Composition, form of production and packaging
Liofilizate for the preparation of a solution for s / c and / in the introduction as an amorphous white powder.
aldesleikin * 18 million
Excipients: mannitol, sodium dodecyl sulfate, sodium phosphate monohydrate monohydrate, sodium phosphate disubstituted, nitrogen.
Vials (1) - packs of cardboard.
* - the non - proprietary international name recommended by WHO, the international name "aldesleikin" was adopted in the Russian Federation.
INSTRUCTION FOR THE SPECIALIST.
The product description was approved by the manufacturer for the 2009 print edition.
Antitumor, immunomodulating drug of the group of cytokines.
Aldesleikin is a recombinant human interleukin-2, a protein with a molecular weight of about 15,600 daltons, obtained by recombinant DNA technology, using an Escherichia coli strain containing a modified human interleukin-2 gene.
Recombinant human interleukin-2 has a number of structural differences from natural interleukin-2 (not glycosylated, has no terminal alanine, in 125 amino acid position, cysteine вЂ‹вЂ‹is substituted for serine), but has the same biological activity.
Stimulates endogenous immune defense; activates T-lymphocytes and natural killer cells involved in the mechanisms of recognition and destruction of tumor cells.
Recombinant interleukin-2 promotes the production of antibodies by B-cells, stimulates the cellular secretion of secondary cytokines (ОІ-interferon, tumor necrosis factor, interleukin-1, granulocyte-macrophage colony stimulating factor), stimulates complement factors, and triggers hormone release mechanisms (ACTH, cortisol ).
The exact mechanism of aldesleukin-mediated immunostimulation with the antitumor effect has not been fully elucidated.
Absorption and Metabolism
Absolute bioavailability is 35-47%.
87% of aldesleukin is metabolized in the kidneys to amino acids (in the cells of the epithelium of the proximal convoluted renal tubules).
The T.sub.l curve of aldesleukin in the blood serum for iv injection is bi-exponential. The T 1/2 ? Phase is 13 minutes, the T 1/2 ? Phase is 85 minutes.
With n / k introduction, the kinetic properties of the drug can be described using a single-chamber model, with T 1/2 being 5.3 hours. A longer half-life, as compared with the intravenous administration, is due to the continued absorption of the drug from the subcutaneous tissue at the site of administration in the course of the elimination phase from the plasma.
The drug is mainly excreted by the kidneys through glomerular filtration and tubular secretion, with most of the dose being metabolized by the kidneys, as a result of which the urine does not contain the biologically active aldesleukin. The secondary pathway is the receptor-mediated capture by target cells. This process is active with a long course of therapy. Between cycles, when the drug is not administered, the clearance of interleukin-2 is restored to its original values. The determined value of clearance in humans as a result of a short-term (within 15 min) and a continuous 24-hour IV injection approximately corresponds to the glomerular filtration rate.
- metastatic renal cell carcinoma;
- metastatic melanoma.
The drug is intended for p / to and / in the introduction.
Dosage regimen with n / k introduction
With n / k introduction, 18 million ME are prescribed daily for 5 days, followed by a two-day break. Over the next 3 weeks - 18 million ME each on the 1st and 2nd days of each week and 9 million ME in the 3rd, 4th and 5th days of the week. After a one-week break, repeat a similar 4-week cycle.
Dosage regimen for intravenous administration
The therapy is carried out in the form of induction and supporting cycles.
When the induction cycle of therapy is prescribed, 18 million IU / m 2 in the form of a 24-hour IV infusion for 5 days, followed by a break of 2-6 days. Within the next 5 days, the drug is administered according to a similar scheme followed by a 3-week break. After the 3-week break, a second induction therapy cycle is prescribed.
Support cycles (18 million IU / m 2 as a 24-hour IV infusion for 5 days) with 4-week intervals are recommended for patients with positive dynamics or stabilization of the tumor process.
Correction of the dosing regimen for p / k and / or introduction
If the drug is intolerant, reduce its dose or stop treatment until the disappearance of toxic effects.
The elderly patients are more likely to develop side effects of Proleukin, so caution should be exercised when prescribing this type of patient.
In children, the safety and efficacy of Proleukin has not been fully established.
Rules for the preparation of an infusion solution
The contents of the vial are dissolved in 1.2 ml of water for injection. A jet of water is directed along the wall of the vial to avoid foaming. Gently mix the contents, carrying out circular movements with a vial, until the lyophilizate is completely dissolved. Do not shake the bottle.
The resulting solution is a colorless transparent liquid with a pH of 7.5 (ranging from 7.2 to 7.8).
To prepare an infusion solution, the daily dose of the prepared aldesleukin solution should be diluted in 500 ml of a 5% dextrose solution containing 0.1% human albumin. The resulting solution is injected infusion for 24 hours.
The addition of human albumin, which is necessary to preserve the biological activity of the drug, to the dextrose solution should be carried out before the addition of Proleukin solution.
Before administration, the reconstituted solution should be brought to room temperature and visually inspected for the absence of mechanical inclusions and discoloration.
The prepared solution contains no preservatives and is intended for single use only. Any unused solution or opened bottle should be disposed of in accordance with the requirements for the handling of biologically hazardous preparations.
When Proleukin is administered, do not use infusion systems with built-in filters.
The frequency and severity of Proleukin's adverse reactions depend on the dosage and mode of administration of the drug. It should be noted that most of the side effects of the drug are reversible and disappear after 1-2 days break.
Determination of the incidence of the following adverse reactions: very often (? 1/10), often (<1/10 to 1/100), infrequently (<1/100 to? 1/1000), rarely (<1 / 1000 to? 1/10000), very rarely (<1/10000).
Frequency of IV infusion of IV injection
From the side of the cardiovascular system
Very often pronounced decrease in blood pressure, sinus tachycardia, decreased blood pressure, pain in the heart (including angina)
Often arrhythmia, increased blood pressure, phlebitis, increased blood pressure, tachycardia
Uncommon angina pectoris, thrombosis, heart palpitations, transient changes in the ECG, myocardial infarction, myocarditis, cardiomyopathy, arrhythmia, myocardial ischemia, myocardial infarction, cerebrovascular disorders
Rarely hypokinesis of the ventricular wall, thromboembolism, heart failure, phlebitis, thrombophlebitis, pulmonary embolism
From the urinary system
Very often, oliguria, an increase in urea and creatinine in the serum -
Often hematuria of oliguria, an increase in urea and creatinine in the serum
Infrequent renal failure of hematuria, renal insufficiency
From the respiratory system
Very often shortness of breath, cough dyspnoea, cough
Often, pulmonary edema, cyanosis, hypoxia, respiratory infections, pleurisy -
Infrequent nasal bleeding infectious respiratory disease
Rarely, respiratory distress syndrome, pulmonary edema, effusion in the pleural cavity
From the digestive system
Very often nausea, vomiting, diarrhea, anorexia nausea, vomiting, diarrhea, anorexia, stomatitis
Often, dysphagia, dyspepsia, constipation, gastrointestinal bleeding, hyperbilirubinemia, increased activity of hepatic transaminases, AFB constipation, gastrointestinal bleeding, increased activity of hepatic transaminases, alkaline phosphatase and lactate dehydrogenase
Infrequently - cheilitis, gastritis, hyperbilirubinemia
Rarely gastritis, cholecystitis, exacerbation of Crohn's disease pancreatitis, intestinal obstruction
From the nervous system
Very often anxiety, confusion, drowsiness, dizziness, dizziness
Often, a violation of mental status, including agitation, paresthesia, syncope, depression, hallucinations, a violation of mental status, including irritability, anxiety, confusion, drowsiness, central and peripheral motor disorders, paresthesia, neuropathies, insomnia
Infrequent central and peripheral motor disorders, paralysis of excitation, convulsions, hallucinations
Rarely convulsions, lethargy, coma, damage to cortical structures -
From the skin and mucous membranes
Very often erythema / rash, itching, peeling of the skin of the erythema / rash
Often conjunctivitis, inflammation of the mucous membranes, alopecia, nasal crust peeling and itching of the skin, increased sweating
Infrequently vitiligo alopecia, inflammation of the mucous membranes
Rarely - conjunctivitis
On the part of the hematopoiesis system
In the course of therapy, most patients experience lymphocytopenia and eosinophilia, followed by compensatory lymphocytosis 24-48 hours after treatment. The above changes are not considered a side effect and can be attributed to manifestations of the antitumor mechanism of Proleukin.
Very often anemia, thrombocytopenia -
Often, leukopenia, clotting disorders, anemia, thrombocytopenia, leukopenia
Infrequent bleeding bleeding
Very often - erythema / rash, pain, inflammation at the injection site
Often - compaction at the injection site
Rarely, necrosis at the injection site
Change in laboratory indicators
Often hyperglycemia, hypocalcemia, hyperkalemia, hyperglycemia
Infrequently, the hypo- or hyperthyroid condition is hypo- or hyperthyroid, hypo- or hypercalcemia, hyperkalemia
Very often, weight gain, swelling, fever, chills, malaise, weakness, headache fever, chills, malaise, headache, weight loss
Often pain, arthralgia, myalgia, ascites arthralgia, overweight, swelling, dehydration, myalgia, hypothermia
Infrequent - myasthenia gravis, hypersensitivity reactions (including Quincke's edema), loss of taste
Rarely hypersensitivity reactions, anaphylaxis, diabetes mellitus anaphylaxis
Heart rhythm disturbances (supraventricular and ventricular arrhythmia), stress angina, myocardial infarction, respiratory failure, gastrointestinal bleeding or ischemia, renal failure, edema and mental status disorders may be associated with a syndrome of increased vascular permeability.
Against the background of simultaneous admission with interferon-alpha, the following undesirable effects rarely occur: sickle-shaped IgA glomerulonephritis, mycenoid gravis oculobulbar, inflammatory arthritis, thyroiditis, bullous pemphigoid, rhabdomyolysis and Stevens-Johnson syndrome.
Bacterial infections or weighting of their course, including septicemia, bacterial endocarditis, septic thrombophlebitis, peritonitis and pneumonia, occur more frequently on the background of intravenous administration.
- the status of patients on the ECOG scale * ? 2;
- the status of patients on the ECOG scale * ? 1 and the presence of metastases in more than one organ, and also less than 24 months after the initial diagnosis of the primary tumor;
- decompensated diseases of the cardiovascular system, incl. in the anamnesis (it is necessary to carry out a stress test);
- acute infectious diseases requiring antibiotic therapy;
- respiratory failure (PaO 2 <60 mmHg at rest);
- the presence of metastatic foci in the central nervous system or epileptic seizures in the anamnesis (except for patients with positive dynamics in the treatment of metastatic foci in the brain (negative results of computed tomography, stable neurological status);
- the period of breastfeeding (safety is not defined);
- Children's age (safety and efficacy not determined);
- Hypersensitivity to the components of the drug.
* - ECOG (Oncological Group of the Eastern Commonwealth): 0 = normal activity of the patient; 1 = patient has ambulatory symptoms; 2 = the patient spends less than 50% of his time in bed; 3 = the patient spends more than 50% of his time in bed.
Caution should be given to the drug with oppression of bone marrow hematopoiesis (leukopenia <4000 / ОјL, thrombocytopenia <100000 / ОјL, anemia (hematocrit <30%), elevated serum bilirubin and creatinine, allo-transplantation of organs in anamnesis, concomitant corticosteroid therapy, autoimmune diseases .
PREGNANCY AND LACTATION
The safety of the drug during pregnancy and during breastfeeding has not been established, therefore, Proleukin should not be prescribed during these periods.
Men and women of childbearing age during Proleukin therapy and within 3 months after therapy should use reliable methods of contraception.
APPLICATION FOR FUNCTIONS OF THE LIVER
The use of proleukin is accompanied by an increase in urea and creatinine in the blood serum. Therefore, the condition of patients with renal insufficiency should be carefully monitored.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
The use of Proleukin is accompanied by a reversible increase in hepatic transaminase activity, an increase in bilirubin, in the blood serum. Therefore, the condition of patients with hepatic impairment should be closely monitored.
APPLICATION FOR CHILDREN
In children, the safety and efficacy of Proleukin has not been fully established.
APPLICATION IN ELDERLY PATIENTS
The elderly patients are more likely to develop side effects of Proleukin, so caution should be exercised when prescribing this type of patient.
Therapy with Proleukin should be carried out only under the supervision of a physician of relevant qualifications who has experience in the use of antitumor drugs.
With / in the use of the drug is recommended hospitalization of the patient in a specialized hospital, which has an intensive care unit, for the purpose of monitoring clinical and laboratory indicators. The drug can be administered by qualified medical personnel on an outpatient basis.
If there are serious side effects, you need to change the dosing regimen. It should be noted that serious or life-threatening adverse reactions, as a rule, but not in all cases, disappear after a 1-2-day interruption of Proleukin therapy. The decision to resume therapy with the drug is made taking into account the severity and nature of the resulting toxic reactions.
The use of Proleukin is accompanied by a reversible increase in hepatic transaminase activity, an increase in bilirubin, urea and creatinine in the blood serum.Therefore, the condition of patients with renal or hepatic insufficiency should be closely monitored.
Proleukin affects the renal and hepatic metabolism, as well as the excretion of concomitant medications. Care should be taken when prescribing other drugs that can have a nephro- or hepatotoxic effect.
One of the manifestations of the adverse effect of the drug is the syndrome of increased vascular permeability, characterized by a decrease in the vascular tone, the release of plasma and fluid proteins into the extravascular space. It should be borne in mind that the incidence and severity of the course of this complication is higher with IV administration of the drug compared with SC injections.
The syndrome of increased vascular permeability is accompanied by a decrease in blood pressure and a decrease in organ perfusion. There is a report of a lethal outcome. The syndrome of increased vascular permeability can develop in the next hours after the beginning of therapy with Proleukin. In some patients, it is possible to resolve arterial hypotension without appropriate treatment. Under other conditions, IV infusion solutions, albumin, and in some cases - vasopressor therapy (dopamine) in low doses are shown. If the treatment is ineffective, therapy should be stopped by Proleukin.
Before the start of infusion therapy, one should evaluate the possibility of increasing the volume of intravascular fluid due to the risk of developing secondary pulmonary edema against a background of increased capillary permeability.
Regular monitoring of the water balance and electrolyte composition of the blood of each patient is necessary, since the use of Proleukin may be the cause of the development of renal insufficiency with the phenomena of oliguria.
Proleukin stimulates secretory processes in the serous membranes, contributing to an increase in the amount of effusion in the serous cavities. Therefore, before the beginning of Proleukin therapy, it is necessary to take measures to prevent conditions accompanied by an increase in the amount of effusion in the serous cavities, especially that localization, an increase in the amount of effusion in which can lead to insufficiency of vital organs (for example, effusion into the pericardial cavity).
Assessment of the functional state of the lungs is mandatory in patients with wheezing or high respiratory rate, as well as with complaints of dyspnea. Kupirovanie symptoms of respiratory failure may require the use of respiratory support with intubation of the trachea. Such cases are noted only in patients on background / in the introduction of the drug.
In the process of Proleukin therapy, patients may experience variations in mental status, manifested by irritability, confusion, or depression. These changes are reversible, but may persist for several days after discontinuation of the drug. PROLEUKIN able to change the patient's response to psychotropic drugs.
With the development of lethargy or drowsiness should discontinue the use of Proleukin, since continued therapy can trigger the development of a deep coma.
PROLEUKIN may increase the severity of clinical symptoms in patients with diagnosed or untreated metastatic disease in the CNS. Therefore, before starting therapy Proleukin all patients are advised to conduct a full diagnostic test to detect metastases in the central nervous system and the appointment of adequate treatment.
Proleukin heavier for autoimmune diseases, leading to complications, life-threatening. Because not all patients associated with interleukin-2 autoimmune phenomena have been marked signs of previous autoimmune disorders should be carefully monitored thyroid function or other potentially dangerous in terms of the development of autoimmune diseases. A number of patients with Crohn's disease exacerbation observed process in the background of Proleukin, require surgery.
Should be considered. that Proleukin therapy should be postponed until full recovery of existing bacterial infections. Toxic effects during treatment with Proleukin can be triggered by an existing infectious process.
Application PROLEUKIN may lead to the spread or worsening of bacterial infection, including septicemia, bacterial endocarditis, septic thrombophlebitis, peritonitis, pneumonia.
These complications occur more frequently in the background I / O administration. Microorganisms causing infectious complications, in most cases, are Staphylococcus aureus and Staphylococcus epidermidis, and only in some cases, Escherichia coli.
The use of Proleukin can cause anemia and thrombocytopenia. Therefore, periodic monitoring of hematological parameters in all patients receiving the drug should be carried out.
In addition to routine tests in patients with renal cell carcinoma PROLEUKIN before therapy and then at regular intervals it is recommended to perform the following studies: standard hematology study (differential count including the number of blood cells); biochemical blood analysis (including analysis of electrolytes, renal and liver function tests); X-ray examination of the chest.
As a complement to a complex examination of the patient before treatment is recommended to remove an electrocardiogram (ECG) and conduct a stress test (if indicated), to evaluate the physical condition of the patient's vital signs, objectively assess the condition of the coronary vessels, as well as to carry out pulmonary function tests with the determination of the gas composition arterial blood for patients who smoke or have a history of respiratory disease.
P / drug administration is often accompanied by reactions at the site of injection, until the development of necrosis. This effect can be reduced by changing the injection place.
Effects on ability to control mechanisms and drive vehicles
In the period of treatment should refrain from activities potentially hazardous activities that require high concentration and speed of psychomotor reactions (including driving vehicles and working with machinery and devices).
Symptoms may be increased manifestations of the described side effects. All undesirable effects are reversible after discontinuation of the drug.
Treatment: while maintaining the clinical symptoms of an overdose symptomatic treatment is shown.
Simultaneous administration of agents with neurotoxic, hepatotoxic, nephrotoxic, myelotoxic or cardiotoxic can lead to increased toxic effect of PROLEUKIN on these organs and systems.
With simultaneous application of corticosteroids may reduce PROLEUKIN activity.
Antihypertensive drugs, including beta-blockers increase the hypotensive effects of Proleukin.
The use of contrast media at the end of Proleukin therapy course can lead to a resumption of toxicity noted in the application of the drug. Most often such conditions are observed within 2 weeks after the last dose of the drug, however, the possibility of development persist for several months following termination of therapy.
In patients receiving high dose combination regimens PROLEUKIN and antitumor drugs (in particular dacarbazine, cisplatin, tamoxifen and interferon alpha) had hypersensitivity reactions.
When the joint application PROLEUKIN (as in / infusion) and interferon-alpha may increase the risk of serious rhabdomyolysis and myocardial injury, including myocardial infarction, myocarditis and ventricular hypokinesia.
When the joint application PROLEUKIN and interferon alpha may increase or manifestation of autoimmune and inflammatory diseases.
Violation of the solution preparation procedures and breeding can lead to a decrease biological activity of the drug and / or formation of biologically inactive protein.During cooking applications bacteriostatic water solution should be avoided for injection or 0.9% sodium chloride solution (these solutions promote aggregation substance).
Proleukin should not be mixed with other drugs.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
List A. The preparation should be stored in reach of children at a temperature of from 2 В° to 8 В° C; Do not freeze! Shelf life - 24 months.
The prepared solution is stable for 48 hours when stored in the refrigerator and at room temperature (2 В° to 30 В° C).
Due to the fact that the product contains no preservatives, the solution is recommended for use immediately after preparation.