Theophylline. Uses. Preparations

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.

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