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 the molecular weight is 567.1. Amlodipine besylate appears as a white crystalline powder, which is slightly soluble in water and sparingly soluble in ethanol.

Amlodipine Besylate Tablets are available in formulations that provide 2.5 mg, 5 mg, and 10 mg of amlodipine for oral administration. Each tablet contains inactive ingredients, including microcrystalline cellulose, dibasic calcium phosphate anhydrous, sodium starch glycolate, and magnesium stearate.

Uses and Indications

Amlodipine is indicated for the treatment of hypertension, effectively lowering blood pressure. This reduction in blood pressure is associated with a decreased risk of both fatal and nonfatal cardiovascular events, including strokes and myocardial infarctions.

Amlodipine may be administered as monotherapy or in conjunction with other antihypertensive and antianginal agents for the management of the following conditions:

• 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.

Dosage and Administration

The usual initial antihypertensive oral dose of amlodipine for adults is 5 mg once daily, with a maximum dose of 10 mg once daily. For small, fragile, or elderly patients, as well as those with hepatic insufficiency, treatment may begin at 2.5 mg once daily. This lower dose may also be appropriate when amlodipine is added to other antihypertensive therapies.

Dosage adjustments should be made according to individual blood pressure goals, with a recommended waiting period of 7 to 14 days between titration steps. More rapid titration may be considered if clinically warranted, provided that the patient is assessed frequently.

For the management of chronic stable or vasospastic angina, the recommended dose is 5 to 10 mg once daily, with the lower dose suggested for elderly patients and those with hepatic insufficiency. Most patients will require 10 mg for adequate therapeutic effect. In patients with coronary artery disease, the recommended dose range is also 5 to 10 mg once daily, with the majority of patients in clinical studies requiring 10 mg.

In pediatric patients aged 6 to 17 years, the effective antihypertensive oral dose is 2.5 mg to 5 mg once daily. Doses exceeding 5 mg daily have not been studied in this population.

Contraindications

Use of this product is contraindicated in patients with a known sensitivity to amlodipine. This is due to the potential for adverse reactions in individuals with hypersensitivity to the active ingredient.

Warnings and Precautions

Symptomatic hypotension may occur, especially in patients diagnosed with severe aortic stenosis. While acute hypotension is generally 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. Common adverse reactions, occurring in more than 1% of participants, include edema, fatigue, nausea, abdominal pain, and somnolence.

Serious adverse reactions have also been reported. Symptomatic hypotension may occur, particularly in patients with severe aortic stenosis, although acute hypotension is unlikely. Additionally, worsening angina can develop after initiating or increasing the dose, especially in patients with severe obstructive coronary artery disease. There is also a risk of acute myocardial infarction under similar circumstances in this patient population.

It is important to note that individuals with known sensitivity to amlodipine may experience adverse reactions as well.

Drug Interactions

There are currently no specific drug interactions or drug and laboratory test interactions identified for this medication. As such, no dosage adjustments or monitoring recommendations are necessary at this time. Healthcare professionals should continue to assess the patient's overall medication regimen and clinical status to ensure safe and effective use.

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 effect of amlodipine on blood pressure in patients younger than 6 years of age has not been established. Caution is advised when considering treatment in this younger age group due to the lack of data on efficacy and safety.

Geriatric Use

Clinical studies of amlodipine did not include a sufficient number of subjects aged 65 and over to determine whether they respond differently from younger patients. However, other reported clinical experiences have not identified significant differences in responses between elderly patients and their younger counterparts.

In general, dose selection for geriatric patients should be approached with caution. It is advisable to start at the lower 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

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 note that poorly controlled hypertension during pregnancy poses significant risks to both the mother and fetus.

In animal reproduction studies, no evidence of adverse developmental effects was 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. Nonetheless, in rats, there was a notable decrease in litter size (approximately 50%) and a significant increase in intrauterine deaths (about 5-fold) at the same doses. Additionally, amlodipine has been shown to prolong both the gestation period and the duration of labor in rats.

The estimated background risk of major birth defects and miscarriage in the general population remains unknown; however, it is acknowledged that all pregnancies carry a baseline risk of adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is approximately 2%-4% and 15%-20%, respectively.

Hypertension in pregnancy is associated with increased maternal risks, including pre-eclampsia, gestational diabetes, premature delivery, and complications during delivery, such as the need for cesarean section and postpartum hemorrhage. Furthermore, fetal risks associated with maternal hypertension include intrauterine growth restriction and intrauterine death. Therefore, pregnant women with hypertension should be closely monitored and managed to mitigate these risks.

In summary, while animal studies have not demonstrated teratogenicity or other embryo/fetal toxicity at certain doses, the potential risks associated with hypertension in pregnancy necessitate careful consideration and management of pregnant patients using amlodipine.

Lactation

Limited available data from a published clinical lactation study indicate that amlodipine is present in human milk at an estimated median relative infant dose of 4.2%. No adverse effects of amlodipine on breastfed infants have been observed. Additionally, there is no available information regarding the effects of amlodipine on milk production in lactating mothers.

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 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 adverse effects, primarily characterized by excessive peripheral vasodilation resulting in marked hypotension, which may be accompanied by 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 led to 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 manifest, immediate cardiovascular support should be provided, which includes elevating the extremities and judiciously administering intravenous fluids.

If hypotension persists despite these conservative measures, the administration of vasopressors, such as phenylephrine, may be warranted. Careful attention must be given to the patient's circulating volume and urine output during this intervention.

Due to the high protein binding of amlodipine, hemodialysis is unlikely to be effective in managing an overdose situation. Therefore, supportive care remains the cornerstone of treatment in cases of amlodipine overdosage.

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 was, on a mg/m² basis, similar to the maximum recommended human dose of 10 mg amlodipine/day. In rats, the highest dose was, on a mg/m² basis, about twice the maximum recommended human dose.

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/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 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. There is also a possible association between extrapyramidal disorder and amlodipine noted in postmarketing reports. Despite these findings, amlodipine 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

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 amlodipine and to confirm whether it is the right medication for them.

Amlodipine is classified as a calcium channel blocker (CCB) and is indicated for the treatment of high blood pressure (hypertension) and a type of chest pain known as angina. Patients should understand that amlodipine can be used 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 works by relaxing blood vessels, facilitating easier blood flow, and ultimately lowering blood pressure, which reduces the risk of stroke or heart attack. Patients should also be informed about angina, which is characterized by recurring pain or discomfort due to insufficient blood supply to the heart. Amlodipine can help alleviate this pain.

Patients must be cautioned against using amlodipine if they have a known allergy to amlodipine or any of its inactive ingredients. Healthcare providers should encourage patients to disclose all prescription and non-prescription medications they are currently taking, including natural or herbal remedies. It is particularly important for patients to inform their doctor if they have a history of heart disease or liver problems, are pregnant or planning to become pregnant, or are breastfeeding, as these factors may influence the appropriateness of amlodipine as a treatment option.

Patients should be instructed to take amlodipine once daily, with or without food, and to establish a routine by taking it at the same time each day. They should be advised not to exceed one dose at a time. If a dose is missed, patients should take it as soon as they remember, unless more than 12 hours have passed since the missed dose, in which case they should wait until the next scheduled dose.

Healthcare providers should inform patients that it is safe to use nitroglycerin in conjunction with amlodipine 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.

Patients should be made aware of potential side effects associated with amlodipine, which may include mild to moderate symptoms such as swelling of the legs or ankles, tiredness, stomach pain, nausea, dizziness, flushing, arrhythmia, heart palpitations, and abnormal muscle movements. It is crucial to inform patients that, although rare, they may experience a heart attack or worsening angina when starting amlodipine or increasing their dose, and they should seek immediate medical attention if this occurs. Patients should be encouraged to report any side effects they experience to their doctor and to consult their doctor or pharmacist for a complete list of possible side effects.

Patients should be reminded to keep amlodipine out of reach of children and to store it at the recommended temperature, away from light and moisture. They should be advised not to use amlodipine for any condition not specified by their doctor and to refrain from sharing their medication with others, as it may be harmful to them.

Storage and Handling

The product is supplied in tight, light-resistant containers to ensure optimal preservation of its integrity. 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) in accordance with USP Controlled Room Temperature guidelines. Proper handling and storage conditions are essential to maintain the product's efficacy and 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 China Resources Saike Pharmaceutical Co. , Ltd.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)