Risedronate is a potent oral second-generation pyridinyl bisphosphonate; it differs structurally from other available bisphosphonates due to the pyridinyl side chain shielding the active amino group. Monthly, weekly, or daily regimens are available for selected conditions. Treatment with risedronate 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 risedronate 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. Risedronate is also effective and indicated for osteoporosis in patients receiving chronic corticosteroid treatment. Risedronate is additionally indicated for Paget's disease; guidelines for Paget's disease include risedronate as an alternative to zoledronic acid for these patients, as risedronate is known to stabilize osteolytic lesions; however, the effect of risedronate may not be as durable as with zoledronic acid and retreatment may be required between 1 and 5 years. As with other bisphosphonates, risedronate 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
Immediate-release tablets (i.e., Actonel):
-Administer after the patient has risen for the day. Administer whole and on an empty stomach; the patient should not chew or suck the tablet. The patient should be sitting or standing. Do not administer to the patient while the patient is lying down.
-Administer in the morning with a full glass (180 to 240 mL or 6 to 8 ounces) of plain water only and at least 30 minutes before the first food, beverage, or other medications of the day. Do not administer with mineral water, coffee, tea, soda, or juice.
-At least 30 minutes should elapse after the dose before the patient eats, drinks beverages other than water, or is administered any other drugs or supplements.
-Calcium supplements, antacids, magnesium-based supplements or laxatives, and iron preparations should be taken at a different time of the day as they interfere with the absorption of risedronate.
-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.
-Missed doses:
--Once daily dosage: If a once-daily dose is missed, do not administer it later in the day. Administer the missed dose the next morning and then return to the normal schedule. The patient should not take 2 doses at the same time.
-Once weekly dosage: If a once-weekly dose is missed, instruct the patient to take the weekly 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.
-Once monthly dosage: Do not administer more than one 150 mg tablet within a 7-day period. If the monthly dose is missed, and the next month's scheduled dose is more than 7 days away, administer the dose the morning after it is remembered. The patient should then return to taking their dose as originally scheduled. If the next month's scheduled dose is 1 to 7 days away, the missed dose should be skipped and the regular schedule resumed.
-Ensure adequate intake of calcium and vitamin D to reduce the risk of treatment-related hypocalcemia.
Delayed-release tablets (i.e., Atelvia):
-Administer immediately after breakfast with at least 4 ounces of plain water. Administer the tablets whole; do not chew, cut, or crush. The patient should be sitting or standing. Do not administer to the patient while the patient is lying down.
-To avoid esophageal irritation, the patient should not lie down for at least 30 minutes after the dose.
-Calcium supplements, antacids, magnesium-based supplements or laxatives, and iron preparations should be taken at a different time of the day as they interfere with the absorption of risedronate.
-Missed dose: If a once-weekly dose is missed, instruct the patient to take the weekly risedronate 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.
Risedronate has been well tolerated in clinical studies; the overall side effect profile of risedronate 5 mg/day PO in these studies was similar to that of placebo, as was the ADR profile of risedronate 35 mg delayed-release tablets to that of risedronate 5 mg immediate-release. Most adverse events (ADRs) were mild or moderate and did not lead to drug discontinuation. For studies involving the immediate-release formulation, the incidence of serious ADRs in the placebo group was 24.9% and in the immediate-release risedronate group was 26.3%. The percentage of patients who withdrew from the studies due to adverse events was 14.4% and 13.5% for the placebo and immediate-release risedronate groups, respectively. In a 1-year, double-blind, multicenter study comparing risedronate 5-mg PO once daily and risedronate 35-mg PO once weekly in postmenopausal women, the overall safety and tolerability were similar.
Conflicting data exists regarding the use of bisphosphonates and an increased risk of serious atrial fibrillation. In a clinical trial of 2-year duration, arrhythmia (unspecified classification, unspecified if new onset or arrhythmia exacerbation) was reported in 2% of osteoporotic men treated with once-weekly immediate-release risedronate as compared to 0 of those treated with placebo; atrial fibrillation is not specifically reported. 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 < 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. 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, such as risedronate. Currently, the FDA does not recommend a change in prescribing practices for this class of drugs; a causal relationship has not been identified.
The incidence of adverse reactions reported in placebo-controlled clinical trials was similar between immediate-release risedronate and the control groups. Compared to immediate-release risedronate 5 mg daily, the once weekly regimen (35 mg) and the Paget's disease regiman (30 mg/day) appear to have higher incidences of gastrointestinal adverse reactions. Side effects reported in study patients receiving daily immediate-release risedronate, weekly immediate-release risedronate, monthly immediate-release risedronate, or weekly delayed-release risedronate include: abdominal pain (2.3-12.2%); abnormal liver function tests (0.1%); asthenia (5.4%); bronchitis (3.9-10%); cataracts (6.5%); chest pain (unspecified) (5-6.6%); constipation (2.9-12.9%; increased cough (5.9% vs. 6.3% placebo); depression (6.8%); diarrhea (4.7-19.7%); dizziness (2.6-7.1%); duodenitis (0.1-1%); dyspepsia (3.9-10.8%); gastritis (1-2.7%); gastroesophageal reflux (1-1.6%); glossitis (0.1-1%); headache (2.6-20%); hypertension (10.5%); infection (31.1%) including upper respiratory tract infections (2.6%-3.6%), influenza (6.2%-7.2%), and urinary tract infections (11.1%); insomnia (5%); nausea (3.6-13.2%); peripheral edema (7.7-8.2%); pharyngitis (6%); rhinitis (6.2%); rash (unspecified) (7.9-11.5%); sinusitis (8.7%); and vomiting (1.6-15%). Of note, clinical study has been conducted over a longer duration, in a larger number of participants, and in a greater number of disease states with daily treatment regimens compared to other regimens. In male osteoporosis trials, the overall safety and tolerability side effect profile of weekly immediate-release risedronate was similar to that reported in postmenopausal osteoporosis trials; however, benign prostatic hyperplasia/benign prostatic hypertrophy (5%), nephrolithiasis (3%), and arrhythmia (2%) were also reported. Oral bisphosphonates have been associated with dysphagia, pyrosis (heartburn), esophagitis, and esophageal ulceration or gastric ulcers, primarily in post-marketing experience. Advise patients to report any new-onset or worsening upper GI symptoms right away. Esophageal ulcers and oral ulceration may also occur if risedronate tablets are chewed or dissolved in the mouth. Patients should take the drug properly to minimize the risk of GI-related ADRs; immediate-release and delayed-release tablets have differing administration instructions (see Administration). During osteoporosis trials, endoscopies of patients with GI complaints (roughly 2%) were performed in equal numbers in risedronate and placebo treatment groups; positive findings were similar between the groups. There was a higher number of reports of duodenitis in the risedronate group and an increased number of duodenal ulcers in the placebo group. Clinically important findings (GI perforation, peptic ulcer, or GI bleeding) among this symptomatic population were similar between groups (51% placebo and 39% risedronate). Of over 5700 patients enrolled in the Phase 3 osteoporosis studies, 21% used H2-blockers and/or proton-pump inhibitors (PPIs). Among these patients, the incidence of upper GI adverse experiences in the risedronate-treated patients was similar to that in placebo-treated patients. Among regular aspirin or NSAID users, the incidence of upper GI adverse experiences in risedronate-treated patients (24.5%) was similar to that in placebo-treated patients (24.8%).
Musculoskeletal adverse events reported during phase III clinical trials of daily immediate-release, weekly immediate-release, and/or weekly delayed-release risedronate, respectively, include: musculoskeletal pain (1.6%, not reported, 2%), pain in extremity (3.9-21%, not reported, 2.3%), muscle spasm (2.3%, not reported, 1%), arthritis (9.6%, not reported, not reported), arthralgia (7.8-32.8%, 13.9-14.2%, 6.8%), joint disorder (unspecified) (7%, not reported, not reported), myalgia (1-6.7%, 5.1-6.2%, 1.3%), bone pain (5.3-10%, not reported, not reported), and back pain (5.9-28%, not reported, 6.8%); many have also been reported during post-marketing surveillance. Pain, particularly dull or achy pain, of the thigh or groin may occur as a prodrome to atypical fracture of the femur; prompt evaluation to rule out incomplete fracture is strongly recommended. Bone, muscle, and/or joint pain can sometimes be severe and even incapacitating. The time to onset of 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 occurs within 3 days of intermittent intravenous, or weekly or monthly oral bisphosphonates and having a duration of 7 days or less. The acute phase reaction tends to resolve with continued use. Flu-like symptoms have been reported in 0 to 10.5% of study patients receiving risedronate. Other adverse effects reported in clinical study of immediate-release risedronate include unspecified pain (adults: 14.1% vs 14% with placebo, children: 15% vs 10% with placebo), neck pain (5.4% vs 4.7% with placebo), and accidental injury (16.9% vs 16.8% with placebo). Bisphosphonates should be considered as a cause for any patient who presents with severe musculoskeletal or joint pain; furthermore, if risedronate is determined to be the cause, temporary or permanent discontinuation in drug therapy should be considered.
Patients treated with risedronate may develop alterations of serum calcium, phosphorus, and/or PTH concentrations. In phase 3 studies of risedronate 5 mg immediate-release given once daily, decreases of 0.8% in serum calcium, decreases of 2.7% in serum phosphorus, and increases of < 30% in serum PTH were observed at 6 months. Hypocalcemia (serum calcium < 8 mg/dl) was observed in 0.2-4.5% of study patients treated with immediate-release risedronate at the end of the first month and in approximately 2% of patients thereafter; in separate study, similar changes to serum calcium were noted with either delayed-release or immediate-release risedronate. In one study, hypophosphatemia (serum phosphorus < 2 mg/dl) was observed in 0.6% of patients treated daily with immediate-release risedronate and in 0.2% receiving placebo; in separate study, similar changes to serum phosphorus were noted with either delayed-release or immediate-release risedronate. There were no significant differences in serum calcium, phosphate, or PTH levels between placebo and immediate-release risedronate at 3 years.
Ocular adverse events have been reported during bisphosphonate therapy. In clinical trials, iritis (including acute iritis) and uveitis were reported in < 0.1% of patients receiving risedronate. In some patients, iritis was treated effectively with topical steroids. 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, including rarely in post-marketing experience with risedronate. 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 3-4 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.
During post-marketing experience, rare and sometimes severe hypersensitivity and skin reactions, including angioedema, acute asthma exacerbations, generalized rash (unspecified), Stevens-Johnson syndrome, toxic epidermal necrolysis, and bullous rash, have been reported with risedronate. Allergic reaction was reported in clinical trials, 3.8% risedronate-treated patients compared to 5.9% with placebo.
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 risedronate. 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. Traumatic bone fracture has been reported in 9.3% of postmenopausal osteoporotic study patients receiving daily immediate-release risedronate and 12.3% of those receiving placebo.
Risedronate is contraindicated in patients with a known hypersensitivity to risedronate or any component of the product. Angioedema, generalized serious rash, bullous skin reactions, Stevens-Johnson syndrome, toxic epidermal necrolysis, and other hypersensitivity reactions have been reported. Angioedema, generalized rash, bullous skin reactions, Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported. Risedronate should be used cautiously in patients with known phosphonate hypersensitivity.
Risedronate therapy is contraindicated in patients with hypocalcemia. Treat hypocalcemia and other disturbances of bone and mineral metabolism before starting risedronate therapy. Similarly, correct vitamin D deficiency. Adequate intake of calcium and vitamin D is important in all patients, especially in patients with Paget's disease in whom bone turnover is significantly elevated.
As oral bisphosphonates are known to cause local irritation to gastric mucosa with prolonged contact, use of risedronate is contraindicated in patients with an inability to stand or sit upright for at least 30 minutes after dose administration (see Administration) and in those with delayed esophageal emptying due to achalasia, esophageal stricture, or other cause. Risedronate should be used with caution in patients with other upper GI disease. Bisphosphonates may cause or worsen symptoms of dysphagia, esophagitis, gastroesophageal reflux disease (GERD), hiatal hernia, gastritis, and esophageal and gastric ulcers. Additionally, exercise caution when administering NSAIDs and aspirin with risedronate, due to the potential for additive GI toxicity. Prescribers and health care professionals should closely monitor patients for any signs or symptoms an esophageal reaction. Advise patients to discontinue risedronate 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, 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.
Safe and effective use of risedronate in pediatric patients (children, infants, neonates) less than 18 years of age has not been established. Bisphosphonates have been used successfully in children and adolescents for treatment of specific disease states (i.e., hypercalcemia of malignancy, idiopathic or glucocorticoid induced osteoporosis, osteogenesis imperfecta, Paget's disease). However, 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 risedronate use during human pregnancy. It is prudent to avoid the use of risedronate during pregnancy. There is a theoretical risk of fetal harm (predominantly skeletal) if a woman becomes pregnant during or after completing a course of bisphosphonate therapy. After a bisphosphonate is incorporated into bone matrix it is gradually released from the bone, over a period of weeks to years. The extent of bisphosphonate incorporation into adult bone, and hence, the amount available for release back into systemic circulation, is directly related to the total dose and duration of bisphosphonate use. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration on this risk has not been established. Bisphosphonates do cause fetal harm in animals, suggesting the uptake of bisphosphonates into fetal bone is greater than into maternal bone. Animal reproductive studies indicate risedronate may induce fetal skeletal changes, decrease maternal calcium and cause protracted parturition, and may have a possible effect on fetal viability.
Risedronate should be used with caution during breast-feeding. It is not known whether risedronate is excreted in human milk; there are no data regarding the effect on the breastfed infant or the effect on lactation physiology or breast milk composition. 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.
It is recommended that patients with renal failure or severe renal impairment with a creatinine clearance < 30 ml/min not receive risedronate. Renal excretion is substantially decreased in patients with a creatinine clearance < 30 ml/min. Patients with a creatinine clearance >= 30 ml/min do not require dosage adjustments.
Dosage adjustments of risedronate are not necessary in geriatric adults based on age alone. No overall differences in safety between geriatric and younger patients were observed in the risedronate trials for the various approved indications, but greater sensitivity of some geriatric individuals cannot be ruled out. Controlled clinical trials with risedronate for postmenopausal osteoporosis, corticosteroid-induced osteoporosis, and for Paget's disease included a good proportion of adults 65 to 75 years of age, as well as over 75 years of age; no overall differences in efficacy were observed between geriatric and younger adults during these controlled trials. In the male osteoporosis trial, the lumbar spine bone mineral density change was lower for treated subjects 65 years and older (2.9%) compared to younger men (5.6%) receiving risedronate.
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 risedronate. 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. Discontinuing the bisphosphonate once osteonecrosis develops is controversial as the estimated half-life of bisphosphonates in the bone is years.
Bisphosphonates are known to interfere with the use of bone-imaging agents. Specific studies with risedronate regarding this laboratory test interference have not been performed.
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):
Adult men and postmenopausal females: 35 mg PO once weekly. If dietary intake is not sufficient, supplement calcium and vitamin D daily. 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 risedronate 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.
Oral dosage (weekly delayed-release tablets):
Adult postmenopausal females: 35 mg PO once weekly. Supplement calcium and vitamin D if dietary intake 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 patients who are initially at very high risk of fracture and remain at high risk. Consider discontinuation after 5 years of stability in high-risk patients. For those patients at low or moderate risk for fracture, consider stopping risedronate 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.
-once monthly regimen for postmenopausal osteoporosis:
Oral dosage (monthly tablets):
Adult postmenopausal females: 150 mg PO once monthly. Supplement with calcium and vitamin D if intake is inadequate. An alternative once-monthly regimen is 75 mg PO on 2 consecutive days each month (for a total of 150 mg each month). 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 patients. For those patients at low or moderate risk for fracture, consider stopping risedronate 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.
-once daily regimen for postmenopausal osteoporosis:
Oral dosage (tablets for daily administration):
Adult postmenopausal females: 5 mg PO once daily. Supplement calcium and vitamin D if dietary intake 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 patients. For those patients at low or moderate risk for fracture, consider stopping risedronate 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.
-once daily regimen for corticosteroid-induced osteoporosis in men and women:
Oral dosage (tablets for daily administration):
Adults: 5 mg PO once daily. Supplement calcium and vitamin D if dietary intake 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 risedronate 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 or weekly delayed-release tablets):
Adult postmenopausal females: 35 mg PO once weekly. Supplement with calcium and vitamin D if 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 risedronate 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 monthly regimen for prevention of postmenopausal osteoporosis:
Oral dosage (monthly tablets):
Adult postmenopausal females: 150 mg PO once monthly. Supplement with calcium and vitamin D if intake is inadequate. An alternative once-monthly regimen is 75 mg PO on 2 consecutive days each month (for a total of 150 mg each month). The optimal treatment duration has not been determined; reevaluate treatment on a periodic basis. For those patients at low risk for fracture, consider stopping risedronate 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 with calcium and vitamin D if 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 risedronate 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 corticosteroid-induced osteoporosis in men and women:
Oral dosage (tablets for daily administration):
Adults: 5 mg PO once daily. Supplement with calcium and vitamin D if 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 risedronate 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: 30 mg PO once daily for 2 months. Supplement calcium and vitamin D if dietary intake is inadequate. Consider retreatment (following an observation period of at least 2 months) if relapse occurs, or if treatment fails to normalize serum alkaline phosphatase. For retreatment, the dose and duration of therapy are the same as for initial treatment. Risedronate is associated with histologic and radiologic evidence of disease improvement, but guidelines suggest that retreatment with risedronate may be necessary within 1 to 5 years. Guidelines also recommend a single dose of zoledronic acid preferentially due to the rare need for retreatment within 5 years, but the risedronate regimen is also an acceptable option. There are long-term data for reducing pain and lytic lesions and improving quality of life.
For osteoporosis prophylaxis to preserve bone density in selected cancer patients and to reduce adverse skeletal events due to bone metastases*:
Oral dosage (weekly tablets):
Adult females: Use not established; not FDA-approved. 35 mg PO once weekly is a common regimen used in trials for adjuvant therapy in women with breast cancer taking aromatase inhibitors. This dosage has been to increase bone density / preserve bone mass. More data are needed, as trials have not been sufficiently powered to detect reduction in fractures or determine effects in breast cancer patients with bone metastases. More data are available for zoledronic acid and ibandronate in these patients.
Oral dosage (weekly tablets):
Adult males: Use not established; not FDA-approved. 35 mg PO once weekly is a common regimen used in trials for adjuvant therapy in men with prostate cancer receiving androgen deprivation therapy. This dosage has been to increase bone density / preserve bone mass. More data are needed, as trials have not been sufficiently powered to detect reduction in fractures or determine effects in prostate cancer patients with bone metastases. More data are available for zoledronic acid in these patients.
For the treatment of osteogenesis imperfecta*:
Oral dosage (daily):
Adults: 5 mg PO once daily.
Children and Adolescents 4 to 17 years weighing more than 30 kg: 5 mg PO once daily.
Children and Adolescents 4 to 17 years weighing 10 to 30 kg: 2.5 mg PO once daily.
Oral dosage (weekly):
Adults: 35 mg PO once weekly.
Children and Adolescents 4 to 17 years weighing 40 kg or more: 30 mg PO once weekly.
Children and Adolescents 4 to 17 years weighing less than 40 kg: 15 mg PO once weekly.
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
5 mg/day PO, 35 mg/week PO, or 150 mg/month PO for osteoporosis. For Paget's disease 30 mg/day PO for 2 months.
-Geriatric
5 mg/day PO, 35 mg/week PO, or 150 mg/month PO for osteoporosis. For Paget's disease 30 mg/day PO for 2 months.
-Adolescents
Weighing 40 kg or more: Safety and efficacy have not been established; however, 5 mg/day PO or 30 mg/week PO has been used off-label for osteogenesis imperfecta.
Weighing 31 to 39 kg: Safety and efficacy have not been established; however, 5 mg/day PO or 15 mg/week PO has been used off-label for osteogenesis imperfecta.
Weighing 10 to 30 kg: Safety and efficacy have not been established; however, 2.5 mg/day PO or 15 mg/week PO has been used off-label for osteogenesis imperfecta.
-Children
4 to 12 years weighing 40 kg or more: Safety and efficacy have not been established; however, 5 mg/day PO or 30 mg/week PO has been used off-label for osteogenesis imperfecta.
4 to 12 years weighing 31 to 39 kg: Safety and efficacy have not been established; however, 5 mg/day PO or 15 mg/week PO has been used off-label for osteogenesis imperfecta.
4 to 12 years weighing 10 to 30 kg: Safety and efficacy have not been established; however, 2.5 mg/day PO or 15 mg/week PO has been used off-label for osteogenesis imperfecta.
1 to 3 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 30 mL/minute or more: No dosage adjustment is needed.
CrCl less than 30 mL/minute: Use is not recommended.
*non-FDA-approved indication
Acetaminophen; Aspirin, ASA; Caffeine: (Minor) Monitor for gastrointestinal adverse events during concurrent use of risedronate 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 risedronate 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 risedronate 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 risedronate 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 risedronate 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 oral risedronate and aluminum hydroxide by at least 2 hours. Aluminum-containing antacids will interfere with the absorption of oral risedronate.
Aluminum Hydroxide; Magnesium Carbonate: (Moderate) Separate administration of oral risedronate and aluminum hydroxide by at least 2 hours. Aluminum-containing antacids will interfere with the absorption of oral risedronate.
Aluminum Hydroxide; Magnesium Hydroxide: (Moderate) Magnesium hydroxide will interfere with the absorption of risedronate. Do not take magnesium hydroxide within 2 hours of taking risedronate. (Moderate) Separate administration of oral risedronate and aluminum hydroxide by at least 2 hours. Aluminum-containing antacids will interfere with the absorption of oral risedronate.
Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Moderate) Magnesium hydroxide will interfere with the absorption of risedronate. Do not take magnesium hydroxide within 2 hours of taking risedronate. (Moderate) Separate administration of oral risedronate and aluminum hydroxide by at least 2 hours. Aluminum-containing antacids will interfere with the absorption of oral risedronate.
Aluminum Hydroxide; Magnesium Trisilicate: (Moderate) Separate administration of oral risedronate and aluminum hydroxide by at least 2 hours. Aluminum-containing antacids will interfere with the absorption of oral risedronate.
Amlodipine; Celecoxib: (Minor) Monitor for gastrointestinal adverse events during concurrent use of risedronate 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) Use of proton pump inhibitors (PPIs) with delayed-release risedronate tablets (Atelvia) is not recommended. Co-administration of drugs that raise stomach pH increases risedronate bioavailability due to faster release of the drug from the enteric coated tablet. This interaction does not apply to risedronate immediate-release tablets. In healthy subjects who received esomeprazole for 6 days, the Cmax and AUC of a single dose of risedronate delayed-release tablets (Atelvia) increased by 60% and 22%, respectively. PPIsare 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 PPIs 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. Study results suggest that the interaction may occur across the class; however, other interactions have not been confirmed and data suggest that fracture protection is not diminished when risedronate is used with PPIs. A post hoc analysis of patients who took risedronate 5 mg daily during placebo-controlled clinical trials determined that risedronate significantly reduced the risk of new vertebral fractures compared to placebo, regardless of concomitant PPI use. PPI users (n = 240) and PPI non-users (n = 2489) experienced fracture risk reductions of 57% (p = 0.009) and 38% (p < 0.001), respectively.
Aspirin, ASA: (Minor) Monitor for gastrointestinal adverse events during concurrent use of risedronate 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 risedronate 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 risedronate 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 risedronate 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 risedronate 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 risedronate 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 risedronate 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) Use of proton pump inhibitors (PPIs) with delayed-release risedronate tablets (Atelvia) is not recommended. Co-administration of drugs that raise stomach pH increases risedronate bioavailability due to faster release of the drug from the enteric coated tablet. This interaction does not apply to risedronate immediate-release tablets. In healthy subjects who received esomeprazole for 6 days, the Cmax and AUC of a single dose of risedronate delayed-release tablets (Atelvia) increased by 60% and 22%, respectively. PPIsare 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 PPIs 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. Study results suggest that the interaction may occur across the class; however, other interactions have not been confirmed and data suggest that fracture protection is not diminished when risedronate is used with PPIs. A post hoc analysis of patients who took risedronate 5 mg daily during placebo-controlled clinical trials determined that risedronate significantly reduced the risk of new vertebral fractures compared to placebo, regardless of concomitant PPI use. PPI users (n = 240) and PPI non-users (n = 2489) experienced fracture risk reductions of 57% (p = 0.009) and 38% (p < 0.001), respectively. (Minor) Monitor for gastrointestinal adverse events during concurrent use of risedronate 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 risedronate 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.
Bupivacaine; Meloxicam: (Minor) Monitor for gastrointestinal adverse events during concurrent use of risedronate 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 risedronate 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 oral risedronate and calcium-containing supplements by at least 2 hours. Calcium will interfere with the absorption of oral risedronate.
Calcium Acetate: (Moderate) Separate administration of oral risedronate and calcium-containing supplements by at least 2 hours. Calcium will interfere with the absorption of oral risedronate.
Calcium Carbonate: (Moderate) Separate administration of oral risedronate and calcium-containing supplements by at least 2 hours. Calcium will interfere with the absorption of oral risedronate.
Calcium Carbonate; Famotidine; Magnesium Hydroxide: (Major) Use of H2-blockers with delayed-release risedronate tablets (Atelvia) is not recommended. Co-administration of drugs that raise stomach pH increases risedronate bioavailability due to faster release of the drug from the enteric coated tablet. This interaction does not apply to risedronate immediate-release tablets. (Moderate) Separate administration of oral risedronate and calcium-containing supplements by at least 2 hours. Calcium will interfere with the absorption of oral risedronate.
Calcium Carbonate; Magnesium Hydroxide: (Moderate) Separate administration of oral risedronate and calcium-containing supplements by at least 2 hours. Calcium will interfere with the absorption of oral risedronate.
Calcium Carbonate; Magnesium Hydroxide; Simethicone: (Moderate) Separate administration of oral risedronate and calcium-containing supplements by at least 2 hours. Calcium will interfere with the absorption of oral risedronate.
Calcium Carbonate; Simethicone: (Moderate) Separate administration of oral risedronate and calcium-containing supplements by at least 2 hours. Calcium will interfere with the absorption of oral risedronate.
Calcium Gluconate: (Moderate) Separate administration of oral risedronate and calcium-containing supplements by at least 2 hours. Calcium will interfere with the absorption of oral risedronate.
Calcium; Vitamin D: (Moderate) Separate administration of oral risedronate and calcium-containing supplements by at least 2 hours. Calcium will interfere with the absorption of oral risedronate.
Celecoxib: (Minor) Monitor for gastrointestinal adverse events during concurrent use of risedronate 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 risedronate 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 risedronate 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 oral risedronate and calcium-containing supplements by at least 2 hours. Calcium will interfere with the absorption of oral risedronate.
Cimetidine: (Major) Use of H2-blockers with delayed-release risedronate tablets (Atelvia) is not recommended. Co-administration of drugs that raise stomach pH increases risedronate bioavailability due to faster release of the drug from the enteric coated tablet. This interaction does not apply to risedronate immediate-release tablets.
Cod Liver Oil: (Minor) Doses in excess of 1,500 to 2,000 mcg per day of Vitamin A may lead to bone loss and will counteract the effects of risedronate therapy.
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 risedronate.
Dexlansoprazole: (Moderate) Use of proton pump inhibitors (PPIs) with delayed-release risedronate tablets (Atelvia) is not recommended. Co-administration of drugs that raise stomach pH increases risedronate bioavailability due to faster release of the drug from the enteric coated tablet. This interaction does not apply to risedronate immediate-release tablets. In healthy subjects who received esomeprazole for 6 days, the Cmax and AUC of a single dose of risedronate delayed-release tablets (Atelvia) increased by 60% and 22%, respectively. PPIsare 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 PPIs 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. Study results suggest that the interaction may occur across the class; however, other interactions have not been confirmed and data suggest that fracture protection is not diminished when risedronate is used with PPIs. A post hoc analysis of patients who took risedronate 5 mg daily during placebo-controlled clinical trials determined that risedronate significantly reduced the risk of new vertebral fractures compared to placebo, regardless of concomitant PPI use. PPI users (n = 240) and PPI non-users (n = 2489) experienced fracture risk reductions of 57% (p = 0.009) and 38% (p < 0.001), respectively.
Diclofenac: (Minor) Monitor for gastrointestinal adverse events during concurrent use of risedronate 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 risedronate 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 risedronate 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 risedronate 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 risedronate 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) Use of proton pump inhibitors (PPIs) with delayed-release risedronate tablets (Atelvia) is not recommended. Co-administration of drugs that raise stomach pH increases risedronate bioavailability due to faster release of the drug from the enteric coated tablet. This interaction does not apply to risedronate immediate-release tablets. In healthy subjects who received esomeprazole for 6 days, the Cmax and AUC of a single dose of risedronate delayed-release tablets (Atelvia) increased by 60% and 22%, respectively. PPIsare 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 PPIs 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. Study results suggest that the interaction may occur across the class; however, other interactions have not been confirmed and data suggest that fracture protection is not diminished when risedronate is used with PPIs. A post hoc analysis of patients who took risedronate 5 mg daily during placebo-controlled clinical trials determined that risedronate significantly reduced the risk of new vertebral fractures compared to placebo, regardless of concomitant PPI use. PPI users (n = 240) and PPI non-users (n = 2489) experienced fracture risk reductions of 57% (p = 0.009) and 38% (p < 0.001), respectively.
Etodolac: (Minor) Monitor for gastrointestinal adverse events during concurrent use of risedronate 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.
Famotidine: (Major) Use of H2-blockers with delayed-release risedronate tablets (Atelvia) is not recommended. Co-administration of drugs that raise stomach pH increases risedronate bioavailability due to faster release of the drug from the enteric coated tablet. This interaction does not apply to risedronate immediate-release tablets.
Fenoprofen: (Minor) Monitor for gastrointestinal adverse events during concurrent use of risedronate 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 oral risedronate and iron supplements by at least 2 hours. Iron will interfere with the absorption of oral risedronate.
Flurbiprofen: (Minor) Monitor for gastrointestinal adverse events during concurrent use of risedronate 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) Any food, including milk products, will decrease the bioavailability of risedronate, and may also increase the risk of esophageal irritation from the medication. Patients should be informed to take risedronate at least 30 minutes before their first food or drink of the day, other than plain water.
H2-blockers: (Major) Use of H2-blockers with delayed-release risedronate tablets (Atelvia) is not recommended. Co-administration of drugs that raise stomach pH increases risedronate bioavailability due to faster release of the drug from the enteric coated tablet. This interaction does not apply to risedronate immediate-release tablets.
Hydrocodone; Ibuprofen: (Minor) Monitor for gastrointestinal adverse events during concurrent use of risedronate 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 risedronate 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: (Major) Use of H2-blockers with delayed-release risedronate tablets (Atelvia) is not recommended. Co-administration of drugs that raise stomach pH increases risedronate bioavailability due to faster release of the drug from the enteric coated tablet. This interaction does not apply to risedronate immediate-release tablets. (Minor) Monitor for gastrointestinal adverse events during concurrent use of risedronate 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 risedronate 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 risedronate 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 risedronate 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 oral risedronate and iron supplements by at least 2 hours. Iron will interfere with the absorption of oral risedronate.
Iron Salts: (Moderate) Separate administration of oral risedronate and iron supplements by at least 2 hours. Iron will interfere with the absorption of oral risedronate.
Iron: (Moderate) Separate administration of oral risedronate and iron supplements by at least 2 hours. Iron will interfere with the absorption of oral risedronate.
Ketoprofen: (Minor) Monitor for gastrointestinal adverse events during concurrent use of risedronate 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 risedronate 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) Use of proton pump inhibitors (PPIs) with delayed-release risedronate tablets (Atelvia) is not recommended. Co-administration of drugs that raise stomach pH increases risedronate bioavailability due to faster release of the drug from the enteric coated tablet. This interaction does not apply to risedronate immediate-release tablets. In healthy subjects who received esomeprazole for 6 days, the Cmax and AUC of a single dose of risedronate delayed-release tablets (Atelvia) increased by 60% and 22%, respectively. PPIsare 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 PPIs 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. Study results suggest that the interaction may occur across the class; however, other interactions have not been confirmed and data suggest that fracture protection is not diminished when risedronate is used with PPIs. A post hoc analysis of patients who took risedronate 5 mg daily during placebo-controlled clinical trials determined that risedronate significantly reduced the risk of new vertebral fractures compared to placebo, regardless of concomitant PPI use. PPI users (n = 240) and PPI non-users (n = 2489) experienced fracture risk reductions of 57% (p = 0.009) and 38% (p < 0.001), respectively.
Lansoprazole; Amoxicillin; Clarithromycin: (Moderate) Use of proton pump inhibitors (PPIs) with delayed-release risedronate tablets (Atelvia) is not recommended. Co-administration of drugs that raise stomach pH increases risedronate bioavailability due to faster release of the drug from the enteric coated tablet. This interaction does not apply to risedronate immediate-release tablets. In healthy subjects who received esomeprazole for 6 days, the Cmax and AUC of a single dose of risedronate delayed-release tablets (Atelvia) increased by 60% and 22%, respectively. PPIsare 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 PPIs 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. Study results suggest that the interaction may occur across the class; however, other interactions have not been confirmed and data suggest that fracture protection is not diminished when risedronate is used with PPIs. A post hoc analysis of patients who took risedronate 5 mg daily during placebo-controlled clinical trials determined that risedronate significantly reduced the risk of new vertebral fractures compared to placebo, regardless of concomitant PPI use. PPI users (n = 240) and PPI non-users (n = 2489) experienced fracture risk reductions of 57% (p = 0.009) and 38% (p < 0.001), respectively.
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 oral risedronate and iron supplements by at least 2 hours. Iron will interfere with the absorption of oral risedronate.
Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate: (Moderate) Separate administration of oral risedronate and iron supplements by at least 2 hours. Iron will interfere with the absorption of oral risedronate.
Magnesium Citrate: (Moderate) Do not administer oral magnesium-containing products within 2 hours of oral bisphosphonates; oral magnesium may significantly reduce the absorption of the oral bisphosphonates (e.g., alendronate, etidronate, ibandronate, risedronate, or tiludronate). All medications should be administered at least 30 minutes after an alendronate or risedronate dose, and at least 1 hour after an ibandronate dose to help prevent absorption interactions. Some recommend that divalent cation-containing products should preferentially be taken at least 2 hours after these drugs or at a different time of day.
Magnesium Hydroxide: (Moderate) Magnesium hydroxide will interfere with the absorption of risedronate. Do not take magnesium hydroxide within 2 hours of taking risedronate.
Magnesium Salts: (Moderate) Oral magnesium may significantly reduce the absorption of the oral bisphosphonates (e.g., risedronate). All medications should be administered at least 30 minutes after a risedronate dose to help prevent these absorption interactions. Some recommend that divalent cation-containing products should preferentially be taken at least 2 hours after oral bisphosphonates or at a completely different time of day.
Magnesium: (Moderate) Oral magnesium may significantly reduce the absorption of the oral bisphosphonates (e.g., risedronate). All medications should be administered at least 30 minutes after a risedronate dose to help prevent these absorption interactions. Some recommend that divalent cation-containing products should preferentially be taken at least 2 hours after oral bisphosphonates or at a completely different time of day.
Meclofenamate Sodium: (Minor) Monitor for gastrointestinal adverse events during concurrent use of risedronate 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 risedronate 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 risedronate 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 risedronate 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 risedronate 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) Use of proton pump inhibitors (PPIs) with delayed-release risedronate tablets (Atelvia) is not recommended. Co-administration of drugs that raise stomach pH increases risedronate bioavailability due to faster release of the drug from the enteric coated tablet. This interaction does not apply to risedronate immediate-release tablets. In healthy subjects who received esomeprazole for 6 days, the Cmax and AUC of a single dose of risedronate delayed-release tablets (Atelvia) increased by 60% and 22%, respectively. PPIsare 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 PPIs 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. Study results suggest that the interaction may occur across the class; however, other interactions have not been confirmed and data suggest that fracture protection is not diminished when risedronate is used with PPIs. A post hoc analysis of patients who took risedronate 5 mg daily during placebo-controlled clinical trials determined that risedronate significantly reduced the risk of new vertebral fractures compared to placebo, regardless of concomitant PPI use. PPI users (n = 240) and PPI non-users (n = 2489) experienced fracture risk reductions of 57% (p = 0.009) and 38% (p < 0.001), respectively. (Minor) Monitor for gastrointestinal adverse events during concurrent use of risedronate 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 risedronate 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.
Nizatidine: (Major) Use of H2-blockers with delayed-release risedronate tablets (Atelvia) is not recommended. Co-administration of drugs that raise stomach pH increases risedronate bioavailability due to faster release of the drug from the enteric coated tablet. This interaction does not apply to risedronate immediate-release tablets.
Nonsteroidal antiinflammatory drugs: (Minor) Monitor for gastrointestinal adverse events during concurrent use of risedronate 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 oral risedronate and iron supplements by at least 2 hours. Iron will interfere with the absorption of oral risedronate.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Separate administration of oral risedronate and iron supplements by at least 2 hours. Iron will interfere with the absorption of oral risedronate.
Omeprazole: (Moderate) Use of proton pump inhibitors (PPIs) with delayed-release risedronate tablets (Atelvia) is not recommended. Co-administration of drugs that raise stomach pH increases risedronate bioavailability due to faster release of the drug from the enteric coated tablet. This interaction does not apply to risedronate immediate-release tablets. In healthy subjects who received esomeprazole for 6 days, the Cmax and AUC of a single dose of risedronate delayed-release tablets (Atelvia) increased by 60% and 22%, respectively. PPIsare 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 PPIs 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. Study results suggest that the interaction may occur across the class; however, other interactions have not been confirmed and data suggest that fracture protection is not diminished when risedronate is used with PPIs. A post hoc analysis of patients who took risedronate 5 mg daily during placebo-controlled clinical trials determined that risedronate significantly reduced the risk of new vertebral fractures compared to placebo, regardless of concomitant PPI use. PPI users (n = 240) and PPI non-users (n = 2489) experienced fracture risk reductions of 57% (p = 0.009) and 38% (p < 0.001), respectively.
Omeprazole; Amoxicillin; Rifabutin: (Moderate) Use of proton pump inhibitors (PPIs) with delayed-release risedronate tablets (Atelvia) is not recommended. Co-administration of drugs that raise stomach pH increases risedronate bioavailability due to faster release of the drug from the enteric coated tablet. This interaction does not apply to risedronate immediate-release tablets. In healthy subjects who received esomeprazole for 6 days, the Cmax and AUC of a single dose of risedronate delayed-release tablets (Atelvia) increased by 60% and 22%, respectively. PPIsare 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 PPIs 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. Study results suggest that the interaction may occur across the class; however, other interactions have not been confirmed and data suggest that fracture protection is not diminished when risedronate is used with PPIs. A post hoc analysis of patients who took risedronate 5 mg daily during placebo-controlled clinical trials determined that risedronate significantly reduced the risk of new vertebral fractures compared to placebo, regardless of concomitant PPI use. PPI users (n = 240) and PPI non-users (n = 2489) experienced fracture risk reductions of 57% (p = 0.009) and 38% (p < 0.001), respectively.
Omeprazole; 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. (Moderate) Use of proton pump inhibitors (PPIs) with delayed-release risedronate tablets (Atelvia) is not recommended. Co-administration of drugs that raise stomach pH increases risedronate bioavailability due to faster release of the drug from the enteric coated tablet. This interaction does not apply to risedronate immediate-release tablets. In healthy subjects who received esomeprazole for 6 days, the Cmax and AUC of a single dose of risedronate delayed-release tablets (Atelvia) increased by 60% and 22%, respectively. PPIsare 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 PPIs 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. Study results suggest that the interaction may occur across the class; however, other interactions have not been confirmed and data suggest that fracture protection is not diminished when risedronate is used with PPIs. A post hoc analysis of patients who took risedronate 5 mg daily during placebo-controlled clinical trials determined that risedronate significantly reduced the risk of new vertebral fractures compared to placebo, regardless of concomitant PPI use. PPI users (n = 240) and PPI non-users (n = 2489) experienced fracture risk reductions of 57% (p = 0.009) and 38% (p < 0.001), respectively.
Oxaprozin: (Minor) Monitor for gastrointestinal adverse events during concurrent use of risedronate 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) Use of proton pump inhibitors (PPIs) with delayed-release risedronate tablets (Atelvia) is not recommended. Co-administration of drugs that raise stomach pH increases risedronate bioavailability due to faster release of the drug from the enteric coated tablet. This interaction does not apply to risedronate immediate-release tablets. In healthy subjects who received esomeprazole for 6 days, the Cmax and AUC of a single dose of risedronate delayed-release tablets (Atelvia) increased by 60% and 22%, respectively. PPIsare 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 PPIs 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. Study results suggest that the interaction may occur across the class; however, other interactions have not been confirmed and data suggest that fracture protection is not diminished when risedronate is used with PPIs. A post hoc analysis of patients who took risedronate 5 mg daily during placebo-controlled clinical trials determined that risedronate significantly reduced the risk of new vertebral fractures compared to placebo, regardless of concomitant PPI use. PPI users (n = 240) and PPI non-users (n = 2489) experienced fracture risk reductions of 57% (p = 0.009) and 38% (p < 0.001), respectively.
Piroxicam: (Minor) Monitor for gastrointestinal adverse events during concurrent use of risedronate 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 risedronate with calcium polycarbophil can interfere with the oral absorption of risedronate; do not administer calcium polycarbophil within 30 minutes of risedronate. Each 625 mg of calcium polycarbophil contains a substantial amount of calcium (approximately 125 mg).
Proton pump inhibitors: (Moderate) Use of proton pump inhibitors (PPIs) with delayed-release risedronate tablets (Atelvia) is not recommended. Co-administration of drugs that raise stomach pH increases risedronate bioavailability due to faster release of the drug from the enteric coated tablet. This interaction does not apply to risedronate immediate-release tablets. In healthy subjects who received esomeprazole for 6 days, the Cmax and AUC of a single dose of risedronate delayed-release tablets (Atelvia) increased by 60% and 22%, respectively. PPIsare 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 PPIs 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. Study results suggest that the interaction may occur across the class; however, other interactions have not been confirmed and data suggest that fracture protection is not diminished when risedronate is used with PPIs. A post hoc analysis of patients who took risedronate 5 mg daily during placebo-controlled clinical trials determined that risedronate significantly reduced the risk of new vertebral fractures compared to placebo, regardless of concomitant PPI use. PPI users (n = 240) and PPI non-users (n = 2489) experienced fracture risk reductions of 57% (p = 0.009) and 38% (p < 0.001), respectively.
Pyridoxine, Vitamin B6: (Moderate) Separate administration of oral risedronate and calcium-containing supplements by at least 2 hours. Calcium will interfere with the absorption of oral risedronate.
Rabeprazole: (Moderate) Use of proton pump inhibitors (PPIs) with delayed-release risedronate tablets (Atelvia) is not recommended. Co-administration of drugs that raise stomach pH increases risedronate bioavailability due to faster release of the drug from the enteric coated tablet. This interaction does not apply to risedronate immediate-release tablets. In healthy subjects who received esomeprazole for 6 days, the Cmax and AUC of a single dose of risedronate delayed-release tablets (Atelvia) increased by 60% and 22%, respectively. PPIsare 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 PPIs 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. Study results suggest that the interaction may occur across the class; however, other interactions have not been confirmed and data suggest that fracture protection is not diminished when risedronate is used with PPIs. A post hoc analysis of patients who took risedronate 5 mg daily during placebo-controlled clinical trials determined that risedronate significantly reduced the risk of new vertebral fractures compared to placebo, regardless of concomitant PPI use. PPI users (n = 240) and PPI non-users (n = 2489) experienced fracture risk reductions of 57% (p = 0.009) and 38% (p < 0.001), respectively.
Ranitidine: (Major) Use of H2-blockers with delayed-release risedronate tablets (Atelvia) is not recommended. Co-administration of drugs that raise stomach pH increases risedronate bioavailability due to faster release of the drug from the enteric coated tablet. This interaction does not apply to risedronate immediate-release tablets.
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 oral risedronate and iron supplements by at least 2 hours. Iron will interfere with the absorption of oral risedronate.
Sodium Sulfate; Magnesium Sulfate; Potassium Chloride: (Moderate) Oral magnesium may significantly reduce the absorption of the oral bisphosphonates (e.g., risedronate). All medications should be administered at least 30 minutes after a risedronate dose to help prevent these absorption interactions. Some recommend that divalent cation-containing products should preferentially be taken at least 2 hours after oral bisphosphonates or at a completely different time of day.
Sulindac: (Minor) Monitor for gastrointestinal adverse events during concurrent use of risedronate 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 risedronate 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 risedronate 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.
Vitamin A: (Minor) Doses in excess of 1,500 to 2,000 mcg per day of Vitamin A may lead to bone loss and will counteract the effects of risedronate therapy.
Vonoprazan: (Major) Avoid concomitant use of vonoprazan with delayed-release risedronate tablets (Atelvia). Concomitant use of drugs that raise gastric pH, such as vonoprazan, increases risedronate bioavailability due to faster release of the drug from the enteric coated tablet. This interaction does not apply to risedronate immediate-release tablets.
Vonoprazan; Amoxicillin: (Major) Avoid concomitant use of vonoprazan with delayed-release risedronate tablets (Atelvia). Concomitant use of drugs that raise gastric pH, such as vonoprazan, increases risedronate bioavailability due to faster release of the drug from the enteric coated tablet. This interaction does not apply to risedronate immediate-release tablets.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Avoid concomitant use of vonoprazan with delayed-release risedronate tablets (Atelvia). Concomitant use of drugs that raise gastric pH, such as vonoprazan, increases risedronate bioavailability due to faster release of the drug from the enteric coated tablet. This interaction does not apply to risedronate immediate-release tablets.
Risedronate is a potent antiresorptive agent that does not affect bone mineralization. The inclusion of an amino group within the heterocyclic ring makes risedronate one of the most potent antiresorptive bisphosphonates. Risedronate binds to bone hydroxyapatite and specifically inhibits the activity of osteoclasts, the bone-resorbing cells. Risedronate reduces bone resorption with no direct effect on bone formation. At the cellular level, risedronate shows preferential localization to sites of bone resorption, specifically inhibiting osteoclasts. The osteoclasts adhere normally to the bone surface but lack the ruffled border that is indicative of active resorption. Histomorphometry in rats, dogs, and minipigs showed that risedronate reduces bone turnover (i.e., the rate at which bone remodeling sites are activated) and bone resorption at remodeling sites, leading to progressive gains in bone mass.
Like other bisphosphonates, the exact mechanism of risedronate'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. Risedronate 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, risedronate 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.
Risedronate is administered orally. Approximately 60% of the absorbed dose is distributed to the bone with the remainder of the dose excreted in the urine. Unabsorbed drug is eliminated in the feces. Risedronate is not metabolized in the liver and does not induce or inhibit hepatic microsomal drug-metabolizing enzymes. Approximately 50% of the absorbed dose is excreted in the urine within 24 hours. Risedronate elimination is biphasic with an initial half-life of 1.5 hours and a terminal half-life of 220 hours. The extended terminal half-life is thought to be due to risedronate release from bone.
-Route-Specific Pharmacokinetics
Oral Route
Risedronate is absorbed throughout the upper GI tract after oral administration. Differences in time to peak plasma concentration and bioavailability exist between the immediate-release and delayed-release dosage forms; both forms are significantly affected by administration with food. Immediate release tablets achieve Tmax approximately 1 hour after administration, while the Tmax of delayed-release tablets occurs approximately 3 hours after the dose. Bioavailability of 35 mg delayed-release tablets given after a high-fat breakfast and 35 mg immediate-release tablets given 4 hours prior to a meal are similar; however, the bioavailability of the delayed-release tablet is 2- to 4-fold higher than that of the immediate-release tablet administered as indicated (at least 30 minutes prior to breakfast). The average bioavailability of immediate-release risedronate taken 4 hours prior to a meal is 0.63%. Absorption of the immediate-release tablet is decreased by 55% if this dosage form is taken either 0.5 hours prior to breakfast or 2 hours after dinner as compared to absorption in the fasting state, while absorption is decreased by 30% when given 1 hour prior to breakfast as compared to the fasting state. The bioavailability of delayed-release risedronate is decreased by approximately 30% when administered 30 minutes after a high-fat breakfast as compared to when administered 4 hours prior to the morning meal; however, in clinical trials, administration of delayed-release risedronate prior to breakfast, resulted in a higher incidence of abdominal pain. Risedronate is considered effective when immediate-release tablets are given at least 30 minutes prior to breakfast and when delayed-release tablets are given after breakfast. Unabsorbed drug is eliminated in the feces.
-Special Populations
Hepatic Impairment
While pharmacokinetic studies of risedronate have not been performed in patients with hepatic impairment, risedronate is not metabolized by the liver. No dosing adjustments are needed in such patients.
Renal Impairment
There is a linear relationship between risedronate clearance and creatinine clearance (CrCl). The renal clearance of risedronate is decreased by roughly 70% in patients with a CrCl of roughly 30 ml/min relative to normal controls. There is a lack of clinical data in patients with CrCl < 30 ml/min; use of either immediate-release or delayed-release risedronate is not recommended in this population.
Pediatrics
No pharmacokinetic data for risedronate, of either the immediate-release or delayed-release formulation, are available for children.
Elderly
In adults, there are no differences in pharmacokinetic parameters for risedronate based on age.
Gender Differences
In adults, there are no differences in pharmacokinetic parameters for immediate-release risedronate based on gender ; no such data is available for delayed-release risedronate use.