Zoledronic Acid (Page 3 of 8)

5.10 Embryo-Fetal Toxicity

Based on findings from animal studies and its mechanism of action, zoledronic acid can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of zoledronic acid to pregnant rats during organogenesis resulted in fetal malformations and embryo-fetal lethality at maternal exposures that were greater than or equal to 2.4 times the human clinical exposure based on area under the curve (AUC). Bisphosphonates, such as zoledronic acid, are incorporated into the bone matrix, from where they are gradually released over periods of weeks to years. There may be a risk of fetal harm (e.g., skeletal and other abnormalities) if a woman becomes pregnant after completing a course of bisphosphonate therapy. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during and after zoledronic acid treatment [see Use in Specific Populations (8.1, 8.3), Clinical Pharmacology (12.1)].

6 ADVERSE REACTIONS

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.

Hypercalcemia of Malignancy

The safety of zoledronic acid was studied in 185 patients with hypercalcemia of malignancy (HCM) who received either zoledronic acid 4 mg given as a 5-minute intravenous infusion (n = 86) or pamidronate 90 mg given as a 2-hour intravenous infusion (n = 103). The population was aged 33 to 84 years, 60% male and 81% Caucasian, with breast, lung, head and neck, and renal cancer as the most common forms of malignancy. NOTE: pamidronate 90 mg was given as a 2-hour intravenous infusion. The relative safety of pamidronate 90 mg given as a 2-hour intravenous infusion compared to the same dose given as a 24-hour intravenous infusion has not been adequately studied in controlled clinical trials.

Renal Toxicity

Administration of zoledronic acid 4 mg given as a 5-minute intravenous infusion has been shown to result in an increased risk of renal toxicity, as measured by increases in serum creatinine, which can progress to renal failure. The incidence of renal toxicity and renal failure has been shown to be reduced when zoledronic acid 4 mg is given as a 15-minute intravenous infusion. Zoledronic acid should be administered by intravenous infusion over no less than 15 minutes [see Warnings and Precautions (5.3), Dosage and Administration (2.4)].

The most frequently observed adverse events were fever, nausea, constipation, anemia, and dyspnea (see Table 4).

Table 4 provides adverse events that were reported by 10% or more of the 189 patients treated with zoledronic acid 4 mg or pamidronate 90 mg from the two HCM trials. Adverse events are listed regardless of presumed causality to study drug.

Table 4: Percentage of Patients With Adverse Events Greater Than or Equal to 10% Reported in Hypercalcemia of Malignancy Clinical Trials by Body System

Zoledronic Acid
4 mg
n (%)
Pamidronate
90 mg
n (%)

Patients Studied

Total No. of Patients Studied

86

(100)

103

(100)

Total No. of Patients with any AE

81

(94)

95

(92)

Body as a Whole

Fever

38

(44)

34

(33)

Progression of Cancer

14

(16)

21

(20)

Cardiovascular

Hypotension

9

(11)

2

(2)

Digestive

Nausea

25

(29)

28

(27)

Constipation

23

(27)

13

(13)

Diarrhea

15

(17)

17

(17)

Abdominal Pain

14

(16)

13

(13)

Vomiting

12

(14)

17

(17)

Anorexia

8

(9)

14

(14)

Hemic and Lymphatic System

Anemia

19

(22)

18

(18)

Infections

Moniliasis

10

(12)

4

(4)

Laboratory Abnormalities

Hypophosphatemia

11

(13)

2

(2)

Hypokalemia

10

(12)

16

(16)

Hypomagnesemia

9

(11)

5

(5)

Musculoskeletal

Skeletal Pain

10

(12)

10

(10)

Nervous

Insomnia

13

(15)

10

(10)

Anxiety

12

(14)

8

(8)

Confusion

11

(13)

13

(13)

Agitation

11

(13)

8

(8)

Respiratory

Dyspnea

19

(22)

20

(19)

Coughing

10

(12)

12

(12)

Urogenital

Urinary Tract Infection

12

(14)

15

(15)

The following adverse events from the two controlled multicenter HCM trials (n = 189) were reported by a greater percentage of patients treated with zoledronic acid 4 mg than with pamidronate 90 mg and occurred with a frequency of greater than or equal to 5% but less than 10%. Adverse events are listed regardless of presumed causality to study drug: asthenia, chest pain, leg edema, mucositis, dysphagia, granulocytopenia, thrombocytopenia, pancytopenia, nonspecific infection, hypocalcemia, dehydration, arthralgias, headache and somnolence.

Rare cases of rash, pruritus, and chest pain have been reported following treatment with zoledronic acid.

Acute Phase Reaction

Within three days after zoledronic acid administration, an acute phase reaction has been reported in patients, with symptoms including pyrexia, fatigue, bone pain and/or arthralgias, myalgias, chills, and influenza-like illness. These symptoms usually resolve within a few days. Pyrexia has been the most commonly associated symptom, occurring in 44% of patients.

Mineral and Electrolyte Abnormalities

Electrolyte abnormalities, most commonly hypocalcemia, hypophosphatemia, and hypomagnesemia, can occur with bisphosphonate use.

Grade 3 and Grade 4 laboratory abnormalities for serum creatinine, serum calcium, serum phosphorus, and serum magnesium observed in two clinical trials of zoledronic acid in patients with HCM are shown in Table 5 and 6.

Table 5: Grade 3 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Two Clinical Trials in Patients with HCM

Grade 3

Laboratory Parameter

Zoledronic Acid

4 mg

Pamidronate

90 mg

n/N

(%)

n/N

(%)

Serum Creatinine1

2/86

(2%)

3/100

(3%)

Hypocalcemia2

1/86

(1%)

2/100

(2%)

Hypophosphatemia3

36/70

(51%)

27/81

(33%)

Hypomagnesemia4

0/71

0

0/84

0

1 Grade 3 (greater than 3x Upper Limit of Normal); Grade 4 (greater than 6x Upper Limit of Normal).

2 Grade 3 (less than 7 mg/dL); Grade 4 (less than 6 mg/dL).

3 Grade 3 (less than 2 mg/dL); Grade 4 (less than 1 mg/dL).

4 Grade 3 (less than 0.8 mEq/L); Grade 4 (less than 0.5 mEq/L).

Table 6: Grade 4 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Two Clinical Trials in Patients With HCM

Grade 4

Laboratory Parameter

Zoledronic Acid

4 mg

Pamidronate

90 mg

n/N

(%)

n/N

(%)

Serum Creatinine1

0/86

0

1/100

(1%)

Hypocalcemia2

0/86

0

0/100

0

Hypophosphatemia3

1/70

(1%)

4/81

(5%)

Hypomagnesemia4

0/71

0

1/84

(1%)

1 Grade 3 (greater than 3x Upper Limit of Normal); Grade 4 (greater than 6x Upper Limit of Normal).

2 Grade 3 (less than 7 mg/dL); Grade 4 (less than 6 mg/dL).

3 Grade 3 (less than 2 mg/dL); Grade 4 (less than 1 mg/dL).

4 Grade 3 (less than 0.8 mEq/L); Grade 4 (less than 0.5 mEq/L).

Injection-Site Reactions

Local reactions at the infusion-site, such as redness or swelling, were observed infrequently. In most cases, no specific treatment is required and the symptoms subside after 24 to 48 hours.

Ocular Adverse Events

Ocular inflammation such as uveitis and scleritis can occur with bisphosphonate use, including zoledronic acid. No cases of iritis, scleritis, or uveitis were reported during these clinical trials. However, cases have been seen in postmarketing use [see Adverse Reactions (6.2)].

Multiple Myeloma and Bone Metastases of Solid Tumors

The safety analysis includes patients treated in the core and extension phases of the trials. The analysis includes the 2042 patients treated with zoledronic acid 4 mg, pamidronate 90 mg, or placebo in the three controlled multicenter bone metastases trials, including 969 patients completing the efficacy phase of the trial, and 619 patients that continued in the safety extension phase. Only 347 patients completed the extension phases and were followed for 2 years (or 21 months for the other solid tumor patients). The median duration of exposure for safety analysis for zoledronic acid 4 mg (core plus extension phases) was 12.8 months for breast cancer and multiple myeloma, 10.8 months for prostate cancer, and 4.0 months for other solid tumors.

Table 7 describes adverse events that were reported by 10% or more of patients. Adverse events are listed regardless of presumed causality to study drug.

Table 7: Percentage of Patients With Adverse Events Greater Than or Equal to 10% Reported in Three Bone Metastases Clinical Trials by Body System

Zoledronic
Acid
4 mg
Pamidronate
90 mg
Placebo
n (%)
n (%)
n (%)
Patients Studied

Total No. of Patients

1031
(100)
556
(100)
455
(100)
Total No. of Patients with any AE
1015
(98)
548
(99)
445
(98)
Blood and Lymphatic

Anemia

344
(33)
175
(32)
128
(28)
Neutropenia
124
(12)
83
(15)
35
(8)
Thrombocytopenia
102
(10)
53
(10)
20
(4)
Gastrointestinal

Nausea

476
(46)
266
(48)
171
(38)
Vomiting
333
(32)
183
(33)
122
(27)
Constipation
320
(31)
162
(29)
174
(38)
Diarrhea
249
(24)
162
(29)
83
(18)
Abdominal Pain
143
(14)
81
(15)
48
(11)
Dyspepsia
105
(10)
74
(13)
31
(7)
Stomatitis
86
(8)
65
(12)
14
(3)
Sore Throat
82
(8)
61
(11)
17
(4)
General Disorders and Administration Site

Fatigue

398
(39)
240
(43)
130
(29)
Pyrexia
328
(32)
172
(31)
89
(20)
Weakness
252
(24)
108
(19)
114
(25)
Edema Lower Limb
215
(21)
126
(23)
84
(19)
Rigors
112
(11)
62
(11)
28
(6)
Infections

Urinary Tract Infection

124
(12)
50
(9)
41
(9)
Upper Respiratory Tract Infection
101
(10)
82
(15)
30
(7)
Metabolism

Anorexia

231
(22)
81
(15)
105
(23)
Weight Decreased
164
(16)
50
(9)
61
(13)
Dehydration
145
(14)
60
(11)
59
(13)
Appetite Decreased
130
(13)
48
(9)
45
(10)
Musculoskeletal

Bone Pain

569
(55)
316
(57)
284
(62)
Myalgia
239
(23)
143
(26)
74
(16)
Arthralgia
216
(21)
131
(24)
73
(16)
Back Pain
156
(15)
106
(19)
40
(9)
Pain in Limb
143
(14)
84
(15)
52
(11)
Neoplasms

Malignant Neoplasm Aggravated

205
(20)
97
(17)
89
(20)
Nervous

Headache

191
(19)
149
(27)
50
(11)
Dizziness (excluding vertigo)
180
(18)
91
(16)
58
(13)
Insomnia
166
(16)
111
(20)
73
(16)
Paresthesia
149
(15)
85
(15)
35
(8)
Hypoesthesia
127
(12)
65
(12)
43
(10)
Psychiatric

Depression

146
(14)
95
(17)
49
(11)
Anxiety
112
(11)
73
(13)
37
(8)
Confusion
74
(7)
39
(7)
47
(10)
Respiratory

Dyspnea

282
(27)
155
(28)
107
(24)
Cough
224
(22)
129
(23)
65
(14)
Skin

Alopecia

125
(12)
80
(14)
36
(8)
Dermatitis
114
(11)
74
(13)
38
(8)

Grade 3 and Grade 4 laboratory abnormalities for serum creatinine, serum calcium, serum phosphorus, and serum magnesium observed in three clinical trials of zoledronic acid in patients with bone metastases are shown in Tables 8 and 9.

Table 8: Grade 3 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Three Clinical Trials in Patients With Bone Metastases

Laboratory
Parameter
Grade 3
Zoledronic Acid
4 mg
Pamidronate
90 mg
Placebo
n/N (%) n/N (%) n/N (%)
Serum Creatinine1*
7/529
(1%)
4/268
(2%)
4/241
(2%)
Hypocalcemia2
6/973
(<1%)
4/536
(<1%)
0/415
0
Hypophosphatemia3
115/973
(12%)
38/537
(7%)
14/415
(3%)
Hypermagnesemia4
19/971
(2%)
2/535
(<1%)
8/415
(2%)
Hypomagnesemia5
1/971
(<1%)
0/535
1/415
(<1%)

*Serum creatinine data for all patients randomized after the 15-minute infusion amendment.

1 Grade 3 (greater than 3x Upper Limit of Normal); Grade 4 (greater than 6x Upper Limit of Normal).

2 Grade 3 (less than 7 mg/dL); Grade 4 (less than 6 mg/dL).

3 Grade 3 (less than 2 mg/dL); Grade 4 (less than 1 mg/dL).

4 Grade 3 (greater than 3 mEq/L); Grade 4 (greater than 8 mEq/L).

5 Grade 3 (less than 0.9 mEq/L); Grade 4 (less than 0.7 mEq/L).

Table 9: Grade 4 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Three Clinical Trials in Patients With Bone Metastases

Laboratory

Parameter

Grade 4

Zoledronic Acid 4 mg

Pamidronate

90 mg

Placebo

n/N

(%)

n/N

(%)

n/N

(%)

Serum Creatinine1*

2/529

(<1%)

1/268

(<1%)

0/241

0

Hypocalcemia2

7/973

(<1%)

3/536

(<1%)

2/415

(<1%)

Hypophosphatemia3

5/973

(<1%)

0/537

0

1/415

(<1%)

Hypermagnesemia4

0/971

0

0/535

0

2/415

(<1%)

Hypomagnesemia5

2/971

(<1%)

1/535

(<1%)

0/415

0

*Serum creatinine data for all patients randomized after the 15-minute infusion amendment.

1 Grade 3 (greater than 3x Upper Limit of Normal); Grade 4 (greater than 6x Upper Limit of Normal).

2 Grade 3 (less than 7 mg/dL); Grade 4 (less than 6 mg/dL).

3 Grade 3 (less than 2 mg/dL); Grade 4 (less than 1 mg/dL).

4 Grade 3 (greater than 3 mEq/L); Grade 4 (greater than 8 mEq/L).

5 Grade 3 (less than 0.9 mEq/L); Grade 4 (less than 0.7 mEq/L).

Among the less frequently occurring adverse events (less than 15% of patients), rigors, hypokalemia, influenza-like illness, and hypocalcemia showed a trend for more events with bisphosphonate administration (zoledronic acid 4 mg and pamidronate groups) compared to the placebo group.

Less common adverse events reported more often with zoledronic acid 4 mg than pamidronate included decreased weight, which was reported in 16% of patients in the zoledronic acid 4 mg group compared with 9% in the pamidronate group. Decreased appetite was reported in slightly more patients in the zoledronic acid 4 mg group (13%) compared with the pamidronate (9%) and placebo (10%) groups, but the clinical significance of these small differences is not clear.

Renal Toxicity

In the bone metastases trials, renal deterioration was defined as an increase of 0.5 mg/dL for patients with normal baseline creatinine (less than 1.4 mg/dL) or an increase of 1.0 mg/dL for patients with an abnormal baseline creatinine (greater than or equal to 1.4 mg/dL). The following are data on the incidence of renal deterioration in patients receiving zoledronic acid 4 mg over 15 minutes in these trials (see Table 10).

Table 10: Percentage of Patients With Treatment-Emergent Renal Function Deterioration by Baseline Serum Creatinine*

Patient Population/Baseline Creatinine

Multiple Myeloma and Breast Cancer

Zoledronic Acid

4 mg

Pamidronate 90 mg

n/N

(%)

n/N

(%)

Normal

27/246

(11%)

23/246

(9%)

Abnormal

2/26

(8%)

2/22

(9%)

Total

29/272

(11%)

25/268

(9%)

Solid Tumors

Zoledronic Acid

4 mg

Placebo

n/N

(%)

n/N

(%)

Normal

17/154

(11%)

10/143

(7%)

Abnormal

1/11

(9%)

1/20

(5%)

Total

18/165

(11%)

11/163

(7%)

Prostate Cancer

Zoledronic Acid

4 mg

Placebo

n/N

(%)

n/N

(%)

Normal

12/82

(15%)

8/68

(12%)

Abnormal

4/10

(40%)

2/10

(20%)

Total

16/92

(17%)

10/78

(13%)

*Table includes only patients who were randomized to the trial after a protocol amendment that lengthened the infusion duration of zoledronic acid to 15 minutes.

The risk of deterioration in renal function appeared to be related to time on study, whether patients were receiving zoledronic acid (4 mg over 15 minutes), placebo, or pamidronate.

In the trials and in postmarketing experience, renal deterioration, progression to renal failure, and dialysis have occurred in patients with normal and abnormal baseline renal function, including patients treated with 4 mg infused over a 15-minute period. There have been instances of this occurring after the initial zoledronic acid dose.

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