Pharmorubicin

Semisynthetic analogue of Doxorubicin, obtained by epimerization of its molecule, cytostatic with antibacterial effect, is used for the treatment of malignant tumors of various genesis and localization. The active ingredient (epicycline hydrochloride) belongs to a series of anthracyclines. Like all drugs used to stop tumor growth, it has cytotoxic properties and requires careful monitoring of treatment by an experienced oncologist. 

[1], [2], [3], [4],

Indications of the pharmorubicin

Intravenously with malignant neoplasms:

• localized in the face and neck;
• breast, lung, ovaries and prostate;
• lymph and blood - lymphogranulomatosis, leukemia, lymphoma and myeloma;
• soft tissues and bones - melanoma and sarcoma;
• organs involved in the digestive process: esophagus, stomach, lower intestine, pancreas.

Intraarterial - malignant neoplasm of the liver (hepatocellular carcinoma).

Instillations are non-invasive malignant (in situ) neoplasm of the bladder.

[5]

Release form

Available in the form of a red lyophilized powdery or dense porous mass, packed in transparent glass bottles of 0.01 or 0.05 g of the active ingredient (epirubicin hydrochloride), they are supplied with a solvent - water for injection in five-milliliters ampoules. 

[6], [7]

Pharmacodynamics

The drug interferes with the division and development of neoplastic cells. The action of Farmorubicin is that its active component is built between two spirals of the DNA molecule of the cancer cell, forming a defect in this place, thereby preventing its replication. In addition, epirubicin hydrochloride is able to inhibit the enzymatic activity of topoisomerase II catalyzing several DNA replication processes (gene transcription, chromosomal segregation). The formation of a strong compound of the active ingredient with the DNA of a cancer cell, changes its structure, functions, reduces the matrix activity and ultimately upsets the production of nucleic acids, and the proliferation of malignant cells ceases.

The appearance of free radicals with the activation of epirubicin by cellular microsomes also contributes to the death of cancer cells, in these places disconnections (single and double) of the DNA helix are formed. However, this ability is associated with the toxic effect of anthracyclines on the cardiac muscle. Nevertheless, the cardiotoxicity of epirubicin is less pronounced than that of its predecessor, Doxorubicin.

Pharmacokinetics

The active ingredient of the drug, injected intravenously, penetrates into organs and tissues at a good rate without overcoming the blood-brain barrier. The association with serum albumin is 77% regardless of the level of epirubicin in the blood. Its metabolism (oxidation) occurs in the liver, the change in the serum level of epirubicinol (metabolic product) is proportional to the residual density of the unchanged active substance. The half-cycle of active substance circulation in the blood is about 40 hours. Its distribution occurs in the tissues of the body widely and evenly, as evidenced by a high coefficient of purification (0.9 l / min). Excreted, mainly through the biliary tract, approximately 10% leaves the body through the kidneys. 

[8], [9],

Dosing and administration

This drug can be prescribed alone or in combination with other drugs that inhibit the processes of cell proliferation, dose it depending on the chosen therapeutic scheme, guided by special recommendations.

Prepare the solution as follows: to the contents of the bottle add a solvent (saline or sterile water for injection) at the rate of 10 mg of epirubicin / 5 ml of solvent, then shake the bottle until the dry substance completely dissolves.

Intravenous infusion. For monotherapy adult patients are recommended to dose the drug per cycle at a rate of 60-90 mg per square meter of the body surface. The infusion cycle is carried out at a frequency of once every 21-28 days. The dose calculated for the cycle can be introduced by one infusion or divided into parts and poured in a jet or drip for two or three consecutive days.

When combined with drugs of a similar effect, the dosage of Pharmorubicin decreases accordingly.

If it is necessary to use large doses, the drug for the cycle is calculated at 90-120 mg per square meter of the body surface and injected once, observing the interval between infusions in three to four weeks.

Repeated infusions of Pharmorubicin are carried out only in the absence of symptoms, indicative of the toxic effect of the previous course, special attention is paid to the normalization of the blood formula and the disappearance of dyspeptic disorders.

Persons suffering from renal dysfunction with a plasma level of creatinine exceeding 5 mg / dL are reduced in dosages of the drug.

Patients with hepatic dysfunctions with a serum bilirubin density of 1.2 to 3.0 mg / dl and / or AST, two to four times the upper limit, the infusion rate per cycle is halved relative to the standard; with a bilirubin score greater than 3.0 mg / dL, or an AST value greater than four times the upper limit, the infusion rate per cycle should be 1/4 standard.

Persons with an anamnesis of cytostatics treatment in high dosages, as well as with bone marrow tumor infiltration, are advised to reduce dosages or prolong the inter-cyclic interim interval.

Dosage of the drug for initial therapy for elderly patients is carried out according to general standards.

To reduce the likelihood of thrombus formation and accidental drug exposure to closely located tissues, it is possible by injecting it into the tube of the infusion system during the drip infusion of solutions - dextrose (5%) or physiological. The duration of the procedure depends on the dosage of Farmorubicin, the volume of the infusion solution and ranges from three minutes to 1/3 hours.

Intravesical infusion. In therapeutic regimens for the treatment of non-invasive neoplasms of the bladder, eight weekly intravesical infusions of Pharmorubicin are included. To do this, use bottles of 50 mg, the contents of which are dissolved in 25-50 ml of saline. The symptoms of local intoxication are manifested by chemical cystitis, the symptoms of which are absence, delay or, on the contrary, frequent and profuse urination, bedwetting or frequent urination at night, all this can be accompanied by pain, burning and other uncomfortable sensations above the pubis, microscopic or macroscopic hematuria. Presence of symptoms of intoxication by Pharmorubicin should motivate a decrease in dosage to 30 mg.

If the malignancy of the tumor is not specified (in situ) and the patient is well tolerated, the dosage can be increased to 80 mg.

To prevent relapse, patients who underwent transurethral removal of the superficial bladder neoplasm usually receive four intravesical injections of 50 mg of epirubicin (one per week). Then, by the end of the year, they perform monthly similar procedures (11 procedures in total).

Infusion of the drug into the bladder is carried out by means of a catheter. Before the procedure for half a day, you should try not to drink at all, to avoid dilution of urine injected solution. The liquid is left in for 60 minutes. At this time, the patient periodically turns from side to side, so that the solution washes all parts of the mucous membrane evenly. After the procedure, the patient must urinate.  

Introduction to the main hepatic artery. The purpose of this method is to ensure an intensive effect of the drug directly at the site of a cancerous tumor with a decrease in its systemic toxic effect. This type of infusion is recommended for diagnosis: primary hepatocellular malignant neoplasm. For this procedure, epirubicin is dispensed per cycle of 60-90 mg per square meter of the body surface of the patient, the time interval between infusions is maintained from three weeks to three months. Dosing at 40-60mg per square meter is possible, the procedures are carried out every four weeks to ensure and simultaneously reduce the overall toxic effect.

[11], [12], [13]

Use of the pharmorubicin during pregnancy

This drug can be prescribed to a woman who carries a baby, only for vital indications. Laboratory studies in animals allow the possibility of its teratogenic effect on the fetus. Studies involving this category of patients were not conducted. Therefore, if it is necessary to prescribe a course of Pharmorubicin during the period of gestation or when pregnancy is detected during the treatment period, the woman is necessarily informed about the possibility of negative consequences for fetal development.

Patients of fertile age during treatment with the drug should strongly recommend the use of reliable contraceptives.

Pharmacological therapy may lead to a lack of menstruation in women and early menopause.

Studies on the penetration of Epirubicin hydrochloride into breast milk have not been carried out, however, it is known that preparations of this series are found in breast milk. Therefore, to prevent the negative effect of the drug on the baby, breast-feeding is interrupted before the beginning of therapy with Pharmarubicin.

The use of this drug can lead to the appearance of chromosomal defects in male sex cells (spermatozoa), so men during treatment should be reliably protected. And, if necessary, to surrender your sperm before the start of treatment, as the result of therapy with Farmorubicin can become irreversible infertility.

Contraindications

General: Known patient allergy to the use of anthracyclines and anthracendones. The period of gestation and breastfeeding.

For intravenous infusion:

• significant reduction in the level of leukocytes and platelets in the blood (myelosuppression);
• severe forms of cardiac and renal organic lesions and functional disorders;
• disturbance of the rhythm of the heart;
• recent myocardial infarction in history;
• a recently conducted course of therapy with high doses of drugs belonging to the anthracycline or anthracenedione group.

For intravesical infusion:

• neoplasms, ingrown into the membrane of the bladder;
• Infectious and inflammatory diseases of the urinary organs.

Side effects of the pharmorubicin

Disorders of hemopoiesis: a decrease in the quantitative indices of blood cells - leukocytes, platelets, hemoglobin, neutrophils (usually has a temporary reversible character, a minimum is observed after a decade or two weeks after the administration of Pharmarubicin, at the end of the third week the rate is restored to normal).

Manifestations of toxicity to the heart muscle:

• The acute (early) manifestation of heart palpitations and heart rhythm, these symptoms may be accompanied by nonspecific modifications of the electrocardiogram in the ST segment and the T wave, there may be a slowing of the pulse, blockage of the bundle of the bundle or atrioventricular (these symptoms do not presage, as a rule, the development of deferred more serious manifestations of cardiotoxicity, have no clinical significance and do not imply the termination of the course of treatment);
• delayed or late manifests itself as a decrease in systolic blood volume with a contraction of the left ventricle; inflammation of the pericardium or myocardium; thromboembolism, including - pulmonary artery, which can result in death of the patient; these signs can arise independently or be accompanied by the symptoms of congestive heart failure (dyspnea, gallop rhythm, edema of the lungs or lower extremities, enlargement of the heart and liver, decrease in the volume of excreted urine, abdominal dropsy, exudative pleurisy) - the most severe side effect of the intake of Farmorubicin, dose of drug accumulation.

Digestive disorders: lack of appetite, inflammation of the gums, hyperpigmentation of the oral mucosa, nausea, vomiting, colitis, diarrhea, inflammation of the esophagus, abdominal pain (cutting and burning), erosive gastropathy, gastroduodenal bleeding.

Hepatic tests: increased ALT and AST, as well as bilirubin concentrations.

Urinary disorders: in the first two days after the drug is administered, urine is red; excess uric acid in the urine.

Eyes: inflammation of the outer shell and / or cornea.

Endocrine disorders: hot flashes, lack of menstruation, which usually recovers after the end of therapy, however, there is a risk of developing early menopause; decrease in the volume of ejaculate, absence of spermatozoa in it (sometimes after a long enough period after the course of therapy these indicators can be restored).

Skin: hair loss, hives, itching, hyperemia, increased pigmentation of the skin, sensitization to ultraviolet, photo allergy.

General: weakness, fatigue, asthenic condition, fever, febrile state, acute lympho- or myeloleukemia, anaphylaxis.

Local effects: a strip of erythematous rash can be observed along the venous vessel into which the solution was infused; With time, the same vessel can develop inflammation, sclerotic changes, or blood clots (especially after repeated infusion). If you get Pharmorubicin past the venous blood flow, flow from the veins to the skin - there is a high probability of local reaction of the affected tissues up to their necrotic changes.

The introduction of the drug into the artery is fraught with negative consequences in the form of general intoxication and, in addition, ulceration of the mucous membranes of the digestive tract (stomach and duodenum), hypothetically, as a result of a reverse cast in the gastric artery and / or sclerosing inflammation of the bile ducts, manifested by their strictures.

[10]

Overdose

The expressed myelosuppressive symptomatology, basically, strong reduction of quantitative parameters of leucocytes and thrombocytes; inflammatory-erosive damage throughout the digestive tract from the oral cavity to the intestine; acute manifestations of toxic effects on the myocardium.

Therapeutic measures are coordinated with the manifested symptoms (antidote to Pharmorubicin is not known).

[14]

Interactions with other drugs

The combination with other medications that inhibit cell proliferation, potentiates their mutual action and enhances drug intoxication, in particular, this concerns the manifestation of myelosuppression and mucositis.

Combination with drugs toxic to the heart muscle, as well as with calcium channel blockers requires careful monitoring of the heart throughout the course of treatment.

It is not recommended to use simultaneously with cimetidine, since this combination reduces the rate of excretion of Pharmorubicin from the body.

This drug should not be mixed with any other drugs, as well as with alkaline solutions (to avoid the hydrolysis of the active ingredient). 

[15]

Storage conditions

Does not require special storage conditions. The finished solution should not be stored for more than two days in a cool (4-10 ℃) and dark place or at room temperature - no more than a day.

[16],

Shelf life

Shelf life is indicated on the package (no more than 4 years).

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