Dosing and uses of Doxil, Lipodox (doxorubicin liposomal)
Adult dosage forms and strengths
injectable solution
- 2mg/mL
Kaposi's Sarcoma
Indicated for AIDS-related Kaposi’s sarcoma in patients after failure of prior systemic chemotherapy or intolerance to such therapy
20 mg/m² IV q3Weeks
Ovarian Cancer
Indicated for ovarian cancer in patients whose disease has progressed or recurred after platinum-based chemotherapy
50 mg/m² IV q4Weeks x 4 courses minimum
Multiple Myeloma
Indicated in combination with bortezomib for multiple myeloma in patients who have not previously received bortezomib and have received at least 1 prior therapy
30 mg/m² IV on day 4 following bortezomib 1.3 mg/m² on days 1, 4, 8 & 11 q3Weeks
Dosage modifications
Hepatic impairment: Reduce dose if serum bilirubin ≥1.2 mg/dL
Hand-foot syndrome or stomatitis
- Grade 1: If no previous grade 3 or 4 toxicity, no dose adjustment required; if previous grade 3 or 4 toxicity, delay up to 2 wk then decrease dose by 25%
- Grade 2: Delay dose up to 2 wk or until resolved to grade 0-1; discontinue if not resolved after 2 wk; if resolve (no previous grades 3-4 toxicity), continue at previous dose; if resolve (hx of previous grades 3-4 toxicity), decrease dose by 25%
- Grade 3: Delay dose up to 2 wk or until resolved to grade 0-1, then decrease dose by 25%; discontinue if no resolution after 2 wk
- Grade 4: Delay dose up to 2 wk or until resolved to grade 0-1, then decrease dose by 25% and return to original dose interval; discontinue if no resolution after 2 wk
Neutropenia or thrombocytopenia
- Grade 1: No dose reduction
- Grade 2 or 3: Delay until ANC ≥1,500 and platelets ≥75,000; resume treatment at previous dose
- Grade 4: Delay until ANC ≥1,500 and platelets ≥75,000; resume at 25% dose reduction or continue previous dose with prophylactic granulocyte growth factor
Other toxicities
- Fever ≥38°C and ANC <1,000/mm³: Withhold dose for this cycle if before Day 4; decrease dose by 25%, if after Day 4 of previous cycle
- On any day of drug administration after Day 1 of each cycle (platelet count <25,000/mm³, Hgb <8 g/dL, ANC <500/mm³): Withhold dose for this cycle if before Day 4; cecrease dose by 25%, if after Day 4 of previous cycle AND if bortezomib is reduced for hematologic toxicity
- Grade 3 or 4 nonhematologic toxicity: Hold dose until recovered to <grade 2, then reduce dose by 25%
Sarcomas (Orphan)
Treatment of soft tissue sarcomas
Orphan indication sponsor
- GP-Pharm SA; Pol. Ind. Els Vinyets els Fogars n 2, Quinti de Mediona; Barcelona, Spain
Hepatocellular Carcinoma (Orphan)
Lyso-thermosensitive liposomal doxorubicin
Orphan indication sponsor
- Celsion Corporation; 10220-L Old Columbia Road; Columbia, MD 21046
Pediatric dosage forms and strengths
Safety and efficacy not established
Doxil, Lipodox (doxorubicin liposomal) adverse (side) effects
>10%
Kaposi's Sarcoma
- Anemia (>50%)
- Thrombocytopenia (>50%)
- Neutropenia (10-50%)
- Anemia (18.2%)
- Nausea (17%)
Ovarian cancer >25%
- Hand-foot syndrome (50%)
- Nausea (46%)
- Stomatitis (41%)
- Asthenia (40.2%)
- Vomiting (32.6%)
- Rash (28%)
- Constipation (>25%)
- Abdominal pain (>25%)
Ovarian cancer 10-25%
- Fever (21.3%)
- Anorexia (20%)
- Diarrhea (20%)
- Peripheral edema
- Dyspepsia
- Pharyngitis
- Dyspnea
- Alopecia
1-10%
Kaposi's Sarcoma 5-10%
- Asthenia (9.9%)
- Fever (9.1%)
- Diarrhea (7.8%)
- Vomiting (7.8%)
- Stomatitis (6.8%)
- Rash (1-5%)
- Alopecia (1-5%)
- Increased alkaline phosphatase
Kaposi's Sarcoma 1-5%
- Hand-foot syndrome (3.4%)
- Hypotension
- Tachycardia
- Dyspnea
- Hemolysis
- Rash
Ovarian cancer (selected)
- Neutropenia (13.3%)
- Anemia (0.4-5.4%)
- Thrombocytopenia (1.3%)
<1%
Abscess
Acute myeloid leukemia
Cardiomegaly
Cardiomyopathy
Erythema nodosum
Hyperkalemia
Hyperuricemia
Ketosis
Warnings
Black box warnings
Myocardial toxicity
- Can cause myocardial damage, including congestive heart failure, as the total cumulative dose of doxorubicin HCl approaches 550 mg/m²
- In a clinical study of 250 patients with advanced cancer who were treated with liposomal doxorubicin, the risk of cardiotoxicity was 11% when the cumulative anthracycline dose was between 450-550 mg/m²
- Prior use of other anthracyclines or anthracenediones should be included in calculations of total cumulative dosage
- The risk of cardiomyopathy may be increased at lower cumulative doses in patients with prior mediastinal irradiation
Infusion-related reactions
- May include flushing, shortness of breath, facial swelling, headache, chills, back pain, tightness in the chest or throat
- Hypotension occurred in 11% of patients with solid tumors treated with liposomal doxorubicin
- Serious, life-threatening and fatal infusion reactions have been reported
Contraindications
History of severe hypersensitivity to doxorubicin, including anaphylaxis
Cautions
Can result in myocardial damage, including acute left ventricular failure; risk of cardiomyopathy is generally proportional to the cumulative exposure (see Black box warnings)
Serious and sometimes life-threatening infusion-related reactions reported; ensure that medications to treat infusion-related reactions and cardiopulmonary resuscitative equipment are available for immediate use prior to initiation (see Black box warnings)
Incidence of hand-foot syndrome in 1 trial was 51%, including 24% grade 3 or 4 toxicity (see Dosage modifications)
Secondary oral cancers, primarily squamous cell carcinoma, have been reported
Based on animal data, can cause fetal harm when administered to pregnant women
Pregnancy and lactation
Pregnancy category: d
Lactation: Unknown whether distributed in breast milk; because many drugs, including anthracyclines, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, discontinue breast feeding during treatment
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Doxil, Lipodox (doxorubicin liposomal)
Mechanism of action
Anthracycline; intercalates between DNA base pairs, impairs topoisomerase II function and subsequently inhibits DNA and RNA replication
Doxorubicin is a strong chelator; doxorubicin-iron complex binds to cell membranes and DNA and produces free hydroxyl radicals that cleaves them
Pharmacokinetics
Peak Plasma: (20 mg/m²): 8.34±0.49 mcg/mL
Half-life: 44-55 hr
AUC (20 mg/m²): 590±59 mcg.hr/mL
Protein binding: 70%
Vd: 2.8 L/m²
Metabolism: Low
Clearance (20 mg/m²): 41 mL/hr/m²
Excretion: Urine (5%)
Administration
IV Incompatibilities
Y-site: ampho B, amphotericin B cholesteryl sulfate, buprenorphine, ceftazidime, cefoperazone, docetaxel, hydroxyzine, mannitol, meperidine, metoclopramide, mitoxantrone, morphine sulfate, ofloxacin, paclitaxel, piperacillin/tazobactam, promethazine, Na-bicarB
IV Compatibilities
Y-site: acyclovir, allopurinol, ampicillin, carboplatin, cimetidine, ciprofloxacin, cisplatin, clindamycin, cyclophosphamide, dexamethasone, diphenhydramine, dobutamine, dopamine, fluconazole, fluorouracil, furosemide, granisetron, heparin, lorazepam, MgSO4, KCl, prochlorperazine, TMP/SMX, vancomycin, zidovudine
IV Preparation
Dilute aseptically <90 mg doses in 250 mL & >90 mg doses in 500 mL D5W (do NOT use other IV fluids)
Refrigerate at 2-8°C & administer within 24 hr
Red translucent dispersion (will not be a clear solution)
IV Administration
Initial infusion at 1 mg/min, if no infusion reaction may increase rate to complete infusion in 1 hr
Do not administer as bolus injection or undiluted suspension
Do not use in-line filter
Use cytotoxic precautions for handling, administration, and disposaL
Extravasation Management
Stop infusion immediately
Do not remove the needle until attempts are made to aspirate extravasated fluid
Do not flush the line
Avoid applying pressure to the site
Apply ice to the site intermittently for 15 minutes 4 x/day for 3 days
If the extravasation is in an extremity, elevate the extremity
Storage
Store vials refrigerated at 2-8°C
