Esat

Postmenopausal Osteoporosis

Esat sodium tablets are indicated for the treatment and prevention of osteoporosis in postmenopausal women. In postmenopausal women with osteoporosis, Esat sodium tablets reduce the incidence of vertebral fractures and a composite endpoint of nonvertebral osteoporosis-related fractures.

Osteoporosis in Men

Esat sodium tablets are indicated for treatment to increase bone mass in men with osteoporosis.

Glucocorticoid-Induced Osteoporosis

Esat sodium tablets are 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 prednisone or equivalent) for chronic diseases. Patients treated with glucocorticoids should receive adequate amounts of calcium and vitamin D.

Paget’s Disease

Esat sodium tablets are 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 Esat sodium tablets 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.

Esat is in a group of medicines called bisphosphonates (bis FOS fo nayts). It alters the cycle of bone formation and breakdown in the body. Esat slows bone loss while increasing bone mass, which may prevent bone fractures.

Esat is used to treat or prevent osteoporosis in men and women. Esat is also used to treat Paget's disease of bone.

Esat may also be used for purposes not listed in this medication guide.

Usual Adult Dose for Paget's Disease:

30 mg orally once a day. Therapy should be continued for 2 months. A drug free interval of at least 2 months should be allowed to assess response. Retreatment may be considered after a 2 month period for patients who have relapsed or did not respond based on a failure to normalize serum alkaline phosphatase levels. Data are not available regarding more than one course of treatment.

Usual Adult Dose for Osteoporosis:

For prevention or treatment of postmenopausal osteoporosis: 5 mg orally once daily or 35 mg orally once a week. Also, Esat 75 mg may be given orally once a day on two consecutive days, for a total of two tablets monthly. Additionally, Esat 150 mg may be given orally once a month.

For treatment of osteoporosis in men: 35 mg orally once a week.

For prevention or treatment of glucocorticoid induced osteoporosis: 5 mg orally once daily.

Patients should receive adequate supplements of calcium and vitamin D.

Patients should be instructed that if they miss a dose of Esat 35 mg once a week, 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 Esat 75 mg on two consecutive days/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 Esat 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 Esat 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 Esat 75 mg on two consecutive days/month as originally scheduled. Patients should not take more than two 75 mg tablets within 7 days. If one or both tablets of Esat 75 mg on two consecutive days/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 Esat 75 mg on two consecutive days/month as originally scheduled.

If the dose of Esat 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 Esat 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 Esat 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 Esat 150 mg once a month as originally scheduled.

Usual Adult Dose for Prevention of Osteoporosis:

For prevention or treatment of postmenopausal osteoporosis: 5 mg orally once daily or 35 mg orally once a week. Also, Esat 75 mg may be given orally once a day on two consecutive days, for a total of two tablets monthly. Additionally, Esat 150 mg may be given orally once a month.

For treatment of osteoporosis in men: 35 mg orally once a week.

For prevention or treatment of glucocorticoid induced osteoporosis: 5 mg orally once daily.

Patients should receive adequate supplements of calcium and vitamin D.

Patients should be instructed that if they miss a dose of Esat 35 mg once a week, 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 Esat 75 mg on two consecutive days/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 Esat 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 Esat 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 Esat 75 mg on two consecutive days/month as originally scheduled. Patients should not take more than two 75 mg tablets within 7 days. If one or both tablets of Esat 75 mg on two consecutive days/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 Esat 75 mg on two consecutive days/month as originally scheduled.

If the dose of Esat 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 Esat 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 Esat 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 Esat 150 mg once a month as originally scheduled.

See also:
What is the most important information I should know about Esat?

Esat sodium is contraindicated in patients with the following conditions:

Use Esat as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Esat comes with an extra patient information sheet called a Medication Guide. Read it carefully. Read it again each time you get Esat refilled.
• Esat is usually taken 1 time each week. Take the calcium on the other 6 days of the week. Be sure you understand how to take Esat. Contact your doctor or pharmacist if you have any questions.
• Take the Esat by mouth on an empty stomach in the morning at least 30 minutes before your first food, drink, or other medication of the day. DO NOT take it at bedtime or before you get out of bed in the morning.
• Swallow Esat whole. Do not break, crush, chew, or suck on the tablet before swallowing.
• Take Esat with a full glass of plain water (8 oz/240 mL). Do not take it with mineral water, coffee, tea, milk, or juice.
• Take the Esat while you are sitting up or standing. Do not lie down for 30 minutes after taking it and until after you eat your first food of the day.
• Do not take antacids; products that contain calcium, aluminum, or magnesium; or certain vitamin products at the same time of day that you take Esat. Ask your pharmacist if you have questions about how to take any of these products with Esat.
• Take calcium by mouth with food.
• If you also take iron, quinolone antibiotics (eg, ciprofloxacin), tetracycline antibiotics (eg, doxycycline), or thyroid hormones (eg, levothyroxine), ask your doctor or pharmacist how to take them with calcium.
• Continue to take Esat even if you feel well. Do not miss any doses.
• If you miss a dose of Esat, do not take it later in the day. Take it the morning after you remember, and then go back to your regular dosing schedule. Do not take 2 doses on the same day. If you miss a dose of the calcium tablet and remember later in the day, you may take it with food. If you miss a dose of the calcium tablet the entire day, and you remember the next day, you may take two tablets in that day at separate times with food. Do not take more than 2 calcium tablets on the same day, unless recommended by your health care provider.

Ask your health care provider any questions you may have about how to use Esat.

Use: Labeled Indications

Osteoporosis:

Actonel: Treatment and prevention of osteoporosis in postmenopausal females; treatment of osteoporosis in males; treatment and prevention of glucocorticoid-induced osteoporosis (daily dosage of ≥7.5 mg prednisone or equivalent).

Atelvia, Actonel DR [Canadian product]: Treatment of osteoporosis in postmenopausal females.

Paget disease: Actonel: Treatment of Paget disease of the bone.

Off Label Uses

Androgen deprivation therapy-associated osteoporosis, prevention

Data from randomized, double-blind placebo-controlled studies with a limited number of patients support the use of Esat for the prevention of bone loss associated with androgen deprivation therapy in prostate cancer.

See also:
What other drugs will affect Esat?

Antacids or Mineral Supplements Containing Divalent Cations (eg, Aluminium, Calcium, Magnesium): Pharmacokinetic interaction (decreased Esat absorption). Administer Esat at least 30 min before an antacid or mineral supplements containing divalent cations are taken.

Drug Affecting Hepatic Microsomal Enzymes: Esat does not induce or inhibit cytochrome P-450 (CYP) isoenzymes and is not metabolized. Pharmacokinetic interaction unlikely.

Nonsteroidal Anti-Inflammatory Agents (NSAIDs): No evidence of increased adverse upper gastrointestinal effects. The levels/effects of Esat may be decreased by NSAIDs.

Histamine H₂ Receptor Antagonists, Proton Pump Inhibitors: No evidence of increased adverse upper gastrointestinal effects.

Phosphate Supplements: Esat may increase the levels/effects of phosphate supplements.

Aminoglycosides: The levels/effects of Esat may be decreased by aminoglycosides.

See also:
What are the possible side effects of Esat?

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 Esat sodium tablets, 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 Esat sodium tablets, 5 mg. Patients with preexisting 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 Esat sodium tablets, 5 mg daily group. The incidence of serious adverse events was 24.6% in the placebo group and 27.2% in the Esat sodium tablets, 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 Esat sodium tablets, 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.

Gastrointestinal Adverse Events: The incidence of adverse events in the placebo and Esat sodium tablets, 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 Esat sodium tablets, 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 Esat sodium tablets, 5 mg daily groups.

Musculoskeletal Adverse Events: The incidence of adverse events in the placebo and Esat sodium tablets, 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 Esat sodium tablets, 5 mg once daily. There were no significant differences in serum calcium, phosphate, or PTH levels between placebo and Esat sodium tablets, 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 Esat sodium tablets, 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 Esat sodium tablets, 5 mg once daily. There have been rare reports (less than 0.1%) of abnormal liver function tests.

Endoscopic Findings: In the Esat 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%) Esat]. Clinically important findings (perforations, ulcers, or bleeding) among this symptomatic population were similar between groups (51% placebo; 39% Esat).

Once-a-Week Dosing

The safety of Esat sodium tablets, 35 mg once-a-week in the treatment of postmenopausal osteoporosis was assessed in a 1-year, double-blind, multicenter study comparing Esat sodium tablets, 5 mg daily and Esat sodium tablets, 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 Esat sodium tablets, 5 mg daily and 485 exposed to Esat sodium tablets, 35 mg once-a-week. Patients with preexisting 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 0.4% in the Esat sodium tablets, 5 mg daily group and 1.0% in the Esat sodium tablets, 35 mg once-a-week group. The incidence of serious adverse events was 7.1% in the Esat sodium tablets, 5 mg daily group and 8.2% in the Esat sodium tablets, 35 mg once-a-week group. The percentage of patients who withdrew from the study due to adverse events was 11.9% in the Esat sodium tablets, 5 mg daily group and 11.5% in the Esat sodium tablets, 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 Esat sodium tablets, 5 mg daily group and the Esat sodium tablets, 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 Esat sodium tablets, 5 mg daily group and 14.2% of patients in the Esat sodium tablets, 35 mg once-a-week group. Myalgia was reported by 4.6% of patients in the Esat sodium tablets, 5 mg daily group and 6.2% of patients in the Esat sodium tablets, 35 mg once-a-week group.

Laboratory Test Findings: The mean percent changes from baseline at 12 months were similar between the Esat sodium tablets, 5 mg daily and Esat sodium tablets, 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 Esat sodium tablets, 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 Esat sodium tablets, 5 mg daily and 616 were exposed to Esat sodium tablets, 75 mg two consecutive days per month. Patients with preexisting 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 Esat sodium tablets, 5 mg daily group and 0.5% for the Esat sodium tablets, 75 mg two consecutive days per month group. The incidence of serious adverse events was 10.8% in the Esat sodium tablets, 5 mg daily group and 14.4% in the Esat sodium tablets, 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 Esat sodium tablets, 5 mg daily group and 13.0% in the Esat sodium tablets, 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 Esat sodium tablets, 5 mg daily and 7.6% of patients on Esat sodium tablets, 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 Esat sodium tablets, 5 mg daily and 0.6% of patients on Esat sodium tablets, 75 mg two consecutive days per month.

Gastrointestinal Adverse Events: The Esat sodium tablets, 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 Esat sodium tablets, 5 mg daily group. Most of these events occurred within a few days of dosing.

Ocular Adverse Events: None of the patients treated with Esat sodium tablets, 75 mg two consecutive days per month reported ocular inflammation such as uveitis, scleritis, or iritis; 1 patient treated with Esat sodium tablets, 5 mg daily reported uveitis.

Laboratory Test Findings: When Esat sodium tablets, 5 mg daily and Esat sodium tablets, 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 Esat sodium tablets, 5 mg daily group, Esat sodium tablets, 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 Esat sodium tablets, 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 Esat sodium tablets, 5 mg daily and 650 exposed to Esat sodium tablets, 150 mg once-a-month. Patients with preexisting 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 Esat sodium tablets, 5 mg daily group and 0.0% for the Esat sodium tablets, 150 mg once-a-month group. The incidence of serious adverse events was 4.2% in the Esat sodium tablets, 5 mg daily group and 6.2% in the Esat sodium tablets, 150 mg once-a-month group. The percentage of patients who withdrew from treatment due to adverse events was 9.5% in the Esat sodium tablets, 5 mg daily group and 8.6% in the Esat sodium tablets, 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 Esat sodium tablets, 5 mg daily group and 5.2% in the Esat sodium tablets, 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 Esat sodium tablets, 5 mg daily and 1.4% of patients on Esat sodium tablets, 150 mg once-a-month.

Gastrointestinal Adverse Events: A greater percentage of patients experienced diarrhea with Esat sodium tablets, 150 mg once-a-month compared to 5 mg daily (8.2% versus 4.7%, respectively). The Esat sodium tablets, 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 Esat sodium tablets, 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 Esat sodium tablets, 150 mg once-a-month reported ocular inflammation such as uveitis, scleritis, or iritis; 2 patients treated with Esat sodium tablets, 5 mg daily reported iritis.

Laboratory Test Findings: When Esat sodium tablets, 5 mg daily and Esat sodium tablets, 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 Esat sodium tablets, 5 mg daily regimen, Esat sodium tablets, 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 Esat sodium tablets, 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 Esat-treated patients was included. The duration of the trial was one year, with 259 exposed to placebo and 261 patients exposed to Esat sodium tablets, 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 Esat sodium tablets, 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 Esat sodium tablets, 5 mg group. The incidence of serious adverse events was 8.9% in the placebo group and 5.4% in the Esat sodium tablets, 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 Esat sodium tablets, 5 mg group. Constipation was reported by 1.9% of the placebo group and 6.5% of Esat sodium tablets, 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 Esat sodium tablets, 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 Esat sodium tablets, 5 mg group. Nausea was reported by 6.4% of patients in the placebo group and 13.2% of patients in the Esat sodium tablets, 5 mg group.

Once-a-Week Dosing

There were no deaths in a 1-year, double-blind, placebo-controlled study of Esat sodium tablets, 35 mg once-a-week for prevention of bone loss in 278 postmenopausal women without osteoporosis. More treated subjects on Esat sodium tablets reported arthralgia (placebo 7.8%; Esat sodium tablets 13.9%), myalgia (placebo 2.1%; Esat sodium tablets 5.1%), and nausea (placebo 4.3%; Esat sodium tablets 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 Esat sodium tablets, 35 mg once-a-week (N = 191). The overall safety and tolerability profile of Esat sodium tablets in men with osteoporosis was similar to the adverse events reported in the Esat sodium tablets postmenopausal osteoporosis clinical trials, with the addition of benign prostatic hyperplasia (placebo 3%; Esat sodium tablets, 35 mg 5%), nephrolithiasis (placebo 0%; Esat sodium tablets, 35 mg 3%), and arrhythmia (placebo 0%; Esat sodium tablets, 35 mg 2%).

Treatment and Prevention of Glucocorticoid-Induced Osteoporosis

The safety of Esat sodium tablets, 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 Esat sodium tablets, 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 Esat sodium tablets, 5 mg daily group. The incidence of serious adverse events was 33.5% in the placebo group and 30.5% in the Esat sodium tablets, 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 Esat sodium tablets, 5 mg daily group. Back pain was reported in 8.8% of patients in the placebo group and 17.8% of patients in the Esat sodium tablets, 5 mg daily group. Arthralgia was reported in 14.7% of patients in the placebo group and 24.7% of patients in the Esat sodium tablets, 5 mg daily group.

Treatment of Paget’s Disease

Esat has been studied in 392 patients with Paget’s disease of bone. As in trials of Esat 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 Esat 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 Esat and 61 patients exposed to etidronate disodium. The adverse event profile was similar for Esat and etidronate disodium: 6.6% (4/61) of patients treated with Esat sodium tablets, 30 mg daily for 2 months discontinued treatment due to adverse events, compared to 8.2% (5/61) of patients treated with etidronate disodium tablets, 400 mg daily for 6 months. Table 2 lists adverse events reported in greater than or equal to 5% of Esat-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.

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 Esat group and 14.8% in the etidronate group; none were serious or resulted in withdrawal.

Ocular Adverse Events: Three patients who received Esat sodium tablets, 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 Esat 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.

Musculoskeletal Pain

Bone, joint, or muscle pain, described as severe or incapacitating, have been reported rarely.

Eye Inflammation

Reactions of eye inflammation including iritis and uveitis have been reported rarely.

Jaw Osteonecrosis

Osteonecrosis of the jaw has been reported rarely.

Pulmonary

Asthma exacerbations

Esat contains reduced minerals whey, blend of vegetable oils (soybean, palm, palm kernel), nonfat milk powder, lactose, soy lecithin, taurine, L-tyrosine, L-tryptophan, nucleotides [cytidine-5'-monophosphate (CMP), disodium uridine-5'-monophosphate (UMP), adenosine-5'-monophosphate (AMP), disodium inosine-5'-monophosphate (IMP), disodium guanosine-5'-monophosphate (GMP)], L-carnitine, lutein (suspended in safflower oil).

Minerals: Calcium chloride, potassium citrate, sodium phosphate, magnesium phosphate, potassium hydroxide, sodium citrate, calcium hydroxide, potassium bicarbonate, potassium chloride, ferrous sulfate, zinc sulfate, magnesium chloride, copper sulfate, manganese sulfate, potassium iodide, sodium selenite.

Vitamins: Ascorbic acid, α-tocopheryl acetate, inositol, choline chloride, niacinamide, vitamin A palmitate, pantothenic acid, thiamine HCl, pyridoxine HCl, riboflavin, cholecalciferol, carotenes, folic acid, phytonadione, biotin, cyanocobalamin.

Average Analysis: Per 100 g powder contains: Protein 12 g (60% whey 7.1 g, 40% casein 4.7 g), carbohydrate 57 g, fat 28 g (linoleic acid 5,512 mg, linolenic acid 449 mg). Vitamins: Vitamin A 1,969 IU, carotene 165 mcg, vitamin D 335 IU, vitamin E 8.7 IU, vitamin K 53 mcg, vitamin B₁ 787 mcg, vitamin B₂ 1,181 mcg, vitamin B₆ 472 mcg, vitamin B₁₂ 1.6 mcg, niacin 3,937 mcg, folic acid 63 mcg, pantothenic acid 2,362 mcg, biotin 16 mcg, vitamin C 71 mg, choline 79 mg and inositol 26 mg. Minerals: Calcium 362 mg, phosphorus 262 mg, magnesium 50 mg, iron 6.3 mg, zinc 4.7 mg, manganese 39 mcg, copper 441 mcg, iodine 79 mcg, sodium 126 mg, potassium 551 mg, chloride 341 mg, selenium 11 mcg. Nucleotides 20 mg (CMP 10 mg, UMP 3.9 mg, AMP 3.1 mg, GMP 1.6 mg, IMP 1.6 mg), taurine 37 mg, L-carnitine 7.9 mg, lutein 20 mcg. Energy: 529 kCal.