INFORMATION FOR HEALTH PROFESSIONALS
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Brondecon Expectorant is a coloured, wild cherry flavoured syrup containing alcohol, saccharin sodium and sucrose.
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 airway disease. The exact mode of action remains unclear. 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 not associated with any demonstrable bronchodilation. Other mechanisms proposed include an effect of 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 proven, however.
In-vitro, theophylline has been shown to act synergistically with beta agonists; there is data which demonstrates an additive effect in-vivo with combined use.
Guaiphenesin stimulates expectoration.
The half-life of theophylline is influenced by a number of known variables. It may be prolonged in patients with chronic alcoholism, 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 PRECAUTIONS, Drug Interactions.) Newborns and neonates have extremely slow clearance rates compared to older pediatric patients, i.e., those over one year. Older pediatric patients have rapid clearance rates while most non-smoking 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.
In pediatric patients, theophylline has a mean half-life of 3.7 hours with a range of 1-9 hours). In non-smoking adults, the mean half-life is 7.7 hours with a range of 3-15 hours. In cigarette smokers (1-2 packs/day) the mean half-life is 4-5 hours, much shorter than in non-smokers.
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 three months to two years before the rate approaches that of the non-smoker.
Brondecon Expectorant is indicated for relief of breathing difficulty and to assist productive cough in acute and chronic bronchitis, bronchial asthma, emphysema and influenza.
Choline theophyllinate is contraindicated in individuals who are hypersensitive to the drug. It is also contraindicated in patients with active peptic ulcer disease, and in individuals with underlying seizure disorders (unless receiving appropriate anticonvulsant medication).
While not completely predictive of toxicity serum theophylline level measurement remains the best method of predicting toxicity. Serum levels of theophylline 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 PRECAUTIONS, Drug Interactions.) In addition reduced theophylline clearance resulting in theophylline toxicity has been associated with viral upper respiratory tract infections. Frequently, patients with the conditions or under the circumstances described above 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. Serious toxicity is not reliably preceded by less severe side effects. Thus 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.
On average, theophylline half-life is shorter in cigarette and marijuana smokers than in non-smokers, but any individual smoker can have a plasma theophylline half-life as long as non-smokers. 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 gastrointestinal tract although gastrointestinal symptoms are more commonly centrally mediated and associated with serum drug concentrations over 20 mcg/mL.
Serum levels should be monitored periodically to determine the theophylline level associated with observed clinical response and as the method for predicting toxicity. For such measurements, the serum sample should be obtained at the time of peak concentration, 1 to 2 hours after administration for non-sustained release products. It is important that the patient will not have missed or taken additional doses during the previous 48 hours and that dosing interval will have been reasonably equally spaced.
Dosage adjustment based on serum theophylline measurements when these instructions have not been followed may result in dosage modifications that present risk of toxicity to the patient.
Toxic synergism with ephedrine has been documented and may occur with other sympathomimetic bronchodilators. In addition, the following drug interactions have been demonstrated.
Increased serum theophylline levels
Decreased serum theophylline levels
Others
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Decreased adenosine effect |
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Increased renal excretion of lithium |
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Increased furosemide diuresis |
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Decreased hexamethonium-induced chronotropic effect |
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Reserpine-induced tachycardia |
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Chlordiazepoxide-induced fatty acid mobilization |
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.
Theophylline and other methylxanthines are known to produce a false elevation in the automated uric acid levels when measured by the Bittner adapted method.
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 of theophylline on fertility have not been performed.
Category A. (Drugs which have been taken by a large number of pregnant women and women of child bearing age without increase in the frequency of malformations or other direct harmful effects on the foetus having been observed.)
There are insufficient adequate and well-controlled studies in lactating women. Therefore, choline theophyllinate should be used in nursing mothers only if clearly needed.
Theophylline is found in 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.
Sufficient numbers of infants under the age of one year have not been studied in clinical trials to support use in this age group. There is evidence recorded that the use (in pediatric patients under one year of age) of dosage recommendations for older pediatric patients (16 mg/kg/24 hours of anhydrous theophylline) 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 underdeveloped 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 guidelines presented in Dosage and Administration.
The following adverse reactions have been observed with choline theophyllinate, 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.
Gastrointestinal: nausea, vomiting, epigastric pain, hematemesis, diarrhea.
Central Nervous System: headaches, irritability, restlessness, insomnia, reflex hyperexcitability, muscle twitching, clonic and tonic generalized convulsions.
Cardiovascular: palpitation, tachycardia, extrasystoles, flushing, hypotension, circulatory failure, ventricular arrhythmias.
Respiratory: tachypnea.
Renal: potentiation of diuresis.
Others: alopecia, hyperglycemia, inappropriate ADH syndrome, rash.
Management
It is suggested that the management principles (consistent with the clinical status of the patient when first seen) outlined below be instituted.
Treatment
- If patient is alert and seen within the early hours after ingestion, induction of emesis may be of value. Gastric lavage may be of greatest value when performed within one hour of ingestion.
- Administer a cathartic. Sorbitol solution is reported to be of value.
- Administer repeated doses of activated charcoal and monitor theophylline serum levels.
- Prophylactic administration of phenobarbital has been shown to increase the seizure threshold in laboratory animals and administration of this drug can be considered.
- Establish an airway.
- Administer oxygen.
- Treat the seizure with intravenous diazepam, according to established procedure. If seizures cannot be controlled, the use of general anesthesia should be considered.
- Monitor vital signs, maintain blood pressure and provide adequate hydration
- Maintain airway and oxygenation.
- If coma is 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 a large bore gastric lavage tube.
- 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.
To be taken four times daily, preferably after meals
Adults: 20 ml
Children: 10 ml per 30 kg body weight
Dosage guidelines are approximations only and the wide range of theophylline clearance between individuals (particularly those with concomitant disease) makes careful dosing essential.
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.
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 (such as cardiac failure, chronic lung disease, impaired hepatic function etc.) 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 that 13 mg/kg/day (of anhydrous theophylline or approximately 20 mg/kg/day of choline theophyllinate), 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.
Caution should be exercised for younger pediatric patients who cannot complain of minor side effects. Older adults, those with cor pulmonale, congestive heart failure and/or liver disease may have unusually low dosage requirements due to reduced theophylline clearance and thus may experience toxicity at the maximal dosage recommended below. Careful dosing and laboratory monitoring is especially important in these individuals. (See WARNINGS.)
When non-sustained release products with rapid absorption are used, dosing to maintain serum levels generally requires administration every 6 hours (4 times a day). This is particularly true in pediatric patients, but dosing intervals up to 8 hours (3 times a day) may be satisfactory in adults since they eliminate the drug at a slower rate. Some pediatric patients and adults requiring higher than average doses (those having rapid rates of clearance, e.g., half-lives of under 6 hours) may benefit when given products with sustained release characteristics since these provide longer dosing intervals and/or less fluctuation in serum concentration between dosing.
The following dosage information relates to initiation and titration of daily dosage requirements. Dosage should be calculated based on lean (ideal) body mass where mg/kg doses are presented since theophylline does not distribute into fatty tissue.
A loading dose may be appropriate for situations which require rapid attainment of serum theophylline levels for bronchodilation
NOTE: Status asthmaticus should always be considered a medical emergency and is defined as that degree of bronchospasm which is not rapidly responsive to usual doses of conventional bronchodilators. Optimal therapy for such patients frequently requires the addition of other medications, parenterally administered, and close monitoring, preferably in an intensive care setting.
Oral choline theophyllinate therapy is not appropriate for severe symptoms of acute bronchospasm. Where oral therapy is appropriate the following guidelines may be used:
For adult and pediatric patients not previously receiving theophylline products the oral loading dose of choline theophyllinate is 7.8 mg/kg (equivalent to 5.0 mg/kg of anhydrous theophylline).
In those patients who have received previous therapy, determine where possible, the time, amount, dosage form, and route of administration of the last dose the patient received. Ideally, the loading dose should be deferred if a serum concentration can be obtained rapidly. If this is not possible, the clinician must exercise judgement in selecting a dose based on the potential for benefit and risk.
The loading dose for theophylline will be based on the ratio that each 0.8 mg/kg choline theophyllinate (equivalent to 0.5 mg/kg of theophylline) administered as a loading dose will result in a 1.0 mcg/mL increase in serum theophylline concentration.
Following the loading dose, the maintenance dosage recommendations in these patients are described below.
| Pediatric Patients age 1-9 years | 6.2 mg/kg every 6 hours |
|---|---|
| Pediatric Patients age 9-16 years; smokers | 4.7 mg/kg every 6 hours |
| Otherwise healthy non-smoking adults | 4.7 mg/kg every 8 hours |
| Older patients and patients with cor pulmonale | 3.1 mg/kg every 8 hours |
| Patients with congestive heart failure | 1.6-3.1 mg/kg every 12 hours |
Theophylline is a treatment for the management of reversible bronchospasm (asthma, chronic bronchitis and emphysema) to prevent symptoms and maintain patent airways. A dosage form which allows small incremental doses is desirable for initiating therapy. A liquid preparation should be considered for pediatric patients to permit both greater ease of and more accurate dosage adjustment. Slow clinical titration is generally preferred to assure acceptance and safety of the medication.
(SEE PRECAUTIONS, Usage in Pediatric Patients.)
Premature Infants:
| Up to 24 days postnatal age: | 1 mg/kg q12h |
|---|---|
| Beyond 24 days postnatal age: | 1.5 mg/kg q12h |
Infants:
6 to 52 Weeks: [(0.2 x age (weeks)) + 5.0] x kg body weight = 24 hour dose (mg)
| Up to 26 weeks: | divide into q8h dosage intervals |
|---|---|
| From 26 - 52 weeks: | divide into q6h dosage intervals |
Final dosage should be guided by serum concentration after a steady state (no
further accumulation of drug) has been achieved.
Initial Dose for Older Pediatric Patients, and Adults:
25 mg*/kg/24 hours or 625 mg/24 hours (whichever is less) of choline theophyllinate in divided doses at 6 or 8 hour intervals.
*25 mg choline theophyllinate = 16 mg theophylline.
Increasing Dose: The above dosage may be increased in approximately 25% increments at 3 day intervals so long as the drug is tolerated, until clinical response is satisfactory, or the maximum dose (as indicated below) is reached. Peak serum concentration (generally one to two hours post dosing) may be checked at these intervals.
When instructing patients to increase dosage according to the schedule above, they should be told not to take a subsequent dose if apparent side effects occur at the previous dose and to resume therapy at a lower dose once adverse effects have disappeared.
WARNING: Reduce dosage at any signs of intolerance.
The maximum dose of choline theophyllinate when the serum concentration is not measured is as follows.
Not to exceed the following: [or 1400 mg** (900 mg) whichever is less]
| Age 1-9 years | 37.5 mg/kg/day | **(24 mg/kg/day) |
|---|---|---|
| Age 9-12 years | 31 mg/kg/day | **(20 mg/kg/day) |
| Age 12-16 years | 28 mg/kg/day | **(18 mg/kg/day) |
| Age 16 years | 20 mg/kg/day | **(13 mg/kg/day) and older |
**Anhydrous theophylline is indicated in ( ).
If the above maximum doses are to be maintained or exceeded, serum theophylline measurement is essential. (See PRECAUTIONS, Laboratory Tests, for guidance.)
The final dosage adjustment after serum theophylline measurement can be found below:
| If serum theophylline is: | Directions | |
|---|---|---|
| Too low: | If clinical response is inadequate increase dosage by 25% at 3 day intervals until the desired serum concentration is achieved. The total daily dosage may need to be administered at more frequent intervals if symptoms occur repeatedly at the end of a dosing interval. | |
| Within desired range: | Maintain dosage if tolerated | |
| Too high: | (20 to 25 mcg/mL) | Decrease doses by about 10% and recheck serum level after 3 days |
| (25 to 30 mcg/mL) | Skip the next dose and decrease subsequent doses by about 25%. Recheck serum level after 3 days | |
| (> 30 mcg/mL) | Skip the next 2 doses and decrease subsequent doses by 50%. Recheck serum level after 3 days. | |
The serum concentration may be rechecked at appropriate intervals, but at least
at the end of any adjustment period. When the patient's condition is otherwise
clinically stable and none of the recognized factors which alter elimination are
present, measurement of serum levels need be repeated only every 6 to 12 months.
Store below 30°C. Protect from light.
Restricted medicine (Pharmacist Only)
Brondecon Expectorant is supplied in 200 mL and 500 mL glass bottles
Pfizer Consumer Healthcare
A division of Pfizer New Zealand Ltd
PO Box 3998
AUCKLAND
Ph: 09 638 0000
Fax: 09 638 0021
17 October 2003
Amended: 9 August 2004
IPI 506/1296