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Tocilizumab

Class: Disease-modifying Antirheumatic Drugs
- Interleukin-6 Antagonists
Chemical Name: Immunoglobulin G1, anti-(human interleukin 6 receptor) (human-mouse monoclonal MRA heavy chain), disulfide with human-mouse monoclonal MRA k-chain, dimer
Molecular Formula: C6428H9976N1720O2018S42
CAS Number: 375823-41-9
Brands: Actemra

Medically reviewed by Drugs.com on Oct 25, 2021. Written by ASHP.

Warning

    Serious Infections
  • Serious, sometimes fatal infections including tuberculosis (pulmonary or extrapulmonary disease), bacterial and viral infections, invasive fungal infections (may be disseminated), and other opportunistic infections reported. (See Infectious Complications under Cautions.)

  • Carefully consider risks and benefits prior to initiating tocilizumab therapy in patients with chronic or recurring infections.

  • Evaluate patients for latent tuberculosis infection prior to and periodically during tocilizumab therapy; if indicated, initiate appropriate antimycobacterial regimen prior to initiating tocilizumab therapy.

  • Closely monitor patients for infection, including active tuberculosis in those with a negative tuberculin skin test, during and after treatment. If serious infection develops, discontinue tocilizumab until infection is controlled.

Introduction

Biologic response modifier and a disease-modifying antirheumatic drug (DMARD); a recombinant humanized IgG1 monoclonal antibody specific for the interleukin-6 (IL-6) receptor.

Uses for Tocilizumab

Rheumatoid Arthritis in Adults

Management of moderately to severely active rheumatoid arthritis in adults who have had an inadequate response to one or more DMARDs.

Can be used alone or in combination with methotrexate or other nonbiologic DMARDs (e.g., hydroxychloroquine, leflunomide, minocycline, sulfasalazine).

Do not use concomitantly with other biologic DMARDs, such as tumor necrosis factor (TNF; TNF-α) blocking agents (e.g., adalimumab, certolizumab, etanercept, golimumab, infliximab), interleukin-1 (IL-1) receptor antagonists (e.g., anakinra), anti-CD20 monoclonal antibodies (e.g., rituximab), and selective costimulation modulators (e.g., abatacept); concomitant use has not been studied and there is a possibility of increased immunosuppression and increased risk of infection.

Juvenile Idiopathic Arthritis (JIA)

Management of active systemic or polyarticular JIA.

Can be used alone or in combination with methotrexate.

Do not use concomitantly with other biologic DMARDs; concomitant use has not been studied, and there is a possibility of increased immunosuppression and increased risk of infection.

Giant Cell Arteritis (GCA)

Management of GCA in adults.

Can be used in combination with a tapering course of corticosteroids or alone following discontinuance of corticosteroids.

Do not use concomitantly with other biologic DMARDs; concomitant use has not been studied, and there is a possibility of increased immunosuppression and increased risk of infection.

Cytokine Release Syndrome (CRS) Associated with Chimeric Antigen Receptor (CAR) T-cell Therapy

Management of chimeric antigen receptor (CAR) T cell-induced severe or life-threatening CRS in adult and pediatric patients ≥2 years of age.

Can be used alone or in combination with corticosteroids.

Do not use concomitantly with other biologic DMARDs; concomitant use has not been studied, and there is a possibility of increased immunosuppression and increased risk of infection.

Coronavirus Disease 2019 (COVID-19)

Has been used in the management of coronavirus disease 2019 (COVID-19). Rationale for tocilizumab's use related to its specificity for the IL-6 receptor, which may help to relieve symptoms of cytokine release syndrome (CRS; e.g., fever, organ failure, death) in severely ill patients with COVID-19.

Case reports and observational and nonrandomized studies describing tocilizumab use in severely ill patients with COVID-19 reported from various countries have indicated that tocilizumab may reduce clinical manifestations associated with CRS and COVID-19 (e.g., fever, breathing difficulty, elevated concentrations of inflammatory cytokines [IL-6] and inflammatory markers [C-reactive protein, D-dimer]).

A manufacturer-sponsored, phase 3 study (COVACTA) in adults hospitalized with severe COVID-19-related pneumonia failed to meet its primary end point or several key secondary end points. Numerous other clinical trials to evaluate tocilizumab in the treatment of COVID-19 are planned or under way.

FDA issued an emergency use authorization (EUA) on June 24, 2021 that permits use of tocilizumab for treatment of COVID-19 in hospitalized adults and pediatric patients ≥2 years of age who are receiving systemic corticosteroids and require supplemental oxygen, non-invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). FDA states that, based on review of data from an open-label, controlled, platform trial (NCT04381936; RECOVERY); a double-blind, placebo-controlled trial (NCT04320615; COVACTA); a double-blind, placebo-controlled trial (NCT04372186; EMPACTA); and a double-blind, placebo-controlled trial (NCT04409262; REMDACTA]), it is reasonable to believe that tocilizumab may be effective for the treatment of COVID-19 in the patient population specified in the tocilizumab EUA and, when used under the conditions described in the EUA, the known and potential benefits of tocilizumab when used to treat COVID-19 in such patients outweigh the known and potential risks. (See Dosage under Dosage and Administration.)

For additional information, consult the tocilizumab EUA letter of authorization ([Web]), EUA fact sheet for healthcare providers ([Web]), and EUA fact sheet for patients, parents and caregivers ([Web]) . For further information on the use of tocilizumab in the treatment of patients with COVID-19, clinicians may also consult the latest COVID-19 treatment guidelines from NIH ([Web]).

Tocilizumab Dosage and Administration

General

  • Do not initiate tocilizumab therapy in patients with ANC <2000/mm3, platelet count <100,000/mm3, or ALT or AST concentration >1.5 times the ULN. Patients with severe or life-threatening CAR T cell-induced CRS frequently have cytopenias or elevated ALT or AST concentrations due to the lymphodepleting chemotherapy or the CRS itself. Consider the potential benefit of treating CRS versus the risks of short-term tocilizumab therapy in such patients.

Concomitant Therapy

  • For the management of rheumatoid arthritis, may use tocilizumab as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs.

  • May use tocilizumab alone or in combination with methotrexate in patients with systemic or polyarticular JIA.

  • For the management of GCA, initially give tocilizumab in combination with a tapering course of corticosteroids; may also use alone following discontinuance of corticosteroids.

  • Do not use concomitantly with other biologic DMARDs. (See Rheumatoid Arthritis in Adults under Uses.)

Administration

Administer by IV infusion or sub-Q injection in the management of rheumatoid arthritis and polyarticular or systemic JIA.

Administer by sub-Q injection in the management of GCA and by IV infusion only for CAR T cell-induced CRS. Not FDA-labeled for IV administration in the management of GCA or for sub-Q administration in the management of CRS.

IV Administration

For solution compatibility information, see Compatibility under Stability.

Administer by IV infusion.

Tocilizumab injection concentrate is commercially available in single-dose vials for IV infusion. The injection concentrate must be diluted prior to IV administration.

Allow tocilizumab infusion solutions to reach room temperature prior to administration. (See Storage under Stability.)

Do not infuse tocilizumab simultaneously through the same IV line with other drugs.

Dilution

Dilute tocilizumab injection concentrate (20 mg/mL) in 0.9 or 0.45% sodium chloride injection to provide a total volume of 50 mL (for patients who weigh <30 kg) or 100 mL (for patients who weigh ≥30 kg).

Remove a volume of diluent equal to the total required volume of the injection concentrate from the bag or bottle of 0.9 or 0.45% sodium chloride injection prior to adding the injection concentrate. Slowly add the total required volume of tocilizumab injection concentrate (0.2, 0.4, 0.5, or 0.6 mL/kg for a dose of 4, 8, 10, or 12 mg/kg, respectively) to the diluent; gently invert bag or bottle to mix the solution and avoid foaming.

Tocilizumab infusion solutions are compatible with polypropylene, polyethylene, and polyvinyl chloride infusion bags and polypropylene, polyethylene, and glass infusion bottles.

Discard any unused portion remaining in the vial since the injection concentrate contains no preservative.

Rate of Administration

Infuse dose over 60 minutes; do not administer by rapid IV injection (e.g., IV push or bolus).

Sub-Q Administration

Tocilizumab for sub-Q use is commercially available in prefilled single-dose syringes and prefilled single-dose autoinjectors. Each syringe or autoinjector delivers 162 mg of tocilizumab in 0.9 mL.

Intended for use under the guidance of a clinician, but may be self-administered if the clinician determines that the patient and/or their caregiver is competent to safely administer the drug after appropriate training. Patients with polyarticular or systemic JIA may self-administer tocilizumab if both clinician and the parent/legal guardian determine it is appropriate.

Allow to sit at room temperature outside of carton for 30 minutes (for the prefilled syringe) or 45 minutes (for the autoinjector) prior to injection; do not warm tocilizumab in any other way (e.g., microwave, hot water).

Administer sub-Q injections into anterior thigh or abdomen (except for the 2-inch area around the umbilicus); may be administered into upper arm by a caregiver. Rotate injection sites. Do not make injections into areas where the skin is tender, bruised, red, hard, or nonintact or into scars or moles.

Do not use the commercially available sub-Q injection for IV administration.

Dosage

Pediatric Patients

Juvenile Idiopathic Arthritis (JIA)
IV

Polyarticular JIA in patients ≥2 years of age: 10 mg/kg once every 4 weeks in those weighing <30 kg; 8 mg/kg once every 4 weeks in those weighing ≥30 kg.

Systemic JIA in patients ≥2 years of age: 12 mg/kg once every 2 weeks in those weighing <30 kg; 8 mg/kg once every 2 weeks in those weighing ≥30 kg.

Do not adjust dosage based solely on patient's weight as measured at a single visit, as weight may fluctuate.

Sub-Q

Polyarticular JIA in patients ≥2 years of age: 162 mg once every 3 weeks in those weighing <30 kg; 162 mg once every 2 weeks in those weighing ≥30 kg.

Systemic JIA in patients ≥2 years of age: 162 mg every 2 weeks in those weighing <30 kg; 162 mg once weekly in those weighing ≥30 kg.

Do not adjust dosage based solely on patient's weight as measured at a single visit, as weight may fluctuate.

When switching from IV to sub-Q administration, administer first sub-Q dose in place of the next scheduled IV dose.

Treatment Interruption or Discontinuance for Toxicity
IV or Sub-Q

If a serious infection, an opportunistic infection, or sepsis develops, discontinue tocilizumab until the infection is controlled.

If certain dose-related laboratory changes (i.e., elevated ALT or AST concentrations, neutropenia, thrombocytopenia) occur, interrupt tocilizumab therapy at values similar to those considered in adults with rheumatoid arthritis (see Tables 1–3). If clinically appropriate, consider dosage reduction or discontinuance of concomitant methotrexate and/or other therapy and withhold tocilizumab pending clinical evaluation. Individualize the decision to discontinue tocilizumab.

Tocilizumab dosage reductions not evaluated in patients with polyarticular or systemic JIA.

CRS Associated with CAR T-cell Therapy
IV

May use tocilizumab alone or in combination with corticosteroids.

Pediatric patients ≥2 years of age who weigh <30 kg: 12 mg/kg by IV infusion over 60 minutes.

Pediatric patients ≥2 years of age who weigh ≥30 kg: 8 mg/kg (maximum 800 mg) by IV infusion over 60 minutes.

If clinical improvement does not occur following the first dose, may administer ≤3 additional doses. The interval between consecutive doses should be ≥8 hours.

Coronavirus Disease 2019 (COVID-19)†
IV

The FDA EUA that permits use of tocilizumab for treatment of COVID-19 in certain hospitalized pediatric patients ≥2 years of age (see Coronavirus Disease 2019 [COVID-19] under Uses) states that those weighing <30 kg can receive a dosage of 12 mg/kg (maximum of 800 mg per infusion) given as a single 60-minute IV infusion; may administer one additional IV infusion ≥8 hours after the first infusion if clinical signs or symptoms worsen or do not improve after the initial dose. Those ≥2 years of age weighing ≥30 kg can receive a dosage of 8 mg/kg (maximum of 800 mg per infusion) given as a single 60-minute IV infusion; may administer one additional IV infusion ≥8 hours after the first infusion if clinical signs or symptoms worsen or do not improve after the initial dose.

Adults

Rheumatoid Arthritis
IV

Initially, 4 mg/kg once every 4 weeks; may increase to 8 mg/kg once every 4 weeks based on clinical response. Doses >800 mg per infusion are not recommended (see Elimination: Special Populations, under Pharmacokinetics).

Sub-Q

Adults weighing <100 kg: 162 mg every other week; may increase to 162 mg every week based on clinical response.

Patients weighing ≥100 kg: 162 mg every week. Patients in clinical study who weighed ≥100 kg had poorer responses to dosage of 162 mg every other week than did patients in lower-weight categories. (See Absorption: Special Populations, under Pharmacokinetics.)

When switching from IV to sub-Q administration, administer first sub-Q dose in place of the next scheduled IV dose.

Dosage Modification or Discontinuance for Toxicity
IV or Sub-Q

If a serious infection, an opportunistic infection, or sepsis develops, discontinue tocilizumab until the infection is controlled.

If certain dose-related laboratory changes (i.e., elevated ALT or AST concentrations, neutropenia, thrombocytopenia) occur in patients receiving tocilizumab 8 mg/kg IV every 4 weeks, reduce tocilizumab dosage to 4 mg/kg IV every 4 weeks or temporarily interrupt or discontinue therapy (see Tables 1–3).

If such dose-related laboratory changes occur in patients receiving sub-Q tocilizumab, reduce frequency of tocilizumab administration from weekly to every other week or temporarily interrupt or discontinue therapy (see Tables 1–3).

Table 1. Recommended Dosage Adjustment Based on Changes in Liver Enzyme Laboratory Values in Adults with Rheumatoid Arthritis or GCA

ALT or AST Value

Recommendation

>1 to 3 times ULN

Modify dosage of concomitant DMARDs (for rheumatoid arthritis) or immunomodulatory agents (for GCA) if appropriate

For persistent increases within this range:

IV: Reduce tocilizumab dosage to 4 mg/kg every 4 weeks or interrupt tocilizumab therapy until ALT/AST values have returned to normal

Sub-Q: Reduce frequency of administration to every other week or interrupt tocilizumab therapy until ALT/AST values have returned to normal; resume sub-Q tocilizumab with administration every other week and then increase frequency to every week as clinically indicated

>3 to 5 times ULN (confirmed by repeat testing)

Interrupt tocilizumab therapy until ALT/AST values are <3 times ULN and follow recommendations for ALT/AST values of >1 to 3 times ULN

For persistent increases of >3 times ULN, discontinue tocilizumab

>5 times ULN

Discontinue tocilizumab

Table 2. Recommended Dosage Adjustment Based on Absolute Neutrophil Count (ANC) in Adults with Rheumatoid Arthritis or GCA

ANC (cells/mm3 )

Recommendation

>1000

Maintain current dosage

500–1000

Interrupt tocilizumab therapy

When ANC is >1000/mm3:

IV: Resume tocilizumab at 4 mg/kg every 4 weeks and increase to 8 mg/kg every 4 weeks as clinically indicated

Sub-Q: Resume tocilizumab with administration every other week and then increase frequency to every week as clinically indicated

<500

Discontinue tocilizumab

Table 3. Recommended Dosage Adjustment Based on Platelet Count in Adults with Rheumatoid Arthritis or GCA

Platelet Count (cells/mm3)

Recommendation

50,000–100,000

Interrupt tocilizumab therapy

When platelet count is >100,000/mm3:

IV: Resume tocilizumab at 4 mg/kg every 4 weeks and increase to 8 mg/kg every 4 weeks as clinically indicated

Sub-Q: Resume tocilizumab with administration every other week and then increase frequency to every week as clinically indicated

<50,000

Discontinue tocilizumab

GCA
Sub-Q

Recommended dosage: 162 mg every week in combination with a tapering course of corticosteroids. A dosage of 162 mg given once every other week also may be prescribed based on clinical considerations. May use tocilizumab alone following discontinuance of corticosteroids. (See Dosage Modification or Discontinuance for Toxicity under Dosage and Administration.)

CRS Associated with CAR T-cell Therapy
IV

May use tocilizumab alone or in combination with corticosteroids.

8 mg/kg (maximum 800 mg) by IV infusion over 60 minutes.

If clinical improvement does not occur following the first dose, may administer ≤3 additional doses. The interval between consecutive doses should be ≥8 hours.

Coronavirus Disease 2019 (COVID-19)†
IV

The FDA EUA that permits use of tocilizumab for treatment of COVID-19 in certain hospitalized adults (see Coronavirus Disease 2019 [COVID-19] under Uses) states that those weighing <30 kg can receive a dosage of 12 mg/kg (maximum of 800 mg per infusion) given as a single 60-minute IV infusion; may administer one additional IV infusion ≥8 hours after the first infusion if clinical signs or symptoms worsen or do not improve after the initial dose. Those weighing ≥30 kg can receive a dosage of 8 mg/kg (maximum of 800 mg per infusion) given as a single 60-minute IV infusion; may administer one additional IV infusion ≥8 hours after the first infusion if clinical signs or symptoms worsen or do not improve after the initial dose.

Prescribing Limits

Pediatric Patients

CRS Associated with CAR T-cell Therapy
IV

Maximum 800 mg per dose.

Adults

Rheumatoid Arthritis
IV

Maximum 800 mg per dose.

CRS Associated with CAR T-cell Therapy
IV

Maximum 800 mg per dose.

Coronavirus Disease 2019 (COVID-19)†
IV

Maximum 800 mg per dose.

Special Populations

Hepatic Impairment

Use is not recommended in patients with active hepatic disease or hepatic impairment.

Renal Impairment

Dosage adjustment not necessary in patients with mild or moderate renal impairment; not evaluated in severe renal impairment.

Geriatric Patients

Manufacturer makes no specific dosage recommendations.

Cautions for Tocilizumab

Contraindications

  • Known hypersensitivity to the drug. (See Sensitivity Reactions under Cautions.)

Warnings/Precautions

Warnings

Infectious Complications

Serious, sometimes fatal infections (including bacterial, mycobacterial, invasive fungal, viral, protozoal, or other opportunistic infections) reported in patients with rheumatoid arthritis, particularly in those receiving concomitant therapy with other immunosuppressive agents (e.g., methotrexate, corticosteroids). Opportunistic infections include tuberculosis, cryptococcal infection, aspergillosis, candidiasis, and pneumocystosis. Infections may be disseminated.

Serious infections also reported in patients with polyarticular or systemic JIA.

Do not initiate tocilizumab in patients with active infections, including localized infections. Consider potential risks and benefits of the drug prior to initiating therapy in patients with a history of chronic, recurring, serious, or opportunistic infections; patients with underlying conditions that may predispose them to infections; and patients who have been exposed to tuberculosis or who have resided or traveled in regions where tuberculosis or mycoses are endemic.

Closely monitor patients during and after treatment with tocilizumab for the development of signs or symptoms of infection. If new infection occurs during therapy, perform thorough diagnostic evaluation (appropriate for immunocompromised patient), initiate appropriate anti-infective therapy, and closely monitor patient. If serious infection, opportunistic infection, or sepsis develops, discontinue tocilizumab until the infection is controlled.

Evaluate all patients for latent tuberculosis and for risk factors for tuberculosis prior to and periodically during therapy. When indicated, initiate an appropriate antimycobacterial regimen for the treatment of latent tuberculosis infection prior to tocilizumab therapy. Consider initiation of antimycobacterial therapy prior to initiation of tocilizumab in individuals with a history of latent or active tuberculosis in whom an adequate course of antimycobacterial treatment cannot be confirmed and in individuals with a negative test for latent tuberculosis who have risk factors for tuberculosis. Consultation with a tuberculosis specialist is recommended when deciding whether to initiate antimycobacterial therapy.

Monitor all patients, including those with a negative test for latent tuberculosis, for active tuberculosis.

Viral reactivation can occur in patients receiving immunosuppressive therapies. Herpes zoster exacerbation reported in patients receiving tocilizumab.

Other Warnings/Precautions

GI Perforation

GI perforation reported in clinical trials, usually as a complication of diverticulitis and most commonly in patients receiving concomitant therapy with NSAIAs, corticosteroids, or methotrexate. The relative contribution of these agents versus IV tocilizumab to the occurrence of GI perforation remains to be determined.

Caution is advised if tocilizumab is used in patients at risk for GI perforation.

Promptly evaluate patients with new-onset abdominal symptoms for evidence of GI perforation.

Hepatotoxicity

Serious hepatic injury observed in patients receiving IV or sub-Q tocilizumab; some cases resulted in liver transplantation or death. Onset of hepatotoxicity occurred months to years following initiation of therapy. Although most cases presented with marked elevations of aminotransferases (>5 times the ULN), some cases presented with signs or symptoms of liver dysfunction and only mildly elevated aminotransferases. During controlled clinical trials, tocilizumab was associated with a higher incidence of aminotransferase elevations than placebo. Increased frequency and magnitude of aminotransferase elevations observed when potentially hepatotoxic drugs (e.g., methotrexate) were used concurrently.

In adults with rheumatoid arthritis or GCA, perform liver function tests (i.e., serum ALT and AST, alkaline phosphatase, and total bilirubin concentrations) prior to initiation of therapy, then every 4–8 weeks during therapy for the first 6 months and every 3 months thereafter. Do not initiate therapy in rheumatoid arthritis or GCA patients with aminotransferases >1.5 times the ULN. In patients with ALT or AST >5 times the ULN, discontinue tocilizumab.

A similar pattern of serum aminotransferase elevations was observed in tocilizumab-treated patients with polyarticular or systemic JIA. Monitor liver function tests at the time of the second infusion and every 4–8 weeks thereafter in patients with polyarticular JIA and at the time of the second infusion and every 2–4 weeks thereafter in patients with systemic JIA.

In patients with symptoms indicative of possible liver injury (e.g., fatigue, anorexia, right upper abdominal discomfort, dark urine, jaundice), perform liver function tests promptly. If liver function tests are abnormal (e.g., ALT >3 times the ULN, total bilirubin >2 times the ULN), interrupt therapy and evaluate patient to determine the probable cause. Do not reinitiate therapy unless another explanation for the liver function test abnormalities is found and values have returned to normal. (See Dosage under Dosage and Administration.)

Hematologic Effects

Possible neutropenia or thrombocytopenia.

Reduction in neutrophil count to <1000/mm3 reported in patients receiving tocilizumab. Infections infrequently reported in association with treatment-related neutropenia in long-term extension studies and postmarketing clinical experience.

In clinical trials, decreases in platelet counts were not associated with severe bleeding.

Monitor neutrophil and platelet counts 4–8 weeks after initiation of therapy and every 3 months thereafter in adults with rheumatoid arthritis or GCA.

Monitor neutrophil and platelet counts at the time of the second tocilizumab administration and every 4–8 weeks thereafter in patients with polyarticular JIA, and at the time of the second administration and every 2–4 weeks thereafter in patients with systemic JIA.

Dosage adjustment, treatment interruption, or discontinuance may be necessary in patients with neutropenia or thrombocytopenia. (See Dosage under Dosage and Administration.)

Effects on Serum Lipids

Increased serum concentrations of total cholesterol, triglycerides, LDL-cholesterol, and/or HDL-cholesterol reported.

Monitor lipoprotein concentrations approximately 4–8 weeks after initiation of tocilizumab therapy in adults with rheumatoid arthritis or GCA or patients with polyarticular or systemic JIA.

Manage lipid disorders as clinically appropriate.

Malignancies

Immunosuppressive therapy may increase the risk of malignancies. Whether treatment with tocilizumab affects development of malignancies remains to be determined. Malignancies were reported in clinical trials.

Sensitivity Reactions

Serious hypersensitivity reactions, including fatal anaphylaxis in patients receiving IV infusions of tocilizumab, reported. Tocilizumab is contraindicated in patients with known hypersensitivity to the drug.

Hypersensitivity reactions requiring treatment discontinuance (e.g., anaphylaxis, generalized erythema, rash, urticaria) reported during clinical trials in various patient populations and with either IV or sub-Q therapy. Hypersensitivity reactions, including anaphylaxis and death, reported during postmarketing experience in patients receiving various IV dosages (with or without concomitant therapy), including in patients who received premedication. Hypersensitivity reactions, including anaphylaxis, have occurred both with and without prior hypersensitivity reactions and as early as the first IV infusion.

Have appropriate agents and equipment available for immediate use in case a serious hypersensitivity reaction occurs during IV tocilizumab infusion. Patients receiving sub-Q therapy should seek immediate medical attention if they experience symptoms of a hypersensitivity reaction (see Advice to Patients).

If a hypersensitivity reaction occurs, immediately stop administration and permanently discontinue the drug.

Demyelinating Disorders

Effect of tocilizumab on demyelinating disorders remains to be determined. Multiple sclerosis and chronic inflammatory demyelinating polyneuropathy reported rarely in patients with rheumatoid arthritis receiving tocilizumab.

Monitor patients receiving tocilizumab for signs and symptoms suggestive of a demyelinating disorder. Exercise caution when considering tocilizumab therapy in patients with preexisting or recent-onset demyelinating disorders.

Immunization

Do not administer live vaccines to patients receiving tocilizumab. Bring vaccinations up to date prior to initiation of tocilizumab therapy. (See Vaccines under Interactions.)

Immunogenicity

Antibodies to tocilizumab, including neutralizing antibodies, may develop; some patients with antibody development have experienced hypersensitivity reactions resulting in treatment discontinuance. Antibody detection rates appear similar with IV or sub-Q administration.

Specific Populations

Pregnancy

Pregnancy registry at 877-311-8972 (for clinicians and patients).

Limited data regarding tocilizumab use in pregnant women not sufficient to determine whether there is a drug-associated risk for major birth defects and miscarriage.

Animal data suggest risk of fetal harm; abortion/embryofetal deaths observed with tocilizumab in animal reproduction studies. Evidence in animals also suggests that inhibition of IL-6 signaling may interfere with cervical ripening and dilatation and myometrial contractile activity, which could potentially result in parturition delays.

As pregnancy progresses, monoclonal antibodies are increasingly transported across the placenta, with the largest amount transferred during the third trimester. Monoclonal antibodies such as tocilizumab are actively transported across the placenta during the third trimester of pregnancy and may affect immune response in infants exposed to the drugs in utero.

Safety of administering live vaccines to infants exposed to tocilizumab in utero is unknown; consider risks and benefits.

Lactation

Not known whether tocilizumab is distributed into milk; effects of the drug on the breast-fed infant and on milk production also not known.

IgG distributes into human milk. If tocilizumab distributes into human milk, effects of local GI tract exposure and potential limited systemic exposure in the infant are unknown. The lack of clinical data during lactation precludes a clear determination of the risk to nursing infants.

Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for tocilizumab and any potential adverse effects on the breast-fed child from the drug or from the underlying maternal condition.

Pediatric Use

Safety and efficacy of IV and sub-Q tocilizumab for management of active polyarticular or systemic JIA and of IV tocilizumab for management of severe or life-threatening CAR T cell-induced CRS established in pediatric patients ≥2 years of age. Safety and efficacy not established in children <2 years of age or for the management of conditions other than polyarticular or systemic JIA and CAR T cell-induced CRS in children.

In an open-label study in 11 patients with systemic JIA <2 years of age treated with IV tocilizumab, serious adverse effects, adverse effects leading to drug discontinuance, and infectious adverse effects were reported in 27.3, 36.4, and 81.8% of patients, respectively. Hypersensitivity reactions reported in 6 patients (54.5%); 3 reactions were serious and led to patient withdrawal from the study. Development of anti-tocilizumab antibodies reported in 3 patients with hypersensitivity reactions (2 with serious hypersensitivity reactions). There were no cases of macrophage activation syndrome (MAS) based on study protocol-specified criteria, but there were 2 cases of suspected MAS based on Ravelli criteria.

A retrospective analysis of pooled outcome data for patients treated with IV tocilizumab for CAR T cell-induced CRS revealed no observed differences in safety or efficacy between pediatric patients (25 children 2–12 years of age and 17 adolescents 12–18 years of age) and adults.

Geriatric Use

Geriatric patients in general may have a higher incidence of infections than younger adults. In clinical trials of tocilizumab in rheumatoid arthritis, serious infections reported more frequently in patients ≥65 years of age than in younger adults. Use tocilizumab with caution in this age group.

Insufficient experience with tocilizumab in patients ≥65 years of age with CAR T cell-induced CRS to determine whether they respond differently than younger adults.

Hepatic Impairment

Safety and efficacy not established in patients with hepatic impairment, including those with serologic evidence of HBV or HCV infection. Use in patients with active hepatic disease or hepatic impairment is not recommended. (See Elimination: Special Populations, under Pharmacokinetics.)

Renal Impairment

Mild renal impairment (Clcr 50–79 mL/minute) does not appear to affect pharmacokinetics. Dosage adjustment not necessary in patients with mild or moderate renal impairment. Not evaluated in patients with severe renal impairment. (See Elimination: Special Populations, under Pharmacokinetics.)

Common Adverse Effects

Upper respiratory tract infection, nasopharyngitis, headache, hypertension, increased ALT concentrations, reactions at the sub-Q injection site (e.g., erythema, pruritus, pain, hematoma).

Adverse effect profiles for IV and sub-Q tocilizumab in rheumatoid arthritis patients are similar except for higher frequency of injection site reactions with sub-Q administration.

The overall adverse effect profile for sub-Q tocilizumab in GCA patients was generally consistent with the known tolerability profile of tocilizumab; however, the incidence of infections was higher in GCA patients than in rheumatoid arthritis patients.

Interactions for Tocilizumab

May alter expression of CYP isoenzymes including 1A2, 2B6, 2C9, 2C19, 2D6, and 3A4; effects on CYP2C8 or transporters (e.g., P-glycoprotein) not elucidated.

Drugs Metabolized by Hepatic Microsomal Enzymes

Possible increased metabolism of drugs metabolized by CYP isoenzymes. Because IL-6 may down-regulate CYP isoenzymes, inhibition of IL-6 by tocilizumab in rheumatoid arthritis patients may restore CYP enzyme activity to higher levels. Effects on CYP enzyme activity may persist for several weeks after drug discontinuance.

Drugs metabolized by CYP isoenzymes that have a low therapeutic index and require individualized dosing: Carefully monitor therapeutic effect and serum concentrations following initiation or discontinuance of tocilizumab; adjust dosage as needed.

Other CYP3A4 substrates: Caution advised when a reduction in efficacy would be undesirable.

Vaccines

Avoid live vaccines.

Information not available regarding immune response to vaccines in patients receiving tocilizumab or regarding secondary transmission of infection from individuals receiving live vaccines to patients receiving tocilizumab.

Inhibition of IL-6 may interfere with normal immune response to new antigens; all patients (particularly pediatric and geriatric patients) should receive all appropriate vaccines recommended by current immunization guidelines prior to initiation of tocilizumab therapy, if possible. Consult current vaccination guidelines regarding interval between administration of live vaccines and initiation of immunosuppressive (e.g., tocilizumab) therapy.

Specific Drugs

Drug

Interaction

Comments

Contraceptives, oral

Possible increased metabolism of oral contraceptive

Caution advised

Corticosteroids

Concomitant use does not appear to affect clearance of tocilizumab

Cyclosporine

Possible increased metabolism of cyclosporine

Carefully monitor therapeutic effect and serum concentrations of cyclosporine following initiation or discontinuance of tocilizumab; adjust dosage as needed

Dextromethorphan

Reduction in exposure to dextromethorphan and dextrorphan following initiation of IV tocilizumab reported in rheumatoid arthritis patients receiving dextromethorphan

(In rheumatoid arthritis patients not receiving tocilizumab, systemic exposure to dextromethorphan is similar to, but exposure to dextrorphan is decreased, compared with values in healthy individuals )

DMARDs, biologic (e.g., TNF blocking agents)

Possible increased immunosuppression and increased risk of infection; concomitant use not studied

Concomitant use not recommended

HMG CoA reductase inhibitors (statins)

Statins metabolized by CYP isoenzymes (e.g., atorvastatin, lovastatin): Possible increased metabolism of the statin

Simvastatin: Reduction in exposure to simvastatin and simvastatin acid following initiation of tocilizumab reported in rheumatoid arthritis patients receiving simvastatin (values were similar to or slightly higher than values observed after simvastatin administration in healthy individuals); exposure to simvastatin and simvastatin acid increased following discontinuance of tocilizumab

(Systemic exposure to simvastatin and simvastatin acid is increased in rheumatoid arthritis patients not receiving tocilizumab compared with healthy individuals)

Caution advised

When selecting simvastatin dosages for patients with rheumatoid arthritis, consider the potential for altered systemic exposure to the drug following initiation or discontinuance of tocilizumab

Methotrexate

Concomitant use does not appear to affect clearance of tocilizumab or exposure to methotrexate

Possible increased risk of hepatotoxicity

NSAIAs

Concomitant use does not appear to affect clearance of tocilizumab

Omeprazole

Reduction in exposure to omeprazole following initiation of IV tocilizumab reported in rheumatoid arthritis patients receiving omeprazole (values were slightly higher than values observed after omeprazole administration in healthy individuals)

(Systemic exposure to omeprazole is increased in rheumatoid arthritis patients not receiving tocilizumab compared with healthy individuals )

Theophylline

Possible increased metabolism of theophylline

Carefully monitor therapeutic effect and serum concentrations of theophylline following initiation or discontinuance of tocilizumab; adjust dosage as needed

Warfarin

Possible increased metabolism of warfarin

Carefully monitor therapeutic effect of warfarin following initiation or discontinuance of tocilizumab; adjust dosage as needed

Tocilizumab Pharmacokinetics

Absorption

Bioavailability

Following sub-Q injection in rheumatoid arthritis and GCA patients, bioavailability is 80%.

Following sub-Q injection in polyarticular and systemic JIA patients, bioavailability is 96 and 95%, respectively.

Plasma Concentrations

Increase in IV dosage from 4 mg/kg to 8 mg/kg every 4 weeks associated with proportional increases in peak plasma concentrations and greater-than-proportional increases in exposure and trough plasma concentrations.

Special Populations

At fixed sub-Q dosage, tocilizumab exposure is inversely related to body weight.

Following IV dose of 8 mg/kg, systemic drug exposure is substantially greater (86%) in individuals weighing >100 kg than in those weighing <60 kg, since linear clearance increases as body size increases.

Distribution

Extent

Not known whether tocilizumab is distributed into milk.

Crosses the placenta.

Elimination

Half-life

Adults with rheumatoid arthritis: Up to 11 days at IV dosage of 4 mg/kg every 4 weeks; up to 13 days at IV dosage of 8 mg/kg every 4 weeks or sub-Q dosage of 162 mg every week; up to 5 days after sub-Q dosage of 162 mg every other week.

Adults with GCA: 18.3–18.9 days at sub-Q dosage of 162 mg once weekly and 4.2–7.9 days at sub-Q dosage of 162 mg every other week.

Pediatric patients with polyarticular JIA: ≤17 and ≤10 days following IV and sub-Q administration, respectively.

Pediatric patients with systemic JIA: ≤16 and ≤14 days following IV and sub-Q administration, respectively.

Eliminated by a combination of linear and nonlinear elimination. Clearance decreases as dose increases. At low tocilizumab concentrations, concentration-dependent nonlinear clearance plays a major role in determining total drug clearance; at higher concentrations, nonlinear pathway is saturated and clearance is determined mainly by linear clearance.

Special Populations

Steady-state pharmacokinetics in systemic JIA patients <2 years of age are similar to those in systemic JIA patients 2–17 years of age.

As body size increases, linear clearance increases. Following a weight-based IV dose of 8 mg/kg, systemic drug exposure is substantially greater in individuals weighing >100 kg than in those weighing <60 kg.

Pharmacokinetics not formally studied in renal or hepatic impairment. Population pharmacokinetic data indicate that mild renal impairment (Clcr ≥50 mL/minute but <80 mL/minute) does not alter pharmacokinetics. Pharmacokinetics not evaluated in patients with severe renal impairment.

Population pharmacokinetic analyses in adult rheumatoid arthritis and GCA patients indicate that age, gender, and race do not affect pharmacokinetics.

Stability

Storage

Parenteral

Injection (for Sub-Q Use)

2–8°C; do not freeze. Keep prefilled syringes and autoinjectors dry and store in original carton to protect from light.

Injection Concentrate (for IV Use)

2–8°C; do not freeze. Store vials in original carton to protect from light.

Following dilution with sodium chloride 0.9%, 2–8°C or room temperature for up to 24 hours. Protect from light.

Following dilution with sodium chloride 0.45%, 2–8°C for up to 24 hours or room temperature for up to 4 hours. Protect from light.

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility

Compatible

Sodium chloride 0.45 or 0.9%

Actions

  • Binds to both soluble and membrane-bound IL-6 receptors and inhibits IL-6-mediated signaling through these receptors, thereby resulting in a reduction in inflammatory mediator production.

  • IL-6, a pleiotropic proinflammatory cytokine, is produced by various cell types (e.g., T-cells, B-lymphocytes, monocytes, fibroblasts, synoviocytes, endothelial cells) and has a broad spectrum of biologic activities, including involvement in T-cell activation, induction of immunoglobulin secretion, initiation of hepatic acute phase protein synthesis, stimulation of hematopoietic precursor cell proliferation and differentiation, and induction of osteoclast differentiation and activation.

  • IL-6 is overexpressed in synovial tissue in patients with rheumatoid arthritis and is thought to contribute to synovial proliferation and joint destruction in patients with the disease. Elevated levels of IL-6 in serum and synovial fluid correlate with clinical and laboratory measures of disease activity in patients with rheumatoid arthritis.

  • IL-6 is elevated in serum and synovial fluid in patients with polyarticular or systemic JIA; elevated IL-6 levels correlate with disease activity.

Advice to Patients

  • Importance of advising patients and/or caregivers about potential benefits and risks of tocilizumab. Importance of advising patients and/or caregivers to read the medication guide.

  • Importance of instructing the patient and/or caregiver regarding proper dosage and administration of tocilizumab, including the use of aseptic technique, and proper disposal of prefilled syringes and autoinjectors if it is determined that the patient and/or caregiver is competent to safely administer sub-Q injections of the drug.

  • Importance of consulting clinician if the sub-Q injection does not deliver the full dose.

  • Risk of increased susceptibility to infection. Importance of informing clinicians immediately if any signs or symptoms suggestive of infection (e.g., fever or chills; sweating; cough; dyspnea; fatigue; diarrhea; burning or pain upon urination; warm, red, or painful skin) develop to assure rapid evaluation and appropriate treatment.

  • Risk of GI perforation. Importance of informing clinician immediately if severe, persistent abdominal pain occurs.

  • Risk of hypersensitivity and serious allergic reactions, including anaphylaxis. Importance of contacting a clinician prior to administering the next dose if manifestations of an allergic reaction (e.g., urticaria, rash, flushing) occur; importance of seeking immediate medical attention if manifestations of a serious allergic reaction (e.g., difficulty breathing, chest pain, feelings of faintness or dizziness, abdominal pain or vomiting, swelling of the lips, tongue, or face) occur.

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription (e.g., biologic antirheumatic drugs, immunizations) and OTC drugs, vitamins, and herbal supplements, as well as any other illnesses (e.g., history of tuberculosis; concomitant, chronic, or recurring infections).

  • Importance of periodic laboratory monitoring.

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed. Importance of clinicians informing women about the existence of and encouraging enrollment in the pregnancy registry for tocilizumab.

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Tocilizumab (recombinant)

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, for subcutaneous use

162 mg/0.9 mL

Actemra (available as single-use prefilled syringe)

Genentech

162 mg/0.9 mL

Actemra ACTPen (available as single-use prefilled autoinjector)

Genentech

Injection concentrate, for IV infusion

20 mg/mL

Actemra

Genentech

AHFS DI Essentials™. © Copyright 2022, Selected Revisions October 25, 2021. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

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