visual impairment
Fosamax Adverse Reactions
Adverse effects with oral alendronate during the clinical trials were reported as generally mild and primarily affected the gastrointestinal system. At doses of 10 mg/day in patients with postmenopausal osteoporosis, abdominal pain was the most commonly reported event (6.6% of patients). More specific events reported are nausea/vomiting (3.6%/1%), constipation (3.1%), diarrhea (3.1%), flatulence (2.6%), acid regurgitation (2%) including pyrosis (heartburn), esophageal ulceration (1.5%), dysphagia (1%), abdominal distention (1%), gastritis (0.5%), and dysgeusia (0.5%). With the exception of esophageal ulceration and dysphagia, patients taking placebo also reported similar adverse events. At doses of 10 mg/day in male patients with osteoporosis, reported adverse events were similar to that of patients with postmenopausal osteoporosis, with slightly different rates. The specific events reported in males are acid regurgitation (4.1%) including pyrosis (heartburn), flatulence (4.1%), gastroesophageal reflux disease (GERD) (0.7%), dyspepsia (3.4%), diarrhea (1.4%), abdominal pain (2.1%), and nausea (2.1%). In children with osteogenesis imperfecta treated with alendronate, adverse events reported were similar to those reported in adults taking alendronate for osteoporosis. However, there was an increased incidence of vomiting in children taking alendronate compared to placebo (29.4% for alendronate vs. 10% for placebo). Rarely, esophageal stricture or GI perforation may develop. The incidence of GI effects is increased in patients taking doses >10 mg/day. In post-marketing reports, more than half the women taking alendronate for osteoporosis do not comply with the dosing instructions, which may lead to decreased compliance and effectiveness of the medication and increased adverse reactions. A large number of cases of esophagitis, esophageal erosions, esophageal ulcers, and gastric and duodenal ulcers with GI bleeding have been reported following the approval of alendronate. In a retrospective analysis, one-third of women developed a new upper gastrointestinal disorder leading to poor compliance. During the Fracture Intervention Trial, the incidence of gastrointestinal adverse events was similar between alendronate 5 - 10 mg/day and placebo (47.5% vs. 46.2%). It should be noted that women were counseled every 6 months during the trial on the proper administration of alendronate. Age, history of GI disease, and NSAID use were independent risk factors for upper GI events during this study, as reported in other studies as well. All patients with these risk factors had an increased incidence of adverse GI events; there was no difference between those patients treated with alendronate and those treated with placebo in this study. To reduce the possibility of esophageal side effects, careful adherence to the dosing instructions (e.g., take with a full glass of water immediately upon arising for the day at least 30 minutes before taking food, and remaining upright for at least 30 minutes after administration) is critical. Esophageal and oral ulceration occur more frequently when alendronate tablets are chewed or dissolved in the mouth. The once weekly administration of alendronate has a similar safety and tolerability profile in postmenopausal women, compared to once daily administration. In men, however, the reported events and rates were slightly different for the once weekly dose compared to the once daily dose. The reported adverse events for alendronate 70 mg once weekly in men are GERD (2.8%), dyspepsia (2.8%), diarrhea (2.8%), and abdominal pain (0.9%).
Additional alendronate-related adverse events reported in more than 1% of patients were headache and musculoskeletal pain. Musculoskeletal, or bone pain has been possibly, probably, or definitely linked to alendronate therapy by investigators in approximately 6% of patients taking 40 mg a day for the treatment of Paget’s disease, compared to 2.4% taking placebo. In addition, arthralgia, bone pain, and myalgia have been reported in patients taking bisphosphonates during post-marketing surveillance. The time to onset of symptoms varies from one day to several months after drug initiation. Most patients had relief of symptoms after stopping medication; a subset of patients had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate. Hypersensitivity reactions including urticaria and, rarely, angioedema have been reported.
In controlled studies, asymptomatic mild and transient hypocalcemia was seen in 18% of patients on alendronate therapy compared to 12% taking placebo; there have been reports of symptomatic hypocalcemia with post-marketing use. In controlled studies, hypophosphatemia was seen in 10% of patients on alendronate therapy compared to 3% taking placebo.
Rash (unspecified), occasionally with photosensitivity, pruritus, and erythema have been reported with alendronate therapy. This rash may be made worse by sun exposure. Post-marketing use of alendronate has been associated with reports of Stevens-Johnson Syndrome and toxic epidermal necrolysis.
In studies involving IV alendronate, fever and elevated hepatic enzymes have been reported. Too rapid IV administration may cause nephrotoxicity secondary to calcium bisphosphonate deposition.
While not specifically reported with alendronate, uveitis, nonspecific conjunctivitis, episcleritis, or scleritis have all been reported with pamidronate and these ocular reactions are expected to occur with other bisphosphonates as well. Nonspecific conjunctivitis seldom requires treatment and usually decreases in intensity during subsequent exposure to a bisphosphonate. However, no reported case of unilateral or bilateral scleritis resolved until the bisphosphonate was discontinued. More than one ocular side effect can occur at the same time; for instance, episcleritis may occur in conjunction with uveitis. In some instances, the drug may need to be discontinued in order for the ocular inflammation to resolve; for scleritis to resolve the bisphosphonate must be discontinued. Patients with visual impairment or ocular pain should be referred to an ophthalmologist.
Osteonecrosis of the jaw has been reported in patients receiving bisphosphonate therapy. Although the majority of patients affected receive either pamidronate or zoledronic acid for the management of metastatic cancer to the bone, there have been reports of osteonecrosis in patients receiving oral bisphosphonate therapy for the treatment of osteoporosis. Most of the reported cases have appeared after dental tooth extraction; however, some cases have appeared spontaneously. It is not possible to determine if the reported events are related to bisphosphonates, concomitant drugs or other therapies (e.g., chemotherapy, radiotherapy, corticosteroid), a patient’s underlying disease state, or other comorbid risk factors (e.g., anemia, infection, preexisting oral disease). Typical signs and symptoms of osteonecrosis of the jaw include pain, swelling, infection, or poor healing of the gums, loosening of the teeth, numbness or a feeling of heaviness in the jaw, and drainage of exposed bone. When the osteonecrosis is severe, sections of the jaw may need to be removed. If osteonecrosis of the jaw does develop during bisphosphonate therapy, it should be noted that dental surgery may exacerbate the condition. For patients requiring dental work, no data are available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of osteonecrosis of the jaw. The treating physician and dentist should use their best clinical judgment to guide the management plan of each patient based on individual benefit and risk assessments.
[ Last revised: 3/7/2006 3:05:00 PM ]
References
. Nussbaum SR, Warrell Jr. RP, Rude R, et al. Dose-response study of alendronate sodium for the treatment of cancer-associated hypercalcemia. J Clin Oncol 1993;11:1618 - 23.
. Bauer DC, Black D, Ensrud K , et al. Upper gastrointestinal tract safety profile of alendronate: The Fracture Intervention Trial. Arch Intern Med 2000;160:517 - 525.
. Fraunfelder FW, Fraunfelder FT. Bisphosphonate and ocular inflammation. N Engl J Med 2003;348:1187 - 8.
. Ruggiero SL, Mehrotra B, Rosenberg TJ, et al. Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg 2004;62:527 - 34.
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