VALSAR PLUS Valsartan / Amlodipine 80mg / 5mg Film-Coated Tablet 1's
RXDRUG-DRP-6900-1pc
Discreet Packaging
FDA-registered Products
FDA-licensed Pharmacies
Indications/Uses
For the treatment of hypertension, to lower blood pressure in patients not adequately controlled on monotherapy.
Dosage/Direction for Use
The recommended dose of Valsartan + Amlodipine (as besilate) 80 mg/5 mg Film-coated tablet (Valsar Plus) is one tablet per day. Valsartan + Amlodipine (as besilate) 80 mg/5 mg Film-coated tablet (Valsar Plus) may be administered in patients whose blood pressure is not adequately controlled with amlodipine 5 mg or valsartan 80 mg alone. Individual dose titration with the components (i.e. amlodipine and valsartan) is recommended before changing to the fixed dose combination. When clinically appropriate, direct change from monotherapy to the fixed-dose combination may be considered. For convenience, patients receiving valsartan and amlodipine from separate tablets/capsules may be switched to Valsartan + Amlodipine (as besilate) 80 mg/5 mg Film-coated tablet (Valsar Plus) containing the same component doses or as prescribed by the physician.
Renal Impairment: Valsartan + Amlodipine (as besilate) 80 mg/5 mg Film-coated tablet (Valsar Plus) is contraindicated in patients with severe renal impairment. No dosage adjustment is required for patients with mild to moderate renal impairment. Monitoring of potassium levels and creatinine is advised in moderate renal impairment. The concomitant use of Valsartan + Amlodipine (as besilate) 80 mg/5 mg Film-coated tablet (Valsar Plus) with aliskiren is contraindicated in patients with renal impairment (GFR <60 mL/min/1.73 m2).
Diabetes Mellitus: The concomitant use of Valsartan + Amlodipine (as besilate) 80 mg/5 mg Film-coated tablet (Valsar Plus) with aliskiren is contraindicated in patients with diabetes mellitus.
Hepatic Impairment: Valsartan + Amlodipine (as besilate) 80 mg/5 mg Film-coated tablet (Valsar Plus) is contraindicated in patients with severe hepatic impairment. Caution should be exercised when administering Valsartan + Amlodipine (as besilate) 80 mg/5 mg Film-coated tablet (Valsar Plus) to patients with hepatic impairment or biliary obstructive disorders. In patients with mild to moderate hepatic impairment without cholestasis, the maximum recommended dose is 80 mg valsartan. Amlodipine dosage recommendations have not been established in patients with mild to moderate hepatic impairment.
Elderly (Age 65 years or over): In elderly patients, caution is required when increasing the dosage.
Paediatric Population: The safety and efficacy of Valsartan + Amlodipine (as besilate) 80 mg/5 mg Film-coated tablet (Valsar Plus) in children aged below 18 years have not been established. No data are available.
Renal Impairment: Valsartan + Amlodipine (as besilate) 80 mg/5 mg Film-coated tablet (Valsar Plus) is contraindicated in patients with severe renal impairment. No dosage adjustment is required for patients with mild to moderate renal impairment. Monitoring of potassium levels and creatinine is advised in moderate renal impairment. The concomitant use of Valsartan + Amlodipine (as besilate) 80 mg/5 mg Film-coated tablet (Valsar Plus) with aliskiren is contraindicated in patients with renal impairment (GFR <60 mL/min/1.73 m2).
Diabetes Mellitus: The concomitant use of Valsartan + Amlodipine (as besilate) 80 mg/5 mg Film-coated tablet (Valsar Plus) with aliskiren is contraindicated in patients with diabetes mellitus.
Hepatic Impairment: Valsartan + Amlodipine (as besilate) 80 mg/5 mg Film-coated tablet (Valsar Plus) is contraindicated in patients with severe hepatic impairment. Caution should be exercised when administering Valsartan + Amlodipine (as besilate) 80 mg/5 mg Film-coated tablet (Valsar Plus) to patients with hepatic impairment or biliary obstructive disorders. In patients with mild to moderate hepatic impairment without cholestasis, the maximum recommended dose is 80 mg valsartan. Amlodipine dosage recommendations have not been established in patients with mild to moderate hepatic impairment.
Elderly (Age 65 years or over): In elderly patients, caution is required when increasing the dosage.
Paediatric Population: The safety and efficacy of Valsartan + Amlodipine (as besilate) 80 mg/5 mg Film-coated tablet (Valsar Plus) in children aged below 18 years have not been established. No data are available.
Overdosage
Information on Amlodipine: Overdosage might be expected to cause excessive peripheral vasodilation with marked hypotension.
If massive overdose should occur, active cardiac and respiratory monitoring should be instituted. Frequent blood pressure measurements are essential. Should hypotension occur, cardiovascular support including elevation of the extremities and the judicious administration of fluids should be initiated. If hypotension remains unresponsive to these conservative measures, administration of vasopressors (such as phenylephrine) should be considered with attention to circulating volume and urine output. Intravenous calcium gluconate may help to reverse the effects of calcium entry blockade. As amlodipine is highly protein bound, hemodialysis is not likely to be of benefit.
Information on Valsartan: Limited data are available related to overdosage in humans. The most likely effect of overdose with valsartan would be peripheral vasodilation, hypotension and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. Depressed level of consciousness, circulatory collapse and shock have been reported. If symptomatic hypotension should occur, supportive treatment should be instituted. Valsartan is not removed from the plasma by hemodialysis.
If massive overdose should occur, active cardiac and respiratory monitoring should be instituted. Frequent blood pressure measurements are essential. Should hypotension occur, cardiovascular support including elevation of the extremities and the judicious administration of fluids should be initiated. If hypotension remains unresponsive to these conservative measures, administration of vasopressors (such as phenylephrine) should be considered with attention to circulating volume and urine output. Intravenous calcium gluconate may help to reverse the effects of calcium entry blockade. As amlodipine is highly protein bound, hemodialysis is not likely to be of benefit.
Information on Valsartan: Limited data are available related to overdosage in humans. The most likely effect of overdose with valsartan would be peripheral vasodilation, hypotension and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. Depressed level of consciousness, circulatory collapse and shock have been reported. If symptomatic hypotension should occur, supportive treatment should be instituted. Valsartan is not removed from the plasma by hemodialysis.
Administration
May be taken with or without food.
Contraindications
Severe hepatic & renal impairment. Concomitant use w/ aliskiren in patients w/ DM; GFR <60 mL/min/1.73 m2.
Special Precautions
Fetal/Neonatal Morbidity and Mortality: Valsar Plus can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
Drugs that act on the renin angiotensin system can cause fetal and neonatal morbidity and mortality when used in pregnancy. In several dozen published cases, ACE inhibitor use during the second and third trimesters of pregnancy was associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death (see Use in Specific Populations as follows).
Hypotension: Excessive hypotension was seen in 0.4% of patients with uncomplicated hypertension treated with Valsar Plus (amlodipine and valsartan) in placebo-controlled studies. In patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients receiving high doses of diuretics, symptomatic hypotension may occur in patients receiving angiotensin receptor blockers. Volume depletion should be corrected prior to administration of Valsar Plus. Treatment with Valsar Plus should start under close medical supervision.
Initiate therapy cautiously in patients with heart failure or recent myocardial infarction and in patients undergoing surgery or dialysis. Patients with heart failure or post-myocardial infarction patients given valsartan commonly have some reduction in blood pressure, but discontinuation of therapy because of continuing symptomatic hypotension usually is not necessary when dosing instructions are followed. If excessive hypotension occurs with Valsar Plus, the patient should be placed in a supine position and, if necessary, given an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized.
Impaired Hepatic Function: Amlodipine: Amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t½) is 56 hours in patients with impaired hepatic function, therefore, caution should be exercised when administering amlodipine to patients with severe hepatic impairment.
Valsartan: As the majority of valsartan is eliminated in the bile, patients with mild-to-moderate hepatic impairment, including patients with biliary obstructive disorders, showed lower valsartan clearance (higher AUCs). Care should be exercised in administering valsartan to these patients.
Impaired Renal Function - Hypertension: In studies of ACE inhibitors in hypertensive patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen have been reported.
As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may occur particularly in volume depleted patients. In patients with severe heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. Similar outcomes have been reported with valsartan.
Congestive Heart Failure: Amlodipine: In general, calcium channel blockers should be used with caution in patients with heart failure.
Valsartan: Some patients with heart failure have developed increases in blood urea nitrogen, serum creatinine, and potassium on valsartan. These effects are usually minor and transient, and they are more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of the diuretic and/or valsartan may be required.
Use in Specific Populations: Use in Pregnancy: Pregnancy Category D.
Valsar Plus, like other drugs that act on the renin angiotensin system, can cause fetal and neonatal morbidity and death when used during the second or third trimester of pregnancy. Valsar Plus can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. When pregnancy occurs in a patient using Valsar Plus, the physician should discontinue Valsar Plus treatment as soon as possible. The physician should inform the patient about potential risks to the fetus based on the time of gestational exposure to Valsar Plus (first trimester only or later).
Use in Lactation: 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. It is not known whether valsartan is excreted in human milk. Valsartan was excreted into the milk of lactating rats; however, animal breast milk drug levels may not accurately reflect human breast milk levels. Because many drugs are excreted into human milk and because of the potential for adverse reactions in nursing infants from Valsar Plus, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
Use in Children: Safety and effectiveness of Valsar Plus in pediatric patients have not been established.
Use in Elderly: No overall differences in the efficacy or safety of Valsartan Plus was observed in this patient population, but greater sensitivity of some older individuals cannot be ruled out.
Amlodipine: In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range. Elderly patients have decreased clearance of amlodipine with a resulting increase of AUC of approximately 40-60%, and a lower initial dose may be required (see Dosage & Administration).
Valsartan: No overall difference in the efficacy or safety of valsartan was observed in this patient population, but greater sensitivity of some older individuals cannot be ruled out.
Drugs that act on the renin angiotensin system can cause fetal and neonatal morbidity and mortality when used in pregnancy. In several dozen published cases, ACE inhibitor use during the second and third trimesters of pregnancy was associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death (see Use in Specific Populations as follows).
Hypotension: Excessive hypotension was seen in 0.4% of patients with uncomplicated hypertension treated with Valsar Plus (amlodipine and valsartan) in placebo-controlled studies. In patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients receiving high doses of diuretics, symptomatic hypotension may occur in patients receiving angiotensin receptor blockers. Volume depletion should be corrected prior to administration of Valsar Plus. Treatment with Valsar Plus should start under close medical supervision.
Initiate therapy cautiously in patients with heart failure or recent myocardial infarction and in patients undergoing surgery or dialysis. Patients with heart failure or post-myocardial infarction patients given valsartan commonly have some reduction in blood pressure, but discontinuation of therapy because of continuing symptomatic hypotension usually is not necessary when dosing instructions are followed. If excessive hypotension occurs with Valsar Plus, the patient should be placed in a supine position and, if necessary, given an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized.
Impaired Hepatic Function: Amlodipine: Amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t½) is 56 hours in patients with impaired hepatic function, therefore, caution should be exercised when administering amlodipine to patients with severe hepatic impairment.
Valsartan: As the majority of valsartan is eliminated in the bile, patients with mild-to-moderate hepatic impairment, including patients with biliary obstructive disorders, showed lower valsartan clearance (higher AUCs). Care should be exercised in administering valsartan to these patients.
Impaired Renal Function - Hypertension: In studies of ACE inhibitors in hypertensive patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen have been reported.
As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may occur particularly in volume depleted patients. In patients with severe heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. Similar outcomes have been reported with valsartan.
Congestive Heart Failure: Amlodipine: In general, calcium channel blockers should be used with caution in patients with heart failure.
Valsartan: Some patients with heart failure have developed increases in blood urea nitrogen, serum creatinine, and potassium on valsartan. These effects are usually minor and transient, and they are more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of the diuretic and/or valsartan may be required.
Use in Specific Populations: Use in Pregnancy: Pregnancy Category D.
Valsar Plus, like other drugs that act on the renin angiotensin system, can cause fetal and neonatal morbidity and death when used during the second or third trimester of pregnancy. Valsar Plus can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. When pregnancy occurs in a patient using Valsar Plus, the physician should discontinue Valsar Plus treatment as soon as possible. The physician should inform the patient about potential risks to the fetus based on the time of gestational exposure to Valsar Plus (first trimester only or later).
Use in Lactation: 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. It is not known whether valsartan is excreted in human milk. Valsartan was excreted into the milk of lactating rats; however, animal breast milk drug levels may not accurately reflect human breast milk levels. Because many drugs are excreted into human milk and because of the potential for adverse reactions in nursing infants from Valsar Plus, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
Use in Children: Safety and effectiveness of Valsar Plus in pediatric patients have not been established.
Use in Elderly: No overall differences in the efficacy or safety of Valsartan Plus was observed in this patient population, but greater sensitivity of some older individuals cannot be ruled out.
Amlodipine: In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range. Elderly patients have decreased clearance of amlodipine with a resulting increase of AUC of approximately 40-60%, and a lower initial dose may be required (see Dosage & Administration).
Valsartan: No overall difference in the efficacy or safety of valsartan was observed in this patient population, but greater sensitivity of some older individuals cannot be ruled out.
Use In Pregnancy & Lactation
Fetal/Neonatal Morbidity and Mortality: Valsar Plus can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
Drugs that act on the renin angiotensin system can cause fetal and neonatal morbidity and mortality when used in pregnancy. In several dozen published cases, ACE inhibitor use during the second and third trimesters of pregnancy was associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death.
Use in Pregnancy: Pregnancy Category D.
Valsar Plus, like other drugs that act on the renin angiotensin system, can cause fetal and neonatal morbidity and death when used during the second or third trimester of pregnancy. Valsar Plus can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. When pregnancy occurs in a patient using Valsar Plus, the physician should discontinue Valsar Plus treatment as soon as possible. The physician should inform the patient about potential risks to the fetus based on the time of gestational exposure to Valsar Plus (first trimester only or later).
Use in Lactation: 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. It is not known whether valsartan is excreted in human milk. Valsartan was excreted into the milk of lactating rats; however, animal breast milk drug levels may not accurately reflect human breast milk levels. Because many drugs are excreted into human milk and because of the potential for adverse reactions in nursing infants from Valsar Plus, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
Drugs that act on the renin angiotensin system can cause fetal and neonatal morbidity and mortality when used in pregnancy. In several dozen published cases, ACE inhibitor use during the second and third trimesters of pregnancy was associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death.
Use in Pregnancy: Pregnancy Category D.
Valsar Plus, like other drugs that act on the renin angiotensin system, can cause fetal and neonatal morbidity and death when used during the second or third trimester of pregnancy. Valsar Plus can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. When pregnancy occurs in a patient using Valsar Plus, the physician should discontinue Valsar Plus treatment as soon as possible. The physician should inform the patient about potential risks to the fetus based on the time of gestational exposure to Valsar Plus (first trimester only or later).
Use in Lactation: 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. It is not known whether valsartan is excreted in human milk. Valsartan was excreted into the milk of lactating rats; however, animal breast milk drug levels may not accurately reflect human breast milk levels. Because many drugs are excreted into human milk and because of the potential for adverse reactions in nursing infants from Valsar Plus, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
Adverse Reactions
Amlodipine and Valsartan combined therapy: Adverse reactions have generally been mild and transient in nature and have only infrequently required discontinuation of therapy.
The overall frequency of adverse reactions was neither dose-related nor related to gender, age, or race. In placebo-controlled clinical trials, discontinuation due to side effects occurred in 1.8% of patients in the Amlodipine and Valsartan combined therapy treated patients and 2.1% in the placebo-treated group. The most common reasons for discontinuation of therapy with Amlodipine and Valsartan combined therapy were peripheral edema (0.4%), and vertigo (0.2%). Orthostatic events (orthostatic hypotension and postural dizziness) were seen in less than 1% of patients.
Post-marketing Experience: Amlodipine: Gynecomastia has been reported infrequently and a causal relationship is uncertain. Jaundice and hepatic enzyme elevations (mostly consistent with cholestasis or hepatitis), in some cases severe enough to require hospitalization, have been reported in association with use of amlodipine.
Valsartan: The following additional adverse reactions have been reported in post-marketing experience with valsartan: Blood and Lymphatic: There are very rare reports of thrombocytopenia.
Hypersensitivity: There are rare reports of angioedema.
Digestive: Elevated liver enzymes and very rare reports of hepatitis.
Renal: Impaired renal function.
Clinical Laboratory Tests: Hyperkalemia.
Dermatologic: Alopecia.
Vascular: Vasculitis Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.
The overall frequency of adverse reactions was neither dose-related nor related to gender, age, or race. In placebo-controlled clinical trials, discontinuation due to side effects occurred in 1.8% of patients in the Amlodipine and Valsartan combined therapy treated patients and 2.1% in the placebo-treated group. The most common reasons for discontinuation of therapy with Amlodipine and Valsartan combined therapy were peripheral edema (0.4%), and vertigo (0.2%). Orthostatic events (orthostatic hypotension and postural dizziness) were seen in less than 1% of patients.
Post-marketing Experience: Amlodipine: Gynecomastia has been reported infrequently and a causal relationship is uncertain. Jaundice and hepatic enzyme elevations (mostly consistent with cholestasis or hepatitis), in some cases severe enough to require hospitalization, have been reported in association with use of amlodipine.
Valsartan: The following additional adverse reactions have been reported in post-marketing experience with valsartan: Blood and Lymphatic: There are very rare reports of thrombocytopenia.
Hypersensitivity: There are rare reports of angioedema.
Digestive: Elevated liver enzymes and very rare reports of hepatitis.
Renal: Impaired renal function.
Clinical Laboratory Tests: Hyperkalemia.
Dermatologic: Alopecia.
Vascular: Vasculitis Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.
Drug Interactions
Drug/Drug Interactions: No drug interaction studies have been conducted with Amlodipine and Valsartan combined therapy.
Amlodipine: In clinical trials, amlodipine has been safely administered with thiazide diuretics, beta-blockers, angiotensin-converting enzyme inhibitors, long-acting nitrates, sublingual nitroglycerin, digoxin, warfarin, non-steroidal anti-inflammatory drugs, antibiotics, and oral hypoglycemic drugs.
Valsartan: No clinically significant pharmacokinetic interactions were observed when valsartan was co-administered with amlodipine, atenolol, cimetidine, digoxin, furosemide, glyburide, hydrochlorothiazide, or indomethacin. The valsartan-atenolol combination was more antihypertensive than either component, but it did not lower the heart rate more than atenolol alone.
CYP 450 Interactions: The enzyme(s) responsible for valsartan metabolism have not been identified but do not seem to be CYP 450 isozymes. The inhibitory or induction potential of valsartan on CYP 450 is also unknown. As with other drugs that block angiotensin II or its effects, concomitant use of potassium sparing diuretics (e.g., spironolactone, triamterene, amiloride), potassium supplements, or salt substitutes containing potassium may lead to increases in serum potassium and in heart failure patients to increases in serum creatinine.
Drug/Food Interactions: The bioavailability of amlodipine and valsartan are not altered by the co-administration of food.
Amlodipine: In clinical trials, amlodipine has been safely administered with thiazide diuretics, beta-blockers, angiotensin-converting enzyme inhibitors, long-acting nitrates, sublingual nitroglycerin, digoxin, warfarin, non-steroidal anti-inflammatory drugs, antibiotics, and oral hypoglycemic drugs.
Valsartan: No clinically significant pharmacokinetic interactions were observed when valsartan was co-administered with amlodipine, atenolol, cimetidine, digoxin, furosemide, glyburide, hydrochlorothiazide, or indomethacin. The valsartan-atenolol combination was more antihypertensive than either component, but it did not lower the heart rate more than atenolol alone.
CYP 450 Interactions: The enzyme(s) responsible for valsartan metabolism have not been identified but do not seem to be CYP 450 isozymes. The inhibitory or induction potential of valsartan on CYP 450 is also unknown. As with other drugs that block angiotensin II or its effects, concomitant use of potassium sparing diuretics (e.g., spironolactone, triamterene, amiloride), potassium supplements, or salt substitutes containing potassium may lead to increases in serum potassium and in heart failure patients to increases in serum creatinine.
Drug/Food Interactions: The bioavailability of amlodipine and valsartan are not altered by the co-administration of food.
Storage
Store at temperatures not exceeding 30°C.
Action
Pharmacology: Pharmacodynamics: Mechanism of Action: Amlodipine: Amlodipine is a dihydropyridine calcium channel blocker that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. Experimental data suggest that amlodipine binds to both dihydropyridine and nondihydropyridine binding sites. 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. Negative inotropic effects can be detected in vitro but such effects have not been seen in intact animals at therapeutic doses. Serum calcium concentration is not affected by amlodipine. Within the physiologic pH range, amlodipine is an ionized compound (pKa=8.6), and its kinetic interaction with the calcium channel receptor is characterized by a gradual rate of association and dissociation with the receptor binding site, resulting in a gradual onset of effect. 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.
Valsartan: Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Valsartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its action is therefore independent of the pathways for angiotensin II synthesis. There is also an AT2 receptor found in many tissues, but AT2 is not known to be associated with cardiovascular homeostasis. Valsartan has much greater affinity (about 20,000-fold) for the AT1 receptor than for the AT2 receptor. The increased plasma levels of angiotensin following AT1 receptor blockade with valsartan may stimulate the unblocked AT2 receptor. The primary metabolite of valsartan is essentially inactive with an affinity for the AT1 receptor about one-200th that of valsartan itself. Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is widely used in the treatment of hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because valsartan does not inhibit ACE (kininase II), it does not affect the response to bradykinin. Whether this difference has clinical relevance is not yet known. Valsartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation. Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and angiotensin II circulating levels do not overcome the effect of valsartan on blood pressure.
Pharmacodynamic effects: Amlodipine: Following administration of therapeutic doses to patients with hypertension, amlodipine produces vasodilation resulting in a reduction of supine and standing blood pressures. These decreases in blood pressure are not accompanied by a significant change in heart rate or plasma catecholamine levels with chronic dosing. Although the acute intravenous administration of amlodipine decreases arterial blood pressure and increases heart rate in hemodynamic studies of patients with chronic stable angina, chronic oral administration of amlodipine in clinical trials did not lead to clinically significant changes in heart rate or blood pressures in normotensive patients with angina. With chronic once daily administration, antihypertensive effectiveness is maintained for at least 24 hours. Plasma concentrations correlate with effect in both young and elderly patients. In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in a decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal plasma flow without change in filtration fraction or proteinuria.
Valsartan: Valsartan inhibits the pressor effect of angiotensin II infusions. An oral dose of 80 mg inhibits the pressor effect by about 80% at peak with approximately 30% inhibition persisting for 24 hours. No information on the effect of larger doses is available. Removal of the negative feedback of angiotensin II causes a 2- to 3-fold rise in plasma renin and consequent rise in angiotensin II plasma concentration in hypertensive patients. Minimal decreases in plasma aldosterone were observed after administration of valsartan; very little effect on serum potassium was observed. In multiple dose studies in hypertensive patients with stable renal insufficiency and patients with renovascular hypertension, valsartan had no clinically significant effects on glomerular filtration rate, filtration fraction, creatinine clearance, or renal plasma flow. Administration of valsartan to patients with essential hypertension results in a significant reduction of sitting, supine, and standing systolic blood pressure, usually with little or no orthostatic change.
Amlodipine and Valsartan combined therapy: Amlodipine and Valsartan combined Therapy as been shown to be effective in lowering blood pressure. Both amlodipine and valsartan lower blood pressure by reducing peripheral resistance, but calcium influx blockade and reduction of angiotensin II vasoconstriction are complementary mechanisms.
Pharmacokinetics: Amlodipine: Peak plasma concentrations of amlodipine are reached 6-12 hours after administration of amlodipine alone. Absolute bioavailability has been estimated to be between 64% and 90%. The bioavailability of amlodipine is not altered by the presence of food.
Amlodipine is extensively (about 90%) converted to inactive metabolites via hepatic metabolism with 10% of the parent compound and 60% of the metabolites excreted in the urine.
Elimination of amlodipine from the plasma is biphasic with a terminal elimination half-life of about 30-50 hours. Steady state plasma levels of amlodipine are reached after 7-8 days of consecutive daily dosing.
Valsartan: Following oral administration of valsartan alone peak plasma concentrations of valsartan are reached in 2-4 hours. Absolute bioavailability is about 25% (range 10%-35%). Food decreases the exposure (as measured by AUC) to valsartan by about 40% and peak plasma concentration (Cmax) by about 50%. Valsartan, when administered as an oral solution, is primarily recovered in feces (about 83% of dose) and urine (about 13% of dose).
Amlodipine and Valsartan combined therapy: Following oral administration of Amlodipine and Valsartan combined therapy normal healthy adults, peak plasma concentrations of valsartan and amlodipine are reached in 3 and 6-8 hours, respectively. The rate and extent of absorption of valsartan and amlodipine from Valsar Plus are the same as when administered as individual tablets.
Valsartan: Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Valsartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its action is therefore independent of the pathways for angiotensin II synthesis. There is also an AT2 receptor found in many tissues, but AT2 is not known to be associated with cardiovascular homeostasis. Valsartan has much greater affinity (about 20,000-fold) for the AT1 receptor than for the AT2 receptor. The increased plasma levels of angiotensin following AT1 receptor blockade with valsartan may stimulate the unblocked AT2 receptor. The primary metabolite of valsartan is essentially inactive with an affinity for the AT1 receptor about one-200th that of valsartan itself. Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is widely used in the treatment of hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because valsartan does not inhibit ACE (kininase II), it does not affect the response to bradykinin. Whether this difference has clinical relevance is not yet known. Valsartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation. Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and angiotensin II circulating levels do not overcome the effect of valsartan on blood pressure.
Pharmacodynamic effects: Amlodipine: Following administration of therapeutic doses to patients with hypertension, amlodipine produces vasodilation resulting in a reduction of supine and standing blood pressures. These decreases in blood pressure are not accompanied by a significant change in heart rate or plasma catecholamine levels with chronic dosing. Although the acute intravenous administration of amlodipine decreases arterial blood pressure and increases heart rate in hemodynamic studies of patients with chronic stable angina, chronic oral administration of amlodipine in clinical trials did not lead to clinically significant changes in heart rate or blood pressures in normotensive patients with angina. With chronic once daily administration, antihypertensive effectiveness is maintained for at least 24 hours. Plasma concentrations correlate with effect in both young and elderly patients. In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in a decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal plasma flow without change in filtration fraction or proteinuria.
Valsartan: Valsartan inhibits the pressor effect of angiotensin II infusions. An oral dose of 80 mg inhibits the pressor effect by about 80% at peak with approximately 30% inhibition persisting for 24 hours. No information on the effect of larger doses is available. Removal of the negative feedback of angiotensin II causes a 2- to 3-fold rise in plasma renin and consequent rise in angiotensin II plasma concentration in hypertensive patients. Minimal decreases in plasma aldosterone were observed after administration of valsartan; very little effect on serum potassium was observed. In multiple dose studies in hypertensive patients with stable renal insufficiency and patients with renovascular hypertension, valsartan had no clinically significant effects on glomerular filtration rate, filtration fraction, creatinine clearance, or renal plasma flow. Administration of valsartan to patients with essential hypertension results in a significant reduction of sitting, supine, and standing systolic blood pressure, usually with little or no orthostatic change.
Amlodipine and Valsartan combined therapy: Amlodipine and Valsartan combined Therapy as been shown to be effective in lowering blood pressure. Both amlodipine and valsartan lower blood pressure by reducing peripheral resistance, but calcium influx blockade and reduction of angiotensin II vasoconstriction are complementary mechanisms.
Pharmacokinetics: Amlodipine: Peak plasma concentrations of amlodipine are reached 6-12 hours after administration of amlodipine alone. Absolute bioavailability has been estimated to be between 64% and 90%. The bioavailability of amlodipine is not altered by the presence of food.
Amlodipine is extensively (about 90%) converted to inactive metabolites via hepatic metabolism with 10% of the parent compound and 60% of the metabolites excreted in the urine.
Elimination of amlodipine from the plasma is biphasic with a terminal elimination half-life of about 30-50 hours. Steady state plasma levels of amlodipine are reached after 7-8 days of consecutive daily dosing.
Valsartan: Following oral administration of valsartan alone peak plasma concentrations of valsartan are reached in 2-4 hours. Absolute bioavailability is about 25% (range 10%-35%). Food decreases the exposure (as measured by AUC) to valsartan by about 40% and peak plasma concentration (Cmax) by about 50%. Valsartan, when administered as an oral solution, is primarily recovered in feces (about 83% of dose) and urine (about 13% of dose).
Amlodipine and Valsartan combined therapy: Following oral administration of Amlodipine and Valsartan combined therapy normal healthy adults, peak plasma concentrations of valsartan and amlodipine are reached in 3 and 6-8 hours, respectively. The rate and extent of absorption of valsartan and amlodipine from Valsar Plus are the same as when administered as individual tablets.
MedsGo Class
Angiotensin II Antagonists / Calcium Antagonists
Features
Brand
Valsar Plus
Full Details
Dosage Strength
80 mg / 5 mg
Drug Ingredients
- Amlodipine
- Valsartan
Drug Packaging
Film-Coated Tablet 1's
Generic Name
Valsartan / Amlodipine Besilate
Dosage Form
Film-Coated Tablet
Registration Number
DRP-6900
Drug Classification
Prescription Drug (RX)
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