Amlodipine besylate/Valsartan/Hydrochlorothiazide

Uses and Indications

Exforge HCT and Amlodipine, Valsartan, and Hydrochlorothiazide tablets are indicated for the treatment of hypertension to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions.

These medications are not indicated for the initial treatment of hypertension.

No teratogenic or nonteratogenic effects have been mentioned for these drugs.

Dosage and Administration

The recommended dosage of Amlodipine, Valsartan, and Hydrochlorothiazide is once daily. The dosage may be titrated up to a maximum of 10 mg of amlodipine, 320 mg of valsartan, and 25 mg of 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, and Hydrochlorothiazide may also be substituted for its individually titrated components, allowing for flexibility in managing patient therapy. It is important to monitor blood pressure and adjust the dosage as necessary to achieve optimal control.

Contraindications

Use is contraindicated in patients with anuria. Hypersensitivity to sulfonamide-derived drugs or any component of the formulation is also a contraindication. Additionally, coadministration of aliskiren with this medication is contraindicated in patients with diabetes due to the associated risks.

Warnings and Precautions

WARNING: FETAL TOXICITY When pregnancy is detected, discontinue amlodipine, valsartan, and hydrochlorothiazide as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.

General Precautions

• Hypotension: Correct volume depletion prior to initiation.

• Increased Angina and/or Myocardial Infarction: Patients may experience increased episodes of angina or myocardial infarction.

• Renal Function and Potassium Monitoring: Monitor renal function and potassium levels in susceptible patients.

• Systemic Lupus Erythematosus: There is a risk of exacerbation or activation of systemic lupus erythematosus.

• Fluid or Electrolyte Imbalance: Observe for signs of fluid or electrolyte imbalance.

• Acute Angle-Closure Glaucoma: There is a potential risk for acute angle-closure glaucoma.

Laboratory Tests

• Regular monitoring of renal function and potassium levels is recommended for susceptible patients.

Emergency Medical Help Instructions

No specific instructions provided.

Stop Taking and Call Your Doctor Instructions

No specific instructions provided.

Side Effects

Patients may experience a range of adverse reactions while using Amlodipine, Valsartan, and Hydrochlorothiazide. The following outlines the most common and serious adverse events associated with these medications.

Most Common Adverse Events (≥ 2% Incidence)

• Dizziness: Reported in 8.2% of clinical trial subjects.

• Peripheral Edema: Observed in 6.5% of subjects.

• Headache: Occurred in 5.2% of patients.

• Dyspepsia: Reported by 2.2% of subjects.

• Fatigue: Also noted in 2.2% of patients.

• Muscle Spasms: Reported in 2.2% of subjects.

• Back Pain: Occurred in 2.1% of patients.

• Nausea: Reported by 2.1% of subjects.

• Nasopharyngitis: Observed in 2.1% of patients.

Serious Adverse Reactions

• Fetal Toxicity: Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. Discontinuation is advised as soon as pregnancy is detected.

• Hypotension: Patients should correct volume depletion prior to initiation of therapy.

• Increased Angina and/or Myocardial Infarction: Patients may experience exacerbation of angina or myocardial infarction.

• Renal Function Impairment: Monitoring of renal function and potassium levels is recommended in susceptible patients.

• Systemic Lupus Erythematosus: Exacerbation or activation may occur.

• Acute Angle-Closure Glaucoma: Patients may develop this condition.

• Anuria: A serious condition that may arise.

• Hypersensitivity Reactions: Including angioedema, particularly in patients with a history of angioedema with other medications.

Postmarketing Experience

• Amlodipine: Rare reports of gynecomastia, jaundice, and hepatic enzyme elevations, some severe enough to require hospitalization.

• Valsartan:

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

  • Hypersensitivity: Angioedema, particularly in patients with prior reactions to ACE inhibitors.

  • Digestive: Elevated liver enzymes and hepatitis.

  • Musculoskeletal: Rhabdomyolysis.

  • Renal: Impaired renal function and renal failure.

  • Dermatologic: Alopecia and bullous dermatitis.

  • Vascular: Vasculitis.

  • Nervous System: Syncope.

• Hydrochlorothiazide:

  • Serious conditions such as acute renal failure, aplastic anemia, erythema multiforme, and worsening of diabetes control.

  • Increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma in white patients taking large cumulative doses.

Overdosage

Overdosage may lead to hypotension, tachycardia, and potentially bradycardia due to parasympathetic stimulation. Severe hypotension, including shock, has been reported. Symptoms may include electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis.

Patients should be monitored closely for these adverse reactions, and appropriate management strategies should be implemented as necessary.

Drug Interactions

Concurrent use of certain medications with Amlodipine, Valsartan, and Hydrochlorothiazide may lead to significant interactions that require careful management.

Pharmacokinetic Interactions

• Simvastatin: When coadministered with amlodipine, the dose of simvastatin should not exceed 20 mg daily to mitigate the risk of adverse effects.

Pharmacodynamic Interactions

• Antidiabetic Drugs: Dosage adjustments may be necessary for antidiabetic medications when used in conjunction with this combination therapy.

• Cholestyramine and Colestipol: These agents can reduce the absorption of thiazides, potentially diminishing their efficacy.

• Lithium: The use of lithium alongside this combination increases the risk of lithium toxicity; it is essential to monitor serum lithium concentrations during concurrent therapy.

• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): The use of NSAIDs may elevate the risk of renal impairment and can lead to a loss of the antihypertensive effect of the combination therapy.

• Dual Inhibition of the Renin-Angiotensin System: This practice can heighten the risk of renal impairment, hypotension, and hyperkalemia, necessitating close monitoring of renal function and electrolyte levels.

Healthcare providers should remain vigilant for these interactions and adjust treatment regimens accordingly to ensure patient safety and therapeutic efficacy.

Pediatric Use

The safety and effectiveness of Exforge HCT, as well as amlodipine, valsartan, and hydrochlorothiazide tablets, have not been established in pediatric patients. There are no available data to support the use of these medications in children or adolescents. Therefore, caution is advised when considering treatment options for 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 patients. However, other reported clinical experience has not identified significant differences in responses between elderly patients and younger individuals.

In general, dose selection for elderly patients should be approached with caution, typically starting at the low end of the dosing range. This recommendation reflects the increased likelihood of decreased hepatic, renal, or cardiac function, as well as the presence of concomitant diseases or other drug therapies in this population.

Elderly patients exhibit decreased clearance of amlodipine, resulting in an increase in the area under the curve (AUC) of approximately 40% to 60%. It is important to consider these factors when prescribing, as the recommended starting dose of 2.5 mg of amlodipine is not available in combination products containing amlodipine, valsartan, and hydrochlorothiazide. Regular monitoring of renal and cardiac function is advised to ensure safe and effective dosing in geriatric patients.

Pregnancy

Amlodipine, valsartan, and hydrochlorothiazide 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, increasing the risk of fetal and neonatal morbidity and mortality. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive medications in the first trimester have not 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 the use of amlodipine, valsartan, and hydrochlorothiazide as soon as possible. The estimated background risk of major birth defects and miscarriage in the U.S. general population is approximately 2-4% and 15-20%, respectively. All pregnancies carry a background risk of birth defects, loss, or other adverse outcomes.

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 elevates the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant patients with hypertension should be closely monitored and managed accordingly.

Oligohydramnios in pregnant women using renin-angiotensin system-affecting drugs 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 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 amlodipine, valsartan, and hydrochlorothiazide should be closely monitored for hypotension, oliguria, and hyperkalemia. In cases of oliguria or hypotension, supportive measures 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 accumulates 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. These medications do not prevent or alter the course of Edema, Proteinuria, Hypertension (EPH) gestosis (preeclampsia) and should not be used to treat hypertension in pregnant women. The use of hydrochlorothiazide for other indications during pregnancy should also be avoided.

Lactation

There is limited information regarding the presence of Exforge HCT (amlodipine, valsartan, and hydrochlorothiazide) 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 studies suggest 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. This recommendation applies to the individual components of the medication as well, including amlodipine, valsartan, and hydrochlorothiazide. Given the uncertainties surrounding the effects on infants and the lack of specific data on excretion in breast milk, caution is warranted.

Renal Impairment

Patients with renal impairment require careful consideration when using Exforge HCT. The safety and effectiveness of this medication have not been established in patients with severe renal impairment, specifically those with a creatinine clearance (CrCl) of less than 30 mL/min. However, no dose adjustment is necessary for patients with mild (CrCl 60 to 90 mL/min) or moderate (CrCl 30 to 60 mL/min) renal impairment.

It is essential to monitor renal function and potassium levels in patients who may be susceptible to changes in these parameters. This precaution is reiterated across multiple sources, emphasizing the importance of regular monitoring to ensure patient safety and optimal therapeutic outcomes.

Hepatic Impairment

Exposure to amlodipine is increased in patients with hepatic impairment. The recommended initial dose of amlodipine for these patients is 2.5 mg; however, this strength is not available with Exforge HCT. For patients with mild-to-moderate hepatic impairment, no dose adjustment is necessary. There are no dosing recommendations for patients with severe liver disease.

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. No specific information regarding dosage adjustments, special monitoring, or precautions for patients with liver problems is provided for the combination of amlodipine, valsartan, and hydrochlorothiazide. Therefore, healthcare providers should exercise caution and consider individual patient factors when treating patients with hepatic impairment.

Overdosage

Limited data are available regarding overdosage in humans. The most likely manifestations of overdosage include hypotension and tachycardia, with bradycardia potentially occurring due to parasympathetic (vagal) stimulation. In the event of symptomatic hypotension, supportive treatment should be instituted.

Single oral doses of amlodipine maleate equivalent to 40 mg/kg and 100 mg/kg in mice and rats have resulted in fatalities. In dogs, doses of 4 mg/kg or more (approximately 11 times the maximum recommended human dose on a mg/m² basis) have caused significant peripheral vasodilation and hypotension. Overdosage may lead to excessive peripheral vasodilation and marked hypotension. Although experience with intentional overdosage of amlodipine in humans is limited, there have been reports of marked and potentially prolonged systemic hypotension, which may progress to shock and result in fatal outcomes.

In cases of massive overdose, active cardiac and respiratory monitoring should be initiated, with frequent blood pressure measurements being essential. Should hypotension occur, cardiovascular support should be provided, including elevation of 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.

Administration of activated charcoal to healthy volunteers within two hours of ingestion of amlodipine has been shown to significantly decrease its absorption. Additionally, depressed levels of consciousness, circulatory collapse, and shock have been reported with valsartan overdose; however, valsartan is not removed from the plasma by hemodialysis. The oral LD50 of hydrochlorothiazide is greater than 10 g/kg in both mice and rats, significantly exceeding the maximum recommended human dose on a mg/m² basis. The degree to which hydrochlorothiazide is removed by hemodialysis has not been established, and the most common signs and symptoms observed in patients are those related to electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalemia may exacerbate cardiac arrhythmias.

Nonclinical Toxicology

Teratogenic Effects

No teratogenic effects have been reported for the combination of Amlodipine, Valsartan, and Hydrochlorothiazide.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity, mutagenicity, or fertility studies have been conducted specifically on the combination of Amlodipine, Valsartan, and Hydrochlorothiazide. However, individual studies on each component have been performed.

Amlodipine

In studies involving Amlodipine maleate, rats and mice treated in the diet for up to two years showed no evidence of carcinogenic effects. Mutagenicity studies indicated no drug-related effects at either the gene or chromosome level. Additionally, there was no observed effect on the fertility of rats treated orally with Amlodipine maleate at doses of up to 10 mg/kg/day.

Valsartan

Valsartan has also 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

Two-year feeding studies in mice and rats indicated no evidence of carcinogenic potential for Hydrochlorothiazide. It was not found to be genotoxic in vitro in 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.

Summary of Nonclinical Toxicology

Overall, the individual components of Amlodipine, Valsartan, and Hydrochlorothiazide have not shown significant toxicological concerns regarding carcinogenicity, mutagenicity, or fertility impairment in animal studies. There is no indication of any toxicologically significant adverse interactions among these components based on preclinical safety and human pharmacokinetic studies.

Storage and Handling

Exforge Hct and Amlodipine, Valsartan and Hydrochlorothiazide are supplied as film-coated tablets.

These products 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) in accordance with USP controlled room temperature guidelines.

It is essential to protect the tablets from moisture and to dispense them in a tight container as specified by USP standards.