Albuterol Sulfate HFA (Page 4 of 7)

10 OVERDOSAGE

The expected symptoms with overdosage are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeration of any of the symptoms listed under ADVERSE REACTIONS, 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.

Hypokalemia may also occur. As with all sympathomimetic medications, cardiac arrest and even death may be associated with abuse of Albuterol Sulfate HFA Inhalation Aerosol.

Treatment consists of discontinuation of Albuterol Sulfate HFA Inhalation Aerosol 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 for overdosage of Albuterol Sulfate HFA Inhalation Aerosol.

The oral median lethal dose of albuterol sulfate in mice is greater than 2,000 mg/kg (approximately 6,800 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis and approximately 3,200 times the maximum recommended daily inhalation dose for children on a mg/m2 basis). In mature rats, the subcutaneous median lethal dose of albuterol sulfate is approximately 450 mg/kg (approximately 3,000 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis and approximately 1,400 times the maximum recommended daily inhalation dose for children on a mg/m2 basis). In young rats, the subcutaneous median lethal dose is approximately 2,000 mg/kg (approximately 14,000 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis and approximately 6,400 times the maximum recommended daily inhalation dose for children on a mg/m2 basis). The inhalation median lethal dose has not been determined in animals.

11 DESCRIPTION

The active ingredient of Albuterol Sulfate HFA Inhalation Aerosol is albuterol sulfate, a racemic salt, of albuterol. Albuterol sulfate has the chemical name α1 -[(tert -butylamino) methyl]-4-hydroxy-m -xylene-α,α’-diol sulfate (2:1) (salt), and has the following chemical structure:

Chemical Structure

The molecular weight of albuterol sulfate is 576.7, and the empirical formula is (C13 H21 NO3 )2 •H2 SO4 . Albuterol sulfate is a white to off-white crystalline powder. It is soluble in water and slightly soluble in ethanol. Albuterol sulfate is the official generic name in the United States, and salbutamol sulfate is the World Health Organization recommended generic name. Albuterol Sulfate HFA Inhalation Aerosol is a pressurized metered-dose aerosol unit with a dose counter. Albuterol Sulfate HFA is for oral inhalation only. It contains a microcrystalline suspension of albuterol sulfate in propellant HFA-134a (1, 1, 1, 2-tetrafluoroethane) and ethanol.

Prime the inhaler before using for the first time and in cases where the inhaler has not been used for more than 2 weeks by releasing three sprays into the air, away from the face. After priming, each actuation delivers 108 mcg albuterol sulfate, from the actuator mouthpiece (equivalent to 90 mcg of albuterol base). Each canister provides 200 actuations (inhalations).

This product does not contain chlorofluorocarbons (CFCs) as the propellant.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Albuterol sulfate is a beta2 -adrenergic agonist. The pharmacologic effects of albuterol sulfate are attributable to activation of beta2 -adrenergic receptors on airway smooth muscle. Activation of beta2 -adrenergic receptors leads to the activation of adenylcyclase and to an increase in the intracellular concentration of cyclic-3′, 5′-adenosine monophosphate (cyclic AMP). This increase of cyclic AMP is associated with the activation of protein kinase A, which in turn inhibits the phosphorylation of myosin and lowers intracellular ionic calcium concentrations, resulting in muscle relaxation. Albuterol relaxes the smooth muscle of all airways, from the trachea to the terminal bronchioles. Albuterol acts as a functional antagonist to relax the airway irrespective of the spasmogen involved, thus protecting against all bronchoconstrictor challenges. Increased cyclic AMP concentrations are also associated with the inhibition of release of mediators from mast cells in the airway. While it is recognized that beta2 -adrenergic receptors are the predominant receptors on bronchial smooth muscle, data indicate that there are beta-receptors in the human heart, 10% to 50% of which are cardiac beta2 -adrenergic receptors. The precise function of these receptors has not been established [see Warnings and Precautions (5.4)].

Albuterol 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. However, 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 electrocardiographic changes [see Warnings and Precautions (5.4)].

12.2 Pharmacokinetics

The systemic levels of albuterol are low after inhalation of recommended doses. In a crossover study conducted in healthy male and female volunteers, high cumulative doses of Albuterol Sulfate HFA Inhalation Aerosol (1,080 mcg of albuterol base administered over one hour) yielded mean peak plasma concentrations (Cmax ) and systemic exposure (AUCinf ) of approximately 4,100 pg/mL and 28,426 pg/mL*hr, respectively compared to approximately 3,900 pg/mL and 28,395 pg/mL*hr, respectively following the same dose of an active HFA-134a albuterol inhaler comparator. The terminal plasma half-life of albuterol delivered by Albuterol Sulfate HFA Inhalation Aerosol was approximately 6 hours. Comparison of the pharmacokinetic parameters demonstrated no differences between the products.

The pharmacokinetic profile of Albuterol Sulfate HFA Inhalation Aerosol was evaluated in a two-way cross-over study in 11 healthy pediatric volunteers, 4 to 11 years of age. A single dose administration of Albuterol Sulfate HFA Inhalation Aerosol (180 mcg albuterol base) yielded a least square mean (SE) Cmax and AUC0-∞ of 1,100 (1.18) pg/mL and 5,120 (1.15) pg/mL*hr, respectively. The least square mean (SE) terminal plasma half-life of albuterol delivered by Albuterol Sulfate HFA Inhalation Aerosol was 166 (7.8) minutes.

Metabolism and Elimination: Information available in the published literature suggests that the primary enzyme responsible for the metabolism of albuterol in humans is SULTIA3 (sulfotransferase). When racemic albuterol was administered either intravenously or via inhalation after oral charcoal administration, there was a 3- to 4-fold difference in the area under the concentration-time curves between the (R)- and (S)-albuterol enantiomers, with (S)-albuterol concentrations being consistently higher. However, without charcoal pretreatment, after either oral or inhalation administration the differences were 8- to 24-fold, suggesting that the (R)-albuterol is preferentially metabolized in the gastrointestinal tract, presumably by SULTIA3.

The primary route of elimination of albuterol is through renal excretion (80% to 100%) of either the parent compound or the primary metabolite. Less than 20% of the drug is detected in the feces. Following intravenous administration of racemic albuterol, between 25% and 46% of the (R)-albuterol fraction of the dose was excreted as unchanged (R)-albuterol in the urine.

Geriatric, Pediatric, Hepatic/Renal Impairment: No pharmacokinetic studies for Albuterol Sulfate HFA Inhalation Aerosol have been conducted in neonates or elderly subjects.

The effect of hepatic impairment on the pharmacokinetics of Albuterol Sulfate HFA Inhalation Aerosol has not been evaluated.

The effect of renal impairment on the pharmacokinetics of albuterol was evaluated in 5 subjects with creatinine clearance of 7 to 53 mL/min, and the results were compared with those from healthy volunteers. Renal disease had no effect on the half-life, but there was a 67% decline in albuterol clearance. Caution should be used when administering high doses of Albuterol Sulfate HFA Inhalation Aerosol to patients with renal impairment [see Use in Specific Populations (8.5)].

13 NONCLINICAL TOXICOLOGY

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