Rubicin

Rubicin

doxorubicin

Manufacturer:

UNILAB, Inc

Distributor:

UNILAB, Inc
Full Prescribing Info
Contents
Doxorubicin hydrochloride.
Description
Each vial contains: Doxorubicin hydrochloride 10 mg or 50 mg.
Indications/Uses
Doxorubicin has been used successfully both as a single agent and also in combination with other cancer chemotherapeutic agents in a number of solid tumors and hematologic malignancies such as: Acute lymphocytic-lymphoblastic leukemias.
Acute myeloblastic leukemia.
Wilm's tumor.
Neuroblastoma.
Soft tissue sarcomas.
Osteosarcoma.
Breast carcinoma.
Ovarian carcinoma.
Thyroid carcinoma.
Gastric carcinoma.
Malignant lymphoma.
Hodgkin's disease.
Non-Hodgkin's lymphoma.
Transitional cell bladder carcinoma.
Bronchogenic carcinoma in which the small cell histologic type is the most responsive.
Squamous cell carcinoma of the head and neck.
Doxorubicin has also shown antitumor activity in the following adult and pediatric malignancies: Endometrial carcinoma.
Primary hepatocellular carcinoma.
Non-seminomatous carcinoma of the testis.
Carcinoma of the prostate.
Ewing's sarcoma.
Rhabdomyosarcoma.
Multiple myeloma.
Chronic leukemias.
Doxorubicin has also been used for the following: As a component of adjuvant therapy in women with evidence of axillary lymph node involvement following resection of primary breast cancer.
By instillation into the bladder for the topical treatment of superficial bladder tumors.
Dosage/Direction for Use
For intravenous (IV) infusion only: Do not administer intramuscularly (IM) or subcutaneously (SC) because of the potential for development of local tissue necrosis if administered through these routes.
The total cumulative dose of doxorubicin hydrochloride should not exceed 550 mg/m2 because of the risk of potentially irreversible cardiotoxicity, but higher cumulative doses may be tolerated when dexrazoxane is used concomitantly as a cardioprotectant. If previous or concomitant therapy includes the use of other potentially cardiotoxic agents (e.g., cyclophosphamide, irradiation of the cardiac region), total doxorubicin hydrochloride should not exceed 400 mg/m2. The total dosage of doxorubicin hydrochloride should include any previous or concomitant therapy with other anthracyclines or related compounds.
As A Single Agent: Commonly Used Adult Dosage Schedule: 60 to 75 mg/m2 body surface area as a single IV injection every 21 days.
Alternative Adult Dosage Schedule: 20 mg/m2 body surface area as a single IV injection in weekly doses has been reported to reduce the incidence of congestive heart failure.
30 mg/m2 body surface area as a single IV injection on each of 3 successive days repeated every 4 weeks has also been used; this schedule is usually associated with a higher incidence of stomatitis.
In Combination Chemotherapy: In combination with other chemotherapy drugs, the most commonly used dosage of Doxorubicin is 40 to 60 mg/m2 body surface area as a single IV injection every 21 to 28 days.
Dosage Adjustments: In a clinical study, patients who experienced neutropenic fever/infection while receiving the combination of doxorubicin/cyclophosphamide could have dose modifications of the regimen up to 75% of the starting doses. When necessary, the next cycle of treatment was delayed until the absolute neutrophil count (ANC) was ≥1000 cells/mm3 and the platelet count was ≥100,000 cells/mm3 and nonhematologic toxicities had resolved.
Dose reduction of Doxorubicin is recommended in patients with hepatic impairment with the following plasma bilirubin concentrations: See table.

Click on icon to see table/diagram/image

Doxorubicin should not be administered to patients with severe hepatic impairment. (see Contraindications).
Contraindications
Hypersensitivity to doxorubicin, other anthracyclines or anthracenediones such as epirubicin, daunorubicin, mitoxantrone or mitomycin C or any component of the product.
Patients with marked persistent myelosuppression induced by previous treatment with other antitumor agents or by radiotherapy (baseline neutrophil count <1, 500 cells/mm3).
Severe hepatic impairment.
Severe myocardial insufficiency.
Recent myocardial infarction.
Severe arrhythmias.
History of severe cardiac disease.
Pregnant or breastfeeding women.
Patients who received previous treatment with maximum cumulative doses of doxorubicin, daunorubicin, idarubicin, and/or other anthracyclines and anthracenediones.
Warnings
Severe local tissue necrosis will occur if there is extravasation during administration. Doxorubicin must not be given by the IM or SC route (see Dosage & Administration).
Myocardial toxicity manifested in its most severe form by potentially fatal congestive heart failure (CHF) may occur either during therapy or months to years after termination of therapy. Cardiac toxicity may occur at lower cumulative doses whether or not cardiac risk factors are present. Children are at increased risk for developing delayed cardiotoxicity.
Secondary acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS), with or without a preleukemic phase, has been reported in patients treated with athracyclines, including doxorubicin. The occurrence of refractory secondary AML or MDS is more common when anthracyclines are given in combination with DNA-damaging antineoplastic agents or radiotherapy, when patients have been heavily pretreated with cytotoxic drugs, or when doses of anthracyclines have been escalated. Secondary leukemia can have a 1- to 3-year latency period, and can occur as late as 10 years following treatment. Children are also at risk of developing secondary AML.
Dosage should be reduced in patients with impaired hepatic function.
Severe myelosuppression may occur.
Doxorubicin should be administered only under the supervision of a physician who is experienced in the use of cancer chemotherapeutic agents.
Special Precautions
Doxorubicin is a toxic drug with a low therapeutic index. Patients should be hospitalized during the initial phase of doxorubicin treatment. Determinations of hepatic, hematopoietic [e.g., blood counts, serum levels of total bilirubin, aspartate aminotransferase (AST) and creatinine], and cardiac function should be performed prior to and at regular intervals during doxorubicin therapy. Before doxorubicin treatment, patients should recover from acute toxicities from prior cytotoxic treatment (e.g., stomatitis, neutropenia, thrombocytopenia, and generalized infections). Patients should be carefully monitored during treatment for possible complications due to myelosuppression and cardiotoxicity. Doxorubicin may potentiate toxicities of other antineoplastic drugs.
Cardiovascular: Cardiotoxicity is a known risk of anthracycline treatment. It may be manifested by early (acute) or late (delayed) effects.
Early (Acute) Events: Early cardiotoxicity of Doxorubicin consists mainly of ECG abnormalities such as non-specific ST-T wave changes, prolongation of the QT interval, and arrhythmias (e.g, sinus tachycardia, ventricular, supraventricular, and junctional tachycardia). Conduction disturbances (including atrioventricular and bundle-branch block) have been reported rarely and are usually associated with late-onset anthracycline-induced cardiotoxicity. Although acute cardiotoxicity is transient, rarely, pericarditis-myocarditis syndrome (e.g., pericardial effusion and/or decreased myocardial contractility) and possible cardiac failure may occur. These effects do not usually predict development of delayed cardiotoxicity and are generally not a consideration for doxorubicin treatment discontinuation.
Late (Delayed) Events: Delayed cardiotoxicity usually develops late in the course of Doxorubicin therapy or within 2 to 3 months after treatment termination, but later events, several months to years after completion of treatment, were also seen in clinical studies. Delayed cardiomyopathy is manifested by reduced left ventricular ejection fraction (LVEF) and/or signs and symptoms of CHF such as dyspnea, pulmonary edema, dependent edema, cardiomegaly, hepatomegaly, oliguria, ascites, pleural effusion, and gallop rhythm. Subacute effects such as pericarditis/myocarditis have also been reported. Life-threatening CHF is the most severe form of anthracycline-induced cardiomyopathy and represents the cumulative dose-limiting toxicity of the drug.
Cardiac function should be assessed before patients undergo treatment with doxorubicin and must be monitored throughout therapy to minimise the risk of incurring severe cardiac impairment. Regular monitoring of LVEF through multi-gated radionuclide angiography (MUGA) or echocardiography (ECHO) is recommended to reduce the risk of cardiac impairment.
Chronic cardiotoxicity, such as heart failure, may occur as total cumulative dosage of doxorubicin hydrochloride approaches or exceeds 550 mg/m2. Cardiotoxicity may occur at a lower total cumulative dosage (e.g., 400 mg/m2) in patients who have received radiotherapy to the mediastinal/pericardial region, concomitant therapy with other potentially cardiotoxic agents (e.g., cyclophosphamide), doxorubicin exposure at an early age, and advanced age. Time of onset of chronic cardiotoxicity may vary but usually is manifested within 1 year of anthracycline therapy. Thereafter, the risk of developing CHF increases rapidly, and it is recommended not to exceed a maximum cumulative dose of 550 mg/m2.
Children, adolescents and females are at an increased risk for developing delayed cardiotoxicity following doxorubicin administration. Periodic follow-up of cardiac functions is recommended for monitoring.
Hematologic Toxicity: Marked myelosuppression is evident with most cytotoxic drugs, including doxorubicin. Leukocyte, erythrocyte, and platelet counts should be performed prior to and at frequent intervals during therapy. Dose-dependent, reversible leukopenia and/or granulocytopenia are the predominant manifestations of hematologic toxicity and are the most common acute dose-limiting toxicity of doxorubicin, the severity of which depends on the dose and the bone marrow's regenerative capacity. Leukocyte counts as low as 1000/mm3 should be anticipated during therapy with appropriate doses of doxorubicin, although severe myelosuppression may occur. Thrombocytopenia and anemia may also occur. Maximum leukopenia, thrombocytopenia, and anemia generally occur during the second week (nadir 10 to 14 days) following administration of the drug and generally return to normal by day 21. Clinical consequences of severe myelosuppression include fever, infections, sepsis/septicemia, septic shock, hemorrhage, tissue hypoxia, or death. Once manifestations of hematologic toxicities occur, dose reduction or suspension or delay of doxorubicin therapy may be required.
Secondary Leukemia: (see Warnings).
Effects at Site of Injection: Injection into a small vessel or from repeated injections into the same vein may result in phlebosclerosis. Proper dosage and administration procedures should be followed to reduce the risk of phlebitis/thrombophlebitis at the injection site (see Dosage & Administration).
Extravasation: Extravasation of doxorubicin during IV injection may give rise to severe tissue lesions (vesication, severe cellulitis) and necrosis. Once extravasation signs or symptoms occur, drug injection or infusion should be terminated immediately (see Dosage & Administration).
Hepatic Impairment: Hepatic function should be evaluated prior to doxorubicin therapy since its toxicity may be increased by hepatic impairment due to its extensive metabolism by the liver. Evaluation of hepatic function can be done using laboratory tests such as AST, alanine transaminase (ALT), alkaline phosphatase, and bilirubin (see Dosage & Administration). Patients with severe hepatic impairment should not receive doxorubicin (see Contraindications).
Vaccine Use: Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents including doxorubicin may result in serious or fatal infections (see Interactions).
Gastrointestinal: Doxorubicin is emetogenic. Antiemetics may reduce nausea and vomiting; prophylactic use of antiemetics should be considered before administration of doxorubicin, particularly when given in conjunction with other emetogenic drugs.
Others: Doxorubicin may potentiate toxicities of other antineoplastic drugs. Exacerbation of cyclophosphamide-induced hemorrhagic cystitis, enhanced hepatotoxicity of 6-mercaptopurine and increased radiation-induced toxicities were reported in studies.
As with other cytotoxic drugs, thrombophlebitis and thromboembolic pneumonia, including pulmonary embolism (in some cases fatal), were observed with Doxorubicin in certain clinical trials.
Advice for Patients: Doxorubicin often imparts a red color to the urine 1 to 2 days after administration, and patients should be advised to expect this effect during therapy.
Patients should be informed of the expected adverse effects of doxorubicin. Patients should also understand associated risks of Doxorubicin treatment such as irreversible myocardial damage and treatment-related leukemia.
Laboratory Tests: Initial treatment with doxorubicin requires observation of the patient and periodic monitoring of complete blood counts, hepatic function tests and LVEF. Abnormalities in hepatic function tests may occur. Like other cytotoxic drugs, doxorubicin may induce "tumor-lysis syndrome" and hyperuricemia in patients with rapidly growing tumors. Blood uric acid levels, potassium, calcium, phosphate, and creatinine should be evaluated after initial treatment. Hydration and urine alkalinization to prevent hyperuricemia may minimize potential complications of tumor-lysis syndrome.
Dental Work: Patients should not undergo dental work during treatment with doxorubicin.
Carcinogenicity, Mutagenicity and Impairment of Fertility: Doxorubicin has been shown to be mutagenic and carcinogenic in experimental models. Secondary AML or MDS have been reported in patients treated with doxorubicin-containing regimens (see Warnings). However, the extent of increased risk of developing secondary malignancies associated with the use of doxorubicin has not been fully established.
Doxorubicin was toxic to male reproductive organs in animal studies, producing testicular atrophy, diffuse degeneration of the seminiferous tubes, and hypospermia. Doxorubicin may potentially induce chromosomal damage in human spermatozoa. Oligospermia or azoospermia were evidenced in men treated with doxorubicin, mainly in combination therapies. This effect may be permanent. However, sperm counts have been reported to return to normal levels in some instances. Men undergoing doxorubicin treatment should use effective contraceptive methods.
In women, doxorubicin may cause infertility during the time of drug administration. Doxorubicin may cause amenorrhea. Ovulation and menstruation may return after termination of therapy, although premature menopause can occur. Recovery of menses is related to age at treatment.
Use in Children: Children are at a greater risk for developing secondary leukemia (including AML) and delayed cardiotoxicity. Doxorubicin-induced cardiomyopathy impairs myocardial growth as children mature and CHF may possibly develop during early adulthood. Periodic long-term cardiac function monitoring is recommended to reduce the risk of delayed cardiotoxicity. Doxorubicin, as a part of intensive chemotherapy in children, may contribute to prepubertal growth failure. Pediatric patients treated with Doxorubicin or other topoisomerase II inhibitors are at a risk for developing secondary leukemia, including acute myelogenous leukemia, and other neoplasms.
Use in Elderly: No overall differences in safety and effectiveness were observed between older and younger patients, but greater sensitivity of some older individuals cannot be ruled out. The decision to use doxorubicin in the treatment of older patients should be based upon a consideration of overall performance status and concurrent illnesses, in addition to the age of the individual patient.
Use In Pregnancy & Lactation
Use in Pregnancy: Category D: Doxorubicin can cause fetal harm when administered to a pregnant woman. Doxorubicin is embryotoxic and teratogenic in rats and embryotoxic and abortifacient in rabbits, and trace amounts of drug have been found in mouse fetuses and in one aborted human fetus following doxorubicin administration.
If doxorubicin is used during pregnancy, or if the patient becomes pregnant while receiving the drug, evaluate potential hazard to the fetus or potential risk of loss of pregnancy. Advise women of childbearing potential to avoid becoming pregnant during doxorubicin therapy.
Use in Lactation: Doxorubicin and doxorubicinol is distributed into breast milk. Mothers should not breastfeed while undergoing chemotherapy.
Adverse Reactions
Dose-limiting toxicities during therapy are cardiotoxicity and myelosuppression.
Cardiac Effects: Sinus tachycardia, ECG abnormalities, tachyarrhythmias, atrio-ventricular and bundle branch block, asymptomatic reductions in the left ventricular ejection fraction (LVEF), CHF, acute life-threatening arrhythmias during or within few hours after Doxorubicin administration.
Hematologic Effects: Leukopenia, neutropenia, anemia, thrombocytopenia, and hemorrhage.
Gastrointestinal (GI) Effects: Acute nausea and vomiting occurs frequently and may be severe, but this may be alleviated by antiemetic therapy. Mucositis (stomatitis and esophagitis) may occur 5 to 10 days after administration and its effect may be severe leading to ulceration and represents a site of origin for severe infections. A dosage regimen of Doxorubicin given on three successive days results in a higher incidence and severity of mucositis. Stomatitis usually begins as a burning sensation accompanied by erythema of the oral mucosa, which in 2 to 3 days may progress to ulceration, particularly in the sublingual and lateral tongue margins and on the palate. Ulceration is sometimes severe enough to result in difficulty in swallowing, but seldom requires cessation of therapy. Stomatitis is maximal during the second week of therapy and lasts an additional 3 to 7 days. GI toxicity (frequently nausea and vomiting and occasionally anorexia and diarrhea) may occur, usually on the day of drug administration. Ulceration and necrosis of the colon, especially the cecum, may occur leading to bleeding or severe infections which can be fatal. These reactions have been reported in patients with acute myelogenous leukemia treated with a 3-day course of doxorubicin combined with cytarabine. Anorexia, abdominal pain, dehydration, diarrhea, hyperpigmentation, GI tract bleeding, and colitis have been occasionally reported.
Dermatological Effects: Reversible complete alopecia occurs in most cases. Regrowth of hair usually begins 2 to 3 months after doxorubicin is discontinued. Hyperpigmentation of nailbeds, pigmented banding of fingernails, and phalangeal and other dermal creases (primarily in pediatric patients) may occur. Oncholysis, plantar callus formation, and epidermolysis have been reported in patients receiving doxorubicin. Recurrence of skin reaction due to prior radiotherapy has occurred; the reaction occurred from 4 to 7 days after each dose was administered and lasted an average of 7 days thereafter. Rash, itching, photosensitivity, acral erythema, and palmar plantar erythrodysesthesia may occur.
Local Effects: Extravasation produces severe local tissue necrosis, as well as possible cellulitis, vesication, lymphangitis, or painful induration and may result in limitation of mobility to the adjacent joints. Erythematous streaking along the vein proximal to the site of injection has been reported. Intravesical instillation can cause bladder and urethral irritation, hematuria, and hemorrhagic cystitis.
Hypersensitivity: Fever, chills, rash, or itching and urticaria have been reported occasionally. Anaphylaxis may occur. A case of apparent cross sensitivity to lincomycin has been reported.
Vascular Effects: Phlebosclerosis has been reported especially when a single vein is used or small veins are used for repeated administration. Facial flushing may occur if the injection is given too rapidly. Phlebitis, thrombophlebitis and thromboembolism can occur.
Neurological Effects: Peripheral neurotoxicity in the form of local-regional sensory and/or motor disturbance has been reported in patients treated with intra-arterial Doxorubicin, mostly in combination with cisplatin. Concomitant use of doxorubicin with cisplatin or vincristine also reported seizures and coma.
Endocrine/Metabolic Effects: Hyperuricemia may occur due to tumor lysis syndrome and serum uric acid concentrations should be monitored. Amenorrhea, hot flushes, oligospermia, azoospermia, and weight gain have been reported.
Ocular Effects: Conjunctivitis, keratitis and lacrimation occur but rarely.
Hepatic Effects: Changes in transaminase level have been reported. Hepatitis and hepatocellular damage have been reported in patients receiving doxorubicin as part of combination therapy. A characteristic hepatotoxicity can also be produced by the combination of radiotherapy with doxorubicin.
Urological Effects: Pain, hemorrhage and occasionally decreased bladder capacity upon instillation, reddish urine for 1 to 2 days after administration.
Others: Malaise/asthenia, shock.
Drug Interactions
Doxorubicin is extensively metabolized by the liver. Changes in hepatic function induced by concomitant therapies may affect doxorubicin metabolism, pharmacokinetics, therapeutic efficacy, and/or toxicity. Toxicities associated with doxorubicin, especially hematologic and gastrointestinal events, may be increased when doxorubicin is used in combination with other cytotoxic drugs.
Bone marrow depressants or radiation therapy: Additive bone marrow depression may occur. Adjust Doxorubicin dosage when two or more bone marrow depressants, including radiation therapy, are used concurrently or consecutively.
Cardiotoxic agents (e.g., trastuzumab): Doxorubicin should not be administered in combination with other cardiotoxic agents unless the patient's cardiac function is closely monitored. Patients receiving doxorubicin after stopping treatment with other cardiotoxic agents, especially those with long half-lives such as trastuzumab, may also be at an increased risk of developing cardiotoxicity. Physicians should avoid doxorubicin-based therapy for up to 24 weeks after stopping trastuzumab when possible. If doxorubicin is used before this time, careful monitoring of cardiac functions is recommended (see Warnings and Precautions).
Cyclophosphamide: The addition of cyclophosphamide to doxorubicin treatment does not affect exposure to Doxorubicin, but may increase exposure to doxorubicinol. Cyclophosphamide-induced hemorrhagic cystitis may be exacerbated and cardiotoxicity may be enhanced. High-dose cyclophosphamide in combination with 2 to 3 times the recommended dosage of doxorubicin has also been reported to cause seizures. Studies show that AML as a second malignancy was shown after treatment with doxorubicin and cyclophosphamide.
Ciclosporin: The use of ciclosporin in combination with doxorubicin may result in an increase in the area under the plasma concentration-time (AUC) for both doxorubicin and doxorubicinol, possibly due to a decrease in doxorubicin clearance and a decrease in metabolism of doxorubicinol. Evidence suggests that the concomitant use of ciclosporin may result in a more severe and prolonged hematologic toxicity associated with doxorubicin. In addition, seizures and/or coma have occurred in patients receiving doxorubicin and ciclosporin concomitantly.
Paclitaxel: Compared with administration of doxorubicin followed by paclitaxel, initial administration of paclitaxel (by infusion over 24 hours) followed by doxorubicin administered over 48 hours) was shown to result in a decrease in doxorubicin clearance and an increase in the severity of neutropenia and stomatitis.
Verapamil: A study of the effects of verapamil on the acute toxicity of doxorubicin in mice showed higher initial peak concentrations of Doxorubicin in the heart with a higher incidence and severity of degenerative changes in cardiac tissue resulting in a shorter survival.
Daunorubicin, Idarubicin, Mitoxantrone, and Irradiation of the cardiac region: Concurrent administration may increase plasma concentrations of doxorubicin and/or its metabolites and increase cardiotoxicity. The maximum cumulative dose of doxorubicin should be reduced.
Phenobarbital: Increases elimination of doxorubicin.
Phenytoin: Phenytoin levels may be decreased by doxorubicin.
Sorafenib: Increases systemic exposure to doxorubicin.
6-mercaptopurine: Concomitant use may enhance hepatotoxicity of 6-mercaptopurine.
Streptozocin, Methotrexate, and Valspodar: Concurrent therapy may inhibit hepatic metabolism of doxorubicin and prolong doxorubicin's half-life. Reduce doxorubicin dose.
Dactinomycin: Concomitant use with doxorubicin therapy produces "recall" acute pneumonitis at variable times after local radiation therapy in children.
Dexrazoxane: A clinical study showed a lower tumor response in women with metastatic breast cancer who were concurrently using the cardioprotectant dexrazoxane with the initiation of a regimen of fluorouracil, doxorubicin and cyclophosphamide. Dexrazoxane is only indicated for women with metastatic breast cancer who have received a cumulative Doxorubicin dose of 300 mg/m2 and are continuing Doxorubicin therapy.
Cytarabine: Doxorubicin given by IV push daily for 3 days with cytarabine given by continuous infusion daily for 7 or more days resulted in necrotizing colitis manifested by typhlitis (cecal inflammation), bloody stools and severe and sometimes fatal infections.
Thalidomide: A clinical study cited that the addition of thalidomide to doxorubicin in patients with multiple myeloma increased the risk of deep-vein thrombosis.
Calcium-channel Blocking Agents: Studies suggest that doxorubicin-induced cardiotoxicity may be potentiated by concomitant use of calcium-channel blocking agents.
Progesterone: Exacerbation of doxorubicin-induced neutropenia and thrombocytopenia has been reported in patients with advanced malignancies receiving high doses of progesterone (up to 10 g IV over 24 hours) concomitantly with doxorubicin (60 mg/m2 by IV bolus).
Other Drugs: Saquinavir in combination with cyclophosphamide, doxorubicin and etoposide increased mucosal toxicity in patients with HIV-associated non-Hodgkin's lymphoma. Doxorubicin is reported to inhibit the intracellular activation of stavudine, inhibiting its antiviral effect.
Seizures and/or coma have occurred in patients receiving Doxorubicin and vincristine concomitantly.
Vaccine use: Concurrent use with a live virus vaccine may potentiate virus replication, may increase side effects of vaccine virus, and/or may decrease patient's antibody response to killed virus vaccines. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient’s ability to respond to the vaccine depends on many factors; estimates vary from 3 months to 1 year.
ATC Classification
L01DB01 - doxorubicin ; Belongs to the class of cytotoxic antibiotics, anthracyclines and related substances. Used in the treatment of cancer.
Presentation/Packing
Inj (vial) 10 mg x 1's. 50 mg x 50 mL x 1's.
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