Each 35- and 150-mg tablet contains risedronate sodium equivalent to risedronic acid 32.5 mg and 139.2 mg, respectively. It also contains the following excipients: Tablet Core: Lactose monohydrate, microcrystalline cellulose, crospovidone, magnesium stearate. Film-Coating: Yellow ferric oxide (E172), red ferric oxide (E172), hypromellose, macrogol 400, hydroxypropyl cellulose, macrogol 8000, silicon dioxide, titanium dioxide (E171).
Pharmacotherapeutic Group: Bisphosphonates. ATC Code: M05BA07.
Pharmacology: Risedronate sodium is a pyridinyl bisphosphonate that binds to bone hydroxyapatite and inhibits osteoclast-mediated bone resorption. The bone turnover is reduced while the osteoblast activity and bone mineralisation are preserved. In preclinical studies, risedronate sodium demonstrated potent anti-osteoclast and antiresorptive activity, and dose dependently increased bone mass and biomechanical skeletal strength. The activity of risedronate sodium was confirmed by measuring biochemical markers for bone turnover during pharmacodynamic and clinical studies. In studies of postmenopausal women, decreases in the biochemical markers of bone turnover were observed within 1 month and reached a maximum in 3-6 months. Decreases in biochemical markers of bone turnover were similar with Actonel 35 mg once a week at 12 months.
In a study in men with osteoporosis, decreases in biochemical markers of bone turnover were observed at the earliest time point of 3 months and continued to be observed at 24 months.
Treatment of Postmenopausal Osteoporosis: A number of risk factors are associated with postmenopausal osteoporosis including low bone mass, low bone mineral density (BMD), early menopause, history of smoking and family history of osteoporosis. The clinical consequence of osteoporosis is fractures. The risk of fractures is increased with the number of risk factors.
Based on effects on mean change in lumbar spine BMD, Actonel 35 mg once a week (n=485) was shown to be equivalent to Actonel 5 mg daily (n=480) in a 1-year, double-blind, multicenter study of postmenopausal women with osteoporosis.
The clinical programme for risedronate sodium administered once daily studied the effect of risedronate sodium on the risk of hip and vertebral fractures and contained early and late postmenopausal women with and without fracture. Daily doses of 2.5 and 5 mg were studied and all groups, including the control groups, received calcium and vitamin D (if baseline levels were low). The absolute and relative risk of new vertebral and hip fractures were estimated by use of a time-to-first-event analysis.
In a double-blind, active-controlled, multicenter study of postmenopausal women with osteoporosis, 1 year of treatment with Actonel 150 mg once a month (n=650) was shown to be non-inferior to Actonel 5 mg daily (n=642). In the primary efficacy analysis of completers, the mean increases from baseline in lumbar spine BMD at 1 year were 3.4% (3, 3.8; 95% CI) in the 5 mg daily group (n=561) and 3.5% (3.1, 3.9; 95% CI) in the 150 mg once a month group (n=561) with a mean difference between groups being -0.1% (-0.5, 2; 95% CI). The 2 treatment groups were also similar with regard to BMD increases at other skeletal sites. The number of patients with new vertebral fractures at month 12 and endpoint were similar in the 150 mg once a month group and the 5 mg daily group (at endpoint, 150 mg 1.4%; 5 mg daily 1.4%).
Two placebo-controlled trials (n=3661) enrolled postmenopausal women <85 years with vertebral fractures at baseline. Risedronate sodium 5 mg daily given for 3 years reduced the risk of new vertebral fractures relative to the control group. In women with respectively at least 2 or at least 1 vertebral fractures, the relative risk reduction was 49% and 41%, respectively (incidence of new vertebral fractures with risedronate sodium 18.1% and 11.3%, with placebo 29% and 16.3%, respectively). The effect of treatment was seen as early as the end of the 1st year of treatment. Benefits were also demonstrated in women with multiple fractures at baseline. Risedronate sodium 5 mg daily also reduced the yearly height loss compared to the control group.
Two further placebo-controlled trials enrolled postmenopausal women >70 years with or without vertebral fractures at baseline. Women 70-79 years were enrolled with femoral neck BMD T-score less than -3 SD (manufacturer's range ie, -2.5 SD using NHANES III) and at least 1 additional risk factor. Women ≥80 years could be enrolled on the basis of at least 1 nonskeletal risk factor for hip fracture or low BMD at the femoral neck. Statistical significance of the efficacy of risedronate versus placebo is only reached when 2 treatment groups 2.5 and 5 mg are pooled. The following results are only based on a-posteriori analysis of subgroups defined by clinical practice and current definitions of osteoporosis: In the subgroup of patients with femoral neck BMD T-score -2.5 SD or less (NHANES III) and at least 1 vertebral fracture at baseline, risedronate sodium given for 3 years reduced the risk of hip fractures by 46% relative to the control group (incidence of hip fractures in combined risedronate sodium 2.5 and 5 mg groups 3.8%, placebo 7.4%).
Data suggest that a more limited protection than this may be observed in the very elderly (≥80 years). This may be due to the increasing importance of nonskeletal factors for hip fracture with increasing age.
In these trials, data analysed as a secondary endpoint indicated a decrease in the risk of new vertebral fractures in patients with low femoral BMD without vertebral fracture and in patients with low femoral neck BMD with or without vertebral fracture.
Risedronate sodium 5 mg daily given for 3 years increased BMD relative to control at the lumbar spine, femoral neck, trochanter and wrist and maintained bone density at the midshaft radius.
In a 1-year follow-up off therapy after 3 years treatment with risedronate sodium 5 mg daily, there was a rapid reversibility of the suppressing effect of risedronate sodium on bone turnover rate.
Bone biopsy samples from postmenopausal women treated with risedronate sodium 5 mg daily for 2-3 years, showed an expected moderate decrease in bone turnover. Bone formed during risedronate sodium treatment was of normal lamellar structure and bone mineralisation. These data together with the decreased incidence of osteoporosis-related fractures at vertebral sites in women with osteoporosis appear to indicate no detrimental effect on bone quality.
Endoscopic findings from a number of patients with a number of moderate to severe gastrointestinal complaints in both risedronate sodium and control patients indicated no evidence of treatment-related gastric, duodenal or oesophageal ulcers in either group, although duodenitis was uncommonly observed in the risedronate sodium group.
Treatment of Osteoporosis in Men: Risedronate sodium 35 mg once a week demonstrated efficacy in men with osteoporosis (age range 36-84 years) in a 2-year, double-blind, placebo-controlled study in 284 patients (risedronate sodium 35 mg, n=191). All patients received supplemental calcium and vitamin D.
Increases in BMD were observed as early as 6 months following initiation of risedronate sodium treatment. Risedronate sodium 35 mg once a week produced mean increases in BMD at the lumbar spine, femoral neck, trochanter and total hip compared to placebo after 2 years of treatment.
Antifracture efficacy was not demonstrated in this study.
The bone effect [BMD increase and bone turnover markers (BTM) decrease] of risedronate sodium is similar in males and females.
Pharmacokinetics: Absorption: Absorption after an oral dose is relatively rapid (tmax approximately 1 hr) and is independent of the dose over the range studied (single-dose study: 2.5-30 mg; multiple-dose studies: 2.5-5 mg daily and up to 50 mg weekly). Mean oral bioavailability of the tablet is 0.63% and is decreased when risedronate sodium is administered with food. Bioavailability was similar in men and women.
Distribution: The mean steady-state volume of distribution is 6.3 L/kg in humans. Plasma protein-binding is about 24%.
Metabolism: There is no evidence of systemic metabolism of risedronate sodium.
Elimination: Approximately ½ of the absorbed dose is excreted in urine within 24 hrs, and 85% of an IV dose is recovered in the urine after 28 days. Mean renal clearance is 105 mL/min and mean total clearance is 122 mL/min, with the difference probably attributed to clearance due to adsorption to bone. The renal clearance is not concentration-dependent, and there is a linear relationship between renal clearance and creatinine clearance. Unadsorbed risedronate sodium is eliminated unchanged in faeces. After oral administration, the concentration-time profile shows 3 elimination phases with a terminal half-life of 480 hrs.
Special Populations: Elderly: No dosage adjustment is necessary.
Acetylsalicylic Acid/NSAID Users: Among regular acetylsalicylic acid or NSAID users (≥3 days per week), the incidence of upper gastrointestinal adverse events in risedronate sodium-treated patients was similar to that in control patients.
Toxicology: Preclinical Safety Data: In toxicological studies in rat and dog, dose-dependent liver toxic effects of risedronate sodium were seen, primarily as enzyme increases with histological changes in rat. The clinical relevance of these observations is unknown. Testicular toxicity occurred in rat and dog at exposures considered in excess of the human therapeutic exposure. Dose-related incidences of upper airway irritation were frequently noted in rodents. Similar effects have been seen with other bisphosphonates. Lower respiratory tract effects were also seen in long-term studies in rodents, although the clinical significance of these findings is unclear. In reproduction toxicity studies at exposures close to clinical exposure, ossification changes were seen in sternum and/or skull of foetuses from treated rats and hypocalcaemia and mortality in pregnant females allowed to deliver. There was no evidence of teratogenesis at 3.2 mg/kg/day in rat and 10 mg/kg/day in rabbit, although data are only available on a small number of rabbits. Maternal toxicity prevented testing of higher doses. Studies on genotoxicity and carcinogenicity did not show any particular risks for humans.
Prevention and treatment of osteoporosis in postmenopausal women with increased risk of osteoporosis, to reduce the risk of vertebral and hip fractures.
Treatment of osteoporosis in men at high risk of fractures.
Prevention and treatment of glucocorticoid-induced osteoporosis in men and women who are either initiating or continuing systemic glucocorticoid treatment (daily dosage equivalent to ≥7.5 mg of prednisone) for chronic diseases.
Strictly follow the recommended dosage unless directed otherwise by the physician.
Recommended Weekly Dose: One 35-mg tab orally at least 30 min before the 1st food or drink (other than water) of the day. The tablet should be taken on the same day each week.
Recommended Monthly Dose: One 150-mg tab orally at least 30 min before the 1st food or drink (other than water) of the day. The tablet should be taken on the same day each month.
Food and drinks may interfere with the absorption of Actonel. Therefore, it is very important not to take it with food, other medicinal products or drinks (other than water).
The tablet must be swallowed whole and not sucked or chewed. To aid delivery of the tablet to the stomach, Actonel is to be taken while in an upright position with a glass of plain water (180-240 mL). Patients should not lie down for 30 min after taking the tablet.
If the patient missed a dose, 1 tab should be taken on the day the tablet is remembered. Continue to take the tablet on the next day. Patients should then return to taking one 35-mg tab once a week on the day the tablet is normally taken. Do not take 2 tabs in 1 day instead of the tablet missed.
If the patient missed to take 150 mg tab and the next monthly dose is >7 days ahead, just take 1 tab the next morning. For the next monthly dose, take 1 tab as originally scheduled. If the patient missed to take 150 mg tab and the next monthly dose is within 7 days, do not take it. Return to taking 1 tab once a month, as originally scheduled on chosen day.
It is important that the diet includes products containing calcium and vitamin D (eg, dairy products). Supplemental calcium and vitamin D should be considered if the dietary intake is inadequate.
Elderly: No dosage adjustment is necessary since bioavailability, distribution and elimination were similar in elderly (>60 years) compared to younger subjects.
This has also been shown in the very elderly and postmenopausal population ≥75 years.
Renal Impairment: No dosage adjustment is required for those patients with mild to moderate renal impairment. The use of risedronate sodium is contraindicated in patients with severe renal impairment (creatinine clearance <30 mL/min) (see Pharmacokinetics under Actions and Contraindications).
In case of overdosage or accidental intoxication, drink a full glass of milk and immediately contact a physician or a hospital.
No specific information is available on the treatment of acute overdose with risedronate sodium.
Decreases in serum calcium following substantial overdose may be expected. Signs and symptoms of hypocalcaemia may also occur in some of these patients.
Milk or antacids containing magnesium, calcium or aluminium should be given to bind risedronate sodium and reduce absorption of the drug. In cases of substantial overdose, gastric lavage may be considered to remove unabsorbed risedronate sodium.
Known hypersensitivity to risedronate sodium or to any of the excipients of Actonel; hypocalcaemia (a low blood calcium level) (see Warnings); severe renal impairment (creatinine clearance <30 mL/min).
Use in pregnancy & lactation: There are no adequate data from the use of risedronate sodium in pregnant women. Studies in animals have shown reproductive toxicity (see Toxicology: Preclinical Safety Data under Actions). The potential risk for humans is unknown.
Actonel must not be used during pregnancy or by breastfeeding women.
Food, drinks (other than plain water) and medicinal products containing polyvalent cations eg, calcium, magnesium, iron or aluminium that may interfere with the absorption of bisphosphonates (see Interactions) should not be taken at the same time as Actonel. In order to achieve the intended efficacy, strict adherence to dosing recommendations is necessary (see Dosage & Administration).
Some bisphosphonates have been associated with oesophagitis and oesophageal ulcerations. Therefore, patients should pay attention to the dosing instructions (see Dosage & Administration). In patients who have a history of oesophageal disorders which delay oesophageal transit or emptying (eg, stricture or achalasia), or who are unable to stay in the upright position for at least 30 min after taking the tablet, Actonel should be used with special caution because of limited clinical experience in these patients. Prescribers should emphasize the importance of the dosing instructions to these patients.
Hypocalcaemia should be treated before starting Actonel therapy. Other disturbances of bone and mineral metabolism (eg, parathyroid dysfunction, hypovitaminosis D) should be treated at the time of starting Actonel therapy. In patients who have a lack of vitamin D, or problem with the parathyroid glands, Actonel should be used with special caution. The evidence to support efficacy of bisphosphonates including Actonel in very elderly women (>80 years) is limited. In case of doubt, the patient should consult the physician or pharmacist.
Osteonecrosis of the jaw, generally associated with tooth extraction and/or local infection (including osteomyelitis), has been reported in patients with cancer receiving treatment regimens including primarily IV-administered bisphosphonates. Many of these patients were also receiving chemotherapy and corticosteroids. Osteonecrosis of the jaw has also been reported in patients with osteoporosis receiving oral bisphosphonates.
A dental examination with appropriate preventive dentistry should be considered prior to treatment with bisphosphonates in patients with concomitant risk factors (eg, cancer, chemotherapy, radiotherapy, corticosteroids, poor oral hygiene).
While on treatment, these patients should avoid invasive dental procedures if possible. For patients who develop osteonecrosis of the jaw while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of osteonecrosis of the jaw.
Clinical judgement of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.
Actonel contains lactose. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take Actonel.
Effects on the Ability to Drive or Operate Machinery: No effects on ability to drive and use machines have been observed with Actonel.
Use in children: Safety and efficacy of Actonel have not been established in children and adolescents.
Use in the elderly: No dosage adjustment is necessary in the elderly.
There are no adequate data from the use of risedronate sodium in pregnant women. Studies in animals have shown reproductive toxicity (see Toxicology: Preclinical Safety Data under Actions). The potential risk for humans is unknown.
Actonel must not be used during pregnancy or by breastfeeding women.
Risedronate sodium has been studied in phase III clinical trials involving >15,000 patients. The majority of the adverse effects observed in clinical trials were mild to moderate in severity and usually did not require cessation of therapy.
Adverse experiences reported in phase III clinical trials in postmenopausal women with osteoporosis treated for up to 36 months with risedronate sodium 5 mg/day (n=5020) or placebo (n=5048) and considered possibly or probably related to risedronate sodium are listed as follows using the following convention (incidences versus placebo are shown in parentheses): Very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (<1/10,000).
Nervous System Disorders:
Common: Headache (1.8% vs 1.4%).
Common: Constipation (5% vs 4.8%), dyspepsia (4.5% vs 4.1%), nausea (4.3% vs 4%), abdominal pain (3.5% vs 3.3%), diarrhoea (3% vs 2.7%). Uncommon: Gastritis (0.9% vs 0.7%), oesophagitis (0.9% vs 0.9%), dysphagia (0.4% vs 0.2%), duodenitis (0.2% vs 0.1%), oesophageal ulcer (0.2% vs 0.2%). Rare: Glossitis (<0.1% vs 0.1%), oesophageal stricture (<0.1% vs 0%).
Musculoskeletal and Connective Tissue Disorders:
Common: Musculoskeletal pain (2.1% vs 1.9%).
Rare: Abnormal liver function tests*.
*No relevant incidences from phase III osteoporosis studies; frequency based on adverse event/laboratory/rechallenge findings in earlier clinical trials.
In a 1-year, double-blind, multicenter study comparing risedronate sodium 5 mg daily (n=480) and risedronate sodium 35 mg weekly (n=485) in postmenopausal women with osteoporosis, the overall safety and tolerability profiles were similar. The following additional adverse experiences considered possibly or probably drug-related by investigators have been reported (incidence greater in risedronate sodium 35-mg than in risedronate sodium 5-mg group): Gastrointestinal disorder (1.6% vs 1%) and pain (1.2% vs 0.8%).
In a 2-year study in men with osteoporosis, the overall safety and tolerability were similar between the treatment and the placebo groups. Adverse experiences were consistent with those previously observed in women.
Early, transient, asymptomatic and mild decreases in serum calcium and phosphate levels have been observed in some patients.
The following additional adverse reactions have been reported during post-marketing use (unknown frequency):
Musculoskeletal and Connective Tissue Disorders:
Osteonecrosis of the jaw.
Skin and Subcutaneous Tissue Disorders:
Hypersensitivity and skin reactions, including angioedema, generalised rash, and bullous skin reactions, some severe.
In order to avoid possible interactions with other drugs, particularly with Actonel, inform the physician or pharmacist about any other current treatment.
No formal interaction studies have been performed, however, no clinically relevant interactions with other medicinal products were found during clinical trials. In the risedronate sodium phase III osteoporosis studies with daily dosing, acetylsalicylic acid or NSAID use was reported by 33% and 45% of patients, respectively. In the phase III once-a-week study in postmenopausal women, acetylsalicylic acid or NSAID use was reported by 57% and 40% of patients, respectively. Among regular acetylsalicylic acid or NSAID users (≥3 days per week), the incidence of upper gastrointestinal adverse events in risedronate sodium-treated patients was similar to that in control patients.
If considered appropriate, Actonel may be used concomitantly with oestrogen supplementation.
Concomitant ingestion of medications containing polyvalent cations (eg, calcium, magnesium, iron and aluminium) will interfere with the absorption of Actonel (see Warnings). These products should be taken at a different time of the day from that of the Actonel dose (see Dosage & Administration).
Risedronate sodium is not systemically metabolised, does not induce cytochrome P-450 enzymes and has low protein-binding.
Store below 30°C.
Shelf-Life: 3 years.
M05BA07 - risedronic acid ; Belongs to the class of bisphosphonates. Used in the treatment of bone diseases.
FC tab 35 mg (light orange, oval with RSN on one side and 35 mg on the other) x 1 x 4's. 150 mg (light blue, oval with RSN marked on one side and 150 mg on the other) x 1 x 1's.