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 a white to almost white 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 empirical formula is C20H25ClN2O5 • C6H6O3S, and it has a molecular weight of 567.1.

Valsartan, a nonpeptide angiotensin II antagonist, is a white to off-white fine hygroscopic powder with a chemical name of N-(1-oxopentyl)-N-[[2′-(1H-tetrazol-5-yl) 1,1′-biphenyl-4-yl]methyl]-L-valine. Its empirical 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 an empirical formula of C7H8ClN3O4S2 and a molecular weight of 297.73.

The inactive ingredients across all tablet strengths include colloidal silicon dioxide, croscarmellose sodium, crospovidone, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, and titanium dioxide. Specific strengths contain additional colorants: the 10/160/12.5 mg strength includes yellow iron oxide; the 5/160/25 mg strength contains red iron oxide and yellow iron oxide; the 10/160/25 mg strength contains black iron oxide, red iron oxide, and yellow iron oxide; and the 10/320/25 mg strength contains iron oxide red. Amlodipine, valsartan and hydrochlorothiazide tablets USP meet USP Dissolution Test 2.

Uses and Indications

Amlodipine, valsartan, and hydrochlorothiazide tablets are 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.

These tablets are 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 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, and hydrochlorothiazide. It is imperative that these medications be discontinued as soon as pregnancy is detected, as they can cause injury or death to the developing fetus due to their direct action on the renin-angiotensin system.

General precautions should be observed when prescribing these medications. 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 renal function and potassium levels is crucial in susceptible patients to prevent complications. Additionally, there is a risk of exacerbation or activation of systemic lupus erythematosus, which necessitates careful observation. Clinicians should also be alert for signs of fluid or electrolyte imbalance, as well as the potential for acute angle-closure glaucoma.

To ensure patient safety, regular laboratory tests to monitor renal function and potassium levels are recommended for those at risk. This proactive approach will aid in the early identification of any adverse effects associated with the use of these medications.

Side Effects

Patients may experience a range of adverse reactions while using the combination of amlodipine, valsartan, and hydrochlorothiazide. Common adverse reactions, occurring in 2% or more of participants, include dizziness, peripheral edema, headache, dyspepsia, fatigue, muscle spasms, back pain, nausea, and nasopharyngitis.

Serious warnings include the potential for fetal toxicity. 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 and death to the developing fetus.

Additional adverse reactions of clinical significance include hypotension, which necessitates correction of volume depletion prior to initiation of therapy. Patients may also experience increased angina and/or myocardial infarction, and it is advised to monitor renal function and potassium levels in susceptible individuals. There have been reports of exacerbation or activation of systemic lupus erythematosus, as well as acute angle-closure glaucoma and anuria. Hypersensitivity reactions may occur in patients with known sensitivities to sulfonamide-derived drugs or any component of the formulation. Furthermore, coadministration of aliskiren with this combination is contraindicated in patients with diabetes.

In cases of overdosage, the most likely manifestations include hypotension and tachycardia, with bradycardia potentially resulting from parasympathetic (vagal) stimulation. Marked and potentially prolonged systemic hypotension, which may lead to shock and fatal outcomes, has been reported. Common signs and symptoms associated with overdosage are primarily due to electrolyte depletion (hypokalemia, hypochloremia, 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.

Antidiabetic medications may require dosage adjustments when used concurrently, as their effects can be altered in the presence of other drugs.

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 administration of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) may elevate the risk of renal impairment and can diminish the antihypertensive effects of certain medications.

When dual inhibition of the renin-angiotensin system is employed, there is 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 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 in pediatric patients have not been established. Therefore, caution is advised when considering the use of these medications in children and adolescents. Further studies are needed to determine appropriate dosing and outcomes in this population.

Geriatric Use

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

In general, dose selection for elderly patients should be approached with caution. It is recommended 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, and hydrochlorothiazide are associated with potential fetal harm when administered to pregnant patients. The use of medications that act on the renin-angiotensin system during the second and third trimesters can lead to reduced fetal renal function, increasing the risk of 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 confirmed, it is recommended to discontinue amlodipine, valsartan, and hydrochlorothiazide as soon as possible. The estimated background risk of major birth defects and miscarriage in the general U.S. population is 2 to 4% and 15 to 20%, respectively; however, the specific background risk for the indicated population remains unknown. All pregnancies carry a baseline risk of birth defects, loss, or other adverse outcomes.

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

The occurrence of oligohydramnios in pregnant women using drugs that affect the renin-angiotensin system during the second and third trimesters can lead to severe fetal complications, including anuria, renal failure, fetal lung hypoplasia, skeletal deformations, hypotension, and death. Serial ultrasound examinations are recommended to assess the intra-amniotic environment, and fetal testing may be warranted based on gestational age. It is crucial for patients and healthcare providers to recognize that oligohydramnios may not manifest until after the fetus has sustained irreversible injury. If oligohydramnios is detected, alternative drug treatments should be considered.

Neonates with a history of in utero exposure to amlodipine, valsartan, and hydrochlorothiazide 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 interventions such as exchange transfusions or dialysis may be necessary to restore renal function.

Thiazides, including hydrochlorothiazide, can cross the placenta, achieving concentrations in the umbilical vein that are comparable to those in maternal plasma. The use of hydrochlorothiazide during pregnancy is associated with risks of fetal or neonatal jaundice and thrombocytopenia. Given that thiazides do not prevent or alter the course of edema, proteinuria, and hypertension (EPH) gestosis (preeclampsia), their use for treating hypertension in pregnant women is not recommended. Furthermore, the use of hydrochlorothiazide for other indications, such as heart disease, during pregnancy should be avoided.

Lactation

There is no specific information available regarding the use of amlodipine, valsartan, and hydrochlorothiazide in lactating mothers or the potential for excretion in breast milk. Additionally, there is no data concerning the effects on breastfed infants or the potential risks associated with breastfeeding while taking these medications. Healthcare professionals should consider the lack of information when advising lactating mothers on the use of these medications.

Renal Impairment

Patients with renal impairment should have their renal function and potassium levels monitored closely. This is particularly important for those with reduced kidney function, as they may be at increased risk for complications. Dosing adjustments may be necessary based on the degree of renal impairment 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 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.

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 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. Should hypotension develop, cardiovascular support should be provided, which includes elevating the extremities and judicious administration of fluids. If hypotension remains unresponsive to 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. Additionally, 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.

Non-teratogenic effects have been evaluated through various studies on the individual components of the combination, namely amlodipine, valsartan, and hydrochlorothiazide. These studies indicate no carcinogenicity, mutagenicity, or fertility concerns associated with these agents when administered alone. Preclinical safety and human pharmacokinetic studies suggest no toxicologically significant adverse interactions among the components.

Amlodipine maleate was administered to rats and mice in their diet for up to two years at daily dosage levels of 0.5, 1.25, and 2.5 mg/kg. No evidence of carcinogenic effects was observed. Additionally, mutagenicity studies indicated no drug-related effects at either the gene or chromosome level. Fertility studies involving oral administration of amlodipine maleate to rats (males for 64 days and females for 14 days prior to mating) at doses up to 10 mg/kg/day demonstrated no adverse effects on fertility, which is approximately ten times the maximum recommended human dose (MRHD) on a mg/m² basis.

Valsartan was also evaluated for carcinogenic potential through dietary administration to mice and rats for up to two years, with doses reaching 160 mg/kg/day in mice and 200 mg/kg/day in rats. No evidence of carcinogenicity was found. Furthermore, mutagenicity assays did not reveal any valsartan-related effects at the gene or chromosome level. 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 assessed in two-year feeding studies conducted under the National Toxicology Program (NTP), which found no evidence of carcinogenic potential in female mice or in male and female rats. It was also shown to be non-genotoxic in vitro, as demonstrated by the Ames mutagenicity assay and the Chinese Hamster Ovary (CHO) test for chromosomal aberrations. Fertility studies indicated that 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, prior to mating and throughout gestation.

Postmarketing Experience

No specific postmarketing experience details are available in the extracted data. As such, there are no reported adverse events or case reports to summarize.

Patient Counseling

Healthcare providers should advise patients to read the FDA-approved patient labeling (Patient Information) thoroughly. This document contains essential information regarding the medication, including its indications, usage, potential side effects, and important safety information. Emphasizing the importance of understanding this material can help patients make informed decisions about their treatment and manage their health effectively.

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 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. Additionally, it is essential to protect the product from moisture to maintain its quality and efficacy.

Additional Clinical Information

Clinicians should periodically monitor renal function in patients whose renal status may be influenced by the renin-angiotensin system. Additionally, serum electrolytes should be assessed regularly, and lithium levels should be monitored in patients taking amlodipine, valsartan, and hydrochlorothiazide concurrently with lithium. Calcium levels should also be checked in patients with hypercalcemia receiving this combination therapy.

Patients are advised to discontinue amlodipine, valsartan, and hydrochlorothiazide as soon as pregnancy is confirmed due to the potential for fetal harm. They should be informed about the importance of monitoring renal function and serum electrolytes during treatment.

FDA Insert (PDF)

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

View full prescribing information (PDF)