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Cough expectorants & mucolytics

Ambroxol is the active metabolite of bromhexine and it has been proven that this metabolite possesses a greater bronchosecretolytic effect than bromhexine. It improves sputum rheology by hydrating mechanism leading to liquefaction of mucus in the lumen of respiratory tract, thus facilitating expectoration of mucus and reducing dyspnea. It stimulates production of phospholipids of surfactant by alveolar cells, thus contributing to the lowering of superficial tension in the alveoli. It also reduces bronchial hyperactivity. Ambroxol has anti inflammatory properties owing to the inhibitory effect on the production of cellular cytokines and arachidonic acid metabolites. In patients with COPD it traditionally improves airway patency.

Average daily dose (preferably after meal):

Pediatric Drops:

• 0-6 months: 0.5 ml 2 times a day
• 6-12 months: 1 ml 2 times a day
• 1-2 years: 1.25 ml 2 times a day

Syrup:

• 2-5 years: 2.5 ml (1/2 teaspoonful) 2-3 times a day
• 5-10 years: 5 ml (1 teaspoonful) 2-3 times a day
• 10 years and adults: 10 ml (2 teaspoonful) 3 times a day.

Sustained release capsule: Adult and children over 12 years old: 1 capsule once daily.

Gastrointestinal side effects like epigastric pain, stomach overfill feeling may occur occasionally. Rarely allergic responses such as eruption, urticaria or angioneurotic edema have been reported.

Contraindicated in known hypersensitivity to Ambroxol or Bromhexine.

Ambroxol should be given cautiously to patients with gastric and duodenal ulceration or convulsive disorders. Patients with hepatic and renal insufficiency should take it with caution.

Ambroxol should not be taken simultaneously with antitussives (e.g.Codeine) because phlegm, which has been liquefied by Ambroxol might not be expectorated.

Teratogenic and fetal toxicity studies have shown no harmful effect of Ambroxol. However, it is advised not to use it in pregnancy, especially during the1st trimester. Safety during lactation has not been established yet.

Protect from direct light exposure, Store in a dry place at a temperature not exceeding 30°C, Keep out of the reach of children.

Cough expectorants & mucolytics

Ambroxol is the active metabolite of bromhexine and it has been proven that this metabolite possesses a greater bronchosecretolytic effect than bromhexine. It improves sputum rheology by hydrating mechanism leading to liquefaction of mucus in the lumen of respiratory tract, thus facilitating expectoration of mucus and reducing dyspnea. It stimulates production of phospholipids of surfactant by alveolar cells, thus contributing to the lowering of superficial tension in the alveoli. It also reduces bronchial hyperactivity. Ambroxol has anti inflammatory properties owing to the inhibitory effect on the production of cellular cytokines and arachidonic acid metabolites. In patients with COPD it traditionally improves airway patency.

Average daily dose (preferably after meal):

Pediatric Drops:

• 0-6 months: 0.5 ml 2 times a day
• 6-12 months: 1 ml 2 times a day
• 1-2 years: 1.25 ml 2 times a day

Syrup:

• 2-5 years: 2.5 ml (1/2 teaspoonful) 2-3 times a day
• 5-10 years: 5 ml (1 teaspoonful) 2-3 times a day
• 10 years and adults: 10 ml (2 teaspoonful) 3 times a day.

Sustained release capsule: Adult and children over 12 years old: 1 capsule once daily.

Gastrointestinal side effects like epigastric pain, stomach overfill feeling may occur occasionally. Rarely allergic responses such as eruption, urticaria or angioneurotic edema have been reported.

Contraindicated in known hypersensitivity to Ambroxol or Bromhexine.

Ambroxol should be given cautiously to patients with gastric and duodenal ulceration or convulsive disorders. Patients with hepatic and renal insufficiency should take it with caution.

Ambroxol should not be taken simultaneously with antitussives (e.g.Codeine) because phlegm, which has been liquefied by Ambroxol might not be expectorated.

Teratogenic and fetal toxicity studies have shown no harmful effect of Ambroxol. However, it is advised not to use it in pregnancy, especially during the1st trimester. Safety during lactation has not been established yet.

Protect from direct light exposure, Store in a dry place at a temperature not exceeding 30°C, Keep out of the reach of children.

Cough expectorants & mucolytics

Ambroxol is the active metabolite of bromhexine and it has been proven that this metabolite possesses a greater bronchosecretolytic effect than bromhexine. It improves sputum rheology by hydrating mechanism leading to liquefaction of mucus in the lumen of respiratory tract, thus facilitating expectoration of mucus and reducing dyspnea. It stimulates production of phospholipids of surfactant by alveolar cells, thus contributing to the lowering of superficial tension in the alveoli. It also reduces bronchial hyperactivity. Ambroxol has anti inflammatory properties owing to the inhibitory effect on the production of cellular cytokines and arachidonic acid metabolites. In patients with COPD it traditionally improves airway patency.

Average daily dose (preferably after meal):

Pediatric Drops:

• 0-6 months: 0.5 ml 2 times a day
• 6-12 months: 1 ml 2 times a day
• 1-2 years: 1.25 ml 2 times a day

Syrup:

• 2-5 years: 2.5 ml (1/2 teaspoonful) 2-3 times a day
• 5-10 years: 5 ml (1 teaspoonful) 2-3 times a day
• 10 years and adults: 10 ml (2 teaspoonful) 3 times a day.

Sustained release capsule: Adult and children over 12 years old: 1 capsule once daily.

Gastrointestinal side effects like epigastric pain, stomach overfill feeling may occur occasionally. Rarely allergic responses such as eruption, urticaria or angioneurotic edema have been reported.

Contraindicated in known hypersensitivity to Ambroxol or Bromhexine.

Ambroxol should be given cautiously to patients with gastric and duodenal ulceration or convulsive disorders. Patients with hepatic and renal insufficiency should take it with caution.

Ambroxol should not be taken simultaneously with antitussives (e.g.Codeine) because phlegm, which has been liquefied by Ambroxol might not be expectorated.

Teratogenic and fetal toxicity studies have shown no harmful effect of Ambroxol. However, it is advised not to use it in pregnancy, especially during the1st trimester. Safety during lactation has not been established yet.

Protect from direct light exposure, Store in a dry place at a temperature not exceeding 30°C, Keep out of the reach of children.

Bambuterol is indicated for Bronchial asthma, chronic bronchitis, emphysema & other lung diseases where bronchospasm is a complicating factor.

Short-acting selective & β2-adrenoceptor stimulants

Bambuterol is an adrenergic β2 receptor agonist which predominantly stimulates β2 receptor, thus producing relaxation of bronchial smooth muscle, inhibition of release of endogenous spasmogens, inhibition of edema caused by endogenous mediators & increased mucocilliary clearance.

Adult or Elderly: The recommended initial dose 10 mg. The dose may be increased to 20 mg after 1-2 weeks depending on the clinical effect.

Children 2-5 years: The recommended normal dose 10 mg (10 ml syrup).

Children 6-12 years: The recommended normal dose 10 mg (10 ml syrup). The dose may be increased to 20 mg.

Common side effects are fatigue, nausea, palpitation, headache, dizziness & tremor.

Bambuterol is contraindicated in hepatic impairment, liver cirrhosis or severely impaired liver function.

Reduce the dose in renal impairment, avoid in cirrhosis and severe hepatic impairment. Caution should be observed in patients with severe cardiovascular disorder, such as ischaemic heart disease, tachyarrhythmias or severe heart failure.

Succinylcholin, MAOIs (monoamine oxidase inhibitors), β2-blockers, corticosteroids, diuretics, muscle relaxants, sympathomimetic xanthine derivatives. Bambuterol may partly or totally inhibit the effect of β-blockers.

Pregnant women: There is no definite evidence of ill consequence during pregnancy. Nevertheless, the drug should not be used during the first trimester of pregnancy, unless the expected benefit is thought to outweigh any possible risk to the fetus.

Lactating mother: It is excreted in breast milk. So, patients taking this drug should not breast-feed.

Impaired renal function (GFR 50 ml/min): The recommended starting dose is 5 mg, which may be increased to 10 mg after one to two weeks, depending on the clinical effect.

Impaired hepatic function: Not recommended because of unpredictable conversion to terbutaline.

Keep away from light, store in a cool and dry place. Keep out of reach of children.

Calcium-channel blockers

Amlodipine is a dihydropyridine calcium-channel blocker, with a long duration of action, used for the treatment of hypertension and angina pectoris. Amlodipine influences the myocardial cells, the cells within the specialized conducting system of the heart, and the cells of vascular smooth muscle. Administration of Amlodipine results primarily in vasodilation, with reduced peripheral resistance, blood pressure and afterload, increased coronary blood flow and a reflex increase in coronary heart rate. This in turn results in an increase in myocardial oxygen supply and cardiac output.

Hypertension: Usual dose is 5 mg once daily. The maximum dose is 10 mg once daily. Elderly patients with hepatic insufficiency may be started on 2.5 mg once daily; this dose may also be used when adding Amlodipine to other antihypertensive therapy.

Angina (Chronic stable or Vasospastic): 5 to 10 mg, using the lower dose for elderly and in patients with hepatic insufficiency. Most patients require 10 mg.

Administrations: May be taken without regard to meals.

The most common adverse effects of amlodipine are associated with vasodilatory action, such as dizziness, flushing, headache, hypotension and peripheral edema. Gastrointestinal disturbances, increased micturition frequency, lethargy, eye pain and mental depression may also occur. A paradoxical increase in ischaemic chest pain may occur at the start of the treatment and in a few patients excessive fall in blood pressure has led to cerebral or myocardial ischaemia or transient blindness. Rashes, fever and abnormalities in liver function due to hypersensitivity reaction of Amlodipine may occur.

Hypersensitivity to dihydropyridine derivatives. Pregnant woman.

Precaution should be taken in patients with hepatic impairment and during pregnancy and breast feeding.

Drug Interactions-

• Potentially hazardous interactions: Little or no data are available in patients with markedly impaired cardiac left ventricular function; however, as with other calcium antagonist drugs, the combination of Amlodipine and p-blockers should be avoided in such patients.

Other Significant Interactions-

• Digoxin: Absence of any interaction between Amlodipine and Digoxin in healthy volunteers has been documented in a controlled clinical study.
• Cimetidine: An unpublished clinical study indicated no interaction between, Amlodipine and Cimetidine in healthy volunteers.
• Warfarin: An unpublished clinical study in healthy volunteers indicates that Amlodipine did not significantly alter the effect of Warfarin on prothrombin time.
• Food: Food does not alter the rate or extent of absorption of Amlodipine.

Pregnancy Category C. There are no adequate and well-controlled studies of Amlodipine in pregnant women. Amlodipine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. It is not known whether Amlodipine is excreted in human milk. In the absence of this information, it is recommended that nursing be discontinued while Amlodipine is administered.

Children with hypertension from 6 years to 17 years of age: 2.5 mg once daily as a starting dose, up-titrated to 5 mg once daily if blood pressure goal is not achieved after 4 weeks. Doses in excess of 5 mg daily have not been studied in pediatric patients.

Children under 6 years old:  The effect of amlodipine on blood pressure in patients less than 6 years of age is not known.

Elderly: Amlodipine used at similar doses in elderly or younger patients is equally well tolerated. Normal dosage regimens are recommended in the elderly, but increase of the dosage should take place with care.

Renal impairment: Changes in amlodipine plasma concentrations are not correlated with degree of renal impairment, therefore the normal dosage is recommended. Amlodipine is not dialysable.

Hepatic impairment: Dosage recommendations have not been established in patients with mild to moderate hepatic impairment; therefore dose selection should be cautions and should start at the lower end of the dosing range. The pharmacokinetics of Amlodipine have not been studied in severe hepatic impairment. Amlodipine should be initiated at the lowest dose (2.5 mg once daily) and titrated slowly in patients with severe hepatic impairment.

Symptoms: Available data suggest that large overdosage could result in excessive peripheral vasodilatation and possibly reflex tachycardia. Marked and probably prolonged systemic hypotension up to and including shock with fatal outcome have been reported.

Management: Clinically significant hypotension due to amlodipine overdosage calls for active cardiovascular support including frequent monitoring of cardiac and respiratory function, elevation of extremities, and attention to circulating fluid volume and urine output. 

A vasoconstrictor may be helpful in restoring vascular tone and blood pressure, provided that there is no contraindication to its use. Intravenous calcium gluconate may be beneficial in reversing the effects of calcium channel blockade. Gastric lavage may be worthwhile in some cases. In healthy volunteers the use of charcoal up to 2 hours after administration of amlodipine 10 mg has been shown to reduce the absorption rate of amlodipine. Since amlodipine is highly protein-bound, dialysis is not likely to be of benefit.

Keep all medicines out of reach of children. Store in a cool & dry place, protected from light.

Calcium-channel blockers

Amlodipine is a dihydropyridine calcium-channel blocker, with a long duration of action, used for the treatment of hypertension and angina pectoris. Amlodipine influences the myocardial cells, the cells within the specialized conducting system of the heart, and the cells of vascular smooth muscle. Administration of Amlodipine results primarily in vasodilation, with reduced peripheral resistance, blood pressure and afterload, increased coronary blood flow and a reflex increase in coronary heart rate. This in turn results in an increase in myocardial oxygen supply and cardiac output.

Hypertension: Usual dose is 5 mg once daily. The maximum dose is 10 mg once daily. Elderly patients with hepatic insufficiency may be started on 2.5 mg once daily; this dose may also be used when adding Amlodipine to other antihypertensive therapy.

Angina (Chronic stable or Vasospastic): 5 to 10 mg, using the lower dose for elderly and in patients with hepatic insufficiency. Most patients require 10 mg.

Administrations: May be taken without regard to meals.

The most common adverse effects of amlodipine are associated with vasodilatory action, such as dizziness, flushing, headache, hypotension and peripheral edema. Gastrointestinal disturbances, increased micturition frequency, lethargy, eye pain and mental depression may also occur. A paradoxical increase in ischaemic chest pain may occur at the start of the treatment and in a few patients excessive fall in blood pressure has led to cerebral or myocardial ischaemia or transient blindness. Rashes, fever and abnormalities in liver function due to hypersensitivity reaction of Amlodipine may occur.

Hypersensitivity to dihydropyridine derivatives. Pregnant woman.

Precaution should be taken in patients with hepatic impairment and during pregnancy and breast feeding.

Drug Interactions-

• Potentially hazardous interactions: Little or no data are available in patients with markedly impaired cardiac left ventricular function; however, as with other calcium antagonist drugs, the combination of Amlodipine and p-blockers should be avoided in such patients.

Other Significant Interactions-

• Digoxin: Absence of any interaction between Amlodipine and Digoxin in healthy volunteers has been documented in a controlled clinical study.
• Cimetidine: An unpublished clinical study indicated no interaction between, Amlodipine and Cimetidine in healthy volunteers.
• Warfarin: An unpublished clinical study in healthy volunteers indicates that Amlodipine did not significantly alter the effect of Warfarin on prothrombin time.
• Food: Food does not alter the rate or extent of absorption of Amlodipine.

Pregnancy Category C. There are no adequate and well-controlled studies of Amlodipine in pregnant women. Amlodipine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. It is not known whether Amlodipine is excreted in human milk. In the absence of this information, it is recommended that nursing be discontinued while Amlodipine is administered.

Children with hypertension from 6 years to 17 years of age: 2.5 mg once daily as a starting dose, up-titrated to 5 mg once daily if blood pressure goal is not achieved after 4 weeks. Doses in excess of 5 mg daily have not been studied in pediatric patients.

Children under 6 years old:  The effect of amlodipine on blood pressure in patients less than 6 years of age is not known.

Elderly: Amlodipine used at similar doses in elderly or younger patients is equally well tolerated. Normal dosage regimens are recommended in the elderly, but increase of the dosage should take place with care.

Renal impairment: Changes in amlodipine plasma concentrations are not correlated with degree of renal impairment, therefore the normal dosage is recommended. Amlodipine is not dialysable.

Hepatic impairment: Dosage recommendations have not been established in patients with mild to moderate hepatic impairment; therefore dose selection should be cautions and should start at the lower end of the dosing range. The pharmacokinetics of Amlodipine have not been studied in severe hepatic impairment. Amlodipine should be initiated at the lowest dose (2.5 mg once daily) and titrated slowly in patients with severe hepatic impairment.

Symptoms: Available data suggest that large overdosage could result in excessive peripheral vasodilatation and possibly reflex tachycardia. Marked and probably prolonged systemic hypotension up to and including shock with fatal outcome have been reported.

Management: Clinically significant hypotension due to amlodipine overdosage calls for active cardiovascular support including frequent monitoring of cardiac and respiratory function, elevation of extremities, and attention to circulating fluid volume and urine output. 

A vasoconstrictor may be helpful in restoring vascular tone and blood pressure, provided that there is no contraindication to its use. Intravenous calcium gluconate may be beneficial in reversing the effects of calcium channel blockade. Gastric lavage may be worthwhile in some cases. In healthy volunteers the use of charcoal up to 2 hours after administration of amlodipine 10 mg has been shown to reduce the absorption rate of amlodipine. Since amlodipine is highly protein-bound, dialysis is not likely to be of benefit.

Keep all medicines out of reach of children. Store in a cool & dry place, protected from light.

This is indicated in-

• Patients with essential hypertension
• Patients with angina pectoris & hypertension as co-existing diseases
• ln post Ml patients
• ln patients with refractory angina pectoris where nitrate therapy has failed.

Combined antihypertensive preparations

This is a fixed-dose combination of Amlodipine and Atenolol. Amlodipine is a dihydropyridine calcium antagonist that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle; it has a greater effect on vascular smooth muscle than on cardiac muscle. Amlodipine is a peripheral vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure. Amlodipine reduces tone, decreases coronary vasoreactivity and lowers cardiac demand by reducing afterload.

Atenolol is a cardioselective beta-blocker. The cardio-selectivity is dose-related. Atenolol causes a reduction in blood pressure by lowering cardiac output, decreasing the plasma renin activity and sympathetic outflow from CNS. Atenolol also causes a reduction in myocardial oxygen demand by virtue of its negative inotropic and negative chronotropic effects.

The recommended dosage is Amlodipine and Atenolol 5/25 mg tablet once daily. If necessary, the dosage may be increased to 5/25 mg two tablets daily or as advised by the physicians. The dosage however should be individualized.

The combination of Amlodipine and Atenolol is well tolerated. Overall side-effects include
fatigue, headache, edema, nausea, drowsiness, anxiety and depression.

Hypersensitivity to either component, sinus bradycardia, second and higher degrees of heart block, cardiogenic shock, hypotension, congestive heart failure, poor left ventricular function.

Bronchospasm: The combination should be used with caution in patients with airway obstruction.

Renal impairment: The combination can be used in patients with renal impairment. However, caution may be necessary if the creatinine clearance is less than 30 ml/min because of possible reduction in the excretion of unchanged Atenolol.

Hepatic impairment: Caution may be necessary in the use of the combination in patients with severe liver damage because of prolongation of the elimination half-life of Amlodipine.

Drug withdrawal: Since coronary heart disease may exist without being recognized, patients should be warned against stopping the drug suddenly. Any discontinuation should be gradual and under observation.

Disopyramide: Atenolol reduces the clearance of disopyramide by 20%. Additive negative inotropic effects on the heart may be produced.

Ampicillin: at doses of 1 gm and above may reduce Atenolol levels.

Oral antidiabetics and insulin: Beta-blockers may decrease tissue sensitivity to insulin and inhibit insulin secretion e.g. in response to oral antidiabetics. Atenolol has less potential for these actions.

The combination should be used during pregnancy only if the expected benefit outweighs the potential fetal risk. The combination should not be used by nursing mothers. If its use is considered necessary, breast-feeding should be stopped.

Though not documented, hypotension and less frequently congestive cardiac failure may occur in cases of overdosage. Unabsorbed drugs may be removed by gastric lavage or administration of activated charcoal. Symptomatic treatment is suggested.

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

Calcium-channel blockers

Amlodipine is a dihydropyridine calcium-channel blocker, with a long duration of action, used for the treatment of hypertension and angina pectoris. Amlodipine influences the myocardial cells, the cells within the specialized conducting system of the heart, and the cells of vascular smooth muscle. Administration of Amlodipine results primarily in vasodilation, with reduced peripheral resistance, blood pressure and afterload, increased coronary blood flow and a reflex increase in coronary heart rate. This in turn results in an increase in myocardial oxygen supply and cardiac output.

Hypertension: Usual dose is 5 mg once daily. The maximum dose is 10 mg once daily. Elderly patients with hepatic insufficiency may be started on 2.5 mg once daily; this dose may also be used when adding Amlodipine to other antihypertensive therapy.

Angina (Chronic stable or Vasospastic): 5 to 10 mg, using the lower dose for elderly and in patients with hepatic insufficiency. Most patients require 10 mg.

Administrations: May be taken without regard to meals.

The most common adverse effects of amlodipine are associated with vasodilatory action, such as dizziness, flushing, headache, hypotension and peripheral edema. Gastrointestinal disturbances, increased micturition frequency, lethargy, eye pain and mental depression may also occur. A paradoxical increase in ischaemic chest pain may occur at the start of the treatment and in a few patients excessive fall in blood pressure has led to cerebral or myocardial ischaemia or transient blindness. Rashes, fever and abnormalities in liver function due to hypersensitivity reaction of Amlodipine may occur.

Hypersensitivity to dihydropyridine derivatives. Pregnant woman.

Precaution should be taken in patients with hepatic impairment and during pregnancy and breast feeding.

Drug Interactions-

• Potentially hazardous interactions: Little or no data are available in patients with markedly impaired cardiac left ventricular function; however, as with other calcium antagonist drugs, the combination of Amlodipine and p-blockers should be avoided in such patients.

Other Significant Interactions-

• Digoxin: Absence of any interaction between Amlodipine and Digoxin in healthy volunteers has been documented in a controlled clinical study.
• Cimetidine: An unpublished clinical study indicated no interaction between, Amlodipine and Cimetidine in healthy volunteers.
• Warfarin: An unpublished clinical study in healthy volunteers indicates that Amlodipine did not significantly alter the effect of Warfarin on prothrombin time.
• Food: Food does not alter the rate or extent of absorption of Amlodipine.

Pregnancy Category C. There are no adequate and well-controlled studies of Amlodipine in pregnant women. Amlodipine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. It is not known whether Amlodipine is excreted in human milk. In the absence of this information, it is recommended that nursing be discontinued while Amlodipine is administered.

Children with hypertension from 6 years to 17 years of age: 2.5 mg once daily as a starting dose, up-titrated to 5 mg once daily if blood pressure goal is not achieved after 4 weeks. Doses in excess of 5 mg daily have not been studied in pediatric patients.

Children under 6 years old:  The effect of amlodipine on blood pressure in patients less than 6 years of age is not known.

Elderly: Amlodipine used at similar doses in elderly or younger patients is equally well tolerated. Normal dosage regimens are recommended in the elderly, but increase of the dosage should take place with care.

Renal impairment: Changes in amlodipine plasma concentrations are not correlated with degree of renal impairment, therefore the normal dosage is recommended. Amlodipine is not dialysable.

Hepatic impairment: Dosage recommendations have not been established in patients with mild to moderate hepatic impairment; therefore dose selection should be cautions and should start at the lower end of the dosing range. The pharmacokinetics of Amlodipine have not been studied in severe hepatic impairment. Amlodipine should be initiated at the lowest dose (2.5 mg once daily) and titrated slowly in patients with severe hepatic impairment.

Symptoms: Available data suggest that large overdosage could result in excessive peripheral vasodilatation and possibly reflex tachycardia. Marked and probably prolonged systemic hypotension up to and including shock with fatal outcome have been reported.

Management: Clinically significant hypotension due to amlodipine overdosage calls for active cardiovascular support including frequent monitoring of cardiac and respiratory function, elevation of extremities, and attention to circulating fluid volume and urine output. 

A vasoconstrictor may be helpful in restoring vascular tone and blood pressure, provided that there is no contraindication to its use. Intravenous calcium gluconate may be beneficial in reversing the effects of calcium channel blockade. Gastric lavage may be worthwhile in some cases. In healthy volunteers the use of charcoal up to 2 hours after administration of amlodipine 10 mg has been shown to reduce the absorption rate of amlodipine. Since amlodipine is highly protein-bound, dialysis is not likely to be of benefit.

Keep all medicines out of reach of children. Store in a cool & dry place, protected from light.

Calcium-channel blockers

Amlodipine is a dihydropyridine calcium-channel blocker, with a long duration of action, used for the treatment of hypertension and angina pectoris. Amlodipine influences the myocardial cells, the cells within the specialized conducting system of the heart, and the cells of vascular smooth muscle. Administration of Amlodipine results primarily in vasodilation, with reduced peripheral resistance, blood pressure and afterload, increased coronary blood flow and a reflex increase in coronary heart rate. This in turn results in an increase in myocardial oxygen supply and cardiac output.

Hypertension: Usual dose is 5 mg once daily. The maximum dose is 10 mg once daily. Elderly patients with hepatic insufficiency may be started on 2.5 mg once daily; this dose may also be used when adding Amlodipine to other antihypertensive therapy.

Angina (Chronic stable or Vasospastic): 5 to 10 mg, using the lower dose for elderly and in patients with hepatic insufficiency. Most patients require 10 mg.

Administrations: May be taken without regard to meals.

The most common adverse effects of amlodipine are associated with vasodilatory action, such as dizziness, flushing, headache, hypotension and peripheral edema. Gastrointestinal disturbances, increased micturition frequency, lethargy, eye pain and mental depression may also occur. A paradoxical increase in ischaemic chest pain may occur at the start of the treatment and in a few patients excessive fall in blood pressure has led to cerebral or myocardial ischaemia or transient blindness. Rashes, fever and abnormalities in liver function due to hypersensitivity reaction of Amlodipine may occur.

Hypersensitivity to dihydropyridine derivatives. Pregnant woman.

Precaution should be taken in patients with hepatic impairment and during pregnancy and breast feeding.

Drug Interactions-

• Potentially hazardous interactions: Little or no data are available in patients with markedly impaired cardiac left ventricular function; however, as with other calcium antagonist drugs, the combination of Amlodipine and p-blockers should be avoided in such patients.

Other Significant Interactions-

• Digoxin: Absence of any interaction between Amlodipine and Digoxin in healthy volunteers has been documented in a controlled clinical study.
• Cimetidine: An unpublished clinical study indicated no interaction between, Amlodipine and Cimetidine in healthy volunteers.
• Warfarin: An unpublished clinical study in healthy volunteers indicates that Amlodipine did not significantly alter the effect of Warfarin on prothrombin time.
• Food: Food does not alter the rate or extent of absorption of Amlodipine.

Pregnancy Category C. There are no adequate and well-controlled studies of Amlodipine in pregnant women. Amlodipine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. It is not known whether Amlodipine is excreted in human milk. In the absence of this information, it is recommended that nursing be discontinued while Amlodipine is administered.

Children with hypertension from 6 years to 17 years of age: 2.5 mg once daily as a starting dose, up-titrated to 5 mg once daily if blood pressure goal is not achieved after 4 weeks. Doses in excess of 5 mg daily have not been studied in pediatric patients.

Children under 6 years old:  The effect of amlodipine on blood pressure in patients less than 6 years of age is not known.

Elderly: Amlodipine used at similar doses in elderly or younger patients is equally well tolerated. Normal dosage regimens are recommended in the elderly, but increase of the dosage should take place with care.

Renal impairment: Changes in amlodipine plasma concentrations are not correlated with degree of renal impairment, therefore the normal dosage is recommended. Amlodipine is not dialysable.

Hepatic impairment: Dosage recommendations have not been established in patients with mild to moderate hepatic impairment; therefore dose selection should be cautions and should start at the lower end of the dosing range. The pharmacokinetics of Amlodipine have not been studied in severe hepatic impairment. Amlodipine should be initiated at the lowest dose (2.5 mg once daily) and titrated slowly in patients with severe hepatic impairment.

Symptoms: Available data suggest that large overdosage could result in excessive peripheral vasodilatation and possibly reflex tachycardia. Marked and probably prolonged systemic hypotension up to and including shock with fatal outcome have been reported.

Management: Clinically significant hypotension due to amlodipine overdosage calls for active cardiovascular support including frequent monitoring of cardiac and respiratory function, elevation of extremities, and attention to circulating fluid volume and urine output. 

A vasoconstrictor may be helpful in restoring vascular tone and blood pressure, provided that there is no contraindication to its use. Intravenous calcium gluconate may be beneficial in reversing the effects of calcium channel blockade. Gastric lavage may be worthwhile in some cases. In healthy volunteers the use of charcoal up to 2 hours after administration of amlodipine 10 mg has been shown to reduce the absorption rate of amlodipine. Since amlodipine is highly protein-bound, dialysis is not likely to be of benefit.

Keep all medicines out of reach of children. Store in a cool & dry place, protected from light.

This is indicated in-

• Patients with essential hypertension
• Patients with angina pectoris & hypertension as co-existing diseases
• ln post Ml patients
• ln patients with refractory angina pectoris where nitrate therapy has failed.

Combined antihypertensive preparations

This is a fixed-dose combination of Amlodipine and Atenolol. Amlodipine is a dihydropyridine calcium antagonist that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle; it has a greater effect on vascular smooth muscle than on cardiac muscle. Amlodipine is a peripheral vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure. Amlodipine reduces tone, decreases coronary vasoreactivity and lowers cardiac demand by reducing afterload.

Atenolol is a cardioselective beta-blocker. The cardio-selectivity is dose-related. Atenolol causes a reduction in blood pressure by lowering cardiac output, decreasing the plasma renin activity and sympathetic outflow from CNS. Atenolol also causes a reduction in myocardial oxygen demand by virtue of its negative inotropic and negative chronotropic effects.

The recommended dosage is Amlodipine and Atenolol 5/25 mg tablet once daily. If necessary, the dosage may be increased to 5/25 mg two tablets daily or as advised by the physicians. The dosage however should be individualized.

The combination of Amlodipine and Atenolol is well tolerated. Overall side-effects include
fatigue, headache, edema, nausea, drowsiness, anxiety and depression.

Hypersensitivity to either component, sinus bradycardia, second and higher degrees of heart block, cardiogenic shock, hypotension, congestive heart failure, poor left ventricular function.

Bronchospasm: The combination should be used with caution in patients with airway obstruction.

Renal impairment: The combination can be used in patients with renal impairment. However, caution may be necessary if the creatinine clearance is less than 30 ml/min because of possible reduction in the excretion of unchanged Atenolol.

Hepatic impairment: Caution may be necessary in the use of the combination in patients with severe liver damage because of prolongation of the elimination half-life of Amlodipine.

Drug withdrawal: Since coronary heart disease may exist without being recognized, patients should be warned against stopping the drug suddenly. Any discontinuation should be gradual and under observation.

Disopyramide: Atenolol reduces the clearance of disopyramide by 20%. Additive negative inotropic effects on the heart may be produced.

Ampicillin: at doses of 1 gm and above may reduce Atenolol levels.

Oral antidiabetics and insulin: Beta-blockers may decrease tissue sensitivity to insulin and inhibit insulin secretion e.g. in response to oral antidiabetics. Atenolol has less potential for these actions.

The combination should be used during pregnancy only if the expected benefit outweighs the potential fetal risk. The combination should not be used by nursing mothers. If its use is considered necessary, breast-feeding should be stopped.

Though not documented, hypotension and less frequently congestive cardiac failure may occur in cases of overdosage. Unabsorbed drugs may be removed by gastric lavage or administration of activated charcoal. Symptomatic treatment is suggested.

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

This is indicated in-

• Patients with essential hypertension
• Patients with angina pectoris & hypertension as co-existing diseases
• ln post Ml patients
• ln patients with refractory angina pectoris where nitrate therapy has failed.

Combined antihypertensive preparations

This is a fixed-dose combination of Amlodipine and Atenolol. Amlodipine is a dihydropyridine calcium antagonist that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle; it has a greater effect on vascular smooth muscle than on cardiac muscle. Amlodipine is a peripheral vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure. Amlodipine reduces tone, decreases coronary vasoreactivity and lowers cardiac demand by reducing afterload.

Atenolol is a cardioselective beta-blocker. The cardio-selectivity is dose-related. Atenolol causes a reduction in blood pressure by lowering cardiac output, decreasing the plasma renin activity and sympathetic outflow from CNS. Atenolol also causes a reduction in myocardial oxygen demand by virtue of its negative inotropic and negative chronotropic effects.

The recommended dosage is Amlodipine and Atenolol 5/25 mg tablet once daily. If necessary, the dosage may be increased to 5/25 mg two tablets daily or as advised by the physicians. The dosage however should be individualized.

The combination of Amlodipine and Atenolol is well tolerated. Overall side-effects include
fatigue, headache, edema, nausea, drowsiness, anxiety and depression.

Hypersensitivity to either component, sinus bradycardia, second and higher degrees of heart block, cardiogenic shock, hypotension, congestive heart failure, poor left ventricular function.

Bronchospasm: The combination should be used with caution in patients with airway obstruction.

Renal impairment: The combination can be used in patients with renal impairment. However, caution may be necessary if the creatinine clearance is less than 30 ml/min because of possible reduction in the excretion of unchanged Atenolol.

Hepatic impairment: Caution may be necessary in the use of the combination in patients with severe liver damage because of prolongation of the elimination half-life of Amlodipine.

Drug withdrawal: Since coronary heart disease may exist without being recognized, patients should be warned against stopping the drug suddenly. Any discontinuation should be gradual and under observation.

Disopyramide: Atenolol reduces the clearance of disopyramide by 20%. Additive negative inotropic effects on the heart may be produced.

Ampicillin: at doses of 1 gm and above may reduce Atenolol levels.

Oral antidiabetics and insulin: Beta-blockers may decrease tissue sensitivity to insulin and inhibit insulin secretion e.g. in response to oral antidiabetics. Atenolol has less potential for these actions.

The combination should be used during pregnancy only if the expected benefit outweighs the potential fetal risk. The combination should not be used by nursing mothers. If its use is considered necessary, breast-feeding should be stopped.

Though not documented, hypotension and less frequently congestive cardiac failure may occur in cases of overdosage. Unabsorbed drugs may be removed by gastric lavage or administration of activated charcoal. Symptomatic treatment is suggested.

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

Bisoprolol & Amlodipine combination is indicated for the treatment of hypertension as substitution therapy in patients adequately controlled with the individual products given concurrently at the same dose level as in the combination, but as separate tablets

Anti-hypertensive

This consists of Amlodipine and Bisoprolol Fumarate. Amlodipine is a dihydropyridine calcium antagonist that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Amlodipine acts directly on vessels to cause a reduction in peripheral vascular resistance and reduction in blood pressure.

Bisoprolol Fumarate is a synthetic, beta1-selective (cardioselective) adrenoceptor blocking agent, lacking intrinsic sympathomimetic and relevant membrane stabilizing activity. It only shows low affinity to the beta2 receptor of the smooth muscles of bronchi and vessels as well as to the beta2-receptors concerned with metabolic regulation. Therefore, bisoprolol is generally not to be expected to influence airway resistance and beta2-mediated metabolic effects. Its beta1-selectivity extends beyond the therapeutic dose range.

One tablet once daily in patients whose blood pressure is adequately controlled with separately administered monocomponent products of the same doses as the recommended fixed-dose combination.

Common: Dizziness, headache, somnolence, palpitations, flushing, feeling of coldness or numbness in the extremities, gastrointestinal complaints such as nausea, vomiting, diarrhea, constipation, abdominal pain; edema (e.g. ankle edema), fatigue.

Uncommon: Insomnia, mood changes (incl. anxiety), depression, sleep disorders, hypaesthesia, paresthesia, dysgeusia, tremor, visual disturbances (incl. diplopia), tinnitus, AV conduction disturbances, worsening of pre existing heart failure, bradycardia, hypotension, syncope, dyspnea, bronchospasm in patients with bronchial asthma or a history of obstructive airway disease, rhinitis, dyspepsia, dry mouth, alopecia, purpura, skin discoloration, pruritus, exanthema, arthralgia, myalgia, muscular weakness, muscle cramps, back pain, micturition disorder, nocturia, pollakisuria, potency disorders, gynecomastia, asthenia, chest pain, pain, malaise, weight increase, weight decrease.

Rare: Allergic reactions mainly affecting the skin, nightmares, hallucinations, confusion, decreased tear secretion, hearing disorders, allergic rhinitis, hepatitis, increased triglycerides, increased liver enzymes (ALAT, ASAT).

Acute heart failure or during episodes of heart failure decompensation, obstruction of the outflow tract of the left ventricle (e.g. high grade aortic stenosis), cardiogenic shock, second or third degree AV block, sick sinus syndrome, sinoatrial block, symptomatic bradycardia or hypotension, severe bronchial asthma, severe forms of peripheral arterial occlusive disease or severe forms of Raynaud’s syndrome, untreated phaeochromocytoma metabolic acidosis, hypersensitivity to bisoprolol, amlodipine, dihydropyridine derivates or to any of the excipients.

Patients with heart failure should be treated with caution. An increased risk of a further deterioration of the ventricular pump function cannot be excluded. Since the abrupt withdrawal of bisoprolol may lead to a transitory worsening of the clinical condition, especially in patients with ischemic heart disease, the treatment must not be stopped abruptly. Caution is advised in patients with impaired hepatic function. Beta-blockers should be avoided in patients with obstructive airways diseases unless there are compelling clinical reasons for their use. Due to the bisoprolol component treatment must be used with caution in: bronchospasm (bronchial asthma, chronic obstructive airways disease; concomitant bronchodilating therapy may be recommended); diabetes mellitus showing large fluctuations in blood glucose values, symptoms of hypoglycemia can be masked; strict fasting; ongoing desensitization therapy; first degree AV block; Prinzmetal’s angina; peripheral arterial occlusive disease. Patients with psoriasis or with a history of psoriasis should only be given beta-blockers (e.g. bisoprolol) after a careful balancing of benefits and risks. Symptoms of thyrotoxicosis may be masked. In patients undergoing general anesthesia, the anesthetist must be aware of beta-blockade. If it is thought necessary to withdraw beta blocker therapy before surgery, this should be done gradually and completed about 48 hours before anesthesia.

Combinations not recommended: Calcium antagonists of the verapamil and diltiazem type, centrally-acting antihypertensive drugs.

Combinations to be used with caution: Strong or moderate CYP3A4 inhibitors, CYP3A4 inducers, simvastatin, Tacrolimus, Cyclosporine, class I antiarrhythmic drugs, class III antiarrhythmic drugs, parasympathomimetic drugs, topical beta-blockers (e.g. eye drops), insulin and oral antidiabetic drugs, anesthetic agents, digitalis glycosides, non-steroidal anti-inflammatory drugs (NSAIDs), sympathomimetic agents, antihypertensive agents and other drugs with blood pressure lowering potential.

Combinations to be considered: Mefloquine, Rifampicin, Ergotamine derivatives, MAO inhibitors (except MAO-B inhibitor).

Pregnancy and Lactation: Not recommended.

Geriatric use: The usual doses can be administered to elderly people; however, caution is advised when the dose is increased.

Pediatric use: The safety and efficacy of Bisoprolol fumarate/amlodipine in children and adolescents below the age of 18 years have not been established. No data are available.

Patients with Liver disease: In case of hepatic impairment elimination of amlodipine may be elongated. Exact dosage recommendations concerning amlodipine have not been established, but the drug should therefore be administered with special caution in these patients. In case of severe hepatic impairment, the daily dose of bisoprolol must not exceed 10 mg.

Patients with Kidney disease: No dosage adjustment is required for patients with mild to moderate renal impairment. Amlodipine is not dialyzable. Amlodipine should be administered with particular caution to patients undergoing dialysis. In case of severe renal impairment (creatinine clearance <20 ml/min) the daily dose of bisoprolol must not exceed 10 mg

Most common signs expected with overdose of a beta-blocker are bradycardia, hypotension, bronchospasm, acute cardiac insufficiency, hypoglycemia. According to available data gross overdose of amlodipine could result in excessive peripheral vasodilation and possibly reflex tachycardia. Marked and probably prolonged systemic hypotension up to and including shock with fatal outcome have been reported. In general, if overdose occurs, discontinuation of treatment and supportive and symptomatic treatment is recommended.

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

Calcium-channel blockers

Amlodipine is a dihydropyridine calcium-channel blocker, with a long duration of action, used for the treatment of hypertension and angina pectoris. Amlodipine influences the myocardial cells, the cells within the specialized conducting system of the heart, and the cells of vascular smooth muscle. Administration of Amlodipine results primarily in vasodilation, with reduced peripheral resistance, blood pressure and afterload, increased coronary blood flow and a reflex increase in coronary heart rate. This in turn results in an increase in myocardial oxygen supply and cardiac output.

Hypertension: Usual dose is 5 mg once daily. The maximum dose is 10 mg once daily. Elderly patients with hepatic insufficiency may be started on 2.5 mg once daily; this dose may also be used when adding Amlodipine to other antihypertensive therapy.

Angina (Chronic stable or Vasospastic): 5 to 10 mg, using the lower dose for elderly and in patients with hepatic insufficiency. Most patients require 10 mg.

Administrations: May be taken without regard to meals.

The most common adverse effects of amlodipine are associated with vasodilatory action, such as dizziness, flushing, headache, hypotension and peripheral edema. Gastrointestinal disturbances, increased micturition frequency, lethargy, eye pain and mental depression may also occur. A paradoxical increase in ischaemic chest pain may occur at the start of the treatment and in a few patients excessive fall in blood pressure has led to cerebral or myocardial ischaemia or transient blindness. Rashes, fever and abnormalities in liver function due to hypersensitivity reaction of Amlodipine may occur.

Hypersensitivity to dihydropyridine derivatives. Pregnant woman.

Precaution should be taken in patients with hepatic impairment and during pregnancy and breast feeding.

Drug Interactions-

• Potentially hazardous interactions: Little or no data are available in patients with markedly impaired cardiac left ventricular function; however, as with other calcium antagonist drugs, the combination of Amlodipine and p-blockers should be avoided in such patients.

Other Significant Interactions-

• Digoxin: Absence of any interaction between Amlodipine and Digoxin in healthy volunteers has been documented in a controlled clinical study.
• Cimetidine: An unpublished clinical study indicated no interaction between, Amlodipine and Cimetidine in healthy volunteers.
• Warfarin: An unpublished clinical study in healthy volunteers indicates that Amlodipine did not significantly alter the effect of Warfarin on prothrombin time.
• Food: Food does not alter the rate or extent of absorption of Amlodipine.

Pregnancy Category C. There are no adequate and well-controlled studies of Amlodipine in pregnant women. Amlodipine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. It is not known whether Amlodipine is excreted in human milk. In the absence of this information, it is recommended that nursing be discontinued while Amlodipine is administered.

Children with hypertension from 6 years to 17 years of age: 2.5 mg once daily as a starting dose, up-titrated to 5 mg once daily if blood pressure goal is not achieved after 4 weeks. Doses in excess of 5 mg daily have not been studied in pediatric patients.

Children under 6 years old:  The effect of amlodipine on blood pressure in patients less than 6 years of age is not known.

Elderly: Amlodipine used at similar doses in elderly or younger patients is equally well tolerated. Normal dosage regimens are recommended in the elderly, but increase of the dosage should take place with care.

Renal impairment: Changes in amlodipine plasma concentrations are not correlated with degree of renal impairment, therefore the normal dosage is recommended. Amlodipine is not dialysable.

Hepatic impairment: Dosage recommendations have not been established in patients with mild to moderate hepatic impairment; therefore dose selection should be cautions and should start at the lower end of the dosing range. The pharmacokinetics of Amlodipine have not been studied in severe hepatic impairment. Amlodipine should be initiated at the lowest dose (2.5 mg once daily) and titrated slowly in patients with severe hepatic impairment.

Symptoms: Available data suggest that large overdosage could result in excessive peripheral vasodilatation and possibly reflex tachycardia. Marked and probably prolonged systemic hypotension up to and including shock with fatal outcome have been reported.

Management: Clinically significant hypotension due to amlodipine overdosage calls for active cardiovascular support including frequent monitoring of cardiac and respiratory function, elevation of extremities, and attention to circulating fluid volume and urine output. 

A vasoconstrictor may be helpful in restoring vascular tone and blood pressure, provided that there is no contraindication to its use. Intravenous calcium gluconate may be beneficial in reversing the effects of calcium channel blockade. Gastric lavage may be worthwhile in some cases. In healthy volunteers the use of charcoal up to 2 hours after administration of amlodipine 10 mg has been shown to reduce the absorption rate of amlodipine. Since amlodipine is highly protein-bound, dialysis is not likely to be of benefit.

Keep all medicines out of reach of children. Store in a cool & dry place, protected from light.

This combination is indicated for the treatment of hypertension. This fixed combination drug is not indicated for the initial therapy of hypertension.

Combined antihypertensive preparations

The combination of Amlodipine and Benazepril is used to treat high blood pressure. Benazepril and benazeprilat inhibit angiotensin-converting enzyme (ACE) in human subjects and in animals. While the mechanism through which Benazepril lowers blood pressure is believed to be primarily suppression of the renin-angiotensin aldosterone system, Benazepril has an antihypertensive effect even in patients with low-renin hypertension. Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist or slow channel blocker) that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure.

The rate and extent of absorption of Benazepril and Amlodipine are not significantly different, respectively, from the rate and extent of absorption of Benazepril and Amlodipine from individual tablet formulations. Following oral administration of this capsule, peak plasma concentrations of Benazepril are reached in 0.5-2 hours. Peak plasma concentrations of Amlodipine are reached 6-12 hours after administration of this capsule; the extent of absorption is 64%-90%. Over 700 patients received Benazepril/Amlodipine once daily in five double-blind, placebo-controlled studies. Benazepril/Amlodipine lowered blood pressure within 1 hour, with peak reductions achieved 2-8 hours after dosing. The antihypertensive effect of a single dose persisted for 24 hours. Once-daily doses of Benazepril/Amlodipine using Benazepril doses of 10-20 mg and Amlodipine doses of 2.5-10 mg decreased seated pressure (systolic/diastolic) 24 hours after dosing by about 10-25/6-13 mmHg.

Amlodipine is an effective treatment of hypertension in once-daily doses of 2.5-10 mg while Benazepril is effective in doses of 10-80 mg.

It is usually appropriate to begin therapy with this capsule only after a patient has either-

• Failed to achieve the desired antihypertensive effect with one or the other monotherapy, or
• Demonstrated inability to achieve adequate antihypertensive effect with Amlodipine therapy without developing edema.

Dose Titration Guided by Clinical Effect: A patient whose blood pressure is not adequately controlled with Amlodipine (or another dihydropyridine) alone or with Benazepril (or another ACE inhibitor) alone may be switched to combination therapy with this capsule. All patient groups benefit from the reduction in Amlodipine-induced edema. Dosage must be guided by clinical response; steady-state levels of Benazepril an Amlodipine will be reached after approximately 2 and 7 days of dosing respectively.

In patients whose blood pressures are adequately controlled with Amlodipine but who experience unacceptable edema, combination therapy may achieve similar (or better) blood-pressure control without edema. Especially in nonblacks, it may be prudent to minimize the risk of excessive response by reducing the dose of Amlodipine as Benazepril is added to the regimen.

Replacement Therapy: For convenience, patients receiving Amlodipine and Benazepril from separate tablets may instead wish to receive this capsule containing the same component doses. In small, elderly, or hepatically impaired patients, the recommended initial dose of Amlodipine, as monotherapy or as a component of combination therapy, is 2.5 mg.

Benazepril/Amlodipine has been evaluated for safety in patients with hypertension for at least 6 months and more than 1 year. The reported side effects were generally mild and transient, and there was no relationship between side effects and age, sex, race or duration of therapy. Discontinuation of therapy due to side effects was required in approximately 4% of patients treated with Benazepril/Amlodipine and in 3% of patients treated with placebo. The most common reasons for discontinuation of therapy with Benazepril/Amlodipine in U.S. studies were cough and edema. The side effects considered possibly or probably related to study drug that occurred in U.S. placebo-controlled trials in more than 1% of patients treated with Benazepril/Amlodipine are cough, headache, dizziness and edema.

The incidence of edema was statistically greater in patients treated with Amlodipine monotherapy than in patients treated with the combination. Edema and certain other side effects are associated with Amlodipine monotherapy in a dose-dependent manner, and appear to affect women more than men. The addition of Benazepril resulted in lower incidences as shown in study; the protective effect of Benazepril was independent of race and (within the range of doses tested) of dose.

Other rare side effects are angioedema, asthenia, fatigue, insomnia, nervousness, anxiety, tremor, decreased libido, flushing, hot flashes, rash, skin nodule, dermatitis, dry mouth, nausea, abdominal pain, constipation, diarrhea, dyspepsia, esophagitis, hypokalemia, pharyngitis etc.

This capsule is contraindicated in patients who are hypersensitive to Benazepril, to any other ACE inhibitor, or to Amlodipine.

Impaired Renal Function: This capsule should be used with caution in patients with severe renal disease.

Hyperkalemia: This may occur in only a few patients but generally are reversible.

Patients With Hepatic Failure: Since Amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t ½) is 56 hours in patients with impaired hepatic function, caution should be exercised when administering this capsule to patients with severe hepatic impairment.

Cough: ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.

Surgery/Anesthesia: In patients undergoing surgery or during anesthesia with agents that produce hypotension, Benazepril will block the angiotensin II formation that could otherwise occur secondary to compensatory renin release. Hypotension that occurs as a result of this mechanism can be corrected by volume expansion.

Carcinogenesis, Mutagenesis, Impairment of Fertility: No evidence of carcinogenicity, mutagenicity or impairment of fertility was found when the Benazepril/Amlodipine combination were given orally.

Diuretics: Patients on diuretics, especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with Benazepril/Amlodipine.

Potassium Supplements and Potassium-Sparing Diuretics: Benazepril can attenuate potassium loss caused by thiazide diuretics. Potassium-sparing diuretics (Spironolactone, Amiloride, Triamterene and others) or potassium supplements can increase the risk of hyperkalemia. If concomitant use of such agents is indicated, they should be given with caution, and the patient's serum potassium should be monitored frequently.

Others: Benazepril has been used concomitantly with oral anticoagulants, beta-adrenergic-blocking agents, calcium-blocking agents, Cimetidine, diuretics, Digoxin, Hydralazine, and Naproxen without evidence of clinically important adverse interactions.

In clinical trials, Amlodipine has been safely administered with thiazide diuretics, beta blockers, ACE inhibitors, long-acting nitrates, sublingual nitroglycerin, Digoxin, Warfarin, nonsteroidal anti-inflammatory drugs, antibiotics, and oral hypoglycemic drugs.

Pregnancy Categories C (first trimester) and D (second and third trimesters). ACE inhibitors can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature. When pregnancy is detected, this capsule should be discontinued as soon as possible. Minimal amounts of unchanged Benazepril and of benazeprilat are excreted into the breast milk of lactating women treated with Benazepril, so that a newborn child ingesting nothing but breast milk would receive less than 0.1% of the maternal doses of Benazepril and benazeprilat. It is not known whether Amlodipine is excreted in human milk. In the absence of this information, it is recommended that nursing be discontinued while this capsule is administered.

Geriatric Use: Clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Pediatric Use: Safety and effectiveness in pediatric patients have not been established.

Human overdoses with any combination of Amlodipine and Benazepril have not been reported. In scattered reports of human overdoses with Benazepril and other ACE inhibitors, there are no reports of death.

Keep below 25°C temperature, away from light & moisture. Keep out of the reach of children.

This combination is indicated for the treatment of hypertension. This fixed combination drug is not indicated for the initial therapy of hypertension.

Combined antihypertensive preparations

The combination of Amlodipine and Benazepril is used to treat high blood pressure. Benazepril and benazeprilat inhibit angiotensin-converting enzyme (ACE) in human subjects and in animals. While the mechanism through which Benazepril lowers blood pressure is believed to be primarily suppression of the renin-angiotensin aldosterone system, Benazepril has an antihypertensive effect even in patients with low-renin hypertension. Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist or slow channel blocker) that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure.

The rate and extent of absorption of Benazepril and Amlodipine are not significantly different, respectively, from the rate and extent of absorption of Benazepril and Amlodipine from individual tablet formulations. Following oral administration of this capsule, peak plasma concentrations of Benazepril are reached in 0.5-2 hours. Peak plasma concentrations of Amlodipine are reached 6-12 hours after administration of this capsule; the extent of absorption is 64%-90%. Over 700 patients received Benazepril/Amlodipine once daily in five double-blind, placebo-controlled studies. Benazepril/Amlodipine lowered blood pressure within 1 hour, with peak reductions achieved 2-8 hours after dosing. The antihypertensive effect of a single dose persisted for 24 hours. Once-daily doses of Benazepril/Amlodipine using Benazepril doses of 10-20 mg and Amlodipine doses of 2.5-10 mg decreased seated pressure (systolic/diastolic) 24 hours after dosing by about 10-25/6-13 mmHg.

Amlodipine is an effective treatment of hypertension in once-daily doses of 2.5-10 mg while Benazepril is effective in doses of 10-80 mg.

It is usually appropriate to begin therapy with this capsule only after a patient has either-

• Failed to achieve the desired antihypertensive effect with one or the other monotherapy, or
• Demonstrated inability to achieve adequate antihypertensive effect with Amlodipine therapy without developing edema.

Dose Titration Guided by Clinical Effect: A patient whose blood pressure is not adequately controlled with Amlodipine (or another dihydropyridine) alone or with Benazepril (or another ACE inhibitor) alone may be switched to combination therapy with this capsule. All patient groups benefit from the reduction in Amlodipine-induced edema. Dosage must be guided by clinical response; steady-state levels of Benazepril an Amlodipine will be reached after approximately 2 and 7 days of dosing respectively.

In patients whose blood pressures are adequately controlled with Amlodipine but who experience unacceptable edema, combination therapy may achieve similar (or better) blood-pressure control without edema. Especially in nonblacks, it may be prudent to minimize the risk of excessive response by reducing the dose of Amlodipine as Benazepril is added to the regimen.

Replacement Therapy: For convenience, patients receiving Amlodipine and Benazepril from separate tablets may instead wish to receive this capsule containing the same component doses. In small, elderly, or hepatically impaired patients, the recommended initial dose of Amlodipine, as monotherapy or as a component of combination therapy, is 2.5 mg.

Benazepril/Amlodipine has been evaluated for safety in patients with hypertension for at least 6 months and more than 1 year. The reported side effects were generally mild and transient, and there was no relationship between side effects and age, sex, race or duration of therapy. Discontinuation of therapy due to side effects was required in approximately 4% of patients treated with Benazepril/Amlodipine and in 3% of patients treated with placebo. The most common reasons for discontinuation of therapy with Benazepril/Amlodipine in U.S. studies were cough and edema. The side effects considered possibly or probably related to study drug that occurred in U.S. placebo-controlled trials in more than 1% of patients treated with Benazepril/Amlodipine are cough, headache, dizziness and edema.

The incidence of edema was statistically greater in patients treated with Amlodipine monotherapy than in patients treated with the combination. Edema and certain other side effects are associated with Amlodipine monotherapy in a dose-dependent manner, and appear to affect women more than men. The addition of Benazepril resulted in lower incidences as shown in study; the protective effect of Benazepril was independent of race and (within the range of doses tested) of dose.

Other rare side effects are angioedema, asthenia, fatigue, insomnia, nervousness, anxiety, tremor, decreased libido, flushing, hot flashes, rash, skin nodule, dermatitis, dry mouth, nausea, abdominal pain, constipation, diarrhea, dyspepsia, esophagitis, hypokalemia, pharyngitis etc.

This capsule is contraindicated in patients who are hypersensitive to Benazepril, to any other ACE inhibitor, or to Amlodipine.

Impaired Renal Function: This capsule should be used with caution in patients with severe renal disease.

Hyperkalemia: This may occur in only a few patients but generally are reversible.

Patients With Hepatic Failure: Since Amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t ½) is 56 hours in patients with impaired hepatic function, caution should be exercised when administering this capsule to patients with severe hepatic impairment.

Cough: ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.

Surgery/Anesthesia: In patients undergoing surgery or during anesthesia with agents that produce hypotension, Benazepril will block the angiotensin II formation that could otherwise occur secondary to compensatory renin release. Hypotension that occurs as a result of this mechanism can be corrected by volume expansion.

Carcinogenesis, Mutagenesis, Impairment of Fertility: No evidence of carcinogenicity, mutagenicity or impairment of fertility was found when the Benazepril/Amlodipine combination were given orally.

Diuretics: Patients on diuretics, especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with Benazepril/Amlodipine.

Potassium Supplements and Potassium-Sparing Diuretics: Benazepril can attenuate potassium loss caused by thiazide diuretics. Potassium-sparing diuretics (Spironolactone, Amiloride, Triamterene and others) or potassium supplements can increase the risk of hyperkalemia. If concomitant use of such agents is indicated, they should be given with caution, and the patient's serum potassium should be monitored frequently.

Others: Benazepril has been used concomitantly with oral anticoagulants, beta-adrenergic-blocking agents, calcium-blocking agents, Cimetidine, diuretics, Digoxin, Hydralazine, and Naproxen without evidence of clinically important adverse interactions.

In clinical trials, Amlodipine has been safely administered with thiazide diuretics, beta blockers, ACE inhibitors, long-acting nitrates, sublingual nitroglycerin, Digoxin, Warfarin, nonsteroidal anti-inflammatory drugs, antibiotics, and oral hypoglycemic drugs.

Pregnancy Categories C (first trimester) and D (second and third trimesters). ACE inhibitors can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature. When pregnancy is detected, this capsule should be discontinued as soon as possible. Minimal amounts of unchanged Benazepril and of benazeprilat are excreted into the breast milk of lactating women treated with Benazepril, so that a newborn child ingesting nothing but breast milk would receive less than 0.1% of the maternal doses of Benazepril and benazeprilat. It is not known whether Amlodipine is excreted in human milk. In the absence of this information, it is recommended that nursing be discontinued while this capsule is administered.

Geriatric Use: Clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Pediatric Use: Safety and effectiveness in pediatric patients have not been established.

Human overdoses with any combination of Amlodipine and Benazepril have not been reported. In scattered reports of human overdoses with Benazepril and other ACE inhibitors, there are no reports of death.

Keep below 25°C temperature, away from light & moisture. Keep out of the reach of children.

This combination is indicated for the treatment of hypertension. This fixed combination drug is not indicated for the initial therapy of hypertension.

Combined antihypertensive preparations

The combination of Amlodipine and Benazepril is used to treat high blood pressure. Benazepril and benazeprilat inhibit angiotensin-converting enzyme (ACE) in human subjects and in animals. While the mechanism through which Benazepril lowers blood pressure is believed to be primarily suppression of the renin-angiotensin aldosterone system, Benazepril has an antihypertensive effect even in patients with low-renin hypertension. Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist or slow channel blocker) that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure.

The rate and extent of absorption of Benazepril and Amlodipine are not significantly different, respectively, from the rate and extent of absorption of Benazepril and Amlodipine from individual tablet formulations. Following oral administration of this capsule, peak plasma concentrations of Benazepril are reached in 0.5-2 hours. Peak plasma concentrations of Amlodipine are reached 6-12 hours after administration of this capsule; the extent of absorption is 64%-90%. Over 700 patients received Benazepril/Amlodipine once daily in five double-blind, placebo-controlled studies. Benazepril/Amlodipine lowered blood pressure within 1 hour, with peak reductions achieved 2-8 hours after dosing. The antihypertensive effect of a single dose persisted for 24 hours. Once-daily doses of Benazepril/Amlodipine using Benazepril doses of 10-20 mg and Amlodipine doses of 2.5-10 mg decreased seated pressure (systolic/diastolic) 24 hours after dosing by about 10-25/6-13 mmHg.

Amlodipine is an effective treatment of hypertension in once-daily doses of 2.5-10 mg while Benazepril is effective in doses of 10-80 mg.

It is usually appropriate to begin therapy with this capsule only after a patient has either-

• Failed to achieve the desired antihypertensive effect with one or the other monotherapy, or
• Demonstrated inability to achieve adequate antihypertensive effect with Amlodipine therapy without developing edema.

Dose Titration Guided by Clinical Effect: A patient whose blood pressure is not adequately controlled with Amlodipine (or another dihydropyridine) alone or with Benazepril (or another ACE inhibitor) alone may be switched to combination therapy with this capsule. All patient groups benefit from the reduction in Amlodipine-induced edema. Dosage must be guided by clinical response; steady-state levels of Benazepril an Amlodipine will be reached after approximately 2 and 7 days of dosing respectively.

In patients whose blood pressures are adequately controlled with Amlodipine but who experience unacceptable edema, combination therapy may achieve similar (or better) blood-pressure control without edema. Especially in nonblacks, it may be prudent to minimize the risk of excessive response by reducing the dose of Amlodipine as Benazepril is added to the regimen.

Replacement Therapy: For convenience, patients receiving Amlodipine and Benazepril from separate tablets may instead wish to receive this capsule containing the same component doses. In small, elderly, or hepatically impaired patients, the recommended initial dose of Amlodipine, as monotherapy or as a component of combination therapy, is 2.5 mg.

Benazepril/Amlodipine has been evaluated for safety in patients with hypertension for at least 6 months and more than 1 year. The reported side effects were generally mild and transient, and there was no relationship between side effects and age, sex, race or duration of therapy. Discontinuation of therapy due to side effects was required in approximately 4% of patients treated with Benazepril/Amlodipine and in 3% of patients treated with placebo. The most common reasons for discontinuation of therapy with Benazepril/Amlodipine in U.S. studies were cough and edema. The side effects considered possibly or probably related to study drug that occurred in U.S. placebo-controlled trials in more than 1% of patients treated with Benazepril/Amlodipine are cough, headache, dizziness and edema.

The incidence of edema was statistically greater in patients treated with Amlodipine monotherapy than in patients treated with the combination. Edema and certain other side effects are associated with Amlodipine monotherapy in a dose-dependent manner, and appear to affect women more than men. The addition of Benazepril resulted in lower incidences as shown in study; the protective effect of Benazepril was independent of race and (within the range of doses tested) of dose.

Other rare side effects are angioedema, asthenia, fatigue, insomnia, nervousness, anxiety, tremor, decreased libido, flushing, hot flashes, rash, skin nodule, dermatitis, dry mouth, nausea, abdominal pain, constipation, diarrhea, dyspepsia, esophagitis, hypokalemia, pharyngitis etc.

This capsule is contraindicated in patients who are hypersensitive to Benazepril, to any other ACE inhibitor, or to Amlodipine.

Impaired Renal Function: This capsule should be used with caution in patients with severe renal disease.

Hyperkalemia: This may occur in only a few patients but generally are reversible.

Patients With Hepatic Failure: Since Amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t ½) is 56 hours in patients with impaired hepatic function, caution should be exercised when administering this capsule to patients with severe hepatic impairment.

Cough: ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.

Surgery/Anesthesia: In patients undergoing surgery or during anesthesia with agents that produce hypotension, Benazepril will block the angiotensin II formation that could otherwise occur secondary to compensatory renin release. Hypotension that occurs as a result of this mechanism can be corrected by volume expansion.

Carcinogenesis, Mutagenesis, Impairment of Fertility: No evidence of carcinogenicity, mutagenicity or impairment of fertility was found when the Benazepril/Amlodipine combination were given orally.

Diuretics: Patients on diuretics, especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with Benazepril/Amlodipine.

Potassium Supplements and Potassium-Sparing Diuretics: Benazepril can attenuate potassium loss caused by thiazide diuretics. Potassium-sparing diuretics (Spironolactone, Amiloride, Triamterene and others) or potassium supplements can increase the risk of hyperkalemia. If concomitant use of such agents is indicated, they should be given with caution, and the patient's serum potassium should be monitored frequently.

Others: Benazepril has been used concomitantly with oral anticoagulants, beta-adrenergic-blocking agents, calcium-blocking agents, Cimetidine, diuretics, Digoxin, Hydralazine, and Naproxen without evidence of clinically important adverse interactions.

In clinical trials, Amlodipine has been safely administered with thiazide diuretics, beta blockers, ACE inhibitors, long-acting nitrates, sublingual nitroglycerin, Digoxin, Warfarin, nonsteroidal anti-inflammatory drugs, antibiotics, and oral hypoglycemic drugs.

Pregnancy Categories C (first trimester) and D (second and third trimesters). ACE inhibitors can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature. When pregnancy is detected, this capsule should be discontinued as soon as possible. Minimal amounts of unchanged Benazepril and of benazeprilat are excreted into the breast milk of lactating women treated with Benazepril, so that a newborn child ingesting nothing but breast milk would receive less than 0.1% of the maternal doses of Benazepril and benazeprilat. It is not known whether Amlodipine is excreted in human milk. In the absence of this information, it is recommended that nursing be discontinued while this capsule is administered.

Geriatric Use: Clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Pediatric Use: Safety and effectiveness in pediatric patients have not been established.

Human overdoses with any combination of Amlodipine and Benazepril have not been reported. In scattered reports of human overdoses with Benazepril and other ACE inhibitors, there are no reports of death.

Keep below 25°C temperature, away from light & moisture. Keep out of the reach of children.

This combination is indicated for the treatment of hypertension. This fixed combination drug is not indicated for the initial therapy of hypertension.

Combined antihypertensive preparations

The combination of Amlodipine and Benazepril is used to treat high blood pressure. Benazepril and benazeprilat inhibit angiotensin-converting enzyme (ACE) in human subjects and in animals. While the mechanism through which Benazepril lowers blood pressure is believed to be primarily suppression of the renin-angiotensin aldosterone system, Benazepril has an antihypertensive effect even in patients with low-renin hypertension. Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist or slow channel blocker) that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure.

The rate and extent of absorption of Benazepril and Amlodipine are not significantly different, respectively, from the rate and extent of absorption of Benazepril and Amlodipine from individual tablet formulations. Following oral administration of this capsule, peak plasma concentrations of Benazepril are reached in 0.5-2 hours. Peak plasma concentrations of Amlodipine are reached 6-12 hours after administration of this capsule; the extent of absorption is 64%-90%. Over 700 patients received Benazepril/Amlodipine once daily in five double-blind, placebo-controlled studies. Benazepril/Amlodipine lowered blood pressure within 1 hour, with peak reductions achieved 2-8 hours after dosing. The antihypertensive effect of a single dose persisted for 24 hours. Once-daily doses of Benazepril/Amlodipine using Benazepril doses of 10-20 mg and Amlodipine doses of 2.5-10 mg decreased seated pressure (systolic/diastolic) 24 hours after dosing by about 10-25/6-13 mmHg.

Amlodipine is an effective treatment of hypertension in once-daily doses of 2.5-10 mg while Benazepril is effective in doses of 10-80 mg.

It is usually appropriate to begin therapy with this capsule only after a patient has either-

• Failed to achieve the desired antihypertensive effect with one or the other monotherapy, or
• Demonstrated inability to achieve adequate antihypertensive effect with Amlodipine therapy without developing edema.

Dose Titration Guided by Clinical Effect: A patient whose blood pressure is not adequately controlled with Amlodipine (or another dihydropyridine) alone or with Benazepril (or another ACE inhibitor) alone may be switched to combination therapy with this capsule. All patient groups benefit from the reduction in Amlodipine-induced edema. Dosage must be guided by clinical response; steady-state levels of Benazepril an Amlodipine will be reached after approximately 2 and 7 days of dosing respectively.

In patients whose blood pressures are adequately controlled with Amlodipine but who experience unacceptable edema, combination therapy may achieve similar (or better) blood-pressure control without edema. Especially in nonblacks, it may be prudent to minimize the risk of excessive response by reducing the dose of Amlodipine as Benazepril is added to the regimen.

Replacement Therapy: For convenience, patients receiving Amlodipine and Benazepril from separate tablets may instead wish to receive this capsule containing the same component doses. In small, elderly, or hepatically impaired patients, the recommended initial dose of Amlodipine, as monotherapy or as a component of combination therapy, is 2.5 mg.

Benazepril/Amlodipine has been evaluated for safety in patients with hypertension for at least 6 months and more than 1 year. The reported side effects were generally mild and transient, and there was no relationship between side effects and age, sex, race or duration of therapy. Discontinuation of therapy due to side effects was required in approximately 4% of patients treated with Benazepril/Amlodipine and in 3% of patients treated with placebo. The most common reasons for discontinuation of therapy with Benazepril/Amlodipine in U.S. studies were cough and edema. The side effects considered possibly or probably related to study drug that occurred in U.S. placebo-controlled trials in more than 1% of patients treated with Benazepril/Amlodipine are cough, headache, dizziness and edema.

The incidence of edema was statistically greater in patients treated with Amlodipine monotherapy than in patients treated with the combination. Edema and certain other side effects are associated with Amlodipine monotherapy in a dose-dependent manner, and appear to affect women more than men. The addition of Benazepril resulted in lower incidences as shown in study; the protective effect of Benazepril was independent of race and (within the range of doses tested) of dose.

Other rare side effects are angioedema, asthenia, fatigue, insomnia, nervousness, anxiety, tremor, decreased libido, flushing, hot flashes, rash, skin nodule, dermatitis, dry mouth, nausea, abdominal pain, constipation, diarrhea, dyspepsia, esophagitis, hypokalemia, pharyngitis etc.

This capsule is contraindicated in patients who are hypersensitive to Benazepril, to any other ACE inhibitor, or to Amlodipine.

Impaired Renal Function: This capsule should be used with caution in patients with severe renal disease.

Hyperkalemia: This may occur in only a few patients but generally are reversible.

Patients With Hepatic Failure: Since Amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t ½) is 56 hours in patients with impaired hepatic function, caution should be exercised when administering this capsule to patients with severe hepatic impairment.

Cough: ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.

Surgery/Anesthesia: In patients undergoing surgery or during anesthesia with agents that produce hypotension, Benazepril will block the angiotensin II formation that could otherwise occur secondary to compensatory renin release. Hypotension that occurs as a result of this mechanism can be corrected by volume expansion.

Carcinogenesis, Mutagenesis, Impairment of Fertility: No evidence of carcinogenicity, mutagenicity or impairment of fertility was found when the Benazepril/Amlodipine combination were given orally.

Diuretics: Patients on diuretics, especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with Benazepril/Amlodipine.

Potassium Supplements and Potassium-Sparing Diuretics: Benazepril can attenuate potassium loss caused by thiazide diuretics. Potassium-sparing diuretics (Spironolactone, Amiloride, Triamterene and others) or potassium supplements can increase the risk of hyperkalemia. If concomitant use of such agents is indicated, they should be given with caution, and the patient's serum potassium should be monitored frequently.

Others: Benazepril has been used concomitantly with oral anticoagulants, beta-adrenergic-blocking agents, calcium-blocking agents, Cimetidine, diuretics, Digoxin, Hydralazine, and Naproxen without evidence of clinically important adverse interactions.

In clinical trials, Amlodipine has been safely administered with thiazide diuretics, beta blockers, ACE inhibitors, long-acting nitrates, sublingual nitroglycerin, Digoxin, Warfarin, nonsteroidal anti-inflammatory drugs, antibiotics, and oral hypoglycemic drugs.

Pregnancy Categories C (first trimester) and D (second and third trimesters). ACE inhibitors can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature. When pregnancy is detected, this capsule should be discontinued as soon as possible. Minimal amounts of unchanged Benazepril and of benazeprilat are excreted into the breast milk of lactating women treated with Benazepril, so that a newborn child ingesting nothing but breast milk would receive less than 0.1% of the maternal doses of Benazepril and benazeprilat. It is not known whether Amlodipine is excreted in human milk. In the absence of this information, it is recommended that nursing be discontinued while this capsule is administered.

Geriatric Use: Clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Pediatric Use: Safety and effectiveness in pediatric patients have not been established.

Human overdoses with any combination of Amlodipine and Benazepril have not been reported. In scattered reports of human overdoses with Benazepril and other ACE inhibitors, there are no reports of death.

Keep below 25°C temperature, away from light & moisture. Keep out of the reach of children.

Anti-anginal & lipid lowering drugs

It is a combination product containing Amlodipine Besilate BP equivalent to 5 mg Amlodipine, a calcium channel blocker and Atorvastatin calcium INN equivalent to 10 mg Atorvastatin, a statin (HMG-CoA reductase inhibitor). Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure. Atorvastatin calcium is a synthetic lipid-lowering agent. It is an inhibitor of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA). This enzyme catalyzes the conversion of HMG-CoAto mevatonate, an early and rate limiting step in the synthesis of cholesterol.

Amlodipine: The usual initial antihypertensive oral dose is 5 mg once daily with a maximum dose of 10 mg once daily. Elderly individuals or patients with hepatic insufficiency may be started on 2.5 mg once daily dose and this dose may be used when adding Amlodipine to other antihypertensive therapy. Dosage should be adjusted according to each patient's need. The recommended dose for chronic stable or vasospastic angina is 5-10 mg, with the lower dose suggested in the elderly and in patients with hepatic insufficiency.

Atorvastatin:

• The patient should be placed on a standard cholesterol-lowering diet before receiving Atorvastatin and should continue on this diet during treatment with Atorvastatin Hypercholesterolemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia (Fredrickson Types IIa and IIb): The recommended starting dose of Atorvastatin is 10 mg daily. The dosage range is 10 to 80 mg once daily. Atorvastatin can be administered as a single dose at any time of the day with or without food.
• Homozygous Familial Hypercholesterolemia: The dosage of Atorvastatin in patients with homozygous FH is 10 to 80 mg daily.
• Patients with renal insufficiency: Renal disease has no influence on the plasma concentrations or lipid effects of Atorvastatin; thus no adjustment of dose is required. Hemodialysis is not expected to significantly enhance the clearance of Atorvastatin since the drug is extensively bound to plasma proteins.
• Patients with hepatic dysfunction: In patients with moderate to severe hepatic dysfunction, the therapeutic response to Atorvastatin is unaffected but exposure to the drug is greatly increased.

Amlodipine: General: Since the vasodilatation induced by Amlodipine is gradual in onset, acute hypotension has rarely been reported after oral administration of Amlodipine. Nonetheless, caution should be exercised when administering Amlodipine as with any other peripheral vasodilator particularly in patients with severe aortic stenosis. Use in Patients with Congestive Heart Failure: Although hemodynamic studies and a controlled trial in Class-II-III heart failure patients have shown that Amlodipine did not lead to clinical deterioration as measured by exercise tolerance, left ventricular ejection fraction, and clinical symptoms. In general, all calcium channel blockers should be used with caution in patients with heart failure. Beta-blocker Rhabdomyolysis with acute renal failure secondary to myoglobinuria has been reported with other drugs in this class.

Atorvastatin: Atorvastatin may cause an elevation in serum creatine phosphokinase levels. This should be considered in the differential diagnosis of chest pain in patients on therapy with Atorvastatin. Uncomplicated myalgia has been reported in Atorvastatin-treated patients. Atorvastatin therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. Side effects: Atorvastatin is generally well tolerated. Adverse effects reported commonly include constipation, flatulence, dyspepsia, abdominal pain, headache, nausea, myalgia, diarrhea, asthenia and insomnia.

Amlodipine: Amlodipine is contraindicated in patients with known hypersensitivity to Amlodipine. Atorvastatin: Contraindicated in hypersensitivity to any component of this medication. Active liver disease or unexplained persistent elevations of serum transaminases exceed three times the upper limit of normal.

Warning: Increased Angina and/or Myocardial Infarction Rarely, patients, particularly those with severe obstructive coronary artery disease, have developed documented increased frequency, duration and/or severity of angina or acute myocardial infarction on starting calcium channel blocker therapy or at the time of dosage increase. The mechanism of this effect has not been elucidated. Liver Dysfunction. HMG-CoA reductase inhibitors, like some other lipid-lowering therapies, have been associated with biochemical abnormalities of liver function. Precaution

Amlodipine: General: Since the vasodilatation induced by Amlodipine is gradual in onset, acute hypotension has rarely been reported after oral administration of Amlodipine. Nonetheless, caution should be exercised when administering Amlodipine as with any other peripheral vasodilator particularly in patients with severe aortic stenosis.

Use in Patients with Congestive Heart Failure: Although hemodynamic studies and a controlled trial in Class-II-III heart failure patients have shown that Amlodipine did not lead to clinical deterioration as measured by exercise tolerance, left ventricular ejection fraction, and clinical symptoms. In general, all calcium channel blockers should be used with caution in patients with heart failure.

Atorvastatin: Rhabdomyolysis with acute renal failure secondary to myoglobinuria has been reported with other drugs in this class. Atorvastatin may cause an elevation in serum creatine phosphokinase levels. This should be considered in the differential diagnosis of chest pain in patients on therapy with Atorvastatin. Uncomplicated myalgia has been reported in Atorvastatin-treated patients. Atorvastatin therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected.

Drug interaction with atorvastatin: The risk of myopathy during treatment with drugs of this class is increased with concurrent administration of cyclosporine, fibric acid derivatives, niacin (nicotinic acid), erythromycin, azole antifungals. When atorvastatin and antacid suspension containing magnesium and aluminum hydroxide were co administered, plasma concentrations of atorvastatin decreased approximately 35%. However, LDL-C reduction was not altered. Plasma concentrations of atorvastatin decreased approximately 25% when colestipol and atorvastatin were co administered. However, LDL-C reduction was greater when atorvastatin and colestipol were co-administered than when either drug was given alone. When multiple doses of atorvastatin and digoxin were co-administered, steady state plasma digoxin concentrations increased by approximately 20%. Patients taking digoxin should be monitored appropriately. In healthy individuals, plasma concentrations of atorvastatin increased approximately 40% with co- administration of atorvastatin and erythromycin. Co- administration of atorvastatin and an oral contraceptive increased AUC values for norethindrone and ethinylestradiol by approximately 30% and 20%. These increases should be considered when selecting an oral contraceptive for a woman taking atorvastatin.
 
Drug interaction with amlodipine: Amlodipine may potentiate the effect of other antihypertensive (e.g.Beta-blockers, ACE inhibitors, Alpha-1-blockers and Diuretics). In clinical interaction studies, Amlodipine did not affect the pharmacokinetics of Atorvastatin, Digoxin, Warfarin or Cyclosporine.

Safety in pregnancy has not been established. Use of HMG-CoA reductase inhibitors during breastfeeding is not recommended.

Pediatrics: Safety and efficacy of Atorvastatin have not been established in children.

Geriatrics: Efficacy and safety in older patients using recommended doses is similar to that seen in the general population.

Store in a cool and dry place. Protect from light and moisture. Keep all medicines out of the reach of children.

This cream is indicated for the short-term treatment of moderate to severe melasma of the face, after starting the treatment avoid presence of sun. Use a sunscreen of at least SPF 30 or more.

Hydroquinone Preparations

This cream contains three active ingredients Fluocinolone Acetonide, Hydroquinone and Tretinoin. All of them are used to treat melasma. However, the mechanism of action of the active ingredients in This cream in the treatment of melasma is unknown but Fluocinolone Acetonide is a corticosteroid for topical dermatological use and is classified therapeutically as an anti-inflammatory. Hydroquinone is classified therapeutically as a depigmenting agent, which may interrupt one or more steps in the tyrosine-tyrosinase pathway of melanin synthesis. Tretinoin is classified therapeutically as a keratolytic agent.

This cream should be applied once daily at night. It should be applied at least 30 minutes before bedtime. Gently wash the face and neck with a mild cleanser. Rinse and pat the skin dry. Apply a thin film of the cream to the hyperpigmented areas of melasma including about ½ inch of normal-appearing skin surrounding each lesion. Rub lightly and uniformly into the skin. During the day, use sunscreen and wear protective clothing. Avoid sunlight exposure. Patients may use moisturizers and/or cosmetics during the day.

Pediatric Use: The safety and effectiveness of this cream in pediatric patients have not been established.

A very few patients may get severe allergic reactions from this cream. They may have trouble breathing or severe asthma attacks. While patients use this cream, skin may develop mild to moderate redness, peeling, burning, dryness or itching.

This cream is contraindicated in individuals with a history of hypersensitivity, allergy or intolerance to this product or any of its components.

This cream contains Hydroquinone and Tretinoin that may cause mild to moderate irritation. Local irritation, such as skin reddening, peeling, mild burning sensation, dryness and pruritus may be expected at the site of application. Transient skin reddening or mild burning sensation does not preclude treatment. If a reaction suggests hypersensitivity or chemical irritation, the use of the medication should be discontinued. This cream also contains the corticosteroid Fluocinolone Acetonide. Systemic absorption of topical corticosteroids can produce reversible Hypothalamic-Pituitary-Adrenal (HPA) axis suppression with the potential for glucocorticosteroid insufficiency after withdrawal of treatment. Manifestations of Cushing's syndrome, hyperglycemia and glucosuria can also be produced by systemic absorption of topical corticosteroid while on treatment. If HPA axis suppression is noted, the use of this cream should be discontinued. Recovery of HPA axis function generally occurs upon discontinuation of topical corticosteroids.

Avoid use of medicated or abrasive soaps, cleansers, soaps, cosmetics with drying effects, products with high concentration of alcohol, astringent & other irritants or keratolytic drugs. Also avoid concomitant use of medications with photosensitizing effects.

Pregnancy Category C. This cream contains the teratogen, tretinoin, which may cause embryo-fetal death, altered fetal growth, congenital malformations and potential neurologic deficits. It is difficult to interpret the animal studies on teratogenicity with this cream, because the availability of the dermal applications in these studies cannot be assured and comparison with clinical dosing is not possible. There are no adequate and well controlled studies in pregnant women. This cream should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Lactation: Corticosteroids, when systemically administered, the drug appear in human milk. It is not known whether topical application of this cream could result in sufficient systemic absorption to produce detectable quantities of Fluocinolone Acetonide, Hydroquinone or Tretinoin in human milk. Because many drugs are secreted in human milk, caution should be exercised when this cream is administered to nursing women.

Store in a cool & dry place, protected from light. Do not freeze. Keep out of reach of children.

Flupentixol and Melitracen tablet is indicated in-

• Anxiety
• Depression
• Apathy
• Psychogenic depression.
• Depressive neurosses.
• Masked depression.
• Psychosomatic affections accompanied by anxiety and apathy.
• Menopausal depressions.
• Dysphoria and depression in alcoholics and drug addicts.

Combined anxiolytics & anti-depressant drugs

This consists of two well known and well proven compounds: flupentixol-a neuroleptic with anxiolytic and antidepressant properties of its own when given in small doses, and melitracen-a bipolar thymoleptic with activating properties in low doses. In combination the compounds render a preparation with antidepressant, anxiolytic and activating properties. Maximal serum concentration is reached in about 4 hours after oral administration of flupentixol and in about 4 hours after oral administration of melitracen. The biological half-life of flupentixol is about 35 hours and that of melitracen is about 19 hours. The combination of flupentixol and melitracen does not seem to influence the pharmacokinetic properties of the individual compounds.

Adults: Usually 2 tablets orally daily in the morning and noon. In severe cases, the morning dose may be increased to 2 tablets.

Elderly patients: 1 tablet in the morning.

Maintenance dose: Usually 1 tablet orally in the morning. In cases of insomnia or severe restlessness, additional treatment with a sedative in the acute phase is recommended.

In the recommended doses side effects are rare. These could be transient restlessness and insomnia.

If previously the patient has been treated with tranquillizers with sedative effect these should be withdrawn gradually.

This tablet may enhance the response to alcohol, barbiturates and other CNS depressants. Simultaneous administration of MAO-inhibitors may cause hypertensive crises. Neuroleptics and thymoleptics reduce the antihypertensive effect of guanethidine and similar acting compounds and thymoleptics enhance the effects of adrenaline and noradrenaline.

This tablet should preferably not be given during pregnancy and lactation.

In cases of overdosage the symptoms of intoxications by melitracen, especially of anticholinergic nature, dominate. More rarely extrapyramidal symptoms due to flupentixol occur. Symptomatic and Supportive. Gastric lavage should be carried out as soon as possible and activated charcoal may be administered. Measures aimed at supporting the respiratory and cardiovascular systems should be instituted. Epinephrine (adrenaline) must not be used for such patients. Convulsions may be treated with diazepam and extrapyramidal symptoms with biperiden.

Store at a temperature not exceeding 30°C in a dry place. Protect from light. Keep out of reach of children.