Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/1907
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ALKERAN (Kit)
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dailymed-instance:dosage |
The usual IV
dose is 16 mg/m. Dosage reduction of up to 50% should
be considered in patients with renal insufficiency (BUN���30 mg/dL)
(see PRECAUTIONS: General). The drug is administered as a single infusion
over 15 to 20 minutes. Melphalan is administered at 2-week intervals
for 4 doses, then, after adequate recovery from toxicity, at
4-week intervals. Available evidence suggests about one third to one
half of the patients with multiple myeloma show a favorable response
to the drug. Experience with oral melphalan suggests that repeated
courses should be given since improvement may continue slowly over
many months, and the maximum benefit may be missed if treatment is
abandoned prematurely. Dose adjustment onthe basis of blood cell
counts at the nadir and day of treatment should be considered.<br/>Administration Precautions: As with other toxic compounds, caution should be
exercised in handling and preparing the solution of ALKERAN. Skin
reactions associated with accidental exposure may occur. The use of
gloves is recommended. If the solution of ALKERAN contacts the skin
or mucosa, immediately wash the skin or mucosa thoroughly with soap
and water. Procedures for proper handling
and disposal of anticancer drugs should be considered. Several guidelines
on this subject have been published.There is no general
agreement that all of the procedures recommended in the guidelines
are necessary or appropriate. Parenteral
drug products should be visually inspected for particulate matter
and discoloration prior to administration whenever solution and container
permit. If either occurs, do not use this product. Care should be taken to avoid possible extravasation of melphalan
and in cases of poor peripheral venous access, consideration should
be given to use of a central venous line (see WARNINGS).<br/>Preparation for Administration/Stability: The time between reconstitution/dilution
and administration of ALKERAN should be kept to a minimum because
reconstituted and diluted solutions of ALKERAN are unstable. Over as short a time as 30 minutes, a citrate derivative of
melphalan has been detected in reconstituted material from the reaction
of ALKERAN with Sterile Diluent for ALKERAN. Upon further dilution
with saline, nearly 1% label strength of melphalan hydrolyzes every
10 minutes. A precipitate forms if
the reconstituted solution is stored at 5��C. DO NOT REFRIGERATE
THE RECONSTITUTED PRODUCT.
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dailymed-instance:descripti... |
Melphalan, also known as L-phenylalanine mustard,
phenylalanine mustard, L-PAM, or L-sarcolysin, is a phenylalanine
derivative of nitrogen mustard. Melphalan is a bifunctional alkylating
agent that is active against selected human neoplastic diseases. It
is known chemically as 4-[bis(2-chloroethyl)amino]-L-phenylalanine. The molecular formula
is CHClNOand the molecular weight is 305.20. The structural formula is: Melphalan is the active L-isomer of the compound and
was first synthesized in 1953 by Bergel and Stock; the D-isomer, known
as medphalan, is less active against certain animal tumors, and the
dose needed to produce effects on chromosomes is larger than that
required with the L-isomer. The racemic (DL-) form is known as merphalan
or sarcolysin. Melphalan is practically
insoluble in water and has a pKaof���2.5. ALKERAN for Injection is supplied as a sterile, nonpyrogenic,
freeze-dried powder. Each single-use vial contains melphalan hydrochloride
equivalent to 50 mg melphalan and 20 mg povidone. ALKERAN
for Injection is reconstituted using the sterile diluent provided.
Each vial of sterile diluent contains sodium citrate 0.2 g, propylene
glycol 6.0 mL, ethanol (96%) 0.52 mL, and Water for Injection
to a total of 10 mL. ALKERAN for Injection is administered intravenously.
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dailymed-instance:clinicalP... |
Melphalan is an alkylating agent of the bischloroethylamine
type. As a result, its cytotoxicity appears to be related to the extent
of its interstrand cross-linking with DNA, probably by binding at
the Nposition of guanine. Like other bifunctional alkylating
agents, it is active against both resting and rapidly dividing tumor
cells.<br/>Pharmacokinetics: The pharmacokinetics of melphalan after IV administration
has been extensively studied in adult patients. Following injection,
drug plasma concentrations declined rapidly in a biexponential manner
with distribution phase and terminal elimination phase half-lives
of approximately 10 and 75 minutes, respectively. Estimates of
average total body clearance varied among studies, but typical values
of approximately 7 to 9 mL/min/kg (250 to 325 mL/min/m) were observed. One study has reported that on repeat dosing
of 0.5 mg/kg every 6 weeks, the clearance of melphalan decreased
from 8.1 mL/min/kg after the first course, to 5.5 mL/min/kg
after the third course, but did not decrease appreciably after the
third course. Mean (��SD) peak melphalan plasma concentrations
in myeloma patients given IV melphalan at doses of 10 or 20 mg/mwere 1.2��0.4 and 2.8��1.9 mcg/mL,
respectively. The steady-state volume of
distribution of melphalan is 0.5 L/kg. Penetration into cerebrospinal
fluid (CSF) is low. The extent of melphalan binding to plasma proteins
ranges from 60% to 90%. Serum albumin is the major binding protein,
while��-acid glycoprotein appears to account for
about 20% of the plasma protein binding. Approximately 30% of the
drug is (covalently) irreversibly bound to plasma proteins. Interactions
with immunoglobulins have been found to be negligible. Melphalan is eliminated from plasma primarily by chemical
hydrolysis to monohydroxymelphalan and dihydroxymelphalan. Aside from
these hydrolysis products, no other melphalan metabolites have been
observed in humans. Although the contribution of renal elimination
to melphalan clearance appears to be low, one study noted an increase
in the occurrence of severe leukopenia in patients with elevated BUN
after 10 weeks of therapy.<br/>Clinical Trial: A randomized trial compared prednisone plus IV melphalan
to prednisone plus oral melphalan in the treatment of myeloma. As
discussed below, overall response rates at week 22 were comparable;
however, because of changes in trial design, conclusions as to the
relative activity of the 2 formulations after week 22 are impossible
to make. Both arms received oral prednisone
starting at 0.8 mg/kg/day with doses tapered over 6 weeks.
Melphalan doses in each arm were: Arm 1Oral
melphalan 0.15 mg/kg/day x 7 followed by 0.05 mg/kg/day
when WBC began to rise. Arm 2IV melphalan
16 mg/mq 2 weeks x 4 (over 6 weeks) followed
by the same dose every 4 weeks. Doses
of melphalan were adjusted according to the following criteria: One hundred seven patients were randomized
to the oral melphalan arm and 203 patients to the IV melphalan
arm. More patients had a poor-risk classification (58% versus 44%)
and high tumor load (51% versus 34%) on the oral compared to the IV
arm (P<0.04). Response rates
at week 22 are shown in the following table: Because of changes in protocol design after
week 22, other efficacy parameters such as response duration
and survival cannot be compared. Severe
myelotoxicity (WBC���1,000 and/or platelets���25,000)
was more common in the IV melphalan arm (28%) than in the oral melphalan
arm (11%). An association was noted between
poor renal function and myelosuppression; consequently, an amendment
to the protocol required a 50% reduction in IV melphalan dose if the
BUN was���30 mg/dL. The rate of severe leukopenia in the
IV arm in the patients with BUN over 30 mg/dL decreased from
50% (8/16) before protocol amendment to 11% (3/28) (P = 0.01) after the amendment. Before the dosing amendment, there was a 10% (8/77)
incidence of drug-related death in the IV arm. After the dosing amendment,
this incidence was 3% (3/108). This compares to an overall 1% (1/100)
incidence of drug-related death in the oral arm.
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Melphalan should not be used in patients whose
disease has demonstrated prior resistance to this agent. Patients
who have demonstrated hypersensitivity to melphalan should not be
given the drug.
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dailymed-instance:supply |
ALKERAN for Injection is supplied in a carton
containing one single-use clear glass vial of freeze-dried melphalan
hydrochloride equivalent to 50 mg melphalan and one 10-mL clear
glass vial of sterile diluent (NDC 59572-301-01). Store at controlled room temperature
15��to 30��C (59��to 86��F) and protect from light.
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dailymed-instance:boxedWarn... |
WARNING: Melphalan should be administered under the supervision
of a qualified physician experienced in the use of cancer chemotherapeutic
agents. Severe bone marrow suppression with resulting infection or
bleeding may occur. Controlled trials comparing intravenous (IV) to
oral melphalan have shown more myelosuppression with the IV formulation.
Hypersensitivity reactions, including anaphylaxis, have occurred in
approximately 2%of patients who received the IV formulation. Melphalan
is leukemogenic in humans. Melphalan produces chromosomal aberrations
in vitro and in vivo and, therefore, should be considered potentially
mutagenic in humans.
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dailymed-instance:precautio... |
General: In all instances where the use of ALKERAN for Injection
is considered for chemotherapy, the physician must evaluate the need
and usefulness of the drug against the risk of adverse events. Melphalan
should be used with extreme caution in patients whose bone marrow
reserve may have been compromised by prior irradiation or chemotherapy
or whose marrow function is recovering from previous cytotoxic therapy. Dose reduction should be considered in patients with
renal insufficiency receiving IV melphalan. In one trial, increased
bone marrow suppression was observed in patients with BUN levels���30 mg/dL.
A 50% reduction in the IV melphalan dose decreased the incidence of
severe bone marrow suppression in the latter portion of this study. Administration of live vaccines to immunocompromised
patients should be avoided.<br/>Information for Patients: Patients should be informed that the major acute
toxicities of melphalan are related to bone marrow suppression, hypersensitivity
reactions, gastrointestinal toxicity, and pulmonary toxicity. The
major long-term toxicities are related to infertility and secondary
malignancies. Patients should never be allowed to take the drug without
close medical supervision and should be advised to consult their physicians
if they experience skin rash, signs or symptoms of vasculitis, bleeding,
fever, persistent cough, nausea, vomiting, amenorrhea, weight loss,
or unusual lumps/masses. Women of childbearing potential should be
advised to avoid becoming pregnant.<br/>Laboratory Tests: Periodic complete blood counts with differentials
should be performed during the course of treatment with melphalan.
At least 1 determination should be obtained prior to each dose. Patients
should be observed closely for consequences of bone marrow suppression,
which include severe infections, bleeding, and symptomatic anemia
(see WARNINGS).<br/>Drug Interactions: The development of severe renal failure has been
reported in patients treated with a single dose of IV melphalan followed
by standard oral doses of cyclosporine. Cisplatin may affect melphalan
kinetics by inducing renal dysfunction and subsequently altering melphalan
clearance. IV melphalan may also reduce the threshold for BCNU lung
toxicity. When nalidixic acid and IV melphalan are given simultaneously,
the incidence of severe hemorrhagic necrotic enterocolitis has been
reported to increase in pediatric patients.<br/>Carcinogenesis, Mutagenesis,
Impairment of Fertility: See WARNINGS section.<br/>Pregnancy:<br/>Teratogenic Effects: Pregnancy Category D: See WARNINGS section.<br/>Nursing Mothers: It is not known whether this drug is excreted in
human milk. IV melphalan should not be given to nursing mothers.<br/>Pediatric Use: The safety and effectiveness in pediatric patients
have not been established.<br/>Geriatric Use: Clinical studies of ALKERAN for Injection did not
include sufficient numbers of subjects aged 65 and over to determine
whether they respond differently from younger subjects. Other reported
clinical experience has not identified differences in responses between
the elderly and younger patients. In general, dose selection for an
elderly patient should be cautious, usually starting at the low end
of the dosing range, reflecting the greater frequency of decreased
hepatic, renal, or cardiac function, and of concomitant disease or
other drug therapy.
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dailymed-instance:overdosag... |
Overdoses resulting in death have been reported.
Overdoses, including doses up to 290 mg/m, have produced
the following symptoms: severe nausea and vomiting, decreased consciousness,
convulsions, muscular paralysis, and cholinomimetic effects. Severe
mucositis, stomatitis, colitis, diarrhea, and hemorrhage of the gastrointestinal
tract occur at high doses (>100 mg/m). Elevations
in liver enzymes and veno-occlusive disease occur infrequently. Significant
hyponatremia caused by an associated inappropriate secretion of ADH
syndrome has been observed. Nephrotoxicity and adult respiratory distress
syndrome have been reported rarely. The principal toxic effect is
bone marrow suppression. Hematologic parameters should be closely
followed for 3 to 6 weeks. An uncontrolled study suggests that
administration of autologous bone marrowor hematopoietic growth factors
(i.e., sargramostim, filgrastim) may shorten the period of pancytopenia.
General supportive measures together with appropriate blood transfusions
and antibiotics should be instituted as deemed necessary by the physician.
This drug is not removed from plasma to any significant degree byhemodialysis or hemoperfusion. A pediatric patient survived a 254-mg/moverdose treated with standard supportive care.
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dailymed-instance:genericMe... |
melphalan hydrochloride
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dailymed-instance:fullName |
ALKERAN (Kit)
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dailymed-instance:warning |
ALKERAN for Injection may cause local tissue damage
should extravasation occur, and consequently it should not be administered
by direct injection into a peripheral vein. It is recommended that
ALKERAN for Injection be administered by injecting slowly into a fast-running
IV infusion via an injection port, or via a central venous line (see
DOSAGE AND ADMINISTRATION: Administration Precautions). Melphalan should be administered
in carefully adjusted dosage by or under the supervision of experienced
physicians who are familiar with the drug's actions and the possible
complications of its use. As with
other nitrogen mustard drugs, excessive dosage will produce marked
bone marrow suppression. Bone marrow suppression is the most significant
toxicity associated with ALKERAN for Injection in most patients. Therefore,
the following tests should be performed at the start of therapy and
prior to each subsequent dose of ALKERAN: platelet count, hemoglobin,
white blood cell count, and differential. Thrombocytopenia and/or
leukopenia are indications towithhold further therapy until the blood
counts have sufficiently recovered. Frequent blood counts are essential
to determine optimal dosage and to avoid toxicity. Dose adjustment
on the basis of blood counts at the nadir and day of treatment should
be considered. Hypersensitivity reactions
including anaphylaxis have occurred in approximately 2% of patients
who received the IV formulation (see ADVERSE REACTIONS). These reactions
usually occur after multiple courses of treatment. Treatment is symptomatic.
The infusion should be terminated immediately, followed by the administration
of volume expanders, pressor agents, corticosteroids, or antihistamines
at the discretion of the physician. If a hypersensitivity reaction
occurs, IV or oral melphalan should not be readministered since hypersensitivity
reactions have also been reported with oral melphalan.<br/>Carcinogenesis: Secondary malignancies, including acute nonlymphocytic
leukemia, myeloproliferative syndrome, and carcinoma, have been reported
in patients with cancer treated with alkylating agents (including
melphalan). Some patients also received other chemotherapeutic agentsor radiation therapy. Precise quantitation of the risk of acute leukemia,
myeloproliferative syndrome, or carcinoma is not possible. Published
reports of leukemia in patients who have received melphalan (and other
alkylating agents) suggest that the risk of leukemogenesis increases
with chronicity of treatment and with cumulative dose. In one study,
the 10-year cumulative risk of developing acute leukemia or myeloproliferative
syndrome after oral melphalan therapy was 19.5% for cumulative doses
ranging from 730 to 9,652 mg. In this same study, as well as
in an additional study, the 10-year cumulative risk of developing
acute leukemia or myeloproliferative syndrome after oral melphalan
therapy was less than 2% for cumulative doses under 600 mg. This
does not mean that there is a cumulative dose below which there is
no risk of the induction of secondary malignancy. The potential benefits
from melphalan therapy must be weighed on an individual basis against
the possible risk of the induction of a second malignancy. Adequate and well-controlled carcinogenicity studies
have not been conducted in animals. However, intraperitoneal (IP)
administration of melphalan in rats (5.4 to 10.8 mg/m) and in mice (2.25 to 4.5 mg/m) 3 times per
week for 6 months followed by 12 months post-dose observation
produced peritoneal sarcoma and lung tumors, respectively.<br/>Mutagenesis: Melphalan has been shown to cause chromatid or chromosome
damage in humans. Intramuscular administration of melphalan at 6 and
60 mg/mproduced structural aberrations of the chromatid
and chromosomes in bone marrow cells of Wistar rats.<br/>Impairment of Fertility: Melphalan causes suppression of ovarian function
in premenopausal women, resulting in amenorrhea in a significant number
of patients. Reversible and irreversible testicular suppression have
also been reported.<br/>Pregnancy: Pregnancy Category D. Melphalan may cause fetal harm when administered to a
pregnant woman. While adequate animal studies have not been conducted
with IV melphalan, oral (6 to 18 mg/m/day for 10 days)
and IP (18 mg/m) administration in rats was embryolethal
and teratogenic. Malformations resulting from melphalan included alterations
of the brain (underdevelopment, deformation, meningocele, and encephalocele)
and eye (anophthalmia and microphthalmos), reduction of the mandible
and tail, as well as hepatocele (exomphaly). There are no adequate
and well-controlled studies in pregnant women. If this drug is used
during pregnancy, or if the patient becomes pregnant while taking
this drug, the patient should be apprised of the potential hazard
to the fetus. Women of childbearing potential should be advised to
avoid becoming pregnant.
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dailymed-instance:indicatio... |
ALKERAN for Injection is indicated for the palliative
treatment of patients with multiple myeloma for whom oral therapy
is not appropriate.
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dailymed-instance:name |
ALKERAN
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