Action And Clinical Pharmacology: Theophylline is a xanthine derivative structurally related to theobromine and caffeine. It has 2 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., nonbronchodilator prophylactic effects).
While its mechanisms of action are not known with certainty, studies in animals suggest that theophylline bronchodilation is mediated by phosphodiesterase inhibition; theophylline also increases the force of diaphragm muscle contraction.
Pharmacokinetics: Immediate Release Formulation: The pharmacokinetics of theophylline varies widely among patients and cannot be predicted by age, sex, body weight or other demographic characteristics. Therefore, careful consideration should be given to dosing and monitoring (see Warnings, Precautions and Dosage).
Theophylline is rapidly and completely absorbed after oral administration in an immediate-release solid oral dosage form (Quibron-T). After a single dose of 5 mg/kg in adults, a mean peak serum concentration of about 10 Âµg/mL (range 5 to 15 Âµg/mL) can be expected 1 to 2 hours after the dose. Coadministration of theophylline with food or antacids does not cause clinically significant changes in absorption.
Sustained Release Formulation: Administration of a sustained release formulation of theophylline (Quibron-T/SR) produces peak blood levels between 5 and 7 hours. Once steady state levels have been reached, the therapeutic plasma levels (between 8 and 15 Âµg/mL) persist for 12 hours in most adults.
Indications And Clinical Uses: For the symptomatic treatment of reversible bronchospasm associated with bronchial asthma, chronic bronchitis, emphysema and related bronchospastic disorders.
Contra-Indications: In those patients who have shown hypersensitivity to theophylline or to other xanthine derivatives or to any other component in the formulations; in coronary artery disease when, in the physician’s judgement, myocardial stimulation might prove harmful; in patients with active peptic ulcer disease; and in patients with seizure disorders.
Manufacturers’ Warnings In Clinical States: Children exhibit a higher degree of sensitivity to xanthines than adults; the margin of safety above the therapeutic dose is small. The use of theophylline tablets and theophylline sustained-release tablets in children less than 9 years of age is not recommended at present as dose schedules for this age group have not been established.
Theophylline should be used with extreme caution in patients with cardiac arrhythmias (not including bradyarrhythmias).
Generalized seizures, life-threatening cardiac arrhythmias, and death may occur at serum theophylline concentrations >30 µg/mL with chronic dosing. Seizures associated with serum theophylline concentrations >30 µg/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 after prolonged generalized seizures or intractable cardiac arrhythmias.
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. In patients with suspected decreased serum protein binding (e.g., patients with cirrhosis or women during the third trimester of pregnancy), the concentration of unbound theophylline should be measured and the dosage adjusted to achieve a concentration of 6 to 12 µg/mL.
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 the risk factors listed below, severe and potentially fatal theophylline toxicity can occur.
Age: elderly (>60 years old).
Pregnancy: (3rd trimester).
Concurrent Diseases: acute pulmonary edema; congestive heart failure; cor-pulmonale; fever (³39°C for 24 hours or more, or lesser temperature elevations for longer periods); hypothyroidism; liver disease (cirrhosis, acute hepatitis); sepsis with multiorgan failure; shock.
Cessation of smoking.
Drug Interactions (see Precautions).
Theophylline dose should not be increased to treat acute exacerbations of chronic lung disease, since increasing the dose elevates the risk of adverse effects and offers little benefit in comparison with other acute treatment options such as the use of b2-selective agonists and systemically administered corticosteroids.
Precautions: There is a marked variation in blood levels achieved in different patients given the same dose of theophylline. This may lead to serious side effects in some patients. This variability in blood levels is probably due to differences in the rate of metabolism. Therefore, it is advisable to individualize the dose regimens. Ideally, all individuals should have serum theophylline levels measured and a theophylline half-life calculated which would enable doses and dosing regimens to be tailored to each patient to maintain a therapeutic level, to insure optimal clinical response and to avoid toxicity. The possibility of overdose must be considered in all patients and especially when large doses are used, because fatalities have been reported. Overdosage of theophylline may cause peripheral vascular collapse.
Special caution is necessary in patients with severe pulmonary or cardiovascular disease and in patients with hepatic dysfunction as metabolism of theophylline may be impaired in these patients leading to the possibility of toxic blood levels on fixed dosage regimens.
Caution should be exercised when theophylline is used concurrently with sympathomimetic amines or other xanthines, as such use may increase the incidence and severity of adverse reactions. Theophylline tablets and theophylline sustained-release tablets should not be given within 12 hours of the ingestion of other xanthines.
Theophylline may cause an elevation of urine catecholamines and plasma free fatty acids.
Carcinogenesis, Mutagenesis, and Impairment of Fertility: Studies in Ames salmonella, in vivo and in vitro cytogenetics, micronucleus and Chinese hamster ovary test systems did not show evidence of genotoxicity with theophylline.
In a study in mice at oral doses approximately 1 to 3 times the human dose (on a mg/mbasis) fertility was impaired, 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 and proportion of live pups in a litter at the mid and high dose. Systemic toxicity was observed in rats and mice in 13-week toxicity studies, at approximately twice the human dose on a mg/mbasis, including decreases in testicular weight.
Pregnancy: Theophylline passes freely across the placenta. There are no adequate and well controlled studies in pregnant women. Theophylline was not shown to be teratogenic in mice at oral doses up to approximately twice the human dose (on a mg/mbasis) or in rats at oral doses up to approximately 3 times the recommended human dose (on a mg/mbasis). At a dose of 220 mg/kg, embryotoxicity was observed in rats in the absence of maternal toxicity. Safe use in pregnancy has not been established relative to possible adverse effects on fetal development, but neither has adverse effects on fetal development been established. Therefore, use of theophylline in pregnant women should be balanced against the risk of uncontrolled asthma.
Lactation: Theophylline is excreted into breast milk and may cause irritability or other signs of mild toxicity in nursing human infants. An infant ingesting a L of breast milk containing 10 to 20 µg/mL of theophylline a day is likely to receive 10 to 20 mg of theophylline a day. The concentration of theophylline in breast milk is approximately equivalent to the maternal serum concentration.
Children: The maintenance dose of theophylline must be selected with caution in pediatric patients since the rate of theophylline clearance is highly variable (see Pharmacology).
Geriatrics: Elderly patients are at significantly greater risk of serious acute or chronic adverse events from theophylline than younger patients. Theophylline clearance is reduced in patients older than 60 years old, resulting in increased serum theophylline concentrations at a given dose. Protein binding may be decreased in the elderly, resulting in a proportionately larger fraction of the total serum theophylline concentration in the pharmacologically active, unbound form. For these reasons, the maximum daily dose of theophylline in patients older than 60 ordinarily should not exceed 400 mg.
Drug Interactions: The drugs listed below can produce clinically significant interactions with theophylline, resulting in altered theophylline levels. Adding a drug that increases theophylline levels or stopping a drug that decreases theophylline levels can lead to serious toxicity.
Drugs that increase serum theophylline concentrations: alcohol, allopurinol (³600 mg/day), clarithromycin, disulfiram, erythromycin, estrogen, interferon (human recombinant a-A) methotrexate, mexiletine, pentoxifylline, propafenone, thiabendazole, ticlopidine, troleandomycin, verapamil.
Inhibitors of cytochrome P450 1A2: cimetidine, ciprofloxacin, enoxacin, fluvoxamine, propranolol, tacrine.
Drugs that decrease serum theophylline concentrations: isoproterenol i.v., moricizine, rifampin, sulfinpyrazone.
Inducers of microsomal enzyme activity: aminoglutethimide, carbamazepine, phenobarbital, phenytoin.
Other Interactions : Adenosine: Higher doses of adenosine may be required to achieve the desired effects because theophylline blocks adenosine receptors.
Benzodiazepines (e.g., diazepam, flurazepam, midazolam, lorazepam): Larger doses of benzodiazepines may be required to produce the desired level of sedation.
Ephedrine may cause increased frequency of nausea, nervousness, and insomnia because of synergistic CNS effects.
Halothane may cause increased risk of ventricular arrhythmias via sensitization of the myocardium to catecholamines by halothane combined with theophylline-induced increases in endogenous catecholamines.
Ketamine may lower the theophylline seizure threshold. Induction of anesthesia with ketamine in patients receiving theophylline has been reported to produce seizures.
Lithium: Theophylline increases renal clearance of lithium, so the dose of lithium may have to be increased.
Pancuronium: Larger doses of pancuronium may be required due the antagonism of the drug’s effects by theophylline.
Effect of Other Drugs on Theophylline Serum Concentration Measurements: Cefazolin and cephalothin may interfere with certain HPLC theophylline assays. In patients with renal dysfunction, caffeine and xanthine metabolites may cause falsely high theophylline readings on assays using a dry reagent office method. The immunoassays that are specific for theophylline may be used, since other xanthines are not detected by these assays.
Xanthine derivatives, such as theophylline, potentiate the diuretic action of thiazide diuretics. They also potentiate the cardiac effect of digitalis glycosides.
Xanthines have been shown to be nephrotoxic with prolonged use at high dosage. Coincident toxicity should therefore be borne in mind when other potentially nephrotoxic drugs are administered concurrently.
The methylxanthines increase blood levels of prothrombin and fibrinogen, shorten the prothrombin time and thus antagonize the effects of coumarin anticoagulants.
Combined use of several xanthines, or concomitant use of xanthines with sympathomimetics, may cause excessive CNS stimulation.
Xanthines may antagonize the antihyperuricemia action of allopurinol.
Xanthines antagonize the uricosuric action of probenecid and of sulfinpyrazone and uricosuric activity of pyrazolon derivatives.
Adverse Reactions: When peak serum concentrations exceed 20 µg/mL, theophylline produces a wide range of adverse events, such as persistent vomiting, cardiac arrhythmias, and potentially intractable and life-threatening seizures (see Warnings and Overdose). Seizures have also been reported rarely in elderly patients or patients with an underlying neurological disease when serum theophylline concentrations were not in the toxic range.
Common adverse events include transient caffeine-like effects such as nausea, vomiting, headache, and insomnia, which occur in about 50% of patients in whom theophylline therapy is initiated at doses higher than the recommended initial doses. In a small percentage of patients (3% of children and 10% of adults) caffeine-like effects persist during maintenance therapy.
The following adverse events have also been reported: Gastrointestinal: abdominal pain, epigastric pain, hematemesis, diarrhea, anorexia, reactivation of peptic ulcer, intestinal bleeding.
Metabolic: hypokalemia, hyperglycemia, acid/base disturbance, and rhabdomyolysis, inappropriate secretion of antidiuretic hormone syndrome.
CNS: nervousness, irritability, restlessness, tremors, reflex hyperexcitability, muscle twitching, disorientation, seizures and death.
Cardiovascular: sinus tachycardia and other supraventricular tachycardias, ventricular premature beats, atrial fibrillation, multifocal atrial tachycardia or flutter (especially in patients with hypoxia secondary to COPD), ventricular arrhythmias with hemodynamic instability and hypotension/shock, flushing, palpitation, circulatory failure.
Renal: albuminuria, transient diuresis and hematuria.
The likelihood of adverse effects may be reduced by initiation of theophylline therapy at a low dose and slow titration to a predetermined age-related maximum dose (see Dosage).
Symptoms And Treatment Of Overdose: Death from theophylline toxicity is most often secondary to cardiorespiratory arrest and/or hypoxic encephalopathy after prolonged generalized seizures or intractable cardiac arrhythmias causing hemodynamic compromise. Seizures associated with serum theophylline concentrations >30 µg/mL are often resistant to anticonvulsant therapy and may result in irreversible brain injury if not rapidly controlled.
In general, patients with an acute overdose are less likely to experience seizures than patients with chronic overdosage, unless the peak serum theophylline concentration is >100 µg/mL. Patients >60 years old are at the greatest risk for severe toxicity and mortality after chronic overdosage. Pre-existing or concurrent disease may also significantly increase the susceptibility of a patient to a particular toxic manifestation, e.g., neurologic disorders predispose to seizures or cardiac disease predispose to cardiac arrhythmias.
Other manifestations of theophylline toxicity include acute myocardial infarction, and urinary retention in men with obstructive uropathy as well as the following laboratory findings: increases in serum calcium, creatine kinase, myoglobin and leukocyte count, and decreases in serum phosphate and magnesium.Symptoms: Insomnia, restlessness, mild excitement or irritability and rapid pulse are the early symptoms, which may progress to mild delirium.
Sensory disturbances such as tinnitus or flashes of light are common. Anorexia, nausea and vomiting are frequently early observations of theophylline overdosage.
Fever, diuresis, dehydration and extreme thirst may be seen. Severe poisoning results in bloody, syrup-like coffee-ground vomitus, tremors, tonic extensor spasm interrupted by clonic convulsions, extra systoles, quickened respiration, stupor and finally coma. Cardiovascular disorders and respiratory collapse, leading to shock, cyanosis and death follow gross overdosages.
Treatment: Charcoal hemoperfusion is the most effective method of extracorporeal removal, increasing theophylline clearance up to 6-fold, but serious complications may occur. Hemodialysis bears a lower risk of serious complications than multiple-dose oral activated charcoal, and is equally effective. Peritoneal dialysis is ineffective for theophylline removal.
Serum theophylline concentrations may rebound 5 to 10 µg/mL after discontinuation of charcoal hemoperfusion or hemodialysis, due to redistribution of theophylline from the tissue compartment.
If potential oral overdose is established and seizure has not occurred: Induce vomiting. Administer a cathartic. Administer activated charcoal.
If the patient is having a seizure: Establish an airway. Administer oxygen. Treat the seizure with i.v. diazepam, 0.1 to 0.3 mg/kg up to 10 mg. Monitor vital signs, maintain blood pressure and provide adequate hydration.
Postseizure Coma: Maintain airway and oxygenation. If as a result of oral medications, follow above recommendations to prevent absorption of 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 a large bore gastric lavage tube. Continue to provide full supportive care and adequate hydration while waiting for drug to be metabolized. In general, the drug is metabolized sufficiently rapidly so as not to warrant consideration of dialysis.
Dosage And Administration: Quibron-T: Table I outlines the usual recommended starting dose for children (9 to 12) and adults (over 12 years).
Dosage should be calculated on the basis of ideal body weight. Doses shown in mg of theophylline should be repeated every 8 hours, when Quibron-T tablets are prescribed.
Quibron-T/SR: The average initial dose for children (age 9 to 12) is 1/2 (150 mg) of a Quibron-T/SR tablet every 12 hours.
The average initial dose for adults is 1 (300 mg) Quibron-T/SR tablet every 12 hours.
Dose Adjustment: Quibron-T and Quibron-T/SR tablets can be divided as follows: 1/3 tablet=100 mg; 1/2 tablet=150 mg; 2/3 tablet=200 mg; 1 tablet=300 mg.
If the desired response is not achieved with the above initial dosage recommendation, and there are no adverse reactions, the dose may be increased by 2 to 3 mg/kg body weight/day at 3-day intervals. Within any 24 hours, a maximum dose of 900 mg or 13 mg/kg (whichever is less) should not be exceeded for adults. For children (9 to 12) maximum daily dose should not exceed 15 mg/kg. Children are extremely sensitive to xanthines and the margin of safety above therapeutic doses is small.
Individual requirements may vary considerably and the physician should be prepared to adjust the patient’s dose accordingly.
Because of the large intersubject variability, monitoring of plasma theophylline concentrations is extremely important, especially in the initial stages of therapy (see Precautions). Concurrent tea, coffee or cocoa administration may affect assay results.
Optimal therapeutic serum levels are considered to be between 8 to 15 µg/mL.
Availability And Storage: Quibron-T: Each rectangular shaped tablet with trisects and bisects contains: theophyllineanhydrous 300 mg. Bottles of 100.
Quibron-T/SR: Each sustained release, rectangular shaped tablet with trisects and bisects contains: theophylline anhydrous 300 mg. Nonmedicinal ingredients: magnesium stearate. Bottles of 100. (Shown in Product Recognition Section)
QUIBRON®-T QUIBRON®-T/SR Bristol Theophylline Bronchodilator
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