Pamidronate Intravenous Infusion

Hypercalcemia of Malignancy

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

Paget’s Disease

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

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)].

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.

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

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

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.

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)].

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)].

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.

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)].

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.

Nephrotoxic Drugs

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

Thalidomide

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

Loop Diuretics

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

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.

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.

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)

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.

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.