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Pamidronate

Pronunciation

Pronunciation

(pa mi DROE nate)

Index Terms

  • Pamidronate Disodium

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous, as disodium:

Generic: 30 mg/10 mL (10 mL); 90 mg/10 mL (10 mL)

Solution, Intravenous, as disodium [preservative free]:

Generic: 30 mg/10 mL (10 mL); 6 mg/mL (10 mL); 90 mg/10 mL (10 mL)

Solution Reconstituted, Intravenous, as disodium:

Generic: 30 mg (1 ea); 90 mg (1 ea)

Pharmacologic Category

  • Bisphosphonate Derivative

Pharmacology

Nitrogen-containing bisphosphonate; inhibits bone resorption and decreases mineralization by disrupting osteoclast activity (Gralow, 2009; Rogers, 2011)

Absorption

Poorly from the GI tract

Distribution

38% to 70% over 120 hours

Metabolism

Not metabolized

Excretion

Biphasic; urine (30% to 62% as unchanged drug; lower in patients with renal dysfunction) within 120 hours

Onset of Action

Hypercalcemia of malignancy (HCM): Reduction of albumin-corrected serum calcium: Children: ~48 hours (Kerdudo, 2005); Adults: ≤24 hours for decrease in albumin-corrected serum calcium; maximum effect: ≤7 days

Paget disease: ~1 month for ≥50% decrease in serum alkaline phosphatase

Maximum effect: Hypercalcemia of malignancy: ≤7 days

Duration of Action

HCM: 7 to 14 days; Paget disease: 1 to 372 days

Half-Life Elimination

28 ± 7 hours

Use: Labeled Indications

Hypercalcemia of malignancy: Treatment of moderate or severe hypercalcemia associated with malignancy, with or without bone metastases, in conjunction with adequate hydration.

Osteolytic bone metastases of breast cancer and osteolytic lesions of multiple myeloma: Treatment of osteolytic bone metastases of breast cancer and osteolytic lesions of multiple myeloma in conjunction with standard antineoplastic therapy.

Paget disease: Treatment of patients with moderate to severe Paget disease of bone.

Use: Unlabeled

Treatment of osteogenesis imperfecta; treatment of symptomatic bone metastases of thyroid cancer; prevention of bone loss associated with androgen deprivation treatment in prostate cancer

Contraindications

Hypersensitivity to pamidronate, other bisphosphonates, or any component of the formulation

Dosing: Adult

Note: Single doses should not exceed 90 mg.

Hypercalcemia of malignancy: IV:

Moderate cancer-related hypercalcemia (corrected serum calcium: 12 to 13.5 mg/dL): 60 to 90 mg, as a single dose over 2 to 24 hours

Severe cancer-related hypercalcemia (corrected serum calcium: >13.5 mg/dL): 90 mg, as a single dose over 2 to 24 hours

Re-treatment in patients who show an initial complete or partial response (allow at least 7 days to elapse prior to re-treatment): May re-treat at the same dose if serum calcium does not return to normal or does not remain normal after initial treatment.

Multiple myeloma, osteolytic bone lesions: IV: 90 mg over 4 hours once monthly:

Lytic disease: American Society of Clinical Oncology (ASCO) guidelines: 90 mg over at least 2 hours once every 3 to 4 weeks for 2 years; discontinue after 2 years in patients with responsive and/or stable disease; resume therapy with new-onset skeletal-related events (Kyle, 2007)

Newly-diagnosed, symptomatic (off-label dose): 30 mg over 2.5 hours once monthly for at least 3 years (Gimsing, 2010)

Breast cancer, osteolytic bone metastases: IV: 90 mg over 2 hours once every 3 to 4 weeks

Paget's disease (moderate-to-severe): IV: 30 mg over 4 hours once daily for 3 consecutive days (total dose = 90 mg); may re-treat at initial dose if clinically indicated

Prevention of androgen deprivation-induced osteoporosis (off-label use): Males: IV: 60 mg over 2 hours once every 3 months (Smith, 2001)

Dosing: Geriatric

Refer to adult dosing. Begin at lower end of adult dosing range.

Dosing: Renal Impairment

Patients with serum creatinine >3 mg/dL were excluded from clinical trials; there are only limited pharmacokinetic data in patients with CrCl <30 mL/minute.

Manufacturer recommends the following guidelines:

Treatment of bone metastases: Use is not recommended in patients with severe renal impairment.

Renal impairment in indications other than bone metastases: Use clinical judgment to determine if benefits outweigh potential risks.

Multiple myeloma: American Society of Clinical Oncology (ASCO) guidelines (Kyle, 2007):

Severe renal impairment (serum creatinine >3 mg/dL or CrCl <30 mL/minute) and extensive bone disease: 90 mg over 4 to 6 hours. However, a reduced initial dose should be considered if renal impairment was pre-existing.

Albuminuria >500 mg/24 hours (unexplained): Withhold dose until returns to baseline, then recheck every 3 to 4 weeks; consider reinitiating at a dose not to exceed 90 mg every 4 weeks and with a longer infusion time of at least 4 hours

Dosing adjustment in renal toxicity: In patients with bone metastases, treatment should be withheld for deterioration in renal function (increase of serum creatinine ≥0.5 mg/dL in patients with normal baseline [serum creatinine <1.4 mg/dL] or ≥1 mg/dL in patients with abnormal baseline [serum creatinine ≥1.4 mg/dL]). Resumption of therapy may be considered when serum creatinine returns to within 10% of baseline.

Dosing: Hepatic Impairment

Mild to moderate impairment: No dosage adjustment necessary.

Severe impairment: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Reconstitution

Hazardous agent; use appropriate precautions for handling and disposal (meets NIOSH 2014 criteria).

Powder for injection: Reconstitute by adding 10 mL of SWFI to each vial of lyophilized powder, the resulting solution will be 30 mg/10 mL or 90 mg/10 mL.

Pamidronate may be further diluted in 250 to 1000 mL of 1/2NS or NS or D5W. (The manufacturers recommend dilution in 1000 mL for hypercalcemia of malignancy, 500 mL for Paget’s disease and bone metastases of myeloma, and 250 mL for bone metastases of breast cancer.)

Administration

IV: Infusion rate varies by indication. Longer infusion times (>2 hours) may reduce the risk for renal toxicity, especially in patients with preexisting renal insufficiency. The manufacturer recommends infusing over 2 to 24 hours for hypercalcemia of malignancy; over 2 hours for osteolytic bone lesions with metastatic breast cancer; and over 4 hours for Paget’s disease and for osteolytic bone lesions with multiple myeloma. The ASCO guidelines for bisphosphonate use in multiple myeloma recommend infusing pamidronate over at least 2 hours; if therapy is withheld due to renal toxicity, infuse over at least 4 hours upon reintroduction of treatment after renal recovery (Kyle, 2007).

Hazardous agent; use appropriate precautions for handling and disposal (meets NIOSH 2014 criteria).

Dietary Considerations

Multiple myeloma or metastatic bone lesions from solid tumors or Paget’s disease: Take adequate daily calcium and vitamin D supplement (if patient is not hypercalcemic).

Compatibility

Stable in D5W, NS; incompatible with calcium-containing infusion solutions such as Ringer's injection.

Storage

Powder for reconstitution: Store at 20°C to 25°C (68°F to 77°F). The reconstituted solution is stable for 24 hours stored under refrigeration at 2°C to 8°C (36°F to 46°F). The diluted solution for infusion is stable in D5W or NS at room temperature for up to 24 hours.

Solution for injection: Store at 20°C to 25°C (68°F to 77°F). The diluted solution for infusion is stable in D5W or NS at room temperature for up to 24 hours.

Drug Interactions

Aminoglycosides: May enhance the hypocalcemic effect of Bisphosphonate Derivatives. Monitor therapy

Deferasirox: Bisphosphonate Derivatives may enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased. Monitor therapy

Nonsteroidal Anti-Inflammatory Agents: May enhance the adverse/toxic effect of Bisphosphonate Derivatives. Both an increased risk of gastrointestinal ulceration and an increased risk of nephrotoxicity are of concern. Monitor therapy

Proton Pump Inhibitors: May diminish the therapeutic effect of Bisphosphonate Derivatives. Monitor therapy

Systemic Angiogenesis Inhibitors: May enhance the adverse/toxic effect of Bisphosphonate Derivatives. Specifically, the risk for osteonecrosis of the jaw may be increased. Monitor therapy

Thalidomide: May enhance the nephrotoxic effect of Pamidronate. Monitor therapy

Test Interactions

Bisphosphonates may interfere with diagnostic imaging agents such as technetium-99m-diphosphonate in bone scans.

Adverse Reactions

Note: Actual percentages may vary by indication and duration of infusion; treatment for multiple myeloma is associated with higher percentage.

>10%:

Central nervous system: Fatigue (≤37%), headache (≤26%), insomnia (≤22%)

Endocrine & metabolic: Hypophosphatemia (≤18%), hypokalemia (4% to 18%), hypocalcemia (≤3% to 17%), hypomagnesemia (10% to 12%)

Gastrointestinal: Nausea (≤54%), vomiting (≤36%), anorexia (≤26%), abdominal pain (≤23%), dyspepsia (≤23%)

Genitourinary: Urinary tract infection (≤19%)

Hematologic & oncologic: Anemia (≤43%), metastases (21% to 31%), granulocytopenia (≤20%)

Local: Infusion site reaction (≤18%; includes induration, pain, redness, and swelling)

Neuromuscular & skeletal: Myalgia (≤26%), weakness (≤22%), arthralgia (≤14%), osteonecrosis of the jaw (cancer patients: 1% to 11%)

Renal: Increased serum creatinine (≤19%)

Respiratory: Dyspnea (≤30%), cough (≤26%), upper respiratory tract infection (≤24%), sinusitis (≤16%), pleural effusion (≤11%)

Miscellaneous: Fever (18% to 39%; transient)

1% to 10%:

Cardiovascular: Atrial fibrillation (≤6%), hypertension (≤6%), syncope (≤6%), tachycardia (≤6%), atrial flutter (≤1%), cardiac failure (≤1%), edema (≤1%)

Central nervous system: Drowsiness (≤6%), psychosis (≤4%), seizure (≤2%)

Endocrine & metabolic: Hypothyroidism (≤6%)

Gastrointestinal: Constipation (≤6%), gastrointestinal hemorrhage (≤6%), diarrhea (≤1%), stomatitis (≤1%)

Genitourinary: Uremia (≤4%)

Hematologic & oncologic: Leukopenia (≤4%), neutropenia (≤1%), thrombocytopenia (≤1%)

Infection: Candidiasis (≤6%)

Neuromuscular & skeletal: Back pain, ostealgia

Respiratory: Rales (≤6%), rhinitis (≤6%)

<1% (Limited to important or life-threatening): Acute renal failure, anaphylactic shock, angioedema, cardiac failure, confusion, episcleritis, focal segmental glomerulosclerosis (including collapsing variant), hallucination (visual), hematuria, herpes virus infection (reactivation), hyperkalemia, hypernatremia, hypersensitivity reaction, hypervolemia, hypotension, inflammation at injection site, injection site phlebitis, iridocyclitis, iritis, left heart failure, lymphocytopenia, nephrotic syndrome, osteonecrosis (other than jaw), renal failure, renal insufficiency, scleritis, uveitis, xanthopsia

Warnings/Precautions

Concerns related to adverse effects:

• Bone fractures: Atypical femur fractures (after minimal or no trauma) have been reported. The fractures include subtrochanteric femur (bone just below the hip joint) and diaphyseal femur (long segment of the thigh bone). Some patients experience prodromal pain weeks or months before the fracture occurs. It is unclear if bisphosphonate therapy is the cause for these fractures. Patients receiving long-term (>3 to 5 years) bisphosphonate therapy may be at an increased risk. Consider discontinuing pamidronate in patients with a suspected femoral shaft fracture. Patients who present with thigh or groin pain in the absence of trauma should be evaluated.

• Musculoskeletal pain: Infrequently, severe (and occasionally debilitating) bone, joint, and/or muscle pain have been reported during bisphosphonate treatment. The onset of pain ranged from a single day to several months. Consider discontinuing therapy in patients who experience severe symptoms; symptoms usually resolve upon discontinuation. Some patients experienced recurrence when rechallenged with same drug or another bisphosphonate; avoid use in patients with a history of these symptoms in association with bisphosphonate therapy.

• Electrolyte abnormalities: Use has been associated with asymptomatic electrolyte abnormalities (including hypophosphatemia, hypokalemia, hypomagnesemia, and hypocalcemia). Rare cases of symptomatic hypocalcemia, including tetany, have been reported.

• Myelosuppression: Patients with preexisting anemia, leukopenia, or thrombocytopenia should be closely monitored during the first 2 weeks of treatment.

• Osteonecrosis of the jaw: Osteonecrosis of the jaw (ONJ), also referred to as medication-related osteonecrosis of the jaw (MRONJ), has been reported in patients receiving bisphosphonates. Known risk factors for MRONJ include invasive dental procedures (eg, tooth extraction, dental implants, boney surgery), cancer diagnosis, concomitant therapy (eg, chemotherapy, corticosteroids, angiogenesis inhibitors), poor oral hygiene, ill-fitting dentures, and comorbid disorders (anemia, coagulopathy, infection, preexisting dental or periodontal disease). Risk may increase with increased duration of bisphosphonate use and/or may be reported at a greater frequency based on tumor type (eg, advanced breast cancer, multiple myeloma). According to a position paper by the American Association of Maxillofacial Surgeons (AAOMS), MRONJ has been associated with bisphosphonates and other antiresorptive agents (denosumab), and antiangiogenic agents (eg, bevacizumab, sunitinib) used for the treatment of osteoporosis or malignancy; risk is significantly higher in cancer patients receiving antiresorptive therapy compared to patients receiving osteoporosis treatment (regardless of medication used or dosing schedule). MRONJ risk is also increased with monthly IV antiresorptive therapy compared to the minimal risk associated with oral bisphosphonate use, although risk appears to increase with oral bisphosphonates when duration of therapy exceeds 4 years. The AAOMS suggests that if medically permissible, initiation of IV bisphosphonates for cancer therapy should be delayed until optimal dental health is attained (if extractions are required, antiresorptive therapy should delayed until the extraction site has mucosalized or until after adequate osseous healing). Once IV bisphosphonate therapy is initiated for oncologic disease, procedures that involve direct osseous injury and placement of dental implants should be avoided. Patients developing ONJ during therapy should receive care by an oral surgeon (AAOMS [Ruggiero 2014]).

• Renal deterioration: Single pamidronate doses should not exceed 90 mg. Initial or single doses have been associated with renal deterioration, progressing to renal failure and dialysis. Glomerulosclerosis (focal segmental) with or without nephrotic syndrome has also been reported. Longer infusion times (>2 hours) may reduce the risk for renal toxicity, especially in patients with pre-existing renal insufficiency. Withhold pamidronate treatment (until renal function returns to baseline) in patients with evidence of renal deterioration.

Disease-related concerns:

• Breast cancer (metastatic): The American Society of Clinical Oncology (ASCO) updated guidelines on the role of bone-modifying agents (BMAs) in the prevention and treatment of skeletal-related events for metastatic breast cancer patients (Van Poznak, 2011). The guidelines recommend initiating a BMA (denosumab, pamidronate, zoledronic acid) in patients with metastatic breast cancer to the bone. There is currently no literature indicating the superiority of one particular BMA. Optimal duration is not yet defined; however, the guidelines recommend continuing therapy until substantial decline in patient’s performance status. The ASCO guidelines are in alignment with prescribing information for dosing, renal dose adjustments, infusion times, prevention and management of osteonecrosis of the jaw, and monitoring of laboratory parameter recommendations. BMAs are not the first-line therapy for pain. BMAs are to be used as adjunctive therapy for cancer-related bone pain associated with bone metastasis, demonstrating a modest pain control benefit. BMAs should be used in conjunction with agents such as NSAIDS, opioid and nonopioid analgesics, corticosteroids, radiation/surgery, and interventional procedures.

• Hypercalcemia of malignancy (HCM): Adequate hydration is required during treatment (urine output ~2 L/day); avoid overhydration, especially in patients with heart failure.

• Hypoparathyroidism: Use caution with a history of thyroid surgery; patients may have relative hypoparathyroidism, predisposing them to pamidronate-related hypocalcemia.

• Multiple myeloma: Patients with Bence-Jones proteinuria and dehydration should be adequately hydrated prior to therapy. The American Society of Clinical Oncology (ASCO) has also published guidelines on bisphosphonates use for prevention and treatment of bone disease in multiple myeloma (Kyle, 2007). Bisphosphonate (pamidronate or zoledronic acid) use is recommended in multiple myeloma patients with lytic bone destruction or compression spine fracture from osteopenia. Bisphosphonates may also be considered in patients with pain secondary to osteolytic disease, adjunct therapy to stabilize fractures or impending fractures, and for multiple myeloma patients with osteopenia but no radiographic evidence of lytic bone disease. Bisphosphonates are not recommended in patients with solitary plasmacytoma, smoldering (asymptomatic) or indolent myeloma, or monoclonal gammopathy of undetermined significance. The guidelines recommend monthly treatment for a period of 2 years. At that time, consider discontinuing in responsive and stable patients, and reinitiate if a new-onset skeletal-related event occurs. The ASCO guidelines are in alignment with the prescribing information for dosing, renal dose adjustments, infusion times, prevention and management of osteonecrosis of the jaw, and monitoring of laboratory parameter recommendations. According to the guidelines, in patients with extensive bone disease with existing severe renal disease (a serum creatinine >3 mg/dL or CrCl <30 mL/minute) pamidronate at a dose of 90 mg over 4 to 6 hours should be used (unless preexisting renal disease in which case a reduced initial dose should be considered). Monitor for albuminuria every 3 to 6 months; in patients with unexplained albuminuria >500 mg/24 hours, withhold the dose until level returns to baseline, then recheck every 3 to 4 weeks. Pamidronate may be reinitiated at a dose not to exceed 90 mg every 4 weeks with a longer infusion time of at least 4 hours.

• Renal impairment: Patients with serum creatinine >3 mg/dL were not studied in clinical trials; limited data are available in patients with CrCl <30 mL/minute. Evaluate serum creatinine prior to each treatment. For the treatment of bone metastases, use is not recommended in patients with severe renal impairment. With indications other than bone metastases, use clinical judgment to determine if benefits outweigh potential risks in patients with renal impairment.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (meets NIOSH 2014 criteria).

Monitoring Parameters

Serum creatinine (prior to each treatment); serum electrolytes, including calcium, phosphate, magnesium, and potassium; CBC with differential; monitor for hypocalcemia for at least 2 weeks after therapy; dental exam and preventive dentistry prior to therapy for patients at risk of osteonecrosis, including all cancer patients; patients with pre-existing anemia, leukopenia, or thrombocytopenia should be closely monitored during the first 2 weeks of treatment; in addition, monitor urine albumin every 3 to 6 months in multiple myeloma patients

Pregnancy Risk Factor

D

Pregnancy Considerations

Adverse events were observed in animal reproduction studies. It is not known if bisphosphonates cross the placenta, but fetal exposure is expected (Djokanovic, 2008; Stathopoulos, 2011). Bisphosphonates are incorporated into the bone matrix and gradually released over time. The amount available in the systemic circulation varies by dose and duration of therapy. Theoretically, there may be a risk of fetal harm when pregnancy follows the completion of therapy; however, available data have not shown that exposure to bisphosphonates during pregnancy significantly increases the risk of adverse fetal events (Djokanovic, 2008; Levy, 2009; Stathopoulos, 2011). Until additional data is available, most sources recommend discontinuing bisphosphonate therapy in women of reproductive potential as early as possible prior to a planned pregnancy; use in premenopausal women should be reserved for special circumstances when rapid bone loss is occurring (Bhalla, 2010; Pereira, 2012; Stathopoulos, 2011). Because hypocalcemia has been described following in utero bisphosphonate exposure, exposed infants should be monitored for hypocalcemia after birth (Djokanovic, 2008; Stathopoulos, 2011).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea, vomiting, lack of appetite, insomnia, cough, rhinorrhea, rhinitis, or injection site pain. Have patient report immediately to prescriber signs of kidney problems (urinary retention, blood in urine, change in amount of urine passed, or weight gain); severe abdominal pain; angina; tachycardia; arrhythmia; polyuria; severe bone pain; severe joint pain; severe muscle pain; groin, hip, or thigh pain; cramps; muscle spasms; seizures; confusion; severe dizziness; passing out; severe headache; severe loss of strength and energy; hallucinations; mood changes; numbness and tingling; shortness of breath; vision changes; thrush; injection site irritation; or jaw pain or edema (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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