Amlodipine besylate

Description

Amlodipine besylate tablets, USP are the besylate salt of amlodipine besylate, a long-acting calcium channel blocker. Amlodipine besylate 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. The compound appears as a white crystalline powder and has a molecular weight of 567.1. It is slightly soluble in water and sparingly soluble in ethanol. Amlodipine besylate tablets, USP are available in strengths of 2.5 mg, 5 mg, and 10 mg for oral administration. Each tablet contains inactive ingredients including lactose monohydrate, magnesium stearate, microcrystalline cellulose, and corn starch.

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 are indicated for the management of coronary artery disease. This includes the treatment of chronic stable angina and vasospastic angina (Prinzmetal’s or variant angina). Amlodipine besylate is also 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 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, 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.

Healthcare professionals should assess individual patient factors when determining the appropriate dosage and adjust as necessary to ensure safety and efficacy.

Contraindications

Use of this product is contraindicated in patients with a known sensitivity to amlodipine. Due to the potential for severe allergic reactions, administration in such cases may pose significant health risks.

Warnings and Precautions

Patients receiving amlodipine besylate tablets should be monitored closely for potential adverse effects, particularly those related to cardiovascular stability and hepatic function.

Cardiovascular Considerations Symptomatic hypotension may occur, especially in individuals with severe aortic stenosis. While acute hypotension is considered unlikely, healthcare professionals should remain vigilant for signs of hypotension in these patients. Additionally, there is a risk of worsening angina and acute myocardial infarction following the initiation or dose escalation of amlodipine besylate, particularly in patients with severe obstructive coronary artery disease. Continuous assessment of cardiac symptoms is recommended during treatment.

Hepatic Impairment In patients with severe hepatic impairment, it is essential to titrate the dosage of amlodipine besylate tablets slowly. Close monitoring of liver function tests may be warranted to ensure patient safety and to adjust the treatment regimen as necessary.

Side Effects

The most common adverse reactions observed in clinical trials include edema, fatigue, nausea, abdominal pain, and somnolence, with incidences greater than 1.0%. Edema is noted to be dose-related, with the following incidences reported: 1.8% at 2.5 mg, 3.0% at 5 mg, and 10.8% at 10 mg, compared to 0.6% in the placebo group. Fatigue was reported in 4.5% of participants, with a placebo incidence of 2.8%. Nausea occurred in 2.9% of subjects, while the placebo group reported an incidence of 1.9%. Abdominal pain was noted in 1.6% of participants, with a placebo incidence of 0.3%. Somnolence was reported in 1.4% of subjects, compared to 0.6% in the placebo group.

Additional adverse reactions with an incidence greater than 1.0% include dizziness (1.1% at 2.5 mg, 3.4% at both 5 mg and 10 mg, and 1.5% in the placebo group), flushing (0.7% at 2.5 mg, 1.4% at 5 mg, and 2.6% at 10 mg, with 0.0% in the placebo group), and palpitations (0.7% at 2.5 mg, 1.4% at 5 mg, and 4.5% at 10 mg, compared to 0.6% in the placebo group).

Serious adverse reactions reported include cardiovascular events such as arrhythmia (including ventricular tachycardia and atrial fibrillation), bradycardia, chest pain, peripheral ischemia, syncope, tachycardia, and vasculitis. Central and peripheral nervous system effects include hypoesthesia, peripheral neuropathy, paresthesia, tremor, and vertigo. Gastrointestinal reactions encompass anorexia, constipation, dysphagia, diarrhea, flatulence, pancreatitis, vomiting, and gingival hyperplasia.

Other notable adverse reactions include allergic reactions, asthenia, back pain, hot flushes, malaise, pain, rigors, weight gain, and weight decrease. Musculoskeletal effects such as arthralgia, arthrosis, muscle cramps, and myalgia have also been reported. Psychiatric adverse reactions include sexual dysfunction, insomnia, nervousness, depression, abnormal dreams, anxiety, and depersonalization. Respiratory issues such as dyspnea and epistaxis, as well as skin reactions including angioedema, erythema multiforme, pruritus, and various rashes, have been documented.

In the urinary system, micturition frequency, micturition disorders, and nocturia have been observed. Autonomic nervous system effects include dry mouth and increased sweating. Metabolic and nutritional adverse reactions such as hyperglycemia and thirst have also been reported, along with hematological issues like leukopenia, purpura, and thrombocytopenia.

Postmarketing experience has revealed infrequent reports of gynecomastia, with an uncertain causal relationship. Jaundice and hepatic enzyme elevations have been noted, primarily consistent with cholestasis or hepatitis, and in some cases, these reactions were severe enough to necessitate hospitalization. Additionally, there is a possible association between amlodipine besylate and extrapyramidal disorders.

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 is indicated for the management of hypertension in pediatric patients aged 6 to 17 years, with an effective 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 effect on blood pressure in this age group is unknown.

Geriatric Use

Clinical studies of amlodipine besylate 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 besylate, 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, including increased maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications, as well as fetal risks such as intrauterine growth restriction and intrauterine death.

Animal reproduction studies have not demonstrated evidence of teratogenicity or other embryo/fetal toxicity when pregnant rats and rabbits were administered amlodipine besylate maleate at doses up to 10 mg amlodipine/kg/day during critical periods of organogenesis. Notably, these doses are approximately 10 and 20 times the maximum recommended human dose (MRHD) based on body surface area. Despite the absence of teratogenic effects, significant adverse outcomes were observed in rats, including a 50% reduction in litter size and a five-fold increase in intrauterine deaths when treated with amlodipine besylate maleate at the aforementioned dose for 14 days prior to mating and throughout gestation. Additionally, this treatment was associated with prolonged gestation and labor duration in rats.

The estimated background risk of major birth defects and miscarriage in the general U.S. population is 2%-4% and 15%-20%, respectively, and all pregnancies carry a baseline risk of birth defects, loss, or other adverse outcomes. Given these considerations, pregnant women with hypertension should be closely monitored and managed to mitigate risks to both maternal and fetal health.

Lactation

Amlodipine is present in human milk, with a reported estimated median relative infant dose of 4.2% based on limited available data from a published clinical lactation study. No adverse effects of amlodipine besylate on breastfed infants have been observed. Additionally, there is no available information regarding the effects of amlodipine besylate 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 lack of data necessitates careful clinical judgment. Regular monitoring of renal function may be advisable in these patients to ensure safety and efficacy.

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.

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.

In animal studies, 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. Additionally, doses of amlodipine besylate maleate equivalent to 4 mg amlodipine/kg or more in dogs have also induced severe peripheral vasodilation and hypotension.

In the event of a massive overdose, it is critical to initiate active cardiac and respiratory monitoring. 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 judicious administration of intravenous fluids.

If hypotension persists despite these conservative measures, the administration of vasopressors, such as phenylephrine, should be considered, ensuring careful monitoring of circulating volume and urine output. It is important to note that due to the high protein binding of amlodipine besylate, hemodialysis is unlikely to provide any therapeutic benefit in cases of overdose.

Nonclinical Toxicology

Rats and mice treated with amlodipine besylate 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 besylate 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 besylate 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 that certain adverse reactions have been reported voluntarily from a population of uncertain size, making it challenging to reliably estimate their frequency or establish a causal relationship to drug exposure. Among the events reported infrequently, gynecomastia has been noted, although the causal relationship remains uncertain.

Additionally, cases of jaundice and hepatic enzyme elevations, primarily consistent with cholestasis or hepatitis, have been documented. In some instances, these events were severe enough to necessitate hospitalization. Furthermore, postmarketing reporting has indicated a possible association between extrapyramidal disorder and the use of amlodipine besylate.

Patient Counseling

Patients should read the provided information carefully before starting amlodipine besylate 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 specific type of chest pain known as angina. It may be prescribed alone or in conjunction with other medications for these conditions. High blood pressure occurs when blood exerts 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 manifests as recurring pain or discomfort due to insufficient blood supply to the heart. Patients may experience a pressing or squeezing sensation, typically in the chest, but it can also radiate to the shoulders, arms, neck, jaws, or back. Amlodipine besylate can alleviate this discomfort.

Patients should not use amlodipine besylate if they are allergic to amlodipine or any of the inactive ingredients. They are encouraged to inform their doctor about all prescription and non-prescription medications they are taking, including natural or herbal remedies. Additionally, patients should disclose any history of heart disease or liver problems, as well as if they are pregnant, plan to become pregnant, or are breastfeeding, since amlodipine besylate can pass into breast milk.

Amlodipine besylate should be taken once daily, with or without food. It may be beneficial for patients to take their dose at the same time each day, such as with breakfast, dinner, or at bedtime. Patients should not take more than one dose at a time. If a dose is missed, it should be taken as soon as remembered, but if more than 12 hours have passed since the missed dose, they should wait and take the next dose at the regular time.

Patients can use nitroglycerin alongside amlodipine besylate; however, they should not discontinue nitroglycerin if it has been prescribed for angina. It is crucial that patients do not stop taking any other prescribed medications, including other blood pressure medications, without consulting their doctor.

In the event of an overdose, patients should contact their doctor, the Poison Control Center, or go to the nearest hospital emergency room immediately.

Common side effects of amlodipine besylate may include mild to moderate swelling of the legs or ankles, tiredness, extreme sleepiness, stomach pain, nausea, dizziness, flushing, arrhythmia, heart palpitations, muscle rigidity, tremors, and abnormal muscle movements. Although rare, patients may experience a heart attack or worsening angina when first starting or increasing the dose of amlodipine besylate. If such symptoms occur, patients should seek immediate medical attention.

Patients should communicate any concerns regarding side effects to their doctor, as this list does not encompass all possible side effects. For a complete list, they should consult their healthcare provider or pharmacist.

Amlodipine besylate tablets should be kept out of reach of children and stored at room temperature (between 59°F and 86°F), away from light, and in a dry place, avoiding storage in the bathroom. Patients should only use amlodipine besylate as directed by their doctor and should not share it with others, even if they exhibit similar symptoms, as it may be harmful to them.

Storage and Handling

The product is supplied in tight, light-resistant, child-resistant containers, in accordance with USP standards. It should be stored at a temperature range of 20°C to 25°C (68°F to 77°F), adhering to USP Controlled Room Temperature guidelines. It is essential to protect the product from light to maintain its integrity.

Additional Clinical Information

Postmarketing experience has revealed several important considerations for clinicians. There have been reports of gynecomastia, although the causal relationship remains uncertain. Additionally, instances of jaundice and hepatic enzyme elevations have been noted, primarily associated with cholestasis or hepatitis, with some cases severe enough to necessitate hospitalization. There is also a possible association between extrapyramidal disorders and amlodipine besylate.

Despite these concerns, amlodipine besylate has been utilized safely in various patient populations, including those with chronic obstructive pulmonary disease, well-compensated congestive heart failure, coronary artery disease, peripheral vascular disease, diabetes mellitus, and abnormal lipid profiles.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Amlodipine Besylate as submitted by PD-Rx Pharmaceuticals, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)