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Doxorubicin Hydrochloride

Pronunciation

Class: Antineoplastic Agents
VA Class: AN200
CAS Number: 25316-40-9
Brands: Adriamycin, Doxil, Rubex

Warning(s)

  • Extravasation
  • Severe local tissue necrosis if extravasation occurs.b Do not administer IM or sub-Q.b

  • Myocardial Toxicity
  • Possible cardiotoxicity and potentially fatal CHF during or months to years after therapy; risk of developing CHF increases rapidly with increasing total cumulative dosages >450 mg/m2.b Toxicity may occur at lower cumulative dosages whether or not risk factors are present.b (See Cardiotoxicity under Cautions.)

  • Probability of developing impaired myocardial function based on combined index of signs, symptoms, and decline in LVEF is estimated to be 1–2, 3–5, 5–8, or 6–20% at total cumulative dosage of 300, 400, 450, or 500 mg/m2, respectively.b

  • Risk factors (active or dormant cardiovascular disease, doxorubicin exposure at an early or advanced age, prior or concomitant mediastinal/pericardial irradiation, previous therapy with other anthracyclines or anthracenediones, concomitant use of other cardiotoxic agents) may increase risk of cardiotoxicity.b

  • Pediatric patients are at increased risk for developing delayed cardiotoxicity.b

  • Experience with liposomal doxorubicin at high cumulative dosages is too limited to have established effects on the myocardium; assume myocardial toxicity is similar to that of conventional doxorubicin formulations.c Administer to patients with history of cardiovascular disease only when benefits outweigh risk.c

  • Secondary Acute Myelogenous Leukemia (AML)
  • Possible secondary AML in patients treated with anthracyclines, including doxorubicin; occurrence of refractory secondary leukemia is more common when such drugs are given in combination with other DNA-damaging antineoplastics, after extensive exposure to cytotoxic agents, or when anthracyline dosages have been escalated. (See Mutagenicity and Carcinogenicity under Cautions.)b

  • Pediatric patients are at risk of developing secondary AML.b

  • Infusion-related Effects
  • Infusion-related reactions (e.g., flushing, shortness of breath, facial swelling, headache, chills, back pain, tightness of chest or throat, hypotension) reported in patients receiving liposomal doxorubicin.c Reactions generally resolve within several hours to a day once infusion terminated; may resolve in some patients with slowing of infusion rate.c

  • Serious and sometimes life-threatening or fatal allergic/anaphylactoid-like infusion reactions reported; appropriate therapy and emergency equipment should be available for immediate use.c

  • Administer liposomal doxorubicin at initial rate of 1 mg/minute to minimize risk of infusion reactions.c

  • Myelosuppression
  • Severe myelosuppression may occur.b c (See Hematologic Effects under Cautions.)

  • Hepatic Impairment
  • Reduce dosage in patients with hepatic impairment.b c (See Special Populations under Dosage and Administration and also see Hepatic Impairment under Cautions.)

  • Accidental Substitution
  • Accidental substitution of liposomal doxorubicin for conventional doxorubicin has resulted in severe adverse effects; do not substitute for conventional doxorubicin on a mg-per-mg basis.c

  • Experience of Supervising Clinician
  • Administer only under the supervision of qualified clinician experienced in the use of cancer chemotherapeutic agents.b c

Introduction

Antineoplastic agent; anthracycline glycoside antibiotic.a b c

Uses for Doxorubicin Hydrochloride

Breast Cancer

Conventional doxorubicin: Treatment (in combination with other antineoplastic agents) of breast cancer.a b

Combination chemotherapy, as adjunct to surgery, increases disease-free (i.e., decreased recurrence) and overall survival in premenopausal and postmenopausal women with node-negative or -positive early (TNM stage I or II) breast cancer.213 221 222 223 224 225 226 227 228 229 230 231 232

Adjuvant combination chemotherapy that includes cyclophosphamide, methotrexate, and fluorouracil has been used most extensively and is considered a regimen of choice for early breast cancer,213 221 222 223 225 227 228 230 231 232 but doxorubicin-containing regimens (e.g., combined cyclophosphamide and doxorubicin with or without fluorouracil; combined cyclophosphamide and doxorubicin with or without tamoxifen) appear to be comparably effective and also are considered regimens of choice; differences in toxicity profiles may influence choice of regimen.221 222 224 225 227 228 229 230

In stage III (locally advanced) breast cancer, commonly employed effective regimens (with or without hormonal therapy) used sequentially after surgery and radiation therapy for operable disease and after biopsy and radiation therapy for inoperable disease include cyclophosphamide, methotrexate, and fluorouracil; cyclophosphamide, doxorubicin, and fluorouracil; and cyclophosphamide, methotrexate, fluorouracil, and prednisone; combined cyclophosphamide and doxorubicin therapy also has been used.213 215 216 217 221 These and other regimens have been used in treatment of more advanced (stage IV) and recurrent disease.213 218 219 220 221

Slideshow: Flashback: FDA Drug Approvals 2013

AIDS-related Kaposi’s Sarcoma

Conventional doxorubicin: Has been used alone or in combination chemotherapy for the palliative treatment of AIDS-related Kaposi’s sarcoma.213 276 277 278

Liposomal doxorubicin: Palliative treatment of AIDS-related Kaposi’s sarcoma in adults intolerant to combination chemotherapy or whose disease has progressed while receiving such therapy.273 275 279 280 281 282 283 284 285 286 287 288 289 328

Combination chemotherapy that includes conventional doxorubicin (with bleomycin and vincristine) has been a preferred regimen, 213 276 277 278 327 328 but many clinicians currently consider a liposomal anthracycline (doxorubicin or daunorubicin) the first-line therapy of choice for advanced AIDS-related Kaposi’s sarcoma.213 276 279 280 296

Ovarian Cancer

Conventional doxorubicin: Has been used in treatment (in combination chemotherapy regimens) of ovarian carcinoma, but other agents currently are preferred.200 206 208 213

Liposomal doxorubicin: Palliative treatment of metastatic ovarian carcinoma that is refractory to both paclitaxel- and platinum-based chemotherapy regimens (designated an orphan drug by FDA for this use).206 213 273 354 353

Further study is needed to establish role of liposomal doxorubicin in the treatment of advanced epithelial ovarian cancer.354

Bladder Cancer

Conventional doxorubicin: Treatment (in combination regimens with cisplatin, methotrexate, and vinblastine) of invasive and advanced bladder carcinoma.213 332 336 347 348

Has been used intravesically for treatment of residual tumor and/or as adjuvant therapy for prophylaxis of superficial bladder carcinoma.213 320 332 333 334 335

Evidence is limited, but other agents (e.g. mitomycin, epirubicin) appear to be similar in efficacy but less toxic than doxorubicin and generally are preferred for prophylaxis or treatment of superficial bladder cancer.341 342 343

Small Cell Lung Cancer

Conventional doxorubicin: Treatment (in combination chemotherapy regimens) of extensive-stage small cell lung cancer.213 349

Other Uses

Conventional doxorubicin hydrochloride: Treatment of solid tumors including thyroid carcinoma, gastric carcinoma, soft-tissue and osteogenic sarcomas, neuroblastoma, and Wilms' tumor; malignant lymphomas of both Hodgkin and non-Hodgkin type; and acute lymphocytic (lymphoblastic) leukemia.200 208

Conventional doxorubicin hydrochloride: Treatment of carcinoid tumors, hepatoblastoma, and retinoblastoma.d

Conventional doxorubicin hydrochloride: Treatment of Ewing’s sarcoma,213 squamous cell carcinoma of the cervix213 and prostate,213 and uterine cancer.a

Conventional doxorubicin hydrochloride: Used in combination therapy (with vincristine and high-dose dexamethasone) for refractory multiple myeloma.202 203 213 214

Although conventional doxorubicin is labeled for use in the treatment of AML,200 208 other agents are preferred.213

Doxorubicin Hydrochloride Dosage and Administration

General

Consult specialized references for procedures for proper handling and disposal of antineoplastics.b

Optimize results and minimize adverse effects by basing dose on clinical, cardiac, hepatic, renal, and hematologic response, patient tolerance, and other chemotherapy or irradiation being used.a

Consider pretreatment with or concomitant use of antiemetic therapy for management of nausea and vomiting.273 a b

Administration

IV Administration

Administer IV.b c Must not administer IM or sub-Q.b c

Avoid extravasation; extremely irritating to tissues.a b c Stinging or burning during IV administration may be a symptom, but extravasation may occur without these symptoms and even when blood returns well during initial aspiration of infusion needle.a b c If manifestations of extravasation occur, immediately stop infusion and restart at another site.a b c Because of progressive nature of extravasation reactions, frequently examine affected area and consult specialist in plastic surgery.a b c Blistering, ulceration, and/or persistent pain are indications for wide excision surgery, followed by split-thickness skin grafting.b (See Local Effects under Cautions.)

Prepare and handle cautiously to avoid adverse local dermatologic reactions.a Use of goggles, latex gloves, and protective gowns is recommended during preparation and administration.a b If skin or mucosal contact occurs, immediately wash affected area(s) thoroughly.a

Conventional Doxorubicin Hydrochloride

Administer commercially available or reconstituted solution slowly into tubing of a freely running IV infusion of 0.9% sodium chloride or 5% dextrose injection, preferably via a Butterfly needle inserted into a large vein.b

When possible, do not use veins over joints or in extremities with compromised venous or lymphatic drainage.b

If sub-Q extravasation occurs or is suspected, application of ice to site for 15 minutes 4 times daily for 3 days may be useful.b Local infiltration with parenteral corticosteroid and irrigation of site with copious amounts of sterile 0.9% sodium chloride solution reported to decrease local reaction;a benefit of local administration of drugs not clearly established.b

Liposomal Doxorubicin Hydrochloride

Administer by IV infusion; do not administer by rapid IV injection or as an undiluted solution.273 Do not use inline filters.273

If extravasation occurs, application of ice packs over site for about 30 minutes may help alleviate local reaction.273

Reconstitution of Conventional Doxorubicin Hydrochloride

Withdraw an appropriate volume of air from vial during reconstitution to avoid excessive pressure build-up.b

Add 5, 10, 25, 50, or 75 mL of 0.9% sodium chloride injection to vial containing 10, 20, 50, 100, or 150 mg of doxorubicin hydrochloride as lyophilized powder, respectively.200 208 Shake vial and allow contents to dissolve; resultant solution contains 2 mg/mL.b

Do not use diluents containing preservatives.b

To avoid potential risks associated with reconstitution of the powder, commercially available injection can be used; however, handling of solution is not without risk.a

Dilution of Liposomal Doxorubicin Hydrochloride

Dilute appropriate dose (maximum 90 mg) in 250 mL of 5% dextrose injection; observe strict aseptic technique since formulation does not contain any preservative or bacteriostatic agent.273

Do not use diluents containing preservatives.273

Rate of Administration of Conventional Doxorubicin Hydrochloride

Rate of injection depends on size of vein and dose, but do not administer faster than over 3–5 minutes; local erythematous streaking along vein and/or facial flushing may indicate that administration rate is too rapid.a b

Rate of Administration of Liposomal Doxorubicin Hydrochloride

In patients receiving the drug for AIDS-related Kaposi's sarcoma, administer diluted solution by IV infusion over 30 minutes.273

In patients receiving the drug for ovarian cancer, administer diluted solution by IV infusion at initial rate of 1 mg/minute; if no infusion-related reactions occur, may increase rate to complete administration of infusion over 1 hour.273

If infusion reactions (flushing, shortness of breath, facial edema, headache, chills, back pain, tightness of chest or throat, and/or hypotension) occur, slow rate or stop infusion.273

Dosage

Available as conventional (nonencapsulated) doxorubicin hydrochloride and PEG-stabilized liposomal doxorubicin hydrochloride; dosage expressed in terms of the salt.b c

Do not substitute liposomal doxorubicin hydrochloride for conventional doxorubicin hydrochloride; the drugs are not equivalent on a mg-per-mg basis.273 Accidental substitution may result in severe adverse effects.273

Dosage reduction may be necessary in patients who have received extensive prior radiation therapy or in those whose bone marrow has been infiltrated with malignant cells, since severe myelosuppression is likely to occur.a b

Dosage is based indirectly on body weight; if patient has abnormal fluid retention, use ideal body weight to calculate body surface area.a

Pediatric Patients

Conventional Doxorubicin Hydrochloride
IV

Consult published protocols for dosages in combination regimens and methods and sequence of administration.a

Adults

Conventional Doxorubicin Hydrochloride
IV

Usual dosage when used as a single agent is 60–75 mg/m2, given as a single dose at 21-day intervals; consider the lower dose for patients with poor performance status, inadequate bone marrow reserves secondary to old age, prior therapy, or marrow infiltration with malignant cells.a b

Alternatively, may use 20 mg/m2 once weekly (this dosage schedule reported to produce a lower incidence of CHF).a

30 mg/m2 daily on 3 successive days every 4 weeks also has been used (this dosage schedule usually associated with higher incidence of stomatitis).a

In combination with other chemotherapy, dosage of 40–60 mg/m2, given as a single dose and repeated at 21- to 28-day intervals, is commonly used.200 b

Consult published protocols for dosages in combination regimens and methods and sequence of administration.a

Liposomal Doxorubicin Hydrochloride
AIDS-related Kaposi's Sarcoma
IV

20 mg/m2 by IV infusion once every 3 weeks.273 279

Duration of therapy depends on patient response and tolerance.273 279

Ovarian Cancer
IV

50 mg/m2 by IV infusion every 4 weeks.273

In patients without disease progression or intolerable toxicity, minimum of 4 courses is recommended (since median time to response in clinical trials for metastatic ovarian cancer was approximately 4 months).273

Dosage Modification for Toxicity

Management of certain adverse effects may require dosage reduction and/or delay of doses.273 Manufacturer recommends the following dosage modifications based on drug-induced adverse effects.273 For further information on reduced dosage of Doxil (liposomal doxorubicin hydrochloride) based on drug-induced adverse effects, consult the manufacturer at (415) 617-3078.

Table 1. Dosage Modification of Liposomal Doxorubicin Hydrochloride for Palmar-Plantar Erythrodysesthesia

Toxicity Grade

Symptoms

Dose Modification

0

No symptoms

None

1

Mild erythema, swelling, or desquamation not interfering with daily activities

Redose unless patient has experienced previous grade 3 or 4 skin toxicity, in which case delay dose up to 2 weeks and decrease dose by 25%; then return to original dose interval

2

Erythema, desquamation, or swelling interfering with, but not precluding, normal physical activities; small blisters or ulcerations <2 cm in diameter

Delay dosing up to 2 weeks or until toxicity has resolved to grade 0–1; if no resolution after 2 weeks, discontinue liposomal doxorubicin

3

Blistering, ulceration, or swelling interfering with walking or normal daily activities; cannot wear regular clothing

Delay dosing up to 2 weeks or until toxicity resolved to grade 0–1, then decrease dose by 25% and return to original dose interval; if no resolution after 2 weeks, discontinue liposomal doxorubicin

4

Diffuse or local process causing infectious complications, or a bedridden state or hospitalization

Delay dosing up to 2 weeks or until toxicity resolved to grade 0–1, then decrease dose by 25% and return to original dose interval; if no resolution after 2 weeks, discontinue liposomal doxorubicin

Table 2. Dosage Modification of Liposomal Doxorubicin Hydrochloride for Hematologic Toxicity

Toxicity Grade

ANC (per mm3)

Platelets (per mm3)

Dose Modification

1

1500–1900

75,000–150,000

None

2

1000–1499

50,000–74,999

Wait until ANC ≥1500 and platelets ≥75,000, then redose with no dose reduction

3

500–999

25,000–49,999

Wait until ANC ≥1500 and platelets ≥75,000, then redose with no dose reduction

4

<500

<25,000

Wait until ANC ≥1500 and platelets ≥75,000, then decrease dose by 25% or continue full dose with cytokine support

Table 3. Dosage Modification of Liposomal Doxorubicin Hydrochloride for Stomatitis

Toxicity Grade

Symptoms

Dose Modification

1

Painless ulcers, erythema, or mild soreness

Redose unless patient has experienced previous grade 3 or 4 toxicity, in which case delay up to 2 weeks and decrease dose by 25%, returning to original dose interval

2

Painful erythema, edema, or ulcers, but can eat

Delay dosing up to 2 weeks or until resolved to grade 0–1; if no improvement after 2 weeks, discontinue liposomal doxorubicin

3

Painful erythema, edema, or ulcers, and cannot eat

Delay dosing up to 2 weeks or until resolved to grade 0–1, then decrease dose by 25% and return to original dose interval; if no improvement after 2 weeks, discontinue liposomal doxorubicin

4

Requires parenteral or enteral support

Delay dosing up to 2 weeks or until resolved to grade 0–1, then decrease dose by 25% and return to original dose interval; if no improvement after 2 weeks, discontinue liposomal doxorubicin

Prescribing Limits

Adults

IV

Risk of developing CHF increases rapidly with increasing total cumulative dosages >450 mg/m2.b

Previously recommended that total cumulative dose of doxorubicin hydrochloride not exceed 550 mg/m2 because of risk of potentially irreversible cardiotoxicity, but higher cumulative doses may be tolerated, particularly when dexrazoxane (Zinecard) is used concomitantly as a cardioprotectant.221 233 234 235 236 241 242

It has been suggested that total cumulative dose not exceed 400 mg/m2 if previous or concomitant therapy includes use of related tetracyclic compounds (e.g., daunorubicin), cyclophosphamide, or irradiation of cardiac region; some evidence suggests that higher cumulative doses may be tolerated if cardioprotection with dexrazoxane is employed.a

Special Populations

Hepatic Impairment

Conventional or Liposomal Doxorubicin Hydrochloride

In patients with serum bilirubin concentrations of 1.2–3 mg/dL, administer 50% of usual dose; in those with serum bilirubin concentrations ≥3 mg/dL, administer 25% of usual dose.273 b c

Cautions for Doxorubicin Hydrochloride

Contraindications

  • Usual precautions and contraindications of doxorubicin apply to both conventional and PEG-stabilized liposomal formulations.a

  • Conventional Doxorubicin
  • Marked myelosuppression induced by previous treatment with other antineoplastic agents or radiation therapy.b

  • Previous treatment with complete cumulative dosages of doxorubicin, daunorubicin, idarubicin, and/or other anthracyclines and anthracenes.b

  • Liposomal Doxorubicin
  • Known hypersensitivity to conventional doxorubicin preparations or any ingredient in the liposomal formulation.273

  • Nursing women.273

Warnings/Precautions

Warnings

Cardiotoxicity

Irreversible myocardial toxicity, including life-threatening or fatal CHF, may occur during therapy or months to years after termination of therapy.b Risk of developing CHF increases rapidly with increasing total cumulative dosages ≥450 mg/m2.b

Probability of developing impaired myocardial function based on combined index of signs, symptoms, and decline in LVEF is estimated to be 1–2, 3–5, 5–8, or 6–20% at a total cumulative dosage of 300, 400, 450, or 500 mg/m2, respectively, in schedules of rapid IV doses given once every 3 weeks.200 b

Active or dormant cardiovascular disease, doxorubicin exposure at an early or advanced age, prior or concomitant mediastinal/pericardial irradiation, previous therapy with other anthracyclines or anthracenediones, or concomitant use of other cardiotoxic agents may increase risk of cardiotoxicity; toxicity may occur at lower cumulative dosages whether or not these risk factors are present.b

Total dosage administered to patient should take into account previous or concomitant therapy with related agents (e.g., daunorubicin, idarubicin, mitoxantrone).b

Pediatric patients are at increased risk for developing delayed cardiotoxicity; doxorubicin-induced cardiomyopathy impairs myocardial growth as pediatric patients mature, leading to possible development of CHF during early adulthood.b

Early recognition of drug-induced cardiac failure appears essential for successful treatment with digoxin, diuretics, afterload reducers (e.g., ACE inhibitors), sodium restriction, and rest.a b Such interventions may relieve symptoms and improve functional status.b

Peform cardiac evaluation (with ECG, LVEF, and/or echocardiogram [ECHO]) prior to initiation and subsequently prior to each dose or course of therapy after a total cumulative dosage of 400 mg/m2; 200 such evaluation is particularly important in patients with preexisting risk factors for cardiotoxicity.200

Continue periodic monitoring of cardiac function with evaluation of ejection fraction throughout the patient’s lifetime, since cardiotoxicity may develop long after discontinuance of therapy.350

Doxorubicin-induced cardiomyopathy has been reported to be associated with persistent reduction in QRS voltage, prolongation of systolic time interval, and reduction of ejection fraction (as determined by echocardiography or radionuclide angiography), but none of these tests consistently identify those patients who are approaching their maximally tolerated cumulative dose.a b If these or other test results indicate changes in cardiac function associated with doxorubicin, carefully weigh benefit of continued therapy against risk of irreversible cardiac damage.a b Fatal cardiotoxicity can occur without antecedent ECG alterations.244 327

Acute life-threatening arrhythmias reported during or within a few hours after administration.b

Hematologic Effects

High incidence of bone marrow suppression, manifested predominantly as leukopenia (principally granulocytopenia); severity depends on dose of drug and on regenerative capacity of bone marrow.a b Anticipate leukocyte counts as low as 1000/mm3, although severe myelosuppression can occur.200 Thrombocytopenia and anemia may also occur.a Maximum leukopenia, thrombocytopenia, and anemia generally occur during second week (nadir at 10–14 days) after administration and generally return to normal by third week.a b

Dosage reduction or temporary suspension or discontinuance of therapy may be required.a Persistent, severe myelosuppression may result in superinfection or hemorrhage.273 Deaths from septicemia have been associated with severe leukopenia.a

Contraindicated in patients with marked preexisting myelosuppression.a b

Careful hematologic monitoring required; perform leukocyte, erythrocyte, and platelet counts prior to and at frequent intervals during therapy.a b If profound drop in blood cell count occurs, closely observe patient and initiate anti-infective therapy if signs of infection appear; suspension of therapy may be necessary.a

Platelet and leukocyte transfusions have proved beneficial in patients with severe bone marrow depression; may also consider use of hematopoietic agents (colony-stimulating factors).a

Principal dose-limiting toxicity in patients with AIDS-related Kaposi’s sarcoma receiving liposomal doxorubicin is myelosuppression, commonly manifested as leukopenia and neutropenia; anemia and thrombocytopenia also occur frequently.273 Occasionally may require dose reduction or delay or suspension of therapy.273 Neutropenic sepsis rarely has resulted in death.273

In patients with ovarian cancer, myelosuppression associated with liposomal doxorubicin generally is moderate and reversible.273 Anemia273 occurred most commonly;273 neutropenia,273 leukopenia,273 and thrombocytopenia273 also occurred.273

Toxicity Potentiation with Concomitant Therapy

May potentiate toxicity of other antineoplastic agents.b

Concomitant or previous administration with cyclophosphamide, irradiation of the cardiac region, daunorubicin, idarubicin, or mitoxantrone may potentiate cardiotoxic effects of doxorubicin; reduce maximum cumulative doxorubicin dosage.a

Combined therapy with other myelosuppressive agents may increase severity of hematologic toxicity.a

Exacerbation of cyclophosphamide-induced hemorrhagic cystitis and enhancement of hepatoxicity of mercaptopurine reported.b c

Doxorubicin reportedly increases radiation-induced toxicity to myocardium, mucosae, skin, and liver.b c Pediatric patients receiving concomitant doxorubicin and dactinomycin have manifested acute “recall” pneumonitis at variable times after local radiation therapy.b

Latent effects of previous irradiation reactivated in some patients, producing erythema with vesiculation, nonpitting edema, severe pain, and moist desquamation in sites previously subjected to radiation therapy which had subsequently returned to normal appearance; occurs from 4–7 days after each doxorubicin dose is administered and lasts an average of 7 days thereafter.a

Necrotizing colitis manifested by typhilitis (cecal inflammation), bloody stools, and severe and sometimes fatal infections, have been associated with combination of doxorubicin (given IV push daily for 3 days) and cytarabine (given by continuous IV infusion daily for ≥7 days).b

Seizures and/or coma have occurred in patients receiving doxorubicin and vincristine concomitantly.200 Seizures also reported in a patient receiving doxorubicin at 2–3 times the approved dosage in combination with high-dose cyclophosphamide.208

Palmar-Plantar Erythrodysesthesia (PPE)

PPE, characterized by swelling, pain, erythema, and occasionally desquamation of hands and feet, reported in patients receiving liposomal doxorubicin; generally developed after 2 or 3 cycles (i.e., ≥6 weeks) of therapy, but occasionally occurred sooner.273

PPE generally is mild and resolves within 1–2 weeks; prolonged delay of therapy usually is not needed, but dose modification may be necessary (see Table 1: Dosage Modification for Palmar-Plantar Erythrodysesthesia under Dosage and Administration); discontinuance may be required in some patients because of severe and debilitating effects.273

Local Effects

Extravasation produces severe local tissue necrosis; cellulitis, vesication, thrombophlebitis, lymphangitis, or painful induration possible.a b May result in limitation of mobility of adjacent joints.a

Erythematous streaking along vein proximal to injection site reported.a Phlebosclerosis may occur, especially when drug is administered into small vein or repeatedly into a single vein.a

Animal evidence suggests that lesions associated with extravasation of liposomal doxorubicin may be minor and reversible compared with the more severe and irreversible lesions associated with conventional doxorubicin; however, consider liposomal doxorubicin an irritant and follow usual precautions to avoid extravasation.273 (See IV Administration under Dosage and Administration.)

Infusion-related Effects

Acute infusion-related reactions (flushing, shortness of breath, facial edema, headache, chills, back pain, tightness of the chest and throat, and/or hypotension) reported in patients receiving liposomal doxorubicin; attributed to liposomes or one of their surface components.273 330 Similar reactions not reported with conventional doxorubicin.273

Reactions typically occur during first infusion and usually resolve over several hours to a day once infusion is stopped; occasionally may resolve simply by slowing infusion rate.273 Minimize risk by infusing at initial rate of 1 mg/minute.273

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm;273 embryotoxic, teratogenic, and abortifacient in animals.b Avoid pregnancy during therapy.b If used during pregnancy or patient becomes pregnant, apprise of potential fetal hazard.b

Sensitivity Reactions

Hypersensitivity Reactions

Fever,200 chills,200 and urticaria200 reported occasionally; anaphylaxis200 may occur. Serious and sometimes life-threatening or fatal allergic/anaphylactoid-like infusion reactions reported with liposomal doxorubicin; appropriate therapy and emergency equipment should be available for immediate use.c

General Precautions

Usual precautions of doxorubicin apply to conventional and PEG-stabilized liposomal formulations.a

Adequate Patient Evaluation and Monitoring

Therapeutic response is not likely to occur without some evidence of toxicity (e.g., effects on bone marrow, GI and oral mucosa, hair follicles).a Consider possible synergism of therapeutic response and toxicity with other antineoplastic agents used in concomitant chemotherapy.a (See Toxicity Potentiation with Concomitant Therapy under Cautions.)

Administer only under constant supervision of qualified clinician experienced in cancer chemotherapy.a b Hospitalize patient during initial phase of treatment; if feasible, perform subsequent therapy and patient evaluation on outpatient basis.a b

Evaluate hepatic, hematopoietic, and cardiac function prior to and at regular intervals during therapy.b

Tumor Lysis Syndrome

Tumor lysis syndrome and hyperuricemia may result from extensive purine catabolism accompanying rapid cellular destruction; monitor serum uric acid concentration.a b Minimize or prevent by adequate hydration, alkalinization of the urine, and/or administration of allopurinol.b

Mutagenicity and Carcinogenicity

Mutagenic and carcinogenic in experimental models.b

Treatment-related AML reported in patients receiving doxorubicin-containing adjuvant chemotherapy regimens.b Risk of developing secondary AML and other neoplasms is increased in pediatric patients receiving doxorubicin or other topoisomerase II inhibitors; extent of increased risk with doxorubicin not fully established.b

In clinical trials of breast cancer patients receiving doxorubicin-containing regimens, estimated risk of developing treatment-related leukemia at 10 years was 2.5 or 0.5% in patients receiving radiation therapy plus chemotherapy or chemotherapy alone, respectively.b

No evidence of mutagenic potential observed in tests with Stealth liposomes devoid of doxorubicin hydrochloride.273

Specific Populations

Pregnancy

Category D.b c (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Conventional doxorubicin and its major metabolite (doxorubicinol) are distributed into milk;200 201 not known whether liposomal doxorubicin is distributed into milk.b 273 Discontinue nursing because of potential risk to nursing infants.b 273

Pediatric Use

Increased risk of developing delayed cardiotoxicity;200 periodic long-term follow-up cardiac evaluations recommended.200 (See Cardiotoxicity under Cautions.)

May contribute to prepubertal growth failure when administered as a component of intensive chemotherapy regimens;200 gonadal impairment (usually reversible) may occur.200

Safety and efficacy of liposomal doxorubicin not established in children.273

Geriatric Use

No substantial differences relative to younger adults observed during clinical trials with liposomal doxorubicin, but increased sensitivity cannot be ruled out; insufficient data for a comparative evaluation of efficacy according to age.273

Hepatic Impairment

Possible increased toxicity if given at usual recommended dosages; reduction of conventional doxorubicin dosage is recommended.b 273 (See Hepatic Impairment under Dosage and Administration.) Perform liver function tests (e.g., AST, ALT, alkaline phosphatase, bilirubin) prior to individual dosing.b 273

Limited experience with liposomal doxorubicin in patients with hepatic impairment; reduce dosage based on experience with coventional doxorubicin.273

Common Adverse Effects

Conventional doxorubicin: Alopecia, nausea, vomiting, mucositis, myelosuppression.b

Liposomal doxorubicin: Myelosuppression (neutropenia, anemia, thrombocytopenia), palmer-plantar erythrodysesthesia, stomatitis, nausea, asthenia, vomiting, rash, alopecia, constipation, anorexia, mucous membrane disorder, diarrhea, abdominal pain, paresthesia, pain, fever, pharyngitis, dry skin, headache.c

Interactions for Doxorubicin Hydrochloride

No formal drug interaction studies conducted with liposomal doxorubicin to date; pending further accumulation of data, consider drugs known to interact with conventional doxorubicin to also interact with the liposomal formulation.273 c

Specific Drugs

Drug

Interaction

Antineoplastic agents

Possible potentiation of toxicities associated with doxorubicin and/or other antineoplastic agentsb (see Toxicity Potentiation with Concomitant Therapy under Cautions)

Antiviral agents

Most patients receiving liposomal doxorubicin to date received antiviral therapy concomitantly, but potential for interaction not evaluated273 c

Calcium-channel blocking agents (e.g., verapamil)

Possible increased risk of doxorubicin-induced cardiotoxicity200 b

Cyclosporine

Possible increased AUCs of doxorubicin and doxorubicinol, possibly due to decreased doxorubicin clearance and decreased metabolism of doxorubicinol200

Potential for more severe and prolonged hematologic toxicity200

Seizures and/or coma reported200

Paclitaxel

Administration sequence of paclitaxel followed by doxorubicin resulted in substantially decreased doxorubicin clearance, with more profound neutropenia and stomatitis, than did the reverse sequence of administrationb

Phenobarbital

Increased elimination of doxorubicin200

Phenytoin

Decreased serum phenytoin concentrations200

Progesterone

Enhanced doxorubicin-induced neutropenia and thrombocytopenia reported200

Streptozocin

Possible inhibition of doxorubicin metabolism200

Vaccines, live

Potentially hazardous in immunosuppressed patients, including those undergoing cytotoxic chemotherapyb

Doxorubicin Hydrochloride Pharmacokinetics

Encapsulation in PEG-stabilized (Stealth) liposomes substantially alters pharmacokinetics relative to conventional IV formulations, with resultant decreased distribution into peripheral compartment, increased distribution into Kaposi's lesions, and decreased plasma clearance.273 283 285

Absorption

Bioavailability

Nonencapsulated doxorubicin hydrochloride is not stable in gastric acid; appears to undergo little, if any, absorption from GI tract.a Must administer IV.a

Distribution

Extent

Conventional doxorubicin: Widely distributed into plasma and tissues; absorbed by cells and binds to cellular components, particularly to nucleic acids.a Does not cross blood-brain barrier or achieve measurable concentration in CSF.a Nonencapsulated drug and its major metabolite (doxorubicinol) distribute into milk.200 201

Liposomal doxorubicin: Encapsulation in PEG-stabilized liposomes slows rate of distribution into extravascular space;273 283 285 distributes mainly into intravascular fluid.273 283 285 Exact mechanism of drug release from liposomal encapsulation is not known.273

Distribution into Kaposi's sarcoma lesions after IV administration as liposomal doxorubicin was 5.2–11.4 times greater than that after comparable IV doses of conventional doxorubicin.285 Liposomal doxorubicin distributes into Kaposi's sarcoma lesions to greater extent than into healthy skin.273 283

Plasma Protein Binding

Conventional doxorubicin: Approximately 50–85%.273 283 299

Liposomal doxorubicin: Not determined.273 283 c

Elimination

Metabolism

Conventional doxorubicin: Metabolized by NADPH-dependent aldoketoreductases to doxorubicinol, which exhibits antineoplastic activity and is the major metabolite; these reductases are present in most if not all cells, but particularly in erythrocytes, liver, and kidney.299 With conventional doxorubicin, >20% of total drug in plasma is present as metabolites as soon as 5 minutes after dose, 70% in 30 minutes, 75% in 4 hours, and 90% in 24 hours.a

Liposomal doxorubicin: Undetectable or low plasma concentrations of doxorubicinol reported after single-dose IV administration;273 285 suggests that drug is not released appreciably from circulating liposomes or that some doxorubicin may be released but the rate of doxorubicinol elimination greatly exceeds the release rate; doxorubicin hydrochloride encapsulated in liposomes that have not been PEG-stabilized is metabolized to doxorubicinol.285

Elimination Route

Conventional doxorubicin: Excreted predominantly in bile as unchanged drug and metabolites; about 4–5% (range: 0.7–23%) of administered dose excreted in urine after 5 days, principally as unchanged drug.a

Half-life

Conventional doxorubicin: Nonencapsulated drug and metabolites decline in a biphasic or triphasic manner.a In triphasic model, half-life during second phase is 16.7 hours; 31.7 hours for metabolites.a In biphasic model, terminal half-life averages about 30 hours.285 299

Liposomal doxorubicin: Biphasic; 273 285 331 terminal half-life averages 39–55 hours.273 283 285

Special Populations

In patients with hepatic impairment, clearance is reduced and plasma concentrations of doxorubicin and its metabolites are elevated.200

In obese women (actual body weight >130% of ideal body weight), systemic clearance of nonencapsulated doxorubicin is reduced.200 Clearance is reduced without any changes in volume of distribution in obese patients compared with patients with an actual body weight <115% of ideal body weight.200

Limited evidence suggests that clearance of nonencapsulated doxorubicin is higher in men than in women; however, terminal elimination half-life was longer in men than women.200

In children >2 years of age, clearance of nonencapsulated doxorubicin was increased compared with that in adults; clearance in children <2 years of age was decreased compared with that in older children and approached range reported for adults.200

Stability

Storage

Parenteral

Injection (Conventional Doxorubicin Hydrochloride)

2–8°C; protect from light.200 b

Powder for Injection (Conventional Doxorubicin Hydrochloride)

15–30°C; protect from light.b

Protect reconstituted solution from exposure to sunlight; use within 7 days (if stored at 15–30°C under normal room light) or 15 days (if stored at 2–8°C).200 208 b

Injection Concentrate (Liposomal Doxorubicin Hydrochloride)

2–8°C; avoid freezing (prolonged freezing may adversely affect stability of liposomal drugs; however, freezing for <1 month does not appear to affect stability of liposomal doxorubicin hydrochloride).273 283

Following dilution as directed, store at 2–8°C and use within 24 hours.273 283

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Conventional Doxorubicin Hydrochloride

Manufacturers state that doxorubicin hydrochloride should not be mixed with heparin or fluorouracil (precipitation reported) and do not recommend mixing with other drugs until specific compatibility data are available.b

Solution Compatibility (for Conventional Doxorubicin Hydrochloride)HID

Compatible

Dextrose 3.3% in sodium chloride 0.3%

Dextrose 5% in water

Normosol R, pH 7.4

Ringer’s injection, lactated

Sodium chloride 0.9%

Drug Compatibility
Admixture Compatibility (for Conventional Doxorubicin Hydrochloride)HID

Compatible

Etoposide phosphate with vincristine sulfate

Ondansetron HCl

Ondansetron HCl with vincristine sulfate

Paclitaxel

Vincristine sulfate

Incompatible

Aminophylline

Diazepam

Fluorouracil

Variable

Dacarbazine with ondansetron HCl

Etoposide with vincristine sulfate

Vinblastine sulfate

Y-site Compatibility (for Conventional Doxorubicin Hydrochloride)HID

Compatible

Amifostine

Aztreonam

Bleomycin sulfate

Chlorpromazine HCl

Cimetidine HCl

Cisplatin

Cladribine

Cyclophosphamide

Dexamethasone sodium phosphate

Diphenhydramine HCl

Droperidol

Etoposide phosphate

Famotidine

Filgrastim

Fludarabine phosphate

Fluorouracil

Gemcitabine HCl

Granisetron HCl

Hydromorphone HCl

Leucovorin calcium

Linezolid

Lorazepam

Melphalan HCl

Methotrexate sodium

Methylprednisolone sodium succinate

Metoclopramide HCl

Mitomycin

Morphine sulfate

Ondansetron HCl

Oxaliplatin

Paclitaxel

Prochlorperazine edisylate

Promethazine HCl

Ranitidine HCl

Sargramostim

Sodium bicarbonate

Teniposide

Thiotepa

Topotecan HCl

Vinblastine sulfate

Vincristine sulfate

Vinorelbine tartrate

Incompatible

Allopurinol sodium

Amphotericin B cholesteryl sulfate complex

Cefepime HCl

Ganciclovir sodium

Gallium nitrate

Lansoprazole

Pemetrexed disodium

Piperacillin sodium–tazobactam sodium

Propofol

Variable

Furosemide

Heparin sodium

Liposomal Doxorubicin Hydrochloride

Manufacturer recommends that liposomal doxorubicin not be mixed with other drugs, diluents other than 5% dextrose injection, or used with any bacteriostatic agent (e.g., benzyl alcohol).c

Drug Compatibility
Y-site Compatibility (for Liposomal Doxorubicin Hydrochloride)HID

Compatible

Acyclovir sodium

Allopurinol sodium

Aminophylline

Ampicillin sodium

Aztreonam

Bleomycin sulfate

Butorphanol tartrate

Calcium gluconate

Carboplatin

Cefazolin sodium

Cefepime HCl

Cefoxitin sodium

Ceftizoxime sodium

Ceftriaxone sodium

Chlorpromazine HCl

Cimetidine HCl

Ciprofloxacin

Cisplatin

Clindamycin phosphate

Co-trimoxazole

Cyclophosphamide

Cytarabine

Dacarbazine

Dexamethasone sodium phosphate

Diphenhydramine HCl

Dobutamine HCl

Dopamine HCl

Droperidol

Enalaprilat

Etoposide

Famotidine

Fluconazole

Fluorouracil

Furosemide

Ganciclovir sodium

Gentamicin sulfate

Granisetron HCl

Haloperidol lactate

Heparin sodium

Hydrocortisone sodium succinate

Hydromorphone HCl

Ifosfamide

Leucovorin calcium

Lorazepam

Magnesium sulfate

Mesna

Methotrexate sodium

Methylprednisolone sodium succinate

Metronidazole

Ondansetron HCl

Potassium chloride

Prochlorperazine edisylate

Ranitidine HCl

Ticarcillin disodium–clavulanate potassium

Tobramycin sulfate

Vancomycin HCl

Vinblastine sulfate

Vincristine sulfate

Vinorelbine tartrate

Zidovudine

Incompatible

Amphotericin B

Amphotericin B cholesteryl sulfate complex

Buprenorphine HCl

Ceftazidime

Docetaxel

Hydroxyzine HCl

Mannitol

Meperidine HCl

Metoclopramide HCl

Mitoxantrone HCl

Morphine sulfate

Ofloxacin

Paclitaxel

Piperacillin sodium–tazobactam sodium

Promethazine HCl

Sodium bicarbonate

Actions

  • Mechanism(s) of antineoplastic action not fully understood but appear to involve free radical formation secondary to metabolic activation by electron reduction, intercalation into DNA, induction of DNA breaks and chromosomal aberrations, and alterations in cell membranes induced by the drug;233 234 237 238 239 240 244 299 apoptosis (programmed cell death) also may be involved.200 These and other mechanisms (chelation of metal ions to produce drug-metal complexes) may contribute to cardiotoxic effects.233 234 237 238 239 240 244 299

  • Cytotoxicity precludes use as anti-infective agent.a

Advice to Patients

  • Importance of recognizing and reporting adverse effects, including GI, dermatologic, and myelosuppressive effects (and related precautions), infectious complications, CHF symptoms, and injection site pain.b c

  • Risk of myocardial toxicity and leukemia.b c

  • Importance of informing caregivers of children receiving doxorubicin to take precautions (e.g., wearing latex gloves) to prevent contact with the patient’s urine and other body fluids for ≥5 days after administration.200 208

  • Advise patients to expect transient red coloration of urine after administration.b

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.b c

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed; necessity for clinicians to advise women to avoid pregnancy.b c

  • Importance of informing patients of other important precautionary information.b c (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Doxorubicin Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for IV use only

10 mg*

Adriamycin (preservative-free)

Bedford

Adriamycin RDF (with methylparaben)

Pfizer

Doxorubicin Hydrochloride for Injection

Baxter, Bedford

20 mg*

Adriamycin (preservative-free)

Bedford

Adriamycin RDF (with methylparaben)

Pfizer

Doxorubicin Hydrochloride for Injection

Bedford

50 mg*

Adriamycin (preservative-free)

Bedford

Adriamycin RDF (with methylparaben)

Pfizer

Doxorubicin Hydrochloride for Injection

Baxter, Bedford

Rubex

Bristol-Myers Squibb

100 mg

Rubex

Bristol-Myers Squibb

150 mg

Adriamycin RDF (with methylparaben)

Pfizer

Injection, for IV use only

2 mg/mL (10, 20, 50, 75, 150, and 200 mg)*

Adriamycin (preservative-free)

Bedford

Adriamycin PFS (preservative-free; available in Cytosafe and glass vials)

Pfizer

Doxorubicin Hydrochloride Injection (preservative-free; available in polymer vials)

Abraxis, Pharmachemie, Sicor

Doxorubicin Hydrochloride Liposomal

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection concentrate, for IV infusion only

2 mg/mL (20 and 50 mg)

Doxil

Centocor Ortho Biotech

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions December 1, 2010. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

Only references cited for selected revisions after 1984 are available electronically.

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