Theophylline 200 MG Extended Release Oral Tablet

Generic Name: THEOPHYLLINE, ANHYDROUS
Brand Name: Theophylline Extended Release
  • Substance Name(s):
  • THEOPHYLLINE

WARNINGS

Concurrent Illness: Theophylline 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 Theophylline Clearance: There are several readily identifiable causes of reduced theophylline clearance.

If the total daily dose is not appropriately reduced in the presence of these risk factors, severe and potentially fatal theophylline toxicity can occur.

Careful consideration must be given to the benefits and risks of theophylline use and the need for more intensive monitoring of serum theophylline concentrations in patients with the following risk factors: Age: Neonates (term and premature), children 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), reduced renal function in infants <3 months of age, sepsis with multi-organ failure, and shock.

Cessation of Smoking.

Drug Interactions: Adding a drug that inhibits theophylline metabolism (e.g., cimetidine, erythromycin, tacrine) or stopping a concurrently administered drug that enhances theophylline metabolism (e.g., carbamazepine, rifampin).

(See PRECAUTIONS, Drug Interactions, Table II.) When Signs or Symptoms of Theophylline Toxicity Are Present: Whenever a patient receiving theophylline develops nausea or vomiting, particularly repetitive vomiting, or other signs or symptoms consistent with theophylline toxicity (even if another cause may be suspected), additional doses of theophylline should be withheld and a serum 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 clinician 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 theophylline should not be made in response to an acute exacerbation of symptoms of chronic lung disease since theophylline provides little added benefit to inhaled beta2-selective agonists and systemically administered cortico-steroids in this circumstance and increases the risk of adverse effects.

A peak steady-state serum 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 theophylline dose on the basis of a low serum concentration, the clinician 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 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 theophylline concentration (see DOSAGE AND ADMINISTRATION, Table VI).

DRUG INTERACTIONS

Drug Interactions Drug-Drug Interactions Theophylline interacts with a wide variety of drugs.

The interaction may be pharmacodynamic, i.e., alterations in the therapeutic response to theophylline or another drug or occurrence of adverse effects without a change in serum theophylline concentration.

More frequently, however, the interaction is pharmacokinetic, i.e., the rate of theophylline clearance is altered by another drug resulting in increased or decreased serum theophylline concentrations.

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 theophylline.

The information in the “Effect” column of Table II assumes that the interacting drug is being added to a steady-state theophylline regimen.

If theophylline is being initiated in a patient who is already taking a drug that inhibits theophylline clearance (e.g., cimetidine, erythromycin), the dose of theophylline required to achieve a therapeutic serum theophylline concentration will be smaller.

Conversely, if theophylline is being initiated in a patient who is already taking a drug that enhances theophylline clearance (e.g., rifampin), the dose of theophylline required to achieve a therapeutic serum theophylline concentration will be larger.

Discontinuation of a concomitant drug that increases theophylline clearance will result in accumulation of theophylline to potentially toxic levels, unless the theophylline dose is appropriately reduced.

Discontinuation of a concomitant drug that inhibits theophylline clearance will result in decreased serum theophylline concentrations, unless the theophylline dose is appropriately increased.

The drugs listed in Table III have either been documented not to interact with theophylline or do not produce a clinically significant interaction (i.e., <15% change in 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 theophylline, especially with new chemical entities.

The clinician should not assume that a drug does not interact with theophylline if it is not listed in Table II.

Before addition of a newly available drug in a patient receiving 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 theophylline has been reported.

Table II.

Clinically significant drug interactions with theophylline.Refer to PRECAUTIONS, Drug Interactions for further information regarding table.

Drug Type of Interaction EffectAverage effect on steady-state theophylline concentration or other clinical effect for pharmacologic interactions.

Individual patients may experience larger changes in serum theophylline concentration than the value listed.

Adenosine Theophylline blocks adenosine receptors.

Higher doses of adenosine may be required to achieve desired effect.

Alcohol A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours 30% increase Allopurinol Decreases theophylline clearance at allopurinol doses ≥ 600 mg/day 25% increase Aminoglutethimide Increases theophylline clearance by induction of microsomal enzyme activity.

25% decrease Carbamazepine Similar to aminoglutethimide.

30% decrease Cimetidine Decreases theophylline clearance by inhibiting cytochrome P450 1A2.

70% increase Ciprofloxacin Similar to cimetidine.

40% increase Clarithromycin Similar to erythromycin.

25% increase Diazepam Benzodiazepines increase CNS concentratrions of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors.

Larger diazepam doses may be required to produce desired level of sedation.

Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.

Disulfiram Decreases theophylline clearance by inhibiting hydroxylation and demethylation.

50% increase Enoxacin Similar to cimetidine.

300% increase Ephedrine Synergistic CNS effects Increased frequency of nausea, nervousness, and insomnia.

Erythromycin Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3.

35% increase.

Erythromycin steady-state serum concentrations decrease by a similar amount.

Estrogen Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion.

The effect of progesterone on theophylline clearance in unknown.

30% increase Flurazepam Similar to diazepam.

Similar to diazepam.

Fluvoxamine Similar to cimetidine.

Similar to cimetidine.

Halothane Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines.

Increased risk of ventricular arrhythmias.

Interferon, human recombinant alpha-A Decreases theophylline clearance.

100% increase Isoproterenol (IV) Increase theophylline clearance.

20% increase Ketamine Pharmacologic May lower theophylline seizure threshold.

Lithium Theophylline increases renal lithium clearance.

Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.

Lorazepam Similar to diazepam.

Similar to diazepam.

Methotrexate (MTX) Decreases theophylline clearance.

20% increase after low dose MTX, higher dose MTX may have a greater effect.

Mexiletine Similar to disulfiram.

80% increase Midazolam Similar to diazepam.

Similar to diazepam.

Moricizine Increases theophylline clearance.

25% increase Pancuronium Theophylline may antagonize non-depolarizing neuromuscular blocking effects;possibly due to phosphodiesterase inhibition.

Larger dose of pancuronium may be required to achieve neuromuscular blockade.

Pentoxifylline Decreases theophylline clearance.

30% increase Phenobarbital (PB) Similar to aminoglutethimide.

25% decrease after two weeks of concurrent PB.

Phenytoin Phenytoin increases theophylline clearance by increasing microsomal enzyme activity.

Serum theophylline and phenytoin concentrations decrease about 40%.

Propafenone Decreases theophylline clearance and pharmacologic interaction.

40% increase.

Beta-2 blocking effect may decrease efficacy of theophylline.

Propranolol Similar to cimetidine and pharmacologic interaction.

100% increase Beta-2 blocking effect may decrease efficacy of theophylline.

Rifampin Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity.

20-40% decrease Sulfinpyrazone Increase theophylline clearance by increasing demethylation and hydroxylation.

Decreases renal clearance of theophylline.

20% increase Tacrine Similar to cimetidine, also increases renal clearance of theophylline.

90% increase Thiabendazole Decreases theophylline clearance.

190% increase Ticlopidine Decreases theophylline clearance.

60% increase Troleandomycin Similar to erythromycin.

33-100% increase depending on troleandomycin dose.

Verapamil Similar to disulfiram.

20% increase Table III.

Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.Refer to PRECAUTIONS, Drug Interactions for information regarding table.

albuterol, famotidine nizatidine systemic and inhaled felodipine norfloxacin amoxicillin finasteride ofloxacin ampicillin, hydrocortisone omeprazole with or without isoflurane prednisone, prednisolone sulbactam isoniazid ranitidine atenolol isradipine rifabutin azithromycin influenza vaccine roxithromycin caffeine, ketoconazole sorbitol dietary digestion lomefloxacin (purgative doses do not cefaclor mebendazole inhibit theophylline co-trimoxazole medroxyprogesterone absorption) (trimethoprim and methylprednisolone sucralfate sulfamethoxazole) metronidazole terbutaline, systemic diltiazem metoprolol terfenadine dirithromycin nadolol tetracycline enflurane nifedipine tocainide Drug-Food Interactions Taking theophylline extended-release tablets immediately after ingesting a high fat content meal (45 g fat, 55 g carbohydrates, 28 g protein, 789 calories) may result in a somewhat higher Cmax and delayed Tmax, and a somewhat greater extent of absorption when compared to taking it in the fasting state.

The influence of the type and amount of other foods, as well as the time interval between drug and food, has not been studied.

The Effect of Other Drugs on Theophylline Serum Concentration Measurements: Most serum theophylline assays in clinical use are immunoassays which are specific for 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 theophylline concentration.

OVERDOSAGE

General The chronicity and pattern of theophylline 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 theophylline clearance.

The most common causes of chronic theophylline overdosage include patient or care giver error in dosing, clinician prescribing of an excessive dose or a normal dose in the presence of factors known to decrease the rate of theophylline clearance, and increasing the dose in response to an exacerbation of symptoms without first measuring the serum theophylline concentration to determine whether a dose increase is safe.

Severe toxicity from theophylline overdose is a relatively rare event.

In one health maintenance organization, the frequency of hospital admissions for chronic overdosage of theophylline was about 1 per 1000 person-years exposure.

In another study, among 6000 blood samples obtained for measurement of serum 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 theophylline concentrations in the 20-30 mcg/mL range had one or more manifestations of toxicity while >90% of patients with serum theophylline concentrations >30 mcg/mL were clinically intoxicated.

Similarly, in other reports, serious toxicity from theophylline is seen principally at serum concentrations >30 mcg/mL.

Several studies have described the clinical manifestations of 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 theophylline concentration is >100 mcg/mL.

After a chronic overdosage, generalized seizures, life-threatening cardiac arrhythmias, and death may occur at serum 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 theophylline concentration; patients >60 years are at the greatest risk for severe toxicity and mortality after a chronic overdosage.

Preexisting 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 theophylline concentration compared to patients without the underlying disease.

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

Other manifestations of 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 theophylline concentrations >30 mcg/mL are often resistant to anticonvulsant therapy and may result in irreversible brain injury if not rapidly controlled.

Death from 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 Theophylline Overdose or Serum Theophylline Concentrations >30 mcg/mL (Note: Serum 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 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 clinician 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 theophylline overdose because fluorinated volatile anesthetics may sensitize the myocardium to endogenous catecholamines released by 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 theophylline overdose who are at high risk for theophylline-induced seizures, e.g., patients with acute overdoses and serum theophylline concentrations >100 mcg/mL or chronic overdosage in patients >60 years of age with serum 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 theophylline (e.g., transfer of a high risk patient from one health care facility to another for extracorporeal removal) and clinical circumstances that significantly interfere with efforts to enhance 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 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 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 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 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 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 theophylline overdoses.

Although ipecac induces emesis, it does not reduce the absorption of 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 theophylline concentration monitoring: The serum 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 theophylline concentrations may continue to increase after presentation of the patient for medical care as a result of continued absorption of theophylline from the gastrointestinal tract.

Serial monitoring of serum 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 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 theophylline: Multiple-dose oral activated charcoal (e.g., 0.5 mg/kg up to 20 g, every two hours) increases the clearance of theophylline at least twofold by absorption of 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 theophylline from the gastrointestinal tract.

Sorbitol alone does not enhance clearance of 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 theophylline removal should be instituted (see , 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 theophylline 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 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 , 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 , Extracorporeal Removal).

Monitor the patient and obtain serial 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 theophylline toxicity) Administer a single dose of oral activated charcoal.

Monitor the patient and obtain a serum 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 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 , 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 (see , Extracorporeal Removal).

Monitor the patient and obtain serial theophylline concentrations every 2-4 hours to gauge the effectiveness of therapy and to guide further treatment decisions.

Extracorporeal Removal Increasing the rate of 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 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 theophylline concentrations may rebound 5-10 mcg/mL after discontinuation of charcoal hemoperfusion or hemodialysis due to redistribution of theophylline from the tissue compartment.

Peritoneal dialysis is ineffective for theophylline removal; exchange transfusions in neonates have been minimally effective.

DESCRIPTION

Theophylline is structurally classified as a methylxanthine.

It occurs as a white, odorless, crystalline powder with a bitter taste.

Anhydrous theophylline has the chemical name 1H-Purine-2,6-dione,3,7-dihydro-1,3-dimethyl-, and is represented by the following structural formula: This product allows a 12-hour dosing interval for a majority of patients and a 24-hour dosing interval for selected patients (see DOSAGE AND ADMINISTRATION section for description of appropriate patient populations).

Each extended-release tablet for oral administration contains either 100 mg, 200 mg, 300 mg or 450 mg of anhydrous theophylline.

Tablets also contain as inactive ingredients: hypromellose, anhydrous lactose, magnesium stearate and povidone.

Theophylline Structural Formula

HOW SUPPLIED

Theophylline Extended-release Tablets: 200 mg – White, oval-shaped, bisected tablets in blisterpacks of 30.

Debossed: PLIVA 482 Dispense in a well-closed container as defined in the USP.

Store at 20°-25°C (68°-77°F) [see USP Controlled Room Temperature].

GERIATRIC USE

Geriatric Use Elderly patients are at significantly greater risk of experiencing serious toxicity from theophylline than younger patients due to pharmacokinetic and pharmacodynamic changes associated with aging.

Theophylline clearance is reduced in patients greater than 60 years of age, resulting in increased serum theophylline concentrations in response to a given theophylline dose.

Protein binding may be decreased in the elderly resulting in a larger proportion of the total serum theophylline concentration in the pharmacologically active unbound form.

Elderly patients also appear to be more sensitive to the toxic effects of theophylline after chronic overdosage than younger patients.

For these reasons, the maximum daily dose of 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 theophylline concentration is <10 mcg/mL (see DOSAGE AND ADMINISTRATION).

Theophylline doses greater than 400 mg/d should be prescribed with caution in elderly patients.

MECHANISM OF ACTION

Mechanism of Action Theophylline 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 theophylline are not known with certainty, studies in animals suggest that bronchodilatation is mediated by the inhibition of two isozymes of phosphodiesterase (PDE lll 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 lll or antagonism of adenosine receptors.

Some of the adverse effects associated with theophylline appear to be mediated by inhibition of PDE lll (e.g., hypotension, tachycardia, headache, and emesis) and adenosine receptor antagonism (e.g., alterations in cerebral blood flow).

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.

INDICATIONS AND USAGE

Theophylline extended-release tablets are 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.

PEDIATRIC USE

Pediatric Use Theophylline is safe and effective for the approved indications in pediatric patients.

The maintenance dose of theophylline must be selected with caution in pediatric patients since the rate of theophylline clearance is highly variable across the age range of neonates to adolescents (see CLINICAL PHARMACOLOGY, Table I, WARNINGS, and DOSAGE AND ADMINISTRATION, Table V).

PREGNANCY

Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women.

Additionally, there are no teratogenicity studies in non-rodents (e.g., rabbits).

Theophylline was not shown to be teratogenic in CD-1 mice at oral doses up to 400 mg/kg, approximately 2.0 times the human dose on a mg/m2 basis or in CD-1 rats at oral doses up to 260 mg/kg, approximately 3.0 times the recommended human dose on a mg/m2 basis.

At a dose of 220 mg/kg, embryotoxicity was observed in rats in the absence of maternal toxicity.

NUSRING MOTHERS

Nursing Mothers Theophylline is excreted into breast milk and may cause irritability or other signs of mild toxicity in nursing human infants.

The concentration of 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 theophylline a day is likely to receive 10-20 mg of theophylline per day.

Serious adverse effects in the infant are unlikely unless the mother has toxic serum theophylline concentrations.

INFORMATION FOR PATIENTS

Information for Patients The patient (or parent/care giver) should be instructed to seek medical advice whenever nausea, vomiting, persistent headache, insomnia or rapid heart beat occurs during treatment with theophylline, even if another cause is suspected.

The patient should be instructed to contact their clinician 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 clinician adds a new medication or discontinues a previously prescribed medication.

Patients should be instructed to inform all clinicians involved in their care that they are taking 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 clinician.

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.

Theophylline extended-release tablets should not be chewed or crushed.

When dosing on a once daily (q24h) basis, tablets should be taken whole and not split.

DOSAGE AND ADMINISTRATION

Taking theophylline extended-release tablets immediately after a high-fat content meal may result in a somewhat higher Cmax and delayed Tmax, and somewhat greater extent of absorption.

However, the differences are usually not great and this product may normally be administered without regard to meals (see CLINICAL PHARMACOLOGY, Drug Interactions, Drug-Food Interactions).

Theophylline extended-release tablets are recommended for chronic or long-term management and prevention of symptoms, and not for use in treating acute symptoms of asthma and reversible bronchospasm.

General Considerations The steady-state peak serum theophylline concentration is a function of the dose, the dosing interval, and the rate of theophylline absorption and clearance in the individual patient.

Because of marked individual differences in the rate of theophylline clearance, the dose required to achieve a peak serum theophylline concentration in the 10-20 mcg/mL range varies fourfold among otherwise similar patients in the absence of factors known to alter 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 theophylline dose that will provide both safe and effective serum concentrations for all patients.

Administration of the median theophylline dose required to achieve a therapeutic serum theophylline concentration in a given population may result in either sub-therapeutic or potentially toxic serum 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 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 theophylline must be individualized on the basis of peak serum 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 theophylline concentrations to reach the new steady state.

Dosage adjustment should be guided by serum theophylline concentration measurement (see PRECAUTIONS, Laboratory Tests and , Table VI).

Health care providers should instruct patients and care givers 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 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 theophylline concentrations should be monitored at frequent intervals, e.g.

every 24 hours.

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

Table V contains theophylline dosing titration schema recommended for patients in various age groups and clinical circumstances.

Table VI contains recommendations for theophylline dosage adjustment based upon serum 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 theophylline concentration.

A.

Children (6-15 years) and adults (16-60 years) without risk factors for impaired clearance.

Table V.

Dosing initiation and titration (as anhydrous theophylline).Patients with more rapid metabolism, clinically identified by higher than average dose requirements, should receive a smaller dose more frequently (every 8 hours) to prevent breakthrough symptoms resulting from low trough concentrations before the next dose.

Titration Step 1.

Starting Dosage Children 45 kg and adults 300 mg/day divided Q12 hrs 2.

After 3 days, if tolerated.

increase dose to: 16 mf/kg/day up to a maximum of 400 mg/day divided Q12 hrs 400 mg/day dividedQ12 hrs 3.

After 3 more days, if tolerated.

increase dose to: 20 mg/kg/day up to a maximum of 600 mg/daydivided Q12 hrs 600 mg/day divided Q12 hrs B.

Patients With Risk Factors For Impaired Clearance, The Elderly (>60 Years), And Those In Whom It Is Not Feasible To Monitor Serum Theophylline Concentrations: In children 6-15 years of age, the final 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 theophylline clearance (see WARNINGS) or if it is not feasible to monitor serum theophylline concentrations.

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

Table VI.

Dosage adjustment guided by serum theophylline concentration.

Peak Serum Concentration Dosage Adjustment <9.9 mcg/mL If symptoms are not controlled and current dosage is tolerated, increase dose about 25%.

Recheck serum concentration after three days for further dosage adjustment.

10 to 14.9 mcg/mL If symptoms are controlled and current dosage is tolerated, maintain dose and recheck serum concentration at 6-12 month intervals.Dose reduction and/or serum theophylline concentration measurement is indicated whenever adverse effects are present, physiologic abnormalities that can reduce theophylline clearance occur (e.g., sustained fever), or a drug that interacts with theophylline is added or discontinued (see WARNINGS).

If symptoms are not controlled and current dosage is tolerated consider adding additional medication(s) to treatment regimen.

15-19.9 mcg/mL Consider 10% decrease in dose to provide greater margin of safety even if current dosage is tolerated.

20-24.9 mcg/mL Decrease dose by 25% even if no adverse effects are present.

Recheck serum concentration after 3 days to guide further dosage adjustment.

25-30 mcg/mL Skip next dose and decrease subsequent doses at least 25% even if no adverse effects are present.

Recheck serum concentration after 3 days to guide further dosage adjustment.

If symptomatic, consider whether overdose treatment is indicated (see recommendations for chronic overdosage).

>30 mcg/mL Treat overdose as indicated (see recommendations for chronic overdosage).

If theophylline is subsequently resumed, decrease dose by at least 50% and recheck serum concentration after 3 days to guide further dosage adjustment.

Once-Daily Dosing: The slow absorption rate of this preparation may allow once-daily administration in adult non-smokers with appropriate total body clearance and other patients with low dosage requirements.

Once-daily dosing should be considered only after the patient has been gradually and satisfactorily titrated to therapeutic levels with q12h dosing.

Once-daily dosing should be based on twice the q12h dose and should be initiated at the end of the last q12h dosing interval.

The trough concentration (Cmin) obtained following conversion to once-daily dosing may be lower (especially in high clearance patients) and the peak concentration (Cmax) may be higher (especially in low clearance patients) than that obtained with q12h dosing.

If symptoms recur, or signs of toxicity appear during the once-daily dosing interval, dosing on the q12h basis should be reinstituted.

It is essential that serum theophylline concentrations be monitored before and after transfer to once-daily dosing.

Food and posture, along with changes associated with circadian rhythm, may influence the rate of absorption and/or clearance rates of theophylline from extended-release dosage forms administered at night.

The exact relationship of these and other factors to nighttime serum concentrations and the clinical significance of such findings require additional study.

Therefore, it is not recommended that theophylline extended-release once-daily dosing be administered at night.