Amlodipine besylate

Description

Amlodipine besylate tablets consist of the besylate salt of amlodipine, a long-acting calcium channel blocker. The chemical structure of amlodipine besylate is defined as 3-Ethyl-5-methyl (±)-2-(2-aminoethoxy)methyl-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridine dicarboxylate, monobenzenesulphonate, with an empirical formula of C20H25ClN2O5 • C6H6O3S. The compound appears as a white crystalline powder and has a molecular weight of 567.1. Amlodipine besylate exhibits slight solubility in water and sparing solubility in ethanol.

The tablets are available for oral administration in strengths of 2.5 mg, 5 mg, and 10 mg of amlodipine. Each tablet contains inactive ingredients, including microcrystalline cellulose, corn starch, sodium starch glycolate, and magnesium stearate.

Uses and Indications

Amlodipine besylate tablets are indicated for the treatment of hypertension and coronary artery disease. This medication 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 and vasospastic angina (Prinzmetal's or variant angina). Additionally, it 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 the use of 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, 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. 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.

Healthcare professionals should ensure that the dosing regimen is tailored to the individual patient's needs, taking into account their specific circumstances and health status.

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. 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 and the risk 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 essential to titrate calcium channel blockers, including amlodipine besylate, slowly. This precaution helps to mitigate the risk of adverse effects and ensures patient safety during therapy. Regular assessment of liver function may be warranted to guide dosing adjustments in this population.

Side Effects

Patients may experience a range of adverse reactions while using the medication. 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. Notably, symptomatic hypotension may occur, particularly in patients with severe aortic stenosis. Additionally, worsening angina and acute myocardial infarction can develop after initiating or increasing the dose of amlodipine besylate tablets, especially in patients with severe obstructive coronary artery disease.

It is 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 has been evaluated for potential drug interactions, with the following observations noted:

Pharmacokinetic Interactions:

• Amlodipine besylate tablets do not affect the plasma protein binding of digoxin, phenytoin, warfarin, or indomethacin.

• The pharmacokinetics of amlodipine besylate are not altered by cimetidine or by the administration of magnesium and aluminum hydroxide antacids.

• Grapefruit juice (240 mL) does not significantly affect the pharmacokinetics of a single oral dose of amlodipine (10 mg).

• A single 100 mg dose of sildenafil does not alter the pharmacokinetic parameters of amlodipine besylate tablets. When used together, both agents independently lower blood pressure.

• Co-administration of multiple 10 mg doses of amlodipine besylate tablets with 80 mg of atorvastatin does not result in significant changes to atorvastatin's steady-state pharmacokinetic parameters.

• Amlodipine besylate tablets do not change serum digoxin levels or renal clearance of digoxin in normal volunteers.

• The pharmacokinetics of ethanol are not significantly affected by single or multiple doses of amlodipine besylate tablets.

• Co-administration with warfarin does not alter the prothrombin response time.

CYP3A4 Interactions:

• The combination of amlodipine besylate tablets with diltiazem (180 mg daily) in elderly hypertensive patients results in a 60% increase in amlodipine systemic exposure.

• Strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, ritonavir) may significantly increase amlodipine plasma concentrations. Patients should be monitored for symptoms of hypotension and edema when these inhibitors are co-administered.

• There is no available information on the quantitative effects of CYP3A4 inducers on amlodipine. Blood pressure should be closely monitored when amlodipine is used with CYP3A4 inducers.

Drug/Laboratory Test Interactions:

• No known interactions have been identified between amlodipine besylate tablets and laboratory tests.

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 besylate tablets have not been studied in pediatric patients under 6 years of age, and the effect on blood pressure in this population is not known. Caution is advised when considering the use of this medication in younger children, as the safety and efficacy have not been established in this age group.

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 approximate 40–60% increase in the area under the curve (AUC). 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 assess the safety and efficacy of amlodipine during pregnancy. 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 was associated with prolonged gestation and an extended duration of labor in rats. These findings suggest potential risks associated with the use of amlodipine during pregnancy, warranting careful consideration and monitoring in 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 tablets are administered.

Renal Impairment

Patients with renal impairment have not been specifically addressed in the available data regarding dosage adjustments, special monitoring, or safety considerations. Therefore, healthcare professionals should exercise caution when prescribing this medication to patients with reduced kidney function, as the lack of information necessitates careful clinical judgment and monitoring.

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 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 besylate tablets in humans is limited, underscoring the need for caution.

Toxicological studies in animal models 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 the maximum recommended human dose by 11 times on a mg/m² basis—produced 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 assessments are crucial to manage the patient's condition effectively. 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. It is essential to monitor circulating volume and urine output closely during this process.

Due to the high protein binding of amlodipine besylate tablets, hemodialysis is unlikely to provide any therapeutic benefit in cases 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 amlodipine mg/kg/day, showed no evidence of a carcinogenic effect of the drug. 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 (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 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

Healthcare providers should advise patients to read the provided information carefully before starting amlodipine besylate tablets and each time they refill their prescription, as there may be new information. It is important to emphasize that this information does not replace discussions with their doctor. Patients should be encouraged to ask their doctor any questions they may have regarding the appropriateness of amlodipine besylate tablets for their condition.

Patients should be informed that amlodipine besylate tablets are classified as a calcium channel blocker (CCB) and are used to treat high blood pressure (hypertension) and a type of chest pain known as angina. It can be prescribed alone or in combination with other medications to manage these conditions.

Healthcare providers should explain that high blood pressure occurs when blood exerts excessive force against blood vessel walls. Amlodipine besylate tablets work by relaxing blood vessels, facilitating easier blood flow, and ultimately lowering blood pressure. This reduction in blood pressure can decrease the risk of stroke or heart attack.

Patients should be made aware that angina is characterized by recurring pain or discomfort due to insufficient blood supply to the heart. This pain may manifest as a pressing or squeezing sensation in the chest, and it can also radiate to the shoulders, arms, neck, jaws, or back. Amlodipine besylate tablets can help alleviate this discomfort.

It is crucial to inform patients not to use amlodipine besylate tablets if they are allergic to amlodipine or any of the inactive ingredients. Healthcare providers should encourage patients to disclose all prescription and non-prescription medications they are currently taking, including any natural or herbal remedies.

Patients should also be advised to inform their doctor if they have a history of heart disease or liver problems, or if they are pregnant or planning to become pregnant, as these factors may influence the suitability of amlodipine besylate tablets for their treatment. Additionally, patients should be instructed not to breast-feed while taking this medication and to consider alternative treatments.

Amlodipine besylate tablets should be taken once daily, with or without food. Patients may find it helpful to take their dose at the same time each day, such as with breakfast, dinner, or at bedtime. They should be cautioned against taking more than 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 tablets 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 be instructed to contact their doctor, the Poison Control Center, or go to the nearest hospital emergency room immediately.

Healthcare providers should inform patients about potential side effects, which may include mild to moderate symptoms such as headache, swelling of the legs or ankles, tiredness, extreme sleepiness, stomach pain, nausea, dizziness, flushing, arrhythmia, and heart palpitations. Patients should be made aware that, although rare, there is a risk of experiencing a heart attack or worsening angina when starting or increasing the dose of amlodipine besylate tablets. They should be advised to seek immediate medical attention if such symptoms occur.

Patients should be encouraged to communicate any concerns regarding side effects to their doctor, and they should be informed that this list does not encompass all possible side effects. For a complete list, they should consult their doctor or pharmacist.

Finally, healthcare providers should remind patients to keep amlodipine besylate tablets out of reach of children and to store them at temperatures between 20° to 25°C (68° to 77°F), with permissible excursions between 15° to 30°C (59° to 86°F). Patients should be advised to protect the medication from light, avoid storing it in the bathroom, and keep it in a dry place.

Patients should be cautioned against using amlodipine besylate tablets for any condition not specified in the patient information leaflets and should not share their medication with others, as it may be harmful to them.

Storage and Handling

Bottles should be stored at a temperature range of 20° to 25°C (68° to 77°F), with permissible excursions between 15° and 30°C (59° to 86°F) in accordance with USP Controlled Room Temperature guidelines.

The product must be dispensed in tight, light-resistant containers that feature a child-resistant closure, as specified by USP standards. It is essential to protect the product from light and moisture to maintain its integrity.

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 Caraco Pharmaceutical Laboratories, Ltd.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)