Soventus® Jr. Syrup

Ambroxol Hydrochloride, Terbutaline Sulphate & Guaiphenesin syrup

Each 5 ml contains:

10 mg

Terbutaline Sulphate USP 0.5 mg

Guaiphenesin USP 25 mg

Excipients q. s.

In a mentholated flavoured syrup base.

Syrup, 60ml

4.1 Therapeutic indication

For symptomatic relief of bronchospasm in bronchial asthma and chronic bronchitis.

4.2 Posology and method of administration

Children (under 6 years): 5 - 10 ml thrice daily

Children (6-12 years): 10 ml thrice daily

4.3 Contraindications

• Hypersensitivity to any of the components of the formulation
• Patients with pre-existing ischaemic heart disease or those patients with significant risk factors for ischaemic heart disease
• Gastric ulceration

4.4 Special warnings and precautions for use

Terbutaline

As for all beta 2-agonists caution should be observed in patients with thyrotoxicosis.

Cardiovascular effects may be seen with sympathomimetic drugs, including terbutaline. There is some evidence from post-marketing data and published literature of myocardial ischaemia associated with beta agonists. Terbutaline, like all other beta-adrenergic agonists, can produce a clinically significant cardiovascular effect in some patients as measured by pulse rate, blood pressure, and/or symptoms. Although such effects are uncommon after administration of terbutaline 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, terbutaline, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

Due to the positive inotropic effect of beta 2-agonists, these drugs should not be used in patients with hypertrophic cardiomyopathy. Terbutaline, as with all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, including ischemic heart disease, hypertension, and cardiac arrhythmias; hyperthyroidism; diabetes mellitus; hypersensitivity to sympathomimetic amines; and convulsive disorders. Significant changes in systolic and diastolic blood pressure have been seen and could be expected to occur in some patients after use of any beta-adrenergic bronchodilator.

Immediate hypersensitivity reactions and exacerbation of bronchospasm have been reported after terbutaline administration. Beta-adrenergic agonist medications 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.

Large doses of intravenous terbutaline have been reported to aggravate preexisting diabetes and ketoacidosis.

Tocolysis

Terbutaline should be used with caution in tocolysis and supervision of cardiorespiratory function, including ECG monitoring, should be considered. Treatment should be discontinued if signs of myocardial ischaemia (such as chest pain or ECG changes) develop. Terbutaline should not be used as a tocolytic agent in patients with significant risk factors for or pre-existing heart disease.

During infusion treatment in pregnant women with beta 2-stimulants in combination with corticosteroids a rare complication with a pathological picture resembling pulmonary oedema, has been reported.

Increased tendency to uterine bleeding has been reported in connection with Caesarean section. However, this can be effectively stopped by propranolol 1-2 mg injected intravenously.

Respiratory indications

Patients with underlying severe heart disease (e.g. ischaemic heart disease, arrhythmia or severe heart failure) who are receiving Terbutaline should be warned to seek medical advice if they experience chest pain or other symptoms of worsening heart disease.

Attention should be paid to assessment of symptoms such as dyspnoea and chest pain, as they may be of either respiratory or cardiac origin.

Due to the hyperglycaemic effects of beta 2-agonists, additional blood glucose controls are recommended initially in diabetic patients.

Potentially serious hypokalaemia may result from beta 2-agonist therapy. Particular caution is recommended in acute severe asthma as the associated risk may be augmented by hypoxia.

The hypokalaemic effect may be potentiated by concomitant treatments. It is recommended that serum potassium levels are monitored in such situations.

If a previously effective dosage regimen no longer gives the same symptomatic relief, the patient should urgently seek further medical advice. Consideration should be given to the requirements for additional therapy (including increased dosages of anti-inflammatory medication). Severe exacerbations of asthma should be treated as an emergency in the usual manner.

There have been rare reports of seizures in patients receiving terbutaline; seizures did not recur in these patients after the drug was discontinued.

Ambroxol

Care to be taken to avoid contact with eye, skin, serious ingestion or inhalation.

Guaiphenesin

Guaiphenesin should be not used for persistent or chronic cough, such as occurs with asthma, or where cough is accompanied by excessive secretions, unless directed by a physician. A persistent cough may be a sign of a serious condition. If cough persists for more than 7 days, tends to recur, or is accompanied by a fever, rash, or persistent headache, a physician should be consulted. Caution should be exercised in the presence of severe renal or severe hepatic impairment. The concomitant use of cough suppressants is not recommended. Patients with rare hereditary problems of fructose intolerance should not take this medicine. Not more than 4 doses should be given in any 24 hours. Avoid with any other cough and cold medicine. Consult a pharmacist or other healthcare professional before use in children under 6 years. Stop use and ask a healthcare professional if your cough lasts for more than 5 days, comes back, or is accompanied by a fever, rash, or persistent headache. Do not take with a cough suppressant. Do not give this medicine with any other cough or cold medicines.

4.5 Drugs interactions

Terbutaline

Beta-blocking agents (including eye drops); especially the non-selective ones such as propranolol, may partially or totally inhibit the effect of beta-stimulants. Therefore, terbutaline preparations and non-selective beta-blockers should not normally be administered concurrently. Terbutaline should be used with caution in patients receiving other sympathomimetics.

Halogenated Anaesthetics

Halothane anaesthesia should be avoided during beta 2-agonists treatment, since it increases the risk of cardiac arrhythmias. Other halogenated anaesthetics should be used cautiously together with beta 2-agonists.

Potassium depleting agents and hypokalaemia

Owing to the hypokalaemic effect of beta-agonists, concurrent administration with terbutaline of serum potassium depleting agents known to exacerbate the risk of hypokalaemia, such as diuretics, methyl xanthines and corticosteroids, should be administered cautiously after careful evaluation of the benefits and risks with special regard to the increased risk of cardiac arrhythmias arising as a result of hypokalaemia. Hypokalaemia also predisposes to digoxin toxicity. Hypokalaemia may result from beta 2-agonist therapy and may be potentiated by concomitant treatment with xanthine derivatives, corticosteroids and diuretics.

Terbutaline 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, since the action of terbutaline on the vascular system may be potentiated.

Ambroxol

No data available

Guaiphenesin

If urine is collected within 24 hours of a dose of Guaiphenesin, its metabolite may cause a colour interference with laboratory determinations of urinary 5-hydroxyindoleacetic acid (5-HIAA) and vanillylmandelic acid (VMA).

Others

Soventus Jr. Syrup should be used with caution in patients with diabetes mellitus, serious cardiovascular disorders, hypertension, hyperthyroidism and peptic ulcers.

4.6 Use in special populations

Pregnancy

However, there are no adequate and well-controlled studies of this combination in pregnant women. Hence this combination should be administered with caution in pregnancy.

Lactation

It is not known whether this combination is secreted in breast milk. However, terbutaline is secreted in breast milk, but effect on the infant is unlikely at therapeutic doses. Therefore, this combination should be used with caution in nursing mothers.

4.7 Effects on ability to drive and use machines

Patients should be cautioned against engaging in activities requiring complete mental alertness, and motor coordination such as operating machinery until their response to Soventus Jr syrup is known.

4.8 Undesirable effects

Ambroxol Hydrochloride

Under individual hypersensitivity to Ambroxol allergic reactions such as skin rash, nettle-rash, and angioneurotic oedema are possible. Under the prolonged administration in large doses pain in epigastrial area, nausea, vomiting can appear.

Gastrointestinal Disorders: Dyspepsia, nausea, vomiting, diarrhoea and abdominal pain.

Respiratory, Mediastinal and Thoracic Disorders: Oral and pharyngeal hypoaesthesia, dry mouth and dry throat.

Nervous System Disorders: Dysgeusia (e.g., changed taste).

Immune System Disorders: Anaphylactic reactions including anaphylactic shock.

Skin and Subcutaneous Tissue Disorders: Angioedema, rash, urticaria, pruritus and other hypersensitivity.

Terbutaline Sulphate

Most of the adverse reactions are characteristic of sympathomimetic amines. The majority of these effects have reversed spontaneously within the first 1-2 weeks of treatment. The frequency of side-effects is low at the recommended doses.

The common adverse reactions to terbutaline are tremor, headache, tachycardia, palpitations, muscle spasms and hypokalaemia, nervousness, somnolence, dizziness, anxiety, insomnia, extra systoles ventricular, vasodilations, nausea, dry mouth, asthenia, sweating.

The following adverse effects each occurred in fewer than 1% of patients: hallucinations, rash, paraesthesia, hypertonia, (muscle cramps), vomiting.

There have been rare reports of elevation in liver enzymes and of hypersensitivity vasculitis.

Rare cases of arrhythmias e.g. atrial fibrillation, supraventricular tachycardia and extra systoles, myocardial ischaemia, peripheral vasodilation, hypersensitivity reactions including angioedema, bronchospasm, hypotension, collapse, nausea, mouth and throat irritation, sleep disorder, behavioural disturbances such as agitation and restlessness, paradoxical bronchospasm, urticaria and rash.

Guaiphenesin

Side effects resulting from Guaiphenesin administration are very rare. Guaiphenesin has occasionally been reported to cause gastro-intestinal discomfort, nausea and vomiting, gastrointestinal discomfort particularly in very high doses. Also, hypersensitivity reactions may occur. The frequency of these guaiphenesin-related adverse reactions is unknown but based on estimate from post-marketing data are likely to be rare: Allergic reactions, angioedema, anaphylactic reactions, dyspnoea (reported in association with other symptoms of hypersensitivity), nausea, vomiting, abdominal discomfort, rash, urticaria.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to: medico@zuventus.com

Website : http://www.zuventus.co.in/safety.aspx

By reporting side effects, you can help provide more information on the safety of this medicine.

4.9 Overdose

Terbutaline

Possible Symptoms and Signs: Headache, anxiety, tremor, nausea, tonic cramp, palpitations, tachycardia, arrhythmia. A fall in blood pressure sometimes occurs.

Laboratory findings like hypokalaemia, hyperglycaemia and lactic acidosis sometimes occur.

Treatment

Mild and moderate cases: Reduce the dose.

Severe cases: Gastric lavage, administration of activated charcoal. Determination of acid-base balance, blood sugar and electrolytes, particularly serum potassium levels. Monitoring of the heart rate and rhythm and blood pressure. Metabolic changes should be corrected.

A cardioselective beta-blocker (e.g. metoprolol) is recommended for the treatment of arrhythmias causing haemodynamic deterioration. The beta-blocker should be used with care because of the possibility of inducing bronchoconstriction: use with caution in patients with a history of bronchospasm. If the beta 2-mediated reduction in the peripheral vascular resistance significantly contributes to the fall in blood pressure, a volume expander should be given.

Preterm labour: Pulmonary oedema: discontinue administration. A normal dose of loop diuretic (e.g. Furosemide) should be given intravenously.

Increased bleeding in connection with Caesarian section: propranolol, 1-2mg intravenously.

Ambroxol

Acute potential health effects include skin irritation, eye irritation, respiratory tract irritation, gastrointestinal tract irritation with decreased motility or constipation, ulceration or bleeding from the stomach or duodenum, peritonitis. It may even affect behavior/central nervous system (tremor, convulsions, ataxia, and somnolence), respiration (dyspnea, respiratory stimulation), liver, blood (changes if white blood cell count), and urinary system. No data available on chronic potential health effects.

Guaiphenesin

The effects of acute toxicity from Guaiphenesin may include gastrointestinal discomfort, nausea and drowsiness. The drug is, however, rapidly metabolised and excreted in the urine. Patients should be kept under observation and treated symptomatically. Overdosage may also give rise to nausea and vomiting. Treatment need only be symptomatic and supportive.

5.1 Pharmacodynamic properties

Terbutaline

Terbutaline is a selective beta 2 - adrenergic causing bronchodilation; increase in mucociliary clearance; suppression of oedema and anti-allergic effects.

The pharmacologic effects of beta-adrenergic agonist drugs, including terbutaline, are at least in part, attributable to stimulation through beta-adrenergic receptors on intracellular adenyl cyclase, the enzyme that catalyses the conversion of adenosine triphosphate (ATP) to cyclic-3′,5′-adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels are associated with relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.

Ambroxol

Ambroxol (group of benzilamides) belongs to secretolitical and secretomotoric medicinal products. It possesses expressed expectorant effect. Mechanism of action of the medicinal product is stipulated by stimulation of serous cells of tonsils of bronchial tubes' mucous membrane, increasing of mucous secretion content and changing of correlation of serous and mucous components of phlegm, breached under pathological processes in lungs. Under this hydrolyzing ferments activate and releasing of lizosoms from Clark's cells strengthens, that causes decreasing of viscosity of phlegm. Ambroxol increases content of surfactant in lungs, which is dealt with strengthening of synthesis of the last and secretion in alveolar pneumocytes, and also with breach of its disintegration. The medicinal product increases mucociliar transport of phlegm. It suppresses coughing insignificantly. Ambroxol well penetrates through the placenta barrier, improving synthesis of surfactants during uterine life of foetus, and also it has an ability to warn syndrome of insufficient breathing in newborn. The medicinal product does not cause immense creating of secretion, reduces spastic hyperactivity of bronchial tubes- one of the main factors of developing of bronchial asthma under allergy. Ambroxol is more effective, than its predecessor - Bromhexine; it is non-toxic one and well endured by patients. Action of retard form of Ambroxol is kept in 9-10 hours after administration inside.

Guaiphenesin

Guaiphenesin is thought to exert its pharmacological action by stimulating receptors in the gastric mucosa. This increases the output from secretory glands of the gastrointestinal system and reflexly increases the flow of fluids from glands lining the respiratory tract. The result is an increase in volume and decrease in viscosity of bronchial secretions. Other actions may include stimulating vagal nerve endings in bronchial secretory glands and stimulating certain centres in the brain, which in turn enhance respiratory fluid flow. Guaiphenesin produces its expectorant action within 24 hours.

5.2 Pharmacokinetic properties

Terbutaline

Basic parameters have been evaluated in man after oral administration of therapeutic doses, e.g.

Renal clearance (CLR): 1.925/ml/min (males)

Renal clearance (CLR): 2.32ml/min (females)

Terminal half-life T½ has been determined after single and multiple dosing (mean values varied between 16-20 h)

Bioavailability: Food reduces bioavailability following oral dosing (10% on average). Fasting values of 14-15% have been obtained.

Metabolism: The main metabolite after oral dosing is the sulphate conjugate and also some glucoronide conjugate can be found in the urine.

Ambroxol

Absorption: Ambroxol is rapidly absorbed (70 - 80%) after oral administration. The time to reach peak plasma concentration is approximately 2 hours.

Distribution: The distribution half-life of ambroxol is around 1.3 hours.

Metabolism: Metabolite is dibromoanthranilic acid (activity unspecified).

Excretion: Excretion is primarily via the kidneys. Renal clearance (rate) is approximately 53 ml/minute; approximately 5-6% of a dose is excreted unchanged in the urine. The elimination half-life of ambroxol is biphasic, with an alpha half-life of 1.3 hours and a beta half-life of 8.8 hours.

Guaiphenesin

Absorption: Guaiphenesin is well absorbed from the gastro-intestinal tract following oral administration, although limited information regarding its pharmacokinetics is available. After the administration of 600 mg Guaiphenesin to healthy adult volunteers, the C max was approximately 1.4ug/ml, with t max occurring approximately 15 minutes after drug administration.

Distribution: No information is available on the distribution of Guaiphenesin in humans.

Metabolism and elimination: Guaiphenesin appears to undergo both oxidation and demethylation. Following an oral dose of 600 mg Guaiphenesin to 3 healthy male volunteers, the t½ was approximately 1 hour and the drug was not detectable in the blood after approximately 8 hours.

Pharmacokinetics in Renal/Hepatic Impairment: There have been no specific studies of Guaiphenesin in subjects with renal or hepatic impairment. Caution is therefore recommended when administering this product to subjects with severe renal or hepatic impairment.

Not Applicable

Soventus Jr. Syrup is a combination of Terbutaline sulphate, Ambroxol hydrochloride and Guaiphenesin.

Terbutaline sulphate is a beta-adrenergic agonist bronchodilator available as syrup for oral administration. Terbutaline sulphate is ±-alpha-[(tert-butylamino) methyl]-3,5-dihydroxybenzyl alcohol sulphate (2:1) (salt).

The empirical formula is (C12H19NO3)2H2SO4 and the structural formula is

Guaiphenesin, a member of methoxybenzenes is an expectorant. The physiologic effect of guaifenesin is by means of decreased respiratory secretion viscosity, and increased respiratory secretions.

Chemical Name: 3-(2-methoxyphenoxy)propane-1,2-diol

Molecular formula: C₁₀H₁₄O₄

Molecular Weight: 198.22 g/mol

Ambroxol hydrochloride is an aromatic amine. A metabolite of Bromhexine that stimulates mucociliary action and clears the air passages in the respiratory tract. It is usually administered as the hydrochloride.

Chemical Name: 4-[(2-amino-3,5-dibromophenyl)methylamino]cyclohexan-1-ol;hydrochloride

Molecular Formula: C₁₃H₁₉Br₂ClN₂O

Molecular Weight: 414.56 g/mol

8.1 List of excipients

Menthol, Disodium Edetate, Sodium Benzoate, Sucralose, Glycerol,Propylene Glycol, Liquid Sorbitol (Non Crystallising), Hydroxyethyl Cellulose , Potassium Sorbate, Colour Tartrazine Supra Soluble , Flavour Honey, Flavour Lemon Lime AF- 2422, Flavour Mixed Fruit AF-2270 ,, Sodium Citrate, Citric Acid Monohydrate.

8.2 Incompatibilities

Not Applicable

8.3 Shelf life

24 months

8.4 Nature and contents of container

Soventus Junior: PET Bottle 1x60ml

8.5 Special precautions for storage and handling

Protect from light. Store below 250C. Keep out of reach of children. No special requirements for disposal. Any unused medicinal product or waste material should be disposed of in accordance with local requirements. Shake Well Before Use.

Do not take with any other cough or cold medicines.

Avoid contact with eye, skin and serious ingestion or inhalation of the Syrup.

Avoid taking the it if you have severe renal or severe hepatic impairment.

Do not take it if you are pregnant or breast-feeding without consulting doctor.

Stop taking Soventus Jr syrup and inform your doctor if your cough persists for more than 1 week, tends to recur, or is accompanied by a fever, rash or persistent headache.

In some patients it may cause common side effects like nausea, vomiting, diarrhea, stomach pain, allergic reaction, dizziness, headache, rash, urticaria, tremor, palpitations, muscle cramp and increased heart rate. Inform your doctor if you experience any persistent problem while taking this medicine.

If you miss a dose of Soventus Jr syrup, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular schedule. Do not double the dose.