PAMIDRONATE DISODIUM INJECTION
PAMIDRONATE DISODIUM FOR INJECTION

For Intravenous Infusion
Rx ONLY

Pamidronate Disodium Injection is a bone resorption inhibitor available in 30 mg vials for intravenous administration. Each mL contains 3 mg of pamidronate disodium; 47 mg of mannitol USP and water for injection q.s.; phosphoric acid and/or sodium hydroxide have been added to adjust pH 6.2 to 7.0.

Pamidronate Disodium for Injection is a bone resorption inhibitor available in 30 mg and 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.

Inactive Ingredients: Mannitol and phosphoric acid (for adjustment to pH 6.5 prior to lyophilization).

The pH of a 1% solution of pamidronate disodium in distilled water is approximately 8.3. Pamidronate disodium, a member of the group of chemical compounds known as bisphosphonates, is an analog of pyrophosphate. Pamidronate disodium is designated chemically as disodium dihydrogen (3-amino-1-hydroxypropylidene) diphosphonate, 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 and its molecular weight is 279.1.

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.

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 4 hours and 90 mg pamidronate disodium over 24 hours (Table 1).

There are no data available on the effects of age, gender, or race on the pharmacokinetics of pamidronate.

Serum phosphate levels have been noted to decrease after administration of pamidronate disodium, presumably because of decreased release of phosphate from bone and increased renal excretion as parathyroid hormone levels, which are usually suppressed in hypercalcemia associated with malignancy, return toward normal. Phosphate therapy was administered in 30% of the patients in response to a decrease in serum phosphate levels. Phosphate levels usually returned toward normal within 7 to 10 days.

Urinary calcium/creatinine and urinary hydroxyproline/creatinine ratios decrease and usually return to within or below normal after treatment with pamidronate disodium. These changes occur within the first week after treatment, as do decreases in serum calcium levels, and are consistent with an antiresorptive pharmacologic action.

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 which 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; renalcell 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 of this type of calculation (see DOSAGE AND ADMINISTRATION).

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 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.

Pamidronate disodium 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 pamidronate disodium. 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 pamidronate disodium in the treatment of hypercalcemia associated with hyperparathyroidism or with other non-tumor-related conditions has not been established.

Pamidronate disodium is indicated for the treatment of patients with moderate to severe Paget’s disease of bone. The effectiveness of pamidronate disodium was demonstrated primarily in patients with serum alkaline phosphatase ≥3 times the upper limit of normal. Pamidronate disodium 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. Pamidronate disodium 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.

Pamidronate disodium is indicated, in conjunction with standard antineoplastic therapy, for the treatment of osteolytic bone metastases of breast cancer and osteolytic lesions of multiple myeloma. The pamidronate disodium 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).

Pamidronate disodium is contraindicated in patients with clinically significant hypersensitivity to pamidronate disodium or other bisphosphonates.

DUE TO THE RISK OF CLINICALLY SIGNIFICANT DETERIORATION IN RENAL FUNCTION, WHICH MAY PROGRESS TO RENAL FAILURE, SINGLE DOSES OFPAMIDRONATE DISODIUM SHOULD NOT EXCEED 90 MG (see DOSAGE AND ADMINISTRATION for appropriate infusion durations).

Bisphosphonates, including pamidronate disodium, have been associated with renal toxicity manifested as deterioration of renal function and potential renal failure.

Patients who receive pamidronate disodium should have serum creatinine assessed prior to each treatment. Patients treated with pamidronate disodium 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 pamidronate disodium.

Two 7-day intravenous infusion studies were conducted in the dog wherein pamidronate disodium was given for 1, 4, or 24 hours at doses of 1 to 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.

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 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).

Pamidronate disodium may cause fetal harm when administered to a pregnant woman. (See PRECAUTIONS, Pregnancy Category D.)

There are no studies in pregnant women using pamidronate disodium. 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.

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 disodium 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 pamidronate disodium showed serum calcium levels below 8 mg/dL.

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).

Pamidronate disodium has not been tested in patients who have class Dc renal impairment (creatinine >5 mg/dL), and has been tested in few multiple myeloma patients with serum creatinine ≥3 mg/dL. (See also 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 (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.

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 pamidronate disodium. 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.

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 2 weeks following treatment.

Concomitant administration of a 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 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 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 a 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 a study.

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 a nursing woman.

Safety and effectiveness of pamidronate disodium in pediatric patients have not been established.

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 rage, reflecting the greater frequency of decreased hepatic, renal,or cardiac function, and of concomitant disease or other drug therapy.

In a study of the safety and efficacy of pamidronate disodium 90 mg (2 hour infusion) versus 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.

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 (primarly 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 pamidronate disodium 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.)

There have been several cases of drug maladministration of intravenous pamidronate disodium in hypercalcemia patients with total doses of 225 mg to 300 mg given over 2 1/2 to 4 days. All of these patients survived, but they experienced hypocalcemia that required intravenous and/or oral administration of calcium. Single doses of pamidronate disodium 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 pamidronate disodium/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.

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.

The recommended dose of pamidronate disodium in patients with moderate to severe Paget’s disease of bone is 30 mg daily, administered as a 4 hour infusionon 3 consecutive days for a total dose of 90 mg.

Pamidronate Disodium Injection is supplied as follows:

30 mg in 10 mL; single dose, flip-top vials as a clear-colorless solution containing pamidronate disodium 3 mg/mL. NDC 55390-204-01, individually boxed.

Store at 25°C (77°F).

Pamidronate Disodium for Injection reconstitated is supplied as follows:

30 mg vials each contains 30 mg of sterile, lyophilized pamidronate disodium and 470 mg of mannitol. NDC 55390-127-01, individually boxed.
90 mg vials each contains 90 mg of sterile, lyophilized pamidronate disodium and 375 mg of mannitol. NDC 55390-129-01, individually boxed.

Do not store above 30°C (86°F).

Manufactured for:  Bedford Laboratories™         Manufactured by:  Ben Venue Laboratories, Inc.
                                 Bedford, OH 44146                                               Bedford, OH 44146

*Albumin-corrected serum calcium (CCa, mg/dL) = serum calcium, mg/dL + 0.8 (4.0-serum albumin, g/dL).

January 2006                                                                                                                      PMD-P04