Adriamycin (Doxorubicin HCl)

ADRIAMYCIN®

Pharmacia & Upjohn

Doxorubicin HCl

Antineoplastic Agent

Action And Clinical Pharmacology: Though not completely elucidated, the mechanism of action of doxorubicin is related to its ability to bind to DNA and inhibit nucleic acid synthesis. Cell culture studies have demonstrated rapid cell penetration and perinucleolar chromatin binding, rapid inhibition of mitotic activity and nucleic acid synthesis, mutagenesis and chromosomal aberrations. Animal studies have shown activity in a wide spectrum of experimental tumors, immunosuppression, carcinogenic properties in rodents, induction of a variety of toxic effects, including delayed and progressive cardiac toxicity, myelosuppression in all species and atrophy of testes in rats and dogs.

Pharmacokinetics: The i.v. administration of normal or radio-labeled doxorubicin for injection is followed by rapid plasma clearance and significant tissue binding. Urinary excretion, as determined by fluorimetric methods, accounts for approximately 4 to 5% of the administered dose in 5 days. Biliary excretion represents the major excretion route, 40 to 50% of the administered dose being recovered in the bile or feces in 7 days. Impairment of liver function results in slower excretion and, consequently, increases retention and accumulation in plasma and tissues. Doxorubicin does not cross the blood brain barrier.

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 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.

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 antineoplastic agents or by radiotherapy. Conclusive data are not available on pre-existing heart disease as a cofactor of 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 received previous treatment with complete cumulative doses of doxorubicin and/or other anthracyclines and anthracenes.

Manufacturers’ Warnings In Clinical States: Doxorubicin is a potent drug and should be used only by physicians experienced with cancer chemotherapeutic 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.

Cardiac Toxicity: 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/mfor the 21 day regimen or a higher dose limit on the order of 700 mg/mfor the weekly regimen. This limit appears to be lower (400 mg/mand 550 mg/m respectively) in patients who received radiotherapy to the mediastinal area or concomitant therapy with other potentially cardiotoxic agents such as cyclophosphamide. 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.

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 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, ST 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 left ventricular ejection fraction as determined by echocardiography or radionuclide angiography. None of these tests have yet been confirmed to consistently identify those individual patients that 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 suppression, 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. WBC 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 suppressed. 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 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.

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 of 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.

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. 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 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.

Doxorubicin is not an antimicrobial agent.

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 non-lymphocytic 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. A case of apparent cross sensitivity to lincomycin has been reported.

Hematological: 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.

Other: Conjunctivitis and lacrimation occur rarely.

Symptoms And Treatment Of Overdose: Symptoms: Acute overdosage enhances the toxic effects of mucositis, leukopenia, and thrombocytopenia.

Treatment: 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 550 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 has 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. Also, 30 mg/mon each of 3 successive days repeated every 4 weeks has been used. Doxorubicin dosage must be reduced if the bilirubin is elevated as follows: serum bilirubin 1.2 to 3 mg/dL: give half of normal dose; >3 mg/dL: give a fourth of normal dose.

When doxorubicin is instilled intravesically for the treatment of superficial bladder carcinomas, the usual dose employed ranges from 50 to 80 mg in a total volume of 50 to 100 mL of 0.9% sodium chloride injection 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 cavity 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 (see 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 infusion 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 cytosine arabinoside, vincristine and prednisone.

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

Acute Non-lymphocytic Leukemia: doxorubicin with cytosine arabinoside or with cytosine arabinoside, vincristine and prednisone.

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

Bronchogenic Carcinoma, Non-small 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 cisplatinum or cisplatinum 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. 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 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; close observation of the lesion; 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 Injection to give a final concentration of 2 mg/mL of doxorubicin. 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. The reconstituted solution is stable for 24 hours at room temperature and 48 hours under refrigeration at 2 to 8°C. The solution should be protected from exposure to direct light. For single dose vials, any unused solution should be discarded.

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 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.

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: 1. Preparation and Handling: 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.

Directions for Dispensing from Pharmacy Bulk Vials: 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 Econ-O-Set Sterile Transfer System. 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.

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 8 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 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. Personnel involved in cleanup should wash with soap and water.

Availability And Storage: Adriamycin RDF: Vials: 10 mg: Each vial contains: doxorubicin HCl USP 10 mg as a sterile red-orange lyophilized powder. Also contains lactose and methylparaben (added to enhance dissolution). Cartons of 10. Protect from light. Store powder at 15 to 30°C.

50 mg: Each vial contains: doxorubicin HCl USP 50 mg as a sterile red-orange lyophilized powder. Also contains lactose and methylparaben (added to enhance dissolution). Cartons of a single vial. Protect from light. Store powder at 15 to 30°C.

Pharmacy Bulk Vials (150 mg): Each vial contains: doxorubicin HCl USP 150 mg as a sterile red-orange lyophilized powder. Also contains lactose and methylparaben (added to enhance dissolution). Cartons of a single vial. Protect from light. Store powder at 15 to 30°C.

Adriamycin PFS: Vials: 10 mg: Each vial of sterile, isotonic, nonpreserved solution contains: doxorubicin HCl USP 10 mg, sodium chloride USP 45 mg, water for injection USP and hydrochloric acid USP for pH adjustment. Vials of 5 mL, cartons of 10. Store under refrigeration (2 to 8°C), protect from light and retain in carton until time of use. Discard unused solution.

50 mg: Each vial of sterile, isotonic, nonpreserved solution contains: doxorubicin HCl USP 50 mg, sodium chloride USP 225 mg, water for injection USP and hydrochloric acid USP for pH adjustment. Vials of 25 mL, cartons of 4. Store under refrigeration (2 to 8°C), protect from light and retain in carton until time of use. Discard unused solution.

Pharmacy Bulk Vials (200 mg): Each vial of sterile, isotonic, nonpreserved solution contains: doxorubicin HCl USP 200 mg, sodium chloride USP 900 mg, water for injection and hydrochloric acid USP for pH adjustment. Vials of 100 mL, cartons of a single vial. Store under refrigeration (2 to 8°C), protect from light and retain in carton until time of use. Discard unused solution.

ADRIAMYCIN® Pharmacia & Upjohn Doxorubicin HCl Antineoplastic Agent

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