VENTOLIN HFA (albuterol sulfate inhalation aerosol)

VENTOLIN HFA (albuterol sulfate inhalation aerosol)

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VENTOLIN HFA (albuterol sulfate inhalation aerosol)

The active component of VENTOLIN HFA is albuterol sulfate, USP, the racemic form of albuterol and a relatively selective beta2-adrenergic bronchodilator. Albuterol sulfate has the chemical name α1 -[(tert-butylamino)methyl]-4-hydroxy-m-xylene-α, α′-diol sulfate (2:1)(salt)

Albuterol sulfate is a white crystalline powder with a molecular weight of 576.7, and the empirical formula is (C13H21NO3)2•H2SO4. It is soluble in water and slightly soluble in ethanol.

The World Health Organization recommended name for albuterol base is salbutamol.

Indications

Bronchospasm: VENTOLIN HFA is indicated for the treatment or prevention of bronchospasm in adult and pediatric patients aged 4 years and older with reversible obstructive airway disease.

Exercise-Induced Bronchospasm: VENTOLIN HFA is indicated for the prevention of exercise-induced bronchospasm in adult and pediatric patients aged 4 years and older.

Mechanism of Action

In vitro studies and in vivo pharmacologic studies have demonstrated that albuterol has a preferential effect on beta2-adrenergic receptors compared with isoproterenol. Although beta2-adrenoceptors are the predominant adrenergic receptors in bronchial smooth muscle and beta1-adrenoceptors are the predominant receptors in the heart, there are also beta2-adrenoceptors in the human heart comprising 10% to 50% of the total beta-adrenoceptors. The precise function of these receptors has not been established, but their presence raises the possibility that even selective beta2-agonists may have cardiac effects.

Activation of beta2-adrenergic receptors on airway smooth muscle leads to the activation of adenyl cyclase and to an increase in the intracellular concentration of cyclic-3′,5′-adenosine monophosphate (cyclic AMP). This increase of cyclic AMP leads to the activation of protein kinase A, which inhibits the phosphorylation of myosin and lowers intracellular ionic calcium concentrations, resulting in relaxation. Albuterol relaxes the smooth muscles 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

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. 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 electrocardiographic changes

Pharmacokinetics

The systemic levels of albuterol are low after inhalation of recommended doses. A trial conducted in 12 healthy male and female subjects using a higher dose (1,080 mcg of albuterol base) showed that mean peak plasma concentrations of approximately 3 ng/mL occurred after dosing when albuterol was delivered using propellant HFA-134a. The mean time to peak concentrations (Tmax) was delayed after administration of VENTOLIN HFA (Tmax = 0.42 hours) as compared with CFC-propelled albuterol inhaler (Tmax = 0.17 hours). Apparent terminal plasma half-life of albuterol is approximately 4.6 hours. No further pharmacokinetic trials for VENTOLIN HFA were conducted in neonates, children, or elderly subjects.

Dosage and administration

Recommended Dosage for Bronchospasm (Acute Episodes or Symptoms Associated with Bronchospasm): Adult and pediatric patients aged 4 years and older: 2 inhalations by oral inhalation repeated every 4 to 6 hours; in some patients, 1 inhalation every 4 hours may be sufficient. More frequent administration or a greater number of inhalations is not recommended.

Recommended Dosage for Prevention of Exercise-Induced Bronchospasm: Adult and pediatric patients aged 4 years and older: 2 inhalations by oral inhalation 15 to 30 minutes before exercise.

VENTOLIN HFA should be administered by the orally inhaled route only.

Priming: Priming VENTOLIN HFA is essential to ensure appropriate albuterol content in each actuation. Prime VENTOLIN HFA before using for the first time, when the inhaler has not been used for more than 2 weeks, or when the inhaler has been dropped. To prime VENTOLIN HFA, release 4 sprays into the air away from the face, shaking well before each spray. Avoid spraying in eyes.

Cleaning: To ensure proper dosing and to prevent actuator orifice blockage, wash the actuator with warm water and let it air-dry completely at least once a week.

Contraindications

VENTOLIN HFA is contraindicated in patients with a history of hypersensitivity to any of the ingredients.

Warnings and precautions

Paradoxical Bronchospasm: VENTOLIN HFA can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with VENTOLIN HFA, it should be discontinued immediately and alternative therapy should be instituted

Deterioration of Asthma: Asthma may deteriorate acutely over a period of hours or chronically over several days or longer. If the patient needs more doses of VENTOLIN HFA than usual, this may be a marker of destabilization of asthma and requires reevaluation of the patient and treatment regimen, giving special consideration to the possible need for anti-inflammatory treatment, e.g., corticosteroids.

Use of Anti-inflammatory Agents: The use of beta-adrenergic agonist bronchodilators alone may not be adequate to control asthma in many patients. Early consideration should be given to adding anti-inflammatory agents, e.g., corticosteroids, to the therapeutic regimen.

Cardiovascular Effects: VENTOLIN HFA, like all other beta2-adrenergic agonists, can produce clinically significant cardiovascular effects in some patients such as changes in pulse rate or blood pressure. If such effects occur, VENTOLIN HFA may need to be discontinued

Do Not Exceed Recommended Dose: Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs in patients with asthma. The exact cause of death is unknown, but cardiac arrest following an unexpected development of a severe acute asthmatic crisis and subsequent hypoxia is suspected.

Hypersensitivity Reactions, including Anaphylaxis: Immediate hypersensitivity reactions (e.g., urticaria, angioedema, rash, bronchospasm, hypotension), including anaphylaxis, may occur after administration of VENTOLIN HFA.

Coexisting Conditions: VENTOLIN HFA, like other sympathomimetic amines, should be used with caution in patients with convulsive disorders, hyperthyroidism, or diabetes mellitus and in patients who are unusually responsive to sympathomimetic amines.

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Hypokalemia: Beta-adrenergic agonist medicines may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects.

Adverse reactions

Most common adverse reactions (incidence ≥3%) are throat irritation, viral, respiratory infections, upper respiratory inflammation, cough, and musculoskeletal pain

Drug interactions

Other short-acting sympathomimetic aerosol bronchodilators should not be used concomitantly with albuterol. If additional adrenergic drugs are to be administered by any route, they should be used with caution to avoid deleterious cardiovascular effects.

Beta-Adrenergic Receptor Blocking Agents: Beta-blockers not only block the pulmonary effect of beta-agonists, such as VENTOLIN HFA, but may also produce severe bronchospasm in patients with asthma. Therefore, patients with asthma should not normally be treated with beta-blockers. However, under certain circumstances, there may be no acceptable alternatives to the use of beta-adrenergic blocking agents for these patients; cardioselective beta-blockers could be considered, although they should be administered with caution.

Non–Potassium-Sparing Diuretics: The ECG changes and/or hypokalemia that may result from the administration of non–potassium-sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the coadministration of VENTOLIN HFA with non–potassium-sparing diuretics.

Digoxin: Mean decreases of 16% to 22% in serum digoxin levels were demonstrated after single-dose intravenous and oral administration of albuterol, respectively, to normal volunteers who had received digoxin for 10 days. The clinical relevance of these findings for patients with obstructive airway disease who are receiving inhaled albuterol and digoxin on a chronic basis is unclear.

Monoamine Oxidase Inhibitors and Tricyclic Antidepressants: VENTOLIN HFA should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of such agents, because the action of albuterol on the vascular system may be potentiated.

Use in specific populations

Pregnancy: There are no randomized clinical studies of use of albuterol sulfate during pregnancy. Available data from epidemiological studies and postmarketing case reports of pregnancy outcomes following inhaled albuterol use do not consistently demonstrate a risk of major birth defects or miscarriage. There are, however, clinical considerations in pregnant women with asthma.

In women with poorly or moderately controlled asthma, there is an increased risk of several perinatal adverse outcomes such as preeclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. Pregnant women with asthma should be closely monitored and medication adjusted as necessary to maintain optimal asthma control.

Because of the potential for beta-agonist interference with uterine contractility, use of VENTOLIN HFA during labor should be restricted to those patients in whom the benefits clearly outweigh the risk. VENTOLIN HFA has not been approved for the management of pre-term labor. Serious adverse reactions, including pulmonary edema, have been reported during or following treatment of premature labor with beta2-agonists, including albuterol.

Lactation: There are no available data on the presence of albuterol or the components of VENTOLIN HFA in human milk, the effects on the breastfed child, or the effects on milk production. However, plasma levels of albuterol after inhaled therapeutic doses are low in humans, and if present in breast milk, are likely to be correspondingly low. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for VENTOLIN HFA and any potential adverse effects on the breastfed child from VENTOLIN HFA or from the underlying maternal condition.

Pediatric Use: The safety and effectiveness of VENTOLIN HFA for treatment or prevention of bronchospasm and for prevention of exercised-induced bronchospasm in pediatric patients aged 4 years and older have been established.

Geriatric Use: Clinical trials of VENTOLIN HFA did not include sufficient numbers of subjects aged 65 years and older to determine whether older subjects respond differently than younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Overdosage

The expected signs and symptoms with overdosage of albuterol are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeration of any of the signs and symptoms of beta-adrenergic stimulation (e.g., seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, muscle cramps, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, insomnia, hyperglycemia, hypokalemia, metabolic acidosis).

As with all inhaled sympathomimetic medicines, cardiac arrest and even death may be associated with an overdose of VENTOLIN HFA.

Treatment consists of discontinuation of VENTOLIN HFA 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 VENTOLIN HFA.

Storage and handling

Contents Under Pressure: Do not puncture. Do not use or store near heat or open flame. Exposure to temperatures above 120°F may cause bursting. Never throw canister into fire or incinerator.

Storage: Store at room temperature between 68°F and 77°F (20°C and 25°C); excursions permitted from 59°F to 86°F (15°C to 30°C) [See USP Controlled Room Temperature]. Store the inhaler with the mouthpiece down. For best results, the inhaler should be at room temperature before use.

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