Ezetimibe and Simvastatin (Page 7 of 11)

12.2 Pharmacodynamics

Clinical studies have demonstrated that elevated levels of total-C, LDL-C and Apo B, the major protein constituent of LDL, promote human atherosclerosis. In addition, decreased levels of HDL-C are associated with the development of atherosclerosis. Epidemiologic studies 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. Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including VLDL, intermediate-density lipoproteins (IDL), and remnants, can also promote atherosclerosis. The independent effect of raising HDL-C or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined.

12.3 Pharmacokinetics

The results of a bioequivalence study in healthy subjects demonstrated that the ezetimibe and simvastatin 10 mg/10 mg to 10 mg/80 mg combination tablets are bioequivalent to co-administration of corresponding doses of ezetimibe (ZETIA®) and simvastatin (ZOCOR®) as individual tablets.

Absorption

Ezetimibe

After oral administration, ezetimibe is absorbed and extensively conjugated to a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide).

Simvastatin

The availability of the β-hydroxyacid to the systemic circulation following an oral dose of simvastatin was found to be less than 5% of the dose, consistent with extensive hepatic first-pass extraction.

Effect of Food on Oral Absorption

Ezetimibe

Concomitant food administration (high-fat or non-fat meals) had no effect on the extent of absorption of ezetimibe when administered as 10-mg tablets. The Cmax value of ezetimibe was increased by 38% with consumption of high-fat meals.

Simvastatin

Relative to the fasting state, the plasma profiles of both active and total inhibitors of HMG-CoA reductase were not affected when simvastatin was administered immediately before an American Heart Association recommended low-fat meal.

Distribution

Ezetimibe

Ezetimibe and ezetimibe-glucuronide are highly bound (>90%) to human plasma proteins.

Simvastatin

Both simvastatin and its β-hydroxyacid metabolite are highly bound (approximately 95%) to human plasma proteins. When radiolabeled simvastatin was administered to rats, simvastatin-derived radioactivity crossed the blood-brain barrier.

Metabolism and Excretion

Ezetimibe

Ezetimibe is primarily metabolized in the small intestine and liver via glucuronide conjugation with subsequent biliary and renal excretion. Minimal oxidative metabolism has been observed in all species evaluated.

In humans, ezetimibe is rapidly metabolized to ezetimibe-glucuronide. Ezetimibe and ezetimibe-glucuronide are the major drug-derived compounds detected in plasma, constituting approximately 10 to 20% and 80 to 90% of the total drug in plasma, respectively. Both ezetimibe and ezetimibe-glucuronide are eliminated from plasma with a half-life of approximately 22 hours for both ezetimibe and ezetimibe-glucuronide. Plasma concentration-time profiles exhibit multiple peaks, suggesting enterohepatic recycling.

Following oral administration of 14 C-ezetimibe (20 mg) to human subjects, total ezetimibe (ezetimibe + ezetimibe-glucuronide) accounted for approximately 93% of the total radioactivity in plasma. After 48 hours, there were no detectable levels of radioactivity in the plasma.

Approximately 78% and 11% of the administered radioactivity were recovered in the feces and urine, respectively, over a 10-day collection period. Ezetimibe was the major component in feces and accounted for 69% of the administered dose, while ezetimibe-glucuronide was the major component in urine and accounted for 9% of the administered dose.

Simvastatin

Simvastatin is a lactone that is readily hydrolyzed in vivo to the corresponding β-hydroxyacid, a potent inhibitor of HMG-CoA reductase. Inhibition of HMG-CoA reductase is a basis for an assay in pharmacokinetic studies of the β-hydroxyacid metabolites (active inhibitors) and, following base hydrolysis, active plus latent inhibitors (total inhibitors) in plasma following administration of simvastatin. The major active metabolites of simvastatin present in human plasma are the β-hydroxyacid of simvastatin and its 6’-hydroxy, 6’-hydroxymethyl, and 6’-exomethylene derivatives.

Following an oral dose of 14 C-labeled simvastatin in man, 13% of the dose was excreted in urine and 60% in feces. Plasma concentrations of total radioactivity (simvastatin plus 14 C-metabolites) peaked at 4 hours and declined rapidly to about 10% of peak by 12 hours postdose.

Specific Populations

Geriatric Patients

Ezetimibe

In a multiple-dose study with ezetimibe given 10 mg once daily for 10 days, plasma concentrations for total ezetimibe were about 2-fold higher in older (≥65 years) healthy subjects compared to younger subjects.

Simvastatin

In a study including 16 elderly patients between 70 and 78 years of age who received simvastatin 40 mg/day, the mean plasma level of HMG-CoA reductase inhibitory activity was increased approximately 45% compared with 18 patients between 18 to 30 years of age.

Pediatric Patients: [see Use in Specific Populations (8.4)].

Gender

Ezetimibe

In a multiple-dose study with ezetimibe given 10 mg once daily for 10 days, plasma concentrations for total ezetimibe were slightly higher (<20%) in women than in men.

Race

Ezetimibe

Based on a meta-analysis of multiple-dose pharmacokinetic studies, there were no pharmacokinetic differences between Black and Caucasian subjects. Studies in Asian subjects indicated that the pharmacokinetics of ezetimibe was similar to those seen in Caucasian subjects.

Hepatic Impairment

Ezetimibe

After a single 10-mg dose of ezetimibe, the mean exposure (based on area under the curve [AUC]) to total ezetimibe was increased approximately 1.7-fold in patients with mild hepatic impairment (Child-Pugh score 5 to 6), compared to healthy subjects. The mean AUC values for total ezetimibe and ezetimibe increased approximately 3- to 4-fold and 5- to 6-fold, respectively, in patients with moderate (Child-Pugh score 7 to 9) or severe hepatic impairment (Child-Pugh score 10 to 15). In a 14-day, multiple-dose study (10 mg daily) in patients with moderate hepatic impairment, the mean AUC for total ezetimibe and ezetimibe increased approximately 4-fold compared to healthy subjects.

Renal Impairment

Ezetimibe

After a single 10-mg dose of ezetimibe in patients with severe renal disease (n=8; mean CrCl ≤30 mL/min/1.73 m2), the mean AUC for total ezetimibe and ezetimibe increased approximately 1.5-fold, compared to healthy subjects (n=9).

Simvastatin

Pharmacokinetic studies with another statin having a similar principal route of elimination to that of simvastatin have suggested that for a given dose level higher systemic exposure may be achieved in patients with severe renal impairment (as measured by creatinine clearance).

Drug Interactions [see also Drug Interactions (7)].

No clinically significant pharmacokinetic interaction was seen when ezetimibe was co-administered with simvastatin. No specific pharmacokinetic drug interaction studies with ezetimibe and simvastatin have been conducted other than the following study with NIASPAN (Niacin extended-release tablets).

Niacin: The effect of ezetimibe and simvastatin (10/20 mg daily for 7 days) on the pharmacokinetics of NIASPAN extended-release tablets (1,000 mg for 2 days and 2,000 mg for 5 days following a low-fat breakfast) was studied in healthy subjects. The mean Cmax and AUC of niacin increased 9% and 22%, respectively. The mean Cmax and AUC of nicotinuric acid increased 10% and 19%, respectively (N=13). In the same study, the effect of NIASPAN on the pharmacokinetics of ezetimibe and simvastatin was evaluated (N=15). While concomitant NIASPAN decreased the mean Cmax of total ezetimibe (1%), and simvastatin (2%), it increased the mean Cmax of simvastatin acid (18%). In addition, concomitant NIASPAN increased the mean AUC of total ezetimibe (26%), simvastatin (20%), and simvastatin acid (35%).

Cases of myopathy/rhabdomyolysis have been observed with simvastatin co-administered with lipid-modifying doses (≥1 g/day niacin) of niacin-containing products [see Warnings and Precautions (5.1) and Drug Interactions (7.4)].

Cytochrome P450: Ezetimibe had no significant effect on a series of probe drugs (caffeine, dextromethorphan, tolbutamide, and IV midazolam) known to be metabolized by cytochrome P450 (1A2, 2D6, 2C8/9 and 3A4) in a “cocktail” study of twelve healthy adult males. This indicates that ezetimibe is neither an inhibitor nor an inducer of these cytochrome P450 isozymes, and it is unlikely that ezetimibe will affect the metabolism of drugs that are metabolized by these enzymes.

In a study of 12 healthy volunteers, simvastatin at the 80-mg dose had no effect on the metabolism of the probe cytochrome P450 isoform 3A4 (CYP3A4) substrates midazolam and erythromycin. This indicates that simvastatin is not an inhibitor of CYP3A4 and, therefore, is not expected to affect the plasma levels of other drugs metabolized by CYP3A4.

Simvastatin acid is a substrate of the transport protein OATP1B1. Concomitant administration of medicinal products that are inhibitors of the transport protein OATP1B1 may lead to increased plasma concentrations of simvastatin acid and an increased risk of myopathy. For example, cyclosporine has been shown to increase the AUC of statins; although the mechanism is not fully understood, the increase in AUC for simvastatin acid is presumably due, in part, to inhibition of CYP3A4 and/or OATP1B1.

Simvastatin is a substrate for CYP3A4. Inhibitors of CYP3A4 can raise the plasma levels of HMG-CoA reductase inhibitory activity and increase the risk of myopathy [see Warnings and Precautions (5.1); Drug Interactions (7.1)].

Ezetimibe

Table 4: Effect of Co-administered Drugs on Total Ezetimibe

Co-administered Drug and Dosing Regimen

Total Ezetimibe*

Change in AUC

Change in Cmax

Cyclosporine-stable dose required (75 mg to 150 mg BID)†,‡

↑240%

↑290%

Fenofibrate, 200 mg QD, 14 days

↑48%

↑64%

Gemfibrozil, 600 mg BID, 7 days

↑64%

↑91%

Cholestyramine, 4 g BID, 14 days

↓55%

↓4%

Aluminum & magnesium hydroxide combination antacid, single dose§

↓4%

↓30%

Cimetidine, 400 mg BID, 7 days

↑6%

↑22%

Glipizide, 10 mg, single dose

↑4%

↓8%

Statins

Lovastatin 20 mg QD, 7 days

↑9%

↑3%

Pravastatin 20 mg QD, 14 days

↑7%

↑23%

Atorvastatin 10 mg QD, 14 days

↓2%

↑12%

Rosuvastatin 10 mg QD, 14 days

↑13%

↑18%

Fluvastatin 20 mg QD, 14 days

↓19%

↑7%

* Based on 10 mg-dose of ezetimibe.

† Post-renal transplant patients with mild impaired or normal renal function. In a different study, a renal transplant patient with severe renal insufficiency (creatinine clearance of 13.2 mL/min/1.73 m2) who was receiving multiple medications, including cyclosporine, demonstrated a 12-fold greater exposure to total ezetimibe compared to healthy subjects.

‡ See 7. Drug Interactions.

§ Supralox, 20 mL.

Table 5: Effect of Ezetimibe Co-administration on Systemic Exposure to Other Drugs

Co-administered Drug and its Dosage Regimen

Ezetimibe Dosage Regimen

Change in AUC of Co-administered Drug

Change in Cmax of Co-administered Drug

Warfarin, 25 mg single dose on Day 7

10 mg QD, 11 days

↓2% (R-warfarin) ↓4% (S-warfarin)

↑3% (R-warfarin) ↑1% (S-warfarin)

Digoxin, 0.5 mg single dose

10 mg QD, 8 days

↑2%

↓7%

Gemfibrozil, 600 mg BID, 7 days*

10 mg QD, 7 days

↓1%

↓11%

Ethinyl estradiol & Levonorgestrel, QD, 21 days

10 mg QD, Days 8 to 14 of 21 day oral contraceptive cycle

Ethinyl estradiol 0% Levonorgestrel 0%

Ethinyl estradiol ↓9% Levonorgestrel ↓5%

Glipizide, 10 mg on Days 1 and 9

10 mg QD, Days 2 to 9

↓3%

↓5%

Fenofibrate, 200 mg QD, 14 days*

10 mg QD, 14 days

↑11%

↑7%

Cyclosporine, 100 mg single dose Day 7*

20 mg QD, 8 days

↑15%

↑10%

Statins

Lovastatin 20 mg QD, 7 days

10 mg QD, 7 days

↑19%

↑3%

Pravastatin 20 mg QD, 14 days

10 mg QD, 14 days

↓20%

↓24%

Atorvastatin 10 mg QD, 14 days

10 mg QD, 14 days

↓4%

↑7%

Rosuvastatin 10 mg QD, 14 days

10 mg QD, 14 days

↑19%

↑17%

Fluvastatin 20 mg QD, 14 days

10 mg QD, 14 days

↓39%

↓27%

* See 7. Drug Interactions.

Simvastatin

Table 6: Effect of Co-administered Drugs or Grapefruit Juice on Simvastatin Systemic Exposure

Co-administered Drug or Grapefruit Juice

Dosing of Co-administered Drug or Grapefruit Juice

Dosing of Simvastatin

Geometric Mean Ratio (Ratio* with / without Co-administered drug) No Effect = 1.00

AUC

Cmax

Contraindicated with ezetimibe and simvastatin [see Contraindications (4) and Warnings and Precautions (5.1)]

Telithromycin

200 mg QD for 4 days

80 mg

simvastatin acid

12

15

simvastatin

8.9

5.3

Nelfinavir

1,250 mg BID for 14 days

20 mg QD for 28 days

simvastatin acid

simvastatin

6

6.2

Itraconazole

200 mg QD for 4 days

80 mg

simvastatin acid

13.1

simvastatin

13.1

Posaconazole

100 mg (oral suspension) QD for 13 days

40 mg

simvastatin acid

7.3

9.2

simvastatin

10.3

9.4

200 mg (oral suspension) QD for 13 days

40 mg

simvastatin acid

8.5

9.5

simvastatin

10.6

11.4

Gemfibrozil

600 mg BID for 3 days

40 mg

simvastatin acid

2.85

2.18

simvastatin

1.35

0.91

Avoid grapefruit juice with ezetimibe and simvastatin [see Warnings and Precautions (5.1)]

Grapefruit Juice§ (high dose)

200 mL of double-strength TID

60 mg single dose

simvastatin acid

7

simvastatin

16

Grapefruit Juice§ (low dose)

8 oz (about 237 mL) of single-strength#

20 mg single dose

simvastatin acid

1.3

simvastatin

1.9

Avoid taking with >10/10 mg ezetimibe and simvastatin , based on clinical and/or postmarketing simvastatin experience [see Warnings and Precautions (5.1)]

Verapamil SR

240 mg QD Days 1 to 7 then 240 mg BID on Days 8 to 10

80 mg on Day 10

simvastatin acid

2.3

2.4

simvastatin

2.5

2.1

Diltiazem

120 mg BID for 10 days

80 mg on Day 10

simvastatin acid

2.69

2.69

simvastatin

3.10

2.88

Diltiazem

120 mg BID for 14 days

20 mg on Day 14

simvastatin

4.6

3.6

Dronedarone

400 mg BID for 14 days

40 mg QD for 14 days

simvastatin acid

1.96

2.14

simvastatin

3.90

3.75

Avoid taking with >10/20 mg ezetimibe and simvastatin, based on clinical and/or postmarketing simvastatin experience [see Warnings and Precautions (5.1)]

Amiodarone

400 mg QD for 3 days

40 mg on Day 3

simvastatin acid

1.75

1.72

simvastatin

1.76

1.79

Amlodipine

10 mg QD for 10 days

80 mg on Day 10

simvastatin acid

1.58

1.56

simvastatin

1.77

1.47

Ranolazine SR

1,000 mg BID for 7 days

80 mg on Day 1 and Days 6 to 9

simvastatin acid

2.26

2.28

simvastatin

1.86

1.75

Avoid taking with >10/20 mg ezetimibe and simvastatin (or 10/40 mg for patients who have previously taken 80 mg simvastatin chronically, e.g., for 12 months or more, without evidence of muscle toxicity), based on clinical experience

Lomitapide

60 mg QD for 7 days

40 mg single dose

simvastatin acid

1.7

1.6

simvastatin

2

2

Lomitapide

10 mg QD for 7 days

20 mg single dose

simvastatin acid

1.4

1.4

simvastatin

1.6

1.7

No dosing adjustments required for the following:

Fenofibrate

160 mg QD for 14 days

80 mg QD on Days 8 to 14

simvastatin acid

0.64

0.89

simvastatin

0.89

0.83

Propranolol

80 mg single dose

80 mg single dose

total inhibitor

0.79

↓ from 33.6 to 21.1 ng∙eq/mL

active inhibitor

0.79

↓ from 7.0 to 4.7 ng∙eq/mL

* Results based on a chemical assay except results with propranolol as indicated.

†Results could be representative of the following CYP3A4 inhibitors: ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors, and nefazodone.

‡ Simvastatin acid refers to the β-hydroxyacid of simvastatin.

§ The effect of amounts of grapefruit juice between those used in these two studies on simvastatin pharmacokinetics has not been studied.

¶ Double-strength: one can of frozen concentrate diluted with one can of water. Grapefruit juice was administered TID for 2 days, and 200 mL together with single dose simvastatin and 30 and 90 minutes following single dose simvastatin on Day 3.

# Single-strength: one can of frozen concentrate diluted with 3 cans of water. Grapefruit juice was administered with breakfast for 3 days, and simvastatin was administered in the evening on Day 3.

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