Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/942
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Theophylline in Dextrose (Injection, Solution)
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General
Considerations:: The
steady-state peak serum theophylline concentration is a function
of the infusion rate and the rate of theophylline clearance in
the individual patient. Because of marked individual differences
in the rate of theophylline clearance, the dose required to
achieve a 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. 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. 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. When
theophylline is used as an acute bronchodilator, the goal of
obtaining a therapeutic serum concentration is best accomplished
with an intravenous loading dose. Because of rapid distribution
into body fluids, the serum concentration (C) obtained from an
initial loading dose (LD) is related primarily to the volume of
distribution (V), the apparent space into which the drug
diffuses: C = LD/V If a mean
volume of distribution of about 0.5 L/kg is assumed (actual
range is 0.3 to 0.7 L/kg), each mg/kg (ideal body weight) of
theophylline administered as a loading dose over 30 minutes
results in an average 2 mcg/mL increase in serum theophylline
concentration. Therefore, in a patient who has received no
theophylline in the previous 24 hours, a loading dose of
intravenous theophylline of 4.6 mg/kg, calculated on the basis
of ideal body weight and administered over 30 minutes, on
average, will produce a maximum post-distribution serum
concentration of 10 mcg/mL with a range of 6-16 mcg/mL. When a
loading dose becomes necessary in the patient who has already
received theophylline, estimation of the serum concentration
based upon the history is unreliable, and an immediate serum
level determination is indicated. The loading dose can then be
determined as follows: D =
(Desired C - Measured C)(V) where D is
the loading dose, C is the serum theophylline concentration, and
V is the volume of distribution. The mean volume of distribution
can be assumed to be 0.5 L/kg and the desired serum
concentration should be conservative (e.g., 10 mcg/mL) to allow for
the variability in the volume of distribution. A loading dose should not be
given before obtaining a serum theophylline
concentration if the patient has received any
theophylline in the previous 24 hours. A serum
concentration obtained 30 minutes after an intravenous loading
dose, when distribution is complete, can be used to assess the
need for and size of subsequent loading doses, if clinically
indicated, and for guidance of continuing therapy. Once a serum
concentration of 10 to 15 mcg/mL has been achieved with the use
of a loading dose(s), a constant intravenous infusion is
started. The rate of administration is based upon mean
pharmacokinetic parameters for the population and calculated to
achieve a target serum concentration of 10 mcg/mL (see Table
VI). For example, in nonsmoking adults, initiation of a constant
intravenous theophylline infusion of 0.4 mg/kg/hr at the
completion of the loading dose, on average, will result in a
steady-state concentration of 10 mcg/mL with a range of 7-26
mcg/mL. The mean and range of steady-state serum concentrations
are similar when the average child (age 1 to 9 years) is given a
loading dose of 4.6 mg/kg theophylline followed by a constant
intravenous infusion of 0.8 mg/kg/hr. Since there is large
interpatient variability in theophylline clearance, serum
concentration will rise or fall when the patient's
clearance is significantly different from the mean population
value used tocalculate the initial infusion rate. Therefore, a
second serum concentration should be obtained one expected
half-life after starting the constant infusion (e.g., approximately 4 hours
for children age 1 to 9 and 8 hours for nonsmoking adults; See
Table II for the expected half-life in additional patient
populations) to determine if the concentration is accumulating
or declining from the post loading dose level. If the level is
declining as a result of a higher than average clearance, an
additional loadingdose can be administered and/or the infusion
rate increased. In contrast, if the second sample demonstrates a
higher level, accumulation of the drug can be assumed, and the
infusion rate should be decreased before the concentration
exceeds 20 mcg/mL. An additional sample is obtained 12 to 24
hours later to determine if further adjustments are required and
then at 24-hour intervals to adjust for changes, if they occur.
This empiric method, based upon mean pharmacokinetic parameters,
will prevent large fluctuations in serum concentration during
the most critical period of the patient's course. In patients
with cor pulmonale, cardiac decompensation, or liver
dysfunction, or in those taking drugs that markedly reduce theophylline clearance (e.g., cimetidine), the initial theophylline infusion rate should not exceed 17 mg/hr unless serum concentrations can
be monitored at 24-hour intervals. In these patients, 5 days may
be required before steady-state is reached. Theophylline distributes poorly into body fat, therefore, mg/kg
dose should be calculated on the basis of ideal body weight. Table VI
contains initial theophylline infusion rates following an
appropriate loading dose recommended for patients in various age
groups and clinical circumstances. Table VII contains
recommendations for final 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. Many
intravenous theophylline products are supplied as aminophylline
where ethylenediamine is added to solubilize theophylline.
Ethylenediamine is not required for solubility of premixed
Theophylline and 5% Dextrose Injection. Each milligram of
aminophylline dihydrate contains approximately 0.8 milligrams of
theophylline anhydrous. Equivalent doses of premixed
Theophylline and 5% Dextrose Injection can be determined by
multiplying those doses specified as aminophylline dihydrate by
0.8. Parenteral
drug products should be inspected visually for particulate
matter and discoloration prior to administration whenever
solution and container permit. Use of a final filter is
recommended during administration of all parenteral solutions,
where possible. Allinjections in VIAFLEX Plus plastic containers are intended for
intravenous administration using sterile equipment. Because
dosages of this drug are titrated to response, no additives should be made to Theophylline
and 5% Dextrose Injections.
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Theophylline in 5%
Dextrose Injection, USP is a sterile, nonpyrogenic solution of
Theophylline, Anhydrous, USP in 5% Dextrose Injection. It contains no
antimicrobial agents. 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
1H-Purine-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. Dextrose Hydrous, USP has the chemical name
D-Glucose monohydrate and is represented by the following structural
formula: Theophylline in 5%
Dextrose Injection, USP is intended for intravenous administration.
Composition, osmolarity, pH and caloric content are shown in Table I. This VIAFLEX Plus
plastic container is fabricated from a specially formulated polyvinyl
chloride (PL 146 Plastic). VIAFLEX Plus on the container indicates the
presence of a drug additive in a drug vehicle. The VIAFLEX Plus plastic
container system utilizes the same container as the VIAFLEX plastic
container system. The amount of water that can permeate from inside the
container into the overwrap is insufficient to affect the solution
significantly. Solutions in contact with the plastic container can leach
out certain of its chemical components in very small amounts within the
expiration period, e.g.,
di-2-ethylhexyl phthalate (DEHP), up to 5 parts per million. However,
the safety of the plastic has been confirmed in tests in animals
according to USP biological tests for plastic containers as well as by
tissue culture toxicity studies.
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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 bronchodilation 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 and pulmonary function has been
found in most studies to require serum theophylline
concentrations>10 mcg/mL. At serum theophylline concentrations>20 mcg/mL, both the frequency and severity of adverse reactions
increase. In general, maintaining the average serum theophylline
concentration 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::<br/>Overview: 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 II) and
co-administration of other drugs (see Table III) 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 receiving
intravenous theophylline (e.g., at 24-hr intervals). More frequent
measurements should be made during the initiation of
therapy and in the presence of any condition that may
significantly alter theophylline clearance .<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 breastmilk 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 mayshow 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.<br/>Metabolism: In
adults and children beyond one year of age,
approximately 90% of the dose is metabolized in the
liver. Biotransformation takes place through
de-methylation 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 de-methylation 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. De-methylation to
1-methylxanthine appears to be catalyzed either by
cytochrome P-450 1A2 or a closely related cytochrome. In
neonates, the N-de-methylation 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-de-methylation 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.<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 renalinsufficiency 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
.<br/>Serum
Concentrations at Steady-State: In
a patient who has received no theophylline in the
previous 24 hours, a loading dose of intravenous
theophylline of 4.6 mg/kg calculated on the basis of
ideal body weight and administered over 30 minutes, on
average, will produce a maximum post-distribution serum
concentration of 10 mcg/mL with a range of 6-16 mcg/mL.
In nonsmoking adults, initiation of a constant
intravenous theophylline infusion of 0.4 mg/kg/hr at the
completion of the loading dose, on average, will result
in a steady-state concentration of 10 mcg/mL with a
range of 7-26 mcg/mL. The mean and range of steady-state
serum concentrations are similar when the average child
(age 1 to 9 years) is given a loadingdose of 4.6 mg/kg
theophylline followed by a constant intravenous infusion
of 0.8 mg/kg/hr.<br/>Special
Populations (See Table II for mean clearance and half-life
values):<br/>Clinical Studies:: Inhaled
beta-2 selective agonists and systemically administered
corticosteroids are the treatments of first choice for
management of acute exacerbations of asthma. The results of
controlled clinical trials on the efficacy of adding intravenous
theophylline to inhaled beta-2 selective agonists and
systemically administered corticosteroids in the management of
acuteexacerbations of asthma have been conflicting. Most
studies in patients treated for acute asthma exacerbations in an
emergency department have shown that addition of intravenous
theophylline does not produce greater bronchodilation and
increases the risk of adverse effects. In contrast, other
studies have shown that addition of intravenous theophylline is
beneficial in the treatment of acute asthma exacerbations in
patients requiring hospitalization, particularly in patients who
are not responding adequately to inhaled beta-2 selective
agonists. 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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Theophylline in 5%
Dextrose Injection, USP is contraindicated in patients with a history of
hypersensitivity to theophylline or other components in the product.
Solutions containing dextrose may be contraindicated in patients with
known allergy to corn or corn products.
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Theophylline in 5%
Dextrose Injection, USP in VIAFLEX Plus plastic container is available
as follows: Exposure of
pharmaceutical products to heat should be minimized. Avoid excessive
heat. It is recommended the product be stored at room temperature
(25��C); brief exposure up to 40��C does not adversely
affect the product. Caution: Federal (USA) law prohibits
dispensing without prescription.
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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 and prior to increases in theophylline dose
.<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: In patients
who have received no theophylline in the previous 24 hours, a
serum concentration should be measured 30 minutes after
completion of the intravenous loading dose to determine whether
the serum concentration is<10 mcg/mL indicating the need
for an additional loading dose or>20 mcg/mL indicating the need
to delay starting the constant IV infusion. Once the infusion is
begun, a second measurement should be obtained after one
expected half-life (e.g.,
approximately 4 hours in children age 1 to 9 years and 8 hours
in nonsmoking adults; See Table II for the expected half-life in
additional patient populations). The second measurement should
be compared to the first to determine the direction in which the
serum concentration has changed. The infusion rate can then be
adjusted before steady-state is reached in an attempt to prevent
an excessive or sub-therapeutic theophylline concentration from
being achieved. If a patient has received theophylline in the
previous 24 hours, the serum concentration should be measured
before administering an intravenous loading dose to make sure
that it is safe to do so. If a loading dose is not indicated
(i.e., the serum
theophylline concentration is���10 mcg/mL), a second
measurement should be obtained as above at the appropriate time
after starting the intravenous infusion. If, on the other hand,
a loading dose is indicated (see DOSAGE AND
ADMINISTRATION for guidance on selection of the
appropriate loading dose), a second blood sample should be
obtained after the loading dose and a third sample should be
obtained one expected half-life after starting the constant
infusion to determine the direction in which the serum
concentration has changed. Once the
above procedures related to initiation of intravenous
theophylline infusion have been completed, subsequent serum
samples for determination of theophylline concentration should
be obtained at 24-hour intervals for the duration of the
infusion. The theophylline infusion rate should be increased or
decreased as appropriate based on the serum theophylline levels.
When signs or symptoms of theophylline toxicity are present, the
intravenous infusion should be stopped and a serum sample for
theophylline concentration 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 ofpregnancy), 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����q/l to 800����q/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/>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 III have the potential to produce clinically
significant pharmacodynamic or pharmacokinetic interactions with
theophylline. The information in the���Effect���column of Table III 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 IV 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
listings of drugs in Tables III and IV are current as of
September 1, 1995. 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 III.
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 and
Mutagenesis and 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 B6C3Fmice at oral doses of 120,
270 and 500 mg/kg (approximately 1.0-3.0 times the human dose on
a mg/mbasis) 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 B6C3Fmice at oral doses of 40-300 mg/kg
(approximately 2.0 times the human dose on a mg/mbasis). At the high dose, systemic toxicity was observed in both
species including decreases in testicular weight.<br/>Pregnancy:<br/>Pregnancy
Category C:<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 receive10-20 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 (See, INDICATIONS
AND USAGE). The constant infusion rate of
intravenous theophylline must be selected with caution in
children since the rate of theophylline clearance is highly
variable across the age range of neonates to adolescents (seeCLINICAL
PHARMACOLOGY, Table II, WARNINGS, and DOSAGE AND
ADMINISTRATION,Table VI). Due to the immaturity
of theophylline metabolic pathways in children 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 infusion
rate. 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 infusion rate of
theophylline in patients greater than 60 years of age ordinarilyshould not exceed 17 mg/hr unless the patient continues to be
symptomatic and the peak steady-state serum theophylline
concentration is<10 mcg/mL (see DOSAGE AND
ADMINISTRATION). Theophylline infusion rates
greater than 17 mg/hr should be prescribed with caution in
elderly patients. Do not
administer unless solution is clear and seal is
intact.
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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., infusion of an excessive
loading dose or excessive maintenance infusion rate for less
than 24 hours, and (2) chronic overdosage, i.e., excessive maintenance infusion rate for greater
than 24 hours. The most common causes of chronic theophylline
overdosage include clinician prescribing of an excessive dose or
a normal dose in the presence offactors known to decrease the
rate of theophylline clearance, and increasing the dose in
response to an exacerbation of symptoms without first measuring
the serum theophylline concentration to determine whether a dose
increase is safe. Several
studies have described the clinical manifestations of
theophylline overdose following oral administration 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 oral
theophylline overdose according to the mode of overdose are
listed in Table V. 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 while receiving
intravenous theophylline.<br/>Specific
Recommendations:: Acute Overdose (e.g., excessive loading
dose or excessive infusion rate for<24
hours) Chronic Overdosage (e.g., excessive infusion
rate for>than 24 hours)<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.
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| dailymed-instance:genericMe... |
Theophylline, anhydrous
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| dailymed-instance:fullName |
Theophylline in Dextrose (Injection, Solution)
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| 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 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 . 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). Reactions which may
occur because of the solution or the technique of administration include
febrile response, infection at the site of injection, venous thrombosis
or phlebitis extending from the site of injection, extravasation and
hypervolemia. If an adverse
reaction does occur, discontinue the infusion, evaluate the patient,
institute appropriate therapeutic countermeasures, and save the
remainder of the fluid for examination if deemed necessary.
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| 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 infusion rate 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). (See PRECAUTIONS, Drug Interactions, Table
III).<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), the intravenous administration
should be stopped and a serum theophylline concentration
measured immediately.<br/>Dosage Increases:: Increases
in the dose of intravenous theophylline should not be made in
response to an acute exacerbation of symptoms unless the
steady-state serum theophylline concentration is<10
mcg/mL. 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 infusion rate increases to about 25% of the previous
infusion rate will reduce the risk of unintended excessive
increases in serum theophylline concentration (see DOSAGE AND
ADMINISTRATION, Table VII). Solutions
containing dextrose should not be administered simultaneously
through the same administration set as blood, as this may result
in pseudoagglutination or hemolysis. The
intravenous administration of solutions may cause fluid
overloading resulting in dilution of serum electrolyte
concentrations, overhydration, congested states or pulmonary
edema.
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| dailymed-instance:indicatio... |
Intravenous
theophylline is indicated as an adjunct to inhaled beta-2 selective
agonists and systemically administered corticosteroids for the treatment
of acute exacerbations of the symptoms and reversible airflow
obstruction associated with asthma and other chronic lung diseases,e.g., emphysema and chronic
bronchitis.
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| dailymed-instance:represent... | |
| dailymed-instance:routeOfAd... | |
| dailymed-instance:name |
Theophylline in Dextrose
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