ATORVASTATIN CALCIUM (Page 5 of 10)

8.6 Hepatic Impairment

Atorvastatin calcium is 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 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 clearance.

11 DESCRIPTION

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.

The drug substance used in atorvastatin calcium tablets, USP is atorvastatin calcium in the form of propylene glycol solvate. The chemical name for atorvastatin calcium propylene glycol solvate is calcium bis((3R,5R)-7-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoate) propylene glycol solvate. The empirical formula of atorvastatin calcium propylene glycol solvate is C₆₆ H₆₈ CaF₂ N₄ O₁₀ * C₃ H₈ O₂ and its molecular weight is 1231.46 g/mol. Its structural formula is:

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

Atorvastatin calcium tablets, USP for oral administration contain 10, 20, 40, or 80 mg atorvastatin and the following inactive ingredients: calcium acetate, colloidal silicon dioxide, croscarmellose sodium, hydroxypropyl cellulose, hypromellose, magnesium stearate (vegetable source), microcrystalline cellulose, polyethylene glycol, sodium carbonate, and titanium dioxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol.

In 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.

12.2 Pharmacodynamics

Atorvastatin, 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 is rapidly absorbed after oral administration; maximum plasma concentrations occur within 1 to 2 hours. Extent of absorption increases in proportion to atorvastatin 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 C_max and AUC, LDL-C reduction is similar whether atorvastatin is given with or without food. Plasma atorvastatin concentrations are lower (approximately 30% for C_max 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 is approximately 381 liters. Atorvastatin is ≥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 is likely to be secreted in human milk [see Contraindications (4) and Use in Specific Populations (8.2)].

Metabolism:

Atorvastatin is 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. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites. In vitro studies suggest the importance of atorvastatin metabolism by cytochrome P450 3A4, consistent with increased plasma concentrations of atorvastatin 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 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 in humans is approximately 14 hours, but the half-life of inhibitory activity for HMG-CoA reductase is 20 to 30 hours due to the contribution of active metabolites. Less than 2% of a dose of atorvastatin is recovered in urine following oral administration.

Specific Populations

Geriatric:

Plasma concentrations of atorvastatin are higher (approximately 40% for C_max 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 in women differ from those in men (approximately 20% higher for C_max and 10% lower for AUC); however, there is no clinically significant difference in LDL-C reduction with atorvastatin between men and women.

Renal Impairment:

Renal disease has no influence on the plasma concentrations or LDL-C reduction of atorvastatin; 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 since the drug is extensively bound to plasma proteins.

Hepatic Impairment:

In patients with chronic alcoholic liver disease, plasma concentrations of atorvastatin are markedly increased. C_max and AUC are each 4-fold greater in patients with Childs-Pugh A disease. C_max 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 6. 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
# Letermovir 480 mg QDa , 10 days	20 mg SDc	3.29	2.17
# 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 to 2.5) and/or C_max (ratio of C_max up to 1.71) have been reported with excessive grapefruit consumption (≥ 750 mL to 1.2 liters per day).

** Ratio based on a single sample taken 8 to 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 7. 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 35 mcg	1.28 1.19	1.23 1.30
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

Atorvastatin calcium had no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin treatment.