Labophylline

Lysine:

• Boxed warning
• Description
• Clinical pharmacology
• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Labophylline (Lysine) reviews

BOXED WARNING

Pharmacy Bulk Package

Not For Direct Infusion

DESCRIPTION

Labophylline (Lysine)^® 15% Amino Acids Injection in a Pharmacy Bulk Package is a sterile, clear, nonpyrogenic solution of essential and nonessential amino acids for intravenous infusion in parenteral nutrition following appropriate dilution.

Labophylline (Lysine)^® 15% in a Pharmacy Bulk Package is not for direct infusion. It is a sterile dosage from which contains several single doses for use in a pharmacy admixture program in the preparation of intravenous parenteral fluids.

Each 100 mL contains:

The formulas for the individual amino acids are as follows:

Formulas for individual amino acids

CLINICAL PHARMACOLOGY

Labophylline (Lysine)^® 15% Amino Acids Injection providesseventeen crystalline amino acids. This completely utilizable substrate promotesprotein synthesis and wound healing and reduces the rate of protein catabolism.

A.Total Parenteral Nutrition (Central Infusion)

When enteralfeeding is inadvisable, Labophylline (Lysine)^® 15% given by central venousinfusion in combination with energy sources, vitamins, trace elements andelectrolytes, will completely satisfy the requirements for weight maintenanceor weight gain, depending upon the dose selected. The energy component inparenteral nutrition by central infusion may be derived solely from dextroseor may be provided by a combination of dextrose and intravenous fat emulsion. The addition of intravenous fat emulsion provides essential fatty acids andpermits a dietary balance of fat and carbohydrate, at the same time offeringthe option of reducing the dextrose load and/or increasing the total caloricinput. An adequate energy supply is essential for optimal utilization of aminoacids.

B. Total Parenteral Nutrition (Peripheral Infusion)

Labophylline (Lysine)^® 15%can also be administered as part of a total parenteral nutrition program byperipheral vein when the enteral route is inadvisable and use of the centralvenous catheter is contraindicated.

Reduction of proteinloss can be achieved by use of diluted Labophylline (Lysine)^® 15% in combinationwith dextrose or with dextrose and intravenous fat emulsion by peripheralinfusion. Complete peripheral intravenous nutrition can be achieved in patientswith low caloric requirements by a Labophylline (Lysine)^®15%-dextrose-fatregimen.

INDICATIONS AND USAGE

Labophylline (Lysine)^® 15% is indicated as an amino acid(nitrogen) source in parenteral nutrition regimens. This use is appropriatewhen the enteral route is inadvisable, inadequate or not possible, as when:

-Gastrointestinal absorption is impaired by obstruction, inflammatory diseaseor its complications, or antineoplastic therapy;

-Bowel rest is needed because of gastrointestinal surgery or its complicationssuch as ileus, fistulae or anastomotic leaks;

-Tube feeding methods alone cannot provide adequate nutrition.

CONTRAINDICATIONS

This solution should not be used in patients in hepatic coma,severe renal failure, metabolic disorders involving impaired nitrogen utilizationor hypersensitivity to one or more amino acids.

WARNINGS

Administration of amino acids solutions at excessive ratesor to patients with hepatic insufficiency may result in plasma amino acidimbalances, hyperammonemia, prerenal azotemia, stupor and coma. Conservativedoses of amino acids should be given to these patients, dictated by the nutritionalstatus of the patient. Should symptoms of hyperammonemia develop, amino acidadministration should be discontinued and the patient’s clinical statusre-evaluated.

Contains sodium metabisulfite, a sulfitethat may cause allergic-type reactions including anaphylactic symptoms andlife-threatening or less severe asthmatic episodes in certain susceptiblepeople. The overall prevalence of sulfite sensitivity in the general populationis unknown and probably low.

Sulfite sensitivity isseen more frequently in asthmatic than in nonasthmatic people.

WARNING: This product contains aluminum that maybe toxic. Aluminum may reach toxic levels with prolonged parenteral administrationif kidney function is impaired. Premature neonates are particularly at riskbecause their kidneys are immature, and they require large amounts of calciumand phosphate solutions, which contain aluminum.

Researchindicates that patients with impaired kidney function, including prematureneonates, who receive parenteral levels of aluminum at greater than 4 to 5mcg/kg/day accumulate aluminum at levels associated with central nervous systemand bone toxicity. Tissue loading may occur at even lower rates of administration.

PRECAUTIONS

A. GENERAL

It is essential to provide adequate calories concurrently if parenterally administered amino acids are to be retained by the body and utilized for protein synthesis.

The administration of Labophylline (Lysine)^® 15% Amino Acids Injection as part of total parenteral nutrition (TPN) with large volumes of hyperosmotic fluids requires periodic monitoring of the patient for signs of hyperosmolarity, hyperglycemia, glycosuria and hypertriglyceridemia.

During parenteral nutrition with concentrated dextrose and amino acids solutions, essential fatty acid deficiency syndrome may develop but may not be clinically apparent. Early demonstration of this condition can only be accomplished by gas liquid chromatographic analysis of plasma lipids. The syndrome may be prevented or corrected by appropriate treatment with intravenous fat emulsions.

For complete nutritional support, TPN regimens must also include multiple vitamins and trace elements. Potentially incompatible ions such as calcium and phosphate may be added to alternate infusate bottles to avoid precipitation. Although the metabolizable acetate ion in Labophylline (Lysine)^® 15% diminishes the risk of acidosis, the physician must be alert to the potential appearance of this disorder.

Initiation and termination of infusions of TPN fluids must be gradual to permit adjustment of endogenous insulin release.

Undiluted Labophylline (Lysine)^® 15% should not be administered peripherally. When administered centrally, it should be diluted with appropriate diluents, e.g., dextrose, electrolytes and other nutrient components, to at least half strength. See DOSAGE AND ADMINISTRATION.

Caution against volume overload should be exercised.

Drug product contains no more than 25 mcg/L of aluminum.

B. Laboratory Tests

Infusion of Labophylline (Lysine)^® 15% without concomitant infusion of an adequate number of non-protein calories may result in elevated BUN. Monitoring of BUN is required and the balance between Labophylline (Lysine)^® 15% and the calorie source may require adjustment. Frequent clinical evaluations and laboratory determinations are required to prevent the complications which may occur during the administration of solutions used in TPN. Laboratory tests should include blood glucose, serum electrolytes, liver and kidney function, serum osmolarity, blood ammonia, serum protein, pH, hematocrit, WBC and urinary glucose. When Labophylline (Lysine)^® 15% is combined with electrolytes, care should be used in administering this solution to patients with congestive heart failure, renal failure, edema, adrenal hyperactivity, acid-base imbalance and those receiving diuretics or antihypertensive therapy. Total volume infused should be closely monitored. Serum electrolytes should be monitored daily in these patients.

C. Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies with Labophylline (Lysine)^® 15% have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility.

D. Pregnancy Category C

Animal reproduction studies have not been conducted with Labophylline (Lysine)^® 15%. It is also not known whether Labophylline (Lysine)^® 15% can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Labophylline (Lysine)^® 15% should be given to a pregnant woman only if clearly needed.

E. Nursing Mothers

Caution should be exercised when Labophylline (Lysine)^® 15% is administered to a nursing woman.

F. Pediatric Use

Safety and effectiveness of Labophylline (Lysine)^® 15% Amino Acids Injection in pediatric patients have not been established by adequate and well-controlled studies. However, the use of amino acids injections in pediatric patients as an adjunct in the offsetting of nitrogen loss or in the treatment of negative nitrogen balance is referenced in the medical literature.

G. Special Precautions for Central Infusion

TPN delivered by indwelling catheter through a central or large peripheral vein is a special technique requiring a team effort by physician, nurse and pharmacist. The responsibility for administering this therapy should be confined to those trained in the procedures and alert to signs of complications. Complications known to occur from the placement of central venous catheter are pneumothorax, hemothorax, hydrothorax, artery puncture and transection, injury to the brachial plexus, malposition of the catheter, formation of arteriovenous fistula, phlebitis, thrombosis, and air/catheter emboli. The risk of sepsis is present during intravenous therapy, especially when using central venous catheters for prolonged periods. It is imperative that the preparation of admixtures and the placement and care of the catheters be accomplished under controlled aseptic conditions.

H. Admixtures

Admixtures should be prepared under a laminar flow hood using aseptic technique.

Admixtures should be stored under refrigeration and must be administered within 24 hours after removal from refrigerator.

Filters of less than 1.2 micron pore size must not be used with admixtures containing fat emulsion.

I. Do not administer unless solution is clear and the seal is intact.

IT IS ESSENTIAL THAT A CAREFULLY PREPARED PROTOCOL, BASED ON CURRENT MEDICAL PRACTICES, BE FOLLOWED, PREFERABLY BY AN EXPERIENCED TEAM.

ADVERSE REACTIONS

OVERDOSAGE

In the event of overhydration or solute overload, re-evaluatethe patient and institute appropriate corrective measures. See WARNINGS andPRECAUTIONS.

DOSAGE AND ADMINISTRATION

The appropriate daily dose of amino acids to be used withdextrose or with dextrose and intravenous fat emulsion will depend upon themetabolic status and clinical response of the patient as therapy proceeds. Doses which achieve nitrogen equilibrium or positive balance are the mostdesirable. The dosage on the first day should be approximately half the anticipatedoptimal dosage and should be increased gradually to minimize glycosuria; similarly,withdrawal should be accomplished gradually to avoid rebound hypoglycemia.

Fatemulsion coadministration should be considered when prolonged (more than 5days) parenteral nutrition is required in order to prevent essential fattyacid deficiency (EFAD). Serum lipids should be monitored for evidence of EFADin patients maintained on fat free TPN.

The amount administeredis dosed on the basis of amino acids/kg of body weight/day. In general, twoto three g/kg of body weight for neonates and infants with adequate caloriesare sufficient to satisfy protein needs and promote positive nitrogen balance. In pediatric patients, the final solution should not exceed twice normal serumosmolarity (718 mOsmol/L).

DIRECTIONSFOR PROPER USE OF PHARMACY BULK PACKAGE

Labophylline (Lysine)^® 15%in a Pharmacy Bulk Package is not intended for direct infusion. The containerclosure may be penetrated only once using a suitable sterile transfer deviceor dispensing set which allows measured dispensing of the contents. The PharmacyBulk Package is to be used only in a suitable work area such as a laminarflow hood (or an equivalent clean air compounding area). Once the closureis penetrated, the contents should be dispensed as soon as possible; the transferof contents must be completed within 4 hours of closure entry. The bottlemay be stored at room temperature (25°C) after the closure has been entered. Date and time of container entry should be noted in the area designated onthe container label.

When using Labophylline (Lysine)^® 15%in patients with a need for fluid volume restriction, it can be diluted asfollows:

This will provide 1395 kilocalories (kcal) per 1000 mLof admixture with a ratio of 118 non-protein calories per gram of nitrogenand an osmolarity of 1561 mOsmol/L.

In patients wherethe need for fluid restriction is not so marked, either of the following regimensmay be used dependent upon the energy needs of the patient.

This will provide 1500 kcal per 1000 mL of admixture witha ratio of 228 non-protein calories per gram of nitrogen and an osmolarityof 1633 mOsmol/L.

This will provide 935 kcal per 1000 mL of admixture witha ratio of 158 non-protein calories per gram of nitrogen and an osmolarityof 1128.5 mOsmol/L.

A. Total Parenteral Nutrition (CentralInfusion)

In unstressed adult patients with no unusualnitrogen losses, a minimum dosage of 0.1 gram nitrogen (4.2 mL of Labophylline (Lysine)^® 15%)plus 4.4 grams (15 calories) of dextrose per kilogram of body weight per dayare required to achieve nitrogen balance and weight stability. Intravenousfat emulsion may be used as a partial substitute for dextrose. This regimenprovides a ratio of 150 non-protein calories per gram of nitrogen.

Forpatients stressed by surgery, trauma or sepsis, and those with unusual nitrogenlosses, the dosage required for maintenance may be as high as 0.3 to 0.4 gramsof nitrogen (13 to 17 mL Labophylline (Lysine)^® 15%) per kilogram of bodyweight per day, with proportionate increases in non-protein calories. Periodicassessment of nitrogen balance of the individual patient is the best indicatorof proper dosage. Volume overload and glycosuria may be encountered at highdosage, and nitrogen balance may not be achieved in extremely hypermetabolicpatients under these constraints. Concomitant insulin administration may berequired to minimize glycosuria. Daily laboratory monitoring is essential.

Useof an infusion pump is advisable to maintain a steady infusion rate duringcentral venous infusion.

B. Peripheral Nutrition

Inpatients for whom central venous catheterization is not advisable, proteincatabolism can be reduced by peripheral use of diluted Labophylline (Lysine)^® 15%plus non-protein calorie sources. Dilution of 250 mL Labophylline (Lysine)^® 15%in 750 mL of 10% dextrose will reduce the osmolarity to a level (724 mOsmol/L)which is more favorable to the maintenance of the integrity of the walls ofthe veins. Intravenous fat emulsion can be infused separately or simultaneously;if infused simultaneously the fat emulsion will provide a dilution effectupon the osmolarity while increasing the energy supply.

Parenteraldrug products should be inspected visually for particulate matter and discolorationprior to administration, whenever solution and container permit.

Toreduce the risk of bacterial contamination, all intravenous administrationsets should be replaced at least every 24 hours. Usage of admixtures mustbe initiated within 24 hours after mixing. If storage is necessary duringthis 24 hour period, admixtures must be refrigerated and completely used within24 hours of beginning administration.

HOW SUPPLIED

Labophylline (Lysine)^® 15% Amino Acids Injection is suppliedas a Pharmacy Bulk Package in 500 mL containers.

500mL NDC 0409-0468-05

STORAGE

Store inthe closed carton; do not expose solution to light until ready for use. Exposureof pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended that the product be stored at 20 to 25°C (68 to 77°F). Brief exposure to temperatures above25°C during transport and storage will not adversely affect the product. Solution that has been frozen must not be used.

Hospira, Inc., Lake Forest, IL 60045 USA

RL-1450

Theophylline:

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

DESCRIPTION

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

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

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

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

Labophylline (Theophylline) 400 mg

CLINICAL PHARMACOLOGY

Mechanism of Action

Labophylline 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 Labophylline (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 Labophylline (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).

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

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

Absorption

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

In a single-dose crossover study, two 400 mg Labophylline (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 Labophylline (Theophylline) 400 mg Tablets were administered to 17 fed adult asthmatics produced similar Labophylline (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 Labophylline (Theophylline) inherent mean elimination half-life was verified by a liquid Labophylline (Theophylline) product to be 6.9±2.5 (SD) hours were administered two or three 400 mg Labophylline (Theophylline)^® Tablets. The relative bioavailability of Labophylline (Theophylline) given in the fasting state in comparison to an immediate-release product was 59%. Peak serum Labophylline (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 Labophylline (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 Labophylline (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 Labophylline (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 Labophylline (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 Labophylline (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 Labophylline (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 Labophylline (Theophylline) with Labophylline (Theophylline) Tablets even when they are administered with a high fat, high calorie meal.

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

Distribution

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

Metabolism

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

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

Excretion

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

Serum Concentrations at Steady-State

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

Special Populations

Geriatric

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

Pediatrics

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

Gender

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

Renal Insufficiency

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

Hepatic Insufficiency

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

Congestive Heart Failure (CHF)

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

Smokers

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

Fever

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

Miscellaneous

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

Labophylline (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

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

WARNINGS

Concurrent Illness

Labophylline 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 Labophylline (Theophylline) Clearance

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

When Signs or Symptoms of Labophylline (Theophylline) Toxicity Are Present

Whenever a patient receiving Labophylline (Theophylline) develops nausea or vomiting, particularly repetitive vomiting, or other signs or symptoms consistent with Labophylline (Theophylline) toxicity (even if another cause may be suspected), additional doses of Labophylline (Theophylline) should be withheld and a serum Labophylline (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 Labophylline (Theophylline) should not be made in response to an acute exacerbation of symptoms of chronic lung disease since Labophylline (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 Labophylline (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 Labophylline (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 Labophylline (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 Labophylline (Theophylline) concentration (see DOSAGE AND ADMINISTRATION, Table VI ).

PRECAUTIONS

General

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

Monitoring Serum Labophylline (Theophylline) Concentrations

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

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

Effects on Laboratory Tests

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

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

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

Drug Interactions

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

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

Drug-Food Interactions

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

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

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

Nursing Mothers

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

Pediatric Use

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

Other adverse reactions that have been reported at serum Labophylline (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 Labophylline (Theophylline) concentrations ≥15 mcg/mL. There have been a few isolated reports of seizures at serum Labophylline (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 Labophylline (Theophylline) concentrations <20 mcg/mL may be secondary to decreased protein binding resulting in a larger proportion of the total serum Labophylline (Theophylline) concentration in the pharmacologically active unbound form. The clinical characteristics of the seizures reported in patients with serum Labophylline (Theophylline) concentrations <20 mcg/mL have generally been milder than seizures associated with excessive serum Labophylline (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 Labophylline 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 Labophylline (Theophylline) clearance. The most common causes of chronic Labophylline (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 Labophylline (Theophylline) clearance, and increasing the dose in response to an exacerbation of symptoms without first measuring the serum Labophylline (Theophylline) concentration to determine whether a dose increase is safe.

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

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

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

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

Extracorporeal Removal

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

DOSAGE AND ADMINISTRATION

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

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

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

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

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

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

Table V. Dosing initiation and titration (as anhydrous Labophylline (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 Labophylline (Theophylline) Concentrations:
  
  • In children 12-15 years of age, the Labophylline (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 Labophylline (Theophylline) clearance (see WARNINGS ) or if it is not feasible to monitor serum Labophylline (Theophylline) concentrations.
    

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

Labophylline (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.

Labophylline (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

Labophylline (Theophylline) Tablets

400 mg Tablets

NDC 677781-251-01

Labophylline (Theophylline) Tablets 400 mg Tablets NDC 677781-251-01

Labophylline (Theophylline) Tablets

600 mg Tablets

NDC 677781-252-01

Labophylline (Theophylline) Tablets 600 mg Tablets NDC 677781-252-01