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 an empirical formula of C24H29N5O3, a molecular weight of 435.5, and a structural formula represented as follows: structural formula. It appears as a white to practically white fine powder, soluble in ethanol and methanol, and slightly soluble in water.

Hydrochlorothiazide, USP, is characterized as 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide, with an empirical formula of C7H8ClN3O4S2, a molecular weight of 297.73, and a structural formula represented as follows: structural formula. It is a white or practically white, odorless crystalline powder, slightly soluble in water, freely soluble in sodium hydroxide solution, n-butylamine, and dimethylformamide, sparingly soluble in methanol, and insoluble in ether, chloroform, and dilute mineral acids.

These tablets are formulated for oral administration and are available in the following strengths: valsartan and hydrochlorothiazide, USP 80/12.5 mg, 160/12.5 mg, 160/25 mg, 320/12.5 mg, and 320/25 mg. The inactive ingredients include colloidal silicon dioxide, crospovidone, hydroxypropyl methylcellulose, iron oxides, magnesium stearate, microcrystalline cellulose, polyethylene glycol, talc, and titanium dioxide.

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 specific teratogenic or nonteratogenic effects mentioned in the available data.

Dosage and Administration

The recommended dosage is to administer the medication once daily. Healthcare professionals should titrate the dose as needed, with a maximum allowable 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, namely valsartan or HCTZ. Additionally, it may be substituted for the titrated components, ensuring that the total daily dosage does not exceed the specified maximum.

Contraindications

Use of this product is contraindicated in patients with anuria due to the potential for renal complications.

Hypersensitivity to any sulfonamide-derived drugs or any component of the formulation is also a contraindication, as it may lead to severe allergic reactions.

Additionally, coadministration 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

Fetal toxicity is a significant concern associated with the use of valsartan and hydrochlorothiazide tablets. It is imperative that these medications be discontinued as soon as pregnancy is detected, as drugs that act directly on the renin-angiotensin system can lead to serious injury or death to the developing fetus.

In terms of general precautions, it is essential to correct any volume depletion prior to initiating treatment with valsartan and hydrochlorothiazide. Healthcare professionals should remain vigilant for signs of fluid or electrolyte imbalance during therapy. Regular monitoring of renal function and potassium levels is recommended, particularly in patients who may be susceptible to these complications. Additionally, there is a risk of exacerbation or activation of systemic lupus erythematosus, as well as the potential for acute angle-closure glaucoma.

To ensure patient safety, it is crucial to conduct laboratory tests that monitor renal function and potassium levels in susceptible individuals. This proactive approach will help mitigate risks associated with the use of valsartan and hydrochlorothiazide tablets.

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 participants 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 coadminister 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. Signs and symptoms of electrolyte depletion, such as hypokalemia, hypochloremia, hyponatremia, and dehydration, may also occur as a result of 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 can lead to reduced absorption of thiazide diuretics, potentially diminishing their therapeutic effects.

The concomitant use of lithium is associated with an increased 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 warranted 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 recommended 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

The safety and effectiveness of valsartan and hydrochlorothiazide tablets in pediatric patients have not been established. Therefore, caution should be exercised when considering the use of this medication in children and adolescents. Further studies are needed to determine appropriate dosing and potential outcomes in this population.

Geriatric Use

In controlled clinical trials involving valsartan and hydrochlorothiazide tablets, a total of 764 patients (17.5%) were aged 65 years and older, with 118 patients (2.7%) being 75 years or older. While no overall differences in efficacy or safety were observed between geriatric patients and their younger counterparts, it is important to note that greater sensitivity to the medication may be present in some elderly individuals.

Healthcare providers should exercise caution when prescribing valsartan and hydrochlorothiazide to geriatric patients. Monitoring for potential adverse effects and therapeutic responses is recommended, as individual responses may vary. Although dosage adjustments were not specifically indicated based on age, careful consideration of the patient's overall health status and concurrent medications is advised to ensure optimal treatment outcomes in this population.

Pregnancy

Valsartan and hydrochlorothiazide tablet 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 increase fetal and neonatal morbidity and mortality. Published reports have documented cases of anhydramnios and oligohydramnios in pregnant women treated with valsartan.

When pregnancy is detected, it is recommended to discontinue valsartan and hydrochlorothiazide tablet 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 2-4% and 15-20%, respectively.

Hypertension in pregnancy poses increased maternal risks, including pre-eclampsia, gestational diabetes, premature delivery, and delivery complications. Additionally, hypertension raises the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be closely monitored and managed accordingly.

Oligohydramnios in pregnant women using drugs affecting the renin-angiotensin system during the second and third trimesters can lead to reduced fetal renal function, resulting in 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 tablet should be closely observed for hypotension, oliguria, and hyperkalemia. In cases where oliguria or hypotension occurs, it is essential to support blood pressure and renal perfusion, and exchange transfusions or dialysis may be required to reverse hypotension and restore renal function.

Thiazides, including hydrochlorothiazide, can cross the placenta, with concentrations in the umbilical vein approaching those in maternal plasma. Hydrochlorothiazide may cause placental hypoperfusion and can accumulate 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 should not be used to treat hypertension in pregnant women. Furthermore, thiazides do not prevent or alter the course of EPH (Edema, Proteinuria, Hypertension) gestosis (pre-eclampsia) and should be avoided for other indications, such as heart disease, during pregnancy. Fetotoxicity has been observed in association with maternal toxicity in animal studies involving rats and rabbits at certain doses of valsartan and hydrochlorothiazide.

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 renal impairment should have their renal function and potassium levels monitored closely, as these individuals may be more susceptible to changes in their condition. Dosing adjustments may be necessary based on the degree of renal impairment to ensure safety and efficacy.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in relation to the use of this medication. Consequently, there are no established dosage adjustments, special monitoring requirements, or precautions outlined for individuals with compromised liver function. It is recommended that healthcare providers exercise caution when prescribing this medication to patients with hepatic impairment, given the lack of data on its safety and efficacy in this population. Regular monitoring of liver function may be prudent in these cases, although specific parameters are not defined in the available information.

Overdosage

Limited data are available regarding overdosage in humans. The most likely manifestations of overdosage include hypotension and tachycardia; however, bradycardia may occur due to parasympathetic (vagal) stimulation. Additional severe effects reported include depressed level of consciousness, circulatory collapse, and shock.

In the event of symptomatic hypotension, it is recommended to initiate supportive treatment. It is important to note that valsartan is not removed from the plasma by dialysis, and the extent to which hydrochlorothiazide is removed by hemodialysis has not been established.

The most common signs and symptoms observed in patients experiencing overdosage are those associated with electrolyte depletion, such as 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 1524 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.

Furthermore, valsartan was found to be without grossly observable adverse effects at single oral doses up to 2000 mg/kg in rats and up to 1000 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 the MRHD on a mg/m² basis, respectively. The oral LD50 of hydrochlorothiazide exceeds 10 g/kg in both mice and rats, equating to 2027 and 4054 times the MRHD on a mg/m² basis.

Nonclinical Toxicology

No teratogenic effects have been reported in the studies conducted.

No carcinogenicity, mutagenicity, or fertility studies have been performed with the combination of valsartan and hydrochlorothiazide. However, individual studies for valsartan and hydrochlorothiazide have been conducted. Based on preclinical safety and human pharmacokinetic studies, there is no evidence of any adverse interaction between valsartan and hydrochlorothiazide.

Valsartan was administered in the diet to mice and rats for up to 2 years at doses of up to 160 mg/kg/day and 200 mg/kg/day, respectively, with no evidence of carcinogenicity observed. These doses are approximately 2.6 and 6 times the maximum recommended human dose (MRHD) on a mg/m² basis, assuming an oral dose of 320 mg/day for a 60-kg patient.

Mutagenicity assays did not indicate any valsartan-related effects at either the gene or chromosome level. These assays included bacterial mutagenicity tests with Salmonella (Ames) 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 did not adversely affect the reproductive performance of male or female rats at oral doses up to 200 mg/kg/day, which is about 6 times the MRHD on a mg/m² basis.

Two-year feeding studies conducted under the auspices of the National Toxicology Program (NTP) found no evidence of carcinogenic potential for 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. However, the NTP did find equivocal evidence for hepatocarcinogenicity in male mice.

Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay using various Salmonella typhimurium strains and in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations. In vivo assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene also showed no genotoxicity. Positive results were observed only in the in vitro CHO Sister Chromatid Exchange (clastogenicity) and Mouse Lymphoma Cell (mutagenicity) assays at concentrations ranging from 43 to 1300 mcg/mL, as well as in the Aspergillus Nidulans non-disjunction assay at an unspecified concentration.

Hydrochlorothiazide did not adversely affect the fertility of mice and rats of either sex in studies where these species were exposed to doses of up to 100 mg/kg and 4 mg/kg, respectively, prior to mating and throughout gestation. These doses represent approximately 19 and 1.5 times the MRHD on a mg/m² basis.

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, worsening of lupus has been noted in some patients, indicating that hydrochlorothiazide may exacerbate this condition.

Fluid and electrolyte imbalances have been observed, 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 gastrointestinal disturbances such as nausea and vomiting. Patients with pre-existing kidney disease may experience worsening kidney function, necessitating monitoring and possible dosage adjustments. Signs of kidney issues include swelling in the extremities and unexplained weight gain.

Reports of unusual skin rashes have prompted recommendations for patients to contact their healthcare provider immediately. Eye problems, which may lead to vision loss, have also been associated with the medication, with symptoms potentially occurring within hours to weeks of initiation. Patients should seek medical attention if they experience a decrease in vision or eye pain.

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

Patient Counseling

Patients should be advised to read the FDA-approved patient labeling (Patient Information) thoroughly to understand the medication's use and potential risks.

For female patients of childbearing age, it is important to discuss the consequences of exposure to valsartan and hydrochlorothiazide tablets during pregnancy. Healthcare providers should engage in conversations about alternative treatment options for women who are planning to become pregnant and encourage patients to report any pregnancies to their physicians as soon as possible.

Women should be informed not to breastfeed while undergoing treatment with valsartan and hydrochlorothiazide tablets, as this may pose risks to the nursing infant.

Patients should be made aware that symptomatic hypotension, such as lightheadedness, can occur, particularly during the initial days of therapy. They should be instructed to report any instances 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 similar symptoms of lightheadedness and potential syncope.

Patients should be advised against using salt substitutes or potassium supplements without prior consultation with their healthcare provider to avoid potential complications.

For those taking hydrochlorothiazide, it is essential to instruct patients to protect their skin from sun exposure and to undergo regular skin cancer screenings, as there is an increased risk of non-melanoma skin cancer associated with this medication.

Storage and Handling

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

Additional Clinical Information

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

Patients should be counseled to discontinue hydrochlorothiazide promptly if symptoms of acute angle-closure glaucoma arise. It is important to note that individuals with a history of sulfonamide or penicillin allergy may be at increased risk for developing this condition.

FDA Insert (PDF)

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

View full prescribing information (PDF)