Atorvastatin Calcium (Page 6 of 11)

8.5 Geriatric Use

Of the 39,828 patients who received atorvastatin calcium tablets 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 tablets should be prescribed with caution in the elderly.

8.6 Hepatic Impairment

Atorvastatin calcium tablets are contraindicated in patients with active liver disease which may include unexplained persistent elevations in hepatic transaminase levels [see Contraindications (4) and Clinical Pharmacology (12.3)] .

10 OVERDOSAGE

There is no specific treatment for atorvastatin calcium tablets 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 tablets clearance.

11 DESCRIPTION

Atorvastatin Calcium Tablets are 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 empirical formula of atorvastatin calcium is (C33 H34 FN2 O5 )2 Ca•3H2 O and its molecular weight is 1209.42. Its structural formula is:

Chemical Structure
(click image for full-size original)

Atorvastatin calcium is a white to off-white crystalline powder that is insoluble in aqueous solutions of pH 4 and below. Atorvastatin calcium is very slightly soluble in distilled water, pH 7.4 phosphate buffer, and acetonitrile; slightly soluble in ethanol; and freely soluble in methanol.

Atorvastatin Calcium Tablets for oral administration contain 10, 20, 40, or 80 mg atorvastatin and the following inactive ingredients: amino methacrylate copolymer, colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate, polyethylene glycol, polyvinyl alcohol, sodium stearyl fumarate, talc, titanium dioxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Atorvastatin calcium tablets are a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3methylglutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol. In animal models, atorvastatin calcium tablets 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 tablets also reduces LDL production and the number of LDL particles.

12.2 Pharmacodynamics

Atorvastatin calcium tablets, as well as some of its metabolites, are pharmacologically active in humans. The liver is the primary site of action and the principal site of cholesterol synthesis and LDL clearance. Drug dosage, rather than systemic drug concentration, correlates better with LDL-C reduction. Individualization of drug dosage should be based on therapeutic response [see Dosage and Administration ( 2) ].

12.3 Pharmacokinetics

Absorption: Atorvastatin calcium tablets are rapidly absorbed after oral administration; maximum plasma concentrations occur within 1 to 2 hours. Extent of absorption increases in proportion to atorvastatin calcium tablets dose. The absolute bioavailability of atorvastatin (parent drug) is approximately 14% and the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic availability is attributed to presystemic clearance in gastrointestinal mucosa and/or hepatic first-pass metabolism. Although food decreases the rate and extent of drug absorption by approximately 25% and 9%, respectively, as assessed by Cmax and AUC, LDL-C reduction is similar whether atorvastatin calcium tablets are given with or without food. Plasma atorvastatin calcium tablets concentrations are lower (approximately 30% for Cmax and AUC) following evening drug administration compared with morning. However, LDL-C reduction is the same regardless of the time of day of drug administration [see Dosage and Administration ( 2) ].

Distribution: Mean volume of distribution of atorvastatin calcium tablets is approximately 381 liters. Atorvastatin calcium tablets are ≥ 98% bound to plasma proteins. A blood/plasma ratio of approximately 0.25 indicates poor drug penetration into red blood cells. Based on observations in rats, atorvastatin calcium tablets are likely to be secreted in human milk [see Contraindications ( 4) and Use in Specific Populations ( 8.2)].

Metabolism: Atorvastatin calcium tablets are extensively metabolized to ortho- and parahydroxylated derivatives and various beta-oxidation products. In vitro inhibition of HMG-CoA reductase by ortho- and parahydroxylated metabolites is equivalent to that of atorvastatin calcium tablets. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites. In vitro studies suggest the importance of atorvastatin calcium tablets metabolism by cytochrome P450 3A4, consistent with increased plasma concentrations of atorvastatin calcium tablets in humans following co-administration with erythromycin, a known inhibitor of this isozyme [see Drug Interactions ( 7.1)]. In animals, the ortho-hydroxy metabolite undergoes further glucuronidation.

Excretion: Atorvastatin calcium tablets and its metabolites are eliminated primarily in bile following hepatic and/or extra-hepatic metabolism; however, the drug does not appear to undergo enterohepatic recirculation. Mean plasma elimination half-life of atorvastatin calcium tablets in humans is approximately 14 hours, but the half-life of inhibitory activity for HMG-CoA reductase is 20 to 30 hours due to the contribution of active metabolites. Less than 2% of a dose of atorvastatin calcium tablets is recovered in urine following oral administration.

Specific Populations

Geriatric: Plasma concentrations of atorvastatin calcium tablets are higher (approximately 40% for Cmax and 30% for AUC) in healthy elderly subjects (age ≥65 years) than in young adults. Clinical data suggest a greater degree of LDL-lowering at any dose of drug in the elderly patient population compared to younger adults [see Use in Specific Populations (8.5) ].

Pediatric: Apparent oral clearance of atorvastatin in pediatric subjects appeared similar to that of adults when scaled allometrically by body weight as the body weight was the only significant covariate in atorvastatin population PK model with data including pediatric HeFH patients (ages 10 years to 17 years of age, n=29) in an open-label, 8-week study.

Gender: Plasma concentrations of atorvastatin calcium tablets in women differ from those in men (approximately 20% higher for Cmax and 10% lower for AUC); however, there is no clinically significant difference in LDL-C reduction with atorvastatin calcium tablets between men and women.

Renal Impairment: Renal disease has no influence on the plasma concentrations or LDL-C reduction of atorvastatin calcium tablets; thus, dose adjustment in patients with renal dysfunction is not necessary [see Dosage and Administration (2.5) and Warnings and Precautions (5.1)].

Hemodialysis: While studies have not been conducted in patients with end-stage renal disease, hemodialysis is not expected to significantly enhance clearance of atorvastatin calcium tablets since the drug is extensively bound to plasma proteins.

Hepatic Impairment: In patients with chronic alcoholic liver disease, plasma concentrations of atorvastatin calcium tablets 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 [see Contraindications (4) ].

Drug Interaction Studies

Atorvastatin is a substrate of the hepatic transporters, OATP1B1 and OATP1B3 transporter. Metabolites of atorvastatin are substrates of OATP1B1. Atorvastatin is also identified as a substrate of the efflux transporter BCRP, which may limit the intestinal absorption and biliary clearance of atorvastatin.

TABLE 4. Effect of Co-administered Drugs on the Pharmacokinetics of Atorvastatin

Co-administered drug and dosing regimen Atorvastatin
Dose (mg) Ratio of AUC& Ratio of Cmax &
# Cyclosporine 5.2 mg/kg/day, stable dose 10 mg QDa for 28 days 8.69 10.66
# Tipranavir 500 mg BIDb /ritonavir 200 mg BIDb , 7 days 10 mg, SDc 9.36 8.58
# Glecaprevir 400 mg QDa /pibrentasvir 120 mg QDa , 7 days 10 mg QDa , for 7 days 8.28 22.00
# Telaprevir 750 mg q8hf , 10 days 20 mg, SDc 7.88 10.60
#,‡ Saquinavir 400 mg BIDb / ritonavir 400 mg BIDb , 15 days 40 mg QDa for 4 days 3.93 4.31
# Elbasvir 50 mg QDa /grazoprevir 200 mg QDa , 13 days 10 mg SDc 1.94 4.34
# Simeprevir 150 mg QDa , 10 days 40 mg SDc 2.12 1.70
# Clarithromycin 500 mg BIDb , 9 days 80 mg QDa for 8 days 4.54 5.38
# Darunavir 300 mg BIDb /ritonavir 100 mg BIDb , 9 days 10 mg QDa for 4 days 3.45 2.25
# Itraconazole 200 mg QDa , 4 days 40 mg SDc 3.32 1.20
# Fosamprenavir 700 mg BIDb / ritonavir 100 mg BIDb , 14 days 10 mg QDa for 4 days 2.53 2.84
# Fosamprenavir 1400 mg BIDb , 14 days 10 mg QDa for 4 days 2.30 4.04
# Nelfinavir 1250 mg BIDb , 14 days 10 mg QDa for 28 days 1.74 2.22
# Grapefruit Juice, 240 mL QDa,* 40 mg, SDc 1.37 1.16
Diltiazem 240 mg QDa , 28 days 40 mg, SDc 1.51 1.00
Erythromycin 500 mg QIDe , 7 days 10 mg, SDc 1.33 1.38
Amlodipine 10 mg, single dose 80 mg, SDc 1.18 0.91
Cimetidine 300 mg QIDe , 2 weeks 10 mg QDa for 2 weeks 1.00 0.89
Colestipol 10 g BIDb , 24 weeks 40 mg QDa for 8 weeks NA 0.74**
Maalox TC® 30 mL QIDe , 17 days 10 mg QDa for 15 days 0.66 0.67
Efavirenz 600 mg QDa , 14 days 10 mg for 3 days 0.59 1.01
# Rifampin 600 mg QDa , 7 days (co-administered) 40 mg SDc 1.12 2.90
# Rifampin 600 mg QDa , 5 days (doses separated) 40 mg SDc 0.20 0.60
# Gemfibrozil 600 mg BIDb , 7 days 40 mg SDc 1.35 1.00
# Fenofibrate 160 mg QDa , 7 days 40 mg SDc 1.03 1.02
Boceprevir 800 mg TIDd , 7 days 40 mg SDc 2.32 2.66

& Represents ratio of treatments (co-administered drug plus atorvastatin vs. atorvastatin alone).

# See Sections 5.1 and 7 for clinical significance.

* Greater increases in AUC (ratio of AUC up 2.5) and/or Cmax (ratio of Cmax up to 1.71) have been reported with excessive grapefruit consumption (≥ 750 mL — 1.2 liters per day).

** Ratio based on a single sample taken 8-16 h post dose.

† Due to the dual interaction mechanism of rifampin, simultaneous co-administration of atorvastatin with rifampin is recommended, as delayed administration of atorvastatin after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations.

‡ The dose of saquinavir plus ritonavir in this study is not the clinically used dose. The increase in atorvastatin exposure when used clinically is likely to be higher than what was observed in this study. Therefore, caution should be applied and the lowest dose necessary should be used.

a Once daily

b Twice daily

c Single dose

d Three times daily

e Four times daily

f Every 8 hours

TABLE 5. Effect of Atorvastatin on the Pharmacokinetics of Co-administered Drugs

Atorvastatin Co-administered drug and dosing regimen
Drug/Dose (mg) Ratio of AUC Ratio of Cmax
80 mg QDa for 15 days Antipyrine, 600 mg SDc 1.03 0.89
80 mg QDa for 10 days # Digoxin 0.25 mg QDa , 20 days 1.15 1.20
40 mg QDa for 22 days

Oral contraceptive QDa , 2 months

- norethindrone 1 mg

- ethinyl estradiol 35μg

1.28

1.23

10 mg, SDc Tipranavir 500 mg BIDb /ritonavir 200 mg BIDb , 7 days 1.08 0.96
10 mg QDa for 4 days Fosamprenavir 1400 mg BIDb , 14 days 0.73 0.82
10 mg QDa for 4 days Fosamprenavir 700 mg BIDb /ritonavir 100 mg BIDb , 14 days 0.99 0.94

# See Section 7 for clinical significance.

a Once daily

b Twice daily

c Single dose

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