Canada Drugs Pharmacy Online
| We serve over 250,000 patients | |
 |
Home | |
 |
FAQ | |
 |
Shopping Cart | |
 |
My Account | |
 |
||
|
||
|
||
|
|
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
 |
|||||||||||||||||||||||||||||||||||||||||||||
* Best Value [What is a Generic?] |
||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||
For multiple quantities, you can edit the amount when you click on Checkout or click Add to Cart until you reach your required amount. |
||||||||||||||||||||||||||||||||||||||||||||||
ACTONEL (risedronate sodium hemi-pentahydrate) is indicated for:
Treatment of Postmenopausal Osteoporosis
In postmenopausal women with osteoporosis, ACTONEL prevents vertebral and nonvertebral osteoporosis-related fractures and increases bone mineral density (BMD) at all measured skeletal sites of clinical importance for osteoporotic fractures, including spine, hip, and wrist. Osteoporosis may be confirmed by the presence or history of osteoporotic fracture, or by the finding of low bone mass (for example, at least 2 SD below the premenopausal mean). Prevention of Postmenopausal Osteoporosis
In postmenopausal patients at risk of developing osteoporosis, ACTONEL preserves or increases BMD at sites of clinical importance for osteoporosis. ACTONEL may be considered in postmenopausal women who are at risk of developing osteoporosis and for whom the desired clinical outcome is to maintain bone mass and to reduce the risk of fracture. Factors such as family history of osteoporosis (particularly maternal history), previous fracture, smoking, moderately low BMD, high bone turnover, thin body frame, Caucasian or Asian race, and early menopause are associated with an increased risk of developing osteoporosis and fractures. Paget's Disease of Bone
ACTONEL is indicated for patients with Paget's disease of bone (osteitis deformans) having alkaline phosphatase levels at least two times the upper limit of normal, or who are symptomatic, or who are at risk for future complications from their disease, to induce remission (normalization of serum alkaline phosphatase). Geriatrics
Of the patients receiving ACTONEL 5 mg daily in postmenopausal osteoporosis studies, 43% were between 65 and 75 years of age, and 20% were over 75. The corresponding proportions were 26% and 11% in glucocorticoid-induced osteoporosis trials. In the 1-year study comparing daily versus weekly oral dosing regimens of ACTONEL in postmenopausal women, 41% of patients receiving ACTONEL 35 mg Once-a-Week were between 65 and 75 years of age and 23% were over 75. Based upon the above study populations, no overall differences in efficacy or safety were observed between these patients and younger patients (<65 years). Pediatrics
Safety and efficacy in children and growing adolescents have not been established.
General
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 Drug Interactions). In post-marketing reporting, osteonecrosis of the jaw has been reported in patients treated with bisphosphonates. The majority of reports occurred following dental procedures such as tooth extractions; and have involved cancer patients treated with intravenous bisphosphonates, but some occurred in patients receiving oral treatment for postmenopausal osteoporosis and other diagnoses. Many had signs of local infection, including osteomyelitis. A dental examination with appropriate preventative dentistry should be considered prior to treatment with bisphosphonates in patients with concomitant risk factors (e.g. cancer, immune suppression, head and neck radiotherapy or poor oral hygiene). While on treatment, these patients should avoid invasive dental procedures if possible. 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 judgment, based on individual risk assessment, should guide the management of patients undergoing dental procedures. Gastrointestinal
Bisphosphonates may cause upper gastrointestinal disorders such as dysphagia, esophagitis, esophageal ulcer, and gastric ulcer (see Adverse Reactions). Since some bisphosphonates have been associated with esophagitis and esophageal ulcerations, to facilitate delivery to the stomach and minimize the risk of these events, patients should take ACTONEL while in an upright position (i.e., sitting or standing) and with sufficient plain water (>120 mL). Patients should not lie down for at least 30 minutes after taking the drug. Health professionals should be particularly careful to emphasize the importance of the dosing instructions to patients with a history of esophageal disorders (e.g., inflammation, stricture, ulcer, or disorders of motility). Renal
ACTONEL is not recommended for use in patients with severe renal impairment (creatinine clearance <30 mL/min). Special Populations
Pregnant Women
ACTONEL is not intended for use during pregnancy. There are no studies of ACTONEL in pregnant women. Nursing Women
ACTONEL is not intended for use with nursing mothers. It is not known whether risedronate is excreted in human milk. Risedronate was detected in feeding pups exposed to lactating rats for a 24-hour period post-dosing, indicating a small degree of lacteal transfer. Since 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.
Actonel Adverse Drug Reaction Overview Bisphosphonates may cause upper gastrointestinal disorders such as dysphagia, esophagitis, esophageal ulcer and gastric ulcer. It is therefore important to follow the recommended dosing instructions (see Dosage and Administration). Musculoskeletal pain, rarely severe, has been reported as a common adverse event in patients who received ACTONEL for all indications. In postmenopausal and glucocorticoid-induced osteoporosis studies with ACTONEL, the most commonly reported adverse reactions were abdominal pain, dyspepsia and nausea. In Paget's disease studies with ACTONEL the most commonly reported adverse reactions were diarrhea, nausea, abdominal pain and headache. Most adverse events (AEs) reported in the Phase III postmenopausal osteoporosis, glucocorticoid-induced osteoporosis, and Paget's trials were mild or moderate in severity and did not generally lead to discontinuation of ACTONEL. Clinical Trial Adverse Drug Reactions
Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and approximate rates of occurrence. Treatment and Prevention of Postmenopausal Osteoporosis
ACTONEL 5 mg daily has been studied for up to 3 years in over 5000 women enrolled in Phase III clinical trials for treatment or prevention of postmenopausal osteoporosis. Most adverse events reported in these trials were either mild or moderate in severity, and did not lead to discontinuation from the study. The distribution of severe adverse events was similar across treatment groups. In addition, the overall incidence of AEs was found to be comparable amongst ACTONEL and placebo-treated patients. Table 1 lists adverse events considered possibly or probably drug related, reported in ≥1% of ACTONEL 5 mg daily-treated patients, in Phase III postmenopausal osteoporosis trials. Discontinuation of therapy due to serious clinical adverse events occurred in 5.5 % of ACTONEL 5 mg daily-treated patients and 6.0% of patients treated with placebo. |
The following adverse drug reactions were reported in ≤1% of patients who received ACTONEL for all indications. Uncommon (0.1-1.0%): duodenitis, iritis. Rare (<0.1%): abnormal liver function tests, glossitis.
Asymptomatic mild decreases in serum calcium and phosphorus levels have been observed in some patients (see Action and Clinical Pharmacology, Pharmacodynamics).
Rare cases of leukemia have been reported following therapy with bisphosphonates. Any causal relationship to either the treatment or to the patients' underlying disease has not been established.
Very rare (<1 report per 10 000 new prescriptions): hypersensitivity and skin reaction, including angioedema, generalized rash, and bullous skin reactions, some severe.
A number of cases of osteonecrosis (primarily of the jaw) have been reported in patients receiving treatment with bisphosphonates. Osteonecrosis has other well documented multiple risk factors. It is not possible to determine if these events are related to bisphosphonates, to concomitant drugs or other therapies (e.g. chemotherapy, radiotherapy, corticosteroids), to the patient's underlying disease or to other co-morbid risk factors (e.g. anemia, infection, pre-existing oral disease).(see Warnings and Precautions, General)
|
No specific drug-drug interaction studies were performed. Animal studies have demonstrated that risedronate is highly concentrated in bone and is retained only minimally in soft tissue. No metabolites have been detected systemically or in bone. The binding of risedronate to plasma proteins in humans is low (24%), resulting in minimal potential for interference with the binding of other drugs. In an additional animal study, there was also no evidence of hepatic microsomal enzyme induction. In summary, ACTONEL is not systemically metabolized, does not induce cytochrome P450 enzymes and has low protein binding. ACTONEL is therefore not expected to interact with other drugs based on the effects of protein binding displacement, enzyme induction or metabolism of other drugs.
| Action and Clinical Pharmacology |
Risedronate sodium, a pyridinyl-bisphosphonate in the form of hemi-pentahydrate with small amounts of monohydrate, inhibits osteoclast bone resorption and modulates bone metabolism. Risedronate has a high affinity for hydroxyapatite crystals in bone and is a potent antiresorptive agent. At the cellular level, risedronate inhibits osteoclasts. The osteoclasts adhere normally to the bone surface, but show evidence of reduced active resorption (e.g., lack of ruffled border). Histomorphometry in rats, dogs, minipigs and humans showed that risedronate treatment reduces bone turnover (i.e., activation frequency, the rate at which bone remodelling sites are activated) and bone resorption at remodelling sites.
Treatment and Prevention of Osteoporosis in Postmenopausal Women: Osteoporosis is a degenerative and debilitating bone disease characterized by decreased bone mass and increased fracture risk at the spine, hip, and wrist. The diagnosis can be confirmed by the finding of low bone mass, evidence of fracture on x-ray, a history of osteoporotic fracture, or height loss or kyphosis indicative of vertebral fracture. Osteoporosis occurs in both men and women but is more common among women following menopause.
In healthy humans, bone formation and resorption are closely linked; old bone is resorbed and replaced by newly-formed bone. In postmenopausal osteoporosis, bone resorption exceeds bone formation, leading to bone loss and increased risk of bone fracture. After menopause, the risk of fractures of the spine and hip increases dramatically; approximately 40% of 50-year-old women will experience an osteoporosis-related fracture of the spine, hip, or wrist during their remaining lifetimes. After experiencing one osteoporosis-related fracture, the risk of future fracture increases 5-fold compared to the risk among a non-fractured population.
ACTONEL treatment decreases the elevated rate of bone turnover and corrects the imbalance of bone resorption relative to bone formation that is typically seen in postmenopausal osteoporosis. In clinical trials, administration of ACTONEL to postmenopausal women resulted in dose-dependent decreases in biochemical markers of bone turnover, including urinary markers of bone resorption and serum markers of bone formation, at doses as low as 2.5 mg daily. At the 5 mg daily dose, decreases in resorption markers were evident within 14 days of treatment. Changes in bone formation markers were observed later than changes in resorption markers, as expected, due to the coupled nature of bone formation and bone resorption; decreases in bone formation of about 20% were evident within 3 months of treatment. Bone turnover markers reached a nadir of about 40% below baseline values by the sixth month of treatment and remained stable with continued treatment for up to 3 years.
These data demonstrate that ACTONEL 5 mg administered daily to postmenopausal women produces a rapid reduction in bone resorption without over-suppression of bone formation. Bone turnover is decreased as early as 2 weeks and maximally within about 6 months of treatment, with achievement of a new steady-state which more nearly approximates the rate of bone turnover seen in premenopausal women.
In a 1-year study comparing ACTONEL 35 mg Once-a-Week to ACTONEL 5 mg daily for the treatment of osteoporosis in postmenopausal women, similar decreases in bone resorption (about 60%) and formation markers (about 40%) were observed for both dosage regimens.
As a result of the inhibition of bone resorption, asymptomatic and usually transient decreases from baseline in serum calcium (about 2%) and serum phosphate levels (about 5%) and compensatory increases in serum PTH levels were observed within 6 months in ACTONEL 5 mg daily-treated patients in postmenopausal osteoporosis trials. No further decreases in serum calcium or phosphate, or increases in PTH were observed in postmenopausal women treated for up to 3 years. In the 1-year study comparing ACTONEL 35 mg Once-a-Week to ACTONEL 5 mg daily for the treatment of osteoporosis in postmenopausal women, similar mean changes from baseline in serum calcium, phosphate and PTH were found for both dosage regimes.
Consistent with the effects of ACTONEL on biochemical markers of bone turnover, daily oral doses as low as 2.5 mg produced dose dependent, significant increases in lumbar spine bone mineral density (BMD) (2.5 mg, 3% to 3.7%; 5 mg, 4% to 4.5%) after 12 months of treatment in large-scale postmenopausal osteoporosis trials. A dose-dependent response to treatment was also observed in the BMD of the femoral neck over the same time (2.5 mg, 0.7% to 0.9%; 5 mg, 1.5% to 2%). In the 1-year study comparing ACTONEL 35 mg Once-a-Week to ACTONEL 5 mg daily for the treatment of osteoporosis in postmenopausal women, similar mean changes from baseline in BMD of the lumbar spine, total proximal femur, femoral neck and femoral trochanter were found for both dosage regimens.
Chronic exposure to glucocorticoids (≥7.5 mg/day prednisone or its equivalent) induces rapid bone loss by decreasing bone formation and increasing bone resorption. The bone loss occurs most rapidly during the first 6 months of therapy with persistent but slowing bone loss for as long as glucocorticoid therapy continues.
Glucocorticoid-induced osteoporosis is characterized by low bone mass that leads to an increased risk of fracture (especially vertebral, hip, and rib). It occurs in both men and women, and approximately 50% of patients on chronic glucocorticoid treatment will experience fractures. The relative risk of a hip fracture in patients on >7.5 mg/day prednisone is more than doubled (RR=2.27); the relative risk of vertebral fracture is increased five-fold (RR=5.18).
ACTONEL treatment decreases bone resorption without directly inhibiting bone formation. In 1-year clinical trials in the treatment and prevention of glucocorticoid-induced osteoporosis, ACTONEL 5 mg daily produced rapid and statistically significant reductions in biochemical markers of bone turnover, similar to those seen in postmenopausal osteoporosis. Urinary collagen cross-linked N-Telopeptide (a marker of bone resorption) and serum bone specific alkaline phosphatase (a marker of bone formation) were decreased by 50% to 55% and 25% to 30%, respectively, within 3 to 6 months after initiation of therapy. The reduction was evident within 14 days and bone turnover markers remained decreased throughout the duration of ACTONEL treatment.
Consistent with the changes in biochemical markers of bone turnover, ACTONEL 5 mg daily provides a beneficial effect on bone mineral density and reduces the risk of vertebral fractures by approximately 70% when compared to placebo.
Paget's disease of bone is a chronic focal skeletal disorder characterized by greatly increased and disordered bone remodelling. Excessive osteoclastic bone resorption is followed by osteoblastic new bone formation, leading to the replacement of the normal bone architecture by disorganized, enlarged, and weakened bone structure.
Clinical manifestations of Paget's disease range from no symptoms to severe morbidity due to bone pain, bone deformity, pathological fractures, and neurological and other complications. Serum alkaline phosphatase, the most frequently used biochemical marker of disease activity, provides an objective measure of disease severity and response to therapy.
ACTONEL is a bisphosphonate that acts primarily to inhibit bone resorption. This effect is related to its inhibitory effect on osteoclasts. In the Phase III clinical trial, ACTONEL 30 mg daily for 2 months produced significant (p<0.001) reductions of 81% to 88% in serum alkaline phosphatase excess, as well as significant reductions in bone-specific serum alkaline phosphatase (Ostase, 67% to 70%) and urinary deoxypyridinoline/creatinine (47% to 51%). Reductions were evident as early as 1 month after the start of treatment, and progressively increased in magnitude (following completion of the 2 month treatment) when measured at monthly intervals over a 6 month period. Clinically meaningful reductions in serum alkaline phosphatase were observed starting at 1 month with levels maintained through 12 months.
Asymptomatic and mild decreases in serum calcium and phosphorus levels have been observed in some patients. These decreases in calcium are associated with increases in serum intact PTH and 1,25-dihydroxy vitamin D, resulting in an increase in tubular reabsorption of calcium.
Markers of bone resorption (such as urinary deoxypyridinoline/creatinine or hydroxyproline/creatinine) usually decrease before markers of bone formation (such as serum alkaline phosphatase). This difference is indicative of the primary antiresorptive effect of ACTONEL.
Bone turnover marker levels continue to decrease when ACTONEL treatment is stopped. Therefore, to assess the full effect of response, patients should be followed for at least 2 months following the 2 month treatment period
Absorption after an oral dose is relatively rapid (tmax ~1 hour) and occurs throughout the upper gastrointestinal tract. Absorption is independent of dose over the range studied (single dose, 2.5 to 30 mg; multiple dose, 2.5 to 5 mg daily; and multiple dose, 35 and 50 mg weekly). Steady-state conditions in the serum are observed within 57 days of daily dosing. Mean oral bioavailability of the tablet is 0.63% and is bioequivalent to a solution. Extent of absorption when administered 30 minutes before breakfast is reduced by 55% compared to dosing in the fasting state (i.e., no food or drink for 10 hours prior to or 4 hours after dosing).
Dosing 1 hour prior to breakfast reduces extent of absorption by 30% compared to dosing in the fasting state. Dosing either 30 minutes prior to breakfast or 2 hours after a meal results in a similar extent of absorption.
The mean steady-state volume of distribution is 6.3 L/kg in humans. Human plasma protein binding of drug is about 24%. Preclinical studies in rats and dogs dosed intravenously with single doses of [14C] risedronate indicate that approximately 60% of the dose is distributed to bone. The remainder of the dose is excreted in the urine. After multiple oral dosing in rats, the uptake of risedronate in soft tissues was found to be minimal (in the range of 0.001% to 0.01%), with drug levels quickly decreasing after the final dose.
There is no evidence that risedronate is systemically metabolized.
Approximately half of the absorbed dose is excreted in urine within 24 hours, and 85% of an intravenous dose is recovered in the urine over 28 days. Mean renal clearance is 105 mL/min (CV=34%) and mean total clearance is 122 mL/min (CV=19%), with the difference primarily reflecting non-renal clearance or 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. Unabsorbed drug is eliminated unchanged in feces. Once risedronate is absorbed, the serum concentration-time profile is multi-phasic with an initial half-life of about 1.5 hours and a terminal exponential half-life of 480 hours. Although the elimination rate of bisphosphonates from human bone is unknown, the 480 hour half-life is hypothesized to represent the dissociation of risedronate from the surface of bone.
Risedronate pharmacokinetics have not been studied in patients <18 years of age.
Bioavailability and disposition are similar in elderly (>65 years of age) and younger subjects. No dosage adjustment is necessary.
Bioavailability and disposition following oral administration are similar in men and women.
Pharmacokinetic differences due to race have not been studied.
No studies have been performed to assess risedronate's safety or efficacy in patients with hepatic impairment. Risedronate is not metabolized in rat, dog, and human liver preparations. Insignificant amounts (<0.1% of intravenous dose) of drug are excreted in the bile in rats. Therefore, dosage adjustment is unlikely to be needed in patients with hepatic impairment.
Risedronate is excreted intact primarily via the kidney. Patients with mild-to-moderate renal impairment (creatinine clearance >30 mL/min) do not require a dosage adjustment. Exposure to risedronate was estimated to increase by 44% in patients with creatinine clearance of 20 mL/min. ACTONEL is not recommended for use in patients with severe renal impairment (creatinine clearance <30 mL/min) because of a lack of clinical experience.
No data are available.
| Information for the Patient |
| Dosage Forms, Composition and Packaging |
Each film-coated, oval-shaped, yellow tablet for oral administration with “RSN” engraved on one face and “5 mg” engraved on the other, contains the equivalent of: anhydrous risedronate sodium 5 mg in the form of the hemi-pentahydrate with small amounts of monohydrate. Nonmedicinal ingredients: crospovidone, ferric oxide yellow, hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, silicon dioxide and titanium dioxide. Cartons of 28 blister packaged tablets. Store at controlled room temperature (15 to 30°C).
Each film-coated, oval-shaped, white tablet for oral administration with “RSN” engraved on one face and “30 mg” engraved on the other, contains the equivalent of: anhydrous risedronate sodium 30 mg in the form of the hemi-pentahydrate with small amounts of monohydrate. Nonmedicinal ingredients: crospovidone, hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, silicon dioxide and titanium dioxide. Bottles of 30 tablets. Store at controlled room temperature (15 to 30°C).
Each film-coated, oval-shaped, orange tablet for oral administration with “RSN” engraved on one face and “35 mg” engraved on the other, contains the equivalent of: anhydrous risedronate sodium 35 mg in the form of the hemi-pentahydrate with small amounts of monohydrate. Nonmedicinal ingredients: crospovidone, ferric oxide red, ferric oxide yellow, hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, silicon dioxide and titanium dioxide. Cartons of 4 blister packaged tablets. Store at controlled room temperature (15 to 30°C).
©2007 www.CanPharm.com