Worst Pills, Best Pills News

Your expert, independent second opinion for prescription drug information
SIDNEY M. WOLFE, M.D., EDITOR 

February 2014 ✦ VOL. 20, NO. 2

The New Diabetes Drug
Canagliflozin (INVOKANA)

In This Issue

T

he FDA has approved a new type
of drug to treat type 2 diabetes,
but patients should not use the drug
because it poses serious risks that
outweigh its benefits.
Canagliflozin (INVOKANA) is the
first member of a new family of diabetes
drugs that was approved by the Food
and Drug Administration (FDA) on
March 29, 2013. The drug, marketed
in the U.S. by Janssen Pharmaceuticals
Inc., is approved for use in conjunction
with diet and exercise to lower blood
glucose levels in patients with type 2, or
non-insulin-dependent, diabetes, which
is the most common type of diabetes in
older Americans.
The fact that a treatment is newer
does not mean it is better. Canagliflozin
has not been shown to offer any unique
clinical benefits in comparison to several
older, safer diabetes drugs. Yet it does
pose serious risks that outweigh any of
its benefits. Therefore, this drug is categorized as Do Not Use.

How does it work?
Canagliflozin is known as a
sodium-glucose transporter 2
(SGLT2) inhibitor. SGLT2 inhibitors
lower blood sugar levels through a
unique mechanism by causing glucose
to be excreted by the kidneys into the
urine and removed from the body.
When blood passes through the
kidneys, toxic waste products are removed, but so are substances such as
glucose and sodium that are essential
for life.
One vitally important function of

DO

NOT USE

the kidneys is reabsorbing those substances that are not waste products so
they are not lost in the urine. Naturally occurring SGLT2s in the kidneys
are responsible for reclaiming most of
the filtered glucose and returning it to
the blood. By blocking the function
of these transporters, canagliflozin
(a SGLT2 inhibitor) prevents some
filtered glucose from being reabsorbed
by the kidneys, resulting in urinary
losses of glucose. As discussed below,
many of the important adverse effects
of canagliflozin are a direct result of
the drug’s effects on glucose reabsorption by the kidneys.

Limited evidence of benefit
Like many other drugs recently
approved for treating type 2 diabetes,
canagliflozin was approved based
solely on its effects on a so-called
surrogate marker — levels of hemoglobin A1c or glycosylated hemoglobin in the blood — rather than any
evidence of improvement in clinically
meaningful outcomes, such as more
patients surviving or fewer patients
experiencing cardiovascular disease or
other diabetic complications.
Glycosylated hemoglobin is a measure of how well a diabetic patient’s
sugar has been controlled during the
preceding two to three months. In

For comprehensive, up-to-date drug information, subscribe to

Passing the Editorial Baton for
Worst Pills, Best Pills News and
WorstPills.org...........................2
Painkiller Patches Cause
Accidental Deaths in Children.... 4
How Effective Are Antidepressants
For Depression?........................ 5

Drugs featured in
this issue, page 8
general, physicians try to maintain
patients’ hemoglobin A1c levels at 7
to 7.5 percent. Levels greater than 10
percent indicate very poorly controlled blood glucose.
The drug’s developer conducted
nine randomized controlled trials of
canagliflozin to determine its effectiveness. These trials lasted six to
12 months and involved a total of
approximately 10,000 subjects. The
results of the trials demonstrated that
the drug only modestly reduced hemoglobin A1c levels when used alone
or in combination with other oral diabetes medications. For example, for
seven trials comparing canagliflozin
to a placebo, the average hemoglobin
A1c levels decreased from baseline before treatment with the drug by 0.29
to 0.91 percent for subjects receiving
the 100 mg dose and by 0.42 to 1.16
percent for subjects receiving the 300
mg dose.
DIABETES, continued on page 3

www.worstpills.org

 Worst Pills, Best Pills News
www.worstpills.org
Editor
Sidney M. Wolfe, M.D.
Health Research Group Director
Michael Carome, M.D.
Contributors
Sammy Almashat, M.D., M.P.H.
Michael Carome, M.D.
Sarah Sorscher, J.D., M.P.H.
Managing Editor
Greta Gorman
Graphic Designer
Erin Hyland
Editorial and Art Director
Bridgette Blair
Public Citizen President
Robert Weissman

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Material in Worst Pills, Best Pills News may
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© Public Citizen 2014.
All rights reserved.
Published monthly by
Public Citizen’s Health
Research Group. ISSN
1080-2479
2

FROM THE EDITOR

Sidney M. Wolfe, M.D. • Founder and Senior Adviser

Passing the Editorial Baton for
Worst Pills, Best Pills News and
WorstPills.org

T

his will be the last issue of our
newsletter for which I will be
the editor.
Following the publication of the
first and second editions of our bestselling book, Worst Pills, Best Pills,
in 1988 and 1993, readers began
to ask us for more
frequent updates to
such information.
Our response was to
start publishing Worst
Pills, Best Pills News
in 1995, now in its
20th year, followed by the launch of
WorstPills.org in 2003. We continue
to receive moving letters from many
of you about how our drug-safety
information has benefitted the health
of you or your loved ones by helping you stay away from dangerous or
ineffective drugs.
Like me, none of you should be
at all concerned about the future of
these publications under the able
editorship of Dr. Michael Carome,
now in his fourth year with Public
Citizen’s Health Research Group and
more than halfway through his first
year as Director of the group. Mike’s
training, as is mine, is in internal
medicine. He completed a fellowship
in nephrology after his residency and
then went on to a position with the
Walter Reed Army Medical Center
Nephrology Service. Prior to starting his work at Public Citizen, he
was a U.S. government expert on the
ethics of clinical trials for more than
a decade, working in the Office for
Human Research Protections. Since
joining the Health Research Group,
he has testified before, or prepared
testimony for, 13 Food and Drug

Worst Pills, Best Pills News ✦ VOL. 20, NO. 2

Administration (FDA) advisory committee meetings concerning prescription drug safety. He has written 23
articles for Worst Pills, Best Pills News
and has been exemplary in editing
reports and articles on a variety of
topics. He has clearly become an
expert on issues of drug and medical
device safety, pharmacy compounding, and FDA oversight.
As for me, my title since June has
been Founder and Senior Adviser of
the Health Research Group. Despite
(or more likely, because of ) serving here for more than 42 years, I
am fortunately in very good health
and still working full-time. I plan to
continue writing articles for Worst
Pills, Best Pills News and researching
drug-safety issues that might require
a ban of or warning on a drug. Last
summer, I also began writing a regular column for the esteemed British
Medical Journal. With the permission of the journal, we have started
reprinting some of these columns
in Worst Pills, Best Pills News, the
first two having just appeared in the
December 2013 and January 2014
issues. The third, regarding escalating
criminal activity by multinational
pharmaceutical companies, will appear in these pages next month.
Mike Carome and I have had an
excellent working relationship while
he has been here. We have learned
a lot from one another, and we will
continue to do so.

 DIABETES, continued from page 1

What ultimately matters to
patients with diabetes, however, is
whether the treatment improves
survival or reduces diabetic complications, the most important being
cardiovascular disease (such as heart
attacks and strokes), kidney failure
and diabetic retinopathy, which can
lead to blindness. Eight of the nine
randomized controlled trials evaluating canagliflozin were not designed
to measure any such clinically
meaningful results, and the one trial
designed to evaluate adverse cardiovascular outcomes actually suggested
worse cardiovascular outcomes in the
subjects who received canagliflozin in
comparison to those receiving other
FDA-approved diabetes drugs.
Treatment with canagliflozin was
associated with small, dosedependent decreases in body weight
and systolic blood pressure. However,
there is no evidence from the clinical
trials that these effects translated into
any improvement in clinical outcomes.

Safety risks, particularly
with geriatric use
Public Citizen’s Health Research
Group testified before the FDA’s
Endocrinologic and Metabolic Drugs
Advisory Committee on Jan. 10,
2013, strongly opposing approval
of canagliflozin because of multiple
serious safety concerns and lack of
evidence for any clinically meaningful benefit. These concerns, identified during clinical trials of the drug,
apply particularly to the geriatric
population. Many of the adverse
events observed with the drug are
completely expected given its mechanism of action.

Volume depletion, hypotension
and impaired kidney function
Canagliflozin causes osmotic diuresis, which means increased urination as body fluids accompany the
increased loss of glucose. This in turn

Eight of the nine randomized controlled trials evaluating canagliflozin were not designed to measure any
… clinically meaningful results, and the one trial designed to evaluate adverse cardiovascular outcomes
actually suggested worse cardiovascular outcomes in
the subjects who received canagliflozin in comparison
to those receiving other FDA-approved diabetes drugs.
can cause a cascade of adverse events,
beginning with volume depletion or
dehydration and progressing to low
blood pressure, dizziness, falls, renal
impairment and adverse cardiovascular events.
Individuals most susceptible to the
osmotic diuretic effects of canagliflozin and related complications
include patients who have moderately impaired baseline kidney function,
are age 75 or older, and are taking
potent loop diuretics (for example,
furosemide [LASIX]).
Patients who develop volume
depletion due to canagliflozin may
develop dry mouth, thirst and
polydipsia (more frequent intake of
fluids). They are also more likely to
experience hypotension (abnormally
low blood pressure), orthostatic
hypotension (drop in blood pressure when standing up) and dizziness upon standing. Drops in blood
pressure and dizziness upon standing
may predispose patients to falls and
serious injuries such as hip fractures.
Older patients and patients with
diabetic neuropathy are more susceptible to such side effects.
Declines in renal function were
also seen in patients exposed to
canagliflozin during the randomized
controlled trials of the drug. Patients
exposed to the highest doses of the
drug were most likely to experience
this adverse effect. The declines in
renal function occurred very soon
after starting the drug and were more
likely to persist in patients who had
abnormal renal function prior to

starting the drug. Because renal function gradually declines as people get
older, geriatric patients are at greater
risk of experiencing the adverse kidney effects of canagliflozin.

Possible increased
cardiovascular risk
Several pieces of evidence from the
randomized controlled trials of canagliflozin suggest that the drug may
increase the risk of adverse cardiovascular events. First, an analysis of
serious cardiovascular adverse events
from all nine randomized controlled
trials combined showed a trend
toward a higher incidence of stroke
in subjects treated with canagliflozin
compared to control subjects treated
with a placebo or other diabetes
drugs. Although the difference was
not statistically significant, the FDA
medical officer reviewing canagliflozin noted that “most of the observed strokes were ischemic, which
is a concern since canagliflozin can
cause volume depletion and hemoconcentration [increased concentration of red cells in the bloodstream
due to dehydration].” Both of these
factors highlighted by the medical reviewer could contribute to an
increased stroke risk.
Further reason for concern was
provided by one of the nine randomized controlled trials that was
specifically designed to evaluate
cardiovascular outcomes. To increase the chances for detecting a
cardiovascular safety signal associDIABETES, continued on page 8
February 2014 ✦ www.worstpills.org

3

 Painkiller Patches Cause Accidental Deaths in Children

O

n Sept. 23, 2013, the FDA announced that it would change
the labeling on fentanyl painkiller
patches (DURAGESIC) to prevent
accidental exposure in children. Two
days later, subscribers to WorstPills.
org received an emailed alert informing them of the risks to children and
advising them of necessary precautions.
Since 1997, the Food and Drug
Administration (FDA) has received
32 reports of children suffering adverse events after accidental exposure
to fentanyl. Most of these incidents
involved children younger than 2
years old. Twelve children have died
from exposure, and 12 more required
hospitalization but did not die. In
2005, we alerted Worst Pills, Best Pills
readers of the concern about special
dangers to children in the FDA black
box warning that stated: “DURAGESIC should be administered to children only if they are opioid-tolerant
and 2 years of age or older.”

About fentanyl
Fentanyl is a synthetic narcotic
that relieves pain. It may be administered as an injection (commonly used
in surgery), a lozenge or a transdermal patch.
The patch is used to treat patients
with persistent, moderate to severe
chronic pain that requires aroundthe-clock opioid administration
for an extended period of time and
cannot be managed by other means.
It works by releasing the medicine
over the course of three days. Patients
may use the fentanyl patch if they
have swallowing difficulties or poor
veins. Others may simply find the
patch formulation to be convenient.
However, it is not used for mild or
intermittent pain, and it is not usually used until doses of oral morphine
have become high and frequent.
An overdose of fentanyl, as can
happen when a patient uses a ripped
or otherwise damaged patch, can
4

Safe Disposal of Unused Medications
Many medicines are harmful, or even fatal, when ingested by children,
pets or others for whom the medication was not intended. Unintentional
exposure to medications represents a leading cause of accidental poisonings in the U.S. Of the 255,732 reported instances of improper medicine
use logged by Poison Control Centers in the U.S. in 2007, roughly
9 percent, or 23,832 cases, involved accidental exposure to medicines.
Of these, about 5,000 cases involved children 6 years of age or younger.
It is unnecessarily risky to keep medicines in the house after they are no
longer needed. Furthermore, you should not rely on child-resistant packaging to protect young people from accessing unused medications. One
study published in 2006 looked at cases in which children were accidentally exposed to their grandparents’ medicine, finding that in nearly half
(45 percent) of these cases, the medication had been stored in containers
with child-resistant packaging.
For most medications, the FDA recommends disposal through either medicine take-back programs, where they are available, or by simply placing
the unused drugs in the household trash. The agency suggests that consumers mix the medicines (being careful to not crush tablets or capsules) with
an unpalatable material like coffee grounds. The mixture should then be
placed in a sealable plastic bag before being thrown in the trash can.
Certain drugs — including fentanyl — present especially harmful or even
deadly risks when taken by someone other than the intended user. The
FDA recommends that these medications should be disposed of by flushing
them down the toilet rather than placing them in the household trash.
The FDA maintains a list of medications that should be flushed down
the toilet for safer disposal. You can view this list, as well as information
regarding environmental concerns, by visiting www.fda.gov and typing
“disposal of unused medicines” in the search box.
For questions about the safe disposal of medications, please contact the
FDA at 1-888-INFO-FDA (1-888-463-6332).

cause death by slowing breathing
and increasing the levels of carbon
dioxide in the blood. Fentanyl is not
recommended for those weighing less
than 110 pounds.

Exposure in children
A child can overdose on fentanyl
patches by putting the patch in his or
her mouth or applying it to the skin
(like an adhesive bandage or sticker),
possibly after finding a patch on the
ground or in the trash. According to
the FDA, there is still some risk to a
child even when a patch is discarded
after having been worn for the full
three days of treatment, because a

Worst Pills, Best Pills News ✦ VOL. 20, NO. 2

used patch retains more than 50
percent of the medication.
Exposure also can occur when an
adult wearing a partially detached
patch picks up an infant or toddler
and fails to notice when the patch
peels off the adult’s body and sticks
to the child.

Labeling changes
The labeling changes announced
by the FDA will apply to the generic
and brand-name versions of the
product. The label will now have the
name of the drug and its strength
printed in long-lasting ink that is
FENTANYL, continued on page 7

 How Effective Are Antidepressants for Depression?

A

ntidepressants are now the third
most widely used class of
chronic medications in the U.S.,
with nearly 22 million users as of
2012. Their use increased more than
fourfold between 1988 and 2008.
Clearly, so many patients would
not continue to take the drugs, and
doctors would not prescribe them, in
the absence of some perceived benefit.
But how much of this perception is
due to a true biological effect of the
drugs as opposed to a placebo effect?
This question has been the focus
of a growing debate in the medical
community, sparked in part by the
publication of two studies suggesting that although some severely
depressed patients are undoubtedly
helped by antidepressants, for a great
many others with milder depression,
the medications may be no better,
but clearly more dangerous, than
a sugar pill. The studies also raised
serious concerns about the integrity
of the evidence for the drugs’ effectiveness presented in the published
literature on which so many physicians rely.

Benefits more modest than
initially thought
Fluoxetine (PROZAC), approved
in 1987, was the first of a wave of
newer-generation antidepressants
known as selective serotonin reuptake inhibitors (SSRIs), which work
by increasing the amount and action
of a chemical known as serotonin in
certain areas of the brain. SSRIs were
considered a breakthrough advancement in the treatment of depression
because they seemed effective while
being considerably safer than an
earlier generation of antidepressants
known as tricyclic antidepressants
(TCAs) and monoamine oxidase inhibitors (MAOIs), both of which had
severe side-effect profiles and were
fatal in excessive doses. (The possibility of intentional overdose is always
a paramount concern in severely

Medications Approved to
Treat Depression in the U.S.
As of December 2013
Generic Name

Brand Name

Selective Serotonin Reuptake Inhibitors†
citalopram**

CELEXA

escitalopram**

LEXAPRO

fluoxetine**

PROZAC, SARAFEM

paroxetine**

PAXIL, PEXEVA

sertraline**

ZOLOFT

vilazodone***

VIIBRYD

vortioxetine***

BRINTELLIX

Serotonin-Norepinephrine
Reuptake Inhibitors
desvenlafaxine***

PRISTIQ, KHEDEZLA

duloxetine*

CYMBALTA

venlafaxine**

EFFEXOR,
EFFEXOR XR

Tricyclic Antidepressants
amitriptyline*

None (only generics)

amoxapine*

None (only generics)

desipramine**

NORPRAMIN

doxepin*

None (only generics)

imipramine*

TOFRANIL,
TOFRANIL-PM

maprotiline*

None (only generics)

nortriptyline**

AVENTYL, PAMELOR

protriptyline**

VIVACTIL

trimipramine**

SURMONTIL

Monoamine Oxidase Inhibitors
isocarboxazid**

MARPLAN

phenelzine**

NARDIL

selegiline**

EMSAM

tranylcypromine**

PARNATE

Other Drugs
bupropion**

APLENZIN, FORFIVO
XL, WELLBUTRIN,
WELLBUTRIN SR,
WELLBUTRIN XL

mirtazapine**

REMERON,
REMERON SOLTAB

nefazodone*

None (only generics)

trazodone*

OLEPTRO

† The SSRI fluvoxamine (LUVOX) is commonly used
off-label in depressed patients and therefore carries the
same black box warning on suicidality as approved
antidepressants.
* Do Not Use
** Limited Use (offers limited benefit or benefits
certain people or conditions)
*** Do Not Use Until Seven Years After Approval

depressed patients.)
Fluoxetine’s approval heralded a
flood of further approvals of “metoo” SSRIs, of which there are now
seven different varieties, including
fluoxetine (see table at left). Another
class of antidepressants known as
selective serotonin-norepinephrine
reuptake inhibitors (SNRIs) also
amplify the activity of serotonin —
as well as another chemical known
as norepinephrine — within certain
areas of the brain.
For the past two-and-a-half
decades, the effectiveness of these
newer-generation antidepressants
in treating depression was generally
assumed by the medical community
based on a plethora of published
studies. However, a study published
in January 2008 in the New England
Journal of Medicine (NEJM) revealed
that this source of information may
have presented a falsely positive
picture.
The NEJM study analyzed a large
number of pre-approval clinical trials for antidepressants submitted to
the Food and Drug Administration
(FDA) to determine how many of
these trials were ultimately published and how accurately this subset
of published reports represented
the results of all of the trials. The
study reviewed 74 trials submitted
to the FDA involving more than
12,000 adult subjects for 12 different antidepressants approved by the
FDA between 1987 and 2004. The
authors searched the medical literature for published reports of each
trial. The study classified the clinical
trial results in the FDA submissions
as “positive,” “negative” or “questionable,” as far as effectiveness based
on the FDA’s assessments for the
purposes of approval.
There were 38 trials labeled
positive, and all but one of them (97
percent) were published. Of the 36
studies whose findings were deemed
SSRIs, continued on page 6
February 2014 ✦ www.worstpills.org

5

 SSRIs, continued from page 5

either negative or questionable by the
FDA, a mere 14 (39 percent) were
published, 11 of which presented the
findings in the publication as positive
despite the FDA’s determination of
negative or questionable results.
The published findings for only
three of these 14 concurred with
the FDA’s analysis. (Overall, of the
74 pre-approval clinical trials, 22
[30 percent] were never published.)
This selective publication of positive studies and results, also known as
publication bias, undoubtedly came
as a surprise to many in the medical
and psychiatric community who had
taken the efficacy of antidepressants
for granted. The study also begged
the question: Just how effective are
antidepressants when considering the
totality of the evidence?
An answer to this important question was provided by a study published in the journal PLoS Medicine
in February 2008, one month after
the publication of the NEJM study.
The PLoS Medicine study examined
all pre-approval randomized controlled trials of antidepressants for
which complete data on the trials’
outcomes were available. The study
reviewed 35 trials of more than 5,000
subjects conducted with four antidepressants: fluoxetine, paroxetine
(PAXIL), venlafaxine (EFFEXOR)
and nefazodone (SERZONE). The
primary outcome of interest was the
difference in subjects’ responses to
a commonly used depression assessment scale, known as the Hamilton
Rating Scale of Depression (HRSD),
before and after subjects took either
an antidepressant medication or a
placebo over the four-to-eight-week
trials.
The study found that subjects
given one of the four antidepressants
displayed an average improvement
of 9.6 points on the HRSD, while
those given placebo improved by
an average of 7.8 points — a difference of just 1.8 points. Although
this treatment effect was statisti6

cally significant, it was considerably smaller than the three-point
threshold deemed clinically relevant
by the U.K.’s National Institute for
Health and Care Excellence (NICE),
a standards-setting body that formulates recommendations for that country’s National Health Service.
Furthermore, the less depressed
subjects were at the start of the trial,
the less effective the drugs were
relative to placebo. For moderately
depressed individuals, and even
many severely depressed subjects, the
antidepressants were not meaningfully, clinically more effective than
placebo. It was only in the most
severely depressed patients that the
drugs reached the NICE threshold
for clinically significant effectiveness
compared to a placebo. Thus, the
effectiveness of the antidepressants
in less depressed patients was largely
due to a placebo effect. Interestingly, the net effectiveness in the
sickest population was due not to an
increased response to the drugs but to
a decreased response to placebo.
In 2011, another study in the Journal of Clinical Psychiatry undertook a
similar analysis with a larger sample
of trials and confirmed the conclusions of the PLoS Medicine paper.
The study evaluated 81 randomized
controlled trials, involving more than
21,000 subjects, submitted to the
FDA for approval to treat depression
between 1983 and 2008. The review
showed that antidepressants were
statistically (not necessarily clinically
meaningfully) better than placebo
in improving HRSD scores in only
53 percent of all trials. The average
improvement in HRSD scores (drug
versus placebo) across all trials was
only 2.5 points, again lower than
the NICE three-point threshold for
clinical relevance. As in the 2008
PLoS Medicine article, the severity
of the depression at the start of the
study tended to be the best predictor
of treatment response, and the drugs
were less effective in milder cases of
depression.

Worst Pills, Best Pills News ✦ VOL. 20, NO. 2

Long-term risks and costs
While the studies discussed up
to this point have focused on the
effectiveness of antidepressants over
the several-week periods studied in
the pre-approval clinical trials, less is
known about the drugs’ effectiveness
for longer periods.
The FDA does not require trials on
antidepressants for depression to last
more than a few weeks to demonstrate short-term efficacy. Furthermore, some antidepressants (such
as fluoxetine and paroxetine) are
approved for long-term use for depression on the basis of clinical trials
that assessed long-term efficacy (six
months to one year) only in those
patients who initially responded to
the drug in the first place. Therefore,
the studies’ findings cannot be generalized to all prospective patients.
In addition, all subjects in the
fluoxetine and paroxetine maintenance trials initially received the
drugs in an unblinded fashion —
they knew they were receiving the
drugs as opposed to placebo pills
— and were then randomized to
continue the same drugs or switch to
placebo pills. Given the drugs’ readily recognizable side effects, many
subjects therefore probably knew
whether they were continued on the
drugs or given a placebo, potentially
falsely inflating the drug’s effectiveness in these long-term studies.
In practice, antidepressants are
routinely used for much longer periods of time than were tested in the
trials. Their effectiveness for chronic
use is therefore uncertain, but their
risks persist for as long as they are
used.
All antidepressants carry a black
box warning on an increased risk
of suicidal thinking and behavior
in children, adolescents and young
adults. Other risks, not included
in the black box warning, include
weight changes, anxiety, insomnia
and sexual dysfunction, as well as
SSRIs, continued on page 7

 SSRIs, continued from page 6

potentially fatal side effects such as
high blood pressure, heart rhythm
disturbances, abnormal bleeding, low
blood sodium, seizures, a disorder
known as serotonin syndrome and
numerous drug interactions. In many
cases, patients end up continuing the
medications because of the uncomfortable withdrawal symptoms (including headache, nausea, agitation
or dizziness) characteristic of several
antidepressants.
This is not to mention the economic costs of long-term antidepressant use, especially for newer, stillpatented versions. To take just one
example, according to a June 2013
analysis by the Medical Letter health
news publication, the price of a 30day supply of duloxetine (CYMBALTA), a brand-name SNRI antidepressant with no generic competition at
the time was $199, compared with
$4 to $7 for the same month supply
of any of five different generic SSRIs.

What You Should Do

Not everyone who is sad is depressed, especially in cases of a
legitimate response to a distressing
life event. The National Institute of
Mental Health defines major depression as a “severely depressed mood
FENTANYL, continued from page 4

clearly visible to patients and caregivers. (Previous ink colors varied by
strength and were sometimes difficult
to spot.)
“We hope that this change will enable patients and caregivers to more
easily find patches that need to be
removed from patients’ bodies and
also to see patches that have fallen
off, which could put children, pets or
other household contacts at risk for
accidental exposure,” says Douglas
Throckmorton, M.D., deputy director of the FDA’s Center for Drug
Evaluation and Research.

and activity level that persists two
weeks or more” and that interferes
with daily functioning. It is estimated that 1 in 6 U.S. adults will
experience a bout of major depression at some point in their lives. Dysthymic disorder, or dysthymia, refers
to milder (not necessarily disabling)
depressive symptoms that last two
years or more. Symptoms of minor
depression can include poor school
or work performance, social withdrawal, shyness, irritable hostility,
conflicts with family and friends, and
sleep irregularities.
There are many causes for depression, and although it is an often
debilitating condition, not everyone
who is depressed is a suitable candidate for antidepressant therapy.
One cause of depression that should
not be treated with drugs is depression caused by other kinds of drugs.
When depression starts after beginning a new drug, the drug may well
be the culprit. Drugs that may cause
depressive symptoms include (but
are not limited to) corticosteroids,
oral contraceptives, beta-blockers and
other blood pressure medications,
and varenicline (CHANTIX). This
is not a comprehensive list, so speak
with your doctor to find out whether
a medication you are taking may be
causing your symptoms. Alcoholism

What You Should Do

If you have children in your house,
you should work to reduce the possibility of their accidental exposure
to fentanyl. The FDA recommends
these precautions:
• Keep fentanyl patches and other
drugs in a secure location out of
children’s sight and reach. Toddlers may think the patch is a
sticker, tattoo or bandage.
• Consider covering the fentanyl
patch with an adhesive film to
make sure the patch doesn’t come
off your body.
• Throughout the day, check to be
sure that the patch is still in place.

or drug abuse are other potential
causes, and those should be treated
before resorting to antidepressants.
Certain medical conditions, such
as hypothyroidism, also can cause
depression symptoms.
If you are depressed, see a doctor
or psychologist to rule out physical
causes and to inquire about psychotherapy as an initial treatment.
Psychotherapy should be tried first
for minor depression and should
always be pursued to treat depression
of all severities, even if medication
is ultimately added. If you and your
health care provider decide to try
antidepressants, be sure to review
the benefits and risks of each treatment option. As a general rule, SSRIs
should be tried first, as these are the
safest antidepressants. If symptoms
do not improve sufficiently on an
SSRI and remain severe, further
treatment with other antidepressants
is warranted.
All antidepressants carry a black
box warning of an increased risk
of suicidal thinking and behavior
in children, adolescents and young
adults. If you experience suicidal
thoughts or urges (whether on or
off an antidepressant), go to the
emergency room or call the National
Suicide Prevention Lifeline at 1-800273-TALK (8255) immediately. ✦
• Dispose of used patches by folding
in half with the sticky sides together, then flushing them down
the toilet (see box on page 4).
As stated above, the FDA recommends disposing of used patches by
folding them in half with the sticky
sides together and then flushing
them down a toilet. They should
not be placed in the household trash
where children or pets can find them.
Early signs of fentanyl exposure
can be hard to identify in children.
If you suspect that a child has been
exposed to a fentanyl patch and the
child seems lethargic, contact emergency medical help right away. ✦

February 2014 ✦ www.worstpills.org

7

 DIABETES, continued from page 3

ated with canagliflozin use, only
patients with a known history of
cardiovascular disease or significant
risk factors for cardiovascular disease
were enrolled in the trial. Subjects
were randomly assigned to receive
either canagliflozin or placebo. Data
from this trial showed that during
the first 30 days after randomization, 13 subjects in the canagliflozin
group (0.45 percent) experienced a
serious adverse cardiovascular event
compared to only one subject in the
placebo group (0.07 percent). Given
the small number of these adverse
events, the results were not deemed
statistically significant. However, the
FDA medical reviewer again highlighted reasons for concern about
these results, noting:
We need to consider that the hemodynamic effect of canagliflozin
is almost immediate, which was
reflected in changes in blood
pressure, electrolytes, renal function, as well as increased incidence
of volume depletion events with
canagliflozin that appear to be related to this hemodynamic changes
[sic] and occur within 6 weeks of
initiating canagliflozin.

Such comments are an acknowledgement that there are biologically
plausible reasons for why the canagliflozin may increase the risk of
stroke, heart attack and other serious
adverse cardiovascular events shortly
after starting the drug.
Canagliflozin also causes increases
in LDL (“bad”) cholesterol, which
may increase cardiovascular disease
risk with long-term use of the drug.

occurs with digoxin [LANOXIN],
a drug used to treat heart failure and
to control the heart rate in patients
with atrial fibrillation, an abnormal
heart rhythm. Canagliflozin increases
blood levels of digoxin. Patients
taking both drugs should have blood
levels of digoxin monitored to avoid
digoxin toxicity.

Genital fungal infections

You should avoid taking
canagliflozin if you are not taking
it currently. If you are taking the
drug, you should consult your
physician about switching to equally
effective and safer drugs for type 2
diabetes. Exercise and diet are often
instrumental in controlling blood
sugar levels.
Consumers may report serious adverse events to the FDA’s MedWatch
Adverse Event Reporting program:

Canagliflozin was found to cause a
significant increase in the incidence
of genital fungal infections in both
women and men. Among women
enrolled in the placebo-controlled
randomized controlled trials, those
receiving canagliflozin had more
than a fourfold higher incidence of
genital fungal infections, such as
yeast vaginitis, than those receiving
placebo. Men receiving the drug had
more than a six- to sevenfold greater
incidence of genital fungal infections.
This increase in fungal infection
is undoubtedly related to the presence of glucose in the urine, which
promotes growth of fungal organisms
and bacteria.

Important interaction with the
cardiac drug digoxin

What You Can Do

Online: www.accessdata.fda.gov/
scripts/medwatch/medwatch-online.
htm
Regular mail: Use postage-paid, preaddressed FDA form 3500 and mail
to MedWatch, 5600 Fishers Lane,
Rockville, MD 20852-9787
Fax: (800) FDA-0178
Phone: (800) FDA-1088 ✦

One clinically significant drug
interaction for canagliflozin

DRUG INDEX
canagliflozin............... 1
digoxin...................... 8
DURAGESIC................ 4
EFFEXOR.................... 6

Drug names in bold indicate the drug is the primary subject of an article. Drug names in ALL CAPS are brand
names. Numbers refer to the page containing the first reference to the drug or supplement in each article.

fentanyl..................... 4
fluoxetine................... 5
furosemide................. 3
INVOKANA................ 1

LANOXIN.................. 8
LASIX......................... 3
nefazodone................ 6
paroxetine................. 6

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8

Worst Pills, Best Pills News ✦ VOL. 20, NO. 2

PAXIL......................... 6
PROZAC.................... 5
SERZONE................... 6
venlafaxine................ 6

In the Next Issue
We will discuss increased
risk of heart problems with
testosterone use.