PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


PRINCIPAL DISPLAY PANEL PRINCIPAL DISPLAY PANEL - 200 mg NDC 53808-0315-1 Theophylline (Anhydrous) Extended-Release Tablets, 200 mg Rx Only Usual Dosage: Read package insert for prescribing information. Store at 20 - 25C (68 - 77F) (See USP Controlled Room Temperature). WARNING: AS WITH ALL MEDICATIONS, KEEP OUT OF REACH OF CHILDREN PRINCIPAL DISPLAY PANEL - 300 mg NDC 53808-0316-1 Theophylline (Anhydrous) Extended-Release Tablets, 300 mg Rx Only Usual Dosage: Read package insert for prescribing information. Store at 20 - 25C (68 - 77F) (See USP Controlled Room Temperature). WARNING: AS WITH ALL MEDICATIONS, KEEP OUT OF REACH OF CHILDREN

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. Percentage of patients reported with sign or symptom Acute Overdose (Large Single Ingestion) Chronic Overdosage (Multiple Excessive Doses) Sign/Symptom Study 1 Study 2 Study 1 Study 2 (n=157) (n=14) (n=92) (n=102) 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 Theophylline (Anhydrous) Extended-Release Tablets 200 or 300 mg Tablets 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 200 or 300 mg Tablets 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 200 mg or 300 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. 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 10-20 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 If caffeine-like adverse effects occur, then consideration should be given to a lower dose and titrating the dose more slowly (see ADVERSE REACTIONS ). 1. Starting Dosage 12-14 mg/kg/day up to a maximum of 300 mg/day admin. QD* 300-400 mg/day1 admin. QD* 2. After 3 days, if , increase dose to: 16 mg/kg/day up to a maximum of 400 mg/day admin. QD* 400-600 mg/day 1 admin. QD* 3. After 3 more days, , and 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 (see Table VI) 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. *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. TABLE VI. Dosage adjustment guided by serum theophylline concentration. 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 ). Peak Serum Concentration Dosage Adjustment 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.


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 beta- 2 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.

HOW SUPPLIED SECTION.


HOW SUPPLIED Theophylline (Anhydrous) Extended-Release Tablets 200 mg are supplied as elliptical, white, bisected, uncoated tablets, embossed with PLIVA 482. Theophylline (Anhydrous) Extended-Release Tablets 300 mg are supplied as capsule, white, bisected, uncoated tablets, embossed with PLIVA 459. They are supplied by State of Florida DOH Central Pharmacy as follows: NDC Strength Quantity/Form Color Source Prod. Code 53808-0315-1 200 mg 30 Tablets in a Blister Pack white 50111-0482 53808-0316-1 300 mg 30 Tablets in a Blister Pack WHITE 50111-0459 Store at 25C (77F); excursions permitted between 15-30C (59-86F). (See USP Controlled Room Temperature) Dispense in tight, light-resistant container as defined in the USP. Manufactured by: PLIVA Inc. Pomona, NY 10970 This Product was Repackaged By: State of Florida DOH Central Pharmacy 104-2 Hamilton Park Drive Tallahassee, FL 32304 United States

DESCRIPTION SECTION.


DESCRIPTION Theophylline (Anhydrous) Extended-Release Tablets in a controlled-release system allows a 24-hour dosing interval for appropriate patients. 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. Each Extended-Release tablet for oral administration, contains 200 or 300 mg of anhydrous theophylline per tablet. Inactive ingredients: glyceryl behenate, silicified microcrystalline cellulose, silicon dioxide, and magnesium stearate.

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 patients rate of theophylline clearance. The most common causes of chronic theophylline overdosage include patient or caregiver 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. 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 patients 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 simultaneously instituting treatment, contact a regional poison center to obtain updated information and advice on individualizing the recommendations that follow. Institute supportive care, including establishment of intravenous access, maintenance of the airway, and electrocardiographic monitoring. 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. 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 patients 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 healthcare 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 LD 50 ). 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. 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. 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. 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 serum concentrations should be continued until it is clear that the concentration is no longer rising and has returned to non-toxic levels. 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. Enhance clearance of theophylline Multiple-dose oral activated charcoal (e.g., 0.5 mg/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 ). Specific Recommendations Acute Overdose Serum Concentration >2030100 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 >2030 mcg/mL in patients 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 sixfold, 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 ). 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 patients clinical response (see DOSAGE AND ADMINISTRATION , Table V ). 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: When initiating therapy to guide final dosage adjustment after titration. Before making a dose increase to determine whether the serum concentration is sub-therapeutic in a patient who continues to be symptomatic. Whenever signs or symptoms of theophylline toxicity are present. Whenever there is a new illness, worsening of a chronic illness or a change in the patients treatment regimen that may alter theophylline clearance (e.g., fever >102F sustained for 24 hours, hepatitis, or drugs listed in Table II are added or discontinued). To guide a dose increase, the blood sample should be obtained at the time of the expected peak serum theophylline concentration; 12 hours after an evening dose or 9 hours after a morning dose at steady-state. 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 immediate-release formulation. If the serum sample is drawn more than 12 hours after the evening dose, or more than 9 hours after a morning 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, a 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. Saliva concentrations of theophylline cannot be used reliably to adjust dosage without special techniques. 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 triiodothyronine (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. Information for Patients The patient (or parent/caregiver) should be instructed to seek medical advice whenever nausea, vomiting, persistent headache, insomnia or rapid heartbeat 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. Johns 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. Johns Wort and theophylline together, they should consult their healthcare professional before stopping the St. Johns 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. Theophylline (Anhydrous) Extended-Release Tablets 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. Patients receiving Theophylline (Anhydrous) Extended-Release Tablets may pass an intact matrix tablet in the stool or via colostomy. These matrix tablets usually contain little or no residual theophylline. 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., 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 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. 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-hour 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) Note: In addition to the factors listed above, theophylline clearance is increased and half-life decreased by low carbohydrate/high protein diets, parenteral nutrition, and daily consumption of charcoal-broiled beef. A high carbohydrate/low protein diet can decrease the clearance and prolong the half-life of theophylline. Absorption Theophylline (Anhydrous) Extended-Release Tablets administered in the fed state is completely absorbed after oral administration. </paragraph In a single-dose crossover study, two 400 mg Theophylline (Anhydrous) Extended-Release Tablets were administered to 19 normal volunteers in the morning or evening immediately following the same standardized meal (769 calories consisting of 97 grams carbohydrates, 33 grams protein and 27 grams fat). There was no evidence of dose dumping nor were there any significant differences in pharmacokinetic parameters attributable to time of drug administration. On the morning arm, the pharmacokinetic parameters were AUC=241.9 83.0 mcg hr/mL, C max</sub =9.3 2.0 mcg/mL, T max</sub =12.8 4.2 hours. On the evening arm, the pharmacokinetic parameters were AUC=219.7 83.0 mcg hr/mL, C max</sub =9.2 2.0 mcg/mL, T max</sub =12.5 4.2 hours.</paragraph A study in which Theophylline (Anhydrous) Extended-Release 400 mg Tablets were administered to 17 fed adult asthmatics produced similar theophylline level-time curves when administered in the morning or evening. Serum levels were generally higher in the evening regimen but there were no statistically significant differences between the two regimens.</paragraph MORNING</th EVENING</th </tr </thead AUC (0-24 hrs) (mcg hr/mL)</td 236.076.7</td 256.080.4</td </tr C max</sub (mcg/mL)</td 14.54.1</td 16.34.5</td </tr C min</sub (mcg/mL)</td 5.52.9</td 5.02.5</td </tr T max</sub (hours)</td 8.13.7</td 10.14.1</td </tr </tbody </table A single-dose study in 15 normal fasting male volunteers whose theophylline inherent mean elimination half-life was verified by a liquid theophylline product to be 6.92.5 (SD) hours were administered two or three Theophylline (Anhydrous) Extended Release 400 mg Tablets. The relative bioavailability of Theophylline (Anhydrous) Extended-Release Tablets given in the fasting state in comparison to an immediate-release product was 59%. Peak serum theophylline levels occurred at 6.95.2 (SD) hours, with a normalized (to 800 mg) peak level being 6.22.1 (SD). The apparent elimination half-life for the 400 mg Theophylline (Anhydrous) Extended-Release Tablets was 17.25.8 (SD) hours.</paragraph Steady-state pharmacokinetics were determined in a study in 12 fasted patients with chronic reversible obstructive pulmonary disease. All were dosed with two 400 mg Theophylline (Anhydrous) Extended-Release Tablets given once daily in the morning and a reference controlled-release BID product administered as two 200 mg tablets given 12 hours apart. The pharmacokinetic parameters obtained for Theophylline (Anhydrous) Extended-Release Tablets given at doses of 800 mg once daily in the morning were virtually identical to the corresponding parameters for the reference drug when given as 400 mg BID. In particular, the AUC, C max</sub and C min</sub values obtained in this study were as follows:</paragraph Theophylline (Anhydrous) Extended-Release Tablets 800 mg Q24hSD</th Reference Drug 400 mg Q12hSD</th </tr </thead AUC, (0-24 hours), mcg hr/mL</td 288.921.5</td 283.538.4</td </tr C max</sub , mcg/mL</td 15.72.8</td 15.22.1</td </tr C min</sub , mcg/mL</td 7.91.6</td 7.81.7</td </tr C max</sub -C min</sub diff.</td 7.71.5</td 7.41.5</td </tr </tbody </table Single-dose studies in which subjects were fasted for twelve (12) hours prior to and an additional four (4) hours following dosing, demonstrated reduced bioavailability as compared to dosing with food. One single-dose study in 20 normal volunteers dosed with two (2) 400 mg tablets in the morning, compared dosing under these fasting conditions with dosing immediately prior to a standardized breakfast (769 calories, consisting of 97 grams carbohydrates, 33 grams protein and 27 grams fat). Under fed conditions, the pharmacokinetic parameters were: AUC=231.792.4 mcg hr/mL, C max</sub =8.42.6 mcg/mL, T max</sub =17.36.7 hours. Under fasting conditions, these parameters were AUC=141.26.53 mcg hr/mL, C max</sub =5.51.5 mcg/mL, T max</sub =6.52.1 hours.</paragraph Another single-dose study in 21 normal male volunteers, dosed in the evening, compared fasting to a standardized high calorie, high fat meal (870-1,020 calories, consisting of 33 grams protein, 55-75 grams fat, 58 grams carbohydrates). In the fasting arm subjects received one Theophylline (Anhydrous) Extended-Release 400 mg Tablet at 8 p.m. after an eight hour fast followed by a further four hour fast. In the fed arm, subjects were again dosed with one 400 mg Theophylline (Anhydrous) Extended-Release Tablet, but at 8 p.m. immediately after the high fat content standardized meal cited above. The pharmacokinetic parameters (normalized to 800 mg) fed were AUC=221.840.9 mcg hr/mL, C max</sub =10.91.7 mcg/mL, T max</sub =11.82.2 hours. In the fasting arm, the pharmacokinetic parameters (normalized to 800 mg) were AUC=146.440.9 mcg hr/mL, C max</sub =6.71.7 mcg/mL, T max</sub =7.32.2 hours.</paragraph Thus, administration of single Theophylline (Anhydrous) Extended-Release doses to healthy normal volunteers, under prolonged fasted conditions (at least 10 hour overnight fast before dosing followed by an additional four (4) hour fast after dosing) results in decreased bioavailability. However, there was no failure of this delivery system leading to a sudden and unexpected release of a large quantity of theophylline with Theophylline (Anhydrous) Extended-Release Tablets even when they are administered with a high fat, high calorie meal.</paragraph Similar studies were conducted with the 600 mg Theophylline (Anhydrous) Extended-Release Tablet. A single-dose study in 24 subjects with an established theophylline clearance of 4 L/hr, compared the pharmacokinetic evaluation of one 600 mg Theophylline (Anhydrous) Extended-Release Tablet and one and one-half 400 mg Theophylline (Anhydrous) Extended-Release Tablets under fed (using a standard high fat diet) and fasted conditions. The results of this 4-way randomized crossover study demonstrate the bioequivalence of the 400 mg and 600 mg Theophylline (Anhydrous) Extended-Release Tablets. Under fed conditions, the pharmacokinetic results for the one and one-half 400 mg tablets were AUC=214.6455.88 mcg hr/mL, C max</sub =10.582.21 mcg/mL and T max</sub =9.002.64 hours, and for the 600 mg tablet were AUC=207.8548.9 mcg hr/mL, C max</sub =10.391.91 mcg/mL and T max</sub =9.581.86 hours. Under fasted conditions the pharmacokinetic results for the one and one-half 400 mg tablets were AUC=191.85 51.1 mcg hr/mL, C max</sub = 7.371.83 mcg/mL and T max</sub =8.084.39 hours; and for the 600 mg tablet were AUC=199.3970.27 mcg hr/mL, C max</sub =7.662.09 mcg/mL and T max</sub =9.674.89 hours.</paragraph In this study the mean fed/fasted ratios for the one and one-half 400 mg tablets and the 600 mg tablet were about 112% and 104%, respectively.</paragraph In another study, the bioavailability of the 600 mg Theophylline (Anhydrous) Extended-Release Tablet was examined with morning and evening administration. This single-dose, crossover study in 22 healthy males was conducted under fed (standard high fat diet) conditions. The results demonstrated no clinically significant difference in the bioavailability of the 600 mg Theophylline (Anhydrous) Extended-Release Tablet administered in the morning or in the evening. The results were: AUC=233.645.1 mcg hr/mL, C max</sub =10.61.3 mcg/mL and T max</sub =12.53.2 hours with morning dosing; AUC=209.846.2 mcg hr/mL, C max</sub =9.71.4 mcg/mL and T max</sub =13.73.3 hours with evening dosing. The PM/AM ratio was 89.3%.</paragraph The absorption characteristics of Theophylline (Anhydrous) Extended-Release Tablets (theophylline, anhydrous) have been extensively studied. A steady-state crossover bioavailability study in 22 normal males compared two Theophylline (Anhydrous) Extended-Release 400 mg Tablets administered q24h at 8 a.m. immediately after breakfast with a reference controlled-release theophylline product administered BID in fed subjects at 8 a.m. immediately after breakfast and 8 p.m. immediately after dinner (769 calories, consisting of 97 grams carbohydrates, 33 grams protein and 27 grams fat).</paragraph The pharmacokinetic parameters for Theophylline (Anhydrous) Extended-Release 400 mg Tablets under these steady-state conditions were AUC=203.387.1 mcg hr/mL, C max</sub =12.13.8 mcg/mL, C min</sub =4.503.6, T max</sub =8.84.6 hours. For the reference BID product, the pharmacokinetic parameters were AUC=219.288.4 mcg hr/mL, C max</sub =11.04.1 mcg/mL, C min</sub =7.283.5, T max</sub =6.93.4 hours. The mean percent fluctuation [(C max</sub -C min</sub /C min</sub )x100]=169% for the once-daily regimen and 51% for the reference product BID regimen.</paragraph The bioavailability of the 600 mg Theophylline (Anhydrous) Extended-Release Tablet was further evaluated in a multiple dose, steady-state study in 26 healthy males comparing the 600 mg Tablet to one and one-half 400 mg Theophylline (Anhydrous) Extended-Release Tablets. All subjects had previously established theophylline clearances of 4 L/hr and were dosed once-daily for 6 days under fed conditions. The results showed no clinically significant difference between the 600 mg and one and one-half 400 mg Theophylline (Anhydrous) Extended-Release Tablet regimens. Steady-state results were:</paragraph 600 MG TABLET FED</th 600 MG (ONE+ONE-HALF 400 MG TABLETS) FED</th </tr </thead AUC 0-24hrs (mcg hr/mL)</td 209.7751.04</td 212.3256.29</td </tr C max</sub (mcg/mL)</td 12.912.46</td 13.173.11</td </tr C min</sub (mcg/mL)</td 5.521.79</td 5.391.95</td </tr T max</sub (hours)</td 8.623.21</td 7.232.35</td </tr Percent Fluctuation</td 183.7354.02</td 179.7228.86</td </tr </tbody </table The bioavailability ratio for the 600/400 mg tablets was 98.8%. Thus, under all study conditions the 600 mg tablet is bioequivalent to one and one-half 400 mg tablets.</paragraph Studies demonstrate that as long as subjects were either consistently fed or consistently fasted, there is similar bioavailability with once-daily administration of Theophylline (Anhydrous) Extended-Release Tablets whether dosed in the morning or evening.</paragraph </text </section </component 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 24-hour intervals, the expected mean trough concentration is approximately 50% 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 these patients administration of theophylline may be required more frequently (every 12 hours).

CONTRAINDICATIONS SECTION.


CONTRAINDICATIONS Theophylline (Anhydrous) Extended-Release Tablets 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; 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). (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 ).