ACTONEL (risedronate sodium hemi-pentahydrate) is indicated for:

• the treatment and prevention of osteoporosis in post-menopausal women

  
  

• the treatment and prevention of glucocorticoid-induced osteoporosis in men and women

  
  

• Paget's disease of bone

  
  

 

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).

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.

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).

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).

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

• Patients who are hypersensitive to this drug or to any ingredient in the formulation. For a complete listing, see Dosage Forms, Composition and Packaging.

  
  

• Hypocalcemia (see Warnings and 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. (see Drug Interactions).

In post-marketing reporting, osteonecrosis of the jaw has been reported in patients treated with bisphosphonates. The majority of reports occurred following dental procedures such as tooth extractions; and have involved cancer patients treated with intravenous bisphosphonates, but some occurred in patients receiving oral treatment for postmenopausal osteoporosis and other diagnoses. Many had signs of local infection, including osteomyelitis. A dental examination with appropriate preventative dentistry should be considered prior to treatment with bisphosphonates in patients with concomitant risk factors (e.g. cancer, immune suppression, head and neck radiotherapy or poor oral hygiene). While on treatment, these patients should avoid invasive dental procedures if possible. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment prior to the procedure reduces the risk of osteonecrosis of the jaw. Clinical judgment, based on individual risk assessment, should guide the management of patients undergoing dental procedures.

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).

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

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

ACTONEL is not intended for use with nursing mothers. It is not known whether risedronate is excreted in human milk. Risedronate was detected in feeding pups exposed to lactating rats for a 24-hour period post-dosing, indicating a small degree of lacteal transfer. Since many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from bisphosphonates, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Bisphosphonates may cause upper gastrointestinal disorders such as dysphagia, esophagitis, esophageal ulcer and gastric ulcer. It is therefore important to follow the recommended dosing instructions (see Dosage and Administration).

Musculoskeletal pain, rarely severe, has been reported as a common adverse event in patients who received ACTONEL for all indications.

In postmenopausal and glucocorticoid-induced osteoporosis studies with ACTONEL, the most commonly reported adverse reactions were abdominal pain, dyspepsia and nausea.

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

Most adverse events (AEs) reported in the Phase III postmenopausal osteoporosis, glucocorticoid-induced osteoporosis, and Paget's trials were mild or moderate in severity and did not generally lead to discontinuation of ACTONEL.

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.

ACTONEL 5 mg daily has been studied for up to 3 years in over 5000 women enrolled in Phase III clinical trials for treatment or prevention of postmenopausal osteoporosis. Most adverse events reported in these trials were either mild or moderate in severity, and did not lead to discontinuation from the study. The distribution of severe adverse events was similar across treatment groups. In addition, the overall incidence of AEs was found to be comparable amongst ACTONEL and placebo-treated patients.

Table 1 lists adverse events considered possibly or probably drug related, reported in ≥1% of ACTONEL 5 mg daily-treated patients, in Phase III postmenopausal osteoporosis trials. Discontinuation of therapy due to serious clinical adverse events occurred in 5.5 % of ACTONEL 5 mg daily-treated patients and 6.0% of patients treated with placebo.

Table 1: ACTONEL

Drug-related^a Adverse Events Reported in ≥1% of ACTONEL 5 mg Daily-treated Patients in Combined Phase III Postmenopausal Osteoporosis Trials

Adverse Event	ACTONEL 5 mg N=1742 (%)	Placebo Control N=1744 (%)
Body as a Whole
Abdominal Pain	4.1	3.3
Headache	2.5	2.3
Asthenia	1.0	0.7
Digestive System
Dyspepsia	5.2	4.8
Nausea	4.8	5.0
Constipation	3.7	3.6
Diarrhea	2.9	2.5
Flatulence	2.1	1.8
Gastritis	1.1	0.9
Skin and Appendages
Rash	1.4	0.9
Pruritus	1.0	0.5

^a. Considered to be possibly or probably causally related by clinical study Investigators.

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.

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 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.

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, 13.9% of patients taking ACTONEL 35 mg Once-a-Week experienced arthralgia compared to 7.8% 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.

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 considered possibly or probably drug-related, reported in ≥1% of ACTONEL 5 mg daily-treated patients, in Phase III glucocorticoid-induced osteoporosis studies.

Table 2: ACTONEL

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

Adverse Event	ACTONEL 5 mg N=174 (%)	Placebo Control N=170 (%)
Body as a Whole
Abdominal Pain	4.0	4.7
Headache	1.1	1.2
Digestive System
Dyspepsia	5.7	2.9
Nausea	5.7	5.3
Constipation	2.9	3.5
Diarrhea	2.9	3.5
Dry Mouth	1.1	0.6
Duodenitis	1.1	0.0
Esophagitis	1.1	0.0
Flatulence	1.1	1.8
Gastrointestinal Disorder	1.1	0.0
Nervous System
Dizziness	1.1	1.2
Skin and Appendages
Rash	1.1	2.4
Skin Disorder	1.1	0.0

^a. Considered to be possibly or probably causally related by clinical study Investigators.

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.

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 tablets) 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.

Table 3 lists adverse events considered possibly or probably drug related, reported in ≥1% of ACTONEL 30 mg daily-treated patients, in Phase III Paget's trial.

Table 3: ACTONEL

Drug-related^a Adverse Events Reported in ≥1% of ACTONEL 30 mg Daily-treated Patients in the Phase III Paget's Trial

^a. Considered to be possibly or probably causally related by clinical study investigators.

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.

The following adverse drug reactions were reported in ≤1% of patients who received ACTONEL for all indications. Uncommon (0.1-1.0%): duodenitis, iritis. Rare (<0.1%): abnormal liver function tests, glossitis.

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

Rare cases of leukemia have been reported following therapy with bisphosphonates. Any causal relationship to either the treatment or to the patients' underlying disease has not been established.

Very rare (<1 report per 10 000 new prescriptions): hypersensitivity and skin reaction, including angioedema, generalized rash, and bullous skin reactions, some severe.

A number of cases of osteonecrosis (primarily of the jaw) have been reported in patients receiving treatment with bisphosphonates. Osteonecrosis has other well documented multiple risk factors. It is not possible to determine if these events are related to bisphosphonates, to concomitant drugs or other therapies (e.g. chemotherapy, radiotherapy, corticosteroids), to the patient's underlying disease or to other co-morbid risk factors (e.g. anemia, infection, pre-existing oral disease).(see Warnings and Precautions, General)

No specific drug-drug interaction studies were performed. Animal studies have demonstrated that risedronate is highly concentrated in bone and is retained only minimally in soft tissue. No metabolites have been detected systemically or in bone. The binding of risedronate to plasma proteins in humans is low (24%), resulting in minimal potential for interference with the binding of other drugs. In an additional animal study, there was also no evidence of hepatic microsomal enzyme induction. In summary, ACTONEL is not systemically metabolized, does not induce cytochrome P450 enzymes and has low protein binding. ACTONEL is therefore not expected to interact with other drugs based on the effects of protein binding displacement, enzyme induction or metabolism of other drugs.

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

The drugs listed in Table 4 are based on either drug interaction case reports or studies, or predicted interactions due to the expected magnitude and seriousness of the interaction (i.e., those identified as contraindicated).

Table 4: ACTONEL

Established or Predicted Drug-Drug Interactions

Risedronate sodium	Reference	Effect	Clinical Comment
Acetylsalicylic acid (ASA)	CT	Among ASA users, the incidence of upper gastrointestinal adverse events were similar between the ACTONEL-treated patients and placebo-treated patients	Of over 5700 patients enrolled in the ACTONEL 5 mg daily Phase III osteoporosis studies; ASA use was reported by 31% of patients.
		Among ASA users, the incidence of upper gastrointestinal adverse experiences was found to be similar between the weekly- and daily-treated groups.	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.
Antacids/supplements which contain polyvalent cations (e.g., calcium, magnesium, aluminum and iron)	T	Interference with the absorption of ACTONEL	Such medications should be administered at a different time of the day (see Dosage and Administration).
Hormone replacement therapy	CT	No clinically significant effect	If considered appropriate, ACTONEL may be used concomitantly with hormone replacement therapy.
H2-blockers and proton pump inhibitors (PPIs)	CT	Among H2-blockers and PPIs users, the incidence of upper gastrointestinal adverse events was similar between the ACTONEL-treated patients and placebo-treated patients.	Of over 5700 patients enrolled in the ACTONEL 5 mg daily Phase III osteoporosis studies, 21% used H2-blockers and/or PPIs.
		Among H2-blockers and PPIs users, the incidence of upper gastrointestinal adverse experiences was found to be similar between the weekly- and daily-treated groups.	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.
Non-steroidal anti-inflammatory drugs (NSAIDs)	CT	Among NSAIDs users, the incidence of upper gastrointestinal adverse events was similar between the ACTONEL-treated patients and placebo-treated patients	Of over 5700 patients enrolled in the ACTONEL 5 mg daily Phase III osteoporosis studies, 48% used NSAIDs.
		Among NSAIDs users, the incidence of upper gastrointestinal adverse experiences was found to be similar between the weekly- and daily-treated groups.	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.

Legend:

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

Interactions with herbs have not been studied.

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

 

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

  
  

• Food and medications containing polyvalent cations (e.g., calcium, magnesium, aluminum, and iron) can interfere with the absorption of ACTONEL. Therefore, food and other medications should be administered at a different time of the day (see Recommended Dose and Dosage Adjustment).

  
  

• The tablet should be swallowed whole while the patient is in an upright position and with sufficient plain water (≥120 mL) to facilitate delivery to the stomach. Patients should not lie down for at least 30 minutes after taking the medication (see Warnings and Precautions, General).

  
  

 

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. The tablet should be swallowed whole—do not chew.

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

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

The recommended regimen is 5 mg daily, 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.

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).

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

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

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.

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