EZETIMIBE AND SIMVASTATIN- ezetimibe and simvastatin tablet
Glenmark Pharmaceuticals Inc., USA
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HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use EZETIMIBE AND SIMVASTATIN TABLETS safely and effectively. See full prescribing information for EZETIMIBE AND SIMVASTATIN TABLETS.
EZETIMIBE AND SIMVASTATIN tablets, for oral use Initial U.S. Approval: 2004 RECENT MAJOR CHANGESINDICATIONS AND USAGEEzetimibe and simvastatin tablets are combination of simvastatin and ezetimibe indicated: (1) • As an adjunct to diet to reduce elevated low density lipoprotein cholesterol (LDL-C): o In adults with primary hyperlipidemia. o In adults and pediatric patients aged 10 years and older with heterozygous familial hypercholesterolemia (HeFH). • As an adjunct to other LDL-C lowering therapies to reduce LDL-C in adults with homozygous familial hypercholesterolemia (HoFH). Simvastatin Simvastatin, when used as a component of ezetimibe and simvastatin tablets, is indicated to reduce the risk of total mortality by reducing risk of coronary heart disease death, non-fatal myocardial infarction and stroke, and the need for coronary and non-coronary revascularization procedures in adults with established coronary heart disease, cerebrovascular disease, peripheral vascular disease, and/or diabetes, who are at high risk of coronary heart disease events. DOSAGE AND ADMINISTRATION
DOSAGE FORMS AND STRENGTHS
CONTRAINDICATIONS
WARNINGS AND PRECAUTIONS
ADVERSE REACTIONS
To report SUSPECTED ADVERSE REACTIONS, contact Glenmark Pharmaceuticals Inc., USA at 1 (888) 721-7115 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS• See full prescribing information for details regarding concomitant use of ezetimibe and simvastatin tablets with other drugs or grapefruit juice that increase the risk of myopathy and rhabdomyolysis. (2.3, 7.1) •Cholestyramine : Combination decreases exposure of ezetimibe. (2.3, 7.2) •Coumarin Anticoagulants : Obtain INR before ezetimibe and simvastatin tablets initiation and monitor INR during ezetimibe and simvastatin tablets dosage initiation or adjustment. (7.3) •Digoxin : During ezetimibe and simvastatin tablets initiation, monitor digoxin levels. (7.3) •Fenofibrates : Combination increases exposure of ezetimibe. If cholelithiasis is suspected in a patient receiving ezetimibe and a fenofibrate, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered. (7.3, 12.3) USE IN SPECIFIC POPULATIONSSee 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 3/2024 |
Simvastatin
Simvastatin, when used as a component of ezetimibe and simvastatin tablets, is indicated to reduce the risk of total mortality by reducing risk of coronary heart disease death, non-fatal myocardial infarction and stroke, and the need for coronary and non-coronary revascularization procedures in adults with established coronary heart disease, cerebrovascular disease, peripheral vascular disease, and/or diabetes, who are at high risk of coronary heart disease events.
The recommended dosage range of ezetimibe and simvastatin tablets 10/10 mg to 10/40 mg once a day.
The recommended dosage range of ezetimibe and simvastatin tablets 10/10 mg to 10/40 mg once a day.
Ezetimibe and simvastatin tablets are contraindicated in the following conditions:
The following serious adverse reactions are discussed in greater detail in other sections of the label:
Ezetimibe and Simvastatin Tablets
% Placebo N = 371 | % Ezetimibe 10 mg N = 302 | % Simvastatin†
(%) N = 1234 | % Ezetimibe and Simvastatin Tablets†
N = 1420 |
|
---|---|---|---|---|
Headache |
5.4 |
6 |
5.9 |
5.8 |
Upper respiratory tract infection |
2.7 |
5 |
5 |
3.6 |
Myalgia |
2.4 |
2.3 |
2.6 |
3.6 |
Diarrhea |
2.2 |
5 |
3.7 |
2.8 |
Pain in extremity |
1.3 |
3 |
2 |
2.3 |
Influenza |
0.8 |
1 |
1.9 |
2.3 |
* Includes two placebo-controlled combination studies in which the active ingredients equivalent to ezetimibe and simvastatin tablets were coadministered and two placebo-controlled studies in which ezetimibe and simvastatin tablets was administered.
†All doses.
Study of Heart and Renal Protection
In SHARP, 9270 patients were allocated to ezetimibe and simvastatin tablets 10/20 mg daily (n=4650) or placebo (n=4620) for a median follow-up period of 4.9 years. The proportion of patients who permanently discontinued trial treatment as a result of either an adverse event or abnormal safety blood result was 10.4% vs. 9.8% among patients allocated to ezetimibe and simvastatin tablets and placebo, respectively. Comparing those allocated to ezetimibe and simvastatin tablets vs. placebo, the incidence of myopathy (defined as unexplained muscle weakness or pain with a serum CK >10 times ULN) was 0.2% vs. 0.1% and the incidence of rhabdomyolysis (defined as myopathy with a CK >40 times ULN) was 0.09% vs. 0.02%, respectively. Consecutive elevations of transaminases (>3 X ULN) occurred in 0.7% vs. 0.6%, respectively. Patients were asked about the occurrence of unexplained muscle pain or weakness at each trial visit: 21.5% vs. 20.9% patients ever reported muscle symptoms in the ezetimibe and simvastatin tablets and placebo groups, respectively. Cancer was diagnosed during the trial in 9.4% vs. 9.5% of patients assigned to ezetimibe and simvastatin tablets and placebo, respectively.
Ezetimibe
Other adverse reactions reported with ezetimibe in placebo-controlled studies, regardless of causality assessment: Musculoskeletal system disorders: arthralgia; Infections and infestations: sinusitis; Body as a whole – general disorders: fatigue.
Simvastatin
Laboratory Tests
Marked persistent increases of hepatic serum transaminases have been noted [see Warnings and Precautions (5.3)]. Elevated alkaline phosphatase and γ-glutamyl transpeptidase have been reported. About 5% of patients taking simvastatin had elevations of CK levels of 3 or more times the normal value on one or more occasions. This was attributable to the noncardiac fraction of CK [see Warnings and Precautions (5.1)].
Ezetimibe and simvastatin tablets
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Table 4 presents ezetimibe and simvastatin tablets effect on other drugs and instructions for preventing or managing them.
Table 4: Ezetimibe and Simvastatin Tablets Effects on Other Drugs
Coumarin Anticoagulants |
|
Clinical Impact: |
Ezetimibe and simvastatin tablets may potentiate the effect of coumarin anticoagulants and increase the INR. The concomitant use of simvastatin (20 to 40 mg) and coumarin anticoagulants increased the INR from a baseline of 1.7 to 1.8 in healthy subjects and from 2.6 to 3.4 in patients with hyperlipidemia. There are postmarketing reports of clinically evident bleeding and/or increased INR in patients taking concomitant statins (with or without ezetimibe) and coumarin anticoagulants. |
Intervention: |
In patients taking coumarin anticoagulants, obtain an INR before starting ezetimibe and simvastatin tablets and frequently enough after initiation, dose titration, or discontinuation to ensure that no significant alteration in INR occurs. Once the INR is stable, monitor INR at regularly recommended intervals. |
Digoxin |
|
Clinical Impact: |
Concomitant use of digoxin with ezetimibe and simvastatin tablets may result in elevated plasma digoxin concentrations [see Clinical Pharmacology (12.3)]. |
Intervention: |
Monitor digoxin levels in patients taking digoxin when ezetimibe and simvastatin tablets is initiated. |
Fenofibrates |
|
Clinical Impact: |
Both ezetimibe and fenofibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. |
Intervention: |
If cholelithiasis is suspected in a patient receiving ezetimibe and simvastatin tablets and a fenofibrate, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered [see the product labeling for fenofibrate and fenofibric acid]. |
Ezetimibe and simvastatin tablets
The safety and effectiveness of ezetimibe in combination with a statin as an adjunct to diet to reduce LDL-C have been established in pediatric patients 10 years of age and older with HeFH. Use of ezetimibe and simvastatin tablets for this indication is based on a double-blind, placebo-controlled clinical trial in 248 pediatric patients (142 males and 106 postmenarchal females) 10 years of age and older with HeFH [see Clinical Studies (14)]. In this limited controlled trial, there was no significant effect on growth or sexual maturation in the adolescent males or females, or on menstrual cycle length in females.
The safety and effectiveness of ezetimibe and simvastatin tablets have not been established in pediatric patients younger than 10 years of age with HeFH, or in pediatric patients with other types of hyperlipidemia.
In a clinical trial in which patients at high risk of CVD were treated with simvastatin 40 mg/day (median follow-up 3.9 years), the incidence of myopathy was approximately 0.05% for non-Chinese patients (n=7367) compared with 0.24% for Chinese patients (n=5468). In this trial the incidence of myopathy for Chinese patients on simvastatin 40 mg/day or ezetimibe and simvastatin 10/40 mg/day coadministered with extended-release niacin 2 g/day was 1.24%.
Chinese patients may be at higher risk for myopathy, monitor these patients appropriately. Coadministration of ezetimibe and simvastatin tablets with lipid-modifying doses of niacin-containing products (≥1 g/day niacin) is not recommended in Chinese patients [see Warnings and Precautions (5.1) and Drug Interactions (7.1)].
No specific antidotes for ezetimibe and simvastatin tablets are known. In the event of an overdose with ezetimibe and simvastatin tablets, consider contacting the Poison Help Line (1-800-222-1222) or a medical toxicologist for overdosage management recommendations.
Ezetimibe and Simvastatin Tablets contain ezetimibe, a selective inhibitor of intestinal cholesterol and related phytosterol absorption, and simvastatin, an HMG-CoA reductase inhibitor.
The chemical name of ezetimibe is 1-(4-fluorophenyl)-3(R)-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4(S)-(4-hydroxyphenyl)-2-azetidinone. The molecular formula is C24H21F2NO3 and its molecular weight is 409.44 g/mol.
Ezetimibe is a white, crystalline powder that is freely soluble in ethanol, methanol and acetone and practically insoluble in water. Its structural formula is:
Simvastatin, an inactive lactone, is hydrolyzed to the corresponding β-hydroxyacid form, which is an inhibitor of HMG-CoA reductase. Simvastatin is butanoic acid, 2,2-dimethyl-,1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)-ethyl]-1-naphthalenyl ester, [1S-[1α,3α,7α,8α(2S*,4S*),-8aβ]]. The molecular formula of simvastatin is C25H38O5 and its molecular weight is 418.57 g/mol.
Simvastatin is a white to off-white, nonhygroscopic powder that is freely soluble in chloroform, methanol and alcohol, sparingly soluble in propylene glycol, very slightly soluble in hexane and practically insoluble in water. Its structural formula is:
Ezetimibe and Simvastatin Tablets are available for oral use as tablets containing 10 mg of ezetimibe, and 10 mg of simvastatin (Ezetimibe and Simvastatin Tablets 10 mg/10 mg), 20 mg of simvastatin (Ezetimibe and Simvastatin Tablets 10 mg/20 mg), 40 mg of simvastatin (Ezetimibe and Simvastatin Tablets 10 mg/40 mg), or 80 mg of simvastatin (Ezetimibe and Simvastatin Tablets 10 mg/80 mg). Each tablet contains the following inactive ingredients: butylated hydroxyanisole, citric acid monohydrate, croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, propyl gallate, and sodium lauryl sulfate.
Ezetimibe and Simvastatin Tablets
Plasma cholesterol is derived from intestinal absorption and endogenous synthesis. Ezetimibe and simvastatin tablets contain ezetimibe and simvastatin, two lipid-lowering compounds with complementary mechanisms of action.
Ezetimibe
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.
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.
Simvastatin
Coadministered Drug and Dosing Regimen | Total Ezetimibe | |
---|---|---|
Change in AUC | Change in Cmax | |
Cyclosporine-stable dose required (75 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 trial, 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 6 displays the effects 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 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 | |||
|
10 mg QD, 7 days |
↑19% |
↑3% |
|
10 mg QD, 14 days |
↓20% |
↓24% |
|
10 mg QD, 14 days |
↓4% |
↑7% |
|
10 mg QD, 14 days |
↑19% |
↑17% |
|
10 mg QD, 14 days |
↓39% |
↓27% |
* See 7. Drug Interactions.
Table 7 displays the effects of coadminstration drugs or grapefruit juice on simvastatin systemic exposure [see Drug Interactions (7)].
Coadministered Drug or Grapefruit Juice | Dosing of Coadministered Drug or Grapefruit Juice | Dosing of Simvastatin | Geometric Mean Ratio
(Ratio with / without coadministered drug) No Effect = 1 |
||
---|---|---|---|---|---|
AUC | Cmax | ||||
Telithromycin† |
200 mg QD for 4 days |
80 mg |
simvastatin acid simvastatin |
12 8.9 |
15 5.3 |
Nelfinavir† |
1250 mg BID for 14 days |
20 mg QD for 28 days |
simvastatin acid simvastatin |
|
|
Itraconazole† |
200 mg QD for 4 days |
80 mg |
simvastatin acid simvastatin |
13.1 13.1 |
|
Posaconazole |
100 mg (oral suspension) QD for 13 days |
40 mg
|
simvastatin acid simvastatin simvastatin |
7.3 10.3 8.5 10.6 |
9.2 9.4 9.5 11.4 |
Gemfibrozil |
600 mg BID for 3 days |
40 mg |
simvastatin acid simvastatin |
2.85 1.35 |
2.18 0.91 |
Grapefruit Juice§ (high dose) |
200 mL of double-strength TID¶ |
60 mg single dose |
simvastatin acid simvastatin |
7 16 | |
Grapefruit Juice§ (low dose) |
8 oz (about 237 mL) of single-strength# |
20 mg single dose |
simvastatin acid simvastatin |
1.3 1.9 | |
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 simvastatin |
2.3 2.5 |
2.4 2.1 |
Diltiazem |
120 mg BID for 10 days |
80 mg on Day 10 |
simvastatin acid simvastatin |
2.69 3.10 |
2.69 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 simvastatin |
1.96 3.90 |
2.14 3.75 |
Amiodarone |
400 mg QD for 3 days |
40 mg on Day 3 |
simvastatin acid simvastatin |
1.75 1.76 |
1.72 1.79 |
Amlodipine |
10 mg QD for 10 days |
80 mg on Day 10 |
simvastatin acid simvastatin |
1.58 1.77 |
1.56 1.47 |
Ranolazine SR |
1000 mg BID for 7 days |
80 mg on Day 1 and Days 6 to 9 |
simvastatin acid simvastatin |
2.26 1.86 |
2.28 1.75 |
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 |
|||
Fenofibrate |
160 mg QD for 14 days |
80 mg QD on Days 8 to 14 |
simvastatin acid simvastatin |
0.64 0.89 |
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 |
* 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.
Ezetimibe and Simvastatin Tablets
Ezetimibe and Simvastatin Tablets
Ezetimibe and simvastatin tablets reduces LDL-C in adult patients with primary hyperlipidemia. Maximal to near maximal response is generally achieved within 2 weeks and maintained during chronic therapy.
Ezetimibe and simvastatin tablets are effective in males and females with primary hyperlipidemia. There were insufficient numbers of patients who self-identified as Black or African American, Asian, or other races to determine if these patients responded differently than White patients.
Five multicenter, double-blind trials conducted with either ezetimibe and simvastatin tablets or coadministered ezetimibe and simvastatin equivalent to ezetimibe and simvastatin tablets in patients with primary hyperlipidemia are reported: two were comparisons with simvastatin, two were comparisons with atorvastatin, and one was a comparison with rosuvastatin.
In a multicenter, double-blind, placebo-controlled, 12-week trial, 1528 patients with primary hyperlipidemia were randomized to one of ten treatment groups: placebo, ezetimibe (10 mg), simvastatin (10 mg, 20 mg, 40 mg, or 80 mg), or ezetimibe and simvastatin tablets (10/10, 10/20, 10/40, or 10/80).
When patients receiving ezetimibe and simvastatin tablets were compared to those receiving all doses of simvastatin, ezetimibe and simvastatin tablets significantly lowered total-C, LDL-C, Apo B, TG, and non-HDL-C. The effects of ezetimibe and simvastatin tablets on HDL-C were similar to the effects seen with simvastatin. Further analysis showed ezetimibe and simvastatin tablets significantly increased HDL-C compared with placebo. (See Table 8.) The lipid response to ezetimibe and simvastatin tablets was similar in patients with TG levels greater than or less than 200 mg/dL.
Treatment
(Daily Dose) | N | Total-C | LDL-C | Apo B | HDL-C | TG | Non-HDL-C |
---|---|---|---|---|---|---|---|
Pooled data (All Ezetimibe and Simvastatin Tablets doses) |
609 |
-38 |
-53 |
-42 |
+7 |
-24 |
-49 |
Pooled data (All simvastatin doses)‡ |
622 |
-28 |
-39 |
-32 |
+7 |
-21 |
-36 |
Ezetimibe 10 mg |
149 |
-13 |
-19 |
-15 |
+5 |
-11 |
-18 |
Placebo |
148 |
-1 |
-2 |
0 |
0 |
-2 |
-2 |
Ezetimibe and Simvastatin Tablets by dose | |||||||
10/10 |
152 |
-31 |
-45 |
-35 |
+8 |
-23 |
-41 |
10/20 |
156 |
-36 |
-52 |
-41 |
+10 |
-24 |
-47 |
10/40 |
147 |
-39 |
-55 |
-44 |
+6 |
-23 |
-51 |
10/80 |
154 |
-43 |
-60 |
-49 |
+6 |
-31 |
-56 |
Simvastatin by dose | |||||||
10 mg |
158 |
-23 |
-33 |
-26 |
+5 |
-17 |
-30 |
20 mg |
150 |
-24 |
-34 |
-28 |
+7 |
-18 |
-32 |
40 mg |
156 |
-29 |
-41 |
-33 |
+8 |
-21 |
-38 |
80 mg |
158 |
-35 |
-49 |
-39 |
+7 |
-27 |
-45 |
In a multicenter, double-blind, controlled, 23-week trial, 710 patients with known CHD or CHD risk equivalents, as defined by the NCEP ATP III guidelines, and an LDL-C ≥130 mg/dL were randomized to one of four treatment groups: coadministered ezetimibe and simvastatin equivalent to ezetimibe and simvastatin tablets (10/10, 10/20, and 10/40) or simvastatin 20 mg. Patients not reaching an LDL-C <100 mg/dL had their simvastatin dose titrated at 6-week intervals to a maximal dose of 80 mg.
At Week 5, the LDL-C reductions with ezetimibe and simvastatin tablets 10/10, 10/20, or 10/40 were significantly larger than with simvastatin 20 mg (see Table 9).
Simvastatin 20 mg | Ezetimibe and Simvastatin Tablets 10/10 | Ezetimibe and Simvastatin Tablets 10/20 | Ezetimibe and Simvastatin Tablets 10/40 |
|
---|---|---|---|---|
N |
253 |
251 |
109 |
97 |
Mean baseline |
174 |
165 |
167 |
171 |
Percent change LDL-C |
-38 |
-47 |
-53 |
-59 |
Table 10: Response to Ezetimibe and Simvastatin Tablets and Atorvastatin in Patients with Primary Hyperlipidemia (Mean* % Change from Untreated Baseline†)
Treatment (Daily Dose) | N | Total-C‡ | LDL-C‡ | Apo B‡ | HDL-C | TG* | Non-HDL-C‡ |
---|---|---|---|---|---|---|---|
Ezetimibe and Simvastatin Tablets by dose |
|||||||
10/10 |
|
-34§ |
-47§ |
-37§ |
+8 |
-26 |
-43§ |
10/20 |
233 |
-37§ |
-51§ |
-40§ |
+7 |
-25 |
-46§ |
10/40 |
236 |
-41§ |
-57§ |
-46§ |
+9§ |
-27 |
-52§ |
10/80 |
224 |
-43§ |
-59§ |
-48§ |
+8§ |
-31 |
-54§ |
Atorvastatin by dose |
|||||||
10 mg |
235 |
-27 |
-36 |
-31 |
+7 |
-21 |
-34 |
20 mg |
230 |
-32 |
-44 |
-37 |
+5 |
-25 |
-41 |
40 mg |
232 |
-36 |
-48 |
-40 |
+4 |
-24 |
-45 |
80 mg |
230 |
-40 |
-53 |
-44 |
+1 |
-32 |
-50 |
* For triglycerides, median % change from baseline.
† Baseline - on no lipid-lowering drug.
‡ Ezetimibe and simvastatin tablets doses pooled (10/10 to 10/80) provided significantly greater reductions in total-C, LDL-C, Apo B, and non-HDL-C compared to atorvastatin doses pooled (10 to 80).
In a multicenter, double-blind, 24-week, forced-titration trial, 788 patients with primary hyperlipidemia, were randomized to receive coadministered ezetimibe and simvastatin equivalent to ezetimibe and simvastatin tablets (10/10 and 10/20) or atorvastatin 10 mg. For all three treatment groups, the dose of the statin was titrated at 6-week intervals to 80 mg. At each pre-specified dose comparison, ezetimibe and simvastatin tablets lowered LDL-C to a greater degree than atorvastatin (see Table 11).
Table 11: Response to Ezetimibe and Simvastatin Tablets and Atorvastatin in Patients with Primary Hyperlipidemia (Mean* % Change from Untreated Baseline†)
Treatment | N | Total-C | LDL-C | Apo B | HDL-C | TG* | Non-HDL-C |
---|---|---|---|---|---|---|---|
Week 6 | |||||||
Atorvastatin 10 mg‡ |
262 |
-28 |
-37 |
-32 |
+5 |
-23 |
-35 |
Ezetimibe and Simvastatin Tablets 10/10§ |
263 |
-34¶ |
-46¶ |
-38¶ |
+8¶ |
-26 |
-43¶ |
Ezetimibe and Simvastatin Tablets 10/20# |
263 |
-36¶ |
-50¶ |
-41¶ |
+10¶ |
-25 |
-46¶ |
Week 12 | |||||||
Atorvastatin 20 mg |
246 |
-33 |
-44 |
-38 |
+7 |
-28 |
-42 |
Ezetimibe and Simvastatin Tablets 10/20 |
250 |
-37¶ |
-50¶ |
-41¶ |
+9 |
-28 |
-46¶ |
Ezetimibe and Simvastatin Tablets 10/40 |
252 |
-39¶ |
-54¶ |
-45¶ |
+12¶ |
-31 |
-50¶ |
Week 18 |
|||||||
Atorvastatin 40 mg |
237 |
-37 |
-49 |
-42 |
+8 |
-31 |
-47 |
Ezetimibe and Simvastatin Tablets 10/40Þ |
482 |
-40¶ |
-56¶ |
-45¶ |
+11¶ |
-32 |
-52¶ |
Week 24 | |||||||
Atorvastatin 80 mg |
228 |
-40 |
-53 |
-45 |
+6 |
-35 |
-50 |
Ezetimibe and Simvastatin Tablets 10/80Þ |
459 |
-43¶ |
-59¶ |
-49¶ |
+12¶ |
-35 |
-55¶ |
* For triglycerides, median % change from baseline.
† Baseline -on no lipid-lowering drug.
‡ Atorvastatin: 10 mg start dose titrated to 20 mg, 40 mg, and 80 mg through Weeks 6, 12, 18, and 24.
§ Ezetimibe and simvastatin tablets: 10/10 start dose titrated to 10/20, 10/40, and 10/80 through Weeks 6, 12, 18, and 24.
¶ p≤0.05 for difference with atorvastatin in the specified week.
# Ezetimibe and simvastatin tablets: 10/20 start dose titrated to 10/40, 10/40, and 10/80 through Weeks 6, 12, 18, and 24.
Ϸ Data pooled for common doses of ezetimibe and simvastatin tablets at Weeks 18 and 24.
In a multicenter, double-blind, 6-week trial, 2959 patients with primary hyperlipidemia, who had not met their NCEP ATP III target LDL-C goal, were randomized to one of six treatment groups: Ezetimibe and simvastatin tablets (10/20, 10/40, or 10/80) or rosuvastatin (10 mg, 20 mg, or 40 mg).
The effects of ezetimibe and simvastatin tablets and rosuvastatin on total-C, LDL-C, Apo B, TG, non-HDL-C and HDL-C are shown in Table 12.
Table 12: Response to Ezetimibe and Simvastatin Tablets and Rosuvastatin in Patients with Primary Hyperlipidemia (Mean* % Change from Untreated Baseline†)
Treatment
(Daily Dose) | N | Total-C‡ | LDL-C‡ | Apo B‡ | HDL-C | TG* | Non-HDL-C‡ |
---|---|---|---|---|---|---|---|
Ezetimibe and simvastatin tablets by dose |
|||||||
10/20 |
476 |
-37§ |
-52§ |
-42§ |
+7 |
-23§ |
-47§ |
10/40 |
477 |
-39¶ |
-55¶ |
-44¶ |
+8 |
-27 |
-50¶ |
10/80 |
474 |
-44# |
-61# |
-50# |
+8 |
-30# |
-56# |
Rosuvastatin by dose |
|||||||
10 mg |
475 |
-32 |
-46 |
-37 |
+7 |
-20 |
-42 |
20 mg |
478 |
-37 |
-52 |
-43 |
+8 |
-26 |
-48 |
40 mg |
475 |
-41 |
-57 |
-47 |
+8 |
-28 |
-52 |
* For triglycerides, median % change from baseline.
† Baseline - on no lipid-lowering drug.
‡ Ezetimibe and simvastatin tablets doses pooled (10/20 to 10/80) provided significantly greater reductions in total-C, LDL-C, Apo B, and non-HDL-C compared to rosuvastatin doses pooled (10 to 40 mg).
§ p<0.05 vs. rosuvastatin 10 mg.
¶ p<0.05 vs. rosuvastatin 20 mg.
♯p<0.05 vs. rosuvastatin 40 mg.
In a multicenter, double-blind, 24-week trial, 214 patients with type 2 diabetes mellitus treated with thiazolidinediones (rosiglitazone or pioglitazone) for a minimum of 3 months and simvastatin 20 mg for a minimum of 6 weeks were randomized to receive either simvastatin 40 mg or the coadministered active ingredients equivalent to ezetimibe and simvastatin tablets 10/20. The median LDL-C and HbA1c levels at baseline were 89 mg/dL and 7.1%, respectively.
Ezetimibe and simvastatin tablets 10/20 was significantly more effective than doubling the dose of simvastatin to 40 mg. The median percent changes from baseline for ezetimibe and simvastatin tablets vs. simvastatin were: LDL-C -25% and -5%; total-C -16% and -5%; Apo B -19% and -5%; and non-HDL-C -23% and -5%. Results for HDL-C and TG between the two treatment groups were not significantly different.
Ezetimibe
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The Heart Protection Trial (Trial HPS) was a randomized, placebo-controlled, double-blind, multi-centered trial with a mean duration of 5 years conducted in 10,269 patients on simvastatin 40 mg and 10,267 on placebo. Patients had a mean age of 64 years (range 40-80 years old), 97% were White, and were at high risk of developing a major coronary event because of existing CHD (65%), diabetes (Type 2, 26%; Type 1, 3%), history of stroke or other cerebrovascular disease (16%), peripheral vascular disease (33%), or they were males ≥65 years with hypertension in (6%). At baseline:
Patients were randomized to simvastatin or placebo using a covariate adaptive method which considered the distribution of 10 important baseline characteristics of patients already enrolled.
The Trial HPS results showed that simvastatin 40 mg/day significantly reduced: total and CHD mortality; and non-fatal MI, stroke, and revascularization procedures (coronary and non-coronary) (see Table 15).
Table 15: CHD Mortality and Cardiovascular Events in Adult Patients with High Risk of Developinga Major Coronary Event in Trial HPS
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Simvastatin use led to significant relative risk reductions for both composite endpoints (27% for MCE and 24% for MVE, p<0.0001) and for all components of the composite endpoints. The risk reductions produced by simvastatin in both MCE and MVE were evident and consistent regardless of cardiovascular disease related medical history at trial entry (i.e., CHD alone; or peripheral vascular disease, cerebrovascular disease, diabetes or treated hypertension, with or without CHD), gender, age, baseline levels of LDL-C, baseline concomitant cardiovascular medications (i.e., aspirin, beta blockers, or calcium channel blockers), smoking status, or obesity. Patients with diabetes showed risk reductions for MCE and MVE due to simvastatin treatment regardless of baseline HbA1c levels or obesity.
Storage
Store at 68°F to 77°F (20°C to 25°C) [see USP Controlled Room Temperature]. Keep container tightly closed.
*Trademarks are the properties of their respective owners.
Manufactured by:
Glenmark Pharmaceuticals Limited
Pithampur, Madhya Pradesh 454775, India
Glenmark Pharmaceuticals Inc., USA
Mahwah, NJ 07430
Questions? 1 (888) 721-7115
www.glenmarkpharma-us.com
March 2024
Patient Information
Ezetimibe and Simvastatin
(e zet' i mibe and sim" va stat' in)
Tablets
Read this Information carefully before you start taking ezetimibe and simvastatin tablets and each time you get a ezetimibe and simvastatin tablets. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment. If you have any questions about ezetimibe and simvastatin tablets, ask your healthcare provider. Only your healthcare provider can determine if ezetimibe and simvastatin tablets are right for you
What are ezetimibe and simvastatin tablets?
Ezetimibe and simvastatin tablets are a prescription medicine that contains the cholesterol lowering medicines, simvastatin and ezetimibe:
• Ezetimibe and simvastatin tablets are used along with diet to lower elevated low-density lipoprotein cholesterol (LDL-C) or bad cholesterol in:
o adults with primary hyperlipidemia (high level of fats in your blood).
o adults and children 10 years of age and older with heterozygous familial hypercholesterolemia (HeFH). HeFH is an inherited condition that causes high levels of bad cholesterol.
• Ezetimibe and simvastatin tablets are also used with other cholesterol lowering treatments to lower elevated LDL-C levels in adults with homozygous familial hypercholesterolemia (HoFH). HoFH is an inherited condition that causes high levels of bad cholesterol.
• Simvastatin when used as a component of ezetimibe and simvastatin tablets is used to lower:
o the risk of death by lowering the risk of heart disease death.
o the risk of heart attacks and strokes.
o the need for certain types of heart and blood vessel procedures to improve blood flow called arterial revascularization in people with known heart, cerebrovascular disease (conditions that affect blood flow and the blood vessels in the brain), peripheral vascular disease (a blood circulation disorder that causes the blood vessels outside of your heart and brain to narrow, block, or spasm), and diabetes, who are at high risk for heart disease problems.
The safety and effectiveness of ezetimibe and simvastatin tablets has not been established in children younger than 10 years of age with inherited heterozygous familial hypercholesterolemia (HeFH) or other types of hyperlipidemia.
Do not take ezetimibe and simvastatin tablets if you:
• take certain medicines called CYP3A4 inhibitors such as:
o certain anti-fungal medicines (such as itraconazole, ketoconazole, posaconazole, voriconazole).
o HIV protease inhibitors (such as indinavir, nelfinavir, ritonavir, saquinavir, tipranavir, or atazanavir and cobicistat-containing products such as
(elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate).
o certain hepatitis C virus protease inhibitors (such as boceprevir or telaprevir).
o the antidepressant nefazodone.
• take medicines called cyclosporine, danazol, or gemfibrozil.
• have liver problems.
• are allergic to simvastatin, ezetimibe, or any of the ingredients in ezetimibe and simvastatin tablets. See the end of this Patient Information leaflet for a complete list of ingredients in ezetimibe and simvastatin tablets.
Ask your healthcare provider or pharmacist if you are not sure if your medicine is listed above.
Before you take ezetimibe and simvastatin tablets, tell your healthcare provider about all of your medical conditions, including if you:
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Talk to your healthcare provider before you start taking any new medicines.
Tell your healthcare provider who prescribes ezetimibe and simvastatin tablets if another healthcare provider increases the dose of another medicine you are taking.
Ezetimibe and simvastatin tablets may affect the way other medicines work, and other medicines may affect how ezetimibe and simvastatin tablets works. Especially tell your healthcare provider if you take:
Taking ezetimibe and simvastatin tablets with certain substances can also increase the risk of muscle problems. Especially tell your healthcare provider if you take:
Ask your healthcare provider or pharmacist for a list of medicines if you are not sure. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.
How should I take ezetimibe and simvastatin tablets?
What are the possible side effects of ezetimibe and simvastatin tablets?
Ezetimibe and simvastatin tablets may cause serious side effects, including:
Tell your healthcare provider right away if:
Your chances of getting muscle problems are higher if you:
The most common side effects of ezetimibe and simvastatin tablets include:
• headache
• increased liver enzyme levels
• muscle pain
• upper respiratory infection
• diarrhea
Tell your healthcare provider if you have any side effect that bothers you or does not go away.
These are not all the possible side effects of ezetimibe and simvastatin tablets.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store ezetimibe and simvastatin tablets?
Keep ezetimibe and simvastatin tablets and all medicines out of the reach of children.
General Information about the safe and effective use of ezetimibe and simvastatin tablets.
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use ezetimibe and simvastatin tablets for a condition for which it was not prescribed. Do not give ezetimibe and simvastatin tablets to other people, even if they have the same symptoms that you have. It may harm them.
You can ask your pharmacist or healthcare provider for information about ezetimibe and simvastatin tablets that is written for health professionals.
For more information, call Glenmark Pharmaceuticals Inc., USA at 1 (888) 721-7115.
What are the ingredients in ezetimibe and simvastatin tablets?
Active Ingredients: ezetimibe and simvastatin
This Patient Information has been approved by the U.S. Food and Drug Administration.
Manufactured by:
Glenmark Pharmaceuticals Limited
Pithampur, Madhya Pradesh 454775, India
Glenmark Pharmaceuticals Inc., USA
Mahwah, NJ 07430
Questions? 1 (888) 721-7115
www.glenmarkpharma-us.com
March 2024
NDC 68462-321-30
Ezetimibe and Simvastatin Tablets
10 mg/10 mg
NDC 68462-322-30
Ezetimibe and Simvastatin Tablets
10 mg/20 mg
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Labeler - Glenmark Pharmaceuticals Inc., USA (130597813) |
Establishment | |||
Name | Address | ID/FEI | Business Operations |
---|---|---|---|
Glenmark Pharmaceuticals Limited | 862603186 | MANUFACTURE(68462-321, 68462-322, 68462-323, 68462-324) , ANALYSIS(68462-321, 68462-322, 68462-323, 68462-324) |