Drug: Actonel

ACTONEL (risedronate sodium) tablets is a pyridinyl bisphosphonate that inhibits osteoclastmediated bone resorption and modulates bone metabolism. Each ACTONEL tablet for oral administration contains the equivalent of 5, 30, 35, 75, or 150 mg of anhydrous risedronate sodium in the form of the hemi-pentahydrate with small amounts of monohydrate. The empirical formula for risedronate sodium hemi-pentahydrate is C7H10NO7P2Na •2.5 H2O. The chemical name of risedronate sodium is [1-hydroxy-2-(3-pyridinyl)ethylidene]bis[phosphonic acid] monosodium salt. The chemical structure of risedronate sodium hemi-pentahydrate is the following: Molecular Weight: Anhydrous: 305.10 Hemi-pentahydrate: 350.13 Risedronate sodium is a fine, white to off-white, odorless, crystalline powder. It is soluble in water and in aqueous solutions, and essentially insoluble in common organic solvents. Inactive Ingredients All dose strengths contain: crospovidone, hydroxypropyl cellulose, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, silicon dioxide, titanium dioxide. Dose strength-specific ingredients include: 5 mg—ferric oxide yellow, lactose monohydrate; 30 mg—lactose monohydrate; 35 mg—ferric oxide red, ferric oxide yellow, lactose monohydrate; 75 mg—ferric oxide red; 150 mg—FD&C blue #2 aluminum lake.

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Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Treatment of Postmenopausal Osteoporosis Daily Dosing The safety of ACTONEL 5 mg once daily in the treatment of postmenopausal osteoporosis was assessed in four randomized, double-blind, placebo-controlled multinational trials of 3232 women aged 38 to 85 years with postmenopausal osteoporosis. The duration of the trials was up to three years, with 1619 patients exposed to placebo and 1613 patients exposed to ACTONEL 5 mg. Patients with pre-existing gastrointestinal disease and concomitant use of non-steroidal anti-inflammatory drugs, proton pump inhibitors, and H2 antagonists were included in these clinical trials. All women received 1000 mg of elemental calcium plus vitamin D supplementation up to 500 international units per day if their 25-hydroxyvitamin D3 level was below normal at baseline. The incidence of all-cause mortality was 2.0% in the placebo group and 1.7% in the ACTONEL 5 mg daily group. The incidence of serious adverse events was 24.6% in the placebo group and 27.2% in the ACTONEL 5 mg group. The percentage of patients who withdrew from the study due to adverse events was 15.6% in the placebo group and 14.8% in the ACTONEL 5 mg group. The most common adverse reactions reported in greater than 10 percent of subjects were: back pain, arthralgia, abdominal pain and dyspepsia. Table 1 lists adverse events from the Phase 3 postmenopausal osteoporosis trials reported in greater than or equal to 5% of patients. Adverse events are shown without attribution of causality. Table 1 : Adverse Events Occurring at a Frequency greater than or equal to 5% in Either Treatment Group Combined Phase 3 Postmenopausal Osteoporosis Treatment Trials
Body System Placebo
N = 1619% 5 mg ACTONEL
N = 1613% Body as a Whole   Infection 29.9 31.1   Back Pain 26.1 28.0   Accidental Injury 16.8 16.9   Pain 14.0 14.1   Abdominal Pain 9.9 12.2   Flu Syndrome 11.6 10.5   Headache 10.8 9.9   Asthenia 4.5 5.4   Neck Pain 4.7 5.4   Chest Pain 5.1 5.0   Allergic Reaction 5.9 3.8 Cardiovascular System   Hypertension 9.8 10.5 Digestive System   Constipation 12.6 12.9   Diarrhea 10.0 10.8   Dyspepsia 10.6 10.8   Nausea 11.2 10.5 Metabolic & Nutritional Disorders   Peripheral Edema 8.8 7.7 Musculoskeletal System   Arthralgia 22.1 23.7   Arthritis 10.1 9.6   Traumatic Bone Fracture 12.3 9.3   Joint Disorder 5.3 7.0   Myalgia 6.2 6.7   Bone Pain 4.8 5.3 Nervous System   Dizziness 5.7 7.1   Depression 6.1 6.8   Insomnia 4.6 5.0 Respiratory System   Bronchitis 10.4 10.0   Sinusitis 9.1 8.7   Rhinitis 5.1 6.2   Pharyngitis 5.0 6.0   Increased Cough 6.3 5.9 Skin and Appendages   Rash 7.1 7.9 Special Senses   Cataract 5.7 6.5 Urogenital System   Urinary Tract Infection 10.4 11.1 Gastrointestinal Adverse Events: The incidence of adverse events in the placebo and ACTONEL 5 mg daily groups were: abdominal pain (9.9% versus 12.2%), diarrhea (10.0% versus 10.8%), dyspepsia (10.6% versus 10.8%), and gastritis (2.3% versus 2.7%). Duodenitis and glossitis have been reported uncommonly in the ACTONEL 5 mg daily group (0.1% to 1%). In patients with active upper gastrointestinal disease at baseline, the incidence of upper gastrointestinal adverse events was similar between the placebo and ACTONEL 5 mg daily groups. Musculoskeletal Adverse Events: The incidence of adverse events in the placebo and ACTONEL 5 mg daily groups were: back pain (26.1% versus 28.0%), arthralgia (22.1% versus 23.7%), myalgia (6.2% versus 6.7%), and bone pain (4.8% versus 5.3%). Laboratory Test Findings: Throughout the Phase 3 studies, transient decreases from baseline in serum calcium (less than 1%) and serum phosphate (less than 3%) and compensatory increases in serum PTH levels (less than 30%) were observed within 6 months in patients in osteoporosis clinical trials treated with ACTONEL 5 mg once daily. There were no significant differences in serum calcium, phosphate, or PTH levels between placebo and ACTONEL 5 mg once daily at 3 years. Serum calcium levels below 8 mg/dL were observed in 18 patients, 9 (0.5%) in each treatment arm (placebo and ACTONEL 5 mg once daily). Serum phosphorus levels below 2 mg/dL were observed in 14 patients, 3 (0.2%) treated with placebo and 11 (0.6%) treated with ACTONEL 5 mg once daily. There have been rare reports (less than 0.1%) of abnormal liver function tests. Endoscopic Findings: In the ACTONEL clinical trials, endoscopic evaluation was encouraged in any patient with moderate-to-severe gastrointestinal complaints, while maintaining the blind. Endoscopies were performed on equal numbers of patients between the placebo and treated groups [75 (14.5%) placebo; 75 (11.9%) ACTONEL]. Clinically important findings (perforations, ulcers, or bleeding) among this symptomatic population were similar between groups (51% placebo; 39% ACTONEL). Once-a-Week Dosing The safety of ACTONEL 35 mg once-a-week in the treatment of postmenopausal osteoporosis was assessed in a 1-year, double-blind, multicenter study comparing ACTONEL 5 mg daily and ACTONEL 35 mg once-a-week in postmenopausal women aged 50 to 95 years. The duration of the trials was one year, with 480 patients exposed to ACTONEL 5 mg daily and 485 exposed to ACTONEL 35 mg once-a-week. Patients with pre-existing gastrointestinal disease and concomitant use of non-steroidal anti-inflammatory drugs, proton pump inhibitors, and H2 antagonists were included in these clinical trials. All women received 1000 mg of elemental calcium plus vitamin D supplementation up to 500 international units per day if their 25hydroxyvitamin D3 level was below normal at baseline. The incidence of all-cause mortality was 0.4% in the ACTONEL 5 mg daily group and 1.0% in the ACTONEL 35 mg once-a-week group. The incidence of serious adverse events was 7.1% in the ACTONEL 5 mg daily group and 8.2% in the ACTONEL 35 mg once-a-week group. The percentage of patients who withdrew from the study due to adverse events was 11.9% in the ACTONEL 5 mg daily group and 11.5% in the ACTONEL 35 mg once-a-week group. The overall safety and tolerability profiles of the two dosing regimens were similar. Gastrointestinal Adverse Events: The incidence of gastrointestinal adverse events was similar between the ACTONEL 5 mg daily group and the ACTONEL 35 mg once-a-week group: dyspepsia (6.9% versus 7.6%), diarrhea (6.3% versus 4.9%), and abdominal pain (7.3% versus 7.6%). Musculoskeletal Adverse Events: Arthralgia was reported in 11.5% of patients in the ACTONEL 5 mg daily group and 14.2% of patients in the ACTONEL 35 mg once-a-week group. Myalgia was reported by 4.6% of patients in the ACTONEL 5 mg daily group and 6.2% of patients in the ACTONEL 35 mg once-a-week group. Laboratory Test Findings: The mean percent changes from baseline at 12 months were similar between the ACTONEL 5 mg daily and ACTONEL 35 mg once-a-week groups, respectively, for serum calcium (0.4% versus 0.7%), phosphate (-3.8% versus -2.6%) and PTH (6.4% versus 4.2%). Monthly Dosing Two Consecutive Days per Month The safety of ACTONEL 75 mg administered on two consecutive days per month for the treatment of postmenopausal osteoporosis was assessed in a double-blind, multicenter study in postmenopausal women aged 50 to 86 years. The duration of the trial was two years; 613 patients were exposed to ACTONEL 5 mg daily and 616 were exposed to ACTONEL 75 mg two consecutive days per month. Patients with pre-existing gastrointestinal disease and concomitant use of non-steroidal anti-inflammatory drugs, proton pump inhibitors, and H2 antagonists were included in this clinical trial. All women received 1000 mg of elemental calcium plus 400 to 800 international units of vitamin D supplementation per day. The incidence of all-cause mortality was 1.0% for the ACTONEL 5 mg daily group and 0.5% for the ACTONEL 75 mg two consecutive days per month group. The incidence of serious adverse events was 10.8% in the ACTONEL 5 mg daily group and 14.4% in the ACTONEL 75 mg two consecutive days per month group. The percentage of patients who withdrew from treatment due to adverse events was 14.2% in the ACTONEL 5 mg daily group and 13.0% in the ACTONEL 75 mg two consecutive days per month group. The overall safety and tolerability profiles of the two dosing regimens were similar. Acute Phase Reactions: Symptoms consistent with acute phase reaction have been reported with bisphosphonate use. The overall incidence of acute phase reaction was 3.6% of patients on ACTONEL 5 mg daily and 7.6% of patients on ACTONEL 75 mg two consecutive days per month. These incidence rates are based on reporting of any of 33 acute phase reaction-like symptoms within 5 days of the first dose. Fever or influenza-like illness with onset within the same period were reported by 0.0% of patients on ACTONEL 5 mg daily and 0.6% of patients on ACTONEL 75 mg two consecutive days per month. Gastrointestinal Adverse Events: The ACTONEL 75 mg two consecutive days per month group resulted in a higher incidence of discontinuation due to vomiting (1.0% versus 0.2%) and diarrhea (1.0% versus 0.3%) compared to the ACTONEL 5 mg daily group. Most of these events occurred within a few days of dosing. Ocular Adverse Events: None of the patients treated with ACTONEL 75 mg two consecutive days per month reported ocular inflammation such as uveitis, scleritis, or iritis; 1 patient treated with ACTONEL 5 mg daily reported uveitis. Laboratory Test Findings: When ACTONEL 5 mg daily and ACTONEL 75 mg two consecutive days per month were compared in postmenopausal women with osteoporosis, the mean percent changes from baseline at 24 months were 0.2% and 0.8% for serum calcium, -1.9% and -1.3% for phosphate, and -10.4% and -17.2% for PTH, respectively. Compared to the ACTONEL 5 mg daily group, ACTONEL 75 mg two consecutive days per month resulted in a slightly higher incidence of hypocalcemia at the end of the first month of treatment (4.5% versus 3.0%). Thereafter, the incidence of hypocalcemia with these regimens was similar at approximately 2%. Once-a-Month The safety of ACTONEL 150 mg administered once-a-month for the treatment of postmenopausal osteoporosis was assessed in a double-blind, multicenter study in postmenopausal women aged 50 to 88 years. The duration of the trial was one year, with 642 patients exposed to ACTONEL 5 mg daily and 650 exposed to ACTONEL 150 mg once-amonth. Patients with pre-existing gastrointestinal disease and concomitant use of non-steroidal anti-inflammatory drugs, proton pump inhibitors, and H2 antagonists were included in this clinical trial. All women received 1000 mg of elemental calcium plus up to 1000 international units of vitamin D supplementation per day. The incidence of all-cause mortality was 0.5% for the ACTONEL 5 mg daily group and 0.0% for the ACTONEL 150 mg once-a-month group. The incidence of serious adverse events was 4.2% in the ACTONEL 5 mg daily group and 6.2% in the ACTONEL 150 mg once-a-month group. The percentage of patients who withdrew from treatment due to adverse events was 9.5% in the ACTONEL 5 mg daily group and 8.6% in the ACTONEL 150 mg once-a-month group. The overall safety and tolerability profiles of the two dosing regimens were similar. Acute Phase Reactions: Symptoms consistent with acute phase reaction have been reported with bisphosphonate use. The overall incidence of acute phase reaction was 1.1% in the ACTONEL 5 mg daily group and 5.2% in the ACTONEL 150 mg once-a-month group. These incidence rates are based on reporting of any of 33 acute phase reaction-like symptoms within 3 days of the first dose and for a duration of 7 days or less. Fever or influenza-like illness with onset within the same period were reported by 0.2% of patients on ACTONEL 5 mg daily and 1.4% of patients on ACTONEL 150 mg once-a-month. Gastrointestinal Adverse Events: A greater percentage of patients experienced diarrhea with ACTONEL 150 mg once-a-month compared to 5 mg daily (8.2% versus 4.7%, respectively). The ACTONEL 150 mg once-a-month group resulted in a higher incidence of discontinuation due to abdominal pain upper (2.5% versus 1.4%) and diarrhea (0.8% versus 0.0%) compared to the ACTONEL 5 mg daily regimen. All of these events occurred within a few days of the first dose. The incidence of vomiting that led to discontinuation was the same in both groups (0.3% versus 0.3%). Ocular Adverse Events: None of the patients treated with ACTONEL 150 mg once-a-month reported ocular inflammation such as uveitis, scleritis, or iritis; 2 patients treated with ACTONEL 5 mg daily reported iritis. Laboratory Test Findings: When ACTONEL 5 mg daily and ACTONEL 150 mg once-a-month were compared in postmenopausal women with osteoporosis, the mean percent changes from baseline at 12 months were 0.1% and 0.3% for serum calcium, -2.3% and -2.3% for phosphate, and 8.3% and 4.8% for PTH, respectively. Compared to the ACTONEL 5 mg daily regimen, ACTONEL 150 mg once-a-month resulted in a slightly higher incidence of hypocalcemia at the end of the first month of treatment (0.2% versus 2.2%). Thereafter, the incidence of hypocalcemia with these regimens was similar at approximately 2%. Prevention of Postmenopausal Osteoporosis Daily Dosing The safety of ACTONEL 5 mg daily in the prevention of postmenopausal osteoporosis was assessed in two randomized, double-blind, placebo-controlled trials. In one study of postmenopausal women aged 37 to 82 years without osteoporosis, the use of estrogen replacement therapy in both placebo-and ACTONEL-treated patients was included. The duration of the trial was one year, with 259 exposed to placebo and 261 patients exposed to ACTONEL 5 mg. The second study included postmenopausal women aged 44 to 63 years without osteoporosis. The duration of the trial was one year, with 125 exposed to placebo and 129 patients exposed to ACTONEL 5 mg. All women received 1000 mg of elemental calcium per day. In the trial with estrogen replacement therapy, the incidence of all-cause mortality was 1.5% for the placebo group and 0.4% for the ACTONEL 5 mg group. The incidence of serious adverse events was 8.9% in the placebo group and 5.4% in the ACTONEL 5 mg group. The percentage of patients who withdrew from treatment due to adverse events was 18.9% in the placebo group and 10.3% in the ACTONEL 5 mg group. Constipation was reported by 1.9% of the placebo group and 6.5% of ACTONEL 5 mg group. In the second trial, the incidence of all-cause mortality was 0.0% for both groups. The incidence of serious adverse events was 17.6% in the placebo group and 9.3% in the ACTONEL 5 mg group. The percentage of patients who withdrew from treatment due to adverse events was 6.4% in the placebo group and 5.4% in the ACTONEL 5 mg group. Nausea was reported by 6.4% of patients in the placebo group and 13.2% of patients in the ACTONEL 5 mg group. Once-a-Week Dosing There were no deaths in a 1-year, double-blind, placebo-controlled study of ACTONEL 35 mg once-a-week for prevention of bone loss in 278 postmenopausal women without osteoporosis. More treated subjects on ACTONEL reported arthralgia (placebo 7.8%; ACTONEL 13.9%), myalgia (placebo 2.1%; ACTONEL 5.1%), and nausea (placebo 4.3%; ACTONEL 7.3%) than subjects on placebo. Treatment to Increase Bone Mass in Men with Osteoporosis In a 2-year, double-blind, multicenter study, 284 men with osteoporosis were treated with placebo (N = 93) or ACTONEL 35 mg once-a-week (N = 191). The overall safety and tolerability profile of ACTONEL in men with osteoporosis was similar to the adverse events reported in the ACTONEL postmenopausal osteoporosis clinical trials, with the addition of benign prostatic hyperplasia (placebo 3%; ACTONEL 35 mg 5%), nephrolithiasis (placebo 0%; ACTONEL 35 mg 3%), and arrhythmia (placebo 0%; ACTONEL 35 mg 2%). Treatment and Prevention of Glucocorticoid-Induced Osteoporosis The safety of ACTONEL 5 mg daily in the treatment and prevention of glucocorticoid-induced osteoporosis was assessed in two randomized, double-blind, placebo-controlled multinational trials of 344 patients [male (123) and female (221)] aged 18 to 85 years who had recently initiated oral glucocorticoid therapy (less than or equal to 3 months, prevention study) or were on long-term oral glucocorticoid therapy (greater than or equal to 6 months, treatment study). The duration of the trials was one year, with 170 patients exposed to placebo and 174 patients exposed to ACTONEL 5 mg daily. Patients in one study received 1000 mg elemental calcium plus 400 international units of vitamin D supplementation per day; patients in the other study received 500 mg calcium supplementation per day. The incidence of all-cause mortality was 2.9% in the placebo group and 1.1% in the ACTONEL 5 mg daily group. The incidence of serious adverse events was 33.5% in the placebo group and 30.5% in the ACTONEL 5 mg daily group. The percentage of patients who withdrew from the study due to adverse events was 8.8% in the placebo group and 7.5% in the ACTONEL 5 mg daily group. Back pain was reported in 8.8% of patients in the placebo group and 17.8% of patients in the ACTONEL 5 mg daily group. Arthralgia was reported in 14.7% of patients in the placebo group and 24.7% of patients in the ACTONEL 5 mg daily group. Treatment of Paget’s Disease ACTONEL has been studied in 392 patients with Paget's disease of bone. As in trials of ACTONEL for other indications, the adverse experiences reported in the Paget's disease trials have generally been mild or moderate, have not required discontinuation of treatment, and have not appeared to be related to patient age, gender, or race. The safety of ACTONEL was assessed in a randomized, double-blind, active-controlled study of 122 patients aged 34 to 85 years. The duration of the trial was 540 days, with 61 patients exposed to ACTONEL and 61 patients exposed to Didronel®. The adverse event profile was similar for ACTONEL and Didronel: 6.6% (4/61) of patients treated with ACTONEL 30 mg daily for 2 months discontinued treatment due to adverse events, compared to 8.2% (5/61) of patients treated with Didronel 400 mg daily for 6 months. Table 2 lists adverse events reported in greater than or equal to 5% of ACTONEL-treated patients in Phase 3 Paget's disease trials. Adverse events shown are considered to be possibly or probably causally related in at least one patient. Table 2 : Adverse Events Reported in greater than or equal to 5% of ACTONEL-Treated Patients* in Phase 3 Paget's Disease Trials
Body System 30 mg/day x 2 months ACTONEL %
(N = 61) 400 mg/day x 6 months Didronel %
(N = 61) Body as a Whole   Flu Syndrome 9.8 1.6   Chest Pain 6.6 3.3 Gastrointestinal   Diarrhea 19.7 14.8   Abdominal Pain 11.5 8.2   Nausea 9.8 9.8   Constipation 6.6 8.2 Metabolic and Nutritional Disorders   Peripheral Edema 8.2 6.6 Musculoskeletal   Arthralgia 32.8 29.5 Nervous   Headache 18.0 16.4   Dizziness 6.6 4.9 Skin and Appendages   Rash 11.5 8.2 *Considered to be possibly or probably causally related in at least one patient. Gastrointestinal Adverse Events: During the first year of the study (treatment and nontreatment follow-up), the proportion of patients who reported upper gastrointestinal adverse events was similar between the treatment groups; no patients reported severe upper gastrointestinal adverse events. The incidence of diarrhea was 19.7% in the ACTONEL group and 14.8% in the Didronel group; none were serious or resulted in withdrawal. Ocular Adverse Events: Three patients who received ACTONEL 30 mg daily experienced acute iritis in 1 supportive study. All 3 patients recovered from their events; however, in 1 of these patients, the event recurred during ACTONEL treatment and again during treatment with pamidronate. All patients were effectively treated with topical steroids. Postmarketing Experience Because these adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hypersensitivity Reactions Hypersensitivity and skin reactions have been reported, including angioedema, generalized rash, bullous skin reactions, Stevens-Johnson syndrome and toxic epidermal necrolysis. Gastrointestinal Adverse Events Events involving upper gastrointestinal irritation, such as esophagitis and esophageal or gastric ulcers, have been reported [see WARNINGS AND PRECAUTIONS]. Musculoskeletal Pain Bone, joint, or muscle pain, described as severe or incapacitating, have been reported rarely [see WARNINGS AND PRECAUTIONS]. Eye Inflammation Reactions of eye inflammation including iritis and uveitis have been reported rarely. Jaw Osteonecrosis Osteonecrosis of the jaw has been reported rarely [see WARNINGS AND PRECAUTIONS]. Pulmonary Asthma exacerbations Read the Actonel (risedronate sodium) Side Effects Center for a complete guide to possible side effectsLearn More »

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Treatment Of Postmenopausal Osteoporosis [see INDICATIONS AND USAGE] The recommended regimen is: one 5 mg tablet orally, taken daily or
  • one 35 mg tablet orally, taken once-a-week or
  • one 75 mg tablet orally, taken on two consecutive days for a total of two tablets each month or
  • one 150 mg tablet orally, taken once-a-month
Prevention Of Postmenopausal Osteoporosis [see INDICATIONS AND USAGE] The recommended regimen is:
  • one 5 mg tablet orally, taken daily or
  • one 35 mg tablet orally, taken once-a-week or
  • alternatively, one 75 mg tablet orally, taken on two consecutive days for a total of two tablets each month may be considered or
  • alternatively, one 150 mg tablet orally, taken once-a-month may be considered
Treatment To Increase Bone Mass In Men With Osteoporosis [see INDICATIONS AND USAGE] The recommended regimen is:
  • one 35 mg tablet orally, taken once-a-week
Treatment And Prevention Of Glucocorticoid-Induced Osteoporosis [see INDICATIONS AND USAGE] The recommended regimen is:
  • one 5 mg tablet orally, taken daily
Treatment Of Paget’s Disease [see INDICATIONS AND USAGE] The recommended treatment regimen is 30 mg orally once daily for 2 months. Retreatment may be considered (following post-treatment observation of at least 2 months) if relapse occurs, or if treatment fails to normalize serum alkaline phosphatase. For retreatment, the dose and duration of therapy are the same as for initial treatment. No data are available on more than 1 course of retreatment. Important Administration Instructions Instruct patients to do the following:
  • Take ACTONEL at least 30 minutes before the first food or drink of the day other than water, and before taking any oral medication or supplementation, including calcium, antacids, or vitamins to maximize absorption and clinical benefit, [see DRUG INTERACTIONS]. Avoid the use of water with supplements, including mineral water, because they may have a higher concentration of calcium.
  • Swallow ACTONEL tablets whole with a full glass of plain water (6 to 8 ounces). Avoid lying down for 30 minutes after taking the medication [see WARNINGS AND PRECAUTIONS]. Do not chew or suck the tablet because of a potential for oropharyngeal ulceration.
  • Do not eat or drink anything except plain water, or take other medications for at least 30 minutes after taking ACTONEL.
Recommendations For Calcium And Vitamin D Supplementation Instruct patients to take supplemental calcium and vitamin D if their dietary intake is inadequate; and to take calcium supplements, antacids, magnesium-based supplements or laxatives, and iron preparations at a different time of the day as they interfere with the absorption of ACTONEL. Administration Instructions For Missed Doses Instruct patients about missing ACTONEL doses as follows:
  • If a dose of ACTONEL 35 mg once-a-week is missed:
    • Take 1 tablet on the morning after they remember and return to taking 1 tablet once-aweek, as originally scheduled on their chosen day.
    • Do not take 2 tablets on the same day.
  • If one or both tablets of ACTONEL 75 mg on two consecutive days per month are missed, and the next month's scheduled doses are more than 7 days away:
    • 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
    • Return to taking their ACTONEL 75 mg on two consecutive days per month as originally scheduled.
    • Do not take more than two 75 mg tablets within 7 days.
  • If one or both tablets of ACTONEL 75 mg on two consecutive days per month are missed, and the next month's scheduled doses are within 7 days:
    • Wait until their next month's scheduled doses and then continue taking ACTONEL 75 mg on two consecutive days per month as originally scheduled.
  • If the dose of ACTONEL 150 mg once-a-month is missed, and the next month's scheduled dose is more than 7 days away:
    • Take the missed tablet in the morning after the day it is remembered and then return to taking their ACTONEL 150 mg once-a-month as originally scheduled.
    • Do not take more than one 150 mg tablet within 7 days.
  • If the dose of ACTONEL 150 mg once-a-month is missed, and the next month's scheduled dose is within 7 days:
    • Wait until their next month's scheduled dose and then continue taking ACTONEL 150 mg once-a-month as originally scheduled.

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No specific drug-drug interaction studies were performed. Risedronate is not metabolized and does not induce or inhibit hepatic microsomal drug-metabolizing enzymes (for example, Cytochrome P450). Calcium Supplements/Antacids Co-administration of ACTONEL and calcium, antacids, or oral medications containing divalent cations will interfere with the absorption of ACTONEL. Hormone Replacement Therapy One study of about 500 early postmenopausal women has been conducted to date in which treatment with ACTONEL 5 mg daily plus estrogen replacement therapy was compared to estrogen replacement therapy alone. Exposure to study drugs was approximately 12 to 18 months and the primary endpoint was change in BMD. If considered appropriate, ACTONEL may be used concomitantly with hormone replacement therapy. Aspirin/Nonsteroidal Anti-Inflammatory Drugs Of over 5700 patients enrolled in the ACTONEL Phase 3 osteoporosis studies, aspirin use was reported by 31% of patients, 24% of whom were regular users (3 or more days per week). Forty-eight percent of patients reported NSAID use, 21% of whom were regular users. Among regular aspirin or NSAID users, the incidence of upper gastrointestinal adverse experiences in placebo-treated patients (24.8%) was similar to that in ACTONEL-treated patients (24.5%). H2 Blockers and Proton Pump Inhibitors (PPIs) Of over 5700 patients enrolled in the ACTONEL Phase 3 osteoporosis studies, 21% used H2 blockers and/or PPIs. Among these patients, the incidence of upper gastrointestinal adverse experiences in the placebo-treated patients was similar to that in ACTONEL-treated patients. Read the Actonel Drug Interactions Center for a complete guide to possible interactions Learn More »

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Postmenopausal Osteoporosis ACTONEL is indicated for the treatment and prevention of osteoporosis in postmenopausal women. In postmenopausal women with osteoporosis, ACTONEL reduces the incidence of vertebral fractures and a composite endpoint of nonvertebral osteoporosis-reltaated fractures [see Clinical Studies]. Osteoporosis In Men ACTONEL is indicated for treatment to increase bone mass in men with osteoporosis. Glucocorticoid-Induced Osteoporosis ACTONEL is indicated for the treatment and prevention of glucocorticoid-induced osteoporosis in men and women who are either initiating or continuing systemic glucocorticoid treatment (daily dosage of greater than or equal to 7.5 mg of prednisone or equivalent) for chronic diseases. Patients treated with glucocorticoids should receive adequate amounts of calcium and vitamin D. Paget’s Disease ACTONEL is indicated for treatment of Paget's disease of bone in men and women. Important Limitations Of Use The optimal duration of use has not been determined. The safety and effectiveness of ACTONEL for the treatment of osteoporosis are based on clinical data of three years duration. All patients on bisphosphonate therapy should have the need for continued therapy re-evaluated on a periodic basis. Patients at low-risk for fracture should be considered for drug discontinuation after 3 to 5 years of use. Patients who discontinue therapy should have their risk for fracture re-evaluated periodically.

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ACTONEL is contraindicated in patients with the following conditions:
  • Abnormalities of the esophagus which delay esophageal emptying such as stricture or achalasia [see WARNINGS AND PRECAUTIONS]
  • Inability to stand or sit upright for at least 30 minutes [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS]
  • Hypocalcemia [see WARNINGS AND PRECAUTIONS]
  • Known hypersensitivity to ACTONEL or any of its excipients. Angioedema, generalized rash, bullous skin reactions, Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported [see ADVERSE REACTIONS]
Last reviewed on RxList: 4/14/2015
This monograph has been modified to include the generic and brand name in many instances.

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Decreases in serum calcium and phosphorus following substantial overdose may be expected in some patients. Signs and symptoms of hypocalcemia may also occur in some of these patients. Milk or antacids containing calcium should be given to bind ACTONEL and reduce absorption of the drug. In cases of substantial overdose, gastric lavage may be considered to remove unabsorbed drug. Standard procedures that are effective for treating hypocalcemia, including the administration of calcium intravenously, would be expected to restore physiologic amounts of ionized calcium and to relieve signs and symptoms of hypocalcemia. Lethality after single oral doses was seen in female rats at 903 mg/kg and male rats at 1703 mg/kg. The minimum lethal dose in mice and rabbits was 4000 mg/kg and 1000 mg/kg, respectively. These values represent 320 to 620 times the 30 mg human dose based on surface area (mg/m²).

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Dosage Forms And Strengths
  • 5 mg film-coated, oval, yellow tablet with RSN on 1 face and 5 mg on the other.
  • 30 mg film-coated, oval, white tablet with RSN on 1 face and 30 mg on the other.
  • 35 mg film-coated, oval, orange tablet with RSN on 1 face and 35 mg on the other.
  • 75 mg film-coated, oval, pink tablet with RSN on 1 face and 75 mg on the other.
  • 150 mg film-coated, oval, blue tablet with RSN on 1 face and 150 mg on the other.
Storage And Handling ACTONEL® is available as follows: 5 mg film-coated, oval, yellow tablets with RSN on 1 face and 5 mg on the other. NDC 0430-0471-15 bottle of 30 30 mg film-coated, oval, white tablets with RSN on 1 face and 30 mg on the other. NDC 0430-0470-15 bottle of 30 35 mg film-coated, oval, orange tablets with RSN on 1 face and 35 mg on the other. NDC 0430-0472-03 dose pack of 4
NDC 0430-0472-07 dose pack of 12 75 mg film-coated, oval, pink tablets with RSN on 1 face and 75 mg on the other. NDC 0430-0477-02 dose pack of 2 150 mg film-coated, oval, blue tablets with RSN on 1 face and 150 mg on the other. NDC 0430-0478-01 dose pack of 1
NDC 0430-0478-02 dose pack of 3 Store at controlled room temperature 20° to 25° C (68° to 77° F) [see USP]. Manufactured by: Warner Chilcott Company, LLC Manati, Puerto Rico 00674 or Norwich Pharmaceuticals, Inc., North Norwich, NY 13814 or Chinoin Pharmaceutical and Chemical Works Private Co. Ltd Veresegyhaz, Hungary. Marketed by: Warner Chilcott (US), LLC Rockaway, NJ 07866 1-800-521-8813. Content updated: March 2015 Last reviewed on RxList: 4/14/2015
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

Drug Products With The Same Active Ingredient ACTONEL contains the same active ingredient found in Atelvia®. A patient being treated with Atelvia should not receive ACTONEL. Upper Gastrointestinal Adverse Reactions ACTONEL, like other bisphosphonates administered orally, may cause local irritation of the upper gastrointestinal mucosa. Because of these possible irritant effects and a potential for worsening of the underlying disease, caution should be used when ACTONEL is given to patients with active upper gastrointestinal problems (such as known Barrett's esophagus, dysphagia, other esophageal diseases, gastritis, duodenitis or ulcers) [see CONTRAINDICATIONS, ADVERSE REACTIONS, PATIENT INFORMATION]. Esophageal adverse experiences, such as esophagitis, esophageal ulcers and esophageal erosions, occasionally with bleeding and rarely followed by esophageal stricture or perforation, have been reported in patients receiving treatment with oral bisphosphonates. In some cases, these have been severe and required hospitalization. Physicians should therefore be alert to any signs or symptoms signaling a possible esophageal reaction and patients should be instructed to discontinue ACTONEL and seek medical attention if they develop dysphagia, odynophagia, retrosternal pain or new or worsening heartburn. The risk of severe esophageal adverse experiences appears to be greater in patients who lie down after taking oral bisphosphonates and/or who fail to swallow it with the recommended full glass (6 to 8 ounces) of water, and/or who continue to take oral bisphosphonates after developing symptoms suggestive of esophageal irritation. Therefore, it is very important that the full dosing instructions are provided to, and understood by, the patient [see DOSAGE AND ADMINISTRATION]. In patients who cannot comply with dosing instructions due to mental disability, therapy with ACTONEL should be used under appropriate supervision. There have been post-marketing reports of gastric and duodenal ulcers with oral bisphosphonate use, some severe and with complications, although no increased risk was observed in controlled clinical trials. Mineral Metabolism Hypocalcemia has been reported in patients taking ACTONEL. Treat hypocalcemia and other disturbances of bone and mineral metabolism before starting ACTONEL therapy. Instruct patients to take supplemental calcium and vitamin D if their dietary intake is inadequate. 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 CONTRAINDICATIONS, ADVERSE REACTIONS, PATIENT INFORMATION]. Jaw Osteonecrosis Osteonecrosis of the jaw (ONJ), which can occur spontaneously, is generally associated with tooth extraction and/or local infection with delayed healing, and has been reported in patients taking bisphosphonates, including ACTONEL. Known risk factors for osteonecrosis of the jaw include invasive dental procedures (for example, tooth extraction, dental implants, boney surgery), diagnosis of cancer, concomitant therapies (for example, chemotherapy, corticosteroids), poor oral hygiene, and co-morbid disorders (for example, periodontal and/or other pre-existing dental disease, anemia, coagulopathy, infection, ill-fitting dentures). The risk of ONJ may increase with duration of exposure to bisphosphonates. For patients requiring invasive dental procedures, discontinuation of bisphosphonate treatment may reduce the risk for ONJ. Clinical judgment of the treating physician and/or oral surgeon should guide the management plan of each patient based on individual benefit/risk assessment. Patients who develop osteonecrosis of the jaw while on bisphosphonate therapy should receive care by an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition. Discontinuation of bisphosphonate therapy should be considered based on individual benefit/risk assessment [see ADVERSE REACTIONS]. Musculoskeletal Pain In postmarketing experience, there have been reports of severe and occasionally incapacitating bone, joint, and/or muscle pain 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 medication. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate. Consider discontinuing use if severe symptoms develop. Atypical Subtrochanteric And Diaphyseal Femoral Fractures Atypical, low-energy, or low trauma fractures of the femoral shaft have been reported in bisphosphonate-treated patients. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are traverse or short oblique in orientation without evidence of comminution. Causality has not been established as these fractures also occur in osteoporotic patients who have not been treated with bisphosphonates. Atypical femur fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. A number of reports note that patients were also receiving treatment with glucocorticoids (for example, prednisone) at the time of fracture. Any patient with a history of bisphosphonate exposure who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Patients presenting with an atypical fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of bisphosphonate therapy should be considered, pending a risk/benefit assessment, on an individual basis. Renal Impairment ACTONEL is not recommended for use in patients with severe renal impairment (creatinine clearance less than 30 mL/min). Glucocorticoid-Induced Osteoporosis Before initiating ACTONEL treatment for the treatment and prevention of glucocorticoidinduced osteoporosis, the sex steroid hormonal status of both men and women should be ascertained and appropriate replacement considered. Laboratory Test Interactions Bisphosphonates are known to interfere with the use of bone-imaging agents. Specific studies with ACTONEL have not been performed. Patient Counseling Information See FDA-approved patient labeling (Medication Guide) Instruct patients to read the Medication Guide before starting therapy with ACTONEL and to reread it each time the prescription is renewed. Instruct patients that Atelvia and ACTONEL contain the same active ingredient and if they are taking Atelvia, they should not take ACTONEL [see WARNINGS AND PRECAUTIONS]. Instruct patients 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 at least 30 minutes before the first food or drink of the day other than water. Instruct patients to take ACTONEL while in an upright position (sitting or standing) with a full glass of plain water (6 to 8 ounces) to facilitate delivery to the stomach, and thus reduce the potential for esophageal irritation. Instruct patients not to lie down for 30 minutes after taking the medication [see WARNINGS AND PRECAUTIONS]. Instruct patients not to chew or suck on the tablet because of a potential for oropharyngeal irritation. Instruct patients that if they develop symptoms of esophageal disease (such as difficulty or pain upon swallowing, retrosternal pain or severe persistent or worsening heartburn) they should consult their physician before continuing ACTONEL. Instruct patients about missing ACTONEL doses as follows:
  • If a dose of ACTONEL 35 mg once-a-week is missed, they should take 1 tablet on the morning after they remember and 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.
  • If one or both tablets of ACTONEL 75 mg on two consecutive days per month 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 on two consecutive days per 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 on two consecutive days per month 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 on two consecutive days per month as originally scheduled.
  • If the dose of ACTONEL 150 mg once-a-month is missed, and the next month's scheduled dose is more than 7 days away, the patient should be instructed to take the missed tablet in the morning after the day it is remembered. Patients should then return to taking their ACTONEL 150 mg once-a-month as originally scheduled. Patients should not take more than one 150 mg tablet within 7 days.
  • If the dose of ACTONEL 150 mg once-a-month is missed, and the next month's scheduled dose is within 7 days, patients should wait until their next month's scheduled dose and then continue taking ACTONEL 150 mg once-a-month as originally scheduled.
Instruct patients to take supplemental calcium and vitamin D if dietary intake is inadequate [see WARNINGS AND PRECAUTIONS]. Weight-bearing exercise should be considered along with the modification of certain behavioral factors, such as excessive cigarette smoking, and/or alcohol consumption, if these factors exist. Instruct patients to take calcium supplements or calcium-, aluminum-, and magnesium-containing medications at a different time of the day than ACTONEL as these medications may interfere with the absorption of ACTONEL. Remind patients to give all of their healthcare providers an accurate medication history. Instruct patients to tell all of their healthcare providers that they are taking ACTONEL. Patients should be instructed that any time they have a medical problem they think may be from ACTONEL, they should talk to their doctor. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility Carcinogenesis In a 104-week carcinogenicity study, rats were administered daily oral doses up to approximately 8 times the maximum recommended human daily dose. There were no significant drug-induced tumor findings in male or female rats. The high dose male group was terminated early in the study (Week 93) due to excessive toxicity, and data from this group were not included in the statistical evaluation of the study results. In an 80-week carcinogenicity study, mice were administered daily oral doses approximately 6.5 times the human dose. There were no significant drug-induced tumor findings in male or female mice. Mutagenesis Risedronate did not exhibit genetic toxicity in the following assays: In vitro bacterial mutagenesis in Salmonella and E. coli (Ames assay), mammalian cell mutagenesis in CHO/HGPRT assay, unscheduled DNA synthesis in rat hepatocytes and an assessment of chromosomal aberrations in vivo in rat bone marrow. Risedronate was positive in a chromosomal aberration assay in CHO cells at highly cytotoxic concentrations (greater than 675 mcg/mL, survival of 6% to 7%). When the assay was repeated at doses exhibiting appropriate cell survival (29%), there was no evidence of chromosomal damage. Impairment of Fertility In female rats, ovulation was inhibited at an oral dose approximately 5 times the human dose. Decreased implantation was noted in female rats treated with doses approximately 2.5 times the human dose. In male rats, testicular and epididymal atrophy and inflammation were noted at approximately 13 times the human dose. Testicular atrophy was also noted in male rats after 13 weeks of treatment at oral doses approximately 5 times the human dose. There was moderate-tosevere spermatid maturation block after 13 weeks in male dogs at an oral dose approximately 8 times the human dose. These findings tended to increase in severity with increased dose and exposure time. Dosing multiples provided above are based on the recommended human dose of 30 mg/day and normalized using body surface area (mg/m²). Actual doses were 24 mg/kg/day in rats, 32 mg/kg/day in mice, and 8, 16 and 40 mg/kg/day in dogs. Use In Specific Populations Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of ACTONEL in pregnant women. ACTONEL should be used during pregnancy only if the potential benefit justifies the potential risk to the mother and fetus. Bisphosphonates are incorporated into the bone matrix, from which they are gradually released over periods of weeks to years. The amount of bisphosphonate incorporation into adult bone, and hence, the amount available for release back into the systemic circulation, is directly related to the dose and duration of bisphosphonate use. There are no data on fetal risk in humans. However, there is a theoretical risk of fetal harm, predominantly skeletal, if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on this risk has not been studied. In animal studies, pregnant rats received risedronate sodium during organogenesis at doses 1 to 26 times the human dose of 30 mg/day. Survival of neonates was decreased in rats treated during gestation with oral doses approximately 5 times the human dose and body weight was decreased in neonates from dams treated with approximately 26 times the human dose. The number of fetuses exhibiting incomplete ossification of sternebrae or skull from dams treated with approximately 2.5 times the human dose was significantly increased compared to controls. Both incomplete ossification and unossified sternebrae were increased in rats treated with oral doses approximately 5 times the human dose. A low incidence of cleft palate was observed in fetuses from female rats treated with oral doses approximately equal to the human dose. The relevance of this finding to human use of ACTONEL is unclear. No significant fetal ossification effects were seen in rabbits treated with oral doses approximately 7 times the human dose (the highest dose tested). However, 1 of 14 litters were aborted and 1 of 14 litters were delivered prematurely. Similar to other bisphosphonates, treatment during mating and gestation with doses of risedronate sodium approximately the same as the 30 mg/day human dose resulted in periparturient hypocalcemia and mortality in pregnant rats allowed to deliver. Dosing multiples provided above are based on the recommended human dose of 30 mg/day and normalized using body surface area (mg/m²). Actual animal doses were 3.2, 7.1 and 16 mg/kg/day in the rat and 10 mg/kg/day in the rabbit. Nursing Mothers Risedronate was detected in feeding pups exposed to lactating rats for a 24-hour period post-dosing, indicating a small degree of lacteal transfer. It is not known whether ACTONEL is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ACTONEL, 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. Pediatric Use ACTONEL is not indicated for use in pediatric patients. The safety and effectiveness of risedronate was assessed in a one-year, randomized, double-blind, placebo controlled study of 143 pediatric patients (94 received risedronate) with osteogenesis imperfecta (OI). The enrolled population was predominantly patients with mild osteogenesis imperfecta (85% Type-I), aged 4 to less than 16 years, 50% male and 82% Caucasian, with a mean lumbar spine BMD Z-score of -2.08 (2.08 standard deviations below the mean for age-matched controls). Patients received either a 2.5 mg (less than or equal to 30 kg body weight) or 5 mg (greater than 30 kg body weight) daily oral dose. After one year, an increase in lumbar spine BMD in the risedronate group compared to the placebo group was observed. However, treatment with risedronate did not result in a reduction in the risk of fracture in pediatric patients with osteogenesis imperfecta. In ACTONEL-treated subjects, no mineralization defects were noted in paired bone biopsy specimens obtained at baseline and month 12. The overall safety profile of risedronate in OI patients treated for up to 12 months was generally similar to that of adults with osteoporosis. However, there was an increased incidence of vomiting compared to placebo. In this study, vomiting was observed in 15% of children treated with risedronate and 6% of patients treated with placebo. Other adverse events reported in greater than or equal to 10% of patients treated with risedronate and with a higher frequency than placebo were: pain in the extremity (21% with risedronate versus 16% with placebo), headache (20% versus 8%), back pain (17% versus 10%), pain (15% versus 10%), upper abdominal pain (11% versus 8%), and bone pain (10% versus 4%). Geriatric Use Of the patients receiving ACTONEL in postmenopausal osteoporosis studies [see Clinical Studies], 47% were between 65 and 75 years of age, and 17% were over 75. The corresponding proportions were 26% and 11% in glucocorticoid-induced osteoporosis trials, and 40% and 26% in Paget's disease trials. No overall differences in efficacy between geriatric and younger patients were observed in these studies. In the male osteoporosis trial, 28% of patients receiving ACTONEL were between 65 and 75 years of age and 9% were over 75. The lumbar spine BMD response for ACTONEL compared to placebo was 5.6% for subjects less than 65 years and 2.9% for subjects greater than or equal to 65 years. No overall differences in safety between geriatric and younger patients were observed in the ACTONEL trials, but greater sensitivity of some older individuals cannot be ruled out. Renal Impairment ACTONEL is not recommended for use in patients with severe renal impairment (creatinine clearance less than 30 mL/min) because of lack of clinical experience. No dosage adjustment is necessary in patients with a creatinine clearance greater than or equal to 30 mL/min. Hepatic Impairment No studies have been performed to assess risedronate's safety or efficacy in patients with hepatic impairment. Risedronate is not metabolized in human liver preparations. Dosage adjustment is unlikely to be needed in patients with hepatic impairment. Last reviewed on RxList: 4/14/2015
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

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