Adriablastin instant - instructions for use, dose, side effects, contraindications

The cytotoxic effect of doxorubicin on malignant cells and its toxic effects on various organs is probably due to the intercalation of nucleotide bases and the ability of doxorubicin to bind to the lipids of the cell membrane. Intercalation inhibits the replication of nucleotides and the activity of DNA and RNA polymerases.The interaction of doxorubicin with topoisomerase II with the formation of DNA-cleavable complexes is considered to be an important mechanism for the cytotoxic effect of doxorubicin.

Pharmacokinetics:

Distribution

The initial half-life is about 5 minutes and indicates a rapid distribution of doxorubicin in tissues; The terminal half-life is 20-48 hours. The association of doxorubicin and its main metabolite, doxorubicinol, with plasma proteins is 74-76% and does not depend on the concentration of doxorubicin in blood plasma (up to 1.1 μg / ml).

Doxorubicin does not penetrate the blood-brain barrier.

Metabolism

Enzymatic reduction in position 7 and splitting of daunosamine sugar leads to the formation of aglycons, which is also accompanied by the formation of free radicals. The latter may cause cardiotoxic effects of doxorubicin. The half-life of doxorubicinol is similar to that of doxorubicin. The ratio between the area under the concentration-time curve (AUC) of doxorubicinol and doxorubicin AUC in comparison with doxorubicin is 0.4-0.6.

Excretion

The clearance of doxorubicin is carried out, mainly, by metabolism and excretion with bile. Approximately 40% of the dose is excreted with bile within 5 days. Only 5 to 12% of doxorubicin and its metabolites are found in the urine over the same period of time. Within 7 days in the form of doxorubicinol, less than 3% of the dose is excreted through the kidneys. Systemic clearance of doxorubicin is significantly reduced in obese women whose body weight is more than 130% of the optimal.

Pharmacokinetics in special groups

Children

The clearance of doxorubicin in children older than 2 years exceeds that of adults. Clearance in children under 2 years of age is close to the values of clearance in adults.

Elderly

Dose adjustment with age is not required.

Floor

The average clearance of doxorubicin in men is significantly higher than that of women. However, the terminal half-life of doxorubicin in men is longer than in women (54 and 35 hours, respectively).

Race

The influence of the race on the pharmacokinetics of doxorubicin has not been studied.

Impaired liver function

In patients with impaired hepatic function, the clearance of doxorubicin and doxorubicinol decreases.

Impaired renal function

The effect of kidney function on the pharmacokinetics of doxorubicin has not been studied.

Indications:Acute lymphoblastic leukemia, acute myeloblastic leukemia, chronic leukemia, lymphogranulomatosis and non-Hodgkin's lymphoma, multiple myeloma, osteogenic sarcoma, Ewing's sarcoma, soft tissue sarcoma, neuroblastoma, rhabdomyosarcoma, Wilms tumor, breast cancer, endometrial cancer, ovarian cancer, germ cell tumors, cancer prostate cancer, transitional cell cancer of the bladder, lung cancer, stomach cancer, primary hepatocellular cancer, head and neck cancer, thyroid cancer.

Contraindications:

Hypersensitivity to doxorubicin or other components of the drug, as well as to other anthracyclines and anthracenedions.

Pregnancy and lactation.

Intravenous administration is contraindicated in persistent myelosuppression, severe liver function abnormalities, severe heart failure and severe arrhythmias, recent myocardial infarction, prior therapy with doxorubicin, daunorubicin, epirubicin, idarubicin, and / or other anthracyclines and anthracenedions at the maximum total doses.

Introduction to the bladder is contraindicated in infections of the urinary tract, inflammation of the bladder, hematuria.

Carefully:Patients with risk factors for cardiotoxicity; patients who received previously intensive chemotherapy, children, elderly patients, patients with obesity, gout, urate nephrolithiasis (including history), heart disease (cardiotoxicity may occur at lower total doses), patients with tumor infiltration of the bone marrow (it may be necessary to reduce starting doses or increase the intervals between doses), oppression of bone marrow hematopoiesis; use in combination antitumor therapy, as well as in combination with radiation or other antitumor therapy; patients with impaired liver function.

Pregnancy and lactation:

The use of the drug during pregnancy and during breastfeeding is contraindicated.

Doxorubicin is excreted in breast milk. Stop breastfeeding during doxorubicin therapy.

Dosing and Administration:

Intravenous, intravesical or intra-arterial.

The reconstituted solution of the preparation is recommended to be used immediately after preparation.

Intravenous administration

As a monotherapy, the recommended standard dose per cycle for adults is 60-90 mg /m² . The total dose of the drug per cycle (every 3-4 weeks) can be administered as one-time,

and divided into several introductions: for 3 consecutive days or on the first and eighth days of the cycle.

Also, a weekly regimen of administration of the drug in a dose of 10-20 mg /m². When doxorubicin is used in combination with other antitumor drugs with similar toxicity, the recommended dose per cycle is 30-60 mg /m².

Repeated administration of the drug is possible only with the disappearance of all signs of toxicity (especially gastrointestinal and hematological). To reduce the risk of thrombosis and extravasation, it is recommended to administer adrenoblastin® rapidly through the tube of the intravenous infusion system, during the infusion of 0.9% sodium chloride solution or 5% dextrose solution. The duration of the infusion should be between 3 and 10 minutes.

The total dose of doxorubicin should not exceed 550 mg /m².

Patients who received previous radiation therapy on mediastinal region / pericardial region or taking other cardiotoxic drugs, if necessary, increasing the total doxorubicin dose to more than 450 mg / m², the drug should be administered under strict monitoring of heart function.

Impaired liver function:

if the serum bilirubin concentration is 1.2-3 mg / dL, the administered dose should be reduced by 50% of the recommended dose;
if the serum bilirubin concentration exceeds 3 mg / dl, the administered dose should be reduced by 75% of the recommended dose.

Other special patient groups It is recommended to use lower doses or increase the intervals between cycles of patients who previously received intensive chemotherapy, children, elderly patients, obese patients (if the body weight is more than 130% of the optimal, there is a decrease in systemic clearance of the drug), and also patients with tumor infiltration of the bone marrow.

Preparation of the solution

Dissolve the lyophilizate with water for injection to patients, or 0.9% solution of sodium chloride.Please note that the contents of the vial are under negative pressure. Care should be taken when piercing the bottle cap with a needle to minimize the formation of aerosol during solution reconstitution. Do not inhale the aerosol of the drug while preparing the solution.

Introduction to the bladder

Introduction to the bladder is used to treat superficial bladder tumors, as well as prevention, to reduce the likelihood of recurrence after transurethral resection. Introduction to the bladder is not indicated for the treatment of invasive tumors with sprouting into the muscular wall of the bladder. The recommended dose for instillation is 30-50 mg in 25-50 ml of 0.9% sodium chloride solution. In case of development of local toxicity (chemical cystitis), the dose should be dissolved in 50-100 ml of 0.9% sodium chloride solution. Instillations can be carried out at intervals of 1 week to 1 month.

Instillation should be performed with a catheter, and the drug should remain in the bladder for 1 -2 hours. To ensure a uniform effect of the drug on the bladder mucosa, turn from side to side.To avoid excessive dilution of the drug with urine, patients should be warned that they should refrain from taking liquid for 12 hours before instillation. At the end of instillation, the patient should empty the bladder.

Intraarterial administration.

Patients with hepatocellular carcinoma and metastases in the liver to ensure intensive local and generalized impact with a simultaneous decrease in the total toxic effect, the drug can be administered intraarterially to the main hepatic artery at a dose of 30-150 mg / m² with an interval of 3 weeks to 3 months. Higher doses should be used only in cases simultaneous

extracorporeal removal of the drug. Lower doses are suitable for administration of doxorubicin in combination with iodinated oil. Since this method is potentially dangerous and can lead to widespread necrosis of tissue, intraarterial administration should be performed only by physicians who are proficient in this technique.

Side effects:

The undesirable reactions, registered in connection with the use of doxorubicin,Listed below by category of organ systems by dictionary MedDRA and frequency of occurrence. Frequency categories are defined as follows:

Often (≥10%),

often (≥1 %,<10%),

infrequently (≥0,1%, < 1 %),

rarely (≥0,01%, <0,1%),

very rarely (<0.01%) and

unknown (can not be determined based on available data).

Table of unwanted reactions

Infectiontional and parasitic diseases

Often

Accession of secondary infections

Often	Sepsis
Benign, malignant and unspecified neoplasms (including cysts and polyps)
Unknown	Acute lymphatic leukemia, acute myelogenous leukemia
Violations of the blood and lymphatic system
Often	Leukopenia, neutropenia, anemia, thrombocytopenia
Immune system disorders
Unknown	Anaphylactic reaction
Disorders from the metabolism and nutrition
Often	Decreased appetite
Unknown	Dehydration, hyperuricemia
Disturbances from the nervous system
Unknown	Peripheral neuropathy (with intra-arterial administration of doxorubicin, usually in combination with cisplatin), convulsions, coma (in combination with cisplatin or vincristine)
Disturbances on the part of the organ of sight
Often	Conjunctivitis
Unknown	Keratitis, increased lacrimation

Heart Disease
Often	Chronic heart failure, sinus tachycardia.
Unknown	Atrioventricular blockade, tachyarrhythmia, blockade of the bundle of the foot of the Hisnus.

Vascular disorders
Infrequently	Embolism
Unknown	Shock, hemorrhage, thrombophlebitis, phlebitis, "tides" of blood to the skin of the face (with a rapid on / in the introduction)
Disorders from the gastrointestinal tract
Often	Inflammation of the mucous membrane of the gastrointestinal tract / stomatitis, diarrhea, vomiting, nausea
Often	Esophagitis, abdominal pain
Unknown	Gastrointestinal bleeding, erosive gastritis, colitis, discoloration of the mucous membrane of the oral cavity
Disturbances from the skin and subcutaneous tissues
Often	Syndrome of palmar dandruff erythrodysesthesia, alopecia

Often

Urticaria, rash, hyperpigmentation of the skin, hyperpigmentation of the nails.

Unknown

Reaction of photosensitivity hypersensitivity of irritated skin (reaction to irradiation in the anamnesis), itching, skin changes, erythema of the extremities, onycholysis.

Disorders from the kidneys and urinary tract
Unknown	Chromaturia (staining urine in red)^a
Violations of the genitals and mammary gland
Unknown	Amenorrhea, azoospermia, oligospermia
General disorders and disorders at the site of administration
Often	Fever, general weakness, chills
Often	Reaction in place of infusion
Unknown	Malaise, fatigue
Laboratory and instrumental research data
Often	Reduction of the left ventricular ejection fraction, deviation from the norm of the parameters of the electrocardiogram, deviation from the activity norm of the "hepatic" transaminases, weight gain^b
^AWithin one or two days after using the drug. ^BRegistered in patients with early breast cancer receiving adjuvant therapy based on doxorubicin (NSABP B-15 study)

With anthracycline therapy, there is a risk of developing cardiotoxicity - early (ie acute) or late (delayed). Manifestation early cardiotoxicity doxorubicin is mainly sinus tachycardia and / or anomalies on the ECG (nonspecific changes in ST-T waves). There may also be tachyarrhythmias (including ventricular extrasystole and ventricular tachycardia), bradycardia, atrioventricular blockade, and blockade of the bundle's legs.These effects are not always a prognostic factor in the development of subsequently delayed cardiotoxicity, are rarely clinically significant and usually do not require withdrawal of drug therapy. Late cardiotoxicity usually develops in the late stages of the course of therapy or within 2-3 months after its termination, however, the development of delayed side effects (several months or even years after the end of therapy) is possible.

Late cardiotoxicity is manifested by a decrease in the left ventricular ejection fraction and / or symptoms of chronic heart failure, such as dyspnea, pulmonary edema, edema, cardiomegaly and hepatomegaly, oliguria, ascites, exudative pleurisy and gallop rhythm. There may also be subacute phenomena, such as pericarditis and myocarditis. The most severe form of anthracycline-induced cardiomyopathy, which limits the cumulative dose of the drug, is a life-threatening chronic heart failure.

With the use of doxorubicin, as well as other cytotoxic agents, thrombophlebitis and thromboembolism have sometimes been observed, including pulmonary embolism (in some cases, fatal).

Local Reactions

Extravasation during intravenous infusion of doxorubicin can lead to the appearance of pain, severe tissue damage (blistering, severe cellulite), and necrosis. When the drug is injected into a small vein or when it is repeated in the same vein, the development of phlebosclerosis is possible.

Introduction to the bladder

Introduction to the bladder can lead to the appearance of symptoms of chemical cystitis (dysuria, polyuria, nocturia, painful urination, hematuria, discomfort in the bladder, necrosis of the bladder wall) and constriction of the bladder.

Viuretriereal injection

The intra-arterial administration of doxorubicin can cause ulceration of the stomach and duodenum (possibly due to reflux of the drug in the gastric artery) in addition to systemic toxicity, and narrowing of the bile ducts (drug sclerosing cholangitis), as well as widespread necrosis of perfused tissue.

Overdose:Patients with risk factors for cardiotoxicity; patients who received previously intensive chemotherapy, children, elderly patients, patients with obesity, gout, urate nephrolithiasis (incl.in a history), heart disease (cardiotoxic effect may occur at lower total doses), patients with tumor infiltration of the bone marrow (may need to reduce starting doses or increase intervals between doses), oppression of bone marrow hematopoiesis; use in combination antitumor therapy, as well as in combination with radiation or other antitumor therapy; patients with impaired liver function.

Interaction:

Doxorubicin is a substrate for the isoenzyme CYP3A4 and CYP2D6, as well as the P-glycoprotein (P-gp). Clinically significant interactions were noted with the use of inhibitors of isoenzymes CYP3A4, CYP2D6 and / or P-gp (for example, verapamil), which led to an increase in the concentration and clinical effect of doxorubicin. Inductors of the isoenzyme CYP3A4 (for example, phenobarbital, phenytoin, St. John's wort preparations) and P-gp inducers can reduce the concentration of doxorubicin.

Simultaneous use of cyclosporine and doxorubicin can lead to an increase in the AUC of both drugs. This effect may be associated with a decrease in the clearance of the unchanged drug and a decrease in the metabolism of doxorubicinol.There are suggestions that simultaneous use of cyclosporine and doxorubicin can lead to more severe and prolonged hematologic toxicity than doxorubicin alone. There are reports of the development of coma and seizures with the simultaneous use of cyclosporine and doxorubicin.

When doxorubicin is used in combination with other cytotoxic agents, additive toxicity is possible, especially with regard to the bone marrow / blood and gastrointestinal system. When doxorubicin is used in combination with other potentially cardiotoxic chemotherapeutic agents, as well as cardiovascular drugs (for example, blockers of "slow" calcium channels), heart function must be monitored. Cases of exacerbation of hemorrhagic cystitis caused by cyclophosphamide and an increase in hepatotoxicity of mercaptopurine have been described. Doxorubicin can enhance the radiation-induced toxic effect on the myocardium, mucous membranes, skin and liver. Changes in liver function caused by concomitant therapy may affect metabolism, pharmacokinetics, therapeutic efficacy, and / or toxicity of doxorubicin.

The introduction of paclitaxel to doxorubicin can lead to an increase in plasma concentrations of doxorubicin and / or its metabolites in blood plasma. This effect is minimal when doxorubicin apply to paclitaxel.

With the simultaneous use of doxorubicin and sorafenib 400 mg twice daily, both AUC (21 - 47%) and no change in this index were noted. The clinical significance of this observation is not known.

In the treatment of hyperuricemia and gout, correction of the dosage regimen of anti-gouty drugs may be required as a result of an increase in the concentration of uric acid against the background of drug treatment.

Doxorubicin should not be mixed with other drugs. Do not allow contact with alkaline solutions, as this can lead to hydrolysis of doxorubicin. Because of chemical incompatibility doxorubicin Do not mix with heparin (a precipitate forms when mixed).

Doxorubicin should not be mixed with fluorouracil (eg, in one infusion bag or injected through a single catheter), as this can lead to precipitation.If it is necessary to simultaneously use these drugs, it is recommended to flush the catheter between the injections of doxorubicin and fluorouracil.

Special instructions:Adriablastin®, a fast-dissolving drug, should be used only under the supervision of physicians experienced in the use of cytotoxic drugs. Prior to treatment, the acute toxic effects of previous cytotoxic therapy (such as stomatitis, neutropenia, thrombocytopenia, and systemic infections) should be stopped.

Before and during therapy with the drug, it is necessary to monitor the function of the heart to minimize the risk of its severe damage. To do this, the fraction of the left ventricular ejection should be regularly determined and the treatment should be stopped immediately if the first signs of a violation of the function of the heart appear. Adequate quantitative analysis of heart function (measurement of left ventricular ejection fraction) include radioisotope angiography (MUGA) and echocardiography. Before starting treatment, it is recommended to evaluate cardiac function with ECG and one of the following methods - radioisotope scanning or echocardiography, especially in patients with risk factors for increased cardiotoxicity (for example,symptomatic or asymptomatic cardiovascular disease, previous or concomitant mediastinal / pericardial radiotherapy, previous therapy with other anthracyclines or anthracendones, and concomitant therapy with drugs that reduce myocardial contractility, such as trastuzumab.
Do not use anthracyclines, including doxorubicin, concomitantly with other cardiotoxic drugs, until the patient's cardiac function has been studied. When using anthracyclines in patients who have recently been treated with other cardiotoxic drugs, especially those with a long half-life (such as trastuzumab), the risk of developing cardiotoxicity may also be increased. The half-life of trastuzumab is approximately 28-38 days, it can be present in the bloodstream for 27 weeks. In this regard, it is recommended to avoid anthracycline therapy whenever possible within 24 weeks after the abolition of trastuzumab. If anthracyclines are required before the end of this period, cardiac function should be carefully monitored.
The left ventricular ejection fraction should be measured in dynamics, especially with an increase in cumulative doses of anthracycline. It is advisable to constantly use the same method.
The risk of developing chronic heart failure is about 1-2% when using a cumulative dose of 300 mg / m², increases slowly until a total cumulative dose of 450-550 mg / m², followed by a sharp increase in risk. In this regard, the maximum cumulative dose should not exceed 550 mg / m². Heart function monitoring should be particularly severe in patients receiving high cumulative doses of the drug and in patients with risk factors for increased cardiotoxicity. However, cardiotoxicity may also develop with lower cumulative doses of doxorubicin, regardless of the presence of risk factors.
Children and adolescents are at increased risk of developing late cardiotoxicity of doxorubicin. In women, this risk may be higher than that of men. It is recommended to periodically check the state of the cardiovascular system after the end of therapy.
The toxicity of doxorubicin and other anthracyclines or anthracendones is probably additive.
Like other cytotoxic agents, doxorubicin can cause myelosuppression.A general blood test, including the leukocyte formula, should be performed before and during each treatment cycle with doxorubicin. Dose-dependent reversible leukopenia and / or granulocytopenia (neutropenia) are the main manifestation of hematological toxicity of doxorubicin and the most frequent sign of acute toxicity, which limits the dose of the drug. Leukopenia and neutropenia in most cases reach a maximum severity 10-14 days after drug administration, with the number of white blood cells / neutrophils returning to normal by the 21st day. Thrombocytopenia and anemia are also possible. Clinical complications of severe myelosuppression include fever, infection, sepsis / septicemia, septic shock, bleeding, tissue hypoxia, or death.
In patients receiving anthracyclines, including doxorubicin, cases of secondary leukemia with or without preleukemic phase are described. Secondary leukemia is more common in the use of these drugs in combination with other
antitumor agents that cause DNA damage, radiation therapy, as well as in patients who received previously intensive cytotoxic therapy or anthracyclines in high doses. Secondary leukemia can have a latent period of 1-3 years.
Mucositis / stomatitis usually develops soon after administration of the drug and in severe cases for several days can lead to ulceration of the oral mucosa. In most patients, these undesirable effects are stopped by the third week of therapy.
Before and during drug therapy in patients, it is necessary to monitor the performance of the liver (the concentration of total bilirubin in the blood serum). In patients with increased bilirubin concentration, the clearance of the drug may slow down and general toxicity may be increased.
When the first signs of extravasation doxorubicin (burning or soreness at the injection site) infusion should immediately stop. Accurate compliance with the instructions for use of the drug can minimize the risk of phlebitis / thrombophlebitis at the injection site.
With intravesical application of the drug, special attention should be given to conditions that create barriers to catheterization (for example, urethral obstruction caused by massive tumors of the bladder).
When doxorubicin is used, hyperuricemia can occur due to the rapid lysis of tumor cells,patients during therapy are recommended to determine the concentration of uric acid, potassium, calcium and creatinine in the blood. Such activities as hydration, alkalization and prevention with allopurinol to prevent hyperuricemia minimize the risk of complications associated with tumor lysis syndrome.
In patients with impaired immunity against the background of cytotoxic therapy (including doxorubicin), the use of live or weakened vaccines can lead to serious infections, in some cases fatal. The use of live vaccines should be avoided in patients receiving doxorubicin. Killed or inactivated vaccines are acceptable, however, the response to the administration of these vaccines may be weakened.
Among women doxorubicin can cause infertility and amenorrhea. Ovulation and menstruation usually recover after cessation of treatment, although early menopause may occur.
In men doxorubicin has a mutagenic effect and can cause damage to chromosomes of spermatozoa. Oligospermia or azoospermia can be irreversible, although in some cases there has been a recovery in the number of spermatozoa, sometimes several years after cessation of treatment.
Men and women receiving doxorubicin therapy should use reliable contraceptive methods.
When working with the drug must comply with the rules for handling cytotoxic substances. It is recommended to treat the contaminated surface with a dilute solution of sodium hypochlorite (containing 1 % chlorine). If the product gets on the skin, immediately flush skin with soap and water or sodium bicarbonate solution, do not use a brush to damage the skin; if the product has got into the eyes - pull eyelids and rinse the eye (eyes) with plenty of water for at least 15 minutes, then you need to see a doctor.

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

With doxorubicin, patients may develop nausea, vomiting, drowsiness, and other symptoms that affect the general condition. In connection with this, with the appearance of the above-mentioned side effects from the management of vehicles and mechanisms that require an increased concentration of attention and speed of psychomotor reactions, it is recommended to abstain during treatment.

Form release / dosage:

Lyophilizate for the preparation of solution for intravascular and intravesical administration of 10 mg and 50 mg.

Packaging:For 10 mg doxorubicin hydrochloride in a colorless glass vial type III, sealed with a rubber stopper and sealed with an aluminum cap with an insert in the form of a polypropylene disk; solvent (water for injection): 5 ml each in a colorless glass ampule of type I.

1 bottle with lyophilizate and 1 ampoule with a solvent, along with instructions for use, are placed in a cardboard box.

50 mg of doxorubicin hydrochloride in a colorless glass vial of type I, sealed with a rubber stopper and sealed with an aluminum cap with an insert in the form of a polypropylene disk.

1 bottle with lyophilizate together with instructions for use is placed in a cardboard box.

Storage conditions:At temperatures from +15⁰From to +25⁰FROM.

Keep out of the reach of children.

Shelf life:Lyophilizate - 4 years.

Solvent - 5 years.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:П N013798 / 01

Date of registration:19.11.2007

Expiration Date:Unlimited

The owner of the registration certificate: Pfizer Inc. Pfizer Inc. USA

Manufacturer: & nbsp

PFIZER, Inc. USA

Representation: & nbspPfizer H. Si. Pi. CorporationPfizer H. Si. Pi. Corporation

Information update date: & nbsp04.02.2017

Illustrated instructions

Instructions

Adriablastin® instantly soluble (Adriblastin® Rapid dissolution)