Hydrochlorothiazide/Valsartan

Description

Valsartan and hydrochlorothiazide tablets USP are a combination of valsartan, an orally active angiotensin II receptor blocker (ARB) targeting 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, characterized by an empirical formula of C24H29N5O3 and a molecular weight of 435.5. It appears as a white to practically white fine powder, soluble in ethanol and methanol, and slightly soluble in water.

Hydrochlorothiazide, chemically identified as 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide, has an empirical formula of C7H8ClN3O4S2 and a molecular weight of 297.73. This compound is presented as 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.

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. Inactive ingredients include colloidal silicon dioxide, croscarmellose sodium, crospovidone, hypromellose, magnesium stearate, microcrystalline cellulose, pregelatinized starch, polyethylene glycol, titanium dioxide, and various colorants specific to each strength. The colorants are as follows: 80 mg/12.5 mg contains iron oxide red and yellow; 160 mg/12.5 mg contains iron oxide red; 160 mg/25 mg includes iron oxide black, red, and yellow; 320 mg/12.5 mg contains iron oxide black and red; and 320 mg/25 mg contains iron oxide yellow.

Uses and Indications

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

Lowering blood pressure with this combination therapy is associated with a reduction in 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 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, namely valsartan or HCTZ. Additionally, it may be substituted for the titrated components, ensuring that the total daily dosage does not exceed the established maximum.

Healthcare professionals should assess the patient's response to therapy and adjust the dosage accordingly to achieve optimal control of blood pressure.

Contraindications

Use of this product is contraindicated in patients with anuria due to the risk of renal impairment. Additionally, individuals with hypersensitivity to any sulfonamide-derived drugs or any component of the formulation should not use this product, as it may lead to severe allergic reactions.

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

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 serum potassium levels is recommended, particularly in patients who may be susceptible to these issues. 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 advised for patients at risk, ensuring timely intervention if abnormalities are detected.

Side Effects

Patients receiving valsartan and hydrochlorothiazide may experience a range of adverse reactions. Common adverse reactions reported include headache, dizziness, and nasopharyngitis, with an incidence of 2.4% in treated patients compared to 1.9% in those receiving placebo.

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 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 have been reports of exacerbation or activation of systemic lupus erythematosus, acute angle-closure glaucoma, anuria, and hypersensitivity reactions in patients with a history of sulfonamide-derived drug allergies or to any component of the formulation.

In cases of overdosage, the most likely manifestations include hypotension and tachycardia, although bradycardia may occur due to parasympathetic (vagal) stimulation. Severe outcomes such as depressed level of consciousness, circulatory collapse, and shock have been documented. Patients may also exhibit signs and symptoms related to electrolyte depletion, including hypokalemia, hypochloremia, and hyponatremia, as well as dehydration resulting from excessive diuresis. If digitalis has been administered concurrently, hypokalemia may further exacerbate the risk of cardiac arrhythmias.

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 electrolytes 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 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 therapeutic outcomes in this population.

Geriatric Use

In controlled clinical trials involving valsartan and hydrochlorothiazide, 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-hydrochlorothiazide between geriatric patients and their younger counterparts. However, 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-hydrochlorothiazide to geriatric patients, considering the potential for increased sensitivity. Monitoring for adverse effects and therapeutic response is recommended to ensure the safety and effectiveness of treatment in this population. Additionally, while no specific dosage adjustments are mandated based solely on age, clinical judgment should guide the management of therapy in elderly patients, particularly those with comorbidities or polypharmacy.

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. Published reports have documented 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 approximately 2 to 4% and 15 to 20%, respectively.

Hypertension in pregnancy poses additional risks, including increased maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications such as the need for cesarean section and postpartum hemorrhage. Furthermore, hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly.

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 be apparent 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 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 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. 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.

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, indicating potential excretion in breast milk. 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. 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

There is no information available regarding the use of this medication in patients with hepatic impairment. Consequently, there are no dosage adjustments, special monitoring requirements, or precautions specified for individuals with compromised liver function. Healthcare professionals should exercise caution and consider the overall clinical context when prescribing this medication to patients with liver problems, as the absence of specific guidance necessitates careful evaluation of potential risks and benefits.

Overdosage

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

In the event of symptomatic hypotension, it is imperative to initiate supportive treatment promptly. Healthcare professionals should monitor the patient's vital signs closely and provide appropriate interventions to stabilize blood pressure.

It is important to note that valsartan is not removed from the plasma by dialysis, which limits the effectiveness of this treatment option in cases of overdose. The extent to which hydrochlorothiazide is removed by hemodialysis remains undetermined.

Common signs and symptoms observed in patients experiencing hydrochlorothiazide overdosage are primarily related to electrolyte depletion, including hypokalemia, hypochloremia, and hyponatremia, as well as dehydration resulting from excessive diuresis. If digitalis has been administered concurrently, hypokalemia may exacerbate the risk of cardiac arrhythmias, necessitating careful monitoring and management of electrolyte levels.

Overall, healthcare professionals should remain vigilant for these potential complications and manage them accordingly to ensure patient safety.

Nonclinical Toxicology

No teratogenic effects have been identified in the studies conducted. While no carcinogenicity, mutagenicity, or fertility studies have been performed on the combination of valsartan and hydrochlorothiazide, individual studies for each compound have been completed. These studies indicate no adverse interactions between valsartan and hydrochlorothiazide based on preclinical safety and human pharmacokinetic data.

Valsartan has been evaluated for carcinogenic potential in long-term dietary studies involving mice and rats, with no evidence of carcinogenicity observed at doses of up to 160 mg/kg/day in mice and 200 mg/kg/day in rats. These doses correspond to 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. Additionally, mutagenicity assays have shown no valsartan-related effects at either the gene or chromosome level. These assays included various tests such as bacterial mutagenicity tests with Salmonella 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.

In terms of reproductive toxicity, valsartan did not adversely affect the reproductive performance of male or female rats at oral doses up to 200 mg/kg/day, which is approximately 6 times the MRHD on a mg/m² basis.

Hydrochlorothiazide has also been 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 did report equivocal evidence for hepatocarcinogenicity in male mice.

Regarding mutagenicity, 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 showed no genotoxic effects. Positive results were noted only in specific in vitro assays, including the CHO Sister Chromatid Exchange and Mouse Lymphoma Cell assays, under certain concentrations.

Hydrochlorothiazide did not demonstrate adverse effects on fertility in studies involving mice and rats, where doses of up to 100 mg/kg and 4 mg/kg, respectively, were administered prior to mating and throughout gestation. These doses represent approximately 19 and 1.5 times the MRHD on a mg/m² basis.

Postmarketing Experience

No postmarketing experience details are available in the provided data.

Patient Counseling

Healthcare providers should advise patients to read the FDA-approved patient labeling (Patient Information) thoroughly. This document contains essential information regarding the medication, including its indications, usage, potential side effects, and important safety information. Emphasizing the importance of understanding this material can help patients make informed decisions about their treatment and enhance adherence to prescribed therapies.

Storage and Handling

The product is supplied in a tight container, in accordance with USP standards. 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 guidelines. It is essential to protect the product from moisture to maintain its integrity 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, including those with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion. Additionally, serum electrolytes should be monitored regularly, along with lithium levels in patients taking both valsartan and hydrochlorothiazide, and calcium levels in those with hypercalcemia receiving the same combination.

Patient counseling should include instructions to discontinue hydrochlorothiazide promptly if symptoms of acute angle-closure glaucoma arise, such as sudden visual acuity changes or ocular pain. Furthermore, patients should be informed of the potential risk 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 Lupin Pharmaceuticals, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)