Link to Original MedWatch: http://bit.ly/2ZoxeNe
AUDIENCE:Patient, Health Professional, Pharmacy, Gastroenterology, Rheumatology
ISSUE: FDA has approved new warnings about an increased risk of blood clots and of death with the 10 mg twice daily dose of tofacitinib (Xeljanz, Xeljanz XR), which is used in patients with ulcerative colitis. In addition, the approved use of tofacitinib for ulcerative colitis will be limited to certain patients who are not treated effectively or who experience severe side effects with certain other medicines. We approved these changes, including adding our most prominent Boxed Warning, after reviewing interim data from an ongoing safety clinical trial of tofacitinib in patients with rheumatoid arthritis (RA) that examined a lower and this higher dose of the medicine.
BACKGROUND:Tofacitinib works by decreasing the activity of the immune system; an overactive immune system contributes to RA, PsA, and ulcerative colitis. Tofacitinib was first approved in 2012 to treat adult patients with RA who did not respond well to the medicine methotrexate. When FDA first approved tofacitinib in 2012, FDA required a post-marketing clinical trial in patients with RA on background methotrexate, to evaluate the risk of heart-related events, cancer, and infections. The trial is studying two different doses of tofacitinib (5 mg twice daily, which is the currently approved dose for RA, and a higher, 10 mg twice daily dosage) in comparison to a TNF blocker. In RA, the body attacks its own joints, causing pain, swelling, and loss of function. An interim analysis of the trial's results found an increased occurrence of blood clots and of death in patients treated with tofacitinib 10 mg twice daily compared to patients treated with tofacitinib 5 mg twice daily or a TNF blocker. In 2017, we approved the medicine to treat patients with a second condition that causes joint pain and swelling, PsA, who did not respond well to methotrexate or other similar medicines. In 2018, we approved tofacitinib to treat ulcerative colitis, which is a chronic, inflammatory disease affecting the colon.
Patients: Tell your health care professionals if you have a history of blood clots or heart problems, and talk to them about any questions or concerns. Stop taking tofacitinib and seek emergency medical attention right away if you experience any unusual symptoms, including those that may signal a blood clot such as:
- Sudden shortness of breath
- Chest pain that worsens with breathing
- Swelling of a leg or arm
- Leg pain or tenderness, or red or discolored skin in the painful or swollen leg or arm
Do not stop taking tofacitinib without first talking to your health care professional, as doing so can worsen your condition.
Healthcare professionals: Discontinue tofacitinib and promptly evaluate patients with symptoms of thrombosis. Counsel patients about the risks and advise them to seek medical attention immediately if they experience any unusual symptoms, including those of thrombosis listed above. Reserve tofacitinib to treat ulcerative colitis for patients who have failed or do not tolerate tumor necrosis factor (TNF) blockers. Avoid tofacitinib in patients who may have a higher risk of thrombosis. When treating ulcerative colitis, use tofacitinib at the lowest effective dose and limit the use of the 10 mg twice daily dosage to the shortest duration needed (See Additional Information for Health Care Professionals for more recommendations).
AUDIENCE: Patient, Health Professional, Pharmacy, Rheumatology
ISSUE: FDA is alerting the public that a safety clinical trial found an increased risk of blood clots in the lungs and death when a 10 mg twice daily dose of tofacitinib (Xeljanz, Xeljanz XR) was used in patients with rheumatoid arthritis (RA). FDA has not approved this 10 mg twice daily dose for RA; this dose is only approved in the dosing regimen for patients with ulcerative colitis
BACKGROUND: When FDA first approved tofacitinib, we required a clinical trial among patients with RA to evaluate the risk of heart-related events, cancer, and opportunistic infections with the medicine at two doses (10 mg twice daily and 5 mg twice daily) in combination with methotrexate in comparison to another drug called a tumor necrosis factor (TNF) inhibitor. RA patients in the trial were required to be at least 50 years old and have at least one cardiovascular risk factor. During the most recent analysis of the trial, an external data safety monitoring committee found an increased occurrence of blood clots in the lungs and death in patients treated with tofacitinib 10 mg twice daily compared to patients treated with tofacitinib 5 mg twice daily or a TNF inhibitor.
RECOMMENDATION: Health care professionals should follow the recommendations in the tofacitinib prescribing information, available at: http://bit.ly/2TFrD5t, for the specific condition they are treating. Monitor patients for the signs and symptoms of pulmonary embolism, and advise them to seek medical attention immediately if they experience them.
Patients should not stop or change your dose of tofacitinib without first talking to your health care professional, as doing so may worsen your condition. Patients taking tofacitinib should seek medical attention immediately if you experience symptoms of a blood clot in your lungs or other unusual symptoms such as:
- Sudden shortness of breath or difficulty breathing
- Chest pain or pain in your back
- Coughing up blood
- Excessive sweating
- Clammy or bluish colored skin
For more information visit the FDA website at: http://www.fda.gov/Safety/MedWatch/SafetyInformation and http://www.fda.gov/Drugs/DrugSafety.
Using tofacitinib may decrease your ability to fight infection and increase the risk that you will get a serious infection, including severe fungal, bacterial, or viral infections that spread through the body. These infections may need to be treated in a hospital and may cause death. Tell your doctor if you often get any type of infection or if you think you may have any type of infection now. This includes minor infections (such as open cuts or sores), infections that come and go (such as cold sores), and chronic infections that do not go away. Also tell your doctor if you have or have ever had diabetes, human immunodeficiency virus (HIV), acquired immunodeficiency syndrome (AIDS), a lung disease, or any other condition that affects your immune system. You should also tell your doctor if you live or have ever lived in areas such as the Ohio or Mississippi river valleys where severe fungal infections are more common. Ask your doctor if you are not sure if these infections are common in your area. Tell your doctor if you are taking medications that decrease the activity of the immune system such as the following: abatacept (Orencia); adalimumab (Humira); anakinra (Kineret); azathioprine (Azasan, Imuran); certolizumab (Cimzia); cyclosporine (Gengraf, Neoral, Sandimmune); etanercept (Enbrel); golimumab (Simponi); infliximab (Remicade); methotrexate (Otrexup, Rasuvo, Trexall); rituximab (Rituxan); steroids including dexamethasone, methylprednisolone (Medrol), prednisolone (Prelone), and prednisone (Rayos); tacrolimus (Astagraf, Envarsus XR, Prograf); and tocilizumab (Actemra).
Your doctor will monitor you for signs of infection during and after your treatment. If you have any of the following symptoms before you begin your treatment or if you experience any of the following symptoms during or shortly after your treatment, call your doctor immediately: fever; sweating; chills; muscle aches; cough; shortness of breath; weight loss; warm, red, or painful skin; sores on the skin; frequent, painful, or burning feeling during urination; diarrhea, or excessive tiredness.
You may already be infected with tuberculosis (TB; a serious lung infection) but not have any symptoms of the disease. In this case, using tofacitinib may make your infection more serious and cause you to develop symptoms. Your doctor will perform a skin test to see if you have an inactive TB infection before you begin your treatment with tofacitinib. If necessary, your doctor will give you medication to treat this infection before you start using tofacitinib. Tell your doctor if you have or have ever had TB, if you have lived in or visited a country where TB is common, or if you have been around someone who has TB. If you have any of the following symptoms of TB, or if you develop any of these symptoms during your treatment, call your doctor immediately: cough, coughing up bloody mucus, weight loss, loss of muscle tone, or fever.
Taking tofacitinib may increase the risk that you will develop a lymphoma (cancer that begins in the cells that fight infection) or other types of cancers. Some people who took tofacitinib with other medications after they had a kidney transplant developed a condition that caused their bodies to produce too many white blood cells. Tell your doctor if you have or have ever had any type of cancer or have had a kidney transplant.
Your doctor or pharmacist will give you the manufacturer's patient information sheet (Medication Guide) when you begin treatment with tofacitinib and each time you refill your prescription. Read the information carefully and ask your doctor or pharmacist if you have any questions. You can also visit the Food and Drug Administration (FDA) website (http://www.fda.gov/Drugs/DrugSafety/ucm085729.htm) or the manufacturer's website to obtain the Medication Guide.
Why is this medication prescribed?
Tofacitinib is used alone or with other medications to treat rheumatoid arthritis (condition in which the body attacks its own joints causing pain, swelling, and loss of function) in people who did not respond to methotrexate (Otrexup, Rasuvo, Trexall). It is also used along with methotrexate or certain similar medications to treat psoriatic arthritis (a condition that causes joint pain and swelling and scales on the skin) in people who did not respond to these medications alone. Tofacitinib is used to treat ulcerative colitis (a condition which causes swelling and sores in the lining of the colon [large intestine] and rectum). Tofacitinib is in a class of medications called Janus kinase (JAK) inhibitors. It works by decreasing the activity of the immune system.
How should this medicine be used?
Tofacitinib comes as a tablet and as an extended-release (long-acting) tablet to take by mouth. For treatment of ulcerative colitis, rheumatoid arthritis, or psoriatic arthritis, the tablet is usually taken with or without food twice a day . For treatment of rheumatoid arthritis or psoriatic arthritis, the extended-release tablet is usually taken with or without food once daily . Take tofacitinib at around the same time(s) every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take tofacitinib exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.
Swallow the extended-release tablets whole; do not split, chew, or crush them.
Your doctor may need to decrease your dose or stop your treatment if you experience certain severe side effects. Be sure to tell your doctor how you are feeling during your treatment.
Tofacitinib may help control your condition but will not cure it. Continue to take tofacitinib even if you feel well. Do not stop taking tofacitinib without talking to your doctor.
Other uses for this medicine
This medication may be prescribed for other uses; ask your doctor or pharmacist for more information.
What special precautions should I follow?
Before taking tofacitinib,
- tell your doctor and pharmacist if you are allergic to tofacitinib, any other medications, or any of the ingredients in tofacitinib preparations. Ask your pharmacist or check the Medication Guide for a list of the ingredients.
- tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, and nutritional supplements you are taking or plan to take. Be sure to mention the medications listed in the IMPORTANT WARNING section and any of the following: certain antifungal medications such as fluconazole (Diflucan), itraconazole (Onmel, Sporanox), and ketoconazole; aspirin and other nonsteroidal anti-inflammatory medications (NSAIDs) such as ibuprofen (Advil, Motrin) and naproxen (Naprosyn, Aleve); carbamazepine (Carbatrol, Tegretol, Equetro, others); clarithromycin (Biaxin, in Prevpac); certain medications for HIV including indinavir (Crixivan), nelfinavir (Viracept), and ritonavir (Norvir, in Kaletra); nefazodone; phenobarbital; phenytoin (Dilantin, Phenytek); rifabutin (Mycobutin), and rifampin (Rifadin, Rimactane, in Rifamate, in Rifater). Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
- tell your doctor what herbal products you are taking, especially St. John's wort.
- tell your doctor if you have stomach pain that has not been diagnosed and if you have or have ever had ulcers (sores in the lining of your stomach or intestine), diverticulitis (swelling of the lining of the large intestine), liver disease including hepatitis B or hepatitis C, herpes zoster (shingles; a rash that can occur in people who have had chickenpox in the past), anemia (a lower than normal number of red blood cells), or kidney disease. If you are taking the extended-release tablets, tell your doctor if you have a narrowing or blockage of your digestive system.
- tell your doctor if you are pregnant or plan to become pregnant. You should not become pregnant while you are taking tofacitinib.If you become pregnant while taking tofacitinib, call your doctor.
- tell your doctor if you are breastfeeding. Do not breastfeed while you are taking tofacitinib and for at least 18 hours after the final dose of the tablet or for at least 36 hours after the final dose of the extended-release tablet.
- you should know that this medication may decrease fertility in women. Talk to your doctor about the risks of taking tofacitinib.
- tell your doctor if you have recently received or are scheduled to receive any vaccinations. If you need any vaccinations, you may have to receive the vaccinations and then wait some time before beginning your treatment with tofacitinib. Do not have any vaccinations during your treatment without talking to your doctor.
What special dietary instructions should I follow?
Unless your doctor tells you otherwise, continue your normal diet.
What should I do if I forget a dose?
Take the missed dose as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.
What side effects can this medication cause?
Tofacitinib may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:
- stuffy or runny nose
Some side effects can be serious. If you experience any of these symptoms or those listed in the IMPORTANT WARNING section, call your doctor immediately or get emergency medical treatment:
- stomach pain, especially if it comes along with fever and diarrhea or constipation
- yellowing of the skin or eyes
- loss of appetite
- dark urine
- clay-colored bowel movements
- pale skin
- shortness of breath
Tofacitinib may cause an increase in your blood cholesterol levels. Your doctor will order tests to monitor your cholesterol levels during your treatment with tofacitinib. Talk to your doctor about the risks of taking this medication.
Tofacitinib may cause other side effects. Call your doctor if you have any unusual problems while taking this medication.
If you experience a serious side effect, you or your doctor may send a report to the Food and Drug Administration's (FDA) MedWatch Adverse Event Reporting program online (http://www.fda.gov/Safety/MedWatch) or by phone (1-800-332-1088).
What should I know about storage and disposal of this medication?
Keep this medication in the container it came in, tightly closed, and out of reach of children. Store it at room temperature and away from excess heat and moisture (not in the bathroom).
It is important to keep all medication out of sight and reach of children as many containers (such as weekly pill minders and those for eye drops, creams, patches, and inhalers) are not child-resistant and young children can open them easily. To protect young children from poisoning, always lock safety caps and immediately place the medication in a safe location – one that is up and away and out of their sight and reach. http://www.upandaway.org
Unneeded medications should be disposed of in special ways to ensure that pets, children, and other people cannot consume them. However, you should not flush this medication down the toilet. Instead, the best way to dispose of your medication is through a medicine take-back program. Talk to your pharmacist or contact your local garbage/recycling department to learn about take-back programs in your community. See the FDA's Safe Disposal of Medicines website (http://goo.gl/c4Rm4p) for more information if you do not have access to a take-back program.
In case of emergency/overdose
In case of overdose, call the poison control helpline at 1-800-222-1222. Information is also available online at https://www.poisonhelp.org/help. If the victim has collapsed, had a seizure, has trouble breathing, or can't be awakened, immediately call emergency services at 911.
What other information should I know?
Keep all appointments with your doctor and the laboratory. Your doctor will order certain lab tests before and during your treatment to check your body's response to tofacitinib.
If you are taking the extended-release tablets you may notice something that looks like a tablet in your bowel movement. This is just the empty tablet shell, and this does not mean that you did not get your full dose of medication.
Do not let anyone else take your medication. Ask your pharmacist any questions you have about refilling your prescription.
It is important for you to keep a written list of all of the prescription and nonprescription (over-the-counter) medicines you are taking, as well as any products such as vitamins, minerals, or other dietary supplements. You should bring this list with you each time you visit a doctor or if you are admitted to a hospital. It is also important information to carry with you in case of emergencies.
- Xeljanz® XR