Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/1660
| Predicate | Object |
|---|---|
| rdf:type | |
| rdfs:label |
Quibron-T (Tablet)
|
| dailymed-instance:dosage |
General Considerations:: 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 the previous 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. Table V. Dosing initiation and titration (as
anhydrous theophylline).*,��� A. Infants<1 year old. 1. Initial Dosage. a. Premature Neonates: i.<24 days postnatal age; 1.0 mg/kg every 12 hr ii.���24
days postnatal age; 1.5 mg/kg every 12 hr b.
Full term infants and infants up to 52 weeks of age: Total daily dose
(mg) = [(0.2 x age in weeks)+5.0] x (Kg body Wt). i. up to age
26 weeks; divide dose into 3 equal amounts administered at 8 hour
intervals. ii.>26 Weeks of age; divide dose into 4 equal amounts administered at
6 hour intervals. 2. Final Dosage. Adjusted to maintain
a peak steady-state serum theophylline concentration of 5-10 mcg/mL
in neonates and 10-15 mcg/mL in older infants (see Table VI). Since the time required to reach
steady-state is a function of theophylline half-life, up to 5 days
may be required to achieve steady-state in a premature neonate while
only 2-3 days may be required in a 6 month old infant without other
risk factors for impaired clearance in the absence of a loading dose.
If a serum theophylline concentration is obtained before steady-state
is achieved, the maintenance dose should not be increased, even if
the serum theophylline concentration is<10 mcg/mL. B. Children (1-15 years) and adults (16-60 years) without risk factors
for impaired clearance. C. Patients With Risk Factors For Impaired Clearance,The
Elderly (>60 Years), And Those In Whom It Is Not Feasible To Monitor
Serum Theophylline Concentrations: In children
1-15 years of age, the final theophylline dose should not exceed 16
mg/kg/day up to a maximum of 400 mg/day in the presence of risk factors
for reduced theophylline clearance (see WARNINGS) or if it is not feasible to monitor serum theophylline
concentrations. In adolescents���16 years
and adults, including the elderly, the final theophylline dose should
not exceed 400 mg/day in the presence of risk factors for reduced
theophylline clearance or if it is not feasible to monitor serum theophylline concentrations. D. Loading Dose for Acute Bronchodilatation: An inhaled beta-2 selective agonist, alone or in combination
with a systemically administered corticosteroid, is the most effective
treatment for acute exacerbations of reversible airways obstruction.
Theophylline is a relatively weak bronchodilator, is less effective
than an inhaled beta-2 selective agonist and provides no added benefit
in the treatment of acute bronchospasm. If an inhaled or parenteral
beta agonist is not available, a loading dose of an oral immediate
release theophylline can be used as atemporary measure. A single
5 mg/kg dose of theophylline, in a patient who has not received any
theophylline in the previous 24 hours, will produce an average peak
serum theophylline concentration of 10 mcg/mL (range 5-15 mcg/mL).
If dosing with theophylline is to be continued beyond the loading
dose, the guidelines in Sections A.1.b., B.3, or C., above, should
be utilized and serum theophylline concentration monitored at 24 hour
intervals to adjust final dosage. * Patients
with more rapid metabolism, clinically identified by higher than average
dose requirements, should receive a smaller dose more frequently to
prevent breakthrough symptoms resulting from low trough concentrations
before the next dose. A reliably absorbed slow-release formulation
will decrease fluctuations and permit longer dosing intervals. ���For products containing theophylline salts, the
appropriate dose of the theophylline salt should be substituted for
the anhydrous theophylline dose. To calculate the equivalent dose
for theophylline salts, divide the anhydrous theophylline dose listed
below by 0.8 for aminophylline, by 0.65 for oxtriphylline, and by
0.5 for the calcium salicylate and sodium glycinate salts.
|
| 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 is available as tablets intended
for oral administration, containing 300 mg of anhydrous theophylline
per tablet. Quibron-T is an oral bronchodilator in
an immediate-release formulation in the ACCUDOSE Tablet
design. With functional trisects and bisects, Quibron-T Tablets can be accurately divided into 100-, 150-, and 200-mg
segments to provide a variety of dosing increments, as required. Inactive Ingredients: microcrystalline cellulose, yellow ferric oxide, hydroxypropyl methylcellulose
2910, lactose monohydrate, magnesium stearate, colloidal silicon dioxide,
and sodium starch glycolate.
|
| dailymed-instance:clinicalP... |
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. Morefrequent measurements should be made in
the presence of any condition that may significantly alter theophylline
clearance . 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.<br/>Absorption: Theophylline is rapidly and completely absorbed after
oral administration in solution or immediate-release solid oral dosage
form. After a single 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.<br/>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 andpotentially
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.<br/>Metabolism: Following oral dosing, theophylline does not undergo
any measurable firstpass 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 decreasesin 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 prior
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.<br/>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 andchildren>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 .<br/>Serum Concentrations at Steady State: After multiple doses of 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.<br/>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 the dose, 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 concentrationsare 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 causesa 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.
|
| dailymed-instance:activeIng... | |
| dailymed-instance:contraind... |
QUIBRON-T ACCUDOSE Tablets are contraindicated in patients with a history of hypersensitivity
to theophylline or other components in the product.
|
| dailymed-instance:supply |
Quibron-T Tablets: Bottles of 100,
ivory, in the ACCUDOSE Tablet design with���M
020���debossed on one side, containing 300 mg of anhydrous theophylline. NDC 61570-020-01 Store from 15��-25��C
(59��-77��F) Rx only. Manufactured for Monarch
Pharmaceuticals, Inc., Bristol, TN 37620 Manufactured by Bristol-Myers Squibb, Princeton, NJ 08543
|
| dailymed-instance:activeMoi... | |
| dailymed-instance:inactiveI... | |
| dailymed-instance:precautio... |
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 .<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;
1-2 hours after a dose at steady-state. 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 been taken
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 interpretedwith 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:: 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 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
consulting their 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:: 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
steadystate 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 October 8, 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.<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 theproportion 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). Dueto 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 bedecreased
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 . Theophylline doses greater than 400 mg/day should be prescribed
with caution in elderly patients.
|
| 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 response to an exacerbationof 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 patients with 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 hemodynamic compromise.<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::<br/>Acute Overdose:<br/>Chronic Overdosage:<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 oral activated 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... |
Theophyllin, anhydrous
|
| dailymed-instance:fullName |
Quibron-T (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 (seeDOSAGE AND ADMINISTRATION, Table
V). 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).
|
| 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: Age Neonates (term
and premature) Children<1
year Elderly (>60 years) Concurrent Diseases Acute
pulmonary edema Congestive
heart failure Cor-pulmonale Fever;���102��for 24 hours
or more; or lesser temperature elevations for longer periods Hypothyroidism Liver disease; cirrhosis, acute hepatitis Reduced renal function in infants<3
months of age Sepsis with
multi-organ failure Shock Cessation of Smoking Drug Interactions Adding a drug that inhibits theophylline metabolism (e.g.,
cimetidine, erythromycin, tacrine) or stopping a concurrently administered
drug that enhances theophylline metabolism (e.g., carbamazepine, rifampin).
.<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 (see PRECAUTIONS, Laboratory
Tests). 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 .
|
| 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
|