3 The technologies
Adalimumab
3.1 Adalimumab (Humira, Abbott Laboratories) is a human-sequence monoclonal antibody that binds specifically to TNF and neutralises its biological function by blocking its interaction with cell-surface TNF receptors. Adalimumab modulates biological responses induced or regulated by TNF, including changes in the concentrations of adhesion molecules responsible for the migration of leukocytes. Adalimumab has a marketing authorisation for the treatment of moderate to severe active rheumatoid arthritis in adults when the response to DMARDs, including methotrexate, has been inadequate. It is also indicated for the treatment of severe, active and progressive rheumatoid arthritis in adults not previously treated with methotrexate. The summary of product characteristics (SPC) states that adalimumab should be given in combination with methotrexate, except when methotrexate is not tolerated or is considered inappropriate.
3.2 Common adverse effects of adalimumab therapy include injection-site reactions and infections. Adalimumab is contraindicated in people with moderate to severe heart failure, those with active tuberculosis or those with other severe or opportunistic infections. Before initiating therapy, physicians should evaluate people for both active and inactive (latent) tuberculosis infection. For full details of adverse effects, contraindications, special warnings and precautions for use, see the SPC.
3.3 Adalimumab is administered at a dose of 40 mg every other week via subcutaneous injection. In monotherapy, if people experience a decrease in response the dose may be increased to 40 mg every week. The net price for a 40-mg prefilled syringe is £357.50 (excluding VAT; 'British National Formulary', edition 59 [BNF59]). The annual cost of adalimumab for 26 doses at a dose of 40 mg every other week is £9295. Costs may vary in different settings because of negotiated procurement discounts.
Etanercept
3.4 Etanercept (Enbrel, Pfizer) is a recombinant human TNF receptor fusion protein. It interferes with the inflammatory cascade by binding to TNF, thereby blocking its interaction with cell-surface receptors. Etanercept has a marketing authorisation for the treatment of moderate to severe active rheumatoid arthritis when the response to DMARDs, including methotrexate, has been inadequate. Etanercept is also indicated in the treatment of severe, active and progressive rheumatoid arthritis in adults not previously treated with methotrexate. The SPC states that etanercept should be given in combination with methotrexate, except when methotrexate is not tolerated or is considered inappropriate.
3.5 Common adverse effects of etanercept therapy include injection-site reactions, infections and allergic reactions. Etanercept is contraindicated in people with sepsis or risk of sepsis, and those with other active infections. Before initiating therapy, physicians should evaluate people for both active and inactive (latent) tuberculosis infection. For the full details of adverse effects, contraindications, special warnings and precautions for use, see the SPC.
3.6 Etanercept is administered by subcutaneous injection at a dose of 25 mg twice weekly. Alternatively, the SPC allows for a dose of 50 mg once weekly. The net price for a 25-mg vial is £89.38 (excluding VAT; BNF59). The annual cost of etanercept using either 52 once-weekly doses of 50 mg or 104 twice-weekly doses of 25 mg is £9295. Costs may vary in different settings because of negotiated procurement discounts.
Infliximab
3.7 Infliximab (Remicade, Schering-Plough) is a chimeric monoclonal antibody that binds with high affinity to TNF, thereby neutralising its activity. Infliximab has a marketing authorisation in combination with methotrexate for the treatment of active rheumatoid arthritis when the response to DMARDs, including methotrexate, has been inadequate, and for people with severe, active and progressive disease not previously treated with methotrexate or other DMARDs.
3.8 Common adverse effects of infliximab therapy include acute infusion-related reactions, infections and delayed hypersensitivity reactions. Infliximab is contraindicated in people with moderate or severe heart failure, and those with tuberculosis or other severe or opportunistic infections. For full details of adverse effects, contraindications, special warnings and precautions for use, see the SPC.
3.9 Infliximab is administered at a dose of 3 mg/kg by intravenous infusion over 2 hours at an initial infusion (week 0) and then at weeks 2 and 6, and thereafter every 8 weeks. If there is an inadequate response or a loss of response after 12 weeks, physicians may consider increasing the dose of infliximab stepwise by approximately 1.5 mg/kg, up to a maximum of 7.5 mg/kg every 8 weeks. Alternatively, administration of 3 mg/kg as often as every 4 weeks may be considered. The net price for a 100-mg vial is £419.62 (excluding VAT; BNF59). The annual drug costs associated with infliximab vary according to body weight and the number of infusions required. Assuming an average weight of 70 kg and a dose of 3 mg/kg, each dose of infliximab requires three vials at a cost of £1259. The three loading doses cost £3777, with an annual cost following the loading doses of between £7553 and £8812 depending on whether six or seven doses are required. Costs may vary in different settings because of negotiated procurement discounts.
Rituximab
3.10 Rituximab (MabThera, Roche Products) is a genetically engineered chimeric monoclonal antibody that depletes the B-cell population by targeting cells bearing the CD20 surface marker. Rituximab has a marketing authorisation for use in combination with methotrexate for the treatment of adults with severe active rheumatoid arthritis who have had an inadequate response or intolerance to other DMARDs including one or more TNF inhibitor therapies.
3.11 Common adverse effects of rituximab therapy include infusion reactions and infections. Rituximab is contraindicated in people with severe heart failure or severe, uncontrolled cardiac disease, and those with active, severe infections. For full details of undesirable effects, contraindications, special warnings and precautions for use see the SPC.
3.12 A course of rituximab consists of two 1000-mg intravenous infusions given 2 weeks apart. The SPC specifies that courses of rituximab should be given at intervals of no less than 16 weeks. The cost to the NHS of 10-ml and 50-ml vials of rituximab is £174.63 and £873.15 respectively (excluding VAT; BNF59). The cost of a single course of rituximab is £3492 (two 1000-mg intravenous infusions). Costs may vary in different settings because of negotiated procurement discounts.
Abatacept
3.13 Abatacept (Orencia, Bristol-Myers Squibb) is a selective T-cell co-stimulation modulator that blocks a key co-stimulatory signal required for T-cell activation. Abatacept has a marketing authorisation for use in combination with methotrexate for the treatment of moderate to severe active rheumatoid arthritis in adults who have had an insufficient response or intolerance to other DMARDs, including at least one TNF inhibitor.
3.14 Common adverse effects of abatacept therapy include infections, including sepsis and pneumonia. Abatacept is contraindicated in people with severe, uncontrolled infections, and opportunistic infections. Before initiating therapy, physicians should evaluate people for both active and inactive (latent) tuberculosis infection. For full details of undesirable effects, contraindications, special warnings and precautions for use, see the SPC.
3.15 Abatacept is administered as a 30-minute intravenous infusion. After an initial infusion (week 0), it is repeated at week 2, week 4 and every 4 weeks thereafter. People require a total of 14 infusions in the first year and 13 infusions in subsequent years. Abatacept is available in 250-mg vials at a cost of £242.17 per vial (excluding VAT; BNF59). The dose of abatacept depends on body weight: people weighing less than 60 kg, 60–100 kg and over 100 kg require 500 mg, 750 mg and 1000 mg respectively. The annual drug costs associated with abatacept vary according to body weight and the number of infusions required. For a person weighing between 60 and 100 kg, the annual drug cost will be £10,171.14 in the first year and £9444.63 in subsequent years. Costs may vary in different settings because of negotiated procurement discounts.