Ervoi® (Yervoy®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceIpilimumabIpilimumab
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  • Ervoi®
    solution d / infusion 
    Bristol-Myers Squibb Company     USA
    • Dosage form: & nbspRAster for infusion.
    Composition:

    1 bottle with solution for infusion contains *:

    active substance: ipilimumab 53.5 mg or 213.0 mg;

    Excipients: trometamol hydrochloride 33.7 mg or 134.3 mg; sodium chloride 62.6 mg or 249.0 mg; Mannitol 107.0 mg or 426.0 mg; pentetic acid 0.42 mg or 1.67 mg; polysorbate 80 1.07 mg or 4.26 mg; sodium hydroxide and hydrochloric acid - q.s. to pH 7.0; water for injections - q.s. up to 10.7 ml or up to 42.6 ml.

    * - Packaging is performed taking into account the re-laying in 3.5 mg (0.7 ml) for 10 ml and in 13 mg (2.6 ml) for a 40 ml bottle, which is necessary to ensure full recovery of the claimed dosage. The recovered amount of ipilimumab (solution volume) in one vial is 50 mg (10.0 ml) and 200 mg (40.0 ml), respectively.

    Description:

    Transparent or slightly opalescent liquid from colorless to light yellow color.

    Pharmacotherapeutic group:antitumor agent - antibodies monoclonal
    ATX: & nbsp

    L.01.X.C.11   Ipilimumab

    Pharmacodynamics:

    Ipilumab is a recombinant human monoclonal antibody that binds to the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). Ipilimumab is an immunoglobulin G1 kappa (IgG1k), which is produced by genetic engineering on the isolated culture of mammalian cells; its approximate molecular weight is 148 kD.

    CTLA-4 is a key regulator of T-lymphocyte activation. Ipilimumab is an inhibitor CTLA-4. Ipilimumab blocks the cascade brake signals CTLA-4 increasing the number of antitumor T-helper cells, which in turn cause an increase in the number of direct T-killers. It is shown that the blockade CTLA-4 also reduces the regulatory function of T cells, which can lead to an enhanced immune antitumor response. Ipilimumab can selectively reduce the number of T-regulatory cells in the tumor region, leading to an increase in the ratio of antitumor T-helper cells to T-regulators, which contributes to the death of tumor cells.

    Pharmacokinetics:

    The pharmacokinetics of ipilimumab were studied in patients with progressive melanoma who received ipilimumab in doses from 0.3 to 10 mg / kg every 3 weeks, cumulatively - 4 doses. It was found that in the studied range of doses the maximum and minimum concentrations (FROMMax and FROMmines respectively), as well as the area under the "concentration / time" curve (AUC) are proportional to the administered dose. With repeated administration every 3 weeks, the clearance was independent of time; The minimum system cumulation index was 1.5 or less for FROMMax, FROMmines and AUC. The equilibrium concentration of ipilimumab in plasma was achieved with the administration of the third dose. The average final half-life was 15 days; the average systemic clearance is 15.3 ml / h (coefficient of variability is 38.5%); the average volume of distribution at the equilibrium concentration is 7.22 L (the coefficient of variability is 10.5%). When administered at a dose of 3 mg / kg, the mean minimum equilibrium concentration of ipilimumab in the blood plasma was 21.8 μg / ml.

    The clearance of ipilimumab increased with increasing body weight of the patient, as well as with increasing lactate dehydrogenase activity; however, dose adjustments are not required in these cases. The clearance does not depend on the age of the patient, sex, liver function, kidney function, physical activity status of the patient, status HLA-A2 * 0201, as well as from previous antitumor therapy.

    Indications:

    Inoperable or metastatic melanoma in adult patients with ineffectiveness or intolerance of previous therapy.

    Contraindications:

    - Hypersensitivity to any component of the drug;

    - children under 18 years of age due to lack of data on effectiveness and safety;

    - pregnancy and the period of breastfeeding.

    Carefully:

    - Severe autoimmune diseases in the active stage, in which further activation of the immune system can pose a potential threat to life;

    - violation of liver function (the activity of hepatic transaminases is 5 times or more than the upper limit of the norm, the concentration of bilirubin is more than 3 times higher than the upper limit of the norm).

    Pregnancy and lactation:

    Studies of the use of the drug ERVOY® in pregnant women have not been conducted. Studies in animals showed reproductive toxicity of the drug. Immunoglobulin G1 can penetrate the placental barrier; the effects of the drug on fetal development have not been studied. The use of the drug ERVOY® during pregnancy is contraindicated.

    During the treatment of women of childbearing period, the use of contraception is recommended.

    In studies on primates, a very low concentration of the drug in breast milk was found. There is no data on whether the ipilimumab in the breast milk of women during lactation. According to general information, the secretion of immunoglobulin Gs in breast milk is severely limited, also immunoglobulin Gs has low bioavailability when ingestion.Due to limited systemic action, breastfeeding is not expected to develop side effects in the child. However, in view of the potential danger of developing serious adverse reactions in a child, the use of the drug ERVOY® during breastfeeding is contraindicated.

    Dosing and Administration:

    The drug should be administered under the guidance of a doctor who has experience in the treatment of cancer.

    The recommended dose of ERVO® to adults is 3 mg / kg body weight as a 90-minute intravenous infusion, administered every 3 weeks. The course of treatment - 4 introductions. If tolerated, the patient should receive a full course of treatment (4 doses), regardless of the appearance of new lesions or the growth of existing foci. Assessment of the condition of the tumor is carried out after the completion of the full course of therapy.

    Before each administration of the drug and throughout the course of treatment with the drug, a check should be performed to identify immuno-mediated adverse reactions, including diarrhea and colitis. Evaluation of liver and thyroid function should be performed before the start of the course, as well as before each administration of the drug.

    Dose calculation

    Calculation of the dose of the drug for administration is made per kg of body weight of the patient; while one patient may need more than one vial of the drug.

    The total dose of ipilimumab in mg = body weight of the patient (in kg) multiplied by the prescribed dose (in mg / kg).

    The volume of the preparation (in ml) required to obtain a dose = total dose (in mg) divided by 5 (concentration of ipilimumab is 5 mg / ml).

    Recommendations for correcting the dose of the drug

    When using the drug, immuno-mediated unwanted reactions may occur, which may require skipping the dose or canceling the drug and administering high doses of glucocorticosteroids. In some cases, additional therapy with other immunosuppressive drugs may be required. Reduce the dose is not recommended.

    1. Skipping the next dose of the drug

    If after the administration of the drug in the patient there are observed immuno-mediated adverse reactions of moderate degree or symptomatic endocrinopathy, a planned The administration of the next dose of the drug should be skipped.

    For patients with complete or partial disappearance of adverse reactions (grade 0-1) in the appointment of glucocorticosteroids (prednisolone or a similar drug) at a dose of less than 7.5 mg per day, the course of treatment with the drug ERVOY® at a dose of 3 mg / kg every 3 weeks is renewed. The therapy is terminated after the introduction of the 4th planned dose or after 16 weeks after the administration of the first dose of the drug.

    Table 1. Transmission of the next dose of HERVO®

    Measures in the development of immuno-mediated adverse reactions requiring a missed dose1 HERVOY®

    Mild and moderate severity of adverse reactions

    Correction measures

    From the gastrointestinal tract:

    An average degree of diarrhea or colitis that can not be treated; relapsing or persisting for 5-7 days

    1. Skip the next introduction, wait for the severity of adverse reactions to decrease to the extent of 1 or 0 (or their return to the baseline level)

    2. If the symptoms have disappeared, enter the planned dose4

    3. If symptoms persist, you must skip the planned dose and resume treatment only after the symptoms have disappeared4

    4. Discontinue therapy with HERVOY® if symptoms do not decrease to 1 or 0 or return to baseline

    From the side of the liver:

    Moderate increase in the activity of "hepatic" transaminases (alanine aminotransferase (ALT), or an increase in activity of aspartate aminotransferase (ACT) 5 to 8 times inclusive above the upper limit of the norm), or the concentration of total bilirubin (3 to 5 times inclusive above the upper limit of the norm)

    From the skin:

    Skin rash from medium to severe degree (grade 3)2, itchy skin or intense rapid spreading itching on a large body surface, regardless of the etiology

    From the endocrine system:

    Severe adverse reactions (eg, hypophysitis or thyroiditis) that are not controlled by hormone replacement therapy or the administration of high doses of immunosuppressants.

    From the nervous system:

    Medium severity (grade 2)2 motor neuropathy of unclear etiology, muscle weakness, sensory neuropathy, lasting more than 4 days

    Other moderate severity of adverse reactions3

    NOTE:

    1 - Reduction of the dose of HERVO® is not recommended.

    2 - Toxicity levels are given in accordance with the criteria of the National Cancer Institute (National Cancer Institute Common Terminology Criteria for Adverse Events. Version 3.0 (NCI-CTCAE v3)).

    3 - The extent of any other adverse reactions that are considered immuno-mediated should be determined in accordance with the criteria of the National Cancer Institute (National Cancer

    Institute Common Terminology Criteria for Adverse Events. Version 3.0 (NCI-CTCAE v3)). The decision to skip the dose is taken depending on the severity of the side reaction.

    4 - Prior to the administration of all 4 doses or expiration of 16 weeks after the administration of the first dose (whichever one comes first).

    2. Cancellation of treatment

    Table 2. Elimination of HERVO®

    Treatment with the drug ERVOY® is canceled without renewal if at least one of the following conditions exists:

    - Continuing adverse reaction of moderate severity or inability to reduce the dose of glucocorticoid (prednisolone or equivalent preparation) to 7.5 mg per day;

    - Impossibility to conduct a course of treatment within 16 weeks after the administration of the first dose of the drug;

    - Severe or life-threatening adverse reactions, including any of the following:

    Severe or life-threatening adverse reactions

    Degree of toxicity of adverse reaction1

    From the gastrointestinal tract:

    Severe colitis or diarrhea, accompanied by pain in the abdominal cavity, increased body temperature, intestinal obstruction or signs of peritonitis; or a significant change in the frequency of bowel movements, stool incontinence, the need for intravenous fluids for 24 hours or more, gastrointestinal bleeding,perforation of the organs of the gastrointestinal tract, admixture of blood in the feces;

    Colitis or diarrhea grade 3 or 4

    From the side of the liver:

    A significant increase in activity of aspartate aminotransferase (ACT) or alanine aminotransferase (ALT) or an increase in total bilirubin or symptoms of hepatotoxicity;

    Increased activity ACT or ALT more than 8 times compared with the upper limit of the norm or an increase in total bilirubin by more than 5 times compared with the upper limit of the norm

    From the skin:

    Life-threatening skin rash (Stevens-Johnson syndrome, toxic epidermal necrolysis) or a rash complicated by ulceration of the skin or necrotic, bullous and hemorrhagic manifestations, or itching and severe itching, disrupting normal life or requiring medical attention;

    Rash (grade 4) or itching (grade 3)

    From the nervous system:

    A newly emerged severe motor or sensory neuropathy or worsening of the existing form of neuropathy;

    Severe motor or sensory neuropathy (grade 3 or 4);

    Other adverse reactions2

    Severe immune reactions developing in any organ or system (eg, nephritis, pneumonitis, pancreatitis, non-infectious myocarditis)

    Degree 3 and higher immunosupplemented adverse reactions3;

    Degree 2 and higher for an immune-mediated adverse reaction from the eye that does not respond to local immunosuppressive therapy

    NOTE:

    1 The degrees of toxicity are given in accordance with the criteria of the National Cancer Institute (National Cancer Institute Common Terminology Criteria for Adverse Events. Version 3.0 (NCI-CTCAE v3)).

    2 The extent of any other adverse reactions that are considered immuno-mediated should be determined in accordance with the criteria of the National Cancer Institute (National Cancer Institute Common Terminology Criteria for Adverse Events. Version 3.0 (NCI-CTCAE v3)). The decision to skip the dose or cancel the drug is taken depending on the severity of the side reaction.

    3 Patients with severe endocrinopathy (grade 3 or 4), controlled by hormone replacement therapy, can continue treatment.

    Impaired renal function:

    The safety and efficacy of ERVOY® in patients with impaired renal function has not been studied. Based on the data on the pharmacokinetics of dose adjustment for a mild to moderate degree of severity, renal dysfunction is not required.

    Impaired liver function:

    The safety and efficacy of ERVOY® in patients with impaired liver function has not been studied.

    With hepatic insufficiency, mild dose correction is not required.Care should be taken when using the drug in patients with the activity of "liver" transaminases, 5 and more times higher than the upper limit of the norm and total bilirubin more than 3 times higher than the upper limit of the norm.

    Elderly patients:

    In general, there was no difference in the efficacy and safety of the drug in patients older than 65 years and in younger people. Correction of the dose of the drug in the elderly is not required.

    Instructions for preparation and administration of the drug

    Do not shake the bottle before use!

    Dilute infusion solution is prepared in aseptic conditions.

    Before the introduction of the drug, inspect the contents of the vial.

    Do not administer the drug in the presence of foreign particles, and if the solution has become cloudy or its color has changed.

    Before the introduction of the drug should be kept at room temperature for 5 minutes. The drug can be used after dilution with a sterile 0.9% solution of sodium chloride for infusion or a sterile 5% solution of dextrose for infusion to a concentration of 1 to 4 mg / ml. The prepared solution is mixed by carefully turning the infusion container.

    HERVOY® is compatible with the following types of infusion equipment:

    - Glass bottles, polyvinylchloride (PVC) and non-polyvinyl chloride (pop-PVC) bags for infusions;

    - Polyvinylchloride (PVC) systems for intravenous administration;

    - Polyethersulfonic (pore size: 0.2-1.2 μm) and nylon (pore size: 0.2 μm) flow filters for infusion systems.

    Partially used bottles with the drug should be disposed of, according to local recommendations.

    Instructions for preparation and administration of the drug

    - Determine the number of vials of the preparation required for administration, remove them from the refrigerator and leave at room temperature for 5 minutes.

    - Remove the protective plastic lid from the vial. The vial is wiped with a sterile cotton wool soaked in alcohol.

    - Transfer the required volume of the drug (concentration 5 mg / ml) with a sterile syringe into the vial of a sterile infusion system. Dilution is performed using a sterile 0.9% sodium chloride solution for infusion or a sterile 5% dextrose solution for infusion to a concentration of 1 to 4 mg / ml. For example: add 4 parts of a sterile 0.9% sodium chloride solution for infusions or a sterile 5% dextrose solution for infusions to one part of the drug in the infusion vessel.

    - The prepared solution is mixed by carefully turning the infusion container.

    - From the point of view of microbiological purity, the prepared solution should be used immediately. Otherwise, the prepared solution can be stored for up to 24 hours at a temperature of (2-8 ° C) or at room temperature (20 to 25 ° C).

    - Unused residue of HERVO® preparation in the vial and empty the vial.

    Administration of solution for infusion

    - The drug HERVOY® can not be administered as a rapid intravenous injection or as a bolus injection.

    - After the administration of each dose of ERVOY® it is necessary to wash the infusion system with a sterile 0.9% isotonic sodium chloride solution for infusions or a sterile 5% solution of dextrose for infusion.

    - Do not mix HERVO® with other medications in one infusion bottle and do not inject it simultaneously with other infusion preparations.

    - The drug should be injected for 90 minutes through a sterile infusion system with a low protein binding capacity with a sterile, pyrogen-free flow filter (pore size 0.2-1,2 μm).

    Side effects:

    In clinical studies with the introduction of different doses in patients with different types of tumors, the ERVO® preparation was used by more than 10,000 patients.

    When using the drug ERVOY, the most frequent adverse reactions are those caused by an increase in the activity of the immune system. Most of these adverse reactions, including severe, can be remedied with appropriate therapy or by discontinuing the drug.

    The most frequent adverse reactions detected in more than 10% of patients in the clinical trials of ERVOY® were diarrhea, rash, itching, fatigue, nausea, vomiting, decreased appetite, and abdominal pain. In most cases, adverse reactions were expressed from mild to moderate (grades 1 and 2). Therapy was discontinued due to adverse reactions in 10% of patients.

    Below are the adverse reactions observed in patients with progressive melanoma who received a 3 mg / kg dose of ERVOY® in clinical trials.

    Adverse reactions with the use of the drug ERVOY® are represented by the frequency of their registration: very frequent (≥1/10), frequent (≥1/100, < 1/10), infrequent (≥1/1 000, <1/100), rare (≥1/10 000, <1/1 000), very rare (<1/10 000).

    The frequency of immuno-mediated adverse reactions in HLA-A2 * 0201-positive patients did not differ from that in the general clinical program.

    Infections and invasions:

    infrequent: sepsis1, septic shock1, meningitis (aseptic), gastroenteritis, diverticulitis, urinary tract infections, respiratory tract infections;

    Neoplasms benign, malignant and unstated nature:

    frequent: pain in the tumor; infrequent: paraneoplastic syndrome;

    From the side of the blood and lymphatic system:

    frequent: anemia, lymphopenia;

    infrequent: neutropenia, thrombocytopenia, eosinophilia, hemolytic anemia;

    From the immune system:

    infrequent: hypersensitivity;

    rarely: anaphylactic reactions (shock);

    From the endocrine system:

    frequent: hypopituitarism (including hypophysitis); hypothyroidism;

    infrequent: insufficiency of adrenal function, hyperthyroidism, hypogonadism.

    Metabolic and nutritional disorders:

    very frequent: decreased appetite;

    Frequent: hypokalemia, dehydration;

    infrequent: hyponatremia, alkalosis, hypophosphatemia, and cytomeolysis of tumor lysis.

    From the nervous system:

    frequent: confusion, peripheral sensory neuropathy, dizziness, headaches, lethargy;

    infrequent: change in mental status, depression, decreased libido, Guillain-Barre syndrome1, syncope, cranial neuropathy, cerebral edema, peripheral neuropathy, ataxia, tremor, myoclonia, speech disorders;

    From the side of the organ of vision:

    frequent: blurred vision, pain in the eyes;

    infrequent: uveitis, vitreous hemorrhage, inflammation of the iris, decreased visual acuity, foreign body sensation in the eye, conjunctivitis;

    From the cardiovascular system:

    Frequent: decrease in blood pressure, hyperemia, "hot flashes" with a feeling of heat;

    infrequent: arrhythmia, atrial fibrillation, vasculitis, angiopathy1, peripheral ischemia, orthostatic hypotension;

    From the respiratory system:

    frequent: shortness of breath, cough;

    infrequent: respiratory failure, acute respiratory distress syndrome1, pulmonary infiltration, pulmonary edema, pneumonitis, allergic rhinitis;

    From the gastrointestinal tract:

    very frequent: diarrhea, vomiting, nausea;

    frequent: gastrointestinal bleeding, colitis1, constipation, gastroesophageal reflux disease, abdominal pain;

    infrequent: gastrointestinal perforation1, perforation of the large intestine1, intestinal perforation1, peritonitis (including infectious)1, pancreatitis (including autoimmune), enterocolitis, gastric ulcer, colon ulcer, esophagitis, intestinal obstruction, inflammation of the mucous membranes;

    From the liver and biliary tract:

    Frequent: abnormal liver function;

    infrequent: liver failure1, hepatitis, hepatomegaly, jaundice;

    From the skin and subcutaneous tissue:

    very frequent: rash, itching;

    frequent: dermatitis, erythema, vitiligo, urticaria, alopecia, night sweats, dry skin;

    infrequent: toxic epidermal necrolysis1,2leukocytoclastic vasculitis, skin exfoliation, eczema, hair color change;

    From the musculoskeletal system:

    Frequent: myalgia, arthralgia, musculoskeletal pain, muscle spasms;

    infrequent: rheumatic polymyalgia, arthritis;

    From the side of the kidneys and urinary tract:

    infrequent: renal insufficiency1glomerulonephritis, acidosis of the renal tubules;

    On the part of the reproductive system:

    infrequent: amenorrhea;

    General disorders and reactions to the administration of the drug:

    very frequent: fatigue, reactions at the injection site, pyrexia;

    Frequent: chills, asthenia, swelling, pain, flu-like illness;

    infrequent: multiple organ failure1, reactions to the administration of the drug rare: syndrome of systemic inflammatory reaction1;

    From the laboratory indicators:

    frequent: increased activity of alanine aminotransferase (ALT), increased activity of aspartate aminotransferase (ACT), increasing the concentration of total bilirubin in the blood, increasing the activity of alkaline phosphatase, reducing body weight;

    infrequent: increased activity of gamma-glutamyltransferase, increased concentration of creatinine in the blood, increasing the concentration of thyroid-stimulating hormone in the blood, reducing the concentration of cortisol in the blood, reducing the concentration of corticotropic hormone in the blood, increasing lipase activity, increasing the activity of amylase in the blood, reducing the concentration of testosterone in the blood;

    rare: abnormal prolactin in the blood.

    NOTE:

    1Including adverse reactions with a fatal outcome.

    2 Additional information on these undesirable phenomena is provided in the section "Special instructions".

    The following adverse reactions (with a frequency of less than 1%) were observed in clinical studies on the use of other doses of the HERVO® preparation as indicated by melanoma (less than 3 mg / kg, more than 3 mg / kg): meningism, myocarditis, pericardial effusion (pericarditis) , cardiomyopathy, autoimmune hepatitis, erythema multiforme, erythema nodosa, autoimmune nephritis, myasthenia gravis-like symptoms, muscle weakness, autoimmune thyroiditis, hyperpituitarism, secondary adrenocortical insufficiency, parathyroid gland failure, thyroid dysfunction diets, episcleritis, blepharitis, eye swelling, scleritis, temporal artery inflammation, Raynaud's syndrome, Raynaud's disease, proctitis, palmar-plantar erythrodysesthesia syndrome, psoriasis, hematuria, proteinuria, a decrease in thyroid-stimulating hormone in the blood, a decrease in gonadotropin concentration in the blood, thyrocoxia in the blood, leukopenia, polycythemia, hypocalcemia, lymphocytosis, cytokine release syndrome, sarcoidosis, sensorineural hearing loss, autoimmune central neuropathy (encephalitis), myositis, polymyositis, myositis of the ophthalmic muscles.

    Overdose:

    The maximum tolerated dose of HERVO® is not established. In clinical studies, doses of the drug up to 20 mg / kg inclusive were used; with the introduction of this dose of obvious toxic effects of the drug was not detected.

    In case of an overdose, the treatment should consist of symptomatic drug therapy in accordance with the emerging adverse reactions, with careful monitoring of the patient.

    Interaction:

    Pharmacokinetic interactions

    The molecule of ipilimumab is a monoclonal antibody, so it is not metabolized with the participation of cytochrome P450 isoenzymes and other isoenzymes that metabolize drugs. Pharmacokinetic interactions of ipilimumab with other drugs are unlikely.

    Other forms of interactions

    Glucocorticosteroids

    In connection with the possibility of pharmacodynamic interaction, the use of glucocorticosteroids should be avoided before prescribing therapy with the HERVO® preparation. After the beginning of therapy with the drug ERVOY®, glucocorticosteroids and other immunosuppressants can be used to correct immune-mediated adverse reactions caused by the effect of the drug on the immune system.The use of systemic glucocorticosteroids after the start of treatment with the drug does not affect the effectiveness of the drug.

    Anticoagulants

    It is known that anticoagulants increase the risk of gastrointestinal bleeding. Due to the fact that this is one of the side reactions of the drug, patients who are simultaneously receiving the HERVO® preparation and anticoagulants should be closely monitored.

    Special instructions:

    The drug HERVOY® can cause serious, including fatal, side reactions, caused by the influence on the immune system and conditioned by the specific mechanism of its action.

    Adverse reactions due to exposure to the immune system can affect the gastrointestinal tract, liver, skin, nervous system, endocrine system organs and other organ systems. They can be severe or life threatening and develop usually during therapy, but there are also cases of their appearance months after the last dose of the drug.

    If no other etiology is established, the following adverse reactions should be considered inflammatory and develop as a result of the use of the HERVO® drug: diarrhea, increased frequency of defecation,admixture of blood in the feces, increased activity of "liver" transaminases, skin rash, endocrinopathy. Their early diagnosis and appropriate treatment are essential to minimize complications that threaten the patient's life. To treat severe adverse reactions caused by exposure to the immune system, it may be necessary to systemically administer high doses of glucocorticosteroids with the additional use of immunosuppressive therapy or without it. To correct the adverse reactions of the drug HERVOY®, you should use specially designed for this treatment scheme.

    Immuno-mediated gastrointestinal side effects

    In clinical studies of the drug ERVOY, immuno-mediated serious side effects from the gastrointestinal tract (grade 3-5), sometimes fatal, were observed on average after 8 weeks (median, 5-13 weeks) after initiation of therapy. Lethal cases were also noted due to gastrointestinal perforation. With the use of specially developed correction methods, improvement (no less than to grade 1 or to the baseline level) occurred in 90% of patients on average after 4 weeks (median, range 0.6-22 weeks).Careful observation of patients is necessary to identify symptoms that may indicate immuno-mediated colitis or perforation of the gastrointestinal tract (diarrhea, increased defecation, abdominal pain, adulteration of blood in the feces, with or without fever). Patients who develop diarrhea or colitis after drug administration should be carefully monitored. It is necessary to exclude the infectious or other etiology of these symptoms. In clinical studies, immuno-mediated colitis was manifested by inflammation of the mucosa with or without ulceration and infiltration of lymphocytes and neutrophils. Methods for correcting diarrhea and colitis are determined by the severity of these side effects. From patients with mild to moderate diarrhea (up to 6 defecations per day) and suspected colitis (abdominal pain, bloody stools) from mild to moderate, the treatment with HERVO® is not canceled. Symptomatic therapy is recommended (loperamide, fluid administration) and careful monitoring of patients' condition. If symptoms from mild to moderate degree are resumed or persist for 5-7 days,the planned dose of the drug ERVOY® is not administered and glucocorticosteroids administered for oral administration at a dose of 1 mg / kg per day (prednisolone or a similar preparation). When the patient's condition improves (grade 0-1 or to the initial level), therapy with HERVO® can be resumed. Treatment with HERVO® is stopped without renewal in patients with severe diarrhea or colitis (grade 3 or 4) who are immediately prescribed high-dose glucocorticosteroid therapy intravenously (in clinical trials, methylprednisolone in a dose of 2 mg / kg / day). When controlling diarrhea and other symptoms, a slow decrease in the dose of glucocorticosteroids begins for at least 1 month. In clinical studies, rapid dose reduction (for periods of less than 1 month) resulted in recurrence of diarrhea or colitis in some patients. It must be ensured that the patient has no gastrointestinal perforation or peritonitis. If diarrhea or colitis persists despite the use of glucocorticosteroids, consideration should be given to the appointment of an alternative immunosuppressant.In clinical studies in such cases, a single administration of infliximab in a dose of 5 mg / kg was prescribed in the absence of contraindications to its use. If suspected gastrointestinal perforation or sepsis infliximab can not be applied.

    Hepatotoxicity caused by immuno-mediated adverse reactions

    In clinical studies of the drug ERVOY, serious adverse liver reactions (grade 2-5), including lethal liver failure, were observed 3-9 weeks after the initiation of therapy. With the use of specially developed methods of correction, the deviations disappeared or decreased in 0.7-2 weeks.

    It is necessary to determine the activity of "hepatic" transaminases and the concentration of bilirubin before each administration of the drug HERVOY®. Violation of the liver can be asymptomatic. If the patient has an increased activity of alanine aminotransferase (ALT) and aspartate aminotransferase (ACT) or the concentration of total bilirubin, it is necessary to exclude such causes of hepatotoxicity as the presence of an infectious disease, the progression of cancer or concomitant therapy and to monitor liver function to improve liver transaminases and bilirubin.Liver biopsy in patients with immuno-mediated hepatotoxicity showed signs of acute inflammation (neutrophils, lymphocytes and macrophages).

    If activity ACT or ALT rises more than 5, but not more than 8 times higher than the upper limit of the norm, and the concentration of total bilirubin is more than 3, but no more than 5 times the upper limit of the norm, the planned subsequent dose of the drug ERVOY® is not administered by monitoring the liver function before the resolution of the indices. After improving the liver function (activity ACT and ALT is no more than 5 times higher than the upper limit of the norm, the concentration of total bilirubin is no more than 3 times higher than the upper limit of the norm), treatment with HERVO® can be resumed.

    If the patient's activity is determined ACT or ALT more than 8 times the upper limit of the norm and bilirubin rises more than 5 times from the upper limit of the norm, there is a suspicion of the association of these changes with the use of the HERVOY® drug, the therapy is stopped without renewal and immediately given to the patient treatment with high doses of glucocorticosteroids eg, methylprednisolone in a dose of 2 mg / kg / day or a similar preparation) intravenously. The function of the liver is monitored, until its normalization. Once the symptoms are resolved and there is a steady improvement in the liver function (or return to baseline), a slow reduction in the glucocorticosteroid dose occurs for at least 1 month. If, during the period of dose reduction, impaired liver function is observed, the dose of glucocorticosteroids is increased again, followed by a slow gradual decrease.

    If significant violations of liver function persist despite the use of glucocorticosteroids, consideration should be given to the additional appointment of an alternative immunosuppressant. In clinical studies in such cases, mycophenolate mofetil.

    Immuno-mediated adverse reactions from the skin

    In clinical trials of the HERVO® preparation, serious adverse skin reactions (grade 2-5) were observed on average 3 weeks later (median, 0.9 to 16 weeks) after initiation of therapy. In clinical studies, cases of lethal toxic epidermal necrosis were noted.With the use of specially developed correction methods, in most cases (87%) after 5 weeks (median, 0.6 to 29 weeks) there was an improvement with the disappearance of symptoms or their return to baseline

    If, in the treatment with the drug ERVOY®, the patient develops immuno-mediated adverse reactions in the form of skin rashes and itching, the measures for their correction depend on the severity of these side reactions. In patients with skin reactions from mild to moderate degree (degree 1-2), treatment with the drug ERVOY® is not canceled. Symptomatic therapy (antihistamines) is recommended. If a skin rash or mild to moderate itching persists for 1-2 weeks and is not amenable to treatment with local glucocorticosteroids, you should begin glucocorticosteroid therapy for oral administration (for example, prednisolone or a similar preparation at a dose of 1 mg / kg orally, once a day).

    In patients with severe (grade 3) skin reactions, the planned subsequent dose of HERVO® is not administered. When the patient's condition improves (degree of adverse reaction 1 or complete disappearance of symptoms), you can resume therapy with HERVOY®.

    Treatment with HERVO® is stopped without renewal in patients with skin rash grade 4 or skin pruritus grade 3, who are immediately prescribed therapy with high doses of glucocorticosteroids (for example, methylprednisolone in a dose of 2 mg / kg / day) intravenously. When the patient's condition improves, the dose of glucocorticosteroids slowly decreases for at least 1 month. Immune mediated neurological side effects In the clinical trials of the HERVO® drug, serious neurological side effects were noted: Guillain-Barre syndrome (including fatal), myasthenia gravis, muscle weakness, sensory neuropathy.

    With motor neuropathy of unclear etiology, muscle weakness or sensory neuropathy, which last more than 4 days, it is necessary to exclude the causes of non-inflammatory nature (progression of cancer, infection, metabolic syndrome, concomitant drug therapy). In patients with moderate neuropathy (grade 2, motor and sensory or motor only), possibly associated with the use of HERVO®,the drug is stopped. When neurologic symptoms are resolved to the initial level, therapy with HERVO® can be resumed.

    Treatment with HERVO® is stopped without resumption in patients with severe sensory neuropathy (grade 3-4) if it is suspected of being associated with HERVOY®. Patients are prescribed therapy in accordance with established methods of treating sensory neuropathy, and immediately begin intravenous administration of glucocorticosteroids (for example, methylprednisolone in a dose of 2 mg / kg / day). Progression of motor neuropathy should be considered as an immuno-mediated adverse reaction and appropriate corrective measures should be applied. Treatment with the drug ERVOY® is canceled without renewal in patients with severe (grade 3-4) motor neuropathy, regardless of the cause of its development.

    Immuno-mediated adverse reactions from the endocrine system

    The drug HERVOY® can cause inflammation of the internal secretion organs, a violation of their function: hypophysitis, hypopituitarism, adrenal cortex insufficiency, hypothyroidism.Patients may experience nonspecific symptoms that may resemble other diseases, such as brain metastases or manifestations of underlying disease. The main symptoms are headache and fatigue. There may also be violations of visual fields, behavioral changes, electrolyte balance disturbance, lowering of arterial pressure. It is necessary to exclude adrenal-adrenal crisis as the reason for the appearance of these symptoms. In clinical studies of the drug ERVOY®, cases of immuno-mediated from medium to severe endocrinopathy (grade 2-4) were observed 7-20 weeks after the start of treatment. Usually, in such cases, the patient's condition could be corrected with immunosuppressants and hormone replacement therapy.

    If any signs of an adrenal-adrenal crisis (severe dehydration, lowering of blood pressure or shock) appear, immediate intravenous administration of glucocorticosteroids with mineralocorticoid activity is recommended. It should be established whether the patient has sepsis or infections.If there are signs of adrenal insufficiency, but the patient is not in adrenal-adrenal crisis, then a patient examination should be performed. If the results of the examination (pituitary scan or laboratory tests) revealed a violation of the endocrine function, a short course of treatment with high doses of glucocorticosteroids should be prescribed to suppress inflammation in the appropriate gland (for example, dexamethasone in a dose of 4 mg every 6 hours). In this case, the planned dose of HERVO® should be canceled. It is not known whether treatment with glucocorticosteroids contributes to the restoration of endocrine gland function. It should also begin substitution hormone therapy, if necessary - long.

    If the clinical symptoms or the results of the patient's laboratory tests improve, the treatment with HERVO® can be resumed, while reducing the dose of glucocorticosteroids slowly and gradually for at least 1 month.

    Other adverse reactions caused by the effect of the drug on the immune system

    In clinical studies of the drug ERVOY, the following adverse reactions were noted,which can be mediated by the effect of the drug on the immune system: uveitis, eosinophilia, increased lipase activity, glomerulonephritis. In addition, there were noted: inflammation of the iris, hemolytic anemia, increased levels of amylase and pneumonia. If these adverse reactions are severe (grade 3-4), immediate use of glucocorticosteroids in high doses and the elimination of HERVO® preparation may be required. When the patient develops against the background of treatment with the drug ERVOY®, uveitis, inflammation of the iris or episcleritis shows the use of local glucocorticosteroids in the form of eye drops.

    Infusion reactions

    The drug HERVOY® can cause severe infusion reactions. In case of severe infusion reaction, infusion of the drug should be discontinued and appropriate medication should be prescribed. Patients with mild or moderate degree of infusion reaction can continue treatment with the drug with the condition of careful monitoring of the patient's condition. You can consider the issue of premedication with antihistamine and antipyretic drugs.

    Special patient groups

    Patients with melanoma of the eye, primary central nervous system melanoma (CNS) and active brain metastases were not included in the main clinical study of the HERVO® preparation.

    Clinical studies also did not include patients with autoimmune diseases in history (except vitiligo and compensated endocrine diseases with function deficiencies, eg, hypothyroidism), including patients who need systemic therapy with immunosuppressants for an autoimmune disease or organ transplant. It should be avoided the use of the drug ERVOY® in patients with severe autoimmune diseases in the active phase, as excessive activation of the immune system can lead to a condition that threatens the patient's life. Care should be taken when prescribing HERVO® to all patients with an autoimmune history, carefully and individually, weighing the risk and benefit of using the drug in each patient.

    Co-administration with vemurafenib

    In clinical studies of the 1st phase, asymptomatic increase in the activity of transaminases of grade 3 (ALT / AST was 5 times higher than the upper limitnorm) and the concentration of bilirubin (total bilirubin is 3 times higher than the upper limit of the norm) with the combined use of the combination of the drug ERVOY® (3 mg / kg) and vemurafenib (960 mg or 720 mg 2 times a day). Therefore, the joint use of these drugs is not recommended.

    Patients on a diet with controlled consumption of sodium salts

    1 ml of HERVO® contains 0.1 mmol (2.30 mg) of sodium, which should be taken into account when appointing patients on a diet with controlled intake of sodium salts.

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

    In view of the possible emergence of unwanted reactions, such as fatigue, patients should refrain from driving vehicles and practicing potentially hazardous activities requiring increased concentration of attention and speed of psychomotor reactions during the period of treatment with the HERVO® drug, until the fact that these adverse reactions are absent.

    Form release / dosage:

    Solution for infusion, 5 mg / ml.

    Packaging:

    By 10 ml or 40 ml into a bottle of clear, colorless glass type I, sealed with a butyl rubber stopper and an aluminum cap with a protective plastic cover.

    On 1 bottle together with the instruction on application place in a pack a cardboard.

    Storage conditions:

    Store at a temperature of 2 to 8 ° C, in a place protected from light.

    Keep out of the reach of children.
    Shelf life:

    3 years.

    Do not use after the expiration date.

    Terms of leave from pharmacies:On prescription
    Registration number:LP-003609
    Date of registration:05.05.2016
    Expiration Date:05.05.2021
    The owner of the registration certificate:Bristol-Myers Squibb CompanyBristol-Myers Squibb Company USA
    Manufacturer: & nbsp
    Representation: & nbspBRISTOL-Majers SKVIBB, LLCBRISTOL-Majers SKVIBB, LLCRussia
    Information update date: & nbsp04.07.2016
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