Indications

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.
  • Systemic Sclerosis-Associated Interstitial Lung Disease (SSc-ILD): Slowing the rate of decline in pulmonary function in adult patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD)
  • 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.

Pharmacology

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 & Administration

Rheumatoid Arthritis: Recommended Adult Intravenous Dosage: When used in combination with 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.
  • 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: Recommended Adult Subcutaneous Dosage: The recommended dose of tocilizumab 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. tocilizumab can be used alone following discontinuation of glucocorticoids. tocilizumab subcutaneous formulation is not intended for intravenous administration.

Systemic Sclerosis-Associated Interstitial Lung Disease (SSc-ILD): Recommended Adult Subcutaneous Dosage: The recommended dose of tocilizumab for adult patients with SSc-ILD is 162 mg given once every week as a subcutaneous injection.

Polyarticular Juvenile Idiopathic Arthritis
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
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
Recommended Intravenous CRS Dosage-
  • Patients less than 30 kg weight: 12 mg per kg
  • Patients at or above 30 kg weight: 8 mg per kg
Alone or in combination with corticosteroids.

General Dosing Information:
  • It is recommended that tocilizumab 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).
  • tocilizumab doses exceeding 800 mg per infusion are not recommended in RA or CRS patients.

Interaction

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 tocilizumab, 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 tocilizumab, 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 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

Contraindications

Hypersensitivity to tocilizumab or to any of the excipients.

Side Effects

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

Pregnancy & Lactation

Based on animal data, may cause fetal harm. Discontinue drug or nursing taking into consideration importance of drug to mother.

Precautions & Warnings

  • Serious Infections- do not administer tocilizumab during an active infection, including localized infections. If a serious infection develops, interrupt tocilizumab until the infection is controlled.
  • Gastrointestinal (GI) perforation- use with caution in patients who may be at increased risk.
  • Hepatotoxicity- Monitor patients for signs and symptoms of hepatic injury. Modify or discontinue tocilizumab if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop.
  • Laboratory monitoring- recommended due to potential consequences of treatment-related changes in neutrophils, platelets, lipids, and liver function tests.
  • Hypersensitivity reactions, including anaphylaxis and death have occurred.
  • Live vaccines- Avoid use with tocilizumab.

Overdose Effects

There are limited data available on overdoses with tocilizumab. 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.

Therapeutic Class

Drugs used for Rheumatoid Arthritis

Storage Conditions

Tocilizumab must be refrigerated at 2ºC to 8ºC. Do not freeze. Protect the vials, syringes, and autoinjectors from light by storage in the original package until time of use, and keep syringes and autoinjectors dry.