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Drug Safety-related Labeling Changes (SrLC)

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TOFIDENCE (BLA-761354)

(TOCILIZUMAB-BAVI)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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12/03/2024 (SUPPL-4)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.6 Hypersensitivity Reactions, Including Anaphylaxis

Additions and/or revisions underlined:

In the postmarketing setting, events of hypersensitivity reactions, including anaphylaxis and death have occurred in patients treated with a range of doses of intravenous tocilizumab products, with or without concomitant therapies. Events have occurred in patients who received premedication. Hypersensitivity, including anaphylaxis events, have occurred both with and without previous hypersensitivity reactions and as early as the first infusion of tocilizumab products. In addition, serious cutaneous reactions, including Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), have been reported in patients with autoinflammatory conditions treated with tocilizumab products.

TOFIDENCE for intravenous use should only be infused by a healthcare professional with appropriate medical support to manage anaphylaxis. If a hypersensitivity reaction occurs immediately discontinue TOFIDENCE; treat promptly and monitor until signs and symptoms resolve.

6 Adverse Reactions

6.6 Postmarketing Experience

Additions and/or revisions underlined:

  • Hypersensitivity Reactions: Fatal anaphylaxis, Stevens-Johnson Syndrome, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) [see Warnings and Precautions (5.6)]

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

  • Hypersensitivity and Serious Allergic Reactions

Inform patients that some patients who have been treated with TOFIDENCE have developed serious allergic reactions, including anaphylaxis and serious skin reactions [see Warnings and Precautions (5.6)]. Advise patients to stop taking TOFIDENCE and seek immediate medical attention if they experience any symptom of serious allergic reactions (including rash, hives, and swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing).

MEDICATION GUIDE

Additions and/or revisions underlined:

What are the possible side effects with TOFIDENCE? TOFIDENCE can cause serious side effects, including:

  • Serious Allergic Reactions. Serious allergic reactions, including death, can happen with TOFIDENCE. These reactions can happen with any infusion of TOFIDENCE, even if they did not occur with an earlier infusion. Stop taking TOFIDENCE, contact healthcare provider, and get emergency help right away if you have any of the following signs of a serious allergic reaction:

    • trouble breathing

    • swelling of your mouth, lips, tongue, or face

    • wheezing

    • severe itching

    • skin rash, hives, redness, or swelling outside of the injection site area

    • dizziness or fainting

    • fast heartbeat or pounding in your chest (tachycardia),

    • sweating

      Tell your healthcare provider about any side effect that bothers you or does not go away. These are not all the possible side effects of TOFIDENCE. For more information, ask your healthcare provider or pharmacist.

07/22/2024 (SUPPL-2)

Approved Drug Label (PDF)

Boxed Warning

Additions and revisions underlined:

. . .

If a serious infection develops, interrupt TOFIDENCE until the infection is controlled. Reported infections include:

  • Active tuberculosis, which may present with pulmonary or extrapulmonary disease.

Patients, except those with COVID-19, should be tested for latent tuberculosis before TOFIDENCE use and during therapy.

. . .

5 Warnings and Precautions

5.1 Serious Infections

Additions and revisions underlined:

. . .

COVID-19

In patients with COVID-19, monitor for signs and symptoms of new infections during and after treatment with TOFIDENCE. There is limited information regarding the use of tocilizumab products in patients with COVID-19 and concomitant active serious infections. The risks and benefits of treatment with TOFIDENCE in COVID-19 patients with other concurrent infections should be considered.

 

Tuberculosis

Evaluate patients for tuberculosis risk factors and test for latent infection prior to initiating TOFIDENCE. In patients with COVID-19, testing for latent infection is not necessary prior to initiating treatment with TOFIDENCE.

. . .

5.3 Hepatotoxicity

Additions and revisions underlined:

. . .

For RA and GCA patients, obtain a liver test panel (serum alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, and total bilirubin) before initiating TOFIDENCE, every 4 to 8 weeks after start of therapy for the first 6 months of treatment and every 3 months thereafter. It is not recommended to initiate TOFIDENCE treatment in RA or GCA patients with elevated transaminases ALT or AST greater than 1.5x ULN.

. . .

Patients hospitalized with COVID-19 may have elevated ALT or AST levels. Multi-organ failure with involvement of the liver is recognized as a complication of severe COVID-19. The decision to administer TOFIDENCE should balance the potential benefit of treating COVID-19 against the potential risks of acute treatment with TOFIDENCE. It is not recommended to initiate TOFIDENCE treatment in COVID-19 patients with elevated ALT or AST above 10 x ULN. Monitor ALT and AST during treatment.

5.4 Changes in Laboratory Parameters

Patients with Rheumatoid Arthritis, Giant Cell Arteritis and Coronavirus Disease 2019

Subsection title revised

Additions and revisions underlined:

. . .

  • It is not recommended to initiate TOFIDENCE treatment in RA and GCA patients with a low neutrophil count, i.e., absolute neutrophil count (ANC) less than 2000 per mm3. In patients who develop an absolute neutrophil count less than 500 per mm3 treatment is not recommended.

  • Monitor neutrophils 4 to 8 weeks after start of therapy and every 3 months thereafter [see Clinical Pharmacology (12.2)]. For recommended modifications based on ANC results see Dosage and Administration (2.8).

  • It is not recommended to initiate TOFIDENCE treatment in COVID-19 patients with an ANC less than 1000 per mm3 . Neutrophils should be monitored.

Thrombocytopenia

Treatment with tocilizumab products was associated with a reduction in platelet counts. Treatment-related reduction in platelets was not associated with serious bleeding events in clinical trials [see Adverse Reactions (6.1)].

  • It is not recommended to initiate TOFIDENCE treatment in RA and GCA patients with a platelet count below 100,000 per mm3. In patients who develop a platelet count less than 50,000 per mm3 treatment is not recommended.
  • Monitor platelets 4 to 8 weeks after start of therapy and every 3 months thereafter. For recommended modifications based on platelet counts see Dosage and Administration (2.8).

In COVID-19 patients with a platelet count less than 50,000 per mm3 , treatment is not recommended. Platelets should be monitored.

6 Adverse Reactions

6.1 Clinical Trials Experience in Rheumatoid Arthritis Patients Treated with Intravenous Tocilizumab (Tocilizumab-IV)

Additions and revisions underlined:

Immunogenicity

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of tocilizumab or of other tocilizumab products.

6.2 Clinical Trials Experience in Giant Cell Arteritis Patients Treated with Intravenous Tocilizumab (Tocilizumab-IV)

Newly added subsection:

The safety of tocilizumab-IV was studied in an open label PK-PD and safety study in 24 patients with GCA who were in remission on tocilizumab-IV at time of enrollment. Patients received tocilizumab 7 mg/kg every 4 weeks for 20 weeks, followed by 6 mg/kg every 4 weeks for 20 weeks. The total patient years exposure to treatment was 17.5 years.

The safety of tocilizumab by another route of administration has been studied in one Phase III study with 251 GCA patients. The total patient years duration was 138.5 patient years during the 12-month double blind, placebo-controlled phase of the study. The overall safety profile observed was generally consistent with the known safety profile of tocilizumab. There was an overall higher incidence of infections in GCA patients relative to RA patients.

The overall safety profile observed for tocilizumab administered intravenously in GCA patients was consistent with the known safety profile of tocilizumab.

6.5 Clinical Trials Experience in COVID-19 Patients Treated with Intravenous Tocilizumab (Tocilizumab-IV)

Newly added subsection, please refer to label

7 Drug Interactions

7.1 Concomitant Drugs for Treatment of Adult Indications

Additions and revisions underlined:

In RA patients, population pharmacokinetic analyses did not detect any effect of methotrexate (MTX), non-steroidal anti-inflammatory drugs or corticosteroids on tocilizumab clearance.

Concomitant administration of a single intravenous dose of 10 mg/kg tocilizumab with 10-25 mg MTX once weekly had no clinically significant effect on MTX exposure. Tocilizumab products have not been studied in combination with biological DMARDs such as TNF antagonists [see Dosage and Administration (2.2)].

In GCA patients, no effect of concomitant corticosteroid on tocilizumab exposure was observed.

8 Use in Specific Populations

8.4 Geriatric Use

Additions and revisions underlined:

Of the 2644 patients who received tocilizumab in Studies I to V [see Clinical Studies (14)], a total of 435 rheumatoid arthritis patients were 65 years of age and older, including 50 patients 75 years and older. The frequency of serious infection among tocilizumab treated subjects 65 years of age and older was higher than those under the age of 65. As there is a higher incidence of infections in the elderly population in general, caution should be used when treating the elderly.

In the EMPACTA, COVACTA, and REMDACTA studies, of the 974 COVID-19 patients in the tocilizumab arm, 375 (39%) were 65 years of age or older. No overall differences in safety or effectiveness of tocilizumab were observed between patients 65 years of age and older and those under the age of 65 years of age in these studies [see Adverse Reactions (6.5) and Clinical Studies (14.5)].

In the RECOVERY study, of the 2022 COVID-19 patients in the tocilizumab arm, 930 (46%) were 65 years of age or older. No overall differences in effectiveness of tocilizumab were observed between patients 65 years of age and older and those under the age 65 years of age in this study [see Clinical Studies (14.5)].

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Medication Guide

Additions and revisions underlined:

TOFIDENCE can cause serious side effects including:

  1. Serious Infections. TOFIDENCE is a medicine that affects your immune system. TOFIDENCE can lower the ability of your immune system to fight infections. Some people have serious infections while taking TOFIDENCE, 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 assess you for TB before starting TOFIDENCE (except if you have COVID-19).

    If you have COVID-19, your healthcare provider should monitor you for signs and symptoms of new infections during and after treatment with TOFIDENCE.

. . .

Your healthcare provider should do blood tests before you start receiving TOFIDENCE. If you have rheumatoid arthritis (RA) or giant cell arteritis (GCA) your healthcare provider should do blood tests every 4 to 8 weeks after you start receiving TOFIDENCE for the first 6 months and then every 3 months after that.

. . .

 

What is TOFIDENCE?

TOFIDENCE is a prescription medicine called an Interleukin-6 (IL-6) receptor antagonist. TOFIDENCE is used:

  • To treat adults with moderately to severely active rheumatoid arthritis (RA), after at least one other medicine called a Disease-Modifying Anti-Rheumatic Drug (DMARD) has been used and did not work well.

  • To treat adults with giant cell arteritis (GCA).

  • To treat people with active PJIA ages 2 and above.

  • To treat people with active SJIA ages 2 and above.

  • To treat hospitalized adults with coronavirus disease 2019 (COVID-19) receiving systemic corticosteroids and requiring supplemental oxygen or mechanical ventilation.

. . .

How will I receive TOFIDENCE?

Into a vein (IV or intravenous infusion) for Rheumatoid Arthritis, Giant Cell Arteritis, PJIA, SJIA, or COVID-19:

  • If your healthcare provider prescribes TOFIDENCE as an IV infusion, you will receive TOFIDENCE from a healthcare provider through a needle placed in a vein in your arm. The infusion will take about 1 hour to give you the full dose of medicine.

  • For rheumatoid arthritis, giant cell arteritis or PJIA you will receive a dose of TOFIDENCE about every 4 weeks.

  • For SJIA you will receive a dose of TOFIDENCE about every 2 weeks.

  • For COVID-19, you will receive a single dose of TOFIDENCE, and if needed one additional dose.

  • While taking TOFIDENCE, you may continue to use other medicines that help treat your rheumatoid arthritis, PJIA, SJIA, or COVID-19 such as methotrexate, non-steroidal anti-inflammatory drugs (NSAIDs) and prescription steroids, as instructed by your healthcare provider.

. . .

You may also report side effects to Biogen MA Inc. at 1-877-422-8360.