Professional Information
Valsartan and Hydrochlorothiazide (Systemic)
VA CLASSIFICATION
Primary: CV401
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).
Category:
Antihypertensive—
Indications
Accepted
Hypertension (treatment)—The combination of valsartan and hydrochlorothiazide is indicated for the treatment of hypertension {01}. However, it is not indicated for initial treatment of hypertension {01}.
—For additional information on initial therapeutic guidelines related to the treatment of hypertension, see Appendix III.
Pharmacology/Pharmacokinetics
Physicochemical characteristics:
Molecular weight—
Valsartan: 435.5 {01}
Hydrochlorothiazide: 297.73 {01}
Mechanism of action/Effect:
Valsartan is a nonpeptide angiotensin II antagonist that selectively blocks the binding of angiotensin II to the AT 1 receptor in tissues such as vascular smooth muscle and the adrenal gland {01}. In the renin-angiotensin system, angiotensin I is converted by angiotensin-converting enzyme (ACE) to form angiotensin II {01}. Angiotensin II stimulates the adrenal cortex to synthesize and secrete aldosterone, which decreases the excretion of sodium and increases the excretion of potassium {01}. Angiotensin II also acts as a vasoconstrictor in vascular smooth muscle {01}. Valsartan, by blocking the binding of angiotensin II to the AT 1 receptor, promotes vasodilation and decreases the effects of aldosterone {01}. The negative feedback regulation of angiotensin II on renin secretion also is inhibited, resulting in a rise in plasma renin concentrations and a consequent rise in angiotensin II plasma concentrations, although these effects do not counteract the blood pressure–lowering effect that occurs {01}.
Hydrochlorothiazide is a thiazide diuretic which acts directly on the kidney to increase the tubular excretion of sodium chloride and water {01}. The resulting decrease in blood volume stimulates the release of renin, the formation of angiotensin, and the secretion of aldosterone and a resulting increase in urinary secretion of potassium {01}. Concurrent administration of an angiotensin II receptor antagonist, such as valsartan, with a thiazide diuretic may help to decrease potassium loss that occurs with thiazide diuretic monotherapy {01}.
When valsartan is given in combination with hydrochlorothiazide, the antihypertensive effects are additive {01}.
Absorption:
Valsartan—Absolute bioavailability for the capsule formulation is approximately 25% (range, 10 to 35%) {01}. Food decreases the area under the plasma concentration–time curve (AUC) and peak plasma concentration (C max) by approximately 40 and 50%, respectively {01}.
Distribution:
Valsartan—Volume of distribution (Vol D) (after intravenous administration): Steady-state—17 L {01}.
Hydrochlorothiazide—Crosses the placenta, but not the blood-brain barrier {01}.
Protein binding:
Valsartan—Very high (95%), mainly to albumin {01}.
Biotransformation:
Valsartan—The enzymes responsible for the metabolism of valsartan have not been identified; however, valsartan is not believed to be metabolized by cytochrome P450 isoenzymes {01}. The primary metabolite, valeryl 4-hydroxy valsartan, is mostly inactive, with an affinity for the AT 1 receptor of about one-two hundredth that of valsartan {01}. About 20% of a dose of valsartan is eliminated as metabolites {01}.
Hydrochlorothiazide—Not metabolized {01}.
Half-life:
Elimination:
Valsartan—Approximately 6 hours {01}. Half-life is increased by 35% in the elderly {01}.
Hydrochlorothiazide—Range, 5.8 to 18.9 hours {01}. In patients with a creatinine clearance of 19 mL/min, the hydrochlorothiazide half-life was increased to 21 hours {01}.
Time to peak concentration:
Valsartan—2 to 4 hours {01}.
Elimination:
Valsartan (after administration of an oral solution)—
Renal: 13% {01}.
Fecal: 83% {01}.
Hydrochlorothiazide (after oral administration)—
Renal {01}.
In dialysis—
Valsartan: Not removable by hemodialysis {01}.
Hydrochlorothiazide: Unknown if completely removable by hemodialysis {01}.
Precautions to Consider
Cross-sensitivity and/or related problems
Patients who are hypersensitive to sulfonamide-derived substances may be hypersensitive to the hydrochlorothiazide component of this medication and should not take the combination.
Carcinogenicity
No evidence of carcinogenicity was found in mice or rats given valsartan for up to 2 years in dietary doses of up to 160 and 200 mg per kg of body weight (mg/kg) per day, respectively {01}. These doses represent approximately 5 and 12 times the maximum recommended human dose (MRHD), respectively, on a mg per square meter of body surface area (mg/m 2) basis, assuming an oral dose of 160 mg per day and a 60-kg patient {01}.
No evidence of carcinogenicity was found in two-year feeding studies in female mice given daily doses of hydrochlorothiazide of up to approximately 600 mg/kg or in male and female rats given daily doses of hydrochlorothiazide of up to approximately 100 mg/kg; however, evidence for hepatocarcinogenicity in male mice was found to be of uncertain significance {01}.
Mutagenicity
Mutagenicity was not detected for valsartan at either the gene or chromosome level in bacterial mutagenicity tests with Salmonella (Ames test) and Escherichia coli , a gene mutation test with Chinese hamster V79 cells, a cytogenetic test with Chinese hamster ovary cells, or a rat micronucleus test {01}.
Genotoxicity was not detected for hydrochlorothiazide in vitro in the Ames mutagenicity assay of Salmonella Typhimurium strains TA 98, TA 100, TA 1535, TA 1537, 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 {01}. Hydrochlorothiazide was found to be genotoxic in the in vitro CHO sister chromatid exchange clastogenicity test and in the mouse lymphoma cell mutagenicity assays, using concentrations of hydrochlorothiazide from 43 to 1300 micrograms per mL (mcg/mL), and in the Aspergillus Nidulans non-disjunction assay at an unspecified concentration {01}.
Pregnancy/Reproduction
Fertility—
No impairment of reproductive performance was found in male or female rats given valsartan in oral doses of up to 200 mg/kg per day {01}. This dose represents approximately 12 times the MRHD on a mg/m 2 basis, assuming an oral dose of 160 mg per day and a 60-kg patient {01}.
Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in studies in which hydrochlorothiazide was given in dietary doses of up to 100 and 4 mg/kg, respectively, prior to mating and throughout gestation {01}.
Pregnancy—
Medications that act directly on the renin-angiotensin system, such as valsartan, can cause fetal and neonatal morbidity and mortality when administered to pregnant women during the second and third trimesters {01}. Valsartan should be discontinued as soon as possible when pregnancy is detected, unless no alternative therapy can be used {01}. In the latter instance, serial ultrasound examinations should be performed to assess the intra-amniotic environment {01}. If oligohydramnios is observed, valsartan should be discontinued unless it is considered lifesaving for the mother {01}. Perinatal diagnostic tests, such as contraction-stress testing (CST), a nonstress test (NST), or biophysical profiling (BPP) also may be appropriate during the applicable week of pregnancy {01}. Oligohydramnios may not appear until after the fetus has sustained irreversible damage {01}.
Fetal exposure to drugs that act directly on the renin-angiotensin system during the second and third trimesters can cause hypotension, reversible or irreversible renal failure, anuria, neonatal skull hypoplasia, and death in the fetus or neonate {01}. Maternal oligohydramnios, which may result from decreased fetal renal function, has been reported, and is associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development {01}. Other adverse effects that have been reported are prematurity, intrauterine growth retardation, and patent ductus arteriosus, although it is not clear how these effects are related to drug exposure {01}. When limited to the first trimester, exposure to this medication does not appear to be associated with these adverse effects {01}.
Infants exposed in utero to angiotensin II receptor antagonists should be observed closely for signs of hypotension, oliguria, and hyperkalemia {01}. Oliguria should be treated with support of blood pressure and renal perfusion {01}. Dialysis or exchange transfusion may be necessary to reverse hypotension and/or substitute for disordered renal function {01}.
Exposure to thiazide diuretics in utero has been associated with fetal or neonatal jaundice, thrombocytopenia, and other adverse reactions {01}.
Teratogenic effects were not observed in pregnant mice or rats given oral doses of up to 600 mg/kg per day or to pregnant rabbits given oral doses of up to 10 mg/kg per day {01}. Studies in rats given oral, maternally toxic (based on a reduction in body weight gain and food consumption) doses of 600 mg/kg per day of valsartan during organogenesis or late gestation and lactation periods resulted in significant decreases in fetal weight, pup birth weight, pup survival rate, and slight delays in developmental milestones {01}. Studies in rabbits given maternally toxic (associated with mortality) doses of 5 and 10 mg/kg per day of valsartan resulted in fetotoxic effects, such as fetal resorptions, litter loss, abortions, and low body weight in pups {01}. No adverse effects were observed in mice, rats, and rabbits given 600, 200, and 2 mg/kg per day, respectively, of valsartan {01}. This represents 18, 12, and 0.2 times, respectively, the MRHD on a mg/m 2 basis, assuming an oral dose of 160 mg per day and a 60-kg patient {01}.
Teratogenic effects were not observed in pregnant mice and rats given doses of hydrochlorothiazide of up to 3000 and 1000 mg per kg of body weight per day, respectively, via gavage on gestation days 6 through 15 {01}. These doses represent 608 and 405 times, respectively, the MRHD on a mg/m 2 basis, assuming an oral dose of 1 mg per day and a 60-kg patient {01}.
Teratogenic effects were not observed in pregnant mice, rats, or rabbits given oral daily doses of valsartan in doses of up to 600, 100, and 10 mg per kg of body weight, respectively, in combination with hydrochlorothiazide in doses of up to 188, 31, and 3 mg per kg of body weight, respectively {01}. These doses represent 18, 7, and 1 times the MRHD of valsartan and 38, 13, and 2 times the MRHD of hydrochlorothiazide, respectively, on a mg/m 2 basis, assuming an oral dose of valsartan of 160 mg per day and hydrochlorothiazide of 25 mg per day and a 60-kg patient {01}.
Studies in rats and rabbits given maternally toxic doses of ³ 200 and 10 mg/kg per day, respectively, of valsartan in combination with hydrochlorothiazide in doses of ³ 63 and 3 mg/kg per day, respectively, resulted in fetotoxic effects {01}. In rats, fetotoxic effects were related to decreased fetal weights and variations of sternebrae, vertebrae, ribs and/or renal papillae {01}. In rabbits, fetotoxic effects included increased numbers of late resorptions with resultant increases in total resorptions, postimplantation losses and decreased numbers of live fetuses {01}.
FDA Pregnancy Category C (first trimester) {01}.
FDA Pregnancy Category D (second and third trimesters) {01}.
Breast-feeding
It is not known whether valsartan is distributed into breast milk {01}. However, valsartan is distributed into the milk of lactating rats {01}. Thiazide diuretics are distributed into breast milk {01}. Administration of valsartan and hydrochlorothiazide combination to nursing mothers is not recommended because of the potential for adverse effects in the nursing infant {01}.
Pediatrics
No information is available on the relationship of age to the effects of valsartan and hydrochlorothiazide combination in pediatric patients. Safety and efficacy have not been established {01}.
Geriatrics
Use of valsartan and hydrochlorothiazide combination in patients 65 years of age and older (16% of patients in clinical studies) has not demonstrated geriatrics-specific problems that would limit the usefulness of valsartan in the elderly {01}. However, the area under the plasma concentration–time curve (AUC) of valsartan is increased by 70% and its half-life is increased by 35% in the elderly when compared to younger individuals {01}. Additionally, elderly patients may experience greater sensitivity to the effects of valsartan and hydrochlorothiazide combination {01}.
Pharmacogenetics
Although drugs that affect the renin-angiotensin system, such as valsartan, have been found to be less effective in patients with low-renin hypertension (predominantly black patients), the overall response to valsartan and hydrochlorothiazide combination has been similar for both black and nonblack patients {01}.
Surgical
Hypokalemia associated with use of hydrochlorothiazide may increase the responsiveness of muscle tissue to nondepolarizing neuromuscular blocking agents, such as tubocurarine {01}.
Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):
Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.
Alcohol{01} or
Barbiturates{01} or
Opioid (narcotic) analgesics{01} (concurrent use with hydrochlorothiazide may increase the risk of orthostatic hypotension {01})
Antidiabetic agents, oral{01} or
Insulin{01} (hydrochlorothiazide may alter blood glucose concentrations which may require a dosage adjustment of the oral antidiabetic agent or insulin {01})
Anti-inflammatory drugs, nonsteroidal (NSAIDs){01} (concurrent use may decrease the antihypertensive effects of hydrochlorothiazide {01})
Cholestyramine{01} or
Colestipol{01} (concurrent use of a single dose may reduce hydrochlorothiazide absorption by up to 85% with cholestyramine and 43% with colestipol {01})
Digitalis glycosides{01} (decreases in serum potassium concentrations, as the result of thiazide diuretic therapy, may increase the sensitivity of the myocardium to the effects of digitalis and may cause cardiac arrhythmia {01})
Hypokalemia-causing medications (see Appendix II ), such as:
Corticosteroids{01} (decreases in serum potassium concentrations may be additive with concurrent use of hydrochlorothiazide {01})
Lithium (concurrent use with hydrochlorothiazide is not recommended because hydrochlorothiazide may potentiate lithium toxicity by decreasing the renal clearance of lithium {01})
Neuromuscular blocking agents, nondepolarizing{01} , such as:
Tubocurarine{01} (hypokalemia that can occur with hydrochlorothiazide therapy may increase the responsiveness of muscle tissue to neuromuscular blocking agents {01})
Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):
With physiology/laboratory test values
Cholesterol, serum{01}
Triglycerides, serum{01} (thiazide diuretics may increase serum cholesterol and triglyceride concentrations {01})
Creatinine, serum{01} (1.4% of patients taking valsartan and hydrochlorothiazide combination experienced minor elevations in serum creatinine, as opposed to 1.1% of those given placebo {01})
» Electrolytes, serum{01} , especially
Calcium{01} and
Chloride{01} and
Magnesium{01} and
Potassium{01} and
Sodium{01} (hypercalcemia, hypochloremia, hypokalemia, hypomagnesemia, and hyponatremia can occur in patients taking thiazide diuretics {01}; hypokalemia may develop, especially with brisk diuresis, when severe cirrhosis is present, or after prolonged thiazide diuretic therapy {01}; chloride depletion may be mild and may only require treatment under special circumstances [such as when hepatic or renal function impairment is present], although replacement may be required in the treatment of metabolic alkalosis {01}; dilutional hyponatremia may occur in edematous patients {01}; thiazide diuretics may decrease urinary calcium excretion and may interfere with parathyroid function testing {01})
(in clinical studies, hyperkalemia [serum potassium > 5.7 mEq per Liter (mEq/L)] occurred in 0.3% of patients and hypokalemia [serum potassium < 3.5 mEq/L] occurred in 4.5% of patients taking valsartan and hydrochlorothiazide combination {01}; the average change in serum potassium in patients taking valsartan/hydrochlorothiazide 160/12.5 mg was near zero; however, patients taking combinations of 80/12.5 mg or 160/25 mg experienced mild reductions in serum potassium {01}; hypokalemia caused the discontinuation of the combination in 2 patients {01})
Glucose, blood{01} (thiazide diuretics may increase blood glucose concentrations {01})
Hematocrit{01} and
Hemoglobin{01} (in clinical studies of patients taking valsartan and hydrochlorothiazide combination, decreases of greater than 20% occurred in 0.1 and 1% of hematocrit and hemoglobin values, respectively, compared with 0% in patients treated with placebo {01})
Leukocyte counts{01} (in clinical studies, neutropenia occurred in 0.6% of patients taking valsartan and hydrochlorothiazide combination, compared with 0% in patients treated with placebo {01})
Liver function tests (elevations of greater than 150% have occurred in patients treated with valsartan and hydrochlorothiazide combination {01})
Uric acid, serum{01} (thiazide diuretics can increase serum uric acid concentrations {01})
Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).
Except under special circumstances, this medication should not be used when the following medical problems exist:
» Hypersensitivity to valsartan or hydrochlorothiazide or other sulfonamide-derived substances{01}
» Anuria{01} (therapy with hydrochlorothiazide may be ineffective in or worsen this condition)
Risk-benefit should be considered when the following medical problems exist
» Congestive heart failure, severe (excessive hypotension resulting from angiotensin receptor antagonist therapy may be associated with oliguria, azotemia, acute renal failure, and/or death in patients who are particularly susceptible to changes in the renin-angiotensin-aldosterone system {01})
Atherosclerosis or
Hyperlipidemia (thiazide diuretics can increase serum cholesterol and triglyceride concentrations {01})
» Electrolyte and/or fluid imbalance{01} (sodium, electrolyte, or volume depletion due to excessive perspiration, inadequate fluid or electrolyte intake, vomiting, diarrhea, dialysis, or dietary salt restriction) (a reduction in salt or fluid volume may increase the risk of symptomatic hypotension in patients treated with valsartan {01}; in patients treated with thiazide diuretics, changes in electrolytes and/or fluid volume may increase the risk of symptomatic hypotension, cardiac arrhythmias and/or digitalis toxicity [as associated with hypokalemia], metabolic alkalosis, and other disorders {01}; see Laboratory value alterations section for changes in serum electrolyte concentrations that can occur with thiazide diuretic therapy)
Diabetes mellitus{01} (thiazide diuretics can increase serum glucose concentrations {01})
Gout{01} (thiazide diuretics can increase serum uric acid concentrations, possibly aggravating or precipitating this condition)
» Hepatic function impairment{01} (use of valsartan in patients with mild to moderate chronic liver disease, including patients with biliary obstructive disorders, has resulted in increases in the area under the plasma concentration–time curve (AUC) {01}; minor alterations in fluid and electrolyte balance that can occur with use of hydrochlorothiazide may precipitate hepatic coma in patients with hepatic function impairment or progressive liver disease {01}; valsartan and hydrochlorothiazide combination should be used with caution in these patients {01})
» Renal artery stenosis, unilateral or bilateral{01} or
» Renal function impairment{01} (increases in serum creatinine or blood urea nitrogen [BUN] may occur with use of valsartan in patients with unilateral or bilateral renal artery stenosis {01}; studies with valsartan have not been done in patients with severe renal function impairment [creatinine clearance < 10 mL/min] {01}; thiazide diuretics should be used with caution in patients with renal function impairment because of the risk of azotemia and/or development of cumulative effects of the diuretic {01}; the hydrochlorothiazide half-life was increased to 21 hours in patients with a mean creatinine clearance of 19 mL/min {01})
Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):
» Blood pressure measurements{01} (periodic monitoring is necessary for titration of dose according to the patient's response {01})
» Electrolytes, serum{01} (periodic monitoring, especially if warning signs or symptoms of hyponatremia, hypochloremia, and/or hypokalemia are present, may be necessary {01})
Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Those indicating need for medical attention
Incidence less frequent
Dizziness —incidence 9% {01}
fatigue —incidence 5% {01}
pharyngitis (sore throat; difficulty swallowing; fever; tender, swollen lymph nodes in the neck; red, raw throat)—incidence 3% {01}
viral infection (cold or flu–like symptoms)—incidence 3% {01}
Note: In clinical trials, the side effects that most often resulted in the discontinuation of valsartan and hydrochlorothiazide combination were fatigue, headache, and dizziness {01}.
Incidence rare
Abdominal pain {01}
allergic reaction {01} (itching, pain, redness, or swelling of eye or eyelid; watering of eyes; troubled breathing or wheezing; severe skin rash or hives; flushing)
gout {01} (sudden occurrence of joint pain, usually in the ankle, knee, or great toe; joint stiffness, or swelling)
hypotension {01} ( dizziness, lightheadedness, or syncope [fainting])
jaundice {01} (yellow eyes or skin)
neutropenia (chills; fever; sore throat )—incidence 0.6% {01}
pancreatitis {01} (bloating or pain of the stomach; fever; nausea; vomiting)
rash {01}
Note: Symptomatic hypotension can occur during the first days of therapy with valsartan and hydrochlorothiazide combination {01}. If syncope occurs, the combination should be discontinued and the patient re-evaluated {01}.
Signs and symptoms of fluid and electrolyte imbalance
Confusion {01}
drowsiness {01}
dryness of mouth {01}
gastrointestinal effects such as nausea and vomiting {01}
hypotension {01} (dizziness, lightheadedness, or fainting)
lethargy {01} (sluggishness)
muscle cramps or pain {01}
muscular fatigue {01}
oliguria {01} (diminished urine output)
restlessness {01}
seizures {01}
tachycardia {01} (fast heart rate)
thirst {01}
weakness {01}
Those indicating need for medical attention only if they continue or are bothersome
Incidence less frequent
Cough {01}
diarrhea {01}
headache —incidence > 2%, similar to placebo {01}
Note: The incidence of cough, in clinical trials comparing valsartan to an angiotensin-converting enzyme (ACE) inhibitor or placebo, was 2.6% for valsartan, 7.9% for the ACE inhibitor, and 1.5% for placebo {01}.
Incidence rare
Anxiety {01}
flushing {01} (redness of face or neck)
impotence {01} (decreased sexual performance)
libido, decreased {01} ( decreased sexual drive)
palpitations {01} (heartbeat sensations)
photosensitivity (increased sensitivity to sunlight)
sweating, increased {01}
Overdose
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).
Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute and/or chronic
Bradycardia{01} (slow heart rate)—as a result of parasympathetic (vagal) stimulation{01}
hypotension{01} (dizziness, lightheadedness, or fainting)
tachycardia{01} (fast heart rate)
Note: The most common signs and symptoms that occur in cases of overdose are those associated with electrolyte depletion and dehydration resulting from excessive diuresis {01}.
Treatment of overdose
Treatment should be symptomatic and supportive {01}.
Supportive care—Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.
Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Valsartan and Hydrochlorothiazide (Systemic).
In providing consultation, consider emphasizing the following selected» information ( = major clinical significance):
Before using this medication
» Conditions affecting use, especially:
Hypersensitivity to valsartan, hydrochlorothiazide, or sulfonamide-derived substances
Pregnancy—Fetal and neonatal hypotension, skull hypoplasia, renal failure, and death have been reported in humans with use of drugs similar to valsartan; fetal or neonatal jaundice, thrombocytopenia, and other adverse effects have occurred with use of thiazide diuretics; valsartan and hydrochlorothiazide combination should be discontinued as soon as possible when pregnancy is detected
Breast-feeding—Valsartan is distributed into milk of lactating rats; hydrochlorothiazide is distributed into breast milk; valsartan and hydrochlorothiazide combination is not recommended in nursing mothers
Use in the elderly—–Area under the plasma concentration time curve (AUC) and half-life of valsartan may be increased; may experience greater sensitivity to the effects of valsartan and hydrochlorothiazide combination
Surgical
Hypokalemia associated with use of hydrochlorothiazide may increase the responsiveness of muscle tissue to nondepolarizing neuromuscular blocking agents
Other medical problems, especially anuria, severe congestive heart failure, electrolyte and/or fluid imbalance, hepatic function impairment, unilateral or bilateral renal artery stenosis, or renal function impairment
Proper use of this medication
» Compliance with therapy; taking medication at the same time each day to maintain the antihypertensive effect
Possible need for control of weight and diet, especially sodium intake; checking with physician before changing diet
» Patient may not experience symptoms of hypertension; importance of taking medication even if feeling well
» Does not cure, but helps control hypertension; possible need for lifelong therapy; checking with physician before discontinuing medication; serious consequences of untreated hypertension
» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next scheduled dose; not doubling doses
» Proper storage
Precautions while using this medication
Making regular visits to physician to check progress
» Notifying physician as soon as possible if pregnancy is suspected because of possibility of fetal or neonatal injury and/or death
» Notifying physician as soon as possible if lightheadedness or fainting occurs
For diabetic patients: checking with physician if any changes in blood glucose concentrations occur
» Not taking other medications without consulting the physician, including potassium supplements or salt substitutes that contain potassium
Caution when driving or doing other things requiring alertness because of possible dizziness, lightheadedness, and syncope due to symptomatic hypotension
Checking with physician if severe nausea, vomiting, or diarrhea occurs and continues because of risk of dehydration, which may result in hypotension
Caution when exercising or during exposure to hot weather because of risk of dehydration (due to excessive perspiration), which may result in hypotension
Caution if any kind of surgery (including dental surgery) or emergency treatment is required
Caution when using alcohol because symptomatic hypotension may occur
Caution when exposed to sunlight because photosensitivity can occur, which may result in sunburn
Side/adverse effects
Signs of potential side effects, especially dizziness, fatigue, pharyngitis, viral infection, abdominal pain, allergic reaction, gout, hypotension, jaundice, neutropenia, pancreatitis, rash, confusion, drowsiness, dryness of mouth, gastrointestinal effects such as nausea and vomiting, lethargy, muscle cramps or pain, muscular fatigue, oliguria, restlessness, seizures, tachycardia, thirst, and weakness
General Dosing Information
Dosage must be adjusted to meet the individual requirements of each patient, on the basis of clinical response.
Combination valsartan and hydrochlorothiazide therapy should only be used in patients who have failed to achieve the desired antihypertensive effect with one or the other as single therapy or when the dose of 25 mg of hydrochlorothiazide as single therapy results in hypokalemia {01}. For dosage ranges for the individual agents when given as single therapy, see • Valsartan (Systemic) monograph; and/or
• Hydrochlorothiazide in Diuretics, Thiazide (Systemic) monograph.
The overall response to valsartan and hydrochlorothiazide combination has been similar for both black and nonblack patients {01}.
The maximal antihypertensive response is attained about four weeks after initiation of combination therapy {01}.
Valsartan and hydrochlorothiazide combination should not be used in patients with a creatinine clearance £ 30 mL/min {01}.
Valsartan and hydrochlorothiazide combination should be used with caution in patients with hepatic function impairment {01}.
Bioequivalence information
Valsartan and hydrochlorothiazide combination may be substituted for the individually titrated components {01}.
For treatment of adverse effects
Recommended treatment consists of the following: • Treatment of symptomatic hypotension involves placing the patient in a supine position and, if needed, administering normal saline intravenously {01}.
Oral Dosage Forms
VALSARTAN AND HYDROCHLOROTHIAZIDE TABLETS
Usual adult dose
Antihypertensive
Oral, 1 or 2 tablets as determined by individual titration with the component agents {01}.
The usual starting dose of the combination in patients with inadequately controlled hypertension and taking valsartan as single therapy is 80 mg/12.5 mg valsartan/hydrochlorothiazide, once daily {01}. If blood pressure remains uncontrolled after about three or four weeks of therapy, either valsartan or both components may be increased, depending on the clinical response {01}.
The usual starting dose of the combination in patients with inadequately controlled hypertension and taking 25 mg of hydrochlorothiazide as single therapy or in patients with adequately controlled hypertension and experiencing hypokalemia with this regimen is 80 mg/12.5 mg valsartan and hydrochlorothiazide, once daily {01}. If blood pressure remains uncontrolled after three or four weeks of therapy, the dose may be titrated up to 160 mg/25 mg valsartan/hydrochlorothiazide {01}.
Usual adult prescribing limits
160 mg valsartan and 25 mg hydrochlorothiazide in combination {01}.
Usual pediatric dose
Safety and efficacy have not been established {01}.
Strength(s) usually available
U.S.—
80 mg valsartan and 12.5 mg hydrochlorothiazide (Rx) [Diovan HCT (colloidal silicon dioxide) (crospovidone) (hydroxypropyl methylcellulose) (iron oxides) (magnesium stearate) (microcrystalline cellulose) (polyethylene glycol) (talc) (titanium dioxide)]
160 mg valsartan and 12.5 mg hydrochlorothiazide (Rx) [Diovan HCT (colloidal silicon dioxide) (crospovidone) (hydroxypropyl methylcellulose) (iron oxides) (magnesium stearate) (microcrystalline cellulose) (polyethylene glycol) (talc) (titanium dioxide)]
Packaging and storage:
Store below 30 ºC (86 ºF) {01}. Protect from moisture {01}. Store in tight container {01}.
Auxiliary labeling:
• Do not take other medications without consulting your physician.
Developed: 09/02/1998
References
- Diovan HCT package insert (Novartis—US), New 2/98, Rec 5/98.
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