Doxvex 50

Doxorubicin for injection USP: Each vial contains: Doxorubicin hydrochloride USP 50 mg; Lactose USP 250 mg (As sterile powder for reconstitution).
Doxvex-50: Orange-Red powder.
Doxorubicin is Red orange, hygroscopic crystalline powder. And Soluble in water, in isotonic sodium chloride solution, and in methanol; practically insoluble in chloroform in ether and in other organic solvents. Doxorubicin hydrochloride chemical name is 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-∞-L-lyxo-hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxylacetyl)-1-methoxy-, hydrochloride (8S-cis)-. (8S,10S)-10-[3-Amino-2,3,6-trideoxy-∞-L-lyxo-hexopyranosyl)-oxy-8-glycoloyl]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12-naphthacenedione hydrochloride and its molecular formula is C₂₇H₂₉NO₁₁·HCl. It's molecular weight is 579.99.

Pharmacological Classification: A 26 Antineoplastic (Cytostatic agent).
Pharmacology: Pharmacodynamics: Doxorubicin is an antimitotic and cytostatic antibiotic, isolated from cultures of Streptomyces peucetius var. caesius, with an antineoplastic action. Its exact mechanism of action of antineoplastic activity is unknown but may involve binding to DNA by intercalation between base pairs and inhibition of DNA and RNA synthesis by template disordering and steric obstruction. Other possible mechanisms of antineoplastic activity include binding to cell membrane lipids, thus altering a variety of cellular functions and interacting with topoisomerase II to form DNA-cleavable complexes.
Pharmacokinetics: Distribution: Doxorubicin is quickly and widely distributed into the extravascular compartments, as indicated by a rapid (5 to 10 min) distribution half-life and by a steady state distribution volume in excess of 20 to 30 litres/kg. However, doxorubicin does not cross the blood-brain barrier in detectable amounts but may cross the placenta and is distributed into breast milk. Binding of doxorubicin to plasma protein is extensive.
Metabolism: Doxorubicin is metabolised to a significant extent by the liver. The major active metabolite is 13-OH-doxorubicinol.
Excretion: The elimination half-life of doxorubicin and 13-OH-doxorubicinol is 20 to 48 hours. Forty to fifty percent of the administered dose is recovered in the bile or in the faeces in seven days, of which about half is as unchanged drug. Renal excretion is modest, accounting for only 5-10 percent of the administered dose in 5 days.

Acute leukaemias (acute lymphoblastic leukaemia - ALL and acute myelogenous leukaemia - AML), lymphomas and a number of solid tumors.
Metastatic adenocarcinoma of the breast, carcinoma of the bladder, bronchogenic carcinoma and neuroblastoma.
Metastatic thyroid carcinoma. Carcinoma of the endometrium, testes, prostate, cervix, head and neck, and plasma-cell myeloma.
It is active against carcinoma of the ovary when administered with cisplatin and cyclophosphamide.
Concurrently with other cytotoxic drugs when administered for carcinoma of the breast and small (oat)-cell carcinoma of the lung.
Wide range of sarcomas including osteogenic, Ewing's and soft-tissue sarcoma.
In the ABVD (doxorubicin/bleomycin/vinblastin/dacarbazine) combination it is effective in Hodgkin's disease.
Concurrently in the BACOP combination in non-Hodgkin's lymphomas.

When possible, to reduce the risk of developing cardiotoxicity in patients receiving doxorubicin after stopping treatment with other cardiotoxic agents, especially those with long half-lives such as trastuzumab, doxorubicin-based therapy should be delayed until the other agents have cleared from the circulation (see Precautions).
Care in the administration of doxorubicin will reduce the chance of perivenous infiltration (see Precautions). It may also decrease the chance of local reactions such as urticaria and erythematous streaking. On intravenous administration of doxorubicin, extravasation may occur with or without an accompanying burning or stinging sensation, even if blood returns well on aspiration of the infusion needle. If any signs or symptoms of extravasation have occurred, the injection or infusion should be immediately terminated and restarted in another vein. If extravasation is suspected, intermittent application of ice to the site for 15 min. q.i.d. x 3 days may be useful. The benefit of local administration of drugs has not been clearly established. Because of the progressive nature of extravasation reactions, close observation and plastic surgery consultation is recommended. Blistering, ulceration and/or persistent pain are indications for wide excision surgery, followed by split-thickness skin grafting.
The most commonly used dose schedule when used as a single agent is 60 to 75 mg/m2 as a single intravenous injection administered at 21-day intervals. The lower dosage should be given to patients with inadequate marrow reserves due to old age, or prior therapy, or neoplastic marrow infiltration.
Doxorubicin has been used concurrently with other approved chemotherapeutic agents. Evidence is available that in some types of neoplastic disease, combination chemotherapy is superior to single agents. The benefits and risks of such therapy continue to be elucidated. When used in combination with other chemotherapy drugs, the most commonly used dosage of doxorubicin is 40 to 60 mg/m2 given as a single intravenous injection every 21 to 28 days.
In a large randomized study (NSABP B-15) of patients with early breast cancer involving axillary lymph nodes. The combination dosage regimen of AC (doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2) was administered intravenously on day 1 of each 21-day treatment cycle. Four cycles of treatment were administered.
Dose Modifications: Patients in the NSABP B-15 study could have dose modifications of AC to 75% of the starting doses for neutropenic fever/infection. When necessary, the next cycle of treatment cycle was delayed until the absolute neutrophil count (ANC) was ≥1000 cells/mm3 and the platelet count was ≥100,000 cells/mm3 and nonhematologic toxicities had resolved.
Doxorubicin dosage must be reduced in case of hyperbilirubinemia as follows: See table.

Click on icon to see table/diagram/image

Acute overdosage with doxorubicin enhances the toxic effects of mucositis, leukopenia, and thrombocytopenia. Treatment of acute overdosage consists of treatment of the severely myelosuppressed patient with hospitalization, antimicrobials, platelet transfusions and symptomatic treatment of mucositis. Use of hemopoietic growth factor (G-CSF, GM-CSF) may be considered.
Cumulative dosage with doxorubicin increases the risk of cardiomyopathy and resultant congestive heart failure (see Precautions). Treatment consists of vigorous management of congestive heart failure with digitalis preparations, diuretics, and after-load reducers such as ACE inhibitors.

Hypersensitivity to doxorubicin or any other component of the product, other anthracyclines or anthracenediones.
Intravenous (IV) use: Persistent myelosuppression; Hepatic impairment; Myocardial insufficiency; Recent myocardial infarction; Severe arrythmias; Previous treatment with maximum cumulative doses of doxorubicin, daunorubicin, epirubicin, idarubicin, and/or other anthracyclines and anthracenediones (see Precautions).
Safety in pregnancy and lactation has not been established.

DOXORUBICIN should be administered only under the supervision of a doctor experienced in cancer chemotherapy.
Patients should be advised not to conceive and the use of contraceptives are advised.
Patients should recover from acute toxicities of prior cytotoxic treatment (such as stomatitis, neutropenia, thrombocytopenia and generalised infections) before beginning treatment with doxorubicin.
Doxorubicin is incompatible with heparin and should also not be mixed with other medicines.
Doxorubicin should be given with great care, in reduced doses, to elderly patients and to those with hepatic impairment.
The systemic clearance of doxorubicin is reduced in obese patients (i.e. >130% ideal body weight; See Dosage & Administration).
Cardiac function: Cardiotoxicity is a risk of anthracycline treatment that may be manifested by early (i.e. acute) or late (i.e. delayed) events.
Early events: This consists mainly of sinus tachycardia and/or ECG abnormalities such as non-specific ST-T wave changes. Tachyarrhythmias, including premature ventricular contractions and ventricular tachycardia, bradycardia as well as atrioventricular and bundle-branch block have also been reported. These events do not usually predict subsequent development of delayed cardiotoxicity, are rarely of clinical importance, and are generally not a consideration for discontinuation of doxorubicin treatment.
Late events: Delayed cardiotoxicity usually develops late in the course of therapy with doxorubicin or within 2 to 3 months after treatment termination, but later events, several months to years after completion of treatment, have also been reported. Delayed cardiomyopathy is manifested by reduced left ventricular ejection fraction (LVEF) and/or signs and symptoms of congestive heart failure (CHF) such as dyspnea, pulmonary oedema, dependent oedema, cardiomegaly and hepatomegaly, oliguria, ascites, pleural effusion and gallop rhythm. Subacute effects such as pericarditis/myocarditis have also been reported. Life-threatening CHF is the most severe form of anthracycline-induced cardiomyopathy and represents the cumulative dose-limiting toxicity of the drug.
Cardiac function should be assessed before patients undergo treatment with doxorubicin and must be monitored throughout therapy to minimise the risk of incurring severe cardiac impairment. The risk may be decreased through regular monitoring of LVEF during the course of treatment with prompt discontinuation of doxorubicin at the first sign of impaired function. The appropriate quantitative method for repeated assessment of cardiac function (evaluations of LVEF) includes multi-gated radionuclide angiography or echocardiography (ECHO). A baseline cardiac evaluation with an ECG and either a multi-gated radionuclide angiography scan or an ECHO is recommended, especially in patients with risk factors for increased cardiotoxicity. Repeated multi-gated radionuclide angiography or ECHO determinations of LVEF should be performed, particularly with higher, cumulative anthracycline doses.
Haematologic toxicity: DOXORUBICIN may produce myelosuppression. Haematologic profiles should be assessed before and during each cycle of therapy with doxorubicin, including differential white blood cell (WBC) counts. A dose-dependent, reversible leukaemia and/or granulocytopenia (neutropenia) is the predominant manifestation of doxorubicin haematologic toxicity and is the most common acute dose-limiting toxicity of this drug. Leukopenia and neutropenia generally reach the nadir between days 10-14 after drug administration; the WBC/neutrophil counts return to normal values in most cases by day 21. Thrombocytopenia and anaemia may also occur. Clinical consequences of severe myelosuppression include fever, infections, sepsis/septicemia, septic shock, haemorrhage, tissue hypoxia or death.
Secondary leukaemia: See Precautions.
Gastro-intestinal: Doxorubicin is emetogenic. Mucositis/stomatitis generally appears early after drug administration and, if severe, may progress over a few days to mucosal ulcerations. Most patients recover from this adverse event by the third week of therapy.
Liver function: The major route of elimination of doxorubicin is the hepatobiliary system. Serum total bilirubin should be monitored before and during treatment with doxorubicin. Patients with elevated bilirubin may experience slower clearance of the drug with an increase in overall toxicity. Lower dose are recommended in these patients (see Dosage & Administration). Patients with severe hepatic impairment should not receive doxorubicin (see Contraindications).
Effects at site of injection: Phlebosclerosis may result from an injection into a small vessel or from repeated injections into the same vein. Following the recommended administration procedures may minimise the risk of phlebitis/thrombophlebitis at the injection site.
Extravasation: Extravasation of doxorubicin during intravenous injection may produce local pain, severe tissue lesions (vesication, severe cellulitis) and necrosis. Should signs or symptoms of extravasation occur during intravenous administration of doxorubicin, the drug infusion should be stopped immediately.
Initial treatment calls for a careful baseline monitoring of various laboratory parameters and cardiac function. Blood counts and measurement of haemoglobin concentration should be carried out routinely.
The occurrence of secondary acute myeloid leukaemia with or without a pre-leukaemic phase has been reported rarely in patients concurrently treated with doxorubicin in association with DNA-damaging antineoplastic agents. Such cases could have a short (1-3 years) latency period.
Fertility impairment: In women, doxorubicin may cause infertility during the time of drug administration. Doxorubicin may cause amenorrhoea. Ovulation and menstruation appear to return after termination of therapy, although premature menopause can occur. Doxorubicin is mutagenic and can induce chromosomal damage in human spermatozoa. Oligospermia or azoospermia may be permanent. Men undergoing doxorubicin treatment should use effective contraceptive methods.

The following adverse events have been reported in association with Adriblastina (doxorubicin) therapy: (Common: approximately 1/100 or =1%, Uncommon: approximately <1/100 or <1%).
Cardiovascular: Common: ECG abnormalities, sinus tachycardia, tachy-arrhythmias, atrio-ventricular and bundle branch block, asymptomatic reductions in left ventricular ejection fraction, congestive heart failure.
Haematologic: Common: leukopenia, anaemia, thrombocytopenia, haemorrhage, neutropenia.
Gastrointestinal: Common: nausea/vomiting, mucositis/stomatitis, oesophagitis, abdominal pain, diarrhea, anorexia, dehydration.
Uncommon: gastric erosions, gastrointestinal bleeding, hyperpigmentation of the oral mucosa, colitis.
Liver: Uncommon: changes in transaminase levels, hyperuricaemia.
Endocrine: Common: amenorrhea, oligospermia, azoospermia.
Uncommon: hot flashes.
Ocular: Uncommon: conjunctivitis/keratitis, lacrimation.
Skin: Common: alopecia, local toxicity, rash/itch, skin changes.
Uncommon: skin and nail hyperpigmentation, hypersensitivity to irradiated skin (radiation recall reaction), photosensitivity, urticaria, acral erythema.
Vascular: Uncommon: phlebitis, thrombophlebitis, thromboembolism.
Urological: Common: red colouration of urine for 1 to 2 days after administration.
Other: Common: malaise/asthenia, fever, infection, sepsis/septicemia, chills, shock.
Uncommon: anaphylaxis, acute lymphocytic leukaemia, acute myelogenous leukaemia.

Doxorubicin is mainly used in combination with other cytotoxic drugs. Additive toxicity may occur especially with regard to bone marrow/haematologic and gastro-intestinal effects (see Precautions). The use of doxorubicin in combination chemotherapy with other potentially cardiotoxic drugs, as well as the concomitant use of other cardioactive compounds (e.g. calcium channel blockers), requires monitoring of cardiac function throughout treatment. Changes in hepatic function induced by concomitant therapies may affect doxorubicin metabolism, pharmacokinetics, therapeutic efficacy and/or toxicity.

Reconstitution Directions: It is recommended that doxorubicin be slowly administered into the tubing of a freely running intravenous infusion of Sodium Chloride Injection or 5% Dextrose Injection. The tubing should be attached to a Butterfly needle inserted preferably into a large vein. If possible, avoid veins over joints or in extremities with compromised venous or lymphatic drainage. The rate of administration is dependent on the size of the vein and the dosage. However, the dose should be administered in not less than 3 to 5 minutes. Local erythematous streaking along the vein as well as facial flushing may be indicative of too rapid an administration. A burning or stinging sensation may be indicative of perivenous infiltration and, if this occurs, the infusion should be immediately terminated and restarted in another vein. Perivenous infiltration may occur painlessly.
Doxorubicin should not be mixed with heparin or fluorouracil since it has been reported that these drugs are incompatible to the extent that a precipitate may form. Contact with alkaline solutions should be avoided since this can lead to hydrolysis of doxorubicin. Until specific compatibility data are available, it is not recommended that doxorubicin be mixed with other drugs.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Reconstituted: Chemical and physical in-use stability after reconstitution has been demonstrated for up to 8 hours at 25°C, and for up to 5 days at 2°C-8°C. From a microbiological point of view, the medicinal product should be used immediately.

Store at temperatures not exceeding 30°C. Protect from light.
Shelf Life: 2 years from the date of manufacturing.

Cytotoxic Chemotherapy

L01DB01 - doxorubicin ; Belongs to the class of cytotoxic antibiotics, anthracyclines and related substances. Used in the treatment of cancer.

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