Reclast Side Effects

Generic Name: zoledronic acid

Please note - some side effects for Reclast may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Side Effects of Reclast - for the Consumer

Reclast

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Reclast:

Diarrhea; dizziness; headache; mild back, joint, or muscle pain; mild flu-like symptoms (eg, mild fever, muscle aches); mild itching, pain, or redness at the injection site; nausea; stomach pain or upset; tiredness; vomiting; weakness.

Seek medical attention right away if any of these SEVERE side effects occur when using Reclast:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, throat, or tongue; unusual hoarseness); change in the amount of urine produced; eye pain, redness, or swelling; fever, chills, or persistent sore throat; irregular heartbeat; jaw pain or swelling; mental or mood changes (eg, depression); muscle cramps or spasms; numbness or tingling (especially around the mouth); severe bone, joint, or muscle pain (especially in the hip, groin, or thigh); severe or persistent dizziness or headache; severe or persistent nausea, vomiting, or diarrhea; severe or persistent tiredness or weakness; shortness of breath; swelling of the hands, ankles, or feet.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

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Reclast Side Effects - for the Professional

Reclast

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.

Table 1. Adverse Reactions Occurring in ≥ 2.0% of Patients with Osteoporosis and More Frequently than in Placebo-Treated Patients

	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.

Table 2. Adverse Reactions Occurring in > 2% of Patients with Osteopenia and More Frequently than in Placebo-Treated Patients

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.

Table 3: Adverse Reactions Occurring in > 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 this Trial

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 within the first 3 days following the dose of Reclast. The majority of these symptoms were mild to moderate and resolved within 3 days of the event onset but resolution could take up to 7-14 days. The incidence of these symptoms decreased with subsequent doses of Reclast.

Atrial Fibrillation

The incidence of all atrial fibrillation adverse events in the Reclast treatment group was 3.3% (5 out of 153) compared to 2.0% (3 out of 148) in the active control group. However, there were no patients with adjudicated serious adverse events of atrial fibrillation in the Reclast treatment group.

Laboratory Findings

There were no patients who had treatment emergent serum calcium levels below 7.5 mg/dL.

Injection Site Reactions

There were 4 patients (2.6%) on Reclast vs. 2 patients (1.4%) on active control with local site reactions.

Osteonecrosis of the Jaw

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

Glucocorticoid-Induced Osteoporosis

The safety of Reclast in men and women in the treatment and prevention of glucocorticoid-induced osteoporosis was assessed in a randomized, multicenter, double-blind, active controlled, stratified study of 833 men and women aged 18-85 years treated with > 7.5 mg/day oral prednisone (or equivalent). Patients were stratified according to the duration of their pre-study corticosteroid therapy: < 3 months prior to randomization (prevention subpopulation), and > 3 months prior to randomization (treatment subpopulation).

The duration of the trial was one year with 416 patients exposed to Reclast administered once as a single 5 mg dose in 100 mL infused over 15 minutes, and 417 patients exposed to a commercially-available oral daily bisphosphonate (active control) for one year. All participants received 1000 mg of elemental calcium plus 400 to 1000 IU of vitamin D supplementation per day.

The incidence of all–cause mortality was similar between treatment groups: 0.9% in the Reclast group and 0.7% in the active control group. The incidence of serious adverse events was similar between the Reclast treatment and prevention groups, 18.4% and 18.1%, respectively, and the active control treatment and prevention groups, 19.8% and 16.0%, respectively. The percentage of subjects who withdrew from the study due to adverse events was 2.2% in the Reclast group vs. 1.4% in the active control group. The overall safety and tolerability were similar between Reclast and active control groups with the exception of a higher incidence of post-dose symptoms in the Reclast group that occurred within 3 days after infusion. The overall safety and tolerability profile of Reclast in glucocorticoid-induced osteoporosis was similar to the adverse events reported in the Reclast postmenopausal osteoporosis clinical trial.

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

Renal Impairment

Renal function measured prior to dosing and at the end of the 12 month study was comparable in the Reclast and active control groups [see Warnings and Precautions (5.3)].

Acute Phase Reaction

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

Atrial Fibrillation 

The incidence of atrial fibrillation adverse events was 0.7% (3 of 416) in the Reclast group compared to no adverse events in the active control group. All subjects had a prior history of atrial fibrillation and no cases were adjudicated as serious adverse events. One patient had atrial flutter in the active control group.

Laboratory Findings

There were no patients who had treatment emergent serum calcium levels below 7.5 mg/dL.

Injection Site Reactions 

There were no local reactions at the infusion site.

Osteonecrosis of the Jaw

In this trial there were no cases of osteonecrosis of the jaw [see 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 > 30 years with moderate to severe disease and with confirmed Paget’s disease of bone, 177 patients were exposed to Reclast and 172 patients exposed to risedronate. Reclast was administered once as a single 5 mg dose in 100 mL solution infused over at least 15 minutes. Risedronate was given as an oral daily dose of 30 mg for 2 months.

The incidence of serious adverse events was 5.1% in the Reclast group and 6.4% in the risedronate group. The percentage of patients who withdrew from the study due to adverse events was 1.7% and 1.2% for the Reclast and risedronate groups, respectively.

Adverse reactions occurring in at least 2% of the Paget’s patients receiving Reclast (single 5 mg IV infusion) or risedronate (30 mg oral daily dose for 2 months) over a 6-month study period are listed by system organ class in Table 4.

Table 4. Adverse Reactions Reported in at Least 2% of Paget’s Patients Receiving Reclast (Single 5 mg IV Infusion) or Risedronate (Oral 30 mg Daily for 2 Months) Over a 6-Month Follow-Up Period

System Organ Class	5 mg IV Reclast % (N = 177)	30 mg/day x 2 Months risedronate % (N = 172)
Infections and Infestations
Influenza	7	5
Metabolism and Nutrition Disorders
Hypocalcemia	3	1
Anorexia	2	2
Nervous System Disorders
Headache	11	10
Dizziness	9	4
Lethargy	5	1
Paresthesia	2	0
Respiratory, Thoracic and Mediastinal Disorders
Dyspnea	5	1
Gastrointestinal Disorders
Nausea	9	6
Diarrhea	6	6
Constipation	6	5
Dyspepsia	5	4
Abdominal Distension	2	1
Abdominal Pain	2	2
Vomiting	2	2
Abdominal Pain Upper	1	2
Skin and Subcutaneous Tissue Disorders
Rash	3	2
Musculoskeletal, Connective Tissue and Bone Disorders
Arthralgia	9	11
Bone Pain	9	5
Myalgia	7	4
Back Pain	4	7
Musculoskeletal Stiffness	2	1
General Disorders and Administrative Site Conditions
Influenza-like Illness	11	6
Pyrexia	9	2
Fatigue	8	4
Rigors	8	1
Pain	5	4
Peripheral Edema	3	1
Asthenia	2	1

Laboratory Findings

In the Paget’s disease trials, early, transient decreases in serum calcium and phosphate levels were observed. Approximately 21% of patients had serum calcium levels <8.4 mg/dL 9-11 days following Reclast administration.

Renal Impairment

In clinical trials in Paget’s disease there were no cases of renal deterioration following a single 5 mg 15-minute infusion [see 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 Reclast administration. The majority of these symptoms resolved within 4 days of onset.

Osteonecrosis of the Jaw

Osteonecrosis of the jaw has been reported with zoledronic acid [see Warnings and Precautions (5.4)].

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 Reclast:

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

Cases of 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 

There have been rare reports of allergic reaction with intravenous zoledronic acid including urticaria, angioedema, and bronchoconstriction. Rare cases of anaphylactic reaction/shock have also been reported.

Hypocalcemia

Rare cases of hypocalcemia have been reported.

Osteonecrosis of the Jaw

Rare cases of osteonecrosis of the jaw have been reported.

Ocular Adverse Events

Rare cases of the following events have been reported: conjunctivitis, iritis, iridocyclitis, uveitis, episcleritis, scleritis and orbital inflammation/edema.

Other

Rare cases of hypotension in patients with underlying risk factors have been reported.

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Side Effects by Body System - for Healthcare Professionals

General

In general, side effects have been mild and transient and similar to other bisphosphonates. Postmarketing reports have included weight gain.

Metabolic

Metabolic side effects have included hypomagnesemia (10.5%), hypokalemia (11.6%), hypophosphatemia (12.8%), and dehydration and hypocalcemia have been reported in 5% to 10% of patients. Grade 3 and 4 laboratory abnormalities have included hypophosphatemia (51.4%, grade 3; 1.4%, grade 4) and hypocalcemia (1.2%, grade 3).

Renal

Renal side effects have included renal toxicity (deterioration of renal function or renal failure). Grade 3 increases (more than 3 times upper limit of normal) in serum creatinine have been reported in 2.3% of patients. Postmarketing reports have included hematuria, proteinuria, hyperkalemia, and hypernatremia.

Hematologic

Hematologic side effects have included anemia (22.1% to 33%) and neutropenia (12%). Granulocytopenia, thrombocytopenia, and pancytopenia have been reported in 5% to 10% of patients.

Gastrointestinal

Gastrointestinal side effects have included nausea (46% to 29.1%), vomiting (14% to 32%), constipation (26.7% to 31%), diarrhea (17.4% to 24%), abdominal pain (14% to 16.3%), dyspepsia (10%), anorexia (9.3%), stomatitis (8%), sore throat (8%), and dysphagia (5% to 10%). Postmarketing reports have included reports of dry mouth.

Ocular

Ocular side effects have included conjunctivitis. Cases of uveitis and episcleritis have been reported during post approval use. Postmarketing reports have included blurred vision. Cases of uveitis, scleritis, episcleritis, conjunctivitis, iritis, and orbital inflammation including orbital edema have been reported during postmarketing use. In some cases, symptoms resolved with topical steroids.

Cardiovascular

Cardiovascular side effects have included hypotension (10.5%). Postmarketing reports have included atrial fibrillation, hypertension, bradycardia, and hypotension.

In the postmenopausal osteoporosis trial, 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.

Musculoskeletal

Musculoskeletal side effects have included bone pain (55%), myalgia (23%0, arthralgia (21%), back pain (15%), and limb pain (14%). Postmarketing reports have included muscle cramps. Severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported with bisphosphonate use. Cases of osteonecrosis (primarily involving the jaws) have been reported predominantly in cancer patients treated with intravenous bisphosphonates including zoledronic acid

Nervous system

Nervous system side effects have included headache (19%), dizziness (18%), insomnia (15.1%), paresthesia (15%), anxiety (14%), confusion (12.8%), agitation (12.8%), hypoesthesia (12%), and somnolence (5% to 10%). Postmarketing reports have included taste disturbance, hyperesthesia, tremor, and vertigo.

Respiratory

Respiratory side effects have included dyspnea (27% to 22.1%), coughing (22% to 11.6%), upper respiratory infection (10%), and pleural effusion (5% to 10%). Postmarketing reports have included bronchoconstriction.

Genitourinary

Genitourinary side effects have included urinary tract infection (14%).

Oncologic

Oncologic side effects have included aggravation of malignant neoplasm and progression of cancer.

Other

Other side effects have included fever (44.2%) and moniliasis (11.6%). Nonspecific infections, asthenia, chest pain, leg edema, and mucositis have been reported in 5% to 10% of patients. Flu-like syndromes have also been reported.

Fever is the most common adverse effect associated with zoledronic acid infusion.

Flu-like syndromes including fever, chills, bone pain, and/or arthralgias and myalgias have also occasionally been reported. These symptoms generally did not require treatment and resolved within 24 to 48 hours.

Local

Local side effects have infrequently included redness or swelling at the injection site. Postmarketing reports have included itching and pain at the injection site.

Dermatologic

Dermatologic side effects have included alopecia (12%) and dermatitis (11%). Rash and pruritus have been reported rarely. Postmarketing reports have included increased sweating and urticaria.

Psychiatric

Psychiatric side effects have included depression (14%), anxiety (11%), and confusion (7%).

Hypersensitivity

Hypersensitivity side effects have included rare cases of urticaria and angioedema and very rare cases of anaphylactic shock.

Other

Other side effects have included postmarketing reports of pyrexia, asthenia, fatigue, or malaise persisting for greater than 30 days.

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