Valsartan/Hydrochlorothiazide

Description

Valsartan and hydrochlorothiazide tablets 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 is presented as a white to practically white fine powder. It is soluble in ethanol and methanol, with slight solubility in water. Hydrochlorothiazide is described as 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide, featuring an empirical formula of C7H8ClN3O4S2 and a molecular weight of 297.73. This compound appears as a white or practically white, odorless crystalline powder, exhibiting slight solubility in water and varying solubility in other solvents.

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, respectively. Inactive ingredients include colloidal silicon dioxide, crospovidone, hydroxypropyl methylcellulose, red iron oxide, yellow iron oxide, black iron oxide, magnesium stearate, microcrystalline cellulose, polyethylene glycol, talc, and titanium dioxide. The drug product complies with the USP Dissolution Test 2.

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 utilized 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 needed, 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, either valsartan or HCTZ. Additionally, it may be substituted for the titrated components, ensuring that the total daily dose 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, patients with a known hypersensitivity to sulfonamide-derived drugs or any component of the formulation should not use this product.

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 or death to the developing fetus.

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

Laboratory tests should include monitoring of renal function and potassium levels in susceptible patients to ensure safe use of the medication.

Side Effects

Patients receiving valsartan and hydrochlorothiazide tablets 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 patients compared to 1.9% in the placebo group.

Serious warnings associated with the use of these tablets include the potential for fetal toxicity. Drugs that act directly on the renin-angiotensin system, such as valsartan, can cause injury and death to the developing fetus. Therefore, it is imperative to discontinue valsartan and hydrochlorothiazide tablets as soon as pregnancy is detected.

Additional adverse reactions of clinical significance include hypotension, which necessitates the 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 assessed in susceptible individuals. There have been reports 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 also advised that valsartan and hydrochlorothiazide tablets not be co-administered with aliskiren 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 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 reduce 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 have not been established in pediatric patients. Therefore, caution is advised when considering the use of this combination therapy in children and adolescents. Further studies are necessary to determine appropriate dosing and safety profiles 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.

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-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 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 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. It also 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 severe fetal complications, including reduced renal function leading to anuria and 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 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 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 risks of fetal or neonatal jaundice and thrombocytopenia. Furthermore, 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.

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. 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 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. Additional symptoms may involve a depressed level of consciousness, circulatory collapse, and shock. 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 unestablished. 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 exhibited no 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 maximum recommended human dose on a mg/m² basis.

The oral LD50 of hydrochlorothiazide is greater than 10 g/kg in both mice and rats, which corresponds to 2027 and 4054 times, respectively, the maximum recommended human dose on a mg/m² basis, assuming an oral dose of 25 mg/day for a 60-kg patient.

Nonclinical Toxicology

No information is available regarding teratogenic effects associated with the combination of valsartan and hydrochlorothiazide.

Non-teratogenic effects have been evaluated through various studies. No carcinogenicity, mutagenicity, or fertility studies have been conducted specifically on the combination of valsartan and hydrochlorothiazide; however, individual studies for each compound have been performed. 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 are approximately 2.6 and 6 times the maximum recommended human dose on a mg/m² basis, assuming an oral dose of 320 mg/day for a 60-kg patient. Additionally, mutagenicity assays did not demonstrate any valsartan-related effects at the gene or chromosome level. These assays included 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. Furthermore, 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 maximum recommended human dose on a mg/m² basis.

Hydrochlorothiazide was evaluated in two-year feeding studies conducted under the auspices of the National Toxicology Program (NTP), which found no evidence of carcinogenic potential 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 involving 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 only observed in the in vitro CHO Sister Chromatid Exchange (clastogenicity) and Mouse Lymphoma Cell (mutagenicity) assays at specific concentrations, 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 19 and 1.5 times the maximum recommended human dose 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 are advised to protect their skin from the sun and to undergo regular skin cancer screenings, as there is a potential association with non-melanoma skin cancer. Instances of low blood pressure (hypotension) have been reported, particularly in patients who are on diuretics, following a low-salt diet, undergoing dialysis, or experiencing conditions such as vomiting, diarrhea, or alcohol consumption.

Allergic reactions have been noted in individuals taking valsartan and hydrochlorothiazide tablets, regardless of prior allergy history or asthma. Additionally, there have been reports of worsening lupus symptoms in patients taking hydrochlorothiazide, which may exacerbate the condition.

Fluid and electrolyte imbalances have been observed, with symptoms including dry mouth, drowsiness, muscle fatigue, thirst, restlessness, low urine output, lethargy, confusion, rapid heartbeat, weakness, seizures, nausea, vomiting, and muscle cramps. Patients with pre-existing kidney disease may experience worsening kidney function, necessitating monitoring and potential dosage adjustments. Signs such as swelling in the extremities or unexplained weight gain should prompt consultation with a healthcare provider.

Unusual skin rashes have been reported, and patients are advised to contact their doctor immediately if such symptoms occur. Eye problems, which may lead to vision loss, have also been associated with the medication, with symptoms potentially manifesting within hours to weeks of initiation. Patients should report any decrease in vision or eye pain to their healthcare provider promptly.

Other side effects have generally been mild and transient, typically not leading to discontinuation of the medication.

Patient Counseling

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. 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.

For female patients of childbearing age, it is crucial to discuss the potential consequences of exposure to valsartan and hydrochlorothiazide tablets during pregnancy. Healthcare providers should explore alternative treatment options with women who are planning to become pregnant and advise them to report any pregnancies to their physician as soon as possible. Additionally, women should be informed not to breastfeed while undergoing treatment with these tablets.

Patients should be made aware that lightheadedness may occur, particularly during the initial days of therapy, and they should report this to their healthcare provider. Instruct patients that if they experience syncope, they should discontinue the medication until they have consulted 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 against using 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 inform their doctor about all medical conditions, 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.

Encourage patients to provide a complete list of all medications they are taking, including prescription and nonprescription drugs, vitamins, and herbal supplements, as interactions with valsartan and hydrochlorothiazide tablets could lead to serious side effects. Specifically, patients should inform their doctor if they are taking other medications for high blood pressure or heart conditions, diuretics, potassium supplements, antidiabetic medications, narcotics, sleeping pills, lithium, NSAIDs, digoxin, muscle relaxants, certain cancer treatments, antibiotics, or medications for transplant rejection or HIV/AIDS.

Patients should be instructed to take valsartan and hydrochlorothiazide tablets exactly as prescribed, with the understanding that their doctor may adjust the dosage as necessary. The medication can be taken once daily, with or without food. If a dose is missed, patients should take it as soon as they remember unless it is close to the time for their next dose; in that case, they should skip the missed dose and resume their regular schedule. If an overdose occurs, patients should contact their doctor, Poison Control Center, or seek emergency medical attention immediately.

Finally, patients should be advised to call their doctor promptly if they notice any unusual skin rashes, a decrease in vision, or eye pain. They should also be reminded to protect their skin from the sun and to undergo regular skin cancer screenings, as one of the components in valsartan and hydrochlorothiazide tablets may increase the risk of non-melanoma skin cancer.

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 controlled room temperature of 25ºC (77ºF), with permissible excursions between 15-30ºC (59-86ºF) as outlined by USP Controlled Room Temperature standards. Additionally, it is essential to protect the product from moisture to maintain its quality and efficacy.

Additional Clinical Information

Clinicians should periodically monitor renal function 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, calcium levels should also be checked.

Patients are advised 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 Alembic Pharmaceuticals Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)