Fetal/Neonatal Morbidity and Mortality
Exforge HCT can cause harm to the fetus 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].
Hypotension in Volume- or Salt-Depleted Patients
Excessive hypotension, including orthostatic hypotension, was seen in 1.7%
of patients treated with the maximum dose of Exforge HCT (10/320/25 mg) compared
to 1.8% of valsartan/HCTZ (320/25 mg) patients, 0.4% of amlodipine/valsartan
(10/320 mg) patients, and 0.2% of HCTZ/amlodipine (25/10 mg) patients in a controlled
trial in patients with moderate to severe uncomplicated hypertension. In patients
with an activated renin-angiotensin system, such as volume- or salt-depleted
patients receiving high doses of diuretics, symptomatic hypotension may occur
in patients receiving angiotensin receptor blockers. Correct this condition
prior to administration of Exforge HCT.
Exforge HCT has not been studied in patients with heart failure, recent myocardial
infarction, or 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. Do not initiate treatment
with Exforge HCT in patients with aortic or mitral stenosis or obstructive hypertrophic
cardiomyopathy.
If excessive hypotension occurs with Exforge HCT, 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.
Increased Angina and/or Myocardial Infarction
Rarely, patients, particularly those with severe obstructive coronary artery
disease, have developed documented increased frequency, duration or severity
of angina or acute myocardial infarction upon starting calcium channel blocker
therapy or at the time of dosage increase. The mechanism of this effect has
not been elucidated.
Impaired Hepatic Function
Amlodipine is extensively metabolized by the liver and the plasma elimination
half-life (t½) is 56 hours in patients with impaired hepatic function.
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).
In patients with impaired hepatic function or progressive liver disease, minor
alterations of fluid and electrolyte balance, such as those resulting from diuretic
use, may precipitate hepatic coma.
Therefore, avoid the use of Exforge HCT in patients with severe hepatic impairment.
When administering Exforge HCT to patients with mild-to-moderate hepatic impairment,
including patients with biliary obstructive disorders, monitor for worsening
of hepatic or renal function, including fluid status and electrolytes, and adverse
reactions.
Impaired Renal Function
As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes
in renal function may be anticipated in susceptible individuals. 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.
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.
In patients with renal disease, thiazides may precipitate azotemia. Cumulative
effects of the drug may develop in patients with impaired renal function.
Avoid use of Exforge HCT in severe renal disease (creatinine clearance ≤ 30
mL/min). The usual regimens of therapy with Exforge HCT may be followed if the
patient's creatinine clearance is > 30 mL/min.
There is no experience in the use of Exforge HCT in patients with a recent
kidney transplant.
Heart Failure
Exforge HCT has not been studied in patients with heart failure.
Studies with amlodipine: In general, calcium channel blockers should
be used with close monitoring, including close follow-up of fluid status, electrolytes,
renal function, and blood pressure 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.
Hypersensitivity Reaction
Hypersensitivity reactions to hydrochlorothiazide may occur in patients with
or without a history of allergy or bronchial asthma, but are more likely in
patients with such a history.
Systemic Lupus Erythematosus
Thiazide diuretics have been reported to cause exacerbation or activation of
systemic lupus erythematosus.
Lithium Interaction
Lithium generally should not be given with thiazides [see DRUG INTERACTIONS,
Hydrochlorothiazide, Lithium].
Electrolytes and Metabolic Imbalances
Amlodipine -Valsartan - Hydrochlorothiazide
In the controlled trial of Exforge HCT in moderate to severe hypertensive patients,
the incidence of hypokalemia (serum potassium < 3.5 mEq/L) at any time post-baseline
with the maximum dose of Exforge HCT (10/320/25 mg) was 10% compared to 25%
with HCTZ/amlodipine (25/10 mg), 7% with valsartan/HCTZ (320/25 mg), and 3%
with amlodipine/valsartan (10/320 mg). One patient (0.2%) discontinued therapy
due to an adverse event of hypokalemia in each of the Exforge HCT and HCTZ/amlodipine
groups. The incidence of hyperkalemia (serum potassium > 5.7 mEq/L) was 0.4%
with Exforge HCT compared to 0.2-0.7% with the dual therapies. Monitor serum
electrolytes periodically based on Exforge HCT use and other factors such as
renal function, other medications, or history of prior electrolyte imbalances.
Hydrochlorothiazide
All patients receiving thiazide therapy should be observed for clinical signs
of fluid or electrolyte imbalance: hyponatremia, hypochloremic alkalosis, and
hypokalemia. Serum and urine electrolyte determinations are particularly important
when the patient is vomiting excessively or receiving parenteral fluids. Warning
signs or symptoms of fluid and electrolyte imbalance, irrespective of cause,
include dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness,
confusion, seizures, muscle pains or cramps, muscular fatigue, hypotension,
oliguria, tachycardia, and gastrointestinal disturbances such as nausea and
vomiting.
Hypokalemia may develop, especially with brisk diuresis, when severe cirrhosis
is present, or after prolonged therapy.
Interference with adequate oral electrolyte intake will also contribute to
hypokalemia. Hypokalemia may cause cardiac arrhythmia and may also sensitize
or exaggerate the response of the heart to the toxic effects of digitalis (e.g.,
increased ventricular irritability).
Although any chloride deficit is generally mild and usually does not require
specific treatment except under extraordinary circumstances (as in liver disease
or renal disease), chloride replacement may be required in the treatment of
metabolic alkalosis.
Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate
therapy is water restriction, rather than administration of salt except in rare
instances when the hyponatremia is life-threatening. In actual salt depletion,
appropriate replacement is the therapy of choice.
Hyperuricemia may occur or frank gout may be precipitated in certain patients
receiving thiazide therapy.
In diabetic patients, dosage adjustments of insulin or oral hypoglycemic agents
may be required. Hyperglycemia may occur with thiazide diuretics. Thus latent diabetes mellitus may become manifest during thiazide therapy.
The antihypertensive effects of the drug may be enhanced in the postsympathectomy
patient.
If progressive renal impairment becomes evident, consider withholding or discontinuing
Exforge HCT therapy or substituting other antihypertensive therapy.
Thiazides have been shown to increase the urinary excretion of magnesium; this
may result in hypomagnesemia.
Thiazides may decrease urinary calcium excretion. Thiazides may cause intermittent
and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcemia may be evidence of hidden hyperparathyroidism.
Exforge HCT should be discontinued or non-thiazide antihypertensive therapy
substituted before carrying out tests for parathyroid function.
Increases in cholesterol and triglyceride levels may be associated with thiazide
diuretic therapy.
Acute Myopia and Secondary Angle-Closure Glaucoma
Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting
in acute transient myopia and acute angle-closure glaucoma. Symptoms include
acute onset of decreased visual acuity or ocular pain and typically occur within
hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can
lead to permanent vision loss. The primary treatment is to discontinue hydrochlorothiazide
as rapidly as possible. Prompt medical or surgical treatments may need to be
considered if the intraocular pressure remains uncontrolled. Risk factors for
developing acute angle-closure glaucoma may include a history of sulfonamide
or penicillin allergy.
Patient Counseling Information
Pregnancy: Female patients of childbearing age should be told that use
of drugs like Exforge HCT that act on the renin-angiotensin system during pregnancy
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
HCT who become pregnant should notify their physician as soon as possible.
Symptomatic Hypotension: A patient receiving Exforge HCT should be cautioned
that lightheadedness can occur, especially during the first days of therapy,
and that it should be reported to the prescribing physician. The patients should
be told that if syncope occurs, Exforge HCT should be discontinued until the
physician has been consulted.
All patients should be cautioned that inadequate fluid intake, excessive perspiration,
diarrhea, or vomiting can lead to an excessive fall in blood pressure, with
the same consequences of lightheadedness and possible syncope.
Potassium Supplements: A patient receiving Exforge HCT should be told
not to use potassium supplements or salt substitutes containing potassium without
consulting the prescribing physician.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
Studies with amlodipine/valsartan/hydrochlorothiazide: No carcinogenicity,
mutagenicity or fertility studies have been conducted with this combination.
However, these studies have been conducted for amlodipine, valsartan and hydrochlorothiazide
alone. Based on the preclinical safety and human pharmacokinetic studies, there
is no indication of any toxicologically significant adverse interaction between
these components.
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.
Studies with hydrochlorothiazide: Two-year feeding studies in mice and
rats conducted under the auspices of the National Toxicology Program (NTP) uncovered
no evidence of a carcinogenic potential of hydrochlorothiazide in female mice
(at doses of up to approximately 600 mg/kg/day) or in male and female rats (at
doses of up to approximately 100 mg/kg/day). The NTP, however, found equivocal
evidence for hepatocarcinogenicity in male mice.
Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay of Salmonella Typhimurium strains TA 98, TA 100, TA 1535, TA 1537, and
TA 1538 and in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations,
or in vivo in assays using mouse germinal cell chromosomes, Chinese hamster
bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait
gene. Positive test results were obtained in the in vitro CHO Sister
Chromatid Exchange (clastogenicity) and Mouse Lymphoma Cell (mutagenicity) assays
and in the Aspergillus Nidulans non-disjunction assay.
Hydrochlorothiazide had no adverse effects on the fertility of mice and rats
of either sex in studies wherein these species were exposed via diet at doses
of up to 100 and 4 mg/kg, respectively, prior to mating and throughout gestation.
These doses of hydrochlorothiazide in mice and rats are 19 and 1.5 times, respectively,
the maximum recommended human dose on a mg/m² basis. (Calculations assume
an oral dose of 25 mg/day and a 60-kg patient.)
Developmental Toxicity
Studies with amlodipine: No evidence of teratogenicity or other embryo/fetal
toxicity was found when pregnant rats and rabbits were treated orally with amlodipine
maleate at doses of up to 10 mg amlodipine/kg/day (respectively, about 10 and
20 times the maximum recommended human dose [MRHD] of 10 mg amlodipine on a
mg/m² basis) during their respective periods of major organogenesis. (Calculations
based on a patient weight of 60 kg.) However, litter size was significantly
decreased (by about 50%) and the number of intrauterine deaths was significantly
increased (about 5-fold) for rats receiving amlodipine maleate at a dose equivalent
to 10 mg amlodipine/kg/day for 14 days before mating and throughout mating and
gestation. Amlodipine maleate has been shown to prolong both the gestation period
and the duration of labor in rats at this dose. There are no adequate and well
controlled studies in pregnant women.
Studies with valsartan: No teratogenic effects were observed when valsartan
was administered to pregnant mice and rats at oral doses of up to 600 mg/kg/day
and to pregnant rabbits at oral doses of up to 10 mg/kg/day. However, significant
decreases in fetal weight, pup birth weight, pup survival rate, and slight delays
in developmental milestones were observed in studies in which parental rats
were treated with valsartan at oral, maternally toxic (reduction in body weight
gain and food consumption) doses of 600 mg/kg/day during organogenesis or late
gestation and lactation. In rabbits, fetotoxicity (i.e., resorptions, litter
loss, abortions, and low body weight) associated with maternal toxicity (mortality)
was observed at doses of 5 and 10 mg/kg/day. The no observed adverse effect
doses of 600, 200 and 2 mg/kg/day in mice, rats and rabbits, respectively, are
about 9, 6 and 0.1 times the MRHD of 320 mg/day on a mg/m² basis. (Calculations
based on a patient weight of 60 kg.)
Studies with hydrochlorothiazide: Under the auspices of the National
Toxicology Program, pregnant mice and rats that received hydrochlorothiazide
via gavage at doses up to 3000 and 1000 mg/kg/day, respectively, on gestation
days 6 through 15 showed no evidence of teratogenicity. These doses of hydrochlorothiazide
in mice and rats are 608 and 405 times, respectively, the maximum recommended
human dose on a mg/m² basis. (Calculations assume an oral dose of 25 mg/day
and a 60-kg patient.)
Studies with amlodipine and valsartan: In the oral embryo-fetal development
study in rats using amlodipine besylate plus valsartan at doses equivalent to
5 mg/kg/day amlodipine plus 80 mg/kg/day valsartan, 10 mg/kg/day amlodipine
plus 160 mg/kg/day valsartan, and 20 mg/kg/day amlodipine plus 320 mg/kg/day
valsartan, treatment-related maternal and fetal effects (developmental delays
and alterations noted in the presence of significant maternal toxicity) were
noted with the high dose combination. The no-observed-adverseeffect level (NOAEL)
for embryo- fetal effects was 10 mg/kg/day amlodipine plus 160 mg/kg/day valsartan.
On a systemic exposure [AUC(0-∞)] basis, these doses are, respectively,
4.3 and 2.7 times the systemic exposure [AUC(0-∞)] in humans receiving
the MRHD (10/320 mg/60 kg).
Studies with valsartan and hydrochlorothiazide: There was no evidence
of teratogenicity in mice, rats, or rabbits treated orally with valsartan at
doses up to 600, 100 and 10 mg/kg/day, respectively, in combination with hydrochlorothiazide
at doses up to 188, 31 and 3 mg/kg/day. These non-teratogenic doses in mice,
rats and rabbits are, respectively, 9, 3.5 and 0.5 times the maximum recommended
human dose (MRHD) of valsartan and 38, 13 and 2 times the MRHD of hydrochlorothiazide
on a mg/m² basis. (Calculations assume an oral dose of 320 mg/day valsartan
in combination with 25 mg/day hydrochlorothiazide in a 60-kg patient.)
Fetotoxicity was observed in association with maternal toxicity in rats at
valsartan/hydrochlorothiazide doses ≥ 200/63 mg/kg/day and in rabbits at valsartan/hydrochlorothiazide
doses of 10/3 mg/kg/day. Evidence of fetotoxicity in rats consisted of decreased
fetal weight and fetal variations of sternebrae, vertebrae, ribs and/or renal
papillae. Evidence of fetotoxicity in rabbits included increased numbers of
late resorptions with resultant increases in total resorptions, postimplantation
losses and decreased number of live fetuses. The no observed adverse effect
doses of the valsartan/hydrochlorothiazide combination in mice, rats and rabbits
were 600/188, 100/31 and 3/1 mg/kg/day, respectively. These doses in mice, rats
and rabbits are, respectively, 9, 3 and 0.18 times the MRHD of valsartan and
38, 13 and 0.5 times the MRHD of hydrochlorothiazide on a mg/m² basis.
(Calculations assume an oral dose of 320 mg/day valsartan in combination with
25 mg/day hydrochlorothiazide in a 60-kg patient.)
Use In Specific Populations
Pregnancy
Pregnancy Category D
Valsartan, 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. If Exforge HCT 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 HCT, the physician should
discontinue Exforge HCT 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 HCT (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 can not 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 HCT 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 HCT 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 Nonclinical Toxicology].
Nursing Mothers
It is not known whether amlodipine and valsartan are excreted in human milk,
but thiazides are excreted in human milk and valsartan is excreted in rat milk.
Because of the potential for adverse effects on the nursing infant, 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
The safety and effectiveness of Exforge HCT in pediatric patients have not
been established.
Geriatric Use
In controlled clinical trials, 82 hypertensive patients treated with Exforge
HCT were ≥ 65 years and 13 were ≥ 75 years. No overall differences in the
efficacy or safety of Exforge HCT were observed in this patient population,
but greater sensitivity of some older individuals cannot be ruled out.
Last reviewed on RxList: 7/11/2011
This monograph has been modified to include the generic and brand name in many instances.