Remikade - instructions for use, doses, side effects, contraindications

Active substanceInfliximabInfliximab

Similar drugsTo uncover

Infliximab

lyophilizate d / infusion

BIOCAD, CJSC Russia

Remicade®

lyophilizate d / infusion

MSD FARMASYUTIKALS, LLC Russia

Flammegis®

lyophilizate d / infusion

Selltrion Halcocea Co., Ltd. The Republic of Korea

Dosage form: & nbsplyophilizate for solution for infusion

Composition:

1 bottle contains:

active substance: infliximab 100 mg;

Excipients: sodium hydrogen phosphate dihydrate 6.1 mg, sodium dihydrogen phosphate monohydrate 2.2 mg, sucrose 500 mg, polysorbate-80 0.5 mg.

Description:

Lyophilizate in the form of a dense mass of white without signs of melting, which does not contain extraneous inclusions.

Pharmacotherapeutic group:immunosuppressive - antibodies monoclonal

ATX: & nbsp

L.04.A.B.02 Infliximab

L.04.A.B Inhibitors of tumor necrosis factor-α (TNF-α)

Pharmacodynamics:

Infliximab is a chimeric mouse-human monoclonal antibody that binds to the soluble and transmembrane forms of TNFα with high affinity, but does not bind to lymphotoxin alpha (LTα).

Infliximab inhibits the functional activity of TNFα in various test samples in vitro. The use of infliximab in transgenic mice prevented the development of polyarthritis associated with the constitutional expression of human TNFα.The introduction of infliximab after the onset of the disease led to the healing of structural damage to the joints. In vivo infliximab rapidly forms stable complexes with human TNFα, which is accompanied by a decrease in the biological activity of TNFα.

Elevated concentrations of TNFα were determined in the joints of patients with rheumatoid arthritis and correlated with disease activity. In patients with rheumatoid arthritis, infliximab therapy resulted in a reduction in infiltration of inflammatory cells into the inflamed joints, as well as a decrease in the expression of molecules mediating cellular adhesion, chemoattraction, and tissue destruction. After treatment with infliximab, there was a decrease in serum concentrations of interleukin-6 (IL-6) and C-reactive protein (CRP), as well as an increase in hemoglobin concentration in patients with rheumatoid arthritis with a lower hemoglobin concentration than baseline. Significant reduction in the number of lymphocytes in the peripheral blood or their proliferative response to mitogenic stimulation compared with the response of cells of untreated patients in vitro it was not revealed. In patients with psoriasis, infliximab therapy resulted in to reduction of inflammation in the epidermal layer and normalization of keratinocyte differentiation in psoriatic plaques. In patients with psoriatic arthritis, short-term therapy with Remicade^® was accompanied by a decrease in the number of T cells and blood vessels in the synovium and skin areas affected by the psoriatic process.

Histological examination of colon biopsy specimens taken before and 4 weeks after the administration of infliximab revealed a significant decrease in the concentration of TNFα. Therapy with infliximab in patients with Crohn's disease was accompanied by a significant decrease in the concentration of the non-specific serum inflammation marker - CRP. The total number of peripheral blood leukocytes during treatment with infliximab changed to a minimal extent, although for lymphocytes, monocytes and neutrophils, there was a tendency to normalize their number. In patients who received infliximab, the proliferative response of peripheral blood mononuclear cells to stimulation did not decrease compared to that of untreated patients. No significant changes in the secretion of cytokines by stimulated mononuclear cells of peripheral blood after treatment with infliximab have been detected.The study of mononuclear cells of biopsy specimens of the intestinal plate of the intestinal mucosa showed that therapy with infliximab causes a decrease in the number of cells expressing TNF-α and interferon-γ. Additional histological studies confirmed that infliximab reduces the infiltration of inflammation cells and the content of markers of inflammation in the affected areas of the intestine.

Endoscopic studies demonstrated the revitalization of the intestinal mucosa in patients who received infliximab.

Pharmacokinetics:

A single intravenous infusion of infliximab at doses of 1, 3, 5, 10 or 20 mg / kg was accompanied by a dose-proportional increase in the maximum serum concentration (C_mOh) and the area under the curve "concentration-time" (AUC). The volume of distribution in the equilibrium state (median 3.0-4.1 L) was independent of the dose and indicated the circulation of infliximab predominantly in the vascular bed. Pharmacokinetics did not depend on time. The ways to remove infliximab are not defined. Unchanged infliximab in the urine was not detected. In patients with rheumatoid arthritis, clearance and volume of distribution did not change with age or body weight. The pharmacokinetics of infliximab in elderly patients have not been studied.Studies in patients with liver or kidney disease have not been conducted.

After a single dose of 3, 5 or 10 mg / kg, the median FROM_max was 77, 118 and 277 μg / ml, respectively. The median of the terminal half-life period was from 8 to 9.5 days. Infliximab was detected in serum for at least 8 weeks in most patients with Crohn's disease (after a single dose of 5 mg / kg) or with rheumatoid arthritis (with maintenance therapy of 3 mg / kg every 8 weeks).

Repeated use of infliximab (5 mg / kg at 0, 2 and 6 weeks in patients with fistula form of Crohn's disease, and 3 or 10 mg / kg every 4 or 8 weeks in patients with rheumatoid arthritis) was accompanied by a small the accumulation of infliximab in the serum after the second dose. In the future, clinically significant accumulation was not observed. Most patients with frontal form of Crohn's disease infliximab was detected in serum for 12 weeks (ranging from 4 to 28 weeks) after administration in this regimen.

Children

Population analysis of pharmacokinetic data of patients with ulcerative colitis (n= 60), Crohn's disease (n= 120), juvenile rheumatoid arthritis (n= 117) and Kawasaki's disease (n= 16) at the age of 2 months to 17 years showed that the effect of infliximab depends on the body weight nonlinearly. When taking 5 mg / kg of Remicade® every 8 weeks, the expected median of the equilibrium state (the area under the concentration-time curve in the equilibrium state (AUCss)) in patients aged 6 to 17 years was approximately 20% less than the estimated median equilibrium exposure in adults. It is assumed that the median AUCss in patients older than 2 and younger than 6 years, 40% lower than in adult patients, although the number of patients whose data support this assumption is limited.

Indications:

- Rheumatoid arthritis. Treatment of patients with rheumatoid arthritis in active form, who had previously treated with basic anti-inflammatory drugs (CPAP), including methotrexate, was ineffective, and treatment of patients with severe progressive rheumatoid arthritis in active form who had not previously been treated with methotrexate or other DMARD. Treatment is carried out in combination with methotrexate. Combined treatment with Remicade® and methotrexate allows to reduce the symptoms of the disease,improving the functional state and slowing the progression of joint damage.

- Crohn's disease in adults. Treatment of patients aged 18 years with Crohn's disease in active form, medium or severe degree, including fistula formation, with inefficiency, intolerance or contraindications to standard therapy including glucocorticosteroids and / or immunosuppressants (in the fistula form - antibiotics, immunosuppressants and drainage). Remikade® treatment helps to reduce symptoms of the disease, achieve and maintain remission, mucosal healing and fistula closure, reduce fistulas, reduce the dose or eliminate glucocorticosteroids, and improve the quality of life of patients.

- Crohn's disease in children and adolescents. Treatment of children and adolescents aged 6 to 17 years inclusive with Crohn's disease in active form, moderate or severe, with ineffectiveness, intolerance or contraindications to standard therapy, including glucocorticosteroids and / or immunosuppressants. Treatment with Remicade^® helps reduce symptoms of the disease, achieve and maintain remission, reduce the dose or eliminate glucocorticosteroids, improve the quality of life of patients.

- Ulcerative colitis in adults. Treatment of patients with ulcerative colitis, in whom traditional therapy was not effective enough. Treatment with Remicade^® promotes the healing of the intestinal mucosa, reduces the symptoms of the disease, reduces the dose or eliminates glucocorticosteroids, reduces the need for inpatient treatment, establishes and maintains remission, and improves the quality of life of patients.

- Ulcerative colitis the children and adolescents. Treatment of children and adolescents aged from 6 up to 17 years with ulcerative colitis of moderate or severe severity with insufficient response to standard therapy with the use of glucocorticosteroids. 6-mercaptopuria or azathioprine, or in the presence of intolerance or contraindications to standard therapy.

- Ankylosing spondylitis. Treatment of patients with ankylosing spondylitis with severe axial symptoms and laboratory signs of inflammatory activity that did not respond to standard therapy. Treatment with Remicade® makes it possible to achieve a reduction in the symptoms of the disease and improve the functional activity of the joints.

- Psoriatic arthritis. Treatment of patients with progressive psoriatic arthritis in active form with an inadequate response to BPH. Remikade® is used in combination with methotrexate or in the form of monotherapy in cases of intolerance or contraindications to methotrexate. Remikade® treatment allows to reduce the symptoms of arthritis and improve the functional activity of patients, as well as reduce the degree of radiologic progression in peripheral psoriatic polyarthritis.

- Psoriasis. Treatment of patients with moderate to severe psoriasis with insufficient response, or contraindications, or intolerance to standard systemic therapy, including ciclosporin, methotrexate or PUVA therapy. Remikade® treatment results in a reduction in inflammatory phenomena in the skin and normalization of the keratinocyte differentiation process.

Contraindications:

- Hypersensitivity reactions to infliximab, other murine proteins, as well as any of the excipients of the preparation;

- a serious infectious process, for example, sepsis, abscess, tuberculosis, opportunistic infections;

- chronic heart failure III-IV functional class by classathe NYON.

- pregnancy and breastfeeding;

- age less than 18 years (with Crohn's disease and ulcerative colitis - less than 6 years).

Carefully:

- Chronic or recurrent infections in the anamnesis, including with concomitant therapy with immunosuppressants;

- intensive therapy with immunosuppressive drugs or long-term PUVA therapy in history;

- carriage of the hepatitis B virus;

- demyelinating diseases;

- increased risk of developing malignant tumors due to smoking;

- malignant neoplasms in the anamnesis, continuation of therapy in patients with developed malignant neoplasms;

- chronic heart failure I-II functional class by classification NYON.

Pregnancy and lactation:

Women of childbearing age during the treatment with Remicade® and for at least 6 months after the end should use reliable methods of contraception.

Pregnancy

Data obtained in approximately 450 patients who received infliximab during pregnancy (including about 230 in the first trimester), do not reveal an unforeseen impact on the outcome of pregnancy.

As a result of inhibition of TNFα, the use of infliximab during pregnancy can affect the normal immune response of the newborn. According to toxicity studies in mice, no evidence of toxicity for pregnant females, embryotoxicity, or teratogenicity was found with a similar antibody (selectively inhibiting mouse TNF-α activity).

The available clinical experience is limited, and to avoid possible risks, the use of infliximab is not recommended during pregnancy.

Infliximab penetrates the placenta and is found in the serum of newborn infants within 6 months after the infusion of infliximab in a pregnant patient. Consequently, such children may be at increased risk of developing infection, and the use of live vaccines is not recommended for them within 6 months after the last infusion of maternal infliximab during pregnancy.

Breastfeeding period

It is not known whether infliximab with milk from people and whether it is absorbed after ingestion. Since human immunoglobulins are excreted in breast milk, a woman should not be breast-fed for at least 6 months after the administration of infliximab.

Impact on fertility

The research data are insufficient to conclude that infliximab influences fertility and reproductive function.

Dosing and Administration:

Remikade® should be administered under the supervision of physicians experienced in the diagnosis and treatment of rheumatoid arthritis, inflammatory bowel disease, ankylosing spondylitis, psoriatic arthritis, or psoriasis. Remicade® is administered intravenously. Infusion of the drug should be carried out under the supervision of a physician trained to detect infusion reactions.

When taking Remicade®, concomitant therapy (glucocorticosteroids or immunosuppressants) should be optimized.

The drug is administered intravenously drip for at least 2 hours. All patients should remain under medical supervision for 1-2 hours after the infusion to prevent acute infusion reactions. When carrying out the infusion, emergency means should be available (such as epinephrine, antihistamines, glucocorticosteroids and artificial ventilation). Preliminary administration of antihistamines, hydrocortisone and / or paracetamol,as well as a reduction in the rate of infusion to reduce the risk of developing infusion reactions, especially in patients whose infusion reactions developed with the previous administration of the drug.

In the treatment of adult patients who have tolerated at least the first three 2-hour infusions of Remicade® (induction phase) and are on maintenance therapy, the duration of subsequent infusions may be shortened to a minimum of 1 hour. If in the future with an accelerated introduction of the drug there will be an infusion reaction, then in the case of continued therapy, a return to slower infusions is recommended.

The possibility of reducing the time of infusion with the administration of the drug in a dose of more than 6 mg / kg has not been studied.

Treatment of rheumatoid arthritis

The initial single dose of Remicade® is 3 mg / kg intravenously. Then the drug is administered in the same dose 2 weeks and 6 weeks after the first administration (induction phase), and every 8 weeks thereafter (maintenance phase of treatment).

Treatment with Remicade® should be carried out simultaneously with the use of methotrexate.

In most patients, a clinical response is achieved within 12 weeks. If there is insufficient response or if the effect of the treatment is lost in the subsequent period, it is possible to increase the dose of Remicade® in steps of 1.5 mg / kg, up to 7.5 mg / kg every 8 weeks, or to reduce the intervals between the administration of Remicade® dose of 3 mg / kg to 4 weeks. When the clinical response is reached, treatment should be continued at the appropriate dose and in the appropriate dosing regimen.

In the absence of the effect of treatment during the first 12 weeks, as well as in response to an increase in the dose of Remicade® or a reduction in the intervals between infusions, consideration should be given to the advisability of continuing treatment.

Treatment of active form of Crohn's disease of severe or moderate degree in adults

The initial dose of Remicade® is 5 mg / kg intravenously, the second infusion at the same dose 2 weeks after the first. If there is no response after two injections, further use of Remicade® is not advisable. For responding patients, treatment with Remicade® can be continued, and one of two possible treatment options should be selected:

- The drug is administered at a dose of 5 mg / kg at 6 weeks after the first administration and then every 8 weeks; in the supporting phase of treatment, some patients may need to increase the dose to 10 mg / kg to achieve the effect;

- The drug is administered again at a dose of 5 mg / kg for a relapse of the disease (see sections "Re-appointment" and "Side-effect").

Despite the inadequacy of the comparative data, the available data indicate that some patients who initially responded to a 5 mg / kg dose but subsequently lost the response may regain their response when the dose is increased. Care should be taken to evaluate the possibility of continuing therapy for patients who did not show signs of therapeutic improvement after a dose change.

The total duration of treatment with Remicade® is determined by the attending physician.

Treatment of active form of Crohn's disease of severe or moderate degree in children and adolescents aged 6 to 17 years inclusive

The initial dose of Remicade® is 5 mg / kg intravenously. Then the drug is administered in the same dose 2 weeks and 6 weeks after the first administration, and then every 8 weeks.In the absence of effect during the first 10 weeks, further use of Remicade® is not recommended.

Some patients may require a shorter interval between infusions to maintain the clinical effect, while for some patients a longer interval may be sufficient. In patients who have an interval between infusions reduced to less than 8 weeks, the risk of developing adverse events may be increased. It is necessary to carefully evaluate the need to continue treatment in the absence of an additional effect of treatment with a change in the dosing interval.

Treatment with Remicade ® should be carried out simultaneously with the use of immunomodulators - 6-mercaptopurine, azathioprine or methotrexate.

If there is a response to treatment with Remicade®, the total duration of treatment is determined by the attending physician.

The efficacy and safety of Remicade® in patients younger than 6 years of age have not been studied.

Treatment of Crohn's disease with fistula in adults

Remicade® is administered at a dose of 5 mg / kg intravenously, then the drug is administered at the same dose 2 weeks and 6 weeks after the first administration.If there is no response after the administration of these three doses, continuing treatment with Remicade® is not advisable. If there is a response, treatment can be continued, and one of two possible treatment options should be selected:

- The drug is administered at a dose of 5 mg / kg at 2 weeks and 6 weeks after the first administration and then every 8 weeks; some patients may need to increase the dose to 10 mg / kg to achieve the effect of treatment;

- the drug is administered again at the same dose for a relapse of the disease (see sections "Re-appointment" and "Side effect").

The total duration of treatment with Remicade® is determined by the attending physician. Comparative studies of these two treatment options for Crohn's disease have not been carried out.The available data on the use of the drug in the second variant of treatment (repeated administration in case of relapse) are limited.

Treatment of ulcerative colitis in adults

The initial dose of Remicade® is 5 mg / kg intravenously. Then the drug is administered in the same dose 2 weeks and 6 weeks after the first injection, and then every 8 weeks. Some patients may need to increase the dose to 10 mg / kg to achieve the effect. The available data indicate the onset of the effect of treatment in the period up to 14 weeks (after the administration of 3 doses). If the effect does not occur during this time, the question of whether to continue treatment should be decided. If there is a response to treatment, the total duration of treatment with Remicade® is determined by the attending physician.

Treatment of ulcerative colitis in children and adolescents from 6 to 17 years inclusive

The initial dose of Remicade® is 5 mg / kg intravenously. Then the drug is administered in the same dose 2 weeks and 6 weeks after the first injection, and then every 8 weeks. The available data do not allow recommending the use of Remicade® in the absence of effect within 8 weeks after the first infusion.

If there is a response to treatment with Remicade®, the total duration of treatment is determined by the attending physician.

The efficacy and safety of Remicade® in patients younger than 6 years of age has not been studied.

Treatment of ankylosing spondylitis

The initial dose of Remicade® is 5 mg / kg intravenously. Then the drug is administered in the same dose 2 weeks and 6 weeks after the first injection, and then every 6-8 weeks. In the absence of effect for 6 weeks (after the introduction of two doses) continue treatment is impractical.

Treatment of psoriatic arthritis

The initial dose of Remicade® is 5 mg / kg intravenously. Then the drug is administered in the same dose 2 weeks and 6 weeks after the first injection, and then every 8 weeks.

Treatment of psoriasis

The initial dose of Remicade® is 5 mg / kg intravenously. Then the drug is administered in the same dose 2 weeks and 6 weeks after the first injection, and then every 8 weeks. In the absence of effect for 14 weeks (after the administration of four doses) continue treatment with infliximab is impractical. The total duration of treatment with Remicade® is determined by the attending physician.

Repeated administration of rheumatoid arthritis and Crohn's disease

If the disease recurs, Remicade® can be reassigned within 16 weeks after the last dose. In clinical studies, hypersensitivity reactions were infrequent and were observed if the interval before repeated administration of Remicade® was less than 1 year. The efficacy and safety of repeated administration of the drug at an interval greater than 16 weeks have not been studied.

Repeated administration for ulcerative colitis

The effectiveness and safety of the drug when it is used repeatedly under a different scheme (not every 8 weeks) have not been studied.

Re-appointment with ankylosing spondylitis

The efficacy and safety of the drug when it is re-applied in a different way (not every 6-8 weeks) has not been studied.

Repeated administration of psoriatic arthritis

The effectiveness and safety of the drug when it is used repeatedly under a different scheme (not every 8 weeks) have not been studied.

Repeated administration of psoriasis

The limited experience of reintroducing a single dose of Remicade® after a 20-week interval suggests that treatment may be less effective and may be accompanied by a higherfrequency of infusion reactions (light and moderate severity) in comparison with the initial induction regime. The limited experience of re-administration of Remicade® in the induction mode after exacerbation of the disease suggests that treatment may be accompanied by a higher incidence of infusion reactions (including severe) compared with the administration regimen every 8 weeks.

Re-appointment regardless of the indications

In the event of a break in maintenance therapy and the need to resume treatment, the repeated administration of Remicade® in induction is not recommended. Renewal of therapy should be carried out in the regime of one infusion with the subsequent administration of infusions in the regime of maintenance therapy.

Patients over 65 years of age

Efficacy and safety of the drug in elderly patients have not been studied. No significant age-related differences in the distribution and excretion of the drug in clinical studies were observed. Correction of the dose is not required.

Patients with impaired renal and hepatic function

The efficacy and safety of the drug in this category of patients have not been studied.

INSTRUCTION FOR PREPARATION OF INFUSION SOLUTION

1) Calculate the dose and the required number of Remikade® vials (each vial contains 100 mg infliximab) and the required volume of the finished drug solution.

2) In aseptic conditions, dissolve the contents of each vial in 10 ml of water for injection using a syringe with a 21 (0.8 mm) needle or a smaller caliber. Before the introduction of the solvent, remove the plastic lid from the vial and wipe the cork with a 70% solution of ethyl alcohol. Insert the needle of the syringe into the vial through the center of the rubber stopper, and direct the water jet along the wall of the bottle.

Gently stir the solution by rotating the vial until the freeze-dried powder is completely dissolved. Avoid prolonged and vibrational mixing.

DO NOT BURST. When dissolving, the formation of foam is possible, in this case allow the solution to stand for 5 minutes.

The resulting solution should be colorless or slightly yellow in color and opalescent. There may be a small amount of fine semitransparent particles in it, since infliximab is a protein. In the case of opaque particles, foreign inclusions and a discolored color, the solution can not be used.

3) Bring the total volume of the prepared dose of Remikade® solution to 250 ml with 0.9% sodium chloride solution for injection. To do this, remove from the glass vial or infusion bag containing 250 ml of a 0.9% solution of sodium chloride, a volume equal to the volume of the preparation of Remicade® prepared with the use of water for injection. After this, slowly add the previously prepared Remicade® solution to a bottle or infusion bag with 0.9% sodium chloride solution and gently mix. DO NOT INDUCE THE UNINTENDED PREPARATION!

4) Infuse for at least the recommended time. Use only an infusion system with a built-in sterile, pyrogen-free filter with low protein-binding activity (pore size not more than 1.2 μm). In connection with the lack of a preservative in the preparation, begin the introduction of the infusion solution as soon as possible, but not later than 3 hours after its preparation. Dissolution and dilution should be carried out in aseptic conditions.

5) Do not administer Remicade® together with any other medicines through a single infusion system.

6) Visually check the infusion solution before starting the injection. In the case of opaque particles, foreign inclusions and a discolored color, the solution can not be used.

7) The unused portion of the infusion solution is not subject to further use and must be destroyed.

Side effects:

Upper respiratory tract infections were the most frequent adverse reactions reported in clinical trials. Their frequency was 25.3% in patients who received infliximab, compared with 16.5% in the control group. The most serious adverse reactions associated with the use of TNF inhibitors that were reported with Remicade® included the reactivation of hepatitis B virus, chronic heart failure, serious infections (including sepsis, opportunistic infections and tuberculosis), serum sickness (delayed-type hypersensitivity reactions), hematological reactions, systemic lupus erythematosus / lupus-like syndrome, demyelinating syndrome, hepatobiliary disorders, lymphoma, hepatolienal T- cell lymphoma, leukemia, Merkel's carcinoma, melanoma,malignant neoplasms in children, sarcoidosis / reactions by type of sarcoidosis, intestinal or personal abscess (with Crohn's disease) and serious infusion reactions.

Table of unwanted reactions

Table 1 lists the undesirable reactions (including fatal) observed in clinical trials and reported during the post-registration period.

Adverse reactions in the body systems are distributed in frequency into the following categories: very frequent (≥1 / 10), frequent (≥1 / 100 and <1/10), infrequent (≥1 / 1000 and <1/100), rare (≥ 1/10000 and <1/1000) and very rare (<1/10000), is unknown (the frequency can not be estimated based on the available data). In each column, unwanted reactions are in order of decreasing severity.

Table 1. Adverse events detected during clinical trials and post-marketing period

Class system/organ	Frequency reactions	The nature of the reaction
Infectious and parasitic diseases	highly frequent	viral infections (eg, influenza, herpes)
	frequent	bacterial infections (eg, sepsis, cellulitis, abscess)
	infrequent	tuberculosis, fungal infections (eg, candidiasis)
	rare	meningitis, opportunistic infections (such as invasive fungal infections (pneumocystosis, histoplasmosis, aspergillosis, coccidiomycosis, cryptococcosis, blastomycosis), bacterial infections (atypical mycobacterial infection, listeriosis, salmonellosis) and viral infections (cytomegalovirus infection)), parasitic infections, hepatitis B reactivation
Benign, malignant and unhealthy neoplasms (including cysts and polyps)	rare	lymphoma, non-Hodgkin's lymphoma, Hodgkin's disease, leukemia, melanoma
	unknown	hepatolienne T-cell lymphoma (adolescents and young people with Crohn's disease and ulcerative colitis), Merkel's carcinoma
Violations of the blood and lymphatic system	frequent	neutropenia, leukopenia, anemia, lymphadenopathy
	infrequent	thrombocytopenia, lymphopenia, lymphocytosis
	rare	agranulocytosis, thrombotic thrombocytopenic purpura, pancytopenia, hemolytic anemia, idiopathic thrombocytopenic purpura
Immune system disorders	frequent	respiratory allergic reactions
	infrequent	anaphylactic reactions, lupus-like syndrome,Serum sickness or serum-type reactions
	rare	anaphylactic shock, vasculitis, reactions of the type of sarcoidosis
Disorders of the psyche	frequent	depression, insomnia
	infrequent	amnesia, anxiety, confusion, drowsiness, nervousness
	rare	apathy
Disturbances from the nervous system	highly frequent	headache
	frequent	vertigo, dizziness, hyposthenia, paresthesia
	infrequent	epileptic seizure, neuropathy
	rare	transverse myelitis, demyelinating disorders of the central nervous system (such as multiple sclerosis, optic neuritis), demyelinating disorders of the peripheral nervous system (Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy and multifocal motor neuropathy)
Disturbances on the part of the organ of sight	frequent	conjunctivitis
	infrequent	keratitis, periorbital edema, meiobite
	rare	endophthalmitis

	unknown	transient loss of vision during or at within 2 hours after the infusion
Heart Disease	frequent	tachycardia, palpitations
	infrequent	heart failure (occurrence and deterioration), arrhythmia, syncope, bradycardia
	rare	cyanosis, pericardial effusion
	unknown	Myocardial ischemia / myocardial infarction during or within 2 hours after infusion
Vascular disorders	frequent	decrease in blood pressure, increased blood pressure, ecchymosis, strong "hot flashes"
	infrequent	violation of peripheral blood circulation, thrombophlebitis, hematoma
	rare	circulatory insufficiency, petechia, vasospasm
Disturbances from the respiratory system, chest and mediastinal organs	highly frequent	upper respiratory tract infection, sinusitis
	frequent	infections of the lower respiratory tract (eg, bronchitis, pneumonia), shortness of breath, nosebleeds
	infrequent	pulmonary edema, bronchospasm, pleurisy, pleural effusion
	highly rare	interstitial lung disease (including rapid disease progression, pulmonary fibrosis and pneumonitis)
Disorders from the gastrointestinal tract	highly frequent	abdominal pain, nausea
	frequent	Gastrointestinal bleeding, diarrhea, dyspepsia, gastroesophageal reflux, constipation
	infrequent	Intestinal perforation, intestinal stenosis, diverticulitis, pancreatitis, cheilitis
Disturbances from the liver and bile ducts	frequent	impaired liver function, increased "hepatic" transaminases
	infrequent	hepatitis, hepatocyte damage, cholecystitis
	rare	autoimmune hepatitis, jaundice
	highly rare	liver failure
Disturbances from the skin and subcutaneous tissues	frequent	the appearance or deterioration of psoriasis, including pustular psoriasis (mainly palmar-plantar form), urticaria, rash, itching, excessive sweating, dry skin, fungal dermatitis, eczema, alopecia
	infrequent	bullous rash, onychomycosis, seborrhea, furunculosis, rosacea, skin papilloma, hyperkeratosis, skin pigmentation disorder
	highly rare	toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, furunculosis
Disturbances from musculoskeletal and connective tissue	frequent	arthralgia, myalgia, back pain
Disorders from the kidneys and urinary tract	frequent	urinary tract infection
Disorders from the kidneys and urinary tract	infrequent	pyelonephritis
Violations of the genitals and mammary gland	infrequent	vaginitis
General disorders and disorders at the site of administration	highly frequent	infusion reactions, pain
	frequent	pain in the chest, fatigue, fever, reactions at the injection site, chills, swelling
	infrequent	delayed wound healing
	rare	formation of granulomatous foci
Laboratory and instrumental data	infrequent	formation of autoantibodies
Laboratory and instrumental data	rare	violation of the development of complement factors

Infusion reactions

As such, clinical trials examined any adverse reactions that occurred during or within 1 hour after infusion. In clinical trials of Phase 3, the incidence of infusion reactions in the Remicade group was about 18% and about 5% in the placebo group. In general, the frequency of infusion reactions in patients treated with infliximab was higher than in patients who received infliximab with the simultaneous use of immunomodulators. Approximately 3% of patients were forced to discontinue therapy due to the development of infusion reactions, while in all patients the reactions were reversible (after drug therapy or without it). Of the patients receiving infliximab and those who underwent infusion reactions in the induction period (for 6 weeks), in 27% of the supporting period (from 7 to 54 weeks), repeated reactions developed. Of patients who had no infusion reactions in the induction period, 9% the development of these reactions in the supporting period was noted.

In a clinical study ASPIRE in patients with rheumatoid arthritis who have undergone at least three 2-hour infusions of Remicade® without serious infusion reactions, the duration of the infusion was allowed to be reduced to at least 40 minutes. In this study, 66% (686 out of 1040) of patients received at least one infusion reduced to 90 minutes or less, 44% (454 out of 1040) of patients received at least one infusion reduced to 60 minutes or less. In patients who received at least one reduced infusion of infliximab. Infusion reactions were recorded in 15% of patients, and serious infusion reactions - in 0.4% of patients.

In a clinical study SONIC In patients with Crohn's disease, infusion reactions were reported in 16.6% (27 of 163) of patients receiving infliximab monotherapy, 5% (9 of 179) of patients receiving combination therapy with infliximab and azathioprine in 5.6% (9 of 161) who received azathioprine monotherapy.One serious infusion reaction was registered (less than 1% of patients) in the group of monotherapy with infliximab.

In the post-marketing period with the use of Remikade®, there were cases of development of seizures and anaphylactoid reactions, including pharyngeal / laryngeal edema and severe bronchospasm. Very rarely reported cases of transient loss of vision, myocardial ischemia or myocardial infarction during infusion or within 2 hours after infusion.

Infusion reactions after repeated administration of Remicade®

A clinical study was conducted in patients with moderate or severe psoriasis to assess the efficacy and safety of long-term maintenance therapy compared to the induction regimen of Remicade® (maximum 4 infusions at 0, 2, 6 and 14 weeks) after the disease worsened. Patients did not receive concomitant therapy with immunosuppressants. In the induction group, severe infusion reactions developed in 4% (8 of 219) patients compared with less than 1% (1 of 222) in the maintenance therapy group. Most serious infusion reactions were noted during the 2nd infusion (week 2).The interval between the last maintenance dose and the first repeated induction dose was from 35 to 231 days. Symptoms included (but were not limited to) dyspnoea, urticaria, edema of the face and lowering blood pressure. In all cases, after stopping therapy with Remicade and / or at the beginning of another therapy, signs and symptoms were completely passed.

Hypersensitivity reactions of delayed type (HRT)

In clinical trials, HRT reactions were infrequent and occurred if the interval before re-introduction of Remicade® was less than 1 year. In studies of psoriasis, HRT reactions occurred at the beginning of the course of therapy. Symptoms and symptoms included myalgia and / or arthralgia, accompanied by a fever and / or rash. Some patients experienced itching, swelling of the face, lips or hands, dysphagia, urticaria, sore throat and headache.

Data on the number of cases of development of HRT reactions if the interval before the repeated administration of Remikade® was more than 1 year is not enough. However, limited data from clinical trials suggest an increased risk of HRT reactions with an increase in the interval without taking Remicade^®(see section "Special instructions").

In a 1-year clinical trial in which infusions were repeated in patients with Crohn's disease (ACCENT I), the number of cases of development of reactions by type of serum sickness was 2.4%.

Immunogenicity

In patients who developed antibodies to infliximab, infusion reactions developed more likely (approximately 2-3 times). Concomitant use of immunosuppressants decreased the likelihood of developing infusion reactions.

In clinical studies, with single and multiple injection of infliximab in doses of 1 to 20 mg / kg, antibodies to infliximab were detected in 14% of patients with simultaneous therapy with any immunosuppressant and in 24% without immunosuppressant therapy. In 8% of patients with rheumatoid arthritis who received the recommended dose of infliximab for re-therapy together with methotrexate, antibodies to infliximab were detected. In 15% of patients with psoriatic arthritis who received infusions of 5 mg / kg infliximab with or without concomitant methotrexate, antibodies to infliximab were detected (in 4% of patients who received methotrexate, and 26% of patients who did not receive methotrexate initially). In patients with Crohn's disease who received maintenance therapy with infliximab, antibodies to infliximab were found in 3.3% of patients receiving immunosuppressants and 13.3% who did not receive immunosuppressants. The number of cases with episodic therapy increased by 2-3 times. Due to the limitations of the method for determining antibodies, a negative result did not exclude the presence of antibodies to infliximab. In some patients with high tiger antibodies, there were signs of a decrease in the effectiveness of infliximab therapy. Approximately 28% of patients with psoriasis who received infliximab therapy in a supportive mode without simultaneous use of immunomodulators, antibodies to infliximab were detected.

Infections

Patients who received Remicade® received tuberculosis, bacterial infections, including sepsis and pneumonia, invasive fungal, viral or other opportunistic infections. Some of these infections were lethal, the most frequently reported opportunistic infections with a mortality rate of more than 5% included pneumocystis, candidiasis, listeriosis and aspergillosis.

In clinical studies in the Remicade® therapy group, 36% of patients received anti-infective therapy in addition to 25% of such patients in a placebo troupe.

In clinical studies of rheumatoid arthritis, the incidence of serious infections, including pneumonia, was higher in the group receiving co-therapy with infliximab and methotrexate, compared with the group receiving only methotrexate, especially with doses of infliximab 6 mg / kg and more.

During the post-registration period, infections were the most frequently reported serious adverse reactions, in some cases fatal. Of all deaths, approximately 50% were due to infectious complications. There have been reports of cases of tuberculosis, including miliary tuberculosis and tuberculosis with extrapulmonary localization, in some cases fatal.

Malignant neoplasms and lymphoproliferative diseases

In clinical studies of infliximab, in which 5780 patients (5,474 patient-years) received therapy, 5 cases of lymphoma and 26 cases of malignant neoplasm were diagnosed (in addition tolymphomas) compared with no cases of lymphoma and 1 case of malignant neoplasm (in addition to lymphoma) in 1600 patients who received a placebo (941 patient-years).

In long-term follow-up (up to 5 years), 3210 patients (6234 patient-years) experienced in clinical studies of infliximab reported 5 cases of lymphoma and 38 cases of malignant neoplasm (in addition to lymphoma).

Cases of malignant neoplasms, including lymphoma, were also reported to the post-marketing period.

In a clinical study involving patients with COPD (moderate or severe) who smoked or were former smokers, 157 adult patients received Remicade® therapy at doses similar to doses for the treatment of rheumatoid arthritis and Crohn's disease. 9 of these patients developed malignant pricing, including 1 case of lymphoma. The median follow-up duration was 0.8 years (incidence of 5.7% (95% CI 2.65-10.6%)). One case of malignancy was registered in the control group of 77 patients (median follow-up duration 0.8 years, frequency 1.3% (95% CI 0.03-7.0%)). Most malignant neoplasms were diagnosed in the lungs or in the head and neck.

In the post-marketing period, rare cases of hepatopetal T-cell lymphoma were reported in patients receiving Remicade. The vast majority of cases have been reported in patients with Crohn's disease and ulcerative colitis and most patients were adolescents or young male adults.

Cardiovascular failure

In II phase of the clinical study of Remicade® in patients with chronic heart failure, there was an increase in mortality due to a rise in heart failure with Remicade®, especially when using an increased dose of 10 mg / kg (twice the maximum recommended therapeutic dose). In this study, 150 patients with chronic heart failure III-IV functional class by classification NYHA (left ventricular ejection fraction ≤35%) received 3 infusions of Remicade® 5 mg / kg, 10 mg / kg or placebo for 6 weeks. At week 38, 9 out of 101 patients receiving Remicade® (2 patients receiving 5 mg / kg and 7 patients receiving 10 mg / kg) died, compared to one death in the placebo group (49 patients).

In the post-marketing period, cases of a rise in heart failure were also reported when Remikade® was used, with or without additional factors. In addition, there were rare reports of a newly diagnosed heart failure, including in patients who had no previous cardiovascular disease. Some of these patients were under the age of 50 years.

Changes in the liver and bile ducts

In clinical studies in patients on the background of therapy with Remicade ®, there was a slight or moderate increase in ALT activity and ACT without the development of severe liver damage. There was an increase in ALT to a level equal to or exceeding the 5-fold upper limit value (see Table 2). Increase in activity of aminotransferases (ALT in a greater degree than ACT) was noted more often in the group of patients receiving Remicade® than in the control group. This increase in aminotransferase activity was noted both with the use of Remikade® as a monotherapy and with its use in combination with other immunosuppressants.In most cases, the increase in aminotransferase activity was transient, but in a small number of patients this increase was longer. In general, the increase in ALT and AST activity was asymptomatic, with a decrease or a return to the initial values of these indicators occurred regardless of whether Remicateid therapy was continued or stopped^® or the concomitant therapy has changed.

In the post-marketing period, there were very few reports of jaundice and hepatitis, and in some cases showing signs of autoimmune hepatitis, in patients receiving Remicade®.

Table 2. Ratio of patients with increased ALT activity in clinical trials

Indication	Number of patients³		Median follow-up (weeks)⁴		≥3 upper limits of the norm		≥5 upper limits of the norm
	Placebo	infliximab	Placebo	infliximab	Placebo	infliximab	Placebo	infliximab
Rheumatoid arthritis¹	375	1087	58,1	58,3	3,2%	3,9%	0,8%	0,9%
Crohn's disease²	324	1034	53,7	54,0	2,2%	4,9%	0,0%	1,5%
Crohn's disease in children	-	139	-	53,0	-	4,4%	-	1,5%
Ulcerative colitis	242	482	30,1	30,8	1,2%	2,5%	0,4%	0,6%
Ulcerative colitis in children	-	60	-	49,4	-	6,7%	-	1,7%
Ankylosing spondylitis	76	275	24,1	101,9	0,0%	9,5%	0,0%	3,6%
Psoriatic arthritis	98	191	18,1	39,1	0,0%	6,8%	0,0%	2,1%
Psoriasis (plaque)	281	1175	16,1	50,1	0,4%	7,7%	0,0%	3,4%

¹ Patients in the placebo group received methotrexate, infliximab group patients received infliximab and methotrexate.

² Patients of the group placebo two clinical trials of the third phase of Crohn's disease (ACCENT I and ACCENT II) received 5 mg / kg infliximab and the beginning of the study and placebo in the supporting stage. Data from patients who were randomized to the placebo group at the supporting stage and subsequently transferred to groupsin infliximab, in the analysis of ALT activity was considered as a group of infliximab. In a clinical study SONIC phase 3b patients in the placebo group in addition to placebo infusions were given azathioprine 2.5 mg / kg / day at quality of active control.

³ The number of patients who evaluated the activity of ALT.

⁴ The median follow-up is based on the number of patients receiving therapy.

Antinuclear antibodies (ANA) / antibodies to double-stranded DNA (dsDNA)

According to clinical studies, about half of the patients who received infliximab, and about 1/5 of the number of patients receiving placebo who did not have antinuclear antibodies (ANA) before therapy, against the background of therapy began to reveal antinuclear antibodies.Antibodies to double-stranded native DNA (anti-dsDNA) began to be detected in approximately 17% of patients who received infliximab, and were not detected in patients receiving placebo. At the final examination in 57% of patients who received infliximab, antibodies to double-stranded DNA were detected. Nevertheless, reports of the development of lupus or lupus-like syndrome remained infrequent.

Patients of childhood

Patients of childhood with Crohn's disease

The following adverse events were more common in children than in adults with Crohn's disease (study data REACH): anemia (10.7%), blood in the stool (9.7%), leukopenia (8.7%), hot flashes (8.7%), viral infections (7.8%), neutropenia (6 , 8%), bone fractures (6.8%), bacterial infections (5.8%), allergic reactions from the respiratory tract (5.8%).

Infusion reactions

According to the research REACH In 17.5% of randomized patients, one or more infusion reactions were observed. Serious infusion reactions were absent, in 2 patients in the study, non-serious anaphylactic reactions were noted.

Immunogenicity

Antibodies to infliximab were found in 3 children (2.9%).

Infections

Attachment of infection was noted in 56.3% of patients randomized in the study REACH. In the study REACH infections were more common in patients who received infusion of Remicade® at an interval of 8 weeks than those who received Remicade® infusions at 12-week intervals (73.6% and 38.0%, respectively). Serious infections were noted in 3 patients from the 8-week interval and 4 patients in the 12-week interval. The most frequent infectious complications were upper respiratory tract infections and pharyngitis, the most common serious infectious complication was an abscess, there were three cases of pneumonia (1 serious) and 2 cases of detection of the virus Herpes zoster (both frivolous).

Patients of childhood with ulcerative colitis

In general, the incidence of adverse events in clinical trials (C0168T72) in pediatric patients with ulcerative colitis was comparable to that in clinical trials (ACT 1 and ACT 2) in adults. In the C0168T72 study, the most frequently reported adverse events were upper respiratory tract infections, pharyngitis, abdominal pain, fever and headache.The most common adverse event was a worsening of the course of ulcerative colitis, the frequency of which was higher in the group of patients who received the drug every 12 weeks compared to the regimen every 8 weeks.

Infusion reactions

One or more infusion reactions were registered in 8 of 60 patients (13.3%), including in maintenance therapy groups: 4 out of 22 patients (18.2%) every 8 weeks and 3 of 23 (13.0% ) patients every 12 weeks. Serious infusion reactions were not recorded, all reactions were mild or moderate in intensity.

Immunogenicity

Antibodies to infliximab were determined in 4 (7.7%) patients up to 54 weeks.

Infections

In the study C0168T72 infections were registered in 31 of 60 patients (51.7%), parenteral or oral antimicrobial therapy required 22 (36.7%) patients. The incidence of infections in pediatric patients with ulcerative colitis in the study C0168T72 was comparable to that in pediatric patients with Crohn's disease (study REACH), but it was slightly higher than in adult patients (studies ACT 1 and ACT 2). In general, the incidence of infections in the study C0168T72 in the maintenance group every 8 weeks was 59%, in the maintenance group every 12 weeks - 60.9%.The most frequently reported adverse events on the part of the respiratory system were upper respiratory tract infections (12%) and pharyngitis (8%). Serious infections were observed in 12% of patients receiving therapy.

In this study, the number of patients aged 12 to 17 years was greater than patients aged 6 to 11 years (45 of 60, 75%). Despite the fact that the number of patients in each subgroup is too small to draw definite conclusions about the effect of age on safety, the number of cases of serious adverse events and discontinuation of therapy due to adverse events was greater in the group of younger patients. Despite the fact that the number of patients with infections was also greater in the group of younger patients, the number of serious infections was comparable in both groups. In general, the number of adverse events and infusion reactions was comparable in both age groups.

Post-registration period data

During the post-registration period, spontaneous serious adverse events in childhood patients included cases of malignant neoplasms (including hepatolienne T-cell lymphoma), transient disorders of "hepatic" enzymes,lupus-like syndrome and the appearance of autoantibodies.

Special patient groups

Elderly patients (≥65 years of age)

In clinical studies of rheumatoid arthritis among patients who received methotrexate and infliximab, the incidence of serious infections (11.3%) in elderly patients (≥65 years) was higher than in patients younger than 65 years (4.6%). Among patients who received only methotrexate, the incidence of serious infections in elderly patients was 5.2%. in patients younger than 65 years - 2.7%.

Overdose:

A single administration of Remicade® at a dose of 20 mg / kg did not cause a toxic effect. Clinical data on overdose is not available. If necessary, symptomatic treatment should be performed.

Interaction:

Special studies of interaction were not conducted.

In patients with rheumatoid arthritis, psoriatic arthritis and Crohn's disease, simultaneous use with methotrexate or other immunomodulators reduces the formation of antibodies to infliximab and increases the concentration of the latter in plasma. However, due to the limitations of the method used to determine the concentration of infliximab and antibodies to infliximab in the blood serum, the results are not unambiguous.

Glucocorticosteroids do not have a clinically significant effect on the pharmacokinetics of infliximab.

It is not recommended simultaneous application of Remikade® and other biological products used for the same indications, including anakinra and abatacept.

It is not recommended simultaneous application of the drug Remicade^® and live vaccines.

It is not recommended simultaneous application of Remikade® and therapeutic preparations containing infectious agents.

Special instructions:

To improve the traceability of the use of biological medicinal products, it is recommended to record the name and series of the drug in the patient's medical record.

Infusion reactions and hypersensitivity reactions

The use of infliximab may be associated with the development of acute infusion reactions, including anaphylactic shock and HRT reactions.

Acute infusion reactions, including anaphylactic, may develop during (within seconds) or within a few hours after infusion. If an acute reaction occurs, the infusion should be stopped immediately.When carrying out the infusion, emergency means should be available (such as epinephrine, antihistamines, hydrocortisone and / or artificial ventilation). Preliminary administration of antihistamines, hydrocortisone and / or paracetamol is possible to prevent mild and transient effects.

Possible formation of antibodies to infliximab, which may be due to an increase in the frequency of infusion reactions. A small part of the infusion reactions were severe allergic reactions. There was a correlation between the formation of antibodies to infliximab and a decrease in the duration of response to treatment. Joint use with immunomodulators was associated with a decrease in the incidence of antibodies to infliximab and a decrease in the frequency of infusion reactions. The effect of joint therapy with immunomodulators was more pronounced in patients receiving episodic treatment than in patients on maintenance therapy. In patients who stopped using immunosuppressants before or during therapy with Remicade®, the risk of antibody formation is increased.Antibodies to infliximab may not always be detected in serum samples. With the development of a serious reaction, symptomatic treatment should be prescribed, no further infusion of Remicade® should be given. In clinical trials, cases of HRT reactions were reported. The available data suggest that an increase in the interval without taking Remicade® increases the risk of HRT reactions. Patients should immediately seek medical attention for any adverse event. When resuming treatment in patients after a long break, you should carefully monitor the signs and symptoms of HRT reactions.

Infections

Before and during and after therapy, close monitoring of the patient should be made to identify signs of possible infection, including tuberculosis. Since the removal of Remicade ® occurs within 6 months, the patient should be monitored during this period. Therapy with Remicade® should be discontinued if the patient develops a serious infection or sepsis.

Caution should be exercised when applying Remicade® to patients with chronic infections or a recurrent history of infection, including those receiving concomitant therapy with immunosuppressants. Patients should avoid exposure to possible risk factors for infection.

TNFα is a mediator of inflammation and a modulator of cellular immunity. Experimental data have shown that TNFα is necessary for purification from intracellular infections. Clinical experience shows that immunological protection against infections can be compromised in some patients receiving treatment with infliximab.

It should be borne in mind that inhibition of TNFα activity may mask such symptoms of infection as fever. Early recognition of atypical clinical manifestations of serious infections and typical clinical manifestations of rare and atypical infections is critical for reducing the delay in diagnosis and treatment. Patients receiving therapy with TNFα inhibitors are at greater risk of developing serious infections.

Tuberculosis, bacterial infections, including sepsis and pneumonia, invasive fungal, viral or other opportunistic infections have been observed in patients receiving infliximab. Some of these infections were fatal. The most frequently reported opportunistic infections with a mortality rate of more than 5% included pneumocystis, candidiasis, listeriosis and aspergillosis.

Patients who developed an infection during therapy with Remicade® should be closely monitored and fully diagnosed. Remikade® should be discontinued if a new serious infection or sepsis develops in the patient and is prescribed antibacterial or antifungal therapy before the control of the infectious process is achieved.

Tuberculosis

There have been reports of the development of active tuberculosis in patients who received Remicade^®. Most cases of tuberculosis were extrapulmonary local or disseminated.

Before starting treatment with Remicade®, the patient should be carefully examined for both active and latent tuberculosis. The examination should include a careful history, including whether the patient had tuberculosis in the past, whether they had contacts with patients with tuberculosis, and whether immunosuppressant therapy has been or is being conducted.It is necessary to conduct the necessary screening tests (chest x-ray, tuberculin test). It should be borne in mind that in patients with severe illness and patients with immunosuppression, a false negative tuberculin test can be obtained.

When diagnosing active tuberculosis, therapy with Remicade® can not be started.

If you suspect a latent tuberculosis, you should seek advice from a phthisiatrician. In all cases described below, the risk / benefit of Remicade® therapy should be carefully evaluated.

When diagnosing latent tuberculosis, appropriate therapy should be initiated before starting therapy with Remicade®.

In patients with multiple or significant risk factors for developing tuberculosis, but whose latent tuberculosis is not confirmed by the test, the need for antituberculous therapy should be considered before initiating therapy with Remicade®. Consideration should be given to the need for the use of antituberculosis therapy before initiating therapy with Remicade® in patients with active or latent tuberculosis in history, for which an adequate course of therapy can not be confirmed.

Several cases of active tuberculosis development have been reported in patients receiving Remicade^® during and after therapy of latent tuberculosis. Patients should consult a doctor if signs or symptoms of tuberculosis appear (persistent cough, weight loss / weight loss, subfebrile fever) during or after therapy with Remicade®.

Invasive fungal infections

In the group of patients who received the drug Remicade^®Suspicion of invasive fungal infections such as aspergillosis, candidiasis, pneumocystis, histoplasmosis, coccidiomycosis or blastomycosis should always occur when the patient develops a serious systemic disease. At an early stage, a specialist should be consulted to diagnose and treat invasive fungal diseases when examining such patients. Invasive fungal infections can be represented by disseminated, not localized lesions, and the result of the analysis on antigens and antibodies in some patients with active infection may be negative. The need to initiate empirical antifungal therapy before the end of laboratory studies should be assessed, taking into account both the risk of developing a serious fungal infection,and the consequences of antifungal therapy.

For patients who have lived or visited regions endemic for invasive fungal infections, such as histoplasmosis, coccidiomycosis or blastomycosis, the benefits and risks of remicade therapy should be carefully evaluated before starting therapy with Remicade^®.

Fistula of the Crohn's disease

Patients with Crohn's disease with acute purulent fistulas should not be treated with Remicade® before identifying and eliminating another possible source of infection, especially an abscess.

Reactivation of the hepatitis B virus

Reactivation of the hepatitis B virus was observed in patients, chronic carriers of the virus, who received TNF antagonists, including infliximab, in some cases with a fatal outcome. Carriers of the hepatitis B virus who require treatment with Remicade® should carefully monitor the signs and symptoms of infection during the course of therapy and for several months after graduation. Sufficient data on the effectiveness of the combined use of antiviral therapy (to prevent the reactivation of the virus) and TNF-α inhibitors in patients with chronic virus carriers are absent.

When reactivating hepatitis B, Remicade® therapy should be discontinued and appropriate antiviral therapy is prescribed.

Dysfunction of the liver and biliary tract

In the post-marketing period of use of Remikade®, cases of jaundice and non-infectious hepatitis, sometimes with signs of autoimmune hepatitis, were very rare. There have been reports of isolated cases of liver failure leading to death or requiring a liver transplant. Patients with signs or symptoms of liver dysfunction should be examined for liver damage. In the case of jaundice or increased activity of ALT to a level exceeding 5 times the upper value of the norm, it is necessary to cancel the Remicade ® preparation and to conduct a thorough investigation of the disturbance that has arisen.

Simultaneous use of the TNFα inhibitor and anakin

The simultaneous use of anakinra and another TNFα (etanercept) inhibitor in clinical studies was accompanied by the development of serious infections and neutropenia and did not result to an additional clinical effect in comparison with monotherapy with etanercept.In view of the nature of side effects observed with simultaneous therapy with anakinro and etanercept. similar types of toxicity can occur with combined therapy with anakinro and other TNFα inhibitors. In this regard, the simultaneous use of Remikade® and anakinra is not recommended.

Simultaneous use of the inhibitor of TNF-α and abatacept

In clinical studies, the combined use of TNF inhibitors and abatacept was associated with an increased risk of infections, including serious infections, compared with the use of only single TNF inhibitors, without increasing clinical benefit. The simultaneous use of Remicade® and abatacept is not recommended.

Simultaneous application with other biological preparations

There is insufficient data on the joint use of infliximab and other biological agents intended for use for the same indications. The simultaneous use of infliximab with these drugs is not recommended because of the possible increase in the risk of infection and other possible pharmacological interactions.

Transfer from another biological preparation

Care should be taken when transferring from one biological product to another, as cross-biological activity may increase the risk of developing adverse events, including infections.

Live vaccines and medications containing infectious agents

Data on the response to vaccination or the possibility of secondary transmission of infection when using live vaccines in patients are insufficient. The use of live vaccines can lead to a clinical manifestation of infections, including disseminated infection. The simultaneous use of Remikade® and live vaccines is not recommended.

The use of drugs containing infectious agents, such as live attenuated bacteria (eg, BCG instillation for the treatment of cancer), can lead to a clinical manifestation of infections, including disseminated infection. It is not recommended simultaneous application of the drug Remicade^® and drugs containing infectious agents.

Autoimmune processes

In rare cases, the relative deficiency of TNFα caused by anti-TNF therapy can initiate the development of an autoimmune process.When there are symptoms of lupus-like syndrome in the treatment with Remicade^®and positive tests for antibodies to double-stranded DNA therapy with Remicade^®should be discontinued.

Neurological disorders

The use of TNF inhibitors, including infliximab, in rare cases was accompanied by the appearance or growth of clinical and / or radiographic signs of demyelinating diseases of the central nervous system (including multiple sclerosis) and the peripheral nervous system, including Guillain-Barre syndrome. In patients with existing or newly emerging demyelinating diseases, the use and risk of anti-TNF therapy should be carefully weighed before the remixade® is prescribed. If such a disease develops, Remicade® should be discontinued.

Malignant neoplasms and lymphoproliferative disorders

When conducting clinical trials using anti-TNF agents, a more frequent development of lymphoma was observed in patients receiving an anti-TNF agent than in patients in the control group.In clinical studies of Remicade ®, for all approved indications, the appearance of lymphoma was rare, although more often than expected in general in the population. In the post-registration period, the development of leukemia in patients receiving TNF antagonists was reported. Since the risk of developing lymphoma and leukemia is elevated in patients with rheumatoid arthritis with a prolonged highly active inflammatory disease, risk assessment is difficult.

In clinical trials to study the use of Remicade® with a possible new indication, chronic obstructive pulmonary disease (COPD) (severe and moderate severity) in smokers (or former smokers), the incidence of neoplasms was higher in the Remicade® group, than in the control group. Caution should be exercised in prescribing anti-TNF therapy to patients who are at increased risk of developing malignant tumors due to smoking.

According to available data, the risk of developing lymphomas or other malignant neoplasms in patients receiving TNF inhibitors can not be ruled out.Caution should be exercised in prescribing TNF inhibitors to patients with malignant neoplasms in history or continuing therapy in patients with advanced malignancy.

Caution should also be exercised in patients with psoriasis or intensive therapy with immunosuppressants or long-term PUVA therapy in history. In the course of post-registration studies, cases of the formation of malignant tumors, some fatal, among children, adolescents and adult young people (under 22 years of age) who received TNF inhibitors (onset of therapy and ≤18 years of age), including Remicade®. Approximately half of the cases reported lymphomas. Other cases are represented by a number of different malignant tumors, including malignant tumors usually associated with immunosuppression. The risk of developing malignant neoplasms in patients receiving TNF inhibitors can not be ruled out.

In the post-marketing period, reports were received of rare cases of hepatolyenal T-cell lymphoma in the treatment of TNF inhibitors, including infliximab. This rare type of T-cell lymphoma is characterized by a very aggressive course of the disease and usually ends in a lethal outcome. Almost all patients received azathioprine or 6-mercaptopurine together with therapy with a TNF inhibitor or directly prior to therapy with a TNF inhibitor. The vast majority of cases with Remicade® therapy have been reported in patients with Crohn's disease or ulcerative colitis, most of which have been observed in adolescents or young adult males. The possible risk of simultaneous use of azathioprine or 6-mercaptopurine and Remicade® should be carefully evaluated. The risk of developing hepatolienneal lymphoma in patients receiving Remicade® can not be ruled out.

There have been reports of the development of Merkel's carcinoma and melanoma in patients receiving TNFα blockers, including infliximab. It is recommended to periodically inspect the skin in patients, especially in patients with risk factors for malignant skin tumors.

All patients with ulcerative colitis who are at increased risk of developing dysplasia or colon carcinoma (for example,in patients with prolonged ulcerative colitis or primary sclerosing cholangitis) or who have previously diagnosed these diseases, should be monitored regularly for dysplasia before and after therapy. Observation should include a colonoscopy and biopsy, depending on the recommendations adopted. It is not known whether treatment with infliximab affects the risk of developing dysplasia or colorectal cancer.

Since the possibility of increasing the risk of developing malignant tumors in patients with newly diagnosed dysplasia who have received Remicade® therapy has not been established, the risks and benefits of Remicade® therapy should be carefully assessed and a decision to continue or discontinue therapy should be made.

Heart failure

Remicade® should be used with caution in patients with chronic heart failure I-II functional class by classification NYHA. Patients should be monitored, and if new or worsening signs of heart failure occur, Remicade® therapy should be discontinued.

Hematologic reactions

There have been reports of pancytopenia, leukopenia, neutropenia and thrombocytopenia in patients receiving TNF inhibitors, including Remicade^®. All patients with development of signs and symptoms of blood dyscrasia (persistent fever, bruising, bleeding, pallor) should be immediately examined. In the case of severe hematologic abnormalities, remicade therapy should be discontinued.

Other

Data on the safety of the use of Remicade® in patients who underwent surgery, including arthroplasty, are limited. When planning an operation, it is necessary to take into account the long half-life of infliximab. When performing operations, patients receiving therapy with Remicade^®, careful monitoring of infections and timely treatment of them in case of occurrence is necessary.

The lack of response to Crohn's disease therapy may indicate the presence of a fixed fibrotic stricture that may require surgical treatment. The available data suggest that infliximab does not contribute to deterioration or the formation of stricture.

Special patient groups

Elderly patients (≥65 years of age)

The incidence of serious infections in elderly patients (≥65 years) was higher than in patients younger than 65 years. Some of these infections led to death. When treating elderly patients, you should be especially careful about the risk of developing infection.

Patients of childhood

Infections

In clinical studies, infections in children were reported more often than in adults.

Vaccination

Patients are recommended, if possible, to undergo a full vaccination according to the current calendar of preventive vaccinations before starting therapy with the drug Remicade^®.

Malignant neoplasms and lymphoproliferative disorders

In the course of post-registration studies, cases of the formation of malignant tumors, some fatal, among children, adolescents and adult young people (under the age of 22 years) who received TNF inhibitors (initiation of therapy ≤18 years), including Remicade®. Approximately half of the cases reported lymphomas. Other cases are represented by a number of different malignant tumors, including malignant tumors usually associated with immunosuppression.The risk of developing malignant neoplasms in patients receiving TNF inhibitors can not be ruled out.

In the post-marketing period, reports were received of rare cases of hepatolyenal T-cell lymphoma in the treatment of TNF inhibitors, including infliximab. This rare type of T-cell lymphoma is characterized by a very aggressive course of the disease and usually ends in a lethal outcome. Almost weight patients received azathioprine or 6-mercaptopurine together with therapy with a TNF inhibitor or directly prior to therapy with a TNF inhibitor. The vast majority of cases with Remicade® therapy have been reported in patients with Crohn's disease or ulcerative colitis, most of which have been observed in adolescents or young adult males. The possible risk of simultaneous use of azathioprine or 6-mercaptopurine and Remicade® should be carefully evaluated. The risk of developing hepatolienneal lymphoma in patients receiving Remicade® can not be ruled out.

Remikade® treatment of children and adolescents up to the age of 17 years with rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis or psoriasis,as well as treatment of children under the age of 6 with Crohn's disease or ulcerative colitis has not been studied. Before receiving data on the safety and efficacy of Remicade, the drug should not be used for these indications in the appropriate age groups.

Effect on the ability to drive transp. cf. and fur:

Remicade® can have little effect on the ability to drive and work with machinery. Care should be taken when driving vehicles and engaging in other potentially hazardous activities requiring increased concentration and speed of psychomotor reactions, since Remicade® can cause dizziness and other side effects that may affect these abilities.

Form release / dosage:

Lyophilizate for solution for infusion, 100 mg.

Packaging:

For 100 mg active substance in glass bottles with a capacity of 20 ml type I, closed with rubber stoppers, crimped aluminum caps and protected plastic caps.

1 bottle with instructions for use in a cardboard pack.

Storage conditions:

At a temperature of 2 to 8 ° C. Do not freeze.

Keep out of reach of children.

Transportation conditions

At a temperature of 2 to 8 ° C. Do not freeze.

Transportation is allowed at temperatures up to 25 ° C for no more than 48 hours.

Shelf life:

3 years.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:П N012948 / 01

Date of registration:15.11.2011

The owner of the registration certificate:MSD FARMASYUTIKALS, LLC MSD FARMASYUTIKALS, LLC Russia

Manufacturer: & nbsp

ORTAT, CJSC Russia

SCHERING-PLOUGH (Brinny) Co. Ireland

MSD INTERNATIONAL GmbH (Singapore Branch) Singapore

Representation: & nbspMSD Pharmaceuticals Ltd.MSD Pharmaceuticals Ltd.

Information update date: & nbsp01.11.2015

Illustrated instructions

Instructions

Remicade® (Remicade® )