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Family Medicine Clinical Pharmacy Forum

Vol. 5, Issue 4 (July/August 2009)
Family Medicine Clinical Pharmacy Forum is a brief bi-monthly publication from the Family Medicine clinical
pharmacists distributed to faculty and residents of the Department of Family Medicine. Our intent is to provide
timely information on broad-based issues of pharmacotherapy, as well as regulatory and practiced-based issues
affecting you as a prescriber. If you have suggestions for things you would like to see, please contact us.

Contents
-Pitavastatin (Livalo) - a new statin gains FDA approval
-Milnacipran (Savella) – a new SNRI for fibromyalgia
-HgbA1c - now for diabetes diagnosis?
-Iowa Prescription Monitoring Program – a useful website for patient care
-Vancomycin - Is "more" better?
-Beers criteria vs. individualized patient review – 61% of “flagged”
medications not deemed to be problematic

Pitavastatin (Livalo)

Pitavastatin has recently been FDA approved for the treatment of hypercholesterolemia
and combined dyslipidemia. Pitavastatin is an HMG CoA reductase inhibitor very
similar to other statins on the market. It will be available as 1, 2, and 4 mg tablets.
Pitavastatin is manufactured by Kowa Pharmaceuticals. They are expected to launch
pitavastatin early next year. Currently there is no label information available from the
FDA.

Pitavastatin has already been on the market in Japan, South Korea, Thailand, and
China for several years, so much of the data comes from clinical trials done in these
countries. Pitavastatin has been proven effective in lowering LDL and triglycerides. So
far there are no published data on pitavastatin's effect on cardiovascular
outcomes. Pitavastatin has been shown to have a similar side effect profile as the other
statins, with the most common side effects being muscle, joint, and back pain, and
constipation.

So what makes pitavastatin different than all the other statins on the market? According
to the manufacturer, pitavastatin is a more effective HMG CoA reductase inhibitor
because of a unique cyclopropyl group in the drug molecule. This may lead to greater
reduction in LDL cholesterol levels. So far there has been no difference in LDL lowering
effects when pitavastatin is compared with other statins. In an 8 week study in Korea,
pitavastatin was compared to atorvastatin and no differences in reduction of LDL,
total cholesterol, or triglycerides, or increases in HDL were found. Another
possible advantage of pitavastatin is that it undergoes minimal CYP450 metabolism.
This may translate into fewer drug-drug interactions compared to the other statins.

Authored by:
Jim Hoehns, Pharm.D., BCPS; Northeast Iowa Family Medicine Residency
Erin Lockard, Pharm.D., Northeast Iowa Family Medicine Residency
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1. Manufacturer drug information. Accessed 8/7/09 from www.kowapharma.com/Press

Releases/news080209.htm

2. Lee SH, Chung N, Kwan J, et al. Comparison of the efficacy and Tolerability of Pitavistatin and
Atorvastatin: An 8-Week, Multicenter, Randomized, Open-Label, Dose-Titration Study in Korean Patients
with Hypercholesterolemia. Clin Ther. 2007 Nov;29(11):2365-73.

Milnacipran (Savella) – A New SNRI for Fibromyalgia

Milnacipran is the 3rd drug approved by the FDA for management of fibromyalgia. It is a
selective serotonin and norepinephrine reuptake inhibitor (SNRI). It inhibits NE
reuptake with a 3-fold greater affinity than for serotonin. It undergoes predominately
renal elimination (55% eliminated unchanged). It is pregnancy category C. Precautions
and warnings for milnacipran are similar to other SNRI’s.

One randomized, double-blind efficacy study evaluated milnacipran 100mg daily,

200mg daily, and placebo in patients with fibromyalgia. At 3 months, the percentage of
patients who rated themselves as “much improved” or “very much improved” were 48%
(100mg), 51% (200mg), and 33% (placebo).

Adverse effects which have been reported are noted below:

Adverse Event Milnacipran-Savella (%) Placebo (%)

(N=1557) (N=652)
Constipation 16 4
Nausea 37 20
Vomiting 7 2
Hypertension 5 2
Hot flush 12 2
Hyperhidrosis 9 2

Milnacipran has notable effects on blood pressure. These are noted in the table below:

Blood Pressure Effect Milnacipran-Savella (%) Placebo (%)

Risk of HTN at study end (in non- 19.5 7.2
hypertensive patients)
>15 mm Hg increase in SBP at study end 2-7 1
(among hypertensive pts at baseline)
>15 mm Hg increase in SBP on 3 6-9 2
consecutive visits

Dosing:
-Day 1: 12.5mg, Day 2-3: 12.5mg BID, Days 4-7: 25mg BID, after day 7: 50mg
BID
Authored by:
Jim Hoehns, Pharm.D., BCPS; Northeast Iowa Family Medicine Residency
Erin Lockard, Pharm.D., Northeast Iowa Family Medicine Residency
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Cost for 1 month supply: Savella 50mg BID ($120); compared to Cymbalta 60mg
QD ($143), and Lyrica 150mg BID ($152).

Summary: Savella is modestly effective at decreasing pain and improving function in

fibromyalgia. Blood pressure will need to be monitored in patients receiving it. Male
patients with a history of obstructive uropathy may experience higher rates of
genitourinary adverse events. Patients will need to be withdrawn gradually following
discontinuation as with other SNRI’s and SSRI’s.

Hgb A1c: A New Diagnostic Marker for Type II Diabetes

A report last month from the International Expert Committee (a committee appointed
jointly by the American Diabetes Association, European Association for the Study of
Diabetes, and the International Diabetes Federation) has proposed expanding the use
of HgbA1c for the diagnosis of Type II diabetes mellitus. Because HbgA1c is a measure
of serum glucose levels over time, it has been used extensively in the management of
diabetes both as a goal of therapy and an indicator of the severity of the disease. For
the same reason, it is being proposed as a tool for diagnosis. Many studies have shown
the correlation between elevated HbgA1c and risk of macro- and microvascular
complications. It would then make sense that patients with an elevated HgbA1c, who
are at higher risk for these complications, should be diagnosed as diabetic and be
treated as such.

In previous Expert Committee reports, HgbA1c has not been recommended as a

diagnostic tool, primarily because of the lack of standardization that lead to
variability in results. Recent advancements in standardization and accuracy have lead
to the revision of their recommendation. Compared to fasting glucose measurements,
the HgbA1c assay is actually easier to do because the samples are stable for a longer
period of time at room temperature. It is also more convenient for the patient because
they do not have to be fasting.

The recommended HbgA1c value for the diagnosis of diabetes is ≥6.5%. They
recommend confirming diagnosis with a followup HgbA1c, unless the patient has
symptoms or a glucose level of >200 mg/dL. This value is based on the correlation of
HgbA1c and risk of retinopathy. Studies have found the risk of retinopathy increases
significantly at HgbA1c values between 6-7%. It is suggested that patients with HgbA1c
levels <6.5% and ≥6.0% are at high risk of developing diabetes and could therefore
benefit from some type of therapy.

There are some limitations of using HgbA1c as a diagnostic tool. The accuracy is
dependent on the hemoglobin. Patients with hemoglobin abnormalities or any
condition that effects red cell turnover such as major bleeding, transfusions, or malaria,
Authored by:
Jim Hoehns, Pharm.D., BCPS; Northeast Iowa Family Medicine Residency
Erin Lockard, Pharm.D., Northeast Iowa Family Medicine Residency
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will have inaccurate results. HgbA1c is not recommended for the diagnosis of Type I
diabetes because of the more rapid onset. It is also not recommended as a
diagnostic test in pregnant women because they have more red blood cell
turnover.

International Expert Committee Report on the Role of the A1C Assay in the Diagnosis of Diabetes.
Diabetes Care. 2009 Jul;32(7):1327-34.

Iowa Prescription Monitoring Program (PMP)

You may have heard about this recently. The Iowa PMP is a free, web-based database
which Iowa prescribers and pharmacists may access to evaluate their patients' use of
controlled substances. The website has been operational now since March 2009. This
site may assist practitioners in determining appropriate treatment options and to
improve the quality of patient care. The Website's address is
https://pmp.iowa.gov/IAPMPWebCenter/.

The PMP is a new health care tool for practitioners by assisting in identifying
potential diversion, misuse, or abuse of controlled substances by their patients
while facilitating the most appropriate and effective medical use of those substances.

Pharmacies across Iowa transfer information into this database twice each month
which lists the controlled substance prescriptions they have filled for patients. The
database contains all controlled substance prescriptions filled since January 1, 2008. If
you need help getting started using this site (e.g. user ID/password) call 515-281-5944
or email: [email protected].

If you are concerned for the potential of a patient abusing or misusing controlled
substances, just go to the website, click on "Requests", then click on "Submit" and enter
your patient's name and date of birth. A report will then be generated in a few seconds.
The site seems to work best if you only enter "last name", "first name", and "date
of birth" in the search parameters.

Commentary: I just started using this site 1-2 weeks ago. I am very pleased with how
fast it is and easy to use. You will never have to wonder again if the patient you are
talking with in the clinic about pain is seeing multiple providers or pharmacies of
which you are unaware. At our clinic, using this website will replace the traditional
phone call to the local pharmacy "hotline" for concerns of potential controlled substance
abuse.

Authored by:
Jim Hoehns, Pharm.D., BCPS; Northeast Iowa Family Medicine Residency
Erin Lockard, Pharm.D., Northeast Iowa Family Medicine Residency
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Vancomycin - An Update on Therapeutic Monitoring

In January 2009, three professional organizations (ASHP, IDSA, and SIDP) published a
joint consensus review regarding therapeutic monitoring of vancomycin in adults (Rybak
M et al. Am J Health-Syst Pharm 2009;66:82-98.)

Historically, the recommended target vancomycin trough concentration was <10 mg/L.
More recently studies have suggested that trough concentrations <10 may predict
therapeutic failure and the potential for emergence of resistant strains of MRSA.

The most notable recommendations from the guidelines are listed below:

Recommendation Level of Evidence

● Troughs should be obtained just prior to the next dose at steady IIB
state (after 4th dose)
● Minimum serum vancomycin trough concentrations should IIIB
always be maintained above 10 mg/L to avoid developing
resistance
● Trough concentrations of 15-20mg/L are considered optimal for IIIB
complicated infections (e.g. endocarditis, osteomyelitis, meningitis,
and pneumonia) caused by Staph aureus
● Daily doses of 15-20 mg/kg (as actual body weight) given every IIIB
8-12 hours are recommended for most patients with normal renal
function to achieve the suggested serum concentration when the
MIC is ≤1 mg/L.
● In seriously ill patients, a loading dose of 25-30mg/kg (based on IIIB
actual body weight) can be used to rapidly attain target
concentrations

The big picture message from these new guidelines seems to be: 1.) Target a
trough >10 in everyone (regardless of type of infection), and 2.) Target a trough
of 15-20 in complicated infections (e.g. bone, joints, bacteremia, etc.).

How Useful are the Beers criteria in Identifying Problem Prescribing?

Drugs-to-avoid criteria are commonly used to evaluate prescribing quality in elderly

patients. Despite the widespread use of such criteria, evidence of their validity as
markers of prescribing quality for elderly patients is mixed.

Steinmen MA et al evaluated the medications from 256 Iowa City VA elderly (>65 years)
outpatients who were taking 5 or more medications. After a comprehensive patient
interview (by physician and pharmacist), the team recommended that certain drugs be
discontinued, substituted, or reduced in dose. The researchers evaluated the degree to
Authored by:
Jim Hoehns, Pharm.D., BCPS; Northeast Iowa Family Medicine Residency
Erin Lockard, Pharm.D., Northeast Iowa Family Medicine Residency
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which drugs considered potentially inappropriate by the “drugs-to-avoid criteria” (of

Beers et al and Zhan et al) were also considered problematic by the study team, and
vice versa.

The 256 patients were using 3678 medications. The physician-pharmacist team
identified 15% of drugs as problematic, while 6% and 2.5% were flagged as potentially
inappropriate by the Beers criteria and Zhan criteria, respectively. Kappa statistics for
concordance were 0.10 – 0.14; showing only slight agreement with the individualized
review. Of note, 61% of drugs identified as potentially inappropriate by the Beers
criteria and 49% of drugs flagged by the Zhan criteria were not judged as
problematic by the expert reviewers. Moreover, the Beers and Zhan criteria
identified only 8-15% of drugs that experts judged to be problematic.

The authors concluded that drugs-to-avoid criteria have limited ability to differentiate
between drugs and patients with and without prescribing problems identified on
individualized expert review.

Notes: Drugs-to-avoid criteria (e.g. Beers and Zhan criteria) have increasingly been
used as quality measures to assess and compare prescribing quality across providers
and health systems. This study highlights substantial problems which exist when these
criteria are used in this manner.

Steinman MA et al. Arch Intern Med 2009;169(14):1326-1332.

Authored by:
Jim Hoehns, Pharm.D., BCPS; Northeast Iowa Family Medicine Residency
Erin Lockard, Pharm.D., Northeast Iowa Family Medicine Residency
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Authored by:
Jim Hoehns, Pharm.D., BCPS; Northeast Iowa Family Medicine Residency
Erin Lockard, Pharm.D., Northeast Iowa Family Medicine Residency