EZALLOR SPRINKLE (Page 4 of 8)

8.2 Lactation

Risk Summary

EZALLOR Sprinkle use is contraindicated during breastfeeding [see Contraindications (4)]. Limited data indicate that rosuvastatin is present in human milk. There is no available information on the effects of the drug on the breastfed infant or the effects of the drug on milk production. Because of the potential for serious adverse reactions in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with EZALLOR Sprinkle.

8.3 Females and Males of Reproductive Potential

Contraception

EZALLOR Sprinkle may cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with EZALLOR Sprinkle.

8.4 Pediatric Use

Pediatric use information for patients 7 to 17 years of age is approved for AstraZeneca’s CRESTOR (rosuvastatin calcium) tablets. However, due to AstraZeneca’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

8.5 Geriatric Use

Of the 10,275 patients in clinical studies with rosuvastatin, 3,159 (31%) were 65 years and older, and 698 (6.8%) were 75 years and older. 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 individuals cannot be ruled out.

Elderly patients are at higher risk of myopathy and EZALLOR Sprinkle should be prescribed with caution in the elderly [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

8.6 Renal Impairment

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 and dose adjustment is required [see Dosage and Administration (2.4), Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

EZALLOR Sprinkle is contraindicated in patients with active liver disease, which may include unexplained persistent elevations of hepatic transaminase levels. Chronic alcohol liver disease is known to increase rosuvastatin exposure; EZALLOR Sprinkle should be used with caution in these patients [see Contraindications (4), Warning and Precautions (5.3) and Clinical Pharmacology (12.3)].

8.8 Asian Patients

Pharmacokinetic studies have demonstrated an approximate 2-fold increase in median exposure to rosuvastatin in Asian subjects when compared with Caucasian controls. EZALLOR Sprinkle dosage should be adjusted in Asian patients [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

10 OVERDOSAGE

There is no specific treatment in the event of overdose. In the event of overdose, the patient should be treated symptomatically and supportive measures instituted as required. Hemodialysis does not significantly enhance clearance of rosuvastatin.

11 DESCRIPTION

Rosuvastatin calcium is a synthetic lipid-lowering agent for oral administration.

The chemical name for rosuvastatin calcium is bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino] pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxyhept-6-enoic acid] calcium salt with the following structural formula:

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

The molecular formula for rosuvastatin calcium is (C22 H27 FN3 O6 S)2 · Ca and the molecular weight is 1,001.14. Rosuvastatin calcium is off-white to light yellow amorphous powder that is slightly soluble in water and methanol, and insoluble in ethanol. Rosuvastatin calcium is a hydrophilic compound with a partition coefficient (octanol/water) of 0.13 at pH of 7.

Each rosuvastatin capsule for oral administration contains 5 mg, 10 mg, 20 mg, or 40 mg of rosuvastatin (present as 5.198 mg, 10.395 mg, 20.790 mg, or 41.580 mg of rosuvastatin calcium) in the form of granules with the following inactive ingredients: microcrystalline cellulose, crospovidone, mannitol, magnesium oxide, ferric oxide, sodium citrate, hypromellose, polyethylene glycol 4000, and silicon dioxide. The capsule shells have the following inactive ingredients: gelatin, titanium dioxide, water, and sodium lauryl sulfate. Additionally following colorants are used in capsules: FD&C Red 40 (5 mg), FD&C Blue 1 (5 mg, 10 mg, 20 mg), D&C Red 28 (5 mg, 10 mg), FD&C Red 3 (20 mg), and FD&C Green 3 (40 mg). The imprinting black ink contains shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonia solution, black iron oxide, purified water, and potassium hydroxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Rosuvastatin is a selective and competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, a precursor of cholesterol. In vivo studies in animals, and in vitro studies in cultured animal and human cells have shown rosuvastatin to have a high uptake into, and selectivity for, action in the liver, the target organ for cholesterol lowering. 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.

12.2 Pharmacodynamics

Rosuvastatin dose dependently reduces elevated LDL-cholesterol and reduces total cholesterol and triglycerides and increases HDL-cholesterol [see Clinical Studies (14)]. A therapeutic response to rosuvastatin is evident within 1 week of commencing therapy and 90% of maximum response is usually achieved in 2 weeks. The maximum response is usually achieved by 4 weeks and is maintained after that. Individualization of drug dosage should be based on the therapeutic response [see Dosage and Administration (2)].

12.3 Pharmacokinetics

Absorption

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%.

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

The AUC of rosuvastatin does not differ following evening or morning drug administration.

Distribution

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.

Elimination

Rosuvastatin is primarily eliminated by excretion in the feces. The elimination half-life of rosuvastatin is approximately 19 hours.

Metabolism

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.

Excretion

Following oral administration, rosuvastatin and its metabolites are primarily excreted in the feces (90%).

After an intravenous dose, approximately 28% of total body clearance was via the renal route, and 72% by the hepatic route.

Specific Populations

Racial or Ethnic Groups

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.

Male and Female Patients

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

Geriatric Patients

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

Patients with Renal Impairment

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).

Hemodialysis

Steady-state plasma concentrations of rosuvastatin in patients on chronic hemodialysis were approximately 50% greater compared with healthy volunteer subjects with normal renal function.

Patients with Hepatic Impairment

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.

Drug Interaction Studies

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 organic anion-transporting polyproteins (OATP1B1, OATP1B3) and efflux transporter breast cancer resistance protein (BCRP). Concomitant administration of rosuvastatin with medications that are inhibitors of these transporter proteins (e.g., cyclosporine, certain HIV protease inhibitors) may result in increased rosuvastatin plasma concentrations [see Dosage and Administration (2.3) and Drug Interactions (7.1, 7.3)].

Table 4. Effect of Coadministered Drugs on Rosuvastatin Systemic Exposure

Coadministered drug and dosing regimen Rosuvastatin
Mean Ratio (ratio with/without coadministered drug) No Effect = 1
Dose (mg)1 Change in AUC Change in Cmax
Sofosbuvir/velpatasvir/voxilaprevir (400 mg-100 mg-100 mg) + Voxilaprevir (100 mg) once daily for 15 days 10 mg single dose 7.392 (6.68 to 8.18) 3 18.882 (16.23 to 21.96) 3
Cyclosporine — stable dose required(75 mg to 200 mg BID) 10 mg QD for 10 days 7.12 112
Darolutamide 600 mg BID, 5 days 5mg, single dose 5.22 ~52
Regorafenib 160mg OD, 14 days 5 mg single dose 3.82 4.62
Atazanavir/ritonavir combination 300 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 to 3.4)3 3.22 (2.6 to 3.9)3
Velpatasvir 100mg once daily 10 mg single dose 2.692 (2.46 to 2.94) 3 2.612 (2.32 to 2.92)3
Ombitasvir 25mg/paritaprevir 150mg/ ritonavir 100mg + dasabuvir 400mg BID 5mg single dose 2.592 (2.09 to 3.21) 3 7.132 (5.11 to 9.96)3
Elbasvir 50mg/grazoprevir 200mg once daily 10mg single dose 2.262 (1.89 to 2.69) 3 5.492 (4.29 to 7.04)3
Glecaprevir 400mg/pibrentasvir 120mg once daily 5mg once daily 2.152 (1.88 to 2.46) 3 5.622 (4.80 to 6.59)3
Lopinavir/ritonavir combination 400 mg/100 mg BID for 17 days 20 mg QD for 7 days 2.12 (1.7 to 2.6)3 52 (3.4 to 6.4)3
Gemfibrozil 600 mg BID for 7 days 80 mg 1.92 (1.6 to 2.2)3 2.22 (1.8 to 2.7)3
Eltrombopag 75 mg QD, 5 days 10 mg 1.6 (1.4 to 1.7)3 2 (1.8 to 2.3)3
Darunavir 600 mg/ritonavir 100 mg BID, 7 days 10 mg QD for 7 days 1.5 (1 to 2.1)3 2.4 (1.6 to 3.6)3
Tipranavir/ritonavir combination 500 mg/200mg BID for 11 days 10 mg 1.4 (1.2 to 1.6)3 2.2 (1.8 to 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 to 1.6)3 1.3 (1.1 to 1.4)3 1.4 (1.2 to 1.5)3 1.2 (0.9 to 1.4)3
Ezetimibe 10 mg QD, 14 days 10 mg QD for 14 days 1.2 (0.9 to 1.6)3 1.2(0.8 to 1.6)3
Fosamprenavir/ritonavir 700 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 to 1.3)3
Rifampicin 450 mg QD, 7 days 20 mg
Aluminum & magnesium hydroxide combination antacidAdministered simultaneouslyAdministered 2 hours apart 40 mg40 mg 0.52 (0.4 to 0.5)3 0.8(0.7 to 0.9)3 0.52 (0.4 to 0.6)3 0.8 (0.7 to 1)3
Ketoconazole 200 BID for 7 days 80 mg 1(0.8 to 1.2)3 1(0.7 to 1.3)3
Fluconazole 200 mg QD for 11 days 80 mg 1.1 (1 to 1.3)3 1.1(0.9 to 1.4)3
Erythromycin 500 mg QID for 7 days 80 mg 0.8 (0.7 to 0.9)3 0.7 (0.5 to 0.9)3

1 Single dose unless otherwise noted.

2 Clinically significant [see Dosage and Administration (2) and Warnings and Precautions (5)]
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)

QD: Once daily

BID: 2 times a day

TID: 3 times a day

QID: 4 times a day

Table 5. Effect of Rosuvastatin Coadministration on Systemic Exposure to Other Drugs

Rosuvastatin Dosage Regimen Coadministered Drug
Mean Ratio (ratio with/without coadministered drug) No Effect = 1
Name and Dose Change in AUC Change in Cmax
40 mg QD for 10 days Warfarin1 25 mg single dose R-Warfarin 1(1 to 1.1)2 S-Warfarin 1.1 (1 to 1.1)2 R-Warfarin 1(0.9 to 1)2 S-Warfarin 1 (0.9 to 1.1)2
40 mg QD for 12 days Digoxin 0.5 mg single dose 1 (0.9 to 1.2)2 1(0.9 to 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 to 1.3)2 NG 1.3(1.3 to 1.4)2 EE 1.3 (1.2 to 1.3)2 NG 1.2 (1.1 to 1.3)2

EE = ethinyl estradiol, NG = norgestrel

1 Clinically significant pharmacodynamic effects [see Warnings and Precautions (5.4)]

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)

QD: Once daily

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