ATC Class:M05BA03
VA Class:HS900
Pamidronate disodium, a synthetic bisphosphonate analog of pyrophosphate, is a bone resorption inhibitor.1, 3, 4, 5, 52, 53
Hypercalcemia Associated with Malignancy
Pamidronate disodium is used in conjunction with achievement and maintenance of adequate hydration for the treatment of moderate to severe hypercalcemia associated with malignant neoplasms, with or without bone metastases.1, 3, 4, 5, 52, 53 Patients both with or without epidermoid tumors have responded to pamidronate therapy.1, 52, 53 The hypocalcemic effect of the drug appears to result principally from inhibition of bone resorption and does not depend on cytotoxic activity or enhancement of renal calcium excretion.1, 5, 10, 33, 38, 52, 53 Prior to initiating pamidronate therapy in the treatment of malignancy-associated hypercalcemia, it is important to establish adequate hydration and urinary output in order to increase renal excretion of calcium; adequate hydration should be maintained throughout therapy with the drug.1, 3, 10, 30, 52, 53 For the treatment of mild or asymptomatic hypercalcemia, measures more conservative (e.g., hydration alone or combined with loop diuretics) than therapy with agents such as pamidronate generally are used.1, 5, 31, 32, 33, 39, 52, 53 Corticosteroid therapy may be beneficial in hypercalcemia associated with hematologic malignancies.1, 52, 53
Controlled clinical studies have shown that single-dose IV pamidronate disodium (30-90 mg infused over 24 hours) preceded by 24-48 hours of saline hydration is more effective in the treatment of moderate to severe malignancy-associated hypercalcemia than hydration alone and is more effective than IV etidronate disodium (7.5 mg/kg daily for 3 days; IV preparation no longer commercially available in the US) or IV plicamycin (a single 20 mcg/kg dose; drug no longer commercially available in the US).1, 3, 12, 37, 52, 53 In one study comparing IV pamidronate disodium and etidronate disodium at these dosages, 70 and 41% of patients, respectively, achieved normal serum calcium concentrations (based on albumin-corrected serum calcium concentration) by day 7 after therapy initiation; by day 14, 43 and 18% of patients, respectively, maintained normal corrected serum calcium concentrations or a partial response.1, 3, 52, 53 It has been suggested that potential advantages of pamidronate compared with other bone resorption inhibitors (e.g., calcitonin, etidronate, plicamycin) may include increased potency, longer duration of effect, lower rate of adverse effects (e.g., mineralization defects), and more convenient dosage regimen.31, 32, 28, 33, 37, 40 IV pamidronate therapy has been effective for the treatment of malignancy-associated hypercalcemia in patients with various tumors, with or without metastases; response rates are not affected by cancer type or by presence or absence of metastases, and patients both with or without epidermoid tumors have responded to therapy with the drug.1, 3, 4, 30, 33, 38, 52, 53 Symptoms associated with hypercalcemia (e.g., nausea and vomiting, anorexia, constipation, impaired mental functioning) decrease or resolve in patients responding to the drug.33, 38
Clinical studies to date suggest that the efficacy of IV pamidronate therapy in the treatment of malignancy-associated hypercalcemia is dose-related.4, 33 Use of a moderate dose of pamidronate disodium (60 mg) can reduce elevated serum calcium concentrations to normal (the primary end point) in patients with moderate malignancy-associated hypercalcemia; a higher dose (90 mg) appears to be necessary to return serum calcium concentrations to normal in patients with more severe disease.3, 30, 32 About 61-100% of patients receiving a single 60- to 90-mg dose achieved a return to normal serum calcium concentrations (based on corrected serum calcium concentration) in clinical studies; response rates with a 30-mg dose were substantially lower.1, 5, 30, 33, 52, 53 Following IV infusion of pamidronate, reduction of serum calcium concentration usually is apparent within 1-3 days3, 4, 33, 38 and generally is maximal within 5-7 days,3, 4, 38 with normal serum calcium concentrations attained within 2-7 days in most responding patients.3, 4, 30, 38 The duration of pamidronate-induced normocalcemia following a single dose generally is about 6-14 days.1, 3, 30, 33, 38, 52, 53
There also is some evidence that response may be affected by the rate of infusion, but only 60-mg doses have been studied in controlled clinical studies to date comparing 4- and 24-hour infusions.1, 52, 53 When a 4- or 24-hour infusion of pamidronate disodium 60 mg that was preceded by saline hydration was compared with saline hydration alone, 78, 61, or 22% of patients, respectively, achieved normal corrected serum calcium concentrations by day 7, and 39 or 26% of those receiving the 4- or 24-hour drug infusion, respectively, maintained normal corrected serum calcium concentrations or a partial response at day 14.1, 52, 53 For responders, the median duration of complete response was 4 or 6.5 days, respectively, for these infusion rates.1, 52, 53 The safety and efficacy of 90-mg doses infused over 4 hours have not been established in controlled clinical trials.1 However, in a controlled trial in patients with cancer and hypercalcemia (corrected serum calcium of at least 12 mg/dL) who were not required to receive IV hydration prior to drug administration but who did receive IV sodium chloride injection concomitantly with the drug infusion, 70% had normal corrected serum calcium concentrations (less than 10.8 mg/dL) by day 10 after receiving 90 mg of pamidronate disodium as a 2-hour infusion.1, 52, 53 In a comparative study of pamidronate and plicamycin (no longer commercially available in the US), time to recurrence was longer with pamidronate than with plicamycin.37
Retreatment with pamidronate may be considered in patients with recurrent or refractory hypercalcemia associated with malignancy.1, 52, 53 Clinical studies in a limited number of patients have shown that a second course of IV pamidronate therapy can effectively reduce or normalize serum calcium concentrations when malignancy-associated hypercalcemia recurs following an adequate response to an initial course of therapy.1, 30, 37, 52, 53 Data from a small study indicated that a second course of therapy with IV pamidronate disodium (60 mg infused over 4 or 24 hours) returned corrected serum calcium concentrations to normal in 41% of patients, and an additional 16% achieved a partial response, and these responders achieved about a 3-mg/dL decrease in corrected serum calcium 7 days after retreatment.1, 52, 53
Safety and efficacy of pamidronate for the treatment of hypercalcemia associated with hyperparathyroidism or with other non-tumor-related conditions have not been established.1, 52, 53
Pamidronate is used in the management of moderate to severe, symptomatic Paget's disease of bone (osteitis deformans).1, 6, 7, 8, 9, 11, 13, 15, 16, 25, 26, 40, 52, 53 Paget's disease of bone is an idiopathic disease characterized by chronic, focal areas of bone destruction complicated by excessive bone repair, affecting one or more bones.1, 52, 53 Signs and symptoms of Paget's disease of bone include bone pain, deformity, fractures, neurologic disorders resulting from cranial and spinal nerve entrapment and spinal cord and brain stem compression, increased cardiac output to the involved bone, and increased serum alkaline phosphatase concentrations (reflecting increased bone formation) and/or urinary hydroxyproline excretion (reflecting increased bone resorption).1, 52, 53
The efficacy of pamidronate has been shown mainly in patients with symptomatic Paget's disease of bone (multiple bone involvement [polyostotic] and elevated concentrations of serum alkaline phosphatase and urinary hydroxyproline).7, 8, 13, 20 In most patients with Paget's disease of bone, only small areas of bone are involved and patients usually are asymptomatic; mild symptoms in such patients usually can be controlled with analgesics alone.6 The principal goal in the treatment of Paget's disease of bone is to provide sustained control of abnormal bone turnover, as indicated by a return of biochemical markers (e.g., serum alkaline phosphatase, urine hydroxyproline concentrations) to near normal.6, 16, 40 Normalization of biochemical markers of bone is associated with symptomatic improvement of Paget's disease, radiologic improvement of bone lesions, and a reduction in the appearance of subsequent fractures.1, 40, 52, 53
Pamidronate decreases bone resorption, with bone formation continuing initially; eventually, the balance between bone formation and resorption is restored at a lower level of bone turnover.19, 40 Reduced urinary excretion of hydroxyproline often is the initial sign of therapeutic response and usually is evident within the first week of initiation of therapy.6, 7, 8, 9, 11, 16, 25, 26, 40 In one study, serum calcium and calcium excretion reached nadirs within 6-8 days after therapy with IV pamidronate given for a mean of 5-7 days.26 Hydroxyproline excretion also declined rapidly, reaching a nadir at 5-10 days; without retreatment, excretion returned to about 50% of pretreatment values within 3-6 months.26 Symptomatic relief of bone pain usually is evident within 0.5-3 months after therapy and is accompanied by an increase in mobility.8, 13, 40 The proportion of patients who achieve normal bone turnover depends on severity of disease.6, 15, 26, 40 A return to normal values of indices of bone turnover generally occurs within 3 months of initiating pamidronate therapy in most patients with mild Paget's disease of bone.8, 11, 14, 16, 26, 40 Patients with more severe disease may not achieve normal bone turnover; a therapeutic response in such patients may be indicated by a 30-50% reduction in indices of bone turnover.1, 9, 10, 11, 14, 15, 16, 17, 26, 40, 52, 53 In a small clinical trial in patients with moderate to severe Paget's disease of bone, at least a 50% reduction in serum alkaline phosphatase concentrations or urinary hydroxyproline/creatinine ratios occurred in 72 or 60% of patients, respectively, receiving the recommended pamidronate disodium dosage of 30 mg IV over 4 hours once daily for 3 consecutive days; substantially less pronounced responses were observed at dosages of 5 or 15 mg once daily for 3 days.1, 52, 53 The median time to therapeutic response (at least a 50% decrease from baseline) for serum alkaline phosphatase at a total dose of 90 mg (30 mg once daily for 3 days) in this study was approximately 1 month, and the response duration ranged from 1-372 days.1, 52, 53 In this study, there were no statistically significant differences between treatment groups nor statistically significant changes from baseline in bone pain response, mobility, and global evaluation for the 45- versus 90-mg total dose groups.1, 52, 53 Improvement in radiologic lesions was apparent in some patients in the 90-mg group.1, 52, 53
Bone histology studies (i.e., bone biopsies, radiology, scintigraphy) in patients with Paget's disease of bone treated with pamidronate may show an increase in the amount of normal lamellar bone, slowing of disease progression, and/or a decrease in marrow fibrosis, thickness of osteoid seams, calcification rate, and resorption surface.7, 8, 15, 26 Patients treated with pamidronate frequently show steady improvement (clinically and biochemically), with a plateau 5-12 months after therapy, and clinical response may still be apparent despite diminution or no further improvement in biochemical parameters.7, 8, 9, 13, 17, 25, 40 The prolonged effect is thought to result from protracted binding of the drug, which is not metabolized, to the bone mineral matrix.1, 4, 15, 20, 22, 26, 52, 53
The cumulative pamidronate disodium dose that may be safely administered for initial therapy and subsequent retreatment remains to be established.17, 18 In many patients, the disease process will be suppressed for a period of at least 1 year (the upper limit of this period has not been established) following discontinuance of therapy.9, 11, 13, 14, 15, 16, 40 Once relapse occurs (i.e., indices of bone turnover begin to rise above prior nadir) or if clinical and biochemical parameters do not return to normal values following initial treatment, patients may be retreated with pamidronate.8, 9, 11, 17, 40 The time to relapse probably depends on the severity of biochemical abnormalities prior to therapy and/or the number of lesions detected.11, 13, 14, 15, 16, 26, 40 In one study in patents retreated with 30 mg of pamidronate disodium once daily for 3 days, at least a 50% reduction from baseline in serum alkaline phosphatase concentrations or urinary hydroxyproline/creatinine ratios occurred in 44 or 39% of patients, respectively.1, 52, 53 Many patients who receive a second course (and subsequent additional courses) of pamidronate therapy after relapse of biochemical and/or clinical symptoms may respond about as well as during the first treatment period.9, 11, 13, 15 However, some patients do not respond to the drug with initial or subsequent courses of therapy, even at the maximum recommended dosage.13, 15, 40 Variable response to therapy is postulated to be the result of differences in the vascularity of lesions, amount of abnormal (i.e., woven) bone present, or the thickness of the involved bone.15
Correction of the biochemical abnormalities of Paget's disease may prevent or slow progression of some complications such as deformities, arthritis, fractures, neurologic manifestations, spinal cord compression, and heart failure, but may not reverse some of these complications (e.g., severe deformities, deafness) once they have become established.11, 26, 40 Therefore, early treatment may be particularly important in patients with bone sites, such as skull, weight-bearing bones, and sites near joints, which may be likely to produce late complications.11, 40
The relative efficacy of pamidronate versus calcitonin or etidronate in the treatment of Paget's disease of bone has not been determined, but patients refractory to calcitonin or etidronatemay respond to a subsequent course of pamidronate.8, 9, 11, 13, 16 It has been suggested that pamidronate may offer a greater potency for decreasing bone resorption and greater possibility of returning bone turnover to normal, as well as a decreased risk of developing mineralization defects, relative to etidronate, but additional study and experience are needed to establish the relative roles of these drugs.8, 9, 11, 13, 16, 18
Osteolytic Bone Metastases of Breast Cancer and Osteolytic Lesions of Multiple Myeloma
Pamidronate is used as an adjunct to antineoplastic therapy for the treatment of osteolytic bone metastases of breast cancer and osteolytic lesions of multiple myeloma.1, 20, 29, 52, 53 These cancers exhibit an extraordinary affinity for bone (osteotropism), and the hematogenous dissemination of tumor cells in these cancers is predominantly to sites in the axial skeleton (e.g., spine, pelvis, ribs) rather than the appendicular skeleton, although lesions in the femur and humerus are not uncommon.1, 21, 52, 53 Trabecular bone is more affected than cortical bone, as the surface-to-volume ratio of trabecular bone is much higher than cortical bone.1, 52, 53 Osteolytic destruction leads to severe bone pain and immobility; such bone pain generally requires either radiation therapy and/or opiate analgesics for symptomatic relief.1, 20, 24, 52, 53 Axial skeletal fractures of vertebrae may lead to spinal compression with neurologic complications.1 Increased bone resorption from osteolytic lesions may lead to episodes of hypercalcemia.1, 24, 29, 52, 53
Osteolytic Metastases Associated with Breast Cancer
The efficacy of pamidronate, usually in combination with antineoplastic therapy (e.g., chemotherapy, hormonal therapy), has been demonstrated in patients with advanced breast cancer and progressive bone metastasis.20, 23, 24, 27 Pamidronate frequently has been used with antineoplastic therapy that included doxorubicin, fluorouracil, cyclophosphamide, methotrexate, mitoxantrone, vinblastine, dexamethasone, prednisone, melphalan, vincristine, megestrol, and/or tamoxifen, and less frequently with antineoplastic therapy that included etoposide, cisplatin, cytarabine, paclitaxel, and/or aminoglutethimide.1, 52, 53 The clinical efficacy of therapy for osteolytic bone metastasis in these studies generally was evaluated in terms of reduction of bone destruction and in the severity of self-rated bone pain.1, 23, 24, 27, 52, 53 The pamidronate treatment effect has been smaller in patients with breast cancer receiving the drug as an adjunct to hormonal therapy compared with those receiving the drug as an adjunct to chemotherapy.1, 52, 53 In several long-term trials, breast cancer patients with osteolytic bone metastases (as indicated by at least one lesion of at least 1 cm in diameter) receiving combined pamidronate disodium (45-90 mg, administered as a 2-hour IV infusion once every 3-4 weeks for 8-24 months) and antineoplastic therapy or antineoplastic therapy alone showed a decrease in the incidence and a delay in the development of bone-related complications (e.g., fractures, spinal cord compression, bone deterioration requiring radiotherapy, orthopedic surgery), and a moderate to marked improvement in bone pain with a reduction in the need for supplemental analgesic therapy.1, 23, 24, 27, 52, 53 Radiographic assessment of bone lesions at 3, 6, and 12 months indicated a response (complete plus partial) to therapy in 33% of patients receiving adjunctive pamidronate therapy and in 18% of patients receiving chemotherapy alone; no differences in bone lesion response were noted between patients receiving combined pamidronate and hormonal therapy versus hormonal therapy alone.1, 27, 52, 53 Symptomatic improvement was associated with reductions in biochemical markers of bone resorption, urinary calcium excretion, and urinary hydroxyproline in patients with breast cancer metastases receiving IV pamidronate.10, 20, 28 Deteriorations in secondary end points of pain, quality of life, and performance status generally were less in patients receiving adjunctive pamidronate.1, 52, 53
Osteolytic Lesions of Multiple Myeloma
The efficacy of pamidronate, usually in combination with antineoplastic therapy (e.g., chemotherapy), has been shown in patients with multiple myeloma and progressive bone lesions.1, 29, 52, 53 In a long-term trial, patients with stage III multiple myeloma (at least one osteolytic bone lesion) receiving combined pamidronate disodium (90 mg, administered as a 4-hour IV infusion, once monthly) and antineoplastic chemotherapy showed a decrease in the incidence and a delay in the development of bone-related complications (e.g., fractures, spinal cord compression, bone deterioration requiring radiotherapy, orthopedic surgery), a decrease in the incidence of hypercalcemia, and a reduction in bone pain and in the need for supplemental analgesic therapy compared with those receiving chemotherapy alone.1, 29, 52, 53 The proportion of multiple myeloma patients experiencing bone-related complications overall was substantially smaller in the adjunctive pamidronate group compared with chemotherapy alone (24 versus 41%, respectively) as was the proportion of those suffering pathologic fractures in particular (17 versus 30%, respectively) or needing radiation therapy of bone (14 versus 22%, respectively)1, 29, 52, 53 Pamidronate-treated patients with pain also experienced a decrease in pain scores from baseline, and unlike those receiving chemotherapy alone, those receiving pamidronate did not experience a significant deterioration in quality of life or Eastern Cooperative Oncology Group (ECOG) performance relative to baseline.1, 52, 53 After 21 months, the proportion of patients experiencing any bone-related complication remained smaller in the group receiving adjunctive pamidronate compared with antineoplastic therapy alone.1 In addition, the mean skeletal morbidity rate (number of bone-related complications per year) was 1.3 versus 2.2, respectively, and the time to first bone-related complication was longer in the group receiving adjunctive pamidronate therapy.1, 52, 53 Fewer patients receiving pamidronate disodium 90 mg once monthly developed pathologic vertebral fractures (16 versus 27%, respectively), although overall survival did not differ between the treatment groups.1, 52, 53
Reconstitution and Administration
Pamidronate disodium is administered by IV infusion for the treatment of malignancy-associated hypercalcemia, Paget's disease of bone, and malignancy-associated osteolytic bone lesions.1, 3, 4, 5, 8, 11, 14, 16, 20, 23, 24, 26, 27, 29, 40, 52, 53
Pamidronate disodium is commercially available as a lyophilized powder for injection1, 53 and as an injection concentrate.52, 53 The lyophilized powder for injection is reconstituted by adding 10 mL of sterile water for injection to a vial labeled as containing 30 or 90 mg of pamidronate disodium; when reconstituted as directed, the resultant solutions contain 3 or 9 mg of pamidronate disodium per mL, respectively.1, 53 The contents of the reconstituted vials should be allowed to dissolve completely before withdrawing a dose.1 Reconstituted solutions of pamidronate disodium are stable for up to 24 hours when refrigerated at 2-8°C.1, 53
Both the reconstituted solution of pamidronate disodium for injection and the injection concentrate must be further diluted before IV infusion.1, 52, 53 The drug should not be mixed with calcium-containing infusion solutions; it should be administered as a single IV infusion in an IV line separate from all other drugs.1, 52, 53, 54 Pamidronate should be infused slowly to decrease the risk of adverse effects (e.g., infusion site reactions, renal impairment).6, 17 For the treatment of malignancy-associated hypercalcemia, the calculated daily dose of pamidronate disodium should be diluted in 1 L of 0.45 or 0.9% sodium chloride solution injection or 5% dextrose injection;1, 52, 53 doses of 60-90 mg should be infused over 2-24 hours.1, 52, 53 When diluted as directed, these infusion solutions are stable for up to 24 hours at room temperature.1, 52, 53 For the treatment of Paget's disease of bone, the appropriate dose of pamidronate disodium should be diluted in 500 mL of 0.45 or 0.9% sodium chloride injection or 5% dextrose injection and infused over a 4-hour period once daily for 3 consecutive days; this dilution volume is recommended to avoid venous irritation at the infusion site.1, 17, 52, 53 For the treatment of osteolytic bone metastases of breast cancer, the appropriate dose of the drug should be diluted in 250 mL of 0.45 or 0.9% sodium chloride injection or 5% dextrose injection and infused over a 2-hour period once every 3-4 weeks.1, 52, 53 For treatment of osteolytic bone lesions of multiple myeloma, the appropriate dose of pamidronate disodium should be diluted in 500 mL of 0.45 or 0.9% sodium chloride injection or 5% dextrose injection and infused over a 4-hour period once monthly.1, 52, 53
The manufacturers state that safety and efficacy of pamidronate in children younger than 18 years of age have not been established.1, 2, 52, 53
Pamidronate should not be used in pregnant women; women of childbearing potential should avoid conception during drug therapy since the drug may cause fetal harm.1, 52, 53 (See Fetal/Neonatal Morbidity and Mortality under Cautions: Warning/Precautions, in Zoledronic Acid 92:24.)
Standard laboratory and clinical parameters of renal function (including serum creatinine) should be monitored prior to each treatment in patients receiving pamidronate therapy.1, 52, 53 Complete blood counts with differential and hematocrit/hemoglobin and standard hypercalcemia-related metabolic parameters, including serum concentrations of calcium, phosphate, magnesium, and potassium, also should be monitored carefully following initiation of pamidronate therapy.1, 52, 53 Cases of asymptomatic hypophosphatemia,1, 3, 30, 31, 33, 52, 53 hypokalemia,1, 52, 53 hypomagnesemia,1, 33, 38, 52, 53 and hypocalcemia1, 3, 9, 11, 30, 33, 52, 53 have been reported in 12, 7, 11, and 5-12% of patients, respectively, receiving the drug in clinical studies.1, 52, 53 Symptomatic hypocalcemia, including tetany, has been reported rarely.1, 52, 53 If hypocalcemia occurs, short-term calcium and/or vitamin D therapy may be necessary.1, 17, 19, 52, 53 In patients with Paget's disease of bone treated with 30 mg of pamidronate disodium once daily for 3 consecutive days, serum calcium concentrations declined to less than 8 mg/dL in 17% of patients in clinical studies.1, 52, 53 Infusion-site reactions (e.g., erythema, edema, induration, pain on palpation, thrombophlebitis) and transient low-grade fever occur commonly with IV infusion of pamidronate.1, 3, 9, 10, 16, 20, 22, 30, 33, 52, 53
Osteonecrosis and osteomyelitis of the jaw have been reported in patients receiving bisphosphonates.1, 41, 42, 43, 44, 45, 46, 47, 52, 53 Most instances of osteonecrosis of the jaw have been observed during IV bisphosphonate therapy, but some patients have experienced this adverse effect during oral bisphosphonate therapy.51, 52, 53 Most of these patients had neoplasms and were receiving concurrent chemotherapy, head and neck radiation therapy, and corticosteroids.1, 46, 47, 52, 53 Postmarketing experience and literature reports suggest a greater frequency of cases associated with tumor type (advanced breast cancer, multiple myeloma) and dental status (e.g., tooth extraction, periodontal disease, poorly fitting dentures).41, 42, 43, 44, 45, 46, 52, 53 Good oral hygiene and a dental examination (panoramic jaw radiograph) to detect dental and periodontal infections, with appropriate preventive dentistry (e.g., removal of abscessed and nonrestorable teeth and involved periodontal tissues, rehabilitation of salvageable dentition, dental prophylaxis and caries control, restorative dental care), are recommended prior to treatment with bisphosphonates in patients with cancer.1, 41, 42, 43, 46, 47, 52, 53 Such patients should avoid invasive dental procedures if possible during treatment with bisphosphonates, as dental surgery may exacerbate the condition.1, 42, 43, 46, 47, 52, 53 (See Musculoskeletal Effects under Cautions: Warnings/Precautions, in Zoledronic Acid 92:24.)
Severe, occasionally incapacitating bone, joint, and/or muscle pain have been reported infrequently during postmarketing experience in patients receiving bisphosphonates, including pamidronate.1, 42, 48, 49, 51, 52, 53 The time to onset of symptoms varied from 1 day to years (mean onset about 3 months) after treatment initiation.1, 42, 48, 51, 52, 53 Musculoskeletal pain has improved following discontinuance of the drug in most patients; however, some patients have reported slow or incomplete resolution of such pain.1, 42, 48, 51, 52, 53 In some patients, musculoskeletal pain recurred upon subsequent rechallenge with the same drug or another bisphosphonate.1, 49, 51, 52, 53 (See Musculoskeletal Effects, under Cautions: Warnings/Precautions, in Zoledronic Acid 92:24.)
While data are conflicting, a possible increased risk of atrial fibrillation has been identified with use of bisphosphonates.50 (See Atrial Fibrillation, under Cautions: Warnings/Precautions, in Zoledronic Acid 92:24.)
When clinically indicated, patients can be retreated with pamidronate; however, the cumulative dose that may be administered in initial and subsequent courses of therapy with the drug remains to be established.1, 17, 18, 52, 53 In patients with hypercalcemia of malignancy, at least 7 days should elapse before retreatment is considered so that the full response to the previous dose can be assessed.1, 52, 53 In patients with Paget's disease of bone, pamidronate therapy can be repeated if clinically necessary.1, 52, 53 In patients with osteolytic bone metastases and lesions of cancer, prolonged therapy generally is required; the drug has been given once every 3-4 weeks for up to at least 21-24 months in clinical studies.1, 52, 53
Patients should be adequately hydrated throughout treatment, but overhydration should be avoided, especially in patients at risk for the development of cardiac failure.1, 52, 53 Vigorous saline hydration alone may be adequate in patients with mild, asymptomatic hypercalcemia of malignancy.1, 52, 53
For the treatment of moderate hypercalcemia (albumin-corrected serum calcium concentration of approximately 12-13.5 mg/dL) associated with malignancy in adults, the manufacturer recommends that pamidronate disodium be infused IV as a single dose of 60-90 mg; such doses should be infused over 2-24 hours.1, 52, 53 For severe malignancy-associated hypercalcemia (albumin-corrected serum calcium concentration exceeding 13.5 mg/dL) in adults, the manufacturer recommends that the drug be infused IV over 2-24 hours as a single 90-mg dose.1, 52, 53 A longer duration of infusion (i.e., exceeding 2 hours) in patients receiving the 60- or 90-mg dose may reduce the risk for renal toxicity, particularly in patients with preexisting renal insufficiency.1, 52, 53 If hypercalcemia recurs, the dose appropriate for the degree of hypercalcemia can be repeated; the manufacturer recommends that the repeat dose not be given sooner than 7 days after the initial dose in order to allow full response to this dose.1, 52, 53 The manufacturer also states that experience with repeat courses of pamidronate currently is limited.1, 52, 53
For the treatment of moderate to severe Paget's disease of bone, the initial adult dosage of IV pamidronate disodium recommended by the manufacturer is 30 mg, administered as a 4-hour infusion, once daily on 3 consecutive days for a total cumulative dose of 90 mg for the course.1, 52, 53 In patients with Paget's disease of bone, the onset of therapeutic response to pamidronate usually is evident within the first week, and therapeutic effects may persist for months after the drug has been withdrawn.1, 17, 52, 53 Therapeutic response to pamidronate for the treatment of Paget's disease of bone generally continues for 5-12 months after a course of therapy, and patients should be monitored periodically (e.g., serum alkaline phosphatase concentrations and urinary hydroxyproline) for recurrence of disease.7, 8, 9, 13, 17, 25, 40
In the absence of hypercalcemia, patients with Paget's disease of bone, who are at risk for calcium or vitamin D deficiency, should be given oral calcium and vitamin D supplementation to minimize the risk of hypocalcemia.1, 52, 53
Osteolytic Bone Metastases of Breast Cancer
For the treatment of osteolytic bone metastases associated with breast cancer, the initial adult dosage regimen of IV pamidronate disodium recommended by the manufacturer is 90 mg, administered as a 2-hour infusion, given once every 3-4 weeks.1, 52, 53 The optimum duration of such therapy is not known, but some patients have received the drug for at least up to 24 months in clinical studies.1, 52, 53 In patients with breast cancer-associated bone metastases, the onset of a decrease in bone pain usually is evident within 2 weeks.1, 20
In the absence of hypercalcemia, patients with predominantly lytic bone metastases, who are at risk for calcium or vitamin D deficiency, should be given oral calcium and vitamin D supplementation to minimize the risk of hypocalcemia.1, 52, 53
Osteolytic Bone Lesions of Multiple Myeloma
In patients with multiple myeloma and marked Bence-Jones proteinuria, it is important that the patient be adequately hydrated with 0.9% sodium chloride injection prior to initiation of the pamidronate infusion.1, 39, 52, 53
For the treatment of osteolytic bone lesions associated with multiple myeloma, the manufacturer recommends an initial IV pamidronate disodium dosage regimen of 90 mg, administered as a 4-hour infusion, given once monthly in adults who have been adequately rehydrated.1, 52, 53 The optimum duration of therapy currently is not known, but monthly doses have been administered for at least up to 21 months in some patients.1, 52, 53
In the absence of hypercalcemia, patients with multiple myeloma, who are at risk for calcium or vitamin D deficiency, should be given oral calcium and vitamin D supplementation to minimize the risk of hypocalcemia.1, 52, 53
Dosage in Renal and Hepatic Impairment
Renal impairment, which may progress to renal failure, has occurred following administration of bisphosphonates, including pamidronate.1, 52, 53 Focal segmental glomerulonephritis (including collapsing variant) with or without nephrotic syndrome has been reported in patients receiving pamidronate, particularly in patients with multiple myeloma or breast cancer; gradual improvement in some patients occurred following drug discontinuance.1, 52, 53 The risk of renal toxicity may be greater in patients with impaired renal function.1, 52, 53 Single doses of pamidronate disodium should not exceed 90 mg and the duration of IV infusion should be no less than 2 hours.1, 52, 53 Serum creatinine should be monitored in all patients receiving pamidronate, and possible deterioration in renal function must be assessed prior to administration of each dose.1, 52, 53 If patients with bone metastases associated with solid tumors or with osteolytic lesions associated with multiple myeloma experience a deterioration in renal function (defined as an increase in serum creatinine concentration of at least 0.5 or 1 mg/dL in patients with normal [less than 1.4 mg/dL] or elevated [1.4 mg/dL or greater] baseline serum creatinine concentrations, respectively) during therapy with pamidronate, the drug should be withheld; in clinical trials, pamidronate therapy was not resumed until serum creatinine concentrations had returned to within 10% of baseline concentrations.1, 52, 53
Safety and efficacy of pamidronate in patients with severe renal impairment (serum creatinine concentration exceeding 5 mg/dL) remain to be established; only a few patients with multiple myeloma and serum creatinine concentrations of 3 mg/dL or greater have received the drug in clinical studies.1 Use of pamidronate in patients with bone metastases and severe renal impairment is not recommended by the manufacturer.1, 52, 53 In other indications, clinicians should carefully weigh the possible benefits and risks of pamidronate therapy in patients with such degrees of renal impairment.1, 52, 53 Cancer patients with renal impairment clear pamidronate more slowly than cancer patients without evidence of renal impairment, and renal clearance of the drug closely correlates with creatinine clearance.1, 52, 53 The manufacturer states that accumulation of pamidronate disodium in renally impaired patients is not anticipated when a dose of 90 mg is infused IV over 4 hours on a monthly basis.1, 52, 53
Following administration of a single dose of pamidronate disodium (90 mg infused over 4 hours) in patients with neoplasms who were at risk for bone metastases and had mild to moderate hepatic dysfunction, peak blood concentrations and area under the blood concentration-time curve (AUC) were increased by 29 and 53%, respectively, and plasma clearance was decreased by 33% compared with values in patients with normal hepatic function.1, 52, 53 Such differences are not considered clinically important, and no dosage adjustments are necessary in patients with mild to moderate hepatic impairment.1, 52, 53 The pharmacokinetics of pamidronate have not been determined in patients with severe hepatic impairment.1, 52, 53
Pamidronate disodium, a synthetic bisphosphonate (also referred to as diphosphonate) analog of pyrophosphate, is an inhibitor of bone resorption.1, 3, 4, 5, 52, 53 Pamidronate is structurally and pharmacologically related to etidronate.3, 5 Unlike pyrophosphate but like etidronate, pamidronate is resistant to enzymatic hydrolysis by phosphatases.5
Additional Information
SumMon® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the labeling be consulted for detailed information on the usual cautions, precautions, and contraindications.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | For injection, for IV infusion | 30 mg* | ||
Pamidronate Disodium for Injection | ||||
90 mg* | Aredia® | Novartis | ||
Pamidronate Disodium for Injection | ||||
Injection, for IV infusion | 30 mg* | Pamidronate Disodium Injection | ||
60 mg* | Pamidronate Disodium Injection | |||
90 mg* | Pamidronate Disodium Injection |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
AHFS® Drug Information. © Copyright, 1959-2025, Selected Revisions July 2, 2012. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
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