Nuelin SR contains 125 mg or 250 mg anhydrous theophylline (1,3-dimethyl
xanthine, also named 3,7-dihydro 1,3-dimethyl-purine-2,6 (1H)-dione) in the
form of sustained release tablets.
Site and Mode of Action:
Theophylline has a direct relaxant effect on the smooth muscle of bronchial
airways and pulmonary blood vessels, serving as a bronchodilator and
It also exhibits activities typical of xanthines such as CNS stimulation
including the respiratory centre, cardiac stimulation, coronary
vasodilatation, diuresis and increased gastric secretion.
The mechanism of action of theophylline in viva has not been fully
elucidated. One mechanism of smooth muscle relaxation may be inhibition of
phosphodiesterase that reduces intracellular hydrolysis of cyclic AMP.
Increased intracellular concentrations of cyclic AMP have been associated
with relaxation of bronchial smooth muscle.
There is no evidence that tolerance develops with continued use of
Relationship to Other Drugs:
Theophylline is closely related to the other xanthines, caffeine and
theobromine. Generally, the xanthines relax smooth muscle, act on the kidney
to produce diuresis, stimulate the central nervous system and stimulate
Nuelin SR is a sustained release formulation appropriate for long term use.
Steady-state conditions are usually achieved after 4 days' therapy.
It is now generally believed that plasma concentrations of 10-20 μg/mL
constitute a therapeutic range, although some patients may benefit from
levels below this.
Theophylline is well absorbed throughout the gastrointestinal tract. The
bioavailability of theophylline from Nuelin SR is approximately 100%. Peak
levels after administration of Nuelin SR usually occur at 4 to 6 hours
Total bioavailability is not altered by food intake. Single dose studies
with Nuelin SR show that food delays the rate of absorption slightly,
especially in children. In multiple dosing situations, a slower rate of
theophylline absorption leads to lower peak-trough fluctuation.
The plasma half-life of theophylline in adults varies considerably. In
healthy adults it ranges from 3 to 12 hours. The half-life is shortened by
The half-life of theophylline is prolonged by reduced hepatic function,
congestive heart failure, pulmonary disease, severe hypoxia, reduced thyroid
function, acute febrile states, viral infections and administration of some
drugs. (See Drug Interactions.) Patients with a prolonged half-life of
theophylline, from whatever cause, require a reduced dosage.
In children aged 1-9 years, the half-life is usually significantly shorter
than in adults, averaging about 3.5 hours. In newborns and neonates,
clearance is extremely slow.
Approximately 50-70% of circulating theophylline is bound to the plasma
proteins of adults, but binding is decreased to about 40% in newborn infants
and in adults with hepatic cirrhosis. Theophylline partitions into saliva
and breast milk and crosses the placental barrier.
Theophylline is metabolised in the liver, principally to 1,3-dimethyluric
acid with other metabolites being 3-methylxanthine and 1-methyluric acid.
3-Methylxanthine has some pharmacological activity, but less than
Theophylline and its metabolites are excreted by the kidney. About 10% of
the administered dose is excreted unchanged in the urine.
For the relief and prophylaxis of reversible bronchospasm associated with
bronchial asthma, bronchitis, emphysema and related conditions.
Nuelin SR should not be used where hypersensitivity to its constituents or
to xanthines generally is known or has been demonstrated.
1. As there is a correlation between plasma levels of theophylline and
therapeutic effect and as patient response can vary considerably due to
variable rates of elimination, monitoring plasma levels in individual
patients is strongly recommended (see THEOPHYLLINE MONITORING). Dosage
should be individualised if optimal therapeutic effect is to be achieved.
However, individual patients also have a widely variable tolerance to
adverse effects and so symptomatology should be considered as well as
2. Acute symptoms of asthma requiring rapid treatment: Sustained release
products are therapeutically inappropriate for acute asthma requiring prompt
3. Theophylline should not be administered concurrently with other xanthine
medications and caution should be exercised when sympathomimetic agents are
also part of the regimen.
4. Theophylline clearance decreases in patients with reduced thyroid
function, congestive heart failure, acute pulmonary oedema, chronic
obstructive pulmonary disease, severe hypoxia, pneumonia, acute febrile
episodes and during acute viral infection. Clearance is markedly decreased
in patients with impaired liver function, such as hepatic cirrhosis. Also
refer to Drug Interactions section.
5. Because of its cardiac side effects, use theophylline with caution in
patients with cardiac arrhythmias, coronary artery disease, unstable angina,
cardiomyopathy and severe hypertension. Theophylline increases gastric acid
secretion and should be used with caution in patients with peptic ulcer or
6. Smoking may increase theophylline clearance and increased doses of
theophylline may be required. (See Drug Interactions.)
7. There is some evidence that theophylline exhibits dose-dependent
kinetics, at least in sick and elderly patients. Care should be exercised by
titration of dosage requirements in small increments and by monitoring serum
8. Xanthine containing beverages leg tea, coffee, cola, cocoa) may interfere
with some serum theophylline assays.
Use in Pregnancy
Theophylline does cross the placental barrier. The effect on foetal
development is not known.
Theophylline clearance is significantly decreased in premature infants.
Therefore, if this drug is administered to the mother near the time of
delivery, the neonate should be monitored closely for the pharmacological
effects of theophylline. Hence the use of theophylline in pregnant women
should be balanced against the risk of uncontrolled asthma.
Use in Lactation
Theophylline is excreted in breast milk and irritability has been reported
in infants of nursing mothers taking theophylline. It is advisable to keep
serum theophylline concentrations as low as possible in nursing mothers
while maintaining adequate asthma control.
The following drugs have been shown to decrease the hepatic clearance of
theophylline, thus increasing its serum concentration: Cimetidine, high dose
allopurinol, propranolol, macrolide antibiotics (eg. erythromycin,
clarithromycin) quinolone antibiotics (eg. ciprofloxacin and enoxacin),
alcohol, oral contraceptives, mexilitene, tacrine, thiabendazole, disulfiram,
Interferon alpha and verapamil.