A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Theodur Warnings, Precautions, Pregnancy, Nursing, Abuse - Theophylline
Theodur Warnings, Precautions, Pregnancy, Nursing, Abuse - Theophylline
WARNINGS
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 total daily dose
is not appropriately reduced in the presence of these risk factors,
severe and potentially fatal
theophylline toxicity
can occur. Careful consideration must be given to the benefits
and risks of theophylline use and the need
for more intensive
monitoring of serum theophylline
concentrations in patients with the following risk
factors:
Age Neonates (term and premature), Children <1 year,
Elderly (>60 years)
Concurrent Diseases Acute pulmonary
edema, Congestive heart
failure, Cor-pulmonale, Fever; ³102°
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
When Signs or Symptoms of Theophylline Toxicity Are Present
Whenever a patient
receiving theophylline
develops nausea or vomiting,
particularly repetitive vomiting,
or other signs or symptoms consistent with theophylline
toxicity (even if another
cause may be suspected),
additional doses of theophylline
should be withheld and a serum
theophylline concentration
measured immediately. Patients should be instructed not to continue
any dosage that causes
adverse effects and to withhold subsequent doses until the symptoms
have resolved, at which time
the clinician may
instruct the patient
to resume the drug at a
lower dosage (see TABLE
4).
Dosage Increases: Increases in the dose
of theophylline
should not be made in response
to an acute exacerbation
of symptoms of chronic lung disease
since theophylline
provides little added benefit
to inhaled beta2-selective agonists and systemically
administered corticosteroids in this circumstance and increases
the risk of adverse effects.
A peak steady-state serum
theophylline concentration
should be measured before increasing the dose
in response to persistent
chronic symptoms to
ascertain whether an increase in dose
is safe. Before increasing the theophylline dose on the basis
of a low serum concentration,
the clinician should
consider whether the blood
sample was obtained at
an appropriate time
in relationship to the dose
and whether the patient
has adhered to the prescribed regimen (see PRECAUTIONS
,
Laboratory Tests).
As the rate of theophylline
clearance may be dose-dependent
(i.e., steady-state serum
concentrations may increase disproportionately to the increase in
dose), an increase in dose
based upon a sub-therapeutic serum concentration measurement should
be conservative. In general,
limiting dose increases to about 25% of the previous total daily
dose will
reduce the risk of unintended
excessive increases in serum
theophylline concentration
(see DOSAGE AND ADMINISTRATION:
TABLE 4).
Serum levels above 20 mcg/ml are rarely found after appropriate
administration of the recommended doses. However, in individuals
in whom theophylline plasma clearance
is reduced for any reason, even conventional doses may result
in increased serum levels
and potential toxicity.
Reduced theophylline
clearance has been
documented in the following readily identifiable groups: 1) patients
with impaired liver function;
2) patients over 55 years of age, particularly males and those with
chronic lung disease; 3) those with cardiac
failure from any cause;
4) patients with sustained high fever; 5) neonates and infants under
1 year of age; and 6) patients taking certain drugs (see DRUG
INTERACTIONS). Frequently, such
patients have markedly prolonged theophylline serum levels following
discontinuation of the drug.
Reduction of dosage
and laboratory monitoring
is especially appropriate in the above individuals.
Serious side effects such
as ventricular arrhythmias,
convulsions or even death
may appear as the first sign
of toxicity without
any previous warning. Less serious signs of theophylline
toxicity (i.e.,
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. A serum concentration
measurement is the only reliable method
of predicting potentially life-threatening toxicity.
Many patients who require theophylline
exhibit tachycardia
due to their underlying disease
process so that the
cause/effect relationship to elevated serum theophylline
concentrations may not be appreciated.
Theophylline products may cause
dysrhythmia and/or
worsen pre-existing arrhythmias and any significant
change in rate and/or rhythm
warrants monitoring and further investigation.
Studies in laboratory
animals (minipigs, rodents, and dogs) recorded the occurrence of
cardiac arrhythmias
and sudden death (with
histologic evidence of myocardial
necrosis) when beta-agonists and methylxanthines were administered
concurrently. The significance of these findings when applied to
humans is currently unknown.
PRECAUTIONS
Immediate Release Products
General
Careful consideration of the various interacting drugs and physiologic
conditions that can alter theophylline clearance
and require dosage adjustment
should occur prior to initiation of theophylline
therapy, prior to increases
in theophylline dose, and during follow up (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).
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 sub-therapeutic 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 (e.g., fever
>102°F sustained for ≥24 hours, hepatitis, or drugs
listed in TABLE 2 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;
1-2 hours after a dose
at steady-state. For most patients, steady-state will
be reached after 3 days of dosing when no
doses have been missed, no
extra doses have been added, and none of the doses have been taken
at unequal intervals. A trough
concentration
(i.e., at the end
of the dosing interval) provides no
additional useful information and may lead
to an inappropriate dose increase since the peak serum
theophylline concentration
can be two or more times greater than the trough
concentration
with an immediate-release formulation. If the serum
sample is drawn more
than two hours after the dose, the results must be interpreted with
caution since the concentration may not be reflective of the peak
concentration. In contrast,
when signs or symptoms of theophylline
toxicity are present,
the serum sample
should be obtained as soon as possible, analyzed immediately, and
the result reported to the clinician
without delay. In patients
in whom decreased serum
protein binding is suspected (e.g., cirrhosis,
women during the third trimester of pregnancy), the concentration
of unbound theophylline
should be measured and the dosage
adjusted to achieve an unbound concentration
of 6-12 mcg/ml.
Saliva concentrations of theophylline
cannot be used reliably to adjust dosage without special techniques.
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.
Information for the Patient
The patient (or parent/care
giver) should be instructed to seek medical advice whenever nausea,
vomiting, persistent
headache, insomnia
or rapid heart beat occurs
during treatment with
theophylline, even if another cause is suspected. The patient
should be instructed to contact
their clinician if they develop a new illness, especially if accompanied
by a persistent fever, if they experience
worsening of a chronic
illness, if they start or stop smoking cigarettes or marijuana,
or if another clinician
and a new medication
or discontinues a previously prescribed medication. Patients should
be instructed to inform all clinicians involved in their care that
they are taking theophylline, especially when a medication
is being added or deleted from their treatment. Patients should
be instructed to not alter the dose, timing of the dose, or frequency
of administration
without first consulting their clinician. If a dose
is missed, the patient
should be instructed to take
the next dose at the usually
scheduled time and to not
attempt to make up for the missed dose.
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 B6C3F1 mice at oral
doses of 120, 270 and 500 mg/kg (approximately 1.0-3.0 times the
human dose
on a mg/m2basis) 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 pigs
born alive at the mid and high dose. In
13 week toxicity studies, theophylline
was administered to F344 rats and B6C3F1 mice at oral
doses of 40-300 mg/kg (approximately 2.0 times the human
dose on a mg/m2basis). At
the high dose, systemic
toxicity was observed
in both species including
decreases in testicular
weight.
Pregnancy
Category C: There are no
adequate and well controlled studies in pregnant
women. Additionally, there are no
teratogenicity studies in non-rodents (e.g., rabbits). Theophylline
was not shown to be teratogenic in CD-1 mice at oral
doses up to 400 mg/kg, approximately 2.0 times the human
dose on a mg/m2
basis or in CD-1 rats
at oral doses up to 260 mg/kg, approximately 3.0 times the recommended
human dose on a mg/m2
basis. At a dose
of 220 mg/kg, embryotoxicity was observed in rats in the absence
of maternal toxicity.
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 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.
Pediatric Use
Theophylline is safe and effective for the approved indications
in pediatric patients
(See INDICATIONS AND USAGE).
The maintenance dose of theophylline
must be selected with caution in pediatric
patients since the rate
of theophylline
clearance is highly
variable across the
age range of neonates to
adolescents (see CLINICAL PHARMACOLOGY,
CLINICAL PHARMACOLOGY:
TABLE 1, WARNINGS
, and DOSAGE
AND ADMINISTRATION). Due to the immaturity of theophylline
metabolic pathways in infants under the age of one year, particular
attention to dosage
selection and frequent
monitoring of serum theophylline
concentrations are required when theophylline is prescribed to pediatric
patients in this age group.
Geriatric Use
Elderly patients are at significantly greater risk
of experiencing serious toxicity
from theophylline than younger patients due to pharmacokinetic and
pharmacodynamic changes associated with aging. Theophylline clearance
is reduced in patients greater than 60 years of age, resulting in
increased serum theophylline
concentrations in response
to a given theophylline
dose. Protein binding may be decreased in the elderly resulting
in a larger proportion of the total serum
theophylline concentration
in the pharmacologically active unbound form. Elderly patients also
appear to be more sensitive
to the toxic effects of theophylline
after chronic overdosage
than younger patients. For these reasons, the maximum
daily dose of theophylline
in patients greater than 60 years of age
ordinarily should not exceed 400 mg/day unless the patient continues
to be symptomatic
and the peak steady state
serum theophylline concentration
is <10 mcg/ml (see DOSAGE AND
ADMINISTRATION). Theophylline doses greater than 400 mg/d
should be prescribed with caution in elderly patients.
Extended-Release Capsules
THE CONTENTS OF A THEO-DUR SPRINKLE CAPSULE SHOULD NOT BE CHEWED
OR CRUSHED.
General
On the average, theophylline
half-life is shorter in cigarette and marijuana
smokers than in non-smokers, but smokers can have half-lives as
long as non-smokers. Theophylline should not be administered concurrently
with other xanthine
medications. Use with caution in patients with hypoxemia, hypertension
or those with history of peptic
ulcer. Theophylline preparations should be used cautiously in patients
with history of peptic
ulcer. Theophylline may occasionally act as a local
irritant to the GI
tract; although gastrointestinal
symptoms are more commonly centrally mediated and associated with
serum drug
concentrations over 20 mcg/ml.
Information for the Patient
This information is intended to aid
in the safe and effective use of this medication. It is not a disclosure
of all possible adverse or intended effects.
The physician should
reinforce the importance of taking only the prescribed dose and
the time interval
between doses. As with any
controlled-release theophylline product, the patient
should alert the physician
of symptoms occur repeatedly, especially near the end
of the dosing interval.
When prescribing administration
by the sprinkle method, details of the proper technique
should be explained to patient
(see DOSAGE AND ADMINISTRATION,
Sprinkling Contents on Food.)
Patients should be informed of the need
to take this drug
in the fasting state, and that drug
administration
should be 1 hour before or 2 hours after meals (see DOSAGE
AND ADMINISTRATION).
Laboratory Tests
Serum levels should be monitored periodically to determine the
theophylline level
associated with observed clinical
response and as the
method of predicting
toxicity. For such measurements,
the serum sample
should be obtained at the time of peak concentration,
(Immediate Release products: 1 to 2 hours after administration)
4-8 hours when medication
is taken every 12 hours, or 3-6 hours when medication
is taken every 8 hours. It is important that the patient
has not missed or taken additional doses during the previous 48
hours and that dosing intervals were reasonably equally spaced.
DOSAGE ADJUSTMENT BASED ON
SERUM THEOPHYLLINE MEASUREMENTS WHEN THESE INSTRUCTIONS HAVE NOT
BEEN FOLLOWED MAY RESULT
IN RECOMMENDATIONS T.A.
PRESENT RISK OF TOXICITY TO
THE PATIENT.
Carcinogenesis, Mutagenesis and Impairment of Fertility
Long-term carcinogenicity studies have not been performed with
theophylline. Chromosome-breaking activity was detected in human
cell cultures at concentrations
of theophylline up to 50 times the therapeutic
serum concentration
in humans. Theophylline was not mutagenic in the dominant
lethal assay
in male mice given theophylline
intraperitoneally in doses up to 30 times the maximum
daily human oral dose.
Studies to determine the effect
on fertility have
not been performed with theophylline.
Pregnancy
Category C: Animal reproduction
studies have not been conducted with theophylline. It is not known
whether theophylline
can cause fetal harm when administered to a pregnant
woman or can affect
reproduction capacity. Xanthines should be given to a pregnant
woman only if clearly
needed.
Nursing Mothers
Theophylline is distributed into breast
milk and may cause
irritability or
other signs of toxicity
in nursing infants.
Because of the potential
of serious adverse reactions in nursing
infants from theophylline, a decision should be made whether to
discontinue nursing
or to discontinue the drug,
taking into account the importance of the drug
to the mother.
Pediatric Use
Safety and efficacy of Theo-Dur Sprinkle in children under 6 years
of age have not been established
with this product.
Safety and effectiveness
of Theo-Dur Extended-Release Tablets administered:
Every 24 hours in children under 12 years of age, have not been
established.
Every 12 hours in children under 6 years of age, have not been
established.
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