PAMIDRIA

Pamidronic acid is a second generation, nitrogen containing bisphosphonate similar to neridronic acid and alendronic acid.

Pamidronic acid was first described in the literature in 1977.

The second generation bisphosphonates are less common as third generation bisphosphonates, such as ibandronic acid, zoledronic acid, minodronic acid, and risedronic acid are becoming more popular.

Pamidronic acid was granted

FDA approval on 31 October 1991.

Pamidronate is indicated to treat moderate to severe hypercalcemia of malignancy, moderate to severe Paget's disease of bone, osteolytic bone metastases of breast cancer, and osteolytic lesions of multiple myeloma.

Pamidronic acid is a second generation, nitrogen containing bisphosphonate that inhibits osteoclast mediated bone loss 2, 3, 11 It has a wide therapeutic index and a long duration of action as it can be given every 3-4 weeks for certain indications.

Patients should be counselled regarding the risk of elevated blood urea nitrogen, renal tubular necrosis, and nephrotoxicity.

In patients with a creatinine clearance >90 mL/min, a 90 mg intravenous dose reached a C max of 1.92±1.08 µg/mL, with a T max of 4h, and an AUC of 10.2±6.95 µg*h/mL.

In patients with a creatinine clearance 61-90 mL/min, a 90 mg intravenous dose reached a C max of 1.86±0.50 µg/mL, with a T max of 4h, and an AUC of 10.7—3.91 µgh/mL.[A203264 In patients with a creatinine clearance 30-60 mL/min, a 90 mg intravenous dose reached a C max of 1.84±0.58 µg/mL, with a T max of 4h, and an AUC of 10.1±3.38 µgh/mL.

In patients with a creatinine clearance <30 mL/min, a 90 mg intravenous dose reached a C max of 1.93±0.53 µg/mL, with a T max of 4h, and an AUC of 34.0±8.37 µg*h/mL.

Pamidronate is exclusively eliminated in the urine.

By 120 hours after administration, 46±16% of the dose has been eliminated in the urine.

The mean elimination half life of pamidronate is 28±7 hours.

The mean total clearance of pamidronate is 107±50 mL/min and the mean renal clearance is 49±28 mL/min.

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Patients experiencing and overdose may present with hypocalcemia, fever, hypotension, and taste perversion.

Overdose can be managed by symptomatic and supportive treatment which may include the administration of steroids and intravenous calcium.

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

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 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 pamidronate disodium.

Focal segmental glomerulosclerosis (including the collapsing variant) with or without nephrotic syndrome, which may lead to renal failure, has been reported in pamidronate disodium-treated patients, particularly in the setting of multiple myeloma and breast cancer.

Some of these patients had gradual improvement in renal status after pamidronate disodium was discontinued.

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.

Bisphosphonates, such as pamidronate disodium, are incorporated into the bone matrix, from where they are gradually released over periods of weeks to years.

Pamidronate disodium may cause fetal harm when administered to a pregnant woman.

In reproductive studies in rats and rabbits, pamidronate doses equivalent to 0.6 to 8.3 times the highest human recommended dose resulted in maternal toxicity and embryo/fetal effects.

There are no adequate and well-controlled studies of pamidronate disodium in pregnant women.

If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus.

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

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.

The recommended dose of pamidronate disodium in moderate hypercalcemia (corrected serum calcium* of approximately to 13.5 mg/dL) is to 90 mg given as a SINGLE DOSE, intravenous infusion over to 24 hours.

Longer infusions (i.e., >2 hours) may reduce the risk for renal toxicity, particularly in patients with preexisting renal insufficiency.

The recommended dose of pamidronate disodium in severe hypercalcemia (corrected serum calcium* >13.5 mg/dL) is 90 mg given as a SINGLE DOSE, intravenous infusion over to 24 hours.

Longer infusions (i.e., >2 hours) may reduce the risk for 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).

A 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 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 pamidronate disodium 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 pamidronate disodium in clinical trials.

When clinically indicated, patients should be retreated at the dose of initial therapy.

The recommended dose of pamidronate disodium 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 pamidronate disodium infusion.

Limited information is available on the use of pamidronate disodium in multiple myeloma patients with a 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 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, 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 a study of patients with myeloma, final analysis after 21 months demonstrated overall benefits.

The recommended dose of pamidronate disodium in patients with osteolytic bone metastases is 90 mg administered over a 2-hour infusion given every to 4 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.

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.

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.

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.

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.

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.

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 to 4 weeks.

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.

Pamidronate disodium 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.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Vials – 3 mg/mL, 10 mL vial.

• each contains 30 mg of Pamidronate Disodium and 470 mg of Mannitol, USP in 10 mL Water for Injection, USP.

NDC 61703-324-18 Carton of 1 Single-dose vial 30 mg/10 mL (3 mg/mL) Vials – 6 mg/mL, 10 mL vial.

• each contains 60 mg of Pamidronate Disodium and 400 mg of Mannitol, USP in 10 mL Water for Injection, USP.

NDC 61703-325-18 Carton of 1 Single-dose vial 60 mg/10 mL (6 mg/mL) Vials – 9 mg/mL, 10 mL vial.

• each contains 90 mg of Pamidronate Disodium and 375 mg of Mannitol, USP in 10 mL Water for Injection, USP.

NDC 61703-326-18 Carton of 1 Single-dose vial 90 mg/10 mL (9 mg/mL) Store at to 25°C (68 to 77°F) .

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