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Product
Anti-asthmatic Products (Theoasthalin)
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Anti-asthmatic Products (Theoasthalin)
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Theoasthalin Theophylline and Salbutamol
COMPOSITION
THEOASTHALIN
Tablets
Each tablet contains ...
Salbutamol sulphate IP equivalent to Salbutamol IP 2 mg
Theophylline anhydrous IP 100 mg .
DOSAGE FORM
Oral tablets .
DESCRIPTION
Theophylline is a methylxanthine which directly relaxes the smooth muscles of the bronchial airways. In addition to its bronchodilatory effect, it also has anti-inflammatory and immunomodulatory effects.
Salbutamol is a beta 2 agonist, which enhances the action of adenylcyclase and brings about bronchodilation.
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PHARMACOLOGY
Pharmacodynamics
Theophylline
Theophylline is a bronchodilator, structurally classified as a methylxanthine. Theophylline has two distinct actions in the airways of patients with reversible obstruction: smooth muscle relaxation and suppression of the response of the airways to stimuli. Theophylline also increases the force of contraction of the diaphragmatic muscles.
Salbutamol
In vitro studies and in vivo pharmacologic studies have demonstrated that salbutamol has a preferential effect on beta 2 -adrenergic receptors compared with isoproterenol. While it is recognized that beta 2 -adrenergic receptors are the predominant receptors in bronchial smooth muscle, data indicates that there is a population of beta 2 -receptors in the human heart existing in a concentration between 10% and 50%. The precise function of these receptors has not been established.
The pharmacologic effects of beta-adrenergic agonist drugs, including salbutamol, are at least in part, attributable to stimulation through beta-adrenergic receptors on intracellular adenyl cyclase, the enzyme that catalyses the conversion of adenosine triphosphate (ATP) to cyclic-3′,5′-adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels are associated with relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.
Salbutamol has been shown in most controlled clinical trials to have more effect on the respiratory tract, in the form of bronchial smooth muscle relaxation, than isoproterenol at comparable doses, while producing fewer cardiovascular effects.
Salbutamol is longer-acting than isoproterenol in most patients by any route of administration because it is not a substrate for the cellular uptake processes, neither for catecholamines nor for catechol-O-methyl transferase.
Pharmacokinetics
Theophylline
Absorption
Theophylline administered in the fed state is completely absorbed after oral administration.
In a single-dose crossover study, two 400 mg theophylline tablets were administered to 19 healthy volunteers in the morning or evening, immediately following the same standardized meal (769 calories, consisting of 97 grams carbohydrates, 33 grams protein and 27 grams fat). There was no evidence of dose dumping nor were there any significant differences in the pharmacokinetic parameters attributable to the time of the drug administration.
A study in which theophylline 400 mg tablets were administered to 17 fed adult asthmatics produced similar theophylline level-time curves when administered in the morning or evening. Serum levels were generally higher in the evening regimen, but there were no statistically significant differences between the two regimens.
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. 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 above 1 year of age, approximately 90% of the dose is metabolized in the liver.
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%). In contrast, in neonates, the large fraction of the theophylline dose excreted in the urine as unchanged theophylline and caffeine requires careful attention to dose reduction and in neonates with reduced renal function, frequent monitoring of serum theophylline concentrations should be done.
Salbutamol
In a single-dose study comparing one 8 mg salbutamol sustained-release tablet with two 4 mg immediate-release salbutamol tablets, USP, in 17 normal adult volunteers, the extent of availability of salbutamol sustained-release tablets was shown to be about 80% of salbutamol tablets, USP, with or without food. In addition, lower mean peak plasma concentration and longer time to reach the peak level were observed with salbutamol sustained-release tablets as compared with salbutamol tablets, USP. The single-dose study results also showed that food decreases the rate of absorption of salbutamol, USP, from salbutamol sustained-release tablets without altering the extent of bioavailability. In addition, the study indicated that food causes a more gradual increase in the fraction of the available dose absorbed from the sustained-release formulation as compared with the fasting condition.
Definitive studies for the effect of food on 4 mg salbutamol sustained-release tablets have not been conducted. However, since food lowers the rate of absorption of 8 mg salbutamol sustained-release tablets, it is expected that food reduces the rate of absorption of 4 mg salbutamol sustained-release tablets also.
Salbutamol sustained-release tablets have been formulated to provide duration of action of up to 12 hours. In an 8-day, multiple-dose, crossover study, 15 normal adult male volunteers were given 8 mg salbutamol sustained-release tablets every 12 hours or 4 mg salbutamol tablets, USP, every 6 hours. Each dose of salbutamol sustained-release tablets and the corresponding doses of salbutamol tablets, USP, were administered in the post-prandial state. Steady-state plasma concentrations were reached within 2 days for both formulations. Fluctuations (C max -C min /C average) in plasma concentrations were similar for salbutamol sustained-release tablets administered at 12-hour intervals and salbutamol tablets, USP, administered every 6 hours. In addition, the relative bioavailability of salbutamol sustained-release tablets was approximately 100% of the immediate-release tablets, USP, at steady state.
Pharmacokinetic studies of 4- and 8-mg salbutamol sustained-release tablets have not been conducted in paediatric patients. Bioavailability of 4- and 8-mg salbutamol sustained-release tablets in paediatric patients relative to 2- and 4-mg immediate-release salbutamol, USP, has been extrapolated from adult studies showing comparability at steady-state dosing and reduced bioavailability after a single dose administration.
INDICATIONS
THEOASTHALIN and THEOASTHALIN Forte are particularly indicated for patients who experience side effects with maximal the¬rapeutic doses of either theophylline or salbutamol alone and patients with severe asthma who require more than one drug from any class of bronchodilators.
THEOASTHALIN SR is indicated for long-term maintenance bronchodilator therapy in patients with obstructive airway disease, i.e. asthma and COPD, including patients with nocturnal asthma.
DOSAGE AND ADMINISTRATION
Optimum dosage must be individualised due to variability of theophylline pharma-cokinetics with age, diet, smoking, cardiac failure and liver disease.
The usual starting dose is one tablet of THEOASTHALIN or 10 ml (one measure) of THEOASTHALIN Syrup , thrice daily. In select patients, if further bronchodilation is required, dosage may be increased to one tablet of THEOASTHALIN Forte thrice daily.
THEOASTHALIN SR should be taken at 12-hourly intervals.
In those asthmatics whose condition deteriorates despite the above therapy, further increase in the recommended dosage is not advisable.
Alternative or additional therapy including corticosteroids and oxygen should be instituted promptly in severe cases.
CONTRAINDICATIONS
Hypersensitivity to xanthine derivatives. It is also contraindicated in patients with active peptic ulcer disease, and in individuals with underlying seizure disorders (unless receiving appropriate anti-convulsant medication).
Pre-existing cardiac tachyarrhythmias, and in patients with known hypersensitivity to salbutamol. Although intravenous salbutamol and, occasionally, salbutamol tablets are used in the management of premature labour, they are contraindicated in antepartum haemorrhage or toxaemia of pregnancy.
Immediate hypersensitivity reactions may occur after administration of salbutamol, as demonstrated by rare cases of urticaria, angio-oedema, rash, bronchospasm, and oropharyngeal oedema.
WARNINGS AND PRECAUTIONS
THEOASTHALIN and especially THEOASTHALIN Forte should be used with caution in patients with coronary artery dis¬ease, congestive heart failure, hyperten¬sion, hyperthyroidism and diabetes.
Frequent clinical cardiac monitoring may be required when treating patients of ischaemic heart disease with myocardial irritability, in presence of hypoxia and electrolyte imbalances, and in patients with congestive cardiac failure and hyper¬tension, who are on routine potassium depleting diuretics.
Care should be exercised in patients re¬quiring additional parenteral therapy with theophylline (intravenous aminophylline injection/infusion) so as to maintain serum theophylline levels between 10-20 mcg/ml with frequent therapeutic drug monitoring, if available, or clinical monitoring.
Due to the theophylline component, caution must be exercised in patients with peptic ulcer, as centrally mediated gastro¬intestinal effects may be associated with serum levels of theophylline over 20 mcg/ml. This is, however, unlikely to occur with the recommended dosage.
Elderly patients with serum concentrations above 20 mcg/ml are more likely to experience serious side effects such as ventricular arrhythmias or convulsions than are younger patients. Less serious signs of theophylline toxicity (i.e., nausea and restlessness) may occur frequently when initiating therapy, but are usually transient.
Drug Interactions
Sympathomimetic agents:
Concomitant use is not recommended since such use may lead to deleterious cardiovascular effects.
Monoamine oxidase inhibitors:
Salbut¬amol should be used with caution in pa¬tients being treated with these drugs, since the action of salbutamol on the vascular system may be potentiated.
Beta-blockers and salbutamol inhibit the effect of each other. Propranolol increases serum theophylline levels.
Cimetidine, erythromycin, oral contra¬ceptive steroids, and ciprofloxacin in¬crease serum theophylline levels.
Carbamazepine, phenobarbital and rif¬ampin decrease levels of theophylline.
Renal Impairment
After appropriate administration, serum levels are rarely found above 20 mcg/ml; however, this may occur in patients with reduced plasma clearance due to impaired liver function, in neonates, and in elderly patients with chronic lung disease.
Pregnancy
There are no adequate and well-controlled studies OF THEOASTHALIN in pregnant women. It is not known whether theophylline can cause foetal harm when administered to pregnant women. THEOASTHALIN should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
Lactation
It is not known whether salbutamol & theophylline is excreted in human milk. Because of the potential for tumorigenicity shown for salbutamol in animal studies, a decision should be made whether to discontinue lactation or to discontinue the drug, taking into account the importance of the drug to the mother.
Theophylline is excreted into breast milk and may cause irritability or other signs of mild toxicity in nursing infants. Serious adverse effects in the infant are unlikely unless the mother has toxic serum theophylline concentrations.
UNDESIRABLE EFFECTS
Theophylline
Side effects associated with theophylline are generally mild when peak serum theophylline concentrations are <20 mcg/ml and mainly consists of transient caffeine- like adverse effects such as nausea, vomiting, headache, restlessness, and insomnia.
Above 20 mcg/ml, side effects such as vomiting, cardiac arrhythmias, and intractable seizures have been reported.
Salbutamol
The adverse reactions to salbutamol are similar in nature to reactions to other sympathomimetic agents. The most frequent adverse reactions to salbutamol are nervousness, tremor, headache, tachycardia, and palpitations. Less frequent adverse reactions are muscle cramps, insomnia, nausea, weakness, dizziness, drowsiness, flushing, restlessness, irritability, chest discomfort, and difficulty in micturition.
Rare cases of urticaria, angio-oedema, rash, bronchospasm, and oropharyngeal oedema have been reported after the use of salbutamol.
In addition, salbutamol, like other sympathomimetic agents, can cause adverse reactions such as hypertension, angina, vomiting, vertigo, central nervous system stimulation, unusual taste, and drying or irritation of the oropharynx.
OVERDOSAGE
Theophylline
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 caregiver error in dosing; healthcare professional prescribing 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.
Salbutamol
The expected symptoms with overdosage are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeration of any of the symptoms, e.g., seizures, angina, hypertension or hypotension, tachycardia (with rates up to 200 beats per minute), arrhythmias, nervousness, headache, tremor, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, and insomnia. Hypokalaemia may also occur. As with all sympathomimetic aerosol medications, cardiac arrest and, even, death may be associated with the abuse of salbutamol sustained-release tablets.
Treatment consists of discontinuation of salbutamol sustained-release tablets together with appropriate symptomatic therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm. There is insufficient evidence to determine if dialysis is beneficial in case of overdosage of salbutamol sustained-release tablets.
PACKAGING INFORMATION
THEOASTHALIN Blister of 10 tablets
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