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 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 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 is chemically defined as 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide, with an empirical formula of C7H8ClN3O4S2 and a molecular weight of 297.73. 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: 80/12.5 mg, 160/12.5 mg, 160/25 mg, 320/12.5 mg, and 320/25 mg of valsartan and hydrochlorothiazide, USP. Inactive ingredients include colloidal silicon dioxide, crospovidone, 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 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 used as initial treatment in patients who are likely to require multiple medications to achieve their blood pressure goals.

Lowering blood pressure with this medication reduces the risk of both fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions.

There are no teratogenic or nonteratogenic effects associated with this drug.

Dosage and Administration

The recommended dosage is once daily, with titration as necessary, up to a maximum dose of 320 mg of valsartan and 25 mg of hydrochlorothiazide (HCTZ). This medication may be utilized as an 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 dosage does not exceed the specified maximum. Healthcare professionals should monitor patients closely during the titration process to achieve optimal therapeutic outcomes.

Contraindications

Use of this product is contraindicated in patients with anuria due to the risk of renal impairment. Additionally, individuals with 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 even death to the developing fetus.

Prior to initiating treatment, 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 during the course of treatment. Regular monitoring of renal function and potassium levels is recommended, particularly in patients who are susceptible to these complications.

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 may arise during treatment.

For patients at risk, it is imperative to conduct laboratory tests to monitor renal function and potassium levels, ensuring that any abnormalities are addressed promptly.

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 valsartan and hydrochlorothiazide tablets 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 even death to the developing fetus.

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 closely observed in susceptible individuals. There have also been reports of exacerbation or activation of systemic lupus erythematosus, acute angle-closure glaucoma, and anuria.

Patients with hypersensitivity to sulfonamide-derived drugs or any component of the formulation should not co-administer aliskiren with valsartan and hydrochlorothiazide tablets, particularly in those with diabetes.

Symptoms of overdosage may manifest as hypotension, tachycardia, bradycardia, depressed level of consciousness, circulatory collapse, and shock. Signs and symptoms observed in patients may include those caused by electrolyte depletion, such as hypokalemia, hypochloremia, hyponatremia, and dehydration resulting from excessive diuresis.

Drug Interactions

Antidiabetic drugs may require dosage adjustments when used concurrently, as their effectiveness can be influenced by the presence of other medications.

Cholestyramine and colestipol 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.

In neonates with a history of in utero exposure to valsartan and hydrochlorothiazide, if oliguria or hypotension occurs, it is essential to direct attention toward the support of blood pressure and renal perfusion. In such cases, exchange transfusions or dialysis may be required to reverse hypotension and/or substitute for disordered renal function.

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 on age alone, careful assessment of each elderly patient's overall health status and concurrent medications is advisable to optimize therapy.

Pregnancy

The use of valsartan and hydrochlorothiazide during pregnancy is associated with significant risks, particularly during the second and third trimesters. These medications fall under Pregnancy Category D, indicating evidence of risk to the fetus. Specifically, drugs that act on the renin-angiotensin system can reduce fetal renal function, leading to increased morbidity and mortality in both the fetus and neonate. Oligohydramnios, a potential consequence of this drug use, may result in fetal lung hypoplasia and skeletal deformations. Adverse neonatal outcomes may include skull hypoplasia, anuria, hypotension, renal failure, and death.

When pregnancy is confirmed, it is imperative to discontinue valsartan and hydrochlorothiazide as soon as possible, particularly due to the associated risks during the later stages of pregnancy. Most epidemiological studies assessing fetal abnormalities following antihypertensive exposure in the first trimester have not specifically differentiated between drugs affecting the renin-angiotensin system and other antihypertensive agents.

Management of maternal hypertension is crucial to optimize outcomes for both the mother and fetus. In rare cases where no suitable alternative therapy exists for a patient requiring treatment with renin-angiotensin system inhibitors, healthcare providers should inform the mother of the potential risks to the fetus. Serial ultrasound examinations should be conducted to monitor the intra-amniotic environment, and if oligohydramnios is detected, valsartan and hydrochlorothiazide should be discontinued unless deemed lifesaving for the mother.

Fetal testing may be warranted depending on the gestational age; however, it is important to note that oligohydramnios may not manifest until after the fetus has sustained irreversible injury. Infants with a history of in utero exposure to these medications should be closely monitored for hypotension, oliguria, and hyperkalemia.

Hydrochlorothiazide, like other thiazide diuretics, can cross the placenta, achieving concentrations in the umbilical vein that are comparable to those in maternal plasma. Additionally, hydrochlorothiazide may cause placental hypoperfusion and can accumulate in the amniotic fluid, with concentrations reported to be up to 19 times higher than in umbilical vein plasma. The use of thiazides during pregnancy is also linked to risks of fetal or neonatal jaundice and thrombocytopenia. Furthermore, these medications do not prevent or alter the course of edema, proteinuria, and hypertension (EPH) gestosis (pre-eclampsia) and should not be utilized for treating hypertension in pregnant women. The use of hydrochlorothiazide for other indications, such as heart disease, during pregnancy is also discouraged.

Lactation

It is not known whether valsartan is excreted in human milk. However, valsartan has been shown to be excreted into the milk of lactating rats, although animal breast milk drug levels may not accurately reflect those in human breast milk. Hydrochlorothiazide is known to be excreted in human breast milk.

Due to the potential for adverse reactions in breastfed infants from both valsartan and hydrochlorothiazide, lactating mothers should make a decision regarding the continuation of nursing or the discontinuation of the drug. This decision should take into account the importance of the medication to the mother’s health.

Renal Impairment

Patients with renal impairment should have their renal function and potassium levels monitored, particularly in those who are susceptible to changes in these parameters. Regular assessment is essential to ensure safe and effective use of the medication in this population.

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, symptoms such as depressed level of consciousness, circulatory collapse, and shock have been reported. In the event of symptomatic hypotension, it is recommended that supportive treatment be initiated.

It is important to note that valsartan is not removed from the plasma by dialysis. 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 typically related to 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, were well tolerated without any 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 demonstrated 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 exceeds 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, based on an oral dose of 25 mg/day for a 60-kg patient.

Nonclinical Toxicology

There was no evidence of teratogenicity in mice, rats, or rabbits treated orally with valsartan at doses up to 600, 100, and 10 mg/kg/day, respectively, in combination with hydrochlorothiazide at doses up to 188, 31, and 3 mg/kg/day. Additionally, no teratogenic effects were observed when valsartan was administered to pregnant mice and rats at oral doses up to 600 mg/kg/day and to pregnant rabbits at oral doses up to 10 mg/kg/day. Under the auspices of the National Toxicology Program, pregnant mice and rats that received hydrochlorothiazide via gavage at doses up to 3000 and 1000 mg/kg/day, respectively, on gestation days 6 through 15 also showed no evidence of teratogenicity.

Fetotoxicity was observed in association with maternal toxicity in rats and rabbits at valsartan doses of ≥200 and 10 mg/kg/day, respectively, in combination with hydrochlorothiazide doses of ≥63 and 3 mg/kg/day. Significant decreases in fetal weight, pup birth weight, pup survival rate, and slight delays in developmental milestones were noted in studies where parental rats were treated with valsartan at oral, maternally toxic doses of 600 mg/kg/day during organogenesis or late gestation and lactation. In rabbits, fetotoxicity associated with maternal toxicity was observed at doses of 5 and 10 mg/kg/day.

No carcinogenicity, mutagenicity, or fertility studies have been conducted with the combination of valsartan and hydrochlorothiazide. There was no evidence of carcinogenicity when valsartan was administered in the diet to mice and rats for up to 2 years at doses up to 160 and 200 mg/kg/day, respectively. Mutagenicity assays did not reveal any valsartan-related effects at either the gene or chromosome level. Valsartan had no adverse effects on the reproductive performance of male or female rats at oral doses up to 200 mg/kg/day.

Two-year feeding studies in mice and rats uncovered no evidence of a carcinogenic potential of hydrochlorothiazide in female mice or in male and female rats. Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay and other tests. Furthermore, hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in studies wherein these species were exposed to doses of up to 100 and 4 mg/kg, respectively, prior to mating and throughout gestation.

Postmarketing Experience

Postmarketing experience has identified several adverse events reported voluntarily or through surveillance programs.

There have been reports of harm to an unborn baby, which may result in injury or death. Instances of low blood pressure (hypotension) have been noted, particularly in patients who are taking diuretics, following a low salt diet, undergoing dialysis, suffering from heart problems, experiencing vomiting or diarrhea, consuming alcohol, or who are otherwise unwell.

Allergic reactions have been observed in individuals with and without a history of allergies or asthma who are taking valsartan and hydrochlorothiazide tablets. Additionally, worsening of lupus has been reported, with hydrochlorothiazide potentially exacerbating this condition.

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

Kidney problems may worsen in patients with pre-existing kidney disease, and some individuals may exhibit changes in blood tests for kidney function, necessitating a lower dose of valsartan and hydrochlorothiazide tablets. Patients are advised to contact their doctor if they experience swelling in the feet, ankles, or hands, or unexplained weight gain. In cases of heart failure, kidney function should be assessed prior to prescribing this medication.

Reports of unusual skin rashes have prompted recommendations for immediate medical consultation. Eye problems, which may lead to vision loss, have also been associated with one of the components of valsartan and hydrochlorothiazide tablets. Symptoms such as decreased vision and eye pain can occur within hours to weeks of initiating treatment, warranting prompt medical attention.

Other side effects reported were generally mild and transient, typically not leading to discontinuation of valsartan and hydrochlorothiazide tablets. Patients are encouraged to seek medical advice regarding side effects and may report them to the FDA at 1-800-FDA-1088.

Patient Counseling

Healthcare providers should advise patients to read the FDA-approved patient labeling (Patient Information) prior to initiating therapy with valsartan and hydrochlorothiazide tablets and each time they receive a refill, as there may be new information available.

Female patients of childbearing age should be informed about the potential consequences of exposure to valsartan and hydrochlorothiazide tablets during pregnancy. It is essential to discuss alternative treatment options with women who are planning to become pregnant. Patients should be encouraged to report any pregnancies to their physicians as soon as possible.

Patients receiving valsartan and hydrochlorothiazide tablets should be cautioned about the possibility of lightheadedness, particularly during the initial days of therapy. They should be instructed to report any instances of lightheadedness or syncope to their prescribing physician. In the event of syncope, valsartan and hydrochlorothiazide tablets should be discontinued until the physician has been consulted.

All patients should be made aware that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting can lead to a significant drop in blood pressure, which may result in lightheadedness and potential syncope. Additionally, patients should be advised against using potassium supplements or salt substitutes containing potassium without prior consultation with their prescribing physician.

Patients should be reminded that this leaflet does not replace discussions with their healthcare provider regarding their condition and treatment. They are encouraged to ask their doctor or pharmacist any questions they may have about valsartan and hydrochlorothiazide tablets.

Patients planning to become pregnant should discuss alternative methods for lowering blood pressure with their doctor. If a patient becomes pregnant while taking valsartan and hydrochlorothiazide tablets, they should inform their doctor immediately.

Patients must 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.

It is important for patients to inform their healthcare provider about all medications they are taking, including prescription and nonprescription drugs, vitamins, and herbal supplements, as interactions may occur that could lead to serious side effects. Patients should maintain an updated list of their medications to present to their doctor or pharmacist when a new medication is prescribed. They should consult their healthcare provider or pharmacist before starting any new medications to ensure safety.

Patients should take valsartan and hydrochlorothiazide tablets exactly as prescribed by their healthcare provider, who may adjust the dosage as necessary. The medication should be taken once daily and can be consumed 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 of the next scheduled dose; in that case, they should skip the missed dose and resume their regular dosing schedule.

In the event of an overdose, patients should contact their doctor, the Poison Control Center, or go to the nearest hospital emergency room. It is crucial to avoid taking valsartan and hydrochlorothiazide tablets during pregnancy.

Patients should seek medical advice regarding any side effects experienced and may report side effects to the FDA at 1-800-FDA-1088. Valsartan and hydrochlorothiazide tablets should be stored at room temperature between 15-30°C (59-86°F) in a closed container in a dry place, and out of reach of children.

Storage and Handling

The product is supplied in a tight container to ensure integrity and compliance with USP standards. It should be stored at a controlled room temperature of 25ºC (77ºF), with permissible excursions between 15-30ºC (59-86ºF) as outlined by USP guidelines. It is essential to protect the product from moisture 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 periodically, along with lithium levels in patients taking both valsartan and hydrochlorothiazide tablets and lithium. Calcium levels should also be monitored in patients with hypercalcemia receiving these tablets.

Patients should be counseled to discontinue hydrochlorothiazide promptly if they experience symptoms indicative of acute angle-closure glaucoma, such as a sudden decrease in visual acuity or ocular pain. Furthermore, patients must be informed about the potential for fetal toxicity and should discontinue valsartan and hydrochlorothiazide tablets as soon as pregnancy is confirmed.

FDA Insert (PDF)

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

View full prescribing information (PDF)