Valsartan/Hydrochlorothiazide

Description

Valsartan and hydrochlorothiazide tablets, USP are a combination formulation containing valsartan, an orally active angiotensin II receptor blocker (ARB) specific to the AT1 receptor subtype, and hydrochlorothiazide, a thiazide diuretic. Valsartan is chemically defined as N-(1-oxopentyl)-N-[[2'-(1H-tetrazol-5-yl)1,1'-biphenyl-4-yl]methyl]-L-Valine, with a molecular formula of C24H29N5O3 and a molecular weight of 435.52 g/mol. It appears as an almost white, hygroscopic powder that is practically insoluble in water, freely soluble in anhydrous ethanol, and sparingly soluble in methylene chloride.

Hydrochlorothiazide is chemically described as 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide, with a molecular formula of C7H8ClN3O4S2 and a molecular weight of 297.74 g/mol. This compound is presented as a white or practically white, practically odorless crystalline powder. Hydrochlorothiazide is slightly soluble in water, freely soluble in sodium hydroxide solution, n-butylamine, and dimethyl formamide, sparingly soluble in methanol, and insoluble in ether, chloroform, and dilute mineral acids.

The tablets are formulated for oral administration and are available in the following strengths: 80 mg/12.5 mg, 160 mg/12.5 mg, 160 mg/25 mg, 320 mg/12.5 mg, and 320 mg/25 mg of valsartan and hydrochlorothiazide, respectively. Inactive ingredients include colloidal silicon dioxide, croscarmellose sodium, hypromellose, iron oxide yellow, polyethylene glycol, magnesium stearate, microcrystalline cellulose, polyvinyl alcohol, talc, and titanium dioxide. Specific formulations also contain additional colorants: the 80 mg/12.5 mg tablets include FD&C Red No. 40 and ferrosoferric oxide; the 160 mg/12.5 mg tablets contain iron oxide red; the 160 mg/25 mg and 320 mg/12.5 mg tablets contain both iron oxide red and ferrosoferric oxide.

Uses and Indications

Valsartan and hydrochlorothiazide tablets are indicated for the treatment of hypertension to lower blood pressure in patients who are not adequately controlled with monotherapy. This combination therapy may also be used as initial treatment in patients who are likely to require multiple medications to achieve their blood pressure goals.

Lowering blood pressure with this medication reduces the risk of both fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions.

There are no teratogenic or nonteratogenic effects associated with this drug.

Dosage and Administration

The recommended dosage is once daily, with titration as needed, up to a maximum dose of 320 mg of valsartan and 25 mg of hydrochlorothiazide (HCTZ). This medication may be utilized as add-on or switch therapy for patients who are not adequately controlled on any of the individual components, valsartan or HCTZ. Additionally, it may be substituted for the titrated components, ensuring that the total daily dosage does not exceed the specified maximum. Healthcare professionals should monitor patients closely during the titration process to achieve optimal therapeutic outcomes.

Contraindications

Use of this product is contraindicated in the following situations:

Patients with anuria, as the absence of urine production may lead to accumulation of the drug and potential toxicity.

Hypersensitivity to any sulfonamide-derived drugs or any component of the formulation is also a contraindication due to the risk of severe allergic reactions.

Additionally, co-administration of aliskiren with valsartan and hydrochlorothiazide tablets is contraindicated in patients with diabetes, as this combination may increase the risk of adverse effects.

Warnings and Precautions

When pregnancy is detected, it is imperative to discontinue the use of valsartan and hydrochlorothiazide tablets as soon as possible due to the risk of fetal toxicity. Medications that directly affect the renin-angiotensin system have the potential to cause serious injury or death to the developing fetus.

Prior to initiating treatment, it is essential to correct any volume depletion to mitigate the risk of hypotension. Healthcare professionals should remain vigilant for signs of fluid or electrolyte imbalance during the course of treatment. Regular monitoring of renal function and serum potassium levels is recommended, particularly in patients who are susceptible to these complications.

There is a noted risk of exacerbation or activation of systemic lupus erythematosus in some patients. Additionally, caution should be exercised in patients with a history of acute angle-closure glaucoma, as this condition may be exacerbated.

For patients at risk, ongoing laboratory tests to monitor renal function and potassium levels are advised to ensure safe use of the medication.

Side Effects

Patients receiving valsartan and hydrochlorothiazide may experience a range of adverse reactions. Common adverse reactions observed in clinical trials include headache, dizziness, and nasopharyngitis, with the latter occurring in 2.4% of patients compared to 1.9% in the placebo group.

Serious warnings associated with the use of valsartan and hydrochlorothiazide include the potential for fetal toxicity. It is imperative that these tablets be discontinued as soon as pregnancy is detected, as drugs that act directly on the renin-angiotensin system can cause injury or death to the developing fetus.

Additional adverse reactions of clinical significance include hypotension, which necessitates correction of volume depletion prior to initiation of therapy. Patients should be monitored for signs of fluid or electrolyte imbalance, and renal function and potassium levels should be closely observed in susceptible individuals. There is also a risk of exacerbation or activation of systemic lupus erythematosus, as well as acute angle-closure glaucoma.

Other notable adverse reactions include anuria and hypersensitivity reactions in patients with a known allergy to sulfonamide-derived drugs or any component of the formulation. It is contraindicated to co-administer aliskiren with valsartan and hydrochlorothiazide in patients with diabetes.

In cases of overdosage, patients may present with hypotension, tachycardia, bradycardia, depressed level of consciousness, circulatory collapse, and shock. Symptoms of electrolyte depletion, such as hypokalemia, hypochloremia, and hyponatremia, as well as dehydration, may occur due to excessive diuresis.

Drug Interactions

Antidiabetic drugs may require dosage adjustments when used concurrently, as their effectiveness can be influenced by the presence of other medications.

Cholestyramine and colestipol have been shown to reduce the absorption of thiazide diuretics, potentially diminishing their therapeutic effects.

The concomitant use of lithium increases the risk of lithium toxicity. It is advised to monitor serum lithium concentrations closely during concurrent administration to ensure safety.

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) may elevate the risk of renal impairment and can also diminish the diuretic, natriuretic, and antihypertensive effects of diuretics. Caution is recommended when these agents are used together.

The dual inhibition of the renin-angiotensin system poses an increased risk of renal impairment, hypotension, and hyperkalemia. Monitoring of renal function and electrolyte levels is advisable in patients receiving such combinations.

Packaging & NDC

The table below lists all NDC Code configurations of Valsartan and Hydrochlorothiazide, the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

Safety and effectiveness of valsartan and hydrochlorothiazide in pediatric patients have not been established. Therefore, caution is advised when considering the use of this combination therapy in children and adolescents. Further studies are needed to determine appropriate dosing and outcomes in this population.

Geriatric Use

In controlled clinical trials involving valsartan and hydrochlorothiazide, a total of 764 patients (17.5%) were aged 65 years and older, while 118 patients (2.7%) were aged 75 years and older. The data indicate that there was no overall difference in the efficacy or safety of valsartan and hydrochlorothiazide between geriatric patients and their younger counterparts.

However, it is important to note that greater sensitivity to the effects of the medication cannot be ruled out in some elderly patients. Therefore, healthcare providers should exercise caution when prescribing valsartan and hydrochlorothiazide to this population. Monitoring for potential adverse effects and considering dose adjustments may be warranted to ensure optimal therapeutic outcomes in geriatric patients.

Pregnancy

Valsartan and hydrochlorothiazide can cause fetal harm when administered to pregnant patients. The use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy is associated with reduced fetal renal function, which can lead to increased fetal and neonatal morbidity and mortality. Epidemiologic studies examining fetal abnormalities following antihypertensive use in the first trimester have not consistently differentiated between drugs affecting the renin-angiotensin system and other antihypertensive agents.

Published reports indicate cases of anhydramnios and oligohydramnios in pregnant women treated with valsartan. When pregnancy is detected, valsartan and hydrochlorothiazide should be discontinued as soon as possible. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown; however, all pregnancies carry a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Oligohydramnios in pregnant women using drugs affecting the renin-angiotensin system during the second and third trimesters can result in reduced fetal renal function, leading to anuria, renal failure, fetal lung hypoplasia, skeletal deformations (including skull hypoplasia), hypotension, and death. Serial ultrasound examinations should be performed to assess the intra-amniotic environment, and fetal testing may be appropriate based on the week of gestation. It is important to note that oligohydramnios may not manifest until after the fetus has sustained irreversible injury. If oligohydramnios is observed, alternative drug treatment should be considered.

Neonates with a history of in utero exposure to valsartan and hydrochlorothiazide should be closely monitored for hypotension, oliguria, and hyperkalemia. In cases where oliguria or hypotension occurs, support for blood pressure and renal perfusion may be necessary, and exchange transfusions or dialysis could be required to reverse hypotension and restore renal function.

Hydrochlorothiazide crosses the placenta, with concentrations in the umbilical vein approaching those in maternal plasma. It can cause placental hypoperfusion and accumulates in the amniotic fluid, with reported concentrations up to 19 times higher than in umbilical vein plasma. The use of thiazides during pregnancy is associated with a risk of fetal or neonatal jaundice or thrombocytopenia, and thiazides do not prevent or alter the course of edema, proteinuria, and hypertension (EPH) gestosis (pre-eclampsia) and should not be used to treat hypertension in pregnant women. Additionally, the use of hydrochlorothiazide for other indications, such as heart disease, during pregnancy should be avoided. Fetotoxicity has been observed in association with maternal toxicity in animal studies at certain doses of valsartan/hydrochlorothiazide, including decreased fetal weight and increased resorptions.

Lactation

There is limited information regarding the presence of valsartan and hydrochlorothiazide in human milk, as well as their effects on breastfed infants and milk production. Valsartan has been detected in the milk of lactating rats 15 minutes after oral administration of a 3 mg/kg dose. Hydrochlorothiazide is known to be present in human breast milk.

Due to the potential for serious adverse reactions in breastfed infants, it is advised that lactating mothers refrain from breastfeeding during treatment with valsartan and hydrochlorothiazide.

Renal Impairment

Patients with severe renal impairment (creatinine clearance CrCl ≤ 30 mL/min) have not been studied for the safety and effectiveness of valsartan and hydrochlorothiazide, and therefore, the use of this combination in such patients is not recommended. For patients with mild (CrCl 60 to 90 mL/min) or moderate (CrCl 30 to 60 mL/min) renal impairment, no dose adjustment is necessary. However, it is important to monitor renal function and potassium levels in susceptible patients to ensure safety and efficacy.

Hepatic Impairment

Patients with hepatic impairment do not require dose adjustments for mild-to-moderate liver disease. However, no dosing recommendations can be provided for patients with severe liver disease due to the lack of available data.

It is important to note that minor alterations in fluid and electrolyte balance may precipitate hepatic coma in patients with impaired hepatic function or progressive liver disease. Therefore, careful monitoring of these parameters is advised in this patient population to prevent potential complications.

Overdosage

Limited data are available regarding overdosage in humans. The most likely manifestations of overdosage include hypotension and tachycardia; bradycardia may occur due to parasympathetic (vagal) stimulation. Additional severe effects such as depressed level of consciousness, circulatory collapse, and shock have been reported. In the event of symptomatic hypotension, it is recommended to initiate supportive treatment.

Valsartan is not effectively removed from the plasma by dialysis. The extent to which hydrochlorothiazide is removed by hemodialysis remains undetermined. The most common signs and symptoms observed in patients experiencing overdosage are typically those associated with electrolyte depletion, including hypokalemia, hypochloremia, and hyponatremia, as well as dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalemia may exacerbate cardiac arrhythmias.

Toxicological studies in rats and marmosets indicate that single oral doses of valsartan up to 1,524 mg/kg and 762 mg/kg, respectively, in combination with hydrochlorothiazide at doses up to 476 mg/kg and 238 mg/kg, did not demonstrate any adverse treatment-related effects. These no adverse effect doses represent 46.5 and 23 times the maximum recommended human dose (MRHD) of valsartan and 188 and 113 times the MRHD of hydrochlorothiazide on a mg/m² basis, assuming an oral dose of 320 mg/day valsartan in combination with 25 mg/day hydrochlorothiazide for a 60 kg patient.

Furthermore, valsartan was found to be without grossly observable adverse effects at single oral doses up to 2,000 mg/kg in rats and up to 1,000 mg/kg in marmosets, with the exception of salivation and diarrhea in rats and vomiting in marmosets at the highest doses, which correspond to 60 and 31 times, respectively, the MRHD on a mg/m² basis.

The oral LD50 of hydrochlorothiazide exceeds 10 g/kg in both mice and rats, which translates to 2,027 and 4,054 times, respectively, the MRHD on a mg/m² basis, based on an oral dose of 25 mg/day for a 60 kg patient.

Nonclinical Toxicology

Valsartan and hydrochlorothiazide have been evaluated for their effects on reproductive performance and fertility in nonclinical studies. Valsartan did not demonstrate any adverse effects on the reproductive performance of male or female rats at oral doses up to 200 mg/kg/day, which is approximately six times the maximum recommended human dose (MRHD) on a mg/m² basis. Similarly, hydrochlorothiazide showed no adverse effects on the fertility of mice and rats of either sex when administered dietary doses of up to 100 mg/kg and 4 mg/kg, respectively, prior to mating and throughout gestation. These doses represent 19 and 1.5 times the MRHD on a mg/m² basis.

No carcinogenicity, mutagenicity, or fertility studies have been conducted with the combination of valsartan and hydrochlorothiazide. However, individual studies for each compound have been performed. Valsartan did not exhibit evidence of carcinogenicity when administered in the diet to mice and rats for up to two years at doses of up to 160 mg/kg/day and 200 mg/kg/day, respectively, which are approximately 2.6 and 6 times the MRHD on a mg/m² basis. Furthermore, mutagenicity assays did not indicate any valsartan-related effects at the gene or chromosome level, including various bacterial mutagenicity tests and cytogenetic evaluations.

Hydrochlorothiazide was also assessed for carcinogenic potential in two-year feeding studies conducted by the National Toxicology Program (NTP). These studies found no evidence of carcinogenicity in female mice at doses up to approximately 600 mg/kg/day or in male and female rats at doses up to approximately 100 mg/kg/day. However, the NTP reported equivocal evidence for hepatocarcinogenicity in male mice.

In terms of genotoxicity, hydrochlorothiazide was not found to be genotoxic in vitro in the Ames mutagenicity assay or in the Chinese Hamster Ovary test for chromosomal aberrations. In vivo assays using mouse germinal cell chromosomes and Chinese hamster bone marrow chromosomes also did not indicate genotoxicity. Positive results were observed only in specific in vitro assays, including the CHO Sister Chromatid Exchange and Mouse Lymphoma Cell assays, at varying concentrations, as well as in the Aspergillus Nidulans non-disjunction assay at an unspecified concentration.

Overall, based on the available preclinical safety and human pharmacokinetic studies, there is no indication of any adverse interaction between valsartan and hydrochlorothiazide.

Postmarketing Experience

Postmarketing experience has identified several adverse events associated with the use of valsartan and hydrochlorothiazide tablets, reported voluntarily or through surveillance programs.

Patients taking hydrochlorothiazide are advised to protect their skin from sun exposure and to undergo regular skin cancer screenings due to the potential risk of non-melanoma skin cancer. Allergic reactions have been reported in individuals with and without a history of allergies or asthma. Additionally, hydrochlorothiazide may exacerbate or activate lupus in susceptible individuals.

Fluid and electrolyte imbalances have been noted, with symptoms including dry mouth, thirst, lethargy, weakness, drowsiness, restlessness, confusion, seizures, muscle pain or cramps, muscle fatigue, very low urine output, fast heartbeat, and nausea or vomiting. Patients with pre-existing kidney disease may experience worsening kidney function, necessitating monitoring and possible dosage adjustments. Signs such as swelling in the feet, ankles, or hands, or unexplained weight gain should prompt consultation with a healthcare provider.

Reports of unusual skin rashes have been documented, and patients are advised to seek medical attention promptly if such symptoms occur. Eye problems, which may lead to vision loss, have also been associated with the medication, with symptoms potentially manifesting within hours to weeks of initiation. Patients should report any decrease in vision or eye pain to their healthcare provider immediately.

While other side effects have generally been mild and transient, they have not typically led to discontinuation of therapy. Patients are encouraged to contact their healthcare provider for medical advice regarding side effects and may report adverse events to the FDA at 1-800-FDA-1088.

Patient Counseling

Healthcare providers should advise patients to read the FDA-approved patient labeling (Patient Information) prior to initiating treatment with valsartan and hydrochlorothiazide and each time they receive a refill, as there may be new information available.

For female patients of childbearing age, it is essential to discuss the potential consequences of exposure to valsartan and hydrochlorothiazide during pregnancy. Providers should encourage these patients to consider alternative treatment options if they are planning to become pregnant and to report any pregnancies to their healthcare provider as soon as possible.

Women who are breastfeeding should be informed not to breastfeed while undergoing treatment with valsartan and hydrochlorothiazide.

Patients should be made aware of the possibility of symptomatic hypotension, particularly during the initial days of therapy. They should be instructed to report any episodes of lightheadedness to their healthcare provider. In cases of syncope, patients should discontinue the medication and consult their physician before resuming treatment. Additionally, patients should be cautioned that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting may lead to a significant drop in blood pressure, resulting in lightheadedness or syncope.

Healthcare providers should advise patients against the use of salt substitutes without prior consultation, as potassium supplements may interact with the medication.

Patients taking hydrochlorothiazide should be instructed to protect their skin from sun exposure and to undergo regular skin cancer screenings due to an increased risk of non-melanoma skin cancer associated with the medication.

Finally, patients should be encouraged to discuss alternative methods for lowering blood pressure with their healthcare provider if they plan to become pregnant. If a patient becomes pregnant while taking valsartan and hydrochlorothiazide, they should notify their doctor immediately.

Storage and Handling

The product is supplied in a tight container as defined by the United States Pharmacopeia (USP) to ensure integrity and stability. It should be stored at a temperature range of 20° to 25°C (68° to 77°F), with permissible excursions between 15° to 30°C (59° to 86°F) in accordance with USP Controlled Room Temperature guidelines. Additionally, it is essential to protect the product from moisture to maintain its quality.

Additional Clinical Information

Clinicians should periodically monitor renal function in patients whose renal function may be influenced by the renin-angiotensin system. Additionally, serum electrolytes should be assessed regularly, along with lithium levels in patients concurrently receiving valsartan and hydrochlorothiazide tablets with lithium. For patients with hypercalcemia, monitoring of calcium levels is also recommended.

Patient counseling should include advising individuals to discontinue hydrochlorothiazide promptly if symptoms of acute angle-closure glaucoma arise. Furthermore, patients should be informed about the potential risks of fetal harm associated with the use of this medication during pregnancy.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Valsartan and Hydrochlorothiazide as submitted by AvKARE. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)