ETHAMBUTOL
DESCRIPTION:
MYAMBUTOL ethambutol hydrochloride is an oral chemotherapeutic agent which is
specifically effective against actively growing microorganisms of the genus
Mycobacterium, including M. Tuberculosis.
ACTIONS/CLINICAL PHARMACOLOGY:
MYAMBUTOL, following a single oral dose of 25 mg/kg of body weight, attains a
peak of 2 to 5 micrograms/mL in serum 2 to 4 hours after administration. When
the drug is administered daily for longer periods of time at this dose, serum
levels are similar. The serum level of MYAMBUTOL falls to undetectable levels by
24 hours after the last dose except in some patients with abnormal renal
function. The intracellular concentrations of erythrocytes reach peak values
approximately twice those of plasma and maintain this ratio throughout the 24
hours.
During the 24-hour period following oral administration of MYAMBUTOL,
approximately 50% of the initial dose is excreted unchanged in the urine, while
an additional 8% to 15% appears in the form of metabolites. The main path of
metabolism appears to be an initial oxidation of the alcohol to an aldehydic
intermediate, followed by conversion to a dicarboxylic acid. From 20% to 22% of
the initial dose is excreted in the feces as unchanged drug. No drug
accumulation has been observed with consecutive single daily doses of 25 mg/kg
in patients with normal kidney function, although marked accumulation has been
demonstrated in patients with renal insufficiency.
MYAMBUTOL diffuses into actively growing Mycobacterium cells such as tubercle
bacilli. MYAMBUTOL appears to inhibit the synthesis of one or more metabolites,
thus causing impairment of cell metabolism, arrest of multiplication, and cell
death. No cross resistance with other available antimycobacterial agents has
been demonstrated.
MYAMBUTOL has been shown to be effective against strains of Mycobacterium
Tuberculosis but does not seem to be active against fungi, viruses, or other
bacteria. Mycobacterium Tuberculosis strains previously unexposed to MYAMBUTOL
have been uniformly sensitive to concentrations of 8 or less micrograms/mL,
depending on the nature of the culture media. When MYAMBUTOL has been used alone
for treatment of tuberculosis, tubercle bacilli from these patients have
developed resistance to MYAMBUTOL ethambutol hydrochloride by In Vitro
susceptibility tests; the development of resistance has been unpredictable and
appears to occur in a step-like manner. No cross resistance between MYAMBUTOL
and other antituberculous drugs has been reported. MYAMBUTOL has reduced the
incidence of the emergence of mycobacterial resistance to isoniazid when both
drugs have been used concurrently.
An agar diffusion microbiologic assay, based upon inhibition of Mycobacterium
Smegmatis (ATCC 607) may be used to determine concentrations of MYAMBUTOL in
serum and urine. This technique has not been published, but further information
can be obtained upon inquiry to Lederle Laboratories.
ANIMAL PHARMACOLOGY:
Toxicological studies in dogs on high prolonged doses produced evidence of
myocardial damage and failure, and depigmentation of the tapetum lucidum of the
eyes, the significance of which is not known. Degenerative changes in the
central nervous system, apparently not dose-related, have also been noted in
dogs receiving ethambutol hydrochloride over a prolonged period.
In the rhesus monkey, neurological signs appeared after treatment with high
doses given daily over a period of several months. These were correlated with
specific serum levels of ethambutol hydrochloride and with definite neuro-
anatomical changes in the central nervous system. Focal interstitial carditis
was also noted in monkeys which received ethambutol hydrochloride in high doses
for a prolonged period.
When pregnant mice or rabbits were treated with high doses of ethambutol
hydrochloride, fetal mortality was slightly but not significantly (P>0.05)
increased. Female rats treated with ethambutol hydrochloride displayed slight
but insignificant (P>0.05) decreases in fertility and litter size.
In fetuses born of mice treated with high doses of MYAMBUTOL during pregnancy, a
low incidence of cleft palate, exencephaly and abnormality of the vertebral
column were observed. Minor abnormalities of the cervical vertebra were seen in
the newborn of rats treated with high doses of ethambutol hydrochloride during
pregnancy. Rabbits receiving high doses of MYAMBUTOL during pregnancy gave birth
to two fetuses with monophthalmia, one with a shortened right forearm
accompanied by bilateral wrist-joint contracture and one with hare lip and cleft
palate.
INDICATIONS AND USAGE:
MYAMBUTOL is indicated for the treatment of pulmonary tuberculosis. It should
not be used as the sole antituberculous drug, but should be used in conjunction
with at least one other antituberculous drug. Selection of the companion drug
should be based on clinical experience, considerations of comparative safety and
appropriate In Vitro susceptibility studies. In patients who have not received
previous antituberculous therapy, ie, initial treatment, the most frequently
used regimens have been the following:
MYAMBUTOL plus isoniazid
MYAMBUTOL plus isoniazid plus streptomycin.
In patients who have received previous antituberculous therapy, mycobacterial
resistance to other drugs used in initial therapy is frequent. Consequently, in
such retreatment patients, MYAMBUTOL should be combined with at least one of the
second line drugs not previously administered to the patient and to which
bacterial susceptibility has been indicated by appropriate In Vitro studies.
Antituberculous drugs used with MYAMBUTOL have included cycloserine,
ethionamide, pyrazinamide, viomycin, and other drugs. Isoniazid, aminosalicylic
acid, and streptomycin have also been used in multiple drug regimens.
Alternating drug regimens have also been utilized.
CONTRAINDICATIONS:
MYAMBUTOL is contraindicated in patients who are known to be hypersensitive to
this drug. It is also contraindicated in patients with known optic neuritis
unless clinical judgment determines that it may be used.
PRECAUTIONS:
The effects of combinations of MYAMBUTOL Ethambutol Hydrochloride with other
antituberculous drugs on the fetus is not known. While administration of this
drug to pregnant human patients has produced no detectable effect upon the
fetus, the possible teratogenic potential in women capable of bearing children
should be weighed carefully against the benefits of therapy. There are published
reports of five women who received the drug during pregnancy without apparent
adverse effect upon the fetus.
MYAMBUTOL is not recommended for use in children under 13 years of age since
safe conditions for use have not been established.
Patients with decreased renal function need the dosage reduced as determined by
serum levels of MYAMBUTOL, since the main path of excretion of this drug is by
the kidneys.
Because this drug may have adverse effects on vision, physical examination
should include ophthalmoscopy, finger perimetry, and testing of color
discrimination. In patients with visual defects such as cataracts, recurrent
inflammatory conditions of the eye, optic neuritis, and diabetic retinopathy,
the evaluation of changes in visual acuity is more difficult, and care should be
taken to be sure the variations in vision are not due to the underlying disease
conditions. In such patients, consideration should be given to relationship
between benefits expected and possible visual deterioration since evaluation of
visual changes is difficult. (For recommended procedures, see next paragraphs
under ADVERSE REACTIONS.)
As with any potent drug, periodic assessment of organ system functions,
including renal, hepatic, and hematopoietic, should be made during long- term
therapy.
ADVERSE REACTIONS:
MYAMBUTOL may produce decreases in visual acuity which appear to be due to optic
neuritis and to be related to dose and duration of treatment. The effects are
generally reversible when administration of the drug is discontinued promptly.
In rare cases recovery may be delayed for up to 1 year or more and the effect
may possibly be irreversible in these cases.
Patients should be advised to report promptly to their physician any change of
visual acuity.
The change in visual acuity may be unilateral or bilateral and hence Each Eye
Must Be Tested Separately And Both Eyes Tested Together. Testing of visual
acuity should be performed before beginning MYAMBUTOL therapy and periodically
during drug administration, except that it should be done monthly when a patient
is on a dosage of more than 15 mg per kilogram per day. Snellen eye charts are
recommended for testing of visual acuity. Studies have shown that there are
definite fluctuations of one or two lines of the Snellen chart in the visual
acuity of many tuberculous patients Not receiving MYAMBUTOL.
The following table may be useful in interpreting possible changes in visual
acuity attributable to MYAMBUTOL.
-----------------------------------------------------
Reading
Initial Indicating Significant Decrease
Snellen Significant Number Number
Reading Decrease of Lines of Points
------- ----------- ----------- ---------
20/13 20/25 3 12
20/15 20/25 2 10
20/20 20/30 2 10
20/25 20/40 2 15
20/30 20/50 2 20
20/40 20/70 2 30
20/50 20/70 1 20
-----------------------------------------------------
In general, changes in visual acuity less than those indicated under
"Significant Number of Lines" and "Decrease-Number of Points," may be due to
chance variation, limitations of the testing method or physiologic variability.
Conversely, changes in visual acuity equaling or exceeding those under
"Significant Number of Lines" and "Decrease-Number of Points" indicate need for
retesting and careful evaluation of the patient's visual status. If careful
evaluation confirms the magnitude of visual change and fails to reveal another
cause, MYAMBUTOL should be discontinued and the patient reevaluated at frequent
intervals. Progressive decreases in visual acuity during therapy must be
considered to be due to MYAMBUTOL.
If corrective glasses are used prior to treatment, these must be worn during
visual acuity testing. During 1 to 2 years of therapy, a refractive error may
develop which must be corrected in order to obtain accurate test results.
Testing the visual acuity through a pinhole eliminates refractive error.
Patients developing visual abnormality during MYAMBUTOL treatment may show
subjective visual symptoms before, or simultaneously with, the demonstration of
decreases in visual acuity, and all patients receiving MYAMBUTOL should be
questioned periodically about blurred vision and other subjective eye symptoms.
months after the drug has been discontinued. Patients have then received
MYAMBUTOL ethambutol hydrochloride again without recurrence of loss of visual
acuity.
Other adverse reactions reported include: anaphylactoid reactions, dermatitis
pruritus and joint pain; anorexia, nausea, vomiting, gastrointestinal upset,
abdominal pain; fever, malaise, headache, and dizziness; mental confusion,
disorientation and possible hallucinations. Numbness and tingling of the
extremities due to peripheral neuritis have been reported infrequently.
Elevated serum uric acid levels occur and precipitation of acute gout has been
reported. Transient impairment of liver function as indicated by abnormal liver
function tests is not an unusual finding. Since MYAMBUTOL is recommended for
therapy in conjunction with one or more other antituberculous drugs, these
changes may be related to the concurrent therapy.
DOSAGE AND ADMINISTRATION:
MYAMBUTOL should not be used alone, in initial treatment or in retreatment.
MYAMBUTOL should be administered on a once every 24-hour basis only. Absorption
is not significantly altered by administration with food. Therapy, in general,
should be continued until bacteriological conversion has become permanent and
maximal clinical improvement has occurred.
MYAMBUTOL is not recommended for use in children under thirteen years of age
since safe conditions for use have not been established.
INITIAL TREATMENT: In patients who have not received previous antituberculous
therapy, administer MYAMBUTOL 15 mg per kilogram (7 mg per pound) of body
weight, as a single oral dose once every 24 hours. In the more recent studies,
isoniazid has been administered concurrently in a single, daily, oral dose.
RETREATMENT: In patients who have received previous antituberculous therapy,
administer MYAMBUTOL 25 mg per kilogram (11 mg per pound) of body weight, as a
single oral dose once every 24 hours. Concurrently administer at least one other
antituberculous drug to which the organisms have been demonstrated to be
susceptible by appropriate In Vitro tests. Suitable drugs usually consist of
those not previously used in the treatment of the patient. After 60 days of
MYAMBUTOL administration, decrease the dose to 15mg per kilogram (7 mg per
pound) of body weight, and administer as a single oral dose once every 24 hours.
During the period when a patient is on a daily dose of 25 mg/kg, monthly eye
examinations are advised.
See Table for easy selection of proper weight- dose tablet(s).
Weight-Dose Table
-----------------
15 mg/kg (7 mg/lb) Schedule
Weight Range Daily Dose
Pounds Kilograms In mg
------ --------- ------
Under 85 lbs Under 37 kg.................. 500
85-94.5 37-43........................ 600
95-109.5 43-50........................ 700
110-124.5 50-57........................ 800
125-139.5 57-64........................ 900
140-154.5 64-71........................ 1000
155-169.5 71-79........................ 1100
170-184.5 79-84........................ 1200
185-199.5 84-90........................ 1300
200-214.5 90-97........................ 1400
215 and Over Over 97...................... 1500
25 mg/kg (11 mg/lb) Schedule
Under 85 lbs Under 38 kg.................. 900
85-92.5 38-42........................ 1000
93-101.5 42-45.5...................... 1100
102-109.5 45.5-50...................... 1200
110-118.5 50-54........................ 1300
119-128.5 54-58........................ 1400
129-136.5 58-62........................ 1500
137-146.5 62-67........................ 1600
147-155.5 67-71........................ 1700
156-164.5 71-75........................ 1800
165-173.5 75-79........................ 1900
174-182.5 79-83........................ 2000
183-191.5 83-87........................ 2100
192-199.5 87-91........................ 2200
200-209.5 91-95........................ 2300
210-218.5 95-99........................ 2400
219 and Over Over 99...................... 2500
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