Theophylline Information
Theophylline () Descriptiontheophylline Is Structurally Classified As A Methylxanthine. It Occurs As A White, Odorless, Crystalline Powder With A Bitter Taste. Anhydrous Theophylline Has The Chemical Name H-purine-,-dione,,-dihydro-,-dimethyl-, And Is Represented By The Following Structural Formula:
The molecular formula of anhydrous Theophylline () is CHNO with a molecular weight of 180.17.
Theophylline () Elixir is available as a liquid intended for oral administration, containing 80 mg of anhydrous Theophylline () and 20% alcohol per 15 mL (one tablespoonful).
Also contains: FD&C Red #40, Artificial Mixed Fruit Flavor, Propylene Glycol, Purified Water, Saccharin Sodium. May contain Citric Acid to adjust pH.
Theophylline () Clinical Pharmacology
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.
Bronchodilation occurs over the serum Theophylline () concentration range of 5-20 mcg/mL. Clinically important improvement in symptom control has been found in most studies to require peak serum Theophylline () concentrations > 10 mcg/mL, but patients with mild disease may benefit from lower concentrations. At serum Theophylline () concentrations > 20 mcg/mL, both the frequency and severity of adverse reactions increase. In general, maintaining peak serum 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.
Overview Theophylline () is rapidly and completely absorbed after oral administration in solution or immediate-release solid oral dosage form. 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 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 Theophylline () . Within-subject variability in metabolism has also been reported in some studies, especially in acutely ill patients. It is, therefore, recommended that serum 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 Theophylline () clearance (see ).
Absorption Theophylline () is rapidly and completely absorbed after oral administration in solution or immediate-release solid oral dosage form. After a single dose of 5 mg/kg in adults, a mean peak serum concentration of about 10 mcg/mL (range 5-15 mcg/mL) can be expected 1-2 hr after the dose. Co-administration of Theophylline () with food or antacids does not cause clinically significant changes in the absorption of Theophylline () from immediate-release dosage forms.
Distribution Once Theophylline () enters the systemic circulation, about 40% is bound to plasma protein, primarily albumin. Unbound Theophylline () distributes throughout body water, but distributes poorly into body fat. The apparent volume of distribution of Theophylline () is approximately 0.45 L/kg (range 0.3-0.7 L/kg) based on ideal body weight. Theophylline () passes freely across the placenta, into breast milk and into the cerebrospinal fluid (CSF). Saliva 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 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 Theophylline () in the therapeutic range (10-20 mcg/mL) due to elevated concentrations of the pharmacologically active unbound drug. Similarly, a patient with decreased 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 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 Theophylline () concentration provides a more reliable means of dosage adjustment than measurement of total serum Theophylline () concentration. Generally, concentrations of unbound Theophylline () should be maintained in the range of 6-12 mcg/mL.
Metabolism Following oral dosing, 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 Theophylline () dose is N-methylated to caffeine. 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 Theophylline () metabolites with pharmacologic activity. 3-methylxanthine has approximately one tenth the pharmacologic activity of Theophylline () and serum concentrations in adults with normal renal function are
Both the N-demethylation and hydroxylation pathways of Theophylline () biotransformation are capacity-limited. Due to the wide intersubject variability of the rate of Theophylline () metabolism, non-linearity of elimination may begin in some patients at serum Theophylline () concentrations
Excretion In neonates, approximately 50% of the Theophylline () dose is excreted unchanged in the urine. Beyond the first three months of life, approximately 10% of the 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 Theophylline () is excreted unchanged in the urine and since active metabolites of 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 Theophylline () dose excreted in the urine as unchanged Theophylline () and caffeine in neonates requires careful attention to dose reduction and frequent monitoring of serum Theophylline () concentrations in neonates with reduced renal function (See ).
Serum Concentrations At Steady StateAfter multiple doses of Theophylline () , steady state is reached in 30-65 hours (average 40 hours) in adults. At steady state, on a dosage regimen with 6-hour intervals, the expected mean trough concentration is approximately 60% of the mean peak concentration, assuming a mean Theophylline () half-life of 8 hours. The difference between peak and trough concentrations is larger in patients with more rapid Theophylline () clearance. In patients with high Theophylline () clearance and half-lives of about 4-5 hours, such as children age 1 to 9 years, the trough serum Theophylline () concentration may be only 30% of peak with a 6-hour dosing interval. In these patients a slow release formulation would allow a longer dosing interval (8-12 hours) with a smaller peak/trough difference.
Special Populations (See Table I For Mean Clearance And Half-Life Values)
Theophylline () 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.
Theophylline () Contraindications
Theophylline () Elixir is contraindicated in patients with a history of hypersensitivity to Theophylline () or other components in the product.
Theophylline () Warnings
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)
There are several readily identifiable causes of reduced Theophylline () clearance 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:
Neonates (term and premature)
Children
Elderly (>60 years)
Acute pulmonary edema
Congestive heart failure
Cor-pulmonale
Fever; 102º for 24 hours or more; or lesser temperature elevations for longer periods
Hypothyroidism
Liver disease; cirrhosis, acute hepatitis
Reduced renal function in infants
Sepsis with multi-organ failure
Shock
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 ).
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 beta-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 ).
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 ).
Theophylline () Precautions
Careful consideration of the various interacting drugs and physiologic conditions that can alter Theophylline () clearance and require dosage adjustment should occur prior to initiation of Theophylline () therapy, prior to increases in Theophylline () dose, and during follow up (see ). The dose of Theophylline () selected for initiation of therapy should be low and, increased slowly over a period of a week or longer with the final dose guided by monitoring serum Theophylline () concentrations and the patient’s clinical response (see ).
Monitoring Serum Theophylline () Concentrations:
Serum Theophylline () concentration measurements are readily available and should be used to determine whether the dosage is appropriate. Specifically, the serum Theophylline () concentration should be measured as follows:
To guide a dose increase, the blood sample should be obtained at the time of the expected peak serum Theophylline () concentration; 1-2 hours after a 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 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 two hours after the 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 Theophylline () toxicity are present, the serum sample should be obtained as soon as possible, analyzed immediately, and the result reported to the clinician 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 Theophylline () should be measured and the dosage adjusted to achieve an unbound concentration of 6-12 mcg/mL.
Saliva concentrations of Theophylline () cannot be used reliably to adjust dosage without special techniques.
Effects On Laboratory Tests:
As a result of its pharmacological effects, Theophylline () 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 μЄq/l to 800 μЄq/l, total cholesterol (from a mean of 140 to 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). 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 Theophylline () ). The clinical importance of these changes should be weighed against the potential therapeutic benefit of Theophylline () in individual patients.
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.,
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.
The Effect Of Other Drugs On Theophylline () Serum Concentration Measurements:
Long term carcinogenicity studies have been carried out in mice (oral doses 30-150 mg/kg) and rats (oral doses 5-75 mg/kg). Results are pending.
Theophylline () has been studied in Ames salmonella, and cytogenetics, micronucleus and Chinese hamster ovary test systems and has not been shown to be genotoxic.
In a 14 week continuous breeding study, Theophylline () , administered to mating pairs of B6C3F mice at oral doses of 120, 270 and 500 mg/kg (approximately 1.0- 3.0 times the human dose on a mg/m 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, Theophylline () was administered to F344 rats and B6C3F mice at oral doses of 40-300 mg/kg (approximately 2.0 times the human dose on a mg/m basis). At the high dose, systemic toxicity was observed in both species including decreases in testicular weight.
Theophylline () Adverse Reactions
Adverse reactions associated with Theophylline () are generally mild when peak serum Theophylline () concentrations are 300 mg/day in adults and >12 mg/kg/day in children beyond >1 year of age). During the initiation of Theophylline () therapy, caffeine-like adverse effects may transiently alter patient behavior, especially in school age children, but this response rarely persists. Initiation of 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 ). In a small percentage of patients (
Other adverse reactions that have been reported at serum Theophylline () concentrations
Theophylline () Overdosage
The chronicity and pattern of Theophylline () overdosage significantly influences clinical manifestations of toxicity, management and outcome. There are two common presentations, 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 , 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. 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.
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.)
Acute overdose
Chronic overdosage
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.
Theophylline () Dosage And Administration
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
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, , 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 and ). 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 ).
If the patient’s symptoms are well controlled, there are no apparent adverse effects, and no intervening factors that might alter dosage requirements (see and ), 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.
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 ) 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 ) or if it is not feasible to monitor serum Theophylline () concentrations.
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.
Theophylline () How Supplied
Theophylline () Elixir, 80 mg/15 mL with 20% alcohol, is a fruit-flavored reddish-orange liquid available in one pint (473 mL) and one gallon (3785 mL) bottles.
Store at controlled room temperature 15º-30ºC (59º-86ºF). Do not refrigerate.
Dispense in a tight, light-resistant container as defined in the USP.
Manufactured byBarre-National Inc.Baltimore, MD 21244an ALPHARMA USPD company
Form No. 1444Rev. 1/97 C1VC1299
