Hivent EM/Hivent DS/Hivent Plus

Hivent EM/Hivent DS: Salbutamol sulfate.
Hivent Plus: Salbutamol, ipratropium bromide.

Hivent EM: Each mL of the solution contains: Salbutamol Sulfate, BP 1.205 mg.
Salbutamol (as sulfate) (HIVENT EM) 1 mg/mL Solution for Nebulization is a sterile, isotonic solution of Salbutamol Sulfate in Water for injection. It contains no preservative. Its chemical formula is (C₁₃H₂₁NO₃)₂ · H₂SO₄. It is also known as Albuterol sulfate (USAN). Salbutamol Sulfate is 1.2 mg is approximately equivalent to 1 mg of salbutamol base.
Hivent DS: Per mL: Salbutamol Sulfate (Salbutamol) 2.410 mg, Sodium Chloride (tonicity adjusting agent) 8.696 mg, Water for Injection q.s. 1.0 mL, 0.1 N Sulfuric Acid (to adjust pH).
Salbutamol (INN) or Albuterol (USAN) is a short-acting selective β₂-adrenergic receptor agonist.
Systematic (IUPAC) name: 2-(hydroxymethyl)-4-[1-hydroxy-2-(tert-butylamino)ethyl.
Chemical Formula: C₁₃H₂₁NO₃.
Molecular mass: 239.311.
Hivent Plus: Each 2.5 mL solution contains: Salbutamol (as sulfate) 2.5 mg, Ipratropium Bromide 500.0 mcg.

Pharmacology: Hivent EM: Salbutamol is a selective Beta₂ adrenergic agonist which, in therapeutic doses, acts selectively on receptors in the bronchial muscles with little or no effect on the cardiac receptors. Its behavior following inhalation depends on the delivery method used, which determines the proportion of inhaled salbutamol relative to the proportion inadvertently swallowed. Its plasma half-life is from 2 to 7 hours, with the longer value following aerosol inhalation.
Hivent DS: Mechanism of Action: Salbutamol like other β-adrenergic drugs stimulate adenyl cyclase, the enzyme that catalyzes the formation of cyclic-3'-5'-adenosine monosphosphate (cAMP) from adenosine triphosphate (ATP). The cAMP thus formed mediates the cellular responses, resulting in the decreased tone of bronchial smooth muscles.
As with other β₂-adrenergic receptor agonists, Salbutamol binds to β₂-adrenergic receptors with a higher affinity than β₁-receptors. Salbutamol is a selective β₂ adrenoceptor agonist. At therapeutic doses it acts on the β₂-adrenoceptors of bronchial muscle, with little or no action on the β₁-adrenoreceptors of the heart.
Inhaled salbutamol sulfate has a rapid onset of action, providing relief within 5-15 minutes of administration.
In tocolysis, the activation of β₂-receptors results in relaxation of uterine smooth muscle, thus delaying labor.
Hivent Plus: Salbutamol is a direct-acting sympathomimetic agent with predominantly beta-adrenergic activity and a selective action on beta₂ receptors (beta agonist). Beta agonists activate pulmonary receptors that relax bronchial smooth muscles and decrease airway resistance (bronchodilation); they inhibit the release of inflammatory mediators from mast cells and increase ciliary motility. Selective beta receptor agonists have less tendency to produce cardiac stimulation than nonselective beta agonist that stimulates beta receptors in cardiac muscle. Thus, the incidence of cardiac side effects such as tachycardia and more serious arrhythmia is lower, but not absent, in selective beta₂ agonists.
Ipratropium Bromide is a quaternary ammonium compound that acts like atropine to block muscarinic receptors. It is formed by the introduction of an isopropyl group to the N atom of atropine. Ipratropium has relatively lack of effect on the function of ciliated bronchial epithelium, compared with the marked inhibition of ciliary beating and mucociliary clearance produced by atropine. When solutions are inhaled, the actions of Ipratropium are confined almost exclusively to the mouth and airways. Even when administered in amounts many times the recommended dosage, little or no change occurs in heart rate, blood pressure, bladder function, intra ocular pressure or pupillary diameter. Hence, it is administered by inhalation to limit its systemic anticholinergic actions and to reduce bronchoconstriction that is present in some patients with Chronic Obstructive Pulmonary Disease (e.g. chronic bronchitis and emphysema).
Rationale of Combination: The fixed-dose combination of Salbutamol + Ipratropium Bromide, with a sympathomimetic (beta₂ agonist) and parasympatholytic (anticholinergic) properties, respectively produces a greater bronchodilating effect than when either drug is used alone.
Pharmacokinetics: Hivent DS: Metabolism: Hepatic.
Half life: 1.6 hours.
Excretion: Renal (majority of a dose of salbutamol given intravenously, orally or by inhalation is excreted within 72 hours).
Hivent Plus: Salbutamol does not appear to be metabolized in the lungs, therefore its ultimate metabolism and excretion following inhalation depends upon the delivery method used, which determines the proportion of inhaled salbutamol relative to the proportion inadvertently swallowed. It has been suggested that the majority of an inhaled dose is swallowed and absorbed from the gut. It is subject to first-pass metabolism in the liver and possibly in the gut wall; the main metabolite is an inactive sulphate conjugate. The plasma half life of salbutamol has been estimated to range from about 2 to as much as 7 hours. It is rapidly excreted in the urine as metabolites and unchanged drug; there is some excretion in the feces.
Following inhalation, only small amount of ipratropium reaches the systemic circulation. Some is advertently swallowed but it is poorly absorbed from the gastrointestinal tract. Ipratropium and its metabolites are eliminated in the urine and feces.

Hivent EM: Salbutamol is used as a bronchodilator for the symptomatic relief of bronchospasm in obstructive airway diseases like bronchial asthma, emphysema, and chronic bronchitis. In moderate to severe or unresponsive asthma, salbutamol is given via a nebulizer.
Hivent DS: Salbutamol is specifically indicated in the following conditions: Acute asthma.
Symptom relief during maintenance therapy of asthma and other conditions with reversible airways obstruction (including COPD).
Protection against exercise-induced asthma.
Hyperkalemia, especially in patients with renal failure.
Can be aerosolized with a nebulizer for patients with cystic fibrosis, along with ipratropium bromide and pulmozyme.
Hivent Plus: It is used as bronchodilator in the management of chronic reversible airway obstructions like asthma and chronic bronchitis. It is also indicated for patients with Chronic Obstructive Pulmonary Disease (COPD) on a regular inhaled bronchodilator who continue to have evidence of bronchospasm and who require a second bronchodilator.

Hivent EM: Salbutamol (as sulfate) (HIVENT EM) 1 mg/mL Solution for Nebulization is given at a dose of 2.5 to 5 mg via a nebulizer, to be repeated up to 4 times daily or as prescribed by the physician. For faster delivery time, this may be used undiluted. If prolonged delivery time is desired, dilution with an equal amount of 0.9% Sodium Chloride solution may be done. E.g. Salbutamol (as sulfate) (HIVENT EM) 1 mg/mL Solution for Nebulization 2.5 mL diluted in 2.5 mL of 0.9% Sodium Chloride Solution, respectively. Discard any solution left in the nebulizer after each treatment.
Hivent DS: By wet inhalation: 2.5 to 5 mg, may be repeated up to 4x daily. Higher dosing up to 40 mg/kg/day can be given under strict medical supervision in hospital for severe airway obstruction.
Nebule: Ventolin 2.5 mg/2.5 mL: Severe bronchospasm and status asthmaticus: Adult & Pedia initially 1 nebule (2.5 mg) but may be increased to 2 nebules (5 mg) and may be repeated up to QID by nebulizer. If prolonged delivery time is desirable, dilute with normal saline for injection.
Hivent Plus: Children 2-12 years old: 3 drops/kg/dose, maximum 2500 mcg (2.5 mg) of salbutamol every 6-8 hours.
Adults: Acute attacks Treatment: 2.5 mL is sufficient for prompt symptom relief.
5 mL may be required in severe cases where an attack has not been relieved by 2.5 mL or as prescribed by a physician.
Maintenance Treatment: 2.5 mL every 6-8 hours daily or as prescribed by a physician.

Hivent EM: Overdosage is manifested by severe muscle tremors and significant tachycardia. The antidote is any cardioselective beta-blocking agent given intravenously.
Hivent DS: The preferred antidote for overdosage with salbutamol is a cardioselective β-blocking agent. However, β-blocking agents should be used with caution in patients with a history of bronchospasm.
Hypokalemia may occur following overdose with salbutamol. Serum potassium levels should be monitored.

Hivent EM: Hypersensitivity to the drug or any of its components.
Thyrotoxicosis.
Threatened abortion during the first and second trimesters of pregnancy. There is no definite proof as to the safety of the drug to the fetus in the early stages of pregnancy.
Hivent DS: Hypersensitivity to any of its components.
Although intravenous salbutamol and occasionally salbutamol tablets are used in the management of premature labor, uncomplicated by conditions such as placenta previa, ante-partum hemorrhage or toxemia of pregnancy, salbutamol presentations should not be used for threatened abortion.
Hivent Plus: It is contraindicated to patients with: Hypersensitivity to any component of the drug product or to atropine and its derivatives.
Hypertrophic obstructive cardiomyopathy or tachyarrhythmia.

Hivent Plus: Paradoxical bronchoconstriction may occur after nebulization therapy with Salbutamol-Ipratropium. It is recommended that first doses of therapy should be inhaled under medical supervision.
Salbutamol + Ipratropium like other beta adrenergic agonists can produce clinically significant cardiovascular effect in some patients.

Hivent EM: Administer with caution to patients with cardiovascular diseases like ischemic heart disease, arrhythmia or tachycardia, hypertension, occlusive vascular disorders including arteriosclerosis, and aneurysms.
Administer with caution in patients with convulsive disorders, hyperthyroidism or diabetes mellitus.
Anginal pain may be precipitated in patients with angina pectoris.
Administer with caution to patients taking other sympathomimetic drugs.
Instruct patients receiving treatment at home to seek medical advice if usual relief is not obtained after the usual dose, or if the usual duration of effectiveness is reduced. The dose should not be increased.
Adjustment of dose and frequency of administration should only be by medical advice.
Salbutamol should be used by lactating mothers only if the overall benefits outweigh any potential risk.
Salbutamol is not indicated for the prevention of premature labor associated with toxemia of pregnancy or antepartum hemorrhage.
Give cautiously to patients with hypokalemia, as this may result in increased susceptibility to digitalis-induced cardiac arrhythmias.
Hivent DS: Salbutamol should be administered cautiously to patients with thyrotoxicosis. Potentially serious hypokalemia may result from β2-agonist therapy mainly from parenteral and nebulized administration. Particular caution is advised in acute severe asthma as this may be potentiated by concomitant treatment with xanthine derivatives, steroids, diuretics and by hypoxia. Serum potassium levels should be monitored in such situations.
As with other β-adrenoceptor agonists, Salbutamol can induce reversible metabolic changes, for example increased blood sugar levels. The diabetic patient may be unable to compensate for this and the development of ketoacidosis has been reported. Concurrent administration of corticosteroids can exaggerate this effect.
Hivent Plus: The drug product should not be given to patients with close-angle and narrow-angle glaucoma.
Administer with caution to conditions characterized by tachycardia such as thyrotoxicosis, heart failure and in cardiac surgery.
Care is required in patients with acute myocardial infarction and cardiovascular disease such as ischemic heart disease, arrhythmia, arteriosclerosis, hypertension and aneurysm.
It should be used with caution in pregnancy and lactation.

Hivent DS: During wordwide marketing experience, rare cases of various congenital anomalies, including cleft palate and limb defects have been reported in the offspring of patients being treated with salbutamol. Some of the mothers were taking multiple medications during their pregnancies.
Because no consistent pattern of defects can be discerned, and baseline rate for congenital anomalies is 2-3%, a relationship with salbutamol use cannot be established.
As salbutamol is probably secreted in breast milk its use in nursing mothers is not recommended unless the expected benefits outweigh any potential risk. It is not known whether salbutamol in breast milk has a harmful effect on the neonate.

Hivent EM: Tachycardia, palpitations, flushing.
Fine tremor of skeletal muscles, particularly of the hands.
Feeling of nervousness and tension, headaches, muscle cramps.
Hivent DS: While salbutamol is well-tolerated, particularly when compared with previous therapies such as theophylline, like all medications, there exists the potential for adverse reactions to occur - especially when in high doses, or when taken orally or intravenously.
Adverse events are listed as follows by system organ class and frequency. Frequencies are defined as: Very common ≥1/10; Common ≥1/100 and <1/10; Uncommon ≥1/1000 and <1/100; Rare ≥1/10,000 and <1/1000; Very rare <1/10,000 including isolated reports.
Very common and common events were generally determined from clinical trial data. Rare and very rare events were generally determined from spontaneous data.
Immune system disorder: Very rare: Hypersensitivity reactions including angioedema, urticaria, bronchospasm, hypotension and collapse.
Metabolism and nutrition disorders: Rare: Hypokalemia.
Potentially serious hypokalemia may result from beta2 agonist therapy.
Nervous system disorders: Very common: Tremor.
Common: Headache.
Very rare: Hyperactivity.
Cardiac disorders: Common: Tachycardia.
Rare: Cardiac arrythmias including atrial fibrillation supraventricular tachycardia and extrasystoles.
Vascular disorders: Rare: Peripheral vasodilation.
Musculoskeletal and connective tissue disorders: Common: Muscle cramps.
Very rare: Feeling of muscle tension.
Common adverse effects: Tremor; Palpitations; Headache.
Infrequent adverse effects: Tachycardia; Muscle cramps; Agitation; Hypokalemia; Tinnitus; Hyperactivity in children; Insomnia.
Hivent Plus: Fine tremor of the hands, muscle cramps, tenseness, headache and peripheral vasodilation.
Difficulty in micturition, vomiting, urinary retention and dyspnea.
Dryness of the mouth with difficulty of swallowing and talking, thirst and reduced bronchial secretions.
Flushing and dryness of the skin.
Transient bradycardia followed by tachycardia with palpitations and arrhythmia.

Hivent EM: Effect of high doses of salbutamol may be exacerbated by concomitant administration of high doses of corticosteroids.
Salbutamol effects are antagonized by propranolol or other beta-receptor blocking agents.
Concomitant aminophylline or xanthine administration may enhance the salbutamol effects.
Hypokalemia associated with high dose of salbutamol may increase the susceptibility to digitalis-induced cardiac arrhythmias.
Hivent DS: Salbutamol and non-selective β-blocking agents, such as propranolol, should not usually be prescribed together.
Salbutamol is not contraindicated in patients under treatment with monoamine oxidase inhibitors (MAOIs).
Hivent Plus: The effects of ipratropium may be enhanced by concomitant administration of drugs with anticholinergic properties.
Administration of beta₂ adrenoceptor blocking agents antagonizes the effects of beta₂ agonists like salbutamol.
Adverse metabolic effects of high dose of beta₂ agonist may be exacerbated by concomitant administration of high doses of corticosteroids.
Sympathomimetics may antagonize the effects of Antihypertensive agents.
Simultaneous administration with Monoamine Oxidase Inhibitors (MAOIs) will potentiate sympathomimetic activities of beta agonists.
Hypokalemia that may result from the administration of non-potassium sparing diuretics, such as loop and thiazide diuretics, can be acutely worsened by beta agonists, especially when the recommended dose of beta agonist is exceeded.

Hivent EM: Instructions For Use: 1. Twist off head to open the ampoule.
2. Place prescribed amount into the nebulizer bowl.

Store at temperatures not exceeding 30°C.
Hivent EM and Hivent Plus: Protect from light. Place inside the aluminum pouch after each use.
Discard unused portion of the ampoule three months after opening the aluminum pouch.

Antiasthmatic & COPD Preparations

R03AL02 - salbutamol and ipratropium bromide ; Belongs to the class of combination of adrenergics with anticholinergics, that may also include a corticosteroid. Used in the treatment of obstructive airway diseases.
R03AC02 - salbutamol ; Belongs to the class of adrenergic inhalants, selective beta-2-adrenoreceptor agonists. Used in the treatment of obstructive airway diseases.

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