ATORVASTATIN CALCIUM (Page 6 of 11)

8.4 Pediatric Use

Heterozygous Familial Hypercholesterolemia (HeFH) The safety and effectiveness of atorvastatin calcium have been established in pediatric patients, 10 years to 17 years of age, with HeFH as an adjunct to diet to reduce total cholesterol, LDL-C, and apo B levels when, after an adequate trial of diet therapy, the following are present:

  • LDL-C ≥ 190 mg/dL, or
  • LDL-C ≥ 160 mg/dL and
    • a positive family history of FH, or premature CVD in a first, or second-degree relative, or
    • two or more other CVD risk factors are present.

Use of atorvastatin calcium for this indication is supported by evidence from [see Dosage and Administration(2.2), Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.6)]:

  • A placebo-controlled clinical trial of 6 months duration in 187 boys and postmenarchal girls, 10 years to 17 years of age. Patients treated with 10 mg or 20 mg daily atorvastatin calcium had an adverse reaction profile generally similar to that of patients treated with placebo. In this limited controlled study, there was no significant effect on growth or sexual maturation in boys or on menstrual cycle length in girls.
  • A three year open-label uncontrolled trial that included 163 pediatric patients 10 to 15 years of age with HeFH who were titrated to achieve a target LDL-C < 130 mg/dL. The safety and efficacy of atorvastatin calcium in lowering LDL-C appeared generally consistent with that observed for adult patients, despite limitations of the uncontrolled study design.

Advise postmenarchal girls of contraception recommendations, if appropriate for the patient [see Use in Specific Populations (8.1), (8.3)] .

The long-term efficacy of atorvastatin calcium therapy initiated in childhood to reduce morbidity and mortality in adulthood has not been established.

The safety and efficacy of atorvastatin calcium have not been established in pediatric patients younger than 10 years of age with HeFH.

Homozygous Familial Hypercholesterolemia (HoFH)

Clinical efficacy of atorvastatin calcium with dosages up to 80 mg/day for 1 year was evaluated in an uncontrolled study of patients with HoFH including 8 pediatric patients [see Clinical Studies (14.5)].

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.

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 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 DESCRIPTION

Atorvastatin calcium, USP 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, USP 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 trihydrate (2:1). The empirical formula of atorvastatin calcium is (C 33 H 34 FN 2 O 5 ) 2 Ca•3H 2 O and its molecular weight is 1209.42. Its structural formula is:

chemical-structure
(click image for full-size original)

Atorvastatin calcium, USP is a white to off-white crystalline powder. Atorvastatin calcium, USP is freely soluble in methanol and insoluble in aqueous solutions of pH 4 and below.

Atorvastatin calcium tablets, USP for oral administration contain 10 mg, 20 mg, 40 mg, or 80 mg atorvastatin and the following inactive ingredients: anhydrous lactose, NF; colloidal silicon dioxide, NF; copovidone, NF; croscarmellose sodium, NF; magnesium stearate, NF; mannitol, USP; silicified microcrystalline cellulose, NF; sodium bicarbonate, USP; sodium carbonate anhydrous, NF; sodium lauryl sulfate, NF; hypromellose, polyethylene glycol, talc, titanium dioxide, and iron oxide yellow.

This product meets the requirements of USP Dissolution Test-2.

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-3methylglutaryl-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 C max 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 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 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. Based on observations in rats, atorvastatin calcium is likely to be secreted in human milk [see Contraindications (4) and Use in Specific Populations (8.2)].

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 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 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 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 calcium 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 calcium between men and women.

Renal Impairment: Renal disease has no influence on the plasma concentrations or LDL-C reduction of atorvastatin calcium; 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 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. 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 C max &
# Cyclosporine 5.2 mg/kg/day, stable dose 10 mg QD a for 28 days 8.69 10.66
# Tipranavir 500 mg BID b /ritonavir 200 mg BID b , 7 days 10 mg, SD c 9.36 8.58
# Glecaprevir 400 mg QD a /pibrentasvir 120 mg QD a , 7 days 10 mg QD a for 7 days 8.28 22.00
# Telaprevir 750 mg q8h f , 10 days 20 mg, SD c 7.88 10.60
# Saquinavir 400 mg BID b / ritonavir 400 mg BID b , 15 days 40 mg QD a for 4 days 3.93 4.31
# Elbasvir 50 mg QD a /grazoprevir 200 mg QD a , 13 days 10 mg SD c 1.94 4.34
# Simeprevir 150 mg QD a , 10 days 40 mg SD c 2.12 1.70
# Clarithromycin 500 mg BID b , 9 days 80 mg QD a for 8 days 4.54 5.38
# Darunavir 300 mg BID b /ritonavir 100 mg BID b , 9 days 10 mg QD a for 4 days 3.45 2.25
# Itraconazole 200 mg QD a , 4 days 40 mg SD c 3.32 1.20
# Letermovir 480 mg QD a , 10 days 20 mg SD c 3.29 2.17
# Fosamprenavir 700 mg BID b /ritonavir 100 mg BID b , 14 days 10 mg QD a for 4 days 2.53 2.84
# Fosamprenavir 1400 mg BID b , 14 days 10 mg QD a for 4 days 2.30 4.04
# Nelfinavir 1250 mg BID b , 14 days 10 mg QD a for 28 days 1.74 2.22
# Grapefruit Juice, 240 mL QD a , * 40 mg, SD c 1.37 1.16
Diltiazem 240 mg QD a , 28 days 40 mg, SD c 1.51 1.00
Erythromycin 500 mg QID e , 7 days 10 mg, SD c 1.33 1.38
Amlodipine 10 mg, single dose 80 mg, SD c 1.18 0.91
Cimetidine 300 mg QID e , 2 weeks 10 mg QD a for 2 weeks 1.00 0.89
Colestipol 10 g BID b , 24 weeks 40 mg QD a for 8 weeks NA 0.74 * *
Maalox TC ® 30 mL QID e , 17 days 10 mg QD a for 15 days 0.66 0.67
Efavirenz 600 mg QD a , 14 days 10 mg for 3 days 0.59 1.01
# Rifampin 600 mg QD a , 7 days (co-administered) 40 mg SD c 1.12 2.90
# Rifampin 600 mg QD a , 5 days (doses separated) 40 mg SD c 0.20 0.60
# Gemfibrozil 600 mg BID b , 7 days 40 mg SD c 1.35 1.00
# Fenofibrate 160 mg QD a , 7 days 40 mg SD c 1.03 1.02
Boceprevir 800 mg TID d , 7 days 40 mg SD c 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 — 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 C max
80 mg QD a for 15 days Antipyrine, 600 mg SD c 1.03 0.89
80 mg QD a for 10 days # Digoxin 0.25 mg QD a , 20 days 1.15 1.20
40 mg QD a for 22 days Oral contraceptive QD a , 2 months — norethindrone 1 mg — ethinyl estradiol 35 μg 1.28 1.19 1.23 1.30
10 mg, SD c Tipranavir 500 mg BID b /ritonavir 200 mg BID b , 7 days 1.08 0.96
10 mg QD a for 4 days Fosamprenavir 1400 mg BID b , 14 days 0.73 0.82
10 mg QD a for 4 days Fosamprenavir 700 mg BID b /ritonavir 100 mg BID b , 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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