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Risedronate Sodium Hemi-pentahydrate

Pharmacology: Risedronate a pyridinylbisphosphonate 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, and minipigs showed that risedronate treatment reduces bone turnover (i.e., activation frequency, the rate at which bone remodelling sites are activated) and bone resorption at remodeling sites. rx canada pharmacy

Pharmacokinetics : Absorption: Absorption after an oral dose is relatively rapid (t _max approximately 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). 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. rx canada pharmacy

Distribution: 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 i.v. 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. rx canada pharmacy

Metabolism: There is no evidence that risedronate is systemically metabolized.

Elimination: Approximately half of the absorbed dose is excreted in urine within 24 hours, and 85% of an i.v. 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 nonrenal 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 multiphasic with an initial half-life of about 1.5 hour 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. rx canada pharmacy

Special Populations: Children: Risedronate pharmacokinetics have not been studied in patients <18 years of age.

Gender: Bioavailability and disposition following oral administration are similar in men and women.

Geriatric: Bioavailability and disposition are similar in elderly (³65 years of age) and younger subjects. No dosage adjustments are necessary (see Precautions, Geriatrics).

Race: Pharmacokinetic differences due to race have not been studied.

Renal Insufficiency: Risedronate is excreted intact primarily via the kidney. Patients with mild-to-moderate renal impairment (creatinine clearance ³30 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. Risedronate is not recommended for use in patients with severe renal impairment (creatinine clearance <30 mL/min) because of lack of clinical experience. rx canada pharmacy

Hepatic Insufficiency: 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 i.v. dose) of drug are excreted in the bile in rats. Therefore, dosage adjustment is unlikely to be needed in patients with hepatic impairment. rx canada pharmacy

Pharmacodynamics: 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. rx canada pharmacy

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 nonfractured population. rx canada pharmacy

Risedronate 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 risedronate 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 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. rx canada pharmacy

These data demonstrate that daily risedronate 5 mg administered 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. 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 risedronate-treated patients in the 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. rx canada pharmacy

Consistent with the effects of risedronate 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%). rx canada pharmacy

Paget's Disease of Bone: 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. rx canada pharmacy

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. rx canada pharmacy

Risedronate 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, risedronate 30 mg/day 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. rx canada pharmacy

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. rx canada pharmacy

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 risedronate. rx canada pharmacy

Bone turnover marker levels continue to decrease when risedronate 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. rx canada pharmacy


Indications: Postmenopausal Osteoporosis: Treatment and prevention of osteoporosis in postmenopausal women. rx canada pharmacy

Treatment of Osteoporosis: In postmenopausal women with osteoporosis, risedronate prevents vertebral and nonvertebral osteoporosis-related fractures and increases BMD at all measured skeletal sites of clinical importance for osteoporotic fractures, including spine, hip, and wrist. rx canada pharmacy

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). rx canada pharmacy

Prevention of Osteoporosis: In postmenopausal patients at risk of developing osteoporosis, risedronate preserves or increases BMD at sites of clinical importance for osteoporosis. rx canada pharmacy

Risedronate 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. rx canada pharmacy

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. rx canada pharmacy

Paget's Disease of Bone: For patients with Paget's disease of bone (osteitis deformans) having alkaline phosphatase levels at least 2 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).

Contraindications: Known hypersensitivity to any component of this product; and hypocalcemia (see Precautions, General). rx canada pharmacy


Warnings: Bisphosphonates may cause upper gastrointestinal disorders such as dysphagia, esophagitis, esophageal ulcer, and gastric ulcer (see Adverse Effects). rx canada pharmacy

Precautions: General: Hypocalcemia and other disturbances of bone and mineral metabolism should be effectively treated before starting risedronate therapy. rx canada pharmacy

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. Coadministration of medications containing polyvalent cations (e.g., calcium, magnesium, aluminum and iron) can interfere with the absorption of risedronate. As with food, such medications should therefore be administered at a different time of the day (see Dosage). rx canada pharmacy

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

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 risedronate while in an upright position (i.e., sitting or standing) and with sufficient plain water (³120 mL). Patients should not lie down for at least 30 minutes after taking the drug. Prescribers 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). rx canada pharmacy

Information to Be Provided to the Patient: The patient should be informed to pay particular attention to the dosing instructions as clinical benefits may be compromised by failure to take the drug according to instructions. Specifically, risedronate should be taken once per day on an empty stomach and may be taken: at least 30 minutes before the first food or drink (other than plain water) of the day, or at other times during the day, at least 2 hours from any food or drink other than plain water (i.e., nothing to eat or drink 2 hours before and 2 hours after dosing). rx canada pharmacy

To facilitate delivery to the stomach and minimize the risk of potential esophageal irritation, patients should take risedronate while in an upright position (i.e., sitting or standing) and with sufficient plain water (³120 mL). Patients should not lie down for at least 30 minutes after taking the medication and should not take risedronate less than 30 minutes before bedtime (see Precautions, General). Patients should not chew or suck on the tablet because of a potential for oropharyngeal irritation. rx canada pharmacy

Patients should receive supplemental calcium and vitamin D if dietary intake is inadequate (see Precautions, General). Coadministration of medications containing polyvalent cations (e.g., calcium, magnesium, aluminum and iron) can interfere with the absorption of risedronate. As with food, such medications should therefore be administered at a different time of the day (see Dosage). rx canada pharmacy

Geriatrics: No dosage adjustment is necessary in elderly patients (see Dosage). Of the patients receiving risedronate in postmenopausal osteoporosis studies, 43% were between 65 and 75 years of age, and 20% were over 75. No overall differences in efficacy or safety were observed between these patients and younger patients (<65 years). rx canada pharmacy

Children: Safety and efficacy in children and growing adolescents have not been established. rx canada pharmacy

Pregnancy: Risedronate is not intended for use during pregnancy. There are no studies of risedronate in pregnant women. rx canada pharmacy

Lactation: Risedronate 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 postdosing, 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. rx canada pharmacy

Drug Interactions : Patients in the clinical trials were exposed to a wide variety of commonly used concomitant medications (including NSAIDs, H ₂-blockers, proton pump inhibitors, antacids, calcium channel blockers, b-blockers, thiazides, glucocorticoids, anticoagulants, anticonvulsants, cardiac glycosides) without evidence of clinically relevant interactions. rx canada pharmacy

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, risedronate is not systemically metabolized, does not induce cytochrome P450 enzymes and has low protein binding. Risedronate is therefore not expected to interact with other drugs based on the effects of protein binding displacement, enzyme induction or metabolism of other drugs. rx canada pharmacy

Supplements/Antacids: Coadministration of medications which contain polyvalent cations (e.g., calcium, magnesium, aluminum and iron) can interfere with the absorption of risedronate. As with food, such medications should therefore be administered at a different time of the day (see Dosage). rx canada pharmacy

Hormone Replacement Therapy: If considered appropriate, risedronate may be used concomitantly with hormone replacement therapy. rx canada pharmacy

ASA: Of over 5000 women enrolled in the risedronate Phase III postmenopausal osteoporosis studies, ASA use was reported by 32% of patients, 23% of whom were regular users (i.e., 3 or more days per week). Among regular ASA users, the incidence of upper gastrointestinal adverse experiences in risedronate-treated patients was similar to that in placebo-treated patients.

Other NSAIDs: Of over 5000 women enrolled in the risedronate Phase III postmenopausal osteoporosis studies, 48% used NSAIDs, 18% of them regularly (i.e., 3 or more days per week). Among regular NSAID users, the incidence of upper gastrointestinal adverse experience in risedronate-treated patients was similar to that in placebo-treated patients. rx canada pharmacy

Laboratory Test Interactions : Bisphosphonates are known to interfere with the use of bone-imaging agents. Specific studies with risedronate have not been performed. rx canada pharmacy

Adverse Effects: Treatment and Prevention of Postmenopausal Osteoporosis: Risedronate 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 adverse effects was found to be comparable amongst risedronate- and placebo-treated patients. rx canada pharmacy

Table I lists adverse events reported in ³2% of risedronate-treated patients and at an incidence higher than in the placebo group in Phase III postmenopausal osteoporosis trials. Adverse events are shown without attribution of causality. Discontinuation of therapy due to serious clinical adverse events occurred in 5.5 % of risedronate 5 mg/day-treated patients and 6.0% of patients treated with placebo. rx canada pharmacy

Glossitis, iritis, and duodenitis have been reported uncommonly (0.1 to 1%). There have been rare reports (<0.1%) of abnormal liver function tests. rx canada pharmacy

Endoscopic Findings: Risedronate clinical studies enrolled over 5000 postmenopausal women and included patients with pre-existing gastrointestinal disease and concomitant use of NSAIDs or ASA. Investigators were encouraged to perform endoscopies in any patients with moderate-to-severe gastrointestinal complaints while maintaining the blind. These endoscopies were ultimately performed on equal numbers of patients between the treated and placebo groups (68 risedronate; 69 placebo). rx canada pharmacy

Across treatment groups, the percentage of patients with normal esophageal, gastric and duodenal mucosa on endoscopy was similar (19%). Positive findings on endoscopy were also generally comparable across treatment groups. There was a higher number of reports of mild duodenitis in the risedronate group; however, there were more duodenal ulcers in the placebo group. The number of patients who had positive findings and withdrew from the studies was similar across treatment groups and there was no evidence of treatment-related esophageal, gastric, or duodenal ulcers/erosions. rx canada pharmacy

Paget's Disease of Bone: Risedronate has been studied in over 390 patients with Paget's disease of bone. The adverse experiences reported have usually been mild or moderate and generally have not required discontinuation of treatment. The occurrence of adverse experiences does not appear to be related to patient age, gender, or race. rx canada pharmacy

In a Phase III clinical study, risedronate and Didronel (etidronate disodium) showed similar adverse event profiles: 6.6% (4/61) of the patients treated with risedronate 30 mg/day for 2 months discontinued treatment due to adverse experiences, compared with 8.2% (5/61) of the patients treated with Didronel 400 mg/day for 6 months. rx canada pharmacy

In the Phase III comparative study versus Didronel, patients with a history of upper gastrointestinal disease or abnormalities were not excluded. Patients were also not excluded based on NSAID or ASA use. The proportion of risedronate-treated patients with mild or moderate upper gastrointestinal experiences was similar to that in the Didronel-treated group, with no severe upper gastrointestinal experiences observed in either treatment group. rx canada pharmacy

Laboratory Test Findings: Asymptomatic mild decreases in serum calcium and phosphorus levels have been observed in some patients (see Pharmacology, Pharmacodynamics, Paget's Disease of Bone). rx canada pharmacy

Other: 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. rx canada pharmacy

Overdose: Symptoms: Decreases in serum calcium following substantial overdose may be expected in some patients. Signs and symptoms of hypocalcemia may also occur in some of these patients. rx canada pharmacy



Treatment: Administration of milk or antacids containing calcium may be helpful to chelate risedronate and reduce absorption of the drug. In cases of substantial overdose, gastric lavage may be considered to remove unabsorbed drug if performed within 30 minutes of ingestion. Standard procedures that are effective for treating hypocalcemia, including the administration of calcium i.v., would be expected to restore physiologic amounts of ionized calcium and to relieve signs and symptoms of hypocalcemia. rx canada pharmacy


Dosage: Treatment and Prevention of Postmenopausal Osteoporosis: The recommended regimen is 5 mg orally/day. rx canada pharmacy

Treatment of Paget's Disease of Bone: The recommended regimen is 30 mg orally/day for 2 months. rx canada pharmacy

Retreatment may be considered (following post-treatment observation of at least 2 months) if relapse has occurred, or if treatment fails to normalize serum alkaline phosphatase. For retreatment, the dose and duration of therapy are the same as for initial treatment. There are no data available on more than one course of retreatment. rx canada pharmacy

For All Indications: Risedronate should be taken once per day on an empty stomach and may be taken: at least 30 minutes before the first food or drink (other than plain water) of the day; or at other times during the day, at least 2 hours from any food or drink other than plain water (i.e., nothing to eat or drink for at least 2 hours before and 2 hours after dosing), and not less than 30 minutes before bedtime (see Precautions, Information to Be Provided to the Patient). To facilitate delivery to the stomach, risedronate should be swallowed while the patient is in an upright position and with sufficient plain water (³120 mL). Patients should not lie down for at least 30 minutes after taking the medication (see Precautions, General). rx canada pharmacy

Patients should receive supplemental calcium and vitamin D if dietary intake is inadequate (see Precautions, General). Coadministration of medications containing polyvalent cations (e.g., calcium, magnesium, aluminum and iron) can interfere with the absorption of risedronate. As with food, such medications should therefore be administered at a different time of the day. rx canada pharmacy

Risedronate is not recommended for use in patients with severe renal impairment (creatinine clearance <30 mL/min). No dosage adjustment is necessary in patients with a creatinine clearance ³30 mL/min or in the elderly. rx canada pharmacy

Information for the Patient: See Blue Section--Information for the Patient Actonel. rx canada pharmacy


Supplied: 5 mg: Each film-coated, oval-shaped, yellow tablet with RSN engraved on one face and 5 mg on the other, contains: 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, hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, silicon dioxide and titanium dioxide. Bottles of 30. rx canada pharmacy

30 mg: Each film-coated, oval-shaped, white tablet with RSN engraved on one face and 30 mg on the other, contains: anhydrous risedronate sodium 30 mg in the form of the hemi-pentahydrate with small amounts of monohydrate. Nonmedicinal ingredients: crospovidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, silicon dioxide and titanium dioxide. Bottles of 30. rx canada pharmacy

Store at controlled room temperature (15 to 30°C).

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