Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/2671
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ALKERAN (Tablet)
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dailymed-instance:dosage |
Multiple Myeloma: The usual oral
dose is 6 mg (3 tablets) daily. The entire daily dose may
be given at one time. The dose is adjusted, as required, on the basis
of blood counts done at approximately weekly intervals. After 2 to
3 weeks of treatment, the drug should be discontinued for up
to 4 weeks, during which time the blood count should be followed
carefully. When the white blood cell and platelet counts are rising,
a maintenance dose of 2 mg daily may be instituted. Because of
the patient-to-patient variation in melphalan plasma levels following
oral administration of the drug, several investigators have recommended
that the dosage of ALKERAN be cautiously escalated until some myelosuppression
is observed in order to assure that potentially therapeutic levels
of the drug have been reached. Other dosage
regimens have been used by various investigators. Osserman and Takatsuki
have used an initial course of 10 mg/day for 7 to 10 days.
They report that maximal suppression of the leukocyte and platelet
counts occurs within 3 to 5 weeks and recovery within 4 to 8 weeks.
Continuous maintenance therapy with 2 mg/day is instituted when
the white blood cell count is greater than 4,000 cells/mcL and
the platelet count is greater than 100,000 cells/mcL. Dosage
is adjusted to between 1 and 3 mg/day depending upon the hematological
response. It is desirable to try to maintain a significant degree
of bone marrow depression so as to keep the leukocyte count in the
range of 3,000 to 3,500 cells/mcL. Hoogstraten
et al have started treatment with 0.15 mg/kg/day for 7 days.
This is followed by a rest period of at least 14 days, but it
may be as long as 5 to 6 weeks. Maintenance therapy is started
when the white blood cell and platelet counts are rising. The maintenance
dose is 0.05 mg/kg/day or less and is adjusted according to the
blood count. Available evidence suggests
that about one third to one half of the patients with multiple myeloma
show a favorable response to oral administration of the drug. One study by Alexanian et al has shown that the use
of ALKERAN in combination with prednisone significantly improves the
percentage of patients with multiple myeloma who achieve palliation.
One regimen has been to administer courses of ALKERAN at 0.25 mg/kg/day
for 4 consecutive days (or, 0.20 mg/kg/day for 5 consecutive
days) for a total dose of 1 mg/kg/course. These 4- to 5-day courses
are then repeated every 4 to 6 weeks if the granulocyte count
and the platelet count have returned to normal levels. It is to be emphasized that response may be very gradual
over many months; it is important that repeated courses or continuous
therapy be given since improvement may continue slowly over many months,
and the maximum benefit may be missed if treatment is abandoned too
soon. In patients with moderate to severe
renal impairment, currently available pharmacokinetic data do not
justify an absolute recommendation on dosage reduction to those patients,
but it may be prudent to use a reduced dose initially.<br/>Epithelial Ovarian Cancer: One commonly employed regimen for the treatment
of ovarian carcinoma has been to administer ALKERAN at a dose of 0.2 mg/kg
daily for 5 days as a single course. Courses are repeated every
4 to 5 weeks depending upon hematologic tolerance.<br/>Administration Precautions: 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.
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dailymed-instance:descripti... |
ALKERAN (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 which is active against selective 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
(melphalan) is available in tablet form for oral administration. Each
film-coated tablet contains 2 mg melphalan and the inactive ingredients
colloidal silicon dioxide, crospovidone, hypromellose, macrogol/PEG 400,
magnesium stearate, microcrystalline cellulose, and titanium dioxide.
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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 ALKERAN after oral administration
has been extensively studied in adult patients. Plasma melphalan levels
are highly variable after oral dosing, both with respect to the time
of the first appearance of melphalan in plasma (range approximately
0 to 6 hours) and to the peak plasma concentration (C) (range 70 to 4,000 ng/mL, depending upon the dose) achieved.
These results may be due to incomplete intestinal absorption, a variable���first pass���hepatic metabolism, or to rapid hydrolysis.
Five patients were studied after both oral and intravenous (IV) dosing
with 0.6 mg/kg as a single bolus dose by each route. The areas
under the plasma concentration-time curves (AUC) after oral administration
averaged 61%��26% (��standard deviation
[SD]; range 25% to 89%) of those following IV administration. In 18 patients
given a single oral dose of 0.6 mg/kg of ALKERAN, the terminal
elimination plasma half-life (t) of parent drug was
1.5��0.83 hours. The 24-hour urinary excretion
of parent drug in these patients was 10%��4.5%, suggesting
that renal clearance is not a major route of elimination of parent
drug. In a separate study in 18 patients given single oral doses
of 0.2 to 0.25 mg/kg of ALKERAN, Cand AUC, when
dose adjusted to a dose of 14 mg, were (mean��SD) 212��74 ng/mL
and 498��137 ng���hr/mL, respectively. Elimination
phase tin these patients was approximately 1 hour
and the median twas 1 hour. One study using universally labeledC-melphalan,
found substantially less radioactivity in the urine of patients given
the drug by mouth (30% of administered dose in 9 days) than in
the urine of those given it intravenously (35% to 65% in 7 days).
Following either oral or IV administration, the pattern of label recovery
was similar, with the majority being recovered in the first 24 hours.
Following oral administration, peak radioactivity occurred in plasma
at 2 hours and then disappeared with a half-life of approximately
160 hours. In 1 patient where parent drug (rather than just radiolabel)
wasdetermined, the melphalan half-disappearance time was 67 minutes. 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 melphalan 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
pharmacokinetic study showed a significant positive correlation between
the elimination rate constant for melphalan and renal function and
a significant negative correlation between renal function and the
area under the plasma melphalan concentration/time curve.
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dailymed-instance:contraind... |
ALKERAN should not be used in patients whose
disease has demonstrated a 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 is supplied
as white, film-coated, round, biconvex tablets containing 2 mg
melphalan in amber glass bottles with child-resistant closures. One
side is engraved with���GX EH3���and the other side is
engraved with an���A.��� Bottle
of 50 (NDC 59572-302-50). Store in a refrigerator, 2��to 8��C (36��to 46��F).Protect from light.
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dailymed-instance:genericDr... | |
dailymed-instance:boxedWarn... |
WARNING: ALKERAN (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. 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 is considered
for chemotherapy, the physician must evaluate the need and usefulness
of the drug against the risk of adverse events. ALKERAN 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. If
the leukocyte count falls below 3,000 cells/mcL, or the platelet
count below 100,000 cells/mcL, ALKERAN should be discontinued
until the peripheral blood cell counts have recovered. A recommendation as to whether or not dosage reduction
should be made routinely in patients with renal insufficiency cannot
be made because: Patients with azotemia should be closely observed,
however, in order to make dosage reductions, if required, at the earliest
possible time. Administration of live vaccines
to immunocompromised patients should be avoided.<br/>Information for Patients: Patients should be informed that the major toxicities
of ALKERAN 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 physician
if they experience skin rash, 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 ALKERAN. At
least one determination should be obtained prior to each treatment
course. Patients should be observed closely for consequences of bone
marrow suppression, which include severe infections, bleeding, and
symptomatic anemia (see WARNINGS).<br/>Drug Interactions: There are no known drug/drug interactions with oral
ALKERAN.<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. ALKERAN should not be given to nursing mothers.<br/>Pediatric Use: The safety and effectiveness of ALKERAN in pediatric
patients have not been established.<br/>Geriatric Use: Clinical studies
of ALKERAN Tablets 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, including doses up to 50 mg/day
for 16 days, have been reported. Immediate effects are likely
to be vomiting, ulceration of the mouth, diarrhea, and hemorrhage
of the gastrointestinal tract. 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 marrow or hematopoietic growth factors (i.e., sargramostim,
filgrastim) may shorten the period of pancytopenia. General supportive
measures, together with appropriateblood transfusions and antibiotics,
should be instituted as deemed necessary by the physician. This drug
is not removed from plasma to any significant degree by hemodialysis.
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dailymed-instance:genericMe... |
melphalan
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dailymed-instance:fullName |
ALKERAN (Tablet)
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dailymed-instance:adverseRe... |
Hematologic: The most common
side effect is bone marrow suppression leading to leukopenia, thrombocytopenia,
and anemia. Although bone marrow suppression frequently occurs, it
is usually reversible if melphalan is withdrawn early enough. However,
irreversible bone marrow failure has been reported.<br/>Gastrointestinal: Nausea, vomiting,
diarrhea, and oral ulceration occur. Hepatic disorders ranging from
abnormal liver function tests to clinical manifestations such as hepatitis
and jaundice have been reported.<br/>Miscellaneous: Other reported adverse reactions include: pulmonary
fibrosis (including fatal outcomes) and interstitial pneumonitis,
skin hypersensitivity, maculopapular rashes, vasculitis, alopecia,
and hemolytic anemia. Allergic reactions, including urticaria, edema,
skin rashes, and rare anaphylaxis, have occurred after multiple courses
of treatment. Cardiac arrest has also been reported rarely in association
with such reports.
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dailymed-instance:warning |
ALKERAN 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 in most patients. Therefore, the
following tests should be performed at the start of therapy and prior
to each subsequent course of ALKERAN: platelet count, hemoglobin,
white blood cell count, and differential. Thrombocytopenia and/or
leukopenia are indications to withhold further therapy until the blood
counts have sufficiently recovered. Frequent blood counts are essential
to determine optimal dosage and to avoid toxicity (see PRECAUTIONS:
Laboratory Tests). Dose adjustment on the basis of blood counts at
the nadir and day of treatment should be considered. Hypersensitivity reactions, including anaphylaxis, have occurred
rarely (see ADVERSE REACTIONS). These reactions have occurred after
multiple courses of treatment and have recurred in patients who experienced
a hypersensitivity reaction to IV ALKERAN. If a hypersensitivity reaction
occurs, oral or IV ALKERAN should not be readministered.<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 agents
or 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 melphalan therapy was 19.5% for cumulative doses ranging
from 730 mg 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 melphalan therapy
was less than 2% for cumulative doses under 600 mg. This does
not meanthat 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, i.p. 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: ALKERAN has been shown to cause chromatid or chromosome
damage in humans. Intramuscular administration of ALKERAN at 6 and
60 mg/mproduced structural aberrations of the chromatid
and chromosomes in bone marrow cells of Wistar rats.<br/>Impairment of Fertility: ALKERAN 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. ALKERAN may cause fetal harm when administered to a pregnant
woman. Melphalan was embryolethal and teratogenic in rats following
oral (6 to 18 mg/m/day for 10 days) and intraperitoneal
(18 mg/m) administration. 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 Tablets are indicated for the palliative
treatment of multiple myeloma and for the palliation of non-resectable
epithelial carcinoma of the ovary.
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dailymed-instance:name |
ALKERAN
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