March 2015 - Department of Pharmacy Practice

DIS News
Col le g e of He a lt h Pr of e s s io ns a n d B iom e d ica l S c i e nce s
Dr ug Infor m a tio n S e r vi ce
PATIENT INFORMATION:
Antiphospholipid Syndrome
Antiphospholipid syndrome (APS) is a disease
that destroys phospholipids, a type of fat.
Without phospholipids in the blood, blood
clots are more likely to form. Clots usually
form in the legs, lungs, or brain. In women,
clots from APS can lead to complications in
pregnancy.
Approximately 40-50 people out of 100,000
have APS. It is usually diagnosed in young to
middle-aged adults, and women are more likely to develop APS than men.
What are the risk factors for APS?
 Autoimmune diseases such as lupus or
rheumatoid arthritis where the immune
system mistakenly destroys healthy cells

Infections such as syphilis, hepatitis C
infection, or HIV infection

Medications that treat heart problems
(e.g., propranolol, quinidine, or hydralazine), medications that treat seizures (e.g.,
phenytoin), or medications that treat infections (e.g., amoxicillin)

Relatives with APS
What are the symptoms of APS?
 Clots in the legs cause leg pain or swelling, sores, or lacy-like rash called livedo
reticularis

Clots in the lungs cause chest pain or difficulty breathing

Clots in the brain cause arm or leg numbness, confusion, or headache

Pregnancy complications like recurrent
miscarriages or premature births
How is APS diagnosed?
APS is diagnosed based on symptoms and the
detection of the antibodies that damage normal
cells in your blood tests. Two blood tests separated by 12 weeks are required to confirm the
diagnosis.
What are the treatments for APS?
Currently, there is no treatment to prevent the
loss of phospholipids. The present treatment is
the use of anticoagulants (blood thinners) to decrease the risk of forming clots.
Heparin or enoxaparin (Lovenox®) are two
blood thinners commonly used to treat APS.
These are injections that work quickly and are
often started in combination with an oral blood
thinner. It can take several days for oral blood
thinners to work, so the injections are used to
prevent clots during that time period. Once the
oral blood thinner starts working, the heparin or
enoxaparin injections are stopped while the oral
blood thinner is continued.
Warfarin (Coumadin®) is the most common oral
blood thinner. It is effective in preventing clot
formation, but may increase the risk of bleeding.
Patients on warfarin or other blood thinners
should report any bruising or bleeding events to
their healthcare provider .
March 2015
Volume 19, Issue 3
Inside this issue:
Harvoni®
(ledipasvir/
sofosbuvir)
2
Cleviprex™
(clevidipine)
3
Light therapy for
seasonal affective
disorder
5
Patient Information: 6
Guillain-Barré Syndrome
Aspirin may be used in addition to warfarin to
further prevent clot formation.
International Normalized Ratio (INR) test:
Patients on warfarin are required to go to a clinic
regularly for INR tests to make sure the warfarin
dosage is appropriate. The INR test measures the
time it takes for blood to clot, and the optimal
result of this test is between 2 and 3. If the INR
is below 2, blood clots are more likely to form.
If the INR is above 3, bleeding is more likely.
Treatment of APS during pregnancy
The typical treatment for APS in pregnant women is the combination of aspirin with heparin or
enoxaparin injections. Warfarin is generally not
recommended to treat APS during pregnancy
because of the risk of birth defects.
We welcome any comments
and suggestions for future
newsletter topics.
Editors in Chief:
By Yawen Deng, PharmD Candidate
References on Page 4
Sherrill Brown, DVM, Pharm.D, BCPS
Christina Buchman, PharmD
Harvoni® (ledipasvir/sofosbuvir) for Hepatitis C
Ledipasvir/sofosbuvir is the first treatment
for HCV genotype 1 that does not require
peginterferon.1 Treatment with ledipasvir/
sofosbuvir is much more convenient than
prior treatment options because it only requires taking one tablet per day. Response
rates in clinical trials were greater than 90%
in patients with or without cirrhosis. Treatment was also effective in patients who had
failed other HCV regimens . Patients can be
treated in as few as 8 weeks or for as long as
24 weeks depending on prior treatment status and the presence of cirrhosis.1
Ledipasvir inhibits HCV NS5A protein.
NS5A interacts with viral RNA and is required for replication, although the mechanism by which NS5A acts is still under investigation.2
Sofosbuvir inhibitis HCV NS5B RNAdependent RNA polymerase.1 Sofosbuvir is
a nucleotide prodrug that is metabolized to
the active uridine analog (GS-461203),
which is incorporated into HCV RNA and
acts as a chain terminator. The active metabolite is not a substrate of human DNA,
RNA, or mitochondrial RNA polymerase.1
consecutive measurements with detectable HCV RNA or a detectable HCV
RNA level at the last available measurement during the post-treatment period
after achieving an undetectable level)
rates were very low in the trials.1,3-5
One tablet (90 mg ledipasvir
and 400 mg sofosbuvir) taken
by mouth once daily with or
without food.
Treatment Duration:1
Ledipasvir/sofosbuvir was not compared
to other treatments for hepatitis C in the
3 studies, so how it compares to other
treatments is unknown. The studies only
included patients with HCV genotype 1,
so the results may not be generalizable to
patients with other genotypes.1,3-5
 Treatment-naïve with or
without cirrhosis: 12
weeks*
 Treatment-experienced
without cirrhosis: 12 weeks
 Treatment-experienced with
cirrhosis: 24 weeks
Adverse reactions to ledipasvir/
sofosbuvir were generally mild and included fatigue (13-18%), headache (1117%), nausea (6-9%), diarrhea (3-7%),
and insomnia (3-6%).1 No absolute contraindications to ledipasvir/sofosbuvir
were identified in the clinical trials.
However, ledipasvir/sofosbuvir may
interact with P-gp inducers and acidreducing agents, leading to reduced efficacy. P-gp inducers (such as rifampin
and St. John’s wort) decrease ledipasvir/
sofosbuvir levels by increasing its elimination. Acid-reducing agents may decrease absorption of ledipasvir because
solubility of ledipasvir decreases with
increased gastric pH. Ledipasvir/
sofosbuvir does not undergo CYP450
metabolism.1
* 8 weeks of therapy may be
considered in treatment-naïve
patients without cirrhosis who
have pre-treatment HCV
RNA levels less than 6 million IU/mL. Relapse was
greater for 8 week treatment
than 12 week treatment in
phase III trial.5
Pregnancy1
Category B. No data in
humans.
Renal Impairment1
By Robert Mayer, PharmD Candidate
Safety has not been established in patients with renal
failure.
REFERENCES:
Hepatic Impairment1
1.
2.
In clinical trials, more than 90% of patients
treated with ledipasvir/sofosbuvir achieved a
sustained virologic response (SVR) 12
weeks after treatment completion.1,3-5 Three
phase III randomized, open- label trials
(ION-1 to 3) evaluated ledipasvir/sofosbuvir 3.
as monotherapy and in combination with
ribavirin. Addition of ribavirin to ledipasvir/sofosbuvir treatment was not associated
with improvement in outcome. Relapse (2
4.
Volume 19, Issue 3
Dosage:1
Safety and efficacy has not
been established in patients
with decompensated cirrhosis.
Harvoni [package insert]. Foster
City, CA: Gilead Sciences; 2014
October.
Ascher DB, Wielens J, Nero TL, et
al. Potent hepatitis C inhibitors bind
directly to NS5A and reduce its affinity for RNA. Sci Rep
2014;4:4765.
Afdhal N, Zeuzem S, Kwo P, et al.
Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection.
N Engl J Med 2014;370:1889-1898.
al. Ledipasvir and sofosbuvir for
previously treated HCV genotype
1 infection. N Engl J Med
2014;370:1483-1493.
5.
Kowdley KV, Gordon SC, Reddy
KR, et al. Ledipasvir and Sofosbuvir for 8 or 12 weeks for chronic
HCV without cirrhosis. N Engl J
Med 2014;370:1879-1888.
Afdhal N, Reddy R, Nelson DR, et
Page 2
Cleviprex™ (clevidipine) Injection for Acute Hypertension
Cleviprex™ (clevidipine) is an intravenous (IV), short-acting, third-generation,
dihydropyridine calcium channel blocker. It was approved for the treatment of
acute hypertension when oral therapy is
not feasible or warranted.1 Clevidipine
effectively decreases blood pressure in
patients undergoing cardiac surgery.2-4
Fewer treatment failures occurred with
clividipine than with placebo in patients
undergoing cardiac surgery in 2 doubleblind trials (ESCAPE-1 and ESCAPE2).2,3 Treatment failure was classified as
lack of efficacy (no reduction in blood
pressure), insufficient efficacy (did not
achieve 15% reduction), or safety failures (adverse events). Clevidipine (0.5
mg/mL in 20% lipid solution) or placebo
(20% lipid emulsion) were administered
via peripheral or central venous infusion
for at least 30 minutes in each trial. The
initial rate of infusion was 0.4 mcg/kg/
min for both treatments. Infusion rates
were titrated to response or to a maximum of 8 mcg/kg/min. 2,3
The ESCAPE-1 trial evaluated clevidipine for the management of preoperative hypertensive episodes in patients
undergoing cardiac surgery.2 Preoperative systolic blood pressure had to be
≥160 mmHg for enrollment in the study.
Fifty-three patients received clevidipine
and 52 patients received placebo. Clevidipine reduced blood pressure to target
levels within a median of 6 minutes.
Fewer patients had treatment failure with
clevidipine (7.5%)
than with placebo
(82.7%; p<0.0001).2
ESCAPE-2 compared
clevidipine to placebo
for the management
of postoperative hypertensive episodes in
patients following
cardiac surgery.3 Patients were included
in the study if their
systolic blood pressure was ≥140 mmHg
within 4 hours of cardiac surgery. SixtyPage 3
one patients received clevidipine and 49
received placebo. Treatment success
was achieved in significantly more patients in the clevidipine group than placebo (91.8% vs. 20.4%, p<0.0001). Median time to target systolic blood pressure was 5.3 minutes with clevidipine
treatment. Five patients in the clevidipine group failed treatment— 1 due to
atrial fibrillation, 2 due to hypotension,
and 2 due to insufficient efficacy.3
Limitations of the ESCAPE studies included potential influence on arterial
blood pressure by other medications
given prior to initiation of the study
drugs. In addition, the data may not be
generalizable since the trials were only
conducted in patients undergoing cardiac
surgery.2,3
Clevidipine was more effective at maintaining systolic blood pressure than nitroglycerin, sodium nitroprusside, and
nicardipine in the ECLIPSE trials.4 The
ECLIPSE studies were 3 randomized,
open-label studies comparing clevidipine
to the active controls either perioperatively (nitroglycerine and sodium nitroprusside) or postoperatively
(nicardipine). The incidences of death,
myocardial infarction, stroke, and renal
dysfunction were similar between clevidipine and the other medications. One
limitation of the study was the openlabel design, although the committees
analyzing safety were blinded. While
clevidipine administration was standard-
ized among the study centers, the comparator drugs were administered according to institution-specific protocols, which may have affected the results and limits generalizability.4
Adverse events reported were similar
between clevidipine and comparator
treatments in the ESCAPE and
ECLIPSE trials.2-4 The most common
events reported in the clevidipine
group in each trial include atrial fibrillation, fever, nausea, acute renal insufficiency, and insomnia.2-4 Clevidipine
use is contraindicated in patients with
soy or egg allergies, patients with defective lipid metabolism, and patients
with severe aortic stenosis.5
Clevidipine should be administered via
a central or peripheral line.5 Clevidipine dosing should be initiated at 12 mg/hour. The dose should be doubled at 90 second intervals initially,
then increased by less than double every 5-10 minutes as the blood pressure
reaches goal. A dose increase of 1-2
mg/hour should reduce the systolic
blood pressure by approximately 2-4
mmHg. The typical maintenance dose
is 4-6 mg/hour to achieve the desired
therapeutic response. The maximum
dose is 16 mg/hour. Because clevidipine is formulated as a lipid emulsion, no more than 1000 mL or an average of 21 mg/hour clevidipine should
be given within 24 hours due to lipid
load restrictions.5
In clinical trials, clevidipine effectively
lowered blood pressure in acute hypertensive episodes when compared to
placebo and standard treatment. Clevidipine appears to be a safe alternative
to commonly used agents, such as sodium nitroprusside and nicardipine,
with the added benefit of providing
superior blood pressure control. Further trials need to be completed to determine efficacy and long-term safety
of clevidipine for blood pressure reduction.
By Teale Steffes, PharmD Candidate
References on Page 4
DIS News
Antiphospholipid Syndrome References (from page 1)
1.
2.
Movva S, Belilos E, Carsons S, et
al. Antiphospholipid syndrome
(6/19/14). Medscape Web site.
Available at: http://emedicine.me
dscape.com/article/333221-ove
rview. Accessed November 30,
2014.
Meroni PL. Antiphospholipid syndrome (3/2013). American College
of Rheumatology Web site. Available at: https://www.rheumatolo
gy.org/Practice/Clinical/Patients/
Diseases_And_Conditions/
Antiphospholipid_Syndrome/. Accessed November 30, 2014.
lipid-syndrome/basics/definition/
con-20028805. Accessed November 30, 2014.
3.
Cohen D, Berger SP, Steup5.
Beekman GM, Bloemenkamp KW,
Bajema IM. Diagnosis and management of the antiphospholipid
syndrome. BMJ 2010;340:c2541.
Lim W, Crowther MA, Eikelboom
JW. Management of antiphospholipid antibody syndrome: a systematic review. JAMA
2006;295:1050-1057.
4.
Antiphospholipid syndrome. Mayo
Clinic Web site. Available at:
http://www.mayoclinic.org/
diseases-conditions/antiphospho
Clevidipine References (from page 3)
1. Cleviprex™ (clevidipine) (n.d.).
CenterWatch Web site. Available at:
https://www. centerwatch.com/druginformation/fda-approved-drugs/
drug/999/cleviprex-clevidipine. Accessed November 21, 2014.
2. Levy JH, Mancao MY, Gitter R, et
al. Clevidipine effectively and rapidly controls blood pressure preoperatively in cardiac surgery patients:
results of the randomized, placebocontrolled efficacy study of clevidipine assessing its preoperative
antihypertensive effect in cardiac
surgery-1. Anesth Analg 2007;
105:918-925.
3. Singla N, Warltier DC, Gandhi SD,
et al. Treatment of acute postoperative hypertension in cardiac surgery
patients: an efficacy study of clevidipine assessing it postoperative
antihypertensive effect in cardiac
surgery-2 (ESCAPE-2), a randomized, double-blind, placebocontrolled trial. Anesth Analg
2008;107:59-67.
tients. Anesth Analg 2008;107:
1110-1121.
5. Cleviprex [package insert]. Parsippany, NJ: The Medicines Company; 2011 December.
4. Aronson S, Dyke CM, Stierer KA,
et al. The ECLIPSE trials: comparative studies of clevidipine, nitroglycerin, sodium nitroprusside, and
nicardipine for acute hypertension
treatment in cardiac surgery pa-
Guillain-Barré Syndrome References (from page 6)
1.
2.
Guillain-Barré Syndrome fact sheet
(7/2011). National Institute of Neurological Disorders and Stroke Web
site. Available at: http://
www.ninds.nih.gov/disorders/gbs/
detail_gbs.htm. Accessed November 24, 2014.
Guillain-Barré Syndrome
(10/22/2014). CDC Web site.
Available at: http://www.cdc.gov/
flu/protect /vaccine/
Page 4
guillainbarre.htm. Accessed November 25, 2014.
3.
Lexi-Comp, Inc. (5-Minute Clinical Consult ™). Lexi-Comp Inc.;
November 24, 2014.
4.
All about GBS (n.d.). GBS/CIDP
Foundation International Web site.
Available at: http://www.gbscidp.org/gbs/all-about-gbs/. Accessed November 24, 2014.
5.
Guillain-Barré Syndrome
(6/3/2014). Mayo Clinic Web site.
Available at: http://www.mayo
clinic.org/diseases-conditions /
guillain-barre-syndrome/. Accessed November 24, 2014.
DIS News
Light Therapy for Seasonal Affective Disorder
Seasonal affective disorder (SAD) afflicts approximately 5 % of US adults.
The definite cause remains unknown.1,2
Several mechanisms are thought to contribute to seasonal depression including a
shift in circadian rhythm, melatonin irregularities, and depleted serotonin
stores.1,2 Many options are available for
the treatment of SAD.1,3-5 Light boxes
are as effective as certain pharmacological treatments, and their minimal side
effects make them a desirable option for
SAD treatment.1,5,6
Signs/Symptoms of SAD
 Hypersomnia
 Changes in diet or unusual weight gain
 Difficulty concentrating
 Easily fatigued
 Depression
 Feeling of lethargy
Light box therapy
Light box therapy is comparable to medications in the treatment of SAD.1,3-5 The
majority of available light boxes consist
of a bank of florescent lights with a UV
filter which blocks the majority of harmful effects. Currently there is no standardized dose or duration of light therapy
for treatment of SAD. However. the general consensus is that about 5,00010,000 light intensity (lux) for a duration
of about 30 minutes is effective for treatment of SAD. Morning light seems to be
better tolerated than evening light. Depending on the light box, patients should
position the light roughly 24 inches
away from themselves.1,3-5
Full effect from light box therapy is usually seen within 2 weeks, with some patients experiencing a response within 4
days of therapy.4,6 As light therapy is
non-invasive with few adverse effects, it
should be considered as a treatment option for most individuals with SAD.1,3-5
Light box therapy combined with medication does not offer any advantages, as
adjunctive therapy is not more effective
than either agent used alone.7
Dawn Light
Studies suggest light therapy that gets
Page 5
progressively brighter in the morning
during hours of sleep is as effective as
light box therapy.3 The dawn stimulation
study supported this hypothesis. Study
subjects were placed in one of three
groups. In the dawn group, light intensity increased from 0430 to 0600 to a
maximal intensity of 250 lux. The light
therapy group was given bright light at
an intensity of 10,000 lux for 30 minutes
each morning. The placebo group was
given a faux dawn light each morning
with an intensity of 0.5 lux. Those in the
dawn group had a 73% greater response
in clinical depression scores compared to
those in the placebo group.3 More studies are needed to determine the proper
administration, duration, and dose of
dawn light.
Medications
Medications, such as SSRIs, appear to be
a safe and effective option for the treatment of seasonal depression.4,8 Some
guidelines recommend that seasonal depression should be treated the same way
as other types of depression with pharmacological agents Many antidepressants take about a month to reach
their full effect and a month to taper off
of. Treating a disease that only lasts a
few months each year with medications
that have such large lag periods is not
ideal. Especially when treatments with
less severe side effects are readily available.4
Bottom line:
Seasonal affective disorder is a common
type of depression that can easily be
treated with light therapy rather than
medication.
By William Rotter, PharmD Candidate
REFERENCES:
1. Avery DH, Eder
DN, Bolte MA,
et al. Dawn simulation and bright
light in the treatment of SAD: a
controlled
study. Biol Psy-
chiatry 2001;50:205-216.
2. Golden RN, Gaynes BN, Ekstrom
RD, et al. The efficacy of light therapy in the treatment of mood disorders: a review and meta-analysis of
the evidence. Am J Psychiatry
2005;162:656-662.
3. Lam RW, Levitt AJ, Levitan RD, et
al. The Can-SAD Study: a randomized controlled trial of the effectiveness of light therapy and fluoxetine
in patients with winter seasonal
affective disorder. Am J Psychiatry
2006;163:805-812.
4. Nussbaumer B, KaminskiHartenthaler A, Forneris Catherine
A, et al. Light therapy for preventing seasonal affective disorder.
Cochrane Database Syst Rev 2014;
(9):CD011269.
5. Lam RW, Levitan RD. Pathophysiology of seasonal affective disorder: a review. J Psychiatry Neurosci
2000;25:469-480.
6. Reeves GM, Nijjar GV, Langenberg P, et al. Improvement in depression scores after 1 hour of light
therapy treatment in patients with
seasonal affective disorder. J Nerv
Ment Dis 2012;200:51-55.
7. Mortimer N. The effectiveness of
light therapy in comparison to antidepressant therapy in the treatment
of seasonal affective disorder
(SAD): a review. RN Ida 2013;35
(4):12-13.
8. Parry BL, Maurer EL. Light treatment of mood disorders. Dialogues
Clin Neurosci 2003;5:353-365.
Amount of evidence supporting light therapy for SAD
Therapy
Level of Evidence
Light box therapy
Strong evidence
(5,000 -10,000 lux)
Dawn Light
Strong evidence
Low Light
Combination with medication
Little evidence
Little evidence
DIS News
PATIENT INFORMATION:
Guillain-Barré Syndrome—An Overview
Guillain-Barré syndrome (GBS) is
caused when a person’s immune system attacks his or her own nerve cells.
This leads to numbness, weakness, and
tingling in the arms and legs. The exact cause of GBS is unknown. GBS is
often preceded by an infection or, in
rare cases, vaccinations. Infections or
vaccinations might change the appearance of nerve cells, so the immune
system attacks the cells.
GBS is rare and can occur even if a
person has not been vaccinated. There
are approximately 1.8 cases of GBS
per 100,000 people each year in the
United States.
Symptoms of GBS:




Symptoms occur on both sides of
the body
Tingling in fingers, toes, ankles, or
wrists
Weakness in legs that spreads to
upper body
Unsteady step




Difficulty with swallowing, eye/
facial movements, and speaking
Severe pain, aches, or cramps that
worsen at night
Hard time breathing
Fast heart rate
Over 50 years old
Male gender
Recent infection (1/2 to 2/3 of people with GBS had previous infection)
Diagnosis of GBS:
Diagnosis is based on a person’s symptoms. GBS can be hard to identify in the
early stages because symptoms are similar to other diseases. Diagnosis can be
confirmed by testing nerve and muscle
function or a spinal fluid sample.
Treatment of GBS:



Two options for treatment
Plasma exchange
Immunoglobulin injections, which
help the immune system, attack invading organisms
Physical therapy
Recovery from GBS:
Risk Factors for GBS:






No known cure
Available treatments decrease
symptom severity
Recovery can take months to years. Muscle aches, pain, and fatigue can occur with
normal activity after recovery.
Things To Remember:





Earliest symptoms are back and leg
pain, numbness, and weakness
An infection followed by weakness
suggests GBS
Lack of knee-jerk reflex is a red flag
for severe GBS
Healthcare providers are your best
resource
If symptoms of GBS occur, contact
your provider for an appointment or
report to an emergency department
By Teale Steffes, PharmD Candidate
From: http://www.medcomic.com/031313.html
College of Health Professions and
Biomedical Sciences
Drug Information Service
The University of Montana
Skaggs School of Pharmacy
Phone: 406-243-5254
Fax: 406-243-5256
Email: druginfo@umontana.edu
www.health.umt.edu/DIS
References on Page 4