INSTRUCTION

for medical use of the preparation

DOXIVITAL 10

Composition:

Active substance: doxorubicin;

1 vial contains doxorubicin hydrochloride 10 mg;

Auxiliary substances: lactose monohydrate, methylparaben (Е 218), sodium hydroxide, hydrochloric acid.

Medical form. Frozen-dried powder for preparation of the solution for infusions.

Pharmacotherapeutical group. Antineoplastic agents. Anthracyclines and related compounds. ATC cose L01D B01.

Clinical characteristics.

Indications.

Treatment of broad spectrum of neoplastic diseases, including acute leukemia, lymphoma, malignant neoplasms in children and solid tumors in adults, in particular breast and lung carcinoma.

Contraindications.

Hypersensitivity to doxorubicin, chemically related compounds or other components of the preparation.

Evident suppression of bone marrow functions by other chemotherapeutic preparations or radiation therapy.

Acute cardiac insufficiency (present or previous).

Severe disturbance of myocardium function.

Severe arrhythmia.

Previous treatment with doxorubicin, daunorubicin and/or other preparation of anthracycline and anthracene groups with introduction of maximal possible cumulative dose.

Doxorubicin cannot be used intravesically for treatment of urinary bladder cancer in patients with urethra stenosis, if catheterization is impossible.

Doxorubicin cannot be used intravesically in case of invasive tumors, which have grown through urinary bladder wall, as well as if there are urinary tract infections, inflammatory processes in the urinary bladder, hematurias.

The preparation is not used for treatment of Kaposi’s sarcoma caused by HIV-infection, which is controlled by local therapy or systemic therapy with α-interferon.

Way of administration and doses.

Way of administration. Doxorubicin is introduced intravenously and intra-arterially or as intravesical instillation. Doxorubicin cannot be used as antibacterial agent.

Intravesical introduction of doxorubicin is an alternative way of introduction at treatment of superficial urinary bladder cancer, including transitional cell carcinoma, papillary bladder tumors and carcinoma in situ, or as adjuvant therapy for low-differentiated and urinary bladder cancer of after transurethral resection.

Intravenous introduction. The restored solution is introduced as intravenous infusion with free liquid flow for not less than 3, but not more than 10 minutes. Solution of sodium chloride for injections, 5% solution of glucose or solution of sodium chloride and glucose are usually used for dilution. Introduction via stream injection is not recommended due to high risk of extravasation, which may happen even at adequate reversible blood flow at aspiration through the pharynx.

Total doxorubicin dose per cycle may vary due to the scheme of treatment (for example, at monotherapy or in combination with other cytotoxic preparations) and indications.

The dose is usually calculated on the basis of body surface. In case of monotherapy, the recommended standard initial dose of doxorubicin per cycle for adults is 60-90 mg/m² of body surface. Total initial dose per cycle may be introduced either at once, be divided for three introductions for three successive days or be introduced during two sessions – on day 1 and day 8. Under condition of normal recovery after toxic influence of the preparation (bone marrow suppression and stomatitis in particular), the course of treatment may be repeated every 3-4 weeks. If the preparation is used in combination with other antitumor agents, which may potentiate toxic influence, it may be necessary to decrease the dose of doxorubicin to 30-40 mg/m² every three weeks.

If the dose is calculated on the basis of body weight, it is necessary to introduce 1.2-2.4 mg/kg of the preparation as a single dose every three weeks.

It has been noted that at introduction of doxorubicin as a single dose every three weeks, there is a significant decrease of unfavorable toxic influence manifestations, mucositis. However, some specialists think that division of the dose for introduction for three successive days (0.4-0.8 mg/kg or 20-25 mg/m² daily) provides greater effectiveness, though at the expense of greater toxicity.

It has been demonstrated that weekly use doxorubicin is as effective as introduction once every third week. The recommended dose is 20 mg/m² once a week, though objective reaction has been observed at 6-12 mg/m². In case of weekly use, cardiotoxicity decreases.

It may be necessary to decrease the dose in patients, who have previously received treatment with other cytotoxic preparations. Introduction of a less dose may also be needed in children, obesity patients and elderly population.

Decrease of initial doses or increase of intervals between the cycles may be reasonable in patients, who have tolerated previous courses of treatment badly, or in patients with neoplastic infiltration of bone marrow (see Section Peculiarities of the use).

Disturbed liver function.

In case of disturbed liver function, the dose of doxorubicin should be decreases as indicated in the table below.

Serum bilirubin levels	Recommended dose
1.2-3 mg/100 ml	50% usual dose
>3 mg/100 ml	25% usual dose

Doxorubicin should not be used in patients with severe disturbances of liver function.

Intra-arterial introduction. Intra-arterial introduction has been used when trying to increase local activity at low total dose and thus decrease total toxicity. It should be underlined that such technique potentially is very risky and may lead to spread necrosis of the perfused tissue, unless adequate protective measures are used. Doses of the preparation and intervals between introductions in case of intra-arterial use may vary. The preparation should be introduced intra-arterially only by specialists having enough expedience of making such injections.

Intravesical introduction. Doxorubicin is used via intravesical introduction more often for treatment of transitional cell cancer, papillary bladder tumors and carcinoma in situ. The preparation should not be introduced intravesically for treatment of invasive tumors, which have grown through urinary bladder wall. Doxorubicin introduction into urinary bladder with certain intervals is also reasonable after transurethral resection of the tumor in order to decrease recurrence possibility. Instillation of 30-50 mg in 25-50 ml of 0.9% solution of sodium chloride is recommended. In case of local toxic influence (chemical cystitis), the dose should be diluted in 50-100 ml of 0.9% solution of sodium chloride. Patients may continue to receive instillations with weekly or monthly interval.

As today numerous treatments are in use, which complicates interpretation, auxiliary information is given below:

• doxorubicin concentration in the bladder should be 50 mg per 50 ml;

• in order to avoid undesirable dilution with urine, patients should be warned to avoid consuming beverages within 12 hours before instillation. It should decrease urine excretion to about 50 ml per hour;

• after introduction of the preparation patients have to change body position by 90 degrees every 15 minutes.

The action of the solution of the preparation for one hour is usually sufficient; after the end of the procedure patient has to empty his/her urinary bladder.

Side effects.

Dose-limiting toxic effects are suppression of bone marrow functioning and cardiotoxicity. Doxorubicin may potentiate side effects caused by radiation therapy and other chemotherapeutic preparations (streptozotocin, methotrexate, cyclophosphamide).

According to their frequency, side reactions are subdivided into the following categories: very frequent (≥ 1/10), frequent (≥ 1/100 – < 1/10), infrequent (≥ 1/1000 – < 1/100), seldom (≥ 1/10,000 – < 1/1,000), single (< 1/10,000).

From the side of cardiac system

Very frequent: cardiomyopathy, impaired cardiac function; symptoms of cardiotoxicity, arrhythmia in particular, may appear immediately after introduction of the preparation; changes in ECG (in particular, signs of heart block, flattening of T-wave and depression of ST-segment) may be observed within two weeks after doxorubicin introduction; pericarditis and myocarditis, arterial hypertension, dyspnea, vasodilation, decrease in ejection fraction are possible.

From the side of blood system and lymphatic system

Very frequent: suppression of bone marrow functioning (transitory leukopenia, neutropenia, febrile neutropenia, anemia, hypochromic anemia, thrombocytopenia, fever, increased risk of infection development are possible). Blood corpuscle count decreases to its minimum in 10-14 days after introduction of the preparation.

From the side of sight organs

Seldom: conjunctivitis, increased tear excretion, indistinct vision, keratitis.

From the side of respiratory system, chest cavity organs and mediastinum

Single: toxic lesion of lungs (with such manifestations as frequent breezing, asphyxia/ pleural effusion, obliterating bronchiolitis with pneumonia, bronchocentric granulomatosis/suppressed breathing, which is life-threatening, syndrome, which resembles post-pulmonectomic one, interstitial pneumonitis, radiation pneumonitis, pulmonary embolism); increased cough, pharyngitis, infections of the upper departments of the respiratory tracts.

From the side of digestive system

Very frequent: in 5-10 days after doxorubicin introduction there may be observed nausea, vomiting, inflammation of mucous membranes (stomatitis, esophagitis, proctitis), diarrhea, abdominal pain, anorexia, constipation, dyspepsia, painful mouth, mouth mucous candidosis, gastritis, dysphagy, dry mouth, meteorism, gingivitis. Lesion of gastro-intestinal tract may cause formation of ulcers, bleedings, bowel necrosis and perforation.

The first sign of mucous membranes inflammation development usually is burning sensation in the mouth and throat in 5-10 days after doxorubicin introduction. Further there may develop ulcers with risk of secondary infection development. Inflammation of mucous membranes of vagina, rectum and esophagus is also possible.

From the side of kidneys and urinary tracts

Frequent: in case of intravesical use of doxorubicin the following side effects are possible: hematuria, irritation of urinary bladder and urethra, painful urination, polyuria. Usually these reactions are of moderate severity and not long-lasting. In case of intravesical use hemorrhagic cystitis may also develop, which may cause decrease in holding capacity of urinary bladder. Doxorubicin may color urine red. Urinary tract infections, dysuria and vaginitis are possible.

From the side of skin and subcutaneous tissues

Very frequent: reversible alopecia develops in most patients. There is a possibility of hyperpigmentation of nail bed and skin folds, abnormal pigmentation, skin decoloration, onycholysis, dry skin; palmoplantar erythrodysesthesia (PPE) syndrome, open skin lesions (nonn-erpetic), fungus infection, bullous rash, dermatitis, erythematous rash, nail deffects, skin peeling, vesiculobullous rash, exfoliative dermatitis, maculapapular rash, hyperhidrosis, acne, herpes zoster, petechias. Doxorubicin causes severe tissue irritation, in case of extravasation at the site of introduction there may occur pain, irritation, inflammation, trombophlebitis and even serious ulcers and skin necrosis.

Infrequent: reactions of hypersensitivity, in particular skin reactions (rash, erythema, itch, urticaria, angioneurotic edema, fever, anaphylactic reaction), photosensitization. Doxorubicin potentiates the reaction of normal tissues to radiation. In case of doxorubicin use, after certain time after the end of radiation therapy course late reaction (recurrence of radiation damage symptoms) may also occur.

From the side of endocrine system

Single: growth disorders and endocrine disorders in children in case of intensive chemotherapy.

From the side of metabolism

Very frequent: hyperuricemy, hyperkaliemia, hypocalcemia, hypokaliemia, hypomagnesemia, hyponatremia.

Malignant and benign neoplasms (including cysts and polyps)

Infrequent: in children there is a possibility of increased risk of future development of secondary neoplastic diseases, especially acute myeloid and lymphoid leukemia.

Seldom: secondary acute myeloid leukemia (with pre-leucosis phase or without it) in patients, who have been treated with doxorubicin in combination with other antineoplastic preparations, which damage DNA. Latent period in such cases may be short (1-3 years).

From the side of vascular system

Single: trombophlebitis, hemorrhages.

From the side of hepatobiliary system

Frequent: insignificant transitory increase of the level of hepatic enzymes, increased level of total bilirubin. In case of concomitant radiation therapy for liver area, there is a possibility of severe hepatotoxic effects, which may lead to liver cirrhosis.

From the side of reproductive system

Amenorrhea, oligospermia or azospermia.

From the side of nervous system

Paresthesia, sleepiness, peripheral neuropathy, headache, dizziness, insomnia, anxiety, depression, neuralgia, lethargy, peripheral sensory neuropathy, taste disorder.

Effects of general character and local reactions

Seldom: asthenia, tiredness, weakness, in case of too rapid introduction of the preparation, flashes are possible.

Other effects

Pain in bones, musculoskeletal pain, folliculitis, pain in the chest, leg convulsions, edemas, leg swelling, nasal bleeding, backache, malaise, decreased body weight, cachexia, increased serum level of creatinine, dehydration.

Overdose.

In case of overdose there are observed the same symptoms as in case of therapeutic use of doxorubicin, however, their intensity is higher. A single doxorubicin dose of 250-500 mg is lethal. Within 24 hours after overdose there may develop acute degeneration of myocardium. Severe myelosupression with decreased count of blood corpuscles to the minimum may is possible within 10-15 days after doxorubicin introduction. Cardiac insufficiency may develop within 6 months after overdose.

In case of overdose it is necessary to use symptomatic maintaining means. Cardiac glycosides and diuretics should be indicated as soon as possible. As due to severe myelo- and immunosuppression there may develop bleedings and infections, it is necessary to take appropriate measures. There may be a necessity of blood transfusion and isolation of patients in sterile hospital boxes. In case of doxorubicin overdose hemodialysis is ineffective.

Use during pregnancy and lactation.

Use of doxorubicin during pregnancy is dangerous and requires careful preliminary comparative analysis of the expected medicinal effect and risk for the fetus.

There are grounds to think that doxorubicin may cause serious damage to fetus development, that is why it should not be used during pregnancy. Animal reproductive toxicity studies have demonstrated that doxorubicin is teratogenic and embriotoxic.

Patients of reproductive age should use effective contraceptive agents during treatment and at least for 3 months after the end of therapy with the preparation.

Doxorubicin is secreted into breast milk. Breastfeeding is contraindicated in women during treatment with doxorubicin.

Children.

The preparation is used in pediatrics.

Doxorubicin is indicated in children in lower doses due to increased risk of cardiotoxic effects (especially delayed). Due to the same reason it is recommended to carry out regular cardiological examinations in patients after the end of doxorubicin therapy.

As a result of suppressed bone marrow function, the count of blood corpuscles in children decreases to the minimum in 10-14 days after treatment initiation, however, then hematological indexes usually recover quickly to the norm owing to great reserves of bone marrow in children in comparison with adults.

Special safety measures.

In order of safe use of the preparation, it is necessary to comply with the following requirements: only trained medical personnel should carry out preparation of the solution of doxorubicin hydrochloride; pregnant women should be excluded from the number of people who deal with the preparation; preparation of the solution should be carried out in special premises with perfect vertical air flow (biological hood, class 2), on the working surface covered with disposable absorbing paper on plastic base; during work with the preparation personal should wear protective clothes: PVC gloves, protective glasses, disposable coats and masks. In case of accidental contact of doxorubicin with skin, the affected area should be washed with great amount of water with soap; if the preparation got into eyes, it is necessary to wash them immediately according to commonly used methods; all syringes and the set of instruments for preparation of the solution of doxorubicin hydrochloride should have Luer lock. The possibility of aerosol formation may be decreased with the use of wide-lumen needles and needles with ventilation withdrawal; all unused materials, needles, syringes, vials and other objects, which contacted with cytotoxic preparation, should be isolated, put into polyethylene bags with double hermetic sealing and burn at temperature of 1000^⁰ С or above. The same should be done with patient’s excrements. Liquid wastes should be washed with great amount of water.

Peculiarities of the use.

Doxorubicin treatment should be carried out under supervision of a qualified doctor-oncologist. It is recommended that at least the first phase of doxorubicin therapy to be carried out in hospital conditions, as it is the time when patients require close monitoring and regular control of main laboratory indexes. Before initiation of doxorubicin treatment it is necessary to carry out investigation of cardiac and hepatic functions, as well as blood analysis with determination of main hematological indexes.

During doxorubicin therapy, nausea, vomiting and inflammation of mucous membranes often are severe and require appropriate treatment.

It is not recommended to repeat courses of treatment in case of existing ulcerative stomatitis (burning sensation in the mouth may precede its development).

Extravasation

Extravasation of doxorubicin causes severe and progressing tissue necrosis. The symptoms of extravasation are pain and/or burning sensation at the site of intravenous introduction of the preparation. In case of suspected extravasation it is necessary to stop introduction of doxorubicin immediately and continue it into another vein. It is necessary to apply ice to the affected site. There have been reports on the use with various degrees of success of such measures as immediate cooling and frequent applications of dimethyl sulfoxide. In case of extravasation it is necessary to consult a plastic surgery specialist on the necessity of broad of the affected area.

Cardiotoxicity

As it has been determined that with increase of cumulative dose of anthracyclines there is an increased risk of cardiomyopathy development, cumulative dose of doxorubicin should not exceed 450-550 mg/m² of body surface. At higher doses, the risk of cardiac failure development increases significantly.

Possible signs of cardiotoxic action of doxorubicin are tachycardia, changes in ECG or cardiac failure, which may develop suddenly both during doxorubicin treatment and in several months or even years after the end of therapy without any preliminary changes in ECG. The risk of cardiac failure development in cancer patients, who received doxorubicin treatment, remains within the whole life. Doxorubicin-induced cardiac failure may be resistant to conventional treatment.

The risk of cardiotoxic lesion development is higher in patients, who have received radiation therapy on mediastinum or pericardium area, have received treatment with anthracyclines and/or anthracenediones, patients with the history of cardiological deseases, elderly patients (aged 70 and over) and children (aged under 15).

Cardiotoxic effects may develop at doses lowed the recommended cumulative dose. Irreversible congestive heart failure may develop even at total dose of 240 mg/m² of body surface. That is why when determining the acceptable cumulative dose for each patient, it is necessary to take into consideration previous or concomitant therapy with other potentially cardiotoxic preparations, in particular cyclophosphamide (intravenously), milomycin С or dacarbazine, other anthracyclines (for example, daunorubicin), as well as radiation therapy on mediastinum or pericardium area.

There have been reports about development of severe arrhythmias during or in several hours after doxorubicin introduction.

During treatment with doxorubicin there may be observed such changes in ECG, as decrease in amplitude of QRS complex and prolongation of systolic interval, as well as decreased left ventricular ejection fraction.

Special caution is required during doxorubicin treatment in patients with a history of cardiological diseases (such as recent myocardial infarction, cardiac failure, cardiomyopathy, pericarditis, arrhythmias), as well as in patients, who have received other cardiotoxic preparations, for example, cyclophosphamide.

Monitoring of cardiac function

It is necessary to excess cardiac function before initiation doxorubicin treatment, control it regularly during treatment, as well as check it after the end of doxorubicin therapy. It is recommended to carry out ECG-examining before and after each introduction of the preparation. Such changes in ECG, as depression or inversion of T-wave, depression of ST-segment or arrhythmias, are common signs of acute, but transitory (reversible) toxic action of doxorubicin and are not the reasons for interruption of therapy with the preparation. However, stable decrease of QRS complex amplitude and prolongation of systolic interval are considered to be the signs of cardiotoxic lesions caused by anthracyclines. In case of 30 % decrease of QRS complex amplitude or 5 % decrease of ejection fraction, it is recommended to stop doxorubicin treatment.

The optimal method of cardiomyopathy development prediction is the assessment of the decrease of left ventricular ejection fraction (LVEF), which is determined with the help of ultrasound or scintigraphy of the heart. It is necessary to estimate LVEF before initiation of doxorubicin treatment and check it every time after increase of cumulative dose by 100 mg/m² of body surface. The investigation should also be carried out in case of any clinical signs of cardiac failure. As a rule, decrease of LVEF absolute value to the level under 50 % or increase by more than 10 % in patients with normal base-line values (LVEF ≥ 50 %) is considered to be the signs of cardiac dysfunction. In such cases it is necessary to estimate carefully the potential risk and benefits of further doxorubicin therapy.

Myelosupression

As in case of doxorubicin therapy suppression of bone marrow function is often observed, it is necessary to conduct regular monitoring of hematologic indexes. In case of combined chemotherapy, myelosupression may be more evident due to additive action of the preparations.

Neutropenia develops most frequently, thrombocytopenia and anemia – less often. Minimal count of blood corpuscles is observed in 10-14 days after doxorubicin introduction. Hematologic indexes usually normalize in 21 days after introduction of the preparation. Doxorubicin therapy should not be initiated or continued, if the count of polynucleus granulocytes is less than 2000/mm³. In case of acute leucosis treatment this limit may be lower due to the situation.

Due to severe myelosupression there may develop bleedings or superinfection, which indicates the necessity of dose decrease or interruption of doxorubicin therapy.

As doxorubicin acts as immune suppressor, it is necessary to take measures to prevent the development of secondary infection.

Lung toxicity

In case of combined chemotherapy with other cytostatic agents (for example, gemcitabine, bleomycin, taxanes or rituximab) in combination with radiation therapy on mediastinum area or without it, as well as in case of treatment patients liable to lung diseases, it is necessary to take into consideration the possibility of toxic action of doxorubicin on the lungs.

Hyperuricemy

Similarly to treatment with other antineoplasic preparations, in case of doxorubicin therapy rapid tumor lysis may cause hyperuricemy with the development of acute gout or urate neuropathy.

It is necessary to control the level of blood uric acid on regular basis. Patients should consume sufficient quantity of liquid (minimum 3 L/m² of body surface per day). If necessary, xanthine oxidase inhibitors (allopurinol) may be used.

Liver dysfunction

As doxorubicin is excreted mainly with bile, in case of existing liver dysfunction or hepatic insufficiency doxorubicin introduction may be delayed and toxic effects increase. That is why before initiation and during therapy it is recommended to conduct functional hepatic tests (determine the levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and bilirubin).

Changes in urine coloration

Patients should be warned that doxorubicin may color urine red, especially soon after introduction. They should not worry about it.

Secondary leucosis. Secondary leucosis with pre-leukemic phase or without it has been noted in patients, who received treatment with anthracyclines. Secondary leucosis develops more often in case of use of these preparations in combination with DNA-damaging antineoplstic agents, when patients tolerated previous treatment with cytotoxic preparations badly or in case of increase of anthracycline doses. In case of such leucosis latent period may last from 1 to 3 years.

Carcinogenesis, mutagenesis, disturbed fertility. Doxorubicin demonstrated genotoxic and mutagenic properties in in vitro and in vivo tests.

In women doxorubicin may cause sterility during the period of use of the preparation. Doxorubicin may cause amenorrhea. Ovulation and menstrual cycle return to their norm after the end of therapy, though premature menopause is possible.

Doxorubicin demonstrates mutagenic properties and may cause chromosome lesions in human sperm. Oligospermia or azoospermia may be permanent; however, it has been reported that the number of sperm in some cases returned back to normal. It may occur in several years after the end of therapy. Men should use effective means of contraception during doxorubicin treatment.

Liver function. The main way of doxorubicin excretion is hepatobiliary system. Before initiation of doxorubicin use and during the therapy it is necessary to control general bilirubin level in serum. In patients with increased bilirubin level there may be observed delayed clearance of the preparation along with increased general toxicity. Such patients are recommended lower doses of the preparation. Patients with severe form of liver dysfunction should not be indicated doxorubicin.

Other. Doxorubicin may potentiate toxicity of other antitumor preparations. There have been reports about exacerbation cases of hemorrhagic cystitis, caused by cyclophosphamides, and increased hepatotoxicity of 6-mercaptopurine. In addition, there has been noted toxic influence of radiation therapy (on miocardium, mucous membranes, skin and liver).

Similar to the use of other cytotoxic agents, at doxorubicin use sometimes there have been cases of trombophlebitis and thromboembolic phenomena, including pulmonary embolism (in some cases lethal).

Tumor lysis syndrome. Doxorubicin may cause hyperuricemy as a result of purine catabolism, which accompanies rapid lysis of neoplastic cells (tumor lysis syndrome), induced by the preparation. That is why after treatment initiation, it is necessary to estimate blood level of uric acid, potassium, calcium phosphate and creatinine. Hydration, alkalization of urine and prevention of hyperuricemy with allopurinol may minimize the possibility of tumor lysis syndrome complications.

Vaccinations. Use live or live attenuated vaccines in patients with weakened immunity due to chemotherapy, including doxorubicin, may lead to serious or lethal infections. It is necessary to avoid vaccination with live vaccines in patients, who receive doxorubicin. Neutralized or inactivated vaccine may be indicated, but response to such vaccination may be weak.

Intravesical introduction of doxorubicin may lead to development of chemical cystitis symptoms (such as dysuria, polyuria, noctiria, complicated urination, hematuria, discomfort feeling in the area of urinary bladder, bladder wall necrosis) and spasm of urinary bladder. Special attention should be paid to cauterization issues (for example, in case of urethra obstruction due to solid intracystic tumors).

Intra-arterial use of doxorubicin (transcatheter arterial embolization) may be used for local or regional therapy for primary hepatocellular carcinoma or liver metastases. Intra-arterial introduction may cause (in addition to manifestations of systemic toxicity, qualitatively similar to those observed in case of intravenous introduction of doxorubicin) peptic ulcer (probably as a result of reflux of the preparation into stomach arteries) and narrowing of bile ducts due to medicament-induced sclerosing cholangitis. This way of introduction may lead to spread tissue necrosis in the perfusion zone.

Ability to influence the reaction rate when driving or operating other mechanisms.

Due to individual sensitivity, doxorubicin may have a negative influence on the ability to drive and operate other mechanisms.

Interaction with other medicinal preparations and other forms of interactions.

Caution should be exercised when doxorubicin is used after or in combination with other cardiotoxic or antitumor (especially myelotoxic) preparations.

Maximal plasma concentration of doxorubicin, terminal half-life and distribution volume may increase at concomitant use of verapamil.

Doxorubicin may cause exacerbation of hemorrhagic cystitis, which has developed due to previous therapy with cyclophosphamide.

As doxorubicin metabolizes quickly and excreted mainly with bile, in case of concomitant use with hepatotoxic chemotherapeutic agents (for example, methotrexate) doxorubicin toxicity potentially may be increased due to decreased hepatic clearance of the preparation.

In case of combined therapy with cyclosporine in high doses and doxorubicin, serum concentrations of both compounds increase. This may cause more evident suppression of bone marrow function and excessive immunosuppression.

Cytochrome Р450 enzyme system inhibitors (for example cimetidine and ranitidin) may delay doxorubicin metabolism, which leads to increase of toxic effects. Cytochrome Р450 enzyme system inducers may stimulate doxorubicin metabolism with possible decrease of therapy effectiveness.

Doxorubicin potentiates the action of radiation and may cause severe symptoms in the irradiated site even in certain time after the end of radiation therapy cause.

In case of combined therapy with docetaxel and doxorubicin, there is a higher possibility of neutropenia development.

In case of combined therapy of doxorubicin and cyclophosphamide, paclitaxel, docetaxel, rituximab, trastuzumab or zosukvid, toxic effects may be increased.

Pharmacological properties.

Pharmacodynamics. Doxorubicin is a cytotoxic antibiotic of anthracycline line, which has glycoside structure, extracted from ray-fungus culture Streptomyces peucetius var.caesius.

Due to high toxicity of the preparation, its antimicrobial activity has not found any clinical use. Mechanism of antineoplastic action of doxorubicin has not been fully studied. There are no predictions as for three main biochemical mechanisms of doxorubicin action. They include intercalation into DNA double spiral, binding with cell membranes and metabolic activation through restoration.

One of the main reasons of inefficiency of treatment with doxorubicin and other anthracyclines is resistance development. In order to overcome cell resistance to doxorubicin calcium antagonists (for example, verapamil) are used. Verapamil blocks slow calcium channels and may increase cell capture of doxorubicin. Experiments on three cell lines of pancreatic gland cancer have demonstrated that verapamil potentiates cytotoxic action of doxorubicin in vitro. It should be noted that in case of combined use of doxorubicin and verapamil severe toxic effects have been observed. Doxorubicinol (the main metabolite of doxorubicin, which is found in human plasma) does not influence on intracellular accumulation and handling of doxorubicin.

Pharmacokinetics. Doxorubicin hydrochloride is not absorbed from gastro-intestinal tract, that is why it is administrated only via parenteral introduction. After intravenous introduction of the preparation there has been observed rapid clearance of doxorubicin from plasma (half-life is10 minutes) and significant tissue binding. Half-life in terminal phase is about 30 hours.

Doxorubicin metabolizes partially with formation of mainly doxorubicinol and to a less extend aglycon doxorubicin with further conjugation with formation of glucuronid and sulphate. Doxorubicin is excreted mainly with bile and feces. About 10 % of the dose is excreted by kidneys. Binding of doxorubicin with plasma proteins is 50-85 %, and the volume of distribution is 800-3500 L/m².

Doxorubicin is not absorbed after oral use. It does not cross blood-brain barrier.

In case of existing hepatic dysfunction, clearance of doxorubicin and its metabolites may decrease.

Pharmaceutical characteristics.

Main physical and chemical properties: orange and red powder.

Incompatibility.

Contact of the preparation with any alkaline solution should be avoided as it induces doxorubicin hydrolysis.

Doxivital 10 should not be mixed with other preparations without compatibility study conduct. In particular it should not be mixed with heparin and 5  fluorouracil due to possibility of residue formation.

Shelf life. 2 years.

Conditions of storage. Store at temperature below 25 °С. Keep out of the reach of children.

Prepared solution is stable within 24 hours at temperature 25 °С when kept in protected from light place or within 48 hours when kept in the refrigerator (2-8 °С).

Package. 1 vial in a carton.

Category of dispensing. On prescription.

Manufacturer. Marksans Pharma Ltd.

Location.

Floor 21, Lotus Business Park, Off New Link Road, Andheri (West), Mumbai – 400053, India;

Village Asaravad, Dudhia, Indor – 453 331, India.

Applicant. Ananta Medicare Ltd.

Location. Suite 1, 2 Station Court, Imperial Wharf, Townmead Road, Fulham, London, United Kingdom

Date of the last review. 25.01.12