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Aredia®
T2007-07
Aredia®
pamidronate disodium for injection
For Intravenous Infusion
Rx only
Prescribing Information
DESCRIPTION
Aredia, pamidronate disodium (APD), is a bone-resorption inhibitor 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-1-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).
CLINICAL PHARMACOLOGY
The principal pharmacologic action of Aredia is inhibition of bone resorption. Although the mechanism of antiresorptive action is not completely understood, several factors are thought to contribute to this action. Aredia 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, Aredia inhibits bone resorption apparently without inhibiting bone formation and mineralization. Of relevance to the treatment of hypercalcemia of malignancy is the finding that Aredia 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 Aredia over 4 hours and 90 mg of Aredia over 24 hours (Table 1).
Special Populations
There are no data available on the effects of age, gender, or race on the pharmacokinetics of pamidronate.
Drug-Drug Interactions
There are no human pharmacokinetic data for drug interactions with Aredia.
| Dose (infusion rate) | Maximum Concentration (µg/mL) | Percent of dose excreted in urine | Total 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%-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 Aredia, 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 24-48 hours. Studies in rats injected with radiolabeled Aredia showed that the compound was rapidly cleared from the circulation and taken up mainly by bones, liver, spleen, teeth, and tracheal cartilage. Radioactivity was eliminated from most soft tissues within 1-4 days; was detectable in liver and spleen for 1 and 3 months, respectively; and remained high in bones, trachea, and teeth for 6 months after dosing. Bone uptake occurred preferentially in areas of high bone turnover. The terminal phase of elimination half-life in bone was estimated to be approximately 300 days.
Pharmacodynamics
Serum phosphate levels have been noted to decrease after administration of Aredia, presumably because of decreased release of phosphate from bone and increased renal excretion as parathyroid hormone levels, which are usually suppressed in hypercalcemia associated with malignancy, return toward normal. Phosphate therapy was administered in 30% of the patients in response to a decrease in serum phosphate levels. Phosphate levels usually returned toward normal within 7-10 days.
Urinary calcium/creatinine and urinary hydroxyproline/creatinine ratios decrease and usually return to within or below normal after treatment with Aredia. 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 a 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. A few less-common malignancies, including vasoactive intestinal-peptide-producing tumors and cholangiocarcinoma, have a high incidence of hypercalcemia as a 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).
Paget’s Disease
Paget’s 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).
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 a 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.
INDICATIONS AND USAGE
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).
CONTRAINDICATIONS
Aredia is contraindicated in patients with clinically significant hypersensitivity to Aredia or other bisphosphonates.
WARNINGS
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 DOSAGE AND ADMINISTRATION for appropriate infusion durations). Renal deterioration, progression to renal failure, and dialysis have been reported in patients after the initial or a single dose of Aredia.
Bisphosphonates, including Aredia, have been associated with renal toxicity manifested as deterioration of renal function and potential renal failure.
Patients who receive Aredia should have serum creatinine assessed prior to each treatment. Patients treated with Aredia for bone metastases should have the dose withheld if renal function has deteriorated. (See DOSAGE AND ADMINISTRATION.)
In both rats and dogs, nephropathy has been associated with intravenous (bolus and infusion) administration of Aredia.
Two 7-day intravenous infusion studies were conducted in the dog wherein Aredia was given for 1, 4, or 24 hours at doses of 1-20 mg/kg for up to 7 days. In the first study, the compound was well tolerated at 3 mg/kg (1.7 x highest recommended human dose [HRHD] for a single intravenous infusion) when administered for 4 or 24 hours, but renal findings such as elevated BUN and creatinine levels and renal tubular necrosis occurred when 3 mg/kg was infused for 1 hour and at doses of ≥10 mg/kg. In the second study, slight renal tubular necrosis was observed in 1 male at 1 mg/kg when infused for 4 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.
Aredia 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 a 1-hour infusion, once a week, for 3 months followed by a 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 6 mg/kg. In both studies, the dose level that produced no adverse renal effects was considered to be 2 mg/kg (1.1 x HRHD for a single intravenous infusion).
PREGNANCY: AREDIA SHOULD NOT BE USED DURING PREGNANCY
Aredia may cause fetal harm when administered to a pregnant woman. (See PRECAUTIONS, Pregnancy Category D.)
There are no studies in pregnant women using Aredia. If the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.
Studies conducted in young rats have reported the disruption of dental dentine formation following single- and multi-dose administration of bisphosphonates. The clinical significance of these findings is unknown.
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 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 who have undergone thyroid surgery may be at risk for developing hypocalcemia due to relative hypoparathyroidism.
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).
Aredia has not been tested in patients who have class Dc renal impairment (creatinine >5.0 mg/dL), and has been tested in few multiple myeloma patients with serum creatinine ≥3.0 mg/dL. (See also 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 in patients with cancer receiving treatment regimens including bisphosphonates. Many of these patients were also receiving chemotherapy and corticosteroids. The majority of reported cases have been associated with dental procedures such as tooth extraction. Many had signs of local infection including osteomyelitis.
A dental examination with appropriate preventive dentistry should be considered prior to treatment with bisphosphonates in patients with concomitant risk factors (e.g., cancer, chemotherapy, corticosteroids, poor oral hygiene).
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.
Musculoskeletal Pain
In post-marketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates. However, such reports have been infrequent. 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.
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.
Drug Interactions
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 dysfunction may be increased when Aredia is used in combination with thalidomide.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 104-week carcinogenicity study (daily oral administration) in rats, there was a 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 Aredia 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 a relatively common spontaneous neoplasm in the rat. Aredia (daily oral administration) was not carcinogenic in an 80-week study in mice.
Aredia 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 Aredia orally; however, this occurred only when animals were mated with members of the same dose group. Aredia 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.
Bolus intravenous studies conducted in rats and rabbits determined that Aredia 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 a single intravenous infusion. As it has been shown that Aredia 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 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.
Nursing Mothers
It is not known whether Aredia is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Aredia is administered to a nursing woman.
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.
ADVERSE REACTIONS
Clinical Studies
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; Gastrointestinal: gastritis; CNS: confusion, visual hallucinations; Skin: rash, pruritus; Special senses: xanthopsia, conjunctivitis; Renal: focal segmental glomerulosclerosis including the collapsing variant, nephrotic syndrome; Laboratory abnormalities: hyperkalemia, hypernatremia, abnormal liver functions tests, 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).
Cases of osteonecrosis (primarily of the jaws) have been reported since market introduction. Osteonecrosis of the jaws has other well documented multiple risk factors. It is not possible to determine if these events are related to Aredia or other bisphosphonates, to concomitant drugs or other therapies (e.g., chemotherapy, radiotherapy, corticosteroid), to patient’s underlying disease, or to other comorbid risk factors (e.g., anemia, infection, preexisting oral disease). (See PRECAUTIONS.)
OVERDOSAGE
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 ½ 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.
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 hematologic malignancies, the use of glucocorticoid therapy may be helpful.
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.
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
HOW SUPPLIED
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).
T2007-07
REV:
FEBRUARY 2007
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
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