Oxtriphylline
Indications: Asthma; Bronchitis, chronic; Emphysema
DESCRIPTION:
Oxtriphylline is the choline salt of theophylline. Theophylline is a bronchodilator structurally classified as a xanthine derivative. It occurs as a white, odorless, crystalline powder having a bitter taste. Theophylline anhydrous has the chemical name 1H -Purine-2, 6-dione, 3,7-dihydro-1,3-dimethyl-.
The molecular formula is C12H21N5O3. The molecular weight is 283.33.
Oxtriphylline tablets are available as enteric, sugar-coated tablets intended for oral administration, containing 100 mg or 200 mg oxtriphylline (64 mg and 127 mg of theophylline anhydrous, respectively). Each tablet also contains acacia, NF; precipitated calcium carbonate, USP; tribasic calcium phosphate, NF; carnauba wax; confectioner's sugar, NF; gelatin, NF; kaolin, USP; magnesium stearate, NF; pharmaceutical glaze; starch, NF; sucrose, NF; talc, USP; titanium dioxide, USP; tragacanth, NF; and white wax, NF. The 100-mg tablet also contains D&C red No. 7 Lake and FD&C yellow No. 6 Lake. The 200-mg tablet also contains D&C yellow No. 10.
Each film-coated Oxtriphylline sustained-action tablet contains 400 mg or 600 mg Oxtriphylline (equivalent to 254 mg or 383 mg anhydrous theophylline, respectively). Each tablet also contains: candelilla wax; confectioner's sugar, NF; magnesium stearate, NF; Opaseal pharmaceutical sealant; talc, USP; and other ingredients. The 400-mg tablet also contains Opaspray pink and triethyl citrate. The 600-mg tablet also contains Opaspray tan.
Each sustained-action tablet contains Oxtriphylline in a tablet matrix specially designed for the prolonged release of the drug in the gastrointestinal tract. Following the release of the drug, the expended wax tablet matrix, which is not absorbed, may be detected in the stool.
CLINICAL PHARMACOLOGY:
Theophylline directly relaxes the smooth muscle of the bronchial airways and pulmonary blood vessels, thus acting mainly as a bronchodilator and smooth muscle relaxant. It has also been demonstrated that aminophylline has a potent effect on diaphragmatic contractility in normal persons and may then be capable of reducing fatigability and thereby improve contractility in patients with chronic obstructive airways disease. The exact mode of action remains unsettled. Although theophylline does cause inhibition of phosphodiesterase with a resultant increase in intracellular cyclic AMP, other agents similarly inhibit the enzyme producing a rise of cyclic AMP but are unassociated with any demonstrable bronchodilation. Other mechanisms proposed include an effect on translocation of intracellular calcium; prostaglandin antagonism; stimulation of catecholamines endogenously; inhibition of cyclic guanosine monophosphate metabolism and adenosine receptor antagonism. None of these mechanisms has been proved, however.
In vitro, theophylline has been shown to act synergistically with beta agonists, and there are now available data which do demonstrate an additive effect in vivo with combined use.
Pharmacokinetics
The half-life of theophylline is influenced by a number of known variables. It may be prolonged in chronic alcoholics, particularly those with liver disease (cirrhosis or alcoholic liver disease), in patients with congestive heart failure, and in those patients taking certain other drugs (see DRUG INTERACTIONS.) Newborns and neonates have extremely slow clearance rates compared to older infants and children, i.e., those over 1 year. Older children have rapid clearance rates while most nonsmoking adults have clearance rates between these two extremes. In premature neonates, the decreased clearance is related to oxidative pathways that have yet to be established (TABLE 1):
TABLE 1 Theophylline Elimination Characteristics
Half-Life (in hours)
Range Children Adults
Mean 1-9 3-15
3.7 7.7
In cigarette smokers (1-2 packs/day) the mean half-life is 4-5 hours, much shorter than in nonsmokers. The increase in clearance associated with smoking is presumably due to stimulation of the hepatic metabolic pathway by components of cigarette smoke. The duration of this effect after cessation of smoking is unknown but may require 6 months to 2 years before the rate approaches that of the nonsmoker.
Additional information for sustained-action tablets: Film coated tablets are less irritating to the gastric mucosa than aminophylline.
Oxtriphylline sustained-action tablets have been formulated to provide therapeutic serum levels when administered every 12 hours and minimize the peaks and valleys of serum levels commonly found with shorter acting theophylline products.
The sustained action characteristic of Oxtriphylline sustained-action has been demonstrated in studies in human subjects. Single and multiple dose studies have shown equivalent steady-state theophylline plasma levels of sustained-action tablets given every 12 hours when compared with an equal total daily dose of (the nonsustained action) Oxtriphylline elixir given every six hours.
INDICATIONS AND USAGE:
Oxtriphylline is indicated for relief and/or prevention of symptoms from asthma and reversible bronchospasm associated with chronic bronchitis and emphysema.
CONTRAINDICATIONS:
Oxtriphylline is contraindicated in individuals who have shown hypersensitivity to its components. It is also contraindicated in patients with active peptic ulcer disease, and in individuals with underlying seizure disorders (unless receiving appropriate anticonvulsant medication).
WARNINGS:
Serum levels above 20 mcg/ml are rarely found after appropriate administration of the recommended doses. However, in individuals in whom theophylline plasma clearance is reduced for any reason , even conventional doses may result in increased serum levels and potential toxicity. Reduced theophylline clearance has been documented in the following readily identifiable groups: 1) patients with impaired liver function; 2) patients over 55 years of age, particularly males and those with chronic lung disease; 3) those with cardiac failure from any cause; 4) patients with sustained high fever; 5) neonates and infants under 1 year of age; and 6) those patients taking certain drugs (see DRUG INTERACTIONS) . Frequently, such patients have markedly prolonged theophylline serum levels following discontinuation of the drug.
Reduction of dosage and laboratory monitoring is especially appropriate in the above individuals.
Serious side effects such as ventricular arrhythmias, convulsions or even death may appear as the first sign of toxicity without any previous warning. Less serious signs of theophylline toxicity (i.e., nausea and restlessness) may occur frequently when initiating therapy, but are usually transient; when such signs are persistent during maintenance therapy, they are often associated with serum concentrations above 20 mcg/ml. Stated differently; serious toxicity is not reliably preceded by less severe side effects. A serum concentration measurement is the only reliable method of predicting potentially life-threatening toxicity.
Many patients who require theophylline exhibit tachycardia due to their underlying disease process so that the cause/effect relationship to elevated serum theophylline concentrations may not be appreciated.
Theophylline products may cause dysrhythmia and/or worsen preexisting arrhythmias and any significant change in rate and/or rhythm warrants monitoring and further investigation.
Studies in laboratory animals (minipigs, rodents, and dogs) recorded the occurrence of cardiac arrhythmias and sudden death (with histologic evidence of myocardial necrosis) when beta-agonists and methylxanthines were administered concurrently. The significance of these findings when applied to humans is currently unknown.
PRECAUTIONS:
General
On the average, theophylline half-life is shorter in cigarette and marijuana smokers than in nonsmokers, but smokers can have half-lives as long as nonsmokers. Theophylline should not be administered concurrently with other xanthines. Use with caution in patients with hypoxemia, hypertension, or those with history of peptic ulcer. Theophylline may occasionally act as a local irritant to the GI tract although gastrointestinal symptoms are more commonly centrally mediated and associated with serum drug concentrations over 20 mcg/ml.
Information for the Patient: Tablets should not be chewed, or crushed or dissolved.
The importance of taking only the prescribed dose and time interval between doses should be reinforced.
Laboratory Tests
Serum levels should be monitored periodically to determine the theophylline level associated with observed clinical response and as the method of predicting toxicity. For such measurements, the serum sample should be obtained at the time of peak concentration, 1 to 2 hours after administration for immediate release products. It is important that the patient will not have missed or taken additional doses during the previous 48 hours and that dosing intervals will have been reasonably equally spaced. DOSAGE ADJUSTMENT BASED ON SERUM THEOPHYLLINE MEASUREMENTS WHEN THESE INSTRUCTIONS HAVE NOT BEEN FOLLOWED MAY RESULT IN RECOMMENDATIONS THAT PRESENT RISK OF TOXICITY TO THE PATIENT.
Drug-Laboratory Test Interactions
Currently available analytical methods, including high pressure liquid chromatography and immunoassay techniques, for measuring serum theophylline levels are specific. Metabolites and other drugs generally do not affect the results. Other new analytic methods are also now in use. The physician should be aware of the laboratory method used and whether other drugs will interfere with the assay for theophylline.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Long-term carcinogenicity studies have not been performed with theophylline.
Chromosome-breaking activity was detected in human cell cultures at concentrations of theophylline up to 50 times the therapeutic serum concentration in humans. Theophylline was not mutagenic in the dominant lethal assay in male mice given theophylline intraperitoneally in doses up to 30 times the maximum daily oral dose.
Studies to determine the effect on fertility have not been performed with theophylline.
Pregnancy
Category C - Animal reproduction studies have not been conducted with oxtriphylline. It is not known whether theophylline can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Oxtriphylline should be given to a pregnant woman only if clearly needed.
Nursing Mothers
Theophylline is distributed into breast milk and may cause irritability or other signs of toxicity in nursing infants. Because of the potential for serious adverse reactions in nursing infants from theophylline, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use
Sufficient numbers of infants under the age of 1 year have not been studied in clinical trials to support use in this age group; however, there is evidence recorded that the use of dosage recommendations for older infants and young children (16 mg/kg/24 hours) may result in the development of toxic serum levels. Such findings very probably reflect differences in the metabolic handling of the drug related to absent or undeveloped enzyme systems. Consequently, the use of the drug in this age group should carefully consider the associated benefits and risks. If used, the maintenance dose must be conservative and in accord with the following guidelines:
Initial Theophylline Maintenance Dosage
Premature Infants:
Up to 24 days postnatal age -1 mg/kg q 12h
Beyond 24 days postnatal age -1.5 mg/kg q 12h
Infants 6 to 52 Weeks:
((0.2 X age in weeks)+5)X kg body wt=24 hour dose in mg.
Up to 26 weeks, divide into q 8h dosing intervals.
From 26-52 weeks, divide into q 6h dosing intervals.
Final dosage should be guided by serum concentration after a steady state no further accumulation of drug) has been achieved.
DRUG INTERACTIONS:
Toxic synergism with ephedrine has been documented and may occur with other sympathomimetic bronchodilators. In addition, the following drug interactions have been demonstrated (TABLE 2):
TABLE 2
Theopylline with
Allopurinol (high-dose)
Increased serum theophylline levels
Cimetidine
Increased serum theophylline levels
Erythromycin, Troleandomycin
Increased serum theophylline levels
Lithium Carbonate
Increased renal excretion of lithium
Oral Contraceptives
Increased serum theophylline levels
Phenytoin
Decreased theophylline and phenytoin
serum levels
Rifampin
Decreased serum theophylline levels
ADVERSE REACTIONS:
The following adverse reactions have been observed, but there has not been enough systematic collection of data to support an estimate of their frequency. The most consistent adverse reactions are usually due to overdosage.
1. Gastrointestinal: nausea, vomiting, epigastric pain, hematemesis, diarrhea.
2. Central nervous system: headaches, irritability, restlessness, insomnia, reflex hyperexcitability, muscle twitching, clonic and tonic generalized convulsions.
3. Cardiovascular: palpitation, tachycardia, extrasystoles, flushing, hypotension, circulatory failure, ventricular arrhythmias.
4. Respiratory: tachypnea.
5. Renal: potentiation of diuresis.
6. Others: alopecia, hyperglycemia, inappropriate ADH syndrome, rash.
OVERDOSAGE:
Management
It is suggested that the management principles (consistent with the clinical status of the patient when first seen) outlined below be instituted and that simultaneous contact with a Regional Poison Control Center be established. In this way both updated information and individualization regarding required therapy may be provided.
1. When potential oral overdose is established and seizure has not occurred:
a. If patient is alert and seen within the early hours after ingestion, induction of emesis may be of value. Gastric lavage has been demonstrated to be of no value in influencing outcome in patients who present more than 1 hour after ingestion.
b. Administer a cathartic. Sorbitol solution is reported to be of value.
c. Administer repeated doses of activated charcoal and monitor theophylline serum levels.
d. Prophylactic administration of phenobarbital has been shown to increase the seizure threshold in laboratory animals, and administration of this drug can be considered.
If patient presents with a seizure:
a. Establish an airway.
b. Administer oxygen.
c. Treat the seizure with intravenous diazepam, 0.1 to 0.3 mg/kg up to 10 mg. If seizures cannot be controlled, the use of general anesthesia should be considered.
d. Monitor vital signs, maintain blood pressure and provide adequate hydration.
If postseizure coma is present:
a. Maintain airway and oxygenation.
b. If a result of oral medication, follow above recommendations to prevent absorption of the drug, but intubation and lavage will have to be performed instead of inducing emesis, and the cathartic and charcoal will need to be introduced via large bore gastric lavage tube.
c. Continue to provide full supportive care and adequate hydration until the drug is metabolized. In general, drug metabolism is sufficiently rapid so as not to warrant dialysis. If repeated oral activated charcoal is ineffective (as noted by stable or rising serum levels), charcoal hemoperfusion may be indicated.
DOSAGE AND ADMINISTRATION:
Tablets should not be chewed, or crushed or dissolved.
Effective use of theophylline (i.e., the concentration of drug in the serum associated with optimal benefit and minimal risk of toxicity) is considered to occur when the theophylline concentration is maintained from 10 to 20 mcg/ml. The early studies from which these levels were derived were carried out in patients immediately or shortly after recovery from acute exacerbations of their disease (some hospitalized with status asthmaticus).
Although the 20 mcg/ml level remains appropriate as a critical value (above which toxicity is more likely to occur) for safety purposes, additional data are now available which indicate that the serum theophylline concentrations required to produce maximum physiologic benefit may, in fact, fluctuate with the degree of bronchospasm present and are variable. Therefore, the physician should individualize the range appropriate to the patient's requirements, based on both symptomatic response and improvement in pulmonary function. It should be stressed that serum theophylline concentrations maintained at the upper level of the 10 to 20 mcg/ml range may be associated with potential toxicity when factors known to reduce theophylline clearance are operative. (See WARNINGS.)
If it is not possible to obtain serum level determinations, restriction of the daily dose (in otherwise healthy adults) to not greater than 13 mg/kg/day (of anhydrous theophylline), to a maximum of 900 mg, in divided doses will result in relatively few patients exceeding serum levels of 20 mcg/ml and the resultant greater risk of toxicity.