Ремикейд®
Producer: Merck Sharp & Dohme Corp. (Merck Sharp and Doum of the Building) USA
Code of automatic telephone exchange: L04AB02
Release form: Liquid dosage forms. Lyophilisate for preparation of solution for infusions.
General characteristics. Structure:
Active ingredient: 100 mg of an infliksimab in 1 bottle.
Excipients: hydrophosphate sodium dihydrate, dihydrophosphate sodium monohydrate, sucrose, polysorbate 80.
Pharmacological properties:
Pharmacodynamics. FNOα inhibitor. Infliksimab represents a chimeric mouse and human monoclone which with high affinity contacts the soluble and transmembrane FNOα forms, but the alpha (ЛТα) does not contact lymphotoxin.
Infliksimab inhibits functional activity ФНОα in various studied in vitro samples. Use of an infliksimab for transgene mice prevented development of the polyarthritis connected with a constitutional expression human ФНОα. Introduction of an infliksimab after an onset of the illness led to healing of structural injuries of joints. In vivo инфликсимаб quickly forms stable complexes with human ФНОα that is followed by decrease in biological activity ФНОα.
The increased concentration ФНОα decided in joints of patients on a pseudorheumatism and correlated with activity of a disease. Patients with a pseudorheumatism have a therapy infliksimaby led to reduction of infiltration of cells of an inflammation to the inflamed sites of joints, and also to decrease in an expression of the molecules mediating cellular adhesion, a hemoattraktion and destruction of fabrics. After therapy infliksimaby decrease in serumal concentration interleykina-6 (IL-6) and the S-reactive Protein (SRP), and also increase in concentration of hemoglobin at patients with a pseudorheumatism with the concentration of hemoglobin lowered in comparison with basic level was noted. Significant decrease in number of lymphocytes in peripheral blood or their proliferative response to mitogenetic stimulation in comparison with the answer of cells of not treated patients of in vitro was not revealed.
Patients with psoriasis have a therapy infliksimaby led to decrease in an inflammation in an epidermal layer and normalization of a differentiation of keratinotsit in psoriasis plaques. At patients with psoriasis arthritis short-term therapy by the drug Remikeyd® was followed by decrease in number of T-cells and blood vessels in the synovial membrane and sites of skin struck with psoriasis process.
At a histologic research of the bioptat of a large intestine taken to and in 4 weeks after introduction of an infliksimab essential decrease in concentration ФНОα was revealed. Therapy infliksimaby patients with a disease Krone was followed by considerable decrease in concentration of a nonspecific seromarker of an inflammation - SRB. Total number of leukocytes of peripheral blood at therapy infliksimaby changed in the minimum degree though for lymphocytes, monocytes and neutrophils the tendency to normalization of their number was observed. At the patients receiving инфликсимаб the proliferative response of mononuclear cells of peripheral blood to stimulation did not decrease in comparison with that at not treated patients. Essential changes of secretion of cytokines by triggered mononuclear cells of peripheral blood after therapy infliksimaby were not revealed. Studying of mononuclear cells of bioptat of own plate of a mucous membrane of a gut showed that therapy infliksimaby causes decrease in number of the cells expressing ФНОα and interferon scale. Additional histologic researches confirmed what инфликсимаб reduces infiltration of cells of an inflammation and the maintenance of markers of an inflammation in affected areas of a gut. Endoscopic researches showed healing of a mucous membrane of a gut at the patients receiving инфликсимаб.
Pharmacokinetics. Distribution. Single in/in infusional introduction of an infliksimab in doses of 1, 3, 5, 10 or 20 mg/kg was followed by increase in Cmax and AUC proportional to a dose.
After single introduction in doses of 3, 5 or 10 mg/kg the median of Cmax made 77, 118 and 277 mkg/ml respectively.
Vd in an equilibrium state (a median of 3.0-4.1 l) did not depend on a dose and demonstrated circulation of an infliksimab preferential in a vascular bed. The pharmacokinetics did not depend on time.
Repeated use of an infliksimab (5 mg/kg on 0, the 2nd and 6th weeks at patients with a fistular form of a disease Krone, and also 3 or 10 mg/kg each 4 or 8 weeks at patients with a pseudorheumatism) was followed by small accumulation of an infliksimab in blood serum after introduction of the second dose. Further clinically significant accumulation was not observed. At most of patients Krone инфликсимаб decided on a fistular form of a disease in blood serum within 12 weeks (ranging from 4 up to 28 weeks) after introduction in the specified mode.
Removal. Ways of removal of an infliksimab are not defined. Not changed инфликсимаб in urine did not come to light.
After single introduction in doses of 3, 5 or 10 mg/kg the median of terminal T1/2 made from 8 to 9.5 days Infliksimab decided in blood serum within, at least, 8 weeks at most of patients on a disease Krone (after single introduction of the recommended dose of 5 mg/kg) or a pseudorheumatism (at a maintenance therapy on 3 mg/kg each 8 weeks).
Pharmacokinetics in special clinical cases. At patients with a pseudorheumatism the clearance and Vd did not change depending on age or body weight. The pharmacokinetics of an infliksimab at patients of advanced age was not studied.
Researches at patients with diseases of a liver or kidneys were not conducted.
Children. The population analysis of pharmacokinetic these patients with ulcer colitis (n=60), a disease Krone (n=120), a juvenile pseudorheumatism (n=117) and a disease of Kawasaki (n=16) aged from 2 months up to 17 years showed, influence of an infliksimab not linearly depends on body weight. At use of the drug Remikeyd® in a dose of 5 mg/kg each 8 weeks the estimated median of influence in an equilibrium state (AUCss) at patients aged from 6 up to 17 years was about 20% less, than an estimated median of influence in an equilibrium state at adults. It is supposed that AUCss median at patients aged from 2 up to less than 6 years is 40% lower, than at adult patients though the number of patients whose data confirm this assumption is limited.
Indications to use:
— pseudorheumatism. Treatment of patients with a pseudorheumatism in an active form who basic antiinflammatory drugs (BPVP), including a methotrexate, had an inefficient the treatment which was carried out earlier, and also treatment of patients with the heavy progressing pseudorheumatism in an active form which did not carry out treatment by a methotrexate or other BPVP earlier. Treatment is carried out to combinations with a methotrexate. The combined treatment by the drug Remikeyd® and a methotrexate allows to achieve reduction of symptoms of a disease, improvement of a functional state and delay of progressing of injury of joints;
— a disease Krone at adults. Treatment of patients at the age of 18 years is also more senior with a disease Krone in an active form, average or heavy degree, including with formation of fistulas, at inefficiency, intolerance or in the presence of contraindications to the standard therapy including GKS and/or immunodepressants (at a fistular form - antibiotics, immunodepressants and a drainage). Treatment by the drug Remikeyd® promotes reduction of symptoms of a disease, achievement and maintenance of remission, healing of mucous membranes and closing of fistulas, reduction of number of fistulas, a dose decline or cancellation of GKS, improvement of quality of life of patients;
— a disease Krone at children and teenagers. Treatment of sick children and teenagers aged from 6 up to 17 years inclusive, with a disease Krone in an active form, average or heavy degree at inefficiency, intolerance or existence of contraindications to the standard therapy including GKS and/or immunodepressants. Treatment by the drug Remikeyd® promotes reduction of symptoms of a disease, achievement and maintenance of remission, a dose decline or cancellation of GKS, improvement of quality of life of patients;
— ulcer colitis at adults. Treatment of patients with ulcer colitis at whom traditional therapy was insufficiently effective. Treatment by the drug Remikeyd® promotes healing of a mucous membrane of intestines, reduction of symptoms of a disease, a dose decline or cancellation of GKS, reduction of need for hospitalization, establishment and maintenance of remission, improvement of quality of life of patients;
— ulcer colitis at children and teenagers. Treatment of children and teenagers aged from 6 up to 17 years inclusive with ulcer colitis of average or heavy severity with the insufficient response to standard therapy using corticosteroids, 6 Mercaptopurinum or Azathioprinum, or with intolerance or contraindications to standard therapy;
— ankylosing spondylitis. Treatment of the patients with an ankylosing spondylitis with the expressed axial symptoms and laboratory signs of inflammatory activity who did not answer standard therapy. Treatment by the drug Remikeyd® allows to reach reduction of symptoms of a disease and improvement of functional activity of joints;
— psoriasis arthritis. Treatment of patients with the progressing psoriasis arthritis in an active form with the inadequate answer to BPVP. Ремикейд® it is applied in a combination with a methotrexate or in the form of monotherapy in cases of intolerance or existence of contraindications to a methotrexate. Treatment by the drug Remikeyd® allows to reach reduction of symptoms of arthritis and improvement of functional activity of patients, and also reduction of extent of radiological progressing at peripheral psoriasis polyarthritis;
— psoriasis. Treatment of patients with medium-weight and heavy psoriasis at insufficient efficiency, either existence of contraindications, or intolerance of standard system therapy, including cyclosporine, a methotrexate or the PADDED STOOL therapy. Treatment by the drug Remikeyd® leads to reduction of the inflammatory phenomena in skin and normalization of process of a differentiation of keratinotsit.
Route of administration and doses:
Administration of the drug Remikeyd® has to be carried out under observation of the doctors having experience of diagnosis and treatment of a pseudorheumatism, ankylosing spondylitis, psoriasis arthritis, psoriasis, inflammatory diseases of intestines.
Ремикейд® enter in/in kapelno. Infusions of drug are carried out under control of the doctor trained to find infusional reactions. At use of the drug Remikeyd® it is necessary to optimize the accompanying therapy (corticosteroids or immunodepressants).
Duration of infusion makes not less than 2 h. All patients have to remain under observation of the doctor during 1-2 h after infusion for the prevention of acute infusional reactions. When performing infusion means of acute management have to be available (such as adrenaline, antihistamines, corticosteroids, IVL). Preliminary administration of antihistamines, a hydrocortisone and/or paracetamol, and also reduction of speed of performing infusion for reduction of risk of development of infusional reactions, especially at patients at whom infusional reactions developed at the previous administration of drug is allowed.
At treatment of adult patients who well transferred at least 3 first 2-hour infusions of the drug Remikeyd® (an induction phase) and are on a maintenance therapy, reduction of duration of the subsequent of infusion before the minimum 1-hour introduction is possible. If in the subsequent at the accelerated administration of drug there is an infusional reaction, then in case of continuation of therapy return is recommended for slower infusions.
The possibility of reduction of time of infusion at administration of drug in a dose more than 6 mg/kg was not studied.
Treatment of a pseudorheumatism. The initial single dose of the drug Remikeyd® makes 3 mg/kg. Then the drug is administered in the same dose in 2 weeks and 6 weeks after the first introduction (an induction phase), and further by each 8 weeks (the supporting treatment phase). Treatment by the drug Remikeyd® should be carried out along with use of a methotrexate.
At most of patients the clinical answer is reached within 12 weeks. At the insufficient answer or if the effect of treatment is lost in the subsequent period, increase in a dose of the drug Remikeyd® with a step to 1.5 mg/kg is possible, up to 7.5 mg/kg each 8 weeks, or reduction of intervals between administrations of the drug Remikeyd® in a dose of 3 mg/kg up to 4 weeks. At achievement of the clinical answer treatment has to be continued in the corresponding dose and the mode of infusions.
In the absence of effect of treatment within 12 first weeks, and also in response to increase in a dose of the drug Remikeyd® or reduction of intervals between infusions it is necessary to consider a question of expediency of continuation of treatment.
Treatment heavy or moderate severity of an active form of a disease Krone at adults. The initial dose of the drug Remikeyd® makes 5 mg/kg, the second infusion is carried out in the same dose in 2 weeks after the first. In the absence of effect after two introductions further use of the drug Remikeyd® is not advisable. For the patients who had positive effect, treatment by the drug Remikeyd® it is possible to continue, at the same time it is necessary to choose one of two possible options of treatment:
— the drug is administered in a dose 5 mg/kg in 6 weeks after the first introduction and then each 8 weeks; in the supporting treatment phase increase in a dose up to 10 mg/kg can be required by some patients for achievement of effect;
— the drug is administered repeatedly in a dose of 5 mg/kg at a disease recurrence.
Despite insufficiency of comparative data, limited data point that at some patients at whom the clinical response to therapy by drug in a dose of 5 mg/kg was observed, but afterwards it was lost, at increase in a dose return of the clinical answer is possible. It is necessary to estimate carefully a possibility of continuation of therapy of patients who had no signs of therapeutic improvement after change of a dose.
The general duration of treatment by the drug Remikeyd® is defined by the attending physician.
Treatment heavy or moderate severity of an active disease Krone at children and teenagers aged from 6 up to 17 years inclusive. The initial dose of the drug Remikeyd® makes 5 mg/kg. Then the drug is administered in the same dose in 2 weeks and 6 weeks after the first introduction and further - each 8 weeks. In the absence of effect of treatment within 10 weeks further use of the drug Remikeyd® is not recommended.
At some patients for maintenance of clinical effect shorter interval between infusions while longer interval can be sufficient for a part of patients can be required. At patients at whom the interval between infusions is reduced to less than 8 weeks the risk of development of side reactions can be increased. It is necessary to estimate carefully need of continuation of treatment in the absence of additional effect of treatment at change of an interval between infusions.
Treatment by the drug Remikeyd® should be carried out along with use of immunomodulators - 6 Mercaptopurinum, Azathioprinum or a methotrexate.
In the presence of the response to treatment by the drug Remikeyd® the general duration of treatment is defined by the attending physician.
Efficiency and safety of the drug Remikeyd® at children are younger than 6 years were not studied.
Treatment of a disease Krone with formation of fistulas at adults. Ремикейд® enter 5 mg/kg in a single dose, then make administration of drug in the same dose in 2 weeks and 6 weeks after the first introduction. In the absence of effect after introduction of these three doses treatment continuation by the drug Remikeyd® not reasonablly. With effect treatment can be continued, at the same time it is necessary to choose one of two possible options of treatment:
— the drug is administered in a dose 5 mg/kg in 2 weeks and 6 weeks after the first introduction, and then by each 8 weeks; at some patients for achievement of effect of treatment increase in a dose up to 10 mg/kg can be required;
— the drug is administered repeatedly in the same dose - at a disease recurrence.
Despite insufficiency of comparative data, limited data point that at some patients at whom the clinical response to therapy by drug in a dose of 5 mg/kg was observed, but afterwards it was lost, at increase in a dose return of the clinical answer is possible. It is necessary to estimate carefully a possibility of continuation of therapy of patients who had no signs of therapeutic improvement after change of a dose.
The general duration of a course of treatment the drug Remikeyd® is defined by the attending physician.
Comparative researches of the specified two options of treatment of a disease Krone were not conducted. The available data on use of drug by the second option of treatment (repeated introduction in case of a recurrence) are limited.
Treatment of ulcer colitis at adults. The initial dose of drug makes 5 mg/kg. Then the drug is administered in the same dose in 2 weeks and 6 weeks after the first introduction, and further - each 8 weeks. At some patients for achievement of effect increase in a dose up to 10 mg/kg can be required. The available data confirm approach of effect of therapy till 14 weeks (after introduction of 3 doses). If during this time of effect did not come, it is necessary to resolve an issue of expediency of continuation of treatment. In the presence of the response to therapy the general duration of treatment by the drug Remikeyd® is defined by the attending physician.
Treatment of ulcer colitis at children and teenagers from 6 to 17 years inclusive. The initial dose of the drug Remikeyd® makes 5 mg/kg. Then the drug is administered in the same dose in 2 weeks and 6 weeks after the first introduction, and further – each 8 weeks. The available data do not support further use of the drug Remikeyd® in the absence of effect within 8 weeks after the first infusion.
In the presence of the response to therapy by the drug Remikeyd® the general duration of treatment is defined by the attending physician. Efficiency and safety of the drug Remikeyd® at children are younger than 6 years was not studied.
Treatment of an ankylosing spondylitis. The initial dose of the drug Remikeyd® makes 5 mg/kg. Then the drug is administered in the same dose in 2 weeks and 6 weeks after the first introduction, and further - each 6-8 weeks. In the absence of effect within 6 weeks (after introduction of two doses) it is inexpedient to continue treatment.
Treatment of psoriasis arthritis. The initial dose of the drug Remikeyd® makes 5 mg/kg. Then the drug is administered in the same dose in 2 weeks and 6 weeks after the first introduction, and further - each 6-8 weeks.
Treatment of psoriasis. The initial dose of the drug Remikeyd® makes 5 mg/kg. Then the drug is administered in the same dose in 2 weeks and 6 weeks after the first introduction, and further - each 8 weeks. In the absence of effect within 14 weeks (after introduction of four doses) it is not reasonable to continue treatment. The general duration of treatment by the drug Remikeyd® is defined by the attending physician.
Repeated purpose of the drug Remikeyd® at a pseudorheumatism and a disease Krone. In case of a recurrence of a disease of Remikeyd® it can be appointed again within 16 weeks after introduction of the last dose. In clinical trials of reaction of hypersensitivity were infrequent and were observed if the interval without use of the drug Remikeyd® before its repeated introduction made less than 1 year. Efficiency and safety of repeated administration of drug more than in 16 weeks without use of drug were not studied.
Repeated purpose of the drug Remikeyd® at ulcer colitis. Efficiency and safety of drug at its repeated use according to other scheme (not each 8 weeks) were not studied.
Repeated purpose of the drug Remikeyd® at an ankylosing spondylitis. Efficiency and safety of drug at its repeated use according to other scheme (not each 6-8 weeks) to were not studied.
Repeated purpose of the drug Remikeyd® at psoriasis arthritis. Efficiency and safety of drug at its repeated use according to other scheme (not each 8 weeks) were not studied.
Repeated purpose of the drug Remikeyd® at psoriasis. Limited experience of repeated introduction of one dose of the drug Remikeyd® after a 20 weeks interval allows to assume that treatment can be less effective and be followed by higher frequency of infusional reactions (easy and moderate severity) in comparison with the initial induction mode.
Limited experience of repeated purpose of the drug Remikeyd® in the induction mode after an exacerbation of a disease allows to assume that treatment can be followed by higher frequency of infusional reactions (including heavy degree) in comparison with the introduction mode each 8 weeks.
Repeated appointment irrespective of indications. In case of a break in a maintenance therapy and need of resuming of treatment repeated purpose of the drug Remikeyd® in the induction mode is not recommended. Resuming of therapy should be carried out in the mode of one infusion with the subsequent purpose of infusions in the mode of a maintenance therapy.
Efficiency and safety of drug at patients of advanced age are more senior than 65 years were not studied. No essential distinctions connected with age in distribution and removal of drug in clinical trials were observed. Dose adjustment is not required.
Efficiency and safety of drug at patients with a renal failure and a liver were not studied.
Rules of preparation of infusion solution:
1. To calculate a dose and necessary quantity of bottles of the drug Remikeyd® (each bottle contains 100 mg of an infliksimab) and required volume of ready solution of drug.
2. To dissolve contents of each bottle in 10 ml of water for injections, using the syringe with a needle of 21 calibers (0.8 mm) or smaller. Before administration of solvent remove a plastic cover from a bottle and wipe a stopper of 70% with alcohol solution. The hypodermic needle is entered into a bottle through the center of a rubber bung, the stream of water is directed on a bottle wall.
It is necessary to mix carefully solution rotation of a bottle before full dissolution of the lyophilized powder. To avoid long and oscillatory hashing.
Not to stir up. At dissolution foaming is possible, in this case solution should allow to stand within 5 min.
The received solution has to be colourless or poorly yellow color and opalescent. At it there can be a small amount of fine translucent particles as инфликсимаб is protein. Solution at which there are dark particles and also with the changed color is not subject to use.
3. To bring the total amount of the prepared drug Remikeyd® solution dose to 250 ml of 0.9% chloride sodium solution for injections. For this purpose delete the volume equal to volume of the prepared drug Remikeyd® solution on water for injections from the glass bottle or an infusional bag containing 250 ml of 0.9% of solution of sodium of chloride. After that slowly add earlier prepared drug Remikeyd® solution to a bottle or an infusional bag from 0.9% solution of sodium of chloride and carefully mix. Not divorced cannot administer the drug!
4. Due to the lack in preservative drug administration of infusion solution should be begun as soon as possible and not later than 3 h after its preparation. It is necessary to use only infusional system with the built-in sterile depyrogenized filter having low belkovosvyazyvayushchy activity (the size of a time no more than 1.2 microns).
5. It is not necessary to enter Remikeyd® together with any other medicines through one infusional system.
6. Infusion solution before introduction should be checked visually. In case of existence of opaque particles, foreign inclusions and the changed color infusion solution is not subject to use.
7. An unused part of infusion solution is not subject to further use and has to be destroyed.
Features of use:
Use at pregnancy and feeding by a breast. The available clinical experience is limited, and for an exception of possible risk use of an infliksimab is not recommended at pregnancy.
Women of childbearing age when performing treatment by the drug Remikeyd® and within, at least, 6 months after its termination have to use reliable methods of contraception.
The data obtained at about 450 patients receiving инфликсимаб at pregnancy (including about 230 in the I trimester), do not indicate a possibility of development of unexpected effects for the result of pregnancy.
As a result of inhibition ФНОα reception of an infliksimab at pregnancy can affect a normal immune response of the newborn. According to toxicity researches at mice at use of a similar antibody (selectively inhibiting activity mouse ФНОα) toxicity signs for pregnant females, embriotoxity or teratogenecity were not revealed.
Infliksimab gets through a placental barrier and it is found in blood serum of newborns within 6 months after infusion of an infliksimab to the pregnant patient. Therefore, at such children the risk of development of an infection can be increased, and use of live vaccines at them is not recommended within 6 months after the last infusion of an infliksimab of mother at pregnancy.
It is unknown whether it is allocated инфликсимаб with breast milk at the person and whether it is absorbed after intake. Since immunoglobulins of the person are excreted with breast milk, the woman should not nurse within at least 6 months after introduction of an infliksimab.
Data of researches are insufficient for the conclusion about influence of an infliksimab on fertility and reproductive function.
Use at abnormal liver functions. Patients with signs of an abnormal liver function have to be inspected regarding identification of damage of a liver. In case of jaundice or increase in activity of ALT to the level exceeding the VGN 5-fold value it is necessary to cancel Remikeyd® and to conduct a careful research of the arisen disturbance.
Chronic carriers of a virus of hepatitis B have to be inspected in a corresponding way before Remikeyd's use and be observed carefully during treatment regarding a possible exacerbation of hepatitis B.
Use for children. It is contraindicated at children's and teenage age up to 18 years, at children's age up to 6 years (at a disease Krone).
Special instructions. Infusional reactions and reactions of hypersensitivity. Introduction of an infliksimab can be connected with development of acute infusional reactions, including an acute anaphylaxis and reactions of hypersensitivity of the slowed-down type.
Acute infusional reactions, including anaphylactic, can develop in time (within several seconds) or within several hours after infusion. At emergence of acute reaction performing infusion should be stopped immediately. When performing infusion means of acute management have to be available (such as adrenaline, antihistamines, hydrocortisone and/or IVL). Preliminary administration of antihistamines, a hydrocortisone and/or paracetamol for prevention of easy and passing effects is allowed.
Antibody formation to an infliksimab is possible that can be connected with increase in frequency of infusional reactions. A small part of infusional reactions were serious allergic reactions. Communication between antibody formation to an infliksimab and reduction of duration of the response to treatment was observed. Combined use with immunomodulators was connected with reduction of number of cases of antibody formation to an infliksimab and reduction of frequency of infusional reactions. The effect of joint therapy with immunomodulators was more expressed at the patients receiving incidental treatment than at patients on a maintenance therapy. At the patients who stopped use of immunosuppressants to or during therapy by the drug Remikeyd®, the risk of antibody formation is increased. Antibodies to an infliksimab can be not always found in serum samples. At development of serious reaction it is necessary to appoint a symptomatic treatment, the subsequent infusions of the drug Remikeyd® should not be carried out. In clinical trials it was reported about cases development of reactions of hypersensitivity of the slowed-down type. The available data allow to assume that increase in an interval without administration of the drug Remikeyd® increases risk of development of reactions of hypersensitivity of the slowed-down type. Patients should ask at once for medical care at development of any side reaction. When resuming treatment at patients after a long break it is necessary to watch signs and symptoms of reactions of hypersensitivity of the slowed-down type carefully.
Infections. To and during therapy and after its termination for the patient it is necessary to conduct careful observation regarding identification of symptoms of a possible infection, including tuberculosis. As removal of an infliksimab happens within 6 months, it is necessary to make observation of the patient during this period. Therapy by the drug Remikeyd® should be stopped in case of development in the patient of a serious infection or sepsis.
It is necessary to show care at use of the drug Remikeyd® for patients with persistent infections or a recurrent infection in the anamnesis, including receiving the accompanying therapy by immunodepressants. Patients should avoid influence of possible risk factors of development of infections.
ФНОα is a mediator of an inflammation and the modulator of cellular immunity. Pilot studies showed that ФНОα it is necessary for cleaning of intracellular infections. Clinical experience shows that immunological protection against infections can be compromised at some patients receiving treatment infliksimaby.
It must be kept in mind that suppression ФНОα can mask such symptoms of an infection as fever. Early recognition of atypical clinical displays of serious infections and typical clinical rare and atypical infections of manifestation crucially for reduction of a delay of diagnosis and treatment.
The patients receiving therapy by FNO inhibitors are subject to bigger risk of development of serious infections.
Tuberculosis, bacterial infections, including sepsis and pneumonia, invasive fungal, viral or other opportunistic infections were observed at the patients receiving инфликсимаб. Some of these infections were with a lethal outcome, opportunistic infections with death rate more than 5% about which it was reported most often, included пневмоцистоцоз, candidiasis, listeriosis and aspergillomycosis.
For patients at whom the infection developed during therapy by the drug Remikeyd® it is necessary to observe and conduct full diagnostic examination carefully. Use of the drug Remikeyd® should be stopped in case of development in the patient of a new serious infection or sepsis, to appoint antibacterial or antifungal therapy before achievement of control of infectious process.
Tuberculosis. Cases of development of active tuberculosis in the patients receiving Remikeyd® were reported. The majority of cases of tuberculosis was extra pulmonary local or disseminated.
Prior to treatment by the drug Remikeyd® of the patient it is necessary to inspect attentively regarding identification of both active, and latent tubercular process. Inspection has to include careful collecting the anamnesis, including it is necessary to find out whether the patient had a disease of tuberculosis in the past, whether there were contacts with TB patients, and also whether therapy was carried out or carried out by immunodepressants. It is necessary to carry out necessary screening tests (X-ray inspection of a thorax, tuberkulinovy test). At the same time it is necessary to consider that at seriously ill patients of patients and at patients with immunosuppression false-negative tuberkulinovy test can be received.
When diagnosing active tuberculosis it is impossible to begin therapy with the drug Remikeyd®.
At suspicion of latent tuberculosis, it is necessary to hold consultation of the phthisiatrician.
In all cases described further it is necessary to estimate carefully risk/advantage of therapy by the drug Remikeyd®.
When diagnosing latent tuberculosis it is necessary to begin the corresponding therapy prior to therapy with the drug Remikeyd®.
Patients with several or considerable risk factors have development of tuberculosis, but at which latent tuberculosis is not confirmed with the test, it is necessary to consider need of antitubercular therapy prior to treatment by the drug Remikeyd®.
It is necessary to consider need of use of antitubercular therapy prior to therapy by the drug Remikeyd® at patients with active or latent tuberculosis for whom in the anamnesis the adequate course of treatment cannot be confirmed.
Patients should see a doctor at emergence of signs or symptoms of tuberculosis (ultimate cough, a body exhaustion/degrowth, subfebrile fever) in time or after therapy by the drug Remikeyd®.
Invasive fungal infections. In group of the patients receiving Remikeyd®, suspicion of invasive fungal infections, such as an aspergillosis, candidiasis, a pneumocystosis, histoplasmosis кокцидиомикоз or a zymonematosis, has to arise always at development in the patient of a serious general disease; at an early stage it is necessary to hold consultation at the specialist in diagnosis and treatment of invasive fungus diseases at inspection of such patients. Invasive fungal infections can be presented by the disseminated, but not localized defeats, and on antigens and antibodies some patients with an active infection can have a negative result of the analysis. It is necessary to estimate need of the beginning of empirical antifungal therapy before the end of laboratory researches, considering both risk of development of a serious fungal infection, and an effect of antifungal therapy.
For the patients living or visiting regions, endemic on invasive fungal infections, such as histoplasmosis кокцидиомикоз or a zymonematosis, it is necessary to estimate carefully advantage and risk of therapy by the drug Remikeyd® prior to treatment by this drug.
Fistular form of a disease Krone. Patients with a disease Krone with acute purulent fistulas should not begin therapy with the drug Remikeyd® before identification and elimination of other possible center of an infection, in particular abscess.
Reactivation of a virus of hepatitis B. Reactivation of a virus of hepatitis B was observed at patients of the chronic carriers of a virus receiving antagonists of FNO including инфликсимаб, in certain cases with a lethal outcome. Carriers of a virus of hepatitis B which need treatment by the drug Remikeyd® should watch carefully signs and symptoms of activation of an infection throughout a course of therapy and within several months after the termination. Sufficient data about efficiency of the combined use of antiviral therapy (for prevention of reactivation of a virus) and FNOα inhibitors at patients of chronic virus carriers are absent.
At reactivation of hepatitis B therapy by the drug Remikeyd® has to be stopped and appointed the corresponding antiviral therapy.
Abnormal liver function and bilious ways. In the post-registration period of use of the drug Remikeyd® cases of jaundice and noninfectious hepatitis, sometimes with symptoms of autoimmune hepatitis were very seldom observed. It was reported about isolated cases of the liver failure which led to a lethal outcome or demanded liver transplantation. Patients with signs or symptoms of an abnormal liver function have to be inspected on existence of damage of a liver. In case of jaundice or increase in activity of ALT to the level exceeding the VGN 5-fold value, Remikeyd® it is necessary to cancel and conduct a careful research of the arisen disturbance.
Simultaneous use of FNOα inhibitor and anakinra. Simultaneous use of an anakinra and other FNOα inhibitor (etanertsept) in clinical trials was followed by development of serious infections and neutropenias and did not result in additional clinical effect in comparison with monotherapy etanertsepty. In view of the nature of the side reactions observed at simultaneous therapy anakinry and etanertsepty similar types of toxicity can arise at a combination therapy anakinry and other FNOα inhibitors. In this regard simultaneous use of the drug Remikeyd® and an anakinra is not recommended.
Simultaneous use of FNOA inhibitor and abatatsept. In clinical trials the combined use of FNO inhibitors and an abatatsept was connected with the increased risk of development of infections, including serious infections, in comparison with use only of one FNO inhibitors, without strengthening of clinical effect. Simultaneous use of the drug Remikeyd® and an abatatsept is not recommended.
Simultaneous use with other biological drugs. There are not enough data on combined use of an infliksimab and other biological drugs intended for use according to the same indications. Simultaneous use of an infliksimab with these drugs is not recommended in a type of possible increase in risk of development of infections and other possible pharmacological interaction.
Transfer from other biological drug. It is necessary to show care at transfer of the patient from one biological drug on another since cross biological activity can increase risk of development of side reactions, including infections.
Vaccination. Now there are no data on how the patients receiving ANTI-FNO therapy react to vaccination by live vaccines or to secondary transmission of infection by live vaccines. It is not recommended to apply live vaccines at such patients.
Autoimmune processes. In rare instances the relative deficit ФНОα caused by ANTI-FNO therapy can initiate development of autoimmune process. At emergence of symptoms of a volchanochnopodobny syndrome against the background of the drug Remikeyd® and at positive tests for antibodies to double-helix DNA, therapy by the drug Remikeyd® should be stopped.
Neurologic disturbances. Use of FNO inhibitors, including инфликсимаб, in rare instances was followed by emergence or increase of clinical and/or radiological symptoms of demyelinating diseases of TsNS (including multiple sclerosis) and a peripheral nervous system, including a syndrome to Giyena-Barra. At patients with the existing or recently developed demyelinating diseases it is necessary to weigh carefully advantage and risk of therapy by FNO inhibitors before purpose of the drug Remikeyd®. In case of development of such diseases therapy by the drug Remikeyd® has to be stopped.
Malignant tumors and limfoproliferativny disturbances. At conduct of clinical trials using FNO inhibitors more frequent development of a lymphoma in the patients receiving FNO inhibitor than in patients of control group is noted. In clinical trials of the drug Remikeyd® according to all approved indications emergence of a lymphoma was noted seldom though more often than it is expected in general at the population. During the post-registration period it was reported about development of leukoses in the patients receiving FNO inhibitors. Since the risk of development of a lymphoma and leukemia is increased at patients with a pseudorheumatism with a prolonged, highly active inflammatory disease, assessment of risk is complicated.
In clinical trials on studying of use of the drug Remikeyd® at the possible new indication - HOBL (heavy and moderate severity) - at patients smokers (or the former smokers) the frequency of development of new growths was higher in group of the patients receiving Remikeyd® than in control group. It is necessary to show care at purpose of FNO inhibitors to patients at whom the risk of development of malignant new growths in connection with smoking is increased.
According to the available data, the risk of development of lymphoma or other malignant new growths in the patients receiving FNO inhibitors cannot be excluded. It is necessary to show care at purpose of FNO inhibitors to patients with malignant new growths in the anamnesis or at continuation of therapy at patients with the developed malignant new growths.
It is also necessary to show care at patients with psoriasis or receiving an intensive care immunodepressants or long the PADDED STOOL therapy in the anamnesis.
During the post-registration researches cases of formation of malignant tumors, some with a lethal outcome, among children, teenagers and full age young people (aged up to 22 years) who received FNO inhibitors (the beginning of therapy at the age of ≤18 years), including Remikeyd® were reported. Approximately in half of cases it was reported about lymphoma. Other cases are presented by a number of various malignant tumors including the malignant tumors which are usually connected with immunosuppression. The risk of development of malignant new growths in the patients receiving FNO inhibitors cannot be excluded.
In the post-registration period messages on exceptional cases developments of a hepatolienal T-cellular lymphoma at therapy by FNO inhibitors, including инфликсимаб were gained. This rare species of the T-cellular lymphoma is characterized by very aggressive course of a disease and usually comes to an end with a lethal outcome. All cases at therapy by the drug Remikeyd® are registered at patients with a disease Krone or ulcer colitis, most of them were reported at teenagers or male young adults. All registered cases of development of a hepatolienal T-cellular lymphoma are noted at the patients who were at the same time receiving Azathioprinum or 6 Mercaptopurinum. It is necessary to estimate carefully possible risk of simultaneous use of Azathioprinum or 6 Mercaptopurinum and the drug Remikeyd®. The risk of development of a hepatolienal lymphoma in the patients receiving the drug Remikeyd® cannot be excluded.
Cases of development of a carcinoma of Merkel and melanoma at the patients receiving FNOα inhibitors including инфликсимаб were reported. It is recommended to perform periodic inspection of integuments at patients, especially patients with existence of risk factors have development of malignant new growths of skin.
All patients with ulcer colitis at whom the risk of development of a dysplasia or a carcinoma of a colon is increased (for example, at patients with prolonged ulcer colitis or primary sclerosing cholangitis) or for whom these diseases diagnosed earlier, it is regularly necessary to observe concerning a dysplasia before therapy. Observation has to include a kolonoskopiya and a biopsy depending on the accepted recommendations. It is unknown whether therapy infliksimaby influences risk of development of a dysplasia or cancer of a colon.
Since the possibility of increase in risk of development of malignant new growths in the patients with for the first time the diagnosed dysplasia receiving therapy by the drug Remikeyd® is not established, it is necessary to estimate carefully risk and advantage of therapy by the drug Remikeyd® and to make the decision on continuation or the termination of therapy.
Heart failure. Ремикейд® it is necessary to apply with care at patients with slight heart failure (the I-II class on NYHA). Patients have to be under observation, and in case of emergence new or deteriorations in the available symptoms of heart failure therapy by the drug Remikeyd® has to be stopped.
Hematologic reactions. The patients receiving FNO inhibitors have messages on a pancytopenia, leukopenia, neutropenia and thrombocytopenia including Remikeyd®. At emergence of symptoms of a dyscrasia of blood (persistent fever, bruises, bleedings, pallor) all patients need immediate inspection. In case of the expressed hematologic disturbances therapy by the drug Remikeyd® it has to be stopped.
Others. Data on safety of use of the drug Remikeyd® for patients at which surgical intervention, including an arthroplasty was carried out are limited. When planning operations it is necessary to consider long T1/2 of an infliksimab. When performing operations careful monitoring of infections and timely therapy in case of their emergence is necessary for the patients receiving therapy by the drug Remikeyd®.
The Krone can indicate lack of the response to therapy of a disease existence of the fixed fibrotichesky stricture which can demand surgical treatment. The available data allow to assume what инфликсимаб does not promote deterioration or formation of a stricture.
Special groups of patients. Patients of advanced age (≥65 years). Frequency of serious infections at patients of advanced age (≥65 years) was higher, than at patients 65 years are younger. A part from these infections led to a lethal outcome. At therapy of elderly patients it is necessary to control risk of development of infections especially carefully.
Patients of children's age. In clinical trials of an infection occurred at patients of children's age more often than at adults.
Patients are recommended to undergo whenever possible full vaccination according to the current calendar of preventive inoculations prior to therapy by the drug Remikeyd®.
During the post-registration researches cases of formation of malignant tumors, some with a lethal outcome, among children, teenagers, full age young people (aged up to 22 years) who received FNO inhibitors (the beginning of therapy at the age of ≤18 years), including Remikeyd® were reported. Approximately in half of cases it was reported about lymphoma. Other cases are presented by a number of various malignant tumors including the malignant tumors which are usually connected with immunosuppression. The risk of development of malignant new growths in the patients receiving FNO inhibitors cannot be excluded.
In the post-registration period messages on exceptional cases developments of a hepatolienal T-cellular lymphoma at therapy by FNO inhibitors, including инфликсимаб were gained. This rare species of the T-cellular lymphoma is characterized by very aggressive course of a disease and usually comes to an end with a lethal outcome. All cases at therapy by the drug Remikeyd® are registered at patients with a disease Krone or ulcer colitis, most of them occurred at teenagers or male young adults. All registered cases of development of a hepatolienal T-cellular lymphoma are noted at the patients who were at the same time receiving Azathioprinum or 6 Mercaptopurinum. It is necessary to estimate carefully possible risk of simultaneous use of Azathioprinum or 6 Mercaptopurinum and the drug Remikeyd®. The risk of development of a hepatolienal lymphoma in the patients receiving the drug Remikeyd® cannot be excluded.
Treatment by the drug Remikeyd® of children and teenagers aged up to 17 years inclusive with a pseudorheumatism, an ankylosing spondylitis, psoriasis arthritis or psoriasis, and also treatment of children under 6 years with a disease Krone or ulcer colitis is not studied. Before data acquisition about safety and efficiency of the drug Remikeyd® it is not necessary to use drug according to these indications in the corresponding age groups
Influence on ability to driving of motor transport and to control of mechanisms. Ремикейд® can exert insignificant impact on ability to manage motor transport and to work with mechanisms. After administration of drug dizziness is possible.
Side effects:
In clinical trials upper respiratory tract infections were most often observed (the patients receiving инфликсимаб have 25.3% in comparison with 16.5% at patients of control group).
The most serious side reactions connected using FNO inhibitors about which it was reported at drug Remikeyd® use: reactivation of a virus of hepatitis B, congestive heart failure, serious infections (including sepsis, opportunistic infections and tuberculosis), a serum disease (reaction of hypersensitivity of the slowed-down type), hematologic reactions, a system red lupus / волчаночноподобный the syndrome demyelinating a syndrome, gepatobiliarny disturbances, a lymphoma, a hepatolienal T-cellular lymphoma, intestinal or perianal abscess (at a disease Krone) and serious infusional reactions.
The side reactions (including with a lethal outcome) observed in clinical trials, and also in post-marketing practice are listed in table 1. Determination of frequency of side reactions: very often (≥ 1/10), it is frequent (≥1/100 and <1/10), infrequently (≥1/1000 and <1/100), is rare (≥1/10 000 and <1/1000), is very rare (<1/10 000), it is unknown (frequency cannot be estimated on the basis of the available data). In each column side reactions are located in decreasing order of gravity.
Table 1. The side reactions revealed at clinical trials and during the post-registration period
| Reaction frequency | Nature of reaction |
| Infectious and parasitic diseases | |
| very often | viral infection (including flu, herpes) |
| often | bacterial infections (including sepsis, cellulitis, abscess) |
| infrequently | tuberculosis, fungal infections (including candidiasis) |
| seldom | meningitis, opportunistic infections (such as invasive fungal infections (pneumocystosis, histoplasmosis, aspergillomycosis, кокцидиомикоз, cryptococcosis, zymonematosis), bacterial infections (atypical mikobakterialny infection, listeriosis, salmonellosis) and viral infections (Cytomegaloviral infection)), parasitic infections, reactivation of hepatitis B |
|
The high-quality, malignant and not specified new growths (including cysts and polyps) |
|
| seldom | lymphoma, nekhodzhkinsky lymphoma, Hodzhkin's disease, leukosis, melanoma |
| it is unknown | hepatolienal T-cellular lymphoma (teenagers and young people with a disease Krone and ulcer colitis), Merkel's carcinoma |
| From system of a hemopoiesis | |
| often | neutropenia, leukopenia, anemia, lymphadenopathy |
| infrequently | thrombocytopenia, lymphopenia, lymphocytosis |
| seldom | agranulocytosis, trombotichesky Werlhof's disease, pancytopenia, hemolitic anemia, idiopathic Werlhof's disease |
| From immune system | |
| often | respiratory allergic reactions |
| infrequently | anaphylactic reactions, volchanochnopodobny syndrome, serum disease or reactions as a serum disease |
| seldom | acute anaphylaxis, vasculitis, reactions as a sarcoidosis |
| From mentality | |
| often | depression, sleeplessness |
| infrequently | amnesia, concern, confusion of consciousness, drowsiness, nervousness |
| seldom | apathy |
| From a nervous system | |
| very often | headache |
| often | вертиго, dizziness, hypesthesia, paresthesia |
| infrequently | convulsive attack, neuropathy |
| seldom | cross myelitis, demyelinating diseases of TsNS (as multiple sclerosis, an optic neuritis), demyelinating diseases of a peripheral nervous system (a syndrome to Giyena-Barra, a chronic inflammatory demyelinating polyneuropathy and a multifocal motor neuropathy) |
| From an organ of sight | |
| often | conjunctivitis |
| infrequently | keratitis, periorbital hypostasis, barley |
| seldom | entophthalmia |
| it is unknown | tranzitorny loss of sight in time or during 2 h after infusion |
| From cardiovascular system | |
| often | tachycardia, heartbeat, arterial hypotension, hypertensia, ecchymoma, "inflows" (sometimes strong) |
| infrequently | the accruing heart failure, arrhythmia, syncope, bradycardia, disturbance of peripheric circulation, thrombophlebitis, hematoma |
| seldom | circulator insufficiency, cyanosis, pericardiac exudate, petechias, vasospasm |
| it is unknown | ischemia a myocardium/myocardial infarction in time or during 2 h after infusion |
| From respiratory system | |
| very often | upper respiratory tract infection, sinusitis |
| often | lower respiratory tract infection (including bronchitis, pneumonia), short wind, nasal bleeding |
| infrequently | fluid lungs, bronchospasm, pleurisy, pleural exudate |
| very seldom | intersticial pulmonary disease (intersticial pneumonitis / pulmonary fibrosis), bystry progressing of an intersticial pulmonary disease |
| From the alimentary system | |
| very often | abdominal pain, nausea |
| often | gastrointestinal bleeding, diarrhea, dyspepsia, gastroesophagal reflux, lock |
| infrequently | perforation of intestines, intestinal stenosis, diverticulitis, pancreatitis, cheilitis |
| From a liver and biliary tract | |
| often | abnormal liver function, increase in activity of hepatic transaminases |
| infrequently | hepatitis, injury of hepatocytes, cholecystitis, |
| seldom | autoimmune hepatitis, jaundice |
| very seldom | liver failure |
| From skin and hypodermic fabrics | |
| often | the psoriasis including which is initially diagnosed and pustular (preferential palmar and bottom form), urticaria, rash, an itch, the increased perspiration, a xeroderma, fungal dermatitis, an alopecia |
| infrequently | violent rash, onychomycosis, seborrhea, furunculosis, rozatsea, skin papilloma, hyperkeratosis, disturbance of a xanthopathy |
| very seldom | toxic epidermal necrolysis, Stephens-Johnson's syndrome, mnogoformny erythema |
| From a musculoskeletal system | |
| often | arthralgia, mialgiya, dorsodynia |
| From an urinary system | |
| often | infection of urinary tract |
| infrequently | pyelonephritis |
| From reproductive system | |
| infrequently | vaginitis |
| From an organism in general | |
| very often | infusional reactions, pain |
| often | stethalgia, fatigue, fever, fever |
| infrequently | the slowed-down healing of wounds |
| seldom | formation of the granulematozny centers |
| Local reactions | |
| often | reactions in the place of an injection (including swelled) |
| From laboratory indicators | |
| infrequently | formation of autoantibodies |
| seldom | disturbance of development of factors of a complement |
Infusional reactions. As those at conduct of clinical trials any undesirable reactions which arose during infusion or during 1 h after it were considered. In clinical trials 3 phases the frequency of development of infusional reactions in group of the patients receiving Remikeyd® made about 18% and about 5% - in group of placebo. In general the frequency of infusional reactions at the patients receiving monotherapy infliksimaby was higher, than at the patients receiving инфликсимаб along with immunomodulators. About 3% of patients were forced to stop therapy in connection with development of infusional reactions, at the same time at all patients of reaction were reversible (after medicamentous therapy or without it). From the patients who were receiving инфликсимаб and transferred infusional reactions in the induction period (till the 6th week), at 27% in the supporting period (from 7 to 54 weeks) repeated reactions developed. From patients at whom in the induction period infusional reactions were not recorded at 9% development of these reactions in the supporting period was noted.
In clinical trial of ASPIRE at the patients with a pseudorheumatism who transferred at least three 2-hour infusions of the drug Remikeyd® without serious infusional reactions reduction of duration of infusion up to not less than 40 min. was allowed. In this research of 66% (686 of 1040) of patients received, at least, 1 infusion reduced to 90 min. or less, 44% (454 of 1040) of patients received, at least, 1 infusion reduced to 60 min. or less. At the patients who received, at least, 1 reduced infusion of an infliksimab, infusional reactions were registered in 15% of cases, and serious infusional reactions - at 0.4% of patients.
In clinical trial of SONIC at patients with a disease the Krone, infusional reactions were registered at 16.6% (27 of 163) the patients receiving monotherapy infliksimaby at 5% (9 of 179) the patients receiving a combination therapy infliksimaby and Azathioprinum at 5.6% (9 of 161) receiving monotherapy by Azathioprinum. One serious infusional reaction was registered (less than 1% of patients) in group of monotherapy infliksimaby. In the post-registration period at use of the drug Remikeyd® cases of development of attacks and anaphylactoid reactions, including hypostasis of drinks/throat and the expressed bronchospasm were noted. It was exclusively seldom reported about cases of passing loss of sight, ischemia of a myocardium or a myocardial infarction during infusion or during 2 h after infusion.
Infusional reactions after repeated administration of the drug Remikeyd®. Clinical trial at patients with psoriasis of average or heavy degree for assessment of efficiency and safety of a long-term maintenance therapy in comparison with the induction mode of use of the drug Remikeyd® (at most 4 infusions on 0, 2, 6 and 14 weeks) after an exacerbation of a disease was conducted. Patients did not receive the accompanying therapy by immunodepressants. In group of induction therapy serious infusional reactions developed at 4% (8 of 219) patients, in comparison with less than 1% (1 of 222) in group of a maintenance therapy. The majority of serious infusional reactions was noted during the 2nd infusion (week 2). The interval between the last maintenance dose and the first repeated induction dose made from 35 to 231 days. Symptoms included (but were not limited) диспноэ, a small tortoiseshell, the father of the person and arterial hypotension. After the therapy termination by the drug Remikeyd® and/or the beginning of other therapy, signs and symptoms completely passed in all cases.
Reactions of hypersensitivity of the slowed-down type. In clinical trials of reaction of hypersensitivity of the slowed-down type were infrequent and occurred during an interval without administration of the drug Remikeyd® less than 1 year. In researches of psoriasis of reaction of hypersensitivity of the slowed-down type occurred at the beginning of a therapy course. Signs and symptoms included the mialgiya and/or an arthralgia which are followed by fever and/or rash, at some patients the itch, a face edema, lips or hands, a dysphagy, a small tortoiseshell, a pharyngalgia and a headache were noted.
The cases of development of reactions of hypersensitivity of the slowed-down type given about number after an interval without administration of the drug Remikeyd® are not enough, however limited data of clinical trials assume the increased risk of development of these reactions at increase in an interval without administration of the drug Remikeyd®.
In clinical trial lasting 1 year in which repeatedly carried out infusions to patients with a disease Krone (ACCENT I) the number of cases of development of reactions as a serum disease made 2.4%.
Immunogenicity. At patients at whom antibodies to an infliksimab were formed more likely (approximately by 2-3 times) infusional reactions developed. The accompanying use of immunodepressants reduced probability of development of infusional reactions.
In clinical trials at single and repeated introduction of an infliksimab in doses from 1 to 20 mg/kg of an antibody to an infliksimab were found in 14% of patients with simultaneous therapy by any immunodepressants and in 24% without therapy by immunodepressants. Found antibodies to an infliksimab in 8% of the patients with a pseudorheumatism receiving the doses of an infliksimab recommended for repeated therapy along with a methotrexate. At 15% of patients with psoriasis arthritis who received infusions of an infliksimab in a dose of 5 mg/kg with or without concomitant use of a methotrexate found antibodies to an infliksimab (in 4% of the patients receiving a methotrexate and in 26% of the patients who were not receiving a methotrexate initially). Patients with a disease have a Krone, receiving a maintenance therapy infliksimaby, antibodies to an infliksimab were found in 3.3% of the patients receiving immunodepressants and in 13.3% which were not receiving immunosuppressants. The number of cases at incidental therapy increased by 2-3 times. Due to the restrictions of a method of definition of antibodies the negative take did not exclude existence of antibodies to an infliksimab. Some patients, with a high antiserum capacity, had signs of reduction of efficiency of therapy infliksimaby. Approximately antibodies to an infliksimab were found in 28% of the patients with psoriasis receiving therapy infliksimaby in the supporting mode without simultaneous use of immunomodulators.
Infections. Tuberculosis, bacterial infections, including sepsis and pneumonia, invasive fungal, viral or other opportunistic infections were observed at the patients receiving the drug Remikeyd®. Some of these infections ended with a lethal outcome, opportunistic infections about which more than 5% were reported most often with death rate included a pneumocystosis, candidiasis, listeriosis and aspergillomycosis.
In clinical trials of 36% of the patients receiving therapy by the drug Remikeyd® received additional therapy from infections in comparison with 25% of the patients receiving placebo.
In clinical trials of a pseudorheumatism the number of cases of serious infections, including pneumonia, was higher in group of the patients receiving joint therapy infliksimaby and a methotrexate in comparison with group of the patients receiving only a methotrexate, especially at doses of an infliksimab of 6 mg/kg and more.
During the post-registration period infections, in some cases with a lethal outcome were serious side reactions about which it was reported most often. From all lethal outcomes about 50% it was connected with infectious complications. It was reported about cases of development of tuberculosis, including miliary tuberculosis and tuberculosis with extra pulmonary localization, in certain cases with a lethal outcome.
Malignant new growths and limfoproliferativny diseases. In clinical trials of an infliksimab in which therapy was received by 5780 patients (5474 patsiyento-years) 5 cases of a lymphoma and 26 cases of a malignant new growth (in addition to a lymphoma) in comparison with lack of cases of a lymphoma and 1 case of a malignant new growth (in addition to a lymphoma) were diagnosed for 1600 patients receiving placebo (941 patsiyento-years).
At long-term observation (up to 5 years) 3210 patients (6234 patsiyento-years) after clinical trials of an infliksimab were reported about 5 cases of a lymphoma and 38 cases of a malignant new growth (in addition to a lymphoma).
Cases of malignant new growths, including a lymphoma, were also reported in the post-registration period.
In the clinical trial including patients with HOBL (average or heavy degree) who smoked or were the former smokers of 157 adult patients received therapy by the drug Remikeyd® in doses similar to doses for therapy of a pseudorheumatism and a disease Krone. At 9 of these patients malignant new growths, including 1 case of a lymphoma developed. The median of duration of the subsequent observation made 0.8 years (frequency of cases of 5.7% (95% of DI of 2.65-10.6%)). There was a message on 1 case of a malignant new growth in control group of 77 patients (a median of duration of the subsequent observation of 0.8 years, the frequency of 1.3% (95% of DI of 0.03-7%)). The majority of malignant new growths were diagnosed in lungs or the head and a neck.
In the post-registration period exceptional cases of a hepatolienal T-cellular lymphoma at the patients with a disease Krone and ulcer colitis receiving Remikeyd® were reported, most of patients were teenagers or male young adults.
Cardiovascular insufficiency. In the II phase of clinical trials of the drug Remikeyd® at patients with congestive heart failure increase in mortality in connection with increase of heart failure against the background of therapy by the drug Remikeyd® was noted, especially at use in the raised dose of 10 mg/kg (double exceeding of the maximum recommended therapeutic dose). In this research of 150 patients with congestive heart failure of a class III-IV on NYHA (fraction of a vyboros of a left ventricle ≤ 35%) 3 infusions of the drug Ремикейд® 5 of mg/kg, 10 mg/kg or placebo within 6 weeks received. On the 38th week of 9 of 101 patients receiving drug (2 patients receiving 5 mg/kg, 7-10 mg/kg) died, in comparison with one death in group of placebo (49 patients).
In post-marketing practice it was also reported about cases of increase of heart failure against the background of use of the drug Remikeyd® at existence or lack of accessory factors. Besides, there were rare messages about for the first time the revealed heart failure, including for the patients who did not have earlier diseases of cardiovascular system. Some of these patients were aged up to 50 years.
Changes from a liver and biliary tract. In clinical trials at patients against the background of treatment the drug Remikeyd® observed weak or moderate increase in activity of ALT and ACT without development of the expressed injury of a liver. Increase in ALT to the level equal or exceeding the VGN 5-fold value (table 2) was observed. Increase in activity of aminotransferases (ALT more than ACT) was noted more often in group of the patients receiving Remikeyd® than in control group. It was noted both in case of use of the drug Remikeyd® as monotherapy, and at its use in a combination with other immunodepressants. In most cases increase in activity of aminotransferases was passing, however at a small number of patients this increase was more long. In general, increase in activity of ALT and ACT proceeded asymptomatically, at the same time reduction or return to the initial level of these indicators occurred irrespective of, treatment by the drug Remikeyd® proceeded or stopped, or the accompanying therapy changed.
In the post-registration period the patients receiving Remikeyd® had very rare messages on emergence of jaundice and the hepatitis in certain cases having symptoms of autoimmune hepatitis.
Table 2. A ratio of patients with increase in activity of ALT in clinical trials.
| Quantity patsiyentov3 | Median of the subsequent observation (week) 4 | ≥ 3 VGN | ≥ 5 VGN | ||||
| placebo | инфликсимаб | placebo | инфликсимаб | placebo | иифликсммаб | placebo | инфликсимаб |
| Rhematoid artrit1 | |||||||
| 375 | 1087 | 58.1 | 58.3 | 3.2% | 3.9% | 0.8% | 0.9% |
| Disease of Krona2 | |||||||
| 324 | 1034 | 53.7 | 54.0 | 2.2% | 4.9% | 0.0% | 1.5% |
| Disease Krone at children | |||||||
| - | 139 | - | 53.0 | - | 4.4% | - | 1.5% |
| Ulcer colitis | |||||||
| 242 | 482 | 30.1 | 30.8 | 1.2% | 2.5% | 0.4% | 0.6% |
| Ulcer colitis at children | |||||||
| - | 60 | - | 49.4 | - | 6.7% | - | 1.7% |
| Ankylosing spondylitis | |||||||
| 76 | 275 | 24.1 | 101.9 | 0.0% | 9.5% | 0.0% | 3.6% |
| Psoriasis arthritis | |||||||
| 98 | 191 | 18.1 | 39.1 | 0.0% | 6.8% | 0.0% | 2.1% |
| Psoriasis (blyashechny) | |||||||
| 281 | 1175 | 16.1 | 50.1 | 0.4% | 7.7% | 0.0% | 3.4% |
Interaction with other medicines:
Special researches of interaction were not conducted.
At patients with a pseudorheumatism, psoriasis arthritis and a disease the Krone simultaneous use of a methotrexate or other immunomodulators reduces antibody formation to an infliksimab and increases concentration of the last in plasma. However in connection with restrictions of the method used for definition of concentration of an infliksimab and antibodies to an infliksimab in blood serum, results are not unambiguous.
Corticosteroids do not exert clinically significant impact on pharmacokinetics of an infliksimab.
Simultaneous use of the drug Remikeyd® with other biological drugs applied according to the same indications including with anakinry and abatatsepty is not recommended.
Simultaneous use of live vaccines and the drug Remikeyd® is not recommended.
Contraindications:
— hypersensitivity to an infliksimab, other mouse proteins, and also to any of drug components;
— heavy infectious process (for example, sepsis, abscess, tuberculosis, opportunistic infections);
— heart failure of average or heavy degree (the III-IV functional classes on NYHA);
— pregnancy;
— breastfeeding period;
— children's and teenage age up to 18 years;
— children's age up to 6 years (at a disease Krone and ulcer colitis).
Overdose:
Single administration of the drug Remikeyd® in a dose of 20 mg/kg did not cause toxic effect. Clinical data on overdose are not available.
Storage conditions:
Drug should be stored in the place, unavailable to children, at a temperature from 2 °C to 8 °C; not to freeze. A period of validity – 3 years. Drug should be transported at a temperature from 2 °C to 8 °C. Transportation is allowed at a temperature up to 25 °C during no more than 48 h. An unused part of infusion solution is liable to destruction.
Issue conditions:
According to the recipe
Packaging:
Bottles glass with a capacity of 20 ml (1) - packs cardboard.
