Project Description

Doxorubicin hydrochloride

powder for preparing solution for injections 0.01g – Doxorubicini hydrochloridum

international nonproprietary name

Doxorubicin

Ref

BP-0041

Pharmacotherapeutic group

Anti-tumor drug. Anti-tumor antibiotic from the group of antracyclines.

Composition of the preparation

One bottle contains doxorubicin hydrochloride – 10 mg, mannite – 40 mg.

Pharmacological action

Pharmacodynamics

Doxorubicin is an anti-tumor antibiotic of the antracyclines line separated from the Streptomyces peucetius or Streptomyces coeruleorubidus culture.

The doxorubicin action main mechanism is its ability to form complexes with DNA through intercalation between the nitrogen bases vapors thus causing the DNA and RNA synthesis suppression. It is supposed that the anti-tumor action may be also caused by changing the cellular functions in the results of its binding with cellular membranes lipids and of the interaction with topoisomerase II.

The doxorubicin action molecular and biochemical mechanisms are similar those of other antibiotics with antracycline structure (rubomycin and carminomycin). It is active during the whole cellular cycle including the interphase.

Pharmacokinetics

Being injected intravenous doxorubicin distributes in the plasma and tissues quickly. In 30 seconds the preparation is found in the liver, lungs, heart and kidneys. It does passes through the hematoencephalic barrier and does not achieve measurable concentrations in the CNS though it passes through the placental barrier and is found in breast milk.

Doxorubicin and its metabolites plasma concentrations reduce in three phases. In the first phase it is metabolized quickly, probably through the effect of the first passage in the liver. The initial period of doxorubicin half elimination is 10 minutes, then the second 1 – 3 hour period of half elimination follows. The final period of half elimination is 30 – 40 hours. About 40 – 50% of doxorubicin and of its active metabolites is excreted with bile and 5 – 10% – with urine.

Indications 

Acute lymphoblast and myeloblast leukemia; malignant lymphomas; breast cancer, lung cancer (small cell carcinoma in particular), urinary bladder  cancer, thyroid carcinoma, ovaries carcinoma; osteogenic sarcomas and soft tissues sarcomas; Ewing’s sarcoma; neuroblastoma; Wilms tumor. The preparation is active in case of other solid tumors such as endometrial carcinoma, carcinoma of the neck of the uterus, malignant tumor of the testis, prostate carcinoma, cancer of the stomach, carcinoma of the liver and carcinoma of the pancreas.

special indication

Not established

special warning

The preparation should be applied by specially trained medical personnel observing the safety measures approved while preparing, diluting solutions for injections (in a sterile box using dispensable surgical gloves and mask) and disposing of the needles, syringes, bottles, vials and residual preparation.

Age younger 2 years and older 70 years (the cardiotoxic effect frequency increase is possible), organic changes of the heart (the cardiotoxic effect risk is possible in case the preparation is used in low doses).

Dosage and method of administration

Doxorubicin is injected intravenous exclusively. Before usage the bottle contents (10 mg of doxorubicin) is dissolved in 5 ml of isotonic solution of sodium chloride or water for injections (concentration 0 2 mg/ml). The injection should last not less than 2 – 5 minutes. In case of any signs appearance evidencing that the preparation is under the skin the infusion should be stopped immediately and another vein should be chosen for injecting. For the urinary bladder carcinoma treating doxorubicin is injected intravesically.

The preparation is injected intravenous in accordance with one of the following regimes: 20 – 30 mg/m2during three days with intervals between the courses of 3 – 4 weeks; 20 – 30 mg/m2 on the 1st, 8th, and 15th days of the course repeated with the interval of 3 – 4 weeks; 60 – 75 mg/m2 as a single injection repeated every 3 weeks.

The recommended dose of one doxorubicin intravesical instillation is 30 – 50 mg the intervals between the instillations being from 1 week to 1 month. The recommended solution concentration is 1 mg/1 ml of water for injections.

As a part of a combined therapy the preparation is applied in the dose 25 – 50 mg/m2 every 3 – 4 weeks.

The doses should be reduced for patients with a decreased bone marrow function caused by the age, the preceding therapy of the tumor infiltration into the bone marrow.

When doxorubicin is prescribed to patients with the liver function disturbances it should be taken into consideration that in case the bilirubin level increases 2 – 3 times the doxorubicin dose should be reduced by 50 – 75% respectively. When the leukocytes number is less 3.3 – 3.5 ∙ 109/l and the thrombocytes number is less 100 – 149 ∙ 109/l the doxorubicin dose should be reduced by 50 – 75% respectively.

The total doxorubicin dose should not exceed 500 – 550 mg/m2. The total doxorubicin dose for the patients having received irradiation therapy on the area of lungs and mediastinum or having received other cardiotoxic preparations should not exceed 400 mg/m2.

overdosage

Symptoms: an acute doxorubicin overdosing is manifested by the toxic effects increase (the mucous membranes inflammation, leucopenia and thrombocytopenia).

Treatment: patients with the evident bone marrow function suppression are hospitalized, they are prescribed antibiotics and granulocytic mass transfusions as well as the symptomatic therapy for the mucous membranes inflammation.

safety measures

Doxorubicin should be applied under a strict hematological control. The blood laboratory analysis should be made at least twice a week. The blood characteristics usually restore on the 21st day. The doxorubicin introduction may be repeated only when all the signs of hematoxicity have disappeared completely. It should applied with care in patients not having a sufficient bone marrow reserve caused by the age, by appliance of cytotoxic drugs before or by irradiation therapy.

Stomatologic interferences should be completed before the therapy is begun or should be postponed to the blood characteristics normalization (microbial infections risk may increase, the healing processes may inhibit, the gingiva may bleed). The preparation should not be applied earlier than in 1 month after the preceding chemotherapy has been completed.

The blood uric acid level and nephropathy development risk increase may require application of uricosuric anti-gouty drugs. In the process of therapy enough volume of liquid should be taken for the urine excretion increase and the uric acid elimination.

Side effects

Cardiovascular system and blood (hemopoiesis, hemostasis): In case the total dose exceeds 550 mg/m2– congestive heart failure (dyspnea, feet and malleolus edema, tachycardia or not rhythmic palpitation) may develop depending on the dose or the therapy duration in several weeks after the therapy has been completed (an immediate therapy break is necessary for an irreversible and in the end a lethal cardiomyopathy are possible); acute auricular and ventricular arrhythmia (mainly during the first hours after the introduction); rarely in several days or weeks after the introduction toxic myocarditis or pericarditis-myocarditis syndrome (tachycardia, heart failure, pericarditis); thrombocytopenia, leucopenia with its peak in 10 – 15 days after the therapy beginning (the blood characteristics usually restore on the 21st day after the introduction has been stopped); phlebosclerosis (when injected into minor veins or re-injected into the same vein), face rush of blood and hyperemia along the vein (when injected too quickly).

Gastrointestinal tract organs: nausea, vomiting, stomatitis or esophagitis (may develop in 5 – 10 days, especially when injected three days running and may exert severe infections development). Ulceration in the GIT; rarely anorexia, diarrhea.

Genitourinary system: hyperurikemia, nephropathy (connected with an increased formation of uric acid), reddish color of urine (disappears within 48 hours). When introduced intravesically feeling of burning in the urinary bladder and urethra, urination disturbances (painful, difficult, etc.), hematuria.

Dermal integument: alopecia (complete and reversible), pelma, palm of the hand and nails darkening, irradiation erythema relapse.

Allergic reactions: dermal eruption, itching, fever, shivering, anaphylaxis.

Other side effects: extravasate, cellulite, necrosis (when the preparation penetrates the surrounding tissues), rarely conjunctivitis, lacrimation.

Contraindications

Pronounced bone marrow function suppression  caused  by other chemotherapeutic preparations intake or by irradiation therapy; receiving antracyclines in the total maximal doses before; hypersensitivity to hydroxybenzoates; pregnancy and breast feeding; leucopenia, anemia, thrombocytopenia; severe heart diseases (myocarditis, pronounced heart rhythm changes, myocardial infarction acute phase), severe hepatic and renal functions disturbances; acute hepatitis, bilirubinemia; peptic ulcers of the stomach and duodenum; bleedings; tuberculosis; cystitis (intravesical introduction).

In patients with the heart organic changes cardiotoxicity may develop when the preparation is received in smaller than the total maximal one doses for this reason doxorubicin is h\not recommended to those patients.

Interactions with other medicinal preparations

Doxorubicin may increase the other anti-tumor drugs toxicity. An exacerbation of hemorrhagic cystitis caused by an accompanying intake of cyclophosphamide as well as 6-merkaptopurine hepatotoxic effect increase is possible. Doxorubicin increases the toxic effect on the myocardium, mucous membranes, skin and liver caused by irradiation.

The preparation is not compatible pharmaceutically with solutions of heparin, dexamethasone, fluoruracyl, hydrocortisone sodium succinate, aminofillin, cephalotin (sedimentation is possible). Streptosocin increases the period of doxorubicin half elimination (T1/2). Doxorubicin reduces the effect if inactivated and live viral vaccines, may increase the side effects of live viral vaccines.

The form of release

Bottles containing 10 mg of the doxorubicin lyophilized powder.