Adriamycin injection, usp

Name: Adriamycin injection, usp

Indications and Usage

Adriamycin (DOXOrubicin HCl) Injection, USP and Adriamycin (DOXOrubicin HCl) for Injection, USP have been used successfully to produce regression in disseminated neoplastic conditions such as acute lymphoblastic leukemia, acute myeloblastic leukemia, Wilms' tumor, neuroblastoma, soft tissue and bone sarcomas, breast carcinoma, ovarian carcinoma, transitional cell bladder carcinoma, thyroid carcinoma, gastric carcinoma, Hodgkin's disease, malignant lymphoma and bronchogenic carcinoma in which the small cell histologic type is the most responsive compared to other cell types.

Drug Interactions

Literature contains the following drug interactions with doxorubicin in humans: cyclosporine (Sandimmune) may induce coma and/or seizures, phenobarbital increases the elimination of doxorubicin, phenytoin levels may be decreased by doxorubicin, streptozocin (Zanosar) may inhibit the hepatic metabolism, and administration of live vaccines to immunosuppressed patients, including those undergoing cytotoxic chemotherapy, may be hazardous.

Paclitaxel:   Two published studies report that initial administration of paclitaxel infused over 24 hours followed by doxorubicin administered over 48 hours resulted in a significant decrease in doxorubicin clearance with more profound neutropenic and stomatitis episodes than the reverse sequence of administration.

Progesterone:   In a published study, progesterone was given intravenously to patients with advanced malignancies (ECOG PS < 2) at high doses (up to 10 g over 24 hours) concomitantly with a fixed doxorubicin dose (60 mg/m 2 ) via bolus. Enhanced doxorubicin-induced neutropenia and thrombocytopenia were observed.

Verapamil:   A study of the effects of verapamil on the acute toxicity of doxorubicin in mice revealed higher intial peak concentrations of doxorubicin in the heart with a higher incidence and severity of degenerative changes in cardiac tissue resulting in a shorter survival.

Cyclosporine:   The addition of cyclosporine to doxorubicin may result in increases in AUC for both doxorubicin and doxorubicinol possibly due to a decrease in clearance of parent drug and a decrease in metabolism of doxorubicinol. Literature reports suggest that adding cyclosporine to doxorubicin results in more profound and prolonged hematologic toxicity than doxorubicin alone. Coma and/or seizures have also been described.

Literature reports have also described the following drug interactions: phenobarbital increases the elimination of doxorubicin, phenytoin levels may be decreased by doxorubicin, streptozocin (Zanosar) may inhibit hepatic metabolism of doxorubicin, and administration of live vaccines to immunosuppressed patients including those undergoing cytotoxic chemotherapy may be hazardous.

Laboratory Tests:   Initial treatment with doxorubicin requires observation of the patient and periodic monitoring of complete blood counts, hepatic function tests, and radionuclide left ventricular ejection fraction (see WARNINGS ).

Like other cytotoxic drugs, doxorubicin may induce "tumor lysis syndrome" and hyperuricemia in patients with rapidly growing tumors. Appropriate supportive and pharmacologic measures may prevent or alleviate this complication.

Carcinogenesis, Mutagenesis, Impairment of Fertility: Formal long-term carcinogenicity studies have not been conducted with doxorubicin. Doxorubicin and related compounds have been shown to have mutagenic and carcinogenic properties when tested in experimental models (including bacterial systems, mammalian cells in culture, and female Sprague-Dawley rats).

The possible adverse effect on fertility in males and females in humans or experimental animals have not been adequately evaluated. Testicular atrophy was observed in rats and dogs.

Treatment-related acute myelogenous leukemia has been reported in patients treated with doxorubicin-containing adjuvant chemotherapy regimens (see ADVERSE REACTIONS , Hematologic ). The exact role of doxorubicin has not been elucidated. Pediatric patients treated with doxorubicin or other topoisomerase II inhibitors are at risk for developing acute myelogenous leukemia and other neoplasms. The extent of increased risk associated with doxorubicin has not been precisely quantified.

Pregnancy Category D:   (See WARNINGS .)

Nursing Mothers:   Because of the potential for serious adverse reactions in nursing infants from doxorubicin, mothers should be advised to discontinue nursing during doxorubicin therapy.

Pediatric Use:   Pediatric patients are at increased risk for developing delayed cardiotoxicity. Follow-up cardiac evaluations are recommended periodically to monitor for this delayed cardiotoxicity (see WARNINGS ).

Doxorubicin, as a component of intensive chemotherapy regimens administered to pediatric patients, may contribute to prepubertal growth failure. It may also contribute to gonadal impairment, which is usually temporary.

Overdosage

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 transfusion and symptomatic treatment of mucositis. Use of hemopoietic growth factor (G-CSF, GM-CSF) may be considered.

The 200 mg Adriamycin (DOXOrubicin HCI) Injection, USP is packaged as a multiple dose vial, and caution should be exercised to prevent inadvertent overdosage.

Cumulative dosage with doxorubicin increases the risk of cardiomyopathy and resultant congestive heart failure (see WARNINGS ). Treatment consists of vigorous management of congestive heart failure with digitalis preparations, diuretics, and afterload reducers such as ACE inhibitors.

Dosage and Administration

Care in the administration of Adriamycin (DOXOrubicin HCl) Injection, USP and Adriamycin (DOXOrubicin HCl) for Injection, USP will reduce the chance of perivenous infiltration (see WARNINGS ). 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. × 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. 1

The most commonly used dose schedule when used as a single agent is 60 to 75 mg/m 2 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. Adriamycin (DOXOrubicin HCl) Injection, USP and Adriamycin (DOXOrubicin HCl) for Injection, USP have 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/m 2 given as a single intravenous injection every 21 to 28 days. Doxorubicin dosage must be reduced in case of hyperbilirubinemia as follows:

Plasma bilirubin
concentration (mg/dL)
Dosage reduction
(%)
1.2-3.0 50
3.1-5.0 75

Reconstitution Directions:    Adriamycin (DOXOrubicin HCl) for Injection, USP 10 mg, 20 mg, and 50 mg vials should be reconstituted with 5 mL, 10 mL, and 25 mL respectively of 0.9% Sodium Chloride Injection to give a final concentration of 2 mg/mL of doxorubicin hydrochloride. An appropriate volume of air should be withdrawn from the vial during reconstitution to avoid excessive pressure build up. Bacteriostatic diluents are not recommended.

After adding the diluent, the vial should be shaken and the contents allowed to dissolve. The reconstituted solution is stable for 7 days at room temperature and under normal room light (100 foot-candles) and 15 days under refrigeration, 2° to 8°C (36° to 46°F). It should be protected from exposure to sunlight. Discard any unused solution from the 10 mg, 20 mg, and 50 mg single dose vials. Unused solutions of the multiple dose vial remaining beyond the recommended storage times should be discarded.

It is recommended that Adriamycin (DOXOrubicin HCl) Injection, USP and Adriamycin (DOXOrubicin HCl) for Injection, USP 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 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. Until specific compatibility data are available, it is not recommended that doxorubicin be mixed with other drugs.

Note:   Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Handling and Disposal:   Skin reactions associated with doxorubicin have been reported. Skin accidently exposed to doxorubicin should be rinsed copiously with soap and warm water, and if the eyes are involved, standard irrigation techniques should be used immediately. The use of goggles, gloves, and protective gowns is recommended during preparation and administration of the drug.

Procedures for proper handling and disposal of anti-cancer drugs should be considered. Several guidelines on this subject have been published. 1-8 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

Caregivers of pediatric patients receiving doxorubicin should be counseled to take precautions (such as wearing latex gloves) to prevent contact with the patient's urine and other body fluids for at least 5 days after each treatment.

How Supplied

Adriamycin (DOXOrubicin HCl) for Injection, USP is supplied as a sterile red-orange lyophilized powder in single dose flip-top vials in the following package strengths:

NDC 55390-231-10:   10 mg vial; carton of 10.

NDC 55390-232-10:   20 mg vial; carton of 10.

NDC 55390-233-01:   50 mg vial; individually boxed.

Store unreconstituted vial at controlled room temperature, 15° to 30°C (59° to 86°F) [see USP]. Protect from light. Retain in carton until time of use. Discard unused portion.

Reconstituted Solution Stability:   After adding the diluent, the vial should be shaken and the contents allowed to dissolve. The reconstituted solution is stable for 7 days at room temperature and under normal room light (100 foot-candles) and 15 days under refrigeration (2° to 8°C). It should be protected from exposure to sunlight. Discard any unused solution from the 10 mg, 20 mg and 50 mg single dose vials. Unused solutions of the multiple dose vial remaining beyond the recommended storage times should be discarded.

Adriamycin (DOXOrubicin HCl) Injection, USP is supplied in single-dose, flip-top vials, as a red-orange solution containing Doxorubicin Hydrochloride, USP 2 mg/mL in the following package strengths:

NDC 55390-235-10:   510 mg in 5 mL; carton of 10.

NDC 55390-236-10:   20 mg in 10 mL; carton of 10.

NDC 55390-237-01:   50 mg in 25 mL; individually boxed.

Store refrigerated, 2° to 8°C (36° to 46°F).

Protect from light. Retain in carton until time of use. Discard unused portion.

Adriamycin (DOXOrubicin HCl) Injection, USP is supplied in a sterile, multiple dose, flip-top vial, as a red-orange solution containing Doxorubicin Hydrochloride, USP 2 mg/mL in the following package strength:

NDC 55390-238-01:   200 mg in 100 mL; individually boxed.

Store refrigerated, 2° to 8°C (36° to 46°F).

Protect from light. Retain in carton until contents are used.

References

  1. Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs. NIH Publication No. 83-2621. For sale by the Superintendent of Documents, U.S. Government Printing Office, Washington, D.C. 20402.
  2. AMA Council Report. Guidelines for Handling Parenteral Antineoplastics. JAMA , 1985; 253 (11): 1590-1592.
  3. National Study Commission on Cytotoxic Exposure -- Recommendation for Handling Cytotoxic Agents. Available from Louis P. Jeffrey, ScD, Chairman, National Study Commission on Cytotoxic Exposure, Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Ave., Boston, Massachusetts 02115.
  4. Clinical Oncological Society of Australia: Guidelines and Recommendations for Safe Handling of Antineoplastic Agents. Med J Australia 1983; 1 :426-428.
  5. Jones RB, et al. Safe Handling of Chemotherapeutic Agents: A Report From the Mount Sinai Medical Center. CA-A Cancer Journal for Clinicians 1983; Sept/Oct, 258-263.
  6. American Society of Hospital Pharmacists Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs. Am J Hosp Pharm 1990; 47 :1033-1049.
  7. Controlling Occupational Exposure to Hazardous Drugs. (OSHA Work-Practice Guidelines), Am J Healthsyst Pharm , 1996; 53 : 1669-1685.
  8. ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines and Recommendations for Practice Pittsburgh, Pa: Oncology Nursing Society; 1999:32-41.

Manufactured by:                                        Manufactured for:

Ben Venue Laboratories, Inc.                      Bedford Laboratories™

Bedford, OH 44146                                    Bedford, OH 44146

December 2002                                                          ADR-P00

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