FDA Issues Sterner Warnings to Manufacturers of Diabetic Drug Actos
Although
the FDA issued recommendations regarding labeling cautions for the drug
Actos to manufacturer Takeda Pharmaceuticals in 2006, following further
safety reviews of the drug they have recently issued more stringent
instructions to the Japanese company. Actos, also known as pioglitazone
is used in the treatment of Type 2 diabetes to help control the levels
of sugar in the blood.
Drugs Included, Safety Updates Required
I
n
a letter to Takeda Pharmaceuticals the FDA states that supplemental new
drug applications for Actos, Actoplus Met, Actoplus Met XR and Duetact
were duly received and processed, and noted receipt of certain
amendments and risk evaluation assessments relating to Actos. Takeda was
notified of new safety information which the FDA deemed to be a
necessary inclusion of any future labeling of Actos. Further, the FDA
stated the safety updates must specifically address the potential risk
in increase of bladder cancer in those taking higher dosages or taking
the drug for extended periods of time.
Specific Changes to Labeling of Actos
The
FDA asked that Takeda include under the warnings and precautions area
of the Actos label a statement that preclinical and clinical trials had
shown pioglitazone users experienced an increase in incidence of bladder
cancer. The Actos labels must state that those who have bladder cancer
or a prior history of bladder cancer should be extremely cautious when
using the drug. The label must additionally state that statistical
significance in bladder cancer risk is reached in those patients taking
Actos for longer than two years. More specifically, the wording that
taking Actos longer than twelve months increases the risk of developing
bladder cancer to a 40% statistical probability is to be included.
Takeda Pharmaceuticals Received FDA Instructions for Diabetic Drug Actos The
drug Actos, also known as pioglitazone, has recently come under fire
due to studies showing a slight increased risk of bladder cancer in
those taking high doses of the drug or those who have taken Actos for
longer than two years. Manufactured by Takeda Pharmaceuticals of Japan,
the drug has shown huge gains in popularity in the past few years as it
quickly replaced the drug Avandia which suffered under claims of
increased risk of heart attack and death. Actos is Takeda’s tenth
best-selling drug, making over $3.4 billion dollars in the past year
alone. While the recent safety reviews have alarmed many who are
currently taking the drug, in fact there have been safety concerns
regarding Actos for several years. Warnings are Not NewAs
far back as 2006, the FDA issued instructions to Takeda regarding Actos
and ActoPlus Met, advising the company to make specific label changes
to the drug’s precautionary statements. These label changes were to
specifically include information regarding reports of bladder cancer in
those taking Actos. Takeda’s supplemental drug applications regarding
Actos were approved conditionally, so long as the agreed-upon text was
included in the drug’s labeling. The
FDA stipulated that the final printed label be identical to the
proposed labeling changes, and required Takeda to submit an electronic
version of the proposed label as well as 20 paper copies and fifteen
copies mounted on heavy-weight paper, however final approval was not
mandated prior to using the labels. Although these FDA instructions took
place nearly five years ago, it was only recently that more stringent
warnings regarding Actos were issued.
FDA Approves Cancer Warning for Diabetic Drug Actos
The
blockbuster drug, Actos, which is prescribed to control Type 2
diabetes, has received new warning language on the label regarding a
potential risk of bladder cancer for those taking the drug. Actos, also
known as pioglitazone, is manufactured by Takeda Pharmaceuticals, a
Japanese-based company, and is currently their best-selling drug, with
sales of $3.4 billion last year alone. Sales of Actos had shown a
significant upswing due to the fact that its primary
competitor—Avandia—has been linked to a higher risk of heart attack and
even death. The updated label warnings came on the heels of an EMA
safety review of the drug as well as a ten-year study conducted by
Takeda. The Takeda study indicated a statistically significant increase
in the risk of bladder cancer for those taking the drug for longer than
two years.
Other Drugs Containing Pioglitazone
Other
than Actos, the drugs ActoPlus Met, ActoPlus Met XR and Duetact will
all carry the same warnings due to containing pioglitazone as an active
ingredient. All of these drugs are used to treat Type 2 diabetes, to
increase sensitivity to insulin and effectively control blood sugar
levels. A combination drug containing metformin and pioglitazone is used
for the same purpose, although all these drugs are expected to be used
in conjunction with a healthy diet and sensible exercise program.
France and Germany Weigh In
Just
this past June, both France and Germany issued recalls of Actos
following a public insurance data review which showed a fairly strong
correlation between pioglitazone and bladder cancer risk. Suggestions
from the EMA study related primarily to including more cautionary
warnings on the labels of the drug as well as a six-month review of each
patient taking Actos.
European Medicines Agency Scientific Studies on Pioglitazone
The
European Medicines Agency released a scientific study on the benefits
and risks of the drug pioglitazone, also known as Actos, in January of
2007. This drug is currently used as a single treatment for Type 2
diabetes or in a dual combination form with metformin or sulphonylurea.
When used alone, pioglitazone is typically used as therapy for the
overweight patient whose Type 2 diabetes is not being controlled through
diet and exercise and for whom the drug metformin is inappropriate. The
combination drug is most often used in those patients who have
insufficient glycemic control despite taking metformin alone or for
those patients who have shown a level of intolerance to metformin. The
results of the study showed that when pioglitazone was prescribed in
conjunction with other anti-diabetic therapies such as insulin, the risk
of macrovascular disease was greatly reduced. Macrovascular disease is
common in those with long-term diabetes and refers to a disease of the
large blood vessels in the body. Clinical Support for Pioglitazone ApplicationEvidence
was submitted which supported the application of pioglitazone,
including four clinical trial reports which studied the safety of the
drug when used in conjunction with insulin therapy. The studies were
conducted according to prevailing ethical standards, and were random,
double-blind, placebo controlled. First Pioglitazone Study—PNFP-014Pioglitazone
was administered both in 15 mg dosages as well as 30 mg dosages in
combination with insulin then compared with using insulin therapy alone.
Participants in the studies were between the ages of 30 and 75, and had
been on a fixed dose of insulin for at least a month prior to beginning
the study. The mean baseline age was 57 years, with an average BMI of
33.6. Nearly 3/4ths of the participants in the study were Caucasian,
with slightly more than half being female. Although the baseline
systolic blood pressure was minimally higher in the group receiving
pioglitazone plus insulin as opposed to the group receiving insulin
alone, there were no other baseline variables involved. The patients who
received both pioglitazone and insulin showed statistical decreases in
the HbA1c levels which measure the average amount of sugar in the blood
over a period of three months, and is different from glucose
measurements. The HbA1c levels essentially give the physician an
indication of how well the diabetes is being controlled.
Pioglitazone Receives New Warnings Due to Slight Increase in Bladder Cancer Risk
The
health review of the Type 2 diabetic drug, pioglitazone, performed by
the European Medicines Agency, confirmed the drug remains a valid
treatment option for certain patients while acknowledging a minimal
increase in bladder cancer risk. The caveat in the conclusions of the
health review centered upon advising physicians to use care and caution
when prescribing the drug. The results further stated that those who are
prescribed pioglitazone—especially those who take relatively high doses
or have taken the drug for longer than a year—must have their overall
health monitored closely. Exclusion of certain higher risk groups, such
as the elderly is also recommended.
Assessing Risk Factors in Potential Patients
Physicians
are warned to screen patients carefully, and avoid prescribing
pioglitazone to those who have a history of bladder cancer or who
currently have bladder cancer. Patients with uninvestigated macroscopic
haematuria are also advised against taking pioglitazone. As stated, age
carries a specific risk, as the elderly are already more likely to
develop bladder cancer based solely on age. Because of this an
alternative diabetes medication with less risk in this area should be
prescribed. Patients taking Actos should undergo regular 3-6 month
reviews to assess and monitor benefit vs. risk.
Sources of Information
In
making its safety recommendations, the Committee for Medicinal Products
for Human Use considered results of pre-clinical and clinical studies
as well as spontaneous reports and epidemiological studies. The
Scientific Advisory Group on Diabetes also weighed in with advice
regarding pioglitazone. The CHMP concluded from this array of evidence
that while there is a slight increase in bladder cancer among those
taking pioglitazone, this risk exists primarily in those who take the
drug for long periods of time or in relatively high doses. That being
said, those who take the drug for a short amount of time cannot be
excluded from the risks.
No Recall Yet for Type 2 Diabetes Drug, ActosThe
FDA has joined forces with France and Germany regarding a warning about
the Type 2 diabetes drug, pioglitazone, however no recall is expected
at this time. Pioglitazone, also known as Actos, is manufactured by
Takeda Pharmaceuticals, a Japanese drug company. The drug currently
accounts for some 27% of Takeda’s annual revenues. 2008 saw this
powerhouse diabetes medication become the tenth best-selling
prescription medication in the United States. Over the past year, Takeda
has accrued nearly $4.8 billion dollars in revenues through worldwide
sales of Actos. Clinical Studies of PioglitazonePre-clinical
studies—in which male rats were given body-weight equivalent doses of
Actos—showed an increase in the incidence of bladder cancer while two
subsequent clinical studies using human subjects also revealed an
elevated risk of bladder cancer. Due to these findings, the FDA mandated
that the potential risks be revealed on the label of the drug, ordering
a safety review in September, 2010. Takeda additionally agreed to
carry out a ten-year observational study in those diabetic patients
currently taking Actos, to be conducted on patients from Kaiser
Permanente Northern California Health Plan.
Benefit-Risk Balance Deemed Positive for Type 2 Diabetics Taking Pioglitazone
Following safety reviews of the drug
pioglitazone—a medicine used in the treatment of Type 2 diabetes—the
European Medicines Agency delivered their decision that while there is a
marginally increased risk of bladder cancer in those taking the drug,
it remains a viable treatment option for some patients. Pioglitazone,
also sold under the brand name Actos, is used along with a sensible diet
and exercise program to increase the body’s sensitivity to insulin,
thereby controlling blood sugar levels.Reducing Potential RisksThe
EMA’s conclusions following extensive study of the drug was that the
slight increased risk of bladder cancer could be alleviated through
implementation of a more stringent screening of potential patients.
Medical professionals are warned against prescribing pioglitazone in any
patients with a history of bladder cancer, and to exercise caution when
prescribing the drug to the elderly as well. Those
patients deemed good candidates for pioglitazone should nonetheless be
monitored closely every three to six months to ensure the benefits
continue to outweigh the risks. High Doses, Significant Duration LinkedThe
results of the controlled epidemiological studies determined that the
small risk associated with pioglitazone was seen primarily in those
patients who took the drug for significant lengths of time and in the
highest doses. Even though the studies showed only a 0.15% increase in
risk of bladder cancer this does not mean that those who are prescribed the drug for short term use have no risk at all of contracting bladder cancer.
