THEOPHYLLINE- theophylline anhydrous_tablet, extended release

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). 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.
Serum Concentration-Effect Relationship
Bronchodilation occurs over the serum theophylline concentration range of 5 to 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.
Pharmacokinetics
Theophylline is rapidly and completely absorbed after oral administration in solution or immediate-release solid oral dosage form. Theophylline does not undergo any appreciable presystemic 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 Table II PRECAUTIONS, Laboratory Tests Table I. Mean and range of total body clearance and half-life of theophylline related to age and altered physiological states. For various North American patient populations from literature reports. Different rates of elimination and consequent dosage requirements have been observed among other peoples. Population Characteristics Total body clearance 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 <20 mcg/mL; clearance may decrease and half-life may increase at higher serum concentrations due to non-linear pharmacokinetics. Reported range or estimated range (mean 2 SD) where actual range not reported. Half-life mean (range Age Premature neonates postnatal age 3 to 15 days 0. 49) 30 (17 to 43) postnatal age 25 to 57 days 0. 6) Term infants postnatal age 1 to 2 days NR NR = not reported or not reported in a comparable format. 7 (25 to 26. 5) postnatal age 3 to 30 weeks NR 11 (6 to 29) Children 1 to 4 years 1. 6) 4 to 12 years 1. 4) NR 13 to 15 years 0. 3) NR 16 to 17 years 1. 9) Adults (16 to 60 years) otherwise healthy non-smoking asthmatics 0. 8) Elderly (>60 years) non-smokers with normal cardiac, liver, and renal function 0. 6 to 18) Concurrent illness or altered physiological state Acute pulmonary edema 0. 33 Median 19 COPD->60 years, stable non-smoker > 1 year 0. 6) COPD with cor pulmonale 0. 88) NR Cystic fibrosis (14 to 28 years) 1. 2) Fever associated with acute viral respiratory illness (children 9 to 15 years) NR 7. 0 to 13) Liver disease-cirrhosis 0. 31 32 acute hepatitis 0. 8) cholestasis 0. 8) Pregnancy-1 st NR 8. 9) 2 nd NR 8. 8) 3 rd NR 13. 6) Sepsis with multi-organ failure 0. 1) Thyroid disease-hypothyroid 0. 2 to 25) hyperthyroid 0. 6) NOTE: Theophylline is rapidly and completely absorbed after oral administration in solution or immediate-release solid oral dosage form. After a single dose immediate release theophylline of 5 mg/kg in adults, a mean peak serum concentration of about 10 mcg/mL (range 5 to 15 mcg/mL) can be expected 1 to 2 hour after the 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. A single-dose crossover study was conducted in twelve healthy male volunteers to compare pharmacokinetic parameters when Theophylline Extended-Release Tablets were administered with and without food. Subjects were fasted overnight and received a single 300 mg tablet early the following morning. When dosing was done under fed conditions, the subjects received a standard breakfast consisting of 2 fried eggs, 2 strips of bacon, 4 oz. hash brown potatoes, 1 slice of toast with a pat of butter, and 8 oz. whole milk 15 minutes pre-dosing. No food was allowed for five hours post-dosing, then a standard lunch was served; at ten hours post-dosing a standard supper was served. Mean peak theophylline serum levels for the two treatments were 3. 7 mcg/mL (fasting) and 4. 4 mcg/mL (with food). The time of peak serum level varied from subject to subject, occurring from 4 to 14 hours after dosing. However, 92% of the subjects had serum levels at least 75% of the maximum value at 4 to 8 hours after dosing, during each phase. Thus, blood samples taken 4 to 8 hours post-dosing should reference the peak serum level for most patients. The mean T max (0-inf. ) A multiple-dose, steady-state study was conducted under fed conditions. Three high fat content meals were served at 6:30 a. , 12 noon, and 6:30 p. Nineteen normal subjects were dosed at 300 mg every 12 hours (7 p. ) for eight doses. Dosing began one-half hour after the evening meal with the test dose occurring one-half hour after breakfast. At steady-state, the mean peak concentration was 8. 8 mcg/mL and the mean trough concentration was 5. The time of peak concentration (T max max min min The subjects used for this study exhibited a mean half-life of 8. 3 hours (range 5. 2) and mean clearance of 3. 5 L/hour (range 2. 6) as determined in a separate single-dose clearance study using 500 mg of immediate-release theophylline, prior to this multiple-dose study. A multiple-dose, steady-state study was conducted under fed conditions with once-a-day dosing. Fed conditions were the same as those previously cited. Sixteen subjects were dosed as 2 × 300 mg tablets every morning at 8 a. for five doses. At steady-state, the mean C max min max The subjects used in the above study exhibited a mean half-life of 7. 9 hours (range 5. 4) and a mean clearance of 3. 8 L/hour (range 2. 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. 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 to 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 to 12 mcg/mL. 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- methyl-xanthine 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 <1 mcg/mL. In patients with end-stage renal disease, 3-methylxanthine may accumulate to concentrations that approximate the unmetabolized theophylline concentration. Caffeine concentrations are usually undetectable in adults regardless of renal function. In neonates, caffeine may accumulate to concentrations that approximate the unmetabolized theophylline concentration and thus, exert a pharmacologic effect. Both the N-demethylation and hydroxylation pathways of theophylline biotransformation are capacity-limited. Due to the wide intersubject variability of the rate of theophylline metabolism, non-linearity of elimination may begin in some patients at serum theophylline concentrations >10 mcg/mL. Since this non-linearity results in more than proportional changes in serum theophylline concentrations with changes in dose, it is advisable to make increases or decreases in dose in small increments in order to achieve desired changes in serum theophylline concentrations (see DOSAGE AND ADMINISTRATION, Table VI a priori In neonates, approximately 50% of the theophylline dose is excreted unchanged in the urine. Beyond the first three months of life, approximately 10% of the theophylline dose is excreted unchanged in the urine. The remainder is excreted in the urine mainly as 1,3-dimethyluric acid (35 to 40%), 1-methyluric acid (20 to 25%) and 3-methylxanthine (15 to 20%). Since little theophylline is excreted unchanged in the urine and since active metabolites of theophylline (i. , 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, 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 After multiple doses of theophylline, steady-state is reached in 30 to 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 to 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 to 12 hours) with a smaller peak/trough difference. (see Table I 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 The clearance of theophylline is very low in neonates (see WARNINGS WARNINGS DOSAGE AND ADMINISTRATION 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. Pharmacokinetic differences in theophylline clearance due to race have not been studied. Only a small fraction, e. , about 10%, of the administered theophylline dose is excreted unchanged in the urine of children greater than three months of age and adults. 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 Theophylline clearance is decreased by 50% or more in patients with hepatic insufficiency (e. , 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 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 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 nonsmoking 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 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. , those who require a dose that is substantially larger than average [e. , >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 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.
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 presystemic 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 Table II PRECAUTIONS, Laboratory Tests Table I. Mean and range of total body clearance and half-life of theophylline related to age and altered physiological states. For various North American patient populations from literature reports. Different rates of elimination and consequent dosage requirements have been observed among other peoples. Population Characteristics Total body clearance 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 <20 mcg/mL; clearance may decrease and half-life may increase at higher serum concentrations due to non-linear pharmacokinetics. Reported range or estimated range (mean 2 SD) where actual range not reported. Half-life mean (range Age Premature neonates postnatal age 3 to 15 days 0.29 (0.09 to 0.49) 30 (17 to 43) postnatal age 25 to 57 days 0.64 (0.04 to 1.2) 20 (9.4 to 30.6) Term infants postnatal age 1 to 2 days NR NR = not reported or not reported in a comparable format. 25.7 (25 to 26.5) postnatal age 3 to 30 weeks NR 11 (6 to 29) Children 1 to 4 years 1.7 (0.5 to 2.9) 3.4 (1.2 to 5.6) 4 to 12 years 1.6 (0.8 to 2.4) NR 13 to 15 years 0.9 (0.48 to 1.3) NR 16 to 17 years 1.4 (0.2 to 2.6) 3.7 (1.5 to 5.9) Adults (16 to 60 years) otherwise healthy non-smoking asthmatics 0.65 (0.27 to 1.03) 8.7 (6.1 to 12.8) Elderly (>60 years) non-smokers with normal cardiac, liver, and renal function 0.41 (0.21 to 0.61) 9.8 (1.6 to 18) Concurrent illness or altered physiological state Acute pulmonary edema 0.33 Median 19 COPD->60 years, stable non-smoker > 1 year 0.54 (0.44 to 0.64) 11 (9.4 to 12.6) COPD with cor pulmonale 0.48 (0.08 to 0.88) NR Cystic fibrosis (14 to 28 years) 1.25 (0.31 to 2.2) 6.0 (1.8 to 10.2) Fever associated with acute viral respiratory illness (children 9 to 15 years) NR 7.0 (1.0 to 13) Liver disease-cirrhosis 0.31 32 acute hepatitis 0.35 (0.25 to 0.45) 19.2 (16.6 to 21.8) cholestasis 0.65 (0.25 to 1.45) 14.4 (5.7 to 31.8) Pregnancy-1 st NR 8.5 (3.1 to 13.9) 2 nd NR 8.8 (3.8 to 13.8) 3 rd NR 13.0 (8.4 to 17.6) Sepsis with multi-organ failure 0.47 (0.19 to 1.9) 18.8 (6.3 to 24.1) Thyroid disease-hypothyroid 0.38 (0.13 to 0.57) 11.6 (8.2 to 25) hyperthyroid 0.8 (0.68 to 0.97) 4.5 (3.7 to 5.6) NOTE:
Absorption
Theophylline is rapidly and completely absorbed after oral administration in solution or immediate-release solid oral dosage form. After a single dose immediate release theophylline of 5 mg/kg in adults, a mean peak serum concentration of about 10 mcg/mL (range 5 to 15 mcg/mL) can be expected 1 to 2 hour after the 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. A single-dose crossover study was conducted in twelve healthy male volunteers to compare pharmacokinetic parameters when Theophylline Extended-Release Tablets were administered with and without food. Subjects were fasted overnight and received a single 300 mg tablet early the following morning. When dosing was done under fed conditions, the subjects received a standard breakfast consisting of 2 fried eggs, 2 strips of bacon, 4 oz. hash brown potatoes, 1 slice of toast with a pat of butter, and 8 oz. whole milk 15 minutes pre-dosing. No food was allowed for five hours post-dosing, then a standard lunch was served; at ten hours post-dosing a standard supper was served. Mean peak theophylline serum levels for the two treatments were 3. 7 mcg/mL (fasting) and 4. 4 mcg/mL (with food). The time of peak serum level varied from subject to subject, occurring from 4 to 14 hours after dosing. However, 92% of the subjects had serum levels at least 75% of the maximum value at 4 to 8 hours after dosing, during each phase. Thus, blood samples taken 4 to 8 hours post-dosing should reference the peak serum level for most patients. The mean T max (0-inf. ) A multiple-dose, steady-state study was conducted under fed conditions. Three high fat content meals were served at 6:30 a. , 12 noon, and 6:30 p. Nineteen normal subjects were dosed at 300 mg every 12 hours (7 p. ) for eight doses. Dosing began one-half hour after the evening meal with the test dose occurring one-half hour after breakfast. At steady-state, the mean peak concentration was 8. 8 mcg/mL and the mean trough concentration was 5. The time of peak concentration (T max max min min The subjects used for this study exhibited a mean half-life of 8. 3 hours (range 5. 2) and mean clearance of 3. 5 L/hour (range 2. 6) as determined in a separate single-dose clearance study using 500 mg of immediate-release theophylline, prior to this multiple-dose study. A multiple-dose, steady-state study was conducted under fed conditions with once-a-day dosing. Fed conditions were the same as those previously cited. Sixteen subjects were dosed as 2 × 300 mg tablets every morning at 8 a. for five doses. At steady-state, the mean C max min max The subjects used in the above study exhibited a mean half-life of 7. 9 hours (range 5. 4) and a mean clearance of 3. 8 L/hour (range 2.
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 to 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 to 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 to 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- methyl-xanthine 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 <1 mcg/mL. In patients with end-stage renal disease, 3-methylxanthine may accumulate to concentrations that approximate the unmetabolized theophylline concentration. Caffeine concentrations are usually undetectable in adults regardless of renal function. In neonates, caffeine may accumulate to concentrations that approximate the unmetabolized theophylline concentration and thus, exert a pharmacologic effect. Both the N-demethylation and hydroxylation pathways of theophylline biotransformation are capacity-limited. Due to the wide intersubject variability of the rate of theophylline metabolism, non-linearity of elimination may begin in some patients at serum theophylline concentrations >10 mcg/mL. Since this non-linearity results in more than proportional changes in serum theophylline concentrations with changes in dose, it is advisable to make increases or decreases in dose in small increments in order to achieve desired changes in serum theophylline concentrations (see DOSAGE AND ADMINISTRATION, Table VI a priori
Excretion
In neonates, approximately 50% of the theophylline dose is excreted unchanged in the urine. Beyond the first three months of life, approximately 10% of the theophylline dose is excreted unchanged in the urine. The remainder is excreted in the urine mainly as 1,3-dimethyluric acid (35 to 40%), 1-methyluric acid (20 to 25%) and 3-methylxanthine (15 to 20%). 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, 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 to 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 to 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 to 12 hours) with a smaller peak/trough difference.
Effects on Laboratory Tests
As a result of its pharmacological effects, theophylline at serum concentrations within the 10 to 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 µEq/L to 800 µEq/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 to 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.">CLINICAL PHARMACOLOGY
Theophylline has two distinct actions in the airways of patients with reversible obstruction; smooth muscle relaxation (i. , bronchodilation) and suppression of the response of the airways to stimuli (i. , 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. , hypotension, tachycardia, headache, and emesis) and adenosine receptor antagonism (e. , 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. Bronchodilation occurs over the serum theophylline concentration range of 5 to 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. Theophylline is rapidly and completely absorbed after oral administration in solution or immediate-release solid oral dosage form. Theophylline does not undergo any appreciable presystemic 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 Table II PRECAUTIONS, Laboratory Tests Table I. Mean and range of total body clearance and half-life of theophylline related to age and altered physiological states. For various North American patient populations from literature reports. Different rates of elimination and consequent dosage requirements have been observed among other peoples. Population Characteristics Total body clearance 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 <20 mcg/mL; clearance may decrease and half-life may increase at higher serum concentrations due to non-linear pharmacokinetics. Reported range or estimated range (mean 2 SD) where actual range not reported. Half-life mean (range Age Premature neonates postnatal age 3 to 15 days 0. 49) 30 (17 to 43) postnatal age 25 to 57 days 0. 6) Term infants postnatal age 1 to 2 days NR NR = not reported or not reported in a comparable format. 7 (25 to 26. 5) postnatal age 3 to 30 weeks NR 11 (6 to 29) Children 1 to 4 years 1. 6) 4 to 12 years 1. 4) NR 13 to 15 years 0. 3) NR 16 to 17 years 1. 9) Adults (16 to 60 years) otherwise healthy non-smoking asthmatics 0. 8) Elderly (>60 years) non-smokers with normal cardiac, liver, and renal function 0. 6 to 18) Concurrent illness or altered physiological state Acute pulmonary edema 0. 33 Median 19 COPD->60 years, stable non-smoker > 1 year 0. 6) COPD with cor pulmonale 0. 88) NR Cystic fibrosis (14 to 28 years) 1. 2) Fever associated with acute viral respiratory illness (children 9 to 15 years) NR 7. 0 to 13) Liver disease-cirrhosis 0. 31 32 acute hepatitis 0. 8) cholestasis 0. 8) Pregnancy-1 st NR 8. 9) 2 nd NR 8. 8) 3 rd NR 13. 6) Sepsis with multi-organ failure 0. 1) Thyroid disease-hypothyroid 0. 2 to 25) hyperthyroid 0. 6) NOTE: Theophylline is rapidly and completely absorbed after oral administration in solution or immediate-release solid oral dosage form. After a single dose immediate release theophylline of 5 mg/kg in adults, a mean peak serum concentration of about 10 mcg/mL (range 5 to 15 mcg/mL) can be expected 1 to 2 hour after the 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. A single-dose crossover study was conducted in twelve healthy male volunteers to compare pharmacokinetic parameters when Theophylline Extended-Release Tablets were administered with and without food. Subjects were fasted overnight and received a single 300 mg tablet early the following morning. When dosing was done under fed conditions, the subjects received a standard breakfast consisting of 2 fried eggs, 2 strips of bacon, 4 oz. hash brown potatoes, 1 slice of toast with a pat of butter, and 8 oz. whole milk 15 minutes pre-dosing. No food was allowed for five hours post-dosing, then a standard lunch was served; at ten hours post-dosing a standard supper was served. Mean peak theophylline serum levels for the two treatments were 3. 7 mcg/mL (fasting) and 4. 4 mcg/mL (with food). The time of peak serum level varied from subject to subject, occurring from 4 to 14 hours after dosing. However, 92% of the subjects had serum levels at least 75% of the maximum value at 4 to 8 hours after dosing, during each phase. Thus, blood samples taken 4 to 8 hours post-dosing should reference the peak serum level for most patients. The mean T max (0-inf. ) A multiple-dose, steady-state study was conducted under fed conditions. Three high fat content meals were served at 6:30 a. , 12 noon, and 6:30 p. Nineteen normal subjects were dosed at 300 mg every 12 hours (7 p. ) for eight doses. Dosing began one-half hour after the evening meal with the test dose occurring one-half hour after breakfast. At steady-state, the mean peak concentration was 8. 8 mcg/mL and the mean trough concentration was 5. The time of peak concentration (T max max min min The subjects used for this study exhibited a mean half-life of 8. 3 hours (range 5. 2) and mean clearance of 3. 5 L/hour (range 2. 6) as determined in a separate single-dose clearance study using 500 mg of immediate-release theophylline, prior to this multiple-dose study. A multiple-dose, steady-state study was conducted under fed conditions with once-a-day dosing. Fed conditions were the same as those previously cited. Sixteen subjects were dosed as 2 × 300 mg tablets every morning at 8 a. for five doses. At steady-state, the mean C max min max The subjects used in the above study exhibited a mean half-life of 7. 9 hours (range 5. 4) and a mean clearance of 3. 8 L/hour (range 2. 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. 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 to 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 to 12 mcg/mL. 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- methyl-xanthine 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 <1 mcg/mL. In patients with end-stage renal disease, 3-methylxanthine may accumulate to concentrations that approximate the unmetabolized theophylline concentration. Caffeine concentrations are usually undetectable in adults regardless of renal function. In neonates, caffeine may accumulate to concentrations that approximate the unmetabolized theophylline concentration and thus, exert a pharmacologic effect. Both the N-demethylation and hydroxylation pathways of theophylline biotransformation are capacity-limited. Due to the wide intersubject variability of the rate of theophylline metabolism, non-linearity of elimination may begin in some patients at serum theophylline concentrations >10 mcg/mL. Since this non-linearity results in more than proportional changes in serum theophylline concentrations with changes in dose, it is advisable to make increases or decreases in dose in small increments in order to achieve desired changes in serum theophylline concentrations (see DOSAGE AND ADMINISTRATION, Table VI a priori In neonates, approximately 50% of the theophylline dose is excreted unchanged in the urine. Beyond the first three months of life, approximately 10% of the theophylline dose is excreted unchanged in the urine. The remainder is excreted in the urine mainly as 1,3-dimethyluric acid (35 to 40%), 1-methyluric acid (20 to 25%) and 3-methylxanthine (15 to 20%). Since little theophylline is excreted unchanged in the urine and since active metabolites of theophylline (i. , 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, 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 After multiple doses of theophylline, steady-state is reached in 30 to 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 to 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 to 12 hours) with a smaller peak/trough difference. (see Table I 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 The clearance of theophylline is very low in neonates (see WARNINGS WARNINGS DOSAGE AND ADMINISTRATION 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. Pharmacokinetic differences in theophylline clearance due to race have not been studied. Only a small fraction, e. , about 10%, of the administered theophylline dose is excreted unchanged in the urine of children greater than three months of age and adults. 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 Theophylline clearance is decreased by 50% or more in patients with hepatic insufficiency (e. , 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 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 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 nonsmoking 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 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. , those who require a dose that is substantially larger than average [e. , >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 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 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.
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). 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.
Serum Concentration-Effect Relationship
Bronchodilation occurs over the serum theophylline concentration range of 5 to 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.
Pharmacokinetics
Theophylline is rapidly and completely absorbed after oral administration in solution or immediate-release solid oral dosage form. Theophylline does not undergo any appreciable presystemic 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 Table II PRECAUTIONS, Laboratory Tests Table I. Mean and range of total body clearance and half-life of theophylline related to age and altered physiological states. For various North American patient populations from literature reports. Different rates of elimination and consequent dosage requirements have been observed among other peoples. Population Characteristics Total body clearance 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 <20 mcg/mL; clearance may decrease and half-life may increase at higher serum concentrations due to non-linear pharmacokinetics. Reported range or estimated range (mean 2 SD) where actual range not reported. Half-life mean (range Age Premature neonates postnatal age 3 to 15 days 0. 49) 30 (17 to 43) postnatal age 25 to 57 days 0. 6) Term infants postnatal age 1 to 2 days NR NR = not reported or not reported in a comparable format. 7 (25 to 26. 5) postnatal age 3 to 30 weeks NR 11 (6 to 29) Children 1 to 4 years 1. 6) 4 to 12 years 1. 4) NR 13 to 15 years 0. 3) NR 16 to 17 years 1. 9) Adults (16 to 60 years) otherwise healthy non-smoking asthmatics 0. 8) Elderly (>60 years) non-smokers with normal cardiac, liver, and renal function 0. 6 to 18) Concurrent illness or altered physiological state Acute pulmonary edema 0. 33 Median 19 COPD->60 years, stable non-smoker > 1 year 0. 6) COPD with cor pulmonale 0. 88) NR Cystic fibrosis (14 to 28 years) 1. 2) Fever associated with acute viral respiratory illness (children 9 to 15 years) NR 7. 0 to 13) Liver disease-cirrhosis 0. 31 32 acute hepatitis 0. 8) cholestasis 0. 8) Pregnancy-1 st NR 8. 9) 2 nd NR 8. 8) 3 rd NR 13. 6) Sepsis with multi-organ failure 0. 1) Thyroid disease-hypothyroid 0. 2 to 25) hyperthyroid 0. 6) NOTE: Theophylline is rapidly and completely absorbed after oral administration in solution or immediate-release solid oral dosage form. After a single dose immediate release theophylline of 5 mg/kg in adults, a mean peak serum concentration of about 10 mcg/mL (range 5 to 15 mcg/mL) can be expected 1 to 2 hour after the 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. A single-dose crossover study was conducted in twelve healthy male volunteers to compare pharmacokinetic parameters when Theophylline Extended-Release Tablets were administered with and without food. Subjects were fasted overnight and received a single 300 mg tablet early the following morning. When dosing was done under fed conditions, the subjects received a standard breakfast consisting of 2 fried eggs, 2 strips of bacon, 4 oz. hash brown potatoes, 1 slice of toast with a pat of butter, and 8 oz. whole milk 15 minutes pre-dosing. No food was allowed for five hours post-dosing, then a standard lunch was served; at ten hours post-dosing a standard supper was served. Mean peak theophylline serum levels for the two treatments were 3. 7 mcg/mL (fasting) and 4. 4 mcg/mL (with food). The time of peak serum level varied from subject to subject, occurring from 4 to 14 hours after dosing. However, 92% of the subjects had serum levels at least 75% of the maximum value at 4 to 8 hours after dosing, during each phase. Thus, blood samples taken 4 to 8 hours post-dosing should reference the peak serum level for most patients. The mean T max (0-inf. ) A multiple-dose, steady-state study was conducted under fed conditions. Three high fat content meals were served at 6:30 a. , 12 noon, and 6:30 p. Nineteen normal subjects were dosed at 300 mg every 12 hours (7 p. ) for eight doses. Dosing began one-half hour after the evening meal with the test dose occurring one-half hour after breakfast. At steady-state, the mean peak concentration was 8. 8 mcg/mL and the mean trough concentration was 5. The time of peak concentration (T max max min min The subjects used for this study exhibited a mean half-life of 8. 3 hours (range 5. 2) and mean clearance of 3. 5 L/hour (range 2. 6) as determined in a separate single-dose clearance study using 500 mg of immediate-release theophylline, prior to this multiple-dose study. A multiple-dose, steady-state study was conducted under fed conditions with once-a-day dosing. Fed conditions were the same as those previously cited. Sixteen subjects were dosed as 2 × 300 mg tablets every morning at 8 a. for five doses. At steady-state, the mean C max min max The subjects used in the above study exhibited a mean half-life of 7. 9 hours (range 5. 4) and a mean clearance of 3. 8 L/hour (range 2. 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. 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 to 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 to 12 mcg/mL. 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- methyl-xanthine 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 <1 mcg/mL. In patients with end-stage renal disease, 3-methylxanthine may accumulate to concentrations that approximate the unmetabolized theophylline concentration. Caffeine concentrations are usually undetectable in adults regardless of renal function. In neonates, caffeine may accumulate to concentrations that approximate the unmetabolized theophylline concentration and thus, exert a pharmacologic effect. Both the N-demethylation and hydroxylation pathways of theophylline biotransformation are capacity-limited. Due to the wide intersubject variability of the rate of theophylline metabolism, non-linearity of elimination may begin in some patients at serum theophylline concentrations >10 mcg/mL. Since this non-linearity results in more than proportional changes in serum theophylline concentrations with changes in dose, it is advisable to make increases or decreases in dose in small increments in order to achieve desired changes in serum theophylline concentrations (see DOSAGE AND ADMINISTRATION, Table VI a priori In neonates, approximately 50% of the theophylline dose is excreted unchanged in the urine. Beyond the first three months of life, approximately 10% of the theophylline dose is excreted unchanged in the urine. The remainder is excreted in the urine mainly as 1,3-dimethyluric acid (35 to 40%), 1-methyluric acid (20 to 25%) and 3-methylxanthine (15 to 20%). Since little theophylline is excreted unchanged in the urine and since active metabolites of theophylline (i. , 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, 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 After multiple doses of theophylline, steady-state is reached in 30 to 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 to 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 to 12 hours) with a smaller peak/trough difference. (see Table I 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 The clearance of theophylline is very low in neonates (see WARNINGS WARNINGS DOSAGE AND ADMINISTRATION 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. Pharmacokinetic differences in theophylline clearance due to race have not been studied. Only a small fraction, e. , about 10%, of the administered theophylline dose is excreted unchanged in the urine of children greater than three months of age and adults. 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 Theophylline clearance is decreased by 50% or more in patients with hepatic insufficiency (e. , 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 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 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 nonsmoking 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 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. , those who require a dose that is substantially larger than average [e. , >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 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.
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 presystemic 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 Table II PRECAUTIONS, Laboratory Tests Table I. Mean and range of total body clearance and half-life of theophylline related to age and altered physiological states. For various North American patient populations from literature reports. Different rates of elimination and consequent dosage requirements have been observed among other peoples. Population Characteristics Total body clearance 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 <20 mcg/mL; clearance may decrease and half-life may increase at higher serum concentrations due to non-linear pharmacokinetics. Reported range or estimated range (mean 2 SD) where actual range not reported. Half-life mean (range Age Premature neonates postnatal age 3 to 15 days 0.29 (0.09 to 0.49) 30 (17 to 43) postnatal age 25 to 57 days 0.64 (0.04 to 1.2) 20 (9.4 to 30.6) Term infants postnatal age 1 to 2 days NR NR = not reported or not reported in a comparable format. 25.7 (25 to 26.5) postnatal age 3 to 30 weeks NR 11 (6 to 29) Children 1 to 4 years 1.7 (0.5 to 2.9) 3.4 (1.2 to 5.6) 4 to 12 years 1.6 (0.8 to 2.4) NR 13 to 15 years 0.9 (0.48 to 1.3) NR 16 to 17 years 1.4 (0.2 to 2.6) 3.7 (1.5 to 5.9) Adults (16 to 60 years) otherwise healthy non-smoking asthmatics 0.65 (0.27 to 1.03) 8.7 (6.1 to 12.8) Elderly (>60 years) non-smokers with normal cardiac, liver, and renal function 0.41 (0.21 to 0.61) 9.8 (1.6 to 18) Concurrent illness or altered physiological state Acute pulmonary edema 0.33 Median 19 COPD->60 years, stable non-smoker > 1 year 0.54 (0.44 to 0.64) 11 (9.4 to 12.6) COPD with cor pulmonale 0.48 (0.08 to 0.88) NR Cystic fibrosis (14 to 28 years) 1.25 (0.31 to 2.2) 6.0 (1.8 to 10.2) Fever associated with acute viral respiratory illness (children 9 to 15 years) NR 7.0 (1.0 to 13) Liver disease-cirrhosis 0.31 32 acute hepatitis 0.35 (0.25 to 0.45) 19.2 (16.6 to 21.8) cholestasis 0.65 (0.25 to 1.45) 14.4 (5.7 to 31.8) Pregnancy-1 st NR 8.5 (3.1 to 13.9) 2 nd NR 8.8 (3.8 to 13.8) 3 rd NR 13.0 (8.4 to 17.6) Sepsis with multi-organ failure 0.47 (0.19 to 1.9) 18.8 (6.3 to 24.1) Thyroid disease-hypothyroid 0.38 (0.13 to 0.57) 11.6 (8.2 to 25) hyperthyroid 0.8 (0.68 to 0.97) 4.5 (3.7 to 5.6) NOTE:
Absorption
Theophylline is rapidly and completely absorbed after oral administration in solution or immediate-release solid oral dosage form. After a single dose immediate release theophylline of 5 mg/kg in adults, a mean peak serum concentration of about 10 mcg/mL (range 5 to 15 mcg/mL) can be expected 1 to 2 hour after the 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. A single-dose crossover study was conducted in twelve healthy male volunteers to compare pharmacokinetic parameters when Theophylline Extended-Release Tablets were administered with and without food. Subjects were fasted overnight and received a single 300 mg tablet early the following morning. When dosing was done under fed conditions, the subjects received a standard breakfast consisting of 2 fried eggs, 2 strips of bacon, 4 oz. hash brown potatoes, 1 slice of toast with a pat of butter, and 8 oz. whole milk 15 minutes pre-dosing. No food was allowed for five hours post-dosing, then a standard lunch was served; at ten hours post-dosing a standard supper was served. Mean peak theophylline serum levels for the two treatments were 3. 7 mcg/mL (fasting) and 4. 4 mcg/mL (with food). The time of peak serum level varied from subject to subject, occurring from 4 to 14 hours after dosing. However, 92% of the subjects had serum levels at least 75% of the maximum value at 4 to 8 hours after dosing, during each phase. Thus, blood samples taken 4 to 8 hours post-dosing should reference the peak serum level for most patients. The mean T max (0-inf. ) A multiple-dose, steady-state study was conducted under fed conditions. Three high fat content meals were served at 6:30 a. , 12 noon, and 6:30 p. Nineteen normal subjects were dosed at 300 mg every 12 hours (7 p. ) for eight doses. Dosing began one-half hour after the evening meal with the test dose occurring one-half hour after breakfast. At steady-state, the mean peak concentration was 8. 8 mcg/mL and the mean trough concentration was 5. The time of peak concentration (T max max min min The subjects used for this study exhibited a mean half-life of 8. 3 hours (range 5. 2) and mean clearance of 3. 5 L/hour (range 2. 6) as determined in a separate single-dose clearance study using 500 mg of immediate-release theophylline, prior to this multiple-dose study. A multiple-dose, steady-state study was conducted under fed conditions with once-a-day dosing. Fed conditions were the same as those previously cited. Sixteen subjects were dosed as 2 × 300 mg tablets every morning at 8 a. for five doses. At steady-state, the mean C max min max The subjects used in the above study exhibited a mean half-life of 7. 9 hours (range 5. 4) and a mean clearance of 3. 8 L/hour (range 2.
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 to 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 to 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 to 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- methyl-xanthine 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 <1 mcg/mL. In patients with end-stage renal disease, 3-methylxanthine may accumulate to concentrations that approximate the unmetabolized theophylline concentration. Caffeine concentrations are usually undetectable in adults regardless of renal function. In neonates, caffeine may accumulate to concentrations that approximate the unmetabolized theophylline concentration and thus, exert a pharmacologic effect. Both the N-demethylation and hydroxylation pathways of theophylline biotransformation are capacity-limited. Due to the wide intersubject variability of the rate of theophylline metabolism, non-linearity of elimination may begin in some patients at serum theophylline concentrations >10 mcg/mL. Since this non-linearity results in more than proportional changes in serum theophylline concentrations with changes in dose, it is advisable to make increases or decreases in dose in small increments in order to achieve desired changes in serum theophylline concentrations (see DOSAGE AND ADMINISTRATION, Table VI a priori
Excretion
In neonates, approximately 50% of the theophylline dose is excreted unchanged in the urine. Beyond the first three months of life, approximately 10% of the theophylline dose is excreted unchanged in the urine. The remainder is excreted in the urine mainly as 1,3-dimethyluric acid (35 to 40%), 1-methyluric acid (20 to 25%) and 3-methylxanthine (15 to 20%). 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, 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 to 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 to 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 to 12 hours) with a smaller peak/trough difference.
Effects on Laboratory Tests
As a result of its pharmacological effects, theophylline at serum concentrations within the 10 to 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 µEq/L to 800 µEq/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 to 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.

Theophylline Extended-Release Tablets are 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.

Once-a-Day Dosing
A multiple-dose, steady-state study was conducted under fed conditions with once-a-day dosing. Fed conditions were the same as those previously cited. Sixteen subjects were dosed as 2 × 300 mg tablets every morning at 8 a.m. for five doses. At steady-state, the mean C max min max The subjects used in the above study exhibited a mean half-life of 7.9 hours (range 5.3 to 13.4) and a mean clearance of 3.8 L/hour (range 2.3 to 5.7).
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 beta-2 -selective agonists and systemically administered cortico-steroids 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
DOSAGE AND ADMINISTRATION
Taking Theophylline Extended-Release Tablets immediately after a high-fat content meal may result in a somewhat higher C max max CLINICAL PHARMACOLOGY PRECAUTIONS, Drug interactions, Drug-Food Interactions Theophylline Extended-Release Tablets are recommended for chronic or long-term management and prevention of symptoms, and not for use in treating acute symptoms of asthma and reversible bronchospasm. The steady-state peak serum theophylline concentration is a function of the dose, the dosing interval, and the rate of theophylline absorption and clearance in the individual patient. Because of marked individual differences in the rate of theophylline clearance, the dose required to achieve a peak serum theophylline concentration in the 10 to 20 mcg/mL range varies fourfold among otherwise similar patients in the absence of factors known to alter theophylline clearance (e. , 400 to 1600 mg/day in adults <60 years old and 10 to 36 mg/kg/day in children 1 to 9 years old). For a given population there is no single theophylline dose that will provide both safe and effective serum concentrations for all patients. Administration of the median theophylline dose required to achieve a therapeutic serum theophylline concentration in a given population may result in either sub-therapeutic or potentially toxic serum theophylline concentrations in individual patients. For example, at a dose of 900 mg/d in adults <60 years or 22 mg/kg/d in children 1 to 9 years, the steady-state peak serum theophylline concentration will be <10 mcg/mL in about 30% of patients, 10 to 20 mcg/mL in about 50% and 20 to 30 mcg/mL in about 20% of patients. The dose of theophylline must be individualized on the basis of peak serum theophylline concentration measurements in order to achieve a dose that will provide maximum potential benefit with minimal risk of adverse effects. Transient caffeine-like adverse effects and excessive serum concentrations in slow metabolizers can be avoided in most patients by starting with a sufficiently low dose and slowly increasing the dose, if judged to be clinically indicated Table V PRECAUTIONS, Laboratory Tests DOSAGE AND ADMINISTRATION, Table VI WARNINGS. If the patient''s symptoms are well controlled, there are no apparent adverse effects, and no intervening factors that might alter dosage requirements (see WARNINGS PRECAUTIONS , Theophylline distributes poorly into body fat; therefore, mg/kg dose should be calculated on the basis of ideal body weight. Table V contains theophylline dosing titration schema recommended for patients in various age groups and clinical circumstances. Table VI contains recommendations for theophylline dosage adjustment based upon serum theophylline concentrations. Application of these general dosing recommendations to individual patients must take into account the unique clinical characteristics of each patient. In general, these recommendations should serve as the upper limit for dosage adjustments in order to decrease the risk of potentially serious adverse events associated with unexpected large increases in serum theophylline concentration. Dosing initiation and titration (as anhydrous theophylline) Patients with more rapid metabolism, clinically identified by higher than average dose requirements, should receive a smaller dose more frequently (every 8 hours) to prevent breakthrough symptoms resulting from low trough concentrations before the next dose. Children (6 to 15 years) and adults (16 to 60 years) without risk factors for impaired clearance. Titration Step Children <45 kg Children >45 kg and adults 1 Starting Dosage 12 to 14 mg/kg/day up to a maximum of 300 mg/day divided Q12 hrs 300 mg/day divided Q12 hrs 2 After 3 days, if tolerated, 16 mg/kg/day up to a maximum of 400 mg/day divided Q12 hrs 400 mg/day divided Q12 hrs 3 After 3 more days, if tolerated, 20 mg/kg/day up to a maximum of 600 mg/day divided Q12 hrs 600 mg/day divided Q12 hrs 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 6 to 15 years of age, the final theophylline dose should not exceed 16 mg/kg/day up to a maximum of 400 mg/day in the presence of risk factors for reduced theophylline clearance (see WARNINGS WARNINGS Table VI. Dosage adjustment guided by serum theophylline concentration. Peak Serum Concentration Dosage Adjustment <9. 9 mcg/mL If symptoms are not 10 to 14. 9 mcg/mL If symptoms are controlled and current dosage is tolerated, maintain dose and recheck serum concentration at 6 to 12 month intervals. Dose reduction and/or serum theophylline concentration measurement is indicated whenever adverse effects are present, physiologic abnormalities that can reduce theophylline clearance occur (e. sustained fever), or a drug that interacts with theophylline is added or discontinued (see WARNINGS If symptoms are not controlled and current dosage is tolerated, consider adding additional medication(s) to treatment regimen. 9 mcg/mL Consider 10% decrease in dose to provide greater margin of safety even if current dosage is tolerated. 9 mcg/mL Decrease dose by 25% even if no adverse effects are present. Recheck serum concentration after 3 days to guide further dosage adjustment. 25 to 30 mcg/mL Skip next dose and decrease subsequent doses at least 25% even if no adverse effects are present. If symptomatic, consider whether overdose treatment is indicated (see recommendations for chronic overdosage >30 mcg/mL Treat overdose as indicated (see recommendations for chronic overdosage The slow absorption rate of this preparation may allow once-daily administration in adult non-smokers with appropriate total body clearance and other patients with low dosage requirements. Once-daily dosing should be considered only after the patient has been gradually and satisfactorily titrated to therapeutic levels with q12h dosing. Once-daily dosing should be based on twice the q12h dose and should be initiated at the end of the last q12h dosing interval. The trough concentration (C min max It is essential that serum theophylline concentrations be monitored before and after transfer to once-daily dosing. 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 theophylline extended-release once-daily dosing be administered at night.
Once-Daily Dosing
The slow absorption rate of this preparation may allow once-daily administration in adult non-smokers with appropriate total body clearance and other patients with low dosage requirements. Once-daily dosing should be considered only after the patient has been gradually and satisfactorily titrated to therapeutic levels with q12h dosing. Once-daily dosing should be based on twice the q12h dose and should be initiated at the end of the last q12h dosing interval. The trough concentration (C min max It is essential that serum theophylline concentrations be monitored before and after transfer to once-daily dosing. 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 theophylline extended-release once-daily dosing be administered at night.

Adverse reactions associated with theophylline are generally mild when peak serum theophylline concentrations are <20 mcg/mL and mainly consist of transient caffeine-like adverse effects such as nausea, vomiting, headache, and insomnia. When peak serum theophylline concentrations exceed 20 mcg/mL, however, theophylline produces a wide range of adverse reactions including persistent vomiting, cardiac arrhythmias, and intractable seizures which can be lethal (see OVERDOSAGE DOSAGE AND ADMINISTRATION, Table V Other adverse reactions that have been reported at serum theophylline concentrations <20 mcg/mL include diarrhea, irritability, restlessness, fine skeletal muscle tremors, and transient diuresis. In patients with hypoxia secondary to COPD, multifocal atrial tachycardia and flutter have been reported at serum theophylline concentrations >=15 mcg/mL. There have been a few isolated reports of seizures at serum theophylline concentrations <20 mcg/mL in patients with an underlying neurological disease or in elderly patients. The occurrence of seizures in elderly patients with serum theophylline concentrations <20 mcg/mL may be secondary to decreased protein binding resulting in a larger proportion of the total serum theophylline concentration in the pharmacologically active unbound form. The clinical characteristics of the seizures reported in patients with serum theophylline concentrations <20 mcg/mL have generally been milder than seizures associated with excessive serum theophylline concentrations resulting from an overdose (i.e. they have generally been transient, often stopped without anticonvulsant therapy, and did not result in neurological residua). Table IV. Manifestations of theophylline toxicity. These data are derived from two studies in patients with serum theophylline concentrations >30 mcg/mL. In the first study (Study #1-Shanon, Ann Intern Med 1993;119:1161 - 67), data were prospectively collected from 249 consecutive cases of theophylline toxicity referred to a regional poison center for consultation. In the second study (Study #2-Sessler, Am J Med 1990;88:567 - 76), data were retrospectively collected from 116 cases with serum theophylline concentrations >30 mcg/mL among 6000 blood samples obtained for measurement of serum theophylline concentrations in three emergency departments. Differences in the incidence of manifestations of theophylline toxicity between the two studies may reflect sample selection as a result of study design (e.g., in Study #1, 48% of the patients had acute intoxications versus only 10% in Study #2) and different methods of reporting results. Percentage of patients reported with sign or symptom Acute Overdose Chronic Overdosage (Large Single Ingestion) (Multiple Excessive Doses) Sign/Symptom Study 1 Study 2 Study 1 Study 2 (n=157) (n=14) (n=92) (n=102) Asymptomatic NR NR=Not reported in a comparable manner. 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 9 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

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

Special Populations
(see Table I 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 The clearance of theophylline is very low in neonates (see WARNINGS WARNINGS DOSAGE AND ADMINISTRATION 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. Pharmacokinetic differences in theophylline clearance due to race have not been studied. Only a small fraction, e. , 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. , 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 Theophylline clearance is decreased by 50% or more in patients with hepatic insufficiency (e. , 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 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 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 nonsmoking 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 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. , those who require a dose that is substantially larger than average [e. , >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 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.
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 WARNINGS 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
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 nonsmoking 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
Pregnancy
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/m 2 2 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/m 2 2 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/m 2 2 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 to 20 mcg/mL of theophylline per day is likely to receive 10 to 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. The maintenance dose of theophylline must be selected with caution in pediatric patients since the rate of theophylline clearance is highly variable across the pediatric age range (see CLINICAL PHARMACOLOGY, Table I WARNINGS DOSAGE AND ADMINISTRATION, Table V
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 ( > PRECAUTIONS: Drug Interactions PRECAUTIONS, Monitoring Serum Theophylline Concentrations DOSAGE AND ADMINISTRATION DOSAGE AND ADMINISTRATION

=600 mg/day. 25% increase Aminoglutethimide Increases theophylline clearance by induction of microsomal enzyme activity. 25% decrease Carbamazepine Similar to aminoglutethimide. 30% decrease Cimetidine Decreases theophylline clearance by inhibiting cytochrome P450 1A2. 70% increase Ciprofloxacin Similar to cimetidine. 40% increase Clarithromycin Similar to erythromycin. 25% increase Diazepam Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors. Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression. Disulfiram Decreases theophylline clearance by inhibiting hydroxylation and demethylation. 50% increase Enoxacin Similar to cimetidine. 300% increase Ephedrine Synergistic CNS effects. Increased frequency of nausea, nervousness, and insomnia. Erythromycin Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3. 35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount. Estrogen Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown. 30% increase Flurazepam Similar to diazepam. Similar to diazepam. Fluvoxamine Similar to cimetidine. Similar to cimetidine. Halothane Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines. Increased risk of ventricular arrhythmias. Interferon, human recombinant alpha-A Decreases theophylline clearance. 100% increase Isoproterenol (IV) Increases theophylline clearance. 20% decrease Ketamine Pharmacologic. May lower theophylline seizure threshold Lithium Theophylline increases renal lithium clearance. Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%. Lorazepam Similar to diazepam. Methotrexate (MTX) Decreases theophylline clearance. 20% increase after low dose MTX, higher dose MTX may have a greater effect. Mexiletine Similar to disulfiram. 80% increase Midazolam Similar to diazepam. Moricizine Increases theophylline clearance. 25% decrease Pancuronium Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition. Larger dose of pancuronium may be required to achieve neuromuscular blockade. Pentoxifylline Decreases theophylline clearance. 30% increase Phenobarbital (PB) Similar to aminoglutethimide. 25% decrease after two weeks of concurrent PB. Phenytoin Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption. Serum theophylline and Propafenone Decreases theophylline clearance and pharmacologic interaction. 40% increase. Beta-2 blocking effect may decrease efficacy of theophylline. Propranolol Similar to cimetidine and pharmacologic interaction. 100% increase. Rifampin Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity. 20 to 40% decrease St. John''s Wort (Hypericum Perforatum) Decrease in theophylline plasma concentrations. Higher doses of theophylline may be required to achieve desired effect. Stopping St. John''s Wort may result in theophylline toxicity. Sulfinpyrazone Increase theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline. 20% decrease Tacrine Similar to cimetidine, also increases renal clearance of theophylline. 90% increase Thiabendazole Decreases theophylline clearance. 190% increase Ticlopidine Decreases theophylline clearance. 60% increase Troleandomycin Similar to erythromycin. 33 to 100% increase depending on troleandomycin dose. Verapamil Similar to disulfiram. 20% increase TABLE III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline. Refer to PRECAUTIONS, Drug Interactions for information regarding table. albuterol, systemic and inhaled mebendazole amoxicillin medroxyprogesterone ampicillin, with or without sulbactam methylprednisolone metronidazole atenolol metoprolol azithromycin nadolol caffeine, dietary ingestion nifedipine cefaclor nizatidine co-trimoxazole (trimethoprim and sulfamethoxazole) norfloxacin ofloxacin diltiazem omeprazole dirithromycin prednisone, prednisolone enflurane ranitidine famotidine rifabutin felodipine roxithromycin finasteride Sorbitol (purgative doses do not inhibit theophylline absorption) hydrocortisone isoflurane sucralfate isoniazid terbutaline, systemic isradipine terfenadine influenza vaccine tetracycline ketoconazole tocainide lomefloxacin Taking Theophylline Extended-Release Tablets immediately after ingesting a high fat content meal (45 g fat, 55 g carbohydrates, 28 g protein, 789 calories) may result in a somewhat higher C max max 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. 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.
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. The drugs listed in Table II have the potential to produce clinically significant pharmacodynamic or pharmacokinetic interactions with theophylline. The information in the "Effect" column of Table II assumes that the interacting drug is being added to a steady-state theophylline regimen. If theophylline is being initiated in a patient who is already taking a drug that inhibits theophylline clearance (e.g., cimetidine, erythromycin), the dose of theophylline required to achieve a therapeutic serum theophylline concentration will be smaller. Conversely, if theophylline is being initiated in a patient who is already taking a drug that enhances theophylline clearance (e.g., rifampin), the dose of theophylline required to achieve a therapeutic serum theophylline concentration will be larger. Discontinuation of a concomitant drug that increases theophylline clearance will result in accumulation of theophylline to potentially toxic levels, unless the theophylline dose is appropriately reduced. Discontinuation of a concomitant drug that inhibits theophylline clearance will result in decreased serum theophylline concentrations, unless the theophylline dose is appropriately increased. The drugs listed in Table III have either been documented not to interact with theophylline or do not produce a clinically significant interaction (i.e., <15% change in theophylline clearance). The listing of drugs in Tables II and III are current as of February 9, 1995. 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 TABLE II. Clinically significant drug interactions with theophylline. Refer to PRECAUTIONS, Drug Interactions for further information regarding table. Drug Type of Interaction Effect 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. Adenosine Theophylline blocks adenosine receptors. Higher doses of adenosine may be required to achieve desired effect. Alcohol A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours. 30% increase Allopurinol Decreases theophylline clearance at allopurinol doses >=600 mg/day. 25% increase Aminoglutethimide Increases theophylline clearance by induction of microsomal enzyme activity. 25% decrease Carbamazepine Similar to aminoglutethimide. 30% decrease Cimetidine Decreases theophylline clearance by inhibiting cytochrome P450 1A2. 70% increase Ciprofloxacin Similar to cimetidine. 40% increase Clarithromycin Similar to erythromycin. 25% increase Diazepam Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors. Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression. Disulfiram Decreases theophylline clearance by inhibiting hydroxylation and demethylation. 50% increase Enoxacin Similar to cimetidine. 300% increase Ephedrine Synergistic CNS effects. Increased frequency of nausea, nervousness, and insomnia. Erythromycin Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3. 35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount. Estrogen Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown. 30% increase Flurazepam Similar to diazepam. Similar to diazepam. Fluvoxamine Similar to cimetidine. Similar to cimetidine. Halothane Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines. Increased risk of ventricular arrhythmias. Interferon, human recombinant alpha-A Decreases theophylline clearance. 100% increase Isoproterenol (IV) Increases theophylline clearance. 20% decrease Ketamine Pharmacologic. May lower theophylline seizure threshold Lithium Theophylline increases renal lithium clearance. Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%. Lorazepam Similar to diazepam. Similar to diazepam. Methotrexate (MTX) Decreases theophylline clearance. 20% increase after low dose MTX, higher dose MTX may have a greater effect. Mexiletine Similar to disulfiram. 80% increase Midazolam Similar to diazepam. Similar to diazepam. Moricizine Increases theophylline clearance. 25% decrease Pancuronium Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition. Larger dose of pancuronium may be required to achieve neuromuscular blockade. Pentoxifylline Decreases theophylline clearance. 30% increase Phenobarbital (PB) Similar to aminoglutethimide. 25% decrease after two weeks of concurrent PB. Phenytoin Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption. Serum theophylline and Propafenone Decreases theophylline clearance and pharmacologic interaction. 40% increase. Beta-2 blocking effect may decrease efficacy of theophylline. Propranolol Similar to cimetidine and pharmacologic interaction. 100% increase. Beta-2 blocking effect may decrease efficacy of theophylline. Rifampin Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity. 20 to 40% decrease St. John''s Wort (Hypericum Perforatum) Decrease in theophylline plasma concentrations. Higher doses of theophylline may be required to achieve desired effect. Stopping St. John''s Wort may result in theophylline toxicity. Sulfinpyrazone Increase theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline. 20% decrease Tacrine Similar to cimetidine, also increases renal clearance of theophylline. 90% increase Thiabendazole Decreases theophylline clearance. 190% increase Ticlopidine Decreases theophylline clearance. 60% increase Troleandomycin Similar to erythromycin. 33 to 100% increase depending on troleandomycin dose. Verapamil Similar to disulfiram. 20% increase TABLE III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline. Refer to PRECAUTIONS, Drug Interactions for information regarding table. albuterol, systemic and inhaled mebendazole amoxicillin medroxyprogesterone ampicillin, with or without sulbactam methylprednisolone metronidazole atenolol metoprolol azithromycin nadolol caffeine, dietary ingestion nifedipine cefaclor nizatidine co-trimoxazole (trimethoprim and sulfamethoxazole) norfloxacin ofloxacin diltiazem omeprazole dirithromycin prednisone, prednisolone enflurane ranitidine famotidine rifabutin felodipine roxithromycin finasteride Sorbitol (purgative doses do not inhibit theophylline absorption) hydrocortisone isoflurane sucralfate isoniazid terbutaline, systemic isradipine terfenadine influenza vaccine tetracycline ketoconazole tocainide lomefloxacin
Drug-Food Interactions
Taking Theophylline Extended-Release Tablets immediately after ingesting a high fat content meal (45 g fat, 55 g carbohydrates, 28 g protein, 789 calories) may result in a somewhat higher C max max
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.">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
Drug Interactions
Theophylline interacts with a wide variety of drugs. The interaction may be pharmacodynamic, i. , 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. , 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. , 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. , 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. , <15% change in theophylline clearance). The listing of drugs in Tables II and III are current as of February 9, 1995. 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 TABLE II. Clinically significant drug interactions with theophylline. Refer to PRECAUTIONS, Drug Interactions for further information regarding table. Drug Type of Interaction Effect 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. Adenosine Theophylline blocks adenosine receptors. Higher doses of adenosine may be required to achieve desired effect. Alcohol A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours. 30% increase Allopurinol Decreases theophylline clearance at allopurinol doses >=600 mg/day. 25% increase Aminoglutethimide Increases theophylline clearance by induction of microsomal enzyme activity. 25% decrease Carbamazepine Similar to aminoglutethimide. 30% decrease Cimetidine Decreases theophylline clearance by inhibiting cytochrome P450 1A2. 70% increase Ciprofloxacin Similar to cimetidine. 40% increase Clarithromycin Similar to erythromycin. 25% increase Diazepam Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors. Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression. Disulfiram Decreases theophylline clearance by inhibiting hydroxylation and demethylation. 50% increase Enoxacin Similar to cimetidine. 300% increase Ephedrine Synergistic CNS effects. Increased frequency of nausea, nervousness, and insomnia. Erythromycin Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3. 35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount. Estrogen Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown. 30% increase Flurazepam Similar to diazepam. Similar to diazepam. Fluvoxamine Similar to cimetidine. Similar to cimetidine. Halothane Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines. Increased risk of ventricular arrhythmias. Interferon, human recombinant alpha-A Decreases theophylline clearance. 100% increase Isoproterenol (IV) Increases theophylline clearance. 20% decrease Ketamine Pharmacologic. May lower theophylline seizure threshold Lithium Theophylline increases renal lithium clearance. Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%. Lorazepam Similar to diazepam. Methotrexate (MTX) Decreases theophylline clearance. 20% increase after low dose MTX, higher dose MTX may have a greater effect. Mexiletine Similar to disulfiram. 80% increase Midazolam Similar to diazepam. Moricizine Increases theophylline clearance. 25% decrease Pancuronium Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition. Larger dose of pancuronium may be required to achieve neuromuscular blockade. Pentoxifylline Decreases theophylline clearance. 30% increase Phenobarbital (PB) Similar to aminoglutethimide. 25% decrease after two weeks of concurrent PB. Phenytoin Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption. Serum theophylline and Propafenone Decreases theophylline clearance and pharmacologic interaction. 40% increase. Beta-2 blocking effect may decrease efficacy of theophylline. Propranolol Similar to cimetidine and pharmacologic interaction. 100% increase. Rifampin Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity. 20 to 40% decrease St. John''s Wort (Hypericum Perforatum) Decrease in theophylline plasma concentrations. Higher doses of theophylline may be required to achieve desired effect. Stopping St. John''s Wort may result in theophylline toxicity. Sulfinpyrazone Increase theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline. 20% decrease Tacrine Similar to cimetidine, also increases renal clearance of theophylline. 90% increase Thiabendazole Decreases theophylline clearance. 190% increase Ticlopidine Decreases theophylline clearance. 60% increase Troleandomycin Similar to erythromycin. 33 to 100% increase depending on troleandomycin dose. Verapamil Similar to disulfiram. 20% increase TABLE III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline. Refer to PRECAUTIONS, Drug Interactions for information regarding table. albuterol, systemic and inhaled mebendazole amoxicillin medroxyprogesterone ampicillin, with or without sulbactam methylprednisolone metronidazole atenolol metoprolol azithromycin nadolol caffeine, dietary ingestion nifedipine cefaclor nizatidine co-trimoxazole (trimethoprim and sulfamethoxazole) norfloxacin ofloxacin diltiazem omeprazole dirithromycin prednisone, prednisolone enflurane ranitidine famotidine rifabutin felodipine roxithromycin finasteride Sorbitol (purgative doses do not inhibit theophylline absorption) hydrocortisone isoflurane sucralfate isoniazid terbutaline, systemic isradipine terfenadine influenza vaccine tetracycline ketoconazole tocainide lomefloxacin Taking Theophylline Extended-Release Tablets immediately after ingesting a high fat content meal (45 g fat, 55 g carbohydrates, 28 g protein, 789 calories) may result in a somewhat higher C max max 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. 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.
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. The drugs listed in Table II have the potential to produce clinically significant pharmacodynamic or pharmacokinetic interactions with theophylline. The information in the "Effect" column of Table II assumes that the interacting drug is being added to a steady-state theophylline regimen. If theophylline is being initiated in a patient who is already taking a drug that inhibits theophylline clearance (e.g., cimetidine, erythromycin), the dose of theophylline required to achieve a therapeutic serum theophylline concentration will be smaller. Conversely, if theophylline is being initiated in a patient who is already taking a drug that enhances theophylline clearance (e.g., rifampin), the dose of theophylline required to achieve a therapeutic serum theophylline concentration will be larger. Discontinuation of a concomitant drug that increases theophylline clearance will result in accumulation of theophylline to potentially toxic levels, unless the theophylline dose is appropriately reduced. Discontinuation of a concomitant drug that inhibits theophylline clearance will result in decreased serum theophylline concentrations, unless the theophylline dose is appropriately increased. The drugs listed in Table III have either been documented not to interact with theophylline or do not produce a clinically significant interaction (i.e., <15% change in theophylline clearance). The listing of drugs in Tables II and III are current as of February 9, 1995. 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 TABLE II. Clinically significant drug interactions with theophylline. Refer to PRECAUTIONS, Drug Interactions for further information regarding table. Drug Type of Interaction Effect 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. Adenosine Theophylline blocks adenosine receptors. Higher doses of adenosine may be required to achieve desired effect. Alcohol A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours. 30% increase Allopurinol Decreases theophylline clearance at allopurinol doses >=600 mg/day. 25% increase Aminoglutethimide Increases theophylline clearance by induction of microsomal enzyme activity. 25% decrease Carbamazepine Similar to aminoglutethimide. 30% decrease Cimetidine Decreases theophylline clearance by inhibiting cytochrome P450 1A2. 70% increase Ciprofloxacin Similar to cimetidine. 40% increase Clarithromycin Similar to erythromycin. 25% increase Diazepam Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors. Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression. Disulfiram Decreases theophylline clearance by inhibiting hydroxylation and demethylation. 50% increase Enoxacin Similar to cimetidine. 300% increase Ephedrine Synergistic CNS effects. Increased frequency of nausea, nervousness, and insomnia. Erythromycin Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3. 35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount. Estrogen Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown. 30% increase Flurazepam Similar to diazepam. Similar to diazepam. Fluvoxamine Similar to cimetidine. Similar to cimetidine. Halothane Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines. Increased risk of ventricular arrhythmias. Interferon, human recombinant alpha-A Decreases theophylline clearance. 100% increase Isoproterenol (IV) Increases theophylline clearance. 20% decrease Ketamine Pharmacologic. May lower theophylline seizure threshold Lithium Theophylline increases renal lithium clearance. Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%. Lorazepam Similar to diazepam. Similar to diazepam. Methotrexate (MTX) Decreases theophylline clearance. 20% increase after low dose MTX, higher dose MTX may have a greater effect. Mexiletine Similar to disulfiram. 80% increase Midazolam Similar to diazepam. Similar to diazepam. Moricizine Increases theophylline clearance. 25% decrease Pancuronium Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition. Larger dose of pancuronium may be required to achieve neuromuscular blockade. Pentoxifylline Decreases theophylline clearance. 30% increase Phenobarbital (PB) Similar to aminoglutethimide. 25% decrease after two weeks of concurrent PB. Phenytoin Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption. Serum theophylline and Propafenone Decreases theophylline clearance and pharmacologic interaction. 40% increase. Beta-2 blocking effect may decrease efficacy of theophylline. Propranolol Similar to cimetidine and pharmacologic interaction. 100% increase. Beta-2 blocking effect may decrease efficacy of theophylline. Rifampin Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity. 20 to 40% decrease St. John''s Wort (Hypericum Perforatum) Decrease in theophylline plasma concentrations. Higher doses of theophylline may be required to achieve desired effect. Stopping St. John''s Wort may result in theophylline toxicity. Sulfinpyrazone Increase theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline. 20% decrease Tacrine Similar to cimetidine, also increases renal clearance of theophylline. 90% increase Thiabendazole Decreases theophylline clearance. 190% increase Ticlopidine Decreases theophylline clearance. 60% increase Troleandomycin Similar to erythromycin. 33 to 100% increase depending on troleandomycin dose. Verapamil Similar to disulfiram. 20% increase TABLE III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline. Refer to PRECAUTIONS, Drug Interactions for information regarding table. albuterol, systemic and inhaled mebendazole amoxicillin medroxyprogesterone ampicillin, with or without sulbactam methylprednisolone metronidazole atenolol metoprolol azithromycin nadolol caffeine, dietary ingestion nifedipine cefaclor nizatidine co-trimoxazole (trimethoprim and sulfamethoxazole) norfloxacin ofloxacin diltiazem omeprazole dirithromycin prednisone, prednisolone enflurane ranitidine famotidine rifabutin felodipine roxithromycin finasteride Sorbitol (purgative doses do not inhibit theophylline absorption) hydrocortisone isoflurane sucralfate isoniazid terbutaline, systemic isradipine terfenadine influenza vaccine tetracycline ketoconazole tocainide lomefloxacin
Drug-Food Interactions
Taking Theophylline Extended-Release Tablets immediately after ingesting a high fat content meal (45 g fat, 55 g carbohydrates, 28 g protein, 789 calories) may result in a somewhat higher C max max
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.

WARNINGS
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 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. Age: Concurrent Diseases: Drug Interactions: Adding a drug that inhibits theophylline metabolism (e. , cimetidine, erythromycin, tacrine) or stopping a concurrently administered drug that enhances theophylline metabolism (e. , carbamazepine, rifampin) (see PRECAUTIONS, Drug Interactions, Table II 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. DOSAGE AND ADMINISTRATION, Dosing Guidelines, Table VI Increases in the dose of theophylline should not be made in response to an acute exacerbation of symptoms of chronic lung disease since theophylline provides little added benefit to inhaled beta-2 -selective agonists and systemically administered cortico-steroids 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. , 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.
Carcinogenesis,Mutagenesis, Impairment of Fertility
Long-term carcinogenicity studies have been carried out in mice (oral doses 30 to 150 mg/kg) and rats (oral doses 5 to 75 mg/kg). Results are pending. Theophylline has been studied in Ames salmonella, in vivo in vitro In a 14-week continuous breeding study, theophylline, administered to mating pairs of B6C3F mice at oral doses of 120, 270 and 500 mg/kg (approximately 1.0 to 3.0 times the human dose on a mg/m 2 2
Teratogenic Effects
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/m 2 2 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/m 2 2 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/m 2 2 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.
OVERDOSAGE
The chronicity and pattern of theophylline overdosage significantly influences clinical manifestations of toxicity, management, and outcome. There are two common presentations: (1) acute overdose chronic overdosage 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 to 30 mcg/mL range and 3% were >30 mcg/mL. Approximately two-thirds of the patients with serum theophylline concentrations in the 20 to 30 mcg/mL range had one or more manifestations of toxicity while >90% of patients with serum theophylline concentrations >30 mcg/mL were clinically intoxicated. Similarly, in other reports, serious toxicity from theophylline is seen principally at serum concentrations >30 mcg/mL. Several studies have described the clinical manifestations of theophylline overdose and attempted to determine the factors that predict life-threatening toxicity. In general, patients who experience an acute overdose are less likely to experience seizures than patients who have experienced a chronic overdosage, unless the peak serum theophylline concentration is >100 mcg/mL. After a chronic overdosage, generalized seizures, life-threatening cardiac arrhythmias, and death may occur at serum theophylline concentrations >30 mcg/mL. The severity of toxicity after chronic overdosage is more strongly correlated with the patient''s age than the peak serum theophylline concentration; patients >60 years are at the greatest risk for severe toxicity and mortality after a chronic overdosage. Preexisting or concurrent disease may also significantly increase the susceptibility of a patient to a particular toxic manifestation, e. , 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. 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. Treatment of seizures 4. Anticipate need for anticonvulsants: but not phenytoin, 50 5. Treatment of cardiac arrhythmias 6. Gastrointestinal decontamination 7. Serum theophylline concentration monitoring 8. General monitoring procedures Monitoring and treatment should be continued until the serum concentration decreases below 20 mcg/mL. Enhance clearance of theophylline OVERDOSAGE, Extracorporeal Removal A. 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 to 4 hours to ensure 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 to 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 C. 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 to 4 hours to gauge the effectiveness of therapy and to guide further treatment decisions. Serum Concentration >20<30 mcg/mL (with manifestations of theophylline toxicity) Administer a single dose of oral activated charcoal. Serum Concentration >30 mcg/mL in patients <60 years of age Administer multiple-dose oral activated charcoal and measures to control emesis. Serum Concentration >30 mcg/mL in patients > 60 years of age. Consider prophylactic anticonvulsant therapy. 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 to 4 hours to gauge the effectiveness of therapy and to guide further treatment decisions. 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 to 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.
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.) 1. 2. 3. Treatment of seizures 4. Anticipate need for anticonvulsants: but not phenytoin, 50 5. Treatment of cardiac arrhythmias 6. Gastrointestinal decontamination 7. Serum theophylline concentration monitoring 8. General monitoring procedures Monitoring and treatment should be continued until the serum concentration decreases below 20 mcg/mL. 9. Enhance clearance of theophylline OVERDOSAGE, Extracorporeal Removal
Specific Recommendations
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 to 4 hours to ensure 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 to 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 C. 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 to 4 hours to gauge the effectiveness of therapy and to guide further treatment decisions. Serum Concentration >20<30 mcg/mL (with manifestations of theophylline toxicity) Administer a single dose of oral activated charcoal. Serum Concentration >30 mcg/mL in patients <60 years of age Administer multiple-dose oral activated charcoal and measures to control emesis. Serum Concentration >30 mcg/mL in patients > 60 years of age. Consider prophylactic anticonvulsant therapy. 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 to 4 hours to gauge the effectiveness of therapy and to guide further treatment decisions.
Acute Overdose
A. 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 to 4 hours to ensure that the concentration is not increasing. B. 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 to 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 C. 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 to 4 hours to gauge the effectiveness of therapy and to guide further treatment decisions.
Chronic Overdosage
A. 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 to 4 hours to ensure that the concentration is not increasing. B. 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 to 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 C. 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 to 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 to 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.">Single-Dose Study
A single-dose crossover study was conducted in twelve healthy male volunteers to compare pharmacokinetic parameters when Theophylline Extended-Release Tablets were administered with and without food. Subjects were fasted overnight and received a single 300 mg tablet early the following morning. When dosing was done under fed conditions, the subjects received a standard breakfast consisting of 2 fried eggs, 2 strips of bacon, 4 oz. hash brown potatoes, 1 slice of toast with a pat of butter, and 8 oz. whole milk 15 minutes pre-dosing. No food was allowed for five hours post-dosing, then a standard lunch was served; at ten hours post-dosing a standard supper was served. Mean peak theophylline serum levels for the two treatments were 3.7 mcg/mL (fasting) and 4.4 mcg/mL (with food). The time of peak serum level varied from subject to subject, occurring from 4 to 14 hours after dosing. However, 92% of the subjects had serum levels at least 75% of the maximum value at 4 to 8 hours after dosing, during each phase. Thus, blood samples taken 4 to 8 hours post-dosing should reference the peak serum level for most patients. The mean T max (0-inf.)
Multiple-Dose Study
A multiple-dose, steady-state study was conducted under fed conditions. Three high fat content meals were served at 6:30 a.m., 12 noon, and 6:30 p.m. Nineteen normal subjects were dosed at 300 mg every 12 hours (7 p.m. and 7 a.m.) for eight doses. Dosing began one-half hour after the evening meal with the test dose occurring one-half hour after breakfast. At steady-state, the mean peak concentration was 8.8 mcg/mL and the mean trough concentration was 5.9 mcg/mL. The time of peak concentration (T max max min min The subjects used for this study exhibited a mean half-life of 8.3 hours (range 5.2 to 12.2) and mean clearance of 3.5 L/hour (range 2.3 to 5.6) as determined in a separate single-dose clearance study using 500 mg of immediate-release theophylline, prior to this multiple-dose study.
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
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.
WARNINGS
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 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. Age: Concurrent Diseases: Drug Interactions: Adding a drug that inhibits theophylline metabolism (e. , cimetidine, erythromycin, tacrine) or stopping a concurrently administered drug that enhances theophylline metabolism (e. , carbamazepine, rifampin) (see PRECAUTIONS, Drug Interactions, Table II 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. DOSAGE AND ADMINISTRATION, Dosing Guidelines, Table VI Increases in the dose of theophylline should not be made in response to an acute exacerbation of symptoms of chronic lung disease since theophylline provides little added benefit to inhaled beta-2 -selective agonists and systemically administered cortico-steroids 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. , 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.
Carcinogenesis,Mutagenesis, Impairment of Fertility
Long-term carcinogenicity studies have been carried out in mice (oral doses 30 to 150 mg/kg) and rats (oral doses 5 to 75 mg/kg). Results are pending. Theophylline has been studied in Ames salmonella, in vivo in vitro In a 14-week continuous breeding study, theophylline, administered to mating pairs of B6C3F mice at oral doses of 120, 270 and 500 mg/kg (approximately 1.0 to 3.0 times the human dose on a mg/m 2 2
Teratogenic Effects
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/m 2 2 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/m 2 2 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/m 2 2 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.
OVERDOSAGE
The chronicity and pattern of theophylline overdosage significantly influences clinical manifestations of toxicity, management, and outcome. There are two common presentations: (1) acute overdose chronic overdosage 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 to 30 mcg/mL range and 3% were >30 mcg/mL. Approximately two-thirds of the patients with serum theophylline concentrations in the 20 to 30 mcg/mL range had one or more manifestations of toxicity while >90% of patients with serum theophylline concentrations >30 mcg/mL were clinically intoxicated. Similarly, in other reports, serious toxicity from theophylline is seen principally at serum concentrations >30 mcg/mL. Several studies have described the clinical manifestations of theophylline overdose and attempted to determine the factors that predict life-threatening toxicity. In general, patients who experience an acute overdose are less likely to experience seizures than patients who have experienced a chronic overdosage, unless the peak serum theophylline concentration is >100 mcg/mL. After a chronic overdosage, generalized seizures, life-threatening cardiac arrhythmias, and death may occur at serum theophylline concentrations >30 mcg/mL. The severity of toxicity after chronic overdosage is more strongly correlated with the patient''s age than the peak serum theophylline concentration; patients >60 years are at the greatest risk for severe toxicity and mortality after a chronic overdosage. Preexisting or concurrent disease may also significantly increase the susceptibility of a patient to a particular toxic manifestation, e. , 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. 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. Treatment of seizures 4. Anticipate need for anticonvulsants: but not phenytoin, 50 5. Treatment of cardiac arrhythmias 6. Gastrointestinal decontamination 7. Serum theophylline concentration monitoring 8. General monitoring procedures Monitoring and treatment should be continued until the serum concentration decreases below 20 mcg/mL. Enhance clearance of theophylline OVERDOSAGE, Extracorporeal Removal A. 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 to 4 hours to ensure 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 to 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 C. 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 to 4 hours to gauge the effectiveness of therapy and to guide further treatment decisions. Serum Concentration >20<30 mcg/mL (with manifestations of theophylline toxicity) Administer a single dose of oral activated charcoal. Serum Concentration >30 mcg/mL in patients <60 years of age Administer multiple-dose oral activated charcoal and measures to control emesis. Serum Concentration >30 mcg/mL in patients > 60 years of age. Consider prophylactic anticonvulsant therapy. 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 to 4 hours to gauge the effectiveness of therapy and to guide further treatment decisions. 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 to 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.
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.) 1. 2. 3. Treatment of seizures 4. Anticipate need for anticonvulsants: but not phenytoin, 50 5. Treatment of cardiac arrhythmias 6. Gastrointestinal decontamination 7. Serum theophylline concentration monitoring 8. General monitoring procedures Monitoring and treatment should be continued until the serum concentration decreases below 20 mcg/mL. 9. Enhance clearance of theophylline OVERDOSAGE, Extracorporeal Removal
Specific Recommendations
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 to 4 hours to ensure 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 to 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 C. 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 to 4 hours to gauge the effectiveness of therapy and to guide further treatment decisions. Serum Concentration >20<30 mcg/mL (with manifestations of theophylline toxicity) Administer a single dose of oral activated charcoal. Serum Concentration >30 mcg/mL in patients <60 years of age Administer multiple-dose oral activated charcoal and measures to control emesis. Serum Concentration >30 mcg/mL in patients > 60 years of age. Consider prophylactic anticonvulsant therapy. 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 to 4 hours to gauge the effectiveness of therapy and to guide further treatment decisions.
Acute Overdose
A. 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 to 4 hours to ensure that the concentration is not increasing. B. 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 to 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 C. 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 to 4 hours to gauge the effectiveness of therapy and to guide further treatment decisions.
Chronic Overdosage
A. 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 to 4 hours to ensure that the concentration is not increasing. B. 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 to 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 C. 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 to 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 to 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.

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