Theophylline. Uses. Preparations

Drug Nomenclature

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.

Theophylline Hydrate

(British Approved Name Modified)

Drug Nomenclature

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°.

Uses and Administration

Theophylline is a xanthine and relaxes bronchial smooth muscle, relieves bronchospasm, and has a stimulant effect on respiration. It stimulates the myocardium and CNS, decreases peripheral resistance and venous pressure, and causes diuresis. It is still not clear how theophylline exerts these effects. Inhibition of phosphodiesterase with a resulting increase in intracellular cyclic adenosine monophosphate (cyclic AMP) occurs, and may play a role. Other proposed mechanisms of action include adenosine receptor antagonism, prostaglandin antagonism, and effects on intracellular calcium. In addition, theophylline may also have an anti-inflammatory effect.

Theophylline is used as a bronchodilator in the management of reversible airways obstruction, such as in asthma. Although selective beta₂ adrenoceptor stimulants (beta₂ agonists) such as salbutamol are generally the preferred bronchodilators for initial treatment, theophylline is commonly used as an adjunct to beta₂ agonist and cortico steroid therapy in patients requiring an additional bronchodilating effect. Some patients with chronic obstructive pulmonary disease also have a beneficial response to theophylline therapy. Theophylline is also used to relieve apnoea in neonates. It was formerly used as an adjunct in the treatment of heart failure, and may occasionally have a role in patients with this condition who are also suffering from obstructive airways disease.

Theophylline may be given in the anhydrous form or as the hydrate. Doses of theophylline are usually expressed as anhydrous theophylline theophylline hydrate 1.1 mg is equivalent to about 1 mg of theophylline.

The pharmacokinetics of theophylline may be altered by factors including age, smoking, disease, diet, and drug interactions (see above under Precautions, Interactions, and Pharmacokinetics). Theophylline doses should therefore be adjusted for each individual patient according to clinical response, adverse effects, and serum-theophylline concentrations.

Optimum therapeutic serum concentrations of theophylline are traditionally considered to range from 10 to 20 micrograms/mL (55 to 110 micromoles/litre) and toxic effects are more common above 20 micrograms/mL. A range of 5 to 15 micrograms/mL may be effective, and associated with fewer adverse effects.

For long-term use, once a maintenance dose has been established, monitoring of serum-theophylline concentrations at 6- to 12-monthly intervals has been recommended.

In the management of acute severe bronchospasm, theophylline may be given by intravenous infusion where available, though usually aminophylline is preferred. (Anhydrous theophylline 1 mg is equivalent to about 1.18 mg anhydrous aminophylline or 1.28 mg aminophylline hydrate.)

In patients who have not received theophylline, aminophylline, or other xanthine-containing medications in the previous 24 hours, a suggested loading dose of 4 to 5 mg/kg may be given by intravenous infusion over 20 to 30 minutes followed by a suggested maintenance dose of 400 to 600 micrograms/kg per hour. Lower doses should be used in the elderly and those with cor pulmonale, heart failure, or liver disease smokers may require a higher maintenance dose. Dosage should be calculated in terms of lean or ideal body-weight.

Intravenous theophylline therapy is best avoided in patients already taking theophylline, aminophylline, or other xanthine-containing medication but, if considered necessaiy, serum-theophylline concentrations should be measured to determine a loading dose. Loading doses are based on the expectation that each 500 micrograms of theophylline/kg of lean body-weight will result in an increase of serum-theophylline concentration of 1 microgram/mL.

In the treatment of acute bronchospasm that has not required intravenous therapy, theophylline has been given orally in conventional dosage forms modified-release preparations are not suitable.

In adults not currently taking theophylline or xanthine-containing products a suggested loading dose is 5 mg/kg, to produce an average peak serum concentration of 10 micrograms/mL. Doses should again be reduced in the elderly and those with cor pulmonale, heart failure, or liver disease smokers may require a higher maintenance dose.

In the long-term management of chronic bronchospasm, theophylline may be given orally in doses ranging from 300 to 1000 mg daily in divided doses as conventional tablets, capsules, liquid preparations, or modified-release preparations. For conventional dosage forms the divided doses are generally given every 6 to 8 hours. However, modified-release preparations are more commonly used as they reduce adverse effects and the need for frequent dosing, especially in patients with a rapid theophylline clearance.

A usual dose of modified-release theophylline is 175 to 500 mg every 12 hours, though the bioavailability of different modified-release theophylline preparations may not be comparable and retitration of dosage is required if the patient is changed from one modified-release preparation to another. Larger doses may be given in either the evening or the morning to achieve optimum therapeutic effect when symptoms are most severe. Modified-release preparations which are given once daily are also available usual doses are 400 or 600 mg daily.

Initially, low doses of theophylline should be given and they should be gradually adjusted according to clinical response and serum-theophylline measurements. In the USA a preferred approach to initial dosage titration in adults may be to begin with 300 mg daily, in divided doses, for 3 days if well tolerated, the total daily dose is increased to 400 mg for 3 days, and then, if tolerated and required, to 600 mg. For doses of theophylline used in children, see Administration in Children, below.

Intramuscular injection and dosage by suppository are not recommended due to severe local irritation and slow unreliable absorption.

Theophylline is an ingredient of some preparations promoted for coughs.

There are topical cosmetic preparations containing theophylline derivatives, particularly aminophylline, that have been promoted for the local reduction of body fat.

Theophylline monoethanolamine (theophylline olamine), theophylline calcium salicylate, theophylline and sodium acetate (theophylline sodium acetate), theophylline sodium glycinate (theophylline sodium aminoacetate), theophylline calcium glycinate, and theophylline glycinate have all been used similarly to theophylline.

Administration

Various methods have been proposed for estimating theophylline pharmacokinetic parameters to enable optimisation of initial dosage but none should be substituted for the subsequent determination of serum-theophylline concentrations and clearance at steady state.

It was noted in 1997 that dosage requirements for theophylline had declined relative to those of historical controls, apparently due to a downward shift in theophylline clearance in the US population (perhaps due to environmental changes, such as a decrease in exposure to tobacco smoke). It was suggested that earlier dosage guidelines for theophylline needed to be revised in the light ofthese data, so that the initial oral dose did not exceed 300 mg daily — for an approach to initial dosage titration consonant with this view, see Uses and Administration, above.

Administration in children

In the management of acute severe bronchospasm in children, theophylline may be given by intravenous infusion where available, although aminophylline is preferred. In children who have not had theophylline, aminophylline or other xanthine-containing medicine in the previous 24 hours, a suggested loading dose of 4 to 5 mg/kg may be given by intravenous infusion over 20 to 30 minutes. Initial maintenance doses are designed to achieve a serum-theophylline concentration of 10 micrograms/mL. The following doses, based on lean or ideal body-weight, have been suggested:

• 1 to 9years of age, 0.8 to 1 mg/kg per hour
• 9 to 12years of age, 0.7 to 0.77 mg/kg per hour Serum-theophylline concentrations should be used to guide further dose adjustments.
• See Administration in Infants, below for doses used in children under 1 year of age.
• Children 12 years of age and over can receive similar doses to adults, see Uses and Administration, above.

If intravenous theophylline therapy is considered necessary in children who are already being given theophylline, aminophylline or other xanthine-containing medicine, serum-theophylline concentrations should be measured to determine a loading dose. Loading doses are based on the expectation that each 500 micrograms of theophylline/kg of lean body-weight will result in a 1-microgram/mL increase in serum-theophylline concentration.

In the treatment of acute bronchospasm that has not required intravenous therapy, theophylline has been given orally using immediate-release preparations to children aged 1 year old and above, using doses similar to those used in adults, see Uses and Administration, above. For doses used in children under 1 year of age, see Administration in Infants, below. Oral modified-release preparations of theophylline are given to children from 6 months of age in the long-term management of chronic bronchospasm. Dose and dosage frequency depend on the preparation being used, and licensed product information should be consulted different formulations are not considered interchangeable.

ADMINISTRATION IN INFANTS

Theophylline clearance is reduced in premature neonates and infants under 1 year of age due to an immature hepatic microsomal enzyme system (see under Metabolism and Excretion in Pharmacokinetics, above). Postconceptional age may have a slight influence on theophylline clearance but postnatal age is thought to be more significant.

Theophylline dosage guidelines for infants under 1 year of age were issued by the FDA in 1985, but a number of clinicians considered that higher doses might be necessary. Subsequent guidelines for oral theophylline, issued in 1995, suggested a modified regimen: premature infants should be given initial doses of 1 mg/kg every 12 hours if less than 24 days postnatal age, or 1.5 mg/kg every 12 hours if more than 24 days in full-term infants up to 1 year of age initial daily dosage (to be given in 3 or 4 divided doses) could be calculated on the basis of the equation:

Daily dose (mg/kg) = (0.2 x age in weeks) + 5.0

Subsequent dosage should be adjusted based on steady-state serum-theophylline concentrations, which might take as long as 5 days to be achieved in premature neonates if a loading dose is not used. The recommended serum concentrations were 5 to 10 micrograms/mL in neonates and 10 to 15 micrograms/mL in older infants. If a loading dose is considered necessary, 5 mg/kg (or 1 mg/kg for each 2 micrograms/mL increase in serum-theophylline concentration in those already being given theophylline) has been suggested.

Other equations and models of population pharmacokinetics have been proposed for the calculation of appropriate theophylline doses in neonates.

Theophylline may be given by intravenous infusion, where available, in the management of acute severe bronchospasm in infants, although aminophylline is preferred. In infants who have not had theophylline, aminophylline or other xanthine-containing medicine in the previous 24 hours, a suggested loading dose of 4 to 5 mg/kg may be given by intravenous infusion over 20 to 30 minutes. In neonates the following initial maintenance doses have been suggested by the American Hospital Formulary Service to achieve a serum-theophylline concentration of 7.5 micrograms/mL :

• neonate, postnatal age 24 days or less, 1 mg/kg every 12 hours
• neonate, postnatal age over 24 days, 1.5 mg/kg every 12 hours

To achieve a serum-theophylline concentration of 10 micrograms/mL the following initial maintenance doses have been suggested by the Canadian Pharmacists Association:

• neonate, 170 micrograms/kg per hour
• 6 weeks to 6 months of age, 430 micrograms/kg per hour
• 6 months to 1 year of age, 500 to 600 micrograms/kg per hour Serum-theophylline concentrations should be used to guide further dose adjustments.

Theophylline may be given prophylactic ally to reduce some of the adverse renal consequences of perinatal asphyxia (see below).

Theophylline has been used in neonatal apnoea, although caffeine is preferred. See Neonatal Apnoea, under Caffeine.

Administration in hepatic impairment

Theophylline clearance is reduced by 50% or more in patients with hepatic insufficiency such as cirrhosis, acute hepatitis, or cholestasis. Careful attention to dose reduction and frequent monitoring of serum-theophylline concentrations are required.

Asthma

Theophylline and its derivatives may be used in the treatment of chronic asthma as an adjunct to beta₂ agonists and corticosteroid therapy when an additional bronchodilator is indicated. Modified-release preparations can be useful in the control of nocturnal asthma. Evidence suggests that adding low-dose oral theophylline to inhaled corticosteroids is as effective as increasing the dose of corticosteroid in patients with moderate asthma and persistent symptoms. A systematic review of studies that compared theophylline with long-acting beta₂ agonists found that they were both effective for control of nocturnal asthma, but that long-acting beta₂ agonists may be more effective in reducing asthma symptoms, including night waking and the need for rescue medication, and are associated with fewer adverse effects.

The use of xanthines in acute asthma attacks is more controversial. UK guidelines permit the use of intravenous aminophylline in patients with severe or life-threatening acute asthma unresponsive to maximal doses of bronchodilators and oral corticosteroids, (a point supported in children but not in adults by systematic review) whereas US guidelines do not consider xanthines have any benefit over the optimal use of beta agonists and consequently do not recommend their use.

Cardiac arrhythmias

Theophylline has been tried in various bradyarrhythmias, usually when other treatment has failed or is contra-indicated. It appears to be of little value in bradyasystolic cardiac arrest.

Cheyne-Stokes respiration

Oral theophylline considerably reduced Cheyne-Stokes respiration (periodic breathing) and episodes of central apnoea in 2 studies in patients with stable heart failure and left ventricular systolic dysfunction. This was associated with an improvement in arterial-oxygen saturation during sleep. One study observed no significant change in cardiac function, although pulmonary function did improve. Theophylline was also effective in a patient with Cheyne-Stokes respiration possibly related to diabetic autonomic neuropathy (the use of the term Cheyne-Stokes respiration to describe this patient’s respiratory disorder has been questioned).

Chronic obstructive pulmonary disease

In the treatment of chronic obstructive pulmonary disease, the bronchodilators of first choice are usually either an antimuscarinic such as ipratropium bromide, or a beta₂ agonist such as salbutamol, given by inhalation. However the addition of an oral xanthine such as theophylline may be of value in some patients to maximise respiratory function and for its positive cardiac ino-tropic effects.

A systematic review of studies comparing oral theophylline with placebo in patients with moderate to severe chronic obstructive pulmonary disease (COPD), found that theophylline treatment improved lung function, ventilatory capacity, and arterial blood gas tensions. A decrease in thoracic gas entrapment and hyperinflation, and an increase in respiratory muscle function and diaphragmatic strength could be responsible for the improvement in symptoms. Improvements in arterial blood gas tensions may result from an increased tidal volume caused by either a direct positive inotropic effect on the respiratory muscles, or a central stimulatory action, or both.

The authors concluded that theophylline produced an improvement in lung function similar to that reported for long acting beta₂ agonists in COPD patients, and that with close monitoring beneficial effects may be obtained from theophylline therapy in those patients who remain symptomatic from COPD despite first-line bronchodilator therapy. Theophylline has been reported to exert an inhibitory effect on airway inflammation in COPD, particularly at plasma concentrations below 10 micrograms/mL. It has also been suggested that low-dose theophylline may restore corticosteroid responsiveness in COPD patients, but further research is required to assess its role.

Contrast nephropathy

For mention of theophylline as a potential protectant against kidney damage induced by iodinated contrast media, see Effects on the Kidneys, under Amidotrizoic Acid.

ECT

For mention of the use of theophylline as an adjunct to electroconvulsive therapy, see under Precautions, above.

Erythrocytosis

When pharmacological treatment is required for secondary erythrocytosis, current UK guidelines recommend an ACE inhibitor or an angiotensin II receptor antagonist as the usual drugs of first choice. Although theophylline appears to be less effective than an ACE inhibitor in post-transplantation erythrocytosis an oral daily dose of 8 mg/kg has produced beneficial effects. Theophylline may be of use given either alone or with an ACE inhibitor in those who fail to respond to first-line therapy. Theophylline treatment may also reduce erythrocytosis associated with chronic obstructive pulmonary disease.

Methotrexate neurotoxicity

For reference to the use of aminophylline or theophylline to relieve the acute neurotoxicity of methotrexate, see Other Drugs, under Treatment of Adverse Effects.

Perinatal asphyxia

Perinatal asphyxia frequently results in damage to the kidneys vasomotor nephropathy or acute renal failure may develop as a result of decreased perfusion to the kidneys. Theophylline has been studied for the prevention of renal dysfunction associated with perinatal asphyxia in both term and preterm neonates. Beneficial effects have been observed after early use of intravenous theophylline, including significant decreases in serum creatinine and urinary p2-microglobulin (an indicator of tubular performance), and a significant increase in creatinine clearance. A single dose of 8 mg/kg theophylline, by slow intravenous injection in the first hour of life, was given to neonates at term. Lower doses were used for preterm neonates 1 mg/kg daily for 3 consecutive days.

Adverse Effects

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.

Precautions

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.

Interactions

The toxic effects of theophylline, aminophylline, and other xanthines are additive. Use with other xanthine medications should therefore be avoided if intravenous aminophylline is to be given for acute bronchospasm in patients who have been taking maintenance theophylline therapy, serum-theophylline concentrations should be measured first and the initial dose reduced as appropriate (see Uses and Administration, below).

Theophylline clearance may be reduced by interaction with other drugs including allopurinol, some antiarrhythmics, cimetidine, disulfiram, fluvoxamine, interferon alfa, macrolide antibacterial s and quinolones, oral contraceptives, tiabendazole, and viloxazine, and the dose of theophylline may need to be reduced. Phenytoin and some other antiepileptics, ritonavir, rifampicin, and sulfinpyrazone may increase theophylline clearance, and require an increase in dose or dosing frequency of theophylline.

Xanthines can potentiate hypokalaemia caused by hypoxia or associated with the use of beta₂-adrenoceptor stimulants (beta₂ agonists), corticosteroids, and diuretics. There is arisk of synergistic toxicity if theophylline is given with halothane or ketamine, and it may antagonise the effects of adenosine and of competitive neuromuscular blockers lithium elimination may be enhanced with a consequent loss of effect. The interaction between theophylline and beta blockers is complex (see below) but use together tends to be avoided on pharmacological grounds since beta blockers produce bronchospasm.

Theophylline is metabolised by several hepatic cytochrome P450 isoenzymes, of which the most important seems to be CYP1A2. Numerous drugs affect the metabolic clearance of theophylline and aminophylline, but the variability in theophylline pharmacokinetics makes the clinical significance of these interactions difficult to predict. Giving theophylline with drugs that inhibit its metabolism should be avoided but, if unavoidable, the dose of theophylline should be halved. There is some evidence to suggest that less of a dose reduction is required in the presence of severe liver dysfunction, aside from that already required by impaired hepatic metabolism, see Administration in Hepatic Impairment, below. Subsequent doses should be adjusted based on serum-theophylline monitoring. Even when introducing medication for which no interaction is suspected, a check on the serum-theophylline concentration within 24 hours of beginning the new drug has been advised.

Theophylline reduces liver plasma flow and may therefore prolong the half-life and increase steady-state levels of hepatically eliminated drugs but it is claimed to have no effect on antipyrine clearance.

Antiarrhythmics

An increase in serum-theophylline concentration from 93.2 to 194.2 micromol/litre with symptoms of tachycardia, nervousness, and tremors occurred in a patient 9 days after starting amiodarone therapy. Elevated theophylline concentrations and/or decreased clearance have also been reported following addition of mexiletine to theophylline therapy. Amiodarone and mexiletine probably interact with theophylline through inhibition of its hepatic metabolism. Tocainide has also been found to impair theophylline metabolism resulting in a reduction in theophylline clearance but the effect was substantially smaller than that of mexiletine. In one patient stabilised on theophylline therapy, an increase in the plasma-theophylline concentration with subsequent toxicity was noted after starting treatment with propafenone. See also under Calcium-channel Blockers.

Antibacterials

IMIPENEM

Seizures have been reported in 3 patients receiving theophylline who were given imipenem, although serum concentrations of theophylline were not affected.

ISONIAZID

Isoniazid inhibits oxidative enzymes in the liver and has been found to impair the elimination of theophylline. Both clearance and volume of distribution of theophylline were reduced with an increase in serum-theophylline concentrations in healthy subjects after 14 days of pretreatment with isoniazid and theophylline toxicity has been reported in a patient one month after adding theophylline to isoniazid therapy.

MACROUDES

There are conflicting reports of the effect of erythromycin on the pharmacokinetics of theophylline. Significant decreases in the clearance of theophylline and prolonged elimination half-life have been reported but other studies have found no interaction. It has also been noted that the serum concentrations and bio availability of erythromycin may be reduced by theophylline. The clearance of theophylline is also markedly decreased by troleandomycin but there have been reports that for clinical purposes the pharmacokinetics of theophylline do not seem to be significantly altered by dirithromycin, josamycin, midecamycin rokitamycin, roxithromycin or spiramycin. Clarithromycin also seems unlikely to have a significant effect in most patients, but in a few theophylline dosage may need to be adjusted. In one case report, serum-theophylline concentrations fell over a few days after the withdrawal of azithromycin

QUINOLONES

The fluoroquinolone antibacterials vary in their propensity to interact with theophylline. Enoxacin shows the most marked interaction and has been reported to cause serious nausea and vomiting, tachycardia, and headaches, associated with unexpectedly high plasma-theophylline concentrations in patients with respiratory-tract infections. Studies, mainly in healthy subjects, have found that enoxacin decreases theophylline clearance by up to 74% with an increase in the elimination half-life and serum-theophylline concentration.

Ciprofloxacin and pefloxacin interact with theophylline to a lesser extent than enoxacin, decreasing theophylline clearance by about 30%. Eight clinically important interactions between ciprofloxacin and theophylline had been reported to the UK CSM including 1 death. A ciprofloxacin-induced seizure has been reported which may have been due to the combined inhibitory effects of the 2 drugs on GABA binding. It has been recommended that ciprofloxacin should not be used in patients treated with theophylline.

Norfloxacin and ofloxacin have been reported to have minor effects on the pharmacokinetics of theophylline. Although their effects were usually considered not to be clinically significant, the US FDA had received 9 reports of theophylline toxicity associated with use with norfloxacin, including 1 death. Fleroxacinflumequine, lomefloxacin moxifloxacin and rufloxacin have been reported to have no significant effect on the pharmacokinetics of theophylline in small studies in healthy subjects.

The mechanism of interaction involves a reduction in the metabolic clearance of theophylline due to inhibition of hepatic microsomal enzymes. However, the exact mechanism is unknown and it is difficult to predict which patients will be at risk. Extreme caution should be used when giving quinolones with theophylline, particularly in the elderly and it may be advisable to use a non-interacting fluoroquinolone, although theophylline concentrations should still be monitored.

Of the non-fluorinated quinolones, nalidixic acid has been reported not to affect theophylline clearance whereas pipemidic acidhas markedly inhibited theophylline clearance.

RIFAMPICIN

Rifampicin induces hepatic oxidative enzymes and a dose of 600 mg daily by mouth for 6 to 14 days has been shown to increase mean plasma-theophylline clearance by 25 to 82% due to enhancement of hepatic theophylline metabolism. This increase in clearance is sufficient to require dosage adjustment in some patients, including children.

TETRACYCUNES

Tetracycline weakly inhibited theophylline clearance after 5 days of therapy in 5 non-smoking adults with chronic obstructive airways disease and theophylline toxicity has been reported in a patient given a 10-day course of tetracycline during theophylline therapy. Doxycycline has been reported not to have any significant effect on theophylline pharmacokinetics in healthy subjects.

Antidepressants

Significantly reduced clearance and increased plasma concentrations of theophylline have been reported when given with viloxazine. The dosage of theophylline should be decreased and its plasma concentrations monitored when viloxazine is also prescribed. The interaction probably involves competition between the two drugs for hepatic microsomal enzymes.

Fluvoxamine has also been associated with a significant reduction in theophylline clearance and theophylline toxicity has been described in patients when fluvoxamine was added to their therapy. This interaction which is due to potent liver enzyme inhibition has been the subject of a warning by the UK CSM in which they issued the standard advice of avoiding the two drugs if at all possible and, where they could not be avoided, of giving half the dose of theophylline and monitoring plasma concentrations. A small study evaluating the effect of liver cirrhosis on the interaction between fluvoxamine and theophylline observed a decrease in fluvoxamine-induced inhibition of theophylline clearance as the severity of liver cirrhosis increased. The authors suggest that theophylline may require less of a dose reduction in the presence of severe liver dysfunction, aside from that already required by impaired hepatic metabolism, see Administration in Hepatic Impairment, below.

St John’s vtwtmay have decreased theophylline concentrations and increased the theophylline dosage requirement in one case report. However, a study in 12 healthy subjects found that 15 days of treatment with St John’s wort did not significantly change theophylline pharmacokinetics.

For a mention of the effect of theophylline on the renal clearance oflithium, see Xanthines, under Interactions of Lithium.

Antiepileptics

Phenytoin markedly decreases the elimination half-life and increases the clearance of theophylline, probably due to hepatic enzyme induction, at therapeutic serum-phenytoin concentrations, at subtherapeutic phenytoin concentrations, and even in heavy smokers. A preliminary report suggested that the serum concentration of phenytoin may be decreased simultaneously, perhaps due to enzyme induction by theophylline or reduced phenytoin absorption. The interaction has been reported to occur within 5 to 14 days of taking phenytoin and theophylline, and theophylline clearance has increased by up to 350%, and reductions in serum half-life have ranged from 25 to 70% of initial values.’

Carbamazepine has also been seen to increase theophylline elimination. In one patient, theophylline serum half-life was decreased by about 24 to 60%, and clearance was increased by about 35 to 100% when carbamazepine was given. In an 11-year-old girl theophylline-serum half-life was almost halved with loss of asthma control after 3 weeks of concurrent carbamazepine therapy. In turn, theophylline has been reported to reduce serum concentrations of carbamazepine. Although phenobarbital was not found to have a significant effect on the pharmacokinetics of a single dose of theophylline given intravenously, enhanced theophylline clearance has been seen in patients after longer periods of treatment with phenobarbital. The magnitude of the changes in theophylline elimination appears to be smaller with phenobarbital than phenytoin.

Pentobarbital in high doses has also been reported to increase theophylline metabolism. A more recent study has also shown that therapeutic doses of pentobarbital (100 mg daily) increase plasma clearance of theophylline by a mean of 40%, although this was subj ect to marked interindividual variations. Renal clearance was not affected, suggesting hepatic enzyme induction as the probable mechanism.

Antifungals

There have been reports that ketoconazole does not appear significantly to alter the pharmacokinetics of theophylline. The manufacturer offluconazole has, however, stated that plasma clearance of theophylline may be decreased by flu-conazole. A 16% reduction in theophylline clearance has been reported after oral fluconazole but fluconazole was considered to have only a minor inhibitory effect on theophylline metabolism and theophylline disposition was not significantly affected. Theophylline metabolism has been inhibited to a similar degree by terbinafine.

Antigout drugs

Allopurinol 300 mg by mouth daily for 7 days was found to have no effect on the pharmacokinetics of theophylline after a single intravenous dose of aminophylline or after oral theophylline given to steady state. However, oral allopurinol 600 mg daily for 28 days has been found to inhibit the metabolism of theophylline, increasing the mean half-life by 25% after 14 days and 29% after 28 days and there has been a report of allopurinol increasing peak plasma-fheophylline concentrations by 38% in one patient within 2 days of use together. Probenecid has been reported to have no effect on the hepatic metabolism or total body clearance of theophylline in a single-dose study in healthy subjects.

Sulfinpyrazone 800 mg daily for 7 days increased the total plasma clearance of theophylline by 22% in healthy subjects due to selective induction of certain cytochrome P450 isoenzymes.

Antineoplasties

There has been a report of increased clearance of theophylline in 3 patients given aminoglutethimide The clearance of theophylline (given as theophylline, aminophylline, or choline theophyllinate) was reported to decrease by an average of 19% in 8 patients with severe corticosteroid-dependent asthma given low-dose weekly intramuscular injections of methotrexate A high degree of interpatient variability was seen. Three patients reported nausea one of whom required a decrease in theophylline dose. The authors reported that the most likely explanation for the change in theophylline clearance was inhibition of microsomal enzyme activity. For reference to a possible interaction between theophylline and lomustine, see Lomustine.

Antivirals

A single injection of recombinant human interferon alfa reduced theophylline clearance by 33 to 81 % in 8 of 9 subjects, resulting in a 1.5 to sixfold increase in the theophylline elimination half-life. Injection of interferon alfa once daily for 3 days in 11 healthy subjects also reduced theophylline clearance and increased elimination half-life, but the magnitude of the changes were of a similar order to normal intra-individual variation and the interaction was considered of minor clinical significance.

Licensed product information for ritonavir states that it substantially increases the clearance of theophylline theophylline dosage may need to be increased to maintain efficacy. There is evidence that aciclovir inhibits theophylline metabolism, resulting in accumulation.

Benzodiazepines

For reference to the antagonism of benzodiazepine sedation by aminophylline, see Xanthines, under Interactions of Diazepam.

Beta blockers

Propranolol reduced theophylline clearance by 36% in healthy subjects given aminophylline intravenously. Metoprolol did not reduce clearance in the group as a whole, but a reduction was noted in some smokers whose theophylline clearance was initially high. Propranolol is thought to exert a dose-dependent selective inhibitory effect on the separate cytochrome P450 isoenzymes involved in theophylline demefhylation and 8-hydroxylation. The less lipophilic beta blockers atenolol and nadolol had no significant effect on the pharmacokinetics of theophylline.

In general, however, beta blockers should be avoided in patients taking theophylline as they can dangerously exacerbate bronchospasm in patients with a history of asthma or chronic obstructive pulmonary disease.

Caffeine

Abstention from dietary methylxanthines by healthy subj ects has resulted in faster elimination of theophylline. While the addition of extra caffeine to the diet has been reported not to alter theophylline disposition, some studies in healthy subjects have indicated that the ingestion of moderate amounts of caffeine (120 to 900 mg daily), which could be consumed by drinking several cups of coffee daily, can have a pronounced influence on the pharmacokinetics of theophylline. In these latter studies the mean theophylline clearance was reduced by 23 and 29% with a corresponding increase in the elimination half-lives.

Calcium-channel blockers

Verapamil has been reported to decrease the clearance of theophylline by a mean of 14% in healthy subjects and although this was not considered to be clinically significant, symptoms of theophylline toxicity, associated with near doubling of the serum-fheophylline concentration have occurred in a 76-year-old woman taking theophylline after 6 days of therapy with verapamil. Studies in healthy subjects and asthmatic patients have produced conflicting results of the effect of nifedipine on the pharmacokinetics of theophylline. Reduced clearance and an increase in the volume of distribution of theophylline have been reported and both decreased and increased serum-fheophylline concentrations theophylline toxicity has been reported. However, most studies have concluded that the effects of nifedipine are unlikely to be of clinical importance.

Serum concentrations of theophylline have been reported to be increased by diltiazem and reduced by felodipine, neither of these effects were considered to be clinically significant.

Cannabis

A search of the literature revealed 2 studies, both published in the 1970s, that showed that marijuana smoking increased the clearance of theophylline.

Corticosteroids

In 3 patients with acute severe asthma given aminophylline intravenously, serum-fheophylline concentrations rose rapidly from the therapeutic range to between 40 and 50 micrograms/mL when hydrocortisone was given intravenously. In studies in healthy subjects, no significant changes in serum-fheophylline concentrations were noted when hydrocortisone, meihylprednisolone, or prednisone were given, although there was a trend towards increased theophylline clearance during corticosteroid therapy. In preterm neonates, exposure to betamethasone in utero stimulated the hepatic metabolism of theophylline, but did not affect dosage requirements. The possibility that adverse effects such as hypokalaemia may be potentiated by use of theophylline with corticosteroids should be borne in mind.

Disulfiram

In a study involving 20 recovering alcoholic patients, disulfiram decreased the plasma clearance and prolonged the elimination half-life of theophylline in a dose-dependent manner. It was concluded that disulfiram exerts a dose-dependent inhibitory effect on the hepatic metabolism of theophylline and that, in order to minimise the risk of toxicity, the dosage of theophylline may need to be reduced by up to 50% if given together.

Diuretics

Although increased mean serum-fheophylline concentrations were noted in 10 patients given continuous intravenous aminophylline infusions after intravenous injection of furosemide, in 8 patients with chronic stable asthma, mean peak serum-theophylline concentrations were reduced from 12.14 micrograms/mL with placebo to 7.16 micrograms/mL when furosemide was given. Reduced concentrations were noted for up to 6 hours after furosemide. Decreased theophylline concentrations were also noted in 4 neonates receiving oral or intravenous theophylline when given furosemide. Serum-theophylline concentrations returned to normal when furosemide and theophylline were given more than 2 hours apart.

The possibility that adverse effects such as hypokalaemia may be potentiated if theophylline is given with diuretics should be borne in mind.

Gastrointestinal drugs

Oral antacids do not appear to affect the total absorption of theophylline from the gut. However, some studies have shown a reduction in the rate of absorption from both immediate- and modified-release theophylline preparations after antacids. Also an increase in peak serum-theophylline concentrations has been noted with certain modified-release formulations.

Cimetidine inhibits the oxidative metabolism of theophylline reducing its clearance by 20 to 35% and prolonging its serum half-life toxic effects have been reported. It has been recommended that the dose of aminophylline should be reduced by about one-third if given with cimetidine. This inhibition of theophylline metabolism may be enhanced by liver disease, but there is wide interindividual variation.

The reduction in clearance may be greater in smokers. Studies have suggested that ranitidine does not significantly inhibit theophylline metabolism, even at very high doses. However, there have been occasional reports of theophylline toxicity after use with ranitidine. Famotidine has also been reported to not alter theophylline disposition but one small study found a significant decrease in theophylline clearance in some patients with chronic obstructive pulmonary disease.

Omeprazole, lansoprazole, and pantoprazole generally have insignificant or no effect on theophylline clearance. In CYP2C19 poor metabolisers there may be an increase in omeprazole concentrations and subsequent induction of CYP1A, a major enzyme of theophylline metabolism. A pharmacokinetic study of this induction in 5 poor metabolisers given omeprazole did find a trend towards an increase in theophylline clearance.

General anaesthetics

There have been several reports’ of increased cardiotoxicity when patients taking theophylline were anaesthetised with halothane. There was also an early report of seizures and tachycardia attributed to an interaction between theophylline and ketamine.

Leukotriene inhibitors and antagonists

Zileuton prolongs the half-life and reduces the clearance of theophylline dosage of theophylline should be reduced to avoid toxicity when both drugs are given together, and plasma-theophylline concentrations should be monitored. Use of zafirlukast with theophylline decreased zafirlukast plasma concentrations but had no effect on theophylline plasma concentrations in clinical trials. However, toxic serum-theophylline concentrations occurred in one patient when zafirlukast was added to therapy, and recurred on rechallenge. A dose of montelukast 10 mg daily did not affect the pharmacokinetics of theophylline, but doses of 200 mg and 600 mg daily reduced the maximum plasma concentration, area under the concentration-time curve, and elimination half-life of theophylline.

Methoxsalen

In a single-dose pharmacokinetic study in 3 healthy subjects, the rate of elimination of theophylline was decreased after a single oral dose of methoxsalen, while urinary excretion of unchanged theophylline increased. Methoxsalen probably inhibits the metabolism of cytochrome P450 isoenzyme CYP1A2, and it has been suggested that theophylline dose reductions are likely to be required when used with systemic methoxsalen but seem unlikely to be necessary with topical PUVA therapy.

Neuromuscular blockers

For reference to resistance to neuromuscular block with pancuronium in patients receiving aminophylline, see Xanthines.

Oral contraceptives

Oral contraceptives have been reported to decrease the clearance of theophylline by about 30%, and serum concentrations may be increased, due to the inhibitory effects of oral contraceptives on hepatic P450 isoenzymes.

Sympathomimetics

The effect of beta-adrenoceptor agonists on the pharmacokinetics of theophylline is unclear. Whereas some studies have found that orciprenaline or terbutaline had no effect on theophylline disposition, others have shown an increase in theophylline clearance after isoprenaline or terbutaline.

Use of theophylline with beta-adrenoceptor agonists can potentiate adverse effects including hypokalaemia, hyperglycaemia, tachycardia, hypertension, and tremor. Of 9 patients reported to the UK CSM with hypokalaemia during such combined therapy, 4 had clinical sequelae of cardiorespiratory arrest, intestinal pseudo-obstruction, or confusion. Monitoring of serum-potassium concentrations was recommended in patients with severe asthma given both beta-adrenoceptor agonists and xanthine derivatives.

The possibility of an interaction with phenylpropanolamine should also be borne in mind, as it has been shown to reduce the clearance of theophylline significantly.

Tacrine

Results of a study in healthy subjects indicated that tacrine reduced theophylline clearance by about 50% and increased plasma-theophylline concentrations. Competitive inhibition by tacrine of theophylline metabolism was proposed.

Tiabendazole

Tiabendazole has been reported’ to increase serum-theophylline concentrations and to decrease theophylline clearance. It has been recommended that theophylline dosage should be reduced by 50% when tiabendazole therapy is started.

Ticlopidine

Theophylline elimination half-life was increased and plasma clearance was decreased in 10 healthy subjects after the use of ticlopidine 500 mg daily by mouth for 10 days.

Vaccines

Transient inhibition of the hepatic metabolism of theophylline, possibly secondary to interferon production, resulting in increased theophylline serum half-life and concentration has been reported after BCG vaccination and influenza vaccination. Other studies have not been able to confirm the interaction with influenza vaccine. The differing findings are probably due to differences in vaccine modern purified subvirion vaccines which do not induce interferon production do not appear to alter theophylline metabolism.

Pharmacokinetics

Theophylline is rapidly and completely absorbed from liquid preparations, capsules, and uncoated tablets the rate, but not the extent, of absorption is decreased by food, and food may also affect theophylline clearance. Peak serum-theophylline concentrations occur 1 to 2 hours after ingestion of liquid preparations, capsules, and uncoated tablets. Modified-release preparations exhibit considerable variability in their absorption characteristics and in the effect of food. They are generally not considered to be interchangeable if a patient needs to be transferred from one such preparation to another then the dose should be retitrated.

Rectal absorption is rapid from enemas, but may be slow and erratic from suppositories. Absorption after intramuscular injection is slow and incomplete. Theophylline is about 40 to 60% bound to plasma proteins, but in neonates, or adults with liver disease, binding is reduced. Optimum therapeutic serum concentrations for bronchodilatation are generally considered to range from 10 to 20 micrograms/mL (55 to 110 micromol/litre) although some consider a lower range appropriate (see Therapeutic Drug Monitoring, below).

Theophylline is metabolised in the liver to 1,3-dimeth-yluric acid, 1-methyluric acid (via the intermediate 1-methylxanthine), and 3-methylxanthine. Demethyla-tion to 3-methylxanthine (and possibly to 1-methylx-anthine) is catalysed by the cytochrome P450 isoen-zyme CYP1A2 hydroxylation to 1, 3-dimethyluric acid is catalysed by CYP2E1 and CYP3A3. Both the demethylation and hydroxylation pathways of theophylline metabolism are capacity-limited, resulting in non-linear elimination. The metabolites are excreted in the urine.

In adults, about 10% of a dose of theophylline is excreted unchanged in the urine, but in neonates around 50% is excreted unchanged, and a large proportion is excreted as caffeine. Considerable interindivid-ual differences in the rate of hepatic metabolism of theophylline result in large variations in clearance, serum concentrations, and half-lives. Hepatic metabolism is further affected by factors such as age, smoking, disease, diet, and drug interactions. The serum half-life of theophylline in an otherwise healthy, non-smoking asthmatic adult is 7 to 9 hours, in children 3 to 5 hours, in cigarette smokers 4 to 5 hours, in neonates and premature infants 20 to 30 hours, and in elderly non-smokers 10 hours. The serum half-life of theophylline may be increased in patients with heart failure or liver disease. Steady state is usually achieved within 48 hours with a consistent dosing schedule. Theophylline crosses the placenta it is also distributed into breast milk.

Absorption

FOOD

Food has substantial but variable effects on the absorption of theophylline from modified-release formulations but it is difficult to predict whether a particular formulation will be affected. Some formulations are not affected by the presence of food but for others increases or decreases in the rate and/or extent of absorption have been reported. The composition and fluid content of the food appears to be important and a rapid release of theophylline (‘dose-dumping’) has occurred with some formulations after a meal, especially one with a high fat content. A diet high in protein and low in carbohydrate has been reported to increase theophylline clearance, and a low-protein, high-carbohydrate diet to decrease theophylline clearance. The consumption of methylxanthines, particularly caffeine, in the diet may decrease theophylline clearance (see Caffeine, under Interactions, above).

Metabolism and excretion

AGE

From about 1 year of age until adolescence, children have a rapid theophylline clearance. Premature infants and those under 1 year of age have a slower clearance due to immature metabolic pathways. In neonates the capacity of hepatic cytochrome P450 enzymes is much reduced compared with older children and adults, and N-demethylation and oxidation reactions play a minor role in the metabolism of theophylline. Neonates are, however, capable of methylating theophylline at the N7 position to form caffeine, which is present at about one-third the concentration of theophylline at steady state. The proportion of theophylline excreted unchanged is also increased in premature neonates and decreases with age as hepatic enzyme systems develop. More rapid clearance on the first day of life in premature neonates has been reported. Some studies have found a progressive decline in clearance throughout adult years whereas others have not. Similarly, some studies have noted a decreased clearance in the elderly’ but others have found no significant change.

ELIMINATION KINETICS

There is evidence that the elimination of theophylline is dose-dependent and that at high serum concentrations, a small change in dose of a theophylline preparation could cause a disproportionate increase in serum-theophylline concentration, due to a reduction in clearance. However, it is not clear that this effect is clinically significant when serum-theophylline concentrations are within the therapeutic range. It has also been suggested that repeated oral dosing of theophylline might result in a decrease of clearance compared with pre-treatment values.

GENDER

A higher theophylline clearance and shorter elimination half-life has been reported in healthy premenopausal women than in healthy men, probably due to sex-related differences in hepatic metabolism. Changes in the pharmacokinetics of theophylline in women have also been reported according to the stage of the menstrual cycle another study found no changes.

Pregnancy and breast feeding

For mention of the pharmacokinetics of theophylline during pregnancy and breast feeding, see under Precautions, above.

Protein binding

Albumin is the major plasma binding protein for theophylline, binding is pH-dependent, and the percentage of theophylline bound at physiological pH is reported to range from about 35 to 45%. Some studies have found the plasma protein binding of theophylline to be concentration dependent, but others have not confirmed this. Protein binding has been reported to be slightly but significantly higher in patients with bronchial asthma than in healthy controls. Reduced protein binding occurs in patients with hypoalbuminaemia it has also been found in obese subjects (possibly due to elevated concentrations of free fatty acids, which can displace theophylline from binding sites).

Therapeutic drug monitoring

Dosage requirements of theophylline preparations vary widely between subjects and even vary with time in individuals, since serum-theophylline concentrations are influenced by factors including disease states, other drugs, diet, smoking, and age. Serious toxicity is related to serum concentration and may not be preceded by minor symptoms. For these reasons it is recommended that serum-theophylline concentrations should be monitored.

The generally accepted optimal serum concentration is between 10 and 20 micrograms/mL, but this should be regarded as a guide and not a rigid barrier and clinical decisions should never be based solely on the serum concentration. The therapeutic range in the treatment of neonatal apnoea is usually considered to be 5 to 15 micrograms/mL although some babies may respond at lower concentrations. Some now consider that this is a more appropriate range in asthma (except perhaps acute severe asthma).

It has been suggested that pulmonary function tests provide a better guide in long-term therapy with theophylline. Serum-theophylline concentrations were originally measured by spectrophotometry but this is subject to considerable interference from other drugs. High performance liquid chromatography is now the method of choice when extreme accuracy is important and the enzyme multiplied immunoassay technique (EMIT) has become popular because of its rapidity and adaptability to processing large batches. Devices are also available that provide serum-theophylline measurements within several minutes using monoclonal antibody technology.

The use of salivary concentrations for monitoring theophylline dosage requirements has been tried, because it is noninvasive, but poor correlations between salivary- and serum-theophylline concentrations mean it has not gained general usage.

Preparations

British Pharmacopoeia 2008: Prolonged-release Theophylline Tablets

The United States Pharmacopeia 31, 2008: Theophylline and Guaifenesin Capsules; Theophylline and Guaifenesin Oral Solution; Theophylline Capsules; Theophylline Extended-release Capsules; Theophylline in Dextrose Injection; Theophylline Oral Solution; Theophylline Sodium Glycinate Elixir; Theophylline Sodium Glycinate Tablets; Theophylline Tablets; Theophylline, Ephedrine Hydrochloride, and Phenobarbital Tablets

Proprietary Preparations

The symbol denotes a preparation no longer actively marketed

Argentina: Aminofilin Asmabiol Crisasma Drilyna Nefoben Teodosis Teosona Teosona Sol Theo-Dur

Australia: Nuelin

Austria: Aerodynef Afonilum Euphyllin Respicur Theoplus Theospirex Unifyl

Belgium: Euphyllin Theo-2 Theolair Xanthium

Brazil: Bermacia Codrinan Talofilina Teofilab Teolong Teophyl Teoston

Canada: Apo-Theo Novo-Theophyl Quibron-T Theo-Dur Theolair Uniphyl

Chile: Elixine

Czech Republic: Afonilum Euphyllin Euphylong Spophyllin Teotard Theo-Dur Theophyllard Theoplus Uni-Dur Unilair

Denmark: Nuelin Pulmo-Timelets Theo-Dur UniXan Uno-Lin

Finland: Euphyllin Nuelin Retafyllin Theo-Dur Theofol

France: Euphylline Theostat Xanthium

Germany: Aerobin Afonilum Afonilum novo afpred-THEO Bronchoparat Bronchoretard Contiphyllin Cronasma duraphyllin Euphylong Pulmidur Pulmo-Timelets Solosin Theo Theolair Tromphyllin Unilair Uniphyllin

Greece: Aberten Nediphyllin Chrono Novaphylline Theo-Bros Theo-Dur Theoplus Uniphyllin

Hong Kong: CP-Theo Euphylong Novo-Theophyl Nuelin Slo-Theo Theo-Dur Theotrim

Hungary: Egifilin Euphylong Retafyllin Theophtard Theospirex

India: Phylobid Phyloday Theo PA Theobid Theoday Theoped Unicontin

Indonesia: Bronchophylin Brondilex Bronsolvan Euphyllin Quibron-T Retaphyl Theobron

Ireland: Nuelin Slo-Phyllin Uniphyllin Continus Zepholin

Israel: Glyphyllin Theotard Theotrim

Italy: Aminomal Diffumal Euphyllina Frivent Paidomal Respicur Tefamin Theo-24 Theo-Dur Theolair

Japan: Theodur Theolong

Malaysia: Apo-Theo Nuelin Numalin Retafyllin Theolin

Mexico: Apoteoprol Elixofilina Fluidasa Pharmafil Slo-Bid Teolong Uni-Dur

The Netherlands: Euphylong Theolair

Norway: Nuelin Theo-Dur

New Zealand: Nuelin

Philippines: Asmasolon Brondil (Reformulated) Nuelin Phenedrine Theo-Dur

Poland: Afonilum Euphyllin Theoplus Theospirex Theovent

Portugal: Eufilina Lepobron Teonibsa Teovent Unicontin

Russia: Teotard

Singapore: Apo-Theo Nuelin Retafylliir Theolin Theoplus Xanthium

Spain: Chantaline Elixifilin Eufilina Histafilin Pulmeno Teolixir Teromol Theo Max Theo-Dur Theolair Theoplus Unilong Vent Retard

Sweden: Euphylong-P Theo-Dur

Switzerland: Euphyllin Sodipphylline Theolair Unifyl

Thailand: Aerobin Almarion Asmasolon Bronoday Franol Ned-Phylline Nuelin Retafyllin Temaco Theotrim Xanthium

Turkey: Bronkolin Pirasmin Talotren Teobag Teokap Teosel Theo-Dur Xanthium

United Arab Emirates: Theophar

UK: Nuelin Slo-Phyllin Uniphyllin Continus

USA: Accurbron Aerolate Aquaphyllin Asmalix Elixomin Elixophyllin Quibron-T Respbid Slo-Bid Slo-Phyllin Sustaire T-Phyl Theo-24 Theo-X Theochron Theoclear Theolair Theovent Uniphyl

Venezuela: Nuelin Teobid

Multi-ingredient

Argentina: Airbronal Bronkasma Dexa Aminofilin Dexa Teosona Fatigan Bronquial lnastmol Sedacris

Austria: Ambredin Asthma 23 D

Brazil: Abacateirol Alergotox Asmatiron Bronquitos Endotussin Franol Narax

Canada: ratio-Theo-Bronc

Czech Republic: Oxantil

Finland: Theofol Comp

France: Hypnasmine

Germany: Broncho-Euphyllin

Greece: Gulamyl

India: Alergin Asmapax Asthmino Broncofol-P Broncofol Dericip Dericip Plus Deriphyllin Narax Tergil-T Theo-Asthalin Theobric

Ireland: Franol Expectorant

Malaysia: Asthma Brondal Grenin Theophylline Expectorant

Mexico: Aminoefedrison

Philippines: Nucophylline

Poland: Baladex

Portugal: Cosmaxil Prelus

Spain: Novofilin Teolixir Compositum

UK: Do-Do ChestEze Franol Plus Franol

USA: Elixophyllin-GG Elixophyllin-Kl Glyceryl-T Hydrophed Narax Neoasma Quadrinal Quibron Slo-Phyllin GG Tedrigen Theodrine Theomax D

Continuation:

Theophylline

Theophylline. Interactions