Generic Name: ATORVASTATIN CALCIUM
Brand Name: Atorvastatin Calcium
- Substance Name(s):
- ATORVASTATIN CALCIUM TRIHYDRATE
7 The risk of myopathy during treatment with statins is increased with concurrent administration of fibric acid derivatives, lipid-modifying doses of niacin, cyclosporine, or strong CYP 3A4 inhibitors (e.g., clarithromycin, HIV protease inhibitors, and itraconazole) [see Warnings and Precautions, Skeletal Muscle (5.1) and Clinical Pharmacology (12.3)].
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3) Interacting Agents Prescribing Recommendations Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) Do not exceed 40 mg atorvastatin daily Other Lipid-Lowering Medications: Use with fibrate products or lipid-modifying doses (≥ 1 g/day) of niacin increases the risk of adverse skeletal muscle effects.
Caution should be used when prescribing with atorvastatin calcium (7).
Digoxin: Patients should be monitored appropriately (7.8).
Oral Contraceptives: Values for norethindrone and ethinyl estradiol may be increased (7.9).
Rifampin should be simultaneously co-administered with atorvastatin calcium (7.7).
7.1 Strong Inhibitors of CYP 3A4 Atorvastatin calcium is metabolized by cytochrome P450 3A4.
Concomitant administration of atorvastatin calcium with strong inhibitors of CYP 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 CYP 3A4.
Clarithromycin: Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin calcium 80 mg with clarithromycin (500 mg twice daily) compared to that of atorvastatin calcium alone [see Clinical Pharmacology (12.3)].
Therefore, in patients taking clarithromycin, caution should be used when the atorvastatin calcium dose exceeds 20 mg [see Warnings and Precautions, Skeletal Muscle (5.1) and Dosage and Administration (2.6)].
Combination of Protease Inhibitors: Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin calcium with several combinations of HIV protease inhibitors, as well as with the hepatitis C protease inhibitor telaprevir, compared to that of atorvastatin calcium alone [see Clinical Pharmacology (12.3)].
Therefore, in patients taking the HIV protease inhibitor tipranavir plus ritonavir, or the hepatitis C protease inhibitor telaprevir, concomitant use of atorvastatin calcium should be avoided.
In patients taking the HIV protease inhibitor lopinavir plus ritonavir, caution should be used when prescribing atorvastatin calcium and the lowest dose necessary should be used.
In patients taking the HIV protease inhibitors saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, or fosamprenavir plus ritonavir, the dose of atorvastatin calcium should not exceed 20 mg and should be used with caution [see Warnings and Precautions, Skeletal Muscle (5.1) and Dosage and Administration (2.6)].
In patients taking the HIV protease inhibitor nelfinavir or the hepatitis C protease inhibitor boceprevir, the dose of atorvastatin calcium should not exceed 40 mg and close clinical monitoring is recommended.
Itraconazole: Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin calcium 40 mg and itraconazole 200 mg [see Clinical Pharmacology (12.3)].
Therefore, in patients taking itraconazole, caution should be used when the atorvastatin calcium dose exceeds 20 mg [see Warnings and Precautions, Skeletal Muscle (5.1) and Dosage and Administration (2.6)].
7.2 Grapefruit Juice Contains one or more components that inhibit CYP 3A4 and can increase plasma concentrations of atorvastatin, especially with excessive grapefruit juice consumption (> 1.2 liters per day).
7.3 Cyclosporine Atorvastatin and atorvastatin-metabolites are substrates of the OATP1B1 transporter.
Inhibitors of the OATP1B1 (e.g., cyclosporine) can increase the bioavailability of atorvastatin.
Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin calcium 10 mg and cyclosporine 5.2 mg/kg/day compared to that of atorvastatin calcium alone [see Clinical Pharmacology (12.3)].
The co-administration of atorvastatin calcium with cyclosporine should be avoided [see Warnings and Precautions, Skeletal Muscle (5.1)].
7.4 Gemfibrozil Due to an increased risk of myopathy/rhabdomyolysis when HMG-CoA reductase inhibitors are co-administered with gemfibrozil, concomitant administration of atorvastatin calcium with gemfibrozil should be avoided [see Warnings and Precautions (5.1)].
7.5 Other Fibrates Because it is known that the risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concurrent administration of other fibrates, atorvastatin calcium should be administered with caution when used concomitantly with other fibrates [see Warnings and Precautions (5.1)].
7.6 Niacin The risk of skeletal muscle effects may be enhanced when atorvastatin calcium is used in combination with niacin; a reduction in atorvastatin calcium dosage should be considered in this setting [see Warnings and Precautions (5.1)].
7.7 Rifampin or other Inducers of Cytochrome P450 3A4 Concomitant administration of atorvastatin calcium 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, simultaneous co-administration of atorvastatin calcium with rifampin is recommended, as delayed administration of atorvastatin calcium after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations.
7.8 Digoxin When multiple doses of atorvastatin calcium and digoxin were co-administered, steady state plasma digoxin concentrations increased by approximately 20%.
Patients taking digoxin should be monitored appropriately.
7.9 Oral Contraceptives Co-administration of atorvastatin calcium and an oral contraceptive increased AUC values for norethindrone and ethinyl estradiol [see Clinical Pharmacology (12.3)].
These increases should be considered when selecting an oral contraceptive for a woman taking atorvastatin calcium.
7.10 Warfarin Atorvastatin calcium had no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin treatment.
7.11 Colchicine Cases of myopathy, including rhabdomyolysis, have been reported with atorvastatin co-administered with colchicine, and caution should be exercised when prescribing atorvastatin with colchicine.
10 There is no specific treatment for atorvastatin calcium overdosage.
In the event of an overdose, the patient should be treated symptomatically, and supportive measures instituted as required.
Due to extensive drug binding to plasma proteins, hemodialysis is not expected to significantly enhance atorvastatin calcium clearance.
11 Atorvastatin calcium is a synthetic lipid-lowering agent.
Atorvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase.
This enzyme catalyzes the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in cholesterol biosynthesis.
Atorvastatin calcium is [R-(R*,R*)]-2-(4-fluorophenyl)-ß, δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid, calcium salt (2:1) trihydrate.
The molecular formula of atorvastatin calcium is (C33H34FN2O5)2Ca•3H2O and its molecular weight is 1209.42.
Its structural formula is: Atorvastatin calcium, USP is a white to off-white crystalline powder.
Atorvastatin calcium is insoluble in aqueous solutions of pH 4 and below.
Atorvastatin calcium is very slightly soluble to insoluble in water and pH 7.4 phosphate buffer; insoluble in acetonitrile; slightly soluble to very slightly soluble in ethanol; and freely soluble to slightly soluble in methanol.
Atorvastatin calcium tablets for oral administration contain 10, 20, 40, or 80 mg atorvastatin and the following inactive ingredients: calcium carbonate; candelilla wax, FCC; croscarmellose sodium; hydroxypropyl cellulose; hypromellose; lactose monohydrate; magnesium stearate; microcrystalline cellulose; polyethylene glycol; polysorbate 80; simethicone emulsion; talc, and titanium dioxide.
14 14.1 Prevention of Cardiovascular Disease In the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), the effect of atorvastatin calcium on fatal and non-fatal coronary heart disease was assessed in 10,305 hypertensive patients 40 to 80 years of age (mean of 63 years), without a previous myocardial infarction and with TC levels ≤ 251 mg/dL (6.5 mmol/L).
Additionally, all patients had at least 3 of the following cardiovascular risk factors: male gender (81.1%), age > 55 years (84.5%), smoking (33.2%), diabetes (24.3%), history of CHD in a first-degree relative (26%), TC:HDL > 6 (14.3%), peripheral vascular disease (5.1%), left ventricular hypertrophy (14.4%), prior cerebrovascular event (9.8%), specific ECG abnormality (14.3%), proteinuria/albuminuria (62.4%).
In this double-blind, placebo-controlled study, patients were treated with anti-hypertensive therapy (Goal BP < 140/90 mm Hg for non-diabetic patients; < 130/80 mm Hg for diabetic patients) and allocated to either atorvastatin calcium 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 calcium on lipid levels was similar to that seen in previous clinical trials.
Atorvastatin calcium significantly reduced the rate of coronary events [either fatal coronary heart disease (46 events in the placebo group vs.
40 events in the atorvastatin calcium group) or non-fatal MI (108 events in the placebo group vs.
60 events in the atorvastatin calcium group)] with a relative risk reduction of 36% [(based on incidences of 1.9% for atorvastatin calcium vs.
3% for placebo), p = 0.0005 (see Figure 1)].
The risk reduction was consistent regardless of age, smoking status, obesity, or presence of renal dysfunction.
The effect of atorvastatin calcium was seen regardless of baseline LDL levels.
Due to the small number of events, results for women were inconclusive.
Figure 1: Effect of Atorvastatin Calcium 10 mg/day on Cumulative Incidence of Non-Fatal Myocardial Infarction or Coronary Heart Disease Death (in ASCOT-LLA) Atorvastatin calcium also significantly decreased the relative risk for revascularization procedures by 42%.
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 calcium 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 calcium on cardiovascular disease (CVD) endpoints was assessed in 2838 subjects (94% white, 68% male), ages 40 to 75 with type 2 diabetes based on WHO criteria, without prior history of cardiovascular disease and with LDL ≤ 160 mg/dL and 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 study.
In this multicenter, placebo-controlled, double-blind clinical trial, subjects were randomly allocated to either atorvastatin calcium 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 calcium 10 mg/day on lipid levels was similar to that seen in previous clinical trials.
Atorvastatin calcium significantly reduced the rate of major cardiovascular events (primary endpoint events) (83 events in the atorvastatin calcium 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 2).
An effect of atorvastatin calcium was seen regardless of age, sex, or baseline lipid levels.
Atorvastatin calcium significantly reduced the risk of stroke by 48% (21 events in the atorvastatin calcium 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 calcium 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 calcium group vs.
82 deaths in the placebo group (HR 0.73, p = 0.059).
Figure 2: Effect of Atorvastatin Calcium 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 calcium 80 mg/day vs.
atorvastatin calcium 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 calcium 10 mg/day.
Subjects were randomly assigned to either 10 mg/day or 80 mg/day of atorvastatin calcium 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 calcium and 99, 177, 152, 129, and 48 mg/dL during treatment with 10 mg of atorvastatin calcium.
Treatment with atorvastatin calcium 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 3 and Table 5).
The overall risk reduction was consistent regardless of age (< 65, ≥ 65) or gender.
Figure 3: Effect of Atorvastatin Calcium 80 mg/day vs.
10 mg/day on Time to Occurrence of Major Cardiovascular Events (TNT) TABLE 5.
Overview of Efficacy Results in TNT a Atorvastatin 80 mg: atorvastatin 10 mg b Component of other secondary endpoints * Secondary endpoints not included in primary endpoint HR = hazard ratio; CHD = coronary heart disease; CI = confidence interval; MI = myocardial infarction; CHF = congestive heart failure; CV = cardiovascular; PVD = peripheral vascular disease; CABG = coronary artery bypass graft Confidence intervals for the Secondary Endpoints were not adjusted for multiple comparisons Endpoint Atorvastatin 10 mg (N = 5006) Atorvastatin 80 mg (N = 4995) HRa (95%CI) PRIMARY ENDPOINT n (%) n (%) First major cardiovascular endpoint 548 (10.9) 434 (8.7) 0.78 (0.69, 0.89) Components of the Primary Endpoint CHD death 127 (2.5) 101 (2) 0.80 (0.61, 1.03) Non-fatal, non-procedure related MI 308 (6.2) 243 (4.9) 0.78 (0.66, 0.93) Resuscitated cardiac arrest 26 (0.5) 25 (0.5) 0.96 (0.56, 1.67) Stroke (fatal and non-fatal) 155 (3.1) 117 (2.3) 0.75 (0.59, 0.96) SECONDARY ENDPOINTS* First CHF with hospitalization 164 (3.3) 122 (2.4) 0.74 (0.59, 0.94) First PVD endpoint 282 (5.6) 275 (5.5) 0.97 (0.83, 1.15) First CABG or other coronary revascularization procedureb 904 (18.1) 667 (13.4) 0.72 (0.65, 0.80) First documented angina endpointb 615 (12.3) 545 (10.9) 0.88 (0.79, 0.99) All-cause mortality 282 (5.6) 284 (5.7) 1.01 (0.85, 1.19) Components of All-Cause Mortality Cardiovascular death 155 (3.1) 126 (2.5) 0.81 (0.64, 1.03) Noncardiovascular death 127 (2.5) 158 (3.2) 1.25 (0.99, 1.57) Cancer death 75 (1.5) 85 (1.7) 1.13 (0.83, 1.55) Other non-CV death 43 (0.9) 58 (1.2) 1.35 (0.91, 2) Suicide, homicide, and other traumatic non-CV death 9 (0.2) 15 (0.3) 1.67 (0.73, 3.82) Of the events that comprised the primary efficacy endpoint, treatment with atorvastatin calcium 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 5).
Of the predefined secondary endpoints, treatment with atorvastatin calcium 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 5).
The proportions of subjects who experienced cardiovascular death, including the components of CHD death and fatal stroke, were numerically smaller in the atorvastatin calcium 80 mg group than in the atorvastatin calcium 10 mg treatment group.
The proportions of subjects who experienced noncardiovascular death were numerically larger in the atorvastatin calcium 80 mg group than in the atorvastatin calcium 10 mg treatment group.
In the Incremental Decrease in Endpoints Through Aggressive Lipid Lowering Study (IDEAL), treatment with atorvastatin calcium 80 mg/day was compared to treatment with simvastatin 20 to 40 mg/day in 8,888 subjects up to 80 years of age with a history of CHD to assess whether reduction in CV risk could be achieved.
Patients were mainly male (81%), white (99%) with an average age of 61.7 years, and an average LDL-C of 121.5 mg/dL at randomization; 76% were on statin therapy.
In this prospective, randomized, open-label, blinded endpoint (PROBE) trial with no run-in period, subjects were followed for a median duration of 4.8 years.
The mean LDL-C, TC, TG, HDL, and non-HDL cholesterol levels at Week 12 were 78, 145, 115, 45, and 100 mg/dL during treatment with 80 mg of atorvastatin calcium and 105, 179, 142, 47, and 132 mg/dL during treatment with 20 to 40 mg of simvastatin.
There was no significant difference between the treatment groups for the primary endpoint, the rate of first major coronary event (fatal CHD, non-fatal MI, and resuscitated cardiac arrest): 411 (9.3%) in the atorvastatin calcium 80 mg/day group vs.
463 (10.4%) in the simvastatin 20 to 40 mg/day group, HR 0.89, 95% CI ( 0.78, 1.01), p = 0.07.
There were no significant differences between the treatment groups for all-cause mortality: 366 (8.2%) in the atorvastatin calcium 80 mg/day group vs.
374 (8.4%) in the simvastatin 20 to 40 mg/day group.
The proportions of subjects who experienced CV or non-CV death were similar for the atorvastatin calcium 80 mg group and the simvastatin 20 to 40 mg group.
figure1 figure2 figure3 14.2 Hyperlipidemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia (Fredrickson Types IIa and IIb) Atorvastatin calcium reduces total-C, LDL-C, VLDL-C, apo B, and TG, and increases HDL-C in patients with hyperlipidemia and mixed dyslipidemia.
Therapeutic response is seen within 2 weeks, and maximum response is usually achieved within 4 weeks and maintained during chronic therapy.
Atorvastatin calcium is effective in a wide variety of patient populations with hyperlipidemia, with and without hypertriglyceridemia, in men and women, and in the elderly.
In two multicenter, placebo-controlled, dose-response studies in patients with hyperlipidemia, atorvastatin calcium given as a single dose over 6 weeks, significantly reduced total-C, LDL-C, apo B, and TG.
(Pooled results are provided in Table 6.) TABLE 6.
Dose Response in Patients With Primary Hyperlipidemia (Adjusted Mean % Change From Baseline)a a Results are pooled from 2 dose-response studies.
Dose N TC LDL-C Apo B TG HDL-C Non-HDL-C/ HDL-C Placebo 21 4 4 3 10 -3 7 10 22 -29 -39 -32 -19 6 -34 20 20 -33 -43 -35 -26 9 -41 40 21 -37 -50 -42 -29 6 -45 80 23 -45 -60 -50 -37 5 -53 In patients with Fredrickson Types IIa and IIb hyperlipoproteinemia pooled from 24 controlled trials, the median (25th and 75th percentile) percent changes from baseline in HDL-C for atorvastatin calcium 10, 20, 40, and 80 mg were 6.4 (-1.4, 14), 8.7 (0, 17), 7.8 (0, 16), and 5.1 (-2.7, 15), respectively.
Additionally, analysis of the pooled data demonstrated consistent and significant decreases in total-C, LDL-C, TG, total-C/HDL-C, and LDL-C/HDL-C.
In three multicenter, double-blind studies in patients with hyperlipidemia, atorvastatin calcium was compared to other statins.
After randomization, patients were treated for 16 weeks with either atorvastatin calcium 10 mg per day or a fixed dose of the comparative agent (Table 7).
Mean Percentage Change From Baseline at Endpoint (Double-Blind, Randomized, Active-Controlled Trials) 1 A negative value for the 95% CI for the difference between treatments favors atorvastatin calcium for all except HDL-C, for which a positive value favors atorvastatin calcium.
If the range does not include 0, this indicates a statistically significant difference.
a Significantly different from lovastatin, ANCOVA, p ≤ 0.05 b Significantly different from pravastatin, ANCOVA, p ≤ 0.05 c Significantly different from simvastatin, ANCOVA, p ≤ 0.05 Treatment Non-HDL-C/ HDL-C (Daily Dose) N Total-C LDL-C Apo B TG HDL-C Study 1 Atorvastatin Calcium 10 mg 707 -27a -36a -28a -17a +7 -37a Lovastatin 20 mg 191 -19 -27 -20 -6 +7 -28 95% CI for Diff1 -9.2, -6.5 -10.7, -7.1 -10, -6.5 -15.2, -7.1 -1.7, 2 -11.1, -7.1 Study 2 Atorvastatin Calcium 10 mg 222 -25b -35b -27b -17b +6 -36b Pravastatin 20 mg 77 -17 -23 -17 -9 +8 -28 95% CI for Diff1 -10.8,-6.1 -14.5, -8.2 -13.4, -7.4 -14.1, -0.7 -4.9, 1.6 -11.5, -4.1 Study 3 Atorvastatin Calcium 10 mg 132 -29c -37c -34c -23c +7 -39c Simvastatin 10 mg 45 -24 -30 -30 -15 +7 -33 95% CI for Diff1 -8.7, -2.7 -10.1, -2.6 -8, -1.1 -15.1, -0.7 -4.3, 3.9 -9.6, -1.9 The impact on clinical outcomes of the differences in lipid-altering effects between treatments shown in Table 7 is not known.
Table 7 does not contain data comparing the effects of atorvastatin calcium 10 mg and higher doses of lovastatin, pravastatin, and simvastatin.
The drugs compared in the studies summarized in the table are not necessarily interchangeable.
14.3 Hypertriglyceridemia (Fredrickson Type IV) The response to atorvastatin calcium in 64 patients with isolated hypertriglyceridemia treated across several clinical trials is shown in the table below (Table 8).
For the atorvastatin calcium-treated patients, median (min, max) baseline TG level was 565 (267 to 1502).
Combined Patients With Isolated Elevated TG: Median (min, max) Percentage Change From Baseline Placebo Atorvastatin Calcium 10 mg Atorvastatin Calcium 20 mg Atorvastatin Calcium 80 mg (N = 12) (N = 37) (N = 13) (N = 14) Triglycerides -12.4 (-36.6, 82.7) -41 (-76.2, 49.4) -38.7 (-62.7, 29.5) -51.8 (-82.8, 41.3) Total-C -2.3 (-15.5, 24.4) -28.2 (-44.9, -6.8) -34.9 (-49.6, -15.2) -44.4 (-63.5, -3.8) LDL-C 3.6 (-31.3, 31.6) -26.5 (-57.7, 9.8) -30.4 (-53.9, 0.3) -40.5 (-60.6,-13.8) HDL-C 3.8 (-18.6, 13.4) 13.8 (-9.7, 61.5) 11(-3.2, 25.2) 7.5 (-10.8, 37.2) VLDL-C -1 (-31.9, 53.2) -48.8 (-85.8, 57.3) -44.6 (-62.2, -10.8) -62 (-88.2, 37.6) non-HDL-C -2.8 (-17.6, 30) -33 (-52.1, -13.3) -42.7 (-53.7, -17.4) -51.5 (-72.9, -4.3) 14.4 Dysbetalipoproteinemia (Fredrickson Type III) The results of an open-label crossover study of 16 patients (genotypes: 14 apo E2/E2 and 2 apo E3/E2) with dysbetalipoproteinemia (Fredrickson Type III) are shown in the table below (Table 9).
Open-Label Crossover Study of 16 Patients With Dysbetalipoproteinemia (Fredrickson Type III) Median (min, max) at Baseline (mg/dL) Median % Change (min, max) Atorvastatin Calcium 10 mg Atorvastatin Calcium 80 mg Total-C 442 (225, 1320) -37 (-85, 17) -58 (-90, -31) Triglycerides 678 (273, 5990) -39 (-92, -8) -53 (-95, -30) IDL-C + VLDL-C 215 (111, 613) -32 (-76, 9) -63 (-90, -8) non-HDL-C 411 (218, 1272) -43 (-87, -19) -64 (-92, -36) 14.5 Homozygous Familial Hypercholesterolemia In a study without a concurrent control group, 29 patients ages 6 to 37 years with homozygous FH received maximum daily doses of 20 to 80 mg of atorvastatin calcium.
The mean LDL-C reduction in this study was 18%.
Twenty-five patients with a reduction in LDL-C had a mean response of 20% (range of 7% to 53%, median of 24%); the remaining 4 patients had 7% to 24% increases in LDL-C.
Five of the 29 patients had absent LDL-receptor function.
Of these, 2 patients also had a portacaval shunt and had no significant reduction in LDL-C.
The remaining 3 receptor-negative patients had a mean LDL-C reduction of 22%.
14.6 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 familial hypercholesterolemia (FH) or severe hypercholesterolemia, were randomized to atorvastatin calcium (n = 140) or placebo (n = 47) for 26 weeks and then all received atorvastatin calcium for 26 weeks.
Inclusion in the study 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 218.6 mg/dL (range: 138.5 to 385 mg/dL) in the atorvastatin calcium group compared to 230 mg/dL (range: 160 to 324.5 mg/dL) in the placebo group.
The dosage of atorvastatin calcium (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 calcium-treated patients who required uptitration to 20 mg after Week 4 during the double-blind phase was 80 (57.1%).
Atorvastatin calcium significantly decreased plasma levels of total-C, LDL-C, triglycerides, and apolipoprotein B during the 26-week double-blind phase (see Table 10).
Lipid-altering Effects of Atorvastatin Calcium in Adolescent Boys and Girls with Heterozygous Familial Hypercholesterolemia or Severe Hypercholesterolemia (Mean Percentage Change From Baseline at Endpoint in Intention-to-Treat Population) DOSAGE N Total-C LDL-C HDL-C TG Apolipoprotein B Placebo 47 -1.5 -0.4 -1.9 1 0.7 Atorvastatin Calcium 140 -31.4 -39.6 2.8 -12 -34 The mean achieved LDL-C value was 130.7 mg/dL (range: 70 to 242 mg/dL) in the atorvastatin calcium group compared to 228.5 mg/dL (range: 152 to 385 mg/dL) in the placebo group during the 26-week double-blind phase.
The safety and efficacy of doses above 20 mg have not been studied in controlled trials in children.
The long-term efficacy of atorvastatin calcium therapy in childhood to reduce morbidity and mortality in adulthood has not been established.
16 /STORAGE AND HANDLING Atorvastatin calcium tablets 20 mg are white, elliptical, film-coated tablets, debossed with ‘ RX 828’ on one side and plain on the other side.
They are supplied as follows: NDC 33261-0972-30 Bottles of 30 NDC 33261-0972-90 Bottles of 90 Storage Store at 20 – 25° C (68 – 77° F) [See USP Controlled Room Temperature].
Dispense in tight containers (USP).
RECENT MAJOR CHANGES
Dosage and Administration (2.6) 10/2012 Warnings and Precautions (5.1) 10/2012 Drug Interactions (7) 02/2012
8.5 Geriatric Use Of the 39,828 patients who received atorvastatin calcium in clinical studies, 15,813 (40%) were ≥ 65 years old and 2,800 (7%) were ≥ 75 years old.
No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older adults cannot be ruled out.
Since advanced age (≥ 65 years) is a predisposing factor for myopathy, atorvastatin calcium should be prescribed with caution in the elderly.
DOSAGE FORMS AND STRENGTHS
3 White, elliptical, film-coated tablets containing 10, 20, 40, and 80 mg atorvastatin calcium, USP.
10, 20, 40, and 80 mg tablets (3).
MECHANISM OF ACTION
12.1 Mechanism of Action Atorvastatin calcium 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.
Cholesterol and triglycerides circulate in the bloodstream as part of lipoprotein complexes.
With ultracentrifugation, these complexes separate into HDL (high-density lipoprotein), IDL (intermediate-density lipoprotein), LDL (low-density lipoprotein), and VLDL (very-low-density lipoprotein) fractions.
Triglycerides (TG) and cholesterol in the liver are incorporated into VLDL and released into the plasma for delivery to peripheral tissues.
LDL is formed from VLDL and is catabolized primarily through the high-affinity LDL receptor.
Clinical and pathologic studies show that elevated plasma levels of total cholesterol (total-C), LDL-cholesterol (LDL-C), and apolipoprotein B (apo B) promote human atherosclerosis and are risk factors for developing cardiovascular disease, while increased levels of HDL-C are associated with a decreased cardiovascular risk.
In animal models, atorvastatin calcium lowers plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver and by increasing the number of hepatic LDL receptors on the cell surface to enhance uptake and catabolism of LDL; atorvastatin calcium also reduces LDL production and the number of LDL particles.
Atorvastatin calcium reduces LDL-C in some patients with homozygous familial hypercholesterolemia (FH), a population that rarely responds to other lipid-lowering medication(s).
A variety of clinical studies have demonstrated that elevated levels of total-C, LDL-C, and apo B (a membrane complex for LDL-C) promote human atherosclerosis.
Similarly, decreased levels of HDL-C (and its transport complex, apo A) are associated with the development of atherosclerosis.
Epidemiologic investigations have established that cardiovascular morbidity and mortality vary directly with the level of total-C and LDL-C, and inversely with the level of HDL-C.
Atorvastatin calcium reduces total-C, LDL-C, and apo B in patients with homozygous and heterozygous FH, nonfamilial forms of hypercholesterolemia, and mixed dyslipidemia.
Atorvastatin calcium also reduces VLDL-C and TG and produces variable increases in HDL-C and apolipoprotein A-1.
Atorvastatin calcium reduces total-C, LDL-C, VLDL-C, apo B, TG, and non-HDL-C, and increases HDL-C in patients with isolated hypertriglyceridemia.
Atorvastatin calcium reduces intermediate density lipoprotein cholesterol (IDL-C) in patients with dysbetalipoproteinemia.
Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including VLDL, intermediate density lipoprotein (IDL), and remnants, can also promote atherosclerosis.
Elevated plasma triglycerides are frequently found in a triad with low HDL-C levels and small LDL particles, as well as in association with non-lipid metabolic risk factors for coronary heart disease.
As such, total plasma TG has not consistently been shown to be an independent risk factor for CHD.
Furthermore, the independent effect of raising HDL or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined.
INDICATIONS AND USAGE
1 Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia.
Drug therapy is recommended as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been inadequate.
In patients with CHD or multiple risk factors for CHD, atorvastatin calcium tablets can be started simultaneously with diet.
Atorvastatin calcium tablets are an inhibitor of HMG-CoA reductase (statin) indicated as an adjunct therapy to diet to: Reduce the risk of MI, stroke, revascularization procedures, and angina in patients without CHD, but with multiple risk factors (1.1).
Reduce the risk of MI and stroke in patients with type 2 diabetes without CHD, but with multiple risk factors (1.1).
Reduce the risk of non-fatal MI, fatal and non-fatal stroke, revascularization procedures, hospitalization for CHF, and angina in patients with CHD (1.1).
Reduce elevated total-C, LDL-C, apo B, and TG levels and increase HDL-C in adult patients with primary hyperlipidemia (heterozygous familial and nonfamilial) and mixed dyslipidemia (1.2).
Reduce elevated TG in patients with hypertriglyceridemia and primary dysbetalipoproteinemia (1.2).
Reduce total-C and LDL-C in patients with homozygous familial hypercholesterolemia (HoFH) (1.2).
Reduce elevated total-C, LDL-C, and apo B levels in boys and postmenarchal girls, 10 to 17 years of age, with heterozygous familial hypercholesterolemia after failing an adequate trial of diet therapy (1.2).
Limitations of Use Atorvastatin calcium tablets have not been studied in Fredrickson Types I and V dyslipidemias.
1.1 Prevention of Cardiovascular Disease In adult patients without clinically evident coronary heart disease, but with multiple risk factors for coronary heart disease such as age, smoking, hypertension, low HDL-C, or a family history of early coronary heart disease, atorvastatin calcium tablets are indicated to: Reduce the risk of myocardial infarction Reduce the risk of stroke Reduce the risk for revascularization procedures and angina In patients with type 2 diabetes, and without clinically evident coronary heart disease, but with multiple risk factors for coronary heart disease such as retinopathy, albuminuria, smoking, or hypertension, atorvastatin calcium tablets are indicated to: Reduce the risk of myocardial infarction Reduce the risk of stroke In patients with clinically evident coronary heart disease, atorvastatin calcium tablets are indicated to: Reduce the risk of non-fatal myocardial infarction Reduce the risk of fatal and non-fatal stroke Reduce the risk for revascularization procedures Reduce the risk of hospitalization for CHF Reduce the risk of angina 1.2 Hyperlipidemia Atorvastatin calcium tablets are indicated: As an adjunct to diet to reduce elevated total-C, LDL-C, apo B, and TG levels and to increase HDL-C in patients with primary hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia (Fredrickson Types IIa and IIb); As an adjunct to diet for the treatment of patients with elevated serum TG levels (Fredrickson Type IV); For the treatment of patients with primary dysbetalipoproteinemia (Fredrickson Type III) who do not respond adequately to diet; To reduce total-C and LDL-C in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are unavailable; As an adjunct to diet to reduce total-C, LDL-C, and apo B levels in boys and postmenarchal girls, 10 to 17 years of age, with heterozygous familial hypercholesterolemia if after an adequate trial of diet therapy the following findings are present: a.
LDL-C remains ≥ 190 mg/dL or b.
LDL-C remains ≥ 160 mg/dL and: there is a positive family history of premature cardiovascular disease or two or more other CVD risk factors are present in the pediatric patient 1.3 Limitations of Use Atorvastatin calcium tablets have not been studied in conditions where the major lipoprotein abnormality is elevation of chylomicrons (Fredrickson Types I and V).
8.4 Pediatric Use Safety and effectiveness in patients 10 to 17 years of age with heterozygous familial hypercholesterolemia have been evaluated in a controlled clinical trial of 6 months’ duration in adolescent boys and postmenarchal girls.
Patients treated with atorvastatin calcium had an adverse experience profile generally similar to that of patients treated with placebo.
The most common adverse experiences observed in both groups, regardless of causality assessment, were infections.
Doses greater than 20 mg have not been studied in this patient population.
In this limited controlled study, there was no significant effect on growth or sexual maturation in boys or on menstrual cycle length in girls [see Clinical Studies (14.6); Adverse Reactions, Pediatric Patients (ages 10 to 17 years) (6.3); and Dosage and Administration, Heterozygous Familial Hypercholesterolemia in Pediatric Patients (10 to 17 years of age) (2.2)].
Adolescent females should be counseled on appropriate contraceptive methods while on atorvastatin calcium therapy [see Contraindications, Pregnancy (4.3) and Use in Specific Populations, Pregnancy (8.1)].
Atorvastatin calcium has not been studied in controlled clinical trials involving pre-pubertal patients or patients younger than 10 years of age.
Clinical efficacy with doses up to 80 mg/day for 1 year have been evaluated in an uncontrolled study of patients with homozygous FH including 8 pediatric patients [see Clinical Studies, Homozygous Familial Hypercholesterolemia (14.5)].
8.1 Pregnancy Pregnancy Category X Atorvastatin calcium is contraindicated in women who are or may become pregnant.
Serum cholesterol and triglycerides increase during normal pregnancy.
Lipid lowering drugs offer no benefit during pregnancy because cholesterol and cholesterol derivatives are needed for normal fetal development.
Atherosclerosis is a chronic process, and discontinuation of lipid-lowering drugs during pregnancy should have little impact on long-term outcomes of primary hypercholesterolemia therapy.
There are no adequate and well-controlled studies of atorvastatin use during pregnancy.
There have been rare reports of congenital anomalies following intrauterine exposure to statins.
In a review of about 100 prospectively followed pregnancies in women exposed to other statins, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed the rate expected in the general population.
However, this study was only able to exclude a three-to-four-fold increased risk of congenital anomalies over background incidence.
In 89% of these cases, drug treatment started before pregnancy and stopped during the first trimester when pregnancy was identified.
Atorvastatin crosses the rat placenta and reaches a level in fetal liver equivalent to that of maternal plasma.
Atorvastatin was not teratogenic in rats at doses up to 300 mg/kg/day or in rabbits at doses up to 100 mg/kg/day.
These doses resulted in multiples of about 30 times (rat) or 20 times (rabbit) the human exposure based on surface area (mg/m2) [see Contraindications, Pregnancy (4.3)].
In a study in rats given 20, 100, or 225 mg/kg/day, from gestation day 7 through to lactation day 21 (weaning), there was decreased pup survival at birth, neonate, weaning, and maturity in pups of mothers dosed with 225 mg/kg/day.
Body weight was decreased on days 4 and 21 in pups of mothers dosed at 100 mg/kg/day; pup body weight was decreased at birth and at days 4, 21, and 91 at 225 mg/kg/day.
Pup development was delayed (rotorod performance at 100 mg/kg/day and acoustic startle at 225 mg/kg/day; pinnae detachment and eye-opening at 225 mg/kg/day).
These doses correspond to 6 times (100 mg/kg) and 22 times (225 mg/kg) the human AUC at 80 mg/day.
Statins may cause fetal harm when administered to a pregnant woman.
Atorvastatin calcium should be administered to women of childbearing potential only when such patients are highly unlikely to conceive and have been informed of the potential hazards.
If the woman becomes pregnant while taking atorvastatin calcium, it should be discontinued immediately and the patient advised again as to the potential hazards to the fetus and the lack of known clinical benefit with continued use during pregnancy.
8.3 Nursing Mothers It is not known whether atorvastatin is excreted in human milk, but a small amount of another drug in this class does pass into breast milk.
Nursing rat pups had plasma and liver drug levels of 50% and 40%, respectively, of that in their mother’s milk.
Animal breast milk drug levels may not accurately reflect human breast milk levels.
Because another drug in this class passes into human milk and because statins have a potential to cause serious adverse reactions in nursing infants, women requiring atorvastatin calcium treatment should be advised not to nurse their infants [see Contraindications (4)].
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Skeletal muscle effects (e.g., myopathy and rhabdomyolysis): Risks increase when higher doses are used concomitantly with cyclosporine and strong CYP3A4 inhibitors (e.g., clarithromycin, itraconazole, HIV protease inhibitors).
Predisposing factors include advanced age (> 65), uncontrolled hypothyroidism, and renal impairment.
Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported.
Advise patients to promptly report to their physician unexplained and/or persistent muscle pain, tenderness, or weakness.
Atorvastatin calcium therapy should be discontinued if myopathy is diagnosed or suspected (5.1, 8.5).
Liver enzyme abnormalities: Persistent elevations in hepatic transaminases can occur.
Check liver enzyme tests before initiating therapy and as clinically indicated thereafter (5.2).
A higher incidence of hemorrhagic stroke was seen in patients without CHD but with stroke or TIA within the previous 6 months in the atorvastatin calcium 80 mg group vs.
5.1 Skeletal Muscle Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with atorvastatin calcium and with other drugs in this class.
A history of renal impairment may be a risk factor for the development of rhabdomyolysis.
Such patients merit closer monitoring for skeletal muscle effects.
Atorvastatin, like other statins, occasionally causes myopathy, defined as muscle aches or muscle weakness in conjunction with increases in creatine phosphokinase (CPK) values > 10 times ULN.
The concomitant use of higher doses of atorvastatin with certain drugs such as cyclosporine and strong CYP3A4 inhibitors (e.g., clarithromycin, itraconazole, and HIV protease inhibitors) increases the risk of myopathy/rhabdomyolysis.
There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use.
IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents.
Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of CPK.
Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing atorvastatin calcium.
Atorvastatin calcium therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected.
The risk of myopathy during treatment with drugs in this class is increased with concurrent administration of cyclosporine, fibric acid derivatives, erythromycin, clarithromycin, the hepatitis C protease inhibitor telaprevir, combinations of HIV protease inhibitors, including saquinavir plus ritonavir, lopinavir plus ritonavir, tipranavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, and fosamprenavir plus ritonavir, niacin, or azole antifungals.
Physicians considering combined therapy with atorvastatin calcium and fibric acid derivatives, erythromycin, clarithromycin, a combination of saquinavir plus ritonavir, lopinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, or fosamprenavir plus ritonavir, azole antifungals, or lipid-modifying doses of niacin should carefully weigh the potential benefits and risks and should carefully monitor patients for any signs or 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.
Lower starting and maintenance doses of atorvastatin should be considered when taken concomitantly with the aforementioned drugs (see Drug Interaction s (7)).
Periodic creatine phosphokinase (CPK) determinations may be considered in such situations, but there is no assurance that such monitoring will prevent the occurrence of severe myopathy.
Prescribing recommendations for interacting agents are summarized in Table 1 [see also Dosage and Administration (2.6), Drug Interactions (7), Clinical Pharmacology (12.3)].
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis *Use with caution and with the lowest dose necessary (12.3) Interacting Agents Prescribing Recommendations Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir*, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) Do not exceed 40 mg atorvastatin daily Cases of myopathy, including rhabdomyolysis, have been reported with atorvastatin co-administered with colchicine, and caution should be exercised when prescribing atorvastatin with colchicine [see Drug Interactions (7.11)].
Atorvastatin calcium 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).
5.2 Liver Dysfunction Statins, like some other lipid-lowering therapies, have been associated with biochemical abnormalities of liver function.
Persistent elevations (> 3 times the upper limit of normal [ULN] occurring on 2 or more occasions) in serum transaminases occurred in 0.7% of patients who received atorvastatin calcium in clinical trials.
The incidence of these abnormalities was 0.2%, 0.2%, 0.6%, and 2.3% for 10, 20, 40, and 80 mg, respectively.
One patient in clinical trials developed jaundice.
Increases in liver function tests (LFT) in other patients were not associated with jaundice or other clinical signs or symptoms.
Upon dose reduction, drug interruption, or discontinuation, transaminase levels returned to or near pretreatment levels without sequelae.
Eighteen of 30 patients with persistent LFT elevations continued treatment with a reduced dose of atorvastatin calcium.
It is recommended that liver enzyme tests be obtained prior to initiating therapy with atorvastatin calcium and repeated as clinically indicated.
There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including atorvastatin.
If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with atorvastatin calcium, promptly interrupt therapy.
If an alternate etiology is not found, do not restart atorvastatin calcium.
Atorvastatin calcium 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 atorvastatin calcium [see Contraindications (4.1)].
5.3 Endocrine Function Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including atorvastatin calcium.
Statins interfere with cholesterol synthesis and theoretically might blunt adrenal and/or gonadal steroid production.
Clinical studies have shown that atorvastatin calcium does not reduce basal plasma cortisol concentration or impair adrenal reserve.
The effects of statins 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 a statin is administered concomitantly with drugs that may decrease the levels or activity of endogenous steroid hormones, such as ketoconazole, spironolactone, and cimetidine.
5.4 CNS Toxicity Brain hemorrhage was seen in a female dog treated for 3 months at 120 mg/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 up to 280 mg/kg/day.
The 120 mg/kg dose resulted in a systemic exposure approximately 16 times the human plasma area-under-the-curve (AUC, 0 to 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 at 10 mg/kg/day and one at 120 mg/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 up to 400 mg/kg/day or in rats at doses up to 100 mg/kg/day.
These doses were 6 to 11 times (mouse) and 8 to 16 times (rat) the human AUC (0 to 24) based on the maximum recommended human dose of 80 mg/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 this 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.
5.5 Use in Patients with Recent Stroke or TIA In a post-hoc analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study where atorvastatin calcium 80 mg vs.
placebo was administered in 4,731 subjects without CHD who had a stroke or TIA within the preceding 6 months, a higher incidence of hemorrhagic stroke was seen in the atorvastatin calcium 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 nonfatal 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)].
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Patients taking atorvastatin calcium tablets should be advised that cholesterol is a chronic condition and they should adhere to their medication along with their National Cholesterol Education Program (NCEP)-recommended diet, a regular exercise program as appropriate, and periodic testing of a fasting lipid panel to determine goal attainment.
Patients should be advised about substances they should not take concomitantly with atorvastatin [see Warnings and Precautions (5.1)].
Patients should also be advised to inform other healthcare professionals prescribing a new medication that they are taking atorvastatin calcium tablets.
17.1 Muscle Pain All patients starting therapy with atorvastatin calcium tablets should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness, or weakness particularly if accompanied by malaise or fever or if these muscle signs or symptoms persist after discontinuing atorvastatin calcium tablets.
The risk of this occurring is increased when taking certain types of medication or consuming larger quantities (> 1 liter) of grapefruit juice.
They should discuss all medication, both prescription and over the counter, with their healthcare professional.
17.2 Liver Enzymes It is recommended that liver enzyme tests be performed before the initiation of atorvastatin calcium tablets and if signs or symptoms of liver injury occur.
All patients treated with atorvastatin calcium tablets should be advised to report promptly any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice.
17.3 Pregnancy Women of childbearing age should be advised to use an effective method of birth control to prevent pregnancy while using atorvastatin calcium tablets.
Discuss future pregnancy plans with your patients, and discuss when to stop atorvastatin calcium tablets if they are trying to conceive.
Patients should be advised that if they become pregnant, they should stop taking atorvastatin calcium tablets and call their healthcare professional.
17.4 Breastfeeding Women who are breastfeeding should be advised to not use atorvastatin calcium tablets.
Patients who have a lipid disorder and are breastfeeding, should be advised to discuss the options with their healthcare professional.
Manufactured for: Ranbaxy Pharmaceuticals Inc.
Jacksonville, FL 32257 USA by: Ohm Laboratories Inc.
North Brunswick, NJ 08902 USA AND BY: Ranbaxy Laboratories Ltd.
New Delhi – 110019, India Repackaged By : Aidarex Pharmaceuticals LLC, Corona, CA 92880 November 2012 PATIENT INFORMATION ATORVASTATIN CALCIUM TABLETS Rx only Read the Patient Information that comes with atorvastatin calcium tablets before you start taking it and each time you get a refill.
There may be new information.
This leaflet does not take the place of talking with your doctor about your condition or treatment.
If you have any questions about atorvastatin calcium tablets, ask your doctor or pharmacist.
What are Atorvastatin Calcium Tablets? Atorvastatin calcium tablets are a prescription medicine that lowers cholesterol in your blood.
It lowers the LDL-C (“bad” cholesterol) and triglycerides in your blood.
It can raise your HDL-C (“good” cholesterol) as well.
Atorvastatin calcium tablets are for adults and children over 10 whose cholesterol does not come down enough with exercise and a low-fat diet alone.
Atorvastatin calcium tablets can 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 HDL-C, heart disease in the family.
Atorvastatin calcium tablets can lower the risk for heart attack or stroke in patients with diabetes and risk factors such as: eye problems, kidney problems, smoking, or high blood pressure.
Atorvastatin calcium tablets start to work in about 2 weeks.
What is Cholesterol? Cholesterol and triglycerides are fats that are made in your body.
They are also found in foods.
You need some cholesterol for good health, but too much is not good for you.
Cholesterol and triglycerides can clog your blood vessels.
It is especially important to lower your cholesterol if you have heart disease, smoke, have diabetes or high blood pressure, are older, or if heart disease starts early in your family.
Who Should Not Take Atorvastatin Calcium Tablets? Do not take atorvastatin calcium tablets if you: are pregnant or think you may be pregnant, or are planning to become pregnant.
Atorvastatin calcium tablets may harm your unborn baby.
If you get pregnant, stop taking atorvastatin calcium tablets and call your doctor right away.
are breast feeding.
Atorvastatin calcium can pass into your breast milk and may harm your baby.
have liver problems.
are allergic to atorvastatin calcium tablets or any of its ingredients.
The active ingredient is atorvastatin calcium, USP.
See the end of this leaflet for a complete list of ingredients in atorvastatin calcium tablets.
Atorvastatin calcium tablets have not been studied in children under 10 years of age.
Before You Start Atorvastatin Calcium Tablets Tell your doctor if you: have muscle aches or weakness drink more than 2 glasses of alcohol daily have diabetes have a thyroid problem have kidney problems Some medicines should not be taken with atorvastatin calcium tablets.
Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.
Atorvastatin calcium tablets and certain other medicines can interact causing serious side effects.
Especially tell your doctor if you take medicines for: your immune system cholesterol infections birth control heart failure HIV or AIDS Know all the medicines you take.
Keep a list of them with you to show your doctor and pharmacist.
How Should I Take Atorvastatin Calcium Tablets? Take atorvastatin calcium tablets exactly as prescribed by your doctor.
Do not change your dose or stop atorvastatin calcium tablets without talking to your doctor.
Your doctor may do blood tests to check your cholesterol levels during your treatment with atorvastatin calcium tablets.
Your dose of atorvastatin calcium tablets may be changed based on these blood test results.
Take atorvastatin calcium tablets each day at any time of day at about the same time each day.
Atorvastatin calcium tablets can be taken with or without food.
Don’t break atorvastatin calcium tablets before taking.
Your doctor should start you on a low-fat diet before giving you atorvastatin calcium tablets.
Stay on this low-fat diet when you take atorvastatin calcium tablets.
If you miss a dose of atorvastatin calcium tablets, take it as soon as you remember.
Do not take atorvastatin calcium 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 atorvastatin calcium tablets at the same time.
If you take too much atorvastatin calcium tablets or overdose, call your doctor or Poison Control Center right away.
Or go to the nearest emergency room.
What Should I Avoid While Taking Atorvastatin Calcium Tablets? Talk to your doctor before you start any new medicines.
This includes prescription and non-prescription medicines, vitamins, and herbal supplements.
Atorvastatin calcium tablets and certain other medicines can interact causing serious side effects.
Do not get pregnant.
If you get pregnant, stop taking atorvastatin calcium tablets right away and call your doctor.
What are the Possible Side Effects of Atorvastatin Calcium Tablets? Atorvastatin calcium tablets can cause serious side effects.
These side effects have happened only to a small number of people.
Your doctor can monitor you for them.
These side effects usually go away if your dose is lowered or atorvastatin calcium tablets are stopped.
These serious side effects include: Muscle problems.
Atorvastatin calcium tablets can cause serious muscle problems that can lead to kidney problems, including kidney failure.
You have a higher chance for muscle problems if you are taking certain other medicines with atorvastatin calcium tablets.
Your doctor should do blood tests to check your liver before you start taking atorvastatin calcium tablets, and if you have symptoms of liver problems while you take atorvastatin calcium tablets.
Call your doctor right away if you have the following symptoms of liver problems: feel tired or weak loss of appetite upper belly pain dark amber colored urine yellowing of your skin or the whites of your eyes Call your doctor right away if you have: muscle problems like weakness, tenderness, or pain that happen without a good reason, especially if you also have a fever or feel more tired than usual.
This may be an early sign of a rare muscle problem.
muscle problems that do not go away even after your doctor has advised you to stop taking atorvastatin calcium tablets.
Your doctor may do further tests to diagnose the cause of your muscle problems.
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.
nausea and vomiting.
passing brown or dark-colored urine.
you feel more tired than usual your skin and whites of your eyes get yellow.
allergic skin reactions.
In clinical studies, patients reported the following common side effects while taking atorvastatin calcium: diarrhea, upset stomach, muscle and joint pain, and alterations in some laboratory blood tests.
The following additional side effects have been reported with atorvastatin calcium tablets: tiredness, tendon problems, memory loss, and confusion.
Talk to your doctor or pharmacist if you have side effects that bother you or that will not go away.
These are not all the side effects of atorvastatin calcium tablets.
Ask your doctor or pharmacist for a complete list.
Call your doctor for medical advice about side effects.
You may report side effects to FDA at 1-800-FDA-1088.
How do I store Atorvastatin Calcium Tablets Store atorvastatin calcium tablets at room temperature, 68 – 77° F (20 – 25° C).
Do not keep medicine that is out of date or that you no longer need.
Keep atorvastatin calcium tablets and all medicines out of the reach of children.
Be sure that if you throw medicine away, it is out of the reach of children.
General Information About Atorvastatin Calcium Tablets Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets.
Do not use atorvastatin calcium tablets for a condition for which it was not prescribed.
Do not give atorvastatin calcium tablets to other people, even if they have the same problem you have.
It may harm them.
This leaflet summarizes the most important information about atorvastatin calcium tablets.
If you would like more information, talk with your doctor.
You can ask your doctor or pharmacist for information about atorvastatin calcium tablets that is written for health professionals.
What are the Ingredients in Atorvastatin Calcium Tablets? Active Ingredient: atorvastatin calcium, USP Inactive Ingredients: calcium carbonate; candelilla wax, FCC; croscarmellose sodium; hydroxypropyl cellulose; hypromellose; lactose monohydrate; magnesium stearate; microcrystalline cellulose; polyethylene glycol; polysorbate 80; simethicone emulsion; talc, and titanium dioxide.
Manufactured for: Ranbaxy Pharmaceuticals Inc.
Jacksonville, FL 32257 USA by: Ohm Laboratories Inc.
North Brunswick, NJ 08902 USA AND BY: Ranbaxy Laboratories Ltd.
New Delhi – 110019, India Repackaged By : Aidarex Pharmaceuticals LLC, Corona, CA 92880 November 2012
DOSAGE AND ADMINISTRATION
2 Dose range: 10 to 80 mg once daily (2.1).
Recommended start dose: 10 or 20 mg once daily (2.1).
Patients requiring large LDL-C reduction (> 45%) may start at 40 mg once daily (2.1).
Pediatric starting dose: 10 mg once daily; maximum recommended dose: 20 mg once daily (2.2).
2.1 Hyperlipidemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia (Fredrickson Types IIa and IIb) The recommended starting dose of atorvastatin calcium tablets is 10 or 20 mg once daily.
Patients who require a large reduction in LDL-C (more than 45%) may be started at 40 mg once daily.
The dosage range of atorvastatin calcium tablets is 10 to 80 mg once daily.
Atorvastatin calcium tablets can be administered as a single dose at any time of the day, with or without food.
The starting dose and maintenance doses of atorvastatin calcium tablets should be individualized according to patient characteristics such as goal of therapy and response (see current NCEP Guidelines).
After initiation and/or upon titration of atorvastatin calcium tablets, lipid levels should be analyzed within 2 to 4 weeks and dosage adjusted accordingly.
2.2 Heterozygous Familial Hypercholesterolemia in Pediatric Patients (10 to 17 years of age) The recommended starting dose of atorvastatin calcium tablets 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 current NCEP Pediatric Panel Guidelines, Clinical Pharmacolog y (12), and Indications and Usage (1.2)].
Adjustments should be made at intervals of 4 weeks or more.
2.3 Homozygous Familial Hypercholesterolemia The dosage of atorvastatin calcium tablets in patients with homozygous FH is 10 to 80 mg daily.
Atorvastatin calcium tablets should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or if such treatments are unavailable.
2.4 Concomitant Lipid-Lowering Therapy Atorvastatin calcium tablets may be used with bile acid resins.
The combination of HMG-CoA reductase inhibitors (statins) and fibrates should generally be used with caution [see Warnings and Precautions, Skeletal Muscle (5.1), Drug Interactions (7)].
2.5 Dosage in Patients With Renal Impairment Renal disease does not affect the plasma concentrations nor LDL-C reduction of atorvastatin calcium tablets; thus, dosage adjustment in patients with renal dysfunction is not necessary [see Warnings and Precautions, Skeletal Muscle (5.1), Clinical Pharmacology, Pharmacokinetics (12.3)].
2.6 Dosage in Patients Taking Cyclosporine, Clarithromycin, Itraconazole, or Certain Protease Inhibitors In patients taking cyclosporine or the HIV protease inhibitors (tipranavir plus ritonavir) or the hepatitis C protease inhibitor (telaprevir), therapy with atorvastatin calcium tablets should be avoided.
In patients with HIV taking lopinavir plus ritonavir, caution should be used when prescribing atorvastatin calcium tablets and the lowest dose necessary employed.
In patients taking clarithromycin, itraconazole, or in patients with HIV taking a combination of saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, or fosamprenavir plus ritonavir, therapy with atorvastatin calcium tablets should be limited to 20 mg, and appropriate clinical assessment is recommended to ensure that the lowest dose necessary of atorvastatin calcium tablets is employed.
In patients taking the HIV protease inhibitor nelfinavir or the hepatitis C protease inhibitor boceprevir, therapy with atorvastatin calcium tablets should be limited to 40 mg, and appropriate clinical assessment is recommended to ensure that the lowest dose necessary of atorvastatin calcium tablets is employed [see Warnings and Precautions, Skeletal Muscle (5.1), Drug Interactions (7)].