Treatment 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 [see Clinical Studies (14.1)].
Prevention of Osteoporosis in Postmenopausal Women
Reclast is indicated for prevention of osteoporosis in postmenopausal women [see Clinical Studies (14.2)].
Osteoporosis in Men
Reclast is indicated for treatment to increase bone mass in men with osteoporosis [see Clinical Studies (14.3)].
Glucocorticoid-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 [see Clinical Studies (14.4)].
Paget'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 [see Clinical Studies (14.5)].
Important 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 re-evaluated on a periodic basis.
Reclast Dosage and Administration
A 5 mg dose of Reclast administered intravenously is recommended for patients with creatinine clearance ≥35 mL/min [see Warnings and Precautions (5.3)].
Reclast is contraindicated in patients with creatinine clearance <35 mL/min and in those with evidence of acute renal impairment [see Contraindications (4.2)].
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 CrCl ≥35 mL/min.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Patients must be appropriately hydrated prior to administration of Reclast [see Warnings and Precautions (5.3)].
The i.v. 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.
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. For osteoporosis treatment, and to reduce the risk of hypocalcemia, patients must be adequately supplemented with calcium and vitamin D if dietary intake is not sufficient. Postmenopausal women require an average of at least 1200 mg calcium and 800-1000 IU vitamin D daily.
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. Patients must be adequately supplemented with calcium and vitamin D if dietary intake is not sufficient. Postmenopausal women require an average of 1200 mg calcium and 800-1000 IU vitamin D daily.
Osteoporosis in Men
The recommended regimen is a 5 mg infusion once a year given intravenously over no less than 15 minutes. Patients must be adequately supplemented with calcium and vitamin D if dietary intake is not sufficient. An average of at least 1200 mg calcium and 800-1000 IU vitamin D daily is recommended.
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. Patients must be adequately supplemented with calcium and vitamin D if dietary intake is not sufficient. An average of at least 1200 mg calcium and 800-1000 IU vitamin D daily is recommended.
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.
To reduce the risk of hypocalcemia, all patients with Paget’s disease should receive 1500 mg elemental calcium daily in divided doses (750 mg two times a day, or 500 mg three times a day) and 800 IU vitamin D daily, particularly in the 2 weeks following Reclast administration. All patients should be instructed on the importance of calcium and vitamin D supplementation in maintaining serum calcium levels, and on the symptoms of hypocalcemia [see Warnings and Precautions (5.2)].
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.
Method of Administration
The Reclast 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.
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–8°C (36°F - 46°F) [see How Supplied/Storage and Handling (16)].
Dosage Forms and Strengths
5 mg in a 100 mL ready to infuse solution.
Contraindications
Hypocalcemia
[See Warnings and Precautions (5.2)]
Renal Failure
Reclast is contraindicated in patients with creatinine clearance < 35 mL/min and in those with evidence of acute renal impairment due to an increased risk of renal failure [see Warnings and Precautions (5.3)].
Hypersensitivity to Zoledronic Acid or Any Components of Reclast
Hypersensitivity reactions including rare cases of urticaria, angioedema, and anaphylactic reaction/shock have been reported [see Post-Marketing Experience (6.2)].
Warnings and Precautions
Drug 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.
Hypocalcemia and Mineral Metabolism
Pre-existing 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 [see Contraindications (4)].
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 [see Dosage and Administration (2), Adverse Reactions (6.1), Information for Patients (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), Adverse Reactions (6.1), Information for Patients (17)].
Renal Impairment
A single dose of Reclast should not exceed 5 mg and the duration of infusion should be no less than 15 minutes [see Dosage and Administration (2.1)].
Reclast is contraindicated in patients with creatinine clearance <35 mL/min and in those with evidence of acute renal impairment [see Contraindications (4.2)]. If history or physical signs suggest dehydration, Reclast therapy should be withheld until normovolemic status has been achieved [see Postmarketing Experience (6.2)].
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 pre-existing 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 [see Post-Marketing Experience (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 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 [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)].
Osteonecrosis 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, radiotherapy, corticosteroids, poor oral hygiene, pre-existing dental disease or infection, anemia, coagulopathy).
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)].
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.
Pregnancy
Reclast SHOULD NOT BE USED DURING PREGNANCY. Reclast 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 Reclast therapy [see Use in Specific Populations (8.1)].
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 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 [see Adverse Reactions (6.2)].
Patients 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.
Adverse Reactions
Clinical Studies Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Treatment of 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 65-89 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 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 IU 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 50-95 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 IU orally or IM) was given to patients and they were started on 1000 to 1500 mg of elemental calcium plus 800 to 1200 IU 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.
| 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 | 5.2 |
| 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 < 30 mL/min (based on actual body weight), urine dipstick ≥2+ protein or increase in serum creatinine of >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 [see Warnings and Precautions (5.3)].
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 [see 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 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 (<0.1%) to 9 (0.2%) patients treated with Reclast and 0 (0%) to 1 (<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 >45 years. Patients were randomized to one of three treatment groups: (1) Reclast 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). 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 IU 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 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.
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 | 0.0 |
| 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 |
* Combined abdominal pain, abdominal pain upper, and abdominal pain lower as one ADR
** Combined musculoskeletal pain and musculoskeletal chest pain as one ADR
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 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 25-86 years. One hundred fifty three (153) 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 IU 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 (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.
System Organ Class | 5 mg IV Reclast once per year % (N=153) | Active Control once weekly % (N=148) |
| Nervous System Disorders | ||
| Headache | 15.0 | 6.1 |
| 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 |
* Combined abdominal pain, abdominal pain upper, and abdominal pain lower as one ADR
** Combined musculoskeletal pain and musculoskeletal chest pain as one ADR
Renal 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 [see Warnings and Precautions (5.3)].
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 wit
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