ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS. Clinical Studies. Hypercalcemia of Malignancy. Transient mild elevation of temperature by at least 1C 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 temperature elevation of at least 1C 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, of whom had preexisting seizure disorders. None of the seizures were considered to be drug-related by the investigators. However, possible relationship between the drug and the occurrence of seizures cannot be ruled out. It should be noted that in the saline arm patient (4%) had seizure.There are no controlled clinical trials comparing the efficacy and safety of 90 mg pamidronate disodium over 24 hours to hours in patients with hypercalcemia of malignancy. However, 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 hours. The only notable differences observed were an increase in the proportion of patients in the pamidronate 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 clinical trial:General Fluid overload, generalized painCardiovascular HypertensionGastrointestinal Abdominal pain, anorexia, constipation, nausea, vomitingGenitourinary Urinary tract infectionMusculoskeletal Bone painLaboratory abnormality Anemia, hypokalemia, hypomagnesemia, hypophosphatemiaMany 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 TrialsPercent of PatientsPamidronate Disodium Editronate disodium Saline 60 mg over hr n=23 60 mg over 24 hr n=73 90 mg over 24 hr n=17 7.5 mg/kg 3 days n=35 n=23 GeneralEdema 1 0 Fatigue 0 12 0 Fever 26 19 18 0 Fluid overlaod 0 6 Infusion-site reaction 4 18 0 Moniliasis 0 0 Rigors 0 0 GastrointestinalAbdominal pain 1 0 Anorexia 1 12 0 Constipation 0 3 Diarrhea 1 0 Dyspepsia 0 0 Gatrointestinal hemorrhage 0 0 Nausea 0 18 0 Stomatitis 1 3 Vomiting 0 0 RespiratoryDyspnea 0 3 Rales 0 0 Rhinitis 0 0 Upper respiratory infection 3 0 CNSAnxiety 0 0 Convulsions 0 3 Insomnia 1 0 Nervousness 0 0 Psychosis 0 0 Somnolence 1 0 Taste perversion 0 3 CardiovascularAtrial fibrillation 0 0 Atrial flutter 1 0 Cardiac failure 1 0 Hypertension 0 0 Syncope 0 0 Tachycardia 0 0 EndocrineHypothyroidism 0 0 Hemic and LymphaticAnemia 0 0 Leukopenia 0 0 Neutropenia 1 0 Thrombocytopenia 1 0 MusculoskeletalMyalgia 1 0 UrogenitalUremia 0 0 Laboratory AbnormalitiesHypocalcemia 1 12 0 Hypokalemia 4 18 0 Hypomagnesemia 10 12 4 Hypophosphatemia 9 18 0 Abnormal liver function 0 3 . Pagets Disease. Transient mild elevation of temperature >1C 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 Pagets 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 Pagets 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 Pagets disease also experienced the following adverse experiences during clinical trials:Cardiovascular HypertensionMusculoskeletal Arthrosis, bone painNervous system HeadacheMost of these adverse experiences may have been related to the underlying disease state.. Osteolytic Bone Metastases of Breaset 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 TrialsPamidronateDisodium90 mgover hoursN=205PlaceboN=187PamidronateDisodium90 mgOver hoursN=367PlaceboN=386AllPamidronate Disodium90 mgN=572PlaceboN=573% % % GeneralAsthenia 16.1 17.1 25.6 19.2 22.2 18.5 Fatigue 31.7 28.3 40.3 28.8 37.2 29 Fever 38.5 38 38.1 32.1 38.5 34 Metastases 3 31.3 24.4 20.5 17.5 Pain 13.2 11.8 15 18.1 14.3 16.1 Digestive systemAnorexia 17.1 17.1 31.1 24.9 26 22.3 Constipation 28.3 31.7 36 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 22.6 17.5 Nausea 35.6 37.4 63.5 59.1 53.5 51.8 Pain Abdominal 19.5 16 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 14 15 Musculoskeletal SystemArthralgias 10.7 15.3 12.7 13.6 10.8 Myalgia 25.4 15 26.4 22.5 26 20.1 Skeletal Pain 61 71.7 70 75.4 66.8 74 CNSAnxiety 7.8 9.1 18 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 Respiratory SystemCoughing 26.3 22.5 25.3 19.7 25.7 20.6 Dyspnea 22.2 21.4 35.1 24.4 30.4 23.4 Pleural Effusion 2.9 4.3 15 9.1 10.7 7.5 Sinusitis 14.6 16.6 16.1 10.4 15.6 12 Upper Respriatory Tract Infection 32.3 28.3 19.6 20.2 24.1 22.9 Urogenital SystemUrinary 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 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, hypophophatemia, 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. In previous hypercalcemia of malignancy trials, patients treated with pamidronate disodium (60 or 90 mg over 24 hours) developed electrolyte abnormalities more frequently (see ADVERSE REACTIONS, Hypercalcemia of Malignancy).Arthralgias and myalgias were reported slightly more frequently in the pamidronate disodium group than in the placebo group (13.6% and 26% vs 10.8% and 20.1%, respectively).In multiple myeloma patients, there were five pamidronate disodium-related serious and unexpected adverse experiences. Four of these were reported during the 12 month extension of the multiple myeloma trial. Three of the reports were of worsening renal function developing in patients with progressive multiple myeloma or multiple myeloma-associated amyloidosis. The fourth report was the adult respiratory distress syndrome developing in patient recovering from pneumonia and acute gangrenous cholecystitis. One pamidronate disodium-treated patient experienced an allergic reaction characterized by swollen and itchy eyes, runny nose, and scratchy throat within 24 hours after the sixth infusion.In the breast cancer trials, there were four pamidronate disodium-related adverse experiences, all moderate in severity, that caused patient to discontinue participation in the trial. One was due to interstitial pneumonitis, another to malaise and dyspnea. One pamidronate disodium patient discontinued the trial due to symptomatic hypocalcemia. Another pamidronate disodium patient discontinued therapy due to severe bone pain after each infusion, which the investigator felt was trial-drug-related.. Renal Toxicity. In study of the safety and efficacy of pamidronate disodium 90 mg (2 hour infusion) versus Zometa(R) mg (15 minute infusion) in bone metastases patients with multiple myeloma or breast cancer, renal deterioration was defined as an increase in serum creatinine of 0.5 mg/dL for patients with normal baseline creatinine (<1.4 mg/dL) or an increase of 1.0 mg/dL for patients with an abnormal baseline creatinine (>=1.4 mg/dL). The following are data on the incidence of renal deterioration in patients in this trial. See table below.Incidence of Renal Function Deterioration in Multiple Myeloma and Breast Cancer Patients with Normal and Abnormal Serum Creatinine at BaselinePatient Population/Baseline CreatininePD 90 mg/2 hoursZometa(R) mg/15 minutes Patients were randomized following the 15 minute infusion amendment for the Zometa(R)arm. Zometa(R)is registered trade of Novartis. n/N (%) n/N (%) Normal 20/246 (8.1%) 23/246 (9.3%) Abnormal 2/22 (9.1%) 1/26 (3.8%) Total 22/268 (8.2%) 24/272 (8.8%) Post-Marketing Experience. The following adverse reactions have been reported in post-marketing use: 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; Renal focal segmental glomerulosclerosis including the collapsing variant, nephrotic syndrome; Laboratory abnormalities hyperkalemia, hypernatremia, hematuria. Rare instances of allergic manifestations have been reported, including hypotension, dyspnea, or angioedema, and very rarely, anaphylactic shock. Pamidronate disodium is contraindicated in patients with clinically significant hypersensitivity to pamidronate disodium or other bisphosphonates (see CONTRAINDICATIONS).Cases of osteonecrosis (primarily involving the jaw) have 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. Data suggest greater frequency of reports of ONJ in certain cancers, such as advanced breast cancer and multiple myeloma. The majority of the reported cases are in cancer patients following invasive dental procedures as recovery may be prolonged. (See PRECAUTIONS.).

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. 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 directly block dissolution of this mineral component of bone. In vitro studies also suggest that inhibition of osteoclast activity contributes to inhibition of bone resorption. In animal studies, at doses recommended for the treatment of hypercalcemia, pamidronate disodium inhibits bone resorption apparently without inhibiting bone formation and mineralization. Of relevance to the treatment of hypercalcemia of malignancy is the finding that pamidronate disodium inhibits the accelerated bone resorption that results from osteoclast hyperactivity induced by various tumors in animal studies.. Pharmacokinetics. Cancer patients (n=24) who had minimal or no bony involvement were given an intravenous infusion of 30, 60, or 90 mg of pamidronate disodium over hours and 90 mg of pamidronate disodium over 24 hours (Table 1).. Distribution. The mean +- SD body retention of pamidronate was calculated to be 54 +- 16% of the dose over 120 hours.. Metabolism. Pamidronate is not metabolized and is exclusively eliminated by renal excretion.. Excretion. After administration of 30, 60, and 90 mg of pamidronate disodium over hours, and 90 mg of pamidronate disodium over 24 hours, an overall mean +- SD of 46 +- 16% of the drug was excreted unchanged in the urine within 120 hours. Cumulative urinary excretion was linearly related to dose. The mean +- SD elimination half-life is 28 +- hours. Mean +- SD 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.. Special Populations. There are no data available on the effects of age, gender, or race on the pharmacokinetics of pamidronate.. Pediatric. Pamidronate is not labeled for use in the pediatric population.. Renal Insufficiency. The pharmacokinetics of pamidronate were studied in cancer patients (n=19) with normal and varying degrees of renal impairment. Each patient received single 90 mg dose of pamidronate disodium infused over hours. The renal clearance of pamidronate in patients was found to closely correlate with creatinine clearance (see Figure 1). trend toward lower percentage of drug excreted unchanged in urine was observed in renally impaired patients. Adverse experiences noted were not found to be related to changes in renal clearance of pamidronate. Given the recommended dose, 90 mg infused over hours, excessive accumulation of pamidronate in renally impaired patients is not anticipated if pamidronate disodium is administered on monthly basis.Figure 1. Pamidronate renal clearance as function of creatinine clearance in patients with normal and impaired renal function.The lines are the mean prediction line and 95% confidence intervals.. image. Hepatic Insufficiency. 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 single 90 mg dose of pamidronate disodium infused over hours. Although there was statistically significant 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%) and Cmax (29%), and decreased plasma clearance (33%) values. Nevertheless, pamidronate was still rapidly cleared from the plasma. Drug levels were not detectable in patients by 12 to 36 hours after drug infusion. Because pamidronate disodium is administered on monthly basis, drug accumulation is not expected. No changes in pamidronate disodium dosing regimen are recommended for patients with mild to moderate abnormal hepatic function. Pamidronate disodium has not been studied in patients with severe hepatic impairment.. Drug Drug Interactions. There are no human pharmacokinetic data for drug interactions with pamidronate disodium.Table 1. Mean (SD, CV %) Pamidronate Pharmacokinetic Parameters in Cancer Patients (n=6 for each group)Dose(infusion rate)Maximum Concentration(mcg/mL)Percent of doseexcreted in urineTotal Clearance(mL/min)Renal Clearance(mL/min)30 mg (4 hrs) 0.73 (0.14, 19.1%) 43.9 (14.0, 31.9%) 136 (44, 32.4%) 58 (27, 46.5%) 60 mg (4 hrs) 1.44 (0.57, 39.6%) 47.4 (47.4, 54.4%) 88 (56, 63.6%) 42 (28, 66.7%) 90 mg (4 hrs) 2.61 (0.74, 28.3%) 45.3 (25.8, 56.9%) 103 (37, 35.9%) 44 (16, 36.4%) 90 mg (24 hrs) 1.38 (1.97, 142.7%) 47.5 (10.2, 21.5%) 101 (58, 57.4%) 52 (42, 80.8%) 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 to days; was detectable in liver and spleen for and months, respectively; and remained high in bones, trachea, and teeth for 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.. 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 decrease in serum phosphate levels. Phosphate levels usually returned toward normal within 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.. Hypercalcemia of Malignancy. Osteoclastic hyperactivity resulting in excessive bone resorption is the underlying pathophysiologic derangement in metastatic bone disease and hypercalcemia of malignancy. Excessive release of calcium into the blood as bone is resorbed results in polyuria and gastrointestinal disturbances, with progressive dehydration and decreasing glomerular filtration rate. This, in turn, results in increased renal resorption of calcium, setting up cycle of worsening systemic hypercalcemia. Correction of excessive bone resorption and adequate fluid administration to correct volume deficits are therefore essential to the management of hypercalcemia.Most cases of hypercalcemia associated with malignancy occur in patients who have breast cancer; squamous-cell tumors of the lung or head and neck; renal-cell carcinoma; and certain hematologic malignancies, such as multiple myeloma and some types of lymphomas. few less-common malignancies, including vasoactive intestinal-peptide-producing tumors and cholangiocarcinoma, have high incidence of hypercalcemia as metabolic complication. Patients who have hypercalcemia of malignancy can generally be divided into two groups, according to the pathophysiologic mechanism involved.In humoral hypercalcemia, osteoclasts are activated and bone resorption is stimulated by factors such as parathyroid-hormone-related protein, which are elaborated by the tumor and circulate systemically. Humoral hypercalcemia usually occurs in squamous-cell malignancies of the lung or head and neck or in genitourinary tumors such as renal-cell carcinoma or ovarian cancer. Skeletal metastases may be absent or minimal in these patients.Extensive invasion of bone by tumor cells can also result in hypercalcemia due to local tumor products that stimulate bone resorption by osteoclasts. Tumors commonly associated with locally mediated hypercalcemia include breast cancer and multiple myeloma.Total serum calcium levels in patients who have hypercalcemia of malignancy may not reflect the severity of hypercalcemia, since concomitant hypoalbuminemia is commonly present. Ideally, ionized calcium levels should be used to diagnose and follow hypercalcemic conditions; however, these are not commonly or rapidly available in many clinical situations. Therefore, adjustment of the total serum calcium value for differences in albumin levels is often used in place of measurement of ionized calcium; several nomograms are in use for this type of calculation (see DOSAGE AND ADMINISTRATION).. Clinical Trials. In one double-blind clinical trial, 52 patients who had hypercalcemia of malignancy were enrolled to receive 30 mg, 60 mg, or 90 mg of pamidronate disodium as single 24 hour intravenous infusion if their corrected serum calcium levels were >=12 mg/dL after 48 hours of saline hydration.The mean baseline-corrected serum calcium for the 30 mg, 60 mg, and 90 mg groups were 13.8 mg/dL, 13.8 mg/dL, and 13.3 mg/dL, respectively.The majority of patients (64%) had decreases in albumin-corrected serum calcium levels by 24 hours after initiation of treatment. Mean-corrected serum calcium levels at days to after initiation of treatment with pamidronate disodium were significantly reduced from baseline in all three dosage groups. As result, by days after initiation of treatment with pamidronate disodium, 40%, 61%, and 100% of the patients receiving 30 mg, 60 mg, and 90 mg of pamidronate disodium, respectively, had normal-corrected serum calcium levels. Many patients (33% to 53%) in the 60 mg and 90 mg dosage groups continued to have normal-corrected serum calcium levels, or partial response (>=15% decrease of corrected serum calcium from baseline), at Day 14.In second double-blind, controlled clinical trial, 65 cancer patients who had corrected serum calcium levels of >=12.0 mg/dL after at least 24 hours of saline hydration were randomized to receive either 60 mg of pamidronate disodium as single 24 hour intravenous infusion or 7.5 mg/kg of etidronate disodium as 2 hour intravenous infusion daily for days. Thirty patients were randomized to receive pamidronate disodium and 35 to receive etidronate disodium.The mean baseline-corrected serum calcium for the pamidronate disodium 60 mg and etidronate disodium groups were 14.6 mg/dL and 13.8 mg/dL, respectively.By Day 7, 70% of the patients in the pamidronate disodium group and 41% of the patients in the etidronate disodium group had normal-corrected serum calcium levels (P<0.05). When partial responders (>=15% decrease of serum calcium from baseline) were also included, the response rates were 97% for the pamidronate disodium group and 65% for the etidronate disodium group (P<0.01). Mean-corrected serum calcium for the pamidronate disodium and etidronate disodium groups decreased from baseline values to 10.4 and 11.2 mg/dL, respectively, on Day 7. At Day 14, 43% of patients in the pamidronate disodium group and 18% of patients in the etidronate disodium group still had normal-corrected serum calcium levels, or maintenance of partial response. For responders in the pamidronate disodium and etidronate disodium groups, the median duration of response was similar (7 and days, respectively). The time course of effect on corrected serum calcium is summarized in the following table.Change in Corrected Serum Calcium by Time from Initiation of TreatmentTime (hr)Mean Change from Baseline in Corrected Serum Calcium (mg/dL)1Comparison between treatment groupsBaselinePamidronate Disodium14.6 Etidronate Disodium13.8 P-Value1 24 -0.3 -0.5 48 -1.5 -1.1 72 -2.6 -2 96 -3.5 -2 <0.01 168 -4.1 -2.5 <0.01 The mean baseline-corrected serum calcium levels for pamidronate disodium 60 mg hour infusion, pamidronate disodium 60 mg 24 hour infusion, and saline infusion were 14.2 mg/dL, 13.7 mg/dL, and 13.7 mg/dL, respectively.By Day after initiation of treatment, 78%, 61%, and 22% of the patients had normal-corrected serum calcium levels for the 60 mg hour infusion, 60 mg 24 hour infusion, and saline infusion, respectively. At Day 14, 39% of the patients in the pamidronate disodium 60 mg hour infusion group and 26% of the patients in the pamidronate disodium 60 mg 24 hour infusion group had normal-corrected serum calcium levels or maintenance of partial response.For responders, the median duration of complete responses was days and 6.5 days for pamidronate disodium 60 mg hour infusion and pamidronate disodium 60 mg 24 hour infusion, respectively.In all three trials, patients treated with pamidronate disodium had similar response rates in 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 second course of 60 mg of pamidronate disodium over 4 or 24 hour period. Of these, 41% showed complete response and 16% showed partial response to the retreatment, and these responders had about 3 mg/dL fall in mean-corrected serum calcium levels days after retreatment.In fourth multicenter, randomized, double-blind trial, 103 patients with cancer and hypercalcemia (corrected serum calcium >=12.0 mg/dL) received 90 mg of pamidronate disodium as 2 hour infusion. The mean baseline corrected serum calcium was 14.0 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).. Pagets Disease. Pagets disease of bone (osteitis deformans) is an idiopathic disease characterized by chronic, focal areas of bone destruction complicated by concurrent excessive bone repair, affecting one or more bones. These changes result in thickened but weakened bones that may fracture or bend under stress. Signs and symptoms may be bone pain, deformity, fractures, neurological disorders resulting from cranial and spinal nerve entrapment and from spinal cord and brain stem compression, increased cardiac output to the involved bone, increased serum alkaline phosphatase levels (reflecting increased bone formation) and/or urine hydroxyproline excretion (reflecting increased bone resorption).. Clinical Trials. In one double-blind clinical trial, 64 patients with moderate to severe Pagets disease of bone were enrolled to receive mg, 15 mg, or 30 mg of pamidronate disodium as single hour infusion on consecutive days, for total doses of 15 mg, 45 mg, and 90 mg of pamidronate disodium.The mean baseline serum alkaline phosphatase levels were 1409 U/L, 983 U/L, and 1085 U/L, and the mean baseline urine hydroxyproline/creatinine ratios were 0.25, 0.19, and 0.19 for the 15 mg, 45 mg, and 90 mg groups, respectively.The effects of pamidronate disodium on serum alkaline phosphatase (SAP) and urine hydroxyproline/creatinine ratios (UOHP/C) are summarized in the following table:Percent of Patients with Significant Decreases in SAP and UOHP/CSAPUOHP/C% Decrease 15 mg 45 mg 90 mg 15 mg 45 mg 90 mg >=50 26 33 60 15 47 72 >=30 40 65 83 35 57 85 The median maximum percent decreases from baseline in serum alkaline phosphatase and urine hydroxyproline/creatinine ratios were 25%, 41%, and 57%, and 25%, 47%, and 61% for the 15 mg, 45 mg, and 90 mg groups, respectively. The median time to response (>=50% decrease) for serum alkaline phosphatase was approximately month for the 90 mg group, and the response duration ranged from to 372 days.No statistically significant differences between treatment groups, or statistically significant changes from baseline were observed for the bone pain response, mobility, and global evaluation in the 45 mg and 90 mg groups. Improvement in radiologic lesions occurred in some patients in the 90 mg group.Twenty-five patients who had Pagets disease were retreated with 90 mg of pamidronate disodium. Of these, 44% had >=50% decrease in serum alkaline phosphatase from baseline after treatment, and 39% had >=50% decrease in urine hydroxyproline/creatinine ratio from baseline after treatment.. Osteolytic Bone Metastases of Breast Cancer and Osteolytic Lesions of Multiple Myeloma. Osteolytic bone metastases commonly occur in patients with multiple myeloma or breast cancer. These cancers demonstrate phenomenon known as osteotropism, meaning they possess an extraordinary affinity for bone. The distribution of osteolytic bone metastases in these cancers is predominantly in the axial skeleton, particularly the spine, pelvis, and ribs, rather than the appendicular skeleton, although lesions in the proximal femur and humerus are not uncommon. This distribution is similar to the red bone marrow in which slow blood flow possibly assists attachment of metastatic cells. The surface-to-volume ratio of trabecular bone is much higher than cortical bone, and therefore disease processes tend to occur more floridly in trabecular bone than at sites of cortical tissue.These bone changes can result in patients having evidence of osteolytic skeletal destruction leading to severe bone pain that requires either radiation therapy or narcotic analgesics (or both) for symptomatic relief. These changes also cause pathologic fractures of bone in both the axial and appendicular skeleton. Axial skeletal fractures of the vertebral bodies may lead to spinal cord compression or vertebral body collapse with significant neurologic complications. Also, patients may experience episode(s) of hypercalcemia.. Clinical Trials. In double-blind, randomized, placebo-controlled trial, 392 patients with advanced multiple myeloma were enrolled to receive pamidronate disodium or placebo in addition to their underlying antimyeloma therapy to determine the effect of pamidronate disodium on the occurrence of skeletal-related events (SREs). SREs were defined as episodes of pathologic fractures, radiation therapy to bone, surgery to bone, and spinal cord compression. Patients received either 90 mg of pamidronate disodium or placebo as monthly hour intravenous infusion for months. Of the 392 patients, 377 were evaluable for efficacy (196 pamidronate disodium, 181 placebo). The proportion of patients developing any SRE was significantly smaller in the pamidronate disodium group (24% vs 41%, P<0.001), and the mean skeletal morbidity rate (SRE/year) was significantly smaller for pamidronate disodium patients than for placebo patients (mean: 1.1 vs 2.1, P<0.02). The times to the first SRE occurrence, pathologic fracture, and radiation to bone were significantly longer in the pamidronate disodium group (P=.001, .006, and .046, respectively). Moreover, fewer pamidronate disodium patients suffered any pathologic fracture (17% vs 30%, P=.004) or needed radiation to bone (14% vs 22%, P=.049). In addition, decreases in pain scores from baseline occurred at the last measurement for those pamidronate disodium patients with pain at baseline (P=.026) but not in the placebo group. At the last measurement, worsening from baseline was observed in the placebo group for the Spitzer quality of life variable (P<.001) and ECOG performance status (P<.011) while there was no significant deterioration from baseline in these parameters observed in pamidronate disodium-treated patients.After 21 months, the proportion of patients experiencing any skeletal event remained significantly smaller in the pamidronate disodium group than the placebo group (P=.015). In addition, the mean skeletal morbidity rate (SRE/year) was 1.3 vs 2.2 for pamidronate disodium patients vs placebo patients (P=.008), and time to first SRE was significantly longer in the pamidronate disodium group compared to placebo (P=.016). Fewer pamidronate disodium patients suffered vertebral pathologic fractures (16% vs 27%, P=.005). Survival of all patients was not different between treatment groups.Two double-blind, randomized, placebo-controlled trials compared the safety and efficacy of 90 mg of pamidronate disodium infused over hours every to weeks for 24 months to that of placebo in preventing SREs in breast cancer patients with osteolytic bone metastases who had one or more predominantly lytic metastases of at least cm in diameter: one in patients being treated with antineoplastic chemotherapy and the second in patients being treated with hormonal antineoplastic therapy at trial entry.382 patients receiving chemotherapy were randomized, 185 to pamidronate disodium and 197 to placebo. 372 patients receiving hormonal therapy were randomized, 182 to pamidronate disodium and 190 to placebo. All but three patients were evaluable for efficacy. Patients were followed for 24 months of therapy or until they went off 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. The efficacy results are shown in the table below:Breast Cancer PatientsReceiving ChemotherapyBreast Cancer PatientsReceiving Hormonal TherapyFractures and radiation to bone were two of several secondary endpoints. The statistical significance of these analyses may be overestimated since numerous analyses were performed. NR Not Reached Any SRE Radiation Fractures Any SRE Radiation Fractures PD PD PD PD PD PD N 185 195 185 195 185 195 182 189 182 189 182 189 Skeletal Morbidity Rate(SRE/Year) Mean 2.5 3.7 0.8 1.3 1.6 2.2 2.4 3.6 0.6 1.2 1.6 2.2 P-value <.001 <.001 .018 .021 .013 .040 Proportion of Patients having an SRE 46% 65% 28% 45% 36% 49% 55% 63% 31% 40% 45% 55% P-value <.001 <.001 <.014 .094 .058 .054 Median Time to SRE(months) 13.9 7.0 NR 14.2 25.8 13.3 10.9 7.4 NR 23.4 20.6 12.8 P-value <.001 <.001 .009 .118 .016 .113 Pain and analgesic scores, ECOG performance status and Spitzer quality of life index were measured at baseline and periodically during the trials. The changes from baseline to the last measurement carried forward are shown in the following table:Mean Change () from Baseline at Last MeasurementBreast Cancer PatientsReceiving ChemotherapyBreast Cancer Patients Receiving Hormonal TherapyDecreases in pain, analgesic scores and ECOG PS, and increases in Spitzer QOL indicate an improvement from baseline. The statistical significance of analyses of these secondary endpoints of pain, quality of life, and performance status in all three trials may be overestimated since numerous analyses were performed.Pamidronate Disodium (PD) Placebo (P) PD vs Pamidronate Disodium (PD) Placebo (P) PD vs N Mean Mean P- value Mean Mean P-value Pain Score 175 +0.93 183 +1.69 .050 173 +0.50 179 +1.60 .007 Analgesic Score 175 +0.74 183 +1.55 .009 173 +0.90 179 +2.28 <.001 ECOG PS 178 +0.81 186 +1.19 .002 175 +0.95 182 +0.90 .773 Spitzer QOL 177 -1.76 185 -2.21 .103 173 -1.86 181 -2.05 .409.

CLINICAL STUDIES SECTION.

Clinical Studies. Hypercalcemia of Malignancy. Transient mild elevation of temperature by at least 1C 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 temperature elevation of at least 1C 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, of whom had preexisting seizure disorders. None of the seizures were considered to be drug-related by the investigators. However, possible relationship between the drug and the occurrence of seizures cannot be ruled out. It should be noted that in the saline arm patient (4%) had seizure.There are no controlled clinical trials comparing the efficacy and safety of 90 mg pamidronate disodium over 24 hours to hours in patients with hypercalcemia of malignancy. However, 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 hours. The only notable differences observed were an increase in the proportion of patients in the pamidronate 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 clinical trial:General Fluid overload, generalized painCardiovascular HypertensionGastrointestinal Abdominal pain, anorexia, constipation, nausea, vomitingGenitourinary Urinary tract infectionMusculoskeletal Bone painLaboratory abnormality Anemia, hypokalemia, hypomagnesemia, hypophosphatemiaMany 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 TrialsPercent of PatientsPamidronate Disodium Editronate disodium Saline 60 mg over hr n=23 60 mg over 24 hr n=73 90 mg over 24 hr n=17 7.5 mg/kg 3 days n=35 n=23 GeneralEdema 1 0 Fatigue 0 12 0 Fever 26 19 18 0 Fluid overlaod 0 6 Infusion-site reaction 4 18 0 Moniliasis 0 0 Rigors 0 0 GastrointestinalAbdominal pain 1 0 Anorexia 1 12 0 Constipation 0 3 Diarrhea 1 0 Dyspepsia 0 0 Gatrointestinal hemorrhage 0 0 Nausea 0 18 0 Stomatitis 1 3 Vomiting 0 0 RespiratoryDyspnea 0 3 Rales 0 0 Rhinitis 0 0 Upper respiratory infection 3 0 CNSAnxiety 0 0 Convulsions 0 3 Insomnia 1 0 Nervousness 0 0 Psychosis 0 0 Somnolence 1 0 Taste perversion 0 3 CardiovascularAtrial fibrillation 0 0 Atrial flutter 1 0 Cardiac failure 1 0 Hypertension 0 0 Syncope 0 0 Tachycardia 0 0 EndocrineHypothyroidism 0 0 Hemic and LymphaticAnemia 0 0 Leukopenia 0 0 Neutropenia 1 0 Thrombocytopenia 1 0 MusculoskeletalMyalgia 1 0 UrogenitalUremia 0 0 Laboratory AbnormalitiesHypocalcemia 1 12 0 Hypokalemia 4 18 0 Hypomagnesemia 10 12 4 Hypophosphatemia 9 18 0 Abnormal liver function 0 3 . Pagets Disease. Transient mild elevation of temperature >1C 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 Pagets 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 Pagets 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 Pagets disease also experienced the following adverse experiences during clinical trials:Cardiovascular HypertensionMusculoskeletal Arthrosis, bone painNervous system HeadacheMost of these adverse experiences may have been related to the underlying disease state.. Osteolytic Bone Metastases of Breaset 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 TrialsPamidronateDisodium90 mgover hoursN=205PlaceboN=187PamidronateDisodium90 mgOver hoursN=367PlaceboN=386AllPamidronate Disodium90 mgN=572PlaceboN=573% % % GeneralAsthenia 16.1 17.1 25.6 19.2 22.2 18.5 Fatigue 31.7 28.3 40.3 28.8 37.2 29 Fever 38.5 38 38.1 32.1 38.5 34 Metastases 3 31.3 24.4 20.5 17.5 Pain 13.2 11.8 15 18.1 14.3 16.1 Digestive systemAnorexia 17.1 17.1 31.1 24.9 26 22.3 Constipation 28.3 31.7 36 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 22.6 17.5 Nausea 35.6 37.4 63.5 59.1 53.5 51.8 Pain Abdominal 19.5 16 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 14 15 Musculoskeletal SystemArthralgias 10.7 15.3 12.7 13.6 10.8 Myalgia 25.4 15 26.4 22.5 26 20.1 Skeletal Pain 61 71.7 70 75.4 66.8 74 CNSAnxiety 7.8 9.1 18 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 Respiratory SystemCoughing 26.3 22.5 25.3 19.7 25.7 20.6 Dyspnea 22.2 21.4 35.1 24.4 30.4 23.4 Pleural Effusion 2.9 4.3 15 9.1 10.7 7.5 Sinusitis 14.6 16.6 16.1 10.4 15.6 12 Upper Respriatory Tract Infection 32.3 28.3 19.6 20.2 24.1 22.9 Urogenital SystemUrinary 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 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, hypophophatemia, 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. In previous hypercalcemia of malignancy trials, patients treated with pamidronate disodium (60 or 90 mg over 24 hours) developed electrolyte abnormalities more frequently (see ADVERSE REACTIONS, Hypercalcemia of Malignancy).Arthralgias and myalgias were reported slightly more frequently in the pamidronate disodium group than in the placebo group (13.6% and 26% vs 10.8% and 20.1%, respectively).In multiple myeloma patients, there were five pamidronate disodium-related serious and unexpected adverse experiences. Four of these were reported during the 12 month extension of the multiple myeloma trial. Three of the reports were of worsening renal function developing in patients with progressive multiple myeloma or multiple myeloma-associated amyloidosis. The fourth report was the adult respiratory distress syndrome developing in patient recovering from pneumonia and acute gangrenous cholecystitis. One pamidronate disodium-treated patient experienced an allergic reaction characterized by swollen and itchy eyes, runny nose, and scratchy throat within 24 hours after the sixth infusion.In the breast cancer trials, there were four pamidronate disodium-related adverse experiences, all moderate in severity, that caused patient to discontinue participation in the trial. One was due to interstitial pneumonitis, another to malaise and dyspnea. One pamidronate disodium patient discontinued the trial due to symptomatic hypocalcemia. Another pamidronate disodium patient discontinued therapy due to severe bone pain after each infusion, which the investigator felt was trial-drug-related.

DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION. Hypercalcemia of Malignancy. Consideration should be given to the severity of as well as the symptoms of hypercalcemia. Vigorous saline hydration alone may be sufficient for treating mild, asymptomatic hypercalcemia. Overhydration should be avoided in patients who have potential for cardiac failure. In hypercalcemia associated with hemotologic malignancies, the use of glucocorticoid therapy may be helpful.. Moderate Hypercalcemia. The recommended dose of pamidronate disodium in moderate hypercalcemia (corrected serum calcium of approximately 12 to 13.5 mg/dL) is 60 to 90 mg given as SINGLE-DOSE, intravenous infusion over to 24 hours. Longer infusions (i.e., >2 hours) may reduce the risk of renal toxicity, particularly in patients with preexisting renal insufficiency.. Severe Hypercalcemia. The recommended dose of pamidronate disodium in severe hypercalcemia (corrected serum calcium >13.5 mg/dL) is 90 mg given as SINGLE-DOSE, intravenous infusion over to 24 hours. Longer infusions (i.e., >2 hours) may reduce the risk of renal toxicity, particularly in patients with preexisting renal insufficiency.Albumin-corrected serum calcium (CCa, mg/dL) serum calcium, mg/dL 0.8 (4.0-serum albumin, g/dL).. Retreatment. limited number of patients have received more than one treatment with pamidronate disodium for hypercalcemia. 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. It is recommended that minimum of days elapse before retreatment, to allow for full response to the initial dose. The dose and manner of retreatment is identical to that of the initial therapy.. Pagets Disease. The recommended dose of pamidronate disodium in patients with moderate to severe Pagets disease of bone is 30 mg daily, administered as 4 hour infusion on consecutive days for total dose of 90 mg.. Retreatment. limited number of patients with Pagets disease have received more than one treatment of pamidronate disodium in clinical trials. When clinically indicated, patients should be retreated at the dose of initial therapy.. 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 4 hour infusion given on monthly basis.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 serum creatinine >=3.0 mg/dL.Patients who receive pamidronate disodium should have serum creatinine assessed prior to each treatment. Treatment should be withheld for renal deterioration. In clinical study, renal deterioration was defined as follows:oFor patients with normal baseline creatinine, increase of 0.5 mg/dL.oFor patients with abnormal baseline creatinine, increase of 1.0 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 yet known, however, in study of patients with myeloma, final analysis after 21 months demonstrated overall benefits (see Clinical Trials section).. oFor patients with normal baseline creatinine, increase of 0.5 mg/dL.. oFor patients with abnormal baseline creatinine, increase of 1.0 mg/dL.. Osteolytic Bone Metastases of Breast Cancer. The recommended dose of pamidronate disodium in patients with osteolytic bone metastases is 90 mg administered over 2 hour infusion given every to weeks.Pamidronate disodium has been frequently used with doxorubicin, fluorouracil, cyclophosphamide, methotrexate, mitoxantrone, vinblastine, dexamethasone, prednisone, melphalan, vincristine, megesterol, and tamoxifen. It has been given less frequently with etoposide, cisplatin, cytarabine, paclitaxel, and aminoglutethimide.Patients who receive pamidronate disodium should have serum creatinine assessed prior to each treatment. Treatment should be withheld for renal deterioration. In clinical study, renal deterioration was defined as follows:oFor patients with normal baseline creatinine, increase of 0.5 mg/dL.oFor patients with abnormal baseline creatinine, increase of 1.0 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 benefit (see Clinical Trials section).. oFor patients with normal baseline creatinine, increase of 0.5 mg/dL.. oFor patients with abnormal baseline creatinine, increase of 1.0 mg/dL.. Calcium and Vitamin Supplementation. In the absence of hypercalcemia, patients with predominantly lytic bone metastases or multiple myeloma, who are at risk of calcium or vitamin deficiency, and patients with Pagets disease of the bone, should be given oral calcium and vitamin supplementation in order to minimize the risk of hypocalcemia.. Method of Administration. 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 WARNINGS.)There must be strict adherence to the intravenous administration recommendations for pamidronate disodium in order to decrease the risk of deterioration in renal function.. Hypercalcemia of Malignancy. The daily dose must be administered as an intravenous infusion over at least 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, USP, or 5% Dextrose Injection, USP. This infusion solution is stable for up to 24 hours at room temperature.. Pagets Disease. The recommended daily dose of 30 mg should be diluted in 500 mL of sterile 0.45% or 0.9% Sodium Chloride, USP, or 5% Dextrose Injection, USP, and administered over 4 hour period for 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, USP, or 5% Dextrose Injection, USP, and administered over 2 hour period every to 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, USP, or 5% Dextrose Injection, USP, and administered over 4 hour period on monthly basis.Pamidronate disodium must not be mixed with calcium-containing infusion solutions, such as Ringers solution, and should be given in single intravenous solution and line separate from all other drugs.Note Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

PRECAUTIONS SECTION.

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 Pagets disease of bone, 17% of patients treated with 90 mg of pamidronate disodium showed serum calcium levels below mg/dL.Patients with 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 judgement 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 biphosphonates, 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 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 dental examination with preventive dentistry prior to treatment with bisphophonates.While on treatment, these patients should avoid invasive dental procedures if possible. For patients who develop ONJ while on bisphosphonate therapy, dental surgey 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 judgement 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 biphosphonates. However, such reports have been infrequent. This category of drugs includes pamidronate disodium injection. 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. subset had recurrence of symptoms when rechallanged with the same drug or another biphosphonate.. 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 weeks following treatment.. Drug Interactions. Concomitant administration of 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 dysfunction may be increased when pamidronate disodium is used in combination with thalidomide.. Carcinogenesis, Mutagenesis, Impairment of Fertility. In 104 week carcinogenicity study (daily oral administration) in rats, there was 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 disodium in rats, the lowest daily dose associated with adrenal pheochromocytoma was similar to the intended clinical dose. Adrenal pheochromocytoma was also observed in low numbers in the control animals and is considered relatively common spontaneous neoplasm in the rat. Pamidronate disodium (daily oral administration) was not carcinogenic in an 80 week study in mice.Pamidronate disodium was nonmutagenic in six mutagenicity assays: Ames test, Salmonella and Escherichia/liver-microsome test, 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 disodium orally; however, this occurred only when animals were mated with members of the same dose group. Pamidronate disodium has not been administered intravenously in such study.. Animal Toxicology. In both rats and dogs, nephropathy has been associated with intravenous (bolus and infusion) administration of pamidronate disodium.Two day intravenous infusion studies were conducted in the dog wherein pamidronate disodium was given for 1, 4, or 24 hours at doses of to 20 mg/kg for up to days. In the first study, the compound was well tolerated at mg/kg (1.7 highest recommended human dose [HRHD] for single intravenous infusion) when administered for or 24 hours, but renal findings such as elevated BUN and creatinine levels and renal tubular necrosis occurred when mg/kg was infused for hour and at doses of >=10 mg/kg. In the second study, slight renal tubular necrosis was observed in male at mg/kg when infused for hours. Additional findings included elevated BUN levels in several treated animals and renal tubular dilation and/or inflammation at >=1 mg/kg after each infusion time.Pamidronate disodium was given to rats at doses of 2, 6, and 20 mg/kg and to dogs at doses of 2, 4, 6, and 20 mg/kg as 1 hour infusion, once week, for months followed by 1 month recovery period. In rats, nephrotoxicity was observed at >=6 mg/kg and included increased BUN and creatinine levels and tubular degeneration and necrosis. These findings were still present at 20 mg/kg at the end of the recovery period. In dogs, moribundity/death and renal toxicity occurred at 20 mg/kg as did kidney findings of elevated BUN and creatinine levels at >=6 mg/kg and renal tubular degeneration at >=4 mg/kg. The kidney changes were partially reversible at mg/kg. In both studies, the dose level that produced no adverse renal effects was considered to be mg/kg (1.1 HRHD for single intravenous infusion).. Pregnancy Category (See WARNINGS). There are no adequate and well-controlled studies in pregnant women.Bolus intravenous studies conducted in rats and rabbits determined that pamidronate disodium produces maternal toxicity and embryo/fetal effects when given during organogenesis at doses of 0.6 to 8.3 times the highest recommended human dose for single intravenous infusion. As it has been shown that pamidronate disodium can cross the placenta in rats and has produced marked maternal and nonteratogenic embryo/fetal effects in rats and rabbits, it should not be given to women during pregnancy.Bisphosphonates are incorporated into the bone matrix, from where they are gradually released over periods of weeks to years. The extent of bisphosphonate incorporation into adult bone, and hence, the amount available for release back into the systematic circulation, is directly related to the total dose and duration of bisphosphonate use. Although there are no data on fetal risk in humans, bisphosphonates do cause fetal harm in animals, and animal data suggest that uptake of bisphosphonates into fetal bone is greater than into maternal bone. Therefore, there is theoretical risk of fetal harm (e.g., skeletal and other abnormalities) if woman becomes pregnant after completing course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on this risk has not been established.. Nursing Mothers. It is not known whether pamidronate disodium is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when pamidronate disodium is administered to nursing woman.. Pediatric Use. Safety and effectiveness of pamidronate disodium in pediatric patients have not been established.. 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.