Amlodipine, Valsartan, Hydrochlorothiazide

Description

Amlodipine/valsartan/hydrochlorothiazide is a fixed combination medication comprising amlodipine besylate, valsartan, and hydrochlorothiazide. Amlodipine besylate, a dihydropyridine calcium channel blocker, is presented as a white to pale yellow crystalline powder, with a chemical name of 3-Ethyl 5-methyl (±)-2-(2-aminoethoxy)methyl4-(o-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate, monobenzenesulfonate. Its empirical formula is C20H25ClN2O5 • C6H6O3S, and it has a molecular weight of 567.1. Valsartan, a nonpeptide angiotensin II antagonist, appears as a white to practically white fine powder, with a chemical name of N-(1-oxopentyl)-N-[[2′-(1H-tetrazol-5-yl) 1,1′-biphenyl-4-yl]methyl]-L-valine. The empirical formula for valsartan is C24H29N5O3, and its molecular weight is 435.5. Hydrochlorothiazide, a thiazide diuretic, is a white or practically white crystalline powder, 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.

The film-coated tablets of amlodipine/valsartan/hydrochlorothiazide are available in five strengths for oral administration: 5/160/12.5 mg, 10/160/12.5 mg, 5/160/25 mg, 10/160/25 mg, and 10/320/25 mg. Inactive ingredients across all strengths include microcrystalline cellulose, crospovidone, colloidal silicon dioxide, and magnesium stearate. Specific strengths contain additional inactive ingredients: the 5/160/12.5 mg and 10/320/25 mg strengths include polyethylene glycol, polyvinyl alcohol, titanium dioxide, and talc; the 5/160/25 mg strength contains lactose monohydrate, hypromellose, triacetin, D&C Yellow #10, and FD&C Yellow #6; the 10/160/12.5 mg strength includes FD&C Yellow #6, triethyl citrate, yellow iron oxide, hypromellose, and lactose monohydrate; and the 10/160/25 mg strength contains hypromellose, titanium dioxide, D&C Yellow #10, macrogol, and polysorbate.

Uses and Indications

Amlodipine/valsartan/hydrochlorothiazide 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.

This drug is not indicated for the initial treatment of hypertension.

Dosage and Administration

The recommended dosage of amlodipine/valsartan/hydrochlorothiazide is once daily. Healthcare professionals should titrate the dose as needed, up to a maximum of 10 mg amlodipine, 320 mg valsartan, and 25 mg hydrochlorothiazide.

This combination therapy 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.

Amlodipine/valsartan/hydrochlorothiazide may also be substituted for its individually titrated components, allowing for flexibility in managing patient treatment regimens.

Contraindications

Use of this product is contraindicated in the following situations:

Patients with anuria, as the absence of urine production may lead to accumulation of the drug and potential toxicity.

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 amlodipine, valsartan, or hydrochlorothiazide 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 amlodipine/valsartan/hydrochlorothiazide. It is imperative that this medication be discontinued as soon as pregnancy is detected, as drugs that act directly on the renin-angiotensin system can lead to serious injury or death to the developing fetus.

General precautions should be observed when prescribing this medication. Prior to initiation, it is essential to correct any volume depletion to mitigate the risk of hypotension. Additionally, healthcare professionals should be vigilant for potential increases in angina and/or myocardial infarction, which may occur in some patients.

Monitoring of renal function and potassium levels is recommended, particularly in patients who are susceptible to these changes. Signs of fluid or electrolyte imbalance should also be closely observed, as these can indicate complications related to the medication. Furthermore, there is a risk of exacerbation or activation of systemic lupus erythematosus, which necessitates careful patient evaluation. Acute angle-closure glaucoma is another potential risk that should be considered.

In summary, regular monitoring of renal function and potassium levels is advised for susceptible patients to ensure safe use of amlodipine/valsartan/hydrochlorothiazide.

Side Effects

Patients receiving amlodipine/valsartan/hydrochlorothiazide may experience a range of adverse reactions. The most common adverse events, occurring in 2% or more of participants, include dizziness, peripheral edema, headache, dyspepsia, fatigue, muscle spasms, back pain, nausea, and nasopharyngitis.

Serious adverse reactions have been noted, including fetal toxicity, which necessitates the discontinuation of the medication as soon as pregnancy is detected, due to the potential for injury and death to the developing fetus from drugs that act directly on the renin-angiotensin system. Other serious concerns include hypotension, which requires correction of volume depletion prior to initiation of therapy, and the potential for increased angina and/or myocardial infarction. It is advised to monitor renal function and potassium levels in susceptible patients, as well as to observe for signs of fluid or electrolyte imbalance.

Additional serious adverse reactions may include exacerbation or activation of systemic lupus erythematosus, acute angle-closure glaucoma, and anuria. Patients with known hypersensitivity to sulfonamide-derived drugs or any component of the formulation should not use this medication. Coadministration of aliskiren with amlodipine/valsartan/hydrochlorothiazide is contraindicated in patients with diabetes.

Overdosage of this medication may lead to hypotension and tachycardia, with bradycardia potentially occurring from parasympathetic (vagal) stimulation. Reports have indicated that a depressed level of consciousness, circulatory collapse, and shock can occur with valsartan. In cases of hydrochlorothiazide overdosage, the most common signs and symptoms are those associated with electrolyte depletion (such as hypokalemia, hypochloremia, and hyponatremia) and dehydration resulting from excessive diuresis.

Drug Interactions

Coadministration of simvastatin with amlodipine should not exceed a daily dose of 20 mg of simvastatin due to the potential for increased risk of adverse effects.

When antidiabetic drugs are used concurrently, dosage adjustments may be necessary to maintain glycemic control.

The use of cholestyramine or colestipol can lead to reduced absorption of thiazide diuretics, which may diminish their therapeutic efficacy.

Concurrent use of lithium increases the risk of lithium toxicity; therefore, it is essential to monitor serum lithium concentrations closely during treatment.

The concomitant use of non-steroidal anti-inflammatory drugs (NSAIDs) may elevate the risk of renal impairment and can diminish the antihypertensive effects of certain medications.

Additionally, dual inhibition of the renin-angiotensin system poses an increased risk of renal impairment, hypotension, and hyperkalemia, necessitating careful monitoring of renal function and electrolyte levels.

Packaging & NDC

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

Pediatric Use

The safety and effectiveness of amlodipine/valsartan/hydrochlorothiazide in pediatric patients have not been established. Therefore, caution should be exercised when considering this medication for use in children and adolescents, as there is insufficient data to support its use in 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 individuals. However, other reported clinical experiences have not identified significant differences in responses between geriatric patients and their younger counterparts.

In general, dose selection for elderly 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

Amlodipine/valsartan/hydrochlorothiazide can cause fetal harm when administered to a pregnant woman. 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 increase fetal and neonatal morbidity and mortality. Epidemiologic studies examining fetal abnormalities following antihypertensive use in the first trimester have not consistently distinguished 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. When pregnancy is detected, Amlodipine/valsartan/hydrochlorothiazide should be discontinued 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 in pregnancy poses increased maternal risks for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications. Additionally, hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly. Oligohydramnios in pregnant women using drugs affecting the renin-angiotensin system during the second and third trimesters can lead to reduced fetal renal function, resulting in 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 observed, alternative drug treatment should be considered.

Neonates with a history of in utero exposure to Amlodipine/valsartan/hydrochlorothiazide should be closely monitored for hypotension, oliguria, and hyperkalemia. In cases where oliguria or hypotension occurs, support for blood pressure and renal perfusion may be necessary, and exchange transfusions or dialysis could 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 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. Thiazides do not prevent or alter the course of edema, proteinuria, and hypertension (EPH) gestosis (preeclampsia) and 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 Amlodipine/valsartan/hydrochlorothiazide in human milk, as well as the 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 nursing mothers refrain from breastfeeding during treatment with Amlodipine/valsartan/hydrochlorothiazide.

Renal Impairment

Patients with renal impairment should have their renal function and potassium levels monitored, particularly in those who are susceptible to changes in these parameters. Regular assessment is essential to ensure safe and effective use of the medication in this 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. In the event of symptomatic hypotension, supportive treatment should be instituted.

Animal studies have demonstrated that single oral doses of amlodipine maleate equivalent to 40 mg/kg in mice and 100 mg/kg in rats resulted in fatalities. In dogs, single oral doses equivalent to 4 mg/kg or more (which is 11 or more times the maximum recommended human dose on a mg/m² basis) led to significant peripheral vasodilation and hypotension. Consequently, overdosage is expected to cause excessive peripheral vasodilation accompanied by marked hypotension. Although human experience with intentional overdosage of amlodipine is limited, reports indicate that marked and potentially prolonged systemic hypotension, which may progress to shock and result in fatal outcomes, has occurred.

In cases of massive overdose, it is crucial to initiate active cardiac and respiratory monitoring. Frequent blood pressure measurements are essential to assess the patient's condition. Should hypotension arise, cardiovascular support should be initiated, which includes elevating the extremities and judiciously administering fluids. If hypotension persists despite these conservative measures, the administration of vasopressors, such as phenylephrine, should be considered, with careful attention to circulating volume and urine output.

Due to the high protein binding of amlodipine, hemodialysis is unlikely to be beneficial in cases of overdosage. However, the administration of activated charcoal to healthy volunteers, either immediately or within two hours after ingestion of amlodipine, has been shown to significantly reduce amlodipine absorption.

Nonclinical Toxicology

No information is available regarding teratogenic effects associated with the Amlodipine/Valsartan/Hydrochlorothiazide combination.

Non-teratogenic effects have been evaluated through individual studies of the components. No carcinogenicity, mutagenicity, or fertility studies have been conducted specifically on the combination. However, extensive studies have been performed on amlodipine, valsartan, and hydrochlorothiazide separately.

Amlodipine maleate was administered to rats and mice in their diet for up to two years, with no evidence of carcinogenic effects observed. Mutagenicity studies indicated no drug-related effects at either the gene or chromosome level. Additionally, oral administration of amlodipine maleate at doses up to 10 mg/kg/day did not affect fertility in rats.

Similarly, valsartan demonstrated no evidence of carcinogenicity when administered in the diet to mice and rats for up to two years. Mutagenicity assays did not reveal 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 also showed no evidence of carcinogenic potential in two-year feeding studies conducted in mice and rats. It was found to be non-genotoxic in vitro, as demonstrated by the Ames mutagenicity assay and the Chinese Hamster Ovary test for chromosomal aberrations. In studies where mice and rats were exposed to hydrochlorothiazide via diet at doses of up to 100 mg/kg and 4 mg/kg, respectively, there were no adverse effects on fertility observed.

Postmarketing Experience

Patients taking hydrochlorothiazide have reported cases of non-melanoma skin cancer. It is advised that these patients protect their skin from sun exposure and undergo regular skin cancer screenings. Additionally, one of the components in the combination medication amlodipine/valsartan/hydrochlorothiazide may also be associated with non-melanoma skin cancer. Patients are encouraged to contact their healthcare provider for medical advice regarding any side effects experienced. Side effects can be reported to the FDA at 1-800-FDA-1088.

Patient Counseling

Advise patients to read the FDA-approved patient labeling (Patient Information) prior to initiating treatment with amlodipine/valsartan/hydrochlorothiazide 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 amlodipine/valsartan/hydrochlorothiazide during pregnancy. Healthcare providers should explore alternative treatment options with women who are planning to become pregnant and encourage patients to report any pregnancies to their physician as soon as possible. It is important to inform patients that amlodipine/valsartan/hydrochlorothiazide can cause harm or death to an unborn baby.

Women should be advised against breastfeeding while undergoing treatment with amlodipine/valsartan/hydrochlorothiazide.

Patients should be made aware of the risk of symptomatic hypotension, particularly during the initial days of therapy. Lightheadedness should be reported to their healthcare provider, and if syncope occurs, patients should discontinue the medication until they have consulted their physician. Caution patients that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting may lead to a significant drop in blood pressure, resulting in lightheadedness or syncope.

Patients should be instructed not to use potassium supplements or salt substitutes without prior consultation with their healthcare provider. Additionally, those taking hydrochlorothiazide should be advised to protect their skin from sun exposure and to undergo regular skin cancer screenings due to the risk of non-melanoma skin cancer.

Patients must inform their healthcare provider about all medical conditions, including any plans for pregnancy or breastfeeding, allergies to any ingredients in amlodipine/valsartan/hydrochlorothiazide, and any history of heart, liver, or kidney problems. It is also important to 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.

Patients should provide a comprehensive list of all medications they are taking, including prescription and nonprescription drugs, vitamins, and herbal supplements, as interactions with amlodipine/valsartan/hydrochlorothiazide could lead to serious side effects.

Instruct patients to take amlodipine/valsartan/hydrochlorothiazide exactly as prescribed, once daily, with or without food. If a dose is missed, patients should take it as soon as they remember unless it is close to the time of their next dose; in that case, they should skip the missed dose and resume their regular schedule.

If an overdose occurs, patients should contact their doctor, the Poison Control Center, or seek emergency medical attention.

Patients should inform all healthcare providers, including doctors and dentists, that they are taking amlodipine/valsartan/hydrochlorothiazide, especially prior to any surgical procedures or kidney dialysis.

Encourage patients to seek medical advice regarding any side effects and inform them that they may report side effects to the FDA at 1-800-FDA-1088.

Storage and Handling

The product is supplied in a tight container as per USP standards. 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). It is essential to protect the product from moisture to maintain its integrity and efficacy.

Additional Clinical Information

No further data are available.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Amlodipine, Valsartan, Hydrochlorothiazide as submitted by Strides Pharma Science Limited. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)