Hydrochlorothiazide/Valsartan

Uses and Indications

Valsartan and hydrochlorothiazide tablets are indicated for the treatment of hypertension, aimed at lowering blood pressure in the following patient populations:

• Patients not adequately controlled with monotherapy.

• Patients likely to need multiple drugs to achieve their blood pressure goals as initial therapy.

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

Limitations of Use

The choice of valsartan and hydrochlorothiazide as initial therapy should be based on an assessment of potential benefits and risks. The decision to use a combination therapy should be individualized, taking into account factors such as baseline blood pressure, target goals, and the likelihood of achieving those goals compared to monotherapy. Individual blood pressure goals may vary based on the patient’s risk profile, particularly in patients with stage 2 hypertension, who are at a higher risk for cardiovascular events, kidney failure, and vision problems.

Dosage and Administration

The recommended dosage of Valsartan and Hydrochlorothiazide is one tablet taken once daily. The initial starting dose is typically 160 mg of valsartan and 12.5 mg of hydrochlorothiazide. Dosage may be titrated as needed, with a maximum allowable dose of 320 mg of valsartan and 25 mg of hydrochlorothiazide.

This medication may be utilized as add-on or switch therapy for patients who are not adequately controlled on either valsartan or hydrochlorothiazide alone. It can also serve as a replacement for the titrated components of the individual medications.

Valsartan and Hydrochlorothiazide may be administered with or without food. The maximum antihypertensive effects are generally observed within 2 to 4 weeks following any dose adjustment.

For elderly patients, no initial dosage adjustment is necessary. In patients with renal impairment, the usual regimen may be followed as long as the creatinine clearance is greater than 30 mL/min. In cases of more severe renal impairment, the use of loop diuretics is preferred over thiazides, and Valsartan and Hydrochlorothiazide is not recommended. Caution should be exercised when dosing in patients with hepatic impairment; starting with a lower dose and titrating slowly is advised.

Healthcare professionals should evaluate the clinical response to therapy after 3 to 4 weeks, and if blood pressure remains uncontrolled, the dosage may be increased to the maximum of 320 mg/25 mg.

Contraindications

Valsartan and hydrochlorothiazide is contraindicated in patients with anuria. It is also contraindicated in individuals who are hypersensitive to any sulfonamide-derived drugs or any component of the formulation. Additionally, coadministration of aliskiren with valsartan and hydrochlorothiazide tablets is not recommended in patients with diabetes.

Warnings and Precautions

WARNING: FETAL TOXICITY When pregnancy is detected, valsartan and hydrochlorothiazide tablets should be discontinued as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.

General Precautions

• Hypotension: Correct volume depletion prior to initiation.

• Fluid and Electrolyte Imbalance: Observe for signs of fluid or electrolyte imbalance.

• Renal Function Monitoring: Monitor renal function and potassium in susceptible patients.

• Systemic Lupus Erythematosus: There is a risk of exacerbation or activation of systemic lupus erythematosus.

• Acute Angle-Closure Glaucoma: This condition may be exacerbated.

Laboratory Tests

• Regular monitoring of renal function and potassium levels is recommended in susceptible patients.

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Side Effects

Common adverse reactions observed in patients taking Valsartan and Hydrochlorothiazide include headache, dizziness, and nasopharyngitis, with an incidence of 2.4% compared to 1.9% in placebo groups.

Serious Adverse Reactions

• Fetal Toxicity: There is a significant risk of injury or death to the developing fetus when drugs that act directly on the renin-angiotensin system are used during pregnancy. It is advised to discontinue the medication as soon as pregnancy is detected.

• Hypotension: Patients should have any volume depletion corrected prior to initiation of therapy. Hypotension may occur, particularly in susceptible individuals.

• Fluid or Electrolyte Imbalance: Patients should be monitored for signs of fluid or electrolyte imbalance, including renal function and potassium levels.

• Systemic Lupus Erythematosus: There may be exacerbation or activation of this condition.

• Acute Angle-Closure Glaucoma: This condition may occur with the use of the medication.

• Anuria: Patients may experience anuria, particularly those with hypersensitivity to sulfonamide-derived drugs or any component of the formulation.

Overdosage

Symptoms of overdosage may include hypotension, tachycardia, and bradycardia, which can occur due to parasympathetic (vagal) stimulation. Other reported symptoms include depressed level of consciousness, circulatory collapse, and shock. Signs of electrolyte depletion such as hypokalemia, hypochloremia, and hyponatremia, as well as dehydration resulting from excessive diuresis, may also be observed.

Less Common Adverse Reactions

In clinical trials and postmarketing experience, additional adverse reactions have been reported, including:

• Hypersensitivity: Rare cases of angioedema, particularly in patients with a history of angioedema with other medications.

• Digestive Issues: Elevated liver enzymes and rare reports of hepatitis.

• Musculoskeletal: Rhabdomyolysis has been reported.

• Renal Impairment: Impaired renal function and acute renal failure.

• Dermatologic Reactions: Alopecia, bullous dermatitis, and increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma in patients taking large cumulative doses of hydrochlorothiazide.

• Nervous System: Syncope and dizziness, including postural dizziness.

Patients should be monitored closely for these adverse reactions, and appropriate measures should be taken to manage any that occur.

Drug Interactions

Concurrent use of Valsartan and Hydrochlorothiazide with certain drug classes may lead to significant interactions that require careful monitoring and potential dosage adjustments.

Pharmacodynamic Interactions

• Antidiabetic Drugs: Dosage adjustments of antidiabetic medications may be necessary when used in conjunction with Valsartan and Hydrochlorothiazide to maintain glycemic control.

• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): The use of NSAIDs may increase the risk of renal impairment and can diminish the diuretic, natriuretic, and antihypertensive effects of the thiazide component.

• Dual Inhibition of the Renin-Angiotensin System: This combination can elevate the risk of renal impairment, hypotension, and hyperkalemia, necessitating close monitoring of renal function and electrolyte levels.

Pharmacokinetic Interactions

• Cholestyramine and Colestipol: These agents may reduce the absorption of thiazides, potentially leading to decreased efficacy of Valsartan and Hydrochlorothiazide.

• Lithium: There is an increased risk of lithium toxicity when used concurrently. It is recommended to monitor serum lithium concentrations during the combined therapy to avoid adverse effects.

In summary, healthcare providers should be vigilant when prescribing Valsartan and Hydrochlorothiazide alongside these medications, ensuring appropriate monitoring and adjustments to therapy as needed.

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 important to direct attention toward the support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required to reverse hypotension and/or substitute for disordered renal function.

Geriatric Use

In controlled clinical trials of valsartan and hydrochlorothiazide, 764 patients (17.5%) were aged 65 years or older, and 118 patients (2.7%) were aged 75 years or older. No overall differences in efficacy or safety were observed between these geriatric patients and younger patients. However, it cannot be ruled out that some older individuals may exhibit greater sensitivity to the medication.

Healthcare professionals should consider these factors when prescribing valsartan and hydrochlorothiazide to elderly patients, and appropriate monitoring may be warranted to ensure safety and efficacy 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, leading to increased fetal and neonatal morbidity and mortality. Published reports indicate 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 in the U.S. general population is 2% to 4% and 15% to 20%, respectively. All pregnancies carry a background risk of birth defects, loss, or other adverse outcomes.

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 patients with hypertension should be closely monitored and managed accordingly.

Oligohydramnios resulting from the use of renin-angiotensin system inhibitors in the second and third trimesters can lead to severe fetal outcomes, including reduced 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 appropriate 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 should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria or hypotension occurs, supportive measures for blood pressure and renal perfusion may be necessary, including potential exchange transfusions or dialysis.

Hydrochlorothiazide can cross the placenta, with concentrations in the umbilical vein approaching those in maternal plasma. It may 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 risks of fetal or neonatal jaundice and thrombocytopenia. Thiazides do not prevent or alter the course of EPH (Edema, Proteinuria, Hypertension) 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. Hydrochlorothiazide is known to be excreted in human breast milk, while valsartan has been detected in the milk of lactating rats shortly after administration. However, it is not established whether valsartan is excreted in human milk.

Due to the potential for serious adverse reactions in breastfed infants, it is advised that nursing mothers discontinue breastfeeding during treatment with valsartan and hydrochlorothiazide. The decision to continue or discontinue nursing should be made after considering the importance of the medication to the mother and the potential risks to the infant.

Renal Impairment

Patients with renal impairment should be carefully monitored when using valsartan and hydrochlorothiazide. The safety and effectiveness of this combination in patients with severe renal impairment, defined as creatinine clearance (CrCl) ≤ 30 mL/min, have not been established.

For patients with mild (CrCl 60 to 90 mL/min) or moderate (CrCl 30 to 60 mL/min) renal impairment, no dose adjustment is necessary. However, it is essential to monitor renal function and potassium levels in susceptible patients to mitigate potential risks associated with altered kidney function. Regular assessments are recommended to ensure patient safety and treatment efficacy.

Hepatic Impairment

No dose adjustment is necessary for patients with mild-to-moderate liver disease when using Valsartan and Hydrochlorothiazide. However, no dosing recommendations can be provided for patients with severe liver disease. It is important to note that minor alterations in fluid and electrolyte balance may precipitate hepatic coma in patients with impaired hepatic function or progressive liver disease.

Currently, there is no specific information regarding dosage adjustments, special monitoring, or precautions for patients with liver problems beyond what has been stated. Therefore, careful consideration and monitoring of these patients are advised.

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. Reports have indicated that symptoms such as depressed level of consciousness, circulatory collapse, and shock may also occur. In the event of symptomatic hypotension, supportive treatment should be instituted.

Valsartan is not removed from the plasma by dialysis, and the extent to which hydrochlorothiazide is removed by hemodialysis has not been established. The most common signs and symptoms observed in patients are related to electrolyte depletion, including hypokalemia, hypochloremia, and hyponatremia, as well as dehydration resulting from excessive diuresis. If digitalis has been administered concurrently, hypokalemia may exacerbate cardiac arrhythmias.

In animal studies, single oral doses of valsartan up to 1,524 mg/kg and hydrochlorothiazide up to 476 mg/kg were well tolerated without any treatment-related adverse 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.

Valsartan demonstrated no grossly observable adverse effects at single oral doses up to 2,000 mg/kg in rats and 1,000 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 the MRHD on a mg/m² basis, respectively. The oral LD50 of hydrochlorothiazide is greater than 10 g/kg in both mice and rats, corresponding to 2,027 and 4,054 times the MRHD on a mg/m² basis, respectively.

Nonclinical Toxicology

Teratogenic Effects

No evidence of teratogenicity was observed 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, pregnant mice and rats administered valsartan at oral doses up to 600 mg/kg/day and pregnant rabbits at doses up to 10 mg/kg/day showed no teratogenic effects. Under the National Toxicology Program, pregnant mice and rats receiving hydrochlorothiazide via gavage at doses up to 3,000 and 1,000 mg/kg/day, respectively, during gestation days 6 through 15 also exhibited no evidence of teratogenicity.

Non-Teratogenic Effects

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 sternebrae, vertebrae, ribs, and/or renal papillae. In rabbits, fetotoxicity included increased late resorptions, total resorptions, postimplantation losses, and decreased numbers 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 maternally toxic doses of 600 mg/kg/day during organogenesis or late gestation and lactation.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity, mutagenicity, or fertility studies have been conducted with the combination of valsartan and hydrochlorothiazide. However, studies have been performed for each component individually. Valsartan did not demonstrate carcinogenicity when 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, including tests with Salmonella (Ames), E. coli, Chinese hamster V79 cells, and rat micronucleus tests.

Hydrochlorothiazide also showed no evidence of carcinogenic potential in two-year feeding studies in female mice and male and female rats at doses up to approximately 600 mg/kg/day and 100 mg/kg/day, respectively. However, equivocal evidence for hepatocarcinogenicity was noted in male mice. Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay and other tests, and it had no adverse effects on the fertility of mice and rats of either sex when exposed to doses of up to 100 and 4 mg/kg, respectively, prior to mating and throughout gestation.

Animal Pharmacology and Toxicology

Based on preclinical safety and human pharmacokinetic studies, there is no indication of any adverse interaction between valsartan and hydrochlorothiazide. Valsartan had no adverse effects on the reproductive performance of male or female rats at oral doses up to 200 mg/kg/day, while hydrochlorothiazide similarly had no adverse effects on the fertility of mice and rats at the specified doses.

Storage and Handling

Valsartan and Hydrochlorothiazide is supplied in film-coated tablet form.

It should be stored at a temperature range of 20° to 25°C (68° to 77°F), with excursions permitted between 15° to 30°C (59° to 86°F) as defined by USP Controlled Room Temperature. The product must be protected from moisture and heat.

Dispensing should occur in a tight container, as specified in the USP, with a child-resistant closure when applicable.