Amlodipine besylate

Description

Amlodipine besylate 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 C₂₀H₂₅ClN₂O₅ • C₆H₆O₃S, and it has a molecular weight of 567.1. Amlodipine besylate appears as a white crystalline powder that is slightly soluble in water and sparingly soluble in ethanol.

Amlodipine besylate is formulated as white tablets for oral administration, available in strengths of 2.5 mg, 5 mg, and 10 mg of amlodipine. Each tablet contains inactive ingredients including microcrystalline cellulose, dibasic calcium phosphate anhydrous, sodium starch glycolate, and magnesium stearate.

Uses and Indications

Amlodipine besylate is indicated for the treatment of hypertension and coronary artery disease. It may be used as monotherapy or in combination with other antihypertensive and antianginal agents.

In the context of coronary artery disease, amlodipine is indicated for the management of chronic stable angina, vasospastic angina (Prinzmetal's or variant angina), and in 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 the use of amlodipine besylate.

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 advised to initiate treatment with a reduced 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 caution should be exercised when considering dosage adjustments.

Healthcare professionals should ensure that patients are monitored for efficacy and tolerability, adjusting the dosage as necessary within the established guidelines.

Contraindications

Use of this product is contraindicated in patients with a known sensitivity to amlodipine.

Warnings and Precautions

Symptomatic hypotension may occur, especially in patients diagnosed with severe aortic stenosis. Due to the gradual onset of action associated with the medication, the likelihood of experiencing acute hypotension is considered low.

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

In patients with severe hepatic impairment, it is essential to titrate calcium channel blockers, including amlodipine besylate, slowly. This precaution helps mitigate the risk of adverse effects and ensures patient safety. Regular assessment of liver function may be warranted to guide dosing decisions in this population.

Side Effects

Patients may experience a range of adverse reactions while receiving treatment. The most common adverse reactions reported include headache and edema.

In clinical trials and postmarketing experiences, other adverse reactions with an incidence greater than 1.0% include headache, fatigue, nausea, abdominal pain, and somnolence.

Warnings associated with the use of this medication indicate that symptomatic hypotension is possible, particularly in patients with severe aortic stenosis. However, due to the gradual onset of action, acute hypotension is unlikely to occur. Additionally, there is a risk of worsening angina and acute myocardial infarction, particularly after initiating or increasing the dose of amlodipine besylate tablets in patients with severe obstructive coronary artery disease.

It is also important to note that some patients may have a known sensitivity to amlodipine, which should be considered when evaluating potential adverse reactions.

Drug Interactions

Co-administration of amlodipine besylate tablets with various medications and substances has been evaluated for potential drug interactions, with the following observations noted:

Pharmacokinetic Interactions:

• CYP3A4 Inhibitors: The combination of amlodipine besylate tablets with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, ritonavir) may lead to increased plasma concentrations of amlodipine. It is advised to monitor patients for symptoms of hypotension and edema when these agents are used concurrently. In contrast, erythromycin did not significantly alter amlodipine systemic exposure.

• CYP3A4 Inducers: There is no available data on the quantitative effects of CYP3A4 inducers on amlodipine. Blood pressure should be closely monitored in patients receiving amlodipine alongside CYP3A4 inducers.

• Diltiazem: Co-administration of a 180 mg daily dose of diltiazem with 5 mg amlodipine in elderly hypertensive patients resulted in a 60% increase in amlodipine systemic exposure.

• Atorvastatin: Multiple doses of amlodipine besylate tablets (10 mg) co-administered with atorvastatin (80 mg) did not result in significant changes in the steady-state pharmacokinetic parameters of atorvastatin.

• Sildenafil: A single 100 mg dose of sildenafil did not affect the pharmacokinetic parameters of amlodipine. When used together, both agents independently lowered blood pressure.

• Digoxin: Co-administration of amlodipine besylate tablets with digoxin did not alter serum digoxin levels or renal clearance in normal volunteers.

• Warfarin: There was no change in the warfarin prothrombin response time when amlodipine besylate tablets were co-administered with warfarin.

• Grapefruit Juice: The intake of 240 mL of grapefruit juice with a single oral dose of amlodipine (10 mg) did not significantly affect the pharmacokinetics of amlodipine.

• Antacids: Co-administration of a magnesium and aluminum hydroxide antacid with a single dose of amlodipine besylate tablets had no significant effect on the pharmacokinetics of amlodipine.

• Ethanol: Single and multiple doses of amlodipine besylate tablets did not significantly affect the pharmacokinetics of ethanol.

Clinical Monitoring:

Given the potential for increased exposure to amlodipine with CYP3A4 inhibitors and the lack of data on inducers, it is recommended that clinicians monitor blood pressure and watch for signs of hypotension and edema in patients receiving these combinations.

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's effect on blood pressure in pediatric patients under 6 years of age has not been established. Therefore, caution is advised when considering the use of amlodipine in this age group, as the safety and efficacy profiles remain unclear. Further studies are needed to determine appropriate dosing and outcomes for this population.

Geriatric Use

Clinical studies of amlodipine besylate tablets 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 40–60%. 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

There are no adequate and well-controlled studies in pregnant patients. Amlodipine is classified as Pregnancy Category C, indicating that it 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 correspond to approximately 8 times and 23 times the maximum recommended human dose of 10 mg on a mg/m² basis.

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 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 individuals with severe hepatic impairment to minimize the risk of adverse effects and ensure optimal therapeutic outcomes. Monitoring of liver function is advised during treatment to assess any potential changes in hepatic status and to adjust the dosage accordingly.

Overdosage

Overdosage may lead to significant peripheral vasodilation, resulting in pronounced hypotension and potentially reflex tachycardia. Clinical experience with intentional overdosage of amlodipine besylate tablets 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 equivalent to 4 mg amlodipine/kg or higher—approximately 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 should be provided, which includes elevating the extremities and judicious administration of fluids. If hypotension persists despite these conservative measures, 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 be effective in managing overdose.

Nonclinical Toxicology

Pregnancy Category C indicates that there are no adequate and well-controlled studies in pregnant women. Amlodipine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In nonclinical studies, no evidence of teratogenicity or other embryo/fetal toxicity was observed when pregnant rats and rabbits were treated orally with amlodipine maleate at doses up to 10 mg amlodipine/kg/day during their respective periods of major organogenesis. However, a significant decrease in litter size (approximately 50%) and a notable increase in the number of intrauterine deaths (about fivefold) were reported in rats receiving amlodipine maleate at a dose equivalent to 10 mg amlodipine/kg/day for 14 days before mating and throughout mating and gestation. Additionally, amlodipine maleate has been shown to prolong both the gestation period and the duration of labor in rats at this dose.

In long-term studies, 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. For mice, the highest dose was, on a mg/m² basis, similar to the maximum recommended human dose of 10 mg amlodipine/day, while for rats, the highest dose was approximately twice the maximum recommended human dose on a mg/m² basis. Mutagenicity studies conducted with amlodipine maleate revealed no drug-related effects at either the gene or chromosome level. Furthermore, there was no effect on the fertility of rats treated orally with amlodipine maleate (males for 64 days and females 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

Infrequent reports of gynecomastia have been documented in the postmarketing experience, with the causal relationship remaining uncertain. Additionally, cases of jaundice and elevations in hepatic enzymes, primarily consistent with cholestasis or hepatitis, have been observed. Some instances were severe enough to necessitate hospitalization in patients using amlodipine.

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. If patients have any questions regarding amlodipine besylate tablets, they should consult their doctor, who can determine if this medication is appropriate for them.

Amlodipine besylate is classified as a calcium channel blocker (CCB) and is utilized for the treatment of high blood pressure (hypertension) and a specific type of chest pain known as angina. It may be prescribed 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 works by relaxing blood vessels, facilitating easier blood flow, and ultimately lowering blood pressure, which reduces the risk of stroke or heart attack. Angina is characterized by recurring pain or discomfort due to insufficient blood supply to the heart, often described as a pressing or squeezing sensation in the chest, which may radiate to the shoulders, arms, neck, jaws, or back. Amlodipine besylate can alleviate this pain.

Patients must inform their healthcare provider if they are allergic to amlodipine or any of the inactive ingredients. It is essential to disclose all prescription and non-prescription medications being taken, including natural or herbal remedies. Patients should also inform their doctor if they have a history of heart disease or liver problems, are pregnant or planning to become pregnant, or are breastfeeding. Amlodipine besylate is not recommended for breastfeeding mothers, who may need to consider alternative treatments.

Patients should take amlodipine besylate tablets once daily, with or without food. It may be beneficial to take the medication at the same time each day, such as with breakfast, dinner, or at bedtime. They should not exceed one dose at a time. If a dose is missed, patients should take it as soon as they remember, but if more than 12 hours have passed since the missed dose, they should skip it and resume their regular dosing schedule.

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

While taking amlodipine besylate, patients should be aware of potential side effects, which may include headache, swelling of the legs or ankles, fatigue, stomach pain, nausea, dizziness, flushing, arrhythmia, and heart palpitations. Although rare, patients may experience a heart attack or worsening angina when starting or increasing the dose of amlodipine besylate. If such symptoms occur, they should contact their doctor or go to the emergency room immediately. Patients should report any side effects of concern to their healthcare provider, as this list does not encompass all possible side effects.

Amlodipine besylate tablets should be stored out of reach of children, at room temperature (between 59° and 86°F), away from light, and in a dry place, avoiding storage in the bathroom. Patients should only use amlodipine besylate as directed by their healthcare provider and should not share it with others, even if they exhibit similar symptoms, as it may be harmful to them.

For additional information about amlodipine besylate, patients can consult their pharmacist or doctor, or contact 1-800-438-1985.

Storage and Handling

Bottles should be stored at controlled room temperature, specifically between 59° to 86°F (15° to 30°C). It is essential to dispense the product in tight, light-resistant containers that comply with United States Pharmacopeia (USP) standards to ensure optimal stability and efficacy.

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 RedPharm Drug Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)