FDA statement from Douglas Throckmorton, M.D., deputy center director for regulatory programs, Center for Drug Evaluation and Research, on new warnings about the use of codeine and tramadol in children & nursing mothers.

The health and safety of children is a top priority at the FDA, which is why today we are requiring a series of changes to the labeling of two types of opioid medications in order to help better protect children from serious risks associated with these medicines – codeine (found in some prescription pain and cough medicines and some over-the-counter cough medicines) and tramadol (found in some prescription pain medicines).

We are requiring these changes because we know that some children who received codeine or tramadol have experienced life-threatening respiratory depression and death because they metabolize (or break down) these medicines much faster than usual (called ultra-rapid metabolism), causing dangerously high levels of active drug in their bodies. This is especially concerning in children under 12 years of age and adolescents who are obese or have conditions that may increase the risk of breathing problems, like obstructive sleep apnea or lung disease. Respiratory depression can also occur in nursing babies, when mothers who are ultra-rapid metabolizers take these types of medicines and pass it along to their children through their breast milk.

This isn’t the first time we have taken action on codeine to better ensure the safety of our children. Since 2013, prescription codeine labeling has contained a Boxed Warning and Contraindication for children up to age 18 years of age regarding the risk of life-threatening respiratory depression following the use of codeine for pain management after the removal of the tonsils (tonsillectomy) and/or adenoids (adenoidectomy). Now, labels for both codeine and tramadol are being updated to include additional Contraindications and Warnings; among the updates are Contraindications for use of codeine or tramadol in all children younger than 12 years of age, warnings about their use in children 12-18 years of age with certain medical conditions, and a stronger warning recommending against their use in nursing mothers. In addition to these labeling changes, labeling for tramadol-containing products will also get a Contraindication for post-operative pain management in children up to age 18 years of age who have undergone tonsillectomy and/or adenoidectomy, which is already in labeling for codeine products.

We urge health care providers, stakeholders and the public to read the Drug Safety Communication that we issued today, which provides more detailed information regarding the new Warnings and Contraindications, and the data that informed them. We also encourage parents to review the ingredients of pain medicines to see whether they include codeine or tramadol, and cough medicines to see if they contain codeine. It’s also important to check non-prescription cough and cold medicines that may be sold over the counter, as some of these medicines also include codeine. In all cases, if the medicine contains codeine or tramadol, parents should consult a health care provider before giving their children the medicines or taking them when nursing.

We understand that there are limited options when it comes to treating pain or cough in children, and that these changes may raise some questions for health care providers and parents. However, please know that our decision today was made based on the latest evidence and with this goal in mind: keeping our kids safe.

The FDA, an agency within the U.S. Department of Health and Human Services, promotes and protects the public health by, among other things, assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

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On Friday, U.S. District Judge Robert G. James for the U.S. District Court for the Western District of Louisiana entered a consent decree of permanent injunction against Pick and Pay Inc./Cili Minerals, a manufacturer and distributor of drugs and dietary supplements, and its owner, Anton S. Botha, requiring the business to immediately cease operations until it comes into compliance with federal laws.

The complaint, filed by the U.S. Department of Justice, sought a permanent injunction against the company and its owners for unlawfully manufacturing and distributing unapproved new drugs, misbranded drugs, adulterated dietary supplements and misbranded dietary supplements. 

The company and its owner marketed their products online at www.ciliminerals.com, www.cilihealthstore.com and www.cil-ergy.com. They also sold their products through a retail location in Lafayette, Louisiana. 

“The FDA works with companies to ensure their processes comply with the public health requirements in our laws and regulations,” said Melinda Plaisier, FDA associate commissioner for regulatory affairs. “But when a company refuses to comply, we will take enforcement action.”

The FDA inspected Pick and Pay Inc./Cili Minerals four times since 2012. During the inspections, the FDA found Pick and Pay Inc./Cili Minerals was manufacturing and distributing misbranded and unapproved new drugs as well as misbranded and adulterated dietary supplements. The defendants marketed their products with claims that they could treat medical conditions such as cancer, cardiovascular disease, multiple sclerosis, autism, bipolar disorder, brain injury and epilepsy. The FDA has not approved Pick and Pay Inc./Cili Minerals’ drugs for any use.

During the inspection, FDA investigators also found numerous violations of the agency’s current Good Manufacturing Practice (cGMP) regulations for dietary supplements, including failing to establish specifications for dietary supplement components and failure to test or verify that components and finished products meet product specifications for identity, purity, strength or composition. Because the defendants failed to follow cGMP regulations, their dietary supplements are adulterated under the Federal Food, Drug, and Cosmetic Act.

In May 2015, the FDA issued a Warning Letter to Pick and Pay Inc./Cili Minerals for similar violations.

The consent decree prohibits the company and its owner from marketing and distributing misbranded or unapproved new drugs and adulterated or misbranded dietary supplements. Before the company and its owners can resume operations, they must, among other things, recall and destroy their existing stock of drugs and dietary supplements, hire labeling and good manufacturing practices experts, and receive written permission from the FDA to resume operations. 

Pick and Pay Inc./Cili Minerals is based in Lafayette, Louisiana.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

The U.S. Food and Drug Administration today approved the Amplatzer PFO Occluder device. The PFO Occluder reduces the risk of a stroke in patients who previously had a stroke believed to be caused by a blood clot that passed through a small hole in the heart, called a patent foramen ovale (PFO), and then traveled to the brain.

“The Amplatzer PFO Occluder provides a non-surgical method for doctors to close a PFO,” said Bram Zuckerman, M.D., director of the Division of Cardiovascular Devices in the FDA’s Center for Devices and Radiological Health. “But as the device labeling clearly states, patients need to be evaluated carefully by a neurologist and cardiologist to rule out other known causes of stroke and help ensure that PFO closure with the device is likely to assist in reducing the risk of a recurrent stroke.”

About 25 to 30 percent of Americans have a PFO, which typically causes no health problems and does not require treatment. The cause of most strokes can be identified, such as poorly controlled high blood pressure, narrowed blood vessels due to cholesterol deposits and scar tissue (atherosclerosis), or a blood clot caused by an abnormal heart rhythm (atrial fibrillation). However, in some patients, medical tests cannot identify the cause of the stroke, which is referred to as a cryptogenic stroke. In a small percentage of these patients, it is believed that the PFO provided a path for a blood clot to travel to the brain where it blocked a blood vessel resulting in a stroke. Patients with a cryptogenic stroke and a PFO may be at an increased risk of having a second stroke.

The Amplatzer PFO Occluder is inserted through a catheter that is placed in a leg vein and advanced to the heart. It is then implanted close to the hole in the heart between the top right chamber (right atrium) and the top left chamber (left atrium). The device had been on the market more than a decade ago under a humanitarian device exemption (HDE), but was voluntarily withdrawn by the manufacturer in 2006 after the FDA concluded that the target population for this device was greater than 4,000 patients and that the device no longer qualified for an HDE approval. For the past 10 years, no FDA-approved heart occluder devices have been on the market specifically indicated to close PFOs to reduce the risk of a recurrent stroke in patients with a prior cryptogenic stroke.

In approving the Amplatzer PFO Occluder, the FDA concluded that the device demonstrated a reasonable assurance of safety and effectiveness. The safety and efficacy was assessed in a randomized study that evaluated 499 participants aged 18 to 60 years old who were treated with the Amplatzer PFO Occluder plus blood-thinning medications compared to 481 participants who were treated with blood-thinning medications alone. While the rate of new strokes in both treatment groups was very low, the study found a 50 percent reduction in the rate of new strokes in participants using the Amplatzer PFO Occluder plus blood-thinning medications compared to participants taking only blood-thinning medications.

Adverse effects associated with the device or the implantation procedure include injury to the heart, irregular and/or rapid heart rate (atrial fibrillation), blood clots in the heart, leg or lung, bleeding and stroke.

The Amplatzer PFO Occluder device should not be used in patients with a heart valve infection or other untreated infections, or a heart tumor or blood clot at the implant site. The device is also contraindicated in patients with other abnormal connections between the heart chambers or in whom the cardiovascular anatomy or blood clots would interfere with the ability to move the catheter used to deliver the device to the heart.

Patients should discuss with their medical team (consisting of a neurologist and a cardiologist) the risks and benefits of PFO closure in comparison to using medications alone.

The Amplatzer PFO Occluder device is manufactured by St. Jude Medical Inc. based in Plymouth, Minnesota.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

The U.S. Food and Drug Administration today approved Opdivo (nivolumab) to treat patients with advanced (metastatic) renal cell carcinoma, a form of kidney cancer, who have received a certain type of prior therapy. “Opdivo provides an important therapy option for patients with renal cell carcinoma,” said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “It is one of few therapies that have demonstrated the ability to extend patients’ survival in treating this disease.” Torisel (temsirolimus), approved in 2007, is the only other FDA-approved therapy that has demonstrated overall survival in renal cell cancer.
Renal cell carcinoma is the most common form of kidney cancer in adults and forms in the tissues of the kidney that make urine. The National Cancer Institute estimates 61,560 new cases and 14,080 deaths from kidney and renal pelvis cancer in the United States this year.

“Additionally, Opdivo’s extended indication, from melanoma and non-small cell lung cancer to renal cell cancer, demonstrates how immune therapies can benefit patients across a wide range of tumors,” continued Dr. Pazdur.

Opdivo works by targeting the cellular pathway known as PD-1/PD-L1 (proteins found on the body’s immune cells and some cancer cells). By blocking this pathway, Opdivo may help the body’s immune system fight cancer cells. Opdivo is intended for use in renal cell carcinoma in patients who have received prior anti-angiogenic therapy (treatments that interfere with the blood vessels that contribute to the growth of cancerous cells).

The safety and efficacy of Opdivo for this use were demonstrated in an open-label, randomized study of 821 patients with advanced renal cell carcinoma whose disease worsened during or after treatment with an anti-angiogenic agent. Patients were treated with Opdivo or another type of kidney cancer treatment called everolimus (marketed as Afinitor). Those treated with Opdivo lived an average of 25 months after starting treatment compared to 19.6 months in those treated with Afinitor. This effect was observed regardless of the PD-L1 expression level of patients’ renal cell tumors. Additionally, 21.5 percent of those treated with Opdivo experienced a complete or partial shrinkage of their tumors, which lasted an average of 23 months, compared to 3.9 percent of those taking Afinitor, lasting an average of 13.7 months.

The most common side effects of Opdivo for this use are conditions relating to abnormal weakness or lack of energy (asthenic conditions), cough, nausea, rash, difficulty breathing (dyspnea), diarrhea, constipation, decreased appetite, back pain and joint pain (arthralgia).

Opdivo also has the potential to cause serious side effects that result from the immune system effect of Opdivo (known as “immune-mediated side effects”). These severe immune-mediated side effects involve healthy organs, including the lung, colon, liver, kidneys, hormone-producing glands and the brain.

The FDA granted the Opdivo application a breakthrough therapy designation, fast track designation, and priority review status. These are distinct programs intended to facilitate and expedite the development and review of certain new drugs in light of their potential to benefit patients with serious or life-threatening conditions.

Opdivo is marketed by Bristol-Myers Squibb based in Princeton, New Jersey. Torisel is marketed by Pfizer, based in New York, New York. Afinitor is marketed by Novartis Pharmaceuticals of East Hanover, New Jersey.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.