|
Apo-Theo LA
Theophylline Anhydrous
Sustained-release Tablets 100, 200 and 300mg
Bronchodilator
PHARMACOLOGY
Theophylline relaxes the smooth muscle of the bronchial
airways and pulmonary blood vessels to relieve bronchospasm and increase
flow mates and vital capacity. It also produces other actions typical of the
xanthine derivatives : coronary vasodilatation, diuresis, increase in
gastric secretion, and cardiac, cerebral, and skeletal muscle stimulation.
The actions of theophylline may be mediated through inhibition of
phosphodiesterase and a resultant increase in intracellular cyclic adenosine
monophosphate, but the exact mechanism(s) has not been determined.
Theophylline is usually readily absorbed and distributed into all body
compartments. Protein binding accounts for some 55 - 65%. The liver is the
primary site of metabolism. The therapeutic serum concentration of
theophylline is accepted as 10 to 20µg/mL (55 - 110µmol/L); levels above
20µg/mL are associated with toxic reactions. The pharmacokinetics of
theophylline are influenced by a number at variables such as : age, disease
stale, smoking, concomitant medication. Therefore the optimum therapeutic
maintenance dose should be determined by individual titration.
APO-THEO LA Tablets are sustained-release tablets which produce peak blood
levels between 5 - 8 hours after dosing in adults. Once the steady state
level has been reached (3 days), the therapeutic blood levels persist for 12
hours in most adult patients. The mean elimination half-life of theophylline
in nonsmoking adults is about 8 hours. The degree of fluctuation between
peak trough theophylline levels can be defined as follows :
| % Theophylline Fluctuation |
Nonsmoking Adults |
| Theophylline sustained-release tablets 200, 300mg |
27% |
| Theophylline sustained-release tablets 100mg |
34% |
INDICATIONS
APO-THEO LA (theophylline) tablets are indicated for the
symptomatic treatment of reversible bronchospasm associated with asthma,
chronic bronchitis, emphysema and related bronchospastic disorders.
ADVERSE REACTIONS
The most common adverse reactions are nausea, vomiting, epigastric pain, headache and tremor. These are usually early signs of
toxicity; however, with high doses cardiac arrhythmias or seizures may be
the first signs to appear. Adverse reactions reported with theophylline
preparations include :
Gastrointestinal: nausea, vomiting, epigastric pain, hematemesis, diarrhea,
anorexia, reactivation of peptic ulcer, intestinal bleeding. Central Nervous
System: headaches, irritability, restlessness, insomnia, hyperactivity.
reflex hyperexcitability, muscle twitching, clonic and tonic generalized
convulsions.
Cardiovascular: palpitation, tachycardia, extrasystoles, flushing,
hypotension, circulatory failure, life-threatening ventricular arrhythmias.
Respiratory: tachypnea.
Renal: albuminuria, diuresis and hematuria.
Others: hyperglycemia and inappropriate ADH syndrome.
WARNINGS
In clinical situations where immediate bronchodilatation is
required, such as status asthmaticus, APO-THEO LA (theophylline) is not
suitable.
Since theophylline has a narrow therapeutic index, the margin of safety
above therapeutic doses is small. In patients showing intolerance to
theophylline, the therapy should be reassessed.
Theophylline clearance can be changed by various disease states, as well as
by the age of the patient, concomitant use of other medications and
lifestyle habits (see PRECAUTIONS).
The use of APO-THEO LA in children under the age of twelve years is not
recommended.
PRECAUTIONS
APO-THEO LA (theophylline) tablets should be swallowed whole.
Do not break, chew or crush.
Marked differences in serum levels may be seen in patients receiving the
same theophylline dose. This may be explained by differences between
patients in the rate of metabolism.
Smokers and children are usually high metabolizers. Dosage regimens should
therefore be individuals.
Theophylline half-life is shorter in smokers than in nonsmokers. Smokers may
require larger or more frequent doses of theophylline. Ideally, serum
theophylline levels should be monitored in all patients and
a theophylline half-life calculated which would enable doses and dosing
regimens to be tailored to each patient to maintain a therapeutic level, to
ensure optimal clinical response and to avoid toxicity.
The incidence of toxicity increases at serum theophylline levels greater
than 15mg/mL (82.5µmol/L) and levels above 20µg/mL (110µmol/L) are usually
quite toxic in most adult patients. High serum levels may be seen in some
patients receiving doses considered to be conventional. The possibility of
overdose should therefore not be considered with large doses only.
Overdosage of theophylline may cause peripheral vascular collapse.
Reduced theophylline clearance has been documented in the following readily
identifiable groups:
1. patients with impaired renal or hepatic 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 taking certain drug (i.e. macrolide antibiotics and cimetidine).
Decreased clearance may be associated with either influenza immunization
or active infection with influenza.
Laboratory monitoring of serum theophylline is especially appropriate in the
above individuals to maintain an appropriate theophylline dosage.
Serious side effects such as tachycardia, arrhythmia, seizures, vascular
collapse and even death may occur without warning and may not be receded by
less severe symptoms such as nausea and restlessness.
Use with caution in patients with severe cardiac disease, severe hypoxemia,
hypertension, hyperthyroidism, acute myocardial injury, cor pulmonale,
congestive heart failure, liver disease, in the elderly (especially males).
Patients with congestive heart failure frequently have markedly prolonged
serum levels with theophylline persisting in serum for long periods
following discontinuation of the drug.
Theophylline may occasionally act as a local irritant to the
gastrointestinal tract although gastrointestinal symptoms are more common
centrally mediated and associated with serum drug concentrations over 20µg/mL
(110µmol/L).
Theophylline increases gastric secretion, and caution should
be exercised in patients with a history of peptic ulcer.
Although APO-THEO LA has pharmacokinetic properties similar to other
controlled-release theophylline products, it is not possible to ensure
interchangeability between different products. Careful clinical monitoring
is required when chancing from one drug product to another.
The concurrent
administration of other theophylline derivatives along with APO-THEO LA is
not recommended.
Laboratory Test Interactions
In the interpretation of biochemistry tests, it should be remembered that
theophylline may cause an elevation of urine catecholamines and plasma free
fatty acids.
When plasma levels of theophylline are measured by spectrophotometric
methods, coffee, tea, cola beverages, chocolate and acetaminophen contribute
to falsely high values.
When a high pressure liquid chromatography (HPLC) method is used, plasma
theophylline concentration may be falsely increased by caffeine, some
cephalosporin and sulfa medications.
Food Interaction
Theophylline clearance is increased when diet includes a low carbohydrate,
high protein intake, or a high carbohydrate, low protein intake and there is
a chronic ingestion of charcoal broiled meats. However, the administration
of APO-THEO LA with meals appears not to significantly effect the amount of theophylline released from APO-THEO LA tablets.
Usage in Pregnancy and Lactation
Theophylline crosses the placental barrier and also passes freely into
breast milk, where concentrations are similar to plasma levels. Safe use in
pregnancy has not been established relative to possible adverse effects on
fetal development, but neither have adverse effects on fetal development
been established. Therefore, use of theophylline for uncontrolled asthma in
pregnant women and nursing mothers should be balanced against the risk of
potential effects on the fetus or on the nursing newborn.
CONTRAINDICATIONS
APO-THEO LA (theophylline) is contraindicated in patients
with :
• hypersensitivity to theophylline or xanthine derivatives;
• peptic ulcer;
• coronary artery disease (when, in the physicians judgement, myocardial
stimulation might prove harmful).
1
2 |
