Questions and Answers - Safety Requirements for Victoza (liraglutide)

Q1. What is FDA announcing today?

A. FDA is approving Victoza (liraglutide), a once-daily injection to treat type 2 diabetes mellitus (T2DM) in adults. Victoza is intended to help lower blood sugar (glucose) levels, along with diet and exercise. Controlling elevated blood sugar levels is important in preventing complications of diabetes, such as kidney disease and blindness.

People with T2DM have difficulty making and using insulin, a hormone that helps prevent glucose from building up in the blood. Victoza works by helping the pancreas release more insulin after eating a meal.

Although there are many anti-diabetic medications already available for use, often people with T2DM will require different or additional anti-diabetic medications to control their blood sugar, given the chronic nature of this disease.Therefore, Victoza is another medication that can be used to help control blood sugar, but it is not recommended as first-line therapy for patients whose blood sugar is not controlled through diet and exercise.

Q2. Should healthcare professionals be aware of any safety issues associated with Victoza?

A. FDA approved Victoza because the Agency believes that the benefits of this drug to patients with T2DM outweigh potential risks associated with its use. There were, however, several safety concerns identified during the Victoza review that had to be evaluated in light of its benefits. These safety concerns included:

• Clinical trials that suggested Victoza may be associated with pancreatitis (see Q3). Other drugs that work through similar mechanisms as Victoza have also been associated with pancreatitis.
• Animal data that showed a rare type of thyroid cancer known as medullary thyroid cancer associated with liraglutide, although the relevance of this finding to humans remains unknown (see Q5).

To ensure that the benefits of Victoza continue to outweigh any risks, FDA has required a Risk Evaluation and Mitigation Strategy (REMS) as part of the Victoza approval. This REMS includes a patient Medication Guide and a Communication Plan. FDA has also required additional studies to better understand the risks associated with this medicine. In addition, FDA has required a large cardiovascular safety trial, that is now required as part of the development of most diabetic medications (See Q7).

Q3. What information did FDA review about pancreatitis associated with the use of Victoza?

A. The Victoza trials were carefully reviewed for cases of pancreatitis, a side effect associated with other diabetic medications that work in a similar manner to this medicine. In five clinical trials including more than 3,900 people, there were seven cases of pancreatitis in patients using Victoza and one case in a patient using another diabetes medicine. This constituted a 4:1 imbalance of pancreatitis cases, when considering the number of patient exposures. Although there were too few cases to know if Victoza causes pancreatitis, healthcare professionals and patients should be aware of this potential risk, and know that some common side effects of Victoza may be similar to the symptoms of pancreatitis (see Q4).

Q4. What steps does FDA recommend patients and healthcare professionals take to reduce the risk of developing pancreatitis while using Victoza?

A. Patients taking Victoza should be aware of the symptoms of pancreatitis, such as severe abdominal pain that may also radiate into the back, possibly with nausea, and vomiting. If patients experience these symptoms, they should immediately talk to their healthcare professional.

As part of the REMS, patients will be given a Medication Guide to provide them with information about pancreatitis, including:

• What conditions, in general, may place them at higher risk for pancreatitis; for example, prior history of pancreatitis, gallstones, excessive use of alcohol, or very high blood triglyceride levels.
• The symptoms of pancreatitis (described above) and what they need to do if they occur.

If healthcare professionals suspect a patient has pancreatitis, Victoza should be stopped right away and the patient should undergo testing to confirm pancreatitis. If pancreatitis is confirmed, Victoza should not be restarted. Victoza has not been studied in enough patients who have had pancreatitis in the past to know if they are at higher risk for developing pancreatitis while using the medicine. For this reason, Victoza should always be used with caution in patients with a history of pancreatitis.

As part of the REMS, the Communication Plan for healthcare professionals highlights how to appropriately select patients for treatment with Victoza. It also reminds healthcare professionals to promptly evaluate patients who develop symptoms suggestive of pancreatitis.

Q5. What information did FDA review about medullary thyroid cancer and Victoza?

A. Studies were done in mice and in rats to look for any evidence that liraglutide might cause cancer in animals. Results of the studies showed that liraglutide caused malignant tumors of the thyroid gland, especially at doses that were 8-times higher than what humans would receive. It is hard to predict whether this finding means that humans who take liraglutide might be at risk for developing medullary thyroid cancer. This specific type of thyroid cancer is very rare in humans (about 600 cases per year in the United States) so even if liraglutide increased the risk for a patient to develop it, cases still might not be detected during the clinical trials.

As a result of the animal study results, the clinical development program for Victoza included blood tests for a biomarker for medullary thyroid cancer-a blood calcitonin test. Data from a two-year study did not show any difference in calcitonin levels between patients treated with Victoza compared to other diabetes medicines. With these data, FDA is of the opinion that this safety concern was adequately addressed during Victoza's development.

However, as part of FDA's commitment to post-marketing safety evaluation, the Agency is requiring the manufacturer of Victoza to conduct a 5-year epidemiological study using a large healthcare claims database to compare the development of thyroid cancer among patients with T2DM who use Victoza to those who are not using this medicine. In addition, FDA is requiring the manufacturer to develop a medullary thyroid cancer registry to monitor how many cases of medullary thyroid cancer occur each year for at least 15 years to see whether there is any association of this specific type of thyroid cancer with Victoza therapy.

Q6. What steps is FDA taking to inform patients and healthcare professionals about the potential risk of medullary thyroid cancer with the use of Victoza?

A. Patients using Victoza will receive a Medication Guide with every prescription that explains the potential risk of medullary thyroid cancer, who should not take the medication, and what symptoms to be aware of that may require additional evaluation by a healthcare professional.

A communication plan has been developed to ensure that healthcare professionals recognize the potential risk of medullary thyroid cancer in patients using Victoza. This communication plan will include:

• A Dear Healthcare Provider letter that will be sent to all healthcare professionals likely to prescribe Victoza.
• Representatives of Novo Nordisk (the maker of Victoza) will distribute Highlighted Information for Prescribers at their first meeting with prescribers.
• A link on the Victoza website that will take healthcare professionals and patients to all of these documents.

FDA is also requiring the manufacturer of Victoza to conduct additional animal studies in mice to further evaluate the potential risk of medullary thyroid cancer in humans.

Q7. Are there any other studies FDA is requiring for Victoza?

A. In December 2008, FDA issued a Guidance for Industry that required manufacturers of new treatments for diabetes to carefully design and evaluate their clinical trials for cardiovascular safety. The Victoza application for approval was submitted before the December 2008 guidance was issued; therefore, the manufacturer had not designed the recommended cardiovascular safety trials. FDA, however, reviewed the available cardiovascular safety data, and determined there was no evidence of excess cardiovascular risk associated with Victoza. The April 2009 FDA Endocrinologic and Metabolic Drugs Advisory Committee met, discussed, and a majority of the members voted that the available data adequately addressed the cardiovascular safety concern to support approval.

Still, FDA is requiring a post-approval study that specifically evaluates cardiovascular safety in a higher risk population as part of the Agency's commitment to post-marketing safety evaluation.