Actonel®

Risedronate Sodium Hemi-pentahydrate

Bone Metabolism Regulator

Procter & Gamble Pharmaceuticals

http://www.pg.com/en_US/index.jhtml

actonel Monograph PDF download here.

 

CPS:PIS_m006550

Date of Preparation: August 4, 1999

Date of Revision: July 9, 2004

 

 

Pharmacology

Actonel (risedronate sodium), a pyridinylbisphosphonate in the form of hemi-pentahydrate with small amounts of monohydrate, inhibits osteoclast bone resorption and modulates bone metabolism. Actonel has a high affinity for hydroxyapatite crystals in bone and is a potent antiresorptive agent. At the cellular level, Actonel 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 Actonel treatment reduces bone turnover (i.e., activation frequency, the rate at which bone remodelling sites are activated) and bone resorption at remodeling sites.

 

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 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.

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] Actonel 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 Actonel 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.

Metabolism: There is no evidence that Actonel 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 Actonel is absorbed, the serum concentration-time profile is multiphasic 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 Actonel from the surface of bone.

Special Populations: Children: Actonel 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 (≥ 65 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: Actonel 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 Actonel 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 lack of clinical experience.

Hepatic Insufficiency: No studies have been performed to assess Actonel's safety or efficacy in patients with hepatic impairment. Actonel 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.

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.

     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.

     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 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.

Glucocorticoid-induced Osteoporosis

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 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

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 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.

 

Indications

Postmenopausal Osteoporosis

Treatment and prevention of osteoporosis in postmenopausal women.

Treatment of Osteoporosis

In postmenopausal women with osteoporosis, Actonel 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.

     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 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.

Glucocorticoid-induced Osteoporosis

Treatment and prevention of glucocorticoid-induced osteoporosis in men and women.

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.

•  Hypocalcemia (see Precautions, General).

 

 

Warnings

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

 

Precautions

 

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. Co-administration of medications containing polyvalent cations (e.g., calcium, magnesium, aluminum and iron) can interfere with the absorption of Actonel. As with food, such medications should therefore be administered at a different time of the day (see Dosage).

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

     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. 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).

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, Actonel should be taken 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).

 

     To facilitate delivery to the stomach and minimize the risk of potential esophageal irritation, 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 medication and should not take Actonel 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.

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

     Patients should be instructed that if they miss a dose of Actonel 35 mg once a week on their regularly scheduled day, they should take 1 tablet on the day they first remember missing their dose (see Dosage). Patients should then return to taking 1 tablet once a week as originally scheduled on their chosen day. Patients should not take 2 tablets on the same day.

Geriatrics

No dosage adjustment is necessary in elderly patients (see Dosage). 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).

 

Children

Safety and efficacy in children and growing adolescents have not been established.

 

Pregnancy

Actonel is not intended for use during pregnancy. There are no studies of Actonel in pregnant women.

 

Lactation

Actonel is not intended for use with nursing mothers. It is not known whether risedronate is excreted in human milk. Actonel 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.

 

Drug Interactions

Patients in the clinical trials were exposed to a wide variety of commonly used concomitant medications (including non-steroidal anti-inflammatory drugs, H₂-blockers, proton pump inhibitors, antacids, calcium channel blockers, β -blockers, thiazides, glucocorticoids, anticoagulants, anticonvulsants, cardiac glycosides) without evidence of clinically relevant interactions.

     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.

Supplements/Antacids

Co-administration of medications which contain polyvalent cations (e.g., calcium, magnesium, aluminum and iron) can interfere with the absorption of Actonel. As with food, such medications should therefore be administered at a different time of the day (see Dosage).

Hormone Replacement Therapy

If considered appropriate, Actonel may be used concomitantly with hormone replacement therapy.

Acetylsalicylic Acid (ASA)

Of over 5700 patients enrolled in the Actonel 5mg daily Phase III osteoporosis studies, ASA use was reported by 31% of patients. Among ASA users, the incidence of upper gastrointestinal adverse experiences in Actonel-treated patients was similar to that in placebo-treated patients. In the 1-year study comparing Actonel 35 mg once a week to Actonel 5 mg daily in postmenopausal women, ASA use was reported by 56% of patients in the Actonel 35 mg once a week and 5 mg daily groups. Among ASA users, the incidence of upper gastrointestinal adverse experiences was found to be similar between the weekly- and daily-treated groups.

Other Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

Of over 5700 patients enrolled in the Actonel Phase 5 mg daily Phase III osteoporosis studies, 48% used NSAIDs. Among NSAID users, the incidence of upper gastrointestinal adverse experiences in Actonel-treated patients was similar to that in placebo-treated patients. In the 1-year study comparing Actonel 35 mg once a week to Actonel 5 mg daily in postmenopausal women, 41% of patients in the Actonel 35 mg once a week and 5 mg daily groups used NSAIDs. Among NSAID users, the incidence of upper gastrointestinal adverse experiences was found to be similar between the weekly- and daily-treated groups.

H₂-Blockers and Proton Pump Inhibitors (PPIs)

Of over 5700 patients enrolled in the Actonel 5 mg daily Phase III osteoporosis studies, 21% used H₂-blockers and/or PPIs. Among these patients, the incidence of upper gastrointestinal adverse experiences in the Actonel-treated patients was similar to that in placebo-treated patients. In the 1-year study comparing Actonel once a week and daily dosing regimens in postmenopausal women, at least 9% of patients in the Actonel 35 mg once a week and 5 mg daily groups used H₂-blockers and/or PPIs. Among these patients, the incidence of upper gastrointestinal adverse experiences was found to be similar between the weekly- and daily-treated groups.

Laboratory Test Interactions

Bisphosphonates are known to interfere with the use of bone-imaging agents. Specific studies with Actonel have not been performed.

 

Adverse Effects

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 adverse effects was found to be comparable amongst Actonel- and placebo-treated patients.

      Table 1 lists adverse events reported in ≥  2% of Actonel 5 mg daily-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 Actonel 5 mg daily-treated patients and 6.0% of patients treated with placebo.

CPS:Actonel_t1Click here for Table 1

Table 1: Actonel

Adverse Events Reported in ≥  2% of Actonel 5 mg Daily-treated Patients^a  and Occurring at ≥  1.1 Times the Placebo Rate in Combined Phase III Postmenopausal Osteoporosis Trials

 

Adverse Event	Placebo Control % (N=1744)	Actonel 5 mg % (N=1742)
Cardiovascular
Hypertension	9.4	10.6
Cardiovascular Disorder	1.8	2.6
Digestive
Abdominal Pain	9.5	11.8
Hernia	2.6	3.1
Gastritis	2.4	2.6
Rectal Disorder	1.9	2.2
Hemic and Lymphatic
Ecchymosis	3.9	4.5
Anemia	1.9	2.5
Musculoskeletal
Joint Disorder	5.5	7.1
Neck Pain	4.6	5.4
Bone Pain	4.5	5.1
Bone Disorder	3.4	4.4
Leg Cramps	2.7	3.6
Tendon Disorder	2.5	3.0
Nervous System
Dizziness	5.5	6.7
Asthenia	4.5	5.1
Anxiety	2.9	4.6
Hypertonia	2.1	2.4
Paresthesia	1.9	2.2
Respiratory
Pharyngitis	5.2	6.0
Rhinitis	5.0	5.9
Dyspnea	3.2	3.7
Pneumonia	2.7	3.0
Skin and Appendages
Pruritus	2.2	2.9
Skin Carcinoma	1.8	2.1
Special Senses
Cataract	5.3	6.1
Conjunctivitis	2.7	3.3
Urogenital
Cystitis	3.6	4.3

 

 ^a AEs shown are without attribution of causality.

 

 

Once a Week Dosing

In the 1-year, double-blind, multicentre study comparing Actonel 35 mg once a week to Actonel 5 mg daily in postmenopausal women, the overall safety and tolerability profiles of the 2 oral dosing regimens were similar.

     Patients with active or a history of upper gastrointestinal disorders at baseline and those taking ASA, NSAIDs or drugs traditionally used for the treatment of peptic ulcers were not specifically excluded from participating in the Actonel once a week dosing study. The proportion of patients who experienced an upper gastrointestinal adverse event and the pattern of those events were found to be similar between the Actonel 35 mg once a week and Actonel 5 mg daily-treated groups.

Glucocorticoid-induced Osteoporosis

Actonel 5 mg daily has been studied in two Phase III glucocorticoid-induced osteoporosis trials enrolling more than 500 patients. The adverse event profile of this population was similar to that seen in postmenopausal osteoporosis trials.

     The overall incidence of adverse events was found to be comparable between the Actonel 5 mg daily and placebo treatment groups, with the exception of back and joint pain. Back pain was reported in 8.8% of placebo-treated patients and 17.8% of Actonel-treated patients; joint pain occurred in 14.7% of placebo patients and 24.7% of Actonel patients. Most adverse experiences reported were either mild or moderate in severity, and did not lead to discontinuation from the study. Discontinuation of therapy due to serious clinical adverse events occurred in 2.9% of Actonel 5 mg daily-treated patients and 5.3% of patients treated with placebo. The occurrence of adverse events does not appear to be related to patient age, gender or race.

      Table 2 lists adverse events reported as possibly or probably causally drug-related in ≥ 2% of Actonel 5 mg daily-treated patients in the Phase III glucocorticoid-induced osteoporosis studies.

CPS:Actonel_t2Click here for Table 2

Table 2: Actonel

Drug-related^a  Adverse Events Reported in ≥ 2% of Actonel 5 mg Daily-treated Patients^a  in the Phase III Glucocorticoid-induced Osteoporosis Trials

 

Adverse Event			Placebo Control % (N=170)	Actonel 5 mg % (N=174)
Body as a Whole
Abdominal Pain			4.7	4.0
Digestive System
Dyspepsia			2.9	5.7
Nausea			5.3	5.7
Constipation			3.5	2.9
Diarrhea			3.5	2.9

 

 ^a Considered to be possibly or probably causally related in at least 1 patient.

 

 

Endoscopic Findings

Actonel 5 mg daily clinical studies enrolled over 5700 patients for the treatment and prevention of postmenopausal and glucocorticoid-induced osteoporosis, many 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 (75 Actonel; 75 placebo).

     Across treatment groups, the percentage of patients with normal esophageal, gastric and duodenal mucosa on endoscopy was similar (21% Actonel; 20% placebo). Positive findings on endoscopy were also generally comparable across treatment groups. There was a higher number of reports of mild duodenitis in the Actonel group; however, there were more duodenal ulcers in the placebo group. Clinically important findings (perforations, ulcers, or bleeding) among this symptomatic population were similar between groups (39% Actonel; 51% placebo).

     In the 1-year study comparing Actonel 35 mg once a week to Actonel 5 mg daily in the treatment of postmenopausal osteoporosis, endoscopies performed during the study revealed no dose dependent pattern in the number of patients with positive endoscopic findings nor in the anatomical location of abnormalities detected.

Paget's Disease of Bone

Actonel 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.

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

     Adverse experiences reported in ≥ 2% of Actonel 30 mg daily-treated patients in the Phase III study are shown in  Table 3.

CPS:Actonel_t3Click here for Table 3

Table 3: Actonel

Adverse Events Reported in ≥ 2% of Actonel 30 mg Daily-treated Patients^a  in the Phase III Paget's Trial

 

Body System			30 mg/day × 2 months Actonel % (N=61)	400 mg/day × 6 months Didronel % (N=61)
Body as a Whole
Flu Syndrome			9.8	1.6
Chest Pain			6.6	3.3
Asthenia			4.9	0
Neoplasm			3.3	1.6
Digestive
Diarrhea			19.7	14.8
Abdominal Pain			11.5	8.2
Nausea			9.8	9.8
Constipation			6.6	8.2
Belching			3.3	1.6
Colitis			3.3	3.3
Metabolic and Nutritional
Peripheral Edema			8.2	6.6
Musculoskeletal
Arthralgia			32.8	29.5
Bone Pain			4.9	4.9
Leg Cramps			3.3	3.3
Myasthenia			3.3	0
Nervous System
Headache			18.0	16.4
Dizziness			6.6	4.9
Respiratory
Bronchitis			3.3	4.9
Sinusitis			4.9	1.6
Skin
Rash			11.5	8.2
Special Senses
Amblyopia			3.3	3.3
Tinnitus			3.3	3.3
Dry Eye			3.3	0

 

 ^a Considered to be possibly or probably causally related in at least 1 patient.

 

 

     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 Actonel 30 mg daily-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.

For All Indications

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

     Musculoskeletal pain has been reported as common (1-10%).

     Hypersensitivity and skin reactions, including angioedema, generalized rash and bullous skin reactions, have been reported as very rare (<1 report per 10 000 new prescriptions) in Post-Marketing Observations.

Laboratory Test Findings

Asymptomatic mild decreases in serum calcium and phosphorus levels have been observed in some patients (see Pharmacology, Pharmacodynamics).

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.

 

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.

 

 

Treatment

Administration of milk or antacids containing calcium may be helpful to chelate Actonel 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.

 

Dosage

Treatment of Postmenopausal Osteoporosis

The recommended regimen is 5 mg daily or 35 mg once a week, taken orally.

Prevention of Postmenopausal Osteoporosis

The recommended regimen is 5 mg daily, taken orally.

Treatment and Prevention of Glucocorticoid-induced Osteoporosis

The recommended regimen is 5 mg daily, taken orally.

Treatment of Paget's Disease of Bone

The recommended regimen is 30 mg daily for 2 months, taken orally.

     Re-treatment 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 re-treatment, the dose and duration of therapy are the same as for initial treatment. There are no data available on more than one course of re-treatment.

For All Indications and Doses

Actonel should be taken 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, Actonel should be swallowed while the patient is in an upright position and with sufficient plain water (≥ 120 mL). Patients should not lie down for at least 30 minutes after taking the medication (see Precautions, General).

     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 Actonel. As with food, such medications should therefore be administered at a different time of the day.

     Actonel 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 ≥ 30 mL/min or in the elderly.

 

Supplied

5 mg (i.e., daily osteoporosis dose)

Each film-coated, oval-shaped, yellow tablet with “RSN” engraved on one face and “5 mg” engraved 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. Cartons of 28 blister packaged tablets. Store at controlled room temperature (15 to 30°C).

30 mg (i.e., daily Paget's dose)

Each film-coated, oval-shaped, white tablet with “RSN” engraved on one face and “30 mg” engraved 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 tablets. Store at controlled room temperature (15 to 30°C).

35 mg (i.e., once a week osteoporosis dose)

Each film-coated, oval-shaped, orange tablet with “RSN” engraved on one face and “35 mg” engraved on the other, contains: 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, hydroxypropyl methylcellulose, 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).