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CADUET(amlodipine besylate and atorvastatin calcium)tablet
DESCRIPTION
CADUET® (amlodipine besylate and atorvastatin calcium) tablets combine the calcium channel blocker amlodipine besylate with the lipid-lowering agent atorvastatin calcium.
The amlodipine besylate component of CADUET is chemically described as 3-ethyl-5-methyl (±)-2-[(2-aminoethoxy)methyl]-4-(o-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate, monobenzenesulphonate. Its empirical formula is C20H25ClN2O5•C6H6O3S.
The atorvastatin calcium component of CADUET is chemically described as [R-(R*, R*)]-2-(4-fluorophenyl)-β, δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid, calcium salt (2:1) trihydrate. Its empirical formula is (C33H34FN2O5)2Ca•3H2O.
The structural formulae for amlodipine besylate and atorvastatin calcium are shown below.
CADUET contains amlodipine besylate, a white to off-white crystalline powder, and atorvastatin calcium, also a white to off-white crystalline powder. Amlodipine besylate has a molecular weight of 567.1 and atorvastatin calcium has a molecular weight of 1209.42. Amlodipine besylate is slightly soluble in water and sparingly soluble in ethanol. Atorvastatin calcium is insoluble in aqueous solutions of pH 4 and below. Atorvastatin calcium is very slightly soluble in distilled water, pH 7.4 phosphate buffer, and acetonitrile; slightly soluble in ethanol, and freely soluble in methanol.
CADUET tablets are formulated for oral administration in the following strength combinations:
Table 1. CADUET Tablet Strengths
|
|
2.5 mg/
10mg |
2.5 mg/
20mg |
2.5 mg/
40mg |
5 mg/10
mg |
5 mg/20
mg |
5 mg/40
mg |
5 mg/80
mg |
10 mg/
10 mg |
10 mg/
20 mg |
10 mg/
40 mg |
10 mg/
80 mg |
amlodipine
equivalent
(mg) |
2.5 |
2.5 |
2.5 |
5 |
5 |
5 |
5 |
10 |
10 |
10 |
10 |
atorvastatin
equivalent
(mg) |
10 |
20 |
40 |
10 |
20 |
40 |
80 |
10 |
20 |
40 |
80 |
Each tablet also contains calcium carbonate, croscarmellose sodium, microcrystalline cellulose, pregelatinized starch, polysorbate 80, hydroxypropyl cellulose, purified water, colloidal silicon dioxide (anhydrous), magnesium stearate, Opadry® II White 85F28751 (polyvinyl alcohol, titanium dioxide, PEG 3000 and talc) or Opadry® II Blue 85F10919 (polyvinyl alcohol, titanium dioxide, PEG 3000, talc and FD&C blue #2). Combinations of atorvastatin with 2.5 mg and 5 mg amlodipine are film coated white, and combinations of atorvastatin with 10 mg amlodipine are film coated blue.
CLINICAL PHARMACOLOGY
Mechanism of Action
CADUET
CADUET is a combination of two drugs, a dihydropyridine calcium channel blocker amlodipine and an HMG-CoA reductase inhibitor atorvastatin. The amlodipine component of CADUET inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. The atorvastatin component of CADUET is a selective, competitive inhibitor of HMG-CoA reductase (statin), the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme A to meva lonate, a precursor of sterols, including cholesterol.
Amlodipine
Experimental data suggest that amlodipine binds to both dihydropyridine and nondihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Negative inotropic effects can be detected in vitro but such effects have not been seen in intact animals at therapeutic doses. Serum calcium concentration is not affected by amlodipine.
Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure.
The precise mechanisms by which amlodipine relieves angina have not been fully delineated, but are thought to include the following:
Exertional Angina: In patients with exertional angina, amlodipine reduces the total peripheral resistance (afterload) against which the heart works and reduces the rate pressure product, and thus myocardial oxygen demand, at any given level of exercise.
Vasospastic Angina: Amlodipine has been demonstrated to block constriction and restore blood flow in coronary arteries and arterioles in response to calcium, potassium epinephrine, serotonin, and thromboxane A2 analog in experimental animal models and in human coronary vessels in vitro. This inhibition of coronary spasm is responsible for the effectiveness of amlodipine in vasospastic (Prinzmetal's or variant) angina.
Atorvastatin
Cholesterol and triglycerides circulate in the bloodstream as part of lipoprotein complexes. With ultracentrifugation, these complexes separate into HDL (high-density lipoprotein), IDL (intermediate-density lipoprotein), LDL (low-density lipoprotein), and VLDL (very-low-density lipoprotein) fractions. Triglycerides (TG) and cholesterol in the liver are incorporated into VLDL and released into the plasma for delivery to peripheral tissues. LDL is formed from VLDL and is catabolized primarily through the high-affinity LDL receptor.
Clinical and pathologic studies show that elevated plasma levels of total cholesterol (total-C), LDL-cholesterol (LDL-C), and apolipoprotein B (apo B) promote human atherosclerosis and are risk factors for developing cardiovascular disease, while increased levels of HDL-C are associated with a decreased cardiovascular risk.
Epidemiologic investigations have established that cardiovascular morbidity and mortality vary directly with the level of total-C and LDL-C, and inversely with the level of HDL-C.
In animal models, atorvastatin lowers plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver and by increasing the number of hepatic LDL receptors on the cell-surface to enhance uptake and catabolism of LDL; atorvastatin also reduces LDL production and the number of LDL particles.
Atorvastatin reduces total-C, LDL-C, and apo B in patients with homozygous and heterozygous familial hypercholesterolemia (FH), nonfamilial forms of hypercholesterolemia, and mixed dyslipidemia. Atorvastatin also reduces VLDL-C and TG and produces variable increases in HDL-C and apolipoprotein A-1. Atorvastatin reduces total-C, LDL-C, VLDL-C, apo B, TG, and non-HDL-C, and increases HDL-C in patients with isolated hypertriglyceridemia. Atorvastatin reduces intermediate density lipoprotein cholesterol (IDL-C) in patients with dysbetalipoproteinemia.
Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including VLDL, intermediate density lipoprotein (IDL), and remnants, can also promote atherosclerosis. Elevated plasma triglycerides are frequently found in a triad with low HDL-C levels and small LDL particles, as well as in association with non-lipid metabolic risk factors for coronary heart disease. As such, total plasma TG has not consistently been shown to be an independent risk factor for CHD. Furthermore, the independent effect of raising HDL or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined.
Pharmacokinetics and Metabolism
Absorption
Studies with amlodipine
After oral administration of therapeutic doses of amlodipine alone, absorption produces peak plasma concentrations between 6 and 12 hours. Absolute bioavailability has been estimated to be between 64% and 90%.
Studies with atorvastatin
After oral administration alone, atorvastatin is rapidly absorbed; maximum plasma concentrations occur within 1 to 2 hours. Extent of absorption increases in proportion to atorvastatin dose. The absolute bioavailability of atorvastatin (parent drug) is approximately 14% and the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic availability is attributed to presystemic clearance in gastrointestinal mucosa and/or hepatic first-pass metabolism. Plasma atorvastatin concentrations are lower (approximately 30% for Cmax and AUC) following evening drug administration compared with morning. However, LDL-C reduction is the same regardless of the time of day of drug administration (see DOSAGE AND ADMINISTRATION).
Studies with CADUET
Following oral administration of CADUET peak plasma concentrations of amlodipine and atorvastatin are seen at 6 to 12 hours and 1 to 2 hours post dosing, respectively. The rate and extent of absorption (bioavailability) of amlodipine and atorvastatin from CADUET are not significantly different from the bioavailability of amlodipine and atorvastatin administered separately (see above).
The bioavailability of amlodipine from CADUET was not affected by food. Food decreases the rate and extent of absorption of atorvastatin from CADUET by approximately 32% and 11%, respectively, as it does with atorvastatin when given alone. LDL-C reduction is similar whether atorvastatin is given with or without food.
Distribution
Studies with amlodipine
Ex vivo studies have shown that approximately 93% of the circulating amlodipine drug is bound to plasma proteins in hypertensive patients. Steady-state plasma levels of amlodipine are reached after 7 to 8 days of consecutive daily dosing.
Studies with atorvastatin
Mean volume of distribution of atorvastatin is approximately 381 liters. Atorvastatin is ≥98% bound to plasma proteins. A blood/plasma ratio of approximately 0.25 indicates poor drug penetration into red blood cells. Based on observations in rats, atorvastatin calcium is likely to be secreted in human milk (see CONTRAINDICATIONS, Pregnancy and Lactation, and PRECAUTIONS, Nursing Mothers).
Metabolism
Studies with amlodipine
Amlodipine is extensively (about 90%) converted to inactive metabolites via hepatic metabolism.
Studies with atorvastatin
Atorvastatin is extensively metabolized to ortho- and parahydroxylated derivatives and various beta-oxidation products. In vitro inhibition of HMG-CoA reductase by ortho- and parahydroxylated metabolites is equivalent to that of atorvastatin. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites. In vitro studies suggest the importance of atorvastatin metabolism by cytochrome P450 3A4, consistent with increased plasma concentrations of atorvastatin in humans following coadministration with erythromycin, a known inhibitor of this isozyme (see PRECAUTIONS, Drug Interactions). In animals, the ortho-hydroxy metabolite undergoes further glucuronidation.
Excretion
Studies with amlodipine
Elimination from the plasma is biphasic with a terminal elimination half-life of about 30–50 hours. Ten percent of the parent amlodipine compound and 60% of the metabolites of amlodipine are excreted in the urine.
Studies with atorvastatin
Atorvastatin and its metabolites are eliminated primarily in bile following hepatic and/or extra-hepatic metabolism; however, the drug does not appear to undergo enterohepatic recirculation. Mean plasma elimination half-life of atorvastatin in humans is approximately 14 hours, but the half-life of inhibitory activity for HMG-CoA reductase is 20 to 30 hours due to the contribution of active metabolites. Less than 2% of a dose of atorvastatin is recovered in urine following oral administration.
Specific Populations
Geriatric
Studies with amlodipine
Elderly patients have decreased clearance of amlodipine with a resulting increase in AUC of approximately 40–60%, and a lower initial dose of amlodipine may be required.
Studies with atorvastatin
Plasma concentrations of atorvastatin are higher (approximately 40% for Cmax and 30% for AUC) in healthy elderly subjects (age ≥65 years) than in young adults. Clinical data suggest a greater degree of LDL-lowering at any dose of atorvastatin in the elderly population compared to younger adults (see PRECAUTIONS, Geriatric Use).
Pediatric
Studies with amlodipine
Sixty-two hypertensive patients aged 6 to 17 years received doses of amlodipine between 1.25 mg and 20 mg. Weight-adjusted clearance and volume of distribution were similar to values in adults.
Studies with atorvastatin
Pharmacokinetic data in the pediatric population are not available.
Gender
Studies with atorvastatin
Plasma concentrations of atorvastatin in women differ from those in men (approximately 20% higher for Cmax and 10% lower for AUC); however, there is no clinically significant difference in LDL-C reduction with atorvastatin between men and women.
Renal Impairment
Studies with amlodipine
The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. Patients with renal failure may therefore receive the usual initial amlodipine dose.
Studies with atorvastatin
Renal disease has no influence on the plasma concentrations or LDL-C reduction of atorvastatin; thus, dose adjustment of atorvastatin in patients with renal dysfunction is not necessary (see DOSAGE AND ADMINISTRATION and WARNINGS, Skeletal Muscle).
Hemodialysis
While studies have not been conducted in patients with end-stage renal disease, hemodialysis is not expected to clear atorvastatin or amlodipine since both drugs are extensively bound to plasma proteins.
Hepatic Impairment
Atorvastatin is contraindicated in patients with active liver disease.
Studies with amlodipine
Elderly patients and patients with hepatic insufficiency have decreased clearance of amlodipine with a resulting increase in AUC of approximately 40–60%.
Studies with atorvastatin
In patients with chronic alcoholic liver disease, plasma concentrations of atorvastatin are markedly increased. Cmax and AUC are each 4-fold greater in patients with Childs-Pugh A disease. Cmax and AUC of atorvastatin are approximately 16-fold and 11-fold increased, respectively, in patients with Childs-Pugh B disease (see CONTRAINDICATIONS).
Heart Failure
Studies with amlodipine
In patients with moderate to severe heart failure, the increase in AUC for amlodipine was similar to that seen in the elderly and in patients with hepatic insufficiency.
Pharmacokinetic Studies of Atorvastatin and Co-Administered Drugs
TABLE 2. Effect of Co-administered Drugs on the Pharmacokinetics of Atorvastatin
|
Co-administered drug and dosing regimen |
Atorvastatin |
|
|
Dose (mg) |
Change in AUC* |
Change in Cmax* |
|
|
|
†Cyclosporine 5.2 mg/kg/day, stable dose |
10 mg QD for 28 days |
↑ 8.7-fold |
↑10.7-fold |
|
†Lopinavir 400 mg BID/ ritonavir 100 mg BID, 14 days |
20 mg QD for 4 days |
↑ 5.9-fold |
↑ 4.7-fold |
|
†Ritonavir 400 mg BID/ saquinavir 400mg BID, 15 days |
40 mg QD for 4 days |
↑ 3.9-fold |
↑ 4.3-fold |
|
†Clarithromycin 500 mg BID, 9 days |
80 mg QD for 8 days |
↑ 4.4-fold |
↑ 5.4-fold |
|
†Itraconazole 200 mg QD, 4 days |
40 mg SD |
↑ 3.3-fold |
↑ 20% |
|
†Grapefruit Juice, 240 mL QD ‡ |
40 mg, SD |
↑ 37% |
↑ 16% |
|
Diltiazem 240 mg QD, 28 days |
40 mg, SD |
↑ 51% |
No change |
|
Erythromycin 500 mg QID, 7 days |
10 mg, SD |
↑ 33% |
↑ 38% |
|
Amlodipine 10 mg, single dose |
80 mg, SD |
↑ 15% |
↓ 12 % |
|
Cimetidine 300 mg QD, 4 weeks |
10 mg QD for 2 weeks |
↓ Less than 1% |
↓ 11% |
|
Colestipol 10 mg BID, 28 weeks |
40 mg QD for 28 weeks |
Not determined |
↓ 26%§ |
|
Maalox TC® 30 mL QD, 17 days |
10 mg QD for 15 days |
↓ 33% |
↓ 34% |
|
Efavirenz 600 mg QD, 14 days |
10 mg for 3 days |
↓ 41% |
↓ 1% |
|
†Rifampin 600 mg QD, 7 days (co-administered) ¶ |
40 mg SD |
↑ 30% |
↑ 2.7-fold |
|
†Rifampin 600 mg QD, 5 days (doses separated) ¶ |
40 mg SD |
↓ 80% |
↓ 40% |
|
†Gemfibrozil 600mg BID, 7 days |
40mg SD |
↑ 35% |
↓ Less than 1% |
|
†Fenofibrate 160mg QD, 7 days |
40mg SD |
↑ 3% |
↑ 2% |
TABLE 3. Effect of Atorvastatin on the Pharmacokinetics of Co-administered Drugs
|
Atorvastatin |
Co-administered drug and dosing regimen |
|
|
Drug/Dose (mg) |
Change in AUC |
Change in Cmax |
|
|
|
80 mg QD for 15 days |
Antipyrine, 600 mg SD |
↑ 3% |
↓ 11% |
|
80 mg QD for 14 days |
* Digoxin 0.25 mg QD, 20 days |
↑ 15% |
↑ 20 % |
|
40 mg QD for 22 days |
Oral contraceptive QD, 2 months
- norethindrone 1mg
- ethinyl estradiol 35µg |
↑ 28%
↑ 19% |
↑ 23%
↑ 30% |
Pharmacodynamics
Hemodynamic Effects of Amlodipine
Following administration of therapeutic doses to patients with hypertension, amlodipine produces vasodilation resulting in a reduction of supine and standing blood pressures. These decreases in blood pressure are not accompanied by a significant change in heart rate or plasma catecholamine levels with chronic dosing. Although the acute intravenous administration of amlodipine decreases arterial blood pressure and increases heart rate in hemodynamic studies of patients with chronic stable angina, chronic administration of oral amlodipine in clinical trials did not lead to clinically significant changes in heart rate or blood pressures in normotensive patients with angina.
With chronic once daily oral administration of amlodipine, antihypertensive effectiveness is maintained for at least 24 hours. Plasma concentrations correlate with effect in both young and elderly patients. The magnitude of reduction in blood pressure with amlodipine is also correlated with the height of pretreatment elevation; thus, individuals with moderate hypertension (diastolic pressure 105–114 mmHg) had about a 50% greater response than patients with mild hypertension (diastolic pressure 90–104 mmHg). Normotensive subjects experienced no clinically significant change in blood pressures (+1/–2 mmHg).
In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in a decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal plasma flow without change in filtration fraction or proteinuria.
As with other calcium channel blockers, hemodynamic measurements of cardiac function at rest and during exercise (or pacing) in patients with normal ventricular function treated with amlodipine have generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on left ventricular end diastolic pressure or volume. In hemodynamic studies, amlodipine has not been associated with a negative inotropic effect when administered in the therapeutic dose range to intact animals and man, even when co-administered with beta-blockers to man. Similar findings, however, have been observed in normal or well-compensated patients with heart failure with agents possessing significant negative inotropic effects.
Electrophysiologic Effects of Amlodipine
Amlodipine does not change sinoatrial nodal function or atrioventricular conduction in intact animals or man. In patients with chronic stable angina, intravenous administration of 10 mg did not significantly alter A-H and H-V conduction and sinus node recovery time after pacing. Similar results were obtained in patients receiving amlodipine and concomitant beta blockers. In clinical studies in which amlodipine was administered in combination with beta-blockers to patients with either hypertension or angina, no adverse effects on electrocardiographic parameters were observed. In clinical trials with angina patients alone, amlodipine therapy did not alter electrocardiographic intervals or produce higher degrees of AV blocks.
LDL-C Reduction with Atorvastatin
Atorvastatin as well as some of its metabolites are pharmacologically active in humans. The liver is the primary site of action and the principal site of cholesterol synthesis and LDL clearance. Drug dosage, rather than systemic drug concentration, correlates better with LDL-C reduction. Individualization of drug dosage should be based on therapeutic response (see DOSAGE AND ADMINISTRATION).
Clinical Studies
Clinical Studies with Amlodipine
Amlodipine Effects in Hypertension
Adult Patients
The antihypertensive efficacy of amlodipine has been demonstrated in a total of 15 double-blind, placebo-controlled, randomized studies involving 800 patients on amlodipine and 538 on placebo. Once daily administration produced statistically significant placebo-corrected reductions in supine and standing blood pressures at 24 hours postdose, averaging about 12/6 mmHg in the standing position and 13/7 mmHg in the supine position in patients with mild to moderate hypertension. Maintenance of the blood pressure effect over the 24-hour dosing interval was observed, with little difference in peak and trough effect. Tolerance was not demonstrated in patients studied for up to 1 year. The 3 parallel, fixed doses, dose response studies showed that the reduct |
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