Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/3813
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Quibron T/SR (Tablet)
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General Considerations:: Quibron-T/SR has not been adequately studied
for its bioavailability when administered with food . The
steady-state peak serum theophylline concentration is a function of the dose,
the dosing interval, and the rate of theophylline absorption and clearance
in the individual patient. Because of marked individual differences in the
rate of theophylline clearance, the dose required to achieve a peak serum
theophylline concentration in the 10-20 mcg/mL range varies fourfold among
otherwise similar patients in the absence of factors known to alter theophylline
clearance (e.g., 400-1600 mg/day in adults<60 years old and 10-36 mg/kg/day
in children 1-9 years old). For a given population there is no single theophylline
dose that will provide both safe and effective serum concentrations for all
patients. Administration of the median theophylline dose required to achieve
a therapeutic serum theophylline concentration in a given population may result
in either sub-therapeutic or potentially toxic serum theophylline concentrations
in individual patients. For example, at a dose of 900 mg/d in adults<60
years or 22 mg/kg/d in children 1-9 years, the steady-state peak serum theophylline
concentration will be<10 mcg/mL in about 30% of patients, 10-20 mcg/mL
in about 50% and 20-30 mcg/mL in about 20% of patients. The dose of theophylline must be individualized
on the basis of peak serum theophylline concentration measurements in order
to achieve a dose that will provide maximum potential benefit with minimal
risk of adverse effects. Transient
caffeine-like adverse effects and excessive serum concentrations in slow metabolizers
can be avoided in most patients by starting with a sufficiently low dose and
slowly increasing the dose, if judged to be
clinically indicated, in small increments (See Table
V). Dose increases should only be made if theprevious dosage is
well tolerated and at intervals of no less than 3 days to allow serum theophylline
concentrations to reach the new steady state. Dosage adjustment should be
guided by serum theophylline concentration measurement . Health care providers should instruct
patients and care givers to discontinue any dosage that causes adverse effects,
to withhold the medication until these symptoms are gone and to then resume
therapy at a lower, previously tolerated dosage . If
the patient's symptoms are well controlled, there are no apparent adverse
effects, and no intervening factors that might alter dosage requirements ,
serum theophylline concentrations should be monitored at 6 month intervals
for rapidly growing children and at yearly intervals for all others. In acutely
ill patients, serum theophylline concentrations should be monitored at frequent
intervals, e.g., every 24 hours. Theophylline distributes
poorly into body fat, therefore, mg/kg dose should be calculated on the basis
of ideal body weight. Table V contains theophylline
dosing titration schema recommended for patients in various age groups and
clinical circumstances. Table VI contains recommendations for theophylline
dosage adjustment based upon serum theophylline concentrations. Application
of these general dosing recommendations to individual patients must take into
account the unique clinical characteristics of each patient. In general, these
recommendations should serve as the upper limit for dosage adjustments in
order to decrease the risk of potentially serious adverse events associated
with unexpected large increases in serum theophylline concentration.
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dailymed-instance:descripti... |
Theophylline is structurally classified as a methylxanthine.
It occurs as a white, odorless, crystalline powder with a bitter taste. Anhydrous
theophylline has the chemical name 1HPurine- 2,6-dione,3,7-dihydro-1,3-dimethyl-,
and is represented by the following structural formula: The
molecular formula of anhydrous theophylline is CHNOwith
a molecular weight of 180.17. Quibron-T/SR
is available as tablets intended for oral administration, containing 300 mg
of anhydrous theophylline per tablet. Quibron-T/SR is an
oral bronchodilator in a sustained-release formulation in the ACCUDOSE Tablet
design. With functional trisects and bisects, Quibron-T/SR
Tablets can be accurately divided into 100-, 150-, and 200- mg segments toprovide a variety of dosing increments, as required. Inactive Ingredient: magnesium
stearate.
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Mechanism of Action:: Theophylline has two distinct actions in the airways of patients
with reversible obstruction; smooth muscle relaxation (i.e., bronchodilation)
and suppression of the response of the airways to stimuli (i.e., non-bronchodilator
prophylactic effects). While the mechanisms of action of theophylline are
not known with certainty, studies in animals suggest that bronchodilatation
is mediated by the inhibition of two isozymes of phosphodiesterase (PDE III
and, to a lesser extent, PDE IV) while non-bronchodilator prophylactic actions
are probably mediated through one or more different molecular mechanisms,
that do not involve inhibition of PDE III or antagonism of adenosine receptors.
Some of the adverse effects associated with theophylline appear to be mediated
by inhibition of PDE III (e.g., hypotension, tachycardia, headache, and emesis)
and adenosine receptor antagonism (e.g., alterations in cerebral blood flow). Theophylline
increases the force of contraction of diaphragmatic muscles. This action appears
to be due to enhancement of calcium uptake through an adenosine-mediated channel.<br/>Serum Concentration-Effect Relationship:: Bronchodilation occurs over the serum theophylline concentration
range of 5-20 mcg/mL. Clinically important improvement in symptom control
has been found in most studies to require peak serum theophylline concentrations>10 mcg/mL, but patients with mild disease may benefit from lower concentrations.
At serum theophylline concentrations>20 mcg/mL, both the frequency and severity
of adverse reactions increase. In general, maintaining peak serum theophylline
concentrations between 10 and 15 mcg/mL will achieve most of the drug's
potential therapeutic benefit while minimizing the risk of serious adverse
events.<br/>Pharmacokinetics:: Overview Theophylline is rapidly and completely absorbed after
oral administration in solution or immediate-release solid oral dosage form.
Theophylline does not undergo any appreciable pre-systemic elimination, distributes
freely into fat-free tissues and is extensively metabolized in the liver. The
pharmacokinetics of theophylline vary widely among similar patients and cannot
be predicted by age, sex, body weight or other demographic characteristics.
In addition, certain concurrent illnesses and alterations in normal physiology
(see Table I) and co-administration of
other drugs (see Table II) can significantly
alter the pharmacokinetic characteristics of theophylline. Within-subject
variability in metabolism has also been reported in some studies, especially
in acutely ill patients. It is, therefore, recommended that serum theophylline
concentrations be measured frequently in acutely ill patients (e.g., at 24-hr
intervals) and periodically in patients receiving long-term therapy, e.g.,
at 6-12 month intervals. More frequent measurements should be made in the
presence of any condition that may significantly alter theophylline clearance
(see PRECAUTIONS, Laboratory
Tests). ��For various North American patient populations from
literature reports. Different rates of elimination and consequent dosage requirements
have been observed among other peoples. * Clearance
represents the volume of blood completely cleared of theophylline by the liver
in one minute. Values listed were generally determined at serum theophylline
concentrations<20 mcg/mL; clearance may decrease and half-life may increase
at higher serum concentrations due to non-linear pharmacokinetics. ������Reported range or estimated range (mean��2 SD) where actual range not
reported. ���NR = not reported or not reported
in a comparable format. ** Median Note: In
addition to the factors listed above, theophylline clearance is increased
and half-life decreased by low carbohydrate/high protein diets, parenteral
nutrition, and daily consumption of charcoal-broiled beef. A high carbohydrate/low
protein diet can decrease the clearance and prolong the half-life of theophylline. Absorption Theophylline
is rapidly and completely absorbed after oral administration in solution or
immediate-release solid oral dosage form. After a single immediate-release
theophylline dose of 5 mg/kg in adults, a mean peak serum concentration of
about 10 mcg/mL (range 5-15 mcg/mL) can be expected 1-2 hr after the dose.
Co-administration of theophylline with food or antacids does not cause clinically
significant changes in the absorption of theophylline from immediate-release
dosage forms. In cigarette smokers (1 to 2 packs/day)
the mean half-life is 4 to 5 hours, much shorter than in nonsmokers. The increase
in clearance associated with smoking is presumably due to stimulation of the
hepatic metabolic pathway by components of cigarette smoke. The duration of
this effect after cessation of smoking is unknown but may require 6 months
to 2 years before the rate approaches that of a nonsmoker. In
a single-dose study of Quibron-T/SR (theophylline, anhydrous),
a 300-mg dose in 12 fasted normal male subjects gave a mean peak plasma level
of 5.26��1.04 (S.D.)��g/mL at 6.25��1.10 (S.D.) hours. In
a multi-dose, steady state study of 16 adult patients with a mean age of 39.0
years, the patients were dose-titrated to a therapeutically effective level
without toxicity. Doses were administered once every 12 hours and ranged from
7.8 mg/kg/24 hours to 18.6 mg/kg/24 hours with a mean dose of 10.0��2.8 (S.D.) mg/kg/24 hours. No food-fasting conditions were imposed in the
study. A mean Cmax of 13.9��3.2 (S.D.)��g/mL, a mean Cmin of 7.7��2.0 (S.D.)��g/mL, and a mean percent fluctuation [(Cmax - Cmin)/Cmin
x 100] of 87.1��49.6 (S.D.) resulted from the study. In
a multi-dose, steady state study of 15 patients with a mean age of 14.4 years,
the patients were dose-titrated to a therapeutically effective level without
toxicity. Doses were administered once every 12 hours and ranged from 9.1
mg/kg/24 hours to 22.6 mg/kg/24 hours with a mean dose of 13.3��3.9
(S.D.) mg/kg/24 hours. No food-fasting conditions were imposed in the study.
A mean Cmax of 13.8��3.9 (S.D.)��g/mL, a mean Cmin of 8.0��2.5 (S.D.)��g/mL, and a mean percent fluctuation [(Cmax - Cmin)/Cmin
x 100] of 85.4��57.7 (S.D.) resulted from the study. In
a multiple-dose bioavailability study in 16 normal volunteers, when tested
against an immediate-release reference tablet, Quibron-T/SR
was found to be 98% bioavailable. Distribution Once theophylline
enters the systemic circulation, about 40% is bound to plasma protein, primarily
albumin. Unbound theophylline distributes throughout body water, but distributes
poorly into body fat. The apparent volume of distribution of theophylline
is approximately 0.45 L/kg (range 0.3-0.7 L/kg) based on ideal body weight.
Theophylline passes freely across the placenta, into breast milk and into
the cerebrospinal fluid (CSF). Saliva theophylline concentrations approximate
unbound serum concentrations, but are not reliable for routine or therapeutic
monitoring unless special techniques are used. An increase in the volume of
distribution of theophylline, primarily due to reduction in plasma protein
binding, occurs in premature neonates, patients with hepatic cirrhosis, uncorrected
acidemia, the elderly and in women during the third trimester of pregnancy.
In such cases, the patient may show signs of toxicity at total (bound + unbound)
serum concentrations of theophylline in the therapeutic range (10-20 mcg/mL)
due to elevated concentrations of the pharmacologically active unbound drug. Similarly,
a patient with decreased theophylline binding may have a sub-therapeutic total
drug concentration while the pharmacologically active unbound concentration
is in the therapeutic range. If only total serum theophylline concentration
is measured, this may lead to an unnecessary and potentially dangerous dose
increase. In patients with reduced protein binding, measurement of unbound
serum theophylline concentration provides a more reliable means of dosage
adjustment than measurement of total serum theophylline concentration. Generally,
concentrations of unbound theophylline should be maintained in the range of
6-12 mcg/mL. Metabolism Following oral dosing, theophylline does not undergo
any measurable first-pass elimination. In adults and children beyond one year
of age, approximately 90% of the dose is metabolized in the liver. Biotransformation
takes place through demethylation to 1-methylxanthine and 3-methylxanthine
and hydroxylation to 1,3-dimethyluric acid. 1- methylxanthine is further hydroxylated,
by xanthine oxidase, to 1-methyluric acid. About 6% of a theophylline dose
is N-methylated to caffeine. Theophylline demethylation to 3- methylxanthine
is catalyzed by cytochrome P-450 1A2, while cytochromes P-450 2E1 and P-450
3A3 catalyze the hydroxylation to 1,3-dimethyluric acid. Demethylation to
1- methylxanthine appears to be catalyzed either by cytochrome P-450 1A2 or
a closely related cytochrome. In neonates, the N-demethylation pathway is
absent while the function of the hydroxylation pathway is markedly deficient.
The activity of these pathways slowly increases to maximal levels by one year
of age. Caffeine and 3-methylxanthine are the only theophylline
metabolites with pharmacologic activity. 3-methylxanthine has approximately
one tenth the pharmacologic activity of theophylline and serum concentrations
in adults with normal renal function are<1 mcg/mL. In patients with end-stage
renal disease, 3-methylxanthine may accumulate to concentrations that approximate
the unmetabolized theophylline concentration. Caffeine concentrations are
usually undetectable in adults regardless of renal function. In neonates,
caffeine may accumulate to concentrations that approximate the unmetabolized
theophylline concentration and thus, exert a pharmacologic effect. Both
the N-demethylation and hydroxylation pathways of theophylline biotransformation
are capacity-limited. Due to the wide intersubject variability of the rate
of theophylline metabolism, non-linearity of elimination may begin in some
patients at serum theophylline concentrations<10 mcg/mL. Since this non-linearity
results in more than proportional changes in serum theophylline concentrations
with changes in dose, it is advisable to make increases or decreases in dose
in small increments in order to achieve desired changes in serum theophylline
concentrations . Accurate prediction of dose-dependency
of theophylline metabolism in patients a priori is not possible, but patients
with very high initial clearance rates (i.e., low steady state serum theophylline
concentrations at above average doses) have the greatest likelihood of experiencing
large changes in serum theophylline concentration in response to dosage changes. Excretion In
neonates, approximately 50% of the theophylline dose is excreted unchanged
in the urine. Beyond the first three months of life, approximately 10% of
the theophylline dose is excreted unchanged in the urine. The remainder is
excreted in the urine mainly as 1,3-dimethyluric acid (35-40%), 1-methyluric
acid (20-25%) and 3- methylxanthine (15-20%). Since little theophylline is
excreted unchanged in the urine and since active metabolites of theophylline
(i.e., caffeine, 3-methylxanthine) do not accumulate to clinically significant
levels even in the face of end-stage renal disease, no dosage adjustment for
renal insufficiency is necessary in adults and children>3 months of age.
In contrast, the large fraction of the theophylline dose excreted in the urine
as unchanged theophylline and caffeine in neonates requires careful attention
to dose reduction and frequent monitoring of serum theophylline concentrations
in neonates with reduced renal function . Serum Concentrations at Steady
State After multiple doses of immediate-release theophylline,
steady state is reached in 30-65 hours (average 40 hours) in adults. At steady
state, on a dosage regimen with 6-hour intervals, the expected mean trough
concentration is approximately 60% of the mean peak concentration, assuming
a mean theophylline half-life of 8 hours. The difference between peak and
trough concentrations is larger in patients with more rapid theophylline clearance.
In patients with high theophylline clearance and half-lives of about 4-5 hours,
such as children age 1 to 9 years, the trough serum theophylline concentration
may be only 30% of peak with a 6-hour dosing interval. In these patients a
slow release formulation would allow a longer dosing interval (8-12 hours)
with a smaller peak/trough difference. Special Populations (See Table
I for mean clearance and half-life values) Geriatric The clearance of theophylline is
decreased by an average of 30% in healthy elderly adults (>60 yrs) compared
to healthy young adults. Careful attention to dose reduction and frequent
monitoring of serum theophylline concentrations are required in elderly patients
. Pediatrics The clearance of theophylline is
very low in neonates .
Theophylline clearance reaches maximal values by one year of age, remains
relatively constant until about 9 years of age and then slowly decreases by
approximately 50% to adult values at about age 16. Renal excretion of unchanged
theophylline in neonates amounts to about 50% of thedose, compared to about
10% in children older than three months and in adults. Careful attention to
dosage selection and monitoring of serum theophylline concentrations are required
in pediatric patients . Gender Gender differences in theophylline
clearance are relatively small and unlikely to be of clinical significance.
Significant reduction in theophylline clearance, however, has been reported
in women on the 20th day of the menstrual cycle and during the third trimester
of pregnancy. Race Pharmacokinetic
differences in theophylline clearance due to race have not been studied. Renal Insufficiency Only a small fraction,
e.g., about 10%, of the administered theophylline dose is excreted unchanged
in the urine of children greater than three months of age and adults. Since
little theophylline is excreted unchanged in the urine and since active metabolites
of theophylline (i.e., caffeine, 3-methylxanthine) do not accumulate to clinically
significant levels even in the face of end-stage renal disease, no dosage
adjustment for renal insufficiency is necessary in adults and children>3
months of age. In contrast, approximately 50% of the administered theophylline
dose is excreted unchanged in the urine in neonates. Careful attention to
dose reduction and frequent monitoring of serum theophylline concentrations
are required in neonates with decreased renal function . Hepatic Insufficiency Theophylline clearance
is decreased by 50% or more in patients with hepatic insufficiency (e.g.,
cirrhosis, acute hepatitis, cholestasis). Careful attention to dose reduction
and frequent monitoring of serum theophylline concentrations are required
in patients with reduced hepatic function . Congestive Heart Failure (CHF) Theophylline
clearance is decreased by 50% or more in patients with CHF. The extent of
reduction in theophylline clearance in patients with CHF appears to be directly
correlated to the severity of the cardiac disease. Since theophylline clearance
is independent of liver blood flow, the reduction in clearance appears to
be due to impaired hepatocyte function rather than reduced perfusion. Careful
attention to dose reduction and frequent monitoring of serum theophylline
concentrations are required in patients with CHF . Smokers Tobacco and marijuana smoking appears
to increase the clearance of theophylline by induction of metabolic pathways.
Theophylline clearance has been shown to increase by approximately 50% in
young adult tobacco smokers and by approximately 80% in elderly tobacco smokers
compared to non-smoking subjects. Passive smoke exposure has also been shown
to increase theophylline clearance by up to 50%. Abstinence from tobacco smoking
for one week causes a reduction of approximately 40% in theophylline clearance.
Careful attention to dose reduction and frequent monitoring of serum theophylline
concentrations are required in patients who stop smoking .
Use of nicotine gum has been shown to have no effect on theophylline clearance. Fever Fever, regardless of its underlying
cause, can decrease the clearance of theophylline. The magnitude and duration
of the fever appear to be directly correlated to the degree of decrease of
theophylline clearance. Precise data are lacking, but a temperature of 39��C
(102��F) for at least 24 hours is probably required to produce a clinically
significant increase in serum theophylline concentrations. Children with rapid
rates of theophylline clearance (i.e., those who require a dose that is substantially
larger than average [e.g.,>22 mg/kg/day] to achieve a therapeutic peak serum
theophylline concentration when afebrile) may be at greater risk of toxic
effects from decreased clearance during sustained fever. Careful attention
to dose reduction and frequent monitoring of serum theophylline concentrations
are required in patients with sustained fever . Miscellaneous Other factors associated with
decreased theophylline clearance include the third trimester of pregnancy,
sepsis with multiple organ failure, and hypothyroidism. Careful attention
to dose reduction and frequent monitoring of serum theophylline concentrations
are required in patients with any of these conditions .
Other factors associated with increased theophylline clearance include hyperthyroidism
and cystic fibrosis.<br/>Clinical Studies:: In patients with chronic asthma, including patients with
severe asthma requiring inhaled corticosteroids or alternate-day oral corticosteroids,
many clinical studies have shown that theophylline decreases the frequency
and severity of symptoms, including nocturnal exacerbations, and decreases
the���as needed���use of inhaled beta-2 agonists. Theophylline
has also been shown to reduce the need for short courses of daily oral prednisone
to relieve exacerbations of airway obstruction that are unresponsive to bronchodilators
in asthmatics. In patients with chronic obstructive
pulmonary disease (COPD), clinical studies have shown that theophylline decreases
dyspnea, air trapping, the work of breathing, and improves contractility of
diaphragmatic muscles with little or no improvement in pulmonary function
measurements.
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QUIBRON-T/SR ACCUDOSE Tablets
are contraindicated in patients with a history of hypersensitivity to theophylline
or other components in the product.
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dailymed-instance:supply |
Quibron-T/SR Tablets: Bottles of 100 and
500, white, in the ACCUDOSE Tablet design with���M
019���debossed on one side, containing 300 mg of anhydrous theophylline. NDC
61570-019-01 . . . . . . . . . . . . . . . Bottles of 100 NDC
61570-019-05 . . . . . . . . . . . . . . . Bottles of 500 Store
from 15��-25��C (59��-77��F) Rx Only. Rev. 8/99 Manufactured
for Monarch Pharmaceuticals, Inc., Bristol, TN 37620 Manufactured
by Bristol-Myers Squibb, Princeton, NJ 0854
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General:: Careful consideration of the various interacting drugs and
physiologic conditions that can alter theophylline clearance and require dosage
adjustment should occur prior to initiation of theophylline therapy, prior
to increases in theophylline dose, and during follow up .
The dose of theophylline selected for initiation of therapy should be low
and, if tolerated, increased slowly over a period of a week or longer with
the final dose guided by monitoring serum theophylline concentrations and
the patient's clinical response (see DOSAGE
AND ADMINISTRATION, Table V).<br/>Monitoring Serum Theophylline Concentrations:: Serum theophylline concentration measurements are readily
available and should be used to determine whether the dosage is appropriate.
Specifically, the serum theophylline concentration should be measured as follows: To guide a dose increase, the blood sample should be obtained
at the time of the expected peak serum theophylline concentration; 5-6 hours
after a dose at steady-state, drawn more than 6 hours after the dose. For
most patients, steady-state will be reached after 3 days of dosing when no
doses have been missed, no extra doses have been added, and none of the doses
have beentaken at unequal intervals. A trough concentration (i.e., at the
end of the dosing interval) provides no additional useful information and
may lead to an inappropriate dose increase since the peak serum theophylline
concentration can be two or more times greater than the trough concentration
with an immediate-release formulation. If the serum sample is drawn more than
two hours after the dose, the results must be interpreted with caution since
the concentration may not be reflective of the peak concentration. In contrast,
when signs or symptoms of theophylline toxicity are present, the serum sample
should be obtained as soon as possible, analyzed immediately, and the result
reported to the clinician without delay. In patients in whom decreased serum
protein binding is suspected (e.g., cirrhosis, women during the third trimester
of pregnancy), the concentration of unbound theophylline should be measured
and the dosage adjusted to achieve an unbound concentration of 6-12 mcg/mL. Saliva
concentrations of theophylline cannot be used reliably to adjust dosage without
special techniques.<br/>Effects on Laboratory Tests:: As a result of its pharmacological effects, theophylline
at serum concentrations within the 10-20 mcg/mL range modestly increases plasma
glucose (from a mean of 88 mg% to 98 mg%), uric acid (from a mean of 4 mg/dL
to 6 mg/dL), free fatty acids (from a mean of 451��eq/l to 800��eq/l,
total cholesterol (from a mean of 140 vs 160 mg/dL), HDL (from a mean of 36
to 50 mg/dL), HDL/LDL ratio (from a mean of 0.5 to 0.7), and urinary free
cortisol excretion (from a mean of 44 to 63 mcg/24 hr). Theophylline at serum
concentrations within the 10-20 mcg/mL range may also transiently decrease
serum concentrations of triiodothyronine (144 before, 131 after one week and
142 ng/dL after 4 weeks of theophylline). The clinical importance of these
changes should be weighed against the potential therapeutic benefit of theophylline
in individual patients.<br/>Information for Patients:: QUIBRON-T/SR Tablets
should not be chewed or crushed. The patient
(or parent/care giver) should be instructed to seek medical advice whenever
nausea, vomiting, persistent headache, insomnia or rapid heart beat occurs
during treatment with theophylline, even if another cause is suspected. The
patient (or parent/care giver) should be instructed to contact their clinician
if they develop a new illness, especially if accompanied by a persistent fever,
if they experience worsening of a chronic illness, if they start or stop smoking
cigarettes or marijuana, or if another clinician adds a new medication or
discontinues a previously prescribed medication. Patients should be instructed
to inform all clinicians involved in their care that they are taking theophylline,
especially when a medication is being added or deleted from their treatment.
Patients should be instructed to not alter the dose, timing of the dose, or
frequency of administration without first consultingtheir clinician. If a
dose is missed, the patient should be instructed to take the next dose at
the usually scheduled time and to not attempt to make up for the missed dose.<br/>Drug Interactions:: Drug-Drug
Interactions Theophylline interacts with a wide variety
of drugs. The interaction may be pharmacodynamic, i.e., alterations in the
therapeutic response to theophylline or another drug or occurrence of adverse
effects without a change in serum theophylline concentration. More frequently,
however, the interaction is pharmacokinetic, i.e., the rate of theophylline
clearance is altered by another drug resulting in increased or decreased serum
theophylline concentrations. Theophylline only rarely alters the pharmacokinetics
of other drugs. The drugs listed in Table II have the
potential to produce clinically significant pharmacodynamic or pharmacokinetic
interactions with theophylline. The information in the���Effect���column of Table II assumes that the interacting drug is being added to a steady-state
theophylline regimen. If theophylline is being initiated in a patient who
is already taking a drug that inhibits theophylline clearance (e.g., cimetidine,
erythromycin), the dose of theophylline required to achieve a therapeutic
serum theophylline concentration will be smaller. Conversely, if theophylline
is being initiated in a patient who is already taking a drug that enhances
theophylline clearance (e.g., rifampin), the dose of theophylline required
to achieve a therapeutic serum theophylline concentration will be larger.
Discontinuation of a concomitant drug that increases theophylline clearance
will result in accumulation of theophylline to potentially toxic levels, unless
the theophylline dose is appropriately reduced. Discontinuation of a concomitant
drug that inhibits theophylline clearance will result in decreased serum theophylline
concentrations, unless the theophylline dose is appropriately increased. The
drugs listed in Table III have either been documented not to interact with
theophylline or do not produce a clinically significant interaction (i.e.,<15% change in theophylline clearance). The listing
of drugs in Tables II and III are current as of January 2, 1996. New interactions
are continuously being reported for theophylline, especially with new chemical
entities. The clinician
should not assume that a drug does not interact with theophylline if it is
not listed in Table II. Before addition of a newly available
drug in a patient receiving theophylline, the package insert of the new drug
and/or the medical literature should be consulted to determine if an interaction
between the new drug and theophylline has been reported. * Refer to PRECAUTIONS,
Drug Interactions for further information regarding table. ** Average effect on steady state theophylline concentration
or other clinical effect for pharmacologic interactions. Individual patients
may experience larger changes in serum theophylline concentration than the
value listed. * Refer to PRECAUTIONS,
Drug Interactions for information regarding table. Drug-Food
Interactions Quibron-T/SR has
not been adequately studied to determine whether its bioavailability is altered
when it is given with food. Available data suggests
that drug administration at the time of food ingestion may influence the absorption
characteristics if some or all theophylline controlled-release products, resulting
in serum values different from those found after administration in the fasting
state. A drug-food effect, if any, would likely have
its greatest clinical significance when high theophylline serum levels are
being maintained and/or when large single doses (>13 mg/kg or 900 mg) of a
controlled-release theophylline product are given. The influence of type and
amount of food on performance of controlled-release theophylline products
is under study at this time.<br/>The Effect of Other Drugs on Theophylline Serum Concentration Measurements:: Most serum theophylline assays in clinical use are immunoassays
which are specific for theophylline. Other xanthines such as caffeine, dyphylline,
and pentoxifylline are not detected by these assays. Some drugs (e.g.,cefazolin,
cephalothin), however, may interfere with certain HPLC techniques. Caffeine
and xanthine metabolites in neonates or patients with renal dysfunction may
cause the reading from some dry reagent office methods to be higher than the
actual serum theophylline concentration.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility:: Long term carcinogenicity studies have been carried out in
mice (oral doses 30-150 mg/kg) and rats (oral doses 5-75 mg/kg). Results are
pending. Theophylline has been studied in Ames salmonella,
in vivo and in vitro cytogenetics, micronucleus and Chinese hamster ovary
test systems and has not been shown to be genotoxic. In
a 14 week continuous breeding study, theophylline, administered to mating
pairs of B6C3F1 mice at oral doses of 120, 270 and 500 mg/kg (approximately
1.0- 3.0 times the human dose on a mg/m2 basis) impaired fertility, as evidenced
by decreases in the number of live pups per litter, decreases in the mean
number of litters per fertile pair, and increases in the gestation period
at the high dose as well as decreases in the proportion of pups born alive
at the mid and high dose. In 13 week toxicity studies, theophylline was administered
to F344 rats and B6C3F1 mice at oral doses of 40-300 mg/kg (approximately
2.0 times the human dose on a mg/m2 basis). At the high dose, systemic toxicity
was observed in both species including decreases in testicular weight.<br/>Pregnancy::<br/>CATEGORY C:: There are no adequate and well-controlled studies in pregnant
women. Additionally, there are no teratogenicity studies in non-rodents (e.g.,
rabbits). Theophylline was not shown to be teratogenic in CD-1 mice at oral
doses up to 400 mg/kg, approximately 2.0 times the human dose on a mg/m2 basis
or in CD-1 rats at oral doses up to 260 mg/kg, approximately 3.0 times the
recommended human dose on a mg/m2 basis. At a dose of 220 mg/kg, embryotoxicity
was observed in rats in the absence of maternal toxicity.<br/>Nursing Mothers:: Theophylline is excreted into breast milk and may cause irritability
or other signs of mild toxicity in nursing human infants. The concentration
of theophylline in breast milk is about equivalent to the maternal serum concentration.
An infant ingesting a liter of breast milk containing 10-20 mcg/mL of theophylline
a day is likely to receive 10-20 mg of theophylline per day. Serious adverse
effects in the infant are unlikely unless the mother has toxic serum theophylline
concentrations.<br/>Pediatric Use:: Theophylline is safe and effective for the approved indications
in pediatric patients. The maintenance dose of theophylline must be selected
with caution in pediatric patients since the rate of theophylline clearance
is highly variable across the age range of neonates to adolescents (see CLINICAL PHARMACOLOGY, Table
I, WARNINGS, and DOSAGE AND ADMINISTRATION, Table V). Due to the immaturity of theophylline
metabolic pathways in infants under the age of one year, particular attention
to dosage selection and frequent monitoring of serum theophylline concentrations
are required when theophylline is prescribed to pediatric patients in this
age group.<br/>Geriatric Use:: Elderly patients are at significantly greater risk of experiencing
serious toxicity from theophylline than younger patients due to pharmacokinetic
and pharmacodynamic changes associated with aging. Theophylline clearance
is reduced in patients greater than 60 years of age, resulting in increased
serum theophylline concentrations in response to a given theophylline dose.
Protein binding may be decreased in the elderly resulting in a larger proportion
of the total serum theophylline concentration in the pharmacologically active
unbound form. Elderly patients also appear to be more sensitive to the toxic
effects of theophylline after chronic overdosage than younger patients. For
these reasons, the maximum daily dose of theophylline in patients greater
than 60 years of age ordinarily should not exceed 400 mg/day unless the patient
continues to be symptomatic and the peak steady state serum theophylline concentration
is<10 mcg/mL (see DOSAGE AND
ADMINISTRATION). Theophylline doses greater than 400 mg/day should
be prescribed with caution in elderly patients.
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dailymed-instance:overdosag... |
General:: The chronicity and pattern of theophylline overdosage significantly
influences clinical manifestations of toxicity, management and outcome. There
are two common presentations: (1) acute overdose, i.e., ingestion of a single
large excessive dose (>10 mg/kg) as occurs in the context of an attempted
suicide or isolated medication error, and (2) chronic overdosage, i.e., ingestion
of repeated doses that are excessive for the patient's rate of theophylline
clearance. The most common causes of chronic theophylline overdosage include
patient or care giver error in dosing, clinician prescribing of an excessive
dose or a normal dose in the presence of factors known to decrease the rate
of theophylline clearance, and increasing the dose in responseto an exacerbation
of symptoms without first measuring the serum theophylline concentration to
determine whether a dose increase is safe. Severe toxicity
from theophylline overdose is a relatively rare event. In one health maintenance
organization, the frequency of hospital admissions for chronic overdosage
of theophylline was about 1 per 1000 person-years exposure. In another study,
among 6000 blood samples obtained for measurement of serum theophylline concentration,
for any reason,from patients treated in an emergency department, 7% were
in the 20-30 mcg/mL range and 3% were>30 mcg/mL. Approximately two-thirds
of the patients with serum theophylline concentrations in the 20-30 mcg/mL
range had one or more manifestations of toxicity while>90% of patients with
serum theophylline concentrations>30 mcg/mL were clinically intoxicated.
Similarly, in other reports, serious toxicity from theophylline is seen principally
at serum concentrations>30 mcg/mL. Several studies
have described the clinical manifestations of theophylline overdose and attempted
to determine the factors that predict life-threatening toxicity. In general,
patients who experience an acute overdose are less likely to experience seizures
than patients who have experienced a chronic overdosage, unless the peak serum
theophylline concentration is>100 mcg/mL. After a chronic overdosage, generalized
seizures, life-threatening cardiac arrhythmias, and death may occur at serum
theophylline concentrations>30 mcg/mL. The severity of toxicity after chronic
overdosage is more strongly correlated with the patient's age than
the peak serum theophylline concentration; patients>60 years are at the greatest
risk for severe toxicity and mortality after a chronic overdosage. Pre-existing
or concurrent disease may also significantly increase the susceptibility of
a patient to a particular toxic manifestation, e.g., patients with neurologic
disorders have an increased risk of seizures and patientswith cardiac disease
have an increased risk of cardiac arrhythmias for a given serum theophylline
concentration compared to patients without the underlying disease. The
frequency of various reported manifestations of theophylline overdose according
to the mode of overdose are listed in Table IV. Other
manifestations of theophylline toxicity include increases in serum calcium,
creatine kinase, myoglobin and leukocyte count, decreases in serum phosphate
and magnesium, acute myocardial infarction, and urinary retention in men with
obstructive uropathy. Seizures associated with serum
theophylline concentrations>30 mcg/mL are often resistant to anticonvulsant
therapy and may result in irreversible brain injury if not rapidly controlled.
Death from theophylline toxicity is most often secondary to cardiorespiratory
arrest and/or hypoxic encephalopathy following prolonged generalized seizures
or intractable cardiac arrhythmias causing hemodynamiccompromise.<br/>Overdose Management:: General
Recommendations for Patients with Symptoms of Theophylline Overdose or Serum
Theophylline Concentrations>30 mcg/mL (Note: Serum theophylline concentrations
may continue to increase after presentation of the patient for medical care.)<br/>Specific Recommendations:: Acute
Overdose B. Serum Concentration>30<100
mcg/mL C. Serum Concentration>100
mcg/mL Chronic Overdosage A. Serum Concentration>20<30 mcg/mL (with manifestations
of theophylline toxicity) B. Serum Concentration>30
mcg/mL in patients<60 years of age C. Serum Concentration>30
mcg/mL in patients���60 years of age.<br/>Extracorporeal Removal:: Increasing the rate of theophylline clearance by extracorporeal
methods may rapidly decrease serum concentrations, but the risks of the procedure
must be weighed against the potential benefit. Charcoal hemoperfusion is the
most effective method of extracorporeal removal, increasing theophylline clearance
up to six fold, but serious complications, including hypotension, hypocalcemia,
platelet consumption and bleeding diatheses may occur. Hemodialysis is about
as efficient as multiple-dose oralactivated charcoal and has a lower risk
of serious complications than charcoal hemoperfusion. Hemodialysis should
be considered as an alternative when charcoal hemoperfusion is not feasible
and multiple-dose oral charcoal is ineffective because of intractable emesis.
Serum theophylline concentrations may rebound 5-10 mcg/mL after discontinuation
of charcoal hemoperfusion or hemodialysis due to redistribution of theophylline
from the tissue compartment. Peritoneal dialysis is ineffective for theophylline
removal; exchange transfusions in neonates have been minimally effective.
|
dailymed-instance:genericMe... |
theophylline, anhydrous
|
dailymed-instance:fullName |
Quibron T/SR (Tablet)
|
dailymed-instance:adverseRe... |
Adverse reactions associated with theophylline are generally
mild when peak serum theophylline concentrations are<20 mcg/mL and mainly
consist of transient caffeine-like adverse effects such as nausea, vomiting,
headache, and insomnia. When peak serum theophylline concentrations exceed
20 mcg/mL, however, theophylline produces a wide range of adverse reactions
including persistent vomiting, cardiac arrhythmias, and intractable seizures
which can be lethal .
The transient caffeine-like adverse reactions occur in about 50% of patients
when theophylline therapy is initiated at doses higher than recommended initial
doses (e.g.,>300 mg/day in adults and>12 mg/kg/day in children beyond>1
year of age). During the initiation of theophylline therapy, caffeine-like
adverse effects may transiently alter patient behavior, especially in school
age children, but this response rarely persists. Initiation of theophylline
therapy at a low dose with subsequent slow titration to a predetermined age-related
maximum dose will significantly reduce the frequency of these transient adverse
effects. In a small percentage of patients (<3%
of children and<10% of adults) the caffeine-like adverse effects persist
during maintenance therapy, even at peak serum theophylline concentrations
within the therapeutic range (i.e., 10-20 mcg/mL). Dosage reduction may alleviate
the caffeine-like adverse effects in these patients, however, persistent adverse
effects should result in a reevaluation of the need for continued theophylline
therapy and the potential therapeutic benefit of alternative treatment. Other
adverse reactions that have been reported at serum theophylline concentrations<20 mcg/mL include diarrhea, irritability, restlessness, fine skeletal
muscle tremors, and transient diuresis. In patients with hypoxia secondary
to COPD, multifocal atrial tachycardia and flutter have been reported at serum
theophylline concentrations���15 mcg/mL. There have been a few isolated
reports of seizures at serum theophylline concentrations<20 mcg/mL in
patients with an underlying neurological disease or in elderly patients. The
occurrence of seizures in elderly patients with serum theophylline concentrations<20 mcg/mL may be secondary to decreased protein binding resulting in a
larger proportion of the total serum theophylline concentration in the pharmacologically
active unbound form. The clinical characteristics of the seizures reported
in patients with serum theophylline concentrations<20 mcg/mL have generally
been milder than seizures associated with excessive serum theophylline concentrations
resulting from an overdose (i.e. they have generally been transient, often
stopped without anticonvulsant therapy, and did not result in neurological
residua). * These data are derived from two studies in patients with
serum theophylline concentrations>30 mcg/mL. In the first study (Study #1
- Shanon, Ann Intern Med 1993;119:1161-67), data were prospectively collected
from 249 consecutive cases of theophylline toxicity referred to a regional
poison center for consultation. In the second study (Study #2 - Sessler, Am
J Med 1990;88:567-76), data were retrospectively collected from 116 cases
with serum theophylline concentrations>30 mcg/mL among 6000 blood samples
obtained for measurement of serum theophylline concentrations in three emergency
departments. Differences in the incidence of manifestations of theophylline
toxicity between the two studies may reflect sample selection as a result
of study design (e.g., in Study #1, 48% of the patients had acute intoxications
versus only 10% in Study #2) and different methods of reporting results. **
NR = Not reported in a comparable manner.
|
dailymed-instance:warning |
Concurrent Illness:: Theophylline should be used with extreme caution in patients
with the following clinical conditions due to the increased risk of exacerbation
of the concurrent condition: Active
peptic ulcer disease Seizure disorders Cardiac
arrhythmias (not including bradyarrhythmias)<br/>Conditions That Reduce Theophylline Clearance:: There are several readily identifiable causes of reduced
theophylline clearance. If the total daily dose is not appropriately
reduced in the presence of these risk factors, severe and potentially fatal
theophylline toxicity can occur. Careful consideration
must be given to the benefits and risks of theophylline use and the need for
more intensive monitoring of serum theophylline concentrations in patients
with the following risk factors:<br/>When Signs or Symptoms of Theophylline Toxicity Are Present:: Whenever
a patient receiving theophylline develops nausea or vomiting, particularly
repetitive vomiting, or other signs or symptoms consistent with theophylline
toxicity (even if another cause may be suspected), additional doses of theophylline
should be withheld and a serum theophylline concentration measured immediately. Patients should be instructed not to continue any dosage
that causes adverse effects and to withhold subsequent doses until the symptoms
have resolved, at which time the clinician may instruct the patient to resume
the drug at a lower dosage (see DOSAGE
AND ADMINISTRATION, Dosing
Guidelines, Table VI).<br/>Dosage Increases:: Increases in the dose of theophylline should not be made
in response to an acute exacerbation of symptoms of chronic lung disease since
theophylline provides little added benefit to inhaled beta2-selective agonists
and systemically administered corticosteroids in this circumstance and increases
the risk of adverse effects. A peak steady-state serum theophylline concentration
should be measured before increasing the dose in response to persistent chronic
symptoms to ascertain whether an increase in dose is safe. Before increasing
the theophylline dose on the basis of a low serum concentration, the clinician
should consider whether the blood sample was obtained at an appropriate time
in relationship to the dose and whether the patient has adhered to the prescribed
regimen . As
the rate of theophylline clearance may be dose-dependent (i.e., steady-state
serum concentrations may increase disproportionately to the increase in dose),
an increase in dose based upon a sub-therapeutic serum concentration measurement
should be conservative. In general, limiting dose increases to about 25% of
the previous total daily dose will reduce the risk of unintended excessive
increases in serum theophylline concentration (see DOSAGE
AND ADMINISTRATION, Table VI).
|
dailymed-instance:indicatio... |
Theophylline is indicated for the treatment of the symptoms
and reversible airflow obstruction associated with chronic asthma and other
chronic lung diseases, e.g., emphysema and chronic bronchitis
|
dailymed-instance:represent... | |
dailymed-instance:routeOfAd... | |
dailymed-instance:name |
Quibron T/SR
|