Pharmacology: Amlodipine/Atorvastatin Pharmacodynamics:
Amlodipine/atorvastatin combines 2 mechanisms of action: The dihydropyridine calcium antagonist (calcium ion antagonist or slow-channel blocker) action of amlodipine and the HMG-CoA reductase inhibition of atorvastatin. The amlodipine component of amlodipine/atorvastatin inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. The atorvastatin component of amlodipine/atorvastatin 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.
Clinical Studies of Combined Amlodipine and Atorvastatin in Patients with Hypertension and Dyslipidemia:
In a double-blind, placebo-controlled study of 1660 patients with co-morbid hypertension and dyslipidemia, once daily treatment with 8 dose combinations of amlodipine and atorvastatin (5/10, 10/10, 5/20, 10/20, 5/40, 10/40, 5/80, or 10/80 mg) was compared versus amlodipine alone (5 or 10 mg), atorvastatin alone (10, 20, 40 or 80 mg), and placebo. In addition to concomitant hypertension and dyslipidemia, 15% of the patients had diabetes mellitus, 22% were smokers and 14% had a positive family history of cardiovascular disease. At 8 weeks, all 8 combination-treatment groups demonstrated statistically significant dose-related reductions in systolic blood pressure (SBP), diastolic blood pressure (DBP) and LDL-C compared to placebo, with no overall modification of effect of either component on SBP, DBP and LDL-C (see Table 1).
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In an open-label trial, 1220 patients with co-morbid hypertension and dyslipidemia received elective dose-titration with amlodipine/atorvastatin over a 14-week period. Patients were required to have uncontrolled blood pressure to enter the trial (whether or not they were using antihypertensive medications at enrollment; patients were allowed to continue on previous antihypertensives, other than calcium-channel blockers, during the 14-week dose-titration period) but could enter with either controlled or uncontrolled LDL-C. As a result, no patient entered the trial with both blood pressure and LDL-C controlled, and neither was controlled in 62% of patients. Treatment with amlodipine/atorvastatin reduced mean blood pressure -17.1 mmHg systolic and -9.6 mmHg diastolic, and reduced mean LDL-C by -32.7%, resulting in control of both blood pressure and LDL-C for 58% of these patients (controlled blood pressure and LDL-C were defined, respectively, as <140/90 mmHg and <160 mg/dL for patients with co-morbid hypertension and dyslipidemia only; <140/90 mmHg and <130 mg/dL for patients with co-morbid hypertension and dyslipidemia plus 1 additional cardiovascular risk factor, excluding known coronary heart disease (CHD) or diabetes mellitus; and <130/85 mmHg and <100 mg/dL for patients with co-morbid hypertension and dyslipidemia plus known CHD, diabetes mellitus, or other atherosclerotic disease). Only 13% of the patients in this trial used amlodipine/atorvastatin as initial therapy for co-morbid hypertension and dyslipidemia, whereas the amlodipine component of amlodipine/atorvastatin comprised add-on therapy for hypertension in 56% of patients, including patients for whom the atorvastatin component of amlodipine/atorvastatin comprised initial therapy for dyslipidemia (20%), a substitution for atorvastatin taken previously (18%), or a switch from another statin (18%). When evaluated according to use of antihypertensive and lipid-lowering medications at enrollment, results showed that both blood pressure and LDL-C were brought under control for 65% of patients who used amlodipine/atorvastatin as initial therapy for co-morbid hypertension and dyslipidemia and for 55-64% of patients for whom the amlodipine component of amlodipine/atorvastatin constituted add-on therapy for hypertension (55% for such patients who had previously used lipid-lowering medications other than atorvastatin, 58% for such patients who had previously used atorvastatin, and 64% for such patients who had not previously used lipid-lowering medications).
Amlodipine is a calcium ion influx inhibitor (slow channel blocker or calcium ion antagonist) and inhibits the transmembrane influx of calcium ions into cardiac and vascular smooth muscle.
The mechanism of the antihypertensive action of amlodipine is due to a direct relaxant effect on vascular smooth muscle. The precise mechanism by which amlodipine relieves angina has not been fully determined but amlodipine reduces total ischemic burden by the following 2 actions.
Amlodipine dilates peripheral arterioles and thus, reduces the total peripheral resistance (afterload) against which the heart works. Since the heart rate remains stable, this unloading of the heart reduces myocardial energy consumption and oxygen requirements.
The mechanism of action of amlodipine also probably involves dilatation of the main coronary arteries and coronary arterioles, both in normal and ischemic regions. This dilatation increases myocardial oxygen delivery in patients with coronary artery spasm (Prinzmetal's or variant angina) and blunts smoking-induced coronary vasoconstriction.
In patients with hypertension, once daily dosing provides clinically significant reductions of blood pressure in both the supine and standing positions throughout the 24-hr interval. Due to the slow onset of action, acute hypotension is not a feature of amlodipine administration.
In patients with angina, once daily administration of amlodipine increases total exercise time, time to angina onset, and time to 1 mm ST segment depression, and decreases both angina attack frequency and nitroglycerine tablet consumption.
Amlodipine has not been associated with any adverse metabolic effects or changes in plasma lipids and is suitable for use in patients with asthma, diabetes and gout.
Use in Patients with Coronary Artery Disease (CAD):
The effects of amlodipine on cardiovascular morbidity and mortality, the progression of coronary atherosclerosis, and carotid atherosclerosis were studied in the Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT). This multicenter, randomized, double blind, placebo-controlled study followed 825 patients with angiographically defined CAD for 3 years. The population included patients with previous myocardial infarction (MI) (45%), percutaneous transluminal coronary angioplasty (PTCA) at baseline (42%) or history of angina (69%). Severity of CAD ranged from 1-vessel disease (45% of patients) to 3+ vessel disease (21%). Patients with uncontrolled hypertension (DBP >95 mmHg) were excluded from the study. Major cardiovascular events were adjudicated by a blinded endpoint committee. Although there were no demonstrable effects on the rate of progression of coronary artery lesions, amlodipine arrested the progression of carotid intima-media thickening. A significant reduction (-31%) was observed in the amlodipine-treated patients in the combined endpoint of cardiovascular death, MI, stroke, PTCA, coronary artery bypass graft (CABG), hospitalization for unstable angina, and worsening congestive heart failure (CHF). A significant reduction (-42%) in revascularization procedures (PTCA and CABG) was also seen in the amlodipine-treated patients. Fewer hospitalizations (-33%) were seen for unstable angina in amlodipine patients than in the placebo group.
Treatment to Prevent Heart Attack Trial (ALLHAT):
A randomized double-blind morbidity-mortality study called the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) was performed to compare newer drug therapies: Amlodipine 2.5-10 mg/day (calcium channel blocker) or lisinopril 10-40 mg/day (ACE inhibitor) as 1st-line therapies to that of the thiazide-diuretic, chlorthalidone 12.5-25 mg/day in mild to moderate hypertension.
A total of 33,357 hypertensive patients ≥55 years were randomized and followed for a mean of 4.9 years. The patients had at least 1 additional CHD risk factor, including MI or stroke >6 months or documentation of other atherosclerotic CVD (overall 51.5%), type 2 diabetes (36.1%), HDL-C <35 mg/dL (11.6%), left ventricular hypertrophy diagnosed by electrocardiogram or echocardiography (20.9%), current cigarette smoking (21.9%).
The primary endpoint was a composite of fatal CHD or non-fatal myocardial infarction. There was no significant difference in the primary endpoint between amlodipine-based therapy and chlorthalidone-based therapy: RR 0.98 95% CI (0.90-1.07) p=0.65. In addition, there was no significant difference in all-cause mortality between amlodipine-based therapy and chlorthalidone-based therapy: RR 0.96 95% CI (0.89-1.02) p=0.20.
Use in Patients with Heart Failure:
Hemodynamic studies and exercise based controlled clinical trials in NYHA Class II-IV heart failure patients have shown that amlodipine did not lead to clinical deterioration as measured by exercise tolerance, left ventricular ejection fraction and clinical symptomatology.
A placebo-controlled study (PRAISE) designed to evaluate patients in NYHA Class III-IV heart failure receiving digoxin, diuretics and angiotensin converting enzyme (ACE) inhibitors has shown that amlodipine did not lead to an increase in risk of mortality or combined mortality and morbidity in patients with heart failure.
In a follow-up, long-term, placebo-controlled study (PRAISE-2) of amlodipine in patients with NYHA III and IV heart failure without clinical symptoms or objective findings suggestive of underlying ischemic disease, on stable doses of ACE inhibitors, digitalis, and diuretics, amlodipine had no effect on total or cardiovascular mortality. In this same population, amlodipine was associated with increased reports of pulmonary edema despite no significant difference in the incidence of worsening heart failure as compared to placebo.
Use in Pediatric Patients (6-17 years):
The efficacy of amlodipine in hypertensive pediatric patients 6-17 years of age was demonstrated in one 8-week double-blind, placebo-controlled randomized withdrawal trial in 268 patients with hypertension. All patients were randomized to the 2.5- or 5-mg treatment arms and followed for 4 weeks after which they were randomized to continue 2.5 or 5 mg amlodipine or placebo for an additional 4 weeks. Compared with baseline, once daily treatment with amlodipine 5 mg resulted in statistically significant reductions in systolic and diastolic blood pressures. Placebo-adjusted, mean reduction in seated systolic blood pressure was estimated to be 5 mmHg for the 5 mg dose of amlodipine and 3.3 mmHg for the 2.5 mg dose of amlodipine. Subgroup analyses indicated that younger pediatric patients aged 6-13 years had efficacy results comparable to those of the older pediatric patients 14-17 years.
Atorvastatin 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. In patients with homozygous and heterozygous familial hypercholesterolemia (FH), nonfamilial forms of hypercholesterolemia and mixed dyslipidemia, atorvastatin reduces total-C (total cholesterol), LDL-C (low-density lipoprotein cholesterol) and apo B (apolipoprotein B). Atorvastatin also reduces VLDL-C (very-low-density lipoprotein cholesterol) and TG (triglycerides) and produces variable increases in HDL-C (high-density lipoprotein cholesterol).
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 for enhanced uptake and catabolism of LDL.
Atorvastatin reduces LDL production and the number of LDL particles. Atorvastatin produces a profound and sustained increase in LDL receptor activity coupled with a beneficial change in the quality of circulating LDL particles. Atorvastatin is effective in reducing LDL in patients with homozygous familial hypercholesterolemia, a population that has not normally responded to lipid-lowering medication.
Atorvastatin and some of its metabolites are pharmacologically active in humans. The primary site of action of atorvastatin is the liver, which is the principal site of cholesterol synthesis and LDL clearance. LDL-C reduction correlates better with drug dose than it does with systemic drug concentration. Individualization of drug dosage should be based on therapeutic response (see Dosage & Administration).
In a dose-response study, atorvastatin (10-80 mg) reduced total-C (30-46%), LDL-C (41-61%), apo B (34-50%) and TG (14-33%). These results are consistent in patients with heterozygous familial hypercholesterolemia, nonfamilial forms of hypercholesterolemia and mixed hyperlipidemia, including patients with non-insulin dependent diabetes mellitus.
In patients with isolated hypertriglyceridemia, atorvastatin reduces total-C, LDL-C, VLDL-C, apo B, TG and non-HDL-C, and increases HDL-C. In patients with dysbetalipoproteinemia, atorvastatin reduces IDL-C (intermediate density lipoprotein cholesterol).
In patients with Fredrickson Types IIa and IIb hyperlipoproteinemia pooled from 24 controlled trials, the median percent increases from baseline in HDL-C for atorvastatin (10-80 mg) were 5.1-8.7% in a non-dose-related manner. Additionally, analysis of this pooled data demonstrated significant dose-related decreases in total-C/HDL-C and LDL-C/HDL-C ratios, ranging from -29 to -44% and -37 to -55%, respectively.
The effects of atorvastatin on ischemic events and total mortality were studied in the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering study (MIRACL). This multi-center, randomized, double-blind, placebo-controlled study followed 3086 patients with acute coronary syndromes; unstable angina or non-Q wave myocardial infarction. Patients were treated with standard care, including diet, and either atorvastatin 80 mg daily or placebo for a median duration of 16 weeks. The final LDL-C, total-C, HDL-C and TG levels were 72, 147, 48 and 139 mg/dL in the atorvastatin group, respectively, and 135, 217, 46 and 187 mg/dL, respectively, in the placebo group. Atorvastatin significantly reduced the risk of ischemic events and death by 16%. The risk of experiencing re-hospitalization for angina pectoris with documented evidence of myocardial ischemia was significantly reduced by 26%. Atorvastatin reduced the risk of ischemic events and death to a similar extent across the range of baseline LDL-C. In addition, atorvastatin reduced the risk of ischemic events and death to similar extents in patients with non-Q wave MI and unstable angina, as well as in males and females and in patients ≤65 years and >65 years.
Prevention of Cardiovascular Complications:
In the Anglo-Scandinavian Cardiac Outcomes Trial Lipid Lowering Arm (ASCOT-LLA), the effect of atorvastatin on fatal and non-fatal CHD was assessed in 10,305 hypertensive patients 40-80 years (mean of 63 years), without a previous myocardial infarction and with TC levels <6.5 mmol/L (251 mg/dL). Additionally all patients had at least 3 of the following cardiovascular risk factors: Male gender, age >55 years, smoking, diabetes, history of CHD in a 1st-degree relative, TC:HDL >6, peripheral vascular disease, left ventricular hypertrophy, prior cerebrovascular event, specific ECG abnormality, proteinuria/albuminuria. In this double-blind, placebo-controlled study patients were treated with antihypertensive therapy (Goal BP <140/90 mmHg for non-diabetic patients, <130/80 mmHg for diabetic patients) and allocated to either atorvastatin 10 mg daily (n=5168) or placebo (n=5137).
As the effect of atorvastatin treatment compared to placebo exceeded the significance threshold during an interim analysis, the ASCOT-LLA was terminated early at 3.3 years instead of 5 years. Additionally, blood pressure was well controlled and similar in patients assigned atorvastatin and placebo. These changes persisted throughout the treatment period.
Atorvastatin significantly reduced the rate of the following events: See Table 2.
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The total mortality and cardiovascular mortality have not been significantly reduced although a favorable trend was observed.
In the Collaborative Atorvastatin Diabetes Study (CARDS), the effect of atorvastatin on fatal and nonfatal cardiovascular disease was assessed in 2838 patients with type 2 diabetes 40-75 years of age, without prior history of cardiovascular disease and with LDL ≤4.14 mmol/L (160 mg/dL) and TG ≤6.78 mmol/L (600 mg/dL). Additionally, all patients had at least 1 of the following risk factors: Hypertension, current smoking, retinopathy, microalbuminuria or macroalbuminuria.
In this randomized, double-blind, multicenter, placebo-controlled trial, patients were treated with either atorvastatin 10 mg daily (n=1428) or placebo (n=1410) for a median follow-up of 3.9 years. As the effect of atorvastatin treatment on the primary endpoint reached the predefined stopping rules for efficacy, CARDS was terminated 2 years earlier than anticipated.
The absolute and relative risk reduction effect of atorvastatin is shown in Table 3.
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There was no evidence of a difference in the treatment effect by patient's gender, age, or baseline LDL-C level.
A relative risk reduction in death of 27% (82 deaths in the placebo group compared to 61 deaths in the treatment arm) has been observed with a borderline statistical significance (p=0.0592).
The overall incidence of adverse events or serious adverse events was similar between the treatment groups.
Heterozygous Familial Hypercholesterolemia in Pediatric Patients:
In a double-blind, placebo-controlled study followed by an open-label phase, 187 boys and postmenarchal girls 10-17 years (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 a baseline LDL-C level ≥190 mg/dL, or a baseline LDL-C ≥160 mg/dL and positive family history of FH or documented premature cardiovascular disease in a 1st- or 2nd-degree relative. The mean baseline LDL-C value was 218.6 mg/dL (range: 138.5-385 mg/dL) in the atorvastatin group compared to 230 mg/dL (range: 160-324.5 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 78 (55.7%).
Atorvastatin significantly decreased plasma levels of total-C, LDL-C, triglycerides, and apolipoprotein B during the 26 weeks double-blind phase (see Table 4).
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The mean achieved LDL-C value was 130.7 mg/dL (range: 70-242 mg/dL) in the atorvastatin group compared to 228.5 mg/dL (range: 152-385 mg/dL) in the placebo group during the 26-week double-blind phase.
In this limited controlled study, there was no detectable effect on growth or sexual maturation in boys or on menstrual cycle length in girls. Atorvastatin has not been studied in controlled clinical trials involving prepubertal patients or patients <10 years. The safety and efficacy of doses >20 mg have not been studied in controlled trials in children. The long-term efficacy of atorvastatin therapy in childhood to reduce morbidity and mortality in adulthood has not been established.
In studies with amlodipine/atorvastatin: Following oral administration of amlodipine/atorvastatin 2 distinct peak plasma concentrations were observed. The first, within 1-2 hrs of administration, is attributable to atorvastatin; the 2nd, between 6 and 12 hrs after dosing is attributable to amlodipine. The rate and extent of absorption (bioavailability) of amlodipine and atorvastatin from amlodipine/atorvastatin are not significantly different from the bioavailability of amlodipine and atorvastatin from co-administration of amlodipine and atorvastatin tablets as assessed by Cmax
: 101% (90% CI: 98, 104) and AUC: 100% (90% CI: 97, 103) for the amlodipine component and Cmax
: 94% (90% CI: 85, 104) and AUC: 105% (90% CI: 99, 111) for the atorvastatin component, respectively.
The bioavailability of the amlodipine component of amlodipine/atorvastatin was not affected under the fed state as assessed by Cmax
: 105% (90% CI: 99, 111) and AUC: 101% (90% CI: 97, 105) relative to the fasted state. Although food decreases the rate and extent of absorption of atorvastatin from amlodipine/atorvastatin by approximately 32% and 11%, respectively, as assessed by Cmax
: 68% (90% CI 60, 79) and AUC: 89% (90% CI 83, 95) relative to the fasted state, similar reductions in plasma concentrations in the fed state have been seen with atorvastatin taken as monotherapy without reduction in LDL-C effect.
In Studies with Amlodipine:
After oral administration of therapeutic doses, amlodipine is well absorbed with peak blood levels between 6-12 hrs post-dose. Absolute bioavailability has been estimated to be between 64% and 80%. The volume of distribution is approximately 21 L/kg. In vitro
studies have shown that approximately 97.5% of circulating amlodipine is bound to plasma proteins.
Absorption of amlodipine is unaffected by consumption of food.
In Studies with Atorvastatin:
Atorvastatin is rapidly absorbed after oral administration; maximum plasma concentrations occur within 1-2 hrs. Extent of absorption and plasma atorvastatin concentrations increase in proportion to atorvastatin dose. Atorvastatin tablets are 95-99% bioavailable compared with solutions. The absolute bioavailability of atorvastatin 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 & Administration).
Distribution: In Studies with Atorvastatin:
Mean volume of distribution of atorvastatin is approximately 381 L. Atorvastatin is ≥98% bound to plasma proteins. A red blood cell/plasma ratio of approximately 0.25 indicates poor drug penetration into red blood cells.
Metabolism and Excretion: In Studies with Amlodipine:
The terminal plasma elimination half-life is about 35-50 hrs and is consistent with once-daily dosing. Steady-state plasma levels are reached after 7-8 days of consecutive dosing. Amlodipine is extensively metabolized by the liver to inactive metabolites with 10% of the parent compound and 60% of metabolites excreted in the urine.
In Studies with Atorvastatin:
Atorvastatin is extensively metabolized to ortho- and para-hydroxylated derivatives and various β-oxidation products. In vitro
inhibition of HMG-CoA reductase by ortho- and para-hydroxylated 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 hepatic cytochrome P-450 3A4, consistent with increased plasma concentrations of atorvastatin in humans following co-administration with erythromycin, a known inhibitor of this isozyme. In vitro
studies also indicate that atorvastatin is a weak inhibitor of cytochrome P-450 3A4. Atorvastatin co-administration did not produce a clinically significant effect in plasma concentrations of terfenadine, a compound predominantly metabolized by cytochrome P-450 3A4; therefore, it is unlikely that atorvastatin will significantly alter the pharmacokinetics of other cytochrome P-450 3A4 substrates (see Interactions). In animals, the ortho-hydroxy metabolite undergoes further glucuronidation.
Atorvastatin and its metabolites are eliminated primarily in bile following hepatic and/or extrahepatic metabolism; however, the drug does not appear to undergo enterohepatic recirculation. Mean plasma elimination half-life of atorvastatin in humans is approximately 14 hrs, but the half-life of inhibitory activity for HMG-CoA reductase is 20-30 hrs due to the contribution of active metabolites. Less than 2% of a dose of atorvastatin is recovered in urine following oral administration.
Special Populations: Hepatic Insufficiency: In Studies with Atorvastatin:
Plasma concentrations of atorvastatin are markedly increased (approximately 16-fold in Cmax
and 11-fold in AUC) in patients with chronic alcoholic liver disease (Child-Pugh B) (see Contraindications).
Renal Insufficiency (see Dosage & Administration): In Studies with Amlodipine:
Changes in amlodipine plasma concentrations are not correlated with degree of renal impairment. Amlodipine is not dialyzable.
In Studies with Atorvastatin:
Renal disease has no influence on the plasma concentrations or lipid effects of atorvastatin. Thus, dose adjustment in patients with renal dysfunction is not necessary.
Gender: In Studies with Atorvastatin:
Plasma concentrations of atorvastatin in women differ (approximately 20% higher for Cmax
and 10% lower for AUC) from those in men. However, there were no clinically significant differences in lipid effects between men and women.
Elderly: In Studies with Amlodipine:
The time to reach peak plasma concentrations of amlodipine is similar in elderly and younger subjects. Amlodipine clearance tends to be decreased with resulting increases in AUC and elimination half-life in elderly patients. Increases in AUC and elimination half-life in patients with congestive heart failure were as expected for the patient age group studied. Amlodipine, used at similar doses in elderly or younger patients, is equally well tolerated.
In Studies with Atorvastatin:
Plasma concentrations of atorvastatin are higher (approximately 40% for Cmax
and 30% for AUC) in healthy, elderly subjects (≥65 years) than in young adults. The ACCESS study specifically evaluated elderly patients with respect to reaching their NCEP treatment goals. The study included 1087 patients <65 years, 815 patients >65 years and 185 patients >75 years. No differences in safety, efficacy or lipid treatment goal attainment were observed between elderly patients and the overall population.
Pediatrics: In Studies with Amlodipine:
In 1 clinical chronic exposure study, 73 hypertensive pediatric patients, ages 12 months to ≤17 years, amlodipine was dosed at an average daily dose of 0.17 mg/kg. Clearance for subjects with the median weight of 45 kg were 23.7 and 17.6 L/hr for males and females, respectively. This is in a similar range to the published estimates of 24.8 L/hr in a 70-kg adult. The average estimate for volume of distribution for a 45-kg patient was 1130 L (25.11 L/kg). Maintenance of the blood pressure effect over the 24-hr dosing interval was observed with little difference in peak and trough variation effect. When compared with historical adult pharmacokinetics the parameters observed in this study indicate that once daily dosing is appropriate.
Toxicology: Preclinical Safety Data: Carcinogenesis: In Studies with Amlodipine:
Rats and mice treated with amlodipine in the diet for 2 years, at concentrations calculated to provide daily dosage levels of 0.5, 1.25 and 2.5 mg/kg/day showed no evidence of carcinogenicity. The highest dose (for mice, similar to, and for rats twice* the maximum recommended clinical dose of 10 mg on a mg/m2
basis) was close to the maximum tolerated dose for mice but not for rats.
In Studies with Atorvastatin:
Atorvastatin was not carcinogenic in rats. The maximum dose used was 63-fold higher than the highest human dose (80 mg/day) on a mg/kg body-weight basis and 8- to 16-fold higher based on AUC(0-24)
values. In a 2-year study in mice, incidences of hepatocellular adenomas in males and hepatocellular carcinomas in females were increased at the maximum dose used, which was 250-fold higher than the highest human dose on a mg/kg body-weight basis. Systemic exposure was 6- to 11-fold higher based on AUC(0-24)
All other chemically similar drugs in this class have induced tumors in both mice and rats at multiples of 12-125 times their highest recommended clinical doses on a mg/kg body-weight basis.
Mutagenesis: In Studies with Amlodipine:
Mutagenicity studies revealed no drug-related effects at either the gene or chromosome levels.
In Studies with Atorvastatin:
Atorvastatin did not demonstrate mutagenic or clastogenic potential in 4 in vitro
tests with and without metabolic activation or in 1 in vivo
assay. It was negative in the Ames test with Salmonella typhimurium
and Escherichia coli
, and in the in vitro
HGPRT forward mutation assay in Chinese hamster lung cells. Atorvastatin did not produce significant increases in chromosomal aberrations in the in vitro
Chinese hamster lung cell assay and was negative in the in vivo
mouse micronucleus test.
Impairment of Fertility: In Studies with Amlodipine:
There was no effect on the fertility of rats treated with amlodipine (males for 64 days and females 14 days prior to mating) at doses up to 10 mg/kg/day (8 times* the maximum recommended human dose of 10 mg on a mg/m2
*Based on patient weight of 50 kg.
In Studies with Atorvastatin:
No adverse effects on fertility or reproduction were observed in male rats given doses of atorvastatin up to 175 mg/kg/day or in female rats given doses up to 225 mg/kg/day. These doses are 100-140 times the maximum recommended human dose on a mg/kg basis. Atorvastatin caused no adverse effects on sperm or semen parameters, or on reproductive organ histopathology in dogs given doses of 10, 40 or 120 mg/kg for 2 years.