Pamidronate Disodium

Hypercalcemia of Malignancy Pamidronate disodium, in conjunction with adequate hydration, is indicated for the treatment of moderate or severe hypercalcemia associated with malignancy, with or without bone metastases. Patients who have either epidermoid or non-epidermoid tumors respond to treatment with pamidronate disodium. Vigorous saline hydration, an integral part of hypercalcemia therapy, should be initiated promptly and an attempt should be made to restore the urine output to about 2 L/day throughout treatment. Mild or asymptomatic hypercalcemia may be treated with conservative measures (i.e., saline hydration, with or without loop diuretics). Patients should be hydrated adequately throughout the treatment, but overhydration, especially in those patients who have cardiac failure, must be avoided. Diuretic therapy should not be employed prior to correction of hypovolemia. 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. Paget’s Disease Pamidronate disodium is indicated for the treatment of patients with moderate to severe Paget’s disease of bone. The effectiveness of pamidronate disodium was demonstrated primarily in patients with serum alkaline phosphatase ≥ 3 times the upper limit of normal. Pamidronate disodium therapy in patients with Paget’s disease has been effective in reducing serum alkaline phosphatase and urinary hydroxyproline levels by ≥ 50% in at least 50% of patients, and by ≥ 30% in at least 80% of patients. Pamidronate disodium therapy has also been effective in reducing these biochemical markers in patients with Paget’s disease who failed to respond, or no longer responded to other treatments. 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. The pamidronate disodium treatment effect appeared to be smaller in the study of breast cancer patients receiving hormonal therapy than in the study of those receiving chemotherapy, however, overall evidence of clinical benefit has been demonstrated (see CLINICAL PHARMACOLOGY , Osteolytic Bone Metastases of Breast Cancer and Osteolytic Lesions of Multiple Myeloma, Clinical Trials section).

Pamidronate disodium is contraindicated in patients with clinically significant hypersensitivity to pamidronate disodium or other bisphosphonates.

Deterioration in Renal Function Bisphosphonates, including pamidronate disodium, have been associated with renal toxicity manifested as deterioration of renal function and potential renal failure. DUE TO THE RISK OF CLINICALLY SIGNIFICANT DETERIORATION IN RENAL FUNCTION, WHICH MAY PROGRESS TO RENAL FAILURE, SINGLE DOSES OF PAMIDRONATE DISODIUM SHOULD NOT EXCEED 90 MG (see DOSAGE AND ADMINISTRATION for appropriate infusion durations). Renal deterioration, progression to renal failure, and dialysis have been reported in patients after the initial or a single dose of pamidronate disodium. Focal segmental glomerulosclerosis (including the collapsing variant) with or without nephrotic syndrome, which may lead to renal failure, has been reported in pamidronate disodium-treated patients, particularly in the setting of multiple myeloma and breast cancer. Some of these patients had gradual improvement in renal status after pamidronate disodium was discontinued. Patients who receive pamidronate disodium should have serum creatinine assessed prior to each treatment. Patients treated with pamidronate disodium for bone metastases should have the dose withheld if renal function has deteriorated (see DOSAGE AND ADMINISTRATION ). PREGNANCY: Bisphosphonates, such as pamidronate disodium, are incorporated into the bone matrix, from where they are 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 PRECAUTIONS ).

General Standard hypercalcemia-related metabolic parameters, such as serum levels of calcium, phosphate, magnesium, and potassium, should be carefully monitored following initiation of therapy with pamidronate disodium. Cases of asymptomatic hypophosphatemia (12%), hypokalemia (7%), hypomagnesemia (11%), and hypocalcemia (5% to 12%), were reported in pamidronate disodium-treated patients. Rare cases of symptomatic hypocalcemia (including tetany) have been reported in association with pamidronate therapy. If hypocalcemia occurs, short-term calcium therapy may be necessary. In Paget’s disease of bone, 17% of patients treated with 90 mg of pamidronate disodium showed serum calcium levels below 8 mg/dL. Patients with a history of thyroid surgery may have relative hypoparathyroidism that may predispose to hypocalcemia with pamidronate disodium. Renal Insufficiency Pamidronate disodium is excreted intact primarily via the kidney, and the risk of renal adverse reactions may be greater in patients with impaired renal function. Patients who receive pamidronate disodium should have serum creatinine assessed prior to each treatment. In patients receiving pamidronate disodium for bone metastases, who show evidence of deterioration in renal function, pamidronate disodium treatment should be withheld until renal function returns to baseline (see WARNINGS and DOSAGE AND ADMINISTRATION ). In clinical trials, patients with renal impairment (serum creatinine >3.0 mg/dL) have not been studied. Limited pharmacokinetic data exist in patients with creatinine clearance <30 mL/min (See Clinical Pharmacology , Pharmacokinetics ). For the treatment of bone metastases, the use of pamidronate disodium in patients with severe renal impairment is not recommended. In other indications, clinical judgment should determine whether the potential benefit outweighs the potential risk in such patients. 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. Post-marketing experience and the literature suggest a greater frequency of reports of ONJ based on tumor type (advanced breast cancer, multiple myeloma), and dental status (dental extraction, periodontal disease, local trauma including poorly fitting dentures). Many reports of ONJ involved patients with signs of local infection including osteomyelitis. Cancer patients should maintain good oral hygiene and should have a dental examination with preventive dentistry prior to treatment with bisphosphonates. While on treatment, these patients should 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 ). Musculoskeletal Pain In post-marketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates. This category of drugs includes pamidronate disodium. The time to onset of symptoms varied from one day to several months after starting the drug. Most patients had relief of symptoms after stopping. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate. 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 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 has also been reported. A number of case reports noted that patients were also receiving treatment 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 suspected of having an atypical fracture and should be evaluated. Discontinuation of pamidronate disodium therapy in patients suspected to have an atypical femur fracture should be considered 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. Laboratory Tests Patients who receive pamidronate disodium should have serum creatinine assessed prior to each treatment. Serum calcium, electrolytes, phosphate, magnesium, and CBC, differential, and hematocrit/hemoglobin must be closely monitored in patients treated with pamidronate disodium. Patients who have preexisting anemia, leukopenia, or thrombocytopenia should be monitored carefully in the first 2 weeks following treatment. Patients receiving pamidronate disodium may be at risk for anemia, leukopenia or thrombocytopenia and should have regular hematology assessments. Drug Interactions Concomitant administration of a loop diuretic had no effect on the calcium-lowering action of pamidronate disodium. Caution is indicated when pamidronate disodium is used with other potentially nephrotoxic drugs. In multiple myeloma patients, the risk of renal function deterioration may be increased when pamidronate disodium is used in combination with thalidomide. 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 in males (P <0.00001). Although this condition was also observed in females, the incidence was not statistically significant. When the dose calculations were adjusted to account for the limited oral bioavailability of pamidronate in rats, systemic exposure with the lowest daily dose associated with adrenal pheochromocytoma resulted in systemic exposures that were similar to the systemic exposure achieved at the intended clinical dose. Adrenal pheochromocytoma was also 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 was nonmutagenic in six mutagenicity assays, including: Ames bacterial mutagenicity assay, (with and without metabolic activation), 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. Pamidronate has not been administered intravenously in such a study. Animal Toxicology In both rats and dogs, nephropathy has been associated with intravenous (bolus and infusion) administration of pamidronate. Two 7-day intravenous infusion studies were conducted in the dog wherein pamidronate was given for 1, 4, or 24 hours at doses of 1 to 20 mg/kg for up to 7 days. […]

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. Clinical Studies 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. In the saline trial, 18% of patients had a temperature elevation of at least 1°C 24 to 48 hours after treatment. Drug-related local soft-tissue symptoms (redness, swelling or induration and pain on palpation) at the site of catheter insertion were most common 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 during the four U.S. controlled hypercalcemia clinical studies were reported to have had seizures, 2 of whom had preexisting seizure disorders. None of the seizures were considered to be drug-related by the investigators. However, a possible relationship between the drug and the occurrence of seizures cannot be ruled out. It should be noted that in the saline arm 1 patient (4%) had a seizure. There are no controlled clinical trials comparing the efficacy and safety of 90 mg pamidronate disodium over 24 hours to 2 hours in patients with hypercalcemia of malignancy. However, a comparison of data from separate clinical trials suggests that the overall safety profile in patients who received 90 mg pamidronate disodium over 24 hours is similar to those who received 90 mg pamidronate disodium over 2 hours. The only notable differences observed were an increase in the proportion of patients in the pamidronate disodium 24-hour group who experienced fluid overload and electrolyte/mineral abnormalities. At least 15% of patients treated with pamidronate disodium for hypercalcemia of malignancy also experienced the following adverse events 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. Many of these adverse experiences may have been related to the underlying disease state. The following table lists the adverse experiences considered to be treatment-related during comparative, controlled U.S. trials. Treatment-Related Adverse Experiences 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 × 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 Fluid overload 0 0 0 6 0 Infusion-site reaction 0 4 18 0 0 Moniliasis 0 0 6 0 0 Rigors 0 0 0 0 4 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 Dyspnea 0 0 0 3 0 Rales 0 0 6 0 0 Rhinitis 0 0 6 0 0 Upper respiratory infection 0 3 0 0 0 CNS Anxiety 0 0 0 0 4 Convulsions 0 0 0 3 0 Insomnia 0 1 0 0 0 Nervousness 0 0 0 0 4 Psychosis 4 0 0 0 0 Somnolence 0 1 6 0 0 Taste perversion 0 0 0 3 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 Abnormal liver function 0 0 0 3 0 Paget’s Disease Transient mild elevation of temperature >1°C above pretreatment baseline was noted within 48 hours after completion of treatment in 21% of the patients treated with 90 mg of pamidronate disodium in clinical trials. Drug-related musculoskeletal pain and nervous system symptoms (dizziness, headache, paresthesia, increased sweating) were more common in patients with Paget’s disease treated with 90 mg of pamidronate disodium than in patients with hypercalcemia of malignancy treated with the same dose. Adverse experiences considered to be related to trial drug, which occurred in at least 5% of patients with Paget’s disease treated with 90 mg of pamidronate disodium in two U.S. clinical trials, were fever, nausea, back pain, and bone pain. At least 10% of all pamidronate disodium-treated patients with Paget’s disease also experienced the following adverse experiences during clinical trials: Cardiovascular: Hypertension Musculoskeletal: Arthrosis, bone pain Nervous system: Headache Most of these adverse experiences may have been related to the underlying disease state. Osteolytic Bone Metastases of Breast Cancer and Osteolytic Lesions of Multiple Myeloma The most commonly reported (>15%) adverse experiences occurred with similar frequencies in the pamidronate disodium and placebo treatment groups, and most of these adverse experiences may have been related to the underlying disease state or cancer therapy. Commonly Reported Adverse Experiences 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 16.1 17.1 25.6 19.2 22.2

18.5 Fatigue 31.7 28.3 40.3 28.8 37.2

29.0 Fever 38.5 38 38.1 32.1 38.5 34 Metastases 1.0 3.0 31.3 24.4 20.5

17.5 Pain 13.2 11.8 15.0 18.1 14.3

16.1 Digestive System Anorexia 17.1 17.1 31.1 24.9 26.0

22.3 Constipation 28.3 31.7 36.0 38.6 33.2

35.1 Diarrhea 26.8 26.8 29.4 30.6 28.5

29.7 Dyspepsia 17.6 13.4 18.3 15.0 22.6

17.5 Nausea 35.6 37.4 63.5 59.1 53.5

51.8 Pain abdominal 19.5 16.0 24.3 18.1 22.6

17.5 Vomiting 16.6 19.8 46.3 39.1 35.7

32.8 Hemic and Lymphatic Anemia 47.8 41.7 39.5 36.8 42.5

38.4 Granulocytopenia 20.5 15.5 19.3 20.5 19.8

18.8 Thrombocytopenia 16.6 17.1 12.5 14.0 14.0

15.0 Musculoskeletal System Arthralgias 10.7 7.0 15.3 12.7 13.6

10.8 Myalgia 25.4 15.0 26.4 22.5 26

20.1 Skeletal Pain 61.0 71.7 70.0 75.4 66.8 74 CNS Anxiety 7.8 9.1 18.0 16.8 14.3

14.3 Headache 24.4 19.8 27.2 23.6 26.2

22.3 Insomnia 17.1 17.2 25.1 19.4 22.2

19.0 Respiratory System Coughing 26.3 22.5 25.3 19.7 25.7

20.6 Dyspnea 22.0 21.4 35.1 24.4 30.4

23.4 Pleural effusion 2.9 4.3 15.0 9.1 10.7

7.5 Sinusitis 14.6 16.6 16.1 10.4 15.6

12.0 Upper respiratory Tract Infection 32.2 28.3 19.6 20.2 24.1

22.9 Urogenital System Urinary Tract Infection 15.6 9.1 20.2 17.6 18.5

15.6 Of the toxicities commonly associated with chemotherapy, the frequency of vomiting, anorexia, and anemia were slightly more common in the pamidronate disodium patients whereas stomatitis and alopecia occurred at a frequency similar to that in placebo patients. In the breast cancer trials, mild elevations of serum creatinine occurred in 18.5% of pamidronate disodium patients and 12.3% of placebo patients. Mineral and electrolyte disturbances, including hypocalcemia, were reported rarely and in similar percentages of pamidronate disodium-treated patients compared with those in the placebo group. The reported frequencies of hypocalcemia, hypokalemia, hypophosphatemia, and hypomagnesemia for pamidronate disodium-treated patients were 3.3%, 10.5%, 1.7%, and 4.4%, respectively, and for placebo-treated patients were 1.2%, 12%, 1.7%, and 4.5%, respectively. […]