Doxorubicin PhaRes IV Infusion

Doxorubicin PhaRes PhaRes is indicated:

• As a component of multiagent adjuvant chemotherapy for treatment of women with axillary lymph node involvement following resection of primary breast cancer.
• For the treatment of acute lymphoblastic leukemia, acute myeloblastic leukemia, Hodgkin lymphoma, Non-Hodgkin lymphoma, metastatic breast cancer, metastatic Wilms' tumor, metastatic neuroblastoma, metastatic soft tissue sarcoma, metastatic bone sarcomas, metastatic ovarian carcinoma, metastatic transitional cell bladder carcinoma, metastatic thyroid carcinoma, metastatic gastric carcinoma, metastatic bronchogenic carcinoma.

Doxorubicin hydrochloride is a cytotoxic, anthracycline topoisomerase IIinhibitor. The cytotoxic effect of Doxorubicin HCl on malignant cells and its toxic effects on various organs are thought to be related to nucleotide base intercalation and cell membrane lipid binding activities of Doxorubicin. Intercalation inhibits nucleotide replication and action of DNA and RNA polymerases. The interaction of Doxorubicin with topoisomerase II to form DNA-cleavable complexes appears to be an important mechanism of Doxorubicin HCl cytocidal activity.

Single agent: 60 to 75 mg/m2 given intravenously every 21 days.

In combination therapy: 40 to 75 mg/m2 given intravenously every 21 to 28 days. Doxorubicin HCl should be discontinued in patients who develop signs or symptoms of cardiomyopathy, and dose should be reduced in patients with hepatic impairment. As an intravenous injection, Doxorubicin HCl is administered through a central intravenous line or a secure and free-flowing peripheral venous line containing 0.9% Sodium Chloride Injection, USP, 0.45% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP over 3 to 10 minutes. The rate of Doxorubicin HCl administration should be decreased if erythematous streaking along the vein proximal to the site of infusion or facial flushing occur. As intravenous Infusion, Doxorubicin HCl is administered only through a central catheter.

Management of Suspected Extravasation: Doxorubicin HCl should be discontinued in case of burning or stinging sensation or other evidence indicating perivenous infiltration or extravasation. Confirmed or suspected extravasation are managed as follows:

• The needle should not be removed until attempts are made to aspirate extravasated fluid
• The line should not be flushed
• Pressure should not be applied to the site
• Ice should be applied to the site intermittently for 15 min 4 times a day for 3 days
• If the extravasation is in an extremity, extremity should be elevated
• In adults, administration of dexrazoxane should be considered

Incompatibility with Other Drugs: Doxorubicin hydrochloride should not be admixed with other drugs. If Doxorubicin HCl is mixed with heparin or fluorouracil a precipitate may form. Avoid contact with alkaline solutions which can lead to hydrolysis of Doxorubicin hydrochloride.

Doxorubicin PhaRes is a major substrate of cytochrome P450 CYP3A4 and CYP2D6, and P-glycoprotein (P-gp). Avoid concurrent use of Doxorubicin PhaRes HCl with inhibitors and inducers of CYP3A4, CYP2D6, or P-gp. Concurrent use of Trastuzumab and Doxorubicin PhaRes HCl results in an increased risk of cardiac dysfunction. Avoid concurrent administration of Doxorubicin PhaRes and Trastuzumab. Paclitaxel, when given prior to Doxorubicin PhaRes HCl, increases the plasma-concentrations of Doxorubicin PhaRes and its metabolites. Administer Doxorubicin PhaRes HCl prior to Paclitaxel if used concomitantly.

Doxorubicin HCl is contraindicated in patients with:

• Severe myocardial insufficiency
• Recent (occurring within the past 4-6 weeks) myocardial infarction
• Severe persistent drug-induced myelosuppression
• Severe hepatic impairment (defined as Child Pugh Class C or serum bilirubin level greater than 5 mg/dl)
• Severe hypersensitivity reaction to Doxorubicin HCl including anaphylaxis

The most common (>10%) adverse drug reactions are alopecia, nausea and vomiting. Other adverse reactions include- cardiomyopathy and arrhythmias, secondary malignancies, extravasation and tissue necrosis, severe myelosuppression, tumor lysis syndrome, radiation sensitization and radiation recall.

Pregnancy Category D. Doxorubicin HCl can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus. Female patients of reproductive potential should be advised to use highly effective contraception during treatment with Doxorubicin HCl and for 6 months after treatment. There is evidence of Doxorubicinbe excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from Doxorubicin HCl, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric use: Pediatric patients treated with Doxorubicin PhaRes HCl are at risk for developing late cardiovascular
dysfunction. Long-term periodic cardiovascular monitoring is recommended for all pediatric patients who have received Doxorubicin PhaRes HCl.

Geriatric use: No overall differences in safety and effectiveness have been found compared with younger patients.

Hepatic impaired patients: The clearance of Doxorubicin PhaRes is reduced in patients with elevated serum bilirubin levels. The dose of Doxorubicin PhaRes HCl should be decreased in patients with serum bilirubin levels greater than 1.2 mg/dl. Doxorubicin PhaRes HCl is contraindicated in patients with severe hepatic impairment.

The symptoms of overdose are likely to be an extension of Doxorubicin PhaRes's pharmacological action. Single doses of 250 mg and 500 mg of Doxorubicin PhaRes have proven to be fatal. Such doses may cause acute myocardial degeneration within 24 hours and severe myelosuppression, the greatest effects of which are seen between 10 and 15 days after administration. Delayed cardiac failure may occur up to six months after the overdose. Patients should be observed carefully and treatment should aim to support the patient during this period.

Cytotoxic Chemotherapy

Preparation for Administration: Reconstitute Doxorubicin PhaRes PhaRes injection with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. Protect from light following preparation until completion of infusion. All parenteral drug products should be inspected visually prior to administration and should not be used if precipitates, visible particles and/or discoloration is present.

Precautions during Handling: Caution should be exercised in handling Doxorubicin PhaRes HCl solution. Procedures for proper handling and disposal of anticancer drugs should be utilized. To minimize the risk of dermal exposure, always wear impervious gloves when handling vials and IV sets containing Doxorubicin PhaRes HCl. If Doxorubicin PhaRes HCl contacts the skin or mucosa, immediately and thoroughly wash the skin with soap and water or sodium bicarbonate solution and flush the mucosa with water.

Store in a dry place at 2°-8° C temperature. Protect from light and do not freeze. Keep out of the reach of children.