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Fetal/Neonatal Morbidity and Mortality
Exforge 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].
Excessive hypotension was seen in 0.4% of patients with uncomplicated hypertension treated with Exforge 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 Exforge. Treatment with Exforge 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. In controlled trials in heart failure patients, the incidence of hypotension in valsartan-treated patients was 5.5% compared to 1.8% in placebo-treated patients. In the Valsartan in Acute Myocardial Infarction Trial (VALIANT), hypotension in post-myocardial infarction patients led to permanent discontinuation of therapy in 1.4% of valsartan-treated patients and 0.8% of captopril-treated patients.
Since the vasodilation induced by amlodipine is gradual in onset, acute hypotension has rarely been reported after oral administration. Nonetheless, caution, as with any other peripheral vasodilator, should be exercised when administering amlodipine, particularly in patients with severe aortic stenosis.
If excessive hypotension occurs with Exforge, 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.
Risk of Myocardial Infarction or Increased Angina
Rarely, patients, particularly those with severe obstructive coronary artery disease, have developed documented increased frequency, duration 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.
Impaired Hepatic Function
Studies with 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.
Studies with 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. In a 4-day trial of valsartan in 12 hypertensive patients with unilateral renal artery stenosis, no significant increases in serum creatinine or blood urea nitrogen were observed. There has been no long-term use of valsartan in patients with unilateral or bilateral renal artery stenosis, but an effect similar to that seen with ACE inhibitors should be anticipated.
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
Studies with Amlodipine
In general, calcium channel blockers should be used with caution in patients with heart failure. Amlodipine (5-10 mg per day) has been studied in a placebo-controlled trial of 1,153 patients with NYHA Class III or IV heart failure on stable doses of ACE inhibitor, digoxin, and diuretics. Follow-up was at least 6 months, with a mean of about 14 months. There was no overall adverse effect on survival or cardiac morbidity (as defined by life-threatening arrhythmia, acute myocardial infarction, or hospitalization for worsened heart failure). Amlodipine has been compared to placebo in four 8-12 week studies of patients with NYHA class II/III heart failure, involving a total of 697 patients. In these studies, there was no evidence of worsened heart failure based on measures of exercise tolerance, NYHA classification, symptoms, or LVEF.
Studies with 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. In the Valsartan Heart Failure Trial, in which 93% of patients were on concomitant ACE inhibitors, treatment was discontinued for elevations in creatinine or potassium (total of 1.0% on valsartan vs. 0.2% on placebo). In the Valsartan in Acute Myocardial Infarction Trial (VALIANT), discontinuation due to various types of renal dysfunction occurred in 1.1% of valsartan-treated patients and 0.8% of captopril-treated patients. Evaluation of patients with heart failure or post-myocardial infarction should always include assessment of renal function.
Patient Counseling Information
Information for Patients
Pregnancy: Female patients of childbearing age should be told that use of drugs like valsartan that act on the renin-angiotensin system can cause serious problems in the fetus and infant including: low blood pressure, poor development of skull bones, kidney failure and death. Discuss other treatment options with female patients planning to become pregnant. Women using Exforge who become pregnant should notify their physicians as soon as possible.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Studies with Amlodipine
Rats and mice treated with amlodipine maleate in the diet for up to two years, at concentrations calculated to provide daily dosage levels of 0.5, 1.25, and 2.5 mg amlodipine/kg/day, showed no evidence of a carcinogenic effect of the drug. For the mouse, the highest dose was, on mg/m² basis, similar to the maximum recommended human dose [MRHD] of 10 mg amlodipine/day. For the rat, the highest dose was, on a mg/m² basis, about two and a half times the MRHD. (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.
There was no effect on the fertility of rats treated orally with amlodipine maleate (males for 64 days and females for 14 days prior to mating) at doses of up to 10 mg amlodipine/kg/day (about 10 times the MRHD of 10 mg/day on a mg/m² basis).
Studies with Valsartan
There was no evidence of carcinogenicity when valsartan was administered in the diet to mice and rats for up to 2 years at concentrations calculated to provide doses of up to 160 and 200 mg/kg/day, respectively. These doses in mice and rats are about 2.4 and 6 times, respectively, the MRHD of 320 mg/day on a mg/m² basis. (Calculations based on a 60 kg patient.)
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. coli, a gene mutation test with Chinese hamster V79 cells, a cytogenetic test with Chinese hamster ovary cells, and a rat micronucleus test.
Valsartan had no adverse effects on the reproductive performance of male or female rats at oral doses of up to 200 mg/kg/day. This dose is about 6 times the maximum recommended human dose on a mg/m² basis.
Use In Specific Populations
Pregnancy Category D [see WARNINGS AND PRECAUTIONS]
Exforge, 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. Exforge 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.
Angiotensin II receptor antagonists, like valsartan, and angiotensin converting enzyme (ACE) inhibitors exert similar effects on the renin-angiotensin system. 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. Oligohydramnios was also reported, presumably from decreased fetal renal function. In this setting, oligohydramnios was associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus were also reported, although it is not clear whether these occurrences were due to exposure to the drug. In a retrospective study, first trimester use of ACE inhibitors, a specific class of drugs acting on the renin angiotensin system, was associated with a potential risk of birth defects.
When pregnancy occurs in a patient using Exforge, the physician should discontinue Exforge 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 Exforge (first trimester only or later). If exposure occurs beyond the first trimester, an ultrasound examination should be done.
In rare cases when another antihypertensive agent cannot be used to treat the pregnant patient, serial ultrasound examinations should be performed to assess the intraamniotic environment. Routine fetal testing with non-stress tests, biophysical profiles, and/or contraction stress tests may be appropriate based on gestational age and standards of care in the community. If oligohydramnios occurs in these situations, individualized decisions about continuing or discontinuing Exforge treatment and about pregnancy management should be made by the patient, her physician, and experts in the management of high risk pregnancy. Patients and physicians should be aware that oligohydramnios may not appear until after the fetus has sustained irreversible injury.
Infants with histories of in utero exposure to Exforge should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, these infants may require blood pressure and renal perfusion support. Exchange transfusion or dialysis may be required to reverse hypotension and/or support decreased renal function.
Healthcare professionals who prescribe drugs acting directly on the renin angiotensin system should counsel women of childbearing potential about the risks of these agents during pregnancy [see Nonclincial Toxicology].
Labor and Delivery
The effect of Exforge on labor and delivery has not been studied.
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.
Safety and effectiveness of Exforge in pediatric patients have not been established.
In controlled clinical trials, 323 (22.5%) hypertensive patients treated with Exforge were ≥ 65 years and 79 (5.5%) were ≥ 75 years. 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.
Amlodipine: 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. 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 AND ADMINISTRATION].
Valsartan: In the controlled clinical trials of valsartan, 1,214 (36.2%) of hypertensive patients treated with valsartan were ≥ 65 years and 265 (7.9%) were ≥ 75 years. 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.
Last reviewed on RxList: 1/3/2012
This monograph has been modified to include the generic and brand name in many instances.
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