Caduet

Caduet

amlodipine + atorvastatin

Manufacturer:

Pfizer

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Amlodipine besylate, atorvastatin calcium.
Description
Caduet also contains the following excipients: Calcium carbonate, croscarmellose sodium, microcrystalline cellulose, pregelatinised starch, polysorbate 80, hydroxypropyl cellulose, purified water, colloidal silicon dioxide (anhydrous), magnesium stearate, opadry II white 85F28751 or opadry II Blue 85F10919.
The amlodipine besylate component of amlodipine/atorvastatin is chemically described as (R.S.) 3-ethyl-5-methyl-2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate benzenesulphonate. Its empirical formula is C20H25ClN2O5·C6H6O3S. The atorvastatin calcium component of amlodipine/atorvastatin 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. The empirical formula of atorvastatin calcium is (C33H34FN2O5)2Ca·3H2O.
Action
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 Pharmacodynamics: 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 Pharmacodynamics: 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.
Pharmacokinetics: Absorption: 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 basis).
*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.
Indications/Uses
The amlodipine/atorvastatin combination product (henceforth in this document termed “amlodipine/atorvastatin”) is indicated for the following patient populations:
(1) Patients at increased cardiovascular risk due to the presence of the 2 modifiable risk factors hypertension and dyslipidemia; and/or chronic angina.
(2) Prevention of cardiovascular complications in hypertensive patients (see Prevention of Cardiovascular Complications as follows). In these patients with multiple cardiovascular risk factors, amlodipine/atorvastatin is indicated for:
Hypertension: The amlodipine component is indicated for the 1st-line treatment of hypertension and can be used as the sole agent to control blood pressure in the majority of patients. Patients not adequately controlled on a single antihypertensive agent (other than amlodipine) may benefit from the addition of the amlodipine component of amlodipine/atorvastatin, in the same manner as they would benefit from the addition of amlodipine alone.
Amlodipine is also indicated to reduce the risk of fatal coronary heart disease and non-fatal myocardial infarction, and to reduce the risk of stroke.
Chronic Stable Angina: The amlodipine component is indicated for the treatment of myocardial ischemia, whether due to fixed obstruction (stable angina) and/or vasospasm/vasoconstriction (Prinzmetal's or variant angina) of coronary vasculature. Amlodipine/atorvastatin may be used where the clinical presentation suggests a possible vasospastic/vasoconstrictive component but where vasospasm/vasoconstriction has not been confirmed. Amlodipine/atorvastatin may be used alone or in combination with other anti-anginal drugs in patients with angina that is refractory to nitrates and/or adequate doses of β-blockers.
Dyslipidemia: The atorvastatin component is indicated as an adjunct to diet for the treatment of patients with elevated total cholesterol, LDL-cholesterol, apolipoprotein B and triglycerides and to increase HDL-cholesterol in patients with primary hypercholesterolemia (heterozygous familial and nonfamilial hypercholesterolemia), combined (mixed) hyperlipidemia (Fredrickson Types IIa and IIb), elevated serum triglyceride levels (Fredrickson Type IV), and for patients with dysbetalipoproteinemia (Fredrickson Type III) who do not respond adequately to diet.
The atorvastatin component is also indicated for the reduction of total cholesterol and LDL-cholesterol in patients with homozygous familial hypercholesterolemia when response to diet and other nonpharmacological measures are inadequate.
Prevention of Cardiovascular Complications: In patients without clinically evident cardiovascular disease and with or without dyslipidemia, but with multiple risk factors for coronary heart disease eg, smoking, hypertension, diabetes, low HDL-C, or a family history of early coronary heart disease, atorvastatin is indicated to: Reduce the risk of fatal coronary heart disease and non-fatal myocardial infarction; reduce the risk of stroke; reduce the risk of revascularization procedures and angina pectoris.
In patients with clinically evident coronary heart disease, atorvastatin is indicated to: Reduce the risk of nonfatal myocardial infarction, fatal and nonfatal stroke, revascularization procedures, hospitalization for CHF and angina.
Pediatric Patients (10-17 years): As an adjunct to diet to reduce total-C, LDL-C, and apo B levels in boys and postmenarchal girls, 10-17 years, with heterozygous familial hypercholesterolemia if after an adequate trial of diet therapy the following findings are present: LDL-C remains ≥190 mg/dL or LDL-C remains ≥160 mg/dL and there is a positive family history of premature cardiovascular disease or ≥2 other CVD risk factors are present in the pediatric patient.
Dosage/Direction for Use
General Considerations: Amlodipine/atorvastatin is a combination product targeting concomitant cardiovascular conditions, hypertension/angina and dyslipidemia.
The dosage range for amlodipine/atorvastatin is 5 mg/10 mg to a maximum dose of 10 mg/80 mg once daily. The starting dose and maintenance dose should be individualized on the basis of both effectiveness and tolerance for each individual component in the treatment of hypertension/angina and dyslipidemia. Current treatment guidelines should be consulted to establish treatment goals for patients based on their baseline characteristics. Doses may be taken at any time of day with or without food.
As a component of multiple-risk factor intervention, amlodipine/atorvastatin should be used in addition to non-pharmacological measures, including an appropriate diet, exercise and weight reduction in obese patients, smoking cessation and to treat underlying medical problems, when the response to these measures have been inadequate.
Following initiation and/or titration of amlodipine/atorvastatin, lipid levels should be analyzed and blood pressure measured within 2-4 weeks, and dosage of amlodipine and atorvastatin components should be adjusted accordingly. Titration for blood pressure response may proceed more rapidly if clinically warranted.
Initial Therapy: Amlodipine/atorvastatin may be used to initiate treatment in patients with hyperlipidemia and either hypertension or angina. The recommended starting dose of amlodipine/atorvastatin should be based on the appropriate combination of recommendations for the amlodipine and atorvastatin components considered separately. The maximum dose of the amlodipine component of amlodipine/atorvastatin is 10 mg once daily. The maximum dose of the atorvastatin component of amlodipine/atorvastatin is 80 mg once daily.
Substitution Therapy: Amlodipine/atorvastatin may be substituted for its individually titrated components. Patients may be given the equivalent dose of amlodipine/atorvastatin or a dose of amlodipine/atorvastatin with increased amounts of amlodipine, atorvastatin or both for additional antianginal effects, blood pressure lowering or lipid-lowering effect.
Amlodipine/atorvastatin may be used to provide additional therapy for patients already on one of its components. As initial therapy for one indication and continuation of treatment of the other, the recommended starting dose of amlodipine/atorvastatin should be selected based on continuation of the component being used previously and on the recommended starting dose for the component being added.
Concomitant Medication (see also Interactions): The amlodipine component of amlodipine/atorvastatin has been safely co-administered with thiazide diuretics, α-blockers, β-blockers, ACE inhibitors, long-acting nitrates and with sublingual nitroglycerine. Amlodipine/atorvastatin has also been safely administered with the aforementioned medicines.
The atorvastatin component of amlodipine/atorvastatin may be used in combination with a bile acid binding resin for additive effect on lipid-lowering. The combination of HMG-CoA reductase inhibitors and fibrates should generally be avoided (see Precautions and Interactions).
Special Populations and Special Considerations for Dosing: Primary Hypercholesterolemia and Combined (Mixed) Hyperlipidemia (Atorvastatin Studies): The majority of patients are controlled with 10 mg atorvastatin once a day. A therapeutic response is evident within 2 weeks, and the maximum response is usually achieved within 4 weeks. The response is maintained during chronic therapy.
Homozygous Familial Hypercholesterolemia (Atorvastatin Studies): In a compassionate-use study of patients with homozygous familial hypercholesterolemia, most patients responded to 80 mg of atorvastatin with a >15% reduction in LDL-C (18-45%).
Patients with Impaired Hepatic Function: Amlodipine/atorvastatin should not be used in patients with hepatic impairment. (See Contraindications and Precautions.)
Patients with Impaired Renal Function: No adjustment of the dose is required in patients with impaired renal function.
Elderly: No adjustment of the dose is required in elderly patients.
Children: There have been no studies conducted to determine the safety or effectiveness of amlodipine/atorvastatin (combination product) in pediatric populations. However, there have been studies with pediatrics with amlodipine alone and atorvastatin alone (see as follows).
Studies with Amlodipine: The recommended antihypertensive oral dose in pediatric patients 6-17 years is 2.5-5 mg once daily. Doses in excess of 5 mg daily have not been studied in pediatric patients (see Pharmacology: Pharmacodynamics and Pharmacokinetics under Actions).
The effect of amlodipine on blood pressure in patients <6 years is not known.
Studies with Atorvastatin: Heterozygous Familial Hypercholesterolemia in Pediatric Patients (10-17 years): The recommended starting dose of atorvastatin is 10 mg/day; the maximum recommended dose is 20 mg/day (doses >20 mg have not been studied in this patient population). Doses should be individualized according to the recommended goal of therapy (see Indications and Pharmacology: Pharmacodynamics under Actions). Adjustments should be made at intervals of ≥4 weeks.
Overdosage
There is no information on overdosage with amlodipine/atorvastatin in humans.
Due to amlodipine's and atorvastatin's extensive drug binding to plasma proteins, hemodialysis is not expected to significantly enhance amlodipine/atorvastatin clearance (see Pharmacokinetics: Renal Insufficiency under Actions).
Additional data on amlodipine ingestion, suggest that gross overdosage could result in excessive peripheral vasodilatation and possibly reflex tachycardia. Marked and probably prolonged systemic hypotension up to and including shock with fatal outcome have been reported. Administration of activated charcoal to healthy volunteers immediately or up to 2 hrs after ingestion of amlodipine 10 mg has been shown to significantly decrease amlodipine absorption. Gastric lavage may be worthwhile in some cases. Clinically significant hypotension due to amlodipine overdosage calls for active cardiovascular support including frequent monitoring of cardiac and respiratory function, elevation of extremities, and attention to circulating fluid volume and urine output. A vasoconstrictor may be helpful in restoring vascular tone and blood pressure, provided that there is no contraindication to its use.
IV calcium gluconate may be beneficial in reversing the effects of calcium-channel blockade.
Additional data on atorvastatin ingestion suggest that there is no specific treatment for atorvastatin overdosage. Should an overdose occur, the patient should be treated symptomatically and supportive measures instituted, as required.
Contraindications
Known hypersensitivity to dihydropyridines, amlodipine, atorvastatin or any component of Caduet.
Active liver disease or unexplained persistent elevations of serum transaminases exceeding 3 times the upper limit of normal.
Pregnant, breastfeeding or of childbearing potential who are not using adequate contraceptive measures. Amlodipine/atorvastatin should be administered to women of childbearing age only when such patients are highly unlikely to conceive and have been informed of the potential hazards to the fetus.
Use in Pregnancy & Lactation: Amlodipine/atorvastatin is contraindicated in pregnancy due to the atorvastatin component. Women of childbearing potential should use adequate contraceptive measures.
Amlodipine/atorvastatin should be administered to women of childbearing age only when such patients are highly unlikely to conceive and have been informed of the potential hazards to the fetus.
Amlodipine/atorvastatin is contraindicated while breastfeeding due to the atorvastatin component. It is not known whether atorvastatin is excreted in human milk. Because of the potential for adverse reactions in nursing infants, women taking amlodipine/atorvastatin should not breastfeed.
Safety of amlodipine in human pregnancy or lactation has not been established. Amlodipine does not demonstrate toxicity in animal reproductive studies other than to delay parturition and prolong labor in rates at a dose level 50 times the maximum recommended dose in humans.
Warnings
Do not use Caduet in pregnant and breastfeeding women. Do not use it in patients with liver disease. If there is myalgia at calf, back or whole body, discontinue Caduet and consult physician. Liver function tests should be performed before taking Caduet and 6 and 12 weeks after taking it. For patients who routinely use the drug, liver function tests should be performed every 6 months or as recommended by a physician. If the transaminase level is >3 times of upper normal limit, discontinue the drug and consult physician.
Use with caution with digoxin, warfarin because the level of these drugs in blood may be high and could be dangerous.
The risk of myopathy/rhabdomyolysis will increase when administered with other following drugs including azole antifungals eg, ketoconazole, itraconazole; macrolides eg, erythromycin, clarithromycin; HIV protease inhibitors eg, indinavir, ritonavir, nelfinavir, saquinavir; verapamil; diltiazem; gemfibrozil; nicotinic acid; cyclosporine; amiodarone.
The risk of rhabdomyolysis will increase under the following conditions eg, use at high dose; the elderly; patients with hepatic/renal insufficiency; alcoholism; patients with hypothyroidism.
Special Precautions
Use in Patients with Heart Failure: In a long-term, placebo-controlled study (PRAISE-2) of amlodipine-treated patients with NYHA III and IV heart failure of non-ischemic etiology, amlodipine was associated with increased reports of pulmonary edema despite no significant difference in the incidence of worsening heart failure as compared to placebo (see Pharmacology: Pharmacodynamics under Actions).
Use in Patients with Impaired Hepatic Function (see also Contraindications): Hepatic Effects: As with other lipid-lowering agents of the HMG-CoA reductase inhibitor class, moderate [>3 times upper limit of normal (ULN)] elevations of serum transaminases have been reported following therapy with atorvastatin. Liver function was monitored during pre-marketing as well as post-marketing clinical studies of atorvastatin given at doses of 10, 20, 40 and 80 mg.
Persistent increases in serum transaminases (>3 times ULN on ≥2 occasions) occurred in 0.7% of patients who received atorvastatin in these clinical trials. The incidence of these abnormalities was 0.2%, 0.2%, 0.6% and 2.3% for 10, 20, 40 and 80 mg respectively. Increases were generally not associated with jaundice or other clinical signs or symptoms. When the dosage of atorvastatin was reduced, or drug treatment interrupted or discontinued, transaminase levels returned to pre-treatment levels. Most patients continued treatment on a reduced dose of atorvastatin without sequelae.
Liver function tests should be performed before the initiation of treatment and periodically thereafter. Patients who develop any signs or symptoms suggesting liver injury should have liver function tests performed. Patients who develop increased transaminase levels should be monitored until the abnormality(ies) resolve(s). Should an increase in ALT or AST of >3 times times the upper limit of normal persist, reduction of dose or withdrawal of amlodipine/atorvastatin is recommended. Atorvastatin can cause an elevation in transaminases (see Adverse Reactions).
Amlodipine/atorvastatin should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of liver disease. Active liver disease or unexplained persistent transaminase elevations are contraindications to the use of amlodipine/atorvastatin (see Contraindications).
Skeletal Muscle Effects: Myalgia has been reported in atorvastatin-treated patients (see Adverse Reactions). Myopathy, defined as muscle aching or muscle weakness in conjunction with increases in creatine phosphokinase (CPK) values >10x ULN, should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of CPK. Patients should be advised to promptly report unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. Amlodipine/atorvastatin therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. The risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concurrent administration of cyclosporine, fibric acid derivatives, erythromycin, niacin, or azole antifungals. Many of these drugs inhibit cytochrome P-450 3A4 metabolism and/or drug transport. CYP3A4 is the primary hepatic isozymes known to be involved in the biotransformation of atorvastatin. Physicians considering combined therapy with atorvastatin and fibric acid derivatives, erythromycin, immunosuppressive drugs, azole antifungals or lipid-lowering doses of niacin should carefully weigh the potential benefits and risks and should carefully monitor patients for any signs and symptoms of muscle pain, tenderness or weakness, particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. Periodic CPK determinations may be considered in such situations, but there is no assurance that such monitoring will prevent the occurrence of severe myopathy (see Interactions). Atorvastatin/amlodipine may cause an elevation of CPK due to the atorvastatin component (see Adverse Reactions).
As with other drugs in the class of HMG-CoA reductase inhibitors, rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria, have been reported. Amlodipine/atorvastatin therapy should be temporarily withheld or discontinued in any patient with an acute, serious condition suggestive of a myopathy or having a risk factor predisposing to the development of renal failure secondary to rhabdomyolysis (eg, severe acute infection, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders, and uncontrolled seizures). Control of hypertension may be continued with the appropriate dose of amlodipine.
Effects on the Ability to Drive or Operate Machinery: Based on the available information on amlodipine and atorvastatin, Caduet is unlikely to impair a patient's ability to drive or use machinery.
Use In Pregnancy & Lactation
Amlodipine/atorvastatin is contraindicated in pregnancy due to the atorvastatin component. Women of childbearing potential should use adequate contraceptive measures.
Amlodipine/atorvastatin should be administered to women of childbearing age only when such patients are highly unlikely to conceive and have been informed of the potential hazards to the fetus.
Amlodipine/atorvastatin is contraindicated while breastfeeding due to the atorvastatin component. It is not known whether atorvastatin is excreted in human milk. Because of the potential for adverse reactions in nursing infants, women taking amlodipine/atorvastatin should not breastfeed.
Safety of amlodipine in human pregnancy or lactation has not been established. Amlodipine does not demonstrate toxicity in animal reproductive studies other than to delay parturition and prolong labor in rates at a dose level 50 times the maximum recommended dose in humans.
Adverse Reactions
Combination therapy with amlodipine and atorvastatin has been evaluated for safety in 1092 patients in double-blind, placebo-controlled studies treated for concomitant hypertension and dyslipidemia. In clinical trials, no adverse events peculiar to combination therapy with amlodipine and atorvastatin have been observed. Adverse events have been limited to those that were reported previously with amlodipine and/or atorvastatin (see respective adverse event experiences as follows).
In general, combination therapy with amlodipine and atorvastatin was well tolerated. For the most part, adverse events have been mild or moderate in severity. In controlled clinical trials, discontinuation of therapy due to adverse events or laboratory abnormalities was required in only 5.1% of patients treated with both amlodipine and atorvastatin compared to 4% of patients given placebo.
The following information is based on clinical trials and post-marketing experience with amlodipine and atorvastatin.
Amlodipine Experience: Amlodipine is well tolerated. In placebo-controlled clinical trials involving patients with hypertension or angina, the most commonly observed side effects were:
Autonomic Nervous System: Flushing.
Body as a Whole: Fatigue.
Cardiovascular, General: Edema.
Central and Peripheral Nervous System: Dizziness, headache.
Gastrointestinal: Abdominal pain, nausea.
Heart Rate/Rhythm: Palpitations.
Psychiatric: Somnolence.
In these clinical trials, no pattern of clinically significant laboratory test abnormalities related to amlodipine has been observed.
Pediatric Patients (6-17 years): Amlodipine is well tolerated in children. Adverse events were similar to those seen in adults. In a study of 268 children, the most frequently reported adverse events were headache, asthenia, dizziness, abdominal pain, vasodilatation and epistaxis. The majority of adverse events were mild or moderate. Severe adverse events (predominantly headache) were experienced by 7.2% with amlodipine 2.5 mg, 4.5% with amlodipine 5 mg and 4.6% with placebo. The most common cause of discontinuation from the study was uncontrolled hypertension. There were no discontinuations due to laboratory abnormalities. There was no significant change in heart rate.
In post-marketing experience, the following additional undesirable effects have been reported with amlodipine:
Autonomic Nervous: Dry mouth, increased sweating.
Body as a Whole: Asthenia, back pain, malaise, pain, increase/decrease weight.
Cardiovascular, General: Hypotension, syncope.
Central and Peripheral Nervous: Hypertonia, hypoesthesia/paresthesia, peripheral neuropathy, tremor.
Endocrine: Gynecomastia.
Gastrointestinal: Altered bowel habits, dyspepsia (including gastritis), gingival hyperplasia, pancreatitis, vomiting.
Metabolic/Nutritional: Hyperglycemia.
Musculoskeletal: Arthralgia, muscle cramps, myalgia.
Platelet/Bleeding/Clotting: Purpura, thrombocytopenia.
Psychiatric: Impotence, insomnia, mood changes.
Respiratory: Coughing, dyspnea, rhinitis.
Skin/Appendages: Alopecia, skin discoloration, urticaria.
Special Senses: Taste perversion, tinnitus.
Urinary: Increased urinary frequency, micturition disorder, nocturia.
Vascular (Extracardiac): Vasculitis.
Vision: Visual disturbances.
White Blood Cell/R.E.S.: Leucopenia.
Hepatobiliary: Hepatitis, jaundice and hepatic enzyme elevations have also been reported very infrequently (mostly consistent with cholestasis). Some cases severe enough to require hospitalization have been reported in association with use of amlodipine. In many instances, causal association is uncertain.
Rarely: Allergic reaction including pruritus, rash, angioedema and erythema multiforme.
As with other calcium-channel blockers the following adverse events have been rarely reported and cannot be distinguished from the natural history of the underlying disease: Myocardial infarction, arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation) and chest pain.
Atorvastatin Experience: Atorvastatin is generally well-tolerated. Adverse reactions have usually been mild and transient. Less than 2% of patients were discontinued from clinical trials due to side effects attributed to atorvastatin.
The most frequent (≥1%) adverse effects associated with atorvastatin therapy, in patients participating in controlled clinical studies were:
Psychiatric Disorders: Insomnia.
Nervous System Disorders: Headache.
Gastrointestinal Disorders: Nausea, diarrhea, abdominal pain, dyspepsia, constipation, flatulence.
Musculoskeletal and Connective Tissue Disorders: Myalgia.
General Disorders and Administration Site Conditions: Asthenia.
The following additional adverse effects have been reported in atorvastatin clinical trials:
Metabolism and Nutrition Disorders: Hypoglycemia, hyperglycemia, anorexia.
Nervous System Disorders: Peripheral neuropathy, paresthesia.
Gastrointestinal Disorders: Pancreatitis, vomiting.
Hepatobiliary Disorders: Hepatitis, cholestatic jaundice.
Skin and Subcutaneous Tissue Disorders: Alopecia, pruritus, rash.
Musculoskeletal and Connective Tissue Disorders: Myopathy, myositis, muscle cramps.
Reproductive System and Breast Disorders: Impotence.
Not all effects listed previously have been causally associated with atorvastatin therapy.
Pediatric Patients (10-17 years): Patients treated with atorvastatin had an adverse experience profile generally similar to that of patients treated with placebo, the most common adverse experiences observed in both groups, regardless of causality assessment, were infections.
In post-marketing experience, the following additional undesirable effects have been reported with atorvastatin:
Blood and Lymphatic System Disorders: Thrombocytopenia.
Immune System Disorders: Allergic reactions (including anaphylaxis).
Metabolism and Nutrition Disorders: Weight gain.
Nervous System Disorders: Hypoesthesia, amnesia, dizziness.
Ear and Labyrinth Disorders: Tinnitus.
Skin and Subcutaneous Tissue Disorders: Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, bullous rashes, urticaria.
Musculoskeletal and Connective Tissue Disorders: Rhabdomyolysis, arthralgia, back pain.
General Disorders and Administration Site Conditions: Chest pain, peripheral edema, malaise, fatigue.
Drug Interactions
Data from a drug-drug interaction study involving 10 mg of amlodipine and 80 mg of atorvastatin in healthy subjects indicate that the pharmacokinetics of amlodipine are not altered when the drugs are co-administered. The effect of amlodipine on the pharmacokinetics of atorvastatin showed no effect on the Cmax: 91% (90% confidence interval: 80-103%), but the AUC of atorvastatin increased by 18% (90% confidence interval: 109-127%) in the presence of amlodipine.
No drug interaction studies have been conducted with amlodipine/atorvastatin and other drugs, although studies have been conducted using the individual amlodipine and atorvastatin components, as described in the following text:
In Studies with Amlodipine: Amlodipine has been safely administered with thiazide diuretics, α-blockers, β-blockers, ACE inhibitors, long-acting nitrates, sublingual nitroglycerine, nonsteroidal anti-inflammatory drugs, antibiotics and oral hypoglycemic drugs.
In vitro data from studies with human plasma indicate that amlodipine has no effect on protein-binding of the drugs tested (digoxin, phenytoin, warfarin or indomethacin).
In the following studies, there were no significant changes in the pharmacokinetics of either amlodipine or another drug within the study, when co-administered.
Special Studies: Effect of Other Agents on Amlodipine:
Cimetidine: Co-administration of amlodipine with cimetidine did not alter the pharmacokinetics of amlodipine.
Grapefruit Juice: Co-administration of 240 mL of grapefruit juice with a single oral dose of amlodipine 10 mg in 20 healthy volunteers had no significant effect on the pharmacokinetics of amlodipine.
Aluminum/Magnesium (Antacid): Co-administration of an aluminum/magnesium antacid with a single dose of amlodipine had no significant effect on the pharmacokinetics of amlodipine.
Sildenafil: A single 100 mg dose of sildenafil in subjects with essential hypertension had no effect on the pharmacokinetic parameters of amlodipine. When amlodipine and sildenafil were used in combination, each agent independently exerted its own blood pressure lowering effect.
Special Studies: Effect of Amlodipine on Other Agents:
Digoxin: Co-administration of amlodipine with digoxin did not change serum digoxin levels or digoxin renal clearance in normal volunteers.
Ethanol (Alcohol): Single and multiple 10 mg doses of amlodipine had no significant effect on the pharmacokinetics of ethanol.
Warfarin: Co-administration of amlodipine with warfarin did not change the warfarin prothrombin response time.
Cyclosporine: Pharmacokinetic studies with cyclosporine have demonstrated that amlodipine does not significantly alter the pharmacokinetics of cyclosporine.
Drug/Laboratory Test Interactions: None known.
In Studies with Atorvastatin: The risk of myopathy during treatment with HMG-CoA reductase inhibitor drugs is increased with concurrent administration of cyclosporine, fibric acid derivatives, erythromycin, azole antifungals or niacin (see Precautions: Skeletal Muscle Effects).
Antacids: Co-administration of atorvastatin with an oral antacid suspension containing magnesium and aluminum hydroxides, decreased atorvastatin plasma concentrations approximately 35%; however, LDL-C reduction was not altered.
Antipyrine: Because atorvastatin does not affect the pharmacokinetics of antipyrine, interactions with other drugs metabolized via the same cytochrome isoenzymes are not expected.
Colestipol: Plasma concentrations of atorvastatin were lower (approximately 25%) when colestipol was administered with atorvastatin. However, lipid effects were greater when atorvastatin and colestipol were co-administered than when either drug was given alone.
Digoxin: When multiple doses of digoxin and 10 mg atorvastatin were co-administered, steady-state plasma digoxin concentrations were unaffected. However, digoxin concentrations increased approximately 20% following administration of digoxin with 80 mg atorvastatin daily. Patients taking digoxin should be monitored appropriately.
Erythromycin/Clarithromycin: Co-administration of atorvastatin and erythromycin (500 mg 4 times daily) or clarithromycin (500 mg twice daily), known inhibitors of cytochrome P-450 3A4, was associated with higher plasma concentrations of atorvastatin (see Precautions: Skeletal Muscle Effects).
Azithromycin: Co-administration of atorvastatin (10 mg once daily) and azithromycin (500 mg once daily) did not alter the plasma concentrations of atorvastatin.
Terfenadine: Co-administration of atorvastatin and terfenadine did not produce a clinically significant effect on the pharmacokinetics of terfenadine.
Oral Contraceptives: Co-administration with an oral contraceptive containing norethindrone and ethinyl estradiol increased AUC values for norethindrone and ethinyl estradiol by approximately 30% and 20%. These increases should be considered when selecting an oral contraceptive for a woman taking atorvastatin.
Warfarin: An atorvastatin interaction study with warfarin was conducted and no clinically significant interactions were observed.
Cimetidine: An atorvastatin interaction study with cimetidine was conducted and no clinically significant interactions were observed.
Protease Inhibitors: Co-administration of atorvastatin and protease inhibitors, known to inhibit cytochrome P-450 3A4, was associated with increased plasma concentrations of atorvastatin.
Other Concomitant Therapy: In clinical studies, atorvastatin was used concomitantly with antihypertensive agents and estrogen replacement therapy without evidence of clinically significant adverse interactions. Interaction studies with specific agents have not been conducted.
Incompatibilities: Not applicable.
Storage
Store at controlled room temperature (15-30°C).
ATC Classification
C10BX03 - atorvastatin and amlodipine ; Belongs to the class of HMG CoA reductase inhibitors, other combinations.
Presentation/Packing
Tab 5/10 mg x 4 x 7's. 10/10 mg x 4 x 7's. 10/20 mg x 4 x 7's. 10/40 mg x 4 x 7's.
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