Tofacitinib

Tofacitinib is a prescription medication used to treat rheumatoid arthritis in adult patients who have been treated with methotrexate without success.

Rheumatoid arthritis is a disease of the immune system. Tofacitinib belongs to a group of drugs called JAK inhibitors which work by suppressing the immune system against the damaging inflammation of rheumatoid arthritis.

This medication comes in tablet form and is taken once or twice daily, with or without food.

Common side effects of tofacitinib include runny or stuffy nose, headaches, and diarrhea.

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Tofacitinib and other medicines may affect each other causing side effects.

Especially tell your healthcare provider if you take:

• any other medicines to treat your rheumatoid arthritis. You should not take tocilizumab (Actemra), etanercept (Enbrel), adalimumab (Humira), infliximab (Remicade), rituximab (Rituxan), abatacept (Orencia), anakinra (Kineret), certolizumab (Cimzia), golimumab (Simponi), azathioprine, cyclosporine, or other immunosuppressive drugs while you are taking tofacitinib. Taking tofacitinib with these medicines may increase your risk of infection.
• medicines that affect the way certain liver enzymes work. Ask your healthcare provider if you are not sure if your medicine is one of these.

Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.

Hepatitis B or C activation infection in people who carry the virus in their blood. Tell your healthcare provider if you have any of the following symptoms of a possible hepatitis B or C infection:

• feel very tired
• skin or eyes look yellow
• little or no appetite
• vomiting
• clay-colored bowel movements
• fevers
• chills
• stomach discomfort
• muscle aches
• dark urine
• skin rash

Serious infections. Tofacitinib can lower the ability of your immune system to fight infections. Some people have serious infections while taking tofacitinib, including tuberculosis (TB), and infections caused by bacteria, fungi, or viruses that can spread throughout the body. Some people have died from these infections.

• Your healthcare provider should test you for TB before starting tofacitinib.
• Your healthcare provider should monitor you closely for signs and symptoms of TB infection during treatment with tofacitinib.

You should not start taking tofacitinib if you have any kind of infection unless your healthcare provider tells you it is okay.

Before starting tofacitinib, tell your healthcare provider if you:

• think you have an infection or have symptoms of an infection such as:
  • fever, sweating, or chills
  • muscle aches 
  • cough 
  • shortness of breath 
  • blood in phlegm 
  • weight loss
  • warm, red, or painful skin or sores on your body 
  • diarrhea or stomach pain 
  • burning when you urinate or urinating more often than normal 
  • feeling very tired
• are being treated for an infection
• get a lot of infections or have infections that keep coming back
• have diabetes, HIV, or a weak immune system. People with these conditions have a higher chance for infections.
• have TB, or have been in close contact with someone with TB
• live or have lived, or have traveled to certain parts of the country (such as the Ohio and Mississippi River valleys and the Southwest) where there is an increased chance for getting certain kinds of fungal infections (histoplasmosis, coccidioidomycosis, or blastomycosis). These infections may happen or become more severe if you use tofacitinib. Ask your healthcare provider if you do not know if you have lived in an area where these infections are common.
• have or have had hepatitis B or C

Cancer and immune system problems. Tofacitinib may increase your risk of certain cancers by changing the way your immune system works.

• Lymphoma and other cancers can happen in patients taking tofacitinib. Tell your healthcare provider if you have ever had any type of cancer.
• Some people who have taken tofacitinib with certain other medicines to prevent kidney transplant rejection have had a problem with certain white blood cells growing out of control (Epstein Barr Virus-associated post transplant lymphoproliferative disorder).

Tears (perforation) in the stomach or intestines. Tell your healthcare provider if you have had diverticulitis (inflammation in parts of the large intestine) or ulcers in your stomach or intestines. Some people taking tofacitinib get tears in their stomach or intestine. This happens most often in people who also take nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, or methotrexate.

• Tell your healthcare provider right away if you have fever and stomach-area pain that does not go away, and a change in your bowel habits.

Changes in certain laboratory test results. Your healthcare provider should do blood tests before you start receiving tofacitinib and while you take tofacitinib to check for the following side effects:

• changes in lymphocyte counts. Lymphocytes are white blood cells that help the body fight off infections.
• low neutrophil counts. Neutrophils are white blood cells that help the body fight off infections.
• low red blood cell count. This may mean that you have anemia, which may make you feel weak and tired.

Your healthcare provider should routinely check certain liver tests.

You should not receive tofacitinib if your lymphocyte count, neutrophil count, or red blood cell count is too low or your liver tests are too high.

Your healthcare provider may stop your tofacitinib treatment for a period of time if needed because of changes in these blood test results.

You may also have changes in other laboratory tests, such as your blood cholesterol levels.

Your healthcare provider should do blood tests to check your cholesterol levels 4 to 8 weeks after you start receiving tofacitinib, and as needed after that. Normal cholesterol levels are important to good heart health.

Medicines can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of tofacitinib there are no specific foods that you must exclude from your diet when receiving tofacitinib.

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Serious and sometimes fatal infections may occur during treatment with tofacitinib. Stop using this medicine and call your doctor right away if you have signs of infection such as:

• fever, chills, tired feeling, night sweats;

• stomach pain, loss of appetite, diarrhea, weight loss, or a change in your bowel habits;

• pain or burning when you urinate;

• body aches, sore throat, cough, flu symptoms, sores in your mouth and throat;

• stabbing chest pain, wheezing, feeling short of breath, cough with mucus or blood; or

• skin redness and swelling.

Tofacitinib may also cause severe liver symptoms. Call your doctor at once if you have any of these liver symptoms:

• low fever, itching, tiredness;

• upper stomach pain, loss of appetite;

• dark urine, clay-colored stools; or

• jaundice (yellowing of the skin or eyes).

Common side effects may include:

• headache;

• diarrhea; or

• cold symptoms such as stuffy nose, sneezing, sore throat.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Bladder pain
• bloody or cloudy urine
• blurred vision
• body aches or pain
• chills
• cough
• difficult, burning, or painful urination
• difficulty breathing
• dizziness
• ear congestion
• fever
• frequent urge to urinate
• headache
• loss of voice
• lower back or side pain
• muscle aches
• nervousness
• pounding in the ears
• slow or fast heartbeat
• sneezing
• sore throat
• stuffy or runny nose
• unusual tiredness or weakness

• Bloating or swelling of the face, arms, hands, lower legs, or feet
• confusion
• dark urine
• decreased urination
• difficult or labored breathing
• dry mouth
• fainting
• increase in heart rate
• light-colored stools
• lightheadedness
• nausea and vomiting
• pale skin
• persistent non-healing sore
• rapid breathing
• rapid weight gain
• reddish patch or irritated area
• sunken eyes
• thirst
• tightness in the chest
• tingling of the hands or feet
• troubled breathing with exertion
• unusual bleeding or bruising
• unusual weight gain or loss
• upper right abdominal or stomach pain
• wrinkled skin
• yellow eyes and skin

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Diarrhea

• Acid or sour stomach
• belching
• burning feeling in the chest or stomach
• burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
• difficulty with moving
• flushing or redness of the skin
• heartburn
• indigestion
• itching skin or rash
• muscle pain or stiffness
• pain in the joints
• stomach discomfort, upset, or pain
• tenderness in the stomach area
• trouble sleeping
• unusually warm skin

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Tofacitinib inhibits Janus kinase (JAK) enzymes, which are intracellular enzymes involved in stimulating hematopoiesis and immune cell function through a signaling pathway. In response to extracellular cytokine or growth factor signaling, JAKs activate signal transducers and activators of transcription (STATs), which regulate gene expression and intracellular activity. Inhibition of JAKs prevents cytokine- or growth factor-mediated gene expression and intracellular activity of immune cells, reduces circulating CD16/56+ natural killer cells, serum IgG, IgM, IgA, and C-reactive protein, and increases B cells.

Absorption

Oral:

Immediate release: Rapid (74%); Cmax is reduced by 32% when administered with high-fat meal, but AUC remains unchanged.

Extended release: Cmax increased by 27% and Tmax was extended by ~1 hour when administered with high-fat meal, but AUC remains unchanged.

Distribution

Vd: 87 L

Metabolism

Hepatic (70%): CYP3A4 and CYP2C19 to inactive metabolites

Excretion

Primarily urine (30%) as unchanged drug

Time to Peak

0.5 to 1 hour (immediate release); 4 hours (extended release)

Half-Life Elimination

~3 hours (immediate release); ~6 hours (extended release)

Protein Binding

~40% (predominantly to albumin)

AUC and Cmax increased ~1.5-fold in moderate hepatic impairment.

Refer to adult dosing.

Mild impairment: No dosage adjustment necessary.

Moderate to severe impairment: Reduce dose to 5 mg (immediate release) once daily. A supplemental dose after dialysis is not necessary in patients with severe impairment on dialysis. Note: Tofacitinib has not been studied in patients with baseline CrCl <40 mL/minute.

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience rhinorrhea, rhinitis, cough, or pharyngitis. Have patient report immediately to prescriber signs of infection; signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes); mole changes; skin growths; bruising; bleeding; severe headache; pain with urination; severe skin irritation; loss of strength and energy; severe abdominal pain; severe diarrhea; black, tarry, or bloody stools; vomiting blood; shortness of breath; muscle pain; muscle weakness; bradycardia; arrhythmia; weight loss; or swelling of arms or legs (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.