Etofyiline
A white crystalline powder. Soluble in water: slightly soluble
in alcohol. Protect from light.
Etofylline is a theophylline derivative used as a bronchodila-
tor and for its cardiovascular effects similarly to
theophylline.
It does not liberate theophylline in the body.
Etofylline nicotinate is also used.
DESCRIPTION:
THEOBID(R) Extended-Release Tablets contain anhydrous theophylline in an
extended-release formulation for oral administration which allows a 12-hour
dosing interval for a majority of patients and a 24-hour dosing interval for
selected patients (see DOSAGE AND ADMINISTRATION) for a description of
appropriate patient populations).
THEOPHYLLINE:
Theophylline is a bronchodilator, 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-.
The molecular formula of anhydrous theophylline is C7H8N4O2 with a molecular
weight of 180.17.
The inactive ingredients for THEOBID 100 mg Extended-Release Tablets include:
acacia, NF; acetone; alcohol, NF; cellulose acetate phthalate, NF; cetyl
alcohol, NF; chloroform; confectioner's sugar 6X, NF; corn starch, NF; diethyl
phthalate, NF; ethyl acetate, NF; glyceryl monostearate; isopropyl alcohol, USP;
hydrous spray dried lactose, NF; magnesium stearate, NF; myristyl alcohol, NF;
nonpareil seeds 18-20 mesh, NF; purified water, USP; sodium lauryl sulfate, NF;
talc, USP; and white wax, NF.
ACTIONS/CLINICAL PHARMACOLOGY:
MECHANISM OF ACTION:
Theophylline has two distinct actions in the airways of patients with reversible
obstruction; smooth muscle relaxation (ie, bronchodilation) and suppression of
the response of the airways to stimuli (ie, nonbronchodilator 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 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 (eg, hypotension, tachycardia, headache, and emesis) and adenosine receptor
antagonism (eg, 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 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.
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 presystemic 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 coadministration 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 (eg,
at 24-hour intervals) and periodically in patients receiving long-term therapy
(eg, at 6- to 12-month intervals). More frequent measurements should be made in
the presence of any condition that may significantly alter theophylline
clearance (see PRECAUTIONS), MONITORING SERUM THEOPHYLLINE CONCENTRATIONS, and
DOSAGE AND ADMINISTRATION).
TABLE I. MEAN AND RANGE OF TOTAL BODY CLEARANCE AND HALF-LIFE OF THEOPHYLLINE
RELATED TO AGE AND ALTERED PHYSIOLOGICAL STATES.#
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Total body clearance*
mean (range)&& Half-life mean (range)&&
Population characteristics (mL/kg/min) (hr)
AGE
Premature neonates
postnatal age 3-15 days 0.29 (0.09-0.49) 30 (17-43)
postnatal age 25-57 days 0.64 (0.04-1.2) 20 (9.4-30.6)
Term infants
postnatal age 1-2 days NR& 25.7 (25-26.5)
postnatal age 3-30 weeks NR& 11 (6-29)
Children
1-4 years 1.7 (0.5-2.9) 3.4 (1.2-5.6)
4-12 years 1.6 (0.8-2.4) NR&
13-15 years 0.9 (0.48-1.3) NR&
6-17 years 1.4 (0.2-2.6) 3.7 (1.5-5.9)
Adults (16-60 years)
otherwise healthy
nonsmoking asthmatics 0.65 (0.27-1.03) 8.7 (6.1-12.8)
Elderly (>60 years)
nonsmokers with normal
cardiac, liver, and
renal function 0.41 (0.21-0.61) 9.8 (1.6-18)
CONCURRENT ILLNESS OR ALTERED PHYSIOLOGICAL STATE
Acute pulmonary edema 0.33** (0.07-2.45 19** (3.1-82)
COPD >60 years,
stable nonsmoker >1 year 0.54 (0.44-0.64) 11 (9.4-12.6)
COPD with cor pulmonale 0.48 (0.08-0.88) NR&
Cystic fibrosis (14-28 years) 1.25 (0.31-2.2) 6.0 (1.8-10.2)
Fever associated with NR& 7.0 (1.0-13)
acute viral respiratory
illness (children 9-15 years)
Liver disease - cirrhosis 0.31**(0.1-0.7) 32** (10-56)
acute hepatitis 0.35 (0.25-0.45) 19.2 (16.6-21.8)
cholestasis 0.65 (0.25-1.45) 14.4 (5.7-31.8)
Pregnancy - 1st trimester NR& 8.5 (3.1-13.9)
2nd trimester NR& 8.8 (3.8-13.8)
3rd trimester NR& 13.0 (8.4-17.6)
Sepsis with multi-organ failure 0.47 (0.19-1.9) 18.8 (6.3-24.1)
Thyroid disease - hypothyroid 0.38 (0.13-0.57) 11.6 (8.2-25)
hyperthyroid 0.8 (0.68-0.97) 4.5 (3.7-5.6)
------------------------------------------------------------------------------------------------------------------------------------------------------------------------
# For various North American patient populations from literature reports.
Different rates of elimination and consequent dosage requirements have been
observed among other peoples.
* Clearance represents the volume of blood completely cleared of theophylline
by the liver in 1 minute. Values listed were generally determined at serum
theophylline concentrations <20 mcg/mL; clearance may decrease and half-life
may increase at higher serum concentrations due to nonlinear
pharmacokinetics.
&& Reported range or estimated range (mean +/- 2 S.D.) where actual range not
reported.
& NR = not reported or not reported in a comparable format.
** Median
-----------------------------------------------------------------------------
NOTE: In addition to the factors listed above, theophylline clearance is
increased and half-life decreased by low-carbohydrate/ high-protein diets,
parenteral nutrition, and daily consumption of charcoal-broiled beef. A high-
carbohydrate/low-protein diet can decrease the clearance and prolong the half-
life of theophylline.
ABSORPTION Theophylline is rapidly and completely absorbed after oral
administration in solution or immediate-release solid oral dosage form. After a
single immediate-release theophylline dose of 5 mg/kg in adults, a mean peak
serum concentration of about 10 mcg/mL (range 5-15 mcg/mL) can be expected 1-2
hours after the dose. Coadministration of theophylline with food or antacids
does not cause clinically significant changes in the absorption of theophylline
from immediate-release dosage forms.
THEOBID PRODUCT PHARMACOKINETICS
THEOBID (100, 200, 300, AND 450 MG) EXTENDED- RELEASE TABLETS:
In single-dose studies with 18 normal fasting subjects, the THEOBID product at
8 mg/kg body weight (300-700 mg/dose) produced mean peak theophylline plasma
levels of 7.5 +/- 1.9 mcg/mL at 9.2 +/- 1.9 hours following administration. In
multiple-dose, steady-state 3- and 5-day studies with 12 normal subjects, THEO-
DUR administered at 8 mg/kg (300-600 mg/dose) twice daily, achieved an average
peak-trough difference of 4 mcg/mL. The Cmax and Cmin were 13.9 +/- 6.9 and 9.9
+/- 6.0, respectively. The mean % fluctuation +/- S.D. of the plasma
concentration at steady state (% fluctuation = 100 (Cmax-Cmin)/Cmin) was 54.2
+/- 45.7%. These pharmacokinetic parameters were measured under fasting
conditions.
THEOBID (200, 300, AND 450 MG) EXTENDED-RELEASE TABLETS:
In a multiple-dose (300-500 mg BID) steady-state, 5-day study involving 14
normal, nonfasting subjects with theophylline half-lives between 5.8 and 12.3
hours (mean 8.0 +/- 1.8 hours), THEOBID dosed twice daily, produced mean Cmax
and Cmin levels of 12.2 +/- 2.0 and 10.2 +/- 1.6 mcg/mL, respectively, over the
AM dosing interval and Cmax and Cmin of 11.6 +/- 1.6 and 8.7 +/- 1.8 mcg/mL,
respectively, over the PM dosing interval. The mean % fluctuation +/- S.D. over
the AM dosing interval was 30.4 +/- 12.9% and 33.7 +/- 13.1% over the PM dosing
interval. In the same subjects, the THEOBID product given once daily, in the
morning, in doses ranging from 600-1000 mg (same daily dose as for BID above)
produced a mean Cmax and Cmin of 14.4 +/- 2.2 and 5.5 +/- 2.0, respectively, and
a mean % fluctuation +/- S.D. of 195.8 +/- 106.0%. Average peak-trough
differences over 24 hours were 8.9 +/- 1.3 and 3.7 +/- 1.2 mcg/mL when THEOBID
was given once or twice daily, respectively. In both the twice-daily and once-
daily dosing regimens, THEOBID exhibited complete bioavailability when compared
to an immediate-release product.
THEOBID (200, 300, AND 450 MG) EXTENDED-RELEASE TABLETS:
In a single-dose bioavailability study in eleven subjects, 1000 mg of the THEO-
DUR product was administered under fasting conditions and immediately following
a high-fat content (62 g) breakfast of approximately 1100 kcal. The rate and
extent of absorption of theophylline from THEOBID administered in fasting and
fed conditions were similar.
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 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 Following oral dosing, theophylline does not undergo any measurable
first-pass elimination. In adults and children beyond 1 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 P450 1A2, while cytochromes P450 2E1
and P450 3A3 catalyze the hydroxylation to 1,3-dimethyluric acid. Demethylation
to 1-methylxanthine appears to be catalyzed either by cytochrome P450 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 1 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 V).
Accurate prediction of dose dependency of theophylline metabolism in patients A
PRIORI is not possible, but patients with very high initial clearance rates (ie,
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 3 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
(ie, caffeine, 3-methylxanthine) do not accumulate to clinically significant
levels even in the face of end-stage renal disease, no dosage adjustment for
renal insufficiency is necessary in adults and children >3 months of age. In
contrast, the large fraction of the theophylline dose excreted in the urine as
unchanged theophylline and caffeine in neonates requires careful attention to
dose reduction and frequent monitoring of serum theophylline concentrations in
neonates with reduced renal function (see WARNINGS).
SERUM CONCENTRATIONS AT STEADY STATE After multiple doses of immediate-release
theophylline, steady state is reached in 30-65 hours (average 40 hours) in
adults. At steady state, on a dosage regimen with 6-hour intervals, the expected
mean trough concentration is approximately 60% of the mean peak concentration,
assuming a mean theophylline half-life of 8 hours. The difference between peak
and trough concentrations is larger in patients with more rapid theophylline
clearance. In patients with high theophylline clearance and half-lives of about
4-5 hours, such as children age 1 to 9 years, the trough serum theophylline
concentration may be only 30% of peak with a 6-hour dosing interval. In these
patients a slow-release formulation would allow a longer dosing interval (8-12
hours) with a smaller peak/trough difference.
SPECIAL POPULATIONS (SEE TABLE I FOR MEAN CLEARANCE AND HALF-LIFE VALUES)
GERIATRIC: The clearance of theophylline is decreased by an average of 30% in
healthy elderly adults (>60 yrs) compared to healthy young adults. Careful
attention to dose reduction and frequent monitoring of serum theophylline
concentrations are required in elderly patients (see WARNINGS).
PEDIATRICS: The clearance of theophylline is very low in neonates (see
WARNINGS). Theophylline clearance reaches maximal values by 1 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 3 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, eg, about 10%, of the administered
theophylline dose is excreted unchanged in the urine of children greater than 3
months of age and adults. Since little theophylline is excreted unchanged in the
urine and since active metabolites of theophylline (ie, 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 (eg, 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 appear 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 1 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 39degC (102degF) for at least 24 hours or lesser
temperature elevations for longer periods, are probably required to produce a
clinically significant increase in serum theophylline concentrations. Children
with rapid rates of theophylline clearance (ie, those who require a dose that is
substantially larger than average (eg, >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 (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.
CLINICAL STUDIES:
In patients with chronic asthma, including patients with severe asthma requiring
inhaled corticosteroids or alternate-day oral corticosteroids, many clinical
studies have shown that theophylline decreases the frequency and severity of
symptoms, including nocturnal exacerbations, and decreases the "as needed" use
of inhaled beta2-agonists. Theophylline has also been shown to reduce the need
for short courses of daily oral prednisone to relieve exacerbations of airway
obstruction that are unresponsive to bronchodilators in asthmatics.
In patients with chronic obstructive pulmonary disease (COPD), clinical studies
have shown that theophylline decreases dyspnea, air trapping, the work of
breathing, and improves contractility of diaphragmatic muscles with little or no
improvement in pulmonary function measurements.
INDICATIONS AND USAGE:
THEOBID Extended-Release Tablets are indicated for the treatment of the
symptoms and reversible airflow obstruction associated with chronic asthma and
other chronic lung diseases, eg, emphysema and chronic bronchitis.
CONTRAINDICATIONS:
THEOBID Extended-Release Tablets are contraindicated in patients with a history
of hypersensitivity to theophylline or other components in the product.
WARNINGS:
Serious side effects such as ventricular arrhythmias, convulsions, or even death
may appear as the first sign of toxicity without any recognized prior warning.
Less serious signs of theophylline toxicity (eg, nausea and restlessness) may
occur frequently when initiating therapy but are usually transient. When such
signs are persistent during maintenance therapy, they are often associated with
serum concentrations above 20 mcg/mL. Stated differently, serious toxicity is
not reliably preceded by less severe side effects.
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 (peptic ulcer disease should be controlled with
appropriate therapy since theophylline is known to increase peptic acid
secretion)
Seizure disorders
Cardiac arrhythmias (not including bradyarrhythmias)
CONDITIONS THAT REDUCE THEOPHYLLINE CLEARANCE:
There are several readily identifiable causes of reduced theophylline clearance.
IF THE TOTAL DAILY DOSE IS NOT APPROPRIATELY REDUCED SO AS TO LOWER SERUM
THEOPHYLLINE LEVELS TO WITHIN THE THERAPEUTIC RANGE 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 deg F 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 (eg, cimetidine,
erythromycin, tacrine) or stopping a concurrently administered drug that
enhances theophylline metabolism (eg, carbamazepine, rifampin). (See
PRECAUTIONS, DRUG INTERACTIONS, TABLE II.)
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 SHOULD
BE 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), DOSAGE
GUIDELINES, TABLE V).
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 systematically
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, MONITORING SERUM THEOPHYLLINE CONCENTRATIONS).
As the rate of theophylline clearance may be dose dependent (ie, 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 dose increases to about 25% of the
previous total daily dose will reduce the risk of unintended excessive increases
in serum theophylline concentration (see DOSAGE AND ADMINISTRATION), TABLE V).
PRECAUTIONS:
THEOBID TABLETS SHOULD NOT BE CHEWED OR CRUSHED AND SHOULD BE BROKEN ONLY AT
THE SCORE.
GENERAL:
Careful consideration of the various interacting drugs (including recently
discontinued medications), physiologic conditions, and other factors such as
smoking 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 (see WARNINGS). The dose of theophylline
selected for initiation of therapy should be low and, IF TOLERATED, increased
slowly over a period of a week or longer with the final dose guided by
monitoring serum theophylline concentrations and the patient's clinical response
(see DOSAGE AND ADMINISTRATION, TABLE IV).
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:
When initiating therapy to guide final dosage adjustment after titration.
Before making a dose increase to determine whether the serum concentration is
subtherapeutic in a patient who continues to be symptomatic.
Whenever signs or symptoms of theophylline toxicity are present.
Whenever there is a new illness, worsening of a chronic illness, or a change in
the patient's treatment regimen that may alter theophylline clearance (eg, fever
(see ACTIONS/CLINICAL PHARMACOLOGY, FEVER, hepatitis, or drugs listed in TABLE
II are added or discontinued).
To guide a dose increase, the blood sample should be obtained at the time of the
expected peak serum theophylline concentration; 4 to 8 hours when medication is
taken every 12 hours or 8 hours when taken once daily. It is important that the
patient has not missed or taken additional doses during the previous 48 hours
and that the dosing intervals were reasonably equally spaced. A trough
concentration (ie, 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 8 hours after the dose, the results must be interpreted with
caution since the concentration may not be reflective of the peak concentration.
In contrast, when signs or symptoms of theophylline toxicity are present, the
serum sample should be obtained as soon as possible, analyzed immediately, and
the result reported to the clinician without delay. In patients in whom
decreased serum protein binding is suspected (eg, 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.
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 Mu-(egr )q/L to 800 Mu-(egr )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 1 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.
INFORMATION FOR PATIENTS:
This information is intended to aid in the safe and effective use of this
medication. It is not a disclosure of all adverse or intended effects.
The patient (or parent/caregiver) should be instructed to seek medical advice
whenever nausea, vomiting, persistent headache, insomnia, restlessness, or rapid
heartbeat 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 informed
that theophylline interacts with a wide variety of drugs (see TABLE II). They
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.
THEOBID Tablets SHOULD NOT BE CHEWED OR CRUSHED. When dosing THEOBID Extended-
Release Tablets on a once-daily (q24h) basis, tablets should be taken whole and
not split.
DRUG INTERACTIONS
DRUG/DRUG INTERACTIONS:
Theophylline interacts with a wide variety of drugs. The interaction may be
pharmacodynamic, ie, 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, ie, the rate of theophylline clearance is altered by another
drug resulting in increased or decreased serum theophylline concentrations.
Theophylline only rarely alters the pharmacokinetics of other drugs.
The drugs listed in TABLE II have the potential to produce clinically
significant pharmacodynamic or pharmacokinetic interactions with theophylline.
The information in the "EFFECT" column of TABLE II assumes that the interacting
drug is being added to a steady-state theophylline regimen. If theophylline is
being initiated in a patient who is already taking a drug that inhibits
theophylline clearance (eg, 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 (eg, 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 listing of drugs in TABLE II is current as of February 9, 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.
TABLE II. CLINICALLY SIGNIFICANT DRUG INTERACTIONS WITH THEOPHYLLINE.*
DRUG TYPE OF INTERACTION EFFECT**
Adenosine Theophylline blocks adenosine Higher doses of
receptors. adenosine may be
required to achieve
desired effect.
Alcohol A single large dose of alcohol 30% increase
(eg, 3 mL/kg of whiskey) decreases
theophylline clearance for up to
24 hours.
Allopurinol Decreases theophylline clearance 25% increase
at allopurinol doses (>/=)600 mg/day.
Aminoglutethimide Increases theophylline clearance 25% decrease
by induction of microsomal enzyme
activity.
Carbamazepine Similar to aminoglutethimide. 30% decrease
Cimetidine Decreases theophylline clearance 70% increase
by inhibiting cytochrome P45 1A2.
Ciprofloxacin Similar to cimetidine. 40% increase
Clarithromycin Similar to erythromycin. 25% increase
Diazepam Benzodiazepines increase CNS Larger diazepam
concentrations of adenosine, doses may be
a potent CNS depressant, while required to
theophylline blocks adenosine produce desired
receptors. level of sedation.
Discontinuation of
theophylline without
reduction of
diazepam dose may
result in
respiratory
depression.
Disulfiram Decreases theophylline clearance 50% increase
inhibiting hydroxylation and
demethylation.
Enoxacin Similar to cimetidine. 300% increase
Ephedrine Synergistic CNS effects. Increased frequency
of nausea,
nervousness, and
insomnia.
Erythromycin Erythromycin metabolite decreases 35% increase.
theophylline clearance by Erythromycin steady-
inhibiting cytochrome P450 3A3. state serum
concentrations
decrease by a
similar amount.
Estrogen Estrogen-containing oral 30% increase
contraceptives decrease theophylline
clearance in a dose-dependent fashion.
The effect of progesterone on
theophylline clearance is unknown.
Flurazepam Similar to diazepam. Similar to diazepam.
Fluvoxamine Similar to cimetidine. Similar to cimetidine.
Halothane Halothane sensitizes the myocardium Increased risk of
to catecholamines; theophylline ventricular
increases release of endogenous arrhythmias.
catecholamines.
Interferon, human Decreases theophylline clearance. 100% increase
recombinant
alpha-A
Isoproterenol (IV) Increases theophylline clearance. 20% decrease
Ketamine Pharmacologic. May lower
theophylline seizure
threshold.
Lithium Theophylline increases renal lithium Lithium dose required
clearance. to achieve a
therapeutic serum
concentration
increased an average
of 60%.
Lorazepam Similar to diazepam. Similar to diazepam.
Methotrexate (MTX) Decreases theophylline clearance. 20% increase after
low dose MTX; higher
dose MTX may have a
greater effect.
Mexiletine Similar to disulfiram. 80% increase
Midazolam Similar to diazepam. Similar to diazepam.
Moricizine Increases theophylline clearance. 25% decrease
Norfloxacin Increases serum theophylline levels.
Ofloxacin Increases serum theophylline levels.
Pancuronium Theophylline may antagonize Larger dose of
nondepolarizing neuromuscular pancuronium may be
blocking effects; possibly due to required to achieve
phosphodiesterase inhibition. neuromuscular
blockade.
Pentoxifylline Decreases theophylline clearance. 30% increase
Phenobarbital (PB) Similar to aminoglutethimide. 25% decrease after
2 weeks of
concurrent PB.
Phenytoin Phenytoin increases theophylline Serum theophylline
clearance by increasing microsomal AND phenytoin
enzyme activity. Theophylline concentrations
decreases phenytoin absorption. decrease about 40%.
Propafenone Decreases theophylline clearance and 40% increase.
pharmacologic interaction. Beta2-blocking effect
may decrease efficacy
of theophylline.
Propranolol Similar to cimetidine and 100% increase.
pharmacologic interaction. Beta2-blocking effect
may decrease efficacy
of theophylline.
Rifampin Increases theophylline clearance 20%-40% decrease
by increasing cytochrome P450 1A2 and
3A3 activity.
Ritonavir Increases theophylline clearance 43% decrease in AUC.
(mechanism unknown).
Sucralfate Reduced absorption of theophylline.
Sulfinpyrazone Increases theophylline clearance by 20% decrease
increasing demethylation and
hydroxylation. Decreases renal
clearance of theophylline.
Tacrine Similar to cimetidine, also increases 90% increase
renal clearance of theophylline.
Thiabendazole Decreases theophylline clearance. 190% increase
Ticlopidine Decreases theophylline clearance. 60% increase
Troleandomycin Similar to erythromycin. 33%-100% increase
depending on
troleandomycin dose.
Verapamil Similar to disulfiram. 20% increase
* Refer to PRECAUTIONS, DRUG INTERACTIONS for further information
regarding table.
** Average effect on steady-state theophylline concentration or other clinical
effect for pharmacologic interactions. Individual patients may experience
larger changes in serum theophylline concentration than the value listed.