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, with a molecular formula of C20H25ClN2O5 • C6H6O3S and 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 formulation of amlodipine besylate tablets includes white tablets that are equivalent to 2.5 mg, 5 mg, and 10 mg of amlodipine for oral administration. Each tablet contains inactive ingredients such as colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate.

Uses and Indications

Amlodipine besylate tablets are indicated for the treatment of hypertension. This medication may be utilized as monotherapy or in conjunction with other antihypertensive agents to achieve optimal blood pressure control.

Additionally, amlodipine besylate tablets are indicated for the symptomatic treatment of chronic stable angina. This drug can be administered alone or in combination with other antianginal agents to alleviate anginal symptoms.

Furthermore, amlodipine besylate tablets are indicated for the treatment of confirmed or suspected vasospastic angina. It may be used as monotherapy or in combination with other antianginal drugs to manage this condition effectively.

There are no teratogenic or nonteratogenic effects associated with amlodipine besylate tablets.

Dosage and Administration

The usual initial antihypertensive oral dose of amlodipine besylate for adults is 5 mg once daily, with a maximum dose of 10 mg once daily. For small, fragile, or elderly individuals, as well as patients with hepatic insufficiency, treatment may be initiated at a lower dose of 2.5 mg once daily. Dosage adjustments should be made based on the individual patient's response, with titration typically occurring over a period of 7 to 14 days. For the management of chronic stable or vasospastic angina, the recommended dose ranges from 5 mg to 10 mg once daily, with the lower dose being advisable for elderly patients and those with hepatic insufficiency.

In pediatric patients aged 6 to 17 years, the effective antihypertensive oral dose is 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.

Contraindications

Amlodipine besylate tablets are contraindicated in patients with a known sensitivity to amlodipine. Use in these patients may lead to adverse reactions due to hypersensitivity.

Warnings and Precautions

Patients with severe obstructive coronary artery disease may experience a rare but significant increase in the frequency, duration, and/or severity of angina or acute myocardial infarction upon initiation of calcium channel blocker therapy or during dosage escalation. The underlying mechanism for this phenomenon remains unclear, necessitating careful monitoring of these patients.

Caution is advised when administering amlodipine, particularly in individuals with severe aortic stenosis, due to the gradual onset of vasodilation associated with this medication. Although acute hypotension is rarely reported following oral administration, the potential for this effect warrants vigilance, similar to that exercised with other peripheral vasodilators.

Healthcare professionals should remain alert to these warnings and exercise appropriate clinical judgment when prescribing and monitoring therapy with amlodipine, especially in at-risk populations. Regular assessment of patient response and symptomatology is recommended to ensure safe and effective use of this medication.

Side Effects

Patients may experience a range of adverse reactions while using the medication. Common adverse reactions observed in clinical trials include headache (7.3% for Amlodipine vs. 7.8% for placebo), fatigue (4.5% for Amlodipine vs. 2.8% for placebo), and nausea (2.9% for Amlodipine vs. 1.9% for placebo). Other common reactions include edema (1.8% at 2.5 mg, 3.0% at 5 mg, and 10.8% at 10 mg vs. 0.6% for placebo), dizziness (1.1% at 2.5 mg, 3.4% at 5 mg, and 3.4% at 10 mg vs. 1.5% for placebo), and flushing (0.7% at 2.5 mg, 1.4% at 5 mg, and 2.6% at 10 mg vs. 0.0% for placebo). Palpitations were reported in 0.7% of patients at 2.5 mg, 1.4% at 5 mg, and 4.5% at 10 mg, compared to 0.6% for placebo. Additional common reactions include abdominal pain (1.6% for Amlodipine vs. 0.3% for placebo), somnolence (1.4% for Amlodipine vs. 0.6% for placebo), and various gastrointestinal symptoms.

In addition to common adverse reactions, patients may experience serious cardiovascular events such as arrhythmias (including ventricular tachycardia and atrial fibrillation), bradycardia, chest pain, hypotension, peripheral ischemia, syncope, tachycardia, postural dizziness, postural hypotension, and vasculitis. Central and peripheral nervous system effects may include hypoesthesia, peripheral neuropathy, paresthesia, tremor, and vertigo. Gastrointestinal reactions can encompass anorexia, constipation, dyspepsia, dysphagia, diarrhea, flatulence, pancreatitis, vomiting, and gingival hyperplasia.

Other adverse reactions reported include general symptoms such as allergic reactions, asthenia, back pain, hot flushes, malaise, pain, rigors, weight gain, and weight decrease. Musculoskeletal issues like arthralgia, arthrosis, muscle cramps, and myalgia may also occur. Psychiatric effects can include sexual dysfunction, insomnia, nervousness, depression, abnormal dreams, anxiety, and depersonalization. Respiratory symptoms such as dyspnea and epistaxis, as well as skin reactions including angioedema, erythema multiforme, pruritus, and various rashes, have been noted. Special senses may be affected, leading to abnormal vision, conjunctivitis, diplopia, eye pain, and tinnitus. Urinary symptoms may include micturition frequency, micturition disorders, and nocturia. Autonomic nervous system effects such as dry mouth and increased sweating, along with metabolic and nutritional changes like hyperglycemia and thirst, have also been reported. Hematological reactions may include leukopenia, purpura, and thrombocytopenia.

Rare adverse reactions include cardiac failure, pulse irregularity, extrasystoles, skin discoloration, urticaria, skin dryness, alopecia, dermatitis, muscle weakness, twitching, ataxia, hypertonia, migraine, cold and clammy skin, apathy, agitation, amnesia, gastritis, increased appetite, loose stools, coughing, rhinitis, dysuria, polyuria, parosmia, taste perversion, abnormal visual accommodation, and xerophthalmia.

Postmarketing experience has revealed additional adverse reactions, including gynecomastia, jaundice, and elevations in hepatic enzymes, which in some cases were severe enough to necessitate hospitalization.

It is important to note that in rare instances, patients with severe obstructive coronary artery disease may experience increased angina and/or myocardial infarction upon initiation of calcium channel blocker therapy or during dosage increases. The mechanism underlying this effect remains unclear.

Drug Interactions

Coadministration of amlodipine with various medications has been evaluated, revealing no significant pharmacokinetic interactions with several agents.

Pharmacokinetic Interactions:

• Digoxin, Phenytoin, Warfarin, and Indomethacin: In vitro studies indicate that amlodipine does not affect the plasma protein binding of these drugs.

• Cimetidine: The pharmacokinetics of amlodipine remain unchanged when coadministered with cimetidine.

• Grapefruit Juice: A study involving 240 mL of grapefruit juice with a single oral dose of amlodipine 10 mg showed no significant impact on the pharmacokinetics of amlodipine.

• Maalox (Antacid): Coadministration with Maalox did not significantly alter the pharmacokinetics of amlodipine.

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

• Atorvastatin: Multiple doses of amlodipine (10 mg) did not significantly change the steady-state pharmacokinetics of atorvastatin (80 mg).

• Ethanol: Both single and multiple doses of amlodipine had no significant effect on the pharmacokinetics of ethanol.

• Warfarin: Coadministration with amlodipine did not alter the prothrombin response time of warfarin.

Clinical Use and Safety:

In clinical trials, amlodipine has been safely administered alongside thiazide diuretics, beta-blockers, angiotensin-converting enzyme inhibitors, long-acting nitrates, sublingual nitroglycerin, digoxin, warfarin, non-steroidal anti-inflammatory drugs, antibiotics, and oral hypoglycemic agents, indicating a broad safety profile in combination therapy.

Drug/Laboratory Test Interactions:

No known interactions have been identified between amlodipine and laboratory tests.

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 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, leading to 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 for geriatric patients.

Pregnancy

Pregnant patients should be aware that amlodipine maleate is classified as Pregnancy Category C. Animal studies have not demonstrated evidence of teratogenicity or other embryo/fetal toxicity when pregnant rats and rabbits were administered oral doses of amlodipine maleate up to 10 mg amlodipine/kg/day during critical periods of organogenesis. However, significant adverse effects were observed in rats, including a reduction in litter size by approximately 50% and a five-fold increase in intrauterine deaths when treated with the same dose for 14 days prior to mating and throughout mating and gestation. Additionally, amlodipine maleate has been associated with prolonged gestation and extended labor duration in these animal models.

Due to the lack of adequate and well-controlled studies in pregnant women, the use of amlodipine during pregnancy should be considered only if the potential benefits outweigh the potential risks to the fetus. Healthcare professionals are advised to carefully evaluate the necessity of amlodipine therapy in pregnant patients and to discuss the potential risks with them.

Lactation

It is not known whether amlodipine is excreted in human milk. In the absence of this information, it is recommended that nursing be discontinued while amlodipine is administered.

Renal Impairment

Patients with renal impairment may not have specific information regarding dosage adjustments, special monitoring, or safety considerations outlined in the prescribing information. Therefore, healthcare professionals should exercise caution when prescribing this medication to patients with reduced kidney function, as the absence of detailed guidance necessitates careful clinical judgment and individualized patient assessment. Regular monitoring of renal function may be advisable to ensure patient safety and therapeutic efficacy.

Hepatic Impairment

There is no information available regarding the use of this medication in patients with hepatic impairment. Consequently, there are no dosage adjustments, special monitoring requirements, or precautions specified for individuals with compromised liver function. Healthcare professionals should exercise caution and consider the overall clinical context when prescribing this medication to patients with liver problems, as the absence of specific guidance necessitates careful evaluation of potential risks and benefits.

Overdosage

In cases of overdosage with amlodipine maleate, significant clinical effects can be anticipated, particularly concerning cardiovascular stability.

Toxicity in Animal Studies Animal studies have demonstrated 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—approximately 11 times the maximum recommended human dose on a mg/m² basis—led to pronounced peripheral vasodilation and hypotension.

Clinical Manifestations in Humans The clinical experience with intentional overdosage in humans is limited. Documented cases include a patient who ingested 250 mg without symptoms and did not require hospitalization, while another patient who ingested 120 mg was hospitalized, underwent gastric lavage, and remained normotensive. A third case involved a patient who ingested 105 mg and presented with hypotension (90/50 mmHg), which resolved following plasma expansion. Additionally, a 19-month-old male accidentally ingested 30 mg (approximately 2 mg/kg) and exhibited stable vital signs, although a heart rate of 180 bpm was noted. After administration of ipecac 3.5 hours post-ingestion, the child was observed overnight without any sequelae.

Management of Overdosage In the event of a massive overdose, it is crucial to initiate active cardiac and respiratory monitoring, with frequent blood pressure assessments. Should hypotension occur, immediate cardiovascular support is necessary, which may include elevating the extremities and judicious fluid administration. If hypotension persists despite these conservative measures, the use of vasopressors, such as phenylephrine, should be considered, ensuring careful monitoring of circulating volume and urine output.

Intravenous calcium gluconate may be beneficial in reversing the effects of calcium entry blockade associated with amlodipine overdosage. It is important to note that due to the high protein binding of amlodipine, hemodialysis is unlikely to be effective in managing overdose cases.

Nonclinical Toxicology

Pregnancy Category C: In nonclinical studies, no evidence of teratogenicity or other embryo/fetal toxicity was observed when pregnant rats and rabbits were administered amlodipine maleate orally 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 intrauterine deaths (about fivefold) 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 was associated with prolonged gestation and extended duration of labor in rats. 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.

In long-term studies, rats and mice treated with amlodipine maleate in the diet for up to two years at calculated 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. Mutagenicity studies indicated no drug-related effects at either the gene or chromosome levels. Furthermore, no adverse effects on fertility were observed in 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 the causal relationship remaining uncertain. Additionally, cases of jaundice and elevations in hepatic enzymes, primarily consistent with cholestasis or hepatitis, have been reported. Some of these cases were severe enough to necessitate hospitalization in association with the use of amlodipine.

Patient Counseling

Patients should read the provided information carefully before starting amlodipine and each time they refill their prescription, as there may be new information. This information does not replace discussions with their healthcare provider. Patients are encouraged to ask their doctor if they have any questions regarding whether amlodipine is the right medication for them.

Amlodipine besylate is a calcium channel blocker (CCB) used to treat high blood pressure (hypertension) and a type of chest pain known as angina. 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. Amlodipine works by relaxing blood vessels, allowing blood to flow more easily, which helps lower blood pressure and reduces the risk of stroke or heart attack. Angina is characterized by 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 also radiate to the shoulders, arms, neck, jaws, or back. Amlodipine can help alleviate this pain.

Patients should not use amlodipine besylate if they are allergic to amlodipine or any of the inactive ingredients. They should inform their healthcare provider about all prescription and non-prescription medications they are taking, including natural or herbal remedies. It is particularly important to notify the doctor if they have a history of heart disease or liver problems, are pregnant or planning to become pregnant, or are breastfeeding. Patients are advised not to breastfeed while taking amlodipine and to discuss alternative treatment options with their doctor.

Amlodipine besylate should be taken once daily, with or without food, and can be consumed with most beverages, including grapefruit juice. To aid in adherence, 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, 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 should not discontinue 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. It is crucial to keep amlodipine away from children and store it at 20° to 25°C (68° to 77°F) in a dry place, protected from light, and not in the bathroom.

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

Finally, patients should only use amlodipine as directed by their healthcare provider 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 containers to ensure optimal preservation of its integrity. It should be stored at a temperature range of 20° to 25°C (68° to 77°F), in accordance with USP Controlled Room Temperature guidelines. Proper storage conditions are essential to maintain the product's efficacy and safety.

Additional Clinical Information

Amlodipine besylate is administered once daily, with or without food. Patients are advised to read the provided information carefully before starting the medication and each time they refill their prescription. It is important for patients to consult their doctor with any questions regarding amlodipine and to disclose all prescription and non-prescription medications they are taking, including natural or herbal remedies. Breastfeeding is not recommended while on amlodipine. In the event of a missed dose, patients should take it as soon as they remember, but should not take the medication if it has been more than 12 hours since the last dose.

Postmarketing experiences have reported infrequent cases of gynecomastia, although a causal relationship remains uncertain. Additionally, there have been reports of jaundice and elevations in hepatic enzymes, primarily associated with cholestasis or hepatitis, some of which were severe enough to necessitate hospitalization.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Amlodipine Besylate as submitted by Dr Reddy's Laboratories. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)