Tocilizumab

FDA Drug Information • Also known as: Actemra, Actemra Actpen, Avtozma, Tocilizumab-Anoh, Tofidence

Brand Names: Actemra, Actemra Actpen, Avtozma, Tocilizumab-Anoh, Tofidence
Dosage Form: INJECTION, SOLUTION
Product Type: DRUG FOR FURTHER PROCESSING

⚠ Boxed Warning (Black Box)

WARNING: RISK OF SERIOUS INFECTIONS Patients treated with tocilizumab products including Tocilizumab-anoh are at increased risk for developing serious infections that may lead to hospitalization or death [see Warnings and Precautions (5.1) , Adverse Reactions (6.1) ] . Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. If a serious infection develops, interrupt Tocilizumab-anoh until the infection is controlled. Reported infections include: Active tuberculosis, which may present with pulmonary or extrapulmonary disease. Patients, except those with COVID-19, should be tested for latent tuberculosis before Tocilizumab-anoh use and during therapy. Treatment for latent infection should be initiated prior to Tocilizumab-anoh use. Invasive fungal infections, including candidiasis, aspergillosis, and pneumocystis. Patients with invasive fungal infections may present with disseminated, rather than localized, disease. Bacterial, viral and other infections due to opportunistic pathogens. The risks and benefits of treatment with Tocilizumab-anoh should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with Tocilizumab-anoh, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy [see Warnings and Precautions (5.1) ] . WARNING: RISK OF SERIOUS INFECTIONS See full prescribing information for complete boxed warning. Serious infections leading to hospitalization or death including tuberculosis (TB), bacterial, invasive fungal, viral, and other opportunistic infections have occurred in patients receiving tocilizumab products . ( 5.1 ) If a serious infection develops, interrupt Tocilizumab-anoh until the infection is controlled. ( 5.1 ) Perform test for latent TB (except patients with COVID-19); if positive, start treatment for TB prior to starting Tocilizumab-anoh . ( 5.1 ) Monitor all patients for active TB during treatment, even if initial latent TB test is negative. ( 5.1 )

Description

11 DESCRIPTION Tocilizumab-anoh is a recombinant humanized anti-human interleukin 6 (IL-6) receptor monoclonal antibody of the immunoglobulin IgG1κ (gamma 1, kappa) subclass with a typical H2L2 polypeptide structure. Each light chain and heavy chain consists of 214 and 448 amino acids, respectively. The four polypeptide chains are linked intra- and inter-molecularly by disulfide bonds. Tocilizumab-anoh has a molecular weight of approximately 148 kDa. The antibody is produced in mammalian (Chinese hamster ovary) cells. Intravenous Infusion Tocilizumab-anoh injection is a sterile, clear to slightly opalescent, colorless to pale yellow, preservative-free solution for further dilution prior to intravenous infusion with a pH of approximately 6.0. Each single-dose vial, formulated with a histidine and L-histidine hydrochloride monohydrate buffered 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 Tocilizumab-anoh. Each mL of solution contains histidine (0.74 mg), L-histidine hydrochloride monohydrate (1.09 mg), methionine (8.95 mg), polysorbate 80 (0.5 mg), threonine (19.06 mg), and Water for Injection, USP. Subcutaneous Injection Tocilizumab-anoh injection is a sterile, clear to slightly opalescent, colorless to yellow, preservative-free, histidine buffered solution for subcutaneous use with a pH of approximately 6.0. It is supplied in a ready-to-use, single-dose 0.9 mL prefilled syringe (PFS) with a needle safety device or a ready- to-use, single-dose 0.9 mL autoinjector that delivers 162 mg tocilizumab-anoh, histidine (0.7 mg), L-histidine hydrochloride monohydrate (1.0 mg), methionine (8.1 mg), polysorbate 80 (0.2 mg), threonine (17.2 mg), and Water for Injection, USP.

What Is Tocilizumab Used For?

1 INDICATIONS AND USAGE Tocilizumab-anoh is an interleukin-6 (IL-6) receptor antagonist indicated for treatment of: Rheumatoid Arthritis (RA) ( 1.1 ) 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) ( 1.2 ) Adult patients with giant cell arteritis. Polyarticular Juvenile Idiopathic Arthritis (PJIA) ( 1.3 ) Patients 2 years of age and older with active polyarticular juvenile idiopathic arthritis. Systemic Juvenile Idiopathic Arthritis (SJIA) ( 1.4 ) Patients 2 years of age and older with active systemic juvenile idiopathic arthritis. Cytokine Release Syndrome (CRS) ( 1.5 ) Adults and pediatric patients with 2 years of age and older with chimeric antigen receptor (CAR) T-cell-induced severe or life-threatening cytokine release syndrome. Coronavirus Disease 2019 (COVID-19) ( 1.6 ) Hospitalized adult patients with coronavirus disease 2019 (COVID-19) who are receiving systemic corticosteroids and require supplemental oxygen, non-invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). 1.1 Rheumatoid Arthritis (RA) Tocilizumab-anoh 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 Giant Cell Arteritis (GCA) Tocilizumab-anoh is indicated for the treatment of giant cell arteritis (GCA) in adult patients. 1.3 Polyarticular Juvenile Idiopathic Arthritis (PJIA) Tocilizumab-anoh is indicated for the treatment of active polyarticular juvenile idiopathic arthritis in patients 2 years of age and older. 1.4 Systemic Juvenile Idiopathic Arthritis (SJIA) Tocilizumab-anoh is indicated for the treatment of active systemic juvenile idiopathic arthritis in patients 2 years of age and older. 1.5 Cytokine Release Syndrome (CRS) Tocilizumab-anoh 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. 1.6 Coronavirus Disease 2019 (COVID-19) Tocilizumab-anoh is indicated for the treatment of coronavirus disease 2019 (COVID-19) in hospitalized adult patients who are receiving systemic corticosteroids and require supplemental oxygen, non- invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO).

Dosage and Administration

2 DOSAGE AND ADMINISTRATION For RA, pJIA and sJIA, Tocilizumab-anoh may be used alone or in combination with methotrexate: and in RA, other non-biologic DMARDs may be used. ( 2 ) General Administration and Dosing Information ( 2.1 ) RA, GCA, PJIA and SJIA It is recommended that Tocilizumab-anoh not be initiated in patients with an absolute neutrophil count (ANC) below 2000 per mm 3 , platelet count below 100,000 per mm 3 , or ALT or AST above 1.5 times the upper limit of normal (ULN) ( 5.3 , 5.4 ) . COVID-19 It is recommended that Tocilizumab-anohnot be initiated in patients with an absolute neutrophil count (ANC) below 1000 per mm 3 , platelet count below 50,000 mm 3 , or ALT or AST above 10 times ULN ( 5.3 , 5.4 ) . In RA, CRS, or COVID-19 patients, Tocilizumab-anohdoses exceeding 800 mg per infusion are not recommended. ( 2.2 , 2.6 , 12.3 ) In GCA patients, Tocilizumab-anohdoses exceeding 600 mg per infusion are not recommended. ( 2.3 , 12.3 ) Rheumatoid Arthritis ( 2.2 ) Recommended Adult Intravenous Dosage: When used in combination with non-biologic DMARDs or as monotherapy the recommended starting dose is 4 mg per kg every 4 weeks followed by an increase to 8 mg per kg every 4 weeks based on clinical response. Recommended Adult Subcutaneous Dosage: Patients less than 100 kg weight 162 mg administered subcutaneously every other week, followed by an increase to every week based on clinical response Patients at or above 100 kg weight 162 mg administered subcutaneously every week Giant Cell Arteritis ( 2.3 ) Recommended Adult Intravenous Dosage: The recommended dose is 6 mg per kg every 4 weeks in combination with a tapering course of glucocorticoids. Tocilizumab-anohcan be used alone following discontinuation of glucocorticoids. Recommended Adult Subcutaneous Dosage: The recommended dose 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. Tocilizumab-anoh can be used alone following discontinuation of glucocorticoids. Polyarticular Juvenile Idiopathic Arthritis ( 2.4 ) Recommended Intravenous PJIA Dosage Every 4 Weeks Patients less than 30 kg weight 10 mg per kg Patients at or above 30 kg weight 8 mg per kg Recommended Subcutaneous PJIA Dosage Patients less than 30 kg weight 162 mg once every three weeks Patients at or above 30 kg weight 162 mg once every two weeks Systemic Juvenile Idiopathic Arthritis ( 2.5 ) Recommended Intravenous SJIA Dosage Every 2 Weeks Patients less than 30 kg weight 12 mg per kg Patients at or above 30 kg weight 8 mg per kg Recommended Subcutaneous SJIA Dosage Patients less than 30 kg weight 162 mg every two weeks Patients at or above 30 kg weight 162 mg every week Cytokine Release Syndrome ( 2.6 ) Recommened Intravenous CRS Dosage Patients less than 30 kg weight 12 mg...

Side Effects (Adverse Reactions)

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in labeling: Serious Infections [see Warnings and Precautions (5.1) ] Gastrointestinal Perforations [see Warnings and Precautions (5.2) ] Laboratory Parameters [see Warnings and Precautions (5.4) ] Immunosuppression [see Warnings and Precautions (5.5) ] Hypersensitivity Reactions, Including Anaphylaxis [see Warnings and Precautions (5.6) ] Demyelinating Disorders [see Warnings and Precautions (5.7) ] Active Hepatic Disease and Hepatic Impairment [see Warnings and Precautions (5.8) ] 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. Most common adverse reactions (incidence of at least 5%): upper respiratory tract infections, nasopharyngitis, headache, hypertension, increased ALT, injection site reactions. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact CELLTRION USA Inc., at 1-800-560-9414 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 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. Overall Infections In the 24 week, controlled clinical studies, the rate of infections in the tocilizumab-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 tocilizumab-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 tocilizumab-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 tocilizumab-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...

Drug Interactions

7 DRUG INTERACTIONS 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) ] . In GCA patients, no effect of concomitant corticosteroid on tocilizumab exposure was observed. 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 Tocilizumab-anoh, 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 Tocilizumab-anoh 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 Tocilizumab-anoh [see Warnings and Precautions (5.9) ] .

Contraindications

4 CONTRAINDICATIONS Tocilizumab-anoh is contraindicated in patients with known hypersensitivity to tocilizumab products [see Warnings and Precautions (5.6) ]. Known hypersensitivity to tocilizumab products. ( 4 )

Pregnancy and Breastfeeding

8.1 Pregnancy Risk Summary The available data with tocilizumab products from a pregnancy exposure registry, retrospective cohort study, pharmacovigilance, and published literature are insufficient to draw conclusions about a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. These studies had methodological limitations, including small sample size of tocilizumab exposed groups, missing exposure and outcomes information, and lack of adjustment for cofounders. Monoclonal antibodies, such as tocilizumab products, are actively transported across the placenta during the third trimester of pregnancy and may affect immune response in the in utero exposed infant [see Clinical Considerations ]. 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 [see Data ] . 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...

Overdosage

10 OVERDOSAGE There are limited data available on overdoses with tocilizumab products. One case of accidental overdose was reported with intravenous tocilizumab 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.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING For Intravenous Infusion Tocilizumab-anoh injection is a preservative-free, sterile clear to slightly opalescent, colorless to pale yellow solution for intravenous infusion supplied in a single-dose vial packaged within cartons in the following strengths and packaging configurations: 80 mg/ 4 mL (20 mg/mL): carton of one vial (NDC 72606-048-01); carton of 4 vials (NDC 72606-048-02). 200 mg/ 10 mL (20 mg/mL): carton of one vial (NDC 72606-049-01); carton of 4 vials (NDC 72606-049-02). 400 mg/ 20 mL (20 mg/mL): carton of one vial (NDC 72606-050-01); carton of 4 vials (NDC 72606-050-02). For Subcutaneous Injection Tocilizumab-anoh injection is supplied as a preservative-free, sterile, clear to slightly opalescent, colorless to yellow solution for subcutaneous administration. The following packaging configurations are available: Each single-dose prefilled syringe delivers 162 mg/0.9 mL: carton of one syringe (NDC 72606-051-01); carton of 4 syringes (NDC 72606-051-02); carton of 3 packs of 4 syringes (NDC 72606-051-03). The syringe plunger stopper and needle cover are not made with natural rubber latex. Each single-dose prefilled autoinjector 162 mg/0.9 mL: carton of one syringe (NDC 72606-051-04); carton of 4 syringes (NDC 72606-051-05); carton of 3 packs of 4 syringes (NDC 72606-051-06). The syringe plunger stopper and needle cover are not made with natural rubber latex. Storage and Handling: Do not use beyond expiration date on the container, package, prefilled syringe, or autoinjector. Tocilizumab-anoh must be refrigerated at 36°F to 46°F (2ºC to 8ºC). Do not freeze. Protect the vials, syringes, and autoinjectors from light by storage in the original carton until time of use, and keep syringes and autoinjectors dry. Once removed from the refrigerator, the prefilled syringe and autoinjector can be stored at room temperature at or below 77°F (25°C) for up to 3 weeks. The prefilled syringe and autoinjector must always be kept in the...

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.