Amlodipine besylate

Description

Amlodipine besylate tablets, USP, contain the besylate salt of amlodipine besylate, a long-acting calcium channel blocker. The chemical structure of amlodipine besylate is 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 the molecular weight is 567.1 g/mol. 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 besylate. Each tablet also 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, which includes the treatment of chronic stable angina and vasospastic angina (Prinzmetal’s or variant angina). Furthermore, this medication 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 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, and caution should be exercised when considering higher doses.

Healthcare professionals should assess individual patient factors when determining the appropriate dosage and administration regimen.

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

Patients receiving amlodipine besylate tablets should be closely monitored for potential adverse effects, particularly those with pre-existing cardiovascular conditions.

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 (5.1).

Additionally, there is a risk of worsening angina and 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 (5.2).

Hepatic Impairment In patients with severe hepatic impairment, it is essential to titrate the dosage of amlodipine besylate tablets slowly. This cautious approach helps mitigate the risk of adverse effects associated with altered drug metabolism (5.3).

Healthcare professionals are advised to conduct regular assessments and monitor relevant parameters to ensure patient safety during treatment with amlodipine besylate tablets.

Side Effects

Patients receiving treatment may experience a range of adverse reactions, which can be categorized by frequency and seriousness.

Most common adverse reactions observed in clinical trials include edema, which is dose-related with an incidence of 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 patients receiving amlodipine versus 2.8% in the placebo group. Other common reactions include nausea (2.9% vs. 1.9% placebo), abdominal pain (1.6% vs. 0.3% placebo), somnolence (1.4% vs. 0.6% placebo), and dizziness, which varied by dose: 1.1% at 2.5 mg, 3.4% at 5 mg, and 3.4% at 10 mg, compared to 1.5% in the placebo group. Flushing and palpitations were also noted, with incidences of 0.7% (2.5 mg), 1.4% (5 mg), and 2.6% (10 mg) for flushing, and 0.7% (2.5 mg), 1.4% (5 mg), and 4.5% (10 mg) for palpitations, against 0.0% and 0.6% in the placebo group, respectively.

Additional 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 may include hypoesthesia, peripheral neuropathy, paresthesia, tremor, and vertigo. Gastrointestinal disturbances such as anorexia, constipation, dysphagia, diarrhea, flatulence, pancreatitis, vomiting, and gingival hyperplasia have also been documented.

General adverse reactions encompass allergic reactions, asthenia, back pain, hot flushes, malaise, pain, rigors, weight gain, and weight decrease. Musculoskeletal issues such as arthralgia, arthrosis, muscle cramps, and myalgia have been reported, along with psychiatric effects including sexual dysfunction, insomnia, nervousness, depression, abnormal dreams, anxiety, and depersonalization. Respiratory symptoms may include dyspnea and epistaxis, while skin reactions can manifest as angioedema, erythema multiforme, pruritus, and various types of rash. Special senses may be affected, leading to abnormal vision, conjunctivitis, diplopia, eye pain, and tinnitus. Urinary system effects include increased micturition frequency and nocturia, and autonomic nervous system reactions may involve dry mouth and increased sweating. Metabolic and nutritional changes such as hyperglycemia and thirst have also been noted, 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 observed, primarily associated with cholestasis or hepatitis, and in some cases, these reactions were severe enough to necessitate hospitalization. Additionally, there may be a possible association between amlodipine besylate and extrapyramidal disorders.

Drug Interactions

There are no specific drug interactions or drug and laboratory test interactions identified in the available data. Therefore, no dosage adjustments or monitoring recommendations are necessary 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 a recommended dosage range of 2.5 to 5 mg daily. The efficacy of amlodipine besylate in lowering blood pressure has been established within this age group. However, the effects of amlodipine besylate on blood pressure in patients younger than 6 years of age have not been determined, and caution is advised when considering treatment in this population.

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 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 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. Careful monitoring and dose adjustments are recommended to optimize treatment outcomes in geriatric patients.

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 note that poorly controlled hypertension during pregnancy poses significant risks to both the mother and fetus.

In animal reproduction studies, no adverse developmental effects were observed in pregnant rats and rabbits treated with amlodipine besylate maleate during organogenesis at doses approximately 10 and 20 times the maximum recommended human dose (MRHD), respectively. Nonetheless, in rats, there was a notable decrease in litter size (approximately 50%) and a significant increase in intrauterine deaths (about 5-fold) at the higher dose. Additionally, amlodipine besylate has been shown to prolong both the gestation period and the duration of labor in rats at this dose.

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

Hypertension during 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. Therefore, pregnant women with hypertension should be closely monitored and managed appropriately to mitigate these risks.

Overall, while animal studies do not indicate teratogenicity or other embryo/fetal toxicity at certain doses, the implications for human pregnancies remain uncertain, necessitating careful consideration and management of hypertension in pregnant patients.

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 besylate on breastfed infants have been observed. Additionally, there is no available information regarding the effects of amlodipine besylate on milk production.

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 to ensure patient safety and to adjust treatment as necessary.

Overdosage

Overdosage may lead to significant peripheral vasodilation, resulting in pronounced hypotension and potentially reflex tachycardia. Clinical experience with intentional overdosage of amlodipine besylate 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 amlodipine besylate maleate equivalent to 4 mg amlodipine/kg or higher—exceeding 11 times the maximum recommended human dose on a mg/m² basis—produced significant peripheral vasodilation and hypotension.

In the event of a massive overdose, it is imperative to initiate active cardiac and respiratory monitoring. Continuous blood pressure assessments are crucial. Should hypotension manifest, cardiovascular support should be provided, which includes elevating the extremities and judiciously administering fluids. If hypotension persists despite these conservative measures, the use of vasopressors, such as phenylephrine, may be warranted, with careful consideration of circulating volume and urine output. Due to the high protein binding of amlodipine besylate, hemodialysis is unlikely to be effective in managing overdose situations.

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, with males treated 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 identified several adverse events reported voluntarily or through surveillance programs. Due to the nature of voluntary reporting from a population of uncertain size, it is not always feasible to reliably estimate the frequency of these events or to establish a causal relationship with drug exposure.

Among the reported events, gynecomastia has been noted 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 of these hepatic events were severe enough to necessitate hospitalization. Furthermore, postmarketing data has suggested a possible association between extrapyramidal disorder and the use of amlodipine besylate.

Patient Counseling

Healthcare providers should advise patients to read the provided information carefully before starting amlodipine besylate 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 amlodipine besylate tablets, USP, to determine if this medication is appropriate for their condition.

Amlodipine besylate is classified as a calcium channel blocker (CCB) and is utilized in the treatment of high blood pressure (hypertension) and a type of chest pain known as angina. Patients should understand that it can be prescribed alone or in conjunction with other medications to manage these conditions.

Healthcare providers should explain that 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. This reduction in blood pressure can decrease the risk of stroke or heart attack. Additionally, patients should be informed that 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 help alleviate this pain.

Patients must be cautioned against using amlodipine besylate if they have a known allergy to amlodipine or any of the inactive ingredients. Healthcare providers should encourage patients to disclose all prescription and non-prescription medications they are currently taking, including any natural or herbal remedies. It is also essential for patients to inform their doctor if they have a history of heart disease or liver problems.

Pregnant patients or those planning to become pregnant should discuss their situation with their doctor, who will determine if amlodipine besylate is suitable for them. Additionally, breastfeeding patients should be informed that amlodipine besylate can pass into breast milk.

Patients should be instructed to take amlodipine besylate once daily, with or without food, and to establish a routine by taking it 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, unless it has been more than 12 hours since the missed dose; in that case, they should skip the missed dose and resume their regular schedule.

Patients can safely use nitroglycerin alongside amlodipine besylate for angina, but they should not discontinue nitroglycerin without consulting their doctor. It is crucial 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 be instructed to contact their doctor, the Poison Control Center, or go to the nearest hospital emergency room immediately.

Healthcare providers should inform patients about potential side effects of 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, muscle rigidity, tremors, and abnormal muscle movements. Patients should be made aware that, although rare, they may experience a heart attack or worsening angina when starting or increasing the dose of amlodipine besylate, and they should seek immediate medical attention if this occurs.

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

It is important to keep amlodipine besylate tablets out of reach of children and to store them at room temperature (between 59°F and 86°F), away from light, and in a dry place, avoiding storage in the bathroom.

Finally, healthcare providers should remind patients that amlodipine besylate should only be used as prescribed by their doctor, 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 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), as defined by USP Controlled Room Temperature. It is essential to protect the product from light to maintain its integrity and efficacy.

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 patients with various conditions, including 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 GSMS, Incorporated. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)