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Zoledronic Acid

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Zoledronic Acid uses


1 INDICATIONS AND USAGE

Zoledronic Acid is a bisphosphonate indicated for:


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 (1.6)

1.1 Treatment of Osteoporosis in Postmenopausal Women

Zoledronic Acid is indicated for treatment of osteoporosis in postmenopausal women. In postmenopausal women with osteoporosis, diagnosed by bone mineral density (BMD) or prevalent vertebral fracture, Zoledronic Acid 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, Zoledronic Acid reduces the incidence of new clinical fractures [see Clinical Studies (14.1)].

1.2 Prevention of Osteoporosis in Postmenopausal Women

Zoledronic Acid is indicated for prevention of osteoporosis in postmenopausal women [see Clinical Studies ].

1.3 Osteoporosis in Men

Zoledronic Acid is indicated for treatment to increase bone mass in men with osteoporosis [see Clinical Studies (14.3 )].

1.4 Glucocorticoid-Induced Osteoporosis

Zoledronic Acid 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 [s ee Clinical Studies ].

1.5 Paget's Disease of Bone

Zoledronic Acid 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 [see Clinical Studies (14.5)].

1.6 Important Limitations of Use

The safety and effectiveness of Zoledronic Acid 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 re-evaluated on a periodic basis. Patients at low-risk for fracture should be considered for drug discontinuation after 3 to 5 years of use. Patients who discontinue therapy should have their risk for fracture re-evaluated periodically.

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2 DOSAGE AND ADMINISTRATION

Infusion given intravenously over no less than 15 minutes:

2.1 Important Administration Instructions

Zoledronic Acid injection must be administered as an intravenous infusion over no less than 15 minutes.

2.2 Treatment of Osteoporosis in Postmenopausal Women

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

2.3 Prevention 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.

2.4 Osteoporosis in Men

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

2.5 Treatment 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.

2.6 Treatment 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 Zoledronic Acid in Paget’s disease an extended remission period is observed. Specific re-treatment data are not available. However, re-treatment with Zoledronic Acid 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.

2.7 Laboratory Testing and Oral Examination Prior to Administration

2.8 Calcium and Vitamin D Supplementation

2.9 Method of Administration

The Zoledronic Acid infusion time must not be less than 15 minutes given over a constant infusion rate.

The i.v. infusion should be followed by a 10 mL normal saline flush of the intravenous line.

Zoledronic Acid 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-8°C (36°F-46°F) [see How Supplied/Storage and Handling (16)].

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3 DOSAGE FORMS AND STRENGTHS

5 mg in a 100 mL ready to infuse solution.

5 mg in a 100 mL ready-to-infuse solution (3)

4 CONTRAINDICATIONS

Zoledronic Acid is contraindicated in patients with the following conditions:

5 WARNINGS AND PRECAUTIONS

5.1 Drug Products with Same Active Ingredient

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

5.2 Hypocalcemia and Mineral Metabolism

Pre-existing hypocalcemia and disturbances of mineral metabolism must be effectively treated before initiating therapy with Zoledronic Acid. Clinical monitoring of calcium and mineral levels (phosphorus and magnesium) is highly recommended for these patients [see Contraindications (4)].

Hypocalcemia following Zoledronic Acid 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 [see Dosage and Administration (2.8), Adverse Reactions (6.1), Patient Counseling Information (17)].

All osteoporosis patients should be instructed on the importance of calcium and vitamin D supplementation in maintaining serum calcium levels [see Dosage and Administration (2.8), Adverse Reactions (6.1), Patient Counseling Information (17)].

5.3 Renal Impairment

A single dose of Zoledronic Acid should not exceed 5 mg and the duration of infusion should be no less than 15 minutes [see Dosage and Administration (2)].

Zoledronic Acid is contraindicated in patients with creatinine clearance less than 35 mL/min and in those with evidence of acute renal impairment [see Contraindications (4)]. If history or physical signs suggest dehydration, Zoledronic Acid therapy should be withheld until normovolemic status has been achieved [see Adverse Reactions (6.2)].

Zoledronic Acid 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 pre-existing renal compromise, advanced age, concomitant nephrotoxic medications, concomitant diuretic therapy, or severe dehydration occurring before or after Zoledronic Acid 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 [see Adverse Reactions (6.2)]. Renal impairment may lead to increased exposure of concomitant medications and/or their metabolites that are primarily renally excreted [see Drug Interactions (7.4)].

Creatinine clearance should be calculated based on actual body weight using Cockcroft-Gault formula before each Zoledronic Acid 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 Zoledronic Acid. Zoledronic Acid should be used with caution with other nephrotoxic drugs [see Drug Interactions (7.3)]. Consider monitoring creatinine clearance in patients at-risk for ARF who are taking concomitant medications that are primarily excreted by the kidney [see Drug Interactions (7.4)].

5.4 Osteonecrosis of the Jaw

Osteonecrosis of the jaw 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, pre-existing 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 [see Adverse Reactions (6.1)].

5.5 Atypical Subtrochanteric and Diaphyseal Femoral Fractures

Atypical, low-energy, or low trauma fractures of the femoral shaft have been reported in bisphosphonate-treated patients. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution. Causality has not been established as these fractures also occur in osteoporotic patients who have not been treated with bisphosphonates.

Atypical femur fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. A number of reports note that patients were also receiving treatment with glucocorticoids (e.g., prednisone) at the time of fracture.

Any patient with a history of bisphosphonate exposure who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Patients presenting with an atypical femur fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of bisphosphonate therapy should be considered, pending a risk/benefit assessment, on an individual basis.

5.6 Pregnancy

Zoledronic Acid SHOULD NOT BE USED DURING PREGNANCY. Zoledronic Acid may cause fetal harm when administered to a pregnant woman. If the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while on Zoledronic Acid therapy [see Use in Specific Populations ].

5.7 Musculoskeletal Pain

In post-marketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain have been infrequently reported in patients taking bisphosphonates, including Zoledronic Acid. The time to onset of symptoms varied from one day to several months after starting the drug. Consider withholding future Zoledronic Acid 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 [see Adverse Reactions (6.2)].

5.8 Patients with Asthma

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

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6 ADVERSE REACTIONS

The most common adverse reactions were pyrexia, myalgia, headache, arthralgia, pain in extremity (6.1). Other important adverse reactions were flu-like illness, nausea, vomiting, diarrhea (6.2), and eye inflammation (6.1).

To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical 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 Zoledronic Acid 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 bone mineral density or the presence of a prevalent vertebral fracture. The duration of the trial was three years with 3862 patients exposed to Zoledronic Acid 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 Zoledronic Acid group and 2.9% in the placebo group. The incidence of serious adverse events was 29.2% in the Zoledronic Acid 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 Zoledronic Acid and placebo groups, respectively.

The safety of Zoledronic Acid 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. Zoledronic Acid 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 Zoledronic Acid group and 13.3% in the placebo group. The incidence of serious adverse events was 38.3% in the Zoledronic Acid 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 Zoledronic Acid 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.

Study 1 Study 2


System Organ Class

5 mg IV

Zoledronic Acid

once per year

%

(N=3862)


Placebo

once per year

%

(N=3852)

5 mg IV

Zoledronic Acid

once per year

%

(N=1054)


Placebo

once per year

%

(N=1057)

Blood and the Lymphatic System Disorders
Anemia 4.4 3.6 5.3 5.2
Metabolism and Nutrition Disorders
Dehydration 0.6 0.6 2.5 2.3
Anorexia 2.0 1.1 1.0 1.0
Nervous System Disorders
Headache 12.4 8.1 3.9 2.5
Dizziness 7.6 6.7 2.0 4.0
Ear and Labyrinth Disorders
Vertigo 4.3 4.0 1.3 1.7
Cardiac Disorders
Atrial Fibrillation 2.4 1.9 2.8 2.6
Vascular Disorders
Hypertension 12.7 12.4 6.8 5.4
Gastrointestinal Disorders
Nausea 8.5 5.2 4.5 4.5
Diarrhea 6.0 5.6 5.2 4.7
Vomiting 4.6 3.2 3.4 3.4
Abdominal Pain Upper 4.6 3.1 0.9 1.5
Dyspepsia 4.3 4.0 1.7 1.6
Musculoskeletal, Connective Tissue and Bone Disorders
Arthralgia 23.8 20.4 17.9 18.3
Myalgia 11.7 3.7 4.9 2.7
Pain in Extremity 11.3 9.9 5.9 4.8
Shoulder Pain 6.9 5.6 0.0 0.0
Bone Pain 5.8 2.3 3.2 1.0
Neck Pain 4.4 3.8 1.4 1.1
Muscle Spasms 3.7 3.4 1.5 1.7
Osteoarthritis 9.1 9.7 5.7 4.5
Musculoskeletal Pain 0.4 0.3 3.1 1.2
General Disorders and Administrative Site Conditions
Pyrexia 17.9 4.6 8.7 3.1
Influenza-like Illness 8.8 2.7 0.8 0.4
Fatigue 5.4 3.5 2.1 1.2
Chills 5.4 1.0 1.5 0.5
Asthenia 5.3 2.9 3.2 3.0
Peripheral Edema 4.6 4.2 5.5 5.3
Pain 3.3 1.3 1.5 0.5
Malaise 2.0 1.0 1.1 0.5
Hyperthermia 0.3 <0.1 2.3 0.3
Chest Pain 1.3 1.1 2.4 1.8
Investigations
Creatinine Renal Clearance Decreased 2.0 2.4 2.1 1.7

Renal 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 Zoledronic Acid 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 [s ee Warnings and Precautions (5.3)].

Acute Phase Reaction

The signs and symptoms of acute phase reaction occurred in Study 1 following Zoledronic Acid 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 Zoledronic Acid 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. Zoledronic Acid 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 Zoledronic Acid.

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 Zoledronic Acid 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 Zoledronic Acid 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 Zoledronic Acid. Both cases resolved after appropriate treatment [s ee Warnings and Precautions (5.4)]. No reports of osteonecrosis of the jaw 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 Zoledronic Acid 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 Zoledronic Acid 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 Zoledronic Acid 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: (1) Zoledronic Acid given at randomization and Month 12 (n=198); (2) Reclast given at randomization and placebo at Month 12 (n=181); and (3) placebo given at randomization and Month 12 (n=202). Zoledronic Acid 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 (1) Reclast at randomization and at Month 12 (10.6%), (2) Reclast at randomization and placebo given at Month 12 (9.4%), and (3) 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 Zoledronic Acid 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.

* Combined abdominal pain, abdominal pain upper, and abdominal pain lower as one ADR

** Combined musculoskeletal pain and musculoskeletal chest pain as one ADR


System Organ Class

5 mg IV Zoledronic Acid

Once Per Year

%

(n =198)

5 mg IV Zoledronic Acid

Once

%

(n =181)

Placebo

once per year

%

(n =202)

Metabolism and nutrition disorders
Anorexia 2.0 0.6 0.0
Nervous system disorders
Headache 14.6 20.4 11.4
Dizziness 7.6 6.1 3.5
Hypoesthesia 5.6 2.2 2.0
Ear and labyrinth disorders
Vertigo 2.0 1.7 1.0
Vascular disorders
Hypertension 5.1 8.3 6.9
Gastrointestinal disorders
Nausea 17.7 11.6 7.9
Diarrhea 8.1 6.6 7.9
Vomiting 7.6 5.0 4.5
Dyspepsia 7.1 6.6 5.0
Abdominal pain* 8.6 6.6 7.9
Constipation 6.6 7.2 6.9
Abdominal discomfort 2.0 1.1 0.5
Abdominal distension 2.0 0.6 0.0
Skin and subcutaneous tissue disorders
Rash 3.0 2.2 2.5
Musculoskeletal and connective tissue disorders
Arthralgia 27.3 18.8 19.3
Myalgia 19.2 22.7 6.9
Back pain 18.2 16.6 11.9
Pain in extremity 11.1 16.0 9.9
Muscle spasms 5.6 2.8 5.0
Musculoskeletal pain** 8.1 7.2 7.9
Bone pain 5.1 3.3 1.0
Neck pain 5.1 6.6 5.0
Arthritis 4.0 2.2 1.5
Joint stiffness 3.5 1.1 2.0
Joint swelling 3.0 0.6 0.0
Flank pain 2.0 0.6 0.0
Pain in jaw 2.0 3.9 2.5
General disorders and administration site conditions
Pain 24.2 14.9 3.5
Pyrexia 21.7 21.0 4.5
Chills 18.2 18.2 3.0
Fatigue 14.6 9.9 4.0
Asthenia 6.1 2.8 1.0
Peripheral edema 5.6 3.9 3.5
Non-cardiac chest pain 3.5 7.7 3.0
Influenza-like illness 1.5 3.3 2.0
Malaise 1.0 2.2 0.5

Ocular 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 Zoledronic Acid and 0 (0%) patients treated with placebo developed iritis/uveitis.

Acute Phase Reaction

In patients given Zoledronic Acid at randomization and placebo at Month 12, Zoledronic Acid 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 Zoledronic Acid. 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 Zoledronic Acid 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 (153) patients were exposed to Zoledronic Acid 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 Zoledronic Acid and active control treatment groups. The percentage of patients experiencing at least one adverse event was comparable between the Zoledronic Acid and active control groups, with the exception of a higher incidence of post-dose symptoms in the Zoledronic Acid group that occurred within 3 days after infusion. The overall safety and tolerability of Zoledronic Acid 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 (1) not reported in the postmenopausal osteoporosis treatment trial or (2) 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.

* Combined abdominal pain, abdominal pain upper, and abdominal pain lower as one ADR

** Combined musculoskeletal pain and musculoskeletal chest pain as one ADR

System Organ Class

5 mg IV Zoledronic Acid

once per year

%

(N=153)

Active Control

once weekly

%

(N=148)

Nervous System Disorders
Headache 15.0 6.1
Lethargy 3.3 1.4
Eye Disorders
Eye pain 2.0 0.0
Cardiac Disorders
Atrial fibrillation 3.3 2.0
Palpitations 2.6 0.0
Respiratory, Thoracic and Mediastinal Disorders
Dyspnea 6.5 4.7
Abdominal pain* 7.9 4.1
Skin and Subcutaneous Tissue Disorders
Hyperhidrosis 2.6 2.0
Musculoskeletal, Connective Tissue and Bone Disorders
Myalgia 19.6 6.8
Musculoskeletal pain** 12.4 10.8
Musculoskeletal stiffness 4.6 0.0
Renal and Urinary Disorders
Blood creatinine increased 2.0 0.7
General Disorders and Administrative Site Conditions
Fatigue 17.6 6.1
Pain 11.8 4.1
Chills 9.8 2.7
Influenza-like illness 9.2 2.0
Malaise 7.2 0.7
Acute phase reaction 3.9 0.0
Investigations
C-reactive protein increased 4.6 1.4

Renal Impairment

Creatinine clearance was measured annually prior to dosing and changes in long-term renal function over 24 months were comparable in the Zoledronic Acid and active control groups [s ee Warnings and Precautions (5.3)].

Acute Phase Reaction

Zoledronic Acid 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 Zoledronic Acid. 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 Zoledronic Acid.

Atrial Fibrillation

The incidence of all atrial fibrillation adverse events in the Zoledronic Acid 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 Zoledronic Acid 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 Zoledronic Acid vs. 2 patients (1.4%) on active control with local site reactions.

Osteonecrosis of the Jaw

In this trial there were no cases of osteonecrosis of the jaw [s ee Warnings and Precautions (5.4)].

Glucocorticoid-Induced Osteoporosis

The safety of Zoledronic Acid 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 Zoledronic Acid 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 Zoledronic Acid group and 0.7% in the active control group. The incidence of serious adverse events was similar between the Zoledronic Acid 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 Zoledronic Acid group vs. 1.4% in the active control group. The overall safety and tolerability were similar between Zoledronic Acid and active control groups with the exception of a higher incidence of post-dose symptoms in the Zoledronic Acid group that occurred within 3 days after infusion. The overall safety and tolerability profile of Zoledronic Acid in glucocorticoid-induced osteoporosis was similar to the adverse events reported in the Zoledronic Acid 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 Zoledronic Acid and active control groups [s ee Warnings and Precautions (5.3)].

Acute Phase Reaction

Zoledronic Acid was associated with signs and symptoms of a transient acute phase reaction that was similar to that seen in the Zoledronic Acid postmenopausal osteoporosis clinical trial.

Atrial Fibrillation

The incidence of atrial fibrillation adverse events was 0.7% (3 of 416) in the Zoledronic Acid 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 osteonecrosis of the jaw [s ee Warnings and Precautions (5.4)].

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 Zoledronic Acid and 172 patients exposed to risedronate. Zoledronic Acid 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 Zoledronic Acid 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 Zoledronic Acid and risedronate groups, respectively.

Adverse reactions occurring in at least 2% of the Paget’s patients receiving Zoledronic Acid (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.


System Organ Class

5 mg IV Zoledronic Acid

%

(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 Zoledronic Acid 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 [s ee Warnings and Precautions (5.3)].

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 Zoledronic Acid 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 [see Warnings and Precautions (5.4)].

6.2 Post-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 Zoledronic Acid:

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 Zoledronic Acid.

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.

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7 DRUG INTERACTIONS

No in vivo drug interaction studies have been performed for Zoledronic Acid. In vitro and ex vivo studies showed low affinity of Zoledronic Acid for the cellular components of human blood. In vitro mean Zoledronic Acid protein binding in human plasma ranged from 28% at 200 ng/mL to 53% at 50 ng/mL. In vivo studies showed that Zoledronic Acid is not metabolized, and is excreted into the urine as the intact drug.

7.1 Aminoglycosides

Caution is advised when bisphosphonates, including Zoledronic Acid, are administered with aminoglycosides, since these agents may have an additive effect to lower serum calcium level for prolonged periods. This effect has not been reported in Zoledronic Acid clinical trials.

7.2 Loop Diuretics

Caution should also be exercised when Zoledronic Acid is used in combination with loop diuretics due to an increased risk of hypocalcemia.

7.3 Nephrotoxic Drugs

Caution is indicated when Zoledronic Acid is used with other potentially nephrotoxic drugs such as nonsteroidal anti-inflammatory drugs.

7.4 Drugs Primarily Excreted by the Kidney

Renal impairment has been observed following the administration of Zoledronic Acid in patients with pre-existing renal compromise or other risk factors [see Warnings and Precautions (5.3)]. In patients with renal impairment, the exposure to concomitant medications that are primarily renally excreted (e.g., digoxin) may increase. Consider monitoring serum creatinine in patients at risk for renal impairment who are taking concomitant medications that are primarily excreted by the kidney.

8 USE IN SPECIFIC POPULATIONS

Nursing Mothers: Zoledronic Acid should not be given to nursing women

Pediatric Use: Not indicated for use in pediatric patients (8.4)

Geriatric Use: Special care to monitor renal function (8.5)

8.1 Pregnancy

Pregnancy Category D [see Warnings and Precautions (5. 6 )].

Zoledronic Acid SHOULD NOT BE USED DURING PREGNANCY. If the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving Zoledronic Acid.

Bisphosphonates are incorporated into the bone matrix, from where they are gradually released over periods of weeks to years. The extent of bisphosphonate incorporation into adult bone, and hence, the amount available for release back into the systemic circulation, is directly related to the total dose and duration of bisphosphonate use. Although there are no data on fetal risk in humans, bisphosphonates do cause fetal harm in animals, and animal data suggest that uptake of bisphosphonates into fetal bone is greater than into maternal bone. Therefore, there is a theoretical risk of fetal harm (e.g., skeletal and other abnormalities) 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 space, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on this risk has not been established.

In female rats given daily subcutaneous doses of Zoledronic Acid beginning 15 days before mating and continuing through gestation, the number of stillbirths was increased and survival of neonates was decreased at approximately greater than or equal to 0.3 times the anticipated human systemic exposure following a 5 mg intravenous dose (based on an AUC comparison). Adverse maternal effects were observed in all dose groups at greater than or equal to 0.1 times the human systemic exposure following a 5 mg intravenous dose (based on an AUC comparison) and included dystocia and periparturient mortality in pregnant rats allowed to deliver. Maternal mortality was considered related to drug-induced inhibition of skeletal calcium mobilization, resulting in periparturient hypocalcemia. This appears to be a bisphosphonate class effect.

In pregnant rats given daily subcutaneous dose of Zoledronic Acid during gestation, adverse fetal effects were observed at about 2 and 4 times human systemic exposure following a 5 mg intravenous dose (based on an AUC comparison). These adverse effects included increases in pre- and post-implantation losses, decreases in viable fetuses, and fetal skeletal, visceral, and external malformations.

In pregnant rabbits given daily subcutaneous doses of Zoledronic Acid during gestation at doses less than or equal to 0.4 times the anticipated human systemic exposure following a 5 mg intravenous dose (based on a mg/m2 comparison) no adverse fetal effects were observed. Maternal mortality and abortion occurred in all treatment groups (at doses greater than or equal to 0.04 times the human 5 mg intravenous dose, based on a mg/m2 comparison). Adverse maternal effects were associated with, and may have been caused by, drug-induced hypocalcemia [s ee Nonclinical Toxicology (13.3 )].

8.3 Nursing Mothers

It is not known whether Zoledronic Acid is excreted in human milk. Because many drugs are excreted in human milk, and because Zoledronic Acid binds to bone long-term, Zoledronic Acid should not be administered to a nursing woman.

8.4 Pediatric Use

Zoledronic Acid is not indicated for use in children.

The safety and effectiveness of Zoledronic Acid was studied in a one-year active controlled trial of 152 pediatric subjects. The enrolled population was subjects with severe osteogenesis imperfecta, aged 1 to 17 years, 55% male, 84% Caucasian, with a mean lumbar spine BMD of 0.431 gm/cm2, which is 2.7 standard deviations below the mean for age-matched controls (BMD Z-score of -2.7). At one year, increases in BMD were observed in the Zoledronic Acid treatment group. However, changes in BMD in individual patients with severe osteogenesis imperfecta did not necessarily correlate with the risk for fracture or the incidence or severity of chronic bone pain. The adverse events observed with Zoledronic Acid use in children did not raise any new safety findings beyond those previously seen in adults treated for Paget’s disease of bone and treatment of osteoporosis including osteonecrosis of the jaw (ONJ) and renal impairment. However, adverse reactions seen more commonly in pediatric patients included pyrexia (61%), arthralgia (26%), hypocalcemia (22%) and headache (22%). These reactions, excluding arthralgia, occurred most frequently within three days after the first infusion and became less common with repeat dosing. No cases of ONJ or renal impairment were observed in this study. Because of long-term retention in bone, Zoledronic Acid should only be used in children if the potential benefit outweighs the potential risk.

Plasma Zoledronic Acid concentration data was obtained from 10 patients with severe osteogenesis imperfecta (4 in the age group of 3 to 8 years and 6 in the age group of 9 to 17 years) infused with 0.05 mg/kg dose over 30 minutes. Mean Cmax and AUC(0-last) was 167 ng/mL and 220 ng.h/mL respectively. The plasma concentration time profile of Zoledronic Acid in pediatric patients represent a multi-exponential decline, as observed in adult cancer patients at an approximately equivalent mg/kg dose.

8.5 Geriatric Use

The combined osteoporosis trials included 4863 Reclast-treated patients who were at least 65 years of age, while 2101 patients were at least 75 years old. No overall differences in efficacy or safety were observed between patients under 75 years of age with those at least 75 years of age, except that the acute phase reactions occurred less frequently in the older patients.

Of the patients receiving Zoledronic Acid in the osteoporosis study in men, glucocorticoid-induced osteoporosis, and Paget’s disease studies, 83, 116, and 132 patients, respectively were 65 years of age or over, while 24, 29, and 68 patients, respectively were at least 75 years of age.

However, because decreased renal function occurs more commonly in the elderly, special care should be taken to monitor renal function.

8.6 Renal Impairment

Zoledronic Acid is contraindicated in patients with creatinine clearance less than 35 mL/min and in those with evidence of acute renal impairment. There are no safety or efficacy data to support the adjustment of the Zoledronic Acid dose based on baseline renal function. Therefore, no dosage adjustment is required in patients with a creatinine clearance of greater than or equal to 35 mL/min [see Warnings and Precautions, Clinical Pharmacology (12.3)]. Risk of acute renal failure may increase with underlying renal disease and dehydration secondary to fever, sepsis, gastrointestinal losses, diuretic therapy, advanced age, etc. [see Adverse Reactions (6.2)].

8.7 Hepatic Impairment

Zoledronic Acid is not metabolized in the liver. No clinical data are available for use of Zoledronic Acid in patients with hepatic impairment.

10 OVERDOSAGE

Clinical experience with acute overdosage of Zoledronic Acid (Reclast) solution for intravenous infusion is limited. Patients who have received doses higher than those recommended should be carefully monitored. Overdosage may cause clinically significant renal impairment, hypocalcemia, hypophosphatemia, and hypomagnesemia. Clinically relevant reductions in serum levels of calcium, phosphorus, and magnesium should be corrected by intravenous administration of calcium gluconate, potassium or sodium phosphate, and magnesium sulfate, respectively.

Single doses of Zoledronic Acid should not exceed 5 mg and the duration of the intravenous infusion should be no less than 15 minutes [see Dosage and Administration (2)].

11 DESCRIPTION

Zoledronic Acid contains Zoledronic Acid, a bisphosphonic acid which is an inhibitor of osteoclastic bone resorption. Zoledronic Acid is designated chemically as phosphonic acid monohydrate and its structural formula is:

The reductions in hip fractures over three years were greater for Zoledronic Acid than placebo regardless of femoral neck BMD T-score.

Effect on All Clinical Fractures

Zoledronic Acid demonstrated superiority to placebo in reducing the incidence of all clinical fractures, clinical (symptomatic) vertebral and non-vertebral fractures (excluding finger, toe, facial, and clinical thoracic and lumbar vertebral fractures). All clinical fractures were verified based on the radiographic and/or clinical evidence. A summary of results is presented in Table 6.

Outcome Zoledronic Acid

(N= 3875)

Event Rate

n (%) +

Placebo

(N= 3861)

Event Rate

n (%) +

Absolute Reduction in Fracture Incidence

%

(95% CI) +

Relative Risk Reduction in Fracture Incidence

%

(95% CI)

Any clinical fracture (1) 308 (8.4) 456 (12.8) 4.4

(3.0, 5.8)

 33

(23, 42)**
Clinical vertebral fracture (2) 19 (0.5) 84 (2.6) 2.1

(1.5, 2.7)

 77

(63, 86)**
Non-vertebral fracture (3) 292 (8.0) 388 (10.7) 2.7

(1.4, 4.0)

 25

(13, 36)*
*p-value < 0.001, **p-value <0.0001

+ Event rates based on Kaplan-Meier estimates at 36 months
(1) Excluding finger, toe, and facial fractures
(2) Includes clinical thoracic and clinical lumbar vertebral fractures

(3) Excluding finger, toe, facial, and clinical thoracic and lumbar vertebral fractures

Effect on Bone Mineral Density (BMD)

Zoledronic Acid significantly increased BMD at the lumbar spine, total hip and femoral neck, relative to treatment with placebo at time points 12, 24, and 36 months. Treatment with Zoledronic Acid resulted in a 6.7% increase in BMD at the lumbar spine, 6.0% at the total hip, and 5.1% at the femoral neck, over 3 years as compared to placebo.

Bone Histology

Bone biopsy specimens were obtained between Months 33 and 36 from 82 postmenopausal patients with osteoporosis treated with 3 annual doses of Zoledronic Acid. Of the biopsies obtained, 81 were adequate for qualitative histomorphometry assessment, 59 were adequate for partial quantitative histomorphometry assessment, and 38 were adequate for full quantitative histomorphometry assessment. Micro CT analysis was performed on 76 specimens. Qualitative, quantitative and micro CT assessments showed bone of normal architecture and quality without mineralization defects.

Effect on Height

In the 3-year osteoporosis study, standing height was measured annually using a stadiometer. The Zoledronic Acid group revealed less height loss compared to placebo (4.2 mm vs. 7.0 mm, respectively [p<0.001]).

Study 2: The efficacy and safety of Reclast in the treatment of patients with osteoporosis who suffered a recent low-trauma hip fracture was demonstrated in Study 2, a randomized, double-blind, placebo-controlled, multinational endpoint study of 2127 men and women aged 50 to 95 years (mean age of 74.5). Concomitant osteoporosis therapies excluding other bisphosphonates and parathyroid hormone were allowed. Zoledronic Acid was administered once a year 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 confirmed clinical fractures in the study population. 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 primary efficacy variable was the incidence of clinical fractures over the duration of the study.

Zoledronic Acid significantly reduced the incidence of any clinical fracture by 35%. There was also a 46% reduction in the risk of a clinical vertebral fracture (Table 7).

Outcome Zoledronic Acid

(N=1065)

Event Rate

n (%) +

Placebo

(N=1062)

Event Rate

n (%) +

Absolute Reduction in

Fracture Incidence

%

(95% CI) +

Relative Risk Reduction in

Fracture Incidence

%

(95% CI)

Any clinical fracture (1) 92 (8.6) 139 (13.9) 5.3

(2.3, 8.3)

 35

(16, 50)**
Clinical vertebral fracture (2) 21 (1.7) 39 (3.8) 2.1

(0.5, 3.7)

 46

(8, 68)*
*p-value <0.05, **p-value <0.005

+ Event rates based on Kaplan-Meier estimates at 24 months

(1) Excluding finger, toe and facial fractures

(2) Including clinical thoracic and clinical lumbar vertebral fractures

Effect on Bone Mineral Density (BMD)

Zoledronic Acid significantly increased BMD relative to placebo at the hip and femoral neck at all timepoints (12, 24, and 36 months). Treatment with Zoledronic Acid resulted in a 6.4% increase in BMD at the total hip and a 4.3% increase at the femoral neck over 36 months as compared to placebo.

14.2 Prevention of Postmenopausal Osteoporosis

The efficacy and safety of Zoledronic Acid 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, who were stratified by years since menopause: Stratum I women less than 5 years from menopause (n=224); Stratum II women greater than or equal to 5 years from menopause (n=357). Patients within Stratum I and II were randomized to one of three treatment groups: (1) Reclast given at randomization and at Month 12 (n=77) in Stratum I and (n=121) in Stratum II; (2) Reclast given at randomization and placebo at Month 12 (n=70) in Stratum I and (n=111) in Stratum II; and (3) Placebo given at randomization and Month 12 (n=202). Zoledronic Acid 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 primary efficacy variable was the percent change of BMD at 24 Months relative to baseline.

Effect on Bone Mineral Density (BMD)

Zoledronic Acid significantly increased lumbar spine BMD relative to placebo at Month 24 across both strata. Zoledronic Acid given once at randomization (and placebo given at Month 12) resulted in 4.0% increase in BMD in Stratum I patients and 4.8% increase in Stratum II patients over 24 months. Placebo given at randomization and at Month 12 resulted in 2.2% decrease in BMD in Stratum I patients and 0.7% decrease in BMD in Stratum II patients over 24 months. Therefore, Zoledronic Acid given once at randomization (and placebo given at Month 12) resulted in a 6.3% increase in BMD in Stratum I patients and 5.4% increase in Stratum II patients over 24 months as compared to placebo (both p<0.0001).

Zoledronic Acid also significantly increased total hip BMD relative to placebo at Month 24 across both strata. Zoledronic Acid given once at randomization (and placebo given at Month 12) resulted in 2.6% increase in BMD in Stratum I patients and 2.1% in Stratum II patients over 24 months. Placebo given at randomization and at Month 12 resulted in 2.1% decrease in BMD in Stratum I patients and 1.0% decrease in BMD in Stratum II patients over 24 months. Therefore, Zoledronic Acid given once at randomization (and placebo given at Month 12) resulted in a 4.7% increase in BMD in Stratum I patients and 3.2% increase in Stratum II patients over 24 months as compared to placebo (both p<0.0001).

14.3 Osteoporosis in Men

The efficacy and safety of Reclast in men with osteoporosis or significant osteoporosis secondary to hypogonadism, was assessed in a randomized, multicenter, double-blind, active controlled, study of 302 men aged 25 to 86 years. The duration of the trial was two years. Patients were randomized to either Zoledronic Acid which was administered once annually as a 5 mg dose in 100 mL infused over 15 minutes for a total of up to two doses, or to an 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.

Effect on Bone Mineral Density (BMD)

An annual infusion of Zoledronic Acid was non-inferior to the oral weekly bisphosphonate active control based on the percentage change in lumbar spine BMD at Month 24 relative to baseline (Reclast: 6.1% increase; active control: 6.2% increase).

14.4 Treatment and Prevention of Glucocorticoid-Induced Osteoporosis

The efficacy and safety of Zoledronic Acid to prevent and treat glucocorticoid-induced osteoporosis (GIO) was assessed in a randomized, multicenter, double-blind, stratified, active controlled study of 833 men and women aged 18 to 85 years (mean age of 54.4 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. Patients were randomized to either Zoledronic Acid which was administered once as a 5 mg dose in 100 mL infused over 15 minutes, or to an 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.

Effect on Bone Mineral Density (BMD)

In the GIO treatment subpopulation, Zoledronic Acid demonstrated a significant mean increase in lumbar spine BMD compared to the active control at one year (Reclast 4.1%, active control 2.7%) with a treatment difference of 1.4% (p<0.001). In the GIO prevention subpopulation, Zoledronic Acid demonstrated a significant mean increase in lumbar spine BMD compared to active control at one year (Reclast 2.6%, active control 0.6%) with a treatment difference of 2.0% (p<0.001).

Bone Histology

Bone biopsy specimens were obtained from 23 patients (12 in the Zoledronic Acid treatment group and 11 in the active control treatment group) at Month 12 treated with an annual dose of Zoledronic Acid or daily oral active control. Qualitative assessments showed bone of normal architecture and quality without mineralization defects. Apparent reductions in activation frequency and remodeling rates were seen when compared with the histomorphometry results seen with Zoledronic Acid in the postmenopausal osteoporosis population. The long-term consequences of this degree of suppression of bone remodeling in glucocorticoid-treated patients is unknown.

14.5 Treatment of Paget’s Disease of Bone

Zoledronic Acid was studied in male and female patients with moderate to severe Paget’s disease of bone, defined as serum alkaline phosphatase level at least twice the upper limit of the age-specific normal reference range at the time of study entry. Diagnosis was confirmed by radiographic evidence.

The efficacy of one infusion of 5 mg Zoledronic Acid vs. oral daily doses of 30 mg risedronate for 2 months was demonstrated in two identically designed 6-month randomized, double-blind trials. The mean age of patients in the two trials was 70. Ninety-three percent (93%) of patients were Caucasian. Therapeutic response was defined as either normalization of serum alkaline phosphatase (SAP) or a reduction of at least 75% from baseline in total SAP excess at the end of 6 months. SAP excess was defined as the difference between the measured level and midpoint of normal range.

In both trials Zoledronic Acid demonstrated a superior and more rapid therapeutic response compared with risedronate and returned more patients to normal levels of bone turnover, as evidenced by biochemical markers of formation (SAP, serum N-terminal propeptide of type I collagen [P1NP]) and resorption (serum CTx 1 [cross-linked C-telopeptides of type I collagen] and urine α-CTx).

The 6-month combined data from both trials showed that 96% (169/176) of Reclast-treated patients achieved a therapeutic response as compared with 74% (127/171) of patients treated with risedronate. Most Zoledronic Acid patients achieved a therapeutic response by the Day 63 visit. In addition, at 6 months, 89% (156/176) of Reclast-treated patients achieved normalization of SAP levels, compared to 58% (99/171) of patients treated with risedronate (p<0.0001).

The therapeutic response to Zoledronic Acid was similar across demographic and disease-severity groups defined by gender, age, previous bisphosphonate use, and disease severity. At 6 months, the percentage of Reclast-treated patients who achieved therapeutic response was 97% and 95%, respectively, in each of the baseline disease severity subgroups (baseline SAP less than 3xULN, greater than or equal to 3xULN) compared to 75% and 74%, respectively, for the same disease severity subgroups of risedronate-treated patients.

In patients who had previously received treatment with oral bisphosphonates, therapeutic response rates were 96% and 55% for Zoledronic Acid and risedronate, respectively. The comparatively low risedronate response was due to the low response rate (7/23, 30%) in patients previously treated with risedronate. In patients naïve to previous treatment, a greater therapeutic response was also observed with Zoledronic Acid (98%) relative to risedronate (86%). In patients with symptomatic pain at screening, therapeutic response rates were 94% and 70% for Zoledronic Acid and risedronate respectively. For patients without pain at screening, therapeutic response rates were 100% and 82% for Zoledronic Acid and risedronate respectively.

Bone histology was evaluated in 7 patients with Paget’s disease 6 months after being treated with Zoledronic Acid 5 mg. Bone biopsy results showed bone of normal quality with no evidence of impaired bone remodeling and no evidence of mineralization defect.

16 HOW SUPPLIED/STORAGE AND HANDLING

Each bottle contains 5 mg per 100 mL. NDC 0078-0435-61

Handling

After opening the solution, it is stable for 24 hours at 2°C–8°C (36°F-46°F).

If refrigerated, allow the refrigerated solution to reach room temperature before administration.

Storage

Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F).

17 PATIENT COUNSELING INFORMATION

See FDA-Approved Medication Guide

Information for Patients

Patients should be made aware that Zoledronic Acid contains the same active ingredient (zoledronic acid) found in Zometa®, and that patients being treated with Zometa should not be treated with Zoledronic Acid.

Zoledronic Acid is contraindicated in patients with creatinine clearance less than 35 mL/min [see Contraindications (4)].

Before being given Zoledronic Acid, patients should tell their doctor if they have kidney problems and what medications they are taking.

Zoledronic Acid should not be given if the patient is pregnant or plans to become pregnant, or if she is breast-feeding [see Warnings and Precautions (5. 6 )].

There have been reports of bronchoconstriction in aspirin-sensitive patients receiving bisphosphonates, including Zoledronic Acid. Before being given Zoledronic Acid, patients should tell their doctor if they are aspirin-sensitive.

If the patient had surgery to remove some or all of the parathyroid glands in their neck, or had sections of their intestine removed, or are unable to take calcium supplements they should tell their doctor.

Zoledronic Acid is given as an infusion into a vein by a nurse or a doctor, and the infusion time must not be less than 15 minutes.

On the day of treatment the patient should eat and drink normally, which includes drinking at least 2 glasses of fluid such as water within a few hours prior to the infusion, as directed by their doctor, before receiving Zoledronic Acid.

After getting Zoledronic Acid it is strongly recommended patients with Paget’s disease take calcium in divided doses (for example, 2 to 4 times a day) for a total of 1500 mg calcium a day to prevent low blood calcium levels. This is especially important for the two weeks after getting Zoledronic Acid [see Warnings and Precautions (5.2)].

Adequate calcium and vitamin D intake is important in patients with osteoporosis and the current recommended daily intake of calcium is 1200 mg and vitamin D is 800 international units – 1000 international units daily. All patients should be instructed on the importance of calcium and vitamin D supplementation in maintaining serum calcium levels.

Patients should be aware of the most commonly associated side effects of therapy. Patients may experience one or more side effects that could include: fever, flu-like symptoms, myalgia, arthralgia, and headache. Most of these side effects occur within the first 3 days following the dose of Zoledronic Acid. They usually resolve within 3 days of onset but may last for up to 7 to 14 days. Patients should consult their physician if they have questions or if these symptoms persist. The incidence of these symptoms decreased markedly with subsequent doses of Zoledronic Acid.

Administration of acetaminophen following Zoledronic Acid administration may reduce the incidence of these symptoms.

Physicians should inform their patients that there have been reports of persistent pain and/or a non-healing sore of the mouth or jaw, primarily in patients treated with bisphosphonates for other illnesses. During treatment with Zoledronic Acid, patients should be instructed to maintain good oral hygiene and undergo routine dental check-ups. If they experience any oral symptoms, they should immediately report them to their physician or dentist.

Severe and occasionally incapacitating bone, joint, and/or muscle pain have been infrequently reported in patients taking bisphosphonates, including Zoledronic Acid. Consider withholding future Zoledronic Acid treatment if severe symptoms develop.

Atypical femur fractures in patients on bisphosphonate therapy have been reported; patients with thigh or groin pain should be evaluated to rule out a femoral fracture.

T2017-76

July 2017

MEDICATION GUIDE

Reclast® (RE-clast)

(zoledronic acid)

Injection

Read the Medication Guide that comes with Zoledronic Acid before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking with your doctor about your medical condition or treatment. Talk to your doctor if you have any questions about Zoledronic Acid.

What is the most important information I should know about Zoledronic Acid?

You should not receive Zoledronic Acid if you are already receiving Zometa. Both Zoledronic Acid and Zometa contain Zoledronic Acid.

Zoledronic Acid can cause serious side effects including:


1. Low calcium levels in your blood (hypocalcemia).

Zoledronic Acid may lower the calcium levels in your blood. If you have low blood calcium before you start taking Zoledronic Acid, it may get worse during treatment. Your low blood calcium must be treated before you take Zoledronic Acid. Most people with low blood calcium levels do not have symptoms, but some people may have symptoms. Call your doctor right away if you have symptoms of low blood calcium such as:


Your doctor may prescribe calcium and vitamin D to help prevent low calcium levels in your blood, while you take Zoledronic Acid. Take calcium and vitamin D as your doctor tells you to.

2. Severe kidney problems.

Severe kidney problems may happen when you take Zoledronic Acid. Severe kidney problems may lead to hospitalization or kidney dialysis and can be life-threatening. Your risk of kidney problems is higher if you:


You should drink at least 2 glasses of fluid within a few hours before receiving Zoledronic Acid to reduce the risk of kidney problems.

3. Severe jaw bone problems (osteonecrosis).

Severe jaw bone problems may happen when you take Zoledronic Acid. Your doctor should examine your mouth before you start Zoledronic Acid. Your doctor may tell you to see your dentist before you start Zoledronic Acid. It is important for you to practice good mouth care during treatment with Zoledronic Acid.

4. Unusual thigh bone fractures.

Some people have developed unusual fractures in their thigh bone. Symptoms of a fracture may include new or unusual pain in your hip, groin, or thigh.

5. Possible harm to your unborn baby.

Zoledronic Acid should not be used if you are pregnant. Tell your doctor right away if you are pregnant or plan to become pregnant. Zoledronic Acid may harm your unborn baby.

6. Bone, joint, or muscle pain.

Some people who take bisphosphonates develop severe bone, joint, or muscle pain.

Call your doctor right away if you have any of these side effects.

What is Zoledronic Acid ?

Zoledronic Acid is a prescription medicine used to:


It is not known how long Zoledronic Acid works for the treatment and prevention of osteoporosis. You should see your doctor regularly to determine if Zoledronic Acid is still right for you.

Zoledronic Acid is not for use in children.

Who should not take Zoledronic Acid?

Do not take Zoledronic Acid if you:


What should I tell my doctor before taking Zoledronic Acid?

Before you start Zoledronic Acid, be sure to talk to your doctor if you:


Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Certain medicines may affect how Zoledronic Acid works.

Especially tell your doctor if you are taking:


Ask your doctor or pharmacist for a list of these medicines, if you are not sure.

Know the medicines you take. Keep a list of them and show it to your doctor and pharmacist each time you get a new medicine.

How will I receive Zoledronic Acid?


What are the possible side effects of Zoledronic Acid?

Zoledronic Acid may cause serious side effects.


The most common side effects of Zoledronic Acid included:


Talk to your doctor about things you can do to help decrease some of these side effects that might happen with a Zoledronic Acid infusion.

You may get allergic reactions, such as hives, swelling of your face, lips, tongue, or throat.

Tell your doctor if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of Zoledronic Acid. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

General information about safe and effective use of Zoledronic Acid.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.

This Medication Guide summarizes the most important information about Zoledronic Acid. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Zoledronic Acid that is written for health professionals.

For more information, go to: www.pharma.us.novartis.com or call 1-888-669-6682.

What are the ingredients in Zoledronic Acid?

Active ingredient: Zoledronic Acid monohydrate.

Inactive ingredients: mannitol and sodium citrate.

Distributed by:

Novartis Pharmaceuticals Corporation

East Hanover, New Jersey 07936

This Medication Guide has been approved by the U.S. Food and Drug Administration.

© Novartis

T2015-32

January 2015

Zoledronic Acid pharmaceutical active ingredients containing related brand and generic drugs:


Zoledronic Acid available forms, composition, doses:


Zoledronic Acid destination | category:


Zoledronic Acid Anatomical Therapeutic Chemical codes:


Zoledronic Acid pharmaceutical companies:


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References

  1. Dailymed."RECLAST (ZOLEDRONIC ACID) INJECTION, SOLUTION [NOVARTIS PHARMACEUTICALS CORPORATION]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."ZOLEDRONIC ACID: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. "Zoledronic acid". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Zoledronic Acid?

Depending on the reaction of the Zoledronic Acid after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Zoledronic Acid not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Zoledronic Acid addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sdrugs.com conducted a study on Zoledronic Acid, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Zoledronic Acid consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

Visitor reports

Visitor reported useful

No survey data has been collected yet

Visitor reported side effects

No survey data has been collected yet

Visitor reported price estimates

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Visitor reported frequency of use

No survey data has been collected yet

One visitor reported doses

What is the dose of Zoledronic Acid drug you are taking?
According to the survey conducted among sdrugs.com website users, the maximum number of people are using the following dose 1-5mg. Few medications come in only one or two doses. Few are specific for adult dose and child dose. The dose of the medicine given to the patient depends on the severity of the symptom/disease. There can be dose adjustments made by the doctor, based on the progression of the disease. Follow-up is important.
Visitors%
1-5mg1
100.0%

Visitor reported time for results

No survey data has been collected yet

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The information was verified by Dr. Rachana Salvi, MD Pharmacology


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