Ezetimibe

Name: Ezetimibe

Adverse Effects

1-10%

Diarrhea (4%)

Upper respiratory tract symptoms (2-4%)

Cough (2-4%)

Pain in extremity (3%)

Sinusitis (3%)

Arthralgia (2-3%)

Fatigue (2%)

Influenza (2%)

Increased liver transaminases (with HMG-CoA reductase inhibitors; ≥3 x ULN; 1%)

Postmarketing Reports

Hepatitis/liver function test abnormalities (LFTs elevated slightly higher in combination with statin than with statin alone)

Hypersensitivity reactions (including anaphylaxis, angioedema, rash, urticaria)

Erythema multiforme

Elevated creatine phosphokinase

Myopathy/rhabdomyolysis

Thrombocytopenia

Back pain

Abdominal pain

Pancreatitis

Nausea

Dizziness

Paresthesia

Depression

Headache

Cholelithiasis and cholecystitis

Is ezetimibe available as a generic drug?

GENERIC AVAILABLE: No

What are the side effects of ezetimibe?

The most common side effects of ezetimibe are:

  • diarrhea,
  • abdominal pain,
  • back pain,
  • joint pain,
  • muscle aches, and
  • sinusitis.

Hypersensitivity reactions, including angioedema (swelling of the skin and underlying tissues of the head and neck that can be life-threatening) and skin rash rarely occur.

Other important side effects include:

  • Nausea,
  • pancreatitis,
  • muscle damage (myopathy or rhabdomyolysis) and
  • hepatitis

Is ezetimibe safe to take if I'm pregnant or breastfeeding?

There are no adequate studies of ezetimibe in pregnant women. Therefore, physicians must weight the benefit of prescribing ezetimibe during pregnancy against potential but unknown risks.

There are no adequate studies of ezetimibe in women who are breastfeeding. Therefore, physicians must weight the benefit of prescribing ezetimibe to nursing women against potential but unknown risks.

Uses of Ezetimibe

Ezetimibe is a prescription medication used with diet and exercise to treat high cholesterol. It may be given with other cholesterol-lowering medications. Ezetimibe is also used to treat a rare genetic condition called sitosterolemia.

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

Ezetimibe Food Interactions

Medicines can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of ezetimibe there are no specific foods that you must exclude from your diet when receiving this medication.

Ezetimibe Overdose

If you take too much ezetimibe, call your local Poison Control Center or seek emergency medical attention right away.

Cautions for Ezetimibe

Contraindications

  • Known hypersensitivity to ezetimibe or any ingredient in the formulation.1

  • Fixed combination of ezetimibe and simvastatin: Contraindicated in patients with active liver disease or unexplained, persistent increases in serum aminotransferase (transaminase) concentrations; in pregnant or nursing women; or in patients receiving concomitant therapy with potent inhibitors of CYP3A4, cyclosporine, danazol, or gemfibrozil.20

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity Reactions

Anaphylaxis, angioedema, rash, and urticaria reported.1 12

Major Toxicities

Hepatic Effects

Transient elevations in serum aminotransferase (AST, ALT) concentrations3 4 >3 times the ULN reported.1 12 Elevations reported more frequently with ezetimibe-statin combination than with statin monotherapy.1 Hepatitis reported; however, causal relationship not established.1 12

ACC/AHA cholesterol management guideline states it is reasonable to obtain baseline hepatic aminotransferase concentrations before initiating ezetimibe.350 When used with a statin, perform liver function tests at initiation of therapy and in accordance with the recommended monitoring schedule for the specific statin and as clinically indicated.1 350 If ALT or AST concentrations increase to ≥3 times the ULN and are persistent, consider discontinuing ezetimibe and/or the statin.1

Musculoskeletal Effects

Marked (>10 times ULN) elevations of CK (CPK) reported.1 Elevations in CK concentrations reported more frequently with ezetimibe-statin combination than with statin monotherapy.1

Myalgia, myopathy (i.e., unexplained muscle pain, tenderness, or weakness and CK concentration >10 times ULN), and/or rhabdomyolysis reported.1 12 Most cases of rhabdomyolysis occurred in patients receiving statin therapy prior to initiating ezetimibe; however, rhabdomyolysis also reported following ezetimibe monotherapy or following addition of ezetimibe to therapy with agents known to be associated with increased risk of rhabdomyolysis (e.g., fibric acid derivatives).1 20

Predisposing factors for the development of myopathy and/or rhabdomyolysis include increased dosages of statins, age >65 years, uncontrolled hypothyroidism, renal impairment, and potential statin-drug interactions.1 20 Immediately discontinue ezetimibe and any concomitant statin or fibric acid derivative (e.g., gemfibrozil, fenofibrate) if myopathy is diagnosed or suspected.1 12

General Precautions

Combination Therapy with Statins or Fenofibrate

When used in combination or fixed combination with a statin or fenofibrate, consult prescribing information of specific statin or fenofibrate for detailed information on usual cautions, precautions, and contraindications of these drugs.1 12

Risk of Cancer

Findings from the SEAS study suggested a possible increased risk of cancer with use of the fixed combination of simvastatin and ezetimibe.15 17 The results of 2 large-scale randomized trials (SHARP and IMPROVE-IT) found no such association.307 308 309 FDA concluded that ezetimibe and the fixed-combination preparation of ezetimibe and simvastatin is not likely to increase the risk of cancer or cancer-related deaths.307

Specific Populations

Pregnancy

Category C.1

Fixed combination of ezetimibe and simvastatin: Category X (due to simvastatin component).20

Lactation

Distributed into milk in rats; not known whether distributed into human milk.1 Use with caution in nursing women; not recommended unless potential benefits justify possible risks to infant.1

Pediatric Use

Safety and efficacy not established in children <10 years of age; use not recommended in these children.1

Safety and efficacy of ezetimibe alone or in fixed combination with simvastatin not established in prepubertal girls or in children ≤10 years of age.1 20

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.1 20

Use fixed combination of ezetimibe and simvastatin with caution, since age ≥65 years is a risk factor for myopathy, including rhabdomyolysis.20

Hepatic Impairment

Safety of increased exposure to ezetimibe in patients with moderate or severe hepatic impairment currently not known; use not recommended in such patients.1

Renal Impairment

In patients with moderate to severe renal impairment receiving ezetimibe 10 mg/simvastatin 20 mg in fixed combination, incidence of certain adverse effects (serious effects; those resulting in drug discontinuance; musculoskeletal effects, liver enzyme abnormalities, or incident cancer) was similar to that with placebo.1 20 Use higher dosages with caution and close monitoring in such patients, since renal impairment increases risk for myopathy.1 20 (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Ezetimibe monotherapy: Upper respiratory tract infection,1 diarrhea,1 3 arthralgia,1 2 sinusitis,1 pain in extremity,1 fatigue,1 influenza.1

Ezetimibe in combination with a statin: Nasopharyngitis,1 myalgia,1 20 upper respiratory tract infection,1 2 4 20 arthralgia,1 headache,20 diarrhea,1 20 back pain,1 influenza,1 20 pain in extremity.1 20

Adverse effects associated with combination therapy generally similar to those reported with monotherapy.1 However, elevations in transaminase concentrations reported more frequently with ezetimibe-statin combination than with statin monotherapy.1

ezetimibe Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Frequency not determined
  • Abdominal fullness
  • black tarry stools
  • bleeding gums
  • bloating
  • blood in urine or stools
  • chills
  • constipation
  • darkened urine
  • fast heartbeat
  • fever
  • gaseous abdominal pain
  • general tiredness or weakness
  • indigestion
  • large, hive-like swelling on face, eyelids, lips, tongue, throat, hands, legs, feet, sex organs
  • loss of appetite
  • light-colored stools
  • muscle cramps or spasms
  • muscular tenderness, wasting or weakness
  • nausea
  • pains in stomach, side or abdomen, possibly radiating to the back
  • pinpoint red spots on skin
  • recurrent fever
  • severe nausea
  • skin rash
  • unusual bleeding or bruising
  • upper right abdominal pain
  • vomiting
  • yellow eyes or skin

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common
  • Fever
  • headache
  • muscle pain
  • runny nose
  • sore throat
Less common
  • Back pain
  • body aches or pain
  • chest pain
  • chills
  • cold or flu-like symptoms
  • congestion
  • coughing
  • diarrhea
  • difficulty in moving
  • dizziness
  • dryness or soreness of throat
  • hoarseness
  • muscle pain or stiffness
  • pain in joints
  • pain or tenderness around eyes and cheekbones
  • shortness of breath or troubled breathing
  • stomach pain
  • stuffy nose
  • tender, swollen glands in neck
  • tightness of chest or wheezing
  • trouble in swallowing
  • unusual tiredness or weakness
  • voice changes

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

If OVERDOSE is suspected

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

Drug Interactions

 [See Clinical Pharmacology (12.3).]

Cyclosporine

Caution should be exercised when using Ezetimibe and cyclosporine concomitantly due to increased exposure to both Ezetimibe and cyclosporine. Cyclosporine concentrations should be monitored in patients receiving Ezetimibe and cyclosporine.

The degree of increase in Ezetimibe exposure may be greater in patients with severe renal insufficiency. In patients treated with cyclosporine, the potential effects of the increased exposure to Ezetimibe from concomitant use should be carefully weighed against the benefits of alterations in lipid levels provided by Ezetimibe.

Fibrates

The efficacy and safety of co-administration of Ezetimibe with fibrates other than fenofibrate have not been studied.

Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, Ezetimibe increased cholesterol in the gallbladder bile [see Nonclinical Toxicology (13.2)]. Co-­administration of Ezetimibe with fibrates other than fenofibrate is not recommended until use in patients is adequately studied.

Fenofibrate

If cholelithiasis is suspected in a patient receiving Ezetimibe and fenofibrate, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered [see Adverse Reactions (6.1) and the product labeling for fenofibrate].

Cholestyramine

Concomitant cholestyramine administration decreased the mean area under the curve (AUC) of total Ezetimibe approximately 55%. The incremental LDL-C reduction due to adding Ezetimibe to cholestyramine may be reduced by this interaction.

Coumarin Anticoagulants

If Ezetimibe is added to warfarin, a coumarin anticoagulant, the International Normalized Ratio (INR) should be appropriately monitored.

Use in specific populations

Pregnancy

Pregnancy Category C:

There are no adequate and well-controlled studies of Ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus.

In oral (gavage) embryo-fetal development studies of Ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 X the human exposure at 10 mg daily based on AUC0-24hr for total Ezetimibe). In rabbits treated with Ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 X the human exposure at 10 mg daily based on AUC0-24hr for total Ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses.

Multiple-dose studies of Ezetimibe given in combination with statins in rats and rabbits during organogenesis result in higher Ezetimibe and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy.

All statins are contraindicated in pregnant and nursing women. When Ezetimibe is administered with a statin in a woman of childbearing potential, refer to the pregnancy category and product labeling for the statin. [See Contraindications (4).]

Nursing Mothers

It is not known whether Ezetimibe is excreted into human breast milk. In rat studies, exposure to total Ezetimibe in nursing pups was up to half of that observed in maternal plasma. Because many drugs are excreted in human milk, caution should be exercised when Ezetimibe is administered to a nursing woman. Ezetimibe should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant.

Pediatric Use

The effects of Ezetimibe co-administered with simvastatin (n=126) compared to simvastatin monotherapy (n=122) have been evaluated in adolescent  boys and girls with heterozygous familial hypercholesterolemia (HeFH). In a multicenter, double-blind, controlled study followed by an open-label phase, 142 boys and 106 postmenarchal girls, 10 to 17 years of age (mean age 14.2 years, 43% females, 82% Caucasians, 4% Asian, 2% Blacks, 13% multi-racial) with HeFH were randomized to receive either Ezetimibe co-administered with simvastatin or simvastatin monotherapy. Inclusion in the study required 1) a baseline LDL-C level between 160 and 400 mg/dL and 2) a medical history and clinical presentation consistent with HeFH. The mean baseline LDL-C value was 225 mg/dL (range: 161 to 351 mg/dL) in the Ezetimibe co-administered with simvastatin group compared to 219 mg/dL (range: 149 to 336 mg/dL) in the simvastatin monotherapy group. The patients received co-administered Ezetimibe and simvastatin (10 mg, 20 mg, or 40 mg) or simvastatin monotherapy (10 mg, 20 mg, or 40 mg) for 6 weeks, co-administered Ezetimibe and 40 mg simvastatin or 40 mg simvastatin monotherapy for the next 27 weeks, and open-label co-administered Ezetimibe and simvastatin (10 mg, 20 mg, or 40 mg) for 20 weeks thereafter.


The results of the study at Week 6 are summarized in Table 3. Results at Week 33 were consistent with those at Week 6.


TABLE 3: Mean Percent Difference at Week 6 Between the Pooled Ezetimibe Co-Administered with Simvastatin Group and the Pooled Simvastatin Monotherapy Group in Adolescent Patients with Heterozygous Familial Hypercholesterolemia


 
Total-C
LDL-C
Apo B
Non-HDL-C
TG*
HDL-C
Mean percent difference between treatment groups
-12%
-15%
-12%
-14%
-2%
+0.1%
95% Confidence Interval
(-15%, -9%)
(-18%, -12%)
(-15%, -9%)
(-17%, -11%)
(-9%, +4%)
(-3%, +3%)

* For triglycerides, median % change from baseline


From the start of the trial to the end of Week 33, discontinuations due to an adverse reaction occurred in 7 (6%) patients in the Ezetimibe co-administered with simvastatin group and in 2 (2%) patients in the simvastatin monotherapy group.


During the trial, hepatic transaminase elevations (two consecutive measurements for ALT and/or AST ≥3 X ULN) occurred in four (3%) individuals in the Ezetimibe co-administered with simvastatin group and in two (2%) individuals in the simvastatin monotherapy group. Elevations of CPK (≥10 X ULN) occurred in two (2%) individuals in the Ezetimibe co-administered with simvastatin group and in zero individuals in the simvastatin monotherapy group.


In this limited controlled study, there was no significant effect on growth or sexual maturation in the adolescent boys or girls, or on menstrual cycle length in girls.


Co-administration of Ezetimibe with simvastatin at doses greater than 40 mg/day has not been studied in adolescents. Also, Ezetimibe has not been studied in patients younger than 10 years of age or in pre­menarchal girls.


Based on total Ezetimibe (Ezetimibe + Ezetimibe-glucuronide), there are no pharmacokinetic differences between adolescents and adults. Pharmacokinetic data in the pediatric population <10 years of age are not available.

Geriatric Use

Monotherapy Studies


Of the 2396 patients who received Ezetimibe in clinical studies, 669 (28%) were 65 and older, and 111 (5%) were 75 and older.

Statin Co-Administration Studies


Of the 11,308 patients who received Ezetimibe + statin in clinical studies, 3587 (32%) were 65 and older, and 924 (8%) were 75 and older.


No overall differences in safety and effectiveness were observed between these patients and younger patients, 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 [see Clinical Pharmacology (12.3)].

Renal Impairment

When used as monotherapy, no dosage adjustment of Ezetimibe is necessary.

In the Study of Heart and Renal Protection (SHARP) trial of 9270 patients with moderate to severe renal impairment (6247 non-dialysis patients with median serum creatinine 2.5 mg/dL and median estimated glomerular filtration rate 25.6 mL/min/1.73 m2, and 3023 dialysis patients), the incidence of serious adverse events, adverse events leading to discontinuation of study treatment, or adverse events of special interest (musculoskeletal adverse events, liver enzyme abnormalities, incident cancer) was similar between patients ever assigned to Ezetimibe 10 mg plus simvastatin 20 mg (n=4650) or placebo (n=4620) during a median follow-up of 4.9 years. However, because renal impairment is a risk factor for statin-associated myopathy, doses of simvastatin exceeding 20 mg should be used with caution and close monitoring when administered concomitantly with Ezetimibe in patients with moderate to severe renal impairment.

Hepatic Impairment

Ezetimibe is not recommended in patients with moderate to severe hepatic impairment [see Warnings and Precautions (5.4) and Clinical Pharmacology (12.3)].

Ezetimibe given concomitantly with a statin is contraindicated in patients with active liver disease or unexplained persistent elevations of hepatic transaminase levels [see Contraindications (4); Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].

Clinical Studies

Primary Hyperlipidemia

Ezetimibe reduces total-C, LDL-C, Apo B, non-HDL-C, and TG, and increases HDL-C in patients with hyperlipidemia. Maximal to near maximal response is generally achieved within 2 weeks and maintained during chronic therapy.

Monotherapy


In two multicenter, double-blind, placebo-controlled, 12-week studies in 1719 patients with primary hyperlipidemia, Ezetimibe significantly lowered total-C, LDL-C, Apo B, non-HDL-C, and TG, and increased HDL-C compared to placebo (see Table 6). Reduction in LDL-C was consistent across age, sex, and baseline LDL-C.


TABLE 6: Response to Ezetimibe in Patients with Primary Hyperlipidemia (Mean* % Change from Untreated Baseline†)



 
Treatment Group
N
Total-C
LDL-C
Apo B
Non-HDL-C
TG*
HDL-C
Study 1‡
Placebo
205
+1
+1
-1
+1
-1
-1
Ezetimibe
622
-12
-18
-15
-16
-7
+1
Study 2‡
Placebo
226
+1
+1
-1
+2
+2
-2
Ezetimibe
666
-12
-18
-16
-16
-9
+1
Pooled Data‡
(Studies 1 & 2)
Placebo
431
0
+1
-2
+1
0
-2
Ezetimibe
1288
-13
-18
-16
-16
-8
+1

* For triglycerides, median % change from baseline

† Baseline - on no lipid-lowering drug

‡ Ezetimibe significantly reduced total-C, LDL-C, Apo B, non-HDL-C, and TG, and increased HDL-C compared to placebo.


Combination with Statins


Ezetimibe Added to On-going Statin Therapy


In a multicenter, double-blind, placebo-controlled, 8-week study, 769 patients with primary hyperlipidemia, known coronary heart disease or multiple cardiovascular risk factors who were already receiving statin monotherapy, but who had not met their NCEP ATP II target LDL-C goal were randomized to receive either Ezetimibe or placebo in addition to their on-going statin.


Ezetimibe, added to on-going statin therapy, significantly lowered total-C, LDL-C, Apo B, non-HDL-C, and TG, and increased HDL-C compared with a statin administered alone (see Table 7). LDL-C reductions induced by Ezetimibe were generally consistent across all statins.


TABLE 7: Response to Addition of Ezetimibe to On-Going Statin Therapy* in Patients with Hyperlipidemia (Mean† % Change from Treated Baseline‡)


Treatment
(Daily Dose)
N
 
Total-C
LDL-C
Apo B
Non-HDL-C
TG†
HDL-C
On-going Statin +
Placebo§
390
-2
-4
-3
-3
-3
+1
On-going Statin +
Ezetimibe §
379
-17
-25
-19
-23
-14
+3

* Patients receiving each statin: 40% atorvastatin, 31% simvastatin, 29% others (pravastatin, fluvastatin,

   cerivastatin, lovastatin)

† For triglycerides, median % change from baseline

‡ Baseline - on a statin alone.

§Ezetimibe + statin significantly reduced total-C, LDL-C, Apo B, non-HDL-C, and TG, and increased HDL-C  compared to statin alone.


Ezetimibe Initiated Concurrently with a Statin

In four multicenter, double-blind, placebo-controlled, 12-week trials, in 2382 hyperlipidemic patients, Ezetimibe or placebo was administered alone or with various doses of atorvastatin, simvastatin, pravastatin, or lovastatin.


When all patients receiving Ezetimibe with a statin were compared to all those receiving the corresponding statin alone, Ezetimibe significantly lowered total-C, LDL-C, Apo B, non-HDL-C, and TG, and, with the exception of pravastatin, increased HDL-C compared to the statin administered alone. LDL-C reductions induced by Ezetimibe were generally consistent across all statins. (See footnote ‡, Tables 8 to 11.)

TABLE 8: Response to Ezetimibe and Atorvastatin Initiated Concurrently in Patients with Primary Hyperlipidemia (Mean* % Change from Untreated Baseline†)


Treatment
(Daily Dose)
N
Total-C
LDL-C
Apo B
Non-HDL-C
TG*
HDL-C
Placebo
60
+4
+4
+3
+4
-6
+4
Ezetimibe
65
-14
-20
-15
-18
-5
+4
Atorvastatin 10 mg
60
-26
-37
-28
-34
-21
+6
Ezetimibe +
Atorvastatin 10 mg
65
-38
-53
-43
-49
-31
+9
Atorvastatin 20 mg
60
-30
-42
-34
-39
-23
+4
Ezetimibe +
Atorvastatin 20 mg
62
-39
-54
-44
-50
-30
+9
Atorvastatin 40 mg
66
-32
-45
-37
-41
-24
+4
Ezetimibe +
Atorvastatin 40 mg
65
-42
-56
-45
-52
-34
+5
Atorvastatin 80 mg
62
-40
-54
-46
-51
-31
+3
Ezetimibe +
Atorvastatin 80 mg
63
-46
-61
-50
-58
-40
+7
Pooled data (All
Atorvastatin Doses)‡
248
-32
-44
-36
-41
-24
+4
Pooled data (All Ezetimibe + Atorvastatin Doses)‡
255
-41
-56
-45
-52
-33
+7

* For triglycerides, median % change from baseline

† Baseline - on no lipid-lowering drug

‡ Ezetimibe + all doses of atorvastatin pooled (10 to 80 mg) significantly reduced total-C, LDL-C, Apo B, non-HDL-C, and TG, and increased HDL-C compared to all doses of atorvastatin pooled (10 to 80 mg).

TABLE 9: Response to Ezetimibe and Simvastatin Initiated Concurrently in Patients with Primary Hyperlipidemia (Mean* % Change from Untreated Baseline↑)


Treatment
(Daily Dose)
N
Total-C
LDL-C
Apo B
Non-HDL-C
TG*
HDL-C
Placebo
70
-1
-1
0
-1
+2
+1
Ezetimibe
61
-13
-19
-14
-17
-11
+5
Simvastatin 10 mg
70
-18
-27
-21
-25
-14
+8
Ezetimibe +
Simvastatin 10 mg
67
-32
-46
-35
-42
-26
+9
Simvastatin 20 mg
61
-26
-36
-29
-33
-18
+6
Ezetimibe +
Simvastatin 20 mg
69
-33
-46
-36
-42
-25
+9
Simvastatin 40 mg
65
-27
-38
-32
-35
-24
+6
Ezetimibe +
Simvastatin 40 mg
73
-40
-56
-45
-51
-32
+11
Simvastatin 80 mg
67
-32
-45
-37
-41
-23
+8
Ezetimibe +
Simvastatin 80 mg
65
-41
-58
-47
-53
-31
+8
Pooled data (All
Simvastatin Doses)‡
263
-26
-36
-30
-34
-20
+7
Pooled data (All Ezetimibe + Simvastatin Doses)‡
274
-37
-51
-41
-47
-29
+9

* For triglycerides, median % change from baseline

† Baseline - on no lipid-lowering drug

‡ Ezetimibe + all doses of simvastatin pooled (10 to 80 mg) significantly reduced total-C, LDL-C, Apo B, non-HDL-C, and TG, and increased HDL-C compared to all doses of simvastatin pooled (10 to 80 mg).

TABLE 10: Response to Ezetimibe and Pravastatin Initiated Concurrently in Patients with Primary Hyperlipidemia (Mean* % Change from Untreated Baseline†)


Treatment
(Daily Dose)
N
Total-C
LDL-C
Apo B
Non-HDL-C
TG*
HDL-C
Placebo
65
0
-1
-2
0
-1
+2
Ezetimibe
64
-13
-20
-15
-17
-5
+4
Pravastatin 10 mg
66
-15
-21
-16
-20
-14
+6
Ezetimibe +
Pravastatin 10 mg
71
-24
-34
-27
-32
-23
+8
Pravastatin 20 mg
69
-15
-23
-18
-20
-8
+8
Ezetimibe +
Pravastatin 20 mg
66
-27
-40
-31
-36
-21
+8
Pravastatin 40 mg
70
-22
-31
-26
-28
-19
+6
Ezetimibe +
Pravastatin 40 mg
67
-30
-42
-32
-39
-21
+8
Pooled data (All Pravastatin Doses)‡
205
-17
-25
-20
-23
-14
+7
Pooled data (All Ezetimibe + Pravastatin Doses)‡
204
-27
-39
-30
-36
-21
+8

* For triglycerides, median % change from baseline

† Baseline - on no lipid-lowering drug

‡ Ezetimibe + all doses of pravastatin pooled (10 to 40 mg) significantly reduced total-C, LDL-C, Apo B, non-HDL-C, and TG compared to all doses of pravastatin pooled (10 to 40 mg).


TABLE 11: Response to Ezetimibe and Lovastatin Initiated Concurrently in Patients with Primary Hyperlipidemia (Mean* % Change from Untreated Baseline†)


Treatment
(Daily Dose)
N
Total-C
LDL-C
Apo B
Non-HDL-C
TG*
HDL-C
Placebo
64
+1
0
+1
+1
+6
0
Ezetimibe
72
-13
-19
-14
-16
-5
+3
Lovastatin 10 mg
73
-15
-20
-17
-19
-11
+5
Ezetimibe +
Lovastatin 10 mg
65
-24
-34
-27
-31
-19
+8
Lovastatin 20 mg
74
-19
-26
-21
-24
-12
+3
Ezetimibe +
Lovastatin 20 mg
62
-29
-41
-34
-39
-27
+9
Lovastatin 40 mg
73
-21
-30
-25
-27
-15
+5
Ezetimibe +
Lovastatin 40 mg
65
-33
-46
-38
-43
-27
+9
Pooled data (All
Lovastatin Doses)‡
220
-18
-25
-21
-23
-12
+4
Pooled data (All Ezetimibe + Lovastatin Doses)‡
192
-29
-40
-33
-38
-25
+9

* For triglycerides, median % change from baseline

† Baseline - on no lipid-lowering drug

‡ Ezetimibe Tablets + all doses of lovastatin pooled (10 to 40 mg) significantly reduced total-C, LDL-C, Apo B, non-HDL-C, and TG, and increased HDL-C compared to all doses of lovastatin pooled (10 to 40 mg).

Combination with Fenofibrate


In a multicenter, double-blind, placebo-controlled, clinical study in patients with mixed hyperlipidemia, 625 patients were treated for up to 12 weeks and 576 for up to an additional 48 weeks. Patients were randomized to receive placebo, Ezetimibe alone, 160 mg fenofibrate alone, or Ezetimibe and 160 mg fenofibrate in the 12-week study. After completing the 12-week study, eligible patients were assigned to Ezetimibe co­-administered with fenofibrate or fenofibrate monotherapy for an additional 48 weeks.


Ezetimibe co-administered with fenofibrate significantly lowered total-C, LDL-C, Apo B, and non-HDL-C compared to fenofibrate administered alone. The percent decrease in TG and percent increase in HDL-C for Ezetimibe co-administered with fenofibrate were comparable to those for fenofibrate administered alone (see Table 12).


TABLE 12: Response to Ezetimibe and Fenofibrate Initiated Concurrently in Patients with Mixed Hyperlipidemia (Mean* % Change from Untreated Baseline† at 12 weeks)


Treatment
(Daily Dose)
N
Total-C
LDL-C
Apo B
TG*
HDL-C
Non-HDL-C
Placebo
63
0
0
-1
-9
+3
0
Ezetimibe
185
-12
-13
-11
-11
+4
-15
Fenofibrate 160 mg
188
-11
-6
-15
-43
+19
-16
Ezetimibe + Fenofibrate 160 mg
183
-22
-20
-26
-44
+19
-30

* For triglycerides, median % change from baseline

† Baseline - on no lipid-lowering drug


The changes in lipid endpoints after an additional 48 weeks of treatment with Ezetimibe co-administered with fenofibrate or with fenofibrate alone were consistent with the 12-week data displayed above.

Homozygous Familial Hypercholesterolemia (HoFH)

A study was conducted to assess the efficacy of Ezetimibe in the treatment of HoFH. This double-blind, randomized, 12-week study enrolled 50 patients with a clinical and/or genotypic diagnosis of HoFH, with or without concomitant LDL apheresis, already receiving atorvastatin or simvastatin (40 mg). Patients were randomized to one of three treatment groups, atorvastatin or simvastatin (80 mg), Ezetimibe administered with atorvastatin or simvastatin (40 mg), or Ezetimibe administered with atorvastatin or simvastatin (80 mg). Due to decreased bioavailability of Ezetimibe in patients concomitantly receiving cholestyramine [see Drug Interactions (7.4)], Ezetimibe was dosed at least 4 hours before or after administration of resins. Mean baseline LDL-C was 341 mg/dL in those patients randomized to atorvastatin 80 mg or simvastatin 80 mg alone and 316 mg/dL in the group randomized to Ezetimibe plus atorvastatin 40 or 80 mg or simvastatin 40 or 80 mg. Ezetimibe, administered with atorvastatin or simvastatin (40 and 80 mg statin groups, pooled), significantly reduced LDL-C (21%) compared with increasing the dose of simvastatin or atorvastatin monotherapy from 40 to 80 mg (7%). In those treated with Ezetimibe plus 80 mg atorvastatin or with Ezetimibe plus 80 mg simvastatin, LDL-C was reduced by 27%.

Homozygous Sitosterolemia (Phytosterolemia)

A study was conducted to assess the efficacy of Ezetimibe in the treatment of homozygous sitosterolemia. In this multicenter, double-blind, placebo-controlled, 8-week trial, 37 patients with homozygous sitosterolemia with elevated plasma sitosterol levels (>5 mg/dL) on their current therapeutic regimen (diet, bile-acid-binding resins, statins, ileal bypass surgery and/or LDL apheresis), were randomized to receive Ezetimibe (n=30) or placebo (n=7). Due to decreased bioavailability of Ezetimibe in patients concomitantly receiving cholestyramine [see Drug Interactions (7.4)], Ezetimibe was dosed at least 2 hours before or 4 hours after resins were administered. Excluding the one subject receiving LDL apheresis, Ezetimibe significantly lowered plasma sitosterol and campesterol, by 21% and 24% from baseline, respectively. In contrast, patients who received placebo had increases in sitosterol and campesterol of 4% and 3% from baseline, respectively. For patients treated with Ezetimibe, mean plasma levels of plant sterols were reduced progressively over the course of the study. The effects of reducing plasma sitosterol and campesterol on reducing the risks of cardiovascular morbidity and mortality have not been established.

Reductions in sitosterol and campesterol were consistent between patients taking Ezetimibe concomitantly with bile acid sequestrants (n=8) and patients not on concomitant bile acid sequestrant therapy (n=21).

Limitations of Use

The effect of Ezetimibe on cardiovascular morbidity and mortality has not been determined.

Pharmacologic Category

  • Antilipemic Agent, 2-Azetidinone

Onset of Action

Within 1 week; Maximum effect: 2-4 weeks

Time to Peak

Plasma: 4-12 hours (ezetimibe); 1-2 hours (active metabolite); Effects: ~2 weeks

Half-Life Elimination

22 hours (ezetimibe and metabolite)

Protein Binding

>90% to plasma proteins

Before taking this medicine

You should not use ezetimibe if you are allergic to it, or if you have:

  • moderate to severe liver disease.

You should not use ezetimibe with a "statin" cholesterol medicine (Zocor, Lipitor, Crestor, and others) if:

  • you have active liver disease;

  • you are pregnant; or

  • you are breast-feeding a baby.

To make sure this medicine is safe for you, tell your doctor if you have:

  • kidney disease; or

  • a thyroid disorder.

Before you start taking this medicine, tell your doctor if you already take a statin cholesterol medicine.

Some cholesterol medications can cause a condition that results in the breakdown of skeletal muscle tissue, leading to kidney failure. This condition may be more likely to occur in older adults and in people who have kidney disease or poorly controlled hypothyroidism (underactive thyroid).

You should not take ezetimibe with a statin medication if you are pregnant or breast-feeding.

It is not known whether ezetimibe alone will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant. Use effective birth control to prevent pregnancy while you are using ezetimibe with a statin medication.

It is not known whether ezetimibe alone passes into breast milk or if it could harm a nursing baby. Tell your doctor if you are breast-feeding a baby. You should not breast-feed if you take this medicine with a statin medication.

For the Consumer

Applies to ezetimibe: oral tablet

Along with its needed effects, ezetimibe may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Frequency not determined
  • Abdominal fullness
  • black tarry stools
  • bleeding gums
  • bloating
  • blood in urine or stools
  • chills
  • constipation
  • darkened urine
  • fast heartbeat
  • fever
  • gaseous abdominal pain
  • general tiredness or weakness
  • indigestion
  • large, hive-like swelling on face, eyelids, lips, tongue, throat, hands, legs, feet, sex organs
  • loss of appetite
  • light-colored stools
  • muscle cramps or spasms
  • muscular tenderness, wasting or weakness
  • nausea
  • pains in stomach, side or abdomen, possibly radiating to the back
  • pinpoint red spots on skin
  • recurrent fever
  • severe nausea
  • skin rash
  • unusual bleeding or bruising
  • upper right abdominal pain
  • vomiting
  • yellow eyes or skin

Some side effects of ezetimibe may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common
  • Fever
  • headache
  • muscle pain
  • runny nose
  • sore throat
Less common
  • Back pain
  • body aches or pain
  • chest pain
  • chills
  • cold or flu-like symptoms
  • congestion
  • coughing
  • diarrhea
  • difficulty in moving
  • dizziness
  • dryness or soreness of throat
  • hoarseness
  • muscle pain or stiffness
  • pain in joints
  • pain or tenderness around eyes and cheekbones
  • shortness of breath or troubled breathing
  • stomach pain
  • stuffy nose
  • tender, swollen glands in neck
  • tightness of chest or wheezing
  • trouble in swallowing
  • unusual tiredness or weakness
  • voice changes

For Healthcare Professionals

Applies to ezetimibe: oral tablet

General

The most frequently reported side effects were upper respiratory tract infection, diarrhea, arthralgia, sinusitis, and pain in extremity.[Ref]

Gastrointestinal

Common (1% to 10%): Abdominal pain, diarrhea, flatulence
Uncommon (0.1% to 1%): Dyspepsia, gastroesophageal reflux disease, nausea
Postmarketing reports: Pancreatitis, constipation[Ref]

Immunologic

Postmarketing reports: Anaphylaxis[Ref]

Musculoskeletal

Common (1% to 10%): Arthralgia, pain in extremity
Uncommon (0.1% to 1%): Muscle spasms, neck pain
Postmarketing reports: Myalgia, myopathy, rhabdomyolysis[Ref]

Respiratory

Common (1% to 10%): Upper respiratory tract infection, sinusitis
Uncommon (0.1% to 1%): Cough
Postmarketing reports: Dyspnea[Ref]

Hypersensitivity

Postmarketing reports: Hypersensitivity reaction[Ref]

Hepatic

Uncommon (0.1% to 1%): Gamma-glutamyltransferase increased, liver function test abnormal, AST/ALT increased
Postmarketing reports: Hepatitis, liver transaminases increased, cholelithiasis, cholecystitis[Ref]

Hematologic

Postmarketing reports: Thrombocytopenia[Ref]

Nervous system

Uncommon (0.1% to 1%): Dizziness
Postmarketing reports: Paresthesia, headache[Ref]

Psychiatric

Postmarketing reports: Depression[Ref]

Cardiovascular

Uncommon (0.1% to 1%): Hot flush, hypertension[Ref]

Dermatologic

Postmarketing reports: Angioedema, rash, urticaria, erythema multiforme[Ref]

Metabolic

Uncommon (0.1% to 1%): Appetite decreased[Ref]

Other

Common (1% to 10%): Fatigue, influenza
Uncommon (0.1% to 1%): Chest pain, pain, creatine phosphokinase increased
Postmarketing reports: Asthenia[Ref]

Some side effects of ezetimibe may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Administrative Information

LactMed Record Number

736

Last Revision Date

20131206

Disclaimer

Information presented in this database is not meant as a substitute for professional judgment. You should consult your healthcare provider for breastfeeding advice related to your particular situation. The U.S. government does not warrant or assume any liability or responsibility for the accuracy or completeness of the information on this Site.

(web3)