Actonel

Interactions with herbs have not been studied.

Clinical benefits may be compromised by failure to take ACTONEL on an empty stomach. For dosing information see Dosage and Administration.

Of over 5700 patients enrolled in the ACTONEL 5 mg daily Phase III osteoporosis studies, acetylsalicyclic acid (ASA) use was reported by 31% of patients and non-steroidal anti-inflammatory drug (NSAID) use by 48%. Among these ASA or NSAID users, the incidence of upper gastrointestinal adverse events was similar between the ACTONEL-treated patients and placebo-treated patients.

In the 1-year study comparing ACTONEL 35 mg Once-a-Week to ACTONEL 5 mg daily, ASA use was reported by 56% and NSAID use by 41%. The incidence of upper gastrointestinal adverse events was similar between the ACTONEL weekly- and daily-treated groups.

In two, 1-year studies comparing ACTONEL 75 mg two consecutive days per month or ACTONEL 150 mg once-a-month to ACTONEL 5 mg daily in postmenopausal women, 55% (75 mg) and 46% (150 mg) of patients reported the use of ASA and/or NSAIDs. Among these ASA or NSAID users, the incidence of upper gastrointestinal adverse events was similar in the ACTONEL monthly-treated groups when compared to the daily-treated groups respectively.

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

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 (risedronate sodium) 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.

No dosage adjustment is necessary in elderly patients (see Indications and Clinical Use, Geriatrics).

The recommended regimen is 35 mg once-a-week, taken orally.

The recommended regimen is 5 mg daily, taken orally.

For all indications and doses: 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 at least 30 minutes before consuming the first food, drink (other than plain water) and/or any other medication of the day. Each tablet should be swallowed whole—do not chew.

Daily: Patients should be instructed that if they miss a dose of ACTONEL 5 mg or 30 mg, they should take 1 tablet of ACTONEL as they normally would for their next dose. Patients should not double their next dose or take 2 tablets on the same day.

Weekly: 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. 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.

Monthly Duet: If one or both tablets of ACTONEL 75 mg monthly duet are missed, and the next month’s scheduled doses are more than 7 days away, the patient should be instructed as follows:

• If both tablets are missed, take one ACTONEL 75 mg tablet in the morning after the day it is remembered and then the other tablet on the next consecutive morning.

  
  

• If only one ACTONEL 75 mg tablet is missed, take the missed tablet in the morning after the day it is remembered.

  
  

Patients should then return to taking their ACTONEL 75 mg monthly duet on two consecutive days each month as originally scheduled. Patients should not take more than two 75 mg tablets within 7 days. If one or both tablets of ACTONEL 75 mg are missed, and the next month’s scheduled doses are within 7 days, patients should wait until their next month’s scheduled doses and then continue taking ACTONEL 75 mg monthly duet on two consecutive days each month as originally scheduled.

Once-a-Month: Patients should be instructed that if they miss a 150 mg dose of ACTONEL (1 tablet of 150 mg), and the next month’s scheduled dose is more than 7 days away, they should take the missed tablet in the morning after the day it is remembered. Patients should then return to taking their ACTONEL 150 mg as originally scheduled.

If a dose of ACTONEL 150 mg is missed, and the next month’s scheduled dose is within 7 days, patients should be instructed to wait until their next month’s scheduled dose and then continue taking ACTONEL 150 mg. Patients should not take more than 150 mg of ACTONEL within 7 days.

The recommended regimens are daily (5 mg), weekly (35 mg Once-a-Week), monthly duet (75 mg on two consecutive days per month, on the same calendar days each month), or monthly (1 tablet of 150 mg Once-a-Month on the same calendar day each month), taken orally.

The recommended regimens are daily (5 mg) or weekly (35 mg Once-a-Week), taken orally.

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.

Patients should receive supplemental calcium and vitamin D if dietary intake is inadequate (see Warnings and Precautions, General).

No dosage adjustment is necessary in patients with a creatinine clearance ≥30 mL/min or in the elderly. Not recommended for use in patients with severe renal impairment (creatinine clearance <30 mL/min).

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.

In a 2 year, double-blind, multicentre study using ACTONEL 35 mg Once-a-Week (n=191) and placebo (n=93) in men with osteoporosis, the overall safety and tolerability profiles of the two treatment groups were similar.

Patients with active or a history of upper gastrointestinal disorders at baseline and those taking ASA, non-steroidal anti-inflammatory drugs (NSAIDs) or drugs traditionally used for the treatment of peptic ulcers were not specifically excluded from participating in the 2-year male osteoporosis study. The proportion of patients who experienced an upper gastrointestinal adverse event and the pattern of those events were higher in placebo (18%) than in ACTONEL 35 mg Once-a-Week treated patients (8%).

In addition to the previously described adverse events reported in ACTONEL osteoporosis clinical trials, the following adverse events were reported in ≥2% of patients and in more ACTONEL-treated patients than placebo-treated patients in the male osteoporosis study (events are included without attribution of causality): hypoaesthesia (ACTONEL 35 mg, 2%; placebo, 1%), nephrolithiasis (ACTONEL 35 mg, 3%; placebo, 0%), benign prostatic hyperplasia (ACTONEL 35 mg, 5%; placebo, 3%), and arrhythmia (ACTONEL 35 mg, 2%; placebo 0%).

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.

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.

(Two Consecutive Days per Month): In a 1-year, double-blind, multicenter study for the treatment of osteoporosis in postmenopausal women comparing ACTONEL 75 mg on two consecutive days per month to ACTONEL 5 mg daily, the overall safety profiles of the dosing regimens were similar. 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 75 mg two consecutive days per month and ACTONEL 5 mg daily treated groups. In addition to the previously described adverse reactions reported in ACTONEL osteoporosis clinical trials, arthralgia (ACTONEL 75 mg, 1.5%; ACTONEL 5 mg, 1.0%), vomiting (ACTONEL 75 mg, 1.1%; ACTONEL 5 mg daily, 1.0%) and gastritis erosive (ACTONEL 75 mg, 1.0%; ACTONEL 5 mg, 0.3%) was reported in ≥1% of patients and in more ACTONEL 75 mg-treated patients than ACTONEL 5 mg daily.

Symptoms consistent with acute phase reactions have been reported. Based on reporting of any 33 acute phase reaction-like symptoms (without regard to causality) within the first 5 days of first dose, the overall incidence of acute phase reaction was 7.6% of patients on ACTONEL 75mg two consecutive days per month and 3.6% of patients on ACTONEL 5 mg daily. Fever or influenza-like illness (without regard to causality) occurring within the first 5 days of first dose were reported by 0.6% of patients in the ACTONEL 75 mg two consecutive days per month and 0.0% in the ACTONEL 5 mg daily groups.

(Once-a-Month): In a 1-year, double-blind, multicentre study for the treatment of osteoporosis in postmenopausal women comparing ACTONEL 150 mg Once-a-Month to ACTONEL 5 mg daily, the overall safety profiles of dosing regimens were similar. The proportion of patients who experienced an upper gastrointestinal adverse event and the pattern of those events were found to be similar between ACTONEL 150 mg Once-a-Month and the ACTONEL 5 mg daily treated groups. In addition to the previously described adverse reactions reported in ACTONEL osteoporosis clinical trials, diarrhea (ACTONEL 150 mg, 3.1%; ACTONEL 5 mg, 0.5), vomiting (ACTONEL 150 mg, 1.5%; ACTONEL 5 mg, 0.6%), arthralgia (ACTONEL 150 mg, 1.5%; ACTONEL 5 mg, 0.9%) and myalgia (ACTONEL 150 mg, 1.1%; ACTONEL 5 mg, 0.3%) were reported in ≥1% of patients and in more ACTONEL 150 mg treated patients than ACTONEL 5 mg daily.

Symptoms consistent with acute phase reactions have been reported. Based on reporting of any 33 acute phase reaction-like symptoms (without regard to causality) within the first 3 days of first dose and lasting less than 7 days, the overall incidence of acute phase reaction was 5.2% of patients in the ACTONEL 150 mg Once-a-Month group and 1.1% in the ACTONEL 5 mg daily group. Fever or influenza-like illness (without regard to causality) occurring within the first 3 days of first dose and lasting less than 7 days was reported by 1.4% of patients in the ACTONEL 150 mg Once-a-Month group and 0.2% of patients in the ACTONEL 5 mg daily group.

Reported rarely, angioedema, generalized rash and bullous skin reactions, some severe.

Reported rarely, iritis and uveitis.

Drug-Related^a Adverse Events Reported in ≥1% of ACTONEL 5 mg Daily-Treated Patients in the Phase III Glucocorticoid-induced Osteoporosis Trials

In the 1-year, double-blind, multicentre study comparing ACTONEL 35 mg Once-a-Week to ACTONEL 5 mg daily for the treatment of osteoporosis in postmenopausal women, the overall safety and tolerability profiles of the 2 oral dosing regimens were similar.

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. In addition to the previously described adverse reactions reported in ACTONEL osteoporosis clinical trials, arthralgia (ACTONEL 35 mg, 2.1%; ACTONEL 5 mg, 1.3%) was reported in ≥1% of patients and in more ACTONEL 35 mg weekly treated patients than ACTONEL 5 mg daily.

In the 1-year, double-blind, multicentre study comparing ACTONEL 35 mg Once-a-Week to placebo for the prevention of osteoporosis in postmenopausal women, the overall safety and tolerability profiles of the two groups were comparable with the exception of “arthralgia”. Specifically, 1.5% of patients taking ACTONEL 35 mg Once-a-Week experienced arthralgia compared to 0.7% of placebo patients. The overall safety profile observed in this study showed no substantive difference from that observed in the ACTONEL 5 mg daily versus ACTONEL 35 mg Once-a-Week treatment study.

Osteonecrosis of the jaw has been reported rarely (see Warnings and Precautions).

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 were 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 or in the anatomical location of abnormalities detected.

In two, 1-year studies for the treatment of osteoporosis in postmenopausal women comparing ACTONEL 75 mg on two consecutive days per month and ACTONEL 150 mg Once-a-Month respectively to ACTONEL 5 mg daily, a similar percentage of patients for each of the intermittent regimens had at least one abnormal endoscopic finding when compared to the daily regimen (ACTONEL 75 mg, 3.2%; ACTONEL 5 mg, 3.1% and ACTONEL 150 mg, 3.4%; ACTONEL 5 mg, 4.2%).

In the Phase III comparative study versus Didronel, patients with a history of upper GI 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 GI experiences was similar to that in the Didronel-treated group, with no severe upper GI experiences observed in either treatment group.

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 (risedronate sodium) 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 addition, upper abdominal pain and diarrhea were the most commonly reported adverse reactions for the highest ACTONEL monthly dose.

In Paget's disease studies with ACTONEL the most commonly reported adverse reactions were diarrhea, nausea, abdominal pain and headache.

In the daily, weekly and monthly postmenopausal osteoporosis dosing studies, 35-43% of patients who received ACTONEL were between 65 and 75 years of age and 12-23% were over 75 years of age. The corresponding proportions were 26% and 11% in glucocorticoid-induced osteoporosis trials. In the male osteoporosis study, 27% of patients receiving ACTONEL were between 65 and 75 years of age and 10% were ≥75 years.

Based upon the above study populations, no overall differences in efficacy or safety were observed between these patients and younger patients (<65 years).

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.

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).

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

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).

Each film-coated, oval-shaped, pink tablet for oral administration with “RSN” engraved on one face and “75 mg” engraved on the other, contains the equivalent of: anhydrous risedronate sodium 75 mg in the form of the hemi-pentahydrate with small amounts of monohydrate. Nonmedicinal ingredients: crospovidone, ferric oxide red, hydroxypropyl cellulose, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, silicon dioxide and titanium dioxide. Cartons of 2 blister packaged tablets.

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.

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.

Each film-coated, oval-shaped, blue tablet for oral administration with “RSN” engraved on one face and “150 mg” engraved on the other, contains the equivalent of: anhydrous risedronate sodium 150 mg in the form of the hemi-pentahydrate with small amounts of monohydrate. Nonmedicinal ingredients: crospovidone, hydroxypropyl cellulose, hypromellose, indigo carmine, magnesium stearate, microcrystalline cellulose, polyethylene glycol, silicon dioxide and titanium dioxide. Cartons of 1 blister packaged tablet.

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.

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

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).

In postmarketing experience, severe and occasionally incapacitating bone, joint and/or muscle pain has been reported in patients taking bisphosphonates (see Adverse Reactions). The time to onset of symptoms varied from one day to several months after starting the drug. Most patients had relief of symptoms after stopping the medication. A subset of patients had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate. Consider discontinuing use if severe symptoms develop.

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. 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, to the patient’s underlying disease or to other co-morbid risk factors (e.g. anemia, infection, pre-existing oral disease). 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.

Hypocalcemia and other disturbances of bone and mineral metabolism should be effectively treated before starting ACTONEL (risedronate sodium) 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).

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

The safety and efficacy of ACTONEL in children and growing adolescents have not been established.

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.

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.

In a 2-year clinical trial in the treatment of osteoporosis in men, ACTONEL 35 mg once a week decreased urinary collagen cross-linked N-telopeptide (NTX) (a marker of bone resorption), and serum bone specific alkaline phosphatase (BAP) (a marker of bone formation) by approximately 40% and 30%, below baseline values, respectively, within 12 months. The BTMs all had statistically significant decreases in bone turnover from baseline compared to placebo at all time points. The decreases in bone turnover were observed within 3 months after initiation of therapy and maintained throughout the 2-year study.

Absorption after an oral dose is relatively rapid (t_max ~1 hour) and occurs throughout the upper gastrointestinal tract. Absorption is independent of dose over the range studied (single dose, from 2.5 to 30 mg; multiple dose, from 2.5 mg/day to 75 mg two consecutive days per month and 35 and 50 mg weekly); systemic exposure increases disproportionally at 150 mg (about 2 fold greater than expected based on dose). 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.

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.

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.

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

There is no evidence that risedronate is systemically metabolized.

No data are available.

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. One in five men older than 50 years will have an osteoporotic fracture, most commonly at the spine, hip and wrist.

ACTONEL (risedronate sodium) 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 (BTMs) 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 weekly and monthly ACTONEL postmenopausal osteoporosis dosing studies, consistent decreases in bone resorption (50-60%) and bone formation (30-40%) markers were observed at Month 12.

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 two 1-year studies for the treatment of osteoporosis in postmenopausal women comparing ACTONEL 35 mg Once-a-Week and ACTONEL 150 mg Once-a-Month respectively to ACTONEL 5 mg daily, similar mean changes from baseline in serum calcium, phosphate and PTH were found for each of the intermittent regimens when compared to the daily dosage regimen. In the 1-year study comparing ACTONEL 75 mg on two consecutive days per month to ACTONEL 5 mg daily, the mean percent changes from baseline were for serum calcium (0.8% and 0.2%), phosphate (−1.1% and −1.9%) and PTH (−11.7% and −3.0%) respectively.

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 three 1-year weekly and monthly dosing studies for the treatment of osteoporosis in postmenopausal women, comparing ACTONEL 35 mg Once-a-Week, ACTONEL 75 mg on two consecutive days per month and ACTONEL 150 mg Once-a-Month respectively to ACTONEL 5 mg daily, similar mean changes from baseline in BMD of the lumbar spine, total proximal femur, femoral neck and femoral trochanter were found for each of the intermittent regimens when compared to the daily regimen.

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.

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 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.

Pharmacokinetic differences due to race have not been studied.

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.

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.