Theophen Comp

Ammonium Chloride:

• Indications and usage
• Contraindications
• Warning
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Theophen Comp (Ammonium Chloride) reviews

INDICATIONS AND USAGE

Theophen Comp (Ammonium Chloride) Lactate Lotion, 12% is indicated for the treatment of dry, scaly skin (xerosis) and ichthyosis vulgaris, and for the temporary relief of itching associated with these conditions.

CONTRAINDICATIONS

Theophen Comp (Ammonium Chloride) Lactate Lotion, 12% is contraindicated in those patients with a history of hypersensitivity to any of the label ingredients.

WARNING

Sun exposure (natural or artificial sunlight) to areas of the skin treated with Theophen Comp (Ammonium Chloride) Lactate Lotion, 12% should be minimized or avoided (see PRECAUTIONS). The use of Theophen Comp (Ammonium Chloride) Lactate Lotion, 12% should be discontinued if any hypersensitivity is observed.

PRECAUTIONS

General -

For external use only. Stinging or burning may occur when applied to skin with fissures, erosions, or that is otherwise abraded. Caution is advised when used on the face because of the potential for irritation. The potential for post-inflammatory hypo- or hyperpigmentation has not been studied.

Information for Patients

Patients using Theophen Comp (Ammonium Chloride) Lactate Lotion, 12% should receive the following information and instructions:

• This medication is to be used as directed by the physician, and should not be used for any disorder other than for which it was prescribed. It is for external use only. Avoid contact with eyes, lips, or mucous membranes.
• Patients should minimize or avoid use of this product on areas of the skin that may be exposed to natural or artificial sunlight, including the face. If sun exposure is unavoidable, clothing should be worn to protect the skin.
• This medication may cause transient stinging or burning when applied to skin with fissures, erosions, or abrasions (for example, after shaving the legs).
• If the skin condition worsens with treatment, the medication should be promptly discontinued.

Carcinogenesis, Mutagenesis, Impairment of Fertility -

The topical treatment of CD-1 mice with 12%, 21% or 30% Theophen Comp lactate formulations for two-years did not produce a significant increase in dermal or systemic tumors in the absence of increased exposure to ultraviolet radiation. The maximum systemic exposure of the mice in this study was 0.7 times the maximum possible systemic exposure in humans. However, a long-term photocarcinogenicity study in hairless albino mice suggested that topically applied 12% Theophen Comp (Ammonium Chloride) lactate formulations enhanced the rate of ultraviolet light-induced skin tumor formation.

The mutagenic potential of Theophen Comp (Ammonium Chloride) lactate formulations was evaluated in the Ames assay and in the mouse in vivo micronucleus assay, both of which were negative.

In dermal Segment I and III studies with Theophen Comp (Ammonium Chloride) lactate formulations there were no effects observed in fertility or pre- or postnatal development parameters in rats at dose levels of 300 mg/kg/day (1800 mg/m²/day), approximately 0.4 times the human topical dose.

Pregnancy:

Teratogenic effects:

Pregnancy Category B -

Animal reproduction studies have been performed in rats and rabbits at doses up to 0.7 and 1.5 times the human dose, respectively and have revealed no evidence of impaired fertility or harm to the fetus due to Theophen Comp (Ammonium Chloride) lactate formulations. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Theophen Comp (Ammonium Chloride) Lactate Lotion, 12% should be used during pregnancy only if clearly needed.

Nursing Mothers -

Although lactic acid is a normal constituent of blood and tissues, it is not known to what extent this drug affects normal lactic acid levels in human milk. Because many drugs are excreted in human milk, caution should be exercised when Theophen Comp (Ammonium Chloride) lactate is administered to a nursing woman.

Pediatric Use -

Safety and effectiveness of Theophen Comp lactate have been demonstrated in infants and children. No unusual toxic effects were reported.

Geriatric Use -

Clinical studies of Theophen Comp (Ammonium Chloride) lactate lotion, 12% did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious.

ADVERSE REACTIONS

The most frequent adverse experiences in patients with xerosis are transient stinging (1 in 30 patients), burning (1 in 30 patients), erythema (1 in 50 patients) and peeling (1 in 60 patients). Other adverse reactions which occur less frequently are irritation, eczema, petechiae, dryness, and hyperpigmentation. Due to the more severe initial skin conditions associated with ichthyosis, there was a higher incidence of transient stinging, burning and erythema (each occurring in 1 in 10 patients).

OVERDOSAGE

The oral administration of Theophen Comp (Ammonium Chloride) lactate to rats and mice showed this drug to be practically non-toxic (LD₅₀>15 mL/kg).

DOSAGE AND ADMINISTRATION

Shake well. Apply to the affected areas and rub in thoroughly. Use twice daily or as directed by a physician.

HOW SUPPLIED

Theophen Comp Lactate Lotion, 12% is available as follows:

225 g bottle (NDC 45802-419-54)

400 g bottle (NDC 45802-419-26)

STORAGE

Store at 20-25°C (68-77°F).

Manufactured By Perrigo, Bronx, NY 10457

Distributed By Perrigo, Allegan, MI 49010

0K5A7 RC F6

Rev 01-17

Diphenylpyraline Hydrochloride:

• Theophen Comp (Diphenylpyraline Hydrochloride) reviews

Indication: For use in the treatment of allergic rhinitis, hay fever, and allergic skin disorders.

Theophen Comp (Diphenylpyraline Hydrochloride) is an antihistamine that prevents, but does not reverse, responses mediated by histamine alone. Theophen Comp (Diphenylpyraline Hydrochloride) antagonizes most of the pharmacological effects of histamine, including urticaria and pruritus. Also, Theophen Comp (Diphenylpyraline Hydrochloride) may exhibit anticholinergic actions (as do most of the antihistamines) and may thus provide a drying effect on the nasal mucosa.

Theophylline:

• Description
• Clinical pharmacology
• Clinical studies
• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Theophen Comp (Theophylline) reviews

DESCRIPTION

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

Theophen Comp (Theophylline) is structurally classified as a methylxanthine. It occurs as a white, odorless, crystalline powder with a bitter taste. Anhydrous Theophen Comp (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 Theophen Comp (Theophylline) is C₇H₈N₄O₂ with a molecular weight of 180.17.

Each controlled-release tablet for oral administration, contains 400 or 600 mg of anhydrous Theophen Comp (Theophylline).

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

Theophen Comp (Theophylline) 400 mg

CLINICAL PHARMACOLOGY

Mechanism of Action

Theophen Comp 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 Theophen Comp (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 Theophen Comp (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).

Theophen Comp (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 Theophen Comp (Theophylline) concentration range of 5-20 mcg/mL. Clinically important improvement in symptom control has been found in most studies to require peak serum Theophen Comp (Theophylline) concentrations >10 mcg/mL, but patients with mild disease may benefit from lower concentrations. At serum Theophen Comp (Theophylline) concentrations >20 mcg/mL, both the frequency and severity of adverse reactions increase. In general, maintaining peak serum Theophen Comp (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: Theophen Comp is rapidly and completely absorbed after oral administration in solution or immediate-release solid oral dosage form. Theophen Comp (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 Theophen Comp (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 Theophen Comp (Theophylline). Within-subject variability in metabolism has also been reported in some studies, especially in acutely ill patients. It is, therefore, recommended that serum Theophen Comp (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 Theophen Comp (Theophylline) clearance (see PRECAUTIONS, Laboratory Tests ).

Note: In addition to the factors listed above, Theophen Comp (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 Theophen Comp (Theophylline).

Absorption

Theophen Comp (Theophylline)^® administered in the fed state is completely absorbed after oral administration.

In a single-dose crossover study, two 400 mg Theophen Comp (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, 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 Theophen Comp (Theophylline) 400 mg Tablets were administered to 17 fed adult asthmatics produced similar Theophen Comp (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.

A single-dose study in 15 normal fasting male volunteers whose Theophen Comp (Theophylline) inherent mean elimination half-life was verified by a liquid Theophen Comp (Theophylline) product to be 6.9±2.5 (SD) hours were administered two or three 400 mg Theophen Comp (Theophylline)^® Tablets. The relative bioavailability of Theophen Comp (Theophylline) given in the fasting state in comparison to an immediate-release product was 59%. Peak serum Theophen Comp (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 Theophen Comp (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 Theophen Comp (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 Theophen Comp (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, 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 Theophen Comp (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 Theophen Comp (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, 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 Theophen Comp (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 Theophen Comp (Theophylline) with Theophen Comp (Theophylline) Tablets even when they are administered with a high fat, high calorie meal.

Similar studies were conducted with the 600 mg Theophen Comp (Theophylline) Tablet. A single-dose study in 24 subjects with an established Theophen Comp (Theophylline) clearance of ≤4 L/hr, compared the pharmacokinetic evaluation of one 600 mg Theophen Comp (Theophylline) Tablet and one and one-half 400 mg Theophen Comp (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 Theophen Comp (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, 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 Theophen Comp (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 Theophen Comp (Theophylline) 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 Theophen Comp (Theophylline)^® Tablets (theophylline, anhydrous) have been extensively studied. A steady-state crossover bioavailability study in 22 normal males compared two Theophen Comp (Theophylline) 400 mg Tablets administered q24h at 8 a.m. immediately after breakfast with a reference controlled-release Theophen Comp (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 Theophen Comp (Theophylline) 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 Theophen Comp (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 Theophen Comp (Theophylline) Tablets. All subjects had previously established Theophen Comp (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 Theophen Comp (Theophylline) 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 Theophen Comp (Theophylline) Tablets whether dosed in the morning or evening.

Distribution

Once Theophen Comp enters the systemic circulation, about 40% is bound to plasma protein, primarily albumin. Unbound Theophen Comp (Theophylline) distributes throughout body water, but distributes poorly into body fat. The apparent volume of distribution of Theophen Comp (Theophylline) is approximately 0.45 L/kg (range 0.3-0.7 L/kg) based on ideal body weight. Theophen Comp (Theophylline) passes freely across the placenta, into breast milk and into the cerebrospinal fluid (CSF). Saliva Theophen Comp (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 Theophen Comp (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 Theophen Comp (Theophylline) in the therapeutic range (10-20 mcg/mL) due to elevated concentrations of the pharmacologically active unbound drug. Similarly, a patient with decreased Theophen Comp (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 Theophen Comp (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 Theophen Comp (Theophylline) concentration provides a more reliable means of dosage adjustment than measurement of total serum Theophen Comp (Theophylline) concentration. Generally, concentrations of unbound Theophen Comp (Theophylline) should be maintained in the range of 6-12 mcg/mL.

Metabolism

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

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

Excretion

In neonates, approximately 50% of the Theophen Comp dose is excreted unchanged in the urine. Beyond the first three months of life, approximately 10% of the Theophen Comp (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 Theophen Comp (Theophylline) is excreted unchanged in the urine and since active metabolites of Theophen Comp (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 Theophen Comp (Theophylline) dose excreted in the urine as unchanged Theophen Comp (Theophylline) and caffeine in neonates requires careful attention to dose reduction and frequent monitoring of serum Theophen Comp (Theophylline) concentrations in neonates with reduced renal function (See WARNINGS ).

Serum Concentrations at Steady-State

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

Special Populations

Geriatric

The clearance of Theophen Comp (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 Theophen Comp (Theophylline) concentrations are required in elderly patients (see WARNINGS ).

Pediatrics

The clearance of Theophen Comp is very low in neonates (see WARNINGS ). Theophen Comp (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 Theophen Comp (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 Theophen Comp (Theophylline) concentrations are required in pediatric patients (see WARNINGS and DOSAGE AND ADMINISTRATION ).

Gender

Gender differences in Theophen Comp (Theophylline) clearance are relatively small and unlikely to be of clinical significance. Significant reduction in Theophen Comp (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 Theophen Comp clearance due to race have not been studied.

Renal Insufficiency

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

Hepatic Insufficiency

Theophen Comp 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 Theophen Comp (Theophylline) concentrations are required in patients with reduced hepatic function (see WARNINGS ).

Congestive Heart Failure (CHF)

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

Smokers

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

Fever

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

Miscellaneous

Other factors associated with decreased Theophen Comp (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 Theophen Comp (Theophylline) concentrations are required in patients with any of these conditions (see WARNINGS ). Other factors associated with increased Theophen Comp (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 Theophen Comp (Theophylline) decreases the frequency and severity of symptoms, including nocturnal exacerbations, and decreases the “as needed” use of inhaled beta-₂ agonists. Theophen Comp (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 Theophen Comp (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

Theophen Comp (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

Theophen Comp (Theophylline)^® is contraindicated in patients with a history of hypersensitivity to Theophen Comp (Theophylline) or other components in the product.

WARNINGS

Concurrent Illness

Theophen Comp 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 Theophen Comp (Theophylline) Clearance

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

When Signs or Symptoms of Theophen Comp (Theophylline) Toxicity Are Present

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

Dosage Increases

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

PRECAUTIONS

General

Careful consideration of the various interacting drugs and physiologic conditions that can alter Theophen Comp clearance and require dosage adjustment should occur prior to initiation of Theophen Comp (Theophylline) therapy, prior to increases in Theophen Comp (Theophylline) dose, and during follow up (see WARNINGS ). The dose of Theophen Comp (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 Theophen Comp (Theophylline) concentrations and the patient’s clinical response (see DOSAGE AND ADMINISTRATION , Table V).

Monitoring Serum Theophen Comp (Theophylline) Concentrations

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

Saliva concentrations of Theophen Comp (Theophylline) cannot be used reliably to adjust dosage without special techniques.

Effects on Laboratory Tests

As a result of its pharmacological effects, Theophen Comp 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). Theophen Comp (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 Theophen Comp (Theophylline)). The clinical importance of these changes should be weighed against the potential therapeutic benefit of Theophen Comp (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 Theophen Comp (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 Theophen Comp (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 Theophen Comp (Theophylline), since it may result in decreased Theophen Comp (Theophylline) levels. If patients are already taking St. John’s Wort and Theophen Comp (Theophylline) together, they should consult their healthcare professional before stopping the St. John’s Wort, since their Theophen Comp (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 Theophen Comp (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.

Theophen Comp (Theophylline)^® Tablets can be taken once a day in the morning or evening. It is recommended that Theophen Comp (Theophylline) be taken with meals. Patients should be advised that if they choose to take Theophen Comp (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.

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

Drug Interactions

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

The drugs listed in Table III have either been documented not to interact with Theophen Comp (Theophylline) or do not produce a clinically significant interaction (i.e., <15% change in Theophen Comp (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 Theophen Comp (Theophylline), especially with new chemical entities. The healthcare professional should not assume that a drug does not interact with Theophen Comp (Theophylline) if it is not listed in Table II. Before addition of a newly available drug in a patient receiving Theophen Comp (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 Theophen Comp (Theophylline) has been reported.

Drug-Food Interactions

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

Most serum Theophen Comp (Theophylline) assays in clinical use are immunoassays which are specific for Theophen Comp (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 Theophen Comp (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.

Theophen Comp (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, Theophen Comp (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, Theophen Comp (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, Theophen Comp (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. Theophen Comp (Theophylline) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

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

Pediatric Use

Theophen Comp (Theophylline) is safe and effective for the approved indications in pediatric patients. The maintenance dose of Theophen Comp (Theophylline) must be selected with caution in pediatric patients since the rate of Theophen Comp (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 Theophen Comp (Theophylline) than younger patients due to pharmacokinetic and pharmacodynamic changes associated with aging. The clearance of Theophen Comp (Theophylline) is decreased by an average of 30% in healthy elderly adults (>60 yrs) compared to healthy young adults. Theophen Comp (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 Theophen Comp (Theophylline) concentration in the pharmacologically active unbound form. Elderly patients also appear to be more sensitive to the toxic effects of Theophen Comp (Theophylline) after chronic overdosage than younger patients. Careful attention to dose reduction and frequent monitoring of serum Theophen Comp (Theophylline) concentrations are required in elderly patients (see PRECAUTIONS, Monitoring Serum Theophen Comp (Theophylline) Concentrations, and DOSAGE AND ADMINISTRATION ). The maximum daily dose of Theophen Comp (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 Theophen Comp (Theophylline) concentration is <10 mcg/mL (see DOSAGE AND ADMINISTRATION ). Theophen Comp (Theophylline) doses greater than 400 mg/d should be prescribed with caution in elderly patients. Theophen Comp (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 Theophen Comp (Theophylline) are generally mild when peak serum Theophen Comp (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 Theophen Comp (Theophylline) concentrations exceed 20 mcg/mL, however, Theophen Comp (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 Theophen Comp (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 Theophen Comp (Theophylline) therapy, caffeine-like adverse effects may transiently alter patient behavior, especially in school age children, but this response rarely persists. Initiation of Theophen Comp (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 Theophen Comp (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 Theophen Comp (Theophylline) therapy and the potential therapeutic benefit of alternative treatment.

Other adverse reactions that have been reported at serum Theophen Comp (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 Theophen Comp (Theophylline) concentrations ≥15 mcg/mL. There have been a few isolated reports of seizures at serum Theophen Comp (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 Theophen Comp (Theophylline) concentrations <20 mcg/mL may be secondary to decreased protein binding resulting in a larger proportion of the total serum Theophen Comp (Theophylline) concentration in the pharmacologically active unbound form. The clinical characteristics of the seizures reported in patients with serum Theophen Comp (Theophylline) concentrations <20 mcg/mL have generally been milder than seizures associated with excessive serum Theophen Comp (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).

OVERDOSAGE

General

The chronicity and pattern of Theophen Comp 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 Theophen Comp (Theophylline) clearance. The most common causes of chronic Theophen Comp (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 Theophen Comp (Theophylline) clearance, and increasing the dose in response to an exacerbation of symptoms without first measuring the serum Theophen Comp (Theophylline) concentration to determine whether a dose increase is safe.

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

Several studies have described the clinical manifestations of Theophen Comp (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 Theophen Comp (Theophylline) concentration is >100 mcg/mL. After a chronic overdosage, generalized seizures, life-threatening cardiac arrhythmias, and death may occur at serum Theophen Comp (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 Theophen Comp (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 Theophen Comp (Theophylline) concentration compared to patients without the underlying disease.

The frequency of various reported manifestations of Theophen Comp (Theophylline) overdose according to the mode of overdose are listed in Table IV.

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

Extracorporeal Removal

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

DOSAGE AND ADMINISTRATION

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

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

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

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

Theophen Comp (Theophylline) distributes poorly into body fat, therefore, mg/kg dose should be calculated on the basis of ideal body weight.

Table V contains Theophen Comp (Theophylline) dosing titration schema recommended for patients in various age groups and clinical circumstances. Table VI contains recommendations for Theophen Comp (Theophylline) dosage adjustment based upon serum Theophen Comp (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 Theophen Comp (Theophylline) concentration.

Table V. Dosing initiation and titration (as anhydrous Theophen Comp (Theophylline)). *

• 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 Theophen Comp (Theophylline) Concentrations:
  
  • In children 12-15 years of age, the Theophen Comp (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 Theophen Comp (Theophylline) clearance (see WARNINGS ) or if it is not feasible to monitor serum Theophen Comp (Theophylline) concentrations.
    

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

HOW SUPPLIED

Theophen Comp (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.

Theophen Comp (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

Theophen Comp (Theophylline) Tablets

400 mg Tablets

NDC 677781-251-01

Theophen Comp (Theophylline) Tablets 400 mg Tablets NDC 677781-251-01

Theophen Comp (Theophylline) Tablets

600 mg Tablets

NDC 677781-252-01

Theophen Comp (Theophylline) Tablets 600 mg Tablets NDC 677781-252-01