Caduet

Caduet

amlodipine + atorvastatin

Manufacturer:

Pfizer
Full Prescribing Info
Contents
Amlodipine besylate, atorvastatin Ca.
Description
The tablets for oral administration contain amlodipine besilate and atorvastatin calcium equivalent to 5 mg/10 mg, 5 mg/20 mg, 10 mg/10 mg, 10 mg/20 mg, amlodipine/atorvastatin dosage strengths respectively.
The amlodipine besilate 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 benzenesulfonate. Its empirical formula is C20H25CIN2O5·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 (C33H34 FN2O5)2Ca·3H2O.
Excipients/Inactive Ingredients: 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.
Action
Pharmacology: Pharmacodynamics: Amlodipine/Atorvastatin Pharmacodynamics: Mechanism of Amlodipine/Atorvastatin: Amlodipine/atorvastatin combines two mechanisms of action: the dihydropyridine calcium antagonist (calcium ion antagonist or slow-channel blocker) action of amlodipine and the HMGCoA 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 HMG-CoA 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 comorbid hypertension and dyslipidemia, once-daily treatment with eight-dose combinations of amlodipine and atorvastatin (5/10 mg, 10/10 mg, 5/20 mg, 10/20 mg, 5/40 mg, 10/40 mg, 5/80 mg, or 10/80 mg) was compared vs. amlodipine alone (5 mg or 10 mg), atorvastatin alone (10 mg, 20 mg, 40 mg, 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 CVD. At 8 weeks, all eight 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 comorbid hypertension and dyslipidemia received elective dose titration with amlodipine/atorvastatin over a 14-week period. Patients were required to have uncontrolled BP 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 BP and LDL-C controlled, and neither was controlled in 62% of patients. Treatment with amlodipine/atorvastatin reduced mean BP -17.1 mmHg systolic and -9.6 mmHg diastolic, and reduced mean LDL-C by -32.7%, resulting in control of both BP and LDL-C for 58% of these patients (controlled BP and LDL-C were defined, respectively, as <140/90 mmHg and <160 mg/dL for patients with comorbid hypertension and dyslipidemia only; <140/90 mmHg and <130 mg/dL for patients with comorbid hypertension and dyslipidemia plus 1 additional cardiovascular risk factor, excluding known CHD or diabetes mellitus; and <130/85 mmHg and <100 mg/dL for patients with comorbid 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 comorbid 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 the use of antihypertensive and lipid-lowering medications at enrollment, results showed that both BP and LDL-C were brought under control for 65% of patients who used amlodipine/atorvastatin as initial therapy for comorbid hypertension and dyslipidemia and for 55% to 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).
Anglo-Scandinavian Cardiac Outcomes Trial: The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) is a randomized 2x2 factorial design study comparing two antihypertensive regimens in a total of 19,342 patients (Blood Pressure Lowering arm - ASCOT-BPLA), as well as the effect of addition of 10 mg of atorvastatin compared to placebo in 10,305 patients (Lipid-Lowering arm - ASCOT-LLA) on fatal and non-fatal coronary events. There are 19,257 and 10,240 efficacy evaluable patients in ASCOT-BPLA and ASCOT-LLA, respectively.
In Anglo-Scandinavian Cardiac Outcomes Trial Blood Pressure Lowering Arm: The effect of treatment regimens based on amlodipine (5-10 mg) (n=9681) or atenolol (50-100 mg) (n=9661) was compared in a prospective randomized open blinded endpoint (PROBE) design in 19,342 hypertensive patients, ≥40 to <80 years of age with no previous MI or treatment for angina, at least three of the following predefined cardiovascular risk factors: male gender, age ≥55 years, smoking, Type 2 diabetes, history of CAD event occurring in a first-degree relative before the age of 55 years (males) or 60 years (females), total-C:HDL ≥6, peripheral vascular disease, left ventricular hypertrophy, prior cerebrovascular event, specific electrocardiogram (ECG) abnormalities, proteinuria/albuminuria.
To attain further BP goals (<140/90 mmHg for non-diabetic patients, <130/80 mmHg for diabetic patients), perindopril (4-8 mg) could be added to the amlodipine group and bendroflumethiazide potassium (1.25-2.5 mg) to the atenolol group. Third-line therapy was doxazosin gastrointestinal therapeutic system (GITS) (4-8 mg) in both arms.
The ASCOT-BPLA study was stopped prematurely after 903 primary events (non-fatal MI and fatal CHD) with median follow-up of 5.5 years due to significant benefit of the amlodipine-based regimen on the following secondary endpoints: all-cause mortality, cardiovascular (CV) mortality and stroke. The study had planned to need at least 1150 primary endpoints.
The primary endpoint of non-fatal MI + fatal CHD did not reach statistical significance when comparing the amlodipine-based group to the atenolol-based group. The secondary endpoints of total coronary events, all-cause mortality, fatal and non-fatal stroke were statistically significantly reduced when comparing amlodipine-based group to the atenolol-based group.
The incidence of the primary and secondary endpoints in the 19,257 efficacy evaluable patients: (see Table 2).


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Blood pressure (SBP/DBP) decreased significantly on both treatment regimens when compared to baseline (p-values <0.001). The SBP/DBP decreases from baseline were significantly more with the amlodipine-based regimen than with the atenolol-based regimen (-27.5/-17.7 mmHg vs. -25.7/- 15.6 mmHg, respectively), and the p-values on differences between the two groups were both <0.001 for SBP and DBP.
In Anglo-Scandinavian Cardiac Outcomes Trial Lipid-Lowering Arm: In the ASCOT-LLA, the effect of atorvastatin on fatal and non-fatal CHD was assessed in 10,305 hypertensive patients 40 to 80 years of age (mean of 63 years), without a previous MI and with TC levels <6.5 mmol/L (251 mg/dL). Additionally, all patients had at least three of the following cardiovascular risk factors: male gender, age >55 years, smoking, diabetes, history of CHD in a first-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, BP was well controlled and similar in patients assigned to atorvastatin and placebo. These changes persisted throughout the treatment period.
Atorvastatin reduced the rate of the following events: (see Table 3).


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The total mortality and cardiovascular mortality have not been significantly reduced, although a favorable trend was observed.
In Anglo-Scandinavian Cardiac Outcomes Trial 2x2: The pre-specified ASCOT 2x2 factorial analysis investigated the potential differential effect (interaction) of adding atorvastatin to the amlodipine vs. the atenolol group in ASCOT- LLA.
For the 10,305 patients enrolled in ASCOT-LLA, there were 5168 patients in the atorvastatin group (2584 patients received amlodipine and 2584 patients received atenolol) and 5137 in the placebo group (2554 patients received amlodipine and 2583 patients received atenolol).
The risk reductions on the composite endpoint of non-fatal MI and fatal CHD were based on the 10,240 efficacy evaluable patients.
The combination of amlodipine with atorvastatin resulted in a significant risk reduction in the composite primary endpoint of fatal CHD and non fatal MI by: 53% (95% CI 31%-68%, p<0.0001) compared to amlodipine + placebo; 39% (95% CI 8%-59%, p<0.016) compared to atenolol +atorvastatin.
The p-value for the interaction was 0.027, which was not statistically significant at the pre-specified 0.01 level.
Blood pressure (SBP/DBP) decreased significantly on all four treatment regimens when compared to baseline (p-values <0.001). The SBP/DBP decreases from baseline were significantly more with the amlodipine-based regimens than with the atenolol-based regimens (-26.5/-15.6 mmHg vs. - 24.7/-13.6 mmHg for amlodipine plus atorvastatin vs. atenolol plus atorvastatin, and -27.1/-15.8 mmHg vs. -24.1/-13.6 mmHg for amlodipine plus placebo vs. atenolol plus placebo, respectively). The p-values on differences between the two groups were all <0.01 for SBP and DBP.
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 two 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 BP in both the supine and standing positions throughout the 24-hour 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 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 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% of patients). Patients with uncontrolled hypertension (DBP >95 mmHg) were excluded from the study. Major cardiovascular events (MCVE) 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 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-treated patients than in the placebo group.
Treatment to Prevent Heart Attack Trial: 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 mg to 10 mg/day (calcium channel blocker) or lisinopril 10 mg to 40 mg/day (ACE-inhibitor) as first-line therapies to that of the thiazide-diuretic, chlorthalidone 12.5 to 25 mg/day in mild to moderate hypertension.
A total of 33,357 hypertensive patients aged 55 or older were randomized and followed for a mean of 4.9 years. The patients had at least one 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 MI. 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 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-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.
Atorvastatin pharmacodynamics: Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts HMG-CoA to mevalonate, a precursor of sterols, including cholesterol. In patients with homozygous and heterozygous FH, nonfamilial forms of hypercholesterolemia, and mixed dyslipidemia, atorvastatin reduces total-C, LDL-C, and apo B. Atorvastatin also reduces very-lowdensity lipoprotein cholesterol (VLDL-C) and TG and produces variable increases in HDL-C.
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 FH, 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 FH, 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 intermediate density lipoprotein cholesterol (IDL-C).
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% to 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.
Prevention of Cardiovascular Complications: The effect of atorvastatin on fatal and non-fatal CHD is discussed in Clinical Studies of Combined Amlodipine and Atorvastatin in Patients with Hypertension and Dyslipidemia under Anglo-Scandinavian Cardiac Outcomes Trial.
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 to 17 years of age (mean age 14.1 years) with heterozygous FH or severe hypercholesterolemia were randomized to atorvastatin (n=140) or placebo (n=47) for 26 weeks and then all received atorvastatin for 26 weeks. Inclusion in the study required 1) a baseline LDL-C level ≥190 mg/dL or 2) a baseline LDL-C ≥160 mg/dL and positive family history of FH or documented premature CVD in a first- or second-degree relative. The mean baseline LDL-C value was 218.6 mg/dL (range: 138.5-385.0 mg/dL) in the atorvastatin group compared to 230.0 mg/dL (range: 160.0-324.5 mg/dL) in the 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, TG, and apo B during the 26 week double-blind phase (see Table 4).


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The mean achieved LDL-C value was 130.7 mg/dL (range: 70.0-242.0 mg/dL) in the Atorvastatin group compared to 228.5 mg/dL (range: 152.0-385.0 mg/dL) in the placebo group during the 26-week double-blind phase.
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 pre-pubertal patients or patients younger than 10 years of age. The safety and efficacy of doses above 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, two distinct peak plasma concentrations were observed. The first, within 1 to 2 hours of administration, is attributable to atorvastatin; the second, between 6 and 12 hours 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 (see as follows).
In studies with amlodipine: After oral administration of therapeutic doses, amlodipine is well absorbed with peak blood levels between 6 to 12 hours 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 to 2 hours. Extent of absorption and plasma atorvastatin concentrations increases in proportion to atorvastatin dose. Atorvastatin tablets are 95% to 99% bioavailable compared to 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 to 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 to 50 hours and is consistent with once daily dosing. Steady-state plasma levels are reached after 7 to 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 beta-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 P450 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 P450 3A4. Atorvastatin co-administration did not produce a clinically significant effect in plasma concentrations of terfenadine, a compound predominantly metabolized by cytochrome P450 3A4; therefore, it is unlikely that atorvastatin will significantly alter the pharmacokinetics of other cytochrome P450 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 hours, but the half-life of inhibitory activity for HMG-CoA reductase is 20 to 30 hours due to the contribution of active metabolites. Less than 2% of a dose of atorvastatin is recovered in urine following oral administration.
Special populations: 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 CHF 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 (aged ≥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 under 65 years of age, 815 patients over 65 years of age, and 185 patients over 75 years of age. No differences in safety, efficacy or lipid treatment goal attainment were observed between elderly patients and the overall population.
Drug Interactions: In studies with atorvastatin: The effect of co-administered drugs on the pharmacokinetics of atorvastatin as well as the effect of atorvastatin on the pharmacokinetics of co-administered drugs are summarized as follows (see Precautions and Interactions). See Table 5.


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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 to 125 times their highest recommended clinical doses, on a mg/kg body weight basis.
*Based on patient weight of 50 kg.
Mutagenesis: In studies with amlodipine: Mutagenicity studies revealed no drug-related effects at either the gene or chromosome level.
In studies with atorvastatin: Atorvastatin did not demonstrate mutagenic or clastogenic potential in four in vitro tests with and without metabolic activation or in one in vivo assay. It was negative in the Ames test with Salmonella typhimurium and Escherichia coli, and in the in vitro hypoxanthine-guanine phosphoribosyl transferase (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 to 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 mg/kg, 40 mg/kg, or 120 mg/kg for 2 years.
Indications/Uses
CADUET (amlodipine and atorvastatin) is indicated in patients for whom treatment with both amlodipine and atorvastatin is appropriate.
Amlodipine is indicated for treatment of hypertension and can be used as the sole agent to control blood pressure (BP) in the majority of patients. Patients not adequately controlled on a single antihypertensive agent may benefit from the addition of amlodipine, which has been used in combination with a thiazide diuretic, beta adrenoreceptor blocking agent, or an angiotensin-converting enzyme inhibitor.
Amlodipine is indicated for treatment of myocardial ischemia, whether due to fixed obstruction (stable angina) and/or vasospasm/vasoconstriction (prinzmetal's or variant angina) or coronary vasculature. Amlodipine may be used where the clinical presentation suggests a possible vasospastic/vasoconstriction has not been confirmed. Amlodipine may be used alone, as monotherapy, or in combination with other antianginal drugs in patients with angina that is refractory to nitrates and/or adequate doses or beta blockers.
Atorvastatin is indicated as an adjunct to diet for the reduction of elevated total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (apo B), and triglycerides (TG) in patients with primary hypercholesterolemia, combined (mixed) hyperlipidemia, and heterozygous and homozygous familial hypercholesterolemia when response to diet and other non-pharmacological measures are inadequate.
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 BP measured within 2 to 4 weeks, and dosage of amlodipine and atorvastatin components should be adjusted accordingly. Titration for BP 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.
If titrated dose is required, atorvastatin can be added separately to the combination of amlodipine/atorvastatin.
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, BP 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, alpha blockers, beta blockers, angiotensin-converting enzyme (ACE) inhibitors, long-acting nitrates, and with sublingual nitroglycerin. 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 3-hydroxy- 3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors and fibrates should generally be avoided (see Precautions and Interactions).
Special Populations and Considerations for Dosing: Primary Hypercholesterolemia and Combined (Mixed) Hyperlipidemia (Atorvastatin Studies): The majority of patients are controlled with 10 mg of atorvastatin once daily. 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 FH, most patients responded to 80 mg of atorvastatin with a greater than 15% reduction in LDL-C (18%-45%).
Use in Patients with Impaired Hepatic Function: Amlodipine/atorvastatin should not be used in patients with hepatic impairment (see Contraindications and Precautions).
Use in Patients with Impaired Renal Function: No adjustment of the dose is required in patients with impaired renal function (see Precautions).
Use in the Elderly: No adjustment of the dose is required in elderly patients.
Use in Children: There have been no studies conducted to determine the safety or effectiveness of amlodipine/atorvastatin (combination product) in pediatric populations. Therefore, use in children population is not recommended.
Studies with amlodipine: The recommended antihypertensive oral dose in pediatric patients aged 6 to 17 years is 2.5 mg to 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 BP in patients less than 6 years of age is not known.
Studies with atorvastatin: Heterozygous Familial Hypercholesterolemia in Pediatric Patients (10-17 years of age): The recommended starting dose of atorvastatin is 10 mg/day; the maximum recommended dose is 20 mg/day (doses greater than 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 or more.
Use in Combination with Other Medicinal Compounds: Studies with atorvastatin: In cases where co-administration of atorvastatin with cyclosporine, telaprevir, boceprevir or the combination tipranavir/ritonavir is necessary, the dose of atorvastatin should not exceed 10 mg.
Pharmacokinetic drug interactions that result in increased systemic concentration of atorvastatin have been noted with HIV protease inhibitors (lopinavir plus ritonavir, saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir and nelfinavir), Hepatitis C protease inhibitor (boceprevir), clarithromycin and itraconazole. Caution should be used when co-prescribing atorvastatin and appropriate clinical assessment is recommended to ensure that the lowest dose necessary of atorvastatin is employed (see Skeletal Muscle Effects under Precautions and Interactions).
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 also Pharmacology: 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 hours 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 BP, provided that there is no contraindication to its use. Intravenous 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
Amlodipine/atorvastatin is contraindicated in patients who: Have known hypersensitivity to dihydropyridines,* amlodipine, atorvastatin or any component of this medication.
Have active liver disease or unexplained persistent elevations of serum transaminases >3 x the upper limit of normal [ULN].
Are pregnant, breast-feeding, 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.
*Amlodipine is a dihydropyridine calcium channel blocker.
Special Precautions
Increased Angina and/or Myocardial Infarction: Rarely, patients, particularly those with severe obstructive coronary artery disease, have developed documented increased frequency, duration and/or severity of angina or acute myocardial infarction on starting calcium channel blocker therapy or at the time of dosage increased. The mechanism of this effect has not been elucidated.
Use in Patients with Heart Failure: In a long-term, placebo-controlled study (PRAISE-2) of amlodipine-treated patients with New York Heart Association (NYHA) class III-IV heart failure of nonischemic 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 x 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 mg, 20 mg, 40 mg and 80 mg.
Persistent increases in serum transaminases (>3 x ULN on two or more 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 mg, 20 mg, 40 mg 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 alanine transaminase (ALT) or aspartate transaminase (AST) >3x ULN 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 >10 x 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, azole antifungals, colchicine, telaprevir, boceprevir or the combination of tipranavir/ritonavir.
Many of these drugs inhibit cytochrome P450 3A4 metabolism and/or drug transport. CYP3A4 is the primary hepatic isozyme 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-modifying 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. Therefore, lower starting and maintenance doses of the atorvastatin component should also be considered when taken concomitantly with the aforementioned drugs. The concurrent use of atorvastatin and fusidic acid is not recommended, therefore, temporary suspension of atorvastatin is advised during fusidic acid therapy (see Interactions). Periodic CPK determinations may be considered in such situations, but there is no assurance that such monitoring will prevent the occurrence of severe myopathy. 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. A history of renal impairment may be a risk factor for the development of rhabdomyolysis. Such patients merit closer monitoring for skeletal muscle effects. 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, (e.g., 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.
Hemorrhagic Stroke: A post-hoc analysis of a clinical study in 4,731 patients without CHD (coronary heart disease) who had a stroke or transient ischemic attack (TIA) within the preceding 6 months and were initiated on atorvastatin 80 mg, revealed a higher incidence of hemorrhagic stroke in the atorvastatin 80 mg group compared to placebo (55 atorvastatin vs. 33 placebo). Patients with hemorrhagic stroke on entry appeared to be at increased risk for recurrent hemorrhagic stroke (7 atorvastatin vs. 2 placebo). However, in patients treated with atorvastatin 80 mg there were fewer strokes of any type (265 atorvastatin vs. 311 placebo) and fewer CHD events (123 atorvastatin vs. 204 placebo) (see Pharmacology: Pharmacodynamics: Recurrent Stroke under Actions).
Endocrine Function: Increases in glycated haemoglobin (HbA1c) and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including atorvastatin. The risk of hyperglycemia, however, is outweighed by the reduction in vascular risk with statins.
HMG-CoA reductase inhibitors, such as the atorvastatin component of CADUET interfere with cholesterol synthesis and theoretically might blunt adrenal and/or gonadal steroid production. Clinical studies have shown that atorvastatin does not reduce basal plasma cortisol concentration or impair adrenal reserve. The effects of HMG-CoA reductase inhibitors on male fertility have not been studied in adequate numbers of patients. The effects, if any, on the pituitary-gonadal axis in premenopausal women are unknown. Caution should be exercised if an HMG-CoA reductase inhibitor is administered concomitantly with drugs that may decrease the levels or activity of endogenous steroid hormones, such as ketoconazole, spironolactone, and cimetidine.
Beta-blocker Withdrawal: The amlodipine component of CADUET is not a beta-blocker and therefore gives no protection against the dangers of abrupt beta-blocker withdrawal; any such withdrawal should be by gradual reduction of the dose of beta-blocker.
CNS Toxicity: Studies with atorvastatin: Brain hemorrhage was seen in a female dog treated with atorvastatin calcium for 3 months at a dose equivalent to 120 mg atorvastatin/kg/day. Brain hemorrhage and optic nerve vacuolation were seen in another female dog that was sacrificed in moribund condition after 11 weeks of escalating doses of atorvastatin calcium equivalent to up to 280 mg atorvastatin/kg/day. The 120 mg/kg dose of atorvastatin resulted in a systemic exposure approximately 16 times the human plasma area-under-the-curve (AUC, 0-24 hours) based on the maximum human dose of 80 mg/day. A single tonic convulsion was seen in each of 2 male dogs (one treated with atorvastatin calcium at a dose equivalent to 10 mg atorvastatin/kg/day and one at a dose equivalent to 120 mg atorvastatin/kg/day) in a 2-year study. No CNS lesions have been observed in mice after chronic treatment for up to 2 years at doses of atorvastatin calcium equivalent to up to 400 mg atorvastatin/kg/day or in rats at doses equivalent to up to 100 mg atorvastatin/kg/day. These doses were 6 to 11 times (mouse) and 8 to 16 times (rat) the human AUC (0-24) based on the maximum recommended human dose of 80 mg atorvastatin/day.
CNS vascular lesions, characterized by perivascular hemorrhages, edema, and mononuclear cell infiltration of perivascular spaces, have been observed in dogs treated with other members of the HMG-CoA reductase class. A chemically similar drug in this class produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in clinically normal dogs in a dose-dependent fashion at a dose that produced plasma drug levels about 30 times higher than the mean drug level in humans taking the highest recommended dose.
Information for the Patient: Patients should be advised to promptly report unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. Adolescent females and women of childbearing potential should be counseled on appropriate contraceptive methods while on amlodipine/atorvastatin therapy (see Use in Pregnancy & Lactation).
Effects on ability to drive and use machines: Based on the available information on amlodipine and atorvastatin, this medication 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 breast-feeding 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 breast-feed.
Safety of amlodipine in human pregnancy or lactation has not been established. Amlodipine did not demonstrate toxicity in animal reproductive studies other than to delay parturition and prolong labor in rats at a dose level 50 times the maximum recommended dose in humans. There was no effect on the fertility of rats treated with amlodipine (See Pharmacology: Toxicology: Preclinical safety data under Actions).
Experience in humans indicates that amlodipine is transferred into human breast milk.
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 5.1% of patients treated with both amlodipine and atorvastatin compared to 4.0% 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: (see Table 6).


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In these clinical trials, no pattern of clinically significant laboratory test abnormalities related to amlodipine has been observed.
The following events occurred in =1% but >0.1% of patients treated with amlodipine in controlled clinical trials or under conditions of open trials or marketing experience where a causal relationship is uncertain; they are listed to alert the physician to a possible relationship: Cardiovascular: arrhythmia (including ventricular tachycardia and atrial fibrillation), bradycardia, chest pain, hypotension, peripheral ischemia, syncope, tachycardia, postural dizziness, postural hypotension, vasculitis.
Central and Peripheral Nervous System: hypoesthesia, neuropathy peripheral, paresthesia, tremor, vertigo.
Gastrointestinal: anorexia, constipation, dyspepsia,** dysphagia, diarrhea, flatulence, pancreatitis, vomiting, gingival hyperplasia.
General: allergic reaction, asthenia,** back pain, hot flushes, malaise, pain, rigors, weight gain, weight decrease.
Musculoskeletal System: arthralgia, arthrosis, muscle cramps,** myalgia.
Psychiatric: sexual dysfunction (male** and female), insomnia, nervousness, depression, abnormal dreams, anxiety, depersonalization.
Respiratory System: dyspnea,** epistaxis.
Skin and Appendages: angioedema, erythema multiforme, pruritus,** rash,** rash erythematous, rash maculopapular.
**These events occurred in less than 1% in placebo-controlled trials, but the incidence of these side effects was between 1% and 2% in all multiple dose studies.
Special Senses: abnormal vision, conjunctivitis, diplopia, eye pain, tinnitus.
Urinary System: micturition frequency, micturition disorder, nocturia.
Autonomic Nervous System: dry mouth, sweating increased.
Metabolic and Nutritional: hyperglycaemia, thirst.
Hemopoietic: leukopenia, purpura, thrombocytopenia.
The following events occurred in ≤0.1% of patients treated with amlodipine in controlled clinical trials or under conditions of open trials or marketing experience: cardiac failure, pulse irregularity, extrasystoles, skin discoloration, urticaria, skin dryness, alopecia, dermatitis, muscle weakness, twitching, ataxia, hypertonia, migraine, cold and clammy skin, apathy, agitation, amnesia, gastritis, increased appetite, loose stools, coughing, rhinitis, dysuria, polyuria, parosmia, taste perversion, abnormal visual accommodation, and xerophthalmia.
Other reactions occurred sporadically and cannot be distinguished from medications or concurrent disease states, such as myocardial infarction and angina.
Amlodipine therapy has not been associated with clinically significant changes in routine laboratory tests. No clinically relevant changes were noted in serum potassium, serum glucose, total triglycerides, total cholesterol, HDL cholesterol, uric acid, blood urea nitrogen, or creatinine.
Less commonly observed side effects in marketing experience with amlodipine include: (see Table 7).


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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 reported events were 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: MI, arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation) and chest pain.
Pediatric Patients (Aged 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: (see Table 8).


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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.
Atorvastatin Experience: Atorvastatin is generally well tolerated. Adverse reactions have usually been mild and transient. In the atorvastatin placebo-controlled clinical trial database of 16,066 (8755 atorvastatin vs. 7311 placebo) patients treated for a median period of 53 weeks, 5.2% of patients on atorvastatin discontinued due to adverse reactions compared to 4.0% of the patients on placebo.
The following adverse events were reported, regardless of causality assessment, in patients treated with atorvastatin in clinical trials. The events in italics occurred in =2% of patients and the events in plain type occurred in <2% of patients.
Body as a Whole: Chest pain, face edema, fever, neck rigidity, malaise, photosensitivity reaction, generalized edema.
Digestive System: Nausea, gastroenteritis, liver function tests abnormal, colitis, vomiting, gastritis, dry mouth, rectal hemorrhage, esophagitis, eructation, glossitis, mouth ulceration, anorexia, increased appetite, stomatitis, biliary pain, cheilitis, duodenal ulcer, dysphagia, enteritis, melena, gum hemorrhage, stomach ulcer, tenesmus, ulcerative stomatitis, hepatitis, pancreatitis, cholestatic jaundice, diarrhea, dyspepsia, flatulence.
Respiratory System: Bronchitis, rhinitis, pneumonia, dyspnea, asthma, epistaxis, pharyngolaryngeal pain.
Nervous System: Insomnia, dizziness, paresthesia, somnolence, amnesia, abnormal dreams, libido decreased, emotional lability, incoordination, peripheral neuropathy, torticollis, facial paralysis, hyperkinesia, depression, hypesthesia, hypertonia.
Musculoskeletal System: Arthritis, leg cramps, bursitis, tenosynovitis, myasthenia, tendinous contracture, myositis, arthralgia, pain in extremity, musculoskeletal pain, muscle spasms, myalgia, joint swelling.
Skin and Appendages: Pruritus, contact dermatitis, alopecia, dry skin, sweating, acne, urticaria, eczema, seborrhea, skin ulcer.
Urogenital System: Urinary tract infection, urinary frequency, cystitis, hematuria, impotence, dysuria, kidney calculus, nocturia, epididymitis, fibrocystic breast, vaginal hemorrhage, albuminuria, breast enlargement, metrorrhagia, nephritis, urinary incontinence, urinary retention, urinary urgency, abnormal ejaculation, uterine hemorrhage.
Special Senses: Amblyopia, tinnitus, dry eyes, refraction disorder, eye hemorrhage, deafness, glaucoma, parosmia, taste loss, taste perversion.
Cardiovascular System: Palpitation, vasodilatation, syncope, migraine, postural hypotension, phlebitis, arrhythmia, angina pectoris, hypertension.
Metabolic and Nutritional Disorders: Peripheral edema, hyperglycemia, creatine phosphokinase increased, gout, weight gain, hypoglycemia.
Hemic and Lymphatic System: Ecchymosis, anemia, lymphadenopathy, thrombocytopenia, petechia.
The most frequent (≥1%) adverse effects that may be associated with atorvastatin therapy, reported in patients participating in placebo-controlled clinical studies include: Infections and infestations: nasopharyngitis.
Metabolism and nutrition disorders: hyperglycaemia.
Respiratory, thoracic and mediastinal disorders: pharyngolaryngeal pain, epistaxis.
Gastrointestinal disorders: diarrhoea, dyspepsia, nausea, flatulence.
Musculoskeletal and connective tissue disorders: arthralgia, pain in extremity, musculoskeletal pain, muscle spasms, myalgia, joint swelling.
Investigations: liver function test abnormal, blood creatine phosphokinase increased.
Additional adverse effects reported in atorvastatin placebo-controlled clinical trials include: Psychiatric disorders: nightmare.
Eye disorders: vision blurred.
Ear and labyrinth disorders: tinnitus.
Gastrointestinal disorders: abdominal discomfort, eructation.
Hepatobiliary disorders: hepatitis, cholestasis.
Skin and subcutaneous tissue disorders: urticaria.
Musculoskeletal and connective tissue disorders: muscle fatigue, neck pain.
General disorders and administration site conditions: malaise, pyrexia.
Investigations: white blood cells urine positive.
Not all effects listed above have been causally associated with atorvastatin therapy.
Post introduction Reports with Atorvastatin: Adverse events associated with atorvastatin therapy reported since market introduction, that are not listed above, regardless of causality assessment, include the following: anaphylaxis, angioneurotic edema, bullous rashes (including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis), and rhabdomyolysis.
Post-marketing Experience: 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).
Injury, Poisoning and Procedural Complications: tendon rupture.
Metabolism and Nutrition Disorders: weight gain.
Nervous System Disorders: hypoesthesia, amnesia, dizziness, dysgeusia.
Gastrointestinal Disorders: pancreatitis.
Ear and Labyrinth Disorders: tinnitus.
Skin and Subcutaneous Tissue Disorders: Stevens-Johnson syndrome, toxic epidermal necrolysis, angioedema, erythema multiforme, bullous rashes.
Musculoskeletal and Connective Tissue Disorders: rhabdomyolysis, immune-mediated necrotising myopathy, myositis, back pain.
General Disorders and Administration Site Conditions: chest pain, peripheral oedema, 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 [CI]: 80% - 103%), but the AUC of atorvastatin increased by 18% (90% CI: 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, described as follows: Amlodipine Interactions: Amlodipine has been safely administered with thiazide diuretics, alpha blockers, beta blockers, ACE inhibitors, long-acting nitrates, sublingual nitroglycerine, non-steroidal anti-inflammatory drugs, antibiotics, and oral hypoglycemic drugs.
CYP3A4 Inhibitors: Co-administration of a 180 mg daily dose of diltiazem with 5 mg of amlodipine in elderly hypertensive patients (69 - 87 years of age) resulted in a 57% increase in amlodipine systemic exposure. Erythromycin co-administration in healthy volunteers (18 - 43 years of age) did not significantly change amlodipine systemic exposure (22% increase in AUC). Although the clinical relevance of these findings is uncertain, the pharmacokinetic variations may be more pronounced in the elderly.
Strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, ritonavir) may increase the plasma concentrations of amlodipine to a greater extent than diltiazem. Amlodipine should be used with caution together with CYP3A4 inhibitors.
Clarithromycin: Clarithromycin is an inhibitor of CYP3A4. There is an increased risk of hypotension in patients receiving clarithromycin with amlodipine. Close observation of patients is recommended when amlodipine is co-administered with clarithromycin.
CYP3A4 Inducers: There are no data available regarding the effect of CYP3A4 inducers on amlodipine. The concomitant use of CYP3A4 inducers (e.g., rifampicin, hypericum perforatum) may give a lower plasma concentration of amlodipine. Amlodipine should be used with caution together with CYP3A4 inducers.
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. The study did not allow examination of the effect of genetic polymorphism in CYP3A4, the primary enzyme responsible for metabolism of amlodipine; therefore, administration of amlodipine with grapefruit or grapefruit juice is not recommended as bioavailability may be increased in some patients resulting in increased BP-lowering effects.
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.
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 BP-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: No drug interaction studies have been conducted with cyclosporine and amlodipine in healthy volunteers or other populations with the exception of renal transplant patients. Various studies in renal transplant patients report that amlodipine co-administration with cyclosporine affect trough concentrations of cyclosporine from no change up to an average increase of 40%. Consideration should be given for monitoring cyclosporine levels in renal transplant patients on amlodipine.
Tacrolimus: There is a risk of increased tacrolimus blood levels when co-administered with amlodipine. In order to avoid toxicity of tacrolimus, administration of amlodipine in a patient treated with tacrolimus requires monitoring of tacrolimus blood levels and dose adjustment of tacrolimus when appropriate.
Mechanistic Target of Rapamycin (mTOR) Inhibitors: mTOR inhibitors such as sirolimus, temsirolimus, and everolimus are CYP3A substrates. Amlodipine is a weak CYP3A inhibitor. With concomitant use of mTOR inhibitors, amlodipine may increase exposure of mTOR inhibitors.
Drug/Laboratory Test Interactions: None known.
Atorvastatin Interactions: The risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concurrent administration of cyclosporine, fibric acid derivatives, lipid-modifying doses of niacin or cytochrome P450 3A4 inhibitors (e.g., erythromycin and azole antifungals) (See as follows and Use in Combination with Other Medicinal Compound under Dosage & Administration and Skeletal Muscle Effects under Precautions).
Inhibitors of cytochrome P450 3A4: Atorvastatin is metabolized by cytochrome P450 3A4. Concomitant administration of atorvastatin with inhibitors of cytochrome P450 3A4 can lead to increases in plasma concentrations of atorvastatin. The extent of interaction and potentiation of effects depend on the variability of effect on cytochrome P450 3A4.
Transporter inhibitors: Atorvastatin and atorvastatin metabolites are substrates of the OATP1B1 transporter. Inhibitors of the OATP1B1 (e.g., cyclosporine) can increase the bioavailability of atorvastatin. Concomitant administration of atorvastatin 10 mg and cyclosporine 5.2 mg/kg/day resulted in an increase in exposure to atorvastatin (ratio of AUC: 8.7; see also Use in Combination with Other Medicinal Compound under Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
Erythromycin/clarithromycin: Co-administration of atorvastatin and erythromycin (500 mg four times daily) or clarithromycin (500 mg twice daily), known inhibitors of cytochrome P450 3A4, was associated with higher plasma concentrations of atorvastatin (see Skeletal Muscle Effects under Precautions and Pharmacology: Pharmacokinetics under Actions).
Protease inhibitors: Co-administration of atorvastatin and protease inhibitors, known inhibitors of cytochrome P450 3A4, was associated with increased plasma concentrations of atorvastatin. (see Pharmacology: Pharmacokinetics under Actions).
Diltiazem hydrochloride: Co-administration of atorvastatin (40 mg) with diltiazem (240 mg) was associated with higher plasma concentrations of atorvastatin (see Pharmacology: Pharmacokinetics under Actions).
Cimetidine: An atorvastatin interaction study with cimetidine was conducted, and no clinically significant interactions were seen (see Pharmacology: Pharmacokinetics under Actions).
Itraconazole: Concomitant administration of atorvastatin (20 - 40 mg) and itraconazole (200 mg) was associated with an increase in atorvastatin AUC (see Pharmacology: Pharmacokinetics under Actions).
Grapefruit juice: Contains one or more components that inhibit CYP3A4 and can increase plasma concentrations of atorvastatin, especially with excessive grapefruit juice consumption (>1.2 L/day) (see Pharmacology: Pharmacokinetics under Actions).
Inducers of cytochrome P450 3A4: Concomitant administration of atorvastatin with inducers of cytochrome P450 3A4 (e.g., efavirenz, rifampin) can lead to variable reductions in plasma concentrations of atorvastatin. Due to the dual interaction mechanism of rifampin (cytochrome P450 3A4 induction and inhibition of hepatocyte uptake transporter OATP1B1), simultaneous co-administration of atorvastatin with rifampin is recommended, as delayed administration of atorvastatin after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations (see Pharmacology: Pharmacokinetics under Actions).
Antacids: Co-administration of atorvastatin with an oral antacid suspension containing magnesium and aluminum hydroxides decreased atorvastatin plasma concentrations (ratio of AUC: 0.66); 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 isozymes are not expected.
Colestipol: Plasma concentrations of atorvastatin were lower (ratio of concentration: 0.74) 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 of atorvastatin were co-administered, steady-state plasma digoxin concentrations were unaffected. However, digoxin concentrations increased (ratio of AUC: 1.15) following administration of digoxin with 80 mg of atorvastatin daily. Patients taking digoxin should be monitored appropriately.
Azithromycin: Co-administration of atorvastatin (10 mg once daily) and azithromycin (500 mg once daily) did not alter the plasma concentrations of atorvastatin.
Oral Contraceptives: Co-administration of atorvastatin with an oral contraceptive containing norethindrone and ethinyl estradiol increased the area under the concentration versus time curve (AUC) values for norethindrone (ratio of AUC: 1.28) and ethinyl estradiol (ratio of AUC: 1.19), respectively. 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.
Fusidic Acid: Although interaction studies with atorvastatin and fusidic acid have not been conducted, there is an increased risk of rhabdomyolysis in patients receiving a combination of statins, including atorvastatin, and fusidic acid. The mechanism of this interaction is not known. In patients where the use of systemic fusidic acid is considered essential, statin treatment should be discontinued throughout the duration of fusidic acid treatment. Statin therapy may be re-introduced seven days after the last dose of fusidic acid.
In exceptional circumstances, where prolonged systemic fusidic acid is needed, e.g., for the treatment of severe infections, the need for co-administration of atorvastatin and fusidic acid should only be considered on a case by case basis and under close medical supervision. The patient should be advised to seek medical advice immediately if they experience any symptoms of muscle weakness, pain or tenderness.
Colchicine: Although interaction studies with atorvastatin and colchicine have not been conducted, cases of myopathy have been reported with atorvastatin co-administered with colchicine, and caution should be exercised when prescribing atorvastatin with colchicine.
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.
Caution For Usage
Incompatibilities: Not applicable.
Storage
Store below 30°C.
ATC Classification
C10BX03 - atorvastatin and amlodipine ; Belongs to the class of HMG CoA reductase inhibitors, other combinations.
Presentation/Packing
5 mg/10 mg FC tab 3 x 10's. 5 mg/20 mg FC tab 3 x 10's. 10 mg/10 mg FC tab 3 x 10's. 10 mg/20 mg FC tab 3 x 10's.
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