The Food and Drug Administration (FDA) is informing healthcare providers of

• By KMFDallas
• Posted July 2, 2009 at 3:23 pm
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More detailed information..............
FDA: Postmarket Reviews - Volume 2, Number 2, 2009

Zolendronic Acid (Marketed as Reclast): Renal Impairment and Acute Renal Failure


--------------------------------------------------------------------------- Zolendronic Acid (Marketed as Reclast): Renal Impairment and Acute Renal Failure
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.

Table 1. Demographics
Age (years) Median 75
Range 61 - 89
Unknown 3
Gender Male 3
Female 19
Unknown 2
Country of Origin U.S. 22
Non-U.S. 2



Table 2. Indications and Outcomes
Reason for Use Osteoporosis 20
Paget's Disease 1
Unknown 3
Outcome* Improvement with IV Fluids 13
Hospitalization 18
Required Dialysis 3
Death** 7

*Outcomes are not mutually exclusive
**Cause of death include renal faillure (n=4), GI cancer (n=1), sepsis (n=1), and unknown causes (n=1)

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.

Box 1

Case 1
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.

Case 2
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.

Case 3
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.


Elements of a comprehensive treatment program for osteoporosis
Nutrition: Calcium and vitamin D are needed for strong bones

Excercise: Can improve bone health, increase muscle strength, coordination, and balance

Therapeutic Medications: There are several medication options available, including the use of bisphosphonates

http://www.niams.nih.gov/Health_Info/Bone/
Osteoporosis/default.asp#aling

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• By Char42
• Posted July 3, 2009 at 1:32 pm
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That is nuts to prescribe Reclast for 80 some year olds or any Bisphosphonate. The heart, liver and kidneys do not handle toxins in the elderly.
Reminds me of a 92 year old neighbor prescribed Fosamax, he already was disabled and in a wheelchair because of arthritis. The Fosamax made him so sick, he died several months later. Shame on any Doctor prescribing Bisphosphonate toxins to the elderly, it is not common sense. Duh

Thanks for the info and detail in print.

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• By LBI1017
• Posted July 5, 2009 at 12:57 pm
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I was on Forteo for 2 years. My density improved a lot. My doctor told me not to take anything for Osteo. after the 2 year period. My bone density returned to the sorry state it was in prior to Forteo. I am guessing it is important to take Actonel or Fosamax after stopping Forteo.

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• By Max3
• Posted July 7, 2009 at 6:02 am
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I am concerned about your reply about reclast. My mom is 83 and the specialist recommended either forteo or reclast. She doesn't want to try either. About a 1 1/2 years ago, she was on Fosomax for over a year. I kept telling the doctor she was having trouble swallowing and he just replied that the benefits outweight the side effects. Eventually, I had to take her to the hospital because she couldn't even swallow a drop of water. They immediately took her off of Fosomax. I don't blame her for not wanting to try these new drugs but I know she needs something more than just calcium. I switched her doctor because he said he wouldn't have done anything different. Can you believe that!

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• By KMFDallas
• Posted July 7, 2009 at 8:49 am
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Unfortunately - Yes. We must always advocate for ourselves and it is good you took her to another physician.

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