Atorvastatin Calcium (Page 5 of 8)

8.4 Pediatric Use

The safety and effectiveness of atorvastatin calcium as an adjunct to diet to reduce LDL-C have been established in pediatric patients 10 years of age and older with HeFH. Use of atorvastatin calcium for this indication is based on a double-blind, placebo-controlled clinical trial in 187 pediatric patients 10 years of age and older with HeFH. In this limited controlled trial, there was no significant effect on growth or sexual maturation in the boys or girls, or on menstrual cycle length in girls.

The safety and effectiveness of atorvastatin calcium as an adjunct to other LDL-C-lowering therapies to reduce LDL-C have been established pediatric patients 10 years of age and older with HoFH. Use of atorvastatin calcium for this indication is based on a trial without a concurrent control group in 8 pediatric patients 10 years of age and older with HoFH [see Clinical Studies (14)].

The safety and effectiveness of atorvastatin calcium have not been established in pediatric patients younger than 10 years of age with HeFH or HoFH, or in pediatric patients with other types of hyperlipidemia (other than HeFH or HoFH).

8.5 Geriatric Use

Of the total number of atorvastatin calcium-treated patients in clinical trials, 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 patients and younger patients.

Advanced age (≥65 years) is a risk factor for atorvastatin calcium-associated myopathy and rhabdomyolysis. Dose selection for an elderly patient should be cautious, recognizing the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of myopathy. Monitor geriatric patients receiving atorvastatin calcium for the increased risk of myopathy [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

8.6 Renal Impairment

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

8.7 Hepatic Impairment

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

10 OVERDOSAGE

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

11 DESCRIPTION

Atorvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase.

Atorvastatin calcium, USP is (3R ,5R)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-(propan-2-yl)-1H -pyrrol-1-yl]-3,5-dihydroxyheptanoate calcium trihydrate. Its structural formula is:

image
(click image for full-size original)

C66 H68 CaF2 N4 O10 •3H2 O M.W. 1209.42

Atorvastatin calcium trihydrate (Form I) is a white to off-white powder that is insoluble in aqueous solutions of pH 4.5 and below. Atorvastatin calcium, USP is very slightly soluble in distilled water, pH 7.8 phosphate buffer, and acetonitrile; slightly soluble in ethanol; and freely soluble in methanol.

Atorvastatin calcium tablets, USP for oral administration contain 10 mg, 20 mg, 40 mg, or 80 mg of atorvastatin and the following inactive ingredients: calcium carbonate, croscarmellose sodium, hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate, talc and titanium dioxide.

12 CLINICAL PHARMACOLOGY

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. 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 calcium, 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 is rapidly absorbed after oral administration; maximum plasma concentrations occur within 1 to 2 hours. Extent of absorption increases in proportion to atorvastatin calcium 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 is given with or without food. Plasma atorvastatin calcium 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.

Distribution

Mean volume of distribution of atorvastatin calcium is approximately 381 liters. Atorvastatin calcium is ≥98% bound to plasma proteins. A blood/plasma ratio of approximately 0.25 indicates poor drug penetration into red blood cells.

Elimination

Metabolism

Atorvastatin calcium 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 calcium. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites. In vitro studies suggest the importance of atorvastatin calcium metabolism by cytochrome P450 3A4, consistent with increased plasma concentrations of atorvastatin calcium in humans following coadministration 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 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 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 is recovered in urine following oral administration.

Specific Populations

Geriatric

Plasma concentrations of atorvastatin calcium are higher (approximately 40% for Cmax and 30% for AUC) in healthy elderly subjects (age ≥65 years) than in young adults.

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 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 between men and women.

Renal Impairment

Renal disease has no influence on the plasma concentrations or LDL-C reduction of atorvastatin calcium [see Use in Specific Populations (8.6 )].

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

Hepatic Impairment

In patients with chronic alcoholic liver disease, plasma concentrations of atorvastatin calcium 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 Use in Specific Populations (8.7)].

Drug Interactions 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 5: Effect of Coadministered Drugs on the Pharmacokinetics of Atorvastatin

Coadministered 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 (coadministered)†

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 (coadministered 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 Cmax (ratio of Cmax 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 coadministration 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 6: Effect of Atorvastatin on the Pharmacokinetics of Coadministered Drugs

Atorvastatin

Coadministered 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.

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