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 a molecular formula of C20H25ClN2O5•C6H6O3S. Amlodipine besylate, USP appears as a white or almost white crystalline powder and has a molecular weight of 567.1. The compound is slightly soluble in water and sparingly soluble in ethanol. Each amlodipine besylate tablet, USP, intended for oral administration, contains 2.5 mg, 5 mg, or 10 mg of amlodipine besylate. The tablets also include inactive ingredients such as colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate.

Uses and Indications

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

This medication may be utilized 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 besylate tablets, USP.

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 dosing is tailored to the individual patient's needs, taking into account factors such as age, weight, and hepatic function.

Contraindications

Use of this product is contraindicated in patients with a known sensitivity to amlodipine. This contraindication is based on the potential for severe allergic reactions in individuals with such sensitivities.

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.

The initiation or dosage increase of amlodipine besylate tablets may lead to worsening angina or acute myocardial infarction, particularly in individuals with severe obstructive coronary artery disease. It is crucial for healthcare providers to monitor patients closely during these periods and to assess the risk versus benefit of continuing therapy in such cases.

In patients with severe hepatic impairment, it is recommended to titrate the dosage of amlodipine besylate tablets slowly. This cautious approach is essential to minimize the risk of adverse effects and to ensure patient safety. Regular monitoring of liver function tests may be warranted to guide appropriate dosing adjustments.

Side Effects

Patients may experience a range of adverse reactions while using the medication. The most common adverse reaction reported is edema, which is dose-related. Other common adverse reactions, occurring in more than 1% of patients, include fatigue, nausea, abdominal pain, and somnolence.

Serious side effects have also been observed. Symptomatic hypotension may occur, particularly in patients with severe aortic stenosis; however, acute hypotension is considered unlikely. 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 taken into consideration when prescribing this medication.

Drug Interactions

There are currently no documented drug interactions associated with this medication. Additionally, there is no information available regarding interactions with laboratory tests. As such, no specific recommendations for dosage adjustments or monitoring are warranted at this time.

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 has been shown to be 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 safety and efficacy of amlodipine besylate in patients younger than 6 years have not been established, and its effects in this age group remain unknown.

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, 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

The available data regarding the use of amlodipine besylate in pregnant women 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 recognize that poorly controlled hypertension during pregnancy poses significant risks to both the mother and fetus.

Animal reproduction studies have demonstrated no evidence of adverse developmental effects 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. Notably, while no teratogenicity or other embryo/fetal toxicity was observed at doses up to 10 mg amlodipine/kg/day, there were significant findings in rats, including a 50% reduction in litter size and a five-fold increase in intrauterine deaths. Additionally, amlodipine maleate was associated with prolonged gestation and extended labor duration in rats at this dosage.

The estimated background risk of major birth defects and miscarriage in the general U.S. population is approximately 2% to 4% and 15% to 20%, respectively. All pregnancies inherently carry a background risk of birth defects, loss, or other adverse outcomes. Furthermore, hypertension in pregnancy is linked to increased maternal risks, including pre-eclampsia, gestational diabetes, premature delivery, and complications during delivery, such as the need for cesarean section and postpartum hemorrhage. Fetal risks associated with maternal hypertension include intrauterine growth restriction and intrauterine death.

Given these considerations, pregnant women with hypertension should be closely monitored and managed to mitigate potential risks to both maternal and fetal health.

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 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 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 clinical manifestations, primarily characterized by excessive peripheral vasodilation resulting in marked hypotension, which may be accompanied by reflex tachycardia.

Toxicological 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 have also been associated with pronounced peripheral vasodilation and hypotension.

In the event of a massive overdose, it is imperative to initiate active cardiac and respiratory monitoring. Continuous and frequent blood pressure measurements are essential to assess the patient's hemodynamic status. Should hypotension occur, it is recommended to provide cardiovascular support, which may include elevating the extremities and administering fluids judiciously.

If hypotension persists despite these conservative measures, the administration of vasopressors, such as phenylephrine, should be considered to restore hemodynamic stability. It is important to note that due to the high protein binding of amlodipine besylate, hemodialysis is unlikely to be effective 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 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, approximately 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, based on a patient weight of 50 kg.

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. There is also a reported possible association between extrapyramidal disorder and amlodipine. Notably, 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

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.

Amlodipine besylate 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 be informed that it can be used alone or in combination 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. Regarding angina, patients should be made aware that it manifests as 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 help alleviate this pain.

Patients must be cautioned against using amlodipine besylate tablets if they have a known allergy to amlodipine or any of the inactive ingredients. They should be encouraged to inform their doctor 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 pregnancy status or plans to become pregnant. Patients who are breastfeeding should be advised not to breastfeed while taking amlodipine besylate tablets and should discuss alternative treatment options with their doctor.

Patients should be instructed to take amlodipine besylate tablets once daily, with or without food, and it may be beneficial to take the medication at the same time each day to aid in adherence. They should not take more than one dose at a time and should be informed about the appropriate action to take if a dose is missed. If more than 12 hours have passed since the missed dose, they should skip it and resume their regular dosing schedule.

Patients can safely use nitroglycerin in conjunction with amlodipine besylate tablets for angina, but they should not discontinue nitroglycerin without consulting their doctor. It is crucial that patients do not stop taking any other prescribed medications, including other antihypertensives, without first discussing it with their healthcare provider.

In the event of an overdose, patients should be instructed to 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 besylate tablets, which may include mild to moderate symptoms such as swelling of the legs or ankles, tiredness, extreme sleepiness, stomach pain, nausea, dizziness, flushing, arrhythmia, heart palpitations, and abnormal muscle movements. They should be informed that while rare, there is a risk of experiencing a heart attack or worsening angina when starting or increasing the dose of amlodipine besylate. Patients should be encouraged to report any side effects to their doctor and to contact the FDA for further reporting if necessary.

Finally, patients should be advised to store amlodipine besylate tablets at room temperature, away from light and moisture, and out of reach of children. They should be reminded not to share their medication with others, even if they exhibit similar symptoms, as it may be harmful to them.

Storage and Handling

The product is supplied in a tight, light-resistant container to ensure its integrity. It should be stored at a temperature range of 20°C to 25°C (68°F to 77°F), in accordance with USP Controlled Room Temperature guidelines. Additionally, it is essential to protect the product from light exposure to maintain its 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 Major Pharmaceuticals. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)