Drug Safety-related Labeling Changes (SrLC)

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ACTEMRA (BLA-125276)

(TOCILIZUMAB)

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

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12/21/2022 (SUPPL-138)

Approved Drug Label (PDF)

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 ACTEMRA. There is limited information regarding the use of ACTEMRA in patients with COVID-19 and concomitant active serious infections. The risks and benefits of treatment with ACTEMRA 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 ACTEMRA. In patients with COVID-19, testing for latent infection is not necessary prior to initiating treatment with ACTEMRA.

5.3 Hepatotoxicity

Newly added information:

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 ACTEMRA should balance the potential benefit of treating COVID-19 against the potential risks of acute treatment with ACTEMRA. It is not recommended to initiate ACTEMRA 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

Additions and revisions underlined:

Patients with Rheumatoid Arthritis, Giant Cell Arteritis, Systemic Sclerosis-Associated Interstitial Lung Disease and Coronavirus Disease 2019

Neutropenia

Treatment with ACTEMRA was associated with a higher incidence of neutropenia. Infections have been uncommonly reported in association with treatment-related neutropenia in long-term extension studies and postmarketing clinical experience.

• It is not recommended to initiate ACTEMRA treatment in RA, GCA and SSc-ILD 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 (2.11).

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

Thrombocytopenia

Treatment with ACTEMRA 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, 6.2)].

It is not recommended to initiate ACTEMRA treatment in RA, GCA and SSc-ILD 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.

6 Adverse Reactions

6.11 Clinical Trials Experience in COVID-19 Patients Treated with Intravenous ACTEMRA (ACTEMRA-IV)

Newly added subsection; please refer to label

8 Use in Specific Populations

8.5 Geriatric Use

Newly added information:

In the EMPACTA, COVACTA, and REMDACTA studies, of the 974 COVID-19 patients in the ACTEMRA arm, 375 (39%) were 65 years of age or older. No overall differences in safety or effectiveness of ACTEMRA 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 (6.1) and Clinical Studies (14.11)].

In the RECOVERY study, of the 2022 COVID-19 patients in the ACTEMRA arm, 930 (46%) were 65 years of age or older. No overall differences in effectiveness of ACTEMRA 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 (14.11)].

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

Medication Guide

Additions and revisions underlined:

ACTEMRA can cause serious side effects including:

1.Serious Infections. ACTEMRA is a medicine that affects your immune system. ACTEMRA can lower the ability of your immune system to fight infections. Some people have serious infections while taking ACTEMRA, 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 ACTEMRA (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 ACTEMRA.

What is ACTEMRA?

ACTEMRA is a prescription medicine called an Interleukin-6 (IL-6) receptor antagonist. ACTEMRA 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).

• For slowing the rate of decline in lung function in adults with systemic sclerosis-associated interstitial lung disease (SSc-ILD) (also known as scleroderma associated ILD).

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

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

• To treat people age 2 years and above who experience severe or life-threatening Cytokine Release Syndrome (CRS) following chimeric antigen receptor (CAR) T cell treatment.

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

• ACTEMRA is not approved for subcutaneous use in people with CRS or COVID-19.

• All vaccines should be brought up-to-date before starting ACTEMRA, unless urgent treatment initiation is required.

 

How will I receive ACTEMRA?

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

• If your healthcare provider prescribes ACTEMRA as an IV infusion, you will receive ACTEMRA 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 ACTEMRA about every 4 weeks.

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

• For CRS you will receive a single dose of ACTEMRA, and if needed, additional doses.

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

While taking ACTEMRA, 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.

PATIENT COUNSELING INFORMATION

Additions and revisions underlined:

Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).

Serious Infections

Inform patients that ACTEMRA may lower their resistance to infections [see Warnings and Precautions (5.1)]. Instruct the patient of the importance of contacting their doctor immediately when symptoms suggesting infection appear in order to assure rapid evaluation and appropriate treatment.

02/28/2022 (SUPPL-134)

Approved Drug Label (PDF)

6 Adverse Reactions

6.4 Clinical Trials Experience in Giant Cell Arteritis Patients Treated With Intravenous ACTEMRA (ACTEMRA-IV)

New subsection added

The safety of ACTEMRA-IV was studied in an open label PK-PD and safety study in 24 patients with GCA who were in remission on ACTEMRA-IV at time of enrollment. Patients received ACTEMRA 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 overall safety profile observed for ACTEMRA administered intravenously in GCA patients was consistent with the known safety profile of ACTEMRA.

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

MEDICATION GUIDE

Additions underlined

…

How will I receive ACTEMRA?

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

• If your healthcare provider prescribes ACTEMRA as an IV infusion, you will receive ACTEMRA 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 ACTEMRA about every 4 weeks.

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

  …

03/04/2021 (SUPPL-131)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.4 Laboratory Parameters

(Additions and/or revisions underlined)

Rheumatoid Arthritis, Giant Cell Arteritis and Systemic Sclerosis-Associated Interstitial Lung Disease

6 Adverse Reactions

6.4 Clinical Trials Experience in Systemic Sclerosis-Associated Interstitial Lung Disease Patients Treated with Subcutaneous ACTEMRA (ACTEMRA-SC)

(Newly added section)

The safety of subcutaneous ACTEMRA was evaluated in two double-blind, placebo-controlled, multicenter studies (WA29767 and WA27788). In the Phase 3 Study WA29767, 212 patients with SSc were randomized to tocilizumab 162 mg administered every week subcutaneously or placebo for 48 weeks, followed by open-label tocilizumab 162 mg administered subcutaneously every week for another 48 weeks. In the Phase 2/3 Study WA27788, 87 patients were randomized to tocilizumab 162 mg administered every week subcutaneously or placebo for 48 weeks, followed by open-label tocilizumab 162 mg administered subcutaneously every week for another 48 weeks.

The safety profile for ACTEMRA through week 48 in WA29767 was comparable for SSc-ILD and SSc patients overall, and in both studies was consistent with the known safety profile of ACTEMRA.

Immunogenicity

In the two clinical studies, WA29767 and WA27788, the incidence of treatment-induced anti-TCZ antibodies at week 96 was low (3 out of 169 patients, 1.8%). These anti-drug antibodies were of neutralizing potential, and none of the patients experienced hypersensitivity reactions.

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

Medication Guide

(Additions and/or revisions underlined)
If you have rheumatoid arthritis (RA), giant cell arteritis (GCA), or systemic sclerosisinterstitial

lung disease (SSc-ILD) your healthcare provider should do blood tests every 4 to 8 weeks after you

start receiving ACTEMRA for the first 6 months and then every 3 months after that.

ACTEMRA 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).

• For slowing the rate of decline in lung function in adults with systemic sclerosis-associated interstitial lung disease

(SSc-ILD) (also known as scleroderma associated ILD)

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

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

• To treat people age 2 years and above who experience severe or life-threatening Cytokine Release Syndrome

06/11/2019 (SUPPL-127)

Approved Drug Label (PDF)

5 Warnings and Precautions

WARNINGS AND PRECAUTIONS

Newly added information:

5.3 Hepatotoxicity

Serious cases of hepatic injury have been observed in patients taking intravenous or subcutaneous ACTEMRA. Some of these cases have resulted in liver transplant or death. Time to onset for cases ranged from months to years after treatment initiation with tocilizumab. While most cases presented with marked elevations of transaminases (> 5 times ULN), some cases presented with signs or symptoms of liver dysfunction and only mildly elevated transaminases.

During randomized controlled studies, treatment with ACTEMRA was associated with a higher incidence of transaminase elevations.

For RA and GCA patients, obtain a liver test panel (serum alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, and total bilirubin) before initiating ACTEMRA, 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 ACTEMRA treatment in RA or GCA patients with elevated transaminases ALT or AST greater than 1.5x ULN. In patients who develop elevated ALT or AST greater than 5x ULN, discontinue ACTEMRA. For recommended modifications based upon increase in transaminases. Measure liver tests promptly in patients who report symptoms that may indicate liver injury, such as fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. In this clinical context, if the patient is found to have abnormal liver tests (e.g., ALT greater than three times the upper limit of the reference range, serum total bilirubin greater than two times the upper limit of the reference range), ACTEMRA treatment should be interrupted and investigation done to establish the probable cause. ACTEMRA should only be restarted in patients with another explanation for the liver test abnormalities after normalization of the liver tests.

A similar pattern of liver enzyme elevation is noted with ACTEMRA treatment in the PJIA and SJIA populations. Monitor liver test panel at the time of the second administration and thereafter every 4 to 8 weeks for PJIA and every 2 to 4 weeks for SJIA.

5.4 Laboratory Parameters

Elevated Liver Enzymes

Addition of the following statement:

Refer to 5.3 Hepatotoxicity. For recommended modifications.

6 Adverse Reactions

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

Elevated Liver Enzymes

Newly added information:

In Study WA25204, of the 1538 patients with moderate to severe RA and treated with tocilizumab, elevations in ALT or AST >3 x ULN occurred in 5.3% and 2.2% patients, respectively. One serious event of drug induced hepatitis with hyperbilirubinemia was reported in association with tocilizumab.

6.9 Postmarketing Experience

Newly added to the bulleted line listing:

• Drug-induced liver injury, Hepatitis, Hepatic failure, Jaundice

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

MEDICATION GUIDE

Additions and/or revisions underlined:

• Liver problems (Hepatotoxicity): Some people have experienced serious life-threatening liver problems, which required a liver transplant or led to death. Your healthcare provider may tell you to stop taking ACTEMRA if you develop new or worse liver problems during treatment with ACTEMRA. Tell your healthcare provider right away if you have any of the following symptoms:

• Feeling tired (fatigue)

• Weakness

• Lack of appetite for several days or longer (anorexia)

• Yellowing of your skin or the whites of your eyes (jaundice)

• Abdominal swelling and pain on the right side of your stomach-area

• Nausea and vomiting

• Confusion

• Dark “tea-colored” urine

• Changes in certain laboratory test results … your healthcare provider should do blood tests every 4 to 8 weeks after you start receiving ACTEMRA for the first 6 months and then every 3 months after that.

Your healthcare provider will determine how often you will have follow-up blood tests. Make sure you get all your follow-up blood tests done as ordered by your healthcare provider.

04/11/2019 (SUPPL-120)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.3 Laboratory Parameters

(additions underlined)

…

Lipid Abnormalities

Treatment with ACTEMRA was associated with increases in lipid parameters such as total cholesterol, triglycerides, LDL cholesterol, and/or HDL cholesterol.

• Assess lipid parameters approximately 4 to 8 weeks following initiation of ACTEMRA therapy.

• Subsequently, manage  patients according to clinical guidelines [e.g., National Cholesterol Educational Program (NCEP)] for the management of hyperlipidemia.

6 Adverse Reactions

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

(additions underlined)

…

In the cardiovascular outcomes Study WA25204, the rate of serious infections in the ACTEMRA 8 mg/kg IV every 4 weeks group, with or without DMARD, was 4.5 per 100 patient-years, and the rate in the etanercept 50 mg weekly SC group, with or without DMARD, was 3.2 per 100 patient-years.

…

04/11/2019 (SUPPL-121)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.3 Laboratory Parameters

(additions underlined)

…

Lipid Abnormalities

Treatment with ACTEMRA was associated with increases in lipid parameters such as total cholesterol, triglycerides, LDL cholesterol, and/or HDL cholesterol.

• Assess lipid parameters approximately 4 to 8 weeks following initiation of ACTEMRA therapy.

• Subsequently, manage  patients according to clinical guidelines [e.g., National Cholesterol Educational Program (NCEP)] for the management of hyperlipidemia.

6 Adverse Reactions

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

(additions underlined)

…

In the cardiovascular outcomes Study WA25204, the rate of serious infections in the ACTEMRA 8 mg/kg IV every 4 weeks group, with or without DMARD, was 4.5 per 100 patient-years, and the rate in the etanercept 50 mg weekly SC group, with or without DMARD, was 3.2 per 100 patient-years.

…

09/12/2018 (SUPPL-122)

Approved Drug Label (PDF)

6 Adverse Reactions

6.7 Clinical Trials Experience in Systemic Juvenile Idiopathic Arthritis Patients Treated with Subcutaneous ACTEMRA (ACTEMRA-SC)

(new subsection added)

The safety profile of ACTEMRA-SC was studied in 51 pediatric patients 1 to 17 years of age with SJIA who had an inadequate clinical response to NSAIDs and corticosteroids. In general, the safety observed for ACTEMRA administered subcutaneously was consistent with the known safety profile of intravenous ACTEMRA, with the exception of ISRs where a higher frequency was observed in ACTEMRA-SC treated SJIA patients compared to PJIA patients and adult RA or GCA patients.

Injection Site Reactions (ISRs)

A total of 41.2% (21/51) SJIA patients experienced ISRs to ACTEMRA-SC. The most common ISRs were erythema, pruritus, pain, and swelling at the injection site. The majority of ISRs reported were Grade 1 events and all ISRs reported were non-serious and none required patient withdrawal from treatment or dose interruption.

Immunogenicity

Forty-six of the 51 (90.2%) patients who were tested for anti-tocilizumab antibodies at baseline had at least one post-baseline screening assay result. No patient developed positive anti-tocilizumab antibodies post-baseline.

8 Use in Specific Populations

8.4 Pediatric Use

(additions underlined)

…

ACTEMRA by subcutaneous use is indicated for the treatment of pediatric patients with:

• Active polyarticular juvenile idiopathic arthritis in patients 2 years of age and older

• Active systemic juvenile idiopathic arthritis in patients 2 years of age and older

The safety and effectiveness of ACTEMRA in pediatric patients with conditions other than PJIA, SJIA or CRS have not been established. The safety and effectiveness in pediatric patients below the age of 2 have not been established in PJIA, SJIA, or CRS.

…

05/11/2018 (SUPPL-115)

Approved Drug Label (PDF)

6 Adverse Reactions

Addition of the following:

6.5 Clinical Trials Experience in Polyarticular Juvenile Idiopathic Arthritis Patients Treated with Subcutaneous ACTEMRA (ACTEMRA-SC)

The safety of ACTEMRA-SC was studied in 52 pediatric patients 1 to 17 years of age with PJIA who had an inadequate clinical response or were intolerant to methotrexate. The total patient exposure in the PJIA ACTEMRA-SC population (defined as patients who received at least one dose of ACTEMRA-SC and accounting for treatment discontinuation) was 49.5 patient years. In general, the safety observed for ACTEMRA administered subcutaneously was consistent with the known safety profile of intravenous ACTEMRA, with the exception of injection site reactions (ISRs), and neutropenia.

Injection Site Reactions

During the 1-year study, a frequency of 28.8% (15/52) ISRs was observed in ACTEMRA-SC treated PJIA patients. These ISRs occurred in a greater proportion of patients at or above 30 kg (44.0%) compared with patients below 30 kg (14.8%). All ISRs were mild in severity and none of the ISRs required patient withdrawal from treatment or dose interruption. A higher frequency of ISRs was observed in ACTEMRA-SC treated PJIA patients compared to what was seen in adult RA or GCA patients.

Immunogenicity

Three patients, 1 patient below 30 kg and 2 patients at or above 30 kg, developed positive anti-tocilizumab antibodies with neutralizing potential without developing a serious or clinically significant hypersensitivity reaction. One patient subsequently withdrew from the study.

Neutropenia

During routine laboratory monitoring in the ACTEMRA-SC all exposure population, a decrease in neutrophil counts below 1 × 109 per L occurred in 15.4% of patients, and was more frequently observed in the patients less than 30 kg (25.9%) compared to patients at or above 30 kg (4.0%). There was no clear relationship between decreases in neutrophils below 1 x 109 per L and the occurrence of serious infections.

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

• … Severe or life-threatening CAR T cell-induced cytokine release syndrome (CRS) in patients 2 years of age and older.

ACTEMRA by subcutaneous use is indicated for the treatment of pediatric patients with:

• Active polyarticular juvenile idiopathic arthritis in patients 2 years of age and older

Safety and effectiveness of ACTEMRA in pediatric patients with conditions other than PJIA, SJIA or CRS have not been established. The safety and effectiveness in pediatric patients below the age of 2 have not been established. Subcutaneous administration has not been studied in SJIA pediatric patients.

Addition of the following:

Systemic Juvenile Idiopathic Arthritis – Intravenous Use

A multi-center, open-label, single arm study to evaluate the PK, safety and exploratory PD and efficacy of ACTEMRA over 12-weeks in SJIA patients (Equals 11) under 2 years of age was conducted. Patients received intravenous ACTEMRA 12 mg/kg every two weeks. Concurrent use of stable background treatment with corticosteroids, MTX, and/or non-steroidal anti-inflammatory drugs was permitted. Patients who completed the 12-week period could continue to the optional extension period (a total of 52-weeks or until the age of 2 years, whichever was longer).

The primary PK endpoints (Cmax, Cmin and AUC2weeks) of ACTEMRA at steady-state in this study were within the ranges of these parameters observed in patients with SJIA aged 2 to 17 years.

The safety and immunogenicity of ACTEMRA for patients with SJIA under 2 years of age was assessed descriptively. SAEs, AEs leading to discontinuation, and infectious AEs were reported by 27.3%, 36.4%, and 81.8% of patients. Six patients (54.5%) experienced hypersensitivity reactions, defined as all adverse events occurring during or within 24 hours after an infusion considered related to ACTEMRA. Three of these patients experienced serious hypersensitivity reactions and were withdrawn from the study. Three patients with hypersensitivity reactions (two with serious hypersensitivity reactions) developed treatment induced anti-tocilizumab antibodies after the event. There were no cases of MAS based on the protocol-specified criteria, but 2 cases of suspected MAS based on Ravelli criteria1.

1 Ravelli A, Minoia F, Davì S on behalf of the Paediatric Rheumatology International Trials Organisation, the Childhood Arthritis and Rheumatology Research Alliance, the Pediatric Rheumatology Collaborative Study Group, and the Histiocyte Society, et al. 2016 Classification Criteria for Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis. Annals of the Rheumatic Diseases 2016; 75:481-489.

Cytokine Release Syndrome – Intravenous Use

In the retrospective analysis …

03/22/2018 (SUPPL-116)

Approved Drug Label (PDF)

6 Adverse Reactions

6.7 Postmarketing Experience

(addition underlined)

The following adverse reactions have been identified during post-approval use of ACTEMRA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Fatal anaphylaxis

• Stevens-Johnson Syndrome

• Pancreatitis

   

08/30/2017 (SUPPL-114)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.3 Laboratory Parameters

Rheumatoid Arthritis and Giant Cell Arteritis replaces Approved Adult Indications

6 Adverse Reactions

Addition of the following:

The following serious adverse reactions are described elsewhere in labeling:

• Serious Infections

• Gastrointestinal Perforations

• Laboratory Parameters

• Immunosuppression

• Hypersensitivity Reactions, Including Anaphylaxis

• Demyelinating Disorders

• Active Hepatic Disease and Hepatic Impairment

6.6 Clinical Trials Experience in Patients with Cytokine Release Syndrome Treated with Intravenous ACTEMRA (ACTEMRA-IV)

In a retrospective analysis of pooled outcome data from multiple clinical trials 45 patients were treated with tocilizumab 8 mg/kg (12 mg/kg for patients less than 30 kg) with or without additional high-dose corticosteroids for severe or life-threatening CAR T-cell-induced CRS. A median of 1 dose of tocilizumab (range, 1-4 doses) was administered. No adverse reactions related to tocilizumab were reported.

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined

ACTEMRA by intravenous use is indicated for the treatment of pediatric patients with:

• Severe or life-threatening CAR T cell-induced cytokine release syndrome (CRS) in patients 2 years of age and older.

Safety and effectiveness of ACTEMRA in pediatric patients with conditions other than PJIA, SJIA or CRS have not been established … no impairment of skeletal growth, immune function and sexual maturation.

In the retrospective analysis of pooled outcome data for patients treated with ACTEMRA for CAR T cell- induced CRS, 25 patients were children (2 years up to 12 years of age), and 17 patients were adolescents (12 years up to 18 years of age). There were no differences between the pediatric patients and the adults for safety or efficacy.

8.5 Geriatric Use

Additions and/or revisions underlined

… caution should be used when treating the elderly.

Clinical studies that included ACTEMRA for CRS did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Advise patients and parents or guardians of minors with PJIA, SJIA, or CRS of the potential benefits and risks of ACTEMRA.

05/22/2017 (SUPPL-112)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.3 Laboratory Parameters

Approved Adult Indications replaces Rheumatoid Arthritis in all instances in this subsection

5.8 Vaccinations

Pediatric or elderly replaces PJIA and SJIA.

6 Adverse Reactions

Addition of the following:

6.3 Clinical Trials Experience in Giant Cell Arteritis Patients Treated with Subcutaneous ACTEMRA (ACTEMRA-SC)

The safety of subcutaneous ACTEMRA (tocilizumab) has been studied in one Phase III study (WA28119) with 251 GCA patients. The total patient years duration in the ACTEMRA GCA all exposure population was 138.5 patient years during the 12-month double blind, placebo-controlled phase of the study. The overall safety profile observed in the ACTEMRA treatment groups was generally consistent with the known safety profile of ACTEMRA. There was an overall higher incidence of infections in GCA patients relative to RA patients. The rate of infection/serious infection events was 200.2/9.7 events per 100 patient years in the ACTEMRA weekly group and 160.2/4.4 events per 100 patient years in the ACTEMRA every other week group as compared to 156.0/4.2 events per 100 patient years in the placebo plus 26 week prednisone taper and 210.2/12.5 events per 100 patient years in the placebo plus 52 week taper groups.

7 Drug Interactions

7.1 Concomitant Drugs for Treatment of Adult Indications

In RA patients, population pharmacokinetic analyses … with biological DMARDs such as TNF antagonists.

Addition of the following:

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

 

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

MEDICATION GUIDE

Additions and/or revisions are underlined:

Healthcare provider replaces doctor throughout this medication guide.

3.   Changes in certain laboratory test results. Your healthcare provider should do blood tests before you start receiving ACTEMRA. If you have rheumatoid arthritis (RA) or giant cell arteritis (GCA) your healthcare provider should do blood tests 4 to 8 weeks after you start receiving ACTEMRA and then every 3 months after that. If you have polyarticular juvenile idiopathic arthritis (PJIA) you will have blood tests done every 4 to 8 weeks during treatment. If you have systemic juvenile idiopathic arthritis (SJIA) you will have blood tests done every 2 to 4 weeks during treatment. These blood tests are to check for the following …

What is ACTEMRA?

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

• Adults with giant cell arteritis (GCA).

  Under the skin (SC or subcutaneous injection) for Rheumatoid Arthritis or Giant Cell Arteritis

  General information about the safe and effective use of ACTEMRA.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.  Do not give ACTEMRA to other people, even if they have the same symptoms that you have. It may harm them.

09/23/2016 (SUPPL-107)

Approved Drug Label (PDF)

6 Adverse Reactions

6.5 Postmarketing Experience

• The following adverse reactions have been identified during postapproval use of intravenous ACTEMRA…

  • Stevens-Johnson Syndrome (addition)

8 Use in Specific Populations

8.1 Pregnancy (PLLR Conversion)

Pregnancy Exposure Registry

• There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ACTEMRA during pregnancy. Physicians are encouraged to register patients and pregnant women are encouraged to register themselves by calling 1-877-311-8972.

Risk Summary

• The limited available data with ACTEMRA in pregnant women are not sufficient to determine whether there is a drug-associated risk for major birth defects and miscarriage. Monoclonal antibodies, such as tocilizumab, are actively transported across the placenta during the third trimester of pregnancy and may affect immune response in the in utero exposed infant. In animal reproduction studies, intravenous administration of tocilizumab to Cynomolgus monkeys during organogenesis caused abortion/embryo-fetal death at doses 1.25 times and higher than the maximum recommended human dose by the intravenous route of 8 mg per kg every 2 to 4 weeks. The literature in animals suggests that inhibition of IL-6 signaling may interfere with cervical ripening and dilatation and myometrial contractile activity leading to potential delays of parturition. Based on the animal data, there may be a potential risk to the fetus.

• The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Fetal/Neonatal adverse reactions

• Monoclonal antibodies are increasingly transported across the placenta as pregnancy progresses, with the largest amount transferred during the third trimester. Risks and benefits should be considered prior to administering live or live-attenuated vaccines to infants exposed to ACTEMRA in utero.

Data

Animal Data

• An embryo-fetal developmental toxicity study was performed in which pregnant Cynomolgus monkeys were treated intravenously with tocilizumab at daily doses of 2, 10, or 50 mg/ kg during organogenesis from gestation day (GD) 20-50. Although there was no evidence for a teratogenic/dysmorphogenic effect at any dose, tocilizumab produced an increase in the incidence of abortion/embryo-fetal death at doses 1.25 times and higher the MRHD by the intravenous route at maternal intravenous doses of 10 and 50 mg/ kg. Testing of a murine analogue of tocilizumab in mice did not yield any evidence of harm to offspring during the pre- and postnatal development phase when dosed at 50 mg/kg intravenously with treatment every three days from implantation (GD 6) until post-partum day 21 (weaning). There was no evidence for any functional impairment of the development and behavior, learning ability, immune competence and fertility of the offspring.

• Parturition is associated with significant increases of IL-6 in the cervix and myometrium. The literature suggests that inhibition of IL-6 signaling may interfere with cervical ripening and dilatation and myometrial contractile activity leading to potential delays of parturition. For mice deficient in IL-6 (ll6-/- null mice), parturition was delayed relative to wild-type (ll6+/+) mice. Administration of recombinant IL-6 to ll6-/- null mice restored the normal timing of delivery.

Lactation (PLLR Conversion)

Risk Summary

• No information is available on the presence of tocilizumab in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. Maternal immunoglobulin G (IgG) is present in human milk. If tocilizumab is transferred into human milk, the effects of local exposure in the gastrointestinal tract and potential limited systemic exposure in the infant to tocilizumab are unknown. The lack of clinical data during lactation precludes clear determination of the risk of ACTEMRA to an infant during lactation; therefore the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ACTEMRA and the potential adverse effects on the breastfed child from tocilizumab or from the underlying maternal condition.

 

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

Patient Counseling Information

Pregnancy Exposure Registry

• Inform patients that there is a pregnancy registry to monitor fetal outcomes of pregnant women exposed to ACTEMRA.

Pregnancy

• Inform female patients of reproductive potential that ACTEMRA may cause fetal harm and to inform their prescriber of a known or suspected pregnancy.