1 INDICATIONS AND USAGE

1.1 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-related fractures [see Clinical Studies (14.1, 14.2)].

1.2 Osteoporosis in Men

ACTONEL is indicated for treatment to increase bone mass in men with osteoporosis.

1.3 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 ≥ 7.5 mg prednisone or equivalent) for chronic diseases. Patients treated with glucocorticoids should receive adequate amounts of calcium and vitamin D.

1.4 Paget’s Disease

ACTONEL is indicated for treatment of Paget’s disease of bone in men and women.

2 DOSAGE AND ADMINISTRATION

ACTONEL should be taken at least 30 minutes before the first food or drink of the day other than water.

To facilitate delivery to the stomach, ACTONEL should be swallowed while the patient is in an upright position and with a full glass of plain water (6 to 8 oz). Patients should not lie down for 30 minutes after taking the medication [see Warnings and Precautions (5.1)].

Patients should receive supplemental calcium and vitamin D if dietary intake is inadequate [see Warnings and Precautions (5.2)]. Calcium supplements and calcium-, aluminum-, and magnesium-containing medications may interfere with the absorption of ACTONEL and should be taken at a different time of the day. ACTONEL is not recommended for use in patients with severe renal impairment (creatinine clearance <30 mL/min). No dosage adjustment is necessary in patients with a creatinine clearance ≥30 mL/min or in the elderly.

2.1 Treatment of Postmenopausal Osteoporosis

[see Indications and Usage (1.1)]

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

2.2 Prevention of Postmenopausal Osteoporosis

[see Indications and Usage (1.1)]

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

2.3 Treatment to Increase Bone Mass in Men with Osteoporosis

[see Indications and Usage (1.2)]

The recommended regimen is:

• one 35 mg tablet orally, taken once a week

2.4 Treatment and Prevention of Glucocorticoid-Induced Osteoporosis

[see Indications and Usage (1.3)]

The recommended regimen is:

• one 5 mg tablet orally, taken daily

2.5 Treatment of Paget’s Disease

[see Indications and Usage (1.4)]

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.

3 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.

4 CONTRAINDICATIONS

• Abnormalities of the esophagus which delay esophageal emptying such as stricture or achalasia [see Warnings and Precautions (5.1)]
• Inability to stand or sit upright for at least 30 minutes [see Dosage and Administration (2), Warnings and Precautions (5.1)]
• Hypocalcemia [see Warnings and Precautions (5.2)]
• Known hypersensitivity to any component of this product [see Adverse Reactions (6.2)]

5 WARNINGS AND PRECAUTIONS

5.1 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 (4), Adverse Reactions (6.1), Information for Patients (17.1)].

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 (6-8 oz) 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 (2)]. 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.

5.2 Mineral Metabolism

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 Contraindications (4), Adverse Reactions (6.1), Information for Patients (17.1)].

5.3 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 takingbisphosphonates, including ACTONEL. Known risk factors for osteonecrosis of the jaw include invasive dental procedures (e.g., tooth extraction, dental implants, boney surgery),diagnosis of cancer, concomitant therapies (e.g., chemotherapy, corticosteroids), poor oral hygiene, and co-morbid disorders (e.g., periodontal and/or other pre-existing dental disease, anemia, coagulopathy, infection, ill-fitting dentures).

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. Inthese patients,extensive dentalsurgery to treat ONJmay exacerbate the condition. Discontinuation of bisphosphonate therapy should be considered based on individual benefit/risk assessment. [see Adverse Reactions (6.2)]

5.4 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 (6.2)]. 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.

5.5 Renal Impairment

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

5.6 Glucocorticoid-Induced Osteoporosis

Before initiating ACTONEL treatment for the treatment and prevention of glucocorticoid-induced osteoporosis, the sex steroid hormonal status of both men and women should be ascertained and appropriate replacement considered.

5.7 Laboratory Test Interactions

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

6 ADVERSE REACTIONS

6.1 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 IU 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. Table 1 lists adverse events from the Phase 3 postmenopausal osteoporosis trials reported in ≥5% of patients. Adverse events are shown without attribution of causality.

Gastrointestinal Adverse Events: The incidence of adverse events in the placebo and ACTONEL 5 mg daily groups were: abdominal pain (9.9% vs. 12.2%), diarrhea (10.0% vs. 10.8%), dyspepsia (10.6% vs. 10.8%), and gastritis (2.3% vs. 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% vs. 28.0%), arthralgia (22.1% vs. 23.7%), myalgia (6.2% vs. 6.7%), and bone pain (4.8% vs. 5.3%).

Laboratory Test Findings: Throughout the Phase 3 studies, transient decreases from baseline in serum calcium (<1%) and serum phosphate (<3%) and compensatory increases in serum PTH levels (<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 5mg once daily. There have been rare reports (<0.1%) of abnormal liver function tests.

Endoscopic Findings: In the ACTONEL clinical trials, endoscopic eva luation was encouraged in any patient with moderate-to-severe gastrointestinal complaints, while maintaining the blind. Endoscopies were performed on equal numbers of patients b