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Hello,
I am a renal pharmacist in Halifax, NS. I am looking into drug access for Rituximab when used for membranous nephropathy. Currently we have limited access to rituximab for this indication (funding). I am looking to gather information from different Canadian centres.
What regimens are you currently using for MN? What is your criteria for rituximab usage?
Thank you,
Maneka Sheffield
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Hi Maneka,
In Manitoba we have to submit a patient specific letter to MB Pharmacare for coverage on an individual basis. We also apply to the Roche Ritux patient assistance program. The hospital does not cover the ritux for this indication so it must be entirely paid by outpatient insurance. Below is the rationale we use in our program for membranous GN which we adopted from BC Renal Agency. We have given the 1 gram x 2 doses as this is generally less costly to the patient (vs BSA dosing) and easier to arrange as only 2 infusion centre appointments needed:
Idiopathic membranous nephropathy
Current standard would be to use cyclophosphamide or CNIs and if one of these fails or is not tolerated to try the other before using rituximab.
Dosing Options:
Rituximab 375mg/m2 qweekly x 4 doses or 1000mg q2weeks x 2 doses, with repeat dosing at 6 months if showing some degree of efficacy.
Remission may be very delayed up to 2 years, so as long as proteinuria is showing some reduction after first course, repeat dosing at 6 months may be indicated, but after that likely wait to observe proteinuria.
Evidence: (UptoDate Treatment of IMN)
Several observational (nonrandomized) studies in patients with idiopathic resistant MN have reported outcomes following the administration of rituximab. A RCT is currently in progress with a completion date of Oct 2017.(Fervenza 2015; clinicaltrials.gov (MENTOR)):
●In a large single-center study, 100 patients with idiopathic MN and persistent proteinuria greater than 3.5 g/day despite six months of angiotensin inhibition were treated with one to four weekly infusions of rituximab (375 mg/m2) [Ruggenenti 2012]. At baseline, 32 patients had previously failed immunosuppressive therapy with other agents; the mean age was 52 years, mean serum creatinine was 106 micromol/L, and mean proteinuria was 9.1 g/day. Patients were followed for a minimum of six months (mean follow-up, 29 months). Complete remission, defined as a reduction in proteinuria to below 0.3 g/day, was achieved in 27 patients; partial remission, defined as a reduction in proteinuria by more than 50 percent to a level below 3 g/day, was achieved in 38 patients. The remaining 35 patients did not achieve remission. The proportion of patients having a complete or partial remission did not differ according to prior therapy with other immunosuppressive agents. Rituximab therapy was generally well tolerated: 28 patients had infusion reactions that were considered minor, and 11 patients had serious adverse events, none of which were considered related to therapy.
A follow-up to this study reported outcomes with rituximab therapy according to anti-phospholipase A2 receptor (anti-PLA2R) autoantibody titers [Ruggenenti 2015]. Complete remission was attained by 33 percent of patients, and partial remission was attained by 31 percent. Although the rate of complete or partial remission was similar among patients with and without detectable anti-PLA2R antibodies, autoantibody-positive patients with lower titers had significantly greater remission rates compared with patients who had higher titers. Specifically, complete or partial remission occurred in 82 percent of patients with titers <87 RU/mL, 59 percent of patients with titers 87 to 204 RU/mL, and in only 37 percent of patients with titers >204 RU/mL.
●In another study, rituximab (1 g given two weeks apart) was given to 15 severely nephrotic patients (6.1 to 23 g/day) with MN; seven had failed previous immunosuppressive therapy and eight had a creatinine clearance below 80 mL/min per 1.73 m2 [Fervenza 2008]. At 12 months, two and six patients had achieved complete or partial remission, respectively; seven of these eight patients had a baseline creatinine clearance above 80 mL/min per 1.73 m2. In contrast, five of the six patients who did not attain remission at 12 months had a baseline creatinine clearance below 75 mL/min per 1.73 m2. The likelihood of remission was not related to previous treatment. Adverse effects were minor and primarily consisted of infusion reactions.
●The same group reported a second observational study in which 20 patients with MN, protein excretion greater than 5.0 g/day, and creatinine clearance greater than 30 mL/min per 1.73, were treated with a different rituximab regimen: four weekly doses of rituximab 375 mg/m2 with retreatment at six months independent of the initial response [Fervenza 2010]. Eleven patients (55 percent) had failed prior immunosuppressive therapy. At 12 months, complete or partial remission had occurred in 10 patients, and, at 24 months, among 18 patients who completed the study, 16 achieved either a complete (4) or partial (12) remission. These data suggest that rituximab may provide benefit to patients who failed prior immunosuppressive therapy, especially those with relatively preserved renal function. In the two studies cited above, four weekly doses of rituximab (375 mg/m2) appear to have the same effect on proteinuria reduction as a regimen of 1 g every two weeks.
We suggest therefore the somewhat simpler and cheaper regimen of a dose of 1 g given intravenously and repeated in two weeks. Patients who continue to have significant proteinuria may have this dose repeated at six months.
Safety
An observational cohort study comparing adverse events in rituximab treated patients versus daily cyclophosphamide with steroids found significantly fewer adverse events in the rituximab group. This included both serious and nonserious adverse events.[van de Brand JAJG 2017]
References:
Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work Group. KDIGO Clinical Practice Guideline for Glomerulonephritis. Kidney inter., Suppl. 2012; 2: 139–274.
Cybulsky AV, Walsh M, Knoll G, et al. Canadian Society of Nephrology Commentary on the 2012 KDIGO clinical practice guideline for glomerulonephritis: management of glomerulonephritis in adults. Am J Kidney Dis. 2014 Mar;63(3):363-77.
Beck L, Bomback AS, Choi MJ, et al. KDOQI US Commentary on the 2012 KDIGO Clinical Practice Guideline for Glomerulonephritis. Am J Kidney Dis. 2013;62(3):403-441.
Remuzzi G, Chiurchiu C, Abbate M, et al. Rituximab for idiopathic membranous nephropathy. Lancet 2002;360(9337):923-924.
Ruggenenti P, Chiurchiu C, Brusegan V, et al. Rituximab in idiopathic membranous nephropathy: a one-year prospective study. J Am Soc Nephrol . 2003;14(7):1851-1857.
Fervenza FC, Cosio FG, Erickson SB, et al. Rituximab treatment of idiopathic membranous nephropathy. Kidney Int 2008;73(1):117-125.
Fervenza FC, Abraham RS, Erickson SB, et al. Rituximab therapy in idiopathic membranous nephropathy: a 2-year study. Clin J Am Soc Nephrol. 2010;5(12):2188-2198.
Ruggenenti P, Cravedi P, Chianca A, et al. Rituximab in idiopathic membranous nephropathy. J Am Soc Nephrol 2012; 23(8):1416-1425.
Bomback AS, Derebail VK, McGregor JG, et al. Rituximab therapy for membranous nephropathy: a systematic review. Clin J Am Soc Nephrol. 2009;4(4):734-744.
Ruggenenti P, Debiec H, Ruggiero B, et al. Anti-Phospholipase A2 Receptor Antibody Titer Predicts Post-Rituximab Outcome of Membranous Nephropathy. J Am Soc Nephrol. 2015 Oct;26(10):2545-58.
Fervenza FC, Canetta PA, Barbour SJ, et al. A Multicenter Randomized Controlled Trial of Rituximab versus Cyclosporine in the Treatment of Idiopathic Membranous Nephropathy (MENTOR). Nephron. 2015;130(3):159-68. (ongoing trial)
Van den Brand JAJG, Ruggenenti P, Chianca A, et al. Safety of rituximab compared with steroid and cyclophosphamide for idiopathic membranous nephropathy. J Am Soc Nephrol 2017 epub ahead of print.
Lori Wazny, Pharm.D.
MB Renal Program
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Refer to the ORN website for Ontario information: https://www.ontariorenalnetwork.ca/en/kidney-care-resources/clinical-tools/glomerulonephritis/drug-funding
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Hi Maneka,
Our approach in Ontario is similar to what Lori described. Now that the MENTOR trial has been published and shows superiority of rituximab over cyclosporine in terms of proteinuria remission/relapse, we have been adding this as an argument in our letters to insurers. Since the trial is so new, I do not yet know how the funders are responding to this.
Clara
Glomerulonephritis Clinic
London Health Sciences Centre -
Hi Maneka,
In BC, rituximab is funded through BC Renal. Here is the link to the rituximab application:
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