1.1 Rheumatoid Arthritis (RA)

TOFIDENCE™ (tocilizumab-bavi) 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).

1.2 Polyarticular Juvenile Idiopathic Arthritis (PJIA)

TOFIDENCE™ (tocilizumab-bavi) is indicated for the treatment of active polyarticular juvenile idiopathic arthritis in patients 2 years of age and older.

1.3 Systemic Juvenile Idiopathic Arthritis (SJIA)

TOFIDENCE™ (tocilizumab-bavi) is indicated for the treatment of active systemic juvenile idiopathic arthritis in patients 2 years of age and older.

2.1 General Considerations for Administration

2.2 Recommended Dosage for Rheumatoid Arthritis

TOFIDENCE may be used as monotherapy or concomitantly with methotrexate or other non-biologic DMARDs as an intravenous infusion.

2.3 Recommended Dosage for Polyarticular Juvenile Idiopathic Arthritis

TOFIDENCE may be used as an intravenous infusion alone or in combination with methotrexate. Do not change dose based solely on a single visit body weight measurement, as weight may fluctuate.

2.4 Recommended Dosage for Systemic Juvenile Idiopathic Arthritis

TOFIDENCE may be used as an intravenous infusion or in combination with methotrexate. Do not change a dose based solely on a single visit body weight measurement, as weight may fluctuate.

2.5 Preparation and Administration Instructions for Intravenous Infusion

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

• Use a sterile needle and syringe to prepare TOFIDENCE.
• Patients less than 30 kg: use a 50 mLinfusion bag or bottle of 0.9% Sodium Chloride Injection, USP, and then follow steps 1 and 2 below.
• Patients at or above 30 kg weight: use a 100 mLinfusion bag or bottle, and then follow steps 1 and 2 below.
• Step 1. Withdraw a volume of 0.9% Sodium Chloride Injection, USP, equal to the volume of the TOFIDENCE injection required for the patient's dose from the infusion bag or bottle [see Dosage and Administration (2.2, 2.3, 2.4)].

• Step 2. Withdraw the amount of TOFIDENCE for intravenous infusion from the vial(s) and add slowly into the 0.9% Sodium Chloride Injection, USP infusion bag or bottle. To mix the solution, gently invert the bag to avoid foaming.
• The fully diluted TOFIDENCE solutions for infusion using 0.9% Sodium Chloride Injection, USP may be stored refrigerated at 36°F to 46°F (2°C to 8°C) for up to 24 hours or room temperature at 68°F to 77°F (20°C to 25°C) for up to 12 hours and should be protected from light.
• TOFIDENCE solutions do not contain preservatives; therefore, unused product remaining in the vials should not be used.
• Allow the fully diluted TOFIDENCE solution to reach room temperature prior to infusion.
• The infusion should be administered over 60 minutes, and must be administered with an infusion set. Do not administer as an intravenous push or bolus.
• TOFIDENCE should not be infused concomitantly in the same intravenous line with other drugs. No physical or biochemical compatibility studies have been conducted to evaluate the co-administration of TOFIDENCE with other drugs.
• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If particulates and discolorations are noted, the product should not be used.
• Fully diluted TOFIDENCE solutions are compatible with infusion bags and/or infusion sets with the following materials: polypropylene, polyethylene, polyolefin, polyvinyl chloride, polyethersulfone, polyurethane, nylon and stainless steel.

2.6 Dosage Modifications due to Serious Infections or Laboratory Abnormalities

Intravenous Infusion

Injection: 80 mg/4 mL, 200 mg/10 mL, 400 mg/20 mL as a clear to opalescent, colorless to light yellow solution in 20 mg/mL single-dose vials for further dilution prior to intravenous infusion.

5.1 Serious Infections

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

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

• with chronic or recurrent infection;
• who have been exposed to tuberculosis;
• with a history of serious or an opportunistic infection;
• who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or
• with underlying conditions that may predispose them to infection.

Closely monitor patients for the development of signs and symptoms of infection during and after treatment with TOFIDENCE, as signs and symptoms of acute inflammation may be lessened due to suppression of the acute phase reactants [see Dosage and Administration (2.1), Adverse Reactions (6.1), and Patient Counseling Information (17)].

Hold TOFIDENCE if a patient develops a serious infection, an opportunistic infection, or sepsis. A patient who develops a new infection during treatment with TOFIDENCE should undergo a prompt and complete diagnostic workup appropriate for an immunocompromised patient, initiate appropriate antimicrobial therapy, and closely monitor the patient.

5.2 Gastrointestinal Perforations

Events of gastrointestinal perforation have been reported in clinical trials, primarily as complications of diverticulitis in patients treated with tocilizumab. Use TOFIDENCE with caution in patients who may be at increased risk for gastrointestinal perforation. Promptly evaluate patients presenting with new onset abdominal symptoms for early identification of gastrointestinal perforation [see Adverse Reactions (6.1)].

5.3 Hepatotoxicity

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

During randomized controlled studies, treatment with tocilizumab was associated with a higher incidence of transaminase elevations [see Adverse Reactions (6.1, 6.2, 6.3)]. Increased frequency and magnitude of these elevations was observed when potentially hepatotoxic drugs (e.g., MTX) were used in combination with tocilizumab.

For RA patients, obtain a liver test panel (serum alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, and total bilirubin) before initiating TOFIDENCE, every 4 to 8 weeks after start of therapy for the first 6 months of treatment and every 3 months thereafter. It is not recommended to initiate TOFIDENCE treatment in RA patients with elevated transaminases ALT or AST greater than 1.5× ULN. In patients who develop elevated ALT or AST greater than 5× ULN, discontinue TOFIDENCE. For recommended modifications based upon increase in transaminases see Dosage and Administration (2.6).

Measure liver tests promptly in patients who report symptoms that may indicate liver injury, such as fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. In this clinical context, if the patient is found to have abnormal liver tests (e.g., ALT greater than three times the upper limit of the reference range, serum total bilirubin greater than two times the upper limit of the reference range), TOFIDENCE treatment should be interrupted and investigation done to establish the probable cause. TOFIDENCE should only be restarted in patients with another explanation for the liver test abnormalities after normalization of the liver tests.

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

5.4 Changes in Laboratory Parameters

5.5 Immunosuppression

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

5.6 Hypersensitivity Reactions, Including Anaphylaxis

Hypersensitivity reactions, including anaphylaxis, have been reported in association with tocilizumab products [see Adverse Reactions (6)] and anaphylactic events with a fatal outcome have been reported with intravenous infusion of tocilizumab products. Anaphylaxis and other hypersensitivity reactions that required treatment discontinuation were reported in 0.1% (3 out of 2644) of patients in the 6-month controlled trials of intravenous tocilizumab and 0.2% (8 out of 4009) of patients in the intravenous all-exposure RA population. In the SJIA controlled trial with intravenous tocilizumab, 1 out of 112 patients (0.9%) experienced hypersensitivity reactions that required treatment discontinuation. In the PJIA controlled trial with intravenous tocilizumab 0 out of 188 patients (0%) in the tocilizumab all-exposure population experienced hypersensitivity reactions that required treatment discontinuation. Reactions that required treatment discontinuation included generalized erythema, rash, and urticaria. Injection site reactions were categorized separately [see Adverse Reactions (6)].

In the postmarketing setting, events of hypersensitivity reactions, including anaphylaxis and death have occurred in patients treated with a range of doses of intravenous tocilizumab products, with or without concomitant therapies. Events have occurred in patients who received premedication. Hypersensitivity, including anaphylaxis events, have occurred both with and without previous hypersensitivity reactions and as early as the first infusion of tocilizumab products [see Adverse Reactions (6.3)]. TOFIDENCE for intravenous use should only be infused by a healthcare professional with appropriate medical support to manage anaphylaxis. If anaphylaxis or other hypersensitivity reaction occurs, stop administration of TOFIDENCE immediately and discontinue TOFIDENCE permanently. Do not administer TOFIDENCE to patients with known hypersensitivity to tocilizumab products [see Contraindications (4) and Adverse Reactions (6)].

5.7 Demyelinating Disorders

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

5.8 Active Hepatic Disease and Hepatic Impairment

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

5.9 Vaccinations

Avoid use of live vaccines concurrently with TOFIDENCE as clinical safety has not been established. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving tocilizumab products.

No data are available on the effectiveness of vaccination in patients receiving tocilizumab products. Because IL-6 inhibition may interfere with the normal immune response to new antigens, it is recommended that all patients, particularly pediatric or elderly patients, if possible, be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating TOFIDENCE therapy. The interval between live vaccinations and initiation of TOFIDENCE therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.

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

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

6.2 Clinical Trials Experience in Polyarticular Juvenile Idiopathic Arthritis Patients Treated with Intravenous Tocilizumab (Tocilizumab-IV)

The safety of tocilizumab-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 tocilizumab-IV all exposure population (defined as patients who received at least one dose of tocilizumab-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 6.3)].

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

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

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

6.4 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of tocilizumab products. 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 (5.6)]
• Stevens-Johnson Syndrome
• Pancreatitis
• Drug-induced liver injury, Hepatitis, Hepatic failure, Jaundice [see Warnings and Precautions (5.3)]

7.1 Concomitant Drugs for Treatment of Adult Indications

In RA patients, population pharmacokinetic analyses did not detect any effect of methotrexate (MTX), non-steroidal anti-inflammatory drugs or corticosteroids on tocilizumab clearance. Concomitant administration of a single intravenous dose of 10 mg/kg tocilizumab with 10-25 mg MTX once weekly had no clinically significant effect on MTX exposure. Tocilizumab products have not been studied in combination with biological DMARDs such as TNF antagonists [see Dosage and Administration (2.2)].

7.2 Interactions with CYP450 Substrates

Cytochrome P450s in the liver are down-regulated by infection and inflammation stimuli including cytokines such as IL-6. Inhibition of IL-6 signaling in RA patients treated with tocilizumab products may restore CYP450 activities to higher levels than those in the absence of tocilizumab products leading to increased metabolism of drugs that are CYP450 substrates. In vitro studies showed that tocilizumab has the potential to affect expression of multiple CYP enzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. Its effect on CYP2C8 or transporters is unknown. In vivo studies with omeprazole, metabolized by CYP2C19 and CYP3A4, and simvastatin, metabolized by CYP3A4, showed up to a 28% and 57% decrease in exposure one week following a single dose of tocilizumab, respectively. The effect of tocilizumab products on CYP enzymes may be clinically relevant for CYP450 substrates with narrow therapeutic index, where the dose is individually adjusted. Upon initiation or discontinuation of TOFIDENCE, in patients being treated with these types of medicinal products, perform therapeutic monitoring of effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) and the individual dose of the medicinal product adjusted as needed. Exercise caution when coadministering TOFIDENCE with CYP3A4 substrate drugs where decrease in effectiveness is undesirable, e.g., oral contraceptives, lovastatin, atorvastatin, etc. The effect of tocilizumab products on CYP450 enzyme activity may persist for several weeks after stopping therapy [see Clinical Pharmacology (12.3)].

7.3 Live Vaccines

Avoid use of live vaccines concurrently with TOFIDENCE [see Warnings and Precautions (5.9)].

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

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

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

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

8.5 Geriatric Use

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

8.6 Hepatic Impairment

The safety and efficacy of tocilizumab products have not been studied in patients with hepatic impairment, including patients with positive HBV and HCV serology [see Warnings and Precautions (5.8)].

8.7 Renal Impairment

No dose adjustment is required in patients with mild or moderate renal impairment. Tocilizumab products have not been studied in patients with severe renal impairment [see Clinical Pharmacology (12.3)].

Intravenous Infusion

TOFIDENCE (tocilizumab-bavi) injection is a sterile, clear to opalescent, colorless to light yellow, preservative-free solution for further dilution prior to intravenous infusion with a pH of approximately 6.2. Each single-dose vial, formulated in an aqueous solution, is available at a concentration of 20 mg/mL containing 80 mg/4 mL, 200 mg/10 mL, or 400 mg/20 mL of TOFIDENCE. Each mL of solution contains arginine hydrochloride (10.53 mg), histidine (0.81 mg), L-histidine hydrochloride monohydrate (1.01 mg), polysorbate 80 (0.5 mg), sucrose (20 mg), and water for injection.

12.1 Mechanism of Action

Tocilizumab products bind to both soluble and membrane-bound IL-6 receptors (sIL-6R and mIL-6R), and has been shown to inhibit IL-6-mediated signaling through these receptors. IL-6 is a pleiotropic pro-inflammatory cytokine produced by a variety of cell types including T- and B-cells, lymphocytes, monocytes and fibroblasts. IL-6 has been shown to be involved in diverse physiological processes such as T-cell activation, induction of immunoglobulin secretion, initiation of hepatic acute phase protein synthesis, and stimulation of hematopoietic precursor cell proliferation and differentiation. IL-6 is also produced by synovial and endothelial cells leading to local production of IL-6 in joints affected by inflammatory processes such as rheumatoid arthritis.

12.2 Pharmacodynamics

In clinical studies in RA patients with the 4 mg per kg and 8 mg per kg intravenous doses decreases in levels of C-reactive protein (CRP) to within normal ranges were seen as early as week 2. Changes in pharmacodynamic parameters were observed (i.e., decreases in rheumatoid factor, erythrocyte sedimentation rate (ESR), serum amyloid A, fibrinogen and increases in hemoglobin) with doses, however the greatest improvements were observed with 8 mg per kg tocilizumab. Pharmacodynamic changes were also observed to occur after tocilizumab administration in PJIA and SJIA patients (decreases in CRP, ESR, and increases in hemoglobin). The relationship between these pharmacodynamic findings and clinical efficacy is not known.

In healthy subjects administered tocilizumab in doses from 2 to 28 mg per kg intravenously, absolute neutrophil counts decreased to the nadir 3 to 5 days following tocilizumab administration. Thereafter, neutrophils recovered towards baseline in a dose dependent manner. Rheumatoid arthritis patients demonstrated a similar pattern of absolute neutrophil counts following tocilizumab administration [see Warnings and Precautions (5.4)].

12.3 Pharmacokinetics

PK of tocilizumab is characterized by nonlinear elimination which is a combination of linear clearance and Michaelis-Menten elimination. The nonlinear part of tocilizumab elimination leads to an increase in exposure that is more than dose-proportional. The pharmacokinetic parameters of tocilizumab do not change with time. Due to the dependence of total clearance on tocilizumab serum concentrations, the half-life of tocilizumab is also concentration-dependent and varies depending on the serum concentration level. Population pharmacokinetic analyses in any patient population tested so far indicate no relationship between apparent clearance and the presence of anti-drug antibodies.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No long-term animal studies have been performed to establish the carcinogenicity potential of tocilizumab products. Literature indicates that the IL-6 pathway can mediate anti-tumor responses by promoting increased immune cell surveillance of the tumor microenvironment. However, available published evidence also supports that IL-6 signaling through the IL-6 receptor may be involved in pathways that lead to tumorigenesis. The malignancy risk in humans from an antibody that disrupts signaling through the IL-6 receptor, such as tocilizumab, is presently unknown.

Fertility and reproductive performance were unaffected in male and female mice that received a murine analogue of tocilizumab administered by the intravenous route at a dose of 50 mg/kg every three days.

14.1 Rheumatoid Arthritis—Intravenous Administration

The efficacy and safety of intravenously administered tocilizumab 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. Tocilizumab 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 (NCT00109408) 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 tocilizumab 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 tocilizumab patients who achieved an ACR 20 response at Week 24.

Study II (NCT00106535) was a 104-week study with an 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 tocilizumab 8 mg per kg, tocilizumab 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 tocilizumab 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 (NCT00106548) evaluated patients with moderate to severe active rheumatoid arthritis who had an inadequate clinical response to MTX. Patients received tocilizumab 8 mg per kg, tocilizumab 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 (NCT00106574) evaluated patients who had an inadequate response to their existing therapy, including one or more DMARDs. Patients received tocilizumab 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 (NCT00106522) 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 tocilizumab 8 mg per kg, tocilizumab 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 tocilizumab-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 tocilizumab 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 tocilizumab 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 tocilizumab 8 mg per kg.

Table 3 Clinical Response at Weeks 24 and 52 in Active and Placebo Controlled Trials of Intravenous Tocilizumab (Percent of Patients)

Percent of Patients
Response Rate	Study I		Study II			Study III			Study IV		Study V
	MTX	Tocilizumab 8 mg per kg	Placebo + MTX	Tocilizumab 4 mg per kg + MTX	Tocilizumab 8 mg per kg + MTX	Placebo + MTX	Tocilizumab 4 mg per kg + MTX	Tocilizumab 8 mg per kg + MTX	Placebo + DMARDs	Tocilizumab 8 mg per kg + DMARDs	Placebo + MTX	Tocilizumab4 mg per kg + MTX	Tocilizumab 8 mg per kg + MTX
	N=284	N=286	N=393	N=399	N=398	N=204	N=213	N=205	N=413	N=803	N=158	N=161	N=170
		(95% CI) *		( 95% CI) *	( 95% CI) *		( 95% CI) *	( 95% CI) *		( 95% CI) *	( 95% CI) *	( 95% CI) *	( 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 tocilizumab + 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 tocilizumab-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 Tocilizumab

Study II
	Placebo + MTX	Tocilizumab 4 mg per kg + MTX	Tocilizumab 8 mg per kg + MTX
	N = 393	N = 399	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 Tocilizumab

	Study III						Study V
	Tocilizumab 4 mg per kg + MTX		Tocilizumab 8 mg per kg + MTX		Placebo + MTX		Tocilizumab 4 mg per kg + MTX		Tocilizumab 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.

* The same patients may not have responded at each timepoint.

Figure 1 Percent of ACR 20 Responders by Visit for Study III (Inadequate Response to MTX) *

14.2 Polyarticular Juvenile Idiopathic Arthritis—Intravenous Administration

The efficacy of tocilizumab was assessed in a three-part study, WA19977 (NCT00988221), 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 tocilizumab 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 tocilizumab at 8 mg/kg intravenously once every four weeks. Patients weighing less than 30 kg were randomized 1:1 to receive either tocilizumab 8 mg/kg or 10 mg/kg intravenously 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 tocilizumab (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.

Tocilizumab 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 tocilizumab showed JIA ACR 30/50/70 responses at Week 40 compared to patients withdrawn to placebo.

14.3 Systemic Juvenile Idiopathic Arthritis—Intravenous Administration

The efficacy of tocilizumab for the treatment of active SJIA was assessed in WA18221 (NCT00642460), a 12-week randomized, double blind, placebo-controlled, parallel group, 2-arm study. Patients treated with or without MTX, were randomized (tocilizumab:placebo = 2:1) to one of two treatment groups: 75 patients received tocilizumab 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 tocilizumab 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 7.

The treatment effect of tocilizumab 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).

Storage and Handling: Do not use beyond expiration date on the container or package. TOFIDENCE must be refrigerated at 36°F to 46°F (2°C to 8°C). Do not freeze. Protect the vials from light by storage in the original package until time of use.

• Serious Infections

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

• Gastrointestinal Perforation

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