Amlodipine

Characterization

Long-acting BCC. Amlodipine besylate is a white crystalline powder, insoluble in water, moderately soluble in ethanol. Molecular mass is 567.1.

Mechanism of action

Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist or slow channel blocker) that inhibits transmembrane calcium ion entry into vascular smooth muscle and cardiac muscle. Experimental data show that amlodipine binds to both dihydropyridine and non-dihydropyridine binding sites. The contraction processes of cardiac muscle and vascular smooth muscle depend on the movement of extracellular calcium ions into these cells through specific ion channels. Amlodipine selectively inhibits the influx of calcium ions across cell membranes, having a greater effect on vascular smooth muscle cells than on cardiac muscle cells. A negative inotropic effect can be detected in vitro but has not been observed in intact animals at therapeutic doses. Amlodipine does not affect serum calcium concentration. Within the physiological pH range, amlodipine is an ionized compound (pKa=8.6), and its kinetic interaction with calcium channel receptors is characterized by a gradual rate of association and dissociation from the receptor binding site, resulting in a gradual onset of effect.

Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle, causing a decrease in total vascular resistance (TPR) and a decrease in blood pressure (BP).

The exact mechanisms by which amlodipine is effective in angina pectoris are not fully defined, but it is hypothesized that in patients with angina pectoris, amlodipine lowers TPR, reduces cardiac afterload and hence myocardial oxygen demand at any given level of exercise. Amlodipine has been demonstrated to eliminate constriction and restore blood flow in coronary arteries and arterioles in response to calcium, adrenaline, serotonin, and thromboxane _A2 analog in experimental animal models and in human coronary vessels in vitro. This suppression of coronary spasm is responsible for the efficacy of amlodipine in vasospastic angina (Prinzmetal’s angina or variant angina).

Pharmacodynamics

Hemodynamics

After taking therapeutic doses in patients with arterial hypertension, amlodipine causes vasodilation, which leads to a decrease in BP in the supine and standing positions. This decrease in BP is not accompanied by a significant change in heart rate (HR) or plasma catecholamine levels with continued use. Although acute IV administration of amlodipine decreases BP and increases HR in hemodynamic studies in patients with chronic stable angina pectoris, chronic oral administration of amlodipine in clinical trials did not result in clinically significant changes in HR or BP in normotensive patients with angina pectoris.

With continuous oral administration once daily, antihypertensive efficacy is maintained for at least 24 h. Plasma concentrations correlate with the effect in both young and elderly patients. The magnitude of BP reduction with amlodipine administration also correlates with the magnitude of BP elevation before treatment; thus, patients with moderate hypertension (DBP 105-114 mm Hg) had approximately 50% greater response than patients with mild hypertension (DBP 90-104 mm Hg). Normotensive patients had no clinically significant changes in BP (+1/-2 mm Hg).

In hypertensive patients with normal renal function therapeutic doses of amlodipine resulted in decreased renal vascular resistance and increased glomerular filtration rate ( GFR ) and effective renal plasma flow without changes in filtration fraction and severity of proteinuria.

As with other calcium channel blockers, hemodynamic measurements of cardiac function at rest and during exercise (or cardiac pacing) in patients with normal ventricular function receiving amlodipine generally demonstrated a small increase in cardiac index without significant effects on left ventricular pressure rise (dP/dt) and end-diastolic pressure or volume. In hemodynamic studies in intact animals and humans, amlodipine administration was not associated with a negative inotropic effect over the therapeutic dose range, even when administered concomitantly with beta-adrenoblockers, in humans. Similar results, however, have been observed in normal or well-compensated patients with heart failure when agents with significant negative inotropic effects are administered.

Electrophysiologic effects

Amlodipine does not alter sinoatrial nodal function or AV conduction in intact animals or humans. In patients with chronic stable angina pectoris, w/v administration of 10 mg caused no significant changes in AH and HV intervals and sinus node recovery time after cardiac pacing. Similar results were seen in patients receiving amlodipine and concomitant beta-adrenoblockers. In clinical trials in which amlodipine was used in combination with beta-adrenoblockers in patients with hypertension or angina pectoris, no adverse effects on ECG parameters were observed. In clinical trials in patients with angina pectoris alone, amlodipine therapy did not alter ECG intervals or result in a higher degree of AV blockade.

Pharmacokinetics

After oral administration of amlodipine at therapeutic doses, _Cmax in plasma is reached between 6 and 12 h. Absolute bioavailability ranges from 64 to 90%. The bioavailability of amlodipine is independent of food intake.

Amlodipine is extensively (about 90%) converted to inactive metabolites by metabolism in the liver, with 10% of the parent compound and 60% of the metabolites being excreted with urine. Ex vivo studies have shown that about 93% of circulating LS binds to plasma proteins in patients with hypertension. Plasma excretion is biphasic with a final _T1/2 of about 30-50 h. The equilibrium plasma level of amlodipine is reached after 7-8 days of consecutive daily administration.

Renal insufficiency does not significantly affect the pharmacokinetics of amlodipine. Consequently, patients with renal impairment can receive the usual initial dose.

In elderly patients and patients with hepatic insufficiency clearance of amlodipine is decreased, which leads to an increase in AUC by about 40-60%, and a lower initial dose may be required. A similar increase in AUC has been observed in patients with moderate to severe heart failure.

Pediatric Patients

Sixty-two hypertensive patients aged 6 to 17 years received amlodipine at doses ranging from 1.25 to 20 mg. Body weight-adjusted clearance and _Vd values were similar to those in adults.

Preclinical Toxicology

Carcinogenicity, mutagenicity, and effects on fertility

In rats and mice receiving amlodipine maleate in the diet for up to 2 years at concentrations calculated to provide daily amlodipine dose levels of 0.5; 1.25 and 2.5 mg/kg/day, no evidence of its carcinogenic effects was found. In mice, the highest dose was, on a ^mg/m2 basis, similar to the human maximum recommended dose for humans of 10 ^mg/day*. In rats, the highest dose was, on a ^mg/m2 basis, approximately twice the maximum recommended dose for humans.

^* Based on patient weight of 50 kg.

Mutagenicity studies performed with amlodipine maleate showed no LS-related effects at either the gene or chromosome level.

No effects on fertility were observed in rats receiving orally amlodipine maleate (males for 64 days and females for 14 days before mating) at doses up to 10 mg amlodipine/kg/day (8 times the maximum recommended dose for humans of 10 mg/day on a ^mg/m2 basis).

Clinical Studies

Effects in hypertension

Adult patients

The antihypertensive efficacy of amlodipine was demonstrated in 15 double-blind placebo-controlled randomized trials involving 800 patients receiving amlodipine and 538 patients receiving placebo. Single daily administration resulted in statistically significant, placebo-adjusted reductions in BP in the supine and standing positions 24 h after dosing, averaging 12/6 mm Hg in the standing position and 13/7 mm Hg in the supine position in patients with mild to moderate arterial hypertension. There was a persistence of the effect on BP for 24 h post-dose with a small difference in maximum and minimum effect. Tolerance was not demonstrated in patients studied over a period of up to 1 year. 3 parallel fixed-dose and dose-dependent studies showed that the reduction in BP in the supine and standing positions was dose-dependent within the recommended dose range. The effect on DBP was similar in young and elderly patients. The effect on sAD was greater in elderly patients, possibly because of higher baseline sAD. Effects were similar in black and white patients.

BP lowering reduces the risk of fatal and nonfatal cardiovascular events, primarily stroke and myocardial infarction. These benefits have been reported in controlled trials of antihypertensive drugs from a wide range of pharmacologic classes, including amlodipine.

Control of high BP should be part of comprehensive cardiovascular risk management, including lipid control, diabetes control, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake, as appropriate. Many patients may require more than one LS to achieve target BP.

In randomized controlled trials, multiple antihypertensive drugs from different pharmacological classes and with different mechanisms of action have been shown to reduce cardiovascular morbidity and mortality, and it can be concluded that it is BP lowering rather than any other pharmacological property of the drug that is largely responsible for this benefit. The largest and most consistent benefit with respect to cardiovascular disease was a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality were also regularly observed.

Elevated sAD or DBP cause an increased risk of cardiovascular disease, and the absolute increase in risk (in mm Hg) is greater with higher BP, so that even moderate reductions in severe hypertension may provide substantial benefit. The reduction in OR with BP lowering is the same in different populations with different absolute risk, so the absolute benefit is greater in higher-risk patients regardless of their hypertension (e.g., patients with diabetes or hyperlipidemia), and more aggressive treatment to lower BP might be expected to be effective in such patients.

Some antihypertensive drugs have a lesser effect on BP (with monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., for angina pectoris, heart failure, or diabetic kidney disease). These considerations may guide the choice of therapy.

Pediatric patients

Two hundred sixty-eight patients with arterial hypertension aged 6 to 17 years were randomized first to receive amlodipine 2.5 or 5 mg once daily for 4 weeks and then randomized again to receive the same dose or placebo for another 4 weeks. Patients receiving 2.5 or 5 mg had a greater reduction in sAD after 8 weeks than patients secondarily randomized to the placebo group. The magnitude of the treatment effect is difficult to interpret, but is likely to be a sAD less than 5 mm Hg at the 5-mg dose and a sAD of 3.3 mm Hg at the 2.5-mg dose. Side effects were similar to those seen in adults.

Effects in chronic stable angina pectoris

The efficacy of amlodipine at a dose of 5-10 mg/day in exercise-induced angina was evaluated in 8 placebo-controlled double-blind clinical trials of up to 6 weeks’ duration involving 1038 patients (684 with amlodipine, 354 with placebo) with chronic stable angina. In 5 of the 8 trials, a significant increase in exercise time (bicycling or treadmill) was noted at the 10 mg dose. The increase in exercise time to symptom onset averaged 12.8% (63 s) for amlodipine 10 mg and averaged 7.9% (38 s) for amlodipine 5 mg. Amlodipine 10 mg also increased the time to ST segment deviation by 1 mm in several studies and reduced the frequency of angina attacks. Sustained efficacy of amlodipine in patients with angina pectoris has been demonstrated with long-term use. There was no clinically significant reduction in BP (4/1 mmHg) or changes in HR (+0.3 beats/min) in patients with angina pectoris.

Effects in vasospastic angina pectoris

In a double-blind placebo-controlled clinical trial of 4 weeks’ duration involving 50 patients, amlodipine therapy reduced attacks by approximately 4 per week compared with a reduction in the placebo group of approximately 1 per week (p < 0.01). Two of 23 patients receiving amlodipine and 7 of 27 patients receiving placebo discontinued participation in the study due to lack of clinical improvement.

Effects in documented ischemic heart disease

In the PREVENT trial, 825 patients with angiographically confirmed ischemic heart disease were randomized to the amlodipine (5-10 mg once daily) or placebo group and were followed for 3 years. Although the study did not show a meaningful outcome for the primary endpoint of change in coronary lumen diameter assessed by quantitative coronary angiography, the data suggest a favorable outcome in terms of fewer angina hospitalizations and revascularization procedures in patients with ischemic heart disease.

The CAMELOT study enrolled 1318 patients with ischemic heart disease recently confirmed by angiography, without left coronary artery changes, heart failure, or left ventricular ejection fraction <40%. Patients (76% male, 89% Caucasian, 93% were enrolled in US centers, 89% had a history of angina pectoris, 52% without percutaneous coronary intervention, 4% with percutaneous coronary intervention without a stent, and 44% with a stent) were randomized to double-blind treatment with either amlodipine (5-10 mg once daily) or placebo in addition to standard treatment, which included Aspirin (89%), statins (83%), beta-adrenoblockers (74%), nitroglycerin (50%), anticoagulants (40%), and diuretics (32%), but other BCCs were excluded. The median duration of follow-up was 19 months. The primary endpoint was time to first occurrence of one of the following events: hospitalization for angina pectoris, coronary revascularization, myocardial infarction, cardiovascular death, resuscitation due to cardiac arrest, hospitalization for heart failure, stroke/transient ischemic attack, or peripheral vascular disease. A total of 110 (16.6%) and 151 (23.1%) first events occurred in the amlodipine and placebo groups, respectively, with a hazard ratio of 0.691 (95% CI: 0.540-0.884, p=0.003). The outcome of this study was largely due to the prevention of angina hospitalizations and avoidance of revascularization procedures (see Table 1).

In an angiographic substudy (n=274) conducted as part of the CAMELOT trial, there was no significant difference between amlodipine and placebo in the change in coronary artery atheroma volume as measured by intravascular ultrasound examination.

Table 1 below summarizes the significant combined endpoints and clinical outcomes for the primary combined endpoints. Other components of the primary endpoint, including cardiovascular death, resuscitation due to cardiac arrest, myocardial infarction, hospitalization for heart failure, stroke/transient ischemic attack, or peripheral vascular disease, showed no significant difference between amlodipine and placebo.

Clinical outcomes n, %	Amlodipine (n=663)	Placebo (n=655)	Risk reduction (p-value)
Combined endpoint CV	110 (16.6)	151 (23.1)	31% (0.003)
Hospitalization for angina*	5.1 (7.7)	84 (12.8)	42% (0.002)
Coronary revascularization*	78 (11.8)	103 (15.7)	27% (0.033)

 

Studies in patients with heart failure

Amlodipine was compared to placebo in four 8- to 12-week studies in patients with NYHA Class II/III heart failure, involving 697 patients. In these studies, there was no evidence of worsening heart failure based on exercise tolerance, NYHA classification, symptoms, or changes in left ventricular ejection fraction. In a long-term (follow-up period of at least 6 months, mean 13.8 months) placebo-controlled mortality/incidence study with amlodipine at a dose of 5-10 mg in 1153 patients with NYHA class III (n=931) and class IV (n=222) heart failure, with stable doses of diuretics, digoxin, and ACE inhibitors, amlodipine had no effect on the primary endpoint of the study, which was the combined endpoint of total mortality and cardiac morbidity (defined as life-threatening arrhythmia, acute myocardial infarction, or hospitalization for worsening heart failure), or NYHA classification class or symptoms of heart failure. Total combined all-cause mortality and cardiac morbidity were 222/571 (39%) for patients receiving amlodipine and 246/583 (42%) for patients receiving placebo; cardiac pathology accounted for about 25% of the study endpoints.

In another study (PRAISE-2), patients with NYHA class III (80%) or IV (20%) heart failure without clinical symptoms or objective evidence of underlying coronary disease on stable doses of ACE inhibitors (99%), digitalis (99%), and diuretics (99%) were randomized to receive placebo (n=827) or amlodipine (n=827) and followed up for a mean of 33 months. There was no statistically significant difference between amlodipine and placebo in the primary endpoint of all-cause mortality (95% CI 8% decrease to 29% increase for amlodipine). There were more reports of pulmonary edema when taking amlodipine.

Use of Amlodipine

Hypertension

Amlodipine is indicated in the treatment of hypertension to lower BP.

Amlodipine can be used alone or in combination with other antihypertensive drugs.

ischemic heart disease

Chronic stable angina pectoris. Amlodipine is indicated for symptomatic treatment of chronic stable angina pectoris. Amlodipine can be used alone or in combination with other antianginal drugs.

Vasospastic angina ( Prinzmetal’s angina or variant angina). Amlodipine is indicated for the treatment of confirmed or suspected vasospastic angina. Amlodipine can be used as monotherapy or in combination with other antianginal drugs.

Angiographically documented ischemic heart disease. In patients with recently angiographically confirmed ischemic heart disease and without heart failure or with an ejection fraction <40%, amlodipine is indicated to reduce the risk of hospitalization for angina pectoris and to reduce the risk of coronary artery revascularization procedures.

Contraindications

Hypersensitivity.

Use in pregnancy and lactation

Pregnancy

Summary of Risks

The limited available data based on postmarketing reports of amlodipine use in pregnant women are insufficient to determine the associated risk of serious birth defects and miscarriage. There are maternal and fetal risks associated with poorly controlled hypertension during pregnancy (see Clinical Considerations). In animal reproduction studies, no evidence of adverse developmental effects was found when pregnant rats and rabbits received oral amlodipine maleate during organogenesis at doses approximately 10 and 20 times the maximum recommended dose for humans, respectively. However, in rats, litter size was significantly reduced (by about 50%) and the number of intrauterine deaths was significantly increased (about 5-fold). Amlodipine at this dose has been shown to prolong both gestation and length of labor in rats (see Data).

The estimated background risk of serious birth defects and miscarriage for the indicated population is unknown. In any pregnancy, there is a background risk of birth defects, loss, or other adverse outcomes. For the general U.S. population, the estimated background risk of serious birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Disease-associated risk to the mother and/or embryo/fetus. Hypertension during pregnancy increases the risk of preeclampsia, gestational diabetes, preterm labor, and maternal complications of delivery (e.g., need for cesarean section and postpartum hemorrhage). Hypertension increases the risk of fetal retardation and intrauterine death.

Pregnant women with hypertension should be closely monitored and treated accordingly.

Data

Data in animals. There was no evidence of teratogenicity or other embryo/fetal toxicity when pregnant rats and rabbits received oral amlodipine maleate at doses up to 10 mg amlodipine/kg/day (approximately 10 and 20 times the maximum recommended dose for humans based on body surface area, respectively) during the respective periods of major organogenesis. However, in rats, litter size was significantly reduced (by approximately 50%) and the number of intrauterine deaths was significantly increased (approximately 5-fold) 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. Amlodipine maleate at this dose was shown to prolong both gestation and the duration of labor in rats.

Breastfeeding

Summary of risks

The limited available data from published clinical studies on lactation indicate that amlodipine is present in breast milk with an estimated median relative to the infant dose of 4.2%. No adverse effects of amlodipine have been observed in breastfed infants. There is no available information on the effect of amlodipine on milk production.

 

Side effects of the Amlodipine

Amlodipine, widely used to treat high blood pressure and angina, is generally well-tolerated but like any medication, it can cause side effects. Some of the common and less serious side effects of amlodipine include:

1. Swelling (edema): This can occur in the feet, ankles, or hands, and is due to the accumulation of fluid.
2. Headache: Some people may experience mild to moderate headaches when starting amlodipine.
3. Fatigue: Feeling unusually tired is a common effect, which may decrease as your body adjusts to the medication.
4. Dizziness: This might occur especially when standing up quickly from a lying or sitting position.
5. Palpitations: Some people may feel their heart beating more noticeably.
6. Nausea: A small number of patients might experience stomach upset or nausea.
7. Flushing: Feeling warm or redness in the face or neck can occur.

There are also several more serious but rare side effects associated with amlodipine that require immediate medical attention:

1. Severe dizziness or fainting: These could be signs of excessively low blood pressure.
2. Chest pain or worsening angina: In rare cases, the medication can cause or worsen chest pain.
3. Irregular heartbeat: Any significant changes in heart rhythm or rate should be evaluated promptly.
4. Severe abdominal pain, nausea, or vomiting: These could indicate a liver problem.
5. Yellowing of the skin or eyes (jaundice): This may indicate liver issues, which are rare but serious.
6. Swelling of the gums: This is an uncommon side effect and may require changes in dental hygiene or treatment adjustments.

Interaction

Effect of other medicinal products on amlodipine

Concomitant use of cimetidine, antacids containing magnesium and aluminum hydroxide, sildenafil and grapefruit juice does not affect the exposure of amlodipine.

CYP3A inhibitors. Co-administration with CYP3A inhibitors (moderate to strong) resulted in increased systemic exposure of amlodipine and may require dose reduction. When amlodipine is co-administered with CYP3A inhibitors, monitoring for symptoms of hypotension and edema is necessary to determine the need for dose adjustment.

Concomitant use of diltiazem at a dose of 180 mg/day with amlodipine at a dose of 5 mg in elderly patients with arterial hypertension resulted in a 60% increase in the systemic exposure of amlodipine. Co-administration with erythromycin in healthy volunteers did not significantly alter the systemic exposure of amlodipine. However, strong CYP3A inhibitors (e.g. itraconazole, clarithromycin) may increase plasma concentrations of amlodipine to a greater extent.

CYP3A inducers. There is no information on the quantitative effect of CYP3A inducers on amlodipine. In concomitant use of amlodipine with CYP3A inducers, BP should be carefully monitored.

Sildenafil. When amlodipine and sildenafil were used in combination, each independently exerted its own BP-lowering effect. When sildenafil is used concomitantly with amlodipine, monitoring for signs of arterial hypotension is necessary.

Effect of amlodipine on other drugs

Simvastatin. Concomitant use of simvastatin with amlodipine increases systemic exposure of simvastatin. It is necessary to reduce the dose of simvastatin in patients receiving amlodipine at a dose of up to 20 mg daily.

Co-administration of multiple doses of amlodipine 10 mg with 80 mg simvastatin resulted in a 77% increase in simvastatin exposure compared to simvastatin alone.

Immunosuppressants. Amlodipine may increase systemic exposure to cyclosporine or tacrolimus when administered concomitantly. Frequent monitoring of minimum blood levels of cyclosporine and tacrolimus and dose adjustment if necessary is recommended.

Cyclosporine. A prospective study in kidney transplant patients (n=11) showed an average 40% increase in cyclosporine levels with concomitant treatment with amlodipine.

Tacrolimus. A prospective study involving healthy Chinese volunteers (n=9), CYP3A5 expressors, showed a 2.5- to 4-fold increase in tacrolimus exposure when concomitantly administered with amlodipine compared with tacrolimus alone. This result was not observed in subjects who do not express CYP3A5 (n=6).

However, a 3-fold increase in tacrolimus plasma exposure was reported in a kidney transplant patient (CYP3A5 non-expressor) after initiation of amlodipine for the treatment of post-transplant hypertension, leading to a tacrolimus dose reduction. Regardless of CYP3A5 genotype status, the possibility of interaction with these drugs cannot be excluded.

In vitro data show that amlodipine does not affect the binding of digoxin, phenytoin, warfarin and indomethacin to human plasma proteins.

Amlodipine is a weak inhibitor of CYP3A and may increase the exposure of CYP3A substrates.

Co-administration of amlodipine has no effect on the exposure of atorvastatin, digoxin, ethanol and the effect of warfarin on SP.

Overdose

Symptoms: overdose can be expected to cause excessive peripheral vasodilation with marked hypotension and possibly reflex tachycardia. In humans, experience with intentional overdose of amlodipine is limited.

Single oral doses of amlodipine maleate equivalent to 40 mg amlodipine/kg and 100 mg amlodipine/kg in mice and rats, respectively, caused death. Single oral doses of amlodipine maleate equivalent to 4 mg or more of amlodipine/kg in dogs (11 or more times the maximum recommended dose for humans on a ^mg/m2 basis) caused marked peripheral vasodilation and hypotension.

Treatment: in the event of a large overdose, active monitoring of cardiac and respiratory function should be initiated. Frequent BP measurements are important. In case of arterial hypotension, it is necessary to ensure maintenance of CCC function, including elevated position of the lower extremities and necessary fluid administration. If hypotension cannot be treated with these conservative measures, vasopressors (such as phenylephrine) should be considered, while controlling ODC and diuresis. Because amlodipine binds strongly to proteins, hemodialysis is unlikely to be effective.

How to use and dosage

Inside. The dose depends on the disease, age and condition of the patient. Adults, 2.5-10 mg once a day, maximum dose – 10 mg.

Children: the effective antihypertensive dose for pediatric patients aged 6 to 17 years is 2.5-5 mg once daily. Doses exceeding 5 mg daily have not been studied in pediatric patients (see Clinical Studies).

Precautions

Hypotension

Symptomatic hypotension may occur, especially in patients with severe aortic stenosis. Due to the gradual onset of action, acute hypotension is unlikely.

Exacerbation of angina pectoris or myocardial infarction

Worsening angina pectoris and acute myocardial infarction may develop after starting or increasing the dose of amlodipine, especially in patients with severe obstructive coronary artery disease.

Liver failure

Since amlodipine is extensively metabolized in the liver and the _T1/2 from plasma is 56 h in patients with impaired hepatic function, the dose of amlodipine should be titrated slowly in patients with severe hepatic impairment.

Pediatric use

Amlodipine (2.5 to 5 mg daily) is effective in lowering BP in patients 6 to 17 years of age (see Clinical Studies).

The effect of amlodipine on BP in patients younger than 6 years of age is unknown.

Use in geriatrics

Clinical trials of amlodipine have not included a sufficient number of patients 65 years of age or older to determine whether their response differs from that of younger adults on therapy. Other reported clinical experience has shown no difference in response between elderly and younger patients. In general, dosing for elderly patients should be administered with caution, usually starting at the lower end of the dose range, due to the greater incidence of decreased hepatic, renal, or cardiac function and the presence of comorbidities or other drug therapy. Clearance of amlodipine decreases in elderly patients, resulting in an increase in AUC of approximately 40-60%, and a lower starting dose may be required.