Adriblastin fast soluble, lyophilizate 10 mg

Pharmacodynamics

Doxorubicin is a cytotoxic anthracycline antibiotic isolated from Streptomyces peucetius var. caesius culture.

The cytotoxic effects of doxorubicin against malignant cells and its toxic effects on various organs are probably due to intercalation of nucleotide bases and the ability of doxorubicin to bind to cell membrane lipids. Intercalation inhibits nucleotide replication and the activity of DNA and RNA polymerases. Interaction of doxorubicin with topoisomerase II to form DNA cleavable complexes is considered an important mechanism of cytotoxic action of doxorubicin.

Pharmacokinetics

Distribution

The initial T_1/2 is about 5 minutes and indicates rapid distribution of doxorubicin in tissues; terminal T_1/2 is 20 to 48 h. The binding of doxorubicin and its main metabolite, doxorubicinol, to plasma proteins is 74-76% and is independent of the plasma concentration of doxorubicin (up to 1.1 µg/mL). Doxorubicin does not penetrate through the blood-brain barrier.

Metabolism

The enzymatic reduction at position 7 and cleavage of daunosamine sugar leads to the formation of aglycones, which is also accompanied by the formation of free radicals. The latter can cause the cardiotoxic effects of doxorubicin. The T_1/2 of doxorubicinol is similar to that of doxorubicin.

The ratio between the AUC of doxorubicinol and the AUC of doxorubicin compared to doxorubicin is 0.4-0.6.

The clearance of doxorubicin is mainly by metabolism and excretion with the bile. Approximately 40% of the dose is excreted with bile within 5 days. Only 5-12% of doxorubicin and its metabolites are detected in the urine during the same time period. Within 7 days, less than 3% of the dose is excreted in the urine as doxorubicinol.

The systemic clearance of doxorubicin is significantly reduced in obese women whose body weight is more than 130% of optimal.

Pharmacokinetics in special groups

Children

The clearance of doxorubicin in children older than 2 years is greater than that of adults. Clearance in children younger than 2 years is close to the clearance values in adults.

Elderly

There is no need for age-appropriate dose adjustment.

Gender

The average clearance of doxorubicin is significantly higher in men than in women. However, the terminal T_1/2 of doxorubicin in men is longer compared to women (54 and 35 h, respectively).

Race

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

Hepatic impairment

The clearance of doxorubicin and doxorubicinol is decreased in patients with hepatic impairment.

Renal dysfunction

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

Indications

Active ingredient

Composition

1 vial contains:

Active ingredients:

Doxorubicin hydrochloride 10 mg.

Solvent:

d/i water – 5 ml.

How to take, the dosage

Intravenously, intravesically or intra-arterially.

Adriblastin® rapidly soluble may be used both in monotherapy and in combination with other antitumor drugs, in connection with which the choice of doses and mode of administration of the drug should be guided by the data of special literature. Reconstituted solution of the drug is recommended to be used immediately after preparation.

Intravenous administration

As monotherapy, the recommended standard dose per cycle for adults is 60-90 mg/m2. The total dose of the drug per cycle (every 3 to 4 weeks) can be administered either at one time or divided into several injections, over 3 consecutive days or on the first and eighth days of the cycle. A weekly regimen of 10-20 mg/m2 is also used. When doxorubicin is used in combination with other anticancer drugs with similar toxicity, the recommended dose per cycle is 30-60 mg/m2.

Repeated administration of the drug is possible only when all signs of toxicity (especially gastrointestinal and hematological) have disappeared.

In order to reduce the risk of thrombosis and extravasation it is recommended to administer Adriblastin® rapidly soluble through a tube of intravenous infusion system, during infusion of 0.9% sodium chloride solution or 5% dextrose solution. The duration of the infusion should be from 3 to 10 minutes.

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

Patients who have previously received radiotherapy to the mediastinal/pericardial area or who have taken other cardiotoxic drugs should have their total dose of doxorubicin greater than 450 mg/m2 administered under close monitoring of cardiac function.

Liver function impairment:

Other special patient groups: Lower doses or longer intervals are recommended for patients who have previously received intensive chemotherapy, children, elderly patients, obese patients (if body weight is greater than 130% of optimal, decreased systemic clearance of the drug is noted), and patients with tumor bone marrow infiltration.

Injection into the bladder

Injection into the bladder is used to treat superficial bladder tumors and as prophylaxis to reduce the likelihood of recurrence after transurethral resection. Injection into the bladder is not appropriate for the treatment of invasive tumors with penetration 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 carried out using a catheter and the drug should remain in the bladder for 1-2 hours. The patient should turn from side to side during instillation to ensure even exposure of the drug to the bladder mucosa. To avoid excessive dilution of the drug with urine, patients should be warned to refrain from taking liquids for 12 hours before instillation. At the end of the instillation, the patient should empty the bladder.

Intra-arterial administration

Patients with hepatocellular cancer may have the drug administered intra-arterially into the main hepatic artery at a dose of 30-150 mg/m2 at intervals of 3 weeks to 3 months to ensure intense local action while reducing overall toxicity. Higher doses should be used only in cases of concomitant extracorporeal excretion of the drug. Lower doses are appropriate for administration of doxorubicin in combination with iodinated oil. Because this method is potentially dangerous and may lead to widespread tissue necrosis, intra-arterial administration should only be performed by physicians who are proficient in this technique.

Interaction

When using doxorubicin in combination with other cytotoxic agents, additive toxicity is possible, especially in relation to the bone marrow/blood system and the gastrointestinal tract. When using doxorubicin in combination with other potentially cardiotoxic chemotherapeutic agents as well as cardiovascular drugs (e.g., calcium channel blockers), heart function should be monitored. Cases of exacerbation of hemorrhagic cystitis caused by cyclophosphamide and increased hepatotoxicity of 6-mercaptopurine have been described. Doxorubicin may exacerbate radiation-induced toxic effects on the myocardium, mucous membranes, skin, and liver. Changes in liver function caused by concomitant therapy may affect the metabolism, pharmacokinetics, therapeutic efficacy and/or toxicity of doxorubicin.

The administration of paclitaxel prior to doxorubicin may result in increased plasma concentrations of doxorubicin and/or its metabolites. This effect is minimal when doxorubicin is administered before paclitaxel.

Doxorubicin should not be mixed with other drugs. Contact with alkaline solutions should not be allowed, as this can lead to hydrolysis of doxorubicin. Because of chemical incompatibility, doxorubicin should not be mixed with heparin (a precipitate will form when mixed).

Special Instructions

Adriblastin® fast-acting should only be used under the supervision of physicians experienced in the use of cytotoxic drugs.

The patient must recover from the acute toxic effects of previous cytotoxic therapy (such as stomatitis, neutropenia, thrombocytopenia and systemic infections) before starting treatment.

Before and during therapy with the drug, heart function should be monitored to minimize the risk of severe heart damage. For this purpose, the left ventricular ejection fraction should be determined regularly and treatment should be stopped immediately if the first signs of worsening of heart function appear. Adequate methods of quantifying cardiac function (measuring left ventricular ejection fraction) include radioisotopic angiography (MUGA) and echocardiography. Before treatment initiation, it is recommended to assess cardiac function using ECG and one of the following methods – radioisotope scanning or echocardiography, especially in patients with risk factors for increased cardiotoxicity (for example, obvious or latent cardiovascular disease, previous or concomitant radiotherapy in the mediastinum/pericardium, previous therapy with other anthracyclines or anthracenedion and concomitant therapy with drugs that reduce heart contractility). Left ventricular ejection fraction should be measured dynamically, especially with increasing cumulative doses of anthracycline. It is advisable to use the same method at all times.

The risk of congestive heart failure, which is about 1-2% at a cumulative dose of 300 mg/m2, increases slowly until a total cumulative dose of 450-550 mg/m2 is reached, after which there is a sharp increase in risk. Therefore, the maximum cumulative dose should not exceed 550 mg/m2.

Cardiac function monitoring should be particularly stringent in patients receiving high cumulative doses of the drug and in patients with risk factors for increased cardiotoxicity. However, cardiotoxicity can also develop with lower cumulative doses of doxorubicin regardless of the presence of risk factors.

Children and adolescents have an increased risk of developing late cardiotoxicity with doxorubicin. This risk may be higher in women than in men.

The toxicity of doxorubicin and other anthracyclines or anthracenedion is probably additive.

Like other cytotoxic agents, doxorubicin can cause myelosuppression. General blood counts, including leukocyte counts, should be performed before and during each cycle of doxorubicin therapy. Dose-dependent reversible leukopenia and/or granulocytopenia (neutropenia) are the main manifestation of hematologic toxicity of doxorubicin and the most frequent sign of acute dose-limiting toxicity of the drug. Leukopenia and neutropenia in most cases reach maximum severity 10-14 days after drug administration, with leukocyte/neutrophil counts returning to normal by day 21. Thrombocytopenia and anemia may also develop. Clinical complications of severe myelosuppression include fever, infection, sepsis/septicemia, septic shock, bleeding, tissue hypoxia or death.

In patients treated with anthracyclines, including doxorubicin, cases of secondary leukemia with or without a preleukemic phase have been described. Secondary leukemia is more common when these drugs are used in combination with other antitumor agents that cause DNA damage, radiation therapy, and in patients who previously received intensive cytotoxic therapy or high-dose anthracyclines. Secondary leukemia may have a latency period of 1-3 years.

Mucositis/stomatitis usually develops soon after drug administration and, in severe cases, can lead to mucosal ulceration within days. Most patients recover from these adverse events by the third week of therapy.

Before and during therapy with the drug, liver function parameters (total serum bilirubin level) should be monitored in patients. In patients with elevated bilirubin level the drug clearance slowdown and increase of general toxicity are possible. If the first signs of doxorubicin extravasation (burning or soreness at the injection site) appear, the infusion should be stopped immediately, and then the infusion should be resumed in another vein until the full dose is administered; locally, measures to eliminate the effects of extravasation should be taken. The use of ice packs is advisable.

Precise adherence to the instructions for use of the drug minimizes the risk of phlebitis/thrombophlebitis at the injection site.

In intravesical administration of the drug, special attention should be paid to conditions that create obstacles to catheterization (e.g., urethral obstruction due to massive bladder tumors).

Hyperuricemia may occur with doxorubicin due to rapid lysis of tumor cells, so patients should have their uric acid, potassium, calcium and creatinine levels determined during therapy. Interventions such as hydration, alkalinization, and prophylaxis with allopurinol to prevent hyperuricemia can minimize the risk of complications associated with tumor lysis syndrome.

In women, doxorubicin can cause infertility and amenorrhea. Ovulation and menstruation usually recover after stopping treatment, although early menopause is possible.

In men, doxorubicin has mutagenic effects and can cause damage to sperm chromosomes. Oligospermia or azoospermia may be irreversible, although in some cases there has been a recovery in sperm count, sometimes several years after stopping treatment.

Men and women treated with Adriblastin® rapidly soluble should use reliable contraception.

The rules for handling cytotoxic substances must be followed when handling the drug. It is recommended to treat surfaces contaminated with the drug with diluted solution of sodium hypochlorite (containing 1% chlorine). If the drug gets on the skin – immediately rinse the skin with soap and water or sodium bicarbonate solution; if it got into the eyes – pull back the eyelids and rinse the eye (eyes) with plenty of water for at least 15 minutes.

Contraindications

Injection is contraindicated if:

Injection into the bladder is contraindicated when:

With caution: Patients with risk factors for cardiotoxicity; patients previously receiving intensive chemotherapy, children, elderly patients, obese patients, patients with tumor infiltration of bone marrow (lower starting doses or longer intervals between doses may be required); use as part of combination antitumor therapy and in combination with radiation or other antitumor therapy; patients with impaired liver function.

Side effects

Blood system disorders: leukopenia, neutropenia, anemia, thrombocytopenia.

Cardiovascular system: sinus tachycardia, tachyarrhythmias, atrio-ventricular block, Gis bundle branch block, congestive heart failure, hemorrhage, flushes, phlebitis, thrombophlebitis, thromboembolism, shock, ECG changes, asymptomatic reduction of left ventricular ejection fraction.

In therapy with anthracyclines, there is a risk of early (i.e., acute) or late (delayed) cardiotoxicity.

The manifestation of early cardiotoxicity of doxorubicin is mainly sinus tachycardia and/or abnormal ECG (non-specific ST-T wave changes). Tachyarrhythmias (including ventricular extrasystole and ventricular tachycardia), bradycardia, atrioventricular block, and Gis bundle branch block may also be noted. These effects are not always predictive of later delayed cardiotoxicity, are rarely clinically significant, and usually do not require withdrawal of therapy with the drug.

Late cardiotoxicity usually develops late in the course of therapy or within 2-3 months after discontinuation, but more delayed side effects are possible (several months or even years after therapy ends). Late cardiotoxicity is manifested by decreased left ventricular ejection fraction and/or symptoms of congestive heart failure, such as dyspnea, pulmonary edema, edema, cardiomegaly and hepatomegaly, oliguria, ascites, exudative pleurisy and galloping rhythm. Subacute phenomena such as pericarditis and myocarditis may also be noted. The most severe form of anthracycline-induced cardiomyopathy, which limits the cumulative dose of the drug, is life-threatening congestive heart failure. When using doxorubicin, as well as other cytotoxic agents, the development of thrombophlebitis and thromboembolism, including pulmonary embolism (in some cases with fatal outcome) has sometimes been observed.

Digestive system disorders: anorexia, nausea/vomiting, mucositis/stomatitis, hyperpigmentation of the oral mucosa, esophagitis, abdominal pain, gastric erosions, gastrointestinal bleeding, diarrhea, colitis, dehydration, changes in transaminase levels.

Urinary system disorders: urine staining red for 1-2 days after drug administration, hyperuricemia.

An organ of vision: conjunctivitis/keratitis, lacrimation.

Skin and skin appendages: alopecia, rash/itching, skin changes, skin and nail hyperpigmentation, photosensitivity, hypersensitivity of irritated skin (acamnestic reaction to irradiation), urticaria, erythema of the extremities, palmar and plantar erythrodisesthesia.

Reproductive system disorders: amenorrhea, oligospermia, azoospermia.

Local reactions: extravasation during intravenous infusion of doxorubicin may lead to pain, severe tissue damage (blistering, marked inflammation of the subcutaneous tissue) and necrosis. If the drug is injected into a small vein or if it is repeatedly injected into the same vein, phlebosclerosis may develop.

Others: malaise/sthenia, fever, chills, anaphylaxis, development of acute lympholeukemia or acute myeloleukemia, accession of secondary infections, sepsis/septicemia, weight gain.

Injection into the bladder may cause symptoms of chemical cystitis (dysuria, polyuria, nycturia, painful urination, hematuria, bladder discomfort, necrosis of the bladder wall) and bladder constriction.

Intra-arterial administration of doxorubicin may cause, in addition to systemic toxicity, gastric and duodenal ulceration (possibly due to reflux of the drug into the gastric artery) and narrowing of the biliary tract (drug-induced sclerosing cholangitis), as well as widespread necrosis of perfused tissue.

Overdose

Acute overdose of doxorubicin can lead to severe myelosuppression (mainly leukopenia and thrombocytopenia), toxic gastrointestinal effects (mainly mucositis) and cause acute heart damage.

The antidote to doxorubicin is not known. In case of overdose, symptomatic therapy is recommended.

Pregnancy use

It is contraindicated during pregnancy and lactation.