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Ipratropium inhaler is indicated for-

• As bronchodilator in treatment of chronic reversible airway obstruction as in asthma and Chronic Obstructive Pulmonary Disease (COPD) including chronic bronchitis and emphysema.
• Treatment of acute reversible airways obstruction.

Anticholinergic bronchodilators

Ipratropium bromide causes bronchodilation by blocking the action of acetylcholine at parasympathetic site in bronchial smooth muscle. It also inhibits serous and seromucous gland secretions by nasal application.

Adults: The usual dose is 1-2 puffs (20 µg/puff) three or four times daily. Single-dose up to 80 µg (4 puffs) may be required to obtain maximum benefit during early treatment. Patients may take additional inhalations as required: however, the total number of inhalations should not exceed 12 puffs in 24 hours.

Children:

• 6-12 years: Usually 1-2 puffs two to three times daily.
• Bellow 6 years: The usual dose is 1 puff (20 µg) three times daily.

In order to ensure that the inhaler is used correctly, the administration should be supervised by an adult.

No specific information on the use of the product in the elderly is available. Clinical trials have included patients over 65 years and no adverse reactions specific to this age group have been reported.

Using an Inhaler seems simple, but most patients do not know how to use it in the right way. If the Inhaler is used in the wrong way, less medicine can reach the lungs. Correct and regular use of the Inhaler will prevent or lessen the severity of asthma attacks.

Following simple steps can help to use Inhaler effectively (According to "National Asthma Guidelines for Medical Practitioners" published by Asthma Association):

• Take off the cap.
• Shake the inhaler (at least six times) vigorously before each use.
• If the inhaler is new or if it has not been used for a week or more, shake it well and release one puff into the air to make sure that it works.
• Breathe out as full as comfortably possible & hold the inhaler upright.
• Place the actuator into mouth between the teeth and close lips around the mouthpiece.
• While breathing deeply and slowly through the mouth, press down firmly add fully on the canister to release medicine.
• Remove the inhaler from mouth. Continue holding breath for at least for 10 seconds or as long as it is comfortable.
• If doctor has prescribed more than one inhalation per treatment, wait 1 minute between puffs (inhalations). Shake the inhaler well and repeat steps 4 to 7.
• After use, replace the cap on the mouthpiece. After each treatment, rinse mouth with water.
• Check your technique in front of a mirror from time to time, if you see a white mist during the inhalation, you may not have closed your lips properly around mouthpiece, or you may not be breathing in as you press the can. This indicates failure of technique. If this happens, repeat the procedure from step 4 carefully.

Instructions for Cleaning Inhaler: Clean your Inhaler at least once a week. Remove canister and rinse the plastic actuator and cap in warm water but do not put the metal canister into water. Dry the actuator and cap thoroughly and gently replace the metal canister into the actuator with a twisting motion. Put the cap on the mouthpiece.

Idiosyncratic reactions to lpratropium bromide are rare. Severe adverse effects due to inhibition of muscarinic receptors and ganglion blockade are theoretically possible but unlikely with the metered-dose aerosol. Regular use of ipratropium can lead to a dry mouth through inhibition of salivary flow.

Other most common adverse reactions reported are - dryness of the oropharynx (5%); cough, exacerbation of symptoms, & imitation from aerosol (3%); headache (2%); nausea, dizziness, blurred vision/difficulty in accommodation & drying of secretions (1%).

Less frequently reported adverse reactions include tachycardia, nervousness, paresthesias, drowsiness, co-ordination difficulty, itching, flushing, alopecia, constipation, tremor & mucosal ulceration. Case of precipitation or worsening of narrow-angle glaucoma, acute eye pain & hypotension also have been reported. Allergic-type reactions such as skin rash, angio-oedema of tongue, lips & face, urticaria (including giant urticaria), laryngospasm and anaphylactic reaction have been also reported; with positive rechallenge in some cases.

Ipratropium bromide dose not produce adverse effects on mucociliary clearance, in contrast to atropine and other muscarinic antagonists. There is no evidence that in the therapeutic does range ipratropium bromide has any adverse effect on bronchial secretion.

Known hypersensitivity to ipratropium bromide, Atropine or its derivative. Also contraindicated in patients with a history of hypersensitivity to soya lecithin or related food products such as soyabean, lecithin and peanut.

Patients should be advised that temporary blurring of vision, precipitation or worsening of narrow angle glaucoma or eye pain may result if the aerosol is sprayed into the eyes. If recommended dosage does not provide relief or symptoms become worse, patients should seek immediate medical attention. While taking ipratropium bromide inhalation aerosol, other inhaled drugs should not be used unless prescribed.

lpratropium bromide inhalation aerosol is not indicated for the initial treatment of acute episodes of bronchospasm where rapid response is required. Drugs with faster onset may be preferable as initial therapy in this situation. Immediate hypersensitivity reactions may occur after administration of ipratropium bromide, as demonstrated by rare cases of urticaria, angio-oedema, rash, bronchospasm and oropharyngeal oedema.

Ipratropium bromide has been used concomitantly with other drugs, including sympathomimetic bronchodilators, methylxanthines, steroids and cromolyn sodium, commonly used in treatment of COPD, without any adverse drug reactions, there are no studies fully evaluating the interaction effects of lpratropium bromide and these drugs in respect to effectiveness.

The safety of Ipratropium Bromide during human pregnancy has not been established. The benefits of using Ipratropium Bromide during a confirmed or suspected pregnancy must be weighed against possible hazards to the unborn child. It is not known whether Ipratropium Bromide is excreted into breast milk.

Acute overdosage by inhalation is unlikely since ipratropium bromide is not well absorbed systematically after administration as aerosol. Inhaled dosage of 5 mg of ipratropium bromide produce an increase in heart rate and palpitation. Single doses of ipratropium bromide 30 mg by mouth caused anticholinergic side effects but which were not considered severe enough to require specific reversal.

The inhaler should be stored in a dry and cool place. Protected from direct sunlight and heat. Keep away from eyes. Keep out of reach of children. The canister should not be broken, punctured or burnt, even when apparently empty.

This inhalation aerosol is indicated for use in patients with chronic obstructive pulmonary disease (COPD) on a regular aerosol bronchodilator who continues to have evidence of bronchospasm and who requires a second bronchodilator.

Combined bronchodilators

This inhalation aerosol is a combination of Salbutamol (as Sulphate) and Ipratropium Bromide. It is a hydrofluoroalkane (HFA) based environment friendly inhaler. Because it does not contain chlorofluorocarbon (CFC) as propellant which is one of the main reasons of ozone layer depletion.

Salbutamol is a short acting beta2-adrenergic bronchodilator and Ipratropium Bromide is an anticholinergic bronchodilator. When used in combination, Ipratropium Bromide prevents the increase in intracellular concentration of cyclic guanosine monophosphate, which are caused by interaction of acetylcholine with the muscarinic receptor on bronchial smooth muscle. This inhalation aerosol is expected to maximize the response of the treatment in patients with chronic obstructive pulmonary disease (COPD) by reducing bronchospasm through two distinctly different mechanisms, anticholinergic (parasympatholytic) and sympathomimetic. Simultaneous administration of an anticholinergic (Ipratropium Bromide) and a beta 2-sympathomimetic (Salbutamol) is designed to benefit the patient by producing a greater bronchodilatory effect than when either drug is utilized alone at its recommended dosage.

Adult dose (Including the elderly): 2 puffs of Salpium 4 times a day (Patients may take additional puffs as required but a total number of puffs should not exceed 12 in 24 hours). Or as directed by the physician.

Using an Inhaler seems simple, but most patients do not know how to use it in the right way. If the Inhaler is used in the wrong way, less medicine can reach the lungs. Correct and regular use of the Inhaler will prevent or lessen the severity of asthma attacks.

Following simple steps can help to use Inhaler effectively (According to "National Asthma Guidelines for Medical Practitioners" published by Asthma Association):

1. Take off the cap.
2. Shake the inhaler (at least six times) vigorously before each use.
3. If the inhaler is new or if it has not been used for a week or more, shake it well and release one puff into the air to make sure that it works.
4. Breathe out as full as comfortably possible & hold the inhaler upright.
5. Place the actuator into mouth between the teeth and close lips around the mouthpiece.
6. While breathing deeply and slowly through the mouth, press down firmly add fully on the canister to release medicine.
7. Remove the inhaler from mouth. Continue holding breath for at least for 10 seconds or as long as it is comfortable.
8. If doctor has prescribed more than one inhalation per treatment, wait 1 minute between puffs (inhalations). Shake the inhaler well and repeat steps 4 to 7.
9. After use, replace the cap on the mouthpiece. After each treatment, rinse mouth with water.
10. Check your technique in front of a mirror from time to time, if you see a white mist during the inhalation, you may not have closed your lips properly around mouthpiece, or you may not be breathing in as you press the can. This indicates failure of technique. If this happens, repeat the procedure from step 4 carefully.

Instructions for Cleaning Inhaler: Clean your Inhaler at least once a week. Remove canister and rinse the plastic actuator and cap in warm water but do not put the metal canister into water. Dry the actuator and cap thoroughly and gently replace the metal canister into the actuator with a twisting motion. Put the cap on the mouthpiece.

Due to presence of Salbutamol, mild tremor and headache have been reported. These usually disappear with continuous treatment. There have been very rare reports of treatments muscle cramp, hypersensitivity reactions including angioedema, urticaria, bronchospasm and hypotension.

For the presence of Ipratropium Bromide headache, influenza, chest pain, nausea, dyspnea, coughing, pharyngitis, sinusitis are rarely reported.

This inhalation aerosol is contraindicated in patients with a history of hypersensitivity to Soya-Lecithin or related food products such as soybean and peanut. This inhalation aerosol is also contraindicated in patients hypersensitive to any other components of the drug product or to atropine or its derivatives.

This inhalation aerosol has been used concomitantly with other drugs, including sympathomimetic bronchodilators, methylxanthines and steroids, commonly used in the treatment of COPD. No formal drug interaction studies have been performed with this inhalation aerosol and these or other medications commonly used in the treatment of COPD. Ipratropium Bromide should be co-administered cautiously with other anticholinergic agents and sympathomimetic agents, which may increase the risk of adverse cardiovascular effects. Beta-2-agonist containing drugs, like this inhalation aerosol, should be administrated with extreme caution in patients with non-potassium sparing diuretics, monoamine oxidase inhibitors or tricyclic antidepressants.

Ipratropium Bromide: Pregnancy category B. Studies have demonstrated no teratogenic effects as a result of ipratropium.

Salbutamol: Pregnancy category C. Salbutamol has been shown to be teratogenic in animals.

There are, however no adequate and well-controlled studies of Salpium Inhalation Aerosol (Salbutamol and Ipratropium Bromide combination) in pregnant woman. This inhalation aerosol should be used during pregnancy only if the potential benefit justifies the potential risk of the fetus. It is not known whether the components of the Salpium InhalationAerosol are excreted in human milk. As many drugs are excreted in human milk, Salpium should be cautiously administered to a nursing mother.

This inhalation aerosol contains Ipratropium Bromide and, therefore, should be used with caution in patients with narrow-angle glaucoma, prostatic hypertrophy or bladder-neck obstruction. Preparations containing sympathomimetic amines such as Salbutamol Sulphate should be used with caution in patients with convulsive disorders, hyperthyroidism, diabetes mellitus and in patients who are unusually responsive to sympathomimetic amines.

The effects of overdosage are expected to be related primarily to Salbutamol Sulphate. Manifestations of overdosage with Salbutamol may include anginal pain, hypertension, hypokalemia and tachycardia.

Do not puncture, break or incinerate the pressurized canister even when apparently empty. Avoid storage in direct sunlight or heat. Store in a cool and dry place. Keep away from children. Keep away from eyes.

Salbutamol sulfate & Ipratropium bromide solution for inhalation is indicated for the treatment of reversible bronchospasm associated with obstructive airway diseases in patients who require more than a single bronchodilator.

Combined bronchodilators

Ipratropium Bromide is quickly absorbed after inhalation. The systemic bioavailability following inhalation is estimated to be less than 10% of the dose. Renal excretion of Ipratropium Bromide is given as 46% of the dose after intravenous administration. The half-life of the terminal elimination phase is about 1.6 hours as determined after intravenous administration. Elimination half-life of drug and metabolites is 3.6 hours as determined after radio labelling. Ipratropium Bromide does not penetrate the blood brain barrier.

Salbutamoi Sulphate is rapidly and completely absorbed following administration either by inhaled or oral route. Peak plasma Salbutamoi concentrations are seen within three hours of administration and it is excreted unchanged in the urine after 24 hours. The elimination half-life is 4 hours. Salbutamoi will cross the blood brain barrier reaching concentrations amounting to about five percent of the plasma concentrations.

It has been shown that co-nebulisation of Ipratropium Bromide and Salbutamoi Sulphate does not potentiate the systemic absorption of either component and that therefore the additive activity of this solution is due to the combined local effect on the lung following inhalation.

Salbutamol sulfate & Ipratropium bromide solution for inhalation in ampoule may be administered from a suitable nebulizer or an intermittent positive pressure ventilator.

• Adults (including elderly): Use one 3 ml ampoule in the nebulizer four times a day. Two additional treatments may be used per day, if needed.
• Children: Use and dose must be determined by doctor.

Patients should be advised to consult a doctor or the nearest hospital immediately in the case of acute or rapidly worsening dyspnoea if additional inhalations do not produce an adequate improvement.

Step 1: Twist off the top of the ampoule. Be careful to hold the ampoule upright.
Step 2: Squeeze the desired amount of the nebulizer solution into the nebulizer chamber.
Step 3: If dilution is needed follow the physician’s direction.

In common with other beta-agonists containing products, side effects of this solution can include fine tremor of skeletal muscles and nervousness and less frequently tachycardia, dizziness, palpitations or headache, especially in hypersensitive patients.

Potentially serious hypokalaemia may result from prolonged and/or high dose beta2 agonist therapy.

As with use of other inhalation therapy, cough, local irritation and less commonly inhalation induced bronchospasm can occur. As with other beta-mimetics, nausea, vomiting, sweating, weakness and myalgia/muscle cramps may occur. In rare cases decrease in diastolic blood pressure, increase in systolic blood pressure, arrhythmias, particularly after higher doses, may occur.

In individual cases psychological alterations have been reported under inhalation therapy with beta-mimetics.

The most frequent non-respiratory anticholinergic related adverse events are dryness of mouth and dysphonia. There have been isolated reports of ocular complications (i.e. mydriasis, increased intraocular pressure, angle closure glaucoma, and eye pain) when aerosolised ipratropium bromide either alone or in combination with adrenergic beta2 agonist, has escaped into the eyes. Ocular side effects, gastrointestinal motility disturbances and urinary retention may occur in rare cases and are reversible.

This is contraindicated in patients with hypertrophic obstructive tachyarrhythmia and in patients with a history of hypersensitivity to atropine or its derivatives, or to any other component of the product.

In the case of acute, rapidly worsening dyspnoea a doctor should be consulted immediately. Immediate hypersensitivity reactions may occur after administration of this solution as demonstrated by rare cases of urticaria, angioedema, rash, bronchospasm and oropharyngeal oedema.

The concurrent administration of other beta-mimetics, systemically absorbed anticholinergics and xanthine derivatives may increase the side effects.

Beta-agonist induced hypokalaemia may be increased by concomitant treatment with xanthine derivatives, glucocorticosteroids and diuretics. This should be taken into account particularly in patients with severe airway obstruction.

Hypokalaemia may result in an increased susceptibility to arrhythmias in patients receiving digoxin. It is recommended that serum potassium levels be monitored in such situations.

A potentially serious reduction in bronchodilator effect may occur during concurrent administration of beta-blockers.

Beta-adrenergic agonists should be administered with caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, since the action of beta adrenergic agonists may be enhanced.

Inhalation of halogenated hydrocarbon anaesthetics such as halothane, trichloroethylene and enflurane may increase the susceptibility to the cardiovascular effects of beta-agonists.

Pregnancy category C. Animal studies with Salbutamoi Sulphate have demonstrated a teratogenic effect. It is not known whether this medication is harmful to the fetus. No evidence of abnormalities has been reported in women receiving albuterol during pregnancy. This solution should be used during pregnancy only if the potential benefit justifies. This solution should be used with caution before childbirth in view of Salbutamol's inhibitory effects on uterine contractions.

Salbutamol Sulphate and Ipratropium Bromide are probably excreted in breast milk and their effects on neonates are not known. Although lipid-insoluble quaternary bases pass into breast milk, it is unlikely that this will happen to any extent especially when taken by inhalation. However, because many drugs are excreted in breast milk, caution should be exercised when This solution is administered to a nursing woman.

The effects of overdosage are expected to be primarily related to Salbutamol because acute overdosage with Ipratropium Bromide is unlikely as it is not well absorbed systemically after inhalation or oral administration.

Symptoms: Manifestations of overdosage with salbutamol may include tachycardia, anginal pain, hypertension, hypotension , palpitations, tremor, widening of the pulse pressure, arrhythmia and flushing.

Therapy: Administration of sedatives, tranquillisers; in severe cases, intensive therapy. Beta-receptor blockers, preferably beta1-selective, are suitable as specific antidotes; however, a possible increase in bronchial obstruction must be taken into account and the dose should be adjusted carefully in patients suffering from bronchial asthma.

Keep below 30°C temperature, away from light & moisture. Keep out of the reach of children.

Salbutamol sulfate & Ipratropium bromide solution for inhalation is indicated for the treatment of reversible bronchospasm associated with obstructive airway diseases in patients who require more than a single bronchodilator.

Combined bronchodilators

Ipratropium Bromide is quickly absorbed after inhalation. The systemic bioavailability following inhalation is estimated to be less than 10% of the dose. Renal excretion of Ipratropium Bromide is given as 46% of the dose after intravenous administration. The half-life of the terminal elimination phase is about 1.6 hours as determined after intravenous administration. Elimination half-life of drug and metabolites is 3.6 hours as determined after radio labelling. Ipratropium Bromide does not penetrate the blood brain barrier.

Salbutamoi Sulphate is rapidly and completely absorbed following administration either by inhaled or oral route. Peak plasma Salbutamoi concentrations are seen within three hours of administration and it is excreted unchanged in the urine after 24 hours. The elimination half-life is 4 hours. Salbutamoi will cross the blood brain barrier reaching concentrations amounting to about five percent of the plasma concentrations.

It has been shown that co-nebulisation of Ipratropium Bromide and Salbutamoi Sulphate does not potentiate the systemic absorption of either component and that therefore the additive activity of this solution is due to the combined local effect on the lung following inhalation.

Salbutamol sulfate & Ipratropium bromide solution for inhalation in ampoule may be administered from a suitable nebulizer or an intermittent positive pressure ventilator.

• Adults (including elderly): Use one 3 ml ampoule in the nebulizer four times a day. Two additional treatments may be used per day, if needed.
• Children: Use and dose must be determined by doctor.

Patients should be advised to consult a doctor or the nearest hospital immediately in the case of acute or rapidly worsening dyspnoea if additional inhalations do not produce an adequate improvement.

Step 1: Twist off the top of the ampoule. Be careful to hold the ampoule upright.
Step 2: Squeeze the desired amount of the nebulizer solution into the nebulizer chamber.
Step 3: If dilution is needed follow the physician’s direction.

In common with other beta-agonists containing products, side effects of this solution can include fine tremor of skeletal muscles and nervousness and less frequently tachycardia, dizziness, palpitations or headache, especially in hypersensitive patients.

Potentially serious hypokalaemia may result from prolonged and/or high dose beta2 agonist therapy.

As with use of other inhalation therapy, cough, local irritation and less commonly inhalation induced bronchospasm can occur. As with other beta-mimetics, nausea, vomiting, sweating, weakness and myalgia/muscle cramps may occur. In rare cases decrease in diastolic blood pressure, increase in systolic blood pressure, arrhythmias, particularly after higher doses, may occur.

In individual cases psychological alterations have been reported under inhalation therapy with beta-mimetics.

The most frequent non-respiratory anticholinergic related adverse events are dryness of mouth and dysphonia. There have been isolated reports of ocular complications (i.e. mydriasis, increased intraocular pressure, angle closure glaucoma, and eye pain) when aerosolised ipratropium bromide either alone or in combination with adrenergic beta2 agonist, has escaped into the eyes. Ocular side effects, gastrointestinal motility disturbances and urinary retention may occur in rare cases and are reversible.

This is contraindicated in patients with hypertrophic obstructive tachyarrhythmia and in patients with a history of hypersensitivity to atropine or its derivatives, or to any other component of the product.

In the case of acute, rapidly worsening dyspnoea a doctor should be consulted immediately. Immediate hypersensitivity reactions may occur after administration of this solution as demonstrated by rare cases of urticaria, angioedema, rash, bronchospasm and oropharyngeal oedema.

The concurrent administration of other beta-mimetics, systemically absorbed anticholinergics and xanthine derivatives may increase the side effects.

Beta-agonist induced hypokalaemia may be increased by concomitant treatment with xanthine derivatives, glucocorticosteroids and diuretics. This should be taken into account particularly in patients with severe airway obstruction.

Hypokalaemia may result in an increased susceptibility to arrhythmias in patients receiving digoxin. It is recommended that serum potassium levels be monitored in such situations.

A potentially serious reduction in bronchodilator effect may occur during concurrent administration of beta-blockers.

Beta-adrenergic agonists should be administered with caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, since the action of beta adrenergic agonists may be enhanced.

Inhalation of halogenated hydrocarbon anaesthetics such as halothane, trichloroethylene and enflurane may increase the susceptibility to the cardiovascular effects of beta-agonists.

Pregnancy category C. Animal studies with Salbutamoi Sulphate have demonstrated a teratogenic effect. It is not known whether this medication is harmful to the fetus. No evidence of abnormalities has been reported in women receiving albuterol during pregnancy. This solution should be used during pregnancy only if the potential benefit justifies. This solution should be used with caution before childbirth in view of Salbutamol's inhibitory effects on uterine contractions.

Salbutamol Sulphate and Ipratropium Bromide are probably excreted in breast milk and their effects on neonates are not known. Although lipid-insoluble quaternary bases pass into breast milk, it is unlikely that this will happen to any extent especially when taken by inhalation. However, because many drugs are excreted in breast milk, caution should be exercised when This solution is administered to a nursing woman.

The effects of overdosage are expected to be primarily related to Salbutamol because acute overdosage with Ipratropium Bromide is unlikely as it is not well absorbed systemically after inhalation or oral administration.

Symptoms: Manifestations of overdosage with salbutamol may include tachycardia, anginal pain, hypertension, hypotension , palpitations, tremor, widening of the pulse pressure, arrhythmia and flushing.

Therapy: Administration of sedatives, tranquillisers; in severe cases, intensive therapy. Beta-receptor blockers, preferably beta1-selective, are suitable as specific antidotes; however, a possible increase in bronchial obstruction must be taken into account and the dose should be adjusted carefully in patients suffering from bronchial asthma.

Keep below 30°C temperature, away from light & moisture. Keep out of the reach of children.

Ipratropium Nebuliser Solution is indicated as a bronchodilator for maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease, including chronic bronchitis and emphysema.

Anticholinergic bronchodilators

Ipratropium Bromide is a quaternary ammonium compound with anticholinergic properties. It appears to inhibit vagal reflexes by antagonising the action of acetylcholine (the transmitter agent released from the vagus nerve). Anticholinergics prevent the increase in intracellular concentration of cyclic guanosine monophosphate (cyclic GMP) caused by interaction of acetylcholine with the muscarinic receptor on bronchial smooth muscle.

Children over 3 years: The usual dose is 0.4-2.0 ml Ipratropium Bromide Solution (100-500 micrograms) up to three times daily. 

Adults (including elderly and adolescents) over 12 years of age: The usual dose is 0.4-2.0 ml Ipratropium Bromide Solution (100-500 micrograms) up to four times daily.

Allergic-type reactions such as skin rash, angio-oedema of the tongue, lips and face, urticaria (including giant urticaria), laryngospasm and anaphylactic reactions have been reported, with positive rechallenge in some cases.

Ipratropium Bromide solution should not be taken by patients with known hypersensitivity to atropine or its derivatives or to any other component of the product.

Ipratropium Bromide should be used with caution in patients predisposed to narrow-angle glaucoma, or with prostatic hyperplasia or bladder-neck obstruction.

The safety of Ipratropium Bromide during human pregnancy has not been established. The benefits of using Ipratropium Bromide during a confirmed or suspected pregnancy must be weighed against possible hazards to the unborn child. It is not known whether Ipratropium Bromide is excreted into breast milk.

Should be stored in cool and dry place

Ipratropium inhaler is indicated for-

• As bronchodilator in treatment of chronic reversible airway obstruction as in asthma and Chronic Obstructive Pulmonary Disease (COPD) including chronic bronchitis and emphysema.
• Treatment of acute reversible airways obstruction.

Anticholinergic bronchodilators

Ipratropium bromide causes bronchodilation by blocking the action of acetylcholine at parasympathetic site in bronchial smooth muscle. It also inhibits serous and seromucous gland secretions by nasal application.

Adults: The usual dose is 1-2 puffs (20 µg/puff) three or four times daily. Single-dose up to 80 µg (4 puffs) may be required to obtain maximum benefit during early treatment. Patients may take additional inhalations as required: however, the total number of inhalations should not exceed 12 puffs in 24 hours.

Children:

• 6-12 years: Usually 1-2 puffs two to three times daily.
• Bellow 6 years: The usual dose is 1 puff (20 µg) three times daily.

In order to ensure that the inhaler is used correctly, the administration should be supervised by an adult.

No specific information on the use of the product in the elderly is available. Clinical trials have included patients over 65 years and no adverse reactions specific to this age group have been reported.

Using an Inhaler seems simple, but most patients do not know how to use it in the right way. If the Inhaler is used in the wrong way, less medicine can reach the lungs. Correct and regular use of the Inhaler will prevent or lessen the severity of asthma attacks.

Following simple steps can help to use Inhaler effectively (According to "National Asthma Guidelines for Medical Practitioners" published by Asthma Association):

• Take off the cap.
• Shake the inhaler (at least six times) vigorously before each use.
• If the inhaler is new or if it has not been used for a week or more, shake it well and release one puff into the air to make sure that it works.
• Breathe out as full as comfortably possible & hold the inhaler upright.
• Place the actuator into mouth between the teeth and close lips around the mouthpiece.
• While breathing deeply and slowly through the mouth, press down firmly add fully on the canister to release medicine.
• Remove the inhaler from mouth. Continue holding breath for at least for 10 seconds or as long as it is comfortable.
• If doctor has prescribed more than one inhalation per treatment, wait 1 minute between puffs (inhalations). Shake the inhaler well and repeat steps 4 to 7.
• After use, replace the cap on the mouthpiece. After each treatment, rinse mouth with water.
• Check your technique in front of a mirror from time to time, if you see a white mist during the inhalation, you may not have closed your lips properly around mouthpiece, or you may not be breathing in as you press the can. This indicates failure of technique. If this happens, repeat the procedure from step 4 carefully.

Instructions for Cleaning Inhaler: Clean your Inhaler at least once a week. Remove canister and rinse the plastic actuator and cap in warm water but do not put the metal canister into water. Dry the actuator and cap thoroughly and gently replace the metal canister into the actuator with a twisting motion. Put the cap on the mouthpiece.

Idiosyncratic reactions to lpratropium bromide are rare. Severe adverse effects due to inhibition of muscarinic receptors and ganglion blockade are theoretically possible but unlikely with the metered-dose aerosol. Regular use of ipratropium can lead to a dry mouth through inhibition of salivary flow.

Other most common adverse reactions reported are - dryness of the oropharynx (5%); cough, exacerbation of symptoms, & imitation from aerosol (3%); headache (2%); nausea, dizziness, blurred vision/difficulty in accommodation & drying of secretions (1%).

Less frequently reported adverse reactions include tachycardia, nervousness, paresthesias, drowsiness, co-ordination difficulty, itching, flushing, alopecia, constipation, tremor & mucosal ulceration. Case of precipitation or worsening of narrow-angle glaucoma, acute eye pain & hypotension also have been reported. Allergic-type reactions such as skin rash, angio-oedema of tongue, lips & face, urticaria (including giant urticaria), laryngospasm and anaphylactic reaction have been also reported; with positive rechallenge in some cases.

Ipratropium bromide dose not produce adverse effects on mucociliary clearance, in contrast to atropine and other muscarinic antagonists. There is no evidence that in the therapeutic does range ipratropium bromide has any adverse effect on bronchial secretion.

Known hypersensitivity to ipratropium bromide, Atropine or its derivative. Also contraindicated in patients with a history of hypersensitivity to soya lecithin or related food products such as soyabean, lecithin and peanut.

Patients should be advised that temporary blurring of vision, precipitation or worsening of narrow angle glaucoma or eye pain may result if the aerosol is sprayed into the eyes. If recommended dosage does not provide relief or symptoms become worse, patients should seek immediate medical attention. While taking ipratropium bromide inhalation aerosol, other inhaled drugs should not be used unless prescribed.

lpratropium bromide inhalation aerosol is not indicated for the initial treatment of acute episodes of bronchospasm where rapid response is required. Drugs with faster onset may be preferable as initial therapy in this situation. Immediate hypersensitivity reactions may occur after administration of ipratropium bromide, as demonstrated by rare cases of urticaria, angio-oedema, rash, bronchospasm and oropharyngeal oedema.

Ipratropium bromide has been used concomitantly with other drugs, including sympathomimetic bronchodilators, methylxanthines, steroids and cromolyn sodium, commonly used in treatment of COPD, without any adverse drug reactions, there are no studies fully evaluating the interaction effects of lpratropium bromide and these drugs in respect to effectiveness.

The safety of Ipratropium Bromide during human pregnancy has not been established. The benefits of using Ipratropium Bromide during a confirmed or suspected pregnancy must be weighed against possible hazards to the unborn child. It is not known whether Ipratropium Bromide is excreted into breast milk.

Acute overdosage by inhalation is unlikely since ipratropium bromide is not well absorbed systematically after administration as aerosol. Inhaled dosage of 5 mg of ipratropium bromide produce an increase in heart rate and palpitation. Single doses of ipratropium bromide 30 mg by mouth caused anticholinergic side effects but which were not considered severe enough to require specific reversal.

The inhaler should be stored in a dry and cool place. Protected from direct sunlight and heat. Keep away from eyes. Keep out of reach of children. The canister should not be broken, punctured or burnt, even when apparently empty.

Ipratropium Nebuliser Solution is indicated as a bronchodilator for maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease, including chronic bronchitis and emphysema.

Anticholinergic bronchodilators

Ipratropium Bromide is a quaternary ammonium compound with anticholinergic properties. It appears to inhibit vagal reflexes by antagonising the action of acetylcholine (the transmitter agent released from the vagus nerve). Anticholinergics prevent the increase in intracellular concentration of cyclic guanosine monophosphate (cyclic GMP) caused by interaction of acetylcholine with the muscarinic receptor on bronchial smooth muscle.

Children over 3 years: The usual dose is 0.4-2.0 ml Ipratropium Bromide Solution (100-500 micrograms) up to three times daily. 

Adults (including elderly and adolescents) over 12 years of age: The usual dose is 0.4-2.0 ml Ipratropium Bromide Solution (100-500 micrograms) up to four times daily.

Allergic-type reactions such as skin rash, angio-oedema of the tongue, lips and face, urticaria (including giant urticaria), laryngospasm and anaphylactic reactions have been reported, with positive rechallenge in some cases.

Ipratropium Bromide solution should not be taken by patients with known hypersensitivity to atropine or its derivatives or to any other component of the product.

Ipratropium Bromide should be used with caution in patients predisposed to narrow-angle glaucoma, or with prostatic hyperplasia or bladder-neck obstruction.

The safety of Ipratropium Bromide during human pregnancy has not been established. The benefits of using Ipratropium Bromide during a confirmed or suspected pregnancy must be weighed against possible hazards to the unborn child. It is not known whether Ipratropium Bromide is excreted into breast milk.

Should be stored in cool and dry place

Salbutamol sulfate & Ipratropium bromide solution for inhalation is indicated for the treatment of reversible bronchospasm associated with obstructive airway diseases in patients who require more than a single bronchodilator.

Combined bronchodilators

Ipratropium Bromide is quickly absorbed after inhalation. The systemic bioavailability following inhalation is estimated to be less than 10% of the dose. Renal excretion of Ipratropium Bromide is given as 46% of the dose after intravenous administration. The half-life of the terminal elimination phase is about 1.6 hours as determined after intravenous administration. Elimination half-life of drug and metabolites is 3.6 hours as determined after radio labelling. Ipratropium Bromide does not penetrate the blood brain barrier.

Salbutamoi Sulphate is rapidly and completely absorbed following administration either by inhaled or oral route. Peak plasma Salbutamoi concentrations are seen within three hours of administration and it is excreted unchanged in the urine after 24 hours. The elimination half-life is 4 hours. Salbutamoi will cross the blood brain barrier reaching concentrations amounting to about five percent of the plasma concentrations.

It has been shown that co-nebulisation of Ipratropium Bromide and Salbutamoi Sulphate does not potentiate the systemic absorption of either component and that therefore the additive activity of this solution is due to the combined local effect on the lung following inhalation.

Salbutamol sulfate & Ipratropium bromide solution for inhalation in ampoule may be administered from a suitable nebulizer or an intermittent positive pressure ventilator.

• Adults (including elderly): Use one 3 ml ampoule in the nebulizer four times a day. Two additional treatments may be used per day, if needed.
• Children: Use and dose must be determined by doctor.

Patients should be advised to consult a doctor or the nearest hospital immediately in the case of acute or rapidly worsening dyspnoea if additional inhalations do not produce an adequate improvement.

Step 1: Twist off the top of the ampoule. Be careful to hold the ampoule upright.
Step 2: Squeeze the desired amount of the nebulizer solution into the nebulizer chamber.
Step 3: If dilution is needed follow the physician’s direction.

In common with other beta-agonists containing products, side effects of this solution can include fine tremor of skeletal muscles and nervousness and less frequently tachycardia, dizziness, palpitations or headache, especially in hypersensitive patients.

Potentially serious hypokalaemia may result from prolonged and/or high dose beta2 agonist therapy.

As with use of other inhalation therapy, cough, local irritation and less commonly inhalation induced bronchospasm can occur. As with other beta-mimetics, nausea, vomiting, sweating, weakness and myalgia/muscle cramps may occur. In rare cases decrease in diastolic blood pressure, increase in systolic blood pressure, arrhythmias, particularly after higher doses, may occur.

In individual cases psychological alterations have been reported under inhalation therapy with beta-mimetics.

The most frequent non-respiratory anticholinergic related adverse events are dryness of mouth and dysphonia. There have been isolated reports of ocular complications (i.e. mydriasis, increased intraocular pressure, angle closure glaucoma, and eye pain) when aerosolised ipratropium bromide either alone or in combination with adrenergic beta2 agonist, has escaped into the eyes. Ocular side effects, gastrointestinal motility disturbances and urinary retention may occur in rare cases and are reversible.

This is contraindicated in patients with hypertrophic obstructive tachyarrhythmia and in patients with a history of hypersensitivity to atropine or its derivatives, or to any other component of the product.

In the case of acute, rapidly worsening dyspnoea a doctor should be consulted immediately. Immediate hypersensitivity reactions may occur after administration of this solution as demonstrated by rare cases of urticaria, angioedema, rash, bronchospasm and oropharyngeal oedema.

The concurrent administration of other beta-mimetics, systemically absorbed anticholinergics and xanthine derivatives may increase the side effects.

Beta-agonist induced hypokalaemia may be increased by concomitant treatment with xanthine derivatives, glucocorticosteroids and diuretics. This should be taken into account particularly in patients with severe airway obstruction.

Hypokalaemia may result in an increased susceptibility to arrhythmias in patients receiving digoxin. It is recommended that serum potassium levels be monitored in such situations.

A potentially serious reduction in bronchodilator effect may occur during concurrent administration of beta-blockers.

Beta-adrenergic agonists should be administered with caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, since the action of beta adrenergic agonists may be enhanced.

Inhalation of halogenated hydrocarbon anaesthetics such as halothane, trichloroethylene and enflurane may increase the susceptibility to the cardiovascular effects of beta-agonists.

Pregnancy category C. Animal studies with Salbutamoi Sulphate have demonstrated a teratogenic effect. It is not known whether this medication is harmful to the fetus. No evidence of abnormalities has been reported in women receiving albuterol during pregnancy. This solution should be used during pregnancy only if the potential benefit justifies. This solution should be used with caution before childbirth in view of Salbutamol's inhibitory effects on uterine contractions.

Salbutamol Sulphate and Ipratropium Bromide are probably excreted in breast milk and their effects on neonates are not known. Although lipid-insoluble quaternary bases pass into breast milk, it is unlikely that this will happen to any extent especially when taken by inhalation. However, because many drugs are excreted in breast milk, caution should be exercised when This solution is administered to a nursing woman.

The effects of overdosage are expected to be primarily related to Salbutamol because acute overdosage with Ipratropium Bromide is unlikely as it is not well absorbed systemically after inhalation or oral administration.

Symptoms: Manifestations of overdosage with salbutamol may include tachycardia, anginal pain, hypertension, hypotension , palpitations, tremor, widening of the pulse pressure, arrhythmia and flushing.

Therapy: Administration of sedatives, tranquillisers; in severe cases, intensive therapy. Beta-receptor blockers, preferably beta1-selective, are suitable as specific antidotes; however, a possible increase in bronchial obstruction must be taken into account and the dose should be adjusted carefully in patients suffering from bronchial asthma.

Keep below 30°C temperature, away from light & moisture. Keep out of the reach of children.

Adjunct anti-epileptic drugs

Adults and adolescents from 16 years of age: The recommended starting dose is 250 mg twice daily which should be increased to an initial therapeutic dose of 500 mg twice daily after two weeks. The dose can be further increased by 250 mg twice daily every two weeks depending upon the clinical response. The maximum dose is 1500 mg twice daily.

Adults (≥18 years) and adolescents (12 to 17 years) weighing 50 kg or more: The initial therapeutic dose is 500 mg twice daily. This dose can be started on the first day of treatment. Depending upon the clinical response and tolerability, the daily dose can be increased up to 1,500 mg twice daily. Dose changes can be made in 500 mg twice daily increases or decrease every two to four weeks.

Pediatric population: The tablet formulation is not adapted for use in infants and children under the age of 6 years. Oral solution is the preferred formulation for use in this population. In addition, the available dose strengths of the tablets are not appropriate for initial treatment in children weighing less than 25 kg, for patients unable to swallow tablets or for the administration of doses below 250 mg. In all of the above cases, oral solution should be used.

• Monotherapy: The safety and efficacy of levetiracetam in children and adolescents below 16 years as monotherapy treatment have not been established.
• Add-on therapy: Oral solution is the preferred formulation for use in infants and children under the age of 6 years. For children 6 years and above, oral solution should be used for doses under 250 mg, for doses not in multiples of 250 mg when dosing recommendation is not achievable by taking multiple tablets and for patients unable to swallow tablets. The lowest effective dose should be used. The starting dose for a child or adolescent of 25 kg should be 250 mg twice daily with a maximum dose of 750 mg twice daily. Dosing for children 50 kg or greater is the same as in adults.
• Add-on therapy: For infants aged from 1 month to less than 6 months: The oral solution is the formulation to use in infants.

Most common adverse reactions (incidence ≥ 5% more than placebo) include:

• Adult patients: somnolence, asthenia, infection and dizziness
• Pediatric patients: fatigue, aggression, nasal congestion, decreased appetite, and irritability

Hypersensitivity to the active substance or other pyrrolidone derivatives or to any of the excipients.

Renal impairment: The administration of levetiracetam to patients with renal impairment may require dose adjustment. In patients with severely impaired hepatic function, assessment of renal function is recommended before dose selection.

Acute kidney injury: The use of levetiracetam has been very rarely associated with acute kidney injury with a time to onset ranging from a few days to several months.

Blood cell counts: Rare cases of decreased blood cell counts (neutropenia, agranulocytosis, leucopenia, thrombocytopenia and pancytopenia) have been described in association with levetiracetam administration, generally at the beginning of the treatment. Complete blood cell counts are advised in patients experiencing important weakness, pyrexia, recurrent infections or coagulation disorders.

Suicide: Suicide, suicide attempt, suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents (including levetiracetam). A meta-analysis of randomized placebo-controlled trials of anti-epileptic medicinal products has shown a small increased risk of suicidal thoughts and behaviour. The mechanism of this risk is not known. Therefore patients should be monitored for signs of depression and/or suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of depression and/or suicidal ideation or behaviour emerge.

Paediatric population: The tablet formulation is not adapted for use in infants and children under the age of 6 years. Available data in children did not suggest an impact on growth and puberty. However, long term effects on learning, intelligence, growth, endocrine function, puberty and childbearing potential in children remain unknown.

Antiepileptic medicinal products: Pre-marketing data from clinical studies conducted in adults indicate that levetiracetam did not influence the serum concentrations of existing antiepileptic medicinal products (phenytoin, carbamazepine, valproic acid, phenobarbital, lamotrigine, gabapentin and primidone) and that these antiepileptic medicinal products did not influence the pharmacokinetics of levetiracetam.

Probenecid: Probenecid (500 mg four times daily), a renal tubular secretion blocking agent, has been shown to inhibit the renal clearance of the primary metabolite but not of levetiracetam. Nevertheless, the concentration of this metabolite remains low.

Methotrexate: Concomitant administration of levetiracetam and methotrexate has been reported to decrease methotrexate clearance, resulting in increased/prolonged blood methotrexate concentration to potentially toxic levels. Blood methotrexate and levetiracetam levels should be carefully monitored in patients treated concomitantly with the two drugs.

Laxatives: There have been isolated reports of decreased levetiracetam efficacy when the osmotic laxative macrogol has been concomitantly administered with oral levetiracetam. Therefore, macrogol should not be taken orally for one hour before and for one hour after taking levetiracetam.

Food and alcohol: The extent of absorption of levetiracetam was not altered by food, but the rate of absorption was slightly reduced. No data on the interaction of levetiracetam with alcohol are available.

Levetiracetam is not recommended during pregnancy and in women of childbearing potential not using contraception unless clinically necessary. Levetiracetam is excreted in human breast milk. Therefore, breastfeeding is not recommended. However, if levetiracetam treatment is needed during breastfeeding, the benefit/risk of the treatment should be weighed considering the importance of breastfeeding. No impact on fertility was detected in animal studies. No clinical data are available, the potential risk for humans is unknown.

Elderly (65 years and older): Adjustment of the dose is recommended in elderly patients with compromised renal function.

Renal impairment: The daily dose must be individualized according to renal function.

Hepatic impairment: No dose adjustment is needed in patients with mild to moderate hepatic impairment. In patients with severe hepatic impairment, the creatinine clearance may underestimate renal insufficiency. Therefore a 50 % reduction of the daily maintenance dose is recommended when the creatinine clearance is < 60 ml/min.

Somnolence, agitation, aggression, depressed level of consciousness, respiratory depression and coma were observed with levetiracetam overdoses. After an acute overdose, the stomach may be emptied by gastric lavage or by induction of emesis. There is no specifc antidote for levetiracetam. Treatment of an overdose will be symptomatic and may include haemodialysis. The dialyser extraction efficiency is 60 % for levetiracetam and 74% for the primary metabolite.

Store at a cool temperature (not exceeding 25°C) and dry place, protected from light.

Adjunct anti-epileptic drugs

Adults and adolescents from 16 years of age: The recommended starting dose is 250 mg twice daily which should be increased to an initial therapeutic dose of 500 mg twice daily after two weeks. The dose can be further increased by 250 mg twice daily every two weeks depending upon the clinical response. The maximum dose is 1500 mg twice daily.

Adults (≥18 years) and adolescents (12 to 17 years) weighing 50 kg or more: The initial therapeutic dose is 500 mg twice daily. This dose can be started on the first day of treatment. Depending upon the clinical response and tolerability, the daily dose can be increased up to 1,500 mg twice daily. Dose changes can be made in 500 mg twice daily increases or decrease every two to four weeks.

Pediatric population: The tablet formulation is not adapted for use in infants and children under the age of 6 years. Oral solution is the preferred formulation for use in this population. In addition, the available dose strengths of the tablets are not appropriate for initial treatment in children weighing less than 25 kg, for patients unable to swallow tablets or for the administration of doses below 250 mg. In all of the above cases, oral solution should be used.

• Monotherapy: The safety and efficacy of levetiracetam in children and adolescents below 16 years as monotherapy treatment have not been established.
• Add-on therapy: Oral solution is the preferred formulation for use in infants and children under the age of 6 years. For children 6 years and above, oral solution should be used for doses under 250 mg, for doses not in multiples of 250 mg when dosing recommendation is not achievable by taking multiple tablets and for patients unable to swallow tablets. The lowest effective dose should be used. The starting dose for a child or adolescent of 25 kg should be 250 mg twice daily with a maximum dose of 750 mg twice daily. Dosing for children 50 kg or greater is the same as in adults.
• Add-on therapy: For infants aged from 1 month to less than 6 months: The oral solution is the formulation to use in infants.

Most common adverse reactions (incidence ≥ 5% more than placebo) include:

• Adult patients: somnolence, asthenia, infection and dizziness
• Pediatric patients: fatigue, aggression, nasal congestion, decreased appetite, and irritability

Hypersensitivity to the active substance or other pyrrolidone derivatives or to any of the excipients.

Renal impairment: The administration of levetiracetam to patients with renal impairment may require dose adjustment. In patients with severely impaired hepatic function, assessment of renal function is recommended before dose selection.

Acute kidney injury: The use of levetiracetam has been very rarely associated with acute kidney injury with a time to onset ranging from a few days to several months.

Blood cell counts: Rare cases of decreased blood cell counts (neutropenia, agranulocytosis, leucopenia, thrombocytopenia and pancytopenia) have been described in association with levetiracetam administration, generally at the beginning of the treatment. Complete blood cell counts are advised in patients experiencing important weakness, pyrexia, recurrent infections or coagulation disorders.

Suicide: Suicide, suicide attempt, suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents (including levetiracetam). A meta-analysis of randomized placebo-controlled trials of anti-epileptic medicinal products has shown a small increased risk of suicidal thoughts and behaviour. The mechanism of this risk is not known. Therefore patients should be monitored for signs of depression and/or suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of depression and/or suicidal ideation or behaviour emerge.

Paediatric population: The tablet formulation is not adapted for use in infants and children under the age of 6 years. Available data in children did not suggest an impact on growth and puberty. However, long term effects on learning, intelligence, growth, endocrine function, puberty and childbearing potential in children remain unknown.

Antiepileptic medicinal products: Pre-marketing data from clinical studies conducted in adults indicate that levetiracetam did not influence the serum concentrations of existing antiepileptic medicinal products (phenytoin, carbamazepine, valproic acid, phenobarbital, lamotrigine, gabapentin and primidone) and that these antiepileptic medicinal products did not influence the pharmacokinetics of levetiracetam.

Probenecid: Probenecid (500 mg four times daily), a renal tubular secretion blocking agent, has been shown to inhibit the renal clearance of the primary metabolite but not of levetiracetam. Nevertheless, the concentration of this metabolite remains low.

Methotrexate: Concomitant administration of levetiracetam and methotrexate has been reported to decrease methotrexate clearance, resulting in increased/prolonged blood methotrexate concentration to potentially toxic levels. Blood methotrexate and levetiracetam levels should be carefully monitored in patients treated concomitantly with the two drugs.

Laxatives: There have been isolated reports of decreased levetiracetam efficacy when the osmotic laxative macrogol has been concomitantly administered with oral levetiracetam. Therefore, macrogol should not be taken orally for one hour before and for one hour after taking levetiracetam.

Food and alcohol: The extent of absorption of levetiracetam was not altered by food, but the rate of absorption was slightly reduced. No data on the interaction of levetiracetam with alcohol are available.

Levetiracetam is not recommended during pregnancy and in women of childbearing potential not using contraception unless clinically necessary. Levetiracetam is excreted in human breast milk. Therefore, breastfeeding is not recommended. However, if levetiracetam treatment is needed during breastfeeding, the benefit/risk of the treatment should be weighed considering the importance of breastfeeding. No impact on fertility was detected in animal studies. No clinical data are available, the potential risk for humans is unknown.

Elderly (65 years and older): Adjustment of the dose is recommended in elderly patients with compromised renal function.

Renal impairment: The daily dose must be individualized according to renal function.

Hepatic impairment: No dose adjustment is needed in patients with mild to moderate hepatic impairment. In patients with severe hepatic impairment, the creatinine clearance may underestimate renal insufficiency. Therefore a 50 % reduction of the daily maintenance dose is recommended when the creatinine clearance is < 60 ml/min.

Somnolence, agitation, aggression, depressed level of consciousness, respiratory depression and coma were observed with levetiracetam overdoses. After an acute overdose, the stomach may be emptied by gastric lavage or by induction of emesis. There is no specifc antidote for levetiracetam. Treatment of an overdose will be symptomatic and may include haemodialysis. The dialyser extraction efficiency is 60 % for levetiracetam and 74% for the primary metabolite.

Store at a cool temperature (not exceeding 25°C) and dry place, protected from light.

Adjunct anti-epileptic drugs

Adults and adolescents from 16 years of age: The recommended starting dose is 250 mg twice daily which should be increased to an initial therapeutic dose of 500 mg twice daily after two weeks. The dose can be further increased by 250 mg twice daily every two weeks depending upon the clinical response. The maximum dose is 1500 mg twice daily.

Adults (≥18 years) and adolescents (12 to 17 years) weighing 50 kg or more: The initial therapeutic dose is 500 mg twice daily. This dose can be started on the first day of treatment. Depending upon the clinical response and tolerability, the daily dose can be increased up to 1,500 mg twice daily. Dose changes can be made in 500 mg twice daily increases or decrease every two to four weeks.

Pediatric population: The tablet formulation is not adapted for use in infants and children under the age of 6 years. Oral solution is the preferred formulation for use in this population. In addition, the available dose strengths of the tablets are not appropriate for initial treatment in children weighing less than 25 kg, for patients unable to swallow tablets or for the administration of doses below 250 mg. In all of the above cases, oral solution should be used.

• Monotherapy: The safety and efficacy of levetiracetam in children and adolescents below 16 years as monotherapy treatment have not been established.
• Add-on therapy: Oral solution is the preferred formulation for use in infants and children under the age of 6 years. For children 6 years and above, oral solution should be used for doses under 250 mg, for doses not in multiples of 250 mg when dosing recommendation is not achievable by taking multiple tablets and for patients unable to swallow tablets. The lowest effective dose should be used. The starting dose for a child or adolescent of 25 kg should be 250 mg twice daily with a maximum dose of 750 mg twice daily. Dosing for children 50 kg or greater is the same as in adults.
• Add-on therapy: For infants aged from 1 month to less than 6 months: The oral solution is the formulation to use in infants.

Most common adverse reactions (incidence ≥ 5% more than placebo) include:

• Adult patients: somnolence, asthenia, infection and dizziness
• Pediatric patients: fatigue, aggression, nasal congestion, decreased appetite, and irritability

Hypersensitivity to the active substance or other pyrrolidone derivatives or to any of the excipients.

Renal impairment: The administration of levetiracetam to patients with renal impairment may require dose adjustment. In patients with severely impaired hepatic function, assessment of renal function is recommended before dose selection.

Acute kidney injury: The use of levetiracetam has been very rarely associated with acute kidney injury with a time to onset ranging from a few days to several months.

Blood cell counts: Rare cases of decreased blood cell counts (neutropenia, agranulocytosis, leucopenia, thrombocytopenia and pancytopenia) have been described in association with levetiracetam administration, generally at the beginning of the treatment. Complete blood cell counts are advised in patients experiencing important weakness, pyrexia, recurrent infections or coagulation disorders.

Suicide: Suicide, suicide attempt, suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents (including levetiracetam). A meta-analysis of randomized placebo-controlled trials of anti-epileptic medicinal products has shown a small increased risk of suicidal thoughts and behaviour. The mechanism of this risk is not known. Therefore patients should be monitored for signs of depression and/or suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of depression and/or suicidal ideation or behaviour emerge.

Paediatric population: The tablet formulation is not adapted for use in infants and children under the age of 6 years. Available data in children did not suggest an impact on growth and puberty. However, long term effects on learning, intelligence, growth, endocrine function, puberty and childbearing potential in children remain unknown.

Antiepileptic medicinal products: Pre-marketing data from clinical studies conducted in adults indicate that levetiracetam did not influence the serum concentrations of existing antiepileptic medicinal products (phenytoin, carbamazepine, valproic acid, phenobarbital, lamotrigine, gabapentin and primidone) and that these antiepileptic medicinal products did not influence the pharmacokinetics of levetiracetam.

Probenecid: Probenecid (500 mg four times daily), a renal tubular secretion blocking agent, has been shown to inhibit the renal clearance of the primary metabolite but not of levetiracetam. Nevertheless, the concentration of this metabolite remains low.

Methotrexate: Concomitant administration of levetiracetam and methotrexate has been reported to decrease methotrexate clearance, resulting in increased/prolonged blood methotrexate concentration to potentially toxic levels. Blood methotrexate and levetiracetam levels should be carefully monitored in patients treated concomitantly with the two drugs.

Laxatives: There have been isolated reports of decreased levetiracetam efficacy when the osmotic laxative macrogol has been concomitantly administered with oral levetiracetam. Therefore, macrogol should not be taken orally for one hour before and for one hour after taking levetiracetam.

Food and alcohol: The extent of absorption of levetiracetam was not altered by food, but the rate of absorption was slightly reduced. No data on the interaction of levetiracetam with alcohol are available.

Levetiracetam is not recommended during pregnancy and in women of childbearing potential not using contraception unless clinically necessary. Levetiracetam is excreted in human breast milk. Therefore, breastfeeding is not recommended. However, if levetiracetam treatment is needed during breastfeeding, the benefit/risk of the treatment should be weighed considering the importance of breastfeeding. No impact on fertility was detected in animal studies. No clinical data are available, the potential risk for humans is unknown.

Elderly (65 years and older): Adjustment of the dose is recommended in elderly patients with compromised renal function.

Renal impairment: The daily dose must be individualized according to renal function.

Hepatic impairment: No dose adjustment is needed in patients with mild to moderate hepatic impairment. In patients with severe hepatic impairment, the creatinine clearance may underestimate renal insufficiency. Therefore a 50 % reduction of the daily maintenance dose is recommended when the creatinine clearance is < 60 ml/min.

Somnolence, agitation, aggression, depressed level of consciousness, respiratory depression and coma were observed with levetiracetam overdoses. After an acute overdose, the stomach may be emptied by gastric lavage or by induction of emesis. There is no specifc antidote for levetiracetam. Treatment of an overdose will be symptomatic and may include haemodialysis. The dialyser extraction efficiency is 60 % for levetiracetam and 74% for the primary metabolite.

Store at a cool temperature (not exceeding 25°C) and dry place, protected from light.

Adjunct anti-epileptic drugs

Adults and adolescents from 16 years of age: The recommended starting dose is 250 mg twice daily which should be increased to an initial therapeutic dose of 500 mg twice daily after two weeks. The dose can be further increased by 250 mg twice daily every two weeks depending upon the clinical response. The maximum dose is 1500 mg twice daily.

Adults (≥18 years) and adolescents (12 to 17 years) weighing 50 kg or more: The initial therapeutic dose is 500 mg twice daily. This dose can be started on the first day of treatment. Depending upon the clinical response and tolerability, the daily dose can be increased up to 1,500 mg twice daily. Dose changes can be made in 500 mg twice daily increases or decrease every two to four weeks.

Pediatric population: The tablet formulation is not adapted for use in infants and children under the age of 6 years. Oral solution is the preferred formulation for use in this population. In addition, the available dose strengths of the tablets are not appropriate for initial treatment in children weighing less than 25 kg, for patients unable to swallow tablets or for the administration of doses below 250 mg. In all of the above cases, oral solution should be used.

• Monotherapy: The safety and efficacy of levetiracetam in children and adolescents below 16 years as monotherapy treatment have not been established.
• Add-on therapy: Oral solution is the preferred formulation for use in infants and children under the age of 6 years. For children 6 years and above, oral solution should be used for doses under 250 mg, for doses not in multiples of 250 mg when dosing recommendation is not achievable by taking multiple tablets and for patients unable to swallow tablets. The lowest effective dose should be used. The starting dose for a child or adolescent of 25 kg should be 250 mg twice daily with a maximum dose of 750 mg twice daily. Dosing for children 50 kg or greater is the same as in adults.
• Add-on therapy: For infants aged from 1 month to less than 6 months: The oral solution is the formulation to use in infants.

Most common adverse reactions (incidence ≥ 5% more than placebo) include:

• Adult patients: somnolence, asthenia, infection and dizziness
• Pediatric patients: fatigue, aggression, nasal congestion, decreased appetite, and irritability

Hypersensitivity to the active substance or other pyrrolidone derivatives or to any of the excipients.

Renal impairment: The administration of levetiracetam to patients with renal impairment may require dose adjustment. In patients with severely impaired hepatic function, assessment of renal function is recommended before dose selection.

Acute kidney injury: The use of levetiracetam has been very rarely associated with acute kidney injury with a time to onset ranging from a few days to several months.

Blood cell counts: Rare cases of decreased blood cell counts (neutropenia, agranulocytosis, leucopenia, thrombocytopenia and pancytopenia) have been described in association with levetiracetam administration, generally at the beginning of the treatment. Complete blood cell counts are advised in patients experiencing important weakness, pyrexia, recurrent infections or coagulation disorders.

Suicide: Suicide, suicide attempt, suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents (including levetiracetam). A meta-analysis of randomized placebo-controlled trials of anti-epileptic medicinal products has shown a small increased risk of suicidal thoughts and behaviour. The mechanism of this risk is not known. Therefore patients should be monitored for signs of depression and/or suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of depression and/or suicidal ideation or behaviour emerge.

Paediatric population: The tablet formulation is not adapted for use in infants and children under the age of 6 years. Available data in children did not suggest an impact on growth and puberty. However, long term effects on learning, intelligence, growth, endocrine function, puberty and childbearing potential in children remain unknown.

Antiepileptic medicinal products: Pre-marketing data from clinical studies conducted in adults indicate that levetiracetam did not influence the serum concentrations of existing antiepileptic medicinal products (phenytoin, carbamazepine, valproic acid, phenobarbital, lamotrigine, gabapentin and primidone) and that these antiepileptic medicinal products did not influence the pharmacokinetics of levetiracetam.

Probenecid: Probenecid (500 mg four times daily), a renal tubular secretion blocking agent, has been shown to inhibit the renal clearance of the primary metabolite but not of levetiracetam. Nevertheless, the concentration of this metabolite remains low.

Methotrexate: Concomitant administration of levetiracetam and methotrexate has been reported to decrease methotrexate clearance, resulting in increased/prolonged blood methotrexate concentration to potentially toxic levels. Blood methotrexate and levetiracetam levels should be carefully monitored in patients treated concomitantly with the two drugs.

Laxatives: There have been isolated reports of decreased levetiracetam efficacy when the osmotic laxative macrogol has been concomitantly administered with oral levetiracetam. Therefore, macrogol should not be taken orally for one hour before and for one hour after taking levetiracetam.

Food and alcohol: The extent of absorption of levetiracetam was not altered by food, but the rate of absorption was slightly reduced. No data on the interaction of levetiracetam with alcohol are available.

Levetiracetam is not recommended during pregnancy and in women of childbearing potential not using contraception unless clinically necessary. Levetiracetam is excreted in human breast milk. Therefore, breastfeeding is not recommended. However, if levetiracetam treatment is needed during breastfeeding, the benefit/risk of the treatment should be weighed considering the importance of breastfeeding. No impact on fertility was detected in animal studies. No clinical data are available, the potential risk for humans is unknown.

Elderly (65 years and older): Adjustment of the dose is recommended in elderly patients with compromised renal function.

Renal impairment: The daily dose must be individualized according to renal function.

Hepatic impairment: No dose adjustment is needed in patients with mild to moderate hepatic impairment. In patients with severe hepatic impairment, the creatinine clearance may underestimate renal insufficiency. Therefore a 50 % reduction of the daily maintenance dose is recommended when the creatinine clearance is < 60 ml/min.

Somnolence, agitation, aggression, depressed level of consciousness, respiratory depression and coma were observed with levetiracetam overdoses. After an acute overdose, the stomach may be emptied by gastric lavage or by induction of emesis. There is no specifc antidote for levetiracetam. Treatment of an overdose will be symptomatic and may include haemodialysis. The dialyser extraction efficiency is 60 % for levetiracetam and 74% for the primary metabolite.

Store at a cool temperature (not exceeding 25°C) and dry place, protected from light.

Adjunct anti-epileptic drugs

Adults and adolescents from 16 years of age: The recommended starting dose is 250 mg twice daily which should be increased to an initial therapeutic dose of 500 mg twice daily after two weeks. The dose can be further increased by 250 mg twice daily every two weeks depending upon the clinical response. The maximum dose is 1500 mg twice daily.

Adults (≥18 years) and adolescents (12 to 17 years) weighing 50 kg or more: The initial therapeutic dose is 500 mg twice daily. This dose can be started on the first day of treatment. Depending upon the clinical response and tolerability, the daily dose can be increased up to 1,500 mg twice daily. Dose changes can be made in 500 mg twice daily increases or decrease every two to four weeks.

Pediatric population: The tablet formulation is not adapted for use in infants and children under the age of 6 years. Oral solution is the preferred formulation for use in this population. In addition, the available dose strengths of the tablets are not appropriate for initial treatment in children weighing less than 25 kg, for patients unable to swallow tablets or for the administration of doses below 250 mg. In all of the above cases, oral solution should be used.

• Monotherapy: The safety and efficacy of levetiracetam in children and adolescents below 16 years as monotherapy treatment have not been established.
• Add-on therapy: Oral solution is the preferred formulation for use in infants and children under the age of 6 years. For children 6 years and above, oral solution should be used for doses under 250 mg, for doses not in multiples of 250 mg when dosing recommendation is not achievable by taking multiple tablets and for patients unable to swallow tablets. The lowest effective dose should be used. The starting dose for a child or adolescent of 25 kg should be 250 mg twice daily with a maximum dose of 750 mg twice daily. Dosing for children 50 kg or greater is the same as in adults.
• Add-on therapy: For infants aged from 1 month to less than 6 months: The oral solution is the formulation to use in infants.

Most common adverse reactions (incidence ≥ 5% more than placebo) include:

• Adult patients: somnolence, asthenia, infection and dizziness
• Pediatric patients: fatigue, aggression, nasal congestion, decreased appetite, and irritability

Hypersensitivity to the active substance or other pyrrolidone derivatives or to any of the excipients.

Renal impairment: The administration of levetiracetam to patients with renal impairment may require dose adjustment. In patients with severely impaired hepatic function, assessment of renal function is recommended before dose selection.

Acute kidney injury: The use of levetiracetam has been very rarely associated with acute kidney injury with a time to onset ranging from a few days to several months.

Blood cell counts: Rare cases of decreased blood cell counts (neutropenia, agranulocytosis, leucopenia, thrombocytopenia and pancytopenia) have been described in association with levetiracetam administration, generally at the beginning of the treatment. Complete blood cell counts are advised in patients experiencing important weakness, pyrexia, recurrent infections or coagulation disorders.

Suicide: Suicide, suicide attempt, suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents (including levetiracetam). A meta-analysis of randomized placebo-controlled trials of anti-epileptic medicinal products has shown a small increased risk of suicidal thoughts and behaviour. The mechanism of this risk is not known. Therefore patients should be monitored for signs of depression and/or suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of depression and/or suicidal ideation or behaviour emerge.

Paediatric population: The tablet formulation is not adapted for use in infants and children under the age of 6 years. Available data in children did not suggest an impact on growth and puberty. However, long term effects on learning, intelligence, growth, endocrine function, puberty and childbearing potential in children remain unknown.

Antiepileptic medicinal products: Pre-marketing data from clinical studies conducted in adults indicate that levetiracetam did not influence the serum concentrations of existing antiepileptic medicinal products (phenytoin, carbamazepine, valproic acid, phenobarbital, lamotrigine, gabapentin and primidone) and that these antiepileptic medicinal products did not influence the pharmacokinetics of levetiracetam.

Probenecid: Probenecid (500 mg four times daily), a renal tubular secretion blocking agent, has been shown to inhibit the renal clearance of the primary metabolite but not of levetiracetam. Nevertheless, the concentration of this metabolite remains low.

Methotrexate: Concomitant administration of levetiracetam and methotrexate has been reported to decrease methotrexate clearance, resulting in increased/prolonged blood methotrexate concentration to potentially toxic levels. Blood methotrexate and levetiracetam levels should be carefully monitored in patients treated concomitantly with the two drugs.

Laxatives: There have been isolated reports of decreased levetiracetam efficacy when the osmotic laxative macrogol has been concomitantly administered with oral levetiracetam. Therefore, macrogol should not be taken orally for one hour before and for one hour after taking levetiracetam.

Food and alcohol: The extent of absorption of levetiracetam was not altered by food, but the rate of absorption was slightly reduced. No data on the interaction of levetiracetam with alcohol are available.

Levetiracetam is not recommended during pregnancy and in women of childbearing potential not using contraception unless clinically necessary. Levetiracetam is excreted in human breast milk. Therefore, breastfeeding is not recommended. However, if levetiracetam treatment is needed during breastfeeding, the benefit/risk of the treatment should be weighed considering the importance of breastfeeding. No impact on fertility was detected in animal studies. No clinical data are available, the potential risk for humans is unknown.

Elderly (65 years and older): Adjustment of the dose is recommended in elderly patients with compromised renal function.

Renal impairment: The daily dose must be individualized according to renal function.

Hepatic impairment: No dose adjustment is needed in patients with mild to moderate hepatic impairment. In patients with severe hepatic impairment, the creatinine clearance may underestimate renal insufficiency. Therefore a 50 % reduction of the daily maintenance dose is recommended when the creatinine clearance is < 60 ml/min.

Somnolence, agitation, aggression, depressed level of consciousness, respiratory depression and coma were observed with levetiracetam overdoses. After an acute overdose, the stomach may be emptied by gastric lavage or by induction of emesis. There is no specifc antidote for levetiracetam. Treatment of an overdose will be symptomatic and may include haemodialysis. The dialyser extraction efficiency is 60 % for levetiracetam and 74% for the primary metabolite.

Store at a cool temperature (not exceeding 25°C) and dry place, protected from light.

Mirabegron is indicated for the symptomatic treatment of urgency, increased micturition frequency and urgency incontinence as may occur in adult patients with overactive bladder (OAB) syndrome.

BPH/ Urinary retention/ Urinary incontinence

Mirabegron is the first beta-3 adrenoceptor agonist. Mirabegron exerts its effect via a dual mechanism, both directly acts on the bladder smooth muscle and also via the sensory nervous system, it increases the levels of cyclic adenosine monophosphate (cyclic AMP) and leads to relaxation of the detrusor smooth muscle during storage phase of urinary bladder fill-void cycle by activation of beta-3 adrenoceptor which increase bladder capacity.

Adults including elderly: The recommended starting dose is Mirabegron 25 mg tablet once daily with or without food. Based on individual patient efficacy and tolerability the dose may be increased to Mirabegron 50 mg tablet once daily.

Renal or hepatic impairment:

• Patients with severe renal impairment (ClCr 15 to 29 mL/min or eGFR 15 to 29 mL/min/1.73 m2) or moderate hepatic impairment (Child-Pugh Class B), the daily dose of Mirabegron should not exceed 25 mg tablet once daily.
• Mirabegron has not been studied in patients with end stage renal disease (GFR <15 mL/min/1.73 m2 or patients requiring haemodialysis) or severe hepatic impairment (Child Pugh Class C) and it is therefore not recommended for use in these patient populations.

Gender: No dose adjustment is necessary according to gender.

Paediatric population: The safety and efficacy of Mirabegron in children below 18 years of age have not yet been established.

Mirabegron tablet is to be taken once daily, with liquids, swallowed whole and is not to be chewed, divided, or crushed.

The most common side effects reported for patients treated with Mirabegron 50 mg during the three 12-week phase 3 double blind, placebo controlled studies are tachycardia and urinary tract infections. The frequency of tachycardia was 1.2% in patients receiving Mirabegron 50 mg. Tachycardia led to discontinuation in 0.1% patients receiving Mirabegron 50 mg. The frequency of urinary tract infections was 2.9% in patients receiving Mirabegron 50 mg. Urinary tract infections led to discontinuation in none of the patients receiving Mirabegron 50 mg. Serious adverse reactions included atrial fibrillation (0.2%).

Mirabegron is contraindicated in patients with hypersensitivity to the active substance or to any of the excipients and severe uncontrolled hypertension defined as systolic blood pressure 180 mm Hg and/or diastolic blood pressure 110 mm Hg.

Renal impairment: Mirabegron has not been studied in patients with end stage renal disease (GFR <15 mL/min/1.73 m2 or patients requiring haemodialysis) and therefore, it is not recommended for use in this patient population. Data are limited in patients with severe renal impairment (GFR 15 to 29 mL/min/1.73 m2); based on a pharmacokinetic study a dose reduction to 25 mg is recommended in this population. Mirabegron is not recommended for use in patients with severe renal impairment (GFR 15 to 29 mL/min/1.73 m2) concomitantly receiving strong CYP3A inhibitors.

Hepatic impairment: Mirabegron has not been studied in patients with severe hepatic impairment (Child-Pugh Class C) and, therefore, it is not recommended for use in this patient population. Mirabegron is not recommended for use in patients with moderate hepatic impairment (Child-Pugh Class B) concomitantly receiving strong CYP3A inhibitors.

Hypertension: Mirabegron can increase blood pressure. Blood pressure should be measured at baseline and periodically during treatment with Mirabegron, especially in hypertensive patients. Data are limited in patients with stage 2 hypertension (systolic blood pressure 160 mm Hg or diastolic blood pressure 100 mm Hg).

Patients with congenital or acquired QT prolongation: Caution should be exercised when administering Mirabegron in patients with congenital or acquired QT prolongation.

Patients with bladder outlet obstruction and patients taking antimuscarinics medications for OAB: A controlled clinical safety study in patients with bladder outlet obstruction (BOO) did not demonstrate increased urinary retention in patients treated with Mirabegron; however, Mirabegron should be administered with caution to patients with clinically significant bladder outlet obstruction. Mirabegron should also be administered with caution to patients taking antimuscarinic medications for the treatment of OAB.

Effect of enzyme inhibitors: Mirabegron exposure (AUC) was increased 1.8-fold in the presence of the strong inhibitor of CYP3A/P-gp ketoconazole in healthy volunteers. No dose adjustment is needed when Mirabegron is combined with inhibitors of CYP3A and/or P-gp. However, in patients with mild to moderate renal impairment or mild hepatic impairment concomitantly receiving strong CYP3A inhibitors, such as itraconazole, ketoconazole, ritonavir and clarithromycin, the recommended dose is 25 mg once daily with or without food. Mirabegron is not recommended in patients with severe renal impairment or patients with moderate hepatic impairment concomitantly receiving strong CYP3A inhibitors.

Effect of enzyme inducers: Substances that are inducers of CYP3A or P-gp decrease the plasma concentrations of Mirabegron. No dose adjustment is needed for Mirabegron when administered with therapeutic doses of rifampicin or other CYP3A or P-gp inducers.

Effect of Mirabegron on CYP2D6 substrates: In healthy volunteers, the inhibitory potency of Mirabegron towards CYP2D6 is moderate and the CYP2D6 activity recovers within 15 days after discontinuation of Mirabegron. Multiple once daily dosing of Mirabegron IR resulted in a 90% increase in Cmax and a 229% increase in AUC of a single dose of metoprolol. Multiple once daily dosing of Mirabegron resulted in a 79% increase in Cmax and a 241% increase in AUC of a single dose of desipramine. Caution is advised if Mirabegron is co-administered with medicinal products with a narrow therapeutic index and significantly metabolised by CYP2D6, such as thioridazine, Type 1 C antiarrhythmics (e.g., flecainide, propafenone) and tricyclic antidepressants (e.g., imipramine, desipramine). Caution is also advised if Mirabegron is co-administered with CYP2D6 substrates that are individually dose titrated.

Effect of Mirabegron on transporters: Mirabegron is a weak inhibitor of P-gp. Mirabegron increased Cmax and AUC by 29% and 27%, respectively, of the P-gp substrate digoxin in healthy volunteers. For patients who are initiating a combination of Mirabegron and digoxin, the lowest dose for digoxin should be prescribed initially. Serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect.

Other interactions: No clinically relevant interactions have been observed when Mirabegron was co-administered with therapeutic doses of solifenacin, tamsulosin, warfarin, metformin or a combined oral contraceptive medicinal product containing ethinylestradiol and levonorgestrel. Dose-adjustment is not recommended.

There are limited amount of data from the use of Mirabegron in pregnant women. Studies in animals have shown reproductive toxicity. Mirabegron is not recommended during pregnancy and in women is planning to be pregnant. Mirabegron is excreted in the milk of rodents and therefore is predicted to be present in human milk. No studies have been conducted to assess the impact of Mirabegron on milk production in humans, its presence in human breast milk, or its effects on the breast-fed child. Mirabegron should not be administered during breast-feeding. There were no treatment-related effects of Mirabegron on fertility in animals. The effect of Mirabegron on human fertility has not been established.

Mirabegron has been administered to healthy volunteers at single doses up to 400 mg. At this dose, adverse events reported included palpitations and increased pulse rate exceeding 100 beats per minute (bpm). Multiple doses of Mirabegron up to 300 mg daily for 10 days showed increases in pulse rate and systolic blood pressure when administered to healthy volunteers. Treatment for overdose should be symptomatic and supportive. In the event of overdose, pulse rate, blood pressure, and ECG monitoring is recommended.

Store in a cool and dry place, protected from light.

Treatment of essential hypertension. Treatment of renal disease in patients with hypertension and type 2 diabetes mellitus as part of an antihypertensive drug regimen.

Angiotensin-ll receptor blocker

Irbesartan is an angiotensin II receptor antagonist. It blocks the vasoconstricting and aldosterone-secreting effects of angiotensin II by binding to AT1 receptors.

Adult: The usual recommended initial and maintenance dose is Irbesartan 150 mg once daily, with or without food. Irbesartan at a dose of 150 mg once daily generally provides a better 24 hour blood pressure control than 75 mg. However, initiation of therapy with Irbesartan 75 mg could be considered, particularly in haemodialysed patients and in the elderly over 75 years. In patients insufficiently controlled with Irbesartan 150 mg once daily, the dose of Irbesartan can be increased to Irbesartan 300 mg, or other anti-hypertensive agents can be added. In particular, the addition of a diuretic such as hydrochlorothiazide has been shown to have an additive effect with Irbesartan. In hypertensive type 2 diabetic patients, therapy should be initiated at Irbesartan 150 mg once daily and titrated up to Irbesartan 300 mg once daily as the preferred maintenance dose for treatment of renal disease. The demonstration of renal benefit of Irbesartan in hypertensive type 2 diabetic patients is based on studies where Irbesartan was used in addition to other antihypertensive agents, as needed, to reach target blood pressure. 

Elderly: although consideration should be given to initiating therapy with Irbesartan 75 mg in patients over 75 years of age, dosage adjustment is not usually necessary for the elderly

Paediatric: Irbesartan is not recommended for use in children and adolescents due to insufficient data on safety and efficacy.

Diarrhoea, fatigue, dyspepsia or heartburn, dizziness, orthostatic hypotension, nausea, vomiting, musculoskeletal pain, thrombocytopaenia, hyperkalaemia, elevated serum creatinine.

Concomitant use with aliskiren in patients with diabetes and renal impairment (GFR <60 ml/min). Pregnancy.

Patients with unilateral or bilateral renal artery stenosis, depletion of intravascular volume, aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy. Renal impairment. Lactation.

Diuretics and other antihypertensive agents: prior treatment with high dose diuretics may result in volume depletion and a risk of hypotension when initiating therapy with Irbesartan.

Potassium supplements and potassium-sparing diuretics: based on experience with the use of other drugs that affect the renin-angiotensin system, concomitant use of potassiumsparing diuretics, potassium supplements, salt substitutes containing potassium or other drugs that may increase serum potassium levels (e.g. heparin) may lead to increases in serum potassium and is, therefore, not recommended.

Lithium: reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin converting enzyme inhibitors. Similar effects have been very rarely reported with irbesartan so far. Therefore, this combination is not recommended. If the combination proves necessary, careful monitoring of serum lithium levels is recommended.

Non-steroidal anti-inflammatory drugs: When angiotensin II antagonists are administered simultaneously with non-steroidal anti- inflammatory drugs (i.e. selective COX-2 inhibitors, acetylsalicylic acid > 3 g/day and non-selective NSAIDs), attenuation of the antihypertensive effect may occur. Additional information on irbesartan interactions: In clinical studies, the pharmacokinetic of irbesartan is not affected by hydrochlorothiazide. Irbesartan is mainly metabolised by CYP2C9 and to a lesser extent by glucuronidation. No significant pharmacokinetic or pharmacodynamic interactions were observed when irbesartan was coadministered with warfarin, a drug metabolised by CYP2C9. The effects of CYP2C9 inducers such as rifampicin on the pharmacokinetic of irbesartan have not been evaluated. The pharmacokinetic of digoxin was not altered by coadministration of irbesartan.

Pregnancy: Irbesartan is contraindicated in the second and third trimesters of pregnancy. In the second and third trimesters, substances that act directly on the renin-angiotensin-system can cause foetal or neonatal renal failure, foetal skull hypoplasia and even foetal death. As precautionary measure, irbesartan should preferably not be used during first trimester of pregnancy. A switch to a suitable alternative treatment should be carried out in advance of a planned pregnancy. If pregnancy is diagnosed, irbesartan should be discontinued as soon as possible, skull and renal function should be checked with echography if, inadvertently, the treatment was taken for a long period.

Lactation: Irbesartan is contraindicated during lactation. It is not known whether irbesartan is excreted in human milk. Irbesartan is excreted in the milk of lactating rats. Precautions: Intravascular volume depletion: symptomatic hypotension, especially after the first dose, may occur in patients who are volume and/or sodium depleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Such conditions should be corrected before the administration of Irbesartan.

Renal impairment: no dosage adjustment is necessary in patients with impaired renal function. A lower starting dose of Irbesartan 75 mg should be considered for patients undergoing haemodialysis. Intravascular volume depletion: volume and/or sodium depletion should be corrected prior to administration of Irbesartan. 

Hepatic impairment: no dosage adjustment is necessary in patients with mild to moderate hepatic impairment. There is no clinical experience in patients with severe hepatic impairment.

Hypertensive patients with type 2 diabetes and renal disease: the effects of irbesartan both on renal and cardiovascular events were not uniform across all subgroups, in an analysis carried out in the study with patients with advanced renal disease. In particular, they appeared less favourable in women and non-white subjects.

Hyperkalaemia: as with other drugs that affect the renin-angiotensin-aldosterone system, hyperkalaemia may occur during the treatment with Irbesartan, especially in the presence of renal impairment, overt proteinuria due to diabetic renal disease, and/or heart failure. Close monitoring of serum potassium in patients at risk is recommended.

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy: as with other vasodilators, special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy.

Primary aldosteronism: patients with primary aldosteronism generally will not respond to anti-hypertensive drugs acting through inhibition of the renin-angiotensin system. Therefore, the use of Irbesartan is not recommended.

General: in patients whose vascular tone and renal function depend predominantly on the activity of the renin-angiotensinaldosterone system (e.g. patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with angiotensin converting enzyme inhibitors or angiotensin-II receptor antagonists that affect this system has been associated with acute hypotension, azotaemia, oliguria, or rarely acute renal failure. As with any anti-hypertensive agent, excessive blood pressure decrease in patients with ischaemic cardiopathy or ischaemic cardiovascular disease could result in a myocardial infarction or stroke.

Experience in adults exposed to doses of up to 900 mg/day for 8 weeks revealed no toxicity. The most likely manifestations of overdosage are expected to be hypotension and tachycardia; bradycardia might also occur from overdose. No specific information is available on the treatment of overdosage with Irbesartan. The patient should be closely monitored, and the treatment should be symptomatic and supportive. Suggested measures include induction of emesis and/or gastric lavage. Activated charcoal may be useful in the treatment of overdosage. Irbesartan is not removed by haemodialysis.

Store in a cool and dry place, protected from light.

Treatment of essential hypertension. Treatment of renal disease in patients with hypertension and type 2 diabetes mellitus as part of an antihypertensive drug regimen.

Angiotensin-ll receptor blocker

Irbesartan is an angiotensin II receptor antagonist. It blocks the vasoconstricting and aldosterone-secreting effects of angiotensin II by binding to AT1 receptors.

Adult: The usual recommended initial and maintenance dose is Irbesartan 150 mg once daily, with or without food. Irbesartan at a dose of 150 mg once daily generally provides a better 24 hour blood pressure control than 75 mg. However, initiation of therapy with Irbesartan 75 mg could be considered, particularly in haemodialysed patients and in the elderly over 75 years. In patients insufficiently controlled with Irbesartan 150 mg once daily, the dose of Irbesartan can be increased to Irbesartan 300 mg, or other anti-hypertensive agents can be added. In particular, the addition of a diuretic such as hydrochlorothiazide has been shown to have an additive effect with Irbesartan. In hypertensive type 2 diabetic patients, therapy should be initiated at Irbesartan 150 mg once daily and titrated up to Irbesartan 300 mg once daily as the preferred maintenance dose for treatment of renal disease. The demonstration of renal benefit of Irbesartan in hypertensive type 2 diabetic patients is based on studies where Irbesartan was used in addition to other antihypertensive agents, as needed, to reach target blood pressure. 

Elderly: although consideration should be given to initiating therapy with Irbesartan 75 mg in patients over 75 years of age, dosage adjustment is not usually necessary for the elderly

Paediatric: Irbesartan is not recommended for use in children and adolescents due to insufficient data on safety and efficacy.

Diarrhoea, fatigue, dyspepsia or heartburn, dizziness, orthostatic hypotension, nausea, vomiting, musculoskeletal pain, thrombocytopaenia, hyperkalaemia, elevated serum creatinine.

Concomitant use with aliskiren in patients with diabetes and renal impairment (GFR <60 ml/min). Pregnancy.

Patients with unilateral or bilateral renal artery stenosis, depletion of intravascular volume, aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy. Renal impairment. Lactation.

Diuretics and other antihypertensive agents: prior treatment with high dose diuretics may result in volume depletion and a risk of hypotension when initiating therapy with Irbesartan.

Potassium supplements and potassium-sparing diuretics: based on experience with the use of other drugs that affect the renin-angiotensin system, concomitant use of potassiumsparing diuretics, potassium supplements, salt substitutes containing potassium or other drugs that may increase serum potassium levels (e.g. heparin) may lead to increases in serum potassium and is, therefore, not recommended.

Lithium: reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin converting enzyme inhibitors. Similar effects have been very rarely reported with irbesartan so far. Therefore, this combination is not recommended. If the combination proves necessary, careful monitoring of serum lithium levels is recommended.

Non-steroidal anti-inflammatory drugs: When angiotensin II antagonists are administered simultaneously with non-steroidal anti- inflammatory drugs (i.e. selective COX-2 inhibitors, acetylsalicylic acid > 3 g/day and non-selective NSAIDs), attenuation of the antihypertensive effect may occur. Additional information on irbesartan interactions: In clinical studies, the pharmacokinetic of irbesartan is not affected by hydrochlorothiazide. Irbesartan is mainly metabolised by CYP2C9 and to a lesser extent by glucuronidation. No significant pharmacokinetic or pharmacodynamic interactions were observed when irbesartan was coadministered with warfarin, a drug metabolised by CYP2C9. The effects of CYP2C9 inducers such as rifampicin on the pharmacokinetic of irbesartan have not been evaluated. The pharmacokinetic of digoxin was not altered by coadministration of irbesartan.

Pregnancy: Irbesartan is contraindicated in the second and third trimesters of pregnancy. In the second and third trimesters, substances that act directly on the renin-angiotensin-system can cause foetal or neonatal renal failure, foetal skull hypoplasia and even foetal death. As precautionary measure, irbesartan should preferably not be used during first trimester of pregnancy. A switch to a suitable alternative treatment should be carried out in advance of a planned pregnancy. If pregnancy is diagnosed, irbesartan should be discontinued as soon as possible, skull and renal function should be checked with echography if, inadvertently, the treatment was taken for a long period.

Lactation: Irbesartan is contraindicated during lactation. It is not known whether irbesartan is excreted in human milk. Irbesartan is excreted in the milk of lactating rats. Precautions: Intravascular volume depletion: symptomatic hypotension, especially after the first dose, may occur in patients who are volume and/or sodium depleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Such conditions should be corrected before the administration of Irbesartan.

Renal impairment: no dosage adjustment is necessary in patients with impaired renal function. A lower starting dose of Irbesartan 75 mg should be considered for patients undergoing haemodialysis. Intravascular volume depletion: volume and/or sodium depletion should be corrected prior to administration of Irbesartan. 

Hepatic impairment: no dosage adjustment is necessary in patients with mild to moderate hepatic impairment. There is no clinical experience in patients with severe hepatic impairment.

Hypertensive patients with type 2 diabetes and renal disease: the effects of irbesartan both on renal and cardiovascular events were not uniform across all subgroups, in an analysis carried out in the study with patients with advanced renal disease. In particular, they appeared less favourable in women and non-white subjects.

Hyperkalaemia: as with other drugs that affect the renin-angiotensin-aldosterone system, hyperkalaemia may occur during the treatment with Irbesartan, especially in the presence of renal impairment, overt proteinuria due to diabetic renal disease, and/or heart failure. Close monitoring of serum potassium in patients at risk is recommended.

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy: as with other vasodilators, special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy.

Primary aldosteronism: patients with primary aldosteronism generally will not respond to anti-hypertensive drugs acting through inhibition of the renin-angiotensin system. Therefore, the use of Irbesartan is not recommended.

General: in patients whose vascular tone and renal function depend predominantly on the activity of the renin-angiotensinaldosterone system (e.g. patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with angiotensin converting enzyme inhibitors or angiotensin-II receptor antagonists that affect this system has been associated with acute hypotension, azotaemia, oliguria, or rarely acute renal failure. As with any anti-hypertensive agent, excessive blood pressure decrease in patients with ischaemic cardiopathy or ischaemic cardiovascular disease could result in a myocardial infarction or stroke.

Experience in adults exposed to doses of up to 900 mg/day for 8 weeks revealed no toxicity. The most likely manifestations of overdosage are expected to be hypotension and tachycardia; bradycardia might also occur from overdose. No specific information is available on the treatment of overdosage with Irbesartan. The patient should be closely monitored, and the treatment should be symptomatic and supportive. Suggested measures include induction of emesis and/or gastric lavage. Activated charcoal may be useful in the treatment of overdosage. Irbesartan is not removed by haemodialysis.

Store in a cool and dry place, protected from light.

Entecavir is indicated for the treatment of chronic hepatitis B virus infection in adults and pediatric patients 2 years of age and older with evidence of active viral replication and either evidence of persistent elevation in serum aminotransferases (ALT or AST) or histologically active disease.

Hepatic viral infections (Hepatitis B)

By competing with the natural substrate deoxyguanosine triphosphate, entecavir functionally inhibits all three activities of the HBV polymerase (reverse transcriptase, rt):

• Base priming,
• Reverse transcription of the negative strand from the pregenomic messenger RNA, and
• Synthesis of the positive strand of HBV DNA. Upon activation by kinases, the drug can be incorporated into the DNA which has the ultimate effect of inhibiting the HBV polymerase activity.

The recommended dose of Entecavir for chronic hepatitis B virus infection in nucleoside-treatment-naive adults and adolescents 16 years of age is 0.5 mg once daily. For Lamivudine-refractory or known Lamivudine or Telbivudine resistance mutations, the recommended dose of Entecavir is 1 mg once daily. For patients with decompensated liver disease (adult) the recommended dose of Entecavir is 1 mg once daily. Entecavir should be administered on an empty stomach (at least 2 hours after a meal or 2 hours before the next meal).

Missed Dose: If it is almost time for next dose, skip the missed dose and take the next dose at the proper time. Nobody should take a double dose to make up for the missed dose.

The most common adverse events are headache, fatigue, dizziness and nausea.

Entecavir is contraindicated in patients with previously demonstrated hypersensitivity to Entecavir or any component of the product.

Lactic acidosis: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases have been reported with the use of nucleoside analogues alone or in combination with antiretrovirals.

Exacerbations of hepatitis after discontinuation of treatment: Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-hepatitis B therapy, including Entecavir.

Co-administration of Entecavir with Lamivudine or Adefovir dipivoxil did not result in significant drug interactions. The effects of co-administration of Entecavir with other drugs that are eliminated through renal or are known to affect renal function have not been evaluated and patients should be monitored closely for adverse events when coadministered with such drugs.

There are no data on the effect of Entecavir on the transmission of HBV from mother to infant. Therefore, appropriate care should be taken. It is not known whether it is excreted in human milk. Mothers should be instructed not to breastfeed if they are taking Entecavir.

Pediatric: Safety and effectiveness of Entecavir in pediatric patients below the age of 2 years have not been established.

Geriatric: Clinical studies of Entecavir did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. But care should be taken in dose selection, and it may be useful to monitor renal function.

Dose adjustment in renal impairment: Dose adjustment is recommended for patients with CrCl <50 ml/min including patients on hemodialysis or continuous ambulatory peritoneal dialysis (CAPD) as shown below:

• CrCl ≥50 ml/min: 0.5 mg every 24 hours
• CrCl 30 to <50 ml/min: 0.5 mg every 48 hours
• CrCl 10 to <30 ml/min: 0.5 mg every 72 hours
• CrCl <10 ml/min or  Hemodialysis or CAPD: 0.5 mg every 7 days

There is no experience of Entecavir overdosage reported in patients. Healthy subjects who received up to 20 mg daily for up to 14 days and single doses up to 40 mg had no unexpected adverse events. If overdosage occurs, the patient must be monitored for evidence of toxicity and standard supportive treatment as necessary.

Keep in a dry place and store below 30°C. Protect from light and keep out of the reach of children.

Entecavir is indicated for the treatment of chronic hepatitis B virus infection in adults and pediatric patients 2 years of age and older with evidence of active viral replication and either evidence of persistent elevation in serum aminotransferases (ALT or AST) or histologically active disease.

Hepatic viral infections (Hepatitis B)

By competing with the natural substrate deoxyguanosine triphosphate, entecavir functionally inhibits all three activities of the HBV polymerase (reverse transcriptase, rt):

• Base priming,
• Reverse transcription of the negative strand from the pregenomic messenger RNA, and
• Synthesis of the positive strand of HBV DNA. Upon activation by kinases, the drug can be incorporated into the DNA which has the ultimate effect of inhibiting the HBV polymerase activity.

The recommended dose of Entecavir for chronic hepatitis B virus infection in nucleoside-treatment-naive adults and adolescents 16 years of age is 0.5 mg once daily. For Lamivudine-refractory or known Lamivudine or Telbivudine resistance mutations, the recommended dose of Entecavir is 1 mg once daily. For patients with decompensated liver disease (adult) the recommended dose of Entecavir is 1 mg once daily. Entecavir should be administered on an empty stomach (at least 2 hours after a meal or 2 hours before the next meal).

Missed Dose: If it is almost time for next dose, skip the missed dose and take the next dose at the proper time. Nobody should take a double dose to make up for the missed dose.

The most common adverse events are headache, fatigue, dizziness and nausea.

Entecavir is contraindicated in patients with previously demonstrated hypersensitivity to Entecavir or any component of the product.

Lactic acidosis: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases have been reported with the use of nucleoside analogues alone or in combination with antiretrovirals.

Exacerbations of hepatitis after discontinuation of treatment: Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-hepatitis B therapy, including Entecavir.

Co-administration of Entecavir with Lamivudine or Adefovir dipivoxil did not result in significant drug interactions. The effects of co-administration of Entecavir with other drugs that are eliminated through renal or are known to affect renal function have not been evaluated and patients should be monitored closely for adverse events when coadministered with such drugs.

There are no data on the effect of Entecavir on the transmission of HBV from mother to infant. Therefore, appropriate care should be taken. It is not known whether it is excreted in human milk. Mothers should be instructed not to breastfeed if they are taking Entecavir.

Pediatric: Safety and effectiveness of Entecavir in pediatric patients below the age of 2 years have not been established.

Geriatric: Clinical studies of Entecavir did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. But care should be taken in dose selection, and it may be useful to monitor renal function.

Dose adjustment in renal impairment: Dose adjustment is recommended for patients with CrCl <50 ml/min including patients on hemodialysis or continuous ambulatory peritoneal dialysis (CAPD) as shown below:

• CrCl ≥50 ml/min: 0.5 mg every 24 hours
• CrCl 30 to <50 ml/min: 0.5 mg every 48 hours
• CrCl 10 to <30 ml/min: 0.5 mg every 72 hours
• CrCl <10 ml/min or  Hemodialysis or CAPD: 0.5 mg every 7 days

There is no experience of Entecavir overdosage reported in patients. Healthy subjects who received up to 20 mg daily for up to 14 days and single doses up to 40 mg had no unexpected adverse events. If overdosage occurs, the patient must be monitored for evidence of toxicity and standard supportive treatment as necessary.

Keep in a dry place and store below 30°C. Protect from light and keep out of the reach of children.

Mebeverine is indicated for the:

• Symptomatic treatment of irritable bowel syndrome (IBS)
• Chronic irritable colon
• Spastic constipation
• Mucous colitis
• Colicky abdominal pain
• Persistent non-specific diarrhoea

Anticholinergics

For adults, elderly and children over 10 years:

• Mebeverine Hydrochloride 135 mg tablet: 1 tablet 03 times daily.
• Mebeverine Hydrochloride 200 mg capsule: 1 capsule 02 times daily.

This is most effective when taken 20 minutes before meals. After several weeks when the desired effect has been obtained, the dosage may be gradually reduced.

Missed dose: If a dose of this medicine is missed, that should be taken as soon as possible. However, if it is almost time for the next dose, then skip the missed dose and the regular dosing schedule should be maintained. Dose should not be doubled at the same time to compensate the missed dose.

Use in children: Mebeverine is not recommended for children under 10 years.

Generally Mebeverine is well tolerated. However, few side-effects like skin rash, urticaria and angioedema may appear

Hypersensitivity to the drug or any other ingredients.

Caution should be exercised in porphyria or allergic reaction to this or any other medicine of this group.

No teratogenicity has been shown in animal experiments. However, the usual precautions concerning the administration of any drug during pregnancy should be exercised. Mebeverine does not excrete in the breast milk after administering at therapeutic dose.

On theoretical grounds it may be predicted that CNS excitability will occur in case of overdosage. No specific antidote is known: gastric lavage and symptomatic treatment is recommended

Do not store above 30°C. Keep away from light and out of the reach of children.

Mebeverine is indicated for the:

• Symptomatic treatment of irritable bowel syndrome (IBS)
• Chronic irritable colon
• Spastic constipation
• Mucous colitis
• Colicky abdominal pain
• Persistent non-specific diarrhoea

Anticholinergics

For adults, elderly and children over 10 years:

• Mebeverine Hydrochloride 135 mg tablet: 1 tablet 03 times daily.
• Mebeverine Hydrochloride 200 mg capsule: 1 capsule 02 times daily.

This is most effective when taken 20 minutes before meals. After several weeks when the desired effect has been obtained, the dosage may be gradually reduced.

Missed dose: If a dose of this medicine is missed, that should be taken as soon as possible. However, if it is almost time for the next dose, then skip the missed dose and the regular dosing schedule should be maintained. Dose should not be doubled at the same time to compensate the missed dose.

Use in children: Mebeverine is not recommended for children under 10 years.

Generally Mebeverine is well tolerated. However, few side-effects like skin rash, urticaria and angioedema may appear

Hypersensitivity to the drug or any other ingredients.

Caution should be exercised in porphyria or allergic reaction to this or any other medicine of this group.

No teratogenicity has been shown in animal experiments. However, the usual precautions concerning the administration of any drug during pregnancy should be exercised. Mebeverine does not excrete in the breast milk after administering at therapeutic dose.

On theoretical grounds it may be predicted that CNS excitability will occur in case of overdosage. No specific antidote is known: gastric lavage and symptomatic treatment is recommended

Do not store above 30°C. Keep away from light and out of the reach of children.