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 approximately reduced in the presence of these risk factors, sever e 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°F 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 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 and 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 corticosteroids 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: 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 pharmacodynamics 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 Table 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*.
Drug Type of Interaction Effect** 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 Amino glutethimide Increases theophylline clearance by induction of microsomal enzyme activity.
25% increase Carbamazepine Similar to aminoglutethimide 30% increase 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 concentrations 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 effect 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 is unknown.
30% increase Flurazepam Similar to diazepam.
Similar to diazepam.
Fluvoxamine Similar to cimetidine.
Similar to cimetidine Halothane Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines.
Increase risk of ventricular arrhythmias.
Interferon, human recombinant alpha-A Decreases theophylline clearance.
100% increase Isoproterenol (IV) Increases theophylline clearance.
20% decrease 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 greater effect.
Mexiletine Similar to disulfiram.
80% increase Midazolam Similar to diazepam.
Similar to diazepam.
Moricizine Increases theophylline clearance.
25% decrease 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 increase theophylline clearance by increasing microsomal enzyme activity.
Theophylline decreases phenytoin absorption.
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 Increases theophylline clearance by increasing demethylation and hydroxylation.
Decreases renal clearance of theophylline.
20% decrease 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 *Refer to PRECAUTIONS, Drug Interactions for further information regarding table.
**Average effect on steady s tate theophylline concentrati on or other clinical effect for pharmacologic interactions .
Individual patients may experience larger changes in serum theophylline c oncentration than the value lis ted.
Table III.
Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.* albuterol, systemic and inhaled felodipinefinasteride nizatidinenorfloxacin amoxicillin hydrocortisone ofloxacin ampicillin, with or without sulbactam isoflurane isoniazid omeprazole prednisone, prednisolone atenolol isradipine ranitidine azithromycin influenze vaccine rifabutin caffeine, dietary ingestion ketoconazo lelomefloxacin Roxithromycin sorbitol (purgative doses do onot inhibit theophylline absorption) cefaclor mebendazole co-trimoxazole (trimethoprim and sulfamethoxazole) medroxyprogesteronemethylprednisolone sucralfate diltiazem metronidazole terbutaline, systemic dirithromycin metoprolol terfenadine enflurane nadolol tetracycline famotidine nifedipine tocainide *Refer to PRECAUTIONS , Drug Interactions for information regarding table.
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 >30mcg/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.
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 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 co ncentrations may continue to increase after presentation of the patient for medical care.) 1.
While simultaneously instituting treatment, contact a regional poison center to obtain updated information and advice on individualizing the recommendations that follow.
2.
Institute supportive care, including establishment of intravenous access, maintenance of the airway, and electrocardiographic monitoring.
3.
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 to 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.
4.
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 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.
5.
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.
6.
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.
7.
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 8.
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.
9.
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 adsorption 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 A.
Serum Concentration >20<30 mcg/mL 1.
Administer a single dose of oral activated charcoal.
2.
Monitor the patient and obtain a serum theophylline concentration in 2-4 hours to insure that the concentration is not increasing.
B.Serum Concentration >30<100 mcg/mL 1.
Administer multiple dose oral activated charcoal and measures to control emesis.
2.
Monitor the patient and obtain serial theophylline concentrations every 2-4 hours to gauge the effectiveness of therapy and to guide further treatment decisions 3.
Institute extracorporeal removal if emesis, seizures, or cardiac arrhythmias cannot be adequately controlled (see , Extracorporeal Removal ).
C.
Serum Concentration >100 mcg/mL 1.
Consider prophylactic anticonvulsant therapy.
2.
Administer multiple-dose oral activated charcoal and measures to control emesis.
3.
Consider extracorporeal removal, even if the patient has not experienced a seizure (see , Extracorporeal Removal ).
4.
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 A.
Serum Concentration >20<30 mcg/mL (with manifestations of theophylline toxicity) 1.
Administer a single dose of oral activated charcoal.
2.
Monitor the patient and obtain a serum theophylline concentration in 2-4 hours to insure that the concentration is not increasing.
B.
Serum Concentration >30 mcg/mL in patients <60 years of age 1.
Administer multiple-dose oral activated charcoal and measures to control emesis.
2.
Monitor the patient and obtain serial theophylline concentrations every 2-4 hours to gauge the effectiveness of therapy and to guide further treatment decisions.
3.
Institute extracorporeal removal if emesis, seizures, or cardiac arrhythmias cannot be adequately controlled (see , Extracorporeal Removal ).
C.
Serum Concentration >30 mcg/mL in patients ≥60 years of age.
1.
Consider prophylactic anticonvulsant therapy.
2.
Administer multiple-dose oral activated charcoal and measures to control emesis.
3.
Consider extracorporeal removal even if the patient has not experienced a seizure (see , Extracorporeal Removal ).
4.
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 six fold, 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: The molecular formula of anhydrous theophylline is C 7 H 8 N 4 0 2 with a molecular weight of 180.17.
THEOPHYLLINE ORAL SOLUTION, USP is available as a liquid intended for oral administration, containing 80 mg of theophylline anhydrous in each 15 mL (tablespoonful).
THEOPHYLLINE ORAL SOLUTION, USP also contains the following inactive ingredients: citric acid, sodium saccharin, sodium benzoate, glycerin, propylene glycol, FD and C Red #40, natural and artificial fruity flavor and purified water.
THEOPHYLLINE ORAL SOLUTION, USP has a pH of 4.0 – 5.0.
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:
CLINICAL STUDIES
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 theophylline decreases the frequency and severity of symptoms, including nocturnal exacerbations, and decreases the “as needed” use of inhaled beta-2 agonists.
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 theophylline decreases dyspnea, air trapping, the work of breathing, and improves contractility of diaphragmatic muscles with little or no improvement in pulmonary function measurements.
HOW SUPPLIED
THEOPHYLLINE ORAL SOLUTION, USP is a clear red solution with a fruit flavor.
Each tablespoonful (15 mL) contains 80 mg theophylline anhydrous.
THEOPHYLLINE ORAL SOLUTION, USP is available in bottles of 473 mL NDC 10135-0604-08 Bottles of 473mL (16 ounces)
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 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 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).
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 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.
PEDIATRIC USE
Pediatric Use: Theophylline is safe and effective for the approved indications in pediatric patients (See INDICATIONS AND USAGE ).
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 ).
Due to the immaturity of theophylline metabolic pathways in infants under the age of one year, particular attention to dosage selection and frequent monitoring of serum theophylline concentrations are required when theophylline is prescribed to pediatric patients in this age group.
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/m 2 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 per 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.
DOSAGE AND ADMINISTRATION
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 dos e of theophylline mus t be individ ualized on the bas is of peak s erum theophylline concentration meas urements in order to achieve a dos e that will provide maximum potential benefit with minimal risk to 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 dos ing recommendat ions to individual patients mus t take into account the unique clinical characteris tics of each patient.
In general, these recommendations should serve as the upper limit for dos age adj ustments in order to decrease the risk of potentially serious adverse events ass ociated with unexpected large increases in s erum theophylline concentration.
A.
Infants <1 year old.
1.
Initial Dosage.
a.
Premature Neonates: i.
<24 days postnatal age; 1.0 mg/kg every 12 hr ii.
≥ 24 days postnatal age; 1.5 mg/kg every 12 hr b.
Full term infants and infants up to 52 weeks of age: Total daily dose (mg) = [(0.2 x age in weeks)+5.0] x (Kg body Wt).
i.
up to age 26 weeks; divide dose into 3 equal amounts administered at 8 hour intervals ii.
≥26 weeks of age; divide dose into 4 equal amounts administered at 6 hour intervals.
2.
Final Dosage.
Adjusted to maintain a peak steady state serum theophylline concentration of 5-10 mcg/ml in neonates and 10-15 mcg/mL in older infants (see Table VI ).
Since the time required to reach steady-state is a function of theophylline half-life, up to 5 days may be required to achieve steady state in a premature neonate while only 2-3 days may be required in a 6 month old infant without other risk factors for impaired clearance in the absence of a loading dose.
If a s erum theophylline concentrati on is obtained before steady s tate is achieved, the maintena nce dose s hould not be increased, even if the s erum theophylline concentration is <10 mcg/mL.
B.
Children (1-15 years ) and ad ults (16-60 years) without ris k factors for impaired clearance.
Table V.
Dosing initation and titration (as anhydrous theophylline).* Titration Step Children 45 kg and adults 1.
Starting Dosage 12-14 mg/kg/day up to a maximum of 300 mg/day divided Q4-6 hrs* 300 mg/day divided Q6-8 hrs* 2.
After 3 days, if tolerated, increase dose to: 16 mg/kg/day up to a maximum of 400 mg/day divided Q4-6 hrs* 400 mg/day divided Q6-8 hrs* 3.
After 3 more days, if tolerated , increase dose to: 20 mg/kg/day up to a maximum of 600 mg/day divided Q4-6 hrs* 600 mg/day divided Q6-8 hrs* C.
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 1-15 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.
D.
Loading Dose for Acute Bronchodilatation : An inhaled beta-2 selective agonist, alone or in combination with a systemically administered corticosteroid, is the most effective treatment for acute exacerbations of reversible airways obstruction.
Theophylline is a relatively weak bronchodilator, is less effective than an inhaled beta-2 selective agonist and provides no added benefit in the treatment of acute bronchospasm.
If an inhaled or parenteral beta agonist is not available, a loading dose of an oral immediate release theophylline can be used as a temporary measure.
A single 5 mg/kg dose of theophylline, in a patient who has not received any theophylline in the previous 24 hours, will produce an average peak serum theophylline concentration of 10 mcg/mL (range 5-15 mcg/mL).
If dosing with theophylline is to be continued beyond the loading dose, the guidelines in Sections A.1.b., B.3, or C., above, should be utilized and serum theophylline concentration monitored at 24 hour intervals to adjust final dosage.
* Patients with more rapid metabolism, clinically identified by higher than average dose requirements, should receive a smaller dose more frequently to prevent breakthrough symptoms resulting from low trough concentrations before the next dose.
A reliably absorbed slow-release formulation will decrease fluctuations and permit longer dosing intervals.
VI Table.
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.
¶ 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.
¶ 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 ).