Bisphosphonates may cause upper gastrointestinal disorders such as dysphagia, esophagitis, and esophageal or gastric ulcer (see PRECAUTIONS).

See PRECAUTIONS

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. ACTONEL is not recommended for use in patients with severe renal impairment (creatinine clearance <30 mL/min).

Bisphosphonates have been associated with gastrointestinal disorders such as dysphagia, esophagitis, and esophageal or gastric ulcers. This association has been reported for bisphosphonates in postmarketing experience, but has not been found in most pre-approval clinical trials, including those conducted with ACTONEL. Patients should be advised that taking the medication according to the instructions is important to minimize the risk of these events. They should take ACTONEL with sufficient plain water (6 to 8 oz) to facilitate delivery to the stomach, and should not lie down for 30 minutes after taking the drug.

Osteonecrosis, primarily in the jaw, has been reported in patients treated with bisphosphonates. Most cases have been in cancer patients undergoing dental procedures such as tooth extraction, but some have occurred in patients with postmenopausal osteoporosis or other diagnoses. Most reported cases have been in patients treated with bisphosphonates intravenously but some have been in patients treated orally.

For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment, prior to the procedure, reduces the risk of osteonecrosis of the jaw. Clinical judgement should guide the management plan of each patient based on individual benefit/risk assessment.

In postmarketing experience, there have been infrequent reports of severe and occasionally incapacitating bone, joint, and/or muscle pain in patients taking bisphosphonates (see ADVERSE REACTIONS). 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.

ACTONEL with CALCIUM should not be used to treat hypocalcemia. Total daily intake of calcium above 1500 mg has not demonstrated additional bone benefits while daily intake above 2000 mg has been associated with increased risk of adverse effects, including hypercalcemia and kidney stones.

Administration of calcium has been associated with a slight increase in the risk of kidney stones.

In patients with a history of kidney stones or hypercalciuria, metabolic assessment to seek treatable causes of these conditions is warranted. If administration of calcium tablets should be needed in these patients, urinary calcium excretion and other appropriate testing should be monitored periodically.

Patients with achlorhydria may have decreased absorption of calcium. Taking calcium with food enhances absorption.

Concomitant use of calcium-containing antacids should be monitored to avoid excessive intake of calcium.

In a 104-week carcinogenicity study, rats were administered daily oral doses of risedronate up to 24 mg/kg/day (approximately 50 times the systemic exposure following a 35 mg/week human dose based on surface area, mg/m²). There were no significant drug-induced tumor findings in male or female rats. The high dose male group of 24 mg/kg/day was terminated early in the study (Week 93) due to excessive toxicity, and data from this group were not included in the statistical evaluation of the study results. In an 80-week carcinogenicity study, mice were administered daily oral doses up to 32 mg/kg/day (approximately 30 times the systemic exposure following a 35 mg/week human dose based on surface area, mg/m²). There were no significant drug-induced tumor findings in male or female mice.

Risedronate did not exhibit genetic toxicity in the following assays: In vitro bacterial mutagenesis in Salmonella and E. coli (Ames assay), mammalian cell mutagenesis in CHO/HGPRT assay, unscheduled DNA synthesis in rat hepatocytes and an assessment of chromosomal aberrations in vivo in rat bone marrow.

In female rats, ovulation was inhibited at an oral dose of risedronate of 16 mg/kg/day (approximately 30 times the systemic exposure following a 35 mg/week human dose based on surface area, mg/m²). Decreased implantation was noted in female rats treated with doses ≥ 7 mg/kg/day (14 times the systemic exposure following a 35 mg/week human dose based on surface area, mg/m²). In male rats, testicular and epididymal atrophy and inflammation were noted at 40 mg/kg/day (80 times the systemic exposure following a 35 mg/week human dose based on surface area, mg/m²). Testicular atrophy was also noted in male rats after 13 weeks of treatment at oral doses of 16 mg/kg/day (approximately 30 times the systemic exposure following a 35 mg/week human dose based on surface area, mg/m²). There was moderate-to-severe spermatid maturation block after 13 weeks in male dogs at an oral dose of 8 mg/kg/day (approximately 50 times the systemic exposure following a 35 mg/week human dose based on surface area, mg/m²).

Survival of neonates was decreased in rats treated during gestation with oral doses of risedronate ≥ 16 mg/kg/day (approximately 30 times the systemic exposure following a 35 mg/week human dose based on surface area, mg/m²). Body weight was decreased in neonates from dams treated with 80 mg/kg (approximately 160 times the 35 mg/week human dose based on surface area, mg/m²). In rats treated during gestation, the number of fetuses exhibiting incomplete ossification of sternebrae or skull was statistically significantly increased at 7.1 mg/kg/day (approximately 14 times the 35 mg/week human dose based on surface area, mg/m²). Both incomplete ossification and unossified sternebrae were increased in rats treated with oral doses ≥ 16 mg/kg/day (approximately 30 times the 35 mg/week human dose based on surface area, mg/m²). A low incidence of cleft palate was observed in fetuses from female rats treated with oral doses ≥ 3.2 mg/kg/day (approximately 20 times the 35 mg/week human dose based on surface area, mg/m²). 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 up to 10 mg/kg/day during gestation (40 times the 35 mg/week human dose based on surface area, mg/m²). However, in rabbits treated with 10 mg/kg/day, 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 as low as 3.2 mg/kg/day (approximately 20 times the 35 mg/week human dose based on surface area, mg/m²) has resulted in periparturient hypocalcemia and mortality in pregnant rats allowed to deliver.

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.

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.

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 risedronate 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 bisphosphonates, 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.

Safety and effectiveness in pediatric patients have not been established.

Of the patients receiving ACTONEL in postmenopausal osteoporosis studies (see CLINICAL STUDIES), 47% were between 65 and 75 years of age, and 17% were over 75. No overall differences in efficacy or safety were observed between these patients and younger patients but greater sensitivity of some older individuals cannot be ruled out.

There are no published data that specifically compare the efficacy and safety between postmenopausal women above and below the age of 65 years.

The safety and effectiveness in men for the treatment of primary osteoporosis have not been established.

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