Actemra

tocilizumab

Dosage Form: injection, solution, concentrate
FULL PRESCRIBING INFORMATION

WARNING: RISK OF SERIOUS INFECTIONS

Patients treated with Actemra are at increased risk for developing serious infections that may lead to hospitalization or death [see Warnings and Precautions (5.1), Adverse Reactions (6.1)]. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.

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

Reported infections include:

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

The risks and benefits of treatment with Actemra 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 Actemra, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy [see Warnings and Precautions (5.1)].

Indications and Usage for Actemra

Rheumatoid Arthritis (RA)

 Actemra® (tocilizumab) is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more TNF antagonist therapies.

Systemic Juvenile Idiopathic Arthritis (SJIA)

Actemra® (tocilizumab) is indicated for the treatment of active systemic juvenile idiopathic arthritis in patients 2 years of age and older.

Actemra Dosage and Administration

Rheumatoid Arthritis

 Actemra may be used as monotherapy or concomitantly with methotrexate or other DMARDs. The recommended dose of Actemra for adult patients given once every 4 weeks as a 60-minute single intravenous drip infusion is:

Recommended Adult Dosage Every 4 Weeks
Patients who have had an inadequate response to one or more TNF antagonists	When used in combination with DMARDs or as monotherapy the recommended starting dose is 4 mg per kg followed by an increase to 8 mg per kg based on clinical response.

• Reduction of dose from 8 mg per kg to 4 mg per kg is recommended for management of certain dose-related laboratory changes including elevated liver enzymes, neutropenia, and thrombocytopenia [see Dosage and Administration (2.4), Warnings and Precautions (5.3), and Adverse Reactions (6.1)].


• Doses exceeding 800 mg per infusion are not recommended in RA patients [see Clinical Pharmacology (12.3)].

Systemic Juvenile Idiopathic Arthritis

Actemra may be used alone or in combination with methotrexate. The recommended dose of Actemra for SJIA patients given once every 2 weeks as a 60-minute single intravenous drip infusion is:

Recommended SJIA Dosage Every 2 Weeks
Patients less than 30 kg weight	12 mg per kg
Patients at or above 30 kg weight	8 mg per kg

• A change in dose should not be made based solely on a single visit body weight measurement, as weight may fluctuate.


• Interruption of dosing may be needed for management of dose-related laboratory abnormalities including elevated liver enzymes, neutropenia, and thrombocytopenia [see Dosage and Administration (2.4)].

General Considerations for Administration

• Actemra has not been studied and its use should be avoided in combination with biological DMARDs such as TNF antagonists, IL-1R antagonists, anti-CD20 monoclonal antibodies and selective co-stimulation modulators because of the possibility of increased immunosuppression and increased risk of infection.


• It is recommended that Actemra not be initiated in patients with an absolute neutrophil count (ANC) below 2000 per mm3, platelet count below 100,000 per mm3, or who have ALT or AST above 1.5 times the upper limit of normal (ULN).

Actemra for intravenous infusion should be diluted by a healthcare professional using aseptic technique as follows:

• Systemic Juvenile Idiopathic Arthritis Patients less than 30 kg: utilize a 50 mL infusion bag or bottle, then follow steps 1 and 2 below.


• Adult Rheumatoid Arthritis and SJIA patients at or above 30 kg weight: utilize a 100 mL infusion bag or bottle, then follow steps 1 and 2 below.
  

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  Step 1. Withdraw a volume of 0.9% Sodium Chloride Injection, USP, equal to the volume of the Actemra solution required for the patient's dose from the infusion bag or bottle.

  
  

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  Step 2. Slowly add Actemra for intravenous infusion from each vial into the infusion bag or bottle. To mix the solution, gently invert the bag to avoid foaming.

  
  



• The fully diluted Actemra solutions for infusion may be stored at 2° to 8°C (36° to 46°F) or room temperature for up to 24 hours and should be protected from light. Actemra solutions do not contain preservatives; therefore, unused product remaining in the vials should not be used.


• Allow the fully diluted Actemra solution to reach room temperature prior to infusion.


• The infusion should be administered over 60 minutes, and must be administered with an infusion set. Do not administer as an intravenous push or bolus.


• Actemra should not be infused concomitantly in the same intravenous line with other drugs. No physical or biochemical compatibility studies have been conducted to evaluate the co-administration of Actemra with other drugs.


• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If particulates and discolorations are noted, the product should not be used. Fully diluted Actemra solutions are compatible with polypropylene, polyethylene and polyvinyl chloride infusion bags and polypropylene, polyethylene and glass infusion bottles.

Dosage Modifications

Actemra treatment should be interrupted if a patient develops a serious infection until the infection is controlled.

Rheumatoid Arthritis

Liver Enzyme Abnormalities [see Warnings and Precautions (5.3)]:
Lab Value	Recommendation
Greater than 1 to 3x ULN	Dose modify concomitant DMARDs if appropriate For persistent increases in this range, reduce Actemra dose to 4 mg per kg or interrupt Actemra until ALT or AST have normalized
Greater than 3 to 5x ULN (confirmed by repeat testing)	Interrupt Actemra dosing until less than 3x ULN and follow recommendations above for greater than 1 to 3x ULN For persistent increases greater than 3x ULN, discontinue Actemra
Greater than 5x ULN	Discontinue Actemra

Low Absolute Neutrophil Count (ANC) [see Warnings and Precautions (5.3)]:
Lab Value (cells per mm3)	Recommendation
ANC greater than 1000	Maintain dose
ANC 500 to 1000	Interrupt Actemra dosing When ANC greater than 1000 cells per mm3 resume Actemra at 4 mg per kg and increase to 8 mg per kg as clinically appropriate
ANC less than 500	Discontinue Actemra

Low Platelet Count [see Warnings and Precautions (5.3)]:
Lab Value (cells per mm3)	Recommendation
50,000 to 100,000	Interrupt Actemra dosing When platelet count is greater than 100,000 cells per mm3 resume Actemra at 4 mg per kg and increase to 8 mg per kg as clinically appropriate
Less than 50,000	Discontinue Actemra

Systemic Juvenile Idiopathic Arthritis:

Dose reduction of Actemra has not been studied in the SJIA population. Dose interruptions of Actemra are recommended for liver enzyme abnormalities, low neutrophil counts, and low platelet counts in patients with SJIA at levels similar to what is outlined above for patients with RA. If appropriate, concomitant methotrexate and/or other medications should be dose modified or stopped and Actemra dosing interrupted until the clinical situation has been evaluated. In SJIA the decision to discontinue Actemra for a laboratory abnormality should be based upon the medical assessment of the individual patient.

Dosage Forms and Strengths

Single-use vials of Actemra (20 mg per mL):

• 80 mg per 4 mL


• 200 mg per 10 mL


• 400 mg per 20 mL

Contraindications

 Actemra should not be administered to patients with known hypersensitivity to Actemra [see Warnings and Precautions (5.5)].

Warnings and Precautions

Serious Infections

Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, protozoal, or other opportunistic pathogens have been reported in patients receiving immunosuppressive agents including Actemra for rheumatoid arthritis. The most common serious infections included pneumonia, urinary tract infection, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis and bacterial arthritis [see Adverse Reactions (6.1)]. Among opportunistic infections, tuberculosis, cryptococcus, aspergillosis, candidiasis, and pneumocystosis were reported with Actemra. Other serious infections, not reported in clinical studies, may also occur (e.g., histoplasmosis, coccidioidomycosis, listeriosis). Patients have presented with disseminated rather than localized disease, and were often taking concomitant immunosuppressants such as methotrexate or corticosteroids which in addition to rheumatoid arthritis may predispose them to infections.

Actemra should not be administered in patients with an active infection, including localized infections. The risks and benefits of treatment should be considered prior to initiating Actemra in patients:

• with chronic or recurrent infection;


• who have been exposed to tuberculosis;


• with a history of serious or an opportunistic infection;


• who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or


• with underlying conditions that may predispose them to infection.

Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with Actemra, as signs and symptoms of acute inflammation may be lessened due to suppression of the acute phase reactants [see Dosage and Administration (2.3), Adverse Reactions (6.1), and Patient Counseling Information (17)].

Actemra should be interrupted if a patient develops a serious infection, an opportunistic infection, or sepsis. A patient who develops a new infection during treatment with Actemra should undergo a prompt and complete diagnostic workup appropriate for an immunocompromised patient, appropriate antimicrobial therapy should be initiated, and the patient should be closely monitored.

Tuberculosis

Patients should be evaluated for tuberculosis risk factors and tested for latent infection prior to initiating Actemra.

Anti-tuberculosis therapy should also be considered prior to initiation of Actemra in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but having risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision whether initiating anti-tuberculosis therapy is appropriate for an individual patient.

Patients should be closely monitored for the development of signs and symptoms of tuberculosis including patients who tested negative for latent tuberculosis infection prior to initiating therapy.

It is recommended that patients be screened for latent tuberculosis infection prior to starting Actemra. The incidence of tuberculosis in worldwide clinical development programs is 0.1%. Patients with latent tuberculosis should be treated with standard antimycobacterial therapy before initiating Actemra.

Viral Reactivation

Viral reactivation has been reported with immunosuppressive biologic therapies and cases of herpes zoster exacerbation were observed in clinical studies with Actemra. No cases of Hepatitis B reactivation were observed in the trials; however patients who screened positive for hepatitis were excluded.

Gastrointestinal Perforations

 Events of gastrointestinal perforation have been reported in clinical trials, primarily as complications of diverticulitis in RA patients. Actemra should be used with caution in patients who may be at increased risk for gastrointestinal perforation. Patients presenting with new onset abdominal symptoms should be evaluated promptly for early identification of gastrointestinal perforation [see Adverse Reactions (6.1)].

Laboratory Parameters

 Rheumatoid Arthritis

Neutrophils

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.

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It is not recommended to initiate Actemra treatment in 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.

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Neutrophils should be monitored every 4 to 8 weeks [see Clinical Pharmacology (12.2)]. For recommended modifications based on ANC results see Dosage and Administration (2.3).

Platelets

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)].

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It is not recommended to initiate Actemra treatment in 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.

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Platelets should be monitored every 4 to 8 weeks. For recommended modifications based on platelet counts see Dosage and Administration (2.3).

Liver Function Tests

Treatment with Actemra was associated with a higher incidence of transaminase elevations. These elevations did not result in apparent permanent or clinically evident hepatic injury in clinical trials [see Adverse Reactions (6.1)]. Increased frequency and magnitude of these elevations was observed when potentially hepatotoxic drugs (e.g., MTX) were used in combination with Actemra.

In one case, a patient who had received Actemra 8 mg per kg monotherapy without elevations in transaminases experienced elevation in AST to above 10x ULN and elevation in ALT to above 16x ULN when MTX was initiated in combination with Actemra. Transaminases normalized when both treatments were held, but elevations recurred when MTX and Actemra were restarted at lower doses. Elevations resolved when MTX and Actemra were discontinued.

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It is not recommended to initiate Actemra treatment in patients with elevated transaminases ALT or AST greater than 1.5x ULN. In patients who develop elevated ALT or AST greater than 5x ULN treatment is not recommended.

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ALT and AST levels should be monitored every 4 to 8 weeks. When clinically indicated, other liver function tests such as bilirubin should be considered. For recommended modifications based on transaminases see Dosage and Administration (2.3).

Lipids

Treatment with Actemra was associated with increases in lipid parameters such as total cholesterol, triglycerides, LDL cholesterol, and/or HDL cholesterol [see Adverse Reactions (6.1)].

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Assessment of lipid parameters should be performed approximately 4 to 8 weeks following initiation of Actemra therapy, then at approximately 24 week intervals.

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Patients should be managed according to clinical guidelines [e.g., National Cholesterol Educational Program (NCEP)] for the management of hyperlipidemia.

Systemic Juvenile Idiopathic Arthritis

A similar pattern of liver enzyme elevation, low neutrophil count, low platelet count and lipid elevations is noted with Actemra treatment in the SJIA population. Neutrophils, Platelets, ALT and AST should be monitored at the time of the second infusion and thereafter every 2 to 4 weeks. Lipids should be monitored as above for RA [see Dosage and Administration (2.3)].

Immunosuppression

The impact of treatment with Actemra on the development of malignancies is not known but malignancies were observed in clinical studies [see Adverse Reactions (6.1)]. Actemra is an immunosuppressant, and treatment with immunosuppressants may result in an increased risk of malignancies.

Hypersensitivity Reactions, Including Anaphylaxis

 Hypersensitivity reactions, including anaphylaxis and death, have been reported in association with infusion of Actemra [see Adverse Reactions (6.1)]. Anaphylaxis and other hypersensitivity reactions that required treatment discontinuation were reported in 0.1% (3 out of 2644) of patients in the 6-month controlled trials, and in 0.2% (8 out of 4009) of patients in the all-exposure rheumatoid arthritis population; and in the SJIA controlled trial, 1 out of 112 patients (0.9%). In the postmarketing setting, a patient with a previous infusion reaction and premedicated with steroids and antihistamines experienced fatal anaphylaxis during subsequent treatment with Actemra [see Adverse Reactions (6.2)]. Actemra should only be administered by a healthcare professional with appropriate medical support to manage anaphylaxis. If anaphylaxis or other clinically significant hypersensitivity reaction occurs, administration of Actemra should be stopped immediately and Actemra should be permanently discontinued. Do not administer Actemra to patients with known hypersensitivity to Actemra [see Contraindications (4) and Adverse Reactions (6)].

Demyelinating Disorders

 The impact of treatment with Actemra on demyelinating disorders is not known, but multiple sclerosis and chronic inflammatory demyelinating polyneuropathy were reported rarely in RA clinical studies. Patients should be closely monitored for signs and symptoms potentially indicative of demyelinating disorders. Prescribers should exercise caution in considering the use of Actemra in patients with preexisting or recent onset demyelinating disorders.

Active Hepatic Disease and Hepatic Impairment

Treatment with Actemra is not recommended in patients with active hepatic disease or hepatic impairment [see Adverse Reactions (6.1), Use in Specific Populations (8.6)].

Vaccinations

 Live vaccines should not be given concurrently with Actemra as clinical safety has not been established. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving Actemra. No data are available on the effectiveness of vaccination in patients receiving Actemra. Because IL-6 inhibition may interfere with the normal immune response to new antigens, it is recommended that all patients, particularly systemic juvenile idiopathic arthritis patients, if possible, be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating Actemra therapy. The interval between live vaccinations and initiation of Actemra therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.

Adverse Reactions

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in clinical practice.

Clinical Trials Experience

 Rheumatoid Arthritis

The Actemra data in rheumatoid arthritis (RA) includes 5 double-blind, controlled, multicenter studies. In these studies, patients received doses of Actemra 8 mg per kg monotherapy (288 patients), Actemra 8 mg per kg in combination with DMARDs (including methotrexate) (1582 patients), or Actemra 4 mg per kg in combination with methotrexate (774 patients).

The all exposure population includes all patients in registration studies who received at least one dose of Actemra. Of the 4009 patients in this population, 3577 received treatment for at least 6 months, 3309 for at least one year; 2954 received treatment for at least 2 years and 2189 for 3 years.

All patients in these studies had moderately to severely active rheumatoid arthritis. The study population had a mean age of 52 years, 82% were female and 74% were Caucasian.

The most common serious adverse reactions were serious infections [see Warnings and Precautions (5.1)]. The most commonly reported adverse reactions in controlled studies up to 24 weeks (occurring in at least 5% of patients treated with Actemra monotherapy or in combination with DMARDs) were upper respiratory tract infections, nasopharyngitis, headache, hypertension and increased ALT.

The proportion of patients who discontinued treatment due to any adverse reactions during the double-blind, placebo-controlled studies was 5% for patients taking Actemra and 3% for placebo-treated patients. The most common adverse reactions that required discontinuation of Actemra were increased hepatic transaminase values (per protocol requirement) and serious infections.

Overall Infections

In the 24 week, controlled clinical studies, the rate of infections in the Actemra monotherapy group was 119 events per 100 patient-years and was similar in the methotrexate monotherapy group. The rate of infections in the 4 mg per kg and 8 mg per kg Actemra plus DMARD group was 133 and 127 events per 100 patient-years, respectively, compared to 112 events per 100 patient-years in the placebo plus DMARD group. The most commonly reported infections (5% to 8% of patients) were upper respiratory tract infections and nasopharyngitis.

The overall rate of infections with Actemra in the all exposure population remained consistent with rates in the controlled periods of the studies.

Serious Infections

In the 24 week, controlled clinical studies, the rate of serious infections in the Actemra monotherapy group was 3.6 per 100 patient-years compared to 1.5 per 100 patient-years in the methotrexate group. The rate of serious infections in the 4 mg per kg and 8 mg per kg Actemra plus DMARD group was 4.4 and 5.3 events per 100 patient-years, respectively, compared to 3.9 events per 100 patient-years in the placebo plus DMARD group.

In the all-exposure population, the overall rate of serious infections remained consistent with rates in the controlled periods of the studies. The most common serious infections included pneumonia, urinary tract infection, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis and bacterial arthritis. Cases of opportunistic infections have been reported [see Warnings and Precautions (5.1)].

Gastrointestinal Perforations

During the 24 week, controlled clinical trials, the overall rate of gastrointestinal perforation was 0.26 events per 100 patient-years with Actemra therapy.

In the all-exposure population, the overall rate of gastrointestinal perforation remained consistent with rates in the controlled periods of the studies. Reports of gastrointestinal perforation were primarily reported as complications of diverticulitis including generalized purulent peritonitis, lower GI perforation, fistula and abscess. Most patients who developed gastrointestinal perforations were taking concomitant nonsteroidal anti-inflammatory medications (NSAIDs), corticosteroids, or methotrexate [see Warnings and Precautions (5.2)]. The relative contribution of these concomitant medications versus Actemra to the development of GI perforations is not known.

Infusion Reactions

In the 24 week, controlled clinical studies, adverse events associated with the infusion (occurring during or within 24 hours of the start of infusion) were reported in 8% and 7% of patients in the 4 mg per kg and 8 mg per kg Actemra plus DMARD group, respectively, compared to 5% of patients in the placebo plus DMARD group. The most frequently reported event on the 4 mg per kg and 8 mg per kg dose during the infusion was hypertension (1% for both doses), while the most frequently reported event occurring within 24 hours of finishing an infusion were headache (1% for both doses) and skin reactions (1% for both doses), including rash, pruritus and urticaria. These events were not treatment limiting.

Anaphylaxis

Clinically significant hypersensitivity reactions, including anaphylaxis associated with Actemra and requiring treatment discontinuation were reported in 0.1% (3 out of 2644) in the 24 week, controlled trials and in 0.2% (8 out of 4009) in the all-exposure population. These reactions were generally observed during the second to fourth infusion of Actemra. Appropriate medical treatment should be available for immediate use in the event of a serious hypersensitivity reaction [see Warnings and Precautions (5.5)].

Laboratory Tests

Neutrophils

In the 24 week, controlled clinical studies, decreases in neutrophil counts below 1000 per mm3 occurred in 1.8% and 3.4% of patients in the 4 mg per kg and 8 mg per kg Actemra plus DMARD group, respectively, compared to 0.1% of patients in the placebo plus DMARD group. Approximately half of the instances of ANC below 1000 per mm3 occurred within 8 weeks of starting therapy. Decreases in neutrophil counts below 500 per mm3 occurred in 0.4% and 0.3% of patients in the 4 mg per kg and 8 mg per kg Actemra plus DMARD, respectively, compared to 0.1% of patients in the placebo plus DMARD group. There was no clear relationship between decreases in neutrophils below 1000 per mm3 and the occurrence of serious infections.

In the all-exposure population, the pattern and incidence of decreases in neutrophil counts remained consistent with what was seen in the 24 week controlled clinical studies [see Warnings and Precautions (5.3)].

Platelets

In the 24 week, controlled clinical studies, decreases in platelet counts below 100,000 per mm3 occurred in 1.3% and 1.7% of patients on 4 mg per kg and 8 mg per kg Actemra plus DMARD, respectively, compared to 0.5% of patients on placebo plus DMARD, without associated bleeding events.

In the all-exposure population, the pattern and incidence of decreases in platelet counts remained consistent with what was seen in the 24 week controlled clinical studies [see Warnings and Precautions (5.3)].

Liver Function Tests

Liver enzyme abnormalities are summarized in Table 1. In patients experiencing liver enzyme elevation, modification of treatment regimen, such as reduction in the dose of concomitant DMARD, interruption of Actemra, or reduction in Actemra dose, resulted in decrease or normalization of liver enzymes [see Dosage and Administration (2.3)]. These elevations were not associated with clinically relevant increases in direct bilirubin, nor were they associated with clinical evidence of hepatitis or hepatic insufficiency [see Warnings and Precautions (5.3)].

Table 1 Incidence of Liver Enzyme Abnormalities in the 24 Week Controlled Period of Studies I to V*

	Actemra 8 mg per kg MONOTHERAPY	Methotrexate	Actemra 4 mg per kg + DMARDs	Actemra 8 mg per kg + DMARDs	Placebo + DMARDs
	N = 288 (%)	N = 284 (%)	N = 774 (%)	N = 1582 (%)	N = 1170 (%)
ULN = Upper Limit of Normal
* For a description of these studies, see Section 14, Clinical Studies.
AST (U/L)
> ULN to 3x ULN	22	26	34	41	17
> 3x ULN to 5x ULN	0.3	2	1	2	0.3
> 5x ULN	0.7	0.4	0.1	0.2	< 0.1
ALT (U/L)
> ULN to 3x ULN	36	33	45	48	23
> 3x ULN to 5x ULN	1	4	5	5	1
> 5x ULN	0.7	1	1.3	1.5	0.3

In the all-exposure population, the elevations in ALT and AST remained consistent with what was seen in the 24 week, controlled clinical trials

Lipids

Elevations in lipid parameters (total cholesterol, LDL, HDL, triglycerides) were first assessed at 6 weeks following initiation of Actemra in the controlled 24 week clinical trials. Increases were observed at this time point and remained stable thereafter. Increases in triglycerides to levels above 500 mg per dL were rarely observed. Changes in other lipid parameters from baseline to week 24 were evaluated and are summarized below:

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Mean LDL increased by 13 mg per dL in the Actemra 4 mg per kg+DMARD arm, 20 mg per dL in the Actemra 8 mg per kg+DMARD, and 25 mg per dL in Actemra 8 mg per kg monotherapy.

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Mean HDL increased by 3 mg per dL in the Actemra 4 mg per kg+DMARD arm, 5 mg per dL in the Actemra 8 mg per kg+DMARD, and 4 mg per dL in Actemra 8 mg per kg monotherapy.

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Mean LDL/HDL ratio increased by an average of 0.14 in the Actemra 4 mg per kg+DMARD arm, 0.15 in the Actemra 8 mg per kg+DMARD, and 0.26 in Actemra 8 mg per kg monotherapy.

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ApoB/ApoA1 ratios were essentially unchanged in Actemra-treated patients.

Elevated lipids responded to lipid lowering agents.

In the all-exposure population, the elevations in lipid parameters remained consistent with what was seen in the 24 week, controlled clinical trials.

Immunogenicity

In the 24 week, controlled clinical studies, a total of 2876 patients have been tested for anti-tocilizumab antibodies. Forty-six patients (2%) developed positive anti-tocilizumab antibodies, of whom 5 had an associated, medically significant, hypersensitivity reaction leading to withdrawal. Thirty patients (1%) developed neutralizing antibodies.

The data reflect the percentage of patients whose test results were positive for antibodies to tocilizumab in specific assays. The observed incidence of antibody positivity in an assay is highly dependent on several factors, including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medication, and underlying disease. For these reasons, comparison of the incidence of antibodies to tocilizumab with the incidence of antibodies to other products may be misleading.

Malignancies

During the 24 week, controlled period of the studies, 15 malignancies were diagnosed in patients receiving Actemra, compared to 8 malignancies in patients in the control groups. Exposure-adjusted incidence was similar in the Actemra groups (1.32 events per 100 patient-years) and in the placebo plus DMARD group (1.37 events per 100 patient-years).

In the all-exposure population, the rate of malignancies remained consistent with the rate observed in the 24 week, controlled period [see Warnings and Precautions (5.4)].

Other Adverse Reactions

Adverse reactions occurring in 2% or more of patients on 4 or 8 mg per kg Actemra plus DMARD and at least 1% greater than that observed in patients on placebo plus DMARD are summarized in Table 2.

Table 2 Adverse Reactions Occurring in at Least 2% or More of Patients on 4 or 8 mg per kg Actemra plus DMARD and at Least 1% Greater Than That Observed in Patients on Placebo plus DMARD

24 Week Phase 3 Controlled Study Population
	Actemra 8 mg per kg MONOTHERAPY	Methotrexate	Actemra 4 mg per kg + DMARDs	Actemra 8 mg per kg + DMARDs	Placebo + DMARDs
Preferred Term	N = 288 (%)	N = 284 (%)	N = 774 (%)	N = 1582 (%)	N = 1170 (%)
Upper Respiratory Tract Infection	7	5	6	8	6
Nasopharyngitis	7	6	4	6	4
Headache	7	2	6	5	3
Hypertension	6	2	4	4	3
ALT increased	6	4	3	3	1
Dizziness	3	1	2	3	2
Bronchitis	3	2	4	3	3
Rash	2	1	4	3	1
Mouth Ulceration	2	2	1	2	1
Abdominal Pain Upper	2	2	3	3	2
Gastritis	1	2	1	2	1
Transaminase increased	1	5	2	2	1

Other infrequent and medically relevant adverse reactions occurring at an incidence less than 2% in rheumatoid arthritis patients treated with Actemra in controlled trials were:

Infections and Infestations: oral herpes simplex

Gastrointestinal disorders: stomatitis, gastric ulcer

Investigations: weight increased, total bilirubin increased

Blood and lymphatic system disorders: leukopenia

General disorders and administration site conditions: edema peripheral

Respiratory, thoracic, and mediastinal disorders: dyspnea, cough

Eye disorders: conjunctivitis

Renal disorders: nephrolithiasis

Endocrine disorders: hypothyroidism

Systemic Juvenile Idiopathic Arthritis

The data described below reflect exposure to Actemra in one randomized, double-blind, placebo-controlled trial of 112 pediatric patients with SJIA 2 to 17 years of age who had an inadequate clinical response to nonsteroidal anti-inflammatory drugs (NSAIDs) or corticosteroids due to toxicity or lack of efficacy. At baseline, approximately half of the patients were taking 0.3 mg/kg/day corticosteroids or more, and almost 70% were taking methotrexate. The trial included a 12 week controlled phase followed by an open-label extension. In the 12 week double-blind, controlled portion of the clinical study 75 patients received treatment with Actemra (8 or 12 mg per kg based upon body weight). After 12 weeks or at the time of escape, due to disease worsening, patients were treated with Actemra in the open-label extension phase.

The most common adverse events (at least 5%) seen in Actemra treated patients in the 12 week controlled portion of the study were: upper respiratory tract infection, headache, nasopharyngitis and diarrhea.

Infections

In the 12 week controlled phase, the rate of all infections in the Actemra group was 345 per 100 patient-years and 287 per 100 patient-years in the placebo group. In the open label extension over an average duration of 73 weeks of treatment, the overall rate of infections was 304 per 100 patient-years.

In the 12 week controlled phase, the rate of serious infections in the Actemra group was 11.5 per 100 patient years. In the open label extension over an average duration of 73 weeks of treatment, the overall rate of serious infections was 11.4 per 100 patient years. The most commonly reported serious infections included pneumonia, gastroenteritis, varicella, and otitis media.

Macrophage Activation Syndrome

In the 12 week controlled study, no patient in any treatment group experienced macrophage activation syndrome (MAS) while on assigned treatment; 3 per 112 (3%) developed MAS during open-label treatment with Actemra. One patient in the placebo group escaped to Actemra 12 mg per kg at Week 2 due to severe disease activity, and ultimately developed MAS at Day 70. Two additional patients developed MAS during the long-term extension. All 3 patients had Actemra dose interrupted (2 patients) or discontinued (1 patient) for the MAS event, received treatment, and the MAS resolved without sequelae. Based on a limited number of cases, the incidence of MAS does not appear to be elevated in the Actemra SJIA clinical development experience; however no definitive conclusions can be made.

Infusion Reactions

Patients were not premedicated, however most patients were on concomitant corticosteroids as part of their background treatment for SJIA. Infusion related reactions were defined as all events occurring during or within 24 hours after an infusion. In the 12 week controlled phase, 4% of Actemra and 0% of placebo treated patients experienced events occurring during infusion. One event (angioedema) was considered serious and life-threatening, and the patient was discontinued from study treatment.

Within 24 hours after infusion, 16% of patients in the Actemra treatment group and 5% of patients in the placebo group experienced an event. In the Actemra group the events included rash, urticaria, diarrhea, epigastric discomfort, arthralgia and headache. One of these events, urticaria, was considered serious.

Anaphylaxis

Anaphylaxis was reported in 1 out of 112 patients (less than 1%) treated with Actemra during the controlled and open label extension study [see Warnings (5.5)].

Immunogenicity

All 112 patients were tested for anti-tocilizumab antibodies at baseline. Two patients developed positive anti-tocilizumab antibodies: one of these patients experienced serious adverse events of urticaria and angioedema consistent with an anaphylactic reaction which led to withdrawal; the other patient developed macrophage activation syndrome while on escape therapy and was discontinued from the study.