NDA 21-540
`Page 3
`
`DESCRIPTION
`
`CADUET
`(amlodipine besylate/atorvastatin calcium) Tablets
`
`CADUET® (amlodipine besylate and atorvastatin calcium) tablets combine the long-acting calcium
`channel blocker amlodipine besylate with the synthetic 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)-ß, δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-
`1H-pyrrole-1-heptanoic acid, calcium salt (2:1) trihydrate. Its empirical formula is (C33H34
`FN2O5)2Ca•3H20.
`
`The structural formulae for amlodipine besylate and atorvastatin calcium are shown below.
`
`Cl
`O
`
`H3C
`
`O
`
`H3C
`
`NH
`
`CH3
`
`O
`
`O
`
`O
`
`C6H6O3S
`
`NH2
`
` Amlodipine besylate
`
`Atorvastatin calcium
`
`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:
`
`CFAD Exhibit 1049
`
`

`
`NDA 21-540
`Page 4
`
`
`Table 1: CADUET Tablet Strengths
`
`
`
`5mg/
`10mg
`5
`
`5mg/
`20mg
`5
`
`5mg/
`40mg
`5
`
`5mg/
`80mg
`5
`
`10mg/
`10mg
`10
`
`10mg/
`20mg
`10
`
`10mg/
`40mg
`10
`
`10mg/
`80mg
`10
`
`10
`
`20
`
`40
`
`80
`
`10
`
`20
`
`40
`
`80
`
`amlodipine
`equivalent
`(mg)
`atorvastatin
`equivalent
`(mg)
`
`
`
`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 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 antagonist (calcium ion
`antagonist or slow-channel blocker) amlodipine (antihypertensive/antianginal agent) and an HMG-
`CoA reductase inhibitor atorvastatin (cholesterol lowering agent). 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, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme A to
`mevalonate, a precursor of sterols, including cholesterol.
`
`The Amlodipine Component of CADUET
`
`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. Within the physiologic pH range, amlodipine is an ionized
`compound (pKa=8.6), and its kinetic interaction with the calcium channel receptor is characterized by
`a gradual rate of association and dissociation with the receptor binding site, resulting in a gradual onset
`of effect.
`
`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.
`
`
`

`
`NDA 21-540
`Page 5
`
`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.
`
`The Atorvastatin Component of CADUET
`
`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 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.
`
`The effect of atorvastatin on cardiovascular morbidity and mortality has not been determined.
`
`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
`
`

`
`NDA 21-540
`Page 6
`
`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%. The bioavailability of amlodipine when administered alone is not
`altered by the presence of food.
`
`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. Although food decreases the rate and extent of drug absorption by
`approximately 25% and 9%, respectively, as assessed by Cmax and AUC, LDL-C reduction is similar
`whether atorvastatin is given with or without food. 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. Although 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).
`
`
`

`
`NDA 21-540
`Page 7
`
`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.
`
`
`
`Special 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 section, 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.
`
`
`

`
`NDA 21-540
`Page 8
`
`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 Insufficiency
`
`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).
`
`Hemodialysis
`
`While studies have not been conducted in patients with end-stage renal disease, hemodialysis is not
`expected to significantly enhance clearance of atorvastatin and/or amlodipine since both drugs are
`extensively bound to plasma proteins.
`
`Hepatic Insufficiency
`
`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%, and a lower initial
`dose may be required.
`
`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.
`
`
`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.
`
`
`

`
`NDA 21-540
`Page 9
`
`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 normals 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
`
`

`
`NDA 21-540
`Page 10
`
`up to 1 year. The 3 parallel, fixed doses, dose response studies showed that the reduction in supine and
`standing blood pressures was dose-related within the recommended dosing range. Effects on diastolic
`pressure were similar in young and older patients. The effect on systolic pressure was greater in older
`patients, perhaps because of greater baseline systolic pressure. Effects were similar in black patients
`and in white patients.
`
`Pediatric Patients: Two-hundred sixty-eight hypertensive patients aged 6 to 17 years were randomized
`first to amlodipine 2.5 or 5 mg once daily for 4 weeks and then randomized again to the same dose or
`to placebo for another 4 weeks. Patients receiving 5 mg amlodipine at the end of 8 weeks had lower
`blood pressure than those secondarily randomized to placebo. The magnitude of the treatment effect is
`difficult to interpret, but it is probably less than 5 mmHg systolic on the 5 mg dose. Adverse events
`were similar to those seen in adults.
`
`Amlodipine Effects in Chronic Stable Angina: The effectiveness of 5-10 mg/day of amlodipine in
`exercise-induced angina has been evaluated in 8 placebo-controlled, double-blind clinical trials of up
`to 6 weeks duration involving 1038 patients (684 amlodipine, 354 placebo) with chronic stable angina.
`In 5 of the 8 studies, significant increases in exercise time (bicycle or treadmill) were seen with the
`10 mg dose. Increases in symptom-limited exercise time averaged 12.8% (63 sec) for amlodipine
`10 mg, and averaged 7.9% (38 sec) for amlodipine 5 mg. Amlodipine 10 mg also increased time to
`1 mm ST segment deviation in several studies and decreased angina attack rate. The sustained efficacy
`of amlodipine in angina patients has been demonstrated over long-term dosing. In patients with angina,
`there were no clinically significant reductions in blood pressures (4/1 mmHg) or changes in heart rate
`(+0.3 bpm).
`
`Amlodipine Effects in Vasospastic Angina: In a double-blind, placebo-controlled clinical trial of
`4 weeks duration in 50 patients, amlodipine therapy decreased attacks by approximately 4/week
`compared with a placebo decrease of approximately 1/week (p<0.01). Two of 23 amlodipine and 7 of
`27 placebo patients discontinued from the study due to lack of clinical improvement.
`
`Amlodipine Effects in Congestive Heart Failure: Amlodipine has been compared to placebo in four
`8-12 week studies of patients with NYHA class II/III heart failure, involving a total of 697 patients. In
`these studies, there was no evidence of worsened heart failure based on measures of exercise tolerance,
`NYHA classification, symptoms, or LVEF. In a long-term (follow-up at least 6 months, mean
`13.8 months) placebo-controlled mortality/morbidity study of amlodipine 5-10 mg in 1153 patients
`with NYHA classes III (n=931) or IV (n=222) heart failure on 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 all-cause mortality and cardiac morbidity (as defined by life-threatening
`arrhythmia, acute myocardial infarction, or hospitalization for worsened heart failure), or on NYHA
`classification, or symptoms of heart failure. Total combined all-cause mortality and cardiac morbidity
`events were 222/571 (39%) for patients on amlodipine and 246/583 (42%) for patients on placebo; the
`cardiac morbid events represented about 25% of the endpoints in the study.
`
`Another study (PRAISE-2) randomized patients with NYHA class III (80%) or IV (20%) heart failure
`without clinical symptoms or objective evidence of underlying ischemic disease, on stable doses of
`ACE inhibitor (99%), digitalis (99%) and diuretics (99%), to placebo (n=827) or amlodipine (n=827)
`and followed them 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% confidence limits from 8%
`reduction to 29% increase on amlodipine). With amlodipine there were more reports of pulmonary
`edema.
`
`

`
`NDA 21-540
`Page 11
`
`
`
`Clinical Studies with Atorvastatin
`
`Atorvastatin Studies in Hypercholesterolemia (Heterozygous Familial and Nonfamilial) and Mixed
`Dyslipidemia (Fredrickson Types IIa and IIb): Atorvastatin reduces total-C, LDL-C, VLDL-C, apo B,
`and TG, and increases HDL-C in patients with hypercholesterolemia and mixed dyslipidemia.
`Therapeutic response is seen within 2 weeks, and maximum response is usually achieved within 4
`weeks and maintained during chronic therapy.
`
`
`Atorvastatin is effective in a wide variety of patient populations with hypercholesterolemia, with and
`without hypertriglyceridemia, in men and women, and in the elderly.
`
`In two multicenter, placebo-controlled, dose-response studies in patients with hypercholesterolemia,
`atorvastatin given as a single dose over 6 weeks significantly reduced total-C, LDL-C, apo B, and TG
`(pooled results are provided in Table 2).
`
`Table 2. Dose-Response in Patients With Primary Hypercholesterolemia (Adjusted Mean %
`Change From Baseline)a
`
`DOSE N TC LDL-C ApoB TG HDL-C Non-HDL/HDL
`Placebo 21 4 4 3 10 -3 7
` 10 22 -29 -39 -32 -19 6 -34
` 20 20 -33 -43 -35 -26 9 -41
` 40 21 -37 -50 -42 -29 6 -45
` 80 23 -45 -60 -50 -37 5 -53
`aResults are pooled from 2 dose-response studies.
`
`In patients with Fredrickson Types IIa and IIb hyperlipoproteinemia pooled from 24 controlled trials,
`the median (25th and 75th percentile) percent changes from baseline in HDL-C for atorvastatin 10, 20,
`40, and 80 mg were 6.4 (-1.4, 14), 8.7 (0, 17), 7.8 (0, 16), and 5.1 (-2.7, 15), respectively. Additionally,
`analysis of the pooled data demonstrated consistent and significant decreases in total-C , LDL-C, TG,
`total-C/HDL-C, and LDL-C/HDL-C.
`
`In three multicenter, double-blind studies in patients with hypercholesterolemia, atorvastatin was
`compared to other HMG-CoA reductase inhibitors. After randomization, patients were treated for 16
`weeks with either atorvastatin 10 mg per day or a fixed dose of the comparative agent (Table 3).
`
`Table 3. Mean Percent Change From Baseline at End Point
`(Double-Blind, Randomized, Active-Controlled Trials)
`
`
`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`HDL-C
`
`
` +7
` +7
`-1.7, 2.0
`
`
` +6
` +8
`-4.9, 1.6
`
`
`LDL-C
`
`-36a
`-27
`-10.7, -7.1
`
`-35b
`-23
`-14.5, -8.2
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Apo B
`
`-28a
`-20
`-10.0, -6.5
`
`-27b
`-17
`-13.4, -7.4
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`TG
`
`-17a
`- 6
`-15.2, -7.1
`
`-17b
`- 9
`-14.1, -0.7
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Total-C
`
`-27a
`-19
`-9.2, -6.5
`
`-25b
`-17
`-10.8, -6.1
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` N
`
`Placebo
`(N=12)
`-12.4 (-36.6, 82.7)
`-2.3 (-15.5, 24.4)
`3.6 (-31.3, 31.6)
`3.8 (-18.6, 13.4)
`-1.0 (-31.9, 53.2)
`-2.8 (-17.6, 30.0)
`
`Atorvastatin 20 mg
`(N=13)
`-38.7 (-62.7, 29.5)
`-34.9 (-49.6, -15.2)
`-30.4 (-53.9, 0.3)
`11.0 (-3.2, 25.2)
`-44.6 (-62.2, -10.8)
`-42.7 (-53.7, -17.4)
`
`Atorvastatin 80 mg
`(N=14)
`-51.8 (-82.8, 41.3)
`-44.4 (-63.5, -3.8)
`-40.5 (-60.6, -13.8)
`7.5 (-10.8, 37.2)
`-62.0 (-88.2, 37.6)
`-51.5 (-72.9, -4.3)
`
`NDA 21-540
`Page 12
`
`
`
`
`
`Non-HDL-C/
`HDL-C
`
`-37a
`-28
`-11.1, -7.1
`
`-36b
`-28
`-11.5, -4.1
`
`Treatment
`(Daily Dose)
`
`Study 1
`
`707
`Atorvastatin 10 mg
`191
`Lovastatin 20 mg
`95% CI for Diff1
`
`Study 2
`
`222
`Atorvastatin 10 mg
` 77
`Pravastatin 20 mg
`95% CI for Diff1
`
`Study 3
`
`
`-39c
`-23c
`-34c
`-37c
`-29c
` +7
`132
`Atorvastatin 10 mg
`-33
` +7
`-15
`-30
`-30
`-24
` 45
`Simvastatin 10 mg
`95% CI for Diff1
`-9.6, -1.9
`-4.3, 3.9
`-15.1, -0.7
`-8.0, -1.1
`-10.1, -2.6
`-8.7, -2.7
`
`1 A negative value for the 95% CI for the difference between treatments favors atorvastatin for all except HDL-C, for which
`a positive value favors atorvastatin. If the range does not include 0, this indicates a statistically significant difference.
`a Significantly different from lovastatin, ANCOVA, p ≤0.05
`b Significantly different from pravastatin, ANCOVA, p ≤0.05
`c Significantly different from simvastatin, ANCOVA, p ≤0.05
`
`The impact on clinical outcomes of the differences in lipid-altering effects between treatments shown
`in Table 3 is not known. Table 3 does not contain data comparing the effects of atorvastatin 10 mg and
`higher doses of lovastatin, pravastatin, and simvastatin. The drugs compared in the studies summarized
`in the table are not necessarily interchangeable.
`
`Atorvastatin Effects in Hypertriglyceridemia (Fredrickson Type IV): The response to atorvastatin in 64
`patients with isolated hypertriglyceridemia treated across several clinical trials is shown in the table
`below. For the atorvastatin-treated patients, median (min, max) baseline TG level was 565 (267-1502).
`
`Table 4. Combined Patients With Isolated Elevated TG:
`Median (min, max) Percent Changes From Baseline
`
`Atorvastatin 10 mg
`(N=37)
`-41.0 (-76.2, 49.4)
`-28.2 (-44.9, -6.8)
`-26.5 (-57.7, 9.8)
`13.8 (-9.7, 61.5)
`-48.8 (-85.8, 57.3)
`-33.0 (-52.1, -13.3)
`
`Triglycerides
`Total-C
`LDL-C
`HDL-C
`VLDL-C
`non-HDL-C
`
`Atorvastatin Effects in Dysbetalipoproteinemia (Fredrickson Type III): The results of an open-label
`crossover study of atorvastatin in 16 patients (genotypes: 14 apo E2/E2 and 2 apo E3/E2) with
`dysbetalipoproteinemia (Fredrickson Type III) are shown in the table below.
`
`Table 5. Open-Label Crossover Study of 16 Patients
`With Dysbetalipoproteinemia (Fredrickson Type III)
`
`

`
`Median % Change (min, max)
`Atorvastatin 10 mg
`Atorvastatin 80 mg
`
`-37 (-85, 17)
`-39 (-92, -8)
`-32 (-76, 9)
`-43 (-87, -19)
`
`-58 (-90, -31)
`-53 (-95, -30)
`-63 (-90, -8)
`-64 (-92, -36)
`
`NDA 21-540
`Page 13
`
`
`
`
`
`Total-C
`Triglycerides
`IDL-C + VLDL-C
`non-HDL-C
`
`
`Median (min, max) at
`Baseline (mg/dL)
`442 (225, 1320)
`678 (273, 5990)
`215 (111, 613)
`411 (218, 1272)
`
`
`Atorvastatin Effects in Homozygous Familial Hypercholesterolemia: In a study without a concurrent
`control group, 29 patients ages 6 to 37 years with homozygous FH received maximum daily doses of
`20 to 80 mg of atorvastatin. The mean LDL-C reduction in this study was 18%. Twenty-five patients
`with a reduction in LDL-C had a mean response of 20% (range of 7% to 53%, median of 24%); the
`remaining 4 patients had 7% to 24% increases in LDL-C. Five of the 29 patients had absent LDL-
`receptor function. Of these, 2 patients also had a portacaval shunt and had no significant reduction in
`LDL-C. The remaining 3 receptor-negative patients had a mean LDL-C reduction of 22%.
`
`Atorvastatin Effects in Heterozygous Familial Hypercholesterolemic Pediatric Patients: In a double-
`blind, placebo-controlled study followed by an open-label phase, 187 boys and postmenarchal girls 10-
`17 years of age (mean age 14.1 years) with heterozygous familial hypercholesterolemia (FH) or severe
`hypercholesterolemia were randomized to atorvastatin (n=140) or placebo (n=47) for 26 weeks and
`then all received atorvastatin for 26 weeks. Inclusion in the study required 1) a baseline LDL-C level ≥
`190 mg/dL or 2) a baseline LDL-C ≥ 160 mg/dL and positive family history of FH or documented
`premature cardiovascular disease in a first- or second-degree relative. The mean baseline LDL-C value
`was 218.6 mg/dL (range: 138.5-385.0 mg/dL) in the atorvastatin group compared to 230.0 mg/dL
`(range: 160.0-324.5 mg/dL) in placebo group. The dosage of atorvastatin (once daily) was 10 mg for
`the first 4 weeks and up-titrated to 20 mg if the LDL-C level was > 130 mg/dL. The number of
`atorvastatin-treated patients who required up-titration to 20 mg after Week 4 during the double-blind
`phase was 80 (57.1%).
`
`Atorvastatin significantly decreased plasma levels of total-C, LDL-C, triglycerides, and apolipoprotein
`B during the 26 week double-blind phase (see Table 6).
`
`Table 6. Lipid-altering Effects of Lipitor in Adolescent Boys and Girls with Heterozygous
`Familial Hypercholesterolemia or Severe Hypercholesterolemia
`(Mean Percent Change from Baseline at Endpoint in Intention-to-Treat Population)
`
`DOSAGE
`
`Placebo
`
`N
`
`47
`
`Total-C
`
`LDL-C
`
`HDL-C
`
`-1.5
`
`-0.4
`
`-1.9
`
`TG
`
`1.0
`
`Apolipoprotein B
`
`0.7
`
`-12.0
`
`-34.0
`
`140
`
`-31.4
`
`-39.6
`
`2.8
`
`Atorvastatin
`
`The mean achieved LDL-C value was 130.7 mg/dL (range: 70.0-242.0 mg/dL) in the atorvastatin
`group compared to 228.5 mg/dL (range: 152.0-385.0 mg/dL) in the placebo group during the 26 week
`double-blind phase.
`
`The safety and efficacy of atorvastatin doses above 20 mg have not been studied in controlled trials in
`children. The long-term efficacy of atorv