Amlodipine besylate

Description

Amlodipine besylate, USP is the besylate salt of amlodipine, a long-acting calcium channel blocker. It is chemically described as 3-Ethyl-5-methyl (±)-2-(2-aminoethoxy)methyl 4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate, monobenzenesulphonate. The molecular formula is C20H25ClN2O5 • C6H6O3S, and it has a molecular weight of 567.1. Amlodipine besylate appears as a white crystalline powder, which is slightly soluble in water and sparingly soluble in ethanol.

Amlodipine besylate Tablets, USP are available in two formulations: yellow tablets equivalent to 2.5 mg of amlodipine and white tablets equivalent to 5 mg and 10 mg of amlodipine for oral administration. Each tablet contains inactive ingredients including colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. The 2.5 mg strength also includes ferric oxide yellow as a coloring agent.

Uses and Indications

Amlodipine besylate tablets are indicated for the treatment of hypertension, serving 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.

In addition to hypertension, amlodipine besylate tablets are indicated for the management of coronary artery disease, which includes the treatment of chronic stable angina and vasospastic angina (Prinzmetal's or variant angina). Furthermore, this medication is indicated for patients with angiographically documented coronary artery disease who do not have heart failure or an ejection fraction less than 40%.

There are no teratogenic or nonteratogenic effects associated with amlodipine besylate tablets.

Dosage and Administration

The recommended starting dose for adults is 5 mg administered once daily, with a maximum allowable dose of 10 mg once daily. For small, fragile, or elderly patients, as well as those with hepatic insufficiency, it is advisable to initiate treatment at a lower dose of 2.5 mg once daily.

In pediatric patients, the starting dose ranges from 2.5 mg to 5 mg once daily. It is important to note that doses exceeding 5 mg daily have not been studied in this population, and therefore should not be administered.

Healthcare professionals should assess individual patient factors when determining the appropriate dosage and adjust as necessary within the specified ranges.

Contraindications

Use of this product is contraindicated in patients with a known sensitivity to amlodipine. This contraindication is based on the potential for severe allergic reactions in individuals with such sensitivities.

Warnings and Precautions

Symptomatic hypotension may occur, especially in patients diagnosed with severe aortic stenosis. While acute hypotension is considered unlikely, healthcare professionals should remain vigilant for signs of symptomatic hypotension in this patient population.

Additionally, there is a risk of worsening angina and acute myocardial infarction following the initiation or dose escalation of amlodipine. This risk is particularly pronounced in patients with severe obstructive coronary artery disease. Close monitoring of these patients is recommended to promptly identify and manage any adverse cardiovascular events.

For patients with severe hepatic impairment, it is essential to titrate the dosage of amlodipine slowly. This precaution helps to mitigate the risk of potential adverse effects associated with altered drug metabolism in this population. Regular assessment of liver function may be warranted to ensure safe and effective dosing.

Side Effects

Patients may experience a range of adverse reactions while receiving treatment. The most common adverse reactions include edema, which is dose-related, as well as fatigue, nausea, abdominal pain, and somnolence, each occurring in more than 1.0% of participants.

Serious adverse reactions have also been reported. Symptomatic hypotension may occur, particularly in patients with severe aortic stenosis; however, acute hypotension is considered unlikely. Additionally, worsening angina and acute myocardial infarction can develop after initiating or increasing the dose of amlodipine, especially in patients with severe obstructive coronary artery disease.

It is important to note that some patients may have a known sensitivity to amlodipine. In cases of overdosage, excessive peripheral vasodilation may lead to marked hypotension and potentially a reflex tachycardia.

Packaging & NDC

The table below lists all NDC Code configurations of Amlodipine Besylate, the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

Amlodipine is effective in lowering blood pressure in pediatric patients aged 6 to 17 years, with a recommended dosage range of 2.5 to 5 mg daily. The safety and efficacy of amlodipine in patients younger than 6 years have not been established, and its effect on blood pressure in this age group is not known. Caution is advised when considering treatment in younger children.

Geriatric Use

Clinical studies of amlodipine did not include a sufficient number of subjects aged 65 and over to determine whether these elderly patients respond differently compared to 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, resulting in an approximate increase in the area under the curve (AUC) of 40–60%. Consequently, a lower initial dose may be necessary to ensure safety and efficacy in this population. Regular monitoring and assessment of the patient's response to therapy are recommended to optimize treatment outcomes.

Pregnancy

The available data regarding the use of amlodipine in pregnant patients is limited, primarily derived from post-marketing reports, and is insufficient to establish a definitive drug-associated risk for major birth defects or miscarriage. However, it is important to recognize that poorly controlled hypertension during pregnancy poses significant risks to both the mother and fetus.

In animal reproduction studies, no adverse developmental effects were observed when pregnant rats and rabbits were administered amlodipine maleate during organogenesis at doses approximately 10 and 20 times the maximum recommended human dose (MRHD), respectively. Notably, while teratogenicity and other embryo/fetal toxicities were not evident at doses up to 10 mg amlodipine/kg/day, significant concerns arose in rats, where litter size was reduced by approximately 50% and the incidence of intrauterine deaths increased five-fold. Additionally, amlodipine maleate was associated with prolonged gestation and extended labor duration in rats at this dosage.

The estimated background risk of major birth defects and miscarriage in the general U.S. population is approximately 2%-4% and 15%-20%, respectively. All pregnancies inherently carry a background risk of birth defects, loss, or other adverse outcomes. Furthermore, hypertension in pregnancy is linked to increased maternal risks, including pre-eclampsia, gestational diabetes, premature delivery, and complications during delivery, such as the need for cesarean section and postpartum hemorrhage. Fetal risks associated with maternal hypertension include intrauterine growth restriction and intrauterine death.

Given these considerations, pregnant women with hypertension should be closely monitored and managed to mitigate potential risks to both maternal and fetal health.

Lactation

No specific information is available regarding the use of this medication in nursing mothers. Additionally, there is no data on the potential for excretion in breast milk or its effects on breastfed infants. Healthcare professionals should consider this lack of information when advising lactating mothers.

Renal Impairment

Patients with renal impairment have not been specifically addressed in the available prescribing information. There are no dosage adjustments, monitoring recommendations, or precautions outlined for individuals with reduced kidney function. Healthcare professionals should consider this lack of information when prescribing and managing treatment in patients with renal impairment.

Hepatic Impairment

Patients with hepatic impairment should be managed with caution. In individuals with severe hepatic impairment, it is recommended to titrate the dosage slowly to minimize the risk of adverse effects. Close monitoring of liver function is advised to ensure patient safety and to adjust treatment as necessary.

Overdosage

Overdosage may lead to significant peripheral vasodilation, resulting in pronounced hypotension and potentially reflex tachycardia. Clinical experience with intentional overdosage of amlodipine in humans is limited, underscoring the need for caution.

Toxicological studies indicate that single oral doses of amlodipine maleate equivalent to 40 mg amlodipine/kg in mice and 100 mg amlodipine/kg in rats have resulted in fatalities. In canine models, doses of 4 mg amlodipine/kg or higher—exceeding 11 times the maximum recommended human dose on a mg/m² basis—have also produced severe peripheral vasodilation and hypotension.

In the event of a massive overdose, it is imperative to initiate active cardiac and respiratory monitoring. Frequent blood pressure assessments are crucial. Should hypotension manifest, cardiovascular support measures should be implemented, including the elevation of the extremities and the careful administration of intravenous fluids. If hypotension persists despite these conservative interventions, the use of vasopressors, such as phenylephrine, may be warranted, with careful monitoring of circulating volume and urine output.

Due to the high protein binding of amlodipine, hemodialysis is unlikely to provide any significant benefit in the management of overdose.

Nonclinical Toxicology

Rats and mice treated with amlodipine maleate in the diet for up to two years, at concentrations calculated to provide daily dosage levels of 0.5, 1.25, and 2.5 mg/kg/day, showed no evidence of a carcinogenic effect of the drug. In mice, the highest dose administered was, on a mg/m² basis, similar to the maximum recommended human dose of 10 mg amlodipine per day. In rats, the highest dose was approximately twice the maximum recommended human dose when adjusted for body surface area.

Mutagenicity studies conducted with amlodipine maleate revealed no drug-related effects at either the gene or chromosome level, indicating a lack of mutagenic potential.

There was no effect on the fertility of rats treated orally with amlodipine maleate, with males receiving treatment for 64 days and females for 14 days prior to mating at doses up to 10 mg/kg/day. This dosage is eight times the maximum recommended human dose of 10 mg per day when adjusted for body surface area.

Postmarketing Experience

Postmarketing experience has revealed several adverse events reported voluntarily or through surveillance programs. Due to the nature of voluntary reporting from a population of uncertain size, it is not always possible to reliably estimate the frequency of these events or establish a causal relationship with drug exposure.

Among the reported events, gynecomastia has been noted infrequently, with an uncertain causal relationship. Additionally, cases of jaundice and hepatic enzyme elevations, primarily consistent with cholestasis or hepatitis, have been documented. Some instances were severe enough to necessitate hospitalization.

Further postmarketing data suggest a possible association between extrapyramidal disorder and amlodipine. It is also noted that amlodipine has been used safely in patients with chronic obstructive pulmonary disease, well-compensated congestive heart failure, coronary artery disease, peripheral vascular disease, diabetes mellitus, and abnormal lipid profiles.

Patient Counseling

Patients should read the provided information carefully before starting amlodipine besylate tablets and each time they refill their prescription, as there may be new information. This information does not replace discussions with their healthcare provider. Patients are encouraged to ask their doctor if they have any questions regarding the appropriateness of amlodipine besylate tablets for their condition.

Amlodipine besylate tablets are classified as a calcium channel blocker (CCB) and are indicated for the treatment of high blood pressure (hypertension) and a type of chest pain known as angina. This medication can be utilized alone or in conjunction with other medications to manage these conditions.

Patients should understand that high blood pressure results from blood exerting excessive force against blood vessel walls. Amlodipine besylate tablets work by relaxing blood vessels, facilitating easier blood flow, and consequently lowering blood pressure. Lowering blood pressure is crucial as it reduces the risk of stroke or heart attack. Angina, characterized by recurring pain or discomfort due to insufficient blood flow to the heart, may present as a pressing or squeezing sensation in the chest, which can also radiate to the shoulders, arms, neck, jaws, or back. Amlodipine besylate tablets can help alleviate this pain.

Patients should not use amlodipine besylate tablets if they are allergic to amlodipine or any of the inactive ingredients. It is important for patients to inform their healthcare provider about all prescription and non-prescription medications they are taking, including natural or herbal remedies. They should also disclose any history of heart disease or liver problems, as well as if they are pregnant, planning to become pregnant, or breastfeeding, since amlodipine can pass into breast milk.

Amlodipine besylate tablets should be taken once daily, with or without food. Patients may find it beneficial to take their dose at the same time each day, such as with breakfast or dinner, or at bedtime. They should not take more than one dose at a time. If a dose is missed, it should be taken as soon as remembered, but if more than 12 hours have passed since the missed dose, patients should wait and take the next dose at the regular time.

Patients can continue using nitroglycerin alongside amlodipine besylate tablets if prescribed for angina, and they should not discontinue any other prescribed medications, including other blood pressure medications, without consulting their healthcare provider. In the event of an overdose, patients should seek immediate medical attention by contacting their doctor, Poison Control Center, or going to the nearest hospital emergency room.

Patients are advised not to start any new prescription or non-prescription medications or supplements without first consulting their healthcare provider.

While most side effects of amlodipine besylate tablets are mild to moderate, patients should be aware of potential side effects, which may include swelling of the legs or ankles, tiredness, extreme sleepiness, stomach pain, nausea, dizziness, flushing, arrhythmia, heart palpitations, and muscle rigidity or tremors. It is rare, but patients may experience a heart attack or worsening angina when first starting the medication or increasing the dose. If such symptoms occur, patients should contact their doctor immediately or go to the nearest hospital emergency room.

Patients should communicate any concerns regarding side effects to their healthcare provider. This information does not encompass all possible side effects; for a complete list, patients should consult their doctor or pharmacist.

Amlodipine besylate tablets should be stored out of reach of children, at temperatures between 20º to 25°C (68° to 77º F), with permissible excursions between 15° to 30°C (59° to 86°F). They should be kept away from light, not stored in the bathroom, and maintained in a dry place.

Patients should only use amlodipine besylate tablets as directed by their healthcare provider and should not share this medication with others, even if they exhibit similar symptoms, as it may be harmful to them. For additional information about amlodipine besylate tablets, patients can consult their pharmacist or healthcare provider, or contact Unichem Pharmaceuticals (USA), Inc., at 1 866-562-4616.

Storage and Handling

The product is supplied in tight, light-resistant containers to ensure its integrity and efficacy. 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) as defined by USP Controlled Room Temperature guidelines. Proper adherence to these storage conditions is essential for maintaining the quality of the product.

Additional Clinical Information

Amlodipine therapy has not been associated with clinically significant changes in routine laboratory tests, with no relevant alterations observed in serum potassium, glucose, triglycerides, cholesterol levels, uric acid, blood urea nitrogen, or creatinine.

Patients are advised to take amlodipine besylate tablets once daily, with or without food, and it may be beneficial to take the medication at the same time each day. It is important for patients to read the provided information carefully before starting treatment and to consult their doctor with any questions. Patients should inform their healthcare provider about all medications they are taking, including natural or herbal remedies, and disclose any history of heart disease or liver problems, as well as pregnancy or breastfeeding status. If a dose is missed, it should be taken as soon as remembered, but not if more than 12 hours have passed since the last dose. Patients should not discontinue other prescribed medications without consulting their doctor.

Postmarketing experiences have reported infrequent events, including gynecomastia, jaundice, and hepatic enzyme elevations, some severe enough to necessitate hospitalization. Additionally, there may be a possible association between extrapyramidal disorder and amlodipine use.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Amlodipine Besylate as submitted by REMEDYREPACK INC.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)