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. Valsartan appears as a white to practically white fine powder, soluble in ethanol and methanol, and slightly soluble in water.

Hydrochlorothiazide is chemically described as 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide, with an empirical formula of C7H8ClN3O4S2 and a molecular weight of 297.73. It 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 dimethylformamide, 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: 80/12.5 mg, 160/12.5 mg, 160/25 mg, 320/12.5 mg, and 320/25 mg of valsartan and hydrochlorothiazide, USP. Inactive ingredients include colloidal silicon dioxide, crospovidone, magnesium stearate, microcrystalline cellulose, polyvinyl alcohol-part hydrolyzed, talc, titanium dioxide, and macrogol/peg 3350. Additionally, the 80/12.5 mg, 160/25 mg, and 320/25 mg strengths contain iron oxide red and FD&C blue #2 aluminum lake, while the 160/12.5 mg and 320/12.5 mg strengths also include FD&C red #40 aluminum lake, FD&C yellow #6 aluminum lake, and FD&C blue #1 aluminum lake.

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 necessary, 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 should not use this product due to the potential for exacerbating renal impairment.

Hypersensitivity to any sulfonamide-derived drugs or any component of this formulation is 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, due to the increased risk of adverse effects.

Warnings and Precautions

When pregnancy is detected, valsartan and hydrochlorothiazide tablets should be discontinued as soon as possible due to the risk of fetal toxicity. Medications that act directly on the renin-angiotensin system have the potential to cause injury or death to the developing fetus.

Healthcare professionals should exercise caution regarding hypotension. It is essential to correct any volume depletion prior to the initiation of treatment. Patients should be closely observed for signs of fluid or electrolyte imbalance, as these can lead to serious complications.

Monitoring of renal function and potassium levels is particularly important in susceptible patients to prevent adverse effects. Additionally, there is a risk of exacerbation or activation of systemic lupus erythematosus, which should be considered when evaluating patient history and symptoms. Acute angle-closure glaucoma is another potential concern that warrants attention.

Regular laboratory tests to monitor renal function and potassium levels are recommended for patients at risk. This proactive approach can help mitigate potential complications associated with the use of valsartan and hydrochlorothiazide tablets.

Side Effects

When pregnancy is detected, valsartan and hydrochlorothiazide tablets should be discontinued as soon as possible due to the risk of fetal toxicity. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.

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.

Additional adverse reactions of clinical significance include hypotension, which necessitates correction of volume depletion prior to initiation of treatment. Patients should be monitored for signs of fluid or electrolyte imbalance, as well as renal function and potassium levels, particularly in those who are susceptible. There have been reports of exacerbation or activation of systemic lupus erythematosus, acute angle-closure glaucoma, and anuria. Patients with hypersensitivity to any sulfonamide-derived drugs or any component of the formulation should not use this medication.

It is also important to note that valsartan and hydrochlorothiazide tablets should not be coadministered with aliskiren in patients with diabetes.

In cases of overdosage, the most likely manifestations include hypotension and tachycardia, although bradycardia may occur due to parasympathetic (vagal) stimulation. Other reported signs and symptoms include depressed level of consciousness, circulatory collapse, and shock, as well as those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from 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

Safety and effectiveness of valsartan and hydrochlorothiazide tablets in pediatric patients have not been established. Therefore, caution is advised when considering the use of this medication in children and adolescents. Further studies are necessary to determine appropriate dosing and 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, while 118 patients (2.7%) were aged 75 years and older.

Although 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. Therefore, healthcare providers should exercise caution when prescribing valsartan and hydrochlorothiazide to geriatric patients.

Monitoring for potential adverse effects and therapeutic response is recommended, particularly in those aged 65 years and older, to ensure optimal treatment outcomes and to mitigate any risks associated with increased sensitivity in this population.

Pregnancy

Valsartan and hydrochlorothiazide tablets 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. Published reports have documented cases of anhydramnios and oligohydramnios in pregnant women treated with valsartan.

When pregnancy is detected, valsartan and hydrochlorothiazide tablets 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 approximately 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 elevates the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be closely monitored and managed accordingly. Oligohydramnios resulting from the use of drugs affecting the renin-angiotensin system in 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 tablets should be closely observed 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.

Thiazides, including hydrochlorothiazide, can cross the placenta, with concentrations in the umbilical vein approaching those in maternal plasma. Hydrochlorothiazide may cause placental hypoperfusion and accumulate in the amniotic fluid. The use of thiazides during pregnancy is associated with risks of fetal or neonatal jaundice and thrombocytopenia. 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. The use of hydrochlorothiazide for other indications, such as heart disease, during pregnancy should also be avoided. While there was no evidence of teratogenicity in animal studies with valsartan and hydrochlorothiazide, fetotoxicity was observed in association with maternal toxicity in rats and rabbits at certain doses.

Lactation

There are no specific statements regarding the use of this medication in lactating mothers or its effects on breastfed infants. Healthcare professionals should consider the absence of data when advising lactating mothers about the use of this medication.

Renal Impairment

Patients with renal impairment should have their renal function and potassium levels monitored closely. This is particularly important for those with reduced kidney function, as they may be at increased risk for complications. 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 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 considered as part of standard clinical practice.

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 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, 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 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 were 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 corresponds to 2027 and 4054 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 nonclinical toxicology profiles, with a focus on reproductive performance, carcinogenicity, mutagenicity, and potential interactions.

No teratogenic effects have been reported. Valsartan demonstrated no adverse effects on the reproductive performance of male or female rats at oral doses up to 200 mg/kg/day. Similarly, hydrochlorothiazide did not adversely affect 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.

No studies have been conducted to assess the carcinogenicity, mutagenicity, or fertility effects of the combination of valsartan and hydrochlorothiazide. However, valsartan was 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, with no evidence of carcinogenicity observed. Additionally, mutagenicity assays indicated no valsartan-related effects at either the gene or chromosome level. Hydrochlorothiazide also showed no evidence of carcinogenic potential in two-year feeding studies involving female mice and male and female rats. Furthermore, hydrochlorothiazide was not genotoxic in vitro, as demonstrated by the Ames mutagenicity assay and other tests.

Based on preclinical safety and human pharmacokinetic studies, there is no indication of any adverse interaction between valsartan and hydrochlorothiazide. However, the National Toxicology Program (NTP) reported equivocal evidence for hepatocarcinogenicity in male mice concerning 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 are advised to protect their skin from the sun and undergo regular skin cancer screenings, as there is a potential association with 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, particularly in patients taking hydrochlorothiazide, which may exacerbate this condition.

Fluid and electrolyte imbalances have been observed, with symptoms including dry mouth, drowsiness, muscle fatigue, thirst, restlessness, very low urine output, lethargy, confusion, fast heartbeat, weakness, seizures, nausea, vomiting, and muscle pain or cramps. 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 immediate consultation with a healthcare provider.

Reports of unusual skin rashes have been documented, and patients are advised to contact their doctor if such symptoms occur. Eye problems leading to potential vision loss have also been associated with the medication, with symptoms manifesting within hours to weeks of initiation. Patients should seek medical attention for any decrease in vision or eye pain.

For any side effects, patients are encouraged to consult their healthcare provider 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 tablets 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 explore 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 tablets.

Patients should be made aware of the risk 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. 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 using salt substitutes or potassium supplements without prior consultation, as these may interact with their treatment.

Patients taking hydrochlorothiazide should be instructed to protect their skin from sun exposure and to undergo regular skin cancer screenings, as there is a risk of non-melanoma skin cancer associated with this medication.

Finally, patients should be reminded to lie down if they experience feelings of faintness or dizziness and to contact their healthcare provider immediately in such instances.

Storage and Handling

The product is supplied in a tight container, in accordance with USP guidelines. It should be stored at a temperature range of 20°C to 25°C (68°F to 77°F), with permissible excursions between 15°C and 30°C (59°F and 86°F) as defined by USP Controlled Room Temperature. Proper handling and storage conditions are essential to maintain the integrity of the product.

Additional Clinical Information

Clinicians should periodically monitor renal function in patients whose renal status may be influenced by the renin-angiotensin system, including those with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion. Additionally, serum electrolytes, lithium levels in patients taking both valsartan and hydrochlorothiazide, and calcium levels in patients with hypercalcemia should be monitored regularly.

Patient counseling should include advising individuals to discontinue hydrochlorothiazide promptly if symptoms of acute angle-closure glaucoma arise and to seek immediate medical or surgical intervention if intraocular pressure remains uncontrolled. Patients should also be informed about the potential risks of fetal harm associated with the medication during pregnancy and the importance of discontinuing use upon detection of pregnancy.

FDA Insert (PDF)

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

View full prescribing information (PDF)