Download 11SUN Handouts.indd - The Collaborative Education Institute

Keynote:
News Worthy
“Unintentional Overdoses”
ACPE UAN 107-000-11-025-L01-P & 107-000-11-025-L01-T
Activity Type: Knowledge-Based
0.1 CEU/1.0 Hr
Program Objectives for Pharmacists & Technicians: Upon completion of this program, participants should
be able to:
1. Define the terminology of unintentional misuse, intentional misuse, and intentional abuse.
2. Explain new stories involving drugs and why they are considered “accidental”.
3. Describe basic toxicology of drugs that have been involved in media-covered accidents.
Speaker: Tama Sawyer, PharmD, DABAT, graduated from Emporia State University with a
double degree in Chemistry and Microbiology in 1980. She then went on and graduated from the
University of Kansas School of Pharmacy in 1984, and earned her PharmD degree in 2004 also from the
University of Kansas. Dr. Sawyer passed the American Board of Applied Toxicology exam in 2007 and
is currently the Director of the Poison Control Center at the University of Kansas Hospital.
Speaker Disclosures: Tama Sawyer report she has no actual or potential conflicts of interest in
relation to this program. The speaker has indicated that off-label use of medications will be discussed
during this presentation.
Faculty Disclosure
News Worthy “Unintentional
Overdoses”

Tama Sawyer reports she has no actual or potential
conflicts of interest associated with this presentation.

Tama Sawyer has indicated that off-label use of medication
will be discussed during this presentation.
Tama Sawyer, PharmD, DABAT
Director
The University of Kansas Poison Control
Center
Learning Objectives

Understand the terminology of unintentional misuse, intentional
misuse and intentional abuse

News stories involving drugs. Why are they all accidental?

Basic toxicology of drugs in the News
Fact

"Unintentional poisoning” is now the
second leading cause of unintentional
injury death in the US.

In 2005 (ages 35 to 54) , unintentional
poisoning surpassed motor vehicle crashes
as the leading cause of unintentional
injury death.
Poison Center Terminology
Pre-Assessment Questions
Unintentional Misuse
Therapeutic Error
 Intentional Misuse
 Intentional Abuse

A 72 yo female bleaches her coffee cup to
remove the stains. She left the cup of
clorox on the counter only to come back
later and drink from it.

A 16 yo passes out after using a keyboard
duster spray.


Pre-Assessment Questions


A 21 yo takes 6 methylprednisolone
tablets thinking it was her Tylenol.
A 21 yo took 6 Tylenol 500 mg tablets
thinking it was her methylprednisolone.
What is a Poison????
Pre-Assessment Questions

A 24 yo male calls because he ingested a
mouthful of gas while siphoning.

A 29 yo male calls because he got gas in
his ear when a gas line broke while he was
working underneath his car.
Oh mama! Does she expect me to
know this?
The Number One Poison
Our number one victims of toxic
substances
Innovative Poison Prevention!
Let’s Look at Drug Related Events
Poison Centers VS Coroners

“Harvey Pekar died from an accidental overdose
of antidepressants, a coroner has determined.”

“Fluoxetine is used as a treatment for major
depression, and bupropion is used for depression
and to aid quitting smoking.”

“Pekar had been suffering from prostate cancer,
asthma, high blood pressure and depression,
according to Cannon. Pekar had gone to bed
about 4:30 p.m. Sunday in good spirits, his wife
told police.”
Last thing I remember I was running for the door
I had to find the passage back to the place I was before
"Relax," said the night man, "We are programmed to
receive
You can check out any time you like but you can never
leave"
Accidental Overdose? Really?




Goes to bed at 4:30
pm
He had fought cancer
twice before and was
recently diagnosed
with cancer yet again.
Fluoxetine and
Bupropion?
Just finished writing
what he called the last
book of his life.
Is this accidental?

This would be a
reasonable depiction
of the amount of pills
Mr. Pekar would have
to have taken.
A brave man once requested me
to answer questions that are key
is it to be or not to be
and I replied 'oh why ask me?'
'Cause suicide is painless it
brings on many changes and I
can take or leave it if I please.
Accidental.......or Not?

A Utah nursing home is facing a wrongful
death lawsuit after a resident allegedly
died due to a fentanyl overdose that
occurred when a staff member applied
three fentanyl pain patches to the
resident’s neck, instead of one patch
every three days.
Recent Drug Events

Greg Giraldo -- The Harvard law graduate turned full time
comedian died September 29, 2010 after 5 days in the
hospital. The comic was found unconscious at a party in
New Jersey just after his initial appearance at New York
drug addiction recovery rally. The cause of death for the
young celebrity? Overdose. Giraldo died from an accidental
overdose of prescription pills leaving his 3 young children
fatherless and family devastated.

Numero Uno Medication in the High
School Crowd
Adverse Drug Reaction



Comedian Greg Giraldo
not so funny anymore
Adverse Reaction to what?
Police report finding an "emotionally disturbed
person" at New York's Plaza Hotel
Actor Charlie Sheen suffered an "adverse
allergic reaction" to medicine while at New
York's Plaza Hotel and was taken to a hospital
early Tuesday, his representative said.
Sheen spent at least a month this year at a
Malibu, California, rehab center, but it was never
disclosed what he was treated for.
Corey Haim - Accidental OD
Dead
Age 38

Disulfiram is being tested to treat cocaine
addiction. Disulfiram may block the pleasurable
and rewarding effects caused by an excessive
release of dopamine in the brain after cocaine
use. Instead of experiencing euphoria and other
feelings of well being associated with cocaine
use, an individual who has taken disulfiram
before using cocaine will experience adverse
reactions such as anxiety, dysphoria or paranoia.



"He got out of bed about 1:30 this morning,
was a little unsteady on his feet," Winter said.
Haim's mother then called the paramedics.
Haim's mother said her son had been suffering from
"flu-like symptoms," Winter said, adding that four
prescription pill bottles were found in the apartment but no
illicit drugs.
Haim struggled with cocaine and Valium addiction and was
reportedly admitted to rehab more than 15 times.
The causes of death include diffuse alveolar damage (from
respiratory distress), pneumonia and hypertrophic
cardiomyopathy (thickening of the heart muscle) with
coronary arteriosclerosis.
No illicit drugs found but…….


Haim bought 195 doses of the anti-anxiety
drug Valium, 194 doses of the muscle
relaxant Soma, 149 doses of the powerful
painkiller Vicodin and 15 Xanax antianxiety pills from February 2 to March 5.
He died March 10, 2010 from an
accidental overdose.
Alcohol and Cocaine…



When you mix Alcohol with Cocaine it forms the
active compound. COCAETHYLENE
This is significant because this compound has a
longer half life than either alcohol or cocaine and
it significantly increases the risk of sudden death
Beta Blockers should be avoided in patients with
cocaine cardiac effects. Cocaine-induced
vasoconstriction appears to be due to alphaadrenergic stimulation. Unopposed alphaadrenergic stimulation, associated with betaadrenergic blocking agents, may result in the
potentiation of coronary vasoconstriction.
Casey Johnson
Similar circumstances



Jimmy Lee Lindsey Jr.
(May 1, 1980 – Jan. 13, 2010), better known
by the stage name Jay Reatard, was an American garage
rock musician from Memphis Tennessee.
Lindsey was found dead in his home in Memphis, around
3:30 a.m. on Wednesday, January 13, 2010. He was found
in his bed by a roommate. Lindsey was 29 years old. A
statement was posted on the website of Goner Records,
that Reatard had died in his sleep. Friends of Lindsey stated
that he had recently complained of flu-like symptoms.
An autopsy was performed reported on February 3 that
Lindsey had died of "cocaine toxicity, and that alcohol was
a contributing factor in his death."
Cocaine drug detection = 3 hours
Metabolites = 24 hours




Many users report flu-like symptoms when coming down
from a high very soon after the effects of the substance
have worn off
Cocaine is thought to be responsible for a quarter of all
heart attacks in people under the age of 45. Cardiac effects
from cocaine usually occur 48 hours after the last use.
Cocaine users risked life-threatening abdominal problems
with symptoms including abdominal pain, nausea, vomiting
and bloody diarrhea, which can occur between one and 48
hours after taking the drug.
Autopsies associated with cocaine abusers frequently
indicate respiratory failure due to pulmonary edema and
pneumonitis caused by the crystals associated with cocaine
being imbedded in the lining of the lungs.
Diabetic Ketoacidosis

Diabetic Socialite daughter of Robert Johnson IV and heir to
the Johnson and Johnson dynasty.


After refusing to seek treatment for drug abuse,was cut off
financially by her family.


An unidentified caller reported that Johnson was ice cold,
and her hands were turning blue. The caller also stated that
Johnson was on medications, and that they often got "all
screwed up".


On February 4, 2010, the Los Angeles Coroner's Office
announced that she had died of diabetic ketoacidosis. She
was reported to have neglected to take her medication, and
died naturally.

There is often a particular problem that has led to
the DKA episode.
Such things as pneumonia, influenza,
gastroenterities, UTI, pregnancy, stroke or the
use of cocaine.
In a retrospective case control study of hospital
admissions for diabetic ketoacidosis, cocaine
users accounted for 102 of 720 admissions
(14%)
Cocaine abusers were less likely to have an
illness as an identified precipitant for DKA, were
more likely to have missed one or more doses of
insulin,
Fame and famine
Former American Idol winner
Fantasia suicide attempt with
painkillers (ASA) and
sleeping pills. (DPH


“Her injuries are not life threatening. She
was dehydrated and exhausted at the
time.” (she was also pregnant)





Andy Irons 32, 11-2-2010




3 times World Surfing
Champion dies of dengue
fever…(or not)
Methadone was found
inside a prescription bottle
labeled zolpidem.
Numerous other
medications were found on
a nightstand.
Irons is survived by wife,
Lyndie and new born child
born in December 2010.
Aspirin is a very bad player in overdoses.
Initial symptoms include GI upset, tinnitus, and
tachypnea/hyperpnea, followed by coma,
seizures, hyperthermia, hypotension, pulmonary
and cerebral edema and finally death.
DPH causes tachycardia, hallucinations, delerium,
hypertension followed by hypotension, seizures
and coma
Aspirin readily crosses the placental barrier and is
found in a higher concentration in the fetal
plasma than in the mothers plasma
Suicide attempt or not?
Methadone
Methadone is a synthetic opioid similar in structure
to propoxyphene
Multicompartmental elimination. Initial elimination
half-life 12 to 24 hours, followed by slower
elimination half-life of 55 hours
There is little margin between a therapeutic
methadone dose for an opioid tolerant person
and a toxic dose with doses of 30 to 40 mg
potentially lethal for a non-tolerant adult.
Children are particularly vulnerable to overdose.
Inadvertent ingestion of methadone was found to
be the most toxic of the opioids; doses as low as
a single tablet can lead to death (10 mg can be
potentially lethal for a 10 kg toddler).
Terrorists in Russia – Oct. 2002
Propoxyphene –Goodbye to a bad drug
Terrorist stormed the Dubrovka Theater in
Moscow in October 2002
 30 -40 terrorist?
 700-900 hostages taken
 Russia shut pumped a super (fentanyl)
gas through the ventilation system.
 130 - 200 people died immediately, many
others have long term medical effects
 Puttin says it was a harmless gas.


Propoxyphene causes various
dysrhythmias including tachycardia,
bradycardia, ventricular dysrhythmias and
atrioventricular blocks have been
reported. QRS and QT intervals may
become prolonged.
 Now add two other components:


Propoxyphene isn’t a very good pain killer
It is almost always in combo with APAP
Antidepressant Death

Authorities said on Sept. 13, 2010 53-year-old woman
intentionally gave her 4 month old grandson a prescription
antidepressant (imipramine)

She was a nurse, but had her license revoked in 1996 for
diverting drugs

She initially denied giving the baby the drugs. She later admitted
to putting pills into the baby’s bottle on two occasions

After discovering that the pills were not dissolving in the milk
quickly, she told police she removed the coating and rubbed the
medication on the baby’s gums until it nearly dissolved, washing it
down with infant formula. She told police she knew the side
effects to look for but didn’t see any.

She went shopping after giving the baby the medication and
didn’t return for 5 hours.
Interesting News from around the
World

We (the USA) aren’t the only country with
problems
Tricyclic Antidepressants

Half life of imipramine 13 + 3 hours

Doses above 3.5 milligrams/kilogram of tricyclic
antidepressants or serum concentrations higher than 150
nanograms/milliliter may increase the risk of asymptomatic
electrocardiographic changes in children and adolescents.
As little as 15mg/kg may be fatal in a child.

CNS depression, lethargy, disorientation, and ataxia are
common. Coma and seizures may develop abruptly.

Uncontrolled seizures may result in brain damage,
hyperthermia, metabolic acidosis, rhabdomyolysis, and
myoglobinuria.
NO Naloxone in Australia


“The radio is blastin', someone's knockin' at the door
I'm lookin' at my girlfriend - she just passed out on
the floor
I've seen so many things I ain't never seen before
Don't know what it is - I don't wanna see no more”


"Australia is the only continent left where there's
no Naloxone distribution," Dr Maxwell told AAP.
She says while there are understandable
concerns about intervening while users are taking
drugs, Naloxone saves lives.
"We're supposed to wait until they are ready to
stop using but in order for them to get better
they need to still be alive," she said.
"Naloxone is inexpensive, it's ridiculously safe,
there's simply no downside to it."
“It’s too bad that stupidity isn’t painful” Anton LaVey
REALLY??? REALLY!!!



Dr Maxwell says the availability of Naloxone
provides a sense of hope to opiate users and
allows them to contemplate a drug-free future.
"If I have to wake up every morning knowing
that I'm going to need to inject two or three
times today and each time I inject I take the
chance of death, that doesn't leave me with a
whole lot of interest for future planning," she
says.
"However, if I have more hope that I'm going to
be alive next week I have a reason to make next
week better than this week."
Marijuana- Crazed?

“Cannabis-crazed schizophrenic free to
murder policeman after care in the
community scaled back his treatment “
History

Cocaine
Illicit drugs have a history in prescription
and OTC products.




Some are quite interesting

Some are just scary
Cocaine and Alcohol
Sweet cousin cocaine, lay your cool cool hand on my head
Ah, come on sister morphine, you better make up my bed
Cause you know and I know in the morning I’ll be dead
Morphine
1914
Sold OTC
Instantaneous Cure!
If you wanna get
down,
down on the gound
……
“She don’t lie,
She don’t lie,
She don’t lie.......
Heroin
I don't ever wanna feel like I did that day
But take me to the place I love, take me all the way
I don't ever wanna feel like I did that day
But take me to the place I love, take me all the way
QUAALUDES
Now, they call you prince charming
Can't speak a word when you're full of
'ludes
Say you'll be alright come tomorrow
But tomorrow might not be here for you
Tobacco
Smokin' cigarettes and writing something nasty on the
wall (you nasty boy)
Teacher sends you to the principal's office down the
hall
You grow up and learn that kinda thing ain't right
But while you were doing it-it sure felt outta sight
Chloroform
I could pay off my tab, pour myself in a cab,
An' be back to work before two.
At a moment like this, I can't help but wonder,
What would Jimmy Buffet do?
Marijuana, Codiene, and Chloroform
Who in particular gave Amphetamines to their “workforce”????
Coca-Cola
Amphetamine -Methamphetamine
Barbiturates

“Many of your patients—
particularly housewives—
are crushed under a load
of dull, routine duties that
leave them in a state of
mental and emotional
fatigue…Dexadrine will give
them a feeling of energy
and well-being, renewing
their interest in life and
living.”
Death of the Dream


“They knew all the right people, they took
all the right pills
They threw outrageous parties, they paid
heavenly bills”
Questionable
Accidental/Unintentional
Deaths
I’ve heard people say that Too much of a
anything is not good for you baby”
Or some with pretty darned good stories.
A
“I used to do a little but a little wouldn’t do it
So a little got more and more
I just keep trying to get a little better
Said a little better than before”
Chris Antley – champion horse-racing jockey, drug-related causes
B
“It all goes back to when I dropped out at school
Having fun, I was living the life
But now I got a problem with that little white rock
See I can't put down the pipe”
Len Bias (22) – basketball star; died of cocaine overdose
before ever playing in the NBA
C
“He's The One They Call Dr.Feelgood
He's The one That Makes Ya Feel Alright
He's The One They Call Dr.Feelgood
He's Gonna Be Your Frankenstein”
Max Cantor – journalist, actor, heroin overdose, he became
an addict while researching heroin addicts in New York.
E and F
“There's a giant doing cartwheels a statue wearin'
high heels.
Look at all the happy creatures dancing on the lawn.
A dinosaur Victrola list'ning to Buck Owens”
Chris Farley (33) – comedian who rose to fame on Saturday
Night Live, cocaine and morphine overdose (speedball)
H
I can see through the mountains
Watch me disappear
I can even touch the sky
Swallowing colors of the sound I hear
Am I just a crazy guy
You bet
Elizabeth Hulette (42) – professional wrestling manager,
accidental overdose of alcohol, meprobamate, carisoprodol,
hydrocodone, and promethazine
D
“Mother needs something today to calm her down
And though she's not really ill
There's a little yellow pill”
Albert Dekkar – actor, unknown drug
G
I want a new drug
One that won’t make me sick
One that won’t make me crash my car
Or make me feel three feet thick
Trevor Goddard – former professional boxer, turned actor,
cocaine, heroin, hydrocodone, and diazepam overdose
(I) J, K
Am I sweating?
Or are these tears on my face
Should I be hungry?
I can’t remember the last time I ate
Call Someone, I need a friend to talk me down
David Kennedy – 4th child of Robert F. Kennedy,
cocaine/meperidine
L
I’m coming down, coming down like a monkey
But it’s alright
Like a load on your back that you can’t see
But it’s alright
Try to shake it loose, cut it free, let it go, get it away from me
Frankie Lymon – musician, doo wop singer, heroin overdose
O, P, Q
It don’t make no difference,
Escape one last time
It’s easier to believe in this sweet madness
Oh this glorious sadness
That brings me to my knees
Elvis Presley, singer, multiple drug overdose
S
I
I
I
I
pushed my soul in a deep dark hole and then I followed it in
watched myself crawling out as I was a crawling in
got up so tight I couldn’t unwind
saw so much I broke my mind
M,N
So send me to the pharmacy
So I can lose my memory
I’m elated
Medicated
Lord knows I tried to find a way to run away
Billy Mays, TV promo salesman-cocaine induced hypertension
R
I was alone, I took a ride
I didn’t know what I would find there
Another road where maybe I
Could see another kind of mind there
Don Rogers (23) – American football player, cocaine
overdose
T, U, V
The higher you are, the farther you fall
The longer the walk, the farther the crawl
My body, my temple, This temple it tilts
Tom Simpson – road racing cyclist, dehydration-exhaustion
while cycling and using amphetamines
D. M. Turner (34) – author, drowned in a bathtub, ketamine
W, (X) ,Y and (Z)
One Pill makes you larger
And one pill makes you small
And the ones that mother gives you
Don’t do anything at all
Thank You for your Attention
They call it Wacky Dust
It’s something you can’t trust
And in the end the rhythm will stop
When it does, then you’ll just drop
From happy wacky dust
Dave Waymer (34) –NFL defensive back, cocaine-induced
heart attack
Wacky Dust
Ella Fitzgerald
1937
Post-Assessment Questions

A 17 yo eats a tablespoon of Nutmeg. He
tells mom he did it on a dare from his
friend.

A mom gives a dose of ibuprofen to her
child, dad repeats the dose about 15
minutes later because he didn’t know
mom had given it.
Post-Assessment Questions


Post-Assessment Questions

What is the medication of choice for
teenagers (pre college age)?
What drug should be avoided when
dealing with a Cocaine OD?
Which is more likely to cause a problem



Cocaine OD
Alcohol OD
Combo of Alcohol and Cocaine
Post-Assessment Questions

What makes Methadone so deadly?
The Clinical Debates
ACPE UAN 107-000-11-026-L01-P & 107-000-11-026-L01-T
Activity Type: Knowledge-Based
0.1 CEU/1.0 Hr
Program Objectives for Pharmacists: Upon completion of this program, participants should be able to:
1. Recognize opportunities for improvement in response and remission rates with current antidepressant therapies.
2. Identify potential benefits and risks of using atypical antipsychotics as adjunctive agents or monotherapy for
treatment of nonpsychotic depression.
3. Discuss the incidence and general trends for cardiovascular disease (CVD) and CVD risk factors in the US
population.
4. Describe results from primary prevention studies - including Jupiter - and how this information applies to
primary prevention of CVD with statins.
5. Select statements that describe pros and cons of statin use in primary prevention of CVD.
Program Objectives for Technicians: Upon completion of this program, participants should be able to:
1. List current antidepressant therapy options.
2. Recognize benefits and risks of using atypical antipsychotics in the treatment of nonpsychotic depression.
3. Recall the incidence of cardiovascular disease (CVD) and CVD risk factors in the US population.
4. Recognize the pros and cons of statin use in primary prevention of CVD.
Speakers:
Round 1: Use of Atypicals for the Treatment of Depression
Sarah E. Grady, PharmD, BCPS, BCPP, is an Associate Professor, Department of Clinical Sciences,
College of Pharmacy and Health Sciences at Drake University. Her clinical practice site is the psychiatric unit
of Broadlawns Medical Center. Dr. Grady received her Doctor of Pharmacy from the University of Illinois in
1999. She then completed an ASHP-accredited pharmacy practice residency at the Chicago VA Healthcare
System in 2000. After completing her residency, Dr. Grady obtained an academic appointment at Midwestern
University Chicago College of Pharmacy, where she taught for nearly 8 years. She is currently a board-certified
pharmacotherapy specialist and a board certified psychiatric pharmacist. Dr. Grady greatly enjoys teaching,
research, and patient care.
Jill Fowler, PharmD, MSPharm, received her Doctor of Pharmacy degree from the University of North
Carolina at Chapel Hill School of Pharmacy in 2006. She subsequently completed a two-year, American Society
of Health-System Pharmacists-accredited residency in psychiatric pharmacy combined with a Master’s program
in Pharmacy Practice and Administration at The University of Texas at Austin. She is currently the Clinical
Pharmacy Specialist in Psychiatry at the University of Iowa Hospitals and Clinics, where she maintains an
active practice in inpatient psychiatric pharmacy, with a focus on patients admitted to the combined medicinepsychiatry service. She also holds a shared appointed as an Assistant Professor (Clinical) at the University of
Iowa College of Pharmacy.
Speaker Disclosures: Sarah Grady and Jill Fowler report they have no actual or potential conflicts of interest
in relation to this program. The speakers have indicated that off-label use of medications will be discussed during
this presentation.
Clinical Debates: Use of
Atypicals for Treatment of
Depression
Faculty Disclosure



Sarah E. Grady, PharmD, BCPS, BCPP
Associate Professor of Clinical Sciences
Drake University College of Pharmacy &
Health Sciences

Dr. Grady has no actual or potential conflicts of interest
associated with this presentation.
Dr. Grady has indicated that off-label use of medication will
be discussed during this presentation.
Dr. Fowler reports she has no actual or potential conflicts of
interest associated with this presentation.
Dr. Fowler has indicated that off-label use of medication will
be discussed during this presentation.
Jill Fowler, PharmD, MSPhr, BCPP
Clinical Pharmacy Specialist, Psychiatry
University of Iowa College of Pharmacy
Learning Objectives


Upon completion of this program pharmacists will be able to:
 Recognize opportunities for improvement in response and
remission rates with current antidepressant therapies
 Identify potential benefits and risks of using atypical
antipsychotics as adjunctive agents or monotherapy for
treatment of nonpsychotic depression
Upon completion of this program pharmacy technicians will be
able to:
 List current antidepressant therapy options
 Recognize benefits and risks of using atypical antipsychotics in
the treatment of nonpsychotic depression
Pre-Assessment Questions
1.
Which of the following atypical
antipsychotics does NOT have a
formulation approved for adjunctive use
in major depressive disorder?
a.
b.
c.
d.
Olanzapine
Quetiapine
Aripiprazole
Ziprasidone
Pre-Assessment Questions
Pre-Assessment Questions
2. Aripiprazole’s antidepressant properties
may be due to which of the following?
3. In the clinical trials studying
antipsychotics as adjuncts to
antidepressant therapy, how quickly did
some participants notice antidepressant
effects?




a. (Dopamine) D2 antagonism
b. (Serotonin) 5HT2 antagonism
c. 5HT reuptake inhibition
d. NE reuptake inhibition




a. 1-2 hours
b. 1-2 days
c. 1-2 weeks
d. 1-2 months
Pre-Assessment Questions
4.
What is the most common adverse effect
reported with aripiprazole when used as
an adjunct for major depressive disorder?
a.
b.
c.
d.
Pre-Assessment Questions
5.
Weight gain
Dry mouth
Akathisia/restlessness
Hyperglycemia
Atypical antipsychotic agents should have
similar within-class tolerability when used
at lower doses for adjunctive therapy in
major depressive disorder.
True or False?
Epidemiology & disease burden
Depression is a common, chronic, &
disabling condition
 Lifetime prevalence = 17-18%
 In 2000, cost of depression = $83.1 billion
 Increased focus on development of more
effective treatment options

Some of these agents have FDA approval…
ARGUMENT FOR ATYPICALS
FOR DEPRESSION
APA 2000
Greenberg et al. J Clin Psychiatry 2003
Antidepressants





Mainstay of treatment for depression
2/3 of patients will fail to achieve remission with
initial treatment
Range of augmentation & combination strategies
have been used
Limited data from double-blind, randomized,
placebo-controlled studies are available
Recently, evidence has shown that adjunctive
therapy with atypical antipsychotics has potential
for antidepressant effects
Fava et al. Psychiatr Clin North Am 2003
American Psychiatric Association
Practice Guidelines

If a patient has not responded to
treatment after an adequate duration:




Increase dose of current antidepressant OR
Switch to a new antidepressant OR
Augment current antidepressant
The challenge is to adjust treatment to the
individual
APA 2000
Combination & augmentation strategies
– common use w/ limited evidence
Combination
Augmentation
Bupropion + SSRI
Lithium
Venlafaxine + mirtazapine
Thyroid supplementation
Mirtazapine + SSRI
Buspirone
Stimulants
Antipsychotic Augmentation



Typical antipsychotics studied for nonpsychotic
depression
Use of typicals for this purpose declined in the
1980s
Use of atypicals for this purpose began in 1999
 Risperidone
 Olanzapine *
 Quetiapine *
 Aripiprazole *
 Ziprasidone
Nelson et al. Neuropsychiatric Disease and Treatment 2008
Atypical Antipsychotics –
Pharmacologic Rationale


Atypicals have
different neurological
profiles that may
translate to different
clinical effects in
depression
Atypicals have 5HT2
antagonist effects


Aripiprazole *
 Partial D2 agonist,
 Partial 5HT1A
agonist
Quetiapine *



Ziprasidone
 5HT & NE reuptake
inhibition
Efficacy of Adjunctive Aripiprazole

Patients entering phase 2 continued their antidepressant
and were randomly assigned to receive either adjunctive
placebo or adjunctive aripiprazole
Primary endpoint







NE reuptake inhibitor
Partial 5HT1A agonist
Nelson et al. Neuropsychiatric Disease and
Treatment 2008

Efficacy of Adjunctive Aripiprazole

Berman RM et al. CNS Spectr 2009
Marcus RN et al. J Clin Psychopharmacol.
Results

Mean change in Montgomery-Asberg Depression Rating Scale
(MADRS) from end of the prospective phase (week 8) to the end of
randomization phase (week 14)
Berman study
 Placebo = 178
 Aripiprazole = 184
Marcus study
 Placebo = 190
 Aripiprazole = 191
Use of benzodiazepines or other sedative hypnotics were
not allowed
Has shown efficacy in two 14-week, double-blind,
randomized trials of identical design
Both trials had a 8 week prospective treatment
phase & a 6 week randomization phase
Patients received escitalopram, fluoxetine,
paroxetine CR, sertraline, or venlafaxine ER +
single-blind adjunctive placebo
Subjects with inadequate response proceeded to
the next phase


In both studies, change in MADRS score was
significantly greater with adjunctive aripiprazole
than placebo
 -10.1 vs. -6.4 p = < 0.001 (Berman et al.)
 -8.5 vs. -5.7 p = 0.001 (Marcus et al.)
In both studies, remission rates were significantly
higher with adjunctive aripiprazole than placebo
 26.0% vs. 15.7% p = 0.01 (Berman et al.)
 25.4% vs. 15.2% p = < 0.05 (Marcus et al.)
Remission was achieved early
 Week 1 in the Berman trial
 Week 2 in the Marcus trial
Safety

Discontinuation due to adverse events:
Efficacy of Adjunctive Quetiapine




Adjunctive aripiprazole 6.2% vs. placebo 1.7%
(Berman et al.)

Adjunctive aripiprazole 3.7% vs. placebo 1.1%
(Marcus et al.)

Has shown efficacy in two 6-week, double-blind,
randomized, placebo-controlled studies
Subjects had to show inadequate response to at least 1
antidepressant
Participants were randomly assigned to
 Quetiapine XR 150mg daily OR
 Quetiapine XR 300mg daily OR
 Placebo +
Adjunctive to continuing antidepressant
Primary endpoint: change in MADRS total score from
randomization to week 6
Bauer et al. J Clin Psychiatry 2009
El-Khalili et al. Int J Neuropsychopharmacol. 2010
Results – Bauer et al.

Change from MADRS score:


MADRS remission:




-15.26 (quetiapine XR 150mg/day) vs. -14.94
(quetiapine XR 300mg/day) vs. -12.21
(placebo) p = < 0.01

Change from MADRS score:





Improvement in depressive
symptoms seen as early as week 1
Discontinuation due to adverse events:



Quetiapine XR 150mg – 6.6%
Quetiapine XR 300mg – 11.7%
Placebo – 3.7%
- 14.7 (quetiapine XR 300mg/day) vs. – 11.7
(placebo) p = <0.01
MADRS remission:

36.1% quetiapine XR 150mg (p = < 0.05 vs.
placebo)
31.1% quetiapine XR 300mg (p = 0.126 vs.
placebo)
23.8% placebo
Safety – Bauer et al.

Results – El-Khalili et al.
42.5% quetiapine XR 300mg/day
24.5% placebo
p = < 0.01
Improvement in depressive symptoms
seen as early as week 1
Safety – El-Khalili et al.

Discontinuation due to adverse events:



Quetiapine XR 150mg – 11.5%
Quetiapine XR 300mg – 19.5%
Placebo – 0.7%
Meta-Analysis


Meta-Analysis
Objective: to determine efficacy & tolerability of adjunctive
atypical antipsychotics agents in major depression
Trials selected included the following parameters:
 Acute-phase
 Parallel-group
 Double-blind
 Random assignment to adjunctive AP or placebo
 Patients had nonpsychotic depression resistant to
antidepressant therapy
 Response, remission, discontinuation rates were either
reported or obtained
16 trials with 3,480 patients were pooled
 Adjunctive atypical antipsychotics were
significantly more effective than placebo


Response



Remission



Odds ratio = 2.00 (CI = 1.69 – 2.37)
P = < 0.00001
Discontinuation rates


Nelson & Popakostas Am J Psychiatry 2009
Odds ratio= 1.69 (CI = 1.46 – 1.95)
P = < 0.00001
Odds ratio = 3.91 (CI = 2.68 – 5.72)
P = < 0.00001
Common Side Effects of Atypicals

Extrapyramidal symptoms (EPS)

Throwing caution to the wind...

ARGUMENT AGAINST
ATYPICALS FOR DEPRESSION
Comparative Side Effect Burden
Sedation
 Orthostatic hypotension
 Hyperprolactinemia
 Weight gain
 Hyperglycemia/diabetes mellitus
 Hyperlipidemia

Antipsychotics and Weight Gain
AntiOrthostasis Prolactin
cholinergic
ARI
+
+
+
+
+
OLZ
++
++
++
++
+
QTP
++
+
+
++
+
RIS
+
++
+
++
++++
+ low, ++ moderate, +++moderately high, ++++ high
OLZ=Olanzapine, ARI=Aripiprazole, QTP=Quetiapine, RIS=Risperidone
Weight Change after 10 wks of Treatment
W eight Change (kg)
Sedation EPS

Pseudoparkinsonism
Akathisia
Dystonia
5
4
3
2
1
0
-1
Antipsychotic Medication
Adpated from: Crismon et al. In: DiPiro, ed. Pharmacotherapy 2008
Adapted from: Allison et al. Am J Psychiatry 1999
Placebo
Ziprasidone
Aripiprazole
Haloperidol
Risperidone
Quetiapine
Olanzapine
Clozapine
Atypical Antipsychotics: Metabolic
Monitoring
Atypicals and Metabolic Effects
Approximate Relative Likelihood of Metabolic Disturbances
Medication Weight
Gain
Glucose
Dysregulation
Dyslipidemia
Metabolic
Syndrome
Aripiprazole
Low
Low
Low
Low
Olanzapine
High
High
High
High
Quetiapine
Moderate
Moderate
High
Moderate
Risperidone
Mild to
Moderate
Mild
Mild
Mild
Adapted from: Hasnain et al. Curr Diab Rep 2010
Less Common but Concerning
Adverse Drug Events

Tardive dyskinesia




Higher prevalence in mood disorders
Other risk factors: older age, female sex,
neuroleptic-induced pseudoparkinsonism
Incidence reduced but not eliminated with
atypicals compared to typical antipsychotics

Evaluating Risk/Benefit of Atypicals
in Depression
Aripiprazole







NNT: Response = 9, Remission = 7
NNH: Dry mouth = 4, Somnolence = 5,
Sedation = 8
For psychotic depression: continue antipsychotic ≥ 4
mos after response
For nonpsychotic depression: continuation therapy at
same dose AT LEAST 6-9 mos
Maintenance therapy: 1 yr to lifetime for high risk
patients
Suehs et al. Texas Medication Algorithm Project Procedural Manual 2008
Evaluating Risk/Benefit of Atypicals
in Depression

Meta-analysis of 16 randomized, doubleblind, placebo controlled trials


Adjunctive therapy in treatment-resistant
nonpsychotic depression
ARI (3), OLZ (5), QTP (5), RIS (3)

Remission

Discontinuation due to adverse effects

Quetiapine

ARI: 6 wks; OLZ: 8-12 wks; QTP: acute 6-8
wks, maintenance up to 52 wks; RIS: 4-8 wks
Expected duration of atypical antipsychotic
therapy (TMAP recommendations)

NNT: Response = 7, Remission = 8
NNH: Akathisia = 6, Restlessness = 11
NNT: Response = 8, Remission = 13
NNH: Weight gain ≥ 7% = 3, Inc. appetite = 6, Dry
mouth = 9, Peripheral edema = 10,
Somnolence = 11
Treatment duration in trials of atypicals
for nonpsychotic depression

Olanzapine/fluoxetine



Incidence 0.5-1%, can be fatal
Possible increased risk when atypicals
combined with SSRIs
Kane J Clin Psychiatry 1999; Correll et al. Am J Psychiatry 2004;
Stevens Ann Pharmacother 2008

Duration of Therapy
Neuroleptic malignant syndrome (NMS)


ADA/APA/ACCE/NAASO Diabetes Care 2004

OR = 2.00 (95%CI: 1.69-2.37), NNT = 9
OR = 3.91 (95%CI: 2.68-5.72), NNH = 17
NNT = Number needed to treat, NNH = Number needed to harm
Citrome Postgrad Med 2010
Nelson & Popakostas Am J Psychiatry 2009
Other augmentation options
Comparative adverse effects
Buspirone
 Liothyronine (T3)
 Another Antidepressant






Active controls in clinical trials

Corya et al. 2006


SSRI
SNRI
Bupropion
Mirtazapine

Cutler et al. 2009


Lithium
 Dopamine Agonist
 ECT
Venlafaxine > OLZ/FLX: headache
OLZ/FLX > venlafaxine: weight gain, somnolence,
inc. appetite, dizziness, dry mouth, peripheral edema
Duloxeine > QTP: nausea, diarrhea, constipation,
insomnia, hyperhidrosis, headache
QTP > duloxetine: sedation, somnolence, dry mouth

Don’t Forget Cost
Atypical
Antipsychotic
Approx. Cost
per Month
Alternative
Agent
Approx. Cost
per Month
Aripiprazole
$500-700
Buspirone*
$4-100
Olanzapine/FLX
$375-600
Liothyronine*
$30-40
Olanzapine
$300-900
SSRIs*
$4-100
Quetiapine
$90-800
SNRIs*
$120-400
Quetiapine XR
$250-500
Bupropion*
$50-130
Risperidone*
$75-150
Mirtazapine*
$50
Lithium*
$4-30
*Generic
product available
And the debate continues…
REBUTTALS
Prices from www.drugstore.com & Walmart $4 Prescription Program
Combination & augmentation strategies – common use
w/ limited evidence
Combination
Augmentation
Bupropion + SSRI
Lithium
Venlafaxine + mirtazapine
Thyroid supplementation
Mirtazapine + SSRI
Buspirone
Stimulants
Closing Pro Argument
Depression is a chronic & costly condition
Therapy needs to be individualized
 More data with atypical antipsychotics
compared to other adjunctive options
 Monitoring for efficacy & safety should
occur in all patients prescribed atypicals


Concerns with Atypicals for
Nonpsychotic Depression
Closing Con Argument

Long-term effects of using atypicals for
depression are not well characterized
 Head-to-head comparisons with other
augmentation strategies are needed
 Responsible prescribing is required

Post-Assessment Questions
Post-Assessment Questions
1.
Which of the following atypical
antipsychotics does NOT have a
formulation approved for adjunctive use
in major depressive disorder?
a.
b.
c.
d.
Must carefully weigh the benefits of
atypical antipsychotics against their
significant side effect burden
 Atypicals are NOT a first-line treatment for
nonpsychotic depression!
2. Aripiprazole’s antidepressant properties
may be due to which of the following?


Aripiprazole
Risperidone
Olanzapine
Ziprasidone


a. (Dopamine) D2 antagonism
b. (Serotonin) 5HT2 antagonism
c. 5HT reuptake inhibition
d. NE reuptake inhibition
Post-Assessment Questions
Post-Assessment Questions
3. In the clinical trials studying
antipsychotics as adjuncts to
antidepressant therapy, how quickly did
some participants notice antidepressant
effects?
4.




a. 1-2 hours
b. 1-2 days
c. 1-2 weeks
d. 1-2 months
What is the most common adverse effect
reported with aripiprazole when used as
an adjunct for major depressive disorder?
a.
b.
c.
d.
Weight gain
Dry mouth
Akathisia/restlessness
Hyperglycemia
Post-Assessment Questions
5.
Atypical antipsychotic agents should have
similar within-class tolerability when used
at lower doses for adjunctive therapy in
major depressive disorder.
True or False?
References
1.
2.
3.
4.
5.
6.
7.
8.
References
9.
10.
11.
12.
13.
14.
15.
Crismon ML, Argo TR, Buckley PF. Schizophrenia. In: Dipiro JT, Talbert RL, Yee GC,
Matzke GF, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic
Approach, 7th ed. Available at: http://www.accesspharmacy.com/
content.aspx?aID=3204771.
Cutler AJ, Montgomery SA, Feifel D, Lazarus A, Astrom M, Brecher M. Extendedrelease quetiapine fumarate monotherapy in major depressive disorder: a placeboand duloxetine-controlled study. J Clin Psychiatry 2009;70:526-539.
El-Khalili N, Joyce M, Atkinson S, et al. Extended-release quetiapine fumarate as
adjunctive therapy in major depressive disorder in patients with an inadequate
response to ongoing antidepressant treatment: a multicentre, randomized, doubleblind, placebo-controlled study. Int J Neuropsychopharmacol. 2010 Aug;13(7):917932.
Fava M, Rush AJ, Trivedi MH, et al. 2003. Background and rationale for the
sequenced treatment alternatives to relieve depression study. Psychiatr Clin North
Am, 26:457-94.
Greenberg PE, Kessler RC, Birnham HG, et al. 2003. The economic burden of
depression in the United States: how did it change between 1990 and 2000? J Clin
Psychiatry, 66: 85-93.
Hasnain M, Fredrickson SJ, Vieweg WVR, Pandurangi AK. Metabolic syndrome
associated with schizophrenia and atypical antipsychotics. Curr Diab Rep
2010;10:209-216.
Kane JM. Tardive dyskinesia in affective disorders. J Clin Psychiatry 1999;60(suppl
5):43-47.
ADA/APA/ACCE/NAASO. Consensus development conference on antipsychotic
drugs and obesity and diabetes. Diabetes Care 2004;27:396-601.
Allison DB, Mentore JL, Heo M, Chandler LP, Cappelleri JC, Infante MC et al.
Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J
Psychiatry 1999;156:1686-1696.
American Psychiatric Association. 2000. Practice guideline for the treatment of
patients with major depressive disorder (revision). American Psychiatric
Association. Am J Psychiatry, 157:1-45.
Bauer M, Pretorius HW, Constant EL, et al. Extended-release quetiapine as adjunct
to an antidepressant in patients with major depressive disorder: results of a
randomized, placebo-controlled, double-blind study. J Clin Psychiatry 2009
Apr;70(4):540-549.
Berman RM, Thase ME, Trivedi MH et al. Aripiprazole augmentation in major
depressive disorder: a double-blind, placebo-controlled study in patients with
inadequate response to antidepressants. CNS Spectr 2009 Apr;14(4):197-206.
Citrome L. Adjunctive aripiprazole, olanzapine, or quetiapine for major depressive
disorder: an analysis of number needed to treat, number needed to harm, and
likelihood to be helped or harmed. Postgrad Med 2010;122:39-48.
Correll CU, Leucht S, Kane JM. Lower risk for tardive dyskinesia associated with
second generation antipsychotics: a systematic review of 1-year studies. Am J
Psychiatry 2004;161:414-425.
Corya SA, Williamson D, Sanger TM, Briggs SD, Case M, Tollefson G. A
randomized, double-blind comparison of olanzapine/fluoxetine combination,
olanzapine, fluoxetine, and venlafaxine in treatment-resistant depression.
Depression Anxiety 2006;23:364-372.
References
16.
17.
18.
19.
20.
Marcus RN, McQuade RD, Carson WH et al. The efficacy and safety of aripiprazole
as adjunctive therapy in major depressive disorder: a second, multicenter,
randomized, double-blind, placebo-controlled study. J Clin Psychopharmacol. 2008
Apr;28(2):156-65.
Nelson JC, Papkostas GI. Atypical antipsychotic augmentation in major depressive
disorder: a meta-analysis of placebo-controlled randomized trials. Am J Psychiatry
2009;166:980-991.
Nelson JC, Pikalov A, Berman RM. Augmentation treatment in major depressive
disorder: focus on aripiprazole. Neuropsychiatric Disease and Treatment 2008:4(5)
937-948.
Stevens DL. Association between selective serotonin-reuptake inhibitors, secondgeneration antipsychotics, and neuroleptic malignant syndrome. Ann Pharmcother
2008;42:1290-1307.
Suehs B, Argo TR, Bendele SD, Crismon ML, Trivedi MH, Kurian B. Texas
Medication Algorithm Project Procedural Manual: Major Depressive Disorder
Algorithms. Texas Department of State Health Services, 2008. Available at:
http://www.dshs.state.tx.us/mhprograms/pdf/TIMA_MDD_Manual_080608.pdf.
The Clinical Debates
Speakers:
Round 2: Statins for Primary Prevention of Cardiovascular Disease
Matthew Cantrell, PharmD, BCPS, is a 2000 graduate of Mt. Mercy College and 2005 graduate from the
University of Iowa College of Pharmacy. He has completed a residency in primary care at the VA Medical Center
in Iowa City. He currently works as a clinical pharmacy specialist at the VA Medical Center in Iowa City and is
Assistant Professor at the University of Iowa. Clinical areas include primary care, lipid, and anticoagulation.
Douglas Geraets, PharmD, obtained his BSc degree in Pharmacy from South Dakota State University and
his post-BS Doctor of Pharmacy degree from the University of Tennessee. Following this he completed a oneyear post-PharmD clinical residency in Adult Internal Medicine at the City of Memphis Hospital. In addition,
he completed a Research Fellowship in cardiology at the Ohio State University. He has held faculty positions at
the Ohio State University, the University of Missouri at Kansas City, and the University of Iowa. Currently he is
Clinical Pharmacy Specialist in Ambulatory Care at the VA Medical Center in Iowa City and Adjunct Professor
at the University of Iowa College of Pharmacy. He co-manages the VA’s ~1200 patient anticoagulation clinic,
is a provider in the ICVA’s pharmacist-managed lipid clinic, and provides pharmaceutical care to a variety of
other general medicine patients. He has published numerous research and clinical papers, is active in several
pharmacy organizations (IPA, ACCP, and ASHP) and is a Fellow of the American College of Clinical Pharmacy.
His main pharmacotherapeutic interests include cardiovascular disease, anticoagulation, and dyslipidemia.
Dr. Geraets’ research interests include issues of anticoagulation therapy particularly warfarin effectiveness and
safety and clinical management of dyslipidemia.
Speaker Disclosures: Matt Cantrell and Doug Geraets report they have no actual or potential conflicts
of interest in relation to this program. The speakers have indicated that off-label use of medications will be
discussed during this presentation.
Statins for Primary
Prevention of CVD
Faculty Disclosure

Dr. Cantrell & Geraets have no actual or potential conflicts
of interest associated with this presentation.

Dr. Cantrell & Geraets have indicated that no off-label use
of medication will be discussed during this presentation.
Douglas R. Geraets, Pharm.D., FCCP
Clinical Pharmacy Specialist – AmCare
VA Medical Center – Iowa City, IA
&
Matthew Cantrell, Pharm.D., BCPS
Clinical Pharmacy Specialist – AmCare
VAMC – Iowa City, IA
Clinical Assistant Professor
UI College of Pharmacy
Learning Objectives

Upon completion of this program
pharmacists (or pharmacy technicians)
will be able to:



Discuss the incidence and general trends for
CVD and CVD risk factors in the U.S.
population.
Describe results from primary prevention
studies—including Jupiter—and how this
information applies to primary prevention with
statins.
Select statements that describe pros & cons of
statin use in primary prevention.
Pre-Assessment Questions
Q. Would you recommend this patient take
a statin for primary prevention of CVD?
Patient Case
48 year old male
Past Medical History:
GERD
Osteoarthritis
Impaired fasting glucose
Gout
Social History:
½ pack per day smoker
4-6 beers per week
Family History:
Non-contributory
Laboratory Results:
Total Chol.
200 mg/dL
LDL
128 mg/dL
HDL
45 mg/dL
Triglycerides 135 mg/dL
ALT
28 IU/L
AST
32 IU/L
Scr
1.3 mg/dL
Fast. glucose 112 mg/dL
hs-CRP
2.3 mg/L
Vital signs:
BP 128/75 mm Hg, HR 72, Resp.
20, Temp. 36.8° C
Body Mass Index: 26
Medications:
Lansoprazole 30 mg daily
APAP 500 mg two tabs twice daily 10 year CHD risk
Febuxostat (Uloric®) 40 mg daily Framingham=11%
Reynolds=5%
Magnitude of the Problem:
Atherosclerotic CVD

Leading cause of death for both men and
women in the U.S.

Mortality decline in last several decades;
slowing of decline in 90’s-00’s
If all major CVD eliminated, life
expectancy 7 years
 Long asymptomatic latent period

Annual Number (in Thousands) of New Cases of
Diagnosed Diabetes Among Adults Aged 18–79 Years,
United States, 1980–2008
Risks for CVD
Increasing Prevalence (%) of Metabolic Syndrome Among
U.S. Adults
NHANES III (‘88-94)
NHANES (‘99-00)
Unadjusted
23.1
26.7
Age-Adjusted
24.1
27.0
Ford ES, et al. Diabetes Care October 2004;27(10):2444-9.
Centers for Disease Control and Prevention (CDC), National Center for Health Statistics, Division of Health Interview
Statistics, data from the National Health Interview Survey.
Treatment vs. Prevention





Current algorithms for preventing CVD
events/death: statins for patients with
established CVD, DM, overt hyperlipidemia
½ of MI/CVA occur among apparently
healthy men/women with LDL-C below
treatment thresholds
Atherosclerosis starts early… progresses
continually throughout life
If individual has an event… then we do
something about it!
Patients want prevention of first event…
Attributes of Ideal Agent for
Primary Prevention CVD
Easy to take
Affordable
 Highly effective (surrogate vs. hard
endpoints)
 Well-tolerated
 No or limited drug-drug, drug-disease,
drug-diet interactions

Prevention of CVD

Nine modifiable risk factors account for
~90% of initial MI risk
1.
2.
3.
4.
5.
6.
7.
8.
9.
Elevated cholesterol
Smoking
Psychosocial events
Hypertension
Abdominal obesity
DM
Unhealthy diet
Excessive alcohol
Lack of exercise
Statins in CVD Prevention


In recent years… large clinical trials of
statins in relatively low-risk groups




Without CVD
With CVD risk factors
Low levels LDL-C
WOSCOPS, AFCAPS/TexCAPS, PROSPER,
ALLHAT-LLT, ASCOT-LLA, HPS, CARDS,
ASPEN, MEGA, and JUPITER
Estimated 5-YR NNT for Primary Prevention of CVD
Trial
Estimated 5-YR NNT for Primary Prevention of CVD Among
Middle-Aged Populations
Population
Endpt
Hypercholesterolemia
MI, stroke, any
death
86
AFCAPS
(pravastatin)
Average cholesterol
MI & cardiac
death
44
JUPITER
(rosuvastatin)
Low LDL, hsCRP
MI, stroke,
death
29
WOSCOPS
(lovastatin)
5-YR NNT
Ridker PM, et al. Circ Cardiovasc Qual 2009; 2:616-23.
Withdrawals
AFCAPS/
TexCAPS
(Lovastatin)
ASCOT-LLA
(Atorvastatin)
JUPITER
(Rosuvastatin)
N/R
No Difference
N/R
No Difference
Myopathic
Event
No Difference
No Difference
N/R
No Difference
CK 10X
ULN
No Difference
No Difference
No Difference
No Difference
AST/ALT
10X ULN
No Difference
No Difference
No Difference
No Difference
N/R
No Difference
No Difference
No Difference
SAE
Endpt
5-YR NNT
Low LDL, hsCRP
MI, stroke, death
29
Diuretics
Hypertension
MI, stroke, any
death
86
-blockers
Hypertension
Fatal/nonfatal CHD
and stroke
140
Aspirin
Men; Women
MI, stroke, CV death
346; 426
Summary
Progressing from secondary prevention to
primary prevention CVD
 Statins with many attributes of ideal
primary preventive agent
 Rosuvastatin in primary prevention (CVD)
with better NNT values than other CVD
preventive therapy
 “Three-quarters of the patients taking
statins are taking them for primary
prevention.” (Arch Int Med 2010; 170(12): 1007-8.)?

WOSCOP
(Pravastatin)
N/R = Not Reported; SAE = Serious Adverse Events
Population
Rosuvastatin
Ridker PM, et al. Circ Cardiovasc Qual 2009; 2:616-23.
Summary of Statin Tolerance in Recent Primary
Prevention Studies (versus placebo)
Parameter
Intervention
Reasons to consider judicious use of
statins for primary prevention
1.
Limited benefits in all-cause mortality
2.
JUPITER trial & limitations
3.
Adverse effects of statin therapy
4.
Pharmacoeconomics
Established indications for statins

In patients with & without established CHD, statins:


In patients with type 2 DM & other CV risk factors

Slow progression of atherosclerosis

High risk patients receive the most benefits


Reduce the risk of MI and stroke


Statin therapy & all cause mortality
Reduce risk of MI, stroke, revasc. procedures, & angina
Primary prevention vs. secondary prevention
Absolute risk reduction vs. relative risk reduction
Relationship between age and all cause mortality rates in
primary prevention statin trials
11 randomized clinical trials
 65,229 patients without CHD
All cause
death
Statin
(32,623)
Placebo
(N=32,606)
Risk Ratio 95% CI
1,346
(4.1%)
1,447
(4.4%)
0.91 (0.83-1.01)

Participant age at baseline accounted for an estimated
66% of the variation in mortality rates

The clinical utility of statins to reduce non-fatal MI and
stroke is not in question
Ray et al. Arch Int Med. 2010;170(12):1024-31
Effect of statins on all-cause mortality in primary
prevention randomized controlled trials
Ray et al. Arch Int Med. 2010;170(12):1024-31
JUPITER

Subjects w/o CV disease with baseline LDL
<130 mg/dl & CRP >2.0 mg/L

Rosuvastatin (Crestor®) 20 mg vs. placebo

Primary endpoint


44% relative risk reduction in primary endpoint

Ray et al. Arch Int Med. 2010;170(12):1024-31
Composite nonfatal MI & stroke, hospit. for unstable
angina, arterial revasc., CV death
142 vs. 251 events (p<0.00001)
Ridker et al. NEJM 2008;359(21):2195-2207.
JUPITER


Adverse effects: myopathy
Absolute risk reduction
 0.59 events/100 person years
 NNT=95 for 2 years
CK elevation
>10,000 U/L
Limitations
1. Excluded those with poor compliance
2. Not so low risk?
3. Generalizability?
4. Role of CRP as biomarker?
5. Potential biases
>1,000 U/L
Cases / 100,000 person years

Statin use resulted in 9% increased risk of diabetes
 (OR = 1.09, 95% CI = 1.02-1.17)

Number needed to harm (NNH) was 255


Atorvastatin dose
Pharmacoeconomics

80% of middle-aged & elderly would meet
criteria for statin therapy

Rosuvastatin 20 mg $1,200 annually

NNT to prevent 1 primary endpoint

Costs associated with screening those not eligible


13 randomized trials of 91,140 participants
50
80 mg
95 for 2 years x $1,200 =$228,000
Where are health care dollars best spent?


Treating a low risk, asymptomatic population?
Targeting high risk secondary prevention patients
where gains are statistically & clinically significant
5-10%

150
10 mg
MYALGIA
Potential adverse effects: Diabetes?
200
0
1/1,000
None
250
Overall risk is
approximately 1.3%
1/10,000
MYOPATHY
Normal or increased
Adverse effects: dose related transaminase
elevations with statin therapy
100
Frequency
RHABDO
Statin therapy for 4 years to produce 1 additional case of
diabetes
Cases of diabetes in JUPITER
 270 (3.0%) vs. 216 (2.4%) (P = 0.01)
Sattar et al. Lancet 2010;375(9716):735-742
Patient Case
48 year old male
Past Medical History:
GERD
Osteoarthritis
Impaired fasting glucose
Gout
Social History:
½ pack per day smoker
4-6 beers per week
Family History:
Non-contributory
Laboratory Results:
Total Chol.
200 mg/dL
LDL
128 mg/dL
HDL
45 mg/dL
Triglycerides 135 mg/dL
ALT
28 IU/L
AST
32 IU/L
Scr
1.3 mg/dL
Fast. glucose 112 mg/dL
hs-CRP
2.3 mg/L
Vital signs:
BP 128/75 mm Hg, HR 72,
Resp. 20, Temp. 36.8° C
Body Mass Index: 26
Medications:
Lansoprazole 30 mg daily
APAP 500 mg two tabs twice daily 10 year CHD risk
Febuxostat (Uloric®) 40 mg daily Framingham=11%
Reynolds=5%
Would you recommend this patient
take a statin for primary prevention?
1.
2.
Yes
No
50%
1
50%
2
Baseline LDL and follow up in primary prevention trials comparing statin
therapy to placebo
Trial; Intervention (follow up) ASCOT‐LLA (2003) atorvastatin 10 mg (3.3 yrs) WOSCOPS (1995) pravastatin 40 mg (4.9 yrs) ALLHAT (2002) pravastatin 40 mg (4.8 yrs) AFCAPS /TexCAPS (1998) lovastatin 20‐40 mg (5.2 yrs) HYRIM (2005) fluvastatin 40 mg (4.0 yrs) CARDS (2004) atorvastatin 10 mg (4.0 yrs) JUPITER (2008) rosuvastatin 20 mg (2.2 yrs) MEGA (2006) pravastatin 10‐20 mg (4.6 yrs) N; (age) 8,715; (63) 5,981; (55) 8,880; (66) 6,605; (58) 568; (57) 2,838; (62) Baseline & Follow up LDL (mg/dL) 131 T: 90 192 T: 142
T: 105
150 T: 114
P: 156
150 T: 117
T: 6.4 P:8.2 T: 24.3 P: 24.3 T: 4.6 P: 4.4 T: 3.5 P: 4.4 T: 10.7 P: 14.5 100% of subjects had Type 2 DM 37% reduction in primary endpoint
T: 12.5 P: 10.0 44% relative risk reduction in primar
endpoint T: 2.4 P: 3.6 100% Japanese population; Event Rate 3.3 vs. 5.5% (p=0.01) P: 120
108 P: 151
Adapted with permission from: Ray et al. Arch Intern Med. 2010;170(12):1024-1031.
36%  in non‐fatal MI & CV death; 27%  in strokes; All cause mortality non‐significantly reduced 13% 22% reduction in total mortality (not
significant (P=0.051); 5.5% vs. 7.9% event rate (p<0.001)
No difference in total mortality or CHD event rate 37%  in CV events (fatal and non‐
fatal MI, unstable angina, or sudden
cardiac death; No difference in total mortality P: 108
156 T: 128
P: 12.4 P: 136
117 T: 54 7,832 (58) P: 129
Comment T: 10.9 P: 192
148 T: 81 17,802 (66) P: 126 Event rate per 1000 Person‐years PREVEND IT (2004) pravastatin 40 mg (3.8 yrs) ASPEN (2006) atoravastatin 10 mg (4.3 yrs) PROSPER (2002) pravastatin 40 mg (3.2 yrs) Cumulative 864; (51) 154 T: 120
1,905; (61) 3,239 (75) T: 10.8 P: 10.2 100% of subjects had Type 2 DM T: 27.2 P: 26.0 T: 10.7 P: 11.4 P: 114
146 T: 96 P: 7.2 P: 158
114 T: 79 T: 7.7 P: 143
65,229 138 (62) T: 94 P: 134
T=subjects randomized to treatment with statin, P=subjects randomized to treatment with placebo Relationship between baseline age of participants and all‐cause mortality rates in primary prevention trials Adapted with permission from: Ray et al. Arch Intern Med. 2010;170(12):1024-1031.
Effect of statin therapy on all cause mortality in primary prevention trials
Adapted with permission from: Ray et al. Arch Intern Med. 2010;170(12):1024-1031.
New Drugs
ACPE UAN 107-000-11-027-L01-P & 107-000-11-027-L01-T
Activity Type: Knowledge-Based
0.2 CEU/2.0 Hr
Program Objectives for Pharmacists: Upon completion of this program, participants should be able to:
1. List new therapeutic agents that were marketed in 2010.
2. Discuss the newly approved agents’ use and properties, indications and routes of administration,
the most important precautions, and practical considerations regarding their use.
3. Identify the important pharmacokinetic properties and the unique characteristics of the new drug.
4. Identify the most important adverse events and precautions of the new drugs.
5. Compare the new drugs to the older therapeutic agents to which they are most similar in activity.
6. Identify information regarding the new drugs that should be communicated to the patient.
Program Objectives for Technicians: Upon completion of this program, participants should be able to:
1. List new therapeutic agents that were marketed in 2010.
2. Recognize the newly approved agents’ general use and properties.
3. List the older therapeutic agents to which the new drugs are most similar in activity.
4. Recognize general differences in the new drugs to the older therapeutic agents to which they are
most similar in activity.
Speaker: Daniel Hussar, PhD, is a Remington Professor of Pharmacy at the Philadelphia College of
Pharmacy at the University of the Sciences in Philadelphia. He is a member of a number of professional
organizations including the American Pharmacists Association, American Society of Health-System
Pharmacists, Drug Information Association, Pennsylvania Pharmacists Association, and Pennsylvania
Society of Health-System Pharmacists. He has served as a member of the Board of Trustees of the
American Pharmacists Association and is a past president of the Drug Information Association and the
Pennsylvania Pharmacists Association. Dr. Hussar is involved in teaching the Pharmacotherapeutics
courses at the Philadelphia College of Pharmacy and has participated in numerous continuing education
programs for practicing pharmacists and other health professionals. His primary interests are in the
areas of new drugs, drug interactions, patient noncompliance, and antibiotic therapy, and he has written
and spoken extensively on these subjects. For a number of years he has published articles in several
professional journals on the new therapeutic agents that have been marketed in the United States.
Speaker Disclosure: Daniel Hussar reports he has no actual or potential conflicts of interest in
relation to this program. The speaker has indicated that off-label use of medications will not be discussed
during this presentation.
New Drugs of 2010*
*Presentation by Daniel A. Hussar, Ph.D.
Remington Professor of Pharmacy
Philadelphia College of Pharmacy
University of the Sciences in Philadelphia
New Drug Comparison Rating (NDCR) system
5 = important advance
4 = significant advantage(s) (e.g., with respect to use/effectiveness, safety,
administration)
3 = no or minor advantage(s)/disadvantage(s), or advantage(s) and disadvantage(s) of
similar importance
2 = significant disadvantage(s) (e.g., with respect to use/effectiveness, safety,
administration)
1 = important disadvantage(s)
Additional information
NEW DRUGS (2005 – 2009) and COMPARISON RATINGS (NDCR), 2010 Edition
website: www.newdrugsNDCR.com
The Pharmacist Activist
website: www.pharmacistactivist.com
Pitavastatin calcium (Livalo – Kowa; Lilly)
2010
Lipid-Regulating Agent
New Drug Comparison Rating (NDCR) =
Indications: As adjunctive therapy to diet to reduce elevated total cholesterol, low-density lipoprotein
cholesterol (LDL-C), apolipoprotein B, triglycerides, and to increase high-density lipoprotein cholesterol in
patients with primary hyperlipidemia or mixed dyslipidemia.
Comparable drugs: Atorvastatin (Lipitor), fluvastatin (e.g., Lescol XL), lovastatin (e.g., Mevacor),
pravastatin (e.g., Pravachol), rosuvastatin (Crestor), simvastatin (e.g., Zocor)
Advantages:
--Lower risk of drug interactions (compared with atorvastatin, lovastatin, and simvastatin)
--May be administered at any time of day (compared with fluvastatin, lovastatin, and simvastatin)
Disadvantages:
--Extent of reduction of LDL-C with the maximum recommended dosage is lower than with the maximum
recommended dosages of atorvastatin, rosuvastatin, and simvastatin
--Labeled indications are limited (e.g., compared with atorvastatin and simvastatin that have been
demonstrated to reduce the risk of myocardial infarction, stroke, and revascularization procedures in
patients with clinically evident coronary heart disease, as well as in patients without clinically evident
coronary heart disease but who have multiple risk factors for such)
--Concurrent use with cyclosporine is contraindicated
Most important risks/adverse events: Contraindicated in patients with active liver disease that may include
unexplained persistent elevations in hepatic transaminase concentrations (liver function tests should be
performed before and at 12 weeks following initiation of treatment and increases in dosage, and
periodically [e.g., semiannually] thereafter; caution should be exercised in patients with a history of liver
disease or who consume substantial quantities of alcohol; contraindicated during pregnancy (Pregnancy
Category X) and in nursing mothers; action may be increased by cyclosporine and concurrent use is
contraindicated; myopathy/rhabdomyolysis (patients should be advised to promptly report unexplained
muscle pain, tenderness, or weakness; treatment should be discontinued if markedly elevated creatine
kinase concentrations occur; risk of myopathy is increased by the concurrent use of a fibrate or lipidlowering doses of niacin); action may be increased by the concurrent use of lopinavir/ritonavir (Kaletra),
erythromycin, and rifampin (use with lopinavir/ritonavir is not recommended; dosage of pitavastatin should
be reduced when used concurrently with erythromycin or rifampin)
Most common adverse events: Back pain (4%), constipation (4%), diarrhea (3%), myalgia (3%)
Usual dosage: 2 mg once a day to initiate treatment; blood lipid concentrations should be determined when
initiating treatment and after 4 weeks, at which time the dosage may be adjusted accordingly; maximum
recommended dosage is 4 mg once a day; in patients with moderate renal impairment or with end-stage
renal disease receiving hemodialysis, the recommended initial dosage is 1 mg once a day and the maximum
dosage 2 mg once a day; in patients treated with erythromycin, the dosage should not exceed 1 mg once a
day and, in patients treated with rifampin, the dosage should not exceed 2 mg once a day
Products: Tablets – 1 mg, 2 mg, 4 mg
Comments: Pitavastatin is a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) with
properties that are generally similar to those of the other statins. In comparative studies, the percent
reduction of LDL-C with the maximum recommended dosage of pitavastatin (4 mg once a day) was
noninferior to atorvastatin (20 mg once a day) and simvastatin (40 mg once a day), and greater than with
pravastatin (40 mg once a day). Higher dosages of the latter agents were not evaluated in these studies.
Pitavastatin is metabolized to only a limited extent via cytochrome P450 metabolic pathways, and is less
likely than lovastatin, simvastatin, and atorvastatin to interact with other medications via this mechanism.
Dabigatran etexilate mesylate (Pradaxa – Boehringer Ingelheim)
2010
Anticoagulant
New Drug Comparison Rating (NDCR) =
Indication: To reduce the risk of stroke and systemic embolism in patients with non-valvular atrial
fibrillation
Comparable drug: Warfarin (e.g., Coumadin)
Advantages:
--More effective in reducing stroke and systemic embolism
--Has a different mechanism of action (thrombin inhibitor)
--Monitoring of blood tests is not necessary
--Interacts with fewer medications
--Not likely to interact with herbal products and dietary items (e.g., those containing vitamin K)
--Not likely to require dosage adjustment
Disadvantages:
--Is administered twice a day (whereas warfarin is usually administered once a day)
--Shorter duration of action may be associated with an increased risk of problems when doses are missed or
treatment is interrupted
--Labeled indications are more limited (warfarin is also indicated for prophylaxis and/or treatment of
thromboembolic complications associated with cardiac valve replacement, the reduction of the risk of
death, recurrent myocardial infarction {MI], and thromboembolic events after an MI, and the prophylaxis
and/or treatment of venous thrombosis and its extension, and pulmonary embolism)
--Antidote is not available (whereas vitamin K is the antidote for an excessive response to warfarin)
Most important risks/adverse events: Contraindicated in patients with active pathological bleeding; risk of
bleeding (risk factors include the use of other medications that may be associated with bleeding events
[e.g., heparin. antiplatelet agents]); missing doses or interruption of treatment may increase the risk of
stroke; is a substrate for P-glycoprotein (P-gp) and action may be reduced by medications that are P-gp
inducers (e.g., rifampin) – concurrent use should be avoided; dosage should be reduced in patients with
severe renal impairment
Most common adverse events: Bleeding events, gastrointestinal adverse events (35%; include gastritis-like
symptoms [e.g., gastroesophageal reflux disease, esophagitis, ulcer] and dyspepsia [e.g., abdominal pain])
Usual dosage: 150 mg twice a day; in patients with severe renal impairment (creatinine clearance of 15-30
mL/minute), the recommended dosage is 75 mg twice a day; capsules should be swallowed whole as
chewing, breaking, or emptying the contents of the capsule may result in increased exposure to the drug; if
a dose is not taken at the scheduled time, the dose should be taken as soon as possible on the same day (the
missed dose should be skipped if it cannot be taken at least 6 hours before the next scheduled dose; the
dose should not be doubled to make up for a missed dose); the product labeling should be consulted for
recommendations for converting from or to warfarin, or from or to a parenteral anticoagulant
Products: Capsules – 75 mg, 150 mg
Comments: Patients with atrial fibrillation are at greater risk of developing blood clots and at an estimated
five-fold increased risk of experiencing a stroke. The vitamin K antagonist warfarin has been the standard
treatment for preventing these problems but its use is associated with serious adverse events and drug
interactions, and requires close monitoring. Dabigatran is a direct thrombin inhibitor and is the first of a
group of investigational oral anticoagulants to be approved in the United States. It is absorbed as the
dabigatran etexilate ester that is then hydrolyzed to dabigatran, the active moiety. Dabigatran is
metabolized to four different acyl glucuronides that have pharmacological activity that is similar to that of
the parent compound. Its effectiveness and safety were evaluated in a clinical trial that included more than
18,000 patients, in which patients received warfarin, dabigatran 150 mg twice a day, or dabigatran 110 mg
twice a day. When used in the dosage of 150 mg twice a day, dabigatran reduced stroke and systemic
embolism by 35% beyond the reduction attained with warfarin. The risk of major bleeding events was
generally similar in the two groups. The 110 mg twice a day regimen of dabigatran was determined to be
noninferior to warfarin, and less likely to cause bleeding events. However, this regimen is not identified in
the dosage recommendations in the labeling and the available capsule potencies do not facilitate the use of
doses of 110 mg. The concern underlying the FDA decision to not approve, at least initially, a product
containing 110 mg is that some prescribers may be overly cautious and not prescribe the 150 mg twice a
day regimen that provides the greatest benefit in reducing the risk of stroke.
The risk of major bleeding events was generally similar with dabigatran (150 mg twice a day) and
warfarin, with the exception of patients aged 75 years and older in whom there was a higher incidence of
bleeding with dabigatran. There was also a higher rate of major GI bleeding events in patients treated with
dabigatran.
In contrast to the recommendations with the use of warfarin, treatment with dabigatran does not
require monitoring of blood tests and resultant dosage adjustments.
Tocilizumab (Actemra – Genentech)
2010
Antiarthritic Agent
New Drug Comparison Rating (NDCR) =
Indication: Administered intravenously for the treatment of adult patients with moderately-to severelyactive rheumatoid arthritis who have had an inadequate response to one or more tumor necrosis factor
(TNF) antagonist therapies
Comparable drugs: TNF antagonists that are indicated for the treatment of rheumatoid arthritis: etanercept
(Enbrel), adalimumab (Humira), certolizumab (Cimzia), golimumab (Simponi), infliximab (Remicade)
Advantages:
--Is effective in some patients who have failed treatment with TNF antagonists
--Has a unique mechanism of action (is an interleukin-6 [IL-6] antagonist)
--May have a lesser risk of congestive heart failure
--Less frequent administration – once every 4 weeks (compared with etanercept that is administered every
week, adalimumab that is administered every 2 weeks, and certolizumab that is used, at least initially, every
2 weeks)
--Indication is not limited to use in combination with methotrexate (compared with infliximab)
Disadvantages:
--Is not indicated for first-line use
--Indication is more limited; indication does not include inducing major clinical response, inhibiting
progression of structural damage, and/or improving physical function (compared with etanercept,
adalimumab, and infliximab)
--Has not been directly compared with other agents in clinical studies
--Fewer labeled indications (compared with etanercept, adalimumab, and infliximab)
--May have a greater risk of gastrointestinal perforation
--Is administered intravenously (compared with etanercept, adalimumab, certolizumab, and golimumab that
are administered subcutaneously)
--Is not indicated for use in patients less than 18 years of age (compared with etanercept and adalimumab
for which the indications include juvenile idiopathic arthritis)
Most important risks/adverse events: Serious infections (boxed warning; e.g., tuberculosis [TB], invasive
fungal infections, and other opportunistic infections [patients should be evaluated for TB risk factors and be
tested for latent TB infection; treatment should not be initiated in patients with active infection, including
localized infection; treatment should be interrupted if a patient develops a serious infection; should not be
used concurrently with a TNF antagonist, abatacept {Orencia}, anakinra {Kineret}, or rituximab {Rituxan}
because of the increased risk of infection]); gastrointestinal perforation (must be used with caution in
patients with risk factors); serious hypersensitivity reactions, including anaphylaxis; malignancies (possible
increased risk because of immunosuppressive action); exacerbation of demyelinating disorders (e.g.,
multiple sclerosis); use is not recommended in patients with active hepatic disease or hepatic impairment;
neutrophils, platelets, ALT, AST, and lipids should be monitored every 4 to 8 weeks; live vaccines should
not be given concurrently
Most common adverse events: Infusion reactions (7%), upper respiratory tract infection (7%),
nasopharyngitis (7%), headache (7%), hypertension (6%), elevated ALT (6%)
Usual dosage: Used as monotherapy or concomitantly with methotrexate or other nonbiological diseasemodifying antirheumatic drugs (DMARDs); treatment should not be initiated in patients with an absolute
neutrophil count below 2000/mm3, platelet count below 100,000/mm3, or who have ALT or AST above 1.5
times the upper limit of normal; administered once every 4 weeks as a 60-minute single intravenous drip
infusion; recommended initial dose is 4 mg/kg followed by an increase to 8 mg/kg based on clinical
response; a reduction in dosage to 4 mg/kg, or discontinuation of treatment, is recommended for the
management of certain dose-related laboratory changes
Products: Single-use vials – 80 mg/4 mL, 200 mg/10 mL, 400 mg/20 mL (should be refrigerated); the
volume of solution needed to provide the appropriate dose should be diluted to 100 mL with 0.9% Sodium
Chloride Injection
Comments: Interleukin-6 (IL-6) is a naturally occurring proinflammatory cytokine that is produced by
synovial and endothelial cells and contributes to the local inflammation experienced by individuals with
rheumatoid arthritis. Tocilizumab is a recombinant humanized monoclonal antibody that binds to soluble
and membrane-bound IL-6. Its mechanism of action is unique among the antiarthritic agents, and it has
been effective in some patients who have had an inadequate response to one or more TNF antagonists. Its
effectiveness has been demonstrated in studies in which it was used as monotherapy, in combination with
methotrexate, in combination with other DMARDs, and in combination with methotrexate in patients who
failed TNF antagonist therapy.
The risks and adverse events associated with tocilizumab are generally similar to those of other
biological therapies for rheumatoid arthritis. As with the TNF antagonists, the labeling for tocilizumab
includes a boxed warning regarding the risk of serious infections.
Like infliximab, abatacept, and rituximab, tocilizumab is administered intravenously, whereas the
other biologicals used for the treatment of rheumatoid arthritis are administered subcutaneously.
Pegloticase (Krystexxa – Savient)
2010
Agent for Gout
New Drug Comparison Rating (NDCR) =
Indication: Administered intravenously for the treatment of chronic gout in adult patients refractory to
conventional therapy; is not recommended for the treatment of asymptomatic hyperuricemia
Comparable drugs: Allopurinol (e.g., Zyloprim), febuxostat (Uloric)
Advantages:
--Is effective in some patients with chronic gout that is refractory to conventional therapy
--Has a unique mechanism of action (reduces serum uric acid concentration by catalyzing the oxidation of
uric acid)
--Less likely to interact with other medications
Disadvantages:
--Must be administered intravenously
--Risk of anaphylaxis and infusion reactions
--May cause exacerbation of congestive heart failure
--Formation of antibodies may reduce effectiveness
Most important risks/adverse events: Contraindicated in patients with glucose-6-phosphate dehydrogenase
(G6PD) deficiency (risk of hemolysis and methemoglobinemia); anaphylaxis (generally manifests within 2
hours of an infusion; should be administered in a healthcare setting by providers who are prepared to
manage anaphylaxis; patients should receive premedication with an antihistamine and corticosteroid, and
be closely monitored for an appropriate period of time following administration); infusion reactions; gout
flares (prophylaxis with a nonsteroidal anti-inflammatory drug or colchicine is recommended for at least
the first 6 months of treatment); exacerbation of congestive heart failure
Most common adverse events: Gout flare (77%; incidence similar to placebo), infusion reaction (26%),
nausea (12%), contusion/ecchymosis (11%), nasopharyngitis (7%), chest pain (6%), anaphylaxis (5%),
vomiting (5%)
Usual dosage: 8 mg every two weeks administered by intravenous infusion over no less than 120 minutes
via gravity feed, syringe-type pump, or infusion pump (must not be administered as an intravenous push or
bolus); patients should be premedicated with an antihistamine and corticosteroid; continued observation of
patients for at least 1 hour following completion of the infusion should be considered; serum uric acid
concentrations should be monitored prior to infusions (discontinuation of treatment should be considered if
concentrations rise to above 6 mg/dL, particularly when two consecutive concentrations above 6 mg/dL are
observed)
Product: Single-use vials – 8 mg/mL (should be stored in a refrigerator); 1 mL is withdrawn from the vial
and injected into a bag of 0.9% Sodium Chloride Injection or 0.45% Sodium Chloride Injection
Comments: Pegloticase is a uric acid specific enzyme that is a PEGylated product. It consists of
recombinant urate oxidase (uricase) that is covalently conjugated to monomethoxypoly(ethylene glycol). It
catalyzes the oxidation of uric acid to allantoin, thereby lowering serum uric acid. Its effectiveness was
demonstrated in two placebo-controlled studies of six months duration in patients with a baseline serum
uric acid of at least 8 mg/dL, at least 3 gout flares in the previous 18 months or at least 1 gout tophus or
gouty arthritis, and had a contraindication to allopurinol or failure to normalize uric acid with at least 3
months of allopurinol treatment at the maximum dosage. The primary endpoint was attainment of plasma
uric acid less than 6 mg/dL for at least 80% of the time during Month 3 and Month 6. This endpoint was
attained in 47% and 38% of the patients in the two studies, compared with 0% of the patients receiving
placebo.
Dalfampridine (Ampyra – Acorda)
2010
Agent for Multiple Sclerosis
New Drug Comparison Rating (NDCR) =
Indication: As a treatment to improve walking in patients with multiple sclerosis (MS)
Comparable drugs: None (The other medications that have been approved for the treatment of patients
with MS are indicated for the management of other symptoms and/or parameters of the disease.)
Advantages:
--Is the first drug to be demonstrated to be effective in increasing walking speed in patients with MS
--Has a unique mechanism of action (potassium channel blockade)
--Is administered orally
Disadvantages/Limitations:
--Most patients in the clinical studies did not experience benefit
--Risk of seizures
--Available only in a restricted distribution program
Most important risks/adverse events: Risk of seizures (contraindicated in patients with a history of
seizures; use should be discontinued in patients who experience a seizure during treatment; clearance is
reduced in patients with renal impairment and seizure risk is increased (contraindicated in patients with
moderate or severe renal impairment; estimated creatinine clearance should be known before initiating
treatment; in patients with mild renal impairment, plasma concentrations may be higher than those
associated with the recommended dosage, and treatment should be closely monitored); should not be used
in patients being treated with another formulation of the drug (also known as 4-aminopyridine and
fampridine); should not be used by a nursing mother;
Most common adverse events: Urinary tract infections (12%), insomnia (9%), dizziness (7%), headache
(7%), nausea (7%), asthenia (7%), back pain (5%), balance disorder (5%)
Usual dosage: 10 mg twice a day, approximately 12 hours apart; this dosage should not be exceeded and, if
a dose is missed, double or extra doses should not be taken
Product: Extended-release tablets – 10 mg; available only through a limited network of specialty
pharmacies and Kaiser Permanente
Comments: The symptoms most often associated with MS include fatigue, vision problems, numbness in
the limbs, loss of balance/coordination, and difficulty walking. The medications that have been approved
to treat various symptoms/stages of MS include interferon beta-1a (Avonex, Rebif). interferon beta 1-b
(Betaseron), glatiramer acetate (Copaxone), mitoxantrone (Novantrone). and natalizumab (Tysabri).
Dalfampridine is also known as fampridine and by its chemical name, 4-aminopyridine. It is a potassium
channel blocker that, in animal studies, has been shown to increase conduction of action potentials in
demyelinated axons. It was evaluated in two clinical trials in which the primary measure of efficacy was
walking speed as measured by the Timed 25-foot walk. A significantly greater number of patients treated
with the drug showed faster walking speed compared with patients receiving placebo (35% vs. 8% and 43%
vs. 9% in the two studies).
The most important concern with the use of dalfampridine is the risk of seizures, which is dose
related, and the contraindications and warnings regarding this risk must be observed. Approximately 90%
of a dose of the drug is excreted unchanged in the urine, thereby increasing the risk of seizures in patients
with impaired renal function.
Unlike most new drugs, dalfampridine was available (as 4-aminopyridine) before it was officially
approved by the FDA, and some physicians have prescribed it in formulations compounded by pharmacists.
Precautions must be observed to prevent patients from taking more than one product containing this active
ingredient.
Fingolimod hydrochloride (Gilenya – Novartis)
2010
Agent for multiple sclerosis
New Drug Comparison Rating (NDCR) =
Indication: Treatment of patients with relapsing forms of multiple sclerosis to reduce the frequency of
clinical exacerbations and to delay the accumulation of physical disability
Comparable drugs: Interferon beta-1a (Avonex, Rebif), interferon beta-1b (Betaseron)
Advantages:
--More effective in reducing frequency of relapses (compared with interferon beta-1a)
--Is administered orally (whereas comparable drugs are administered parenterally)
--Labeled indication includes delaying accumulation of physical disability (compared with interferon beta1b)
--Has a unique mechanism of action
--Appears less likely to be associated with the occurrence of depression
Disadvantages:
--More likely to cause cardiovascular adverse events (bradyarrhythmias and atrioventricular blocks)
--Interacts with a greater number of medications
--More likely to cause ocular adverse events (macular edema)
Most important risks/adverse events: Bradyarrhythmias and atrioventricular blocks (patients should be
observed for 6 hours after the first dose; risk factors include existing cardiovascular disorders [e.g.,
congestive heart failure] and use of a beta-blocker, calcium channel blocker, and/or Class Ia or Class III
antiarrhythmic agent); infection (treatment should not be initiated in patients with active acute or chronic
infections; risk is increased in patients taking other agents that suppress immune function); macular edema
(patients with diabetes or a history of uveitis are at increased risk); elevations in liver transaminases;
baseline or recent electrocardiogram, ophthalmologic exam, liver function tests, and blood pressure should
be evaluated prior to starting treatment and during treatment as clinically indicated; decrease in certain
pulmonary function tests (forced expiratory volume over 1 second [FEV1]); administration of live
attenuated vaccines should be avoided during treatment and for 2 months after stopping treatment; patients
who have never had chickenpox or have not been vaccinated against varicella zoster virus (VZV) should be
tested for antibodies to VZV (vaccination should be considered for patients who are antibody-negative,
prior to initiating treatment with fingolimod); exposure is increased in patients with severe hepatic
impairment and treatment must be closely monitored; exposure is increased by the concurrent use of
ketoconazole; may cause fetal harm (Pregnancy Category C) and women of childbearing potential should
use contraception during and for 2 months after stopping treatment
Most common adverse events: Headache (25%), influenza (13%), back pain (12%), diarrhea (12%), cough
(10%), hypertension (5%), liver transaminase (ALT/AST) elevations (14%)
Usual dosage: 0.5 mg once a day; patients should be observed for 6 hours after the first dose to monitor for
bradycardia
Product: Capsules – 0.5 mg
Comments: Fingolimod is metabolized by sphingosine kinase to its active metabolite, fingolimod
phosphate. It is designated as a sphingosine 1-phosphate receptor modulator and binds with high affinity to
sphingosine 1-phosphate receptors 1, 3, 4, and 5. Fingolimod phosphate blocks the capacity of
lymphocytes to egress from lymph nodes, thereby reducing the number of lymphocytes in peripheral blood
that are available for migration into the central nervous system. Its unique mechanism of action and
effectiveness following oral administration are advantages over the interferon beta and glatiramer acetate
(Copaxone) products that must be administered parenterally.
In a placebo-controlled study, the annualized relapse rates for patients treated with fingolimod and
placebo were 0.18 and 0.40, respectively, and the percentages of patients without relapse were 70% and
46%, respectively. In a study in which fingolimod was compared against interferon beta-1a, the annualized
relapse rates were 0.16 and 0.33 and the percentages of patients without relapse were 83% and 70%,
respectively. In MRI evaluations, the mean number of new or newly enlarging T2 lesions was lower in
patients treated with fingolimod in both studies.
Following the administration of the first dose, a decrease in heart rate starts within an hour and is
maximal (a mean decrease of approximately 13 beats per minute) at approximately 6 hours. All patients
should be observed for a period of 6 hours following the first dose. With continuing use the heart rate
returns to baseline within a month. Because the action of fingolimod results in a reversible sequestration of
lymphocytes in lymphoid tissues, there is a dose-dependent reduction in the peripheral lymphocyte count to
20-30% of baseline values, resulting in an increased risk of infection.
When treatment with fingolimod is discontinued, some of the drug persists in the system and its
action continues for up to 2 months following the last dose, including decreased blood lymphocyte counts.
IncobotulinumtoxinA (Xeomin – Merz)
2010
Agent for Cervical Dystonia
New Drug Comparison Rating (NDCR) =
Indications: Administered intramuscularly for the treatment of adults with cervical dystonia to decrease the
severity of abnormal head position and neck pain in both botulinum toxin-naïve and previously treated
patients; also indicated for the treatment of adults with blepharospasm who were previously treated with
onabotulinumtoxinA
Comparable drugs: Abobotulinumtoxin A (Dysport), onabotulinumtoxinA (Botox), rimabotulinumtoxinB
(Myobloc)
Advantages:
--May be effective in some patients who have not experienced an adequate response with other botulinum
toxin products
--Product does not require refrigeration
--Product does not contain complexing proteins (e.g., hemagglutinins; however, clinical differences have
not been demonstrated between the products based on the presence or absence of these proteins)
Disadvantages:
--Is not a first-line treatment for blepharospasm (indication is for patients previously treated with
onabotulinumtoxinA)
--Labeled indications are more limited (compared with onabotulinumtoxinA that also has indications for
the treatment of strabismus, upper limb spasticity, and severe axillary hyperhidrosis, and for the
prophylaxis of chronic migraine headache)
--Has not been directly compared with other botulinum toxin products in clinical studies
Most important risks/adverse events: Contraindicated in patients who have infection at the proposed
injection site(s); distant spread of toxin effect (boxed warning; action of drug may spread from the area of
injection and may cause swallowing and breathing difficulties that may be life-threatening); must be used
with caution in patients with compromised respiratory function or dysphagia (immediate medical attention
may be required in cases of respiratory, speech, or swallowing difficulties); clinical response may be
increased in patients with concomitant neuromuscular disorders (e.g., myasthenia gravis); action may be
increased by the concurrent use of aminoglycoside antibiotics or other agents that interfere with
neuromuscular transmission; use of anticholinergic drugs may potentiate systemic anticholinergic effects;
product contains human albumin that is associated with an extremely remote risk of transmission of viral
disease and Creutzfeldt-Jakob disease; potency units are not interchangeable with those of other botulinum
toxin products; use in the treatment of blepharospasm may be associated with corneal exposure and
ulceration; lower eyelid injections should not be repeated if diplopia occurred with previous botulinum
toxin injections
Most common adverse events: Cervical dystonia: dysphagia (13%), injection site pain (9%), neck pain
(7%), muscular weakness (7%), musculoskeletal pain (7%); Blepharospasm: eyelid ptosis (19%), dry eye
(16%), visual impairment (12%), dry mouth (16%), diarrhea (8%), headache (7%), nasopharyngitis (5%),
dyspnea (5%), respiratory tract infection (5%)
Usual dosage: Administered intramuscularly; if proposed injection sites are marked with a pen, the product
must not be injected through the pen marks or a permanent tattooing effect may occur; repeat treatments
should generally be no more frequent than every 12 weeks; Cervical dystonia: initially, 120 units per
treatment session; dose, number, and location of injection sites should be based on the number and location
of muscles involved, severity of dystonia, and response to any previous botulinum toxin injections;
Blepharospasm: dose, number, and location of injections should be based on the previous dosing of
onabotulinumtoxinA (if the previous dose of this agent is not known, the recommended starting dose is
1.25-2.5 units per injection site); in the clinical trials, the mean dose per injection site was 5.6 units, the
mean number of injections per eye was 6, and the mean dose per eye was 33.5 units
Products: Single-use vials – 50 units, 100 units; should be reconstituted with 0.9% Sodium Chloride
Injection
Comments: Botulinum toxin products block cholinergic transmission at the neuromuscular junction by
inhibiting the release of acetylcholine from peripheral cholinergic nerve endings. This interruption of
cholinergic transmission results in a localized reduction of muscle activity that gradually reverses over
time. IncobotulinumtoxinA is produced from fermentation of Hall strain of Clostridium botulinum
serotype A. The active ingredient is separated from the proteins (hemagglutinins and non-hemagglutinins)
in a process that yields the active neurotoxin without the accessory proteins. Its effectiveness in the
treatment of cervical dystonia and blepharospasm was demonstrated in placebo-controlled trials in which
the results in the patients treated with the medication were significantly better compared with those in the
patients receiving placebo.
Collagenase clostridium histolyticum (Xiaflex – Auxilium)
2010
Agent for Dupuyten’s
Contracture
New Drug Comparison Rating (NDCR) =
Indication: For intralesional administration for the treatment of adult patients with Dupuytren’s contracture
with a palpable cord
Comparable drugs: None
Advantages:
--First drug to be approved for the treatment of patients with Dupuytren’s contracture
--Recurrence rate is lower than with surgical procedures
Disadvantages/Limitations:
--Risk of tendon rupture
Most important risks/adverse events: Tendon rupture or other serious injury to the injected extremity (drug
should be injected only into the collagen cord with a metacarpophalangeal [MP] or a proximal
interphalangeal [PIP] joint contracture, and care should be taken to avoid injections into tendons, nerves,
blood vessels, or other collagen-containing structures of the hand); allergic reactions; risk of bleeding may
be increased by the concurrent use of warfarin, clopidogrel (Plavix), prasugrel (Effient), or aspirin (dosages
higher than 150 mg/day)
Most common adverse events: Peripheral edema (73%), contusion/ecchymosis (70%), injection site
hemorrhage (38%), injection site reaction (35%), pain in extremity (35%)
Usual dosage: Administered intralesionally into a palpable cord; 0.58 mg per injection (i.e., 0.25 mL of
reconstituted solution in cords affecting MP joints, and 0.20 mL for cords affecting PIP joints);
approximately one-third of the dose is administered at each of 3 positions in the cord; if a contracture
remains when the patient is evaluated the following day, a passive finger extension procedure should be
performed to facilitate cord disruption; if the cord has not been disrupted after the first treatment and the
contracted cord persists for 4 weeks, a second treatment may be performed
Product: Single-use vials – 0.9 mg (should be stored in a refrigerator); is reconstituted with 0.39 mL (for a
MP joint) or 0.31 mL (for a PIP joint) of the sterile diluent supplied with the medication (0.3 mg/mL
calcium chloride dihydrate in 0.9% sodium chloride); injection should be administered by a healthcare
provider experienced in treating Dupuytren’s contracture; product labeling should be consulted for detailed
guidelines for reconstitution, preparation prior to injection, and the injection procedure
Comments: Dupuytren’s contracture is a connective tissue disease in which collagen is deposited beneath
the skin in the palm of the hand. When too much collagen builds up, thick, rope-like cords of tissue are
formed that extend to the base of the fingers and may reduce the ability to straighten and use the fingers in
the normal manner.
Collagenase clostridium histolyticum consists of two microbial collagenases obtained from the
fermentation of Clostridium histolyticum bacteria. The two enzymes are thought to act synergistically in
hydrolyzing collagen with a resultant lysis of collagen deposits. The effectiveness of the new product was
demonstrated in two studies in which the primary endpoint was a reduction in contracture of the selected
primary joint (MP or PIP joint). Treatment was successful in 64% and 44% of the patients treated with the
new drug, compared with 7% and 5%, respectively, of the patients receiving placebo. Patients treated with
the medication also showed a greater increase from baseline in the range of motion of the joints.
Prior to the availability of collagenase clostridium histolyticum, the only effective treatment for
Dupuytren’s contracture was surgery. However, surgery is usually associated with a long recovery and a
need for physical therapy. The availability of the new product represents an important advance in the
treatment of this condition. In addition, the recurrence rate with the new drug (4%) is considerably lower
than that following surgery.
Liraglutide (Victoza – Novo Nordisk)
2010
Antidiabetic Agent
New Drug Comparison Rating (NDCR) =
Indication: Administered subcutaneously as an adjunct to diet and exercise to improve glycemic control in
adults with type 2 diabetes mellitus
Comparable drug: Exenatide (Byetta)
Advantages:
--Provides a greater reduction in glycosylated hemoglobin (A1C) and fasting plasma glucose
--Is administered once a day (whereas exenatide is administered twice a day)
Disadvantages:
--Provides a smaller reduction in postprandial glucose after breakfast and dinner
--Labeled indication is more limited (i.e., is not recommended for first-line therapy whereas the labeling for
exenatide does not include this limitation)
--Has caused thyroid C-cell tumors in rodents and is contraindicated in patients with risk factors
Most important risks/adverse events: Thyroid C-cell tumors have been reported in rodents (boxed warning;
contraindicated in patients with a personal or family history of medullary thyroid carcinoma and in patients
with Multiple Endocrine Neoplasia syndrome type 2); pancreatitis (should be used with caution in patients
with a history of pancreatitis; if pancreatitis is suspected, treatment should be discontinued); hypoglycemia
(risk exists when used concurrently with an insulin secretagogue [e.g., sulfonylureas], and a reduction in
dosage of the insulin secretagogue should be considered)
Most common adverse events: Nausea (28%), diarrhea (17%), vomiting (11%), constipation (10%), upper
respiratory tract infection (10%), headache (9%)
Usual dosage: Administered subcutaneously in the abdomen, thigh, or upper arm; treatment is initiated
with a dosage of 0.6 mg once a day for 1 week; after 1 week, the dosage should be increased to 1.2 mg
once a day; if this dosage does not provide the anticipated glycemic control, the dosage may be increased to
1.8 mg once a day
Products: Prefilled multidose pens that deliver 0.6 mg, 1.2 mg, or 1.8 mg (should be stored in a
refrigerator); after initial use, may be stored for 30 days at controlled room temperature
Comments: Liraglutide is an analog of glucagon-like peptide-1 (GLP-1) and acts as a GLP-1 receptor
agonist. Its properties are most similar to those of exenatide, and both agents are administered
subcutaneously. Liraglutide may be used as monotherapy or in combination with one or more oral
antidiabetic drugs such as metformin, glimepiride, or a thiazolidinedione. However, it is not recommended
as first-line therapy for patients inadequately controlled on diet and exercise, whereas the labeling for
exenatide does not include this limitation. In a study in which liraglutide monotherapy was compared with
glimepiride monotherapy, the new drug provided significantly greater reductions in glycosylated
hemoglobin after 52 weeks. In one study, either liraglutide (1.8 mg once a day) or exenatide (10 mcg twice
a day) was added to metformin and/or glimepiride. After 26 weeks, patients receiving liraglutide achieved
a significantly greater reduction in A1C from baseline (-1.2%) compared with -0.79% in patients receiving
exenatide. Liraglutide also provided significantly greater reductions in fasting plasma glucose, but patients
treated with exenatide experienced a greater reduction in postprandial glucose after breakfast and dinner.
As with exenatide, many patients treated with liraglutide lose weight (approximately 3 kg on average).
Liraglutide has been reported to cause malignant thyroid C-cell tumors in rodents. The labeling
for exenatide does not address this problem, but recent observations suggest the possibility of an increased
cancer risk with its use. The once-a-day dosage regimen for liraglutide is an advantage over exenatide that
is administered twice a day. However, this advantage is likely to be short-lived as it is anticipated that a
longer-acting formulation of exenatide that is administered once a week will soon be approved.
Denosumab (Prolia – Amgen)
2010
Agent for Osteoporosis
New Drug Comparison Rating (NDCR) =
Indication: Administered subcutaneously for the treatment of postmenopausal women with osteoporosis at
high risk of fracture (defined as a history of osteoporotic fracture, or multiple risk factors for fracture; or
patients who have failed or are intolerant to other therapies for osteoporosis); (an additional formulation
[Xgeva] was subsequently approved in late 2010 for the prevention of skeletal-related events in patients
with bone metastases from solid tumors)
Comparable drugs: Alendronate (e.g., Fosamax), ibandronate (Boniva), risedronate (Actonel), zoledronic
acid (Reclast)
Advantages:
--Has a unique mechanism of action (prevents a protein [RANKL] from activating its receptor on
osteoclasts)
--May be effective and/or better tolerated in some patients who have failed or can’t tolerate other therapies
--Has been demonstrated to reduce the incidence of nonvertebral and hip fractures, as well as vertebral
fractures (compared with ibandronate for which effectiveness has been demonstrated in reducing vertebral
fractures)
--Is administered less frequently (compared with alendronate, ibandronate, and risedronate)
--Is administered subcutaneously (compared with zoledronic acid that is administered intravenously)
Disadvantages:
--Labeled indication is more limited (i.e., for patients at high risk of fracture; not indicated for prevention
of osteoporosis)
--Has fewer labeled indications (compared with alendronate, risedronate, and zoledronic acid that are also
indicated for the treatment of osteoporosis in men, glucocorticoid-induced osteoporosis, and Paget’s
disease)
--Has not been directly compared with other agents in clinical studies
--Has a greater risk of being associated with the occurrence of serious infections
--Must be administered parenterally (compared with alendronate, ibandronate, and risedronate)
--Must be administered by a health professional (compared with alendronate, ibandronate, and risedronate)
Most important risks/adverse events: Contraindicated in patients with hypocalcemia (pre-existing
hypocalcemia should be corrected before initiating treatment; supplementation with calcium and vitamin D
should be provided); serious infections may occur (e.g., skin, abdominal, urinary tract, ear, endocarditis);
dermatologic reactions (e.g., dermatitis, eczema); osteonecrosis of the jaw (ONJ; oral exam should be
performed prior to initiating treatment with a dental exam considered for patients with risk factors for ONJ;
patients should be advised to inform their dentist about their treatment before having dental work done)
Most common adverse events: Back pain (35%), pain in extremity (12%), musculoskeletal pain (8%),
cystitis (6%), hypercholesterolemia (7%)
Usual dosage: Should be administered by a health professional and is administered subcutaneously in the
upper arm, upper thigh, or abdomen; 60 mg once every 6 months; calcium (1000 mg) and vitamin D (at
least 400 IU) should be taken daily; (when used for the prevention of skeletal-related events in patients with
bone metastases from solid tumors, the recommended dosage is 120 mg every 4 weeks)
Products: Single-use prefilled syringes and single-use vials – 60 mg/mL in a volume of 1 mL (should be
stored in a refrigerator); (the Xgeva formulation for the prevention of skeletal-related events in patients
with bone metastases from solid tumors is supplied in single-use vials containing 120 mg/1.7 mL [70
mg/mL])
Comments: Denosumab is a human monoclonal antibody that binds to receptor activator of nuclear factor
kappa-B ligand (RANKL) and prevents it from activating its receptor on the surface of osteoclasts, with a
resultant decrease in bone resorption and increase in bone mass and strength. Its effectiveness was
demonstrated in placebo-controlled studies, in which it reduced the incidence (denosumab and placebo
groups, respectively) of new fractures at year 3 of vertebral (2.3%; 7.2%), nonvertebral (6.5%; 8%), and
hip (0.7%; 1.2%) fractures.
In late 2010, denosumab was approved for the additional indication of prevention of skeletalrelated events in patients from bone metastases from solid tumors. It is supplied in a different formulation
with a different trade name (Xgeva) for this indication that is used in a higher dosage.
Dienogest/estradiol valerate (Natazia – Bayer)
2010
Contraceptive
New Drug Comparison Rating (NDCR) =
Indication: For use by women to prevent pregnancy; efficacy in women with a mass body index (BMI) of
greater than 30 kg/m2 has not been evaluated
Comparable drugs: Combination hormonal oral contraceptives (e.g., drospirenone/ethinyl estradiol [Yaz])
Advantages:
--Four-phase dosage regimen may reduce the occurrence of breakthrough bleeding
--Does not cause hyperkalemia (compared with the drospirenone component of Yaz)
Disadvantages:
--Labeled indication is more limited (i.e., efficacy has not been evaluated in women with a BMI greater
than 30 kg/m2)
--Has fewer labeled indications (e.g., compared with drospirenone/ethinyl estradiol that is also indicated for
the treatment of symptoms of premenstrual dysphoric disorder [PMDD] and the treatment of acne vulgaris)
--May interact with more medications
--Backup nonhormonal contraception should be used during the first 9 days of use
Most important risks/adverse events: Thrombotic and other vascular events, and use is contraindicated in
women who have deep vein thrombosis or pulmonary embolism, cerebrovascular disease, coronary artery
disease, thrombogenic valvular or thrombogenic rhythm diseases of the heart, inherited or acquired
hypercoagulopathies, uncontrolled hypertension, diabetes with vascular disease, headaches with focal
neurological symptoms, or migraine headaches if over age 35; also contraindicated in women over age 35
who smoke (boxed warning); contraindicated in women with undiagnosed abnormal genital bleeding,
breast cancer or other estrogen- or progestin-sensitive cancer, liver tumors or liver disease, or who are
pregnant (Pregnancy Category X); action may be reduced by the concurrent use of CYP3A4 inducers
(women taking a strong CYP3A4 inducer [e.g., carbamazepine, phenytoin, St. John’s wort] should not use
dienogest/estradiol valerate as their contraceptive or for at least 28 days following the discontinuation of
the inducer; women who are using a moderate or weak inducer should use an alternative method of
contraception or a back-up method to the oral contraceptive); women receiving thyroid hormone
replacement therapy may require increased doses of thyroid hormone; may decrease plasma concentrations
and activity of lamotrigine (e.g., Lamictal)
Most common adverse events: Headache (13%), metorrhagia and irregular menstruation (8%), breast pain,
discomfort, or tenderness (7%), nausea or vomiting (7%), acne (4%), increased weight (3%)
Usual dosage: One tablet once a day in the following sequence:
-- 2 dark-yellow tablets each containing 3 mg estradiol valerate
-- 5 medium-red tablets each containing 2 mg estradiol valerate and 2 mg dienogest
-- 17 light-yellow tablets each containing 2 mg estradiol valerate and 3 mg dienogest
-- 2 dark-red tablets each containing 1 mg estradiol valerate
-- 2 white tablets (inert)
Use should be started on day 1 of the menstrual cycle (i.e., the first day of menstrual bleeding); one tablet
should be taken at the same time every day; a nonhormonal contraceptive should be used as backup during
the first 9 days of use; if severe vomiting or diarrhea is experienced, additional contraceptive measures
should be used; if vomiting or diarrhea occurs within 4 hours after taking a colored tablet, this should be
considered as a missed tablet
Product: Blister pack containing 28 tablets to be used in the potencies and sequence identified above
Comments: Dienogest is a new progestin that also exhibits antiandrogenic activity that is similar to that of
drospirenone. However, unlike drospirenone, dienogest does not cause hyperkalemia. The new
combination oral contraceptive formulation is the first to use estradiol valerate as the estrogen component
(most use ethinyl estradiol), although estradiol valerate has been used alone in other formulations for other
indications. Estradiol valerate is a prodrug that is converted during absorption and its first pass through the
liver to 17-beta estradiol, an endogenous estrogen that is biotransformed to estradiol and subsequently to
other metabolites (e.g., estrone).
The dienogest/estradiol valerate product is the first combination oral contraceptive to be used in a
four-phase dosage regimen, in which the dosage of the estrogen is decreased and the dosage of the
progestin is increased during the cycle in an effort to avoid breakthrough bleeding. The new product is
highly effective in preventing pregnancy but no data suggest that it is more or less effective than
comparable products.
The contraindications and precautions associated with the use of dienogest/estradiol valerate are
generally similar to those for the other combination oral contraceptives. Both dienogest and estradiol
valerate are extensively metabolized via the CYP3A4 pathway and their action may be decreased or
increased by the concurrent use of other agents that induce or inhibit, respectively, this metabolic pathway.
It is recommended that women who are using a strong CYP3A4 inducer (e.g., carbamazepine, phenytoin,
rifampin, St. John’s wort) not use dienogest/estradiol valerate as their contraceptive while using these
inducers and for at least 28 days following the discontinuation of the inducer. This represents a stronger
restriction to such concurrent use than is provided with other combination oral contraceptives.
Ulipristal acetate (ella – Watson)
2010
Contraceptive
New Drug Comparison Rating (NDCR) =
Indication: Emergency contraception for the prevention of pregnancy following unprotected intercourse or
a known or suspected contraceptive failure
Comparable drug: Levonorgestrel (e.g., Plan B One-Step)
Advantages:
--Is effective when used within 120 hours following unprotected intercourse (compared with use within 72
hours that is recommended with levonorgestrel)
Disadvantages:
--May reduce the action of regular hormonal contraceptive methods for the remaining part of the menstrual
cycle in which it is used (a barrier method of contraception should be used)
--May be more likely to cause fetal harm if inadvertently administered during pregnancy
--Requires a prescription (whereas levonorgestrel is available without a prescription from behind the
pharmacy counter for women 17 years of age and older)
Most important risks/adverse events: Contraindicated in known or suspected pregnancy (Pregnancy
Category X; pregnancy should be excluded before using drug); in women who become pregnant or who
experience lower abdominal pain following use, the possibility of ectopic pregnancy should be considered;
should not replace a regular method of contraception and repeated use within the same menstrual cycle is
not recommended; may reduce the contraceptive action of regular hormonal contraceptive methods and,
following its use, a barrier method of contraception should be used with subsequent acts of intercourse that
occur in the same menstrual cycle; should not be used by a nursing mother; is a substrate for the CYP3A4
metabolic pathway and effectiveness may be reduced by the use of a CYP3A4 inducer
Most common adverse events: Headache (18%), abdominal pain (12%), nausea (12%), dysmenorrhea
(9%), fatigue (6%), dizziness (5%)
Usual dosage: 30 mg as soon as possible within 120 hours (5 days) after unprotected intercourse or a
known or suspected contraceptive failure; if vomiting occurs within 3 hours of administration,
consideration should be given to repeating the dose
Product: Tablets – 30 mg
Comments: Ulipristal is a synthetic progesterone agonist/antagonist that is used for emergency
contraception and can best be compared with levonorgestrel, the synthetic progestogen that is used in other
emergency contraception products. The primary mechanism of action of ulipristal is thought to be
inhibition or delay of ovulation. Its actions depend on the timing of its administration during the menstrual
cycle, and may also include alterations to the endometrium that may affect implantation in the uterus. This
latter action is considered by some to be equivalent to abortion, a position supported by the structural and
pharmacologic (i.e., progesterone antagonist activity) similarities to the abortifacient mifepristone
(Mifeprex; RU-486). However, ulipristal has been evaluated only for the prevention of pregnancy and not
as an abortifacient.
In the clinical studies, ulipristal reduced the pregnancy rate when used within 120 hours of
unprotected intercourse, compared with the expected pregnancy rate in the absence of emergency
contraception. Although some studies suggest that levonorgestrel also prevents pregnancy when used as
long as 120 hours following unprotected intercourse, the labeling for the levonorgestrel products
recommends use within 72 hours. Although the data are not definitive, ulipristal, as well as levonorgestrel,
may be less effective in women with a body mass index (BMI) > 30 kg/m2. Ulipristal is available only on
prescription, whereas levonorgestrel is available without a prescription from behind the pharmacy counter
for women 17 years of age and older, and with a prescription for individuals less than 17 years.
Eribulin mesylate (Halaven – Eisai)
2010
Antineoplastic Agent
New Drug Comparison Rating (NDCR) =
Indication: Administered intravenously for the treatment of patients with metastatic breast cancer who
have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease;
prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting
Comparable drug: Ixabepilone (Ixempra)
Advantages:
--May be effective in some patients with breast cancer who do not respond, or no longer respond, to other
therapies
--Is less likely to cause hypersensitivity reactions
--Is less likely to interact with other medications (e.g., CYP3A inhibitors and inducers)
Disadvantages:
--More likely to cause prolongation of the QT interval
--Labeled indications are more limited (ixabepilone is also indicated for use in combination with
capecitabine for the treatment of metastatic or locally advanced breast cancer in patients after failure of an
anthracycline and a taxane)
Most important risks/adverse events: Neutropenia (complete blood counts should be monitored prior to
each dose, and more frequently in patients who develop Grade 3 or 4 cytopenias; patients with ALT and/or
AST elevations are at greater risk of severe neutropenias); peripheral neuropathy (treatment should be
withheld in patients who experience Grade 3 or 4 peripheral neuropathy); prolongation of QT interval (use
should be avoided in patients with congenital long QT syndrome; hypokalemia or hypomagnesemia should
be corrected prior to initiating therapy, and these electrolytes should be monitored during therapy; ECG
monitoring is recommended in patients with congestive heart failure, bradyarrhythmias, or electrolyte
abnormalities, and in patients taking antiarrhythmic medications or other medications known to prolong the
QT interval); may cause fetal harm if used during pregnancy (Pregnancy Category D)
Most common adverse events: Neutropenia (82%), anemia (58%), asthenia/fatigue (54%), alopecia (45%),
peripheral neuropathy (35%), nausea (35%), constipation (25%)
Usual dosage: 1.4 mg/m2 administered intravenously over 2 to 5 minutes on Days 1 and 8 of a 21-day
cycle; dosage should be reduced in patients with hepatic impairment and moderate renal impairment;
treatment should be delayed and/or dosage reduced as needed based on assessment of complete blood cell
counts and peripheral neuropathy
Product: Single-use vials – 1 mg/2 mL; may be administered undiluted or diluted in 100 mL of 0.9%
Sodium Chloride Injection; must not be diluted in or administered through an intravenous line containing
solutions with dextrose
Comments: Eribulin is a synthetic analogue of halichondrin B, a product isolated from the sea sponge.
Like the taxane derivatives (e.g., docetaxel) and ixabepilone, it acts as a microtubule inhibitor. It exerts its
effects via a tubulin-based antimitotic mechanism that leads to apoptotic cell death after prolonged mitotic
blockage. Its effectiveness was demonstrated in a study of patients with metastatic breast cancer who
received at least two chemotherapeutic regimens (including anthracycline- and taxane-based regimens) for
the treatment of metastatic disease and experienced disease worsening within 6 months of their last
chemotherapeutic regimen. The control arm of the study included patients receiving other agents (e.g.,
vinorelbine [Navelbine], gemcitabine [Gemzar], capecitabine [Xeloda], a taxane) as single-agent therapy.
An improvement in overall survival was observed in patients treated with eribulin (median of 13.1 months)
compared with patients in the control arm (median of 10.6 months).
Cabazitaxel (Jevtana – Sanofi-Aventis)
2010
Antineoplastic Agent
New Drug Comparison Rating (NDCR) =
Indication: Administered intravenously for the treatment of patients with hormone-refractory metastatic
prostate cancer previously treated with a docetaxel-containing treatment regimen; regimen also includes
prednisone (administered orally)
Comparable drug: Docetaxel (Taxotere)
Advantages:
--Has greater activity in cancer cell lines that have acquired resistance to docetaxel
--Is the first drug to be approved for advanced, hormone-refractory prostate cancer that has worsened
during or after treatment with docetaxel
--May be less likely to cause fluid retention
Disadvantages:
--May be more likely to cause gastrointestinal and renal adverse events
--Labeled indications are more limited (docetaxel also has indications for breast cancer, non-small cell lung
cancer, gastric adenocarcinoma, and squamous cell carcinoma of the head and neck)
Most important risks/adverse events: Neutropenia including neutropenic deaths (boxed warning; is
contraindicated if neutrophil count is 1,500/mm3 or less; complete blood counts should be monitored on a
weekly basis during cycle 1 and before each treatment cycle thereafter); primary prophylaxis with
granulocyte-colony stimulating factor [G-CSF] should be considered in patients at high risk); severe
hypersensitivity (boxed warning; is contraindicated in patients with a history of severe hypersensitivity to
the drug or to polysorbate 80); gastrointestinal adverse events (nausea, vomiting, diarrhea; rehydration and
treatment with antiemetics and antidiarrheals may be necessary); renal failure; hepatic impairment (use
should be avoided in patients with hepatic impairment because of the likely increase in drug concentration
and activity); greater risk of adverse events in elderly patients; may cause fetal harm if used during
pregnancy (Pregnancy Category D); activity may be increased by medications that inhibit CYP3A (e.g.,
clarithromycin) and decreased by agents that induce CYP3A (e.g., carbamazepine, St. John’s wort)
Most common adverse events: Almost all patients experience neutropenia, leukopenia, and anemia;
thrombocytopenia (48%), diarrhea (47%), fatigue (37%), nausea (34%), vomiting (22%), constipation
(20%), asthenia (20%), hematuria (17%), abdominal pain (17%), anorexia (16%), back pain (16%)
Usual dosage: 25 mg/m2 administered every 3 weeks as a one-hour intravenous infusion in combination
with oral prednisone 10 mg once a day administered throughout the period of treatment; premedications
should be administered intravenously at least 30 minutes before each dose of cabazitaxel, including
diphenhydramine 25 mg or its equivalent, dexamethasone 8 mg or its equivalent, and ranitidine 50 mg or its
equivalent (prophylaxis with an antiemetic is also recommended and may be administered orally or
intravenously); treatment should be delayed and dosage reduced in patients who experience severe
neutropenia, febrile neutropenia, or severe or persisting diarrhea
Product: Single-use vials – 60 mg (in 1.5 mL polysorbate 80); supplied in a kit that also includes a vial of
diluent that contains approximately 5.7 mL of 13% (w/w) ethanol in water for injection; preparation of a
dose requires two dilutions before administration; for the first dilution, the entire contents of the supplied
diluent are added to the vial containing the drug, resulting in a solution that contains a drug concentration
of 10 mg/mL; the second dilution should be done within 30 minutes to prepare the final infusion; the
volume of the solution prepared with the first dilution that is needed to provide the recommended dose is
withdrawn from the vial and further diluted into a sterile 250-mL PVC-free container of either 0.9%
sodium chloride solution or 5% dextrose solution for infusion; the concentration of the final solution should
be between 0.1 and 0.26 mg/mL; PVC infusion containers or polyurethane infusion sets should not be used
for the preparation and administration of cabazitaxel infusion solutions
Comments: Cabazitaxel is a taxane antineoplastic agent with properties that are most similar to those of
docetaxel. It is a microtubule inhibitor that binds to tubulin and promotes its assembly into microtubules
while also inhibiting disassembly. This leads to the stabilization of microtubules, which results in the
inhibition of mitotic and interphase cellular functions. Although cabazitaxel and docetaxel appear to have
similar activity in docetaxel-sensitive cell lines, cabazitaxel has greater activity in cell lines that have
acquired resistance to docetaxel.
Cabazitaxel is the first drug to be approved for advanced, hormone-refractory prostate cancer that
has worsened during or after treatment with docetaxel. Its effectiveness has been demonstrated in a study
in which its use with prednisone was compared with a regimen of mitoxantrone and prednisone. All of the
patients in the study had been previously treated with a regimen that included docetaxel. The median
overall survival for the patients treated with the cabazitaxel regimen was 15.1 months compared with 12.7
months for those who received the mitoxantrone regimen.
Sipuleucel-T (Provenge – Dendreon)
2010
Antineoplastic Agent
New Drug Comparison Rating (NDCR) =
Indication: Administered intravenously for the treatment of asymptomatic or minimally symptomatic
metastatic castrate resistant (hormone refractory) prostate cancer
Comparable drug: Docetaxel (Taxotere)
Advantages:
--Is effective in some patients who have not experienced an adequate response with other agents (i.e.,
castration resistant [hormone refractory])
--Has a unique mechanism of action (autologous cellular immunotherapy)
--Less likely to cause severe adverse events
Disadvantages:
--Has not been directly compared with other agents in clinical studies
--Treatment involves complex procedures
--Treatment is very expensive
Most important risks/adverse events: Acute infusion reactions (e.g., fever, chills, dyspnea, hypertension,
tachycardia; patients should be premedicated orally with acetaminophen and an antihistamine); action may
be reduced by the concurrent use of an immunosuppressant drug; universal precautions should be observed
to reduce risk of transmissible infectious diseases
Most common adverse events: Chills (53%), fatigue (41%), fever (31%), back pain (30%), nausea (22%),
joint ache (20%), headache (18%)
Usual dosage: A course of treatment consists of three doses at approximately 2-week intervals, that are
administered intravenously over approximately 60 minutes; each dose consists of a minimum of 50 million
autologous CD54+ cells that have been activated; medication is for autologous use only and, before
infusion, the patient’s identity must be matched with the patient identifiers on the infusion bag and the
pertinent form provided with the product; patients should be premedicated with acetaminophen and an
antihistamine (e.g., diphenhydramine) approximately 30 minutes before administration of the drug; patients
should be observed for at least 30 minutes following each infusion
Product: Preparation of the product initially requires the collection of the patient’s peripheral blood
mononuclear cells using a leukapheresis procedure approximately 3 days before the date of each infusion;
cells are sent to a center at which they are activated; the product contains autologous antigen-presenting
cells (APCs) that have been activated in a culture medium with a recombinant human protein, PAP-GMCSF, that consists of prostatic acid phosphatase (PAP; an antigen expressed in most prostate cancers)
linked to granulocyte-macrophage colony-stimulating factor (GM-CSF; an immune cell activator); product
is supplied as a suspension in Lactated Ringer’s Injection in an infusion bag containing a volume of 250
mL in a special insulated polyurethane container that is placed in a cardboard shipping box and sent to the
provider for infusion administration
Comments: Sipuleucel-T is an autologous cellular immunotherapy that involves the collection and
activation of a patient’s cells in a process designed to induce an immune response targeted against prostatic
acid phosphatase. The effectiveness of the treatment was demonstrated in placebo-controlled studies in
which those in the control group also underwent leukapheresis procedures but received autologous
peripheral blood mononuclear cells that had not been activated. Although the times to disease progression
did not differ enough to be considered statistically significant, the median survival was significantly longer
in the group of patients receiving sipuleucel-T (25.8 months vs. 21.7 months in the largest study).
The cost of the drug is approximately $93,000 for the 3-dose course of treatment.
Romidepsin (Istodax – Gloucester)
2010
Antineoplastic Agent
New Drug Comparison Rating (NDCR) =
Indication: Administered intravenously for the treatment of cutaneous T-cell lymphoma (CTCL) in
patients who have received at least one prior systemic therapy
Comparable drug: Vorinostat (Zolinza)
Advantages:
--May be effective in some patients who have not experienced an adequate response with other therapies
--Indicated for use in patients who have received at least one prior systemic therapy (whereas vorinostat is
indicated in patients who have received two prior systemic therapies
--Clinical benefit may be of longer duration
--May be less likely to be associated with the occurrence of pulmonary embolism
--May be less likely to cause gastrointestinal adverse events
--May be less likely to cause hyperglycemia
Disadvantages:
--Must be administered intravenously (whereas vorinostat is administered orally)
--Has not been directly compared with vorinostat in clinical studies
--May be more likely to cause electrocardiographic changes including prolongation of the QT interval
--Interacts with more medications, including estrogen-containing contraceptives
Most important risks/adverse events: Electrocardiographic changes (potassium and magnesium
concentrations should be monitored; caution must be observed in patients with congenital long QT
syndrome, considerable cardiovascular disease, and in those who are taking antiarrhythmic agents or other
medications that may cause substantial QT prolongation); thrombocytopenia, neutropenia, lymphopenia,
and anemia (hematological parameters should be monitored); may cause fetal harm if administered during
pregnancy (Pregnancy Category D); may reduce the effectiveness of estrogen-containing contraceptives;
action may be increased by strong CYP3A4 inhibitors (e.g., clarithromycin) and reduced by potent
CYP3A4 inducers (e.g., carbamazepine, St. John’s wort), and concurrent use should be avoided;
prothrombin time and INR should be closely monitored in patients also being treated with warfarin
Most common adverse events: Incidence of adverse events differed substantially in the two studies: study
1: nausea (56%), fatigue (53%), infection (46%),vomiting (34%), anorexia (23%), pyrexia (20%); study 2:
nausea (86%), fatigue (77%), anemia (72%), thrombocytopenia (65%), electrocardiogram ST-T wave
changes (63%), neutropenia (57%), lymphopenia (57%), leukopenia (46%)
Usual dosage: 14 mg/m2 administered intravenously over a 4-hour period on days 1, 8, and 15 of a 28-day
cycle; cycles of treatment are repeated every 28 days provided that the patient continues to benefit from and
tolerate the therapy; treatment discontinuation or interruption with or without dose reduction to 10 mg/m2
may be necessary to manage adverse events
Product: Single-use vial – 10 mg (and 20 mg of the bulking agent povidone); supplied in a kit that also
includes a vial containing 2 mL of the diluent consisting of 80% propylene glycol and 20% dehydrated
alcohol; medication is reconstituted with the diluent supplied and then diluted in 500 mL of 0.9% Sodium
Chloride Injection
Comments: Histone deacetylases (HDACs) catalyze the removal of acetyl groups from the lysine residues
of proteins, and are overexpressed by some cancer cells. Romidepsin is the second HDAC inhibitor to be
approved for the treatment of CTCL, joining vorinostat. However, vorinostat is administered orally, while
romidepsin is administered intravenously. The effectiveness of romidepsin was demonstrated in 2 studies
in patients who had received prior therapies. The overall response rate was 35%, and 6% of patients had a
complete response. The median duration of response was 15 months and 11 months in the 2 studies.
Polidocanol (Asclera – BioForm Medical)
2010
Sclerosing Agent
New Drug Comparison Rating (NDCR) =
Indications: For intravenous administration to sclerose uncomplicated spider veins (varicose veins 1 mm or
less in diameter) and uncomplicated reticular veins (varicose veins 1 to 3 mm in diameter) in the lower
extremity
Comparable drug: Sodium tetradecyl sulfate (Sotradecol)
Advantages:
--Satisfaction with treatment reported by a higher percentage of patients
--Lower incidence of adverse events
--Fewer contraindications (e.g., sodium tetradecyl sulfate is contraindicated in patients in uncontrolled
systemic diseases such as diabetes and asthma)
Disadvantages:
--None
Most important risks/adverse events: Contraindicated in patients with acute thromboembolic diseases and
in patients with known allergy (anaphylaxis) to the drug; severe allergic reactions, including fatal
anaphylactic reactions (risk is greater with the use of volumes greater than 3 mL of the injection; following
injection, patients should be under supervision for at least 20 minutes); accidental intra-arterial injection;
inadvertent perivascular injection
Most common adverse events: Injection site reactions (usually mild in severity) – hematoma (42%),
irritation (41%), discoloration (38%), pain (24%), pruritus (19%), warmth (16%)
Usual dosage: For intravenous administration - the 0.5% solution should be used for the treatment of
spider veins, and the 1% solution for reticular veins; a syringe with a fine needle (26- or 30-gauge) should
be used and the solution should be injected slowly; a volume of 0.1 to 0.3 mL should be used for each
injection, and no more than 10 mL should be injected per session; repeat treatments may be needed if the
extent of the varicose veins requires more than 10 mL of solution; treatments should be separated by 1 to 2
weeks; following injection, compression in the form of a stocking or bandage should be applied and the
patients should be encouraged to walk for 15-20 minutes; compression should be maintained for 2 to 3 days
following treatment of spider veins, and for 5 to 7 days for reticular veins
Products: Ampules – 5 mg (0.5%) and 10 mg (1%) in water for injection with 5% (v/v) ethanol
Comments: Varicose veins most commonly occur in the legs and are characterized by weak or damaged
valves that result in pooling of blood and swelling. Although symptoms may not occur, some individuals
experience mild to moderate pain, blood clots, and/or skin ulcers. Spider veins involve the capillaries and
have the appearance of a spider web, and reticular veins are flat blue veins that are usually seen behind the
knees. Sclerosing agents have been used in the treatment of smaller varicose veins. Following injection,
they cause irritation and scarring inside the vein, resulting in the vein closing off and fading away.
Polidocanol is a non-ionic detergent that consists of two components – a polar hydrophilic
(dodecyl alcohol) chain and an apolar hydrophobic (polyethylene oxide) chain. Its properties and use are
most similar to those of sodium tetradecyl sulfate, an anionic surface active agent. The effectiveness of
polidocanol was demonstrated in a study in which it was compared with sodium tetradecyl sulfate and
placebo. Treatment was determined to be successful at both 12 and 24 weeks in more than 90% of the
patients treated with polidocanol or sodium tetradecyl sulfate, but in less than 10% of those receiving
placebo. Patient satisfaction was evaluated and approximately 85%, 64%, and 15% were satisfied or very
satisfied with their treatment with polidocanol, sodium tetradecyl sulfate, and placebo, respectively. The
incidence of injection site reactions was considerably lower in patients receiving polidocanol compared
with their incidence in patients treated with sodium tetradecyl sulfate.
Carglumic acid (Carbaglu – Orphan Europe)
2010
Agent for Hyperammonemia
New Drug Comparison Rating (NDCR) =
Indications: As adjunctive therapy for the treatment of acute hyperammonemia due to the deficiency of the
hepatic enzyme N-acetylglutamate synthase (NAGS); also indicated as maintenance therapy for the
treatment of chronic hyperammonemia due to the deficiency of the hepatic enzyme NAGS
Comparable drugs: Other ammonia-lowering therapies: sodium benzoate/sodium phenylacetate
(Ammonul, Ucephan), sodium phenylbutyrate (Buphenyl)
Advantages:
--Unique mechanism of action (replacement for N-acetylglutamate [NAG] in patients with NAG synthase
[NAGS] deficiency)
--May permit reduction or discontinuation of other ammonia-lowering therapies
Disadvantages:
--Labeled indication is more limited
Most important risks/adverse events: Plasma ammonia concentrations must be monitored; protein
restriction is usually necessary during initial treatment
Most common adverse events: Vomiting (26%), abdominal pain (17%), pyrexia (17%), tonsillitis (17%),
anemia (13%), ear infection (13%), nasopharyngitis (13%), headache (13%), diarrhea (13%)
Usual dosage: Acute hyperammonemia – 100 to 250 mg/kg/day initially; total daily dosage should be
divided into two to four doses that, in the treatment of adult patients, should be rounded to the nearest 100
mg; maintenance dosages are usually less than 100 mg/kg/day; in pediatric patients, doses are administered
using an oral syringe; in both adult and pediatric patients, may also be administered via a nasogastric tube
Product: Tablets – 200 mg ; should not be swallowed whole or crushed; for use in adults, each tablet
should be dispersed in a minimum of 2.5 mL of water and taken immediately; the container should be
rinsed with an additional volume of water and the contents swallowed immediately; in pediatric patients,
each tablet is mixed in a container with 2.5 mL of water to provide a concentration of 80 mg/mL; the
appropriate volume of the dispersion is drawn up in an oral syringe and administered immediately; the oral
syringe should be refilled with 1-2 mL of water and administered immediately
Comments: Carbamoyl phosphate synthetase (CPS)-1 is the first enzyme of the urea cycle, which converts
ammonia into urea. This enzyme is activated by N-acetylglutamate (NAG), which is the product of the
hepatic enzyme NAGS. Some individuals experience a rare genetic disorder that is caused by a deficiency
of NAGS and which can result in a rapid increase in ammonia concentrations. Carglumic acid is a
synthetic analog of NAG that acts as a replacement for NAG and activates CPS-1 in patients with NAGS
deficiency. Its effectiveness has been evaluated in a retrospective review of the clinical course of 23
patients with NAGS deficiency who were treated with carglumic acid for a median of approximately 8
years. Plasma ammonia concentrations were reduced within 24 hours following initiation of treatment and,
by the third day of treatment, normal plasma ammonia concentrations were attained for all patients with
available data.
In treating patients with acute hyperammonemia, other ammonia-lowering therapies and
hemodialysis should be used concurrently with carglumic acid. Protein restriction and hypercaloric intake
are also recommended to block ammonia-generating catabolic pathways. During maintenance treatment,
the concomitant use of other ammonia-lowering therapies may be reduced or discontinued based on plasma
ammonia concentrations. When these concentrations are normalized, protein intake usually can be
increased, and the goal is to permit unrestricted protein intake.
Ecallantide (Kalbitor – Dyax)
2010
Agent for Hereditary Angioedema
New Drug Comparison Rating (NDCR) =
Indication: Administered subcutaneously for the treatment of acute attacks of hereditary angioedema (HAE)
in patients 16 years of age and older
Comparable drugs: C1 esterase inhibitor (Cinryze, Berinert)
Advantages:
--Indicated for the treatment of acute attacks of HAE (compared with Cinryze that is indicated for prophylaxis
of attacks
--Labeled indication for treatment of HAE attacks is broader (compared with Berinert that is indicated for the
treatment of abdominal and facial attacks)
--Has a unique mechanism of action (plasma kallikrein inhibitor)
--Is administered subcutaneously (whereas Cinryze and Berinert are administered intravenously)
Disadvantages:
--Labeled indication does not include prophylaxis against HAE attacks (compared with Cinryze)
--Has not been directly compared with C1 esterase inhibitor in clinical studies
--May be more likely to cause anaphylaxis (labeling includes a boxed warning)
Most important risks/adverse events: Anaphylaxis (boxed warning; should only be administered by a
healthcare professional with appropriate medical support to manage anaphylaxis and HAE)
Most common adverse events: Headache (16%), nausea (13%), fatigue (12%), diarrhea (11%), upper
respiratory tract infection (8%), injection-site reactions (7%), nasopharyngitis (6%), vomiting (6%), pruritus
(5%), upper abdominal pain (5%), pyrexia (5%)
Usual dosage: Administered subcutaneously in the abdomen, thigh, or upper arm; 30 mg administered in
three injections containing 10 mg each (i.e., using 3 vials)
Product: Vials – 10 mg (in 1 mL); a 10-mg dose should be withdrawn from the vial using a large-bore
needle; the needle on the syringe should then be changed to a needle suitable for subcutaneous administration
(27 gauge); this procedure is repeated for each of the 3 vials to provide the total dose of 30 mg; injection site
for each of the 3 injections may be in the same or different anatomic location; injection sites should be
separated by at least 5 cm and away from the anatomical site of the HAE attack
Comments: Hereditary angioedema is a rare, genetic disorder that is characterized by severe and often
painful swelling that most often occurs in the extremities, face, gastrointestinal tract, and/or larynx. It is
caused by a mutation of the C1-INH gene that results in a deficiency of C1 esterase inhibitor (C1-INH).
C1-INH regulates inflammatory and clotting reactions, primarily by acting as an inhibitor of plasma
kallikrein. The kallikrein-kinin system is a complex proteolytic cascade, and unregulated activity of plasma
kallikrein results in the excessive production of bradykinin, a vasodilator that is thought to be responsible for
the symptoms that are characteristic of HAE. Ecallantide is a 60-amino acid protein produced by
recombinant DNA technology. It is a selective, reversible inhibitor of plasma kallikrein that reduces the
formation of bradykinin, thereby reducing the symptoms of an acute episodic attack of HAE. Its
effectiveness was evaluated in two placebo-controlled studies in which patients treated with ecallantide
experienced greater reduction in symptoms and improved outcomes compared with those receiving placebo.
More patients in the placebo group (50%) required medical intervention to treat unresolved symptoms within
24 hours compared with the ecallantide-treated group (33%).
Anaphylaxis was experienced by 4% of the patients in the clinical studies, and the reactions
occurred within the first hour after administration. The symptoms of a hypersensitivity reaction and the
symptoms of HAE are similar, and patients should be monitored closely for an appropriate period of time
following administration of the drug.
Velaglucerase alfa (Vpriv – Shire)
2010
Agent for Gaucher disease
New Drug Comparison Rating (NDCR) =
Indication: Administered intravenously for long-term enzyme replacement therapy for pediatric and adult
patients with type 1 Gaucher disease
Comparable drug: Imiglucerase (Cerezyme)
Advantages:
--May be less likely to be associated with antibody formation
Disadvantages:
--Has not been directly compared with imiglucerase in clinical studies
--Effectiveness and safety have not been established in children less than 4 years of age (whereas
imiglucerase is indicated in children as young as 2 years)
Most important risks/adverse events: Hypersensitivity reactions; infusion-related reactions (e.g., headache,
dizziness, pyrexia)
Most common adverse events: Headache (35%), upper respiratory tract infections (32%), dizziness (22%),
pyrexia (22%), abdominal pain (19%), back pain (17%), joint pain (15%), asthenia/fatigue (13%),
hypotension (<10%), hypertension (<10%), prolongation of activated partial thromboplastin time (aPTT;
11%)
Usual dosage: 60 units/kg every other week administered as a 60-minute intravenous infusion
Products: Single-use vials – 200 units, 400 units (should be stored in a refrigerator); contents of each vial
should be reconstituted with 2.2 mL or 4.3 mL Sterile Water for Injection, respectively (resultant solution
contains 100 units/mL); the volume of solution needed to provide the dose should be withdrawn and diluted
in 100 mL of 0.9% sodium chloride solution suitable for intravenous administration
Comments: Gaucher disease is a lysosome storage disorder caused by mutations in the glucosidase beta
acid gene that result in a deficiency of beta-glucocerebrosidase. This enzyme deficiency results in an
accumulation of glucocerebroside in the lysosomal compartment of macrophages. Type 1 Gaucher disease
is the most common form, and anemia, thrombocytopenia, and organomegaly are the most common
manifestations. Velaglucerase alfa has the same amino acid sequence as the human enzyme
glucocerebrosidase and its action as a hydrolytic lysosomal glucocerebroside-specific enzyme is essentially
the same as imiglucerase. Its effectiveness was demonstrated in two studies in patients who were not
currently receiving Gaucher disease-specific therapy. There was a clinically meaningful increase in
hemoglobin concentration, which was the primary endpoint, and an increase in platelet count, as well as a
reduction in liver volume and spleen volume.
Infusion-related reactions were the most commonly reported adverse events. They were usually
mild and occurred most often during the first 6 months of treatment and less frequently thereafter. In
patients for whom treatment of symptoms of infusion reactions is required, pretreatment with an
antihistamine and/or corticosteroid may prevent subsequent reactions.
Iowa Pharmacy Law Update & Luncheon
ACPE UAN 107-000-11-028-L03-P & 107-000-11-028-L03-T
Activity Type: Knowledge-Based
0.1 CEU/1.0 Hr
Program Objectives for Pharmacists & Technicians: Upon completion of this program, participants should
be able to:
1. Describe the implications of the Iowa Board of Pharmacy’s recently adopted rules.
2. List the Iowa Board of Pharmacy’s 2011 legislative priorities.
3. Discuss the Iowa Board of Pharmacy’s proposed list of rule changes for 2011.
Speakers: Susan Frey, RPh, is a consultant pharmacist specializing in long term care for older adults.
Her clients include assisted-living facilities, skilled, intermediate, and residential nursing facilities. The
focus of her consulting practice is to provide all aspects of medication therapy management to maintain
or improve the residents’ quality of life. She provides seminars and in-service training for the faculty staff
as well as develops policies and procedures for the administration and accountability of medications in
the facilities. She has presented continuing education programs for Iowa Pharmacy Association and the
Iowa Health Care Association. Susan is a graduate of the University of Nebraska Medical Center College
of Pharmacy with a residency at the University of Florida Shands Teaching Hospital in Gainesville, FL.
Her practice is based at the Hy-Vee, Inc. pharmacy in Red Oak, IA. Susan is currently serving a second
three-year term on the State of Iowa Board of Pharmacy, serving as vice-chair. She is an active member
of the Iowa Pharmacy Association and the American Pharmacy Association.
Ed Maier, RPh, is a member of the Iowa Board of Pharmacy and was appointed for this position by
Governor Culver in 2008. Ed is the owner of Maier Family Pharmacy in Mapleton, IA for 30 years and
the owner of Western Iowa Compounding Solutions also in Mapleton, IA for 10 years.
Speaker Disclosures: Susan Frey and Ed Maier report they have no actual or potential conflicts of
interest in relation to this program. The speakers have indicated that off-label use of medications will
not be discussed during this presentation.
Board of Pharmacy
Law Update
Faculty Disclosure
The speakers report they have no actual or
potential conflicts of interest associated with this
presentation.
Susan Frey, R.Ph., and Edward Maier, R.Ph.
Board Members
Iowa Board of Pharmacy
Learning Objectives
Pre-Assessment Questions
Upon completion of this program, pharmacists and
pharmacy technicians will be able to:





Describe the implications of the Iowa Board of Pharmacy’s
recently adopted new rules or revised rules.
Discuss the Iowa Board of Pharmacy’s proposed list of rule
changes for 2011 (rules not in effect yet).
List the Iowa Board of Pharmacy’s 2011 regulatory
priorities.
Articulate the usefulness and benefits of the Iowa
Prescription Drug Monitoring Program (PMP).
Identify regulatory agencies other than the Iowa Board of
Pharmacy.
Board Officers—2010/2011
Vern Benjamin, R.Ph.
Chairperson
Shopko Pharmacy, Ft. Madison
Susan Frey, R.Ph.
Vice Chairperson
Hy-Vee, Red Oak
1. Pharmacies may store Rx records more than 12 months old
in a secure area outside the prescription department.
True or False
2. Up to 50% of pharmacist CE credits may come from nonACPE courses. True or False
3. Pharmacy support persons may handle Rx drugs as part of
the dispensing process. True or False
4. A person purchasing pseudoephedrine without a
prescription must present a current government-issued
photo ID to the pharmacist at the time of sale.
True or False
5. The Prescription Monitoring Program must be utilized before
dispensing a controlled substance prescription.
True or False
Other Board Members
•
DeeAnn Wedemeyer-Oleson, Pharm.D., Adair
•
Mark Anliker, R.Ph., Emmetsburg
•
Ed Maier, R.Ph., Mapleton
•
Peggy Whitworth, Public Member, Cedar Rapids
•
Ann Diehl, ARNP, Public Member, Osceola
Board Compliance Officers
Compliance Officer Territories
Jean Rhodes
•
Jean Rhodes, R.Ph, Madrid
•
Jennifer Tiffany, R.Ph., Des Moines
•
Jennifer O’Toole, R.Ph., Urbandale
•
Jim Wolfe, R.Ph., Marion
•
Bernie Berntsen, R.Ph., Marion
Bernie Berntsen
Jennifer Tiffany
Jim Wolfe
Jennifer O’Toole
Board Meeting Calendar—2011
Board Regulatory Plan & Priority Issues
•
•
•
•
•
•
•
January 11-12
March 8-9
April 26-27
June 28-29
September 13-14
November 15
•
•
•
•
•
•
•
•
Outline of Rules and Areas of Change
Pharmacy Continuing Education
Pharmacy Support Persons
Expansion of Immunizations by Pharmacists
Drugs in Emergency Medical Service Programs
Limited Drug and Device Distributors
Internet Pharmacy Sites
Controlled Substance Schedules
Tech-Check-Tech Programs
Pharmacy Technician Functions
Rule Changes Effective in 2010
Storage of Prescriptions and Other
Pharmacy Records:
Original Rxs and other records more than 12
months old may be maintained in a secure
storage area outside the licensed pharmacy
department, as long as the storage area is
within the same physical structure that houses
the pharmacy.
Rules 6.16, 8.9 and 10.34
Rule Changes Effective in 2010
Rule Changes Effective in 2010
Animals in the Pharmacy:
Pharmacy Continuing Education:
Animals are not allowed in a pharmacy unless
the pharmacy is providing services for the
treatment of animals or unless the animal is a
service dog or assistive animal as defined in
Iowa Code § 216C.11(1)
Not more than 50% of pharmacy C.E. credits
may be obtained through completion of
non-ACPE courses.
Rule 8.5(4)
Rule Changes Effective in 2010
Correctional Facility Pharmacy Practice:
The Board has adopted a new chapter of rules
for correctional facility pharmacy practice. The
PIC is required to develop and implement
written P&Ps for the pharmacy drug distribution
system.
Rules Chapter 15
Non-ACPE courses must be provided by an
accredited health-professional continuing
education provider.
Rule 2.12(1)”a”
Rule Changes Effective in 2010
Pharmacy Support Persons (PSPs) may
perform the following tasks:
Clerical duties
Receipt and processing of incoming drugs
Filing processed prescription records
Updating or changing patient demographic
information in the pharmacy computer
Receipt of a refill request from a patient
Performing drug inventory duties
Delivery of drugs
Rules Chapter 5
Rule Changes Effective in 2010
Pharmacy Support Persons (PSPs)
may not perform the following tasks:
Entering Rx information into computer
Handling Rx drugs as part of the dispensing
process
Preparing or affixing Rx labels
Packaging Rx drugs
Reconstituting medications
Receipt of new or refill Rxs from prescriber
Other tasks reserved for technicians and
pharmacists
Rules Chapter 5
Rule Changes Effective in 2010
Designation of Imitation Controlled
Substances:
The Board identified four synthetic cannabinoids
as imitation controlled substances.
Examples include products such as K2, Red
Dragon Smoke, Spice, K2 Spice, Mojo, Smoke,
Skunk, K2 Summit, and Pandora Potpourri.
Board Rule 10.41
Rule Changes Effective in 2010
Rule Changes Effective in 2010
Pharmacy Technicians:
Hospital Pharmacy Practice:
The Board modified the rules for pharmacy
technicians after unexpected legislation
extended the deadline for technician
certification from July 1, 2010, to December 31,
2013. Rules which restricted the activities of
uncertified technicians were subsequently
stayed pending further discussion and
rulemaking.
The Board adopted new rules for Outpatient
Services and Drugs in the Emergency
Department. The rules specifically address the
use of an InstyMeds dispensing system in a
hospital emergency department.
Board Rules 7.11 and 7.12
Rules Chapter 3
Rule Changes Effective in 2010
Dispensing Certain Products Without a Rx:
The Board clarified the form of ID that must be
presented by the patient and reviewed by the
pharmacist prior to dispensing products
containing ephedrine, pseudoephedrine, or
phenylpropanolamine without a prescription.
The ID must be a current government-issued
photo identification, including proof of age.
Board Rule 10.32
Rule Changes Effective in 2010
Sterile Compounding Practices:
The Board clarified the definition of “beyonduse date” for a sterile compounded product and
also clarified the storage periods for high-risk
compounded preparations based on the
temperature of the preparations during storage.
Board Rules 13.2 and 13.13(1)”e”
Rule Changes Effective in 2010
Iowa Real-Time Electronic
Pseudoephedrine Tracking System (PTS):
The Governor’s Office of Drug Control Policy
(ODCP) adopted new rules which established a
real-time electronic program for monitoring and
controlling the sale of Schedule V products that
contain any amount of ephedrine,
pseudoephedrine, or phenylpropanolamine .
Rules Chapter 100
Rule Changes Proposed in 2011
1. Written format for oral controlled substance Rxs.
Rule 10.22(2)”c”
2. Requirements for closing a pharmacy.
Rules 8.11, 8.16(3), 8.35(6), and 8.35(7)
3. Drugs in emergency service programs.
Rules Chapter 11
4. Pharmacy technician—Technical functions—Tasks
that may be performed by pharmacy technician
trainees and uncertified pharmacy technicians.
Rule 3.22(2)
Rule Changes Proposed in 2011
Rule Changes Proposed in 2011
5. Hospital Pharmacy Practice—When the pharmacy
is closed—Pharmacist identified.
Board Rule 7.7(7)
8. Certified pharmacy technicians must maintain both an
Iowa technician registration and national technician
certification.
Board Rules 3.3, 3.5 and 3.12
6. Sterile Compounding Practices—Anteroom
requirements.
Board Rule 13.27(4)
7. Pharmacist Licenses—Pharmacists in pharmacy
residency programs exempt from pharmacy C.E.
Board Rule 2.12(1)”b”
Legislative Changes Proposed in 2011
1.Controlled Substance Schedules (1274DP) – BOP
2.Pharmacist License Surcharge (1290DP) – BOP
9. A log of the initials or unique ID codes of all pharmacy
support persons, pharmacy technicians, pharmacists,
and pharmacy interns shall be maintained by the
pharmacy for two years.
Board Rule 8.4
10. Pharmacy Reference Library Requirements—Iowa
Pharmacy Law and Information Manual.
Board Rules 6.3, 7.3, 15.4 and 16.5
PMP Results for 2010


3.Prescription Monitoring Program (1292DP) – BOP
4.Marijuana as Scheduled Controlled Substance
(1203DP) – ODCP
5.Prescription Drug Monitoring Program (1315DP) ODCP
PMP Results for 2010

1,020 Pharmacists currently registered
(32.5% of current Iowa pharmacists)

26 Regulatory officers currently registered

65 Law enforcement officers currently
registered


January 1, 2010, through December 31,
2010
52,850 Requests for PMP data reports
submitted (84% from prescribers; 15%
from pharmacists)
4,289,823 Prescription records recorded in
the PMP database
2,254 Prescribers currently registered
(14.7% of eligible prescribers)
PMP Results for 2010
Top Ten Controlled Substances
Dispensed to Patients in Iowa
(Percentage of Total)
1.Hydrocodone 29.2%
2.Alprazolam 10.9%
3.Oxycodone 9.0%
4.Lorazepam 6.3%
5.Clonazepam 6.1%
6.Methylphenidate 5.8%
7.Zolpidem 4.7%
8.Amphetamine 4.5%
9.Propoxyphene 3.6%
10.Codeine 2.8%
Iowa Board of Pharmacy Website
www.state.ia.us/ibpe/
Iowa Board of Pharmacy Rules
The Board’s rules (all 271 pages)
may be viewed on the Board’s website at:
www.state.ia.us/ibpe/pdf/IAC657rules.pdf
Iowa Board of Medicine
Mark Bowden, Executive Director
Iowa Board of Medicine
RiverPoint Business Park
400 SW Eighth Street, Suite C
Des Moines, IA 50309
(515) 242-3268
E-mail: [email protected]
Iowa Medical Board website address:
http://medicalboard.iowa.gov/
Link to file a complaint against a physician:
http://medicalboard.iowa.gov/forms/ComplaintForm.html
Des Moines FDA Office
Brent T. Hall
Room 469 HFR-SW3510
210 South Walnut
Suite 469
Des Moines, IA 50309
(515) 323-2761
Email: [email protected]
Consumer Information:
www.fda.gov/ForConsumers/ProtectYourself/default.htm
NABP
National Association of Boards of Pharmacy
Carmen A. Catizone, Executive Dir./Secretary
1600 Feehanville Drive
Mount Prospect, IL 60056
(847) 391-4406
Fax: (847) 391-450
Customer Service E-mail:
[email protected]
Des Moines DEA Office
Thomas Cox
Federal Building, Room 937
210 Walnut Street
Des Moines, IA 50309
(515) 284-4709
Fax: (515) 323-2656
E-mail: [email protected]
Post-Assessment Questions
Use of the Iowa Real-Time Electronic Pseudoephedrine
Tracking System is optional. True or False
2. Storage periods for high-risk compounded
preparations are based on the temperature of the
preparations during storage. True or False
3. The most often prescribed controlled substance in
Iowa is hydrocodone. True or False
4. The vast majority of PMP requests for data are
submitted by pharmacists. True or False
5. The Prescription Monitoring Program is an important
health care tool for prescribers and pharmacists. True
or False
Conclusion
1.
Q&A
Thank You
Fields of Opportunities
CHESTER J. CULVER
GOVERNOR
STATE OF IOWA
B O A R D O F P H A R MA C Y
LLOYD K. J ESSEN, RPh, J D,
DIRECTOR
PATTY JUDGE
LT. GOVERNOR
December 30, 2010
Governor Chester J. Culver
Governor-Elect Terry E. Branstad
Members of the 84th General Assembly
Iowa State Capitol
Des Moines, IA 50319
Honorable Governor, Governor-Elect, and Members:
Re: Iowa Prescription Monitoring Program
Pursuant to the requirements of section 124.554, subsection 2, of the Iowa Uniform Controlled
Substances Act, the Board of Pharmacy submits the following information.
The Iowa Prescription Monitoring Program (PMP) provides authorized prescribers and
pharmacists with information regarding their patients’ use of controlled substances and is used as
a tool in determining appropriate prescribing and treatment of patients without fear of
contributing to a patient’s abuse or dependence on addictive drugs or diversion of those drugs to
illicit use. Iowa pharmacies are required to report to the Iowa PMP all Schedule II, III, and IV
controlled substances dispensed by the pharmacy to ambulatory patients.
The Iowa PMP became fully operational on March 25, 2009. The cost of initial implementation
of the Iowa PMP was paid by federal grant and amounted to $411,250. Annual costs of $97,608
provide for the receipt and delivery of pharmacy data and database software maintenance.
Annual costs are paid from license fees retained by the Board of Pharmacy for the support of
Board programs and activities. No additional fees or surcharges have been imposed to pay for
activities or support of the Iowa PMP.
The Iowa PMP is administered by the Board of Pharmacy with the assistance and guidance of an
advisory council consisting of governor-appointed pharmacists and prescribers. The advisory
council meets at least annually to review the progress of the Iowa PMP, the cost of maintaining
the Iowa PMP and the benefits of the program, possible improvements to the program, and
information, comments, and suggestions received from program users and members of the
public. A sampling of those comments is attached as Exhibit 1.
400 S.W. EIGHTH STREET, SUITE E / DES MOINES, IOWA 50309-4688
515/281-5944 / FAX: 515/281-4609 / WEBSITE: HTTP://WWW.STATE.IA.US/IBPE
PMP Report 2011
December 30, 2010
Page 2
The Board of Pharmacy and the PMP Advisory Council also review statistics regarding the use
of the Iowa PMP by prescribers, pharmacists, and law enforcement or regulatory agents; the
number of prescriptions filled each year; the top drugs dispensed in Iowa each year; and indices
of excessive pharmacy-shopping or doctor-shopping for controlled substances. Attached Exhibit
2 includes some of the data compiled since the establishment of the Iowa PMP.
The data indicate steady increases in the number of pharmacists and prescribers registering to use
the Iowa PMP and in the number of requests for patient prescription history being submitted and
used by those authorized users. The data also demonstrates that the prescribing and dispensing of
these controlled substances has not been unnecessarily or adversely affected by the
implementation of the Iowa PMP. The number of prescriptions dispensed and the number of
doses dispensed have increased each year for which data has been compiled in the database.
A number of regulatory and law enforcement agents have also registered to use the Iowa PMP. A
member of this user community may receive Iowa PMP data only for an existing investigation or
case where there has been a determination of probable cause for the information and the request
for prescription information is accompanied by an order, subpoena, or other means of legal
compulsion. Less than one percent of all processed requests are attributable to law enforcement
or regulatory agents but those agents who have used information available from the Iowa PMP
report improved efficiency and reduced investigative hours due to the central availability of the
prescription information compiled in the Iowa PMP database.
A chart identifying the top ten controlled substances dispensed in Iowa during 2010 is attached
as Exhibit 3. Although this chart includes the specific data for calendar year 2010, these
substances have consistently been identified, with similar quantities, as the top ten controlled
substances dispensed during calendar years 2008, 2009, and 2010.
As evidenced by the comments received from prescribers and pharmacists, users have found the
Iowa PMP to be a valuable assistive tool in determining appropriate health care treatment for
their patients. The Board of Pharmacy and the PMP Advisory Council concur that the Iowa
PMP provides proportionally more value for the health care community and their patients than
the program costs. The Board of Pharmacy has pre-filed a bill for consideration during the 2011
legislative session that provides for the continuation of the Iowa PMP and that includes a
recommended improvement to the Iowa PMP.
Respectfully submitted,
Lloyd K. Jessen, R.Ph., J.D.
Executive Secretary/Director
LKJ:tmw
Attachments
IOWA PRESCRIPTION MONITORING PROGRAM REPORT 2011
EXHIBIT 1 – A SAMPLING AND EXCERPTS OF
COMMENTS AND SUGGESTIONS RECEIVED FROM USERS
From Prescribers:
I have found it helpful in following several patients and having information to discuss with them
regarding their prescription usage, and at times misusage.
Who would I write to, to express how awesome of a tool this is to have. I wish I’d had access to this
info years ago!
As an ER doc the PMP really helps me sort things out. At some point it would be helpful if it also
included non controlled substances.
Thank you very much for this program. I’m sure you hear very often about patients abusing physicians
without them realizing it. My last request indicated that a patient had received narcotics from different
providers that I would never have known about. Thanks again.
Can nurses in our clinic have access to the monitoring program or is it physician only?
I just wanted to drop a note when it was fresh on my mind how wonderful the web site is for
prescription drug monitoring. We have found it immensely helpful in both weeding out some
prescription narcotic seekers and for easing our mind that a patient we may suspect is not seeking.
This is a great program to prevent abuse of controlled medications, and to help patients get the help
they need by addressing their abuse immediately. I hope the system continues!
I think this is a great tool that will help to eliminate concerns in my mind about patients who may be
“hunting” for drugs. I view Iowa PMP as another tool at our disposal to help provide better, more
consistent care to our patients.
I am very happy this program is being instituted. Thank you.
= = = = = = = = = = = = = = = = = = = = =
From Pharmacists:
I love this program and anything I can do to help will be worth the investment!
What an unbelievable tool for us as pharmacists. Thank you.
= = = = = = = = = = = = = = = = = = = = =
From Regulatory and Law enforcement agents:
Many drug diversion cases would not be feasible to investigate due to the sheer volume of information
and vast amount of work/man hours that these types of cases require. From past experience with these
types of cases, when the PMP was not available, with an extensive amount of work I was only able to
capture a portion of the abuse out there instead of the entire picture. It is nearly impossible to track
down all controlled drug prescriptions in a particular case without this system, even if extra time was
allotted to do so. The PMP is a necessity in investigating drug diversion cases for law enforcement. I
am pleased with the turnaround time for receipt of the document as well as the organization of the
information into a digestible format. Due to the growth of abuse of prescription drugs, law
enforcement investigators are getting tasked with investigating these cases on a more frequent basis.
Providing a time-efficient and simplistic method to get data for their investigations will ensure that
these cases are handled appropriately.
We really do appreciate the service you and this program provides us. Sure makes the work much
easier!
IOWA PRESCRIPTION MONITORING PROGRAM REPORT 2011
EXHIBIT 2 -- DATA COMPILATION
MARCH 26, 2009, TO DECEMBER 31, 2010
3/26/2009 6/30/2009
12,819
966
3,253
7/1/2009 12/31/2009
13,074
939
3,269
1/1/2010 6/30/2010
13,228
940
3,319
7/1/2010 12/31/2010
15,367
943
3,314
Prescribers Registered
Pharmacists Registered
Regulators Registered
Law Enforcement Agents Registered
1,064
609
13
22
1,436
758
15
29
1,862
909
19
44
2,254
1,020
26
65
Prescriber Requests Processed
Pharmacist Requests Processed
LE/Regulator Requests Processed
Total # Requests Processed
2,404
1,318
44
3,766
14,402
4,385
207
18,994
19,240
3,891
194
23,325
25,266
4,113
146
29,525
1/1/2008 12/31/2008
182,755
437
18
5
1/1/2009 12/31/2009
198,795
501
22
4
1/1/2010 12/31/2010
291,748
197
4
-
# Individual patients filling CII or CIII Prescriptions
...from 5 or more prescribers or pharmacies
…from 10 or more prescribers or pharmacies
…from 15 or more prescribers or pharmacies
598,684
2,117
171
41
611,040
2,270
171
40
806,449
1,273
64
10
# Individual patients filling CII, CIII, CIV Prescriptions
...from 5 or more prescribers or pharmacies
…from 10 or more prescribers or pharmacies
…from 15 or more prescribers or pharmacies
800,956
3,050
234
53
822,577
3,293
232
57
1,151,872
1,888
91
15
4,059,807
223,544,782
4,239,890
228,149,732
4,289,823
234,234,060
Period:
Total CSA Registrant/Prescribers
Total Iowa Pharmacies
Total Iowa-resident Pharmacists
Filled prescriptions for period:
# Individual patients filling CII Prescriptions
...from 5 or more prescribers or pharmacies
…from 10 or more prescribers or pharmacies
…from 15 or more prescribers or pharmacies
Total # Prescriptions dispensed for period:
Total # Doses dispensed for period:
All Other C2-C4
17.1%
Oxycodone
9.0%
Alprazolam
10.9%
Hydrocodone
29.2%
IOWA PRESCRIPTION MONITORING PROGRAM REPORT 2011
EXHIBIT 3 -- CONTROLLED SUBSTANCE DOSES DISPENSED
JANUARY 1 TO DECEMBER 31, 2010
Zolpidem
4.7%
Propoxyphene
3.6%
Codeine
2.8%
Amphetamine
4.5%
Methylphenidate
5.8%
Clonazepam
6.1%
Lorazepam
6.3%
1/6/2011