Azmasol Plus Inhaler (90 mcg+80 mcg)/puff

Uses

This is indicated for the as-needed treatment or prevention of bronchoconstriction and to reduce the risk of exacerbations in patients with asthma 18 years of age and older.

Azmasol Plus Inhaler (90 mcg+80 mcg)/puff is also used to associated treatment for these conditions: Allergic Rhinitis (AR), Allergies, Asthma, Chronic Obstructive Pulmonary Disease (COPD), Collagenous Colitis, Crohn's Disease (CD), Nasal Congestion, Oesophagitis, Eosinophilic, Polyps, Nasal, Pruritus, Rhinosinusitis, Ulcerative Colitis, Vasomotor Rhinitis, Corticosteroid-responsive dermatoses, Mild Crohn’s Disease, Moderate Crohn’s DiseaseAsthma, Asthmatic Bronchitis, Bronchial Asthma, Bronchospasm, Chronic Asthma, Chronic Bronchitis, Cough, Emphysema, Exercise-Induced Bronchospasm, Hyperkalemia, Wheezing, Excess mucus or phlegm, Airway secretion clearance therapy, Bronchodilation

How Azmasol Plus Inhaler (90 mcg+80 mcg)/puff works

The short term effects of corticosteroids are decreased vasodilation and permeability of capillaries, as well as decreased leukocyte migration to sites of inflammation. Corticosteroids binding to the glucocorticoid receptor mediates changes in gene expression that lead to multiple downstream effects over hours to days.

Glucocorticoids inhibit neutrophil apoptosis and demargination; they inhibit phospholipase A2, which decreases the formation of arachidonic acid derivatives; they inhibit NF-Kappa B and other inflammatory transcription factors; they promote anti-inflammatory genes like interleukin-10.

Lower doses of corticosteroids provide an anti-inflammatory effect, while higher doses are immunosuppressive. High doses of glucocorticoids for an extended period bind to the mineralocorticoid receptor, raising sodium levels and decreasing potassium levels.

In vitro studies and in vivo pharmacologic studies have shown that salbutamol 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. Salbutamol relaxes the smooth muscles of all airways, from the trachea to the terminal bronchioles. Salbutamol 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.

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. 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.

A measurable decrease in airway resistance is typically observed within 5 to 15 minutes after inhalation of salbutamol. The maximum improvement in pulmonary function usually occurs 60 to 90 minutes after salbutamol treatment, and significant bronchodilator activity has been observed to persist for 3 to 6 hours.

Dosage

Azmasol Plus Inhaler (90 mcg+80 mcg)/puff dosage

The recommended dosage of this inhaler is salbutamol 180 µg and budesonide 160 ug (administered as 2 actuation of this inhaler) as needed for asthma symptoms by oral inhalation. Do not take more than 6 doses (12 inhalations) in a 24-hour period. Prime this inhaler before using for the first time. To prime this inhaler, release 4 sprays into the air away from the face, shaking well before each spray. This inhaler must be re-primed when the inhaler has not been used for more than 7 days, is dropped or after cleaning. To re-prime this inhaler, release 2 sprays into the air away from the face, shaking well before each spray.

Side Effects

Significant adverse reactions may include: deterioration of asthma, paradoxical bronchospasm, cardiovascular effects. hypersensitivity reactions, including anaphylaxis, hypokalemia, immunosuppression and risk of infections, oropharyngeal candidiasis, hypercorticism and adrenal suppression, reduction in bone mineral density, glaucoma and cataracts, effects on growth in pediatric patients.

Toxicity

Acute overdose of corticosteroids is rare, however prolonged high dosing of corticosteroids can lead to hypercorticism and adrenal axis suppression. In the case of overdose, reduce the dosage of corticosteroids temporarily.

A 200mg oral dose is lethal to female mice while a 400mg oral dose is lethal to male mice.

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). In particular, the signs of salbutamol overdosage are significant tachycardia and/or significant muscle tremor.

Hypokalaemia may occur following overdosage with salbutamol. Serum potassium levels should be monitored.

Lactic acidosis has been reported in association with high therapeutic doses as well as overdoses of short-acting beta-agonist therapy, therefore monitoring for elevated serum lactate and consequent metabolic acidosis (particularly if there is persistence or worsening of tachypnea despite resolution of other signs of bronchospasm such as wheezing) may be indicated in the setting of overdose.

Salbutamol is categorized as Pregnancy Category C. There are no adequate and well-controlled trials with salbutamolc or albuterol sulfate in pregnant women. During worldwide marketing experience, 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. No consistent pattern of defects can be discerned, and a relationship between salbutamol use and congenital anomalies has not been established. Animal reproduction studies in mice and rabbits revealed evidence of teratogenicity. Salbutamol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetusLabel]. Women should be advised to contact their physicians if they become pregnant while taking salbutamol.

Since there exists a potential for beta-agonist interference with uterine contractility, the use of salbutamol during labour should be restricted to those patients in whom the benefits clearly outweigh the risk.

Plasma levels of albuterol sulfate and HFA-134a after inhaled therapeutic doses are very low in humans, but it is not known whether the components of salbutamol are excreted in human milk. Because of the potential for tumorigenicity shown for albuterol in animal studies and lack of experience with the use of salbutamol by nursing mothers, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Caution should be exercised when salbutamol is administered to a nursing woman.

The safety and effectiveness of salbutamol in children younger than 4 years of age has not yet been established.

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.

The LD₅₀ value was determined to be 1100 mg/kg (orally in mice).

Precaution

Asthma may deteriorate acutely over a period of hours or chronically over several days or longer. If the patient continues to experience symptoms after using this inhaler or requires more doses of this inhaler than usual, this may be a marker of destabilization of asthma and requires evaluation of the patient and their treatment regimen. This inhaler can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with this inhaler, it should be discontinued immediately, and alternative therapy should be instituted. this inhaler, like other drugs containing beta-adrenergic agonists, can produce clinically significant cardiovascular effects in some patients as measured by increases in pulse rate, blood pressure, and/or other symptoms. If such effects occur, this inhaler may need to be discontinued. As with other inhaled drugs containing beta-adrenergic agents, this inhaler should not be used more than the maximum daily as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Hypersensitivity reactions can occur after administration of salbutamol sulfate and budesonide, components of this inhaler, as demonstrated by cases of anaphylaxis, angioedema, bronchospasm, oropharyngeal edema, rash, and urticaria. Discontinue this inhaler if such reactions occur. this inhaler, like all therapies containing 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 Beta-adrenergic agonist medicines may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects. Patients who are using drugs that suppress the immune system are more susceptible to infection. Chicken pox and measles, for example, can have a more serious or even fatal course in susceptible patients using corticosteroids. In patients who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure.This inhaler contains budesonide, an inhaled corticosteroid (ICS), Localized infections of the mouth and pharynx with Candida albicans have occurred in patients treated with ICS agents. Monitor patients periodically. Budesonide, a component of this inhaler, will often help control asthma symptoms with less suppression of hypothalamic-pituitary-adrenal (HPA) function than therapeutically equivalent oral doses of prednisone, Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing ICS. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, post-menopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass should be monitored and treated with established standards of care. Glaucoma, increased intraocular pressure, and cataracts have been reported following the long-term administration of ICS, including budesonide, a component of this inhaler. Caution should be exercised when considering the co-administration of this inhaler with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g.. ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) because adverse effects related to increased systemic exposure to budesonide may occur. Orally inhaled corticosteroids, including budesonide, may cause a reduction in growth velocity when administered to pediatric patients. The safety and effectiveness of this inhaler have not been established in pediatric patients, and this inhaler is not indicated for use in this population.

Interaction

Avoid Cytochrome P450 3A4 inhibitors (e.g. ketoconazole, grapefruit juice). It may cause increased systemic corticosteroid effects. Budesonide does not affect the plasma levels of oral contraceptives.

Salbutamol and non-selective beta-blocking drugs such as propranolol should generally not be prescribed together. Potentially serious hypokalaemia may result from beta2-agonist therapy. Particular caution is advised in acute severe asthma as this effect may be potentiated by concomitant treatment with xanthine derivatives, steroids, diuretics, and by hypoxia. It is recommended that serum potassium levels are monitored in such situations.

Volume of Distribution

The volume of distribution of budesonide is 2.2-3.9L/kg.

The volume of distribution recorded for intravenously administered salbutamol has been recorded as 156 +/- 38 L.

Elimination Route

Extended release oral capsules are 9-21% bioavailable. A 9mg dose reaches a C_max of 1.50±0.79ng/mL with a T_max of 2-8h and an AUC of 7.33ng*hr/mL. A high fat meal increases the T_max by 2.3h but otherwise does not affect the pharmacokinetics of budesonide.

180-360µg metered inhaled doses of budesonide are 34% deposited in the lungs, 39% bioavailable, and reach a C_max of 0.6-1.6nmol/L with a T_max of 10 minutes.

A 1mg nebulized dose is 6% bioavailable, reaching a C_max of 2.6nmol/L with a T_max of 20 minutes.

A 9mg oral extended release tablet reaches a C_max of 1.35±0.96ng/mL with a T_max of 13.3±5.9h and an AUC of 16.43±10.52ng*hr/mL.

Budesonide rectal foam 2mg twice daily has an AUC of 4.31ng*hr/mL.

Following inhalation, salbutamol acts topically on bronchial smooth muscle and the drug is initially undetectable in the blood. After 2 to 3 hours low concentrations are seen, due presumably to the portion of the dose which is swallowed and absorbed in the gut.

In particular, the systemic levels of salbutamol 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 salbutamol was delivered using propellant HFA-134a. The mean time to peak concentrations (Tmax) was delayed after administration of VENTOLIN (salbutamol) HFA (Tmax = 0.42 hours) as compared with CFC-propelled salbutamol inhaler (Tmax = 0.17 hours).

Half Life

Budesonide has a plasma elimination half life of 2-3.6h. The terminal elimination half life in asthmatic children 4-6 years old is 2.3h.

The elimination half-life of inhaled or oral salbutamol has been recorded as being between 2.7 and 5 hours while the apparent terminal plasma half-life of albuterol has been documented as being approximately 4.6 hours.

Clearance

Budesonide has a plasma clearance of 0.9-1.8L/min. The 22R form has a clearance of 1.4L/min while the 22S form has a clearance of 1.0L/min. The clearance in asthmatic children 4-6 years old is 0.5L/min.

The renal clearance of salbutamol has been documented as 272 +/- 38 ml/min after oral administration and 291 +/- 70 ml/min after intravenous administration. Furthermore, the renal clearance of the predominant sulfate conjugate metabolite was recorded as 98.5 +/- 23.5 ml/min following oral administration.

Elimination Route

Approximately 60% of a budesonide dose is recovered in the urine as the major metabolites 6beta-hydroxybudesonide, 16alpha-hydroxyprednisolone, and their conjugates. No unchanged budesonide is recovered in urine.

After oral administration, 58-78% of the dose is excreted in the urine in 24 hours, approximately 60% as metabolites. A small fraction is excreted in the feces.

Pregnancy & Breastfeeding use

Pregnancy: There are no adequate and well-controlled studies with this inhaler in pregnant women to inform a drug-associated risk. However, available data from epidemiological studies and postmarketing case reports of pregnancy outcomes following inhaled salbutamol use do not consistently demonstrate a risk of major birth defects or miscarriage. Reviews with budesonide use in pregnant women have not identified a drug-related risk of major birth defects. miscarriage or other adverse maternal or fetal outcomes. Lactation: There are no available data on the effects of with this inhaler on the breastfed child or on milk production.

Contraindication

This is contraindicated for patients showing hypersensitivity to salbutamol, budesonide, or to any of the excipients.

Acute Overdose

This inhaler contains both salbutamol and budesonide, therefore, the risks associated with overdosage for the individual components described below apply to this inhaler.Salbutamol: The expected symptoms with overdosage are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeration of any of the symptoms of beta-adrenergic stimulation (e.g., seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/minute, arrhythmias, nervousness, headache, tremor, muscle cramps, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, insomnia, hyperglycemia, and metabolic acidosis), Hypokalemia may also occur. Budesonide: If used at excessive doses for prolonged periods, systemic corticosteroid effects such as hypercorticism may occur.

Storage Condition

Pressurized canister, do not puncture, break or incinerate even when empty as the canister may explode. Avoid exposure to direct sunlight or heat. Clean your inhaler regularly as per directions. Do not store above 30°C. Keep in a dry place. Protect from light and keep out of the reach of children. Keep away from eyes. Use within six months after removing from the foil pouch: For best results, the canister should be at room temperature before use. Shake well before each use.

Innovators Monograph

You find simplified version here Azmasol Plus Inhaler (90 mcg+80 mcg)/puff