Opdivo concentrate 10mg/ml 10ml vial, 1pc

Composition

1 bottle of concentrate for preparing an infusion solution contains: Active ingredient: nivolumab 107.0 mg, excipients: sodium citrate dihydrate 62.9 mg; sodium chloride 31.2 mg; mannitol 321.0 mg; pentetic acid 0.0856 mg; polysorbate 80 2.14 mg; sodium hydroxide and hydrochloric acid-q. s. up to pH 6.0;water for injection-q. s. up to 10.7 ml

Pharmacological action

Nivolumab is a human monoclonal antibody that blocks the interaction between the programmed death receptor (PD-1) and its ligands (PD-L1 and PD-L2). Nivolumab is an immunoglobulin G4 (IgG4) with an approximate molecular weight of 146 kDa. The PD-I receptor is a negative regulator of T cell activity. Binding of PD-1 to the PD-L1 and PD-L2 ligands, which can be expressed by tumor cells or other cells of the tumor microenvironment, leads to inhibition of T cell proliferation and cytokine secretion. Nivolumab potentiates the immune response by blocking the binding of PD-1 to the PD-L1 and PD-L2 ligands. In mouse model studies, blocking PD-1 activity resulted in reduced tumor growth. Pharmacokineticspharmacokinetics of nivolumab is linear in the dose range from 0.1 to 10 mg / kg. In a population pharmacokinetic analysis, the average systemic clearance of nivolumab was 9.5 ml / h (coefficient of variability -49.7%); the average volume of distribution at steady state was 8.0 l (coefficient of variability – 30.4%); the average half – life (half-life) was 26.7 days (coefficient of variability -101%). The maximum, minimum, and average plasma concentrations of nivolumab after 2 weeks of 3 mg/kg use were 57.116 and 75.3 mcg / ml, respectively. The clearance of nivolumab increased with increasing body weight, but the above method of calculating the dose led to equilibrium therapeutic concentrations of the drug in the blood of patients with different body weights (from 34 to 162 kg). The metabolism of nivolumab is not described, however, due to the identity of the structure of nivolumab with the human monoclonal antibody IgG4, the proposed pathway of drug metabolism corresponds to the metabolism of endogenous immunoglobulin-breakdown into amino acids in the catalytic pathway of protein metabolism. Special patient groupspopulation pharmacokinetic analysis showed no dependence of nivolumab clearance on the patient’s age, gender, race, tumor type, tumor size, or the presence of liver function disorders. Although there was a weak relationship between ECG clearance, glomerular filtration rate, serum albumin level, and body weight in studies, this relationship was not clinically significant. Patients with impaired renal function The pharmacokinetic properties of nivolumab were studied in patients with mild (creatinine clearance from 60 to 2), moderate (creatinine clearance from 30 to 15 ml/min/1.73 m2) degree of renal insufficiency in comparison with patients with normal renal function (creatinine clearance >90 ml/min/1.73 m2). There were no clinically significant differences in the clearance of nivolumab in patients with mild to moderate renal insufficiency and in patients with normal renal function. The clearance of nivolumab in patients with severe renal insufficiency is poorly understood. Patients with hepatic dysfunctionpharmacokinetic properties were studied in patients with mild hepatic insufficiency (total bilirubin increased by 1.0-1.5 times ULN or ACT above ULN, classification of the National Cancer Institute) in comparison with patients with normal liver function (total bilirubin and ACT within normal limits). There were no differences in the clearance of nivolumab between the above groups of patients. The pharmacokinetics of the drug have not been studied in patients with moderate hepatic insufficiency (increase in total bilirubin 1.5-3.0 times higher than ULN and ACT above ULN) and severe hepatic insufficiency (increase in total bilirubin more than 3.0 times higher than ULN and ACT above ULN).

Indications

As monotherapy for inoperable or metastatic melanoma in adult patients. As monotherapy for locally advanced or metastatic non-small cell lung cancer (HMPJI) in adults after previous chemotherapy. As monotherapy for advanced renal cell carcinoma (RCC) in adults after previous systemic therapy.

Contraindications

Hypersensitivity to any component of the drug. Children under 18 years of age due to the lack of efficacy and safety data. Pregnancy and breast-feeding period.

Side effects

When using Opdivo, immuno-mediated adverse reactions were most often observed. Most of these adverse reactions, including severe ones, were stopped with appropriate therapy or by discontinuing the drug. In clinical trials using Opdivo as monotherapy at a dose of 3 mg/kg by tumor type, the most common (>10%) adverse reactions were fatigue (34%), rash (19%), pruritus (14%), diarrhea (13%), nausea (13%) and decreased appetite (10%). In most cases, adverse reactions were mild to moderate (grade 1 and 2). The following adverse reactions have been reported in patients receiving Opdivo therapy. Adverse reactions are presented by the frequency of their registration: very frequent (>1/10), frequent (>>1/100,1/1000,1/10 000, Infections and infestations: Common: upper respiratory tract infection; Uncommon: bronchitis, pneumonia; Rare: encephalitis. Neoplasms that are benign, malignant, or unidentified (including cysts and polyps): Rare: histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis)From the blood and lymphatic system: Infrequent: eosinophilia from the immune system: Frequent: infusion reactions; Infrequent: anaphylactic reactions, hypersensitivity. From the endocrine system: Frequent: hyperglycemia, hypothyroidism, hyperthyroidism; Infrequent: adrenal insufficiency, hypopituitarism, pituitary gland, thyroiditis, diabetic ketoacidosis, diabetes mellitus. Metabolic and nutritional disorders: Very common: decreased appetite; Infrequent: dehydration, metabolic acidosis. Nervous system disorders: Common: peripheral neuropathy, headache, dizziness; Uncommon: polyneuropathy; Rare: Guillain-Barre syndrome, demyelination, myasthenic syndrome, autoimmune neuropathy (including paresis of the facial and abductor nerves). From the side of the visual organs: Frequent: blurred vision, dry eyes; Infrequent: uveitis. From the cardiovascular system: Frequent: increased blood pressure; Infrequent: tachycardia, vasculitis; Rare: arrhythmia (including ventricular arrhythmia), atrial fibrillation. Respiratory system disorders: Common: pneumonitis, shortness of breath, cough; Uncommon: pleurisy; Rare: lung infiltration. Gastrointestinal disorders: Very common: diarrhea, nausea; Common: colitis, stomatitis, vomiting, abdominal pain, constipation, dry mouth; Uncommon: pancreatitis; Rare: gastritis, duodenal ulcer. Liver and biliary tract disorders: Infrequent: hepatitis, hyperbilirubinemia; Rare: cholestasis. Skin and subcutaneous tissue disorders: Very common: rash, pruritus; Common: vitiligo, dry skin, erythema, alopecia; Uncommon: erythema multiforme, psoriasis, rosacea, urticaria; Rare: toxic epidermal necrolysis. Musculoskeletal system disorders: Common: musculoskeletal pain, arthralgia; Uncommon: polymyalgia rheumatica; Kidney and urinary tract disorders: Infrequent: tubulointerstitial nephritis, renal failure. General disorders and reactions to drug use: Very frequent: fatigue; Frequent: increased body temperature, edema (including peripheral edema); Infrequent: chest pain;From laboratory parameters: Very frequent: weight loss; Frequent: increased transaminase activity, increased lipase activity, increased amylase activity, increased alkaline phosphatase activity, increased creatinine, lymphopenia, leukopenia, thrombocytopenia, anemia, hyponatremia; Infrequent: increased total body fat concentration hypercalcemia, hypocalcemia, hyperkalemia, hypokalemia, hypomagnesemia, neutropenia, decreased absolute neutrophil count, hypernatremia; Rare: hypermagnesemia. Note: 1-Including fatal adverse reactions. 2-Including life-threatening adverse reactions. 3 – Including maculopapular rash, erythematous rash, pruritic rash, vesicular rash, macular rash, scab-like rash, papular rash, pustular rash, papulo-squamous rash, vesicular rash, geniralized rash, dermatitis, acne-like dermatitis, allergic dermatitis, atopic dermatitis, bullous dermatitis, exfoliative dermatitis, psoriasis-like dermatitis, drug-induced rash. 4-Including back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, limb pain, spinal pain.

Interaction

Pharmacokinetic interactions Nivolumab is a human monoclonal antibody. Due to the fact that antibodies are not metabolized with the participation of cytochrome P450 isoenzymes and other isoenzymes, inhibition or induction of these enzymes when co-administered with other drugs does not affect the pharmacokinetics of nivolumab. Other forms of interaction Systemic immunosuppression Due to the possibility of pharmacodynamic interactions, the use of systemic glucocorticosteroids and other immunosuppressants should be avoided before Opdivo therapy. After starting therapy with Opdivoglucocorticosteroids and other immunosuppressants can be used to correct immuno-mediated adverse reactions caused by the drug’s effect on the immune system.The use of systemic glucocorticosteroids after starting treatment with the drug does not reduce the effectiveness of Opdivo.

How to take, course of use and dosage

The drug should be administered under the supervision of a doctor who has experience in the treatment of cancer. The recommended dose of Opdivo for adults is 3 mg / kg body weight as a 60-minute intravenous infusion administered every 2 weeks. Treatment should be continued if there is a clinical effect or until signs of intolerable toxicity appear. Increasing or decreasing the dose of the drug is not recommended. Delay in the next dose or discontinuation may be due to individual safety or tolerability of the drug.

Overdose

No cases of overdose were detected. In case of overdose, treatment should consist of symptomatic drug therapy in accordance with the side effects that occur, with careful monitoring of the patient.

Special instructions

Opdivo can cause severe, including fatal, adverse reactions caused by its effect on the immune system and due to its specific mechanism of action. Patients should be continuously monitored (at least 5 months after the last dose), as adverse reactions due to Opdivo exposure may develop at any time during use or after discontinuation of therapy. If an immuno-mediated adverse reaction is suspected, an adequate assessment should be performed to confirm or exclude a different etiology. Based on the severity of the adverse reaction, Opdivo should be discontinued, with or without the resumption of corticosteroid therapy. In the case of immunosuppressive therapy with glucocorticosteroids, designed to eliminate adverse reactions, after improving the condition, the dose of glucocorticosteroids is reduced slowly, for at least 1 month. Rapid dose reduction may lead to a worsening of the severity or recurrence of adverse reactions. Immunosuppressive therapy with drugs other than glucocorticosteroids is prescribed if there is a deterioration or lack of improvement in the use of glucocorticosteroids. Opdivo should be discontinued while the patient is receiving an immunosuppressive dose of glucocorticosteroids or undergoing immunosuppressive therapy. Opdivo should be discontinued for any recurrent immuno-mediated adverse reactions of moderate to severe severity and discontinued without resumption for severe immuno-mediated pneumonitis and immuno-mediated hepatitis, as well as life-threatening immuno-mediated adverse reactions. Opdivo use in patients with rapidly progressing melanoma Physicians should discuss the delayed effect of Opdivo before starting treatment in patients with rapidly progressing melanoma. Immuno-mediated pneumonitis Cases of severe pneumonitis or interstitial lung disease, including fatal cases, have been reported with Opdivo. Patients should be monitored for signs and symptoms of pneumonitis, such as radiographic changes (for example, darkening like frosted glass, foci of inflammation), shortness of breath and hypoxia. Infections and disease-related symptoms should be excluded. In patients with grade 3 or 4 pneumonitis, the use of Opdivo should be discontinued without resumption and glucocorticosteroids should be started at a dose equivalent to 2-4 mg/kg/day of methylprednisolone. In patients with grade 2 (symptomatic) pneumonitis, the use of Opdivo should be suspended and glucocorticosteroids should be started at a dose equivalent to 1-2 mg/kg/day of methylprednisolone. If improvement occurs, the use of Opdivo can be continued after a slow reduction in the dose of glucocorticosteroids. In case of deterioration or lack of improvement that continues despite taking glucocorticosteroids, the dose of glucocorticosteroids should be increased to the equivalent of 2-4 mg/kg/day of methylprednisolone and the use of nivolumab should be discontinued without resumption. Immuno-mediated colitis Cases of severe diarrhea or colitis have been reported with Opdivo. Patients should be monitored 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. In patients with grade 4 diarrhoea or colitis, the use of Opdivo should be permanently discontinued and glucocorticosteroids should be started at a dose equivalent to 1-2 mg/kg / day of methylprednisolone. In patients with grade 3 diarrhoea or colitis, the use of nivolumab should be suspended and the use of glucocorticosteroids should be started at a dose equivalent to 1-2 mg/kg/day of methylprednisolone. If improvement occurs, the use of Opdivo can be continued after a slow reduction in the dose of glucocorticosteroids. In the event of deterioration or lack of improvement that continues despite taking glucocorticosteroids, nivolumab should be discontinued without resumption. If diarrhoea or colitis is grade 2 severe, the use of Opdivo should be suspended. Persistent diarrhea or colitis should be treated with a glucocorticoid equivalent of 0.5-1 mg/kg/day of methylprednisolone. If improvement occurs, nivolumab may be continued after a slow reduction in the dose of corticosteroids. In case of deterioration or lack of improvement that continues despite taking 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 discontinued without resumption. Immuno-mediated hepatitis Cases of severe hepatitis have been reported with Opdivo. Patients should be monitored for signs and symptoms of hepatitis, such as elevated levels of transaminases and total bilirubin. Infections and disease-related symptoms should be excluded. If the level of transaminases and total bilirubin increases in 3 or 4 degrees of severity, Opdivo should be discontinued without resumption and glucocorticosteroids should be started at a dose equivalent to 1-2 mg / kg / day of methylprednisolone. If the level of transaminases and total bilirubin increases in 2 degrees of severity, the use of Opdivo should be suspended. Persistent elevation of these laboratory parameters should be eliminated by use of glucocorticosteroids at a dose equivalent to 1-2 mg / kg / day of methylprednisolone. If improvement occurs, nivolumab may be continued after a slow reduction in the dose of corticosteroids. In case of deterioration or lack of improvement that continues despite taking 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 discontinued without resumption. Immuno-mediated nephritis and renal dysfunction Cases of severe nephritis or renal dysfunction have been reported with Opdivo, so patients should be monitored for signs and symptoms. Most patients showed an asymptomatic increase in serum creatinine. The etiology associated with the disease should be excluded. In patients with a grade 4 increase in serum creatinine, the use of Opdivo should be permanently discontinued and glucocorticosteroids should be started at a dose equivalent to I-2 mg / kg / day of methylprednisolone. If the increase in serum creatinine level is 2 or 3 degrees of severity, the use of Opdivo should be suspended and the use of glucocorticosteroids should be started at a dose equivalent to 0.5 – 1 mg/kg/day of methylprednisolone. If improvement occurs, nivolumab may be continued after a slow reduction in the dose of corticosteroids. In case of deterioration or lack of improvement that continues despite taking glucocorticosteroids, the dose of glucocorticosteroids should be increased to the equivalent of I – 2 mg/kg/day of methylprednisolone and the use of nivolumab should be discontinued without resumption. Immuno-mediated endocrinopathy Cases of severe endocrinopathy, including hypothyroidism, hyperthyroidism, adrenal insufficiency, pituitary gland, diabetes mellitus, and diabetic ketoacidosis, have been reported with Opdivo. Patients should be monitored for signs and symptoms of endocrinopathies and changes in thyroid function (at the beginning of treatment, periodically during treatment, and based on clinical evaluation). Patients may experience fatigue, headache, a change in mental state, abdominal pain, an unusual bowel rhythm and hypotension, or non-specific symptoms that may have similarities to other conditions, such as brain metastases or concomitant diseases. In the absence of detection of a different etiology, signs and symptoms of endocrinopathies should be considered immuno-mediated. In case of symptomatic hypothyroidism, the use of Opdivo should be suspended and, if necessary, thyroid hormone replacement therapy should be performed. With symptomatic hyperthyroidism, the use of Opdiv should be suspended, and if necessary, antithyroid therapy should be carried out. In the case of acute thyroiditis, glucocorticosteroids should be administered at a dose equivalent to 1-2 mg/kg/day of methylprednisolone. If improvement occurs, Opdivo may be continued after a slow reduction in the dose of glucocorticosteroids. It is necessary to continue monitoring the function of the thyroid gland to monitor the adequacy of hormone replacement therapy with thyroid hormones.If there is symptomatic grade 2 adrenal insufficiency, the use of nivolumab should be suspended and, if necessary, physiological replacement of glucocorticosteroids should be performed. In case of symptomatic adrenal insufficiency of 3-4 degrees, the use of nivolumab should be permanently discontinued and, if necessary, physiological replacement of glucocorticosteroids should be performed. It is necessary to continue monitoring the adrenal function and hormone levels to monitor the adequacy of glucocorticoid replacement therapy. With symptomatic pituitary gland of 2-3 degrees, the use of Opdivo should be suspended and, if necessary, hormone replacement therapy should be carried out. In the case of acute pituitary gland, glucocorticosteroids are prescribed at a dose equivalent to 1-2 mg / kg / day of methylprednisolone. If improvement occurs, the use of Opdivo can be continued after a slow reduction in the dose of glucocorticosteroids. Nivolumab therapy should be permanently discontinued in patients with symptomatic pituitary gland of the 4th degree. It is necessary to continue monitoring pituitary function and hormone levels to monitor the adequacy of hormone replacement therapy. In patients with symptomatic diabetes, the use of nivolumab should be suspended and, if necessary, insulin replacement therapy should be carried out. It is necessary to monitor blood sugar levels to monitor the adequacy of the insulin replacement therapy. Immuno-mediated rash Cases of severe rash (including rare cases of lethal toxic epidermal necrolysis) that may be immuno-mediated have been reported with Opdivo therapy. Nivolumab should be discontinued for grade 3 rash and discontinued without recovery for grade 4 rash. If the rash is severe, treatment with glucocorticosteroids is prescribed at a dose equivalent to 1-2 mg / kg / day of methylprednisolone. Opdivo should be prescribed with caution in patients who have previously experienced severe or life-threatening adverse skin reactions during treatment with other immunostimulating antitumor drugs. Other immuno-mediated adverse reactionsthe following immuno-mediated adverse reactions were observed in less than 1% of patients treated with Opdivo during clinical trials at any dosage and type of tumor: pancreatitis, uveitis, demyelination, autoimmune neuropathy (including facial and abductor nerve paresis), Guillain-Barre syndrome, hypopituitarism, myasthenic syndrome and encephalitis. If immuno-mediated adverse reactions are suspected, an adequate assessment should be carried out to confirm their etiology or exclude other causes of their occurrence. Based on the severity of the adverse reaction, Opdivo should be discontinued and glucocorticoid therapy initiated. If improvement occurs, nivolumab may be continued after a slow reduction in the dose of corticosteroids. Opdivo should be discontinued without resumption if any relapsing severe immuno-mediated adverse reactions and any life-threatening immuno-mediated adverse reactions occur. Infusion reactionsin clinical trials, there have been cases of severe infusion reactions. In case of severe infusion reactions, the use of Opdivo should be discontinued with the appointment of appropriate drug therapy. Patients with mild or moderate infusion reactions can continue Opdivo therapy under continuous monitoring and premedication in accordance with current standards for the prevention of infusion reactions. Patients on a controlled sodium diet Each milliliter of Opdivo contains 0.1 mmol (or 2.5 mg) of sodium, which should be taken into account when treating patients on a controlled sodium diet.

Form of production

Concentrate for preparing an infusion solution of 10 mg / ml.

Storage conditions

Store at a temperature of 2 to 8°C in a place protected from light. Do not freeze it. Do not shake.

Shelf life

2 years

Active ingredient

Nivolumab

Conditions of release from pharmacies

Prescription