Etofylline 231 mg, Salbutamol 4 mg, Theophylline Hydrate 69 mg (SR) Tablets

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 bronchodilation 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.

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 to 12 month intervals. More frequent measurements should be made in the presence of any condition that may significantly alter theophylline clearance (see PRECAUTIONS,Laboratory Tests).

NOTE: In addition to the factors listed above, theophylline clearance is increased and half-life decreased by low carbohydrate/high protein diets, parenteral nutrition, and daily consumption of charcoal-broiled beef. A high carbohydrate/low protein diet can decrease the clearance and prolong the half-life of theophylline.

Absorption: Theophylline is rapidly and completely absorbed after oral administration in solution or immediate-release solid oral dosage form. After a single dose immediate release theophylline of 5 mg/kg in adults, a mean peak serum concentration of about 10 mcg/mL (range 5 to 15 mcg/mL) can be expected 1 to 2 hour 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.

(450 mg) — A single-dose, two-way crossover study was conducted in sixteen healthy male volunteers under fasting conditions with one 450 mg tablet being administered at 7 a.m. with a 6 oz. glass of water. No food or liquid (other than water) was allowed for 4 hours after which a standard lunch was served. Mean peak theophylline serum levels (Cmax) was 6.69 mcg/mL and mean time of peak serum concentration (Tmax) was 8.31 hours.

(300 mg) — A single-dose crossover study was conducted in twelve healthy male volunteers to compare pharmacokinetic parameters when theophylline extended-release tablets were administered with and without food. Subjects were fasted overnight and received a single 300 mg tablet early the following morning.

When dosing was done under fed conditions, the subjects received a standard breakfast consisting of 2 fried eggs, 2 strips of bacon, 4 oz. h.ash brown potatoes, 1 slice of toast with a pat of butter, and 8 oz. whole milk 15 minutes pre-dosing. No food was allowed for five hours post-dosing, then a standard lunch was served; at ten hours post-dosing a standard supper was served. Mean peak theophylline serum levels for the two treatments were 3.7 mcg/mL (fasting) and 4.4 mcg/mL (with food). The time of peak serum level varied from subject to subject, occurring from 4 to 14 hours after dosing. However, 92% of the subjects had serum levels at least 75% of the maximum value at 4 to 8 hours after dosing, during each phase.

Thus, blood samples taken 4 to 8 hours post-dosing should reference the peak serum level for most patients. The mean Tmax was 6.2 hours (fasting) and 8.7 hours (with food). The respective AUC (0-inf.) for these treatments were 73.3 mcg x hr/mL and 82.2 mcg x hr/mL, respectively

The primary action of beta-adrenergic agonist drugs, including albuterol, is to stimulate adenyl cyclase, the enzyme which catalyzes the formation of cyclic-3',5'- adenosine monophosphate (cyclic AMP) from adenosine triphosphate (ATP) in beta-adrenergic cells. The cyclic AMP thus formed mediates the cellular responses. 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.

In vitro studies and in vivo pharmacologic studies have demonstrated that albuterol has a preferential effect on beta2 -adrenergic receptors compared with isoproterenol. While it is recognized that beta2- adrenergic receptors are the predominant receptors in bronchial smooth muscle, data indicate that there is a population of beta2-receptors in the human heart existing in a concentration between 10% and 50%. The precise function of these receptors has not been established.

In controlled clinical trials, albuterol has been shown 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. Controlled clinical studies and other clinical experience have shown that inhaled albuterol, like other beta-adrenergic agonist drugs, can produce a significant cardiovascular effect in some patients, as measured by pulse rate, blood pressure, symptoms, and/or ECG changes.

Albuterol is longer acting than isoproterenol in most patients by any route of administration because it is not a substrate for the cellular uptake processes for catecholamines nor for catechol-O-methyl transferase.

Intravenous studies in rats with albuterol sulfate have demonstrated that albuterol crosses the blood-brain barrier and reaches brain concentrations amounting to approximately 5% of the plasma concentrations. In structures outside the blood-brain barrier (pineal and pituitary glands), albuterol concentrations were found to be 100 times those in the whole brain.

Studies in laboratory animals (minipigs, rodents, and dogs) have demonstrated the occurrence of cardiac arrhythmias and sudden death (with histologic evidence of myocardial necrosis) when beta-agonists and methylxanthines are administered concurrently. The clinical significance of these findings is unknown.

Albuterol is rapidly and well absorbed following oral administration.

In studies involving normal volunteers, the mean steady-state peak and trough plasm levels of albuterol were 6.7 ng/mL and 3.8 ng/mL, respectively, following dosing with a 2 mg albuterol tablet every 6 hours and 14.8 ng/mL and 8.6 ng/mL, respectively following dosing with a 4 mg albuterol tablet every 6 hours. Maximum albuterol plasma levels are usually obtained between 2 and 3 hours after dosing, and the elimination half-life is 5 to 6 hours. These data indicate that albuterol administered orally is dose proportional and exhibits dose independent pharmacokinetics.

Albuterol extended-release tablets have been formulated to provide a duration of action of up to 12 hours. In studies conducted in normal volunteers, the mean steady-state peak and trough plasma levels of albuterol were 6.5 ng/mL and 3.0 ng/mL, respectively, following dosing with a 4 mg albuterol extended-release tablet every 12 hours. In addition, it has been shown that administration of a 4 mg albuterol extended-release tablets every 12 hours, and a 2 mg albuterol tablet every 6 hours for 5 days gave comparable peak albuterol levels and similar extent of absorption at steady state.

In other studies, the analysis of urine samples of patients given tritiated albuterol (4 mg to 10 mg) orally showed that 65% to 90% of the dose was excreted over 3 days, with the majority of the dose being excreted within the first 24 hours. Sixty percent of this radioactivity was shown to be the metabolite. Feces collected over this period contained 4% of the administered dose.

In controlled clinical trials in patients with asthma, the onset of improvement in pulmonary function, as measured by maximum midexpiratory flow rate (MMEF), was noted within 30 minutes after a dose of albuterol tablets, with peak improvement occurring between 2 and 3 hours. In controlled clinical trials in which measurements were conducted for 6 hours, significant clinical improvement in pulmonary function (defined as maintaining a 15% or more increase in FEV1 and a 20% or more increase in MMEF over baseline values) was observed in 60% of patients at 4 hours and in 40% at 6 hours. In other single-dose, controlled clinical trials, clinically significant improvement was observed in at least 40% of the patients at 8 hours with the 4 mg albuterol tablet. No decrease in the effectiveness of albuterol tablets has been reported in patients who received long-term treatment with the drug in uncontrolled studies for periods up to 6 months.

In another controlled clinical study in asthmatic patients, it has been demonstrated that the initiation of therapy with either the 4 mg albuterol extended-release tablet dosed every 12 hours, or the 2 mg albuterol tablet dosed every 6 hours, achieve therapeutically comparable effects.

A 1981 crossover study in healthy volunteers compared single 200 mg oral and intravenous etofylline doses. Etofylline is an N-7-substituted theophylline derivative that did not release theophylline in the reported experiments. Following intravenous administration, the terminal phase had a half-life of 4.1 hours and approximately 20% was excreted unchanged in urine. Oral absorption was rapid but incomplete, with estimated bioavailability near 80%. These findings concern the studied single doses, not sustained-release products or etofylline/theophylline combinations. The investigators did not establish pharmacodynamic effectiveness, so the study cannot supply a verified molecular mechanism or therapeutic-benefit claim.