Valsartan/Hydrochlorothiazide

Description

Valsartan and hydrochlorothiazide tablets, USP are a combination formulation containing valsartan, an orally active angiotensin II receptor blocker (ARB) that selectively targets the AT1 receptor subtype, and hydrochlorothiazide, a thiazide diuretic. Valsartan is a nonpeptide molecule with the chemical designation N-(1-oxopentyl)-N-[[2'-(1H-tetrazol-5-yl)1,1'-biphenyl-4-yl]methyl]-L-Valine, exhibiting 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 identified 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, odorless crystalline powder, which 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 specific teratogenic or nonteratogenic effects associated with this drug as per the available data.

Dosage and Administration

The recommended dosage is once daily, with titration as necessary, up to a maximum dose of 320 mg/25 mg. This medication may be utilized as add-on or switch therapy for patients who are not adequately controlled on any of the individual components, such as valsartan or hydrochlorothiazide (HCTZ). Additionally, it may be substituted for the titrated components, ensuring that the overall therapeutic regimen remains effective and tailored to the patient's needs.

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.

Individuals with hypersensitivity to any sulfonamide-derived drugs or any component of the formulation, due to the risk of severe allergic reactions.

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, 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 and death to the developing fetus.

Healthcare professionals should take precautions regarding hypotension. It is essential to correct any volume depletion prior to the initiation of treatment. Additionally, practitioners should remain vigilant for signs of fluid or electrolyte imbalance, as these can occur during therapy.

Monitoring of renal function and potassium levels is recommended, particularly in patients who are susceptible to these issues. This is crucial to ensure patient safety and to mitigate the risk of adverse effects. Furthermore, there is a potential for exacerbation or activation of systemic lupus erythematosus, which should be considered when evaluating patient history and treatment plans.

Acute angle-closure glaucoma is another condition that may be exacerbated by the use of valsartan and hydrochlorothiazide tablets, necessitating careful assessment of patients with a history of this condition.

In summary, regular monitoring of renal function and potassium levels is advised for susceptible patients to ensure safe use of this 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 participants compared to 1.9% in the placebo group.

Serious warnings associated with the use of valsartan and hydrochlorothiazide include 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 and 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 may also include electrolyte depletion, such as hypokalemia, hypochloremia, and hyponatremia, along with 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 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 electrolytes 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 may be present 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 has been associated with reduced fetal renal function, leading 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 remains 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% 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 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 warranted based on gestational age. 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, supportive measures for blood pressure and renal perfusion may be necessary, and exchange transfusions or dialysis might 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 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. 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 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 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

No information is available regarding teratogenic effects.

The combination of valsartan and hydrochlorothiazide has not been evaluated for carcinogenicity, mutagenicity, or fertility. However, individual studies have been conducted for valsartan and hydrochlorothiazide separately. Preclinical safety and human pharmacokinetic studies indicate no adverse interactions between valsartan and hydrochlorothiazide.

Valsartan was administered in the diet to mice and rats for up to 2 years at doses of 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 demonstrate any valsartan-related effects at 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 National Toxicology Program (NTP) found no evidence of carcinogenic potential for hydrochlorothiazide 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.

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 1,300 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, there have been cases of worsening lupus, as hydrochlorothiazide may exacerbate this condition.

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 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, particularly in patients with heart failure.

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 generally been mild and transient, they have not typically led to discontinuation of the medication. 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) to understand the medication's uses and potential risks.

For female patients of childbearing age, it is important to discuss the consequences of exposure to valsartan and hydrochlorothiazide 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, 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 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 similar symptoms.

Patients should be advised against using salt substitutes without prior consultation with their healthcare provider, as potassium supplements may interact with the medication.

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 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 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 should be assessed regularly, and lithium levels should be monitored in patients taking valsartan and hydrochlorothiazide in conjunction with lithium. For patients with hypercalcemia, calcium levels should also be checked.

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 Amneal Pharmaceuticals of New York LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)