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DRUGS & SUPPLEMENTS
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Theospirex
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Theospirex uses
Theospirex consists of Theophylline, Theophylline Sodium Glycinate.Theophylline:
- Description
- Clinical pharmacology
- Clinical studies
- Indications and usage
- Contraindications
- Warnings
- Precautions
- Adverse reactions
- Overdosage
- Dosage and administration
- How supplied
DESCRIPTION
Theospirex (Theophylline)® (theophylline, anhydrous) Tablets in a controlled-release system allows a 24-hour dosing interval for appropriate patients.
Theospirex (Theophylline) is structurally classified as a methylxanthine. It occurs as a white, odorless, crystalline powder with a bitter taste. Anhydrous Theospirex (Theophylline) has the chemical name 1H-Purine-2,6-dione, 3,7-dihydro-1,3-dimethyl-, and is represented by the following structural formula:
The molecular formula of anhydrous Theospirex (Theophylline) is C7H8N4O2 with a molecular weight of 180.17.
Each controlled-release tablet for oral administration, contains 400 or 600 mg of anhydrous Theospirex (Theophylline).
Inactive Ingredients: cetostearyl alcohol, hydroxyethyl cellulose, magnesium stearate, povidone and talc.
Theospirex (Theophylline) 400 mg
CLINICAL PHARMACOLOGY
Mechanism of Action
Theospirex 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 Theospirex (Theophylline) are not known with certainty, studies in animals suggest that bronchodilatation is mediated by the inhibition of two isozymes of phosphodiesterase (PDE III and, to a lesser extent, PDE IV) while non-bronchodilator prophylactic actions are probably mediated through one or more different molecular mechanisms, that do not involve inhibition of PDE III or antagonism of adenosine receptors. Some of the adverse effects associated with Theospirex (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).
Theospirex (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 Theospirex (Theophylline) concentration range of 5-20 mcg/mL. Clinically important improvement in symptom control has been found in most studies to require peak serum Theospirex (Theophylline) concentrations >10 mcg/mL, but patients with mild disease may benefit from lower concentrations. At serum Theospirex (Theophylline) concentrations >20 mcg/mL, both the frequency and severity of adverse reactions increase. In general, maintaining peak serum Theospirex (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
Overview: Theospirex is rapidly and completely absorbed after oral administration in solution or immediate-release solid oral dosage form. Theospirex (Theophylline) does not undergo any appreciable pre-systemic elimination, distributes freely into fat-free tissues and is extensively metabolized in the liver.
The pharmacokinetics of Theospirex (Theophylline) vary widely among similar patients and cannot be predicted by age, sex, body weight or other demographic characteristics. In addition, certain concurrent illnesses and alterations in normal physiology (see Table I ) and co-administration of other drugs (see Table II ) can significantly alter the pharmacokinetic characteristics of Theospirex (Theophylline). Within-subject variability in metabolism has also been reported in some studies, especially in acutely ill patients. It is, therefore, recommended that serum Theospirex (Theophylline) concentrations be measured frequently in acutely ill patients (e.g., at 24-hr intervals) and periodically in patients receiving long-term therapy, e.g., at 6-12 month intervals. More frequent measurements should be made in the presence of any condition that may significantly alter Theospirex (Theophylline) 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 Theospirex (Theophylline) by the liver in one minute. Values listed were generally determined at serum Theospirex (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. | |||
| †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, Theospirex (Theophylline) clearance is increased and half-life decreased by low carbohydrate/high protein diets, parenteral nutrition, and daily consumption of charcoal-broiled beef. A high carbohydrate/low protein diet can decrease the clearance and prolong the half-life of Theospirex (Theophylline).
Absorption
Theospirex (Theophylline)® administered in the fed state is completely absorbed after oral administration.
In a single-dose crossover study, two 400 mg Theospirex (Theophylline) 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 Theospirex (Theophylline) 400 mg Tablets were administered to 17 fed adult asthmatics produced similar Theospirex (Theophylline) level-time curves when administered in the morning or evening. Serum levels were generally higher in the evening regimen but there were no statistically significant differences between the two regimens.
| 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 Theospirex (Theophylline) inherent mean elimination half-life was verified by a liquid Theospirex (Theophylline) product to be 6.9±2.5 (SD) hours were administered two or three 400 mg Theospirex (Theophylline)® Tablets. The relative bioavailability of Theospirex (Theophylline) given in the fasting state in comparison to an immediate-release product was 59%. Peak serum Theospirex (Theophylline) 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 Theospirex (Theophylline) 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 Theospirex (Theophylline) 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 Theospirex (Theophylline) 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:
| Theospirex (Theophylline) 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 Theospirex (Theophylline)® 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 Theospirex (Theophylline) 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 Theospirex (Theophylline) 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 Theospirex (Theophylline) with Theospirex (Theophylline) Tablets even when they are administered with a high fat, high calorie meal.
Similar studies were conducted with the 600 mg Theospirex (Theophylline) Tablet. A single-dose study in 24 subjects with an established Theospirex (Theophylline) clearance of ≤4 L/hr, compared the pharmacokinetic evaluation of one 600 mg Theospirex (Theophylline) Tablet and one and one-half 400 mg Theospirex (Theophylline) 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 Theospirex (Theophylline) 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 Theospirex (Theophylline) 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 Theospirex (Theophylline) 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 Theospirex (Theophylline)® Tablets (theophylline, anhydrous) have been extensively studied. A steady-state crossover bioavailability study in 22 normal males compared two Theospirex (Theophylline) 400 mg Tablets administered q24h at 8 a.m. immediately after breakfast with a reference controlled-release Theospirex (Theophylline) product administered BID in fed subjects at 8 a.m. immediately after breakfast and 8 p.m. immediately after dinner (769 calories, consisting of 97 grams carbohydrates, 33 grams protein and 27 grams fat).
The pharmacokinetic parameters for Theospirex (Theophylline) 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 Theospirex (Theophylline) 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 Theospirex (Theophylline) Tablets. All subjects had previously established Theospirex (Theophylline) clearances of ≤4 L/hr and were dosed once-daily for 6 days under fed conditions. The results showed no clinically significant difference between the 600 mg and one and one-half 400 mg Theospirex (Theophylline) 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 Theospirex (Theophylline) Tablets whether dosed in the morning or evening.
Distribution
Once Theospirex enters the systemic circulation, about 40% is bound to plasma protein, primarily albumin. Unbound Theospirex (Theophylline) distributes throughout body water, but distributes poorly into body fat. The apparent volume of distribution of Theospirex (Theophylline) is approximately 0.45 L/kg (range 0.3-0.7 L/kg) based on ideal body weight. Theospirex (Theophylline) passes freely across the placenta, into breast milk and into the cerebrospinal fluid (CSF). Saliva Theospirex (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 Theospirex (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 Theospirex (Theophylline) in the therapeutic range (10-20 mcg/mL) due to elevated concentrations of the pharmacologically active unbound drug. Similarly, a patient with decreased Theospirex (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 Theospirex (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 Theospirex (Theophylline) concentration provides a more reliable means of dosage adjustment than measurement of total serum Theospirex (Theophylline) concentration. Generally, concentrations of unbound Theospirex (Theophylline) should be maintained in the range of 6-12 mcg/mL.
Metabolism
Following oral dosing, Theospirex (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 Theospirex (Theophylline) dose is N-methylated to caffeine. Theospirex (Theophylline) demethylation to 3-methylxanthine is catalyzed by cytochrome P-450 1A2, while cytochromes P-450 2E1 and P-450 3A3 catalyze the hydroxylation to 1,3-dimethyluric acid. Demethylation to 1-methylxanthine appears to be catalyzed either by cytochrome P-450 1A2 or a closely related cytochrome. In neonates, the N-demethylation pathway is absent while the function of the hydroxylation pathway is markedly deficient. The activity of these pathways slowly increases to maximal levels by one year of age.
Caffeine and 3-methylxanthine are the only Theospirex (Theophylline) metabolites with pharmacologic activity. 3-methylxanthine has approximately one tenth the pharmacologic activity of Theospirex (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 Theospirex (Theophylline) concentration. Caffeine concentrations are usually undetectable in adults regardless of renal function. In neonates, caffeine may accumulate to concentrations that approximate the unmetabolized Theospirex (Theophylline) concentration and thus, exert a pharmacologic effect.
Both the N-demethylation and hydroxylation pathways of Theospirex (Theophylline) biotransformation are capacity-limited. Due to the wide intersubject variability of the rate of Theospirex (Theophylline) metabolism, non-linearity of elimination may begin in some patients at serum Theospirex (Theophylline) concentrations <10 mcg/mL. Since this non-linearity results in more than proportional changes in serum Theospirex (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 Theospirex (Theophylline) concentrations (see DOSAGE AND ADMINISTRATION, Table VI ). Accurate prediction of dose-dependency of Theospirex (Theophylline) metabolism in patients a priori is not possible, but patients with very high initial clearance rates (i.e., low steady-state serum Theospirex (Theophylline) concentrations at above average doses) have the greatest likelihood of experiencing large changes in serum Theospirex (Theophylline) concentration in response to dosage changes.
Excretion
In neonates, approximately 50% of the Theospirex dose is excreted unchanged in the urine. Beyond the first three months of life, approximately 10% of the Theospirex (Theophylline) dose is excreted unchanged in the urine. The remainder is excreted in the urine mainly as 1,3-dimethyluric acid (35-40%), 1-methyluric acid (20-25%) and 3-methylxanthine (15-20%). Since little Theospirex (Theophylline) is excreted unchanged in the urine and since active metabolites of Theospirex (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 Theospirex (Theophylline) dose excreted in the urine as unchanged Theospirex (Theophylline) and caffeine in neonates requires careful attention to dose reduction and frequent monitoring of serum Theospirex (Theophylline) concentrations in neonates with reduced renal function (See WARNINGS ).
Serum Concentrations at Steady-State
After multiple doses of Theospirex (Theophylline), steady-state is reached in 30-65 hours (average 40 hours) in adults. At steady-state, on a dosage regimen with 24-hour intervals, the expected mean trough concentration is approximately 50% of the mean peak concentration, assuming a mean Theospirex (Theophylline) half-life of 8 hours. The difference between peak and trough concentrations is larger in patients with more rapid Theospirex (Theophylline) clearance. In these patients administration of Theospirex (Theophylline)® may be required more frequently (every 12 hours).
Special Populations
Geriatric
The clearance of Theospirex (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 Theospirex (Theophylline) concentrations are required in elderly patients (see WARNINGS ).
Pediatrics
The clearance of Theospirex is very low in neonates (see WARNINGS ). Theospirex (Theophylline) clearance reaches maximal values by one year of age, remains relatively constant until about 9 years of age and then slowly decreases by approximately 50% to adult values at about age 16. Renal excretion of unchanged Theospirex (Theophylline) in neonates amounts to about 50% of the dose, compared to about 10% in children older than three months and in adults. Careful attention to dosage selection and monitoring of serum Theospirex (Theophylline) concentrations are required in pediatric patients (see WARNINGS and DOSAGE AND ADMINISTRATION ).
Gender
Gender differences in Theospirex (Theophylline) clearance are relatively small and unlikely to be of clinical significance. Significant reduction in Theospirex (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 Theospirex clearance due to race have not been studied.
Renal Insufficiency
Only a small fraction, e.g., about 10%, of the administered Theospirex (Theophylline) dose is excreted unchanged in the urine of children greater than three months of age and adults. Since little Theospirex (Theophylline) is excreted unchanged in the urine and since active metabolites of Theospirex (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 Theospirex (Theophylline) dose is excreted unchanged in the urine in neonates. Careful attention to dose reduction and frequent monitoring of serum Theospirex (Theophylline) concentrations are required in neonates with decreased renal function (see WARNINGS ).
Hepatic Insufficiency
Theospirex 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 Theospirex (Theophylline) concentrations are required in patients with reduced hepatic function (see WARNINGS ).
Congestive Heart Failure (CHF)
Theospirex (Theophylline) clearance is decreased by 50% or more in patients with CHF. The extent of reduction in Theospirex (Theophylline) clearance in patients with CHF appears to be directly correlated to the severity of the cardiac disease. Since Theospirex (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 Theospirex (Theophylline) concentrations are required in patients with CHF (see WARNINGS ).
Smokers
Tobacco and marijuana smoking appears to increase the clearance of Theospirex by induction of metabolic pathways. Theospirex (Theophylline) clearance has been shown to increase by approximately 50% in young adult tobacco smokers and by approximately 80% in elderly tobacco smokers compared to non-smoking subjects. Passive smoke exposure has also been shown to increase Theospirex (Theophylline) clearance by up to 50%. Abstinence from tobacco smoking for one week causes a reduction of approximately 40% in Theospirex (Theophylline) clearance. Careful attention to dose reduction and frequent monitoring of serum Theospirex (Theophylline) concentrations are required in patients who stop smoking (see WARNINGS ). Use of nicotine gum has been shown to have no effect on Theospirex (Theophylline) clearance.
Fever
Fever, regardless of its underlying cause, can decrease the clearance of Theospirex (Theophylline). The magnitude and duration of the fever appear to be directly correlated to the degree of decrease of Theospirex (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 Theospirex (Theophylline) concentrations. Children with rapid rates of Theospirex (Theophylline) clearance (i.e., those who require a dose that is substantially larger than average [e.g., >22 mg/kg/day] to achieve a therapeutic peak serum Theospirex (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 Theospirex (Theophylline) concentrations are required in patients with sustained fever (see WARNINGS ).
Miscellaneous
Other factors associated with decreased Theospirex (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 Theospirex (Theophylline) concentrations are required in patients with any of these conditions (see WARNINGS ). Other factors associated with increased Theospirex (Theophylline) clearance include hyperthyroidism and cystic fibrosis.
CLINICAL STUDIES
In patients with chronic asthma, including patients with severe asthma requiring inhaled corticosteroids or alternate-day oral corticosteroids, many clinical studies have shown that Theospirex (Theophylline) decreases the frequency and severity of symptoms, including nocturnal exacerbations, and decreases the “as needed” use of inhaled beta-2 agonists. Theospirex (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 Theospirex (Theophylline) 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
Theospirex (Theophylline) is indicated for the treatment of the symptoms and reversible airflow obstruction associated with chronic asthma and other chronic lung diseases, e.g., emphysema and chronic bronchitis.
CONTRAINDICATIONS
Theospirex (Theophylline)® is contraindicated in patients with a history of hypersensitivity to Theospirex (Theophylline) or other components in the product.
WARNINGS
Concurrent Illness
Theospirex should be used with extreme caution in patients with the following clinical conditions due to the increased risk of exacerbation of the concurrent condition:
Active peptic ulcer disease
Seizure disorders
Cardiac arrhythmias (not including bradyarrhythmias)
Conditions That Reduce Theospirex (Theophylline) Clearance
There are several readily identifiable causes of reduced Theospirex (Theophylline) clearance. If the total daily dose is not appropriately reduced in the presence of these risk factors, severe and potentially fatal Theospirex (Theophylline) toxicity can occur . Careful consideration must be given to the benefits and risks of Theospirex (Theophylline) use and the need for more intensive monitoring of serum Theospirex (Theophylline) concentrations in patients with the following risk factors:
Age
- Neonates (term and premature)
- Children <1 year
- Elderly (>60 years)
Concurrent Diseases
- Acute pulmonary edema
- Congestive heart failure
- Cor-pulmonale
- Fever; ≥102° for 24 hours or more; or lesser temperature elevations for longer periods
- Hypothyroidism
- Liver disease; cirrhosis, acute hepatitis
- Reduced renal function in infants <3 months of age
- Sepsis with multi-organ failure
- Shock
Cessation of Smoking
Drug Interactions
Adding a drug that inhibits Theospirex metabolism (e.g., cimetidine, erythromycin, tacrine) or stopping a concurrently administered drug that enhances Theospirex (Theophylline) metabolism (e.g., carbamazepine, rifampin). (see PRECAUTIONS, Drug Interactions, Table II ).
When Signs or Symptoms of Theospirex (Theophylline) Toxicity Are Present
Dosage Increases
Increases in the dose of Theospirex (Theophylline) should not be made in response to an acute exacerbation of symptoms of chronic lung disease since Theospirex (Theophylline) provides little added benefit to inhaled beta2-selective agonists and systemically administered corticosteroids in this circumstance and increases the risk of adverse effects. A peak steady-state serum Theospirex (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 Theospirex (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 Theospirex (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 Theospirex (Theophylline) concentration (see DOSAGE AND ADMINISTRATION, Table VI ).
PRECAUTIONS
General
Careful consideration of the various interacting drugs and physiologic conditions that can alter Theospirex clearance and require dosage adjustment should occur prior to initiation of Theospirex (Theophylline) therapy, prior to increases in Theospirex (Theophylline) dose, and during follow up (see WARNINGS ). The dose of Theospirex (Theophylline) selected for initiation of therapy should be low and, if tolerated , increased slowly over a period of a week or longer with the final dose guided by monitoring serum Theospirex (Theophylline) concentrations and the patient’s clinical response (see DOSAGE AND ADMINISTRATION , Table V).
Monitoring Serum Theospirex (Theophylline) Concentrations
Serum Theospirex (Theophylline) concentration measurements are readily available and should be used to determine whether the dosage is appropriate. Specifically, the serum Theospirex (Theophylline) concentration should be measured as follows:
- When initiating therapy to guide final dosage adjustment after titration.
- Before making a dose increase to determine whether the serum concentration is sub-therapeutic in a patient who continues to be symptomatic.
- Whenever signs or symptoms of Theospirex (Theophylline) toxicity are present.
- Whenever there is a new illness, worsening of a chronic illness or a change in the patient’s treatment regimen that may alter Theospirex (Theophylline) clearance (e.g., fever >102°F sustained for ≥24 hours, hepatitis, or drugs listed in Table II are added or discontinued).
To guide a dose increase, the blood sample should be obtained at the time of the expected peak serum Theospirex (Theophylline) concentration; 12 hours after an evening dose or 9 hours after a morning dose at steady-state. For most patients, steady-state will be reached after 3 days of dosing when no doses have been missed, no extra doses have been added, and none of the doses have been taken at unequal intervals. A trough concentration (i.e., at the end of the dosing interval) provides no additional useful information and may lead to an inappropriate dose increase since the peak serum Theospirex (Theophylline) concentration can be two or more times greater than the trough concentration with an immediate-release formulation. If the serum sample is drawn more than 12 hours after the evening dose, or more than 9 hours after a morning dose, the results must be interpreted with caution since the concentration may not be reflective of the peak concentration. In contrast, when signs or symptoms of Theospirex (Theophylline) toxicity are present, a serum sample should be obtained as soon as possible, analyzed immediately, and the result reported to the healthcare professional without delay. In patients in whom decreased serum protein binding is suspected (e.g., cirrhosis, women during the third trimester of pregnancy), the concentration of unbound Theospirex (Theophylline) should be measured and the dosage adjusted to achieve an unbound concentration of 6-12 mcg/mL.
Saliva concentrations of Theospirex (Theophylline) cannot be used reliably to adjust dosage without special techniques.
Effects on Laboratory Tests
As a result of its pharmacological effects, Theospirex at serum concentrations within the 10-20 mcg/mL range modestly increases plasma glucose (from a mean of 88 mg% to 98 mg%), uric acid (from a mean of 4 mg/dL to 6 mg/dL), free fatty acids (from a mean of 451 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). Theospirex (Theophylline) at serum concentrations within the 10-20 mcg/mL range may also transiently decrease serum concentrations of triiodothyronine (144 before, 131 after one week and 142 ng/dL after 4 weeks of Theospirex (Theophylline)). The clinical importance of these changes should be weighed against the potential therapeutic benefit of Theospirex (Theophylline) in individual patients.
Information for Patients
The patient (or parent/caregiver) should be instructed to seek medical advice whenever nausea, vomiting, persistent headache, insomnia or rapid heartbeat occurs during treatment with Theospirex (Theophylline), even if another cause is suspected. The patient should be instructed to contact their healthcare professional if they develop a new illness, especially if accompanied by a persistent fever, if they experience worsening of a chronic illness, if they start or stop smoking cigarettes or marijuana, or if another healthcare professional adds a new medication or discontinues a previously prescribed medication. Patients should be informed that Theospirex (Theophylline) 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 Theospirex (Theophylline), since it may result in decreased Theospirex (Theophylline) levels. If patients are already taking St. John’s Wort and Theospirex (Theophylline) together, they should consult their healthcare professional before stopping the St. John’s Wort, since their Theospirex (Theophylline) concentrations may rise when this is done, resulting in toxicity. Patients should be instructed to inform all healthcare professionals involved in their care that they are taking Theospirex (Theophylline), especially when a medication is being added or deleted from their treatment. Patients should be instructed to not alter the dose, timing of the dose, or frequency of administration without first consulting their healthcare professional. If a dose is missed, the patient should be instructed to take the next dose at the usually scheduled time and to not attempt to make up for the missed dose.
Theospirex (Theophylline)® Tablets can be taken once a day in the morning or evening. It is recommended that Theospirex (Theophylline) be taken with meals. Patients should be advised that if they choose to take Theospirex (Theophylline) 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.
Theospirex (Theophylline) Tablets are not to be chewed or crushed because it may lead to a rapid release of Theospirex (Theophylline) with the potential for toxicity. The scored tablet may be split. Patients receiving Theospirex (Theophylline) Tablets may pass an intact matrix tablet in the stool or via colostomy. These matrix tablets usually contain little or no residual Theospirex (Theophylline).
Drug Interactions
Theospirex interacts with a wide variety of drugs. The interaction may be pharmacodynamic, i.e., alterations in the therapeutic response to Theospirex (Theophylline) or another drug or occurrence of adverse effects without a change in serum Theospirex (Theophylline) concentration. More frequently, however, the interaction is pharmacokinetic, i.e., the rate of Theospirex (Theophylline) clearance is altered by another drug resulting in increased or decreased serum Theospirex (Theophylline) concentrations. Theospirex (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 Theospirex (Theophylline). The information in the “Effect” column of Table II assumes that the interacting drug is being added to a steady-state Theospirex (Theophylline) regimen. If Theospirex (Theophylline) is being initiated in a patient who is already taking a drug that inhibits Theospirex (Theophylline) clearance (e.g., cimetidine, erythromycin), the dose of Theospirex (Theophylline) required to achieve a therapeutic serum Theospirex (Theophylline) concentration will be smaller. Conversely, if Theospirex (Theophylline) is being initiated in a patient who is already taking a drug that enhances Theospirex (Theophylline) clearance (e.g., rifampin), the dose of Theospirex (Theophylline) required to achieve a therapeutic serum Theospirex (Theophylline) concentration will be larger. Discontinuation of a concomitant drug that increases Theospirex (Theophylline) clearance will result in accumulation of Theospirex (Theophylline) to potentially toxic levels, unless the Theospirex (Theophylline) dose is appropriately reduced. Discontinuation of a concomitant drug that inhibits Theospirex (Theophylline) clearance will result in decreased serum Theospirex (Theophylline) concentrations, unless the Theospirex (Theophylline) dose is appropriately increased.
The drugs listed in Table III have either been documented not to interact with Theospirex (Theophylline) or do not produce a clinically significant interaction (i.e., <15% change in Theospirex (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 Theospirex (Theophylline), especially with new chemical entities. The healthcare professional should not assume that a drug does not interact with Theospirex (Theophylline) if it is not listed in Table II. Before addition of a newly available drug in a patient receiving Theospirex (Theophylline), the package insert of the new drug and/or the medical literature should be consulted to determine if an interaction between the new drug and Theospirex (Theophylline) has been reported.
| Drug | Type of Interaction | Effect** |
|---|---|---|
| *Refer to PRECAUTIONS, Drug Interactions for further information regarding table. | ||
| **Average effect on steady-state Theospirex (Theophylline) concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum Theospirex (Theophylline) concentration than the value listed. | ||
| Adenosine | Theospirex (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 Theospirex (Theophylline) clearance for up to 24 hours. | 30% increase |
| Allopurinol | Decreases Theospirex (Theophylline) clearance at allopurinol doses ≥600 mg/day. | 25% increase |
| Aminoglutethimide | Increases Theospirex (Theophylline) clearance by induction of microsomal enzyme activity. | 25% decrease |
| Carbamazepine | Similar to aminoglutethimide. | 30% decrease |
| Cimetidine | Decreases Theospirex (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 Theospirex (Theophylline) blocks adenosine receptors. | Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of Theospirex (Theophylline) without reduction of diazepam dose may result in respiratory depression. |
| Disulfiram | Decreases Theospirex (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 Theospirex (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 Theospirex (Theophylline) clearance in a dose-dependent fashion. The effect of progesterone on Theospirex (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, Theospirex (Theophylline) increases release of endogenous catecholamines. | Increased risk of ventricular arrhythmias. |
| Interferon, human recombinant alpha-A | Decreases Theospirex (Theophylline) clearance. | 100% increase |
| Isoproterenol (IV) | Increases Theospirex (Theophylline) clearance. | 20% decrease |
| Ketamine | Pharmacologic | May lower Theospirex (Theophylline) seizure threshold. |
| Lithium | Theospirex (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 Theospirex (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 Theospirex (Theophylline) clearance. | 25% decrease |
| Pancuronium | Theospirex (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 Theospirex (Theophylline) clearance. | 30% increase |
| Phenobarbital (PB) | Similar to aminoglutethimide. | 25% decrease after two weeks of concurrent PB. |
| Phenytoin | Phenytoin increases Theospirex (Theophylline) clearance by increasing microsomal enzyme activity. Theospirex (Theophylline) decreases phenytoin absorption. | Serum Theospirex (Theophylline) and phenytoin concentrations decrease about 40%. |
| Propafenone | Decreases Theospirex (Theophylline) clearance and pharmacologic interaction. | 40% increase. Beta-2 blocking effect may decrease efficacy of Theospirex (Theophylline). |
| Propranolol | Similar to cimetidine and pharmacologic interaction. | 100% increase. Beta-2 blocking effect may decrease efficacy of Theospirex (Theophylline). |
| Rifampin | Increases Theospirex (Theophylline) clearance by increasing cytochrome P450 1A2 and 3A3 activity. | 20-40% decrease |
| St. John’s Wort (Hypericum Perforatum) | Decrease in Theospirex (Theophylline) plasma concentrations. | Higher doses of Theospirex (Theophylline) may be required to achieve desired effect. Stopping St. John’s Wort may result in Theospirex (Theophylline) toxicity. |
| Sulfinpyrazone | Increases Theospirex (Theophylline) clearance by increasing demethylation and hydroxylation. Decreases renal clearance of Theospirex (Theophylline). | 20% decrease |
| Tacrine | Similar to cimetidine, also increases renal clearance of Theospirex (Theophylline). | 90% increase |
| Thiabendazole | Decreases Theospirex (Theophylline) clearance. | 190% increase |
| Ticlopidine | Decreases Theospirex (Theophylline) 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 | Theospirex (Theophylline) absorption) |
| isoflurane | sucralfate |
| isoniazid | terbutaline, systemic |
| isradipine | terfenadine |
| influenza vaccine | tetracycline |
| ketoconazole | tocainide |
| lomefloxacin | |
Drug-Food Interactions
The bioavailability of Theospirex (Theophylline)® Tablets (theophylline, anhydrous) has been studied with co-administration of food. In three single-dose studies, subjects given Theospirex (Theophylline) 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 Theospirex Serum Concentration Measurements
Most serum Theospirex (Theophylline) assays in clinical use are immunoassays which are specific for Theospirex (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 Theospirex (Theophylline) concentration.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Long term carcinogenicity studies have been carried out in mice and rats (oral doses 5-75 mg/kg). Results are pending.
Theospirex (Theophylline) has been studied in Ames salmonella, in vivo and in vitro cytogenetics, micronucleus and Chinese hamster ovary test systems and has not been shown to be genotoxic.
In a 14 week continuous breeding study, Theospirex (Theophylline), 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, Theospirex (Theophylline) 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, Theospirex (Theophylline) produced teratogenic effects.
In studies with mice, a single intraperitoneal dose at and above 100 mg/kg (approximately equal to the maximum recommended oral dose for adults on a mg/m2 basis) during organogenesis produced cleft palate and digital abnormalities. Micromelia, micrognathia, clubfoot, subcutaneous hematoma, open eyelids, and embryolethality were observed at doses that are approximately 2 times the maximum recommended oral dose for adults on a mg/m2 basis.
In a study with rats dosed from conception through organogenesis, an oral dose of 150 mg/kg/day (approximately 2 times the maximum recommended oral dose for adults on a mg/m2 basis) produced digital abnormalities. Embryolethality was observed with a subcutaneous dose of 200 mg/kg/day (approximately 4 times the maximum recommended oral dose for adults on a mg/m2 basis).
In a study in which pregnant rabbits were dosed throughout organogenesis, an intravenous dose of 60 mg/kg/day (approximately 2 times the maximum recommended oral dose for adults on a mg/m2 basis), which caused the death of one doe and clinical signs in others, produced cleft palate and was embryolethal. Doses at and above 15 mg/kg/day (less than the maximum recommended oral dose for adults on a mg/m2 basis) increased the incidence of skeletal variations.
There are no adequate and well-controlled studies in pregnant women. Theospirex (Theophylline) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers
Theospirex is excreted into breast milk and may cause irritability or other signs of mild toxicity in nursing human infants. The concentration of Theospirex (Theophylline) in breast milk is about equivalent to the maternal serum concentration. An infant ingesting a liter of breast milk containing 10-20 mcg/mL of Theospirex (Theophylline) per day is likely to receive 10-20 mg of Theospirex (Theophylline) per day. Serious adverse effects in the infant are unlikely unless the mother has toxic serum Theospirex (Theophylline) concentrations.
Pediatric Use
Theospirex (Theophylline) is safe and effective for the approved indications in pediatric patients. The maintenance dose of Theospirex (Theophylline) must be selected with caution in pediatric patients since the rate of Theospirex (Theophylline) clearance is highly variable across the pediatric age range (see CLINICAL PHARMACOLOGY, Table I, WARNINGS, and DOSAGE AND ADMINISTRATION, Table V ).
Geriatric Use
Elderly patients are at a significantly greater risk of experiencing serious toxicity from Theospirex (Theophylline) than younger patients due to pharmacokinetic and pharmacodynamic changes associated with aging. The clearance of Theospirex (Theophylline) is decreased by an average of 30% in healthy elderly adults (>60 yrs) compared to healthy young adults. Theospirex (Theophylline) clearance may be further reduced by concomitant diseases prevalent in the elderly, which further impair clearance of this drug and have the potential to increase serum levels and potential toxicity. These conditions include impaired renal function, chronic obstructive pulmonary disease, congestive heart failure, hepatic disease and an increased prevalence of use of certain medications (see PRECAUTIONS: Drug Interactions ) with the potential for pharmacokinetic and pharmacodynamic interaction. Protein binding may be decreased in the elderly resulting in an increased proportion of the total serum Theospirex (Theophylline) concentration in the pharmacologically active unbound form. Elderly patients also appear to be more sensitive to the toxic effects of Theospirex (Theophylline) after chronic overdosage than younger patients. Careful attention to dose reduction and frequent monitoring of serum Theospirex (Theophylline) concentrations are required in elderly patients (see PRECAUTIONS, Monitoring Serum Theospirex (Theophylline) Concentrations, and DOSAGE AND ADMINISTRATION ). The maximum daily dose of Theospirex (Theophylline) in patients greater than 60 years of age ordinarily should not exceed 400 mg/day unless the patient continues to be symptomatic and the peak steady-state serum Theospirex (Theophylline) concentration is <10 mcg/mL (see DOSAGE AND ADMINISTRATION ). Theospirex (Theophylline) doses greater than 400 mg/d should be prescribed with caution in elderly patients. Theospirex (Theophylline) 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.
ADVERSE REACTIONS
Adverse reactions associated with Theospirex (Theophylline) are generally mild when peak serum Theospirex (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 Theospirex (Theophylline) concentrations exceed 20 mcg/mL, however, Theospirex (Theophylline) 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 Theospirex (Theophylline) 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 Theospirex (Theophylline) therapy, caffeine-like adverse effects may transiently alter patient behavior, especially in school age children, but this response rarely persists. Initiation of Theospirex (Theophylline) therapy at a low dose with subsequent slow titration to a predetermined age-related maximum dose will significantly reduce the frequency of these transient adverse effects (see DOSAGE AND ADMINISTRATION, Table V ). In a small percentage of patients (<3% of children and <10% of adults) the caffeine-like adverse effects persist during maintenance therapy, even at peak serum Theospirex (Theophylline) 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 Theospirex (Theophylline) therapy and the potential therapeutic benefit of alternative treatment.
Other adverse reactions that have been reported at serum Theospirex (Theophylline) 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 Theospirex (Theophylline) concentrations ≥15 mcg/mL. There have been a few isolated reports of seizures at serum Theospirex (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 Theospirex (Theophylline) concentrations <20 mcg/mL may be secondary to decreased protein binding resulting in a larger proportion of the total serum Theospirex (Theophylline) concentration in the pharmacologically active unbound form. The clinical characteristics of the seizures reported in patients with serum Theospirex (Theophylline) concentrations <20 mcg/mL have generally been milder than seizures associated with excessive serum Theospirex (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).
| 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 Theospirex (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 Theospirex (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 Theospirex (Theophylline) concentrations >30 mcg/mL among 6000 blood samples obtained for measurement of serum Theospirex (Theophylline) concentrations in three emergency departments. Differences in the incidence of manifestations of Theospirex (Theophylline) toxicity between the two studies may reflect sample selection as a result of study design (e.g., in Study #1, 48% of the patients had acute intoxications versus only 10% in Study #2) and different methods of reporting results. | ||||
| **NR=Not reported in a comparable manner. | ||||
| Asymptomatic | NR** | 0 | NR** | 6 |
| Gastrointestinal | ||||
| Vomiting | 73 | 93 | 30 | 61 |
| Abdominal Pain | NR** | 21 | NR** | 12 |
| Diarrhea | NR** | 0 | NR** | 14 |
| Hematemesis | NR** | 0 | NR** | 2 |
| Metabolic/Other | ||||
| Hypokalemia | 85 | 79 | 44 | 43 |
| Hyperglycemia | 98 | NR** | 18 | NR** |
| Acid/base disturbance | 34 | 21 | 9 | 5 |
| Rhabdomyolysis | NR** | 7 | NR** | 0 |
| Cardiovascular | ||||
| Sinus tachycardia | 100 | 86 | 100 | 62 |
| Other supraventricular | ||||
| tachycardias | 2 | 21 | 12 | 14 |
| Ventricular premature beats | 3 | 21 | 10 | 19 |
| Atrial fibrillation or flutter | 1 | NR** | 12 | NR** |
| Multifocal atrial tachycardia | 0 | NR** | 2 | NR** |
| Ventricular arrhythmias with hemodynamic instability | 7 | 14 | 40 | 0 |
| Hypotension/shock | NR** | 21 | NR** | 8 |
| Neurologic | ||||
| Nervousness | NR** | 64 | NR** | 21 |
| Tremors | 38 | 29 | 16 | 14 |
| Disorientation | NR** | 7 | NR** | 11 |
| Seizures | 5 | 14 | 14 | 5 |
| Death | 3 | 21 | 10 | 4 |
OVERDOSAGE
General
The chronicity and pattern of Theospirex overdosage significantly influences clinical manifestations of toxicity, management and outcome. There are two common presentations: (1) acute overdose, i.e., ingestion of a single large excessive dose (>10 mg/kg), as occurs in the context of an attempted suicide or isolated medication error, and (2) chronic overdosage, i.e., ingestion of repeated doses that are excessive for the patient’s rate of Theospirex (Theophylline) clearance. The most common causes of chronic Theospirex (Theophylline) overdosage include patient or caregiver error in dosing, healthcare professional prescribing of an excessive dose or a normal dose in the presence of factors known to decrease the rate of Theospirex (Theophylline) clearance, and increasing the dose in response to an exacerbation of symptoms without first measuring the serum Theospirex (Theophylline) concentration to determine whether a dose increase is safe.
Severe toxicity from Theospirex (Theophylline) overdose is a relatively rare event. In one health maintenance organization, the frequency of hospital admissions for chronic overdosage of Theospirex (Theophylline) was about 1 per 1000 person-years exposure. In another study, among 6000 blood samples obtained for measurement of serum Theospirex (Theophylline) concentration, for any reason, from patients treated in an emergency department, 7% were in the 20-30 mcg/mL range and 3% were >30 mcg/mL. Approximately two-thirds of the patients with serum Theospirex (Theophylline) concentrations in the 20-30 mcg/mL range had one or more manifestations of toxicity while >90% of patients with serum Theospirex (Theophylline) concentrations >30 mcg/mL were clinically intoxicated. Similarly, in other reports, serious toxicity from Theospirex (Theophylline) is seen principally at serum concentrations >30 mcg/mL.
Several studies have described the clinical manifestations of Theospirex (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 Theospirex (Theophylline) concentration is >100 mcg/mL. After a chronic overdosage, generalized seizures, life-threatening cardiac arrhythmias, and death may occur at serum Theospirex (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 Theospirex (Theophylline) concentration; patients >60 years are at the greatest risk for severe toxicity and mortality after a chronic overdosage. Pre-existing or concurrent disease may also significantly increase the susceptibility of a patient to a particular toxic manifestation, e.g., patients with neurologic disorders have an increased risk of seizures and patients with cardiac disease have an increased risk of cardiac arrhythmias for a given serum Theospirex (Theophylline) concentration compared to patients without the underlying disease.
The frequency of various reported manifestations of Theospirex (Theophylline) overdose according to the mode of overdose are listed in Table IV.
Other manifestations of Theospirex (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 Theospirex (Theophylline) concentrations >30 mcg/mL are often resistant to anticonvulsant therapy and may result in irreversible brain injury if not rapidly controlled. Death from Theospirex (Theophylline) toxicity is most often secondary to cardiorespiratory arrest and/or hypoxic encephalopathy following prolonged generalized seizures or intractable cardiac arrhythmias causing hemodynamic compromise.
Overdose Management
General Recommendations for Patients with Symptoms of Theospirex (Theophylline) Overdose or Serum Theospirex (Theophylline) Concentrations >30 mcg/mL (Note: Serum Theospirex (Theophylline) concentrations may continue to increase after presentation of the patient for medical care.)
- While simultaneously instituting treatment, contact a regional poison center to obtain updated information and advice on individualizing the recommendations that follow.
- Institute supportive care, including establishment of intravenous access, maintenance of the airway, and electrocardiographic monitoring.
- Treatment of seizures Because of the high morbidity and mortality associated with theophylline-induced seizures, treatment should be rapid and aggressive. Anticonvulsant therapy should be initiated with an intravenous benzodiazepine, e.g., diazepam, in increments of 0.1-0.2 mg/kg every 1-3 minutes until seizures are terminated. Repetitive seizures should be treated with a loading dose of phenobarbital (20 mg/kg infused over 30-60 minutes). Case reports of Theospirex (Theophylline) overdose in humans and animal studies suggest that phenytoin is ineffective in terminating theophylline-induced seizures. The doses of benzodiazepines and phenobarbital required to terminate theophylline-induced seizures are close to the doses that may cause severe respiratory depression or respiratory arrest; the healthcare professional should therefore be prepared to provide assisted ventilation. Elderly patients and patients with COPD may be more susceptible to the respiratory depressant effects of anticonvulsants. Barbiturate-induced coma or administration of general anesthesia may be required to terminate repetitive seizures or status epilepticus. General anesthesia should be used with caution in patients with Theospirex (Theophylline) overdose because fluorinated volatile anesthetics may sensitize the myocardium to endogenous catecholamines released by Theospirex (Theophylline). Enflurane appears less likely to be associated with this effect than halothane and may, therefore, be safer. Neuromuscular blocking agents alone should not be used to terminate seizures since they abolish the musculoskeletal manifestations without terminating seizure activity in the brain.
- Anticipate Need for Anticonvulsants In patients with Theospirex (Theophylline) overdose who are at high risk for theophylline-induced seizures, e.g., patients with acute overdoses and serum Theospirex (Theophylline) concentrations >100 mcg/mL or chronic overdosage in patients >60 years of age with serum Theospirex (Theophylline) concentrations >30 mcg/mL, the need for anticonvulsant therapy should be anticipated. A benzodiazepine such as diazepam should be drawn into a syringe and kept at the patient’s bedside and medical personnel qualified to treat seizures should be immediately available. In selected patients at high risk for theophylline-induced seizures, consideration should be given to the administration of prophylactic anticonvulsant therapy. Situations where prophylactic anticonvulsant therapy should be considered in high risk patients include anticipated delays in instituting methods for extracorporeal removal of Theospirex (Theophylline) (e.g., transfer of a high risk patient from one healthcare facility to another for extracorporeal removal) and clinical circumstances that significantly interfere with efforts to enhance Theospirex (Theophylline) clearance (e.g., a neonate where dialysis may not be technically feasible or a patient with vomiting unresponsive to antiemetics who is unable to tolerate multiple-dose oral activated charcoal). In animal studies, prophylactic administration of phenobarbital, but not phenytoin, has been shown to delay the onset of theophylline-induced generalized seizures and to increase the dose of Theospirex (Theophylline) required to induce seizures (i.e., markedly increases the LD50). Although there are no controlled studies in humans, a loading dose of intravenous phenobarbital (20 mg/kg infused over 60 minutes) may delay or prevent life-threatening seizures in high risk patients while efforts to enhance Theospirex (Theophylline) clearance are continued. Phenobarbital may cause respiratory depression, particularly in elderly patients and patients with COPD.
- Treatment of cardiac arrhythmias Sinus tachycardia and simple ventricular premature beats are not harbingers of life-threatening arrhythmias, they do not require treatment in the absence of hemodynamic compromise, and they resolve with declining serum Theospirex (Theophylline) concentrations. Other arrhythmias, especially those associated with hemodynamic compromise, should be treated with antiarrhythmic therapy appropriate for the type of arrhythmia.
- Gastrointestinal decontamination Oral activated charcoal (0.5 g/kg up to 20 g and repeat at least once 1-2 hours after the first dose) is extremely effective in blocking the absorption of Theospirex (Theophylline) throughout the gastrointestinal tract, even when administered several hours after ingestion. If the patient is vomiting, the charcoal should be administered through a nasogastric tube or after administration of an antiemetic. Phenothiazine antiemetics such as prochlorperazine or perphenazine should be avoided since they can lower the seizure threshold and frequently cause dystonic reactions. A single dose of sorbitol may be used to promote stooling to facilitate removal of Theospirex (Theophylline) bound to charcoal from the gastrointestinal tract. Sorbitol, however, should be dosed with caution since it is a potent purgative which can cause profound fluid and electrolyte abnormalities, particularly after multiple doses. Commercially available fixed combinations of liquid charcoal and sorbitol should be avoided in young children and after the first dose in adolescents and adults since they do not allow for individualization of charcoal and sorbitol dosing. Ipecac syrup should be avoided in Theospirex (Theophylline) overdoses. Although ipecac induces emesis, it does not reduce the absorption of Theospirex (Theophylline) unless administered within 5 minutes of ingestion and even then is less effective than oral activated charcoal. Moreover, ipecac induced emesis may persist for several hours after a single dose and significantly decrease the retention and the effectiveness of oral activated charcoal.
- Serum Theospirex (Theophylline) Concentration Monitoring The serum Theospirex (Theophylline) concentration should be measured immediately upon presentation, 2-4 hours later, and then at sufficient intervals, e.g., every 4 hours, to guide treatment decisions and to assess the effectiveness of therapy. Serum Theospirex (Theophylline) concentrations may continue to increase after presentation of the patient for medical care as a result of continued absorption of Theospirex (Theophylline) from the gastrointestinal tract. Serial monitoring of serum Theospirex (Theophylline) serum concentrations should be continued until it is clear that the concentration is no longer rising and has returned to non-toxic levels.
- General Monitoring Procedures Electrocardiographic monitoring should be initiated on presentation and continued until the serum Theospirex (Theophylline) level has returned to a non-toxic level. Serum electrolytes and glucose should be measured on presentation and at appropriate intervals indicated by clinical circumstances. Fluid and electrolyte abnormalities should be promptly corrected. Monitoring and treatment should be continued until the serum concentration decreases below 20 mcg/mL.
- Enhance clearance of Theospirex (Theophylline) Multiple-dose oral activated charcoal (e.g., 0.5 mg/kg up to 20 g, every two hours) increases the clearance of Theospirex (Theophylline) at least twofold by adsorption of Theospirex (Theophylline) secreted into gastrointestinal fluids. Charcoal must be retained in, and pass through, the gastrointestinal tract to be effective; emesis should therefore be controlled by administration of appropriate antiemetics. Alternatively, the charcoal can be administered continuously through a nasogastric tube in conjunction with appropriate antiemetics. A single dose of sorbitol may be administered with the activated charcoal to promote stooling to facilitate clearance of the adsorbed Theospirex (Theophylline) from the gastrointestinal tract. Sorbitol alone does not enhance clearance of Theospirex (Theophylline) and should be dosed with caution to prevent excessive stooling which can result in severe fluid and electrolyte imbalances. Commercially available fixed combinations of liquid charcoal and sorbitol should be avoided in young children and after the first dose in adolescents and adults since they do not allow for individualization of charcoal and sorbitol dosing. In patients with intractable vomiting, extracorporeal methods of Theospirex (Theophylline) removal should be instituted (see OVERDOSAGE, Extracorporeal Removal ).
Specific Recommendations
Acute Overdose
- Serum Concentration >20<30 mcg/mL
- Administer a single dose of oral activated charcoal.
- Monitor the patient and obtain a serum Theospirex concentration in 2-4 hours to insure that the concentration is not increasing.
- Serum Concentration >30<100 mcg/mL
- Administer multiple dose oral activated charcoal and measures to control emesis.
- Monitor the patient and obtain serial Theospirex (Theophylline) concentrations every 2-4 hours to gauge the effectiveness of therapy and to guide further treatment decisions.
- Institute extracorporeal removal if emesis, seizures, or cardiac arrhythmias cannot be adequately controlled (see OVERDOSAGE, Extracorporeal Removal ).
- Serum Concentration>100 mcg/mL
- Consider prophylactic anticonvulsant therapy.
- Administer multiple-dose oral activated charcoal and measures to control emesis.
- Consider extracorporeal removal, even if the patient has not experienced a seizure (see OVERDOSAGE, Extracorporeal Removal ).
- Monitor the patient and obtain serial Theospirex (Theophylline) concentrations every 2-4 hours to gauge the effectiveness of therapy and to guide further treatment decisions.
Chronic Overdosage
- Serum Concentration >20<30 mcg/mL (with manifestations of Theospirex (Theophylline) toxicity)
- Administer a single dose of oral activated charcoal.
- Monitor the patient and obtain a serum Theospirex (Theophylline) concentration in 2-4 hours to insure that the concentration is not increasing.
- Serum Concentration >30 mcg/mL in patients <60 years of age
- Administer multiple-dose oral activated charcoal and measures to control emesis.
- Monitor the patient and obtain serial Theospirex (Theophylline) concentrations every 2-4 hours to gauge the effectiveness of therapy and to guide further treatment decisions.
- Institute extracorporeal removal if emesis, seizures, or cardiac arrhythmias cannot be adequately controlled (see OVERDOSAGE, Extracorporeal Removal ).
- Serum Concentration >30 mcg/mL in patients ≥ 60 years of age
- Consider prophylactic anticonvulsant therapy.
- Administer multiple-dose oral activated charcoal and measures to control emesis.
- Consider extracorporeal removal even if the patient has not experienced a seizure.
- Monitor the patient and obtain serial Theospirex (Theophylline) concentrations every 2-4 hours to gauge the effectiveness of therapy and to guide further treatment decisions.
Extracorporeal Removal
Increasing the rate of Theospirex (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 Theospirex (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 Theospirex (Theophylline) concentrations may rebound 5-10 mcg/mL after discontinuation of charcoal hemoperfusion or hemodialysis due to redistribution of Theospirex (Theophylline) from the tissue compartment. Peritoneal dialysis is ineffective for Theospirex (Theophylline) removal; exchange transfusions in neonates have been minimally effective.
DOSAGE AND ADMINISTRATION
Theospirex ® 400 or 600 mg Tablets can be taken once a day in the morning or evening. It is recommended that Theospirex (Theophylline) be taken with meals. Patients should be advised that if they choose to take Theospirex (Theophylline) 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.
Theospirex (Theophylline)® Tablets are not to be chewed or crushed because it may lead to a rapid release of Theospirex (Theophylline) with the potential for toxicity. The scored tablet may be split. Infrequently, patients receiving Theospirex (Theophylline) 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 Theospirex (Theophylline).
Stabilized patients, 12 years of age or older, who are taking an immediate-release or controlled-release Theospirex (Theophylline) product may be transferred to once-daily administration of 400 mg or 600 mg Theospirex (Theophylline) Tablets on a mg-for-mg basis.
It must be recognized that the peak and trough serum Theospirex (Theophylline) levels produced by the once-daily dosing may vary from those produced by the previous product and/or regimen.
General Considerations
The steady-state peak serum Theospirex (Theophylline) concentration is a function of the dose, the dosing interval, and the rate of Theospirex (Theophylline) absorption and clearance in the individual patient. Because of marked individual differences in the rate of Theospirex (Theophylline) clearance, the dose required to achieve a peak serum Theospirex (Theophylline) concentration in the 10-20 mcg/mL range varies fourfold among otherwise similar patients in the absence of factors known to alter Theospirex (Theophylline) 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 Theospirex (Theophylline) dose that will provide both safe and effective serum concentrations for all patients. Administration of the median Theospirex (Theophylline) dose required to achieve a therapeutic serum Theospirex (Theophylline) concentration in a given population may result in either sub-therapeutic or potentially toxic serum Theospirex (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 1-9 years, the steady-state peak serum Theospirex (Theophylline) 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 Theospirex (Theophylline) must be individualized on the basis of peak serum Theospirex (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, 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 Theospirex (Theophylline) concentrations to reach the new steady-state. Dosage adjustment should be guided by serum Theospirex (Theophylline) 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 Theospirex (Theophylline) concentrations should be monitored at 6 month intervals for rapidly growing children and at yearly intervals for all others. In acutely ill patients, serum Theospirex (Theophylline) concentrations should be monitored at frequent intervals, e.g., every 24 hours.
Theospirex (Theophylline) distributes poorly into body fat, therefore, mg/kg dose should be calculated on the basis of ideal body weight.
Table V contains Theospirex (Theophylline) dosing titration schema recommended for patients in various age groups and clinical circumstances. Table VI contains recommendations for Theospirex (Theophylline) dosage adjustment based upon serum Theospirex (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 Theospirex (Theophylline) concentration.
Table V. Dosing initiation and titration (as anhydrous Theospirex (Theophylline)). *
- A. Children (12-15 years) and adults (16-60 years) without risk factors for impaired clearance.
| 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 ). | ||
| 12-14 mg/kg/day up to a maximum of 300 mg/day admin. QD* | 300-400 mg/day1 admin. QD* |
| 16 mg/kg/day up to a maximum of 400 mg/day admin. QD* | 400-600 mg/day1 admin. QD* |
| 20 mg/kg/day up to a maximum of 600 mg/day admin. QD* | As with all Theospirex (Theophylline) products, doses greater than 600 mg should be titrated according to blood level |
- B. Patients With Risk Factors For Impaired Clearance, The Elderly (>60 Years), And Those In Whom It Is Not Feasible To Monitor Serum Theospirex (Theophylline) Concentrations:
- In children 12-15 years of age, the Theospirex (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 Theospirex (Theophylline) clearance (see WARNINGS ) or if it is not feasible to monitor serum Theospirex (Theophylline) concentrations.
- In adolescents ≥16 years and adults, including the elderly, the Theospirex (Theophylline) dose should not exceed 400 mg/day in the presence of risk factors for reduced Theospirex (Theophylline) clearance (see WARNINGS ) or if it is not feasible to monitor serum Theospirex (Theophylline) concentrations.
- In children 12-15 years of age, the Theospirex (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 Theospirex (Theophylline) clearance (see WARNINGS ) or if it is not feasible to monitor serum Theospirex (Theophylline) concentrations.
*Patients with more rapid metabolism clinically identified by higher than average dose requirements, should receive a smaller dose more frequently (every 12 hours) to prevent breakthrough symptoms resulting from low trough concentrations before the next dose.
| Peak Serum Concentration | Dosage Adjustment |
| ¶Dose reduction and/or serum Theospirex (Theophylline) concentration measurement is indicated whenever adverse effects are present physiologic abnormalities that can reduce Theospirex (Theophylline) clearance occur (e.g. sustained fever), or a drug that interacts with Theospirex (Theophylline) 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 Theospirex (Theophylline) is subsequently resumed, decrease dose by at least 50% and recheck serum concentration after 3 days to guide further dosage adjustment. |
HOW SUPPLIED
Theospirex (Theophylline)® (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.
Theospirex (Theophylline)® (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
Theospirex (Theophylline) Tablets
400 mg Tablets
NDC 677781-251-01
Theospirex (Theophylline) Tablets 400 mg Tablets NDC 677781-251-01
Theospirex (Theophylline) Tablets
600 mg Tablets
NDC 677781-252-01
Theospirex (Theophylline) Tablets 600 mg Tablets NDC 677781-252-01
Theophylline Sodium Glycinate:
- Description
- Clinical pharmacology
- Clinical studies
- Indications and usage
- Contraindications
- Warnings
- Precautions
- Adverse reactions
- Overdosage
- Dosage and administration
- How supplied
DESCRIPTION
Theospirex (Theophylline Sodium Glycinate)® (theophylline, anhydrous) Tablets in a controlled-release system allows a 24-hour dosing interval for appropriate patients.
Theospirex (Theophylline Sodium Glycinate) is structurally classified as a methylxanthine. It occurs as a white, odorless, crystalline powder with a bitter taste. Anhydrous Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) is C7H8N4O2 with a molecular weight of 180.17.
Each controlled-release tablet for oral administration, contains 400 or 600 mg of anhydrous Theospirex (Theophylline Sodium Glycinate).
Inactive Ingredients: cetostearyl alcohol, hydroxyethyl cellulose, magnesium stearate, povidone and talc.
Theospirex (Theophylline Sodium Glycinate) 400 mg
CLINICAL PHARMACOLOGY
Mechanism of Action
Theospirex 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 Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) 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).
Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) concentration range of 5-20 mcg/mL. Clinically important improvement in symptom control has been found in most studies to require peak serum Theospirex (Theophylline Sodium Glycinate) concentrations >10 mcg/mL, but patients with mild disease may benefit from lower concentrations. At serum Theospirex (Theophylline Sodium Glycinate) concentrations >20 mcg/mL, both the frequency and severity of adverse reactions increase. In general, maintaining peak serum Theospirex (Theophylline Sodium Glycinate) 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: Theospirex is rapidly and completely absorbed after oral administration in solution or immediate-release solid oral dosage form. Theospirex (Theophylline Sodium Glycinate) does not undergo any appreciable pre-systemic elimination, distributes freely into fat-free tissues and is extensively metabolized in the liver.
The pharmacokinetics of Theospirex (Theophylline Sodium Glycinate) vary widely among similar patients and cannot be predicted by age, sex, body weight or other demographic characteristics. In addition, certain concurrent illnesses and alterations in normal physiology (see Table I ) and co-administration of other drugs (see Table II ) can significantly alter the pharmacokinetic characteristics of Theospirex (Theophylline Sodium Glycinate). Within-subject variability in metabolism has also been reported in some studies, especially in acutely ill patients. It is, therefore, recommended that serum Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) by the liver in one minute. Values listed were generally determined at serum Theospirex (Theophylline Sodium Glycinate) 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, Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate).
Absorption
Theospirex (Theophylline Sodium Glycinate)® administered in the fed state is completely absorbed after oral administration.
In a single-dose crossover study, two 400 mg Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) 400 mg Tablets were administered to 17 fed adult asthmatics produced similar Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) inherent mean elimination half-life was verified by a liquid Theospirex (Theophylline Sodium Glycinate) product to be 6.9±2.5 (SD) hours were administered two or three 400 mg Theospirex (Theophylline Sodium Glycinate)® Tablets. The relative bioavailability of Theospirex (Theophylline Sodium Glycinate) given in the fasting state in comparison to an immediate-release product was 59%. Peak serum Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) 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:
| Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate)® 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 Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) with Theospirex (Theophylline Sodium Glycinate) Tablets even when they are administered with a high fat, high calorie meal.
Similar studies were conducted with the 600 mg Theospirex (Theophylline Sodium Glycinate) Tablet. A single-dose study in 24 subjects with an established Theospirex (Theophylline Sodium Glycinate) clearance of ≤4 L/hr, compared the pharmacokinetic evaluation of one 600 mg Theospirex (Theophylline Sodium Glycinate) Tablet and one and one-half 400 mg Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate)® Tablets (theophylline, anhydrous) have been extensively studied. A steady-state crossover bioavailability study in 22 normal males compared two Theospirex (Theophylline Sodium Glycinate) 400 mg Tablets administered q24h at 8 a.m. immediately after breakfast with a reference controlled-release Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) Tablets. All subjects had previously established Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) Tablets whether dosed in the morning or evening.
Distribution
Once Theospirex enters the systemic circulation, about 40% is bound to plasma protein, primarily albumin. Unbound Theospirex (Theophylline Sodium Glycinate) distributes throughout body water, but distributes poorly into body fat. The apparent volume of distribution of Theospirex (Theophylline Sodium Glycinate) is approximately 0.45 L/kg (range 0.3-0.7 L/kg) based on ideal body weight. Theospirex (Theophylline Sodium Glycinate) passes freely across the placenta, into breast milk and into the cerebrospinal fluid (CSF). Saliva Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate), 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 Theospirex (Theophylline Sodium Glycinate) in the therapeutic range (10-20 mcg/mL) due to elevated concentrations of the pharmacologically active unbound drug. Similarly, a patient with decreased Theospirex (Theophylline Sodium Glycinate) binding may have a sub-therapeutic total drug concentration while the pharmacologically active unbound concentration is in the therapeutic range. If only total serum Theospirex (Theophylline Sodium Glycinate) concentration is measured, this may lead to an unnecessary and potentially dangerous dose increase. In patients with reduced protein binding, measurement of unbound serum Theospirex (Theophylline Sodium Glycinate) concentration provides a more reliable means of dosage adjustment than measurement of total serum Theospirex (Theophylline Sodium Glycinate) concentration. Generally, concentrations of unbound Theospirex (Theophylline Sodium Glycinate) should be maintained in the range of 6-12 mcg/mL.
Metabolism
Following oral dosing, Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) dose is N-methylated to caffeine. Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) metabolites with pharmacologic activity. 3-methylxanthine has approximately one tenth the pharmacologic activity of Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) concentration. Caffeine concentrations are usually undetectable in adults regardless of renal function. In neonates, caffeine may accumulate to concentrations that approximate the unmetabolized Theospirex (Theophylline Sodium Glycinate) concentration and thus, exert a pharmacologic effect.
Both the N-demethylation and hydroxylation pathways of Theospirex (Theophylline Sodium Glycinate) biotransformation are capacity-limited. Due to the wide intersubject variability of the rate of Theospirex (Theophylline Sodium Glycinate) metabolism, non-linearity of elimination may begin in some patients at serum Theospirex (Theophylline Sodium Glycinate) concentrations <10 mcg/mL. Since this non-linearity results in more than proportional changes in serum Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) concentrations (see DOSAGE AND ADMINISTRATION, Table VI ). Accurate prediction of dose-dependency of Theospirex (Theophylline Sodium Glycinate) metabolism in patients a priori is not possible, but patients with very high initial clearance rates (i.e., low steady-state serum Theospirex (Theophylline Sodium Glycinate) concentrations at above average doses) have the greatest likelihood of experiencing large changes in serum Theospirex (Theophylline Sodium Glycinate) concentration in response to dosage changes.
Excretion
In neonates, approximately 50% of the Theospirex dose is excreted unchanged in the urine. Beyond the first three months of life, approximately 10% of the Theospirex (Theophylline Sodium Glycinate) dose is excreted unchanged in the urine. The remainder is excreted in the urine mainly as 1,3-dimethyluric acid (35-40%), 1-methyluric acid (20-25%) and 3-methylxanthine (15-20%). Since little Theospirex (Theophylline Sodium Glycinate) is excreted unchanged in the urine and since active metabolites of Theospirex (Theophylline Sodium Glycinate) (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 Theospirex (Theophylline Sodium Glycinate) dose excreted in the urine as unchanged Theospirex (Theophylline Sodium Glycinate) and caffeine in neonates requires careful attention to dose reduction and frequent monitoring of serum Theospirex (Theophylline Sodium Glycinate) concentrations in neonates with reduced renal function (See WARNINGS ).
Serum Concentrations at Steady-State
After multiple doses of Theospirex (Theophylline Sodium Glycinate), 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 Theospirex (Theophylline Sodium Glycinate) half-life of 8 hours. The difference between peak and trough concentrations is larger in patients with more rapid Theospirex (Theophylline Sodium Glycinate) clearance. In these patients administration of Theospirex (Theophylline Sodium Glycinate)® may be required more frequently (every 12 hours).
Special Populations
Geriatric
The clearance of Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) concentrations are required in elderly patients (see WARNINGS ).
Pediatrics
The clearance of Theospirex is very low in neonates (see WARNINGS ). Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) concentrations are required in pediatric patients (see WARNINGS and DOSAGE AND ADMINISTRATION ).
Gender
Gender differences in Theospirex (Theophylline Sodium Glycinate) clearance are relatively small and unlikely to be of clinical significance. Significant reduction in Theospirex (Theophylline Sodium Glycinate) 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 Theospirex clearance due to race have not been studied.
Renal Insufficiency
Only a small fraction, e.g., about 10%, of the administered Theospirex (Theophylline Sodium Glycinate) dose is excreted unchanged in the urine of children greater than three months of age and adults. Since little Theospirex (Theophylline Sodium Glycinate) is excreted unchanged in the urine and since active metabolites of Theospirex (Theophylline Sodium Glycinate) (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 Theospirex (Theophylline Sodium Glycinate) dose is excreted unchanged in the urine in neonates. Careful attention to dose reduction and frequent monitoring of serum Theospirex (Theophylline Sodium Glycinate) concentrations are required in neonates with decreased renal function (see WARNINGS ).
Hepatic Insufficiency
Theospirex 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 Theospirex (Theophylline Sodium Glycinate) concentrations are required in patients with reduced hepatic function (see WARNINGS ).
Congestive Heart Failure (CHF)
Theospirex (Theophylline Sodium Glycinate) clearance is decreased by 50% or more in patients with CHF. The extent of reduction in Theospirex (Theophylline Sodium Glycinate) clearance in patients with CHF appears to be directly correlated to the severity of the cardiac disease. Since Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) concentrations are required in patients with CHF (see WARNINGS ).
Smokers
Tobacco and marijuana smoking appears to increase the clearance of Theospirex by induction of metabolic pathways. Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) clearance by up to 50%. Abstinence from tobacco smoking for one week causes a reduction of approximately 40% in Theospirex (Theophylline Sodium Glycinate) clearance. Careful attention to dose reduction and frequent monitoring of serum Theospirex (Theophylline Sodium Glycinate) concentrations are required in patients who stop smoking (see WARNINGS ). Use of nicotine gum has been shown to have no effect on Theospirex (Theophylline Sodium Glycinate) clearance.
Fever
Fever, regardless of its underlying cause, can decrease the clearance of Theospirex (Theophylline Sodium Glycinate). The magnitude and duration of the fever appear to be directly correlated to the degree of decrease of Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) concentrations. Children with rapid rates of Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) concentrations are required in patients with sustained fever (see WARNINGS ).
Miscellaneous
Other factors associated with decreased Theospirex (Theophylline Sodium Glycinate) clearance include the third trimester of pregnancy, sepsis with multiple organ failure, and hypothyroidism. Careful attention to dose reduction and frequent monitoring of serum Theospirex (Theophylline Sodium Glycinate) concentrations are required in patients with any of these conditions (see WARNINGS ). Other factors associated with increased Theospirex (Theophylline Sodium Glycinate) clearance include hyperthyroidism and cystic fibrosis.
CLINICAL STUDIES
In patients with chronic asthma, including patients with severe asthma requiring inhaled corticosteroids or alternate-day oral corticosteroids, many clinical studies have shown that Theospirex (Theophylline Sodium Glycinate) decreases the frequency and severity of symptoms, including nocturnal exacerbations, and decreases the “as needed” use of inhaled beta-2 agonists. Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) 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
Theospirex (Theophylline Sodium Glycinate) 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
Theospirex (Theophylline Sodium Glycinate)® is contraindicated in patients with a history of hypersensitivity to Theospirex (Theophylline Sodium Glycinate) or other components in the product.
WARNINGS
Concurrent Illness
Theospirex should be used with extreme caution in patients with the following clinical conditions due to the increased risk of exacerbation of the concurrent condition:
Active peptic ulcer disease
Seizure disorders
Cardiac arrhythmias (not including bradyarrhythmias)
Conditions That Reduce Theospirex (Theophylline Sodium Glycinate) Clearance
There are several readily identifiable causes of reduced Theospirex (Theophylline Sodium Glycinate) clearance. If the total daily dose is not appropriately reduced in the presence of these risk factors, severe and potentially fatal Theospirex (Theophylline Sodium Glycinate) toxicity can occur . Careful consideration must be given to the benefits and risks of Theospirex (Theophylline Sodium Glycinate) use and the need for more intensive monitoring of serum Theospirex (Theophylline Sodium Glycinate) concentrations in patients with the following risk factors:
Age
- Neonates (term and premature)
- Children <1 year
- Elderly (>60 years)
Concurrent Diseases
- Acute pulmonary edema
- Congestive heart failure
- Cor-pulmonale
- Fever; ≥102° for 24 hours or more; or lesser temperature elevations for longer periods
- Hypothyroidism
- Liver disease; cirrhosis, acute hepatitis
- Reduced renal function in infants <3 months of age
- Sepsis with multi-organ failure
- Shock
Cessation of Smoking
Drug Interactions
Adding a drug that inhibits Theospirex metabolism (e.g., cimetidine, erythromycin, tacrine) or stopping a concurrently administered drug that enhances Theospirex (Theophylline Sodium Glycinate) metabolism (e.g., carbamazepine, rifampin). (see PRECAUTIONS, Drug Interactions, Table II ).
When Signs or Symptoms of Theospirex (Theophylline Sodium Glycinate) Toxicity Are Present
Dosage Increases
Increases in the dose of Theospirex (Theophylline Sodium Glycinate) should not be made in response to an acute exacerbation of symptoms of chronic lung disease since Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) concentration (see DOSAGE AND ADMINISTRATION, Table VI ).
PRECAUTIONS
General
Careful consideration of the various interacting drugs and physiologic conditions that can alter Theospirex clearance and require dosage adjustment should occur prior to initiation of Theospirex (Theophylline Sodium Glycinate) therapy, prior to increases in Theospirex (Theophylline Sodium Glycinate) dose, and during follow up (see WARNINGS ). The dose of Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) concentrations and the patient’s clinical response (see DOSAGE AND ADMINISTRATION , Table V).
Monitoring Serum Theospirex (Theophylline Sodium Glycinate) Concentrations
Serum Theospirex (Theophylline Sodium Glycinate) concentration measurements are readily available and should be used to determine whether the dosage is appropriate. Specifically, the serum Theospirex (Theophylline Sodium Glycinate) concentration should be measured as follows:
- When initiating therapy to guide final dosage adjustment after titration.
- Before making a dose increase to determine whether the serum concentration is sub-therapeutic in a patient who continues to be symptomatic.
- Whenever signs or symptoms of Theospirex (Theophylline Sodium Glycinate) toxicity are present.
- Whenever there is a new illness, worsening of a chronic illness or a change in the patient’s treatment regimen that may alter Theospirex (Theophylline Sodium Glycinate) clearance (e.g., fever >102°F sustained for ≥24 hours, hepatitis, or drugs listed in Table II are added or discontinued).
To guide a dose increase, the blood sample should be obtained at the time of the expected peak serum Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) should be measured and the dosage adjusted to achieve an unbound concentration of 6-12 mcg/mL.
Saliva concentrations of Theospirex (Theophylline Sodium Glycinate) cannot be used reliably to adjust dosage without special techniques.
Effects on Laboratory Tests
As a result of its pharmacological effects, Theospirex at serum concentrations within the 10-20 mcg/mL range modestly increases plasma glucose (from a mean of 88 mg% to 98 mg%), uric acid (from a mean of 4 mg/dL to 6 mg/dL), free fatty acids (from a mean of 451 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). Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate)). The clinical importance of these changes should be weighed against the potential therapeutic benefit of Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate), 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 Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate), since it may result in decreased Theospirex (Theophylline Sodium Glycinate) levels. If patients are already taking St. John’s Wort and Theospirex (Theophylline Sodium Glycinate) together, they should consult their healthcare professional before stopping the St. John’s Wort, since their Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate), 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.
Theospirex (Theophylline Sodium Glycinate)® Tablets can be taken once a day in the morning or evening. It is recommended that Theospirex (Theophylline Sodium Glycinate) be taken with meals. Patients should be advised that if they choose to take Theospirex (Theophylline Sodium Glycinate) 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.
Theospirex (Theophylline Sodium Glycinate) Tablets are not to be chewed or crushed because it may lead to a rapid release of Theospirex (Theophylline Sodium Glycinate) with the potential for toxicity. The scored tablet may be split. Patients receiving Theospirex (Theophylline Sodium Glycinate) Tablets may pass an intact matrix tablet in the stool or via colostomy. These matrix tablets usually contain little or no residual Theospirex (Theophylline Sodium Glycinate).
Drug Interactions
Theospirex interacts with a wide variety of drugs. The interaction may be pharmacodynamic, i.e., alterations in the therapeutic response to Theospirex (Theophylline Sodium Glycinate) or another drug or occurrence of adverse effects without a change in serum Theospirex (Theophylline Sodium Glycinate) concentration. More frequently, however, the interaction is pharmacokinetic, i.e., the rate of Theospirex (Theophylline Sodium Glycinate) clearance is altered by another drug resulting in increased or decreased serum Theospirex (Theophylline Sodium Glycinate) concentrations. Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate). The information in the “Effect” column of Table II assumes that the interacting drug is being added to a steady-state Theospirex (Theophylline Sodium Glycinate) regimen. If Theospirex (Theophylline Sodium Glycinate) is being initiated in a patient who is already taking a drug that inhibits Theospirex (Theophylline Sodium Glycinate) clearance (e.g., cimetidine, erythromycin), the dose of Theospirex (Theophylline Sodium Glycinate) required to achieve a therapeutic serum Theospirex (Theophylline Sodium Glycinate) concentration will be smaller. Conversely, if Theospirex (Theophylline Sodium Glycinate) is being initiated in a patient who is already taking a drug that enhances Theospirex (Theophylline Sodium Glycinate) clearance (e.g., rifampin), the dose of Theospirex (Theophylline Sodium Glycinate) required to achieve a therapeutic serum Theospirex (Theophylline Sodium Glycinate) concentration will be larger. Discontinuation of a concomitant drug that increases Theospirex (Theophylline Sodium Glycinate) clearance will result in accumulation of Theospirex (Theophylline Sodium Glycinate) to potentially toxic levels, unless the Theospirex (Theophylline Sodium Glycinate) dose is appropriately reduced. Discontinuation of a concomitant drug that inhibits Theospirex (Theophylline Sodium Glycinate) clearance will result in decreased serum Theospirex (Theophylline Sodium Glycinate) concentrations, unless the Theospirex (Theophylline Sodium Glycinate) dose is appropriately increased.
The drugs listed in Table III have either been documented not to interact with Theospirex (Theophylline Sodium Glycinate) or do not produce a clinically significant interaction (i.e., <15% change in Theospirex (Theophylline Sodium Glycinate) clearance).
The listing of drugs in Tables II and III are current as of February 9, 1995. New interactions are continuously being reported for Theospirex (Theophylline Sodium Glycinate), especially with new chemical entities. The healthcare professional should not assume that a drug does not interact with Theospirex (Theophylline Sodium Glycinate) if it is not listed in Table II. Before addition of a newly available drug in a patient receiving Theospirex (Theophylline Sodium Glycinate), 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 Theospirex (Theophylline Sodium Glycinate) has been reported.
| Drug | Type of Interaction | Effect** |
|---|---|---|
| *Refer to PRECAUTIONS, Drug Interactions for further information regarding table. | ||
| **Average effect on steady-state Theospirex (Theophylline Sodium Glycinate) concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum Theospirex (Theophylline Sodium Glycinate) concentration than the value listed. | ||
| Adenosine | Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) clearance for up to 24 hours. | 30% increase |
| Allopurinol | Decreases Theospirex (Theophylline Sodium Glycinate) clearance at allopurinol doses ≥600 mg/day. | 25% increase |
| Aminoglutethimide | Increases Theospirex (Theophylline Sodium Glycinate) clearance by induction of microsomal enzyme activity. | 25% decrease |
| Carbamazepine | Similar to aminoglutethimide. | 30% decrease |
| Cimetidine | Decreases Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) blocks adenosine receptors. | Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of Theospirex (Theophylline Sodium Glycinate) without reduction of diazepam dose may result in respiratory depression. |
| Disulfiram | Decreases Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) clearance by inhibiting cytochrome P450 3A3. | 35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount. |
| Estrogen | Estrogen containing oral contraceptives decrease Theospirex (Theophylline Sodium Glycinate) clearance in a dose-dependent fashion. The effect of progesterone on Theospirex (Theophylline Sodium Glycinate) 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, Theospirex (Theophylline Sodium Glycinate) increases release of endogenous catecholamines. | Increased risk of ventricular arrhythmias. |
| Interferon, human recombinant alpha-A | Decreases Theospirex (Theophylline Sodium Glycinate) clearance. | 100% increase |
| Isoproterenol (IV) | Increases Theospirex (Theophylline Sodium Glycinate) clearance. | 20% decrease |
| Ketamine | Pharmacologic | May lower Theospirex (Theophylline Sodium Glycinate) seizure threshold. |
| Lithium | Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) clearance. | 25% decrease |
| Pancuronium | Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) clearance. | 30% increase |
| Phenobarbital (PB) | Similar to aminoglutethimide. | 25% decrease after two weeks of concurrent PB. |
| Phenytoin | Phenytoin increases Theospirex (Theophylline Sodium Glycinate) clearance by increasing microsomal enzyme activity. Theospirex (Theophylline Sodium Glycinate) decreases phenytoin absorption. | Serum Theospirex (Theophylline Sodium Glycinate) and phenytoin concentrations decrease about 40%. |
| Propafenone | Decreases Theospirex (Theophylline Sodium Glycinate) clearance and pharmacologic interaction. | 40% increase. Beta-2 blocking effect may decrease efficacy of Theospirex (Theophylline Sodium Glycinate). |
| Propranolol | Similar to cimetidine and pharmacologic interaction. | 100% increase. Beta-2 blocking effect may decrease efficacy of Theospirex (Theophylline Sodium Glycinate). |
| Rifampin | Increases Theospirex (Theophylline Sodium Glycinate) clearance by increasing cytochrome P450 1A2 and 3A3 activity. | 20-40% decrease |
| St. John’s Wort (Hypericum Perforatum) | Decrease in Theospirex (Theophylline Sodium Glycinate) plasma concentrations. | Higher doses of Theospirex (Theophylline Sodium Glycinate) may be required to achieve desired effect. Stopping St. John’s Wort may result in Theospirex (Theophylline Sodium Glycinate) toxicity. |
| Sulfinpyrazone | Increases Theospirex (Theophylline Sodium Glycinate) clearance by increasing demethylation and hydroxylation. Decreases renal clearance of Theospirex (Theophylline Sodium Glycinate). | 20% decrease |
| Tacrine | Similar to cimetidine, also increases renal clearance of Theospirex (Theophylline Sodium Glycinate). | 90% increase |
| Thiabendazole | Decreases Theospirex (Theophylline Sodium Glycinate) clearance. | 190% increase |
| Ticlopidine | Decreases Theospirex (Theophylline Sodium Glycinate) 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 | Theospirex (Theophylline Sodium Glycinate) absorption) |
| isoflurane | sucralfate |
| isoniazid | terbutaline, systemic |
| isradipine | terfenadine |
| influenza vaccine | tetracycline |
| ketoconazole | tocainide |
| lomefloxacin | |
Drug-Food Interactions
The bioavailability of Theospirex (Theophylline Sodium Glycinate)® Tablets (theophylline, anhydrous) has been studied with co-administration of food. In three single-dose studies, subjects given Theospirex (Theophylline Sodium Glycinate) 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 Theospirex Serum Concentration Measurements
Most serum Theospirex (Theophylline Sodium Glycinate) assays in clinical use are immunoassays which are specific for Theospirex (Theophylline Sodium Glycinate). 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 Theospirex (Theophylline Sodium Glycinate) concentration.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Long term carcinogenicity studies have been carried out in mice and rats (oral doses 5-75 mg/kg). Results are pending.
Theospirex (Theophylline Sodium Glycinate) 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, Theospirex (Theophylline Sodium Glycinate), 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, Theospirex (Theophylline Sodium Glycinate) 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, Theospirex (Theophylline Sodium Glycinate) produced teratogenic effects.
In studies with mice, a single intraperitoneal dose at and above 100 mg/kg (approximately equal to the maximum recommended oral dose for adults on a mg/m2 basis) during organogenesis produced cleft palate and digital abnormalities. Micromelia, micrognathia, clubfoot, subcutaneous hematoma, open eyelids, and embryolethality were observed at doses that are approximately 2 times the maximum recommended oral dose for adults on a mg/m2 basis.
In a study with rats dosed from conception through organogenesis, an oral dose of 150 mg/kg/day (approximately 2 times the maximum recommended oral dose for adults on a mg/m2 basis) produced digital abnormalities. Embryolethality was observed with a subcutaneous dose of 200 mg/kg/day (approximately 4 times the maximum recommended oral dose for adults on a mg/m2 basis).
In a study in which pregnant rabbits were dosed throughout organogenesis, an intravenous dose of 60 mg/kg/day (approximately 2 times the maximum recommended oral dose for adults on a mg/m2 basis), which caused the death of one doe and clinical signs in others, produced cleft palate and was embryolethal. Doses at and above 15 mg/kg/day (less than the maximum recommended oral dose for adults on a mg/m2 basis) increased the incidence of skeletal variations.
There are no adequate and well-controlled studies in pregnant women. Theospirex (Theophylline Sodium Glycinate) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers
Theospirex is excreted into breast milk and may cause irritability or other signs of mild toxicity in nursing human infants. The concentration of Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) per day is likely to receive 10-20 mg of Theospirex (Theophylline Sodium Glycinate) per day. Serious adverse effects in the infant are unlikely unless the mother has toxic serum Theospirex (Theophylline Sodium Glycinate) concentrations.
Pediatric Use
Theospirex (Theophylline Sodium Glycinate) is safe and effective for the approved indications in pediatric patients. The maintenance dose of Theospirex (Theophylline Sodium Glycinate) must be selected with caution in pediatric patients since the rate of Theospirex (Theophylline Sodium Glycinate) clearance is highly variable across the pediatric age range (see CLINICAL PHARMACOLOGY, Table I, WARNINGS, and DOSAGE AND ADMINISTRATION, Table V ).
Geriatric Use
Elderly patients are at a significantly greater risk of experiencing serious toxicity from Theospirex (Theophylline Sodium Glycinate) than younger patients due to pharmacokinetic and pharmacodynamic changes associated with aging. The clearance of Theospirex (Theophylline Sodium Glycinate) is decreased by an average of 30% in healthy elderly adults (>60 yrs) compared to healthy young adults. Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) concentration in the pharmacologically active unbound form. Elderly patients also appear to be more sensitive to the toxic effects of Theospirex (Theophylline Sodium Glycinate) after chronic overdosage than younger patients. Careful attention to dose reduction and frequent monitoring of serum Theospirex (Theophylline Sodium Glycinate) concentrations are required in elderly patients (see PRECAUTIONS, Monitoring Serum Theospirex (Theophylline Sodium Glycinate) Concentrations, and DOSAGE AND ADMINISTRATION ). The maximum daily dose of Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) concentration is <10 mcg/mL (see DOSAGE AND ADMINISTRATION ). Theospirex (Theophylline Sodium Glycinate) doses greater than 400 mg/d should be prescribed with caution in elderly patients. Theospirex (Theophylline Sodium Glycinate) 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.
ADVERSE REACTIONS
Adverse reactions associated with Theospirex (Theophylline Sodium Glycinate) are generally mild when peak serum Theospirex (Theophylline Sodium Glycinate) concentrations are <20 mcg/mL and mainly consist of transient caffeine-like adverse effects such as nausea, vomiting, headache, and insomnia. When peak serum Theospirex (Theophylline Sodium Glycinate) concentrations exceed 20 mcg/mL, however, Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) therapy, caffeine-like adverse effects may transiently alter patient behavior, especially in school age children, but this response rarely persists. Initiation of Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) therapy and the potential therapeutic benefit of alternative treatment.
Other adverse reactions that have been reported at serum Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) concentrations ≥15 mcg/mL. There have been a few isolated reports of seizures at serum Theospirex (Theophylline Sodium Glycinate) concentrations <20 mcg/mL in patients with an underlying neurological disease or in elderly patients. The occurrence of seizures in elderly patients with serum Theospirex (Theophylline Sodium Glycinate) concentrations <20 mcg/mL may be secondary to decreased protein binding resulting in a larger proportion of the total serum Theospirex (Theophylline Sodium Glycinate) concentration in the pharmacologically active unbound form. The clinical characteristics of the seizures reported in patients with serum Theospirex (Theophylline Sodium Glycinate) concentrations <20 mcg/mL have generally been milder than seizures associated with excessive serum Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) concentrations >30 mcg/mL among 6000 blood samples obtained for measurement of serum Theospirex (Theophylline Sodium Glycinate) concentrations in three emergency departments. Differences in the incidence of manifestations of Theospirex (Theophylline Sodium Glycinate) 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 |
OVERDOSAGE
General
The chronicity and pattern of Theospirex overdosage significantly influences clinical manifestations of toxicity, management and outcome. There are two common presentations: (1) acute overdose, i.e., ingestion of a single large excessive dose (>10 mg/kg), as occurs in the context of an attempted suicide or isolated medication error, and (2) chronic overdosage, i.e., ingestion of repeated doses that are excessive for the patient’s rate of Theospirex (Theophylline Sodium Glycinate) clearance. The most common causes of chronic Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) clearance, and increasing the dose in response to an exacerbation of symptoms without first measuring the serum Theospirex (Theophylline Sodium Glycinate) concentration to determine whether a dose increase is safe.
Severe toxicity from Theospirex (Theophylline Sodium Glycinate) overdose is a relatively rare event. In one health maintenance organization, the frequency of hospital admissions for chronic overdosage of Theospirex (Theophylline Sodium Glycinate) was about 1 per 1000 person-years exposure. In another study, among 6000 blood samples obtained for measurement of serum Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) concentrations in the 20-30 mcg/mL range had one or more manifestations of toxicity while >90% of patients with serum Theospirex (Theophylline Sodium Glycinate) concentrations >30 mcg/mL were clinically intoxicated. Similarly, in other reports, serious toxicity from Theospirex (Theophylline Sodium Glycinate) is seen principally at serum concentrations >30 mcg/mL.
Several studies have described the clinical manifestations of Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) concentration is >100 mcg/mL. After a chronic overdosage, generalized seizures, life-threatening cardiac arrhythmias, and death may occur at serum Theospirex (Theophylline Sodium Glycinate) concentrations >30 mcg/mL. The severity of toxicity after chronic overdosage is more strongly correlated with the patient’s age than the peak serum Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) concentration compared to patients without the underlying disease.
The frequency of various reported manifestations of Theospirex (Theophylline Sodium Glycinate) overdose according to the mode of overdose are listed in Table IV.
Other manifestations of Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) concentrations >30 mcg/mL are often resistant to anticonvulsant therapy and may result in irreversible brain injury if not rapidly controlled. Death from Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) Overdose or Serum Theospirex (Theophylline Sodium Glycinate) Concentrations >30 mcg/mL (Note: Serum Theospirex (Theophylline Sodium Glycinate) concentrations may continue to increase after presentation of the patient for medical care.)
- While simultaneously instituting treatment, contact a regional poison center to obtain updated information and advice on individualizing the recommendations that follow.
- Institute supportive care, including establishment of intravenous access, maintenance of the airway, and electrocardiographic monitoring.
- Treatment of seizures Because of the high morbidity and mortality associated with theophylline-induced seizures, treatment should be rapid and aggressive. Anticonvulsant therapy should be initiated with an intravenous benzodiazepine, e.g., diazepam, in increments of 0.1-0.2 mg/kg every 1-3 minutes until seizures are terminated. Repetitive seizures should be treated with a loading dose of phenobarbital (20 mg/kg infused over 30-60 minutes). Case reports of Theospirex (Theophylline Sodium Glycinate) overdose in humans and animal studies suggest that phenytoin is ineffective in terminating theophylline-induced seizures. The doses of benzodiazepines and phenobarbital required to terminate theophylline-induced seizures are close to the doses that may cause severe respiratory depression or respiratory arrest; the healthcare professional should therefore be prepared to provide assisted ventilation. Elderly patients and patients with COPD may be more susceptible to the respiratory depressant effects of anticonvulsants. Barbiturate-induced coma or administration of general anesthesia may be required to terminate repetitive seizures or status epilepticus. General anesthesia should be used with caution in patients with Theospirex (Theophylline Sodium Glycinate) overdose because fluorinated volatile anesthetics may sensitize the myocardium to endogenous catecholamines released by Theospirex (Theophylline Sodium Glycinate). Enflurane appears less likely to be associated with this effect than halothane and may, therefore, be safer. Neuromuscular blocking agents alone should not be used to terminate seizures since they abolish the musculoskeletal manifestations without terminating seizure activity in the brain.
- Anticipate Need for Anticonvulsants In patients with Theospirex (Theophylline Sodium Glycinate) overdose who are at high risk for theophylline-induced seizures, e.g., patients with acute overdoses and serum Theospirex (Theophylline Sodium Glycinate) concentrations >100 mcg/mL or chronic overdosage in patients >60 years of age with serum Theospirex (Theophylline Sodium Glycinate) concentrations >30 mcg/mL, the need for anticonvulsant therapy should be anticipated. A benzodiazepine such as diazepam should be drawn into a syringe and kept at the patient’s bedside and medical personnel qualified to treat seizures should be immediately available. In selected patients at high risk for theophylline-induced seizures, consideration should be given to the administration of prophylactic anticonvulsant therapy. Situations where prophylactic anticonvulsant therapy should be considered in high risk patients include anticipated delays in instituting methods for extracorporeal removal of Theospirex (Theophylline Sodium Glycinate) (e.g., transfer of a high risk patient from one healthcare facility to another for extracorporeal removal) and clinical circumstances that significantly interfere with efforts to enhance Theospirex (Theophylline Sodium Glycinate) clearance (e.g., a neonate where dialysis may not be technically feasible or a patient with vomiting unresponsive to antiemetics who is unable to tolerate multiple-dose oral activated charcoal). In animal studies, prophylactic administration of phenobarbital, but not phenytoin, has been shown to delay the onset of theophylline-induced generalized seizures and to increase the dose of Theospirex (Theophylline Sodium Glycinate) required to induce seizures (i.e., markedly increases the LD50). Although there are no controlled studies in humans, a loading dose of intravenous phenobarbital (20 mg/kg infused over 60 minutes) may delay or prevent life-threatening seizures in high risk patients while efforts to enhance Theospirex (Theophylline Sodium Glycinate) clearance are continued. Phenobarbital may cause respiratory depression, particularly in elderly patients and patients with COPD.
- Treatment of cardiac arrhythmias Sinus tachycardia and simple ventricular premature beats are not harbingers of life-threatening arrhythmias, they do not require treatment in the absence of hemodynamic compromise, and they resolve with declining serum Theospirex (Theophylline Sodium Glycinate) concentrations. Other arrhythmias, especially those associated with hemodynamic compromise, should be treated with antiarrhythmic therapy appropriate for the type of arrhythmia.
- Gastrointestinal decontamination Oral activated charcoal (0.5 g/kg up to 20 g and repeat at least once 1-2 hours after the first dose) is extremely effective in blocking the absorption of Theospirex (Theophylline Sodium Glycinate) throughout the gastrointestinal tract, even when administered several hours after ingestion. If the patient is vomiting, the charcoal should be administered through a nasogastric tube or after administration of an antiemetic. Phenothiazine antiemetics such as prochlorperazine or perphenazine should be avoided since they can lower the seizure threshold and frequently cause dystonic reactions. A single dose of sorbitol may be used to promote stooling to facilitate removal of Theospirex (Theophylline Sodium Glycinate) bound to charcoal from the gastrointestinal tract. Sorbitol, however, should be dosed with caution since it is a potent purgative which can cause profound fluid and electrolyte abnormalities, particularly after multiple doses. Commercially available fixed combinations of liquid charcoal and sorbitol should be avoided in young children and after the first dose in adolescents and adults since they do not allow for individualization of charcoal and sorbitol dosing. Ipecac syrup should be avoided in Theospirex (Theophylline Sodium Glycinate) overdoses. Although ipecac induces emesis, it does not reduce the absorption of Theospirex (Theophylline Sodium Glycinate) unless administered within 5 minutes of ingestion and even then is less effective than oral activated charcoal. Moreover, ipecac induced emesis may persist for several hours after a single dose and significantly decrease the retention and the effectiveness of oral activated charcoal.
- Serum Theospirex (Theophylline Sodium Glycinate) Concentration Monitoring The serum Theospirex (Theophylline Sodium Glycinate) concentration should be measured immediately upon presentation, 2-4 hours later, and then at sufficient intervals, e.g., every 4 hours, to guide treatment decisions and to assess the effectiveness of therapy. Serum Theospirex (Theophylline Sodium Glycinate) concentrations may continue to increase after presentation of the patient for medical care as a result of continued absorption of Theospirex (Theophylline Sodium Glycinate) from the gastrointestinal tract. Serial monitoring of serum Theospirex (Theophylline Sodium Glycinate) serum concentrations should be continued until it is clear that the concentration is no longer rising and has returned to non-toxic levels.
- General Monitoring Procedures Electrocardiographic monitoring should be initiated on presentation and continued until the serum Theospirex (Theophylline Sodium Glycinate) level has returned to a non-toxic level. Serum electrolytes and glucose should be measured on presentation and at appropriate intervals indicated by clinical circumstances. Fluid and electrolyte abnormalities should be promptly corrected. Monitoring and treatment should be continued until the serum concentration decreases below 20 mcg/mL.
- Enhance clearance of Theospirex (Theophylline Sodium Glycinate) Multiple-dose oral activated charcoal (e.g., 0.5 mg/kg up to 20 g, every two hours) increases the clearance of Theospirex (Theophylline Sodium Glycinate) at least twofold by adsorption of Theospirex (Theophylline Sodium Glycinate) secreted into gastrointestinal fluids. Charcoal must be retained in, and pass through, the gastrointestinal tract to be effective; emesis should therefore be controlled by administration of appropriate antiemetics. Alternatively, the charcoal can be administered continuously through a nasogastric tube in conjunction with appropriate antiemetics. A single dose of sorbitol may be administered with the activated charcoal to promote stooling to facilitate clearance of the adsorbed Theospirex (Theophylline Sodium Glycinate) from the gastrointestinal tract. Sorbitol alone does not enhance clearance of Theospirex (Theophylline Sodium Glycinate) and should be dosed with caution to prevent excessive stooling which can result in severe fluid and electrolyte imbalances. Commercially available fixed combinations of liquid charcoal and sorbitol should be avoided in young children and after the first dose in adolescents and adults since they do not allow for individualization of charcoal and sorbitol dosing. In patients with intractable vomiting, extracorporeal methods of Theospirex (Theophylline Sodium Glycinate) removal should be instituted (see OVERDOSAGE, Extracorporeal Removal ).
Specific Recommendations
Acute Overdose
- Serum Concentration >20<30 mcg/mL
- Administer a single dose of oral activated charcoal.
- Monitor the patient and obtain a serum Theospirex concentration in 2-4 hours to insure that the concentration is not increasing.
- Serum Concentration >30<100 mcg/mL
- Administer multiple dose oral activated charcoal and measures to control emesis.
- Monitor the patient and obtain serial Theospirex (Theophylline Sodium Glycinate) concentrations every 2-4 hours to gauge the effectiveness of therapy and to guide further treatment decisions.
- Institute extracorporeal removal if emesis, seizures, or cardiac arrhythmias cannot be adequately controlled (see OVERDOSAGE, Extracorporeal Removal ).
- Serum Concentration>100 mcg/mL
- Consider prophylactic anticonvulsant therapy.
- Administer multiple-dose oral activated charcoal and measures to control emesis.
- Consider extracorporeal removal, even if the patient has not experienced a seizure (see OVERDOSAGE, Extracorporeal Removal ).
- Monitor the patient and obtain serial Theospirex (Theophylline Sodium Glycinate) concentrations every 2-4 hours to gauge the effectiveness of therapy and to guide further treatment decisions.
Chronic Overdosage
- Serum Concentration >20<30 mcg/mL (with manifestations of Theospirex (Theophylline Sodium Glycinate) toxicity)
- Administer a single dose of oral activated charcoal.
- Monitor the patient and obtain a serum Theospirex (Theophylline Sodium Glycinate) concentration in 2-4 hours to insure that the concentration is not increasing.
- Serum Concentration >30 mcg/mL in patients <60 years of age
- Administer multiple-dose oral activated charcoal and measures to control emesis.
- Monitor the patient and obtain serial Theospirex (Theophylline Sodium Glycinate) concentrations every 2-4 hours to gauge the effectiveness of therapy and to guide further treatment decisions.
- Institute extracorporeal removal if emesis, seizures, or cardiac arrhythmias cannot be adequately controlled (see OVERDOSAGE, Extracorporeal Removal ).
- Serum Concentration >30 mcg/mL in patients ≥ 60 years of age
- Consider prophylactic anticonvulsant therapy.
- Administer multiple-dose oral activated charcoal and measures to control emesis.
- Consider extracorporeal removal even if the patient has not experienced a seizure.
- Monitor the patient and obtain serial Theospirex (Theophylline Sodium Glycinate) concentrations every 2-4 hours to gauge the effectiveness of therapy and to guide further treatment decisions.
Extracorporeal Removal
Increasing the rate of Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) concentrations may rebound 5-10 mcg/mL after discontinuation of charcoal hemoperfusion or hemodialysis due to redistribution of Theospirex (Theophylline Sodium Glycinate) from the tissue compartment. Peritoneal dialysis is ineffective for Theospirex (Theophylline Sodium Glycinate) removal; exchange transfusions in neonates have been minimally effective.
DOSAGE AND ADMINISTRATION
Theospirex ® 400 or 600 mg Tablets can be taken once a day in the morning or evening. It is recommended that Theospirex (Theophylline Sodium Glycinate) be taken with meals. Patients should be advised that if they choose to take Theospirex (Theophylline Sodium Glycinate) 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.
Theospirex (Theophylline Sodium Glycinate)® Tablets are not to be chewed or crushed because it may lead to a rapid release of Theospirex (Theophylline Sodium Glycinate) with the potential for toxicity. The scored tablet may be split. Infrequently, patients receiving Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate).
Stabilized patients, 12 years of age or older, who are taking an immediate-release or controlled-release Theospirex (Theophylline Sodium Glycinate) product may be transferred to once-daily administration of 400 mg or 600 mg Theospirex (Theophylline Sodium Glycinate) Tablets on a mg-for-mg basis.
It must be recognized that the peak and trough serum Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) concentration is a function of the dose, the dosing interval, and the rate of Theospirex (Theophylline Sodium Glycinate) absorption and clearance in the individual patient. Because of marked individual differences in the rate of Theospirex (Theophylline Sodium Glycinate) clearance, the dose required to achieve a peak serum Theospirex (Theophylline Sodium Glycinate) concentration in the 10-20 mcg/mL range varies fourfold among otherwise similar patients in the absence of factors known to alter Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) dose that will provide both safe and effective serum concentrations for all patients. Administration of the median Theospirex (Theophylline Sodium Glycinate) dose required to achieve a therapeutic serum Theospirex (Theophylline Sodium Glycinate) concentration in a given population may result in either sub-therapeutic or potentially toxic serum Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) must be individualized on the basis of peak serum Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) concentrations to reach the new steady-state. Dosage adjustment should be guided by serum Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) concentrations should be monitored at 6 month intervals for rapidly growing children and at yearly intervals for all others. In acutely ill patients, serum Theospirex (Theophylline Sodium Glycinate) concentrations should be monitored at frequent intervals, e.g., every 24 hours.
Theospirex (Theophylline Sodium Glycinate) distributes poorly into body fat, therefore, mg/kg dose should be calculated on the basis of ideal body weight.
Table V contains Theospirex (Theophylline Sodium Glycinate) dosing titration schema recommended for patients in various age groups and clinical circumstances. Table VI contains recommendations for Theospirex (Theophylline Sodium Glycinate) dosage adjustment based upon serum Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) concentration.
Table V. Dosing initiation and titration (as anhydrous Theospirex (Theophylline Sodium Glycinate)). *
- A. Children (12-15 years) and adults (16-60 years) without risk factors for impaired clearance.
| 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 ). | ||
| 12-14 mg/kg/day up to a maximum of 300 mg/day admin. QD* | 300-400 mg/day1 admin. QD* |
| 16 mg/kg/day up to a maximum of 400 mg/day admin. QD* | 400-600 mg/day1 admin. QD* |
| 20 mg/kg/day up to a maximum of 600 mg/day admin. QD* | As with all Theospirex (Theophylline Sodium Glycinate) products, doses greater than 600 mg should be titrated according to blood level |
- B. Patients With Risk Factors For Impaired Clearance, The Elderly (>60 Years), And Those In Whom It Is Not Feasible To Monitor Serum Theospirex (Theophylline Sodium Glycinate) Concentrations:
- In children 12-15 years of age, the Theospirex (Theophylline Sodium Glycinate) dose should not exceed 16 mg/kg/day up to a maximum of 400 mg/day in the presence of risk factors for reduced Theospirex (Theophylline Sodium Glycinate) clearance (see WARNINGS ) or if it is not feasible to monitor serum Theospirex (Theophylline Sodium Glycinate) concentrations.
- In adolescents ≥16 years and adults, including the elderly, the Theospirex (Theophylline Sodium Glycinate) dose should not exceed 400 mg/day in the presence of risk factors for reduced Theospirex (Theophylline Sodium Glycinate) clearance (see WARNINGS ) or if it is not feasible to monitor serum Theospirex (Theophylline Sodium Glycinate) concentrations.
- In children 12-15 years of age, the Theospirex (Theophylline Sodium Glycinate) dose should not exceed 16 mg/kg/day up to a maximum of 400 mg/day in the presence of risk factors for reduced Theospirex (Theophylline Sodium Glycinate) clearance (see WARNINGS ) or if it is not feasible to monitor serum Theospirex (Theophylline Sodium Glycinate) concentrations.
*Patients with more rapid metabolism clinically identified by higher than average dose requirements, should receive a smaller dose more frequently (every 12 hours) to prevent breakthrough symptoms resulting from low trough concentrations before the next dose.
| Peak Serum Concentration | Dosage Adjustment |
| ¶Dose reduction and/or serum Theospirex (Theophylline Sodium Glycinate) concentration measurement is indicated whenever adverse effects are present physiologic abnormalities that can reduce Theospirex (Theophylline Sodium Glycinate) clearance occur (e.g. sustained fever), or a drug that interacts with Theospirex (Theophylline Sodium Glycinate) 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 Theospirex (Theophylline Sodium Glycinate) is subsequently resumed, decrease dose by at least 50% and recheck serum concentration after 3 days to guide further dosage adjustment. |
HOW SUPPLIED
Theospirex (Theophylline Sodium Glycinate)® (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.
Theospirex (Theophylline Sodium Glycinate)® (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
Theospirex (Theophylline Sodium Glycinate) Tablets
400 mg Tablets
NDC 677781-251-01
Theospirex (Theophylline Sodium Glycinate) Tablets 400 mg Tablets NDC 677781-251-01
Theospirex (Theophylline Sodium Glycinate) Tablets
600 mg Tablets
NDC 677781-252-01
Theospirex (Theophylline Sodium Glycinate) Tablets 600 mg Tablets NDC 677781-252-01
Theospirex pharmaceutical active ingredients containing related brand and generic drugs:
Theospirex available forms, composition, doses:
Theospirex destination | category:
Theospirex Anatomical Therapeutic Chemical codes:
Theospirex pharmaceutical companies:
References
- Dailymed."THEOPHYLLINE SOLUTION [SILARX PHARMACEUTICALS, INC]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
- 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).
- "theophylline". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).
Frequently asked Questions
Can i drive or operate heavy machine after consuming Theospirex?Depending on the reaction of the Theospirex after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Theospirex 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 Theospirex 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.
Review
sdrugs.com conducted a study on Theospirex, 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 Theospirex 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.Visitor reports
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| 16-29 | 1 | 100.0% | |
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The information was verified by Dr. Rachana Salvi, MD Pharmacology