Lyrica Linked to Birth Defects

By Pat Anson, Editor

A drug widely prescribed to treat fibromyalgia, neuropathy and other chronic pain conditions increases the risk of major birth defects, according to a new study published in Neurology, the medical journal of the American Academy of Neurology.

Women taking pregabalin were six times more likely to have a pregnancy with a major defect than women who were not taking the drug, the study found. The birth defects included heart defects and structural problems with the central nervous system (CNS) or other organs. Birth defects due to chromosomal abnormalities were not included in the results.

Pregabalin is the generic name of Lyrica, which is approved by the FDA to treat diabetic nerve pain, fibromyalgia, epilepsy, post-herpetic neuralgia caused by shingles and spinal cord injury. It is also prescribed “off label” to treat a variety of other conditions. Lyrica is Pfizer’s top selling drug, generates over $5 billion in annual sales, and is currently approved for use in over 130 countries.

The international study involved nearly 700 pregnant women in seven different countries. Four of the 125 women who took pregabalin during pregnancy had children with central nervous system defects, or 3.2 percent. That compares to a birth defect rate of just 0.5% in the 570 women who did not take pregabalin.

Of the women taking pregabalin, 115 were taking it to treat neuropathic pain, 39 were taking it for psychiatric disorders, including depression and anxiety, five were taking it for epilepsy, and one for restless leg syndrome.

Most of the women started taking pregabalin before they became pregnant. All of them stopped taking the drug at an average of six weeks into their pregnancies.

A small number of women also took another anti-seizure drug during their pregnancy. Women in that group had a 6 percent chance of a major birth defect, compared to 2 percent of the women who did not take another anti-seizure medication.

“We can’t draw any definitive conclusions from this study, since many of the women were taking other drugs that could have played a role in the birth defects and because the study was small and the results need to be confirmed with larger studies, but these results do signal that there may be an increased risk for major birth defects after taking pregabalin during the first trimester of pregnancy,” said study author Ursula Winterfeld, PhD, of the Swiss Teratogen Information Service and Lausanne University Hospital in Lausanne, Switzerland.

“Pregabalin should be prescribed for women of child-bearing age only after making sure that the benefits of the drug outweigh the risks and after counseling them about using effective birth control. In cases where women have taken pregabalin during pregnancy, extra fetal monitoring may be warranted.”

A spokesman for Pfizer said the study was small and the findings could have been influenced by other factors.

"As the authors agree, the study has significant limitations and cannot be used to draw definitive conclusions," Steven Danehy said in an email to Pain News Network. "The study was small, did not account for other medical conditions or medications, and the women taking Lyrica had higher rates of smoking and diabetes, all of which can negatively affect pregnancy outcomes."  

Because women are more likely than men to have a chronic pain condition such as fibromyalgia, they are the biggest consumers of Lyrica.

The FDA warning label for Lyrica does not specifically warn pregnant women not to take the drug. But it does caution them to consult with a doctor if they are pregnant or plan to become pregnant.

“It is not known if Lyrica will harm your unborn baby. You and your healthcare provider will have to decide if you should take Lyrica while you are pregnant. If you become pregnant while taking Lyrica, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry,” the label says.

The label also cautions men to see a doctor if they plan to father a child while taking Lyrica. 

“Animal studies have shown that pregabalin, the active ingredient in Lyrica, made male animals less fertile and caused sperm to change. Also, in animal studies, birth defects were seen in the offspring (babies) of male animals treated with pregabalin. It is not known if these problems can happen in people who take Lyrica,” the warning label states.

FDA Orders Stronger Warning Labels for Opioids

By Pat Anson, Editor

The U.S. Food and Drug Administration is strengthening the warning labels on the nation’s most widely used opioid painkillers. The FDA is adding a “black box” warning to immediate release (IR) opioid pain medications, such as hydrocodone and oxycodone, stating that they pose serious risks of misuse, abuse, addiction, overdose and death.

The FDA will also require additional safety labeling changes on all other opioid medications, warning they can interact with antidepressants and migraine medications, or cause impotence and infertility.

The actions are the latest in a series of steps taken by the Obama administration to combat the so-called epidemic of opioid abuse and addiction by reining in the use of opioid pain medications. Last week the Centers for Disease Control and Prevention released new guidelines that discourage primary care physicians from prescribing opioids for chronic pain,

The updated warning will state that IR opioids should be reserved for pain severe enough to require opioid treatment and for which alternative treatment options (non-opioid analgesics or opioid combination products) are inadequate or not tolerated. Dosing information will also provide clearer instructions about the initial recommended dosage, dosage changes during therapy, and a warning not to abruptly stop treatment in a physically dependent patient.

A sample of the new black box warning label can be seen here:

"Opioid addiction and overdose have reached epidemic levels over the past decade, and the FDA remains steadfast in our commitment to do our part to help reverse the devastating impact of the misuse and abuse of prescription opioids,” said Robert Califf, MD, FDA commissioner.

“Today’s actions are one of the largest undertakings for informing prescribers of risks across opioid products, and one of many steps the FDA intends to take this year as part of our comprehensive action plan to reverse this epidemic.”

Califf, a cardiologist who was recently confirmed by the U.S. Senate, has also pledged to prioritize development of non-opioid alternatives for pain and to convene an expert advisory committee before approving any new drug applications for opioids that do not have abuse deterrent properties. 

In 2013, the FDA ordered labeling changes only for extended release opioids, a move that angered some politicians and addiction treatment specialists, who wanted stronger warning labels on all opioids. At the time, the agency said there was not enough evidence to support stronger warnings for IR opioids, which are intended for use every four to six hours.

Today’s action sweeps that earlier objection away.

“The broad set of actions announced today is reflective of the FDA’s efforts to improve informed prescribing of opioids across the board,” said Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research, who opposed IR labeling changes three years ago.

“We have been and will continue to evaluate all new data to ensure that labels of opioid drugs contain appropriate prescribing information about the benefits and risks of prescription opioids,” she said.

As part of the new boxed warning on IR opioids, the FDA will requires a statement that chronic use of opioids by pregnant women could result in neonatal opioid withdrawal syndrome (NOWS), which may occur in a newborn exposed to opioids for a prolonged period while in utero.

“We know that there is persistent abuse, addiction, overdose mortality and risk of NOWS associated with IR opioid products,” said Douglas Throckmorton, M.D., deputy center director of regulatory programs, FDA’s Center for Drug Evaluation and Research.

Last week, the head of the American College of Obstetricians and Gynecologists (ACOG), disputed that claim in a response to the CDC guidelines, saying they overstated the risk to pregnant women and newborns.

“Neonatal abstinence syndrome is the most established risk to newborns from use of opioids in pregnancy, but it is expected and treatable, and does not appear to pose permanent risks to the neonate,” said ACOG president Mark DeFrancesco, MD.

“However, evidence shows that withdrawal from opioid use during pregnancy may be associated with complications including fetal demise.  While some studies have suggested an association between birth defects and other adverse outcomes with opioid use in pregnancy, the absolute risk of these problems is low and data demonstrating a causal connection are lacking.”

Sen. Edward Markey (D-Mass) applauded the label changes by the FDA, but said they should have come sooner.

“Today’s announced changes to the labels of opioid products will finally reflect what we have known about these drugs for decades - they are dangerous and addictive and can lead to dependency, overdose and death,” said Markey in a statement. “Whether it's immediate or extended release, or abuse-deterrent, the labels given by the FDA have done little to prevent opioid addiction. Unfortunately, it has taken FDA far too long to address the grave risks of these drugs that have claimed the lives of thousands this year alone.”

Markey said the FDA also needs to convene an external advisory committee whenever it considers a new opioid for approval, something Califf has promised to do.