ACTEMRA® (tocilizumab) injection

ACTEMRA® (tocilizumab) injection

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ACTEMRA® (tocilizumab) injection

Tocilizumab 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 intraand inter-molecularly by disulfide bonds. ACTEMRA has a molecular weight of approximately 148 kDa. The antibody is produced in mammalian (Chinese hamster ovary) cells.

Intravenous Infusion

ACTEMRA (tocilizumab) injection is a sterile, clear, colorless to pale yellow, preservative-free solution for further dilution prior to intravenous infusion with a pH of approximately 6.5. Each single-dose vial, formulated with a disodium phosphate dodecahydrate/sodium dihydrogen phosphate dihydrate 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 ACTEMRA. Each mL of solution contains polysorbate 80 (0.5 mg), sucrose (50 mg), and Water for Injection, USP.

Subcutaneous Injection

ACTEMRA (tocilizumab) injection is a sterile, clear, colorless to slightly yellowish, 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 readyto-use, single-dose 0.9 mL autoinjector that delivers 162 mg tocilizumab, L-arginine hydrochloride (19 mg), Lhistidine (1.52 mg), L-histidine hydrochloride monohydrate (1.74 mg), L-methionine (4.03 mg), polysorbate 80 (0.18 mg), and Water for Injection, USP.

Indications and usage

ACTEMRA® (tocilizumab) is an interleukin-6 (IL-6) receptor antagonist indicated for treatment of:

Rheumatoid Arthritis (RA)

  • 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)

  • Adult patients with giant cell arteritis.

Polyarticular Juvenile Idiopathic Arthritis (PJIA)

  • Patients 2 years of age and older with active polyarticular juvenile idiopathic arthritis.

Systemic Juvenile Idiopathic Arthritis (SJIA)

  • Patients 2 years of age and older with active systemic juvenile idiopathic arthritis.

Cytokine Release Syndrome (CRS)

  • Adults and pediatric patients 2 years of age and older with chimeric antigen receptor (CAR) T cell-induced severe or life-threatening cytokine release syndrome.

Mechanism of Action

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

Dosage and administration

Rheumatoid Arthritis

ACTEMRA 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 Dosage Regimen: The recommended dosage of ACTEMRA 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 Dosage Regimen:

Patients less than 100 kg weight162 mg administered subcutaneously every other week, followed by an increase to every week based on clinical response
Patients at or above 100 kg weight162 mg administered subcutaneously every week

Giant Cell Arteritis

The recommended dose of ACTEMRA 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.

ACTEMRA 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

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

Recommended Intravenous Dosage Regimen: The recommended dosage of ACTEMRA for PJIA patients given once every 4 weeks as a 60-minute single intravenous drip infusion is:

Patients less than 30 kg weight10 mg per kg
Patients at or above 30 kg weight 8 mg per kg8 mg per kg

Recommended Subcutaneous Dosage Regimen:

Patients less than 30 kg weight162 mg once every 3 weeks
Patients at or above 30 kg weight162 mg once every 2 weeks

Systemic Juvenile Idiopathic Arthritis

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

Recommended Intravenous Dosage Regimen: The recommended dose of ACTEMRA for SJIA patients given once every 2 weeks as a 60-minute single intravenous drip infusion is:

Patients less than 30 kg weight12 mg per kg
Patients at or above 30 kg weight8 mg per kg

Recommended Subcutaneous Dosage Regimen:

Patients less than 30 kg weight162 mg once every two weeks
Patients at or above 30 kg weight162 mg once every week

Cytokine Release Syndrome (CRS)

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

Patients less than 30 kg weight12 mg per kg
Patients at or above 30 kg weight8 mg per kg

Contraindications

ACTEMRA is contraindicated in patients with known hypersensitivity to ACTEMRA.

Adverse reactions

Most common adverse reactions (incidence of at least 5%): upper respiratory tract infections, nasopharyngitis, headache, hypertension, increased ALT, injection site reactions.

Warnings and precautions

Serious Infections: Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, protozoal, or other opportunistic pathogens have been reported in patients receiving immunosuppressive agents including ACTEMRA. 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 ACTEMRA. Other serious infections, not reported in clinical studies, may also occur (e.g., histoplasmosis, coccidioidomycosis, listeriosis).

Gastrointestinal Perforations: Events of gastrointestinal perforation have been reported in clinical trials, primarily as complications of diverticulitis in patients treated with ACTEMRA. Use ACTEMRA 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

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

Immunosuppression: The impact of treatment with ACTEMRA on the development of malignancies is not known but malignancies were observed in clinical studies. ACTEMRA 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 ACTEMRA and anaphylactic events with a fatal outcome have been reported with intravenous infusion of ACTEMRA.

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

Active Hepatic Disease and Hepatic Impairment: Treatment with ACTEMRA is not recommended in patients with active hepatic disease or hepatic impairment

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

Drug interactions

Concomitant Drugs for Treatment of Adult Indications: In RA patients, population pharmacokinetic analyses did not detect any effect of methotrexate (MTX), nonsteroidal anti-inflammatory drugs or corticosteroids on tocilizumab clearance. Concomitant administration of a single intravenous dose of 10 mg/kg ACTEMRA with 10-25 mg MTX once weekly had no clinically significant effect on MTX exposure. ACTEMRA has not been studied in combination with biological DMARDs such as TNF antagonists

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 may restore CYP450 activities to higher levels than those in the absence of tocilizumab 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 ACTEMRA, respectively. The effect of tocilizumab 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 ACTEMRA, 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 ACTEMRA with CYP3A4 substrate drugs where decrease in effectiveness is undesirable, e.g., oral contraceptives, lovastatin, atorvastatin, etc. The effect of tocilizumab on CYP450 enzyme activity may persist for several weeks after stopping therapy

Use in specific populations

Pregnancy: The limited available data with ACTEMRA 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

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 ACTEMRA in utero

Lactation: 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 ACTEMRA to an infant during lactation; therefore the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ACTEMRA and the potential adverse effects on the breastfed child from tocilizumab or from the underlying maternal condition.

Pediatric Use: ACTEMRA 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.

ACTEMRA by subcutaneous use is indicated for the treatment of pediatric patients with:

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

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

Hepatic Impairment: The safety and efficacy of ACTEMRA 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. ACTEMRA has not been studied in patients with severe renal impairment

Overdosage

There are limited data available on overdoses with ACTEMRA. One case of accidental overdose was reported with intravenous ACTEMRA 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.

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