Actemra

Name: Actemra

Is tocilizumab available as a generic drug?

No

What is the most important information I should know about tocilizumab?

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.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Introduction

Biologic response modifier and a disease-modifying antirheumatic drug (DMARD); a recombinant humanized IgG1 monoclonal antibody specific for interleukin-6 (IL-6) receptor.1 3 4 5 6 9 10 11 13

Actemra Dosage and Administration

General

  • Do not initiate tocilizumab therapy in patients with ANC <2000/mm3, platelet count <100,000/mm3, or ALT or AST concentration >1.5 times the ULN.1

Concomitant Therapy

  • Methotrexate, other nonbiologic DMARDs, NSAIAs, and corticosteroids may be continued in patients with rheumatoid arthritis.1

  • Methotrexate, NSAIAs, and corticosteroids may be continued in patients with systemic or polyarticular JIA.1 20 21

  • Do not use concomitantly with other biologic DMARDs.1 (See Uses.)

Administration

Administer by IV infusion.1 Also may administer by sub-Q injection in the management of rheumatoid arthritis in adults.1 Not currently FDA-labeled for sub-Q use in the management of polyarticular or systemic JIA.1

IV Administration

For solution compatibility information, see Compatibility under Stability.

Administer by IV infusion.1

Tocilizumab injection concentrate must be diluted prior to IV administration.1

Allow tocilizumab infusion solutions to reach room temperature prior to administration.1 (See Storage under Stability.)

Do not infuse tocilizumab simultaneously through the same IV line with other drugs.1

Dilution

Dilute tocilizumab injection concentrate (20 mg/mL) in 0.9% sodium chloride injection to provide a total volume of 50 mL (for patients with polyarticular or systemic JIA who weigh <30 kg) or 100 mL (for adults with rheumatoid arthritis or patients with polyarticular or systemic JIA who weigh ≥30 kg).1

Remove a volume of diluent equal to the total required volume of the injection concentrate from the bag or bottle of 0.9% sodium chloride injection prior to adding the injection concentrate.1 Slowly add the total required volume of tocilizumab injection concentrate (0.2, 0.4, 0.5, or 0.6 mL/kg for a dose of 4, 8, 10, or 12 mg/kg, respectively) to the diluent; gently invert bag or bottle to mix the solution.1

Tocilizumab infusion solutions are compatible with polypropylene, polyethylene, and polyvinyl chloride infusion bags and polypropylene, polyethylene, and glass infusion bottles.1

Discard any unused portion remaining in the vial since the injection concentrate contains no preservative.1

Rate of Administration

Infuse dose over 60 minutes; do not administer by rapid IV injection (e.g., IV push or bolus).1

Sub-Q Administration

Intended for use under the guidance and supervision of a clinician, but may be self-administered if the clinician determines that the patient and/or their caregiver is competent to safely administer the drug after appropriate training.1

Allow prefilled syringe to sit at room temperature outside of carton for 30 minutes prior to injection; do not warm tocilizumab in any other way (e.g., microwave, hot water).1 19

Administer sub-Q injections into anterior thigh or abdomen (except for the 2-inch area around the umbilicus); may be administered into upper arm by a caregiver.19 Rotate injection sites.1 Do not make injections into areas where the skin is tender, bruised, red, hard, or nonintact or into scars or moles.1

Do not use the commercially available sub-Q injection for IV administration.1

Dosage

Pediatric Patients

Juvenile Idiopathic Arthritis (JIA) IV

Polyarticular JIA in patients ≥2 years of age: 10 mg/kg once every 4 weeks in those weighing <30 kg; 8 mg/kg once every 4 weeks in those weighing ≥30 kg.1

Systemic JIA in patients ≥2 years of age: 12 mg/kg once every 2 weeks in those weighing <30 kg; 8 mg/kg once every 2 weeks in those weighing ≥30 kg.1

Do not adjust dosage based solely on patient's weight as measured at a single visit, as weight may fluctuate.1

Treatment Interruption or Discontinuance for Toxicity IV

If a serious infection, an opportunistic infection, or sepsis develops, discontinue tocilizumab until the infection is controlled.1

If certain dose-related laboratory changes (i.e., elevated ALT or AST concentrations, neutropenia, thrombocytopenia) occur, interrupt tocilizumab therapy at values similar to those considered in adults with rheumatoid arthritis (see tables).1 If clinically appropriate, consider dosage reduction or discontinuance of concomitant methotrexate and/or other therapy and withhold tocilizumab pending clinical evaluation.1 Individualize the decision to discontinue tocilizumab.1

Tocilizumab dosage reductions not evaluated in patients with polyarticular or systemic JIA.1

Adults

Rheumatoid Arthritis IV

Initially, 4 mg/kg once every 4 weeks; may increase to 8 mg/kg once every 4 weeks based on clinical response.1 Doses >800 mg are not recommended (see Elimination: Special Populations, under Pharmacokinetics).1

Sub-Q

Adults weighing <100 kg: 162 mg every other week; may increase to 162 mg every week based on clinical response.1

Patients weighing ≥100 kg: 162 mg every week.1 Patients in clinical study who weighed ≥100 kg had poorer responses to dosage of 162 mg every other week than did patients in lower-weight categories.22 (See Absorption: Special Populations, under Pharmacokinetics.)

When switching from IV to sub-Q administration, administer first sub-Q dose in place of the next scheduled IV dose.1

Dosage Modification or Discontinuance for Toxicity IV or Sub-Q

If a serious infection, an opportunistic infection, or sepsis develops, discontinue tocilizumab until the infection is controlled.1

If certain dose-related laboratory changes (i.e., elevated ALT or AST concentrations, neutropenia, thrombocytopenia) occur in patients receiving tocilizumab 8 mg/kg IV every 4 weeks, reduce tocilizumab dosage to 4 mg/kg IV every 4 weeks or temporarily interrupt or discontinue therapy (see tables).1

If such dose-related laboratory changes occur in patients receiving sub-Q tocilizumab, reduce frequency of tocilizumab administration from weekly to every other week or temporarily interrupt or discontinue therapy (see tables).1

Table 1. Recommended Dosage Adjustment Based on Changes in Liver Enzyme Laboratory Value

ALT or AST Value

Recommendation

>1 to 3 times ULN

Modify dosage of concomitant DMARDs if appropriate1

 

For persistent increases within this range:

 

IV: Reduce tocilizumab dosage to 4 mg/kg every 4 weeks or interrupt tocilizumab therapy until ALT/AST values have returned to normal1

 

Sub-Q: Reduce frequency of administration to every other week or interrupt tocilizumab therapy until ALT/AST values have returned to normal; resume sub-Q tocilizumab with administration every other week and increase frequency to every week as clinically indicated1

>3 to 5 times ULN (confirmed by repeat testing)

Interrupt tocilizumab therapy until ALT/AST values are <3 times ULN and follow recommendations for ALT/AST values of >1 to 3 times ULN1

 

For persistent increases of >3 times ULN, discontinue tocilizumab1

>5 times ULN

Discontinue tocilizumab1

Table 2. Recommended Dosage Adjustment Based on Absolute Neutrophil Count (ANC)

ANC (cells/mm3 )

Recommendation

>1000

Maintain current dosage1

500–1000

Interrupt tocilizumab therapy1

 

When ANC is >1000/mm3:

 

IV: Resume tocilizumab at 4 mg/kg every 4 weeks and increase to 8 mg/kg every 4 weeks as clinically indicated1

 

Sub-Q: Resume tocilizumab with administration every other week and increase frequency to every week as clinically indicated1

<500

Discontinue tocilizumab1

Table 3. Recommended Dosage Adjustment Based on Platelet Count

Platelet Count (cells/mm3)

Recommendation

50,0000–100,000

Interrupt tocilizumab therapy1

 

When platelet count is >100,000/mm3:

 

IV: Resume tocilizumab at 4 mg/kg every 4 weeks and increase to 8 mg/kg every 4 weeks as clinically indicated1

 

Sub-Q: Resume tocilizumab with administration every other week and increase frequency to every week as clinically indicated1

<50,000

Discontinue tocilizumab1

Prescribing Limits

Adults

Rheumatoid Arthritis IV

Maximum 800 mg per dose.1

Special Populations

Hepatic Impairment

Use is not recommended.1

Renal Impairment

Dosage adjustment not necessary in patients with mild renal impairment; not evaluated in moderate or severe renal impairment.1

Geriatric Patients

Manufacturer makes no specific dosage recommendations.1

Actemra Pharmacokinetics

Absorption

Bioavailability

Following sub-Q injection, bioavailability is 80%.1

Plasma Concentrations

Increase in IV dosage from 4 mg/kg to 8 mg/kg every 4 weeks associated with greater-than-proportional increases in AUC and trough plasma concentrations.1

Special Populations

At fixed sub-Q dosage, tocilizumab exposure is inversely related to body weight.1

Following IV dose of 8 mg/kg, systemic drug exposure is substantially greater in individuals weighing >100 kg than in those weighing <60 kg, since linear clearance increases as body size increases.1

Distribution

Extent

Not known whether tocilizumab is distributed into milk.1

Elimination

Half-life

Adults with rheumatoid arthritis: Up to 11 days at IV dosage of 4 mg/kg every 4 weeks; up to 13 days at IV dosage of 8 mg/kg every 4 weeks or sub-Q dosage of 162 mg every week; up to 5 days after sub-Q dosage of 162 mg every other week.1

Pediatric patients with polyarticular JIA: Up to 16 days.1

Pediatric patients with systemic JIA: Up to 23 days.1

Clearance decreases as dose increases.1 At low tocilizumab concentrations, concentration-dependent nonlinear clearance plays a major role in determining total drug clearance; at higher concentrations, nonlinear pathway is saturated and clearance is determined mainly by linear clearance.1

Special Populations

As body size increases, linear clearance increases.1 Following a weight-based IV dose of 8 mg/kg, systemic drug exposure is substantially greater in individuals weighing >100 kg than in those weighing <60 kg.1

Pharmacokinetics not formally studied in renal or hepatic impairment.1 Population pharmacokinetic data indicate that mild renal impairment (Clcr ≥50 mL/minute but <80 mL/minute) does not alter pharmacokinetics.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 Disease-Modifying Anti-Rheumatic Drugs (DMARDs).

Giant Cell Arteritis (GCA)

Actemra® (tocilizumab) is indicated for the treatment of giant cell arteritis (GCA) in adult patients.

Polyarticular Juvenile Idiopathic Arthritis (PJIA)

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

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.

Cytokine Release Syndrome (CRS)

Actemra® (tocilizumab) is indicated for the treatment of chimeric antigen receptor (CAR) T cell-induced severe or life-threatening cytokine release syndrome in adults and pediatric patients 2 years of age and older.

Contraindications

Actemra is contraindicated in patients with known hypersensitivity to Actemra [see Warnings and Precautions (5.5)].

Adverse Reactions

The following serious adverse reactions are described elsewhere in labeling:

  • Serious Infections [see Warnings and Precautions (5.1)]
  • Gastrointestinal Perforations [see Warnings and Precautions (5.2)]
  • Laboratory Parameters [see Warnings and Precautions (5.3)]
  • Immunosuppression [see Warnings and Precautions (5.4)]
  • Hypersensitivity Reactions, Including Anaphylaxis [see Warnings and Precautions (5.5)]
  • Demyelinating Disorders [see Warnings and Precautions (5.6)]
  • Active Hepatic Disease and Hepatic Impairment [see Warnings and Precautions (5.7)]

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 in Rheumatoid Arthritis Patients Treated with Intravenous Actemra (Actemra-IV)

The Actemra-IV data in rheumatoid arthritis (RA) includes 5 double-blind, controlled, multicenter studies. In these studies, patients received doses of Actemra-IV 8 mg per kg monotherapy (288 patients), Actemra-IV 8 mg per kg in combination with DMARDs (including methotrexate) (1582 patients), or Actemra-IV 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-IV. 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-IV 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-IV and 3% for placebo-treated patients. The most common adverse reactions that required discontinuation of Actemra-IV 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-IV 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-IV 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-IV 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-IV 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-IV 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-IV 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-IV 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-IV 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

Hypersensitivity reactions requiring treatment discontinuation, including anaphylaxis, associated with Actemra-IV 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-IV. Appropriate medical treatment should be available for immediate use in the event of a serious hypersensitivity reaction [see Warnings and Precautions (5.5)].

Laboratory Abnormalities

Neutropenia

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-IV 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-IV 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)].

Thrombocytopenia

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-IV 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)].

Elevated Liver Enzymes

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-IV, or reduction in Actemra-IV dose, resulted in decrease or normalization of liver enzymes [see Dosage and Administration (2.6)]. 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 3× ULN 22 26 34 41 17
> 3× ULN to 5× ULN 0.3 2 1 2 0.3
> 5× ULN 0.7 0.4 0.1 0.2 < 0.1
ALT (U/L)
> ULN to 3× ULN 36 33 45 48 23
> 3× ULN to 5× ULN 1 4 5 5 1
> 5× 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-IV 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:

– 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. – 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. – 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. – 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

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to tocilizumab in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

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.

Malignancies

During the 24 week, controlled period of the studies, 15 malignancies were diagnosed in patients receiving Actemra-IV, compared to 8 malignancies in patients in the control groups. Exposure-adjusted incidence was similar in the Actemra-IV 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-IV 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-IV 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

Clinical Trials Experience in Rheumatoid Arthritis Patients Treated with Subcutaneous Actemra (Actemra-SC)

The Actemra-SC data in rheumatoid arthritis (RA) includes 2 double-blind, controlled, multicenter studies. Study SC-I was a non-inferiority study that compared the efficacy and safety of tocilizumab 162 mg administered every week subcutaneously (SC) and 8 mg/kg intravenously (IV) every four weeks in 1262 adult subjects with rheumatoid arthritis. Study SC-II was a placebo controlled superiority study that evaluated the safety and efficacy of tocilizumab 162 mg administered every other week SC or placebo in 656 patients. All patients in both studies received background non-biologic DMARDs.

The safety observed for Actemra administered subcutaneously was consistent with the known safety profile of intravenous Actemra, with the exception of injection site reactions, which were more common with Actemra-SC compared with placebo SC injections (IV arm).

Injection Site Reactions

In the 6-month control period, in SC-I, the frequency of injection site reactions was 10.1% (64/631) and 2.4% (15/631) for the weekly Actemra-SC and placebo SC (IV-arm) groups, respectively. In SC-II, the frequency of injection site reactions was 7.1% (31/437) and 4.1% (9/218) for the every other week SC Actemra and placebo groups, respectively. These injection site reactions (including erythema, pruritus, pain and hematoma) were mild to moderate in severity. The majority resolved without any treatment and none necessitated drug discontinuation.

Immunogenicity

In the 6-month control period in SC-I, 0.8% (5/625) in the Actemra-SC arm and 0.8% (5/627) in the IV arm developed anti-tocilizumab antibodies; of these, all developed neutralizing antibodies. In SC-II, 1.6% (7/434) in the Actemra-SC arm compared with 1.4 % (3/217) in the placebo arm developed anti- tocilizumab antibodies; of these, 1.4% (6/434) in the Actemra-SC arm and 0.5% (1/217) in the placebo arm also developed neutralizing antibodies.

A total of 1454 (>99%) patients who received Actemra-SC in the all exposure group have been tested for anti-tocilizumab antibodies. Thirteen patients (0.9%) developed anti-tocilizumab antibodies, and, of these, 12 patients (0.8%) developed neutralizing antibodies.

The rate is consistent with previous intravenous experience. No correlation of antibody development to adverse events or loss of clinical response was observed.

Laboratory Abnormalities

Neutropenia

During routine laboratory monitoring in the 6-month controlled clinical trials, a decrease in neutrophil count below 1 × 109/L occurred in 2.9% and 3.7% of patients receiving Actemra-SC weekly and every other week, respectively.

There was no clear relationship between decreases in neutrophils below 1 × 109/L and the occurrence of serious infections.

Thrombocytopenia

During routine laboratory monitoring in the Actemra-SC 6-month controlled clinical trials, none of the patients had a decrease in platelet count to ≤50,000/mm3.

Elevated Liver Enzymes

During routine laboratory monitoring in the 6-month controlled clinical trials, elevation in ALT or AST ≥3 × ULN occurred in 6.5% and 1.4% of patients, respectively, receiving Actemra-SC weekly and 3.4% and 0.7% receiving Actemra SC every other week.

Lipid Parameters Elevations

During routine laboratory monitoring in the Actemra-SC 6-month clinical trials, 19% of patients dosed weekly and 19.6% of patients dosed every other week and 10.2% of patients on placebo experienced sustained elevations in total cholesterol > 6.2 mmol/l (240 mg/dL), with 9%, 10.4% and 5.1% experiencing a sustained increase in LDL to 4.1 mmol/l (160 mg/dL) receiving Actemra-SC weekly, every other week and placebo, respectively.

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 + 26 week prednisone taper and 210.2/12.5 events per 100 patient years in the placebo + 52 week taper groups.

Clinical Trials Experience in Polyarticular Juvenile Idiopathic Arthritis Patients Treated With Intravenous Actemra (Actemra-IV)

The safety of Actemra-IV was studied in 188 pediatric patients 2 to 17 years of age with PJIA who had an inadequate clinical response or were intolerant to methotrexate. The total patient exposure in the Actemra-IV all exposure population (defined as patients who received at least one dose of Actemra-IV) was 184.4 patient years. At baseline, approximately half of the patients were taking oral corticosteroids and almost 80% were taking methotrexate. In general, the types of adverse drug reactions in patients with PJIA were consistent with those seen in RA and SJIA patients [see Adverse Reactions (6.1 and 6.5)].

Infections

The rate of infections in the Actemra-IV all exposure population was 163.7 per 100 patient years. The most common events observed were nasopharyngitis and upper respiratory tract infections. The rate of serious infections was numerically higher in patients weighing less than 30 kg treated with 10 mg/kg tocilizumab (12.2 per 100 patient years) compared to patients weighing at or above 30 kg, treated with 8 mg/kg tocilizumab (4.0 per 100 patient years). The incidence of infections leading to dose interruptions was also numerically higher in patients weighing less than 30 kg treated with 10 mg/kg tocilizumab (21%) compared to patients weighing at or above 30 kg, treated with 8 mg/kg tocilizumab (8%).

Infusion Reactions

In PJIA patients, infusion-related reactions are defined as all events occurring during or within 24 hours of an infusion. In the Actemra-IV all exposure population, 11 patients (6%) experienced an event during the infusion, and 38 patients (20.2%) experienced an event within 24 hours of an infusion. The most common events occurring during infusion were headache, nausea and hypotension, and occurring within 24 hours of infusion were dizziness and hypotension. In general, the adverse drug reactions observed during or within 24 hours of an infusion were similar in nature to those seen in RA and SJIA patients [see Adverse Reactions (6.1 and 6.5)].

No clinically significant hypersensitivity reactions associated with tocilizumab and requiring treatment discontinuation were reported.

Immunogenicity

One patient, in the 10 mg/kg less than 30 kg group, developed positive anti-tocilizumab antibodies without developing a hypersensitivity reaction and subsequently withdrew from the study.

Laboratory Abnormalities

Neutropenia

During routine laboratory monitoring in the Actemra-IV all exposure population, a decrease in neutrophil counts below 1 × 109 per L occurred in 3.7% of patients.

There was no clear relationship between decreases in neutrophils below 1 × 109 per L and the occurrence of serious infections.

Thrombocytopenia

During routine laboratory monitoring in the Actemra-IV all exposure population, 1% of patients had a decrease in platelet count at or less than 50,000 per mm3 without associated bleeding events.

Elevated Liver Enzymes

During routine laboratory monitoring in the Actemra-IV all exposure population, elevation in ALT or AST at or greater than 3 × ULN occurred in 4% and less than 1% of patients, respectively.

Lipids

During routine laboratory monitoring in the tocilizumab all exposure population, elevation in total cholesterol greater than 1.5-2 × ULN occurred in one patient (0.5%) and elevation in LDL greater than 1.5-2 × ULN occurred in one patient (0.5%).

Clinical Trials Experience in Systemic Juvenile Idiopathic Arthritis Patients Treated with Intravenous Actemra (Actemra-IV)

The data described below reflect exposure to Actemra-IV 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-IV (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-IV in the open-label extension phase.

The most common adverse events (at least 5%) seen in Actemra-IV 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-IV 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-IV 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-IV. One patient in the placebo group escaped to Actemra-IV 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-IV 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-IV 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-IV 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-IV treatment group and 5% of patients in the placebo group experienced an event. In the Actemra-IV 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-IV during the controlled and open label extension study [see Warnings and Precautions (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.

Laboratory Abnormalities

Neutropenia

During routine monitoring in the 12 week controlled phase, a decrease in neutrophil below 1 × 109 per L occurred in 7% of patients in the Actemra-IV group, and in no patients in the placebo group. In the open label extension over an average duration of 73 weeks of treatment, a decreased neutrophil count occurred in 17% of the Actemra-IV group. There was no clear relationship between decrease in neutrophils below 1 × 109 per L and the occurrence of serious infections.

Thrombocytopenia

During routine monitoring in the 12 week controlled phase, 1% of patients in the Actemra-IV group and 3% in the placebo group had a decrease in platelet count to no more than 100,000 per mm3.

In the open label extension over an average duration of 73 weeks of treatment, decreased platelet count occurred in 4% of patients in the Actemra-IV group, with no associated bleeding.

Elevated Liver Enzymes

During routine laboratory monitoring in the 12 week controlled phase, elevation in ALT or AST at or above 3× ULN occurred in 5% and 3% of patients, respectively in the Actemra-IV group and in 0% of placebo patients.

In the open label extension over an average duration of 73 weeks of treatment, the elevation in ALT or AST at or above 3× ULN occurred in 13% and 5% of Actemra-IV treated patients, respectively.

Lipids

During routine laboratory monitoring in the 12 week controlled phase, elevation in total cholesterol greater than 1.5× ULN – 2× ULN occurred in 1.5% of the Actemra-IV group and in 0% of placebo patients. Elevation in LDL greater than 1.5× ULN – 2× ULN occurred in 1.9% of patients in the Actemra-IV group and 0% of the placebo group.

In the open label extension study over an average duration of 73 weeks of treatment, the pattern and incidence of elevations in lipid parameters remained consistent with the 12 week controlled study data.

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 [see Clinical Studies (14.6)].

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of intravenous 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 [see Warnings and Precautions (5.5)]
  • Stevens-Johnson Syndrome

Clinical Studies

Rheumatoid ArthritisIntravenous Administration

The efficacy and safety of intravenously administered Actemra was assessed in five randomized, double-blind, multicenter studies in patients greater than 18 years with active rheumatoid arthritis diagnosed according to American College of Rheumatology (ACR) criteria. Patients had at least 8 tender and 6 swollen joints at baseline. Actemra was given intravenously every 4 weeks as monotherapy (Study I), in combination with methotrexate (MTX) (Studies II and III) or other disease-modifying anti-rheumatic drugs (DMARDs) (Study IV) in patients with an inadequate response to those drugs, or in combination with MTX in patients with an inadequate response to TNF antagonists (Study V).

Study I evaluated patients with moderate to severe active rheumatoid arthritis who had not been treated with MTX within 24 weeks prior to randomization, or who had not discontinued previous methotrexate treatment as a result of clinically important toxic effects or lack of response. In this study, 67% of patients were MTX-naïve, and over 40% of patients had rheumatoid arthritis less than 2 years. Patients received Actemra 8 mg per kg monotherapy or MTX alone (dose titrated over 8 weeks from 7.5 mg to a maximum of 20 mg weekly). The primary endpoint was the proportion of Actemra patients who achieved an ACR 20 response at Week 24.

Study II was a 104-week study with an ongoing optional 156-week extension phase that evaluated patients with moderate to severe active rheumatoid arthritis who had an inadequate clinical response to MTX. Patients received Actemra 8 mg per kg, Actemra 4 mg per kg, or placebo every four weeks, in combination with MTX (10 to 25 mg weekly). Upon completion of 52-weeks, patients received open-label treatment with Actemra 8 mg per kg through 104 weeks or they had the option to continue their double-blind treatment if they maintained a greater than 70% improvement in swollen/tender joint count. Two pre-specified interim analyses at week 24 and week 52 were conducted. The primary endpoint at week 24 was the proportion of patients who achieved an ACR 20 response. At weeks 52 and 104, the primary endpoints were change from baseline in modified total Sharp-Genant score and the area under the curve (AUC) of the change from baseline in HAQ-DI score.

Study III evaluated patients with moderate to severe active rheumatoid arthritis who had an inadequate clinical response to MTX. Patients received Actemra 8 mg per kg, Actemra 4 mg per kg, or placebo every four weeks, in combination with MTX (10 to 25 mg weekly). The primary endpoint was the proportion of patients who achieved an ACR 20 response at week 24.

Study IV evaluated patients who had an inadequate response to their existing therapy, including one or more DMARDs. Patients received Actemra 8 mg per kg or placebo every four weeks, in combination with the stable DMARDs. The primary endpoint was the proportion of patients who achieved an ACR 20 response at week 24.

Study V evaluated patients with moderate to severe active rheumatoid arthritis who had an inadequate clinical response or were intolerant to one or more TNF antagonist therapies. The TNF antagonist therapy was discontinued prior to randomization. Patients received Actemra 8 mg per kg, Actemra 4 mg per kg, or placebo every four weeks, in combination with MTX (10 to 25 mg weekly). The primary endpoint was the proportion of patients who achieved an ACR 20 response at week 24.

Clinical Response

The percentages of intravenous Actemra-treated patients achieving ACR 20, 50 and 70 responses are shown in Table 3. In all intravenous studies, patients treated with 8 mg per kg Actemra had higher ACR 20, ACR 50, and ACR 70 response rates versus MTX- or placebo-treated patients at week 24.

During the 24 week controlled portions of Studies I to V, patients treated with Actemra at a dose of 4 mg per kg in patients with inadequate response to DMARDs or TNF antagonist therapy had lower response rates compared to patients treated with Actemra 8 mg per kg.

Table 3 Clinical Response at Weeks 24 and 52 in Active and Placebo Controlled Trials of Intravenous Actemra (Percent of Patients)
Percent of Patients
Study I Study II Study III Study IV Study V
MTX Actemra
8 mg per kg
Placebo + MTX Actemra
4 mg per kg + MTX
Actemra
8 mg per kg + MTX
Placebo + MTX Actemra
4 mg per kg + MTX
Actemra
8 mg per kg + MTX
Placebo + DMARDs Actemra
8 mg per kg + DMARDs
Placebo + MTX Actemra
4 mg per kg + MTX
Actemra
8 mg per kg + MTX
Response Rate N=284 N=286
(95% CI)*
N=393 N=399
( 95% CI)*
N=398
(95% CI)*
N=204 N=213
( 95% CI)*
N=205
(95% CI)*
N=413 N=803
(95% CI)*
N=158 N=161
( 95% CI)*
N=170
(95% CI)*
* CI: 95% confidence interval of the weighted difference to placebo adjusted for site (and disease duration for Study I only) † Major clinical response is defined as achieving an ACR 70 response for a continuous 24 week period
ACR 20
Week 24 53% 70%
(0.11, 0.27)
27% 51%
(0.17, 0.29)
56%
(0.23, 0.35)
27% 48%
(0.15, 0.32)
59%
(0.23, 0.41)
24% 61%
(0.30, 0.40)
10% 30%
(0.15, 0.36)
50%
(0.36, 0.56)
Week 52 N/A N/A 25% 47%
(0.15, 0.28)
56%
(0.25, 0.38)
N/A N/A N/A N/A N/A N/A N/A N/A
ACR 50
Week 24 34% 44%
(0.04, 0.20)
10% 25%
(0.09, 0.20)
32%
(0.16, 0.28)
11% 32%
(0.13, 0.29)
44%
(0.25, 0.41)
9% 38%
(0.23, 0.33)
4% 17%
(0.05, 0.25)
29%
(0.21, 0.41)
Week 52 N/A N/A 10% 29%
(0.14, 0.25)
36%
(0.21, 0.32)
N/A N/A N/A N/A N/A N/A N/A N/A
ACR 70
Week 24 15% 28%
(0.07, 0.22)
2% 11%
(0.03, 0.13)
13%
(0.05, 0.15)
2% 12%
(0.04, 0.18)
22%
(0.12, 0.27)
3% 21%
(0.13, 0.21)
1% 5%
(-0.06, 0.14)
12%
(0.03, 0.22)
Week 52 N/A N/A 4% 16%
(0.08, 0.17)
20%
(0.12, 0.21)
N/A N/A N/A N/A N/A N/A N/A N/A
Major Clinical Responses †
Week 52 N/A N/A 1% 4%
(0.01, 0.06)
7%
(0.03, 0.09)
N/A N/A N/A N/A N/A N/A N/A N/A

In study II, a greater proportion of patients treated with 4 mg per kg and 8 mg per kg Actemra + MTX achieved a low level of disease activity as measured by a DAS 28-ESR less than 2.6 compared with placebo +MTX treated patients at week 52. The proportion of Actemra-treated patients achieving DAS 28-ESR less than 2.6, and the number of residual active joints in these responders in Study II are shown in Table 4.

Table 4 Proportion of Patients with DAS28-ESR Less Than 2.6 with Number of Residual Active Joints in Trials of Intravenous Actemra
Study II
Placebo + MTX
N = 393
Actemra 4 mg per kg + MTX
N = 399
Actemra 8 mg per kg + MTX
N = 398
*n denotes numerator of all the percentage. Denominator is the intent-to-treat population. Not all patients received DAS28 assessments at Week 52.
DAS28-ESR less than 2.6
Proportion of responders at week 52 (n)
95% confidence interval
3% (12) 18% (70)
0.10, 0.19
32% (127)
0.24, 0.34
Of responders, proportion with 0 active joints (n) 33% (4) 27% (19) 21% (27)
Of responders, proportion with 1 active joint (n) 8% (1) 19% (13) 13% (16)
Of responders, proportion with 2 active joints (n) 25% (3) 13% (9) 20% (25)
Of responders, proportion with 3 or more active joints (n) 33% (4) 41% (29) 47% (59)

The results of the components of the ACR response criteria for Studies III and V are shown in Table 5. Similar results to Study III were observed in Studies I, II and IV.

Table 5 Components of ACR Response at Week 24 in Trials of Intravenous Actemra
Study III Study V
Actemra
4 mg per kg + MTX
Actemra
8 mg per kg + MTX
Placebo + MTX Actemra
4 mg per kg + MTX
Actemra
8 mg per kg + MTX
Placebo + MTX
N=213 N=205 N=204 N=161 N=170 N=158
Component (mean) Baseline Week 24* Baseline Week 24 * Baseline Week 24 Baseline Week 24 * Baseline Week 24 * Baseline Week 24
* Data shown is mean at week 24, difference in adjusted mean change from baseline compared with placebo + MTX at week 24 and 95% confidence interval for that difference † Visual analog scale: 0 = best, 100 = worst ‡ Health Assessment Questionnaire: 0 = best, 3 = worst; 20 questions; 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities
Number of tender joints (0-68) 33 19
-7.0
(-10.0, -4.1)
32 14.5
-9.6
(-12.6, -6.7)
33 25 31 21
-10.8
(-14.6, -7.1)
32 17
-15.1
(-18.8, -11.4)
30 30
Number of swollen joints (0-66) 20 10
-4.2
(-6.1, -2.3)
19.5 8
-6.2
(-8.1, -4.2)
21 15 19.5 13
-6.2
(-9.0, -3.5)
19 11
-7.2
(-9.9, -4.5)
19 18
Pain† 61 33
-11.0
(-17.0, -5.0)
60 30
-15.8
(-21.7, -9.9)
57 43 63.5 43
-12.4
(-22.1, -2.1)
65 33
-23.9
(-33.7, -14.1)
64 48
Patient global assessment† 66 34
-10.9
(-17.1, -4.8)
65 31
-14.9
(-20.9, -8.9)
64 45 70 46
-10.0
(-20.3, 0.3)
70 36
-17.4
(-27.8, -7.0)
71 51
Physician global assessment† 64 26
-5.6
(-10.5, -0.8)
64 23
-9.0
(-13.8, -4.2)
64 32 66.5 39
-10.5
(-18.6, -2.5)
66 28
-18.2
(-26.3, -10.0)
67.5 43
Disability index (HAQ)‡ 1.64 1.01
-0.18
(-0.34, -0.02)
1.55 0.96
-0.21
(-0.37, -0.05)
1.55 1.21 1.67 1.39
-0.25
(-0.42, -0.09)
1.75 1.34
-0.34
(-0.51, -0.17)
1.70 1.58
CRP (mg per dL) 2.79 1.17
-1.30
(-2.0, -0.59)
2.61 0.25
-2.156
(-2.86, -1.46)
2.36 1.89 3.11 1.77
-1.34
(-2.5, -0.15)
2.80 0.28
-2.52
(-3.72, -1.32)
3.705 3.06

The percent of ACR 20 responders by visit for Study III is shown in Figure 1. Similar response curves were observed in studies I, II, IV, and V.

Figure 1 Percent of ACR 20 Responders by Visit for Study III (Inadequate Response to MTX)*
* The same patients may not have responded at each timepoint.

Radiographic Response

In Study II, structural joint damage was assessed radiographically and expressed as change in total Sharp-Genant score and its components, the erosion score and joint space narrowing score. Radiographs of hands/wrists and forefeet were obtained at baseline, 24 weeks, 52 weeks, and 104 weeks and scored by readers unaware of treatments group and visit number. The results from baseline to week 52 are shown in Table 6. Actemra 4 mg per kg slowed (less than 75% inhibition compared to the control group) and Actemra 8 mg per kg inhibited (at least 75% inhibition compared to the control group) the progression of structural damage compared to placebo plus MTX at week 52.

Table 6 Mean Radiographic Change from Baseline to Week 52 in Study II
Placebo + MTX Actemra
4 mg per kg + MTX
Actemra
8 mg per kg + MTX
N=294 N=343 N=353
SD = standard deviation
* Week 52 analysis employs linearly extrapolated data for patients after escape, withdrawal, or loss to follow up. † Difference between the adjusted means (Actemra + MTX - Placebo + MTX)
Week 52*
Total Sharp-Genant Score, Mean (SD) 1.17
(3.14)
0.33
(1.30)
0.25
(0.98)
  Adjusted Mean difference†
  (95%CI)
-0.83
(-1.13, -0.52)
-0.90
(-1.20, -0.59)
Erosion Score, Mean (SD) 0.76
(2.14)
0.20
(0.83)
0.15
(0.77)
  Adjusted Mean difference†
  (95%CI)
-0.55
(-0.76, -0.34)
-0.60
(-0.80, -0.39)
Joint Space Narrowing Score, Mean (SD) 0.41
(1.71)
0.13
(0.72)
0.10
(0.49)
  Adjusted Mean difference†
  (95%CI)
-0.28
(-0.44, -0.11)
-0.30
(-0.46, -0.14)

The mean change from baseline to week 104 in Total Sharp-Genant Score for the Actemra 4 mg per kg groups was 0.47 (SD = 1.47) and for the 8 mg per kg groups was 0.34 (SD = 1.24). By the week 104, most patients in the control (placebo + MTX) group had crossed over to active treatment, and results are therefore not included for comparison. Patients in the active groups may have crossed over to the alternate active dose group, and results are reported per original randomized dose group.

In the placebo group, 66% of patients experienced no radiographic progression (Total Sharp-Genant Score change ≤ 0) at week 52 compared to 78% and 83% in the Actemra 4 mg per kg and 8 mg per kg, respectively. Following 104 weeks of treatment, 75% and 83% of patients initially randomized to Actemra 4 mg per kg and 8 mg per kg, respectively, experienced no progression of structural damage compared to 66% of placebo treated patients.

Health Related Outcomes

In Study II, physical function and disability were assessed using the Health Assessment Questionnaire Disability Index (HAQ-DI). Both dosing groups of Actemra demonstrated a greater improvement compared to the placebo group in the AUC of change from baseline in the HAQ-DI through week 52. The mean change from baseline to week 52 in HAQ-DI was 0.6, 0.5, and 0.4 for Actemra 8 mg per kg, Actemra 4 mg per kg, and placebo treatment groups, respectively. Sixty-three percent (63%) and sixty percent (60%) of patients in the Actemra 8 mg per kg and Actemra 4 mg per kg treatment groups, respectively, achieved a clinically relevant improvement in HAQ-DI (change from baseline of ≥ 0.3 units) at week 52 compared to 53% in the placebo treatment group.

Other Health-Related Outcomes

General health status was assessed by the Short Form Health Survey (SF-36) in Studies I – V. Patients receiving Actemra demonstrated greater improvement from baseline compared to placebo in the Physical Component Summary (PCS), Mental Component Summary (MCS), and in all 8 domains of the SF-36.

Rheumatoid ArthritisSubcutaneous Administration

The efficacy and safety of subcutaneously administered Actemra was assessed in two double-blind, controlled, multicenter studies in patients with active RA. One study (SC-I) was a non-inferiority study that compared the efficacy and safety of Actemra 162 mg administered every week subcutaneously (SC) to 8 mg per kg intravenously every four weeks. The second study (SC-II) was a placebo controlled superiority study that evaluated the safety and efficacy of Actemra 162 mg administered every other week SC to placebo. Both SC-I and SC-II required patients to be >18 years of age with moderate to severe active rheumatoid arthritis diagnosed according to ACR criteria who had at least 4 tender and 4 swollen joints at baseline (SC-I) or at least 8 tender and 6 swollen joints at baseline (SC-II), and an inadequate response to their existing DMARD therapy, where approximately 20% also had a history of inadequate response to at least one TNF inhibitor. All patients in both SC studies received background non-biologic DMARD(s).

In SC-I, 1262 patients were randomized 1:1 to receive Actemra SC 162 mg every week or Actemra intravenous 8 mg/kg every four weeks in combination with DMARD(s). In SC-II, 656 patients were randomized 2:1 to Actemra SC 162 mg every other week or placebo, in combination with DMARD(s). The primary endpoint in both studies was the proportion of patients who achieved an ACR20 response at Week 24.

The clinical response to 24 weeks of Actemra SC therapy is shown in Table 7. In SC-I, the primary outcome measure was ACR20 at Week 24. The pre-specified non-inferiority margin was a treatment difference of 12%. The study demonstrated non-inferiority of Actemra with respect to ACR20 at Week 24; ACR50, ACR70, and DAS28 responses are also shown in Table 7. In SC-II, a greater portion of patients treated with Actemra 162 mg SC every other week achieved ACR20, ACR50, and ACR70 responses compared to placebo-treated patients (Table 7). Further, a greater proportion of patients treated with Actemra 162 mg SC every other week achieved a low level of disease activity as measured by a DAS28-ESR less than 2.6 at Week 24 compared to those treated with placebo (Table 7).

Table 7 Clinical Response at Week 24 in Trials of Subcutaneous Actemra (Percent of Patients)
SC-I* SC-II†
TCZ SC 162 mg every week
+ DMARD
TCZ IV 8mg/kg
+ DMARD
TCZ SC 162 mg every other week
+ DMARD
Placebo
+ DMARD
N=558 N=537 N=437 N=219
TCZ = tocilizumab
* Per Protocol Population † Intent To Treat Population
ACR20
Week 24 69% 73.4% 61% 32%
Weighted difference (95% CI) -4% (-9.2, 1.2) 30% (22.0, 37.0)
ACR50
Week 24 47% 49% 40% 12%
Weighted difference (95% CI) -2% (-7.5, 4.0) 28% (21.5, 34.4)
ACR70
Week 24 24% 28% 20% 5%
Weighted difference (95% CI) -4% (-9.0, 1.3) 15% (9.8, 19.9)
Change in DAS28 [Adjusted mean]
Week 24 -3.5 -3.5 -3.1 -1.7
Adjusted mean difference (95% CI) 0 (-0.2, 0.1)
-1.4 (-1.7; -1.1)
DAS28 < 2.6
Week 24 38.4% 36.9% 32.0% 4.0%
Weighted difference (95% CI) 0.9 (-5.0, 6.8) 28.6 (22.0, 35.2)

The results of the components of the ACR response criteria and the percent of ACR20 responders by visit for Actemra-SC in Studies SC-I and SC-II were consistent with those observed for Actemra-IV.

Radiographic Response

In study SC-II, the progression of structural joint damage was assessed radiographically and expressed as a change from baseline in the van der Heijde modified total Sharp score (mTSS). At week 24, significantly less radiographic progression was observed in patients receiving Actemra SC every other week plus DMARD(s) compared to placebo plus DMARD(s); mean change from baseline in mTSS of 0.62 vs. 1.23, respectively, with an adjusted mean difference of -0.60 (-1.1, -0.1). These results are consistent with those observed in patients treated with intravenous Actemra.

Health Related Outcomes

In studies SC-I and SC-II, the mean decrease from baseline to week 24 in HAQ-DI was 0.6, 0.6, 0.4 and 0.3, and the proportion of patients who achieved a clinically relevant improvement in HAQ-DI (change from baseline of ≥ 0.3 units) was 65%, 67%, 58% and 47%, for the SC every week, IV 8 mg/kg, SC every other week, and placebo treatment groups, respectively.

Other Health-Related Outcomes

General health status was assessed by the SF-36 in Studies SC-I and SC-II. In Study SC-II, patients receiving Actemra every other week demonstrated greater improvement from baseline compared to placebo in the PCS, MCS, and in all 8 domains of the SF-36. In Study SC-I, improvements in these scores were similar between Actemra SC every week and Actemra IV 8 mg/kg.

Giant Cell ArteritisSubcutaneous Administration

The efficacy and safety of subcutaneously administered Actemra was assessed in a single, randomized, double-blind, multicenter study in patients with active GCA. In Study WA28119, 251 screened patients with new-onset or relapsing GCA were randomized to one of four treatment arms. Two SC doses of Actemra (162 mg every week and 162 mg every other week) were compared to two different placebo control groups (pre-specified prednisone-taper regimen over 26 weeks and 52 weeks) randomized 2:1:1:1. The study consisted of a 52-week blinded period, followed by a 104-week open-label extension.

All patients received background glucocorticoid (prednisone) therapy. Each of the Actemra-treated groups and one of the placebo-treated groups followed a pre-specified prednisone-taper regimen with the aim to reach 0 mg by 26 weeks, while the second placebo-treated group followed a pre-specified prednisone-taper regimen with the aim to reach 0 mg by 52 weeks designed to be more in keeping with standard practice.

The primary efficacy endpoint was the proportion of patients achieving sustained remission from Week 12 through Week 52. Sustained remission was defined by a patient attaining a sustained (1) absence of GCA signs and symptoms from Week 12 through Week 52, (2) normalization of erythrocyte sedimentation rate (ESR) (to < 30 mm/hr without an elevation to ≥ 30 mm/hr attributable to GCA) from Week 12 through Week 52, (3) normalization of C-reactive protein (CRP) (to < 1 mg/dL, with an absence of successive elevations to ≥ 1mg/dL) from Week 12 through Week 52, and (4) successful adherence to the prednisone taper defined by not more than 100 mg of excess prednisone from Week 12 through Week 52. Actemra 162 mg weekly and 162 mg every other week + 26 weeks prednisone taper both showed superiority in achieving sustained remission from Week 12 through Week 52 compared with placebo + 26 weeks prednisone taper (Table 8). Both Actemra treatment arms also showed superiority compared to the placebo + 52 weeks prednisone taper (Table 8).

Table 8 Efficacy Results from Study WA28119
PBO + 26 weeks prednisone taper
N=50
PBO + 52 weeks prednisone taper
N=51
TCZ 162mg SC QW + 26 weeks prednisone taper
N=100
TCZ 162 mg SC Q2W + 26 weeks prednisone taper
N=49
Patients not completing the study to week 52 were classified as non-responders in the primary and key secondary analysis: PBO+26: 6 (12.0%), PBO+52: 5 (9.8%), TCZ QW: 15 (15.0%), TCZ Q2W: 9 (18.4%).
CRP = C-reactive protein
ESR = erythrocyte sedimentation rate
PBO = placebo
Q2W = every other week dose
QW = every week dose
TCZ = tocilizumab
* Sustained remission was achieved by a patient meeting all of the following components: absence of GCA signs and symptoms†, normalization of ESR‡, normalization of CRP§ and adherence to the prednisone taper regimen¶. † Patients who did not have any signs or symptoms of GCA recorded from Week 12 up to Week 52. ‡ Patients who did not have an elevated ESR ≥30 mm/hr which was classified as attributed to GCA from Week 12 up to Week 52. § Patients who did not have two or more consecutive CRP records of ≥ 1mg/dL from Week 12 up to Week 52. ¶ Patients who did not enter escape therapy and received ≤ 100mg of additional concomitant prednisone from Week 12 up to Week 52.
Sustained remission*
  Responders, n (%) 7 (14.0%) 9 (17.6%) 56 (56.0%) 26 (53.1%)
  Unadjusted difference in proportions vs PBO + 26 weeks taper
  (99.5% CI)
N/A N/A 42.0%
(18.0, 66.0)
39.1%
(12.5 , 65.7)
  Unadjusted difference in proportions vs PBO + 52 weeks taper
  (99.5% CI)
N/A N/A 38.4%
(14.4, 62.3)
35.4%
(8.6, 62.2)
Components of Sustained Remission
  Sustained absence of GCA signs and symptoms†, n (%) 20 (40.0%) 23 (45.1%) 69 (69.0%) 28 (57.1%)
  Sustained ESR<30 mm/hr‡, n (%) 20 (40.0%) 22 (43.1%) 83 (83.0%) 37 (75.5%)
  Sustained CRP normalization§, n (%) 17 (34.0%) 13 (25.5%) 72 (72.0%) 34 (69.4%)
  Successful prednisone tapering¶, n (%) 10 (20.0%) 20 (39.2%) 60 (60.0%) 28 (57.1%)

The estimated annual cumulative prednisone dose was lower in the two Actemra dose groups (medians of 1887 mg and 2207 mg on Actemra QW and Q2W, respectively) relative to the placebo arms (medians of 3804 mg and 3902 mg on placebo + 26 weeks prednisone and placebo + 52 weeks prednisone taper, respectively).

Polyarticular Juvenile Idiopathic ArthritisIntravenous Administration

The efficacy of Actemra was assessed in a three-part study including an open-label extension in children 2 to 17 years of age with active polyarticular juvenile idiopathic arthritis (PJIA), who had an inadequate response to methotrexate or inability to tolerate methotrexate. Patients had at least 6 months of active disease (mean disease duration of 4.2 ± 3.7 years), with at least five joints with active arthritis (swollen or limitation of movement accompanied by pain and/or tenderness) and/or at least 3 active joints having limitation of motion (mean, 20 ± 14 active joints). The patients treated had subtypes of JIA that at disease onset included Rheumatoid Factor Positive or Negative Polyarticular JIA, or Extended Oligoarticular JIA. Treatment with a stable dose of methotrexate was permitted but was not required during the study. Concurrent use of disease modifying antirheumatic drugs (DMARDs), other than methotrexate, or other biologics (e.g., TNF antagonists or T cell costimulation modulator) were not permitted in the study.

Part I consisted of a 16-week active Actemra treatment lead-in period (n=188) followed by Part II, a 24-week randomized double-blind placebo-controlled withdrawal period, followed by Part III, a 64-week open-label period. Eligible patients weighing at or above 30 kg received Actemra at 8 mg/kg IV once every four weeks. Patients weighing less than 30 kg were randomized 1:1 to receive either Actemra 8 mg/kg or 10 mg/kg IV every four weeks. At the conclusion of the open-label Part I, 91% of patients taking background MTX in addition to tocilizumab and 83% of patients on tocilizumab monotherapy achieved an ACR 30 response at week 16 compared to baseline and entered the blinded withdrawal period (Part II) of the study. The proportions of patients with JIA ACR 50/70 responses in Part I were 84.0%, and 64%, respectively for patients taking background MTX in addition to tocilizumab and 80% and 55% respectively for patients on tocilizumab monotherapy.

In Part II, patients (ITT, n=163) were randomized to Actemra (same dose received in Part I) or placebo in a 1:1 ratio that was stratified by concurrent methotrexate use and concurrent corticosteroid use. Each patient continued in Part II of the study until Week 40 or until the patient satisfied JIA ACR 30 flare criteria (relative to Week 16) and qualified for escape.

The primary endpoint was the proportion of patients with a JIA ACR 30 flare at week 40 relative to week 16. JIA ACR 30 flare was defined as 3 or more of the 6 core outcome variables worsening by at least 30% with no more than 1 of the remaining variables improving by more than 30% relative to Week 16.

Actemra treated patients experienced significantly fewer disease flares compared to placebo-treated patients (26% [21/82] versus 48% [39/81]; adjusted difference in proportions -21%, 95% CI: -35%, -8%).

During the withdrawal phase (Part II), more patients treated with Actemra showed JIA ACR 30/50/70 responses at Week 40 compared to patients withdrawn to placebo.

Systemic Juvenile Idiopathic ArthritisIntravenous Administration

The efficacy of Actemra for the treatment of active SJIA was assessed in a 12-week randomized, double blind, placebo-controlled, parallel group, 2-arm study. Patients treated with or without MTX, were randomized (Actemra:placebo = 2:1) to one of two treatment groups: 75 patients received Actemra infusions every two weeks at either 8 mg per kg for patients at or above 30 kg or 12 mg per kg for patients less than 30 kg and 37 were randomized to receive placebo infusions every two weeks. Corticosteroid tapering could occur from week six for patients who achieved a JIA ACR 70 response. After 12 weeks or at the time of escape, due to disease worsening, patients were treated with Actemra in the open-label extension phase at weight appropriate dosing.

The primary endpoint was the proportion of patients with at least 30% improvement in JIA ACR core set (JIA ACR 30 response) at Week 12 and absence of fever (no temperature at or above 37.5°C in the preceding 7 days). JIA ACR (American College of Rheumatology) responses are defined as the percentage improvement (e.g., 30%, 50%, 70%) in 3 of any 6 core outcome variables compared to baseline, with worsening in no more than 1 of the remaining variables by 30% or more. Core outcome variables consist of physician global assessment, parent per patient global assessment, number of joints with active arthritis, number of joints with limitation of movement, erythrocyte sedimentation rate (ESR), and functional ability (childhood health assessment questionnaire-CHAQ).

Primary endpoint result and JIA ACR response rates at Week 12 are shown in Table 9.

Table 9 Efficacy Findings at Week 12
Actemra
N=75
Placebo
N=37
* The weighted difference is the difference between the Actemra and Placebo response rates, adjusted for the stratification factors (weight, disease duration, background oral corticosteroid dose and background methotrexate use). † CI: confidence interval of the weighted difference.
Primary Endpoint: JIA ACR 30 response + absence of fever
Responders 85% 24%
Weighted difference
(95% CI)
62
(45, 78)
-
JIA ACR Response Rates at Week 12
JIA ACR 30
Responders 91% 24%
Weighted difference*
(95% CI)†
67
(51, 83)
-
JIA ACR 50
Responders 85% 11%
Weighted difference*
(95% CI) †
74
(58, 90)
-
JIA ACR 70
Responders 71% 8%
Weighted difference*
(95% CI) †
63
(46, 80)
-

The treatment effect of Actemra was consistent across all components of the JIA ACR response core variables. JIA ACR scores and absence of fever responses in the open label extension were consistent with the controlled portion of the study (data available through 44 weeks).

Systemic Features

Of patients with fever or rash at baseline, those treated with Actemra had fewer systemic features; 35 out of 41 (85%) became fever free (no temperature recording at or above 37.5°C in the preceding 14 days) compared to 5 out of 24 (21%) of placebo-treated patients, and 14 out of 22 (64%) became free of rash compared to 2 out of 18 (11%) of placebo-treated patients. Responses were consistent in the open label extension (data available through 44 weeks).

Corticosteroid Tapering

Of the patients receiving oral corticosteroids at baseline, 8 out of 31 (26%) placebo and 48 out of 70 (69%), Actemra patients achieved a JIA ACR 70 response at week 6 or 8 enabling corticosteroid dose reduction. Seventeen (24%) Actemra patients versus 1 (3%) placebo patient were able to reduce the dose of corticosteroid by at least 20% without experiencing a subsequent JIA ACR 30 flare or occurrence of systemic symptoms to week 12. In the open label portion of the study, by week 44, there were 44 out of 103 (43%) Actemra patients off oral corticosteroids. Of these 44 patients 50% were off corticosteroids 18 weeks or more.

Health Related Outcomes

Physical function and disability were assessed using the Childhood Health Assessment Questionnaire Disability Index (CHAQ-DI). Seventy-seven percent (58 out of 75) of patients in the Actemra treatment group achieved a minimal clinically important improvement in CHAQ-DI (change from baseline of ≥ 0.13 units) at week 12 compared to 19% (7 out of 37) in the placebo treatment group.

Cytokine Release SyndromeIntravenous Administration

The efficacy of Actemra for the treatment of CRS was assessed in a retrospective analysis of pooled outcome data from clinical trials of CAR T-cell therapies for hematological malignancies. Evaluable patients had been treated with tocilizumab 8 mg/kg (12 mg/kg for patients < 30 kg) with or without additional high-dose corticosteroids for severe or life-threatening CRS; only the first episode of CRS was included in the analysis. The study population included 24 males and 21 females (total 45 patients) of median age 12 years (range, 3–23 years); 82% were Caucasian. The median time from start of CRS to first dose of tocilizumab was 4 days (range, 0–18 days). Resolution of CRS was defined as lack of fever and off vasopressors for at least 24 hours. Patients were considered responders if CRS resolved within 14 days of the first dose of tocilizumab, no more than 2 doses of tocilizumab were needed, and no drugs other than tocilizumab and corticosteroids were used for treatment. Thirty-one patients (69%; 95% CI: 53%–82%) achieved a response. Achievement of resolution of CRS within 14 days was confirmed in a second study using an independent cohort that included 15 patients (range: 9–75 years old) with CAR T cell-induced CRS.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Patient Counseling

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

Infections:

Inform patients that Actemra may lower their resistance to infections. 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.

  • Gastrointestinal Perforation:
    Inform patients that some patients who have been treated with Actemra have had serious side effects in the stomach and intestines. Instruct the patient of the importance of contacting their doctor immediately when symptoms of severe, persistent abdominal pain appear to assure rapid evaluation and appropriate treatment.
  • Hypersensitivity and Serious Allergic Reactions
    Assess patient suitability for home use for SC injection. Inform patients that some patients who have been treated with Actemra have developed serious allergic reactions, including anaphylaxis. Advise patients to seek immediate medical attention if they experience any symptom of serious allergic reactions.

Instruction on Injection Technique

Perform the first injection under the supervision of a qualified healthcare professional. If a patient or caregiver is to administer subcutaneous Actemra, instruct him/her in injection techniques and assess his/her ability to inject subcutaneously to ensure proper administration of subcutaneous Actemra and the suitability for home use [See Patient Instructions for Use].

Prior to use, remove the prefilled syringe from the refrigerator and allow to sit at room temperature outside of the carton for 30 minutes, out of the reach of children. Do not warm Actemra in any other way.

Advise patients to consult their healthcare provider if the full dose is not received.

A puncture-resistant container for disposal of needles and syringes should be used and should be kept out of the reach of children. Instruct patients or caregivers in the technique as well as proper syringe and needle disposal, and caution against reuse of these items.

Pregnancy Exposure Registry

Inform patients that there is a pregnancy registry to monitor fetal outcomes of pregnant women exposed to Actemra [see Use in Specific Populations (8.1)].

Pregnancy

Inform female patients of reproductive potential that Actemra may cause fetal harm and to inform their prescriber of a known or suspected pregnancy [see Use in Specific Populations (8.1)].

Actemra® (tocilizumab)
Manufactured by:
Genentech, Inc.
A Member of the Roche Group
1 DNA Way
South San Francisco, CA 94080-4990
US License No. 1048

This Medication Guide has been approved by the U.S. Food and Drug Administration Revised: 08/2017
MEDICATION GUIDE
Actemra® (AC-TEM-RA)
(tocilizumab) Injection
For Intravenous Infusion
Actemra® (AC-TEM-RA)
(tocilizumab) Injection
For Subcutaneous Administration

What is the most important information I should know about Actemra?
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 test you for TB before starting Actemra. Your healthcare provider should monitor you closely for signs and symptoms of TB during treatment with Actemra.
  • You should not start taking Actemra if you have any kind of infection unless your healthcare provider says it is okay.

Before starting Actemra, tell your healthcare provider if you:

  • think you have an infection or have symptoms of an infection, with or without a fever, such as:
  • sweating or chills
  • shortness of breath
  • warm, red, or painful skin or sores on your body
  • feel very tired
  • muscle aches
  • blood in phlegm
  • diarrhea or stomach pain
  • cough
  • weight loss
  • burning when you urinate or urinating more often than normal
  • are being treated for an infection
  • get a lot of infections or have infections that keep coming back
  • have diabetes, HIV, or a weak immune system. People with these conditions have a higher chance for infections.
  • have TB, or have been in close contact with someone with TB
  • live or have lived, or have traveled to certain parts of the country (such as the Ohio and Mississippi River valleys and the Southwest) where there is an increased chance for getting certain kinds of fungal infections (histoplasmosis, coccidiomycosis, or blastomycosis). These infections may happen or become more severe if you use Actemra. Ask your healthcare provider, if you do not know if you have lived in an area where these infections are common.
  • have or have had hepatitis B

After starting Actemra, call your healthcare provider right away if you have any symptoms of an infection. Actemra can make you more likely to get infections or make worse any infection that you have.

2. Tears (perforation) of the stomach or intestines.
  • Tell your healthcare provider if you have had diverticulitis (inflammation in parts of the large intestine) or ulcers in your stomach or intestines. Some people taking Actemra get tears in their stomach or intestine. This happens most often in people who also take nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, or methotrexate.
  • Tell your healthcare provider right away if you have fever and stomach-area pain that does not go away, and a change in your bowel habits.
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 test are to check for the following side effects of Actemra:
  • low neutrophil count. Neutrophils are white blood cells that help the body fight off bacterial infections.
  • low platelet count. Platelets are blood cells that help with blood clotting and stop bleeding.
  • increase in certain liver function tests.
  • increase in blood cholesterol levels. You may also have changes in other laboratory tests, such as your blood cholesterol levels. Your healthcare provider should do blood tests to check your cholesterol levels 4 to 8 weeks after you start receiving Actemra, and then every 6 months after that.
You should not receive Actemra if your neutrophil or platelet counts are too low or your liver function tests are too high.
Your healthcare provider may stop your Actemra treatment for a period of time or change your dose of medicine if needed because of changes in these blood test results.
4. Cancer. Actemra may increase your risk of certain cancers by changing the way your immune system works. Tell your healthcare provider if you have ever had any type of cancer.

See "What are the possible side effects with Actemra?" for more information about side effects.

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.
  • Adults with giant cell arteritis (GCA).
  • People with active PJIA ages 2 and above.
  • People with active SJIA ages 2 and above.
  • People who experience severe or life-threatening CRS following chimeric antigen receptor T cell treatment age 2 years and above
Actemra is not approved for subcutaneous use in people with PJIA, SJIA or CRS.
It is not known if Actemra is safe and effective in children with PJIA or SJIA under 2 years of age, in children with CRS under 2 years of age, or in children with conditions other than PJIA, SJIA or CRS.
Do not take Actemra: if you are allergic to tocilizumab, or any of the ingredients in Actemra. See the end of this Medication Guide for a complete list of ingredients in Actemra.
Before you receive Actemra, tell your healthcare provider about all of your medical conditions, including if you:
  • have an infection. See "What is the most important information I should know about Actemra?"
  • have liver problems.
  • have any stomach-area (abdominal) pain or been diagnosed with diverticulitis or ulcers in your stomach or intestines.
  • have had a reaction to tocilizumab or any of the ingredients in Actemra before.
  • have or had a condition that affects your nervous system, such as multiple sclerosis.
  • have recently received or are scheduled to receive a vaccine:
    • All vaccines should be brought up-to-date before starting Actemra.
    • People who take Actemra should not receive live vaccines.
    • People taking Actemra can receive non-live vaccines.
  • plan to have surgery or a medical procedure.
  • have any other medical conditions
  • plan to become pregnant or are pregnant. It is not known if Actemra will harm your unborn baby.
    Pregnancy Registry: Genentech has a registry for pregnant women who take Actemra. The purpose of this registry is to check the health of the pregnant mother and her baby. If you are pregnant or become pregnant while taking Actemra, talk to your healthcare provider about how you can join this pregnancy registry or you may contact the registry at 1-877-311-8972 to enroll.
  • plan to breastfeed or are breastfeeding. You and your healthcare provider should decide if you will take Actemra or breast-feed. You should not do both.
Tell your healthcare provider about all of the medicines you take, including prescription, over-the-counter medicines, vitamins and herbal supplements. Actemra and other medicines may affect each other causing side effects.
Especially tell your healthcare provider if you take:
  • any other medicines to treat your RA. You should not take etanercept (Enbrel®), adalimumab (Humira®), infliximab (Remicade®), rituximab (Rituxan®), abatacept (Orencia®), anakinra (Kineret®), certolizumab (Cimzia®), or golimumab (Simponi®), while you are taking Actemra. Taking Actemra with these medicines may increase your risk of infection.
  • medicines that affect the way certain liver enzymes work. Ask your healthcare provider if you are not sure if your medicine is one of these.
Know the medicines you take. Keep a list of them to show to your healthcare provider and pharmacist when you get a new medicine.
How will I receive Actemra?
Into a vein (IV or intravenous infusion) for Rheumatoid Arthritis, 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 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.
  • While taking Actemra, you may continue to use other medicines that help treat your rheumatoid arthritis, PJIA, or SJIA such as methotrexate, non-steroidal anti-inflammatory drugs (NSAIDs) and prescription steroids, as instructed by your healthcare provider.
  • Keep all of your follow-up appointments and get your blood tests as ordered by your healthcare provider.
Under the skin (SC or subcutaneous injection) for Rheumatoid Arthritis or Giant Cell Arteritis:
  • See the Instructions for Use at the end of this Medication Guide for instructions about the right way to prepare and give your Actemra injections at home.
  • Actemra is available as a single-use Prefilled Syringe.
  • You may also receive Actemra as injection under your skin (subcutaneous). If your healthcare provider decides that you or a caregiver can give your injections of Actemra at home, you or your caregiver should receive training on the right way to prepare and inject Actemra. Do not try to inject Actemra until you have been shown the right way to give the injections by your healthcare provider.
  • Your healthcare provider will tell you how much Actemra to use and when to use it.

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

  • See "What is the most important information I should know about Actemra?"
  • Hepatitis B infection in people who carry the virus in their blood. If you are a carrier of the hepatitis B virus (a virus that affects the liver), the virus may become active while you use Actemra. Your healthcare provider may do blood tests before you start treatment with Actemra and while you are using Actemra. Tell your healthcare provider if you have any of the following symptoms of a possible hepatitis B infection:
  • feel very tired
  • vomiting
  • chills
  • dark urine
  • skin or eyes look yellow
  • clay-colored bowel movements
  • stomach discomfort
  • skin rash
  • little or no appetite
  • fevers
  • muscle aches
  • Serious Allergic Reactions. Serious allergic reactions, including death, can happen with Actemra. These reactions can happen with any infusion or injection of Actemra, even if they did not occur with an earlier infusion or injection. Tell your healthcare provider before your next dose if you had hives, rash or flushing after your injection. Seek medical attention right away if you have any of the following signs of a serious allergic reaction:
    • shortness of breath or trouble breathing
    • swelling of the lips, tongue, or face
    • chest pain
    • feeling dizzy or faint
    • moderate or severe abdominal pain or vomiting
  • Nervous system problems. While rare, Multiple Sclerosis has been diagnosed in people who take Actemra. It is not known what effect Actemra may have on some nervous system disorders.
The most common side effects of Actemra include:
  • upper respiratory tract infections (common cold, sinus infections)
  • headache
  • increased blood pressure (hypertension)
  • injection site reactions
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Genentech at 1-888-835-2555.
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. You can ask your pharmacist or healthcare provider for information about Actemra that is written for health professionals.
What are the ingredients in Actemra?
Active ingredient: tocilizumab
Inactive ingredients of Intravenous Actemra: sucrose, polysorbate 80, disodium phosphate dodecahydrate, sodium dihydrogen phosphate dihydrate.
Inactive ingredients of Subcutaneous Actemra: L-arginine, L-arginine hydrochloride, L-methionine, L-histidine, L-histidine hydrochloride monohydrate.
Actemra is a registered trademark of Chugai Seiyaku Kabushiki Kaisha Corp., a member of the Roche Group.
Genentech, Inc.,1 DNA Way, South San Francisco, CA 94080-4990 US License No.1048
© 2017 Genentech, Inc. All rights reserved.
For more information, go to www.Actemra.com or call 1-800-Actemra.

Representative sample of labeling (see the HOW SUPPLIED section for complete listing):

Uses of Actemra

Actemra is a prescription medicine used to treat: 

  • Adults with moderate to severe rheumatoid arthritis (RA) after at least one other medicine called Disease Modifying Anti-Rheumatic Drug (DMARD) has been used and did not work well.
  • People with active polyarticular juvenile idiopathic arthritis (PJIA) ages 2 and above.
  • People with active systemic juvenile idiopathic arthritis (SJIA) ages 2 and above.
  • Adults with giant cell arteritis. 

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

Actemra Interactions

Tell your doctor about all of the medicines you take, including prescription and nonĀ­-prescription medicines, vitamins and herbal supplements. Actemra and other medicines may affect each other causing side effects. Especially tell your doctor if you take:

  • any other medicines to treat Rheumatoid Arthritis 
  • etanercept (Enbrei)
  • adalimumab (Humira) 
  • infliximab (Remicade) 
  • rituximab (Rituxan)
  • abatacept (Orencia) 
  • anakinra (Kineret)
  • certolizumab (Cimzia)
  • golimumab (Simponi)

Taking Actemra with these medicines may increase your risk of infection.

This is not a complete list of Actemra drug interactions. Ask your doctor or pharmacist for more information.

 

Patient Handout

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Before taking this medicine

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

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 Actemra 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 Actemra 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 Actemra on the baby.

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

For the Consumer

Applies to tocilizumab: intravenous solution

Along with its needed effects, tocilizumab (the active ingredient contained in Actemra) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur while taking tocilizumab:

More common
  • Black, tarry stools
  • bloody or cloudy urine
  • blurred vision
  • body aches or pain
  • chest pain
  • cough with or without mucus
  • diarrhea
  • difficult, burning, or painful urination
  • difficulty breathing
  • difficulty swallowing
  • dizziness
  • ear congestion
  • fast heartbeat
  • feeling of warmth
  • fever or chills
  • frequent urge to urinate
  • headache
  • hives, itching, skin rash
  • loss of appetite
  • loss of consciousness
  • loss of voice
  • lower back or side pain
  • nasal congestion
  • nausea
  • nervousness
  • pain or tenderness around the eyes and cheekbones
  • painful blisters on the trunk of the body
  • pale skin
  • pounding in the ears
  • puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
  • redness of the face, neck, arms, and occasionally, upper chest
  • slow or fast heartbeat
  • sneezing
  • sore throat
  • stomach pain
  • stuffy or runny nose
  • sudden sweating
  • tightness of the chest
  • ulcers, sores, or white spots in the mouth
  • unusual bleeding or bruising
  • unusual tiredness or weakness
Less common
  • Bladder pain
  • burning feeling in the chest or stomach
  • confusion
  • dark urine
  • decrease in height
  • difficulty moving
  • dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
  • fast, irregular, pounding, or racing heartbeat or pulse
  • feeling hot
  • general feeling of discomfort or illness
  • heartburn
  • indigestion
  • itching, pain, redness, swelling, tenderness, or warmth on the skin at the injection site
  • joint pain
  • light-colored stools
  • muscle aches and pains
  • muscle cramps or stiffness
  • pain in the back, ribs, arms, legs, or groin or genitals
  • pale skin
  • severe stomach pain
  • sharp back pain just below the ribs
  • shivering
  • stomach upset
  • sweating
  • swollen joints
  • swollen, painful, or tender lymph glands in the face, neck, armpit, or groin
  • tenderness in the stomach area
  • trouble with sleeping
  • troubled breathing with exertion
  • unexplained runny nose or sneezing
  • vomiting
  • yellow eyes and skin
Rare
  • Belching
  • changes in skin color
  • coughing or spitting up blood
  • fainting
  • gaseous stomach pain
  • lightheadedness
  • neck pain
  • night sweats
  • noisy breathing
  • rapid, shallow breathing
  • recurrent fever
  • red, tender, or oozing skin at the wounded area
  • sudden high fever or low-grade fever for months
  • swelling of the foot or leg
  • weight loss
Incidence not known
  • Dilated neck veins
  • extreme fatigue
  • severe stomach pain, cramping, or burning
  • swelling of the face, fingers, feet, or lower legs
  • vomiting of material that looks like coffee grounds, severe and continuing
  • weight gain

Some side effects of tocilizumab may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common
  • Burning, dry, or itching eyes
  • constipation
  • discharge, excessive tearing
  • redness, pain, or swelling of the eye, eyelid, or inner lining of the eyelid
  • skin rash, encrusted, scaly and oozing
  • swelling or inflammation of the mouth
  • warmth on the skin
Less common
  • Abnormal or decreased touch sensation
  • accumulation of pus
  • bleeding or redness and swelling of the gums
  • blemishes on the skin
  • bloody eye
  • chapped, red, or swollen lips
  • earache
  • feeling of constant movement of self or surroundings
  • irritation in the mouth
  • loose teeth
  • persistent breath odor or bad taste in your mouth
  • pimples
  • redness of the eye or skin
  • redness or swelling in the ear
  • scaling, redness, burning, pain, or other signs of inflammation on the lips
  • sensation of spinning
  • sore mouth or tongue
  • swollen, red, or tender area of infection
  • white patches in the mouth or on the tongue
Rare
  • Bleeding after passing stool
  • blindness
  • bloody nose
  • burning, numbness, tingling, or painful sensations
  • change in hearing
  • continuing ringing or buzzing or other unexplained noise in the ears
  • coughing or spitting up blood
  • decreased vision or other changes in vision
  • dry mouth
  • ear drainage
  • flushed, dry skin
  • fruit-like breath odor
  • hearing loss
  • increased hunger, thirst, urination
  • itching ears
  • loss of consciousness
  • uncomfortable swelling around the anus
  • unexplained weight loss
  • unsteadiness or awkwardness
  • weakness in the arms, hands, legs, or feet

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