Doxorubicin Hydrochloride Injection, USP

DOXORUBICIN HCl FOR INJECTION USP

Faulding

Antineoplastic Agent

Action And Clinical Pharmacology: The precise mechanism(s) of the antineoplastic action of doxorubicin is not fully understood. Experimental evidence indicates that doxorubicin forms a complex with DNA by intercalation between base pairs, causing inhibition of DNA synthesis and DNA-dependent RNA synthesis by the resulting template disordering and steric obstruction. Doxorubicin also inhibits protein synthesis. Doxorubicin is active throughout the cell cycle including interphase.

Of the cell types tested in vitro, cardiac cells are the most sensitive to the effects of doxorubicin, followed by sarcoma and melanoma cells, normal muscle fibroblasts, and normal skin fibroblasts. Normal, rapidly proliferating tissues such as those of bone marrow, gastrointestinal and oral mucosa, and hair follicles are also affected to varying degrees. Doxorubicin also has immunosuppressive activity.

Pharmacokinetics: Absorption: Doxorubicin is not stable in gastric acid, and animal studies indicate that it is not absorbed from the gastrointestinal tract.

Distribution: Doxorubicin is widely distributed in the plasma and in tissues. As early as 30 seconds after i.v. administration, doxorubicin is present in the liver, lungs, heart, and kidneys. Doxorubicin is absorbed by cells and binds to cellular components, particularly to nucleic acids. Doxorubicin does not cross the blood-brain barrier or achieve a measurable concentration in the CSF.

Trace amounts of doxorubicin have been found in fetal mice whose mothers received the drug during pregnancy, and there are limited data which indicate that doxorubicin crosses the human placenta. Limited data indicate that doxorubicin is distributed into milk, achieving concentrations that often exceed those in plasma; doxorubicinol (the major metabolite) also distributes into milk.

Elimination: Plasma concentrations of doxorubicin and its metabolites decline in a triphasic manner. In the first phase, doxorubicin is rapidly metabolized, presumably by a first-pass effect through the liver. It appears that most of this metabolism is completed before the entire dose is administered. Doxorubicin and its metabolites are rapidly distributed into the extravascular compartment with a plasma half-life of approximately 0.6 hours for doxorubicin and 3.3 hours for the metabolites. This is followed by relatively prolonged plasma concentrations of doxorubicin and its metabolites, probably resulting from tissue binding. During the second phase, the plasma half-life of doxorubicin is 16.7 hours and that of its metabolites is 31.7 hours. Patients with impaired hepatic function have prolonged and elevated plasma concentrations of both the drug and its metabolites. Plasma protein binding is approximately 50%.

Doxorubicin is metabolized in the liver and other tissues by an aldo-keto reductase enzyme, yielding doxorubicinol (adriamycinol), the major metabolite which has antineoplastic activity. Other metabolites which are therapeutically inactive include doxorubicinone (adriamycinone), aglycones and conjugates. More than 20% of the total drug in plasma is present as metabolites as soon as 5 minutes after a dose, 70% in 30 minutes, 75% in 4 hours, and 90% in 24 hours.

Doxorubicin is excreted predominantly in bile. Ten to 20% of a single dose is excreted in feces in 24 hours, and 40 to 50% of a dose is excreted in bile or feces within 7 days. About 50% of the drug in bile is unchanged drug, 23% is doxorubicinol, and the remainder is other metabolites including aglycones and conjugates. About 4 to 5% of the administered drug is excreted in urine after 5 days, principally as unchanged doxorubicin. It appears that very little further urinary excretion of the drug occurs after 5 days.

Indications And Clinical Uses: Doxorubicin 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’ tumor, neuroblastomas, soft tissue sarcomas, bone sarcomas, breast carcinoma, gynecologic carcinomas, testicular carcinomas, bronchogenic carcinoma, lymphomas of both Hodgkin and non-hodgkin types, thyroid carcinoma, bladder carcinomas, squamous cell carcinoma of the head and neck, hepatic and gastric carcinoma. Doxorubicin has also been used by instillation into the bladder for the topical treatment of superficial bladder tumors.

A number of other solid tumors have also shown some responsiveness to doxorubicin alone or in combination with other drugs (see Dosage). Studies to date have shown malignant melanoma, kidney carcinoma, large bowel carcinomas, brain tumors and metastases to the CNS not to be significantly responsive to doxorubicin therapy.

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

Manufacturers’ Warnings In Clinical States: Caution: Doxorubicin is a potent drug and should be used only by physicians experienced with cancer chemotherapy drugs (see Precautions). Blood counts and hepatic function tests should be performed 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 who have received prior doxorubicin cumulative doses exceeding 400 mg/mwith the 21-day regimen and 550 mg/mutilizing the weekly regimen.

Special attention must be given to the cardiac toxicity exhibited by doxorubicin. Although uncommon, acute left ventricular failure has occurred, particularly in patients who have received a total dosage of the drug exceeding the currently recommended limit of 550 mg/mbody surface area for the 21-day regimen or a higher dose limit of the order of 700 mg/mfor the weekly regimen. These limits appear to be lower (400 mg/mand 500 mg/m respectively) in patients who received radiotherapy to the mediastinal area or concomitant therapy with other potentially cardiotoxic agents such as cyclophosphamide. The total dose of doxorubicin administered to the patient should also take into account previous or concomitant therapy with related compounds such as daunorubicin or with mitoxantrone. Congestive heart failure and/or cardiomyopathy may be encountered several weeks after discontinuation of doxorubicin therapy.

Cardiac failure is often not favorably affected by presently known medical or physical therapy for cardiac support. Early clinical diagnosis of drug-induced heart failure appears to be essential for successful treatment with digitalis, diuretics, low salt diet, 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. 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 presently 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 ejection fraction as determined by echocardiography or radionuclide angiography. None of these tests have yet been confirmed to consistently identify those individual patients who are approaching their maximally tolerated cumulative dose of doxorubicin. If test results indicate change in cardiac function associated with doxorubicin, 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 doxorubicin administration.

There is a high incidence of bone marrow depression, primarily of leukocytes, requiring careful hematologic monitoring. With the recommended dosage schedule, leukopenia is usually transient, reaching its nadir 10 to 14 days after treatment with recovery usually occurring by the 21st day. White blood cell counts as low as 1 000/mmare to be expected during treatment with appropriate doses of doxorubicin. Red blood cell and platelet levels should also be monitored since they may also be depressed. Hematologic toxicity may require dose reduction or suspension or delay of doxorubicin therapy. Persistent severe myelosuppression may result in superinfection or hemorrhage.

Doxorubicin 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 doxorubicin.

Toxicity to recommended doses of doxorubicin is enhanced by hepatic impairment, therefore, prior to the individual dosing, evaluation of hepatic function is recommended using conventional clinical laboratory tests such as AST, ALT, alkaline phosphatase and bilirubin (see Dosage).

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.

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

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

Pregnancy and Lactation: The safe use of doxorubicin in pregnancy has not been established. Doxorubicin is embryotoxic and teratogenic in rats and embryotoxic and abortifacient in rabbits. Therefore, the benefits to the pregnant patient should be carefully weighed against the potential toxicity to fetus and embryo. The possible adverse effects on fertility in males and females in humans or experimental animals have not been adequately evaluated.

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.

Like other cytotoxic drugs, doxorubicin 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 such supportive and pharmacologic measures as might be necessary to control this problem.

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.

Adverse Reactions: Dose limiting toxicities of therapy are myelosuppression and cardiotoxicity (see Warnings). Other reactions reported are: Cutaneous: Reversible complete alopecia occurs in most cases. Hyperpigmentation of nailbeds and dermal creases, primarily in children, have been reported in a few cases. Recall of skin reaction due to prior radiotherapy has occurred with doxorubicin administration.

Gastrointestinal: Acute nausea and vomiting occurs frequently and may be severe. This may be alleviated by antiemetic therapy. Mucositis (stomatitis and esophagitis) may occur 5 to 10 days after administration. The effect may be severe leading to ulceration and represents 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.

Vascular: Phlebosclerosis has been reported especially when small veins are used or a single vein is used for repeated administration. Facial flushing may occur if the injection is given too rapidly.

Local: Severe cellulitis, vesication and tissue necrosis will occur if doxorubicin is extravasated during administration. Erythematous streaking along the vein proximal to the site of the injection has been reported (see Dosage).

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

Hypersensitivity: Fever, chills and urticaria have been reported occasionally. Anaphylaxis may occur.

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. Treatment of acute overdosage consists of treatment of the severely myelosuppressed patient with hospitalization, antibiotics, 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 has been recommended.

Dosage And Administration: Refer to Guidelines for Safe Preparation and Handling.

A variety of dose schedules have been used. The following recommendations are for use 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 is weekly doses of 20 mg/mwhich has been reported to produce a lower incidence of congestive heart failure. Thirty mg/mon each of 3 successive days repeated every 4 weeks has also been used. Doxorubicin dosage must be reduced if the bilirubin is elevated as follows: Serum bilirubin 1.2 to 3.0 mg/dL – give 1/2 normal dose, >3 mg/dL – give 1/4 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 USP with a contact time of 1 to 2 hours. Care should be taken to ensure that the tip of the catheter is in the bladder lumen before instilling the doxorubicin solution. Instillation is repeated weekly for 4 weeks and subsequently at monthly intervals. Therapy may continue for 1 year or longer as no significant systematic 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 decolorizing 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 i.v. infusion utilizing appropriate pumps.

Clinical studies support the efficacy of doxorubicin used concurrently with other chemotherapeutic agents. Listed below are tumor types and drugs used concurrently with doxorubicin: Acute lymphocytic leukemia in adults: doxorubicin with vincristine and prednisone or with cytarabine, vincristine and prednisone.

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

Acute Nonlymphocytic Leukemia: doxorubicin with cytarabine or with cytarabine, 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 etoposide, vincristine and cyclophosphamide.

Hodgkin’s Disease: doxorubicin with bleomycin, vincristine, vinblastine, mechlorethamine and dacarbazine.

non-hodgkin’s Lymphoma: doxorubicin with cyclophosphamide, vincristine and prednisone, or bleomycin, cyclophosphamide, vincristine and prednisone, or with etoposide, methotrexate with leucovorin rescue, mechlorethamine or procarbazine.

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 cisplatin and cyclophosphamide or with 5-fluorouracil, methotrexate and vinblastine.

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. It may also decrease the chance of local reactions such as urticaria and erythematous streaking. On i.v. administration of doxorubicin, extravasation may occur with or without an accompanying stinging or burning sensation and 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 it is known or suspected that s.c. extravasation has occurred, the injection or infusion of doxorubicin should immediately be terminated. The following subsequent steps are recommended: an attempt should be made to aspirate the infiltrate; intermittent local application of ice for up to 3 days; elevation of affected limb; consultation with a plastic surgeon if local pains persist 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 Sodium Chloride Injection USP (0.9%) or 5% Dextrose Injection 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 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 administration.

Reconstituted Solutions: Reconstitute doxorubicin for injection USP to approximately 2 mg/mL doxorubicin with Sterile Water for Injection, 5% Dextrose Injection or 0.9% Sodium Chloride Injection, as follows: See Table I.

Note: Reconstitution with 0.9% Sodium Chloride Injection will take considerably longer than is seen with other reconstituting solutions.

The reconstituted solutions remain chemically stable for up to 24 hours when stored at room temperature or for 72 hours when stored refrigerated, in glass containers or in plastic disposable syringes, under fluorescent light.

Further diluted solutions of doxorubicin prepared for bladder instillation at a concentration of 0.8 mg/mL in 0.9% sodium chloride in plastic bags, have been determined to be chemically stable for 24 hours when kept at room temperature in the presence of light, or for 72 hours when refrigerated.

Unpreserved reconstituted solutions should not be stored for more than 24 hours at room temperature or 72 hours under refrigeration, due to the possibility of microbial contamination during preparation.

Warning: As with all parenteral drug products, i.v. admixtures should be inspected visually for clarity, particulate matter, precipitate, discoloration and leakage prior to administration, whenever solution and container permit. Solutions showing haziness, particulate matter, precipitate, discoloration or leakage should not be used.

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

Guidelines for Safe Preparation and Handling: Preparation and Handling: 1. Preparation of antineoplastic solutions should be done in a vertical laminar flow hood (Biological Safety Cabinet – Class II). 2. 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. 3. Personnel regularly involved in the preparation and handling of antineoplastics should have blood examinations on a regular basis.

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 1 000°C or higher. Sealed containers may explode if a tight seal exists. 3. 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 clothing. 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 polyethylene bag; seal, double bag and mark as hazardous waste. Dispose of waste by incineration or by other methods approved for hazardous materials. Pesonnel involved in clean-up should wash with soap and water.

Availability And Storage: Each single dose vial contains: doxorubicin HCl USP 10, 50 or 150 mg as a sterile lyophilized red powder or plug. Also contains lactose (26.3 mg, 32.89 mg and 52.63 mg respectively) in each vial. Store intact vials below 25°C, protected from light.

DOXORUBICIN HCl FOR INJECTION USP Faulding Antineoplastic Agent

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Breast Cancer

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Bladder Cancer

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