PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


PRINCIPAL DISPLAY PANEL - 400 mg Bottle Label

ADVERSE REACTIONS SECTION.


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 #1Shanon, 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 #2Sessler, 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. Asymptomatic NR 0 NR 6 Gastrointestinal Vomiting 73 93 30 61 Abdominal pain NR 21 NR 12 Diarrhea NR 0 NR 14 Hematemesis NR 0 NR 2 Metabolic/Other Hypokalemia 85 79 44 43 Hyperglycemia 98 NR 18 NR Acid/base disturbance 34 21 9 5 Rhabdomyolysis NR 7 NR 0 Cardiovascular Sinus tachycardia 100 86 100 62 Other supraventricular tachycardias 2 21 12 14 Ventricular premature beats 3 21 10 19 Atrial fibrillation or flutter 1 NR 12 NR Multifocal atrial tachycardia 0 NR 2 NR Ventricular arrhythmias with hemodynamic instability 7 14 40 0 Hypotension/shock NR 21 NR 8 Neurologic Nervousness NR 64 NR 21 Tremors 38 29 16 14 Disorientation NR 7 NR 11 Seizures 5 14 14 5 Death 3 21 10 4

INDICATIONS & USAGE SECTION.


INDICATIONS AND USAGE Theophylline 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 & ADMINISTRATION SECTION.


DOSAGE AND ADMINISTRATION General Considerations: Theo-24, like other extended-release theophylline products, is intended for patients with relatively continuous or recurring symptoms who have a need to maintain therapeutic serum levels of theophylline. It is not intended for patients experiencing an acute episode of bronchospasm (associated with asthma, chronic bronchitis, or emphysema). Such patients require rapid relief of symptoms and should be treated with an immediate-release or intravenous theophylline preparation (or other bronchodilators) and not with extended-release products. Patients who metabolize theophylline at a normal or slow rate are reasonable candidates for once-daily dosing with Theo-24. Patients who metabolize theophylline rapidly (e.g., the young, smokers, and some nonsmoking adults) and who have symptoms repeatedly at the end of a dosing interval, will require either increased doses given once a day or preferably, are likely to be better controlled by a schedule of twice-daily dosing. Those patients who require increased daily doses are more likely to experience relatively wide peak-trough differences and may be candidates for twice-a-day dosing with Theo-24. Patients should be instructed to take this medication each morning at approximately the same time and not to exceed the prescribed dose. Recent studies suggest that dosing of extended-release theophylline products at night (after the evening meal) results in serum concentrations of theophylline which are not identical to those recorded during waking hours and may be characterized by early trough and delayed peak levels. This appears to occur whether the drug is given as an immediate-release, extended-release, or intravenous product. To avoid this phenomenon when two doses per day are prescribed, it is recommended that the second dose be given 10 to 12 hours after the morning dose and before the evening meal. Food and posture, along with changes associated with circadian rhythm, may influence the rate of absorption and/or clearance rates of theophylline from extended-release dosage forms administered at night. The exact relationship of these and other factors to nighttime serum concentrations and the clinical significance of such findings require additional study. Therefore, it is not recommended that Theo-24 (when used as a once-a-day product) be administered at night. Patients who require a relatively high dose of theophylline (i.e., a dose equal to or greater than 900 mg or 13 mg/kg, whichever is less) should not take Theo-24 less than 1 hour before a high-fat-content meal since this may result in a significant increase in peak serum level and in the extent of absorption of theophylline as compared to administration in the fasted state (see PRECAUTIONS, Drug/Food Interactions). 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 45 kg and adults 1. Starting Dosage 12 - 14 mg/kg/day up to a maximum of 300 mg/day divided Q 24 hrs* 300 - 400 mg/day1 divided Q 24 hrs* 2. After 3 days, if tolerated , increase dose to: 16 mg/kg/day up to a maximum of 400 mg/day divided Q 24 hrs* 400 - 600 mg/day1 divided Q 24 hrs* 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 divided Q 24 hrs* As with all theophylline products, doses greater than 600 mg should be titrated according to blood level (see Table VI) 1 If caffeine-like adverse effects occur, then consideration should be given to a lower dose and titrating the dose more slowly (see ADVERSE REACTIONS). 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 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. Table VI. Dosage adjustment guided by serum theophylline concentration. Peak Serum Concentration Dosage Adjustment * 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). 30 mcg/mL Treat overdose as indicated (see recommendations for chronic overdosage). If theophylline is subsequently resumed, decrease dose by at least 50% and recheck serum concentration after 3 days to guide further dosage adjustment.

SPL UNCLASSIFIED SECTION.


FOR MEDICAL INFORMATION Contact: Endo Pharmaceuticals Inc. Phone: 1-800-462-3636 Distributed by: Endo Pharmaceuticals Inc. Malvern, PA 19355 Manufactured by: Neolpharma, Inc. Caguas, PR 00725 Revised 11/2016 P08997

HOW SUPPLIED SECTION.


HOW SUPPLIED Theo-24 (theophylline anhydrous) is supplied in extended-release capsules containing 100, 200, 300 or 400 mg of anhydrous theophylline. Theo-24 100 mg capsules are orange opaque and natural, with markings Theo-24, 100 mg, AP, and 2832, supplied as: NDC Number Size 52244-100-10 bottle of 100 Theo-24 200 mg capsules are orange opaque and clear, with markings Theo-24, 200 mg, AP, and 2842, supplied as: NDC Number Size 52244-200-10 bottle of 100 Theo-24 300 mg capsules are Swedish orange and natural, with markings Theo-24, 300 mg, AP, and 2852, supplied as: NDC Number Size 52244-300-10 bottle of 100 Theo-24 400 mg capsules are pink opaque and natural, with markings Theo-24, 400 mg, AP, and 2902, supplied as: NDC Number Size 52244-400-10 bottle of 100 STORAGE Store below 77 F (25 C).

DESCRIPTION SECTION.


DESCRIPTION Theophylline 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: The molecular formula of anhydrous theophylline is C7H8N4O2 with a molecular weight of 180.17. Theo-24 is available as capsules intended for oral administration, containing 100 mg, 200 mg, 300 mg, or 400 mg of anhydrous theophylline per capsule, in an extended-release formulation which allows a 24-hour dosing interval for appropriate patients. Inactive ingredients are edible ink (which contains synthetic black iron oxide, FD&C Blue No. 1, FD&C Blue No. 2, FD&C Yellow No. 6, D&C Yellow No. 10, FD&C Red No. 40), ethylcellulose, gelatin, pharmaceutical glaze, colloidal silicon dioxide, starch, sucrose, talc, titanium dioxide, and coloring agents: 100 mg - includes FD&C Yellow No. 6; 200 mg - FD&C Red No. 3 and D&C Yellow No. 10; 300 mg - FD&C Blue No. 1 and FD&C Red No. 40; 400 mg - FD&C Red No. 40 and D&C Red No. 28. Theo-24 Extended-release capsules meet Drug Release Test 6 as published in the current USP monograph for Theophylline Extended-release Capsules.

OVERDOSAGE SECTION.


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, healthcare professional 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.</paragraph 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.</paragraph 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.</paragraph The frequency of various reported manifestations of theophylline overdose according to the mode of overdose are listed in Table IV.</paragraph 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.</paragraph 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.</paragraph </text </section </component 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.) </paragraph While simultaneously instituting treatment, contact a regional poison center to obtain updated information and advice on individualizing the recommendations that follow.</item Institute supportive care, including establishment of intravenous access, maintenance of the airway, and electrocardiographic monitoring.</item Treatment of seizures Because of the high morbidity and mortality associated with theophylline-induced seizures, treatment should be rapid and aggressive. Anticonvulsant therapy should be initiated with an intravenous benzodiazepine, e.g., diazepam, in increments of 0.1 - 0.2 mg/kg every 1 - 3 minutes until seizures are terminated. Repetitive seizures should be treated with a loading dose of phenobarbital (20 mg/kg infused over 30 - 60 minutes). Case reports of theophylline overdose in humans and animal studies suggest that phenytoin is ineffective in terminating theophylline-induced seizures. The doses of benzodiazepines and phenobarbital required to terminate theophylline-induced seizures are close to the doses that may cause severe respiratory depression or respiratory arrest; the healthcare professional should therefore be prepared to provide assisted ventilation. Elderly patients and patients with COPD may be more susceptible to the respiratory depressant effects of anticonvulsants. Barbiturate-induced coma or administration of general anesthesia may be required to terminate repetitive seizures or status epilepticus. General anesthesia should be used with caution in patients with theophylline overdose because fluorinated volatile anesthetics may sensitize the myocardium to endogenous catecholamines released by theophylline. Enflurane appears less likely to be associated with this effect than halothane and may, therefore, be safer. Neuromuscular blocking agents alone should not be used to terminate seizures since they abolish the musculoskeletal manifestations without terminating seizure activity in the brain.</item Anticipate need for anticonvulsants In patients with theophylline overdose who are at high risk for theophylline-induced seizures, e.g., patients with acute overdoses and serum theophylline concentrations >100 mcg/mL or chronic overdosage in patients >60 years of age with serum theophylline concentrations >30 mcg/mL, the need for anticonvulsant therapy should be anticipated. A benzodiazepine such as diazepam should be drawn into a syringe and kept at the patient's bedside and medical personnel qualified to treat seizures should be immediately available. In selected patients at high risk for theophylline-induced seizures, consideration should be given to the administration of prophylactic anticonvulsant therapy. Situations where prophylactic anticonvulsant therapy should be considered in high risk patients include anticipated delays in instituting methods for extracorporeal removal of theophylline (e.g., transfer of a high risk patient from one health care facility to another for extracorporeal removal) and clinical circumstances that significantly interfere with efforts to enhance theophylline clearance (e.g., a neonate where dialysis may not be technically feasible or a patient with vomiting unresponsive to antiemetics who is unable to tolerate multiple-dose oral activated charcoal). In animal studies, prophylactic administration of phenobarbital, but not phenytoin, has been shown to delay the onset of theophylline-induced generalized seizures and to increase the dose of theophylline required to induce seizures (i.e., markedly increases the LD50</sub). Although there are no controlled studies in humans, a loading dose of intravenous phenobarbital (20 mg/kg infused over 60 minutes) may delay or prevent life-threatening seizures in high risk patients while efforts to enhance theophylline clearance are continued. Phenobarbital may cause respiratory depression, particularly in elderly patients and patients with COPD.</item Treatment of cardiac arrhythmias Sinus tachycardia and simple ventricular premature beats are not harbingers of life-threatening arrhythmias, they do not require treatment in the absence of hemodynamic compromise, and they resolve with declining serum theophylline concentrations. Other arrhythmias, especially those associated with hemodynamic compromise, should be treated with antiarrhythmic therapy appropriate for the type of arrhythmia.</item Gastrointestinal decontamination Oral activated charcoal (0.5 g/kg up to 20 g and repeat at least once 1 - 2 hours after the first dose) is extremely effective in blocking the absorption of theophylline throughout the gastrointestinal tract, even when administered several hours after ingestion. If the patient is vomiting, the charcoal should be administered through a nasogastric tube or after administration of an antiemetic. Phenothiazine antiemetics such as prochlorperazine or perphenazine should be avoided since they can lower the seizure threshold and frequently cause dystonic reactions. A single dose of sorbitol may be used to promote stooling to facilitate removal of theophylline bound to charcoal from the gastrointestinal tract. Sorbitol, however, should be dosed with caution since it is a potent purgative which can cause profound fluid and electrolyte abnormalities, particularly after multiple doses. Commercially available fixed combinations of liquid charcoal and sorbitol should be avoided in young children and after the first dose in adolescents and adults since they do not allow for individualization of charcoal and sorbitol dosing. Ipecac syrup should be avoided in theophylline overdoses. Although ipecac induces emesis, it does not reduce the absorption of theophylline unless administered within 5 minutes of ingestion and even then is less effective than oral activated charcoal. Moreover, ipecac induced emesis may persist for several hours after a single dose and significantly decrease the retention and the effectiveness of oral activated charcoal.</item Serum theophylline concentration monitoring The serum theophylline concentration should be measured immediately upon presentation, 2 - 4 hours later, and then at sufficient intervals, e.g., every 4 hours, to guide treatment decisions and to assess the effectiveness of therapy. Serum theophylline concentrations may continue to increase after presentation of the patient for medical care as a result of continued absorption of theophylline from the gastrointestinal tract. Serial monitoring of serum theophylline concentrations should be continued until it is clear that the concentration is no longer rising and has returned to non-toxic levels.</item General monitoring procedures Electrocardiographic monitoring should be initiated on presentation and continued until the serum theophylline level has returned to a non-toxic level. Serum electrolytes and glucose should be measured on presentation and at appropriate intervals indicated by clinical circumstances. Fluid and electrolyte abnormalities should be promptly corrected. Monitoring and treatment should be continued until the serum concentration decreases below 20 mcg/mL. </item Enhance clearance of theophylline Multiple-dose oral activated charcoal (e.g., 0.5 g/kg up to 20 g, every two hours) increases the clearance of theophylline at least twofold by adsorption of theophylline secreted into gastrointestinal fluids. Charcoal must be retained in, and pass through, the gastrointestinal tract to be effective; emesis should therefore be controlled by administration of appropriate antiemetics. Alternatively, the charcoal can be administered continuously through a nasogastric tube in conjunction with appropriate antiemetics. A single dose of sorbitol may be administered with the activated charcoal to promote stooling to facilitate clearance of the adsorbed theophylline from the gastrointestinal tract. Sorbitol alone does not enhance clearance of theophylline and should be dosed with caution to prevent excessive stooling which can result in severe fluid and electrolyte imbalances. Commercially available fixed combinations of liquid charcoal and sorbitol should be avoided in young children and after the first dose in adolescents and adults since they do not allow for individualization of charcoal and sorbitol dosing. In patients with intractable vomiting, extracorporeal methods of theophylline removal should be instituted (see OVERDOSAGE, Extracorporeal Removal</linkHtml).</item </list </text </section </component Specific Recommendations: Acute Overdose Serum Concentration > 20 < 30 mcg/mL Administer a single dose of oral activated charcoal. Monitor the patient and obtain a serum theophylline concentration in 2 - 4 hours to insure that the concentration is not increasing. Serum Concentration > 30 < 100 mcg/mL Administer multiple dose oral activated charcoal and measures to control emesis. Monitor the patient and obtain serial theophylline concentrations every 2 - 4 hours to gauge the effectiveness of therapy and to guide further treatment decisions. Institute extracorporeal removal if emesis, seizures, or cardiac arrhythmias cannot be adequately controlled (see OVERDOSAGE, Extracorporeal Removal). Serum Concentration > 100 mcg/mL Consider prophylactic anticonvulsant therapy. Administer multiple-dose oral activated charcoal and measures to control emesis. Consider extracorporeal removal, even if the patient has not experienced a seizure (see OVERDOSAGE, Extracorporeal Removal). Monitor the patient and obtain serial theophylline concentrations every 2 - 4 hours to gauge the effectiveness of therapy and to guide further treatment decisions. Chronic Overdosage Serum Concentration > 20 < 30 mcg/mL (with manifestations of theophylline toxicity) Administer a single dose of oral activated charcoal. Monitor the patient and obtain a serum theophylline concentration in 2 - 4 hours to insure that the concentration is not increasing. Serum Concentration > 30 mcg/mL in patients < 60 years of age Administer multiple-dose oral activated charcoal and measures to control emesis. Monitor the patient and obtain serial theophylline concentrations every 2 - 4 hours to gauge the effectiveness of therapy and to guide further treatment decisions. Institute extracorporeal removal if emesis, seizures, or cardiac arrhythmias cannot be adequately controlled (see OVERDOSAGE, Extracorporeal Removal). Serum Concentration > 30 mcg/mL in patients 60 years of age. Consider prophylactic anticonvulsant therapy. Administer multiple-dose oral activated charcoal and measures to control emesis. Consider extracorporeal removal even if the patient has not experienced a seizure (see OVERDOSAGE, Extracorporeal Removal). Monitor the patient and obtain serial theophylline concentrations every 2 - 4 hours to gauge the effectiveness of therapy and to guide further treatment decisions. Extracorporeal Removal: Increasing the rate of theophylline clearance by extracorporeal methods may rapidly decrease serum concentrations, but the risks of the procedure must be weighed against the potential benefit. Charcoal hemoperfusion is the most effective method of extracorporeal removal, increasing theophylline clearance up to six fold, but serious complications, including hypotension, hypocalcemia, platelet consumption and bleeding diatheses may occur. Hemodialysis is about as efficient as multiple-dose oral activated charcoal and has a lower risk of serious complications than charcoal hemoperfusion. Hemodialysis should be considered as an alternative when charcoal hemoperfusion is not feasible and multiple-dose oral charcoal is ineffective because of intractable emesis. Serum theophylline concentrations may rebound 5 - 10 mcg/mL after discontinuation of charcoal hemoperfusion or hemodialysis due to redistribution of theophylline from the tissue compartment. Peritoneal dialysis is ineffective for theophylline removal; exchange transfusions in neonates have been minimally effective.

PRECAUTIONS SECTION.


PRECAUTIONS General: Careful consideration of the various interacting drugs and physiologic conditions that can alter theophylline clearance and require dosage adjustment should occur prior to initiation of theophylline therapy, prior to increases in theophylline dose, and during follow up (see WARNINGS</linkHtml). The dose of theophylline selected for initiation of therapy should be low and, if tolerated, increased slowly over a period of a week or longer with the final dose guided by monitoring serum theophylline concentrations and the patient's clinical response (see DOSAGE AND ADMINISTRATION</linkHtml, Table V).</paragraph </text </section </component Monitoring Serum Theophylline Concentrations: Serum theophylline concentration measurements are readily available and should be used to determine whether the dosage is appropriate. Specifically, the serum theophylline concentration should be measured as follows:</paragraph When initiating therapy to guide final dosage adjustment after titration.</item Before making a dose increase to determine whether the serum concentration is sub-therapeutic in a patient who continues to be symptomatic.</item Whenever signs or symptoms of theophylline toxicity are present.</item Whenever there is a new illness, worsening of a chronic illness or a change in the patient's treatment regimen that may alter theophylline clearance (e.g., fever >102 F sustained for 24 hours, hepatitis, or drugs listed in Table II are added or discontinued).</item </list To guide a dose increase, the blood sample should be obtained at the time of the expected peak serum theophylline concentration; 12 hours after a dose at steady-state (expected peak serum theophylline concentration range is between 5 15 mcg/mL). For most patients, steady-state will be reached after 3 days of dosing when no doses have been missed, no extra doses have been added, and none of the doses have been taken at unequal intervals. A trough concentration (i.e., at the end of the dosing interval) provides no additional useful information and may lead to an inappropriate dose increase since the peak serum theophylline concentration can be two or more times greater than the trough concentration with an extended-release formulation. If the serum sample is drawn more or less than twelve (12) hours after the dose, the results must be interpreted with caution since the concentration may not be reflective of the peak concentration. In contrast, when signs or symptoms of theophylline toxicity are present, the serum sample should be obtained as soon as possible, analyzed immediately, and the result reported to the healthcare professional without delay. In patients in whom decreased serum protein binding is suspected (e.g., cirrhosis, women during the third trimester of pregnancy), the concentration of unbound theophylline should be measured and the dosage adjusted to achieve an unbound concentration of 6 - 12 mcg/mL.</paragraph Saliva concentrations of theophylline cannot be used reliably to adjust dosage without special techniques.</paragraph </text </section </component Effects on Laboratory Tests: As a result of its pharmacological effects, theophylline at serum concentrations within the 10 - 20 mcg/mL range modestly increases plasma glucose (from a mean of 88 mg% to 98 mg%), uric acid (from a mean of 4 mg/dL to 6 mg/dL), free fatty acids (from a mean of 451 Eq/L to 800 Eq/L, total cholesterol (from a mean of 140 vs 160 mg/dL), HDL (from a mean of 36 to 50 mg/dL), HDL/LDL ratio (from a mean of 0.5 to 0.7), and urinary free cortisol excretion (from a mean of 44 to 63 mcg/24 hr). Theophylline at serum concentrations within the 10 - 20 mcg/mL range may also transiently decrease serum concentrations of tri-iodothyronine (144 before, 131 after one week and 142 ng/dL after 4 weeks of theophylline). The clinical importance of these changes should be weighed against the potential therapeutic benefit of theophylline in individual patients.</paragraph </text </section </component Information for Patients: The patient (or parent/care giver) should be instructed to seek medical advice whenever nausea, vomiting, persistent headache, insomnia or rapid heart beat occurs during treatment with theophylline, even if another cause is suspected. The patient should be instructed to contact their healthcare professional if they develop a new illness, especially if accompanied by a persistent fever, if they experience worsening of a chronic illness, if they start or stop smoking cigarettes or marijuana, or if another healthcare professional adds a new medication or discontinues a previously prescribed medication. Patients should be informed that theophylline interacts with a wide variety of drugs (see Table II). The dietary supplement St. John's Wort (Hypericum perforatum) should not be taken at the same time as theophylline, since it may result in decreased theophylline levels. If patients are already taking St. John's Wort and theophylline together, they should consult their healthcare professional before stopping the St. John's Wort, since their theophylline concentrations may rise when this is done, resulting in toxicity. Patients should be instructed to inform all healthcare professionals involved in their care that they are taking theophylline, especially when a medication is being added or deleted from their treatment. Patients should be instructed to not alter the dose, timing of the dose, or frequency of administration without first consulting their healthcare professional. If a dose is missed, the patient should be instructed to take the next dose at the usually scheduled time and to not attempt to make up for the missed dose.</paragraph Patients should be instructed to take this medication each morning at approximately the same time and not to exceed the prescribed dose.</paragraph Patients who require a relatively high dose of theophylline should be informed of important considerations relating to time of drug administration and meal content (see PRECAUTIONS, Drug/Food Interactions</linkHtml; and DOSAGE AND ADMINISTRATION</linkHtml).</paragraph </text </section </component Drug Interactions: Drug/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.</paragraph 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.</paragraph 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., The listing of drugs in Table II is current as of June 2004. The listing of drugs in Table III is current as of January 2, 1996. New interactions are continuously being reported for theophylline, especially with new chemical entities. The healthcare professional 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.</paragraph Table II. Clinically significant drug interactions with theophylline*.</caption Drug</th Type of Interaction</th Effect</th </tr </thead * Refer to PRECAUTIONS, Drug Interactions</linkHtml for further information regarding table. Average effect on steady state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed. </td </tr </tfoot Adenosine</td Theophylline blocks adenosine receptors.</td Higher doses of adenosine may be required to achieve desired effect.</td </tr Alcohol</td A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours.</td 30% increase</td </tr Allopurinol</td Decreases theophylline clearance at allopurinol doses 600 mg/day.</td 25% increase</td </tr Aminoglutethimide</td Increases theophylline clearance by induction of microsomal enzyme activity.</td 25% decrease</td </tr Carbamazepine</td Similar to aminoglutethimide.</td 30% decrease</td </tr Cimetidine</td Decreases theophylline clearance by inhibiting cytochrome P450 1A2.</td 70% increase</td </tr Ciprofloxacin</td Similar to cimetidine.</td 40% increase</td </tr Clarithromycin</td Similar to erythromycin.</td 25% increase</td </tr Diazepam</td Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors.</td 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.</td </tr Disulfiram</td Decreases theophylline clearance by inhibiting hydroxylation and demethylation.</td 50% increase</td </tr Enoxacin</td Similar to cimetidine.</td 300% increase</td </tr Ephedrine</td Synergistic CNS effects.</td Increased frequency of nausea, nervousness, and insomnia.</td </tr Erythromycin</td Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3.</td 35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.</td </tr Estrogen</td Estrogen containing oral contraceptives decrease theophylline clearance in a dose- dependent fashion. The effect of progesterone on theophylline clearance is unknown.</td 30% increase</td </tr Flurazepam</td Similar to diazepam.</td Similar to diazepam.</td </tr Fluvoxamine</td Similar to cimetidine.</td Similar to cimetidine</td </tr Halothane</td Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines.</td Increased risk of ventricular arrhythmias.</td </tr Interferon, human recombinant alpha-A</td Decreases theophylline clearance.</td 100% increase</td </tr Isoproterenol (IV)</td Increases theophylline clearance.</td 20% decrease</td </tr Ketamine</td Pharmacologic.</td May lower theophylline seizure threshold.</td </tr Lithium</td Theophylline increases renal lithium clearance.</td Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.</td </tr Lorazepam</td Similar to diazepam.</td Similar to diazepam.</td </tr Methotrexate (MTX)</td Decreases theophylline clearance.</td 20% increase after low dose MTX, higher dose MTX may have a greater effect.</td </tr Mexiletine</td Similar to disulfiram.</td 80% increase</td </tr Midazolam</td Similar to diazepam.</td Similar to diazepam.</td </tr Moricizine</td Increases theophylline clearance.</td 25% decrease</td </tr Pancuronium</td Theophylline may antagonize non-depolarizing neuromuscular blocking effects, possibly due to phosphodiesterase inhibition.</td Larger dose of pancuronium may be required to achieve neuromuscular blockade</td </tr Pentoxifylline</td Decreases theophylline clearance.</td 30% increase</td </tr Phenobarbital (PB)</td Similar to aminoglutethimide.</td 25% decrease after two weeks of concurrent PB.</td </tr Phenytoin</td Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption.</td Serum theophylline and phenytoin concentrations decrease about 40%.</td </tr Propafenone</td Decreases theophylline clearance and pharmacologic interaction.</td 40% increase. Beta2</sub blocking effect may decrease efficacy of theophylline</td </tr Propranolol</td Similar to cimetidine and pharmacologic interaction.</td 100% increase. Beta2</sub blocking effect may decrease efficacy of theophylline</td </tr Rifampin</td Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity.</td 20-40% decrease</td </tr St. John's Wort (Hypericum Perforatum)</td Decrease in theophylline plasma concentrations.</td Higher doses of theophylline may be required to achieve desired effect. Stopping St. John's Wort may result in theophylline toxicity.</td </tr Sulfinpyrazone</td Increases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline.</td 20% decrease</td </tr Tacrine</td Similar to cimetidine, also increases renal clearance of theophylline.</td 90% increase</td </tr Thiabendazole</td Decreases theophylline clearance.</td 190% increase</td </tr Ticlopidine</td Decreases theophylline clearance.</td 60% increase</td </tr Troleandomycin</td Similar to erythromycin.</td 33-100% increase depending on troleandomycin dose.</td </tr Verapamil</td Similar to disulfiram.</td 20% increase</td </tr </tbody </table Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.*</caption * Refer to PRECAUTIONS, Drug Interactions </linkHtmlfor information regarding table. </td </tr </tfoot albuterol, systemic and inhaled</td hydrocortisone</td ofloxacin</td </tr amoxicillin</td isoflurane</td omeprazole</td </tr ampicillin, with or without</td isoniazid</td prednisone, prednisolone</td </tr sulbactam</td isradipine</td ranitidine</td </tr atenolol</td influenza vaccine</td rifabutin</td </tr azithromycin</td ketoconazole</td roxithromycin</td </tr caffeine, dietary ingestion</td lomefloxacin</td sorbitol</td </tr cefaclor</td mebendazole</td (purgative doses do</td </tr co-trimoxazole (trimethoprim</td medroxyprogesterone</td not inhibit theophylline</td </tr and sulfamethoxazole)</td methylprednisolone</td absorption)</td </tr diltiazem</td metronidazole</td sucralfate</td </tr dirithromycin</td metoprolol</td terbutaline, systemic</td </tr enflurane</td nadolol</td terfenadine</td </tr famotidine</td nifedipine</td tetracycline</td </tr felodipine</td nizatidine</td tocainide</td </tr finasteride</td norfloxacin</td </td </tr </tbody </table </text </section </component Drug/Food Interactions Taking Theo-24 less than one hour before a high-fat-content meal, such as 8 oz whole milk, 2 fried eggs, 2 bacon strips, 2 oz hashed brown potatoes, and 2 slices of buttered toast (about 985 calories, including approximately 71 g of fat) may result in a significant increase in peak serum level and in the extent of absorption of theophylline as compared to administration in the fasted state. In some cases (especially with doses of 900 mg or more taken less than one hour before a high-fat-content meal) serum theophylline levels may exceed the 20 mcg/mL level, above which theophylline toxicity is more likely to occur.</paragraph </text </section </component </section </component The Effect of Other Drugs on Theophylline Serum Concentration Measurements: Most serum theophylline assays in clinical use are immunoassays which are specific for theophylline. Other xanthines such as caffeine, dyphylline, and pentoxifylline are not detected by these assays. Some drugs (e.g., cefazolin, cephalothin), however, may interfere with certain HPLC techniques. Caffeine and xanthine metabolites in neonates or patients with renal dysfunction may cause the reading from some dry reagent office methods to be higher than the actual serum theophylline concentration.</paragraph </text </section </component Carcinogenesis, Mutagenesis, and Impairment of Fertility: Long term carcinogenicity studies have been carried out in mice (oral doses 30 - 150 mg/kg) and rats (oral doses 5 - 75 mg/kg). Results are pending.</paragraph Theophylline has been studied in Ames salmonella, in vivo and in vitro cytogenetics, micronucleus and Chinese hamster ovary test systems and has not been shown to be genotoxic.</paragraph In a 14 week continuous breeding study, theophylline, administered to mating pairs of B6C3F1</sub mice at oral doses of 120, 270 and 500 mg/kg (approximately 1.0 - 3.0 times the human dose on a mg/m2 basis) impaired fertility, as evidenced by decreases in the number of live pups per litter, decreases in the mean number of litters per fertile pair, and increases in the gestation period at the high dose as well as decreases in the proportion of pups born alive at the mid and high dose. In 13 week toxicity studies, theophylline was administered to F344 rats and B6C3F1</sub mice at oral doses of 40 - 300 mg/kg (approximately 2.0 times the human dose on a mg/m2 basis). At the high dose, systemic toxicity was observed in both species including decreases in testicular weight.</paragraph </text </section </component Pregnancy: CATEGORY C: In studies in which pregnant mice, rats and rabbits were dosed during the period of organogenesis, theophylline produced teratogenic effects. In studies with mice, a single intraperitoneal dose at and above 100 mg/kg (approximately equal to the maximum recommended oral dose for adults on a mg/m2 basis) during organogenesis produced cleft palate and digital abnormalities. Micromelia, micrognathia, clubfoot, subcutaneous hematoma, open eyelids, and embryolethality were observed at doses that are approximately 2 times the maximum recommended oral dose for adults on a mg/m2 basis. In a study with rats dosed from conception through organogenesis, an oral dose of 150 mg/kg/day (approximately 2 times the maximum recommended oral dose for adults on a mg/m2 basis) produced digital abnormalities. Embryolethality was observed with a subcutaneous dose of 200 mg/kg/day (approximately 4 times the maximum recommended oral dose for adults on a mg/m2 basis). In a study in which pregnant rabbits were dosed throughout organogenesis, an intravenous dose of 60 mg/kg/day (approximately 2 times the maximum recommended oral dose for adults on a mg/m2 basis), which caused the death of one doe and clinical signs in others, produced cleft palate and was embryolethal. Doses at and above 15 mg/kg/day (less than the maximum recommended oral dose for adults on a mg/m2 basis) increased the incidence of skeletal variations. There are no adequate and well-controlled studies in pregnant women. Theophylline should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers: 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. Pediatric Use: Theophylline is safe and effective for the approved indications in pediatric patients (see INDICATIONS AND USAGE). The maintenance dose of theophylline must be selected with caution in pediatric patients since the rate of theophylline clearance is highly variable across the age range of neonates to adolescents (see CLINICAL PHARMACOLOGY, Table I, WARNINGS, and DOSAGE AND ADMINISTRATION, Table V). Due to the immaturity of theophylline metabolic pathways in infants under the age of one year, particular attention to dosage selection and frequent monitoring of serum theophylline concentrations are required when theophylline is prescribed to pediatric patients in this age group. Geriatric Use: Elderly patients are at a 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 (see PRECAUTIONS: Drug Interactions) 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 (see PRECAUTIONS, Monitoring Serum Theophylline Concentrations, and DOSAGE AND ADMINISTRATION). 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.

CLINICAL PHARMACOLOGY SECTION.


CLINICAL PHARMACOLOGY 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 bronchodilation 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).</paragraph 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.</paragraph </text </section </component Serum Concentration-Effect Relationship: Bronchodilation occurs over the serum theophylline concentration range of 5 - 20 mcg/mL. Clinically important improvement in symptom control has been found in most studies to require peak serum theophylline concentrations >10 mcg/mL, but patients with mild disease may benefit from lower concentrations. At serum theophylline concentrations >20 mcg/mL, both the frequency and severity of adverse reactions increase. In general, maintaining peak serum theophylline concentrations between 10 and 15 mcg/mL will achieve most of the drug's potential therapeutic benefit while minimizing the risk of serious adverse events.</paragraph </text </section </component Pharmacokinetics: Overview Theophylline is rapidly and completely absorbed after oral administration in solution or immediate-release solid oral dosage form. Theophylline does not undergo any appreciable pre-systemic elimination, distributes freely into fat-free tissues and is extensively metabolized in the liver. The pharmacokinetics of theophylline vary widely among similar patients and cannot be predicted by age, sex, body weight or other demographic characteristics. In addition, certain concurrent illnesses and alterations in normal physiology (see Table I) and co-administration of other drugs (see Table II) can significantly alter the pharmacokinetic characteristics of theophylline. Within-subject variability in metabolism has also been reported in some studies, especially in acutely ill patients. It is, therefore, recommended that serum theophylline concentrations be measured frequently in acutely ill patients (e.g., at 24-hr intervals) and periodically in patients receiving long-term therapy, e.g., at 6-12 month intervals. More frequent measurements should be made in the presence of any condition that may significantly alter theophylline clearance (see PRECAUTIONS, Laboratory Tests). Table I. Mean and range of total body clearance and half-life of theophylline related to age and altered physiological states.* Population characteristics Total body clearance mean (range) (mL/kg/min) Half-life Mean (range) (hr) * For various North American patient populations from literature reports. Different rates of elimination and consequent dosage requirements have been observed among other peoples. Clearance represents the volume of blood completely cleared of theophylline by the liver in one minute. Values listed were generally determined at serum theophylline concentrations 60 years) non-smokers with normal cardiac, liver, and renal function 0.41 (0.21 - 0.61) 9.8 (1.6 - 18) Concurrent illness or altered physiological state Acute pulmonary edema 0.33 (0.07 - 2.45) 19 (3.1 - 82) COPD >60 years, stable non-smoker >1 year 0.54 (0.44 - 0.64) 11 (9.4 - 12.6) COPD with cor-pulmonale 0.48 (0.08 - 0.88) NR Cystic fibrosis (14 - 28 years) 1.25 (0.31 - 2.2) 6.0 (1.8 - 10.2) Fever associated with acute viral respiratory illness (children 9 - 15 years) NR 7.0 (1.0 - 13) Liver disease cirrhosis 0.31 (0.1 - 0.7) 32 (10 - 56) acute hepatitis 0.35 (0.25 - 0.45) 19.2 (16.6 - 21.8) cholestasis 0.65 (0.25 - 1.45) 14.4 (5.7 - 31.8) Pregnancy 1st trimester NR 8.5 (3.1 - 13.9) 2nd trimester NR 8.8 (3.8 - 13.8) 3rd trimester NR 13.0 (8.4 - 17.6) Sepsis with multi-organ failure 0.47 (0.19 - 1.9) 18.8 (6.3 - 24.1) Thyroid disease hypothyroid 0.38 (0.13 - 0.57) 11.6 (8.2 - 25) hyperthyroid 0.8 (0.68 - 0.97) 4.5 (3.7 - 5.6) Absorption Theophylline is rapidly and completely absorbed after oral administration in solution or immediate-release solid oral dosage form. After a single immediate-release dose of 5 mg/kg in adults, a mean peak serum concentration of about 10 mcg/mL (range 5 - 15 mcg/mL) can be expected 1 - 2 hr after dose. Co-administration of theophylline with food or antacids does not cause clinically significant changes in the absorption of theophylline from immediate-release dosage forms. Theo-24 capsules contain hundreds of coated beads of theophylline. Each bead is an individual extended-release delivery system. After dissolution of the capsules these beads are released and distributed in the gastrointestinal tract, thus minimizing the probability of high local concentrations of theophylline at any particular site. In a 6-day multiple-dose study involving 18 subjects (with theophylline clearance rates between 0.57 and 1.02 mL/kg/min) who had fasted overnight and 2 hours after morning dosing, Theo-24 given once daily in a dose of 1500 mg produced serum theophylline levels that ranged between 5.7 mcg/mL and 22 mcg/mL. The mean minimum and maximum values were 11.6 mcg/mL and 18.1 mcg/mL, respectively, with an average peak-trough difference of 6.5 mcg/mL. The mean percent fluctuation [(Cmax Cmin /Cmin) 100] equals 80%. A 24-hour single-dose study demonstrated an approximately proportional increase in serum levels as the dose was increased from 600 to 1500 mg. Taking Theo-24 with a high-fat-content meal may result in a significant increase in the peak serum level and in the extent of absorption of theophylline as compared to administration in the fasted state (see PRECAUTIONS, Drug/Food Interactions). Following the single-dose administration (8 mg/kg) of Theo-24 to 20 normal subjects who had fasted overnight and 2 hours after morning dosing, peak serum theophylline concentrations of 4.8 1.5 (SD) mcg/mL were obtained at 13.3 4.7 (SD) hours. The amount of the dose absorbed was approximately 13% at 3 hours, 31% at 6 hours, 55% at 12 hours, 70% at 16 hours, and 88% at 24 hours. The extent of theophylline bioavailability from Theo-24 was comparable to the most widely used 12-hour extended-release product when both products were administered every 12 hours. Distribution Once theophylline enters the systemic circulation, about 40% is bound to plasma protein, primarily albumin. Unbound theophylline distributes throughout body water, but distributes poorly into body fat. The apparent volume of distribution of theophylline is approximately 0.45 L/kg (range 0.3 - 0.7 L/kg) based on ideal body weight. Theophylline passes freely across the placenta, into breast milk and into the cerebrospinal fluid (CSF). Saliva theophylline concentrations approximate unbound serum concentrations, but are not reliable for routine or therapeutic monitoring unless special techniques are used. An increase in the volume of distribution of theophylline, primarily due to reduction in plasma protein binding, occurs in premature neonates, patients with hepatic cirrhosis, uncorrected acidemia, the elderly and in women during the third trimester of pregnancy. In such cases, the patient may show signs of toxicity at total (bound+unbound) serum concentrations of theophylline in the therapeutic range (10 - 20 mcg/mL) due to elevated concentrations of the pharmacologically active unbound drug. Similarly, a patient with decreased theophylline binding may have a sub-therapeutic total drug concentration while the pharmacologically active unbound concentration is in the therapeutic range. If only total serum theophylline concentration is measured, this may lead to an unnecessary and potentially dangerous dose increase. In patients with reduced protein binding, measurement of unbound serum theophylline concentration provides a more reliable means of dosage adjustment than measurement of total serum theophylline concentration. Generally, concentrations of unbound theophylline should be maintained in the range of 6 - 12 mcg/mL. Metabolism Following oral dosing, theophylline does not undergo any measurable first-pass elimination. In adults and children beyond one year of age, approximately 90% of the dose is metabolized in the liver. 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. Theophylline demethylation to 3-methylxanthine is catalyzed by cytochrome P-450 1A2, while cytochromes P-450 2E1 and P-450 3A3 catalyze the hydroxylation to 1,3-dimethyluric acid. Demethylation to 1-methylxanthine appears to be catalyzed either by cytochrome P-450 1A2 or a closely related cytochrome. In neonates, the N-demethylation pathway is absent while the function of the hydroxylation pathway is markedly deficient. The activity of these pathways slowly increases to maximal levels by one year of age. Caffeine and 3-methylxanthine are the only theophylline metabolites with pharmacologic activity. 3-methylxanthine has approximately one tenth the pharmacologic activity of theophylline and serum concentrations in adults with normal renal function are 3 months of age. In contrast, the large fraction of the theophylline dose excreted in the urine as unchanged theophylline and caffeine in neonates requires careful attention to dose reduction and frequent monitoring of serum theophylline concentrations in neonates with reduced renal function (see WARNINGS). Serum Concentrations at Steady State After multiple doses of theophylline, steady state is reached in 30 65 hours (average 40 hours) in adults. At steady state, on a dosage regimen with 6-hour intervals, the expected mean trough concentration is approximately 60% of the mean peak concentration, assuming a mean theophylline half-life of 8 hours. The difference between peak and trough concentrations is larger in patients with more rapid theophylline clearance. In patients with high theophylline clearance and half-lives of about 4-5 hours, such as children age 1 to 9 years, the trough serum theophylline concentration may be only 30% of peak with a 6-hour dosing interval. In these patients a slow release formulation would allow a longer dosing interval (8 - 12 hours) with a smaller peak/trough difference. Special Populations (See Table I for mean clearance and half-life values) Geriatric The clearance of theophylline is decreased by an average of 30% in healthy elderly adults (>60 yrs) compared to healthy young adults. Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in elderly patients (see WARNINGS). Pediatrics The clearance of theophylline is very low in neonates (see WARNINGS). Theophylline clearance reaches maximal values by one year of age, remains relatively constant until about 9 years of age and then slowly decreases by approximately 50% to adult values at about age 16. 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. Careful attention to dosage selection and monitoring of serum theophylline concentrations are required in pediatric patients (see WARNINGS and DOSAGE AND ADMINISTRATION). Gender Gender differences in theophylline clearance are relatively small and unlikely to be of clinical significance. Significant reduction in theophylline clearance, however, has been reported in women on the 20th day of the menstrual cycle and during the third trimester of pregnancy. Race Pharmacokinetic differences in theophylline clearance due to race have not been studied. Renal Insufficiency Only a small fraction, e.g., about 10%, of the administered theophylline dose is excreted unchanged in the urine of children greater than three months of age and adults. Since little theophylline is excreted unchanged in the urine and since active metabolites of theophylline (i.e., caffeine, 3-methylxanthine) do not accumulate to clinically significant levels even in the face of end-stage renal disease, no dosage adjustment for renal insufficiency is necessary in adults and children >3 months of age. In contrast, approximately 50% of the administered theophylline dose is excreted unchanged in the urine in neonates. Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in neonates with decreased renal function (see WARNINGS). Hepatic Insufficiency Theophylline clearance is decreased by 50% or more in patients with hepatic insufficiency (e.g., cirrhosis, acute hepatitis, cholestasis). Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in patients with reduced hepatic function (see WARNINGS). Congestive Heart Failure (CHF) Theophylline clearance is decreased by 50% or more in patients with CHF. The extent of reduction in theophylline clearance in patients with CHF appears to be directly correlated to the severity of the cardiac disease. Since theophylline clearance is independent of liver blood flow, the reduction in clearance appears to be due to impaired hepatocyte function rather than reduced perfusion. Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in patients with CHF (see WARNINGS). Smokers Tobacco and marijuana smoking appears to increase the clearance of theophylline by induction of metabolic pathways. Theophylline clearance has been shown to increase by approximately 50% in young adult tobacco smokers and by approximately 80% in elderly tobacco smokers compared to non-smoking subjects. Passive smoke exposure has also been shown to increase theophylline clearance by up to 50%. Abstinence from tobacco smoking for one week causes a reduction of approximately 40% in theophylline clearance. Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in patients who stop smoking (see WARNINGS). Use of nicotine gum has been shown to have no effect on theophylline clearance. Fever Fever, regardless of its underlying cause, can decrease the clearance of theophylline. The magnitude and duration of the fever appear to be directly correlated to the degree of decrease of theophylline clearance. Precise data are lacking, but a temperature of 39 C (102 F) for at least 24 hours is probably required to produce a clinically significant increase in serum theophylline concentrations. Children with rapid rates of theophylline clearance (i.e., those who require a dose that is substantially larger than average [e.g., >22 mg/kg/day] to achieve a therapeutic peak serum theophylline concentration when afebrile) may be at greater risk of toxic effects from decreased clearance during sustained fever. Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in patients with sustained fever (see WARNINGS). Miscellaneous Other factors associated with decreased theophylline clearance include the third trimester of pregnancy, sepsis with multiple organ failure, and hypothyroidism. Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in patients with any of these conditions (see WARNINGS). Other factors associated with increased theophylline clearance include hyperthyroidism and cystic fibrosis. Clinical Studies: In patients with chronic asthma, including patients with severe asthma requiring inhaled corticosteroids or alternate-day oral corticosteroids, many clinical studies have shown that theophylline decreases the frequency and severity of symptoms, including nocturnal exacerbations, and decreases the "as needed" use of inhaled beta2 agonists. Theophylline has also been shown to reduce the need for short courses of daily oral prednisone to relieve exacerbations of airway obstruction that are unresponsive to bronchodilators in asthmatics. In patients with chronic obstructive pulmonary disease (COPD), clinical studies have shown that theophylline decreases dyspnea, air trapping, the work of breathing, and improves contractility of diaphragmatic muscles with little or no improvement in pulmonary function measurements.

CONTRAINDICATIONS SECTION.


CONTRAINDICATIONS Theo-24 is contraindicated in patients with a history of hypersensitivity to theophylline or other components in the product.

WARNINGS SECTION.


WARNINGS Concurrent Illness: 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 60 years) Concurrent Diseases Acute pulmonary edema Congestive heart failure Cor-pulmonale Fever; 102F 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) (see PRECAUTIONS, Drug Interactions, Table II). 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). Dosage Increases: 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 (see PRECAUTIONS, Laboratory Tests). 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).