Home > Drugs A-Z > Pamidronate Disodium

Pamidronate Disodium (Teva Parenteral Medicines, Inc.)

Available Formats

Dosage Form Package Information Links
INJECTION, SOLUTION 1 VIAL, SINGLE-DOSE in 1 CARTON (0703-4075-51) > 10 mL in 1 VIAL, SINGLE-DOSE Label Information

Complete Pamidronate Disodium Information

  • HIGHLIGHTS OF PRESCRIBING INFORMATION
    These highlights do not include all the information needed to use pamidronate disodium injection safely and effectively. See full prescribing information for pamidronate disodium injection.

    PAMIDRONATE DISODIUM injection, for intravenous use

    Initial U.S. Approval: 1991

    INDICATIONS AND USAGE

    Pamidronate disodium injection is a bisphosphonate indicated for the treatment of:

    • moderate or severe hypercalcemia associated with malignancy, with or without bone metastases ( 1.1)
    • patients with moderate to severe Paget’s disease of bone ( 1.2)
    • osteolytic bone metastases of breast cancer or osteolytic lesions of multiple myeloma, in conjunction with standard antineoplastic therapy ( 1.3)

    Limitations of use

    Safety and efficacy of pamidronate disodium injection in the treatment of hypercalcemia associated with hyperparathyroidism or with other non-tumor-related conditions have not been established. (1.4)

    DOSAGE AND ADMINISTRATION

    • Hypercalcemia of malignancy: 60 mg to 90 mg pamidronate disodium injection as a single dose infused over 2 hours to 24 hours for moderate hypercalcemia, or 90 mg as a single dose infused over 2 hours to 24 hours for severe hypercalcemia. If warranted, retreat after a minimum of 7 days. ( 2.1)
    • Paget’s disease of bone: 30 mg pamidronate disodium injection daily as a 4-hour infusion on 3 consecutive days. ( 2.2)
    • Osteolytic Bone Metastases of Breast Cancer: 90 mg pamidronate disodium injection as a 2-hour infusion every 3 to 4 weeks. Retreat after recovery of renal function. ( 2.3)
    • Osteolytic Bone Lesions of Multiple Myeloma: 90 mg pamidronate disodium injection as a 4-hour infusion once every four weeks. Retreat after recovery of renal function. ( 2.3)
    • Administer through a separate infusion line. Do not allow pamidronate disodium injection infusion to come in contact with any calcium or divalent cation-containing solutions. ( 2.8)

    DOSAGE FORMS AND STRENGTHS

    • Injection: 30 mg/10 mL solution in single-use vial ( 3)
    • Injection: 90 mg/10 mL solution in single-use vial ( 3)

    CONTRAINDICATIONS

    Hypersensitivity to pamidronate, other bisphosphonates, or mannitol (4)

    WARNINGS AND PRECAUTIONS

    • Renal failure: Do not exceed single doses of 90 mg pamidronate disodium. Assess renal function before each treatment. In patients with bone metastases with severe renal impairment, use of pamidronate disodium is not recommended. ( 5.1)
    • Embryo-Fetal Toxicity: May cause fetal harm. Advise females of the potential risk to a fetus and to avoid pregnancy. ( 5.2)
    • Electrolyte disorders (e.g., hypophosphatemia, hypokalemia, hypomagnesemia, hypocalcemia): Monitor phosphorus, potassium, magnesium, calcium and vitamin D and adequately supplement as appropriate. ( 5.3)
    • Osteonecrosis of the jaw: Perform preventive dental procedures prior to initiating pamidronate disodium. Avoid invasive procedures if possible in patients receiving pamidronate disodium. ( 5.4)
    • Atypical fractures of the femur can occur after minimal or no trauma. Evaluate patients with thigh or groin pain for possible fracture. ( 5.5)

    ADVERSE REACTIONS

    Most common adverse reactions per indication:

    • Hypercalcemia of malignancy (≥15%): Fever, nausea, infusion site reactions, hypocalcemia, hypophosphatemia ( 6.1)
    • Paget’s disease (≥10%): Temperature increase, hypertension, arthrosis, bone pain, headache ( 6.1)
    • Osteolytic bone metastases of breast cancer or osteolytic lesions of multiple myeloma (≥30%): Skeletal pain, nausea, anemia, fever, fatigue, vomiting, dyspnea ( 6.1)

    To report SUSPECTED ADVERSE REACTIONS, contact TEVA USA, PHARMACOVIGILANCE at 1-866-832-8537 or drug.safety@tevapharm.com; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

    DRUG INTERACTIONS

    • Nephrotoxic drugs: Use with caution. ( 7.1)
    • Thalidomide: Increased risk of renal dysfunction in patients with multiple myeloma. ( 7.2)

    See 17 for PATIENT COUNSELING INFORMATION.

    Revised: 2/2015


  • FULL PRESCRIBING INFORMATION: CONTENTS*

    1 INDICATIONS AND USAGE

    1.1 Hypercalcemia of Malignancy 1.2 Paget’s Disease 1.3 Osteolytic Bone Metastases of Breast Cancer and Osteolytic Lesions of Multiple Myeloma 1.4 Limitations of Use

    2 DOSAGE AND ADMINISTRATION

    2.1 Hypercalcemia of Malignancy 2.2 Paget’s Disease 2.3 Osteolytic Bone Metastases of Breast Cancer and Osteolytic Lesions of Multiple Myeloma 2.5 Dilution for Administration 2.6 Incompatibilities, Inspection before Use

    3 DOSAGE FORMS AND STRENGTHS

    4 CONTRAINDICATIONS

    5 WARNINGS AND PRECAUTIONS

    5.1 Deterioration in Renal Function, Use in Patients with Renal Impairment 5.2 Embryo-Fetal Toxicity 5.3 Electrolyte Disorders 5.4 Osteonecrosis of the Jaw 5.5 Atypical Fractures of the Femur

    6 ADVERSE REACTIONS

    6.1 Clinical Trials Experience 6.2 Postmarketing Experience

    7 DRUG INTERACTIONS

    7.1 Nephrotoxic Drugs 7.2 Thalidomide 7.3 Loop Diuretics

    8 USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Females of Reproductive Potential 8.7 Patients with Renal Impairment 8.8 Patients with Hepatic Impairment

    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 13.2 Animal Toxicology and/or Pharmacology

    14 CLINICAL STUDIES

    14.1 Hypercalcemia of Malignancy 14.2 Paget’s Disease 14.3 Osteolytic Bone Metastases of Breast Cancer and Osteolytic Lesions of Multiple Myeloma

    16 HOW SUPPLIED/STORAGE AND HANDLING

    17 PATIENT COUNSELING INFORMATION

    Pamidronate Disodium Injection 30 mg/10 mL, Single-Use Vial, Carton Text Pamidronate Disodium Injection 90 mg/10 mL, Single-Use Vial, Carton Text
    *
    • Sections or subsections omitted from the full prescribing information are not listed.

  • 1 INDICATIONS AND USAGE

    1.1 Hypercalcemia of Malignancy

    Pamidronate disodium injection is indicated for the treatment of moderate or severe hypercalcemia associated with malignancy, with or without bone metastases.

    1.2 Paget’s Disease

    Pamidronate disodium injection is indicated for the treatment of patients with moderate to severe Paget’s disease of bone.

    1.3 Osteolytic Bone Metastases of Breast Cancer and Osteolytic Lesions of Multiple Myeloma

    Pamidronate disodium injection is indicated in conjunction with standard antineoplastic therapy, for the treatment of osteolytic bone metastases of breast cancer and osteolytic lesions of multiple myeloma [see Clinical Studies (14.3)].

    1.4 Limitations of Use

    The safety and efficacy of pamidronate disodium injection in the treatment of hypercalcemia associated with hyperparathyroidism or with other non-tumor-related conditions has not been established.


  • 2 DOSAGE AND ADMINISTRATION

    2.1 Hypercalcemia of Malignancy

    Vigorous saline hydration, should be initiated promptly along with pamidronate therapy and if possible the urine output should be about 2 L/day throughout treatment [see Warnings and Precautions (5.2)].

    Patients who receive pamidronate disodium injection should have serum creatinine assessed prior to each treatment [see Warnings and Precautions (5.1)]. Treatment should be withheld for renal deterioration.

    Moderate Hypercalcemia

    The recommended dose of pamidronate disodium injection in moderate hypercalcemia (corrected serum calcium* of approximately 12 mg/dL to 13.5 mg/dL) is 60 mg to 90 mg given as a single-dose, intravenous infusion over 2 hours to 24 hours. Longer infusions (i.e., greater than 2 hours) may reduce the risk for renal toxicity, particularly in patients with preexisting renal impairment.

    Severe Hypercalcemia

    The recommended dose of pamidronate disodium injection in severe hypercalcemia (corrected serum calcium* >13.5 mg/dL) is 90 mg given as a single-dose, intravenous infusion over 2 to 24 hours. Longer infusions (i.e., greater than 2 hours) may reduce the risk for renal toxicity, particularly in patients with preexisting renal insufficiency/impairment.

    *Albumin-corrected serum calcium = serum calcium, mg/dL + 0.8 (4-serum albumin, g/dL).

    Retreatment

    Retreatment with pamidronate disodium injection in patients who show complete or partial response initially may be carried out if serum calcium does not return to normal or remain normal after initial treatment. A minimum of 7 days between treatments is recommended to allow for full response to the initial dose. The dose and manner of retreatment is identical to that of the initial therapy.

    2.2 Paget’s Disease

    The recommended dose of pamidronate disodium injection in patients with moderate to severe Paget’s disease of bone is 30 mg daily, administered as a 4-hour infusion on 3 consecutive days for a total dose of 90 mg. When clinically indicated, patients should be retreated at the dose of initial therapy.

    2.3 Osteolytic Bone Metastases of Breast Cancer and Osteolytic Lesions of Multiple Myeloma

    Osteolytic Bone Metastases of Breast Cancer

    The recommended dose of pamidronate disodium injection in patients with osteolytic bone metastases is 90 mg administered over a 2-hour infusion given every 3 to 4 weeks.

    In a clinical study, renal deterioration was defined as follows:

    • With normal baseline creatinine, an increase of 0.5 mg/dL.
    • With abnormal baseline creatinine, an increase of 1 mg/dL.

    In this clinical study, pamidronate disodium treatment was resumed only when the creatinine returned to within 10% of the baseline value.

    The optimal duration of therapy is not known; however, in two breast cancer studies, final analyses performed after 24 months of therapy demonstrated overall benefits [see Clinical Studies (14.3)].

    Osteolytic Bone Lesions of Multiple Myeloma

    The recommended dose of pamidronate disodium injection in patients with osteolytic bone lesions of multiple myeloma is 90 mg administered as a 4-hour infusion administered every four weeks.

    Patients with marked Bence-Jones proteinuria and dehydration should receive adequate hydration prior to pamidronate disodium injection infusion.

    Limited information is available on the use of pamidronate disodium injection in multiple myeloma patients with a serum creatinine greater than or equal to 3 mg/dL.

    Patients who receive pamidronate disodium injection should have serum creatinine assessed prior to each treatment. Treatment should be withheld for renal deterioration.

    In a clinical study, renal deterioration was defined as follows:

    • With normal baseline creatinine, an increase of 0.5 mg/dL.
    • With abnormal baseline creatinine, an increase of 1 mg/dL.

    In this clinical study, pamidronate disodium treatment was resumed only when the creatinine returned to within 10% of the baseline value.

    The optimal duration of therapy is not known. However, in a study of patients with myeloma, final analysis after 21 months demonstrated overall benefits [see Clinical Studies (14.3)].

    2.5 Dilution for Administration

    Hypercalcemia of Malignancy

    The daily dose must be administered as an intravenous infusion over at least 2 hours and up to 24 hours for the 60 mg and 90 mg doses. The recommended dose should be diluted in 1000 mL of sterile 0.45% or 0.9% sodium chloride injection or 5% dextrose injection. This infusion solution is stable for up to 24 hours at room temperature.

    Paget’s Disease

    The recommended daily dose of 30 mg should be diluted in 500 mL of sterile 0.45% or 0.9% sodium chloride injection, or 5% dextrose injection and administered over a 4-hour period daily for 3 consecutive days.

    Osteolytic Bone Metastases of Breast Cancer

    The recommended dose of 90 mg should be diluted in 250 mL of sterile 0.45% or 0.9% sodium chloride injection or 5% dextrose injection and administered over a 2-hour period once every 3 to 4 weeks.

    Osteolytic Bone Lesions of Multiple Myeloma

    The recommended dose of 90 mg should be diluted in 500 mL of sterile 0.45% or 0.9% sodium chloride injection, or 5% dextrose injection, and administered over a 4-hour period every four weeks.

    2.6 Incompatibilities, Inspection before Use

    Pamidronate disodium injection must not be mixed with calcium-containing infusion solutions such as Ringer’s solution. Administer as a single intravenous solution and infuse using an intravenous line reserved for pamidronate alone.

    Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.


  • 3 DOSAGE FORMS AND STRENGTHS

    Injection: 30 mg/10 mL solution in single-use vial

    Injection: 90 mg/10 mL solution in single-use vial


  • 4 CONTRAINDICATIONS

    Pamidronate disodium is contraindicated in patients with hypersensitivity to pamidronate disodium, other bisphosphonates, or mannitol. Reactions to pamidronate disodium injection and to mannitol have included anaphylaxis.


  • 5 WARNINGS AND PRECAUTIONS

    5.1 Deterioration in Renal Function, Use in Patients with Renal Impairment

    Bisphosphonates, such as pamidronate disodium, have been associated with renal toxicity, including focal segmental glomerulosclerosis. This toxicity has been manifested as nephritic syndrome, deterioration of renal function, and renal failure. Renal failure has been reported in patients after a single dose of pamidronate disodium. Some patients had gradual improvement in renal status after pamidronate disodium was discontinued.

    Do not administer single doses of pamidronate disodium in excess of 90 mg due to the risk of clinically significant deterioration in renal function, [see Dosage and Administration (2.5)].

    Assess serum creatinine prior to each treatment. Withhold treatment until renal function returns to baseline in patients who show evidence of deterioration in renal function. Do not administer pamidronate in patients with severe renal impairment for the treatment of bone metastases [see Dosage and Administration (2.1, 2.2, 2.3)].

    5.2 Embryo-Fetal Toxicity

    Bisphosphonates, such as pamidronate disodium, are incorporated into the bone matrix, and gradually released over periods of weeks to years. Pamidronate disodium may cause fetal harm when administered to a pregnant woman. In reproductive studies in rats and rabbits, pamidronate doses equivalent to 0.6 to 8.3 times the highest human recommended dose resulted in maternal toxicity and embryo/fetal effects.

    There are no adequate and well-controlled studies of pamidronate disodium in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus [see Use in Specific Populations (8.1)].

    5.3 Electrolyte Disorders

    Cases of asymptomatic hypophosphatemia (12%), hypokalemia (7%), hypomagnesemia (11%), and hypocalcemia (5% to 17%), were reported in pamidronate disodium-treated patients. Rare cases of symptomatic hypocalcemia (including tetany) have been reported in association with pamidronate disodium therapy. Monitor serum levels of calcium, phosphate, magnesium, and potassium, following initiation of therapy with pamidronate disodium. If hypocalcemia occurs, short-term calcium therapy may be necessary. In the absence of hypercalcemia, supplement with oral calcium and vitamin D in order to minimize the risk of hypocalcemia.

    5.4 Osteonecrosis of the Jaw

    Osteonecrosis of the jaw (ONJ) has been reported predominantly in cancer patients treated with intravenous bisphosphonates, including pamidronate disodium. Many of these patients were also receiving chemotherapy and corticosteroids, which may be risk factors for ONJ. Postmarketing experience and the literature suggest a greater frequency of ONJ with certain tumor type (advanced breast cancer, multiple myeloma), and dental status (dental extraction, periodontal disease, local trauma including poorly fitting dentures). Local infection including osteomyelitis has been reported with ONJ.

    Patients receiving pamidronate should maintain good oral hygiene and have a dental examination with preventive dentistry prior to initiation of treatment.

    While on treatment, avoid invasive dental procedures if possible. For patients who develop ONJ while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of ONJ. Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment [see Adverse Reactions (6.2)].

    5.5 Atypical Fractures of the Femur

    Atypical subtrochanteric and diaphyseal femoral fractures have been reported in patients receiving bisphosphonate therapy, including pamidronate disodium. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to just above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution. These fractures may occur after minimal or no trauma. Patients may experience thigh or groin pain weeks to months before presenting with a completed femoral fracture. Fractures are often bilateral; therefore, the contralateral femur should be examined in bisphosphonate-treated patients who have sustained a femoral shaft fracture. Poor healing of these fractures also has been reported. A number of case reports noted that patients were receiving treatment also with glucocorticoids (such as prednisone or dexamethasone) at the time of fracture. Causality with bisphosphonate therapy has not been established.

    Any patient with a history of bisphosphonate exposure who presents with thigh or groin pain in the absence of trauma should be evaluated for an atypical fracture. Consider discontinuation of pamidronate disodium therapy in patients suspected to have an atypical femur fracture pending evaluation of the patient, based on an individual benefit risk assessment. It is unknown whether the risk of atypical femur fracture continues after stopping therapy.


  • 6 ADVERSE REACTIONS

    The following adverse reactions are described, or described in greater detail, in other sections:

    -
    • Deterioration in renal function [see Warnings and Precautions (5.1)]
    -
    • Electrolyte disorders [see Warnings and Precautions (5.3)]
    -
    • Osteonecrosis of the jaw [see Warnings and Precautions (5.4)]
    -
    • Atypical fractures of the femur [see Warnings and Precautions (5.5)]

    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

    Transient mild elevation of temperature by at least 1°C was noted 24 to 48 hours after administration of pamidronate disodium in 34% of patients in clinical trials. Local soft-tissue reactions (redness, swelling or induration and pain on palpation) at the site of catheter insertion were observed, most commonly in patients treated with 90 mg of pamidronate disodium. Symptomatic treatment resulted in rapid resolution in all patients.

    Rare cases of uveitis, iritis, scleritis, and episcleritis have been reported, including one case of scleritis and one case of uveitis upon separate rechallenges.

    Five of 231 patients (2%) who received pamidronate disodium while enrolled on controlled clinical trials for management of hypercalcemia were reported to have seizures, including two patients with pre-existing seizure disorders. One patient on the control (saline arm) also had a seizure. At least 15% of patients treated with pamidronate disodium for hypercalcemia of malignancy experienced the following adverse reactions during a clinical trial:

    General: Fluid overload, generalized pain

    Cardiovascular: Hypertension

    Gastrointestinal: Abdominal pain, anorexia, constipation, nausea, vomiting

    Genitourinary: Urinary tract infection

    Musculoskeletal: Bone pain

    Laboratory abnormality: Anemia, hypokalemia, hypomagnesemia, hypophosphatemia

    Table 1 lists the adverse reactions reported during comparative, controlled trials.

    Table 1 Adverse Reactions Reported in Three U.S. Controlled Clinical Trials

    Percent of Patients
    Pamidronate Disodium Etidronate Disodium Saline
    60 mg 60 mg 90 mg 7.5 mg/kg
    over 4 hr over 24 hr over 24 hr x 3 days
    n=23 n=73 n=17 n=35 n=23

    General

    Edema

    0

    1

    0

    0

    0

    Fatigue

    0

    0

    12

    0

    0

    Fever

    26

    19

    18

    9

    0

    Infusion-site reaction

    0

    4

    18

    0

    0

    Moniliasis

    0

    0

    6

    0

    0

    Gastrointestinal

    Abdominal pain

    0

    1

    0

    0

    0

    Anorexia

    4

    1

    12

    0

    0

    Constipation

    4

    0

    6

    3

    0

    Diarrhea

    0

    1

    0

    0

    0

    Dyspepsia

    4

    0

    0

    0

    0

    Gastrointestinal hemorrhage

    0

    0

    6

    0

    0

    Nausea

    4

    0

    18

    6

    0

    Stomatitis

    0

    1

    0

    3

    0

    Vomiting

    4

    0

    0

    0

    0

    Respiratory

    Rales

    0

    0

    6

    0

    0

    Rhinitis

    0

    0

    6

    0

    0

    Upper respiratory infection

    0

    3

    0

    0

    0

    CNS

    Insomnia

    0

    1

    0

    0

    0

    Psychosis

    4

    0

    0

    0

    0

    Somnolence

    0

    1

    6

    0

    0

    Cardiovascular

    Atrial fibrillation

    0

    0

    6

    0

    4

    Atrial flutter

    0

    1

    0

    0

    0

    Cardiac failure

    0

    1

    0

    0

    0

    Hypertension

    0

    0

    6

    0

    4

    Syncope

    0

    0

    6

    0

    0

    Tachycardia

    0

    0

    6

    0

    4

    Endocrine

    Hypothyroidism

    0

    0

    6

    0

    0

    Hemic and Lymphatic

    Anemia

    0

    0

    6

    0

    0

    Leukopenia

    4

    0

    0

    0

    0

    Neutropenia

    0

    1

    0

    0

    0

    Thrombocytopenia

    0

    1

    0

    0

    0

    Musculoskeletal

    Myalgia

    0

    1

    0

    0

    0

    Urogenital

    Uremia

    4

    0

    0

    0

    0

    Laboratory Abnormalities

    Hypocalcemia

    0

    1

    12

    0

    0

    Hypokalemia

    4

    4

    18

    0

    0

    Hypomagnesemia

    4

    10

    12

    3

    4

    Hypophosphatemia

    0

    9

    18

    3

    0

    Paget’s Disease

    Adverse reactions that occurred in at least 5% of patients with Paget’s disease treated with 90 mg of pamidronate disodium in two clinical trials included fever, nausea, back pain, and bone pain. Dizziness, headaches, parathesias, and increased sweating were also reported and occurred more frequently than reported in patients treated with pamidronate for hypercalcemia of malignancy.

    At least 10% of all pamidronate disodium-treated patients with Paget’s disease also experienced the following adverse reactions during clinical trials:

    Cardiovascular: Hypertension

    Musculoskeletal: Arthrosis, bone pain

    Nervous system: Headache

    Osteolytic Bone Metastases of Breast Cancer and Osteolytic Lesions of Multiple Myeloma

    The most commonly reported (>15%) adverse reactions occurred with similar frequencies in the pamidronate disodium and in the placebo group (see Table 2).

    Table 2 Commonly Reported Adverse Reactions in Three U.S. Controlled Clinical Trials

    Pamidronate Disodium 90 mg over 4 hours Placebo Pamidronate Disodium 90 mg over 2 hours Placebo All Pamidronate Disodium 90 mg Placebo
    N=205 N=187 N=367 N=386 N=572 N=573
    % % % % % %

    General

    Asthenia

    16

    17

    26

    19

    22

    19

    Fatigue

    32

    28

    40

    29

    37

    29

    Fever

    39

    38

    38

    32

    39

    34

    Metastases

    1

    3

    31

    24

    21

    18

    Pain

    13

    12

    15

    18

    14

    16

    Digestive System

    Anorexia

    17

    17

    31

    25

    26

    22

    Diarrhea

    27

    27

    29

    31

    29

    30

    Dyspepsia

    18

    13

    18

    15

    23

    18

    Nausea

    36

    37

    64

    59

    54

    52

    Pain Abdominal

    20

    16

    24

    18

    23

    18

    Vomiting

    17

    20

    46

    39

    36

    33

    Hemic and Lymphatic

    Anemia

    48

    42

    40

    37

    43

    38

    Granulocytopenia

    21

    16

    19

    21

    20

    19

    Musculoskeletal System

    Arthralgias

    11

    7

    15

    13

    14

    11

    Myalgia

    25

    15

    26

    23

    26

    20

    Skeletal Pain

    61

    72

    70

    75

    67

    74

    CNS

    Anxiety

    8

    9

    18

    17

    14

    14

    Headache

    24

    20

    27

    24

    26

    22

    Insomnia

    17

    17

    25

    19

    22

    19

    Respiratory System

    Coughing

    26

    23

    25

    20

    26

    21

    Dyspnea

    22

    21

    35

    24

    30

    23

    Pleural Effusion

    3

    4

    15

    9

    11

    8

    Sinusitis

    15

    17

    16

    10

    16

    12

    Upper Respiratory Tract Infection

    32

    28

    20

    20

    24

    23

    Urogenital System

    Urinary Tract Infection

    16

    9

    20

    18

    19

    16

    In the breast cancer trials, four pamidronate disodium-related adverse reactions, interstitial pneumonitis, malaise and dyspnea, symptomatic hypocalcemia, and severe bone pain, resulted in discontinuation of therapy.

    6.2 Postmarketing Experience

    The following adverse reactions have been identified during postapproval pamidronate sodium use. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

    General: reactivation of Herpes simplex and Herpes zoster, influenza-like symptoms

    CNS: confusion and visual hallucinations, sometimes in the presence of electrolyte imbalance;

    Skin: rash, pruritus

    Special senses: conjunctivitis, orbital inflammation;

    Renal and urinary disorders: focal segmental glomerulosclerosis including the collapsing variant, nephrotic syndrome; renal tubular disorders (RTD); tubulointerstitial nephritis, and glomerulonephropathies.

    Laboratory abnormalities: hyperkalemia, hypernatremia, hematuria. Rare instances of allergic manifestations have been reported, including hypotension, dyspnea, or angioedema, and, very rarely, anaphylactic shock. Pamidronate disodium is contraindicated in patients with clinically significant hypersensitivity to pamidronate disodium or other bisphosphonates (see CONTRAINDICATIONS).

    Respiratory, thoracic and mediastinal disorders: adult respiratory distress syndrome (ARDS), interstitial lung disease (ILD).

    Musculoskeletal and connective tissue disorders: severe, occasionally incapacitating bone, joint, and/or muscle pain.


  • 7 DRUG INTERACTIONS

    7.1 Nephrotoxic Drugs

    Caution is indicated when pamidronate disodium is used with other potentially nephrotoxic drugs.

    7.2 Thalidomide

    In multiple myeloma patients, the risk of renal deterioration may be increased when pamidronate disodium is used in combination with thalidomide.

    7.3 Loop Diuretics

    Concomitant administration of a loop diuretic had no effect on the calcium-lowering action of pamidronate disodium.


  • 8 USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy

    Pregnancy Category D [see Warnings and Precautions (5.2)]

    Risk Summary

    There are no adequate and well-controlled studies in pregnant women. Pamidronate disodium may cause fetal harm when administered to a pregnant woman. Bisphosphonates, such as pamidronate disodium, are incorporated into the bone matrix, from where they 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 pamidronate disodium is used during pregnancy or if the patient becomes pregnant while taking or after taking this drug, apprise the patient of the potential hazard to the fetus.

    Animal Data

    Intravenous bolus dosing of pregnant rats and rabbits with pamidronate resulted in maternal toxicity and embryo/fetal effects when given during organogenesis at doses of 0.6 to 8.3 times the highest recommended human dose for a single intravenous infusion. Pamidronate can cross the placenta in rats, and has produced marked maternal and nonteratogenic embryo/fetal effects in both rats and rabbits.

    8.3 Nursing Mothers

    It is not known whether pamidronate is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from pamidronate disodium, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

    8.4 Pediatric Use

    Safety and effectiveness of pamidronate disodium in pediatric patients have not been established.

    8.5 Geriatric Use

    Of the total number of subjects in clinical studies of pamidronate disodium, approximately 20% were 65 and over, while approximately 15% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

    8.6 Females of Reproductive Potential

    Contraception

    Pamidronate disodium may cause fetal harm when administered during pregnancy. Advise females of reproductive potential to avoid becoming pregnant while taking pamidronate disodium. Since pamidronate disodium is incorporated into bone and is gradually released over periods of weeks to years, advise females of reproductive potential of the potential risk to a fetus if pregnancy occurs after completing treatment with this drug. If contraceptive methods are being considered, use effective contraception while taking and after taking pamidronate disodium. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking or after taking pamidronate disodium [see Use in Specific Populations (8.1)].

    8.7 Patients with Renal Impairment

    The renal clearance of pamidronate was reduced in patients with reduced creatinine clearance. Because pamidronate disodium is administered on a monthly basis, drug accumulation is not expected. No changes in pamidronate disodium dosing regimen are recommended for patients with mild to moderate renal impairment (creatinine clearance > 30 mL/min). Limited pharmacokinetic data exist in patients with creatinine clearance <30 mL/min [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

    8.8 Patients with Hepatic Impairment

    Patients with moderate hepatic impairment exhibited higher mean pamidronate AUC and Cmax. Because pamidronate disodium is administered on a monthly basis, drug accumulation is not expected. No changes in pamidronate disodium dosing regimen are recommended for patients with mild to moderate hepatic impairment. Pamidronate disodium has not been studied in patients with severe hepatic impairment [see Clinical Pharmacology (12.3)].


  • 10 OVERDOSAGE

    Several cases of drug overdose have been reported in hypercalcemia patients treated with total doses of 225 mg to 300 mg pamidronate disodium given over 2.5 to 4 days. All patients survived, but all developed hypocalcemia that required intravenous and/or oral administration of calcium. If overdosage occurs, treat symptomatic hypocalcemia patients with short-term intravenous calcium.

    Single doses of pamidronate disodium should not exceed 90 mg, and the duration of the intravenous infusion should be no less than 2 hours [see Dosage and Administration (2.5) and Warnings and Precautions (5.1)].

    In addition, one obese woman (95 kg) who was treated with 285 mg of pamidronate disodium/day for 3 days experienced high fever (39.5°C), hypotension (from 170/90 mmHg to 90/60 mmHg), and transient taste perversion, occurring about 6 hours after the first infusion. Fever and hypotension rapidly reversed with steroid therapy.


  • 11 DESCRIPTION

    Pamidronate disodium injection is a sterile bisphosphonate available in 30 mg or 90 mg vials for intravenous administration. Each mL of the 30 mg vial contains: 3 mg pamidronate disodium; 47 mg mannitol USP; water for injection, USP, q.s.; phosphoric acid to adjust pH 6.5. Each mL of the 90 mg vial contains: 9 mg pamidronate disodium; 37.5 mg mannitol USP; water for injection, USP, q.s.; phosphoric acid to adjust pH to 6.5.

    The pH of a 1% solution of pamidronate disodium in distilled water is approximately 8.3. Pamidronate disodium, a member of the group of chemical compounds known as bisphosphonates, is an analog of pyrophosphate. Pamidronate disodium is designated chemically as phosphonic acid (3-amino-1-hydroxypropylidene) bis-, disodium salt, pentahydrate, and its structural formula is:

    structural formula

    C3H9NO7P2Na25H2O M.W. 369.1

    Pamidronate disodium is a white to practically white powder. It is soluble in water and in 2N sodium hydroxide, sparingly soluble in 0.1N hydrochloric acid and in 0.1N acetic acid, and practically insoluble in organic solvents.


  • 12 CLINICAL PHARMACOLOGY

    12.1 Mechanism of Action

    The principal pharmacologic action of pamidronate disodium is inhibition of bone resorption. Although the mechanism of antiresorptive action is not completely understood, several factors are thought to contribute to this action. Pamidronate disodium adsorbs to calcium phosphate (hydroxyapatite) crystals in bone and may block dissolution of this mineral component of bone. In vitro, pamidronate disodium inhibited osteoclast activity. In animal studies, pamidronate disodium inhibited bone resorption, but did not inhibit bone formation and mineralization. In animal tumor models, pamidronate disodium inhibited the increased osteoclast activity induced by tumors.

    12.2 Pharmacodynamics

    Serum phosphate levels have been noted to decrease after administration of pamidronate disodium, presumably because of decreased release of phosphate from bone and increased renal excretion as parathyroid hormone levels, which are usually suppressed in hypercalcemia associated with malignancy, return toward normal. Phosphate therapy was administered in 30% of the patients in response to a decrease in serum phosphate levels. Phosphate levels usually returned toward normal within 7 to 10 days.

    Urinary calcium/creatinine and urinary hydroxyproline/creatinine ratios decrease and usually return to within or below normal after treatment with pamidronate disodium. These changes occur within the first week after treatment, as do decreases in serum calcium levels, and are consistent with an antiresorptive pharmacologic action.

    12.3 Pharmacokinetics

    Table 3 shows maximum concentration, percent of dose excreted in urine, total clearance, and renal clearance of pamidronate after an intravenous infusion of 30, 60, or 90 mg of pamidronate disodium over 4 hours and 90 mg of pamidronate disodium over 24 hours in cancer patients (n=24) who had minimal or no bony involvement.

    Table 3 Mean (Standard Deviation, CV%) Pamidronate Pharmacokinetic Parameters in Cancer Patients (n=6 for each group)

    Dose
    (infusion rate)
    Maximum Concentration
    (mcg/mL)
    Percent of dose excreted in urine Total Clearance
    (mL/min)
    Renal Clearance
    (mL/min)

    30 mg

    0.73

    43.9

    136

    58

    (4 hrs)

    (0.14, 19.1%)

    (14, 31.9%)

    (44, 32.4%)

    (27, 46.5%)

    60 mg

    1.44

    47.4

    88

    42

    (4 hrs)

    (0.57, 39.6%)

    (47.4, 54.4%)

    (56, 63.6%)

    (28, 66.7%)

    90 mg

    2.61

    45.3

    103

    44

    (4 hrs)

    (0.74, 28.3%)

    (25.8, 56.9%)

    (37, 35.9%)

    (16, 36.4%)

    90 mg

    1.38

    47.5

    101

    52

    (24 hrs)

    (1.97, 142.7%)

    (10.2, 21.5%)

    (58, 57.4%)

    (42, 80.8%)

    Distribution

    The body retention of pamidronate was 54 ± 16% (mean ± standard deviation) of the dose over 120 hours.

    Metabolism

    Pamidronate is not metabolized.

    Elimination

    The elimination half-life is 28 ± 7 hours (mean ± standard deviation). Total and renal clearances of pamidronate were 107 ± 50 mL/min and 49 ± 28 mL/min, respectively. The rate of elimination from bone has not been determined.

    After administration of 30, 60, and 90 mg of pamidronate disodium over 4 hours, and 90 mg of pamidronate disodium over 24 hours, 46 ± 16% (mean ± standard deviation) of the drug was excreted unchanged in the urine within 120 hours. Cumulative urinary excretion was linearly related to dose.

    Specific Populations

    Renal Impairment

    The pharmacokinetics of pamidronate were studied in cancer patients (n=19) with normal and varying degrees of renal impairment. Each patient received a single 90 mg dose of pamidronate disodium infused over 4 hours. Renal clearance correlated with creatinine clearance (see Figure 1). Because pamidronate disodium is administered on a monthly basis, drug accumulation is not expected.

    Figure 1: Pamidronate renal clearance as a function of creatinine clearance in patients with normal and impaired renal function. The lines are the mean prediction line and 95% confidence intervals.

    Figure 1

    Hepatic Impairment

    The pharmacokinetics of pamidronate were studied in male cancer patients at risk for bone metastases with normal hepatic function (n=6) and mild to moderate hepatic dysfunction (n=7). Each patient received a single 90 mg dose of pamidronate disodium infused over 4 hours. Although there was a difference in the pharmacokinetics between patients with normal and impaired hepatic function, the difference was not considered clinically relevant. Patients with hepatic impairment exhibited higher mean AUC (53% increase) and Cmax (29% increase), and decreased plasma clearance (33% decrease) values. Because pamidronate disodium is administered on a monthly basis, drug accumulation is not expected.


  • 13 NONCLINICAL TOXICOLOGY

    13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

    In a 104-week carcinogenicity study with daily oral administration of pamidronate in rats, there was a positive dose-response relationship for benign adrenal pheochromocytoma. The lowest daily dose associated with adrenal pheochromocytoma resulted in systemic exposures that were similar to the systemic exposure achieved in patients at the intended clinical dose. Adrenal pheochromocytoma also was observed in low numbers in the control animals and is considered a relatively common spontaneous neoplasm in the rat. Pamidronate given daily by oral administration was not carcinogenic in an 80 week study in mice.

    Pamidronate did not cause genetic toxicity in the Ames bacterial mutagenicity assay, nucleus-anomaly test, sister-chromatid-exchange study, point-mutation test and micronucleus test in the rat.

    In rats, decreased fertility occurred in first-generation offspring of parents who had received 150 mg/kg of pamidronate orally; however, this occurred only when animals were mated with members of the same dose group.

    13.2 Animal Toxicology and/or Pharmacology

    After intravenous administration of radiolabeled pamidronate in rats, approximately 50% to 60% of the compound was rapidly adsorbed by bone and slowly eliminated from the body by the kidneys. In rats given 10 mg/kg bolus injections of radiolabeled pamidronate disodium, approximately 30% of the compound was found in the liver shortly after administration and was then redistributed to bone or eliminated by the kidneys over 24 to 48 hours. Studies in rats injected with radiolabeled pamidronate disodium showed that the compound was rapidly cleared from the circulation and taken up mainly by bones, liver, spleen, teeth, and tracheal cartilage. Radioactivity was eliminated from most soft tissues within 1 to 4 days; was detectable in liver and spleen for 1 and 3 months, respectively; and remained high in bones, trachea, and teeth for 6 months after dosing. Bone uptake occurred preferentially in areas of high bone turnover. The terminal phase of elimination half-life in bone was estimated to be approximately 300 days.


  • 14 CLINICAL STUDIES

    14.1 Hypercalcemia of Malignancy

    In one double-blind clinical trial, 52 patients who had hypercalcemia of malignancy received 30 mg, 60 mg, or 90 mg of pamidronate disodium as a single 24-hour intravenous infusion if their corrected serum calcium levels were ≥ 12 mg/dL after 48-hours of saline hydration (See Table 4).

    Table 4: Comparison of Calcium Normalization Following a 24-hour Infusion of Pamidronate Disodium

    Pamidronate Disodium

    30 mg

    60 mg

    90 mg

    Mean Baseline Corrected Serum Calcium (after 48 hours saline hydration)

    13.8 mg/dL

    13.8 mg/dL

    13.3 mg/dL

    % Patients with Normalized Serum Calcium (N=52)

    Day 7

    41%

    61%

    100%

    Day 14

    ----

    33%

    53%

    In a second double-blind, controlled clinical trial, 65 cancer patients who had corrected serum calcium levels of ≥12 mg/dL after at least 24-hours of saline hydration were randomized to receive either 60 mg of pamidronate disodium as a single 24-hour intravenous infusion or 7.5 mg/kg of etidronate disodium as a 2-hour intravenous infusion daily for 3 days. Results are shown in Table 5.

    Table 5: Calcium Levels, Percentage of Patients with Response over Time, and Median Duration of Response

    Pamidronate Disodium
    60 mg/24-hours
    (N=30)

    Etidronate Disodium
    7.5 mg/kg/2-hours
    (N=35)

    P-value

    Mean Corrected Serum Calcium Level

    Baseline

    14.6 mg/dL

    13.8 mg/dL

    At Day 7

    10.4 mg/dL

    11.2 mg/dL

    % Patients with Normalized Serum Calcium Level or > 15% from Baseline

    At Day 7

    97%

    65%

    P< 0.01

    At Day 14

    43%

    18%

    Median Duration of Response

    7 days

    5 days

    In a third multicenter, randomized, parallel, double-blind trial, 69 patients with cancer, who had a corrected serum calcium level of ≥ 12 mg/dL after 24 hours of saline hydration, received 60 mg of pamidronate disodium as a 4- or 24-hour infusion or a saline control (Table 6).

    Table 6: Comparison of Pamidronate Disodium 4-hour, 24-hours Infusion with Saline Control

    Pamidronate Disodium
    60 mg/4 hours

    Pamidronate Disodium
    60 mg/24 hours

    Saline Control

    Baseline Corrected
    Serum Calcium

    14.2 mg/dL

    13.7 mg/dL

    13.7 mg/dL

    % Patients with Normalized Serum Calcium (N=69)

    At Day 7

    78%

    61%

    22%

    At Day 14

    39%

    26%

    ---

    Median Duration of Complete Response

    Days

    4

    6.5

    In all three trials, similar response rates were observed with pamidronate disodium treatment regardless of the presence or absence of bone metastases. Concomitant administration of furosemide did not affect response rates.

    Thirty-two patients who had recurrent or refractory hypercalcemia of malignancy were given a second course of 60 mg of pamidronate disodium over a 4- or 24-hour period. Of these, 41% showed a complete response and 16% showed a partial response to the retreatment, and these responders had about a 3 mg/dL fall in mean-corrected serum calcium levels 7 days after retreatment.

    In a fourth multicenter, randomized, double-blind trial, 103 patients with cancer and hypercalcemia (corrected serum calcium ≥12 mg/dL) received 90 mg of pamidronate disodium as a 2-hour infusion. The mean baseline corrected serum calcium was 14 mg/dL. Patients were not required to receive IV hydration prior to drug administration, but all subjects did receive at least 500 mL of IV saline hydration concomitantly with the pamidronate infusion. By day 10 after drug infusion, 70% of patients had normal corrected serum calcium levels (<10.8 mg/dL).

    14.2 Paget’s Disease

    In a double-blind clinical trial, 64 patients with moderate to severe Paget’s disease of bone received 5 mg, 15 mg, or 30 mg of pamidronate disodium as a single 4-hour infusion daily on 3 consecutive days, for total doses of 15 mg, 45 mg, and 90 mg of pamidronate disodium.

    For the 15 mg, 45 mg, and 90 mg groups, mean baseline serum alkaline phosphatase levels were 1409 U/L, 983 U/L, and 1085 U/L, and mean baseline urine hydroxyproline/creatinine ratios were 0.25, 0.19, and 0.19, respectively.

    The effects of pamidronate disodium on serum alkaline phosphatase (SAP) and urine hydroxyproline/creatinine ratios (UOHP/C) are summarized in Table 7.

    Table 7 Percent of Patients with Decrease in SAP and UOHP/C

    SAP

    UOHP/C

    % Decrease

    15 mg

    45 mg

    90 mg

    15 mg

    45 mg

    90 mg

    ≥50

    26%

    33%

    60%

    15%

    47%

    72%

    ≥30

    40%

    65%

    83%

    35%

    57%

    85%

    For the 15 mg, 45 mg, and 90 mg groups, median maximum percent decreases from baseline in serum alkaline phosphatase were 25%, 41%, and 57%, and urine hydroxyproline/creatinine ratios were 25%, 47%, and 61%, respectively. The median time to response (≥50% decrease) for serum alkaline phosphatase was approximately 1 month for the 90 mg group, and the response duration ranged from 1 to 372 days.

    Twenty-five patients who had Paget’s disease were retreated with 90 mg of pamidronate disodium. Of these, 44% had a ≥50% decrease in serum alkaline phosphatase from baseline after treatment, and 39% had a ≥50% decrease in urine hydroxyproline/creatinine ratio from baseline after treatment.

    14.3 Osteolytic Bone Metastases of Breast Cancer and Osteolytic Lesions of Multiple Myeloma

    Breast Cancer

    Two double-blind, randomized, placebo-controlled trials compared the safety and efficacy of pamidronate disodium 90 mg infused over 2 hours every 3 to 4 weeks for 24 months to placebo for prevention of SREs in breast cancer patients with osteolytic bone metastases who had one or more predominantly lytic metastases of at least 1 cm in diameter. The first trial enrolled 382 patients receiving chemotherapy, of whom 185 were randomized to pamidronate disodium and 197 to placebo. The second trial enrolled 372 patients receiving hormonal therapy, of whom 182 were randomized to pamidronate disodium and 190 to placebo. All but three patients were evaluable for efficacy. Bone lesion response was radiographically assessed at baseline and at 3, 6, and 12 months. Therapy continued for 24 months unless patient discontinued study.

    Median duration of follow-up was 13 months in patients receiving chemotherapy and 17 months in patients receiving hormone therapy. Twenty-five percent of the patients in the chemotherapy study and 37% of the patients in the hormone therapy study received pamidronate disodium for 24 months. Efficacy results are shown in Table 8:

    Table 8 Efficacy Results in Breast Cancer Patients

    *
    • Fractures and radiation to bone were two of several secondary endpoints. The statistical significance of these analyses may be overestimated since numerous analyses were performed.
    †
    • NR = Not Reached

    N

    Breast Cancer Patients Receiving Chemotherapy

    Any SRE

    Radiation

    Fractures

    Pamidronate disodium

    Placebo

    Pamidronate disodium

    Placebo

    Pamidronate disodium

    Placebo

    185

    195

    185

    195

    185

    195

    Skeletal Morbidity Rate
    (#SRE/year)
    Mean

    2.5

    3.7

    0.8

    1.3

    1.6

    2.2

    P-Value

    <.001

    <.001*

    .018*

    Proportion of patients having an SRE

    46%

    65%

    28%

    45%

    36%

    49%

    P-Value

    <.001

    <.001*

    .014*

    Median Time to SRE (months)

    13.9

    7

    NR†

    14.2

    25.8

    13.3

    P-Value

    <.001

    <.001*

    .009*

    N

    Breast Cancer Patients Receiving Hormonal Therapy

    Any SRE

    Radiation

    Fractures

    Pamidronate disodium

    Placebo

    Pamidronate disodium

    Placebo

    Pamidronate disodium

    Placebo

    182

    189

    182

    189

    182

    189

    Skeletal Morbidity Rate
    (#SRE/year)
    Mean

    2.4

    3.6

    0.6

    1.2

    1.6

    2.2

    P-Value

    .021

    .013*

    .040*

    Proportion of patients having an SRE

    55%

    63%

    31%

    40%

    45%

    55%

    P-Value

    .094

    .058*

    .054*

    Median Time to SRE (months)

    10.9

    7.4

    NR†

    23.4

    20.6

    12.8

    P-Value

    .118

    .016*

    .113*

    Advanced Multiple Myeloma

    In a double-blind, randomized, placebo-controlled trial, 392 patients on therapy for advanced multiple myeloma received pamidronate disodium or placebo to determine the effect on the occurrence of skeletal-related events (SREs). SREs were defined as the occurrence of new or additional pathologic fractures, radiation therapy or surgery for bony fracture, impending fracture, or spinal cord compression. Pamidronate disodium 90 mg or placebo was administered as a 4-hour infusion every 4 weeks for 9 months. Of the 392 patients enrolled, 377 were evaluable for efficacy. Results are shown in Table 9.

    Table 9: SRE Outcomes in Multiple Myeloma

    Pamidronate disodium 90 mg /4 hours (N=196)

    Placebo (N=181)

    P-value

    At 1 year
    % of Patients with SRE

    24%

    41%

    P< 0.001

    % with Pathological Fracture

    17%

    30%

    P<0.004

    % with Radiation to Bone

    14%

    21%

    P<0.049

    At 1.75 years (21 Months)
    % Pathologic Vertebral Fractures

    16%

    27%

    P=0.005

    The times to the first SRE occurrence, pathologic fracture, and radiation to bone were significantly longer in the pamidronate disodium group (P=0.001, 0.006, and 0.046, respectively). After 21 months, the proportion of patients experiencing any skeletal event remained significantly less in the pamidronate disodium group compared to the placebo group (P=0.015). Time to first SRE was significantly longer in the pamidronate disodium group compared to placebo (P=0.016). Survival was not different between treatment groups.


  • 16 HOW SUPPLIED/STORAGE AND HANDLING

    Pamidronate Disodium Injection is available as follows:

    NDC Number Strength Size

    0703-4075-51

    30 mg per 10 mL

    single-use vial (3 mg/mL)

    Packaged individually

    0703-4085-51

    90 mg per 10 mL

    single-use vial (9 mg/mL)

    Packaged individually


    Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].


  • 17 PATIENT COUNSELING INFORMATION

    • Inform female patients that pamidronate can cause fetal harm when administered to a pregnant woman. Advise patients to avoid becoming pregnant and to report any pregnancies while receiving or after cessation of pamidronate therapy [see Warnings and Precautions (5.2)].
    • Inform patients that the risk of osteonecrosis of the jaw is increased in patients undergoing invasive dental procedures. Advise patients to avoid such procedures, if possible, and to maintain good dental hygiene and routine dental care [see Warnings and Precautions (5.4)].
    • Inform patients that atypical femur fractures have occurred in patients taking bisphosphonates. Advise patients to report any thigh or groin pain [see Warnings and Precautions (5.5)].

    TEVA PHARMACEUTICALS USA, INC.

    North Wales, PA 19454

    Rev. C 12/2014


  • Package/Label Display Panel

    Pamidronate Disodium Injection 30 mg/10 mL, Single-Use Vial, Carton

    Pamidronate Disodium Injection 30 mg/10 mL, Single-Use Vial, Carton Text

    NDC 0703-4075-51       Rx only

    Pamidronate
    Disodium Injection

    30 mg/10 mL

    (3 mg/mL)

    For Intravenous Infusion

    Do not mix with
    calcium-containinginfusion

    solutions.

    Sterile

    Single-Use Vial

    TEVA


  • Package/Label Display Panel

    Pamidronate Disodium Injection 90 mg/10 mL, Single-Use Vial, Carton

    Pamidronate Disodium Injection 90 mg/10 mL, Single-Use Vial, Carton Text

    NDC 0703-4085-51       Rx only

    Pamidronate
    Disodium Injection

    90 mg/10 mL

    (9 mg/mL)

    For Intravenous Infusion

    Do not mix with
    calcium-containinginfusion

    solutions.

    Sterile

    Single-Use Vial

    TEVA


  • INGREDIENTS AND APPEARANCE
    PAMIDRONATE DISODIUM 
    pamidronate disodium injection, solution
    Product Information
    Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0703-4075
    Route of Administration INTRAVENOUS
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    PAMIDRONATE DISODIUM (UNII: 8742T8ZQZA) (PAMIDRONIC ACID - UNII:OYY3447OMC) PAMIDRONATE DISODIUM 3 mg  in 1 mL
    Inactive Ingredients
    Ingredient Name Strength
    MANNITOL (UNII: 3OWL53L36A)  
    WATER (UNII: 059QF0KO0R)  
    PHOSPHORIC ACID (UNII: E4GA8884NN)  
    Packaging
    # Item Code Package Description Marketing Start Date Marketing End Date
    1 NDC:0703-4075-51 1 in 1 CARTON 11/08/2005
    1 10 mL in 1 VIAL, SINGLE-USE; Type 0: Not a Combination Product
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    ANDA ANDA076153 04/01/2002
    PAMIDRONATE DISODIUM 
    pamidronate disodium injection, solution
    Product Information
    Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0703-4085
    Route of Administration INTRAVENOUS
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    PAMIDRONATE DISODIUM (UNII: 8742T8ZQZA) (PAMIDRONIC ACID - UNII:OYY3447OMC) PAMIDRONATE DISODIUM 9 mg  in 1 mL
    Inactive Ingredients
    Ingredient Name Strength
    MANNITOL (UNII: 3OWL53L36A)  
    WATER (UNII: 059QF0KO0R)  
    PHOSPHORIC ACID (UNII: E4GA8884NN)  
    Packaging
    # Item Code Package Description Marketing Start Date Marketing End Date
    1 NDC:0703-4085-51 1 in 1 CARTON 11/08/2005
    1 10 mL in 1 VIAL, SINGLE-USE; Type 0: Not a Combination Product
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    ANDA ANDA076153 04/01/2002
    Labeler - Teva Parenteral Medicines, Inc. (794362533)