# **Ezetimibe (Zetia or Vytorin®) Criteria for Nonformulary Use**

VHA Pharmacy Benefits Management Services and the Medical Advisory Panel

September 2005 (Updated January 2007, May 2008)

*The following recommendations are based on current medical evidence.
The content of the document is dynamic and will be revised as new
clinical data become available. The purpose of this document is to
assist practitioners in clinical decision making, to standardize and
improve the quality of patient care, and to promote cost-effective drug
prescribing. The clinician, however, must make the ultimate judgment
regarding the propriety of any course of treatment in light of
individual patient situations.*

Ezetimibe (Zetia) is the first in a class of cholesterol lowering
agents called the cholesterol absorption inhibitors. It acts by
selectively inhibiting absorption of cholesterol (dietary and biliary)
at the brush border of the small intestine. In addition to other rare,
more severe forms of hypercholesterolemia, ezetimibe is FDA approved in
combination with statins or alone for the management of primary
hypercholesterolemia.

Most of the large statin trials, demonstrating a reduction in adverse
cardiovascular health outcomes, utilized moderate to higher statin doses
versus placebo (e.g. 4S-simvastatin 20-40 mg/d, HPS-simvastatin 40
mg/d). In addition, incremental effect has been observed with high dose
statin versus lower dose statin (TNT-atorvastatin 10 vs 80 mg).^1^ It is
not known whether the same clinical effect will be seen if a low dose
statin is combined with ezetimibe or another agent (bile acid
sequestrant or niacin). Additionally, there is emerging evidence to
suggest that there may be differing effects of high versus lower dose
statins or ezetimibe in measures of endothelial function (pleiotropic
effects).

At this time, there is no evidence to support a reduction in
cardiovascular outcomes (nonfatal myocardial infarction, cardiovascular
death, etc.) with ezetimibe monotherapy or when combined with a statin.
However, there is one clinical outcomes trial underway (IMPROVE-IT) that
will seek to determine the incremental effect of adding ezetimibe to
statins in patients with acute coronary syndrome. The results of this
trial are not expected until 2011 or 2012. Results from the ENHANCE
trial (atherosclerotic regression trial in 720 patients with familial
heterozygous hypercholesterolemia) were recently published. Both the
primary and secondary endpoints dealt with changes in the mean carotid
(primary and secondary endpoints) and femoral (secondary endpoint)
artery intima-media thickness (CA IMT) between simvastatin 80 mg daily
versus simvastatin 80 mg in combination with ezetimibe 10 mg daily.
Despite a 41% vs. 59% reduction in LDL-C, respectively, there was no
difference in the primary, secondary or safety endpoints in this patient
population.^2,15-16^

Authors of an analysis of clinical outcome trials (with lipid-lowering
drugs) concluded that the efficacy (reduction in CV events) and safety
of achieving lipid targets with lipid-lowering therapies (e.g.
combination therapy) other than statin monotherapy is not known because
of the lack of trials focused on important clinical outcomes (e.g.
reducing MI, CV mortality).^14^ **As a result, monotherapy with statins
should be maximized or statin therapy should be switched to a higher
potency statin before considering combination therapy**. If combination
therapy is considered necessary, clinicians are advised to consider
add-on therapy with niacin prior to combination therapy with ezetimibe
(because of ezetimibe's lack of clinical outcome data) especially in
those patients with mixed dyslipidemia. It should be emphasized that the
incremental benefit of adding niacin to statins versus use of statins
alone on important cardiovascular outcomes is not known. One study
underway (AIM-HIGH), sponsored by the National Institutes of Health
(NIH), will help answer this question. AIM-HIGH will compare the effect
of simvastatin versus simvastatin combined with niacin on the incidence
of major cardiovascular events. Expected enrollment is 3300 patients and
results are not expected until 2011.^17^ In HATS (HATS-Brown 2001), the
combination of statins plus niacin led to net regression of
atherosclerosis and a relative reduction in clinical events of 90%
compared to placebo.^3^ However, in the ARBITER 2 trial, the addition of
niacin to simvastatin did not improve atherosclerotic progression versus
simvastatin alone.^4^ In a third study by Hecht, et al,^5^ patients with
evidence of subclinical atherosclerosis received a combination of
statins plus niacin or statins alone. In this particular study, the
patient's treating physician chose the lipid-lowering agent and dose
based upon clinical considerations that were not dictated by the study.
As a result, significantly more patients on combination therapy had
lower baseline HDL and higher baseline triglycerides (TG) than those
receiving statin monotherapy. Calcified plaque progression was similar
between the statin monotherapy group (who had normal HDL-C and TG) and
the group receiving the statin-niacin combination (with elevated TG and
low HDL-C). As a result, the authors concluded that similar benefit was
seen between statins alone and the niacin-statin combination despite the
less desirable lipid levels in the combination group at baseline.

There are some patients that may not be candidates for niacin including
those with a history of confirmed peptic ulcer disease (perforation,
ulceration or upper gastrointestinal bleeding), gouty attacks
(preferably, as evidenced by the presence of intra-articular uric acid
crystals in an affected joint) and/or poorly controlled diabetes.
However, two recent trials demonstrated the safety and efficacy of an
extended release niacin product (Niaspan 1000-3000mg/d) in diabetics
managed by diet, oral hypoglycemics, or insulin.^6-7^ Although
hemoglobin A1C was statistically increased at higher niacin doses in one
study, the changes may not be considered clinically significant
(Baseline and end of study hemoglobin A1C changed from 7.2% to 7.5% in
the niacin 1500 mg group-p=0.048).^6^ There were no significant changes
in hemoglobin A1C in the niacin 1000 mg group. In the second study,
there were no significant changes in hemoglobin A1C in patients using up
to 3 grams daily of niacin.^7^ In those patients not reaching their
LDL-C goals with add-on niacin; unable to tolerate niacin; or are not
candidates for niacin, addition of either a bile acid sequestrant (BAS)
or ezetimibe (nonformulary) can be considered. (\*See appendix A, page 4
for considerations with niacin therapy).

Ezetimibe should [not]{.underline} be considered first line for patients
with elevated LDL-C who cannot tolerate statins since there are other
lipid-lowering therapies (niacin or BAS) with clinical trial evidence to
support reductions in coronary heart disease (CHD) outcomes. However,
ezetimibe may be considered as monotherapy in patients unable to
tolerate statins and having an inadequate LDL-C lowering response,
intolerance or contraindication to therapeutic doses of niacin and BAS.

### 1. Candidates for Ezetimibe (Patients who have met their LDL-C goal on statin monotherapy should [NOT]{.underline} be switched to combination therapy with ezetimibe) 

> **[A.]{.underline} [In Combination with Statins:]{.underline} \*VA/DoD
> Dyslipidemia Guideline recommends an LDL-C goal of \<100 mg/dL in high
> risk patients. http://www.oqp.med.va.gov/cpg/DL/LIP_CPG/GOL.htm**
>
> \_\_\_\_\_\_\_\_\_\_ LDL-C goal not achieved with moderate^1^ to
> high-dose statin or maximally tolerated or recommended dose of statin
> (drug-drug interaction, etc.) **\[[Guidance:]{.underline} Monotherapy
> with statins should be maximized or statin therapy should be switched
> to a higher potency statin before considering combination therapy**.

#### 

#### AND

> \_\_\_\_\_\_\_\_\_\_ LDL-C goal not achieved with niacin, unable to
> tolerate niacin or may not be a candidate for niacin (e.g. history of
> confirmed peptic ulcer disease \[perforation, ulceration or upper GI
> bleeding\] gouty attacks \[preferably, as evidenced by the presence of
> intra-articular uric acid crystals in an affected joint\] and/or
> poorly controlled diabetes).

B.  **[Monotherapy:]{.underline}**

> \_\_\_\_\_\_\_ Unable to tolerate statins^5^

#### AND

> \_\_\_\_\_\_\_\_ Inadequate LDL-C lowering response, intolerance or
> contraindication to therapeutic doses of niacin and bile acid
> sequestrants.^4^

### ^1^Moderate to high-dose statins: simvastatin 40-80 mg, lovastatin 80 mg, fluvastatin 80 mg, atorvastatin 40-80 mg (nonformulary), rosuvastatin 20 mg (nonformulary), pravastatin 80 mg (nonformulary). 

### ^2^Since there are limited data examining the safety and efficacy of combining ezetimibe with fibrates, caution should be used when using this combination. 

### ^3^If BAS are combined with ezetimibe, ezetimibe should be taken 1-2 hours before or 4-6 hours after the BAS. 

### ^4^Monotherapy with BAS is contraindicated in patients with triglyceride levels \>400 mg/dL and in familial dysbetalipoproteinemia. Avoid in patients with triglyceride levels \>400 mg/dL 

### ^5^There is emerging evidence suggesting patients with common features of impaired fatty acid oxidation may have recurrence of their myopathic symptoms on ezetimibe as well as niacin, fibrates and statins. 

### ^6^For other possible LDL-C lowering strategies and considerations, refer to page 4. Refer to pages 4 and 5 for niacin dose titration.

### 

2.  **Criterion For Discontinuing Ezetimibe**

> There is potential variability in response to cholesterol absorption
> inhibitors. Generally response to new lipid treatment should be gauged
> at two follow-up clinic visits. If a patient does not experience a
> substantive response to addition of ezetimibe, usually a decrease in
> LDL-C by 10 to 15% toward goal, ezetimibe should be discontinued.

3.  **Safety Considerations**

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a.  Ezetimibe is not recommended in patients with moderate or severe
    liver impairment because the effects of increased exposure to
    ezetimibe are not known.

b.  Clinically significant elevation (\>3 times upper limit of normal)
    in liver function tests were seen in a significantly greater number
    of patients receiving ezetimibe plus a statin (1.3%-2%) versus a
    statin alone (0.4%). When ezetimibe is used in combination with
    statins, LFTs must be monitored (see section 5 below).

c.  Several cases of myopathy have been reported in patients receiving
    high-dose statins upon initiation of ezetimibe. As a result, caution
    should be used when adding ezetimibe to statins, especially in
    patients more susceptible to statin myopathy (e.g. advanced age,
    frailty, female gender, drug-drug interactions, hypothyroidism,
    alcoholism, etc.)^10-11^

d.  Fibrates work by increasing cholesterol excretion into the bile,
    which can lead to cholelithiasis. In an animal study, ezetimibe
    increased cholesterol in the gallbladder bile. Upon FDA approval of
    ezetimibe, the manufacturer recommended against combining ezetimibe
    with fibrates until human studies had been completed because of a
    potential for an increased risk of cholelithiasis. In a study
    published in 2005, 625 patients with no known coronary artery
    disease were randomized to receive placebo, fenofibrate 160 mg,
    ezetimibe 10 mg or the combination for 12 weeks. The combination
    grouped experienced the greatest mean percent LDL-C reduction. In
    the 48-week extension study, similar results were observed. Although
    there were no significant differences in planned or performed
    cholecystectomies between groups in either trial, the trials were
    not of sufficient size or duration to adequately compare gallstone
    development between groups.^12-13^ As a result, there is not
    sufficient evidence to conclude whether or not the combination will
    result in an increased risk of cholelithiasis or cholecystectomy.

e.  Triple therapy with statins, BAS or niacin, and ezetimibe is
    generally not recommended since efficacy and long-term safety are
    uncertain.

f.  The combination of ezetimibe with BAS or niacin is generally not
    recommended since there are no published data demonstrating safety
    and efficacy of the combination, unless no other alternatives exist.
    In addition, the LDL-C lowering effect of ezetimibe may be reduced
    in the presence of BAS.

g.  All patients receiving statins, including those receiving
    combination therapy with ezetimibe, should be informed regarding the
    recognition and reporting of any unexplained muscle pain, tenderness
    or weakness.

h.  For additional data on safety, including drug-drug interactions, see
    the ezetimibe monograph at
    http://[www.pbm.va.gov](http://www.pbm.va.gov/) or
    [http://vaww.pbm.va.gov](http://vaww.pbm.med.va.gov/)

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4.  **Dosage and Administration**

The manufacturer's recommended dose is 10 mg daily without regard to
meals. However, some advocate using a 5 mg dose. In a pooled analysis of
two-phase II studies, the LDL-C lowering response of 0.25 mg, 1 mg, 5 mg
and 10 mg of ezetimibe (monotherapy) was examined in 432 patients for 12
weeks. The 5 mg dose reduced LDL-C by 15.7% and the 10 mg by 18.5%
(P\<0.05 in favor of 10 mg dose). In the 5 mg group, 54% of patients had
a reduction in their LDL-C of [\>]{.underline}15% and 67.8% of those in
the 10 mg group had reductions in their LDL-C of [\>]{.underline}15%.^8^
In another study, a small number of patients (n=8 in each group) were
randomized to lovastatin 20 mg, lovastatin 20 mg + ezetimibe 5 mg,
lovastatin 20 mg + ezetimibe 10 mg, lovastatin 20 mg + ezetimibe 20 mg
or lovastatin 40 mg + ezetimibe 10 mg for 2 weeks. Addition of ezetimibe
resulted in an additional reduction in LDL-C of 16-18% compared to
lovastatin alone. There were no differences in LDL-C lowering response
observed between 5, 10 or 20 mg of ezetimibe.^9^

5.  **Monitoring**

When ezetimibe is administered in combination with a statin, LFTs should
be performed prior to initiation of therapy and according to the
recommendations of the statin (e.g. simvastatin: within the first 12
weeks, and periodically thereafter).

6.  **References**

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1.  LaRosa JC, Grundy SM, Waters MD, et al. Intensive Lipid Lowering
    With Atorvastatin in Patients with Stable Coronary Artery Disease.
    NEJM 2005;352: (published online 3-05)
    <http://content.nejm.org/cgi/reprint/NEJMoa050461v1.pdf>

2.  Kastelein JP, Sager PT, deGroot E, Veltri E. Comparison of Ezetimibe
    Plus Simvastatin Versus Simvastatin Monotherapy on Atherosclerosis
    Progression in Familial Hypercholesterolemia: Design and Rationale
    of the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances
    Atherosclerosis Regression (ENHANCE) Trial. Am Heart J
    2005;149:234-239

3.  Brown BG, Zhao XQ, Chait A, et al. Simvastatin and Niacin,
    Antioxidant Vitamins, or The Combination For The Prevention of
    Coronary Disease. N Engl J Med 2001;345:1583-1592.

4.  Taylor AJ, Sullenberger LE, Lee HJ, et al. Arterial Biology for the
    Investigation of the Treatment Effects of Reducing Cholesterol
    (ARBITER) 2. A Double-Blind, Placebo-Controlled Study of
    Extended-Release Niacin on Atherosclerosis Progression in Secondary
    Prevention Patients Treated with Statins. Circulation
    2004;110:3512-3517.

5.  Hecht HS, Harman SM. Comparison of Effectiveness of Statin
    Monotherapy Versus Statin and Niacin Combination Therapy in Primary
    Prevention and Effects on Calcified Plaque Burden. Am J Cardiol
    2003;91:348-351.

6.  Grundy SM, Vega GL, McGovern ME, et al. Efficacy and Safety, and
    Tolerability of Once-Daily Niacin for the Treatment of Dyslipidemia
    Associated with Type 2 Diabetes. Arch Intern Med 2002;162:1568-1576.

7.  Elam MB, Hunninghake DB, Davis KB, et al. Effect of Niacin on Lipid
    and Lipoprotein Levels and Glycemic Control in Patients with
    Diabetes and Peripheral Artery Disease. The ADMIT study: A
    Randomized Trial. JAMA 2000;284:1263-1270.

8.  Bays HE, Moore PB, Drehobl MA, et al. Effectiveness and Tolerability
    of Ezetimibe in Patients with Primary Hypercholesterolemia: Pooled
    Analysis of Two Phase II Studies. Clin Ther 2001;23:1209-1230.

9.  Kosoglou T, Statkevich P, Meyer I, et al. Effects of Ezetimibe on
    the Pharmacodynamics and Pharmacokinetics of Lovastatin. Curr Med
    Res and Opin 2004;20:955-965.

10. Fux, et al. Ezetimibe and Statin-Associated Myopathy. Ann Intern Med
    2004;140:671-672.

11. Phillips PS. Ezetimibe and Statin-Associated Myopathy Ann Intern Med
    2004;141:649.

12. Farnier M, Freeman MW, MacDonell G, et al. Efficacy and Safety of
    the Coadministration of Ezetimibe with Fenofibrate in Patients with
    Mixed Hyperlipidemia. Eur Heart J 2005;26:897-905.

13. McKenney JM, Farnier M, Lo, KW, et al. Safety and Efficacy of
    Long-Term Co-Administration of Fenofibrate and Ezetimibe in Patients
    With Mixed Hyperlipidemia.

14. Hayward RA, Hofer TP, Vijan S. Narrative Review: Lack of Evidence
    for Recommended Low-Density Lipoprotein Treatment Targets: A
    Solvable Problem. Ann Intern Med 2006;145:520-530.

15. Kastelein JJP, Akdim F, Stroes ESG, et al. Simvastatin with or
    without Ezetimibe in Familial Hypercholesterolemia. N Engl J Med
    2008;358:1431-1443.

16. [http://vaww.national.cmop.va.gov/PBM/Clinical%20Guidance/Clinical%20Recommendations/Ezetimibe%20and%20Ezetimibe+Simvastatin%20Guidance%20(Based%20upon%20Preliminary%20Results%20from%20ENHANCE)%20final.doc](http://vaww.national.cmop.va.gov/PBM/Clinical Guidance/Clinical Recommendations/Ezetimibe and Ezetimibe+Simvastatin Guidance (Based upon Preliminary Results from ENHANCE) final.doc)

17. <http://clinicaltrials.gov/ct/show/NCT00120289> (Accessed 4-17-08)

**Considerations for Various LDL-C Lowering Strategies (When switching
from or adding to simvastatin 40 or 80 mg daily)**

+----------------------+-----------------------------------------------+
| ###### LDL           | **Considerations**                            |
| -C Lowering Strategy |                                               |
+----------------------+-----------------------------------------------+
| Doubling statin dose | -   Additional LDL-C reduction 6-7%           |
|                      |                                               |
|                      | -   As the dose of statins increase, so does  |
|                      |     the risk for LFT elevation and myopathy   |
+----------------------+-----------------------------------------------+
| Switch to            | -   Rosuva: Additional LDL-C reduction 5-15%  |
| rosuvastatin 10-20   |                                               |
| mg or atorvastatin   | -   Atorva: Additional LDL-C reduction 5-12%  |
| 80 mg                |                                               |
|                      | -   Rosuva 40 mg should [only]{.underline} be |
|                      |     used in patients [not]{.underline}        |
|                      |     reaching their LDL-C goal with the 20 mg  |
|                      |     dose.                                     |
|                      |                                               |
|                      | -   In those patients on rosuvastatin 40 mg   |
|                      |     daily, the MAP recommends baseline and    |
|                      |     periodic urinary and renal function       |
|                      |     monitoring. If unexplained, persistent    |
|                      |     proteinuria is noted in a patient         |
|                      |     receiving rosuvastatin 40 mg daily, the   |
|                      |     manufacturer recommends reducing the dose |
|                      |     of rosuvastatin.                          |
|                      |                                               |
|                      | -   Clinically significant LFT elevation      |
|                      |     occurred more often in the high-dose      |
|                      |     atorvastatin vs. high-dose simvastatin    |
|                      |     group in two head to head studies.        |
+----------------------+-----------------------------------------------+
| Addition of niacin   | -   Additional LDL-C reductions 15%           |
| 1-2 grams            |                                               |
|                      | -   Combination of niacin and statins may     |
|                      |     increase risk for myopathy.               |
|                      |                                               |
|                      | -   Most common adverse event of niacin is    |
|                      |     flushing. To limit niacin-associated      |
|                      |     flushing, niacin must be titrated (see    |
|                      |     below for titration schedules). Prior to  |
|                      |     initiation of niacin, discussion of the   |
|                      |     potential for flushing with patient and   |
|                      |     strategies for reducing occurrence and    |
|                      |     severity of flushing is recommended.      |
|                      |     (e.g. improves with continued             |
|                      |     administration, can be improved by taking |
|                      |     ASA or other nonsteroidal                 |
|                      |     anti-inflammatory agent (e.g. ibuprofen)  |
|                      |     30 minutes prior to niacin and avoiding   |
|                      |     alcohol, spicy foods and hot drinks       |
|                      |     around the time of niacin                 |
|                      |     administration.)                          |
|                      |                                               |
|                      | -   Avoid in patients with a history of       |
|                      |     confirmed perforation, ulcer or GI        |
|                      |     bleeding.                                 |
|                      |                                               |
|                      | -   Avoid in patients with a history of       |
|                      |     confirmed gout (as evidenced by           |
|                      |     intra-articular uric acid crystals in the |
|                      |     affected joint).                          |
|                      |                                               |
|                      | -   Use with caution in diabetics, may alter  |
|                      |     glycemic control                          |
|                      |                                               |
|                      | -   Can reduce TG by 20-35% and increase      |
|                      |     HDL-C by 15-30%                           |
+----------------------+-----------------------------------------------+
| Addition of bile     | -   Additional LDL-C reduction 15%            |
| acid sequestrant     |                                               |
|                      | -   May increase triglyceride concentrations. |
| (BAS)                |     Avoid in patients with TG levels in       |
|                      |     excess of 400 mg/dL and those with        |
|                      |     complete biliary obstruction.             |
|                      |                                               |
|                      | -   GI intolerability                         |
|                      |                                               |
|                      | -   Drug-Drug interaction if BAS not          |
|                      |     separated from other oral medications     |
|                      |     (other medications 1 or 2 hours before or |
|                      |     4-6 hours after the BAS)                  |
+----------------------+-----------------------------------------------+
| Addition of          | -   Additional LDL-C reduction 15%, minimal   |
| ezetimibe 10 mg      |     effect on TG and HDL-C                    |
|                      |                                               |
|                      | -   The combination of ezetimibe plus statins |
|                      |     has resulted in a greater incidence of    |
|                      |     clinically significant (\>3x ULN)         |
|                      |     elevation in LFTs vs. statins alone. LFTs |
|                      |     should be monitored                       |
|                      |                                               |
|                      | -   There are some reports of myopathy after  |
|                      |     adding ezetimibe to high dose statins,    |
|                      |     use caution in those patients more        |
|                      |     susceptible to myopathy (e.g. older age,  |
|                      |     frailty, alcohol abuse, renal or liver    |
|                      |     impairment, hypothyroidism)               |
+----------------------+-----------------------------------------------+

LDL-C reductions are only approximates. ASA=aspirin, LFTs=liver function
tests, TG=triglycerides, ULN=upper limit of normal

###### 

###### Niaspan Titration Schedule

+-----------------------+-----------------------+-----------------------+
| **Weeks**             | **Daily Dose**        | **Administration      |
|                       |                       | Schedule**            |
+-----------------------+-----------------------+-----------------------+
| 1 to 4                | 500 mg                | 1X 500 mg-at bedtime  |
+-----------------------+-----------------------+-----------------------+
| 5 to 8                | 1000 mg               | 2X 500 mg-at bedtime  |
+-----------------------+-----------------------+-----------------------+
| After week 8, titrate | 1500 mg               | 2X 750 mg-at bedtime  |
| to patient response   |                       | or                    |
| and tolerance. Daily  | 2000 mg               |                       |
| dose of Niaspan       |                       | 3X 500 mg-at bedtime  |
| should not be         |                       |                       |
| increased by more     |                       | 2X 1000 mg-at bedtime |
| than 500 mg in any    |                       | or                    |
| 4-week period and     |                       |                       |
| daily doses greater   |                       | 4X 500 mg-at bedtime  |
| than 2000 mg are not  |                       |                       |
| recommended.          |                       |                       |
+-----------------------+-----------------------+-----------------------+

Manufacturer recommends administering Niaspan at bedtime after a low fat
snack. Administration on an empty stomach is not recommended.

###### 

###### 

###### Crystalline Niacin (Immediate-release) Example titration schedule

  ----------------------- ----------------------- -----------------------
  **Weeks**               **Daily Dose**          **Administration
                                                  Schedule**

  1                       300 mg                  100 mg three times
                                                  daily

  2                       600 mg                  2X 100 mg three times
                                                  daily

  3                       900 mg                  3X 100 mg three times
                                                  daily

  4                       1200 mg                 4X 100 mg three times
                                                  daily

  5                       1500 mg                 1X 500 mg three times
                                                  daily
  ----------------------- ----------------------- -----------------------

Further adjustments as tolerated using 500 or 750 mg tablets up to a
maximum of 4.5 g/day