Ruxolitinib

Ruxolitinib may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• dizziness
• headache
• tiredness
• weakness
• shortness of breath
• weight gain
• gas

Some side effects can be serious. If you experience any of these symptoms, call your doctor immediately:

• unusual bleeding or bruising
• fever, sore throat, chills, cough, and other signs of infection
• burning, tingling, itching, or skin sensitivity on one side of the body or face with painful rash or blisters appearing several days later.

Ruxolitinib 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).

Contraindications

Hypersensitivity

Cautions

Nonmelanoma skin cancers reporrted including basal cell, squamous cell, and Merkel cell carcinoma

Thrombocytopenia, anemia, & neutropenia

• CBC must be performed before initiating therapy and should be monitored as clinically indicated and dosing adjusted as required
• Patients with platelet counts <200 x10^9/L at the start of therapy are more likely to develop thrombocytopenia during treatment
• Thrombocytopenia was generally reversible and was usually managed by reducing the dose or temporarily withholding dose (see Adult Dosing); if clinically indicated, platelet transfusions may be administered
• Anemia may require blood transfusions; dose modifications may also be considered
• Neutropenia (ANC <0.5 x10^9/L) was generally reversible and was managed by temporarily withholding dose

Infections

• Patients should be assessed for the risk of developing serious bacterial, mycobacterial, fungal, and viral infections
• Active serious infections should have resolved before starting therapy
• Tuberculosis (TB) infection has been reported; before initiating, evaluate patients for TB risk factors, and those at higher risk should be tested for latent infection
• Carefully observe patients for signs and symptoms of infection and initiate appropriate treatment promptly
• Herpes zoster: Inform patients about early signs and symptoms of herpes zoster and advise to seek treatment as early as possible
• Progressive multifocal leukoencephalopathy (PML): Reported with ruxolitinib treatment for myelofibrosis; if suspected, discontinue drug and evaluate
• Hepatitis B viral load (HBV-DNA titer) increases, with or without associated elevations in alanine aminotransferase and aspartate aminotransferase, reported in patients with chronic HBV infection; effect of ruxolitinib on viral replication unknown; treat and monitor patients with chronic HBV infection according to clinical guidelines

CYP3A4 inhibitors

• Ruxolitinib is predominantly metabolized by CYP3A4
• Strong CYP3A4 inhibitors increase ruxolitinib Cmax and AUC 33% and 91%, respectively
• Dose modification recommended when coadministered with strong CYP3A4 inhibitors (such as but not limited to boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole); see Adult Dosing

Symptoms with dose interruption, dose tapering, or discontinuing

• Following discontinuation/interruption, myelofibrosis symptoms may be exacerbated and general return to pretreatment levels after 1 week
• Other adverse effects reported include fever, respiratory distress, hypotension, DIC, or multiorgan failure
• If these symptoms occur after discontinuation or dose tapering, evaluate and treat any intercurrent illness and consider restarting ruxolitinib or increase the dose
• Instruct patients not to interrupt or discontinue ruxolitinib without consulting their physician
• When discontinuing or interrupting therapy for reasons other than thrombocytopenia or neutropenia, consider tapering the dose gradually rather than discontinuing abruptly

Hyperlipidemia

• Treatment has been associated with increases in lipid parameters including total cholesterol, low density lipoprotein, and triglycerides; assess lipid parameters approximately 8-12 weeks following initiation of therapy; monitor according to clinical guidelines for management of hyperlipidemia

• Leukemia

• Take ruxolitinib exactly as your healthcare provider tells you.
• Do not change your dose or stop taking ruxolitinib without first talking to your healthcare provider.
• You can take ruxolitinib with or without food.
• Ruxolitinib may also be given through certain nasogastric tubes.
  • Tell your healthcare provider if you cannot take ruxolitinib by mouth. Your healthcare provider will decide if you can take ruxolitinib through a nasogastric tube.
  • Ask your healthcare provider to give you specific instruction on how to properly take ruxolitinib through a nasogastric tube.
• Do not drink grapefruit juice while taking ruxolitinib. Grapefruit juice can affect the amount of ruxolitinib in your blood.
• If you take too much ruxolitinib call your healthcare provider or go to the nearest hospital emergency room department right away. Take the bottle of ruxolitinib with you.
• If you miss a dose of ruxolitinib, take your next dose at your regular time. Do not take 2 doses at the same time.
• You will have regular blood tests during your treatment with ruxolitinib. Your healthcare provider may change your dose of ruxolitinib or stop your treatment based on the results of your blood tests.

• Store ruxolitinib at room temperature between 68°F and 77°F (20°C and 25°C).
• Keep this and all medicines out of the reach of children.

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

Some side effects may be similar to the symptoms of myelofibrosis. Call your doctor at once if you have a serious side effect such as:

• pain or burning when you urinate;

• nausea, vomiting, weakness;

• blisters or painful skin rash;

• unusual pain or general ill feeling;

• changes in the size, shape, or color of a mole or skin lesion;

• low red blood cells (anemia)--pale skin, feeling light-headed or short of breath, rapid heart rate, trouble concentrating;

• low platelets--easy bruising, unusual bleeding (nose, mouth, vagina, or rectum), purple or red pinpoint spots under your skin; or

• low white blood cell counts--fever, swollen gums, painful mouth sores, pain when swallowing, skin sores, cold or flu symptoms, cough, trouble breathing.

Common side effects may include:

• anemia;

• low platelets (easy bruising);

• dizziness; or

• headache.

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.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of infection like fever, chills, very bad sore throat, ear or sinus pain, cough, more sputum or change in color of sputum, pain with passing urine, mouth sores, or wound that will not heal.
• Signs of bleeding like throwing up blood or throw up that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; vaginal bleeding that is not normal; bruises without a reason or that get bigger; or any bleeding that is very bad or that you cannot stop.
• Painful skin rash with blisters.
• Upset stomach or throwing up.
• Shortness of breath.
• Feeling tired or weak.
• Swelling.
• A very bad brain problem called progressive multifocal leukoencephalopathy (PML) has happened with ruxolitinib. It may cause disability or can be deadly. Tell your doctor right away if you have signs like confusion, memory problems, low mood (depression), change in the way you act, change in strength on 1 side is greater than the other, trouble speaking or thinking, change in balance, or change in eyesight.
• Certain types of skin cancer have happened in people taking this medicine. Call your doctor right away if you have a change in color or size of a mole, or any new or changing skin lump or growth.

Oral: May be administered orally with or without food. If a dose is missed, return to the usual dosing schedule and do not administer an additional dose.

If unable to ingest tablets, may administer through a nasogastric (NG) tube (≥8 Fr): Suspend 1 tablet in ~40 mL water and stir for ~10 minutes and administer (within 6 hours after dispersion) with appropriate syringe; rinse NG tube with ~75 mL water (effect of enteral tube feeding on ruxolitinib exposure has not been evaluated)

Aprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Bradycardia-Causing Agents: Ruxolitinib may enhance the bradycardic effect of Bradycardia-Causing Agents. Management: Ruxolitinib Canadian product labeling recommends avoiding use with bradycardia-causing agents to the extent possible. Monitor therapy

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Ruxolitinib. Management: This combination should be avoided under some circumstances. See monograph for details. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Fluconazole: May increase the serum concentration of Ruxolitinib. Management: This combination should be avoided under some circumstances. See monograph for details. Consider therapy modification

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Grapefruit Juice: May increase the serum concentration of Ruxolitinib. Management: This combination should be avoided under some circumstances. See monograph for details. Consider therapy modification

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates. Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

Mitotane: May decrease the serum concentration of CYP3A4 Substrates. Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Netupitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

St John's Wort: May decrease the serum concentration of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Consider therapy modification

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination

Increased resorptions (late) and reduced fetal weights were observed in animal reproduction studies.

Applies to ruxolitinib: oral tablet

Along with its needed effects, ruxolitinib 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 while taking ruxolitinib:

• Black, tarry stools
• bladder pain
• bleeding gums
• blood in the urine or stools
• bruising
• chills
• cloudy urine
• collection of blood under the skin
• cough
• deep, dark purple bruise
• difficult, burning, or painful urination
• fever
• frequent urge to urinate
• itching, pain, redness, or swelling
• large, flat, blue or purplish patches in the skin
• lower back or side pain
• painful or difficult urination
• pale skin
• pinpoint red spots on the skin
• pus in the urine
• shortness of breath
• small, red or purple spots on the skin
• sore throat
• troubled breathing with exertion
• ulcers, sores, or white spots in the mouth
• unusual bleeding or bruising
• unusual tiredness or weakness

• Painful blisters on the trunk of the body

Some side effects of ruxolitinib 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:

• Bloated or full feeling
• dizziness or lightheadedness
• excess air or gas in the stomach or intestines
• feeling of constant movement of self or surroundings
• headache
• passing gas
• sensation of spinning
• weight gain

Hepatic impairment:
-Platelets 100 to 150 x 10(9)/L: Initial dose: 10 mg twice a day
-Platelets less than 100 x 10(9)/L: Not recommended