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 molecular formula is C20H25ClN2O5•C6H6O3S, and it has a molecular weight of 567.1. Amlodipine besylate appears as a white crystalline powder, which is slightly soluble in water and sparingly soluble in ethanol. The tablets are formulated for oral administration and are 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, colloidal silicon dioxide, and magnesium stearate.

Uses and Indications

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

In addition to hypertension, amlodipine besylate tablets may be utilized in the management of coronary artery disease. This includes the treatment 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%.

No teratogenic or nonteratogenic effects have been reported for 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, 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

Symptomatic hypotension may occur, especially in patients diagnosed with severe aortic stenosis. While the risk of acute hypotension is considered low, healthcare professionals should remain vigilant in monitoring these patients for any signs of symptomatic changes.

Additionally, there is a potential risk for 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. It is essential for healthcare providers to assess the cardiovascular status of these patients closely and to consider the potential for adverse events when managing their treatment.

In patients with severe hepatic impairment, it is recommended to titrate the dosage of amlodipine slowly. This cautious approach is necessary 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 and to detect any potential complications early.

Side Effects

Patients may experience a range of adverse reactions while receiving treatment. The most common adverse reactions observed in clinical trials, with an incidence greater than 1.0%, include edema, fatigue, nausea, abdominal pain, and somnolence.

Serious warnings associated with the use of this medication include the potential for symptomatic hypotension, particularly in patients with severe aortic stenosis, although acute hypotension is considered unlikely. Additionally, there is a risk of worsening angina and acute myocardial infarction, especially after initiating or increasing the dose in patients with severe obstructive coronary artery disease.

Patients with known sensitivity to amlodipine should exercise caution. In cases of overdosage, excessive peripheral vasodilation may occur, leading to marked hypotension and possibly reflex tachycardia. Experience with intentional overdosage in humans is limited.

In the event of a massive overdose, it is crucial to initiate active cardiac and respiratory monitoring, with frequent blood pressure measurements. Should hypotension arise, cardiovascular support measures should be implemented, including elevation of 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 attention to circulating volume and urine output. Due to the high protein binding of amlodipine, hemodialysis is unlikely to provide benefit in cases of overdose.

Drug Interactions

There are currently no documented drug interactions associated with the use of 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 tablets, administered at doses of 2.5 to 5 mg daily, have been shown to be effective in lowering blood pressure in pediatric patients aged 6 to 17 years. The safety and efficacy of amlodipine in patients younger than 6 years of age have not been established, and its effect on blood pressure in this age group is not known.

Geriatric Use

Clinical studies of amlodipine 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 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 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 this animal model.

The estimated background risk of major birth defects and miscarriage in the general U.S. population is approximately 2%-4% and 15%-20%, respectively, and all pregnancies carry a baseline risk of adverse outcomes. 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.

Given these considerations, pregnant women with hypertension should be closely monitored and managed to mitigate 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

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 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 during treatment to ensure patient safety and therapeutic efficacy. Adjustments to the dosing regimen may be necessary based on the patient's response and any changes in liver function.

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.

In animal studies, single oral doses of amlodipine maleate equivalent to 40 mg amlodipine/kg in mice have resulted in fatalities. Similarly, doses of 4 mg amlodipine/kg or more in dogs have induced pronounced peripheral vasodilation and hypotension.

In the event of a massive overdose, it is crucial to initiate active cardiac and respiratory monitoring. Frequent blood pressure measurements are essential to assess the patient's hemodynamic status. Should hypotension occur, immediate cardiovascular support is recommended. This may include elevating the extremities and judicious administration of intravenous fluids to restore hemodynamic stability.

If hypotension persists despite these conservative measures, the administration of vasopressors, such as phenylephrine, should be considered. Careful attention must be paid to the patient's circulating volume and urine output during this process.

It is important to note that due to the high protein binding of amlodipine, 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 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 when adjusted for body surface area.

Mutagenicity studies conducted with amlodipine maleate revealed no drug-related effects at either the gene or chromosome level. Additionally, there was no observed effect on the fertility of rats treated orally with amlodipine maleate. Male rats were treated for 64 days, and female rats 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

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 the use of amlodipine. Notably, 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

Patients should be advised to read the provided information carefully before starting amlodipine besylate tablets, USP, 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, USP, 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 indicated 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 combination with other medications to manage these conditions. Patients should understand that high blood pressure results from excessive force exerted by blood 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.

Patients experiencing angina may feel recurring pain or discomfort due to insufficient blood supply to the heart. This discomfort typically manifests 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.

It is crucial for patients to inform their healthcare provider if they have a known allergy to amlodipine or any of the inactive ingredients in the tablets. Additionally, patients should disclose all prescription and non-prescription medications they are currently taking, including any 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, as amlodipine can pass into breast milk. The healthcare provider will assess whether amlodipine besylate is the most suitable treatment option.

Amlodipine besylate tablets, USP, 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 not take more than one dose at a time. If a dose is missed, patients should take it as soon as they remember, but if it has been more than 12 hours since the missed dose, they should skip it and resume their regular dosing schedule.

Patients can use nitroglycerin in conjunction with amlodipine besylate. If they are prescribed nitroglycerin for angina, they should not discontinue its use while taking amlodipine besylate. It is important for patients to continue taking all other prescribed medications, including other blood pressure medications, unless directed otherwise by 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 hospital emergency room.

Patients should be made aware of potential side effects associated with amlodipine besylate, 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 muscle rigidity or tremors. Although rare, patients should be informed that starting amlodipine besylate or increasing the dose may lead to a heart attack or worsening angina. If such symptoms occur, patients should contact their doctor or go to the emergency room immediately.

Patients should communicate any concerns regarding side effects to their healthcare provider. For a comprehensive list of possible side effects, they should consult their doctor or pharmacist.

Amlodipine besylate tablets, USP, should be stored out of reach of children and kept at a temperature of 20° to 25°C (68° to 77°F), with permissible excursions between 15° to 30°C (59° to 86°F). They should be protected from light and stored in a dry place, away from the bathroom.

Patients should only use amlodipine besylate tablets, USP, as prescribed by their healthcare provider, even if they have similar symptoms to others. Sharing this medication with others is not advised, as it may cause harm.

Storage and Handling

The product is supplied in a tight, light-resistant container, in accordance with USP standards. 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) as defined by USP Controlled Room Temperature guidelines. Proper storage conditions are essential to maintain the integrity and efficacy of the product.

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 REMEDYREPACK INC.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)