Actemra

Dosage Forms And Strengths

Intravenous Infusion Injection

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

Subcutaneous Injection Injection

162 mg/0.9 mL clear, colorless to slightly yellowish solution in a single-dose prefilled syringe

Storage And Handling

For Intravenous Infusion

%medicine_name% (tocilizumab) injection is a preservative-free, sterile clear, colorless to pale yellow solution. %medicine_name% is supplied as 80 mg/4 mL (NDC 50242-135-01), 200 mg/10 mL (NDC 50242-136-01), and 400 mg/20 mL (NDC 50242-137-01) individually packaged 20 mg/mL single-dose vials for further dilution prior to intravenous infusion.

For Subcutaneous Injection

%medicine_name% (tocilizumab) injection is supplied as a preservative-free, sterile, clear, colorless to slightly yellowish solution for subcutaneous administration. Each single-dose prefilled syringe delivers 162 mg/0.9 mL (NDC 50242-138-01).

Storage And Stability

Do not use beyond expiration date on the container, package or prefilled syringe. %medicine_name% must be refrigerated at 2°C to 8°C (36°F to 46°F). Do not freeze. Protect the vials and syringes from light by storage in the original package until time of use, and keep syringes dry. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If visibly opaque particles, discoloration or other foreign particles are observed, the solution should not be used.

Manufactured by: Genentech, Inc., A Member of the Roche Group 1 DNA Way South San Francisco, CA 94080-4990 US License No. 1048. Revised: Mar 2018

Rheumatoid Arthritis (RA)

%medicine_name%® (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)

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

Polyarticular Juvenile Idiopathic Arthritis (PJIA)

%medicine_name%® (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)

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

Cytokine Release Syndrome (CRS)

%medicine_name%® (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.

Rheumatoid Arthritis

%medicine_name% may be used as monotherapy or concomitantly with methotrexate or other non-biologic DMARDs as an intravenous infusion or as a subcutaneous injection.

Recommended Intravenous (IV) Dosage Regimen

The recommended dosage of %medicine_name% for adult patients given as a 60-minute single intravenous drip infusion is 4 mg per kg every 4 weeks followed by an increase to 8 mg per kg every 4 weeks based on clinical response.

• Reduction of dose from 8 mg per kg to 4 mg per kg is recommended for management of certain dose-related laboratory changes including elevated liver enzymes, neutropenia, and thrombocytopenia.
• Doses exceeding 800 mg per infusion are not recommended in RA patients.

Recommended Subcutaneous (SC) Dosage Regimen

When transitioning from %medicine_name% intravenous therapy to subcutaneous administration administer the first subcutaneous dose instead of the next scheduled intravenous dose.

Interruption of dose or reduction in frequency of administration of subcutaneous dose from every week to every other week dosing is recommended for management of certain dose-related laboratory changes including elevated liver enzymes, neutropenia, and thrombocytopenia.

Giant Cell Arteritis

The recommended dose of %medicine_name% for adult patients with GCA is 162 mg given once every week as a subcutaneous injection in combination with a tapering course of glucocorticoids.

A dose of 162 mg given once every other week as a subcutaneous injection in combination with a tapering course of glucocorticoids may be prescribed based on clinical considerations.

%medicine_name% can be used alone following discontinuation of glucocorticoids.

• Interruption of dosing may be needed for management of dose-related laboratory abnormalities including elevated liver enzymes, neutropenia, and thrombocytopenia.
• Intravenous administration is not approved for GCA.

Polyarticular Juvenile Idiopathic Arthritis

%medicine_name% may be used alone or in combination with methotrexate. The recommended dosage of %medicine_name% for PJIA patients given once every 4 weeks as a 60-minute single intravenous drip infusion is:

Recommended Intravenous PJIA Dosage Every 4 Weeks

• Do not change dose based solely on a single visit body weight measurement, as weight may fluctuate.
• Interruption of dosing may be needed for management of dose-related laboratory abnormalities including elevated liver enzymes, neutropenia, and thrombocytopenia.
• Subcutaneous administration is not approved for PJIA.

Systemic Juvenile Idiopathic Arthritis

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

Recommended Intravenous SJIA Dosage Every 2 Weeks

• Do not change a dose based solely on a single visit body weight measurement, as weight may fluctuate.
• Interruption of dosing may be needed for management of dose-related laboratory abnormalities including elevated liver enzymes, neutropenia, and thrombocytopenia.
• Subcutaneous administration is not approved for SJIA.

Cytokine Release Syndrome (CRS)

Use only the intravenous route for treatment of CRS. The recommended dose of %medicine_name% for treatment of CRS given as a 60-minute intravenous infusion is:

Recommended Intravenous CRS Dosage

• If no clinical improvement in the signs and symptoms of CRS occurs after the first dose, up to 3 additional doses of %medicine_name% may be administered. The interval between consecutive doses should be at least 8 hours.
• Doses exceeding 800 mg per infusion are not recommended in CRS patients.
• Subcutaneous administration is not approved for CRS.

General Considerations For Administration

• %medicine_name% has not been studied in combination with biological DMARDs such as TNF antagonists, IL-1R antagonists, anti-CD20 monoclonal antibodies and selective co-stimulation modulators because of the possibility of increased immunosuppression and increased risk of infection. Avoid using %medicine_name% with biological DMARDs.
• It is recommended that %medicine_name% not be initiated in patients with an absolute neutrophil count (ANC) below 2000 per mm³, platelet count below 100,000 per mm³, or who have ALT or AST above 1.5 times the upper limit of normal (ULN).
  • Patients with severe or life-threatening CRS frequently have cytopenias or elevated ALT or AST due to the lymphodepleting chemotherapy or the CRS. The decision to administer %medicine_name% should take into account the potential benefit of treating the CRS versus the risks of short-term treatment with %medicine_name%.

Preparation And Administration Instructions For Intravenous Infusion

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

• Patients less than 30 kg: use a 50 mL infusion bag or bottle of 0.9% or 0.45% Sodium Chloride Injection, USP, and then follow steps 1 and 2 below.
• Patients at or above 30 kg weight: use a 100 mL infusion bag or bottle, and then follow steps 1 and 2 below.
  • Step 1. Withdraw a volume of 0.9% or 0.45% Sodium Chloride Injection, USP, equal to the volume of the %medicine_name% injection required for the patient's dose from the infusion bag or bottle.

For Intravenous Use: Volume of %medicine_name% Injection per kg of Body Weight

• Step 2. Withdraw the amount of %medicine_name% for intravenous infusion from the vial(s) and add slowly into the 0.9% or 0.45% Sodium Chloride Injection, USP infusion bag or bottle. To mix the solution, gently invert the bag to avoid foaming.
• The fully diluted %medicine_name% solutions for infusion using 0.9% Sodium Chloride Injection, USP may be stored at 2° to 8°C (36° to 46°F) or room temperature for up to 24 hours and should be protected from light.
• The fully diluted %medicine_name% solutions for infusion using 0.45% Sodium Chloride Injection, USP may be stored at 2° to 8°C (36° to 46°F) for up to 24 hours or room temperature for up to 4 hours and should be protected from light.
• %medicine_name% solutions do not contain preservatives; therefore, unused product remaining in the vials should not be used.
• Allow the fully diluted %medicine_name% 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.
• %medicine_name% 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 %medicine_name% 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 %medicine_name% solutions are compatible with polypropylene, polyethylene and polyvinyl chloride infusion bags and polypropylene, polyethylene and glass infusion bottles.

Preparation And Administration Instructions For Subcutaneous Injection

• %medicine_name% for subcutaneous injection is only approved for adult indications and is not indicated for the treatment of pediatric patients with PJIA or SJIA. %medicine_name% for subcutaneous injection is not intended for intravenous drip infusion.
• Assess suitability of patient for SC home use and instruct patients to inform a healthcare professional before administering the next dose if they experience any symptoms of allergic reaction. Patients should seek immediate medical attention if they develop symptoms of serious allergic reactions. %medicine_name% subcutaneous injection is intended for use under the guidance of a healthcare practitioner. After proper training in subcutaneous injection technique, a patient may self-inject %medicine_name% or the patient’s caregiver may administer %medicine_name% if a healthcare practitioner determines that it is appropriate. Patients, or patient caregivers, should be instructed to follow the directions provided in the Instructions for Use (IFU) for additional details on medication administration.
• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use %medicine_name% prefilled syringes (PFS) exhibiting particulate matter, cloudiness, or discoloration. %medicine_name% for subcutaneous administration should be clear and colorless to pale yellow. Do not use if any part of the PFS appears to be damaged.
• Patients using %medicine_name% for subcutaneous administration should be instructed to inject the full amount in the syringe (0.9 mL), which provides 162 mg of %medicine_name%, according to the directions provided in the IFU.
• Injection sites should be rotated with each injection and should never be given into moles, scars, or areas where the skin is tender, bruised, red, hard, or not intact.

Dosage Modifications Due To Serious Infections Or Laboratory Abnormalities

Hold %medicine_name% treatment if a patient develops a serious infection until the infection is controlled.

Rheumatoid Arthritis And Giant Cell Arteritis

Liver Enzyme Abnormalities

Polyarticular And Systemic Juvenile Idiopathic Arthritis

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

%medicine_name% is contraindicated in patients with known hypersensitivity to %medicine_name%.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Serious Infections

Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, protozoal, or other opportunistic pathogens have been reported in patients receiving immunosuppressive agents including %medicine_name%. The most common serious infections included pneumonia, urinary tract infection, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis and bacterial arthritis. Among opportunistic infections, tuberculosis, cryptococcus, aspergillosis, candidiasis, and pneumocystosis were reported with %medicine_name%. 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 %medicine_name% in patients with an active infection, including localized infections. The risks and benefits of treatment should be considered prior to initiating %medicine_name% 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 %medicine_name%, as signs and symptoms of acute inflammation may be lessened due to suppression of the acute phase reactants.

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

Tuberculosis

Evaluate patients for tuberculosis risk factors and test for latent infection prior to initiating %medicine_name%.

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

Closely monitor patients for the development of signs and symptoms of tuberculosis including patients who tested negative for latent tuberculosis infection prior to initiating therapy.

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

Viral Reactivation

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

Gastrointestinal Perforations

Events of gastrointestinal perforation have been reported in clinical trials, primarily as complications of diverticulitis in patients treated with %medicine_name%. Use %medicine_name% 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.

Laboratory Parameters

Rheumatoid Arthritis and Giant Cell Arteritis

Neutropenia

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

• It is not recommended to initiate %medicine_name% treatment in patients with a low neutrophil count, i.e., absolute neutrophil count (ANC) less than 2000 per mm³. In patients who develop an absolute neutrophil count less than 500 per mm³ treatment is not recommended.
• Monitor neutrophils 4 to 8 weeks after start of therapy and every 3 months thereafter. For recommended modifications based on ANC results see DOSAGE AND ADMINISTRATION).

Thrombocytopenia

Treatment with %medicine_name% was associated with a reduction in platelet counts. Treatment-related reduction in platelets was not associated with serious bleeding events in clinical trials.

• It is not recommended to initiate %medicine_name% treatment in patients with a platelet count below 100,000 per mm³. In patients who develop a platelet count less than 50,000 per mm³ treatment is not recommended.
• Monitor platelets 4 to 8 weeks after start of therapy and every 3 months thereafter. For recommended modifications based on platelet counts see DOSAGE AND ADMINISTRATION.

Elevated Liver Enzymes

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

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

• It is not recommended to initiate %medicine_name% treatment in patients with elevated transaminases ALT or AST greater than 1.5x ULN. In patients who develop elevated ALT or AST greater than 5x ULN treatment is not recommended.
• Monitor ALT and AST levels 4 to 8 weeks after start of therapy and every 3 months thereafter. When clinically indicated, other liver function tests such as bilirubin should be considered. For recommended modifications based on transaminases.

Lipid Abnormalities

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

• Assess lipid parameters approximately 4 to 8 weeks following initiation of %medicine_name% therapy, then at approximately 24 week intervals.
• Manage patients according to clinical guidelines [e.g., National Cholesterol Educational Program (NCEP)] for the management of hyperlipidemia.

Polyarticular And Systemic Juvenile Idiopathic Arthritis

A similar pattern of liver enzyme elevation, low neutrophil count, low platelet count and lipid elevations is noted with %medicine_name% treatment in the PJIA and SJIA populations. Monitor neutrophils, platelets, ALT and AST at the time of the second infusion and thereafter every 4 to 8 weeks for PJIA and every 2 to 4 weeks for SJIA. Monitor lipids as above for approved adult indications.

Immunosuppression

The impact of treatment with %medicine_name% on the development of malignancies is not known but malignancies were observed in clinical studies . %medicine_name% is an immunosuppressant, and treatment with immunosuppressants may result in an increased risk of malignancies.

Hypersensitivity Reactions, Including Anaphylaxis

Hypersensitivity reactions, including anaphylaxis, have been reported in association with %medicine_name% and anaphylactic events with a fatal outcome have been reported with intravenous infusion of %medicine_name%. 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 %medicine_name%, 0.2% (8 out of 4009) of patients in the intravenous all-exposure RA population, 0.7% (8 out of 1068) in the subcutaneous 6-month controlled RA trials, and in 0.7% (10 out of 1465) of patients in the subcutaneous all-exposure population. In the SJIA controlled trial with intravenous %medicine_name%, 1 out of 112 patients (0.9%) experienced hypersensitivity reactions that required treatment discontinuation. In the PJIA controlled trial with intravenous %medicine_name%, 0 out of 188 patients (0%) in the %medicine_name% 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.

In the postmarketing setting, events of hypersensitivity reactions, including anaphylaxis and death have occurred in patients treated with a range of doses of intravenous %medicine_name%, 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 %medicine_name%. %medicine_name% for intravenous use should only be infused by a healthcare professional with appropriate medical support to manage anaphylaxis. For %medicine_name% subcutaneous injection, advise patients to seek immediate medical attention if they experience any symptoms of a hypersensitivity reaction. If anaphylaxis or other hypersensitivity reaction occurs, stop administration of %medicine_name% immediately and discontinue %medicine_name% permanently. Do not administer %medicine_name% to patients with known hypersensitivity to %medicine_name%.

Demyelinating Disorders

The impact of treatment with %medicine_name% 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 %medicine_name% in patients with preexisting or recent onset demyelinating disorders.

Active Hepatic Disease And Hepatic Impairment

Treatment with %medicine_name% is not recommended in patients with active hepatic disease or hepatic impairment.

Vaccinations

Avoid use of live vaccines concurrently with %medicine_name% 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 %medicine_name%.

No data are available on the effectiveness of vaccination in patients receiving %medicine_name%. 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 %medicine_name% therapy. The interval between live vaccinations and initiation of %medicine_name% therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.

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 %medicine_name%.

Infections

Inform patients that %medicine_name% 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 %medicine_name% 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 %medicine_name% 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 %medicine_name%, instruct him/her in injection techniques and assess his/her ability to inject subcutaneously to ensure proper administration of subcutaneous %medicine_name% and the suitability for home 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 %medicine_name% 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 %medicine_name%.

Pregnancy

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

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

No long-term animal studies have been performed to establish the carcinogenicity potential of tocilizumab. 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.

Use In Specific Populations

Pregnancy

Pregnancy Exposure Registry

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

Risk Summary

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

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

Clinical Considerations

Fetal/Neonatal Adverse Reactions

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

Data

Animal Data

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

Parturition is associated with significant increases of IL-6 in the cervix and myometrium. The literature suggests that inhibition of IL-6 signaling may interfere with cervical ripening and dilatation and myometrial contractile activity leading to potential delays of parturition. For mice deficient in IL-6 (Il6-/-null mice), parturition was delayed relative to wild-type (ll6+/+) mice. Administration of recombinant IL-6 to ll6-/-null mice restored the normal timing of delivery.

Lactation

Risk Summary

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

Pediatric Use

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

Safety and effectiveness of %medicine_name% in pediatric patients with conditions other than PJIA, SJIA or CRS have not been established. Children under the age of two have not been studied. SC administration has not been studied in pediatric patients. Testing of a murine analogue of tocilizumab did not exert toxicity in juvenile mice. In particular, there was no impairment of skeletal growth, immune function and sexual maturation.

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

Geriatric Use

Of the 2644 patients who received %medicine_name% in Studies I to V , a total of 435 rheumatoid arthritis patients were 65 years of age and older, including 50 patients 75 years and older. Of the 1069 patients who received %medicine_name%-SC in studies SC-I and SC-II there were 295 patients 65 years of age and older, including 41 patients 75 years and older. The frequency of serious infection among %medicine_name% 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.

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

Hepatic Impairment

The safety and efficacy of %medicine_name% have not been studied in patients with hepatic impairment, including patients with positive HBV and HCV serology.

Renal Impairment

No dose adjustment is required in patients with mild or moderate renal impairment. %medicine_name% has not been studied in patients with severe renal impairment.

Drug Abuse And Dependence

No studies on the potential for %medicine_name% to cause dependence have been performed. However, there is no evidence from the available data that %medicine_name% treatment results in dependence.

In vitro data suggested that IL-6 reduced mRNA expression for several CYP450 isoenzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4, and this reduced expression was reversed by co-incubation with tocilizumab at clinically relevant concentrations. Accordingly, inhibition of IL-6 signaling in RA patients treated with tocilizumab may restore CYP450 activities to higher levels than those in the absence of tocilizumab leading to increased metabolism of drugs that are CYP450 substrates. Its effect on CYP2C8 or transporters (e.g., P-gp) is unknown. This is clinically relevant for CYP450 substrates with a narrow therapeutic index, where the dose is individually adjusted. Upon initiation of %medicine_name%, in patients being treated with these types of medicinal products, therapeutic monitoring of the effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) should be performed and the individual dose of the medicinal product adjusted as needed. Caution should be exercised when %medicine_name% is coadministered with drugs where decrease in effectiveness is undesirable, e.g., oral contraceptives (CYP3A4 substrates).

Simvastatin

Simvastatin is a CYP3A4 and OATP1B1 substrate. In 12 RA patients not treated with %medicine_name%, receiving 40 mg simvastatin, exposures of simvastatin and its metabolite, simvastatin acid, was 4-to 10-fold and 2-fold higher, respectively, than the exposures observed in healthy subjects. One week following administration of a single infusion of %medicine_name% (10 mg per kg), exposure of simvastatin and simvastatin acid decreased by 57% and 39%, respectively, to exposures that were similar or slightly higher than those observed in healthy subjects. Exposures of simvastatin and simvastatin acid increased upon withdrawal of %medicine_name% in RA patients. Selection of a particular dose of simvastatin in RA patients should take into account the potentially lower exposures that may result after initiation of %medicine_name% (due to normalization of CYP3A4) or higher exposures after discontinuation of %medicine_name%.

Omeprazole

Omeprazole is a CYP2C19 and CYP3A4 substrate. In RA patients receiving 10 mg omeprazole, exposure to omeprazole was approximately 2 fold higher than that observed in healthy subjects. In RA patients receiving 10 mg omeprazole, before and one week after %medicine_name% infusion (8 mg per kg), the omeprazole AUCinf decreased by 12% for poor (N=5) and intermediate metabolizers (N=5) and by 28% for extensive metabolizers (N=8) and were slightly higher than those observed in healthy subjects.

Dextromethorphan

Dextromethorphan is a CYP2D6 and CYP3A4 substrate. In 13 RA patients receiving 30 mg dextromethorphan, exposure to dextromethorphan was comparable to that in healthy subjects. However, exposure to its metabolite, dextrorphan (a CYP3A4 substrate), was a fraction of that observed in healthy subjects. One week following administration of a single infusion of %medicine_name% (8 mg per kg), dextromethorphan exposure was decreased by approximately 5%. However, a larger decrease (29%) in dextrorphan levels was noted after %medicine_name% infusion.

Pregnancy Exposure Registry

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

Risk Summary

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

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

Clinical Considerations

Fetal/Neonatal Adverse Reactions

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

Data

Animal Data

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

Parturition is associated with significant increases of IL-6 in the cervix and myometrium. The literature suggests that inhibition of IL-6 signaling may interfere with cervical ripening and dilatation and myometrial contractile activity leading to potential delays of parturition. For mice deficient in IL-6 (Il6-/-null mice), parturition was delayed relative to wild-type (ll6+/+) mice. Administration of recombinant IL-6 to ll6-/-null mice restored the normal timing of delivery.

The following serious adverse reactions are described elsewhere in labeling:

• Serious Infections
• Gastrointestinal Perforations
• Laboratory Parameters
• Immunosuppression
• Hypersensitivity Reactions, Including Anaphylaxis
• Demyelinating Disorders
• Active Hepatic Disease and Hepatic Impairment

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 %medicine_name% (%medicine_name%-IV)

The %medicine_name%-IV data in rheumatoid arthritis (RA) includes 5 double-blind, controlled, multicenter studies. In these studies, patients received doses of %medicine_name%-IV 8 mg per kg monotherapy (288 patients), %medicine_name%-IV 8 mg per kg in combination with DMARDs (including methotrexate) (1582 patients), or %medicine_name%-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 %medicine_name%-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. The most commonly reported adverse reactions in controlled studies up to 24 weeks (occurring in at least 5% of patients treated with %medicine_name%-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 %medicine_name%-IV and 3% for placebo-treated patients. The most common adverse reactions that required discontinuation of %medicine_name%-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 %medicine_name%-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 %medicine_name%-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 %medicine_name%-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 %medicine_name%-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 %medicine_name%-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.

Gastrointestinal Perforations

During the 24 week, controlled clinical trials, the overall rate of gastrointestinal perforation was 0.26 events per 100 patient-years with %medicine_name%-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. The relative contribution of these concomitant medications versus %medicine_name%-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 %medicine_name%-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 %medicine_name%-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 %medicine_name%-IV. Appropriate medical treatment should be available for immediate use in the event of a serious hypersensitivity reaction.

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 %medicine_name%-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 %medicine_name%-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.

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 %medicine_name%-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.

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 %medicine_name%-IV, or reduction in %medicine_name%-IV dose, resulted in decrease or normalization of liver enzymes. These elevations were not associated with clinically relevant increases in direct bilirubin, nor were they associated with clinical evidence of hepatitis or hepatic insufficiency.

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

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 %medicine_name%-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 %medicine_name% 4 mg per kg+DMARD arm, 20 mg per dL in the %medicine_name% 8 mg per kg+DMARD, and 25 mg per dL in %medicine_name% 8 mg per kg monotherapy.
• Mean HDL increased by 3 mg per dL in the %medicine_name% 4 mg per kg+DMARD arm, 5 mg per dL in the %medicine_name% 8 mg per kg+DMARD, and 4 mg per dL in %medicine_name% 8 mg per kg monotherapy.
• Mean LDL/HDL ratio increased by an average of 0.14 in the %medicine_name% 4 mg per kg+DMARD arm, 0.15 in the %medicine_name% 8 mg per kg+DMARD, and 0.26 in %medicine_name% 8 mg per kg monotherapy.
• ApoB/ApoA1 ratios were essentially unchanged in %medicine_name%-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 %medicine_name%-IV, compared to 8 malignancies in patients in the control groups. Exposure-adjusted incidence was similar in the %medicine_name%-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.

Other Adverse Reactions

Adverse reactions occurring in 2% or more of patients on 4 or 8 mg per kg %medicine_name%-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 %medicine_name% plus DMARD and at Least 1% Greater Than That Observed in Patients on Placebo plus DMARD

Other infrequent and medically relevant adverse reactions occurring at an incidence less than 2% in rheumatoid arthritis patients treated with %medicine_name%-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: leucopenia

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 %medicine_name% (%medicine_name%-SC)

The %medicine_name%-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 %medicine_name% administered subcutaneously was consistent with the known safety profile of intravenous %medicine_name%, with the exception of injection site reactions, which were more common with %medicine_name%-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 %medicine_name%-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 %medicine_name% 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 %medicine_name%-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 %medicine_name%-SC arm compared with 1.4 % (3/217) in the placebo arm developed anti-tocilizumab antibodies; of these, 1.4% (6/434) in the %medicine_name%-SC arm and 0.5% (1/217) in the placebo arm also developed neutralizing antibodies.

A total of 1454 (>99%) patients who received %medicine_name%-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 x 10⁹/L occurred in 2.9% and 3.7% of patients receiving %medicine_name%-SC weekly and every other week, respectively.

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

Thrombocytopenia

During routine laboratory monitoring in the %medicine_name%-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 x ULN occurred in 6.5% and 1.4% of patients, respectively, receiving %medicine_name%-SC weekly and 3.4% and 0.7% receiving %medicine_name% SC every other week.

Lipid Parameters Elevations

During routine laboratory monitoring in the %medicine_name%-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 %medicine_name%-SC weekly, every other week and placebo, respectively.

Clinical Trials Experience In Giant Cell Arteritis Patients Treated With Subcutaneous %medicine_name% (%medicine_name%-SC)

The safety of subcutaneous %medicine_name% (tocilizumab) has been studied in one Phase III study (WA28119) with 251 GCA patients. The total patient years duration in the %medicine_name% 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 %medicine_name% treatment groups was generally consistent with the known safety profile of %medicine_name%. 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 %medicine_name% weekly group and 160.2/4.4 events per 100 patient years in the %medicine_name% 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 %medicine_name% (%medicine_name%-IV)

The safety of %medicine_name%-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 %medicine_name%IV all exposure population (defined as patients who received at least one dose of %medicine_name%-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.

Infections

The rate of infections in the %medicine_name%-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 %medicine_name%-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.

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 %medicine_name%-IV all exposure population, a decrease in neutrophil counts below 1 x 10⁹ per L occurred in 3.7% of patients.

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

Thrombocytopenia

During routine laboratory monitoring in the %medicine_name%-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 %medicine_name%-IV all exposure population, elevation in ALT or AST at or greater than 3 x 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 x ULN occurred in one patient (0.5%) and elevation in LDL greater than 1.5-2 x ULN occurred in one patient (0.5%).

Clinical Trials Experience In Systemic Juvenile Idiopathic Arthritis Patients Treated With Intravenous %medicine_name% (%medicine_name%-IV)

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

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

Immunogenicity

All 112 patients were tested for anti-tocilizumab antibodies at baseline. Two patients developed positive antitocilizumab 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 x 10⁹ per L occurred in 7% of patients in the %medicine_name%-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 %medicine_name%-IV group. There was no clear relationship between decrease in neutrophils below 1 x 10⁹ per L and the occurrence of serious infections.

Thrombocytopenia

During routine monitoring in the 12 week controlled phase, 1% of patients in the %medicine_name%-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 %medicine_name%-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 3x ULN occurred in 5% and 3% of patients, respectively in the %medicine_name%-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 3x ULN occurred in 13% and 5% of %medicine_name%-IV treated patients, respectively.

Lipids

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

Postmarketing Experience

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

• Fatal anaphylaxis
• Stevens-Johnson Syndrome
• Pancreatitis

There are limited data available on overdoses with %medicine_name%. One case of accidental overdose was reported with intravenous %medicine_name% in which a patient with multiple myeloma received a dose of 40 mg per kg. No adverse drug reactions were observed. No serious adverse drug reactions were observed in healthy volunteers who received single doses of up to 28 mg per kg, although all 5 patients at the highest dose of 28 mg per kg developed dose-limiting neutropenia.

In case of an overdose, it is recommended that the patient be monitored for signs and symptoms of adverse reactions. Patients who develop adverse reactions should receive appropriate symptomatic treatment.

In clinical studies in RA patients with the 4 mg per kg and 8 mg per kg IV doses or the 162 mg weekly and every other weekly SC doses of %medicine_name%, 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 and increases in hemoglobin) with doses, however the greatest improvements were observed with 8 mg per kg %medicine_name%. Pharmacodynamic changes were also observed to occur after %medicine_name% administration in GCA, 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 %medicine_name% in doses from 2 to 28 mg per kg intravenously and 81 to 162 mg subcutaneously, absolute neutrophil counts decreased to the nadir 3 to 5 days following %medicine_name% administration. Thereafter, neutrophils recovered towards baseline in a dose dependent manner. Rheumatoid arthritis and GCA patients demonstrated a similar pattern of absolute neutrophil counts following %medicine_name% administration.

Rheumatoid Arthritis - Intravenous Administration

The pharmacokinetics characterized in healthy subjects and RA patients suggested that PK is similar between the two populations. The clearance (CL) of tocilizumab decreased with increased doses. At the 10 mg per kg single dose in RA patients, mean CL was 0.29 ± 0.10 mL per hr per kg and mean apparent terminal t½ was 151 ± 59 hours (6.3 days).

The pharmacokinetics of tocilizumab were determined using a population pharmacokinetic analysis of 1793 rheumatoid arthritis patients treated with %medicine_name% 4 and 8 mg per kg every 4 weeks for 24 weeks.

The pharmacokinetic parameters of tocilizumab did not change with time. A more than dose-proportional increase in area under the curve (AUC) and trough concentration (Cmin) was observed for doses of 4 and 8 mg per kg every 4 weeks. Maximum concentration (Cmax) increased dose-proportionally. At steady-state, estimated AUC and Cmin were 2.7 and 6.5-fold higher at 8 mg per kg as compared to 4 mg per kg, respectively. In a longterm study with dosing for 104 weeks, observed Cmin was sustained over time.

For doses of %medicine_name% 4 mg per kg given every 4 weeks, the estimated mean (± SD) steady-state AUC, Cmin and Cmax of tocilizumab were 13000 ± 5800 mcg•h per mL, 1.49 ± 2.13 mcg per mL, and 88.3 ± 41.4 mcg per mL, respectively. The accumulation ratios for AUC and Cmax were 1.11 and 1.02, respectively. The accumulation ratio was higher for Cmin (1.96). Steady-state was reached following the first administration for Cmax and AUC, respectively, and after 16 weeks Cmin. For doses of %medicine_name% 8 mg per kg given every 4 weeks, the estimated mean (± SD) steady-state AUC, Cmin and Cmax of tocilizumab were 35000 ± 15500 mcg•h per mL, 9.74 ± 10.5 mcg per mL, and 183 ± 85.6 mcg per mL, respectively. The accumulation ratios for AUC and Cmax were 1.22 and 1.06, respectively. The accumulation ratio was higher for Cmin (2.35). Steady-state was reached following the first administration and after 8 and 20 weeks for Cmax, AUC, and Cmin, respectively. Tocilizumab AUC, Cmin and Cmax increased with increase of body weight. At body weight at or above 100 kg, the estimated mean (± SD) steady-state AUC, Cmin and Cmax of tocilizumab were 55500 ± 14100 mcg•h per mL, 19.0 ± 12.0 mcg per mL, and 269 ± 57 mcg per mL, respectively, which are higher than mean exposure values for the patient population. Therefore, %medicine_name% doses exceeding 800 mg per infusion are not recommended.

Rheumatoid Arthritis - Subcutaneous Administration

The pharmacokinetics of tocilizumab was characterized using a population pharmacokinetic analysis using a database composed of 1759 rheumatoid arthritis patients treated with 162 mg SC every week, 162 mg SC every other week, and 8 mg/kg every 4 weeks for 24 weeks.

The pharmacokinetic parameters of tocilizumab did not change with time. For the 162 mg every week dose, the estimated mean (±SD) steady-state AUC1week, Cmin and Cmax of tocilizumab were 8200 ± 3600 mcg•h/mL, 44.6 ± 20.6 mcg/mL, and 50.9 ± 21.8 mcg/mL, respectively. The accumulation ratios for AUC, Cmin, and Cmax were 6.83, 6.37, and 5.47, respectively. Steady state was reached after 12 weeks for AUC, Cmin, and Cmax.

For the 162 mg every other week dose, the estimated mean (±SD) steady-state AUC2week, Cmin, and Cmax of tocilizumab were 3200 ± 2700 mcg•h/mL, 5.6 ± 7.0 mcg/mL, and 12.3 ± 8.7 mcg/mL, respectively. The accumulation ratios for AUC, Cmin, and Cmax were 2.67, 5.6, and 2.12, respectively. Steady state was reached after 12 weeks for AUC and Cmin, and after 10 weeks for Cmax.

Giant Cell Arteritis – Subcutaneous Administration

The pharmacokinetics of tocilizumab in GCA patients was determined using a population pharmacokinetic analysis on a dataset composed of 149 GCA patients treated with 162 mg SC every week or with 162 mg SC every other week.

For the 162 mg every week dose, the estimated mean (±SD) steady-state Cavg, Cmin and Cmax of tocilizumab were 71.3 ± 30.1 mcg/mL, 68.1± 29.5 mcg/mL, and 73 ± 30.4 mcg/mL, respectively. The accumulation ratios for Cavg or AUCtau, Cmin, and Cmax were 10.9, 9.6, and 8.9, respectively. Steady state was reached after 17 weeks.

For the 162 mg every other week dose, the estimated mean (±SD) steady-state Cavg, Cmin, and Cmax of tocilizumab were 16.2 ± 11.8 mcg/mL, 11.1 ± 10.3 mcg/mL, and 19.3 ± 12.8 mcg/mL, respectively. The accumulation ratios for Cavg or AUCtau, Cmin, and Cmax were 2.8, 5.6, and 2.3 respectively. Steady-state was reached after 14 weeks.

Polyarticular Juvenile Idiopathic Arthritis - Intravenous Administration

The pharmacokinetics of tocilizumab was determined using a population pharmacokinetic analysis on a database composed of 188 patients with polyarticular juvenile idiopathic arthritis.

For doses of 8 mg/kg tocilizumab (patients with a body weight at or above 30 kg) given every 4 weeks, the estimated mean (± SD) AUC4weeks, Cmax and Cmin of tocilizumab were 29500 ± 8660 mcg•hr/mL, 182 ± 37 mcg/mL and 7.49 ± 8.2 mcg/mL, respectively.

For doses of 10 mg/kg tocilizumab (patients with a body weight less than 30 kg) given every 4 weeks, the estimated mean (± SD) AUC4weeks, Cmax and Cmin of tocilizumab were 23200 ± 6100 mcg•hr/mL, 175 ± 32 mcg/mL and 2.35 ± 3.59 mcg/mL, respectively.

The accumulation ratios were 1.05 and 1.16 for AUC4weeks, and 1.43 and 2.22 for Cmin for 10 mg/kg (BW less than 30 kg) and 8 mg/kg (BW at or above 30 kg) doses, respectively. No accumulation for Cmax was observed.

Systemic Juvenile Idiopathic Arthritis - Intravenous Administration

The pharmacokinetics of tocilizumab were determined using a population pharmacokinetic analysis on a database composed of 75 patients with SJIA treated with 8 mg per kg (patients with a body weight at or above 30 kg) or 12 mg per kg (patients with a body weight less than 30 kg), given every 2 weeks. The estimated mean (± SD) AUC2weeks, Cmax and Cmin of tocilizumab were 32200 ± 9960 mcg•hr per mL, 245 ± 57.2 mcg per mL and 57.5 ± 23.3 mcg per mL, respectively. The accumulation ratio for Cmin (week 12 over week 2) was 3.2 ± 1.3. Steady state was reached on or after week 12. Mean estimated tocilizumab exposure parameters were similar between the two dose groups defined by body weight.

Absorption

Following SC dosing in RA and GCA patients, the absorption half-life was around 4 days. The bioavailability for the SC formulation was 0.8.

In RA patients the median values of Tmax were 2.8 days after the tocilizumab every week dose and 4.7 days after the tocilizumab every other week dose.

In GCA patients, the median values of Tmax were 3 days after the tocilizumab every week dose and 4.5 days after the tocilizumab every other week dose.

Distribution

Following intravenous dosing, tocilizumab undergoes biphasic elimination from the circulation. In rheumatoid arthritis patients the central volume of distribution was 3.5 L and the peripheral volume of distribution was 2.9 L, resulting in a volume of distribution at steady state of 6.4 L.

In GCA patients, the central volume of distribution was 4.09 L, the peripheral volume of distribution was 3.37 L resulting in a volume of distribution at steady state of 7.46 L.

In pediatric patients with PJIA, the central volume of distribution was 1.98 L, the peripheral volume of distribution was 2.1 L, resulting in a volume of distribution at steady state of 4.08 L.

In pediatric patients with SJIA, the central volume of distribution was 0.94 L, the peripheral volume of distribution was 1.60 L resulting in a volume of distribution at steady state of 2.54 L.

Elimination

%medicine_name% is eliminated by a combination of linear clearance and nonlinear elimination. The concentration-dependent nonlinear elimination plays a major role at low tocilizumab concentrations. Once the nonlinear pathway is saturated, at higher tocilizumab concentrations, clearance is mainly determined by the linear clearance. The saturation of the nonlinear elimination leads to an increase in exposure that is more than dose-proportional. The pharmacokinetic parameters of %medicine_name% do not change with time.

Population pharmacokinetic analyses in any patient population tested so far indicate no relationship between apparent clearance and the presence of anti-drug antibodies.

The linear clearance in the population pharmacokinetic analysis was estimated to be 12.5 mL per h in RA patients, 6.7 mL per h in GCA patients, 5.8 mL per h in pediatric patients with PJIA, and 7.1 mL per h in pediatric patients with SJIA.

Due to the dependence of total clearance on %medicine_name% serum concentrations, the half-life of %medicine_name% is also concentration-dependent and varies depending on the serum concentration level.

For IV administration in RA patients, the concentration-dependent apparent t½ is up to 11 days for 4 mg per kg and up to 13 days for 8 mg per kg every 4 weeks in patients with RA at steady-state. For SC administration in RA patients, the concentration-dependent apparent t½ is up to 13 days for 162 mg every week and 5 days for 162 mg every other week in patients with RA at steady-state.

In GCA patients at steady state, the effective t½ of tocilizumab varied between 18.3 and 18.9 days for 162 mg SC every week dosing regimen and between 4.2 and 7.9 days for 162 mg SC every other week dosing regimen.

The t½ of tocilizumab in children with PJIA is up to 16 days for the two body weight categories (8 mg/kg for body weight at or above 30 kg or 10 mg/kg for body weight below 30 kg) during a dosing interval at steady state.

The t½ of tocilizumab in pediatric patients with SJIA is up to 23 days for the two body weight categories at week 12.