Osteoporosis Medication
New restricted indication and monitoring recommendations for the use of Protelos (strontium ranelate)
Protelos a medicine which is used in treating osteoporosis in women after the menopause and treating osteoporosis in men.
Dear Healthcare Professional,
This letter is to inform you of the new restricted indication and monitoring recommendations for Protelos following the European Medicines Agency’s full evaluation of the benefits and risks of strontium ranelate. Available data does not show evidence of an increased cardiovascular risk in patients without cardiovascular contra-indications introduced in April 2013.
Summary: The use of Protelos is now restricted to the treatment of severe osteoporosis: in postmenopausal women, in adult men, at high risk of fracture, for whom treatment with other medicinal products approved for the treatment of osteoporosis is not possible due to, for example, contraindications or intolerance. In postmenopausal women, strontium ranelate reduces the risk of vertebral and hip fractures. The current cardiovascular contraindications remain in place. Patients with established, current or past history of ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease or uncontrolled hypertension should not be treated with Protelos. Prescribers are advised to: assess patients’ risk of developing cardiovascular disease before starting treatment. monitor patients’ cardiovascular risk on a regular basis, generally every 6 - 12 months. stop treatment if the patient develops ischaemic heart disease, peripheral arterial disease, cerebrovascular disease or if hypertension is uncontrolled. Treatment should only be initiated by a physician with experience in the treatment of osteoporosis. Educational materials regarding the current indications and restrictions of Protelos will be provided for healthcare professionals and patients. This letter is sent in agreement with the European Medicines Agency (EMA) and the Medicines and Healthcare products Regulatory Agency (MHRA)
Source MHRA (March 2014)
FDA Drug Safety Communication: New contraindication and updated warning on kidney impairment for Reclast (zoledronic acid)
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 (see Additional Information for Healthcare Professionals below).
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
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.
References
Facts about Reclast (zoledronic acid)
Source : FDA (Sept 2011)
Link to Source
FDA Drug Safety Communication: Ongoing safety review of oral osteoporosis drugs (bisphosphonates) and potential increased risk of esophageal cancer
Osteoporosis Drugs - oral bisphosphonates
[07-21-2011] The U.S. Food and Drug Administration (FDA) is continuing to review data from published studies to evaluate whether use of oral bisphosphonate drugs is associated with an increased risk of cancer of the esophagus (esophageal cancer). There have been conflicting findings from studies evaluating this risk.
At this time, FDA believes that the benefits of oral bisphosphonate drugs in reducing the risk of serious fractures in people with osteoporosis continue to outweigh their potential risks.
FDA's review is ongoing and the Agency has not concluded that patients taking oral bisphosphonate drugs have an increased risk of esophageal cancer. It is also important to note that esophageal cancer is rare, especially in women.
The largest studies that FDA has reviewed, thus far, are two epidemiologic studies using one patient database (the U.K. General Practice Research Database or GPRD). One study found no increase in the risk of esophageal cancer.1 The second study found a doubling of the risk of esophageal cancer among patients who had 10 or more prescriptions of the drugs, or who had taken the drugs over 3 years.2 Other external researchers investigating this issue, using different patient databases, have reported no increase in risk, or a reduced risk.3 [See Data Summary for additional information on the studies]
Patients should talk with their healthcare professionals about the benefits and risks of taking oral bisphosphonates. Patients who take oral bisphosphonates should pay particular attention to the directions for use to minimize any potential adverse events.
FDA will continue to evaluate all available data supporting the safety and effectiveness of bisphosphonate drugs and will update the public when more information becomes available.
Additional Information for Patients
In January 2009, a case series was published describing reports submitted to the FDA of esophageal cancer in patients prescribed oral bisphosphonates.4 Since then, several epidemiological studies looking at the association between oral bisphosphonates and esophageal cancer have been published, with discrepant findings. The two largest published studies used data from the U.K.'s General Practice Research Database (GPRD).
One study compared the rate of esophageal cancer in patients taking an oral bisphosphonate to patients not taking an oral bisphosphonate. This study found no increase in the risk of esophageal cancer.1 Using the same database, a second study found a doubling of the risk of esophageal cancer among patients who had 10 or more prescriptions of oral bisphosphonates, or who had taken the drugs over 3 years.2
Other investigators are researching this issue. In a large cohort of Danish patients with fractures, investigators found that bisphosphonate users (who had taken them for a median of 1.5 years) had a significantly reduced risk for esophageal cancer compared to patients with fractures who had not taken any bisphosphonate.3 Longer term follow-up of alendronate (Fosamax) users and non-alendronate users showed that alendronate users had a higher frequency of endoscopic examination of the esophagus, no greater incidence of esophageal cancer, and no increase in esophageal cancer deaths.5
Differences in methodologies in these studies may account for the discrepant findings. Also, since these studies are observational rather than randomized, they are subject to bias and confounding. For example, it is possible that the gastrointestinal side effects of bisphosphonates increase a patient's likelihood of undergoing an endoscopy, which could lead to earlier detection of a cancer or drug discontinuation. At this time, there is not enough information to make definitive conclusions about a possible association. FDA's safety review is ongoing. Additional studies conducted in different databases may be warranted.
References
Link to Source
Revisiting Bone Drugs and Femur Fractures
By JANE E. BRODY
Nearly six years ago in this column, I discussed what was then a little-known problem associated with long-term use of bisphosphonates, the valuable drugs that protect against fractures caused by bone loss. The drugs, among them Fosamax, Actonel and Boniva, can slow bone loss, increase bone density and cut fracture rates in half in women with established osteoporosis.
Reports had begun to emerge that some women taking bisphosphonates for many years suffered an unusual fracture of the femur, the long bone of the thigh. There was little or no trauma; in most cases the women were simply standing or walking when the femur snapped in half. In some, breaks occurred in both thighs, and many of the fractures were unusually slow to heal.
Experts think the fractures happened because of the way the drugs work: by slowing the rate of bone remodeling, the normal process by which injured bone heals. As a result, microfractures that occur through normal wear and tear are not repaired. Although bone density may be normal, the bone can become brittle and crack under minor stress.
In the years since, hundreds of cases of atypical femur fractures have been reported among women and some men taking bisphosphonates for five or more years. A number of studies have tried to assess the risk, and last fall the Food and Drug Administration issued a “safety announcement” and required that the drugs’ labels warn physicians and patients to be alert for this potential complication.
Weighing the Research
But many questions remain, including who is most at risk for femur fractures and whether the risks outweigh the important benefits of taking a bisphosphonate for many years. The latest assessment was published Feb. 23 in The Journal of the American Medical Association by a team of physicians and epidemiologists in Toronto.
The team, led by Laura Y. Park-Wyllie, an epidemiologist who is a doctor of pharmacology at St. Michael’s Hospital, gathered treatment and fracture data among all 205,466 women in Ontario aged 68 or older who had been treated with a bisphosphonate. They identified those who had suffered femur fractures occurring below the hip and above the knee — called subtrochanteric or femoral shaft fractures — and compared each case with those of up to five other women the same age who had been free of this injury.
Those who had taken the drugs for five years or longer were more than twice as likely to have had such a fracture as those who took them only briefly. But because X-rays of the bone were not reviewed, it is not certain that the fractures were linked to the drugs. At the same time, long-term use of bisphosphonates prevented many more fractures than it might have caused; the risk of osteoporotic femur fractures, a far more common injury, was reduced by 25 percent, Dr. Park-Wyllie said in an interview.
“Compared to the number of fractures prevented,” she said, “the actual risk of a subtrochanteric femur fracture is small” — 1 case in 1,000 in the sixth year of therapy and 2.2 cases in 1,000 the seventh year.
A report published last year in The New England Journal of Medicine found no increase in atypical femur fractures, but that study did not include enough patients taking bisphosphonates for many years to produce a reliable result. Preliminary data from a much larger study has indicated that the risk of atypical femur fractures increased from 2 cases a year per 100,000 users after two years of bisphosphonate therapy to 78 cases a year per 100,000 after eight years on the drug.
In a report from a 27-member task force of the American Society for Bone and Mineral Research (published online in September in The Journal of Bone and Mineral Research), the experts noted that the way bisphosphonates work can reduce the “toughness” of bones. “It is highly likely that case reports and case series of atypical femur fractures will continue to accumulate,” the task force wrote, noting that another 47 cases had been reported since their analysis was prepared. Many cases are not reported, and in an unknown number of cases physicians may not recognize the fractures as atypical.
The task force called for an international registry of cases, including details that could help define who is most at risk.
First, an Evaluation
What should patients and doctors do?
“Relative to the millions of fractures that occur every year in the United States, the number of atypical femur fractures should not discourage the use of these effective drugs by patients with osteoporosis who are at high risk of fracture,” a leader of the task force, Dr. Elizabeth Shane, said in an interview. (Dr. Shane is a bone specialist at Columbia University Medical Center.)
Initial excitement about bone-protecting drugs led to prescriptions for millions of women who were not necessarily at high fracture risk, and many experts now urge a thorough evaluation before a bisphosphonate is prescribed. In addition to bone density test results, the evaluation should take into account a patient’s smoking and drinking habits, thinness, family history of osteoporosis, previous osteoporotic fractures, drug prescriptions and weight-bearing exercise regimen. An online evaluation tool developed by the World Health Organization is at www.shef.ac.uk/FRAX, though some experts have criticized it as incomplete.
The task force said a decision to treat should be “based on an assessment of benefits and risks,” and added, “patients who are deemed to be at low risk of osteoporotic-related fractures should not be started on bisphosphonates.”
Even those with osteoporosis in the spine but little or no problem in their hips, the experts concluded, should consider alternative remedies.
While no one knows what the optimal length of drug treatment should be, five years on a bisphosphonate seems to confer an adequate benefit; after that, patients should consider taking a “drug holiday.”
Before resuming therapy, the patient’s risk factors for fracture should be reassessed. The task force noted that half of currently known patients with atypical fractures had been on bisphosphonates for seven years.
Furthermore, in 70 percent of cases, patients reported experiencing pain or discomfort in the thigh or groin for weeks or months before the femur fractured. Anyone on a bone drug who develops such a pain should be carefully evaluated, first with an X-ray and, if nothing is seen but the cause is uncertain, by a bone scan or M.R.I.
When a problem like a defect in the shell of the femur is found and the patient has pain, a fracture is highly likely, Dr. Shane said, and the task force recommended inserting a rod in the bone to keep it from breaking.
Furthermore, Dr. Jennifer Schneider of Tucson, an internist who after seven years on Fosamax suffered a nontraumatic femur fracture that took two years to heal, notes that the damage is often bilateral — so when a problem is found in one leg, the other leg should be thoroughly examined. Among patients in an online support and information group she established, some reported suffering a second atypical fracture in the other thigh.
Dr. Schneider invites patients who have had such a fracture to write to her at [email protected].
Source : The New York Times
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FDA warns of thigh fractures with bone drugs
Osteoporosis drugs used by millions of women to prevent bones from breaking may increase the chances for an unusual type of thigh fracture, U.S. health officials warned on Wednesday.
The drugs known as bisphosphonates include Merck & Co Inc's Fosamax, Roche Holding AG's Boniva, Novartis AG's Reclast and Warner Chilcott Plc's Actonel.
The action could drive patients to Amgen Inc's just-launched rival medicine, Prolia, a different type of osteoporosis drug that is the company's most important future growth driver.
Food and Drug Administration officials said all bisphosphonates used for osteoporosis will carry a new warning about rare but serious fractures of the thigh bone, even though it remains unclear if the medicines caused the fractures.
The agency advised doctors to consider if patients on therapy for more than five years still need the drugs.
The new warning "should not cause patients taking bisphosphonates to be fearful of their medicine," said Dr. Sandra Kweder, deputy director of the FDA's new drugs office.
The drugs "are an important mainstay of osteoporosis management" and "have prevented innumerable fractures in their years of use," Kweder told reporters on a conference call.
More than 5 million U.S. patients filled prescriptions for bisphosphonates in 2009, the FDA said.
Concern about thigh fractures may lead patients to seek alternatives such as Amgen's Prolia, Bernstein & Co analyst Geoff Porges said. A positive impact on Prolia could been seen as early as the fourth quarter, he said.
"Today's label change is likely to raise the level of concern among patients about the safety of bisphosphonates significantly," Porges said in a research note.
Osteoporosis is a progressive bone-thinning condition most common in women after menopause. Actonel and Reclast are injectable. The other drugs are taken orally.
The most common fractures seen with osteoporosis typically occur in the hip, wrist or spine. They can cause pain and require hospitalization or surgery.
A study of hospital discharge data showed hip fractures dropped to 428 from 598 per 100,000 people in the 10 years after approval of the first bisphosphonate in 1996, FDA officials said. No treatment eliminates fracture risk completely.
Thigh fractures also can occur from osteoporosis, but the ones reported in recent years were unusual because they often appeared after little or no trauma and were seen in younger patients, the FDA's Kweder said. In most cases, patients felt a dull, aching pain in the thigh or groin months before a complete fracture.
People with those symptoms should contact a doctor to try and prevent the fracture, FDA officials said. The agency is requiring consumer-friendly guides to be dispensed with bisphosphonates to explain possible risks.
The unusual fractures appeared to account for less than 1 percent of all hip and femur fractures, the FDA said.
Dr. Felicia Cosman, clinical director of the National Osteoporosis Foundation, said there was little evidence bisphosphonates help after five to seven years and that may be the time when thigh fracture rates increase.
"If the safety profile is changing and the efficacy is not clear, then many people should consider having an interruption in continuous use of the drug" after that time, she said.
Merck said Fosamax had not been associated with any increased fracture risk in clinical studies of more than 28,000 patients. Still, the company voluntarily added information about the unusual thigh fractures to the drug's prescribing instructions in July 2009.
Fosamax also is sold as a cheaper generic under the name alendronate.
Roche unit Genentech said it would work with the FDA to provide information to doctors and patients "to make informed decisions."
Merck shares gained 1.4 percent on Wednesday to close at $37.16, while Novartis shares rose 0.4 percent to $59.45, both on the New York Stock Exchange. Warner Chilcott shares rose 4 cents to $25.00 on Nasdaq.
Source : Rueters 13/10/2010
(Reporting by Lisa Richwine and Bill Berkrot; editing by Lisa Von Ahn and Andre Grenon)
LINK TO SOURCE
MERCK TO PAY $8M, IN DAMAGES IN FOSAMAX TRIAL
In replay of a courtroom battle that ended in a mistrial last fall, a federal jury today voted unanimously that Merck’s Fosamax osteoporosis drug was responsible for causing jawbone deterioration suffered by a Florida woman, who was awarded $8 million in compensatory damages (here is the lawsuit). Merck, which argued 71-year-old Shirley Boles was at increased risk for dental and jaw problems if she was not taking Fosamax, quickly indicated it would appeal the decision. “We disagree with the jury’s verdict. We believe the jury verdict was a result of the plaintiff’s counsel’s gross mischaracteraization, and inflammatory and prejudicial remarks,” Paul Strain, an attorney representing Merck, tells us. “We believe the court, from his remarks, made it clear he shares those concerns about the improper closing argument by plaintiff’s counsel. That gives us a strong foundation moving forward.”
This was the second bellwether case over whether Merck failed to warn docs and patients that Fosamax may cause osteonecrosis, which is the painful death of jawbone tissue. Merck won the first trial last month (see here). As of March 31, the drugmaker faces 1,039 lawsuits in and federal and state courts that were feild by 1,417 plaintiffs.
Source:pharmalot.com
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FDA Drug Safety Communication: Ongoing safety review of oral bisphosphonates and atypical subtrochanteric femur fractures
Safety Announcement
[03-10-2010] Patients and healthcare professionals may have questions about oral bisphosphonate medications and atypical subtrochanteric femur fractures – fractures in the bone just below the hip joint. Oral bisphosphonates are commonly prescribed to prevent or treat osteoporosis in postmenopausal women. Common brand names of medications in this class include Fosamax, Actonel, Boniva, and Reclast.
Recent news reports have raised the question about whether there is an increased risk of this type of fracture in patients with osteoporosis using these medications. At this point, the data that FDA has reviewed have not shown a clear connection between bisphosphonate use and a risk of atypical subtrochanteric femur fractures. FDA is working closely with outside experts, including members of the recently convened American Society of Bone and Mineral Research Subtrochanteric Femoral Fracture Task Force, to gather additional information that may provide more insight into this issue.
LINK TO FULL ARTICLE
Protelos a medicine which is used in treating osteoporosis in women after the menopause and treating osteoporosis in men.
Dear Healthcare Professional,
This letter is to inform you of the new restricted indication and monitoring recommendations for Protelos following the European Medicines Agency’s full evaluation of the benefits and risks of strontium ranelate. Available data does not show evidence of an increased cardiovascular risk in patients without cardiovascular contra-indications introduced in April 2013.
Summary: The use of Protelos is now restricted to the treatment of severe osteoporosis: in postmenopausal women, in adult men, at high risk of fracture, for whom treatment with other medicinal products approved for the treatment of osteoporosis is not possible due to, for example, contraindications or intolerance. In postmenopausal women, strontium ranelate reduces the risk of vertebral and hip fractures. The current cardiovascular contraindications remain in place. Patients with established, current or past history of ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease or uncontrolled hypertension should not be treated with Protelos. Prescribers are advised to: assess patients’ risk of developing cardiovascular disease before starting treatment. monitor patients’ cardiovascular risk on a regular basis, generally every 6 - 12 months. stop treatment if the patient develops ischaemic heart disease, peripheral arterial disease, cerebrovascular disease or if hypertension is uncontrolled. Treatment should only be initiated by a physician with experience in the treatment of osteoporosis. Educational materials regarding the current indications and restrictions of Protelos will be provided for healthcare professionals and patients. This letter is sent in agreement with the European Medicines Agency (EMA) and the Medicines and Healthcare products Regulatory Agency (MHRA)
Source MHRA (March 2014)
FDA Drug Safety Communication: New contraindication and updated warning on kidney impairment for Reclast (zoledronic acid)
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 (see Additional Information for Healthcare Professionals below).
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.
- 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.
References
- 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
Facts about Reclast (zoledronic acid)
- Used to treat or prevent osteoporosis in women after menopause. Reclast helps reduce the chance of having a hip or spinal fracture (break).
- Used to increase bone mass in men with osteoporosis.
- Used to treat or prevent osteoporosis in either men or women who take corticosteroid medications for at least one year.
- Used to treat men and women who have Paget's disease of the bone.
- Given as an intravenous infusion in a single dose, once every 1 to 2 years. The infusion time should be no less than 15 minutes.
- Marketed under the brand name Aclasta outside the United States.
Source : FDA (Sept 2011)
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FDA Drug Safety Communication: Ongoing safety review of oral osteoporosis drugs (bisphosphonates) and potential increased risk of esophageal cancer
Osteoporosis Drugs - oral bisphosphonates
- Commonly used for the prevention and treatment of osteoporosis as well as to treat other bone diseases such as Paget's disease. Osteoporosis is a disease that makes bones weak and more likely to break.
- Include: Fosamax (alendronate), Actonel (risedronate), Boniva (ibandronate), Atelvia (risedronate delayed release), Didronel (etidronate), and Skelid (tiludronate).
- May cause irritation of the esophagus. Irritation of the esophagus can lead to esophagitis (inflammation) or esophageal ulcers (sores), which may bleed. The risk of these esophageal events is low when oral bisphosphonates are prescribed appropriately and the specific directions for use are followed by patients.
[07-21-2011] The U.S. Food and Drug Administration (FDA) is continuing to review data from published studies to evaluate whether use of oral bisphosphonate drugs is associated with an increased risk of cancer of the esophagus (esophageal cancer). There have been conflicting findings from studies evaluating this risk.
At this time, FDA believes that the benefits of oral bisphosphonate drugs in reducing the risk of serious fractures in people with osteoporosis continue to outweigh their potential risks.
FDA's review is ongoing and the Agency has not concluded that patients taking oral bisphosphonate drugs have an increased risk of esophageal cancer. It is also important to note that esophageal cancer is rare, especially in women.
The largest studies that FDA has reviewed, thus far, are two epidemiologic studies using one patient database (the U.K. General Practice Research Database or GPRD). One study found no increase in the risk of esophageal cancer.1 The second study found a doubling of the risk of esophageal cancer among patients who had 10 or more prescriptions of the drugs, or who had taken the drugs over 3 years.2 Other external researchers investigating this issue, using different patient databases, have reported no increase in risk, or a reduced risk.3 [See Data Summary for additional information on the studies]
Patients should talk with their healthcare professionals about the benefits and risks of taking oral bisphosphonates. Patients who take oral bisphosphonates should pay particular attention to the directions for use to minimize any potential adverse events.
FDA will continue to evaluate all available data supporting the safety and effectiveness of bisphosphonate drugs and will update the public when more information becomes available.
Additional Information for Patients
- There is conflicting information on whether oral bisphosphonate drugs can affect your chance of developing esophageal cancer.
- Directions for use of the oral bisphosphonate drug should be followed carefully. All oral bisphosphonate drugs, except Atelvia, should be taken first thing in the morning after awakening, with a full glass of plain water. Atelvia should be taken immediately following breakfast. Do not lie down or eat or drink anything for at least 30 to 60 minutes after taking any oral bisphosphonate drug.
- Talk to your healthcare professional if you develop swallowing difficulties, chest pain, new or worsening heartburn, or have trouble or pain when you swallow. These may be signs of problems of the esophagus.
- You should not take oral bisphosphonates if you have esophageal conditions that delay emptying of the esophagus, or if you cannot stand or sit upright for at least 30 to 60 minutes, or have low calcium levels in your blood.
- Talk to your healthcare professional about the benefits and risks of taking oral bisphosphonates and how long you should expect to take them.
- Discuss any questions or concerns about your oral bisphosphonate drug with your healthcare professional.
- Report any side effects you experience to the FDA MedWatch program using the information in the "Contact Us" box at the bottom of the page.
- FDA has not concluded that taking an oral bisphosphonate drug increases the risk of esophageal cancer and there are conflicting data on this risk.
- There are insufficient data to recommend endoscopic screening of asymptomatic patients.
- Esophagitis and other esophageal events have been reported, particularly in patients who do not follow the specific directions for use of oral bisphosphonates.
- Instruct patients to carefully follow the directions for use of the oral bisphosphonate drug they are prescribed.
- Report adverse events involving bisphosphonate drugs to the FDA MedWatch program, using the information in the "Contact Us" box at the bottom of the page.
In January 2009, a case series was published describing reports submitted to the FDA of esophageal cancer in patients prescribed oral bisphosphonates.4 Since then, several epidemiological studies looking at the association between oral bisphosphonates and esophageal cancer have been published, with discrepant findings. The two largest published studies used data from the U.K.'s General Practice Research Database (GPRD).
One study compared the rate of esophageal cancer in patients taking an oral bisphosphonate to patients not taking an oral bisphosphonate. This study found no increase in the risk of esophageal cancer.1 Using the same database, a second study found a doubling of the risk of esophageal cancer among patients who had 10 or more prescriptions of oral bisphosphonates, or who had taken the drugs over 3 years.2
Other investigators are researching this issue. In a large cohort of Danish patients with fractures, investigators found that bisphosphonate users (who had taken them for a median of 1.5 years) had a significantly reduced risk for esophageal cancer compared to patients with fractures who had not taken any bisphosphonate.3 Longer term follow-up of alendronate (Fosamax) users and non-alendronate users showed that alendronate users had a higher frequency of endoscopic examination of the esophagus, no greater incidence of esophageal cancer, and no increase in esophageal cancer deaths.5
Differences in methodologies in these studies may account for the discrepant findings. Also, since these studies are observational rather than randomized, they are subject to bias and confounding. For example, it is possible that the gastrointestinal side effects of bisphosphonates increase a patient's likelihood of undergoing an endoscopy, which could lead to earlier detection of a cancer or drug discontinuation. At this time, there is not enough information to make definitive conclusions about a possible association. FDA's safety review is ongoing. Additional studies conducted in different databases may be warranted.
References
- Cardwell CR, Abnet CC, Cantwell MM, Murray LJ. Exposure to oral bisphosphonates and risk of esophageal cancer. JAMA 2010;304:657-63.
- Green J, Czanner G, Reeves G, Watson J, Wise L, Beral V. Oral bisphosphonates and risk of cancer of the oesophagus, stomach, and colorectum: case-control analysis within a UK primary care cohort. BMJ 2010;341:doi:10.1136/bmj.c4444.
- Abrahamsen B, Eiken P, Eastell R. More on reports of esophageal cancer with oral bisphophonate use. N Engl J Med 2009; 360:1789.
- Wysowski DK. Reports of esophageal cancer with oral bisphosphonate use. N Engl J Med 2009;360:89-90.
- Abrahamsen B, et. al. The risk of oesophageal and cancer incidence and mortality in alendronate users: a national cohort study. 3rd Joint Meeting of the European Calcified Tissue Society and the International Bone and Mineral Society, May 2011.
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Revisiting Bone Drugs and Femur Fractures
By JANE E. BRODY
Nearly six years ago in this column, I discussed what was then a little-known problem associated with long-term use of bisphosphonates, the valuable drugs that protect against fractures caused by bone loss. The drugs, among them Fosamax, Actonel and Boniva, can slow bone loss, increase bone density and cut fracture rates in half in women with established osteoporosis.
Reports had begun to emerge that some women taking bisphosphonates for many years suffered an unusual fracture of the femur, the long bone of the thigh. There was little or no trauma; in most cases the women were simply standing or walking when the femur snapped in half. In some, breaks occurred in both thighs, and many of the fractures were unusually slow to heal.
Experts think the fractures happened because of the way the drugs work: by slowing the rate of bone remodeling, the normal process by which injured bone heals. As a result, microfractures that occur through normal wear and tear are not repaired. Although bone density may be normal, the bone can become brittle and crack under minor stress.
In the years since, hundreds of cases of atypical femur fractures have been reported among women and some men taking bisphosphonates for five or more years. A number of studies have tried to assess the risk, and last fall the Food and Drug Administration issued a “safety announcement” and required that the drugs’ labels warn physicians and patients to be alert for this potential complication.
Weighing the Research
But many questions remain, including who is most at risk for femur fractures and whether the risks outweigh the important benefits of taking a bisphosphonate for many years. The latest assessment was published Feb. 23 in The Journal of the American Medical Association by a team of physicians and epidemiologists in Toronto.
The team, led by Laura Y. Park-Wyllie, an epidemiologist who is a doctor of pharmacology at St. Michael’s Hospital, gathered treatment and fracture data among all 205,466 women in Ontario aged 68 or older who had been treated with a bisphosphonate. They identified those who had suffered femur fractures occurring below the hip and above the knee — called subtrochanteric or femoral shaft fractures — and compared each case with those of up to five other women the same age who had been free of this injury.
Those who had taken the drugs for five years or longer were more than twice as likely to have had such a fracture as those who took them only briefly. But because X-rays of the bone were not reviewed, it is not certain that the fractures were linked to the drugs. At the same time, long-term use of bisphosphonates prevented many more fractures than it might have caused; the risk of osteoporotic femur fractures, a far more common injury, was reduced by 25 percent, Dr. Park-Wyllie said in an interview.
“Compared to the number of fractures prevented,” she said, “the actual risk of a subtrochanteric femur fracture is small” — 1 case in 1,000 in the sixth year of therapy and 2.2 cases in 1,000 the seventh year.
A report published last year in The New England Journal of Medicine found no increase in atypical femur fractures, but that study did not include enough patients taking bisphosphonates for many years to produce a reliable result. Preliminary data from a much larger study has indicated that the risk of atypical femur fractures increased from 2 cases a year per 100,000 users after two years of bisphosphonate therapy to 78 cases a year per 100,000 after eight years on the drug.
In a report from a 27-member task force of the American Society for Bone and Mineral Research (published online in September in The Journal of Bone and Mineral Research), the experts noted that the way bisphosphonates work can reduce the “toughness” of bones. “It is highly likely that case reports and case series of atypical femur fractures will continue to accumulate,” the task force wrote, noting that another 47 cases had been reported since their analysis was prepared. Many cases are not reported, and in an unknown number of cases physicians may not recognize the fractures as atypical.
The task force called for an international registry of cases, including details that could help define who is most at risk.
First, an Evaluation
What should patients and doctors do?
“Relative to the millions of fractures that occur every year in the United States, the number of atypical femur fractures should not discourage the use of these effective drugs by patients with osteoporosis who are at high risk of fracture,” a leader of the task force, Dr. Elizabeth Shane, said in an interview. (Dr. Shane is a bone specialist at Columbia University Medical Center.)
Initial excitement about bone-protecting drugs led to prescriptions for millions of women who were not necessarily at high fracture risk, and many experts now urge a thorough evaluation before a bisphosphonate is prescribed. In addition to bone density test results, the evaluation should take into account a patient’s smoking and drinking habits, thinness, family history of osteoporosis, previous osteoporotic fractures, drug prescriptions and weight-bearing exercise regimen. An online evaluation tool developed by the World Health Organization is at www.shef.ac.uk/FRAX, though some experts have criticized it as incomplete.
The task force said a decision to treat should be “based on an assessment of benefits and risks,” and added, “patients who are deemed to be at low risk of osteoporotic-related fractures should not be started on bisphosphonates.”
Even those with osteoporosis in the spine but little or no problem in their hips, the experts concluded, should consider alternative remedies.
While no one knows what the optimal length of drug treatment should be, five years on a bisphosphonate seems to confer an adequate benefit; after that, patients should consider taking a “drug holiday.”
Before resuming therapy, the patient’s risk factors for fracture should be reassessed. The task force noted that half of currently known patients with atypical fractures had been on bisphosphonates for seven years.
Furthermore, in 70 percent of cases, patients reported experiencing pain or discomfort in the thigh or groin for weeks or months before the femur fractured. Anyone on a bone drug who develops such a pain should be carefully evaluated, first with an X-ray and, if nothing is seen but the cause is uncertain, by a bone scan or M.R.I.
When a problem like a defect in the shell of the femur is found and the patient has pain, a fracture is highly likely, Dr. Shane said, and the task force recommended inserting a rod in the bone to keep it from breaking.
Furthermore, Dr. Jennifer Schneider of Tucson, an internist who after seven years on Fosamax suffered a nontraumatic femur fracture that took two years to heal, notes that the damage is often bilateral — so when a problem is found in one leg, the other leg should be thoroughly examined. Among patients in an online support and information group she established, some reported suffering a second atypical fracture in the other thigh.
Dr. Schneider invites patients who have had such a fracture to write to her at [email protected].
Source : The New York Times
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FDA warns of thigh fractures with bone drugs
Osteoporosis drugs used by millions of women to prevent bones from breaking may increase the chances for an unusual type of thigh fracture, U.S. health officials warned on Wednesday.
The drugs known as bisphosphonates include Merck & Co Inc's Fosamax, Roche Holding AG's Boniva, Novartis AG's Reclast and Warner Chilcott Plc's Actonel.
The action could drive patients to Amgen Inc's just-launched rival medicine, Prolia, a different type of osteoporosis drug that is the company's most important future growth driver.
Food and Drug Administration officials said all bisphosphonates used for osteoporosis will carry a new warning about rare but serious fractures of the thigh bone, even though it remains unclear if the medicines caused the fractures.
The agency advised doctors to consider if patients on therapy for more than five years still need the drugs.
The new warning "should not cause patients taking bisphosphonates to be fearful of their medicine," said Dr. Sandra Kweder, deputy director of the FDA's new drugs office.
The drugs "are an important mainstay of osteoporosis management" and "have prevented innumerable fractures in their years of use," Kweder told reporters on a conference call.
More than 5 million U.S. patients filled prescriptions for bisphosphonates in 2009, the FDA said.
Concern about thigh fractures may lead patients to seek alternatives such as Amgen's Prolia, Bernstein & Co analyst Geoff Porges said. A positive impact on Prolia could been seen as early as the fourth quarter, he said.
"Today's label change is likely to raise the level of concern among patients about the safety of bisphosphonates significantly," Porges said in a research note.
Osteoporosis is a progressive bone-thinning condition most common in women after menopause. Actonel and Reclast are injectable. The other drugs are taken orally.
The most common fractures seen with osteoporosis typically occur in the hip, wrist or spine. They can cause pain and require hospitalization or surgery.
A study of hospital discharge data showed hip fractures dropped to 428 from 598 per 100,000 people in the 10 years after approval of the first bisphosphonate in 1996, FDA officials said. No treatment eliminates fracture risk completely.
Thigh fractures also can occur from osteoporosis, but the ones reported in recent years were unusual because they often appeared after little or no trauma and were seen in younger patients, the FDA's Kweder said. In most cases, patients felt a dull, aching pain in the thigh or groin months before a complete fracture.
People with those symptoms should contact a doctor to try and prevent the fracture, FDA officials said. The agency is requiring consumer-friendly guides to be dispensed with bisphosphonates to explain possible risks.
The unusual fractures appeared to account for less than 1 percent of all hip and femur fractures, the FDA said.
Dr. Felicia Cosman, clinical director of the National Osteoporosis Foundation, said there was little evidence bisphosphonates help after five to seven years and that may be the time when thigh fracture rates increase.
"If the safety profile is changing and the efficacy is not clear, then many people should consider having an interruption in continuous use of the drug" after that time, she said.
Merck said Fosamax had not been associated with any increased fracture risk in clinical studies of more than 28,000 patients. Still, the company voluntarily added information about the unusual thigh fractures to the drug's prescribing instructions in July 2009.
Fosamax also is sold as a cheaper generic under the name alendronate.
Roche unit Genentech said it would work with the FDA to provide information to doctors and patients "to make informed decisions."
Merck shares gained 1.4 percent on Wednesday to close at $37.16, while Novartis shares rose 0.4 percent to $59.45, both on the New York Stock Exchange. Warner Chilcott shares rose 4 cents to $25.00 on Nasdaq.
Source : Rueters 13/10/2010
(Reporting by Lisa Richwine and Bill Berkrot; editing by Lisa Von Ahn and Andre Grenon)
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MERCK TO PAY $8M, IN DAMAGES IN FOSAMAX TRIAL
In replay of a courtroom battle that ended in a mistrial last fall, a federal jury today voted unanimously that Merck’s Fosamax osteoporosis drug was responsible for causing jawbone deterioration suffered by a Florida woman, who was awarded $8 million in compensatory damages (here is the lawsuit). Merck, which argued 71-year-old Shirley Boles was at increased risk for dental and jaw problems if she was not taking Fosamax, quickly indicated it would appeal the decision. “We disagree with the jury’s verdict. We believe the jury verdict was a result of the plaintiff’s counsel’s gross mischaracteraization, and inflammatory and prejudicial remarks,” Paul Strain, an attorney representing Merck, tells us. “We believe the court, from his remarks, made it clear he shares those concerns about the improper closing argument by plaintiff’s counsel. That gives us a strong foundation moving forward.”
This was the second bellwether case over whether Merck failed to warn docs and patients that Fosamax may cause osteonecrosis, which is the painful death of jawbone tissue. Merck won the first trial last month (see here). As of March 31, the drugmaker faces 1,039 lawsuits in and federal and state courts that were feild by 1,417 plaintiffs.
Source:pharmalot.com
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FDA Drug Safety Communication: Ongoing safety review of oral bisphosphonates and atypical subtrochanteric femur fractures
Safety Announcement
[03-10-2010] Patients and healthcare professionals may have questions about oral bisphosphonate medications and atypical subtrochanteric femur fractures – fractures in the bone just below the hip joint. Oral bisphosphonates are commonly prescribed to prevent or treat osteoporosis in postmenopausal women. Common brand names of medications in this class include Fosamax, Actonel, Boniva, and Reclast.
Recent news reports have raised the question about whether there is an increased risk of this type of fracture in patients with osteoporosis using these medications. At this point, the data that FDA has reviewed have not shown a clear connection between bisphosphonate use and a risk of atypical subtrochanteric femur fractures. FDA is working closely with outside experts, including members of the recently convened American Society of Bone and Mineral Research Subtrochanteric Femoral Fracture Task Force, to gather additional information that may provide more insight into this issue.
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