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. The formulation for oral administration includes tablets that are white and equivalent to 2.5, 5, and 10 mg of amlodipine. Each tablet contains inactive ingredients such as 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 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.

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.

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 adverse reactions in individuals with a documented hypersensitivity to the active ingredient.

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 minimal.

Healthcare professionals should be vigilant for the potential exacerbation of angina or the onset of acute myocardial infarction following the initiation or dosage increase of amlodipine besylate tablets. This risk is particularly pronounced in patients with severe obstructive coronary artery disease, necessitating careful monitoring during treatment adjustments.

In patients with severe hepatic impairment, it is essential to titrate calcium channel blockers, including amlodipine besylate, slowly. This precaution helps mitigate the risk of adverse effects and ensures patient safety. Regular assessment of liver function may be warranted to guide dosing decisions in this population.

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, there is a risk of worsening angina and acute myocardial infarction, especially after initiating or increasing the dose of amlodipine besylate tablets in patients with severe obstructive coronary artery disease.

Drug Interactions

Co-administration of amlodipine with various medications has been evaluated, revealing several important interactions that may influence clinical management.

Pharmacokinetic Interactions

• CYP3A4 Inhibitors: The co-administration of amlodipine besylate tablets with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, ritonavir) may lead to increased plasma concentrations of amlodipine. It is advised to monitor patients for symptoms of hypotension and edema in such cases. In contrast, erythromycin does not significantly alter amlodipine systemic exposure.

• CYP3A4 Inducers: There is no available data on the quantitative effects of CYP3A4 inducers on amlodipine. Patients should be monitored for adequate clinical effect when amlodipine is used in conjunction with these inducers.

• Diltiazem: In elderly hypertensive patients, the co-administration of a 180 mg daily dose of diltiazem with 5 mg amlodipine resulted in a 1.6-fold increase in amlodipine systemic exposure.

• Atorvastatin: Co-administration of multiple 10 mg doses of amlodipine besylate tablets with 80 mg of atorvastatin did not result in significant changes in the steady-state pharmacokinetic parameters of atorvastatin.

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

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

• Warfarin: The combination of amlodipine besylate tablets with warfarin did not change the prothrombin response time.

• Antacids: The use of magnesium and aluminum hydroxide antacids with a single dose of amlodipine besylate tablets had no significant effect on the pharmacokinetics of amlodipine.

• Ethanol: Both single and multiple doses of amlodipine besylate tablets did not significantly affect the pharmacokinetics of ethanol.

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

Pharmacodynamic Interactions

• Amlodipine has been shown to have no effect on the plasma protein binding of digoxin, phenytoin, warfarin, and indomethacin, indicating a lack of pharmacodynamic interaction in this regard.

Drug/Laboratory Test Interactions

• No known drug or laboratory test interactions have been identified with amlodipine.

In summary, while amlodipine exhibits a favorable interaction profile with many commonly used medications, careful monitoring is recommended when co-administered with strong CYP3A4 inhibitors and in the presence of CYP3A4 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 profiles remain unclear. Further studies are needed to determine appropriate dosing and outcomes for this population.

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 careful assessment of the patient's overall health status 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; 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, 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, significant adverse effects were observed in rats receiving this dose, including a reduction in litter size by approximately 50% and an increase in intrauterine deaths by about 5-fold when treated with amlodipine maleate for 14 days prior to mating and throughout mating and gestation. 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 the potential risks and benefits when prescribing amlodipine to pregnant patients.

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. The potential effects on breastfed infants have not been established due to the lack of data on excretion in breast milk.

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 individuals with severe hepatic impairment to minimize the risk of adverse effects and ensure optimal therapeutic outcomes. Monitoring of liver function may be necessary to assess the patient's response to treatment and 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 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 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. 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 any therapeutic 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 treated orally with amlodipine maleate at doses up to 10 mg amlodipine/kg/day during their respective periods of major organogenesis. However, a significant decrease in litter size (approximately 50%) and a notable increase in the number of intrauterine deaths (about five-fold) were reported in rats receiving amlodipine maleate at a dose equivalent to 10 mg amlodipine/kg/day for 14 days before mating and throughout mating and gestation. Additionally, amlodipine maleate was shown to prolong both the gestation period and the duration of labor in rats at this dose.

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 a carcinogenic effect. For mice, the highest dose was, on a mg/m² basis, similar to the maximum recommended human dose of 10 mg amlodipine/day, 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 revealed no drug-related effects at either the gene or chromosome level. Furthermore, 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 on a mg/m² basis.

Postmarketing Experience

Infrequent reports of gynecomastia have been documented in the postmarketing experience, with an uncertain causal relationship. 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 inform patients that amlodipine besylate is a calcium channel blocker (CCB) used to treat high blood pressure (hypertension) and angina, a type of chest pain. It can be prescribed alone or in combination with other medications for these conditions. Patients should understand that high blood pressure occurs when blood exerts excessive force against blood vessel walls, and that amlodipine besylate works 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 manifests as recurring pain or discomfort due to insufficient blood flow 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.

It is crucial to advise patients not to use amlodipine besylate if they have a known allergy to amlodipine or any of the inactive ingredients. Patients should be encouraged to disclose all medications they are currently taking, including over-the-counter drugs and herbal supplements. They should specifically inform their healthcare provider 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 besylate for their treatment.

Patients should be instructed to take amlodipine besylate tablets once daily, with or without food, and to establish a routine, such as taking the medication at the same time each day. If a dose is missed, they should take it as soon as they remember, but not if it has been more than 12 hours since the missed dose; in that case, they should wait until the next scheduled dose.

Patients can continue using nitroglycerin alongside amlodipine besylate for angina, but they should not discontinue any other prescribed medications, including other antihypertensives, without consulting their healthcare provider. In the event of an overdose, patients should seek immediate medical attention.

Healthcare providers should emphasize that breastfeeding is not recommended while taking amlodipine besylate, as it is unclear whether the medication passes into breast milk. Patients should also be cautioned against starting any new medications or supplements without prior consultation with their healthcare provider.

Patients should be informed of potential side effects, which may include headache, leg or ankle swelling, fatigue, stomach pain, nausea, dizziness, flushing, arrhythmia, and heart palpitations. While most side effects are mild to moderate, patients should be advised to contact their healthcare provider if they experience any concerning symptoms, particularly if they notice worsening angina or signs of a heart attack after starting or increasing their dose of amlodipine besylate.

Finally, patients should be instructed to store amlodipine besylate tablets at room temperature, away from light and moisture, and out of reach of children. They should only use the medication as directed by their healthcare provider and should not share it with others, even if they exhibit similar symptoms.

Storage and Handling

Bottles should be stored at a controlled room temperature ranging from 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 Contract Pharmacy Services-PA. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)