Home – Zoledronic Acid

Zoledronic Acid

Sun Pharma Global FZE

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use zoledronic acid injection safely and effectively. See full prescribing information for zoledronic acid injection. Zoledronic Acid Injection Concentrate for Intravenous InfusionInitial U.S. Approval: 2001 RECENT MAJOR CHANGES5.6INDICATIONS AND USAGEZoledronic acid injection is a bisphosphonate indicated for the treatment of: Hypercalcemia of malignancy (1.1) Patients with multiple myeloma and patients with documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least one hormonal therapy (1.2) 1.3DOSAGE AND ADMINISTRATIONHypercalcemia of malignancy (2.1) 4 mg as a single-use intravenous infusion over no less than 15 minutes 4 mg as retreatment after a minimum of 7 days 2.2 4 mg as a single-use intravenous infusion over no less than 15 minutes every 3 to 4 weeks for patients with creatinine clearance of greater than 60 mL/min Reduce the dose for patients with renal impairment Coadminister oral calcium supplements of 500 mg and a multiple vitamin containing 400 IU of Vitamin D daily. 2.3DOSAGE FORMS AND STRENGTHS3CONTRAINDICATIONS4WARNINGS AND PRECAUTIONS Patients being treated with zoledronic acid injection should not be treated with Reclast®* (5.1) Adequately rehydrate patients with hypercalcemia of malignancy prior to administration of zoledronic acid injection and monitor electrolytes during treatment (5.2) Renal toxicity may be greater in patients with renal impairment. Do not use doses greater than 4 mg. Treatment in patients with severe renal impairment is not recommended. Monitor serum creatinine before each dose (5.3) Osteonecrosis of the jaw has been reported. Preventive dental exams should be performed before starting zoledronic acid injection. Avoid invasive dental procedures (5.4) Severe incapacitating bone, joint, muscle pain may occur. Discontinue zoledronic acid injection if severe symptoms occur (5.5) Zoledronic acid injection can cause fetal harm. Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant (5.9, 8.1) Atypical subtrochanteric and diaphyseal femoral fractures have been reported in patients receiving bisphosphonate therapy. These fractures may occur after minimal or no trauma. Evaluate patients with thigh or groin pain to rule out a femoral fracture. Consider drug discontinuation in patients suspected to have an atypical femur fracture. (5.6) Side Effects6.1To report SUSPECTED ADVERSE REACTIONS, contact CARACO Pharmaceutical Laboratories Ltd. at 1-800-818-4555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.DRUG INTERACTIONS Aminoglycosides: May have an additive effect to lower serum calcium for prolonged periods (7.1) Loop diuretics: Concomitant use with zoledronic acid injection may increase risk of hypocalcemia (7.2) Nephrotoxic drugs: Use with caution (7.3) USE IN SPECIFIC POPULATIONS Nursing Mothers: It is not known whether zoledronic acid is excreted in human milk (8.3) Pediatric Use: Not indicated for use in pediatric patients (8.4) Geriatric Use: Special care to monitor renal function (8.5)

FULL PRESCRIBING INFORMATION: CONTENTS*

1 ZOLEDRONIC ACID INDICATIONS AND USAGE
2 ZOLEDRONIC ACID DOSAGE AND ADMINISTRATION
3 DOSAGE FORMS AND STRENGTHS
4 ZOLEDRONIC ACID CONTRAINDICATIONS
- 4.1 Hypersensitivity to Zoledronic Acid or Any Components of Zoledronic Acid Injection
5 WARNINGS AND PRECAUTIONS
6 ZOLEDRONIC ACID ADVERSE REACTIONS
- 6.1 Clinical Studies Experience
- 6.2 Postmarketing Experience
7 DRUG INTERACTIONS
8 USE IN SPECIFIC POPULATIONS
10 OVERDOSAGE
11 ZOLEDRONIC ACID DESCRIPTION
12 CLINICAL PHARMACOLOGY
13 NONCLINICAL TOXICOLOGY
- 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
- 14.1 Hypercalcemia of Malignancy
- 14.2 Clinical Trials in Multiple Myeloma and Bone Metastases of Solid Tumors
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - LABEL
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - CARTON

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

1.1 Hypercalcemia of Malignancy

1.2 Multiple Myeloma and Bone Metastases of Solid Tumors

1.3 Important Limitation of Use

zoledronic acid injection

2 DOSAGE AND ADMINISTRATION

2.1 Hypercalcemia of Malignancy

no less than 15 minutes

see Warnings And Precautions (5.2)

see Warnings And Precautions (5.2)

2.2 Multiple Myeloma and Metastatic Bone Lesions of Solid Tumors

no less than 15 minutes

see Warnings And Precautions (5.2)

Table 1: Reduced Doses for Patients with Baseline CrCl less than or equal to 60 mL/min
Baseline Creatinine Clearance (mL/min)	Zoledronic Acid Injection Recommended DoseDoses calculated assuming target AUC of 0.66(mg•hr/L) (CrCl = 75 mL/min)
greater than 60	4 mg
50 to 60	3.5 mg
40 to 49	3.3 mg
30 to 39	3 mg

2.3 Preparation of Solution

4 mg/5 mL Single-Use Vial

Table 2: Preparation of Reduced Doses- Zoledronic Acid Injection Concentrate
Remove and Use Zoledronic Acid Injection Volume (mL)	Dose (mg)
4.4	3.5
4.1	3.3
3.8	3

The withdrawn concentrate must be diluted in 100 mL of sterile 0.9% Sodium Chloride, USP, or 5% Dextrose Injection, USP.

If not used immediately after dilution with infusion media, for microbiological integrity, the solution should be refrigerated at 2°C to 8°C (36°F to 46°F). The refrigerated solution should then be equilibrated to room temperature prior to administration. The total time between dilution, storage in the refrigerator, and end of administration must not exceed 24 hours.

2.4 Method of Administration

see Warnings And Precautions (5.2)

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

4.1 Hypersensitivity to Zoledronic Acid or Any Components of Zoledronic Acid Injection

see Adverse Reactions (6.2)

5 WARNINGS AND PRECAUTIONS

5.1 Drugs with Same Active Ingredient or in the Same Drug Class

^®^{5.2 Hydration and Electrolyte Monitoring
Patients with hypercalcemia of malignancy must be adequately rehydrated prior to administration of zoledronic acid injection. Loop diuretics should not be used until the patient is adequately rehydrated and should be used with caution in combination with zoledronic acid injection in order to avoid hypocalcemia. Zoledronic acid injection should be used with caution with other nephrotoxic drugs.
Standard hypercalcemia-related metabolic parameters, such as serum levels of calcium, phosphate, and magnesium, as well as serum creatinine, should be carefully monitored following initiation of therapy with zoledronic acid injection. If hypocalcemia, hypophosphatemia, or hypomagnesemia occur, short-term supplemental therapy may be necessary.
5.3 Renal Impairment

see Adverse Reactions (6.1)
.

see Clinical Pharmacology (12.3)
.5.4 Osteonecrosis of the Jaw

see Adverse Reactions (6.2)
.5.5 Musculoskeletal Pain

see Adverse Reactions (6.2)
5.6 Atypical subtrochanteric and diaphyseal femoral fractures
Atypical

5.7 Patients with Asthma

5.8 Hepatic Impairment

5.9 Use in Pregnancy

[see Use in Specific Populations (8.1)].6 ADVERSE REACTIONS
6.1 Clinical Studies Experience

Hypercalcemia of Malignancy

Renal Toxicity

see Warnings And Precautions (5) and Dosage And Administration (2)

Table 3: Percentage of Patients with Adverse Events ≥10% Reported in Hypercalcemia of Malignancy Clinical Trials by Body System

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

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)

Acute Phase Reaction

Mineral and Electrolyte Abnormalities

Table 4: 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 Injection 4 mg
Pamidronate
90 mg

n/N

(%)

n/N

(%)

Serum CreatinineGrade 3 (greater than 3x Upper Limit of Normal); Grade 4 (greater than 6x Upper Limit of Normal)

2/86

(2%)

3/100

(3%)

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

1/86

(1%)

2/100

(2%)

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

36/70

(51%)

27/81

(33%)

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

0/71

—

0/84

—

Table 5: 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 Injection 4 mg
Pamidronate
90 mg

n/N
(%)
n/N
(%)

Serum CreatinineGrade 3 (greater than 3x Upper Limit of Normal); Grade 4 (greater than 6x Upper Limit of Normal)

0/86

—

1/100

(1%)

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

0/86

—

0/100

—

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

1/70

(1%)

4/81

(5%)

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

0/71

—

1/84

(1%)

Injection Site Reactions

Ocular Adverse Events

Adverse Reactions (6.2)

Multiple Myeloma and Bone Metastases of Solid Tumors

Table 6: Percentage of Patients with Adverse Events ≥10% Reported in Three Bone Metastases Clinical Trials by Body System

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

n (%)

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)

Table 7: 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
Zoledronic Acid Injection 4 mg
Pamidronate
90 mg
Placebo

n/N
(%)
n/N
(%)
n/N
(%)

Serum CreatinineSerum creatinine data for all patients randomized after the 15-minute infusion amendment
Grade 3 (greater than 3 x Upper Limit of Normal); Grade 4 (greater than 6x Upper Limit of Normal)

7/529

(1%)

4/268

(2%)

4/241

(2%)

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

6/973

(<1%)

4/536

(<1%)

0/415

—

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

115/973

(12%)

38/537

(7%)

14/415

(3%)

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

19/971

(2%)

2/535

(<1%)

8/415

(2%)

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

1/971

(<1%)

0/535

—

1/415

(<1%)

Table 8: 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
Zoledronic Acid Injection 4 mg
Pamidronate
90 mg
Placebo

n/N

(%)

n/N

(%)

n/N

(%)

Serum CreatinineSerum creatinine data for all patients randomized after the 15-minute infusion amendment
Grade 3 (greater than 3 x Upper Limit of Normal); Grade 4 (greater than 6 x Upper Limit of Normal

2/529

(<1%)

1/268

(<1%)

0/241

—

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

7/973

(<1%)

3/536

(<1%)

2/415

(<1%)

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

5/973

(<1%)

0/537

—

1/415

(<1%)

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

0/971

—

0/535

—

2/415

(<1%)

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

2/971

(<1%)

1/535

(<1%)

0/415

—

Renal Toxicity

Table 9: Percentage of Patients with Treatment Emergent Renal Function Deterioration by Baseline Serum CreatinineTable includes only patients who were randomized to the trial after a protocol amendment that lengthened the infusion duration of zoledronic acid injection to 15 minutes.

Patient Population/Baseline Creatinine

Multiple Myeloma and Breast Cancer
Zoledronic Acid Injection 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 Injection 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 Injection 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%)

6.2 Postmarketing Experience

Osteonecrosis of the Jaw

see Warnings And Precautions (5)

Acute Phase Reaction-

Musculoskeletal Pain

see Warnings And Precautions (5 )

Atypical subtrochanteric and diaphyseal femoral fractures

see Warnings and Precautions (5.6)

Ocular Adverse Events

Hypersensitivity Reactions

CNS
:
Special Senses
:
Gastrointestinal
:
Skin
:
Musculoskeletal
:
Cardiovascular
:
Respiratory:

Renal
:
General Disorders and Administration Site
:
Laboratory Abnormalities
: 7 DRUG INTERACTIONS

In-vitro In-vitro In-vivo 7.1 Aminoglycosides

7.2 Loop Diuretics

7.3 Nephrotoxic Drugs

7.4 Thalidomide
No dose adjustment for zoledronic acid injection 4 mg is needed when coadministered with thalidomide. In a pharmacokinetic study of 24 patients with multiple myeloma, zoledronic acid injection 4 mg given as a 15 minute infusion was administered either alone or with thalidomide (100 mg once daily on days 1 to 14 and 200 mg once daily on days 15 to 28). Coadministration of thalidomide with zoledronic acid injection did not significantly change the pharmacokinetics of zoledronic acid or creatinine clearance.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy

Pregnancy Category D [see Warnings and Precaution (5.9)]

There are no adequate and well-controlled studies of zoledronic acid injection in pregnant women. Zoledronic acid injection may cause fetal harm when administered to a pregnant woman. Bisphosphonates, such as zoledronic acid injection, are incorporated into the bone matrix and are gradually released over periods of weeks to years. The extent of bisphosphonate incorporation into adult bone, and hence, the amount available for release back into the systemic circulation, is directly related to the total dose and duration of bisphosphonate use. Although there are no data on fetal risk in humans, bisphosphonates do cause fetal harm in animals, and animal data suggest that uptake of bisphosphonates into fetal bone is greater than into maternal bone. Therefore, there is a theoretical risk of fetal harm (e.g., skeletal and other abnormalities) if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on this risk has not been established. If this drug is used during pregnancy or if the patient becomes pregnant while taking or after taking this drug, the patient should be apprised of the potential hazard to the fetus.

8.3 Nursing Mothers

8.4 Pediatric Use

²

_max_(0-last)8.5 Geriatric Use

10 OVERDOSAGE

see Dosage And Administration (2.4)
11 DESCRIPTION

₅₁₀₂₇₂₂

Inactive Ingredients:
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action

In vitro12.2 Pharmacodynamics

see Dosage And Administration (2)
.12.3 Pharmacokinetics

Distribution

_max_1/2α_1/2β_1/2γ_0-24h_0-24h

In-vitro ex-vivo In vitro

Metabolism

in vitroin vivo¹⁴

Excretion

Special Populations

Pediatrics

see Pediatric Use (8.4)

Geriatrics

Race

Hepatic Insufficiency

Renal Insufficiency

^0.4_0-∞_0-24_0-∞see Warnings And Precautions (5.2)
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

in-vivo

14 CLINICAL STUDIES
14.1 Hypercalcemia of Malignancy

NOTEAdministration of zoledronic acid injection 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 injection 4 mg is given as a 15-minute intravenous infusion. Zoledronic acid injection should be administered by intravenous infusion over no less than 15 minutes [see Warnings And Precautions (5.1, 5.2) and Dosage And Administration (2.4)
].

In these studies, no additional benefit was seen for zoledronic acid injection 8 mg over zoledronic acid injection 4 mg; however, the risk of renal toxicity of zoledronic acid injection 8 mg was significantly greater than that seen with zoledronic acid injection 4 mg.

Table 10: Secondary Efficacy Variables in Pooled HCM Studies

Zoledronic Acid Injection 4 mg

Pamidronate 90 mg

Complete Response
N
Response Rate
N
Response Rate

By Day 4

86

45.3%

99

33.3%

By Day 7

86

82.6%P less than 0.05 versus pamidronate 90 mg.

99

63.6%

Duration of Response

N

Median Duration (Days)

N

Median Duration (Days)

Time to Relapse

86

30P less than 0.05 versus pamidronate 90 mg.

99

17

Duration of Complete Response

76

32

69

18

14.2 Clinical Trials in Multiple Myeloma and Bone Metastases of Solid Tumors

Table 11: Overview of Efficacy Population for Phase III Studies

Patient Population
No. of Patients
Zoledronic Acid Injection Dose
Control
Median Duration (Planned Duration) Zoledronic Acid Injection 4 mg

Multiple myeloma or metastatic breast cancer

1,648

4 and 8Patients who were randomized to the 8 mg zoledronic acid injection group are not included in any of the analyses in this package insert. mg Q3 to 4 weeks

Pamidronate 90 mg Q3 to 4 weeks

12 months (13 months)

Metastatic prostate cancer

643

4 and 8Patients who were randomized to the 8 mg zoledronic acid injection group are not included in any of the analyses in this package insert. mg Q3 weeks

Placebo

10.5 months (15 months)

Metastatic solid tumor other than breast or prostate cancer

773

4 and 8Patients who were randomized to the 8 mg zoledronic acid injection group are not included in any of the analyses in this package insert. mg Q3 weeks

Placebo

3.8 months (9 months)

Table 12: Zoledronic Acid Injection Compared to Placebo in Patients with Bone Metastases from Prostate Cancer or Other Solid Tumors

I. Analysis of Proportion of Patients with a SRESRE=Skeletal-Related Event

II. Analysis of Time to the First SRE

Study

Study Arm & Patient Number
Proportion
DifferenceDifference for the proportion of patients with a SRE of zoledronic acid injection 4 mg versus placebo. & 95% CI
P-value
Median (Days)
Hazard RatioHazard ratio for the first occurrence of a SRE of zoledronic acid injection 4 mg versus placebo. & 95% CI
P-value

Prostate Cancer

Zoledronic acid injection 4 mg (n=214)
Placebo
(n=208)

33%

44%
-11%

(-20%, -1%)
0.02

Not Reached

321

0.67

(0.49, 0.91)
0.011

Solid

Tumors

Zoledronic acid injection 4 mg (n=257)
Placebo
(n=250)

38%

44%
-7%

(-15%, 2%)
0.13

230

163
0.73

(0.55, 0.96)
0.023

Table 13: Zoledronic Acid Injection Compared to Pamidronate in Patients with Multiple Myeloma or Bone Metastases from Breast Cancer

I. Analysis of Proportion of Patients with a SRESRE=Skeletal-Related Event

II. Analysis of Time to the First SRE

Study

Study Arm & Patient Number
Proportion
DifferenceDifference for the proportion of patients with a SRE of zoledronic acid injection 4 mg versus pamidronate 90 mg. & 95% CI
P-value
Median (Days)
Hazard RatioHazard ratio for the first occurrence of a SRE of zoledronic acid injection 4 mg versus pamidronate 90 mg. & 95% CI
P-value

Multiple Myeloma &

Breast Cancer

Zoledronic acid injection 4 mg (n=561)
Pamidronate (n=555)

44%

46%
-2%
(-7.9%, 3.7%)

0.46

373

363
0.92
(0.77, 1.09)

0.32

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

Patients should be instructed to tell their doctor if they have kidney problems before being given zoledronic acid injection.
Patients should be informed of the importance of getting their blood tests (serum creatinine) during the course of their zoledronic acid injection therapy.
Zoledronic acid injection should not be given if the patient is pregnant or plans to become pregnant, or if she is breast-feeding.
Patients should be advised to have a dental examination prior to treatment with zoledronic acid injection and should avoid invasive dental procedures during treatment.
Patients should be informed of the importance of good dental hygiene and routine dental care.
Patients with multiple myeloma and bone metastasis of solid tumors should be advised to take an oral calcium supplement of 500 mg and a multiple vitamin containing 400 IU of Vitamin D daily.
Patients should be advised to report any thigh, hip or groin pain. It is unknown whether the risk of atypical femur fracture continues after stopping therapy.
Patients should be aware of the most common side effects including: anemia, nausea, vomiting, constipation, diarrhea, fatigue, fever, weakness, lower limb edema, anorexia, decreased weight, bone pain, myalgia, arthralgia, back pain, malignant neoplasm aggravated, headache, dizziness, insomnia, paresthesia, dyspnea, cough, and abdominal pain.
There have been reports of bronchoconstriction in aspirin-sensitive patients receiving bisphosphonates, including zoledronic acid. Before being given zoledronic acid, patients should tell their doctor if they are aspirin-sensitive.

Caraco Pharmaceutical Laboratories, Ltd.

Sun Pharmaceutical Ind. Ltd.

PJPI0320
ISS. 12/2012
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - LABEL

NDC 47335-035-40
Zoledronic Acid Injection
4 mg/5mL (0.8 mg/mL)
Concentrate for Intravenous Infusion
Not for direct injection
Dose must be diluted.
Rx only
5 mL Sterile Single-Use Vial
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - CARTON

NDC 47335-035-40
Zoledronic Acid Injection
4 mg/5 mL (0.8 mg/mL)
Concentrate for Intravenous Infusion
Sterile Concentrate
Not for direct injection.
Dose must be diluted.
Do not mix with calcium-containing infusion solutions.
See package insert for Preparation of Solution.
Rx only
One 5 mL Single-Use Vial
SUN PHARMA

Zoledronic Acid

Zoledronic Acid INJECTION, SOLUTION, CONCENTRATE

Product Information

Product Type

Human prescription drug label

Item Code (Source)

NDC:47335-035

Route of Administration

INTRAVENOUS

DEA Schedule

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Strength

ZOLEDRONIC ACID ZOLEDRONIC ACID ANHYDROUS

4 mg

Inactive Ingredients

Ingredient Name

Strength

mannitol

SODIUM CITRATE

water

Packaging

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

5 in 1 VIAL

2

NDC:47335-035-40

1 in 1 CARTON

Marketing Information

Marketing Category

Application Number or Monograph Citation

Marketing Start Date

Marketing End Date

ANDA

ANDA202746

2013-03-04}

Table 3: Percentage of Patients with Adverse Events ≥10% Reported in Hypercalcemia of Malignancy Clinical Trials by Body System
Patients Studied	Zoledronic Acid Injection 4 mg n (%)	Pamidronate 90 mg n (%)
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)

Table 4: Grade 3 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Two Clinical Trials in Patients with HCM
	Grade 3
	n/N	(%)	n/N	(%)
Serum CreatinineGrade 3 (greater than 3x Upper Limit of Normal); Grade 4 (greater than 6x Upper Limit of Normal)	2/86	(2%)	3/100	(3%)
HypocalcemiaGrade 3 (less than 7 mg/dL); Grade 4 (less than 6 mg/dL)	1/86	(1%)	2/100	(2%)
HypophosphatemiaGrade 3 (less than 2 mg/dL); Grade 4 (less than 1 mg/dL)	36/70	(51%)	27/81	(33%)
HypomagnesemiaGrade 3 (less than 0.8 mEq/L); Grade 4 (less than 0.5 mEq/L)	0/71	—	0/84	—

Table 5: Grade 4 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Two Clinical Trials in Patients with HCM
	Grade 4
Serum CreatinineGrade 3 (greater than 3x Upper Limit of Normal); Grade 4 (greater than 6x Upper Limit of Normal)	0/86	—	1/100	(1%)
HypocalcemiaGrade 3 (less than 7 mg/dL); Grade 4 (less than 6 mg/dL)	0/86	—	0/100	—
HypophosphatemiaGrade 3 (less than 2 mg/dL); Grade 4 (less than 1 mg/dL)	1/70	(1%)	4/81	(5%)
HypomagnesemiaGrade 3 (less than 0.8 mEq/L); Grade 4 (less than 0.5 mEq/L)	0/71	—	1/84	(1%)

Table 6: Percentage of Patients with Adverse Events ≥10% Reported in Three Bone Metastases Clinical Trials by Body System
Patients Studied	Zoledronic Acid Injection 4 mg n (%)	Pamidronate 90 mg n (%)	Placebo n (%)
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)

Table 7: 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
Serum CreatinineSerum creatinine data for all patients randomized after the 15-minute infusion amendment Grade 3 (greater than 3 x Upper Limit of Normal); Grade 4 (greater than 6x Upper Limit of Normal)	7/529	(1%)	4/268	(2%)	4/241	(2%)
HypocalcemiaGrade 3 (less than 7 mg/dL); Grade 4 (less than 6 mg/dL)	6/973	(<1%)	4/536	(<1%)	0/415	—
HypophosphatemiaGrade 3 (less than 2 mg/dL); Grade 4 (less than 1 mg/dL)	115/973	(12%)	38/537	(7%)	14/415	(3%)
HypermagnesemiaGrade 3 (greater than 3 mEq/L); Grade 4 (greater than 8 mEq/L)	19/971	(2%)	2/535	(<1%)	8/415	(2%)
HypomagnesemiaGrade 3 (less than 0.9 mEq/L); Grade 4 (less than 0.7 mEq/L)	1/971	(<1%)	0/535	—	1/415	(<1%)

Table 8: 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
	n/N	(%)	n/N	(%)	n/N	(%)
Serum CreatinineSerum creatinine data for all patients randomized after the 15-minute infusion amendment Grade 3 (greater than 3 x Upper Limit of Normal); Grade 4 (greater than 6 x Upper Limit of Normal	2/529	(<1%)	1/268	(<1%)	0/241	—
HypocalcemiaGrade 3 (less than 7 mg/dL); Grade 4 (less than 6 mg/dL)	7/973	(<1%)	3/536	(<1%)	2/415	(<1%)
HypophosphatemiaGrade 3 (less than 2 mg/dL); Grade 4 (less than 1 mg/dL)	5/973	(<1%)	0/537	—	1/415	(<1%)
HypermagnesemiaGrade 3 (greater than 3 mEq/L); Grade 4 (greater than 8 mEq/L)	0/971	—	0/535	—	2/415	(<1%)
HypomagnesemiaGrade 3 (less than 0.9 mEq/L); Grade 4 (less than 0.7 mEq/L)	2/971	(<1%)	1/535	(<1%)	0/415	—

Table 9: Percentage of Patients with Treatment Emergent Renal Function Deterioration by Baseline Serum CreatinineTable includes only patients who were randomized to the trial after a protocol amendment that lengthened the infusion duration of zoledronic acid injection to 15 minutes.
Patient Population/Baseline Creatinine
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 Injection 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 Injection 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 10: Secondary Efficacy Variables in Pooled HCM Studies
		Zoledronic Acid Injection 4 mg		Pamidronate 90 mg
By Day 4	86	45.3%	99	33.3%
By Day 7	86	82.6%P less than 0.05 versus pamidronate 90 mg.	99	63.6%
Duration of Response	N	Median Duration (Days)	N	Median Duration (Days)
Time to Relapse	86	30P less than 0.05 versus pamidronate 90 mg.	99	17
Duration of Complete Response	76	32	69	18

Table 11: Overview of Efficacy Population for Phase III Studies
Patient Population	No. of Patients	Zoledronic Acid Injection Dose	Control	Median Duration (Planned Duration) Zoledronic Acid Injection 4 mg
Multiple myeloma or metastatic breast cancer	1,648	4 and 8Patients who were randomized to the 8 mg zoledronic acid injection group are not included in any of the analyses in this package insert. mg Q3 to 4 weeks	Pamidronate 90 mg Q3 to 4 weeks	12 months (13 months)
Metastatic prostate cancer	643	4 and 8Patients who were randomized to the 8 mg zoledronic acid injection group are not included in any of the analyses in this package insert. mg Q3 weeks	Placebo	10.5 months (15 months)
Metastatic solid tumor other than breast or prostate cancer	773	4 and 8Patients who were randomized to the 8 mg zoledronic acid injection group are not included in any of the analyses in this package insert. mg Q3 weeks	Placebo	3.8 months (9 months)

Table 12: Zoledronic Acid Injection Compared to Placebo in Patients with Bone Metastases from Prostate Cancer or Other Solid Tumors
	I. Analysis of Proportion of Patients with a SRESRE=Skeletal-Related Event	II. Analysis of Time to the First SRE
Prostate Cancer	Zoledronic acid injection 4 mg (n=214) Placebo (n=208)	33% 44%	-11% (-20%, -1%)	0.02	Not Reached 321	0.67 (0.49, 0.91)	0.011
Solid Tumors	Zoledronic acid injection 4 mg (n=257) Placebo (n=250)	38% 44%	-7% (-15%, 2%)	0.13	230 163	0.73 (0.55, 0.96)	0.023

Table 13: Zoledronic Acid Injection Compared to Pamidronate in Patients with Multiple Myeloma or Bone Metastases from Breast Cancer
	I. Analysis of Proportion of Patients with a SRESRE=Skeletal-Related Event	II. Analysis of Time to the First SRE
Multiple Myeloma & Breast Cancer	Zoledronic acid injection 4 mg (n=561) Pamidronate (n=555)	44% 46%	-2% (-7.9%, 3.7%)	0.46	373 363	0.92 (0.77, 1.09)	0.32

PLEASE, BE CAREFUL!

Be sure to consult your doctor before taking any medication!

	Grade 3
Laboratory Parameter	Zoledronic Acid Injection 4 mg		Pamidronate 90 mg
	n/N	(%)	n/N	(%)
Serum CreatinineGrade 3 (greater than 3x Upper Limit of Normal); Grade 4 (greater than 6x Upper Limit of Normal)	2/86	(2%)	3/100	(3%)
HypocalcemiaGrade 3 (less than 7 mg/dL); Grade 4 (less than 6 mg/dL)	1/86	(1%)	2/100	(2%)
HypophosphatemiaGrade 3 (less than 2 mg/dL); Grade 4 (less than 1 mg/dL)	36/70	(51%)	27/81	(33%)
HypomagnesemiaGrade 3 (less than 0.8 mEq/L); Grade 4 (less than 0.5 mEq/L)	0/71	—	0/84	—

	Grade 4
Laboratory Parameter	Zoledronic Acid Injection 4 mg		Pamidronate 90 mg
	n/N	(%)	n/N	(%)
Serum CreatinineGrade 3 (greater than 3x Upper Limit of Normal); Grade 4 (greater than 6x Upper Limit of Normal)	0/86	—	1/100	(1%)
HypocalcemiaGrade 3 (less than 7 mg/dL); Grade 4 (less than 6 mg/dL)	0/86	—	0/100	—
HypophosphatemiaGrade 3 (less than 2 mg/dL); Grade 4 (less than 1 mg/dL)	1/70	(1%)	4/81	(5%)
HypomagnesemiaGrade 3 (less than 0.8 mEq/L); Grade 4 (less than 0.5 mEq/L)	0/71	—	1/84	(1%)

Patient Population/Baseline Creatinine
Multiple Myeloma and Breast Cancer	Zoledronic Acid Injection 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 Injection 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 Injection 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%)

		Zoledronic Acid Injection 4 mg		Pamidronate 90 mg
Complete Response	N	Response Rate	N	Response Rate
By Day 4	86	45.3%	99	33.3%
By Day 7	86	82.6%P less than 0.05 versus pamidronate 90 mg.	99	63.6%
Duration of Response	N	Median Duration (Days)	N	Median Duration (Days)
Time to Relapse	86	30P less than 0.05 versus pamidronate 90 mg.	99	17
Duration of Complete Response	76	32	69	18

	I. Analysis of Proportion of Patients with a SRESRE=Skeletal-Related Event				II. Analysis of Time to the First SRE
Study	Study Arm & Patient Number	Proportion	DifferenceDifference for the proportion of patients with a SRE of zoledronic acid injection 4 mg versus placebo. & 95% CI	P-value	Median (Days)	Hazard RatioHazard ratio for the first occurrence of a SRE of zoledronic acid injection 4 mg versus placebo. & 95% CI	P-value
Prostate Cancer	Zoledronic acid injection 4 mg (n=214) Placebo (n=208)	33% 44%	-11% (-20%, -1%)	0.02	Not Reached 321	0.67 (0.49, 0.91)	0.011
Solid Tumors	Zoledronic acid injection 4 mg (n=257) Placebo (n=250)	38% 44%	-7% (-15%, 2%)	0.13	230 163	0.73 (0.55, 0.96)	0.023

Zoledronic Acid description, usages, side effects, indications, overdosage, supplying and lots more!

Zoledronic Acid

FULL PRESCRIBING INFORMATION: CONTENTS*

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

1.1 Hypercalcemia of Malignancy

1.2 Multiple Myeloma and Bone Metastases of Solid Tumors

1.3 Important Limitation of Use

2 DOSAGE AND ADMINISTRATION

2.1 Hypercalcemia of Malignancy

2.2 Multiple Myeloma and Metastatic Bone Lesions of Solid Tumors

2.3 Preparation of Solution

2.4 Method of Administration

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

4.1 Hypersensitivity to Zoledronic Acid or Any Components of Zoledronic Acid Injection

5 WARNINGS AND PRECAUTIONS

5.1 Drugs with Same Active Ingredient or in the Same Drug Class

5.2 Hydration and Electrolyte Monitoring

5.3 Renal Impairment

5.4 Osteonecrosis of the Jaw

5.5 Musculoskeletal Pain

5.6 Atypical subtrochanteric and diaphyseal femoral fractures

5.7 Patients with Asthma

5.8 Hepatic Impairment

5.9 Use in Pregnancy

6 ADVERSE REACTIONS

6.1 Clinical Studies Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 Aminoglycosides

7.2 Loop Diuretics

7.3 Nephrotoxic Drugs

7.4 Thalidomide

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

14.1 Hypercalcemia of Malignancy

14.2 Clinical Trials in Multiple Myeloma and Bone Metastases of Solid Tumors

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - LABEL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - CARTON

Zoledronic Acid

Product Information

Active Ingredient/Active Moiety

Inactive Ingredients

Packaging

Marketing Information