PAMIDRONATE DISODIUM

Pamidronate Disodium Injection is a bisphosphonate available in 30 mg and 90 mg vials for intravenous administration. Each mL of the 30 mg/10 mL vial contains 3 mg pamidronate disodium, 47 mg mannitol; water for injection, q.s.; and phosphoric acid to adjust pH 6.0 to 7.0. Each mL of the 90 mg/10 mL vial contains, 9 mg pamidronate disodium, 37.5 mg mannitol; water for injection, q.s.; and phosphoric acid to adjust pH 6.0 to 7.0. 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, and its structural formula is: Pamidronate disodium is a 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. Its molecular formula is C 3 H 9 NO 7 P 2 Na 2 and its molecular weight is 279.1 (calculated as the anhydrous form). structural formula

Pamidronate disodium 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 in the treatment of hypercalcemia associated with hyperparathyroidism or with other non-tumor-related conditions have not been established. ( 1.4 ) 1.1 Hypercalcemia of Malignancy Pamidronate disodium 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 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 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 in the treatment of hypercalcemia associated with hyperparathyroidism or with other non-tumor-related conditions has not been established.

• Hypercalcemia of malignancy: 60 mg to 90 mg pamidronate disodium 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 daily as a 4-hour infusion on 3 consecutive days. ( 2.2 ) • Osteolytic Bone Metastases of Breast Cancer: 90 mg pamidronate disodium 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 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 infusion to come in contact with any calcium or divalent cation-containing solutions. ( 2.6 ) 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 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 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 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 (4.0-serum albumin, g/dL). Retreatment Retreatment with pamidronate disodium 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 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 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 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 infusion. Limited information is available on the use of pamidronate disodium in multiple myeloma patients with a serum creatinine greater than or equal to 3 mg/dL. Patients who receive pamidronate disodium 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 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.

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

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) ] 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 Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 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 resolution in all patients. 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 over 4 hr 60 mg over 24 hr 90 mg over 24 hr 7.5 mg/kg 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. Cases of allergic manifestations have been reported, including hypotension, dyspnea, or angioedema, and anaphylactic shock. Pamidronate disodium is contraindicated in patients with clinically significant hypersensitivity to pamidronate disodium or other bisphosphonates [see Contraindications (4) ] . 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.

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