"June 21, 2011 -- New technology now makes it possible to create atomic-scale drug particles, diagnostic tools, and biological medical devices -- and the FDA is struggling to regulate the fast-growing field.
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Doxorubicin HCl can result in myocardial damage, including acute left ventricular failure. The risk of cardiomyopathy with doxorubicin HCl is generally proportional to the cumulative exposure. The relationship between cumulative DOXIL dose and the risk of cardiac toxicity has not been determined.
In a clinical study in 250 patients with advanced cancer who were treated with DOXIL, the risk of cardiotoxicity was 11% when the cumulative anthracycline dose was between 450-550 mg/m² . Cardiotoxicity was defined as > 20% decrease in resting left ventricular ejection fraction (LVEF) from baseline where LVEF remained in the normal range or a > 10% decrease in LVEF from baseline where LVEF was less than the institutional lower limit of normal. Two percent of patients developed signs and symptoms of congestive heart failure without documented evidence of cardiotoxicity.
Assess left ventricular cardiac function (e.g. MUGA or echocardiogram) prior to initiation of DOXIL, during treatment to detect acute changes, and after treatment to detect delayed cardiotoxicity. Administer DOXIL to patients with a history of cardiovascular disease only when the potential benefit of treatment outweighs the risk.
Serious and sometimes life-threatening infusion-related reactions characterized by one or more of the following symptoms can occur with DOXIL: flushing, shortness of breath, facial swelling, headache, chills, chest pain, back pain, tightness in the chest and throat, fever, tachycardia, pruritus, rash, cyanosis, syncope, bronchospasm, asthma, apnea, and hypotension. The majority of infusion-related events occurred during the first infusion. Of 239 patients with ovarian cancer treated with DOXIL in Trial 4, 7% of patients experienced acute infusion-related reactions resulting in dose interruption. All occurred during cycle 1 and none during subsequent cycles. Across multiple studies of DOXIL monotherapy including this and other studies enrolling 760 patients with various solid tumors, 11% of patients had infusion-related reactions.
Ensure that medications to treat infusion-related reactions and cardiopulmonary resuscitative equipment is available for immediate use prior to initiation of DOXIL. Initiate DOXIL infusions at a rate of 1 mg/min and increase rate as tolerated [see DOSAGE AND ADMINISTRATION]. In the event of an infusion-related reaction, temporarily stop the drug until resolution then resume at a reduced infusion rate. Discontinue DOXIL infusion for serious or life-threatening infusion-related reactions.
Hand-Foot Syndrome (HFS)
In Trial 4, the incidence of HFS was 51% of patients in the DOXIL arm and 0.9% of patients in the topotecan arm, including 24% Grade 3 or 4 cases of HFS in DOXIL-treated patients and no Grade 3 or 4 cases in topotecan-treated patients. HFS or other skin toxicit y required discontinuation of DOXIL in 4.2% of patients.
HFS was generally observed after 2 or 3 cycles of treatment but may occur earlier. Delay DOXIL for the first episode of Grade 2 or greater HFS [see DOSAGE AND ADMINISTRATION]. Discontinue DOXIL if HFS is severe and debilitating.
Secondary Oral Neoplasms
Secondary oral cancers, primarily squamous cell carcinoma, have been reported from post-marketing experience in patients with long-term (more than one year) exposure to DOXIL. These malignancies were diagnosed both during treatment with DOXIL and up to 6 years after the last dose. Examine patients at regular intervals for the presence of oral ulceration or with any oral discomfort that may be indicative of secondary oral cancer.
The altered pharmacokinetics and preferential tissue distribution of liposomal doxorubicin that contributes to enhanced skin toxicity and mucositis compared to free doxorubicin may play a role in the development of oral secondary malignancies with long-term use.
Based on animal data, DOXIL can cause fetal harm when administered to a pregnant woman. At doses approximately 0.12 times the recommended clinical dose, DOXIL was embryotoxic and abortifacient in rabbits. Advise pregnant women of the potential risk to a fetus. Advise females and males of reproductive potential to use effective contraception during and for 6 months after treatment with DOXIL [see Use in Specific Populations].
Carcinogenesis, Mutagenesis, And Impairment Of Fertility
Mutagenicity or carcinogenicity studies have not been conducted with DOXIL, however doxorubicin was shown to be mutagenic in the in vitro Ames assay, and clastogenic in multiple in vitro assays (CHO cell, V79 hamster cell, human lymphoblast, and SCE assays) and the in vivo mouse micronucleus assay. The possible adverse effects on fertility in animals have not been adequately evaluated. DOXIL resulted in mild to moderate ovarian and testicular atrophy in mice after administration of a single dose of 36 mg/kg (about 2 times the 50 mg/m² human dose on a mg/m² basis). Decreased testicular weights and hypospermia were observed in rats after repeat doses ≥ 0.25 mg/kg/day (about 0.03 times the 50 mg/m² human dose on a mg/m² basis), and diffuse degeneration of the seminiferous tubules and a marked decrease in spermatogenesis were observed in dogs after repeat doses of 1 mg/kg/day (about 0.4 times the 50 mg/m² human dose on a mg/m² basis).
Use In Specific Populations
Based on findings in animals, DOXIL can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, DOXIL was embryotoxic in rats and abortifacient in rabbits following intravenous administration during organogenesis at doses approximately 0.12 times the recommended clinical dose [see Data]. There are no available human data informing the drug-associated risk. Advise pregnant women of the potential risk to a fetus.
The background risk of major birth defects and miscarriage for the indicated populations are unknown. However, the background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies.
DOXIL was embryotoxic at doses of 1 mg/kg/day in rats and was embryotoxic and abortifacient at 0.5 mg/kg/day in rabbits (both doses are about 0.12 times the recommended dose of 50 mg/m² human dose on a mg/m² basis). Embryotoxicity was characterized by increased embryo-fetal deaths and reduced live litter sizes.
It is not known whether DOXIL is present in human milk. Because many drugs, including anthracyclines, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from DOXIL, discontinue breastfeeding during treatment with DOXIL.
Females And Males Of Reproductive Potential
DOXIL can cause fetal harm when administered to a pregnant woman [see Use In Specific Populations]. Advise females of reproductive potential to use effective contraception during and for 6 months after treatment with DOXIL.
DOXIL may damage spermatozoa and testicular tissue, resulting in possible genetic fetal abnormalities. Males with female sexual partners of reproductive potential should use effective contraception during and for 6 months after treatment with DOXIL [see Nonclinical Toxicology].
In females of reproductive potential, DOXIL may cause infertility and result in amenorrhea. Premature menopause can occur with doxorubicin HCl. Recovery of menses and ovulation is related to age at treatment.
DOXIL may result in oligospermia, azoospermia, and permanent loss of fertility. Sperm counts have been reported to return to normal levels in some men. This may occur several years after the end of therapy [see Nonclinical Toxicology].
The safety and effectiveness of DOXIL in pediatric patients have not been established.
Clinical studies of DOXIL conducted in patients with either epithelial ovarian cancer (Trial 4) or with AIDS-related Kaposi's sarcoma (Trial 5) did not contain sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger subjects.
In Trial 6, of 318 patients treated with DOXIL in combination with bortezomib for multiple myeloma, 37% were 65 years of age or older and 8% were 75 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients.
The pharmacokinetics of DOXIL has not been adequately evaluated in patients with hepatic impairment. Doxorubicin is eliminated in large part by the liver. Reduce DOXIL for serum bilirubin of 1.2 mg/dL or higher.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 3/10/2015
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