Nsw therapeutic Advisory Group Level 5, 376 Victoria Street po box 766




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Current subsidy status


The Schedule of Pharmaceutical Benefits (www.pbs.gov.au) lists the following for infliximab.
Repatriation Pharmaceutical Benefits

Initial treatment, in combination with methotrexate, of specific accepted war-caused or service-related disability of refractory RA. Continuing treatment, in combination with methotrexate, of specific accepted war-caused or service-related disability of refractory RA.



Section 100 items


Treatment of adult patients with active ankylosing spondylitis, severe active psoriatic arthritis or severe active RA.

Public summary documents


Date of PBAC Consideration: July 2006

This submission sought to extend the Section 100 (Highly Specialised Drug) listing for infliximab to include the treatment of severe plaque psoriasis.The PBAC recommended this listing in patients who meet certain criteria on a cost-minimisation basis with efalizumab.


Date of PBAC Consideration: March 2007

This re-submission requested an extension to the Section 100 Authority Required listing to include the treatment of severe refractory Crohn’s disease. The PBAC recommended this listing of infliximab for the treatment of patients with severe Crohn’s disease (Crohn’s Disease Activity Index ≥ 300) or patients with an ileostomy or colectomy due to Crohn’s disease on the basis of high and acceptable cost-effectiveness compared to placebo.


Treatment recommendations

Disease resistant to conventional therapy


A Cochrane review concluded that infliximab is effective in patients with moderate-to-severe UC where the disease is resistant to conventional therapy using corticosteroids and/or immunosuppressive agents. The primary outcome measure was the number of patients achieving remission as defined by the primary studies. Infliximab was shown to induce clinical remission and response, promote mucosal healing and reduce the need for colectomy in the short term. Thukral et al (2006) commented that a significant number of patients who were receiving oral corticosteroids at the start of the 2 main randomized controlled trials (RCTs) (ACT1 and ACT2) remained on corticosteroids despite infliximab therapy. However, the proportions of patients who were in clinical remission and had discontinued corticosteroids at week 30 in both studies (and at week 54 in ACT1) were higher in the infliximab groups than in the placebo groups. Also, the decreases in the median daily corticosteroid doses (20mg at baseline) were greater among patients in the infliximab groups than in the placebo groups.
In the systematic review by Gisbert et al (2007), they agreed that infliximab is more effective than placebo in treating moderate-to-severe UC, with a number needed to treat from 3 to 5 and 40% of patients achieving clinical remission after 9 months. Cottone et al (2006) comment that the long-term effectiveness of infliximab, in comparison to placebo, is not clinically impressive even if it is statistically significant.
The Cochrane review states the evidence is unclear on whether both corticosteroids and immunosuppressive agents should be used prior to infliximab therapy.
Thukral et al (2006) state there is insufficient evidence to recommend the use of infliximab as a first-line agent for UC patients with mild or moderate-to-severe disease.

Disease that is not steroid refactory


Cochrane states there is no evidence to show infliximab is more effective than high-dose corticosteroids in patients who are not steroid-refractory.

Preventing colectomy


The Cochrane review concluded that infliximab helps to avoid colectomy in the short term but that long-term studies are required to determine whether infliximab can prevent colectomy. A recent retrospective cohort study of 30 UC patients treated with infliximab showed that 16 required colectomy after a median of 140 days after first infusion (Jakobovits et al 2007)

Safety

General


ADRAC has received 319 reports involving TNFα inhibitors since 2000. The more serious of these are: malignant melanoma (3 reports), lymphoma (5), tuberculosis (4, TB), pneumonia/lower respiratory tract infections (23), sepsis (10), lupus or lupus-like syndrome (22) and anaphylaxis (9).
The Cochrane review stated that serious adverse events with infliximab in UC patients are not common but uncommon adverse events such as anaphylactic reactions and infections may occur. In the systematic review by Gisbert et al (2007), they stated that adverse effects were reported in 83% and 75% of infliximab and placebo-treated patients in UC studies, respectively (odds ratio [OR] = 1.52; 95% confidence interval [CI] 1.03-2.24; number-needed-to-harm was 14).
A review of adverse events in 500 consecutive CD patients treated with infliximab at the Mayo Clinic for a median follow-up of 17 months showed that 43 patients (8.6%) experienced a serious adverse event, of which 30 (6%) were related to infliximab (Colombel et al 2004). Acute infusion reactions occurred in 19 (3.8%), serum sickness-like disease in 19 (attributed to infliximab in 14, 2.8%), drug-induced lupus in 3. Forty-eight patients had an infectious event, of which 41 (8.2%) were attributed to infliximab. Twenty patients had a serious infection. Nine patients had a malignant disorder, 3 of which were possibly related to infliximab. A total of 10 deaths were observed - 5 were possibly related to infliximab.

Malignancy


TNFα inhibitors may predispose patients to an increased risk of malignancies or accelerate their development. Australian product information advises caution when prescribing TNFα inhibitors in patients with a history of malignancy or when considering continuing treatment in patients who develop a malignancy.
Early evidence of a potential cancer risk came from a case series in 2002 where a post market surveillance system run by the US Food and Drug Administration found 26 cases of lymphoproliferative disorders following treatment with etanercept (18 cases) or infliximab (8 cases) (Brown et al 2002). Bandolier (2006) summarised the results from a series of observational studies in RA patients (ie, Askling et al papers in this document) using etanercept and infliximab mainly. The relative risk of malignancy was 1.1 (95% CI 0.6 - 2.1) - solid cancers occurred at rates little greater than in the general population.
In the Bongartz et al (2006) meta-analysis of infliximab or adalimumab in RA, it was found that malignancies developed in 29 of 3192 (0.9%) patients treated with infliximab or adalimumab, compared with 3 of 1428 (0.2%) patients given placebo. The risk of malignancies was not different from placebo with low dose TNFα inhibitors but was 4-fold greater with high doses of infliximab or adalimumab. The Bongartz study calculated a pooled OR for malignancy following anti-TNF therapy of 3.3 (95% CI, 1 2 - 9.1). The number needed to harm was 154 (95% CI, 91 - 500) for 1 additional malignancy within a treatment period of 6 to 12 months. They concluded there is evidence of a dose-dependent increased risk of malignancies in patients with RA treated with TNFα inhibitors. Similar results were reported in a recent ACP Journal Club analysis (2006). They found that the malignancy risk was greater in RA patients receiving a high dose of TNFα inhibitors compared with placebo (OR 4.3, 95% CI 1.6 - 12) than in those receiving a low dose (OR 1.4, CI 0.3 to 5.7). Direct comparison of high and low dose also showed increased risk for malignancy with high-dose treatment (OR 3.4, CI 1.4 - 8.2).

Infection


ADRAC advises that patients receiving TNFα inhibitors should not receive concurrent vaccination with live vaccines, and that consideration should be given to screening patients for preexisting infections, particularly hepatitis B and TB, prior to use of TNFα inhibitors.
Early evidence of a potential infection risk came from a case series in 2001 where a post-market surveillance system run by the US Food and Drug Administration found 70 cases of TB after treatment with infliximab (Keane et al 2001). The estimated incidence of TB associated with infliximab in RA patients was 1,893 per 100,000 in the year 2000 and 1,113 per 100,000 in the year 2001 in a multicentre active-surveillance report in Spain (Gomez-Reino et al 2003). A prospective cohort study in 83 rheumatoid patients suggested that older age and high-dose corticosteroid therapy were associated with an increased risk of severe pyogenic infection during infliximab therapy (Maillard et al 2005).
A recent ACP Journal Club meta-analysis (2006) found that that serious infection risk with TNFα inhibitors was increased in patients with RA. A dose effect was not observed for serious infection (high dose vs low dose, OR 1.4, CI 1.0 - 2.0). The Bongartz et al (2006) meta-analysis showed a 2-fold increased risk of serious infections with TNFα inhibitors, regardless of dose. The number needed to harm was 59 (95% CI, 39 - 125) for 1 serious infection within a treatment period of 3 to 12 months. They concluded there is evidence of an increased risk of serious infections in patients with RA treated with TNFα inhibitor therapy.

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