Diovan Hct

Description

Diovan HCT (valsartan and hydrochlorothiazide, USP) is a combination of valsartan, an orally active, specific angiotensin II receptor blocker (ARB), and hydrochlorothiazide, a diuretic. Valsartan is chemically described as N-(1-oxopentyl)-N-[[2′-(1H-tetrazol-5-yl)1,1′-biphenyl-4-yl]methyl]-L-Valine, with 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 described 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. Hydrochlorothiazide is a white, or practically white, practically odorless, crystalline powder, slightly soluble in water and freely soluble in sodium hydroxide solution, n-butylamine, and dimethylformamide. Diovan HCT tablets are formulated for oral administration and contain valsartan and hydrochlorothiazide in the following strengths: 80/12.5 mg, 160/12.5 mg, 160/25 mg, 320/12.5 mg, and 320/25 mg. The inactive ingredients of the tablets include colloidal silicon dioxide, crospovidone, hydroxypropyl methylcellulose, iron oxides, magnesium stearate, microcrystalline cellulose, polyethylene glycol, talc, and titanium dioxide.

Uses and Indications

Diovan HCT is indicated for the treatment of hypertension to lower blood pressure in patients who are not adequately controlled with monotherapy. It may also be used as initial therapy in patients who are likely to require multiple medications to achieve their blood pressure goals.

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

There are no teratogenic or nonteratogenic effects associated with Diovan HCT.

Dosage and Administration

The recommended dosage is once daily, with titration as needed, up to a maximum dose of 320 mg of valsartan and 25 mg of hydrochlorothiazide (HCTZ). This medication may be utilized as add-on or switch therapy for patients who are not adequately controlled on any of the individual components, valsartan or HCTZ. Additionally, it may be substituted for the titrated components, ensuring that the total daily dose 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 the following situations:

Patients with anuria or hypersensitivity to any sulfonamide-derived drugs or any component of the formulation should not use this product. Additionally, aliskiren should not be coadministered with Diovan HCT in patients with diabetes due to potential adverse effects.

Warnings and Precautions

When pregnancy is detected, Diovan HCT should be discontinued as soon as possible due to the risk of fetal toxicity. Medications that act directly on the renin-angiotensin system have the potential to cause injury or death to the developing fetus.

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

For patients at risk, it is imperative to conduct laboratory tests to monitor renal function and potassium levels to ensure safe use of the medication.

Side Effects

Patients receiving Diovan HCT have reported a range of adverse reactions, which can be categorized by frequency and seriousness.

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. Dizziness was noted in 6% of patients treated with Diovan HCT as initial therapy. Less common adverse reactions include dose-related orthostatic effects, which were reported in fewer than 1% of participants.

Postmarketing experience has revealed additional serious adverse reactions. Hypersensitivity reactions, including angioedema, have been reported, particularly in patients with a history of angioedema associated with other medications, such as ACE inhibitors; Diovan HCT should not be re-administered to these individuals. Other serious adverse reactions include elevated liver enzymes, reports of hepatitis, rhabdomyolysis, impaired renal function, and syncope.

Specific to hydrochlorothiazide, several adverse reactions have been identified, including acute renal failure, renal disorders, aplastic anemia, erythema multiforme, pyrexia, muscle spasms, asthenia, and acute angle-closure glaucoma. Patients may also experience worsening of diabetes control, hypokalemia, increased blood lipids, hyponatremia, hypomagnesemia, hypercalcemia, hypochloremic alkalosis, impotence, and visual impairment.

Furthermore, hydrochlorothiazide has been associated with an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC) in white patients who have received large cumulative doses.

Clinicians should be aware of important warnings associated with Diovan HCT. Fetal toxicity is a significant concern, as drugs affecting the renin-angiotensin system can cause injury or death to a developing fetus; therefore, discontinuation of Diovan HCT is advised upon detection of pregnancy. It is also crucial to correct any volume depletion prior to initiation of therapy to avoid hypotension. Monitoring for signs of fluid or electrolyte imbalance is recommended, along with renal function and potassium levels in susceptible patients. Additionally, exacerbation or activation of systemic lupus erythematosus may occur with use, and acute angle-closure glaucoma is a potential risk.

Drug Interactions

There are currently no documented drug interactions associated with this medication. Additionally, there are no known interactions with laboratory tests. As such, no specific recommendations for dosage adjustments or monitoring are warranted at this time.

Packaging & NDC

The table below lists all NDC Code configurations of Diovan Hct (valsartan and hydrochlorothiazide), the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

The safety and effectiveness of Diovan HCT in pediatric patients have not been established. Therefore, its use in this population is not recommended until further data are available.

Geriatric Use

In controlled clinical trials of Diovan HCT, 764 patients (17.5%) treated with valsartan-hydrochlorothiazide were aged 65 years and older, while 118 patients (2.7%) were aged 75 years and older. The data indicate that there is no overall difference in the efficacy or safety of valsartan-hydrochlorothiazide between geriatric patients and younger patients.

However, it is important to note that greater sensitivity to the medication may be present in some elderly individuals. Therefore, healthcare providers should exercise caution when prescribing valsartan-hydrochlorothiazide to geriatric patients, considering potential variations in response and the need for careful monitoring. Dose adjustments may be warranted based on individual patient characteristics and clinical response.

Pregnancy

Diovan HCT can cause fetal harm when administered to pregnant patients. The use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy is associated with reduced fetal renal function, which can lead to increased fetal and neonatal morbidity and mortality. Published reports have documented cases of anhydramnios and oligohydramnios in pregnant women treated with valsartan, a component of Diovan HCT.

When pregnancy is detected, it is recommended to discontinue Diovan HCT 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 approximately 2-4% and 15-20%, respectively.

Hypertension in pregnancy poses increased maternal risks, including pre-eclampsia, gestational diabetes, premature delivery, and delivery complications such as the need for cesarean section and postpartum hemorrhage. Additionally, hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Therefore, pregnant women with hypertension should be carefully monitored and managed.

Oligohydramnios in pregnant women using drugs affecting the renin-angiotensin system during the second and third trimesters can result in reduced fetal renal function, leading to 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 the week of gestation. It is important to note that oligohydramnios may not manifest until after the fetus has sustained irreversible injury. If oligohydramnios is observed, alternative drug treatment should be considered.

Neonates with a history of in utero exposure to Diovan HCT should be closely observed for hypotension, oliguria, and hyperkalemia. In cases where oliguria or hypotension occurs, it is essential to support blood pressure and renal perfusion, and exchange transfusions or dialysis may be required to reverse hypotension and restore renal function.

Thiazides, including hydrochlorothiazide, can cross the placenta, with concentrations in the umbilical vein approaching those in maternal plasma. Hydrochlorothiazide has been associated with placental hypoperfusion and can accumulate in the amniotic fluid, with reported concentrations up to 19 times higher than in umbilical vein plasma. The use of thiazides during pregnancy is linked to a risk of fetal or neonatal jaundice or thrombocytopenia. Furthermore, thiazides do not prevent or alter the course of edema, proteinuria, and hypertension (EPH) gestosis (pre-eclampsia) and should not be used to treat hypertension in pregnant women. The use of hydrochlorothiazide for other indications, such as heart disease, during pregnancy should also be avoided.

Lactation

There is limited information regarding the presence of Diovan HCT in human milk, as well as its effects on breastfed infants and milk production. Valsartan, one of the components of Diovan HCT, has been detected in the milk of lactating rats 15 minutes after oral administration of a 3 mg/kg dose. Hydrochlorothiazide, the other component, is also present in human breast milk.

Due to the potential for serious adverse reactions in breastfed infants, it is advised that nursing women refrain from breastfeeding during treatment with Diovan HCT.

Renal Impairment

Patients with severe renal impairment (creatinine clearance CrCl ≤ 30 mL/min) have not had the safety and effectiveness of Diovan HCT 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. It is recommended to monitor renal function and potassium levels in susceptible patients to ensure safety during treatment.

Hepatic Impairment

Patients with hepatic impairment do not require dose adjustments for mild-to-moderate liver disease. However, no dosing recommendations can be provided for patients with severe liver disease due to the lack of available data.

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. Therefore, careful monitoring of these parameters is advised in this patient population to prevent potential complications.

Overdosage

Limited data are available regarding overdosage in humans. Manifestations of overdosage may include hypotension, tachycardia, bradycardia, depressed level of consciousness, circulatory collapse, and shock. In the event of symptomatic hypotension, it is recommended to institute supportive treatment to manage the patient's condition effectively.

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; however, potential signs and symptoms of overdosage may include electrolyte depletion and dehydration resulting from excessive diuresis.

Toxicological studies in rats and marmosets have demonstrated that single oral doses of valsartan up to 1524 mg/kg and hydrochlorothiazide up to 476 mg/kg did not show adverse effects. These doses represent 46.5 and 23 times the maximum recommended human dose (MRHD) of valsartan, and 188 and 113 times the MRHD of hydrochlorothiazide, respectively. Furthermore, valsartan exhibited no grossly observable adverse effects at single oral doses up to 2000 mg/kg in rats and 1000 mg/kg in marmosets, with the exception of salivation, diarrhea, and vomiting observed at the highest doses.

The oral LD50 of hydrochlorothiazide is greater than 10 g/kg in both mice and rats, which corresponds to 2027 and 4054 times the MRHD on a mg/m² basis. This information underscores the need for careful monitoring and management in cases of suspected overdosage.

Nonclinical Toxicology

No information is available regarding teratogenic effects.

Non-teratogenic effects have been evaluated for valsartan and hydrochlorothiazide, both individually and in combination. No carcinogenicity, mutagenicity, or fertility studies have been conducted specifically on the combination; however, studies on each compound have been performed. Preclinical safety and human pharmacokinetic studies indicate no adverse interactions between valsartan and hydrochlorothiazide.

Valsartan was administered in the diet to mice and rats for up to 2 years at doses of 160 mg/kg/day and 200 mg/kg/day, respectively, with no evidence of carcinogenicity observed. These doses correspond to 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. Additionally, valsartan did not adversely affect the reproductive performance of male or female rats at oral doses up to 200 mg/kg/day, which is approximately 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.

In terms of genotoxicity, hydrochlorothiazide was not found to be genotoxic in vitro in the Ames mutagenicity assay using various Salmonella typhimurium strains and in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations. In vivo assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene also showed no genotoxic effects. Positive results were noted 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 at an unspecified concentration.

Hydrochlorothiazide did not adversely affect the fertility of either male or female mice and rats 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, respectively.

Postmarketing Experience

The following additional adverse reactions have been reported in the postmarketing experience with valsartan and valsartan/hydrochlorothiazide. These reactions are derived from voluntary reports and surveillance programs, and their frequency and causal relationship to drug exposure cannot be reliably established.

Hypersensitivity reactions, including angioedema, have been noted, with some patients having a history of angioedema associated with other medications, such as ACE inhibitors. It is advised that Diovan HCT not be re-administered to patients with a history of angioedema.

Digestive system-related events include elevated liver enzymes and reports of hepatitis. Musculoskeletal events such as rhabdomyolysis have also been reported. Renal adverse events include impaired renal function. Dermatologic reactions consist of alopecia and bullous dermatitis, while vascular events include vasculitis. Additionally, syncope has been reported as a nervous system-related event.

In the postmarketing experience with hydrochlorothiazide, a range of additional adverse reactions has been documented, including acute renal failure, renal disorders, aplastic anemia, erythema multiforme, pyrexia, muscle spasms, asthenia, acute angle-closure glaucoma, bone marrow failure, worsening of diabetes control, hypokalemia, increased blood lipids, hyponatremia, hypomagnesemia, hypercalcemia, hypochloremic alkalosis, impotence, and visual impairment.

Pathological changes in the parathyroid gland have been observed in a limited number of patients on prolonged thiazide therapy, particularly in those with hypercalcemia and hypophosphatemia, necessitating further diagnostic evaluation if hypercalcemia occurs.

Hydrochlorothiazide has been associated with an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC), in white patients receiving large cumulative doses. Data from a study conducted in the Sentinel System indicate that the overall increased risk for SCC is approximately one additional case per 16,000 patients per year, with a higher risk of approximately one additional SCC case for every 6,700 patients per year among white patients taking a cumulative dose of ≥ 50,000 mg.

Patient Counseling

Advise patients to read the FDA-approved patient labeling (Patient Information) prior to initiating treatment with Diovan HCT and with each refill, as there may be new information. It is important to emphasize that this leaflet does not replace discussions with their healthcare provider regarding their condition and treatment. Patients should be encouraged to ask their doctor or pharmacist any questions they may have about Diovan HCT.

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

Patients should be informed about the risk of symptomatic hypotension, particularly during the initial days of therapy. Lightheadedness may occur, and patients should be instructed to report this to their healthcare provider. In the event of syncope, patients should discontinue Diovan HCT and consult their physician. It is important to caution all patients that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting can lead to a significant drop in blood pressure, resulting in lightheadedness and potential syncope.

Advise patients against using salt substitutes without prior consultation with their healthcare provider, as potassium supplements may interact with Diovan HCT. For those taking hydrochlorothiazide, instruct patients to protect their skin from sun exposure and to undergo regular skin cancer screenings due to the risk of non-melanoma skin cancer.

Patients should be reminded to inform their healthcare provider about all medical conditions, including pregnancy status, breastfeeding, liver or kidney problems, history of gallstones, lupus, low potassium or magnesium levels, high calcium levels, high uric acid levels, and any previous reactions such as angioedema to other blood pressure medications.

It is essential for patients to disclose all medications they are currently taking, including prescription and nonprescription drugs, vitamins, and herbal supplements, as interactions with Diovan HCT could lead to serious side effects. Patients should maintain an updated list of their medications to share with their healthcare provider and should consult their doctor or pharmacist before starting any new medications to ensure safety.

Patients are encouraged to seek medical advice regarding any side effects experienced during treatment. They may also report side effects to the FDA at 1-800-FDA-1088.

Storage and Handling

The product is supplied in a tight container to ensure its integrity and stability. It should be stored at a temperature range of 20°C to 25°C (68°F to 77°F), with permissible excursions between 15°C and 30°C (59°F and 86°F) as defined by USP Controlled Room Temperature guidelines. It is essential to protect the product from moisture to maintain its quality and efficacy.

Additional Clinical Information

Postmarketing experience has revealed several additional adverse reactions associated with valsartan and valsartan/hydrochlorothiazide. Clinicians should be aware that angioedema has been reported, particularly in patients with a history of angioedema related to ACE inhibitors; thus, Diovan HCT should not be re-administered to these individuals. Other reported adverse reactions include elevated liver enzymes, hepatitis, rhabdomyolysis, impaired renal function, alopecia, bullous dermatitis, vasculitis, and syncope.

For hydrochlorothiazide, additional adverse reactions noted include acute renal failure, aplastic anemia, erythema multiforme, pyrexia, muscle spasm, asthenia, acute angle-closure glaucoma, bone marrow failure, worsening diabetes control, hypokalemia, increased blood lipids, hyponatremia, hypomagnesemia, hypercalcemia, hypochloremic alkalosis, impotence, and visual impairment. Prolonged thiazide therapy has been associated with pathological changes in the parathyroid gland in patients with hypercalcemia and hypophosphatemia, necessitating further diagnostic evaluation if hypercalcemia occurs. Furthermore, hydrochlorothiazide is linked to an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC) in white patients receiving high cumulative doses, with an estimated risk increase of one additional SCC case per 6,700 patients per year for those taking ≥ 50,000 mg.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Diovan Hct as submitted by Novartis Pharmaceuticals Corporation. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)