Exforge Hct

Description

Exforge HCT is a fixed combination of amlodipine, valsartan, and hydrochlorothiazide. It contains the besylate salt of amlodipine, a dihydropyridine calcium channel blocker (CCB). Amlodipine besylate, USP is a white to pale yellow crystalline powder, slightly soluble in water and sparingly soluble in ethanol. Its chemical name is 3-Ethyl 5-methyl (±)-2-(2-aminoethoxy)methyl-4-(o-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate, monobenzenesulfonate, with an empirical formula of C20H25ClN2O5 • C6H6O3S and a molecular weight of 567.1.

Valsartan, USP is a nonpeptide, orally active, and specific angiotensin II antagonist acting on the AT1 receptor subtype. It is a white to practically white fine powder, soluble in ethanol and methanol, and slightly soluble in water. Valsartan’s chemical name is 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.

Hydrochlorothiazide, USP is a white or practically white, practically odorless, crystalline powder. It 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. Hydrochlorothiazide is chemically described as 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide and is classified as a thiazide diuretic. Its empirical formula is C7H8ClN3O4S2, and its molecular weight is 297.73.

Exforge HCT is available as film-coated tablets containing amlodipine besylate (6.9 mg or 13.9 mg, equivalent to 5 mg or 10 mg of amlodipine respectively), with valsartan 160 mg or 320 mg, and hydrochlorothiazide 12.5 mg or 25 mg. The inactive ingredients for all strengths of the tablets include microcrystalline cellulose, crospovidone, colloidal anhydrous silica, magnesium stearate, hypromellose, macrogol 4000, and talc. The 5/160/12.5 mg strength contains titanium dioxide; the 10/160/12.5 mg strength contains titanium dioxide and yellow and red iron oxides; the 5/160/25 mg strength contains titanium dioxide and yellow iron oxide; the 10/160/25 mg and 10/320/25 mg strengths both contain yellow iron oxide.

Uses and Indications

Exforge HCT is indicated for the treatment of hypertension to lower blood pressure. Effective blood pressure reduction is associated with a decreased risk of both fatal and nonfatal cardiovascular events, including strokes and myocardial infarctions.

Exforge HCT is not indicated for the initial treatment of hypertension.

Dosage and Administration

The recommended dosing regimen for Exforge HCT is once daily. Healthcare professionals should titrate the dose as necessary, with a maximum allowable dose of 10/320/25 mg.

Exforge HCT may be utilized as an add-on or switch therapy for patients who are not adequately controlled on any two of the following antihypertensive classes: calcium channel blockers, angiotensin receptor blockers, and diuretics.

Additionally, Exforge HCT can be substituted for its individually titrated components, allowing for flexibility in managing patient therapy.

Contraindications

Use of this product is contraindicated in the following situations:

Patients with anuria, as the drug's efficacy may be compromised.

Individuals with hypersensitivity to sulfonamide-derived drugs or any component of the formulation, due to the risk of severe allergic reactions.

Coadministration of aliskiren with Exforge HCT is contraindicated in patients with diabetes, as this combination may increase the risk of adverse effects.

Warnings and Precautions

Fetal toxicity is a significant concern associated with the use of Exforge HCT. It is imperative that the medication be discontinued as soon as pregnancy is detected, as drugs that directly affect the renin-angiotensin system may lead to serious injury or death of the developing fetus.

Healthcare professionals should exercise caution regarding hypotension. It is essential to correct any volume depletion prior to initiating treatment with Exforge HCT to mitigate the risk of significant blood pressure drops. Additionally, there is a potential for increased angina and/or myocardial infarction in patients receiving this medication, necessitating careful monitoring of cardiovascular status.

Patients who are susceptible should have their renal function and potassium levels monitored regularly. This is particularly important as Exforge HCT may exacerbate or activate systemic lupus erythematosus, and healthcare providers should remain vigilant for any signs of fluid or electrolyte imbalance. Furthermore, there is a risk of acute angle-closure glaucoma, which requires immediate attention if symptoms arise.

In summary, regular laboratory tests to monitor renal function and potassium levels are recommended for patients at risk. These precautions are critical to ensure the safe use of Exforge HCT and to prevent adverse outcomes.

Side Effects

Patients receiving Exforge HCT may experience a range of adverse reactions. The most common adverse events, occurring in at least 2% of participants during clinical trials, include dizziness (8.2%), peripheral edema (6.5%), headache (5.2%), dyspepsia (2.2%), fatigue (2.2%), muscle spasms (2.2%), back pain (2.1%), nausea (2.1%), and nasopharyngitis (2.1%). Additionally, orthostatic events, such as orthostatic hypotension and postural dizziness, were observed in 0.5% of patients.

Serious adverse reactions have also been reported. A boxed warning highlights the potential for fetal toxicity; when pregnancy is detected, Exforge HCT should be discontinued as soon as possible, as drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.

Postmarketing experiences have revealed additional adverse reactions associated with the components of Exforge HCT. Amlodipine has been infrequently associated with gynecomastia, with a causal relationship remaining uncertain. Severe jaundice and hepatic enzyme elevations, consistent with cholestasis or hepatitis, have also been reported, occasionally necessitating hospitalization.

Valsartan has been linked to various blood and lymphatic disorders, including decreases in hemoglobin and hematocrit, as well as neutropenia. Hypersensitivity reactions such as angioedema have occurred, particularly in patients with a history of angioedema related to other medications, including ACE inhibitors. Other reported adverse reactions include elevated liver enzymes, hepatitis, rhabdomyolysis, impaired renal function, renal failure, alopecia, bullous dermatitis, vasculitis, and syncope.

Hydrochlorothiazide has been associated with serious conditions such as acute renal failure, aplastic anemia, erythema multiforme, pyrexia, muscle spasm, 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. Notably, hydrochlorothiazide is also associated with an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC) in white patients receiving large cumulative doses.

Drug Interactions

Co-administration of simvastatin with amlodipine should be approached with caution. It is recommended that the daily dose of simvastatin not exceed 20 mg to mitigate the risk of adverse effects.

Antidiabetic medications may require dosage adjustments when used concurrently, necessitating careful monitoring of blood glucose levels to ensure optimal glycemic control.

The absorption of thiazide diuretics can be significantly reduced by the use of bile acid sequestrants such as cholestyramine and colestipol. Therefore, it is advisable to separate the administration of these agents to maintain the therapeutic efficacy of thiazides.

Concurrent use of lithium increases the risk of lithium toxicity. It is essential to monitor serum lithium concentrations closely during this combination therapy to prevent potential toxicity.

The use of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) may elevate the risk of renal impairment and diminish the antihypertensive effects of certain medications. Clinicians should consider alternative pain management strategies and monitor renal function in patients receiving both NSAIDs and antihypertensive therapy.

Finally, dual inhibition of the renin-angiotensin system can lead to an increased risk of renal impairment, hypotension, and hyperkalemia. It is crucial to monitor renal function and serum potassium levels in patients receiving this combination to avoid serious complications.

Packaging & NDC

The table below lists all NDC Code configurations of Exforge Hct (amlodipine 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 Exforge HCT in pediatric patients have not been established. There are currently no available data to support its use in children or adolescents. Healthcare professionals should exercise caution when considering treatment options for this population.

Geriatric Use

Clinical studies of amlodipine besylate tablets did not include a sufficient number of subjects aged 65 and over to determine whether these elderly patients respond differently from younger patients. However, other reported clinical experiences have not identified significant differences in responses between elderly and younger patients.

In general, dose selection for geriatric patients should be approached with caution. It is advisable to start at the low end of the dosing range, taking into account the increased likelihood of decreased hepatic, renal, or cardiac function, as well as the presence of concomitant diseases or other drug therapies.

Elderly patients exhibit decreased clearance of amlodipine, leading to an increase in the area under the curve (AUC) of approximately 40% to 60%. This pharmacokinetic change underscores the importance of careful monitoring and potential dose adjustments in this population to ensure safety and efficacy.

Pregnancy

Exforge 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. Epidemiologic studies examining fetal abnormalities following antihypertensive use in the first trimester have not consistently differentiated between drugs affecting the renin-angiotensin system and other antihypertensive agents.

Published reports indicate cases of anhydramnios and oligohydramnios in pregnant women treated with valsartan, a component of Exforge HCT. When pregnancy is detected, it is recommended to discontinue Exforge 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 2-4% and 15-20%, respectively.

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

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 gestational age. It is important for patients and healthcare providers to recognize 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 Exforge 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 necessary 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 may cause 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 associated with risks of fetal or neonatal jaundice and thrombocytopenia, and they should not be used to treat hypertension in pregnant women. Additionally, the use of hydrochlorothiazide for other indications, such as heart disease, during pregnancy should be avoided.

Lactation

There is limited information regarding the presence of Exforge HCT in human milk, as well as its effects on breastfed infants and milk production. Hydrochlorothiazide is known to be present in human milk, while valsartan has been detected in the milk of lactating rats shortly after administration. Limited published studies indicate that amlodipine may also be present in human milk.

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

Renal Impairment

Patients with severe renal impairment (creatinine clearance CrCl < 30 mL/min) have not had the safety and effectiveness of Exforge 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 required. It is recommended to monitor renal function and potassium levels in susceptible patients.

Hepatic Impairment

Patients with hepatic impairment may experience increased exposure to amlodipine. For these individuals, the recommended initial dose of amlodipine is 2.5 mg; however, this strength is not available with Exforge HCT.

For patients with mild-to-moderate hepatic disease, no dose adjustment is necessary. Conversely, no dosing recommendations can be provided for patients with severe liver disease due to a lack of 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.

Overdosage

In cases of overdosage, limited data are available regarding the effects in humans. The most likely manifestations include hypotension and tachycardia, with the potential for bradycardia resulting from parasympathetic stimulation. Animal studies indicate that single oral doses of amlodipine maleate equivalent to 40 mg/kg and 100 mg/kg in mice and rats resulted in fatalities. Additionally, doses of 4 mg/kg or more in dogs led to significant peripheral vasodilation and hypotension.

Overdosage may result in excessive peripheral vasodilation accompanied by marked hypotension. Although experience with intentional overdosage of amlodipine in humans is limited, there have been reports of prolonged systemic hypotension and shock, which can lead to fatal outcomes.

In the event of a massive overdose, it is crucial to initiate active cardiac and respiratory monitoring, with frequent blood pressure measurements being essential. Should hypotension occur, cardiovascular support should be initiated, which includes elevating the extremities and judicious administration of fluids. If the patient remains unresponsive, the use of vasopressors such as phenylephrine should be considered.

Administration of activated charcoal to healthy volunteers within 2 hours following ingestion of amlodipine has been shown to significantly reduce the absorption of the drug.

It is also important to note that in cases of valsartan overdose, symptoms such as depressed level of consciousness, circulatory collapse, and shock have been reported. Valsartan is not effectively removed from the plasma through hemodialysis. In animal studies, single oral doses of valsartan up to 1524 mg/kg in rats and 762 mg/kg in marmosets, when combined with hydrochlorothiazide, were well tolerated without any treatment-related adverse effects. The oral LD50 of hydrochlorothiazide exceeds 10 g/kg in both mice and rats, significantly surpassing the maximum recommended human dose (MRHD) on a mg/m² basis.

Nonclinical Toxicology

No teratogenic effects have been identified in the studies conducted.

Carcinogenicity, mutagenicity, and fertility studies have not been performed with the combination of Amlodipine/Valsartan/Hydrochlorothiazide. However, individual studies on amlodipine, valsartan, and hydrochlorothiazide have been carried out. Preclinical safety and human pharmacokinetic studies indicate no toxicologically significant adverse interactions among these components.

In studies involving amlodipine maleate, rats and mice fed the drug for up to two years exhibited no evidence of carcinogenic effects. Mutagenicity studies also demonstrated no drug-related effects at either the gene or chromosome level. Additionally, there was no impact on the fertility of rats treated orally with amlodipine maleate at doses up to 10 mg amlodipine/kg/day.

For valsartan, two-year dietary administration in mice and rats revealed no evidence of carcinogenicity. Mutagenicity assays did not indicate any valsartan-related effects at the gene or chromosome level. Furthermore, valsartan did not adversely affect the reproductive performance of male or female rats at oral doses of up to 200 mg/kg/day.

Hydrochlorothiazide was evaluated in two-year feeding studies in mice and rats, which uncovered no evidence of carcinogenic potential. It was also found to be non-genotoxic in vitro, as demonstrated by the Ames mutagenicity assay and other tests. Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex at doses of up to 100 mg/kg and 4 mg/kg, respectively.

Postmarketing Experience

The following additional adverse reactions have been reported in the postmarketing experience. 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.

Amlodipine: Infrequent reports of gynecomastia have been noted, with an uncertain causal relationship. Additionally, jaundice and elevations in hepatic enzymes, primarily consistent with cholestasis or hepatitis, have been reported, with some cases severe enough to necessitate hospitalization.

Valsartan: The following adverse reactions have been reported in association with valsartan or valsartan/hydrochlorothiazide:

• Blood and Lymphatic: Decrease in hemoglobin, decrease in hematocrit, and neutropenia.

• Hypersensitivity: Cases of angioedema have been documented, particularly in patients with a history of angioedema related to other medications, including ACE inhibitors. Exforge HCT should not be re-administered to patients with a history of angioedema.

• Digestive: Reports of elevated liver enzymes and hepatitis.

• Musculoskeletal: Instances of rhabdomyolysis.

• Renal: Impaired renal function and renal failure.

• Dermatologic: Alopecia and bullous dermatitis.

• Vascular: Cases of vasculitis.

• Nervous System: Reports of syncope.

Hydrochlorothiazide: The following additional adverse reactions have been reported:

• Acute renal failure, renal disorder, aplastic anemia, erythema multiforme, pyrexia, muscle spasm, 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 few patients with hypercalcemia and hypophosphatemia on prolonged thiazide therapy, necessitating further diagnostic evaluation if hypercalcemia occurs.

• Hydrochlorothiazide is associated with an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC) in white patients taking large cumulative doses. The increased risk for SCC in the overall population 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 in white patients taking a cumulative dose of ≥ 50,000 mg.

Patient Counseling

Healthcare providers should advise patients to read the FDA-approved patient labeling (Patient Information) prior to initiating treatment with Exforge HCT and each time they receive a refill, as there may be new information.

For female patients of childbearing age, it is crucial to discuss the potential consequences of exposure to Exforge HCT during pregnancy. Providers should explore alternative treatment options with women who are planning to become pregnant and encourage patients to report any pregnancies to their healthcare provider as soon as possible.

In terms of lactation, healthcare providers should inform women that breastfeeding is not recommended during treatment with Exforge HCT.

Patients should be made aware of 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 Exforge HCT and consult their physician. Additionally, providers should caution patients that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting can lead to a significant drop in blood pressure, resulting in lightheadedness or syncope.

Healthcare providers should advise patients against using salt substitutes without prior consultation, as potassium supplements may interact with Exforge HCT.

For patients taking hydrochlorothiazide, it is important to instruct them 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 plans, allergies to any ingredients in Exforge HCT, and any history of heart, liver, or kidney problems. They should also disclose any instances of vomiting or diarrhea, gallstones, lupus, low potassium or magnesium levels, high calcium levels, high uric acid levels, or previous reactions such as angioedema to other blood pressure medications.

It is essential for patients to provide a complete list of all medications they are taking, including prescription and nonprescription drugs, vitamins, and herbal supplements, as interactions with Exforge HCT could lead to serious side effects. Patients should be encouraged to maintain this list and present it to their healthcare provider or pharmacist when receiving new medications.

Patients should be instructed to take Exforge HCT exactly as prescribed, once daily, and can take it with or without food. If a dose is missed, they should take it as soon as they remember unless it is close to the time of the next dose; in that case, they should skip the missed dose and resume the regular dosing schedule. Patients should be informed to seek immediate medical attention if they suspect an overdose.

Finally, patients should be advised to inform all healthcare providers, including dentists, that they are taking Exforge HCT, especially prior to undergoing surgery or kidney dialysis. They should also report any side effects that are bothersome or persistent to their healthcare provider.

Storage and Handling

The product is supplied in a tight container to ensure integrity and stability, in accordance with USP guidelines. 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 standards. Additionally, it is essential to protect the product from moisture to maintain its quality and efficacy.

Additional Clinical Information

Postmarketing experience has revealed several adverse effects associated with the components of the combination therapy. Amlodipine has been infrequently associated with gynecomastia, though the causal relationship remains uncertain. Additionally, jaundice and hepatic enzyme elevations, primarily linked to cholestasis or hepatitis, have been reported, with some cases necessitating hospitalization.

Valsartan has been associated with a range of hematological effects, including decreases in hemoglobin and hematocrit, as well as neutropenia. Clinicians should be aware of the risk of angioedema, particularly in patients with a history of this reaction to other medications, such as ACE inhibitors; re-administration of Exforge HCT is contraindicated in these cases. Other reported effects include elevated liver enzymes, hepatitis, rhabdomyolysis, impaired renal function, renal failure, alopecia, bullous dermatitis, vasculitis, and syncope.

Hydrochlorothiazide has been linked to acute renal failure, renal disorders, aplastic anemia, erythema multiforme, pyrexia, muscle spasms, asthenia, acute angle-closure glaucoma, and worsening of diabetes control. It may also cause electrolyte imbalances, including hypokalemia, hyponatremia, hypomagnesemia, and hypercalcemia, as well as hypochloremic alkalosis and impotence. Notably, prolonged thiazide therapy has been associated with pathological changes in the parathyroid gland in patients with hypercalcemia and hypophosphatemia. 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 additional risk of one SCC case per 16,000 patients per year in the general population and one case per 6,700 patients per year in those taking ≥ 50,000 mg cumulatively.

FDA Insert (PDF)

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

View full prescribing information (PDF)