Pamidronate -aredia ®

Pamidronate (Aredia ®)

Usual Diluents

Standard Dilutions   [Amount of drug] [Infusion volume] [Infusion rate]

Minimum dilution:
[60-90mg] [500ml] [Usually over 4 hours] (Range: 2 to 24 hr)

Stability / Miscellaneous

Restricted to oncology. Serum calcium levels should be corrected for serum albumin before determining dose.
Corrected calcium= serum calcium + 0.8 (4 - serum albumin).

Dosage:
Moderate hypercalcemia (12- 13.5 mg/dl): 60 to 90 mg.
Severe hypercalcemia (> 13.5 mg/dl): 90 mg.

The manufacturer recommends that the repeat dose not be given sooner than 7 days after the initial dose in order to allow full response to this dose.
Mechanism of action: bisphosphonate compound-inhibits bone resorption (anti-osteoclast activity). Has little effect on bone remineralization.

Relative potency of bisphosphonate agents: Risedronate (Actonel)>> (pamidronate & alendronate (Fosamax)) >>Etidronate(Didronel)

WARNINGS
Deterioration in Renal Function
Bisphosphonates, including Aredia, 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 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.

Focal segmental glomerulosclerosis (including the collapsing variant) with or without nephrotic syndrome, which may lead to renal failure, has been reported in Aredia-treated patients, particularly in the setting of multiple myeloma and breast cancer. Some of these patients had gradual improvement in renal status after Aredia was discontinued.

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.)

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 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 real 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 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.

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.

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

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 package insert 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 package insert 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 package insert for 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 particulate 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.

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).
T2007-98
REV: November 2007
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
© Novartis

Source: [package insert]