AHFS Class:

• Respiratory Smooth Muscle Relaxants 86:16

Generic Name(s):

• Aminophylline

• Dyphylline

• Oxtriphylline

• Theophylline

• Dyphylline and Guaifenesin

• Theophylline and Guaifenesin

Theophylline, a xanthine derivative, directly relaxes smooth muscle of the respiratory tract, producing relief of bronchospasm and increasing flow rates and vital capacity.

Bronchospasm

Theophylline is used as a bronchodilator in the symptomatic treatment of asthma and reversible bronchospasm that may occur in association with chronic bronchitis or emphysema.

Asthma

Theophylline is used as a bronchodilator in the symptomatic treatment of asthma. The drug relieves the primary manifestations of asthma, including shortness of breath, wheezing and dyspnea, and improves pulmonary function as measured by increased flow rates and vital capacity. Theophylline also suppresses exercise-induced bronchospasm and, in doses that maintain therapeutic serum concentrations, prevents symptoms of chronic asthma.

Drugs for asthma may be categorized as relievers (e.g., bronchodilators taken as needed for acute symptoms) or controllers (principally inhaled corticosteroids or other anti-inflammatory agents taken regularly to achieve long-term control of asthma).212,213 In the stepped-care approach to antiasthmatic drug therapy, a reliever drug such as a selective, short-acting, inhaled β₂-adrenergic agonist (e.g., albuterol, levalbuterol, pirbuterol) is recommended on an as-needed basis to control occasional acute symptoms (e.g., cough, wheezing, dyspnea) of short duration; such use of an inhaled short-acting β₂-agonist alone generally is sufficient as initial treatment for newly diagnosed patients whose asthma severity is initially classified as intermittent (e.g., patients with daytime symptoms of asthma not more than twice weekly and nocturnal symptoms not more than twice a month).213 Short-acting theophylline (provided extended-release theophylline is not already used) is considered by some clinicians to be one of several less effective alternatives (e.g., an inhaled anticholinergic agent or a short-acting oral β₂-agonist) to short-acting inhaled β₂-agonists for relief of acute asthma symptoms, but these alternatives have a slower onset of action and/or a greater risk of adverse effects.212,213

Extended-release theophylline may be administered orally for long-term symptom control in mild-to-moderate persistent asthma. While theophylline provides mild-to-moderate bronchodilation, the drug generally is considered an alternative, but not preferred therapy to a low-dose orally inhaled corticosteroid (e.g., 88-264, 88-176, or 176 mcg of fluticasone propionate [or its equivalent] daily via a metered-dose inhaler in adolescents and adults, children 5-11 years of age, or children 4 years of age or younger, respectively) for mild persistent asthma (e.g., daytime symptoms of asthma more than twice weekly but less than once daily, and nocturnal symptoms of asthma 3-4 times per month) because of theophylline's lower effectiveness, increased risk of adverse effects, and more difficult therapeutic monitoring requirements compared with inhaled β₂-agonist and corticosteroid therapy.211,212,213,215 Other experts do not consider mast-cell stabilizers or extended-release theophylline to be acceptable alternatives to inhaled corticosteroids for routine use as initial long-term therapy in patients with mild persistent asthma.212 In children 4 years of age or younger with mild persistent asthma, theophylline is not recommended by the National Asthma Education and Prevention Program (NAEPP) as an alternative to orally inhaled corticosteroids because of erratic metabolism of the drug during viral infections and febrile illnesses necessitating careful monitoring of serum theophylline concentrations.213 Infants and young children have frequent febrile illnesses, which may increase theophylline concentrations and the potential for adverse effects.211,213 Other experts state that a few studies in children 5 years of age or younger suggest some benefit for asthma control with theophylline, but such therapy is less effective than therapy with low-dose orally inhaled corticosteroids.212

Extended-release theophylline or certain leukotriene modifiers (i.e., montelukast, zafirlukast) also are considered less-effective alternatives to long-acting, inhaled β₂-adrenergic agonists that may be added to a low dosage of inhaled corticosteroids for long-term control of symptoms in adults and children 5 years of age or older with moderate persistent asthma.212,213 In comparative studies in patients with moderate persistent asthma, the addition of theophylline to low-dose orally inhaled corticosteroid therapy has not been shown to be more effective than doubling the dosage of inhaled corticosteroids alone.211,213 Considerations favoring theophylline in combination with orally inhaled corticosteroids include marked preference for oral therapy and cost.213

Maintenance therapy with an inhaled corticosteroid at medium dosages or high dosages (e.g., exceeding 440 mcg of fluticasone propionate in adults and adolescents or 352 mcg of the drug in children 5-11 years of age [or its equivalent] daily via a metered-dose inhaler) and a long-acting inhaled β₂-agonist is the preferred treatment in adults and children 5 years of age or older with severe persistent asthma (i.e., continuous daytime asthma symptoms, nighttime symptoms 7 times per week).212,213 Alternatives to a long-acting inhaled β₂-agonist for severe persistent asthma in adults and children 5 years of age or older receiving medium-dose inhaled corticosteroids include extended-release theophylline or certain leukotriene modifiers (i.e., montelukast, zafirlukast), but these therapies are generally not preferred.212,213 Theophylline is not recommended as add-on therapy to medium dosages of an orally inhaled corticosteroid in infants and children 4 years of age or younger with severe persistent asthma because of the erratic metabolism of the drug during viral infections and febrile illnesses that necessitates careful monitoring of serum concentrations of the drug.213 In children 5-11 years of age with severe persistent asthma, theophylline may be added to high dosages of orally inhaled corticosteroid and oral corticosteroid therapy as an alternative to an inhaled long-acting β₂-adrenergic agonist; such recommendations are based on consensus and clinical experience.213 Some experts suggest extended-release theophylline or a leukotriene modifier as adjunctive therapy to medium or high dosages of orally inhaled corticosteroids and a long-acting inhaled β₂-adrenergic agonist in adults and children older than 5 years of age with severe persistent asthma.212

Limited evidence suggests that an IV xanthine derivative (e.g., theophylline, aminophylline) could be beneficial as add-on therapy in children who are admitted to an intensive care unit (ICU) for severe exacerbations of asthma not controlled by inhaled and IV β₂-adrenergic agonists, ipratropium bromide, and IV corticosteroids;212,213 however, the efficacy of such add-on IV theophylline therapy has not been established in adults.212,213 Initial management of patients with impending respiratory failure in the emergency department includes intubation and mechanical ventilation with 100% oxygen, an inhaled short-acting β₂-adrenergic agonist in combination with ipratropium via nebulization given hourly or continuously, and an IV corticosteroid.212,213 However, experts from the NAEPP do not recommend use of methylxanthines for management of asthma exacerbations in acute care settings.213

Aminophylline and dyphylline generally share the same indications as theophylline. Because of its short half-life, some clinicians believe that dyphylline is impractical for chronic bronchodilator therapy. Most clinicians believe that the use of special theophylline vehicles, salts, and preparations is unnecessary and that uncoated oral theophylline tablets provide the most efficacious and convenient formulation for chronic therapy in many patients. Reliably absorbed extended-release preparations allow longer dosing intervals with less variation in serum theophylline concentration and can improve compliance.

Many clinicians have questioned the routine, prolonged administration of drug combinations containing theophylline derivatives, sympathomimetic agents (e.g., ephedrine), sedatives (e.g., phenobarbital), and/or expectorants to asthmatic patients. Theophylline doses in most combination preparations are inadequate. Single-ingredient preparations are more effective, facilitate necessary dosage adjustment, and are safer than combination preparations. Concomitant administration of sympathomimetics and theophylline is usually no more effective than either drug alone and synergistic toxicity may result. For example, one study in children with severe asthma showed that a combination of ephedrine and theophylline was no more effective than therapeutic doses of theophylline alone and that the incidence of adverse effects was greater when the drugs were given in combination than when they were used separately. Addition of sympathomimetics to theophylline therapy (or vice versa) may be reasonable, however, in some patients.

Chronic Obstructive Pulmonary Disease

In the stepped-care approach to drug therapy for chronic obstructive pulmonary disease (COPD), theophylline (as an extended-release oral preparation) may be added to or substituted for therapy with long-acting bronchodilators (e.g., tiotropium, a selective inhaled β₂-agonist) in patients with severe COPD who require additional therapy because of inadequate response or limiting adverse effects.216,217,218,220 The role of theophylline derivatives in patients with acute exacerbations of COPD is controversial; some clinicians do not consider them to be beneficial, and even suggest that they may have deleterious effects, in such patients.216,219

Other Uses

IV theophylline (often as aminophylline) has been used to relieve the periodic apnea and increase arterial blood pH in patients with Cheyne-Stokes respiration†. Oral and IV theophylline have also been used in infants to stimulate respiration and myocardial contractility associated with apnea† and to reduce severe bronchospasm associated with cystic fibrosis† and acute descending respiratory infections†.

IV theophylline has been used as an adjunct in the treatment of pulmonary edema or paroxysmal nocturnal dyspnea caused by left-sided heart failure†, but its use in these situations has been supplanted by more effective therapy. Theophylline has been used in the prophylaxis of angina pectoris†, but its value in this disease is controversial and its usage is not recommended.Theophylline has also been used to increase cerebrovascular resistance in the treatment of hypertensive headaches†, but its use has been superseded by more potent antihypertensive agents. Theophylline should not be used in the treatment of coronary thrombosis.

Aminophylline has been used to augment the diuretic action of the thiazides and carbonic anhydrase inhibitors†, and to relieve dyspnea, decrease venous filling pressure, and increase cardiac output when used as an adjunct in the treatment of congestive heart failure†. However, use of aminophylline has largely been replaced by more effective diuretics such as furosemide and ethacrynic acid.

General Administration

Theophyllines (e.g., theophylline, aminophylline) and dyphylline usually are administered orally. For faster absorption, conventional oral theophylline dosage forms may be taken with a full glass of water on an empty stomach 30-60 minutes before meals or 2 hours after meals; to minimize local GI irritation, oral theophyllines may be taken with meals or immediately after meals, with a full glass of liquid, or with antacids. Extended-release preparations should not be chewed or crushed; the contents of some extended-release capsules may be mixed with soft food and taken without chewing in patients who have difficulty swallowing solid dosage forms. Administration of some extended-release theophylline preparations with food may affect the rate and/or extent of absorption of the drug, and the manufacturer's recommendations for administration of specific products should be followed. Extended-release preparations should be administered in a consistent manner, either always with or always without food.222,223,224 Patients should not alter the administration schedule of theophylline preparations without consulting their clinician.221,222,223,224,225,226,229

Extended-release theophylline preparations are indicated in patients with relatively continuous or frequently recurring asthma symptoms, and may be particularly useful in patients in whom theophylline elimination is rapid (e.g., children, adult smokers). Extended-release preparations designed for once-daily dosing (e.g., Uniphyl^® tablets) should be administered at the same time each day, either morning or evening.223 The manufacturer of Theo-24^® capsules states that this preparation should be administered at the same time each morning when given once daily; once-daily administration at night is not recommended because the effect of circadian rhythm, food, posture, and other factors on theophylline absorption and/or clearance rates requires additional study.222 The manufacturer of Theo-24^® capsules suggests that patients who require twice-daily dosing should receive the second dose 10-12 hours after the morning dose and before the evening meal.222 Patients with more rapid metabolism (e.g., young individuals, smokers, some nonsmoking adults) may require smaller doses administered more frequently (e.g., twice daily) to avoid breakthrough symptoms resulting from low trough concentrations.222,223

Aminophylline and theophylline also may be administered undiluted by slow IV injection or, preferably, in large volume parenteral fluids by slow IV infusion.227,228 Aminophylline solutions may be prepared by diluting an appropriate volume of a commercially available injection or pharmacy bulk package injection in a compatible IV infusion fluid. Loading doses usually are given over 30 minutes.227,228 If patients experience acute adverse effects while IV loading doses of theophylline are being infused, the infusion may be stopped for 5-10 minutes or administered at a slower rate.228

Aminophylline has been, and dyphylline may be administered IM, but this route is rarely used; IM injection of aminophylline causes intense local pain and is not recommended.

Dosage

Theophyllines

Theophylline has a low therapeutic index; therefore, cautious dosage determination is essential. Because individuals metabolize theophylline at different rates, appropriate dosages must be determined for each patient by carefully monitoring patient response and tolerance, pulmonary function, and serum theophylline concentrations. Dosages required to achieve a therapeutic serum theophylline concentration vary fourfold among otherwise similar patients in the absence of factors known to alter theophylline clearance.221 Although extended-release preparations have been formulated to release the drug at various rates suitable for dosing every 8-12, 12, or 24 hours, the actual dosing frequency for a given patient and preparation depends on the patient's individual pharmacokinetic parameters. Dosage should be calculated on the basis of lean body weight.

For maintenance therapy, serum theophylline concentrations should be obtained after a patient has received a given dosage for 3 days. Peak serum concentrations can be estimated by obtaining blood samples 30 minutes after administration of an IV loading dose,227,228 1-2 hours after administration of an oral solution or uncoated tablet, or 3-12 (usually 3-8) hours (depending on the specific formulation) after administration of an extended-release preparation. Trough concentrations of theophylline can be determined by taking blood samples just before the next dose. When the recommended maximum dosage is exceeded, dosage adjustment should be based on measurement of peak serum theophylline concentrations. For dosage adjustments based on serum theophylline concentrations determined in such circumstances, it is important that dosage in the previous 48 hours be reasonably typical of the prescribed regimen and that the patient not have missed a dose nor taken an additional dose in this time period. Dosage adjustments based on serum theophylline concentrations when these conditions have not been fulfilled may result in dosages that present risk of toxicity to the patient. Therapeutic serum concentrations for bronchospastic disease generally range from 5-15 mcg/mL at steady state.213,232 When serum theophylline concentrations exceed 20 mcg/mL, toxicity often becomes apparent.

Dosage of theophylline preparations may be conveniently expressed in terms of anhydrous theophylline. The approximate anhydrous theophylline content in the various theophylline derivatives is shown in Table 1.

Acute Bronchospasm

For the treatment of acute bronchospasm, theophylline (or aminophylline) is preferably administered IV.

For the treatment of acute bronchospasm in patients who have not received any theophylline in the previous 24 hours , a theophylline loading dose of 4.6 mg/kg (approximately equivalent to 5.7 mg/kg of hydrous aminophylline) based on ideal body weight will produce an average serum theophylline concentration of 10 mcg/mL.227,228 In general, each 1 mg/kg (based on ideal body weight) of theophylline given by IV infusion over 30 minutes results in an average 2-mcg/mL increase in serum theophylline concentration.227,228 Serum theophylline concentration should be measured 30 minutes after administration of a loading dose to determine the need for and size of subsequent loading doses.228 After a therapeutic serum theophylline concentration is attained, maintenance dosage by continuous IV infusion should be adjusted depending on the patient's age, clinical characteristics, pharmacokinetic parameters, and target serum theophylline concentration (generally 5-15 mcg/mL).227,228

Following a loading dose, the following dosages by continuous IV infusion are recommended:

A serum theophylline concentration should be measured at 1 expected half-life after starting the continuous IV infusion (i.e., after approximately 4 hours for children 1-9 years of age, after 8 hours for nonsmoking adults) to determine if theophylline concentrations are decreasing or increasing from the postloading dose drug concentration.228 If theophylline concentrations are decreasing from the postloading drug concentration, an additional loading dose may be administered and/or the rate of infusion may be increased.228 If the theophylline concentration after initiation of the continuous infusion is higher than the postloading drug concentration, the infusion rate should be decreased before the theophylline concentration exceeds 20 mcg/mL.228 An additional serum theophylline concentration should be measured 12-24 hours later to determine if dosage adjustments are required, then at 24-hour intervals, to adjust for changes in theophylline concentrations in the initial period of theophylline administration.228

In patients who are currently receiving theophylline preparations, estimation of serum theophylline concentration based upon patient history is unreliable, and a serum theophylline concentration should be measured immediately to determine a loading dose.228 A loading dose should not be given before obtaining a serum theophylline concentration if the patient has received any theophylline in the past 24 hours.228 Loading doses of theophylline are based on the general expectation that each 0.5 mg/kg (of lean body weight) of theophylline will result in a 1-mcg/mL increase in serum theophylline concentration. A loading dose in patients who are currently receiving theophylline preparations should be determined using the following formula:

Loading dose = (desired serum concentration - measured serum concentration) × volume of distribution.228

Volume of distribution for this calculation is assumed to be approximately 0.5 L/kg.228 The desired drug concentration should be conservative (e.g., 10 mcg/mL) to allow for variability in the volume of distribution.228

IV dosage adjustments should be based on peak serum theophylline concentrations and the clinical response and tolerance of the patient as shown in Table 3:

IV theophylline is preferred over other routes of administration for the treatment of acute bronchospasm. Oral extended-release dosage forms should not be used for the treatment of acute bronchospasm.222,224 An inhaled, short-acting β₂-adrenergic agonist alone or in combination with systemic corticosteroids is the most effective treatment for acute exacerbations of reversible airway obstruction.211,212,225,226,229 If an inhaled or parenteral β₂-adrenergic agonist is not available, a loading dose of oral theophylline using immediate-release preparations can be used as a temporary measure.225,226,229 Patients who have not received any theophylline preparations in the previous 24 hours may receive a theophylline loading dose of 5 mg/kg using an immediate-release preparation.225,226,229

Following the loading dose, theophylline dosage for subsequent therapy using an immediate-release preparation in children 1 year of age or older and adults may be titrated as follows:

Serum theophylline concentrations should be monitored at 24-hour intervals to adjust final dosage.225,226

Chronic Bronchospasm

Extended-release preparations of theophylline may be administered every 8, 12, or 24 hours to provide therapeutic serum theophylline concentrations in patients who have relatively continuous or recurrent symptoms.221,222,223,224 For chronic maintenance bronchodilator therapy in patients receiving certain extended-release preparations designed to be given every 8-12 hours, dosage titration is shown in Table 5.

For the long-term management of asthma in children 5 years of age or older, experts from the National Asthma Education and Prevention Program (NAEPP) suggest an initial dosage of 10 mg/kg daily of theophylline oral solution, extended-release tablets, or capsules with dosage adjusted to maintain serum drug concentrations of 5-15 mcg/mL at steady state (at least 48 hours receiving the same dosage).213 If additional control of asthma is needed in such children, theophylline dosage may be titrated up to a usual maximum dosage of 16 mg/kg daily.213 NAEPP does not generally recommend use of oral theophylline in children 4 years of age or younger.213 If theophylline is used in infants and children 1-4 years of age, the usual initial dosage of oral theophylline is 10 mg/kg daily, with titration up to a usual maximum dosage of 16 mg/kg daily.213

For the long-term management of asthma in adults and adolescents 12 years of age or older, NAEPP suggests initiating therapy with a theophylline dosage of 10 mg/kg (up to 300 mg) daily in divided doses, with titration up to a usual maximum daily dosage of 800 mg.213 Dosage should be adjusted to maintain serum drug concentrations of 5-15 mcg/mL at steady state.213

Regardless of oral dosage form, dosage for the treatment of chronic bronchospasm should not exceed the 600 mg maximum daily dosage without measurement of serum theophylline concentration .221,222,223,224,225,226,229

When extended-release preparations are to be administered, it is generally recommended that the daily dosage requirement first be established by monitoring serum theophylline concentrations while the patient is receiving a rapidly absorbed dosage form; then, therapy with an extended-release preparation may be started by administering one-half of the total daily dose every 12 hours. When transferring therapy from conventional tablets or 8-12 hour extended-release preparations to a once-daily (24-hour) extended-release preparation (i.e., Uniphyl^®) in patients 12 years of age and older, substitution of Uniphyl dosage using the 400- or 600-mg tablets on a mg-for-mg basis is recommended.223

Oral dosage adjustments may be based on peak serum theophylline concentrations and the clinical response and tolerance of the patient as follows:

When adjusting dosage in this manner, it is important that dosage in the previous 48 hours be reasonably typical of the prescribed regimen and that the patient not have missed a dose nor taken an additional dose in this time period.

IV dosage adjustments may be based on peak serum theophylline concentrations and the clinical response and tolerance of the patient as follows:

Dosage in Children Younger than 1 Year of Age

Dosage of theophylline in children younger than 1 year of age, particularly in premature and term neonates, must be carefully individualized. Elimination of the drug in children younger than 1 year of age, especially in neonates, generally appears to be reduced. Because of potential toxicity, use of the drug in children younger than 1 year of age should be carefully considered and, if used, the initial and maintenance dosages (particularly the latter) should be conservative. Maintenance dosage should not be exceeded and therapy with the drug should not be continued unless the drug is well tolerated and clinically beneficial. Recommended initial maintenance dosages for neonates and infants for the treatment of bronchospasm are shown in the following table:

Other Uses

In infants with cystic fibrosis†, IV theophylline (as aminophylline) maintenance dosages of 10-12 mg/kg daily have been given. In adults, IV theophylline doses of approximately 200-400 mg by slow IV infusion have been used to promote diuresis† and to treat Cheyne-Stokes respiration† and paroxysmal nocturnal dyspnea†.227,228

Dyphylline

For acute bronchospasm in adults, the usual oral dosage of dyphylline recommended by the manufacturer is 15 mg/kg or 200-400 mg every 6 hours.230,231 Dosage must be carefully adjusted according to individual requirements and response. In patients with renal impairment, dosage reduction should be considered.230 Pediatric dosage has not been established.

GI and Nervous System Effects

Theophyllines produce GI irritation and CNS stimulation following administration by any route. Theophyllines are all somewhat irritating to gastric mucosa; the importance of reported differences among the individual agents is doubtful. The most common adverse GI effects (both locally and centrally mediated) include nausea, vomiting, epigastric pain, abdominal cramps, anorexia, and, rarely, diarrhea. Hematemesis has also occurred. Adverse CNS effects, which are often more severe in children than in adults, include headache, irritability, restlessness, nervousness, insomnia, dizziness, reflex hyperexcitability, and seizures. Reduction of theophylline dosage usually reduces the incidence and severity of adverse gastric and CNS effects; however, if these adverse effects persist, the drug may have to be withdrawn. The drugs may be administered orally before or after meals, with a full glass of liquid, or with antacids to minimize locally mediated GI irritation.

Cardiovascular Effects

Adverse cardiovascular effects of theophyllines include palpitation, sinus tachycardia, extrasystoles, and increased pulse rate. These adverse cardiovascular effects are usually mild and transient. Flushing, hypotension, circulatory failure, and ventricular arrhythmias may also occur.

Other Adverse Effects

Theophyllines may also produce transiently increased urinary frequency, dehydration, twitching of fingers and hands, tachypnea, and elevated serum AST (SGOT) concentrations. Hypersensitivity reactions characterized by urticaria, generalized pruritus, and angioedema have been reported with aminophylline administration. A contact-type dermatitis, caused by hypersensitivity to the ethylenediamine component of aminophylline, has also been reported. Bone marrow suppression, leukopenia, thrombocytopenia, and hemorrhagic diathesis have also been reported, but their association with theophylline therapy is questionable. Other adverse effects of theophyllines include albuminuria, increased urinary excretion of renal tubular cells and erythrocytes, hyperglycemia, and syndrome of inappropriate secretion of antidiuretic hormone (SIADH).

Adverse Effects Associated with Route and Method of Administration

Rapid IV injection of aminophylline may produce dizziness, faintness, lightheadedness, palpitation, syncope, precordial pain, flushing, profound bradycardia, ventricular premature complexes (VPCs, PVCs), severe hypotension, or cardiac arrest. IM injection of aminophylline produces intense local pain and sloughing of tissue; IM dyphylline reportedly produces little tissue irritation. When administered rectally as suppositories (dosage form no longer commercially available in the US), theophyllines have caused rectal irritation and inflammation.

Precautions and Contraindications

When therapeutic doses of theophylline are administered simultaneously by more than one route or in more than one preparation, the hazard of serious toxicity is increased; theophyllines should not be administered concomitantly with other xanthine drugs. Smokers (cigarettes and/or marijuana) may require larger than usual or more frequent doses, since theophylline clearance may be increased and its half-life decreased in smokers when compared with nonsmokers. Theophylline should be administered cautiously to young children. Theophylline should be administered cautiously to patients older than 60 years of age (particularly males and those with chronic obstructive pulmonary disease),221,222,223,224,225,226,228 neonates and infants under 1 year of age, patients receiving concomitant therapy with certain drugs, patients undergoing influenza immunization or who have an active influenza infection, patients with sustained high fever, and patients who have cardiac failure from any cause, chronic obstructive pulmonary disease, cor pulmonale, or renal (in infants younger than 3 months of age)228 or hepatic dysfunction, since clearance of theophylline is usually decreased, often resulting in higher and potentially toxic serum concentrations; dosage should generally be reduced and serum theophylline concentrations should be monitored cautiously in these patients. In addition, these patients may have markedly prolonged serum theophylline concentrations following discontinuance of the drug.

The drugs should be used with caution in patients with peptic ulcer, hyperthyroidism, glaucoma, diabetes mellitus, severe hypoxemia, hypertension, or in patients with compromised cardiac or circulatory function. Theophylline preparations should be used cautiously in patients with angina pectoris or acute myocardial injury when myocardial stimulation would be harmful. Since theophylline may cause dysrhythmia and/or worsen preexisting arrhythmias, any substantial change in rate and/or rhythm warrants electrocardiographic (ECG) monitoring and further investigation.

Some commercially available formulations of theophyllines contain sulfites that may cause allergic-type reactions, including anaphylaxis and life-threatening or less severe asthmatic episodes, in certain susceptible individuals. The overall prevalence of sulfite sensitivity in the general population is unknown but probably low; such sensitivity appears to occur more frequently in asthmatic than in nonasthmatic individuals.

Theophyllines are contraindicated in patients who are allergic to any of the theophyllines, caffeine, or theobromine; aminophylline should not be used in patients hypersensitive to ethylenediamine. At least one manufacturer states that theophyllines also are contraindicated in patients with active peptic ulcer disease and in those with underlying seizure disorders, unless the latter patients are receiving adequate anticonvulsant therapy.

Because of their erratic and unpredictable absorption and accumulation, theophylline rectal suppositories (no longer commercially available in the US) have been associated with toxicity more frequently than other formulations.

Pregnancy and Lactation

Pregnancy

Animal reproduction studies have not been performed with theophyllines. It is not known whether theophyllines can cause fetal harm when administered to pregnant women. Although safe use of theophyllines during pregnancy has not been established relative to the potential risk to the fetus, the drugs have been used during pregnancy without teratogenicity or other adverse fetal effect; because of the risk of uncontrolled asthma, their safety during pregnancy when clearly needed is generally not seriously questioned.

Lactation

Theophylline is distributed into milk and may occasionally induce irritability or other signs of toxicity in nursing infants. The risk to the breast-fed infant must be weighed against the benefit of nursing in lactating women who are receiving theophylline.

Theophylline increases excretion of lithium and may decrease its therapeutic effectiveness. Higher doses of lithium may be required during concurrent administration of theophylline. The direct stimulatory effect of theophylline on the myocardium may enhance the sensitivity and toxic potential of the cardiac glycosides. Theophylline may exhibit synergistic toxicity with ephedrine and other sympathomimetics and, when administered concomitantly, these agents may further predispose the patient to the development of cardiac arrhythmias.

Theophylline may enhance the effects of the oral anticoagulants by increasing plasma prothrombin and factor V, but therapeutic theophylline dosages will probably have little or no effect on anticoagulant response.

Cimetidine, high-dose allopurinol (e.g., 600 mg daily), oral contraceptives, propranolol, ciprofloxacin, erythromycin, and troleandomycin may increase serum theophylline concentrations by decreasing theophylline's hepatic clearance. Rifampin may decrease serum theophylline concentrations by increasing theophylline's hepatic clearance. Concomitant theophylline and phenytoin administration can result in decreased serum concentrations of either or both agents by increasing hepatic metabolism.

Methotrexate may decrease clearance of theophylline; plasma theophylline concentrations should be monitored in patients receiving theophylline concomitantly with methotrexate.

There is some evidence from animal studies that concomitant administration of a β-adrenergic agonist (e.g., isoproterenol) and a theophylline derivative (e.g., aminophylline) may produce increased cardiotoxic effects. Although such an interaction has not been established in humans, a few reports have suggested that such a combination may have the potential for producing cardiac arrhythmias. Further accumulation of clinical data is needed to determine whether this potential interaction exists in humans.

Laboratory Test Interferences

Theophylline produces false-positive elevations of serum uric acid as measured by the Bittner or colorimetric method but will not affect serum uric acid when measured by the uricase method.

In vitro, serum theophylline concentrations, as measured by spectrophotometric methods, may be falsely elevated by furosemide, sulfathiazole, phenylbutazone, probenecid, theobromine, caffeine-containing beverages, chocolate, and acetaminophen. These substances do not interfere with results when theophylline concentrations are measured by high-pressure liquid chromatography.

Acute Toxicity

Manifestations

Theophylline has a low therapeutic index. Theophylline toxicity is most likely to occur when serum concentrations exceed 20 mcg/mL and becomes progressively more severe at higher serum concentrations. Tachycardia, in the absence of hypoxia, fever, or administration of sympathomimetic drugs, may be an indication of theophylline toxicity. Anorexia, nausea and occasional vomiting, diarrhea, insomnia, irritability, restlessness, and headache commonly occur. The distinguishing symptoms of toxicity may include agitated maniacal behavior, frequent vomiting, extreme thirst, slight fever, tinnitus, palpitation, and arrhythmias. Patients may experience delirium, muscle twitching, severe dehydration, albuminuria, emesis of a “coffee ground” material, hyperthermia, and profuse diaphoresis. Seizures may occur even without other preceding symptoms of toxicity and often result in death.

Fatalities in adults have generally occurred during or following IV administration of large doses of aminophylline in patients with renal, hepatic, or cardiovascular complications. In other patients, the rapidity of the injection, rather than the dose used, appears to be the more important factor precipitating acute hypotension, seizures, coma, cardiac standstill, ventricular fibrillation, and death. IV aminophylline or theophylline should therefore be given slowly. In children, fatalities usually are a result of overdosage and marked sensitivity to the CNS stimulation of theophylline.

Treatment

Treatment of theophylline overdosage is supportive and includes withdrawal of the drug. If seizures have not occurred following acute overdosage, the stomach should be emptied immediately by inducing emesis or by gastric lavage, followed by administration of activated charcoal and a cathartic (particularly when extended-release preparations have been taken). If the patient is comatose, having seizures, or lacks the gag reflex, gastric lavage may be performed if an endotracheal tube with cuff inflated is in place to prevent aspiration of gastric contents; activated charcoal and/or a cathartic may be administered via a large-bore gastric lavage tube. If the patient is having seizures, an adequate airway should first be established and maintained and oxygen administered; seizures may be treated with IV diazepam 0.1-0.3 mg/kg up to 10 mg. Some clinicians recommend the use of barbiturates or anesthetics to control seizures. In one clinical report, however, theophylline-induced seizures were relatively refractory to IV diazepam, phenytoin, and phenobarbital. Restoration of fluid and electrolyte balance is necessary. Administration of phenothiazines for intractable hyperthermia and propranolol for extreme tachycardia may be warranted in life-threatening situations.

In general, theophylline is metabolized rapidly and hemodialysis is not warranted. In patients with congestive heart failure or liver disease, hemodialysis or charcoal hemoperfusion may increase theophylline clearance by as much as twofold. Charcoal hemoperfusion can rapidly remove theophylline and may be clinically indicated when the serum theophylline concentration exceeds 50 mcg/mL, even in the absence of obvious signs of toxicity. Some clinicians recommend that charcoal hemoperfusion generally be used for all patients whose serum theophylline concentration 4 hours after ingestion exceeds 60 mcg/mL. When the serum theophylline concentration is 40-50 mcg/mL, the risks of hemoperfusion (e.g., hypotension, thrombocytopenia) must be carefully weighed against the potential benefits of the procedure; when the serum concentration is less than 40 mcg/mL, the risks of hemoperfusion probably outweigh any potential benefits. Some clinicians recommend that charcoal hemoperfusion be used in patients with a serum theophylline concentration of 30 mcg/mL or greater and 3 of the following 4 risk factors: the patient is 60 years of age or older, the patient has substantial liver disease and/or congestive heart failure, the theophylline half-life for the patient is calculated to be 24 hours or more, and/or the patient's serum theophylline concentration is 50 mcg/mL or greater. If hemoperfusion is not performed, some clinicians recommend oral administration of activated charcoal every 4 hours until the serum theophylline concentration decreases to less than 20 mcg/mL.

Pharmacology

Theophyllines and dyphylline exert identical pharmacologic actions. Theophylline competitively inhibits phosphodiesterase, the enzyme that degrades cyclic 3',5'-adenosine monophosphate (cAMP). Increased concentrations of intracellular cAMP may mediate most of the pharmacologic effects of the drug. The actions of theophylline on the myocardium and on neuromuscular transmission may result from intracellular translocation of ionized calcium. The ubiquitous nature of calcium and cAMP accounts for the diversity of theophylline's pharmacologic actions.

Pulmonary Effects

Theophylline directly relaxes smooth muscle of the respiratory tract, producing relief of bronchospasm and increasing flow rates and vital capacity. The bronchodilator effect of the drug is minimal if bronchospasm is not the principal cause of respiratory distress. Theophylline also dilates pulmonary arterioles, reduces pulmonary hypertension and alveolar carbon dioxide tension, and increases pulmonary blood flow. Unlike sympathomimetics, tolerance to the bronchodilator effects of theophylline rarely occurs.

Nervous System Effects

Theophylline stimulates all levels of the CNS, but to a lesser degree than does caffeine. Stimulation of the vasomotor and vagal centers promotes vasoconstriction and bradycardia, respectively, but the overall effect of theophylline on heart rate and blood pressure depends on whether CNS or peripheral effects predominate. In the medulla, theophylline also lowers the threshold of the respiratory center to carbon dioxide, but substantial increases in rate and depth of respiration occur only if respiration is depressed. Alleviation of neonatal apnea and the apnea of Cheyne-Stokes respiration by these drugs may be caused by direct stimulation of the medullary respiratory center. Theophylline constricts cerebral vasculature; in some patients, the resultant decrease in cerebral blood flow and increase in carbon dioxide tension may result in respiratory center stimulation. The ethylenediamine component of aminophylline reportedly contributes to the respiratory stimulant action of theophylline; however, the importance and validity of this action are doubtful. Therapeutic serum concentrations of theophylline may stimulate the vomiting center while toxic serum concentrations activate all levels of the cortex and spinal cord, often producing seizures. Tolerance of a low magnitude may develop to the sleep-disturbing effect of theophylline.

Cardiovascular Effects

In doses larger than those required for bronchodilation, theophylline produces a positive inotropic effect on the myocardium and a positive chronotropic effect at the sinoatrial (SA) node. Although heart rate, force of contraction, cardiac output, and myocardial oxygen demand may be increased transiently, theophylline rarely alters heart rate to a substantial degree with usual doses. At high serum concentrations, however, the central vagal effects of the drug may be masked by increased sinus rate, and acute hypotension, tachycardia, extrasystoles, or ventricular arrhythmia may result. The ethylenediamine component of aminophylline reportedly contributes to the positive inotropic action of theophylline; however, the importance and validity of this action are doubtful.

Theophylline directly dilates coronary, pulmonary, renal, and general systemic arterioles and veins, decreasing peripheral vascular resistance and venous pressure. The effect of this decrease in peripheral resistance (and possibly that of vagal stimulation) on blood pressure is offset by increased cardiac output (and possibly stimulation of the medullary vasomotor area); there is generally only a slight increase in blood pressure following administration of moderate doses of theophylline. Rapid IV injection, however, may cause transient hypotension. In a similar manner, peripheral blood flow increases initially, but this increase is of short duration. Dilation of coronary blood vessels may be a direct effect of theophylline or may result from increased cardiac work. Coronary blood flow increases and, theoretically, myocardial oxygen supply is improved by theophylline. However, some studies report an increase in myocardial oxygen consumption resulting from increased heart work. In contrast to its peripheral vasodilation, theophylline constricts cerebral vasculature.

Renal Effects

The diuretic effect of theophylline is more potent than that of theobromine but is of shorter duration. Mild diuresis is produced by the combined effect of theophylline on renal hemodynamics and on tubular reabsorption. Increased cardiac output and dilation of efferent and afferent renal arterioles result in increased glomerular filtration rate (GFR) and renal blood flow. In congestive heart failure, theophylline-induced changes in GFR are variable. Theophylline also inhibits sodium and chloride reabsorption at the proximal tubule. Potassium excretion is not markedly increased. Tolerance of a low magnitude may develop to the diuretic effect of theophylline.

Endocrine and Metabolic Effects

At therapeutic serum concentrations, theophylline may stimulate release of catecholamines from the adrenal medulla and increase the urinary excretion of epinephrine. Theophylline exhibits many of the β-adrenergic effects of epinephrine; their cardiac and hyperglycemic effects may be synergistic. Conversely, theophylline may potentiate corticotropin and catecholamine-induced insulin secretion. The net effect on blood glucose is variable. The lipolytic action of theophylline requires the presence of growth hormone or glucocorticoid to produce maximum increase in plasma free fatty acids. Theophylline may potentiate the calcemic response to parathyroid hormone and inhibit that of calcitonin. Theophylline may also increase basal metabolic rate.

Other Effects

Theophylline relaxes smooth muscle of the biliary and GI tract, and stimulates gastric secretion. Theophylline stimulates skeletal muscle in vitro, increasing the force of contraction and decreasing muscular fatigue; this action of theophylline may be mediated by acetylcholine.

Pharmacokinetics

Absorption

Dissolution appears to be the rate-limiting step in the absorption of oral theophylline. Under the acidic conditions of the stomach, the theophylline salts and compounds release free theophylline. Dyphylline is absorbed through the gastric mucosa and appears in the plasma intact. Microcrystalline dosage forms and oral solutions of theophyllines are absorbed more rapidly, but not to a greater extent, than are uncoated tablets. Although the rate of absorption is slower, extended-release preparations (capsules and tablets) of theophylline are generally absorbed to the same extent as uncoated tablets; however, the actual rate of absorption of extended-release preparations may differ. Extended-release preparations of theophyllines have been formulated to release the drug at various rates suitable for dosing every 8-12, 12, or 24 hours; however, the actual dosing frequency for a given patient depends on their individual pharmacokinetic parameters. Since the rate and extent of absorption may differ between various extended-release preparations and sometimes between different dosage sizes of the same preparation, patients should generally be stabilized on a given preparation; substitution of one extended-release preparation for another should generally only be made when the preparations have been shown to be equivalent and/or the patient is evaluated pharmacokinetically during the transition period. Absorption of theophyllines may also be delayed, but is generally not reduced, by the presence of food in the GI tract; however, the effect of food on the absorption of extended-release preparations appears to be variable, and the manufacturer's recommendations for administration of specific preparations should be followed. When administered IM, theophylline is usually absorbed slowly and incompletely. Rectal suppositories (no longer commercially available in the US) are slowly and erratically absorbed, regardless of whether the suppository base is hydrophilic or lipophilic.

Serum theophylline concentrations of about 5-15 mcg/mL are usually recommended to produce a bronchodilator response.213,232 The therapeutic range of plasma concentrations of dyphylline that may be expected to produce effective bronchodilation has not been determined.233 Some patients with mild pulmonary disease will experience relief of bronchospasm with serum theophylline concentrations of 5 mcg/mL. With serum concentrations ranging from 8-20 mcg/mL, a linear relationship exists between improvement in pulmonary function and the logarithm of serum theophylline concentration. In premature infants, serum theophylline concentrations of about 7-14 mcg/mL may be sufficient to reverse apnea. Serum theophylline concentrations of about 10 mcg/mL produce a transient diuretic response. Adverse reactions to theophylline often occur when serum concentrations exceed 20 mcg/mL.

IV theophylline produces the highest and most rapid serum theophylline concentration. Following a single IV dose of theophylline (as aminophylline) of about 5 mg/kg over 30 minutes to healthy adults, mean peak serum theophylline concentrations of about 10 mcg/mL are reached. Slightly lower or equal peak serum concentrations are reached after oral administration of equal amounts of theophylline in uncoated tablet, capsule, or liquid formulations. Following oral administration of theophylline capsules or uncoated tablets, peak serum concentrations are usually reached in 1-2 hours. Peak serum theophylline concentrations are usually obtained after about 1 hour when theophylline oral solutions or microcrystalline tablets are administered. Enteric-coated theophylline tablets produce variable serum concentrations which usually peak at about 5 hours. Single doses of extended-release theophylline capsules or tablets usually produce peak serum concentrations after 4 hours, but commercial products vary in their rates and completeness of absorption. Extended-release theophylline preparations are generally associated with relatively small fluctuations in steady-state peak and trough serum concentration; however, clinically important steady-state peak-trough differences may occur in individuals who rapidly eliminate theophylline. Theophylline retention enemas usually produce peak serum concentrations in 1-2 hours. Serum theophylline concentrations generally have been apparent 3-5 hours after administration of the drug as rectal suppositories (no longer commercially available in the US).

Distribution

Theophylline is rapidly distributed throughout extracellular fluids and body tissues with distribution equilibrium being reached 1 hour after an IV loading dose. The drug partially penetrates erythrocytes and readily crosses the placenta.

The drug is also distributed into milk in concentrations about 70% those in serum.

The apparent volume of distribution of theophylline ranges from 0.3-0.7 L/kg and averages about 0.45 L/kg in children and adults. In premature infants, theophylline's apparent volume of distribution is generally almost 2 times that in adults. At serum concentrations of 17 mcg/mL, approximately 56% of theophylline in adults and children, and 36% of that in premature infants, is bound to plasma proteins. Although saliva concentrations of theophylline have been reported to be 50% of serum concentrations in relatively healthy patients, saliva concentrations ranged from 50-100% of serum concentrations in one study in severely ill patients.

Elimination

In maintenance-dose theophylline schedules, serum concentrations among patients vary at least sixfold and serum half-lives (t_½) exhibit wide interpatient variation because of differences in rate of metabolism. Serum t_½ ranges from about 3-12.8 (average 7-9) hours in otherwise healthy, nonsmoking asthmatic adults, from about 1.5-9.5 hours in children, and from about 15-58 hours in premature infants. Theophylline clearances (mean ± standard deviation) have been reported to be 1.45 ± 0.58 mL/kg per minute in children older than 6 months of age and 0.65 ± 0.19 mL/kg per hour in otherwise healthy, nonsmoking asthmatic adults. In adults, a shorter serum t_½ of about 2 hours has been demonstrated for dyphylline. When compared with that of otherwise healthy, nonsmoking asthmatic adults, the serum t_½ of theophylline may be increased and total body clearance decreased in patients with congestive heart failure, chronic obstructive pulmonary disease, cor pulmonale, or liver disease, and in geriatric patients. In cigarette and/or marijuana smokers, theophylline serum t_½ averages 4-5 hours and total body clearance is increased compared with nonsmokers.

Theophylline is metabolized by the liver to 1,3-dimethyluric acid, 1-methyluric acid, and 3-methylxanthine. The metabolism of dyphylline has not been fully elucidated, but the drug is not metabolized to theophylline. Individuals metabolize theophylline at different rates; however, individual metabolism of the drug is generally reproducible. Theophylline and its metabolites are excreted mainly by the kidneys. Renal clearance of the drug, however, contributes only 8-12% of the overall plasma clearance of theophylline. Small amounts of theophylline are excreted in feces unchanged.

Chemistry

Theophylline

Like caffeine and theobromine, theophylline may be structurally classified as a xanthine derivative. Theophylline occurs naturally in tea, but it is prepared synthetically for commercial use. The drug may contain one molecule of water or be anhydrous. At physiologic pH, theophylline functions as a weak base (pK_b 13-14). Tautomeric shift of the hydrogen from the unsubstituted 7 nitrogen is possible at high pH, creating a weak organic acid (pK_a 8.79) that reacts with alkali salts of weak organic acids and certain organic amines. Theophylline occurs as a white, odorless, crystalline powder having a bitter taste and is sparingly soluble in alcohol. The drug is only slightly soluble in water at pH 7; the water solubility increases with increases in pH.

Aminophylline

Aminophylline is a water-soluble theophylline compound with ethylenediamine and occurs as white or slightly yellowish granules or powder having a slight ammoniacal odor and a bitter taste. Aminophylline is soluble in water and insoluble in alcohol. Aminophylline has a pK_a of 5. Aminophylline may be anhydrous or may contain not more than 2 molecules of water of hydration. Upon exposure to air, aminophylline and aminophylline solutions gradually lose ethylenediamine, absorb carbon dioxide, and liberate free theophylline; aminophylline solutions should not be used if they contain crystals. Aminophylline injection has a pH of 8.6-9 and should be stored in single-dose containers from which carbon dioxide has been excluded.

Aminophylline injections reportedly are not stable in solutions having a pH substantially less than 8; however, the drug appears to be relatively stable in large volume parenteral solutions over a wide pH range (3.5-8.6) if aminophylline concentrations do not exceed 40 mg (31.6 mg of anhydrous theophylline) per mL. The activity of alkali-sensitive drugs will be reduced by aminophylline; these drugs should not be added to IV fluids containing aminophylline. Published data on specific incompatibilities of aminophylline are varied and/or limited; specialized references should be consulted for specific compatibility information.

Dyphylline

Dyphylline, which is a distinct chemical entity, is structurally and pharmacologically similar to theophylline but has a 2,3-dihydroxypropyl radical at position 7. Dyphylline is not metabolized to theophylline in vivo. Dyphylline occurs as a white, odorless, amorphous or crystalline solid having an extremely bitter taste. Dyphylline is freely soluble in water and sparingly soluble in alcohol. Dyphylline injection has a pH of 6.4-7.4 and should be protected from light.

Oxtriphylline

Oxtriphylline (no longer commercially available in the US), the choline salt of theophylline, occurs as a white, crystalline powder having an amine-like odor and a slightly saline taste. Oxtriphylline is freely soluble in water and in alcohol.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Only references cited for selected revisions after 1984 are available electronically.

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