- Aust Prescr 2009;32:112-5
- 1 August 2009
- DOI: 10.18773/austprescr.2009.054
Some of the views expressed in the following notes on newly approved products should be regarded as preliminary, as there may have been limited published data at the time of publication, and little experience in Australia of their safety or efficacy. However, the Editorial Executive Committee believes that comments made in good faith at an early stage may still be of value. Before new drugs are prescribed, the Committee believes it is important that more detailed information is obtained from the manufacturer's approved product information, a drug information centre or some other appropriate source.
4 mL, 10 mL and 20 mL vials containing 20 mg/mL
Approved indication: rheumatoid arthritis
Australian Medicines Handbook section 15.2
Patients with moderate to severe rheumatoid arthritis, which does not respond to disease-modifying antirheumatic drugs, can be treated with biological therapies such as the inhibitors of tumour necrosis factor alpha (see 'Tumour necrosis factor alpha inhibitors for the treatment of adult rheumatoid arthritis', Aust Prescr 2004;27:43-6). One of the actions of tumour necrosis factor is regulating the production of pro-inflammatory molecules such as the interleukins. High concentrations of interleukin-6 have been associated with inflammatory disorders including rheumatoid arthritis. The inflammatory action may be blocked by antibodies against interleukin-6 receptors, such as tocilizumab.
Tocilizumab is a humanised monoclonal antibody (IgG) produced in Chinese hamster ovary cells by genetic engineering. It binds to the interleukin-6 receptors throughout the body leading to rapid reductions in erythrocyte sedimentation rate and concentrations of C-reactive protein.
Tocilizumab has to be diluted and given by infusion over one hour. The infusion is repeated every four weeks. Although clearance is concentration dependent, the pharmacokinetics of tocilizumab may be nonlinear at low concentrations. At steady state the half-life of the drug is 8-14 days, but this is prolonged at higher concentrations. The activity of cytochrome P450 1A2, 2C9, 2C19 and 3A4 may increase with tocilizumab, potentially affecting the metabolism of other drugs.
After development in Japan, a phase II trial was carried out in Europe. It randomised 359 patients who had experienced an inadequate response to methotrexate. They were given tocilizumab 2 mg, 4 mg or 8 mg/kg, with or without methotrexate, or methotrexate alone, for 16 weeks. Using the criteria of the American College of Rheumatology, a 20% improvement occurred in 41% of the patients taking methotrexate, 31-63% of those taking tocilizumab and 63-74% of those taking both drugs.1
Phase III studies then used doses of 4 mg or 8 mg/kg. In one randomised study 418 patients received these doses and 204 had placebo infusions. Although the patients had had an inadequate response, they all continued their weekly doses of methotrexate for the 24 weeks of the trial. The response to the combined treatment was significantly greater than to methotrexate alone. A 20% improvement was achieved by 59% of the patients taking tocilizumab 8 mg/kg, 48% of those taking 4 mg/kg, but only 26% of the control group.2
Another trial included patients whose rheumatoid arthritis had persisted despite treatment with disease-modifying antirheumatic drugs. A group of 805 patients were randomised to add tocilizumab 8 mg/kg while 415 added a placebo. The patients were treated every four weeks for 24 weeks. A 20% improvement was obtained by 61% of the tocilizumab group and 25% of the placebo group. Concentrations of C-reactive protein fell to normal within two weeks of starting tocilizumab.3
The SAMURAI study in Japan compared the radiological effects of tocilizumab monotherapy to those of disease-modifying antirheumatic drugs. A total of 265 patients were treated for 52 weeks. There was no progression of joint damage in 56% of the patients given tocilizumab compared with 39% of the others.4
Tocilizumab has also been studied in patients whose rheumatoid arthritis had not responded to tumour necrosis factor inhibitors. These drugs were stopped, and the 499 patients were given methotrexate for at least 12 weeks before being randomised to also have infusions of tocilizumab (4 mg or 8 mg/kg) or placebo every four weeks. After 24 weeks, there had been a 20% improvement in 50% of the patients given 8 mg/kg, 30% of those given 4 mg/kg, but only 10% of those who took methotrexate and placebo. This response was not influenced by whichever tumour necrosis factor inhibitors had been used previously.5
As tocilizumab affects the immune system, patients are at risk of infections. There may be a decline in the neutrophil count (and platelets) so the full blood cell count should be monitored. Serious infections, such as pneumonia and cellulitis, are more common with the higher doses of tocilizumab. Patients should be tested for latent tuberculosis before starting treatment.
There is an increased risk of cancer in patients with rheumatoid arthritis and this could be elevated by tocilizumab. In the SAMURAI study three cancers were found in the tocilizumab group with none in the group given disease-modifying antirheumatic drugs.4
As tocilizumab is an immunoglobulin some patients will have infusion reactions, including anaphylaxis. Approximately 6% of the patients given 8 mg/kg had infusion reactions.
Gastrointestinal disorders are common. Although they are mainly mouth ulceration and gastritis, a few patients have suffered perforation of the gut, mainly as a complication of diverticulitis.
Particularly when given with methotrexate, tocilizumab can alter liver function. Regular monitoring of liver function is required and the dose should be adjusted according to the results. It is uncertain if treatment increases overall cardiovascular risk, but tocilizumab can cause a rise in lipids and blood pressure.
Tocilizumab appears to work best in combination with other drugs. It is therefore approved for use with methotrexate or non-biological disease-modifying antirheumatic drugs when previous therapy has been unsatisfactory or not tolerated. Monotherapy can be used if the patient has moderate to severe disease and cannot take methotrexate. The long-term safety of monthly infusions is unknown, but studies are continuing.
manufacturer provided the clinical evaluation
The Transparency Score () is explained in New drugs: transparency', Vol 37 No 1, Aust Prescr 2014;37:27.
At the time the comment was prepared, a scientific discussion about this drug was available on the website of the European Medicines Agency (www.emea.europa.eu).