Product Monograph - Adriamycin Rdf

INDICATIONS AND CLINICAL USE

ADRIAMYCIN has been used successfully both as a single agent and also in combination with other approved cancer chemotherapeutic agents to produce regression in neoplastic conditions such as acute lymphoblastic leukemia, acute myeloblastic leukemia, Wilms’ tumour, neuroblastomas, soft tissue sarcomas, bone sarcomas, breast carcinomas, gynecologic carcinomas, testicular carcinomas, bronchogenic carcinoma, Hodgkin's disease, non-Hodgkin's lymphoma, thyroid carcinoma, bladder carcinomas, squamous cell carcinoma of the head and neck, and gastric carcinoma.

ADRIAMYCIN has also been used by instillation into the bladder for the topical treatment of superficial bladder tumours.

A number of other solid tumours have also shown some responsiveness to ADRIAMYCIN alone or in combination with other drugs. (Refer to DOSAGE AND ADMINISTRATION) Studies to date have shown malignant melanoma, kidney carcinoma, large bowel carcinomas, brain tumours and metastases to the central nervous system not to be significantly responsive to ADRIAMYCIN therapy.

CONTRAINDICATIONS

Hypersensitivity to doxorubicin or any other component of the product, other anthracyclines or anthracenediones such as PHARMORUBICIN (epirubicin hydrochloride), daunorubicin hydrochloride, mitoxantrone or mitomycin C. • marked persistent myelosupression induced by prior treatment with other antitumor agents or by radiotherapy
severe hepatic impairment
severe myocardial insufficiency
recent myocardial infarction
severe arrhythmias
history of severe cardiac disease
previous treatment with maximum cumulative doses of doxorubicin, daunorubicin, epirubicin, idarubicin and/or other anthracyclines and anthracenediones (See WARNINGS and PRECAUTIONS)

Intravesical use:

invasive tumors that have penetrated the bladder wall
urinary infections
inflammation of the bladder

WARNINGS

Cardiac Function - Cardiotoxicity is a risk of anthracycline treatrment that may be manifested by early (i.e. acute) or late (i.e. delayed) events.

Early (i.e., Acute) Events. Early cardiotoxicity of doxorubicin 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, and atrioventricular and bundle-branch block have alsobeen reported. Those effects usually do not predict subsequent development of delayed cardiotoxicity, are rarely of clinical importance and generally do not necessitate discontinuation of doxorubicin treatment.

Late (i.e., Delayed) Events. Delayed cardiotoxicity usually develops late in the course of therapy with doxorubicin or within 2 to 3 months after treatment termination; however, events occuring 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 edema, dependent edema, cardiomegaly and hepatomegaly, oliguria, ascites, pleural effusion and gallop rhythm. Subacute effects such as pericarditis/myocarditis also have been reported. Life-threatening CHF is the most severe form of anthracycline induced cardiomyopathy and is the cumulative dose-limiting toxicity of anthracycline drugs.

Cardiac function should be assessed before patients undergo treatment with doxorubicin and must be monitored throughout therapy to minimize 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 (evaluation of LVEF) includes multi-gated radionuclide angiography (MUGA) or echocardiography (ECHO). A baseline cardiac evaluation with an ECG and either a MUGA scan or an ECHO is recommended, especially in patients with risk factors for increased cardiotoxicity. Repeated MUGA or ECHO determinations of LVEF should be performed, particularly with higher cumulative anthracycline doses. The technique used for assessment should be consistent throughout follow-up.

The probability of developing CHF, estimated around 1% to 2% at a cumulative dose of 300 mg/m², slowly increases up to the total cumulative dose of 450-550 mg/m². Thereafter, the risk of developing CHF increases steeply. IT IS RECOMMENDED NOT TO EXCEED A MAXIMUM CUMULATIVE DOSE OF 550 mg/m²of ADRIAMYCIN.

Risk factors for cardiac toxicity include active or dormant cardiovascular disease, prior or concomitant radiotherapy to the mediastinal/pericardial area, previous therapy with other anthracyclines or anthracenediones and concomitant use of drugs with the ability to suppress cardiac contractility. Cardiac function must be carefully monitored in patients receiving high cumulative doses and in those with risk factors. While cardiotoxicity with doxorubicin may occur at lower cumulative doses whether or not cardiac risk factors are present, it may be more likely to occur at lower cumulative doses in patients with these risk factors. The total dose of ADRIAMYCIN administered to a patient should take into account: prior or concomitant therapy with related compounds such as epirubicin and daunorubicin or anthracene derivatives; and/or radiotherapy to the mediastinal area.

Acute life-threatening arrhythmias have been reported to occur during or within a few hours after ADRIAMYCIN administration. (See ADVERSE REACTIONS)

Hematologic Toxicity

As with other cytotoxic agents, doxorubicin may produce myelosuppression. Hematologic profiles should be assessed before and during each cycle of therapy with doxorubicin, including differential white blood cell (WBC) counts. A dose-dependent, reversible leukopenia and/or granulocytopenia (neutropenia) is the predominant manifestation of doxorubicin hematologic toxicity and is the most common acute dose-limiting toxicity of this drug. Leukopenia and neutropenia generally reach the nadir between days 10 and 14 after drug administration; the WBC/neutrophil counts return to normal values in most cases by day 21. Thrombocytopenia and anemia may also occur. Clinical consequences of severe myelosuppression include fever, infections, sepsis/septicemia, septic shock, hemorrhage, tissue hypoxia, or death. Haematologic toxicity may require dose reduction or suspension or delay of ADRIAMYCIN therapy. Persistent severe myelosuppression may result in superinfection or haemorrhage.

Secondary Leukemia

Secondary leukemia, with or without a preleukemic phase, has been reported in patients treated with anthracyclines. Secondary leukemia is more common when anthracyclines are given in combination with DNA-damaging antineoplastic agents. Secondary leukemia can have a 1 to 3 year latency period.

Hepatic Impairment

Doxorubicin is extensively metabolized by the liver and its major route of elimination is the hepatobiliary system. Toxicity to recommended doses of ADRIAMYCIN is enhanced by hepatic impairment, therefore, prior to the individual dosing and during treatment, evaluation of hepatic function is recommended using conventional clinical laboratory tests such as SGOT, SGPT, alkaline phosphatase and bilirubin. Patients with elevated bilirubin may experience slower clearance of doxorubicin with an increase in overall toxicity. Lower doses of doxorubicin are recommended in these patients (See DOSAGE AND ADMINISTRATION). Patients with severe hepatic impairment should not receive doxorubicin (See CONTRAINDICATIONS).

Urological Effects

ADRIAMYCIN PFS may impart a red colouration to the urine for 1 to 2 days after administration and patients should be advised to expect this during active therapy.

Gastrointestinal Events

Doxorubicin is emetigenic. 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.

Necrotizing colitis manifested by typhlitis (cecal inflammation), bloody stools and severe and sometimes fatal infections have been associated with a combination of ADRIAMYCIN given by i.v. push daily for 3 days and cytarabine given by continuous infusion daily for 7 or more days.

Vascular Effects

Phlebosclerosis may result from an injection into a small vessel or from repeated injections into the same vein. Following the recommended administration procedures may minimize the risk of phlebitis/thrombophlebitis at the injection site (see DOSAGE AND ADMINISTRATION).

As with other cytotoxic agents, thrombophlebitis and thromboembolic phenomena, including pulmonary embolism (in some cases fatal), have been coincidentally reported with the use of doxorubicin.

Extravasation

Extravasation of doxorubicin during intravenous injection may produce local pain, severe tissue lesions (vesication, severe cellulitis) and necrosis. If any signs or symptoms of extravasation have occurred the injection or infusion should be immediately stopped.

Toxicites With Co-administration of Antineoplastic Agents

ADRIAMYCIN may potentiate the toxicity of other anticancer therapies. Exacerbation of cyclophosphamide induced hemorrhagic cystitis and enhancement of the hepatotoxicity of 6-mercaptopurine have been reported. Radiation-induced toxicity to the myocardium, mucosae, skin and liver has been reported to be increased by the administration of ADRIAMYCIN.

Patients should recover from acute toxicities of prior cytotoxic treatment (such as stomatitis, neutropenia, thrombocytopenia, and generalized infections) before beginning treatment with doxorubicin.

Additional Warnings and Precautions for Other Routes of Administration

Intravesical Route of Administration

Administration of doxorubicin by the intravesical route may produce symptoms of chemical cystitis (such as dysuria, polyuria, nocturia, stranguria, hematuria, bladder discomfort, necrosis of the bladder wall) and bladder constriction. Special attention is required for catheterization problems (e.g., uretheral obstruction due to massive intravesical tumors.

Carcinogenesis & Mutagenesis, Impairment of Fertility

Doxorubicin was genotoxic in a battery of in vitro or in vivo tests. An increase in the incidence of mammary tumors was reported in rats, and a trend for delay or arrest of follicular maturation was seen in female dogs.

In women, doxorubicin may cause infertility during the time of drug administration. Doxorubicin may cause amenorrhea. Ovulation and menstruation appear to return after termination of therapy, although premature menopause can occur.

Doxorubicin was toxic to male reproductive organs in animal studies, producing testicular atrophy, diffuse degeneration of the seminiferous tubules, and hypospermia.

Doxorubicin is mutagenic and can induce chromosomal damage in human spermatozoa. Oligospermia or azoospermia may be permanent; however, sperm counts have been reported to return to normospermic levels in some instances. This may occur several years after the end of therapy. Men undergoing doxorubicin treatment should use effective contraceptive methods.

Pregnancy and Lactation

The embryotoxic potential of doxorubicin was confirmed in vitro and in vivo. When given to female rats before and during mating, pregnancy, and lactation, doxorubicin was toxic to both dams and fetuses.

Doxorubicin has been implicated in causing fetal harm when administered to a pregnant woman. If a woman receives doxorubicin during pregnancy or becomes pregnant while taking the drug, she should be informed of the potential hazard to the fetus.

Doxorubicin is secreted into breast milk. Mothers should not breast-feed while undergoing chemotherapy with ADRIAMYCIN.

PRECAUTIONS

Initial treatment with ADRIAMYCIN RDF requires close observation of the patient and extensive laboratory monitoring. Like other cytotoxic drugs, ADRIAMYCIN RDF may induce hyperuricemia secondary to rapid lysis of neoplastic cells, particularly in patients with leukemia. The clinician should monitor the patient's serum chemistry and blood uric acid level and be prepared to use such supportive and pharmacologic measures as might be necessary to control this problem. Hydration, urine alkalinization and allopurinol administration will help to prevent or minimize potential complications of tumor-lysis syndrome.

The systemic clearance of doxorubicin has been found to be reduced in obese patients (i.e., > 130% ideal body weight); see DOSAGE AND ADMINISTRATION, Other Special Populations).

ADRIAMYCIN RDF is not an anti-microbial agent.

Interactions

Doxorubicin is mainly used in combination with other cytotoxic drugs. Additive toxicity may occur especially with regard to bone marrow/hematologic and gastrointestinal effects (see WARNINGS and 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.

ADVERSE REACTIONS

The following adverse events have been reported in association with doxorubicin therapy:

Cardiovascular: sinus tachycardia, ECG abnormalities, tachyarrhythmias, atrio-ventricular and bundle branch block, asymptomatic reductions in left ventricular ejection fraction, congestive heart failure (See WARNINGS)

Hematologic: leukopenia, neutropenia, anemia, thrombocytopenia, hemorrhage Gastrointestinal: anorexia, nausea/vomiting, dehydration, mucositis/stomatitis, hyperpigmentation of the oral mucosa, esophagitis, abdominal pain, gastric erosions, gastrointestinal tract bleeding, diarrhea, colitis Liver: changes in transaminase levels, hyperuricemia Endocrine: amenorrhea, hot flashes, oligospermia, azoospermia Ocular: conjunctivitis/keratitis, lacrimation

Skin: alopecia, local toxicity, rash/itch, skin changes, skin and nail hyperpigmentation, photosensitivity, hypersensitivity to irradiated skin (‘radiation recall reaction’), urticaria, acral erythema Vascular: phlebitis, thrombophlebitis, thromboembolism Urological: red coloration of urine for 1 to 2 days after administration Bladder, local: pain, hemorrhage, and occasionally decreased bladder capacity upon instillation

Local: severe cellulitis, vesication, tissue necrosis upon extravasation, erythematous streaking along the vein proximal to the site of the injection (see DOSAGE AND ADMINISTRATION) Other: anaphylaxis, infection, sepsis/septicemia, acute lymphocytic leukemia, acute myelogenous leukemia, malaise/asthenia, fever, chills, shock, cross sensitivity to lincomycin

OVERDOSAGE

Acute overdosage with ADRIAMYCIN RDF enhances the toxic effects of mucositis, leukopenia and thrombocytopenia. Treatment of acute overdosage consists of treatment of the severely myelosuppressed patient with hospitalization, antibiotics, platelet and granulocyte transfusions and symptomatic treatment of mucositis. Acute overdosage with doxorubicin will result in severe myelosuppression (mainly leukopenia and thrombocytopenia), gastrointestinal toxic effects (mainly mucositis) and acute cardiac alterations.

Chronic overdosage with cumulative doses exceeding 550 mg/m²increases the risk of cardiomyopathy and resultant congestive heart failure. Treatment consists of vigorous management of congestive heart failure with digitalis preparations and diuretics. The use of peripheral vasodilators has been recommended.

DOSAGE AND ADMINISTRATION

REFER TO GUIDELINES FOR SAFE PREPARATION AND HANDLING

Dosage

A variety of dose schedules has been used. The following recommendations are for use as a single agent only.

Intravenous (I.V.) Administration

The total doxorubicin dose per cycle may differ according to its use within a specific treatment regimen (e.g. given as a single agent or in combination with other cytotoxic drugs) and according to the indication.

The most commonly used dosage schedule is 60-75 mg/m²as a single intravenous injection administered at 21-day intervals. An alternative dose schedule is weekly doses of 20 mg/m²which has been reported to produce a lower incidence of congestive heart failure. A dose of 30 mg/m²on each of three successive days repeated every 4 weeks has also been used.

Hepatic Dysfunction. ADRIAMYCIN dosage must be reduced if the bilirubin is elevated as follows: Serum Bilirubin 1.2-3.0 mg/dL -- give ½ of recommended starting dose, > 3 mg/dL -- give ¼ of recommended starting dose. Doxorubicin should not be administered to patients with severe hepatic impairment (See CONTRAINDICATIONS).

Other Special Populations. Lower starting doses or longer intervals between cycles may need to be considered for heavily pretreated patients, children, elderly patients, obese patients, or patients with neoplastic bone marrow infiltration. (See WARNINGS, PRECAUTIONS)

Intravesical Administration

When ADRIAMYCIN RDF is instilled intravesically for the treatment of superficial bladder carcinomas, the usual dose employed ranges from 50-80 mg in a total volume of 50-100 mL of 0.9% Sodium Chloride Solution USP with a contact time of 1-2 hours. Care should be taken to ensure that the tip of the catheter is in the bladder cavity before instilling the ADRIAMYCIN solution. Instillation is repeated weekly for 4 weeks and subsequently at monthly intervals. Therapy may continue for one year or longer as no significant systemic toxicity has been reported. Care should be exercised in the handling and disposal of the voided urine. (Refer to GUIDELINES FOR SAFE PREPARATION AND HANDLING). PVC gloves should be worn and the urine should be inactivated by decolourizing it with 10 mL or more of sodium hypochlorite solution (household bleach).

Other methods of administration have been investigated including intra-arterial administration and also continuous or long term intravenous infusion utilizing appropriate infusion pumps.

Clinical studies support the efficacy of ADRIAMYCIN used concurrently with other chemotherapeutic agents. Listed below are tumour types and drugs used concurrently with ADRIAMYCIN:

Acute lymphocytic leukemia in adults: ADRIAMYCIN with vincristine and prednisone or with cytosine arabinoside, vincristine and prednisone.

Acute lymphocytic leukemia in children: ADRIAMYCIN with L-asparaginase, vincristine and prednisone.

Acute non-lymphocytic leukemia: ADRIAMYCIN with cytosine arabinosyl or with arabinosyl cytosine, vincristine and prednisone.

Carcinoma of the breast: ADRIAMYCIN with 5-fluorouracil and/or cyclophosphamide or with vincristine with or without cyclophosphamide.

Bronchogenic carcinoma, non-small cell: ADRIAMYCIN with cyclophosphamide, methotrexate and procarbazine or with cyclophosphamide and cisplatinum.

Bronchogenic carcinoma, small cell: ADRIAMYCIN with vincristine or etoposide (VP-16) and cyclophosphamide.

Hodgkin's disease: ADRIAMYCIN with bleomycin, vincristine and dacarbazine.

Non-Hodgkin's lymphoma: ADRIAMYCIN with cyclophosphamide, vincristine and prednisone, or bleomycin, cyclophosphamide, vincristine and prednisone.

Carcinoma of the ovary: ADRIAMYCIN with cisplatinum.

Soft tissue sarcoma: ADRIAMYCIN with dacarbazine, or with dacarbazine, cyclophosphamide and vincristine.

Carcinoma of the bladder: ADRIAMYCIN with methotrexate, vinblastine and cisplatinum or cisplatinum and cyclophosphamide or with 5-fluorouracil.

Carcinoma of the stomach: ADRIAMYCIN with 5-fluorouracil and mitomycin-C.

ADMINISTRATION:

Intravenous Administration

Care in the administration of ADRIAMYCIN RDF will reduce the chance of perivenous infiltration. It may also decrease the chance of local reactions such as urticaria and erythematous streaking. On intravenous administration of ADRIAMYCIN RDF, extravasation may occur with or without an accompanying stinging or burning sensation even if the 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 it is known or suspected that subcutaneous extravasation has occurred, the following steps are recommended:

1. Attempt aspiration of the infiltrated ADRIAMYCIN solution.
2. Local intermittent application of ice for up to 3 days.
3. Elevation of the affected limb.
4. Close observation of the lesion.
5. Consultation with a plastic surgeon familiar with drug extravasations if local pain persists or skin changes progress after 3 to 4 days. If ulceration begins, early wide excision of the involved area should be considered.

ADRIAMYCIN RDF 10 mg, 50 mg and 150 mg vials should be reconstituted with 5 mL, 25 mL and 75 mL respectively of 0.9% Sodium Chloride Solution USP to give a final concentration of 2 mg/mL of doxorubicin hydrochloride. Bacteriostatic diluents are not recommended.

After adding the diluent, the vial should be shaken until the contents are dissolved. A slight suspension may form which will completely dissolve on further shaking. The vials are under negative pressure and care should be taken to avoid a pressure build up. To minimize aerosol formation during reconstitution; particular care should be taken when the needle is inserted. Inhalation of any aerosol produced during reconstitution should also be avoided. The reconstituted solution is stable for 24 hours at room temperature and 48 hours under refrigeration 2-8^oC. The solution should be protected from exposure to direct light. For single dose vials, any unused solution should be discarded.

ADRIAMYCIN RDF should be slowly administered into the tubing of a freely running intravenous infusion of Sodium Chloride Solution USP (0.9%) or 5% Dextrose Solution USP. The tubing should be attached to a Butterfly^*needle, or other suitable device and 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 dosage should be administered for not less than 3 minutes and not more than 10 minutes to minimize the risk of thrombosis or perivenous extravasation. Local erythematous streaking along the vein as well as facial flushing may be indicative of too rapid administration. A direct push injection is not recommended due to the risk of extravasation, which may occur even in the presence of adequate blood return upon needle aspiration (see WARNINGS and PRECAUTIONS).

Unless specific compatibility data are available, the mixing of ADRIAMYCIN solutions with other drugs is not recommended. Precipitation occurs with 5-fluorouracil and heparin.

Intravesical administration

Doxorubicin should be instilled using a catheter and retained intravesically for 1 to 2 hours. Care should be taken to ensure that the tip of the catheter is in the bladder cavity before instilling the ADRIAMYCIN solution. During instillation, the patient should be rotated to ensure that the vesical mucosa of the pelvis receives the most extensive contact with the solution. To avoid dilution with urine, the patient should be instructed not to drink any fluid in the 12 hours prior to instillation. The patient should be instructed to void at the end of the instillation.

GUIDELINES FOR SAFE PREPARATION AND HANDLING

Preparation and Handling

1.
Personnel should be trained in good techniques for reconstitution and handling.
Pregnant staff should be excluded from working with this drug.
2.
Preparation of antineoplastic solutions should be done in a vertical laminar flow hood
(Biological Safety Cabinet - Class II). The work surface should be protected by disposable, plastic-backed absorbent paper.
3. Personnel handling ADRIAMYCIN solutions should wear PVC gloves, safety glasses and protective clothing such as disposable gowns and masks. If ADRIAMYCIN contacts the skin or mucosa, the area should be washed with soap and water or sodium bicarbonate immediately. Do not abrade the skin by using a scrub brush and always wash hands after removing gloves.
4.
In case of contact with the eye(s), hold back the eyelid(s) and flush the affected eye(s)
with copious amounts of water for at least 15 minutes, proceed to a physician for a medical evaluation.
5. Personnel regularly involved in the preparation and handling of antineoplastics should have blood examinations on a regular basis.
6.
Directions for Dispensing from Pharmacy Bulk Vial
The use of Pharmacy Bulk Vials is restricted to hospitals with a recognized intravenous admixture program. The Pharmacy Bulk Vial is intended for single puncture, multiple dispensing and for intravenous use only.
Entry into the vial must be made with a sterile dispensing device such as the Econ-O-Set® Sterile Transfer System. Multiple use of a syringe with needle is not recommended since it may cause leakage as well as increasing the potential for microbial and particulate contamination.
Swab the vial stopper with an antiseptic solution. Following carefully the manufacturer's instructions, insert the device into the vial. Withdraw contents of vial into syringes, using aseptic technique. Discard any unused portion within eight hours of initial entry. Disposal
1. Avoid contact with skin and inhalation of airborne particles by use of PVC gloves and disposable gowns and masks.
2. All needles, syringes, vials and other materials which have come in contact with doxorubicin should be segregated in plastic bags, sealed, and marked as hazardous waste. Incinerate at 1000/C or higher. Sealed containers may explode if a tight seal exists.
3. If incineration is not available, ADRIAMYCIN may be detoxified by adding sodium hypochlorite solution (household bleach) to the vial, in sufficient quantity to decolourize the doxorubicin, care being taken to vent the vial to avoid a pressure build-up of the chlorine gas which is generated. Dispose of detoxified vials in a safe manner.

Needles, syringes, disposable and non-disposable equipment:

Rinse equipment with an appropriate quantity of sodium hypochlorite solution. Discard the solution in the sewer system with running water and discard disposable equipment in a safe manner. Thoroughly wash non-disposable equipment in soap and water.

Spillage/Contamination:

Wear gloves, mask, protective clothing. Treat spilled powder or liquid with dilute sodium hypochlorite solution (1% available chlorine). Carefully absorb solution with gauze pads or towels, wash area with water and absorb with gauze or towels again and place in polyethylene bag; seal, double bag and mark as hazardous waste. Dispose of waste by incineration or by other methods approved for hazardous materials. Personnel involved in clean-up should wash with soap and water.

PHARMACEUTICAL INFORMATION

CHEMISTRY

Trade Name: ADRIAMYCIN^*RDF^*

Proper Name: Doxorubicin Hydrochloride

Chemical Name: (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 (USAN).

Structural Formula:

Molecular Formula: C₂₇H₂₉NO₁₁.HCl

Molecular Weight: 579.98

Description: Doxorubicin hydrochloride is the hydrochloric acid salt of a glycoside antibiotic produced by S. peucetius var. caesius. It is a red-orange, almost odourless, hygroscopic powder, m.p. 205°C (dec.),

["]²⁰+ 248°(c = 0.1 methanol), and soluble in water and dilute D

alcohols.

Composition:

ADRIAMYCIN RDF is a sterile, red-orange lyophilized powder. Methylparaben is added to enhance dissolution.

10 mg Vials - Each vial contains 10 mg of Doxorubicin Hydrochloride USP, 50 mg of lactose NF and 1 mg of methylparaben NF.

50 mg Vials - Each vial contains 50 mg of Doxorubicin Hydrochloride USP, 250 mg of lactose NF and 5 mg of methylparaben NF.

150 mg Pharmacy - Each vial contains 150 mg of Doxorubicin

Bulk Vial Hydrochloride USP, 750 mg of lactose NF and 15 mg of methylparaben NF.

Incompatibility:

Unless specific compatibility data are available, ADRIAMYCIN RDF should not be mixed with other drugs. Contact with alkaline solutions should be avoided since this can lead to hydrolysis of doxorubicin. Doxorubicin should not be mixed with heparin due to chemical incompatibility that may lead to precipitation. Precipitation also occurs with 5-fluorouracil.

RECONSTITUTION

Solutions for Reconstitution

0.9% Sodium Chloride Injection USP

(without bacteriostatic agent)

RECONSTITUTION TABLE

Diluent Approximate Approximate

Added Available Concentration Vial Size to Vial (mL) Volume (mL) (mg/mL)

10 mg 5 5 2 50 mg 25 25 2 150 mg 57 75 2

See Preparation of Solution for instructions.

DOSAGE FORMS

Availability:

ADRIAMYCIN RDF (DOXORUBICIN HYDROCHLORIDE FOR INJECTION) is supplied as a sterile lyophilized powder. The following single dose vial sizes are available:

10 mg vials supplied in 10 vial cartons.

50 mg vials supplied in single vial cartons.

Pharmacy Bulk Vial:

150 mg vials supplied in single vial cartons.

NOTE:

THE USE OF PHARMACY BULK VIALS IS RESTRICTED TO HOSPITALS WITH A RECOGNIZED INTRAVENOUS ADMIXTURE PROGRAM. THE PHARMACY BULK VIAL IS INTENDED FOR SINGLE PUNCTURE, MULTIPLE DISPENSING AND FOR INTRAVENOUS USE ONLY.

Entry into the vial must be made with a suitable, sterile transfer or dispensing device. Multiple use of a syringe with needle is not recommended since it may cause leakage as well as it may increase the potential for microbial and particulate matter contamination.

In a suitable work area such as a laminar flow hood, swab the vial stopper with an antiseptic solution. Insert the device into the vial. Withdraw contents of the vial into sterile syringes using strict aseptic techniques. Dispensing from the Pharmacy Bulk Vial should be completed within eight hours of the initial entry because of the potential for microbial contamination. Discard any unused portion. The contents of the syringes filled from the Pharmacy Bulk Vial should be used within 24 hours at room temperature or 48 hours when refrigerated from the time of the initial entry into the Pharmacy Bulk Vial. Storage:

Store ADRIAMYCIN RDF sterile lyophilized powder for injection at 15-30^oC and protected from light.

Stability of Solution

The reconstituted solution is stable for 24 hours at room temperature or for 48 hours under refrigeration. The solution should be protected from exposure to direct light and any unused solution should be discarded.

Dispensing from the Pharmacy Bulk Vial should be completed within eight hours of initial entry because of the potential for microbial contamination.

PHARMACOLOGY

ADRIAMYCIN, when administered i.v., is rapidly cleared from the plasma of rodents, with concentration of the drug being seen in the liver, spleen, kidney, lung and heart. Drug excretion is prolonged and occurs predominantly via the liver.

In man, ADRIAMYCIN has also been shown to have a rapid plasma clearance and a large volume of distribution that suggests an extensive drug distribution into the tissues. Urinary excretion is minimal, with only 5% of the drug excreted during the first five days as measured by fluorimetric methods, suggesting prolonged tissue binding. After an injection of 1.5 mg/kg of tritium labelled ADRIAMYCIN approximately 50% of the administered radioactivity was detected in the feces in seven days, while in patients with impaired liver function, the fecal excretion accounted for only 20%. ADRIAMYCIN is metabolized predominantly by the liver to adriamycinol and several aglycone derivatives; approximately half of the drug excreted in bile was unchanged ADRIAMYCIN and 30% conjugates. Biliary excretion of ADRIAMYCIN was measured in one patient. A total of 40% of the administered dose was recovered as fluorescent material in the bile over a one week period.

The predominant fluorescent material in both urine and bile was ADRIAMYCIN followed by adriamycinol. Pharmacokinetic studies in patients with hepatic dysfunction show significant and prolonged plasma levels of ADRIAMYCIN metabolites associated with exaggerated clinical cytotoxicity. These observations are the basis of a requirement for dose de-escalation in patients with impaired hepatic function.

Neither ADRIAMYCIN nor any of its fluorescent metabolites were detectable in human cerebrospinal fluid obtained at varying intervals after drug administration in a variety of patients, including some with meningeal leukemia and cerebral metastasis, situations in which the blood brain barrier might be expected to be altered.

ANIMAL TOXICITY

Toxicology

The acute toxicity of ADRIAMYCIN in Swiss mice varies greatly according to the route of administration. The LD₅₀is 8.5 mg/kg by the intra-peritoneal route, 21.1 mg/kg by the intravenous route, and greater than 750 mg/kg by the oral route.

Chronic toxicity was studied in the rabbit and in the dog. ADRIAMYCIN when administered i.v. for three months at a daily dose of 0.125 mg/kg of body weight did not cause mortality or any measurable morphologic and functional changes in either species. At a dose of 0.25 mg/kg/day a few lesions were observed in the rabbit and more serious lesions in the dog, where the mortality rate reached 30%. The 0.5 mg/kg/day dose produced death in 40% of the treated rabbits within two months, and in 100% of the treated dogs within 10 days. Organs affected were gastrointestinal mucosa, hemopoietic tissues, and testes in both species, kidneys in the rabbit and skin (alopecia and melanosis) in the dog.

Teratology

ADRIAMYCIN when administered intravenously to rats at doses of 0.8 mg/kg/day during the period of organogenesis, resulted in an increased incidence of fetal resorption and fetal skeletal and soft tissue malformations. Rats treated intraperitoneally with doses of 1 mg/kg/day or greater also demonstrated skeletal and soft tissue malformations. The intravenous administration of ADRIAMYCIN to rabbits at doses of 0.1 mg/kg/day interfered with implantation and caused fetal resorption and at doses of 0.6 mg/kg/day was abortifacient. In addition, high single doses of 2 or 4 mg/kg in rabbits were shown to block implantation when administered on day 3 of pregnancy, to be embryotoxic when administered on day 7 of pregnancy, and to be abortifacient when administered on days 11, 15 or 20 of pregnancy.

Carcinogenicity

ADRIAMYCIN has been shown to be carcinogenic in the rat. The drug caused the appearance of breast fibroadenomas after a single i.v. dose of 8.0 mg/kg at an average of 33 weeks in 6 of 25 animals. Another animal developed a breast adenocarcinoma.

General

ADRIAMYCIN RDF was compared to the regular ADRIAMYCIN lyophilized formulation administered i.p. in P388 leukemic mice and i.v. to Gross leukemic mice. No difference in activity or toxicity was noted between the two formulations.

In local tolerance studies conducted in mice, rats, rabbits, and dogs, either by the intravenous or intradermal routes, the lesions induced by the ADRIAMYCIN RDF formulation appeared to be similar to those obtained with the ADRIAMYCIN lyophilized formulation.In other tests using ADRIAMYCIN RDF, there was no evidence of incompatibility with human blood, plasma or serum.

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Adriamycin Rdf Product Monograph