ANNEX 1: Phvwp Assessment Report on Bisphosphonates and Atrial Fibrillation (For Use by Ncas for Interactions with Mahs for Pamidronic Acid, As Needed)

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ANNEX 1: PhVWP assessment report on Bisphosphonates and Atrial fibrillation (for use by NCAs for interactions with MAHs for pamidronic acid, as needed).

PhVWP Assessment Report on Bisphosphonates and Atrial fibrillation

The possible class effect of atrial fibrillation associated with the use of bisphosphonates was brought to the attention of the CHMP Pharmacovigilance Working Party (PhVWP), following results from a clinical trial with Aclasta® (zoledronic acid) (HORIZON study). In this trial there was an increased rate of atrial fibrillation serious adverse events in patients receiving zoledronic acid (1.3%) compared with patients receiving placebo (0.6%) (P<0.001). Moreover, a review of the Fracture Intervention Trial (FIT), a randomized study of alendronate, revealed a trend toward an increased risk of atrial fibrillation SAEs in alendronate treated patients compared to placebo (P=0.07). The PhVWP agreed that a class review of all bisphosphonates concerning this potential risk was warranted and information has been obtained from the MAHs of the 9 different bisphosphonates (alendronic acid, clodronic acid, etidronic acid, ibandronic acid, neridronic acid, pamidronic acid, risedronic acid, tiludronic acid and zoledronic acid) on pre-clinical and clinical study results, post-marketing reports, potential pathophysiologial mechanisms for bisphosphonate induced atrial fibrillation, planned safety studies and planned/performed risk minimisation activities in relation to this potential risk.

Following the overall assessment of responses from the MAHs the PhVWP concluded that the risk of atrial fibrillation in association with bisphosphonate treatment seems low and that the risk/benefit ratio for bisphoshonates remains favourable. The presented results of clinical trials and post-marketing reports for clodronic acid, etidronic acid, ibandronic acid, neridronic acid, risedronic acid, tiludronic acid did not identify a convincing risk increase of atrial fibrillation and no safety studies or risk minimization activities are considered needed at present for any of these bisphosphonates.

Clinical trial results have so far indicated an increased risk of atrial fibrillation for zoledronic acid and this information has already been included in the SPCs for Aclasta® and Zometa®. Long-term safety studies including investigation of cardiovascular risk are planned for zoledronic acid (Aclasta®).

The non-significant atrial fibrillation risk increase observed in the FIT (alendronic acid) was not confirmed by results from any of the other alendronic acid trials. A meta-analysis of cardio- and cerebrovascular events that occurred in the various alendronate trials is, however, planned by the MAH. The need for updates of the alendronate SPCs will be considered following these results.

Analysis of data on atrial fibrillation for pamidronic acid revealed that in the largest presented study in which pamidronic acid (Aredia®) was compared with zoledronic acid (Zometa®) 4 mg there was a higher atrial fibrillation risk, RR 4.05 (95% CI 1.15-14.28), P=0.018. When a comparison was made with the 4 mg and 4/8 mg doses of Zometa® combined together, again a significant higher risk was observer, although of lower magnitude, RR 2.61 (95% CI 1.11-6.15), P=0.023. This is a concern due to the established risk increase for zoledronic acid and an update of the pamidronic acid SPCs/PLs with the following wording is therefore recommended;

SPC section 4.8 (pamidronic acid) “When the effects of zoledronic acid (4 mg) and pamidronate (90 mg) were compared in one clinical trial, the number of atrial fibrillation adverse events was higher in the pamidronate group (12/556, 2.2%) than in the zoledronic acid group (3/563, 0.5%). Previously, it has been observed in a clinical trial, investigating patients with postmenopausal osteoporosis, that zoledronic acid treated patients (5 mg) had an increased rate of atrial fibrillation serious adverse events compared to placebo (1.3% compared to 0.6%). The mechanism behind the increased incidence of atrial fibrillation in association with zoledronic acid and pamidronate treatment is unknown.”

PhVWP October 2008 1(5)

PL section 4 (pamidronic acid) “Irregular heart rhythm (atrial fibrillation) has been seen in patients receiving pamidronate. It is currently unclear whether pamidronate causes this irregular heart rhythm. You should report to your doctor if you experience irregular heart rhythm during treatment with pamidronate.”

PhVWP October 2008 2(5)