DIFFUMAX

A methylxanthine derivative from tea with diuretic, smooth muscle relaxant, bronchial dilation, cardiac and central nervous system stimulant activities.

Mechanistically, theophylline acts as a phosphodiesterase inhibitor, adenosine receptor blocker, and histone deacetylase activator.

Theophylline is marketed under several brand names such as Uniphyl and Theochron, and it is indicated mainly for asthma, bronchospasm, and COPD.

For the treatment of the symptoms and reversible airflow obstruction associated with chronic asthma and other chronic lung diseases, such as emphysema and chronic bronchitis.

Theophylline, an xanthine derivative chemically similar to caffeine and theobromine, is used to treat asthma and bronchospasm.

Theophylline has two distinct actions in the airways of patients with reversible (asthmatic) obstruction; smooth muscle relaxation (i.e., bronchodilation) and suppression of the response of the airways to stimuli (i.e., non-bronchodilator prophylactic effects).

Adenosine receptor

A1 Antagonist Adenosine receptor A2a Antagonist Adenosine receptor A2b Antagonist + 7 more targets.

Theophylline is rapidly and completely absorbed after oral administration in solution or immediate-release solid oral dosage form.

Biotransformation takes place through demethylation to 1-methylxanthine and 3-methylxanthine and hydroxylation to 1,3-dimethyluric acid. 1-methylxanthine is further hydroxylated, by xanthine oxidase, to 1-methyluric acid.

About 6% of a theophylline dose is N-methylated to caffeine.

Caffeine and 3-methylxanthine are the only theophylline metabolites with pharmacologic activity.

Hover over products below to view reaction partners Theophylline 1-Methylxanthine 3-methylxanthine 1,3-dimethyluric acid Caffeine.

Theophylline does not undergo any appreciable pre-systemic elimination, distributes freely into fat-free tissues and is extensively metabolized in the liver.

Renal excretion of unchanged theophylline in neonates amounts to about 50% of the dose, compared to about 10% in children older than three months and in adults.

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Symptoms of overdose include seizures, arrhythmias, and GI effects.

Theophylline should be used with extreme caution in patients with the following clinical conditions due to the increased risk of exacerbation of the concurrent condition: Active peptic ulcer disease Seizure disorders Cardiac arrhythmias (not including bradyarrhythmias) Conditions That Reduce Theophylline Clearance There are several readily identifiable causes of reduced theophylline clearance.

If the total daily dose is not appropriately reduced in the presence of these risk factors, severe and potentially fatal theophylline toxicity can occur.

Careful consideration must be given to the benefits and risks of theophylline use and the need for more intensive monitoring of serum theophylline concentrations in patients with the following risk factors: Age Neonates (term and premature) Children <1 year Elderly (>60 years) Concurrent Diseases Acute pulmonary edema Congestive heart failure Cor-pulmonale Fever; ≥102° for 24 hours or more; or lesser temperature elevations for longer periods Hypothyroidism Liver disease; cirrhosis, acute hepatitis Reduced renal function in infants <3 months of age Sepsis with multi-organ failure Shock Cessation of Smoking Drug Interactions Adding a drug that inhibits theophylline metabolism (e.g., cimetidine, erythromycin, tacrine) or stopping a concurrently administered drug that enhances theophylline metabolism (e.g., carbamazepine, rifampin). .

When Signs or Symptoms of Theophylline Toxicity Are Present Whenever a patient receiving theophylline develops nausea or vomiting, particularly repetitive vomiting, or other signs or symptoms consistent with theophylline toxicity (even if another cause may be suspected), additional doses of theophylline should be withheld and a serum theophylline concentration measured immediately.

Patients should be instructed not to continue any dosage that causes adverse effects and to withhold subsequent doses until the symptoms have resolved, at which time the healthcare professional may instruct the patient to resume the drug at a lower dosage See DOSAGE AND ADMINISTRATION, Dosing Guidelines, Table VI.

Increases in the dose of theophylline should not be made in response to an acute exacerbation of symptoms of chronic lung disease since theophylline provides little added benefit to inhaled beta2-selective agonists and systemically administered corticosteroids in this circumstance and increases the risk of adverse effects.

A peak steady‑state serum theophylline concentration should be measured before increasing the dose in response to persistent chronic symptoms to ascertain whether an increase in dose is safe.

Before increasing the theophylline dose on the basis of a low serum concentration, the healthcare professional should consider whether the blood sample was obtained at an appropriate time in relationship to the dose and whether the patient has adhered to the prescribed regimen.

As the rate of theophylline clearance may be dose-dependent (i.e., steady-state serum concentrations may increase disproportionately to the increase in dose), an increase in dose based upon a sub-therapeutic serum concentration measurement should be conservative.

In general, limiting dose increases to about 25% of the previous total daily dose will reduce the risk of unintended excessive increases in serum theophylline concentration See DOSAGE AND ADMINISTRATION, Table VI.

Theophylline (Anhydrous) Extended-Release Tablets are contraindicated in patients with a history of hypersensitivity to theophylline or other components in the product.

Theophylline (Anhydrous) Extended-Release Tablets 400 or 600 mg can be taken once a day in the morning or evening.

It is recommended that

Theophylline (Anhydrous) Extended-Release Tablets be taken with meals.

Patients should be advised that if they choose to take Theophylline (Anhydrous) Extended-Release Tablets with food it should be taken consistently with food and if they take it in a fasted condition it should routinely be taken fasted.

It is important that the product whenever dosed be dosed consistently with or without food.

Theophylline (Anhydrous) Extended-Release Tablets are not to be chewed or crushed because it may lead to a rapid release of theophylline with the potential for toxicity.

The scored tablet may be split.

Infrequently, patients receiving Theophylline (Anhydrous) Extended-Release Tablets 400 or 600 mg may pass an intact matrix tablet in the stool or via colostomy.

These matrix tablets usually contain little or no residual theophylline.

Stabilized patients, 12 years of age or older, who are taking an immediate-release or controlled-release theophylline product may be transferred to once-daily administration of 400 or 600 mg Theophylline (Anhydrous) Extended-Release Tablets on a mg-for-mg basis.

It must be recognized that the peak and trough serum theophylline levels produced by the once-daily dosing may vary from those produced by the previous product and/or regimen.

The steady-state peak serum theophylline concentration is a function of the dose, the dosing interval, and the rate of theophylline absorption and clearance in the individual patient.

Because of marked individual differences in the rate of theophylline clearance, the dose required to achieve a peak serum theophylline concentration in the 10-20 mcg/mL range varies fourfold among otherwise similar patients in the absence of factors known to alter theophylline clearance (e.g., 400‑1600 mg/day in adults <60 years old and 10-36 mg/kg/day in children 1-9 years old).

For a given population there is no single theophylline dose that will provide both safe and effective serum concentrations for all patients.

Administration of the median theophylline dose required to achieve a therapeutic serum theophylline concentration in a given population may result in either sub-therapeutic or potentially toxic serum theophylline concentrations in individual patients.

For example, at a dose of 900 mg/d in adults <60 years or 22 mg/kg/d in children 1-9 years, the steady-state peak serum theophylline concentration will be <10 mcg/mL in about 30% of patients, 10-20 mcg/mL in about 50% and 20-30 mcg/mL in about 20% of patients.

The dose of theophylline must be individualized on the basis of peak serum theophylline concentration measurements in order to achieve a dose that will provide maximum potential benefit with minimal risk of adverse effects.

Transient caffeine-like adverse effects and excessive serum concentrations in slow metabolizers can be avoided in most patients by starting with a sufficiently low dose and slowly increasing the dose, if judged to be clinically indicated, in small increments.

Dose increases should only be made if the previous dosage is well tolerated and at intervals of no less than 3 days to allow serum theophylline concentrations to reach the new steady-state.

Dosage adjustment should be guided by serum theophylline concentration measurement.

Healthcare providers should instruct patients and caregivers to discontinue any dosage that causes adverse effects, to withhold the medication until these symptoms are gone and to then resume therapy at a lower, previously tolerated dosage See WARNINGS.

If the patient's symptoms are well controlled, there are no apparent adverse effects, and no intervening factors that might alter dosage requirements, serum theophylline concentrations should be monitored at 6 month intervals for rapidly growing children and at yearly intervals for all others.

In acutely ill patients, serum theophylline concentrations should be monitored at frequent intervals, e.g., every 24 hours.

Theophylline distributes poorly into body fat, therefore, mg/kg dose should be calculated on the basis of ideal body weight.

V contains theophylline dosing titration schema recommended for patients in various age groups and clinical circumstances.

VI contains recommendations for theophylline dosage adjustment based upon serum theophylline concentrations.

Application of these general dosing recommendations to individual patients must take into account the unique clinical characteristics of each patient.

In general, these recommendations should serve as the upper limit for dosage adjustments in order to decrease the risk of potentially serious adverse events associated with unexpected large increases in serum theophylline concentration.

Dosing initiation and titration (as anhydrous theophylline).

Patients with more rapid metabolism clinically identified by higher than average dose requirements, should receive a smaller dose more frequently (every 12 hours) to prevent breakthrough symptoms resulting from low trough concentrations before the next dose.

A. Children (12-15 years) and adults (16-60 years) without risk factors for impaired clearance.

Children <45 kg Children >45 kg and adults 1.

Dosage 12-14 mg/kg/day up to a maximum of 300 mg/day admin.

QD 300 mg/day If caffeine-like adverse effects occur, then consideration should be given to a lower dose and titrating the dose more slowly See ADVERSE REACTIONS. admin.

QD 2.

After 3 days, if tolerated, increase dose to: 16 mg/kg/day up to a maximum of 400 mg/day admin.

QD 400-600 mg/day admin.

QD 3.

After 3 more days, if tolerated, and if needed increase dose to: 20 mg/kg/day up to a maximum of 600 mg/day admin.

QD As with all theophylline products, doses greater than 600 mg should be titrated according to blood level.

B. Patients With Risk Factors For Impaired Clearance, The Elderly (>60 Years), And Those In Whom It Is Not Feasible To Monitor Serum Theophylline Concentrations: In children 12-15 years of age, the theophylline dose should not exceed 16 mg/kg/day up to a maximum of 400 mg/day in the presence of risk factors for reduced theophylline clearance See WARNINGS or if it is not feasible to monitor serum theophylline concentrations.

In adolescents ≥16 years and adults, including the elderly, the theophylline dose should not exceed 400 mg/day in the presence of risk factors for reduced theophylline clearance See WARNINGS or if it is not feasible to monitor serum theophylline concentrations.

Dosage adjustment guided by serum theophylline concentration.

Adjustment <9.9 mcg/mL If symptoms are not controlled and current dosage is tolerated, increase dose about 25%.

Recheck serum concentration after three days for further dosage adjustment. 10-14.9 mcg/mL If symptoms are controlled and current dosage is tolerated, maintain dose and recheck serum concentration at 6-12 month intervals.

Dose reduction and/or serum theophylline concentration measurement is indicated whenever adverse effects are present physiologic abnormalities that can reduce theophylline clearance occur (e.g., sustained fever), or a drug that interacts with theophylline is added or discontinued See WARNINGS.

If symptoms are not controlled and current dosage is tolerated consider adding additional medication(s) to treatment regimen. 15-19.9 mcg/mL Consider 10% decrease in dose to provide greater margin of safety even if current dosage is tolerated. 20-24.9 mcg/mL Decrease dose by 25% even if no adverse effects are present.

Recheck serum concentration after 3 days to guide further dosage adjustment. 25-30 mcg/mL Skip next dose and decrease subsequent doses at least 25% even if no adverse effects are present.

Recheck serum concentration after 3 days to guide further dosage adjustment.

If symptomatic, consider whether overdose treatment is indicated. >30 mcg/mL Treat overdose as indicated.

If theophylline is subsequently resumed, decrease dose by at least 50% and recheck serum concentration after 3 days to guide further dosage adjustment.

Theophylline (Anhydrous) Extended-Release Tablets 400 mg are supplied as white, round, bisected tablets debossed with "N" above the bisect and "T4" below the bisect, available in bottles of 100 tablets (NDC 69367-414-01).

Theophylline (Anhydrous) Extended-Release Tablets 600 mg are supplied as white, oblong, bisected tablets on one side and debossed with "NT6" on the other side, available in bottles of 100 tablets (NDC 69367-415-01).

Store at 20° to 25°C (68° to 77°F) .

Dispense in tight, light-resistant container.

Store at 20° to 25°C (68° to 77°F) .

Dispense in tight, light-resistant container.

Theophylline is excreted into breast milk and may cause irritability or other signs of mild toxicity in nursing human infants.

The concentration of theophylline in breast milk is about equivalent to the maternal serum concentration.

An infant ingesting a liter of breast milk containing 10-20 mcg/mL of theophylline per day is likely to receive 10-20 mg of theophylline per day. Serious adverse effects in the infant are unlikely unless the mother has toxic serum theophylline concentrations.

Theophylline is safe and effective for the approved indications in pediatric patients.

The maintenance dose of theophylline must be selected with caution in pediatric patients since the rate of theophylline clearance is highly variable across the pediatric age range.

Elderly patients are at significantly greater risk of experiencing serious toxicity from theophylline than younger patients due to pharmacokinetic and pharmacodynamic changes associated with aging.

The clearance of theophylline is decreased by an average of 30% in healthy elderly adults (>60 yrs) compared to healthy young adults.

Theophylline clearance may be further reduced by concomitant diseases prevalent in the elderly, which further impair clearance of this drug and have the potential to increase serum levels and potential toxicity.

These conditions include impaired renal function, chronic obstructive pulmonary disease, congestive heart failure, hepatic disease and an increased prevalence of use of certain medications with the potential for pharmacokinetic and pharmacodynamic interaction.

Protein binding may be decreased in the elderly resulting in an increased proportion of the total serum theophylline concentration in the pharmacologically active unbound form.

Elderly patients also appear to be more sensitive to the toxic effects of theophylline after chronic overdosage than younger patients.

Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in elderly patients.

The maximum daily dose of theophylline in patients greater than 60 years of age ordinarily should not exceed 400 mg/day unless the patient continues to be symptomatic and the peak steady-state serum theophylline concentration is <10 mcg/mL See DOSAGE AND ADMINISTRATION.

Theophylline doses greater than 400 mg/d should be prescribed with caution in elderly patients.

Theophylline should be prescribed with caution in elderly male patients with pre-existing partial outflow obstruction, such as prostatic enlargement, due to the risk of urinary retention.