U.S. Food and Drug Administration Expands Indication for PROGRAF® for Prevention of Organ Rejection in Adult and Pediatric Lung Transplant Recipients

NORTHBROOK, Ill., July 20, 2021 /PRNewswire/ -- Astellas Pharma Inc. (TSE: 4503, President and CEO: Kenji Yasukawa, Ph.D., "Astellas") announced that the U.S. Food and Drug Administration (FDA) has approved its supplemental New Drug Application (sNDA) for PROGRAF^® (tacrolimus) for the prevention of organ rejection in adult and pediatric lung transplant recipients.

"We are pleased with this FDA approval and the Agency's continued recognition of PROGRAF, which was first approved for liver transplant recipients nearly three decades ago," said Salim Mujais, Senior Vice President, Therapeutic Area Head, Medical Specialties, Astellas. "The current approval expands the indications for PROGRAF from liver, kidney and heart transplants to adult and pediatric patients who receive a lung transplant in combination with other medicines to help prevent organ rejection."

The sNDA submission was based on Real World Evidence (RWE) generated from a retrospective observational study of data from the U.S. Scientific Registry of Transplant Recipients (SRTR), which captures data on all transplants performed in the U.S. The study analyzed outcomes based on discharge immunosuppression treatment regimens in recipients of a primary lung transplant between 1999 and 2017 who were alive at the time of discharge. In adult (n=15,478) and pediatric (n=450) patients receiving tacrolimus immediate-release (IR) products in combination with mycophenolate mofetil (MMF), the one-year graft survival estimates from time of discharge were 90.9% (adult) and 91.7% (pediatric). In adult (n=4,263) and pediatric (n=72) patients receiving tacrolimus IR in combination with azathioprine (AZA), the one-year graft survival estimates from time of discharge were 90.8% (adult) and 84.7% (pediatric). The number of lung transplants performed annually increased from 724 in 1999 to 2,248 in 2017, and in recent years, over 85.5% of lung transplant recipients are treated with tacrolimus, MMF and steroids.^i,ii

Based on the SRTR study results, published clinical trials and postmarketing reports, the safety profile for lung transplant patients treated with PROGRAF is consistent with the safety profile in liver, kidney and heart transplant patients treated with PROGRAF.  The primary adverse reactions described include renal dysfunction, infection, diabetes, gastrointestinal disturbances (e.g., diarrhea), hypertension, and neurological events (e.g., tremor). As expected, lung transplant patients have a higher incidence of pulmonary complications (e.g., pneumonia, bronchiolitis obliterans syndrome) than other solid organ transplant patients, which is in part due to the underlying disease and to the nature of the transplanted organ.

The FDA granted Orphan Drug Designation (ODD) to PROGRAF for the prevention of rejection after lung transplant in September 2019.  PROGRAF, which was discovered and developed by Astellas, is currently marketed in approximately 100 countries/areas and has greatly contributed to medical transplantation globally as a first-line immunosuppressant for organ transplantation.

About PROGRAF^® (tacrolimus)

PROGRAF^® was initially approved by the FDA in 1994. PROGRAF^® is a calcineurin-inhibitor immunosuppressant indicated for the prophylaxis of organ rejection in adult and pediatric patients receiving allogeneic liver, kidney, heart or lung transplants, in combination with other immunosuppressants.

What is PROGRAF?

• PROGRAF is a prescription medicine used with other medicines to help prevent organ rejection in people who have had a kidney, liver, heart or lung transplant.
• PROGRAF capsules and PROGRAF Granules are types of tacrolimus immediate-release drugs and they are not the same as tacrolimus extended-release tablets or tacrolimus extended-release capsules. Your healthcare provider should decide what medicine is right for you.

IMPORTANT SAFETY INFORMATION

What is the most important information I should know about PROGRAF?

PROGRAF can cause serious side effects, including:

1. Increased risk of cancer. People who take PROGRAF have an increased risk of getting some kinds of cancer, including skin and lymph gland cancer (lymphoma).
2. Increased risk of infection. PROGRAF is a medicine that affects your immune system. PROGRAF can lower the ability of your immune system to fight infections. Serious infections can happen in people receiving PROGRAF that can cause death. Call your healthcare provider right away if you have any symptoms of an infection, including: fever, sweats or chills, cough or flu-like symptoms, muscle aches, warm, red, or painful areas on your skin.

Do not take PROGRAF if you are allergic to tacrolimus or any of the ingredients in PROGRAF.

What should I tell my healthcare provider before taking PROGRAF?

Before you take PROGRAF, tell your healthcare provider about all of your medical conditions, including if you:

• plan to receive any vaccines (people taking PROGRAF should not receive live vaccines)
• have or have had liver, kidney, heart or lung problems
• are pregnant or plan to become pregnant. PROGRAF can harm your unborn baby.
• If you are able to become pregnant, you should use effective birth control before and during treatment with PROGRAF. Talk to your healthcare provider before starting treatment with PROGRAF about birth control methods that may be right for you.
• Males who have female partners who are able to become pregnant should also use effective birth control before and during treatment with PROGRAF. Talk to your healthcare provider before starting treatment with PROGRAF about birth control methods that may be right for you.
• are breastfeeding or plan to breastfeed. PROGRAF passes into your breast milk. You and your healthcare provider should decide if you will breastfeed while taking PROGRAF.
• plan to have children. PROGRAF may affect the ability to have children in females and males (fertility problems).

Tell your healthcare provider about all the medicines you take, and when you start a new medicine or stop taking a medicine, including prescription and over-the-counter medicines; vitamins; natural, herbal or nutritional supplements. Especially tell your healthcare provider if you take: sirolimus (RAPAMUNE^®): You should not take PROGRAF if you take sirolimus; cyclosporine (GENGRAF^®, NEORAL^®, and SANDIMMUNE^®), medicines called aminoglycosides that are used to treat bacterial infections, ganciclovir (CYTOVENE^® IV, VALCYTE^®), amphotericin B (ABELCET^®, AMBISOME^®), cisplatin, antiviral medicines called nucleoside reverse transcriptase inhibitors, antiviral medicines called protease inhibitors, water pill (diuretic), medicine to treat high blood pressure, nelfinavir (VIRACEPT^®), telaprevir (INCIVEK^®), boceprevir, ritonavir (KALETRA^®, NORVIR^®, TECHNIVIE^TM, VIEKIRA PAK^®, VIEKIRA XR^TM), letermovir (PREVYMIS^TM), ketoconazole, itraconazole (ONMEL^®, SPORANOX^®), voriconazole (VFEND^®), clarithromycin (BIAXIN^®, BIAXIN^® XL, PREVPAC^®), rifampin (RIFADIN^®, RIFAMATE^®, RIFATER^®, RIMACTANE^®), rifabutin (MYCOBUTIN^®), amiodarone (NEXTERONE^®, PACERONE^®).

Ask your healthcare provider or pharmacist if you are not sure if you take any of the medicines listed above. PROGRAF may affect the way other medicines work, and other medicines may affect how PROGRAF works. Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine.

How Should I Take PROGRAF?

• Take PROGRAF exactly as your healthcare provider tells you to take it.
• Your healthcare provider may change your PROGRAF dose if needed. Do not stop taking or change your dose of PROGRAF without talking to your healthcare provider.
• Take PROGRAF with or without food, the same way every day. For example, if you choose to take PROGRAF with food, you should always take PROGRAF with food.
• Take PROGRAF at the same time each day, 12 hours apart. For example, if you take your first dose at 7:00 a.m., you should take your second dose at 7:00 p.m. Taking PROGRAF at the same time each day helps to keep the amount of medicine in your body at a steady level.
• If you take too much PROGRAF, call your healthcare provider or go to the nearest hospital emergency room right away.

PROGRAF capsules:

• Do not open or crush PROGRAF capsules.

PROGRAF Granules:

• Children who have trouble swallowing capsules can be given PROGRAF Granules.
• Give the dose of PROGRAF Granules right after preparing. Do not save prepared PROGRAF Granules as a liquid to take at a later time.
• See the Instructions for Use at the end of the Patient Information for detailed instructions about how to mix and give PROGRAF Granules as a liquid.
• If you get the granules, or prepared oral suspension on your skin, wash the area well with soap and water.
• If you get the granules, or prepared oral suspension in your eyes, rinse with plain water.

What should I avoid while taking PROGRAF?

• While you take PROGRAF you should not receive any live vaccines.
• Limit the amount of time you spend in sunlight and avoid exposure to ultraviolet (UV) light, such as tanning machines. Wear protective clothing and use a sunscreen with a high sun protection factor (SPF).
• Do not eat grapefruit or drink grapefruit juice during treatment with PROGRAF.

PROGRAF may cause serious side effects, including:

• problems from medicine errors. People who take PROGRAF have sometimes been given the wrong type of tacrolimus product. Tacrolimus extended-release medicines are not the same as PROGRAF capsules or granules and cannot be substituted for each other. Check your PROGRAF when you get a new prescription and before you take it to make sure you have received PROGRAF capsules or PROGRAF Granules. Check with the pharmacist and call your healthcare provider if you think you were given the wrong medicine.
• high blood sugar (diabetes). Your healthcare provider may do blood tests to check for diabetes. Call your healthcare provider right away if you have any symptoms of high blood sugar, including: frequent urination, increased thirst or hunger, blurred vision, confusion, drowsiness, loss of appetite, fruity smell on your breath, nausea, vomiting, or stomach pain.
• kidney problems. Kidney problems are a serious and common side effect of PROGRAF. Your healthcare provider may do blood tests to check your kidney function.
• nervous system problems. Nervous system problems are a serious and common side effect of PROGRAF. Call your healthcare provider right away if you get any of these symptoms that could be signs of a serious nervous system problem: headache, confusion, seizures, changes in your vision, changes in behavior, coma, tremors, numbness and tingling.
• high levels of potassium in your blood. Your healthcare provider may do blood tests to check your potassium level.
• high blood pressure. High blood pressure is a serious and common side effect of PROGRAF. Your healthcare provider will monitor your blood pressure and may prescribe blood pressure medicine for you, if needed. Your healthcare provider may instruct you to check your blood pressure at home.
• changes in the electrical activity of your heart (QT prolongation).
• heart problems (myocardial hypertrophy). Tell your healthcare provider right away if you get any of these symptoms of heart problems: shortness of breath, chest pain, feel lightheaded, feel faint.
• severe low red blood cell count (anemia).

The most common side effects of PROGRAF in people who have received a kidney, liver, heart or lung transplant are: infections in general, including cytomegalovirus (cmv) infection, tremors (shaking of the body), constipation, diarrhea, headache, stomach pain, trouble sleeping, nausea, high blood sugar (diabetes), low levels of magnesium in your blood, low levels of phosphate in your blood, swelling of the hands, legs, ankles, or feet, weakness, pain, high levels of fat in your blood, high levels of potassium in your blood, low red blood cell count (anemia), low white blood cell count, fever, numbness or tingling in your hands and feet, inflammation of your airway (bronchitis), fluid around your heart.

Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of PROGRAF. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects.

General information about the safe and effective use of PROGRAF.

• Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use PROGRAF for a condition for which it was not prescribed. Do not give PROGRAF to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about PROGRAF that is written for health professionals.
• The Patient Information leaflet summarizes the most important information about PROGRAF. If you would like more information, talk to your healthcare provider.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088.

For full prescribing information, including boxed warning, please visit www.prograf.com or call Astellas at 1-800-727-7003.

About Astellas

Astellas Pharma Inc. is a pharmaceutical company conducting business in more than 70 countries around the world. We are promoting the Focus Area Approach that is designed to identify opportunities for the continuous creation of new drugs to address diseases with high unmet medical needs by focusing on Biology and Modality. Furthermore, we are also looking beyond our foundational Rx focus to create Rx+^® healthcare solutions that combine our expertise and knowledge with cutting-edge technology in different fields of external partners. Through these efforts, Astellas stands on the forefront of healthcare change to turn innovative science into value for patients. For more information, please visit our website at https://www.astellas.com/en.

Astellas Cautionary Notes

In this press release, statements made with respect to current plans, estimates, strategies and beliefs and other statements that are not historical facts are forward-looking statements about the future performance of Astellas. These statements are based on management's current assumptions and beliefs in light of the information currently available to it and involve known and unknown risks and uncertainties. A number of factors could cause actual results to differ materially from those discussed in the forward-looking statements. Such factors include, but are not limited to: (i) changes in general economic conditions and in laws and regulations, relating to pharmaceutical markets, (ii) currency exchange rate fluctuations, (iii) delays in new product launches, (iv) the inability of Astellas to market existing and new products effectively, (v) the inability of Astellas to continue to effectively research and develop products accepted by customers in highly competitive markets, and (vi) infringements of Astellas' intellectual property rights by third parties.

Information about pharmaceutical products (including products currently in development), which is included in this press release is not intended to constitute an advertisement or medical advice.

ⁱ Data on file. Northbrook, IL: Astellas Inc.

ⁱⁱ M. Valapour, C. J. Lehr, M. A. Skeans, J. M. Smith, K. Uccellini, R. Goff, J. Foutz, A. K. Israni, J. J. Snyder, B. L. Kasiske. "OPTN/SRTR 2018 Annual Data Report: Lung." American Journal of Transplantation, vol. 20, no. s1, 2020, pp. 427–508, doi:10.1111/ajt.15677.

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