Reclast

Reclast is a bisphosphonate indicated for: • Treatment and prevention of postmenopausal osteoporosis ( 1.1 , 1.2 ) • Treatment to increase bone mass in men with osteoporosis • Treatment and prevention of glucocorticoid-induced osteoporosis • Treatment of Paget’s disease of bone in men and women Limitations of Use Optimal duration of use has not been determined. For patients at low-risk for fracture, consider drug discontinuation after 3 to 5 years of use

1.1Treatment of Osteoporosis in Postmenopausal Women Reclast

is indicated for treatment of osteoporosis in postmenopausal women. In postmenopausal women with osteoporosis, diagnosed by bone mineral density (BMD) or prevalent vertebral fracture, Reclast reduces the incidence of fractures (hip, vertebral, and non-vertebral osteoporosis-related fractures). In patients at high risk of fracture, defined as a recent low-trauma hip fracture, Reclast reduces the incidence of new clinical fractures .

1.2Prevention of Osteoporosis in Postmenopausal Women Reclast

is indicated for prevention of osteoporosis in postmenopausal women .

1.3Osteoporosis in Men Reclast

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

1.4Glucocorticoid-Induced Osteoporosis Reclast

is indicated for the treatment and prevention of glucocorticoid-induced osteoporosis in men and women who are either initiating or continuing systemic glucocorticoids in a daily dosage equivalent to 7.5 mg or greater of prednisone and who are expected to remain on glucocorticoids for at least 12 months .

1.5Paget's Disease of Bone Reclast

is indicated for treatment of Paget's disease of bone in men and women. Treatment is indicated in patients with Paget’s disease of bone with elevations in serum alkaline phosphatase of two times or higher than the upper limit of the age-specific normal reference range, or those who are symptomatic, or those at risk for complications from their disease .

1.6Important Limitations of Use The

safety and effectiveness of Reclast for the treatment of osteoporosis is based on clinical data of three years duration. The optimal duration of use has not been determined. All patients on bisphosphonate therapy should have the need for continued therapy reevaluated 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 reevaluated periodically.

Infusion given intravenously over no less than 15 minutes: • Treatment of postmenopausal osteoporosis; treatment to increase bone mass in men with osteoporosis: treatment and prevention of glucocorticoid-induced osteoporosis: 5 mg once a year • Prevention of postmenopausal osteoporosis: 5 mg once every 2 years • Treatment of Paget’s disease of bone: a single 5 mg infusion. Patients should receive 1500 mg elemental calcium and 800 international units vitamin D daily

2.1Important Administration Instructions Reclast

injection must be administered as an intravenous infusion over no less than 15 minutes. • Patients must be appropriately hydrated prior to administration of Reclast . • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. • Intravenous infusion should be followed by a 10 mL normal saline flush of the intravenous line. • Administration of acetaminophen following Reclast administration may reduce the incidence of acute-phase reaction symptoms.

2.2Treatment of Osteoporosis in Postmenopausal Women The

recommended regimen is a 5 mg infusion once a year given intravenously over no less than 15 minutes.

2.3Prevention of Osteoporosis in Postmenopausal Women The

recommended regimen is a 5 mg infusion given once every 2 years intravenously over no less than 15 minutes.

2.4Osteoporosis in Men The

recommended regimen is a 5 mg infusion once a year given intravenously over no less than 15 minutes.

2.5Treatment and Prevention of Glucocorticoid-Induced Osteoporosis The

recommended regimen is a 5 mg infusion once a year given intravenously over no less than 15 minutes.

2.6Treatment of Paget’s Disease of Bone The

recommended dose is a 5 mg infusion. The infusion time must not be less than 15 minutes given over a constant infusion rate. Re-treatment of Paget’s Disease After a single treatment with Reclast in Paget’s disease an extended remission period is observed. Specific re-treatment data are not available.

However, re-treatment with Reclast may be considered in patients who have relapsed, based on increases in serum alkaline phosphatase, or in those patients who failed to achieve normalization of their serum alkaline phosphatase, or in those patients with symptoms, as dictated by medical practice.

2.7Laboratory Testing and Oral Examination Prior

to Administration • Prior to administration of each dose of Reclast, obtain a serum creatinine and creatinine clearance should be calculated based on actual body weight using Cockcroft-Gault formula before each Reclast dose. Reclast is contraindicated in patients with creatinine clearance less than 35 mL/min and in those with evidence of acute renal impairment. A 5 mg dose of Reclast administered intravenously is recommended for patients with creatinine clearance greater than or equal to 35 mL/min.

There are no safety or efficacy data to support the adjustment of the Reclast dose based on baseline renal function. Therefore, no dose adjustment is required in patients with creatinine clearance greater than or equal to 35 mL/min . • A routine oral examination should be performed by the prescriber prior to initiation of Reclast treatment .

2.8Calcium and Vitamin D Supplementation

• Instruct patients being treated for Paget’s disease of bone on the importance of calcium and vitamin D supplementation in maintaining serum calcium levels, and on the symptoms of hypocalcemia. All patients should take 1500 mg elemental calcium daily in divided doses (750 mg two times a day, or 500 mg three times a day) and 800 international units vitamin D daily, particularly in the 2 weeks following Reclast administration . • Instruct patients being treated for osteoporosis to take supplemental calcium and vitamin D if their dietary intake is inadequate. An average of at least 1200 mg calcium and 800-1000 international units vitamin D daily is recommended.

2.9Method of Administration The Reclast

infusion time must not be less than 15 minutes given over a constant infusion rate. The intravenous infusion should be followed by a 10 mL normal saline flush of the intravenous line. Reclast solution for infusion must not be allowed to come in contact with any calcium or other divalent cation-containing solutions, and should be administered as a single intravenous solution through a separate vented infusion line.

If refrigerated, allow the refrigerated solution to reach room temperature before administration. After opening, the solution is stable for 24 hours at 2°C to 8°C (36°F to 46°F) .

5 WARNINGS AND PRECAUTIONS • Products Containing Same Active Ingredient: Patients receiving Zometa should not receive Reclast • Hypocalcemia may worsen during treatment . Patients must be adequately supplemented with calcium and vitamin D • Renal Impairment: A single dose should not exceed 5 mg and the duration of infusion should be no less than 15 minutes. Renal toxicity may be greater in patients with underlying renal impairment or with other risk factors, including advanced age or dehydration. Monitor creatinine clearance before each dose ( 2.7 , 5.3 ) • Osteonecrosis of the Jaw (ONJ) has been reported. All patients should have a routine oral exam by the prescriber prior to treatment • Atypical Fractures Including Femoral Fractures have been reported. Patients with thigh or groin pain should be evaluated to rule out a femoral fracture. Risk/benefit of continuing bisphosphonate therapy should be re-evaluated in these patients and interruption of bisphosphonate therapy should be considered • Severe Bone, Joint, and Muscle Pain may occur. Withhold future doses of Reclast if severe symptoms occur

5.1Drug Products With Same Active Ingredient

Reclast contains the same active ingredient found in Zometa, used for oncology indications, and a patient being treated with Zometa should not be treated with Reclast.

5.2Hypocalcemia and Mineral Metabolism Preexisting

hypocalcemia and disturbances of mineral metabolism (e.g., hypoparathyroidism, thyroid surgery, parathyroid surgery; malabsorption syndromes, excision of small intestine) must be effectively treated before initiating therapy with Reclast. Clinical monitoring of calcium and mineral levels (phosphorus and magnesium) is highly recommended for these patients . Hypocalcemia following Reclast administration is a significant risk in Paget’s disease. All patients should be instructed about the symptoms of hypocalcemia and the importance of calcium and vitamin D supplementation in maintaining serum calcium levels . All osteoporosis patients should be instructed on the importance of calcium and vitamin D supplementation in maintaining serum calcium levels .

5.3Renal Impairment A

single dose of Reclast should not exceed 5 mg and the duration of infusion should be no less than 15 minutes . Reclast is contraindicated in patients with creatinine clearance less than 35 mL/min and in those with evidence of acute renal impairment . If history or physical signs suggest dehydration, Reclast therapy should be withheld until normovolemic status has been achieved . Reclast should be used with caution in patients with chronic renal impairment. Acute renal impairment, including renal failure, has been observed following the administration of zoledronic acid, especially in patients with preexisting renal compromise, advanced age, concomitant nephrotoxic medications, concomitant diuretic therapy, or severe dehydration occurring before or after Reclast administration. Acute renal failure (ARF) has been observed in patients after a single administration.

Rare reports of hospitalization and/or dialysis or fatal outcome occurred in patients with underlying moderate to severe renal impairment or with any of the risk factors described in this section . Renal impairment may lead to increased exposure of concomitant medications and/or their metabolites that are primarily renally excreted . Creatinine clearance should be calculated based on actual body weight using Cockcroft-Gault formula before each Reclast dose. Transient increase in serum creatinine may be greater in patients with impaired renal function; interim monitoring of creatinine clearance should be performed in at-risk patients. Elderly patients and those receiving diuretic therapy are at increased risk of acute renal failure.

These patients should have their fluid status assessed and be appropriately hydrated prior to administration of Reclast. Reclast should be used with caution with other nephrotoxic drugs . Consider monitoring creatinine clearance in patients at-risk for ARF who are taking concomitant medications that are primarily excreted by the kidney .

5.4Osteonecrosis of the Jaw Osteonecrosis of the

jaw (ONJ) has been reported in patients treated with bisphosphonates, including zoledronic acid. Most cases have been in cancer patients treated with intravenous bisphosphonates undergoing dental procedures. Some cases have occurred in patients with postmenopausal osteoporosis treated with either oral or intravenous bisphosphonates.

A routine oral examination should be performed by the prescriber prior to initiation of bisphosphonate treatment. A dental examination with appropriate preventive dentistry should be considered prior to treatment with bisphosphonates in patients with a history of concomitant risk factors (e.g., cancer, chemotherapy, angiogenesis inhibitors, radiotherapy, corticosteroids, poor oral hygiene, preexisting dental disease or infection, anemia, coagulopathy). The risk of ONJ may increase with duration of exposure to bisphosphonates.

Concomitant administration of drugs associated with ONJ may increase the risk of developing ONJ. While on treatment, patients with concomitant risk factors should avoid invasive dental procedures if possible. For patients who develop ONJ while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of ONJ. The clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment .

5.5Atypical Fractures Including Femoral Fractures

Atypical, low-energy, or low trauma fractures of the femoral shaft have been reported during treatment with bisphosphonates, including zolendronic acid, in patients with osteoporosis. Atypical femur and other fractures most commonly occur with minimal or no trauma to the affected area. These fractures occurred anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution.

Atypical fractures of other bones have also been reported. They may be bilateral. These fractures can also occur in osteoporotic patients who have not been treated with bisphosphonates. Concomitant treatment with glucocorticoids may also induce these fractures. Prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs.

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. Bony pain in other locations should also be considered for evaluation of atypical fracture. Patients presenting with an atypical femur fracture should also be assessed for symptoms and signs of fracture in the contralateral limb.

Risk/benefit of continuing bisphosphonate therapy should be re-evaluated in these patients and interruption of bisphosphonate therapy should be considered.

5.6Musculoskeletal Pain In

post-marketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain have been infrequently reported in patients taking bisphosphonates, including Reclast. The time to onset of symptoms varied from one day to several months after starting the drug. Consider withholding future Reclast treatment if severe symptoms develop.

Most patients had relief of symptoms after stopping. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate .

5.7Patients With Asthma While

not observed in clinical trials with Reclast, there have been reports of bronchoconstriction in aspirin-sensitive patients receiving bisphosphonates. Use Reclast with caution in aspirin-sensitive patients.

Reclast is contraindicated in patients with the following conditions: • Hypocalcemia • Creatinine clearance less than 35 mL/min and in those with evidence of acute renal impairment due to an increased risk of renal failure . • Known hypersensitivity to zoledronic acid or any components of Reclast. Hypersensitivity reactions, including urticaria, angioedema, and anaphylactic reaction/shock have been reported . • Hypocalcemia • Patients with creatinine clearance less than 35 mL/min and in those with evidence of acute renal impairment ( 4 , 5.3 ) • Hypersensitivity to any component of Reclast ( 4 , 6.2 )

8.1Pregnancy Risk Summary Available

data on the use of Reclast in pregnant women are insufficient to inform a drug-associated risk of adverse maternal or fetal outcomes. Discontinue Reclast when pregnancy is recognized. In animal reproduction studies, daily subcutaneous administration of zoledronic acid to pregnant rats during organogenesis resulted in increases in fetal skeletal, visceral, and external malformations, decreases in postimplantation survival, and decreases in viable fetuses and fetal weight starting at doses equivalent to 2 times the recommended human 5 mg intravenous dose (based on AUC).

Subcutaneous administration of zoledronic acid to rabbits during organogenesis did not cause adverse fetal effects at up to 0.4 times the human 5 mg intravenous dose (based on body surface area, mg/m 2 ), but resulted in maternal mortality and abortion associated with hypocalcemia starting at doses equivalent to 0.04 times the human 5 mg intravenous dose. Subcutaneous dosing of female rats from before mating through gestation and lactation and allowed to deliver caused maternal dystocia and periparturient mortality, increases in stillbirths and neonatal deaths, and reduced pup body weight starting at doses equivalent to 0.1 times the human 5 mg intravenous dose (based on AUC) . Bisphosphonates are incorporated into the bone matrix, from which they are gradually released over a period of years. The amount of bisphosphonate incorporated into adult bone, and available for release into the systemic circulation is directly related to the dose and duration of bisphosphonate use.

Consequently, based on the mechanism of action of bisphosphonates, there is a potential 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 the risk has not been studied. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown.

All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively. Data Animal Data In pregnant rats given daily subcutaneous doses of zoledronic acid of 0.1, 0.2, or 0.4 mg/kg during organogenesis, fetal skeletal, visceral, and external malformations, increases in pre-and post-implantation loss, and decreases in viable fetuses and fetal weight were observed at 0.2 and 0.4 mg/kg/day (equivalent to 2 and 4 times the human 5 mg intravenous dose, based on AUC).

Adverse fetal skeletal effects at 0.4 mg/kg/day (4 times the human 5 mg dose) included unossified or incompletely ossified bones, thickened, curved or shortened bones, wavy ribs, and shortened jaw. Other adverse fetal effects at this dose included reduced lens, rudimentary cerebellum, reduction or absence of liver lobes, reduction of lung lobes, vessel dilation, cleft palate, and edema. Skeletal variations were observed in all groups starting at 0.1 mg/kg/day (1.2 times the human 5 mg dose).

Signs of maternal toxicity, including reduced body weight and food consumption were observed at 0.4 mg/kg/day (4 times the human 5 mg dose). In pregnant rabbits given daily subcutaneous doses of zoledronic acid of 0.01, 0.03, or 0.1 mg/kg during gestation, no adverse fetal effects were observed up to 0.1 mg/kg/day (0.4 times the human 5 mg intravenous dose, based on body surface area, mg/m 2 ). Maternal mortality and abortion were observed in all dose groups (starting at 0.04 times the human 5 mg dose).

Adverse maternal effects were associated with drug-induced hypocalcemia. In female rats given daily subcutaneous doses of 0.01, 0.03, or 0.1 mg/kg, beginning 15 days before mating and continuing through gestation, parturition and lactation, dystocia and periparturient mortality were observed in pregnant rats allowed to deliver starting at 0.01 mg/kg/day (0.1 times the human 5 mg intravenous dose, based on AUC). Also, there was an increase in stillbirths and a decrease in neonate survival starting at 0.03 mg/kg/day (0.3 times the human 5 mg dose), while the number of viable newborns and pup body weight on postnatal Day 7 were decreased at 0.1 mg/kg/day (equivalent to the human 5 mg dose).

Maternal and neonatal deaths were considered related to drug-induced periparturient hypocalcemia.

The following clinically significant adverse drug reactions are described elsewhere in the labeling: • Drugs with Same Active Ingredient • Hypocalcemia and Mineral Metabolism • Renal Impairment • Osteonecrosis of the Jaw • Atypical Fractures Including Femoral Fractures • Musculoskeletal Pain • Patients with Asthma The most common adverse reactions (greater than 10%) were pyrexia, myalgia, headache, arthralgia, pain in extremity. Other important adverse reactions were flu-like illness, nausea, vomiting, diarrhea, and eye inflammation. To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical Trials 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 Osteoporosis in Postmenopausal Women The safety of Reclast in the treatment of postmenopausal osteoporosis was assessed in Study 1, a large, randomized, double-blind, placebo-controlled, multinational study of 7736 postmenopausal women aged 65 to 89 years with osteoporosis, diagnosed by BMD or the presence of a prevalent vertebral fracture. The duration of the trial was three years with 3862 patients exposed to Reclast and 3852 patients exposed to placebo administered once annually as a single 5 mg dose in 100 mL solution infused over at least 15 minutes, for a total of three doses.

All women received 1000 to 1500 mg of elemental calcium plus 400 to 1200 international units of vitamin D supplementation per day. The incidence of all-cause mortality was similar between groups: 3.4% in the Reclast group and 2.9% in the placebo group. The incidence of serious adverse events was 29.2% in the Reclast group and 30.1% in the placebo group.

The percentage of patients who withdrew from the study due to adverse events was 5.4% and 4.8% for the Reclast and placebo groups, respectively. The safety of Reclast in the treatment of osteoporosis patients with a recent (within 90 days) low-trauma hip fracture was assessed in Study 2, a randomized, double-blind, placebo-controlled, multinational endpoint-driven study of 2127 men and women aged 50 to 95 years; 1065 patients were randomized to Reclast and 1062 patients were randomized to placebo. Reclast was administered once annually as a single 5 mg dose in 100 mL solution infused over at least 15 minutes.

The study continued until at least 211 patients had a confirmed clinical fracture in the study population who were followed for an average of approximately 2 years on study drug. Vitamin D levels were not routinely measured but a loading dose of vitamin D (50,000 to 125,000 international units orally or IM) was given to patients and they were started on 1000 to 1500 mg of elemental calcium plus 800 to 1200 international units of vitamin D supplementation per day for at least 14 days prior to the study drug infusions. The incidence of all-cause mortality was 9.6% in the Reclast group and 13.3% in the placebo group.

The incidence of serious adverse events was 38.3% in the Reclast group and 41.3% in the placebo group. The percentage of patients who withdrew from the study due to adverse events was 5.3% and 4.7% for the Reclast and placebo groups, respectively. Adverse reactions reported in at least 2% of patients with osteoporosis and more frequently in the Reclast-treated patients than placebo-treated patients in either osteoporosis trial are shown below in Table 1.

Table 1. Adverse Reactions Occurring in Greater Than or Equal to 2.0% of Patients with Osteoporosis and More Frequently Than in Placebo-Treated Patients Abbreviation: IV, intravenous or intravenously. Study 1 Study 2 System Organ Class 5 mg IV Reclast once per year % (N = 3862) Placebo once per year % (N = 3852) 5 mg IV Reclast once per year % (N = 1054) Placebo once per year % (N = 1057) Blood and the Lymphatic System Disorders Anemia 4.4 3.6 5.3

5.2Metabolism and Nutrition Disorders Dehydration

0.6 0.6 2.5

2.3Anorexia

2.0 1.1 1.0

1.0Nervous System Disorders Headache

12.4 8.1 3.9

2.5Dizziness

7.6 6.7 2.0

4.0Ear and Labyrinth Disorders Vertigo

4.3 4.0 1.3

1.7Cardiac Disorders Atrial

fibrillation 2.4 1.9 2.8

2.6Vascular Disorders Hypertension

12.7 12.4 6.8

5.4Gastrointestinal Disorders Nausea

8.5 5.2 4.5

4.5Diarrhea

6.0 5.6 5.2

4.7Vomiting

4.6 3.2 3.4

3.4Abdominal

pain upper 4.6 3.1 0.9

1.5Dyspepsia

4.3 4.0 1.7

1.6Musculoskeletal, Connective Tissue and Bone Disorders

Arthralgia 23.8 20.4 17.9

18.3Myalgia

11.7 3.7 4.9

2.7Pain in

extremity 11.3 9.9 5.9

4.8Shoulder

pain 6.9 5.6 0.0

0.0Bone

pain 5.8 2.3 3.2

1.0Neck

pain 4.4 3.8 1.4

1.1Muscle

spasms 3.7 3.4 1.5

1.7Osteoarthritis

9.1 9.7 5.7

4.5Musculoskeletal

pain 0.4 0.3 3.1

1.2General Disorders and Administrative-Site Conditions Pyrexia

17.9 4.6 8.7

3.1Influenza-like

illness 8.8 2.7 0.8

0.4Fatigue

5.4 3.5 2.1

1.2Chills

5.4 1.0 1.5

0.5Asthenia

5.3 2.9 3.2

3.0Peripheral

edema 4.6 4.2 5.5

5.3Pain

3.3 1.3 1.5

0.5Malaise

2.0 1.0 1.1

0.5Hyperthermia

0.3 < 0.1 2.3

0.3Chest Pain

1.3 1.1 2.4

1.8Investigations Creatinine

renal clearance decreased 2.0 2.4 2.1

1.7Renal Impairment Treatment with

intravenous bisphosphonates, including zoledronic acid, has been associated with renal impairment manifested as deterioration in renal function (i.e., increased serum creatinine) and in rare cases, acute renal failure. In the clinical trial for postmenopausal osteoporosis, patients with baseline creatinine clearance less than 30 mL/min (based on actual body weight), urine dipstick greater than or equal to 2+ protein or increase in serum creatinine of greater than 0.5 mg/dL during the screening visits were excluded. The change in creatinine clearance (measured annually prior to dosing) and the incidence of renal failure and impairment was comparable for both the Reclast and placebo treatment groups over 3 years, including patients with creatinine clearance between 30-60 mL/min at baseline.

Overall, there was a transient increase in serum creatinine observed within 10 days of dosing in 1.8% of Reclast-treated patients versus 0.8% of placebo-treated patients which resolved without specific therapy . Acute Phase Reaction The signs and symptoms of acute phase reaction occurred in Study 1 following Reclast infusion, including fever (18%), myalgia (9%), flu-like symptoms (8%), headache (7%), and arthralgia (7%). The majority of these symptoms occurred within the first 3 days following the dose of Reclast and usually resolved within 3 days of onset but resolution could take up to 7-14 days. In Study 2, patients without a contraindication to acetaminophen were provided with a standard oral dose at the time of the IV infusion and instructed to use additional acetaminophen at home for the next 72 hours as needed.

Reclast was associated with fewer signs and symptoms of a transient acute phase reaction in this trial: fever (7%) and arthralgia (3%). The incidence of these symptoms decreased with subsequent doses of Reclast. Laboratory Findings In Study 1, in women with postmenopausal osteoporosis, approximately 0.2% of patients had notable declines of serum calcium levels (less than 7.5 mg/dL) following Reclast administration.

No symptomatic cases of hypocalcemia were observed. In Study 2, following pre-treatment with vitamin D, no patients had treatment emergent serum calcium levels below 7.5 mg/dL. Injection-Site Reactions In the osteoporosis trials, local reactions at the infusion site, such as itching, redness and/or pain have been reported in 0% to 0.7% of patients following the administration of Reclast and 0% to 0.5% of patients following administration of placebo. Osteonecrosis of the Jaw In the postmenopausal osteoporosis trial, Study 1, in 7736 patients, after initiation of therapy, symptoms consistent with ONJ occurred in one patient treated with placebo and one patient treated with Reclast.

Both cases resolved after appropriate treatment . No reports of ONJ were reported in either treatment group in Study 2. Atrial Fibrillation In the postmenopausal osteoporosis trial, Study 1, adjudicated serious adverse events of atrial fibrillation in the zoledronic acid treatment group occurred in 1.3% of patients (50 out of 3862) compared to 0.4% (17 out of 3852) in the placebo group. The overall incidence of all atrial fibrillation adverse events in the zoledronic acid treatment group was reported in 2.5% of patients (96 out of 3862) in the Reclast group vs. 1.9% of patients (75 out of 3852) in the placebo group.

Over 90% of these events in both treatment groups occurred more than a month after the infusion. In an ECG sub-study, ECG measurements were performed on a subset of 559 patients before and 9 to 11 days after treatment. There was no difference in the incidence of atrial fibrillation between treatment groups suggesting these events were not related to the acute infusions.

In Study 2, adjudicated serious adverse events of atrial fibrillation in the zoledronic acid treatment group occurred in 1.0% of patients (11 out of 1054) compared to 1.2% (13 out of 1057) in the placebo group demonstrating no difference between treatment groups. Ocular Adverse Events Cases of iritis/uveitis/episcleritis/conjunctivitis have been reported in patients treated with bisphosphonates, including zoledronic acid. In the osteoporosis trials, 1 (less than 0.1%) to 9 (0.2%) patients treated with Reclast and 0 (0%) to 1 (less than 0.1%) patient treated with placebo developed iritis/uveitis/episcleritis.

Prevention of Osteoporosis in Postmenopausal Women The safety of Reclast in postmenopausal women with osteopenia (low bone mass) was assessed in a 2-year randomized, multi-center, double-blind, placebo-controlled study of 581 postmenopausal women aged greater than or equal to 45 years. Patients were randomized to one of three treatment groups: Reclast given at randomization and Month 12 (n=198); Reclast given at randomization and placebo at Month 12 (n=181); and placebo given at randomization and Month 12 (n=202). Reclast was administered as a single 5 mg dose in 100 mL solution infused over at least 15 minutes.

All women received 500 to 1200 mg elemental calcium plus 400 to 800 international units vitamin D supplementation per day. The incidence of serious adverse events was similar for subjects given Reclast at randomization and at Month 12 (10.6%), Reclast at randomization and placebo given at Month 12 (9.4%), and placebo at randomization and at Month 12 (11.4%). The percentages of patients who withdrew from the study due to adverse events were 7.1%, 7.2%, and 3.0% in the two Reclast groups and placebo group, respectively.

Adverse reactions reported in at least 2% of patients with osteopenia and more frequently in the Reclast-treated patients than placebo-treated patients are shown in Table 2. Table 2. Adverse Reactions Occurring in Greater Than or Equal to 2% of Patients with Osteopenia and More Frequently Than in Placebo-Treated Patients Abbreviation: IV, intravenous or intravenously.

System Organ Class 5 mg IV Reclast once per year % (n = 198) 5 mg IV Reclast once % (n = 181) Placebo once per year % (n = 202) Metabolism and nutrition Disorders Anorexia 2.0 0.6

0.0Nervous

system Disorders Headache 14.6 20.4

11.4Dizziness

7.6 6.1

3.5Hypoesthesia

5.6 2.2

2.0Ear and Labyrinth Disorders Vertigo

2.0 1.7

1.0Vascular Disorders Hypertension

5.1 8.3

6.9Gastrointestinal Disorders Nausea

17.7 11.6

7.9Diarrhea

8.1 6.6

7.9Vomiting

7.6 5.0

4.5Dyspepsia

7.1 6.6

5.0Abdominal

pain Combined abdominal pain, abdominal pain upper, and abdominal pain lower as one Adverse Drug Reaction (ADR). 8.6 6.6

7.9Constipation

6.6 7.2

6.9Abdominal

discomfort 2.0 1.1

0.5Abdominal

distension 2.0 0.6

0.0Skin and Subcutaneous Tissue Disorders Rash

3.0 2.2

2.5Musculoskeletal and Connective Tissue Disorders Arthralgia

27.3 18.8

19.3Myalgia

19.2 22.7

6.9Back

pain 18.2 16.6

11.9Pain in

extremity 11.1 16.0

9.9Muscle

spasms 5.6 2.8

5.0Musculoskeletal

pain Combined musculoskeletal pain and musculoskeletal chest pain as one ADR. 8.1 7.2

7.9Bone

pain 5.1 3.3

1.0Neck

pain 5.1 6.6

5.0Arthritis

4.0 2.2

1.5Joint

stiffness 3.5 1.1

2.0Joint

swelling 3.0 0.6

0.0Flank

pain 2.0 0.6

0.0Pain in

jaw 2.0 3.9

2.5General Disorders and Administration-Site Conditions Pain

24.2 14.9

3.5Pyrexia

21.7 21.0

4.5Chills

18.2 18.2

3.0Fatigue

14.6 9.9

4.0Asthenia

6.1 2.8

1.0Peripheral

edema 5.6 3.9

3.5Non-cardiac

chest pain 3.5 7.7

3.0Influenza-like

illness 1.5 3.3

2.0Malaise

1.0 2.2

0.5Ocular Adverse Events Cases of

iritis/uveitis/episcleritis/conjunctivitis have been reported in patients treated with bisphosphonates, including zoledronic acid. In the osteoporosis prevention trial, 4 (1.1%) patients treated with Reclast and 0 (0%) patients treated with placebo developed iritis/uveitis. Acute Phase Reaction In patients given Reclast at randomization and placebo at Month 12, Reclast was associated with signs and symptoms of an acute phase reaction: myalgia (20.4%), fever (19.3%), chills (18.2%), pain (13.8%), headache (13.3%), fatigue (8.3%), arthralgia (6.1%), pain in extremity (3.9%), influenza-like illness (3.3%), and back pain (1.7%), which occurred within the first 3 days following the dose of Reclast.

The majority of these symptoms were mild to moderate and resolved within 3 days of the event onset but resolution could take up to 7-14 days. Osteoporosis in Men The safety of Reclast in men with osteoporosis or osteoporosis secondary to hypogonadism was assessed in a two year randomized, multicenter, double-blind, active controlled group study of 302 men aged 25 to 86 years. One hundred fifty three patients were exposed to Reclast administered once annually with a 5 mg dose in 100 mL infused over 15 minutes for up to a total of two doses, and 148 patients were exposed to a commercially-available oral weekly bisphosphonate (active control) for up to two years.

All participants received 1000 mg of elemental calcium plus 800 to 1000 international units of vitamin D supplementation per day. The incidence of all-cause mortality (one in each group) and serious adverse events were similar between the Reclast and active control treatment groups. The percentage of patients experiencing at least one adverse event was comparable between the Reclast and active control groups, with the exception of a higher incidence of post-dose symptoms in the Reclast group that occurred within 3 days after infusion.

The overall safety and tolerability of Reclast was similar to the active control. Adverse reactions reported in at least 2% of men with osteoporosis and more frequently in the Reclast-treated patients than the active control-treated patients and either not reported in the postmenopausal osteoporosis treatment trial or reported more frequently in the trial of osteoporosis in men are presented in Table 3. Therefore, Table 3 should be viewed in conjunction with Table 1.

Table 3: Adverse Reactions Occurring in Greater Than or Equal to 2% of Men with Osteoporosis and More Frequently in the Reclast-Treated Patients Than the Active Control-Treated Patients and Either Not Reported in the Postmenopausal Osteoporosis Treatment Trial or Reported More Frequently in This Trial Abbreviation: IV, intravenous or intravenously. System Organ Class 5 mg IV Reclast once per year % (N = 153) Active Control once weekly % (N = 148) Nervous System Disorders Headache 15.0

6.1Lethargy

3.3

1.4Eye Disorders Eye

pain 2.0

0.0Cardiac Disorders Atrial

fibrillation 3.3

2.0Palpitations

2.6

0.0Respiratory, Thoracic and Mediastinal Disorders Dyspnea

6.5

4.7Abdominal

pain Combined abdominal pain, abdominal pain upper, and abdominal pain lower as one Adverse Drug Reaction (ADR). 7.9

4.1Skin and Subcutaneous Tissue Disorders Hyperhidrosis

2.6

2.0Musculoskeletal, Connective Tissue and Bone Disorders

Myalgia 19.6

6.8Musculoskeletal

pain Combined musculoskeletal pain and musculoskeletal chest pain as one ADR. 12.4

10.8Musculoskeletal

stiffness 4.6

0.0Renal and Urinary Disorders Blood

creatinine increased 2.0

0.7General Disorders and Administrative-Site Conditions Fatigue

17.6

6.1Pain

11.8

4.1Chills

9.8

2.7Influenza-like

illness 9.2

2.0Malaise

7.2

0.7Acute

phase reaction 3.9

0.0Investigations C-reactive

protein increased 4.6

1.4Renal Impairment Creatinine

clearance was measured annually prior to dosing and changes in long-term renal function over 24 months were comparable in the Reclast and active control groups . Acute Phase Reaction Reclast was associated with signs and symptoms of an acute phase reaction: myalgia (17.1%), fever (15.7%), fatigue (12.4%), arthralgia (11.1%), pain (10.5%), chills (9.8%), headache (9.8%), influenza-like illness (8.5%), malaise (5.2%), and back pain (3.3%), which occurred within the first 3 days following the dose of Reclast. The majority of these symptoms were mild to moderate and resolved within 3 days of the event onset but resolution could take up to 7-14 days. The incidence of these symptoms decreased with subsequent doses of Reclast.

Atrial Fibrillation The incidence of all atrial fibrillation adverse events in the Reclast treatment group was 3.3% (5 out of 153) compared to 2.0% (3 out of 148) in the active control group. However, there were no patients with adjudicated serious adverse events of atrial fibrillation in the Reclast treatment group. Laboratory Findings There were no patients who had treatment emergent serum calcium levels below 7.5 mg/dL. Injection-Site Reactions There were 4 patients (2.6%) on Reclast vs. 2 patients (1.4%) on active control with local-site reactions.

Osteonecrosis of the Jaw In this trial, there were no cases of ONJ . Glucocorticoid-Induced Osteoporosis The safety of Reclast in men and women in the treatment and prevention of glucocorticoid-induced osteoporosis was assessed in a randomized, multicenter, double-blind, active controlled, stratified study of 833 men, and women aged 18 to 85 years treated with greater than or equal to 7.5 mg/day oral prednisone (or equivalent). Patients were stratified according to the duration of their pre-study corticosteroid therapy: less than or equal to 3 months prior to randomization (prevention subpopulation), and greater than 3 months prior to randomization (treatment subpopulation). The duration of the trial was one year with 416 patients exposed to Reclast administered once as a single 5 mg dose in 100 mL infused over 15 minutes, and 417 patients exposed to a commercially-available oral daily bisphosphonate (active control) for one year.

All participants received 1000 mg of elemental calcium plus 400 to 1000 international units of vitamin D supplementation per day. The incidence of all-cause mortality was similar between treatment groups: 0.9% in the Reclast group and 0.7% in the active control group. The incidence of serious adverse events was similar between the Reclast treatment and prevention groups, 18.4% and 18.1%, respectively, and the active control treatment and prevention groups, 19.8% and 16.0%, respectively.

The percentage of subjects who withdrew from the study due to adverse events was 2.2% in the Reclast group vs. 1.4% in the active control group. The overall safety and tolerability were similar between Reclast and active control groups with the exception of a higher incidence of post-dose symptoms in the Reclast group that occurred within 3 days after infusion. The overall safety and tolerability profile of Reclast in glucocorticoid-induced osteoporosis was similar to the adverse events reported in the Reclast postmenopausal osteoporosis clinical trial.

Adverse reactions reported in at least 2% of patients that were either not reported in the postmenopausal osteoporosis treatment trial or reported more frequently in the treatment and prevention of glucocorticoid-induced osteoporosis trial included the following: abdominal pain (Reclast 7.5%; active control 5.0%), and musculoskeletal pain (Reclast 3.1%; active control 1.7%). Other musculoskeletal events included back pain (Reclast 4.3%, active control 6.2%), bone pain (Reclast 3.1%, active control 2.2%), and pain in the extremity (Reclast 3.1%, active control 1.2%). In addition, the following adverse events occurred more frequently than in the postmenopausal osteoporosis trial: nausea (Reclast 9.6%; active control 8.4%), and dyspepsia (Reclast 5.5%; active control 4.3%).

Renal Impairment Renal function measured prior to dosing and at the end of the 12-month study was comparable in the Reclast and active control groups . Acute Phase Reaction Reclast was associated with signs and symptoms of a transient acute phase reaction that was similar to that seen in the Reclast postmenopausal osteoporosis clinical trial. Atrial Fibrillation The incidence of atrial fibrillation adverse events was 0.7% (3 of 416) in the Reclast group compared to no adverse events in the active control group. All subjects had a prior history of atrial fibrillation and no cases were adjudicated as serious adverse events.

One patient had atrial flutter in the active control group. Laboratory Findings There were no patients who had treatment emergent serum calcium levels below 7.5 mg/dL. Injection-Site Reactions There were no local reactions at the infusion site. Osteonecrosis of the Jaw In this trial there were no cases of ONJ . Paget’s Disease of Bone In the Paget’s disease trials, two 6-month, double-blind, comparative, multinational studies of 349 men, and women aged greater than 30 years with moderate to severe disease and with confirmed Paget’s disease of bone, 177 patients were exposed to Reclast and 172 patients exposed to risedronate.

Reclast was administered once as a single 5 mg dose in 100 mL solution infused over at least 15 minutes. Risedronate was given as an oral daily dose of 30 mg for 2 months. The incidence of serious adverse events was 5.1% in the Reclast group and 6.4% in the risedronate group. The percentage of patients who withdrew from the study due to adverse events was 1.7% and 1.2% for the Reclast and risedronate groups, respectively.

Adverse reactions occurring in at least 2% of the Paget’s patients receiving Reclast (single 5 mg intravenous infusion) or risedronate (30 mg oral daily dose for 2 months) over a 6-month study period are listed by system organ class in Table 4. Table 4. Adverse Reactions Reported in at Least 2% of Paget’s Patients Receiving Reclast (Single 5 mg Intravenous Infusion) or Risedronate (Oral 30 mg Daily for 2 Months) Over a 6-Month Follow-up Period Abbreviation: IV, intravenous or intravenously.

System Organ Class 5 mg IV Reclast % (N = 177) 30 mg/day x 2 Months risedronate % (N = 172) Infections and Infestations Influenza 7 5 Metabolism and Nutrition Disorders Hypocalcemia 3 1 Anorexia 2 2 Nervous System Disorders Headache 11 10 Dizziness 9 4 Lethargy 5 1 Paresthesia 2 0 Respiratory, Thoracic and Mediastinal Disorders Dyspnea 5 1 Gastrointestinal Disorders Nausea 9 6 Diarrhea 6 6 Constipation 6 5 Dyspepsia 5 4 Abdominal distension 2 1 Abdominal pain 2 2 Vomiting 2 2 Abdominal pain upper 1 2 Skin and Subcutaneous Tissue Disorders Rash 3 2 Musculoskeletal, Connective Tissue and Bone Disorders Arthralgia 9 11 Bone pain 9 5 Myalgia 7 4 Back pain 4 7 Musculoskeletal stiffness 2 1 General Disorders and Administrative-Site Conditions Influenza-like illness 11 6 Pyrexia 9 2 Fatigue 8 4 Rigors 8 1 Pain 5 4 Peripheral edema 3 1 Asthenia 2 1 Laboratory Findings In the Paget’s disease trials, early, transient decreases in serum calcium and phosphate levels were observed. Approximately 21% of patients had serum calcium levels less than 8.4 mg/dL 9-11 days following Reclast administration. Renal Impairment In clinical trials in Paget’s disease, there were no cases of renal deterioration following a single 5 mg 15-minute infusion . Acute Phase Reaction The signs and symptoms of acute phase reaction (influenza-like illness, pyrexia, myalgia, arthralgia, and bone pain) were reported in 25% of patients in the Reclast-treated group compared to 8% in the risedronate-treated group.

Symptoms usually occur within the first 3 days following Reclast administration. The majority of these symptoms resolved within 4 days of onset. Osteonecrosis of the Jaw Osteonecrosis of the jaw has been reported with zoledronic acid .

6.2Post-Marketing Experience Because

these 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. The following adverse reactions have been identified during post approval use of Reclast or bisphosphonate products: Acute Phase Reactions Fever, headache, flu-like symptoms, nausea, vomiting, diarrhea, arthralgia, and myalgia. Symptoms may be significant and lead to dehydration.

Acute Renal Failure Acute renal failure requiring hospitalization and/or dialysis or with a fatal outcome have been rarely reported. Increased serum creatinine was reported in patients with 1) underlying renal disease, 2) dehydration secondary to fever, sepsis, gastrointestinal losses, or diuretic therapy, or 3) other risk factors, such as advanced age, or concomitant nephrotoxic drugs in the post-infusion period. Transient rise in serum creatinine can be correctable with intravenous fluids.

Allergic Reactions Allergic reactions with intravenous zoledronic acid, including anaphylactic reaction/shock, urticaria, angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis, and bronchoconstriction have been reported. Asthma Exacerbations Asthma exacerbations have been reported. Hypocalcemia Hypocalcemia has been reported.

Hypophosphatemia Hypophosphatemia has been reported. Osteonecrosis of the Jaw Osteonecrosis of the jaw has been reported. Osteonecrosis of Other Bones Cases of osteonecrosis of other bones (including femur, hip, knee, ankle, wrist and humerus) have been reported; causality has not been determined in the population treated with Reclast.

Musculoskeletal Low-energy femoral shaft and subtrochanteric fractures, and atypical fractures of other bones Ocular Adverse Events Cases of the following events have been reported: conjunctivitis, iritis, iridocyclitis, uveitis, episcleritis, scleritis, and orbital inflammation/edema. Other Hypotension in patients with underlying risk factors has been reported.