Source: FDA, National Drug Code (US) Revision Year: 2014
Plasma cholesterol is derived from intestinal absorption and endogenous synthesis. LIPTRUZET contains ezetimibe and atorvastatin, two lipid-lowering compounds with complementary mechanisms of action.
Ezetimibe reduces blood cholesterol by inhibiting the absorption of cholesterol by the small intestine. The molecular target of ezetimibe has been shown to be the sterol transporter, Niemann-Pick C1-Like 1 (NPC1L1), which is involved in the intestinal uptake of cholesterol and phytosterols. In a 2-week clinical study in 18 hypercholesterolemic patients, ezetimibe inhibited intestinal cholesterol absorption by 54%, compared with placebo. Ezetimibe had no clinically meaningful effect on the plasma concentrations of the fat-soluble vitamins A, D, and E and did not impair adrenocortical steroid hormone production.
Ezetimibe does not inhibit cholesterol synthesis in the liver or increase bile acid excretion. 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; this distinct mechanism is complementary to that of statins [see Clinical Studies (14)].
In animal models, atorvastatin 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 also reduces LDL production and the number of LDL particles.
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 very-low-density lipoproteins (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.
Atorvastatin 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)].
LIPTRUZET has been shown to be bioequivalent to coadministration of corresponding doses of ezetimibe and atorvastatin tablets.
After oral administration, ezetimibe is absorbed and extensively conjugated to a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide).
Maximum plasma atorvastatin concentrations after oral administration occur within 1 to 2 hours. Extent of absorption increases in proportion to atorvastatin 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. Plasma atorvastatin concentrations are lower (approximately 30% for Cmax 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.
When LIPTRUZET 10/80 tablet was administered with a high-fat meal, atorvastatin Cmax decreased by 7% and no effect on atorvastatin AUC was observed. A high-fat meal had no effect on the pharmacokinetics of unconjugated ezetimibe.
LIPTRUZET can be taken with or without food [see Dosage and Administration (2.1)].
Ezetimibe and ezetimibe-glucuronide are highly bound (>90%) to human plasma proteins.
Mean volume of distribution of atorvastatin is approximately 381 liters. Atorvastatin 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 is likely to be secreted in human milk [see Contraindications (4); Use in Specific Populations (8.3)].
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 ezetimibeglucuronide 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 ezetimibeglucuronide. Plasma concentration-time profiles exhibit multiple peaks, suggesting enterohepatic recycling.
Following oral administration of 14C-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.
Atorvastatin is extensively metabolized to ortho- and parahydroxylated derivatives and various betaoxidation products. In vitro inhibition of HMG-CoA reductase by ortho- and parahydroxylated metabolites is equivalent to that of atorvastatin. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites. In vitro studies suggest the importance of atorvastatin metabolism by cytochrome P450 3A4, consistent with increased plasma concentrations of atorvastatin in humans following coadministration with erythromycin, a known inhibitor of this isozyme [see Drug Interactions (7.1)]. In animals, the ortho-hydroxy metabolite undergoes further glucuronidation.
Atorvastatin 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 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 is recovered in urine following oral administration.
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.
Atorvastatin:
Plasma concentrations of atorvastatin are higher (approximately 40% for Cmax 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 (8.4)]
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. Atorvastatin Plasma concentrations of atorvastatin in women differ from those in men (approximately 20% higher for Cmax and 10% lower for AUC); however, there is no clinically significant difference in LDL-C reduction with atorvastatin between men and women.
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.
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 (ChildPugh 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.
Atorvastatin:
In patients with chronic alcoholic liver disease, plasma concentrations of atorvastatin are markedly increased. Cmax and AUC are each 4-fold greater in patients with Child-Pugh A disease. Cmax and AUC are approximately 16-fold and 11-fold increased, respectively, in patients with Child-Pugh B disease [see Contraindications (4)].
[See Warnings and Precautions (5.1), Use in Specific Populations (8.7)]
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 values for total ezetimibe, ezetimibe-glucuronide, and ezetimibe were increased approximately 1.5-fold, compared to healthy subjects (n=9).
Atorvastatin:
Renal disease has no influence on the plasma concentrations or LDL-C reduction of atorvastatin.
Atorvastatin:
While studies have not been conducted in patients with end-stage renal disease, hemodialysis is not expected to significantly enhance clearance of atorvastatin since the drug is extensively bound to plasma proteins.
No clinically significant pharmacokinetic interaction was seen when ezetimibe was coadministered with atorvastatin. Specific pharmacokinetic drug interaction studies with LIPTRUZET have not been performed.
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.
Atorvastatin is metabolized by cytochrome P450 3A4. Concomitant administration of LIPTRUZET with inhibitors of cytochrome P450 3A4 can lead to increases in plasma concentrations of the atorvastatin component of LIPTRUZET. The extent of interaction and potentiation of effects depends on the variability of effect on cytochrome P450 3A4.
Table 5. Effect of Coadministered 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)†,‡ | ↑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 impairment (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 Drug Interactions (7)
§ Supralox, 20 mL
Table 6. 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 & Levonorgestrel, QD, 21 days | 10 mg QD, Days 8-14 of 21 d 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 2-9 | ↓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)
Table 7. Effect of Coadministered Drugs on the Pharmacokinetics of Atorvastatin:
| Coadministered Drug and Dosing Regimen | Atorvastatin | ||
|---|---|---|---|
| Dose (mg) | Change in AUC* | Change in Cmax* | |
| Cyclosporine 5.2 mg/kg/day, stable dose† | 10 mg QD for 28 days | ↑8.7 fold | ↑10.7 fold |
| Tipranavir 500 mg BID/ritonavir 200 mg BID, 7 days† | 10 mg, SD | ↑9.4 fold | ↑8.6 fold |
| Telaprevir 750 mg q8h, 10 days† | 20 mg, SD | ↑7.88 fold | ↑10.6 fold |
| Saquinavir 400 mg BID/ritonavir 400 mg BID, 15 days†,# | 40 mg QD for 4 days | ↑3.9 fold | ↑4.3 fold |
| Clarithromycin 500 mg BID, 9 days† | 80 mg QD for 8 days | ↑4.4 fold | ↑5.4 fold |
| Darunavir 300 mg BID/ritonavir 100 mg BID, 9 days† | 10 mg QD for 4 days | ↑3.4 fold | ↑2.25 fold |
| Itraconazole 200 mg QD, 4 days† | 40 mg, SD | ↑3.3 fold | ↑20% |
| Fosamprenavir 700 mg BID/ritonavir 100 mg BID, 14 days† | 10 mg QD for 4 days | ↑2.53 fold | ↑2.84 fold |
| Fosamprenavir 1400 mg BID, 14 days† | 10 mg QD for 4 days | ↑2.3 fold | ↑4.04 fold |
| Nelfinavir 1250 mg BID, 14 days† | 10 mg QD for 28 days | ↑74% | ↑2.2 fold |
| Grapefruit Juice, 240 mL QD†,‡ | 40 mg, SD | ↑37% | ↑16% |
| Diltiazem 240 mg QD, 28 days | 40 mg, SD | ↑51% | No change |
| Erythromycin 500 mg QID, 7 days | 10 mg, SD | ↑33% | ↑38% |
| Amlodipine 10 mg, single dose | 80 mg, SD | ↑15% | ↓12% |
| Cimetidine 300 mg QD, 4 weeks | 10 mg QD for 2 weeks | ↓Less than 1% | ↓11% |
| Colestipol 10 mg BID, 28 weeks | 40 mg QD for 28 weeks | Not determined | ↓26%§ |
| Maalox TC 30 mL QD, 17 days | 10 mg QD for 15 days | ↓33% | ↓34% |
| Efavirenz 600 mg QD, 14 days | 10 mg for 3 days | ↓41% | ↓1% |
| Rifampin 600 mg QD, 7 days (coadministered)†,¶ | 40 mg, SD | ↑30% | ↑2.7 fold |
| Rifampin 600 mg QD, 5 days (doses separated)†,¶ | 40 mg, SD | ↓80% | ↓40% |
| Gemfibrozil 600 mg BID, 7 days† | 40 mg, SD | ↑35% | ↓Less than 1% |
| Fenofibrate 160 mg QD, 7 days† | 40 mg, SD | ↑3% | ↑2% |
| Boceprevir 800 mg TID, 7 days | 40 mg, SD | ↑2.30 fold | ↑2.66 fold |
* Data given as x-fold change represent a simple ratio between coadministration and atorvastatin alone (i.e., 1-fold = no change). Data given as % change represent % difference relative to atorvastatin alone (i.e., 0% = no change).
† See Warnings and Precautions (5.1) and Drug Interactions (7) for clinical significance.
‡ Greater increases in AUC (up to 2.5 fold) and/or Cmax (up to 71%) have been reported with excessive grapefruit consumption (≥ 750 mL – 1.2 liters per day).
§ Single sample taken 8-16 h post-dose.
¶ Due to the dual interaction mechanism of rifampin, simultaneous coadministration 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.
Table 8. Effect of Atorvastatin on the Pharmacokinetics of Coadministered Drugs:
| Atorvastatin | Coadministered Drug and Dosing Regimen | ||
|---|---|---|---|
| Drug/Dose (mg) | Change in AUC | Change in Cmax | |
| 80 mg QD for 15 days | Antipyrine, 600 mg SD | ↑3% | ↓11% |
| 80 mg QD for 14 days | Digoxin 0.25 mg QD, 20 days* | ↑15% | ↑20% |
| 40 mg QD for 22 days | Oral contraceptive QD, 2 months – norethindrone 1 mg - ethinyl estradiol 35 μg | ↑28% ↑19% | ↑23% ↑30% |
| 10 mg, SD | Tipranavir 500 mg BID/ritonavir 200 mg BID, 7 days | No change | No change |
| 10 mg QD for 4 days | Fosamprenavir 1400 mg BID, 14 days | ↓27% | ↓18% |
| 10 mg QD for 4 days | Fosamprenavir 700 mg BID/ritonavir 100 mg BID, 14 days | No change | No change |
* See Drug Interactions (7) for clinical significance.
No animal carcinogenicity or fertility studies have been conducted with the combination of ezetimibe and atorvastatin. The combination of ezetimibe with atorvastatin did not show evidence of mutagenicity in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with ezetimibe and atorvastatin with or without metabolic activation. There was no evidence of genotoxicity at doses up to 250 mg/kg with the combination of ezetimibe and atorvastatin (1:1) in the in vivo mouse micronucleus test.
A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice.
No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test.
In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (~7 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe).
In a 2-year carcinogenicity study in rats at dose levels of 10, 30, and 100 mg/kg/day, 2 rare tumors were found in muscle in high-dose females: in one, there was a rhabdomyosarcoma and, in another, there was a fibrosarcoma. This dose represents a plasma AUC0-24hr value of approximately 16 times the mean human plasma drug exposure after an 80-mg oral dose.
A 2-year carcinogenicity study in mice given 100, 200, or 400 mg/kg/day resulted in a significant increase in liver adenomas in high-dose males and liver carcinomas in high-dose females. These findings occurred at plasma AUC0-24hr values of approximately 6 times the mean human plasma drug exposure after an 80-mg oral dose.
In vitro, atorvastatin was not mutagenic or clastogenic in the following tests with and without metabolic activation: the Ames test with Salmonella typhimurium and Escherichia coli, the HGPRT forward mutation assay in Chinese hamster lung cells, and the chromosomal aberration assay in Chinese hamster lung cells. Atorvastatin was negative in the in vivo mouse micronucleus test.
Studies in rats performed at doses up to 175 mg/kg (15 times the human exposure) produced no changes in fertility. There was aplasia and aspermia in the epididymis of 2 of 10 rats treated with 100 mg/kg/day of atorvastatin for 3 months (16 times the human AUC at the 80-mg dose); testis weights were significantly lower at 30 and 100 mg/kg and epididymal weight was lower at 100 mg/kg. Male rats given 100 mg/kg/day for 11 weeks prior to mating had decreased sperm motility, spermatid head concentration, and increased abnormal sperm. Atorvastatin caused no adverse effects on semen parameters, or reproductive organ histopathology in dogs given doses of 10, 40, or 120 mg/kg for two years.
In a rat model, where the glucuronide metabolite of ezetimibe (ezetimibe-glucuronide) was administered intraduodenally, the metabolite was as potent as ezetimibe in inhibiting the absorption of cholesterol, suggesting that the glucuronide metabolite had activity similar to the parent drug.
In 1-month studies in dogs given ezetimibe (0.03 to 300 mg/kg/day), the concentration of cholesterol in gallbladder bile increased ~2- to 4-fold. However, a dose of 300 mg/kg/day administered to dogs for one year did not result in gallstone formation or any other adverse hepatobiliary effects. In a 14-day study in mice given ezetimibe (0.3 to 5 mg/kg/day) and fed a low-fat or cholesterol-rich diet, the concentration of cholesterol in gallbladder bile was either unaffected or reduced to normal levels, respectively.
A series of acute preclinical studies was performed to determine the selectivity of ezetimibe for inhibiting cholesterol absorption. Ezetimibe inhibited the absorption of 14C-cholesterol with no effect on the absorption of triglycerides, fatty acids, bile acids, progesterone, ethinyl estradiol, or the fat-soluble vitamins A and D.
In 4- to 12-week toxicity studies in mice, ezetimibe did not induce cytochrome P450 drug metabolizing enzymes. In toxicity studies, a pharmacokinetic interaction of ezetimibe with statins (parents or their active hydroxy acid metabolites) was seen in rats, dogs, and rabbits.
LIPTRUZET reduces total-C, LDL-C, Apo B, TG, and non-HDL-C, and increases HDL-C in patients with hypercholesterolemia.
LIPTRUZET is effective in men and women with hyperlipidemia. Experience in non-Caucasians is limited and does not permit a precise estimate of the magnitude of the effects of LIPTRUZET. In a multicenter, double-blind, placebo-controlled, clinical study in patients with hyperlipidemia, 628 patients were treated for up to 12 weeks and 246 for up to an additional 48 weeks. Patients were randomized to receive placebo, ezetimibe (10 mg), atorvastatin (10 mg, 20 mg, 40 mg, or 80 mg), or coadministered ezetimibe and atorvastatin equivalent to LIPTRUZET (10/10, 10/20, 10/40, and 10/80) in the 12-week study. After completing the 12-week study, patients who agreed to participate in the study extension were assigned to coadministered ezetimibe and atorvastatin equivalent to LIPTRUZET (10/10-10/80) or atorvastatin (10-80 mg/day) for an additional 48 weeks.
The patient population was: 59% female; 85% Caucasian, 6% Black, 3% Asian, 5% Hispanic, 1% American Indian, <1% other; 18 to 86 years of age (mean age 57 years).
Patients receiving all doses of LIPTRUZET were compared to those receiving all doses of atorvastatin. LIPTRUZET lowered total-C, LDL-C, Apo B, TG, and non-HDL-C, and increased HDL-C significantly more than atorvastatin alone. (See Table 9.)
Table 9. Response to LIPTRUZET in Patients with Primary Hyperlipidemia (Mean* % Change from Untreated Baseline† at 12 weeks):
| Treatment (Daily Dose) | N | Total-C [Baseline§] | LDL-C [Baseline§] | Apo B [Baseline§] | TG* [Baseline§] | HDL-C [Baseline§] | Non-HDL-C [Baseline§] |
|---|---|---|---|---|---|---|---|
| Pooled data (All LIPTRUZET doses)‡ | 255 | -41% 267 | -56% 182 | -45% 170 | -33% 165 | +7% [50.8] | -52% 217 |
| Pooled data (All atorvastatin doses)‡ | 248 | -32% 269 | -44% 181 | -36% 168 | -24% 155 | +4% [53.7] | -41% 215 |
| Ezetimibe 10 mg | 65 | -14% 259 | -20% 177 | -15% 167 | -5% 145 | +4% [50.6] | -18% 209 |
| Placebo | 60 | +4% 262 | +4% 180 | +3% 168 | -6% 143 | +4% [50.4] | +4% 212 |
| LIPTRUZET by dose | |||||||
| 10/10 | 65 | -38% 262 | -53% 177 | -43% 165 | -31% 158 | +9% [51.9] | -49% 211 |
| 10/20 | 62 | -39% 269 | -54% 184 | -44% 174 | -30% 165 | +9% [49.3] | -50% 220 |
| 10/40 | 65 | -42% 271 | -56% 184 | -45% 173 | -34% 180 | +5% [51.1] | -52% 220 |
| 10/80 | 63 | -46% 267 | -61% 183 | -50% 169 | -40% 146 | +7% [50.9] | -58% 216 |
| Atorvastatin by dose | |||||||
| 10 mg | 60 | -26% 271 | -37% 185 | -28% 168 | -21% 153 | +6% [53.7] | -34% 217 |
| 20 mg | 60 | -30% 267 | -42% 177 | -34% 164 | -23% 147 | +4% [55.5] | -39% 211 |
| 40 mg | 66 | -32% 266 | -45% 180 | -37% 167 | -24% 159 | +4% [53.0] | -41% 213 |
| 80 mg | 62 | -40% 270 | -54% 184 | -46% 171 | -31% 163 | +3% [52.7] | -51% 218 |
* For triglycerides, median % change from baseline
† Baseline – on no lipid-lowering drug
‡ LIPTRUZET pooled (10/10-10/80) significantly reduced total-C, LDL-C, Apo B, TG, non-HDL-C, and significantly increased HDL-C compared to all doses of atorvastatin pooled (10-80 mg).
§ Baseline units: mg/dL; medians for TG, means for all other values
The changes in lipid endpoints after an additional 48 weeks of treatment with LIPTRUZET (all doses) or with atorvastatin (all doses) were generally consistent with the 12-week data displayed above in the 245 subjects (out of the 576 who completed the 12-week study) who agreed to participate in the study extension.
A multicenter, double-blind, controlled, 14-week study was conducted in 621 patients with heterozygous familial hypercholesterolemia (HeFH), coronary heart disease (CHD), or multiple cardiovascular risk factors (≥2), adhering to an NCEP Step I or stricter diet. All patients received atorvastatin 10 mg for a minimum of 4 weeks prior to randomization. Patients were then randomized to receive either coadministered ezetimibe and atorvastatin (equivalent to LIPTRUZET 10/10) or atorvastatin 20 mg/day monotherapy. Patients who did not achieve their LDL-C target goal after 4 and/or 9 weeks of randomized treatment were titrated to double the atorvastatin dose.
The patient population was: 47% female; 91% Caucasian, 2% Black, 2% Asian, 5% Hispanic, <1% other; 18 to 82 years of age (mean age 61 years).
LIPTRUZET 10/10 was significantly more effective than doubling the dose of atorvastatin to 20 mg in further reducing total-C, LDL-C, TG, and non-HDL-C. Results for HDL-C between the two treatment groups were not significantly different. (See Table 10.) In addition, at Week 4 significantly more patients receiving LIPTRUZET 10/10 attained LDL-C <100 mg/dL (<2.6 mmol/L) compared to those receiving atorvastatin 20 mg, 12% vs. 2%. The baseline mean LDL-C levels for patients receiving LIPTRUZET 10/10 and atorvastatin 20 mg were 186 mg/dL and 187 mg/dL, respectively.
Table 10. Response to LIPTRUZET after 4 Weeks in Patients with CHD or Multiple Cardiovascular Risk Factors and an LDL-C ≥130 mg/dL (Mean* % Change from Baseline†):
| Treatment (Daily Dose) | N | Total-C [Baseline‡] | LDL-C [Baseline‡] | HDL-C [Baseline‡] | TG* [Baseline‡] | Non-HDL-C [Baseline‡] |
|---|---|---|---|---|---|---|
| LIPTRUZET 10/10 | 305 | -17%§ 262 | -24%§ 186 | +2% [50.0] | -9%§ 117 | -22%§ 212 |
| Atorvastatin 20 mg | 316 | -6% 264 | -9% 187 | +1% [49.9] | -4% 119 | -8% 214 |
* For triglycerides, median % change from baseline
† Patients on atorvastatin 10 mg, then switched to LIPTRUZET 10/10 or titrated to atorvastatin 20 mg
‡ Baseline units: mg/dL; medians for TG, means for all other values
§ p<0.05 for difference with atorvastatin
The Titration of Atorvastatin Versus Ezetimibe Add-On to Atorvastatin in Patients with Hypercholesterolemia (TEMPO) study, a multicenter, double-blind, controlled, 6-week study, included 184 patients with an LDL-C level ≥100 mg/dL and ≤160 mg/dL (≥2.6 mmol/L and ≤4.1 mmol/L) and at moderate high risk for coronary heart disease (CHD). All patients received atorvastatin 20 mg for a minimum of 4 weeks prior to randomization. Patients not at the optional NCEP ATP III LDL-C level (<100 mg/dL [<2.6 mmol/L]) were randomized to receive either coadministered ezetimibe and atorvastatin (equivalent to LIPTRUZET 10/20) or atorvastatin 40 mg for 6 weeks.
The patient population was: 45% female; 60% Caucasian, 26% Multi-racial, 6% Black, 8% Asian, <1% American Indian or Alaska native; 24 to 78 years of age (mean age 58 years).
LIPTRUZET 10/20 was significantly more effective than doubling the dose of atorvastatin to 40 mg in further reducing total-C, LDL-C, Apo B and non-HDL-C. Results for HDL-C and TG between the two treatment groups were not significantly different. (See Table 11.) In addition, significantly more patients receiving LIPTRUZET 10/20 attained LDL-C <100 mg/dL (<2.6 mmol/L) compared to those receiving atorvastatin 40 mg, 84% vs. 49%.
Table 11. Response to LIPTRUZET in Patients with Primary Hypercholesterolemia (Mean* % Change from Baseline†):
| Treatment (Daily Dose) | N | Total-C [Baseline‡] | LDL-C [Baseline‡] | Apo B [Baseline‡] | HDL-C [Baseline‡] | TG* [Baseline‡] | Non-HDL-C [Baseline‡] |
|---|---|---|---|---|---|---|---|
| LIPTRUZET 10/20 | 92 | -20%§ 203 | -31%§ 120 | -21%§ 123 | +3% [50.9] | -18% 155 | -27%§ 152 |
| Atorvastatin 40 mg | 92 | -7% 201 | -11% 118 | -8% 120 | +1% [52.1] | -6% 148 | -10% 149 |
* For triglycerides, median % change from baseline
† Patients on atorvastatin 20 mg, then switched to LIPTRUZET 10/20 or titrated to atorvastatin 40 mg
‡ Baseline units: mg/dL; medians for TG, means for all other values
§ p<0.05 for difference with atorvastatin
The Ezetimibe Plus Atorvastatin Versus Atorvastatin Titration in Achieving Lower LDL-C Targets in Hypercholesterolemic Patients (EZ-PATH) study, a multicenter, double-blind, controlled, 6-week study, included 556 patients with an LDL-C level ≥70 mg/dL and ≤160 mg/dL (≥1.8 mmol/L and ≤4.1 mmol/L) and at high risk for coronary heart disease (CHD). All patients received atorvastatin 40 mg for a minimum of 4 weeks prior to randomization. Patients not at the optional NCEP ATP III LDL-C level <70 mg/dL (<1.8 mmol/L) were randomized to receive either coadministered ezetimibe and atorvastatin (equivalent to LIPTRUZET 10/40) or atorvastatin 80 mg for 6 weeks.
The patient population was: 39% female; 81% Caucasian, 11% Black, 6% Multi-racial, 2% Asian; 31 to 80 years of age (mean age 52 years).
LIPTRUZET 10/40 was significantly more effective than doubling the dose of atorvastatin to 80 mg in further reducing total-C, LDL-C, Apo B, TG, and non-HDL-C. Results for HDL-C between the two treatment groups were not significantly different. (See Table 12.) In addition, significantly more patients receiving LIPTRUZET 10/40 attained LDL-C <70 mg/dL (<1.8 mmol/L) compared to those receiving atorvastatin 80 mg, 74% vs. 32%.
Table 12. Response to LIPTRUZET in Patients with Primary Hypercholesterolemia (Mean* % Change from Baseline†):
| Treatment (Daily Dose) | N | Total-C [Baseline‡] | LDL-C [Baseline‡] | Apo B [Baseline‡] | HDL-C [Baseline‡] | TG* [Baseline‡] | Non-HDL-C [Baseline‡] |
|---|---|---|---|---|---|---|---|
| LIPTRUZET 10/40 | 277 | -17%§ 165 | -27%§ 89 | -18%§ 101 | 0% [47.7] | -12%§ 131 | -23%§ 117 |
| Atorvastatin 80 mg | 279 | -7% 165 | -11% 90 | -8% 102 | -1% [46.9] | -6% 136 | -9% 118 |
* For triglycerides, median % change from baseline
† Patients on atorvastatin 20 mg, then switched to LIPTRUZET 10/40 or titrated to atorvastatin 80 mg
‡ Baseline units: mg/dL; medians for TG, means for all other values
§ p<0.05 for difference with atorvastatin
A double-blind, randomized, 12-week study was performed in patients with a clinical and/or genotypic diagnosis of HoFH. Data were analyzed from a subgroup of patients (n=36) receiving atorvastatin 40 mg at baseline. Increasing the dose of atorvastatin from 40 to 80 mg (n=12) produced a reduction of LDL-C of 2% from baseline on atorvastatin 40 mg. Coadministered ezetimibe and atorvastatin equivalent to LIPTRUZET (10/40 and 10/80 pooled, n=24), produced a reduction of LDL-C of 19% from baseline on atorvastatin 40 mg. In those patients coadministered ezetimibe and atorvastatin equivalent to LIPTRUZET (10/80, n=12), a reduction of LDL-C of 25% from baseline on atorvastatin 40 mg was produced.
After completing the 12-week study, eligible patients (n=35), who were receiving atorvastatin 40 mg at baseline, were assigned to coadministered ezetimibe and atorvastatin equivalent to LIPTRUZET 10/40 for up to an additional 24 months. Following at least 4 weeks of treatment, the atorvastatin dose could be doubled to a maximum dose of 80 mg.
At the end of the 24 months, LIPTRUZET (10/40 and 10/80 pooled) produced a reduction of LDL-C that was consistent with that seen in the 12-week study.
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