T-Phyl

How is the drug helping you?  No   Yes

T-Phyl uses

• Description
• Clinical pharmacology
• Clinical studies
• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• T-Phyl reviews

DESCRIPTION

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

T-Phyl is structurally classified as a methylxanthine. It occurs as a white, odorless, crystalline powder with a bitter taste. Anhydrous T-Phyl 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 T-Phyl is C₇H₈N₄O₂ with a molecular weight of 180.17.

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

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

T-Phyl 400 mg

CLINICAL PHARMACOLOGY

Mechanism of Action

T-Phyl has two distinct actions in the airways of patients with reversible obstruction; smooth muscle relaxation and suppression of the response of the airways to stimuli (i.e., non-bronchodilator prophylactic effects). While the mechanisms of action of T-Phyl 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 T-Phyl 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).

T-Phyl 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 T-Phyl concentration range of 5-20 mcg/mL. Clinically important improvement in symptom control has been found in most studies to require peak serum T-Phyl concentrations >10 mcg/mL, but patients with mild disease may benefit from lower concentrations. At serum T-Phyl concentrations >20 mcg/mL, both the frequency and severity of adverse reactions increase. In general, maintaining peak serum T-Phyl 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: T-Phyl is rapidly and completely absorbed after oral administration in solution or immediate-release solid oral dosage form. T-Phyl does not undergo any appreciable pre-systemic elimination, distributes freely into fat-free tissues and is extensively metabolized in the liver.

The pharmacokinetics of T-Phyl vary widely among similar patients and cannot be predicted by age, sex, body weight or other demographic characteristics. In addition, certain concurrent illnesses and alterations in normal physiology and co-administration of other drugs (see Table II ) can significantly alter the pharmacokinetic characteristics of T-Phyl. Within-subject variability in metabolism has also been reported in some studies, especially in acutely ill patients. It is, therefore, recommended that serum T-Phyl 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 T-Phyl clearance (see PRECAUTIONS, Laboratory Tests ).

Note: In addition to the factors listed above, T-Phyl 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 T-Phyl.

Absorption

T-Phyl^® administered in the fed state is completely absorbed after oral administration.

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

A study in which T-Phyl 400 mg Tablets were administered to 17 fed adult asthmatics produced similar T-Phyl 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.

A single-dose study in 15 normal fasting male volunteers whose T-Phyl inherent mean elimination half-life was verified by a liquid T-Phyl product to be 6.9±2.5 (SD) hours were administered two or three 400 mg T-Phyl^® Tablets. The relative bioavailability of T-Phyl given in the fasting state in comparison to an immediate-release product was 59%. Peak serum T-Phyl 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 T-Phyl 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 T-Phyl 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 T-Phyl Tablets given at doses of 800 mg once daily in the morning were virtually identical to the corresponding parameters for the reference drug when given as 400 mg BID. In particular, the AUC, C_max and C_min values obtained in this study were as follows:

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, C_max=8.4±2.6 mcg/mL, T_max=17.3±6.7 hours. Under fasting conditions, these parameters were AUC=141.2±6.53 mcg hr/mL, C_max=5.5±1.5 mcg/mL, T_max=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 T-Phyl^® 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 T-Phyl 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, C_max=10.9±1.7 mcg/mL, T_max=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, C_max=6.7±1.7 mcg/mL, T_max=7.3±2.2 hours.

Thus, administration of single T-Phyl 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 T-Phyl with T-Phyl Tablets even when they are administered with a high fat, high calorie meal.

Similar studies were conducted with the 600 mg T-Phyl Tablet. A single-dose study in 24 subjects with an established T-Phyl clearance of ≤4 L/hr, compared the pharmacokinetic evaluation of one 600 mg T-Phyl Tablet and one and one-half 400 mg T-Phyl 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 T-Phyl 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, C_max=10.58±2.21 mcg/mL and T_max=9.00±2.64 hours, and for the 600 mg tablet were AUC=207.85±48.9 mcg hr/mL, C_max=10.39±1.91 mcg/mL and T_max=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, C_max= 7.37±1.83 mcg/mL and T_max=8.08±4.39 hours; and for the 600 mg tablet were AUC=199.39±70.27 mcg hr/mL, C_max=7.66±2.09 mcg/mL and T_max=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 T-Phyl 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 T-Phyl Tablet administered in the morning or in the evening. The results were: AUC=233.6±45.1 mcg hr/mL, C_max=10.6±1.3 mcg/mL and T_max=12.5±3.2 hours with morning dosing; AUC=209.8±46.2 mcg hr/mL, C_max=9.7±1.4 mcg/mL and T_max=13.7±3.3 hours with evening dosing. The PM/AM ratio was 89.3%.

The absorption characteristics of T-Phyl^® Tablets (theophylline, anhydrous) have been extensively studied. A steady-state crossover bioavailability study in 22 normal males compared two T-Phyl 400 mg Tablets administered q24h at 8 a.m. immediately after breakfast with a reference controlled-release T-Phyl 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 T-Phyl 400 mg Tablets under these steady-state conditions were AUC=203.3±87.1 mcg hr/mL, C_max=12.1±3.8 mcg/mL, C_min=4.50±3.6, T_max=8.8±4.6 hours. For the reference BID product, the pharmacokinetic parameters were AUC=219.2±88.4 mcg hr/mL, C_max =11.0±4.1 mcg/mL, C_min=7.28±3.5, T_max=6.9±3.4 hours. The mean percent fluctuation [(C_max-C_min/C_min)x100]=169% for the once-daily regimen and 51% for the reference product BID regimen.

The bioavailability of the 600 mg T-Phyl 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 T-Phyl Tablets. All subjects had previously established T-Phyl 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 T-Phyl Tablet regimens. Steady-state results were:

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 T-Phyl Tablets whether dosed in the morning or evening.

Distribution

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

Metabolism

Following oral dosing, T-Phyl 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 T-Phyl dose is N-methylated to caffeine. T-Phyl 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 T-Phyl metabolites with pharmacologic activity. 3-methylxanthine has approximately one tenth the pharmacologic activity of T-Phyl 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 T-Phyl concentration. Caffeine concentrations are usually undetectable in adults regardless of renal function. In neonates, caffeine may accumulate to concentrations that approximate the unmetabolized T-Phyl concentration and thus, exert a pharmacologic effect.

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

Excretion

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

Serum Concentrations at Steady-State

After multiple doses of T-Phyl, 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 T-Phyl half-life of 8 hours. The difference between peak and trough concentrations is larger in patients with more rapid T-Phyl clearance. In these patients administration of T-Phyl^® may be required more frequently (every 12 hours).

Special Populations

Geriatric

The clearance of T-Phyl 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 T-Phyl concentrations are required in elderly patients (see WARNINGS ).

Pediatrics

The clearance of T-Phyl is very low in neonates. T-Phyl 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 T-Phyl 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 T-Phyl concentrations are required in pediatric patients (see WARNINGS and DOSAGE AND ADMINISTRATION ).

Gender

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

Renal Insufficiency

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

Hepatic Insufficiency

T-Phyl 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 T-Phyl concentrations are required in patients with reduced hepatic function (see WARNINGS ).

Congestive Heart Failure

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

Smokers

Tobacco and marijuana smoking appears to increase the clearance of T-Phyl by induction of metabolic pathways. T-Phyl 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 T-Phyl clearance by up to 50%. Abstinence from tobacco smoking for one week causes a reduction of approximately 40% in T-Phyl clearance. Careful attention to dose reduction and frequent monitoring of serum T-Phyl concentrations are required in patients who stop smoking. Use of nicotine gum has been shown to have no effect on T-Phyl clearance.

Fever

Fever, regardless of its underlying cause, can decrease the clearance of T-Phyl. The magnitude and duration of the fever appear to be directly correlated to the degree of decrease of T-Phyl 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 T-Phyl concentrations. Children with rapid rates of T-Phyl 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 T-Phyl 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 T-Phyl concentrations are required in patients with sustained fever (see WARNINGS ).

Miscellaneous

Other factors associated with decreased T-Phyl clearance include the third trimester of pregnancy, sepsis with multiple organ failure, and hypothyroidism. Careful attention to dose reduction and frequent monitoring of serum T-Phyl concentrations are required in patients with any of these conditions (see WARNINGS ). Other factors associated with increased T-Phyl 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 T-Phyl decreases the frequency and severity of symptoms, including nocturnal exacerbations, and decreases the “as needed” use of inhaled beta-₂ agonists. T-Phyl 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 T-Phyl 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

T-Phyl 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

T-Phyl^® is contraindicated in patients with a history of hypersensitivity to T-Phyl or other components in the product.

WARNINGS

Concurrent Illness

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

Active peptic ulcer disease

Seizure disorders

Cardiac arrhythmias

Conditions That Reduce T-Phyl Clearance

There are several readily identifiable causes of reduced T-Phyl clearance. If the total daily dose is not appropriately reduced in the presence of these risk factors, severe and potentially fatal T-Phyl toxicity can occur . Careful consideration must be given to the benefits and risks of T-Phyl use and the need for more intensive monitoring of serum T-Phyl 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 T-Phyl metabolism or stopping a concurrently administered drug that enhances T-Phyl metabolism (e.g., carbamazepine, rifampin). (see PRECAUTIONS, Drug Interactions, Table II ).

When Signs or Symptoms of T-Phyl Toxicity Are Present

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

Dosage Increases

Increases in the dose of T-Phyl should not be made in response to an acute exacerbation of symptoms of chronic lung disease since T-Phyl 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 T-Phyl 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 T-Phyl 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 T-Phyl 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 T-Phyl concentration (see DOSAGE AND ADMINISTRATION, Table VI ).

PRECAUTIONS

General

Careful consideration of the various interacting drugs and physiologic conditions that can alter T-Phyl clearance and require dosage adjustment should occur prior to initiation of T-Phyl therapy, prior to increases in T-Phyl dose, and during follow up. The dose of T-Phyl 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 T-Phyl concentrations and the patient’s clinical response (see DOSAGE AND ADMINISTRATION , Table V).

Monitoring Serum T-Phyl Concentrations

Serum T-Phyl concentration measurements are readily available and should be used to determine whether the dosage is appropriate. Specifically, the serum T-Phyl 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 T-Phyl 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 T-Phyl 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 T-Phyl 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 T-Phyl 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 T-Phyl 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 T-Phyl should be measured and the dosage adjusted to achieve an unbound concentration of 6-12 mcg/mL.

Saliva concentrations of T-Phyl cannot be used reliably to adjust dosage without special techniques.

Effects on Laboratory Tests

As a result of its pharmacological effects, T-Phyl at serum concentrations within the 10-20 mcg/mL range modestly increases plasma glucose, uric acid (from a mean of 4 mg/dL to 6 mg/dL), free fatty acids (from a mean of 451 µEq/L to 800 µEq/L, total cholesterol (from a mean of 140 vs 160 mg/dL), HDL (from a mean of 36 to 50 mg/dL), HDL/LDL ratio (from a mean of 0.5 to 0.7), and urinary free cortisol excretion (from a mean of 44 to 63 mcg/24 hr). T-Phyl 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 T-Phyl). The clinical importance of these changes should be weighed against the potential therapeutic benefit of T-Phyl 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 T-Phyl, 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 T-Phyl 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 T-Phyl, since it may result in decreased T-Phyl levels. If patients are already taking St. John’s Wort and T-Phyl together, they should consult their healthcare professional before stopping the St. John’s Wort, since their T-Phyl 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 T-Phyl, 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.

T-Phyl^® Tablets can be taken once a day in the morning or evening. It is recommended that T-Phyl be taken with meals. Patients should be advised that if they choose to take T-Phyl 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.

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

Drug Interactions

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

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

The listing of drugs in Tables II and III are current as of February 9, 1995. New interactions are continuously being reported for T-Phyl, especially with new chemical entities. The healthcare professional should not assume that a drug does not interact with T-Phyl if it is not listed in Table II. Before addition of a newly available drug in a patient receiving T-Phyl, 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 T-Phyl has been reported.

Drug-Food Interactions

The bioavailability of T-Phyl^® Tablets (theophylline, anhydrous) has been studied with co-administration of food. In three single-dose studies, subjects given T-Phyl 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 T-Phyl Serum Concentration Measurements

Most serum T-Phyl assays in clinical use are immunoassays which are specific for T-Phyl. Other xanthines such as caffeine, dyphylline, and pentoxifylline are not detected by these assays. Some drugs, however, may interfere with certain HPLC techniques. Caffeine and xanthine metabolites in neonates or patients with renal dysfunction may cause the reading from some dry reagent office methods to be higher than the actual serum T-Phyl concentration.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

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

T-Phyl 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, T-Phyl, 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, T-Phyl 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, T-Phyl produced teratogenic effects.

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

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

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

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

Nursing Mothers

T-Phyl is excreted into breast milk and may cause irritability or other signs of mild toxicity in nursing human infants. The concentration of T-Phyl 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 T-Phyl per day is likely to receive 10-20 mg of T-Phyl per day. Serious adverse effects in the infant are unlikely unless the mother has toxic serum T-Phyl concentrations.

Pediatric Use

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

Geriatric Use

Elderly patients are at a significantly greater risk of experiencing serious toxicity from T-Phyl than younger patients due to pharmacokinetic and pharmacodynamic changes associated with aging. The clearance of T-Phyl is decreased by an average of 30% in healthy elderly adults (>60 yrs) compared to healthy young adults. T-Phyl 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 T-Phyl concentration in the pharmacologically active unbound form. Elderly patients also appear to be more sensitive to the toxic effects of T-Phyl after chronic overdosage than younger patients. Careful attention to dose reduction and frequent monitoring of serum T-Phyl concentrations are required in elderly patients (see PRECAUTIONS, Monitoring Serum T-Phyl Concentrations, and DOSAGE AND ADMINISTRATION ). The maximum daily dose of T-Phyl 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 T-Phyl concentration is <10 mcg/mL (see DOSAGE AND ADMINISTRATION ). T-Phyl doses greater than 400 mg/d should be prescribed with caution in elderly patients. T-Phyl 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 T-Phyl are generally mild when peak serum T-Phyl concentrations are <20 mcg/mL and mainly consist of transient caffeine-like adverse effects such as nausea, vomiting, headache, and insomnia. When peak serum T-Phyl concentrations exceed 20 mcg/mL, however, T-Phyl 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 T-Phyl 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 T-Phyl therapy, caffeine-like adverse effects may transiently alter patient behavior, especially in school age children, but this response rarely persists. Initiation of T-Phyl 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 T-Phyl 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 T-Phyl therapy and the potential therapeutic benefit of alternative treatment.

Other adverse reactions that have been reported at serum T-Phyl 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 T-Phyl concentrations ≥15 mcg/mL. There have been a few isolated reports of seizures at serum T-Phyl concentrations <20 mcg/mL in patients with an underlying neurological disease or in elderly patients. The occurrence of seizures in elderly patients with serum T-Phyl concentrations <20 mcg/mL may be secondary to decreased protein binding resulting in a larger proportion of the total serum T-Phyl concentration in the pharmacologically active unbound form. The clinical characteristics of the seizures reported in patients with serum T-Phyl concentrations <20 mcg/mL have generally been milder than seizures associated with excessive serum T-Phyl concentrations resulting from an overdose (i.e., they have generally been transient, often stopped without anticonvulsant therapy, and did not result in neurological residua).

OVERDOSAGE

General

The chronicity and pattern of T-Phyl overdosage significantly influences clinical manifestations of toxicity, management and outcome. There are two common presentations: acute overdose, i.e., ingestion of a single large excessive dose (>10 mg/kg), as occurs in the context of an attempted suicide or isolated medication error, and (2) chronic overdosage, i.e., ingestion of repeated doses that are excessive for the patient’s rate of T-Phyl clearance. The most common causes of chronic T-Phyl 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 T-Phyl clearance, and increasing the dose in response to an exacerbation of symptoms without first measuring the serum T-Phyl concentration to determine whether a dose increase is safe.

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

Several studies have described the clinical manifestations of T-Phyl 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 T-Phyl concentration is >100 mcg/mL. After a chronic overdosage, generalized seizures, life-threatening cardiac arrhythmias, and death may occur at serum T-Phyl concentrations >30 mcg/mL. The severity of toxicity after chronic overdosage is more strongly correlated with the patient’s age than the peak serum T-Phyl 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 T-Phyl concentration compared to patients without the underlying disease.

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

Other manifestations of T-Phyl 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 T-Phyl concentrations >30 mcg/mL are often resistant to anticonvulsant therapy and may result in irreversible brain injury if not rapidly controlled. Death from T-Phyl 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 T-Phyl Overdose or Serum T-Phyl Concentrations >30 mcg/mL (Note: Serum T-Phyl 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 T-Phyl 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 T-Phyl overdose because fluorinated volatile anesthetics may sensitize the myocardium to endogenous catecholamines released by T-Phyl. 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 T-Phyl overdose who are at high risk for theophylline-induced seizures, e.g., patients with acute overdoses and serum T-Phyl concentrations >100 mcg/mL or chronic overdosage in patients >60 years of age with serum T-Phyl 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 T-Phyl (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 T-Phyl 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 T-Phyl 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 T-Phyl 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 T-Phyl 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 T-Phyl 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 T-Phyl 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 T-Phyl overdoses. Although ipecac induces emesis, it does not reduce the absorption of T-Phyl 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 T-Phyl Concentration Monitoring The serum T-Phyl 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 T-Phyl concentrations may continue to increase after presentation of the patient for medical care as a result of continued absorption of T-Phyl from the gastrointestinal tract. Serial monitoring of serum T-Phyl 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 T-Phyl 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 T-Phyl Multiple-dose oral activated charcoal (e.g., 0.5 mg/kg up to 20 g, every two hours) increases the clearance of T-Phyl at least twofold by adsorption of T-Phyl 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 T-Phyl from the gastrointestinal tract. Sorbitol alone does not enhance clearance of T-Phyl 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 T-Phyl 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 T-Phyl 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 T-Phyl 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.
• 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 T-Phyl 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 T-Phyl toxicity)
  • Administer a single dose of oral activated charcoal.
  • Monitor the patient and obtain a serum T-Phyl 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 T-Phyl 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 T-Phyl concentrations every 2-4 hours to gauge the effectiveness of therapy and to guide further treatment decisions.

Extracorporeal Removal

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

DOSAGE AND ADMINISTRATION

T-Phyl^® 400 or 600 mg Tablets can be taken once a day in the morning or evening. It is recommended that T-Phyl be taken with meals. Patients should be advised that if they choose to take T-Phyl 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.

T-Phyl^® Tablets are not to be chewed or crushed because it may lead to a rapid release of T-Phyl with the potential for toxicity. The scored tablet may be split. Infrequently, patients receiving T-Phyl 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 T-Phyl.

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

It must be recognized that the peak and trough serum T-Phyl 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 T-Phyl concentration is a function of the dose, the dosing interval, and the rate of T-Phyl absorption and clearance in the individual patient. Because of marked individual differences in the rate of T-Phyl clearance, the dose required to achieve a peak serum T-Phyl concentration in the 10-20 mcg/mL range varies fourfold among otherwise similar patients in the absence of factors known to alter T-Phyl 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 T-Phyl dose that will provide both safe and effective serum concentrations for all patients. Administration of the median T-Phyl dose required to achieve a therapeutic serum T-Phyl concentration in a given population may result in either sub-therapeutic or potentially toxic serum T-Phyl 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 T-Phyl 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 T-Phyl must be individualized on the basis of peak serum T-Phyl 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 T-Phyl concentrations to reach the new steady-state. Dosage adjustment should be guided by serum T-Phyl 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 T-Phyl concentrations should be monitored at 6 month intervals for rapidly growing children and at yearly intervals for all others. In acutely ill patients, serum T-Phyl concentrations should be monitored at frequent intervals, e.g., every 24 hours.

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

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

Table V. Dosing initiation and titration (as anhydrous T-Phyl). *

• A. Children (12-15 years) and adults (16-60 years) without risk factors for impaired clearance.

• B. Patients With Risk Factors For Impaired Clearance, The Elderly (>60 Years), And Those In Whom It Is Not Feasible To Monitor Serum T-Phyl Concentrations:
  
  • In children 12-15 years of age, the T-Phyl dose should not exceed 16 mg/kg/day up to a maximum of 400 mg/day in the presence of risk factors for reduced T-Phyl clearance (see WARNINGS ) or if it is not feasible to monitor serum T-Phyl concentrations.
    

  • In adolescents ≥16 years and adults, including the elderly, the T-Phyl dose should not exceed 400 mg/day in the presence of risk factors for reduced T-Phyl clearance (see WARNINGS ) or if it is not feasible to monitor serum T-Phyl 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.

HOW SUPPLIED

T-Phyl^® (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.

T-Phyl^® (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

T-Phyl Tablets

400 mg Tablets

NDC 677781-251-01

T-Phyl Tablets 400 mg Tablets NDC 677781-251-01

T-Phyl Tablets

600 mg Tablets

NDC 677781-252-01

T-Phyl Tablets 600 mg Tablets NDC 677781-252-01

T-Phyl pharmaceutical active ingredients containing related brand and generic drugs:

• Theophylline

T-Phyl available forms, composition, doses:

• Tablets, Extended Release; Oral; Theophylline 200 mg

T-Phyl destination | category:

• Human:
• Antiasthmatic and COPD preparations
• Respiratory smooth muscle relaxants

T-Phyl Anatomical Therapeutic Chemical codes:

• R03DA04 - Theophylline

T-Phyl pharmaceutical companies:

• Purdue Pharma

References

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

Frequently asked Questions

Depending on the reaction of the T-Phyl after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider T-Phyl 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.

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

Visitor reports

Visitor reviews

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