Diovan Hct

Description

Diovan HCT (valsartan and hydrochlorothiazide, USP) is a pharmaceutical formulation that combines valsartan, an orally active angiotensin II receptor blocker (ARB) specific to the AT1 receptor subtype, with hydrochlorothiazide, a thiazide diuretic. Valsartan is a nonpeptide molecule with the chemical structure N-(1-oxopentyl)-N-[[2′-(1H-tetrazol-5-yl)1,1′-biphenyl-4-yl]methyl]-L-Valine, characterized by 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, chemically defined as 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide, is a white or practically white, odorless crystalline powder. Its empirical formula is C7H8ClN3O4S2, with a molecular weight of 297.73. Hydrochlorothiazide is 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.

Diovan HCT tablets are designed 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. The formulation includes inactive ingredients such as colloidal silicon dioxide, crospovidone, hydroxypropyl methylcellulose, iron oxides, magnesium stearate, microcrystalline cellulose, polyethylene glycol, talc, and titanium dioxide.

Uses and Indications

Diovan HCT (valsartan and hydrochlorothiazide, USP) is indicated for the treatment of hypertension. This medication may be utilized in patients whose blood pressure is not adequately controlled with monotherapy. Additionally, Diovan HCT may serve as initial therapy in patients who are likely to require multiple medications to achieve their blood pressure goals.

The selection of Diovan HCT as initial therapy for hypertension should be based on a thorough assessment of the potential benefits and risks associated with its use. It is particularly relevant for patients with stage 2 hypertension, who are at an increased risk for cardiovascular events, including strokes, heart attacks, heart failure, kidney failure, and vision problems. Therefore, prompt treatment in this population is clinically significant.

The decision to initiate combination therapy with Diovan HCT should be individualized, taking into account factors such as baseline blood pressure, target blood pressure goals, and the likelihood of achieving these goals with a combination therapy compared to monotherapy. It is important to recognize that individual blood pressure targets may vary based on the patient's specific risk profile.

Dosage and Administration

The usual starting dose of Diovan HCT is 160/12.5 mg administered once daily. After 1 to 2 weeks of therapy, the dosage may be increased as needed to achieve optimal blood pressure control, with a maximum dose of 320/25 mg once daily.

Diovan HCT can be taken with or without food and may be used in conjunction with other antihypertensive agents. The maximum antihypertensive effects are typically observed within 2 to 4 weeks following any dose adjustment.

For elderly patients, no initial dosage adjustment is necessary. In patients with renal impairment, Diovan HCT may be administered 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 Diovan HCT is not recommended.

In patients with hepatic impairment, caution is advised when dosing Diovan HCT. It is recommended to initiate treatment with a lower dose and to titrate slowly.

For patients whose blood pressure is inadequately controlled with valsartan (or another angiotensin receptor blocker) alone or hydrochlorothiazide alone, a switch to combination therapy with Diovan HCT may be considered. The clinical response should be evaluated after 3 to 4 weeks of therapy, and if blood pressure remains uncontrolled, the dose may be titrated up to a maximum of 320/25 mg.

Diovan HCT may also be used as a replacement therapy for the titrated components.

Contraindications

Diovan HCT (valsartan and hydrochlorothiazide, USP) is contraindicated in patients with a known hypersensitivity to any component of the formulation. Additionally, due to the presence of hydrochlorothiazide, the use of this product is contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs.

Warnings and Precautions

The use of Diovan HCT is contraindicated in pregnancy. It is imperative that the medication be discontinued immediately upon confirmation of pregnancy, as agents that directly affect the renin-angiotensin system have the potential to cause significant harm, including injury or death, to the developing fetus.

No additional general precautions or specific laboratory tests have been identified for the safe use of Diovan HCT. Healthcare professionals are advised to remain vigilant and monitor patients for any adverse effects or changes in health status while on this medication.

Side Effects

Patients receiving valsartan-hydrochlorothiazide may experience a range of adverse reactions, which can be categorized by frequency and seriousness.

Common adverse reactions observed in clinical trials include nasopharyngitis (2.4% vs. 1.9% in placebo), headache, and dizziness. Other adverse reactions occurring in more than 0.2% of patients treated with valsartan-hydrochlorothiazide in controlled clinical trials encompass various systems:

• Cardiovascular: Palpitations, tachycardia

• Ear and Labyrinth: Tinnitus, vertigo

• Gastrointestinal: Dyspepsia, diarrhea, flatulence, dry mouth, nausea, abdominal pain, upper abdominal pain, vomiting

• General and Administration Site Conditions: Asthenia, chest pain, fatigue, peripheral edema, pyrexia

• Infections and Infestations: Bronchitis, acute bronchitis, influenza, gastroenteritis, sinusitis, upper respiratory tract infection, urinary tract infection

• Investigations: Increased blood urea

• Musculoskeletal: Arthralgia, back pain, muscle cramps, myalgia, pain in extremity

• Nervous System: Postural dizziness, paresthesia, somnolence

• Psychiatric: Anxiety, insomnia

• Renal and Urinary: Pollakiuria

• Reproductive System: Erectile dysfunction

• Respiratory, Thoracic and Mediastinal: Dyspnea, cough, nasal congestion, pharyngolaryngeal pain, sinus congestion

• Skin and Subcutaneous Tissue: Hyperhidrosis, rash

• Vascular: Hypotension

Less frequent adverse reactions include abnormal vision, anaphylaxis, bronchospasm, constipation, depression, dehydration, decreased libido, dysuria, epistaxis, flushing, gout, increased appetite, muscle weakness, pharyngitis, pruritus, sunburn, syncope, and viral infection.

Specific to valsartan, dry cough was reported in 2.6% of patients compared to 7.9% in those receiving ACE inhibitors. Other reactions associated with valsartan include chest pain, syncope, anorexia, vomiting, and angioedema. Hydrochlorothiazide has been linked to additional adverse reactions, including weakness, pancreatitis, intrahepatic cholestatic jaundice, sialadenitis, cramping, gastric irritation, aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, thrombocytopenia, hypersensitivity reactions such as purpura and photosensitivity, metabolic changes like hyperglycemia and hyperuricemia, muscle spasm, restlessness, renal failure, interstitial nephritis, and severe skin reactions such as erythema multiforme and exfoliative dermatitis.

Postmarketing experience has revealed rare occurrences of hypersensitivity reactions, including angioedema, elevated liver enzymes, impaired renal function, hyperkalemia, alopecia, vasculitis, and syncope. Additionally, there have been rare reports of rhabdomyolysis in patients receiving angiotensin II receptor blockers.

A boxed warning is included to advise against the use of valsartan-hydrochlorothiazide in pregnancy. It is critical to discontinue the medication 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.

Drug Interactions

Valsartan may interact with other antihypertensive agents, resulting in additive effects on blood pressure. Caution is advised when combining these medications, and monitoring of blood pressure is recommended to ensure therapeutic efficacy and safety.

Coadministration of potassium supplements or salt substitutes containing potassium with Diovan HCT should be avoided unless specifically directed by a physician, as this combination may lead to hyperkalemia. Regular monitoring of potassium levels is advisable in patients receiving this combination.

The concomitant use of non-steroidal anti-inflammatory drugs (NSAIDs) may diminish the antihypertensive effect of valsartan. Patients should be monitored for blood pressure changes when these agents are used together.

Lithium levels may increase when administered with valsartan, necessitating regular monitoring of lithium concentrations to avoid toxicity.

Hydrochlorothiazide, when used in conjunction with other antihypertensive agents, may enhance their effects and increase the risk of hypotension. Additionally, it may cause hypokalemia when combined with other diuretics, warranting careful monitoring of serum potassium levels.

Hydrochlorothiazide may also induce changes in laboratory test results, including elevated blood urea nitrogen (BUN) and serum creatinine levels. Monitoring of renal function is recommended during treatment.

Furthermore, hydrochlorothiazide can affect glucose tolerance, potentially leading to hyperglycemia. Patients with diabetes or at risk for diabetes should have their blood glucose levels monitored regularly.

Electrolyte imbalances, particularly hypokalemia, may occur with hydrochlorothiazide use; therefore, monitoring of serum electrolytes is recommended. Additionally, this medication may elevate uric acid levels, which could precipitate gout in susceptible individuals. Regular assessment of uric acid levels may be warranted in these patients.

Packaging & NDC

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

Pediatric Use

Diovan HCT has not been studied in pediatric patients under 18 years of age. Therefore, safety and efficacy in this population have not been established. Healthcare professionals should exercise caution when considering the use of Diovan HCT in children and adolescents, as there is insufficient data to support its use in these age groups.

Geriatric Use

Elderly patients exhibit a 70% higher exposure to valsartan, as measured by the area under the curve (AUC), and a 35% longer half-life compared to younger patients. Despite these pharmacokinetic differences, no dosage adjustment is necessary for elderly patients. Initial dosage adjustments are also not required for this population.

Elderly patients may follow the usual regimens of therapy with Diovan HCT, provided that their creatinine clearance is greater than 30 mL/min. In cases of more severe renal impairment, the use of loop diuretics is preferred over thiazides; therefore, Diovan HCT is not recommended for these patients.

Healthcare providers should exercise caution and monitor renal function closely in geriatric patients, particularly those with compromised renal status.

Pregnancy

Diovan HCT (valsartan and hydrochlorothiazide) is associated with significant risks to the fetus and infant, including low blood pressure, poor development of skull bones, kidney failure, and potential death. Due to these serious risks, it is advised that Diovan HCT be discontinued as soon as pregnancy is detected.

Female patients of childbearing age are encouraged to discuss alternative treatment options with their healthcare provider if they are planning to become pregnant. Additionally, women who become pregnant while using Diovan HCT should notify their physician immediately to ensure appropriate management and care.

In summary, the use of Diovan HCT during pregnancy is contraindicated due to the potential for severe fetal harm, and healthcare professionals should counsel patients accordingly to avoid exposure during this critical period.

Lactation

Hydrochlorothiazide is excreted in breast milk. While it crosses the placenta, it does not cross the blood-brain barrier. Due to the potential effects on the nursing infant, lactating mothers should choose either to take Diovan HCT or to breast-feed, but not both.

Renal Impairment

There is no specific information regarding dosage adjustments, special monitoring, or safety considerations for patients with renal impairment. Healthcare professionals should exercise caution when prescribing to patients with reduced kidney function, as the absence of detailed guidance necessitates careful clinical judgment. Regular monitoring of renal function may be advisable in this patient 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; however, bradycardia may occur due to parasympathetic (vagal) stimulation. Additional severe effects reported include depressed level of consciousness, circulatory collapse, and shock.

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, and 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 those associated with electrolyte depletion, such as 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.

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 maximum recommended human dose on a mg/m² basis. The oral LD50 of hydrochlorothiazide exceeds 10 g/kg in both mice and rats, equating to 2027 and 4054 times, respectively, the maximum recommended human dose on a mg/m² basis.

Nonclinical Toxicology

Drugs that act directly on the renin-angiotensin system have been associated with potential injury and even death to the developing fetus. Therefore, it is recommended to discontinue Diovan HCT as soon as pregnancy is detected.

There are rare reports of angioedema associated with the use of this medication. Additionally, hydrochlorothiazide, one of the components of Diovan HCT, may exacerbate or activate lupus in susceptible individuals.

In nonclinical studies, single oral doses of valsartan up to 1524 mg/kg in rats and 762 mg/kg in marmosets, in combination with hydrochlorothiazide at doses up to 476 mg/kg and 238 mg/kg, respectively, were very 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.

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 observed in rats and vomiting in marmosets at the highest dose. 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.

Postmarketing Experience

Additional adverse reactions have been reported in the postmarketing experience of valsartan and valsartan/hydrochlorothiazide. These include rare cases of angioedema classified under hypersensitivity, elevated liver enzymes and very rare instances of hepatitis within the digestive category, and impaired renal function noted in renal assessments. Clinical laboratory tests have indicated occurrences of hyperkalemia. Dermatologic reactions include reports of alopecia, while vascular events have involved vasculitis. Additionally, syncope has been documented in the nervous system category.

There have also been rare reports of rhabdomyolysis in patients receiving angiotensin II receptor blockers. It is important to note that these reactions are reported voluntarily from a population of uncertain size, making it challenging to reliably estimate their frequency or establish a causal relationship to drug exposure.

Patient Counseling

Healthcare providers should advise female patients of childbearing age that the use of Diovan HCT, which acts on the renin-angiotensin system, during pregnancy can lead to serious complications for the fetus and infant. These complications may include low blood pressure, poor development of skull bones, kidney failure, and even death. It is important to discuss alternative treatment options with women who are planning to become pregnant. Patients who become pregnant while using Diovan HCT should notify their physician immediately.

Patients receiving Diovan HCT should be cautioned about the potential for symptomatic hypotension, particularly during the initial days of therapy. They should be informed that lightheadedness may occur and should be reported to the prescribing physician. In the event of syncope, patients should discontinue Diovan HCT and consult their physician before resuming treatment. Additionally, patients should be made aware that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting can exacerbate the risk of significant drops in blood pressure, leading to lightheadedness and possible syncope.

Patients should also be instructed not to use potassium supplements or salt substitutes containing potassium without first consulting their prescribing physician.

It is critical to emphasize to patients the importance of avoiding the use of Diovan HCT during pregnancy. If pregnancy is detected, Diovan HCT should be discontinued as soon as possible, as medications that act directly on the renin-angiotensin system can cause injury or death to the developing fetus.

Storage and Handling

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

Additional Clinical Information

Patients receiving Diovan HCT should be aware that the medication can be taken with or without food and may be combined with other antihypertensive agents. It is crucial for patients to adhere to the prescribed dosage, which is typically once daily, as adjustments may be necessary based on individual response.

Clinicians should counsel female patients of childbearing age about the potential risks associated with the use of Diovan HCT during pregnancy, including serious fetal and infant complications. Patients should also be informed about the possibility of symptomatic hypotension, particularly during the initial days of treatment, and advised to report any occurrences of lightheadedness or syncope. Additionally, patients should be cautioned against the use of potassium supplements or salt substitutes containing potassium without prior consultation. Postmarketing experience has revealed rare adverse reactions, including angioedema, elevated liver enzymes, impaired renal function, hyperkalemia, alopecia, vasculitis, syncope, and rare cases of rhabdomyolysis.

FDA Insert (PDF)

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

View full prescribing information (PDF)