Dihydroxypropyl theophylline.
A white odourless amorphous or crystalline powder. Freely
soluble in water; sparingly or slightly soluble in alcohol:
sparingly soluble in chloroform: practically insoluble in ether.
A I % solution in water has a pH of 5.0 to 7.5.
Store in airtight containers. Protect from light.
Adverse Effects and Precautions as for Theophylline which are displayed below :
THEOPHYLLINE
ADVERSE REACTIONS:
Adverse reactions associated with theophylline are generally mild when peak
serum theophylline concentrations are <20 mcg/mL and mainly consist of transient
caffeine-like adverse effects such as nausea, vomiting, headache, and insomnia.
When peak serum theophylline concentrations exceed 20 mcg/mL, however,
theophylline produces a wide range of adverse reactions including persistent
vomiting, cardiac arrhythmias, and intractable seizures which can be lethal (see
OVERDOSAGE). The transient caffeine-like adverse reactions occur in about 50% of
patients when theophylline therapy is initiated at doses higher than recommended
initial doses (eg, >300 mg/day in adults and >12 mg/kg/day in children beyond >1
year of age). During the initiation of theophylline therapy, caffeine-like
adverse effects may transiently alter patient behavior, especially in school-age
children, but this response rarely persists. Initiation of theophylline therapy
at a low dose with subsequent slow titration to a predetermined age- related
maximum dose will significantly reduce the frequency of these transient adverse
effects (see DOSAGE AND ADMINISTRATION, TABLE IV). In a small percentage of
patients (<3% of children and <10% of adults), the caffeine-like adverse effects
persist during maintenance therapy, even at peak serum theophylline
concentrations within the therapeutic range (ie, 10-20 mcg/mL). Dosage reduction
may alleviate the caffeine-like adverse effects in these patients, however,
persistent adverse effects should result in a reevaluation of the need for
continued theophylline therapy and the potential therapeutic benefit of
alternative treatment.
Other adverse reactions that have been reported to occur at serum theophylline
concentrations less than 20 mcg/mL include diarrhea, irritability, restlessness,
fine skeletal muscle tremors, alopecia, muscle twitching/spasms, palpitations,
rash, reflex hyperexcitability, transient diuresis, and ventricular arrhythmia.
Whether or not theophylline caused these reported events is not known. 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
concentration <20 mcg/mL have generally been milder than seizures associated
with excessive serum theophylline concentrations resulting from an overdose (ie,
they have generally been transient, often stopped without anticonvulsant
therapy, and did not result in neurological residua).
TABLE III. MANIFESTATIONS OF THEOPHYLLINE TOXICITY.(*)
Percentage of patients reported with sign or symptom
Acute Overdose Chronic Overdosage
(Large Single Ingestion) (Multiple Excessive Doses)
Study 1 Study 2 Study 1 Study 2
Sign/Symptom (n=157) (n=14) (n=92) (n=102)
ASYMPTOMATIC NR** 0 NR** 6
GASTROINTESTINAL
Vomiting 73 93 30 61
Abdominal pain NR** 21 NR** 12
Diarrhea NR** 0 NR** 14
Hematemesis NR** 0 NR** 2
METABOLIC/OTHER
Hypokalemia 85 79 44 43
Hyperglycemia 98 NR** 18 NR**
Acid/base disturbance 34 21 9 5
Rhabdomyolysis NR** 7 NR** 0
CARDIOVASCULAR
Sinus tachycardia 100 86 100 62
Other supraventricular 2 21 12 14
tachycardias
Ventricular premature 3 21 10 19
beats
Atrial fibrillation 1 NR** 12 NR**
or flutter
Multifocal atrial 0 NR** 2 NR**
tachycardia
Ventricular arrhythmias
with hemodynamic 7 14 40 0
instability
Hypotension/shock NR** 21 NR** 8
NEUROLOGIC
Nervousness NR** 64 NR** 21
Tremors 38 29 16 14
Disorientation NR** 7 NR** 11
Seizures 5 14 14 5
DEATH 3 21 10 4
* These data are derived from two studies in patients with serum theophylline
concentrations >30 mcg/mL. In the first study (Study #1-Shanon, ANN
INTERN MED. 1993;119:1161-67), data were prospectively collected from 249
consecutive cases of theophylline toxicity referred to a regional poison
center for consultation. In the second study (Study #2-Sessler, AM J MED.
1990;88:567-76), data were retrospectively collected from 116 cases with
serum theophylline concentrations >30 mcg/mL among 6000 blood samples obtained
for measurement of serum theophylline concentrations in three emergency
departments. Differences in the incidence of manifestations of theophylline
toxicity between the two studies may reflect sample selection as a result of
study design (eg, in Study #1, 48% of the patients had acute intoxications
versus only 10% in Study #2) and different methods of reporting results.
** NR = Not reported in a comparable manner.
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.
Dihydroxypropyl theophylline is primarily
excreted unchanged in the urine and should therefore be used
with caution in patients with renal impairment; however.
unlike theophylline. plasma concentrations of dihydroxypropyl
theophylline are not greatly affected by liver function or hepatic enzyme
activity.
Interactions
Since dihydroxypropyl theophylline does not undergo metabolism
by hepatic microsomal cytochrome P450 it does not exhibit the numer-
ous interactions seen with theophylline . However, the
possibility of synergistic effects should be borne in mind if
it is prescribed concomitantly with other xanthines.
Probenecid. Probenecid has been reported to decrease the
clearance of dihydroxypropyl theophylline thus prolonging its
half-life.
Pharmacokinetics
Dihydroxypropyl theophylline is rapidly absorbed from the
gastro-intestinal
tract and from the site of intramuscular injections. Diprophyl-
line does not liberate theophylline in the body and is largely
excreted unchanged in the urine with an elimination half-life
of approximately 2 hours.
Breast feeding. In a study of 20 lactating women given
dihydroxypropyl theophylline by intramuscular injection.
dihydroxypropyl theophylline was
found to concentrate in breast milk, with a milk to serum con-
centration ratio of approximately 2, However, it was felt that
the quantity of dihydroxypropyl theophylline a breast-feeding
infant would ingest was unlikely to produce any pharmacological action
unless the child was very sensitive.
Uses and Administration
Dihydroxypropyl theophylline is a theophylline derivative which
is used similarly to theophylline as a bronchodilator .
The usual dose of dihydroxypropyl theophylline by mouth is up to
15 mg per kg body-weight every 6 hours, It has also been given intra-
muscularly in doses of 250 to 500 mg every 6 hours as required.
Improvements in measurements of lung function after dipro-
phylline in doses of 15 and 20 mg per kg body-weight by
mouth were only one-third to one-half those obtained after
theophylline 6 mg per kg by mouth.