Valsartan/Hydrochlorothiazide

Description

Valsartan and hydrochlorothiazide is a combination medication consisting of 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 435.5. It appears as a white, fine hygroscopic powder, soluble in ethanol and methanol, but practically insoluble in water.

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 297.73. 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.

Valsartan and hydrochlorothiazide tablets, USP, are designed 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. The inactive ingredients include colloidal silicon dioxide, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, sodium lauryl sulfate, talc, and titanium dioxide. Specific formulations contain additional colorants: the 80 mg/12.5 mg and 160 mg/12.5 mg strengths include iron oxide red and iron oxide yellow; the 160 mg/25 mg strength contains iron oxide black, red, and yellow; the 320 mg/12.5 mg strength includes iron oxide black and red; and the 320 mg/25 mg strength contains iron oxide yellow.

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. This medication may be utilized as add-on or switch therapy for patients who are not adequately controlled on either valsartan or hydrochlorothiazide alone. Additionally, it may be substituted for the titrated components of the individual medications.

Healthcare professionals should assess the patient's response to therapy and adjust the dosage accordingly to achieve optimal control of blood pressure while monitoring for potential side effects.

Contraindications

Use 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, the 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 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.

General precautions must be observed when administering this medication. Prior to initiation, it is essential to correct any volume depletion to prevent hypotension. Healthcare professionals should remain vigilant for signs of fluid or electrolyte imbalance, as these can occur during treatment. Regular monitoring of renal function and potassium levels is recommended, particularly in patients who are susceptible to these issues. Additionally, there is a risk of exacerbation or activation of systemic lupus erythematosus, and acute angle-closure glaucoma may also occur.

Laboratory tests should include monitoring of renal function and potassium levels in susceptible patients to ensure safety and efficacy during treatment.

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 this medication include fetal toxicity. It is imperative that valsartan and hydrochlorothiazide 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 overdosage 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 should be exercised when considering the use of this medication in children and adolescents. Further studies are necessary to determine appropriate dosing and potential 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 elderly 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 older individuals. Therefore, healthcare providers should exercise caution when prescribing valsartan and hydrochlorothiazide to geriatric patients. Monitoring for potential adverse effects and considering dose adjustments may be warranted to ensure optimal therapeutic outcomes in this population.

Pregnancy

Valsartan and hydrochlorothiazide can cause fetal harm when administered to pregnant women. 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, 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.

Hypertension in pregnancy poses increased maternal risks, including pre-eclampsia, gestational diabetes, premature delivery, and delivery complications such as the need for cesarean section and postpartum hemorrhage. Additionally, 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 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 for patients and physicians to recognize 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.

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 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 fetotoxicity of valsartan/hydrochlorothiazide has been observed in association with maternal toxicity in animal studies at certain doses.

Lactation

There is no specific information available regarding the use of valsartan and hydrochlorothiazide in lactating mothers. Additionally, there is no data on the potential for excretion of valsartan and hydrochlorothiazide in breast milk or any associated risks to breastfed infants. Healthcare professionals should consider the lack of information when advising lactating mothers on 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 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; bradycardia may occur due to parasympathetic (vagal) stimulation. Additionally, cases of depressed level of consciousness, circulatory collapse, and shock have been reported.

In the event of symptomatic hypotension, it is recommended to institute 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 resulting from electrolyte depletion, including hypokalemia, hypochloremia, and hyponatremia, as well as dehydration due to 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 (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.

Nonclinical Toxicology

No teratogenic effects have been reported in the studies conducted.

Carcinogenicity and mutagenicity studies have not been performed on the combination of valsartan and hydrochlorothiazide; however, individual studies for each compound have been completed. 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 two years at doses of 160 mg/kg/day and 200 mg/kg/day, respectively, with no evidence of carcinogenicity observed. 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.

Mutagenicity assays did not demonstrate any valsartan-related effects at the gene or chromosome level. The 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. Additionally, 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.

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 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, assuming an oral dose of 25 mg/day for a 60 kg patient.

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 is a possibility that 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 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, who should have their kidney function assessed prior to treatment initiation.

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 one of the components of the medication, with symptoms potentially occurring within hours to weeks of starting treatment. Patients should seek medical attention if they experience a decrease in vision or eye pain.

Other side effects reported were generally mild and transient, typically not leading 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

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. It is important to emphasize that this leaflet does not replace discussions with their healthcare provider regarding their condition and treatment. Patients should be encouraged to ask their doctor or pharmacist any questions they may have about the medication.

Healthcare providers should inform female patients of childbearing age about the potential consequences of exposure to valsartan and hydrochlorothiazide during pregnancy. It is essential to discuss alternative treatment options with women who are planning to become pregnant and to advise them to report any pregnancies to their physician as soon as possible. Additionally, women should be counseled against breastfeeding while undergoing treatment with valsartan and hydrochlorothiazide.

Patients should be made aware that lightheadedness may occur, particularly during the initial days of therapy, and they should report this symptom to their healthcare provider. Instruct patients that if they experience syncope, they should discontinue the medication and consult their physician. Caution all patients that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting can lead to a significant drop in blood pressure, which may result in lightheadedness or syncope.

Advise patients not to use salt substitutes without prior consultation with their healthcare provider. For those taking hydrochlorothiazide, it is important to instruct them to protect their skin from sun exposure and to undergo regular skin cancer screenings.

Patients should be reminded to disclose all medical conditions to their healthcare provider, including pregnancy status, breastfeeding, liver or kidney problems, history of gallstones, lupus, low potassium or magnesium levels, high calcium or uric acid levels, and any previous reactions such as angioedema to other blood pressure medications. Furthermore, patients should inform their doctor about all medications they are taking, including prescription and nonprescription drugs, vitamins, and herbal supplements, as interactions could lead to serious side effects.

Instruct patients to take valsartan and hydrochlorothiazide exactly as prescribed, with the understanding that their doctor may adjust the dosage as necessary. The medication should be taken once daily, with or without food. If a dose is missed, patients should take it as soon as they remember, but if it is close to the time of the next dose, they should skip the missed dose and resume their regular schedule.

In the event of an overdose, patients should be advised to contact their doctor, the Poison Control Center, or go to the nearest hospital emergency room. It is critical to inform patients that valsartan and hydrochlorothiazide should not be taken during pregnancy.

Patients should be encouraged to call their doctor for medical advice regarding any side effects and may report side effects to the FDA at 1-800-FDA-1088. Finally, instruct patients to store valsartan and hydrochlorothiazide tablets at room temperature between 20° to 25°C (68° to 77°F), protecting them from moisture and heat, and to keep the medication out of reach of children.

Storage and Handling

The product is supplied in a tight container to ensure integrity and stability, in accordance with USP guidelines. It should be stored at a temperature range of 20° to 25°C (68° to 77°F), adhering to USP Controlled Room Temperature standards. Care must be taken to protect the product from moisture and heat 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, 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 patients with hypercalcemia receiving these medications.

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. Patients should also be informed about the potential risk of fetal harm associated with the use of valsartan and hydrochlorothiazide during pregnancy, emphasizing the importance of discontinuation upon detection of pregnancy.

FDA Insert (PDF)

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

View full prescribing information (PDF)