Tocilizumab

Common Side Effects of Actemra

Tell your doctor if any of the following side effects become severe or don't go away:

• Headache
• Sneezing
• Runny nose
• Mild itching, redness, pain, or swelling at the injection site

Serious Side Effects of Actemra

Tell your doctor right away if you experience any of the side effects listed in the Actemra Warnings section above, or any of the following symptoms:

• Flushing
• Itching
• Rash or hives
• Swelling of the eyes, face, lips, tongue, throat, arms, hands, ankles, feet, or lower legs
• Difficulty swallowing
• Vomiting
• Dizziness or fainting
• Changes in bowel habits
• Unusual bruising or bleeding

Actemra is given as an intravenous infusion or a subcutaneous injection (just under the skin).

Your dose will depend on your age and medical condition, plus other factors.

The medicine is typically given once a week, once every two weeks, or once every four weeks.

An Actemra infusion is administered at a hospital or doctor's office and typically takes about an hour.

You may be shown how to inject Actemra under the skin at home, using a prefilled syringe. Be sure to follow your doctor's instructions carefully.

Each prefilled syringe is for one use only. Don't reuse a syringe.

You can inject Actemra on the front of your thighs, or anywhere on your stomach except your navel and the area 2 inches around it.

Try to choose a different injection site each time you give yourself Actemra.

Be sure to use this medicine before the expiration date on the drug label.

Don't use Actemra if the medicine has changed colors or has particles in it.

Actemra Overdose

If you suspect an overdose, contact a poison control center or emergency room immediately.

You can get in touch with a poison control center at 800-222-1222.

Missed Dose of Actemra

Call your doctor if you miss an appointment to receive a dose of Actemra.

If you forget to inject the medicine, give yourself an injection as soon as you remember.

But if it's almost time for your next scheduled dose, skip the missed dose and continue with your regular injection schedule.

Don't inject two doses of Actemra to make up for a missed dose.

Serious and sometimes fatal infections may occur during treatment with tocilizumab. Stop using this medicine and call your doctor right away if you have signs of infection such as: fever, chills, body aches, flu symptoms, cough, sweating, feeling short of breath, diarrhea, weight loss, sores on your skin, painful urination, or feeling very tired.

Before you start treatment with tocilizumab, your doctor may perform tests to make sure you do not have tuberculosis or other infections. While using tocilizumab, you may need frequent medical tests.

You should not use tocilizumab if you are allergic to it.

Tell your doctor if you have ever had tuberculosis, if anyone in your household has tuberculosis, or if you have recently traveled to an area where certain infections are common (Ohio River Valley, Mississippi River Valley, and the Southwest).

Tell your doctor if you have any signs of infection such as fever, chills, cough, body aches, tiredness, open sores or skin wounds, diarrhea, stomach pain, weight loss, painful urination, or coughing up blood.

To make sure tocilizumab is safe for you, tell your doctor if you have ever had:

• an infection such as herpes, pneumonia, or yeast infection;

• liver disease;

• diverticulitis, stomach ulcer, or stomach or intestinal bleeding;

• diabetes;

• HIV or AIDS;

• a weak immune system;

• hepatitis B (or if you are a carrier of the virus);

• a nerve-muscle disease such as multiple sclerosis;

• cancer; or

• if you have received or are scheduled to receive any vaccines.

Treatment with tocilizumab may increase your risk of developing certain types of cancer. Talk to your doctor about your specific risk.

It is not known whether this medicine will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant.

If you are pregnant, your name may be listed on a pregnancy registry. This is to track the outcome of the pregnancy and to evaluate any effects of tocilizumab on the baby.

It is not known whether tocilizumab passes into breast milk. You should not breast-feed while you are using tocilizumab.

Avoid being near people who are sick or have infections. Tell your doctor at once if you develop signs of infection.

Do not receive a "live" vaccine while using tocilizumab. The vaccine may not work as well during this time, and may not fully protect you from disease. Live vaccines include measles, mumps, rubella (MMR), polio, rotavirus, typhoid, yellow fever, varicella (chickenpox), zoster (shingles), and nasal flu (influenza) vaccine.

Get emergency medical help if you have signs of an allergic reaction: hives; chest pain, difficulty breathing, feeling like you might pass out; swelling of your face, lips, tongue, or throat.

Serious and sometimes fatal infections may occur during treatment with tocilizumab. Call your doctor right away if you have signs of infection such as:

• fever, chills, muscle pain, night sweats, mouth sores, white patches in your throat, weight loss, feeling very tired;

• fast heart rate, rapid breathing, chest pain, wheezing, cough, shortness of breath;

• redness or swelling under your skin, painful skin sores, blistering skin rash with burning or tingly feeling;

• watery diarrhea, pain or burning when you urinate;

• blurred vision, bone pain, confusion, headache, nausea, swollen glands.; or

• severe skin reaction--fever, sore throat, swelling in your face or tongue, burning in your eyes, skin pain, followed by a red or purple skin rash that spreads (especially in the face or upper body) and causes blistering and peeling.

Also call your doctor at once if you have:

• severe stomach cramps, bloating, diarrhea or constipation;

• black, bloody, or tarry stools;

• coughing up blood or vomit that looks like coffee grounds; or

• signs of perforation (a hole or tear) in your stomach or intestines--fever, ongoing stomach pain, change in bowel habits.

Common side effects may include:

• runny or stuffy nose, sinus pain, sore throat;

• headache;

• high blood pressure (blurred vision, buzzing in your ears, anxiety, confusion, shortness of breath, uneven heartbeats); or

• pain, swelling, burning, or irritation around the IV needle or where an injection was given.

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.

• Actemra

Cytokine release syndrome (severe or life-threatening)

Data from small retrospective reviews, case reports, and clinical experience suggest that tocilizumab may be effective in adult and pediatric patients for the management of severe or life-threatening cytokine release syndrome associated with T-cell engaging treatments for cancer [Abboud 2016], [Fitzgerald 2017], [Lee 2014], [Maude 2014a]. Additional data may be necessary to further define the role of tocilizumab in the treatment of this condition.

Known hypersensitivity to tocilizumab or any component of the formulation

Canadian labeling: Additional contraindications (not in the US labeling): Active infections

Patients treated with tocilizumab are at an increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants, such as methotrexate or corticosteroids.

If a serious infection develops, interrupt tocilizumab until the infection is controlled.

Reported infections include the following:

Active tuberculosis, which may present with pulmonary or extrapulmonary disease. Patients should be tested for latent tuberculosis before tocilizumab use and during therapy. Treatment for latent infection should be initiated prior to tocilizumab use.

Invasive fungal infections, including candidiasis, aspergillosis, and pneumocystis. Patients with invasive fungal infections may present with disseminated rather than localized disease.

Bacterial, viral, and other infections caused by opportunistic pathogens.

The risks and benefits of treatment with tocilizumab should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection.

Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with tocilizumab, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy.

Concerns related to adverse effects:

• Elevated liver enzymes: Tocilizumab is associated with transaminase elevations. Monitor transaminases. Treatment should be discontinued in patients who develop elevated ALT or AST >5 x ULN. Patients receiving concomitant hepatotoxic drugs (eg, methotrexate) are at an increased risk of developing elevated transaminases; elevations are typically reversible and do not result in clinically evident hepatic injury.

• GI perforation: Use with caution in patients at increased risk for GI perforation; perforation has been reported, typically secondary to diverticulitis. Monitor for new-onset abdominal symptoms; promptly evaluate if new symptoms occur.

• Hematologic effects: Neutropenia and thrombocytopenia may occur; may require treatment interruption, dose or interval modification, or discontinuation. Monitor neutrophils and platelets. Do not initiate treatment in patients with an ANC <2,000/mm3 or platelet count <100,000/mm3; discontinue treatment for ANC <500/mm3 or platelet count <50,000/mm3.

• Herpes zoster reactivation: Herpes zoster reactivation has been reported.

• Hyperlipidemia: Therapy is associated with increases in total cholesterol, triglycerides, LDL, and/or HDL; monitor ~4 to 8 weeks after initiation, then approximately every 6 months. Hyperlipidemia should be managed according to current guidelines.

• Hypersensitivity: May cause hypersensitivity or anaphylaxis; anaphylactic events including fatalities have been reported with IV administration; hypersensitivity reactions have occurred in patients who were premedicated, in patients with and without a prior history of hypersensitivity, and as early as the first infusion. Medications for the treatment of hypersensitivity reactions should be available for immediate use. Patients should seek medical attention if symptoms of hypersensitivity reaction occur with SubQ use. Stop immediately and permanently discontinue treatment in patients who develop a hypersensitivity reaction to tocilizumab. In clinical studies, reactions requiring treatment discontinuation included generalized erythema, rash, and urticaria.

• Infections: [US Boxed Warning]: Serious and potentially fatal infections (including active tuberculosis, invasive fungal, bacterial, viral, protozoal, and other opportunistic infections) have been reported in patients receiving tocilizumab; infection may lead to hospitalization or death. Most of the serious infections have occurred in patients on concomitant immunosuppressive therapy. Patients should be closely monitored for signs and symptoms of infection during and after treatment. If serious infection occurs during treatment, withhold tocilizumab until infection is controlled. Prior to treatment initiation, carefully consider risk versus benefit in patients with chronic or recurrent infections, tuberculosis exposure, history of or current opportunistic infection, underlying conditions predisposing to infection, or patients residing in or with travel to areas of endemic tuberculosis or endemic mycosis. The most common serious infections occurring have included pneumonia, UTI, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis, and bacterial arthritis. Do not administer tocilizumab to a patient with an active infection, including localized infection. Interrupt treatment for serious infection, opportunistic infection, or sepsis.

• Malignancy: Use of tocilizumab may affect defenses against malignancies; impact on the development and course of malignancies is not fully defined; however, malignancies were observed in clinical trials.

• Tuberculosis: [US Boxed Warning]: Tuberculosis (pulmonary or extrapulmonary) has been reported in patients receiving tocilizumab; both reactivation of latent infection and new infections have been reported. Patients should be tested for latent tuberculosis infection before and during therapy; consider treatment of latent tuberculosis used prior to tocilizumab treatment. Some patients who test negative prior to therapy may develop active infection; monitor for signs and symptoms of tuberculosis during and after treatment in all patients. Patients should be evaluated for tuberculosis risk factors with a tuberculin skin test prior to starting therapy. Consider antituberculosis treatment in patients with a history of latent or active tuberculosis if adequate treatment course cannot be confirmed, and for patients with risk factors for tuberculosis despite a negative test.

Disease-related concerns:

• Demyelinating CNS disease: Use with caution in patients with preexisting or recent onset CNS demyelinating disorders; rare cases of CNS demyelinating disorders (multiple sclerosis and chronic inflammatory demyelinating polyneuropathy) have occurred. All patients should be monitored for signs and symptoms of demyelinating disorders.

• Hepatic impairment: Use is not recommended in patients with active hepatic disease or hepatic impairment. Monitor ALT and AST. Do not initiate treatment if ALT or AST is >1.5 times ULN.

Concurrent drug therapy issues:

• Biological disease-modifying antirheumatic drugs (DMARDs): Concomitant use with other biological DMARDs (eg, TNF blockers, IL-1 receptor blockers, anti-CD20 monoclonal antibodies, selective costimulation modulators) has not been studied and should be avoided due to the increased risk of infection.

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: Infection has been reported at a higher incidence in elderly patients compared with younger adults; use with caution in elderly patients.

Dosage form specific issues:

• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer's labeling.

Other warnings/precautions:

• Appropriate use: SubQ administration is only indicated for adult patients with rheumatoid arthritis and giant cell arteritis (GCA). Do not use SubQ injection for IV infusion. Do not administer IV for the treatment of GCA.

• Immunizations: Patients should be brought up to date with all immunizations before initiating therapy. Live vaccines should not be given concurrently; there is no data available concerning secondary transmission of infection from live vaccines in patients receiving therapy.