LEVOLIN Inhaler (Levosalbutamol tartarate)

Table of Content

For the use of a Registered Medical Practitioner or a Hospital or a Laboratory only

Qualitative and Quantitative Composition

Each actuation delivers

Levosalbutamol Tartrate equivalent to Levosalbutamol…............... 50mcg

Suspended in propellant HFA 134a…………………………………      q.s.

Absolute Alcohol Content…………………………………………………7.4% v/v

Dosage Form and Strength

Inhalation aerosol: LEVOLIN Inhaler is a pressurized, metered dose aerosol.

Each LEVOLIN Inhaler 15 gram canister contains 200 metered actuations (or inhalations).

Each canister is fitted with a dose indicator and is supplied with a blue plastic actuator mouthpiece and a red mouthpiece cap.  After priming, each actuation of the inhaler delivers 59 mcg of Levosalbutamol tartrate (equivalent to 45 mcg of Levosalbutamol free base) from the actuator mouthpiece

Clinical Particulars

Therapeutic Indications

LEVOLIN Inhaler is indicated for the prevention and treatment of bronchospasm in adults, adolescents, and children 4 years of age and older with reversible obstructive airway disease.

Posology and Method of Administration

The recommended dosage of LEVOLIN Inhaler for adults and children 4 years of age and older is 2 inhalations (90 mcg of Levosalbutamol free base) repeated every 4 to 6 hours; in some patients, 1 inhalation (45 mg 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 LEVOLIN Inhaler, 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 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, wash the actuator to remove the blockage.
  • The canister is fitted with a dose indicator, which indicates how many inhalations remain.  The dose indicator display will move after every tenth actuation.  When nearing the end of the usable inhalations, the color behind the number in the dose indicator window changes to red. Discard the inhaler when the dose indicator display window shows zero, corresponding to the use of 200 actuations.

Contraindications

Hypersensitivity to any of the components of the formulation. Reactions with levosalbutamol have included urticaria, angioedema, rash, bronchospasm, anaphylaxis, and oropharyngeal edema.

Special Warnings and Precautions for Use

Paradoxical Bronchospasm

Like other inhaled beta-adrenergic agonists, LEVOLIN Inhaler can produce paradoxical bronchospasm, which may be life-threatening. If paradoxical bronchospasm occurs, LEVOLIN Inhaler 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 LEVOLIN Inhaler than usual, this may be a marker of destabilization of asthma and requires re-evaluation of the patient and treatment regimen, with 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

LEVOLIN Inhaler, like other beta-adrenergic agonists, can produce clinically significant cardiovascular effects in some patients, as measured by heart rate, blood pressure, and/or symptoms. Although such effects are uncommon after administration of LEVOLIN Inhaler at recommended doses, if they occur, the drug may need to be discontinued. In addition, beta-agonists have been reported to produce 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 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, angio-oedema, rash, bronchospasm, anaphylaxis, and oropharyngeal oedema. The potential for hypersensitivity must be considered in the clinical evaluation of patients who experience immediate hypersensitivity reactions while receiving LEVOLIN Inhaler.

Coexisting Conditions

LEVOLIN Inhaler, 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 pre-existing diabetes mellitus and ketoacidosis.

Hypokalemia

As with other beta-adrenergic agonist medications, LEVOLIN Inhaler 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.

Drug Interactions

Other short-acting sympathomimetic bronchodilators or epinephrine should not be used concomitantly with levosalbutamol. 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, 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 for patients with asthma. In this setting, cardioselective beta-blockers should be considered, although they should be administered with caution.

Diuretics

The ECG changes and/or hypokalaemia 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 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 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.

Monoamine Oxidase Inhibitors or Tricyclic Antidepressants

LEVOLIN Inhaler 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.

Use in Special Population

Pregnancy 

Risk Summary

There are no adequate and well-controlled studies of levosalbutamol in pregnant women. There are clinical considerations with the use of levosalbutamol 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 ; however, racemic salbutamol was teratogenic in mice (cleft palate) and rabbits (cranioschisis) at doses slightly higher than the human therapeutic range (see Data).

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 LEVOLIN Inhaler for the treatment of bronchospasm during labor should be restricted to those patients in whom the benefits clearly outweigh the risk.

Levosalbutamol has not been approved for the management of preterm labor. The benefit:risk ratio when levosalbutamol 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.

Data

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 for adults on a mg/m2 basis). In a rat developmental study, a racemic salbutamol (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, 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 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 and any potential adverse effects on the breastfed child from levosalbutamol or from the underlying maternal condition.

Pediatric Use

Pediatric Patients 4 Years of Age and Older

The safety and efficacy of levosalbutamol HFA inhalation aerosol have been established in pediatric patients, 4 years of age and older, in an adequate and well-controlled clinical trial.

Pediatric Patients less than 4 Years of Age

Levosalbutamol is not indicated for pediatric patients less than 4 years of age. A clinical trial in pediatric patients below the age of 4 years showed no statistical significant difference between treatment groups in the primary efficacy endpoint. There was an increased incidence of asthma-related adverse reactions reported in pediatric patients below the age of 4 years treated with Levosalbutamol compared to placebo.

Levosalbutamol was evaluated in one 4-week, multicenter, randomized, modified-blind, placebo-controlled, parallel group trial of 196 pediatric patients ages birth to <4 years of age with asthma or reactive airway disease (68 patients birth to <2 years of age and 128 patients 2 to <4 years of age).

Levosalbutamol 45 mcg (N=23), Levosalbutamol 90 mcg (N=42), Levosalbutamol inhalation solution 0.31 mg (N=63), and placebo HFA (N=68) were administered three times daily. Levosalbutamol or placebo HFA was delivered with the Monaghan AeroChamber MAX™ Valved Holding Chamber with mask. The primary efficacy endpoint was the mean change in Pediatric Asthma Caregiver Assessment (PACA) total score from baseline over the 4 week treatment period. There was no statistical difference in the change in PACA total score between Levosalbutamol and placebo. Regarding safety, an increased number of treatment-emergent asthma-related adverse reactions were reported in Levosalbutamol-treated patients. Eight subjects reported asthma-related adverse reactions for Levosalbutamol compared to 3 subjects for placebo. There was one subject that discontinued treatment due to asthma in the Levosalbutamol group compared to zero subjects in the placebo group (Table 1). Other adverse reactions were consistent with those observed in the clinical trial population of patients 4 years of age and older.

Table 1. Asthma-related Adverse Reactions in a 4-Week Clinical Trial in Children Birth to <4 Years of Age*

 

Levosalbutamol 45-90 mcg

(n=65)

Levosalbutamol inhalation solution 0.31 mg

(n=63)

Placebo

(n=68)

Asthma-related adverse reactions*, n (%)

8 (12%)

6 (10%)

3 (4%)

Treatment discontinuations due to asthma, n (%)

1 (2%)

2 (3%)

0

*This table includes the following Preferred Terms (whether considered by the investigator to be related or unrelated to drug): asthma, cough, hypoxia, status asthmaticus, tachypnea

Geriatric Use

Clinical studies of levosalbutamol HFA inhalation aerosol did not include sufficient numbers of subjects aged 65 years 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.

Renal Impairment

Racemic salbutamol is known to be substantially excreted by the kidney, and risk of toxic reactions may be greater in patients with renal impairment. 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.

Undesirable Effects

Use of LEVOLIN Inhaler may be associated with the following:

  • Paradoxical bronchospasm
  • Cardiovascular effects
  • Immediate hypersensitivity reactions
  • Hypokalemia

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adults and Adolescents 12 Years of Age and Older

Adverse reaction information concerning Levosalbutamol in adults and adolescents is derived from two 8-week, multicenter, randomized, double-blind, active- and placebo-controlled trials in 748 adult and adolescent patients with asthma that compared Levosalbutamol, a marketed salbutamol HFA inhaler, and an HFA-134a placebo inhaler. Table 2 lists the incidence of all adverse reactions (whether considered by the investigator to be related or unrelated to drug) from these trials that occurred at a rate of 2% or greater in the group treated with Levosalbutamol and more frequently than in the HFA-134a placebo inhaler group.

Table 2: Adverse Reaction Incidence (% of Patients) in Two 8-Week Clinical Trials in Adults and Adolescents ≥ 12 Years of Age*

Body System

Preferred Term

Levosalbutamol

90 mcg (n=403)

Racemic salbutamol HFA 180 mcg   (n=179)

Placebo (n=166)

Respiratory System

Asthma

9%

7%

6%

Pharyngitis

8%

2%

2%

Rhinitis

7%

2%

3%

Body as a Whole

Pain

4%

3%

4%

Central Nervous System

Dizziness

3%

1%

2%

* This table includes all adverse reactions (whether considered by the investigator to be related or unrelated to drug) from these trials that occurred at a rate of 2% or greater in the group treated with Levosalbutamol and more frequently than in the HFA-134a placebo inhaler group.

Adverse reactions reported by less than 2% and at least 2 or more of the adolescent and adult patients receiving Levosalbutamol and by a greater proportion than receiving HFA-134a placebo inhaler include cyst, flu syndrome, viral infection, constipation, gastroenteritis, myalgia, hypertension, epistaxis, lung disorder, acne, herpes simplex, conjunctivitis, ear pain, dysmenorrhea, hematuria, and vaginal moniliasis. There were no significant laboratory abnormalities observed in these studies.

Pediatric Patients 4 to 11 Years of Age

Adverse reaction information concerning Levosalbutamol in children is derived from a 4-week, randomized, double-blind trial of Levosalbutamol, a marketed salbutamol HFA inhaler, and an HFA-134a placebo inhaler in 150 children aged 4 to 11 years with asthma. Table 3 lists the adverse reactions reported for Levosalbutamol in children at a rate of 2% or greater and more frequently than for placebo.

Table 3: Adverse Reaction Incidence (% of Patients) in a 4-Week Clinical Trial in Children 4-11 Years of Age*

Body System

Preferred Term

Levosalbutamol 90 mcg (n=76)

Racemic salbutamol HFA 180 mcg (n=39)

Placebo (n=35)

Digestive System

Vomiting

11%

8%

6%

Body as a Whole

Accidental injury

9%

10%

6%

Respiratory System

Pharyngitis

7%

13%

6%

Bronchitis

3%

0%

0%

* This table includes all adverse reactions (whether considered by the investigator to be related or unrelated to drug) from the trial that occurred at a rate of 2% or greater in the group treated with Levosalbutamol and more frequently than in the HFA-134a placebo inhaler group.

The incidence of systemic beta-adrenergic adverse reactions (e.g., tremor, nervousness) was low and comparable across all treatment groups, including placebo.

Postmarketing Experience

In addition to the adverse events reported in clinical trials, the following adverse events have been observed in post approval use of levosalbutamol. 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, gastroesophageal reflux disease (GERD), metabolic acidosis, nausea, nervousness, rash, tachycardia, tremor, and urticaria.

In addition, levosalbutamol, like other sympathomimetic agents, can cause adverse reactions such as hypertension, angina, vertigo, central nervous system stimulation, hallucination, sleeplessness, headache, and drying or irritation of the oropharynx.

If you experience any side-effects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the national pharmacovigilance program of India by calling on 1800 180 3024 or you can report to Cipla ltd. on 18002677779. By reporting side-effects, you can help provide more information on the safety of this product.

Overdosage

The expected symptoms with overdosage are those of excessive beta-adrenergic receptor stimulation, e.g., seizures, angina, hypertension or hypotension, tachycardia with rates up to 200beats/minute, arrhythmias, nervousness, headache, tremor, dry mouth, palpitations, nausea, dizziness, fatigue, malaise, and sleeplessness. Hypokalaemia also may occur. As with all sympathomimetics, cardiac arrest and even death may be associated with the abuse of LEVOLIN Inhaler. Treatment consists of discontinuation of LEVOLIN Inhaler together with appropriate symptomatic therapy.

The judicious use of cardioselective beta-receptor blockers may be considered, bearing in mind that such medication can produce bronchospasm. There is insufficient evidence to determine if dialysis is beneficial in treating overdosage of LEVOLIN Inhaler.

Pharmacological Properties

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 that relaxes the airway irrespective of the spasmogen involved, thereby 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, 10–50% 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 (ECG) changes.

Pharmacokinetics

A population pharmacokinetics (PPK) 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, yielded mean peak plasma concentrations (Cmax) and systemic exposure (AUC0-6) 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, yielded Cmax and AUC0-6 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 pharmacokinetics data indicate that mean exposure to (R)-salbutamol was 13–16% less in adult and 30–32% less in paediatric patients given levosalbutamol HFA inhalation aerosol as compared to those given a comparable dose of racemic salbutamol. When compared to adult patients, paediatric patients given 90 mcg of levosalbutamol had a 17% lower mean exposure to (R)-salbutamol.

Metabolism and Elimination

Information available in published literature suggests that the primary enzyme responsible for the metabolism of salbutamol enantiomers in humans is sulphotransferase 1A3 (SULT1A3). 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 (AUC) between the (R)- and (S)-salbutamol enantiomers, with (S)-salbutamol concentrations being consistently higher. However, after either inhalation or oral administration without charcoal pre-treatment, 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 (80–100%) of either the parent compound or the primary metabolite. Less than 20% of the drug is detected in the faeces. Following intravenous administration of racemic salbutamol, between 25–46% 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 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 to patients with renal impairment.

Nonclinical Properties

Carcinogenesis, Mutagenesis, Impairment of Fertility

Although there have been no carcinogenesis studies with levosalbutamol, 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 for adults and approximately 15 times the MRHDID of levosalbutamol 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 for adults and approximately 1800 times the MRHDID of levosalbutamol 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 for adults on a mg/m2 basis and approximately 240 times the MRHDID of levosalbutamol 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. 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 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 (tmax) 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.

Description

The active component of LEVOLIN Inhaler inhalation aerosol is Levosalbutamol Tartrate, the (R)enantiomer of Levosalbutamol.  Levosalbutamol Tartrate is a relatively selective beta2-adrenergic receptor agonist.  Levosalbutamol Tartrate has the chemical name (R)-α1methyl]-4-hydroxy-1,3-benzenedimethanol L-tartrate (2:1 salt), and it has the following chemical structure:

The molecular weight of Levosalbutamol Tartrate is 628.71, and its empirical formula is (C13H21NO3)2 · C4H6O6. It is a white to light-yellow solid, freely soluble in water and very slightly soluble in ethanol.

Levosalbutamol Tartrate is the generic name for (R)-salbutamol in the United States. Levosalbutamol inhalation aerosol is a pressurized metered-dose aerosol inhaler (MDI) fitted with a dose indicator, which produces an aerosol for oral inhalation.  It contains a suspension of micronized Levosalbutamol tartrate, propellant HFA-134a (1,1,1,2-tetrafluoroethane), Dehydrated Alcohol USP, and Oleic Acid NF.

After priming with 4 actuations, each actuation of the inhaler delivers 67.8 mcg of Levosalbutamol Tartrate (equivalent to 51.6 mcg of Levosalbutamol free base) from the valve and 59 mcg of Levosalbutamol Tartrate (equivalent to 45 mcg of Levosalbutamol free base) from the actuator mouthpiece.  Each 15 g canister provides 200 actuations (or inhalations).

Pharmaceutical Particulars

Incompatibilities

Not Applicable

Shelf-Life

See on the pack

Packaging Information

LEVOLIN Inhaler with Dose Counter ............Canister containing 200 metered doses

Storage and Handling Instructions

Store between 20° and 25°C (68° and 77°F; see USP controlled room temperature).  Protect from freezing temperatures and direct sunlight.  Store inhaler with the actuator mouthpiece down.

Patient Counselling Information

Frequency of Use

The action of LEVOLIN Inhaler should last for 4 to 6 hours. Do not use LEVOLIN Inhaler more frequently than recommended. Instruct patients to not increase the dose or frequency of doses of LEVOLIN Inhaler without consulting their physician. If patients find that treatment with LEVOLIN Inhaler 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 LEVOLIN Inhaler is essential to ensure appropriate Levosalbutamol content in each actuation.  Patients should prime LEVOLIN Inhaler 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 FDA-approved patient labeling.

Storage: Store canister between 20° and 25°C (68° and 77°F).  Protect from freezing temperatures and direct sunlight.

Paradoxical Bronchospasm

Inform patients that LEVOLIN Inhaler can produce paradoxical bronchospasm. Instruct patients to discontinue LEVOLIN Inhaler if paradoxical bronchospasm occurs.

Concomitant Drug Use

While patients are using LEVOLIN Inhaler 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 LEVOLIN Inhaler.

General Information on Use

Shake the inhaler well immediately before each use.

Use LEVOLIN Inhaler only with the actuator supplied with the product. When the dose indicator display window shows a red zone, approximately 20 inhalations are left, and a refill is required. Discard the inhaler when the dose indicator display window shows zero, indicating that 200 sprays have been used. Never immerse the canister in water to determine how full the canister is (“float test”).

In general, the technique for administering LEVOLIN Inhaler to children is similar to that for adults.  Children should use LEVOLIN Inhaler under adult supervision, as instructed by the patient’s physician.

LEVOLIN Inhaler with Dose Counter

What is LEVOLIN Inhaler?

  • LEVOLIN Inhaler is an inhaled prescription medicine used for the treatment or prevention of asthma in people 4 years of age and older.
  • LEVOLIN Inhaler has not been shown to be safe and effective in children younger than 4 years of age.

Do not use LEVOLIN Inhaler if you:

  • are allergic to levosalbutamol, racemic salbutamol or any of the ingredients in LEVOLIN Inhaler.

Before you use LEVOLIN Inhaler, 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 LEVOLIN Inhaler 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 LEVOLIN Inhaler passes into your breast milk. Talk to your doctor about the best way to feed your baby if you use LEVOLIN Inhaler.

Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. LEVOLIN Inhaler may affect the way other medicines work, and other medicines may affect how LEVOLIN Inhaler 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 LEVOLIN Inhaler?

  • LEVOLIN Inhaler is for oral inhalation use only.
  • Use LEVOLIN Inhaler 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 LEVOLIN Inhaler.
  • An adult should help a child use LEVOLIN Inhaler. Your doctor should show you how your child should use LEVOLIN Inhaler.
  • Do not use your LEVOLIN Inhaler more often than your doctor tells you to.
  • Get medical help right away if LEVOLIN Inhaler:
  • does not work as well for your asthma  symptoms
  • your asthma symptoms get worse
  • you need to use LEVOLIN Inhaler more often than usual
  • While you are using LEVOLIN Inhaler, do not use other inhaled medicines and asthma medicines unless your doctor tells you to.

What are the possible side effects of LEVOLIN Inhaler?

LEVOLIN Inhaler can cause serious side effects including:

  • sudden shortness of breath (broncho spasm).  Sudden shortness of breath can happen right away after using DUOLIN FORTE Rotacaps.
  • worsening asthma.
  • heart problems.
  • death. If you use too much LEVOLIN Inhaler you can have heart or lung problems that can lead to death.
  • serious allergic reactions. Call your doctor and stop using LEVOLIN Inhaler 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 above or if you have  worsening lung  symptoms.

The most common side effects of LEVOLIN Inhaler 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 LEVOLIN Inhaler. Call your doctor for medical advice about side effects.

How should I store LEVOLIN Inhaler?

  • Store LEVOLIN Inhaler at room temperature between 68°F to 77°F (20°C to 25°C).
  • Do not use or store LEVOLIN Inhaler inhaler near heat or open flame. Temperatures above 120°F may cause the canister to burst.
  • Do not freeze LEVOLIN Inhaler.
  • Keep LEVOLIN Inhaler out of direct sunlight.
  • Do not put a hole in the DUOLIN LEVOLIN Inhaler canister.
  • Store LEVOLIN Inhaler with the mouthpiece down.
  • Throw away LEVOLIN Inhaler when the dose indicator display window reaches zero “0”, showing that all 200 sprays (actuations) have been used.
  • Do not throw LEVOLIN Inhaler into a fire or an incinerator.

Keep LEVOLIN Inhaler and all medicines out of the reach of children.

General information about the safe and effective use of LEVOLIN Inhaler Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use LEVOLIN Inhaler for a condition for which it was not prescribed. Do not give LEVOLIN Inhaler 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 LEVOLIN Inhaler that is written for health professionals.

What are the ingredients in DUOLIN FORTE Rotacaps?

Active ingredient: Levosalbutamol tartrate

Inactive ingredients: propellant HFA-134a, Dehydrated Alcohol USP, Oleic Acid NF

Instructions for Use

LEVOLIN Inhaler with Dose Counter

(Levosalbutamol tartrate)

Inhalation aerosol, for oral inhalation use

The parts of your LEVOLIN Inhaler

  • LEVOLIN Inhaler comes as a canister that fits into an actuator with a dose indicator.
  • Do not use the LEVOLIN Inhaler actuator with a canister of medicine from any other inhaler.
  • Do not use the LEVOLIN Inhaler canister with an actuator from any other inhaler.
  • The dose indicator display window will show you how many sprays of medicine you have left in your inhaler. A spray of medicine is released each time you press down on the center of the dose indicator.
  • It is important that you pay attention to the number of sprays left in your LEVOLIN Inhaler inhaler by reading the dose indicator. You should also keep track of the number of sprays used from your inhaler.

Each canister of LEVOLIN Inhaler contains enough medicine for you to spray your medicine 200 times.

  • The pointer will be pointing between 180 and 200 after you take 10 sprays. This means that there are 190 sprays of medicine left in the canister.
  • The pointer will be pointing to 180 after you take 10 more sprays. This means that there are 180 sprays of medicine left in the canister.
  • The dose indicator display window will continue to move after every 10 sprays. The number on the dose indicator display window will continue to change after every 20 sprays.
  • The dose indicator display window will change to red, as shown in the shaded area, when there are only 20 sprays of medicine left in your inhaler. You should refill your prescription or ask your doctor if you need another prescription for LEVOLIN Inhaler.
  • When the number in the dose indicator display window reaches zero “0”, this means that 200 sprays of medicine have been used. Throw away your LEVOLIN Inhaler nhaler.

Note: Do not place the canister under water to find out the amount of medicine left in the canister.

Preparing your LEVOLIN Inhaler inhaler for use:

  • Your LEVOLIN Inhaler inhaler should be at room temperature before you use it.
  • Shake the inhaler well before each use.

Priming your LEVOLIN Inhaler inhaler:

Before you use LEVOLIN Inhaler for the first time or if you have not taken your medicine for 3 days in a row, you must prime the inhaler.

  • Look at the dose indicator on top of the inhaler. Make sure that the pointer on the dose indicator is pointing to the “200” inhalation mark before you use your LEVOLIN Inhaler inhaler for the first time.
  • 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 on the center of the dose indicator to release a spray of medicine from the mouthpiece. You may hear a soft click from the dose indicator as it counts down during use.
  • Avoid spraying in your eyes.
  • Repeat the priming steps 3 more times to finish priming the inhaler.
  • After priming 4 times the first time you use your LEVOLIN Inhaler inhaler, the dose indicator should be pointing to “200” and your inhaler is now ready to use.

If you do not use your LEVOLIN Inhaler inhaler for more than 3 days, you will need to prime the inhaler again before use.

Using your LEVOLIN Inhaler 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 targeting rings until a spray of medicine has been released. Then stop pressing the dose indicator.

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 LEVOLIN Inhaler.

Step 8: Put the cap back on the mouthpiece right away after use. Make sure the cap snaps firmly into place.

Cleaning your LEVOLIN Inhaler 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 above in the section “To clean the actuator”.

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 targeting rings 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 above in the section “To clean the actuator”.

Details of Manufacturer

Mfg by Cipla Ltd

Registered Office: Cipla House, Peninsula Business Park, Ganpatrao Kadam Marg Lower Parel, Mumbai – 400 013, India

Details of Permission or Licence Number with Date

721/(762)/MFG/DFDA/09/13019

Date: 17/12/19

Date of Revision

Last Updated: 2nd June 2022