Product Index

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

Qualitative and Quantitative Composition

LEVOLIN respules 0.31 mg

Each 2.5 mL contains:

Levosalbutamol Sulphate, IP

Equivalent to Levosalbutamol…….. 0.31 mg

In normal saline solution …………...q.s.

LEVOLIN respules 0.63 mg

Each 2.5 mL contains:

Levosalbutamol Sulphate, IP

Equivalent to Levosalbutamol…….. 0.63 mg

In normal saline solution …………...........q.s.

LEVOLIN respules 1.25 mg

Each 2.5 mL contains:

Levosalbutamol Sulphate, IP

Equivalent to Levosalbutamol…….. 1.25 mg

In normal saline solution …………...........q.s. 

Dosage Form(s) and Strength(s)

LEVOLIN respules are supplied as a sterile, clear, colourless, aqueous solution for inhalation in a unit-dose, single-use LDPE respule. Each unit-dose respule of 2.5 mL is available in three dosage strengths of levosalbutamol – 0.31 mg, 0.63 mg, and 1.25 mg.

Clinical Particulars

Therapeutic Indications

LEVOLIN respules are indicated for the treatment or prevention of bronchospasm in adults, adolescents, and children (6 to 11 years old) with reversible obstructive airway disease.

Posology and Method of Administration

LEVOLIN respule contains Levosalbutamol inhalation solution. Levosalbutamol inhalation solution is for oral inhalation only. Administer by nebulisation using with a standard jet nebuliser (with a face mask or mouthpiece) connected to an air compressor. Do not exceed the recommended dose.

Paediatric Patients (6 to 11 Years Old): The recommended dosage of levosalbutamol inhalation solution, for patients 6–11 years old is 0.31 mg administered three times a day, by nebulisation. Routine dosing should not exceed 0.63 mg three times a day.

Adults and Adolescents 12 Years of Age and Older: The recommended starting dosage of levosalbutamol inhalation solution, USP, for patients 12 years of age and older is 0.63 mg administered three times a day, every 6–8 hours, by nebulisation.

Patients 12 years of age and older with more severe asthma or patients who do not respond adequately to a dose of 0.63 mg of levosalbutamol inhalation solution, USP, may benefit from a dosage of 1.25 mg three times a day.

Patients receiving the highest dose of levosalbutamol inhalation solution, USP, should be monitored closely for adverse systemic effects, and the risks of such effects should be balanced against the potential for improved efficacy.

The use of levosalbutamol inhalation solution, USP, can be continued as medically indicated to help control recurring bouts of bronchospasm. During this time, most patients gain optimal benefit from regular use of the inhalation solution.

If a previously effective dosage regimen fails to provide the usual response this may be a marker of destabilisation 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.

The drug compatibility (physical and chemical), efficacy, and safety of levosalbutamol inhalation solution, USP, when mixed with other drugs in a nebuliser have not been established.

Contraindications

Levosalbutamol inhalation solution is contraindicated in patients with a history of hypersensitivity to levosalbutamol or racemic albuterol. Reactions have included urticaria, angio-oedema, rash, bronchospasm, anaphylaxis, and oropharyngeal oedema.

Special Warnings and Precautions for Use

Hypokalaemia

As with other beta-adrenergic agonist medications, levosalbutamol inhalation solution may produce significant hypokalaemia in some patients, possibly through intracellular shunting which has the potential to produce adverse cardiovascular effects. The decrease is usually transient, not requiring supplementation.

Paradoxical Bronchospasm

Levosalbutamol inhalation solution can produce paradoxical bronchospasm, which may be life-threatening. If paradoxical bronchospasm occurs, levosalbutamol inhalation solution should be discontinued immediately, and alternative therapy instituted. It should be recognised that paradoxical bronchospasm, when associated with inhaled formulations, frequently occurs with the first use of a new canister or respule.

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 inhalation solution than usual, this may be a marker of destabilisation 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

Levosalbutamol inhalation solution is not a substitute for corticosteroids. 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 inhalation solution, 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 levosalbutamol inhalation solution 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 sulphate inhalation solution, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

Do Not Exceed the Recommended Dose

Do not exceed the 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 levosalbutamol inhalation solution

Coexisting Conditions

Levosalbutamol inhalation solution, 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.

Changes in blood glucose may occur. Large doses of intravenous racemic albuterol have been reported to aggravate pre-existing diabetes mellitus and ketoacidosis.

Drug Interactions

Short-Acting Bronchodilators

Avoid concomitant use of other short-acting sympathomimetic bronchodilators or epinephrine in patients being treated 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 also 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, use of beta-adrenergic blocking agents could 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 coadministration of beta-agonists with non-potassium-sparing diuretics. Consider monitoring potassium levels.

Digoxin

Mean decreases of 16% and 22% in serum digoxin levels were demonstrated after single-dose intravenous and oral administration, respectively, of racemic salbutamol 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 inhalation solution 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 inhalation solution.

Monoamine Oxidase Inhibitors or Tricyclic Antidepressants

Levosalbutamol inhalation solution should be administered with extreme caution to patients being treated with monoamine oxidase (MAO) inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of such agents, because the action of levosalbutamol on the vascular system may be potentiated. Consider alternative therapy in patients taking MAO inhibitors or tricyclic antidepressants.

Use in Special Populations

Patients with Renal Impairment

Albuterol is known to be substantially excreted by the kidneys, 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.

Pregnant Women

Risk Summary

There are no adequate and well-controlled studies of levosalbutamol inhalation solution in pregnant women. There are clinical considerations with the use of levosalbutamol inhalation solution in pregnant women.

Following oral administration of levosalbutamol hydrochloride (HCl) to pregnant rabbits, there was no evidence of teratogenicity at doses up to 25 mg/kg/day ; however, racemic albuterol sulphate was teratogenic in mice (cleft palate) and rabbits (cramioschisis) 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 US general population, the estimated risk of major birth defects and miscarriage in clinically recognised pregnancies is –4% and 15–20%, respectively.

Clinical Considerations

DISEASE-ASSOCIATED MATERNAL AND/OR EMBRYO/FOETAL RISK

In women with poorly or moderately controlled asthma, there is an increased risk of pre-eclampsia 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.

LABOUR OR DELIVERY

Because of the potential for beta-adrenergic agonists to interfere with uterine contractility, the use of levosalbutamol inhalation solution for the treatment of bronchospasm during labour should be restricted to those patients for whom the benefits clearly outweigh the risk. Levosalbutamol inhalation solution has not been approved for the management of preterm labour. The benefit-risk ratio when levosalbutamol inhalation solution is administered for tocolysis has not been established. Serious adverse reactions, including maternal pulmonary oedema, have been reported during or following treatment of premature labour with beta-agonists, including racemic albuterol.

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 108 times the MRHDID of levosalbutamol HCl for adults on an mg/m² basis). In a rat developmental study, racemic albuterol sulphate administered by inhalation did not produce any teratogenic effects at exposures approximately 63 times the MRHDID (on an mg/m² basis at a maternal dose of 10.5 mg/kg).

However, other developmental studies with the racemic albuterol sulphate did result in teratogenic effects in mice and rabbits at doses slightly higher than the human therapeutic range. In a rabbit developmental study, orally administered albuterol sulphate induced cranioschisis in 7 of 19 foetuses (37%) at approximately 215 times the MRHDID for adults (on an mg/m² basis at a maternal dose of 50 mg/kg). In a mouse developmental study, subcutaneously administered albuterol sulphate produced cleft palate formation in 5 of 111 (4.5%) foetuses at an exposure approximately 0.3 times the MRHDID for adults (on an mg/m² basis at a maternal dose of 0.25 mg/kg/day) and in 10 of 108 (9.3%) foetuses at approximately 3 times the MRHDID (on an mg/m² basis at a maternal dose of 2.5 mg/kg/day). Similar effects were not observed at approximately 0.03 times the MRHDID for adults on an mg/m² basis at a maternal dose of 0.025 mg/kg/day (i.e. less than the therapeutic dose). Cleft palate also occurred in 22 of 72 (30.5%) foetuses from females treated subcutaneously with isoproterenol (positive control).

Lactating Women

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 inhalation solution and any potential adverse effects on the breastfed child from levosalbutamol inhalation solution, or from the underlying maternal condition.

Paediatric Patients

Paediatric Patients (6 Years of Age and Older)

The safety and efficacy of levosalbutamol inhalation solution have been established in paediatric patients 6 years of age and older in an adequate and well-controlled clinical trial.

Paediatric Patients (Less than 6 Years of Age)

Levosalbutamol inhalation solution is not indicated for paediatric patients less than 6 years of age. Clinical trials with levosalbutamol inhalation solution in this age group failed to meet the primary efficacy endpoint and demonstrated an increased number of asthma-related adverse reactions following chronic levosalbutamol inhalation solution treatment. Levosalbutamol inhalation solution was studied in 379 paediatric patients less than 6 years of age with asthma or reactive airway disease (291 patients 2 to 5 years of age, and 88 patients from birth to less than 2 years of age). Efficacy and safety data for levosalbutamol inhalation solution in this age group are primarily available from one 3-week, multicentre, randomised, double-blind, active and placebo-controlled study (Study 1) in 211 paediatric patients between the ages of 2 and 5 years, of whom 119 received levosalbutamol inhalation solution. Over the 3-week treatment period, there were no significant treatment differences in the Paediatric Asthma Questionnaire (PAQ) total score between groups receiving levosalbutamol inhalation solution 0.31 mg, levosalbutamol inhalation solution 0.63 mg, racemic albuterol, and placebo. Additional safety data following chronic dosing is available from a 4-week, multicentre, randomised, modified-blind, placebo-controlled study (Study 2) of 196 patients between the ages of birth and 3 years, of whom 63 received open-label levosalbutamol inhalation solution. In these two studies, treatment-emergent asthma exacerbations or asthma-related adverse reactions and treatment discontinuations due to asthma occurred at a higher frequency in levosalbutamol inhalation solution-treated subjects compared with control (Table 5). Other adverse reactions were consistent with those observed in the clinical trial population of patients 6 years of age and older

		Asthma Exacerbations n (%)	Treatment Discontinuations due to Asthma n (%)	Asthma-related Adverse Reactions n (%)
Study 1	Levosalbutamol Inhalation Solution, USP, 0.31 mg, n=58	6 (10)	4 (7)	--
	Levosalbutamol Inhalation Solution, USP, 0.63 mg, n=51	7 (14)	6 (12)	--
	Racemic albuterol, n=52	3 (6)	2 (4)	--
	Placebo, n=50	2 (4)	2 (4)	--
Study 2	Levosalbutamol Inhalation Solution, USP, 0.31 mg, n=63	--	2 (3)	6 (10)
	Levosalbutamol HFA inhalation aerosol, n=65	--	1 (2)	8 (12)
	Placebo, n=68	--	0	3 (4)

* Asthma exacerbation defined as worsening of asthma symptoms or pulmonary function that required any of the following: emergency department visit, hospitalisation, therapeutic intervention with oral or parenteral steroids, or unscheduled clinic visit to treat acute asthma symptoms.

^† Includes the following preferred terms (whether considered by the investigator to be related or unrelated to drug): asthma, cough, hypoxia, status asthmaticus, tachypnoea.

Geriatric Patients

Clinical studies of levosalbutamol sulphate inhalation aerosol did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. Only 5 patients of age 65 years and older were treated with levosalbutamol inhalation solution in a 4-week clinical study (n=2 for 0.63 mg and n=3 for 1.25 mg). In these patients, bronchodilation was observed after the first dose on day 1 and after 4 weeks of treatment. In general, patients 65 years of age and older should be started at a dose of 0.63 mg of levosalbutamol inhalation solution. If clinically warranted due to insufficient bronchodilator response, the dose of levosalbutamol inhalation solution may be increased in elderly patients as tolerated, in conjunction with frequent clinical and laboratory monitoring, to the maximum recommended daily dose

Effects on Ability to Drive and Use Machines

Not known.

Undesirable Effects

The following serious adverse reactions are described below and elsewhere in the labelling:

• Paradoxical bronchospasm
• Cardiovascular effects
• Immediate hypersensitivity reactions
• Hypokalaemia
• Headache
• Dizziness
• Tremor
• Nervousness

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of the 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 inhalation solution in adults and adolescents is derived from one 4-week, multicentre, randomised, double-blind, active- and placebo-controlled trial in 362 patients with asthma 12 years of age and older. Adverse reactions reported in ≥2% of patients receiving levosalbutamol inhalation solution or racemic albuterol and more frequently than in patients receiving placebo are listed in Table 2.

* One treatment group, racemic albuterol 1.25 mg, with 68 subjects is omitted.

Body System Preferred Term	Percent of Patients*
	Placebo (n=75)	Levosalbutamol Inhalation Solution 1.25 mg (n=73)	Levosalbutamol Inhalation Solution 0.63 mg (n=72)	Racemic Albuterol 2.5 mg (n=74)
Body as a Whole
Allergic reaction	1.3	0	0	2.7
Flu syndrome	0	1.4	4.2	2.7
Accidental injury	0	2.7	0	0
Pain	1.3	1.4	2.8	2.7
Back pain	0	0	0	2.7
Cardiovascular System
Tachycardia	0	2.7	2.8	2.7
Migraine	0	2.7	0	0
Digestive System
Dyspepsia	1.3	2.7	1.4	1.4
Musculoskeletal System
Leg cramps	1.3	2.7	0	1.4
Central Nervous System
Dizziness	1.3	2.7	1.4	0
Hypertonia	0	0	0	2.7
Nervousness	0	9.6	2.8	8.1
Tremor	0	6.8	0	2.7
Anxiety	0	2.7	0	0
Respiratory System
Cough increased	2.7	4.1	1.4	2.7
Infection viral	9.3	12.3	6.9	12.2
Rhinitis	2.7	2.7	11.1	6.8
Sinusitis	2.7	1.4	4.2	2.7
Turbinate oedema	0	1.4	2.8	0

The incidence of certain systemic beta-adrenergic adverse reactions (e.g. tremor, nervousness) was slightly less in the levosalbutamol inhalation solution 0.63 mg group compared with the other active treatment groups. The clinical significance of these small differences is unknown.

Changes in heart rate 15 minutes after drug administration and in plasma glucose and potassium 1 hour after drug administration on day 1 and day 29 were clinically comparable in the levosalbutamol inhalation solution 1.25 mg and racemic albuterol 2.5 mg groups. Changes in heart rate and plasma glucose were slightly less in the levosalbutamol inhalation solution 0.63 mg group compared with the other active treatment groups. The clinical significance of these small differences is unknown. After 4 weeks, effects on heart rate, plasma glucose, and plasma potassium were generally diminished compared with day 1 in all active treatment groups.

Treatment	Mean Changes (Day 1)
	Heart Rate (bpm)	Glucose (mg/dL)	Potassium (mEq/L)
Levosalbutamol Inhalation Solution, 0.63 mg, n=72	2.4	4.6	–0.2
Levosalbutamol Inhalation Solution, 1.25 mg, n=73	6.9	10.3	–0.3
Racemic albuterol 2.5 mg, n=74	5.7	8.2	–0.3
Placebo, n=75	–2.8	–0.2	–0.2

No other clinically relevant laboratory abnormalities related to the administration of levosalbutamol inhalation solution were observed in this study.

In the clinical trials, a slightly greater number of serious adverse events, discontinuations due to adverse events, and clinically significant ECG changes were reported in patients who received levosalbutamol inhalation solution 1.25 mg compared with the other active treatment groups.

The following adverse reactions, considered potentially related to levosalbutamol inhalation solution occurred in less than 2% of the 292 subjects who received levosalbutamol inhalation solution and more frequently than in patients who received placebo in any clinical trial:

Body as a Whole	chills, pain, chest pain
Cardiovascular System	ECG abnormal, ECG change, hypertension, hypotension syncope
Digestive System	diarrhoea, dry mouth, dry throat, dyspepsia, gastroenteritis, nausea
Hemic and Lymphatic System	lymphadenopathy
Musculoskeletal System	leg cramps, myalgia
Nervous System	anxiety, hyperaesthesia of the hand, insomnia, paraesthesia, tremor
Special Senses	eye itch

The following reactions, considered potentially related to levosalbutamol inhalation solution, occurred in less than 2% of the treated subjects but at a frequency less than in patients who received placebo: asthma exacerbation, cough increased, wheezing, sweating, and vomiting.

Paediatric Patients (6 to 11 Years of Age)

Adverse reaction information concerning levosalbutamol inhalation solution in paediatric patients is derived from one 3-week, multicentre, randomised, double-blind, active- and placebo-controlled trial in 316 paediatric patients 6 to 11 years of age. Adverse reactions reported in ≥2% of patients in any treatment group and more frequently than in patients receiving placebo are listed in Table 4.

Body System Preferred Term	Placebo (n=59)	Levo salbutamol Inhalation Solution 0.31 mg (n=66)	Levo salbutamol Inhalation Solution 0.63 mg (n=67)	Racemic Albuterol 1.25 mg (n=64)	Racemic Albuterol 2.5 mg (n=60)
Body as a Whole
Abdominal pain	3.4	0	1.5	3.1	6.7
Accidental injury	3.4	6.1	4.5	3.1	5.0
Asthenia	0	3.0	3.0	1.6	1.7
Fever	5.1	9.1	3.0	1.6	6.7
Headache	8.5	7.6	11.9	9.4	3.3
Pain	3.4	3.0	1.5	4.7	6.7
Viral infection	5.1	7.6	9.0	4.7	8.3
Digestive System
Diarrhoea	0	1.5	6.0	1.6	0
Haemic and Lymphatic
Lymphadenopathy	0	3.0	0	1.6	0
Musculoskeletal System
Myalgia	0	0	1.5	1.6	3.3
Respiratory System
Asthma	5.1	9.1	9.0	6.3	10.0
Pharyngitis	6.8	3.0	10.4	0	6.7
Rhinitis	1.7	6.1	10.4	3.1	5.0
Skin and Appendages
Eczema	0	0	0	0	3.3
Rash	0	0	7.5	1.6	0
Urticaria	0	0	3.0	0	0
Special Senses
Otitis media	1.7	0	0	0	3.3

Note: Subjects may have more than one adverse event per body system and preferred term.

Changes in heart rate, plasma glucose, and serum potassium are shown in Table 5. The clinical significance of these small differences is unknown.

Treatment	Mean Changes (Day 1)
	Heart Rate (bpm)	Glucose (mg/dL)	Potassium (mEq/L)
Levosalbutamol Inhalation Solution, 0.31 mg, n=66	0.8	4.9	–0.31
Levosalbutamol Inhalation Solution, 0.63 mg, n=67	6.7	5.2	–0.36
Racemic albuterol 1.25 mg, n=64	6.4	8.0	–0.27
Racemic albuterol 2.5 mg, n=60	10.9	10.8	–0.56
Placebo, n=59	–1.8	0.6	–0.05
Treatment	Mean Changes (Day 21)
	Heart Rate (bpm)	Glucose (mg/dL)	Potassium (mEq/L)
Levosalbutamol Inhalation Solution, 0.31 mg, n=60	0	2.6	–0.32
Levosalbutamol Inhalation Solution, 0.63 mg, n=66	3.8	5.8	–0.34
Racemic albuterol 1.25 mg, n=62	5.8	1.7	–0.18
Racemic albuterol 2.5 mg, n=54	5.7	11.8	–0.26
Placebo, n=55	–1.7	1.1	–0.04

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: angio-oedema, anaphylaxis, arrhythmias (including atrial fibrillation, supraventricular tachycardia, extrasystoles), asthma, chest pain, cough increased, dysphonia, dyspnoea, gastro-oesophageal reflux disease (GORD), metabolic acidosis, nausea, nervousness, rash, tachycardia, tremor, urticaria.

In addition, levosalbutamol inhalation solution, 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.

Reporting of Side Effects

To report SUSPECTED ADVERSE REACTIONS, contact your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the national Pharmacovigilance Programme of India by calling on 1800 180 3024 or you can report to Cipla Ltd on 1800 267 7779. By reporting adverse events, you can help provide more information on the safety of this product.

Overdose

The expected symptoms with overdosage are those of excessive beta-adrenergic receptor stimulation, e.g. seizures, angina, hypertension or hypotension, tachycardia with rates upto 200 beats/min, arrhythmias, nervousness, headache, tremor, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, cardiac arrest and sleeplessness. Hypokalaemia also may occur. As with all sympathomimetic medications, cardiac arrest and even death may be associated with the abuse of levosalbutamol inhalation solution. Treatment consists of discontinuation of levosalbutamol inhalation solution 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 for overdosage of levosalbutamol inhalation solution.

Pharmacological Properties

Mechanism of Action

Activation of beta-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 release of mediators from mast cells in the airway. Levosalbutamol acts as a functional antagonist to relax the airway irrespective of the spasmogen involved, thus protecting against all bronchoconstrictor challenges. While it is recognised that beta-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 beta-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 ECG changes.

Pharmacodynamic Properties

Adults and Adolescents 12 Years of Age and Older

In a randomised, double-blind, placebo-controlled, cross-over study, 20 adults with mild-to-moderate asthma received single doses of levosalbutamol inhalation solution (0.31 mg, 0.63 mg, and 1.25 mg) and racemic albuterol sulphate inhalation solution (2.5 mg). All doses of active treatment produced a significantly greater degree of bronchodilation (as measured by percent change from pre-dose mean FEV) than placebo, and there were no significant differences between any of the active treatment arms. The bronchodilator responses to 1.25 mg of levosalbutamol inhalation solution and 2.5 mg of racemic albuterol sulphate inhalation solution were clinically comparable over the 6-hour evaluation period, except for a slightly longer duration of action (>15% increase in FEV₁ from baseline) after administration of 1.25 mg of levosalbutamol inhalation solution. Systemic beta-adrenergic adverse effects were observed with all active doses and were generally dose-related for (R)-albuterol. Levosalbutamol inhalation solution at a dose of 1.25 mg produced a slightly higher rate of systemic beta-adrenergic adverse effects than the 2.5 mg dose of racemic albuterol sulphate inhalation solution.

In a randomised, double-blind, placebo-controlled, crossover study, 12 adults with mild-to-moderate asthma were challenged with inhaled methacholine chloride 20 and 180 minutes following administration of a single dose of 2.5 mg of racemic albuterol sulphate, 1.25 mg of levosalbutamol inhalation solution 1.25 mg of (S)-albuterol, or placebo using a nebuliser. Racemic albuterol sulphate, levosalbutamol inhalation solution, and (S)-albuterol had a protective effect against methacholine-induced bronchoconstriction 20 minutes after administration, although the effect of (S)-albuterol was minimal. At 180 minutes after administration, the bronchoprotective effect of 1.25 mg of levosalbutamol inhalation solution was comparable with that of 2.5 mg of racemic albuterol sulphate. At 180 minutes after administration, 1.25 mg of (S)-albuterol had no bronchoprotective effect.

In a clinical study in adults with mild-to-moderate asthma, comparable efficacy (as measured by change from baseline FEV₁) and safety (as measured by heart rate, blood pressure, ECG, serum potassium, and tremor) were demonstrated after a cumulative dose of 5 mg of levosalbutamol inhalation solution (four consecutive doses of 1.25 mg administered every 30 minutes) and 10 mg of racemic albuterol sulphate inhalation solution (four consecutive doses of 2.5 mg administered every 30 minutes).

Pharmacokinetic Properties

Adults and Adolescents 12 Years of Age and Older

The inhalation pharmacokinetics of levosalbutamol inhalation solution were investigated in a randomised crossover study in 30 healthy adults, following administration of a single dose of 1.25 mg and a cumulative dose of 5 mg of levosalbutamol inhalation solution, and a single dose of 2.5 mg and a cumulative dose of 10 mg of racemic salbutamol inhalation solution by nebulisation, using the nebuliser with a compressor.

Following administration of a single 1.25 mg dose of levosalbutamol inhalation solution, exposure to (R)-salbutamol was approximately 2-fold higher than following administration of a single 2.5 mg dose of racemic salbutamol inhalation solution (AUC of 1.7 ng·hr/mL) (see Table 6 below).

Following administration of a cumulative 5 mg dose of levosalbutamol inhalation solution (1.25 mg given every 30 minutes for a total of four doses) or a cumulative 10 mg dose of racemic salbutamol inhalation solution (2.5 mg given every 30 minutes for a total of four doses), C_max and AUC of (R)-salbutamol were comparable.

	Single Dose		Cumulative Dose
	Levo salbutamol 1.25 mg	Racemic Salbutamol 2.5 mg		Levo salbutamol 5 mg	Racemic Salbutamol 10 mg
Cmax (ng/mL) (R)-salbutamol	1.1 (0.45)	0.8 (0.41) **		4.5 (2.20)	4.2 (1.51) **
tmax (h) (gamma)      (R)-salbutamol	0.2 (0.17, 0.37)	0.2 (0.17, 1.50)		0.2 (-0.18 *, 1.25)	0.2 (-0.28 *, 1.00)
AUC (ng·h/mL)  (R)-salbutamol	3.3 (1.58)	1.7 (0.99) **		17.4 (8.56)	16.0 (7.12) **
T½ (h)   (R)-salbutamol	3.3 (2.48)	1.5 (0.61)		4.0 (1.05)	4.1 (0.97)

*Values reflect only (R)-albuterol and do not include (S)-albuterol.

^gamma Median (Min, Max) reported for T_max.

**A negative T_max indicates C_max occurred between first and last nebulisations.

Paediatric Patients (6 to 11 Years Old)

The pharmacokinetic parameters of (R)- and (S)-salbutamol in children with asthma were obtained using population pharmacokinetics analysis. These data are presented in Table 7. For comparison, adult data obtained by conventional pharmacokinetics analysis from a different study also are presented in Table 7 below.

In children, AUC and C_max of (R)-salbutamol following administration of 0.63 mg levosalbutamol inhalation solution were comparable with those following administration of 1.25 mg racemic salbutamol inhalation solution.

When the same dose of 0.63 mg of levosalbutamol was given to children and adults, the predicted C_max of (R)-salbutamol in children was similar to that in adults (0.52 versus 0.56 ng/mL), while predicted AUC in children (2.55 ng·hr/mL) was about 1.5-fold higher than that in adults (1.65 ng·hr/mL). These data support lower doses for children aged 6 to 11 years old, compared with the adult doses.

	Children (6 to 11 Years Old)				Adults and Adolescents12 years of Age and Older
Treatment	Levo salbutamol 0.31 mg	Levo salbutamol 0.63 mg	Racemic Salbutamol 1.25 mg	Racemic Salbutamol 2.5 mg		Levo salbutamol 0.63 mg	Levo salbutamol 1.25 mg
AUC(0-infinity) (ng·hr/mL)c	1.36	2.55	2.65	5.02		1.65a	3.3b
Cmax (ng/mL)d	0.303	0.521	0.553	1.08		0.56a	1.1b
aThe values are predicted by assuming linear pharmacokinetics. bThe data obtained from Table 1. cArea under the plasma concentration curve from time 0 to infinity. d Maximum plasma concentration

Metabolism and Elimination

Information available in published literature suggests that the primary enzyme responsible for the metabolism of salbutamol enantiomers in humans is SULT1A3 (sulphotransferase). When racemic salbutamol was administered either intravenously or via inhalation after oral charcoal administration, there was a 3- to 4-fold difference in the AUCs 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 metabolised 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 and 46% of the (R)-salbutamol fraction of the dose was excreted as unchanged (R)-salbutamol in the urine.

Special Populations

Patients with Hepatic Impairment

The effect of hepatic impairment on the pharmacokinetics of levosalbutamol inhalation solution has not been evaluated.

Patients with Renal Impairment

The effect of renal impairment on the pharmacokinetics of racemic albuterol was evaluated in 5 subjects with creatinine clearance of 7–53 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 albuterol clearance. Caution should be used when administering high doses of levosalbutamol inhalation solution to patients with renal impairment

Nonclinical Properties

Carcinogenesis, Mutagenesis, Impairment of Fertility

Although there have been no carcinogenesis studies with levosalbutamol HCl, racemic albuterol sulphate has been evaluated for its carcinogenic potential.

In a 2-year study in Sprague-Dawley rats, dietary administration of racemic albuterol sulphate 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 4 times the MRHDID of levosalbutamol HCl for adults and approximately 5 times the MRHDID of levosalbutamol HCl for children on an 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 albuterol sulphate showed no evidence of tumourigenicity. Dietary doses in CD-1 mice were up to 500 mg/kg/day (approximately 540 times the MRHDID of levosalbutamol HCl for adults and approximately 630 times the MRHDID of levosalbutamol HCl for children on an mg/m² basis) and doses in the golden hamster study were up to 50 mg/kg/day (approximately 90 times the MRHDID of levosalbutamol HCl for adults on an mg/m² basis and approximately 105 times the MRHDID of levosalbutamol HCl for children on an 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 albuterol sulphate was not clastogenic in an in vitro chromosomal aberration assay in CHO cell cultures.

No fertility studies have been conducted with levosalbutamol HCl. Reproduction studies in rats using racemic albuterol sulphate demonstrated no evidence of impaired fertility at oral doses up to 50 mg/kg/day (approximately 108 times the maximum recommended daily inhalation dose of levosalbutamol HCl for adults on an mg/m² basis).

Description

Levosalbutamol inhalation solution is a sterile, clear, colourless, preservative-free solution of the sulphate salt of levosalbutamol, the (R)-enantiomer of the drug substance racemic albuterol. Levosalbutamol sulphate is a relatively selective beta-adrenergic receptor agonist. The IUPAC name for levosalbutamol sulphate is, 4--2-(hydroxymethyl)phenol.

Chemical Structure for Levosalbutamol Sulphate

The molecular weight of levosalbutamol sulphate is 576.7 g/mol, and its empirical formula is C₂₆H₄₄N₂O₁₀S

Pharmaceutical Particulars

Incompatibilities

LEVOLIN respules are compatible with IPRAVENT respules, BUDECORT respules, FLOHALE respules, INHALEX respules and MUCINAC respules. Admixtures should be immediately used for nebulisation after opening and mixing the contents of the individual respules.

Shelf-Life

As on the pack.

Packaging Information

LEVOLIN respules 0.31 mg, 0.63 mg and 1.25 mg are available as respules of 2.5 mL.

LEVOLIN respules 0.31 mg is available in a pack of 5 strips . Each strip contains 8 unit-dose respules of 2.5 mL .

LEVOLIN respules 0.63 mg is available in a pack of 5 strips . Each strip contains 4 unit-dose respules of 2.5 mL .

LEVOLIN respules 1.25 mg is available in a pack of 5 strips . Each strip contains 8 unit-dose respules of 2.5 mL .

Storage and Handling Instructions

Protect from light. Store at 20°–25°C (68°–77°F).

Keep out of the reach of children.

Patient Counselling Information

What is LEVOLIN respules?

LEVOLIN respules contain levosalbutamol inhalation solution, which is a prescription medicine to be used for the treatment or prevention of bronchospasm in people 6 years of age and older.

Levosalbutamol inhalation solution has not been shown to be safe and effective in children younger than 6 years of age.

Levosalbutamol inhalation solution is supplied in 2.5 mL unit-dose respules in three different strengths of levosalbutamol (0.31 mg, 0.63 mg, 1.25 mg). The liquid inside the respules does not require dilution before use.

Who should not use LEVOLIN respules?

Do not use if you are allergic to levosalbutamol, racemic albuterol, or any of the ingredients in LEVOLIN respules (levosalbutamol inhalation solution).

What should I tell my doctor before using LEVOLIN respules?

Before you use LEVOLIN respules, tell your doctor about the following:

• Had an allergic reaction to levosalbutamol or racemic albuterol
• Heart problems
• High blood pressure
• Seizures
• Diabetes
• Thyroid problems
• Any other medical conditions
• Are pregnant or planning to become pregnant. It is not known if LEVOLIN respules 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 respules passes into your breast milk. You and your doctor should decide if you will use LEVOLIN respules or breastfeed. You should not do both.

Tell your doctor about all the medicines you take including prescription and over-the-counter medicines, vitamins, and herbal supplements. LEVOLIN respules may affect the way other medicines work, and other medicines may affect how LEVOLIN respules works. Especially tell your doctor if you take

• other asthma medicines
• heart medicines
• medicines that increase urination (diuretics)
• antidepressants
• medicine to treat chronic obstructive pulmonary disease (COPD)

Ask your doctor if you are not sure if any of your medicines are the kinds listed above.

Know the medicines you take. Keep a list of them and show it to your doctor and pharmacist when you get a new medicine.

How should I use LEVOLIN respules?

• Read the step-by-step ‘Instructions for Using LEVOLIN respules’ at the end of this leaflet.
• Use LEVOLIN respules 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 respules.
• An adult should help a child use LEVOLIN respules.
• Do not us e your LEVOLIN respules more often than your doctor tells you to.
• Get medical help right away if LEVOLIN respules
  
  • does not work as well for your asthma symptoms or
  • your asthma symptoms get worse or
  • you need to use your LEVOLIN respules more often than usual

• If you also use another medicine by inhalation, you should ask your doctor for instructions on when to use it while you are also using LEVOLIN respules.
• Do not mix LEVOLIN respules with other medicines in your nebuliser.
• Only use LEVOLIN respules if it is colourless. Throw away the LEVOLIN respules vial if the liquid medicine is not colourless.

• Do not use LEVOLIN respules after the expiration date on the vial.

What are the possible side effects of LEVOLIN respules?

LEVOLIN Respules can cause serious side effects, including the following:

• Sudden shortness of breath (bronchospasm). Sudden shortness of breath can happen right away after using LEVOLIN respules.
• Worsening asthma
• Heart problems
• Death. If you use too much LEVOLIN respules you can have heart or lung problems that can lead to death.
• Serious allergic reactions. Call your doctor and stop using levosalbutamol in case of the following:

• Swelling of the face, throat or tongue
• Hives
• Rash
• 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 respules include

• palpitations
• chest pain
• fast heart rate
• headache
• dizziness
• tremor
• nervousness

Reporting of side effects

To report SUSPECTED ADVERSE REACTIONS, contact your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the national Pharmacovigilance Programme of India by calling on 1800 180 3024 or you can report to Cipla Ltd on 1800 267 7779. By reporting adverse events, you can help provide more information on the safety of this product.

How should I store LEVOLIN respules?

• Store unopened LEVOLIN respules in the protective foil pouch they come in at 20°–25°C (68°–77°F).
• Keep LEVOLIN respules away from light and heat.

Details of The Manufacturer/Marketer

LEVOLIN respules 0.31 mg

Mfd. by: Ambica Estate, Ahmedabad.

Marketed by: Cipla Ltd

Regd. Office: Cipla House, Peninsula Business Park, Ganpatrao Kadam Marg, Lower Parel, Mumbai – 400013, India.

LEVOLIN respules 0.63 mg and 1.25 mg

Mfd. by: Cipla Ltd

Regd. Office: Cipla House, Peninsula Business Park, Ganpatrao Kadam Marg, Lower Parel, Mumbai – 400013, India.

Details of Permission or Licence Number with Date

LEVOLIN respules 0.31 mg: G/25A/4564-A Dated 04.01.2016

LEVOLIN respules 0.63 mg: 536 Dated 24.05.2002

LEVOLIN respules 1.25 mg: M/447/2007 Dated 23.12.2016

Date of Revision

17/02/2021