ACTONEL WITH CALCIUM (COPACKAGED)
Clinical safety rating: caution
Comprehensive clinical and safety monograph for ACTONEL WITH CALCIUM (COPACKAGED) (ACTONEL WITH CALCIUM (COPACKAGED)).
ACTONEL WITH CALCIUM (COPACKAGED) contains risedronate sodium, a bisphosphonate that inhibits osteoclast-mediated bone resorption by binding to hydroxyapatite crystals in bone and inhibiting farnesyl pyrophosphate synthase (FPPS), an enzyme in the mevalonate pathway. This leads to reduced bone turnover and increased bone mineral density. The calcium component is for supplementation to prevent hypocalcemia.
| Metabolism | Risedronate is not metabolized and is eliminated unchanged primarily via renal excretion. |
| Excretion | Risedronate is eliminated primarily via renal excretion, with approximately 50% of an absorbed dose excreted unchanged in urine. Unabsorbed drug is eliminated in feces. Total clearance is about 100 mL/min. |
| Half-life | Terminal elimination half-life of risedronate is approximately 20 hours for the 5 mg daily dose and 480 hours for the 35 mg weekly dose due to prolonged retention in bone; clinically, the drug accumulates in bone and is slowly released. |
| Protein binding | Risedronate is approximately 24% bound to plasma proteins. |
| Volume of Distribution | Volume of distribution for risedronate is approximately 6.3 L/kg, indicating extensive distribution into bone and other tissues. |
| Bioavailability | Oral bioavailability of risedronate is low, averaging 0.63% for the 5 mg tablet when taken under fasting conditions; administration with food reduces bioavailability significantly (by up to 50%). |
| Onset of Action | Onset of action for risedronate in osteoporosis is not immediate; reduction in bone turnover markers is observed within weeks, but fracture risk reduction is evident after 6-12 months of continuous therapy. |
| Duration of Action | Pharmacodynamic effects on bone resorption persist for weeks after discontinuation due to bone binding; however, for optimal efficacy, continuous dosing (daily or weekly) is recommended. |
| Molecular Weight | Risedronate: 350.13 Da; Calcium: 40.08 Da |
Actonel (risedronate) 35 mg orally once weekly, taken with 6-8 oz of plain water at least 30 minutes before breakfast. Calcium supplement (e.g., 1250 mg calcium carbonate) taken with food at a different time of day.
| Dosage form | TABLET |
| Renal impairment | Contraindicated if CrCl <30 mL/min. For CrCl 30-49 mL/min: no dose adjustment needed. For CrCl ≥50 mL/min: no adjustment. |
| Liver impairment | No dose adjustment required for mild to moderate hepatic impairment (Child-Pugh A or B). Not studied in severe impairment (Child-Pugh C). |
| Pediatric use | Not indicated for use in pediatric patients. Safety and efficacy not established. |
| Geriatric use | No specific dose adjustment required. Caution in patients with decreased renal function; monitor renal status. Increased risk of hypocalcemia if calcium intake inadequate. |
| 1st trimester | Risedronate is pregnancy category C. No adequate studies in humans; animal studies show fetal harm. Use only if benefit outweighs risk. |
| 2nd trimester | Same as t1; avoid due to potential effects on fetal skeletal development. |
| 3rd trimester | Same as t1; avoid due to potential for maternal hypocalcemia and fetal effects. |
Clinical note
Comprehensive clinical and safety monograph for ACTONEL WITH CALCIUM (COPACKAGED) (ACTONEL WITH CALCIUM (COPACKAGED)).
| Placental transfer | Risedronate is known to cross the placenta in animals; human data limited but likely occurs. |
| Breastfeeding | Risedronate is excreted in rat milk at low concentrations; unknown in human milk. Calcium is normal milk component. Use with caution; consider benefit to mother. |
■ FDA Black Box Warning
None
| Serious Effects |
HypocalcemiaSevere renal impairment (CrCl <30 mL/min)Esophageal stricture or achalasiaInability to stand or sit upright for at least 30 minutes
| Precautions | Hypocalcemia must be corrected before therapy, Severe renal impairment (CrCl <30 mL/min) is not recommended, Esophageal irritation: instruct patients to swallow with full glass of water and not to lie down for 30 minutes, Osteonecrosis of the jaw (rare, mainly with cancer doses), Atypical femur fractures (rare, with long-term use), Avoid concomitant use with other bisphosphonates |
| Food/Dietary | Risedronate absorption is significantly reduced by food, especially dairy products, calcium-rich foods, and beverages other than plain water. Avoid all food, beverages (except plain water), and other medications for at least 30 minutes after the dose. Calcium supplement should be taken with a meal to enhance absorption. |
Loading safety data…
| Lactation Rating |
| L3 |
| Teratogenic Risk | Risedronate: Pregnancy Category C. Bisphosphonates accumulate in bone and are released slowly; theoretical risk of fetal skeletal abnormalities if exposure occurs before or during pregnancy. No adequate studies in pregnant women; use only if clearly needed. Calcium carbonate: Generally considered safe but excessive doses may cause hypercalcemia-related fetal risks. First trimester: Limited data, avoid if possible. Second/third trimester: Use only if maternal benefit outweighs fetal risk. |
| Fetal Monitoring | Monitor serum calcium, phosphate, and magnesium in mothers on prolonged therapy. Assess renal function before and during treatment. In pregnancy, consider fetal ultrasound to assess skeletal development if bisphosphonate exposure occurred. Monitor for maternal hypocalcemia symptoms. |
| Fertility Effects | Risedronate: No known adverse effects on fertility in animal studies. Calcium: Essential for normal reproductive function; deficiency may impair fertility. No negative fertility effects expected at recommended doses. |
| Clinical Pearls | Actonel (risedronate) with calcium (copackaged) is used for osteoporosis. Administer risedronate on an empty stomach with plain water, at least 30 minutes before first food, drink, or other medications. Wait at least 30 minutes after risedronate before taking the calcium supplement. Calcium can interfere with risedronate absorption. |
| Patient Advice | Take the risedronate tablet first thing in the morning, at least 30 minutes before eating or drinking anything except plain water. · Swallow the risedronate tablet whole with a full glass of plain water (6-8 oz). Do not crush, chew, or suck the tablet. · Do not lie down for at least 30 minutes after taking risedronate to reduce risk of esophageal irritation. · After taking risedronate, wait at least 30 minutes before taking the calcium supplement provided in the copack. · Take the calcium supplement with food or after a meal to improve absorption and reduce stomach upset. · Report any symptoms of esophageal problems (difficulty or pain on swallowing, heartburn, or retrosternal pain) or jaw pain (possible osteonecrosis of the jaw). |