Theo-Bros

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Theo-Bros uses


DESCRIPTION

Theo-Bros® (theophylline, anhydrous) Tablets in a controlled-release system allows a 24-hour dosing interval for appropriate patients.

Theo-Bros is structurally classified as a methylxanthine. It occurs as a white, odorless, crystalline powder with a bitter taste. Anhydrous Theo-Bros has the chemical name 1H-Purine-2,6-dione, 3,7-dihydro-1,3-dimethyl-, and is represented by the following structural formula:

The molecular formula of anhydrous Theo-Bros is C7H8N4O2 with a molecular weight of 180.17.

Each controlled-release tablet for oral administration, contains 400 or 600 mg of anhydrous Theo-Bros.

Inactive Ingredients: cetostearyl alcohol, hydroxyethyl cellulose, magnesium stearate, povidone and talc.

Theo-Bros 400 mg

CLINICAL PHARMACOLOGY

Mechanism of Action

Theo-Bros has two distinct actions in the airways of patients with reversible obstruction; smooth muscle relaxation and suppression of the response of the airways to stimuli (i.e., non-bronchodilator prophylactic effects). While the mechanisms of action of Theo-Bros are not known with certainty, studies in animals suggest that bronchodilatation is mediated by the inhibition of two isozymes of phosphodiesterase (PDE III and, to a lesser extent, PDE IV) while non-bronchodilator prophylactic actions are probably mediated through one or more different molecular mechanisms, that do not involve inhibition of PDE III or antagonism of adenosine receptors. Some of the adverse effects associated with Theo-Bros 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).

Theo-Bros 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 Theo-Bros concentration range of 5-20 mcg/mL. Clinically important improvement in symptom control has been found in most studies to require peak serum Theo-Bros concentrations >10 mcg/mL, but patients with mild disease may benefit from lower concentrations. At serum Theo-Bros concentrations >20 mcg/mL, both the frequency and severity of adverse reactions increase. In general, maintaining peak serum Theo-Bros 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

Overview: Theo-Bros is rapidly and completely absorbed after oral administration in solution or immediate-release solid oral dosage form. Theo-Bros does not undergo any appreciable pre-systemic elimination, distributes freely into fat-free tissues and is extensively metabolized in the liver.

The pharmacokinetics of Theo-Bros 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 and co-administration of other drugs (see Table II ) can significantly alter the pharmacokinetic characteristics of Theo-Bros. Within-subject variability in metabolism has also been reported in some studies, especially in acutely ill patients. It is, therefore, recommended that serum Theo-Bros concentrations be measured frequently in acutely ill patients (e.g., at 24-hr intervals) and periodically in patients receiving long-term therapy, e.g., at 6-12 month intervals. More frequent measurements should be made in the presence of any condition that may significantly alter Theo-Bros clearance (see PRECAUTIONS, Laboratory Tests ).

Population Characteristics Total body clearance*

mean (range)††

(mL/kg/min)

Half-life mean (range)††

(hr)

For various North American patient populations from literature reports. Different rates of elimination and consequent dosage requirements have been observed among other peoples.
*Clearance represents the volume of blood completely cleared of Theo-Bros by the liver in one minute. Values listed were generally determined at serum Theo-Bros 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.
†NR=not reported or not reported in a comparable format.
**Median
Age
Premature neonates
postnatal age 3-15 days 0.29 (0.09-0.49) 30 (17-43)
postnatal age 25-57 days 0.64 (0.04-1.2) 20 (9.4-30.6)
Term infants
postnatal age 1-2 days NR 25.7 (25-26.5)
postnatal age 3-30 weeks NR 11 (6-29)
Children
1-4 years 1.7 (0.5-2.9) 3.4 (1.2-5.6)
4-12 years 1.6 (0.8-2.4) NR
13-15 years 0.9 (0.48-1.3) NR
6-17 years 1.4 (0.2-2.6) 3.7 (1.5-5.9)
Adults (16-60 years)
otherwise healthy
non-smoking asthmatics 0.65 (0.27-1.03) 8.7 (6.1-12.8)
Elderly (>60 years)
non-smokers with normal

cardiac,

liver, and renal function

0.41 (0.21-0.61) 9.8 (1.6-18)
Concurrent illness or altered physiological state
Acute pulmonary edema 0.33** (0.07-2.45) 19** (3.1-82)
COPD->60 years, stable
non-smoker >1 year 0.54 (0.44-0.64) 11 (9.4-12.6)
COPD with cor pulmonale 0.48 (0.08-0.88) NR
Cystic fibrosis (14-28 years) 1.25 (0.31-2.2) 6.0 (1.8-10.2)
Fever associated with
acute viral respiratory illness
(children 9-15 years) NR 7.0 (1.0-13)
Liver disease
cirrhosis 0.31** (0.1-0.7) 32** (10-56)
acute hepatitis 0.35 (0.25-0.45) 19.2 (16.6-21.8)
cholestasis 0.65 (0.25-1.45) 14.4 (5.7-31.8)
Pregnancy
1st trimester NR 8.5 (3.1-13.9)
2nd trimester NR 8.8 (3.8-13.8)
3rd trimester NR 13.0 (8.4-17.6)
Sepsis with multi-organ failure 0.47 (0.19-1.9) 18.8 (6.3-24.1)
Thyroid disease
hypothyroid 0.38 (0.13-0.57) 11.6 (8.2-25)
hyperthyroid 0.8 (0.68-0.97) 4.5 (3.7-5.6)

Note: In addition to the factors listed above, Theo-Bros clearance is increased and half-life decreased by low carbohydrate/high protein diets, parenteral nutrition, and daily consumption of charcoal-broiled beef. A high carbohydrate/low protein diet can decrease the clearance and prolong the half-life of Theo-Bros.

Absorption

Theo-Bros® administered in the fed state is completely absorbed after oral administration.

In a single-dose crossover study, two 400 mg Theo-Bros Tablets were administered to 19 normal volunteers in the morning or evening immediately following the same standardized meal (769 calories consisting of 97 grams carbohydrates, 33 grams protein and 27 grams fat). There was no evidence of dose dumping nor were there any significant differences in pharmacokinetic parameters attributable to time of drug administration. On the morning arm, the pharmacokinetic parameters were AUC=241.9±83.0 mcg hr/mL, Cmax=9.3±2.0 mcg/mL, Tmax=12.8±4.2 hours. On the evening arm, the pharmacokinetic parameters were AUC=219.7±83.0 mcg hr/mL, Cmax=9.2±2.0 mcg/mL, Tmax=12.5±4.2 hours.

A study in which Theo-Bros 400 mg Tablets were administered to 17 fed adult asthmatics produced similar Theo-Bros level-time curves when administered in the morning or evening. Serum levels were generally higher in the evening regimen but there were no statistically significant differences between the two regimens.

MORNING EVENING
AUC (0-24 hrs) (mcg hr/mL) 236.0±76.7 256.0±80.4
Cmax (mcg/mL) 14.5±4.1 16.3±4.5
Cmin (mcg/mL) 5.5±2.9 5.0±2.5
Tmax (hours) 8.1±3.7 10.1±4.1

A single-dose study in 15 normal fasting male volunteers whose Theo-Bros inherent mean elimination half-life was verified by a liquid Theo-Bros product to be 6.9±2.5 (SD) hours were administered two or three 400 mg Theo-Bros® Tablets. The relative bioavailability of Theo-Bros given in the fasting state in comparison to an immediate-release product was 59%. Peak serum Theo-Bros levels occurred at 6.9±5.2 (SD) hours, with a normalized (to 800 mg) peak level being 6.2±2.1 (SD). The apparent elimination half-life for the 400 mg Theo-Bros Tablets was 17.2±5.8 (SD) hours.

Steady-state pharmacokinetics were determined in a study in 12 fasted patients with chronic reversible obstructive pulmonary disease. All were dosed with two 400 mg Theo-Bros Tablets given once daily in the morning and a reference controlled-release BID product administered as two 200 mg tablets given 12 hours apart. The pharmacokinetic parameters obtained for Theo-Bros Tablets given at doses of 800 mg once daily in the morning were virtually identical to the corresponding parameters for the reference drug when given as 400 mg BID. In particular, the AUC, Cmax and Cmin values obtained in this study were as follows:

Theo-Bros Tablets

800 mg

Q24h±SD

Reference Drug

400 mg

Q12h±SD

AUC, (0-24 hours), mcg hr/mL 288.9±21.5 283.5±38.4
Cmax, mcg/mL 15.7±2.8 15.2±2.1
Cmin, mcg/mL 7.9±1.6 7.8±1.7
Cmax-Cmin diff. 7.7±1.5 7.4±1.5

Single-dose studies in which subjects were fasted for twelve (12) hours prior to and an additional four (4) hours following dosing, demonstrated reduced bioavailability as compared to dosing with food. One single-dose study in 20 normal volunteers dosed with two (2) 400 mg tablets in the morning, compared dosing under these fasting conditions with dosing immediately prior to a standardized breakfast (769 calories, consisting of 97 grams carbohydrates, 33 grams protein and 27 grams fat). Under fed conditions, the pharmacokinetic parameters were: AUC=231.7±92.4 mcg hr/mL, Cmax=8.4±2.6 mcg/mL, Tmax=17.3±6.7 hours. Under fasting conditions, these parameters were AUC=141.2±6.53 mcg hr/mL, Cmax=5.5±1.5 mcg/mL, Tmax=6.5±2.1 hours.

Another single-dose study in 21 normal male volunteers, dosed in the evening, compared fasting to a standardized high calorie, high fat meal (870-1,020 calories, consisting of 33 grams protein, 55-75 grams fat, 58 grams carbohydrates). In the fasting arm subjects received one Theo-Bros® 400 mg Tablet at 8 p.m. after an eight hour fast followed by a further four hour fast. In the fed arm, subjects were again dosed with one 400 mg Theo-Bros Tablet, but at 8 p.m. immediately after the high fat content standardized meal cited above. The pharmacokinetic parameters (normalized to 800 mg) fed were AUC=221.8±40.9 mcg hr/mL, Cmax=10.9±1.7 mcg/mL, Tmax=11.8±2.2 hours. In the fasting arm, the pharmacokinetic parameters (normalized to 800 mg) were AUC=146.4±40.9 mcg hr/mL, Cmax=6.7±1.7 mcg/mL, Tmax=7.3±2.2 hours.

Thus, administration of single Theo-Bros doses to healthy normal volunteers, under prolonged fasted conditions (at least 10 hour overnight fast before dosing followed by an additional four (4) hour fast after dosing) results in decreased bioavailability. However, there was no failure of this delivery system leading to a sudden and unexpected release of a large quantity of Theo-Bros with Theo-Bros Tablets even when they are administered with a high fat, high calorie meal.

Similar studies were conducted with the 600 mg Theo-Bros Tablet. A single-dose study in 24 subjects with an established Theo-Bros clearance of ≤4 L/hr, compared the pharmacokinetic evaluation of one 600 mg Theo-Bros Tablet and one and one-half 400 mg Theo-Bros Tablets under fed (using a standard high fat diet) and fasted conditions. The results of this 4-way randomized crossover study demonstrate the bioequivalence of the 400 mg and 600 mg Theo-Bros Tablets. Under fed conditions, the pharmacokinetic results for the one and one-half 400 mg tablets were AUC=214.64±55.88 mcg hr/mL, Cmax=10.58±2.21 mcg/mL and Tmax=9.00±2.64 hours, and for the 600 mg tablet were AUC=207.85±48.9 mcg hr/mL, Cmax=10.39±1.91 mcg/mL and Tmax=9.58±1.86 hours. Under fasted conditions the pharmacokinetic results for the one and one-half 400 mg tablets were AUC=191.85 ±51.1 mcg hr/mL, Cmax= 7.37±1.83 mcg/mL and Tmax=8.08±4.39 hours; and for the 600 mg tablet were AUC=199.39±70.27 mcg hr/mL, Cmax=7.66±2.09 mcg/mL and Tmax=9.67±4.89 hours.

In this study the mean fed/fasted ratios for the one and one-half 400 mg tablets and the 600 mg tablet were about 112% and 104%, respectively.

In another study, the bioavailability of the 600 mg Theo-Bros Tablet was examined with morning and evening administration. This single-dose, crossover study in 22 healthy males was conducted under fed (standard high fat diet) conditions. The results demonstrated no clinically significant difference in the bioavailability of the 600 mg Theo-Bros Tablet administered in the morning or in the evening. The results were: AUC=233.6±45.1 mcg hr/mL, Cmax=10.6±1.3 mcg/mL and Tmax=12.5±3.2 hours with morning dosing; AUC=209.8±46.2 mcg hr/mL, Cmax=9.7±1.4 mcg/mL and Tmax=13.7±3.3 hours with evening dosing. The PM/AM ratio was 89.3%.

The absorption characteristics of Theo-Bros® Tablets (theophylline, anhydrous) have been extensively studied. A steady-state crossover bioavailability study in 22 normal males compared two Theo-Bros 400 mg Tablets administered q24h at 8 a.m. immediately after breakfast with a reference controlled-release Theo-Bros product administered BID in fed subjects at 8 a.m. immediately after breakfast and 8 p.m. immediately after dinner (769 calories, consisting of 97 grams carbohydrates, 33 grams protein and 27 grams fat).

The pharmacokinetic parameters for Theo-Bros 400 mg Tablets under these steady-state conditions were AUC=203.3±87.1 mcg hr/mL, Cmax=12.1±3.8 mcg/mL, Cmin=4.50±3.6, Tmax=8.8±4.6 hours. For the reference BID product, the pharmacokinetic parameters were AUC=219.2±88.4 mcg hr/mL, Cmax =11.0±4.1 mcg/mL, Cmin=7.28±3.5, Tmax=6.9±3.4 hours. The mean percent fluctuation [(Cmax-Cmin/Cmin)x100]=169% for the once-daily regimen and 51% for the reference product BID regimen.

The bioavailability of the 600 mg Theo-Bros Tablet was further evaluated in a multiple dose, steady-state study in 26 healthy males comparing the 600 mg Tablet to one and one-half 400 mg Theo-Bros Tablets. All subjects had previously established Theo-Bros clearances of ≤4 L/hr and were dosed once-daily for 6 days under fed conditions. The results showed no clinically significant difference between the 600 mg and one and one-half 400 mg Theo-Bros Tablet regimens. Steady-state results were:

600 MG TABLET

FED

600 MG

(ONE+ONE-HALF

400 MG TABLETS)

FED

AUC 0-24hrs (mcg hr/mL) 209.77±51.04 212.32±56.29
Cmax (mcg/mL) 12.91±2.46 13.17±3.11
Cmin (mcg/mL) 5.52±1.79 5.39±1.95
Tmax (hours) 8.62±3.21 7.23±2.35
Percent Fluctuation 183.73±54.02 179.72±28.86

The bioavailability ratio for the 600/400 mg tablets was 98.8%. Thus, under all study conditions the 600 mg tablet is bioequivalent to one and one-half 400 mg tablets.

Studies demonstrate that as long as subjects were either consistently fed or consistently fasted, there is similar bioavailability with once-daily administration of Theo-Bros Tablets whether dosed in the morning or evening.

Distribution

Once Theo-Bros enters the systemic circulation, about 40% is bound to plasma protein, primarily albumin. Unbound Theo-Bros distributes throughout body water, but distributes poorly into body fat. The apparent volume of distribution of Theo-Bros is approximately 0.45 L/kg based on ideal body weight. Theo-Bros passes freely across the placenta, into breast milk and into the cerebrospinal fluid (CSF). Saliva Theo-Bros 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 Theo-Bros, 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 Theo-Bros in the therapeutic range (10-20 mcg/mL) due to elevated concentrations of the pharmacologically active unbound drug. Similarly, a patient with decreased Theo-Bros binding may have a sub-therapeutic total drug concentration while the pharmacologically active unbound concentration is in the therapeutic range. If only total serum Theo-Bros concentration is measured, this may lead to an unnecessary and potentially dangerous dose increase. In patients with reduced protein binding, measurement of unbound serum Theo-Bros concentration provides a more reliable means of dosage adjustment than measurement of total serum Theo-Bros concentration. Generally, concentrations of unbound Theo-Bros should be maintained in the range of 6-12 mcg/mL.

Metabolism

Following oral dosing, Theo-Bros 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 Theo-Bros dose is N-methylated to caffeine. Theo-Bros demethylation to 3-methylxanthine is catalyzed by cytochrome P-450 1A2, while cytochromes P-450 2E1 and P-450 3A3 catalyze the hydroxylation to 1,3-dimethyluric acid. Demethylation to 1-methylxanthine appears to be catalyzed either by cytochrome P-450 1A2 or a closely related cytochrome. In neonates, the N-demethylation pathway is absent while the function of the hydroxylation pathway is markedly deficient. The activity of these pathways slowly increases to maximal levels by one year of age.

Caffeine and 3-methylxanthine are the only Theo-Bros metabolites with pharmacologic activity. 3-methylxanthine has approximately one tenth the pharmacologic activity of Theo-Bros 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 Theo-Bros concentration. Caffeine concentrations are usually undetectable in adults regardless of renal function. In neonates, caffeine may accumulate to concentrations that approximate the unmetabolized Theo-Bros concentration and thus, exert a pharmacologic effect.

Both the N-demethylation and hydroxylation pathways of Theo-Bros biotransformation are capacity-limited. Due to the wide intersubject variability of the rate of Theo-Bros metabolism, non-linearity of elimination may begin in some patients at serum Theo-Bros concentrations <10 mcg/mL. Since this non-linearity results in more than proportional changes in serum Theo-Bros 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 Theo-Bros concentrations (see DOSAGE AND ADMINISTRATION, Table VI ). Accurate prediction of dose-dependency of Theo-Bros metabolism in patients a priori is not possible, but patients with very high initial clearance rates (i.e., low steady-state serum Theo-Bros concentrations at above average doses) have the greatest likelihood of experiencing large changes in serum Theo-Bros concentration in response to dosage changes.

Excretion

In neonates, approximately 50% of the Theo-Bros dose is excreted unchanged in the urine. Beyond the first three months of life, approximately 10% of the Theo-Bros dose is excreted unchanged in the urine. The remainder is excreted in the urine mainly as 1,3-dimethyluric acid, 1-methyluric acid (20-25%) and 3-methylxanthine (15-20%). Since little Theo-Bros is excreted unchanged in the urine and since active metabolites of Theo-Bros (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 Theo-Bros dose excreted in the urine as unchanged Theo-Bros and caffeine in neonates requires careful attention to dose reduction and frequent monitoring of serum Theo-Bros concentrations in neonates with reduced renal function (See WARNINGS ).

Serum Concentrations at Steady-State

After multiple doses of Theo-Bros, steady-state is reached in 30-65 hours (average 40 hours) in adults. At steady-state, on a dosage regimen with 24-hour intervals, the expected mean trough concentration is approximately 50% of the mean peak concentration, assuming a mean Theo-Bros half-life of 8 hours. The difference between peak and trough concentrations is larger in patients with more rapid Theo-Bros clearance. In these patients administration of Theo-Bros® may be required more frequently (every 12 hours).

Special Populations


Geriatric

The clearance of Theo-Bros 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 Theo-Bros concentrations are required in elderly patients (see WARNINGS ).

Pediatrics

The clearance of Theo-Bros is very low in neonates. Theo-Bros clearance reaches maximal values by one year of age, remains relatively constant until about 9 years of age and then slowly decreases by approximately 50% to adult values at about age 16. Renal excretion of unchanged Theo-Bros in neonates amounts to about 50% of the dose, compared to about 10% in children older than three months and in adults. Careful attention to dosage selection and monitoring of serum Theo-Bros concentrations are required in pediatric patients (see WARNINGS and DOSAGE AND ADMINISTRATION ).

Gender

Gender differences in Theo-Bros clearance are relatively small and unlikely to be of clinical significance. Significant reduction in Theo-Bros 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 Theo-Bros clearance due to race have not been studied.

Renal Insufficiency

Only a small fraction, e.g., about 10%, of the administered Theo-Bros dose is excreted unchanged in the urine of children greater than three months of age and adults. Since little Theo-Bros is excreted unchanged in the urine and since active metabolites of Theo-Bros 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 Theo-Bros dose is excreted unchanged in the urine in neonates. Careful attention to dose reduction and frequent monitoring of serum Theo-Bros concentrations are required in neonates with decreased renal function (see WARNINGS ).

Hepatic Insufficiency

Theo-Bros 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 Theo-Bros concentrations are required in patients with reduced hepatic function (see WARNINGS ).

Congestive Heart Failure

Theo-Bros clearance is decreased by 50% or more in patients with CHF. The extent of reduction in Theo-Bros clearance in patients with CHF appears to be directly correlated to the severity of the cardiac disease. Since Theo-Bros 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 Theo-Bros concentrations are required in patients with CHF (see WARNINGS ).

Smokers

Tobacco and marijuana smoking appears to increase the clearance of Theo-Bros by induction of metabolic pathways. Theo-Bros clearance has been shown to increase by approximately 50% in young adult tobacco smokers and by approximately 80% in elderly tobacco smokers compared to non-smoking subjects. Passive smoke exposure has also been shown to increase Theo-Bros clearance by up to 50%. Abstinence from tobacco smoking for one week causes a reduction of approximately 40% in Theo-Bros clearance. Careful attention to dose reduction and frequent monitoring of serum Theo-Bros concentrations are required in patients who stop smoking. Use of nicotine gum has been shown to have no effect on Theo-Bros clearance.

Fever

Fever, regardless of its underlying cause, can decrease the clearance of Theo-Bros. The magnitude and duration of the fever appear to be directly correlated to the degree of decrease of Theo-Bros 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 Theo-Bros concentrations. Children with rapid rates of Theo-Bros clearance (i.e., those who require a dose that is substantially larger than average [e.g., >22 mg/kg/day] to achieve a therapeutic peak serum Theo-Bros 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 Theo-Bros concentrations are required in patients with sustained fever (see WARNINGS ).

Miscellaneous

Other factors associated with decreased Theo-Bros clearance include the third trimester of pregnancy, sepsis with multiple organ failure, and hypothyroidism. Careful attention to dose reduction and frequent monitoring of serum Theo-Bros concentrations are required in patients with any of these conditions (see WARNINGS ). Other factors associated with increased Theo-Bros clearance include hyperthyroidism and cystic fibrosis.

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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 Theo-Bros decreases the frequency and severity of symptoms, including nocturnal exacerbations, and decreases the “as needed” use of inhaled beta-2 agonists. Theo-Bros 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 Theo-Bros decreases dyspnea, air trapping, the work of breathing, and improves contractility of diaphragmatic muscles with little or no improvement in pulmonary function measurements.

INDICATIONS AND USAGE

Theo-Bros is indicated for the treatment of the symptoms and reversible airflow obstruction associated with chronic asthma and other chronic lung diseases, e.g., emphysema and chronic bronchitis.

CONTRAINDICATIONS

Theo-Bros® is contraindicated in patients with a history of hypersensitivity to Theo-Bros or other components in the product.

WARNINGS

Concurrent Illness

Theo-Bros should be used with extreme caution in patients with the following clinical conditions due to the increased risk of exacerbation of the concurrent condition:

Active peptic ulcer disease

Seizure disorders

Cardiac arrhythmias

Conditions That Reduce Theo-Bros Clearance

There are several readily identifiable causes of reduced Theo-Bros clearance. If the total daily dose is not appropriately reduced in the presence of these risk factors, severe and potentially fatal Theo-Bros toxicity can occur . Careful consideration must be given to the benefits and risks of Theo-Bros use and the need for more intensive monitoring of serum Theo-Bros concentrations in patients with the following risk factors:

Age


Concurrent Diseases


Cessation of Smoking

Drug Interactions

Adding a drug that inhibits Theo-Bros metabolism or stopping a concurrently administered drug that enhances Theo-Bros metabolism (e.g., carbamazepine, rifampin). (see PRECAUTIONS, Drug Interactions, Table II ).

When Signs or Symptoms of Theo-Bros Toxicity Are Present

Whenever a patient receiving Theo-Bros develops nausea or vomiting, particularly repetitive vomiting, or other signs or symptoms consistent with Theo-Bros toxicity (even if another cause may be suspected), additional doses of Theo-Bros should be withheld and a serum Theo-Bros concentration measured immediately . Patients should be instructed not to continue any dosage that causes adverse effects and to withhold subsequent doses until the symptoms have resolved, at which time the healthcare professional may instruct the patient to resume the drug at a lower dosage (see DOSAGE AND ADMINISTRATION, Dosing Guidelines, Table VI ).

Dosage Increases

Increases in the dose of Theo-Bros should not be made in response to an acute exacerbation of symptoms of chronic lung disease since Theo-Bros provides little added benefit to inhaled beta2-selective agonists and systemically administered corticosteroids in this circumstance and increases the risk of adverse effects. A peak steady-state serum Theo-Bros 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 Theo-Bros 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 Theo-Bros 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 Theo-Bros concentration (see DOSAGE AND ADMINISTRATION, Table VI ).

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PRECAUTIONS

General

Careful consideration of the various interacting drugs and physiologic conditions that can alter Theo-Bros clearance and require dosage adjustment should occur prior to initiation of Theo-Bros therapy, prior to increases in Theo-Bros dose, and during follow up. The dose of Theo-Bros selected for initiation of therapy should be low and, if tolerated , increased slowly over a period of a week or longer with the final dose guided by monitoring serum Theo-Bros concentrations and the patient’s clinical response (see DOSAGE AND ADMINISTRATION , Table V).

Monitoring Serum Theo-Bros Concentrations

Serum Theo-Bros concentration measurements are readily available and should be used to determine whether the dosage is appropriate. Specifically, the serum Theo-Bros concentration should be measured as follows:


To guide a dose increase, the blood sample should be obtained at the time of the expected peak serum Theo-Bros concentration; 12 hours after an evening dose or 9 hours after a morning dose at steady-state. For most patients, steady-state will be reached after 3 days of dosing when no doses have been missed, no extra doses have been added, and none of the doses have been taken at unequal intervals. A trough concentration (i.e., at the end of the dosing interval) provides no additional useful information and may lead to an inappropriate dose increase since the peak serum Theo-Bros concentration can be two or more times greater than the trough concentration with an immediate-release formulation. If the serum sample is drawn more than 12 hours after the evening dose, or more than 9 hours after a morning dose, the results must be interpreted with caution since the concentration may not be reflective of the peak concentration. In contrast, when signs or symptoms of Theo-Bros toxicity are present, a serum sample should be obtained as soon as possible, analyzed immediately, and the result reported to the healthcare professional without delay. In patients in whom decreased serum protein binding is suspected (e.g., cirrhosis, women during the third trimester of pregnancy), the concentration of unbound Theo-Bros should be measured and the dosage adjusted to achieve an unbound concentration of 6-12 mcg/mL.

Saliva concentrations of Theo-Bros cannot be used reliably to adjust dosage without special techniques.

Effects on Laboratory Tests

As a result of its pharmacological effects, Theo-Bros at serum concentrations within the 10-20 mcg/mL range modestly increases plasma glucose, 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). Theo-Bros at serum concentrations within the 10-20 mcg/mL range may also transiently decrease serum concentrations of triiodothyronine (144 before, 131 after one week and 142 ng/dL after 4 weeks of Theo-Bros). The clinical importance of these changes should be weighed against the potential therapeutic benefit of Theo-Bros in individual patients.

Information for Patients

The patient (or parent/caregiver) should be instructed to seek medical advice whenever nausea, vomiting, persistent headache, insomnia or rapid heartbeat occurs during treatment with Theo-Bros, even if another cause is suspected. The patient should be instructed to contact their healthcare professional if they develop a new illness, especially if accompanied by a persistent fever, if they experience worsening of a chronic illness, if they start or stop smoking cigarettes or marijuana, or if another healthcare professional adds a new medication or discontinues a previously prescribed medication. Patients should be informed that Theo-Bros interacts with a wide variety of drugs. The dietary supplement St. John’s Wort (Hypericum perforatum) should not be taken at the same time as Theo-Bros, since it may result in decreased Theo-Bros levels. If patients are already taking St. John’s Wort and Theo-Bros together, they should consult their healthcare professional before stopping the St. John’s Wort, since their Theo-Bros concentrations may rise when this is done, resulting in toxicity. Patients should be instructed to inform all healthcare professionals involved in their care that they are taking Theo-Bros, especially when a medication is being added or deleted from their treatment. Patients should be instructed to not alter the dose, timing of the dose, or frequency of administration without first consulting their healthcare professional. If a dose is missed, the patient should be instructed to take the next dose at the usually scheduled time and to not attempt to make up for the missed dose.

Theo-Bros® Tablets can be taken once a day in the morning or evening. It is recommended that Theo-Bros be taken with meals. Patients should be advised that if they choose to take Theo-Bros with food it should be taken consistently with food and if they take it in a fasted condition it should routinely be taken fasted. It is important that the product whenever dosed be dosed consistently with or without food.

Theo-Bros Tablets are not to be chewed or crushed because it may lead to a rapid release of Theo-Bros with the potential for toxicity. The scored tablet may be split. Patients receiving Theo-Bros Tablets may pass an intact matrix tablet in the stool or via colostomy. These matrix tablets usually contain little or no residual Theo-Bros.

Drug Interactions

Theo-Bros interacts with a wide variety of drugs. The interaction may be pharmacodynamic, i.e., alterations in the therapeutic response to Theo-Bros or another drug or occurrence of adverse effects without a change in serum Theo-Bros concentration. More frequently, however, the interaction is pharmacokinetic, i.e., the rate of Theo-Bros clearance is altered by another drug resulting in increased or decreased serum Theo-Bros concentrations. Theo-Bros 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 Theo-Bros. The information in the “Effect” column of Table II assumes that the interacting drug is being added to a steady-state Theo-Bros regimen. If Theo-Bros is being initiated in a patient who is already taking a drug that inhibits Theo-Bros clearance, the dose of Theo-Bros required to achieve a therapeutic serum Theo-Bros concentration will be smaller. Conversely, if Theo-Bros is being initiated in a patient who is already taking a drug that enhances Theo-Bros clearance (e.g., rifampin), the dose of Theo-Bros required to achieve a therapeutic serum Theo-Bros concentration will be larger. Discontinuation of a concomitant drug that increases Theo-Bros clearance will result in accumulation of Theo-Bros to potentially toxic levels, unless the Theo-Bros dose is appropriately reduced. Discontinuation of a concomitant drug that inhibits Theo-Bros clearance will result in decreased serum Theo-Bros concentrations, unless the Theo-Bros dose is appropriately increased.

The drugs listed in Table III have either been documented not to interact with Theo-Bros or do not produce a clinically significant interaction (i.e., <15% change in Theo-Bros clearance).

The listing of drugs in Tables II and III are current as of February 9, 1995. New interactions are continuously being reported for Theo-Bros, especially with new chemical entities. The healthcare professional should not assume that a drug does not interact with Theo-Bros if it is not listed in Table II. Before addition of a newly available drug in a patient receiving Theo-Bros, the package insert of the new drug and/or the medical literature should be consulted to determine if an interaction between the new drug and Theo-Bros has been reported.

Drug Type of Interaction Effect**
*Refer to PRECAUTIONS, Drug Interactions for further information regarding table.
**Average effect on steady-state Theo-Bros concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum Theo-Bros concentration than the value listed.
Adenosine Theo-Bros 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 Theo-Bros clearance for up to 24 hours. 30% increase
Allopurinol Decreases Theo-Bros clearance at allopurinol doses ≥600 mg/day. 25% increase
Aminoglutethimide Increases Theo-Bros clearance by induction of microsomal enzyme activity. 25% decrease
Carbamazepine Similar to aminoglutethimide. 30% decrease
Cimetidine Decreases Theo-Bros 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 Theo-Bros blocks adenosine receptors. Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of Theo-Bros without reduction of diazepam dose may result in respiratory depression.
Disulfiram Decreases Theo-Bros 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 Theo-Bros clearance by inhibiting cytochrome P450 3A3. 35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
Estrogen Estrogen containing oral contraceptives decrease Theo-Bros clearance in a dose-dependent fashion. The effect of progesterone on Theo-Bros 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, Theo-Bros increases release of endogenous catecholamines. Increased risk of ventricular arrhythmias.
Interferon, human recombinant alpha-A Decreases Theo-Bros clearance. 100% increase
Isoproterenol (IV) Increases Theo-Bros clearance. 20% decrease
Ketamine Pharmacologic May lower Theo-Bros seizure threshold.
Lithium Theo-Bros 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 Theo-Bros 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 Theo-Bros clearance. 25% decrease
Pancuronium Theo-Bros 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 Theo-Bros clearance. 30% increase
Phenobarbital (PB) Similar to aminoglutethimide. 25% decrease after two weeks of concurrent PB.
Phenytoin Phenytoin increases Theo-Bros clearance by increasing microsomal enzyme activity. Theo-Bros decreases phenytoin absorption. Serum Theo-Bros and phenytoin concentrations decrease about 40%.
Propafenone Decreases Theo-Bros clearance and pharmacologic interaction. 40% increase. Beta-2 blocking effect may decrease efficacy of Theo-Bros.
Propranolol Similar to cimetidine and pharmacologic interaction. 100% increase. Beta-2 blocking effect may decrease efficacy of Theo-Bros.
Rifampin Increases Theo-Bros clearance by increasing cytochrome P450 1A2 and 3A3 activity. 20-40% decrease
St. John’s Wort (Hypericum Perforatum) Decrease in Theo-Bros plasma concentrations. Higher doses of Theo-Bros may be required to achieve desired effect. Stopping St. John’s Wort may result in Theo-Bros toxicity.
Sulfinpyrazone Increases Theo-Bros clearance by increasing demethylation and hydroxylation. Decreases renal clearance of Theo-Bros. 20% decrease
Tacrine Similar to cimetidine, also increases renal clearance of Theo-Bros. 90% increase
Thiabendazole Decreases Theo-Bros clearance. 190% increase
Ticlopidine Decreases Theo-Bros clearance. 60% increase
Troleandomycin Similar to erythromycin. 33-100% increase depending on troleandomycin dose.
Verapamil Similar to disulfiram. 20% increase
*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
hydrocortisone Theo-Bros absorption)
isoflurane sucralfate
isoniazid terbutaline, systemic
isradipine terfenadine
influenza vaccine tetracycline
ketoconazole tocainide
lomefloxacin

Drug-Food Interactions

The bioavailability of Theo-Bros® Tablets (theophylline, anhydrous) has been studied with co-administration of food. In three single-dose studies, subjects given Theo-Bros 400 mg or 600 mg Tablets with a standardized high-fat meal were compared to fasted conditions. Under fed conditions, the peak plasma concentration and bioavailability were increased; however, a precipitous increase in the rate and extent of absorption was not evident (see Pharmacokinetics , Absorption). The increased peak and extent of absorption under fed conditions suggests that dosing should be ideally administered consistently either with or without food.

The Effect of Other Drugs on Theo-Bros Serum Concentration Measurements

Most serum Theo-Bros assays in clinical use are immunoassays which are specific for Theo-Bros. Other xanthines such as caffeine, dyphylline, and pentoxifylline are not detected by these assays. Some drugs, 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 Theo-Bros concentration.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Long term carcinogenicity studies have been carried out in mice (oral doses 30-150 mg/kg) and rats (oral doses 5-75 mg/kg). Results are pending.

Theo-Bros has been studied in Ames salmonella, in vivo and in vitro cytogenetics, micronucleus and Chinese hamster ovary test systems and has not been shown to be genotoxic.

In a 14 week continuous breeding study, Theo-Bros, administered to mating pairs of B6C3F1 mice at oral doses of 120, 270 and 500 mg/kg (approximately 1.0-3.0 times the human dose on a mg/m2 basis) impaired fertility, as evidenced by decreases in the number of live pups per litter, decreases in the mean number of litters per fertile pair, and increases in the gestation period at the high dose as well as decreases in the proportion of pups born alive at the mid and high dose. In 13 week toxicity studies, Theo-Bros was administered to F344 rats and B6C3F1 mice at oral doses of 40-300 mg/kg (approximately 2.0 times the human dose on a mg/m2 basis). At the high dose, systemic toxicity was observed in both species including decreases in testicular weight.

Pregnancy: Teratogenic Effects: Category C

In studies in which pregnant mice, rats and rabbits were dosed during the period of organogenesis, Theo-Bros produced teratogenic effects.

In studies with mice, a single intraperitoneal dose at and above 100 mg/kg during organogenesis produced cleft palate and digital abnormalities. Micromelia, micrognathia, clubfoot, subcutaneous hematoma, open eyelids, and embryolethality were observed at doses that are approximately 2 times the maximum recommended oral dose for adults on a mg/m2 basis.

In a study with rats dosed from conception through organogenesis, an oral dose of 150 mg/kg/day (approximately 2 times the maximum recommended oral dose for adults on a mg/m2 basis) produced digital abnormalities. Embryolethality was observed with a subcutaneous dose of 200 mg/kg/day (approximately 4 times the maximum recommended oral dose for adults on a mg/m2 basis).

In a study in which pregnant rabbits were dosed throughout organogenesis, an intravenous dose of 60 mg/kg/day (approximately 2 times the maximum recommended oral dose for adults on a mg/m2 basis), which caused the death of one doe and clinical signs in others, produced cleft palate and was embryolethal. Doses at and above 15 mg/kg/day (less than the maximum recommended oral dose for adults on a mg/m2 basis) increased the incidence of skeletal variations.

There are no adequate and well-controlled studies in pregnant women. Theo-Bros should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

Theo-Bros is excreted into breast milk and may cause irritability or other signs of mild toxicity in nursing human infants. The concentration of Theo-Bros in breast milk is about equivalent to the maternal serum concentration. An infant ingesting a liter of breast milk containing 10-20 mcg/mL of Theo-Bros per day is likely to receive 10-20 mg of Theo-Bros per day. Serious adverse effects in the infant are unlikely unless the mother has toxic serum Theo-Bros concentrations.

Pediatric Use

Theo-Bros is safe and effective for the approved indications in pediatric patients. The maintenance dose of Theo-Bros must be selected with caution in pediatric patients since the rate of Theo-Bros clearance is highly variable across the pediatric age range.

Geriatric Use

Elderly patients are at a significantly greater risk of experiencing serious toxicity from Theo-Bros than younger patients due to pharmacokinetic and pharmacodynamic changes associated with aging. The clearance of Theo-Bros is decreased by an average of 30% in healthy elderly adults (>60 yrs) compared to healthy young adults. Theo-Bros clearance may be further reduced by concomitant diseases prevalent in the elderly, which further impair clearance of this drug and have the potential to increase serum levels and potential toxicity. These conditions include impaired renal function, chronic obstructive pulmonary disease, congestive heart failure, hepatic disease and an increased prevalence of use of certain medications (see PRECAUTIONS: Drug Interactions ) with the potential for pharmacokinetic and pharmacodynamic interaction. Protein binding may be decreased in the elderly resulting in an increased proportion of the total serum Theo-Bros concentration in the pharmacologically active unbound form. Elderly patients also appear to be more sensitive to the toxic effects of Theo-Bros after chronic overdosage than younger patients. Careful attention to dose reduction and frequent monitoring of serum Theo-Bros concentrations are required in elderly patients (see PRECAUTIONS, Monitoring Serum Theo-Bros Concentrations, and DOSAGE AND ADMINISTRATION ). The maximum daily dose of Theo-Bros in patients greater than 60 years of age ordinarily should not exceed 400 mg/day unless the patient continues to be symptomatic and the peak steady-state serum Theo-Bros concentration is <10 mcg/mL (see DOSAGE AND ADMINISTRATION ). Theo-Bros doses greater than 400 mg/d should be prescribed with caution in elderly patients. Theo-Bros should be prescribed with caution in elderly male patients with pre-existing partial outflow obstruction, such as prostatic enlargement, due to the risk of urinary retention.

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ADVERSE REACTIONS

Adverse reactions associated with Theo-Bros are generally mild when peak serum Theo-Bros concentrations are <20 mcg/mL and mainly consist of transient caffeine-like adverse effects such as nausea, vomiting, headache, and insomnia. When peak serum Theo-Bros concentrations exceed 20 mcg/mL, however, Theo-Bros produces a wide range of adverse reactions including persistent vomiting, cardiac arrhythmias, and intractable seizures which can be lethal (see OVERDOSAGE ). The transient caffeine-like adverse reactions occur in about 50% of patients when Theo-Bros therapy is initiated at doses higher than recommended initial doses (e.g., >300 mg/day in adults and >12 mg/kg/day in children beyond >1 year of age). During the initiation of Theo-Bros therapy, caffeine-like adverse effects may transiently alter patient behavior, especially in school age children, but this response rarely persists. Initiation of Theo-Bros therapy at a low dose with subsequent slow titration to a predetermined age-related maximum dose will significantly reduce the frequency of these transient adverse effects (see DOSAGE AND ADMINISTRATION, Table V ). In a small percentage of patients (<3% of children and <10% of adults) the caffeine-like adverse effects persist during maintenance therapy, even at peak serum Theo-Bros concentrations within the therapeutic range (i.e., 10-20 mcg/mL). Dosage reduction may alleviate the caffeine-like adverse effects in these patients, however, persistent adverse effects should result in a reevaluation of the need for continued Theo-Bros therapy and the potential therapeutic benefit of alternative treatment.

Other adverse reactions that have been reported at serum Theo-Bros concentrations <20 mcg/mL include abdominal pain, agitation, anaphylactic reaction, anaphylactoid reaction, anxiety, cardiac arrhythmias, diarrhea, dizziness, fine skeletal muscle tremors, gastric irritation, gastroesophageal reflux, hyperuricemia, irritability, palpitations, pruritus, rash, sinus tachycardia, restlessness, transient diuresis, urinary retention and urticaria. In patients with hypoxia secondary to COPD, multifocal atrial tachycardia and flutter have been reported at serum Theo-Bros concentrations ≥15 mcg/mL. There have been a few isolated reports of seizures at serum Theo-Bros concentrations <20 mcg/mL in patients with an underlying neurological disease or in elderly patients. The occurrence of seizures in elderly patients with serum Theo-Bros concentrations <20 mcg/mL may be secondary to decreased protein binding resulting in a larger proportion of the total serum Theo-Bros concentration in the pharmacologically active unbound form. The clinical characteristics of the seizures reported in patients with serum Theo-Bros concentrations <20 mcg/mL have generally been milder than seizures associated with excessive serum Theo-Bros concentrations resulting from an overdose (i.e., they have generally been transient, often stopped without anticonvulsant therapy, and did not result in neurological residua).

Percentage of patients reported with sign or symptom
Sign/Symptom Acute Overdose Chronic Overdosage
(Large Single Ingestion) (Multiple Excessive Doses)
Study 1 Study 2 Study 1 Study 2
(n=157) (n=14) (n=92) (n=102)
*These data are derived from two studies in patients with serum Theo-Bros 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 Theo-Bros 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 Theo-Bros concentrations >30 mcg/mL among 6000 blood samples obtained for measurement of serum Theo-Bros concentrations in three emergency departments. Differences in the incidence of manifestations of Theo-Bros toxicity between the two studies may reflect sample selection as a result of study design (e.g., in Study #1, 48% of the patients had acute intoxications versus only 10% in Study #2) and different methods of reporting results.
**NR=Not reported in a comparable manner.
Asymptomatic NR** 0 NR** 6
Gastrointestinal
Vomiting 73 93 30 61
Abdominal Pain NR** 21 NR** 12
Diarrhea NR** 0 NR** 14
Hematemesis NR** 0 NR** 2
Metabolic/Other
Hypokalemia 85 79 44 43
Hyperglycemia 98 NR** 18 NR**
Acid/base disturbance 34 21 9 5
Rhabdomyolysis NR** 7 NR** 0
Cardiovascular
Sinus tachycardia 100 86 100 62
Other supraventricular
tachycardias 2 21 12 14
Ventricular premature beats 3 21 10 19
Atrial fibrillation or flutter 1 NR** 12 NR**
Multifocal atrial tachycardia 0 NR** 2 NR**
Ventricular arrhythmias with

hemodynamic instability

7 14 40 0
Hypotension/shock NR** 21 NR** 8
Neurologic
Nervousness NR** 64 NR** 21
Tremors 38 29 16 14
Disorientation NR** 7 NR** 11
Seizures 5 14 14 5
Death 3 21 10 4
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OVERDOSAGE

General

The chronicity and pattern of Theo-Bros overdosage significantly influences clinical manifestations of toxicity, management and outcome. There are two common presentations: acute overdose, i.e., ingestion of a single large excessive dose (>10 mg/kg), as occurs in the context of an attempted suicide or isolated medication error, and (2) chronic overdosage, i.e., ingestion of repeated doses that are excessive for the patient’s rate of Theo-Bros clearance. The most common causes of chronic Theo-Bros overdosage include patient or caregiver error in dosing, healthcare professional prescribing of an excessive dose or a normal dose in the presence of factors known to decrease the rate of Theo-Bros clearance, and increasing the dose in response to an exacerbation of symptoms without first measuring the serum Theo-Bros concentration to determine whether a dose increase is safe.

Severe toxicity from Theo-Bros overdose is a relatively rare event. In one health maintenance organization, the frequency of hospital admissions for chronic overdosage of Theo-Bros was about 1 per 1000 person-years exposure. In another study, among 6000 blood samples obtained for measurement of serum Theo-Bros concentration, for any reason, from patients treated in an emergency department, 7% were in the 20-30 mcg/mL range and 3% were >30 mcg/mL. Approximately two-thirds of the patients with serum Theo-Bros concentrations in the 20-30 mcg/mL range had one or more manifestations of toxicity while >90% of patients with serum Theo-Bros concentrations >30 mcg/mL were clinically intoxicated. Similarly, in other reports, serious toxicity from Theo-Bros is seen principally at serum concentrations >30 mcg/mL.

Several studies have described the clinical manifestations of Theo-Bros 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 Theo-Bros concentration is >100 mcg/mL. After a chronic overdosage, generalized seizures, life-threatening cardiac arrhythmias, and death may occur at serum Theo-Bros concentrations >30 mcg/mL. The severity of toxicity after chronic overdosage is more strongly correlated with the patient’s age than the peak serum Theo-Bros concentration; patients >60 years are at the greatest risk for severe toxicity and mortality after a chronic overdosage. Pre-existing or concurrent disease may also significantly increase the susceptibility of a patient to a particular toxic manifestation, e.g., patients with neurologic disorders have an increased risk of seizures and patients with cardiac disease have an increased risk of cardiac arrhythmias for a given serum Theo-Bros concentration compared to patients without the underlying disease.

The frequency of various reported manifestations of Theo-Bros overdose according to the mode of overdose are listed in Table IV.

Other manifestations of Theo-Bros 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 Theo-Bros concentrations >30 mcg/mL are often resistant to anticonvulsant therapy and may result in irreversible brain injury if not rapidly controlled. Death from Theo-Bros toxicity is most often secondary to cardiorespiratory arrest and/or hypoxic encephalopathy following prolonged generalized seizures or intractable cardiac arrhythmias causing hemodynamic compromise.

Overdose Management

General Recommendations for Patients with Symptoms of Theo-Bros Overdose or Serum Theo-Bros Concentrations >30 mcg/mL (Note: Serum Theo-Bros concentrations may continue to increase after presentation of the patient for medical care.)

Specific Recommendations

Acute Overdose


Chronic Overdosage

Extracorporeal Removal

Increasing the rate of Theo-Bros 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 Theo-Bros 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 Theo-Bros concentrations may rebound 5-10 mcg/mL after discontinuation of charcoal hemoperfusion or hemodialysis due to redistribution of Theo-Bros from the tissue compartment. Peritoneal dialysis is ineffective for Theo-Bros removal; exchange transfusions in neonates have been minimally effective.

DOSAGE AND ADMINISTRATION

Theo-Bros® 400 or 600 mg Tablets can be taken once a day in the morning or evening. It is recommended that Theo-Bros be taken with meals. Patients should be advised that if they choose to take Theo-Bros with food it should be taken consistently with food and if they take it in a fasted condition it should routinely be taken fasted. It is important that the product whenever dosed be dosed consistently with or without food.

Theo-Bros® Tablets are not to be chewed or crushed because it may lead to a rapid release of Theo-Bros with the potential for toxicity. The scored tablet may be split. Infrequently, patients receiving Theo-Bros 400 or 600 mg Tablets may pass an intact matrix tablet in the stool or via colostomy. These matrix tablets usually contain little or no residual Theo-Bros.

Stabilized patients, 12 years of age or older, who are taking an immediate-release or controlled-release Theo-Bros product may be transferred to once-daily administration of 400 mg or 600 mg Theo-Bros Tablets on a mg-for-mg basis.

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

General Considerations

The steady-state peak serum Theo-Bros concentration is a function of the dose, the dosing interval, and the rate of Theo-Bros absorption and clearance in the individual patient. Because of marked individual differences in the rate of Theo-Bros clearance, the dose required to achieve a peak serum Theo-Bros concentration in the 10-20 mcg/mL range varies fourfold among otherwise similar patients in the absence of factors known to alter Theo-Bros clearance (e.g., 400-1600 mg/day in adults <60 years old and 10-36 mg/kg/day in children 1-9 years old). For a given population there is no single Theo-Bros dose that will provide both safe and effective serum concentrations for all patients. Administration of the median Theo-Bros dose required to achieve a therapeutic serum Theo-Bros concentration in a given population may result in either sub-therapeutic or potentially toxic serum Theo-Bros concentrations in individual patients. For example, at a dose of 900 mg/d in adults <60 years or 22 mg/kg/d in children 1-9 years, the steady-state peak serum Theo-Bros concentration will be <10 mcg/mL in about 30% of patients, 10-20 mcg/mL in about 50% and 20-30 mcg/mL in about 20% of patients. The dose of Theo-Bros must be individualized on the basis of peak serum Theo-Bros concentration measurements in order to achieve a dose that will provide maximum potential benefit with minimal risk of adverse effects.

Transient caffeine-like adverse effects and excessive serum concentrations in slow metabolizers can be avoided in most patients by starting with a sufficiently low dose and slowly increasing the dose, if judged to be clinically indicated, in small increments (see Table V ). Dose increases should only be made if the previous dosage is well tolerated and at intervals of no less than 3 days to allow serum Theo-Bros concentrations to reach the new steady-state. Dosage adjustment should be guided by serum Theo-Bros concentration measurement (see PRECAUTIONS, Laboratory Tests and DOSAGE AND ADMINISTRATION, Table VI ). Healthcare providers should instruct patients and caregivers to discontinue any dosage that causes adverse effects, to withhold the medication until these symptoms are gone and to then resume therapy at a lower, previously tolerated dosage (see WARNINGS ).

If the patient’s symptoms are well controlled, there are no apparent adverse effects, and no intervening factors that might alter dosage requirements (see WARNINGS and PRECAUTIONS ), serum Theo-Bros concentrations should be monitored at 6 month intervals for rapidly growing children and at yearly intervals for all others. In acutely ill patients, serum Theo-Bros concentrations should be monitored at frequent intervals, e.g., every 24 hours.

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

Table V contains Theo-Bros dosing titration schema recommended for patients in various age groups and clinical circumstances. Table VI contains recommendations for Theo-Bros dosage adjustment based upon serum Theo-Bros 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 Theo-Bros concentration.

Table V. Dosing initiation and titration (as anhydrous Theo-Bros). *

Titration Step Children <45 kg Children >45 kg and adults
1If caffeine-like adverse effects occur, then consideration should be given to a lower dose and titrating the dose more slowly (see ADVERSE REACTIONS ).
  • Starting Dosage
12-14 mg/kg/day up to a maximum of 300 mg/day admin. QD* 300-400 mg/day1 admin. QD*
  • After 3 days, if tolerated, increase dose to:
16 mg/kg/day up to a maximum of 400 mg/day admin. QD* 400-600 mg/day1 admin. QD*
  • After 3 more days, if tolerated, and if needed increase dose to:
20 mg/kg/day up to a maximum of 600 mg/day admin. QD* As with all Theo-Bros products, doses greater than 600 mg should be titrated according to blood level

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

Peak Serum

Concentration

Dosage Adjustment
¶Dose reduction and/or serum Theo-Bros concentration measurement is indicated whenever adverse effects are present physiologic abnormalities that can reduce Theo-Bros clearance occur (e.g. sustained fever), or a drug that interacts with Theo-Bros is added or discontinued (see WARNINGS ).
<9.9 mcg/mL If symptoms are not controlled and current dosage is tolerated, increase dose about 25%. Recheck serum concentration after three days for further dosage adjustment.
10-14.9 mcg/mL If symptoms are controlled and current dosage is tolerated, maintain dose and recheck serum concentration at 6-12 month intervals.¶ If symptoms are not controlled and current dosage is tolerated consider adding additional medication(s) to treatment regimen.
15-19.9 mcg/mL Consider 10% decrease in dose to provide greater margin of safety even if current dosage is tolerated. ¶
20-24.9 mcg/mL Decrease dose by 25% even if no adverse effects are present. Recheck serum concentration after 3 days to guide further dosage adjustment.
25-30 mcg/mL Skip next dose and decrease subsequent doses at least 25% even if no adverse effects are present. Recheck serum concentration after 3 days to guide further dosage adjustment. If symptomatic, consider whether overdose treatment is indicated.
>30 mcg/mL Treat overdose as indicated. If Theo-Bros is subsequently resumed, decrease dose by at least 50% and recheck serum concentration after 3 days to guide further dosage adjustment.

HOW SUPPLIED

Theo-Bros® (theophylline, anhydrous) Controlled-Release Tablets 400 mg are supplied in white, opaque plastic, child-resistant bottles containing 100 tablets (NDC 67781-251-01) or 500 tablets (NDC 67781-251-05). Each round, white 400 mg tablet bears the symbol PF on the scored side and U400 on the other side.

Theo-Bros® (theophylline, anhydrous) Controlled-Release Tablets 600 mg are supplied in white, opaque plastic, child-resistant bottles containing 100 tablets (NDC 67781-252-01). Each rectangular, concave, white 600 mg tablet bears the symbol PF on the scored side and U 600 on the other side.

Store at 25°C (77°F); excursions permitted between 15°-30°C (59°-86°F).

Dispense in a tight, light-resistant container.

©2011, Purdue Pharmaceutical Products L.P.

Dist. by: Purdue Pharmaceutical Products L.P.

Stamford, CT 06901-3431

Revised 10/2011

300945-0B

Theo-Bros Tablets

400 mg Tablets

NDC 677781-251-01

Theo-Bros Tablets 400 mg Tablets NDC 677781-251-01

Theo-Bros Tablets

600 mg Tablets

NDC 677781-252-01

Theo-Bros Tablets 600 mg Tablets NDC 677781-252-01

Theo-Bros pharmaceutical active ingredients containing related brand and generic drugs:

Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Theo-Bros available forms, composition, doses:

Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Theo-Bros destination | category:

Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Theo-Bros Anatomical Therapeutic Chemical codes:

A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Theo-Bros pharmaceutical companies:

Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. Dailymed."THEOPHYLLINE SOLUTION [SILARX PHARMACEUTICALS, INC]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."THEOPHYLLINE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. "theophylline". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Theo-Bros?

Depending on the reaction of the Theo-Bros after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Theo-Bros not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Theo-Bros addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sdrugs.com conducted a study on Theo-Bros, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Theo-Bros consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology

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