Amlodipine besylate

Uses and Indications

Amlodipine besylate tablets are indicated for the treatment of hypertension, aimed at lowering blood pressure. This reduction in blood pressure decreases the risk of both fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions.

Amlodipine besylate may be used alone or in combination with other antihypertensive and antianginal agents for the treatment of the following conditions:

Hypertension

• Amlodipine besylate is indicated for the treatment of hypertension to lower blood pressure.

Coronary Artery Disease

• Chronic Stable Angina

• Vasospastic Angina (Prinzmetal's or Variant Angina)

• Angiographically Documented Coronary Artery Disease in patients without heart failure or an ejection fraction < 40%

Amlodipine besylate may be utilized as monotherapy or in conjunction with other antihypertensive and antianginal medications for the aforementioned conditions.

No teratogenic or nonteratogenic effects have been mentioned in the provided information.

Dosage and Administration

The recommended starting dose of amlodipine besylate for adults is 5 mg taken orally once daily, with a maximum dose of 10 mg once daily. For small, fragile, or elderly patients, or those with hepatic insufficiency, the starting dose may be reduced to 2.5 mg once daily.

In pediatric patients aged 6 to 17 years, the starting dose is between 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.

Amlodipine besylate can be taken with or without food. To enhance adherence, it is advisable for patients to take their dose at the same time each day, such as with breakfast, dinner, or at bedtime.

If a dose is missed, it should be taken as soon as the patient remembers. However, if more than 12 hours have passed since the missed dose, the patient should skip that dose and resume the regular dosing schedule. Patients should not take more than one dose at a time.

Dosage adjustments should be made based on individual patient response, with titration generally occurring over a period of 7 to 14 days.

Contraindications

Amlodipine besylate is contraindicated in patients with known sensitivity to amlodipine.

Warnings and Precautions

Symptomatic hypotension is possible, particularly in patients with severe aortic stenosis; however, acute hypotension is unlikely due to the gradual onset of action.

Worsening Angina and Myocardial Infarction

Worsening angina and acute myocardial infarction can develop after starting or increasing the dose of amlodipine besylate tablets, especially in patients with severe obstructive coronary artery disease. It is crucial to monitor these patients closely during treatment initiation and dose adjustments.

Titration in Hepatic Impairment

In patients with severe hepatic impairment, amlodipine should be titrated slowly. Caution is advised when administering calcium channel blockers to this population to avoid exacerbating potential adverse effects.

General Precautions

While acute hypotension is rarely reported following oral administration of amlodipine, caution should still be exercised, particularly in patients with severe aortic stenosis. Regular monitoring and assessment of patient response to therapy are recommended to mitigate risks associated with these conditions.

Side Effects

• Edema is the most common adverse reaction associated with amlodipine besylate, and it is dose-related. Clinical trial data indicate the incidence of edema as follows: 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. Other common adverse reactions include:

  • Fatigue (incidence >1.0%)

  • Nausea (incidence >1.0%)

  • Abdominal pain (incidence >1.0%)

  • Somnolence (incidence >1.0%)

• Serious adverse reactions may occur, particularly in patients with severe aortic stenosis. These include:

  • Symptomatic hypotension (possible, but acute hypotension is unlikely)

  • Worsening angina, which can develop after starting or increasing the dose, especially in patients with severe obstructive coronary artery disease

  • Acute myocardial infarction, which can also develop under similar circumstances

• Additional adverse reactions or important notes include:

  • Known sensitivity to amlodipine

  • Overdosage may lead to excessive peripheral vasodilation, marked hypotension, and possibly reflex tachycardia. In cases of massive overdose, active cardiac and respiratory monitoring is recommended, along with frequent blood pressure measurements. If hypotension occurs, cardiovascular support should be provided, including elevation of the extremities and judicious administration of fluids. If hypotension remains unresponsive to these measures, administration of vasopressors may be considered. Hemodialysis is unlikely to be beneficial due to the high protein binding of amlodipine.

• Other adverse reactions reported in clinical trials and postmarketing experience include:

  • Cardiovascular: arrhythmia (including ventricular tachycardia and atrial fibrillation), bradycardia, chest pain, peripheral ischemia, syncope, tachycardia, vasculitis

  • Central and peripheral nervous system: hypoesthesia, peripheral neuropathy, paresthesia, tremor, vertigo

  • Gastrointestinal: anorexia, constipation, dysphagia, diarrhea, flatulence, pancreatitis, vomiting, gingival hyperplasia

  • General: allergic reactions, asthenia, back pain, hot flushes, malaise, pain, rigors, weight gain, weight decrease

  • Musculoskeletal: arthralgia, arthrosis, muscle cramps, myalgia

  • Psychiatric: sexual dysfunction (male and female), insomnia, nervousness, depression, abnormal dreams, anxiety, depersonalization

  • Respiratory: dyspnea, epistaxis

  • Skin and appendages: angioedema, erythema multiforme, pruritus, rash

  • Special senses: abnormal vision, conjunctivitis, diplopia, eye pain, tinnitus

  • Urinary: micturition frequency, micturition disorder, nocturia

  • Autonomic nervous system: dry mouth, increased sweating

  • Metabolic and nutritional: hyperglycemia, thirst

  • Hematologic: leukopenia, purpura, thrombocytopenia

• Postmarketing experience has reported rare cases of gynecomastia, jaundice, and hepatic enzyme elevations, with some cases severe enough to require hospitalization.

Drug Interactions

Amlodipine besylate has been evaluated for potential drug interactions, and the following information summarizes the findings:

Pharmacokinetic Interactions

• CYP3A4 Inhibitors: Co-administration of amlodipine with strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, ritonavir) may increase plasma concentrations of amlodipine. Patients should be monitored for symptoms of hypotension and edema when these combinations are used.

• 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 these inducers.

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

• Grapefruit Juice: A study indicated that co-administration of 240 mL of grapefruit juice with a single oral dose of amlodipine 10 mg had no significant effect on the pharmacokinetics of amlodipine.

• Antacids: Co-administration of a magnesium and aluminum hydroxide antacid with a single dose of amlodipine did not significantly affect its pharmacokinetics.

• Sildenafil: A single 100 mg dose of sildenafil had no effect on the pharmacokinetic parameters of amlodipine. When used together, both agents independently exert their own blood pressure-lowering effects.

• Atorvastatin: Co-administration of multiple 10 mg doses of amlodipine with 80 mg of atorvastatin resulted in no significant change in the steady-state pharmacokinetic parameters of atorvastatin.

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

• Warfarin: Co-administration with warfarin did not alter the warfarin prothrombin response time.

• Ethanol: Single and multiple doses of amlodipine 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.

Pharmacodynamic Interactions

• Simvastatin: If simvastatin is co-administered with amlodipine, the daily dose of simvastatin should not exceed 20 mg.

Drug/Laboratory Test Interactions

• No specific drug or laboratory test interactions have been identified for amlodipine besylate. In vitro data indicate that amlodipine has no effect on the human plasma protein binding of digoxin, phenytoin, warfarin, and indomethacin.

Overall, while amlodipine besylate has a favorable interaction profile, careful monitoring is advised when used in combination with certain medications, particularly those affecting CYP3A4.

Pediatric Use

Amlodipine besylate is indicated for the treatment of hypertension in pediatric patients aged 6 to 17 years. The effective dosage range is 2.5 to 5 mg daily, which has been shown to lower blood pressure in this age group.

The safety and effectiveness of amlodipine besylate in patients less than 6 years of age have not been established, and the effects of the medication on blood pressure in this younger population are not known.

Geriatric Use

Clinical studies of amlodipine besylate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger patients. However, other reported clinical experience has not identified significant differences in responses between elderly and younger patients.

In general, dose selection for elderly patients should be approached with caution. It is recommended 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% to 60%. Therefore, a lower initial dose may be required to ensure safety and efficacy in this population. Regular monitoring of therapeutic response and potential side effects is advised when treating geriatric patients with amlodipine.

Pregnancy

The limited available data based on post-marketing reports with amlodipine besylate use in pregnant patients are not sufficient to inform a drug-associated risk for major birth defects and miscarriage. There are inherent risks to both the mother and fetus associated with poorly controlled hypertension during pregnancy.

In animal reproduction studies, no evidence of adverse developmental effects was observed when pregnant rats and rabbits were treated orally with amlodipine maleate during organogenesis at doses approximately 10 and 20 times the maximum recommended human dose (MRHD), respectively. However, in rats, litter size was significantly decreased (by about 50%), and the number of intrauterine deaths was significantly increased (about 5-fold). Amlodipine has also been shown to prolong both the gestation period and the duration of labor in rats at these doses.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies carry a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications, such as the need for cesarean section and postpartum hemorrhage. Additionally, hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Therefore, pregnant patients with hypertension should be carefully monitored and managed accordingly.

No evidence of teratogenicity or other embryo/fetal toxicity was found 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, for rats, litter size was significantly decreased, and the number of intrauterine deaths was significantly increased in those receiving amlodipine maleate at a dose equivalent to 10 mg amlodipine/kg/day for 14 days before mating and throughout mating and gestation.

Amlodipine maleate has been shown to prolong both the gestation period and the duration of labor in rats at this dose. Given the potential risks, amlodipine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Lactation

Amlodipine is excreted in human breast milk, with limited available data indicating an estimated median relative infant dose of 4.2%. While no adverse effects of amlodipine on breastfed infants have been observed, the effects on the breastfed infant remain unknown. Caution should be exercised when administering amlodipine to lactating mothers, considering the potential for excretion in breast milk and the mother's clinical need for the medication.

The decision to continue breastfeeding or to discontinue amlodipine should be made based on the importance of the drug to the mother, alongside the developmental and health benefits of breastfeeding. There is no available information regarding the effects of amlodipine on milk production. In the absence of definitive data, some sources recommend discontinuing nursing while amlodipine is administered.

Renal Impairment

Patients with renal impairment do not require specific dosage adjustments or special monitoring when using Amlodipine Besylate. The available data across multiple sources indicates that there is no information provided regarding safety considerations or necessary precautions for this patient population. Consequently, healthcare professionals may not need to alter the standard dosing regimen based on renal function, as no creatinine clearance thresholds or related guidelines are specified in the product labeling. It is advisable for clinicians to continue to monitor patients as clinically indicated, but no additional renal-specific adjustments are recommended.

Hepatic Impairment

Patients with severe hepatic impairment should be titrated slowly when administered Amlodipine Besylate. This caution is necessary due to the altered pharmacokinetics in this population, which may affect drug metabolism and clearance. There are no specific dosage adjustments or additional monitoring parameters provided for patients with hepatic impairment in the available data. It is essential for healthcare providers to closely monitor these patients for any adverse effects or changes in therapeutic response during treatment.

Overdosage

Overdosage of amlodipine besylate may lead to excessive peripheral vasodilation, resulting in marked hypotension and potentially reflex tachycardia. In humans, the experience with intentional overdose is limited. However, animal studies indicate that single oral doses equivalent to 40 mg amlodipine/kg in mice and 100 mg amlodipine/kg in rats have resulted in fatalities. Additionally, doses of 4 mg amlodipine/kg or higher in dogs, which is significantly above the maximum recommended human dose on a mg/m² basis, have caused marked peripheral vasodilation and hypotension.

In the event of a massive overdose, it is crucial to initiate active cardiac and respiratory monitoring, with frequent blood pressure measurements being essential. Should hypotension occur, cardiovascular support should be provided, which includes elevating the extremities and administering fluids judiciously. If hypotension remains unresponsive to these conservative measures, the administration of vasopressors, such as phenylephrine, should be considered, with careful attention to circulating volume and urine output.

As amlodipine besylate is highly protein bound, hemodialysis is unlikely to be beneficial in cases of overdose.

Nonclinical Toxicology

Teratogenic Effects

Amlodipine maleate is classified as Pregnancy Category C. 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, 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, litter size was significantly decreased (by approximately 50%), and the number of intrauterine deaths was significantly increased (about five-fold). Additionally, this dose has been shown to prolong both the gestation period and the duration of labor in rats. There are no adequate and well-controlled studies in pregnant women, and amlodipine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in rats and mice treated with amlodipine 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. For the mouse, the highest dose was, on a mg/m² basis, similar to the maximum recommended human dose of 10 mg amlodipine/day, while for the rat, the highest dose was approximately twice the maximum recommended human dose.

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.

Storage and Handling

Amlodipine Besylate is supplied in tablet form. It should be stored at a controlled room temperature of 20° to 25°C (68° to 77°F), with excursions permitted between 15° to 30°C (59° to 86°F) as per USP guidelines.

The tablets must be dispensed in tight, light-resistant containers, which may include child-resistant closures as required. It is essential to protect the tablets from light and moisture.

Additionally, the tablets should be kept away from children and stored in a dry place. They should not be stored in the bathroom or exposed to excessive humidity.