Zoledronic acid (Aclasta®) and rare reports of renal impairment

HSA would like to bring to the attention of healthcare professionals, post-marketing reports of renal impairment and renal failure associated with the use of intravenous zoledronic acid.

Zoledronic acid (Aclasta®, Novartis (Singapore) Pte Ltd) is a bisphosphonate drug that works by inhibiting osteoclast-mediated bone resorption, thereby slowing the breakdown of bone to reduce the risk of fractures. It has been licensed locally for use since March 2006 as a once-yearly intravenous treatment for osteoporosis in post-menopausal women and in men at increased risk of fractures; and for the treatment of Paget's disease of the bone.

Post-marketing reports of renal impairment

As of 14 August 2009, 139 post-marketing reports of renal impairment following Aclasta® infusion have been received by Novartis worldwide. This corresponds to an estimated reporting rate of 18 cases per 100,000 patient years. Majority of these cases have been reported in patients with pre-existing medical conditions or risk factors (advanced age, renal impairment, and concurrent or preceding dehydration) or who had concurrent exposure to nephrotoxic agents (e.g. NSAIDs). Rare cases of renal failure requiring dialysis or with a fatal outcome have been reported in patients with pre-existing renal impairment and concomitant risk factors.

US Food and Drug Administration (FDA)

From April 2007 to February 2009, the FDA's Adverse Event Reporting System (AERS) received 24 evaluable post-market reports of renal impairment and acute renal failure associated with the use of Reclast® (the equivalent of Aclasta® in US).¹ The median time-to-onset from the date of infusion until the event was 11 days. The median age of the patients was 75 years old (range 61 – 89 years) with osteoporosis being the most frequent indication for the use of Reclast®. Although confounding factors such as underlying medical conditions and concomitant medications were noted in some of the cases, there were others whereby a reasonably possible association with Aclasta® could not be ruled out.

Of these 24 reports of renal impairment and acute renal failure, transient increases in serum creatinine were documented in 13 (54%) of the patients following infusion of the drug. The median increase in serum creatinine was 4mg/dl. Fourteen (58%) patients had underlying medical conditions (e.g. diabetes mellitus, congestive heart failure or chronic kidney disease) or had concurrent exposure to nephrotoxic medications (e.g. NSAIDs) that may have contributed to their risk of developing renal impairment or acute renal failure.

Majority (54%) of the 24 cases of renal impairment and acute renal failure improved following hydration with intravenous fluid administration. In several cases, acute renal failure, dialysis, and death were reported in patients with pre-existing renal insufficiency.

The package insert (PI) of Reclast® in the US has been updated to include data on acute renal failure following these post-marketing reports of renal impairment and acute renal failure.

UK Medicines and Healthcare products Regulatory Agency (MHRA)

As of 5 March 2010, there have been six suspected reports of renal impairment or renal failure following administration of Aclasta® in the United Kingdom (UK).² Majority of these cases generally occurred after the first dose and in patients with pre-existing renal dysfunction or other risk factors such as advanced age, the use of concomitant nephrotoxic drugs, diuretic therapy or dehydration. Renal failure requiring dialysis or resulting in death occurred in some high-risk patients.

A letter was sent to healthcare professionals in March 2010 highlighting the updated UK PI for Aclasta®.

Local situation

To date, HSA has received two reports of renal-related adverse reactions following Aclasta® infusion. The first patient was a female (age not reported) who experienced acute renal failure with elevated serum creatinine. The second patient was a 60 year-old female who developed renal impairment nine months after receiving Aclasta® infusion. The patient was noted to be also on concomitant medications such as amlodipine, esomeprazole, calcitrol, paracetamol and sodium bicarbonate.

A Dear Healthcare Professional Letter^3,4 was sent out on 1 April 2010 by Novartis (Singapore) Pte Ltd, highlighting these post-marketing reports of renal failure and renal impairment following Aclasta® infusion. The local PI for Aclasta® has been updated to include these adverse reactions.

Physicians are advised to consider their patient's renal function and assess their patient's serum creatinine before treatment with Aclasta®. When prescribing Aclasta® to patients, physicians are encouraged to refer to the latest updated PI for Aclasta®, available on the HSA's website and to report all adverse drug reactions associated with the use of Aclasta® to the Vigilance Branch of HSA.

References

1. FDA Drug Safety Newsletter Volume 2, No. 2, 2009. Zoledronic acid (marketed as Reclast): Renal impairment and acute renal failure.
   http://www.fda.gov/Drugs/DrugSafety/DrugSafetyNewsletter/ucm167883.htm

2. MHRA Drug Safety Update: Volume 3, Issue 9, April 2010. Intravenous zoledronic acid: adverse effects on renal function.
   http://www.mhra.gov.uk/Publications/Safetyguidance/DrugSafetyUpdate/CON076501

3. HSA website. Dear Healthcare professional Letters (DHCPL)
   https://www.hsa.gov.sg/announcements/Dear-Healthcare-Professional-Letters 

4. MOH-Health Professionals Portal
   http://www.hpp.moh.gov.sg