Doxorubicin Hydrochloride Injection, USP

DOXORUBICIN HYDROCHLORIDE INJECTION USP

Novopharm

Antineoplastic Agent

Action And Clinical Pharmacology: Doxorubicin is the hydrochloric acid salt of a glycoside antibiotic produced by S. peucetius var. caesiu. Although not completely elucidated, the mechanism of action of doxorubicin is related mainly to its ability to bind specifically with DNA, by intercalation between adjacent base pairs of the double-helical structure, thereby inhibiting nucleic acid synthesis. Binding to cell membranes as well as to plasma proteins may also be involved. The following have been demonstrated by cell culture studies: rapid cell penetration and perinucleolar chromatin binding, rapid inhibition of mitotic activity and nucleic acid synthesis, mutagenesis and chromosomal aberrations.

Animal studies have shown immunosuppression, activity in a spectrum of experimental tumors, induction of a variety of toxic effects, including delayed and progressive cardiac toxicity, carcinogenic properties in rodents, atrophy of testes in rats and dogs and myelosuppression in all species.

Pharmacokinetic studies show that i.v. administration of doxorubicin has been shown to have a rapid plasma clearance, a large volume of distribution and prolonged tissue binding. Doxorubicin undergoes metabolism in the liver, is eliminated in bile with only minute amounts appearing in the urine. Doxorubicin does not appear to cross the blood-brain barrier.

Indications And Clinical Uses: Doxorubicin has been used successfully as a single agent and in combination with other chemotherapeutic agents, to produce regression in a variety of tumor types such as acute lymphoblastic and acute myeloblastic leukemia, Wilms’ tumor, neuroblastoma, soft tissue and bone sarcomas, breast carcinoma, ovarian carcinoma, testicular carcinoma, transitional cell bladder carcinoma, thyroid carcinoma, squamous cell carcinoma of the head and neck, lymphomas of both Hodgkin’s and non-Hodgkin’s types, gastric carcinoma and bronchogenic carcinoma.

Doxorubicin has also been used by instillation into the bladder for the topical treatment of superficial bladder tumors.

Studies to date have shown that malignant melanoma, kidney carcinoma, large bowel carcinomas, brain tumors and metastases to the CNS are not significantly responsive to doxorubicin treatment.

Contra-Indications: Doxorubicin therapy should not be initiated in patients who have marked myelosuppression induced by previous treatment with other antitumor agents or by radiotherapy. Conclusive data are not available on pre-existing heart disease as a cofactor of increased risk of doxorubicin induced cardiotoxicity. Preliminary data suggest that in such cases, cardiotoxicity may occur at doses lower than the recommended cumulative limit. It is therefore not recommended to initiate doxorubicin therapy in such cases. Doxorubicin hydrochloride treatment is contraindicated in patients who have received previous treatment with complete cumulative doses of doxorubicin and/or other anthracyclines and anthracenes. tag_WarningWarnings

Manufacturers’ Warnings In Clinical States: Doxorubicin is a potent drug and should be used only by physicians experienced with cancer chemotherapeutic drugs (see Precautions). Perform blood counts and hepatic function tests regularly. Because of the experience with cardiac toxicity, a total dose of doxorubicin exceeding 550 mg/mwith the 21-day regimen and 700 mg/mwith the weekly regimen is not recommended. Cardiac monitoring is advised in those patients who have received mediastinal radiotherapy, other anthracycline or anthracene therapy, with pre-existing cardiac disease, or those who have received prior doxorubicin cumulative doses exceed- ing 400 mg/m2 with the 21-day regimen and 550 mg/mwith the weekly regimen.

Cardiac Toxicity: Attention must be given to the cardiac toxicity exhibited by doxorubicin. Although uncommon, left ventricular failure has occurred particularly in patients who have received total dosage of the drug exceeding the current recommended limit of 550 mg/mfor the 21-day regimen or a higher dose limit on the order of 700 mg/mfor the weekly regimen. These limits appear to be lower, 400 mg/mand 500 mg/mrespectively, in patients who received concomitant therapy with other potentially cardiotoxic agents such as cyclophosphamide or radiotherapy to the mediastinal area. Congestive heart failure and/or cardiomyopathy may occur several weeks after discontinuation of doxorubicin therapy. Children appear to be at particular risk for development of delayed doxorubicin cardiotoxicity in that doxorubicin impairs myocardial growth as they mature, leading to subsequent possible development of congestive heart failure during early adulthood. Dose limitation should be used to prevent doxorubicin cardiomyopathy.

Available evidence appears to indicate that cardiotoxicity is cumulative across members of the anthracycline and anthracene class of drugs. Patients who have previously received other anthracyclines and anthracenes are at particular risk for possible cardiotoxic effects of doxorubicin at a lower total dose than previously untreated patients and, therefore, should be carefully monitored.

Cardiac failure is often unresponsive to presently known medical or physical therapy for cardiac support. Early clinical diagnosis of drug-induced heart failure seems to be essential for successful treatment with diuretics, digitalis, low-salt diet, peripheral vasodilators, and bed rest. Reduction of afterload with vasodilating agents appears to be beneficial in refractory doxorubicin-induced heart failure. Severe cardiac toxicity may occur precipitously without antecedent ECG changes. It is suggested to perform a baseline ECG and ECGs prior to each dose or course after a 300 mg/m2 cumulative dose has been given.

Transient ECG changes consisting of T-wave flattening, S-T depression and arrhythmias lasting for up to 2 weeks after a dose or course of doxorubicin are currently not considered indications for suspension of doxorubicin therapy. Doxorubicin cardiomyopathy has been reported to be associated with a persistent reduction in the voltage of the QRS wave, a prolongation of the systolic time interval, and a reduction of the left ventricular ejection fraction (LVEF) as determined by echocardiography or radionuclide angiography (MUGA scan). None of these tests have yet been confirmed to consistently identify those individual patients who are approaching their maximally tolerated cumulative doses of doxorubicin. If test results indicate change in cardiac function associated with doxorubicin therapy, the benefit of continued therapy must be carefully evaluated against the risk of producing irreversible cardiac damage.

Because of the experience with cardiac toxicity, a total dose of doxorubicin exceeding 550 mg/mwith the 21-day regimen and 700 mg/mwith the weekly regimen is not recommended.

Acute life-threatening arrhythmias have been reported to occur during or within a few hours after administration of doxorubicin.

Bone Marrow Suppression: There is a high incidence of bone marrow depression, primarily of leukocytes, occuring in over 60% of patients requiring careful hematologic monitoring. Leukopenia is usually transient with the recommended dosage schedule, reaching its nadir at 10 to 14 days after treatment, with recovery usually occurring by the 21st day. During treatment with doxorubicin, white blood cell counts as low as 1 000/mmare to be expected. Since red blood cell and platelet levels may also be depressed, these should also be monitored. Upon hematologic toxicity, dose reduction or discontinuation or delay of doxorubicin therapy may be required. Persistent severe myelosuppression may result in superinfection or hemorrhage.

Drug Interactions: The toxicity of other anticancer therapies may be potentiated by doxorubicin. There have been reports of exacerbation of cyclophosphamide-induced hemorrhagic cystitis and enhancement of the hepatotoxicity of 6-mercaptopurine. Radiation-induced toxicity to the myocardium, skin, liver and mucosae has been reported to be increased by the administration of doxorubicin.

Since toxicity to recommended doses of doxorubicin is enhanced by hepatic impairment, evaluation of hepatic function using conventional clinical laboratory tests such as AST, ALT, alkaline phosphatase and bilirubin is recommended.

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

Carcinogenicity: Doxorubicin and related compounds have also been shown to have mutagenic and carcinogenic properties when tested in experimental models.

Local Reactions: Upon i.v. administration of doxorubicin, extravasation may occur with or without an accompanying stinging or burning sensation even if blood returns well upon aspiration of the infusion needle (see Dosage). The injection or infusion should be immediately terminated and restarted in another vein if any signs or symptoms of extravasation occur.

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

Pregnancy: There is no conclusive information about doxorubicin adversely affecting human fertility, or causing teratogenesis; however, doxorubicin is embryotoxic and teratogenic in rats and embryotoxic and abortifacient in rabbits. Therefore, women with childbearing potential should be advised to avoid pregnancy. If doxorubicin is to be used during pregnancy, or if the patient becomes pregnant during therapy, the patient should be informed of the potential hazard to the fetus. The benefits to the pregnant patient should be carefully weighed against the potential toxicity to fetus and embryo.

Lactation: Mothers should be advised not to breast-feed while undergoing chemotherapy with doxorubicin.

Precautions: Initial treatment with doxorubicin requires close observation of the patient and extensive laboratory monitoring.

Doxorubicin, like other cytotoxic drugs, may induce hyperuricemia secondary to rapid lysis of neoplastic cells, particularly in patients with leukemia. The clinician should monitor the patient’s blood uric acid level and be prepared to use any supportive and pharmacologic measures necessary to control this problem.

Doxorubicin is not an antimicrobial agent.

Adverse Reactions: Dose limiting toxicities of doxorubicin are myelosuppression, cardiotoxicity (see Warnings). Other reactions reported are as follows:

Cutaneous: In most cases, reversible partial or complete alopecia occurs. Hair growth usually resumes during treatment or within 2 to 3 months after cessation of drug therapy.

Hyperpigmentation of nailbeds and dermal creases, primarily in children, have been reported in a few cases. Recall of skin reaction associated with prior radiotherapy has occurred with doxorubicin administration.

Gastrointestinal: Acute nausea and vomiting are the immediate effects of doxorubicin therapy, which usually last for 24 to 48 hours. Antiemetic therapy may alleviate these symptoms. Mucositis (stomatitis and esophagitis) may occur 5 to 10 days after administration. This may be severe and in turn may lead to ulceration, representing a site of origin for severe infections. The dose regimen consisting of administration of doxorubicin on 3 successive days results in the greater incidence and severity of mucositis. Ulceration and necrosis of the colon, especially the cecum, may occur leading to bleeding or severe infections which can be fatal. This reaction has been reported in patients with acute nonlymphocytic leukemia treated with a 3-day course of doxorubicin combined with cytarabine. Anorexia and diarrhea have been occasionally reported.

Myelosuppression: Leukopenia is the predominant hematologic toxicity. Thrombocytopenia and anemia may also occur.

The occurrence of secondary acute myeloid leukemia with or without a preleukemic 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 to 3 years) latency period.

Vascular: When small veins are used or a single vein is used for repeated administration, chemical phlebitis and phlebosclerosis have been reported. If the injection is given too rapidly, facial flushing may occur.

Local: Severe cellulitis, vesication and tissue necrosis may occur if doxorubicin is extravasated during administration. Normal precautions in i.v. administration can prevent this toxicity. Erythematous streaking along the vein proximal to the site of the infection has been reported.

Bladder: Instillation of the doxorubicin compound into the urinary bladder may cause pain, hemorrhage and occasionally decreased bladder capacity.

Hypersensitivity: Fever and chills, facial flushing associated with too rapid drug injection and urticaria have been reported occasionally. Anaphylaxis may occur. A case of apparent cross-sensitivity to lincomycin has been reported.

Other: Conjunctivitis and lacrimation occur rarely.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Acute overdosage with doxorubicin enhances the toxic effects of mucositis, leukopenia and thrombopenia. The severely myelosuppressed patient (due to acute overdosage) should be hospitalized, and should receive antibiotic therapy, platelet and granulocyte transfusions and symptomatic treatment of mucositis.

Chronic overdosage with cumulative doses exceeding 500 mg/mincreases 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 may be considered in the management of congestive heart failure.

Dosage And Administration: A variety of dose schedules have been used. The following recommendations are for the use of doxorubicin as a single agent only.

The most commonly used dosage schedule is 60 to 75 mg/mas a single i.v. injection administered at 21-day intervals. The lower dose should be given to patients with inadequate marrow reserves due to old age or prior therapy, or neoplastic marrow infiltration. An alternative dose schedule consists of weekly doses of 20 mg/mmay produce a lower incidence of congestive heart failure. A dose of 30 mg/mon each of 3 successive days repeated every 4 weeks has been used as well. If bilirubin is elevated, doxorubicin hydrochloride dosage must be reduced as follows: serum bilirubin 1.2 to 3 mg/dL: give half of normal dose; >3 mg/dL: give one quarter of normal dose.

When doxorubicin is intravesically instilled for the treatment of superficial bladder carcinomas, the usual dose employed ranges from 50 to 80 mg in 50 to 100 mL of 0.9% Sodium Chloride Injection with a contact time of 1 to 2 hours. Before instilling the doxorubicin solution, care should be taken to ensure that the tip of the catheter is in the bladder lumen. Instillation is repeated weekly for 4 weeks and then at monthly intervals following this period. Therapy may continue for 12 months or for longer, since no significant systematic toxicity has been demonstrated. Care should be exercised in the handling and disposal of the voided urine. PVC gloves should be worn and the urine should be inactivated by decolorizing it with 10 mL or more of sodium hypochlorite solution (household bleach).

Clinical studies support the efficacy of doxorubicin used concurrently with other chemotherapeutic agents. Included below are tumor types and drugs used concurrently with doxorubicin.

Acute Lymphocytic Leukemia in Adults: doxorubicin with vincristine and prednisone or with cytosine arabinoside, vincristine and prednisone.

Acute Lymphocytic Leukemia in Children: doxorubicin with L-asparaginase, vincristine and prednisone.

Acute Nonlymphocytic Leukemia: doxorubicin with arabinosyl cytosine or with arabinosyl cytosine, vincristine and prednisone.

Carcinoma of the Breast: doxorubicin with 5-fluorouracil and/or cyclophosphamide or with vincristine with or without cyclophosphamide.

Bronchogenic Carcinoma, Nonsmall Cell: doxorubicin with cyclophosphamide, methotrexate and procarbazine or with cyclophosphamide and cisplatin.

Bronchogenic Carcinoma, Small Cell: doxorubicin with vincristine or etoposide (VP-16) and cyclophosphamide.

Hodgkin’s disease: doxorubicin with bleomycin, vincristine and dacarbazine.

Non-Hodgkin’s Lymphoma: doxorubicin with cyclophosphamide, vincristine and prednisone, or bleomycin, cyclophosphamide, vincristine and prednisone.

Carcinoma of the Ovary: doxorubicin with cisplatin.

Soft Tissue Sarcoma: doxorubicin with dacarbazine, or with dacarbazine, cyclophosphamide and vincristine.

Carcinoma of the Bladder: doxorubicin with methotrexate, vinblastine and cisplatin, or cisplatin and cyclophosphamide or with 5-fluorouracil.

Carcinoma of the Stomach: doxorubicin with 5-fluorouracil and mitomycin-C.

Administration: Care in the administration of doxorubicin will reduce the chance of perivenous infiltration. This may decrease the chance of local reactions (such as urticaria and erythematous streaking) as well. Upon i.v. administration of doxorubicin, extravasation may occur with or without an accompanying stinging or burning sensation. This may occur even if blood returns well on aspiration of the infusion needle. If signs or symptoms of extravasation occur, the injection or infusion should be immediately terminated and restarted in another vein.

Once it is known or suspected that s.c. extravasation has occurred, the following steps are recommended: attempt aspiration of the infiltrated doxorubicin solution; local intermittent application of ice for up to 3 days; elevation of the affected limb.

The area of injection should be frequently examined and plastic surgeon consultation should be consulted 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.

Doxorubicin should be slowly administered into the tubing of a freely running i.v. infusion of 0.9% Sodium Chloride Injection, or 5% Dextrose Injection. The tubing should be attached to a Butterfly needle inserted preferably into a large vein. Where possible, avoid veins over joints or in extremities with compromised venous or lymphatic drainage. The administration rate is dependent on the size of the vein and the dosage, however, the dosage should be administered in not less than 3 to 5 minutes. Facial flushing as well as erythematous streaking along the vein may be indicative of too rapid administration.

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

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

Guidelines for Safe Preparation and Handling: Preparation and Handling: Preparation of antineoplastic solutions should be done in a vertical laminar flow hood. (Biological Safety Cabinet-Class II). Personnel preparing doxorubicin solutions should wear PVC gloves, safety glasses and protective clothing such as disposable gowns and masks. If doxorubicin contacts the skin or mucosa, the area should be washed with soap and water immediately. Personnel regularly involved in the preparation and handling of antineoplastics should have blood examinations on a regular basis.

Directions for Dispensing from Pharmacy Bulk Vial: The use of pharmacy bulk vials is restricted to hospitals with a recognized i.v. admixture program. The pharmacy bulk vial is intended for single puncture, multiple dispensing and for i.v. use only.

Entry into the vial must be made with a sterile dispensing device such as the Econo-O-Set Sterile Transfer Systems. 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.

In a suitable work area such as a laminar flow hood, 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.

Dispensing from the pharmacy bulk vial should be completed within 8 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.

Disposal: Avoid contact with skin and inhalation of airborne particles by use of PVC gloves and disposable gowns and masks.

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 1 000°C or higher. Sealed containers may explode if a tight seal exists.

If incineration is not available, doxorubicin may be detoxified by adding sodium hypochlorite solution (household bleach) to the vial, in sufficient quantity to decolorize 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 Nondisposable 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 nondisposable equipment in soap and water.

Spillage/Contamination: Wear gloves, mask, protective cloth- ing. Treat spilled powder or liquid with sodium hypochlorite solution. Carefully absorb solution with gauze pads, or towels. Wash area with water and absorb with gauze or towels again and place in a 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 a clean-up should wash with soap and water.

Availability And Storage: Vials: 10 mg: Each mL of isotonic, sterile, red-orange solution for i.v. use only, contains: doxorubicin HCl 2 mg. Nonmedicinal ingredients: sodium chloride, water for injection and hydrochloric acid to adjust the pH (3.0). Preservative-free. Single use, flip-top vials of 5 mL, boxes of 10.

50 mg: Each mL of isotonic, sterile, red-orange solution for i.v. use only, contains: doxorubicin HCl 2 mg. Nonmedicinal ingredients: sodium chloride, water for injection and hydrochloric acid to adjust the pH (3.0). Preservative-free. Single use, flip-top vials of 25 mL, boxes of 1.

Pharmacy Bulk Vials: 200 mg: Each mL of isotonic, sterile, red-orange solution for i.v. use only, contains: doxorubicin HCl 2 mg. Nonmedicinal ingredients: sodium chloride, water for injection and hydrochloric acid to adjust the pH (3.0). Preservative-free. Single use, flip-top vials of 100 mL, boxes of 1.

Store at refrigeration (2 to 8°C) and protect form light. Discard any unused solution.

DOXORUBICIN HYDROCHLORIDE INJECTION USP Novopharm Antineoplastic Agent

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