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, with an empirical formula of C20H25ClN2O5 • C6H6O3S. Amlodipine besylate appears as a white crystalline powder and has a molecular weight of 567.1. It is slightly soluble in water and sparingly soluble in ethanol.

Amlodipine besylate tablets are available in white tablet form, with each tablet containing 2.5 mg, 5 mg, or 10 mg of amlodipine for oral administration. In addition to the active ingredient, the tablets contain the following inactive ingredients: sodium starch glycolate, mannitol, microcrystalline cellulose, dibasic calcium phosphate anhydrous, colloidal silicon dioxide, 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. Specifically, it is indicated for the management of:

• Hypertension

• Coronary Artery Disease, which encompasses:

  • Chronic Stable Angina

  • Vasospastic Angina (Prinzmetal’s or Variant Angina)

  • Angiographically Documented Coronary Artery Disease in patients who do not have heart failure or an ejection fraction less than 40%.

There are no teratogenic or nonteratogenic effects associated with 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 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 caution should be exercised when considering higher doses.

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

Patients receiving treatment with amlodipine besylate should be closely monitored for potential adverse cardiovascular effects.

Symptomatic Hypotension Healthcare professionals should be aware that symptomatic hypotension may occur, particularly in patients with severe aortic stenosis. Although the onset of action is gradual, the risk of acute hypotension remains low. Continuous monitoring of blood pressure is recommended to ensure patient safety.

Worsening Angina and Myocardial Infarction There is a risk of worsening angina and acute myocardial infarction following the initiation or dose escalation of amlodipine besylate, especially in patients with severe obstructive coronary artery disease. Clinicians should evaluate the patient's cardiovascular status and consider appropriate monitoring strategies when adjusting dosages.

Hepatic Impairment In patients with severe hepatic impairment, it is crucial to titrate calcium channel blockers, including amlodipine besylate, slowly. This precaution helps mitigate the risk of adverse effects associated with altered drug metabolism. Regular assessment of liver function tests may be warranted to guide dosing adjustments and ensure safe administration.

Side Effects

Patients may experience a range of adverse reactions while receiving treatment. Common adverse reactions reported include headache, edema, fatigue, nausea, abdominal pain, and somnolence.

In addition to these common reactions, there are important considerations regarding more serious adverse events. Symptomatic hypotension may occur, particularly in patients with severe aortic stenosis; however, due to the gradual onset of action, acute hypotension is unlikely. Furthermore, worsening angina and acute myocardial infarction have been observed following the initiation or dose escalation of amlodipine besylate, especially 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 taken into account when considering treatment options.

Drug Interactions

Amlodipine besylate exhibits a favorable interaction profile with several commonly used medications, as detailed below.

Pharmacokinetic Interactions

• Digoxin, Phenytoin, Warfarin, and Indomethacin: In vitro studies indicate that amlodipine besylate does not affect the plasma protein binding of these agents, suggesting no significant pharmacokinetic interactions.

• Cimetidine: Co-administration with cimetidine does not alter the pharmacokinetics of amlodipine besylate, indicating that dosage adjustments are not necessary when these drugs are used together.

• Grapefruit Juice: A study involving 240 mL of grapefruit juice with a single oral dose of amlodipine 10 mg showed no significant effect on the pharmacokinetics of amlodipine, allowing for concurrent consumption without concern for interaction.

• Magnesium and Aluminum Hydroxide Antacids: The co-administration of these antacids with a single dose of amlodipine besylate did not significantly affect its pharmacokinetics, suggesting that no dosage adjustments are required.

• Sildenafil: A single 100 mg dose of sildenafil did not impact the pharmacokinetic parameters of amlodipine. When used in combination, both agents independently lowered blood pressure without necessitating dosage modifications.

• Atorvastatin: Co-administration of multiple 10 mg doses of amlodipine besylate with 80 mg of atorvastatin resulted in no significant changes in the steady-state pharmacokinetics of atorvastatin, indicating that dosage adjustments are not required.

• Ethanol: Both single and multiple doses of amlodipine besylate had no significant effect on the pharmacokinetics of ethanol, allowing for concurrent use without concern for interaction.

• Warfarin: Co-administration with warfarin did not alter the prothrombin response time, suggesting that no dosage adjustments are necessary when these medications are used together.

Pharmacodynamic Interactions

• Amlodipine besylate does not change serum digoxin levels or renal clearance of digoxin when co-administered, indicating a lack of pharmacodynamic interaction.

Drug/Laboratory Test Interactions

• There are no known drug or laboratory test interactions associated with amlodipine besylate.

Overall, the interaction profile of amlodipine besylate suggests a low potential for clinically significant interactions with the listed medications, and routine monitoring or dosage adjustments are generally not required.

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

Geriatric Use

Clinical studies of amlodipine besylate 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 besylate, 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. Regular monitoring and assessment of the patient's response to therapy are recommended to optimize treatment outcomes.

Pregnancy

Amlodipine is classified as a Pregnancy Category C medication. There are no adequate and well-controlled studies in pregnant women to establish its safety profile during pregnancy. 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. However, significant adverse effects were observed in rats receiving this dose, including a reduction in litter size by approximately 50% and an increase in the number of intrauterine deaths by about five-fold. Additionally, amlodipine maleate has been shown to prolong both the gestation period and the duration of labor in rats at this dosage.

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

Lactation

It is not known whether amlodipine is excreted in human milk. In the absence of this information, it is recommended that nursing be discontinued while amlodipine besylate is administered.

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 these patients to ensure safety and efficacy.

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 clinical manifestations, primarily characterized by excessive peripheral vasodilation resulting in marked hypotension, which may be accompanied by reflex tachycardia. The clinical experience regarding intentional overdosage of amlodipine besylate in humans is limited.

Animal studies have demonstrated 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—induced significant peripheral vasodilation and hypotension.

In the event of a massive overdose, it is imperative to initiate active cardiac and respiratory monitoring. Frequent blood pressure measurements are essential to assess the patient's hemodynamic status. Should hypotension occur, cardiovascular support should be provided, which includes elevating the extremities and judiciously administering fluids. If hypotension persists despite these conservative measures, the use of vasopressors, such as phenylephrine, may be warranted, with careful attention to circulating volume and urine output.

Due to the high protein binding of amlodipine besylate, hemodialysis is unlikely to be beneficial in managing an overdose situation.

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/day. In 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. Additionally, there was no effect on the fertility of rats treated orally with amlodipine maleate, with males treated for 64 days and females for 14 days prior to mating at doses up to 10 mg/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 identified several events reported voluntarily or through surveillance programs. Gynecomastia has been reported 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. Amlodipine besylate has 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

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 will determine if this medication is appropriate for them.

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 used alone or in combination with other treatments for these conditions. Patients should understand that high blood pressure results from excessive force against blood vessel walls. Amlodipine besylate tablets work 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 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. They should 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. Amlodipine besylate tablets are not recommended during breastfeeding.

Patients are advised to take amlodipine besylate tablets once daily, with or without food, and can consume it with most beverages, including grapefruit juice. To aid in adherence, it may be beneficial to take the medication at the same time each day, such as with breakfast or dinner. Patients 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, they should skip it and resume their regular dosing schedule.

Patients can continue using nitroglycerin alongside amlodipine besylate tablets for angina, but 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 emergency room.

Patients should be aware of potential side effects associated with amlodipine besylate tablets, which may include headache, swelling of the legs or ankles, tiredness, extreme sleepiness, stomach pain, nausea, dizziness, flushing, arrhythmia, and heart palpitations. While most side effects are mild to moderate, there is a rare risk of heart attack or worsening angina when starting or increasing the dose of amlodipine besylate tablets. Patients should contact their doctor immediately if they experience these serious effects or have concerns about any side effects.

It is essential to keep amlodipine besylate tablets out of reach of children and store them at controlled room temperature (20° to 25°C or 68° to 77°F), away from light and moisture, and not in the bathroom. Patients should only use amlodipine besylate tablets as prescribed by their healthcare provider and should not share this medication with others, even if they have similar symptoms, as it may be harmful to them.

Storage and Handling

The product is supplied in tight, light-resistant containers to ensure optimal stability and efficacy. It should be stored at a temperature range of 20° to 25°C (68° to 77°F), in accordance with USP Controlled Room Temperature guidelines. Proper storage conditions are essential to maintain the integrity of the product throughout its shelf life.

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 WOCKHARDT LIMITED. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)