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Special Alerts
Bisphosphonates: Possible Association with Severe Musculoskeletal Pain - January 2008
The Food and Drug Administration (FDA) is informing healthcare practitioners of the possible association between bisphosphonate use and the development of severe (possibly incapacitating) bone, muscle, and/or joint pain. The severe musculoskeletal pain may develop days, months, or years after initiating a bisphosphonate. This is a distinct event from the acute phase response (eg, fever, chills, bone pain, myalgia, arthralgia) that may occur following initial bisphosphonate administration which generally resolves within several days of continued use.
Frequency of and contributing risk factors between severe musculoskeletal pain and bisphosphonate use are currently unknown.
Further information is available at http://www.fda.gov/medwatch/safety/2008/safety08.htm#Bisphosphonates
Medication Safety Issues
Sound-alike/look-alike issues:
Fosamax® may be confused with Flomax®
International issues:
Fosamax® may be confused with Fisamox® which is a brand name for amoxicillin in Australia
Pronunciation
(a LEN droe nate)
U.S. Brand Names
Index Terms
Generic Available
Yes: Tablet
Canadian Brand Names
Pharmacologic Category
Use: Labeled Indications
Treatment and prevention of osteoporosis in postmenopausal females; treatment of osteoporosis in males; Paget's disease of the bone in patients who are symptomatic, at risk for future complications, or with alkaline phosphatase ?2 times the upper limit of normal; treatment of glucocorticoid-induced osteoporosis in males and females with low bone mineral density who are receiving a daily dosage ?7.5 mg of prednisone (or equivalent)
Pregnancy Risk Factor
C
Pregnancy Considerations
Safety and efficacy have not been established in pregnant women. Animal studies have shown delays in delivery and fetal/neonatal death (secondary to hypocalcemia). Bisphosphonates are incorporated into the bone matrix and gradually released over time. Theoretically, there may be a risk of fetal harm when pregnancy follows the completion of therapy. Based on limited case reports with pamidronate, serum calcium levels in the newborn may be altered if administered during pregnancy.
Lactation
Excretion in breast milk unknown/use caution
Contraindications
Hypersensitivity to alendronate, other bisphosphonates, or any component of the formulation; hypocalcemia; abnormalities of the esophagus which delay esophageal emptying such as stricture or achalasia; inability to stand or sit upright for at least 30 minutes; oral solution should not be used in patients at risk of aspiration
Warnings/Precautions
Concerns related to adverse effects:
• Bone/joint/muscle pain: Infrequently, severe (and occasionally debilitating) bone, joint, and/or muscle pain have been reported during bisphosphonate treatment. The onset of pain ranged from a single day to several months. Symptoms usually resolve upon discontinuation. Some patients experienced recurrence when rechallenged with same drug or another bisphosphonate; avoid use in patients with a history of these symptoms in association with bisphosphonate therapy.
• Gastrointestinal mucosa irritation: May cause irritation to upper gastrointestinal mucosa. Esophagitis, esophageal ulcers, esophageal erosions, and esophageal stricture (rare) have been reported with oral bisphosphonates; risk increases in patients unable to comply with dosing instructions. Use with caution in patients with dysphagia, esophageal disease, gastritis, duodenitis, or ulcers (may worsen underlying condition).
• Osteonecrosis of the jaw: Bisphosphonate therapy has been associated with osteonecrosis, primarily of the jaw; this has been observed mostly in cancer patients, but also in patients with postmenopausal osteoporosis and other diagnoses. Risk factors include a diagnosis of cancer, with concomitant chemotherapy, radiotherapy, or corticosteroids; anemia, coagulopathy, infection, or pre-existing dental disease. Symptoms included nonhealing extraction socket or an exposed jawbone. There are no data addressing whether discontinuation of therapy reduces the risk of developing osteonecrosis; however, as a precautionary measure, dental exams and preventative dentistry should be performed prior to placing patients with risk factors on chronic bisphosphonate therapy. Invasive dental procedures should be avoided during treatment.
Disease-related concerns:
• Hypocalcemia: Before therapy initiation hypocalcemia must be corrected; ensure adequate calcium and vitamin D intake.
• Renal impairment: Use with caution in patients with renal impairment (not recommended for use in patients with Clcr <35 mL/minute).
Special populations:
• Pediatrics: Safety and efficacy have not been established in children.
Adverse Reactions
Note: Incidence of adverse effects (mostly GI) increases significantly in patients treated for Paget's disease at 40 mg/day.
>10%: Endocrine & metabolic: Hypocalcemia (transient, mild, 18%); hypophosphatemia (transient, mild, 10%)
1% to 10%:
Cardiovascular: Atrial fibrillation (1% to 2%)
Central nervous system: Headache (up to 3%)
Gastrointestinal: Abdominal pain (1% to 7%), acid reflux (1% to 4%), dyspepsia (1% to 4%), nausea (1% to 4%), flatulence (up to 4%), diarrhea (1% to 3%), gastroesophageal reflux disease (1% to 3%), constipation (up to 3%), esophageal ulcer (up to 2%), abdominal distension (up to 1%), gastritis (up to 1%), vomiting (up to 1%), dysphagia (up to 1%), gastric ulcer (1%), melena (1%)
Neuromuscular & skeletal: Musculoskeletal pain (up to 6%), muscle cramps (up to 1%)
<1%, postmarketing, and/or case reports: Anastomotic ulcer, angioedema; bone, muscle, or joint pain (occasionally severe, considered incapacitating in rare cases); dizziness, duodenal ulcer, episcleritis, erythema, esophageal erosions, esophageal perforation, esophageal stricture, esophagitis, fever, flu-like syndrome, hypersensitivity reactions, hypocalcemia (symptomatic), joint swelling, lymphocytopenia, malaise, myalgia, oropharyngeal ulceration, osteonecrosis (jaw), peripheral edema, photosensitivity (rare), pruritus, rash, scleritis (rare), Stevens-Johnson syndrome, taste perversion, toxic epidermal necrolysis, urticaria, uveitis (rare), vertigo, weakness
Drug Interactions
Aminoglycosides: May enhance the hypocalcemic effect of Bisphosphonate Derivatives. Risk C: Monitor therapy
Antacids: May decrease the absorption of Bisphosphonate Derivatives. Antacids containing aluminum, calcium, or magnesium are of specific concern. Exceptions: Magaldrate; Sodium Bicarbonate. Risk D: Consider therapy modification
Aspirin: May enhance the adverse/toxic effect of Alendronate. Specifically gastrointestinal adverse events. Risk C: Monitor therapy
Calcium Salts: May decrease the absorption of Bisphosphonate Derivatives. Risk D: Consider therapy modification
Iron Salts: May decrease the absorption of Bisphosphonate Derivatives. Only oral iron salts are of concern. Exceptions: Ferric Gluconate; Iron Dextran Complex; Iron Sucrose. Risk D: Consider therapy modification
Magnesium Salts: May decrease the absorption of Bisphosphonate Derivatives. Only oral magnesium salts are of concern. Risk D: Consider therapy modification
Nonsteroidal Anti-Inflammatory Agents: May enhance the adverse/toxic effect of Bisphosphonate Derivatives. Both an increased risk of gastrointestinal ulceration and an increased risk of nephrotoxicity are of concern. Risk C: Monitor therapy
Phosphate Supplements: Bisphosphonate Derivatives may enhance the hypocalcemic effect of Phosphate Supplements. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Ethanol: Avoid ethanol (may increase risk of osteoporosis and gastric irritation).
Food: All food and beverages interfere with absorption. Coadministration with caffeine may reduce alendronate efficacy. Coadministration with dairy products may decrease alendronate absorption. Beverages (especially orange juice and coffee) and food may reduce the absorption of alendronate as much as 60%.
Storage
Store tablets and oral solution at room temperature of 15°C to 30°C (59°F to 86°F). Keep in well-closed container.
Mechanism of Action
A bisphosphonate which inhibits bone resorption via actions on osteoclasts or on osteoclast precursors; decreases the rate of bone resorption, leading to an indirect increase in bone mineral density. In Paget's disease, characterized by disordered resorption and formation of bone, inhibition of resorption leads to an indirect decrease in bone formation; but the newly-formed bone has a more normal architecture.
Pharmacodynamics/Kinetics
Distribution: 28 L (exclusive of bone)
Protein binding: ?78%
Metabolism: None
Bioavailability: Fasting: 0.6%; reduced 60% with food or drink
Half-life elimination: Exceeds 10 years
Excretion: Urine; feces (as unabsorbed drug)
Dosage
Oral: Adults: Note: Patients treated with glucocorticoids and those with Paget's disease should receive adequate amounts of calcium and vitamin D.
Osteoporosis in postmenopausal females:
Prophylaxis: 5 mg once daily or 35 mg once weekly
Treatment: 10 mg once daily or 70 mg once weekly
Osteoporosis in males: 10 mg once daily or 70 mg once weekly
Osteoporosis secondary to glucocorticoids in males and females: Treatment: 5 mg once daily; a dose of 10 mg once daily should be used in postmenopausal females who are not receiving estrogen.
Paget's disease of bone in males and females: 40 mg once daily for 6 months
Retreatment: Relapses during the 12 months following therapy occurred in 9% of patients who responded to treatment. Specific retreatment data are not available. Following a 6-month post-treatment evaluation period, retreatment with alendronate may be considered in patients who have relapsed based on increases in serum alkaline phosphatase, which should be measured periodically. Retreatment may also be considered in those who failed to normalize their serum alkaline phosphatase.
Elderly: No dosage adjustment is necessary
Dosage adjustment in renal impairment:
Clcr 35-60 mL/minute: None necessary
Clcr <35 mL/minute: Alendronate is not recommended due to lack of experience
Dosage adjustment in hepatic impairment: None necessary
Administration: Oral
Alendronate must be taken with plain water (tablets 6-8 oz; oral solution follow with 2 oz) first thing in the morning and ?30 minutes before the first food, beverage, or other medication of the day. Do not take with mineral water or with other beverages. Patients should be instructed to stay upright (not to lie down) for at least 30 minutes and until after first food of the day (to reduce esophageal irritation). Patients should receive supplemental calcium and vitamin D if dietary intake is inadequate.
Monitoring Parameters
Alkaline phosphatase should be periodically measured; serum calcium and phosphorus; monitor pain and fracture rate; hormonal status (male and female) prior to therapy; bone mineral density (should be done prior to initiation of therapy and after 6-12 months of combined glucocorticoid and alendronate treatment)
Reference Range
Calcium (total): Adults: 9.0-11.0 mg/dL (2.05-2.54 mmol/L), may slightly decrease with aging; phosphorus: 2.5-4.5 mg/dL (0.81-1.45 mmol/L)
Test Interactions
Bisphosphonates may interfere with diagnostic imaging agents such as technetium-99m-diphosphonate in bone scans.
Dietary Considerations
Ensure adequate calcium and vitamin D intake; however, wait at least 30 minutes after taking alendronate before taking any supplement. Alendronate must be taken with plain water first thing in the morning and at least 30 minutes before the first food or beverage of the day.
Patient Education
Do not take any new medication during therapy unless approved by prescriber. Take as directed, with a full glass of water first thing in the morning and at least 30 minutes before the first food or beverage of the day. Wait at least 30 minutes after taking Alendronate before taking anything else. Stay in sitting or standing position for 30 minutes following administration and until after the first food of the day to reduce potential for esophageal irritation. Consult prescriber to determine necessity of lifestyle changes (eg, decreased smoking, decreased alcohol intake, dietary supplements of calcium or vitamin D). May cause flatulence, bloating, nausea, or acid regurgitation; small, frequent meals may help. Bone, joint, and/or muscle pain have been reported, especially at the beginning of treatment; report persistent pain to prescriber. Report acute headache or gastric pain, unresolved GI upset, or acid stomach. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Consult prescriber if breast-feeding.
Geriatric Considerations
Since many elderly patients receive diuretics, evaluation of electrolyte status (calcium, phosphate, magnesium, potassium) may need to be done periodically due to the drug class (bisphosphonate).
Dental Health: Effects on Dental Treatment
Osteonecrosis of the jaw (ONJ), generally associated with local infection and/or tooth extraction and often with delayed healing, has been reported in patients taking bisphosphonates. Symptoms included nonhealing extraction socket or an exposed jawbone. Most reported cases of bisphosphonate-associated osteonecrosis have been in cancer patients treated with intravenous bisphosphonates. However, some have occurred in patients with postmenopausal osteoporosis taking oral bisphosphonates. Dental surgery may exacerbate ONJ. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of ONJ. Patients who develop ONJ while on bisphosphonate therapy should receive care by an oral surgeon. See Dental Comment.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Dental Comment
A report by the Council of Scientific Affairs of the American Dental Association (accessed at: http://www.ada.org/prof/resources/topics/osteonecrosis.asp) as of July 2006 gave an estimated incidence of 0.7 cases for every 100,000 person-years of exposure to alendronate (Fosamax®). This translates to one case for every 142,857 person-years exposure. This figure from the ADA report was based on information received from Merck & Co citing 170 worldwide cases for alendronate (Fosamax®). In addition, Procter & Gamble Pharmaceuticals has cited 20 cases for risedronate (Actonel®) and Roche Laboratories has cited one case for ibandronate (Boniva®).
Consumer Reports On Health stated that the risk of jaw bone osteoporosis due to alendronate (Fosamax®), risedronate (Actonel®), or ibandronate (Boniva®) taken to prevent osteoporosis is very low and is estimated to be one out of every 20,000 users. That report mentioned that tooth extraction or implants increase the risk of developing osteonecrosis in patients taking any of these drugs for osteoporosis. The report also recommended that patients should stop taking any of these oral drugs 1-2 months before and after such dental treatment. No evidence was presented to support this statement.
In terms of length of exposure to oral bisphosphonates prior to onset of ONJ, data from large population studies or controlled studies is lacking. A report by Marx et al, observed that of three cases of ONJ associated with Fosamax® exposure, one patient had been taking 10 mg/day by mouth for 6 years and the other two patients 10 mg/day by mouth for 3 and 2 years respectively. In contrast, they observed that in cancer patients receiving intravenous bisphosphonates, the time period between the first doses of the bisphosphonate to first recognition of exposed bone either by the patients or by the clinician, was 9.4 months for zoledronate (Zometa®), 14.3 months for pamidronate (Aredia®), and 12.1 months for pamidronate then to zoledronate.
Information on Fosamax® use in Australia and the incidence of ONJ has been reported. A survey form was sent to all of the Australian members of the Australian and New Zealand Association of Oral and Maxillofacial Surgeons requesting cases that they had identified as ONJ in 2004 and 2005. The definition of ONJ for the survey was an area of exposed bone in the jawbones that failed to heal within 6 weeks in patients taking bisphosphonates for bone disease. The frequency of ONJ in osteoporotic patients mainly on weekly oral alendronate was 1 in 8470 to 1 in 2260 (0.01% to 0.04%) patients. If extractions were carried out, the calculated frequency was 1 in 1130 to 1 in 296 (0.09% to 0.34%) patients. The minimum values in these cases were determined from the survey whereas the maximum values were obtained from the extrapolation to the entire Australia of the South Australian survey data. The median time to onset of ONJ in alendronate patients was 24 months.
A study from a Harvard group, shows that there may be a decrease in the incidence of ONJ in Fosamax® users compared to the normal population, and adds new data to the concerns about the Fosamax® user and the risk of developing ONJ. This new study used medical claims data from 714,217 people with osteoporosis or cancer to identify diagnostic codes or procedural codes for inflammatory conditions of the jaw, including osteonecrosis. Oral administration of bisphosphonates (BPs) decreased the risk of inflammatory conditions of the jaw. At the same time, intravenous administration significantly increased the risk of adverse jaw outcomes. While the data from the oral BPs counters previous reports, the intravenous BP data were consistent with reports showing the increased risk of ONJ after intravenous BP use in cancer patients.
The study, published in the Journal of the American Dental Association (Cartsos, 2008), collected data from the medical claims for inflammatory condition of the jaw (defined by the study authors as osteonecrosis of the jaw bone), from 2000-2006. There were 150 claims per 176,889 patients taking oral BPs, giving a ratio of 0.85 claims per 1000 individuals. Among patients with no BP association, there were more claims (339 claims per 263,352 patients) giving a ration of 1.3 claims per 1000 individuals. When statistics were used to calculate significance with a 95% confidence level, there was a definite decrease in the incidence of jaw bone adverse effects in the population taking oral BPs compared with those patients who did not take oral BPS.
Mental Health: Effects on Mental Status
None reported
Mental Health: Effects on Psychiatric Treatment
None reported
Nursing: Physical Assessment/Monitoring
Assess history for any previous adverse response to bisphosphonates and ability to comply with administration instructions. Use caution with renal impairment. Correct any hypocalcemia prior to beginning treatment. Patients at risk for osteonecrosis (eg, chemotherapy, corticosteroids, poor oral hygiene) should have dental exams and necessary preventive dentistry should be done before beginning bisphosphonate therapy. Assess results of periodic laboratory tests, therapeutic effectiveness (eg, pain, fracture rate, bone density), and adverse reactions (eg, immediate or long-term musculoskeletal pain). Teach appropriate use and specific administration directions, lifestyle and dietary changes that will have a beneficial impact on Paget's disease or osteoporosis, possible side effects/appropriate interventions, and adverse symptoms to report.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, oral:
Fosamax®: 70 mg/75 mL [contains parabens; raspberry flavor]
Tablet: 5 mg, 10 mg, 35 mg, 40 mg, 70 mg
Fosamax®: 5 mg, 10 mg, 35 mg, 40 mg, 70 mg
Pricing: U.S. (www.drugstore.com)
Solution (Fosamax)
70 mg/75 mL (75): $30.99
Tablets (Alendronate Sodium)
5 mg (100): $255.98
10 mg (100): $234.99
35 mg (4): $49.99
70 mg (4): $32.99
Tablets (Fosamax)
5 mg (30): $85.99
10 mg (30): $88.99
35 mg (4): $81.99
70 mg (4): $83.99
References
Author Unknown, “Safety Update: Bone-Building Drugs: Risks Explained,” Consum Rep Health, 2006, 18(5):3.
Cartsos VM, Zhu S, and Zavras AI, “Bisphosphonate Use and the Risk of Adverse Jaw Outcomes: A Medical Claims Study of 714,217 People,” J Am Dent Assoc, 2008, 139(1):23-30.
Chesnut CH 3rd, McClung MR, Ensrud KE, et al, “Alendronate Treatment of the Postmenopausal Osteoporatic Woman: Effect of Multiple Dosages on Bone Mass and Bone Remodeling,” Am J Med, 1995, 99(2):144-52.
French AE, Kaplan N, Lishner M, et al, “Taking Bisphosphonates During Pregnancy,” Can Fam Physician, 2003, 49:1281-2.
Orwoll E, Ettinger M, Weiss S, et al, “Alendronate for the Treatment of Osteoporosis in Men,” N Engl J Med, 2000, 343(9):604-10.
Marx RE, Sawatari Y, Fortin M, et al, “Bisphosphonate-Induced Exposed Bone (Osteonecrosis/Osteopetrosis) of the Jaws: Risk Factors, Recognition, Prevention, and Treatment,” J Oral Maxillofac Surg, 2005, 63(11):1567-75.
Mavrokokki T, Cheng A, Stein B, et al, “Nature and Frequency of Bisphosphonate-Associated Osteonecrosis of the Jaws in Australia,” J Oral Maxillofac Surg, 2007, 65(3):415-23.
Watts NB, “Treatment of Osteoporosis With Bisphosphonates,” Rheum Dis Clin North Am, 1994, 20(3):717-34.
International Brand Names
Lexi-Comp.com
Last full review/revision August 2008
Content last modified August 2008
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