Drug: Aredia

Aredia, pamidronate disodium (APD), is a bisphosphonate available in 30-mg or 90-mg vials for intravenous administration. Each 30-mg and 90-mg vial contains, respectively, 30 mg and 90 mg of sterile, lyophilized pamidronate disodium and 470 mg and 375 mg of mannitol, USP. The pH of a 1% solution of pamidronate disodium in distilled water is approximately 8.3. Aredia, a member of the group of chemical compounds known as bisphosphonates, is an analog of pyrophosphate. Pamidronate disodium is designated chemically as phosphonic acid (3-amino-l-hydroxypropylidene) bis-, disodium salt, pentahydrate, (APD), and its structural formula is Pamidronate disodium is a white-to-practically-white powder. It is soluble in water and in 2N sodium hydroxide, sparingly soluble in 0.1N hydrochloric acid and in 0.1N acetic acid, and practically insoluble in organic solvents. Its molecular formula is C3H9NO7P2Na2•5H2O and its molecular weight is 369.1. Inactive Ingredients. Mannitol, USP, and phosphoric acid (for adjustment to pH 6.5 prior to lyophilization).

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Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Clinical Studies Hypercalcemia of Malignancy Transient mild elevation of temperature by at least 1°C was noted 24 to 48 hours after administration of Aredia in 34% of patients in clinical trials. In the saline trial, 18% of patients had a temperature elevation of at least 1°C 24 to 48 hours after treatment. Drug-related local soft-tissue symptoms (redness, swelling or induration and pain on palpation) at the site of catheter insertion were most common in patients treated with 90 mg of Aredia. 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 Aredia during the four U.S. controlled hypercalcemia clinical studies were reported to have had seizures, 2 of whom had preexisting seizure disorders. None of the seizures were considered to be drug-related by the investigators. However, a possible relationship between the drug and the occurrence of seizures cannot be ruled out. It should be noted that in the saline arm 1 patient (4%) had a seizure. There are no controlled clinical trials comparing the efficacy and safety of 90-mg Aredia over 24 hours to 2 hours in patients with hypercalcemia of malignancy. However, a comparison of data from separate clinical trials suggests that the overall safety profile in patients who received 90-mg Aredia over 24 hours is similar to those who received 90-mg Aredia over 2 hours. The only notable differences observed were an increase in the proportion of patients in the Aredia 24-hour group who experienced fluid overload and electrolyte/mineral abnormalities. At least 15% of patients treated with Aredia for hypercalcemia of malignancy also experienced the following adverse events during a clinical trial: General: Fluid overload, generalized pain Cardiovascular: Hypertension Gastrointestinal: Abdominal pain, anorexia, constipation, nausea, vomiting Genitourinary: Urinary tract infection Musculoskeletal: Bone pain Laboratory Abnormality: Anemia, hypokalemia, hypomagnesemia, hypophosphatemia Many of these adverse experiences may have been related to the underlying disease state. The following table lists the adverse experiences considered to be treatment-related during comparative, controlled U.S. trials. Treatment-Related Adverse Experiences Reported in Three U.S. Controlled Clinical Trials
  Percent of Patients Aredia® Etidronate Disodium Saline 60 mg
over 4 hr
n=23 60 mg
over 24 hr
n=73 90 mg
over 24 hr
n=17 7.5 mg/kg x 3 days
n=35 n=23 General   Edema 0 1 0 0 0   Fatigue 0 0 12 0 0   Fever 26 19 18 9 0   Fluid overload 0 0 0 6 0   Infusion-site reaction 0 4 18 0 0   Moniliasis 0 0 6 0 0   Rigors 0 0 0 0 4 Gastrointestinal   Abdominal pain 0 1 0 0 0   Anorexia 4 1 12 0 0   Constipation 4 0 6 3 0   Diarrhea 0 1 0 0 0   Dyspepsia 4 0 0 0 0   Gastrointestinal hemorrhage 0 0 6 0 0   Nausea 4 0 18 6 0   Stomatitis 0 1 0 3 0   Vomiting 4 0 0 0 0 Respiratory   Dyspnea 0 0 0 3 0   Rales 0 0 6 0 0   Rhinitis 0 0 6 0 0   Upper respiratory infection 0 3 0 0 0 CMS   Anxiety 0 0 0 0 4   Convulsions 0 0 0 3 0   Insomnia 0 1 0 0 0   Nervousness 0 0 0 0 4   Psychosis 4 0 0 0 0   Somnolence 0 1 6 0 0   Taste perversion 0 0 0 3 0 Cardiovascular   Atrial fibrillation 0 0 6 0 4   Atrial flutter 0 1 0 0 0   Cardiac failure 0 1 0 0 0   Hypertension 0 0 6 0 4   Syncope 0 0 6 0 0   Tachycardia 0 0 6 0 4 Endocrine   Hypothyroidism 0 0 6 0 0 Hemic and Lymphatic   Anemia 0 0 6 0 0   Leukopenia 4 0 0 0 0   Neutropenia 0 1 0 0 0   Thrombocytopenia 0 1 0 0 0 Musculoskeletal   Myalgia 0 1 0 0 0 Urogenital   Uremia 4 0 0 0 0 Laboratory Abnormalities   Hypocalcemia 0 1 12 0 0   Hypokalemia 4 4 18 0 0   Hypomagnesemia 4 10 12 3 4   Hypophosphatemia 0 9 18 3 0   Abnormal liver function 0 0 0 3 0 Paget's Disease Transient mild elevation of temperature > 1°C above pretreatment baseline was noted within 48 hours after completion of treatment in 21% of the patients treated with 90 mg of Aredia in clinical trials. Drug-related musculoskeletal pain and nervous system symptoms (dizziness, headache, paresthesia, increased sweating) were more common in patients with Paget's disease treated with 90 mg of Aredia than in patients with hypercalcemia of malignancy treated with the same dose. Adverse experiences considered to be related to trial drug, which occurred in at least 5% of patients with Paget's disease treated with 90 mg of Aredia in two U.S. clinical trials, were fever, nausea, back pain, and bone pain. At least 10% of all Aredia-treated patients with Paget's disease also experienced the following adverse experiences during clinical trials: Cardiovascular: Hypertension Musculoskeletal: Arthrosis, bone pain Nervous system: Headache Most of these adverse experiences may have been related to the underlying disease state. Osteolytic Bone Metastases of Breast Cancer and Osteolytic Lesions of Multiple Myeloma The most commonly reported ( > 15%) adverse experiences occurred with similar frequencies in the Aredia- and placebo- treatment groups, and most of these adverse experiences may have been related to the underlying disease state or cancer therapy. Commonly Reported Adverse Experiences in Three U.S. Controlled Clinical Trials
  Aredia 90 mg over
4 hours
N=205
% Placebo
N=187
% Aredia 90 mg over
2 hours
N=367
% Placebo
N=386
% All Aredia®
90 mg
N=572
% Placebo
N=573
% General   Asthenia 16.1 17.1 25.6 19.2 22.2 18.5   Fatigue 31.7 28.3 40.3 28.8 37.2 29.0   Fever 38.5 38 38.1 32.1 38.5 34   Metastases 1.0 3.0 31.3 24.4 20.5 17.5   Pain 13.2 11.8 15.0 18.1 14.3 16.1 Digestive System   Anorexia 17.1 17.1 31.1 24.9 26.0 22.3   Constipation 28.3 31.7 36.0 38.6 33.2 35.1   Diarrhea 26.8 26.8 29.4 30.6 28.5 29.7   Dyspepsia 17.6 13.4 18.3 15.0 22.6 17.5   Nausea 35.6 37.4 63.5 59.1 53.5 51.8   Pain Abdominal 19.5 16.0 24.3 18.1 22.6 17.5   Vomiting 16.6 19.8 46.3 39.1 35.7 32.8 Hemic and Lymphatic   Anemia 47.8 41.7 39.5 36.8 42.5 38.4   Granulocytopenia 20.5 15.5 19.3 20.5 19.8 18.8   Thrombocytopenia 16.6 17.1 12.5 14.0 14.0 15.0 Musculoskeletal System   Arthralgias 10.7 7.0 15.3 12.7 13.6 10.8   Myalgia 25.4 15.0 26.4 22.5 26 20.1   Skeletal Pain 61.0 71.7 70.0 75.4 66.8 74 CMS   Anxiety 7.8 9.1 18.0 16.8 14.3 14.3   Headache 24.4 19.8 27.2 23.6 26.2 22.3   Insomnia 17.1 17.2 25.1 19.4 22.2 19.0 Respiratory System   Coughing 26.3 22.5 25.3 19.7 25.7 20.6   Dyspnea 22.0 21.4 35.1 24.4 30.4 23.4   Pleural Effusion 2.9 4.3 15.0 9.1 10.7 7.5   Sinusitis 14.6 16.6 16.1 10.4 15.6 12.0   Upper Respiratory Tract Infection 32.2 28.3 19.6 20.2 24.1 22.9 Urogenital System   Urinary Tract Infection 15.6 9.1 20.2 17.6 18.5 15.6 Of the toxicities commonly associated with chemotherapy, the frequency of vomiting, anorexia, and anemia were slightly more common in the Aredia patients whereas stomatitis and alopecia occurred at a frequency similar to that in placebo patients. In the breast cancer trials, mild elevations of serum creatinine occurred in 18.5% of Aredia patients and 12.3% of placebo patients. Mineral and electrolyte disturbances, including hypocalcemia, were reported rarely and in similar percentages of Aredia-treated patients compared with those in the placebo group. The reported frequencies of hypocalcemia, hypokalemia, hypophosphatemia, and hypomagnesemia for Aredia-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 Aredia (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 Aredia group than in the placebo group (13.6% and 26% vs 10.8% and 20.1%, respectively). In multiple myeloma patients, there were five Aredia-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 a patient recovering from pneumonia and acute gangrenous cholecystitis. One Aredia-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 Aredia-related adverse experiences, all moderate in severity, that caused a patient to discontinue participation in the trial. One was due to interstitial pneumonitis, another to malaise and dyspnea. One Aredia patient discontinued the trial due to a symptomatic hypocalcemia. Another Aredia patient discontinued therapy due to severe bone pain after each infusion, which the investigator felt was trial-drug-related. Renal Toxicity In a study of the safety and efficacy of Aredia 90 mg (2-hour infusion) vs Zometa 4 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 Baseline*
Patient Population/Baseline Creatinine Aredia® 90 mg/2 hours Zometa® 4 mg/15 minutes 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%) *Patients were randomized following the 15-minute infusion amendment for the Zometa arm. Post-Marketing Experience The following adverse reactions have been reported during post-approval use of Aredia. Because these reports are from a population of uncertain size and are subject to confounding factors, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. 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, orbital inflammation; Renal and urinary disorders: focal segmental glomerulosclerosis including the collapsing variant, nephrotic syndrome; renal tubular disorders (RTD); tubulointerstitial nephritis, and glomerulonephropathies. Laboratory abnormalities: hyperkalemia, hypernatremia, hematuria. Rare instances of allergic manifestations have been reported, including hypotension, dyspnea, or angioedema, and, very rarely, anaphylactic shock. Aredia is contraindicated in patients with clinically significant hypersensitivity to Aredia or other bisphosphonates (see CONTRAINDICATIONS). Respiratory, thoracic and mediastinal disorders: adult respiratory distress syndrome (ARDS), interstitial lung disease (ILD). Musculoskeletal and connective tissue disorders: severe and occasionally incapacitating bone, joint, and/or muscle pain. Cases of osteonecrosis (primarily involving the jaw) have been reported predominantly in cancer patients treated with intravenous bisphosphonates, including Aredia. Many of these patients were also receiving chemotherapy and corticosteroids which may be risk factors for ONJ. Data suggest a 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, such as tooth extraction. It is therefore prudent to avoid invasive dental procedures as recovery may be prolonged. (See PRECAUTIONS.) Atypical subtrochanteric and diaphyseal femoral fractures have been reported with bisphosphonate therapy, including Aredia. (See PRECAUTIONS.) Read the Aredia (pamidronate disodium) Side Effects Center for a complete guide to possible side effectsLearn More »

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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 hematologic malignancies, the use of glucocorticoid therapy may be helpful. Moderate Hypercalcemia The recommended dose of Aredia in moderate hypercalcemia (corrected serum calcium* of approximately 12-13.5 mg/dL) is 60 to 90 mg given as a SINGLE-DOSE, intravenous infusion over 2 to 24 hours. Longer infusions (i.e., > 2 hours) may reduce the risk for renal toxicity, particularly in patients with preexisting renal insufficiency. Severe Hypercalcemia The recommended dose of Aredia in severe hypercalcemia (corrected serum calcium* > 13.5 mg/dL) is 90 mg given as a SINGLE-DOSE, intravenous infusion over 2 to 24 hours. Longer infusions (i.e., > 2 hours) may reduce the risk for renal toxicity, particularly in patients with preexisting renal insufficiency. Retreatment A limited number of patients have received more than one treatment with Aredia for hypercalcemia. Retreatment with Aredia, 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 a minimum of 7 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. Paget's Disease The recommended dose of Aredia in patients with moderate to severe Paget's disease of bone is 30 mg daily, administered as a 4-hour infusion on 3 consecutive days for a total dose of 90 mg. Retreatment A limited number of patients with Paget's disease have received more than one treatment of Aredia 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 Aredia in patients with osteolytic bone lesions of multiple myeloma is 90 mg administered as a 4-hour infusion given on a monthly basis. Patients with marked Bence-Jones proteinuria and dehydration should receive adequate hydration prior to Aredia infusion. Limited information is available on the use of Aredia in multiple myeloma patients with a serum creatinine > 3.0 mg/dL. Patients who receive Aredia should have serum creatinine assessed prior to each treatment. Treatment should be withheld for renal deterioration. In a clinical study, renal deterioration was defined as follows:
  • For patients with normal baseline creatinine, increase of 0.5 mg/dL.
  • For patients with abnormal baseline creatinine, increase of 1.0 mg/dL.
In this clinical study, Aredia 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 a study of patients with myeloma, final analysis after 21 months demonstrated overall benefits (see Clinical Trials section). Osteolytic Bone Metastases of Breast Cancer The recommended dose of Aredia in patients with osteolytic bone metastases is 90 mg administered over a 2-hour infusion given every 3-4 weeks. Aredia 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 Aredia should have serum creatinine assessed prior to each treatment. Treatment should be withheld for renal deterioration. In a clinical study, renal deterioration was defined as follows:
  • For patients with normal baseline creatinine, increase of 0.5 mg/dL.
  • For patients with abnormal baseline creatinine, increase of 1.0 mg/dL.
In this clinical study, Aredia 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 benefits (see Clinical Trials section). Calcium and Vitamin D Supplementation In the absence of hypercalcemia, patients with predominantly lytic bone metastases or multiple myeloma, who are at risk of calcium or vitamin D deficiency, and patients with Paget's disease of the bone, should be given oral calcium and vitamin D supplementation in order to minimize the risk of hypocalcemia. Preparation of Solution Reconstitution Aredia is reconstituted by adding 10 mL of Sterile Water for Injection, USP, to each vial, resulting in a solution of 30 mg/10 mL or 90 mg/10 mL. The pH of the reconstituted solution is 6.0-7.4. The drug should be completely dissolved before the solution is withdrawn. Method of Administration DUE TO THE RISK OF CLINICALLY SIGNIFICANT DETERIORATION IN RENAL FUNCTION, WHICH MAY PROGRESS TO RENAL FAILURE, SINGLE DOSES OF AREDIA SHOULD NOT EXCEED 90 MG. (SEE WARNINGS.) There must be strict adherence to the intravenous administration recommendations for Aredia 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 2 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. Paget's 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 a 4-hour period for 3 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 a 2-hour period every 3-4 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 a 4-hour period on a monthly basis. Aredia must not be mixed with calcium-containing infusion solutions, such as Ringer's solution, and should be given in a single intravenous solution and line separate from all other drugs. Note: Parenteral drug products should be inspected visually for participate matter and discoloration prior to administration, whenever solution and container permit. Aredia reconstituted with Sterile Water for Injection may be stored under refrigeration at 2°C-8°C (36°F-46°F) for up to 24 hours. *Albumin-corrected serum calcium (CCa,mg/dL) = serum calcium, mg/dL + 0.8 (4.0-serum albumin, g/dL).

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Concomitant administration of a loop diuretic had no effect on the calcium-lowering action of Aredia. Caution is indicated when Aredia is used with other potentially nephrotoxic drugs. In multiple myeloma patients, the risk of renal function deterioration may be increased when Aredia is used in combination with thalidomide. Read the Aredia Drug Interactions Center for a complete guide to possible interactions Learn More »

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

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Aredia is contraindicated in patients with clinically significant hypersensitivity to Aredia or other bisphosphonates. Last reviewed on RxList: 6/21/2012
This monograph has been modified to include the generic and brand name in many instances.

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There have been several cases of drug maladministration of intravenous Aredia in hypercalcemia patients with total doses of 225 mg to 300 mg given over 2 1A to 4 days. All of these patients survived, but they experienced hypocalcemia that required intravenous and/or oral administration of calcium. Single doses of Aredia should not exceed 90 mg and the duration of the intravenous infusion should be no less than 2 hours. (See WARNINGS.) In addition, one obese woman (95 kg) who was treated with 285 mg of Aredia/day for 3 days experienced high fever (39.5°C), hypotension (from 170/90 mmHg to 90/60 mmHg), and transient taste perversion, noted about 6 hours after the first infusion. The fever and hypotension were rapidly corrected with steroids. If overdosage occurs, symptomatic hypocalcemia could also result; such patients should be treated with short-term intravenous calcium.

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Vials -30 mg - each contains 30 mg of sterile, lyophilized pamidronate disodium and 470 mg of mannitol, USP. Carton of 4 vials..........................................................NDC 0078-0463-91 Vials - 90 mg - each contains 90 mg of sterile, lyophilized pamidronate disodium and 375 mg of mannitol, USP. Carton of 1 vial...........................................................NDC 0078-0464-61 Do not store above 30°C (86°F). Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936. Revised: 05/2012 Last reviewed on RxList: 6/21/2012
This monograph has been modified to include the generic and brand name in many instances.

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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 Aredia. Cases of asymptomatic hypophosphatemia (12%), hypokalemia (7%), hypomagnesemia (11%), and hypocalcemia (5%-12%), were reported in Aredia-treated patients. Rare cases of symptomatic hypocalcemia (including tetany) have been reported in association with Aredia therapy. If hypocalcemia occurs, short-term calcium therapy may be necessary. In Paget's disease of bone, 17% of patients treated with 90 mg of Aredia showed serum calcium levels below 8 mg/dL. Patients with a history of thyroid surgery may have relative hypoparathyroidism that may predispose to hypocalcemia with Aredia. Renal Insufficiency Aredia 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 Aredia should have serum creatinine assessed prior to each treatment. In patients receiving Aredia for bone metastases, who show evidence of deterioration in renal function, Aredia 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 Aredia in patients with severe renal impairment is not recommended. In other indications, clinical judgment should determine whether the potential benefit outweighs the potential risk in such patients. Osteonecrosis of the Jaw Osteonecrosis of the jaw (ONJ) has been reported predominantly in cancer patients treated with intravenous bisphosphonates, including Aredia. Many of these patients were also receiving chemotherapy and corticosteroids which may be risk factors for ONJ. Postmarketing experience and the literature suggest a greater frequency of reports of ONJ based on tumor type (advanced breast cancer, multiple myeloma), and dental status (dental extraction, periodontal disease, local trauma including poorly fitting dentures). Many reports of ONJ involved patients with signs of local infection including osteomyelitis. Cancer patients should maintain good oral hygiene and should have a dental examination with preventive dentistry prior to treatment with bisphosphonates. While on treatment, these patients should avoid invasive dental procedures if possible. For patients who develop ONJ while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of ONJ. Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment (See ADVERSE REACTIONS). Musculoskeletal Pain In post-marketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates.. This category of drugs includes Aredia (pamidronate disodium for 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. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate. Atypical fractures of the femur Atypical subtrochanteric and diaphyseal femoral fractures have been reported in patients receiving bisphosphonate therapy, including Aredia. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to just above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution. These fractures occur after minimal or no trauma. Patients may experience thigh or groin pain weeks to months before presenting with a completed femoral fracture. Fractures are often bilateral; therefore the contralateral femur should be examined in bisphosphonate-treated patients who have sustained a femoral shaft fracture. Poor healing of these fractures has also been reported. A number of case reports noted that patients were also receiving treatment with glucocorticoids (such as prednisone or dexamethasone) at the time of fracture. Causality with bisphosphonate therapy has not been established. Any patient with a history of bisphosphonate exposure who presents with thigh or groin pain in the absence of trauma should be suspected of having an atypical fracture and should be evaluated. Discontinuation of Aredia therapy in patients suspected to have an atypical femur fracture should be considered pending evaluation of the patient, based on an individual benefit risk assessment. It is unknown whether the risk of atypical femur fracture continues after stopping therapy. Laboratory Tests Patients who receive Aredia 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 Aredia. Patients who have preexisting anemia, leukopenia, or thrombocytopenia should be monitored carefully in the first 2 weeks following treatment. Patients receiving Aredia may be at risk for anemia, leukopenia or thrombocytopenia and should have regular hematology assessments. Carcinogenesis, Mutagenesis, Impairment of Fertility In a 104-week carcinogenicity study with daily oral administration of pamidronate in rats, there was a positive dose response relationship for benign adrenal pheochromocytoma in males (PO.00001). Although this condition was also observed in females, the incidence was not statistically significant. When the dose calculations were adjusted to account for the limited oral bioavailability of pamidronate in rats, systemic exposure with the lowest daily dose associated with adrenal pheochromocytoma resulted in systemic exposures that were similar to the systemic exposure achieved at the intended clinical dose. Adrenal pheochromocytoma was also observed in low numbers in the control animals and is considered a relatively common spontaneous neoplasm in the rat. Pamidronate given daily by oral administration was not carcinogenic in an 80-week study in mice. Pamidronate was nonmutagenic in six mutagenicity assays, including: the Ames bacterial mutagenicity assay, (with and without metabolic activation), nucleus-anomaly test, sister-chromatid-exchange study, point-mutation test, and micronucleus test in the rat. In rats, decreased fertility occurred in first-generation offspring of parents who had received 150 mg/kg of pamidronate orally; however, this occurred only when animals were mated with members of the same dose group. Pamidronate has not been administered intravenously in such a study. Pregnancy Category D (See WARNINGS) There are no adequate and well-controlled studies in pregnant women. Aredia may cause fetal harm when administered to a pregnant woman. Bisphosphonates, such as Aredia, 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 systemic 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 a theoretical risk of fetal harm (e.g., skeletal and other abnormalities) if a woman becomes pregnant after completing a 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. If Aredia is used during pregnancy or if the patient becomes pregnant while taking or after taking this drug, the patient should be apprised of the potential hazard to the fetus. Intravenous bolus dosing of pregnant rats and rabbits with pamidronate resulted in 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 a single intravenous infusion. Pamidronate can cross the placenta in rats, and has produced marked maternal and nonteratogenic embryo/fetal effects in both rats and rabbits. Nursing Mothers It is not known whether pamidronate is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from Aredia, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness of Aredia in pediatric patients have not been established. Geriatric Use Of the total number of subjects in clinical studies of Aredia, 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. Last reviewed on RxList: 6/21/2012
This monograph has been modified to include the generic and brand name in many instances.

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