Tocilizumab (Actemra®)

Subject:tocilizumab injection for intravenous infusion (Actemra)

Date revised:02/24/2010

Description

Tocilizumab is an interleukin-6 (IL-6) receptor inhibitor. IL-6 is a pro-inflammatory cytokine that is involved in many physiologic processes. Tocilizumab is approved by the Food and Drug Administration (FDA) for the following indication.

The treatment of rheumatoid arthritis (RA) in adults with moderate to severe active RA who have had an inadequate response to one or more tumor necrosis factor (TNF) antagonists. Tocilizumab can be given alone or in combination with disease modifying antirheumatic drugs (DMARDs) such as methotrexate (MTX) or other nonbiologic DMARDs.

Tocilizumab is available as a 20 mg/mL preservative-free solution in single-use vials: 80 mg/4 mL, 200 mg/10 mL and 400 mg/20 mL. Tocilizumab should be diluted before administration. Using a 100 mL bottle or bag, a volume of 0.9% Sodium Chloride Injection equal to the volume of tocilizumab is withdrawn. Then tocilizumab injection is added to the infusion bottle or bag. The diluted solution is infused intravenously (IV) over 60 minutes. It should not be given IV push.

Indications, Medically Necessary

  1. RA in adults: Indicated for the treatment of moderate to severe active RA in patients who meet all of the following criteria.
  • Tocilizumab is prescribed by a rheumatologist, and
  • Patient has had an inadequate response to at least 2 months of therapy with one of the following non-biologic DMARDs: methotrexate (MTX), hydroxychloroquine, leflunomide (Arava®), or sulfasalazine, and

Exceptions to having tried a non-biologic DMARD for 2 months can be made in the following circumstances:

The patient could not tolerate the non-biologic DMARDs or if there are contraindications to all four of these agents.

  • Patient has tried a TNF antagonist, adalimumab (Humira), certolizumab pegol (Cimzia), etanercept (Enbrel), golimumab (Simponi) or infliximab (Remicade) for at least 2 months and had an inadequate response or was intolerant to one of these TNF antagonists, and
  • The patient will be receiving tocilizumab in combination with MTX or another nonbiologic DMARD (e.g., hydroxychloroquine, leflunomide, sulfasalazine), and

Note: patients are not required to use MTX concurrently with tocilizumab if there are contraindications to MTX or the patient has a history of intolerance to MTX or to use other nonbiologic DMARDs if there are contraindications or a history of intolerance.

  • Patients who are starting tocilizumab must have an absolute neutrophil count (ANC) ≥ 2000 cells/mm3, platelet count ≥ 100,000 cells/ mm3, and an alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 1.5 times the upper limit of normal.

For patients who are continuing with tocilizumab there must be documentation that the patient is or is not on another DMARD in conjunction with tocilizumab and the other drug therapies that have been used to treat RA.

Dosing in RA: the starting dose is 4 mg/kg once every 4 weeks. Depending on clinical response the dose can be increased to 8 mg/kg every 4 weeks. The maximum dose is 800 mg every 4 weeks. Note: patients starting on tocilizumab must have baseline laboratory tests. See Criteria above and Labs/Diagnostics required below.

Many dose modifications are recommended for the management of dose-related laboratory changes such as increased liver enzymes, neutropenia, and thrombocytopenia. Dosing modifications recommended in the prescribing information are as follows.

Liver Enzyme (ALT, AST) Abnormalities. Recommendations for Patients on Tocilizumab.

Lab Value / Recommendation
> 1 to 3 times ULN / Modify dose of concomitant DMARDs if appropriate.
For persistent increases in this range, reduce tocilizumab dose to
4 mg/kg or interrupt tocilizumab until ALT/AST have normalized.
> 3 to 5 times ULN (confirmed with repeat testing) / Interrupt tocilizumab dosing until < 3 times ULN and follow recommendations above for > 1 to 3 times ULN.
For persistent increases > 3 times ULN, discontinue tocilizumab.
> 5 times ULN / Discontinue tocilizumab.

ULN = upper limit of normal. Some DMARDs such as methotrexate, leflunomide (Arava), or sulfasalazine may increase liver enzymes.

Low Absolute Neutrophil Count (ANC). Recommendations for Patients on Tocilizumab.

Lab Value (cells/mm3) / Recommendation
ANC > 1000 / Maintain dose.
ANC 500 to 1000 / Interrupt tocilizumab dosing.
When ANC > 1000 cells/mm3 resume tocilizumab at 4 mg/kg and increase to 8 mg/kg as clinically appropriate.
ANC < 500 / Discontinue tocilizumab.

Low Platelet Count. Recommendations for Patients on Tocilizumab.

Lab Value (cells/mm3) / Recommendation
50,000 to 100,000 / Interrupt tocilizumab dosing.
When platelet count is > 100,000 cells/mm3 resume tocilizumab at 4 mg/kg and increase to 8 mg/kg as clinically appropriate.
< 50,000 / Discontinue tocilizumab.

Initial approval/extended approval: Initial approval is for 4 months (4 doses) of therapy with 4 mg/kg initially and then every 4 weeks (weeks 0, 4, 8, and 12). Patients are evaluated for response after the fourth dose.

Approve for an additional 12 months of therapy if the patient has responded (less joint pain, morning stiffness, or fatigue; improved function or activities of daily living; decreased soft tissue swelling in joints or tendon sheaths; improved laboratory values; reduced dosage of corticosteroids) as determined by the prescribing rheumatologist. The patient may not have a full response after 4 doses, but there should be some response.

If the response is inadequate after 1 or more doses of 4 mg/kg, the dose can be increased to 8 mg/kg every 4 weeks. Doses are also adjusted depending on laboratory tests for ANC, platelets, and liver function tests. See tables above.

Duration of therapy in RA: indefinite if the patient is responding and tolerates the drug.

Labs/Diagnostics required: Patient should be screened for latent tuberculosis (TB) infection prior to starting therapy and then every year while on tocilizumab. Screening may include any of the following: history, tuberculin skin testing, interferon gamma release assay (IGRA), chest x-ray. In general, patients with latent TB infection should begin preventive therapy before starting tocilizumab.

Patients starting tocilizumab must have baseline labs including ANC, platelet counts, and liver function tests (either ALT or AST) and these labs should be repeated every 4 to 8 weeks. Lipid parameters (total cholesterol, triglycerides, low density lipoprotein (LDL) cholesterol, and/or high density lipoprotein (HDL) cholesterol) must be assessed at baseline and then again about 4 to 8 weeks after starting tocilizumab.

Waste management: The initial dose in RA is 4 mg/kg and may be increased to 8 mg/kg. For patients who are already on tocilizumab, the dose should be calculated and the number of vials needed assessed. Usually the dose should be rounded to the next whole number of vials to avoid wasting unused medication left in the vial. The maximum dose is 800 mg, so persons with body weight > 100 kg should receive 800 mg maximum.

Exclusions: See below.

  1. Systemic-onset juvenile idiopathic arthritis (JIA): Indicated for the treatment of systemic-onset JIA in children or adolescents who meet all of the following criteria. [NOT FDA-APPROVED INDICATION]
  • Tocilizumab is prescribed by a rheumatologist, and
  • Patient has tried at least one nonsteroidal anti-inflammatory drug(NSAID), and
  • Patient has tried at least one systemic corticosteroid (e.g., prednisone), and
  • Patient has had an inadequate response to a non-biologic DMARDsuch as methotrexate (MTX) or sulfasalazine or a biologic DMARD such as etanercept (Enbrel), and

Exceptions to having tried a DMARD can be made in the following circumstances:

The patient could not tolerate a DMARD or if there are contraindications to all of these agents.

  • Patients who are starting tocilizumab must have an absolute neutrophil count (ANC) ≥ 2000 cells/mm3, platelet count ≥ 100,000 cells/ mm3, and an alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 1.5 times the upper limit of normal.

For patients who are continuing with tocilizumab there must be documentation of the other drug therapies that have been used to treat systemic-onset JIA.

Dosing in systemic-onset JIA: the starting dose is 8 mg/kg once every 2 weeks. Limited information is available on adjusting the dose or the interval for this indication. The maximum dose is 8 mg/kg or 800 mg. Note: patients starting on tocilizumab must have baseline laboratory tests. See Criteria above and Labs/Diagnostics required below.

Many dose modifications are recommended for the management of dose-related laboratory changes such as increased liver enzymes, neutropenia, and thrombocytopenia. Dosing modifications recommended in the prescribing information for RA in adults are as follows.

Liver Enzyme (ALT, AST) Abnormalities. Recommendations for Patients on Tocilizumab.

Lab Value / Recommendation
> 1 to 3 times ULN / Modify dose of concomitant DMARDs if appropriate.
For persistent increases in this range, reduce tocilizumab dose to
4 mg/kg or interrupt tocilizumab until ALT/AST have normalized.
> 3 to 5 times ULN (confirmed with repeat testing) / Interrupt tocilizumab dosing until < 3 times ULN and follow recommendations above for > 1 to 3 times ULN.
For persistent increases > 3 times ULN, discontinue tocilizumab.
> 5 times ULN / Discontinue tocilizumab.

ULN = upper limit of normal. Some DMARDs such as methotrexate, leflunomide (Arava), or sulfasalazine may increase liver enzymes.

Low Absolute Neutrophil Count (ANC). Recommendations for Patients on Tocilizumab.

Lab Value (cells/mm3) / Recommendation
ANC > 1000 / Maintain dose.
ANC 500 to 1000 / Interrupt tocilizumab dosing.
When ANC > 1000 cells/mm3 resume tocilizumab at 4 mg/kg and increase to 8 mg/kg as clinically appropriate.
ANC < 500 / Discontinue tocilizumab.

Low Platelet Count. Recommendations for Patients on Tocilizumab.

Lab Value (cells/mm3) / Recommendation
50,000 to 100,000 / Interrupt tocilizumab dosing.
When platelet count is > 100,000 cells/mm3 resume tocilizumab at 4 mg/kg and increase to 8 mg/kg as clinically appropriate.
< 50,000 / Discontinue tocilizumab.

Initial approval/extended approval: Initial approval is for 4 months (8 doses) of therapy with 4 or 8 mg/kg initially and then every 2 weeks (weeks 0, 2, 4, 6, 8, 10, 12, and 14). Patients are evaluated for response after the eighth dose.

Approve for an additional 12 months of therapy if the patient has responded (e.g., has improvement in limitation of motion; less joint pain or tenderness; improved function or activities of daily living; decreased duration of morning stiffness or fatigue; reduced dosage of corticosteroids; decreased soft tissue swelling in joints or tendon sheaths; improved laboratory values), as determined by the prescribing rheumatologist. Doses are also adjusted depending on laboratory tests for ANC, platelets, and liver function tests. See tables above.

Duration of therapy in RA: indefinite if the patient is responding and tolerates the drug.

Labs/Diagnostics required: Patient should be screened for latent tuberculosis (TB) infection prior to starting therapy and then every year while on tocilizumab. Screening may include any of the following: history, tuberculin skin testing, interferon gamma release assay (IGRA), chest x-ray. In general, patients with latent TB infection should begin preventive therapy before starting tocilizumab.

Patients starting tocilizumab must have baseline labs including ANC, platelet counts, and liver function tests (either ALT or AST) and these labs should be repeated every 4 to 8 weeks. Lipid parameters (total cholesterol, triglycerides, LDL cholesterol, and/or HDL cholesterol) must be assessed at baseline and then again about 4 to 8 weeks after starting tocilizumab.

Waste management: The initial dose in systemic onset JIA is usually 8 mg/kg every 2 weeks. For patients who are already on tocilizumab, the dose should be calculated and the number of vials needed assessed. Usually the dose should be rounded to the next whole number of vials to avoid wasting unused medication left in the vial.

Exclusions: See below.

Exclusions:

  • Concomitant use with anakinra (Kineret), any TNF antagonist (such as etanercept [Enbrel], adalimumab [Humira], golimumab [Simponi], infliximab [Remicade], certolizumab pegol [Cimzia]), abatacept (Orencia), or rituximab (Rituxan).
  • Tocilizumab is contraindicated in patients with significant active infections.
  • Children and adolescents ≤ 18 years of age, except those with systemic-onset JIA.
  • Juvenile idiopathic arthritis (JIA), any subtype beside systemic.
  • Crohn’s disease.
  • Castleman’s disease.

References

  • Actemra® injection for intravenous infusion [package insert]. South San Francisco, CA: Genentech; January, 2010.

Rheumatoid arthritis

  • Jones G, Sebba A, Gu J, et al. Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study. Ann Rheum Dis. 2010;69:88-96.
  • Data on file. South San Francisco, CA: Genentech; January 15, 2010.
  • Fleischmann R, Burgos-Varga R, Ambs E, et al. LITHE: Tocilizumab inhibits radiographic progression and improves physical function in rheumatoid arthritis (RA) patients (pts) at 2 yrs with increasing clinical efficacy over time [abstract 637]. Presented at: the American College of Rheumatology (ACR) 73rd Annual Meeting; Philadelphia, PA; October 16-21, 2009.
  • Smolen JS, Beaulieu A, Rubbert-Roth A, et al; OPTION Investigators. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial. Lancet. 2008;371:987-997.
  • Genovese MC, McKay JD, Nasonov EL, et al. Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs: the tocilizumab in combination with traditional disease-modifying antirheumatic drug therapy study. Arthritis Rheum. 2008;58:2968-2980.
  • Emery P, Keystone E, Tony HP, et al. IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial. Ann Rheum Dis. 2008;67:1516-1523.
  • Smolen JS, Gomez-Reino JJ, Davies C, et al. Long-term efficacy of tocilizumab in rheumatoid arthritis for up to 3.5 years. [abstract 413]. Presented at: the American College of Rheumatology (ACR) 73rd Annual Meeting; Philadelphia, PA; October 16-21, 2009.
  • Nishimoto N, Yoshizaki K, Miyasaka N, et al. Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody: a multicenter, double-blind, placebo-controlled trial. Arthritis Rheum. 2004;50:1761-1769.
  • Nishimoto N, Hashimoto J, Miyasaka N, et al. Study of active controlled monotherapy used for rheumatoid arthritis, an IL-6 inhibitor (SAMURAI): evidence of clinical and radiographic benefit from an x ray reader-blinded randomised controlled trial of tocilizumab. Ann Rheum Dis. 2007;66:1162-1167.
  • Nishimoto N, Miyasaka N, Yamamoto K, et al. Study of active controlled tocilizumab monotherapy for rheumatoid arthritis patients with an inadequate response to methotrexate (SATORI): significant reduction in disease activity and serum vascular endothelial growth factor by IL-6 receptor inhibition therapy. Mod Rheumatol. 2009;19:12-19.
  • Maini RN, Taylor PC, Szechinski J, et al; CHARISMA Study Group. Double-blind randomized controlled clinical trial of the interleukin-6 receptor antagonist, tocilizumab, in European patients with rheumatoid arthritis who had an incomplete response to methotrexate. Arthritis Rheum. 2006;54:2817-2829.
  • Nishimoto N, Miyasaka N, Yamamoto K, et al. Long-term safety and efficacy of tocilizumab, an anti-IL-6 receptor monoclonal antibody, in monotherapy, in patients with rheumatoid arthritis (the STREAM study): evidence of safety and efficacy in a 5-year extension study. Ann Rheum Dis. 2009;68:1580-1584.
  • Oldfield V, Dhillon S, Plosker GL. Tocilizumab: a review of its use in the management of rheumatoid arthritis. Drugs. 2009;69:609-632.

Juvenile idiopathic arthritis [NOT FDA-APPROVED INDICATION]

  • Woo P, Wilkinson N, Prieur AM, et al. Open label phase II trial of single, ascending doses of MRA in Caucasian children with severe systemic juvenile idiopathic arthritis: proof of principle of the efficacy of IL-6 receptor blockade in this type of arthritis and demonstration of prolonged clinical improvement. Arthritis Res Ther. 2005;7:R1281-1288.
  • Yokota S, Imagawa T, Mori M, et al. Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled, withdrawal phase III trial. Lancet. 2008;371:998-1006.
  • Hoffmann-La Roche. A study of tocilizumab in patients with active systemic juvenile idiopathic arthritis. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000-[cited 2010 January 17] Available from: NLM Identifier: NCT00642460.
  • Yokota S, Hara T, Kikuchi M, et al. Drug-free remission of patients with systemic juvenile idiopathic arthritis receiving tocilizumab for treatment [abstract 2054]. Arthritis Rheum. 2009;60Suppl:s768-769.
  • Hoffmann-La Roche. A study of tocilizumab in patients with active polyarticular-course juvenile idiopathic arthritis. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000-[cited 2010 January 17] Available from: NLM Identifier: NCT00988221.

Crohn’s disease [NOT FDA-APPROVED INDICATION]

  • Ito H, Takazoe M, Fukuda Y, et al. A pilot randomized trial of a human anti-interleukin-6 receptor monoclonal antibody in active Crohn’s disease. Gastroenterology. 2004;126:989-996.

Castleman’s disease[NOT FDA-APPROVED INDICATION]

  • Matsuyama M, Suzuki T, Tsuboi H, et al. Anti-interleukin-6 receptor antibody (tocilizumab) treatment of multicentric Castleman's disease. Intern Med. 2007;46:771-774.
  • Nishimoto N, Sasai M, Shima Y, et al. Improvement in Castleman's disease by humanized anti-interleukin-6 receptor antibody therapy. Blood. 2000;95:56-61.
  • Nishimoto N, Kanakura Y, Aozasa K, et al. Humanized anti-interleukin-6 receptor antibody treatment of multicentric Castleman disease. Blood. 2005;106:2627-2632.
  • Sullivan RJ, Pantanowitz L, Casper C, et al. HIV/AIDS: epidemiology, pathophysiology, and treatment of Kaposi sarcoma-associated herpesvirus disease: Kaposi sarcoma, primary effusion lymphoma, and multicentric Castleman disease. Clin Infect Dis. 2008;47:1209-1215.
  • Dispenzieri A. Castleman disease. Cancer Treat Res. 2008;142:293-330.
  • Stebbing J, Pantanowitz L, Dayyani F, et al. HIV-associated multicentric Castleman's disease. Am J Hematol. 2008;83:498-503.

Abbreviations

ALT = alanine aminotransferase

ANC = absolute neutrophil count

AST = aspartate aminotransferase

DMARD = disease modifying antirheumatic drug

FDA = Food and Drug Administration

HDL = high density lipoprotein

IGRA = interferon gamma release assay

IL-6 = interleukin-6

IV = intravenous

JIA = juvenile idiopathic arthritis

LDL = low density lipoprotein

mL = milliliter

MTX = methotrexate

RA = rheumatoid arthritis

TB = tuberculosis

TNF = tumor necrosis factor

ULN = upper limit of normal.

Disease Modifying Antirheumatic Drugs (DMARDs).

Generic Name / Trade Name
Traditional (Synthetic) DMARDs
azathioprine (oral) / generics, Imuran
cyclosporine (oral) / generics, Neoral, Sandimmune
d-penicillamine (oral) / Cuprimine, Depen
gold compounds
gold sodium thiomalate (injection) / Myochrysine®
auranofin (oral) / Ridaura
hydroxychloroquine (oral) / generics, Plaquenil
leflunomide (oral) / generics, Arava
methotrexate [MTX] (oral, injection) / generics, Rheumatrex
minocycline (oral) / generics, Minocin®
sulfasalazine (oral) / generics, Azulfidine En-tabs, Azulfidine
Biologic DMARDs
abatacept (injection) / Orencia
adalimumab (injection) / Humira
anakinra (injection) / Kineret
certolizumab pegol (injection) / Cimzia®
etanercept (injection) / Enbrel
golimumab (injection) / Simponi®
infliximab (injection) / Remicade
rituximab (injection) / Rituxan®
tocilizumab (injection) / Actemra®

Nonsteroidal anti-inflammatory drugs (NSAIDs) list.