WARNINGS AND PRECAUTIONS
Upper Gastrointestinal Adverse Reactions
ACTONEL, like other bisphosphonates administered orally, may cause local irritation of the upper gastrointestinal mucosa. Because of these possible irritant effects and a potential for worsening of the underlying disease, caution should be used when ACTONEL is given to patients with active upper gastrointestinal problems (such as known Barrett’s esophagus, dysphagia, other esophageal diseases, gastritis, duodenitis or ulcers) [see
Contraindications (4), Adverse Reactions (6.1), Information for Patients (17.1)].
Esophageal adverse experiences, such as esophagitis, esophageal ulcers and esophageal erosions, occasionally with bleeding and rarely followed by esophageal stricture or perforation, have been reported in patients receiving treatment with oral bisphosphonates. In some cases, these have been severe and required hospitalization. Physicians should therefore be alert to any signs or symptoms signaling a possible esophageal reaction and patients should be instructed to discontinue ACTONEL and seek medical attention if they develop dysphagia, odynophagia, retrosternal pain or new or worsening heartburn.
The risk of severe esophageal adverse experiences appears to be greater in patients who lie down after taking oral bisphosphonates and/or who fail to swallow it with the recommended full glass (6-8 oz) of water, and/or who continue to take oral bisphosphonates after developing symptoms suggestive of esophageal irritation. Therefore, it is very important that the full dosing instructions are provided to, and understood by, the patient [see Dosage and Administration (2)]. In patients who cannot comply with dosing instructions due to mental disability, therapy with ACTONEL should be used under appropriate supervision.
There have been post-marketing reports of gastric and duodenal ulcers with oral bisphosphonate use, some severe and with complications, although no increased risk was observed in controlled clinical trials.
Hypocalcemia and other disturbances of bone and mineral metabolism should be effectively treated before starting ACTONEL therapy. 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 [see
Contraindications (4), Adverse Reactions (6.1), Information for Patients (17.1)].
Osteonecrosis of the jaw (ONJ), which can occur spontaneously, is generally associated with tooth extraction and/or local infection with delayed healing, and has been reported in patients taking bisphosphonates, including ACTONEL. Known risk factors for osteonecrosis of the jaw include invasive dental procedures (e.g., tooth extraction, dental implants, boney surgery), diagnosis of cancer, concomitant therapies (e.g., chemotherapy, corticosteroids), poor oral hygiene, and co-morbid disorders (e.g., periodontal and/or other pre-existing dental disease, anemia, coagulopathy, infection, ill-fitting dentures).
For patients requiring invasive dental procedures, discontinuation of bisphosphonate treatment may reduce the risk for ONJ. Clinical judgment of the treating physician and/or oral surgeon should guide the management plan of each patient based on individual benefit/risk assessment.
Patients who develop osteonecrosis of the jaw while on bisphosphonate therapy should receive care by an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition. Discontinuation of bisphosphonate therapy should be considered based on individual benefit/risk assessment. [see
Adverse Reactions (6.2)]
In postmarketing experience, there have been reports of severe and occasionally incapacitating bone, joint, and/or muscle pain in patients taking bisphosphonates [see
Adverse Reactions (6.2)]. The time to onset of symptoms varied from one day to several months after starting the drug. Most patients had relief of symptoms after stopping medication. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate. Consider discontinuing use if severe symptoms develop.
ACTONEL is not recommended for use in patients with severe renal impairment (creatinine clearance <30 mL/min).
Before initiating ACTONEL treatment for the treatment and prevention of glucocorticoid-induced osteoporosis, the sex steroid hormonal status of both men and women should be ascertained and appropriate replacement considered.
Laboratory Test Interactions
Bisphosphonates are known to interfere with the use of bone-imaging agents. Specific studies with ACTONEL have not been performed.
USE IN SPECIFIC POPULATIONS
Pregnancy Category C: There are no adequate and well-controlled studies of ACTONEL in pregnant women. ACTONEL should be used during pregnancy only if the potential benefit justifies the potential risk to the mother and fetus.
Bisphosphonates are incorporated into the bone matrix, from which they are gradually released over periods of weeks to years. The amount of bisphosphonate incorporation into adult bone, and hence, the amount available for release back into the systemic circulation, is directly related to the dose and duration of bisphosphonate use. There are no data on fetal risk in humans. However, there is a theoretical risk of fetal harm, predominantly skeletal, if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on this risk has not been studied.
In animal studies, pregnant rats received risedronate sodium during organogenesis at doses 1 to 26 times the human dose of 30 mg/day. Survival of neonates was decreased in rats treated during gestation with oral doses approximately 5 times the human dose and body weight was decreased in neonates from dams treated with approximately 26 times the human dose. The number of fetuses exhibiting incomplete ossification of sternebrae or skull from dams treated with approximately 2.5 times the human dose was significantly increased compared to controls. Both incomplete ossification and unossified sternebrae were increased in rats treated with oral doses approximately 5 times the human dose. A low incidence of cleft palate was observed in fetuses from female rats treated with oral doses approximately equal to the human dose. The relevance of this finding to human use of ACTONEL is unclear.
No significant fetal ossification effects were seen in rabbits treated with oral doses approximately 7 times the human dose (the highest dose tested). However, 1 of 14 litters were aborted and 1 of 14 litters were delivered prematurely.
Similar to other bisphosphonates, treatment during mating and gestation with doses of risedronate sodium approximately the same as the 30 mg/day human dose resulted in periparturient hypocalcemia and mortality in pregnant rats allowed to deliver.
Dosing multiples provided above are based on the recommended human dose of 30 mg/day and normalized using body surface area (mg/m2). Actual animal doses were 3.2, 7.1 and 16 mg/kg/day in the rat and 10 mg/kg/day in the rabbit.
Risedronate was detected in feeding pups exposed to lactating rats for a 24-hour period post-dosing, indicating a small degree of lacteal transfer. It is not known whether ACTONEL is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ACTONEL, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
ACTONEL is not indicated for use in pediatric patients.
The safety and effectiveness of risedronate was assessed in a one-year, randomized, double-blind, placebo controlled study of 143 pediatric patients (94 received risedronate) with osteogenesis imperfecta (OI). The enrolled population was predominantly patients with mild osteogenesis imperfecta (85% Type-I), aged 4 to <16 years, 50% male and 82% Caucasian, with a mean lumbar spine BMD Z-score of -2.08 (2.08 standard deviations below the mean for age-matched controls). Patients received either a 2.5 mg (≤30 kg body weight) or 5 mg (>30 kg body weight) daily oral dose. After one year, an increase in lumbar spine BMD in the risedronate group compared to the placebo group was observed. However, treatment with risedronate did not result in a reduction in the risk of fracture in pediatric patients with osteogenesis imperfecta. In ACTONEL-treated subjects, no mineralization defects were noted in paired bone biopsy specimens obtained at baseline and month 12.
The overall safety profile of risedronate in OI patients treated for up to 12 months was generally similar to that of adults with osteoporosis. However, there was an increased incidence of vomiting compared to placebo. In this study, vomiting was observed in 15% of children treated with risedronate and 6% of patients treated with placebo. Other adverse events reported in ≥10% of patients treated with risedronate and with a higher frequency than placebo were: pain in the extremity (21% with risedronate versus 16% with placebo), headache (20% versus 8%), back pain (17% versus 10%), pain (15% versus 10%), upper abdominal pain (11% versus 8%), and bone pain (10% versus 4%).
Of the patients receiving ACTONEL in postmenopausal osteoporosis studies [see
Clinical Studies (14)], 47% were between 65 and 75 years of age, and 17% were over 75. The corresponding proportions were 26% and 11% in glucocorticoid-induced osteoporosis trials, and 40% and 26% in Paget’s disease trials. No overall differences in efficacy between geriatric and younger patients were observed in these studies. In the male osteoporosis trial, 28% of patients receiving ACTONEL were between 65 and 75 years of age and 9% were over 75. The lumbar spine BMD response for ACTONEL compared to placebo was 5.6% for subjects <65 years and 2.9% for subjects ≥65 years. No overall differences in safety between geriatric and younger patients were observed in the ACTONEL trials, but greater sensitivity of some older individuals cannot be ruled out.
ACTONEL is not recommended for use in patients with severe renal impairment (creatinine clearance <30 mL/min) because of lack of clinical experience. No dosage adjustment is necessary in patients with a creatinine clearance ≥30 mL/min.
No studies have been performed to assess risedronate’s safety or efficacy in patients with hepatic impairment. Risedronate is not metabolized in human liver preparations. Dosage adjustment is unlikely to be needed in patients with hepatic impairment.