACT and IMPACT 2 are outlined below
Table 9
Effects on ACR and PASI in IMPACT and IMPACT 2
* ITT-analysis in which subjects with missing data were included as Not-responders
at Week 98 IMPACT data includes patients from the placebo group and infliximab-treated patients who entered the open-label extension
b Based on patients with PASI ≥ 2.5 at baseline for IMPACT, and patients with psoriatic body surface area (BSA) involvement at baseline ≥ 3% in IMPACT 2
** PASI 75 response for IMPACT not included due to low N; p
In IMPACT and IMPACT 2, clinical response was observed as early as week 2 and was maintained through week 98 and week 54, respectively. The efficacy has been demonstrated with and without the concomitant use of methotrexate. Decreases in peripheral activity parameters characteristic of psoriatic arthritis (such as number of swollen joints, number of painful / sensitive joints, dactylitis and presence of enthesopathies) have been observed in patients treated with infliximab.
Radiographic changes were evaluated in IMPACT2. Radiographs of hands and feet were collected at baseline, week 24 and week 54. Infliximab treatment reduced the rate of progression of peripheral joint damage compared to placebo treatment at the primary end point of week 24, measured as change from baseline in modified total score vdH-S (mean ± SD score was 0.82 ± 2.62 in the placebo group versus - 0.70 ± 2.53 in the infliximab group; p
Significant improvement in physical function as assessed by HAQ has been demonstrated in patients treated with infliximab. Significant improvements in quality of life measured by the summary score of the physical and mental components of SF-36 in IMPACT 2 have also been demonstrated.
Psoriasis in adults
The efficacy of infliximab was evaluated in two randomized, double-blind, multicenter studies, SPIRIT and EXPRESS. Patients in both studies had plaque psoriasis (BSA [Body Surface Area] ≥ 10% and PASI score [Psoriasis Area and Severity Index] ≥ 12) The primary endpoint in both studies was the proportion of patients achieving ≥ 75% improvement from baseline in PASI score at week 10.
SPIRIT evaluated the efficacy of infliximab induction therapy in 249 patients with plaque psoriasis previously treated with PUVA or systemic therapy. Patients received infusions of 3 or 5 mg / kg of infliximab or placebo at weeks 0, 2 and 6. Patients with a PGA ≥ 3 were eligible to receive an additional infusion of the same treatment at week 26.
In SPIRIT, the proportion of patients achieving PASI 75 at week 10 was 71.7% in the infliximab 3 mg / kg group, 87.9% in the infliximab 5 mg / kg group, and in the infliximab 5 mg / kg group. 5.9% in the placebo group (p 20 weeks. No rebound phenomena were observed.
EXPRESS evaluated the efficacy of induction and maintenance therapy with infliximab in 378 patients with plaque psoriasis. Patients received 5 mg / kg infliximab or placebo infusions at weeks 0, 2 and 6 followed by every 8 maintenance therapy. weeks through week 22 in the placebo group and through week 46 in the infliximab group. At week 24, the placebo group switched to infliximab induction therapy (5 mg / kg) followed by infliximab maintenance therapy (5 mg / kg) Nail psoriasis was assessed using the Nail Psoriasis Severity Index (NAPSI) Previous therapy with PUVA, methotrexate, cyclosporine or acitretin was received by 71.4% of patients, although these were not necessarily resistant to therapy. The most significant results are presented in Table 10. In infliximab-treated subjects, significant responses to PASI 50 were evident at the first v isita (week 2) and responses to PASI 75 at the second visit (week 6). The efficacy in the subgroup of patients who had previously undergone systemic therapies was similar to that of the overall study population.
Table 10
Summary of PASI responses, PGA responses and percentage of patients with all nails healed at weeks 10, 24 and 50. EXPRESS.
on p
b n = 292
c Analysis was performed on subjects with nail psoriasis at baseline (81.8% of subjects). Mean baseline NAPSI scores were 4.6 and 4.3 in the infliximab and placebo groups.
Significant improvements from baseline were evident in the DLQI (p
Pediatric population
Crohn's disease in pediatric patients (6-17 years)
In the REACH study, 112 patients (aged 6-17 years, mean age 13 years) with moderate to severe active Crohn's disease (pediatric CDAI mean of 40) and with an inadequate response to conventional therapies, were were treated with 5 mg / kg infliximab at weeks 0, 2 and 6. A stable dose of 6-MP, AZA or MTX was required for all patients (35% were also on corticosteroids at baseline). Patients considered by the investigator to have clinical response at week 10 were then randomized into two groups and received infliximab 5 mg / kg every 8 weeks or every 12 weeks as maintenance therapy. If response was lost during maintenance, a switch to a higher dose (10 mg / kg) and / or at shorter intervals between infusions (every 8 weeks) was allowed. Thirty-two pediatric patients evaluable for the purposes of the study underwent this switch (9 subjects in the group treated every 8 weeks and 23 subjects in the group treated every 12 weeks). Twenty-four of these patients (75.0%) regained a clinical response after this switch.
The percentage of patients in clinical response at week 10 was 88.4% (99/112). The percentage of subjects achieving clinical remission at week 10 was 58.9% (66/112).
At week 30, the percentage of patients in clinical remission was higher in the every 8 week group (59.6%, 31/52) than that of patients in the every 12 week maintenance group (35.3%, 18/51; p = 0.013). At week 54, the data were as follows: 55.8% (29/52) in the maintenance group treated every 8 weeks and 23.5% (12/51) in the maintenance group treated every 12 weeks (p
Data on fistulas was extracted from PCDAI scores. Of the 22 patients who had fistulas at baseline, 63.6% (14/22), 59.1% (13/22), and 68.2% (15/22) were in complete response with respect to the fistula. at weeks 10, 30 and 54, respectively, considering overall the maintenance groups both those treated every 8 weeks and those treated every 12 weeks.
In addition, a statistically and clinically significant improvement in quality of life and height as well as a significant reduction in corticosteroid use was observed from baseline.
Pediatric ulcerative colitis (6-17 years)
The safety and efficacy of infliximab were evaluated in a multicenter, randomized, open-label, parallel group clinical trial (C0168T72) in 60 pediatric patients aged 6-17 years (median age 14.5 years) with colitis. Moderate to severe active ulcer disease (Mayo score 6 to 12; endoscopic subscore ≥ 2) with inadequate response to conventional therapies. At baseline, 53% of patients were receiving immunomodulatory therapy (6-MP, AZA and / or MTX) and 62% of patients were receiving corticosteroids. Discontinuation of immunomodulators and tapering of corticosteroids was allowed after week 0.
All patients received an induction regimen of infliximab 5 mg / kg at weeks 0, 2, and 6. Patients who had failed to respond to infliximab at week 8 (n = 15) received no medication and returned for an safety assessment follow-up. At week 8, 45 patients were randomized and received maintenance treatment with infliximab 5 mg / kg every 8 weeks or every 12 weeks.
The proportion of patients in clinical response at week 8 was 73.3% (44/60). Clinical response at week 8 was similar between patients with and without concomitant use of immunomodulators at baseline. Clinical remission at week 8 was 33.3% (17/51) as measured by the Pediatric Ulcerative Colitis Activity Index (PUCAI) score.
At week 54, the proportion of patients in clinical remission as measured by the PUCAI score was 38% (8/21) in the every 8 week maintenance group and 18% (4/22) in the every 12 week maintenance group. weeks. For patients receiving corticosteroids at baseline, the proportion of patients in remission and not receiving corticosteroids at week 54 was 38.5% (5/13) in the every 8 weeks maintenance group and 0% (0 / 13) in the maintenance group treated every 12 weeks.
In this study, there were more patients in the 12 to 17 year age group than in the 6 to 11 year age group (45/60 vs. 15/60). Although the number of patients in each subgroup was too small to draw firm conclusions regarding the "effect of age," there was a higher number of patients in the younger age group who increased the dose or discontinued treatment. due to inadequate efficacy.
Other pediatric indications
The European Medicines Agency has waived the obligation to submit the results of studies with Remicade in all subsets of the pediatric population in rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, psoriasis and Crohn's disease (see section 4.2 for information on pediatric use).
05.2 "Pharmacokinetic properties
Single intravenous infusions of 1, 3, 5, 10 or 20 mg / kg of infliximab increased both the maximum serum concentration (Cmax) and the area under the concentration-time curve (AUC) in a dose proportional manner.The volume of distribution at steady state (median Vd 3.0-4.1 liters) was independent of the administered dose thus showing that infliximab is mainly distributed into the vascular compartment. No time dependence of the pharmacokinetic characteristics was observed. The route of elimination of infliximab was not characterized. Unmodified infliximab was not found in urine. No major differences in clearance or volume of distribution related to age or weight have been observed in patients with rheumatoid arthritis. The pharmacokinetics of infliximab in elderly patients have not been studied. No studies have been conducted in patients with hepatic or liver function. impaired renal.
At single doses of 3, 5, or 10 mg / kg, the mean Cmax values were 77, 118, and 277 mcg / mL, respectively. The mean terminal half-life at these doses ranged from 8 to 9.5 days. In most patients, at the recommended single dose of 5 mg / kg for Crohn's disease and 3 mg / kg every 8 weeks for maintenance. in rheumatoid arthritis, infliximab could be detected in serum for at least 8 weeks.
Repeated administration of infliximab (5 mg / kg at weeks 0, 2 and 6 in fistulising Crohn's disease, 3 or 10 mg / kg every 4 or 8 weeks in rheumatoid arthritis) resulted in a slight accumulation of infliximab in serum after second dose No further clinically relevant accumulation was observed In most patients with fistulising Crohn's disease, infliximab was detected in serum for 12 weeks (range 4-28 weeks) following administration of the regimen.
Pediatric population
A "population pharmacokinetic analysis based on data from patients with ulcerative colitis (N = 60), Crohn's disease (N = 112), juvenile rheumatoid arthritis (N = 117), and Kawasaki disease (N = 16) with a ages 2 months to 17 years overall indicated that infliximab exposure was non-linearly dependent on body weight. Following administration of 5 mg / kg of Remicade every 8 weeks, the expected median exposure to infliximab at steady state (area under the concentration-time curve at steady state, AUCss) in pediatric patients 6 to 17 years of age was approximately 20% lower than the median predicted steady state drug exposure in adults. The median AUCss in pediatric patients 2 to less than 6 years of age was predicted to be approximately 40% lower than in adults, although the number of patients supporting this estimate is limited.
05.3 Preclinical safety data
Infliximab does not cross-react with TNFα in animal species other than humans and chimpanzees. Therefore, conventional preclinical safety data with infliximab are limited. In a mouse developmental toxicity study using a similar antibody that selectively inhibits the functional activity of the mouse TNFα was not found, maternal toxicity, embryotoxicity, teratogenicity. In a fertility and general reproductive function study, the number of pregnant mice was reduced after administration of the same analog antibody. It is not known whether these findings were due to effects on males and / or females. In a 6-month repeat dose toxicity study in rats, using the same analogous antibodies to murine TNFα, crystalline deposits were observed on the lens capsule of some of the treated male rats. No specific ophthalmological examination was performed on patients to assess the relevance of this event in humans. Long-term studies have not been performed to evaluate the carcinogenic potential of infliximab. In studies performed in TNFα-deficient mice it has been shown that there is no increase in tumors when provoked with known tumor initiators and / or promoters.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Sucrose
Polysorbate 80
Monobasic sodium phosphate
Dibasic sodium phosphate
06.2 Incompatibility
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
06.3 Period of validity
Before reconstitution:
3 years at 2 ° C - 8 ° C.
Remicade can be stored at temperatures no higher than 25 ° C for a single period of up to 6 months, but not beyond the original expiration date. The new expiration date must be written on the box. After removal from the refrigerator, Remicade should not be stored in the refrigerator again.
After reconstitution:
The chemical and physical in-use stability of the reconstituted solution has been demonstrated for 24 hours at 25 ° C. From a microbiological point of view, the product should be used as soon as possible and in any case within 3 hours of reconstitution and dilution. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and should in no case exceed 24 hours at 2 ° C to 8 ° C.
06.4 Special precautions for storage
Store in a refrigerator (2 ° C - 8 ° C).
For storage conditions up to 25 ° C before reconstitution of the medicinal product, see section 6.3.
For storage conditions after reconstitution of the medicinal product, see section 6.3.
06.5 Nature of the immediate packaging and contents of the package
Type I glass vial with rubber stopper and aluminum crimp protected by a plastic cap, containing 100 mg of infliximab.
Remicade is available in packs of 1, 2, 3, 4 or 5 vials. Not all pack sizes may be marketed.
06.6 Instructions for use and handling
1. Calculate the dose and number of Remicade vials needed. Each vial of Remicade contains 100 mg of infliximab. Calculate the total volume required of the reconstituted Remicade solution.
2. Under aseptic conditions, reconstitute each Remicade vial with 10 ml of water for injections using a syringe with a 21 gauge (0.8 mm) or smaller needle. Remove the aluminum tab from the vial and clean the cap with a cotton swab dipped in 70% alcohol. Insert the syringe needle into the vial through the center of the rubber stopper and direct the flow of water for injections to the glass wall of the vial. Gently swirl the solution to completely dissolve the lyophilized powder. Do not shake vigorously or for a long time. DO NOT SHAKE. Foaming may occur during reconstitution. Allow the reconstituted solution to stand for 5 minutes. Check that the solution is colorless to yellow and opalescent, the solution may have some small translucent particles, as infliximab is a protein. Do not use the solution if you notice dull particles, color change or other foreign bodies.
3. Dilute the total volume of the dose of Remicade reconstituted solution to 250 ml using sodium chloride 9 mg / ml (0.9%) solution for infusion. Do not dilute the Remicade reconstituted solution with any other diluent. This can be done by withdrawing a volume of sodium chloride 9 mg / ml (0.9%) solution for infusion from the 250 ml glass bottle or infusion bag equal to the volume of reconstituted Remicade. Slowly add the total volume of Remicade reconstituted solution to the 250 ml bottle or infusion bag. Gently mix.
4. Administer the infusion solution over an infusion time of not less than the recommended infusion time (see section 4.2). Use only an infusion set with a sterile, non-pyrogenic, low protein binding in-line filter (pore diameter 1.2 micrometers or less). Since no preservative is contained, it is recommended to start administration of the solution for intravenous infusion as soon as possible and within 3 hours of reconstitution and dilution. If reconstitution and dilution are done under aseptic conditions, Remicade infusion solution can be used within 24 hours when stored at 2 ° C to 8 ° C. Unused solution should not be stored for later. use.
5. Physical and biochemical compatibility studies have not been conducted to evaluate the combination of Remicade with other agents. Do not administer Remicade concomitantly with other medicinal products in the same intravenous line.
6. Before administration, visually inspect Remicade to ensure no particles or discolouration are observed. If opaque particles, discolouration or foreign particles are observed, do not use.
7. Unused medicine and wastes 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 / 1/99/116/001
034528012
EU / 1/99/116/002
EU / 1/99/116/003
EU / 1/99/116/004
EU / 1/99/116/005
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 13 August 1999. Date of most recent renewal: 02 July 2009.
10.0 DATE OF REVISION OF THE TEXT
September 24, 2015
