(British Approved Name)
Pharmacopoeias. In Europe, Japan, US. Some pharmacopoeias include anhydrous and hydrated theophylline in one monograph.
European Pharmacopoeia, 6th ed. (Theophylline). Awhite or almost white, crystalline powder. Slightly soluble in water sparingly soluble in dehydrated alcohol. It dissolves in solutions of alkali hydroxides, in ammonia, and in mineral acids.
The United States Pharmacopeia 31, 2008 (Theophylline). It contains one molecule of water of hy-dration or is anhydrous. It is a white, odourless, crystalline powder. Slightly soluble in water, more soluble in hot water sparingly soluble in alcohol, in chloroform, and in ether freely soluble in solutions of alkali hydroxides and in ammonia.
(British Approved Name Modified)
Pharmacopoeias. In China, Europe, US. Some pharmacopoeias include anhydrous and hydrated theophylline in one monograph.
European Pharmacopoeia, 6th ed. (Theophylline Monohydrate; Theophylline Hydrate British Pharmacopoeia 2008). A white or almost white, crystalline powder. Slightly soluble in water sparingly soluble in dehydrated alcohol. It dissolves in solutions of alkali hydroxides, in ammonia, and in mineral acids.
The United States Pharmacopeia 31, 2008 (Theophylline). It contains one molecule of water of hydration or is anhydrous. It is a white, odourless, crystalline powder. Slightly soluble in water, more soluble in hot water sparingly soluble in alcohol, in chloroform, and in ether freely soluble in solutions of alkali hydroxides and in ammonia.
Stability. Alcohol-free theophylline liquid repackaged in clear or amber polypropylene oral syringes could be stored at room temperature under continuous fluorescent lighting for at least 180 days without significant change in the concentration of theophylline. However, it was recommended that solutions be protected from light because of the potential for discoloration. Extemporaneous oral preparations of theophylline 5 mg/mL in commercial suspension vehicles were found to be stable for up to 90 days in amber plastic bottles stored at 23° to 25°.
The adverse effects commonly encountered with theophylline and xanthine derivatives irrespective of the route, are gastrointestinal irritation and stimulation of the CNS. Serum concentrations of theophylline greater than 20 micrograms/mL (110 micromol/litre) are associated with an increased risk of adverse effects (but see below).
Theophylline may cause nausea, vomiting, abdominal pain, diarrhoea, and other gastrointestinal disturbances, insomnia, headache, anxiety, irritability, restlessness, tremor, and palpitations. Overdosage may also lead to agitation, diuresis and repeated vomiting (sometimes haematemesis) and consequent dehydration, cardiac arrhythmias including tachycardia, hypotension, electrolyte disturbances including profound hypokalaemia, hyperglycaemia, hypomagnesaemia, metabolic acidosis, rhabdomyolysis, convulsions, and death. Severe toxicity may not be preceded by milder symptoms. Convulsions, cardiac arrhythmias, severe hypotension, or cardiac arrest may follow rapid intravenous injection, and fatalities have been reported. The drug is too irritant for intramuscular use. Proctitis may follow repeated use of suppositories.
Adverse effects are uncommon at serum-theophylline concentrations of 5 to 10 micrograms/mL but become more frequent at 15 micrograms/mL or above, and are greatly increased in frequency and severity at concentrations greater than 20 micrograms/mL. The severity of toxicity is generally correlated with age, underlying disease, and serum-theophylline concentration, but a distinction has been made between acute and chronic theophylline intoxication symptoms appear to occur at a lower theophylline concentration in chronic toxicity than after acute ingestion of large amounts. Young infants and the elderly (over 60 years) appear to be at particular risk from chronic intoxication with theophylline. Older patients with chronic intoxication may be at greater risk of major toxic effects, such as arrhythmias, seizures, and death, than those with acute intoxication.
Common clinical manifestations of theophylline toxicity after overdosage of aminophylline or theophylline include nausea, vomiting, diarrhoea, agitation, tremor, hypertonicity, hyperventilation, supraventricular and ventricular arrhythmias, hypotension, and seizures. Metabolic disturbances such as hypokalaemia, hyperglycaemia, hypophosphataemia, hypercalcaemia, metabolic acidosis, and respiratory alkalosis often occur. Other toxic effects reported include dementia, toxic psychosis, symptoms of acute pancreatitis, rhabdomyolysis with associated renal failure, and acute compartment syndrome. Serious toxic symptoms may not be preceded by minor symptoms. In acute intoxication with sustained-release preparations the onset of major toxic symptoms may be delayed for up to 24 hours and prolonged monitoring of such patients is required. Patients have recovered despite serum-theophylline concentrations in excess of 200 micrograms/mL but fatalities have occurred with much lower serum concentrations. Mortality in severe poisoning may be as high as 10%.
Effects on carbohydrate metabolism. Hyperglycaemia is frequent in theophylline intoxication, and is thought to be secondary to theophylline-induced adrenal catecholamine release. Whether the effects on blood glucose are significant at more modest serum concentrations of theophylline is unclear, although in 29 preterm infants, mean plasma-glucose concentrations were significantly higher after treatment with intravenous aminophylline and oral theophylline than in those not treated. Two of 15 treated infants developed clinically significant hyperglycaemia and glycosuria. It was recommended that plasma-glucose concentrations be monitored in preterm infants receiving theophylline.
Effects on electrolytes. Hypokalaemia is a common metabolic disturbance in theophylline intoxication, but it has also been reported in patients with plasma-theophylline concentrations within the therapeutic range. It is considered to be secondary to theophylline-induced adrenal catecholamine release, with cellular influx of potassium ions. It is recommended that plasma-potassium is monitored during intravenous theophylline therapy particularly if other drugs predisposing to hypokalaemia are also given (see also Interactions, below). Hypophosphataemia and hyponatraemia can also occur at therapeutic plasma-theophylline concentrations. Hypomagnesaemia and hypercalcaemia have occurred in theophylline overdose.
Effects on the heart. ARRHYTHMIAS. Theophylline or aminophylline can precipitate sinus tachycardia and supraventricular and ventricular premature contractions at therapeutic serum-theophylline concentrations and in overdose. Multifocal atrial tachycardia has also been associated with both theophylline overdose and serum-theophylline concentrations within the generally accepted therapeutic range of 10 to 20 micrograms/mL. Use of theophylline with oral beta-adrenoceptor stimulants is associated with a significant increase in the mean heart rate.
Effects on the kidneys. For a report of rhabdomyolysis-induced acute renal failure occurring after aminophylline overdose, see the general discussion on toxicity, above.
Effects on mental function. As mentioned in the general discussion on toxicity above, theophylline toxicity has been associated with reports of dementia and toxic psychosis, as well as the more common adverse effects of anxiety and restlessness.
LEARNING AND BEHAVIOUR PROBLEMS. Several small studies have suggested that theophylline may be associated with learning and behaviour problems in children, especially those with a low IQ. However, the FDA has concluded that such studies provide insufficient evidence to support an adverse effect of theophylline on learning behaviour or school performance. Other studies have found no marked behavioural adverse effects that could be attributed to theophylline. Additionally, academic achievement generally appeared to be unaffected by either asthma or by treatment with appropriate doses of theophylline.
Effects on the nervous system. CONVULSIONS. The risk of convulsions with acute theophylline toxicity is low at serum theophylline concentrations less than 60 micrograms/mL seizures are most likely in patients with peak concentrations above 100 micrograms/mL. However, the risk of seizures is much greater after chronic overdosage seizure activity has been reported at serum concentrations just above or even within the therapeutic range. Elderly patients or those with previous brain injury or neurological disease may be at increased risk, although some have questioned the association. The outcome of seizures appears to be variable: death and severe neurological deficit have occurred, but other series have recorded recovery without serious morbidity.
Effects on the skin. For reports of cutaneous reactions to theophylline and aminophylline, see under Hypersensitivity, below.
Effects on the urinary tract. Although diuresis is more commonly seen, urinary retention has been reported in male patients during therapy with aminophylline or theophylline.
Hypersensitivity. Hypersensitivity reactions have been reported after oral or intravenous doses of aminophylline. Reactions include erythematous rash with pruritus, ery thro derma, and exfoliative dermatitis. Aminophylline can produce both type I (immediate) and type IV (delayed) hypersensitivity reactions, the latter being due to the ethylenediamine component and can be confirmed by skin patch tests. If hypersensitivity to ethylenediamine is confirmed it is recommended that aminophylline is avoided and treatment continued with theophylline or another theophylline salt. Hypersensitivity reactions to theophylline have been reported rarely but type I reactions have occurred. An erythematous, maculopapular rash has been reported during treatment with a modified-release theophylline preparation, which did not occur when another modified-release theophylline product was given.
Hyperuricaemia. In a study of 112 asthmatic patients receiving modified-release theophylline 200 to 400 mg 12-hourly, there was a significant correlation of serum-uric acid concentrations and serum-theophylline concentrations. Gout has been reported in a woman receiving theophylline and aminophylline her serum-uric acid concentration was increased while receiving the xanthines, but subsequently fell when they were stopped, and rose again when treatment was resumed.
Necrotising enterocolitis. Although there have been reports of neonatal necrotising enterocolitis associated with oral theophylline or aminophylline, a study of 275 infants concluded that theophylline did not significantly contribute to its development. It has been suggested that the high osmolality of liquid feeds and drugs including oral theophylline preparations may be involved in the aetiology of necrotising enterocolitis.
Withdrawal syndromes. Episodes of apnoea beginning 28 hours after birth and increasing in frequency and severity over the next 4 days occurred in a neonate whose mother had taken aminophylline and theophylline throughout pregnancy. Measurement of serum-theophylline concentration showed the increasing apnoea coincided with falling theophylline concentration. The infant’s apnoea resolved on giving theophylline treatment was stopped after 4 months.
Worsening asthma control may occur when theophylline is withdrawn there is some evidence of a rebound deterioration in lung function due to the development of tolerance.
Treatment of Adverse Effects
After theophylline or aminophylline overdosage, elimination may be enhanced by repeated oral doses of activated charcoal regardless of the route of overdose (see below). An osmotic laxative may also be considered. Treatment is symptomatic and supportive ECG monitoring is recommended. Serum-theophylline concentrations should be monitored and if modified-release preparations have been taken monitoring should be prolonged. Metabolic abnormalities, particularly hypokalaemia, should be corrected hypokalaemia may be so severe as to require intravenous infusion of potassium. In the non-asthmatic patient severe tachycardia, hypokalaemia, and hyperglycaemia may be reversed by a non-selective beta blocker (see also below). Patients with asthma or chronic obstructive pulmonary disease (COPD) who, after correction of hypokalaemia, have severe tachycardia, may be treated with intravenous verapamil. Alternatively direct current (DC) cardioversion may be considered. Ventricular arrhythmias causing haemodynamic compromise should also be treated with DC cardioversion. Isolated convulsions may be controlled by intravenous diazepam or a barbiturate phenytoin may be less effective. In the most refractory cases general anaesthesia, and neuromuscular blockade, with ventilation, may be required.
Charcoal haemoperfusion or haemodialysis may be required.
Activated charcoal. Multiple-dose oral activated charcoal is considered the cornerstone of treatment for theophylline and xanthine poisoning. It reduces the absorption of oral theophylline, and also enhances the elimination of theophylline from the body even after absorption or intravenous doses of xanthine. Aggressive antiemetic therapy may be required to allow use and retention of activated charcoal, since theophylline toxicity causes protracted vomiting. A cathartic such as sorbitol may be given with the activated charcoal to aid elimination of theophylline, but can cause fluid and electrolyte disturbances. For oral theophylline overdose the use of gastric lavage before oral activated charcoal may not be better than activated charcoal alone.
Beta blockers. Infusion of propranolol after theophylline overdose in 2 patients was associated with improvement in hyperglycaemia, hypokalaemia, tachycardia, and hypotension. Beta-adrenergic blockade may therefore be of benefit in the management of the metabolic changes of theophylline poisoning, especially in the non-asthmatic patient. However, in asthmatic patients, beta blockers should be reserved for those with severe hypokalaemia or cardiac arrhythmias when mechanical ventilation is available as beta blockers can cause bronchoconstriction. Propranolol reduces the clearance of theophylline (see under Interactions, below) and it has been suggested that a non-interacting beta blocker may be more appropriate. Esmolol has been used successfully to manage cardiovascular symptoms of overdosage.
Endoscopy. Absorption is delayed after overdosage with modified-release oral preparations of aminophylline or theophylline and may be further prolonged by the formation of tablet aggregates, or bezoars, in the stomach. Of 11 patients admitted with overdosage, one vomited a bezoar, 2 had bezoars removed at gastroscopy, and in one a bezoar was found at necropsy. If bezoar formation occurs gastric lavage and activated charcoal will have little if any effect and the patient may appear to stabilise before experiencing increasing serum-theophylline concentration and clinical deterioration fatalities have been reported. Endoscopy should be considered in cases of modified-release theophylline overdosage in which clinical signs and serial concentration measurements suggest continuing drug absorption.
Haemodialysis and haemoperfusion. Extracorporeal theophylline removal techniques after overdosage of aminophylline or theophylline have been reviewed. Neither peritoneal dialysis nor exchange transfusion produced a significant increase in the total body clearance of theophylline, whereas haemodialysis could be expected to double clearance, and haemoperfusion results in four- to sixfold increases in clearance. Charcoal haemoperfusion should be considered if the plasma-theophylline concentration exceeds 100 micrograms/mL in an acute intoxication, or 60 micrograms/mL in chronic overdose (40 micrograms/mL if there is significant respiratory or heart failure, or liver disease) though plasma concentrations alone should not determine its use (see under Adverse Effects, above). If there is intractable vomiting, arrhythmias, or seizures charcoal haemoperfusion should be started without delay. In most patients a 4-hour haemoperfusion allows significant clinical improvement, but treatment should continue until plasma concentrations are below 15 micrograms/mL. Plasma concentrations should be followed at least every 4 hours for the first 12 hours post-perfusion, as rebound increases have been noted on terminating perfusion.
Haemodialysis may rarely be an alternative if haemoperfusion is not available, or in series with haemoperfusion if significant rhabdomyolysis is present. There has been a case report of continuous venovenous haemofiltration used to treat severe theophylline toxicity.
Theophylline or aminophylline should be given with caution to patients with peptic ulceration, porphyria, hyperthyroidism, hypertension, cardiac arrhythmias or other cardiovascular disease, or epilepsy, as these conditions may be exacerbated. They should also be given with caution to patients with heart failure, hepatic dysfunction, acute febrile illness, and to neonates and the elderly, since in all of these circumstances theophylline clearance may be decreased, resulting in increases in serum-theophylline concentrations and serum half-life. Conversely, smoking and alcohol consumption increase theophylline clearance. Many drugs interact with theophylline for details see Interactions, below.
Intravenous injections of theophylline or aminophylline must be given very slowly to prevent dangerous CNS and cardiovascular adverse effects resulting from the direct stimulant effect.
Dosage requirements of theophylline vary widely between subjects in view of the many factors affecting theophylline pharmacokinetics, serum concentration monitoring is necessary to ensure concentrations are within the therapeutic range.
Patients should not be transferred from one modified-release theophylline or aminophylline preparation to another without clinical assessment and the measurement of serum-theophylline concentrations because of bioavailability differences.
Acute febrile illness. A reduction in theophylline clearance has been noted in patients presenting with acute respiratory illness and appears to be associated with the severity of the underlying pulmonary disease and the rate of change in the patient’s condition. Caution has been advised in giving theophylline to patients with chronic obstructive pulmonary disease with acute exacerbations, since these patients appear most likely to exhibit altered theophylline metabolism.
Similarly, a decrease in theophylline clearance and an increase in the incidence of adverse effects has been reported during acute viral infections such as influenza in children receiving theophylline therapy for chronic asthma. Another study in asthmatic children found that acute febrile illness accompanied by increased C-Reactive Protein (CRP) level may affect theophylline metabolism. The authors postulated that cytokines released in the process of acute illness were responsible. Influenza vaccination has also been reported to reduce theophylline clearance (see under Interactions, below). The mechanism by which theophylline metabolism is reduced in these patients may be related to increased interferon production during the acute febrile response. A dosage reduction of one half has been recommended in children receiving chronic theophylline therapy who are febrile for more than 24 hours. Further dose adjustments should be based on serum-theophylline concentrations until the patients have recovered from their acute illness and are restabilised on their usual dosage. However, conflicting results have been reported and in one controlled study RS V infection was found to have no significant effect on theophylline disposition in children.
Age. For the effects of age on the metabolism and excretion of theophylline see under Pharmacokinetics, below. Dosage regimens for infants are discussed under Administration in Infants, in Uses and Administration, below.
Breast feeding. From one study of 3 women it was estimated that less than 1 % of the total theophylline eliminated was found in breast milk. Another study of 5 women estimated that a breast-fed infant would receive less than 10% of the maternal dose of theophylline. These amounts were considered unlikely to cause toxicity, but it has been reported that irritability in one infant seemed to occur on the intermittent days when the mother took aminophylline. The American Academy of Pediatrics states that theophylline is usually compatible with breast feeding, although it noted that irritability has been reported in infants whose mothers were receiving theophylline.
ECT. Patients receiving theophylline are at risk of prolonged seizures during ECT, and status epilepticus has been reported. The ability of theophylline to prolong seizures has led to it being used as an adjunct in ECT. Caffeine has been used similarly.
Porphyria. Theophylline has been associated with acute attacks of porphyria and is considered unsafe in porphyric patients.
Pregnancy. It has been recommended that serum-theophylline concentrations are measured at monthly intervals throughout pregnancy and 1 and 4 weeks after delivery since the pharmacokinetics of theophylline may be altered. An increase in the volume of distribution of theophylline, a decrease in plasma-protein binding, and a continuing decrease in clearance throughout pregnancy have been noted in some patients, especially during the later part of pregnancy, but other studies have noted an increase in theophylline clearance during pregnancy. Some studies have found that after delivery there is a return of clearance values to those existing before pregnancy, while others have not.
In a study of 12 neonates whose mothers received various theophylline preparations throughout their pregnancies maternal, cord, and neonatal heelstick theophylline concentrations ranged from 2.3 to 19.6 micrograms/mL. Transient jitteriness was seen in 2 neonates and tachycardia in one, at cord theophylline concentrations of 11.7 to 17 micrograms/mL. There were no instances of vomiting, seizure, arrhythmias, diarrhoea, or feeding disturbances, which had been reported previously.
Renal impairment. Theophylline is eliminated mainly by hepatic metabolism and usual doses of aminophylline or theophylline can be given to patients with renal impairment. In patients undergoing haemodialysis the clearance of theophylline is increased and its elimination half-life reduced mean values of 84.8 and 83 mL/minute and 2.5 and 2.3 hours respectively have been reported. Haemodialysis removes up to 40% of a dose of theophylline. Peritoneal dialysis has little effect on the pharmacokinetics of theophylline removing about 3.2% of a dose.
Smoking. Certain components of tobacco smoke, notably aromatic hydrocarbons, induce hepatic drug-metabolising enzymes and cigarette smoking has been reported to increase theophylline clearance and shorten its elimination half-life. The effect of smoking may override factors that tend to decrease theophylline clearance, such as old age. The duration of enzyme induction after stopping smoking is uncertain theophylline clearance decreased by 38% after one week of abstinence from smoking in one study, while others have found changes in clearance persisting for at least 3 months. Tobacco chewing has also been reported to increase theophylline clearance, but nicotine chewing gum appears to have no effect.
Theophylline. Uses. Preparations