pamidronate (Rx)

>10%

Anemia (42.5%)

Urinary tract infectious disease (18.5%)

Hypokalemia (18%)

Hypophosphatemia (18%)

Hypocalcemia (12%)

Hypomagnesemia (12%)

1-10%

Seizure (2%)

Frequency Not Defined

Common

• HTN
• Fever
• Abdominal pain, appetite loss, dyspepsia, nausea, vomiting
• Injection site reaction
• Bone pain
• Cough. dyspnea, URI, sinusitis

Serious

• Osteonecrosis (primarily involving the jaw) reported predominantly in pts w/ cancer
• Focal segmental glomerulosclerosis

Postmarketing Reports

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: Renal tubular disorders (RTD); tubulointerstitial nephritis, focal segmental glomerulosclerosis including the collapsing variant, nephrotic syndrome

Laboratory abnormalities: hyperkalemia, hypernatremia, hematuria

Allergy: Rare instances of allergic manifestations have been reported, including hypotension, dyspnea, or angioedema, and, very rarely, anaphylactic shock

Osteonecrosis (primarily involving the jaw) reported predominantly in cancer patients treated with IV bisphosphonates; many of these patients were also receiving chemotherapy and corticosteroids which may be risk factors for ONJ

Respiratory, thoracic and mediastinal disorders: ARDS, interstitial lung disease

Musculoskeletal and connective tissue disorders: Severe and occasionally incapacitating bone, joint, and/or muscle pain; atypical subtrochanteric and diaphyseal femoral fractures

Contraindications

Hypersensitivity to drug, other bisphosphonates, or excipients, including mannitol

Cautions

Bisphosphonates are incorporated into bone matrix, and gradually released over periods of weeks to years; may cause fetal harm when administered to a pregnant woman

Electrolyte disorders

• Cases of asymptomatic hypophosphatemia, hypokalemia, hypomagnesemia, and hypocalcemia, reported in association with pamidronate disodium-treated patients; rare cases of symptomatic hypocalcemia (including tetany) reported in association with pamidronate disodium therapy
• Monitor serum levels of calcium, phosphate, magnesium, and potassium, following initiation of therapy with pamidronate disodium; if hypocalcemia occurs, short-term calcium therapy may be necessary; in the absence of hypercalcemia, supplement with oral calcium and vitamin D in order to minimize risk of hypocalcemia

Osteonecrosis of the jaw (ONJ)

• ONJ reported predominantly in cancer patients treated with intravenous bisphosphonates; many of these patients were also receiving chemotherapy and corticosteroids, which may be risk factors for ONJ
• Postmarketing experience and literature suggest greater frequency of ONJ with certain tumor type (advanced breast cancer, multiple myeloma), and dental status (dental extraction, periodontal disease, local trauma including poorly fitting dentures)
• Local infection including osteomyelitis reported with ONJ; patients receiving pamidronate should maintain good oral hygiene and have a dental examination with preventive dentistry prior to initiation of treatment
• While on treatment, 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 risk of ONJ; clinical judgment of treating physician should guide management plan of each patient based on individual benefit/risk assessment

Atypical fractures of femur

• Atypical subtrochanteric and diaphyseal femoral fractures reported in patients receiving bisphosphonate therapy, including pamidronate disodium; 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 may 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, contralateral femur should be examined in bisphosphonate-treated patients who have sustained a femoral shaft fracture
• Poor healing of these fractures also reported; a number of case reports noted that patients were receiving treatment also with glucocorticoids (such as prednisone or dexamethasone) at time of fracture; causality with bisphosphonate therapy has not been established; any patient with history of bisphosphonate exposure who presents with thigh or groin pain in the absence of trauma should be evaluated for atypical fracture
• Consider discontinuation of pamidronate disodium therapy in patients suspected to have atypical femur fracture pending evaluation of patient, based on individual benefit-risk assessment; it is unknown whether risk of atypical femur fracture continues after stopping therapy

Renal impairment

• Bisphosphonates, such as pamidronate disodium, have been associated with renal toxicity, including focal segmental glomerulosclerosis; this toxicity has been manifested as nephritic syndrome, deterioration of renal function, and renal failure
• Renal failure has been reported in patients after a single dose of pamidronate disodium; some patients had gradual improvement in renal status after pamidronate disodium was discontinued
• Do not administer single doses of pamidronate disodium in excess of 90 mg due to risk of clinically significant deterioration in renal function
• Assess serum creatinine prior to each treatment; withhold treatment until renal function returns to baseline in patients who show evidence of deterioration in renal function; do not administer pamidronate in patients with severe renal impairment for treatment of bone metastases

Pregnancy

There are no adequate and well-controlled studies in pregnant women; therapy may cause fetal harm when administered to a pregnant woman

Bisphosphonates are incorporated into bone matrix, from where they are gradually released over periods of weeks to years; the extent of bisphosphonate incorporation into adult bone, and hence, amount available for release back into systemic circulation, is directly related to 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 (eg, skeletal and other abnormalities) if a woman becomes pregnant after completing a course of bisphosphonate therapy

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

Animal data

• In reproductive studies in rats and rabbits, doses equivalent to 0.6 to 8.3 times the highest human recommended dose resulted in maternal toxicity and embryo/fetal effects; the drug can cross the placenta in rats and has produced marked maternal and nonteratogenic embryo/fetal effects in both rats and rabbits

Lactation

It is not known whether pamidronate is excreted in human milk; because many drugs are excreted in human milk, and because of potential for serious adverse reactions in nursing infants from pamidronate disodium, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Bisphosphonate which inhibits bone resorption via actions on osteoclast activity, leading to an indirect increase in bone density

Pharmacokinetics

Half-Life: 21-35 hours

Duration: hypercalcemia of malignancy (IV): 2 wk to 2 mth

Bioavailability: Poor; pharmacokinetic studies not available

Metabolism: None

Renal clearance: 49 mL/min

Excretion: Urine

Onset

• Hypercalcemia of malignancy: Initial effect 1-2 days; max effect 5-7 days (IV)
• Paget's disease: 1-3 months (maximum effect IV)

IV Incompatibilities

Calcium-containing diluents such as LR

IV Preparation

Reconstitute by adding 10 mL of SWI to a vial

May be further diluted in 250-1000 mL of 1/2NS, NS or D5W

IV Administration

Slowly infuse over 2-24 hours

Longer infusion may reduce risk of nephrotoxicity

Storage

Do not store powder for reconstitution above 30°C (86°F)