In the United States, tocilizumab isindicated for the treatment of rheumatoid arthritis, giant cell arteritis, systemic sclerosis-associated interstitial lung disease, polyarticular juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis, cytokine release syndrome, and COVID‑19.[13]
In the European Union, tocilizumab is indicated for the treatment of rheumatoid arthritis, systemic juvenile idiopathic arthritis, juvenile idiopathic polyarthritis, giant cell arteritis, cytokine release syndrome, and COVID‑19.[17]
Tocilizumab is used for the treatment of moderate to severe rheumatoid arthritis, applied in combination withmethotrexate, if other drugs likedisease-modifying antirheumatic drugs (DMARDs) andTNF alpha blockers have proven to be ineffective or were not tolerated. It can be used as a monotherapy for patients who do not tolerate methotrexate.[23][24] The drug slows down the progression of the disease and can improve physical function of patients.[25]
The treatment ofsystemic juvenile idiopathic arthritis is similar to rheumatoid arthritis treatment: tocilizumab is combined with methotrexate unless the latter is not tolerated. General safety and effectiveness is established for children of two years and older.[26] In 2011, the USFood and Drug Administration (FDA) approved tocilizumab for the treatment of active systemic juvenile idiopathic arthritis.[27]
In June 2021, the USFood and Drug Administration (FDA) issued anemergency use authorization (EUA) for tocilizumab for the treatment of COVID‑19 in hospitalized people aged two years of age and older who are receiving systemic corticosteroids and require supplemental oxygen, non-invasive or invasive mechanical ventilation, orextracorporeal membrane oxygenation (ECMO).[31][14][32] The FDA approved tocilizumab for those indications in December 2022.[33]
The most common adverse effects observed in clinical trials wereupper respiratory tract infections (more than 10% of patients),nasopharyngitis (common cold), headache, and high blood pressure (at least 5%). The enzymealanine transaminase was also elevated in at least 5% of patients, but in most cases without symptoms. Elevated total cholesterol levels were common.[34] Among the less common side effects were dizziness, various infections, as well as reactions of the skin andmucosae like mild rashes,gastritis andmouth ulcer. Rare but severe reactions weregastrointestinal perforations (0.26% in six months) andanaphylaxis (0.2%).[35]
There are no certain interactions with other drugs. The blood plasma levels ofsimvastatin were reduced by 57% after a single dose of tocilizumab, but it is not known whether this is clinically relevant. A possible mechanism is that the elevated IL-6 levels of patients with rheumatoid arthritis suppress the biosynthesis of variouscytochrome P450 enzymes, notablyCYP1A2,CYP2C9,CYP2C19 andCYP3A4. Tocilizumab lowers IL-6 and thus normalises cytochrome levels, increasing the metabolization of simvastatin (and possibly other cytochrome metabolised drugs).[35]
Besides other functions,interleukin 6 (IL-6) is involved in the development of immunological and inflammatory reactions. Someautoimmune diseases like rheumatoid arthritis are associated with abnormally high IL-6 levels. Tocilizumab binds soluble as well as membrane bound interleukin-6 receptors, hindering IL-6 from exerting its pro-inflammatory effects.[35][36] It has been noted that the membrane bound form and soluble form of the IL-6 receptor may have different effects in the pathogenesis of rheumatoid arthritis with the soluble form being more implicated in disease progression.[37]
Interleukin 6 and its receptor were discovered and cloned atOsaka University, Japan, byTadamitsu Kishimoto in the 1980s. In 1997,Chugai Pharmaceuticals began the clinical development of tocilizumab for the treatment of rheumatoid arthritis. Clinical studies for Castleman's disease and systemic juvenile idiopathic arthritis started in 2001 and 2002, respectively. Hoffmann–La Roche co-developed the drug due to a license agreement in 2003.[38]
Data presented in 2008 showed the effectiveness of tocilizumab in combination therapy with methotrexate for rheumatoid arthritis treatment.[39]In further studies, it was effective and generally well tolerated when administered either as monotherapy or in combination with conventional DMARDs in adult patients with moderate to severe rheumatoid arthritis.[40]
In June 2005, tocilizumab was approved in Japan for Castleman's disease.[23] In January 2009, the drug was approved by theEuropean Medicines Agency (EMA) asRoactemra for the treatment of rheumatoid arthritis under the mentioned restrictions. On 11 January 2010, it was approved by the U.S. FDA asActemra for the same purpose.[41] Tocilizumab was approved by Australia'sTherapeutic Goods Administration on 27 May 2009[42] and was listed on thePharmaceutical Benefits Scheme from August 2010.[43] In New Zealand, tocilizumab was approved for distribution in July 2009,[44] andPharmac approved subsidising it with special authority restrictions in July 2013, for systemic juvenile idiopathic arthritis[45] and in July 2014, for rheumatoid arthritis.[46] The FDA approved tocilizumab for the treatment of systemic juvenile idiopathic arthritis for children from two years of age in April 2011, and the EMA followed in August the same year.[citation needed]
Tocilizumab is marketed by Chugai in some countries, especially in Japan and other Asian countries, and jointly by Chugai and Roche (Hoffmann–La Roche'sholding company) in others, for example Great Britain, France and Germany.[38]
In September 2023, Tyenne became the first tocilizumab biosimilar authorized for medical use in the European Union,[8][47] and in March 2024, became the first biosimilar with bothintravenous andsubcutaneous formulations to be approved in the United States.[48][49]
In April 2024, theCommittee for Medicinal Products for Human Use (CHMP) of theEuropean Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Tofidence, intended for the treatment of rheumatoid arthritis (RA), systemic juvenile idiopathic arthritis (sJIA), polyarticular juvenile idiopathic arthritis (pJIA) and coronavirus disease 2019 (COVID-19).[6][50] The applicant for this medicinal product is Biogen Netherlands B.V.[6] Tofidence is a biosimilar medicinal product.[6] Tofidence was authorized for medical use in the European Union in June 2024.[7]
Tyenne was approved for medical use in Canada in October 2024.[51]
In December 2024, the CHMP adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Avtozma, intended for the treatment of rheumatoid arthritis, systemic juvenile idiopathic arthritis, polyarticular juvenile idiopathic arthritis, giant cell arteritis, CAR-T cell-induced severe or life-threatening cytokine release syndrome and COVID-19.[15] The applicant for this medicinal product is Celltrion Healthcare Hungary Kft.[15] Avtozma is a biosimilar medicinal product.[15]
Tocilizumab was approved for the treatment of COVID‑19 in the European Union in December 2021,[17] and in the United States in December 2022.[33]
In September 2021, Indian pharmaceutical firm Hetero obtained emergency use approval from the country's health authority, Drugs Controller General of India (DCGI), to produce a generic version of tocilizumab to treat COVID‑19 in adults.[52]
In December 2021, tocilizumab was granted a provisional approval by the Australian regulator,Therapeutic Goods Administration, for treatment of adults.[53]
Tocilizumab was granted anemergency use authorization (EUA) for the treatment ofCOVID‑19 in the United States in June 2021.[31][14][32] It was approved for the treatment of COVID‑19 in the European Union in December 2021,[17][54][55] and in the United States in December 2022.[33]
Tocilizumab is being studied forpulmonary arterial hypertension (PAH).[56]Tocilizumab is under evaluation in a multicenter clinical trial (ALL-IN) for the prevention of acute cellular rejection in status post heart transplant patients.[57]
There is good evidence tocilizumab can help reduce the need for mechanical ventilation for people in hospital with COVID‑19, and some evidence it can help prevent secondary infections.[58]
^abcde"Tofidence EPAR".European Medicines Agency. 25 April 2024.Archived from the original on 30 April 2024. Retrieved27 April 2024. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
^ab"Tofidence PI".Union Register of medicinal products. 21 June 2024. Retrieved26 June 2024.
^abc"Tyenne EPAR".European Medicines Agency. 2 October 2023.Archived from the original on 5 October 2023. Retrieved5 October 2023.
^abcde"Avtozma EPAR".European Medicines Agency (EMA). 12 December 2024. Retrieved16 December 2024. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
^abcdef"Roactemra EPAR".European Medicines Agency. 17 September 2018.Archived from the original on 18 December 2021. Retrieved18 December 2021.
^"Tyenne Product information".Union Register of medicinal products. 18 September 2023.Archived from the original on 1 October 2023. Retrieved1 October 2023.
^"COVID-19 medicines".European Medicines Agency (EMA). 14 October 2024. Retrieved14 October 2024.
^Markus Harwart (2008)."Die Entwicklung von Tocilizumab" [The development of tocilizumab] (in German). Krankenpflege-Journal. Archived fromthe original on 15 October 2018. Retrieved30 April 2016.
^Komai T, Shoda H, Yamaguchi K, Sakurai K, Shibuya M, Kubo K, et al. (9 December 2013). "Neuromyelitis optica spectrum disorder complicated with Sjogren syndrome successfully treated with tocilizumab: A case report".Modern Rheumatology.26 (2):294–296.doi:10.3109/14397595.2013.861333.PMID24313919.S2CID21195912.
^Perez-Moreiras JV, Gomez-Reino JJ, Maneiro JR, Perez-Pampin E, Romo Lopez A, Rodríguez Alvarez FM, et al. (November 2018). "Efficacy of Tocilizumab in Patients With Moderate-to-Severe Corticosteroid-Resistant Graves Orbitopathy: A Randomized Clinical Trial".American Journal of Ophthalmology.195:181–190.doi:10.1016/j.ajo.2018.07.038.PMID30081019.S2CID51925569.
Clinical trial numberNCT00109408 for "A Study to Assess the Safety and Efficacy of Tocilizumab in Patients With Active Rheumatoid Arthritis" atClinicalTrials.gov
Clinical trial numberNCT00106535 for "A Study to Assess the Effect of Tocilizumab + Methotrexate on Prevention of Structural Joint Damage in Patients With Moderate to Severe Active Rheumatoid Arthritis (RA)" atClinicalTrials.gov
Clinical trial numberNCT00106548 for "A Study to Assess the Effect of Tocilizumab + Methotrexate on Signs and Symptoms in Patients With Moderate to Severe Active Rheumatoid Arthritis" atClinicalTrials.gov
Clinical trial numberNCT00106574 for "A Study to Assess the Effect of Tocilizumab + DMARD Therapy on Signs and Symptoms in Patients With Moderate to Severe Active Rheumatoid Arthritis" atClinicalTrials.gov
Clinical trial numberNCT00106522 for "A Study to Assess the Effect of Tocilizumab + Methotrexate on Signs and Symptoms in Patients With Moderate to Severe Active Rheumatoid Arthritis Currently on Methotrexate Therapy" atClinicalTrials.gov
Clinical trial numberNCT01331837 for "A Study of Tocilizumab in Comparison to Etanercept in Participants With Rheumatoid Arthritis and Cardiovascular Disease Risk Factors" atClinicalTrials.gov
Clinical trial numberNCT00988221 for "A Study of Tocilizumab in Patients With Active Polyarticular Juvenile Idiopathic Arthritis" atClinicalTrials.gov
Clinical trial numberNCT00642460 for "A Study of Roactemra/Actemra (Tocilizumab) in Patients With Active Systemic Juvenile Idiopathic Arthritis (JIA)" atClinicalTrials.gov
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