Valsartan/Hydrochlorothiazide

Description

Valsartan and hydrochlorothiazide tablets, USP, 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-[p-(o-1H-Tetrazol-5-ylphenyl)benzyl-N-valeryl-L-valine, with a molecular 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 described 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. It 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.

These tablets are formulated for oral administration 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, polydextrose, polyethylene glycol, povidone, pregelatinized starch (corn), sodium lauryl sulfate, titanium dioxide, triacetin, and vanillin. The 80 mg/12.5 mg, 160 mg/12.5 mg, 160 mg/25 mg, and 320 mg/12.5 mg tablets also contain red iron oxide and yellow iron oxide, while the 320 mg/25 mg tablet includes FD&C Blue No. 2 Aluminum Lake and FD&C Yellow No. 6 Aluminum Lake.

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 to administer the medication once daily. Healthcare professionals should titrate the dose as necessary, with a maximum allowable 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 overall therapeutic regimen remains effective and tailored to the patient's needs.

Contraindications

Use of this product is contraindicated in the following situations:

Patients with anuria, as the absence of urine production may lead to accumulation of the drug and potential toxicity.

Hypersensitivity to any sulfonamide-derived drugs or any component of the formulation is also a contraindication due to the risk of severe allergic reactions.

Additionally, 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. Additionally, practitioners should remain vigilant for signs of fluid or electrolyte imbalance in patients receiving this therapy. Regular monitoring of renal function and potassium levels is recommended, particularly in patients who may be susceptible to these complications.

There is a risk of exacerbation or activation of systemic lupus erythematosus in some patients. Furthermore, acute angle-closure glaucoma may occur, necessitating careful assessment of patients with a history of this condition.

To ensure patient safety, it is imperative to monitor renal function and potassium levels in susceptible individuals throughout the course of treatment.

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 participants compared to 1.9% in the placebo group.

Serious warnings associated with the use of these tablets include fetal toxicity. It is imperative that valsartan and hydrochlorothiazide tablets be discontinued as soon as pregnancy is detected, as drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.

Additional adverse reactions of clinical significance include hypotension, which necessitates correction of volume depletion prior to initiation of therapy. Patients should be monitored for signs of fluid or electrolyte imbalance, and renal function and potassium levels should be closely observed in susceptible individuals. There have also been reports of exacerbation or activation of systemic lupus erythematosus, acute angle-closure glaucoma, and anuria. Patients with hypersensitivity to any sulfonamide-derived drugs or any component of the formulation should not use these tablets. Furthermore, coadministration of aliskiren with valsartan and hydrochlorothiazide tablets is contraindicated in patients with diabetes.

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 reported. Symptoms observed in patients may also include those resulting from electrolyte depletion, such as hypokalemia, hypochloremia, hyponatremia, and dehydration due to excessive diuresis.

Drug Interactions

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

Cholestyramine and colestipol have been shown to reduce the absorption of thiazide diuretics, potentially diminishing their therapeutic effects.

The concomitant use of lithium increases the risk of lithium toxicity. It is advised to monitor serum lithium concentrations closely during concurrent administration to ensure safety.

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) may elevate the risk of renal impairment and can also diminish the diuretic, natriuretic, and antihypertensive effects of diuretics. Caution is recommended when these agents are used together.

The dual inhibition of the renin-angiotensin system poses an increased risk of renal impairment, hypotension, and hyperkalemia. Monitoring of renal function and electrolytes is advisable in patients receiving such combinations.

Packaging & NDC

The table below lists all NDC Code configurations of Valsartan and Hydrochlorothiazide, the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

Safety and effectiveness of valsartan and hydrochlorothiazide in pediatric patients have not been established. Therefore, caution is advised when considering the use of this medication in children and adolescents. Further studies are necessary to determine appropriate dosing and outcomes in this population.

Geriatric Use

In controlled clinical trials involving valsartan and hydrochlorothiazide tablets, a total of 764 patients (17.5%) were aged 65 years and older, with 118 patients (2.7%) being 75 years or older. While 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.

Healthcare providers should exercise caution when prescribing valsartan and hydrochlorothiazide to geriatric patients. Monitoring for potential adverse effects and therapeutic responses is recommended, as individual responses may vary. Although no specific dosage adjustments are mandated based solely on age, clinicians should remain vigilant and consider the overall health status and comorbidities of elderly patients when determining treatment plans.

Pregnancy

Valsartan and hydrochlorothiazide tablets 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. Epidemiologic studies examining fetal abnormalities following antihypertensive use in the first trimester have not specifically distinguished between drugs affecting the renin-angiotensin system and other antihypertensive agents. Published reports have documented cases of anhydramnios and oligohydramnios in pregnant women treated with valsartan.

When pregnancy is detected, valsartan and hydrochlorothiazide tablets 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 2-4% and 15-20%, respectively.

Hypertension during pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications, such as the need for cesarean section and postpartum hemorrhage. Additionally, hypertension poses a fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be closely monitored and managed accordingly.

The use of valsartan in the second and third trimesters can lead to oligohydramnios, which may result in reduced fetal renal function, anuria, renal failure, fetal lung hypoplasia, skeletal deformations (including skull hypoplasia), hypotension, and death. Serial ultrasound examinations should be performed to assess the intra-amniotic environment, and fetal testing may be warranted based on gestational age. It is important to note that oligohydramnios may not manifest until after the fetus has sustained irreversible injury. If oligohydramnios is observed, alternative drug treatment should be considered. Neonates with a history of in utero exposure to valsartan and hydrochlorothiazide tablets should be closely observed for hypotension, oliguria, and hyperkalemia. In cases of oliguria or hypotension, 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.

Hydrochlorothiazide can cross the placenta, with concentrations in the umbilical vein approaching those in maternal plasma. Like other diuretics, hydrochlorothiazide can cause placental hypoperfusion and accumulates in the amniotic fluid, with reported concentrations up to 19 times higher than in umbilical vein plasma. The use of thiazides during pregnancy is associated with a risk of fetal or neonatal jaundice or thrombocytopenia. Since thiazides do not prevent or alter the course of edema, proteinuria, and hypertension (EPH) gestosis (pre-eclampsia), they 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 tablets.

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 severe effects such as depressed level of consciousness, circulatory collapse, and shock have been reported. In the event of symptomatic hypotension, it is recommended to initiate supportive treatment.

Valsartan is not effectively removed from the plasma by dialysis. The extent to which hydrochlorothiazide is removed by hemodialysis remains undetermined. The most common signs and symptoms observed in patients experiencing overdosage are typically those associated with electrolyte depletion, including hypokalemia, hypochloremia, and hyponatremia, as well as dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalemia may exacerbate cardiac arrhythmias.

Toxicological studies in rats and marmosets indicate that single oral doses of valsartan up to 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 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, which correspond to 60 and 31 times, respectively, the MRHD on a mg/m² basis.

The oral LD50 of hydrochlorothiazide exceeds 10 g/kg in both mice and rats, which translates to 2027 and 4054 times, respectively, the MRHD on a mg/m² basis, based on an oral dose of 25 mg/day for a 60-kg patient.

Nonclinical Toxicology

No information is available regarding teratogenic effects 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 on valsartan and hydrochlorothiazide 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 up to 160 mg/kg/day and 200 mg/kg/day, respectively, with no evidence of carcinogenicity observed. These doses are approximately 2.6 and 6 times the maximum recommended human dose (MRHD) on a mg/m² basis, assuming an oral dose of 320 mg/day for a 60-kg patient.

Mutagenicity assays conducted with valsartan did not reveal any effects at the gene or chromosome level. These assays included bacterial mutagenicity tests with Salmonella (Ames) and E. coli, a gene mutation test with Chinese hamster V79 cells, a cytogenetic test with Chinese hamster ovary cells, and a rat micronucleus test.

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 about 6 times the MRHD on a mg/m² basis.

Hydrochlorothiazide was evaluated in two-year feeding studies conducted by 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 using various Salmonella Typhimurium strains or 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 specific concentrations, as well as in the Aspergillus Nidulans non-disjunction assay.

Hydrochlorothiazide did not adversely affect the fertility of mice and rats of either sex in studies where these species were exposed to doses of up to 100 mg/kg and 4 mg/kg, respectively, prior to mating and throughout gestation. These doses represent approximately 19 and 1.5 times the MRHD on a mg/m² basis.

Postmarketing Experience

Postmarketing experience has identified several adverse events associated with the use of valsartan and hydrochlorothiazide tablets, reported voluntarily or through surveillance programs.

Patients taking hydrochlorothiazide are advised to protect their skin from sun exposure and to undergo regular skin cancer screenings due to the potential risk of non-melanoma skin cancer. Instances of low blood pressure (hypotension) have been noted, 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 reported in individuals with and without a history of allergies or asthma. Additionally, there have been cases of worsening lupus, which may be exacerbated by hydrochlorothiazide.

Fluid and electrolyte imbalances have also been observed, 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 nausea or vomiting.

While other side effects have generally been mild and transient, they have not typically led to discontinuation of the medication. Patients are encouraged to consult their healthcare provider for medical advice regarding side effects and may report any 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 tablets and each time they receive a refill, as there may be new information available.

Inform female patients of childbearing age about the potential consequences of exposure to valsartan and hydrochlorothiazide tablets during pregnancy. Discuss alternative treatment options with women who are planning to become pregnant, and encourage them to report any pregnancies to their healthcare provider as soon as possible. Additionally, advise women 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. They should be instructed to report any episodes of lightheadedness to their healthcare provider. Instruct patients that if syncope occurs, they should discontinue the use of valsartan and hydrochlorothiazide tablets until they have consulted with 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, instruct them to protect their skin from sun exposure and to undergo regular skin cancer screenings.

Encourage patients to discuss all medical conditions with their healthcare provider, including any plans for pregnancy, breastfeeding status, 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.

Patients should be reminded to inform their healthcare provider about all medications they are currently taking, including prescription and nonprescription drugs, vitamins, and herbal supplements, as interactions with valsartan and hydrochlorothiazide tablets could lead to serious side effects. It is advisable for patients to 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.

Patients should be instructed to contact their healthcare provider if they experience swelling in their feet, ankles, or hands, or if they notice unexplained weight gain. For patients with heart failure, it is important that their kidney function is evaluated by their doctor before prescribing valsartan and hydrochlorothiazide tablets.

Advise patients to seek immediate medical attention if they develop an unusual skin rash, experience a decrease in vision, or have eye pain.

Storage and Handling

The product is supplied in a tight, light-resistant container that complies with USP standards and features a child-resistant closure. It should be stored at a temperature range of 20° to 25°C (68° to 77°F), in accordance with USP Controlled Room Temperature guidelines. It is essential to protect the product from moisture and heat to maintain its integrity and efficacy.

Additional Clinical Information

No further data are available.

FDA Insert (PDF)

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

View full prescribing information (PDF)