A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Zometa Side Effects, and Drug Interactions - Zoledronic Acid
Zometa Side Effects, and Drug Interactions - Zoledronic Acid
SIDE EFFECTS
Hypercalcemia of Malignancy
Adverse reactions to Zometa® (zoledronic acid) Injection are usually mild and transient and similar to those reported for other bisphosphonates. Intravenous administration has been most commonly associated with fever. Occasionally, patients experience a flu-like syndrome consisting of fever, chills, bone pain and/or arthralgias, and myalgias. Gastrointestinal reactions such as nausea and vomiting have been reported following intravenous infusion of Zometa. 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 24-48 hours.
Rare cases of rash, pruritus, and chest pain have been reported following treatment with Zometa.
As with other bisphosphonates, cases of conjunctivitis and hypomagnesemia have been reported following treatment with Zometa.
Grade 3 and Grade 4 laboratory abnormalities for serum creatinine, serum calcium, serum phosphorus, and serum magnesium observed in two clinical trials of Zometa in patients with HCM are shown in Table 6.
|
Table 6: Grade 3-4 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Two Clinical Trials in Patients with HCM |
| |
Grade 3 |
Grade 4 |
|
Laboratory Parameter |
Zometa®4 mg |
Pamidronate90 mg |
Zometa®4 mg |
Pamidronate90 mg |
| |
n/N |
(%) |
n/N |
(%) |
n/N |
(%) |
n/N |
(%) |
|
Serum Creatinine1 |
2/86 |
(2.3%) |
3/100 |
(3.0%) |
0/86 |
— |
1/100 |
(1.0%) |
|
Hypocalcemia2 |
1/86 |
(1.2%) |
2/100 |
(2.0%) |
0/86 |
— |
0/100 |
— |
|
Hypophosphatemia3 |
36/70 |
(51.4%) |
27/81 |
(33.3%) |
1/70 |
(1.4%) |
4/81 |
(4.9%) |
|
Hypomagnesemia4 |
0/71 |
— |
0/84 |
— |
0/71 |
— |
1/84 |
(1.2%) |
|
1 Grade 3 (>3x Upper Limit of Normal); Grade 4 (>6x Upper Limit of Normal) |
|
2 Grade 3 (<7 mg/dL); Grade 4 (<6 mg/dL) |
|
3 Grade 3 (<2 mg/dL); Grade 4 (<1 mg/dL) |
|
4 Grade 3 (<0.8 mEq/L); Grade 4 (<0.5 mEq/L) |
Table 7 provides adverse events that were reported by 10% or more of the 189 patients treated with Zometa 4 mg or pamidronate 90 mg from the two controlled multicenter HCM trials. Adverse events are listed regardless of presumed causality to study drug.
|
Table 7: Percentage of Patients with Adverse Events >10%
Reported in Hypercalcemia of Malignancy Clinical Trials by Body System
|
| |
Zometa®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
|
(94.2)
|
95
|
(92.2)
|
|
Body as a Whole
|
|
Fever
|
38
|
(44.2)
|
34
|
(33.0)
|
|
Progression of Cancer
|
14
|
(16.3)
|
21
|
(20.4)
|
|
Digestive
|
|
Nausea
|
25
|
(29.1)
|
28
|
(27.2)
|
|
Constipation
|
23
|
(26.7)
|
13
|
(12.6)
|
|
Diarrhea
|
15
|
(17.4)
|
17
|
(16.5)
|
|
Abdominal Pain
|
14
|
(16.3)
|
13
|
(12.6)
|
|
Vomiting
|
12
|
(14.0)
|
17
|
(16.5)
|
|
Anorexia
|
8
|
(9.3)
|
14
|
(13.6)
|
|
Cardiovascular
|
|
Hypotension
|
9
|
(10.5)
|
2
|
(1.9)
|
|
Hemic and Lymphatic System
|
|
Anemia
|
19
|
(22.1)
|
18
|
(17.5)
|
|
Infections
|
|
Moniliasis
|
10
|
(11.6)
|
4
|
(3.9)
|
|
Laboratory Abnormalities
|
|
Hypophosphatemia
|
11
|
(12.8)
|
2
|
(1.9)
|
|
Hypokalemia
|
10
|
(11.6)
|
16
|
(15.5)
|
|
Hypomagnesemia
|
9
|
(10.5)
|
5
|
(4.9)
|
|
Musculoskeletal
|
|
Skeletal Pain
|
10
|
(11.6)
|
10
|
(9.7)
|
|
Nervous
|
|
Insomnia
|
13
|
(15.1)
|
10
|
(9.7)
|
|
Anxiety
|
12
|
(14.0)
|
8
|
(7.8)
|
|
Confusion
|
11
|
(12.8)
|
13
|
(12.6)
|
|
Agitation
|
11
|
(12.8)
|
8
|
(7.8)
|
|
Respiratory
|
|
Dyspnea
|
19
|
(22.1)
|
20
|
(19.4)
|
|
Coughing
|
10
|
(11.6)
|
12
|
(11.7)
|
|
Urogenital
|
|
Urinary Tract Infection
|
12
|
(14.0)
|
15
|
(14.6)
|
The following adverse events from the two controlled multicenter HCM trials (n=189) were reported by a greater percentage of patients treated with Zometa 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.
Body as a Whole: asthenia, chest pain, leg edema, mucositis, and metastases
Digestive System: dysphagia
Hemic and Lymphatic System: granulocytopenia, thrombocytopenia, and pancytopenia
Infection: non-specific infection
Laboratory Abnormalities: hypocalcemia
Metabolic and Nutritional: dehydration
Musculoskeletal: arthralgias
Nervous System: headache, somnolence
Respiratory System: pleural effusion
NOTE: In the HCM clinical trials, 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.
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 Zometa 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 two years (or 21 months for the other solid tumor patients). The median duration of exposure for safety analysis for Zometa 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 8 describes adverse events that were reported by 10% of patients. Adverse events are listed regardless of presumed causality to study drug.
|
Table 8: Percentage of Patients with Adverse Events 10%
Reported in Three Bone Metastases Clinical Trials by Body System
|
|
|
Zometa® 4 mg n (%)
|
Pamidronate 90 mg n (%)
|
Placebo 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 Zometa in patients with Bone Metastases are shown in Tables 9 and 10.
|
Table 9: Grade 3 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Three Clinical Trials in Patients with Bone Metastases |
| |
Grade 3 |
|
Laboratory Parameter |
Zometa®4 mg |
Pamidronate90 mg |
Placebo |
| |
n/N |
(%) |
n/N |
(%) |
n/N |
(%) |
|
Serum Creatinine1* |
7/529 |
(1.3%) |
4/268 |
(1.5%) |
4/241 |
(1.7%) |
|
Hypocalcemia2 |
6/973 |
(0.6%) |
4/536 |
(0.7%) |
0/415 |
— |
|
Hypophosphatemia3 |
115/973 |
(11.8%) |
38/537 |
(7.1%) |
14/415 |
(3.4%) |
|
Hypermagnesemia4 |
19/971 |
(2.0%) |
2/535 |
(0.4%) |
8/415 |
(1.9%) |
|
Hypomagnesemia5 |
1/971 |
(0.1%) |
0/535 |
— |
1/415 |
(0.2%) |
|
1 Grade 3 (>3x Upper Limit of Normal); Grade 4 (>6x Upper Limit of Normal) |
|
* Serum creatinine data for all patients randomized after the 15-minute infusion amendment |
|
2 Grade 3 (<7 mg/dL); Grade 4 (<6 mg/dL) |
|
3 Grade 3 (<2 mg/dL); Grade 4 (<1 mg/dL) |
|
4 Grade 3 (>3 mEq/L); Grade 4 (>8 mEq/L) |
|
5 Grade 3 (<0.9 mEq/L); Grade 4 (<0.7 mEq/L) |
|
Table 10: Grade 4 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Three Clinical Trials in Patients with Bone Metastases |
| |
Grade 4 |
|
Laboratory Parameter |
Zometa®4 mg |
Pamidronate90 mg |
Placebo |
| |
n/N |
(%) |
n/N |
(%) |
n/N |
(%) |
|
Serum Creatinine1* |
2/529 |
(0.4%) |
1/268 |
(0.4%) |
0/241 |
— |
|
Hypocalcemia2 |
7/973 |
(0.7%) |
3/536 |
(0.6%) |
2/415 |
(0.5%) |
|
Hypophosphatemia3 |
5/973 |
(0.5%) |
0/537 |
— |
1/415 |
(0.2%) |
|
Hypermagnesemia4 |
0/971 |
— |
0/535 |
— |
2/415 |
(0.5%) |
|
Hypomagnesemia5 |
2/971 |
(0.2%) |
1/535 |
(0.2%) |
0/415 |
— |
|
1 Grade 3 (>3x Upper Limit of Normal); Grade 4 (>6x Upper Limit of Normal) |
|
* Serum creatinine data for all patients randomized after the 15-minute infusion amendment |
|
2 Grade 3 (<7 mg/dL); Grade 4 (<6 mg/dL) |
|
3 Grade 3 (<2 mg/dL); Grade 4 (<1 mg/dL) |
|
4 Grade 3 (>3 mEq/L); Grade 4 (>8 mEq/L) |
|
5 Grade 3 (<0.9 mEq/L); Grade 4 (<0.7 mEq/L) |
Among the less frequently occurring adverse events (<15% of patients), rigors, hypokalemia, influenza-like illness, and hypocalcemia showed a trend for more events with bisphosphonate administration (Zometa 4 mg and pamidronate groups) compared to the placebo group.
Less common adverse events reported more often with Zometa 4 mg than pamidronate included decreased weight, which was reported in 16% of patients in the Zometa 4-mg group compared with 9% in the pamidronate group. Decreased appetite was reported in slightly more patients in the Zometa 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 (<1.4 mg/dL) or an increase of 1.0 mg/dL for patients with an abnormal baseline creatinine (>1.4 mg/dL). The following are data on the incidence of renal deterioration in patients receiving Zometa 4 mg over 15 minutes in these trials. (See Table 11.)
|
Table 11: Percentage of Patients with Renal Function Deterioration Who Were Randomized Following the 15-Minute Infusion Amendment |
|
Patient Population/Baseline Creatinine |
|
Multiple Myeloma |
|
and Breast Cancer |
Zometa® 4 mg |
Pamidronate 90 mg |
| |
n/N |
(%) |
n/N |
(%) |
|
Normal |
27/246 |
(11%) |
23/246 |
(9.3%) |
|
Abnormal |
2/26 |
(7.7%) |
2/22 |
(9.1%) |
|
Total |
29/272 |
(10.7%) |
25/268 |
(9.3%) |
|
Solid Tumors |
Zometa® 4 mg |
Placebo |
| |
n/N |
(%) |
n/N |
(%) |
|
Normal |
17/154 |
(11%) |
10/143 |
(7%) |
|
Abnormal |
1/11 |
(9.1%) |
1/20 |
(5%) |
|
Total |
18/165 |
(10.9%) |
11/163 |
(6.7%) |
|
Prostate Cancer |
Zometa® 4 mg |
Placebo |
| |
n/N |
(%) |
n/N |
(%) |
|
Normal |
12/82 |
(14.6%) |
8/68 |
(11.8%) |
|
Abnormal |
4/10 |
(40%) |
2/10 |
(20%) |
|
Total |
16/92 |
(17.4%) |
10/78 |
(12.8%) |
The risk of deterioration in renal function appeared to be related to time on study, whether patients were receiving Zometa (4 mg over 15 minutes), placebo, or pamidronate.
Evaluation of serum creatinine is recommended prior to each cycle of therapy with Zometa. In patients receiving Zometa for multiple myeloma and bone metastases of solid tumors, who show evidence of deterioration in renal function, Zometa treatment should be withheld until serum creatinine returns to within 10% of baseline.
In the trials and in post-marketing 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 Zometa dose.
Post-Marketing Experience
Cases of osteonecrosis (primarily involving the jaws) have been reported in patients treated with bisphosphonates. The majority of the reported cases are in cancer patients attendant to a dental procedure. Osteonecrosis of the jaws has multiple well-documented risk factors including a diagnosis of cancer, concomitant therapies (e.g., chemotherapy, radiotherapy, corticosteroids) and co-morbid conditions (e.g., anemia, coagulopathies, infection, preexisting oral disease). Although causality cannot be determined, it is prudent to avoid dental surgery as recovery may be prolonged. (See PRECAUTIONS.)
DRUG INTERACTIONS
In vitro studies indicate that zoledronic acid is approximately 22% bound to plasma proteins. In vitro studies also indicate that zoledronic acid does not inhibit microsomal CYP450 enzymes. In vivo studies showed that zoledronic acid is not metabolized, and is excreted into the urine as the intact drug. However, no in vivo drug interaction studies have been performed.
Caution is advised when bisphosphonates are administered with aminoglycosides, since these agents may have an additive effect to lower serum calcium level for prolonged periods. This has not been reported in Zometa clinical trials. Caution should also be exercised when Zometa is used in combination with loop diuretics due to an increased risk of hypocalcemia. Caution is indicated when Zometa is used with other potentially nephrotoxic drugs.
In multiple myeloma patients, the risk of renal dysfunction may be increased when Zometa is used in combination with thalidomide.
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