Reclast Bone drug (zoledronic acid: once-yearly intravenous infusion) Gets FDA Kidney Failure Warning
Published: September 01, 2011
The FDA warns that the osteoporosis drug Reclast (zoledronic acid) raises the risk of kidney failure.. Medications other than Reclast may be more suitable for you if you have kidney problems. The FDA warning says that kidney failure is a rare but serious complication for at-risk patients taking Reclast. The drug was approved in April 2007. Reclast is manufactured by Novartis. It is prescribed to treat or prevent osteoporosis among postmenopausal women. In those women the drug reduces the risk of hip and spinal fractures. Reclast is administered in infusions every one to two years.
Risk factors for renal failure including underlying moderate to severe renal impairment, use of nephrotoxic or diuretic medications at the same time as Reclast, or severe dehydration occurring before or after Reclast is given.
The agency ordered the new label warning for the drug after receiving 20 reports of acute kidney failure resulting in death or requiring dialysis.
The new warning indicates that patients with creatinine clearance of less than 35 mL/min or evidence of acute renal impairment should not be given zoledronic acid for osteoporosis.
It also identifies risk factors that physicians should take into consideration when prescribing the product. These include advanced age, concurrent treatment with other nephrotoxic drugs, and dehydration secondary to fever, sepsis, gastrointestinal losses, or diuretic therapy.
Previously, the Reclast label recommended serum creatinine measurement before each dose, normally given once a year, and noted that kidney failure is a risk. That language was added in 2009 after the FDA learned of five deaths from acute kidney failure among patients taking the drug. Since then, the agency said, it has received reports of 11 additional deaths and nine cases of kidney failure requiring dialysis, suggesting that the label warning needed to be strengthened.
The updated information also suggests that physicians measure creatinine clearance between Reclast doses in at-risk patients. The FDA recommends using a patient's actual body weight and the Cockcroft-Gault formula for calculating creatinine clearance.
FDA Drug Safety Communication: New contraindication and updated warning on kidney impairment for Reclast (zoledronic acid)
[09-01-2011] The U.S. Food and Drug Administration (FDA) has approved an update to the drug label for Reclast (zoledronic acid) to better inform healthcare professionals and patients of the risk of kidney (renal) failure. Kidney failure is a rare, but serious, condition associated with the use of Reclast in patients with a history of or risk factors for renal impairment. Cases of acute renal failure requiring dialysis or having a fatal outcome following Reclast use have been reported to FDA.
These labeling changes are being made to the Reclast label only, although zoledronic acid, also sold as Zometa, is approved for treatment of cancer-related indications. Renal toxicity is already addressed in the Warnings and Precautions section of the Zometa label. Dose reductions for Zometa are provided for patients with renal impairment.
Risk factors for developing renal failure include underlying moderate to severe renal impairment, use of kidney-damaging (nephrotoxic) or diuretic medications at the same time as Reclast, or severe dehydration occurring before or after Reclast is given. The risk of developing renal failure in patients with underlying renal impairment also increases with age.
The revised drug label will enhance the safe use of Reclast by providing healthcare professionals updated instructions for prescribing and patient monitoring. The revised label states that Reclast should not be used (is contraindicated) in patients with creatinine clearance less than 35 mL/min or in patients with evidence of acute renal impairment. The label also recommends that healthcare professionals screen patients prior to administering Reclast in order to identify at-risk patients. Healthcare professionals should also monitor renal function in patients who are receiving Reclast.
The Reclast Medication Guide for patients is being updated to contain information about the risk of severe kidney problems. In addition, the manufacturer of Reclast will issue a Dear Healthcare Provider letter to inform healthcare professionals about this risk.
Additional Information for Patients
· Kidney failure is a rare, but serious, side effect associated with the use of Reclast.
· Your healthcare professional will order a serum creatinine level (a blood test) before and after each dose of Reclast to assess how well your kidneys are functioning.
· If you have kidney disease, discuss the necessity of Reclast treatment with your healthcare professional. There may be other treatment choices available to you.
· Make sure your healthcare professional knows about all the medications you are taking. It is helpful to keep a list of all your current medications in your wallet or another location where it is easily retrieved.
· Report any side effects with Reclast to FDA's MedWatch program using the information at the bottom of the page in the "Contact Us" box.
Additional Information for Healthcare Professionals
· Reclast is contraindicated in patients with creatinine clearance less than 35 mL/min or in patients with evidence of acute renal impairment.
· Continue to screen patients prior to each administration of Reclast to identify those with underlying acute or chronic renal impairment, advanced age, or dehydration. Patients with underlying renal impairment appear to be at highest risk for kidney failure. Reclast should be used with caution in this population.
· The risk of acute renal failure may increase with underlying renal disease and dehydration secondary to fever, sepsis, gastrointestinal losses, diuretic therapy, etc. The risk of developing renal failure in patients with renal impairment also increases with age.
· Calculate creatinine clearance before each dose of Reclast. Interim monitoring of creatinine clearance should be performed after Reclast dosing in at-risk patients. Creatinine clearance should be calculated based on actual body weight using the Cockcroft-Gault formula.
· Report any adverse events with Reclast to FDA's MedWatch program using the information at the bottom of the page in the "Contact Us" box
A January 2009 FDA post-market safety review identified five deaths from acute renal failure following Reclast infusion. Based on that review, the Warnings and Precautions section of the Reclast label was updated in March 2009, with a recommendation to monitor serum creatinine before each dose of Reclast and included reports of renal impairment from clinical studies. An FDA Drug Safety Newsletter article was also published in 2009 reporting the post-marketing cases of renal impairment and acute renal failure.
FDA continued to note reports of renal failure to the Agency's Adverse Event Reporting System (AERS) after the March 2009 label revision. A follow-up review in April 2011 showed an additional 11 cases of fatal acute renal failure and nine cases of renal injury requiring dialysis after Reclast infusion.
Based on the available information provided in the AERS cases, FDA concluded that several risk factors identified as promoting nephrotoxicity with the use of Reclast should be added to the label. Appropriate selection of patients and patient monitoring by healthcare professionals can reduce the likelihood of adverse events occurring and help ensure the safe use of Reclast.
National Center for Biotechnology Information. U.S. National Library of Medicine. PubMed Health Diseases and Conditions Monograph Kidney Failure. Available at: http://www.nlm.nih.gov/medlineplus/kidneyfailure.html. Accessed July 10, 2011
Zolendronic Acid (Marketed as Reclast): Renal Impairment and Acute Renal Failure
FDA Postmarket Reviews - Volume 2, Number 2, 2009
Abstract: Reclast (zoledronic acid) is an FDA-approved bisphosphonate administered as a once-yearly intravenous infusion for the treatment of osteoporosis in postmenopausal women and men, Paget's disease of bone, and prevention and treatment of glucocorticoid-induced osteoporosis in patients expected to be on glucocorticoids for at least 12 months. FDA's Adverse Event Reporting System (AERS) has received 24 cases of renal impairment and some cases of acute renal failure associated with the use of Reclast. As the label indicates, Reclast is not recommended for use in patients with severe renal impairment (creatinine clearance ≤ 35 mL/min). Physicians should monitor serum creatinine in patients with pre-existing renal compromise or other risk factors, including concomitant nephrotoxic medications or diuretic therapy, or severe dehydration, before and after each infusion. Based on new postmarket reports, the manufacturer has recently updated Warnings and Precautions, Post-Marketing Experience, and Drug Interactions sections of the Reclast label to include data on acute renal failure.
Keywords: Reclast, zoledronic acid, dehydration, acute renal failure
Zoledronic acid (marketed as Reclast and Zometa) is a bisphosphonate drug that works by inhibiting osteoclast-mediated bone resorption, slowing the breakdown of bone to help reduce the risk of fractures.1 Reclast 5 mg was approved in 2007 as a once-yearly intravenous treatment for osteoporosis in postmenopausal women and for the treatment of Paget's disease of bone. In 2008, Reclast was approved for the treatment of osteoporosis in men and, in 2009, it was approved for the treatment and prevention of glucocorticoid-induced osteoporosis in patients expected to be on glucocorticoids for at least 12 months. Zometa was FDA-approved in 2001 for the treatment of hypercalcemia of malignancy, multiple myeloma, and in conjunction with standard antineoplastic therapy in solid tumor patients with documented bone metastases.2 Zometa is not discussed in this review given its different indication, patient population, and frequency of administration.
From April 2007 until February 17, 2009, FDA's Adverse Event Reporting System (AERS) received 24 evaluable postmarket cases of renal impairment and acute renal failure associated with the use of Reclast. Although some cases noted underlying medical conditions and/or concomitant medications, there were cases in which it was possible to establish a reasonable association between Reclast and the event.
Tables 1 and 2 list the characteristics of the 24 cases of renal impairment and acute renal failure after Reclast use. In this case series, osteoporosis was the most frequently cited reason for Reclast use. The median time-to-onset from the infusion until the event was 11 days.
Over half of the patients (14/24) had underlying medical conditions (e.g., diabetes mellitus, congestive heart failure, chronic kidney disease) that may have contributed to their risk of renal impairment or acute renal failure; or had concurrent exposure to known nephrotoxic medications (e.g., NSAIDs).
Fifty-four percent of Reclast-associated acute renal impairment and failure cases (13/24) had documented transient increases in serum creatinine following drug infusion (median increase in serum creatinine was 4 mg/dL).
As noted in Table 2, many patients improved following intravenous fluid administration or other supportive care. Three patients required hemodialysis during their hospitalization. Seven deaths were reported. The cause of death was reported as acute renal failure in four patients. In these cases of death, however, there were other underlying medical conditions, concomitant medications, or a lack of information making any association between Reclast use and death due to acute renal failure difficult to establish.
Three representative cases associated with acute renal impairment and failure are described in Box 1. These cases were selected based on a close temporal relationship of acute renal failure to drug administration, and seriousness of the event. Of note, the patient in Case 2 was not a candidate for Reclast based on pre-infusion glomerular filtration rate (GFR) ≤ 35 mL/min, indicating pre-existing renal impairment.
A 74-year old female with peripheral vascular disease including a history of aorto-iliac thrombosis, chronic diabetic renal disease, chronic obstructive pulmonary disease, and hypertension received Reclast 5 mg intravenously for the treatment of osteoporosis. She was previously treated with alendronate which was discontinued due to dyspepsia. Her baseline serum creatinine ranged from 1.3 to 1.6 mg/dL (normal reference range: <1.5 mg/dL) prior to her infusion. Seventeen days following the Reclast infusion, her serum creatinine level increased to 10.3 mg/dL. She experienced rapid deterioration of her renal function which led to her hospitalization. Her renal function did not improve with hemodialysis. The patient died, reportedly due to "complications from worsening of her other medical conditions." There were no concomitant medications listed in the report.
An 83-year old female with chronic obstructive pulmonary disease, peripheral vascular disease, hypertension, and hyperlipidemia received Reclast 5 mg intravenously. Her concomitant medications included furosemide, atorvastatin, amlodipine, warfarin, diltiazem, pantoprazole, mirtazapine, Duonebs (albuterol/ipratropium), and pain medication. Her pre-infusion GFR was approximately 31 mL/min with an average serum creatinine of 1.4 mg/dL. Ten days after her Reclast infusion, she was admitted to the hospital with acute renal impairment (creatinine: 5.2 mg/dL). The reporter noted that that the patient took an unspecified diuretic and "may not have been hydrated enough." Dialysis was refused by the family. The patient died due to renal failure.
A 84-year old female with atrial fibrillation, congestive heart failure, hypertension, chronic gastritis, hyperlipidemia and osteoporosis received Reclast 5 mg intravenously. Concomitant medications included lasix, zaroxlyn, warfarin, and digoxin. Her baseline serum creatinine was 1.1 mg/dL. She developed flu-like illness and was seen seven days after infusion. Other symptoms included constant nausea and occasional vomiting. She was admitted to hospital with dehydration and acute renal insufficiency (described as prerenal azotemia) with a blood urea nitrogen level of 64 mg/dL, creatinine of 4.1 mg/dL and digoxin level of 1.8 nmol/L. She received intravenous hydration and her creatinine improved to 1.5 mg/dL after three days. Her diuretic and digoxin medications were held until she was adequately hydrated. Symptoms improved, her dehydration resolved and she was subsequently discharged with a creatinine of 1.3 mg/dL.
The majority of the patients with renal impairment and acute renal failure associated with Reclast described in the AERS reports responded to hydration with intravenous fluids. In several cases, acute renal failure, dialysis, and death were reported in patients with pre-existing renal insufficiency. These postmarket reports occurred in at-risk patients - those with underlying moderate to severe renal impairment or other risk factors including concomitant nephrotoxic medications, concomitant diuretic therapy, or severe dehydration.
Information outlined in the Warnings and Precautions, Renal Impairment section of the current label reports a transient increase in creatinine occurring within 10 days of dosing in 1.8% of Reclast-treated patients compared to 0.8% of placebo-treated patients. Based on postmarket reports, the manufacturer has recently updated Warnings and Precautions, Post-Marketing Experience, and Drug Interactions sections of the Reclast label to include data on acute renal failure.
Physicians are encouraged to:
· Avoid the use of Reclast in patients with severe renal impairment (creatinine clearance: < 35 mL/min).
· Monitor serum creatinine before each dose of Reclast.
· Consider interim monitoring of serum creatinine in at-risk patients; transient increases in serum creatinine may be greater in patients with impaired renal function.
· Assure that patients are adequately hydrated prior to administration of Reclast.
· Infuse Reclast over a period of at least 15 minutes.
· Report cases of renal impairment and acute renal failure in patients taking Reclast to FDA's MedWatch Program.