DOXORUBICIN HCL
DESCRIPTION:
WARNING
-------------------------------------------------------------------------------------------
* 1. Severe local tissue necrosis will occur *
* if there is extravasation during *
* administration (See DOSAGE AND *
* ADMINISTRATION). Doxorubicin must not be *
* given by the intramuscular or subcutaneous *
* route. *
* 2. Myocardial toxicity manifested in its *
* most severe form by potentially fatal *
* congestive heart failure may occur either *
* during therapy or months to years after *
* termination of therapy. The probability of *
* developing impaired myocardial function *
* based on a combined index of signs, *
* symptoms and decline in left ventricular *
* ejection fraction (LVEF) is estimated to be *
* 1 to 2% at a total cumulative dose of *
* 300 mg/m(squared) of doxorubicin, 3 to 5% *
* at a dose of 400 mg/m(squared), 5 to 8% at *
* 450 mg/m(squared) and 6 to 20% at *
* 500 mg/m(squared).* The risk of developing *
* CHF increases rapidly with increasing total *
* cumulative doses of doxorubicin in excess *
* of 450 mg/m(squared). This toxicity may *
* occur at lower cumulative doses in patients *
* with prior mediastinal irradiation or on *
* concurrent cyclophosphamide therapy or with *
* pre-existing heart disease. *
* 3. Dosage should be reduced in patients *
* with impaired hepatic function. *
* 4. Severe myelosuppression may occur. *
* 5. Doxorubicin should be administered only *
* under the supervision of a physician who is *
* experienced in the use of cancer *
* chemotherapeutic agents. *
* * Data on file at Pharmacia & Upjohn *
* *
------------------------------------------------------------------------------------------------
Doxorubicin is a cytotoxic anthracycline antibiotic isolated from cultures of
Streptomyces Peucetius var. Caesius.
Doxorubicin consists of a naphthacenequinone nucleus linked through a glycosidic
bond at ring atom 7 to an amino sugar, daunosamine.
Chemically, doxorubicin hydrochloride is:
5,12-Naphthacenedione, 10-((3-amino- 2,3,6-trideoxy-(alpha)-L-LYXO-
hexopyranosyl)oxy)-7,8,9, 10-tetrahydro- 6,8,11-trihydroxy-8-(hydroxylacetyl)-1-
methoxy-, hydrochloride (8S-CIS)-. The structural formula is as follows:
Doxorubicin binds to nucleic acids, presumably by specific intercalation of the
planar anthracycline nucleus with the DNA double helix. The anthracycline ring
is lipophilic, but the saturated end of the ring system contains abundant
hydroxyl groups adjacent to the amino sugar, producing a hydrophilic center. The
molecule is amphoteric, containing acidic functions in the ring phenolic groups
and a basic function in the sugar amino group. It binds to cell membranes as
well as plasma proteins.
ACTIONS/CLINICAL PHARMACOLOGY:
The cytotoxic effect of doxorubicin on malignant cells and its toxic effects on
various organs are thought to be related to nucleotide base intercalation and
cell membrane lipid binding activities of doxorubicin. Intercalation inhibits
nucleotide replication and action of DNA and RNA polymerases. The interaction of
doxorubicin with topoisomerase II to form DNA-cleavable complexes appears to be
an important mechanism of doxorubicin cytocidal activity. Doxorubicin cellular
membrane binding may effect a variety of cellular functions. Enzymatic electron
reduction of doxorubicin by a variety of oxidases, reductases and dehydrogenases
generate highly reactive species including the hydroxyl free radical OH*. Free
radical formation has been implicated in doxorubicin cardiotoxicity by means of
Cu (II) and Fe (III) reduction at the cellular level.
Animal studies have shown activity in a spectrum of experimental tumors,
immunosuppression, carcinogenic properties in rodents, induction of a variety of
toxic effects, including delayed and progressive cardiac toxicity,
myelosuppression in all species and atrophy to testes in rats and dogs.
Pharmacokinetic studies, determined in patients with various types of tumors
undergoing either single or multi-agent therapy have shown that doxorubicin
follows a multiphasic disposition after intravenous injection. The initial
distributive half-life of approximately 5.0 minutes suggests rapid tissue uptake
of doxorubicin, while its slow elimination from tissues is reflected by a
terminal half-life of 20 to 48 hours. Steady-state distribution volumes exceed
20 to 30 L/kg and are indicative of extensive drug uptake into tissues. Plasma
clearance is in the range of 8 to 20 mL/min/kg and is predominately by
metabolism and biliary excretion. Approximately 40% of the dose appears in the
bile in 5 days, while only 5 to 12% of the drug and its metabolites appear in
the urine during the same time period. Binding of doxorubicin and its major
metabolite, doxorubicinol to plasma proteins is about 74 to 76% and is
independent of plasma concentration of doxorubicin up to 2 mcgm. Enzymatic
reduction at the 7 position and cleavage of the daunosamine sugar yields
aglycones which are accompanied by free radical formation, the local production
of which may contribute to the cardiotoxic activity of doxorubicin. Disposition
of doxorubicinol (DOX-OL) in patients is formation rate limited. The terminal
half-life of DOX-OL is similar to doxorubicin. The relative exposure of DOX-OL,
compared to doxorubicin ranges between 0.4 to 0.6. In urine, <3% of the dose was
recovered as DOX-OL over 7 days. The literature contains no information
regarding gender related differences in the pharmacokinetics of doxorubicin and
doxorubicinol.
IN FOUR PATIENTS, dose-independent pharmacokinetics have been shown for
doxorubicin in the dose range of 30 to 70 mg/m(squared). Systemic clearance of
doxorubicin is SIGNIFICANTLY reduced in obese women with ideal body weight
greater than 130%. There was a significant reduction in clearance without any
change in volume of distribution in obese patients when compared with normal
patients with less than 115% ideal body weight. The clearance of doxorubicin and
doxorubicinol was also reduced in patients with impaired hepatic function.
Doxorubicin was excreted in the milk of one lactating patient, with peak milk
concentration at 24 hours after treatment being approximately 4.4 -fold greater
than the CORRESPONDING PLASMA CONCENTRATION. Doxorubicin was detectable in the
milk up to 72 hours after therapy with 70 mg/m(squared) of doxorubicin given as
a 15 minute intravenous infusion and 100 mg/m(squared) of cisplatin as a 26 hour
intravenous infusion. The peak concentration of doxorubicinol in milk at 24
hours was 0.2 mcgm and AUC up to 24 hours was 16.5 mcgm.hr while the AUC for
doxorubicin was 9.9 mcgm.hr.
Doxorubicin does not cross the blood brain barrier.
INDICATIONS AND USAGE:
ADRIAMYCIN PFS and ADRIAMYCIN have been used successfully to produce
regression in disseminated neoplastic conditions such as acute lymphoblastic
leukemia, acute myeloblastic leukemia, Wilms' tumor, neuroblastoma, soft tissue
and bone sarcomas, breast carcinoma, ovarian carcinoma, transitional cell
bladder carcinoma, thyroid carcinoma, gastric carcinoma, Hodgkin's disease,
malignant lymphoma and bronchogenic carcinoma in which the small cell histologic
type is the most responsive compared to other cell types.
CONTRAINDICATIONS:
Doxorubicin therapy should not be started in patients who have marked
myelosuppression induced by previous treatment with other antitumor agents or by
radiotherapy. Doxorubicin treatment is contraindicated in patients who received
previous treatment with complete cumulative doses of doxorubicin, daunorubicin,
idarubicin, and/or other anthracyclines and anthracenes.
WARNINGS:
*************************************************
* *
* WARNING *
* 1. Severe local tissue necrosis will occur *
* if there is extravasation during *
* administration (See DOSAGE AND *
* ADMINISTRATION). Doxorubicin must not be *
* given by the intramuscular or subcutaneous *
* route. *
* 2. Myocardial toxicity manifested in its *
* most severe form by potentially fatal *
* congestive heart failure may occur either *
* during therapy or months to years after *
* termination of therapy. The probability of *
* developing impaired myocardial function *
* based on a combined index of signs, *
* symptoms and decline in left ventricular *
* ejection fraction (LVEF) is estimated to be *
* 1 to 2% at a total cumulative dose of *
* 300 mg/m(squared) of doxorubicin, 3 to 5% *
* at a dose of 400 mg/m(squared), 5 to 8% at *
* 450 mg/m(squared) and 6 to 20% at *
* 500 mg/m(squared).* The risk of developing *
* CHF increases rapidly with increasing total *
* cumulative doses of doxorubicin in excess *
* of 450 mg/m(squared). This toxicity may *
* occur at lower cumulative doses in patients *
* with prior mediastinal irradiation or on *
* concurrent cyclophosphamide therapy or with *
* pre-existing heart disease. *
* 3. Dosage should be reduced in patients *
* with impaired hepatic function. *
* 4. Severe myelosuppression may occur. *
* 5. Doxorubicin should be administered only *
* under the supervision of a physician who is *
* experienced in the use of cancer *
* chemotherapeutic agents. *
* * Data on file at Pharmacia & Upjohn *
* *
*************************************************
Special attention must be given to the cardiotoxicity induced by doxorubicin.
Irreversible myocardial toxicity, manifested in its most severe form by life-
threatening and potentially fatal congestive heart failure, may occur either
during therapy or months to years after termination of therapy. The probability
of developing impaired myocardial function, based on a combined index of signs,
symptoms and decline in left ventricular ejection fraction (LVEF) is estimated
to be 1 to 2% at a total cumulative dose of 300 mg/m(squared) of doxorubicin, 3
to 5% at a dose of 400 mg/m(squared), 5 to 8% at a dose of 450 mg/m(squared) and
6 to 20% at a dose of 500 mg/m(squared) given in a schedule of a bolus injection
once every 3 weeks (data on file at Pharmacia & Upjohn). In a retrospective
review by Von Hoff et al, the probability of developing congestive heart failure
was reported to be 5/168 (3%) at a cumulative dose of 430 mg/m(squared) of
doxorubicin, 8/110 (7%) at 575 mg/m(squared) and 3/14 (21%) at 728
mg/m(squared). The cumulative incidence of CHF was 2.2%. In a prospective study
of doxorubicin in combination with cyclophosphamide, fluorouracil and/or
vincristine in patients with breast cancer or small cell lung cancer, the
cumulative incidence of congestive heart failure was 5 to 6%. The probability of
CHF at various cumulative doses of doxorubicin was 1.5% at 300 mg/m(squared),
4.9% at 400 mg/m(squared), 7.7% at 450 mg/m(squared) and 20.5% at 500
mg/m(squared).
Cardiotoxicity may occur at lower doses in patients with prior mediastinal
irradiation, concurrent cyclophosphamide therapy and advanced age. Data also
suggest that pre-existing heart disease is a co-factor for increased risk of
doxorubicin cardiotoxicity. In such cases, cardiac toxicity may occur at doses
lower than the respective recommended cumulative dose of doxorubicin. Studies
have suggested that concomitant administration of doxorubicin and calcium
channel entry blockers may increase the risk of doxorubicin cardiotoxicity. The
total dose of doxorubicin administered to the individual patient should also
take into account previous or concomitant therapy with related compounds such as
daunorubicin, idarubicin and mitoxantrone. Cardiomyopathy and/or congestive
heart failure may be encountered several months or years after discontinuation
of doxorubicin therapy.
The risk of congestive heart failure and other acute manifestations of
doxorubicin cardiotoxicity in children may be as much or lower than in adults.
Children appear to be at particular risk for developing delayed cardiac toxicity
in that doxorubicin induced cardiomyopathy impairs myocardial growth as children
mature, subsequently leading to possible development of congestive heart failure
during early adulthood. As many as 40% of children may have subclinical cardiac
dysfunction and 5 to 10% of children may develop congestive heart failure on
long term follow-up. This late cardiac toxicity may be related to the dose of
doxorubicin. The longer the length of follow-up the greater the increase in the
detection rate.
Treatment of doxorubicin induced congestive heart failure includes the use of
digitalis, diuretics, after load reducers such as angiotensin I converting
enzyme (ACE) inhibitors, low salt diet, and bed rest. Such intervention may
relieve symptoms and improve the functional status of the patient.
Monitoring Cardiac Function
In adult patients severe cardiac toxicity may occur precipitously without
antecedent ECG changes. Cardiomyopathy induced by anthracyclines is usually
associated with very characteristic histopathologic changes on an endomyocardial
biopsy (EM biopsy), and a decrease of left ventricular ejection fraction (LVEF),
as measured by multi-gated radionuclide angiography (MUGA scans) and/or
echocardiogram (ECHO), from pretreatment baseline values. However, it has not
been demonstrated that monitoring of the ejection fraction will predict when
individual patients are approaching their maximally tolerated cumulative dose of
doxorubicin. Cardiac function should be carefully monitored during treatment to
minimize the risk of cardiac toxicity. A baseline cardiac evaluation with an
ECG, LVEF, and/or an echocardiogram (ECHO) is recommended especially in patients
with risk factors for increased cardiac toxicity (pre-existing heart disease,
mediastinal irradiation, or concurrent cyclophosphamide therapy). Subsequent
evaluations should be obtained at a cumulative dose of doxorubicin of at least
400 mg/m(squared) and periodically thereafter during the course of therapy.
Children are at increased risk for developing delayed cardiotoxicity following
doxorubicin administration and therefore a follow-up cardiac evaluation is
recommended periodically to monitor for this delayed cardiotoxicity.
In adults, a 10% decline in LVEF to below the lower limit of normal or an
absolute LVEF of 45%, or a 20% decline in LVEF at any level is indicative of
deterioration in cardiac function. In children, deterioration in cardiac
function during or after the completion of therapy with doxorubicin is indicated
by a drop in fractional shortening (FS) by an absolute value of (>/=)10
percentile units or below 29%, and a decline in LVEF of 10 percentile units or
an LVEF below 55%. In general, if test results indicate deterioration in cardiac
function associated with doxorubicin, the benefit of continued therapy should be
carefully evaluated against the risk of producing irreversible cardiac damage.
Acute life-threatening arrhythmias have been reported to occur during or within
a few hours after doxorubicin administration.
There is a high incidence of bone marrow depression, primarily of leukocytes,
requiring careful hematologic monitoring. With the recommended dose schedule,
leukopenia is usually transient, reaching its nadir 10 to 14 days after
treatment with recovery usually occurring by the 21st day. White blood counts as
low as 1000/mm(raised to the power of 3) are to be expected during treatment
with appropriate doses of doxorubicin. Red blood cell and platelet levels should
also be monitored since they may also be depressed. Hematologic toxicity may
require dose reduction or suspension or delay of doxorubicin therapy. Persistent
severe myelosuppression may result in superinfection or hemorrhage.
Doxorubicin may potentiate the toxicity of other anticancer therapies.
Exacerbation of cyclophosphamide induced hemorrhagic cystitis and enhancement of
the hepatotoxicity of 6-mercaptopurine have been reported. Radiation induced
toxicity to the myocardium, mucosae, skin and liver have been reported to be
increased by the administration of doxorubicin.
Since metabolism and excretion of doxorubicin occurs predominantly by the
hepatobiliary route, toxicity to recommended doses of doxorubicin can be
enhanced by hepatic impairment; therefore, prior to the individual dosing,
evaluation of hepatic function is recommended using conventional laboratory
tests such as SGOT, SGPT, alkaline phosphatase and bilirubin (See DOSAGE AND
ADMINISTRATION).
Necrotizing colitis manifested by typhlitis (cecal inflammation), bloody stools
and severe and sometimes fatal infections have been associated with a
combination of doxorubicin given by i.v. push daily for 3 days and cytarabine
given by continuous infusion daily for 7 or more days.
On intravenous administration of doxorubicin, extravasation may occur with or
without an accompanying stinging or burning sensation, even if blood returns
well on aspiration of the infusion needle (See DOSAGE AND ADMINISTRATION). If
any signs or symptoms of extravasation have occurred, the injection or infusion
should be immediately terminated and restarted in another vein.
PREGNANCY CATEGORY D-Safe use of doxorubicin in pregnancy has not been
established. Doxorubicin is embryotoxic and teratogenic in rats and embryotoxic
and abortifacient in rabbits. There are no adequate and well-controlled studies
in pregnant women. If doxorubicin is to be used during pregnancy, or if the
patient becomes pregnant during therapy, the patient should be apprised of the
potential hazard to the fetus. Women of childbearing age should be advised to
avoid becoming pregnant.
PRECAUTIONS:
GENERAL
Doxorubicin is not an anti-microbial agent.
INFORMATION FOR PATIENTS
ADRIAMYCIN PFS and ADRIAMYCIN impart a red coloration to the urine for 1 to
2 days after administration, and patients should be advised to expect this
during active therapy.
DRUG INTERACTIONS
Literature contain the following drug interactions with doxorubicin in humans:
cyclosporine (Sandimmune) may induce coma and/or seizures, phenobarbital
increases the elimination of doxorubicin, phenytoin levels may be decreased by
doxorubicin, streptozocin (Zanosar) may inhibit the hepatic metabolism, and
administration of live vaccines to immunosuppressed patients, including those
undergoing cytotoxic chemotherapy, may be hazardous. Information on other
potential drug interactions may be found in the literature.
LABORATORY TESTS
Initial treatment with doxorubicin requires observation of the patient and
periodic monitoring of complete blood counts, hepatic function tests, and
radionuclide left ventricular ejection fraction (See WARNINGS section).
Like other cytotoxic drugs, doxorubicin may induce "tumor lysis syndrome" and
hyperuricemia in patients with rapidly growing tumors. Appropriate supportive
and pharmacologic measures may prevent or alleviate this complication.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
Formal long-term carcinogenicity studies have not been conducted with
doxorubicin. Doxorubicin and related compounds have been shown to have mutagenic
and carcinogenic properties when tested in experimental models (including
bacterial systems, mammalian cells in culture, and female Sprague-Dawley rats).
The possible adverse effect on fertility in males and females in humans or
experimental animals have not been adequately evaluated. Testicular atrophy was
observed in rats and dogs.
A variant of chemotherapy-related acute non- lymphocytic leukemia has been
reported to occur infrequently a few years after multiple drug treatment of some
neoplasms, which sometimes included doxorubicin. The exact role of doxorubicin
has not been elucidated.
PREGNANCY CATEGORY D
(See WARNINGS section.)
NURSING MOTHERS:
Because of the potential for serious adverse reactions in nursing infants from
doxorubicin, mothers should be advised to discontinue nursing during doxorubicin
therapy.
DRUG INTERACTIONS:
Literature contain the following drug interactions with doxorubicin in humans:
cyclosporine (Sandimmune) may induce coma and/or seizures, phenobarbital
increases the elimination of doxorubicin, phenytoin levels may be decreased by
doxorubicin, streptozocin (Zanosar) may inhibit the hepatic metabolism, and
administration of live vaccines to immunosuppressed patients, including those
undergoing cytotoxic chemotherapy, may be hazardous. Information on other
potential drug interactions may be found in the literature.
ADVERSE REACTIONS:
Dose limiting toxicities of therapy are myelosuppression and cardiotoxicity.
Other reactions reported are:
CARDIOTOXICITY
-(See WARNINGS section.)
CUTANEOUS
-Reversible complete alopecia occurs in most cases. Hyperpigmentation of
nailbeds and dermal crease, primarily in children, and onycholysis have been
reported in a few cases. Recall of skin reaction due to prior radiotherapy has
occurred with doxorubicin administration.
GASTROINTESTINAL
-Acute nausea and vomiting occurs frequently and may be severe. This may be
alleviated by antiemetic therapy. Mucositis (stomatitis and esophagitis) may
occur 5 to 10 days after administration. The effect may be severe leading to
ulceration and represents a site of origin for severe infections. The dosage
regimen consisting of administration of doxorubicin on three successive days
results in greater incidence and severity of mucositis. Ulceration and necrosis
of the colon, especially the cecum, may occur leading to bleeding or severe
infections which can be fatal. This reaction has been reported in patients with
acute nonlymphocytic leukemia treated with a 3-day course of doxorubicin
combined with cytarabine. Anorexia and diarrhea have been occasionally
reported.
VASCULAR
-Phlebosclerosis has been reported especially when small veins are used or a
single vein is used for repeated administration. Facial flushing may occur if
the injection is given too rapidly.
LOCAL
-Severe cellulitis, vesication and tissue necrosis will occur if extravasation
of doxorubicin occurs during administration. Erythematous streaking along the
vein proximal to the site of injection had been reported (See DOSAGE AND
ADMINISTRATION).
HEMATOLOGIC
-The occurrence of secondary acute myeloid leukemia with or without a
preleukemic phase has been reported rarely in patients concurrently treated with
doxorubicin in association with DNA- damaging antineoplastic agents. Such cases
could have a short (1-3 years) latency period.
HYPERSENSITIVITY
-Fever, chills and urticaria have been reported occasionally. Anaphylaxis may
occur. A case of apparent cross sensitivity to lincomycin has been reported.
OTHER
-Conjunctivitis and lacrimation occur rarely.
OVERDOSAGE:
Acute overdosage with doxorubicin enhances the toxic effect of mucositis,
leukopenia and thrombocytopenia. Treatment of acute overdosage consists of
treatment of the severely myelosuppressed patient with hospitalization,
antimicrobials, platelet transfusions and symptomatic treatment of mucositis.
Use of hemopoietic growth factor (G-CSF, GM-CSF) may be considered.
THE 150 MG ADRIAMYCIN AND THE 100 ML (2 MG/ML) ADRIAMYCIN PFS VIALS ARE
PACKAGED AS MULTIPLE DOSE VIALS AND CAUTION SHOULD BE EXERCISED TO PREVENT
INADVERTENT OVERDOSAGE.
Cumulative dosage with doxorubicin increases the risk of cardiomyopathy and
resultant congestive heart failure (See WARNINGS Section). Treatment consists of
vigorous management of congestive heart failure with digitalis preparations,
diuretics, and after-load reducers such as ACE inhibitors.
DOSAGE AND ADMINISTRATION:
Care in the administration of ADRIAMYCIN PFS and ADRIAMYCIN will reduce the
chance of perivenous infiltration (See WARNINGS). It may also decrease the
chance of local reactions such as urticaria and erythematous streaking. On
intravenous administration of doxorubicin, extravasation may occur with or
without an accompanying burning or stinging sensation, even if blood returns
well on aspiration of the infusion needle. If any signs or symptoms of
extravasation have occurred, the injection or infusion should be immediately
terminated and restarted in another vein. If extravasation is suspected,
intermittent application of ice to the site for 15 min. q.i.d. X 3 days may be
useful. The benefit of local administration of drugs has not been clearly
established. Because of the progressive nature of extravasation reactions, close
observation and plastic surgery consultation is recommended. Blistering,
ulceration and/or persistent pain are indications for wide excision surgery,
followed by split- thickness skin grafting. (REF. 1)
The most commonly used dose schedule when used as a single agent is 60 to 75
mg/m(squared) as a single intravenous injection administered at 21-day
intervals. The lower dosage should be given to patients with inadequate marrow
reserves due to old age, or prior therapy, or neoplastic marrow infiltration.
ADRIAMYCIN PFS and ADRIAMYCIN have been used concurrently with other
approved chemotherapeutic agents. Evidence is available that in some types of
neoplastic disease combination chemotherapy is superior to single agents. The
benefits and risks of such therapy continue to be elucidated. When used in
combination with other chemotherapy drugs, the most commonly used dosage of
doxorubicin is 40 to 60 mg/m(squared) given as a single intravenous injection
every 21 to 28 days. Doxorubicin dosage must be reduced in case of
hyperbilirubinemia as follows:
Plasma bilirubin concentration (mg/dL) Dosage reduction (%)
------------------------------------------------------------- -------------------------------------
1.2 - 3.0 50
3.1 - 5.0 75
RECONSTITUTION DIRECTIONS:
ADRIAMYCIN 10 mg, 20 mg, 50 mg, and 150 mg vials should be reconstituted
with 5 mL, 10 mL, 25 mL, and 75 mL, respectively, of Sodium Chloride Injection,
USP (0.9%), to give a final concentration of 2 mg/mL of doxorubicin
hydrochloride. An appropriate volume of air should be withdrawn from the vial
during reconstitution to avoid excessive pressure buildup. Bacteriostatic
diluents are not recommended.
After adding the diluent, the vial should be shaken and the contents allowed to
dissolve. The reconstituted solution is stable for 7 days at room temperature
and under normal room light (100 foot-candles) and 15 days under refrigeration
(2 deg to 8 deg C). It should be protected from exposure to sunlight. Discard
any of the unused solution from the 10 mg, 20 mg, and 50 mg single dose vials.
Unused solutions of the multiple dose vial remaining beyond the recommended
storage times should be discarded.
It is recommended that ADRIAMYCIN PFS and ADRIAMYCIN be slowly administered
into the tubing of a freely running intravenous infusion of Sodium Chloride
Injection, USP, or 5% Dextrose Injection, USP. The tubing should be attached to
a Butterfly(R) needle inserted preferably into a large vein. If possible, avoid
veins over joints or in extremities with compromised venous or lymphatic
drainage. The rate of administration is dependent on the size of the vein, and
the dosage. However, the dose should be administered in not less than 3 to 5
minutes. Local erythematous streaking along the vein as well as facial flushing
may be indicative of too rapid an administration. A burning or stinging
sensation may be indicative of perivenous infiltration and the infusion should
be immediately terminated and restarted in another vein. Perivenous infiltration
may occur painlessly.
Doxorubicin should not be mixed with heparin or fluorouracil since it has been
reported that these drugs are incompatible to the extent that a precipitate may
form. Until specific compatibility data are available, it is not recommended
that doxorubicin be mixed with other drugs.
Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration, whenever solution and container permit.
HANDLING AND DISPOSAL:
Skin reactions associated with doxorubicin have been reported. Skin accidentally
exposed to doxorubicin should be rinsed copiously with soap and warm water, and
if the eyes are involved, standard irrigation techniques should be used
immediately. The use of goggles, gloves, and protective gowns is recommended
during preparation and administration of the drug.
Procedures for proper handling and disposal of anti-cancer drugs should be
considered. Several guidelines on this subject have been published. (REF. 2-8)
There is no general agreement that all the procedures recommended in the
guidelines are necessary or appropriate.
REFERENCES:
1. Rudolph R., Larson DL: Etiology and Treatment of Chemotherapeutic Agent
Extravasation Injuries: A Review J. Clin Oncol 5:1116-1126, 1987.
2. Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs. NIH
Publication No. 83-2621. For sale by the Superintendent of Documents, US
Government Printing Office, Washington, DC 20402.
3. AMA Council Report, Guidelines for Handling Parenteral Antineoplastics, JAMA.
1985; 253 (11): 1590-1592.
4. National Study Commission on Cytotoxic Exposure-Recommendations for Handling
Cytotoxic Agents. Available from Louis P. Jeffrey, Sc.D., Chairman, National
Study Commission on Cytotoxic Exposure, Massachusetts College of Pharmacy and
Allied Health Sciences, 179 Longwood Avenue, Boston, Massachusetts 02115.
5. Clinical Oncological Society of Australia. Guidelines and Recommendations for
Safe Handling of Antineoplastic Agents. Med J Australia. 1983; 1:426-428.
6. Jones RB, et al: Safe Handling of Chemotherapeutic Agents: A Report from the
Mount Sinai Medical Center. CA - A Cancer Journal for Clinicians. 1983;
(Sept/Oct) 258-263.
7. American Society of Hospital Pharmacists Technical Assistance Bulletin on
Handling Cytotoxic and Hazardous Drugs. Am J Hosp Pharm. 1990; 47:1033-1049.
8. OSHA Work-Practice Guidelines for Personnel Dealing with Cytotoxic
(Antineoplastic) Drugs. Am J Hosp Pharm. 1986; 43:1193-1204.
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