DOXORUBICIN HCL
Chemistry - An anthracycline glycoside antibiotic antineoplastic, doxorubicin HCl occurs as alyophilized, red-orange powder that is freely soluble in water, slightly soluble in normal saline, andvery slightly soluble in alcohol. The commercially available powder for injection also containslactose and methylparaben to aid dissolution. After reconstituting, the solution has a pH from 3.8 - 6.5. The commercially available solution for injection has a pH of approximately 3. Doxorubicin
HCl may also be known as Hydroxydaunomycin HCl, Hydroxydaunorubicin HCl, ADR, or as the commonly known proprietary product, Adriamycin® (Adria).
Lyophilized powder for injection should be stored away from direct sunlight and in a dry place.
After reconstituting with sodium chloride 0.9%, the single-use lyophilized powder product is reportedly stable for 24 hours at room temperature and 48 hours when refrigerated. The manufacturer recommends protecting from sunlight. They also recommend not freezing the product and discarding any unused portion. However, one study found that powder reconstituted with sterile water to a concentration of 2 mg/ml lost only about 1.5% of its potency per month over 6 months when stored in the refrigerator. When frozen at -20°C, no potency loss after 30 days was detected and sterility was maintained by filtering the drug through a 0.22 micron filter before injection.
The manufacturer states that after reconstitution, the multi-dose vials may be stored for up to 7 days at room temperature in normal room light, and for up to 15 days in the refrigerator.
Doxorubicin HCl is reportedly compatible with the following intravenous solutions and drugs:dextrose 3.3% in sodium chloride 3%, D5W, Normosol R (pH 7.4), lactated Ringer's injection, and sodium chloride 0.9%. In syringes with: bleomycin sulfate, cisplatin, cyclophosphamide, droperidol, fluorouracil, leucovorin calcium, methotrexate sodium, metoclopramide HCl, mitomycin, and vincristine sulfate. The drug is compatible during Y-site injection with bleomycin sulfate, cisplatin, cyclophosphamide, droperidol, fluorouracil, leucovorin calcium, methotrexate sodium, metoclopramide HCl, mitomycin, vinblastine sulfate and vincristine sulfate.
Doxorubicin HCl compatibility information conflicts or is dependent on diluent or concentration factors with the following drugs or solutions: vinblastine sulfate (in syringes and as an IVadditive). Compatibility is dependent upon factors such as pH, concentration, temperature anddiluents used. It is suggested to consult specialized references for more specific information (e.g.,
Handbook on Injectable Drugs by Trissel; see bibliography).
Doxorubicin HCl is reportedly incompatible with the following solutions or drugs: aminophylline, cephalothin sodium, dexamethasone sodium phosphate, diazepam, fluorouracil (as an IV additive only), furosemide, heparin sodium and hydrocortisone sodium succinate.
Doxorubicin is most cytotoxic to cardiac cells, followed by melanoma, sarcoma cells, and normalmuscle and skin fibroblasts. Other rapidly proliferating "normal" cells, such as bone marrow, hairfollicles, GI mucosa, may also be affected by the drug.
Uses, Indications - Doxorubicin is perhaps the most widely used antineoplastic agent at present insmall animal medicine. It may be useful in the treatment of a variety of carcinomas and sarcomas inboth the dog and cat. Refer to the Dosage references or the Protocols found in the appendix formore information.
Doxorubicin is metabolized extensively by the liver and other tissues via aldo-keto reductaseprimarily to doxorubicinol, which is active. Other inactive metabolites are also formed. Doxorubicinand its metabolites are primarily excreted in the bile and feces. Only about 5% of the drug isexcreted in the urine within 5 days of dosing. Doxorubicin is eliminated in a triphasic manner.
During the first phase (t1/2 » 0.6 hours) doxorubicin is rapidly metabolized, via the "first pass"effect followed by a second phase (t1/2 » 3.3 hours). The third phase has a much slowerelimination half-life (17 hours for doxorubicin and 32 hours for metabolites), presumably due tothe slow release of the drug from tissue proteins.
Because doxorubicin can be very irritating to skin, gloves should be worn when administering orpreparing the drug. Ideally, doxorubicin injection should be prepared in a vertical laminar flowhood. Should accidental skin or mucous membrane contact occur, wash the area immediately usingsoap and copious amounts of water.
Doxorubicin is teratogenic and embryotoxic in laboratory animals. It is unknown if it affects malefertility.
An immediate hypersensitivity reaction may be seen, characterized by urticaria, facial swelling, vomiting, arrhythmias (see below) and/or hypotension. Pretreatment with a histamine1 blocker suchas diphenhydramine (IV prior to treatment at 10 mg for dogs up to 9 kg; 20 mg for dogs 9-27 kg;and 30 mg for dogs over 27 kg) or alternatively, dexamethasone (0.55 mg/kg IV), is oftenrecommended to reduce or eliminate these effects.
Cardiac toxicity of doxorubicin falls into two categories, acute and cumulative. Acute cardiactoxicity may occur during IV administration or several hours subsequent, and is manifested bycardiac arrest preceded by ECG changes (T-wave flattening, S-T depression, voltage reduction, arrhythmias). Rarely, an acute hypertensive crisis has been noted after infusion. Acute cardiactoxicity does not preclude further use of the drug, but additional treatment should be delayed. Theadministration of diphenhydramine and/or glucocorticoids before doxorubicin administration mayprevent these effects.
Cumulative cardiac toxicity requires halting any further therapy and can be extremely serious.
Diffuse cardiomyopathy with severe congestive heart failure refractory to traditional therapies isgenerally noted. It is believed that the risk of cardiac toxicity is greatly increased in dogs when thecumulative dose exceeds 250 mg/m2, but may be seen at doses as low as 100 mg/m2. Therefore, itis not recommended to exceed 240 mg/m2 total dose in dogs. It is unknown what the incidence ofcardiotoxicity or the dosage ceiling for doxorubicin is in cats, but most clinicians believe that 240mg/m2 should also be used as the upper limit cumulative dose in cats.
In cats, doxorubicin is a potential nephrotoxin and they should have renal function monitored before and during therapy.
Doxorubicin should be administered IV slowly, over at least 10 minutes, in a free flowing line.
Extravasation injuries secondary to perivascular administration of doxorubicin can be quite serious, with severe tissue ulceration and necrosis possible. Prevention of extravasation should be a priority and animals should be frequently checked during the infusion. Should extravasation occur, one author (Coppoc 1988) makes the following recommendations for veterinary patients:
Immediately flood the area with 5 ml of sodium bicarbonate injection 8.4%, 15-30 ml of 0.9% sodium chloride, and 4 mg dexamethasone. Then apply a steroid/DMSO (concentrations not noted) solution topically to the site and cover with an occlusive dressing (e.g., plastic wrap).
Continue to treat using the occlusive dressing for 3-5 days. In humans with severe extravasation injuries due to doxorubicin, site excision and plastic surgery has been necessary.
Drug/Laboratory Interactions - Doxorubicin may significantly increase both blood and urineconcentrations of uric acid.
HCl may also be known as Hydroxydaunomycin HCl, Hydroxydaunorubicin HCl, ADR, or as the commonly known proprietary product, Adriamycin® (Adria).
Storage, Stability, Compatibility
The commercially available solution for injection is stable for18 months when stored in the refrigerator (2-8°C) and protected from light.Lyophilized powder for injection should be stored away from direct sunlight and in a dry place.
After reconstituting with sodium chloride 0.9%, the single-use lyophilized powder product is reportedly stable for 24 hours at room temperature and 48 hours when refrigerated. The manufacturer recommends protecting from sunlight. They also recommend not freezing the product and discarding any unused portion. However, one study found that powder reconstituted with sterile water to a concentration of 2 mg/ml lost only about 1.5% of its potency per month over 6 months when stored in the refrigerator. When frozen at -20°C, no potency loss after 30 days was detected and sterility was maintained by filtering the drug through a 0.22 micron filter before injection.
The manufacturer states that after reconstitution, the multi-dose vials may be stored for up to 7 days at room temperature in normal room light, and for up to 15 days in the refrigerator.
Doxorubicin HCl is reportedly compatible with the following intravenous solutions and drugs:dextrose 3.3% in sodium chloride 3%, D5W, Normosol R (pH 7.4), lactated Ringer's injection, and sodium chloride 0.9%. In syringes with: bleomycin sulfate, cisplatin, cyclophosphamide, droperidol, fluorouracil, leucovorin calcium, methotrexate sodium, metoclopramide HCl, mitomycin, and vincristine sulfate. The drug is compatible during Y-site injection with bleomycin sulfate, cisplatin, cyclophosphamide, droperidol, fluorouracil, leucovorin calcium, methotrexate sodium, metoclopramide HCl, mitomycin, vinblastine sulfate and vincristine sulfate.
Doxorubicin HCl compatibility information conflicts or is dependent on diluent or concentration factors with the following drugs or solutions: vinblastine sulfate (in syringes and as an IVadditive). Compatibility is dependent upon factors such as pH, concentration, temperature anddiluents used. It is suggested to consult specialized references for more specific information (e.g.,
Handbook on Injectable Drugs by Trissel; see bibliography).
Doxorubicin HCl is reportedly incompatible with the following solutions or drugs: aminophylline, cephalothin sodium, dexamethasone sodium phosphate, diazepam, fluorouracil (as an IV additive only), furosemide, heparin sodium and hydrocortisone sodium succinate.
Pharmacology - DOXORUBICIN HCL
Although possessing antimicrobial properties, doxorubicin's cytotoxic effectsprecludes its use as an anti-infective agent. The drug causes inhibition of DNA synthesis, DNA-dependent RNA synthesis and protein synthesis, but the precise mechanism(s) for these effects is(are) not well understood. The drug acts throughout the cel cycle and also possesses some immunosuppressant activity.Doxorubicin is most cytotoxic to cardiac cells, followed by melanoma, sarcoma cells, and normalmuscle and skin fibroblasts. Other rapidly proliferating "normal" cells, such as bone marrow, hairfollicles, GI mucosa, may also be affected by the drug.
Uses, Indications - Doxorubicin is perhaps the most widely used antineoplastic agent at present insmall animal medicine. It may be useful in the treatment of a variety of carcinomas and sarcomas inboth the dog and cat. Refer to the Dosage references or the Protocols found in the appendix formore information.
Pharmacokinetics - DOXORUBICIN HCL
Doxorubicin must be administered IV as it is not absorbed from the GI tractand is extremely irritating to tissues if administered SQ or IM. After IV injection, the drug israpidly and widely distributed, but does not appreciably enter the CSF. It is highly bound to tissueand plasma proteins, probably crosses the placenta and is distributed into milk.Doxorubicin is metabolized extensively by the liver and other tissues via aldo-keto reductaseprimarily to doxorubicinol, which is active. Other inactive metabolites are also formed. Doxorubicinand its metabolites are primarily excreted in the bile and feces. Only about 5% of the drug isexcreted in the urine within 5 days of dosing. Doxorubicin is eliminated in a triphasic manner.
During the first phase (t1/2 » 0.6 hours) doxorubicin is rapidly metabolized, via the "first pass"effect followed by a second phase (t1/2 » 3.3 hours). The third phase has a much slowerelimination half-life (17 hours for doxorubicin and 32 hours for metabolites), presumably due tothe slow release of the drug from tissue proteins.
Contraindications, Precautions, Reproductive Safety
Doxorubicin is contraindicated or relatively contraindicated (measure risk vs. benefit) in patients with myelosuppression, impaired cardiacfunction, or who have reached the total cumulative dose level of doxorubicin and/or daunorubicin. Itshould be used with caution in patients with hyperuricemia/hyperuricuria, or impaired hepaticfunction. Dosage adjustments are necessary in patients with hepatic impairment.Because doxorubicin can be very irritating to skin, gloves should be worn when administering orpreparing the drug. Ideally, doxorubicin injection should be prepared in a vertical laminar flowhood. Should accidental skin or mucous membrane contact occur, wash the area immediately usingsoap and copious amounts of water.
Doxorubicin is teratogenic and embryotoxic in laboratory animals. It is unknown if it affects malefertility.
Adverse Effects, Warnings
Doxorubicin may cause several adverse effects including bonemarrow suppression, cardiac toxicity, alopecia, gastroenteritis (vomiting, diarrhea) and stomatitis.An immediate hypersensitivity reaction may be seen, characterized by urticaria, facial swelling, vomiting, arrhythmias (see below) and/or hypotension. Pretreatment with a histamine1 blocker suchas diphenhydramine (IV prior to treatment at 10 mg for dogs up to 9 kg; 20 mg for dogs 9-27 kg;and 30 mg for dogs over 27 kg) or alternatively, dexamethasone (0.55 mg/kg IV), is oftenrecommended to reduce or eliminate these effects.
Cardiac toxicity of doxorubicin falls into two categories, acute and cumulative. Acute cardiactoxicity may occur during IV administration or several hours subsequent, and is manifested bycardiac arrest preceded by ECG changes (T-wave flattening, S-T depression, voltage reduction, arrhythmias). Rarely, an acute hypertensive crisis has been noted after infusion. Acute cardiactoxicity does not preclude further use of the drug, but additional treatment should be delayed. Theadministration of diphenhydramine and/or glucocorticoids before doxorubicin administration mayprevent these effects.
Cumulative cardiac toxicity requires halting any further therapy and can be extremely serious.
Diffuse cardiomyopathy with severe congestive heart failure refractory to traditional therapies isgenerally noted. It is believed that the risk of cardiac toxicity is greatly increased in dogs when thecumulative dose exceeds 250 mg/m2, but may be seen at doses as low as 100 mg/m2. Therefore, itis not recommended to exceed 240 mg/m2 total dose in dogs. It is unknown what the incidence ofcardiotoxicity or the dosage ceiling for doxorubicin is in cats, but most clinicians believe that 240mg/m2 should also be used as the upper limit cumulative dose in cats.
In cats, doxorubicin is a potential nephrotoxin and they should have renal function monitored before and during therapy.
Doxorubicin should be administered IV slowly, over at least 10 minutes, in a free flowing line.
Extravasation injuries secondary to perivascular administration of doxorubicin can be quite serious, with severe tissue ulceration and necrosis possible. Prevention of extravasation should be a priority and animals should be frequently checked during the infusion. Should extravasation occur, one author (Coppoc 1988) makes the following recommendations for veterinary patients:
Immediately flood the area with 5 ml of sodium bicarbonate injection 8.4%, 15-30 ml of 0.9% sodium chloride, and 4 mg dexamethasone. Then apply a steroid/DMSO (concentrations not noted) solution topically to the site and cover with an occlusive dressing (e.g., plastic wrap).
Continue to treat using the occlusive dressing for 3-5 days. In humans with severe extravasation injuries due to doxorubicin, site excision and plastic surgery has been necessary.
Overdosage, Acute Toxicity
Inadvertent acute overdosage may be manifested by exacerbationsof the adverse effects outlined above. A lethal dose for dogs has been reported as 72 mg/m2(O'Keefe and Harris 1990). Supportive and symptomatic therapy is suggested should an overdoseoccur.Drug Interactions
Although doxorubicin is used in conjunction with other antineoplastic agents, toxicity may be also be potentiated. This is particularly true (in humans) with cyclophosphamide. Doxorubicin may exacerbate cyclophosphamide-induced hemorrhagic cystitis andmercaptopurine-associated hepatotoxicity. Cyclophosphamide may also potentiate the cardiotoxiceffects of doxorubicin.Drug/Laboratory Interactions - Doxorubicin may significantly increase both blood and urineconcentrations of uric acid.