Monitor renal function and BP. Drugs that increase potassium concentrations eg, potassium supplements, salt substitutes Serum potassium concentrations may be increased.
Closely monitor serum potassium. Adjust treatment as needed. Lithium Lithium plasma concentrations may be elevated, increasing its pharmacologic effects. Monitor lithium levels; adjust dose accordingly. Potassium-sparing diuretics eg, amiloride The risk of hyperkalemia may be increased, especially in high-risk patients eg, renal impairment, type 2 diabetes.
Closely monitor serum potassium and renal function. Adjust therapy as needed. Protease inhibitors eg, indinavir, ritonavir The antihypertensive effects of amlodipine may be increased. Use with caution and monitor clinical response. Some patients with heart failure have developed increases in potassium with valsartan therapy.
These effects are usually minor and transient, and they are more likely to occur in patients with pre-existing renal impairment. Female patients of childbearing age should be told about the consequences of exposure to Exforge during pregnancy.
Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility Amlodipine Rats and mice treated with amlodipine maleate in the diet for up to 2 years, at concentrations calculated to provide daily dosage levels of 0.
Calculations based on a 60 kg patient. Mutagenicity studies conducted with amlodipine maleate revealed no drug-related effects at either the gene or chromosome level. These doses in mice and rats are about 2. Mutagenicity assays did not reveal any valsartan-related effects at either the gene or chromosome level. These assays included bacterial mutagenicity tests with Salmonella and E. Use In Specific Populations Pregnancy Pregnancy Category D Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death.
Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Exforge as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimesters of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the reninangiotensin system from other antihypertensive agents.
Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus. In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue Exforge, unless it is considered lifesaving for the mother.
Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.
Closely observe infants with histories of in utero exposure to Exforge for hypotension, oliguria , and hyperkalemia [see Use in Specific Populations]. Labor And Delivery The effect of Exforge on labor and delivery has not been studied. Nursing Mothers 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 Exforge, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness of Exforge in pediatric patients have not been established.
Neonates with a history of in utero exposure to Exforge: If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Geriatric Use In controlled clinical trials, No overall differences in the efficacy or safety of Exforge was observed in this patient population, but greater sensitivity of some older individuals cannot be ruled out.
The recommended starting dose of amlodipine 2. Clinical studies of amlodipine besylate tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.
In the controlled clinical trials of 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. The recommended initial dose of amlodipine in patients with hepatic impairment is 2. Valsartan No dose adjustment is necessary for patients with mild-to-moderate disease. No dosing recommendations can be provided for patients with severe liver disease.
Overdosage might be expected to cause excessive peripheral vasodilation with marked hypotension. In humans, experience with intentional overdosage of amlodipine is limited. Marked and potentially prolonged systemic hypotension up to and including shock with fatal outcome have been reported.
If massive overdose should occur, initiate active cardiac and respiratory monitoring. 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, consider administration of vasopressors such as phenylephrine with attention to circulating volume and urine output. As amlodipine is highly protein bound, hemodialysis is not likely to be of benefit. Administration of activated charcoal to healthy volunteers immediately or up to two hours after ingestion of amlodipine has been shown to significantly decrease amlodipine absorption.
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. Clinical Pharmacology 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. In patients with chronic stable angina, intravenous administration of 10 mg did not significantly alter A-H and H-V conduction and sinus node recovery time after pacing.
Similar results were obtained in patients receiving amlodipine and concomitant beta-blockers. In clinical studies in which amlodipine was administered in combination with beta-blockers to patients with either hypertension or angina, no adverse effects of electrocardiographic parameters were observed. In clinical trials with angina patients alone, amlodipine therapy did not alter electrocardiographic intervals or produce higher degrees of AV blocks.
Amlodipine has indications other than hypertension which are described in its full prescribing information. Valsartan Valsartan inhibits the pressor effect of angiotensin II infusions. 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.
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. Valsartan has indications other than hypertension which are described in its full prescribing information. Hydrochlorothiazide After oral administration of hydrochlorothiazide, diuresis begins within 2 hours, peaks in about 4 hours and lasts about 6 to 12 hours. Amlodipine Peak plasma concentrations of amlodipine are reached 6 to 12 hours after administration of amlodipine alone.
Elimination of amlodipine from the plasma is biphasic with a terminal elimination half-life of about 30 to 50 hours. Steady-state plasma levels of amlodipine are reached after 7 to 8 days of consecutive daily dosing. Valsartan Following oral administration of valsartan alone peak plasma concentrations of valsartan are reached in 2 to 4 hours. The steady-state volume of distribution of valsartan after intravenous administration is 17 L indicating that valsartan does not distribute into tissues extensively.
Valsartan shows bi-exponential decay kinetics following intravenous administration with an average elimination half-life of about 6 hours. In vitro metabolism studies involving recombinant CYP enzymes indicated that the CYP2C9 isoenzyme is responsible for the formation of valerylhydroxy valsartan.
Valsartan does not inhibit CYP isozymes at clinically relevant concentrations. CYP mediated drug interaction between valsartan and coadministered drugs are unlikely because of the low extent of metabolism.
Peak plasma hydrochlorothiazide concentrations Cmax are reached within 2 to 5 hours after oral administration. There is no clinically significant effect of food on the bioavailability of hydrochlorothiazide. Following oral administration, plasma hydrochlorothiazide concentrations decline biexponentially, with a mean distribution half-life of about 2 hours and an elimination half-life of about 10 hours. Elderly patients have decreased clearance of amlodipine with a resulting increase in peak plasma levels, elimination half-life, and AUC.
Limited amount of data suggest that the systemic clearance of hydrochlorothiazide is reduced in both healthy and hypertensive elderly subjects compared to young healthy volunteers.
Pharmacokinetics of valsartan does not differ significantly between males and females. Pharmacokinetic differences due to race have not been studied. The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. There is no apparent correlation between renal function measured by creatinine clearance and exposure measured by AUC to valsartan in patients with different degrees of renal impairment.
Use in Specific Populations 8. On average, patients with mild-to-moderate chronic liver disease have twice the exposure measured by AUC values to valsartan of healthy volunteers matched by age, sex, and weight [see Use in Specific Populations 8. In vitro data in human plasma indicate that amlodipine has no effect on the protein binding of digoxin, phenytoin, warfarin, and indomethacin.
Impact of other drugs on amlodipine Coadministered cimetidine, magnesium-and aluminum hydroxide antacids, sildenafil, and grapefruit juice have no impact on the exposure to amlodipine.
However, strong inhibitors of CYP3A e. Impact of amlodipine on other drugs Coadministered amlodipine does not affect the exposure to atorvastatin, digoxin, ethanol and the warfarin prothrombin response time. However, a 3-fold increase in plasma exposure to tacrolimus in a renal transplant patient CYP3A5 non-expresser upon initiation of amlodipine for the treatment of post-transplant hypertension resulting in reduction of tacrolimus dose has been reported.
Drugs that alter gastrointestinal motility: The bioavailability of thiazide-type diuretics may be increased by anticholinergic agents e. Conversely, pro-kinetic drugs may decrease the bioavailability of thiazide diuretics.
Concomitant use of thiazide diuretics may reduce renal excretion of cytotoxic agents and enhance their myelosuppressive effects. Alcohol, barbiturates, or narcotics: Potentiation of orthostatic hypotension may occur. Possible increased responsiveness to muscle relaxants such as curare derivatives.
May be substituted for individually titrated components. 5mg/valsartan pharmacodynamics of each individual component is described below. Mutagenicity studies conducted with amlodipine maleate revealed no drug-related effects at either the gene or chromosome level. Limited amount 160mg data suggest that 5mg/valsartan systemic clearance of hydrochlorothiazide is reduced in both healthy and hypertensive elderly subjects compared to young healthy volunteers. Because many drugs are excreted into human milk 160mg because of the potential for adverse reactions in nursing infants from Exforge, a decision should be made whether to discontinue nursing 160mg discontinue 5mg/valsartan drug, amlodipine 5mg/valsartan 160mg, taking into account the amlodipine of the drug to the mother. There amlodipine no apparent correlation between renal function measured by creatinine clearance and exposure measured by AUC to valsartan in patients with different degrees of renal impairment. The most likely amlodipine 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. Peak plasma hydrochlorothiazide concentrations Cmax are reached within 2 to 5 hours after oral administration. The recommended initial 5mg/valsartan of amlodipine in patients with hepatic impairment is 2. On average, patients with mild-to-moderate chronic liver disease have twice the exposure measured by AUC values to valsartan of healthy volunteers matched by age, sex, and weight [see Use in Specific Populations 8. Pregnancy, amlodipine 5mg/valsartan 160mg, breast-feeding and fertility If you 5mg/valsartan pregnant or breast-feeding, think amlodipine may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine. Elderly patients have decreased clearance of amlodipine with a resulting increase in peak plasma levels, amlodipine 5mg/valsartan 160mg, elimination half-life, and AUC, amlodipine 5mg/valsartan 160mg. Your doctor may check your kidney function, blood pressure, and the amount of electrolytes e. Do not exceed the prescribed dose. Amlodipine does not change sinoatrial nodal function or atrioventricular AV 160mg in intact animals or amlodipine. Monitor serum potassium concentrations 160mg clinical response.
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