AMINOPHYLLINE

General Administration Information
For storage information, see the specific product information within the the How Supplied section.

Route-Specific Administration

Oral Administration
Oral Solid Formulations
-Immediate-release formulations: Administration with food or antacids does not have a clinically significant impact on absorption.
-Enteric-coated or timed-release capsules or tablets: Do not crush or chew. For patients with difficulty swallowing, the capsule formulations may be opened and mixed with soft food; do not chew or crush medication beads.
-Theo-24 capsules: Do not crush or chew. Administer on an empty stomach; administration with a high-fat-content meal may increase the peak serum theophylline concentration which could result in toxicity. Administration is usually in the morning at approximately the same time daily; when two doses per day are prescribed, administer the second dose 10-12 hours after the morning dose and before the evening meal.

Oral Liquid Formulations
-Administer theophylline using a calibrated measuring device to ensure accurate dosing.



Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Discard solution if it is not clear.
-Do not use if crystals are present.
Intravenous Administration
Intermittent Intravenous Infusion
-If the patient has received any theophylline within 24 hours, obtain serum theophylline concentration prior to administration of a theophylline/aminophylline loading dose.

-Infuse over 30 minutes.
-Monitor heart rate; consider holding dose if patient is tachycardic.

Continuous Intravenous Infusion
-Infusion rate should be individualized and is dependent on goal serum concentrations and patient's clinical response..
-Monitor patient clinically as appropriate during infusion.

Adverse reactions to theophylline therapy are usually mild when peak serum concentrations are < 20 mcg/ml in non-neonatal patients and mainly include mild gastrointestinal symptoms and difficulty sleeping. Neonates are more likely to experience adverse effects at lower serum concentrations due to the increased amount of unbound theophylline in the circulation, and one of the more notable adverse effects in this population is an increase in heart rate and irritable behavior. As serum concentrations increase above the therapeutic range, a wide range of adverse effects are possible, some being life-threatening.

Theophylline has been shown to increase energy expenditure in premature neonates. Monitor weight gain carefully in neonates receiving chronic theophylline; these patients may have an increased caloric requirement.

Adverse GI reactions can be either a local irritant effect on the gastric mucosa or a centrally mediated effect. Transient caffeine-like adverse reactions, such as nausea and vomiting, can occur especially during initiation of theophylline. Initiate theophylline at a low dose and slowly titrate to decrease the occurrence of these reactions. These reactions may persist in a small percentage of patients (less than 3% pediatrics and less than 10% adults). A reduction in dosage may eliminate caffeine-like adverse reactions, but if they continue or become severe, theophylline may have to be discontinued. Diarrhea has also been reported as an adverse reaction in patients with therapeutic serum concentrations of theophylline. Nausea/vomiting and abdominal pain may be caused by gastroesophageal reflux; this effect is more likely to occur if the patient is lying down. Infants and children 2 years or younger and debilitated patients are more likely to suffer from this effect. Other GI effects include abdominal cramps, anorexia, and possible hematemesis. Local irritation can be minimized by taking the oral drug before or after meals, with a full glass of water or milk, or with antacids. Both adverse GI and CNS effects can be minimized if the dose is titrated over a period of 1 week. Repetitive vomiting may indicate theophylline toxicity and should be investigated. In studies evaluating signs and symptoms of theophylline overdose, vomiting was reported in 73% to 93% of patients after a large single ingestion (acute overdose) and 30% to 61% of patients after multiple excessive doses (chronic overdose).

The most common CNS adverse reactions associated with theophylline use are headache, insomnia, and irritability. Transient caffeine-like adverse reactions, such as headache and insomnia, are most common during initiation of theophylline. Initiate theophylline at a low dose and slowly titrate to decrease the occurrence of these reactions. Irritability, restlessness, and tremor have also been reported as adverse reactions in patients with therapeutic serum concentrations of theophylline. Anxiety, agitation, hyperactivity, and dizziness may also occur. Serum theophylline concentrations greater than 30 mcg/mL have also resulted in nervousness, tremors, and disorientation. These reactions may persist in a small percentage of patients (less than 3% pediatrics and less than 10% adults). A reduction in dosage may eliminate caffeine-like adverse reactions, but if they continue or become severe, theophylline may have to be discontinued. In school aged children, theophylline adverse effects may transiently alter patient behavior. A study of 29 children receiving either theophylline or cromolyn sodium was conducted to assess cognition and behavior in children age 7 to 12 years. All patients received both theophylline and cromolyn for 3 weeks and then were randomized to either theophylline or cromolyn for at least 2 weeks. Patients receiving cromolyn sodium had greater improvement on all tests of memory and concentration compared to those receiving theophylline. Additionally, there were significant correlations between the length of theophylline therapy and scores on the depression (p is less than 0.03) and obsessive-compulsive (p is less than 0.04) subscales of the Child Behavior Checklist.

Seizures are one of the most serious potential adverse events associated with theophylline use. Seizures occurring in patients with serum theophylline concentrations less than 20 mcg/mL are uncommon and are usually milder than those occurring in patients with supratherapeutic serum concentrations; they are typically transient, may resolve without anticonvulsant therapy, and do not result in neurological residual. In contrast, seizures associated with excessive serum concentrations can be life-threatening. Seizures associated with chronic overdosage can be generalized and often do not respond to traditional anti-seizure medications. Counsel patients and/or caregivers about the importance of taking theophylline exactly as prescribed and alerting their healthcare provider of any changes that may affect theophylline clearance (e.g., febrile illness, change in smoking status).

Theophylline is a weak diuretic and inotrope, and can cause a mild diuresis.

Hypercalciuria has been reported in premature neonates receiving theophylline. In 20 premature neonates randomly assigned to receive 5 days of either theophylline or caffeine, a statistically significant increase in urine calcium excretion of 10- to 15-fold was observed and was most evident in the theophylline group. Hypercalcemia has been reported in a patient with hyperthyroid disease at therapeutic theophylline concentrations.

Hypersensitivity and dermatologic reactions reported with theophylline at concentrations less than 20 mcg/mL include anaphylactic reaction, anaphylactoid reactions, pruritus, rash, and urticaria. Severe allergic skin reactions, such as exfoliative dermatitis, can develop rarely after systemic administration of aminophylline in patients previously sensitized to ethylenediamine via topical administration of an ethylenediamine-containing product. Urticaria or contact dermatitis can develop in individuals who physically handle aminophylline from a hypersensitivity to the ethylenediamine salt.

Increased heart rate (sinus tachycardia) is one of the most common adverse effects associated with theophylline use in neonates and can also occur in other populations as well. In neonates, measure heart rate before each dose and consider holding the dose if the patient's heart rate is above the upper range of acceptable for age. Theophylline decreases peripheral resistance, increases cardiac output, causes a central vagal effect, and reduces cerebral blood flow after administration. Palpitations, hypotension, ventricular tachycardia, premature ventricular contractions (PVCs), and cardiac arrest have been reported. Although cardiovascular effects are generally mild and transient, serious reactions, such as ventricular arrhythmias, can develop without warning. Patients should be carefully monitored.

Theophylline toxicity appears to occur at lower serum concentrations after chronic overmedication than after acute overdose. In addition, acute overdose patients are more likely to exhibit hypotension, hypokalemia, and/or metabolic acidosis than are patients receiving chronic overmedication. Patients suffering chronic overmedication can develop seizures and serious arrhythmias with serum concentrations of 28 to 70 mcg/mL. Cardiac arrhythmias include atrial fibrillation or atrial flutter, multifocal atrial tachycardia, sinus tachycardia, supraventricular tachycardia (SVT), premature ventricular contractions (PVCs), and other ventricular arrhythmias with hemodynamic instability. In studies evaluating signs and symptoms of theophylline overdose, sinus tachycardia was the most common cardiac symptom occurring in 86% to 100% of patients after a large single ingestion (acute overdose) and 62% to 100% of patients after multiple excessive doses (chronic overdose). Multifocal atrial tachycardia and atrial flutter have been reported at serum concentrations of 15 mcg/mL or more in patients with hypoxia secondary to COPD.

Rhabdomyolysis is a manifestation of theophylline toxicity and has been reported in studies where the theophylline concentrations were greater than 30 mcg/mL.

Hyperglycemia is a manifestation of theophylline toxicity and has been reported in studies where the theophylline concentrations were greater than 30 mcg/mL.

Serum concentrations of glucose, uric acid, free fatty acids (cholesterol, HDL), and urinary free cortisol excretion may all be increased during theophylline therapy. Also, transient decreases in triiodothyronine concentrations have been reported. The clinician should be aware of these alterations and should weigh the clinical importance of these changes to the benefits of theophylline therapy.

Theophylline and aminophylline are contraindicated in patients who have demonstrated a hypersensitivity reaction to theophylline or any component in the commercial product. Some pre-mixed theophylline in dextrose intravenous infusions may be manufactured using corn or corn products and may be contraindicated in patients with corn hypersensitivity.

Use theophylline cautiously in patients with tachycardia. Theophylline may cause increased heart rate in patients with a normal baseline heart rate or worsen tachycardia. Monitor heart rate, especially in neonates. Patients with cardiac disease should be monitored more closely for adverse reactions to theophylline. Lower doses may be necessary for patients with congestive heart failure, including cor pulmonale, due to decreased theophylline clearance (>= 50% decrease). Also, theophylline can exacerbate existing cardiac arrhythmias and should be used with caution in patients at risk. Similarly, because theophylline can increase oxygen demand, it should be prescribed carefully in patients with coronary artery disease, especially those with a history of myocardial infarction.

Patients with hypothyroidism, acute pulmonary edema, sepsis with multiple organ failure, or shock may have decreased theophylline clearance. Any patients with any of the above conditions should be monitored carefully while receiving theophylline; a dosage reduction may be required.

Theophylline clearance is decreased by >= 50% in patients with hepatic disease. In patients with moderate to severe hepatic disease (i.e. cirrhosis, acute hepatitis, or cholestasis), theophylline doses may need to be lower and serum concentrations measured more frequently. Because neonates and young infants have a higher percentage of unchanged theophylline excreted via the kidneys (approximately 50% in newborns as compared to 10% in those older than 3 months), neonates and infants less than 3 months with renal impairment require lower doses. Additionally, clearance is variable in pediatric patients less than 1 year of age so more frequent monitoring is recommended.

Fever, regardless of the cause, can decrease theophylline clearance and increase the risk of toxicity. The magnitude and duration of the fever appear to correlate to the degree of the reduction in clearance. A temperature of at least 39 degrees C (102 degrees F) for at least 24 hours is probably necessary to have a clinically significant impact on theophylline clearance; however, exact data are not available. Careful monitoring is necessary in patients with a prolonged febrile illness. Although fever associated with respiratory illness, specifically, has been associated with decreased clearance; respiratory syncytial virus (RSV) infection in children does not appear to affect theophylline clearance.

Increased theophylline clearance may occur in patients with hyperthyroidism or cystic fibrosis. Hypercalcemia has been reported in a patient with hyperthyroid disease at therapeutic theophylline concentrations. Any patients with cystic fibrosis or conditions affecting the thyroid should be monitored carefully while receiving theophylline.

Patients with uncorrected acidemia can have an increase in the volume of distribution of theophylline due to a decrease in plasma protein binding. If the test is available, unbound serum theophylline concentrations should be monitored in these patients to avoid toxicity.

Theophylline should be used cautiously in patients with a history of seizure disorder due to the risk of exacerbating their condition.

Because theophylline can stimulate gastric secretions, it should be used with caution in patients with gastritis or active peptic ulcer disease. Theophylline may aggravate symptoms related to hiatal hernia or gastroesophageal reflux disease (GERD).

Tobacco smoking has been shown to increase the clearance of theophylline by about 50% in young adult tobacco smokers; marijuana smoking also increases clearance (actual percentage unknown). Also, passive smoke exposure may cause a an increase in theophylline clearance by up to 50%. Because the effect of tobacco on hepatic microsomal enzymes is not related to the nicotine component, sudden smoking cessation may result in a reduced clearance of theophylline, despite the initiation of nicotine replacement products. After 1 week of abstinence from chronic tobacco smoking, theophylline clearance may decrease by roughly 40%, leading to an increase in serum theophylline concentrations. Theophylline serum concentrations should be monitored carefully when changes in smoking status occur.

In adult patients with hypoxemia secondary to COPD, there have been reports of atrial tachycardia and flutter at serum concentrations as low as 15 mcg/ml ; it is unclear if pediatric patients with hypoxemia secondary to other causes may also be at increased risk for cardiovascular adverse events.

Description: Theophylline is a xanthine derivative that is used both orally or intravenously in the treatment of apnea of prematurity and asthma. Theophylline occurs naturally in tea and is chemically similar to caffeine and theobromine. While theophylline was commonly used to treat asthma in the past, its use is much less common today because there are effective alternatives with better safety profiles. Oral theophylline is not recommended for asthma maintenance therapy in children less than 12 years. In adolescents and adults, low-dose sustained-release oral theophylline is considered an alternate, but not preferred, therapy to the use of inhaled corticosteroids (ICSs) or may be used as an alternate, adjunctive treatment to ICS in those with persistent asthma symptoms. Intravenous aminophylline and theophylline are not recommended for the management of acute asthma exacerbations because it appears to provide no additional benefit to optimal inhaled beta-2-agonist therapy and may increase risk of adverse effects. Theophylline is also approved for the treatment of apnea of prematurity; however, it is generally a second-line treatment option after caffeine due to its narrow therapeutic window for serum concentrations. Theophylline has been used off-label for the management of renal impairment and facilitation of extubation in neonates, the prevention of apnea during prostaglandin E1 infusion, the treatment of acute asthma exacerbations not responding to other therapies, and the treatment of methotrexate toxicity. Aminophylline, a salt of theophylline, is the form frequently used for IV therapy. Because 100 mg of aminophylline is equivalent to 80 mg of theophylline, errors in dosing are possible, and clinicians should carefully assess dosage adjustments and calculations when switching between aminophylline and theophylline. Theophylline is approved in pediatric patients as young as neonates.

General dosing information:
-When rapid attainment of therapeutic serum concentrations is desired, IV "loading" doses can be given, although oral administration with regular-release formulations is equally effective in patients who can tolerate enteral administration.
-Calculate initial mg/kg dose based on ideal body weight as theophylline distributes poorly into body fat.


For the treatment of neonatal apnea of prematurity:
Intravenous loading dosage (aminophylline or theophylline):
Neonates: 5 to 8 mg/kg (aminophylline or theophylline) IV infused over 30 minutes. In a randomized controlled trial that included 61 premature neonates, a loading dose of 8 mg/kg of aminophylline achieved therapeutic serum concentrations more frequently than 6 mg/kg.
Intravenous or Oral maintenance dosage (aminophylline or theophylline):
Premature Neonates: 0.8 to 3 mg/kg/dose (aminophylline or theophylline) IV or PO every 8 to 12 hours have been used in clinical trials. The manufacturer recommends 1 mg/kg (theophylline) IV or PO every 12 hours in premature neonates (postnatal age younger than 24 days) and 1.5 mg/kg (theophylline) IV or PO every 12 hours for premature neonates (postnatal age 24 days and older). Monitor clinical status and theophylline serum concentrations frequently. Dosage of theophylline must be individualized. When switching from IV aminophylline to PO theophylline in preterm infants, no initial dosage adjustment is necessary.
Term Neonates and Infants: The total daily dose should be divided and given PO every 8 hours. Calculate initial dose using the following equation:
Total daily dose (mg) = [(0.2 x age in weeks) + 5] x (body weight in kg)
Monitor clinical status and theophylline serum concentrations frequently.

For asthma maintenance treatment:
Guidelines generally recommend against the routine use of aminophylline or theophylline in the treatment of asthma for most patients. Not a preferred treatment, but may be used adjunctively in selected patients.
Oral dosage (immediate-release; dosage is expressed as theophylline):
Term Neonates: 10 mg/kg/day PO divided every 8 hours, initially. Alternately, calculate initial total daily dose using the following equation: Total daily dose (mg) = [(0.2 x age in weeks) + 5] x (kg body weight). Divide dose and administer every 8 hours. Adjust dose based on serum theophylline concentrations. Consider increased monitoring and dose reductions in neonates with renal impairment. Theophylline is not a preferred treatment per asthma guidelines.
Infants 4 to 25 weeks: 10 mg/kg/day PO divided every 8 hours, initially. Alternately, calculate initial total daily dose using the following equation: Total daily dose (mg) = [(0.2 x age in weeks) + 5] x (kg body weight). Divide dose and administer every 8 hours. Adjust dose based on serum theophylline concentrations. Reduced doses may be needed for infants with risk factors for reduced theophylline clearance (e.g., cardiac or liver dysfunction, renal dysfunction). Theophylline is not a preferred treatment per asthma guidelines.
Infants 26 to 51 weeks: 10 mg/kg/day PO divided every 6 hours, initially. Alternately, calculate initial total daily dose using the following equation: Total daily dose (mg) = [(0.2 x age in weeks) + 5] x (kg body weight). Divide dose and administer every 6 hours. Adjust dose based on serum theophylline concentrations. Reduced doses may be needed for infants with risk factors for reduced theophylline clearance (e.g., cardiac or liver dysfunction, renal dysfunction). Theophylline is not a preferred treatment per asthma guidelines.
Children 1 to 11 years weighing 45 kg or less: 12 to 14 mg/kg/day (Max: 300 mg/day) PO divided every 4 to 6 hours, initially. After 3 days, increase the dose to 16 mg/kg/day (Max: 400 mg/day) and then 20 mg/kg/day (Max: 600 mg/day) if tolerated. Alternately, 10 mg/kg/day (Max: 300 mg/day) PO, initially. Adjust dose based on serum theophylline concentrations. Usual Max: 16 mg/kg/day. Do not exceed 16 mg/kg/day (Max: 400 mg/day) in persons with risk factors for decreased theophylline clearance or who cannot receive recommended serum concentration monitoring. Theophylline is not a preferred treatment per asthma guidelines.
Children 1 to 11 years weighing more than 45 kg: 300 mg/day PO divided every 6 to 8 hours, initially. After 3 days, increase the dose to 400 mg/day and then 600 mg/day if tolerated. Alternately, 10 mg/kg/day (Max: 300 mg/day) PO, initially. Adjust dose based on serum theophylline concentrations; doses of 400 to 1,600 mg/day may be needed. Usual Max: 16 mg/kg/day. Do not exceed 400 mg/day in persons with risk factors for decreased theophylline clearance and in those who cannot receive recommended serum concentration monitoring. Consider smaller, more frequent doses of immediate-release products or use of extended-release products in persons with rapid metabolism, identified by higher than average dose requirements. Theophylline is not a preferred treatment per asthma guidelines.
Children and Adolescents 12 to 15 years weighing 45 kg or less: 12 to 14 mg/kg/day (Max: 300 mg/day) PO divided every 4 to 6 hours, initially. After 3 days, increase the dose to 16 mg/kg/day (Max: 400 mg/day) and then 20 mg/kg/day (Max: 600 mg/day) if tolerated. Alternately, 10 mg/kg/day (Max: 300 mg/day) PO, initially. Adjust dose based on serum theophylline concentrations. Usual Max: 800 mg/day. Do not exceed 16 mg/kg/day (Max: 400 mg/day) in persons with risk factors for decreased theophylline clearance or who cannot receive recommended serum concentration monitoring. Theophylline is not a preferred treatment per asthma guidelines.
Children and Adolescents 12 to 15 years weighing more than 45 kg: 300 mg/day PO divided every 6 to 8 hours, initially. After 3 days, increase the dose to 400 mg/day and then 600 mg/day if tolerated. Alternately, 10 mg/kg/day (Max: 300 mg/day) PO, initially. Adjust dose based on serum theophylline concentrations; doses of 400 to 1,600 mg/day may be needed. Usual Max: 800 mg/day. Do not exceed 400 mg/day in persons with risk factors for decreased theophylline clearance and in those who cannot receive recommended serum concentration monitoring. Consider smaller, more frequent doses of immediate-release products or use of extended-release products in persons with rapid metabolism, identified by higher than average dose requirements. Theophylline is not a preferred treatment per asthma guidelines.
Adolescents 16 to 17 years: 300 mg/day PO divided every 6 to 8 hours, initially. After 3 days, increase the dose to 400 mg/day and then 600 mg/day if tolerated. Alternately, 10 mg/kg/day (Max: 300 mg/day) PO, initially. Adjust dose based on serum theophylline concentrations; doses of 400 to 1,600 mg/day may be needed. Usual Max: 800 mg/day. Do not exceed 400 mg/day in persons with risk factors for decreased theophylline clearance and in those who cannot receive recommended serum concentration monitoring. Consider smaller, more frequent doses of immediate-release products or use of extended-release products in persons with rapid metabolism, identified by higher than average dose requirements. Theophylline is not a preferred treatment per asthma guidelines.
Oral dosage (extended-release, e.g., Theolair-SR; dosage is expressed as theophylline):
Children 6 to 11 years weighing 45 kg or less: 12 to 14 mg/kg/day (Max: 300 mg/day) PO divided every 8 to 12 hours, initially. After 3 days, increase the dose to 16 mg/kg/day (Max: 400 mg/day) and then 20 mg/kg/day (Max: 600 mg/day) if tolerated. Alternately, 10 mg/kg/day (Max: 300 mg/day) PO, initially. Adjust dose based on serum theophylline concentrations. Usual Max: 16 mg/kg/day. Do not exceed 16 mg/kg/day (Max: 400 mg/day) in persons with risk factors for decreased theophylline clearance or who cannot receive recommended serum concentration monitoring. Extended-release products are not to be used to treat acute symptoms. Theophylline is not a preferred treatment per asthma guidelines.
Children 6 to 11 years weighing more than 45 kg: 300 mg/day PO divided every 8 to 12 hours, initially. After 3 days, increase the dose to 400 mg/day and then 600 mg/day if tolerated. Alternately, 10 mg/kg/day (Max: 300 mg/day) PO, initially. Adjust dose based on serum theophylline concentrations; doses of 400 to 1,600 mg/day may be needed. Usual Max: 16 mg/kg/day. Do not exceed 400 mg/day in persons with risk factors for decreased theophylline clearance and in those who cannot receive recommended serum concentration monitoring. Consider smaller, more frequent doses in persons with rapid metabolism, identified by higher than average dose requirements. Extended-release products are not to be used to treat acute symptoms. Theophylline is not a preferred treatment per asthma guidelines.
Children and Adolescents 12 to 15 years weighing 45 kg or less: 12 to 14 mg/kg/day (Max: 300 mg/day) PO divided every 8 to 12 hours, initially. After 3 days, increase the dose to 16 mg/kg/day (Max: 400 mg/day) and then 20 mg/kg/day (Max: 600 mg/day) if tolerated. Alternately, 10 mg/kg/day (Max: 300 mg/day) PO, initially. Adjust dose based on serum theophylline concentrations. Usual Max: 800 mg/day. Do not exceed 16 mg/kg/day (Max: 400 mg/day) in persons with risk factors for decreased theophylline clearance or who cannot receive recommended serum concentration monitoring. Extended-release products are not to be used to treat acute symptoms. Theophylline is not a preferred treatment per asthma guidelines.
Children and Adolescents 12 to 15 years weighing more than 45 kg: 300 mg/day PO divided every 8 to 12 hours, initially. After 3 days, increase the dose to 400 mg/day and then 600 mg/day if tolerated. Alternately, 10 mg/kg/day (Max: 300 mg/day) PO, initially. Adjust dose based on serum theophylline concentrations; doses of 400 to 1,600 mg/day may be needed. Usual Max: 800 mg/day. Do not exceed 400 mg/day in persons with risk factors for decreased theophylline clearance and in those who cannot receive recommended serum concentration monitoring. Consider smaller, more frequent doses in persons with rapid metabolism, identified by higher than average dose requirements. Extended-release products are not to be used to treat acute symptoms. Theophylline is not a preferred treatment per asthma guidelines.
Adolescents 16 to 17 years: 300 mg/day PO divided every 8 to 12 hours, initially. After 3 days, increase the dose to 400 mg/day and then 600 mg/day if tolerated. Alternately, 10 mg/kg/day (Max: 300 mg/day) PO, initially. Adjust dose based on serum theophylline concentrations; doses of 400 to 1,600 mg/day may be needed. Usual Max: 800 mg/day. Do not exceed 400 mg/day in persons with risk factors for decreased theophylline clearance and in those who cannot receive recommended serum concentration monitoring. Consider smaller, more frequent doses in persons with rapid metabolism, identified by higher than average dose requirements. Extended-release products are not to be used to treat acute symptoms. Theophylline is not a preferred treatment per asthma guidelines.
Oral dosage (controlled-release, e.g., Theo-24 Capsules; dosage is expressed as theophylline):
Children and Adolescents 12 to 15 years weighing less than 45 kg: 12 to 14 mg/kg/day (Max: 300 mg/day) PO once daily, initially. After 3 days, increase the dose to 16 mg/kg/day (Max: 400 mg/day) and then 20 mg/kg/day (Max: 600 mg/day) if tolerated. Alternately, 10 mg/kg/day (Max: 300 mg/day) PO, initially. Adjust dose based on serum theophylline concentrations. Usual Max: 800 mg/day. Do not exceed 16 mg/kg/day (Max: 400 mg/day) in persons with risk factors for decreased theophylline clearance or who cannot receive recommended serum concentration monitoring. Consider twice daily dosing in persons with rapid metabolism and who repeatedly have symptoms at the end of a 24-hour dosing interval. Extended-release products are not to be used to treat acute symptoms. Theophylline is not a preferred treatment per asthma guidelines.
Children and Adolescents 12 to 15 years weighing more than 45 kg: 300 to 400 mg PO once daily, initially. After 3 days, increase the dose to 400 mg/day and then 600 mg/day if tolerated. Alternately, 10 mg/kg/day (Max: 300 mg/day) PO, initially. Adjust dose based on serum theophylline concentrations; doses of 400 to 1,600 mg/day may be needed. Usual Max: 800 mg/day. Do not exceed 400 mg/day in persons with risk factors for decreased theophylline clearance and in those who cannot receive recommended serum concentration monitoring. Consider twice daily dosing in persons with rapid metabolism and who repeatedly have symptoms at the end of a 24-hour dosing interval. Extended-release products are not to be used to treat acute symptoms. Theophylline is not a preferred treatment per asthma guidelines.
Adolescents 16 to 17 years: 300 to 400 mg PO once daily, initially. After 3 days, increase the dose to 400 mg/day and then 600 mg/day if tolerated. Alternately, 10 mg/kg/day (Max: 300 mg/day) PO, initially. Adjust dose based on serum theophylline concentrations; doses of 400 to 1,600 mg/day may be needed. Usual Max: 800 mg/day. Do not exceed 400 mg/day in persons with risk factors for decreased theophylline clearance and in those who cannot receive recommended serum concentration monitoring. Consider twice daily dosing in persons with rapid metabolism and who repeatedly have symptoms at the end of a 24-hour dosing interval. Extended-release products are not to be used to treat acute symptoms. Theophylline is not a preferred treatment per asthma guidelines.

For the treatment of acute exacerbations of reversible airways obstruction (including status asthmaticus) in patients who are not responding to first-line therapies:
Guidelines do not recommend theophylline for acute exacerbations because it appears to provide no additional benefit to optimal inhaled beta-2 agonist therapy and may increase risk of adverse effects.
Intravenous loading dosage (dosage is expressed as theophylline):
Children and Adolescents: 4.6 mg/kg IV loading dose infused over 30 minutes in a patient who has received no theophylline in the previous 24 hours will produce an average peak serum theophylline concentration of 10 mcg/mL (range 6 to 16 mcg/mL); calculate mg/kg dose based on ideal body weight. In patients who have received theophylline within the previous 24 hours, a theophylline serum concentration must be drawn and loading dose, if needed, calculated accordingly. If dosing with theophylline is continued, follow maintenance dosage below.
Oral loading dosage (dosage is expressed as theophylline - NOTE: do not use sustained-release dosage forms):
Children and Adolescents: 5 mg/kg PO loading dose using an immediate-release product in a patient who has received no theophylline in the previous 24 hours will produce an average peak serum theophylline concentration of 10 mcg/mL (range 5 to 15 mcg/mL); calculate mg/kg dose based on ideal body weight. If dosing with theophylline is continued, follow maintenance dosage below.
Continuous intravenous infusion dosage (dosage is expressed as theophylline):
Infants 6 to 52 weeks: Calculate initial dosage using the following equation: (0.008 x age in weeks) + 0.21 = theophylline dosage in mg/kg/hour IV; reduced doses may be needed in patients with risk factors for reduced theophylline clearance (e.g. drug interactions, cardiac or hepatic impairment, renal dysfunction in infants younger than 3 months). Adjust dosage based on subsequent serum concentrations and clinical response.
Children 1 to 8 years: Initially, 0.8 mg/kg/hour IV; reduced doses may be needed in patients receiving other drugs that decrease theophylline clearance. Begin with 0.2 mg/kg/hour IV (Max: 400 mg/day) in patients with cardiac decompensation, cor pulmonale, liver dysfunction, sepsis with multiorgan failure, or shock. Adjust dosage based on subsequent serum concentrations.
Children 9 to 11 years: Initially, 0.7 mg/kg/hour IV. Reduced doses may be needed in patients receiving other drugs that decrease theophylline clearance. Begin with 0.2 mg/kg/hour IV (Max: 400 mg/day) to patients with cardiac decompensation, cor pulmonale, liver dysfunction, sepsis with multiorgan failure, or shock. Adjust dosage based on subsequent serum concentrations and clinical response.
Children and Adolescents 12 to 15 years: Initially, 0.5 mg/kg/hour IV in otherwise healthy nonsmokers (Max: 900 mg/day); 0.7 mg/kg/hour IV in smokers. Reduced doses may be needed in patients receiving other drugs that decrease theophylline clearance. Begin with 0.2 mg/kg/hour IV (Max: 400 mg/day) in patients with cardiac decompensation, cor pulmonale, liver dysfunction, sepsis with multiorgan failure, or shock. Adjust dosage based on subsequent serum concentrations and clinical response.
Adolescents 16 to 17 years: Initially, 0.4 mg/kg/hour IV (Max: 900 mg/day) in otherwise healthy nonsmokers; although no specific dosing guidance is available, patients who smoke may require an increased dose. Begin with 0.2 mg/kg/hour IV (Max: 400 mg/day) to patients with CHF, cor pulmonale, liver dysfunction, sepsis with multiorgan failure, shock, or other factors for reduced theophylline clearance. Reduced doses may be needed in patients receiving other drugs that decrease theophylline clearance. Adjust dosage based on subsequent serum concentrations and clinical response.

Therapeutic Drug Monitoring:
Usual target serum concentrations:
- Neonatal apnea: 6-12 mcg/ml
- Bronchodilation: 10-15 mcg/ml
- Add-on therapy for severe asthma not controlled by inhaled corticosteroids: 5-10 mcg/ml

The dosage of theophylline must be individualized. Base initial dosage on lean body weight and dosage adjustments should be based on serum theophylline concentrations and clinical response. In addition to respiratory status, monitor heart rate and assess for agitation/irritability and feeding intolerance in neonates.

Guidelines for monitoring serum concentrations in the acute setting:
-To assess an IV loading dose, measure peak concentration 30 minutes after completion of IV infusion. If the concentration is within the desired range, a continuous infusion may be started or intermittent doses scheduled as appropriate. If the concentration is below the desired range, an additional loading dose may be given, which is calculated based on the desired and measured concentrations.
-To assess a dosage given by continuous infusion:-Measure serum concentration approximately 1 half-life after the beginning of the infusion (approximately 4 hours for children 1-9 years). Adjust the infusion rate if needed and reassess approximately 12-24 hours later.
-Measure serum concentration at 24-hour intervals or if signs of toxicity/inadequate effect.

-For intermittent dosing, consult local institution-specific practice standards. While some measure peak concentrations, other experts base dosing off of trough concentrations.

Dosage adjustment guidelines for patients with asthma (based on steady-state peak serum theophylline concentrations) :
-< 9.9 mcg/ml-If symptoms are not controlled and current dosage is tolerated, increase dose by about 25% and recheck concentration after 3 days. If a serum theophylline concentration is obtained before steady state is achieved at a given dosage, do not increase the maintenance dose even if concentration is < 10 mcg/ml.

-10-14.9 mcg/ml-If symptoms are controlled and current dosage is tolerated, maintain dose and recheck theophylline concentration at 6-12 month intervals or with any changes in clinical status that may affect theophylline clearance. If symptoms are not controlled and current dosage is tolerated, consider adding additional medication to treatment.

-15-19.9 mcg/ml-To provide a greater margin of safety, consider decreasing dose by 10% even if current dose is tolerated.

-20-24.9 mcg/ml-Decrease dose by 25% even if no adverse effects are present and recheck concentration after 3 days.

-25-30 mcg/ml-Skip next dose and reduce subsequent doses by at least 25% even if no adverse effects are present and recheck concentration after 3 days. If patient is symptomatic, consider whether overdose treatment may be necessary.

-> 30 mcg/ml-Hold theophylline, treat as an overdose as necessary (consult specialized resources). Monitor the patient and obtain serial theophylline concentrations every 2-4 hours to gauge the effectiveness of therapy and to guide further treatment decisions. If theophylline is resumed later, decrease previous dose by at least 50% and recheck concentration after 3 days.


Maximum Dosage Limits:
Theophylline has a narrow therapeutic index. The maximum dosage is individualized based on therapeutic drug concentration monitoring and assessment of efficacy and safety parameters. The following are general guidelines in chronic use (dosage expressed as theophylline):
-Neonates
Must individualize dosage; loading doses of 8 mg/kg IV or PO have been used.
-Infants
Must individualize dosage; infant dosing is based on age/weight.
-Children
Individualize dosage; do not exceed 16 mg/kg/day up to 400 mg/day PO if risk factors for decreased clearance are present or recommended serum theophylline concentration monitoring is not possible.
-Adolescents
< 16 years: Individualize dosage; do not exceed 16 mg/kg/day up to 400 mg/day PO if risk factors for decreased clearance are present or recommended serum concentration monitoring is not possible.
>= 16 years: Individualize dosage; do not exceed 400 mg/day PO if risk factors for decreased clearance are present or recommended serum concentration monitoring is not possible.

Patients with Hepatic Impairment Dosing
Reduced dosage is needed in patients with hepatic insufficiency. Maximum initial dose via continuous infusion (theophylline) = 0.2 mg/kg/hour IV (Max: 400 mg/day) in patients >= 1 year. Do not exceed 16 mg/kg/day (Max: 400 mg/day) PO in patients < 16 years or 400 mg/day PO in patients >= 16 years unless serum theophylline concentration and patient condition warrant higher dose; careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required.

Patients with Renal Impairment Dosing
Reduced dosage is needed in neonates and infants < 3 months as roughly 50% of the administered theophylline dose is excreted unchanged in the urine; careful attention to dosage titration and frequent monitoring of serum theophylline concentrations are required. In infants > 3 months of age, children, and adolescents, no dosage adjustment is necessary.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Despite decades of research, the mechanism of action for theophylline is still being debated. While its bronchoprotective effects are most well-known, theophylline appears to also possess antiinflammatory and immunomodulatory actions. Theophylline relaxes the smooth muscle of the bronchial airways and pulmonary blood vessels. In patients with asthma, theophylline reduces airway responsiveness to histamine, methacholine, adenosine, and allergen. The ability of theophylline to control chronic asthma, however, is disproportionately greater than is explainable by its relatively weak bronchodilatory action. Theophylline may even possess antiinflammatory actions as evidenced by its ability to attenuate late-phase reactions in asthma.

Originally theophylline was believed to exert its effects via the inhibition of type III or type IV phosphodiesterase (PDE), which is responsible for breaking down cyclic AMP in smooth muscle cells. While theophylline does possess this property, it is negligible at therapeutic serum concentrations, and there is no evidence that intracellular concentrations of theophylline in airway smooth muscle cells are higher than serum concentrations. Drugs that exert greater inhibition of PDE than theophylline (e.g., dipyridamole, papaverine) have no bronchodilator effect.

Other explanations for theophylline's action have been proposed including changes in smooth muscle calcium ion concentration, inhibition of histamine release, and adenosine antagonism. Adenosine antagonism has been considered as an explanation for theophylline's bronchodilating effects. Supporting this theory are the facts that adenosine and theophylline are structurally similar, adenosine can provoke bronchoconstriction in asthmatic patients, and adenosine can antagonize theophylline-induced bronchodilation. In addition, theophylline can antagonize adenosine's actions in other tissues. However, controversy surrounds this explanation also. Contradicting the theory that theophylline bronchodilation is mediated by adenosine antagonism is the fact that enprofylline, another xanthine that is five times as potent a bronchodilator as theophylline, does not antagonize adenosine. Thus, most clinicians do not believe adenosine antagonism explains the bronchoprotective actions of theophylline.

Actions of theophylline other than bronchodilation, particularly those that are excitatory, may indeed be a function of adenosine antagonism. Because adenosine is a CNS depressant, antagonism of adenosine may explain theophylline's stimulant action on the medullary respiratory center, increasing the sensitivity to carbon dioxide. Further support of adenosine antagonism as an explanation for the extrapulmonary actions of theophylline was demonstrated by theophylline's ability to attenuate methotrexate-induced neurotoxicity, a syndrome believed due to elevated adenosine CNS concentrations. As a bronchodilator, theophylline's cellular mechanism of action is still uncertain.

Theophylline relaxes other types of smooth muscle but can stimulate cardiac and skeletal muscle contraction. Increased cardiac output can lead to diuresis, but tolerance may develop to this effect. Other extrapulmonary effects attributed to theophylline include CNS stimulation, improved diaphragmatic contractility, and prostaglandin inhibition. A central mechanism appears to be responsible for theophylline's ability to reduce central sleep apnea in patients with heart failure.

Pharmacokinetics: Theophylline is administered orally and intravenously. Theophylline pharmacokinetics vary among patients and cannot be easily predicted. Intra-patient variations have also been reported, particularly among acutely ill patients. Protein binding is approximately 40% in healthy adults. Unbound theophylline is distributed throughout extracellular body fluids and tissues; however, distribution into body fat is poor. Theophylline crosses the blood-brain barrier. In general, the volume of distribution (Vd) is approximately 0.45 L/kg (range 0.3-0.7 L/kg) based on ideal body weight; however, due to decreased protein binding, Vd is increased in premature neonates, patients with hepatic cirrhosis, and uncorrected acidemia.

In patients > 1 year of age, approximately 90% of the dose is metabolized in the liver. Biotransformation occurs through multiple hepatic cytochrome P-450 enzymes, primarily through demethylation and hydroxylation. Approximately 6% of a theophylline dose is N-methylated to caffeine. Caffeine and 3-methylxanthine are the only theophylline metabolites with pharmacologic activity.

Theophylline elimination is a first-order process at lower plasma concentrations; however, both N-demethylation and hydroxylation pathways are capacity limited. Once this threshold is reached, theophylline undergoes zero-order elimination. Theophylline's half-life varies with patient age, hepatic function, smoking status, and drug interactions. Nonsmoking adults usually have a half-life of 6.5-10.5 hours. In smokers, the half-life of theophylline can be as short as 4-5 hours, whereas cor pulmonale and pulmonary edema can prolong the half-life of theophylline to as long as 24 hours. Theophylline metabolites are eliminated renally, with only about 10% excreted as unchanged theophylline in patients > 3 months of age.

Affected cytochrome P450 isoenzymes: CYP1A2, CYP2E1, and CYP3A4
Theophylline is primarily metabolized by CYP1A2 isoenzymes, with secondary pathways by CYP2E1 and CYP3A4. In vitro data suggest that while theophylline metabolism is mediated by CYP1A2 at low theophylline plasma concentrations, metabolism shifts to CYP2E1 at higher concentrations, and metabolism by CYP3A4 is minor, independent of theophylline plasma concentration. The manufacturer states that theophylline is a substrate of hepatic enzymes CYP1A2, 2E1, and 3A3 without mention of 3A4 ; however, cytochrome P450 genome experts no longer support the existence of CYP3A3 and instead attribute this isoform to a coding error of or a variant of CYP3A4. Because the therapeutic range is narrow for theophylline, it is prudent to monitor theophylline serum concentrations upon initiation, dosage adjustment, or discontinuation of medications that may alter the function of CYP1A2, CYP2E1, and/or CYP3A4 isoforms.


-Route-Specific Pharmacokinetics
Oral Route
Immediate-release formulations: Immediate-release liquid and solid formulations are rapidly and completely absorbed. Peak serum concentrations occur 1-2 hours after administration. Administration with food does not significantly alter absorption.
Controlled release formulations: Controlled-release preparations vary in the rate of absorption. Peak concentrations are reached approximately 6 hours after administration of the extended-release tablet (12-hour preparation) and 13 hours after the sustained-release capsule (24-hour preparation). Food can affect the rate and extent of absorption of some controlled release preparations; consistent administration with regard to time of day and proximity to meals is recommended.


-Special Populations
Pediatrics
Neonates and Infants
Theophylline metabolism and clearance changes significantly during the neonatal and infant periods. Neonates exhibit lower protein binding compared to older children, and a higher percentage of the theophylline dose is converted to caffeine compared to other populations. In a study of 7 premature neonates given theophylline for apnea, approximately one-third of the dose was converted to caffeine. Caffeine concentrations up to 8 mg/L were reported in neonates treated with theophylline.
In neonates, the N-demethylation pathway is absent and the hydroxylation pathway is markedly immature, resulting in a significantly longer half-life in these patients. In neonates, approximately 50% of a theophylline dose is excreted unchanged in the urine, compared to approximately 10% in infants > 3 months of age and children. Neonates and infants receiving extracorporeal membrane oxygenation (ECMO) have a lower clearance and higher volume of distribution, compared with patients not receiving ECMO.

Half-life and Clearance (when reported) :
Premature Neonates (postnatal age 3-15 days): mean half-life = 30 hours (17-43 hours); total body clearance = 0.29 ml/kg/min (0.09-0.49 ml/kg/min)
Premature Neonates (postnatal age 25-57 days): mean half-life = 20 hours (9.4-30.6 hours); total body clearance = 0.64 ml/kg/min (0.04-1.2 ml/kg/min)
Term Neonates (postnatal age 1-2 days): mean half-life = 25.7 hours (25-26.5 hours)
Term Neonates/Infants (postnatal age 3-30 weeks): mean half-life = 11 hours (6-29 hours)


Children and Adolescents
By 1 year of age, theophylline clearance is at its peak and remains relatively constant until approximately age 9, when it slowly decreases by approximately 50% to adult values by the end of adolescence. In patients greater than 1 year of age, 90% of the dose is metabolized in the liver and about 6% of the dose is N-methylated to caffeine. Approximately 10% of theophylline is excreted unchanged in the urine.

Half-life (when reported) and Clearance :
Children 1-4 years: mean half-life = 3.4 hours (1.2-5.6 hours); total body clearance = 1.7 ml/kg/min (0.5-2.9 ml/kg/min)
Children 4-12 years: total body clearance = 1.6 ml/kg/min (0.8-2.4 ml/kg/min)
Adolescents 13-15 years: total body clearance = 0.9 ml/kg/min (0.48-1.3 ml/kg/min)
Adolescents 16-17 years: mean half-life = 3.7 hours (1.5-5.9 hours); total body clearance = 1.4 ml/kg/min (0.2-2.6 ml/kg/min)
Healthy Adults (non-smokers): mean half-life = 8.7 hours (6.1-12.8 hours); total body clearance = 0.65 ml/kg/min (0.27-1.03ml/kg/min)

Hepatic Impairment
Theophylline clearance is decreased up to 50% in patients with hepatic insufficiency (e.g., acute hepatitis, cholestasis).

Renal Impairment
In neonates and infants < 3 months of age, approximately 50% of theophylline is excreted as unchanged drug in the urine; therefore, renal insufficiency in this population can result in significant accumulation of theophylline and caffeine. In contrast, renal impairment does not significantly affect the pharmacokinetics of theophylline in patients > 3 months of age.

Other
Fever: Fever can decrease theophylline clearance. Magnitude and duration of fever appear to be directly correlated to the degree of clearance reduction. A temperature of 39 degrees C (102 degrees F) for > 24 hours is most likely required to produce a clinically significant increase in plasma theophylline concentrations.
Heart Failure: Theophylline clearance is reduced by 50% or more in patients with congestive heart failure.
Sepsis: Theophylline clearance is reduced in patients with sepsis and multi-organ failure.
Cystic Fibrosis: Theophylline clearance is increased in patients with cystic fibrosis.
Smoking: Tobacco smoking increases theophylline clearance by approximately 50% in young smokers; marijuana smoking also increases clearance (exact percentage unknown).
Thyroid Conditions: Theophylline clearance is increased in patients with hyperthyroidism and decreased in patients with hypothyroidism.