Alendronate is an oral second-generation bisphosphonate; weekly or daily regimens are available for selected conditions. Treatment with alendronate is associated with significant increases in bone mineral density (BMD) and reduces the risk for radiographic vertebral and non-vertebral fractures (e.g., hip fractures) in postmenopausal women. Bisphosphonates such as alendronate are generally considered to be first-line therapy for the treatment of osteoporosis in postmenopausal women. Bisphosphonates are effective in men with osteoporosis to increase bone density and reduce the risk for vertebral fracture; however, study data are less robust in men regarding reductions in nonvertebral fracture. For osteoporosis prevention, the second and third-generation bisphosphonates appear to offer similar benefits across the class to increase bone mineral density; the balance of costs, benefits, and harms of treating osteopenic patients with bisphosphonates is most favorable when the estimated risk for fracture is high. Alendronate is also effective and indicated for osteoporosis in patients receiving chronic corticosteroid treatment. Alendronate also treats Paget's disease; guidelines for Paget's disease include alendronate as an alternative to zoledronic acid for these patients, as alendronate is known to stabilize osteolytic lesions; however, the effect of alendronate may not be as durable as with zoledronic acid and retreatment may be required between 2 and 6 years. As with other bisphosphonates, alendronate has been investigated for hypercalcemia of malignancy and for adjuvant therapy in selected cancer patients to reduce the risk of osteopenia and related skeletal events; more study is needed.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
-Administer after the patient has risen for the day. The patient should be sitting or standing. Do not administer alendronate to the patient while the patient is lying down.
-Administer with plain water only and at least 30 minutes before the first food, beverage, or other medications of the day. At least 30 minutes should elapse after an alendronate dose before taking any other drugs.
-To avoid esophageal irritation, the patient should not lie down for at least 30 minutes after the dose and until after their first food of the day. Do not administer at bedtime or before the patient has risen for the day.
-Missed dose of a daily regimen: Instruct the patient not to take a dose later in the day. Instruct the patient to skip the missed dose and to return to the usual schedule the next morning. They should not take 2 doses on the same day.
-Missed doses of a once-weekly dose regimen: If a once-weekly dose is missed, instruct the patient to take the dose on the morning after they remember. They should not take 2 doses on the same day but should return to taking 1 dose once a week, as originally scheduled on their chosen day.
-Ensure adequate intake of calcium and vitamin D to reduce the risk of treatment-related hypocalcemia.
Oral Solid Formulations
Tablets:
-Administer in the morning with a full glass of plain water (180 to 240 mL or 6 to 8 ounces).
Oral Liquid Formulations
Oral Solution:
-Use an oral syringe or other calibrated device for accurate dosage.
-Administer in the morning with at least 60 mL (2 ounces) of water.
Effervescent tablets for oral solution:
-Do not have patient swallow the undissolved effervescent tablet; do not chew or allow the tablet to dissolve in the mouth due to the risk of oropharyngeal irritation.
-Dissolve 1 tablet in 120 mL (4 ounces) of plain, unflavored, room temperature water only.
-After completion of the effervescence, wait at least 5 minutes and then stir the solution for approximately 10 seconds and have the patient ingest.
Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
NOTE: Alendronate is not approved by the FDA for intravenous administration. An intravenous product is not available in the U.S.
-Dilute dose in 250 mL or 500 mL 0.9% Sodium Chloride Injection.
-Do not mix with any other drug products.
-An IV infusion time of 2 to 6 hours has been recommended.
In studies involving IV alendronate , elevated body temperature and elevated hepatic enzymes have been reported. Too rapid IV administration may cause nephrotoxicity secondary to calcium bisphosphonate deposition.
Conflicting data exists regarding the use of bisphosphonates and an increased risk of serious atrial fibrillation. Atrial fibrillation is not specifically reported in pre-marketing study of alendronate. In the HORIZON Pivotal Fracture Trial, the incidence of serious atrial fibrillation (life-threatening or resulting in hospitalization or disability) was significantly higher in patients receiving zoledronic acid than placebo (50 patients or 1.3% versus 20 patients or 0.5%, p value < 0.001), although the incidence of any atrial fibrillation (serious and non-serious) was not different between the 2 groups. Similarly, in a re-analysis of the Fracture Intervention Trial, patients taking alendronate also experienced a trend towards a higher incidence of serious atrial fibrillation versus those taking placebo (47 patients or 1.5% vs. 31 patients or 1%, HR 1.51, 95% CI 0.97-2.40, p=0.07). Similar to the HORIZON trial, any atrial fibrillation was not higher in patients taking alendronate. Post-marketing surveillance of reports of atrial fibrillation in patients receiving oral and intravenous bisphosphonates has not revealed a subset of patients at risk for the adverse effect. In the majority of cases in patients who received zoledronic acid, atrial fibrillation occurred more than 1 month after drug infusion. In order to review the potential risk of atrial fibrillation in patients receiving bisphosphonates, the FDA requested placebo-controlled clinical trial data from manufacturers. Information submitted to the FDA by the 4 manufacturers included data from 19,687 bisphosphonate-treated patients and 18,358 placebo-treated patients who were followed up for 6 months-3 years. After reviewing these data, the FDA concluded that most studies contained 2 or fewer events of atrial fibrillation. The absolute difference in event rates between each of the bisphosphonate and placebo arms varied from 0-3 per 1,000. No association between bisphosphonate exposure and the rate of serious or non-serious atrial fibrillation was found. In addition, an increase in dose or duration of bisphosphonate therapy did not correlate with an increased rate of atrial fibrillation. Because of the conflicting data in the literature, the FDA is exploring the feasibility of conducting additional epidemiologic studies to gather more data. The FDA continues to monitor post-marketing reports of atrial fibrillation in patients who have taken bisphosphonates. Currently, the FDA does not recommend a change in prescribing practices for this class of drugs; a causal relationship has not been identified.
Adverse effects associated with alendronate during the clinical trials were reported as generally mild and primarily affected the gastrointestinal system. Careful instruction on administration by health care providers and adherence by patients may minimize risk. Abdominal pain was usually the most commonly reported event (0.9% to 6.6%). The following were also reported: nausea (0 to 3.6%), constipation (0 to 3.1%), diarrhea (0 to 3.1%), dyspepsia (1.1% to 3.6%), flatulence (0 to 4.1%), acid regurgitation (0 to 4.2%) including pyrosis (heartburn), esophageal ulceration (0.1 to 1.5%), gastric or peptic ulcer (0 to 1.1%), dysphagia (0.1% to 1%), abdominal distention (0 to 1.4%), gastritis (0.2% to 1.1%), and taste perversion or dysgeusia (0.1% to 0.5%). With the exception of esophageal ulceration and dysphagia, patients taking placebo also reported similar adverse events. Vomiting (0.2% to 1% of adults) was reported more frequently in children in a 24-month treatment period for osteogenesis imperfecta; 32 of 109 (29.4%) children experienced vomiting compared to 3 of 30 (10%) who received placebo. Effects unique to one study population include gastroesophageal reflux disease (GERD) (0.7% to 2.8%) in osteoporosis studies in men and melena (0 to 1.3%) in glucocorticoid-induced-osteoporosis patients. Other reported adverse events were similar between alendronate-treated postmenopausal women, men with osteoporosis, and glucocorticoid-induced-osteoporosis patients, with slightly different rates. Patients with Paget's disease taking 40 mg/day appeared to have an increased incidence of upper GI adverse effects compared to post-menopausal osteoporosis patients receiving 10 mg/day. The following additional adverse GI effects have been reported during post-marketing experience: esophagitis, esophageal erosions, esophageal ulcers, and gastric and duodenal ulcers with GI bleeding, esophageal stricture, GI perforation, and oropharyngeal or oral ulceration. Esophageal and oral ulceration occur more frequently when alendronate tablets are chewed or dissolved in the mouth. 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. 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.
Headache was reported in 0 to 2.6% of patients taking alendronate during clinical trials. An acute-phase response has been associated with initiation of bisphosphonate therapy, including alendronate. When this reaction occurs in adults (incidence unreported) it usually consists of asthenia, malaise, muscle pain, and rarely fever. In a single dose pharmacokinetic study of pediatric patients with osteogenesis imperfecta, fever, flu-like symptoms, and/or mild lymphopenia were reported within 24 to 48 hours of dose receipt in 6 of the 24 children (i.e., 25%); these effects had a 2 to 3 day duration and responded to acetaminophen. Dizziness, vertigo, and peripheral edema have also been reported in clinical practice with adult patients.
Musculoskeletal pain of the bone, muscle, or joint has been reported in 0.4% to 6% of patients receiving alendronate in clinical trials, the highest incidence among those treated for Paget's disease. Muscle cramps have been reported in 0 to 1.1% of study patients. In addition, bone pain, arthralgia, joint swelling, and myalgia have been reported in patients taking alendronate during post-marketing surveillance. The bone, muscle, and/or joint pain can sometimes be severe and even incapacitating. Pain, particularly dull or achy pain, of the thigh or groin may occur as a prodrome to atypical fracture of the femur; evaluation to rule out incomplete fracture is strongly recommended. The time to onset of musculoskeletal pain symptoms varies from one day to years after drug initiation. Most patients have relief of symptoms after stopping the medication; a subset of patients have had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate. Risk factors for and the incidence of bone, muscle, and/or joint pain are not known. This reaction is different than the acute phase reaction of fever, chills, and bone, muscle, and/or joint pain that accompanies intermittent intravenous or weekly or monthly oral bisphosphonates. The acute phase reaction tends to resolve with continued use. Bisphosphonates should be considered as a cause for any patient who presents with severe musculoskeletal or joint pain; furthermore, if alendronate is determined to be the cause, temporary or permanent discontinuation in drug therapy should be considered.
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.
Hypersensitivity reactions including urticaria, angioedema, and acute asthma exacerbations have been reported in post-marketing experience with alendronate. Other reported reactions include pruritus, erythema, alopecia and rash (unspecified) occasionally with photosensitivity. Post-marketing use of alendronate has been associated with reports of Stevens-Johnson Syndrome and toxic epidermal necrolysis.
Certain ocular reactions are expected to occur with bisphosphonates. There have been post-marketing reports of uveitis, scleritis, and episcleritis with alendronate. Uveitis, nonspecific conjunctivitis, episcleritis, or scleritis have all been reported with pamidronate and 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, including in postmarketing experience of alendronate. 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). The risk may increase with duration of exposure to the bisphosphonate. 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. 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. Based on a review of the available literature, treatments that have been used include local debridement, bone resection or other surgery, antimicrobials, antiseptic mouthwash, and hyperbaric oxygen. While a consensus on the best treatment strategies does not exist, the American Academy of Oral Medicine recommends prevention. Preventive measure include evaluation by a dentist prior to intravenous bisphosphonate initiation and within 3 months of oral bisphosphonate initiation, correction of dental complications prior to drug initiation, and continued regular follow-up with a dentist. For the treatment of osteonecrosis, recommendations include superficial debridement, bone resection when indicated, systemic antimicrobial for infections with culture-directed therapy or penicillin, amoxicillin, or clindamycin empirically, or use of chlorhexidine mouthwash 3 to 4 times daily. Discontinuation of the bisphosphonate once osteonecrosis occurs is controversial as the half-life of bisphosphonates within the bone is estimated to be years. In addition, cholesteatoma of the external auditory canal (a type of focal osteonecrosis) has been reported with the postmarketing use.
In October 2010, the FDA issued a safety communication warning of atypical bone fractures of the femur in patients receiving long-term bisphosphonate therapy for osteoporosis, including alendronate. Definitive risk is not known, but most atypical fractures have been reported in patients taking long-term bisphosphonates. The FDA encourages patients to continue bisphosphonate therapy as directed, and encourages clinicians to periodically reevaluate the need for continued therapy. If an atypical fracture occurs, discontinue the anti-resorptive agent. Advise patients to report new onset of groin or thigh pain, and evaluate the patient to rule out femoral fracture. Of note, this warning does not apply to those bisphosphonates used to treat Paget's disease or hypercalcemia of malignancy. Unlike most hip fractures, which usually occur at the femoral neck and/or in the intertrochanteric regions of the femur, these atypical femoral fractures occur in the subtrochanteric and/or proximal diaphyseal region of the femur; further, the atypical fractures are characterized as simple transverse or short oblique fractures within hypertrophied cortices, and are sustained with little to no trauma and without comminution. The estimated incidence of subtrochanteric fractures has increased since the introduction of bisphosphonates and yet constitutes less than 1% of all hip and femur fractures in the United States. Other co-morbid conditions associated with the development of atypical femoral fracture include: use of other anti-resorptive agents, glucocorticoid or proton pump inhibitor use, diabetes mellitus, rheumatoid arthritis, and vitamin D-deficiency. The manufacturer states that the optimal duration of treatment for osteoporosis is unknown and suggests that patients at low-risk for fracture be considered for drug discontinuation after 3-5 year of therapy. Continue to periodically re-evaluate for fracture risk after discontinuation of therapy.
A history of GI disease is an independent risk factor for the development of GI adverse reactions during alendronate therapy. Severe reactions requiring hospitalization have occurred. Alendronate should be used with caution in patients with esophageal and GI disease, including dysphagia, esophagitis, gastritis, gastroesophageal reflux disease (GERD), hiatal hernia, duodenitis, ulcers, or GI perforation. Alendronate is contraindicated in patients with abnormalities of the esophagus that delay esophageal emptying such as esophageal stricture or achalasia. Alendronate is contraindicated in patients who are at an increased risk of aspiration. Further, use is contraindicated in patients with an inability to stand or sit upright for at least 30 minutes after dose administration as the risk of esophagitis and esophageal ulceration/erosion appears to be greater in patients who lay down after taking this medicine. Prescribers and health care professionals should closely monitor patients for any signs or symptoms an esophageal reaction. Advise patients to discontinue alendronate and seek medical attention if they develop dysphagia, odynophagia, or retrosternal pain. The risk of esophageal reactions increases in patients who do not follow the administration instructions. It is very important that patients understand and follow these instructions; direct observation may be required in those who cannot independently follow dosing instructions due to mental disability. In 2011, the FDA announced an ongoing review of data from published studies to evaluate whether use of oral bisphosphonate drugs is associated with an increased risk of esophageal cancer. There have been conflicting findings from studies evaluating this risk. At the time of the announcement, the FDA states that the benefits of oral bisphosphonate drugs in reducing the risk of serious fractures in people with osteoporosis continue to outweigh their potential risks.
Geriatric adults may be at increased risk for the development of adverse GI reactions during alendronate therapy. Increased age has been identified as an independent risk factor particularly for GI perforations, ulcers, or bleeding, but not necessarily esophageal events.
Preexistent hypocalcemia must be corrected before initiating alendronate therapy. Similarly, vitamin D deficiency must also be corrected. Adequate intake of calcium and vitamin D during treatment are essential. This is most important for patients with Paget's disease who are to receive alendronate. Alendronate can decrease serum calcium and phosphate in these patients, who may have a higher rate of bone turnover.
About 50% of a single IV dose of alendronate is excreted in the urine. Studies in animals indicated that any alendronate not deposited in bone was rapidly excreted. Renal failure in animals led to increased amounts of alendronate in plasma, kidney, spleen, and tibia. No human study results are available, but it is likely that patients with severe renal impairment will accumulate alendronate. No dosage adjustment is recommended by the manufacturer if creatinine clearance is > 35 mL/min (mild to moderate renal insufficiency). Until further evidence is available, alendronate is not recommended for patients with creatinine clearance < 35 mL/min (renal failure).
Alendronate is not FDA approved for use in neonates, infants, children, or adolescents. Bisphosphonates have been used successfully in children for treatment of specific disease states (i.e., hypercalcemia of malignancy, idiopathic or glucocorticoid induced osteoporosis, osteogenesis imperfecta, Paget's disease). The efficacy and safety of alendronate in children aged 4 to 18 years of age with osteogenesis imperfecta has been evaluated. In a 2-year study, 109 patients were randomized to either 5 mg of alendronate once daily (weight less than 40 kg) or 10 mg of alendronate once daily (weight 40 kg or more), and 30 patients were randomized to placebo. The mean change in BMD Z-score from baseline was 1.3 in the alendronate-treated groups and 0.1 in the placebo group; treatment with alendronate did not reduce fracture rates. Of the patients who sustained a radiologically-confirmed fracture by month 12 of the study, 16% of alendronate-treated compared with only 9% of placebo-treated patients had delayed fracture healing or fracture non-union when assessed radiographically at month 24. In addition, at month 24, patients treated with alendronate demonstrated decreased bone turnover and delayed mineralization time. There were no differences between the alendronate-treated and the placebo-treated patients with respect to bone pain. Extreme caution must be used to ensure appropriate use in children; excessive doses of bisphosphonates may compromise skeletal quality during growth, despite concomitant increases in bone density. In a case report, inappropriate and excessive doses of pamidronate in a child resulted in osteopetrosis (abnormally dense and misshapen bone predisposed to fracture). It may be advisable to monitor biochemical markers of skeletal turnover when bisphosphonates are used in children to help assure clinicians that skeletal resorption is not excessively suppressed.
There are no studies of alendronate use during pregnancy. It is prudent to avoid alendronate use during pregnancy unless the potential benefit to the mother justifies any possible risk to the fetus. Bisphosphonates are incorporated into the bone matrix, from which they are gradually released over a period of years. The amount of bisphosphonate incorporated into adult bone, and hence, the amount available for release back into the systemic circulation, is directly related to the dose and duration of bisphosphonate use. There are no data on fetal risk in humans. However, there is a theoretical risk of fetal harm, predominantly skeletal, if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on the risk has not been studied. Bisphosphonates do cause fetal harm (predominantly skeletal) in animals, suggesting the uptake of bisphosphonates into fetal bone is greater than into maternal bone. Animal reproductive studies indicate alendronate may induce fetal skeletal changes, a decrease in maternal serum calcium and protracted parturition, as well as a possible effect on fetal viability.
Alendronate should be used with caution during breast-feeding. It is not known if alendronate is excreted into human milk. The effects of alendronate on a breastfed infant are not known. Bisphosphonates are incorporated into the bone matrix, from which they are gradually released over a period of years. The amount of bisphosphonate incorporated into adult bone, and hence, the amount available for release back into the systemic circulation for potential excretion into breast milk, is directly related to the dose and duration of bisphosphonate use. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition.
Alendronate should be used cautiously in patients with known phosphonate hypersensitivity. Alendronate is contraindicated in patients with alendronate hypersensitivity or hypersensitivity to any of the components in the formulation.
Alendronate may cause a rash that is worsened by sunlight (UV) exposure. However, patients should be advised that inadequate sunlight exposure can increase the risk of vitamin D insufficiency.
Osteonecrosis of the jaw has been reported in patients with cancer receiving treatment regimens which included bisphosphonates (most commonly pamidronate and zoledronic acid), but also occasionally in patients receiving chronic oral bisphosphonate therapy for osteoporosis including alendronate. The risk may increase with duration of exposure to the bisphosphonate. In patients with cancer receiving intravenous bisphosphonates, many patients were also receiving chemotherapy and corticosteroids. The majority of reported cases have been associated with dental procedures, such as tooth extraction, and many of these patients had signs of local infection including osteomyelitis; however, cases have appeared spontaneously. It would be prudent for all patients including those with concomitant risk factors (e.g. anemia, cancer, chemotherapy, coagulopathy, corticosteroid therapy, dental disease, infection, poor oral hygiene) initiating bisphosphonate therapy to receive a dental examination with appropriate preventive dentistry and correction of dental complications prior to beginning treatment. Preventive measures such as these as well as continued regular follow-up with a dentist during bisphosphonate therapy are recommended by the American Academy of Oral Medicine as the best way to minimize the risk of osteonecrosis. Invasive dental procedures should be avoided, if possible, during treatment, but if they are necessary, should be performed by an experienced dentist with close patient follow-up. 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. In addition, discontinuing the bisphosphonate once osteonecrosis develops is controversial as the estimated half-life of bisphosphonates in the bone is years.
The alendronate effervescent tablet dosage form contains 603 mg of sodium, which is equivalent to approximately 1,532 mg of salt (NaCl). Use this formulation with caution in patients who require sodium restriction, including those with heart failure, hypertension, or other cardiac disease.
Recommendations for calcium and vitamin D intake:
-To promote general bone health, guidelines for the prevention and treatment of osteoporosis recommend a target daily intake of 1,200 mg of elemental calcium for females older than 50 years and males older than 70 years. Target daily elemental calcium intake for males 70 years or younger is 1,000 mg. Daily vitamin D intake of 20 to 25 mcg (800 to 1,000 international units) is recommended for patients 50 years of age and older.
For the treatment of osteoporosis:
-once-weekly regimen for postmenopausal osteoporosis or osteoporosis in men:
Oral dosage (weekly tablets, oral solution, or effervescent-tablets for oral solution):
Adult men and postmenopausal females: 70 mg PO once weekly. Supplement calcium and vitamin D if dietary intake is inadequate. The optimal treatment duration has not been determined; reevaluate treatment on a periodic basis. Continue an oral bisphosphonate for up to 10 years in postmenopausal women who are initially at very high risk of fracture and remain at high risk. Consider discontinuation after 5 years of stability in high-risk postmenopausal women. For those patients at low or moderate risk for fracture, consider stopping alendronate after 3 to 5 years. After discontinuation of therapy, continue to periodically reassess fracture risk. Bisphosphonates are first-line therapy for the treatment of osteoporosis in postmenopausal women; the drug is additionally effective in men with osteoporosis.
-once daily regimen for postmenopausal osteoporosis or osteoporosis in men:
Oral dosage (tablets for daily administration):
Adult men and postmenopausal females: 10 mg PO once daily. Supplement calcium and vitamin D if dietary intake is inadequate. The optimal treatment duration has not been determined; reevaluate treatment on a periodic basis. Continue an oral bisphosphonate for up to 10 years in postmenopausal women who are initially at very high risk of fracture and remain at high risk. Consider discontinuation after 5 years of stability in high-risk postmenopausal women. For those patients at low or moderate risk for fracture, consider stopping alendronate after 3 to 5 years. After discontinuation of therapy, continue to periodically reassess fracture risk. Bisphosphonates are first-line therapy for the treatment of osteoporosis in postmenopausal women; the drug is additionally effective in men with osteoporosis.
-once daily regimen for corticosteroid-induced osteoporosis in men and women:
Oral dosage (tablets for daily administration):
Adults: 5 mg PO once daily. For postmenopausal women who are not taking estrogen hormonal replacement, the dose is 10 mg PO daily. Supplement calcium and vitamin D if dietary intake is inadequate. For use in patients taking systemic corticosteroids (i.e., equivalent to prednisone 7.5 mg/day PO or more). The optimal treatment duration has not been determined; reevaluate treatment on a periodic basis. For those patients at low risk for fracture, consider stopping alendronate after 3 to 5 years. After discontinuation of therapy, continue to periodically reassess fracture risk. Per guidelines, only use in patients with moderate to high risk for fracture; not recommended if low fracture risk.
For osteoporosis prophylaxis:
-once-weekly regimen for prevention of postmenopausal osteoporosis:
Oral dosage (weekly tablets):
Adult postmenopausal females: 35 mg PO once weekly. Supplement calcium and vitamin D if dietary intake is inadequate. The optimal treatment duration has not been determined; reevaluate treatment on a periodic basis. For those patients at low risk for fracture, consider stopping alendronate after 3 to 5 years. After discontinuation of therapy, continue to periodically reassess fracture risk. Use of bisphosphonates to prevent bone loss can be considered in postmenopausal women with low bone mineral density (T-score less than -1) and other risk factors for fracture who do not meet criteria for osteoporosis treatment.
-once daily regimen for prevention of postmenopausal osteoporosis:
Oral dosage (tablets for daily administration):
Adult postmenopausal females: 5 mg PO once daily. Supplement calcium and vitamin D if dietary intake is inadequate. The optimal treatment duration has not been determined; reevaluate treatment on a periodic basis. For those patients at low risk for fracture, consider stopping alendronate after 3 to 5 years. After discontinuation of therapy, continue to periodically reassess fracture risk. Use of bisphosphonates to prevent bone loss can be considered in postmenopausal women with low bone mineral density (T-score less than -1) and other risk factors for fracture who do not meet criteria for osteoporosis treatment.
-for prevention of corticosteroid-induced osteoporosis in men and women:
Oral dosage (tablets for daily administration):
Adults: 5 mg PO once daily. For postmenopausal women who are not taking estrogen hormonal replacement, the dose is 10 mg PO daily. Supplement calcium and vitamin D if dietary intake is inadequate. For use in patients taking systemic corticosteroids (i.e., equivalent to prednisone 7.5 mg/day PO or more). The optimal treatment duration has not been determined; reevaluate treatment on a periodic basis. For those patients at low risk for fracture, consider stopping alendronate after 3 to 5 years. After discontinuation of therapy, continue to periodically reassess fracture risk. Per guidelines, only use in patients with moderate to high risk for fracture; not recommended if low fracture risk.
For the treatment of Paget's disease:
Oral dosage (tablets for daily administration):
Adults: 40 mg PO once daily for 6 months. Supplement calcium and vitamin D if dietary intake is inadequate. Retreatment may be considered after a 6-month post-treatment evaluation period, based on increases in serum alkaline phosphatase. Alendronate is associated with histologic and radiologic evidence of disease improvement, but guidelines suggest that retreatment with alendronate may be necessary within 2 to 6 years. Guidelines also recommend a single dose of zoledronic acid preferentially due to the rare need for retreatment within 5 years, but the alendronate regimen is also an acceptable option. There are long-term data for reducing pain and lytic lesions and improving quality of life.
For the treatment of malignant hypercalcemia*:
Intravenous dosage*:
Adults: Safety and efficacy have not been established. This dosage form is not available in the U.S. Doses of 5 mg, 7.5 mg, or 10 mg of alendronate IV infusion over 2 to 6 hours appear to be effective. While doses of 12.5 and 15 mg have also been studied, they may not provide any significant benefit over lower doses in terms of achieving serum calcium reduction.
For the treatment of osteogenesis imperfecta*:
Oral dosage (daily):
Adults: 10 mg PO once daily.
Children and Adolescents 3 to 17 years weighing 40 kg or more: 10 mg PO once daily.
Children and Adolescents 3 to 17 years weighing 30 to 39 kg: 5 to 10 mg PO once daily.
Children and Adolescents 3 to 17 years weighing less than 30 kg: 5 mg PO once daily.
Oral dosage (weekly):
Adults: 70 mg PO once weekly.
Children and Adolescents 3 to 17 years: 70 mg PO once weekly.
For the treatment of complex regional pain syndrome*:
Oral dosage (tablets for daily administration):
Adults: 40 mg PO once daily for 8 weeks.
Therapeutic Drug Monitoring:
In patients receiving prevention or treatment of osteoporosis, evidence suggests that bone mineral density (BMD) monitoring during the period of active treatment (3 to 5 years) is not needed for most patients. However, reassess fracture risk periodically to help determine the need for continued treatment. The FRAX calculator or Fracture Risk Assessment Tool, developed by World Health Organization, is available for download or online calculation via the World Wide Web.
Maximum Dosage Limits:
-Adults
10 mg/day PO or 70 mg/week PO for osteoporosis. For Paget's disease 40 mg/day PO for 6 months.
-Geriatric
10 mg/day PO or 70 mg/week PO for osteoporosis. For Paget's disease 40 mg/day PO for 6 months.
-Adolescents
Weighing 30 kg or more: Safety and efficacy have not been established; however, 10 mg/day PO has been used off-label for osteogenesis imperfecta.
Weighing less than 30 kg: Safety and efficacy have not been established; however, 5 mg/day PO has been used off-label for osteogenesis imperfecta.
-Children
3 to 12 years weighing 30 kg or more: Safety and efficacy have not been established; however, 10 mg/day PO has been used off-label for osteogenesis imperfecta.
3 to 12 years weighing less than 30 kg: Safety and efficacy have not been established; however, 5 mg/day PO has been used off-label for osteogenesis imperfecta.
1 to 2 years: Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
No dosage adjustment is needed.
Patients with Renal Impairment Dosing
CrCl 35 mL/minute or more: No dosage adjustment is needed.
CrCl less than 35 mL/minute: Not recommended.
*non-FDA-approved indication
Acetaminophen; Aspirin, ASA; Caffeine: (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and aspirin. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Acetaminophen; Aspirin, ASA; Caffeine: (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and aspirin. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Acetaminophen; Aspirin: (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and aspirin. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Acetaminophen; Aspirin; Diphenhydramine: (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and aspirin. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Acetaminophen; Ibuprofen: (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and nonsteroidal antiinflammatory drugs. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Aluminum Hydroxide: (Moderate) Separate administration of alendronate and aluminum hydroxide by at least 30 minutes. Aluminum-containing antacids will interfere with the absorption of alendronate.
Aluminum Hydroxide; Magnesium Carbonate: (Moderate) Separate administration of alendronate and aluminum hydroxide by at least 30 minutes. Aluminum-containing antacids will interfere with the absorption of alendronate.
Aluminum Hydroxide; Magnesium Hydroxide: (Moderate) Separate administration of alendronate and aluminum hydroxide by at least 30 minutes. Aluminum-containing antacids will interfere with the absorption of alendronate.
Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Moderate) Separate administration of alendronate and aluminum hydroxide by at least 30 minutes. Aluminum-containing antacids will interfere with the absorption of alendronate.
Aluminum Hydroxide; Magnesium Trisilicate: (Moderate) Separate administration of alendronate and aluminum hydroxide by at least 30 minutes. Aluminum-containing antacids will interfere with the absorption of alendronate.
Amlodipine; Celecoxib: (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and nonsteroidal antiinflammatory drugs. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Amoxicillin; Clarithromycin; Omeprazole: (Moderate) Proton pump inhibitors (PPIs) are widely used and are frequently coadministered in users of oral bisphosphonates. A national register-based, open cohort study of 38,088 elderly patients suggests that those who use proton pump inhibitors in conjunction with alendronate have a dose-dependent loss of protection against hip fracture. While causality was not investigated, the dose-response relationship noted during the study suggested that PPIs may reduce oral alendronate efficacy, perhaps through an effect on absorption or other mechanism, and therefore PPIs may not be optimal agents to control gastrointestinal complaints. It is not yet clear if all bisphosphonates would exhibit a loss of efficacy when PPIs are coadministered, but the results suggest that the interaction may occur across the class.
Aspirin, ASA: (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and aspirin. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Aspirin, ASA; Butalbital; Caffeine: (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and aspirin. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Aspirin, ASA; Caffeine: (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and aspirin. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Aspirin, ASA; Caffeine; Orphenadrine: (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and aspirin. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Aspirin, ASA; Carisoprodol; Codeine: (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and aspirin. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Moderate) Sodium bicarbonate can reduce the absorption of the oral bisphosphonates. Wait at least 30 minutes after oral alendronate, 1 hour after ibandronate, and 2 hours after oral etidronate, risedronate, or tiludronate before taking a sodium bicarbonatecontaining product. (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and aspirin. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Aspirin, ASA; Dipyridamole: (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and aspirin. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Aspirin, ASA; Omeprazole: (Moderate) Proton pump inhibitors (PPIs) are widely used and are frequently coadministered in users of oral bisphosphonates. A national register-based, open cohort study of 38,088 elderly patients suggests that those who use proton pump inhibitors in conjunction with alendronate have a dose-dependent loss of protection against hip fracture. While causality was not investigated, the dose-response relationship noted during the study suggested that PPIs may reduce oral alendronate efficacy, perhaps through an effect on absorption or other mechanism, and therefore PPIs may not be optimal agents to control gastrointestinal complaints. It is not yet clear if all bisphosphonates would exhibit a loss of efficacy when PPIs are coadministered, but the results suggest that the interaction may occur across the class. (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and aspirin. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Aspirin, ASA; Oxycodone: (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and aspirin. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Bumetanide: (Moderate) When the intravenous formulation of alendronate is used for the treatment of hypercalcemia of malignancy, combination therapy with loop diuretics should be used with caution in order to avoid hypocalcemia. In patients with hypercalcemia of malignancy, the initial treatment typically includes the use of loop diuretics, in combination with saline hydration, however, diuretic therapy should not be employed prior to correction of hypovolemia and dehydration.
Bupivacaine; Meloxicam: (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and nonsteroidal antiinflammatory drugs. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Butalbital; Aspirin; Caffeine; Codeine: (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and aspirin. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Calcium (oral): (Moderate) Separate administration of alendronate and calcium-containing supplements by at least 30 minutes. Calcium will interfere with the absorption of alendronate.
Calcium Acetate: (Moderate) Separate administration of alendronate and calcium-containing supplements by at least 30 minutes. Calcium will interfere with the absorption of alendronate.
Calcium Carbonate: (Moderate) Separate administration of alendronate and calcium-containing supplements by at least 30 minutes. Calcium will interfere with the absorption of alendronate.
Calcium Carbonate; Famotidine; Magnesium Hydroxide: (Moderate) Separate administration of alendronate and calcium-containing supplements by at least 30 minutes. Calcium will interfere with the absorption of alendronate.
Calcium Carbonate; Magnesium Hydroxide: (Moderate) Separate administration of alendronate and calcium-containing supplements by at least 30 minutes. Calcium will interfere with the absorption of alendronate.
Calcium Carbonate; Magnesium Hydroxide; Simethicone: (Moderate) Separate administration of alendronate and calcium-containing supplements by at least 30 minutes. Calcium will interfere with the absorption of alendronate.
Calcium Carbonate; Simethicone: (Moderate) Separate administration of alendronate and calcium-containing supplements by at least 30 minutes. Calcium will interfere with the absorption of alendronate.
Calcium Gluconate: (Moderate) Separate administration of alendronate and calcium-containing supplements by at least 30 minutes. Calcium will interfere with the absorption of alendronate.
Calcium; Vitamin D: (Moderate) Separate administration of alendronate and calcium-containing supplements by at least 30 minutes. Calcium will interfere with the absorption of alendronate.
Calcium; Vitamin D: (Moderate) Separate administration of alendronate and calcium-containing supplements by at least 30 minutes. Calcium will interfere with the absorption of alendronate.
Celecoxib: (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and nonsteroidal antiinflammatory drugs. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Celecoxib; Tramadol: (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and nonsteroidal antiinflammatory drugs. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and nonsteroidal antiinflammatory drugs. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Chromium: (Moderate) Separate administration of alendronate and calcium-containing supplements by at least 30 minutes. Calcium will interfere with the absorption of alendronate.
Deferasirox: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including alendronate.
Dexlansoprazole: (Moderate) Proton pump inhibitors (PPIs) are widely used and are frequently coadministered in users of oral bisphosphonates. A national register-based, open cohort study of 38,088 elderly patients suggests that those who use proton pump inhibitors in conjunction with alendronate have a dose-dependent loss of protection against hip fracture. While causality was not investigated, the dose-response relationship noted during the study suggested that PPIs may reduce oral alendronate efficacy, perhaps through an effect on absorption or other mechanism, and therefore PPIs may not be optimal agents to control gastrointestinal complaints. It is not yet clear if all bisphosphonates would exhibit a loss of efficacy when PPIs are coadministered, but the results suggest that the interaction may occur across the class.
Diclofenac: (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and nonsteroidal antiinflammatory drugs. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Diclofenac; Misoprostol: (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and nonsteroidal antiinflammatory drugs. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Diflunisal: (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and nonsteroidal antiinflammatory drugs. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Diphenhydramine; Ibuprofen: (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and nonsteroidal antiinflammatory drugs. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Diphenhydramine; Naproxen: (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and nonsteroidal antiinflammatory drugs. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Esomeprazole: (Moderate) Proton pump inhibitors (PPIs) are widely used and are frequently coadministered in users of oral bisphosphonates. A national register-based, open cohort study of 38,088 elderly patients suggests that those who use proton pump inhibitors in conjunction with alendronate have a dose-dependent loss of protection against hip fracture. While causality was not investigated, the dose-response relationship noted during the study suggested that PPIs may reduce oral alendronate efficacy, perhaps through an effect on absorption or other mechanism, and therefore PPIs may not be optimal agents to control gastrointestinal complaints. It is not yet clear if all bisphosphonates would exhibit a loss of efficacy when PPIs are coadministered, but the results suggest that the interaction may occur across the class.
Ethacrynic Acid: (Moderate) When the intravenous formulation of alendronate is used for the treatment of hypercalcemia of malignancy, combination therapy with loop diuretics should be used with caution in order to avoid hypocalcemia. In patients with hypercalcemia of malignancy, the initial treatment typically includes the use of loop diuretics, in combination with saline hydration, however, diuretic therapy should not be employed prior to correction of hypovolemia and dehydration.
Etodolac: (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and nonsteroidal antiinflammatory drugs. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Fenoprofen: (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and nonsteroidal antiinflammatory drugs. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Ferric Maltol: (Moderate) Separate administration of alendronate and iron supplements by at least 30 minutes. Iron will interfere with the absorption of alendronate.
Flurbiprofen: (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and nonsteroidal antiinflammatory drugs. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Food: (Major) Absorption of alendronate is very poor; oral bioavailability is less than 1%. Because of this, food interactions can be very significant. Alendronate oral absorption becomes almost negligible if alendronate is taken within 2 hours of breakfast. Even orange juice or coffee can reduce bioavailability by about 60%. To achieve maximum possible bioavailability alendronate must be taken in the fasting state and at least 2 hours before a standard breakfast.
Furosemide: (Moderate) When the intravenous formulation of alendronate is used for the treatment of hypercalcemia of malignancy, combination therapy with loop diuretics should be used with caution in order to avoid hypocalcemia. In patients with hypercalcemia of malignancy, the initial treatment typically includes the use of loop diuretics, in combination with saline hydration, however, diuretic therapy should not be employed prior to correction of hypovolemia and dehydration.
Hydrocodone; Ibuprofen: (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and nonsteroidal antiinflammatory drugs. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Ibuprofen: (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and nonsteroidal antiinflammatory drugs. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Ibuprofen; Famotidine: (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and nonsteroidal antiinflammatory drugs. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Ibuprofen; Oxycodone: (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and nonsteroidal antiinflammatory drugs. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Ibuprofen; Pseudoephedrine: (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and nonsteroidal antiinflammatory drugs. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Indomethacin: (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and nonsteroidal antiinflammatory drugs. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Iron Salts: (Moderate) Separate administration of alendronate and iron supplements by at least 30 minutes. Iron will interfere with the absorption of alendronate.
Iron Salts: (Moderate) Separate administration of alendronate and iron supplements by at least 30 minutes. Iron will interfere with the absorption of alendronate.
Iron Sucrose, Sucroferric Oxyhydroxide: (Moderate) Separate administration of alendronate and iron supplements by at least 30 minutes. Iron will interfere with the absorption of alendronate.
Iron: (Moderate) Separate administration of alendronate and iron supplements by at least 30 minutes. Iron will interfere with the absorption of alendronate.
Ketoprofen: (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and nonsteroidal antiinflammatory drugs. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Ketorolac: (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and nonsteroidal antiinflammatory drugs. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Lansoprazole: (Moderate) Proton pump inhibitors (PPIs) are widely used and are frequently coadministered in users of oral bisphosphonates. A national register-based, open cohort study of 38,088 elderly patients suggests that those who use proton pump inhibitors in conjunction with alendronate have a dose-dependent loss of protection against hip fracture. While causality was not investigated, the dose-response relationship noted during the study suggested that PPIs may reduce oral alendronate efficacy, perhaps through an effect on absorption or other mechanism, and therefore PPIs may not be optimal agents to control gastrointestinal complaints. It is not yet clear if all bisphosphonates would exhibit a loss of efficacy when PPIs are coadministered, but the results suggest that the interaction may occur across the class.
Lansoprazole; Amoxicillin; Clarithromycin: (Moderate) Proton pump inhibitors (PPIs) are widely used and are frequently coadministered in users of oral bisphosphonates. A national register-based, open cohort study of 38,088 elderly patients suggests that those who use proton pump inhibitors in conjunction with alendronate have a dose-dependent loss of protection against hip fracture. While causality was not investigated, the dose-response relationship noted during the study suggested that PPIs may reduce oral alendronate efficacy, perhaps through an effect on absorption or other mechanism, and therefore PPIs may not be optimal agents to control gastrointestinal complaints. It is not yet clear if all bisphosphonates would exhibit a loss of efficacy when PPIs are coadministered, but the results suggest that the interaction may occur across the class.
Lanthanum Carbonate: (Moderate) To limit absorption problems, the oral bisphosphonates should not be taken within 2 hours of dosing with lanthanum carbonate. Oral drugs known to interact with cationic antacids, like the oral bisphosphonates, may also be bound by lanthanum carbonate. Separating times of administration will maximize absorption and clinical benefit of the bisphosphonate. Separate the times of administration appropriately. Monitor the patient's clinical status and bone density as recommended to ensure the appropriate response to bisphosphonate therapy is obtained.
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Moderate) Separate administration of alendronate and iron supplements by at least 30 minutes. Iron will interfere with the absorption of alendronate.
Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate: (Moderate) Separate administration of alendronate and iron supplements by at least 30 minutes. Iron will interfere with the absorption of alendronate.
Levothyroxine: (Moderate) Separating times of administration of alendronate from levothyroxine and other medications will maximize alendronate absorption and clinical benefit. For example, administering the levothyroxine dose at bedtime can avoid this interaction with alendronate. The bioavailability of alendronate was slightly decreased when alendronate and levothyroxine were co-administered to healthy subjects The mean AUC and Cmax of alendronate decreased by 7% and 9%, respectively. Alendronate should always be administered upon arising for the day and at least 30 minutes before the first food, beverage, or other medication of the day. To minimize interactions, levothyroxine is also best taken on an empty stomach with a glass of water.
Levothyroxine; Liothyronine (Porcine): (Moderate) Separating times of administration of alendronate from levothyroxine and other medications will maximize alendronate absorption and clinical benefit. For example, administering the levothyroxine dose at bedtime can avoid this interaction with alendronate. The bioavailability of alendronate was slightly decreased when alendronate and levothyroxine were co-administered to healthy subjects The mean AUC and Cmax of alendronate decreased by 7% and 9%, respectively. Alendronate should always be administered upon arising for the day and at least 30 minutes before the first food, beverage, or other medication of the day. To minimize interactions, levothyroxine is also best taken on an empty stomach with a glass of water.
Levothyroxine; Liothyronine (Synthetic): (Moderate) Separating times of administration of alendronate from levothyroxine and other medications will maximize alendronate absorption and clinical benefit. For example, administering the levothyroxine dose at bedtime can avoid this interaction with alendronate. The bioavailability of alendronate was slightly decreased when alendronate and levothyroxine were co-administered to healthy subjects The mean AUC and Cmax of alendronate decreased by 7% and 9%, respectively. Alendronate should always be administered upon arising for the day and at least 30 minutes before the first food, beverage, or other medication of the day. To minimize interactions, levothyroxine is also best taken on an empty stomach with a glass of water.
Loop diuretics: (Moderate) When the intravenous formulation of alendronate is used for the treatment of hypercalcemia of malignancy, combination therapy with loop diuretics should be used with caution in order to avoid hypocalcemia. In patients with hypercalcemia of malignancy, the initial treatment typically includes the use of loop diuretics, in combination with saline hydration, however, diuretic therapy should not be employed prior to correction of hypovolemia and dehydration.
Magnesium Citrate: (Moderate) Separate administration of alendronate and magnesium-containing supplements by at least 30 minutes. Magnesium will interfere with the absorption of alendronate.
Magnesium Salts: (Moderate) Separate administration of alendronate and magnesium-containing supplements by at least 30 minutes. Magnesium will interfere with the absorption of alendronate.
Magnesium: (Moderate) Separate administration of alendronate and magnesium-containing supplements by at least 30 minutes. Magnesium will interfere with the absorption of alendronate.
Meclofenamate Sodium: (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and nonsteroidal antiinflammatory drugs. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Mefenamic Acid: (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and nonsteroidal antiinflammatory drugs. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Meloxicam: (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and nonsteroidal antiinflammatory drugs. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Nabumetone: (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and nonsteroidal antiinflammatory drugs. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Naproxen: (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and nonsteroidal antiinflammatory drugs. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Naproxen; Esomeprazole: (Moderate) Proton pump inhibitors (PPIs) are widely used and are frequently coadministered in users of oral bisphosphonates. A national register-based, open cohort study of 38,088 elderly patients suggests that those who use proton pump inhibitors in conjunction with alendronate have a dose-dependent loss of protection against hip fracture. While causality was not investigated, the dose-response relationship noted during the study suggested that PPIs may reduce oral alendronate efficacy, perhaps through an effect on absorption or other mechanism, and therefore PPIs may not be optimal agents to control gastrointestinal complaints. It is not yet clear if all bisphosphonates would exhibit a loss of efficacy when PPIs are coadministered, but the results suggest that the interaction may occur across the class. (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and nonsteroidal antiinflammatory drugs. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Naproxen; Pseudoephedrine: (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and nonsteroidal antiinflammatory drugs. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Nonsteroidal antiinflammatory drugs: (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and nonsteroidal antiinflammatory drugs. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Separate administration of alendronate and iron supplements by at least 30 minutes. Iron will interfere with the absorption of alendronate.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Separate administration of alendronate and iron supplements by at least 30 minutes. Iron will interfere with the absorption of alendronate.
Omeprazole: (Moderate) Proton pump inhibitors (PPIs) are widely used and are frequently coadministered in users of oral bisphosphonates. A national register-based, open cohort study of 38,088 elderly patients suggests that those who use proton pump inhibitors in conjunction with alendronate have a dose-dependent loss of protection against hip fracture. While causality was not investigated, the dose-response relationship noted during the study suggested that PPIs may reduce oral alendronate efficacy, perhaps through an effect on absorption or other mechanism, and therefore PPIs may not be optimal agents to control gastrointestinal complaints. It is not yet clear if all bisphosphonates would exhibit a loss of efficacy when PPIs are coadministered, but the results suggest that the interaction may occur across the class.
Omeprazole; Amoxicillin; Rifabutin: (Moderate) Proton pump inhibitors (PPIs) are widely used and are frequently coadministered in users of oral bisphosphonates. A national register-based, open cohort study of 38,088 elderly patients suggests that those who use proton pump inhibitors in conjunction with alendronate have a dose-dependent loss of protection against hip fracture. While causality was not investigated, the dose-response relationship noted during the study suggested that PPIs may reduce oral alendronate efficacy, perhaps through an effect on absorption or other mechanism, and therefore PPIs may not be optimal agents to control gastrointestinal complaints. It is not yet clear if all bisphosphonates would exhibit a loss of efficacy when PPIs are coadministered, but the results suggest that the interaction may occur across the class.
Omeprazole; Sodium Bicarbonate: (Moderate) Proton pump inhibitors (PPIs) are widely used and are frequently coadministered in users of oral bisphosphonates. A national register-based, open cohort study of 38,088 elderly patients suggests that those who use proton pump inhibitors in conjunction with alendronate have a dose-dependent loss of protection against hip fracture. While causality was not investigated, the dose-response relationship noted during the study suggested that PPIs may reduce oral alendronate efficacy, perhaps through an effect on absorption or other mechanism, and therefore PPIs may not be optimal agents to control gastrointestinal complaints. It is not yet clear if all bisphosphonates would exhibit a loss of efficacy when PPIs are coadministered, but the results suggest that the interaction may occur across the class. (Moderate) Sodium bicarbonate can reduce the absorption of the oral bisphosphonates. Wait at least 30 minutes after oral alendronate, 1 hour after ibandronate, and 2 hours after oral etidronate, risedronate, or tiludronate before taking a sodium bicarbonatecontaining product.
Oxaprozin: (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and nonsteroidal antiinflammatory drugs. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Pantoprazole: (Moderate) Proton pump inhibitors (PPIs) are widely used and are frequently coadministered in users of oral bisphosphonates. A national register-based, open cohort study of 38,088 elderly patients suggests that those who use proton pump inhibitors in conjunction with alendronate have a dose-dependent loss of protection against hip fracture. While causality was not investigated, the dose-response relationship noted during the study suggested that PPIs may reduce oral alendronate efficacy, perhaps through an effect on absorption or other mechanism, and therefore PPIs may not be optimal agents to control gastrointestinal complaints. It is not yet clear if all bisphosphonates would exhibit a loss of efficacy when PPIs are coadministered, but the results suggest that the interaction may occur across the class.
Parathyroid Hormone: (Moderate) Coadministration of alendronate with parathyroid hormone (PTH) is not recommended as concomitant use leads to a reduction in the calcium sparing effect, which can interfere with the normalization of serum calcium. The use of PTH alone was superior to use in combination with alendronate in clinical trials. In clinical trials, there was no evidence of synergy between PTH and alendronate. Changes in the volumetric density of trabecular bone, the cortical volume at the hip, and levels of markers of bone turnover suggest that the concurrent use of alendronate may reduce the anabolic effects of PTH. Concurrent use with other bisphosphonates is also controversial. However, sequential use (e.g., PTH followed by anti-resorptive treatment with bisphosphonates) appears to be beneficial and to help maintain beneficial bone effects.
Piroxicam: (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and nonsteroidal antiinflammatory drugs. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Polycarbophil: (Moderate) Coadministration of alendronate with calcium polycarbophil can interfere with the oral absorption of alendronate; do not administer calcium polycarbophil within 30 minutes of alendronate. Each 625 mg of calcium polycarbophil contains a substantial amount of calcium (approximately 125 mg).
Proton pump inhibitors: (Moderate) Proton pump inhibitors (PPIs) are widely used and are frequently coadministered in users of oral bisphosphonates. A national register-based, open cohort study of 38,088 elderly patients suggests that those who use proton pump inhibitors in conjunction with alendronate have a dose-dependent loss of protection against hip fracture. While causality was not investigated, the dose-response relationship noted during the study suggested that PPIs may reduce oral alendronate efficacy, perhaps through an effect on absorption or other mechanism, and therefore PPIs may not be optimal agents to control gastrointestinal complaints. It is not yet clear if all bisphosphonates would exhibit a loss of efficacy when PPIs are coadministered, but the results suggest that the interaction may occur across the class.
Pyridoxine, Vitamin B6: (Moderate) Separate administration of alendronate and calcium-containing supplements by at least 30 minutes. Calcium will interfere with the absorption of alendronate.
Rabeprazole: (Moderate) Proton pump inhibitors (PPIs) are widely used and are frequently coadministered in users of oral bisphosphonates. A national register-based, open cohort study of 38,088 elderly patients suggests that those who use proton pump inhibitors in conjunction with alendronate have a dose-dependent loss of protection against hip fracture. While causality was not investigated, the dose-response relationship noted during the study suggested that PPIs may reduce oral alendronate efficacy, perhaps through an effect on absorption or other mechanism, and therefore PPIs may not be optimal agents to control gastrointestinal complaints. It is not yet clear if all bisphosphonates would exhibit a loss of efficacy when PPIs are coadministered, but the results suggest that the interaction may occur across the class.
Sodium Bicarbonate: (Moderate) Sodium bicarbonate can reduce the absorption of the oral bisphosphonates. Wait at least 30 minutes after oral alendronate, 1 hour after ibandronate, and 2 hours after oral etidronate, risedronate, or tiludronate before taking a sodium bicarbonatecontaining product.
Sodium Ferric Gluconate Complex; ferric pyrophosphate citrate: (Moderate) Separate administration of alendronate and iron supplements by at least 30 minutes. Iron will interfere with the absorption of alendronate.
Sodium Sulfate; Magnesium Sulfate; Potassium Chloride: (Moderate) Separate administration of alendronate and magnesium-containing supplements by at least 30 minutes. Magnesium will interfere with the absorption of alendronate.
Sucralfate: (Moderate) Concomitant administration of oral alendronate with aluminum-containing medications (e.g., sucralfate) may interfere with the absorption of alendronate. Separation of administration is advised. At least 30 minutes should elapse after an alendronate dose before taking aluminum-containing drugs.
Sulindac: (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and nonsteroidal antiinflammatory drugs. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Sumatriptan; Naproxen: (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and nonsteroidal antiinflammatory drugs. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Tolmetin: (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and nonsteroidal antiinflammatory drugs. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Torsemide: (Moderate) When the intravenous formulation of alendronate is used for the treatment of hypercalcemia of malignancy, combination therapy with loop diuretics should be used with caution in order to avoid hypocalcemia. In patients with hypercalcemia of malignancy, the initial treatment typically includes the use of loop diuretics, in combination with saline hydration, however, diuretic therapy should not be employed prior to correction of hypovolemia and dehydration.
Alendronate is a second-generation bisphosphonate that binds to bone hydroxyapatite and specifically inhibits the activity of osteoclasts, the bone-resorbing cells. Alendronate reduces bone resorption with no direct effect on bone formation, although the latter process is ultimately reduced because bone resorption and formation are coupled during bone turnover. At the cellular level, alendronate shows preferential localization to sites of bone resorption, specifically under osteoclasts. The osteoclasts adhere normally to the bone surface but lack the ruffled border that is indicative of active resorption. Alendronate does not interfere with osteoclast recruitment or attachment, but it does inhibit osteoclast activity. Studies in mice on the localization of radioactive alendronate in bone showed about 10-fold higher uptake on osteoclast surfaces than on osteoblast surfaces. Bones examined 6 and 49 days after radioactive alendronate administration in rats and mice, respectively, showed that normal bone was formed on top of the alendronate, which was incorporated inside the matrix. While incorporated in bone matrix, alendronate is not pharmacologically active. Thus, alendronate must be continuously administered to suppress osteoclasts on newly formed resorption surfaces. Histomorphometry in baboons and rats showed that alendronate treatment reduces bone turnover (i.e., the number of sites at which bone is remodeled). In addition, bone formation exceeds bone resorption at these remodeling sites, leading to progressive gains in bone mass.
Like other bisphosphonates, the exact mechanism of alendronate's therapeutic effect in patients with Paget's disease has not been established. Paget's disease is a progressive, idiopathic disease of bone. Increasing numbers of unusually large osteoclasts are produced at affected sites. Increased osteoclastic bone resorption follows, which is compensated for by an increase in osteoblastic bone formation, leading to the replacement of the normal bone architecture by disorganized, enlarged, and weakened bone structure. This new bone architecture is inferior and often deformed, and can fracture easily. Bisphosphonates are believed to reduce the solubility of the mineralized bone matrix by adsorption to hydroxyapatite crystals in the matrix. The matrix becomes less soluble and resistant to osteoclastic resorption, which helps stabilize osteolytic lesions. Alendronate and other bisphosphonates can also block the formation of mature osteoclasts by affecting the attachment of osteoclast precursors to the mineralized matrix. In patients with Paget's disease, alendronate directly decreases bone resorption, resulting in a significant decrease in serum alkaline phosphatase and urinary markers of bone collagen degradation. Bisphosphonates cause histological and radiological evidence of Paget's disease improvement and also reduce pain.
Some bisphosphonates cause a significant decrease in serum calcium and urinary calcium levels in patients with hypercalcemia of malignancy, and some bisphosphonate agents in selected cancer patients may reduce osteopenia related to cancer treatment and thus help reduce skeletal events.
Alendronate is administered orally. Transient distribution into soft tissue is rapidly followed by redistribution to bone or urinary excretion. Alendronate is approximately 78% bound to protein in human plasma. There is no evidence that any metabolism takes place. Once alendronate is bound to bone, the half-life is more than 10 years. Inhibition of bone resorption diminishes after completion of treatment, suggesting that not all the alendronate sequestered in bone is biologically active.
Bone resorption in individual remodeling units normally continues for approximately 2 weeks. Due to the long half-life of alendronate in the bone, weekly administration of alendronate should inhibit bone resorption and provide benefits on bone mass and strength to a similar extent as daily administration.
-Route-Specific Pharmacokinetics
Oral Route
Absorption of alendronate is poor, with oral bioavailability of less than 1%. Cations (e.g., calcium, magnesium) reduce bioavailability. If alendronate is taken within 2 hours of breakfast its bioavailability becomes almost negligible. Even orange juice or coffee can reduce bioavailability by about 60%. To achieve maximum possible bioavailability, alendronate must be taken in the fasting state and at least 2 hours before a standard breakfast. Estimations suggest that the amount of alendronate released from the skeleton daily, after 10 years of daily dosing with 10 mg of alendronate, is 25% of that absorbed from the GI tract.
Intravenous Route
Elimination of alendronate from plasma is rapid, falling 95% within 6 hours of an IV dose. Approximately 50% of a single IV dose is excreted in the urine within 72 hours.
-Special Populations
Renal Impairment
The elimination of alendronate in animals with renal impairment is reduced. Although clinical data does not exist, it is likely that elimination of alendronate in patients with renal insufficiency will also be reduced. Therefore, somewhat greater accumulation of alendronate in the bone of patients with renal impairment may occur. Alendronate is not recommended for use in patients with a CrCl of < 35 mL/min due to a lack of experience and insufficient data in this population.
Pediatrics
The bioavailability of single doses of alendronate 35 mg or 70 mg in children 4-16 years of age with osteogenesis imperfecta is less than 0.6%, which is comparable to the bioavailability of alendronate in adults.