Airlevo

Each actuation delivers (ex-actuator): Levosalbutamol Tartrate 59 mcg Equivalent to Levosalbutamol 45 mcg, Ethanol anhydrous Ph. Eur. 4.7% w/w.
Excipients/Inactive Ingredients: Ethanol anhydrous, Oleic Acid, Norflurane (Propellant HFA 134a).

Pharmacology: Pharmacodynamics: Mechanism of action: Activation of beta₂-adrenergic receptors on airway smooth muscle leads to the activation of adenylate cyclase and to an increase in the intracellular concentration of cyclic-3', 5'-adenosine monophosphate (cyclic AMP). The increase in 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. Levosalbutamol relaxes the smooth muscles of all airways, from the trachea to the terminal bronchioles. Increased cyclic AMP concentrations are also associated with the inhibition of the release of mediators from mast cells in the airways. Levosalbutamol acts as a functional antagonist to relax the airway irrespective of the spasmogen involved, thus protecting against all bronchoconstrictor challenges. 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 beta₂-adrenergic receptors.
The precise function of these receptors has not been established. However, all 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.
Clinical Studies: Bronchospasm Associated with Asthma: Adults and Adolescent Patients 12 Years of Age and Older: The efficacy and safety of levosalbutamol tartrate inhalation aerosol were established in two 8-week, multicenter, randomized, double-blind, active- and placebo-controlled trials in adults and adolescents with asthma between the ages of 12 and 81 years. In these two trials, levosalbutamol tartrate inhalation aerosol was compared to an HFA-134a placebo MDI, and the trials included a marketed salbutamol HFA-134a MDI as an active control. Serial forced expiratory volume in 1 second (FEV₁) measurements demonstrated that 90 mcg (2 inhalations) of levosalbutamol tartrate inhalation aerosol produced significantly greater improvement in FEV₁ over the pretreatment value than placebo. The results from one of the trials are shown in Figure as the mean percent change in FEV₁ from test-day baseline at Day 1 (n=445) and Day 56 (n=387). The results from the second trial were similar. (See Figure.)

Click on icon to see table/diagram/image

For levosalbutamol tartrate inhalation aerosol on Day 1, the median time to onset of a 15% increase in FEV₁ ranged from 5.5 to 10.2 minutes and the median time to peak effect ranged from 76 to 78 minutes. In the responder population, on Day 1 the median duration of effect as measured by a 15% increase in FEV₁ was 3 to 4 hours, with duration of effect in some patients of up to 6 hours.
Glenmark Phase-III Study No. GPL/CT/2018/003/III: Adult patients (aged ≥18 to ≤65): A randomized cross-over three-period three-sequence placebo-controlled clinical study with open-label (non-blind) active comparator, intended to assess efficacy and safety of the medicinal product, Levosalbutamol tartrate, metered dose inhalation aerosol, 45 μg/dose (manufactured by Glenmark Pharmaceuticals Limited, India) vs placebo and Ventolin (racemic Salbutamol 100 μg/dose), metered dose inhalation aerosol (manufactured by GlaxoSmithKline Pharmaceuticals SIA) in adult patients with mild and moderate bronchial asthma, was conducted. The duration of treatment consisted of 2 oral inhalations of the comparator (investigational product, placebo or comparator) in each treatment period (periods 1-3). The primary endpoint was baseline-adjusted area under curve FEV₁ from 0 h to 6 h (FEV₁ AUC_0-6h). 91 patients were randomized. 90/91 (98.9%) patients completed the study under the protocol. 1/91 (1.1%) patient withdrew from the study prematurely because of an AE (headache, nasal congestion).
Comparison of the investigation product with placebo: In the mITT set, the treatment effect for Levosalbutamol (root-mean square FEV₁ AUC_0-6h ± error of the mean) was 2.307±0.062 L*hour, the placebo effect was 2.090±0.062 L*hour. The root-mean square difference between treatment effects with Levosalbutamol and Placebo came to 0.216±0.027 L*hour, with 95% CI [0.163; 0.269] L*hour and was statistically significant (p < 0.001).
The sensitivity test in PP set corresponds to the findings for mITT set: the treatment effect for the medicinal product of Levosalbutamol was 2.280±0.068 L*hour, Placebo effect, 2.050±0.068 L*hour. The root-mean square difference of effects between treatment effects with Levosalbutamol and Placebo in PP set came to 0.230±0.028 L*hour, with 95% CI [0.175; 0.286] L*hour and was statistically significant (p < 0.001).
Comparison of investigational product vs. active comparator: The comparative assessment of treatment with Levosalbutamol and Ventolin showed that the treatment effects for these medicinal products are very similar: the root-mean square difference of treatment effects with Levosalbutamol and Ventolin for mITT set came to 0.015±0.027 L*hour with 95% CI [-0.039; 0.068] L*hour.
The sensitivity analysis for PP set corresponds to the results for mITT set and yields similar results and conclusions. For instance, the root-mean square difference of treatment effects with Levosalbutamol and Ventolin in mITT set came to 0.012±0.028 L*hour, with 95% CI [-0.043; 0.068] L*hour favouring levosalbutamol.
The study findings demonstrated the efficacy of the medicinal product, Levosalbutamol tartrate, metered dose inhalation aerosol, 45 μg/dose (Glenmark Pharmaceuticals Limited) vs placebo in the primary (FEV₁ AUC0-6 h) and secondary end points (FEV₁ and FVC, start of action). The comparative efficacy assessment of the medicinal product, Levosalbutamol tartrate, metered dose inhalation aerosol 45 μg/dose (Glenmark Pharmaceuticals Limited) and the drug authorized in the Russian Federation, Ventolin (Salbutamol), metered dose inhalation aerosol, 100 μg/dose (Glaxo Wellcome Production) showed there were no statistically significant differences in efficacy of the compared products (delivered doses of Levosalbutamol 90 μg and Salbutamol 180 μg) for the primary and secondary endpoints.
Pharmacokinetics: A population pharmacokinetic model was developed using plasma concentrations of (R) salbutamol obtained from 632 asthmatic patients aged 4 to 81 years in three large trials. For adolescent and adult patients 12 years and older, following 90 mcg dose of levosalbutamol tartrate inhalation aerosol, yielded mean peak plasma concentrations (C_max) and systemic exposure (AUC_0-6) of approximately 199 pg/mL and 695 pg•h/mL, respectively, compared to approximately 238 pg/mL and 798 pg•h/mL, respectively, following 180 mcg dose of Racemic salbutamol HFA metered-dose inhaler. For pediatric patients from 4 to 11 years of age, following 90 mcg dose of levosalbutamol tartrate inhalation aerosol, yielded C_max and AUC_0-6 of approximately 163 pg/mL and 579 pg•h/mL, respectively, compared to approximately 238 pg/mL and 828 pg•h/mL, respectively, following 180 mcg dose of Racemic salbutamol HFA metered-dose inhaler.
These pharmacokinetic data indicate that mean exposure to (R)-salbutamol was 13% to 16% less in adult and 30% to 32% less in pediatric patients given levosalbutamol tartrate inhalation aerosol as compared to those given a comparable dose of racemic salbutamol. When compared to adult patients, pediatric patients given 90 mcg of levosalbutamol have a 17% lower mean exposure to (R)-salbutamol.
Metabolism and Elimination: Information available in the published literature suggests that the primary enzyme responsible for the metabolism of salbutamol enantiomers in humans is SULT1A3 (sulfotransferase). When racemic salbutamol 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)-salbutamol enantiomers, with (S)-salbutamol concentrations being consistently higher. However, without charcoal pretreatment, after either oral or inhalation administration the differences were 8- to 24-fold, suggesting that (R)-salbutamol is preferentially metabolized in the gastrointestinal tract, presumably by SULT1A3.
The primary route of elimination of salbutamol enantiomers 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 salbutamol, between 25% and 46% of the (R)-salbutamol fraction of the dose was excreted as unchanged (R)-salbutamol in the urine.
Special Populations: Hepatic Impairment: The effect of hepatic impairment on the pharmacokinetics of levosalbutamol tartrate inhalation aerosol has not been evaluated.
Renal Impairment: The effect of renal impairment on the pharmacokinetics of racemic salbutamol 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 racemic salbutamol clearance. Caution should be used when administering high doses of levosalbutamol tartrate inhalation aerosol to patients with renal impairment.
Toxicology: Preclinical safety data: Carcinogenesis, Mutagenesis, Impairment of Fertility: Although there have been no carcinogenesis studies with levosalbutamol tartrate, racemic salbutamol sulfate has been evaluated for its carcinogenic potential.
In a 2-year study in Sprague-Dawley rats, dietary administration of racemic salbutamol sulfate resulted in a significant dose-related increase in the incidence of benign leiomyomas of the mesovarium at doses of 2 mg/kg/day and greater (approximately 30 times the MRHDID) of levosalbutamol tartrate for adults and approximately 15 times the MRHDID of levosalbutamol tartrate for children on a mg/m² basis). In an 18-month study in CD-1 mice and a 22-month study in the golden hamster, dietary administration of racemic salbutamol sulfate showed no evidence of tumorigenicity. Dietary doses in CD-1 mice were up to 500 mg/kg/day (approximately 3800 times the MRHDID of levosalbutamol tartrate for adults and approximately 1800 times the MRHDID of levosalbutamol tartrate for children on a mg/m² basis) and doses in the golden hamster study were up to 50 mg/kg/day (approximately 500 times the MRHDID of levosalbutamol tartrate for adults on a mg/m² basis and approximately 240 times the MRHDID of levosalbutamol tartrate for children on a mg/m² basis).
Levosalbutamol HCl was not mutagenic in the Ames test or the CHO/HPRT Mammalian Forward Gene Mutation Assay. Levosalbutamol HCl was not clastogenic in the in vivo micronucleus test in mouse bone marrow. Racemic salbutamol sulfate was not clastogenic in an in vitro chromosomal aberration assay in CHO cell cultures.
No fertility studies have been conducted with levosalbutamol tartrate. Reproduction studies in rats using racemic salbutamol sulfate demonstrated no evidence of impaired fertility at oral doses up to 50 mg/kg/day (approximately 750 times the MRHDID of levosalbutamol tartrate for adults on a mg/m² basis).
Animal Toxicology and/or Pharmacology: Propellant HFA-134a: In animals and humans, propellant HFA-134a was found to be rapidly absorbed and rapidly eliminated, with an elimination half-life of 3 to 27 minutes in animals and 5 to 7 minutes in humans. Time to maximum plasma concentration (t_max) and mean residence time are both extremely short, leading to a transient appearance of HFA-134a in the blood with no evidence of accumulation. Based on studies in animals, the propellant HFA-134a had no detectable toxicological activity at amounts less than 380 times the maximum human exposure based on comparisons of AUC values. The toxicological effects observed at these very high doses included ataxia, tremors, dyspnea, or salivation, similar to effects produced by the structurally-related chlorofluorocarbons (CFCs) used in metered-dose inhalers, that were extensively used in the past.
Patients should be given the following information: Frequency of Use: The action of Levosalbutamol Tartrate Inhalation Aerosol should last for 4 to 6 hours. Do not use Levosalbutamol Tartrate Inhalation Aerosol more frequently than recommended. Instruct patients to not increase the dose or frequency of doses of Levosalbutamol Tartrate Inhalation Aerosol without consulting their physician. If patients find that treatment with Levosalbutamol Tartrate Inhalation Aerosol becomes less effective for symptomatic relief, symptoms become worse, or they need to use the product more frequently than usual, they should seek medical attention immediately.
Priming, Cleaning and Storage: Priming: Shake well before using. Patients should be instructed that priming Levosalbutamol Tartrate Inhalation Aerosol is essential to ensure appropriate levosalbutamol content in each actuation. Patients should prime Levosalbutamol Tartrate Inhalation Aerosol before using for the first time and in cases where the inhaler has not been used for more than 3 days by releasing 4 test sprays into the air, away from the face.
Cleaning: To ensure proper dosing and prevent actuator orifice blockage, instruct patients to wash the actuator in warm water and air-dry thoroughly at least once a week. Patients should be informed that detailed cleaning instructions are included in the patient information leaflet.
Storage: Store below 25°C. Protect from freezing temperatures and direct sunlight.
Paradoxical Bronchospasm: Inform patients that Levosalbutamol Tartrate Inhalation Aerosol can produce paradoxical bronchospasm. Instruct patients to discontinue Levosalbutamol Tartrate Inhalation Aerosol if paradoxical bronchospasm occurs.
Concomitant Drug Use: While patients are using Levosalbutamol Tartrate Inhalation Aerosol, other inhaled drugs and asthma medications should be taken only as directed by the physician.
Common Adverse Reactions: Common adverse effects of treatment with inhaled beta-agonists include palpitations, chest pain, rapid heart rate, tremor, and nervousness.
Pregnancy: Patients who are pregnant or nursing should contact their physicians about the use of Levosalbutamol Tartrate Inhalation Aerosol.
General Information on Use: Effective and safe use of Levosalbutamol Tartrate Inhalation Aerosol includes an understanding of the way that it should be administered.
Shake the inhaler well immediately before each use.
Use Levosalbutamol Tartrate Inhalation Aerosol only with the actuator supplied with the product.

Levosalbutamol Tartrate Inhalation Aerosol is indicated for the treatment or prevention of bronchospasm in adults, with reversible obstructive airway disease.

Recommended Dosages: The recommended dosage of Levosalbutamol Tartrate Inhalation Aerosol for adults is 2 inhalations (90 mcg of levosalbutamol free base) repeated every 4 to 6 hours; in some patients, 1 inhalation (45 mcg of levosalbutamol free base) every 4 hours may be sufficient. More frequent administration or a larger number of inhalations is not routinely recommended.
If a previously effective dosage regimen fails to provide the usual response, this may be a marker of destabilization of asthma and requires re-evaluation of the patient and the treatment regimen, giving special consideration to the possible need for anti-inflammatory treatment, e.g., corticosteroids.
Administration Information: For oral inhalation only.
Shake well before use.
Avoid spraying in the eyes.
Prime the inhaler before using for the first time and when the inhaler has not been used for more than 3 days by releasing 4 test sprays into the air, away from the face.
To maintain proper use of Levosalbutamol Tartrate Inhalation Aerosol, it is critical to wash the actuator with warm water and air-dry thoroughly at least once a week. The inhaler may cease to deliver levosalbutamol tartrate if not properly cleaned and dried thoroughly. Keep the plastic actuator clean to prevent medication build-up and blockage. If the actuator becomes blocked with levosalbutamol tartrate, wash the actuator to remove the blockage.

The expected symptoms with overdosage are those of excessive beta-adrenergic receptor 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/minute, arrhythmias, nervousness, headache, tremor, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, and sleeplessness. Hypokalemia also may occur. As with all sympathomimetic medications, cardiac arrest and even death may be associated with the abuse of levosalbutamol tartrate inhalation aerosol. Treatment consists of discontinuation of levosalbutamol tartrate 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 levosalbutamol tartrate inhalation aerosol.

Levosalbutamol Tartrate Inhalation Aerosol is contraindicated in patients with a history of hypersensitivity to levosalbutamol, racemic salbutamol, or any other component of this product.
Reactions have included urticaria, angioedema, rash, bronchospasm, anaphylaxis and oropharyngeal edema.

Paradoxical Bronchospasm: Levosalbutamol Tartrate Inhalation Aerosol can produce paradoxical bronchospasm, which may be life-threatening. If paradoxical bronchospasm occurs, Levosalbutamol Tartrate Inhalation Aerosol should be discontinued immediately and alternative therapy instituted. It should be recognized that paradoxical bronchospasm, when associated with inhaled formulations, frequently occurs with the first use of a new canister.
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 Levosalbutamol Tartrate Inhalation Aerosol 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 a beta-adrenergic agonist 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: Levosalbutamol Tartrate Inhalation Aerosol, like other beta-adrenergic agonists, can produce clinically significant cardiovascular effects in some patients, as measured by heart rate, blood pressure, and symptoms. Although such effects are uncommon after administration of Levosalbutamol Tartrate Inhalation Aerosol at recommended doses, if they occur, the drug may need to be discontinued. In addition, beta-agonists have been reported to produce electrocardiogram (ECG) changes, such as flattening of the T-wave, prolongation of the QTc interval, and ST segment depression. The clinical significance of these findings is unknown. Therefore, Levosalbutamol Tartrate Inhalation Aerosol, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.
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.
Immediate Hypersensitivity Reactions: Immediate hypersensitivity reactions may occur after administration of racemic salbutamol, as demonstrated by rare cases of urticaria, angioedema, rash, bronchospasm, anaphylaxis, and oropharyngeal edema. The potential for hypersensitivity must be considered in the clinical evaluation of patients who experience immediate hypersensitivity reactions while receiving Levosalbutamol Tartrate Inhalation Aerosol.
Coexisting Conditions: Levosalbutamol Tartrate Inhalation Aerosol, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, hypertension, and cardiac arrhythmias; in patients with convulsive disorders, hyperthyroidism, or diabetes mellitus; and in patients who are unusually responsive to sympathomimetic amines. Clinically significant changes in systolic and diastolic blood pressure have been seen in individual patients and could be expected to occur in some patients after the use of any beta-adrenergic bronchodilator.
Large doses of intravenous racemic salbutamol have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.
Hypokalemia: As with other beta-adrenergic agonist medications, Levosalbutamol Tartrate Inhalation Aerosol may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects. The decrease is usually transient, not requiring supplementation.
Renal Impairment: Salbutamol is known to be substantially excreted by the kidney, and the risk of toxic reactions may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
Effects on ability to drive and use machines: Levosalbutamol Tartrate Inhalation Aerosol can cause dizziness. The ability to drive or use machines may be affected. Patients experiencing this undesirable effect should not drive or use machines.
Use in the Elderly: Clinical studies of levosalbutamol tartrate inhalation aerosol did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from 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 diseases or other drug therapy.

Pregnancy: Risk Summary: There are no adequate and well-controlled studies of Levosalbutamol Tartrate Inhalation Aerosol in pregnant women. There are clinical considerations with the use of Levosalbutamol Tartrate Inhalation Aerosol in pregnant women.
Following oral administration of levosalbutamol HCl to pregnant rabbits, there was no evidence of teratogenicity at doses up to 25 mg/kg/day [approximately 750 times the maximum recommended human daily inhalation dose (MRHDID) of levosalbutamol tartrate for adults on a mg/m2 basis]; however, racemic salbutamol sulfate was teratogenic in mice (cleft palate) and rabbits (cranioschisis) at doses slightly higher than the human therapeutic range.
The estimated background risk of major birth defects and miscarriage for the indicated population(s) are unknown. In the U.S. general population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Clinical Considerations: Disease-Associated Maternal and/or Embryo/Fetal Risk: In women with poorly or moderately controlled asthma, there is an increased risk of preeclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. Pregnant women should be closely monitored and medication adjusted as necessary to maintain optimal control.
Labor or Delivery: Because of the potential for beta-adrenergic agonists to interfere with uterine contractility, the use of Levosalbutamol Tartrate Inhalation Aerosol for the treatment of bronchospasm during labor should be restricted to those patients in whom the benefits clearly outweigh the risk.
Levosalbutamol Tartrate Inhalation Aerosol has not been approved for the management of preterm labor. The benefit:risk ratio when levosalbutamol tartrate is administered for tocolysis has not been established. Serious adverse reactions, including maternal pulmonary edema, have been reported during or following treatment of premature labor with beta2-agonists, including racemic salbutamol.
Animal Data: The oral administration of levosalbutamol HCl to pregnant New Zealand White rabbits during the period of organogenesis found no evidence of teratogenicity at doses up to 25 mg/kg/day (approximately 750 times the MRHDID of levosalbutamol tartrate for adults on a mg/m² basis). In a rat developmental study, a racemic salbutamol sulfate (comprising approximately 50% levosalbutamol) HFA-134a formulation administered by inhalation did not produce any teratogenic effects at exposures approximately 160 times the MRHDID (on a mg/m² basis at a maternal dose of 10.5 mg/kg).
However, other developmental studies with the racemic salbutamol sulfate, did result in teratogenic effects in mice and rabbits at doses slightly higher than the human therapeutic range. In a rabbit development study, orally administered salbutamol sulfate induced cranioschisis in 7 of 19 fetuses (37%) at approximately 1500 times the MRHDID (on a mg/m² basis at a maternal dose of 50 mg/kg). In a mouse developmental study, subcutaneously administered salbutamol sulfate produced cleft palate formation in 5 of 111 (4.5%) fetuses at an exposure approximately 2 times MRHDID for adults (on a mg/m² basis at a maternal dose of 0.25 mg/kg/day) and in 10 of 108 (9.3%) fetuses at approximately 20 times MRHDID (on a mg/m² basis at a maternal dose of 2.5 mg/kg/day). Similar effects were not observed at approximately 0.2 times MRHDID of levosalbutamol tartrate for adults on a mg/m² basis (i.e., less than the therapeutic dose). Cleft palate also occurred in 22 of 72 (30.5%) fetuses from females treated subcutaneously with isoproterenol (positive control).
Lactation: Risk Summary: There are no available data on the presence of levosalbutamol in human milk, the effects on the breastfed child, or the effects on milk production.
The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Levosalbutamol Tartrate Inhalation Aerosol and any potential adverse effects on the breastfed child from Levosalbutamol Tartrate Inhalation Aerosol or from the underlying maternal condition.

Use of Levosalbutamol Tartrate Inhalation Aerosol may be associated with the following: Paradoxical bronchospasm; Cardiovascular effects; Immediate hypersensitivity reactions; Hypokalemia.
Clinical Trials Experience: Glenmark Phase-III Study No. GPL/CT/2018/003/III: Safety and tolerability - Adult patients (aged ≥18 to ≤65): A randomized cross-over three-period three-sequence placebo-controlled clinical study with open-label (non-blind) active comparator, intended to assess efficacy and safety of the medicinal product, Levosalbutamol tartrate, metered dose inhalation aerosol, 45 μg/dose (Glenmark Pharmaceuticals Limited, India) vs placebo and Ventolin (racemic Salbutamol 100 μg/dose), metered dose inhalation aerosol (GlaxoSmithKline Pharmaceuticals SIA) in adult patients with mild and moderate bronchial asthma, was conducted.
Over the study period, no SAEs arising after the use of the investigational product, no moderate and severe AEs arising after the use of the investigational product, no AEs/SAEs related to the use of the investigational product were reported. The study findings also demonstrated the good safety profile of the medicinal product, Levosalbutamol tartrate, metered dose inhalation aerosol, 45 μg/dose (Glenmark Pharmaceuticals Limited, India). All AEs (TEAEs) recorded during the study were mild and unrelated to the investigational product use.
During the study, 19/91 (20.9%) patients from the safety set reported the total of 24 AEs (TEAEs). Of them 2 AEs developed in 1/91 (1.1%) patients and resulted in his early withdrawal from the study.
The most frequent AEs that emerged post-administration of Levosalbutamol was cough from the class of Respiratory, Thoracic and Mediastinal Disorders: 3 cases of these AEs were seen in 3/90 (3.3%) patients.
Details of the prevalence of AEs (TEAEs) in treatment arms are shown in Table as follows. (See table.)

Click on icon to see table/diagram/image

Post-marketing Experience: In addition to the adverse reactions reported in clinical trials, the following adverse reactions have been observed in post-approval use of levosalbutamol inhalation solution. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events have been chosen for inclusion due to their seriousness, their frequency of reporting, or their likely beta-mediated mechanism: angioedema, anaphylaxis, arrhythmias (including atrial fibrillation, supraventricular tachycardia, extrasystoles), asthma, chest pain, cough increased, dysphonia, dyspnea, gastrooesophageal reflux disease (GERD), metabolic acidosis, nausea, nervousness, rash, tachycardia, tremor, urticaria.
In addition, levosalbutamol tartrate inhalation aerosol, like other sympathomimetic agents, can cause adverse reactions such as hypertension, angina, vertigo, central nervous system stimulation, sleeplessness, headache, and drying or irritation of the oropharynx.

Other short-acting sympathomimetic aerosol bronchodilators or epinephrine should not be used concomitantly with Levosalbutamol Tartrate Inhalation Aerosol. If additional adrenergic drugs are to be administered by any route, they should be used with caution to avoid deleterious cardiovascular effects.
Beta-blockers: Beta-adrenergic receptor blocking agents not only block the pulmonary effect of beta-adrenergic agonists, such as Levosalbutamol Tartrate Inhalation Aerosol, but may produce severe bronchospasm in asthmatic patients. Therefore, patients with asthma should not normally be treated with beta-blockers. However, under certain circumstances, e.g., as prophylaxis after myocardial infarction, there may be no acceptable alternatives to the use of beta-adrenergic blocking agents in patients with asthma. In this setting, cardio-selective beta-blockers should be considered, although they should be administered with caution.
Diuretics: The ECG changes or 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 the beta-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the co-administration of beta-agonists with non-potassium-sparing diuretics. Consider monitoring potassium levels.
Digoxin: Mean decreases of 16% to 22% in serum digoxin levels were demonstrated after single-dose intravenous and oral administration of racemic salbutamol, respectively, to normal volunteers who had received digoxin for 10 days. The clinical significance of these findings for patients with obstructive airway disease who are receiving levosalbutamol tartrate inhalation aerosol and digoxin on a chronic basis is unclear. Nevertheless, it would be prudent to carefully evaluate the serum digoxin levels in patients who are currently receiving digoxin and Levosalbutamol Tartrate Inhalation Aerosol.
Monoamine Oxidase Inhibitors or Tricyclic Antidepressants: Levosalbutamol Tartrate Inhalation Aerosol 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 salbutamol on the vascular system may be potentiated. Consider alternative therapy in patients taking MAO inhibitors or tricyclic antidepressants.

Incompatibilities: Not applicable.
Special precautions for disposal and other handling: Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Special precautions for storage: Store at temperatures not exceeding 30°C. Protect from freezing temperatures and direct sunlight.
The canister contains a pressurised liquid. Do not expose to temperatures higher than 50°C. Do not pierce or burn the canister even when empty.
As with most inhaled medicinal products in pressurised canisters, the therapeutic effect of this medicinal product may decrease when the canister is cold.
Shelf life: 24 months.

What is Levosalbutamol Tartrate Inhalation Aerosol: Levosalbutamol Tartrate Inhalation Aerosol is an inhaled prescription medicine used for the treatment or prevention of asthma in adults.
Do not use Levosalbutamol Tartrate Inhalation Aerosol if you: are allergic to levosalbutamol, racemic salbutamol or any of the ingredients in Levosalbutamol Tartrate Inhalation Aerosol. See the end of this Patient Information leaflet for a complete list of ingredients in Levosalbutamol Tartrate.
Before you use Levosalbutamol Tartrate Inhalation Aerosol, tell your doctor about all of your medical conditions, including if you: Have heart problems.
Have high blood pressure.
Have seizures.
Have diabetes.
Have thyroid problems.
Are pregnant or plan to become pregnant. It is not known if Levosalbutamol Tartrate Inhalation Aerosol will harm your unborn baby. Talk to your doctor if you are pregnant or plan to become pregnant.
Are breastfeeding or plan to breastfeed. It is not known if Levosalbutamol Tartrate Inhalation Aerosol passes into your breast milk. Talk to your doctor about the best way to feed your baby if you use Levosalbutamol Tartrate Inhalation Aerosol.
Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Levosalbutamol Tartrate Inhalation Aerosol may affect the way other medicines work, and other medicines may affect how Levosalbutamol Tartrate Inhalation Aerosol works.
Especially tell your doctor if you take: other inhaled medicines or asthma medicines, heart medicines, medicines that increase urination (diuretics), antidepressants, medicine to treat chronic obstructive pulmonary disease (COPD).
Ask your doctor or pharmacist for a list of these medicines if you are not sure. Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.
How should I use Levosalbutamol Tartrate Inhalation Aerosol: Read the step-by-step Instructions for using Levosalbutamol Tartrate Inhalation Aerosol as follows.
Levosalbutamol Tartrate Inhalation Aerosol is for oral inhalation use only.
Use Levosalbutamol Tartrate Inhalation Aerosol exactly as your doctor tells you to. Do not change your dose without talking to your doctor first.
Your doctor will tell you how many times and when to use your Levosalbutamol Tartrate Inhalation Aerosol.
An adult should help a child use Levosalbutamol Tartrate Inhalation Aerosol. Your doctor should show you how your child should use Levosalbutamol Tartrate Inhalation Aerosol.
Do not use your Levosalbutamol Tartrate Inhalation Aerosol more often than your doctor tells you to.
Get medical help right away if Levosalbutamol Tartrate Inhalation Aerosol: does not work as well for your asthma symptoms, your asthma symptoms get worse, you need to use Levosalbutamol Tartrate Inhalation Aerosol more often than usual.
While you are using Levosalbutamol Tartrate Inhalation Aerosol, do not use other inhaled medicines and asthma medicines unless your doctor tells you to.
What are the possible side effects of Levosalbutamol Tartrate Inhalation Aerosol: Levosalbutamol Tartrate Inhalation Aerosol can cause serious side effects including: sudden shortness of breath (bronchospasm). Sudden shortness of breath can happen right away after using Levosalbutamol Tartrate Inhalation Aerosol.
Worsening asthma.
Heart problems.
Death. If you use too much Levosalbutamol Tartrate Inhalation Aerosol you can have heart or lung problems that can lead to death.
Serious allergic reactions. Call your doctor and stop using Levosalbutamol Tartrate Inhalation Aerosol right away if you have any symptoms of an allergic reaction such as: swelling of the face, throat or tongue; rash; hives; breathing problems.
Low potassium levels in your blood.
Call your doctor or go to the nearest hospital emergency room right away if you have any of the serious side effects listed previously or if you have worsening lung symptoms.
The most common side effects of Levosalbutamol Tartrate Inhalation Aerosol include: accidental injury, sore throat, chest pain, bronchitis, runny nose, fast heart rate, dizziness, vomiting, tremors, pain, palpitations, nervousness.
These are not all the possible side effects of Levosalbutamol Tartrate Inhalation Aerosol.
Call your doctor for medical advice about side effects.
How should I store Levosalbutamol Tartrate Inhalation Aerosol: Store at temperatures not exceeding 30°C.
Protect from freezing temperatures and direct sunlight.
The canister contains a pressurised liquid.
Do not expose to temperatures higher than 50°C.
Do not pierce or burn the canister even when empty.
General information about the safe and effective use of Levosalbutamol Tartrate Inhalation Aerosol: Medicines are sometimes prescribed for purposes other than those listed previously. Do not use Levosalbutamol Tartrate Inhalation Aerosol for a condition for which it was not prescribed. Do not give Levosalbutamol Tartrate Inhalation Aerosol to other people, even if they have the same symptoms that you have. It may harm them.
You can ask your pharmacist or doctor for information about Levosalbutamol Tartrate Inhalation Aerosol that is written for health professionals.
What are the ingredients in Levosalbutamol Tartrate Inhalation Aerosol: Active ingredient: Levosalbutamol tartrate.
Inactive ingredients: Ethanol anhydrous, Oleic Acid, Norflurane (Propellant HFA 134a).
Instructions for Use: Important Information: For oral inhalation use only.
Use Levosalbutamol Tartrate Inhalation Aerosol exactly as your doctor tells you to.
If you have any questions about the use of your inhaler, ask your doctor or pharmacist.
The parts of your Levosalbutamol Tartrate Inhalation Aerosol inhaler: Levosalbutamol Tartrate Inhalation Aerosol comes as a canister that fits into an actuator.
Do not use the Levosalbutamol Tartrate Inhalation Aerosol actuator with a canister of medicine from any other inhaler.
Do not use the Levosalbutamol Tartrate Inhalation Aerosol canister with an actuator from any other inhaler.
Preparing your Levosalbutamol Tartrate Inhalation Aerosol inhaler for use: Your Levosalbutamol Tartrate Inhalation Aerosol inhaler should be at room temperature before you use it.
Shake the inhaler well before each use.
Priming your Levosalbutamol Tartrate Inhalation Aerosol inhaler: Before you use Levosalbutamol Tartrate Inhalation Aerosol for the first time or if you have not taken your medicine for 3 days in a row, you must prime the inhaler.
Take the cap off the mouthpiece of the actuator. Check inside the mouthpiece for objects before use.
Hold the inhaler in the upright position away from the face and shake the inhaler well.
Press down fully to release a spray of medicine from the mouthpiece.
Avoid spraying in your eyes.
Repeat the priming steps 3 more times to finish priming the inhaler.
Your inhaler is now ready to use.
If you do not use your Levosalbutamol Tartrate Inhalation Aerosol inhaler for more than 3 days, you will need to prime the inhaler again before use.
Using your Levosalbutamol Tartrate Inhalation Aerosol inhaler: Step 1: Take the cap off the mouthpiece of the actuator. Check inside the mouthpiece for objects. Make sure the canister fits firmly in the actuator.
Step 2: Shake the inhaler well for 5 seconds before use.
Step 3: Hold the inhaler upright with the mouthpiece pointing towards you. Before you put the mouthpiece in your mouth, breathe out through your mouth and push out as much air from your lungs as you can.
Step 4: Put the mouthpiece in your mouth and close your lips around it.
Step 5: While breathing in deeply and slowly, press down on the center of the Canister until a spray of medicine has been released.
Step 6: When you have finished breathing in, remove the mouthpiece from your mouth. Close your mouth and hold your breath for 10 seconds if possible. Then breathe out gently.
Step 7: Wait about 1 minute, then shake the inhaler well. Repeat steps 3 through 6 to take your second spray of Levosalbutamol Tartrate Inhalation Aerosol.
Step 8: Put the cap back on the mouthpiece right away after use. Make sure the cap snaps firmly into place.
Cleaning your Levosalbutamol Tartrate Inhalation Aerosol inhaler: Clean the inhaler 1 time each week. It is very important to keep the actuator clean so that medicine will not build up and block the spray from the mouthpiece.
To clean the actuator: Step 1: Take the canister out of the actuator. Do not clean the canister or let it get wet.
Step 2: Take the cap off the mouthpiece.
Step 3: Hold the actuator under the faucet and run warm water through it for at least 30 seconds. Turn the actuator upside down and rinse the actuator again through the mouthpiece for at least 30 seconds.
Step 4: Shake off as much water from the actuator as you can.
Step 5: Look inside the actuator and mouthpiece to make sure any medicine build-up has been completely washed away. Medicine build-up is more likely to happen if the actuator is not allowed to air-dry completely.
Step 6: Let the actuator air-dry overnight. Do not put the canister back into the actuator if it is still wet.
Step 7: When the actuator is dry, put the canister back in the actuator and put the cap back on the mouthpiece. Make sure to firmly press the canister down in the actuator.
Note: If your actuator becomes blocked, it means that little or no medicine is coming out of the mouthpiece. Repeat Steps 1 through 7 in the section "To clean the actuator" mentioned previously.
If you need to use your inhaler before the plastic actuator is completely dry: Shake off as much water from the actuator as you can.
Put the canister back into the actuator and shake the inhaler well.
To remove most of the water from your inhaler, press down on the center of the canister 2 times to release a total of 2 sprays into the air away from your face.
Take your prescribed dose of medicine.
Repeat Steps 1 through 7 in the section "To clean the actuator" mentioned previously.
How should I store Levosalbutamol Tartrate Inhalation Aerosol: Store at temperatures not exceeding 30°C.
Protect from freezing temperatures and direct sunlight.
Keep Inhaler away from heat or open flame.
Do not puncture the Inhaler.
Store Inhaler with the mouthpiece down.

Antiasthmatic & COPD Preparations

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