Amlodipine and atorvastatin tablets

Dosage of amlodipine and atorvastatin tablets must be individualized on the basis of both effectiveness and tolerance for each individual component in the treatment of hypertension/angina and hyperlipidemia. Select doses of amlodipine and atorvastatin independently.

Amlodipine and atorvastatin tablets may be substituted for its individually titrated components. Patients may be given the equivalent dose of amlodipine and atorvastatin tablets or a dose of amlodipine and atorvastatin tablets with increased amounts of amlodipine, atorvastatin, or both for additional antianginal effects, blood pressure lowering, or lipid-lowering effect.

Amlodipine and atorvastatin tablets may be used to provide additional therapy for patients already on one of its components. Amlodipine and atorvastatin tablets may be used to initiate treatment in patients with hyperlipidemia and either hypertension or angina.

Amlodipine

The usual initial antihypertensive oral dosage of amlodipine is 5 mg once daily, and the maximum dose is 10 mg once daily.

Pediatric (age > 6 years), small adult, fragile, or elderly patients, or patients with hepatic insufficiency may be started on 2.5 mg once daily and this dose may be used when adding amlodipine to other antihypertensive therapy.

Adjust dosage according to blood pressure goals. In general, wait 7 to 14 days between titration steps. Titration may proceed more rapidly, however, if clinically warranted, provided the patient is assessed frequently.

Atorvastatin

5.1 Myopathy and Rhabdomyolysis

Amlodipine and atorvastatin tablets may cause myopathy (muscle pain, tenderness, or weakness associated with elevated creatine kinase [CK]) and rhabdomyolysis. Acute kidney injury secondary to myoglobinuria and rare fatalities have occurred as a result of rhabdomyolysis in patients treated with statins, including amlodipine and atorvastatin tablets.

5.2 Immune-Mediated Necrotizing Myopathy

There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use, including reports of recurrence when the same or a different statin was administered. IMNM is characterized by proximal muscle weakness and elevated serum creatine kinase, that persists despite discontinuation of statin treatment; positive anti-HMG-CoA reductase antibody; muscle biopsy showing necrotizing myopathy; and improvement with immunosuppressive agents. Additional neuromuscular and serologic testing may be necessary. Treatment with immunosuppressive agents may be required. Discontinue ‎amlodipine and atorvastatin tablets if IMNM is suspected.

5.3 Hepatic Dysfunction

Increases in serum transaminases have been reported with use of atorvastatin [see Adverse Reactions (6.1)]. In most cases, these changes appeared soon after initiation, were transient, were not accompanied by symptoms, and resolved or improved on continued therapy or after a brief interruption in therapy. Persistent increases to more than three times the ULN in serum transaminases have occurred in approximately 0.7% of patients receiving atorvastatin in clinical trials. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including atorvastatin.

Patients who consume substantial quantities of alcohol and/or have a history of liver disease may be at increased risk for hepatic injury [see Use in Specific Populations (8.7)].

Consider liver enzyme testing before atorvastatin initiation and when clinically indicated thereafter. Atorvastatin is contraindicated in patients with acute liver failure or decompensated cirrhosis [see Contraindications (4)]. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue atorvastatin.

5.4 Increased Angina and Myocardial Infarction

Worsening angina and acute myocardial infarction can develop after starting or increasing the dose of amlodipine, particularly in patients with severe obstructive coronary artery disease.

5.5 Hypotension

Symptomatic hypotension is possible with use of amlodipine, particularly in patients with severe aortic stenosis. Because of the gradual onset of action, acute hypotension is unlikely.

5.6 Increases in HbA1c and Fasting Serum Glucose Levels

Increases in HbA1c and fasting serum glucose levels have been reported with statins, including atorvastatin. Optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices.

5.7 Increased Risk of Hemorrhagic Stroke in Patients on Atorvastatin 80 mg with Recent Hemorrhagic Stroke

In a post-hoc analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial where 2365 adult patients, without CHD who had a stroke or Transient Ischemic Attack (TIA) within the preceding 6 months, were treated with atorvastatin 80 mg, a higher incidence of hemorrhagic stroke was seen in the atorvastatin 80 mg group compared to placebo (55, 2.3% atorvastatin vs. 33, 1.4% placebo; HR: 1.68, 95% CI: 1.09, 2.59; p=0.0168). The incidence of fatal hemorrhagic stroke was similar across treatment groups (17 vs. 18 for the atorvastatin and placebo groups, respectively). The incidence of non-fatal hemorrhagic stroke was significantly higher in the atorvastatin group (38, 1.6%) as compared to the placebo group (16, 0.7%). Some baseline characteristics, including hemorrhagic and lacunar stroke on study entry, were associated with a higher incidence of hemorrhagic stroke in the atorvastatin group [see Adverse Reactions (6.1)]. Consider the risk/benefit of use of atorvastatin 80 mg in patients with recent hemorrhagic stroke.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of amlodipine and atorvastatin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

7.1 Impact of Other Drugs on Amlodipine

7.2 Impact of Amlodipine on Other Drugs

7.3 Drug Interactions that may Increase the Risk of Myopathy and Rhabdomyolysis with Atorvastatin

Atorvastatin is a substrate of CYP3A4 and transporters (e.g., OATP1B1/1B3, P-gp, or BCRP). Atorvastatin plasma levels can be significantly increased with concomitant administration of inhibitors of CYP3A4 and transporters. Table 3 includes a list of drugs that may increase exposure to atorvastatin and may increase the risk of myopathy and rhabdomyolysis when used concomitantly and instructions for preventing or managing them [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

7.4 Drug Interactions that may Decrease Exposure to Atorvastatin

Table 4 presents drug interactions that may decrease exposure to atorvastatin and instructions for preventing or managing them.

7.5 Atorvastatin Effects on Other Drugs

Table 5 presents atorvastatin's effect on other drugs and instructions for preventing or managing them.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and effectiveness of amlodipine and atorvastatin tablets have not been established in pediatric populations.

8.5 Geriatric Use

Safety and effectiveness of amlodipine and atorvastatin tablets have not been established in geriatric populations.

8.6 Renal Impairment

Renal impairment is a risk factor for myopathy and rhabdomyolysis. Monitor all patients with renal impairment for development of myopathy. Renal impairment does not affect the plasma concentrations of atorvastatin, therefore there is no dosage adjustment in patients with renal impairment [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

In patients with chronic alcoholic liver disease, plasma concentrations of atorvastatin are markedly increased. Cmax and AUC are each 4-fold greater in patients with Childs-Pugh A disease. Cmax and AUC are approximately 16-fold and 11-fold increased, respectively, in patients with Childs-Pugh B disease. Amlodipine and atorvastatin tablets are contraindicated in patients with acute liver failure or decompensated cirrhosis [see Contraindications (4)].

Amlodipine

Overdosage might be expected to cause excessive peripheral vasodilation with marked hypotension and possibly a reflex tachycardia. In humans, experience with intentional overdosage of amlodipine is limited.

Single oral doses of amlodipine maleate equivalent to 40 mg amlodipine/kg and 100 mg amlodipine/kg in mice and rats, respectively, caused deaths. Single oral amlodipine maleate doses equivalent to 4 or more mg amlodipine/kg or higher in dogs (11 or more times the MRHD on a mg/m2 basis) caused a marked peripheral vasodilation and hypotension.

If overdose should occur with amlodipine, initiate active cardiac and respiratory monitoring. Perform frequent blood pressure measurements. Should hypotension occur, provide cardiovascular support including elevation of the extremities and administration of fluids. If hypotension remains unresponsive to these conservative measures, consider administration of vasopressors (such as phenylephrine) with specific attention to circulating volume and urine output. As amlodipine is highly protein bound, hemodialysis is not likely to be of benefit.

Atorvastatin

No specific antidotes for atorvastatin are known. Contact Poison Control (1-800-222-1222) for latest recommendations. Due to extensive drug binding to plasma proteins, hemodialysis is not expected to significantly enhance atorvastatin clearance.

12.1 Mechanism of Action

Amlodipine and atorvastatin tablets are a combination of two drugs, a dihydropyridine calcium channel blocker (amlodipine) and an HMG-CoA reductase inhibitor (atorvastatin). The amlodipine component of amlodipine and atorvastatin tablets inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. The atorvastatin component of amlodipine and atorvastatin tablets 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.

12.2 Pharmacodynamics

Amlodipine

Following administration of therapeutic doses to patients with hypertension, amlodipine produces vasodilation resulting in a reduction of supine and standing blood pressures. These decreases in blood pressure are not accompanied by a significant change in heart rate or plasma catecholamine levels with chronic dosing. Although the acute intravenous administration of amlodipine decreases arterial blood pressure and increases heart rate in hemodynamic studies of patients with chronic stable angina, chronic oral administration of amlodipine in clinical trials did not lead to clinically significant changes in heart rate or blood pressures in normotensive patients with angina.

With chronic once daily oral administration, antihypertensive effectiveness is maintained for at least 24 hours. Plasma concentrations correlate with effect in both young and elderly patients. The magnitude of reduction in blood pressure with amlodipine is also correlated with the height of pretreatment elevation; thus, individuals with moderate hypertension (diastolic pressure 105–114 mmHg) had about a 50% greater response than patients with mild hypertension (diastolic pressure 90–104 mmHg). Normotensive subjects experienced no clinically significant change in blood pressures (+1/–2 mmHg).

In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in a decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal plasma flow without change in filtration fraction or proteinuria.

As with other calcium channel blockers, hemodynamic measurements of cardiac function at rest and during exercise (or pacing) in patients with normal ventricular function treated with amlodipine have generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on left ventricular end diastolic pressure or volume. In hemodynamic studies, amlodipine has not been associated with a negative inotropic effect when administered in the therapeutic dose range to intact animals and man, even when co-administered with beta-blockers to man. Similar findings, however, have been observed in normal or well-compensated patients with heart failure with agents possessing significant negative inotropic effects.

Amlodipine does not change sinoatrial nodal function or atrioventricular conduction in intact animals or man. In patients with chronic stable angina, intravenous administration of 10 mg did not significantly alter A-H and H-V conduction and sinus node recovery time after pacing. Similar results were obtained in patients receiving amlodipine and concomitant beta-blockers. In clinical studies in which amlodipine was administered in combination with beta-blockers to patients with either hypertension or angina, no adverse effects on electrocardiographic parameters were observed. In clinical trials with angina patients alone, amlodipine therapy did not alter electrocardiographic intervals or produce higher degrees of AV blocks.

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14.1 Amlodipine for Hypertension

14.2 Amlodipine for Chronic Stable Angina

The effectiveness of 5–10 mg/day of amlodipine in exercise-induced angina has been evaluated in 8 placebo-controlled, double-blind clinical trials of up to 6 weeks duration involving 1038 patients (684 amlodipine, 354 placebo) with chronic stable angina. In 5 of the 8 studies, significant increases in exercise time (bicycle or treadmill) were seen with the 10 mg dose. Increases in symptom-limited exercise time averaged 12.8% (63 sec) for amlodipine 10 mg, and averaged 7.9% (38 sec) for amlodipine 5 mg. Amlodipine 10 mg also increased time to 1 mm ST segment deviation in several studies and decreased angina attack rate. The sustained efficacy of amlodipine in angina patients has been demonstrated over long-term dosing. In patients with angina, there were no clinically significant reductions in blood pressures (4/1 mmHg) or changes in heart rate (+0.3 bpm).

14.3 Amlodipine for Vasospastic Angina

In a double-blind, placebo-controlled clinical trial of 4 weeks duration in 50 patients, amlodipine therapy decreased attacks by approximately 4/week compared with a placebo decrease of approximately 1/week (p < 0.01). Two of 23 amlodipine and 7 of 27 placebo patients discontinued from the study for lack of clinical improvement.

14.4 Amlodipine for Coronary Artery Disease

In PREVENT, 825 patients with angiographically documented CAD were randomized to amlodipine (5–10 mg once daily) or placebo and followed for 3 years. Although the study did not show significance on the primary objective of change in coronary luminal diameter as assessed by quantitative coronary angiography, the data suggested a favorable outcome with respect to fewer hospitalizations for angina and revascularization procedures in patients with CAD.

CAMELOT enrolled 1318 patients with CAD recently documented by angiography, without left main coronary disease and without heart failure or an ejection fraction < 40%. Patients (76% males, 89% Caucasian, 93% enrolled at U.S. sites, 89% with a history of angina, 52% without PCI, 4% with PCI and no stent, and 44% with a stent) were randomized to double-blind treatment with either amlodipine (5–10 mg once daily) or placebo in addition to standard care that included aspirin (89%), statins (83%), beta-blockers (74%), nitroglycerin (50%), anticoagulants (40%), and diuretics (32%), but excluded other calcium channel blockers. The mean duration of follow-up was 19 months. The primary endpoint was the time to first occurrence of one of the following events: hospitalization for angina pectoris, coronary revascularization, myocardial infarction, cardiovascular death, resuscitated cardiac arrest, hospitalization for heart failure, stroke/TIA, or peripheral vascular disease. A total of 110 (16.6%) and 151 (23.1%) first events occurred in the amlodipine and placebo groups, respectively, for a hazard ratio of 0.691 (95% CI: 0.540–0.884, p=0.003). The primary endpoint is summarized in Figure 1 below. The outcome of this study was largely derived from the prevention of hospitalizations for angina and the prevention of revascularization procedures (see Table 8). Effects in various subgroups are shown in Figure 2.

In an angiographic substudy (n=274) conducted within CAMELOT, there was no significant difference between amlodipine and placebo on the change of atheroma volume in the coronary artery as assessed by intravascular ultrasound.

Figure 1. Kaplan-Meier Analysis of Composite Clinical Outcomes for Amlodipine versus Placebo

Figure 2. Effects on Primary Endpoint of Amlodipine versus Placebo across Sub-Groups

Table 8 below summarizes the significant composite endpoint and clinical outcomes from the composites of the primary endpoint. The other components of the primary endpoint including cardiovascular death, resuscitated cardiac arrest, myocardial infarction, hospitalization for heart failure, stroke/TIA, or peripheral vascular disease did not demonstrate a significant difference between amlodipine and placebo.

14.5 Amlodipine for Heart Failure

Amlodipine has been compared to placebo in four 8–12 week studies of patients with NYHA Class II/III heart failure, involving a total of 697 patients. In these studies, there was no evidence of worsened heart failure based on measures of exercise tolerance, NYHA classification, symptoms, or left ventricular ejection fraction. In a long-term (follow-up at least 6 months, mean 13.8 months) placebo-controlled mortality/morbidity study of amlodipine 5–10 mg in 1153 patients with NYHA Classes III (n=931) or IV (n=222) heart failure on stable doses of diuretics, digoxin, and ACE inhibitors, amlodipine had no effect on the primary endpoint of the study which was the combined endpoint of all-cause mortality and cardiac morbidity (as defined by life-threatening arrhythmia, acute myocardial infarction, or hospitalization for worsened heart failure), or on NYHA classification, or symptoms of heart failure. Total combined all-cause mortality and cardiac morbidity events were 222/571 (39%) for patients on amlodipine and 246/583 (42%) for patients on placebo; the cardiac morbid events represented about 25% of the endpoints in the study.

Another study (PRAISE-2) randomized patients with NYHA Class III (80%) or IV (20%) heart failure without clinical symptoms or objective evidence of underlying ischemic disease, on stable doses of ACE inhibitors (99%), digitalis (99%), and diuretics (99%), to placebo (n=827) or amlodipine (n=827) and followed them for a mean of 33 months. There was no statistically significant difference between amlodipine and placebo in the primary endpoint of all-cause mortality (95% confidence limits from 8% reduction to 29% increase on amlodipine). With amlodipine there were more reports of pulmonary edema.

14.6 Atorvastatin for Prevention of Cardiovascular Disease

In the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), the effect of atorvastatin on fatal and non-fatal coronary heart disease was assessed in 10,305 patients with hypertension, 40-80 years of age (mean of 63 years; 19% women; 95% White, 3% Black, 1% South Asian, 1% other), without a previous myocardial infarction and with total cholesterol (TC) levels ≤ 251 mg/dL. Additionally, all patients had at least 3 of the following cardiovascular risk factors: male gender (81%), age > 55 years (85%), smoking (33%), diabetes (24%), history of CHD in a first-degree relative (26%), TC:HDL > 6 (14%), peripheral vascular disease (5%), left ventricular hypertrophy (14%), prior cerebrovascular event (10%), specific ECG abnormality (14%), proteinuria/albuminuria (62%). In this double-blind, placebo-controlled trial, patients were treated with antihypertensive therapy (goal BP < 140/90 mm Hg for patients without diabetes; < 130/80 mm Hg for patients with diabetes) and allocated to either atorvastatin 10 mg daily (n=5168) or placebo (n=5137), using a covariate adaptive method which took into account the distribution of nine baseline characteristics of patients already enrolled and minimized the imbalance of those characteristics across the groups. Patients were followed for a median duration of 3.3 years.

The effect of 10 mg/day of atorvastatin on lipid levels was similar to that seen in previous clinical trials.

Atorvastatin significantly reduced the rate of coronary events [either fatal coronary heart disease (46 events in the placebo group vs. 40 events in the atorvastatin group) or non-fatal MI (108 events in the placebo group vs. 60 events in the atorvastatin group)] with a relative risk reduction of 36% [(based on incidences of 1.9% for atorvastatin vs. 3.0% for placebo), p=0.0005 (see Figure 3)]. The risk reduction was consistent regardless of age, smoking status, obesity, or presence of renal dysfunction. The effect of atorvastatin was seen regardless of baseline LDL levels.

Figure 3. Effect of Atorvastatin 10 mg/day on Cumulative Incidence of Non-Fatal Myocardial Infarction or Coronary Heart Disease Death (in ASCOT-LLA)

Atorvastatin also significantly decreased the relative risk for revascularization procedures by 42% (incidences of 1.4% for atorvastatin and 2.5% for placebo). Although the reduction of fatal and non-fatal strokes did not reach a pre-defined significance level (p=0.01), a favorable trend was observed with a 26% relative risk reduction (incidences of 1.7% for atorvastatin and 2.3% for placebo). There was no significant difference between the treatment groups for death due to cardiovascular causes (p=0.51) or noncardiovascular causes (p=0.17).

In the Collaborative Atorvastatin Diabetes Study (CARDS), the effect of atorvastatin on cardiovascular disease (CVD) endpoints was assessed in 2838 subjects (94% White, 2% Black, 2% South Asian, 1% other, 68% male), ages 40–75 with type 2 diabetes based on WHO criteria, without prior history of cardiovascular disease, and with LDL ≤ 160 mg/dL and triglycerides (TG) ≤ 600 mg/dL. In addition to diabetes, subjects had 1 or more of the following risk factors: current smoking (23%), hypertension (80%), retinopathy (30%), or microalbuminuria (9%) or macroalbuminuria (3%). No subjects on hemodialysis were enrolled in the trial. In this multicenter, placebo-controlled, double-blind clinical trial, subjects were randomly allocated to either atorvastatin 10 mg daily (1429) or placebo (1411) in a 1:1 ratio and were followed for a median duration of 3.9 years. The primary endpoint was the occurrence of any of the major cardiovascular events: myocardial infarction, acute CHD death, unstable angina, coronary revascularization, or stroke. The primary analysis was the time to first occurrence of the primary endpoint.

Baseline characteristics of subjects were: mean age of 62 years; mean HbA1c 7.7%; median LDL-C 120 mg/dL; median TC 207 mg/dL; median TG 151 mg/dL; median HDL-C 52 mg/dL.

The effect of atorvastatin 10 mg/day on lipid levels was similar to that seen in previous clinical trials.

Atorvastatin significantly reduced the rate of major cardiovascular events (primary endpoint events) (83 events in the atorvastatin group vs. 127 events in the placebo group) with a relative risk reduction of 37%, HR 0.63, 95% CI (0.48, 0.83) (p=0.001) (see Figure 4). An effect of atorvastatin was seen regardless of age, sex, or baseline lipid levels.

Atorvastatin significantly reduced the risk of stroke by 48% (21 events in the atorvastatin group vs. 39 events in the placebo group), HR 0.52, 95% CI (0.31, 0.89) (p=0.016) and reduced the risk of MI by 42% (38 events in the atorvastatin group vs. 64 events in the placebo group), HR 0.58, 95.1% CI (0.39, 0.86) (p=0.007). There was no significant difference between the treatment groups for angina, revascularization procedures, and acute CHD death.

There were 61 deaths in the atorvastatin group vs. 82 deaths in the placebo group (HR 0.73, p=0.059).

Figure 4. Effect of Atorvastatin 10 mg/day on Time to Occurrence of Major Cardiovascular Event (myocardial infarction, acute CHD death, unstable angina, coronary revascularization, or stroke) in CARDS

In the Treating to New Targets Study (TNT), the effect of atorvastatin 80 mg/day vs. atorvastatin 10 mg/day on the reduction in cardiovascular events was assessed in 10,001 subjects (94% White, 81% male, 38% ≥ 65 years) with clinically evident coronary heart disease who had achieved a target LDL-C level < 130 mg/dL after completing an 8-week, open-label, run-in period with atorvastatin 10 mg/day. Subjects were randomly assigned to either 10 mg/day or 80 mg/day of atorvastatin and followed for a median duration of 4.9 years. The primary endpoint was the time to first occurrence of any of the following major cardiovascular events (MCVE): death due to CHD, non-fatal myocardial infarction, resuscitated cardiac arrest, and fatal and non-fatal stroke. The mean LDL-C, TC, TG, non-HDL, and HDL-cholesterol levels at 12 weeks were 73, 145, 128, 98, and 47 mg/dL during treatment with 80 mg of atorvastatin and 99, 177, 152, 129, and 48 mg/dL during treatment with 10 mg of atorvastatin.

Treatment with atorvastatin 80 mg/day significantly reduced the rate of MCVE (434 events in the 80 mg/day group vs. 548 events in the 10 mg/day group) with a relative risk reduction of 22%, HR 0.78, 95% CI (0.69, 0.89), p=0.0002 (see Figure 5 and Table 9). The overall risk reduction was consistent regardless of age (< 65, ≥ 65) or sex.

Figure 5. Effect of Atorvastatin 80 mg/day vs. 10 mg/day on Time to Occurrence of Major Cardiovascular Events (TNT)

Of the events that comprised the primary efficacy endpoint, treatment with atorvastatin 80 mg/day significantly reduced the rate of non-fatal, non-procedure related MI and fatal and non-fatal stroke, but not CHD death or resuscitated cardiac arrest (Table 9). Of the predefined secondary endpoints, treatment with atorvastatin 80 mg/day significantly reduced the rate of coronary revascularization, angina, and hospitalization for heart failure, but not peripheral vascular disease. The reduction in the rate of CHF with hospitalization was only observed in the 8% of patients with a prior history of CHF.

There was no significant difference between the treatment groups for all-cause mortality (Table 9). The proportions of subjects who experienced cardiovascular death, including the components of CHD death and fatal stroke, were numerically smaller in the atorvastatin 80 mg group than in the atorvastatin 10 mg treatment group. The proportions of subjects who experienced noncardiovascular death were numerically larger in the atorvastatin 80 mg group than in the atorvastatin 10 mg treatment group.

14.7 Atorvastatin for Primary Hyperlipidemia in Adults

Atorvastatin reduces total-C, LDL-C, apo B, and TG, and increases HDL-C in patients with hyperlipidemia (heterozygous familial and nonfamilial) and mixed dyslipidemia. Therapeutic response is seen within 2 weeks, and maximum response is usually achieved within 4 weeks and maintained during chronic therapy.

In two multicenter, placebo-controlled, dose-response trials in patients with hyperlipidemia, atorvastatin given as a single dose over 6 weeks significantly reduced total-C, LDL-C, apo B, and TG. (Pooled results are provided in Table 10.)

In three multicenter, double-blind trials in patients with hyperlipidemia, atorvastatin was compared to other statins. After randomization, patients were treated for 16 weeks with either atorvastatin 10 mg per day or a fixed dose of the comparative agent (Table 11).

Table 11 does not contain data comparing the effects of atorvastatin 10 mg and higher doses of lovastatin, pravastatin, and simvastatin. The drugs compared in the trials summarized in the table are not necessarily interchangeable.

14.8 Atorvastatin for Hypertriglyceridemia in Adults

The response to atorvastatin in 64 patients with isolated hypertriglyceridemia treated across several clinical trials is shown in the table below (Table 12). For the atorvastatin-treated patients, median (min, max) baseline TG level was 565 (267–1,502).

14.9 Atorvastatin for Dysbetalipoproteinemia in Adults

The results of an open-label crossover trial of 16 patients (genotypes: 14 apo E2/E2 and 2 apo E3/E2) with dysbetalipoproteinemia are shown in the table below (Table 13).

14.10 Atorvastatin for Homozygous Familial Hypercholesterolemia in Adults and Pediatric Patients

In a trial without a concurrent control group, 29 patients (mean age of 22 years, median age of 24 years, 31% < 18 years) with HoFH received maximum daily doses of 20 to 80 mg of atorvastatin. The mean LDL-C reduction in this trial was 18%. Twenty-five patients with a reduction in LDL-C had a mean response of 20% (range of 7% to 53%, median of 24%); the remaining 4 patients had 7% to 24% increases in LDL-C. Five of the 29 patients had absent LDL-receptor function. Of these, 2 patients also had a portacaval shunt and had no significant reduction in LDL-C. The remaining 3 receptor-negative patients had a mean LDL-C reduction of 22%.

14.11 Atorvastatin for Heterozygous Familial Hypercholesterolemia in Pediatric Patients

In a double-blind, placebo-controlled trial followed by an open-label phase, 187 boys and post-menarchal girls 10 years to 17 years of age (mean age 14.1 years; 31% female; 92% White, 1.6% Black, 1.6% Asian, 4.8% other) with HeFH 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 trial required 1) a baseline LDL-C level ≥ 190 mg/dL or 2) a baseline LDL-C level ≥ 160 mg/dL and positive family history of FH or documented premature cardiovascular disease in a first or second-degree relative. The mean baseline LDL-C value was 219 mg/dL (range: 139-385 mg/dL) in the atorvastatin group compared to 230 mg/dL (range: 160.0–325 mg/dL) in the placebo group. The dosage of atorvastatin (once daily) was 10 mg for the first 4 weeks and uptitrated to 20 mg if the LDL-C level was > 130 mg/dL. The number of atorvastatin-treated patients who required uptitration to 20 mg after Week 4 during the double-blind phase was 78 (56%).

Atorvastatin significantly decreased plasma levels of total-C, LDL-C, triglycerides, and apolipoprotein B during the 26-week double-blind phase (see Table 14).

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.

Atorvastatin was also studied in a three year open-label, uncontrolled trial that included 163 patients with HeFH who were 10 years to 15 years old (82 boys and 81 girls). All patients had a clinical diagnosis of HeFH confirmed by genetic analysis (if not already confirmed by family history). Approximately 98% were White, and less than 1% were Black or Asian. Mean LDL-C at baseline was 232 mg/dL. The starting atorvastatin dosage was 10 mg once daily and doses were adjusted to achieve a target of <130 mg/dL LDL-C. The reductions in LDL-C from baseline were generally consistent across age groups within the trial as well as with previous clinical trials in both adult and pediatric placebo-controlled trials.

14.12 Amlodipine and Atorvastatin Tablets for Hypertension and Dyslipidemia

In a double-blind, placebo-controlled study, a total of 1660 patients with co-morbid hypertension and dyslipidemia received once daily treatment with eight dose combinations of amlodipine and atorvastatin (5/10, 10/10, 5/20, 10/20, 5/40, 10/40, 5/80, or 10/80 mg), amlodipine alone (5 mg or 10 mg), atorvastatin alone (10 mg, 20 mg, 40 mg, or 80 mg), or 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 eight weeks, all eight combination-treatment groups of amlodipine and atorvastatin 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 (Table 15).

Store at 25°C (77°F); excursions permitted to 15°C –30°C (59°F –86°F) [see USP Controlled Room Temperature].

Myopathy and Rhabdomyolysis

Advise patients that amlodipine and atorvastatin tablets may cause myopathy and rhabdomyolysis. Inform patients that the risk is also increased when taking certain types of medication or consuming large quantities of grapefruit juice and they should discuss all medication, both prescription and over the counter, with their healthcare provider. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever [see Warnings and Precautions (5.1), Drug Interactions (7.1)].

Lactation

Advise patients that breastfeeding is not recommended during treatment with amlodipine and atorvastatin tablets [see Usein Specific Populations (8.2)].

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LAB-1464-4.0

Amlodipine and Atorvastatin Tablets

Read the patient information that comes with amlodipine and atorvastatin tablets before you start taking them, and each time you get a refill. There may be new information. This information does not replace talking with your doctor about your condition or treatment. If you have any questions about amlodipine and atorvastatin tablets, ask your doctor or pharmacist.

What are amlodipine and atorvastatin tablets?

Amlodipine and atorvastatin tablets are a prescription drug that combines Norvasc® (amlodipine besylate) and Lipitor® (atorvastatin calcium) in one pill.

Amlodipine and atorvastatin tablets are used in adults who need both Norvasc and Lipitor.

Norvasc is used to treat:

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High blood pressure (hypertension) and

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Chest pain (angina) and

•

Blocked arteries of the heart (coronary artery disease)

Lipitor is used to lower the levels of “bad” cholesterol and triglycerides in your blood. It can also raise the levels of “good” cholesterol.

Lipitor is also used to lower the risk for heart attack, stroke, certain types of heart surgery, and chest pain in patients who have heart disease or risk factors for heart disease such as:

•

age, smoking, high blood pressure, low levels of “good” cholesterol, heart disease in the family.

Lipitor can lower the risk for heart attack or stroke in patients with diabetes and risk factors such as:

•

diabetic eye or kidney problems, smoking, or high blood pressure.

Amlodipine and atorvastatin tablets have not been studied in children.

Who should not use amlodipine and atorvastatin tablets?

 

Do not use amlodipine and atorvastatin tablets if you:

•

Have liver problems (acute liver failure or decompensated cirrhosis).

•

Are allergic to anything in amlodipine and atorvastatin tablets. The active ingredients are atorvastatin calcium and amlodipine besylate. Stop using amlodipine and atorvastatin tablets and get medical help right away if you have symptoms of a serious allergic reaction including:

o

swelling of your face, lips, tongue or throat

o

problems breathing or swallowing

o

fainting or feeling dizzy

o

very rapid heartbeat

o

severe skin rash or itching

o

flu-like symptoms including fever, sore throat, cough, tiredness, and joint pain

 

See the end of this leaflet for a complete list of ingredients.

What should I tell my doctor before taking amlodipine and atorvastatin tablets?

Tell your doctor about all of your health conditions, including, if you:

•

have unexplained muscle aches or weakness

•

drink more than 2 glasses of alcohol daily

•

have heart disease

•

have diabetes

•

have thyroid problems

•

have kidney problems

•

had a stroke

•

are pregnant or plan to become pregnant. Amlodipine and atorvastatin tablets may harm your unborn baby. If you become pregnant, stop taking amlodipine and atorvastatin tablets and call your doctor right away.

•

are breastfeeding or plan to breastfeed. You and your doctor should decide if you will take amlodipine and atorvastatin tablets or breastfeed. You should not do both. Talk to your doctor about the best way to feed your baby if you take amlodipine and atorvastatin tablets.

Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Amlodipine and atorvastatin tablets and certain other medicines can increase the risk of muscle problems or other side effects. Especially tell your doctor if you take medicines for:

•

your immune system

•

cholesterol (gemfibrozil)

•

infections (erythromycin, clarithromycin, itraconazole, ketoconazole, posaconazole, and

•

voriconazole)

•

birth control pills

•

heart failure (digoxin)

•

gout (colchicine)

•

niacin

•

fibrates

•

viruses that treat HIV, AIDS, or hepatitis C (anti-virals)

You can use nitroglycerin and amlodipine and atorvastatin tablets together. If you take nitroglycerin for chest pain (angina), do not stop taking it while taking amlodipine and atorvastatin tablets.

Ask your doctor or pharmacist for a list of medicines if you are not sure. Know all the medicines you take. Keep a list of them with you to show your doctor and pharmacist when you get a new medicine.

How should I take amlodipine and atorvastatin tablets?

•

Take amlodipine and atorvastatin tablets exactly as your doctor tells you to take it.

•

Do not change your dose or stop amlodipine and atorvastatin tablets without talking to your doctor.

•

Your doctor may do blood tests to check your cholesterol levels during your treatment with amlodipine and atorvastatin tablets. Your dose of amlodipine and atorvastatin tablets may be changed based on these blood test results.

•

Take amlodipine and atorvastatin tablets each day at any time of day. Amlodipine and atorvastatin tablets can be taken with or without food.

•

Do not break the tablets before taking them. Talk to your doctor if you have a problem swallowing pills.

•

Your doctor may start you on a cholesterol-lowering diet before giving you amlodipine and atorvastatin tablets. Stay on this low-fat diet when you take amlodipine and atorvastatin tablets.

•

If you miss a dose, take it as soon as you remember. Do not take amlodipine and atorvastatin tablets if it has been more than 12 hours since you missed your last dose. Wait and take the next dose at your regular time. Do not take 2 doses of amlodipine and atorvastatin tablets at the same time. If you take too much amlodipine and atorvastatin tablets or overdose, call your doctor or Poison Control Center at 1-800-222-1222 or go to the nearest emergency room right away.

What should I avoid while taking amlodipine and atorvastatin tablets?

•

Avoid drinking more than 1.2 liters of grapefruit juice each day.

What are possible side effects of amlodipine and atorvastatin tablets?

Amlodipine and atorvastatin tablets can cause serious side effects including:

•

Muscle pain, tenderness and weakness (myopathy). Muscle problems, including muscle breakdown, can be serious in some people and, rarely, cause kidney damage that can lead to death.

 

Tell your doctor right away if you have:

o

unexplained muscle pain, tenderness, or weakness, especially if you also have a fever or feel more tired than usual while you take amlodipine and atorvastatin tablets.

o

muscle problems that do not go away after your doctor has told you to stop taking amlodipine and atorvastatin tablets. Your doctor may do further tests to diagnose the cause of your muscle problems.

Your chances of getting muscle problems are higher if you:

o

are taking certain other medicines while you take amlodipine and atorvastatin tablets

o

drink large amounts of grapefruit juice

o

are 65 years of age or older

o

have thyroid problems (hypothyroidism) that are not controlled

o

have kidney problems

o

are taking higher doses of amlodipine and atorvastatin tablets

•

Liver problems. Your doctor should do blood tests to check your liver before you start taking amlodipine and atorvastatin tablets and if you have symptoms of liver problems while you take amlodipine and atorvastatin tablets. Call your doctor right away if you have the following symptoms of liver problems:

o

feel tired or weak

o

nausea or vomiting

o

loss of appetite

o

upper belly pain

o

dark amber colored urine

o

yellowing of your skin or the whites of your eyes

•

Low blood pressure or dizziness

•

Muscle rigidity, tremor and/or abnormal muscle movement

•

Increase in blood sugar level. Your blood sugar level may increase while you are taking amlodipine and atorvastatin tablets.

 

Exercise regularly and make healthy food choices to maintain healthy body weight.

 

Call your doctor right away if:

•

allergic reactions including swelling of the face, lips, tongue, and/or throat that may cause difficulty in breathing or swallowing which may require treatment right away

•

you have allergic skin reactions

•

Chest pain that does not go away or gets worse. Sometimes when you start amlodipine and atorvastatin tablets or increase your dose, chest pain can get worse or a heart attack can happen. If this happens, call your doctor or go to the emergency room right away.

 

Common side effects of amlodipine and atorvastatin tablets include:

Additional side effects have been reported: tiredness, tendon problems, memory loss, and confusion.

Talk to your doctor or pharmacist about side effects that bother you or do not go away.

There are other side effects of amlodipine and atorvastatin tablets. Ask your doctor or pharmacist for a complete list.

How do I store amlodipine and atorvastatin tablets?

•

Store amlodipine and atorvastatin tablets at room temperature, 68°F to 77°F (20°C to 25°C).

•

Do not keep medicine that is out-of-date or that you no longer need.

•

Keep amlodipine and atorvastatin tablets and all medicines out of the reach of children.

General information about the safe and effective use of amlodipine and atorvastatin tablets

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use amlodipine and atorvastatin tablets for a condition for which it was not prescribed. Do not give amlodipine and atorvastatin tablets to other people, even if they have the same symptoms that you have. It may harm them.

If you want more information about amlodipine and atorvastatin tablets, talk with your doctor. You can ask your pharmacist or doctor for information about amlodipine and atorvastatin tablets that is written for health professionals.

What is high blood pressure (hypertension)?

You have high blood pressure when the force of blood against the walls of your arteries stays high. This can damage your heart and other parts of your body. Drugs that lower blood pressure lower your risk of having a stroke or heart attack.

What is angina (chest pain)?

Angina is a pain that keeps coming back when part of your heart does not get enough blood. It feels like something is pressing or squeezing your chest under the breastbone. Sometimes you can feel it in your shoulders, arms, neck, jaw, or back.

What is cholesterol?

Cholesterol is a fat-like substance made in your body. It is also found in foods. You need some cholesterol for good health, but too much is not good for you. Cholesterol can clog your blood vessels.

What is a heart attack?

A heart attack occurs when heart muscle does not get enough blood. Symptoms include chest pain, trouble breathing, nausea, and weakness. Heart muscle cells may be damaged or die. The heart cannot pump well or may stop beating.

What is a stroke?

A stroke occurs when nerve cells in the brain do not get enough blood. The cells may be damaged or die. The damaged cells may cause weakness or problems speaking or thinking.

WHAT ARE THE INGREDIENTS IN AMLODIPINE AND ATORVASTATIN TABLETS?

Active ingredients: amlodipine besylate, atorvastatin calcium

Inactive ingredients: calcium carbonate, croscarmellose sodium, microcrystalline cellulose, pregelatinized starch, polysorbate 80, hydroxypropyl cellulose, purified water, colloidal silicon dioxide (anhydrous), magnesium stearate

Film coating: Opadry® II White 85F28751 (polyvinyl alcohol, titanium dioxide, PEG 3000, and talc) or Opadry® II Blue 85F10919 (polyvinyl alcohol, titanium dioxide, PEG 3000, talc, and FD&C blue #2)

Distributed by:

Prasco Laboratories

Mason, OH 45040 USA

LAB-1465-3.0

Revised: September 2024