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.

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.

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

2.5 Dilution for Administration

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.

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

Based on findings in animals and its mechanism of action, pamidronate disodium can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. In reproductive studies, administration of pamidronate to pregnant rats and rabbits at doses equivalent to 0.6 to 8.3 times the highest human recommended dose resulted in maternal toxicity and embryo-fetal effects.

Bisphosphonates, such as pamidronate disodium, are incorporated into the bone matrix, from where they are gradually released over periods of weeks to years. There may be a risk of fetal harm (e.g., skeletal and other abnormalities) if a woman becomes pregnant after completing a course of bisphosphonate therapy. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during and after pamidronate disodium treatment [see Use in Specific Populations (8.1, 8.3)].

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. 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.

6.1 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.

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.

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.

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

Pamidronate disodium can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

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 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)].

8.7 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)].

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.

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.

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 was not genotoxic in the Ames bacterial mutagenicity assay, nucleus-anomaly test, sister-chromatid-exchange study, and point-mutation test. Pamidronate was not genotoxic in the in vivo rat micronucleus assay.

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.

14.1 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).

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.

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).

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.

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:

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.

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.