Doxorubicin, lyophilizate 10 mg

Antitumor antibiotic of the anthracycline series isolated from the culture of Streptomyces peucetius var. caesius.

Indications

Active ingredient

Composition

Interaction

Directions for use

Doxorubicin can be used both as monotherapy and in combination with other antitumor drugs in different doses depending on the therapy regimen. Individual selection of the dose should be guided by data from the literature.

Intravenous infusion:

As monotherapy, the recommended dose per cycle is 60-75 mg/m2 every three weeks. The drug is usually administered once during a cycle; however, the cycle dose can be divided into multiple doses (e.g., administered on the first three consecutive days, or on the first and eighth day of the cycle), with cycles repeated every 3 to 4 weeks.

– To reduce the toxic effects of doxorubicin, especially cardiotoxicity, a weekly regimen of 10-20 mg/m2 is used;

In combination with other antitumor drugs, doxorubicin is prescribed in a cycle dose of 30-60 mg/m2 every 3-4 weeks.

Hepatic dysfunction. In patients with hyperbilirubinemia the dose of doxorubicin should be decreased according to the concentration of total bilirubin:

– by 50% if serum bilirubin concentration is 12-30 mg/l;

– by 75% if serum bilirubin concentration is above 30 mg/l.

Other special patient groups. Lower doses or longer intervals between cycles are recommended in patients who have previously received massive antitumor therapy, children, elderly patients, obese patients (if body weight is more than 130% of ideal, decreased systemic clearance of doxorubicin is noted), and patients with bone marrow tumor infiltration. Re-injection of the drug is possible only when all signs of toxicity (especially gastrointestinal and hematological) have disappeared.

Rules for solution preparation and administration: Doxorubicin lyophilisate is dissolved with 0.9% sodium chloride solution or water for injection. The resulting solution with the required amount of doxorubicin is further diluted with 0.9% sodium chloride solution 4 or water for injection to a concentration of no more than 1mg/1ml. The drug is administered intravenously slowly (within 3-5 minutes) into the injection port of the IV system, during a rapid infusion of 5% dextrose solution or 0.9% sodium chloride solution. Before the injection it is necessary to make sure that the needle or catheter is placed exactly in the vein. Small veins and veins above joints should be avoided; caution should be exercised not to perform venipuncture and subsequent administration of doxorubicin on extremities with impaired venous and lymphatic outflow.

The total dose of doxorubicin should not exceed 550 mg/m2 . In patients who have previously received radiotherapy to the mediastinum/pericardial area or who have taken other cardiotoxic drugs, if it is necessary to increase the total dose of doxorubicin above 450 mg/m2, the drug should be administered under close monitoring of heart function. Before injection, the required dose of the drug should be dissolved in 0.9% sodium chloride solution or water for injection to a concentration of 2 mg/ml. The drug is administered by intravenous stream slowly.

Injection into the bladder.

The recommended dose for intravesical administration is 30-50 mg per instillation, with intervals between injections of 1 week to 1 month, depending on the purpose of therapy – treatment or prevention. Recommended solution concentration is 1 mg/1 ml of water for injection or 0.9% sodium chloride solution. After completing instillation, patients should be turned from side to side every fifteen minutes to ensure even exposure of the drug to the bladder mucosa. As a rule, the drug should remain in the bladder for 1-2 hours.

At the end of the instillation, the patient should empty the bladder. To prevent excessive dilution of the drug with urine, patients should be warned to refrain from taking liquids for 12 hours before instillation. The systemic absorption of doxorubicin when instilled into the bladder is very low.

In case of local toxic effect (chemical cystitis which may be manifested by dysuria, polyuria, nycturia, painful urination, hematuria, discomfort in the bladder, necrosis of the bladder wall) the dose intended for repeated instillation should be diluted in 50-100 ml of 0.9 % sodium chloride solution. Particular attention should be paid to problems associated with catheterization (e.g., in cases of urethral obstruction due to massive intravesical tumors).

Intra-arterial administration.

In patients with hepatocellular cancer, doxorubicin may be 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 provide intense local effects while reducing overall toxic effects. Higher doses should be used only when extracorporeal excretion of the drug is performed simultaneously. Because this method is potentially dangerous and may result in widespread tissue necrosis, intra-arterial administration should only be performed by physicians who are proficient in this technique.

Special Instructions

With caution, use in patients with heart disease (including a history), varicella (including recent or after exposure), herpes zoster, other acute infectious diseases, gout or nephrolithiasis (including a history), and in patients with previous mediastinal radiotherapy or those receiving concurrent cyclophosphamide.

When treating it is necessary to regularly monitor peripheral blood count, laboratory parameters of liver function, ECG and cardiac ultrasound (with determination of left ventricular ejection fraction). If leukocyte count is less than 3500/μL and platelet count is less than 100,000/μL, the dose of doxorubicin is reduced by 50%.

In cases of severe, life-threatening arrhythmias immediately or within hours after doxorubicin administration have been described.

The vaccination of patients and family members is not recommended.

Doxorubicin may cause urine to turn red for 1-2 days after administration.

The carcinogenic and mutagenic effects of doxorubicin have been established in experimental studies.

Contraindications

Side effects

Blood organs: dose-dependent, reversible leukopenia and neutropenia. The development of thrombocytopenia and anemia is also possible. Leukopenia usually reaches its lowest value 10-14 days after drug administration; recovery of the blood picture is usually observed by 21 days.

Cardiovascular system disorders: There is a risk of early (i.e. acute) or late (delayed) cardiotoxicity during therapy with anthracyclines. Cardiotoxicity usually occurs within 1-6 months after the start of treatment. The manifestation of early (acute) cardiotoxicity of doxorubicin is primarily sinus tachycardia and/or abnormal ECG (nonspecific changes in ST-T waves). Tachyarrhythmias (including ventricular tachycardia), ventricular extrasystoles, as well as bradycardia, atrioventricular block and Gis bundle block may also be noted. The occurrence of these phenomena is not always a prognostic factor for subsequent delayed cardiotoxicity; they are rarely clinically significant and do not require discontinuation of doxorubicin therapy.

Late (delayed) myocardial damage is manifested by decreased left ventricular ejection fraction without clinical symptoms and/or symptoms of congestive heart failure (CHF) (dyspnea, pulmonary edema, peripheral edema, cardiomegaly and hepatomegaly, oliguria, ascites, exudative pleurisy, galloping rhythm). Subacute phenomena (pericarditis/myocarditis) may also be noted. The most severe form of anthracycline-induced cardiomyopathy is life-threatening ZSN, which is a toxicity that limits the cumulative dose of the drug. Phlebitis, thrombophlebitis, thromboembolic complications, including pulmonary embolism (in some cases fatal).

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

Uses of the urinary system: staining of urine red for 1-2 days after doxorubicin administration.

Sensory system disorders: conjunctivitis, keratitis, lacrimation.

Reproductive system disorders: amenorrhea (at the end of therapy ovulation is restored, but premature menopause may occur); oligospermia, azoospermia (in some cases sperm count is restored to normal levels; this may occur several years after therapy ends).

Skin and skin appendages: in most cases reversible complete alopecia develops. Resumption of hair growth usually begins 2-3 months after discontinuation of the drug. Hyperpigmentation of the skin and nails, photosensitivity, urticaria, rash, itching may also occur. Some patients who had previously received radiation therapy after doxorubicin infusion (usually 4-7 days) experienced hypersensitivity of the irritated skin, erythema with blistering, edema, severe pain, moist epidermitis in the areas corresponding to the radiation fields.

Allergic reactions: skin rash, dermatitis, urticaria, skin hyperemia of the palms and soles, bronchospasm, anaphylaxis (rare).

Local reactions: erythematous striation is often seen along the vein into which the infusion was made, then local phlebitis or thrombophlebitis may occur. Phlebosclerosis may also develop, especially if doxorubicin is re-injected into a small vein. Local soreness, severe subcutaneous inflammation and tissue necrosis may occur if the drug enters the surrounding tissue.

In intra-arterial administration: in addition to systemic toxicity, gastric and duodenal ulcers may occur (probably due to reflux of the drug into the gastric artery); narrowing of the bile ducts due to drug-induced sclerosing cholangitis, widespread necrosis of perfused tissue.

In intravesical administration: cystitis, bladder constriction.

Others: malaise, asthenia, fever, chills, “rush” of blood to the skin of the face (with rapid intravenous injection), hyperuricemia or nephropathy associated with increased uric acid formation, development of acute lymphocytic or myelocytic leukemia, accession of secondary infections, sepsis/septicemia, staining of urine red.

Overdose

Pregnancy use

Doxorubicin is contraindicated in pregnancy. Breastfeeding should be stopped if it is necessary to use it during lactation.

Women of childbearing age should use reliable contraception when using doxorubicin.

The teratogenic and embryotoxic effects of doxorubicin have been established in experimental studies.