Topamax Birth Defects: What You Should Know

By Independent Staff Writer Topamax, also known as topiramate, is a prescription drug used to treat epilepsy in adults and children.  The drug is also approved by the Food and Drug Administration to treat migraine headaches, and has been prescribed to treat bipolar disorder, obesity, and alcoholism.

Research studies have identified a risk of birth defects in children associated with mothers who took Topamax during pregnancy.  Topamax has been linked to serious birth defects including cleft palate and cleft lip.  These defects result in a notch or groove in the lip that can extend into the roof of the mouth and the nose, possibly causing ear infections and problems with eating and speaking.  Cleft lip and palate can possibly be corrected with surgical procedures.  Other birth defects potentially connected with Topamax include heart, lung, brain, and limb defects.
 

According to data from the North American Antiepileptic Drug Pregnancy Registry (NAAED), there is an increased risk of cleft palate and cleft lip in children born to women who took Topamax during the first trimester of pregnancy.  This data shows that cleft palate or cleft lip is over twice as likely to occur in a newborn baby exposed to Topamax compared to a different epilepsy drug, and over twenty times as likely to occur in a newborn not exposed to any epilepsy drug.  This research is of concern because many women may not know they are pregnant during the first trimester. 

In response to the data indicating birth defect risks for Topamax, the Food and Drug Administration (FDA) recently increased the warnings in Topamax packaging to inform patients of the risks of birth defects while taking this drug.  Topamax has been placed in Pregnancy Category D, which means that there is positive identification of a fetal risk based on human data, although the benefits of taking the drug for pregnant women may be acceptable in certain situations despite the risk.

The FDA has also recommended that women who intend to become pregnant should discuss the use of alternative therapies with their health care professionals before taking Topamax.  Physicians are recommended to consider prescribing drugs for their patients with lower risks of cleft palate and cleft lip.  Women who are concerned about the risks of taking Topamax should consult with a qualified healthcare professional. 

Depakote Birth Defects: Real Risks

By Independent Staff Writer Depakote is a prescription drug used to treat epileptic seizures, psychological disorders such as bipolar disorder, and migraine headaches.  Depakote is marketed under several brand names and generic versions of the drug, including Depakote ER, Depakote Sprinkles, Depakene, and Valproate.

Research studies strongly indicate that women who take Depakote during pregnancy are at a substantially greater risk for having children born with birth defects.  One of the most severe and disabling of these defects is spina bifida.  Spina bifida causes incomplete development of the bones of the spine, leading to protrusion of the spinal cord and fluid through a gap in the bones.  Other birth defects associated with Depakote are malformed head and facial structures including cleft palate, anencephaly, which causes a baby to be born without a brain, and fetal death.
 
Additional research has shown that children born to mothers who took Depakote during pregnancy are more likely to have cognitive defects resulting in lower IQ test scores.  In response to this research, the Food and Drug Administration (FDA) recently issued a Safety Communication to inform the public about the increased risk from Depakote of children with lower cognitive test scores compared to children born to mothers taking a different anti-seizure drug.  The FDA warns of the risk of these and other birth defects associated with Depakote, and recommends that doctors counsel their patients about these risks.

Actos Discussions Part 1: Your Actos Case

By Independent Staff Writer

Determining Whether You Have an Actos Case
Hundreds of thousands of patients who have taken the drug Actos over the past few years—believing the drug to be safe—have been very disillusioned to find that the drug can have some potentially very serious side effects. Actos is a drug which was developed for the treatment of Type 2 diabetes and works by helping the body restore its normal response to insulin, effectively lowering blood sugar. When high blood sugar is not consistently controlled, kidney damage, blindness, nerve problems and even the loss of limbs become possible medical issues. The control of Type 2 diabetes is also necessary to avoid a debilitating heart attack or stroke. Therefore, when a drug such as Actos seems to do a good job of lowering blood sugar, it becomes a very popular prescription drug. So popular that in spite of the recent rash of lawsuits against Takeda—the manufacturers of Actos—profits have only been dampened by approximately 13%. The pharmaceutical giant is still enjoys some $2.2 billion dollars in annual profits, down from an all-time high of over 4 billion dollars in annual profits. If you have taken Actos you may be wondering whether you might have an Actos case and be entitled to damages.

The FDA issued a warning which cautions patients with a history, diagnosis or heightened risk of bladder cancer to consider an alternative diabetes treatment to Actos. Although this warning sounds fairly mild, drug safety watchdogs are urging anyone who is currently taking Actos to speak to their doctor about an alternative drug with less risk factor and are strongly urging those who have taken the drug in the past to ask their doctor to set up a bladder cancer screening. The common side effects of Actos generally include upper respiratory infections, headache, sinus infection, muscle pain, tooth problems, sore throat and swelling or water weight gain. Anyone who has had symptoms which can suggest bladder cancer such as blood in the urine, pain upon urination, back or stomach pain, or an urgent need to urinate should immediately seek medical attention. Because Actos has also been tied to an increased risk of heart failure, any patient who notices swelling of the feet, a sudden increase in weight and shortness of breath should also seek immediate medical attention. In conjunction these symptoms can suggest congestive heart failure and a buildup of fluid in the lungs. In short, if you took Actos for a period of more than twelve months, or in very high dosages, you may be eligible to file an Actos lawsuit.

Could Harm from Actos Translate Into Damages?
Lawsuits resulting from bladder cancer believed to be caused by Actos started in August of 2011 with thousands expected to follow as the harmful effects of the drug continue to be investigated. Many of these lawsuits allege that Takeda either knew or should have known the long-term effects of the drug, primarily the increased risk of bladder cancer in those taking higher dosages or taking Actos for an extended period of time. The FDA did not release a safety communication regarding these risks until June 15, 2011, basing their decision on an ongoing ten-year study of the serious side effects of Actos. Among this group of 193,000 patients taking Actos, a five-year interim study revealed no overall increase in bladder cancer, however showed significantly increased risks of the disease in those taking Actos for an extended period of time or in higher dosages.

Actos Discussions Part 2: Dangers of the Drug

By Independent Staff Writer

Could Your Heart Failure Be Linked to Actos?
Links to higher heart disease rates have been associated with the use of Actos, and, in fact, Actos may cause as many heart problems as GlaxoSmithKline’s drug, Avandia. The American Heart Association reported that studies showed patients taking either diabetes drug were at least four times as likely to experience heart attacks, heart failure or even death. When a 2007 study on Avandia showed a 43 percent higher chance of heart attack, Actos quickly became the market leader. A subsequent study on both drugs showed that 602 Avandia users and 599 Actos users in the study suffered either a heart attack, heart failure or both, with 217 deaths in each group.  The latest study regarding Actos in the journal Lancet found the risk for heart failure greatest among those patients with a prior history of heart disease and heart failure, however overall the relative risk when taking Actos was as much as 72 percent higher than those not taking the drug. Both Glaxo and Takeda dispute the results of these negative studies, citing a study published in the Journal of the American Medical Association which suggests Actos might actually cut the risk of heart attack, stroke and death.

Link between Actos and Heart Failure
Actos is in a class of drugs known as thiazolidinediones, whose use has long been attributed to certain liver and cardiovascular health issues. A listed side effect of Actos includes the threat of congestive heart failure with the link between Actos and congestive heart failure being so undeniable that in 2007 the FDA escalated warnings regarding heart disease when taking the drug. Actos causes the body to retain excess fluid, leading to swelling and weight gain. This extra body fluid can worsen some heart problems, leading to heart failure or can actually cause heart problems.

When Actos causes swelling in the body, this swelling also occurs around the heart, rendering it unable to effectively pump blood throughout the body. As fluid builds up around the heart and lungs, it becomes more difficult for the heart to pump, causing it to become less and less efficient. This can lead to shortness of breath, trouble breathing when lying down, a feeling of excessive tiredness or an unusually rapid increase in weight. After an intense debate over the cardiovascular risks of Actos, the FDA agreed to surround the heart risk warnings on Actos with an emphatic black outline commonly known as a black box warning. This black box warning is the strongest FDA label change which can be added to any drug on the market.

Link Between Actos and Bladder Cancer
The FDA issued its safety announcement regarding the connection between using Actos for more than one year and the risk of bladder cancer on June 15, 2011. The bladder lies in the center of the lower part of the abdomen, and its primary purpose is to store urine prior to excreting it from the body. When cells in the bladder become cancerous, a tumor can form. Actos helps diabetics use their own insulin better by hitting at least two of the three main PPAR receptors known as the Gamma and Alpha receptors. The Gamma receptor works on glucose while the Alpha receptor affects cholesterol. Actos appears to have a higher affinity with the Alpha receptor which is why it does a good job on raising good cholesterol and lowering triglycerides.

Actos® Adverse Effects

By Independent Staff Writer

Many of us would be very surprised to find that a drug can be approved by the FDA yet still have serious—and undisclosed—side effects.  The drug Actos, used in the treatment of Type 2 diabetes, is one such drug. Actos works by decreasing the body’s resistance to insulin as a way of controlling blood sugar levels. Actos is currently being used by millions of people across the globe, with sales jumping from around $2.9 billion in 2006 to over $4.3 billion in 2010.  Actos has often been prescribed in place of the drug Avandia, which was found to carry significant risks of heart disease and possibly even death in 2007. Actos, which is manufactured by the Japanese pharmaceutical giant Takeda Pharmaceuticals, has recently fallen under scrutiny as well as studies have linked it to an increased risk of bladder cancer as well as correlating it to other serious diseases such as heart attack, stroke and liver failure.

“Minor” Side Effects of Actos
The truth is, all prescription medicines as well as most over-the-counter medications, carry some risk of adverse effects.  Fortunately the incidence of serious side effects is rare and for the most part the majority of people have either no side effects or relatively minor ones. Minor side effects associated with Actos include flu-like symptoms, headaches, toothache, sore throat or sinus pain and weight gain.  More serious side effects which should prompt the user to seek medical attention include an allergic reaction which includes difficulty breathing or chest tightness, blurry vision, symptoms of heart or liver failure including breathing difficulties, a sudden gain in weight, stomach pains, dark urine, jaundice or vomiting, low blood sugar symptoms such as tremors, anxiety or chills, severe and unusual bone pain and total exhaustion along with feeling weak and shaky.

More Serious Adverse Effects from Actos
In general, the side effects of Actos were found to be similar to the side effects of Actos used in combination with sulfonylurea, metformin or insulin other than an increase in edema when Actos was combined with insulin therapy.  Almost 200,000 patients with Type 2 Diabetes who took Actos to control their disease, were involved in a Northern California research study. Alarmingly, the study found that those taking Actos for any length of time past twelve months were at a 40% higher risk of developing bladder cancer than those not taking the drug. Prior to the release of this study, Takeda disclosed no cancer warnings on their labeling information sheet or the patient medication guide.  Other studies are now indicating that those patients who took the highest dosages of Actos or took it for at least two years with a cumulative dosage of greater than 28,000 mg faced the highest risks of developing bladder cancer.

While the FDA has compelled Takeda to adjust their labeling to include warnings about possible increased risks of bladder cancer, the United States is holding off pulling the drug until results of further studies are in.  Other countries are not so relaxed about the drug with New Zealand scheduling a recall of Actos, and France and Germany already suspending sales of the drug. The French National Health Insurance Plan studied data from a million and a half patients with Type 2 diabetes, finding a “statistically significant increase” in the risk of bladder cancer in those taking Actos as compared with those taking other anti-diabetic drugs.  Unfortunately the bladder cancer risk is not the only serious adverse effect noted in those taking Actos.

Actos® and Bladder Cancer

By Independent Staff Writer
Recent studies have shown that patients taking the drug Actos for longer than one year may suffer significantly increased risks of developing bladder cancer. The FDA warnings are being issued on the heels of France and Germany banning the use of Actos, and New Zealand also beginning the process of removing Actos from patient use. Takeda Pharmaceuticals, the Japanese corporation who began manufacturing Actos in 1999, is at the midway point in a ten-year study of the drug’s potentially serious side effects. While the five-year data shows no clear evidence of an overall increased risk of bladder cancer, patients who have taken the drug in the highest dosages or for the longest period of time appeared to be at a much greater risk of developing bladder cancer.

Actos is in a class of drugs known as thiazolidinediones, and is the second medication of its class to be associated with serious side effects.  Avandia, the sister-drug of Actos, recently had its use severely restricted due to evidence of increased heart attack risk and even death. When metformin alone no longer works well for patients suffering from type 2 diabetes, doctors typically prescribe a drug such as Actos which increases the body’s insulin sensitivity, controlling blood sugar levels in the process. Type 2 diabetes, when left untreated, can potentially lead to serious health effects such as damage to the retina which can lead to blindness, injury to the kidneys, impairment of the nerves which could lead to amputations of limbs and an acceleration of the development of fat plaques on the interior of the arteries which can potentially lead to blood clots, blockages, cardiovascular disease, stroke and a lessening of critical circulation. 

Shaped like a balloon, the bladder resides in the lower regions of the abdomen and its primary function is storage for urine.  Urine is a liquid waste made by the kidneys when they clean the body’s blood—until it is passed from the body. Bladder cancer typically begins in the cells which line the bladder and risk factors include smoking, certain infections, being male, white and elderly, eating a diet which is high in fats and fried foods, and being exposed to specific carcinogenic chemicals commonly used in hairdressing, textile production, paints and rubber manufacturing.  Symptoms of bladder cancer include frequent urination, blood in the urine or pain during urination, and lower back pain.  Procedures for determining bladder cancer include CT scans, urinalysis, an internal exam, or a cystoscopy.

The chances of recovering from bladder cancer depends largely on what stage the cancer is in when discovered as well as the patient’s age and overall health status. Treatments include chemotherapy, surgery and radiation. The five-year survival rate for patients with early stage bladder cancer is approximately 85%, however in patients with more advanced bladder cancer who have undergone chemotherapy and/or radiation, the five-year survival rate is only 60-75%. Over 14,000 deaths occur each year from bladder cancers.

Several studies have linked the use of Actos for periods of longer than a year or in higher dosages to as much as a 42% increase in the incidence of bladder cancer. The potential risk of Actos users developing bladder cancer has been known for some time; the FDA’s Adverse Event Reporting System has found that 31 cases of bladder cancer were recorded between 2004 and 2009 in patients being treated with an anti-diabetic drug containing pioglitazone, such as Actos. A study of more than 190,000 patients with Type 2 diabetes who were enrolled in the Kaiser Permanente Northern California health plan showed that while there was not a significant overall increased risk of bladder cancer, those patients who were taking higher doses or were taking Actos for longer than twelve months had as much as a 40% increased chance of developing bladder cancer as compared to patients who had never used the drug. The participants in this study were at least forty years old.

Actos® and Congestive Heart Failure

By Independent Staff Writer

The drug Actos, also known as pioglitazone is marketed by Takeda Pharmaceuticals and Eli Lilly for the treatment of Type 2 diabetes. The drug was approved in 1999, and although the manufacturer touts it as a miracle drug which has reduced the number of diabetes cases by as much as 70%, the side effects may far outweigh the benefits. A study done in 2003 by the Mayo Clinic definitively linked Actos to swelling in the feet, lung fluid retention, shortness of breath and congestive heart failure. The most recent studies have strongly indicated that Actos may also be responsible for a number of incidences of bladder cancer in those who have taken the drug in higher dosages or for longer than twelve months. 

The American Diabetes Association presented a research report at a meeting in San Diego this past June which reported that Actos enhanced the risk of macular edema by as much as six times, causing thickening and swelling of the retina and leading to blindness. Another study which was reported in the American Heart Association Journal in August, 2010, associated Actos with an increased risk of death due to congestive heart failure. Although the FDA had mandated a black box warning for Actos regarding possible heart failure risks in 2007, the warnings became even more stringent this past June.

When the heart is unable to pump adequate amounts of oxygen-rich blood to the body, congestive heart failure can occur and can also affect the kidneys, causing them to lose their capacity to expel harmful levels of sodium and fluids, and triggering the body to stubbornly hang on to even more water. Congestion of the lungs with fluids or harmful liquids which gather in the liver can occur, damaging the patient’s ability to breathe as well as to clear the body of harmful toxins. Actos can also cause the extremities to swell from the accumulation of fluids, especially in the ankles and feet. This means that the person who takes Actos may be at a considerably higher risk of congestive heart failure than a person not taking the drug.  One of the warnings on the Actos patient guide states that any edema which is directly caused by Actos is generally reversible when the drug is discontinued, and that edema of this type will not normally require hospitalization unless there is corresponding congestive heart failure.

Actos® and Myocardial Infarction

By Independent Staff Writer

After a Journal of American Medical Association publication of a meta-analysis suggested that long-term use of the diabetes drug Avandia was associated with an increased risk of myocardial infarction, the maker of Avandia, GlaxoSmithKline, declared there was little difference in the safety profile of their drug, Avandia and the “other” drug for Type 2 diabetes, Takeda Pharmaceutical’s Actos. Further studies however have not completely backed up that declaration. In nineteen separate controlled trials, involving over 16,000 patients, the end results demonstrated that while 4.4 percent of the patients who received Actos underwent myocardial infarction or stroke 5.7 percent of patients receiving control therapy suffered a myocardial infarction.

In the same studies, serious heart failure was reported in 2.3 percent of those taking Actos, while only occurring in 1.8 percent of those in the control group. The author of the results of the studies, Michael Lincoff, stated that not only does Actos—also known as pioglitazone—not appear to have the same level of detrimental effects as Avandia, but it could potentially have a protective effect on the heart. Takeda Pharmaceuticals, currently struggling under the rash of lawsuits filed against them due to evidence that Actos may significantly increase the risk of bladder cancer, does not believe their drug is responsible for episodes of myocardial infarction, or heart attack.

Other studies are not so quick to absolve Takeda Pharmaceuticals from their drug’s responsibility to potentially cause myocardial infarction, and the FDA has mandated that all those who take Actos be thoroughly warned about the possibility that it could bring about a serious or fatal heart attack.  Actos is Takeda’s primary drug, accounting for over 15% of all new prescriptions in the United States.  Type 2 diabetes affects as many as twenty million Americans, and is characterized by the body’s inability to respond to insulin as it should. When Type 2 diabetes is left untreated, it can lead to a myriad of other health problems, including cardiovascular disease.

Actos® European Recall and FDA Stance

By Independent Staff Writer

A wave of recent studies which definitively link the prescription drug Actos—prescribed for Type 2 diabetes—to bladder cancer gives a fairly clear indication that Takeda Pharmaceuticals may soon be flooded with Actos lawsuits. August, 2011, saw the first Actos lawsuit filed by a 54-year old woman from Pennsylvania who had taken Actos for over a decade, then was diagnosed with bladder cancer. It is likely this particular victim may end up having her bladder removed and be subject to chemotherapy treatments due to the unexpected and severe side effects of Actos. Although the FDA has made substantial changes in labeling for Actos, they have refused to go as far out on the limb as other countries who have issued recalls of the drug.

France’s Medical Regulatory Agency made the decision to recall Actos once the serious side effects became known. Some 230,000 people regularly take Actos in France, and the possibility of an increase in bladder cancer was felt to be too great to allow patients to continue to take the drug. Soon after, Germany’s health regulators advised physicians to stop prescribing Actos for their patients with Type 2 diabetes due to the potentially dangerous side effects of the drug. These recalls and prohibitions were made after the European Medicines Agency conducted its own study of drugs which contained pioglitazone.

This study led Germany to change their initial warnings to physicians to include the statement that no new patients should be prescribed Actos due to its dangerous side effects.  While the EMA did not issue an Actos recall for the entire European Union, it confirmed that this particular Type 2 diabetes drug put its users at a much greater risk for developing severe side effects, including bladder cancer. New Zealand has now scheduled its own recall of Actos due to perceived risks including heart failure, heart attack, stroke and bladder cancer just like the drug’s predecessor, Avandia. 

Germany and France based their recall of Actos on a French study indicating an increased risk of bladder cancer in those taking the drug. The study was done on over 150,000 study participants who had taken Actos between 2006 and 2009, with findings of a 22% increase in bladder cancer in those who took Actos to control their Type 2 diabetes. In those who were using higher dosages of Actos, that figure was as high as a 50% increased risk of bladder cancer.

In 2007 the FDA recalled Actos for improper warning labels, however once that issue was resolved they allowed the drug back on the market. At present the FDA continues to examine the results of a ten year study done on over a million patients who have regularly taken Actos. Although mid-point results from the study indicated a possibility of increased bladder cancer risk, the results were less than definitive, leading the FDA to allow Actos to remain on the market until further results are in.

Actos® FDA Safety Review/Warning

By Independent Staff Writer

On June 15, 2011, the United States Food and Drug Administration informed the public that using the drug Actos, commonly prescribed in the treatment of Type 2 diabetes, has been positively associated with an increased risk of bladder cancer. Actos is manufactured by a Japanese pharmaceutical company, Takeda Pharmaceuticals, and is typically sold either as a single-ingredient product or in combination with the drug metformin. Actos is prescribed, along with diet and exercise, to help control blood sugar in adults. Initially the FDA’s safety warnings were based on a five-year interim analysis of an ongoing ten year study regarding the risks for those taking Actos. 

While the study at the five-year mark noted an increased risk of bladder cancer among those who had taken Actos in the highest dosages and for the longest periods of time, it was unclear about the overall increased bladder cancer risk. Two other countries, France and Germany, have taken more definitive actions regarding Actos, believing it poses serious health risks. While France has suspended the use of Actos altogether, Germany has recommended to physicians that they not start new patients on the drug. New Zealand is currently in the midst of recalling the drug, yet the FDA continues to maintain that further study is warranted before issuing more stringent warnings.

Summary of the Ten-Year Study
The study the FDA is basing their opinions on was actually conducted by Takeda Pharmaceuticals, the manufacturer of Actos. Takeda simultaneously conducted case-control studies on patients with Type 2 diabetes who were also members of Kaiser Permanente Northern California health plan. The participants in these studies were over the age of forty at the onset of the study, and any patients who had been diagnosed with bladder cancer prior to the study were excluded.

The larger cohort study included over 190,000 patients and the median duration of the Actos therapy was two years, with a range of three months to eight and a half years. Once the study was adjusted for age, sex, use of tobacco products as well as the use of other diabetes drugs it showed no significant increase in bladder cancer risk for those simply “exposed” to Actos. On the contrary, the risk appeared to increase significantly in those taking the drug for longer than twelve months or in higher dosages—as much as a 40% increase in the risk of bladder cancer.

French National Health Insurance Plan Study
The FDA also took a passing look at another cohort study conducted by the French National Health Insurance Plan which included approximately a million and a half patients with Type 2 diabetes and lasted for four years. After the normal adjustments for age, sex, and the use of other anti-diabetic medications, the French study showed a significant increase in the risk for patients taking Actos to contract bladder cancer as compared to other anti-diabetic drugs. The French study correlated a cumulative dosage of more than 28,000 mg of Actos or exposures of longer than twelve months with a significantly elevated risk of bladder cancer.

No Recall Yet for Type 2 Diabetes Drug, Actos

By Independent Staff Writer

The 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 Pioglitazone
Pre-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.

Results of Safety Review
Although the results of the FDA-ordered safety review of pioglitazone were less than positively conclusive, the French Agency for the Safety of Health Products nonetheless pulled Actos from the French market this June due to health concerns. France conducted their own safety study, using over 1.5 million diabetic patients who were currently being treated with the drug—a study which more definitively showed a positive correlation between bladder cancer and pioglitazone. This study also pointed to the fact that the risk increases in patients who take the drug for a longer time period than one year. Following on the heels of the French decision, the German Federal Institute for Drugs and Medical Devices advised doctors against prescribing Actos, based on the French study results. As of September, 2011, no other countries have pulled the drug due to safety concerns.

FDA Approves Cancer Warning for Diabetic Drug Actos

By Independent Staff Writer

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.

Takeda Pharmaceuticals Received FDA Instructions for Diabetic Drug Actos

By Independent Staff Writer

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 New
As 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 Issues Sterner Warnings to Manufacturers of Diabetic Drug Actos

By Independent Staff Writer

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
In 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.

Patient Counseling Information
The FDA’s advice to patients taking the drug includes immediately reporting any signs or symptoms of urinary urgency, dysuria or macroscopic hematuria to their treating physician, as these can be signs of bladder cancer. Blood or red color in the urine or pain while urinating are all serious side effects and should be relayed immediately to the patient’s doctor. Actoplus Met, Actoplus Met XR and Duetact must all be labeled in the same manner as Actos according to FDA findings.

FDA Postmarketing Requirements
In the same letter to Takeda, the FDA offered specific postmarketing requirements which included directing Takeda Pharmaceuticals to continue and modify their ten-year study which assessed the related risk of bladder cancer in those taking Actos. The Final Protocol Amendment Submission must be submitted to the FDA by December 16, 2011, the 4^th Interim Report Submission by June 30, 2012, the Study Completion by December 31, 2012, and the Final Report Submission by December 31, 2013.  Takeda is asked to report periodically on studies and trials conducted on Actos however the Risk Evaluation and Mitigation Strategy Requirements submitted were approved with no further changes required.

Postapproval Clinical Trial
The FDA directs Takeda to include the status of any postapproval clinical trials, including when the enrollment began, how many patients were enrolled, the date of expected completion, and any difficulties encountered in the trial. Generic products for the drug Actos must have a REMS, supporting documents and appended documents prior to marketing the product.

As a final admonishment to Takeda, the FDA warns that all promotional materials and package inserts for the drug Actos as well as other drugs containing pioglitazone be submitted at the time of publication, and that all promotional materials must be revised to be consistent with mandated label changes.