DESCRIPTION:
Albend (albendazole) is an orally administered broad-spectrum anthelmintic.
Chemically it is Methyl 5-(propylthio)-2-benzimidazolecarbamate. Its molecular
formula is C12H15N3O2S. Its molecular weight is 265.34.
albendazole
Albendazole is a white to off-white powder. It is soluble in dimethylsulfoxide,
strong acids and strong bases. It is slightly soluble in methanol, chloroform,
ethyl acetate and acetonitrile. Albendazole is practically insoluble in water.
Each white to off-white, film-coated tablet contains 200 mg of albendazole.
Inactive ingredients consist of: carnauba wax, hydroxypropyl methylcellulose,
lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone,
sodium lauryl sulfate, sodium saccharin, sodium starch glycolate, and starch.
ACTIONS/CLINICAL PHARMACOLOGY:
PHARMACOKINETICS
ABSORPTION AND METABOLISM
Albendazole is poorly absorbed from the gastrointestinal tract due to its low
aqueous solubility. Albendazole concentrations are negligible or undetectable in
plasma as it is rapidly converted to the sulfoxide metabolite prior to reaching
the systemic circulation. The systemic anthelmintic activity has been attributed
to the primary metabolite, albendazole sulfoxide. Oral bioavailability appears
to be enhanced when albendazole is coadministered with a fatty meal (estimated
fat content 40 g) as evidenced by higher (up to 5-fold on average) plasma
concentrations of albendazole sulfoxide as compared to the fasted state.
Maximal plasma concentrations of albendazole sulfoxide are typically achieved 2
to 5 hours after dosing and are on average 1.31 mcg/mL (range 0.46 to 1.58
mcg/mL) following oral doses of albendazole (400 mg) in six hydatid disease
patients, when administered with a fatty meal. Plasma concentrations of
albendazole sulfoxide increase in a dose-proportional manner over the
therapeutic dose range following ingestion of a fatty meal (fat content 43.1 g).
The mean apparent terminal elimination half-life of albendazole sulfoxide
typically ranges from 8 to 12 hours in twenty-five normal subjects, as well as
in fourteen hydatid and eight neurocysticercosis patients.
Following 4 weeks of treatment with albendazole (200 mg three times daily),
twelve patients' plasma concentrations of albendazole sulfoxide were
approximately 20% lower than those observed during the first half of the
treatment period, suggesting that albendazole may induce its own metabolism.
DISTRIBUTION
Albendazole sulfoxide is 70% bound to plasma protein and is widely distributed
throughout the body; it has been detected in urine, bile, liver, cyst wall, cyst
fluid, and cerebral spinal fluid (CSF). Concentrations in plasma were 3- to 10-
fold and 2- to 4-fold higher than those simultaneously determined in cyst fluid
and CSF, respectively. Limited In Vitro and clinical data suggest that
albendazole sulfoxide may be eliminated from cysts at a slower rate than
observed in plasma.
METABOLISM AND EXCRETION
Albendazole is rapidly converted in the liver to the primary metabolite,
albendazole sulfoxide, which is further metabolized to albendazole sulfone and
other primary oxidative metabolites that have been identified in human urine.
Following oral administration, albendazole has not been detected in human urine.
Urinary excretion of albendazole sulfoxide is a minor elimination pathway with
less than 1% of the dose recovered in the urine. Biliary elimination presumably
accounts for a portion of the elimination as evidenced by biliary concentrations
of albendazole sulfoxide similar to those achieved in plasma.
SPECIAL POPULATIONS
PATIENTS WITH IMPAIRED RENAL FUNCTION: The pharmacokinetics of albendazole in
patients with impaired renal function have not been studied. However, since
renal elimination of albendazole and its primary metabolite, albendazole
sulfoxide, is negligible, it is unlikely that clearance of these compounds would
be altered in these patients.
BILIARY EFFECTS: In patients with evidence of extrahepatic obstruction (n=5),
the systemic availability of albendazole sulfoxide was increased, as indicated
by a 2-fold increase in maximum serum concentration and a 7-fold increase in
area under the curve. The rate of absorption/conversion and elimination of
albendazole sulfoxide appeared to be prolonged with mean Tmax and serum
elimination half-life values of 10 hours and 31.7 hours, respectively. Plasma
concentrations of parent albendazole were measurable in only one of five
patients.
PEDIATRICS: Following single-dose administration of 200 mg to 300 mg
(approximately 10 mg/kg) albendazole to three fasted and two fed pediatric
patients with hydatid cyst disease (age range 6 to 13 years), albendazole
sulfoxide pharmacokinetics were similar to those observed in fed adults.
ELDERLY PATIENTS: Although no studies have investigated the effect of age on
albendazole sulfoxide pharmacokinetics, data in twenty-six hydatid cyst patients
(up to 79 years) suggest pharmacokinetics similar to those in young healthy
subjects.
MICROBIOLOGY
The principal mode of action for albendazole is by its inhibitory effect on
tubulin polymerization which results in the loss of cytoplasmic microtubules.
In the specified treatment indications albendazole appears to be active against
the larval forms of the following organisms:
Echinococcus Granulosus
Taenia Solium
INDICATIONS AND USAGE:
Albend (albendazole) is indicated for the treatment of the following
infections:
NEUROCYSTICERCOSIS. Albend is indicated for the treatment of parenchymal
neurocysticercosis due to active lesions caused by larval forms of the pork
tapeworm, Taenia Solium.
Lesions considered responsive to albendazole therapy appear as nonenhancing
cysts with no surrounding edema on contrast-enhanced computerized tomography.
Clinical studies in patients with lesions of this type demonstrate a 74% to 88%
reduction in number of cysts; 40% to 70% of albendazole-treated patients showed
resolution of all active cysts.
HYDATID DISEASE. Albend is indicated for the treatment of cystic hydatid
disease of the liver, lung, and peritoneum, caused by the larval form of the dog
tapeworm, Echinococcus Granulosus.
This indication is based on combined clinical studies which demonstrated non-
infectious cyst contents in approximately 80-90% of patients given Albend for 3
cycles of therapy of 28 days each. (See DOSAGE AND ADMINISTRATION.) Clinical
cure (disappearance of cysts) was seen in approximately 30% of these patients,
and improvement (reduction in cyst diameter of >/=25%) was seen in an additional
40%.
NOTE: When medically feasible, surgery is considered the treatment of choice for
hydatid disease. When administering Albend in the pre- or post-surgical
setting, optimal killing of cyst contents is achieved when three courses of
therapy have been given.
NOTE: The efficacy of albendazole in the therapy of alveolar hydatid disease
caused by Echinococcus Multilocularis has not been clearly demonstrated in
clinical studies.
CONTRAINDICATIONS:
Albend (albendazole) is contraindicated in patients with known hypersensitivity
to the benzimidazole class of compounds or any components of Albend.
WARNINGS:
Rare fatalities associated with the use of Albend have been reported due to
granulocytopenia or pancytopenia. (See PRECAUTIONS.) Blood counts should be
monitored at the beginning of each 28-day cycle of therapy, and every 2 weeks
while on therapy with albendazole. Albendazole may be continued if the total
white blood cell count and absolute neutrophil count decrease appear modest and
do not progress.
Albendazole should not be used in pregnant women except in clinical
circumstances where no alternative management is appropriate. Patients should
not become pregnant for at least 1 month following cessation of albendazole
therapy. If a patient becomes pregnant while taking this drug, albendazole
should be discontinued immediately. If pregnancy occurs while taking this drug,
the patient should be apprised of the potential hazard to the fetus.
PRECAUTIONS:
GENERAL: Patients being treated for neurocysticercosis should receive
appropriate steroid and anticonvulsant therapy as required. Oral or intravenous
corticosteroids should be considered to prevent cerebral hypertensive episodes
during the first week of anticysticeral therapy.
Cysticercosis may, in rare cases, involve the retina. Before initiating therapy
for neurocysticercosis, the patient should be examined for the presence of
retinal lesions. If such lesions are visualized, the need for anticysticeral
therapy should be weighed against the possibility of retinal damage caused by
albendazole-induced changes to the retinal lesion.
INFORMATION FOR PATIENTS
Patients should be advised that:
-- Albendazole may cause fetal harm, therefore, women of childbearing age should
begin treatment after a negative pregnancy test.
-- Women of childbearing age should be cautioned against becoming pregnant while
on albendazole or within 1 month of completing treatment.
-- During albendazole therapy, because of the possibility of harm to the liver
or bone marrow, routine (every 2 weeks) monitoring of blood counts and liver
function tests should take place.
-- Albendazole should be taken with food.
LABORATORY TESTS
WHITE BLOOD CELL COUNT: Albendazole has been shown to cause occasional (less
than 1% of treated patients) reversible reductions in total white blood cell
count. Rarely, more significant reductions may be encountered including
granulocytopenia, agranulocytosis, or pancytopenia. Blood counts should be
performed at the start of each 28-day treatment cycle and every 2 weeks during
each 28-day cycle. Albendazole may be continued if the total white blood cell
count decrease appears modest and does not progress.
LIVER FUNCTION: In clinical trials, treatment with albendazole has been
associated with mild to moderate elevations of hepatic enzymes in approximately
16% of patients. These have returned to normal upon discontinuation of therapy.
Liver function tests (transaminases) should be performed before the start of
each treatment cycle and at least every 2 weeks during treatment. If enzymes are
significantly increased, albendazole therapy should be discontinued. Therapy can
be reinstituted when liver enzymes have returned to pretreatment levels, but
laboratory tests should be performed frequently during repeat therapy.
Patients with abnormal liver function test results prior to commencing
albendazole therapy should be carefully evaluated, since the drug is metabolized
by the liver and has been associated with hepatotoxicity in a few patients.
THEOPHYLLINE: Although single doses of albendazole have been shown not to
inhibit theophylline metabolism (see DRUG INTERACTIONS), albendazole does induce
cytochrome P450 1A in human hepatoma cells. Therefore, it is recommended that
plasma concentrations of theophylline be monitored during and after treatment
with Albend (albendazole).
DRUG INTERACTIONS
Dexamethasone: Steady-state trough concentrations of albendazole sulfoxide were
about 56% higher when 8 mg dexamethasone was coadministered with each dose of
albendazole (15 mg/kg/day) in eight neurocysticercosis patients.
Praziquantel: In the fed state, praziquantel (40 mg/kg) increased mean maximum
plasma concentration and area under the curve of albendazole sulfoxide by about
50% in healthy subjects (n=10) compared with a separate group of subjects (n=6)
given albendazole alone. Mean Tmax and mean plasma elimination half-life of
albendazole sulfoxide were unchanged. The pharmacokinetics of praziquantel were
unchanged following coadministration with albendazole (400 mg).
Cimetidine: Albendazole sulfoxide concentrations in bile and cystic fluid were
increased (about 2-fold) in hydatid cyst patients treated with cimetidine (10
mg/kg/day) (n=7) compared with albendazole (20 mg/kg/day) alone (n=12).
Albendazole sulfoxide plasma concentrations were unchanged 4 hours after dosing.
Theophylline: The pharmacokinetics of theophylline (aminophylline 5.8 mg/kg
infused over 20 minutes) were unchanged following a single oral dose of
albendazole (400 mg) in 6 healthy subjects.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
Long-term carcinogenicity studies were conducted in mice and rats. In the mouse
study, albendazole was administered in the diet at doses of 25, 100 and 400
mg/kg/day (0.1, 0.5, and 2 times the recommended human dose based on body
surface area in mg/M(squared), respectively) for 108 weeks. In the rat study,
albendazole was administered in the diet at doses of 3.5, 7, and 20 mg/kg/day
(0.04, 0.08, and 0.21 times the recommended human dose based on body surface
area in mg/M(squared), respectively) for 117 weeks. There was no evidence of
increased incidence of tumors in the treated mice and rats when compared to the
control group.
In genotoxicity tests, albendazole was found negative in an Ames
Salmonella/Microsome Plate mutation assay with and without metabolic activation
or with and without pre-incubation, cell-mediated Chinese Hamster Ovary
chromosomal aberration test and In Vivo mouse micronucleus test. In the In Vitro
BALB/3T3 cells transformation assay, albendazole produced weak activity in the
presence of metabolic activation while no activity was found in the absence of
metabolic activation.
Albendazole did not adversely affect male or female fertility in the rat at an
oral dose of 30mg/kg/day (0.32 times the recommended human dose based on body
surface area in mg/M(squared)).
PREGNANCY
TERATOGENIC EFFECTS--PREGNANCY CATEGORY C: Albendazole has been shown to be
teratogenic (to cause embryotoxicity and skeletal malformations) in pregnant
rats and rabbits. The teratogenic response in the rat was shown at oral doses of
10 and 30 mg/kg/day (0.10 times and 0.32 times the recommended human dose based
on body surface area in mg/M(squared), respectively) during gestation days 6 to
15 and in pregnant rabbits at oral doses of 30 mg/kg/day (0.60 times the
recommended human dose based on body surface area in mg/M(squared)) administered
during gestation days 7 to 19. In the rabbit study, maternal toxicity (33%
mortality) was noted at 30 mg/kg/day. In mice, no teratogenic effects were
observed at oral doses up to 30 mg/kg/day (0.16 times the recommended human dose
based on body surface area in mg/M(squared)), administered during gestation days
6 to 15.
There are no adequate and well-controlled studies of albendazole administration
in pregnant women. Albendazole should be used during pregnancy only if the
potential benefit justifies the potential risk to the fetus. (See WARNINGS.)
NURSING MOTHERS: Albendazole is excreted in animal milk. It is not known whether
it is excreted in human milk. Because many drugs are excreted in human milk,
caution should be exercised when albendazole is administered to a nursing woman.
PEDIATRIC USE: Experience in children under the age of 6 years is limited. In
hydatid disease, infection in infants and young children is uncommon, but no
problems have been encountered in those who have been treated. In
neurocysticercosis, infection is more frequently encountered. In five published
studies involving pediatric patients as young as 1 year, no significant problems
were encountered, and the efficacy appeared similar to the adult population.
GERIATRIC USE: Experience in patients 65 years of age or older is limited. The
number of patients treated for either hydatid disease or neurocysticercosis is
limited, but no problems associated with an older population have been observed.
DRUG INTERACTIONS:
Dexamethasone: Steady-state trough concentrations of albendazole sulfoxide were
about 56% higher when 8 mg dexamethasone was coadministered with each dose of
albendazole (15 mg/kg/day) in eight neurocysticercosis patients.
Praziquantel: In the fed state, praziquantel (40 mg/kg) increased mean maximum
plasma concentration and area under the curve of albendazole sulfoxide by about
50% in healthy subjects (n=10) compared with a separate group of subjects (n=6)
given albendazole alone. Mean Tmax and mean plasma elimination half-life of
albendazole sulfoxide were unchanged. The pharmacokinetics of praziquantel were
unchanged following coadministration with albendazole (400 mg).
Cimetidine: Albendazole sulfoxide concentrations in bile and cystic fluid were
increased (about 2-fold) in hydatid cyst patients treated with cimetidine (10
mg/kg/day) (n=7) compared with albendazole (20 mg/kg/day) alone (n=12).
Albendazole sulfoxide plasma concentrations were unchanged 4 hours after dosing.
Theophylline: The pharmacokinetics of theophylline (aminophylline 5.8 mg/kg
infused over 20 minutes) were unchanged following a single oral dose of
albendazole (400 mg) in 6 healthy subjects.
(See Also PRECAUTIONS)
ADVERSE REACTIONS:
The adverse event profile of albendazole differs between hydatid disease and
neurocysticercosis. Adverse events occurring with a frequency of >/=1% in either
disease are described in the table below.
These symptoms were usually mild and resolved without treatment. Treatment
discontinuations were predominantly due to leukopenia (0.7%) or hepatic
abnormalities (3.8% in hydatid disease). The following incidence reflects events
that were reported by investigators to be at least possibly or probably related
to albendazole.
ADVERSE EVENT INCIDENCE >/=1% IN HYDATID DISEASE AND NEUROCYSTICERCOSIS
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ADVERSE EVENT HYDATID DISEASE NEUROCYSTI-CERCOSIS
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Abnormal Liver
Function Tests 15.6 <1.0
Abdominal Pain 6.0 0
Nausea/Vomiting 3.7 6.2
Headache 1.3 11.0
Dizziness/Vertigo 1.2 <1.0
Raised Intracranial Pressure 0 1.5
Meningeal Signs 0 1.0
Reversible Alopecia 1.6 <1.0
Fever 1.0 0
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The following adverse events were observed at an incidence of <1%:
HEMATOLOGIC: Leukopenia. There have been rare reports of granulocytopenia,
pancytopenia, agranulocytosis, or thrombocytopenia. (See WARNINGS.)
DERMATOLOGIC: Rash, urticaria.
HYPERSENSITIVITY: Allergic reactions.
RENAL: Acute renal failure related to albendazole therapy has been observed.
OVERDOSAGE:
Significant toxicity and mortality were shown in male and female mice at doses
exceeding 5,000 mg/kg; in rats, at estimated doses between 1,300 and 2,400
mg/kg; in hamsters, at doses exceeding 10,000 mg/kg; and in rabbits, at
estimated doses between 500 and 1,250 mg/kg. In the animals, symptoms were
demonstrated in a dose-response relationship and included diarrhea, vomiting,
tachycardia, and respiratory distress.
One overdosage has been reported with Albend (albendazole) in a patient who
took at least 16 grams over 12 hours. No untoward effects were reported. In case
of overdosage, symptomatic therapy (e.g., gastric lavage and activated charcoal)
and general supportive measures are recommended.
DOSAGE AND ADMINISTRATION:
Dosing of Albend will vary, depending upon which of the following parasitic
infections is being treated.
Indication Patient Weight Dose Duration
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Hydatid Disease 60 kg or greater 400 mg b.i.d., with meals 28-day cycle followed by a
14-day albendazole-free interval,
for a total of 3 cycles
less than 60 kg 15 mg/kg/day given in divided
doses b.i.d. with meals (maximum
total daily dose 800 mg)
NOTE: When administering Albend in the pre- or post-surgical setting, optimal killing of cyst
contents is achieved when three courses of therapy have been given.
Neurocysticercosis 60 kg or greater 400 mg b.i.d., with meals 8-30 days
less than 60 kg 15 mg/kg/day given in divided
doses b.i.d. with meals (maximum
total daily dose 800 mg)
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Patients being treated for neurocysticercosis should receive appropriate steroid
and anticonvulsant therapy as required. Oral or intravenous corticosteroids
should be considered to prevent cerebral hypertensive episodes during the first
week of treatment.
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