Theophylline

INDICATIONS AND USAGE Theophylline oral solution is indicated for the treatment of the symptoms and reversible airflow obstruction associated with chronic asthma and other chronic lung diseases, e.g., emphysema and chronic bronchitis.

DOSAGE AND ADMINISTRATION General Considerations: 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 to 20 mcg/mL range varies fourfold among otherwise similar patients in the absence of factors known to alter theophylline clearance (e.g., 400 to 1600 mg/day in adults 26 weeks of age; divide dose into 4 equal amounts administered at 6 hour intervals. 2. Final Dosage. Adjusted to maintain a peak steady-state serum theophylline concentration of 5 to 10 mcg/mL in neonates and 10 to 15 mcg/mL in older infants (see Table VI ). Since the time required to reach steady-state is a function of theophylline half-life, up to 5 days may be required to achieve steady-state in a premature neonate while only 2 to 3 days may be required in a 6 month old infant without other risk factors for impaired clearance in the absence of a loading dose. If a serum theophylline concentration is obtained before steady-state is achieved, the maintenance dose should not be increased, even if the serum theophylline concentration is 45 kg and adults 1. Starting Dosage 12 to 14 mg/kg/day up to a maximum of 300 mg/day divided Q4 to 6 hrs* 300 mg/day divided Q6 to 8 hrs* 2. After 3 days, if tolerated, increase dose to: 16 mg/kg/day up to a maximum of 400 mg/day divided Q4 to 6 hrs* 400 mg/day divided Q6 to 8 hrs* 3. After 3 more days, if tolerated, increase dose to: 20 mg/kg/day up to a maximum of 600 mg/day divided Q4 to 6 hrs* 600 mg/day divided Q6 to 8 hrs* C. 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 1 to 15 years of age, the final 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 final 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. D. Loading Dose for Acute Bronchodilatation: An inhaled beta-2 selective agonist, alone or in combination with a systemically administered corticosteroid, is the most effective treatment for acute exacerbations of reversible airways obstruction. Theophylline is a relatively weak bronchodilator, is less effective than an inhaled beta-2 selective agonist and provides no added benefit in the treatment of acute bronchospasm. If an inhaled or parenteral beta agonist is not available, a loading dose of an oral immediate release theophylline can be used as a temporary measure. A single 5 mg/kg dose of theophylline, in a patient who has not received any theophylline in the previous 24 hours, will produce an average peak serum theophylline concentration of 10 mcg/mL (range 5 to 15 mcg/mL). If dosing with theophylline is to be continued beyond the loading dose, the guidelines in Sections A.1.b., B.3, or C., above, should be utilized and serum theophylline concentration monitored at 24 hour intervals to adjust final dosage. * Patients with more rapid metabolism, clinically identified by higher than average dose requirements, should receive a smaller dose more frequently to prevent breakthrough symptoms resulting from low trough concentrations before the next dose. A reliably absorbed slow-release formulation will decrease fluctuations and permit longer dosing intervals. Table VI. Dosage adjustment guided by serum theophylline concentration. Peak Serum Concentration Dosage Adjustment 30 mcg/mL Treat overdose as indicated (see recommen …

CONTRAINDICATIONS Theophylline Oral Solution USP is contraindicated in patients with a history of hypersensitivity to theophylline or other components in the product.

ADVERSE REACTIONS Adverse reactions associated with theophylline are generally mild when peak serum theophylline concentrations are 300 mg/day in adults and > 12 mg/kg/day in children beyond > 1 year of age). During the initiation of theophylline therapy, caffeine-like adverse effects may transiently alter patient behavior, especially in school age children, but this response rarely persists. Initiation of theophylline therapy at a low dose with subsequent slow titration to a predetermined age-related maximum dose will significantly reduce the frequency of these transient adverse effects (see DOSAGE AND ADMINISTRATION, Table V ). In a small percentage of patients ( 30 mcg/mL. In the first study (Study #1 - Shanon, Ann Intern Med 1993; 119:1161-67), data were prospectively collected from 249 consecutive cases of theophylline toxicity referred to a regional poison center for consultation. In the second study (Study #2 - Sessler, Am J Med 1990;88:567-76), data were retrospectively collected from 116 cases with serum theophylline concentrations > 30 mcg/mL among 6000 blood samples obtained for measurement of serum theophylline concentrations in three emergency departments. Differences in the incidence of manifestations of theophylline toxicity between the two studies may reflect sample selection as a result of study design (e.g., in Study #1, 48% of the patients had acute intoxications versus only 10% in Study #2) and different methods of reporting results. ** NR = Not reported in a comparable manner. To report SUSPECTED ADVERSE REACTIONS, contact Cranbury Pharmaceuticals, LLC at (732) 940-0358 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

Drug Interactions Theophylline interacts with a wide variety of drugs. The interaction may be pharmacodynamic, i.e., alterations in the therapeutic response to theophylline or another drug or occurrence of adverse effects without a change in serum theophylline concentration. More frequently, however, the interaction is pharmacokinetic, i.e., the rate of theophylline clearance is altered by another drug resulting in increased or decreased serum theophylline concentrations. Theophylline only rarely alters the pharmacokinetics of other drugs. The drugs listed in Table II have the potential to produce clinically significant pharmacodynamic or pharmacokinetic interactions with theophylline. The information in the "Effect" column of Table II assumes that the interacting drug is being added to a steady-state theophylline regimen. If theophylline is being initiated in a patient who is already taking a drug that inhibits theophylline clearance (e.g., cimetidine, erythromycin), the dose of theophylline required to achieve a therapeutic serum theophylline concentration will be smaller. Conversely, if theophylline is being initiated in a patient who is already taking a drug that enhances theophylline clearance (e.g., rifampin), the dose of theophylline required to achieve a therapeutic serum theophylline concentration will be larger. Discontinuation of a concomitant drug that increases theophylline clearance will result in accumulation of theophylline to potentially toxic levels, unless the theophylline dose is appropriately reduced. Discontinuation of a concomitant drug that inhibits theophylline clearance will result in decreased serum theophylline concentrations, unless the theophylline dose is appropriately increased. The drugs listed in Table III have either been documented not to interact with theophylline or do not produce a clinically significant interaction (i.e., <15% change in theophylline clearance). The listing of drugs in Table II and III are current as of February 9, 1995. New interactions are continuously being reported for theophylline, especially with new chemical entities. The clinician should not assume that a drug does not interact with theophylline if it is not listed in Table II. Before addition of a newly available drug in a patient receiving theophylline, the package insert of the new drug and/or the medical literature should be consulted to determine if an interaction between the new drug and theophylline has been reported. Table II. Clinically significant drug interactions with theophylline*. Drug Type of Interaction Effect** Adenosine Theophylline blocks adenosine receptors. Higher doses of adenosine may be required to achieve desired effect. Alcohol A single large dose of alcohol (3 ml/kg of whiskey) decreases theophylline clearance for up to 24 hours. 30% increase Allopurinol Decreases theophylline clearance doses at ≥600 mg/day. 25% increase at allopurinol Amino glutethimide Increases theophylline clearance by induction of microsomal enzyme activity. 25% decrease Carbamazepine Similar to aminoglutethimide. 30% decrease Cimetidine Decreases theophylline clearance by inhibiting cytochrome P450 1A2. 70% increase Ciprofloxacin Similar to cimetidine. 40% increase Clarithromycin Similar to erythromycin. 25% increase Diazepam Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors. Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression. Disulfiram Decreases theophylline clearance by inhibiting hydroxylation and demethylation. 50% increase Enoxacin Similar to cimetidine. 300% increase Ephedrine Synergistic CNS effects. Increased frequency of nausea, nervousness, and insomnia. Erythromycin Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3. 35% increase. Erythromycin steady-state ser …

Mechanism of Action Theophylline has two distinct actions in the airways of patients with reversible obstruction; smooth muscle relaxation (i.e., bronchodilation) and suppression of the response of the airways to stimuli (i.e., non-bronchodilator prophylactic effects). While the mechanisms of action of theophylline are not known with certainty, studies in animals suggest that bronchodilatation is mediated by the inhibition of two isozymes of phosphodiesterase (PDE III and, to a lesser extent, PDE IV) while non-bronchodilator prophylactic actions are probably mediated through one or more different molecular mechanisms, that do not involve inhibition of PDE III or antagonism of adenosine receptors. Some of the adverse effects associated with theophylline appear to be mediated by inhibition of PDE III (e.g., hypotension, tachycardia, headache, and emesis) and adenosine receptor antagonism (e.g., alterations in cerebral blood flow). Theophylline increases the force of contraction of diaphragmatic muscles. This action appears to be due to enhancement of calcium uptake through an adenosine-mediated channel.

DESCRIPTION Theophylline is structurally classified as a methylxanthine. It occurs as a white, odorless, crystalline powder with a bitter taste. Anhydrous theophylline has the chemical name 1H-Purine-2,6-dione,3,7-dihydro-1,3-dimethyl-, and is represented by the following structural formula: Structure Structure The molecular formula of anhydrous theophylline is C 7 H 8 N 4 O 2 with a molecular weight of 180.17. Theophylline Oral Solution, USP is available as a solution intended for oral administration, containing 80 mg of theophylline anhydrous per 15 mL (one tablespoonful). Theophylline Oral Solution is alcohol free. Theophylline Oral Solution also contains the following inactive ingredients: anhydrous citric acid, glycerin, methylparaben, orange oil, polysorbate 80, propylene glycol, purified water, sodium benzoate, sodium citrate, sodium saccharin, and sorbitol solution. Theophylline Oral Solution has pH of 4.3 to 4.7. Structure formula

OVERDOSAGE General The chronicity and pattern of theophylline overdosage significantly influences clinical manifestations of toxicity, management and outcome. There are two common presentations: (1) acute overdose , i.e., ingestion of a single large excessive dose (>10 mg/kg) as occurs in the context of an attempted suicide or isolated medication error, and (2) chronic overdosage , i.e., ingestion of repeated doses that are excessive for the patient's rate of theophylline clearance. The most common causes of chronic theophylline overdosage include patient or care giver error in dosing, clinician prescribing of an excessive dose or a normal dose in the presence of factors known to decrease the rate of theophylline clearance, and increasing the dose in response to an exacerbation of symptoms without first measuring the serum theophylline concentration to determine whether a dose increase is safe. Severe toxicity from theophylline overdose is a relatively rare event. In one health maintenance organization, the frequency of hospital admissions for chronic overdosage of theophylline was about 1 per 1000 person-years exposure. In another study, among 6000 blood samples obtained for measurement of serum theophylline concentration, for any reason, from patients treated in an emergency department, 7% were in the 20-30 mcg/mL range and 3% were >30 mcg/mL. Approximately two-thirds of the patients with serum theophylline concentrations in the 20-30 mcg/mL range had one or more manifestations of toxicity while >90% of patients with serum theophylline concentrations >30 mcg/mL were clinically intoxicated. Similarly, in other reports, serious toxicity from theophylline is seen principally at serum concentrations >30 mcg/mL. Several studies have described the clinical manifestations of theophylline overdose and attempted to determine the factors that predict life-threatening toxicity. In general, patients who experience an acute overdose are less likely to experience seizures than patients who have experienced a chronic overdosage, unless the peak serum theophylline concentration is >100 mcg/mL. After a chronic overdosage, generalized seizures, life-threatening cardiac arrhythmias, and death may occur at serum theophylline concentrations >30 mcg/mL. The severity of toxicity after chronic overdosage is more strongly correlated with the patient's age than the peak serum theophylline concentration; patients >60 years are at the greatest risk for severe toxicity and mortality after a chronic overdosage. Pre-existing or concurrent disease may also significantly increase the susceptibility of a patient to a particular toxic manifestation, e.g., patients with neurologic disorders have an increased risk of seizures and patients with cardiac disease have an increased risk of cardiac arrhythmias for a given serum theophylline concentration compared to patients without the underlying disease. The frequency of various reported manifestations of theophylline overdose according to the mode of overdose are listed in Table IV. Other manifestations of theophylline toxicity include increases in serum calcium, creatine kinase, myoglobin and leukocyte count, decreases in serum phosphate and magnesium, acute myocardial infarction, and urinary retention in men with obstructive uropathy. Seizures associated with serum theophylline concentrations >30 mcg/mL are often resistant to anticonvulsant therapy and may result in irreversible brain injury if not rapidly controlled. Death from theophylline toxicity is most often secondary to cardiorespiratory arrest and/or hypoxic encephalopathy following prolonged generalized seizures or intractable cardiac arrhythmias causing hemodynamic compromise. Overdose Management General Recommendations for Patients with Symptoms of Theophylline Overdose or Serum Theophylline Concentrations >30 mcg/mL (Note: Serum theophylline concentrations may continue to increase after presentation of the patient for medical care). While simultaneou …

HOW SUPPLIED Theophylline Oral Solution USP is a clear red solution with a berry flavor. Each tablespoonful (15 mL) contains 80 mg theophylline anhydrous. Theophylline Oral Solution USP is available in the following oral dosage forms: NDC 0121-0820-04: 4 fl oz (118 mL) bottle NDC 0121-0820-16: 16 fl oz (473 mL) bottle NDC 0121-4820-15: 15 mL unit dose cup. Case contains 40 unit-dose cups of 15 mL (NDC 0121-4820-40), packaged in 4 trays of 10 unit-dose cups each. RECOMMENDED STORAGE Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Dispense in tight, light-resistant container. MANUFACTURED BY Pharmaceutical Associates, Inc. Greenville, SC 29605 www.paipharma.com R03/22