Posthma

Uses

Bromhexineis used for the treatment of respiratory disorders associated with productive cough. These include; tracheobronchitis, bronchitis with emphysema, bronchiectasis, bronchitis with bronchospasm, chronic inflammatory pulmonary conditions and pneumoconiosis.

Salbutamol Respirator Solution is used for the treatment of severe acute asthma (status asthmaticus) and also forms of bronchospasm.

Salbutamol tablet/injection is used for a bronchodilator for use in Asthma, Chronic Bronchitis, Emphysema and other conditions associated with airways obstruction.

Salbutamol inhaler is used for the treatment and prophylaxis of bronchial asthma and for the treatment of reversible airways obstruction associated with bronchitis and emphysema.

Salbutamol inhaler may be used to relieve attacks of acute dyspnoea and may also be taken prophylactically before exertion or to prevent exercise-induced asthma.

Salbutamol inhaler is suitable for treating bronchospasm in patients with coexisting heart disease or hypertension, including those taking beta blockers, because of its selective action on the bronchial receptors and lack of effects on the cardiovascular system. At therapeutic levels, it has little effect on cardiac receptors.

This is used for the symptomatic treatment of reversible bronchoconstriction associated with bronchial asthma, chronic obstructive pulmonary emphysema, chronic bronchitis and related bronchospastic disorders.

Posthma is also used to associated treatment for these conditions: Bronchiectasis, Common Cold, Cough, Cough caused by Common Cold, Nasal Congestion, Whooping Cough, Airway secretion clearance therapyAsthma, Asthmatic Bronchitis, Bronchial Asthma, Bronchospasm, Chronic Asthma, Chronic Bronchitis, Cough, Emphysema, Exercise-Induced Bronchospasm, Hyperkalemia, Wheezing, Excess mucus or phlegm, Airway secretion clearance therapy, BronchodilationAsthma, Bronchitis, Bronchoconstriction, Bronchospasm, Chronic Obstructive Pulmonary Disease (COPD), Chronic bronchial inflammation, Airway secretion clearance therapy, Bronchodilation

How Posthma works

Inflammation of the airways, increased mucus secretion, and altered mucociliary clearance are the hallmarks of various diseases of the respiratory tract. Mucus clearance is necessary for lung health; bromhexine aids in mucus clearance by reducing the viscosity of mucus and activating the ciliary epithelium, allowing secretions to be expelled from the respiratory tract.

Recent have studies have demonstrated that bromhexine inhibits the transmembrane serine protease 2 receptor (TMPRSS2) in humans. Activation of TMPRSS2 plays an important role in viral respiratory diseases such as influenza A and Middle East Respiratory Syndrome (MERS). Inhibition of receptor activation and viral entry by bromhexine may be effective in preventing or treating various respiratory illnesses, including COVID-19. In vitro studies have suggested the action of ambroxol (a metabolite of bromhexine) on the angiogensin-converting enzyme receptor 2 (ACE2), prevents entry of the viral envelope-anchored spike glycoprotein of SARS-Cov-2 into alveolar cells or increases the secretion of surfactant, preventing viral entry.

In vitro studies and in vivo pharmacologic studies have shown that salbutamol has a preferential effect on beta2-adrenergic receptors compared with isoproterenol. Although beta2­ adrenoceptors are the predominant adrenergic receptors in bronchial smooth muscle and beta1 adrenoceptors are the predominant receptors in the heart, there are also beta2-adrenoceptors in the human heart comprising 10% to 50% of the total beta-adrenoceptors. The precise function of these receptors has not been established, but their presence raises the possibility that even selective beta2-agonists may have cardiac effects.

Activation of beta2-adrenergic receptors on airway smooth muscle leads to the activation of adenyl cyclase and to an increase in the intracellular concentration of cyclic-3′,5′-adenosine monophosphate (cyclic AMP). This increase of cyclic AMP leads to the activation of protein kinase A, which inhibits the phosphorylation of myosin and lowers intracellular ionic calcium concentrations, resulting in relaxation. Salbutamol relaxes the smooth muscles of all airways, from the trachea to the terminal bronchioles. Salbutamol acts as a functional antagonist to relax the airway irrespective of the spasmogen involved, thus protecting against all bronchoconstrictor challenges. Increased cyclic AMP concentrations are also associated with the inhibition of release of mediators from mast cells in the airway.

Salbutamol has been shown in most controlled clinical trials to have more effect on the respiratory tract, in the form of bronchial smooth muscle relaxation, than isoproterenol at comparable doses while producing fewer cardiovascular effects. Controlled clinical studies and other clinical experience have shown that inhaled albuterol, like other beta-adrenergic agonist drugs, can produce a significant cardiovascular effect in some patients, as measured by pulse rate, blood pressure, symptoms, and/or electrocardiographic changes.

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

Theophylline relaxes the smooth muscle of the bronchial airways and pulmonary blood vessels and reduces airway responsiveness to histamine, methacholine, adenosine, and allergen. Theophylline competitively inhibits type III and type IV phosphodiesterase (PDE), the enzyme responsible for breaking down cyclic AMP in smooth muscle cells, possibly resulting in bronchodilation. Theophylline also binds to the adenosine A2B receptor and blocks adenosine mediated bronchoconstriction. In inflammatory states, theophylline activates histone deacetylase to prevent transcription of inflammatory genes that require the acetylation of histones for transcription to begin.

Dosage

Posthma dosage

BromhexineTablet:

Adults and children over 10 years: 8-16 mg 3 times daily. Children 5-10 years: 4 mg 3 times daily.

BromhexineSyrup:

Adults: The recommended daily dose is 2 to 4 teaspoonful 3 times. Initially 4 teaspoonful 3 times daily and then as required.

Children: Suggested dosage for children under 2 years is 1/4 teaspoonful 3 times daily, for 2-5 years 1/2 teaspoonful 3 times daily and for children aged 5-10 years 1 teaspoonful 3 times daily.

Salbutamol Oral-

Children:

• 2-6 years: 2.5 ml syrup, 3-4 times daily
• 6-12 years: 5 ml syrup, 3-4 times daily
• Over 12 years: 5-10 ml syrup, 3-4 times daily (2-4 mg tablet, 3-4 times daily)

Adults: 2-4 mg tablet, 3-4 times daily. Maximum single dose is 8 mg tablet.

Injection-

salbutamol Injection may be administered by the subcutaneous, intramuscular or intravenous route, under the direction of a physician.

Adults:

• Subcutaneous route:500 mcg (8 mcg/kg) and repeated every four hours as required.
• Intramuscular route:500 mcg (8 mcg/kg) and repeated every four hours as required.

Slow intravenous injection: 250 mcg (4 mcg/kg) injected slowly. If necessary the dose may be repeated. The use of salbutamol Injection 500 mcg in 1 ml (500 mcg/ml, for intravenenous administration may be facilitated by dilution to 10 ml with Water for Injection BP (final concentration of 50 mcg/ml) and 5 ml of the diluted preparation (250 mcg/5 ml) administered by slow intravenous injection.

PediatricPopulation:The safety and efficacy of salbutamol Injection in children under the age of 12 has not been established. From the available data no recommendation on posology can be made.

Children aged 12 years and over: Dose as per adult population

Salbutamol inhaler is administered by the inhaled route only. Shake SalbutamolInhaler well before each spray. As there may be adverse effects associated with excessive dosing, the dosage or frequency of administration should only be increased on medical advice.

Adults:

• For the relief of acute bronchospasm and for managing intermittent episodes of asthma: One or two puffs as a single dose
• For chronic maintenance or prophylactic therapy: Two puffs three or four times daily
• For prevention of exercise induced bronchospasm: Two puffs before exertion
• For prevention of exercise induced bronchospasm: Two puffs should be taken at least 15 minutes before exertion

Children:

• For the relief of acute bronchospasm, management of episodic asthma and for prevention of exercise induced bronchospasm: One puff may be administered as a single dose. Only for the use of medical professionals
• For routine maintenance and prophylaxis: One puff three or four times daily, increasing if necessary to two puffs three or four times daily

Elderly: The dosage is the same as that for adults.

By Intermittent Administration:

Adult: salbutamol Respirator Solution 0.5-4.0 ml should be diluted to final volume of 2.0-4.0 ml with normal saline for injection. The resulting solution is inhaled from a suitably driven nebuliser until aerosol generation ceases. Using a correctly matched nebuliser and driving source this should take about 10 minutes.Salbutamol Respirator Solution may be used undiluted for intermittent administration. For this 2.0 ml of the solution is placed in the nebuliser and the patient allowed to inhale until bronchodilatation is achieved. This usually takes 3-5 minutes. Some adult patients may require higher doses of salbutamol upto 10 mg in which case nebulisation may continue until aerosol generation ceases.

Children under 12 years age: 0.5 ml of the solution diluted to 2-4 ml with normal saline. Some children may however require higher doses of upto 1 ml of the solution. Intermittent treatment may be repeated four times a day.

By Continuous Administration:

Salbutamol Respirator Solution is diluted with normal saline for injection, 1-2 ml solution made upto 100 ml with diluent. The diluted solution is administered as an aerosol by a suitably driven nebuliser. The usual rate of administration is 1 to 2 mg/hour. Delivery of the aerosol may be by face mask or via an endotracheal tube. Intermittent positive pressure may be used but is rarely necessary. When there is risk of anoxia through hypoventilation, oxygen should be added to the inspired air.

Dosages are adjusted to maintain serum theophylline concentrations that provide optimal relief of symptoms with minimal side effects. Most of the controlled release preparations may be administered every 12 hours in adults while administration every 8 hours may be necessary in some children with markedly rapid hepatic metabolism of theophylline. The recommended dosages for achieving serum theophylline concentrations within the accepted therapeutic range is as follow:

• 1-6 months: 10mg/Kg/day
• 6 months-1 year: 15mg/Kg/day
• 1-9 years: 24mg/Kg/day
• 10-16 years: 18mg/Kg/day
• Adults: 10-15mg/Kg/day

Side Effects

Gastrointestinal side-effects may occur occasionally with Bromhexine and a transient rise in serum aminotransferase values has been reported. Other reported adverse effects include headache, dizziness, sweating and skin rash.

Salbutamol may cause fine tremor of skeletal muscles (particularly the hands), palpitations and muscle cramps. Tachycardia, tenseness, headaches and peripheral vasodilatation have been reported after large doses.

Mild tremor and headache have been rarely reported. These usually disappear with continuous treatment. There have been very rare reports of transient muscle cramp. Hypersensitivity reactions including angioedema, urticaria, bronchospasm, hypotension and collapse have been reported very rarely. As with other inhalation therapy, the potential for paradoxical bronchospasm should be kept in mind. If it occurs, the preparation should be discontinued immediately and alternative therapy should be instituted.

The following side effects have been observed:

Gastrointestinal: Nausea, vomiting, epigastric pain and diarrhoea.

Central nervous system: Headache, irritability, restlessness, insomnia, muscles twitching.

Cardiovascular: Palpitation, tachycardia, hypotension. circulatory failure.

Respiratory: Tachypnoea.Renal: Potentiation of diuresis.

Others: Alopecia, hyperglycemia, rash etc.

Toxicity

The oral LD50 of bromhexine in rats is 6 g/kg. The observed symptoms of accidental overdose with bromhexine are consistent with the known adverse effects of bromhexine, including headache, nausea, and vomiting, among other symptoms. Provide symptomatic treatment and contact poison control services if an overdose is confirmed or suspected.

The expected signs and symptoms with overdosage of albuterol are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeration of any of the signs and symptoms of beta-adrenergic stimulation (e.g., seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, muscle cramps, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, insomnia, hyperglycemia, hypokalemia, metabolic acidosis). In particular, the signs of salbutamol overdosage are significant tachycardia and/or significant muscle tremor.

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

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

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

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

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

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

Clinical trials of VENTOLIN HFA did not include sufficient numbers of subjects aged 65 years and older to determine whether older subjects respond differently than younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

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

Symptoms of overdose include seizures, arrhythmias, and GI effects.

Precaution

Since mucolytics may disrupt the gastric mucosa so Bromhexine should be used with care in patients with a history of peptic ulceration.

Salbutamol should be used with caution in patients with hyperthyroidism, cardiovascular disease, occlusive vascular disorders, hypertension and aneurysms. Hypokalaemia associated with high doses of Salbutamol may result in increased susceptibility to digitalis-induced cardiac arrhythmia. Tachyphylaxis with resistance may occur with prolonged use of high dosage. Care is necessary when treating patients with diabetes mellitus or closed-angle glaucoma, and in those receiving antihypertensive therapy.

Salbutamol should be administered cautiously to patients suffering from thyrotoxicosis. In the event of previously effective dose of salbuatmol inhaler failing to give relief for at least three hours, the patient should be advised to seek medical advice in order that any necessary additional steps may be taken.

The management of asthma should normally a stepwise programme, and patient response should be monitored clinically and by lung function test. Increasing use of short acting inhaled agonists to control symptoms indicates deterioration of asthma control. Under these conditions, the patient’s therapy plan should be reassessed. Sudden and progressive deterioration in asthma control is potentially life threatening and consideration should be given to starting or increasing corticosteroid therapy. In patients considered at risk, daily peak flow monitoring may be instituted. Patients inhaler techinique should be checked to make sure that aerosl actuation is synchronized with inspiration of breath for optimum delivery of the drugs to the lungs.

Careful consideration is needed for various interacting drugs and physiologic conditions that can alter Theophylline clearance. Dosage adjustment is required prior to initiation of Theophylline therapy, prior to increases in Theophylline dose, and during follow up. The dose of Theophylline selected for initiation of therapy should be low and, if tolerated, increased slowly over a period of time.

Interaction

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

Allopurinol, cimetidine, norfloxacin, ciprofloxacin, erythromycin, oral contraceptives and propranolol increase serum theophylline levels. Phenytoin, methotrexate and rifampicin lead to decreased serum theophylline levels

Volume of Distribution

After intravenous administration in a pharmacokinetic study, bromhexine was found to be widely distributed. Bromhexine is known to cross the blood-brain barrier; small concentrations may cross the placenta. The average volume of distribution of bromhexine was 1209 ± 206 L (19 L/kg). Lung tissue concentrations of bromhexine two hours after a dose were 1.5 to 3.2 times higher in bronchial tissues than plasma concentrations. Pulmonary parynchema concentrations were 3.4 to 5.9 times higher when compared to plasma concentrations.

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

• 0.3 to 0.7 L/kg

Elimination Route

After oral administration, bromhexine demonstrates linear pharmacokinetics when given in doses of 8-32 mg. Bromhexine is readily absorbed in the gastrointestinal tract at a rapid rate. This drug undergoes extensive first-pass effect in the range of 75-80%. The bioavailability is therefore reduced to approximately 22-27%.

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

In particular, the systemic levels of salbutamol are low after inhalation of recommended doses. A trial conducted in 12 healthy male and female subjects using a higher dose (1,080 mcg of albuterol base) showed that mean peak plasma concentrations of approximately 3 ng/mL occurred after dosing when salbutamol was delivered using propellant HFA-134a. The mean time to peak concentrations (Tmax) was delayed after administration of VENTOLIN (salbutamol) HFA (Tmax = 0.42 hours) as compared with CFC-propelled salbutamol inhaler (Tmax = 0.17 hours).

Theophylline is rapidly and completely absorbed after oral administration in solution or immediate-release solid oral dosage form.

Half Life

Following single oral doses ranging from 8 and 32 mg, the terminal half-life of bromhexine has been measured between 6.6 and 31.4 hours.

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

8 hours

Clearance

The clearance of bromhexine ranges from 843-1073 mL/min, within the range of the hepatic circulation.

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

• 0.29 mL/kg/min [Premature neonates, postnatal age 3-15 days]
• 0.64 mL/kg/min [Premature neonates, postnatal age 25-57 days]
• 1.7 mL/kg/min [Children 1-4 years]
• 1.6 mL/kg/min [Children 4-12 years]
• 0.9 mL/kg/min [Children 13-15 years]
• 1.4 mL/kg/min [Children 16-17 years]
• 0.65 mL/kg/min [Adults (16-60 years), otherwise healthy non-smoking asthmatics]
• 0.41 mL/kg/min [Elderly (>60 years), non-smokers with normal cardiac, liver, and renal function]
• 0.33 mL/kg/min [Acute pulmonary edema]
• 0.54 mL/kg/min [COPD >60 years, stable, non-smoker >1 year]
• 0.48 mL/kg/min [COPD with cor pulmonale]
• 1.25 mL/kg/min [Cystic fibrosis (14-28 years)]
• 0.31 mL/kg/min [Liver disease cirrhosis]
• 0.35 mL/kg/min [acute hepatitis]
• 0.65 mL/kg/min [cholestasis]
• 0.47 mL/kg/min [Sepsis with multi-organ failure]
• 0.38 mL/kg/min [hypothyroid]
• 0.8 mL/kg/min [hyperthyroid]

Elimination Route

After a dose of bromhexine was administered during a pharmacokinetic study, approximately 97% of the radiolabeled dose was detected in the urine; under 1% was detected as the parent drug.

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

Theophylline does not undergo any appreciable pre-systemic elimination, distributes freely into fat-free tissues and is extensively metabolized in the liver. Renal excretion of unchanged theophylline in neonates amounts to about 50% of the dose, compared to about 10% in children older than three months and in adults.

Pregnancy & Breastfeeding use

Pregnancy Category B. Bromhexine has been taken by a large number of pregnant women and women of child bearing age without any proven increase in the frequency of malformations or other direct or indirect harmful effects on the fetus having been observed.

It is not known whether bromhexine is excreted in breast milk or whether it has a harmful effect on the breastfeeding infant. Therefore it is not recommended for breast feeding mothers unless the potential benefits to the patient are weighed against the possible risk to the infant.

Salbutamol is known to cross the placental barrier in humans. Safety for use in pregnancy has not been demonstrated, therefore the drug should not be used in pregnant women, or those likely to become pregnant, unless the expected benefit outweighs any potential risk. Oral administration of salbutamol to rats and rabbits during pregnancy showed no teratogenic effects in offspring, but evidence of retardation of fetal development was recorded in an inhalational teratology study in rabbits at an estimated dose of 149 μg/kg/day. Although intravenous salbutamol and occasionally salbutamol tablets are used in the management of uncomplicated premature labour, Salbutamol presentations should not be used for threatened abortion during the first or second trimesters of pregnancy.

Intravenous salbutamol is contra-indicated in cases of ante-partum haemorrhage because of the risk of further haemorrhage from an atonic uterus and there is the risk of the same problem arising inadvertently in asthmatics using salbutamol. Profuse uterine bleeding following spontaneous abortion has been reported after the use of salbutamol. Special care is required in pregnant diabetic women. As salbutamol is probably secreted in breast milk, its use in nursing mothers is not recommended unless the expected benefit to the mother is greater than any possible risk to the infant.

Pregnancy: It is not known whether Theophylline can cause foetal harm when administered to pregnant woman.Xanthines should be given to a pregnant woman only if clearly needed.

Nursing mother: Theophylline is excreted into breast milk and may cause irritability or other signs of mild toxicity in nursing human infants. Serious adverse effects in the infant are unlikely unless the mother has toxic serum Theophylline concentrations.

Contraindication

Contraindicated to those who are hypersensitive to Bromhexine Hydrochloride.

History of hypersensitivity to any of its components. Salbutamol presentation should not be used for threatened abortion during the first or second trimester of pregnancy. It should be used with care in patients known to have received large doses of other sympathomimetic drugs.

Salbutamol tablet/injection is contraindicated in patients with a history of hypersensitivity to Salbutamol or any of its components.

Salbuatmol inhaler is contraindicated in patients with a history of hypersensitivity to any of its components. Although intravenous salbutamol, and occasionally salbutamol tablets, is used in the management of premature labour uncomplicated by conditions such as placenta praevia, ante-partum haemorrhage or toxaemia of pregnancy, salbutamol inhaler preparations are not appropriate for managing premature labour. Salbutamol preparation should not be used for threatened abortion during the first or second trimesters of pregnancy.

Hypersensitivity to xanthine derivatives. It is also contraindicated in patients with active peptic ulcer disease and in individuals with underlying seizure disorders (unless receiving appropriate anti-convulsing medication).

Theophylline should not be administered concurrently with other xanthine. Use with caution in patients with hypoxemia, hypertension, or those with history of peptic ulcer. Do not attempt to maintain any dose that is not tolerated.

Acute Overdose

The symptoms with overdosage are angina, headache, nausea, vomiting, tremor etc. The preferred antidote for overdosage with Salbutamol is a cardio-selective beta-blocking agent but beta-blocking drugs should be used with caution in patients with a history of bronchospasm.

Symptoms may include nausea, vomiting, gastrointestinal irritation, cramps, convulsions, tachycardia & hypotension. The stomach contents should be emptied & supportive measures employed to maintain circulation, respiration & fluid & electrolyte balance. Electrocardiographic monitoring should be carried out & in severe poisoning charcoal haemoperfusion should be used.

Storage Condition

Store below 25° C. Protect from light. Keep the container tightly closed.

Store at a cool & dry place, protected from light. Once a bottle has been opened the contents should be discarded after one month.

Store in a cool and dry place, protect from light and moisture. Keep out of the reach of children

Innovators Monograph

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