DOXORUBICIN HYDROCHLORIDE 
■DOXORUBICIN HYDROCHLORIDE LIPOSOMAL INJECTION
Pronounciation
- (dox-oh-ROO-bih-sin hy-droh-KLOR-eyed)
Trade Name(s)
- (dox-oh-ROO-bih-sin hy-droh-KLOR-eyed LIP-oh-sohm-ul)
DOXORUBICIN HYDROCHLORIDE ■DOXORUBICIN HYDROCHLORIDE LIPOSOMAL INJECTION
Pronounciation
Trade Name(s)
Verify pregnancy status. Assessment required before dosing; see Precautions and Monitor.
60 to 75 mg/M2 once every 21 days as a single agent. When used in combination with other agents, the most common dose of doxorubicin is 40 to 75 mg/M2 every 21 to 28 days.
Breast cancer with lymph node involvement after resection:
Doxorubicin 60 mg/M2 in combination with cyclophosphamide 600 mg/M2 given IV sequentially on Day 1 of each 21-day treatment cycle. Four cycles have been administered.
Adjuvant treatment of operable node-positive breast cancer:
Treatment protocol includes doxorubicin, cyclophosphamide, and docetaxel. Administer doxorubicin 50 mg/M2 and cyclophosphamide 500 mg/M2. One hour later, give docetaxel 75 mg/M2. Repeat every 3 weeks for 6 cycles. See docetaxel and cyclophosphamide monographs.
Do not substitute Doxil for conventional doxorubicin.
AIDS-related Kaposi’s sarcoma:
20 mg/M2 as an IV infusion over 60 minutes every 21 days until disease progression or unacceptable toxicity.
50 mg/M2 as an IV infusion over 60 minutes every 28 days until disease progression or unacceptable toxicity.
Given in combination with bortezomib (Velcade).
Administer 1.3 mg/M2 as an IV bolus on Days 1, 4, 8, and 11 of each 21-day cycle; see bortezomib monograph.
Administer 30 mg/M2 as an IV infusion over 60 minutes on Day 4 of each 21-day cycle following bortezomib. Continue regimen for 8 cycles or until disease progression or the occurrence of unacceptable toxicity.
50 mg/M2 as an IV infusion over 60 minutes every 4 weeks. Other combination protocols are in use.
In combination with other chemotherapeutic agents as first-line treatment, 30 to 60 mg/M2 every 21 to 42 days. See Maternal/Child.
Safety for use in pediatric patients not established.
Reduce dose in patients with impaired hepatic function. Elevated serum bilirubin: Give 50% of above doses for serum bilirubin from 1.2 to 3 mg/mL and 25% of above doses for serum bilirubin above 3 mg/mL. Discontinue therapy for serum bilirubin greater than 5 mg/dL. ■ See Precautions. ■ Consider lower-end doses or longer intervals between cycles for heavily pretreated patients, elderly patients, or obese patients.
Breast cancer with lymph node involvement after resection:
Reduce dose to 75% of the starting dose for neutropenic fever/infection. If necessary, delay the next cycle of treatment until the ANC is 1,000 cells/mm3 or more and the platelet count is 100,000 cells/mm3 or more and nonhematologic toxicities have resolved.
Reduce dose for serum bilirubin of 1.2 or higher. ■ Dose adjustments are required in hematologic toxicity (see the following chart) and in patients with stomatitis or hand-foot syndrome (HFS) (see product literature for guidelines). Adjust or delay a dose as described in the product literature at the first sign of a Grade 1 or higher adverse event. ■ Do not increase Doxil dose after a dose reduction for toxicity.
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Dose adjustments for Doxil in combination therapy with bortezomib for treatment of multiple myeloma are listed in the following chart. See bortezomib monograph for bortezomib dose adjustments.
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seePrecautions.
Each 10 mg must be diluted with 5 mL of NS to obtain a final concentration of 2 mg/mL. Do not use bacteriostatic diluent. Shake gently to dissolve completely. Also available in preservative-free solutions. May be further diluted in 50 mL or more D5W or NS and given as a continuous infusion through a central venous line.
Doses up to 90 mg must be diluted in 250 mL D5W. Not a clear solution, but a translucent red liposomal dispersion. Do not use filters. Doses over 90 mg should be diluted in 500 mL D5W. See Compatibility.
Data not available from manufacturer; however, one source indicates no evidence of drug loss when administered through a 0.2-micron in-line nylon filter, and another source indicates no significant drug loss using various types of 0.2-micron filters.
Do not use filters during preparation or administration.
Retain vials in carton until time of use. Refrigerate unopened vials containing solution. Refrigeration can result in the formation of a gelled product. If this occurs, place vial at RT for 2 to 4 hours to return the product to a slightly viscous mobile solution. Vials containing lyophilized powder may be stored at CRT. All forms should be protected from light.
Refrigerate unopened vials at 2° to 8° C (36° to 46° F). Do not freeze. Refrigerate diluted solution and use within 24 hours.
Manufacturer lists fluorouracil and heparin as incompatible and states mixing with other drugs is not recommended unless specific compatibility data available. Avoid contact with alkaline solutions; can lead to hydrolysis of doxorubicin.
Other sources suggest specific compatibilities dependent on concentration and manufacturer; consult a pharmacist.
Manufacturer states, “Do not mix Doxil with other drugs. Do not use any other diluent (use D5W only). Do not use any bacteriostatic agents (e.g., benzyl alcohol).”
Other sources suggest specific compatibilities dependent on concentration and manufacturer; consult a pharmacist.
A single dose of properly diluted medication over a minimum of 3 to 10 minutes. Should be given through a central line or a secure and free-flowing peripheral venous line containing NS, ½NS, or D5W. Slow injection rate further for erythematous streaking along the vein or facial flushing.
Central venous line required. Equally distributed over time interval outlined in given protocol.
Do not administer as an undiluted suspension or as an IV bolus. For IV infusion only. Rapid infusion may increase risk of acute infusion-related reactions. Primarily occurs during the first infusion; may resolve with a reduced rate or may take up to a day after infusion completed to resolve.
Begin with an initial rate of 1 mg/min to minimize the risk of infusion reactions. If no adverse infusion-related effects, the rate may be increased from the initial rate of 1 mg/min to evenly distribute and complete infusion over 1 hour. Avoid rapid flushing of the infusion line.
A highly cytotoxic anthracycline topoisomerase II inhibitor that is cell-cycle specific for the S phase. Widely distributed and rapidly cleared from plasma, it interferes with cell division by binding with DNA to slow production of nucleic acid synthesis. Metabolized in the liver. Elimination half-life is 20 to 48 hours. Does not cross blood-brain barrier. Slowly excreted in bile and urine. Secreted in breast milk.
Doxorubicin encapsulated in long-circulating STEALTH liposomes (phospholipids). The small size of these liposomes and their persistence in the circulation enable them to evade immune system detection and penetrate the often altered and/or compromised vasculature of tumors. Once distributed to tumor tissue, the doxorubicin is released by an unknown mechanism. It differs from conventional doxorubicin because it mostly confines itself to vascular fluid volume. Metabolized and eliminated renally. Plasma clearance is slower. Half-life is extended to 55 hours. Concentration in Kaposi’s sarcoma lesions is much higher than in normal skin (range is 3 to 53 times higher).
Adjuvant therapy in women with evidence of axillary lymph node involvement following resection of primary breast cancer. ■ Treatment of acute lymphoblastic leukemia, acute myeloblastic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, metastatic breast cancer, metastatic Wilms’ tumor, metastatic neuroblastoma, metastatic soft tissue sarcoma, metastatic bone sarcoma, metastatic ovarian carcinoma, metastatic transitional cell bladder carcinoma, metastatic thyroid carcinoma, metastatic gastric carcinoma, metastatic bronchogenic carcinoma.
Treatment of AIDS-related Kaposi’s sarcoma in patients after failure of prior systemic chemotherapy or in patients who are intolerant to such therapy. ■ Treatment of patients with ovarian cancer whose disease has progressed or recurred after platinum-based chemotherapy (e.g., cisplatin, carboplatin). ■ Treatment of multiple myeloma in combination with bortezomib (Velcade) in patients who have received one prior therapy but have not previously received bortezomib.
Treatment of refractory metastatic breast cancer.
Severe myocardial insufficiency, recent myocardial infarction (occurring within the last 4 to 6 weeks), severe persistent drug-induced myelosuppression, severe hepatic impairment (Child-Pugh Class C or serum bilirubin level greater than 5 mg/dL).
History of hypersensitivity to conventional or liposomal formulations of doxorubicin or to their components.
Follow guidelines for handling cytotoxic agents and patient excreta. Precautions recommended for up to 5 days after a dose. See Appendix A. ■ Usually administered by or under the direction of a physician specialist, with facilities for monitoring the patient and responding to any medical emergency. ■ For IV use only. Do not give IM or SC.■ Do Not Substitute Doxil for conventional doxorubicin. Severe side effects have resulted. Differences in liposomal products as well as conventional products can substantially affect the functional properties of these agents; do not substitute one agent for another.■ Use extreme caution in pre-existing drug-induced bone marrow suppression, existing heart disease, hepatic impairment, previous treatment with other anthracyclines (e.g., daunorubicin), anthracenediones (e.g., mitoxantrone), other cardiotoxic agents (e.g., bleomycin), concurrent cyclophosphamide therapy, or radiation therapy encompassing the heart; risk of cardiotoxicity increased and may occur at lower doses. ■ All forms of doxorubicin may cause cardiotoxicity. May be manifest by acute (e.g., arrhythmias, including life-threatening arrhythmias, ECG abnormalities) or delayed (e.g., reduction in LVEF, CHF) events. Life-threatening or fatal left ventricular failure may occur during therapy or months after therapy is completed. Cardiotoxicity occurs with increasing frequency as cumulative doses increase above 300 mg/M2. The risk of developing CHF increases rapidly with increasing total cumulative doses above 400 mg/M2; see Antidote. Prior use of other anthracyclines or anthracenediones should be included in calculations of total cumulative dose. Patients with active or dormant cardiovascular disease or patients who have received radiotherapy to the mediastinal area or concomitant therapy with other anthracyclines (e.g., daunorubicin, idarubicin), anthracenediones, or other cardiotoxic agents (e.g., bleomycin, cyclophosphamide, mitoxantrone, mitomycin C, trastuzumab) may be at greater risk. Patients receiving doxorubicin after stopping treatment with trastuzumab may also be at an increased risk of developing cardiotoxicity. Trastuzumab may persist in the circulation for up to 7 months. When possible, avoid anthracycline-based therapy for up to 7 months after stopping trastuzumab. If anthracyclines are used before this time, carefully monitor cardiac function. Consider the use of dexrazoxane to reduce the incidence and severity of cardiomyopathy due to doxorubicin in patients who have received a cumulative dose of 300 mg/M2 and who will continue to receive doxorubicin. ■ May cause severe myelosuppression resulting in serious infection, septic shock, required transfusions, hospitalization, hemorrhage, and death.■ See Maternal/Child and Side Effects.
In addition to cardiomyopathy, pericarditis and myocarditis have been reported during or after therapy with doxorubicin. ■ Secondary acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) have been reported and generally occur within 1 to 3 years of treatment. ■ Tumor lysis syndrome may occur; see Monitor.
Benefits must outweigh risks if Doxil is used in patients with a history of cardiovascular disease. ■ Serious, life-threatening and fatal infusion-related reactions and serious, sometimes life-threatening or fatal hypersensitivity/anaphylactoid-like reactions have been reported; see Monitor. ■ Has caused hand-foot syndrome (HFS). Incidence may be increased with higher doses or increased frequency. Generally seen after 2 or 3 cycles, but may occur earlier. May be severe and require a dose adjustment or discontinuation of Doxil. ■ Secondary oral cancers, primarily squamous cell carcinoma, have been reported in patients who have received Doxil for a year or longer. Malignancies have been diagnosed both during treatment and up to 6 years after completion of therapy. ■ Severe, additive myelosuppression may occur in Kaposi’s sarcoma patients and may be dose limiting.
Monitoring of CBC including differential and platelet count, uric acid levels, electrolytes, liver function (AST, ALT, alkaline phosphatase, and bilirubin), kidney function, ECG, chest x-ray, echocardiogram, and left ventricular ejection fraction (LVEF) is necessary before and during therapy. At a minimum, CBC with platelets should be monitored before each dose. Testing for renal and hepatic function may also be indicated; see Dose Adjustments. ■ Observe for S/S of cardiotoxicity (e.g., fast or irregular HR, shortness of breath, swelling of the feet or lower legs). Endomyocardial biopsy or gated radionuclide scans have been used to monitor potential cardiac toxicity. Increase frequency of assessment as cumulative dose exceeds 300 mg/M2. Use same method of assessment of LVEF at all time points. ■ Be alert for signs of bone marrow suppression, bleeding, or infection. ■ Monitor for thrombocytopenia (platelet count less than 50,000/mm3). Initiate precautions to prevent excessive bleeding (e.g., inspect IV sites, skin, and mucous membranes; use extreme care during invasive procedures; test urine, emesis, stool, and secretions for occult blood). ■ Use of prophylactic antibiotics may be indicated pending C/S in a febrile, neutropenic patient. Sepsis in a neutropenic patient has resulted in discontinuation of treatment and, in rare cases, death. ■ Prophylactic antiemetics are indicated. ■ See Drug/Lab Interactions.
Monitor for tumor lysis syndrome. S/S include hyperkalemia, hyperphosphatemia, hyperuricemia, hypocalcemia, metabolic acidosis, urate crystalluria, and renal failure. Prevent or alleviate tumor lysis syndrome with appropriate supportive and pharmacologic measures. ■ Maintain adequate hydration. ■ Uric acid–lowering drugs (e.g., allopurinol [Aloprim]) may prevent formation of uric acid crystals. ■ Use only large veins. Avoid veins over joints or in extremities with compromised venous or lymphatic drainage. Determine absolute patency of vein. A stinging or burning sensation indicates extravasation; severe cellulitis and tissue necrosis will result. Extravasation may occur with or without stinging or burning and even if blood returns well on aspiration of infusion needle. Observe and touch site frequently to feel air and/or liquid under the skin. If extravasation occurs, discontinue injection; use another vein; see Antidote.
Monitor for S/S of acute infusion reactions and/or hypersensitivity (e.g., apnea, asthma, back pain, bronchospasm, chills, cyanosis, facial swelling, fever, flushing, headache, hypotension, pruritus, rash, shortness of breath, syncope, tachycardia, tightness in the chest or throat). The majority of infusion-related reactions occur during the first infusion. ■ Monitor for HFS (skin eruptions characterized by swelling, pain, erythema, and possible desquamation of the skin on the hands and feet). ■ Monitor for the presence of oral ulceration or oral discomfort that may be indicative of secondary oral cancer. ■ Extravasation may cause irritation at infusion site. Discontinue and use another vein.
Urine and other body fluids will be reddish for several days (from dye, not hematuria). ■ Effective birth control required for females of reproductive potential during treatment and for 6 months after the last dose and for males with female partners of reproductive potential during treatment and for 3 months after the last dose. May cause infertility in both men and women. ■ Effects may be additive with current medications. Review all medications (prescription and nonprescription) with nurse and/or physician. ■ Promptly report cough, fast heartbeat, shortness of breath, and/or swelling of the feet or lower legs. ■ Report S/S of infection (e.g., chills, fever, painful urination), stomatitis, bothersome side effects, or any unusual bleeding (e.g., bruising, tarry stools). ■ Report IV site burning, stinging, puffiness, or the feeling of liquid under the skin and any other side effects promptly. ■ Report tingling, burning, redness, flaking, swelling, blisters or small sores on the palms of hands or soles of feet. ■ See Precautions. ■ See Appendix D.
Avoid pregnancy. Based on its mechanism of action, can cause fetal harm. ■ Has been used only when benefits outweigh risks (see Doxil). ■ Discontinue breast-feeding during treatment and for 10 days after the final dose.
Treatment during childhood may result in abnormal cardiac function. ■ Infants and children are at increased risk for developing delayed cardiotoxicity; follow-up cardiac evaluation is recommended; see Precautions. ■ In infants under 2 years of age, doxorubicin clearance is similar to adults, but clearance may be increased in pediatric patients over 2 years of age. ■ May contribute to prepubertal growth failure and/or gonadal impairment (which is usually temporary). ■ See Precautions, extended recommendations for handling patient excreta.
If use during pregnancy is considered, avoid use during the first trimester. ■ Safety for use in pediatric patients not established.
Response similar to that seen in younger adults, but greater sensitivity of some older individuals cannot be ruled out. ■ Cardiotoxicity and myelotoxicity may be more severe in patients over 70 years of age. ■ Consider age-related organ impairment and concomitant disease and/or drug therapy; see Dose Adjustments.
Studies not yet completed for Doxil; interactions may be similar to conventional doxorubicins. ■ Doxorubicin is a major substrate for cytochrome P450 CYP3A4 and CYP2D6 and P-glycoprotein. Clinically significant interactions have been reported with inhibitors of CYP3A4 and CYP2D6 and P-glycoprotein (e.g., verapamil), resulting in increased concentrations and clinical effects of doxorubicin. Inducers of CYP3A4 (e.g., phenobarbital, phenytoin, St. John’s wort) and P-glycoprotein may decrease the concentration of doxorubicin. Avoid concurrent use with inhibitors or inducers of CYP3A4 and CYP2D6 and P-glycoprotein.■ Avoid concurrent administration of doxorubicin and trastuzumab; results in an increased risk of cardiac dysfunction. Patients receiving doxorubicin after stopping treatment with trastuzumab may also be at an increased risk of developing cardiotoxicity. Trastuzumab may persist in the circulation for up to 7 months. When possible, avoid anthracycline-based therapy for up to 7 months after stopping trastuzumab. If anthracyclines are used before this time, carefully monitor cardiac function. ■ May exacerbate cyclophosphamide-induced hemorrhagic cystitis or increase hepatotoxicity of 6-mercaptopurine.■ May increase bone marrow toxicity of other chemotherapeutic agents and radiation.■ Barbiturates increase clearance and decrease effects. ■ May decrease serum levels of digoxin.■ May decrease serum levels of anticonvulsants (e.g., phenytoin, carbamazepine, valproate). ■ Risk of cardiotoxicity increased in patients previously treated with other anthracyclines (e.g., idarubicin) and/or radiation encompassing the heart.■ Cyclosporine and streptozocin may decrease clearance and increase toxicity of doxorubicin. ■ Paclitaxel appears to decrease the clearance of doxorubicin. Administration of doxorubicin before paclitaxel is recommended to prevent increased toxicity. ■ Coadministration with high-dose progesterone may increase doxorubicin toxicity. ■ Many drug interactions possible; observe patient closely. ■ Do not administer live virus vaccines to patients receiving antineoplastic drugs. ■ Increased toxicity to mucosa, myocardium, skin (including redness and exfoliative changes), and liver possible when given concurrently with or after radiation.■ Dexrazoxane is given with doxorubicin to reduce cardiotoxic effects. May also decrease antitumor effectiveness if given before a cumulative dose of doxorubicin 300 mg/M2 is reached or other chemotherapeutic agents are included in the protocol (e.g., fluorouracil). ■ See Precautions.
Abdominal pain; alopecia (complete); anorexia; asthenia; bone marrow suppression (e.g., anemia, hypochromic anemia, leukopenia, neutropenia [ANC less than 1,000/mm3], thrombocytopenia may be dose-limiting); cardiac toxicity (e.g., CHF); constipation; decreased serum calcium; depressed QRS voltage; diarrhea; dry skin; esophagitis; fatigue; fever; gonadal suppression; headache; hyperpigmentation of nail beds and dermal creases; hypersensitivity reactions (including life-threatening or fatal anaphylaxis); hyperuricemia; increase in alkaline phosphatase, ALT, AST, bilirubin, BUN, glucose, SCr; infection; mucositis; nausea; oral moniliasis; paresthesia; prolonged PT; rash; recall of skin reactions due to prior radiotherapy; stomatitis; weakness; vomiting.
In addition to all of the above, acute infusion reactions, hand-foot syndrome, secondary oral cancer. Kaposi’s sarcoma patients may be taking numerous other drugs that may confuse the overall side effect picture (e.g., didanosine [ddl], stavudine [D4T], sulfamethoxazole/trimethoprim, zalcitabine [ddC], zidovudine [AZT, Retrovir]).
Muscle spasms, myelogenous leukemia, pulmonary embolism, and skin and subcutaneous tissue disorders (e.g., erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis).
Increase in bone marrow suppression and mucositis.
Most side effects will either be tolerated or treated symptomatically. Keep the physician informed. Bone marrow toxicity may require cessation of therapy. Administration of whole blood products (e.g., packed RBCs, platelets, leukocytes) and/or blood modifiers (e.g., darbepoetin alfa, epoetin alfa, filgrastim, pegfilgrastim, sargramostim) may be indicated to treat bone marrow toxicity. Acute cardiac failure occurs suddenly (most common when total cumulative dosage approaches 550 mg/M2) and frequently does not respond to currently available treatment (digoxin, diuretics [e.g., furosemide], ACE inhibitors [e.g., enalapril]). Close monitoring of accumulated dosage, bone marrow, ECG, chest x-ray, echocardiography, and systolic ejection fraction may prevent most serious and potentially fatal cardiac side effects. There is no specific antidote. Supportive therapy as indicated will help sustain the patient in toxicity. Treat hypersensitivity reactions as required; discontinue therapy if severe.
Discontinue doxorubicin in patients who develop signs or symptoms of cardiomyopathy. For extravasation, attempt to aspirate extravasated fluid before removing needle. Do not flush line or apply pressure to site. Elevate the extremity and apply ice for 15 minutes four times a day for 3 days. If appropriate, administer dexrazoxane at the site of extravasation as soon as possible and within the first 6 hours after extravasation. Site should be observed promptly by a reconstructive surgeon.
In addition to all of the above, treatment may have to be interrupted or discontinued for severe hand-foot syndrome or acute infusion reactions. Infusion reactions may resolve with slowing of infusion rate. May be able to control hand-foot syndrome by allowing it to resolve and by increasing intervals between subsequent cycles. For extravasation, discontinue infusion and apply ice over site for 30 minutes to alleviate local reaction.