Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/3844
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Theophylline in Dextrose (Injection, Solution)
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These solutions are for intravenous use only. General Considerations: The steady-state 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
subtherapeutic or potentially toxic serum theophylline concentrations
in individual patients. The dose of theophylline
must be individualized on the basis of 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: 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 alreadyreceived 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: 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 V). 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 pediatric patient (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 concentrations will rise
or fall when the patient's clearance is significantly different
from the mean population value used to calculate 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:
SeeTable I 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 loading dose 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 V contains
initial theophylline infusion rates following an appropriate loading
dose recommended for patients in various age groups and clinical circumstances.
Table VI 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 unexpectedlarge
increases in serum theophylline concentration. Parenteral drug products should be inspected visually
for particulate matter and discoloration prior to administration,
whenever solution and container permit. Preparation for Administration (Use aseptic technique) WARNING: DO NOT USE FLEXIBLE
CONTAINER IN SERIES CONNECTIONS.
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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, USP is chemically designated D-glucose, monohydrate (CHO���HO), a hexose
sugar freely soluble in water. It has the following structural formula: The molecular weight is
198.17. Water for Injection, USP is chemically
designated HO. Theophylline 200,
400 and 800 mg in 5% Dextrose Injection, USP are sterile, nonpyrogenic
solutions of theophylline, anhydrous and dextrose in water for injection.
See Table in HOW SUPPLIED for summary of contents and characteristics of these solutions. The solutions contain no bacteriostatic, antimicrobial
agent or added buffer and are intended only for use as a single-dose
administration. When smaller doses are required, the unused portion
should be discarded. The flexible plastic container
is fabricated from a specially formulated polyvinylchloride. Water
can permeate from inside the container into the overwrap but not in
amounts sufficient to affect the solution significantly. Solutions
in contact with the plastic container may leach out certain of its
chemical components from the plastic in very small amounts; however,
biological testing was supportive of the safety of the plastic container
materials. Exposure to temperatures above 25��C/77��F during
transport and storage will lead to minor losses in moisture content.
Higher temperatures lead to greater losses. It is unlikely that these
minor losses will lead to clinically significant changes within the
expiration period.
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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 nonbronchodilator 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. 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. Pharmacokinetics: 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 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 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
(see PRECAUTIONS, Effects on Laboratory Tests). 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. 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 withhepatic 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 subtherapeutic 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 In adults and pediatric
patients 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,
nonlinearity of elimination may begin in some patients at serum theophylline
concentrations<10 mcg/mL. Since this nonlinearity 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 (see DOSAGE AND ADMINISTRATION, Table VI). 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 pediatric patients>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 (see WARNINGS). 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 pediatric patient (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. (See DOSAGE AND ADMINISTRATION.) Special Populations
(see Table I for mean clearance and half-life values) Geriatrics 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 (see WARNINGS). Pediatrics The clearance
of theophylline is very low in neonates (see WARNINGS). 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 (see WARNINGS and DOSAGE AND ADMINISTRATION). 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 (see WARNINGS). 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 (see WARNINGS). 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 (see WARNINGS). 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 nonsmoking 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 (see WARNINGS). 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. Careful
attention to dose reduction and frequent monitoring of serum theophylline
concentrations are required in patients with sustained fever (see WARNINGS). 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 (see WARNINGS). Other factors associated with increased theophylline clearance
include hyperthyroidism and cystic fibrosis.
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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 200, 400 and 800 mg in 5% Dextrose Injection,
USP is supplied in single-dose containers in various sizes and concentrations
as shown in the accompanying Table. Protect from freezing. Store at 20 to 25��C
(68 to 77��F). [See USP Controlled Room Temperature.] Revised: July, 2008
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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 (see WARNINGS). 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 has
begun, a second measurement should be obtained after one expected
half life (e.g., approximately 4 hours in pediatric patients
age 1 to 9 years and 8 hours in nonsmoking adults; See Table I 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 subtherapeutic 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 theophyllinetoxicity 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
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. Clinical evaluation and periodic laboratory determinations
are necessary to monitor changes in fluid balance, electrolyte concentrations,
and acid-base balance during prolonged therapy or whenever the condition
of the patient warrants such evaluation. Do
not use plastic container in series connection. If administration is controlled by a pumping device, care must
be taken to discontinue pumping action before the container runs dry
or air embolism may result. These solutions
are intended for intravenous administration using sterile equipment.
It is recommended that intravenous administration apparatus be replaced
at least once every 24 hours. Use only if
solution is clear and container and seals are intact.<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/>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
onlyrarely 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 toxiclevels, 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 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
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. 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, 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 - 3 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 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 Category C:: Teratogenic Effects There are no adequate and well-controlled
studies in pregnant women. In animal reproduction studies, maternal
doses of theophylline less than one to two times the recommended oral
dose in humans caused fetal harm, including fetal malformations. Asthma
is a serious and potentially life-threatening condition. Poorly controlled
asthmaduring pregnancy is associated with adverse outcomes for mother
and fetus. Theophylline should be used during pregnancy only if the
potential benefit justifies the potential risk to the fetus. Population-based studies and post-marketing adverse eventreporting of theophylline used during human pregnancy have not demonstrated
an increased risk of major congenital anomalies. However, most studies
were not large enough to detect a less than two fold increase in risk
for congenital anomalies. Post-marketing data are reported voluntarily
and do not always reliably estimate the frequency of particular adverse
outcomes. In animal reproduction studies, theophylline
produced teratogenic effects when pregnant mice, rats and rabbits
were dosed during the period of organogenesis. In mice, a single intraperitoneal dose at and above 100 mg/kg (approximately
equal to the maximum recommended oral dose for adults on a mg/mbasis) produced a cleft palate and digital abnormalities.
Micromelia, micrognathia, club foot, subcutaneous hematoma, open eyelids,
and embryolethality were observed at doses approximately 2 times the
maximum recommended oral dose for adults on a mg/mbasis. In rats dosed from conception through organogenesis, an
oral dose of 150 mg/kg/day (approximately 2 times the maximum recommended
oral dose for adults on a mg/mbasis) produced digital
abnormalities. Embryolethality occurred at a subcutaneous dose of
200 mg/kg/day (approximately 4 times the maximum recommended oral
dose for adults on a mg/mbasis). In rabbits dosed intravenously
throughout organogenesis with 60 mg/kg/day (approximately 2 times
the maximum recommended oral dose for adults on a mg/mbasis), caused cleft palate and was embryolethal. This dose was
maternally toxic as one doe died and clinical signs of toxicity occurred
in others. Doses at and above 15 mg/kg/day (less than the maximum
recommended oral dose for adults on a mg/mbasis) increased
the incidence of skeletal variations.<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
per 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 (see INDICATIONS AND USAGE). The constant infusion rate of intravenous
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 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 ordinarily should
not exceed 17 mg/hr unless the patient continues to be symptomatic
and the steady stateserum 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.
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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., 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 of factors 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 concentrationto 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 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. Hypercalcemia has been reported in
a patient with hyperthyroid disease at therapeutic theophylline concentrations. 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. Overdose Management: General
Recommendations for Patients with Symptoms of Theophylline Overdose
or Serum Theophylline Concentrations>30 mcg/mL While Receiving Intravenous
Theophylline Specific Recommendations: Acute
Overdose (e.g., excessive loading dose or excessive infusion rate
for<24 hours) A. Serum Concentration>20<30 mcg/mL B. Serum Concentration>30<100 mcg/mL C. Serum Concentration>100 mcg/mL Chronic Overdosage
(e.g., excessive infusion rate for greater than 24 hours) 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 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 sixfold, 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
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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 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 (see OVERDOSAGE). 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). Hypercalcemia has been reported
in a patient with hyperthyroid disease at therapeutic theophylline
concentrations (see OVERDOSAGE). 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.
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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) 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: 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
infusion should be stopped and a serum theophylline concentration
measured immediately. 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 subtherapeutic
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 VI). Solutions containing dextrose without electrolytes should not be
administered simultaneously with blood through the same infusion set
because of the possibility of agglomeration of erythrocytes. The intravenous administration of these solutions may
cause fluid overloading resulting in dilution of serum electrolyte
concentrations, overhydration, congested states or pulmonary edema.
Because dosages of these drugs are titrated to response (see DOSAGE AND ADMINISTRATION), no additives should be made to Theophylline in 5%
Dextrose Injection USP.
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| dailymed-instance:indicatio... |
Theophylline in 5% Dextrose Injection USP 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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