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

Amlodipine besylate is formulated as white tablets for oral administration, 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, 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.

In the context of coronary artery disease, amlodipine is indicated for the management 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%.

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 therefore should not be administered.

Healthcare professionals should ensure that dosing is tailored to the individual patient's needs, taking into consideration factors such as age, weight, and hepatic function.

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. It is important to note that due to the gradual onset of action of the medication, the risk of acute hypotension is considered low.

Healthcare professionals should be vigilant for the potential exacerbation of angina or the onset 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.

When prescribing calcium channel blockers to individuals with severe hepatic impairment, it is crucial to titrate the dosage slowly. This approach helps to mitigate the risk of adverse effects associated with rapid dose adjustments in this patient population. Regular assessment of liver function may be warranted to ensure safe administration.

Side Effects

Patients may experience a range of adverse reactions while using the medication. The most common adverse reactions reported include headache and edema.

In clinical trials and postmarketing experiences, other adverse reactions with an incidence greater than 1.0% include headache, fatigue, nausea, abdominal pain, and somnolence.

It is important to note specific warnings associated with the use of this medication. Symptomatic hypotension may occur, particularly in patients with severe aortic stenosis; however, due to the gradual onset of action, acute hypotension is 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.

Drug Interactions

Co-administration of amlodipine besylate tablets with various medications and substances has been evaluated for potential drug interactions, with the following observations noted:

Pharmacokinetic Interactions:

• Cimetidine: Co-administration with cimetidine did not alter the pharmacokinetics of amlodipine.

• 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.

• Antacids: The combination of a magnesium and aluminum hydroxide antacid with a single dose of amlodipine besylate tablets did not significantly affect the pharmacokinetics of amlodipine.

• Sildenafil: A single 100 mg dose of sildenafil did not impact the pharmacokinetic parameters of amlodipine. When used together, both agents independently lowered blood pressure.

• Atorvastatin: Co-administration of multiple 10 mg doses of amlodipine besylate tablets with 80 mg of atorvastatin resulted in no significant changes in the steady-state pharmacokinetics of atorvastatin.

• Digoxin: Co-administration with digoxin did not alter serum digoxin levels or renal clearance in normal volunteers.

• Warfarin: There was no change in the warfarin prothrombin response time when amlodipine besylate tablets were co-administered with warfarin.

• Ethanol: Single and multiple doses of amlodipine besylate tablets had no significant effect on the pharmacokinetics of ethanol.

• Diltiazem: Co-administration of a 180 mg daily dose of diltiazem with 5 mg amlodipine in elderly hypertensive patients resulted in a 60% increase in amlodipine systemic exposure.

• CYP3A4 Inhibitors: Strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, ritonavir) may significantly increase plasma concentrations of amlodipine. Patients should be monitored for symptoms of hypotension and edema when amlodipine is used with these inhibitors.

• CYP3A4 Inducers: There is no available information on the quantitative effects of CYP3A4 inducers on amlodipine. Blood pressure should be closely monitored when amlodipine is co-administered with CYP3A4 inducers.

Pharmacodynamic Interactions:

• No significant pharmacodynamic interactions have been reported that would necessitate dosage adjustments or additional monitoring beyond what is indicated for the individual agents involved.

Overall, while amlodipine has a favorable interaction profile with many commonly used medications, careful monitoring is advised when used in conjunction with CYP3A4 inhibitors or inducers.

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's effect on blood pressure in pediatric patients under 6 years of age has not been established. Therefore, caution is advised when considering the use of amlodipine in this age group, as the safety and efficacy data are insufficient to support its use. Further studies are needed to determine appropriate dosing and outcomes in younger children.

Geriatric Use

Clinical studies of amlodipine besylate tablets did not include a sufficient number of subjects aged 65 and older 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 40–60%. Consequently, a lower initial dose may be necessary to ensure safety and efficacy in this population. Regular monitoring and careful assessment of the patient's overall health status are recommended to optimize treatment outcomes.

Pregnancy

Pregnant patients should be aware that amlodipine is classified as Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women; 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 treated orally with amlodipine maleate at doses up to 10 mg amlodipine/kg/day, which corresponds to 8 times and 23 times the maximum recommended human dose of 10 mg on a mg/m² basis during their respective periods of major organogenesis. However, it is important to note that in rats receiving amlodipine maleate at this dose for 14 days before mating and throughout mating and gestation, there was a significant decrease in litter size (approximately 50%) and a significant increase in the number of intrauterine deaths (about 5-fold). Additionally, amlodipine maleate has been shown to prolong both the gestation period and the duration of labor in rats at this dose.

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

Lactation

It is not known whether amlodipine is excreted in human milk. In the absence of this information, it is recommended that lactating mothers discontinue breastfeeding while receiving amlodipine.

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 may require careful consideration when administering calcium channel blockers. It is recommended to titrate the dosage slowly in individuals with severe hepatic impairment to minimize the risk of adverse effects and ensure optimal therapeutic outcomes. Monitoring of liver function is advised during treatment to assess any potential changes in hepatic status and to adjust the dosage accordingly.

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 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 11 times the maximum recommended human dose on a mg/m² basis—produced marked 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. Should hypotension manifest, cardiovascular support measures should be implemented, including the elevation of the extremities and the careful administration of fluids. If hypotension persists despite these conservative interventions, the use of vasopressors, such as phenylephrine, may be warranted, with careful monitoring of circulating volume and urine output.

Due to the high protein binding of amlodipine, hemodialysis is unlikely to provide significant benefit in cases of overdose.

Nonclinical Toxicology

Pregnancy Category C indicates that there are no adequate and well-controlled studies in pregnant women. Amlodipine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In nonclinical studies, no evidence of teratogenicity or other embryo/fetal toxicity was observed when pregnant rats and rabbits were administered oral doses of amlodipine maleate up to 10 mg amlodipine/kg/day during their respective periods of major organogenesis. These doses correspond to approximately 8 times and 23 times the maximum recommended human dose of 10 mg on a mg/m² basis. However, a significant decrease in litter size (approximately 50%) and a notable increase in intrauterine deaths (about 5-fold) were reported 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. Additionally, this dose of amlodipine maleate was associated with prolonged gestation and extended duration of labor in rats.

In long-term studies, rats and mice treated with amlodipine maleate in the diet for up to two years, at concentrations providing daily dosage levels of 0.5, 1.25, and 2.5 mg/kg/day, showed no evidence of carcinogenic effects. For mice, the highest dose was comparable to the maximum recommended human dose of 10 mg amlodipine/day on a mg/m² basis, while for rats, the highest dose was approximately twice the maximum recommended human dose on a mg/m² basis. Mutagenicity studies conducted with amlodipine maleate demonstrated no drug-related effects at either the gene or chromosome level. Furthermore, there was no observed effect on the fertility of rats treated orally with amlodipine maleate at doses up to 10 mg amlodipine/kg/day (8 times the maximum recommended human dose of 10 mg/day on a mg/m² basis) when males were treated for 64 days and females for 14 days prior to mating.

Postmarketing Experience

Infrequent reports of gynecomastia have been documented in the 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

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 can determine if this medication is appropriate for them.

Amlodipine besylate is classified as a calcium channel blocker (CCB) and is utilized to treat high blood pressure (hypertension) and a type of chest pain known as angina. It may be prescribed alone or in conjunction with other medications for 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. 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 can alleviate this pain.

Patients should not use amlodipine besylate if they are allergic to amlodipine or any of the inactive ingredients. It is essential for patients to inform their healthcare provider about all prescription and non-prescription medications they are taking, including natural or herbal remedies. They should also disclose any history of heart disease or liver problems, as well as if they are pregnant or planning to become pregnant. The healthcare provider will assess whether amlodipine besylate is the best treatment option. Additionally, patients should not breast-feed while taking amlodipine besylate tablets and may need to consider stopping breast-feeding or switching to a different medication.

Patients are advised to take amlodipine besylate tablets once daily, with or without food. It may be beneficial to take the medication 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 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 alongside amlodipine besylate. If they are prescribed nitroglycerin for angina, they should not discontinue its use while taking amlodipine besylate. It is crucial for patients to continue taking their other prescribed medications, including any other blood pressure medications, unless directed otherwise by their healthcare provider. In the event of an overdose, patients should contact their doctor, the Poison Control Center, or go to the nearest hospital emergency room immediately.

Patients should be aware of potential side effects associated with amlodipine besylate, 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, it is rare for patients to experience a heart attack or worsening angina when starting or increasing the dose of amlodipine besylate. If such symptoms occur, patients should seek immediate medical attention. They should communicate any concerns regarding side effects to their healthcare provider, as this list does not encompass all possible side effects.

Patients should store amlodipine besylate tablets away from children, at room temperature (between 59° and 86°F), protected from light, and in a dry place, avoiding storage in the bathroom. It is important for patients to use amlodipine besylate tablets only as prescribed by their healthcare provider and not to share the medication with others, even if they exhibit similar symptoms, as it may be harmful to them.

For additional information about amlodipine besylate, patients can consult their pharmacist or healthcare provider, or contact 1-800-438-1985.

Storage and Handling

Bottles should be stored at controlled room temperature, specifically between 59° to 86°F (15° to 30°C). It is essential to dispense the product in tight, light-resistant containers that comply with United States Pharmacopeia (USP) standards to ensure optimal stability and 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 RedPharm Drug Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)