Theophylline Other names: Dimethylxanthine

The incidence of toxic effects may be enhanced by the concomitant use of ephedrine.

^† 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.

Use with caution in patients with chronic alcoholism.

Hypokalaemia resulting from diuretics may be potentiated by xanthines. Particular care is advised in patients suffering from severe asthma who require hospitalisation. It is recommended that serum potassium concentrations are monitored in such situations.

Propranolol: 100% increase of theophylline clearance.

Beta-2 blocking effect may decrease efficacy of theophylline.

^† 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.

Theophylline has been shown to interact with some quinolone antibiotics including ciprofloxacin and enoxacin which may result in elevated plasma theophylline levels.

^† 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.

^† 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.

^† 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.

^† 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.

^† 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.

Concurrent administration of theophylline may increase urinary lithium clearance.

^† 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.

^† 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.

^† 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.

Propranolol reduces clearance and a reduced dosage may therefore be necessary to avoid side-effects. Beta-2 blocking effect may decrease efficacy of theophylline.

^† 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.

^† 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.

Smoking can increase clearance of theophylline.

Theophylline may act as a gastrointestinal tract irritant and increase gastric secretion, therefore caution should be exercised in patients with peptic ulcers.

Due to potential increased theophylline clearance, dose increase and monitoring of serum theophylline concentrations may be required in patients with cystic fibrosis.

Due to potential decreased theophylline clearance, dose reduction and monitoring of serum theophylline concentrations may be required in patients with:

• exacerbations of lung disease
• hypothyroidism

Due to potential increased theophylline clearance, dose increase and monitoring of serum theophylline concentrations may be required in patients with hyperthyroidism (and when starting acute hyperthyroidism treatment).

Use with caution in patients with severe hypertension.

Due to potential decreased theophylline clearance, dose reduction and monitoring of serum theophylline concentrations may be required in elderly patients and patients with:

• cardiac disease
• hepatic disease
• fever
• viral infections

Theophylline may exacerbate cardiac arrhythmias and therefore caution should be exercised in patients with cardiac disorders.

Theophylline may exacerbate frequency and duration of seizures and therefore caution should be exercised in patients with history of seizures and alternative treatment considered.

There are no adequate data from well controlled studies of the use of theophylline in pregnant women. Theophylline has been reported to give rise to teratogenic effects in mice, rats and rabbits. The potential risk for humans is unknown. Theophylline should not be administered during pregnancy unless clearly necessary.

In animal reproduction studies, maternal doses of theophylline less than one to two times the maximum recommended oral dose in humans caused fetal harm, including fetal malformations. Asthma is a serious and potentially life-threatening condition. Poorly controlled asthma during pregnancy is associated with adverse outcomes for mother and fetus. Theophylline should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Population-based studies and post-marketing adverse event reporting of theophylline use during human pregnancy have not demonstrated an increased risk of major congenital anomalies. However, most studies were not large enough to detect a less than two fold increase in risk for congenital anomalies. Post-marketing data are reported voluntarily and do not always reliably estimate the frequency of particular adverse outcomes.

In animal reproduction studies, theophylline produced teratogenic effects when pregnant mice, rats and rabbits were dosed during the period of organogenesis.

In mice, a single intraperitoneal dose at and above 100 mg/kg (approximately equal to the maximum recommended oral dose for adults on a mg/m² basis) produced cleft palate and digital abnormalities. Micromelia, micrognathia, clubfoot, subcutaneous hematoma, open eyelids, and embryolethality were observed at doses approximately 2 times the maximum recommended oral dose for adults on a mg/m² basis.

In rats dosed from conception through organogenesis, an oral dose of 150 mg/kg/day (approximately 2 times the maximum recommended oral dose for adults on a mg/m² basis) produced digital abnormalities. Embryolethality occurred at a subcutaneous dose of 200 mg/kg/day (approximately 4 times the maximum recommended oral dose for adults on a mg/m² basis). In rabbits dosed intravenously throughout organogenesis 60 mg/kg/day (approximately 2 times the maximum recommended oral dose for adults on a mg/m² basis), caused cleft palate and was embryolethal. This dose was maternally toxic as one doe died and clinical signs of toxicity occurred in others. Doses at and above 15 mg/kg/day (less than the maximum recommended oral dose for adults on a mg/m² basis) increased the incidence of skeletal variations.

Theophylline is secreted in breast milk, and may be associated with irritability in the infant, therefore it should only be given to breast feeding women when the anticipated benefits outweigh the risk to the child.

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 per 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.

Theophylline has no or negligible influence on the ability to drive and use machines.

Oral administration

The following adverse drug reactions have been reported in the post-marketing setting for theophylline. Frequencies of “not known” have been assigned as accurate frequencies cannot be estimated from the available clinical trial data.

Immune system disorders: Anaphylactic reaction, Anaphylactoid reaction, Hypersensitivity

Metabolism and nutrition disorders: Hyperuricaemia

Psychiatric disorders: Agitation, Anxiety, Insomnia, Sleep disorder

Nervous system disorders: Convulsions, Dizziness, Headache, Tremor

Cardiac disorders: Atrial tachycardia, Palpitations, Sinus tachycardia

Gastrointestinal disorders: Abdominal pain, Diarrhoea, Gastric irritation, Gastro-oesophageal reflux, Nausea, Vomiting

Skin and subcutaneous tissue disorders: Pruritus, Rash

Renal and urinary disorders: Diuresis, Urinary retention

IV administration

Adverse reactions associated with theophylline are generally mild when serum theophylline concentrations are less than 20 mcg/mL and mainly consist of transient caffeine-like adverse effects such as nausea, vomiting, headache, and insomnia. When 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.

Other adverse reactions that have been reported at serum theophylline concentrations less than 20 mcg/mL include diarrhea, irritability, restlessness, fine skeletal muscle tremors, and transient diuresis. In patients with hypoxia secondary to COPD, multifocal atrial tachycardia and flutter have been reported at serum theophylline concentrations greater than or equal to 15 mcg/mL. There have been a few isolated reports of seizures at serum theophylline concentrations less than 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 less than 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 concentrations less than 20 mcg/mL have generally been milder than seizures associated with excessive serum theophylline concentrations resulting from an overdose (i.e., they have generally been transient, often stopped without anticonvulsant therapy, and did not result in neurological residua). There have been reports of non-convulsive status epilepticus in patients receiving theophylline, and this possibility should be considered in patients with abnormal central nervous system function and a history of theophylline administration. Hypercalcemia has been reported in a patient with hyperthyroid disease at therapeutic theophylline concentrations.

Manifestations of theophylline toxicity*:

^* These data are derived from two studies in patients with serum theophylline concentrations greater than 30 mcg/mL. In the first study (Study #1 – Shanon, Ann lntern Med 1993;119:1161–67), data were prospectively collected from 24 9 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 greater than 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 (e.g., in Study #1, 4 8% 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.

Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia.