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-(1-oxopentyl)-N-[[2'-(1H-tetrazol-5-yl)1,1'-biphenyl-4-yl]methyl]-L-Valine, with a molecular formula of C24H29N5O3 and a molecular weight of 435.52 g/mol. It appears as an almost white, hygroscopic powder that is practically insoluble in water, freely soluble in anhydrous ethanol, and sparingly soluble in methylene chloride.

Hydrochlorothiazide is described chemically 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 297.74 g/mol. It is presented as a white or practically white, practically odorless crystalline powder, slightly soluble in water, freely soluble in sodium hydroxide solution, n-butylamine, and dimethyl formamide, sparingly soluble in methanol, and insoluble in ether, chloroform, and dilute mineral acids.

These tablets are formulated for oral administration and are available in the following strengths: 80 mg/12.5 mg, 160 mg/12.5 mg, 160 mg/25 mg, 320 mg/12.5 mg, and 320 mg/25 mg of valsartan and hydrochlorothiazide, respectively. The inactive ingredients include colloidal silicon dioxide, croscarmellose sodium, hypromellose, iron oxide yellow, polyethylene glycol, magnesium stearate, microcrystalline cellulose, polyvinyl alcohol, talc, and titanium dioxide. Specific formulations also contain additional colorants: the 80 mg/12.5 mg tablets include FD&C Red No. 40 and ferrosoferric oxide; the 160 mg/12.5 mg tablets contain iron oxide red; the 160 mg/25 mg and 320 mg/12.5 mg tablets contain both iron oxide red and ferrosoferric oxide.

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 is associated with a reduction in the risk of both fatal and nonfatal cardiovascular events, including strokes and myocardial infarctions.

Dosage and Administration

The recommended dosage is once daily, with titration as necessary, up to a maximum dose of 320 mg of valsartan and 25 mg of hydrochlorothiazide (HCTZ). This medication may be utilized as add-on or switch therapy for patients who are not adequately controlled on any of the individual components, 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 assess the patient's response and adjust the dosage accordingly to achieve optimal therapeutic outcomes.

Contraindications

Use of this product is contraindicated in patients with anuria and in those with hypersensitivity to any sulfonamide-derived drugs or any component of the formulation.

Additionally, co-administration of aliskiren with valsartan and hydrochlorothiazide tablets is contraindicated in patients with diabetes due to the potential for 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 and 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, as these can occur during therapy.

Monitoring of renal function and serum potassium levels is recommended for patients who may be susceptible to these changes. This is particularly important in patients with pre-existing renal impairment or those on concomitant medications that may affect renal function.

There is a risk of exacerbation or activation of systemic lupus erythematosus in some patients, necessitating careful monitoring and assessment of symptoms. Furthermore, acute angle-closure glaucoma may occur, and patients should be evaluated for any ocular symptoms.

In summary, regular laboratory tests to monitor renal function and potassium levels are advised for susceptible patients to ensure safe use of valsartan and hydrochlorothiazide tablets.

Side Effects

Patients receiving valsartan and hydrochlorothiazide may experience a range of adverse reactions. Common adverse reactions 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 this medication include fetal toxicity. It is imperative to discontinue valsartan and hydrochlorothiazide tablets 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 been reports of exacerbation or activation of systemic lupus erythematosus, as well as acute angle-closure glaucoma. Other noted reactions include anuria and hypersensitivity to sulfonamide-derived drugs or any component of the formulation. It is also advised that aliskiren not be co-administered with valsartan and hydrochlorothiazide 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 be attributed to electrolyte depletion (including hypokalemia, hypochloremia, and hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has been administered concurrently, hypokalemia may exacerbate cardiac arrhythmias.

Drug Interactions

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

Cholestyramine and colestipol 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 electrolyte levels 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 supporting 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, a total of 764 patients (17.5%) were aged 65 years and older, with 118 patients (2.7%) being 75 years or older. The data indicate that there was no overall difference in the efficacy or safety of valsartan and hydrochlorothiazide when comparing these geriatric patients to their younger counterparts.

However, it is important to note that greater sensitivity to the effects of the medication may be present in some elderly 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

The use of valsartan and hydrochlorothiazide during pregnancy is classified as Pregnancy Category D. Administration of drugs that act on the renin-angiotensin system during the second and third trimesters is associated with significant risks, including reduced fetal renal function, increased fetal and neonatal morbidity, and mortality. Oligohydramnios resulting from such use can lead to fetal lung hypoplasia and skeletal deformations. Potential adverse effects in neonates may include skull hypoplasia, anuria, hypotension, renal failure, and death.

It is imperative that valsartan and hydrochlorothiazide be discontinued as soon as pregnancy is detected. The adverse outcomes are primarily linked to the use of these medications during the later stages of pregnancy. While most epidemiologic 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, appropriate management of maternal hypertension is crucial to optimize outcomes for both the mother and fetus.

In cases where there is no suitable alternative to therapy with renin-angiotensin system-affecting drugs, 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. 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 valsartan and hydrochlorothiazide should be closely monitored for hypotension, oliguria, and hyperkalemia. Hydrochlorothiazide is known to cross the placenta, achieving concentrations in the umbilical vein that are comparable to those in maternal plasma, and it can cause placental hypoperfusion. Additionally, hydrochlorothiazide accumulates 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 associated with risks of fetal or neonatal jaundice and thrombocytopenia, and they do not prevent or alter the course of EPH (Edema, Proteinuria, Hypertension) gestosis (pre-eclampsia). Therefore, thiazides should not be utilized to treat hypertension in pregnant women, and their use for other indications, such as heart disease, should also be avoided.

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 consider the importance of the drug to their health when making a decision to either discontinue nursing or discontinue the 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

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

Overdosage

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 that supportive treatment be initiated.

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 1,524 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 2,000 mg/kg in rats and up to 1,000 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 2,027 and 4,054 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

There was no evidence of teratogenicity in studies involving 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 3,000 and 1,000 mg/kg/day, respectively, on gestation days 6 through 15 also showed no evidence of teratogenicity.

Fetotoxicity was noted 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. In rats, fetotoxicity was linked to decreased fetal weights and included variations in the development of sternebrae, vertebrae, ribs, and/or renal papillae. In rabbits, fetotoxicity was characterized by increased numbers of late resorptions, leading to higher total resorptions, postimplantation losses, and a decreased number of live fetuses. Significant decreases in fetal weight, pup birth weight, pup survival rate, and slight delays in developmental milestones were observed 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, including resorptions, litter loss, abortions, and low body weight, associated with maternal toxicity (mortality) 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 in the Chinese Hamster Ovary test for chromosomal aberrations. 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.

Postmarketing Experience

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

Hypotension has been observed, particularly in patients who are on diuretics, following a low-salt diet, undergoing dialysis, or those with pre-existing heart conditions. Additionally, episodes of hypotension may occur in individuals experiencing vomiting, diarrhea, or alcohol consumption.

Allergic reactions have been reported in both patients with a history of allergies or asthma and those without such conditions while taking valsartan and hydrochlorothiazide tablets.

Worsening of lupus has been noted, with hydrochlorothiazide potentially exacerbating this condition in susceptible individuals.

Fluid and electrolyte imbalances have been associated with the medication. Patients are advised to inform their healthcare provider if they experience symptoms such as dry mouth, excessive thirst, lethargy, weakness, drowsiness, restlessness, confusion, seizures, muscle pain or cramps, muscle fatigue, significantly reduced urine output, rapid heartbeat, or gastrointestinal disturbances like nausea and vomiting.

Patients with pre-existing kidney disease may experience worsening kidney function, necessitating monitoring and possible dosage adjustments. Signs such as swelling in the extremities or unexplained weight gain should prompt immediate consultation with a healthcare provider. It is recommended that kidney function be assessed in patients with heart failure prior to initiating treatment with valsartan and hydrochlorothiazide tablets.

Unusual skin rashes have been reported, and patients are advised to seek medical attention promptly if such symptoms occur.

Eye problems, potentially leading to vision loss, have also been associated with the medication. Symptoms may manifest within hours to weeks of starting treatment and include decreased vision and eye pain, warranting immediate medical consultation.

Other side effects reported were generally mild and transient, typically not leading to discontinuation of the medication. Patients are encouraged to contact their healthcare provider for any side effects experienced and may report adverse events to the FDA at 1-800-FDA-1088.

Patient Counseling

Healthcare providers should advise patients to read the FDA-approved patient labeling (Patient Information) associated with valsartan and hydrochlorothiazide. It is essential to inform female patients of childbearing age about the potential consequences of exposure to valsartan and hydrochlorothiazide during pregnancy. Providers should discuss alternative treatment options with women who are planning to become pregnant and encourage patients to report any pregnancies to their physicians as soon as possible.

Patients receiving valsartan and hydrochlorothiazide 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 to their prescribing physician. In cases of syncope, patients must discontinue the medication and consult their physician before resuming treatment.

All patients should be made aware that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting can lead to a significant drop in blood pressure, resulting 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 are encouraged to read the Patient Information that accompanies valsartan and hydrochlorothiazide tablets before starting the medication and each time they receive a refill, as there may be new information available. Providers should discuss alternative methods for lowering blood pressure with patients who plan to become pregnant and emphasize the importance of notifying their doctor immediately if they become pregnant while taking this medication.

Patients should disclose all medical conditions to their healthcare provider, including any current or planned pregnancies. It is important to inform patients that they must choose between taking valsartan and hydrochlorothiazide tablets or breastfeeding, but not both.

Patients should also be reminded to inform their healthcare provider about all medications they are taking, including prescription and nonprescription drugs, vitamins, and herbal supplements, as interactions could lead to serious side effects. Maintaining an updated list of medications to share with their doctor and pharmacist is advisable, and patients should consult their healthcare provider or pharmacist before starting any new medications.

Patients must take valsartan and hydrochlorothiazide tablets exactly as prescribed, with the understanding that their doctor may adjust the dosage if necessary. The medication should be taken once daily and can be ingested 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 scheduled dose, they should skip the missed dose and continue with 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 inform patients that valsartan and hydrochlorothiazide tablets should not be taken during pregnancy.

Storage and Handling

The product is supplied in a tight container as defined by the United States Pharmacopeia (USP) to ensure integrity and stability. It should be stored at a temperature range of 20° to 25°C (68° to 77°F), with permissible excursions between 15° to 30°C (59° to 86°F) in accordance with USP Controlled Room Temperature guidelines. 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 status 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 valsartan and hydrochlorothiazide in conjunction with lithium. Calcium levels should also be assessed in patients with hypercalcemia receiving these tablets.

Patient counseling should include advising individuals to discontinue hydrochlorothiazide immediately if they experience acute onset of decreased visual acuity or ocular pain, as these symptoms may suggest acute angle-closure glaucoma. Patients should also be informed about the risk of hypersensitivity reactions, particularly those with a history of allergies or bronchial asthma.

FDA Insert (PDF)

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

View full prescribing information (PDF)