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 empirical formula is C₂₀H₂₅CIN₂O₅ • 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 dosages of 2.5 mg, 5 mg, and 10 mg for oral administration, formulated as white tablets. Each tablet contains inactive ingredients including dibasic calcium phosphate anhydrous, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate.

Uses and Indications

Amlodipine besylate tablets, USP, are indicated for the treatment of hypertension, coronary artery disease, chronic stable angina, and vasospastic angina (Prinzmetal’s or variant angina). This medication functions as a calcium channel blocker and may be utilized as monotherapy or in conjunction with other antihypertensive and antianginal agents.

Limitations of Use: There are no specified teratogenic or nonteratogenic effects associated with amlodipine besylate.

Dosage and Administration

The recommended starting dose of amlodipine besylate 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, the initial dose may be reduced to 2.5 mg once daily.

In pediatric patients, the starting dose ranges from 2.5 mg to 5 mg once daily; however, it is important to note that doses exceeding 5 mg daily have not been studied in this population.

Amlodipine besylate can be taken once daily, with or without food. To enhance adherence, it is advisable for patients to take their dose at the same time each day, such as during breakfast, dinner, or at bedtime.

Patients should not take more than one dose of amlodipine besylate at a time. In the event of a missed dose, it should be taken as soon as the patient remembers, provided it is within 12 hours of the scheduled dose. If more than 12 hours have passed since the missed dose, the patient should skip the missed dose and resume the regular dosing schedule.

Contraindications

Use of this product is contraindicated in patients with a known sensitivity to amlodipine. Due to the potential for adverse reactions, individuals with this sensitivity should not be administered this medication.

Warnings and Precautions

Symptomatic hypotension may occur, especially in patients diagnosed with severe aortic stenosis. It is important to note that due to the gradual onset of action associated with the medication, the risk of acute hypotension is considered low.

Healthcare professionals should be vigilant for the potential exacerbation of angina or the occurrence of acute myocardial infarction following the initiation or dose escalation of amlodipine besylate tablets. This risk is particularly pronounced in patients with severe obstructive coronary artery disease, necessitating careful monitoring of these patients during treatment.

In patients with severe hepatic impairment, it is recommended to titrate calcium channel blockers, including amlodipine besylate, slowly. This cautious approach is essential to minimize the risk of adverse effects and ensure patient safety. Regular assessment of liver function may be warranted to guide dosing adjustments in this population.

Side Effects

Patients receiving treatment with amlodipine besylate tablets may experience a range of adverse reactions. Common adverse reactions reported include headache, edema, fatigue, nausea, abdominal pain, and somnolence. These reactions are generally mild to moderate in severity.

Serious side effects have also been observed, particularly in patients with specific cardiovascular conditions. Symptomatic hypotension may occur, especially in individuals with severe aortic stenosis. Additionally, worsening angina and acute myocardial infarction can develop after initiating or increasing the dose of amlodipine besylate, particularly in patients with severe obstructive coronary artery disease.

It is important to note that some patients may have a known sensitivity to amlodipine, which could predispose them to adverse reactions. In cases of overdosage, excessive peripheral vasodilation may lead to marked hypotension and potentially a reflex tachycardia. Monitoring and management of these adverse reactions are essential for patient safety.

Drug Interactions

Co-administration of simvastatin with amlodipine may result in increased plasma concentrations of simvastatin due to the inhibitory effects of amlodipine on its metabolism. Therefore, it is recommended that the dosage of simvastatin not exceed 20 mg daily when used in conjunction with amlodipine to mitigate the risk of adverse effects associated with elevated simvastatin levels.

No other significant drug interactions have been identified.

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

The effect of amlodipine on blood pressure in pediatric patients less than 6 years of age is not known. Caution is advised when considering the use of amlodipine in this age group due to the lack of established efficacy and safety data.

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 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, resulting in an increase in the area under the curve (AUC) of approximately 40 to 60%. Consequently, a lower initial dose may be necessary to ensure safety and efficacy in this population. Careful monitoring and dose adjustments are recommended to optimize treatment outcomes for geriatric patients.

Pregnancy

Pregnant patients should be aware that amlodipine is classified as Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women; therefore, amlodipine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Animal studies have not demonstrated evidence of teratogenicity or other embryo/fetal toxicity when pregnant rats and rabbits were administered amlodipine maleate at doses up to 10 mg amlodipine/kg/day during their respective periods of major organogenesis. Notably, these doses are significantly higher than the maximum recommended human dose of 10 mg on a mg/m² basis, being approximately 8 times and 23 times higher, respectively.

However, it is important to note that in rats receiving amlodipine maleate at a dose equivalent to 10 mg amlodipine/kg/day for 14 days prior to mating and throughout mating and gestation, there was a significant decrease in litter size (approximately 50%) and a marked increase in the number of intrauterine deaths (about 5-fold). Additionally, this dose has been associated with prolonged gestation and an extended duration of labor in rats.

Healthcare professionals should carefully consider these findings when prescribing amlodipine to pregnant patients and weigh the potential risks against the benefits.

Lactation

It is not known whether amlodipine is excreted in human milk. In the absence of this information, it is recommended that lactating mothers discontinue breastfeeding while receiving amlodipine.

Renal Impairment

There is no specific information available regarding dosage adjustments, special monitoring, or safety considerations for patients with renal impairment. Healthcare professionals should exercise caution when prescribing to patients with reduced kidney function, as the absence of detailed guidance necessitates careful clinical judgment. Regular monitoring of renal function may be advisable in this patient population.

Hepatic Impairment

Patients with hepatic impairment may require careful consideration when administering calcium channel blockers. It is recommended to titrate the dosage slowly in this population, particularly for those with severe hepatic impairment. This approach helps to mitigate the risk of adverse effects and ensures that the medication is used safely and effectively in patients with compromised liver function. Regular monitoring of liver function may also be warranted to assess the patient's response to treatment and to adjust the dosage 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 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—produced marked 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 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 significant benefit in managing an 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 mg, 1.25 mg, or 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. Additionally, there was no observed effect on the fertility of rats treated orally with amlodipine maleate. Male rats were treated for 64 days, and female rats for 14 days prior to mating, at doses up to 10 mg amlodipine/kg/day, which is eight times the maximum recommended human dose of 10 mg/day on a mg/m² basis.

Postmarketing Experience

Postmarketing experience has revealed infrequent reports of gynecomastia, with an uncertain causal relationship. Additionally, cases of jaundice and elevations in hepatic enzymes, primarily consistent with cholestasis or hepatitis, have been documented. Some of these cases were severe enough to necessitate hospitalization. Amlodipine besylate tablets have been utilized 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

Advise patients to read the provided information carefully before starting amlodipine besylate and each time they refill their prescription, as there may be new information. Emphasize that this information does not replace discussions with their healthcare provider. Patients should feel encouraged to ask their doctor any questions regarding whether amlodipine besylate is appropriate for their condition.

Inform patients that amlodipine besylate is classified as a calcium channel blocker (CCB) and is utilized to treat high blood pressure (hypertension) and a specific type of chest pain known as angina. It can be prescribed alone or in conjunction with other medications for these conditions. Explain that high blood pressure results from blood exerting excessive force against blood vessel walls, and that amlodipine besylate works by relaxing these vessels, facilitating easier blood flow and lowering blood pressure, which in turn reduces the risk of stroke or heart attack.

Discuss the nature of angina, describing it as recurring pain or discomfort due to insufficient blood supply to the heart. Patients may experience a pressing or squeezing sensation in the chest, which can radiate to the shoulders, arms, neck, jaws, or back. Amlodipine besylate can help alleviate this pain.

Instruct patients not to use amlodipine besylate if they are allergic to amlodipine or any of the inactive ingredients. Encourage them to inform their healthcare provider about all prescription and non-prescription medications they are taking, including natural or herbal remedies. It is particularly important to disclose any history of heart disease or liver problems, as well as if they are pregnant, planning to become pregnant, or breastfeeding. Advise that breastfeeding is not recommended while taking amlodipine besylate, and patients should discuss alternative options with their doctor.

Patients should take amlodipine besylate once daily, with or without food, and it may be beneficial to take it at the same time each day. If a dose is missed, they should take it as soon as they remember, but not if it has been more than 12 hours since the missed dose; in that case, they should wait until the next scheduled dose. Stress the importance of not discontinuing any other prescribed medications, including other blood pressure medications, without consulting their healthcare provider.

Instruct patients to seek immediate medical attention if they suspect an overdose of amlodipine besylate by contacting their doctor, Poison Control Center, or going to the nearest emergency room.

Discuss potential side effects, noting that while most are mild to moderate, they may include headache, swelling of the legs or ankles, fatigue, stomach pain, nausea, dizziness, flushing, arrhythmia, and heart palpitations. Advise patients to report any concerning side effects to their healthcare provider. It is important to inform them that, although rare, a heart attack or worsening angina may occur when starting or increasing the dose of amlodipine besylate, and they should seek immediate medical help if this happens.

Remind patients to keep amlodipine besylate tablets out of reach of children and to store them at room temperature, away from light and moisture, and not in the bathroom.

Encourage patients to use amlodipine besylate only as prescribed by their healthcare provider and to avoid sharing it with others, even if they exhibit similar symptoms, as it may be harmful to them.

Patients can obtain further information about amlodipine besylate from their pharmacist or healthcare provider, or by visiting the Amneal website or calling the provided contact number. Advise them to report any side effects to their healthcare provider and to the FDA if necessary.

Storage and Handling

Amlodipine besylate tablets are supplied in tight, light-resistant containers as defined by the United States Pharmacopeia (USP). The recommended storage conditions are 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 keep the tablets away from light and to store them in a dry place. Amlodipine besylate tablets should not be stored in the bathroom and must be kept out of reach of children to ensure safety.

Additional Clinical Information

No further data are available.

FDA Insert (PDF)

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

View full prescribing information (PDF)