Rosuvastatin Calcium (Page 5 of 8)
Rosuvastatin 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 rosuvastatin.
8.3 Females and Males of Reproductive Potential
Rosuvastatin 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 rosuvastatin.
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, 3159 (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 rosuvastatin 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 (CL cr ≥ 30 mL/min/1.73 m 2). Exposure to rosuvastatin is increased to a clinically significant extent in patients with severe renal impairment (CL cr < 30 mL/min/1.73 m 2) who are not receiving hemodialysis and dose adjustment is required [see Dosage and Administration (2.5) , Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)] .
8.7 Hepatic Impairment
Rosuvastatin 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; rosuvastatin should be used with caution in these patients [see Contraindications (4) , Warning and Precautions (5.2) 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. Rosuvastatin dosage should be adjusted in Asian patients [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)] .
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.
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:
The empirical formula for rosuvastatin calcium is (C 22 H 27 FN 3 O 6 S) 2 Ca and the molecular weight is 1001.14. 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.
Rosuvastatin calcium tablets for oral administration contain 5, 10, 20, or 40 mg of rosuvastatin and the following inactive ingredients: Each tablet contains: anhydrous dibasic calcium phosphate, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, microscrystalline cellulose, titanium dioxide, and triacetin; in addition, the 5 mg and 40 mg strengths contain ferric oxide red, and the 10 mg and 20 mg strength contain ferric oxide yellow.
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.
Rosuvastatin calcium 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 calcium 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)] .
In clinical pharmacology studies in man, peak plasma concentrations of rosuvastatin were reached 3 to 5 hours following oral dosing. Both C max 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.
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.
Rosuvastatin is primarily eliminated by excretion in the feces. The elimination half-life of rosuvastatin is approximately 19 hours.
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%).
After an intravenous dose, approximately 28% of total body clearance was via the renal route, and 72% by the hepatic route.
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 C max ) 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.
Pediatric use information for patients ages 8 to less than 10 years 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.
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 (CL cr ≥ 30 mL/min/1.73 m 2) 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 (CL cr < 30 mL/min/1.73 m 2) not receiving hemodialysis compared with healthy subjects (CL cr > 80 mL/min/1.73 m 2).
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, C max and AUC were increased by 60% and 5%, respectively, as compared with patients with normal liver function. In patients with Child-Pugh B disease, C max and AUC were increased 100% and 21%, respectively, compared with patients with normal liver function.
Drug Interactions 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 transporter organic anion-transporting polyprotein 1B1 (OATP1B1) 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 (2.4) 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 = 1.0
|Dose (mg) 1||Change in AUC||Change in C max|
|Sofosbuvir/velpatasvir/voxilaprevir (400 mg-100 mg-100 mg) + Voxilaprevir (100 mg) once daily for 15 days||10mg single dose||7.39 2 (6.68-8.18) 3||18.88 2 (16.23-21.96) 3|
Cyclosporine – stable dose required (75 mg — 200 mg BID)
10 mg QD for 10 days
|7.1 2||11 2|
|Darolutamide 600 mg BID, 5 days||5mg, single dose||5.2 2||~5 2|
|Regorafenib 160mg OD, 14 days||5 mg single dose||3.8 2||4.6 2|
|Atazanavir/ritonavir combination 300 mg/100 mg QD for 8 days||10 mg||3.1 2||7 2|
|Simeprevir 150 mg QD, 7 days||10 mg, single dose|| |
2.8 2 (2.3-3.4) 3
|3.2 2 (2.6-3.9) 3|
|Velpatasvir 100mg once daily||10 mg single dose||2.69 2 (2.46-2.94) 3||2.61 2 (2.32-2.92) 3|
|Ombitasvir 25mg/paritaprevir 150mg/ ritonavir 100mg + dasabuvir 400mg BID||5mg single dose||2.59 2 (2.09-3.21) 3||7.13 2 (5.11-9.96) 3|
|Elbasvir 50mg/grazoprevir 200mg once daily||10mg single dose||2.26 2 (1.89-2.69) 3||5.49 2 (4.29-7.04) 3|
|Glecaprevir 400mg/pibrentasvir 120mg once daily||5mg once daily||2.15 2 (1.88-2.46) 3||5.62 2 (4.80-6.59) 3|
|Lopinavir/ritonavir combination 400 mg/100 mg BID for 17 days|| |
20 mg QD for
|2.1 2 (1.7-2.6) 3||5 2 (3.4-6.4) 3|
|Gemfibrozil 600 mg BID for 7 days||80 mg||1.9 2 (1.6-2.2) 3||2.2 2 (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 combination 500 mg/200mg 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/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 (1.1-1.3) 3|
|Rifampicin 450 mg QD, 7 days||20 mg||↔|
|Aluminum & magnesium hydroxide combination antacid Administered simultaneously Administered 2 hours apart|| |
|0.5 2 (0.4-0.5) 3 0.8 (0.7-0.9) 3||0.5 2 (0.4-0.6) 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) 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)
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 = 1.0|
|Name and Dose||Change in AUC||Change in C max|
|40 mg QD for 10 days||Warfarin 1 25 mg single dose||R- Warfarin 1.0 (1.0-1.1) 2 S-Warfarin 1.1 (1.0-1.1) 2||R-Warfarin 1.0 (0.9-1.0) 2 S-Warfarin 1.0 (0.9-1.1) 2|
|40 mg QD for 12 days||Digoxin 0.5 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 Warnings and Precautions (5.3)]
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)
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