ROSUVASTATIN AND EZETIMIBE (Page 5 of 8)

8.4 Pediatric Use

The safety and effectiveness of rosuvastatin and ezetimibe tablets have not been established in pediatric patients.

8.5 Geriatric Use

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

Rosuvastatin
Of the 10,275 patients in clinical studies with rosuvastatin, 3159 (31%) were 65 years and older, and 698 (6.8%) were 75 years and older.

Ezetimibe
Of the 2396 patients who received ezetimibe monotherapy in clinical studies, 669 (28%) were 65 and older, and 111 (5%) were 75 and older. Of the 11,308 patients who received ezetimibe + statin in clinical studies, 3587 (32%) were 65 and older, and 924 (8%) were 75 and older. No overall differences in safety and effectiveness were observed between these patients and younger patients. In a multiple-dose study with ezetimibe, plasma concentrations for ezetimibe were about 2-fold higher in older (≥65 years) healthy subjects compared to younger subjects [See Clinical Pharmacology (12.3)].

8.6 Renal Impairment

Renal impairment is a risk factor for myopathy and rhabdomyolysis. Monitor patients with renal impairment for development of myopathy. In patients with severe renal impairment not on hemodialysis, the recommended starting dosage is 5 mg/10 mg daily and should not exceed 10 mg/10 mg daily [see Dosage and Administration (2.5) and Warnings and Precautions (5.1)].

Rosuvastatin
Rosuvastatin exposure is not influenced by mild to moderate renal impairment (CLcr≥30 mL/min/1.73 m2). Exposure to rosuvastatin is increased to a clinically significant extent in patients with severe renal impairment (CLcr<30 mL/min/1.73 m2) who are not receiving hemodialysis [see Clinical Pharmacology (12.3)].

Ezetimibe
In a trial of 9270 patients with moderate to severe renal impairment (6247 non-dialysis patients with median serum creatinine 2.5 mg/dL and median estimated glomerular filtration rate 25.6 mL/min/1.73 m2 , and 3023 dialysis patients), the incidence of serious adverse events, adverse events leading to discontinuation of study treatment, or adverse events of special interest (musculoskeletal adverse events, liver enzyme abnormalities, incident cancer) was similar between patients ever assigned to ezetimibe 10 mg plus simvastatin 20 mg (n=4650) or placebo (n=4620) during a median follow-up of 4.9 years.

8.7 Hepatic Impairment

Rosuvastatin and ezetimibe tablets is contraindicated in patients with acute liver failure or decompensated cirrhosis [see Contraindications (4), Warnings and Precautions (5.3), and Clinical Pharmacology (12.3)].

8.8 Asian Population

Pharmacokinetic studies have demonstrated an approximate 2-fold increase in median exposure to rosuvastatin in Asian subjects when compared with Caucasian controls. Adjust the rosuvastatin and ezetimibe tablets dosage in Asian patients [see Dosage and Administration (2.2)]

10 OVERDOSAGE

No specific treatments of over dosage with rosuvastatin and ezetimibe tablets are known. Hemodialysis does not significantly enhance clearance of rosuvastatin. Contact Poison Control (1-800-222-1222) for latest recommendations.

11 DESCRIPTION

Rosuvastatin and ezetimibe tablets contain rosuvastatin calcium and ezetimibe. Rosuvastatin is a 3-hydroxy-3- methylglutaryl coenzyme A (HMG CoA)-reductase inhibitor. Ezetimibe is a dietary cholesterol absorption inhibitor.The chemical name of ezetimibe is (3R,4S)-1-(p-Fluorophenyl)-3-[(3S)-3-(p-fluorophenyl)-3- hydroxypropyl]-4-(p-hydroxyphenyl)-2-azetidinone. The empirical formula is C24 H21 F2 NO3 . Its molecular weight is 409.43 g.mol-1. Ezetimibe is a white, crystalline powder, which is insoluble in water. Its structural formula is:

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

The chemical name for rosuvastatin calcium is bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2[methyl(methyl sulfonyl)amino] pyrimidin-5-yl] (3R,5S)-3,5-dihydroxyhept-6-enoic acid] calcium salt to [S-[R*,S*-(E)]]-7-[4-(4-Fluorophenyl)-6-(1-methylethyl)-2-[methyl(methylsulfonyl)amino]-5-pyrimidinyl]-3,5-dihydroxy-6-heptenoic acid, calcium salt (2:1). The empirical formula for rosuvastatin calcium is (C22 H27 FN3 O6 S)2 Ca and the molecular weight is 1001.14 g.mol-1. Rosuvastatin calcium is a white amorphous powder that is sparingly soluble in water and methanol, and slightly soluble in ethanol. Rosuvastatin calcium is a hydrophilic compound with a partition coefficient (octanol/water) of 0.13 at pH of 7.0. Its structural formula is:

rosuvastatin-calcium-structure
(click image for full-size original)

Rosuvastatin and ezetimibe tablets 5 mg/10 mg, 10 mg/10 mg, 20 mg/10 mg, and 40 mg/10 mg contain the equivalent of 5, 10, 20, and 40 mg rosuvastatin (provided as rosuvastatin calcium 5.2, 10.4, 20.8, and 41.7 mg) and 10 mg ezetimibe. Each film-coated tablet of rosuvastatin and ezetimibe tablets contains the following inactive ingredients: pregelatinized starch, microcrystalline cellulose, meglumine, dibasic calcium phosphate dihydrate , crospovidone, colloidal silicon dioxide, sodium stearyl fumarate, mannitol, sodium lauryl sulfate, croscarmellose sodium, povidone, ferric oxide, and magnesium stearate. In addition, the film coating contains the following inactive ingredients: hypromellose, titanium dioxide, polyethylene glycol, and ferric oxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Rosuvastatin
Rosuvastatin is an inhibitor of HMG CoA-reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, a precursor of cholesterol. In in vivo and in vitro studies, rosuvastatin produces its lipid-modifying effects in two ways. First, it increases the number of hepatic LDL receptors on the cell-surface to enhance uptake and catabolism of LDL. Second, rosuvastatin inhibits hepatic synthesis of VLDL, which reduces the total number of VLDL and LDL particles.

Ezetimibe
The molecular target of ezetimibe is the sterol transporter, Niemann-Pick C1-Like 1 (NPC1L1), which is involved in the intestinal uptake of cholesterol and phytosterols. Ezetimibe localizes at the brush border of the small intestine and inhibits the absorption of cholesterol, leading to a decrease in the delivery of intestinal cholesterol to the liver. This causes a reduction of hepatic cholesterol stores and an increase in clearance of cholesterol from the blood.

12.2 Pharmacodynamics

The maximum therapeutic response of rosuvastatin is usually achieved by 4 weeks and is maintained after that. The maximum therapeutic response of ezetimibe is generally achieved within 2 weeks and is maintained during chronic therapy.

12.3 Pharmacokinetics

Absorption
Rosuvastatin
In clinical pharmacology studies in man, peak plasma concentrations of rosuvastatin were reached 3 to 5 hours following oral dosing. Both Cmax and AUC increased in approximate proportion to rosuvastatin dose. The absolute bioavailability of rosuvastatin is approximately 20%.The AUC of rosuvastatin does not differ following evening or morning drug administration.

Administration of rosuvastatin with food did not affect the AUC of rosuvastatin.

Ezetimibe
After oral administration, ezetimibe is absorbed and extensively conjugated to a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide). After a single 10-mg dose of ezetimibe to fasted adults, mean ezetimibe peak plasma concentrations (Cmax) of 3.4 to 5.5 ng/mL were attained within 4 to 12 hours (Tmax). Ezetimibe-glucuronide mean Cmax values of 45 to 71 ng/mL were achieved between 1 and 2 hours (Tmax). There was no substantial deviation from dose proportionality between 5 and 20 mg. The absolute bioavailability of ezetimibe cannot be determined, as the compound is virtually insoluble in aqueous media suitable for injection.

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

Distribution
Rosuvastatin
Mean volume of distribution at steady-state of rosuvastatin is approximately 134 liters. Rosuvastatin is 88% bound to plasma proteins, mostly albumin. This binding is reversible and independent of plasma concentrations.

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

Elimination
Rosuvastatin
Rosuvastatin is not extensively metabolized; approximately 10% of a radiolabeled dose is recovered as metabolite. The major metabolite is N-desmethyl rosuvastatin, which is formed principally by cytochrome P450 \ 2C9, and in vitro studies have demonstrated that N-desmethyl rosuvastatin has approximately one-sixth to one-half the HMG-CoA reductase inhibitory activity of the parent compound. Overall, greater than 90% of active plasma HMG-CoA reductase inhibitory activity is accounted for by the parent compound.

Following oral administration, rosuvastatin and its metabolites are primarily excreted in the feces (90%). The elimination half-life (t1/2 ) of rosuvastatin is approximately 19 hours. After an intravenous dose, approximately 28% of total body clearance was via the renal route, and 72% by the hepatic route.

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.

Specific Populations
Geriatric Patients
Rosuvastatin
There were no differences in plasma concentrations of rosuvastatin between the nonelderly and elderly populations (age ≥65 years).

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.

Gender
Rosuvastatin
There were no differences in plasma concentrations of rosuvastatin between men and women.

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
Rosuvastatin
A population pharmacokinetic analysis revealed no clinically relevant differences in pharmacokinetics among Caucasian, Hispanic, and Black or Afro-Caribbean groups. However, pharmacokinetic studies, including one conducted in the US, have demonstrated an approximate 2-fold elevation in median exposure (AUC and Cmax ) in Asian subjects when compared with a Caucasian control group. [See Dosage and Administration (2.1) and Specific Populations (8.8).]

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 were similar to those seen in Caucasian subjects.

Hepatic Impairment
Rosuvastatin
In patients with chronic alcohol liver disease, plasma concentrations of rosuvastatin were modestly increased. In patients with Child-Pugh A disease, Cmax and AUC were increased by 60% and 5%, respectively, as compared with patients with normal liver function. In patients with Child-Pugh B disease, Cmax and AUC were increased 100% and 21%, respectively, compared with patients with normal liver function [see Contraindications (4) and Warnings and Precautions (5.2)].

Ezetimibe
After a single 10-mg dose of ezetimibe, the mean AUC for 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 on both Day 1 and Day 14 when compared to healthy subjects [see Contraindications (4) and Warnings and Precautions (5.2), and Specific Populations (8.7)].

Renal Impairment
Rosuvastatin
Mild to moderate renal impairment (CLcr ≥30 mL/min/1.73 m2) had no influence on plasma concentrations of rosuvastatin. However, plasma concentrations of rosuvastatin increased to a clinically significant extent (about 3-fold) in patients with severe renal impairment (CLcr <30 mL/min/1.73 m2) not receiving hemodialysis compared with healthy subjects (CLcr >80 mL/min/1.73 m2). Steady-state plasma concentrations of rosuvastatin in patients on chronic hemodialysis were approximately 50% greater compared with healthy volunteer subjects with normal renal function.

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

Drug Interactions
No clinically significant pharmacokinetic interaction was seen when ezetimibe was coadministered with rosuvastatin. Specific pharmacokinetic drug interaction studies with rosuvastatin and ezetimibe tablets have not been performed.

Cytochrome P450
Rosuvastatin clearance is not dependent on metabolism by cytochrome P450 3A4 to a clinically significant extent. Rosuvastatin is a substrate for certain transporter proteins including the hepatic uptake transporter organic anion-transporting polyprotein 1B1 (OATP1B1) and efflux transporter breast cancer resistance protein (BCRP) [see Dosage and Administration (2.3) and Drug Interactions (7.1, 7.3)].

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.

Rosuvastatin Table 8: Effect of Coadministered Drugs on Rosuvastatin Systemic Exposure

Coadministered drug and dosing regimen Rosuvastatin
Mean Ratio (ratio with/without coadministered drug) No Effect=1.0
Dose (mg) 1 Change in AUC Change in Cmax

Sofosbuvir/velpatasvir/voxilaprevir (400 mg-100 mg-100 mg)

+ Voxilaprevir (100 mg) QD for 15 days

10 mg single dose 7.392 (6.68-8.18)3 18.882 (16.23-21.96)3
Cyclosporine – stable dose required(75 mg – 200 mg BID) 10 mg QD for 10 days 7.12 112
Darolutamide 600 mg BID, 5 days 5 mg, single dose 5.22 ~52
Regorafenib 160 mg OD, 14 days 5 mg single dose 3.82 4.62
Atazanavir/ritonavir combination300 mg/100 mg QD for 8 days 10 mg 3.12 72
Simeprevir 150 mg QD, 7 days 10 mg, single dose

2.82

(2.3-3.4)3

3.22 (2.6-3.9)3
Velpatasvir 100 mg once daily 10 mg single dose 2.692 (2.46-2.94)3 2.612 (2.32-2.92)3
Ombitasvir 25 mg/paritaprevir 150 mg/ritonavir 100 mg + dasabuvir 400 mg BID 5 mg single dose 2.592 (2.09-3.21)3 7.132 (5.11-9.96)3
Elbasvir 50 mg/grazoprevir 200 mg QD 10 mg single dose 2.262 (1.89-2.69)3 5.492 (4.29-7.04)3
Glecaprevir 400 mg/pibrentasvir 120 mg QD 5 mg once daily 2.152 (1.88-2.46)3 5.622 (4.80-6.59)3
Lopinavir/ritonavir combination400 mg/100 mg BID for 17 days 20 mg QD for 7 days 2.12 (1.7-2.6)3 52 (3.4-6.4)3
Gemfibrozil 600 mg BID for 7 days 80 mg 1.92 (1.6-2.2)3 2.22 (1.8-2.7)3
Eltrombopag 75 mg QD, 5 days 10 mg 1.6(1.4-1.7)3 2(1.8-2.3)3
Darunavir 600 mg/ritonavir 100 mg BID, 7 days 10 mg QD for 7 days 1.5(1.0-2.1)3 2.4(1.6-3.6)3
Tipranavir/ritonavir combination500 mg/200 mg BID for 11 days 10 mg 1.4(1.2-1.6)3 2.2(1.8-2.7)3
Dronedarone 400 mg BID 10 mg 1.4
Itraconazole 200 mg QD, 5 days 10 mg or 80 mg 1.4(1.2-1.6)3 1.3(1.1-1.4)3 1.4(1.2-1.5)3 1.2(0.9-1.4)3
Ezetimibe 10 mg QD, 14 days 10 mg QD for 14 days 1.2(0.9-1.6)3 1.2(0.8-1.6)3
Fosamprenavir/ritonavir700 mg/100 mg BID for 7 days 10 mg 1.1 1.5
Fenofibrate 67 mg TID for 7 days 10 mg 1.2(1.1-1.3)3
Rifampicin 450 mg QD, 7 days 20 mg

Aluminum & magnesium hydroxide

combination antacid

Administered simultaneously

40 mg

0.52 (0.4-0.5)3

0.52 (0.4-0.6)3

Administered 2 hours apart 40 mg 0.8(0.7-0.9)3 0.8(0.7-1.0)3
Ketoconazole 200 mg BID for 7 days 80 mg 1.0(0.8-1.2)3 1.0(0.7-1.3)3
Fluconazole 200 mg QD for 11 days 80 mg 1.1(1.0-1.3)3 1.1(0.9-1.4)3
Erythromycin 500 mg QID for 7 days 80 mg 0.8(0.7-0.9)3 0.7(0.5-0.9)3

QD= Once daily, BID= Twice daily, TID= Three times daily, QID= Four times daily
1 Single dose unless otherwise noted.2 Clinically significant [See Dosage and Administration (2), Warnings and Precautions (5), and Drug Interactions (7)]

3 Mean ratio with 90% CI (with/without coadministered drug, e.g., 1= no change, 0.7 = 30% decrease, 11=11 fold increase in exposure)

Table 9: Effect of Rosuvastatin Coadministration on Systemic Exposure to Other Drugs

Rosuvastatin Dosage Regimen Coadministered Drug

Mean Ration (ratio with/without coadministered drug)

No Effect=1.0

Name and Dose Change in AUC Change in Cmax
40 mg QD for 10 days Warfarin 1 25 mg single dose R- Warfarin1.0(1.0-1.1)2 S-Warfarin1.1(1.0-1.1)2 R-Warfarin1.0(0.9-1.0)2 S-Warfarin1.0(0.9-1.1)2
40 mg QD for 12 days Digoxin0.5 mg single dose 1.0(0.9-1.2)2 1.0(0.9-1.2)2
40 mg QD for 28 days Oral Contraceptive(ethinyl estradiol 0.035 mg & norgestrel 0.180,0.215 and 0.250 mg) QD for 21 Days EE 1.3(1.2-1.3)2 NG 1.3(1.3-1.4)2 EE 1.3(1.2-1.3)2 NG 1.2(1.1-1.3)2

EE = ethinyl estradiol, NG = norgestrel, QD= Once daily

1 Clinically significant pharmacodynamic effects [see Drug Interactions (7)]
2 Mean ratio with 90% CI (with/without coadministered drug, e.g., 1= no change, 0.7=30% decrease, 11=11-fold increase in exposure)

Ezetimibe Table 10: Effect of Co-Administered Drugs on Total Ezetimibe

Coadministered Drug and Dosing Regimen Total Ezetimibe*
Change in AUC Change in Cmax
Cyclosporine-stable dose required (75-150 mg BID)1,2 ↑240% ↑290%
Fenofibrate, 200 mg QD, 14 days2 ↑48% ↑64%
Gemfibrozil, 600 mg BID, 7 days2 ↑64% ↑91%
Cholestyramine, 4 g BID, 14 days2 ↓55% ↓4%
Aluminum & magnesium hydroxide combination antacid, single dose3 ↓4% ↓30%
Cimetidine, 400 mg BID, 7 days ↑6% ↑22%
Glipizide, 10 mg, single dose ↑4% ↓8%
Statins Lovastatin 20 mg QD, 7 days Pravastatin 20 mg QD, 14 days Atorvastatin 10 mg QD, 14 days Rosuvastatin 10 mg QD, 14 days Fluvastatin 20 mg QD, 14 days

↑9%↑7%↓2%↑13%↓19%

↑3%↑23%↑12%↑18%↑7%

* Based on 10-mg dose of ezetimibe
1 Post-renal transplant patients with mild impaired or normal renal function. In a different study, a renal transplant patient with severe renal impairment (creatinine clearance of 13.2 mL/min/1.73m2) who was receiving multiple medications, including cyclosporine, demonstrated a 12-fold greater exposure to total ezetimibe compared to healthy subjects.
2 See Drug Interactions (7) 3 Supralox® , 20 mL

Table 11: Effect of Ezetimibe Coadministration on Systemic Exposure to Other Drugs

Coadministered Drug and its Dosage Regimen Ezetimibe Dosage Regimen Change in AUC of Coadministered Drug Change in Cmax of Coadministered 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 and levonorgestrel, QD, 21 days 10 mg QD, Days 8-14 of 21 day oral contraceptive cycle Ethinyl estradiol0%Levonorgestrel0%

Ethinyl estradiol↓9%

Levonorgestrel↓5%

Glipizide, 10 mg on Days 1 and 9 10 mg QD, Days 2-9 ↓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 Drug Interactions (7)

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