Opportunity® (Opdivo®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceNivolumabNivolumab
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  • Opportunity®
    concentrate d / infusion 
    Bristol-Myers Squibb Company     USA
    • Dosage form: & nbspconcentrate for solution for infusion
    Composition:

    1 bottle with concentrate for solution for infusion contains *:

    active substance: niwolumab 47.0 mg or 107.0 mg,

    Excipients: sodium citrate dihydrate 27.6 mg or 62.9 mg; sodium chloride 13.7 mg or 31.2 mg; Mannitol 141.0 mg or 321.0 mg; pentetic acid 0.0376 mg or 0.0856 mg; polysorbate 80 0.940 mg or 2.14 mg; sodium hydroxide and hydrochloric acid - q.s. to pH 6.0; water for injections - q.s. up to 4.7 ml or up to 10.7 ml,

    * - Packaging is performed taking into account the 0.7 ml re-laying, which is necessary to ensure full recovery of the claimed dosage. The recoverable amount of nivolumab (solution volume) in one vial is 40 mg (4.0 ml) and 100 mg (10.0 ml), respectively.

    Description:

    Transparent or opalescent solution from colorless to light yellow color.

    Pharmacotherapeutic group:Antineoplastic agent, monoclonal antibodies
    ATX: & nbsp

    L.01.X.C.17   Nivolumab

    Pharmacodynamics:

    Nivolumab is a human monoclonal antibody that blocks the interaction between the receptor for programmed death (PD-1) and its ligands (PD-L1 and PD-L2). Nivolumab is an immunoglobulin G4 (IgG4), its approximate molecular weight is 146 kDa.

    PD-1 receptor is a negative regulator of T-cell activity. Binding PD-1 with ligands PD-L1 and PD-L2, which can be expressed by tumor cells or other tumor microenvironment cells, results in inhibition of T cell proliferation and cytokine secretion. Nivolumab potentiates the immune response through binding blockade PD-1 with ligands PD-L1 and PD-L2. In studies on mouse models, blocking activity PD-1 led to a decrease in tumor growth.

    Pharmacokinetics:

    The pharmacokinetics of nivolumab is linear in the dose range of 0.1 to 10 mg / kg.

    In the population pharmacokinetic analysis it was established that the average systemic clearance of nivolumab is-9.5 ml / h (coefficient of variability is 49.7%); the average volume of distribution in the equilibrium state is 8.0 liters (variability factor is 30.4%); mean half-life (t1/2) was 26.7 days (coefficient of variability - 101%). The maximum, minimum and average concentrations of niwolumab in plasma after administration for 2 weeks at a dose of 3 mg / kg were 57.116 and 75.3 mcg / ml, respectively.

    Nivolumab clearance increased with increasing patient's body weight, however, the above dose calculation technique led to equilibrium therapeutic concentrations of the drug in the blood of patients with different body weight (34 to 162 kg).

    The metabolism of nivolumab is not described, however, due to the identity of the structure of niwolumab with a human monoclonal antibody IgG4, the proposed pathway of metabolism of the drug corresponds to the metabolism of endogenous immunoglobulin - the breakdown of amino acids in the catalytic pathway of protein metabolism.

    Special patient groups

    Population pharmacokinetic analysis showed no dependence of niwolumab clearance from the age of the patient, sex, race, type of tumor, tumor size and the presence of liver function disorders. Although there was a weak dependence of clearance on ECG readings, glomerular filtration level, serum albumin and body weight in studies, this association was not clinically significant.

    Patients with impaired renal function

    The pharmacokinetic properties of nivolumab have been studied in patients with mild (creatinine clearance from 60 to <90 mL / min / 1.73 m2), moderate (creatinine clearance from 30 to <60 ml / min / 1.73 m2), severe (creatinine clearance <30 mL / min and ≥ 15 mL / min / 1.73 m2) degree of renal failure in comparison with patients with normal renal function (creatinine clearance ≥90 ml / min / 1.73 m2). There were no clinically significant differences in niwolumab clearance in patients with mild to moderate renal failure and in patients with normal renal function. The clearance of nivolumab in patients with severe renal insufficiency has not been adequately studied.

    Patients with impaired hepatic function

    Pharmacokinetic properties were studied in patients with mild hepatic insufficiency (an increase in total bilirubin 1.0-1.5 times higher than ULN or ACT above ULN, classification of the national cancer institute) in comparison with patients with normal liver function (total bilirubin and ACT within the limits of the norm). Differences in the clearance of nivolumab between the above groups of patients were not detected. The pharmacokinetics of the drug has not been studied in patients with moderate hepatic insufficiency (an increase in total bilirubin is 1.5-3.0 times higher than ULN and ACT higher than UGN) and severe degree of hepatic insufficiency (an increase in total bilirubin is more than 3.0 VGN and ACT above ULN).

    Indications:

    - As a monotherapy for inoperable or metastatic melanoma in adult patients.

    - As a monotherapy for locally advanced or metastatic non-small cell lung cancer (NSCLC) in adults after previous chemotherapy.

    - As a monotherapy for advanced renal cell carcinoma (RCC) in adults after previous systemic therapy.

    Contraindications:

    - Hypersensitivity to any component of the drug;

    - dEthnic age under 18 years due to lack of data on efficiency 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;

    - Mr.abnormal liver function of medium and severe degree;

    - impaired renal function of severe severity.

    Experience of using the drug Opdivo® in the treatment of melanoma with a positive BRAF The mutation in patients who had not previously received treatment is limited.

    Patients with concomitant metastases to the brain, active autoimmune disease or diseases requiring systemic immunosuppressive therapy were excluded from the main clinical study of the PAC. In the absence of data nivolumab should be used with caution in these patient groups after a thorough assessment of the benefit-risk relationship based on individual measures.

    Individual patient groups

    In clinical trials, the following groups of patients did not participate:

    - Patients with initial functional status indicators ≥ 2, untreated cerebral metastases, autoimmune diseases, and patients receiving systemic immunosuppresants before the study;

    - patients with symptomatic interstitial lung diseases and melanoma of the eye were excluded from clinical trials of NSCLC and melanoma;

    - Patients with 4 degrees of severity of unwanted reactions associated with previously conducted anti-STLA-4 therapy in the anamnesis.

    Due to the lack of data, the Optiv® drug should be used with caution in these patient groups after assessing the risk-benefit relationship based on individual indicators.

    Pregnancy and lactation:

    Studies of the use of the drug Opdivo® in pregnant women was not carried out. Studies in animals have shown the reproductive toxicity of nivolumab.Immunoglobulin IgG4 can penetrate through the placental barrier, so probably the effect of the drug on the fetus. The use of the drug Opti® during pregnancy is contraindicated.

    During the treatment and for a period of at least 5 months after the last injection of the Optido® drug, contraceptive use is recommended for women of childbearing age.

    Studies of the penetration of niwolumab into breast milk of women during lactation were not conducted. According to general information, the ingestion of antibodies in breast milk is possible, therefore, it is impossible to exclude the risk for a newborn when applying the drug during breastfeeding. In view of the potential danger of developing serious adverse reactions in the child, the use of the drug Opdivo® during the period of 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 Optigo® to adults is 3 mg / kg of body weight as a 60-minute intravenous infusion with administration every 2 weeks. Treatment should continue if there is a clinical effect or signs of intolerable toxicity.

    Increasing or lowering the dose is not recommended.The delay in the introduction of a regular dose or the withdrawal of admission may be related to individual safety or tolerability of the drug. Recommendations for the final cancellation or omission of the ODDIVO® preparation are given in Table 1. Detailed recommendations for the elimination of immuno-mediated adverse reactions are given in the section "Specific guidance".

    Table 1. Cancellation or skipping of the dose of OPIDO®

    Immuno-mediated undesirable reactions

    Heaviness

    Modification of treatment

    Immunosuppressed pneumonitis

    2 severity of pneumonitis.

    Stop the use of Optigo® before the disappearance of symptoms, positive X-ray dynamics and relief of unwanted reactions with glucocorticosteroids

    3 or 4 degrees of severity of pneumonitis

    Cancellation of Opdivo® without resumption

    Immuno-mediated colitis

    2 or 3 severity of diarrhea or colitis

    Stop taking the Opdiv® until the symptoms disappear and stopping the unwanted reactions with glucocorticosteroids.

    4 severity of diarrhea or colitis

    Cancellation of Opdivo® without resumption

    Immuno-mediated hepatitis

    2 severity of increase in activity of aspartate aminotransferase (ACT), alanine aminotransferase (ALT) or a level of total bilirubin

    Stop taking the drug OptiVivo until the laboratory indicators return to the baseline level and stop the undesirable reactions of glucocorticosteroids.

    3 or 4 severity of increase in activity ACT, ALT or a level of total bilirubin

    Cancellation of Opdivo® without resumption

    Immune-mediated nephritis and renal dysfunction

    2 or 3 severity of increase in creatinine level

    Stop the use of Optigo® before the level of creatinine returns to the initial level of relief of unwanted reactions with glucocorticosteroids.

    4 severity of increase in creatinine level

    Cancellation of Opdivo® without resumption

    Immuno-mediated endocrinopathy

    Symptomatic endocrinopathy of grade 2 or 3 (including hypothyroidism, hyperthyroidism, hypophysitis, insufficiency of the adrenal cortex, and diabetes)

    Stop taking the drug Opti® before the disappearance of symptoms and relief of unwanted reactions of glucocorticosteroids (if necessary to remove the symptoms of acute inflammation).Admission Opdivo® medication should be continued in the case of hormone replacement therapy, up to as long as there are signs

    Hypophysitis 4 degrees of severity

    Insufficiency of the adrenal cortex of the 4th degree of severity

    Cancellation of Opdivo® without resumption

    Immune-mediated rash

    Rash 3 degrees of severity

    Stop taking the Opdiv® until the symptoms disappear and stopping the unwanted reactions with glucocorticosteroids.

    Rash 4 degrees of severity

    Cancellation of Opdivo® without resumption

    Other immunosupplemented adverse reactions

    3 degree of severity

    Opdivo® stop taking the drug until symptoms and relief of adverse reactions glucocorticosteroids

    - 4 degree of severity

    - Repeated 3rd severity 2 or 3 while maintaining the degree of severity of reactions despite the suspension of the treatment or when it is impossible to reduce the daily dose glucocorticosteroids equivalent to 10 mg of prednisone.

    Cancellation of Opdivo® without resumption

    Note: the degree of toxicity corresponds to the general terminology of the criteria for the adverse events of the National Cancer Institute, Version 4.0 (NCI-CTCAE v4)

    Impaired renal function

    Correction of the dose of the drug for mild and moderate severity of renal dysfunction is not required.

    Impaired liver function

    With liver failure, mild degree of dose adjustment is not required.

    Elderly patients

    Correction of the dose of the drug in patients older than 65 years and older is not required.

    Instructions on preparation and introduction preparation

    Do not shake the bottle before use!

    Diluted infusion solution is prepared under aseptic conditions.

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

    Do not administer the drug in the presence of foreign matter in it, and also 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.

    Opdivo® can be used after dilution with a sterile 0.9% sodium chloride solution for infusions or a sterile 5% dextrose solution for infusions to a concentration of 1 to 10 mg / ml. The prepared solution is mixed by carefully turning the infusion container.

    The drug Opdivo® compatible with the following types of infusion equipment:

    - Glass bottles, polyvinylchloride (PVC) and polyolefin bags for infusion;

    - Polyvinylchloride (PVC) systems for intravenous administration;

    - Polyethersulfone (pore size: 0.2-1.2 μm) and nylon (pore size: 0.2 μm) flow-through 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

    - The dosage of the drug is defined as mg / kg. Based on the dose prescribed to the patient, determine the number of vials of the drug required for administration. For one patient, more than 1 vial may be required to prepare a single dose for administration.

    - 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 10 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 10 mg / ml.

    - The prepared solution is mixed by carefully turning the infusion container. Do not shake!

    - Before administration, it is necessary to visually check the prepared solution of the preparation for the presence of mechanical inclusions and discoloration. Opdivo® solution is a clear or opalescent solution, from colorless to light yellow in color.

    - It is not allowed to use the vial if the solution is cloudy, has changed its color, or contains extraneous mechanical inclusions that differ from the matte white protein particles. The bottle should not be shaken.

    - From the point of view of microbiological purity, the prepared solution should be used immediately. Otherwise, the prepared solution can be stored in the dark place for up to 24 hours at a temperature of 2-8 ° C. (Of the indicated 24 hours, the solution of the preparation can be at room temperature (20-25 ° C) and daylight for no more than 4 hours, including the time required to administer the drug).

    - Unused remedy of Opdyvo® in the vial and empty the vial to destroy.

    The introduction of a solution of infusions

    - The drug should not be administered as a rapid intravenous injection or as a bolus injection.

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

    - Do not mix Opdiva® with other medications in one vial or infusion system and do not inject it simultaneously with other infusion preparations

    - The drug should be administered within 60 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:

    When using the drug Opdivo® most often there were immuno-mediated adverse reactions. Most of these adverse reactions, including severe ones, were stopped by appropriate therapy or by withdrawal of the drug.

    In clinical trials with the use of the drug Opdivo® as monotherapy at a dose of 3 mg / kg by type of tumors, the most frequent (≥ 10%) adverse reactions were fatigue (34%), rash (19%), pruritus (14%), diarrhea (13%), nausea (13 %) and decreased appetite (10%). In most cases, adverse reactions were expressed from mild to moderate degree (grades 1 and 2).

    The following are side effects observed in patients receiving OCD therapy. Adverse reactions 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).

    Infections and invasions:

    Frequent: upper respiratory tract infection;

    Infrequent: bronchitis, pneumonia;

    Rare: encephalitis.

    Neoplasms benign, malignant and unstated nature (including cysts and polyps):

    Rare: histiocytic necrotic lymphadenitis (Kikuchi lymphadenitis)

    On the part of the blood and lymphatic system:

    Infrequent: eosinophilia.

    From the immune system:

    Frequent: infusion reactions2;

    Infrequent: anaphylactic reaction2, hypersensitivity2.

    From the endocrine system:

    Frequent: hyperglycemia, hypothyroidism, hyperthyroidism;

    Infrequent: insufficiency of adrenal function, hypopituitarism, hypophysitis, thyroiditis, diabetic ketoacidosis, diabetes mellitus.

    Disorders of metabolism and nutrition:

    Very Frequent: decreased appetite;

    Infrequent: dehydration, metabolic acidosis.

    From the nervous system:

    Frequent: peripheral neuropathy, headache, dizziness;

    Infrequent: polyneuropathy;

    Rare: Guillain-Barre syndrome, demyelination, myasthenic syndrome, autoimmune neuropathy (including paresis of facial and abnormal nerves).

    From the side of the organs of sight:

    Frequent: blurred vision, dry eyes;

    Infrequent: uveitis.

    From the side of the cardiovascular system:

    Frequent: increased blood pressure;

    Infrequent: tachycardia, vasculitis;

    Rare: arrhythmia (including ventricular arrhythmia), atrial fibrillation.

    From the respiratory system:

    Frequent: pneumonitis2, shortness of breath, cough;

    Infrequent: pleurisy;

    Rare: infiltration of the lungs.

    From the gastrointestinal tract:

    Very Frequent: diarrhea, nausea;

    Frequent: colitis, stomatitis, vomiting, abdominal pain, constipation, dry mouth;

    Infrequent: pancreatitis;

    Rare: gastritis, ulcer of the duodenum.

    From the liver and biliary tract:

    Infrequent: hepatitis2, hyperbilirubinemia;

    Rare: cholestasis.

    From the skin and subcutaneous tissue:

    Very Frequent: rash3, itching;

    Frequent: vitiligo, dry skin, erythema, alopecia;

    Infrequent: erythema multiforme, psoriasis, rosacea, urticaria;

    Rare: toxic epidermal necrolysis1.

    From the side of the musculoskeletal system:

    Frequent: musculoskeletal pain4, arthralgia;

    Infrequent: rheumatic polymyalgia;

    From the side of the kidneys and urinary tract:

    Infrequent: tubulointerstitial nephritis, renal failure1,2.

    General disorders and reactions to drug administration:

    Very Frequent: fatigue;

    Frequent: increased body temperature, swelling (including peripheral edema);

    Infrequent: chest pain;

    From the laboratory indicators:

    Very Frequent: decreased body weight;

    Frequent: increased transaminase activity, increased lipase activity, increased amylase activity, increased alkaline phosphatase activity, increased creatinine, lymphopenia, leukopenia, thrombocytopenia, anemia, hyponatremia;

    Infrequent: increasing the concentration of total bilirubin, hypercalcemia, hypocalcemia, hyperkalemia, hypokalemia, hypomagnesemia, neutropenia, decrease in the absolute number of neutrophils, hypernatremia;

    Rare: hypermagnesia.

    NOTE:

    1 - Including adverse reactions with fatal outcome.

    2 - Including life-threatening adverse reactions.

    3 - Including a patchy-papular rash, erythema rash, itching rash, vesicular rash, macular rash, korepodobnuyu rash,papular rash, pustular rash, papulosquamous rash, vesicular rash, genitalized rash, dermatitis, acneiform dermatitis, allergic dermatitis, atopic dermatitis, bullous dermatitis, exfoliative dermatitis, isoriaziform dermatitis, medical rash.

    4 - Including back pain, bone pain, musculoskeletal pain in the chest, musculoskeletal discomfort, myalgia, neck pain, pain in the extremities, spinal pain.

    Immunogenicity

    The drug Opdiv®, like other monoclonal antibodies, has immunogenicity.

    In 11% of patients who received OCD therapy, antibodies to nivolumab were observed. Neutralization of antibodies was determined in two patients (0.6%). However, the dependence of the presence of antibodies in the blood plasma and changes in pharmacokinetic parameters, the severity of the clinical effect and the development of side effects were not revealed.

    Overdose:

    There were no cases of overdose.

    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

    Nivolumab is a human monoclonal antibody. In view of the fact that the antibodies are not metabolized with the participation of cytochrome P450 isoenzymes and other isoenzymes, the inhibition or induction of these enzymes, when combined with other drugs, does not affect the pharmacokinetics of niwolumab.

    Other forms of interactions

    Systemic immunosuppression

    In connection with the possibility of pharmacodynamic interaction, it is necessary to avoid the use of systemic glucocorticosteroids and other immunosuppressants before prescribing therapy with the drug Opdivo®. After the beginning of therapy with ODDIVO® glucocorticosteroids and other immunosuppressants can be used to correct immune-mediated adverse reactions caused by exposure to the immune system. The use of systemic glucocorticosteroids after the start of treatment with the drug does not reduce the effectiveness of the drug Opdivo®.

    Special instructions:

    The drug Opdivo® can cause serious, including fatal, adverse reactions, caused by the influence on the immune system and conditioned by the specific mechanism of its action.Patients should be under continuous monitoring (at least 5 months after the last dose), since unwanted reactions caused by the effect of the Optodiva® can develop at any time during or after the treatment is discontinued. If there is a suspicion of the development of an immune-mediated undesirable reaction, an adequate evaluation should be made to confirm or exclude another etiology. Based on the severity of the undesirable reaction, the use of the drug Opdivo® should be discontinued with or without the administration of glucocorticosteroids.

    In the case of carrying out immunosuppressive therapy with glucocorticosteroids designed to eliminate unwanted reactions, after the improvement of the condition, a decrease in the dose of glucocorticosteroids is carried out slowly, for at least 1 month. Rapid dose reduction can lead to worsening of the severity or relapse of adverse reactions. Immunosuppressive therapy, drugs other than glucocorticosteroids, is prescribed if there is a deterioration or lack of improvement with glucocorticosteroids.

    Application of the drug Opdivo® should be discontinued when the patient receives an immunosuppressive dose of glucocorticosteroids or immunosuppressive therapy.

    The drug Opdivo® should be abolished in any recrudescent immuno-mediated adverse reactions from medium to severe and canceled without resumption in severe immuno-mediated pneumonitis and immune-mediated hepatitis as well as life-threatening immune-mediated adverse reactions.

    Use of the Optodiva® in patients with rapid progression of melanoma

    Doctors should discuss the effect of the delayed action of the drug Opdivo® before starting treatment in patients with rapidly progressive disease.

    Immunosuppressed pneumonitis

    When treated with the Optodivo®, cases of severe pneumonitis or interstitial lung disease, including fatal cases, were noted. Patients should be observed for signs and symptoms of pneumonitis, such as radiographic changes (for example, blackout as a frosted glass, foci of inflammation), dyspnea and hypoxia. Infections and disease-related symptoms should be excluded.

    At 3 or 4 degrees of severity of pneumonitis, the use of the drug Opdivo® should be canceled without renewal and start taking glucocorticosteroids at a dose equivalent to 2-4 m g / kg / day of methyl prednisolone.

    At 2 degrees of severity (symptomatic) pneumonitis, the use of the drug Opdivo® should be suspended and start taking glucocorticosteroids at a dose equivalent to 1-2 mg / kg / day of methylprednisolone. With the onset of improvement, the use of the drug Opdivo® can be continued after a slow decrease in the dose of glucocorticosteroids. In the event of impairment or lack of improvement that continues despite the use of glucocorticosteroids, the dose of glucocorticosteroids should be increased to an equivalent 2-4 mg / kg / day of methylprednisolone and the use of nivolumab should be withdrawn without resumption.

    Immuno-mediated colitis

    When therapy with ODDIVO® cases of severe diarrhea or colitis have been reported. Patients should be observed for signs of diarrhea and additional symptoms of colitis, such as abdominal pain, mucus or blood in the stool. Infections and disease-related symptoms should be excluded.

    With the 4th degree of severity of diarrhea or colitis, the use of the drug Opdivo® should be abolished definitively and start taking glucocorticosteroids at a dose equivalent to 1-2 mg / kg / day of methylprednisolone.

    At 3 degrees of severity of diarrhea or colitis, nivolumab should be stopped and glucocorticosteroids administered at a dose equivalent to 1-2 mg / kg / day of methylprednisolone. With the onset of improvement, the use of the drug Opdivo® can be continued after a slow decrease in the dose of glucocorticosteroids. In the event of impairment or lack of improvement, which continues despite the use of glucocorticosteroids, the use of nivolumab should be canceled without resumption.

    At 2 degrees of severity of diarrhea or colitis, the use of the drug Opdivo® should be paused. Persistent diarrhea or colitis should be eliminated by the administration of glucocorticosteroids at a dose equivalent to 0.5-1 mg / kg / day of methylprednisolone. With the onset of improvement, the use of nivolumab can be continued after a slow decrease in the dose of glucocorticosteroids. In the event of an impairment or lack of improvement that continues,despite the intake of glucocorticosteroids, the dose of glucocorticosteroids should be increased to the equivalent of 1-2 mg / kg / day of methylprednisolone and the use of nivolumab should be canceled without resumption.

    Immuno-mediated hepatitis

    When therapy with ODDIVO® cases of severe hepatitis were noted. Patients should be observed for signs and symptoms of hepatitis, such as increased levels of transaminases and total bilirubin. Infections and disease-related symptoms should be excluded.

    At 3 or 4 degrees of severity of the increase in the level of transaminases and total bilirubin, the use of the drug Opdivo® should be canceled without renewal and start taking glucocorticosteroids at a dose equivalent to 1 to 2 mg / kg / day of methylprednisolone.

    At 2 degrees of severity of the increase in the level of transaminases and total bilirubin, the use of the drug Opdivo® should be paused. The persistent elevation in the level of these laboratory parameters should be eliminated by the administration of glucocorticosteroids at a dose equivalent to 1-2 mg / kg / day of methylprednisolone. With the onset of improvement, the use of nivolumab can be continued after a slow decrease in the dose of glucocorticosteroids.In case of impairment or absence of improvement, which continues despite the use of glucocorticosteroids, the dose of glucocorticosteroids should be increased to the equivalent of 1 to 2 mg / kg / day of methylprednisolone and the use of nivolumab should be withdrawn without renewal.

    Immune-mediated nephritis and renal dysfunction

    In the treatment with Optodivo®, cases of severe nephritis or renal dysfunction were noted, so patients should be observed for signs and symptoms. The majority of patients showed an asymptomatic increase in serum creatinine. The etiology associated with the disease should be excluded.

    At 4 degrees of severity of the increase in serum creatinine level, the use of the drug Opdivo® should be abolished definitively and begin taking glucocorticosteroids at a dose equivalent to 1 to 2 mg / kg / day of methylprednisolone.

    At 2 or 3 degrees of severity of the increase in serum creatinine, the use of the drug Opdivo® should be suspended and begin taking glucocorticosteroids at a dose equivalent to 0.5-1 mg / kg / day of methylprednisolone. With the onset of improvement, the use of nivolumab can be continued after a slow decrease in the dose of glucocorticosteroids.In the event of impairment or lack of improvement that continues, despite the use of glucocorticosteroids, the dose of glucocorticosteroids should be increased to an equivalent of 1-2 mg / kg / day of methylprednisolone and the use of nivolumab should be withdrawn without renewal.

    Immuno-mediated endocrinopathy

    When therapy with ODDIVO® cases of severe endocrinopathy, including hypothyroidism, hyperthyroidism, adrenocortical insufficiency, hypophysitis, diabetes mellitus, and diabetic ketoacidosis have been reported.

    Patients should be observed for signs and symptoms of endocrinopathies and thyroid function changes (at the beginning of treatment, periodically during treatment and based on clinical evaluation). Patients may experience fatigue, headache, mental changes, abdominal pain, unusual bowel rhythms and hypotension, or non-specific symptoms that may be similar to other conditions, such as brain metastases or concomitant diseases. In the absence of detecting another etiology, signs and symptoms of endocrinopathies should be considered immune-mediated.

    With symptomatic hypothyroidism, the use of the drug Opdivo® should be suspended and, if necessary, carried out substitution therapy with thyroid hormones. With symptomatic hyperthyroidism, the use of the drug Opdivo® should be suspended, and if necessary, to conduct therapy with antithyroid drugs. In the case of acute thyroiditis, glucocorticosteroids should be given at a dose equivalent to 1-2 mg / kg / day of methylprednisolone. With the onset of improvement, the use of the drug Opdivo® can be continued after a slow decrease in the dose of glucocorticosteroids. It is necessary to continue monitoring the function of the thyroid gland to monitor the adequacy of hormone replacement hormone therapy with thyroid hormones.

    With symptomatic adrenocortical failure of grade 2 adrenal glands, the use of nivolumab should be stopped and, if necessary, physiological replacement of glucocorticosteroids should be performed. With symptomatic insufficiency of the adrenal cortex of 3-4 degrees, the use of nivolumab should be abolished definitively and, if necessary, physiological replacement of glucocorticosteroids should be performed.It is necessary to continue to monitor the function of the adrenal glands and the level of hormones to monitor the adequacy of ongoing glucocorticosteroid replacement therapy.

    With symptomatic hypophysitis 2-3 degrees, the use of the drug Opdivo® it is necessary to suspend and carry out, if necessary, hormone replacement therapy. In the case of acute hypophysitis, glucocorticosteroids are prescribed at a dose equivalent to 1-2 mg / kg / day of methylprednisolone. With the onset of improvement, the use of the drug Opdivo® can be continued after a slow decrease in the dose of glucocorticosteroids.

    With symptomatic hypophysitis of the 4th degree, therapy with nivolumab should be abolished definitively. It is necessary to continue monitoring the function of the pituitary gland and the level of hormones to monitor the adequacy of hormone replacement therapy.

    With symptomatic diabetes, the use of nivolumab should be stopped and, if necessary, carried out by insulin replacement therapy. It is necessary to monitor the blood sugar level to monitor the adequacy of insulin replacement therapy.

    Immune-mediated rash

    When therapy with ODDIVO® cases of severe rash (including rare cases of lethal toxic epidermal necrolysis) have been reported, which may be of an immuno-mediated nature. Use nivolumab should be discontinued with a rash of 3 severity and undo without restoring at 4 degrees of severity. With a severe rash, treatment with glucocorticosteroids is prescribed at a dose equivalent to 1-2 mg / kg / day of methylprednisolone.

    The drug Opdivo® should be administered with caution in patients who previously had severe or life threatening unwanted skin reactions when treated with other immunostimulatory antitumor drugs.

    Other immuno-mediated adverse reactions

    The following immuno-mediated adverse reactions were observed in less than 1% of patients treated with Opdiva® during clinical trials with any dosing and type of tumor: pancreatitis, uveitis, demyelination, autoimmune neuropathy (including paresis of facial and abnormal nerves), Guillain-Barre syndrome, hypopituitarism, myasthenic syndrome and encephalitis.

    If suspected immuno-mediated adverse reactions should be made adequateAssessment to confirm their etiology or exclude other causes of their appearance. Based on the severity of the unwanted reaction, the use of the Optido® drug should be discontinued and glucocorticosteroid therapy initiated. With the onset of improvement, taking nivolumab may be continued after a slow decrease in the dose of glucocorticosteroids. The drug Opdivo® should be withdrawn without renewal if any relapsing severe immune-mediated adverse reactions occur and any life-threatening immune-mediated adverse reactions.

    Infusion reactions

    During clinical trials, cases of severe infusion reactions were noted. In case of development of severe infusion reactions, the introduction of the drug Opti® should be discontinued with the appointment of appropriate drug therapy. Patients with mild or moderate infusion reaction can continue therapy with the drug Opdivo® under continuous supervision and premedication in accordance with the current standards of prevention of infusion reactions.

    Patients on a diet with a controlled sodium content

    Each milliliter of the drug Opti® contains 0.1 mmol (or 2.5 mg) of sodium, which should be taken into account in the treatment of patients on a diet with controlled sodium content.

    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 dangerous activities that require increased concentration and speed of psychomotor reactions during the period of treatment with the drug Opdivo® before establishing the fact that these adverse reactions are absent.

    Form release / dosage:

    Concentrate for solution for infusion, 10 mg / ml.

    Packaging:

    By 10 ml or 4 ml into a bottle of transparent colorless glass type I, hermetically 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.

    Do not freeze. Do not shake.

    Keep out of the reach of children.

    Shelf life:

    2 years.

    Do not use after the expiration date.

    Terms of leave from pharmacies:On prescription
    Registration number:LP-004026
    Date of registration:22.12.2016
    Expiration Date:22.12.2021
    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: & nbsp09.06.2017
    Illustrated instructions
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