Active ingredients: Adalimumab
Humira 40 mg / 0.8 ml solution for injection for pediatric use
Humira package inserts are available for pack sizes:- Humira 40 mg / 0.8 ml solution for injection for pediatric use
- Humira 40 mg solution for injection in pre-filled syringe
- Humira 40 mg solution for injection in pre-filled syringe with needle safety device
- Humira 40 mg solution for injection in pre-filled pen
Why is Humira used? What is it for?
Humira contains the active substance adalimumab, a selective immune suppressive agent. Humira is indicated for the treatment of polyarticular juvenile idiopathic arthritis in children aged 2-17 years, enthesitis associated arthritis in children aged 6-17 years, Crohn's disease in children aged 6-17 years. 17 years and plaque psoriasis in children aged 4 to 17 years. It is a drug that reduces the inflammatory process of these diseases. The active substance, adalimumab, is a human monoclonal antibody produced by cell cultures. Monoclonal antibodies are proteins that recognize and bind to other proteins. Adalimumab binds to a specific protein (tumor necrosis factor or TNFα) that is present at high levels in inflammatory diseases such as polyarticular juvenile idiopathic arthritis, enthesitis-associated arthritis, Crohn's disease and plaque psoriasis .
Polyarticular juvenile idiopathic arthritis and enthesitis-associated arthritis
Polyarticular juvenile idiopathic arthritis and enthesitis-associated arthritis are inflammatory diseases. Humira is used to treat polyarticular juvenile idiopathic arthritis and enthesitis-associated arthritis. Disease-modifying drugs, such as methotrexate, may be given at diagnosis. If the response to these drugs is not adequate, the child will be given Humira for the treatment of polyarticular juvenile idiopathic arthritis or enthesitis-associated arthritis.
Crohn's disease in children
Crohn's disease is an inflammatory disease of the digestive tract. Humira is indicated for the treatment of Crohn's disease in children 6 to 17 years of age. The child will be given other medicines first. If the child does not respond well enough to these medicines, he or she will be given Humira to reduce the signs and symptoms of Crohn's disease.
Pediatric plaque psoriasis
Plaque psoriasis is a skin condition that causes reddish, scaly, hardened patches of skin covered with silvery scales. Psoriasis is thought to be caused by a problem with the body's immune system that leads to increased production of skin cells. Humira is used to treat severe plaque psoriasis in children and adolescents aged 4 to 17 years in whom topical therapy and phototherapy have not worked optimally or are not indicated.
Contraindications When Humira should not be used
Do not use Humira
- If your child is allergic to adalimumab or any of the other ingredients of this medicine (listed in section 6).
- If you have a "severe infection, including active tuberculosis (see" Warnings and precautions "). It is important to tell your doctor if your child has symptoms of infection, such as fever, wounds, tiredness, dental problems.
- In the presence of moderate or severe heart failure. It is important to tell your doctor if there has been or is a serious heart condition (see "Warnings and precautions").
Precautions for use What you need to know before you take Humira
Talk to your child's doctor or pharmacist before using Humira
- If you have any allegic reactions with symptoms such as chest tightness, wheezing, dizziness, swelling or rash, stop giving Humira and contact your doctor immediately.
- If you have an infection, including long-term or localized infections (for example, leg ulcers) consult your doctor before starting treatment with Humira. If you are unsure, contact your doctor.
- You can get infections more easily while being treated with Humira. This risk may increase if the baby's lung function is impaired. These infections can be serious and include tuberculosis, infections caused by viruses, fungi, parasites or bacteria, or other opportunistic infections and sepsis which can, in rare cases, be life-threatening. It is important to tell your doctor about symptoms such as fever, wounds, tiredness, or dental problems. Your doctor may recommend stopping Humira temporarily.
- Since there have been cases of tuberculosis in patients receiving Humira, the doctor will need to check if the child has typical signs or symptoms of tuberculosis before starting Humira therapy. This will involve collecting a detailed medical evaluation including the child's medical history and appropriate clinical tests (eg a chest X-ray and tuberculin test). The performance and results of such tests must be recorded in the Alert Card. for the Patient. It is very important to tell the doctor if the child has ever had tuberculosis, or if he has had close contact with tuberculosis patients. Tuberculosis can occur during therapy even though the child has received preventive treatment for tuberculosis. Contact your doctor immediately if symptoms of tuberculosis (persistent cough, weight loss, listlessness, moderate fever) or other infections appear during or after therapy.
- Tell your doctor if your child resides in or travels to regions where fungal infections, such as histoplasmosis, coccidioidomycosis, or blastomycosis, are endemic.
- Tell your doctor if your child has had recurring infections or if they have conditions that increase the risk of infection.
- Tell your doctor if your child is a carrier of the hepatitis B virus (HBV), if he has an active hepatitis B virus infection or if you think he may be at risk of contracting the hepatitis B virus. doctor must test the child for hepatitis B virus infection. Taking Humira can cause the hepatitis B virus to become reactivated in people who are carriers of this virus. In some rare cases, especially if the patient is undergoing therapy with other drugs that suppress the immune system, reactivation of the hepatitis B virus can be life-threatening.
- It is important to tell your child's doctor if symptoms of infections such as fever, wounds, tiredness, or dental problems appear.
- Before surgery or dental procedures, tell your doctor that your child is taking Humira. Your doctor may recommend temporary suspension.
- If your child has demyelinating diseases such as multiple sclerosis, the doctor will decide if Humira should be started.
- Certain vaccines can cause infections and should not be given while being treated with Humira. Consult your doctor before giving your child any vaccinations. In children, it is recommended, if possible, to implement the planned vaccination schedule, in accordance with current vaccination guidelines, before starting Humira therapy. If you have taken Humira during your pregnancy, your baby may have an increased risk of getting this infection up to about 5 months after the last dose you took during pregnancy. It is important that you tell your pediatrician or other healthcare professional. use of Humira during pregnancy, so they can decide when your baby should receive any type of vaccination.
- In case of mild heart failure and concomitant treatment with Humira, the doctor will need to carefully evaluate and monitor the status of the baby's heart. It is important to tell your doctor about any heart problems, both past and present. If new symptoms of heart failure appear or if existing symptoms worsen (for example, shortness of breath or swelling of the feet), contact your doctor immediately. The doctor will decide whether the child can take Humira.
- In some patients, the body may not be able to produce enough blood cells to help fight infection or stop bleeding. If your child has persistent fever, bruising or bleeding easily or paleness, see your doctor immediately. The latter may decide to stop the therapy.
- Some types of cancers have occurred very rarely in patients, both children and adults, receiving treatment with Humira or other anti-TNF drugs. Patients with long-term severe rheumatoid arthritis may have a higher than average risk of developing lymphoma (a type of cancer that affects the lymphatic system) and leukemia (a type of cancer that affects the blood and bone marrow) . If your child takes Humira, the risk of getting lymphoma, leukemia or other cancers may increase. In rare circumstances, a specific and severe type of lymphoma has been observed in patients receiving Humira. Some of these patients were also on azathioprine or 6-mercaptopurine therapy. Tell your doctor if you are taking azathioprine or 6-mercaptopurine with Humira. In addition, cases of non-melanotic skin cancer have been observed in patients taking Humira. If new skin lesions appear during or after therapy, or if the appearance of existing lesions changes, please tell your doctor.
- There have been cases of malignancies, in addition to lymphoma, in patients with a specific type of lung disease called Chronic Obstructive Pulmonary Disease (COPD) treated with another anti-TNF. If your child has COPD, or smokes a lot, you should discuss with your doctor whether treatment with an anti-TNF is appropriate.
Children and adolescents
- Vaccinations: If possible, your child should have already had all vaccinations before using Humira.
- Do not give Humira to children with polyarticular juvenile idiopathic arthritis younger than 2 years of age.
Interactions Which drugs or foods may change the effect of Humira
Other medicines and Humira
Tell your child's doctor or pharmacist if your child is taking, has recently taken or might take any other medicines.
Humira can be taken with either methotrexate or other disease-modifying antirheumatic drugs (sulfasalazine, hydroxychloroquine, leflunomide and parenteral gold salts), steroids or analgesics, including non-steroidal anti-inflammatory drugs (NSAIDs).
Humira must not be taken concomitantly with medicines containing anakinra or abatacept as the active ingredient. If you are unsure, ask your doctor.
Humira with food and drink
As Humira is injected under the skin (subcutaneously), food and drink do not interfere with Humira.
Warnings It is important to know that:
Pregnancy and breastfeeding
The effects of Humira in pregnant women are not known, so the use of Humira in pregnant women is not recommended. It is recommended that pregnancy be avoided by using adequate contraception during treatment with Humira and for at least 5 months after treatment. "last drug therapy. If your baby gets pregnant, you should see the baby's doctor.
It is not known whether adalimumab passes into breast milk.
If the person taking Humira is a young woman who is breastfeeding, she must stop breastfeeding during Humira therapy and for at least 5 months after her last treatment with Humira. If you have taken Humira during pregnancy, your baby may have an increased risk of getting an infection. It is important that you tell your pediatrician or other healthcare professional about your use of Humira during pregnancy, before your baby gets any kind of medication. vaccine (see the section on vaccination for more information).
If you suspect that your daughter has started or is planning to become pregnant, ask your doctor or pharmacist for advice before using this medicine.
Driving and using machines
Humira may affect the ability to drive, ride a bicycle or use machines, although only modestly. After taking Humira, you may have visual disturbances and a feeling that your environment is spinning.
Dosage and method of use How to use Humira: Dosage
Always use this medicine exactly as your child's doctor or pharmacist has told you. If in doubt, consult your child's doctor or pharmacist.
Children with polyarticular juvenile idiopathic arthritis
The recommended dose of Humira for polyarticular juvenile idiopathic arthritis patients aged 2 to 12 years depends on the height and weight of the child. Your child's doctor will advise you on the correct dose to use. The recommended dose of Humira for polyarticular juvenile idiopathic arthritis patients aged 13-17 years is 40 mg every other week.
Children with arthritis associated with enthesitis
The recommended dose of Humira for patients with enthesitis-associated arthritis aged 6 to 17 years depends on the height and weight of the child.
Children or adolescents with Crohn's disease
Children or adolescents who weigh less than 40 kg:
The usual dose regimen is 40 mg at the start followed by 20 mg two weeks later. If a faster response is required, the doctor may prescribe a starting dose of 80 mg (as two injections in one day) followed by 40 mg two weeks later. Thereafter, the usual dose is 20 mg every other week. Depending on your child's response, your doctor may increase the frequency of the dose to 20 mg every week.
Children or adolescents weighing 40 kg or more:
The usual dose regimen is 80 mg at the start followed by 40 mg two weeks later. If a faster response is required, the doctor may prescribe a starting dose of 160 mg (as 4 injections in a day or as 2 injections per day for 2 consecutive days) followed by 80 mg two weeks later. Thereafter, the usual dose is 40 mg every other week. Depending on the child's response, the doctor may increase the dose frequency to 40 mg For patients prescribed a full dose of 40 mg Humira, 40 mg pens and 40 mg pre-filled syringes are also available.
Children or adolescents with psoriasis
The recommended dose of Humira for patients 4 to 17 years of age with plaque psoriasis depends on the weight of your child. Your child's doctor will advise you on the correct dose to use.
Method and route of administration
Humira is given by injection under the skin (by subcutaneous injection).
Instructions for preparing and injecting Humira:
The following instructions explain how to inject Humira. Read the instructions carefully and follow them step by step. You will be instructed by your doctor or his assistant on self-administration technique and how much to give to your child. Do not inject until you are sure you understand how to prepare and administer the administration. After proper instruction, the injection can be given by you or by others such as a family member or friend.
Failure to follow the instructions below, as described, may result in contamination which could in turn cause infection in the baby. The contents of the syringe must not be mixed with other drugs in the same syringe or vial.
1) Preparation
- Make sure you know the appropriate amount (volume) needed for your dose. If you don't know the amount, STOP and contact your doctor for further instructions.
- You will need a special waste container, such as a container for sharp objects or as directed by your nurse, doctor or pharmacist. Place the container on your work surface.
- Wash your hands thoroughly.
- Remove a box containing a syringe, a vial adapter, a vial, 2 alcohol swabs and a needle from the carton. If there is a second box in the carton to use for your next administration, return it to the refrigerator immediately.
- Check the expiry date on the carton. DO NOT use any of the items in the box after the expiration date.
- Arrange the following items on a clean surface, WITHOUT taking any items out of their packaging yet. One 1 ml syringe One vial adapter One pediatric vial of Humira solution for injection Two alcohol pads or One needle
- Humira is a clear, colorless liquid. DO NOT use it if the liquid is opaque, discolored or has flocculations or particles inside.
2) Preparing the dose of Humira for injection
General Instructions: DO NOT discard any items until the injection is complete.
- Prepare the needle by partially opening the package from the end closest to the yellow connector of the syringe. Open the package just enough to expose the yellow syringe connector. Place the package with the light side facing up.
- Remove the plastic cap from the vial until you see the top of the vial stopper.
- Use one of the alcohol swabs to clean the vial cap. DO NOT touch the vial cap after cleaning it with the swab.
- Remove the cover from the vial adapter package without taking it out of the package.
- Hold the vial with the cap upside down.
- With the sickle adapter still in the clear package, attach it to the vial stopper by pushing it until the adapter clicks.
- When you are sure that the adapter is attached to the vial, pull the pack away from the vial.
- Gently place the vial and adapter on a clean work surface, being careful not to drop. DO NOT touch the adapter.
- Prepare the syringe by partially opening the package from the end closest to the white plunger.
- Open the clear package just enough to expose the white plunger without taking the syringe out of its package.
- Holding the syringe package, SLOWLY pull the plunger out 0.1ml above the prescribed dose (for example, if the prescribed dose is 0.5ml, push the plunger to 0.6ml). NEVER exceed the position corresponding to 0.9 ml regardless of the prescribed dose.
- The volume will be adjusted up to the prescribed dose in a subsequent step.
- DO NOT push the white plunger all the way out of the syringe.
NOTE: If the white plunger is pushed all the way out of the syringe, discard the syringe and contact your Humira supplier for replacement. DO NOT try to insert the white plunger again.
- DO NOT use the white plunger to remove the syringe from the package. Hold the syringe on the graduated side and take it out of its package. DO NOT put down the syringe at any time.
- While holding the adapter, insert the tip of the syringe into the adapter and turn the syringe clockwise with one hand until it stops. DO NOT over tighten.
- While holding the vial, push the white plunger all the way in. This step is important to get the right dose. Hold the white plunger rod in and turn the vial and syringe upside down.
- SLOWLY pull the white plunger to 0.1ml above the prescribed dose. It is important to withdraw the appropriate dose. The volume equivalent to the prescribed dose will be established in step 4, Preparing the dose. If the prescribed dose is 0.5ml, pull the white plunger to a volume of 0.6ml. The liquid will pass from the vial to the syringe.
- Push the white plunger back all the way to push the liquid back into the vial. Again, SLOWLY pull on the white plunger until it reaches 0.1ml above the prescribed dose; it is important to withdraw the appropriate dose and prevent the formation of air bubbles in the liquid or empty spaces. The volume equivalent to the prescribed dose will be established in step 4, Preparing the dose.
- If any air bubbles or gaps remain in the syringe, you can repeat this up to three times. DO NOT shake the syringe.
NOTE: If the white plunger is pushed all the way out of the syringe, discard the syringe and contact your Humira supplier for replacement. DO NOT try to insert the white plunger again.
- While still holding the syringe upright on the graduated side, remove the vial adapter by unscrewing the adapter with your other hand. Be sure to remove the vial adapter from the syringe. DO NOT touch the tip of the syringe.
- If you notice a large air bubble or empty space near the syringe tip, SLOWLY push the white plunger into the syringe until fluid begins to enter the syringe tip. DO NOT push the white plunger once past the dose position.
- For example, if the prescribed dose is 0.5ml, DO NOT push the white plunger past the 0.5ml position.
- Verify that the fluid left in the syringe is at least equivalent to the dose drawn. If it is lower DO NOT use the syringe and contact your healthcare professional.
- With your free hand, pick up the needle pack with the yellow syringe connector facing down.
- Keeping the syringe pointing upward, insert the syringe tip into the yellow connector and rotate the syringe as indicated by the arrow in the figure until it stops. The needle is now attached to the syringe.
- Take the needle out of the package, but DO NOT remove the clear needle cap.
- Place the syringe on a clean work surface. Immediately continue with the administration site and dose preparation steps.
3) Choice and preparation of an injection site
- Choose a spot on your thigh or belly: DO NOT use the same site that was used for the last injection.
- The new injection should be given at least 3 cm from the site of the last injection.
- DO NOT inject into areas where the skin is red, bruised, or hard. This could indicate an infection; therefore, you should contact your doctor.
- To reduce the chance of getting infections, wipe the injection site with the other alcohol swab. DO NOT touch the area again before injecting.
4) Preparing the dose
- Pick up the syringe with the needle pointing up.
- Use your other hand to turn the pink needle cover towards the syringe
- Remove the clear needle cap by pulling it up with your other hand.
- The needle is clean.
- DO NOT touch the needle.
- DO NOT point the syringe down after the clear needle cap has been removed.
- DO NOT try to put the clear cap back on the needle.
- Hold the syringe at eye level with the needle pointing up to see the amount of liquid clearly. Be careful not to get the medicine in your eyes.
- Check the amount of medicine you have taken again.
- Gently push the white plunger into the syringe until the syringe contains the amount of medicine prescribed. Excess liquid may leak out of the needle while the plunger is being pressed. DO NOT remove the needle or syringe.
Humira injection
- With your free hand, gently take the area already rubbed with alcohol and hold it still.
- With your other hand, hold the syringe at a 45 ° angle to the injection site.
- With one firm, quick motion, push the entire needle into the skin.
- Let go of the skin with your hand.
- Push the white plunger to inject the medicine until the syringe is empty.
- When the syringe is empty, remove the needle from the skin by pulling it away at the same angle as when it was inserted.
- With your free hand, gently take the area already rubbed with alcohol and hold it still.
- With your other hand, hold the syringe at a 45 ° angle to the injection site.
- With one firm, quick motion, push the entire needle into the skin.
- Let go of the skin with your hand.
- Push the white plunger to inject the medicine until the syringe is empty.
- When the syringe is empty, remove the needle from your skin by pulling it out at the same angle as when it was inserted.
- Gently pull the pink needle cover up, over the needle, and snap it open, and place the syringe with the needle on the work surface. DO NOT put the clear cap back on the needle.
- With a piece of gauze, apply pressure to the injection site for 10 seconds. A little bleeding may occur. DO NOT massage the injection site. If you wish, apply a patch.
Disposal of materials
- You will need a special waste container, such as a container for sharp objects, or as instructed by your nurse, doctor or pharmacist.
- Place the syringe with needle, vial and adapter in a special container for sharp objects. DO NOT put these items in your household trash container.
- The syringe, needle, vial and adapter MUST NEVER be reused.
- Always keep this container out of the sight and reach of children.
- Dispose of all other used materials in your household trash container.
Overdose What to do if you have taken too much Humira
If you use more Humira than you should:
If you accidentally inject more Humira, or if you inject it more frequently than your doctor told you to, contact your doctor and tell them that your child has taken more medicine. Always keep the medicine box or vial, even if empty.
If you use less Humira than you should:
If you accidentally inject less Humira, or if you inject less frequently than directed by your child's doctor or pharmacist, contact your child's doctor or pharmacist and tell them that your child has taken less medicine. Always keep the medicine box or vial, even if empty.
If you forget to use Humira:
If you forget to give your child an injection of Humira, he should inject the dose of Humira as soon as he remembers. Then give the child the next dose regularly according to the prescribed schedule.
If your child stops taking Humira
The decision to discontinue use of Humira should be discussed with the child's doctor. The child's symptoms may return after discontinuation. If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Side Effects What are the side effects of Humira
Like all medicines, this medicine can cause side effects, although not everybody gets them. Most side effects are mild to moderate. However, some can be severe and require treatment. Side effects may occur up to 4 months after the last Humira injection.
Tell your doctor immediately if you notice any of the following reactions:
- severe skin rash, hives or other signs of an allergic reaction;
- swelling of the face, hands, feet;
- difficulty breathing, difficulty swallowing;
- shortness of breath with exertion or when lying down or swollen feet.
Tell your doctor as soon as possible if you notice any of the following reactions:
- signs of infection such as fever, feeling unwell, wounds, dental problems, burning when urinating;
- tiredness or weakness;
- cough;
- tingling;
- numbness;
- double vision;
- weakness in the arms or legs;
- swelling or open sore that does not heal
- signs and symptoms that suggest the appearance of disturbances affecting the haematopoietic system, such as the presence of persistent fever, bruises, haemorrhages, paleness.
The symptoms described above may be signs of the following side effects, which have been seen with Humira:
Very common (may affect more than 1 in 10 people):
- injection site reactions (including pain, swelling, redness or itching);
- respiratory tract infections (including colds, rhinorrhea, sinusitis and pneumonia);
- headache;
- abdominal pain;
- nausea and vomit;
- rash;
- musculoskeletal pain.
Common (may affect up to 1 in 10 people):
- severe infections (including septicemia and flu);
- skin infections (including cellulitis and herpes zoster infection);
- ear infections;
- oral infections (including tooth infections and herpes simplex);
- infections of the reproductive system;
- urinary tract infections;
- fungal infections;
- joint infections;
- benign tumors;
- skin cancer;
- allergic reactions (including seasonal allergy);
- dehydration;
- mood changes (including depression);
- anxiety;
- sleep disorders;
- sensitivity disorders such as tingling, twitching, or numbness;
- migraine;
- nerve root compression (including lower back pain and leg pain);
- visual disturbances;
- eye inflammation;
- inflammation of the eyelids and swelling of the eyes;
- dizziness;
- feeling of rapid heartbeat;
- hypertension;
- hot flashes;
- hematoma;
- cough;
- asthma;
- shortness of breath;
- gastrointestinal bleeding;
- dyspepsia (indigestion, bloating, heartburn);
- acid reflux disorder;
- sicca syndrome (including dry eyes and mouth);
- itch;
- itchy rash;
- bruise;
- inflammation of the skin (such as eczema);
- breaking of the nails of the fingers and toes;
- increased sweating;
- hair loss;
- onset or worsening of psoriasis;
- muscle spasms;
- blood in the urine;
- kidney problems;
- chest pain;
- edema;
- fever;
- reduction of platelets in the sanggue which increases the risk of bleeding or bruising;
- difficulty in healing.
Uncommon (may affect up to 1 in 100 people):
- opportunistic infections (which include tuberculosis and other infections that occur when the immune defenses are reduced);
- neurological infections (including viral meningitis);
- eye infections;
- bacterial infections;
- diverticulitis (inflammation and infection of the large intestine);
- tumors;
- tumors of the lymphatic system;
- melanoma;
- immune system disorders which can affect the lungs, skin and lymph nodes (most commonly presenting as sarcoidosis);
- vasculitis (inflammation of the blood vessels);
- tremor;
- stroke;
- neuropathy;
- double vision;
- hearing loss, ringing;
- feeling of irregular heartbeat such as palpitations;
- heart problems which can cause shortness of breath or swelling of the ankles;
- acute myocardial infarction;
- formation of a sac in the wall of a main artery, inflammation and clot in a vein, obstruction of a blood vessel;
- lung disease causing shortness of breath (including inflammation);
- pulmonary embolism (occlusion of a pulmonary artery);
- pleural effusion (abnormal collection of fluid in the pleural space);
- inflammation of the pancreas which causes severe pain in the abdomen and back;
- difficulty in swallowing;
- facial edema;
- inflammation of the gallbladder, gallbladder stones;
- fat liver;
- night sweats;
- scar;
- abnormal muscle catabolism;
- systemic lupus erythematosus (including inflammation of the skin, heart, lung, joints and other organs)
- interrupted sleep;
- impotence;
- inflammations.
Rare (may affect up to 1 in 1,000 people):
- leukemia (malignant neoplasm affecting the hematopoietic system at the peripheral level (blood) and bone marrow);
- severe allergic reaction with shock;
- multiple sclerosis;
- neurological disorders (such as inflammation of the optic nerve and Guillain-Barré syndrome which can cause muscle weakness, abnormal sensations, tingling in the arms and upper body);
- cardiac arrest;
- pulmonary fibrosis (scarring of the lung);
- intestinal perforation;
- hepatitis;
- reactivation of hepatitis B;
- autoimmune hepatitis (inflammation of the liver caused by your own immune system);
- cutaneous vasculitis (inflammation of the blood vessels in the skin);
- Stevens-Johnson syndrome (early symptoms include malaise, fever, headache, and rash);
- facial edema associated with allergic reactions;
- erythema multiforme (inflammatory skin rash);
- lupus-like syndrome.
Not known (frequency cannot be estimated from the available data):
- hepato-splenic T-cell lymphoma (a rare blood cancer that is often fatal);
- Merkel cell carcinoma (a type of skin cancer);
- Liver failure;
- worsening of a condition called dermatomyositis (manifesting as a rash accompanied by muscle weakness).
Some of the side effects seen with Humira may be asymptomatic and can only be found in blood tests. These include:
Very common (may affect more than 1 in 10 people):
- low white blood cell count;
- low red blood cell count;
- increased blood lipids;
- increased liver enzymes.
Common (may affect up to 1 in 10 people):
- increased white blood cell count;
- reduced platelet count;
- increased uric acid in the blood;
- alteration of sodium in the blood;
- reduction of calcium in the blood;
- reduction of phosphorus in the blood;
- increased blood sugar;
- increased blood lactate dehydrogenase;
- presence of autoantibodies in the blood.
Rare (may affect up to 1 in 1,000 people):
- low counts of white blood cells, red blood cells and platelets.
Not known (frequency cannot be estimated from the available data):
- liver failure.
Reporting of side effects
If your child gets any side effects, talk to your child's doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the label / blister / carton after EXP. The expiry date refers to the last day of that month.
Store in a refrigerator (2 ° C - 8 ° C). Do not freeze.
Keep the vial in the appropriate packaging to protect the medicine from light.
Do not throw away any medicines via wastewater or household waste. Ask your doctor or pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Composition and pharmaceutical form
What Humira contains
The active ingredient is adalimumab.
The other ingredients are mannitol, citric acid monohydrate, sodium citrate, sodium dihydrogen phosphate dihydrate, disodium phosphate dihydrate, sodium chloride, polysorbate 80, sodium hydroxide and water for injections.
This medicinal product contains less than 1 mmol sodium (23 mg) per 0.8 ml dose, therefore it is essentially "sodium free" and contains no preservatives.
What Humira vials look like and contents of the pack
Humira 40 mg solution for injection in vials is supplied as a sterile solution of 40 mg adalimumab dissolved in 0.8 ml of solution.
Humira vials consist of an adalimumab solution contained in a glass vial. One pack contains 2 cartons, each containing 1 vial, one empty sterile syringe, 1 needle, 1 vial adapter and 2 alcohol swabs.
Humira is also available in a pre-filled syringe or pre-filled pen.
+ 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
HUMIRA 40 MG / 0.8 ML SOLUTION FOR INJECTION FOR PEDIATRIC USE
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each 0.8 ml single-dose vial contains 40 mg of adalimumab.
Adalimumab is a recombinant human monoclonal antibody expressed in Chinese Hamster Ovary cells.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Clear solution for injection.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Juvenile idiopathic arthritis
Polyarticular juvenile idiopathic arthritis
Humira in combination with methotrexate is indicated for the treatment of active polyarticular juvenile idiopathic arthritis in patients from 2 years of age who have had an inadequate response to one or more disease-modifying anti-rheumatic drugs (DMARDs). Humira may be administered as monotherapy in case of intolerance to methotrexate or when continued treatment with methotrexate is inappropriate (for efficacy in monotherapy see section 5.1). Humira has not been studied in patients less than 2 years of age.
Arthritis associated with enthesitis
Humira is indicated for the treatment of active forms of enthesitis-associated arthritis in patients from 6 years of age who have had an inadequate response or who are intolerant to conventional therapy (see section 5.1).
Crohn's disease in pediatric patients
Humira is indicated for the treatment of severe active Crohn's disease in pediatric patients (from 6 years of age) who have had an inadequate response to conventional therapy, including primary nutritional therapy, corticosteroid therapy and an immunomodulator, or who are intolerant or have contraindications to such therapies.
04.2 Posology and method of administration
Dosage
Humira therapy should be initiated and monitored by specialist physicians experienced in the diagnosis and treatment of the conditions for which Humira is indicated. Patients treated with Humira must be given a special alert card.
After proper instruction on the Humira injection technique, patients can inject themselves if their physician deems appropriate, and with periodic medical check-ups as needed.
Pediatric population
Juvenile idiopathic arthritis
Polyarticular juvenile idiopathic arthritis from 2 to 12 years of age.
The recommended dose of Humira for polyarticular juvenile idiopathic arthritis patients 2 to 12 years of age is 24 mg / m2 body surface area up to a maximum single dose of 20 mg of adalimumab (for patients aged 2-subcutaneously. Volume d " injection is selected based on the patient's height and weight (Table 1).
Table 1. Humira dose in milliliters (ml) by height and weight of patients with polyarticular juvenile idiopathic arthritis and arthritis associated with enthesitis
* The maximum single dose is 40 mg (0.8 ml)
Polyarticular juvenile idiopathic arthritis from 13 years of age
For patients 13 years of age and older, a dose of 40 mg is administered every other week, regardless of body surface area.
For such patients, 40 mg pens and 40 mg pre-filled syringes are also available for administering a full 40 mg dose.
Available data suggest that clinical response is usually achieved within 12 weeks of treatment. In patients whose response to therapy is inadequate within this time period, the need for continued therapy should be carefully considered.
There is no relevant use of Humira in patients less than 2 years of age in this indication
Arthritis associated with enthesitis
The recommended dose of Humira in patients with enthesitis-associated arthritis, aged 6 years and older, is 24 mg / m2 body surface area, up to a maximum single dose of 40 mg adalimumab administered every other week by subcutaneous injection. The injection volume is chosen based on the height and weight of the patient (Table 1).
Humira has not been studied in patients less than 6 years of age with enthesitis-associated arthritis.
Crohn's disease in pediatric patients
Crohn's disease in pediatric patients
The recommended induction dose of Humira in pediatric subjects with severe Crohn's disease is 40 mg at week 0 followed by 20 mg at week 2. If a more rapid response to therapy is required, a regimen of 80 mg at week 0 can be used. (dose can be given as two injections in one day), and 40 mg at week 2, with the understanding that the risk of adverse events may be higher with use of the higher induction dose.
After induction treatment, the recommended dose is 20 mg every other week via a subcutaneous injection. Some individuals with insufficient response may benefit from an increase in dose frequency to Humira 20 mg every week.
Crohn's disease in pediatric patients ≥ 40 kg:
The recommended induction dose of Humira in pediatric subjects with severe Crohn's disease is 80 mg at week 0 followed by 40 mg at week 2. If a more rapid response to therapy is required, a regimen of 160 mg at week 0 can be used. (the dose can be given as four injections in one day or as two injections per day for two consecutive days), and 80 mg at week 2, with the understanding that the risk of adverse events may be higher with the use of the dose of higher induction.
After induction treatment, the recommended dose is 40 mg every other week via a subcutaneous injection. Some individuals with insufficient response may benefit from an increase in dose frequency to 40 mg of Humira each week.
Continued therapy should be carefully considered in a subject unresponsive at week 12.
A 40 mg pen and a 40 mg pre-filled syringe are also available for administration for patients who need a full 40 mg dose.
There is no relevant use of Humira in children aged less than 6 years in this indication
Renal and / or hepatic insufficiency
Humira has not been studied in this type of population. No dosage recommendations can be given.
Method of administration
Humira is given by injection under the skin. Full instructions for use are provided in the package leaflet.
04.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Active tuberculosis or other serious infections such as sepsis and opportunistic infections (see section 4.4).
Moderate to severe heart failure (NYHA class III / IV) (see section 4.4).
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).
Infections
Patients being treated with TNF antagonists are more susceptible to severe infections. Impaired lung function may increase the risk of developing infections, therefore patients should be carefully screened for infections, including tuberculosis, before, during and after treatment with Humira. Since elimination of adalimumab can take up to four months, monitoring should be continued during this period.
Humira therapy should not be initiated in patients with active infections, including chronic or localized infections, until these are under control. In patients who have been exposed to tuberculosis and in patients who have traveled to areas at high risk of tuberculosis or endemic mycosis, such as histoplasmosis, coccidioidomycosis or blastomycosis, the risk and benefit of Humira treatment should be considered before initiating therapy. (to see Other opportunistic infections).
Patients who develop a new infection during Humira therapy should be followed closely and undergo a full diagnostic evaluation. If a new severe infection or sepsis develops, administration of Humira should be discontinued and appropriate antimicrobial or antifungal therapy instituted until the infection is controlled. Physicians should exercise caution when using Humira. in patients with a history of relapsing infections or with concomitant conditions that may predispose patients to infections, including concomitant use of immunosuppressive drugs.
Severe infections:
There have been reports of serious infections, including sepsis, caused by bacteria, mycobacteria, invasive fungi, parasites, viruses or other opportunistic infections such as listeriosis, legionellosis and pneumocystosis in patients treated with Humira.
Other serious infections seen in clinical trials include pneumonia, pyelonephritis, septic arthritis, and septicemia. Cases of hospitalization or fatal events associated with infections have been reported.
Tuberculosis:
Tuberculosis, including reactivation and new onset of tuberculosis, has been reported in patients using Humira. Cases of pulmonary and extra-pulmonary (i.e. disseminated) tuberculosis have been reported.
Before initiating therapy with Humira, all patients should be examined for the presence of active or inactive ("latent") tuberculosis. This evaluation should include a "detailed medical history of patients with a previous history of tuberculosis or any contact with people with active tuberculosis, and with previous and / or concomitant immunosuppressive therapies. Appropriate screening tests (ie skin test at tuberculin and chest X-ray) in all patients (local guidelines may be followed). It is recommended that the performance and results of such tests be recorded in the patient alert card.Physicians should be alert to the risk of false negative tuberculin skin test results, especially in seriously ill or immunocompromised patients.
If active tuberculosis is diagnosed, Humira therapy must not be initiated (see section 4.3).
In all situations described below, a "careful evaluation of the risk / benefit ratio of Humira therapy should be carried out.
If latent tuberculosis is suspected, it is advisable to consult a doctor who specializes in treating tuberculosis.
If latent tuberculosis is diagnosed, anti-tuberculosis prophylaxis treatment should be instituted according to local recommendations before initiating therapy with Humira.
The institution of anti-tuberculosis prophylaxis treatment should also be considered before starting Humira treatment in patients with different or significant risk factors for tuberculosis despite a negative test for tuberculosis and in those patients who they have a personal history of latent or active tuberculosis in which it is not possible to confirm whether the course of treatment they have undergone was adequate.
Despite prophylactic treatment for tuberculosis, cases of reactivation of tuberculosis have occurred in patients treated with Humira. Some patients successfully treated for active tuberculosis have experienced tuberculosis again during treatment with Humira.
Patients should be advised to seek medical attention if signs / symptoms suggestive of possible tuberculous infection (e.g. persistent cough, wasting, weight loss, moderate fever, listlessness) occur during or after Humira therapy.
Other opportunistic infections:
Cases of opportunistic infections, including invasive fungal infections, have been observed in patients taking Humira. These infections have not been correctly diagnosed in patients taking TNF-antagonists and this has resulted in a delay in appropriate treatment, sometimes with a fatal outcome.
In patients who develop signs and symptoms such as fever, malaise, weight loss, sweating, cough, dyspnoea and / or pulmonary infiltrate or other serious systemic disease with or without concomitant shock, an invasive fungal infection should be suspected and treatment should be promptly stopped. Administration of Humira Diagnosis and administration of empirical antifungal therapy in these patients should be made in consultation with a physician who specializes in the treatment of patients with invasive fungal infections.
Reactivation of Hepatitis B
Reactivation of hepatitis B (eg surface antigen positive) has occurred in chronic hepatitis B virus carriers treated with TNF antagonists including Humira. Some cases have had a fatal outcome. Before starting treatment with Humira, patients should be tested for hepatitis B virus infection. Consultation of a physician experienced in treating hepatitis B is recommended for those patients who test positive for Hepatitis B virus. hepatitis B.
Carriers of the hepatitis B virus requiring treatment with Humira should be closely monitored for signs and symptoms of active hepatitis B virus infection not only throughout therapy, but also during the months following the discontinuation of therapy. Adequate data are not available from the treatment of patients with hepatitis B virus undergoing anti-viral therapy in order to avoid reactivation of the hepatitis B virus concomitantly with TNF-antagonist therapy. In patients who develop hepatitis B virus reactivation, administration of Humira should be discontinued and effective anti-viral therapy instituted accompanied by adequate supportive treatment.
Neurological events
TNF-antagonists, including Humira, have been associated in rare cases with new onset or exacerbation of clinical symptoms and / or radiographic evidence of central nervous system demyelinating diseases including multiple sclerosis, optic neuritis and peripheral demyelinating diseases, including Guillain-Barrè syndrome. Caution should be exercised in the use of Humira in those patients with previous or recent onset of central or peripheral nervous system demyelinating disorders.
Allergic reactions
In clinical trials, serious allergic reactions associated with Humira were rare. Non-serious allergic reactions associated with Humira during clinical trials were uncommon. There have been reports of serious allergic reactions including anaphylaxis following administration of Humira. If anaphylactic reactions or other severe allergic manifestations occur, administration of Humira should be discontinued immediately and appropriate therapy initiated.
Immunosuppression
In a study of 64 patients with rheumatoid arthritis, receiving treatment with Humira, there was no evidence of inhibition of delayed hypersensitivity, nor reduction of immunoglobulin levels or changes in the number of T, B, NK, monocyte / cell lymphocytes. macrophages and neutrophils.
Neoplasms and lymphoproliferative diseases
In the controlled sections of the TNF-antagonist clinical trials, more cases of malignancies, including lymphoma, were observed in patients receiving TNF-blockers than in the control group. However, cases were rare. In postmarketing studies, cases of leukemia have been reported in patients treated with a TNF-antagonist. There is a greater increased risk of developing lymphomas and leukemia for patients with severely active and long-lasting rheumatoid arthritis, an inflammatory disease that complicates risk assessment. With current knowledge, the development of lymphomas cannot be ruled out. leukemia and other malignancies in patients treated with anti-TNF drugs.
Cases of cancers, some fatal, have been reported in children, adolescents and young adults (up to age 22 years) treated with TNF antagonists (initiation of therapy ≤ 18 years), including adalimumab, in postmarketing studies. . About half of the cases were lymphomas. The other cases represented a multiplicity of different cancers and included rare cancers usually associated with immunosuppression. A risk for the development of tumors in children and adolescents treated with TNF antagonists cannot be excluded
Rare postmarketing cases of hepatosplenic T-cell lymphoma have been observed in patients treated with adalimumab. This rare type of T-cell lymphoma has a very aggressive clinical course and is often fatal. Some of these cases of hepatosplenic T-cell lymphoma occurred in young adult patients treated with Humira and receiving concomitant therapy with azathioprine or 6-mercaptopurine, drugs used to treat inflammatory bowel disease. The potential risk from the combination of azathioprine or 6-mercaptopurine and Humira should be carefully considered. A risk of developing hepatosplenic T-cell lymphoma cannot be excluded in patients treated with Humira (see section 4.8).
No clinical studies have been conducted in patients with a history of cancer or in patients whose treatment with Humira continued after the development of cancer. Therefore, treatment with Humira in this patient population should be considered with additional caution (see section 4.8).
Before and during treatment with Humira, all patients, particularly those with a history of extensive immunosuppressive therapy or those with psoriasis who have a history of treatment with PUVA, should be examined for the presence of a possible non-melanotic skin cancer. Melanoma and Merkel cell carcinoma have also been reported in patients treated with TNF antagonists, including adalimumab (see section 4.8).
In an exploratory clinical study evaluating the use of another TNF antagonist, infliximab, in patients with moderate to severe chronic obstructive pulmonary disease (COPD), more malignancies were reported in patients treated with infliximab than in control patients. , especially in the lung or head and neck. All patients had a history of heavy smokers. Therefore, caution should be used when using any TNF-antagonist in COPD patients, as well as in patients with increased risk of malignancy due to to excessive smoking.
Based on current data, it is not known whether adalimumab treatment affects the risk of developing dysplasia or colon cancer. All patients with ulcerative colitis who are at increased risk of colon dysplasia or carcinoma (for example, patients with longstanding ulcerative colitis or primary sclerosing cholangitis), or who have had a previous history of dysplasia or cancer of the colon colon should be screened regularly for dysplasia throughout the course of the disease. This evaluation should include colonoscopies and biopsies based on local recommendations.
Reactions affecting the hematopoietic system
Rare cases of pancytopenia, including the occurrence of aplastic anemia, have been reported following the use of anti-TNF drugs. Adverse events affecting the haematopoietic system, including significant cytopenias, have been reported in patients treated with Humira. from a medical point of view (for example, thrombocytopenia, leukopenia). During treatment with Humira all patients should be advised of the need to consult a physician immediately in order to obtain adequate assistance in the event of signs and symptoms suggesting the presence of blood dyscrasia (eg persistent fever, bruising, haemorrhage, paleness) In the case of patients with confirmed significant changes in the haematopoietic system, the need to discontinue Humira therapy should be considered.
Vaccinations
Similar antibody responses to the standard 23-valent pneumococcal vaccine and the trivalent influenza virus vaccine were observed in a study involving 226 adult subjects with rheumatoid arthritis who were treated with adalimumab or placebo. No data available. on secondary transmission of infection from live vaccines in patients taking Humira.
In pediatric patients, it is recommended that the planned vaccination schedule be implemented, if possible, in accordance with current vaccination guidelines before initiating Humira-based therapy.
Humira-treated patients may receive simultaneous vaccinations, with the exception of live vaccines. Administration of live vaccines to infants exposed to adalimumab in utero is not recommended for 5 months following the mother's last adalimumab administration during pregnancy.
Congestive heart failure
Worsening of congestive heart failure and associated mortality have been observed in a clinical trial with another anti-TNF drug. Worsening of congestive heart failure has also been observed in patients treated with Humira. Humira should be used with caution in patients with mild heart failure (NYHA class I / II). Humira is contraindicated in moderate or severe heart failure (see section 4.3). Treatment with Humira should be discontinued in patients with worsening or new symptoms of congestive heart failure.
Autoimmune processes
Treatment with Humira can induce the formation of autoimmune antibodies. The impact of long-term treatment with Humira on the development of autoimmune diseases is not known. If a patient develops symptoms suggestive of lupus-like syndrome following treatment with Humira and is positive for antibodies to double stranded DNA, do not further treatment with Humira should be given (see section 4.8).
Concomitant administration of biological DMARDS or TNF antagonists
Serious infections with no clinical benefit compared to etanercept alone have been observed in clinical trials of combination therapy with anakinra and another anti-TNF drug, etanercept. Given the type of adverse events observed with the combination of anakinra and etanercept, similar side effects may occur following the combination of anakinra and another anti-TNF drug. Therefore, the combination of adalimumab with anakinra is not recommended (see section 4.5).
Concomitant administration of adalimumab with other biological DMARDS (e.g. anakinra and abatacept) or other TNF antagonists is not recommended based on a possible increased risk of infections, including serious infections and other potential drug interactions (see section 4.5).
Surgical interventions
There is "limited" experience with respect to the safety of surgical procedures in patients treated with Humira. The long half-life of adalimumab should be considered when planning surgery. A patient who undergoes surgery while being treated with Humira should be followed closely for the development of infections, in which case action should be taken. There is "limited" experience regarding safety in patients undergoing joint replacement surgery while on Humira.
Small bowel obstruction
Failure to respond to treatment for Crohn's disease may indicate the presence of rigid fibrotic stenosis that may require surgery. Available data suggests that Humira does not worsen or cause strictures.
Older people
The frequency of serious infections among Humira treated patients over 65 years of age (3.5%) was higher than those under 65 years of age (1.5%). Some of these have had a fatal outcome. Particular attention regarding the risk of infection should be paid in the treatment of elderly patients.
Pediatric population
See Vaccinations above.
04.5 Interactions with other medicinal products and other forms of interaction
Humira therapy has been studied as monotherapy and in combination with methotrexate in patients with rheumatoid arthritis, polyarticular juvenile idiopathic arthritis and psoriatic arthritis. Antibody formation was lower when Humira was given in combination with methotrexate than with monotherapy. Administration of Humira without methotrexate resulted in increased antibody formation, increased clearance and decreased efficacy of adalimumab (see section 5.1).
The combination of Humira and anakinra is not recommended (see section 4.4 "Concomitant administration of biologic DMARDs or TNF antagonists").
The combination of Humira and abatacept is not recommended (see section 4.4 "Concomitant administration of biologic DMARDs or TNF antagonists").
04.6 Pregnancy and lactation
Pregnancy
For Humira, limited clinical data on exposed pregnancies are available.
In a developmental toxicity study conducted in monkeys, no maternal toxicity, embryotoxicity or teratogenicity was found. No preclinical data on postnatal toxicity of adalimumab are available (see section 5.3).
Due to TNFα inhibition, administration of adalimumab during pregnancy may interfere with the normal immune response of the newborn. Adalimumab administration is therefore not recommended in pregnancy.
Adalimumab can cross the placenta and reach the serum of babies born to mothers treated with adalimumab during pregnancy. Consequently, these children are subject to a greater risk of infection. Administration of live vaccines to infants exposed to adalimumab in utero is not recommended for 5 months following the mother's last adalimumab administration during pregnancy.
Feeding time
It is unknown whether adalimumab is excreted in human milk or absorbed systemically after ingestion.
However, because human immunoglobulins are excreted in milk, women should not breastfeed for at least five months after their last treatment with Humira.
Fertility
No preclinical data on the effects of adalimumab on fertility are available.
Women of childbearing age. Contraception in men and women
Women of childbearing potential must use adequate contraception to prevent pregnancy and continue its use for at least five months after the last Humira treatment.
04.7 Effects on ability to drive and use machines
Humira has minor effects on the ability to drive or use machines. Dizziness and visual disturbances may occur following administration of Humira (see section 4.8).
04.8 Undesirable effects
Humira has been studied in 8,198 patients in pivotal controlled and open-label clinical trials for up to 60 months or longer. These studies were performed on patients with early onset and long-lasting rheumatoid arthritis, juvenile idiopathic arthritis (polyarticular juvenile idiopathic arthritis and enthesitis-associated arthritis) as well as patients with axial spondyloarthritis (ankylosing spondylitis and axial spondyloarthritis without radiographic evidence of ankylosing spondylitis), psoriatic arthritis, Crohn's disease, ulcerative colitis and psoriasis.The pivotal controlled studies were conducted in 5,343 patients receiving Humira and 3,148 patients receiving placebo or an active comparator during the control period.
The percentage of patients who discontinued treatment due to adverse events during the double-blind, controlled phase of the pivotal studies was 6.1% for patients taking Humira and 5.7% for treated patients. with control.
Summary of the safety profile
The most commonly reported adverse reactions are infections (such as nasopharyngitis, upper respiratory tract infection and sinusitis), administration site reactions (erythema, pruritus, haemorrhage, pain or swelling), headache and musculoskeletal pain.
Serious adverse reactions have been reported for Humira. TNF-blocking drugs, such as Humira, affect the immune system and their use can affect the body's defenses against infections and cancer.
Cases of fatal infections (including cases of sepsis, opportunistic infections and TB), reactivation of HBV infection and various types of malignancies (including cases of leukemia, lymphoma and hepato-lymphoma) have also been reported following administration of Humira. splenic T-HSTCL cells).
Severe haematological, neurological and autoimmune reactions have also been reported. The latter include rare cases of pancytopenia, aplastic anemia, central and peripheral demyelination events and cases of lupus, lupus-related conditions and Stevens-Johnson syndrome.
Pediatric population
Undesirable effects in pediatric patients
In general, adverse events in pediatric patients were similar to those seen in adult patients in terms of both frequency and type.
Adverse Reaction List Table
The following list of adverse reactions is based on experience from clinical trials and post marketing experience and is classified by system / organ involved and frequency (very common ≥1 / 10; common ≥1 / 100 to
Table 2
Side effects
* there is further information contained in sections 4.3, 4.4 and 4.8
** including open label extension studies
1) including data from spontaneous reports
Description of selected adverse reactions
Reactions at the injection site
In pivotal controlled clinical trials in adults and children, 13.6% of patients treated with Humira experienced injection site reactions (erythema and / or pruritus, haemorrhage, pain or edema), versus 7.6% of patients treated with placebo or active control. Injection site reactions did not generally require drug discontinuation.
Infections
In the pivotal controlled clinical trials in adults and children, the infection rate was 1.52 per patient / year in the Humira group and 1.45 per patient / year in the placebo and active control groups. infections were mainly represented by nasopharyngitis, upper respiratory tract infections and urinary tract infection. Most patients continued to take Humira after the infection cleared.
The incidence of serious infections was 0.04 per patient / year in the Humira group and 0.03 per patient / year in the placebo and active controlled groups.
In controlled and open-label studies with Humira in adults and children, serious infections (including fatal infections, which occurred only rarely), including case reports of tuberculosis (including miliary and extra-pulmonary locations) have been reported ) and invasive opportunistic infections (for example, disseminated or extrapulmonary histoplasmosis, blastomycosis, coccidioidomycosis, pneumocystosis, candidiasis, aspergillosis, and listeriosis). Most cases of tuberculosis occurred within the first eight months after initiation of therapy and can be interpreted as a resurgence of latent disease.
Neoplasms and lymphoproliferative diseases
In studies performed by administering Humira to patients with juvenile idiopathic arthritis (polyarticular juvenile idiopathic arthritis and enthesitis-associated arthritis), no malignancies were observed in 249 pediatric patients with an exposure of 655.6 patient-years. In addition No malignancies were observed in 192 pediatric patients with an exposure of 258.9 patient-years during a study administered Humira to pediatric patients with Crohn's disease.
In controlled sections of adult pivotal studies with Humira lasting at least 12 weeks in patients with moderate to severe active rheumatoid arthritis, ankylosing spondylitis, axial spondyloarthritis without radiographic evidence of ankylosing spondylitis, psoriatic arthritis, psoriasis, Crohn's disease and ulcerative colitis, neoplasms, as well as lymphoma and non-melanotic skin cancer were observed at a rate (95% confidence interval) of 6.0 (3.7, 9.8) per 1,000 patient-years among 4,622 treated patients with Humira to a rate of 5.1 (2.4, 10.7) per 1,000 patient-years of 2,828 control patients (median duration of treatment was 5.1 months for Humira-treated patients and 4.0 months for patients check). The rate (95% confidence interval) of non-melanotic skin cancers was 9.7 (6.6; 14.3) per 1,000 patient-years in Humira-treated patients and 5.1 (2.4; 10 , 7) per 1,000 patient-years in control patients. Of these skin cancers, squamous cell carcinomas occurred at rates (95% confidence interval) of 2.6 (1.2; 5.5) per 1,000 patient-years in Humira-treated patients and 0.7 ( 0.1; 5.2) per 1,000 patient-years in control patients. The rate (95% confidence interval) of lymphomas was 0.7 (0.2, 3.0) per 1,000 patient-years in Humira-treated patients and 1.5 (0.4, 5.8) per 1,000 patient-years in control patients.
When parts of these studies and both ongoing and completed open label extension studies are combined, with a mean duration of approximately 3.4 years including 5,727 patients and more than 24,568 patient-years of therapy, the observed neoplasms rate, apart from lymphoma and non-melanotic skin cancer, is approximately 8.8 per 1,000 patient-years. The observed rate of non-melanotic skin cancer is approximately 10.3 per 1,000 patient-years and the observed rate of lymphomas is approximately 1.4 per 1,000 patient-years.
In a post-marketing experience from January 2003 to December 2010, mainly in patients with rheumatoid arthritis, the reported rate of neoplasms is approximately 2.7 per 1,000 treatment / patient years. The reported rates for non-melanotic skin cancers and lymphomas are approximately 0.2 and 0.3 per 1,000 treatment / patient years, respectively (see section 4.4).
Rare cases of hepatosplenic T-cell lymphoma have been reported in post-marketing experience in patients treated with adalimumab (see section 4.4).
Autoantibodies
In rheumatoid arthritis IV studies, patient serum samples were tested on various occasions for autoantibodies. In these studies, 11.9% of patients treated with Humira and 8.1% % of placebo- and active-controlled patients who had negative antinuclear antibody values at enrollment had positive values at week 24. Two of 3,441 patients treated with Humira in all rheumatoid arthritis and Psoriatic arthritis exhibited clinical signs indicating the onset of a lupus-like syndrome. Patients improved after discontinuation of therapy. No patient developed lupus nephritis or central nervous system symptoms.
Hepato-biliary events
In controlled Phase 3 clinical trials of Humira in patients with rheumatoid arthritis and psoriatic arthritis with a control period duration of 4 to 104 weeks, ALT transaminase elevations greater than or equal to 3 times the maximum normal value occurred in the 3.7% of Humira-treated patients and 1.6% of control-treated patients.
In controlled Phase 3 clinical trials of Humira in patients with plaque psoriasis with a control period duration ranging from 12 to 24 weeks, ALT elevations greater than or equal to 3 times the maximum normal value occurred in " 1.8% of Humira-treated patients and 1.8% of control-treated patients.
In controlled Phase 3 clinical trials of Humira in polyarticular juvenile idiopathic arthritis patients who were 4 to 17 years of age and in patients with enthesitis-associated arthritis, 6 to 17 years of age, ALT elevations greater than or equal to a 3-fold ULN occurred in 6.1% of Humira-treated patients and 1.3% of control-treated patients. Most ALT transaminase elevations occurred with concomitant use of methotrexate. There were no ALT transaminase elevations ≥ 3 x ULN in the Phase 3 clinical trial of Humira in patients with polyarticular juvenile idiopathic arthritis. 2 and
In controlled Phase 3 clinical trials of Humira in patients with Crohn's disease and ulcerative colitis with a control period ranging from 4 to 52 weeks, ALT transaminase elevations greater than or equal to 3 times the maximum normal value occurred in the 0.9% of Humira-treated patients and 0.9% of control-treated patients.
In the Phase 3 study of Humira in pediatric patients with Chron's disease, which evaluated the safety and efficacy of two weight-adjusted dosing regimens for maintenance therapy following weight-adjusted induction therapy up to 52 weeks, ALT levels ≥ 3 x ULN were found in 2.6% of all patients exposed to concomitant treatment with baseline immunosuppressants.
In clinical trials, across all indications, patients with elevated transaminase levels were asymptomatic and elevations were transient and resolved during treatment in most cases. However, post-marketing cases of hepatic failure as well as less severe liver disorders that may precede liver failure, such as hepatitis including autoimmune hepatitis, have also been reported in patients treated with adalimumab.
Concomitant treatment with azathioprine / 6-mercaptopurine
In adult Crohn's disease studies, higher incidences of adverse events related to serious infections and malignancies were observed with the combination of Humira and azathioprine / 6-mercaptopurine compared to Humira alone.
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 via the Italian Medicines Agency. , website: http://www.agenziafarmaco.gov.it/it/responsabili.
04.9 Overdose
No dose-related toxicity was observed during clinical studies. The highest dose evaluated was multiple doses of 10 mg / kg intravenously; this dose is equivalent to approximately 15 times the recommended dose.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: Selective immunosuppressive agents. ATC code: L04AB04
Mechanism of action
Adalimumab selectively binds to TNF and neutralizes its biological function by blocking its interaction with the cell membrane TNF receptors, p55 and p75.
Adalimumab also modulates biological responses that are induced or regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 0.1-0, 2 nM).
Pharmacodynamic effects
After treatment with Humira, a rapid decrease in acute phase proteins, inflammation indices (C reactive protein -PCR, erythrocyte sedimentation rate -VES) and serum cytokines (IL-6) was observed in patients with rheumatoid arthritis compared to the basal. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3), involved in tissue remodeling responsible for cartilage destruction, were also decreased following administration of Humira. Humira-treated patients generally showed improvement in blood chemistry signs of chronic inflammation.
A rapid decrease in CRP (C reactive protein) levels was also observed in patients with Polyarticular Juvenile Idiopathic Arthritis, Crohn's disease and ulcerative colitis after treatment with Humira. reduction in the number of cells expressing inflammatory markers in the colon including a significant reduction in TNFα expression. Endoscopic studies of the intestinal mucosa have shown mucosal healing in patients treated with adalimumab.
Clinical efficacy and safety
Juvenile Idiopathic Arthritis (JIA)
Polyarticular Juvenile Idiopathic Arthritis (pJIA)
The safety and efficacy of Humira were evaluated in two studies (pJIA I and II) in children with active polyarticular or polyarticular course juvenile idiopathic arthritis, who had different types of JIA onset (most frequently rheumatoid factor negative or positive polyarthritis and extensive oligoarthritis).
pJIA-I
The safety and efficacy of Humira were evaluated in a multicentre, randomized, double-blind, parallel-group study in 171 children (aged 4-17 years) with polyarticular juvenile idiopathic arthritis (JIA). . During the open-label lead in phase = OL LI, patients were stratified into two groups, the MTX (methotrexate) group and the MTX untreated group. untreated arm with MTX had either never been treated with MTX before or had stopped taking MTX at least two weeks prior to study drug administration. Patients were given constant doses of non-steroidal anti-inflammatory drugs (NSAIDs) and / or prednisone (≤0.2 mg / kg / day or a maximum of 10 mg / day) During the OL LI phase, all patients received Humira 24 mg / m2 up to a maximum dose of 40 mg. every other week for 16 weeks The distribution of patients by age and the minimum, mean and maximum dose administered during the OL LI phase are shown in Table 3.
Table 3
Distribution of patients by age and adalimumab dose administered during the OL LI phase
Patients who demonstrated a pediatric ACR30 response at week 16 were eligible to be randomized to the Double Blind (DB) phase and received Humira 24 mg / m2 up to a maximum of 40 mg or placebo. every other week for an additional 32 weeks or until disease flare-up. The criteria for defining the disease exacerbation were defined on the basis of a worsening greater than or equal to 30% (≥ 30%) compared to the baseline value of 3 or more of the 6 main criteria of the "ACR Paediatric core", in the presence of 2 or more active joints, and based on a greater than 30% improvement in no more than 1 of the above 6 criteria. After 32 weeks or when the disease flare-up occurred, patients were deemed eligible to be admitted to the open extension phase.
Table 4
PedACR 30 response during the JIA study
a PedACR 30/50/70 responses at week 48 were significantly greater than those achieved in placebo-treated patients
b p = 0.015
c p = 0.031
Among those who responded to treatment at week 16 (n = 144), Ped ACR 30/50/70/90 responses were maintained for up to six years during the OLE phase in patients who received Humira during the course of the whole studio. Overall, 19 subjects, including 11 from the base group aged 4 to 12 and 8 from the base group aged 13 to 17, were treated for 6 years or more.
Overall responses were generally better And few patients developed antibodies when treated with Humira and MTX combination therapy compared to Humira treatment given alone. Taking these results into consideration, the use of Humira is recommended in combination with MTX and as monotherapy in patients for whom the use of MTX is not recommended (see section 4.2).
pJIA II
The safety and efficacy of Humira was evaluated in an open-label multicenter study in 32 children (2-2 body surface area of Humira up to a maximum of 20 mg every other week as a single subcutaneous dose for at least 24 weeks. in the study, most subjects were concurrently using MTX, with some subjects reporting use of corticosteroids or non-steroidal anti-inflammatory drugs (NSAIDs).
At week 12 and week 24, the PedACR30 response was 93.5% and 90.0%, respectively, using the observed data approach. The proportions of subjects with PedACR50 / 70/90 at week 12 and week 24 were , respectively, 90.3% / 61.3% / 38.7% and 83.3% / 73.3% / 36.7%. Among those responding (PedACR30) at week 24 (n = 27 of 30 patients ), PedACR30 responses were maintained for up to 60 weeks in patients receiving Humira during this period in the open-label extension study. In total, 20 subjects were treated for 60 weeks or longer.
Arthritis associated with enthesitis
The safety and efficacy of Humira were evaluated in a multicentre, randomized, double-blind study in 46 pediatric patients (6 to 17 years of age) with moderate arthritis-associated enthesitis. Patients were randomized to receive or Humira 24 mg / m2 body surface area, up to a maximum of 40 mg, or placebo every other week for 12 weeks. The double-blind period was followed by an open-label study period, during which patients received Humira 24 mg / m2 body surface area, up to a maximum of 40 mg subcutaneously every other week, for an additional 192 weeks. The primary endpoint was the percent change in the number of joints with active arthritis from baseline to at week 12 (swelling not due to deformity or joints with loss of motion plus pain and / or tenderness), and was achieved with a mean percentage decrease of -62.6% (median percentage change - 88.9%) in patients in the Humira group versus -11.6% (median percent change - 50.0%) in patients in the placebo group. The improvement in the number of active joints with arthritis was maintained during the open label period of the study up to week 52. Although not statistically significant, most patients demonstrated clinical improvement in the secondary endpoint, such as the number of sites of enthesitis, painful joint count (TJC), swollen joint count (SJC), Pediatric ACR 50 response, and Pediatric ACR 70 response.
Adult rheumatoid arthritis
Humira has been evaluated in over 3,000 patients in all clinical trials in rheumatoid arthritis. The efficacy and safety of Humira were evaluated in five randomized, double-blind, well-controlled studies. Some patients have been treated for up to 120 months.
RA study I was conducted in 271 patients ≥ 18 years of age with moderate to severe rheumatoid arthritis refractory to at least one DMARD including methotrexate at doses ranging from 12.5 to 25 mg (10 mg if intolerant to methotrexate) per week and whose methotrexate dose remained constant at 10-25 mg per week. Humira 20, 40, or 80 mg or placebo was given every other week for 24 weeks.
Study AR II studied 544 patients aged ≥ 18 years with moderate to severe rheumatoid arthritis with insufficient response to at least one DMARD drug. Doses of 20 or 40 mg of Humira were given by subcutaneous injection every two weeks with placebo every other week, or every week for 26 weeks; placebo was given every week for the same duration. The use of other DMARDs was not allowed.
Study AR III involved 619 patients, ≥ 18 years of age, with moderate to severe active rheumatoid arthritis with inadequate response to methotrexate therapy at doses ranging from 12.5 to 25 mg, or intolerant to 10 mg methotrexate every week. In this study, 3 groups were formed. The former received placebo injections every week for 52 weeks. The second received Humira 20 mg per week for 52 weeks, while the third received Humira 40 mg every two weeks and placebo injections every other week. Upon completion of the first 52 weeks, 457 patients were enrolled in an open-label extension phase where Humira / MTX was administered at a dose of 40 mg every other week for up to 10 years.
The AR IV study first assessed the safety of Humira in 636 patients with moderate to severe active rheumatoid arthritis aged ≥ 18 years. The study population consisted of both patients never treated with DMARDs and patients who had continued pre-existing anti-rheumatic therapy provided that this was stable for a minimum of 28 days. These therapies include methotrexate, leflunomide, hydroxychloroquine, sulfasalazine and / or gold salts. Patients were randomized to receive Humira 40 mg or placebo every two weeks for 24 weeks.
The AR study V evaluated 799 adult patients who had never been treated with methotrexate before and had moderate to severe early active rheumatoid arthritis (mean duration of disease less than 9 months). This study evaluated the efficacy of Humira 40 mg given every other week in combination with methotrexate, Humira 40 mg given as monotherapy every other week and methotrexate alone in reducing the signs and symptoms of disease and index of progression of joint damage caused by rheumatoid arthritis for 104 weeks.
The primary endpoint of AR studies I, II, III, and the secondary endpoints of AR IV, was to assess the proportion of patients achieving an ACR 20 response at week 24 or 26. The primary objective of the AR V study was to evaluate of the percentage of patients achieving an ACR 50 response at week 52. In addition, the AR studies III and V had the main objective of demonstrating inhibition of disease progression (through radiographic examinations) at week 52. The AR study III it also had the primary objective of demonstrating improved quality of life.
ACR response
The percentages of Humira-treated patients achieving ACR 20, 50, and 70 responses were comparable in AR studies I, II and III. Results for treatment with 40 mg every two weeks are summarized in Table 5.
In AR studies I-IV, all parameters evaluated for the definition of the ACR response (number of painful and swollen joints, evaluation of disease activity by the doctor and patient, evaluation of pain by the patient, disability index - HAQ) and CRP values (mg / dL) improved at 24 or 26 weeks compared to placebo. In study AR III, these improvements were maintained over 52 weeks.
In the open-label extension phase of the AR III study, most patients who experienced an ACR response maintained the response when they continued treatment for 10 years. Of a total of 207 patients, 114 continued on Humira 40 mg every other week for 5 years. Of these, 86 patients (75.4%) had ACR 20 responses; 72 patients (63.2%) had ACR 50 responses; and 41 patients (36%) had ACR 70 responses. Of a total of 207 patients, 81 continued treatment with Humira 40 mg every other week for 10 years. Of these, 64 patients (79.0%) had ACR 20 responses; 56 patients (69.1%) had ACR 50 responses; and 43 patients (53.1%) had ACR 70 responses.
In the AR IV study, the ACR 20 response of patients treated with Humira, in combination with conventional therapy, was statistically significantly better than in patients treated with placebo combined with traditional drugs (p
In RA studies I-IV, Humira-treated patients achieved statistically significantly higher ACR 20 and 50 responses than placebo as early as 1-2 weeks after starting treatment.
In RA study V, in patients with early rheumatoid arthritis who had never previously been treated with methotrexate, Humira / methotrexate combination therapy resulted in faster and significantly greater ACR responses than methotrexate monotherapy and Humira monotherapy at week 52 and these responses persisted over 104 weeks (see Table 6).
At week 52, 42.9% of patients receiving Humira / methotrexate combination therapy achieved clinical remission (DAS28
Radiological response
In the AR study III, in which Humira-treated patients had a mean disease duration of approximately 11 years, structural damage was assessed radiographically and expressed as a change in the modified Total Sharp Score (TSS) and related components, erosion and joint space narrowing (JSN) indices. Humira / MTX-treated patients showed significantly less radiological progression than patients who received MTX alone, at 6 and 12 months (see Table 7).
In the open-label extension of the AR study III, the reduction in the rate of progression of structural damage is maintained for 8 and 10 years in a subset of patients. At 8 years, 81 of 207 patients originally treated with Humira 40 mg every other week are Among these, 48 patients showed no progression of structural damage defined by a change in mTSS of 0.5 or less from baseline. At 10 years, 79 of 207 patients originally treated with Humira 40 mg every other week of these, 40 patients did not demonstrate progression of structural damage defined by a change in mTSS of 0.5 or less from baseline.
Table 7
Mean radiographic change after 12 months in the AR III study
to methotrexate
b 95% confidence interval for differences in index changes between methotrexate and Humira.
c Based on rank analysis.
d Joint Space Narrowing (joint gap reduction).
In the AR study V, structural joint damage was assessed radiographically and is expressed in terms of the change in the modified Total Sharp Score (see Table 8).
After 52 weeks and 104 weeks of treatment, the proportion of patients who did not progress (change from baseline in modified Total Sharp Score ≤ 0.5) was significantly higher with Humira / methotrexate combination therapy ( 63.8% and 61.2% respectively) compared to methotrexate monotherapy (37.4% and 33.5%, respectively, p
Quality of life and physical function
Quality of life and physical function were assessed with the disability index obtained through the Health Assessment Questionnaire (HAQ), in four original, adequate and well-controlled studies, and was one of the primary endpoints of the AR study III at week 52. All Humira regimens in the four studies showed statistically significant improvements in the disability index of HAQ between baseline and month 6 compared to placebo and in the AR study III the same result was observed at week 52. The analysis of general health status, assessed by the Short Form Health Survey (SF -36) in the four studies, supports these conclusions for all Humira dosing regimens with statistically significant results. as regards the indices of physical activity, pain and well-being, recorded with Humira 40 mg per weeks alternating. A statistically significant decrease in the sense of fatigue as shown by the indices of the functional evaluation relating to the treatment of chronic disease (FACIT) was found in all three studies in which it was evaluated (studies AR I, III, IV).
In the AR III study, the majority of subjects who achieved improvement in physical function and who continued treatment maintained improvement for 520 weeks (120 months) of open-label treatment. The improvement in quality of life was measured up to week 156 (36 months) and the improvement was maintained over time.
In the AR study V, the disability index assessed on the basis of the HAQ and the physical component of the SF 36 showed a superior improvement (p
Crohn's disease in pediatric patients
Humira was tested in a multicentre, randomized, double-blind clinical study designed to evaluate the efficacy and safety of weight-dependent dose-dependent induction and maintenance treatment (30. Subjects must have failed conventional therapy (including a corticosteroid and / or an immunomodulator) for CD, and subjects may have previously lost response or been intolerant to infliximab.
All subjects received open-label induction therapy with a dose based on their body weight at baseline: 160 mg at week 0 and 80 mg at week 2 for subjects weighing ≥ 40 kg, and 80 mg and 40 mg, respectively. for subjects with weight
At week 4, based on their body weight, subjects were randomized 1: 1 to either the Low Dose or Standard Dose maintenance regimens, as shown in Table 9.
Effectiveness results
The primary endpoint of the study was clinical remission at week 26, defined by a PCDAI score ≤ 10.
Clinical remission and clinical response rates (defined as PCDAI score reduction of at least 15 points from baseline) are shown in Table 10. Corticosteroid or immunomodulator discontinuation rates are shown in Table 11.
Statistically significant increases (improvements) in Body Mass Index and rate of growth rate from baseline to Week 26 and 52 were observed for both treatment groups.
Statistically and clinically significant improvements from baseline in quality of life parameters (including IMPACT III) were also observed in both treatment groups.
Crohn's disease in adults
The safety and efficacy of Humira have been evaluated in over 1,500 patients with moderately to severely active Crohn's Disease (Crohn's Disease Activity Index (CDAI) ≥ 220 and ≤ 450) in randomized, double-blind, placebo-controlled trials. Concomitant administration of constant doses of aminosalicylates, corticosteroids, and / or immunomodulatory agents was allowed and 80% of patients continued to take at least one of these drugs.
The induction of clinical remission (defined as CDAI
Maintenance of clinical remission was evaluated in CD study III (CHARM). In CD study III, 854 patients received open-label Humira 80 mg at week 0 and 40 mg at week 2. At week 4, patients were randomized to receive 40 mg every other week, 40 mg every week, or placebo; the total duration of the study was 56 weeks. Patients who exhibited an adequate clinical response (CDAI decrease ≥ 70) at week 4 were stratitized and analyzed separately from those who did not exhibit an adequate clinical response at week 4. A gradual reduction in dose was allowed. corticosteroids after week 8.
The induction rates of clinical remission and response from CD study I and CD study II are shown in Table 12.
Similar remission rates were observed in the induction dose group of 160/80 mg and 80/40 mg by week 8 and adverse events occurred more frequently in the 160/80 mg dose group. 80 mg.
In CD study III, at week 4, 58% (499/854) of patients experienced an adequate clinical response and were evaluated in the primary analysis. Of the patients who experienced an adequate clinical response at week 4, 48 % had previously been exposed to therapy with other TNF antagonist drugs. The percentages for maintenance of remission and clinical response are shown in Table 13. The results for clinical remission remained relatively constant regardless of previous exposure to anti-drug drugs. -TNF.
At week 56, hospitalizations and disease-related surgery were statistically significantly reduced with adalimumab compared with placebo.
Among patients who did not show adequate response at week 4, 43% of patients treated with Humira maintenance therapy experienced an adequate response by week 12 compared with 30% of patients treated with placebo. These results suggest that some patients who did not exhibit an adequate response at week 4 benefit from continued maintenance therapy through week 12. Therapy continued beyond 12 weeks did not lead to a significantly higher number of responses (see section 4.2 ).
117/276 patients from CD study I and 272/777 patients from CD studies II and III were followed for at least 3 years of open-label adalimumab therapy. 88 and 189 patients, respectively, continued to maintain clinical remission. Clinical response (CR-100) was maintained in 102 and 233 patients, respectively.
Quality of life
In Studies CD I and CD II, statistically significant improvement in disease-specific inflammatory bowel disease questionnaire (IBDQ) total score was achieved at week 4 in patients randomized to Humira 80/40 mg and 160/80 mg compared to placebo and was seen at week 26 and 56 in Study D III as well as between the Humira treatment groups compared to the placebo group
Immunogenicity
Formation of anti-adalimumab antibodies is associated with increased clearance and decreased efficacy of adalimumab. There is no clear correlation between the presence of anti-adalimumab antibodies and the onset of adverse events.
In polyarticular juvenile idiopathic arthritis patients aged 4-17 years, anti-adalimumab antibodies were identified in 15.8% of patients (27/171) treated with adalimumab. In patients not given methotrexate with Humira, the incidence was 25.6% (22/86) versus 5.9% (5/85) when adalimumab was used in combination with methotrexate. .
In patients with enthesitis-associated arthritis, anti-adalimumab antibodies were identified in 10.9% (5/46) of patients treated with adalimumab. In patients who did not receive methotrexate concomitantly with Humira, the incidence was 13.6% (3/22), compared with 8.3% (2/24) when adalimumab was used in combination with methotrexate.
Patients in the rheumatoid arthritis studies were screened at various time intervals for antibodies to adalimumab during the 6 to 12 month period. In the pivotal clinical studies, antibodies to adalimumab were detected in 5.5% (58/1053) of patients treated with adalimumab, compared with 0.5% (2/370) of patients treated with placebo. In patients not given concomitant methotrexate, the incidence was 12.4% , compared with 0.6% when adalimumab was used in combination with methotrexate.
Since immunogenicity assays are product specific, comparison of antibody quantities with other products is not appropriate.
05.2 Pharmacokinetic properties
Absorption and distribution
After subcutaneous administration of 24mg / m2 (up to a maximum of 40mg) every other week to patients aged 4 to 17 years with polyarticular juvenile idiopathic arthritis (JIA) the mean minimum equilibrium value of serum adalimumab concentration (measured values from weeks 20 to 48) was 5.6 ± 5.6 μg / mL (102% CV) with adalimumab without concomitant use of methotrexate and 10.9 ± 5.2 μg / mL (47 , 7% CV) co-administered with methotrexate.
In patients with polyarticular JIA ages 2 to 2, the mean trough equilibrium serum concentration of adalimumab was 6.0 ± 6.1 μg / mL (101% CV) with adalimumab without concomitant use of methotrexate. and 7.9 ± 5.6 mcg / mL (71.2% CV) when co-administered with methotrexate.
Following subcutaneous administration of 24 mg / m2 (up to a maximum of 40 mg) every other week to patients 6-17 years of age with enthesitis-associated arthritis, the mean minimum value of adalimumab serum concentrations at steady-state (measured values at week 24) were 8.8 ± 6.6 mcg / mL with adalimumab without concomitant use of methotrexate and 11.8 ± 4.3 mcg / mL when co-administered with methotrexate.
In pediatric patients with moderate to severe CD, the induction dose of open-label adalimumab was 160/80 mg or 80/40 mg at weeks 0 and 2, respectively, depending on the body weight cut-off at 40 kg. . At week 4, patients were randomized 1: 1 based on body weight into either the Standard Dose (40/20 mg every other week) or Low Dose (20/10 mg every other week) treatment group. Mean (± SD) serum concentrations of adalimumab trough levels reached at week 4 were 15.7 ± 6.6 mg / mL for patients ≥ 40 kg (160/80 mg) and 10.6 ± 6.1 mg / mL for patients
For patients remaining on their randomized therapy, mean (± SD) trough concentrations of adalimumab at week 52 were 9.5 ± 5.6 mg / mL for the standard dose group and 3.5 ± 2.2 mg / mL for the Low Dose group. Mean trough concentrations were maintained in patients who continued to receive adalimumab treatment every other week for 52 weeks. For patients increasing the dose from an alternate-week to a weekly regimen, the mean (± SD) serum concentrations of adalimumab at week 52 were 15.3 ± 11.4 mcg / mL (40/20 mg, per week) and 6.7 ± 3.5 mcg / mL (20/10 mg, per week).
Adults
Following subcutaneous administration of a single 40 mg dose, the absorption and distribution of adalimumab was slow, with peak serum concentrations occurring approximately 5 days after administration. The mean absolute bioavailability of adalimumab from the three studies following one dose subcutaneous dose of 40 mg was 64%. After single intravenous doses of 0.25 to 10 mg / kg, concentrations were dose proportional. After doses of 0.5 mg / kg (≈40 mg), clearance ranged from 11 to 15 mL / hour, the volume of distribution (Vss) ranged from 5 to 6 liters, and the mean half-life of the final phase was approximately two weeks. Concentrations of adalimumab in synovial fluid in various rheumatoid arthritis patients ranged from 31-96% of those in serum.
Following subcutaneous administration of 40 mg adalimumab every two weeks in adult patients with rheumatoid arthritis (RA), trough concentrations averaged approximately 5 mg / mL (without concomitant methotrexate) and 8-9 mg / mL (in combination with methotrexate). The trough serum levels of adalimumab at equilibrium following subcutaneous doses of 20, 40 and 80 mg every 2 weeks or weekly increased in an almost dose-dependent manner.
Elimination
Population pharmacokinetic analyzes on a sample of more than 1,300 RA patients showed a tendency for an apparent increase in adalimumab clearance as body weight increases. After correction for body weight, gender and age differences are found to have minimal effect on adalimumab clearance. Serum levels of free adalimumab (unbound to anti-adalimumab antibodies - AAA) were lower in patients with measurable AAA titers. Humira has not been studied in patients with renal insufficiency or hepatic.
Hepatic or renal insufficiency
Humira has not been studied in patients with hepatic or renal insufficiency.
05.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on single dose toxicity, repeated dose toxicity and genotoxicity studies.
An embryo-fetal development / perinatal development toxicity study was conducted in cynomologous monkeys with dosages of 0, 30 and 100 mg / kg (9-17 monkeys / group); this study revealed no fetal harm caused by adalimumab. Carcinogenicity testing and standard fertility and postnatal toxicity assessments were not conducted due to lack of appropriate models for an antibody with limited cross-reactivity to TNF in rodents and development of neutralizing antibodies in rodents.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Mannitol
Citric acid monohydrate
Sodium citrate
Sodium monobasic phosphate dihydrate
Disodium phosphate dihydrate
Sodium chloride
Polysorbate 80
Sodium hydroxide
Water for injections.
06.2 Incompatibility
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
06.3 Period of validity
24 months
06.4 Special precautions for storage
Store in a refrigerator (2 ° C - 8 ° C). Do not freeze. Keep the vial in the carton to protect the medicine from light.
06.5 Nature of the immediate packaging and contents of the package
Humira 40 mg solution for injection is contained in a single-dose vial (type I glass), closed with rubber stoppers, covered with an aluminum layer and a flip-off closure.
1 pack of 2 boxes each containing:
1 vial (0.8 ml sterile solution), 1 empty sterile syringe, 1 needle, 1 vial adapter and 2 alcohol swabs.
06.6 Instructions for use and handling
Humira 40 mg solution for injection contains no preservatives. Unused medicine and wastes derived from this medicine must be disposed of in accordance with local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
Maidenhead
SL6 4XE
UK
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/03/256/001 40 mg solution for injection 1 vial 0.8 ml + 1 syringe + 2 swabs for subcutaneous use 035946019 / E
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 8 September 2003
Date of most recent renewal: 8 September 2008
10.0 DATE OF REVISION OF THE TEXT
09/2014
