[Posted 07/21/2011] ISSUE: FDA notified healthcare professionals and patients about its ongoing review of data from published studies to evaluate whether use of oral bisphosphonate drugs is associated with an increased risk of cancer of the esophagus. FDA has not concluded that taking an oral bisphosphonate drug increases the risk of esophageal cancer. There are insufficient data to recommend endoscopic screening of asymptomatic patients. 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.
BACKGROUND: Oral bisphosphonates are commonly used for the prevention and treatment of osteoporosis as well as to treat other bone diseases such as Paget’s disease. There have been conflicting findings from studies evaluating the risk of esophageal cancer. Esophagitis and other esophageal events have been reported, particularly in patients who do not follow the specific directions for use of oral bisphosphonates. See the Data Summary in the Drug Safety Communication for additional details at: [Web].
RECOMMENDATION: Patients should talk with their healthcare professional about the benefits and risks of taking oral bisphosphonates and how long they should expect to take them. Patients should talk with their healthcare professional if they develop swallowing difficulties, chest pain, new or worsening heartburn, or have trouble or pain when swallowing. Patients should be instructed to carefully follow the directions for use of the oral bisphosphonate drug they are prescribed. For more information visit the FDA website at: [Web] and [Web].
[Posted 10/13/2010] ISSUE: FDA is updating the public regarding information previously communicated describing the risk of atypical fractures of the thigh, known as subtrochanteric and diaphyseal femur fractures, in patients who take bisphosphonates for osteoporosis. This information will be added to the Warnings and Precautions section of the labels approved to treat osteoporosis, including alendronate (Fosamax), alendronate with cholecalciferol (Fosamax Plus D), risedronate (Actonel and Atelvia), risedronate with calcium carbonate (Actonel with Calcium), ibandronate (Boniva), tiludronate (Skelid), and zoledronic acid (Reclast) and their generic products. A Medication Guide will also be required to be given to patients when they pick up their bisphosphonate prescription.
BACKGROUND: Atypical subtrochanteric femur fractures are fractures in the bone just below the hip joint. Diaphyseal femur fractures occur in the long part of the thigh bone. These fractures are very uncommon and appear to account for less than 1% of all hip and femur fractures overall. Although it is not clear if bisphosphonates are the cause, these unusual femur fractures have been predominantly reported in patients taking bisphosphonates.
RECOMMENDATIONS: Patients should continue to take their medication unless told to stop by their healthcare professional. FDA recommends that healthcare professionals should discontinue potent antiresorptive medications (including bisphosphonates) in patients who have evidence of a femoral shaft fracture. For more information visit the FDA website at: [Web] and [Web].
[Posted 03/11/2010] FDA notified healthcare professionals and patients that 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 with outside experts, including members of the recently convened American Society of Bone and Mineral Research Subtrochanteric Femoral Fracture Task Force, to gather more information and evaluate the issue further.
FDA recommends that healthcare professionals follow the recommendations in the drug label when prescribing oral bisphosphonates.
Patients should continue taking oral bisphosphonates unless told by their healthcare professional to stop. Patients should talk to their healthcare professional if they develop new hip or thigh pain or have any concerns with their medications. For more information visit the FDA website at: [Web] and [Web].
[Posted 11/12/2008] FDA issued an update to the Agency’s review of safety data regarding the potential increased risk of atrial fibrillation in patients treated with a bisphosphonate drug. Bisphosphonates are a class of drugs used primarily to increase bone mass and reduce the risk for fracture in patients with osteoporosis, slow bone turnover in patients with Paget’s disease of the bone, and to treat bone metastases and lower elevated levels of blood calcium in patients with cancer. FDA reviewed data on 19,687 bisphosphonate-treated patients and 18,358 placebo-treated patients who were followed for 6 months to 3 years. The occurrence of atrial fibrillation was rare within each study, with most studies containing 2 or fewer events. Across all studies, no clear association between overall bisphosphonate exposure and the rate of serious or non-serious atrial fibrillation was observed. Additionally, increasing dose or duration of bisphosphonate therapy was not associated with an increase rate of atrial fibrillation. Healthcare professionals should not alter their prescribing patterns for bisphosphonates and patients should not stop taking their bisphosphonate medication. For more information visit the FDA website at: [Web], and [Web].
[Posted 01/07/2008] FDA informed healthcare professionals and patients of the possibility of severe and sometimes incapacitating bone, joint, and/or muscle (musculoskeletal) pain in patients taking bisphosphonates. Although severe musculoskeletal pain is included in the prescribing information for all bisphosphonates, the association between bisphosphonates and severe musculoskeletal pain may be overlooked by healthcare professionals, delaying diagnosis, prolonging pain and/or impairment, and necessitating the use of analgesics. The severe musculoskeletal pain may occur within days, months, or years after starting a bisphosphonates. Some patients have reported complete relief of symptoms after discontinuing the bisphosphonate, whereas others have reported slow or incomplete resolution. The risk factors for and incidence of severe musculoskeletal pain associated with bisphosphonates are unknown.
Healthcare professionals should consider whether bisphosphonate use might be responsible for severe musculoskeletal pain in patients who present with these symptoms and consider temporary or permanent discontinuation of the drug. For more information visit the FDA website at: [Web] and [Web].
[Posted 10/01/2007] FDA issued an early communication about the ongoing review of new safety data regarding the association of atrial fibrillation with the use of bisphosphonates. Bisphosphonates are a class of drugs used primarily to increase bone mass and reduce the risk for fracture in patients with osteoporosis, slow bone turnover in patients with Paget’s disease of the bone, treat bone metastases, and lower elevated levels of blood calcium in patients with cancer.
FDA reviewed spontaneous postmarketing reports of atrial fibrillation reported in association with oral and intravenous bisphosphonates and did not identify a population of bisphosphonate users at increased risk of atrial fibrillation. In addition, as part of the data review for the recent approval of once-yearly Reclast for the treatment of postmenopausal osteoporosis, FDA evaluated the possible association between atrial fibrillation and the use of Reclast (zoledronic acid). Most cases of atrial fibrillation occurred more than a month after drug infusion. Also, in a subset of patients monitored by electrocardiogram up to the 11th day following infusion, there was no significant difference in the prevalence of atrial fibrillation between patients who received Reclast and patients who received placebo.
Upon initial review, it is unclear how these data on serious atrial fibrillation should be interpreted. Therefore, FDA does not believe that healthcare providers or patients should change either their prescribing practices or their use of bisphosphonates at this time. For more information visit the FDA website at: [Web] and [Web].
REMS:
FDA approved a REMS for risedronate to ensure that the benefits of a drug outweigh the risks. However, FDA later rescinded REMS requirements. See the FDA REMS page ([Web]) or the ASHP REMS Resource Center ([Web]).
Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.
Osteoporosis
Prevention of osteoporosis in postmenopausal women with risk factors for development of osteoporosis. Risk factors include premature ovarian failure; family history of osteoporosis; a small, slim body frame; cigarette smoking; excessive alcohol use; low dietary calcium intake; sedentary lifestyle; or Caucasian or Asian race.
Treatment of osteoporosis in postmenopausal women.
Prevention of corticosteroid-induced osteoporosis in patients initiating therapy with corticosteroids (daily dosage ≥7.5 mg of prednisone).
Treatment of corticosteroid-induced osteoporosis in patients receiving corticosteroids (daily dosage ≥7.5 mg of prednisone).
American College of Rheumatology considers patients receiving ≥5 mg of prednisone daily for ≥3 months at risk for bone loss. Recommends bisphosphonate therapy for all long-term corticosteroid-treated men, premenopausal women (with caution), and postmenopausal women with or without hormone replacement therapy (combined estrogen and progestin therapy).
Paget’s Disease of Bone
Treatment of Paget's disease of bone (osteitis deformans) in patients with serum alkaline phosphatase concentrations at least twice ULN or who are symptomatic or at risk for future complications.
Dosage and Administration
General
Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.
Use adjunctively with other measures (e.g., weight-bearing exercise, reduction in smoking and alcohol use) to retard further bone loss.
Supplemental calcium and vitamin D recommended if daily dietary intake is inadequate, particularly in patients with Paget’s disease of bone or receiving corticosteroids.
Administration
Administer orally with a full glass (180–240 mL) of plain water at least 30 minutes before the first food or beverage of the day.
Administer in an upright position (sitting or standing). Avoid lying down for at least 30 minutes following administration. (See GI Effects under Cautions.)
Do not suck or chew tablets; potential for oropharyngeal irritation. (See GI Effects under Cautions.)
Do not administer at the same time as other beverages, foods, or mineral supplements containing calcium, aluminum, or magnesium. (See Antacids or Mineral Supplements Containing Divalent Cations under Interactions.)
If a weekly dose is missed, administer the missed dose the morning after it is remembered, followed by resumption of the regular weekly schedule. Do not take 2 risedronate sodium 35-mg tablets on the same day.
Dosage
Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.
Available as risedronate sodium; dosage expressed in terms of the salt.
Continue risedronate as long as patient continues to receive corticosteroid therapy.
Paget’s Disease of Bone
Oral
30 mg once daily for 2 months.
Consider retreatment (same dosage and duration) after a 2-month posttreatment evaluation period if relapse occurs or if initial treatment failed to normalize serum alkaline phosphatase concentrations.
Prescribing Limits
Adults
Paget’s Disease of Bone
Oral
Safety and efficacy not established for >1 course of retreatment.
Special Populations
Hepatic Impairment
Dosage adjustments are not necessary.
Renal Impairment
Dosage adjustments are not necessary in patients with mild to moderate impairment (Clcr ≥30 mL/minute). Use is not recommended in patients with severe impairment (Clcr <30 mL/minute).
Inability to stand or sit upright for at least 30 minutes.
Warnings/Precautions
Warnings
Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.
GI Effects
Possible dysphagia, esophagitis, or esophageal or gastric ulcer. (See Administration under Dosage and Administration.)
General Precautions
Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.
Metabolic Effects
Possible asymptomatic decreases in serum calcium and phosphorus concentrations.
Correct hypocalcemia and other disturbances of bone and mineral metabolism before initiating therapy. If daily dietary intake is inadequate, administer supplemental calcium and vitamin D.
Endocrine Effects
Before initiating therapy in patients receiving long-term corticosteroid therapy, measure sex hormones and consider replacement therapy, if appropriate.
Specific Populations
Pregnancy
Category C.
Lactation
Distributed into milk in rats. Discontinue nursing or the drug.
Pediatric Use
Safety and efficacy not established.
Geriatric Use
No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.
Men
Safety and efficacy not established for treatment of osteoporosis unrelated to corticosteroid use.
Hepatic Impairment
Safety and efficacy not established.
Renal Impairment
Decreased clearance; use not recommended in patients with severe renal impairment (Clcr <30 mL/minute). (See Renal Impairment under Dosage and Administration.)
Reduction of bone turnover evident within 14 days of beginning therapy; maximal effects observed in about 6 months.
Food
When administered 30 minutes or 1 hour prior to breakfast, the extent of absorption is reduced by 55 or 30%, respectively, compared to the fasting state. However, drug is effective when administered at least 30 minutes before breakfast.
Distribution
Extent
Mean steady-state volume of distribution is 6.3 L/kg. In animal studies, 60% of a dose distributed into bone.
Animal data indicate that the drug crosses placenta and is distributed into fetal bones.
Distributed into milk in animals. Not known whether the drug is distributed into human milk.
Plasma Protein Binding
About 24%.
Elimination
Metabolism
There is no evidence of systemic metabolism.
Elimination Route
Eliminated mainly in urine; only unabsorbed drug is excreted in feces.
Half-life
Initial half-life is about 1.5 hours and terminal exponential half-life is 480 hours. The terminal half-life is thought to represent the dissociation of the drug from the surface of bone.
Special Populations
Renal clearance is decreased by 70% in patients with severe renal impairment (i.e., Clcr <30 mL/minute).
Stability
Storage
Oral
Tablets
20–25 °C.
Actions
Inhibits osteoclast-mediated bone resorption.
Maintains or increases bone mineral density.
Advice to Patients
Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.
Importance of providing a copy of the manufacturer’s patient information.
Importance of proper administration (e.g., avoiding foods and beverages other than plain water, not lying down for 30 minutes following administration).
Importance of swallowing tablets whole, without crushing, chewing, or sucking.
Importance of discontinuing and informing clinician if symptoms of esophageal disease (e.g., difficulty or pain on swallowing; retrosternal, abdominal, or esophageal pain; severe or persistent heartburn) develop.
Importance of adhering to recommended life-style modifications (e.g., weight-bearing exercise, calcium and vitamin D consumption, avoidance of excessive cigarette smoking and/or alcohol consumption).
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.
Importance of informing clinicians of severe kidney disease.
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.
Importance of advising patients of other important precautionary information. (See Cautions.)
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 09/2009. For the most current and up-to-date pricing information, please visit www.drugstore.com. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.
Remember, keep this and all other medicines out of the reach of children,
never share your medicines with others, and use this medication only for the indication prescribed.
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