Amlodipine besylate/Valsartan/Hydrochlorothiazide

Description

Amlodipine, valsartan and hydrochlorothiazide tablets, USP are a fixed combination of amlodipine besylate, valsartan, and hydrochlorothiazide, formulated for oral administration in five strengths: 5/160/12.5 mg, 10/160/12.5 mg, 5/160/25 mg, 10/160/25 mg, and 10/320/25 mg.

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)methyl-4(o-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate, monobenzenesulfonate. Its molecular 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. Its molecular formula 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 a molecular formula of C7H8ClN3O4S2 and a molecular weight of 297.73.

The inactive ingredients across all tablet strengths include colloidal silicon dioxide, crospovidone, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, and talc. Specific strengths contain additional components: the 5/160/12.5 mg strength includes titanium dioxide; the 10/160/12.5 mg strength contains titanium dioxide and yellow and red iron oxides; the 5/160/25 mg strength has titanium dioxide and yellow iron oxide; while the 10/160/25 mg and 10/320/25 mg strengths both contain yellow iron oxide.

Uses and Indications

Amlodipine, valsartan and hydrochlorothiazide tablet is indicated for the treatment of hypertension to lower blood pressure. The reduction of blood pressure is associated with a decreased risk of both fatal and nonfatal cardiovascular events, including strokes and myocardial infarctions.

This combination therapy is not indicated for the initial treatment of hypertension.

There are no teratogenic or nonteratogenic effects associated with this medication.

Dosage and Administration

The recommended dosing regimen for amlodipine, valsartan, and hydrochlorothiazide tablets is once daily. Healthcare professionals should titrate the dose as necessary, with a maximum allowable dose of 10 mg amlodipine, 320 mg valsartan, and 25 mg hydrochlorothiazide.

These tablets may be utilized as 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, amlodipine, valsartan, and hydrochlorothiazide tablets can be substituted for their individually titrated components, ensuring that the overall therapeutic regimen remains effective and tailored to the patient's needs.

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, and hydrochlorothiazide tablets is contraindicated in patients with diabetes, as this combination may increase the risk of adverse effects.

Warnings and Precautions

When pregnancy is detected, it is imperative to discontinue the use of amlodipine, valsartan, and hydrochlorothiazide tablets as soon as possible. Medications that act directly on the renin-angiotensin system have been associated with potential injury and death to the developing fetus, necessitating immediate cessation of therapy.

General precautions should be observed when prescribing this combination therapy. Prior to initiation, it is essential to correct any volume depletion to mitigate the risk of hypotension. Healthcare professionals should be vigilant for signs of increased angina or myocardial infarction, particularly in patients with a history of cardiovascular issues.

Monitoring of renal function and serum potassium levels is recommended for patients who may be susceptible to renal impairment or electrolyte disturbances. Additionally, clinicians should be aware of the potential for exacerbation or activation of systemic lupus erythematosus in certain individuals. It is also important to observe patients for any signs of fluid or electrolyte imbalance, as these can complicate treatment.

Acute angle-closure glaucoma is another serious condition that may arise, warranting careful assessment and monitoring of patients at risk. Regular laboratory tests to evaluate renal function and potassium levels should be conducted in susceptible patients to ensure safe use of this medication regimen.

Side Effects

Patients receiving amlodipine, valsartan, and hydrochlorothiazide tablets 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 identified, including fetal toxicity, which poses a significant risk to the developing fetus when drugs acting on the renin-angiotensin system are administered. It is crucial to discontinue the medication as soon as pregnancy is detected. Other serious concerns include hypotension, which necessitates correction of volume depletion prior to initiation of therapy, and the potential for increased angina and/or myocardial infarction. Patients should be monitored for renal function and potassium levels, particularly those who are susceptible.

Additional adverse reactions of note include exacerbation or activation of systemic lupus erythematosus, acute angle-closure glaucoma, anuria, and hypersensitivity reactions, particularly in individuals with known hypersensitivity to sulfonamide-derived drugs or any component of the formulation. Coadministration of aliskiren with amlodipine, valsartan, and hydrochlorothiazide tablets is contraindicated in patients with diabetes.

In cases of overdosage, the most likely manifestations include hypotension and tachycardia, with bradycardia potentially occurring due to parasympathetic (vagal) stimulation. Reports have indicated that marked and potentially prolonged systemic hypotension, which may lead to shock and fatal outcomes, can occur. Symptoms associated with overdosage may also include those resulting from electrolyte depletion, such as hypokalemia, hypochloremia, hyponatremia, and dehydration due to excessive diuresis.

Drug Interactions

Co-administration 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.

In patients taking antidiabetic medications, 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 this combination therapy.

The use of non-steroidal anti-inflammatory drugs (NSAIDs) in conjunction with antihypertensive agents may result in an increased risk of renal impairment and a reduction in the antihypertensive effect.

When dual inhibition of the renin-angiotensin system is employed, there is an elevated 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 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 amlodipine, valsartan, and hydrochlorothiazide tablets in pediatric patients have not been established. Therefore, caution is advised when considering the use of this medication in children and adolescents. Further studies are necessary to determine appropriate dosing and outcomes in this population.

Geriatric Use

Clinical studies of amlodipine besylate tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. However, other reported clinical experience has not identified significant differences in responses between elderly patients 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, which results in 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, and hydrochlorothiazide tablets 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 increase 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. When pregnancy is detected, it is recommended to discontinue amlodipine, valsartan, and hydrochlorothiazide tablets 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 fetal risks such as 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 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 warranted 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 treatments should be considered.

Neonates with a history of in utero exposure to amlodipine, valsartan, and hydrochlorothiazide tablets should be closely monitored for hypotension, oliguria, and hyperkalemia. In cases where oliguria or hypotension occurs, it is essential to support blood pressure and renal perfusion, and interventions such as 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. The use of hydrochlorothiazide during pregnancy is associated with risks of fetal or neonatal jaundice and thrombocytopenia. Since thiazides do not prevent or alter the course of edema, proteinuria, and hypertension (EPH) gestosis (preeclampsia), they should not be used to treat hypertension in pregnant women. Furthermore, 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, and 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 lactating mothers refrain from breastfeeding during treatment with amlodipine, valsartan, and hydrochlorothiazide tablets.

Renal Impairment

Patients with renal impairment should have their renal function and potassium levels monitored closely, as they may be at increased risk for complications. Dosing adjustments may be necessary based on the degree of reduced kidney function to ensure safety and efficacy.

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 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 initiated.

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 result in 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 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 provided, 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 overdose. However, the administration of activated charcoal to healthy volunteers, either immediately or within two hours following ingestion of amlodipine, has been shown to significantly reduce the absorption of the drug.

Nonclinical Toxicology

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

The individual components, Amlodipine, Valsartan, and Hydrochlorothiazide, have been evaluated in separate studies. There have been no carcinogenicity, mutagenicity, or fertility studies conducted specifically on the combination. However, the preclinical safety and human pharmacokinetic studies suggest no toxicologically significant adverse interactions among these components.

Animal studies involving Amlodipine maleate demonstrated no evidence of carcinogenic effects when administered in the diet to rats and mice for up to two years. Additionally, mutagenicity studies indicated no drug-related effects at either the gene or chromosome level. Fertility assessments in rats treated orally with Amlodipine maleate at doses up to 10 mg/kg/day revealed no adverse effects.

Similarly, Valsartan has shown no evidence of carcinogenicity in two-year dietary studies conducted in mice and rats. 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 exhibited no evidence of carcinogenic potential in two-year feeding studies in mice and rats. It was not found to be genotoxic in vitro, as demonstrated in the Ames mutagenicity assay and the Chinese Hamster Ovary test for chromosomal aberrations. Additionally, Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex when exposed via diet at doses of up to 100 mg/kg and 4 mg/kg, respectively.

Postmarketing Experience

Patients taking hydrochlorothiazide have been advised to protect their skin from sun exposure and to undergo regular skin cancer screenings due to reports of non-melanoma skin cancer associated with the medication. Additionally, it is recommended that patients using amlodipine, valsartan, and hydrochlorothiazide tablets also take similar precautions, as one of the components may contribute to the risk of non-melanoma skin cancer. Patients are encouraged to contact their healthcare provider for medical advice regarding any side effects experienced and may report adverse events 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, and hydrochlorothiazide tablets and each time they receive a refill, as there may be new information. It is crucial to discuss the potential consequences of exposure to these medications during pregnancy with female patients of childbearing age. Healthcare providers should encourage women planning to become pregnant to explore alternative treatment options and to report any pregnancies to their physician as soon as possible.

Instruct women not to breastfeed while undergoing treatment with amlodipine, valsartan, and hydrochlorothiazide tablets. Patients should be made aware that symptomatic hypotension, including lightheadedness, may occur, particularly during the initial days of therapy. They should be advised to report any such symptoms to their healthcare provider. If syncope occurs, patients should discontinue the medication and consult their physician. Additionally, caution patients that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting can lead to a significant drop in blood pressure, resulting in similar symptoms.

Patients should be advised against using salt substitutes without prior consultation with their healthcare provider, as potassium supplements may interact with the medication. For those 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 associated with this medication.

Encourage patients to maintain an updated list of all medications they are taking, including prescription and nonprescription drugs, vitamins, and herbal supplements, and to share this list with their healthcare provider. Patients should take amlodipine, valsartan, and hydrochlorothiazide tablets exactly as prescribed, once daily, and may take the medication 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 scheduled dose; in that case, they should skip the missed dose and resume their regular dosing schedule.

Instruct patients to seek immediate medical attention if they suspect an overdose of amlodipine, valsartan, and hydrochlorothiazide tablets by contacting their doctor, Poison Control Center, or going to the emergency room. It is essential for patients to inform all healthcare providers, including dentists, that they are taking this medication, especially prior to any surgical procedures or kidney dialysis. Lastly, patients should be encouraged to report any side effects that are bothersome or persistent to their healthcare provider.

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 and Hydrochlorothiazide as submitted by Macleods Pharmaceuticals Limited. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)