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  • CLASSES

    Injectable Bisphosphonates

    DEA CLASS

    Rx

    DESCRIPTION

    Intravenous second-generation intravenous bisphosphonate
    Used primarily for hypercalcemia of malignancy and to reduce skeletal adverse events in selected cancer patients
    For other indications, more potent bisphosphonates are preferred

    COMMON BRAND NAMES

    Aredia

    HOW SUPPLIED

    Aredia/Pamidronate Disodium Intravenous Inj Pwd F/Sol: 30mg, 90mg
    Pamidronate Disodium Intravenous Inj Sol: 1mL, 3mg, 6mg, 9mg

    DOSAGE & INDICATIONS

    For the treatment of hypercalcemia.
    For hypercalcemia associated with malignancy.
    Intravenous dosage
    Adults

    IF ALBUMIN-CORRECTED SERUM CALCIUM IS 12 to 13.5 mg/dL: 60 mg or 90 mg IV infusion as a single dose; administer over 2 to 24 hours. IF ALBUMIN-CORRECTED SERUM CALCIUM IS MORE THAN 13.5 mg/dL: Give 90 mg IV infusion as a single dose; administer over 2 to 24 hours. RETREATMENT: To allow time for a full response after an initial dose, wait a minimum of 7 days before retreatment. CONCURRENT THERAPY: Vigorous saline hydration is an integral part of hypercalcemia treatment. Urine output should be maintained at approximately 2 L/day. DETERMINING WHICH DOSE TO USE: When treating hypercalcemia of malignancy, the serum calcium should be corrected based upon the serum albumin level to determine the appropriate dose. The following equation may be used: Albumin-corrected serum calcium (mg/dL) = serum calcium (mg/dL) + 0.8(4 - serum albumin [grams/dL]).

    For hypercalcemia associated with primary hyperparathyroidism†.
    Intravenous dosage
    Adults

    Limited data are available. In 1 report of 9 patients (median age 81 years) with moderate to severe hypercalcemia due to primary hyperparathyroidism, a single IV dose of 15 to 60 mg resulted in a therapeutic response in 8 patients with 6 achieving normocalcemia within 1 week. In a case report of a man with primary hyperparathyroidism, a dose of 90 mg IV infusion over 24 hours was effective in reducing his calcium concentration from 13.6 mg/dL to 9.4 mg/dL after 1 week; the patient required a second 60-mg dose approximately 2 months after the first dose and later died of a gastrointestinal hemorrhage. A second case reports the effectiveness of 60 mg IV followed by 60 mg IV 1 month later and 90 mg IV 2 weeks after the second dose in a patient with primary hyperparathyroidism. This patient eventually required surgery to treat the hyperparathyroidism.

    For hypercalcemia associated with end-stage renal failure† including patients with secondary hyperparathyroidism†.
    Intravenous dosage
    Adults

    Limited data are available. In 1 report, 10 patients with renal failure who developed symptomatic hypercalcemia secondary to use of calcium-based phosphate binders were given pamidronate. Doses ranged between 30 to 60 mg IV with a median dose of 60 mg IV. Serum calcium declined to within normal limits within 3 days in all 10 patients. In a 12-month study of 13 patients on hemodialysis with secondary hyperparathyroidism and mild hypercalcemia, 60 mg IV during hemodialysis every 2 months decreased serum calcium concentrations from a baseline of greater than 12 g/dL to approximately 10 g/dL and significantly decreased iPTH concentrations by 460 pg/mL (p < 0.001). Additionally, calcitriol dosages were increased from a mean dose of 1 mcg/week at baseline to 3 mcg/week after 6 months. Bone mineral density increased by 33% at the lumbar spine and femoral neck after 12 months of therapy (p < 0.01).

    Adolescents

    A case report describes a dose of 15 mg IV infusion (0.4 mg/kg) given over 2 hours in a boy aged 14 years with end-stage renal disease and secondary hyperparathyroidism; the serum calcium decreased from 12.5 mg/dL to 9.7 mg/dL. Although the serum calcium was controlled for 26 days and allowed for optimization of calcitriol treatment, surgical treatment was eventually required. The patient received acetaminophen prior to the infusion; no adverse reactions were reported.

    For the treatment of osteolytic lesions of multiple myeloma or osteolytic bone metastases due to breast cancer.
    Patients with multiple myeloma.
    Intravenous dosage
    Adults

    90 mg IV infusion once a month; administer the dose over 4 hours. Supplement with calcium and vitamin D if intake inadequate and no hypercalcemia is present. Limited data are available in patients with a serum creatinine greater than 3 mg/dL. Withhold treatment if the renal function deteriorates. The optimal duration of therapy is not known; however data from a clinical study in myeloma patients indicate that treatment for 21 months is beneficial.

    Patients with breast cancer and bone metastases.
    Intravenous dosage
    Adults

    90 mg IV infusion once every 3 to 4 weeks, administered over 2 hours. Supplement with calcium and vitamin D if intake inadequate and no hypercalcemia is present. Withhold treatment if renal function deteriorates. The optimal duration of therapy is not known; however, data from a clinical study in breast cancer patients indicate that treatment for 24 months is beneficial.

    For the treatment of moderate to severe Paget's disease.
    Intravenous dosage
    Adults

    30 mg IV infusion once daily for 3 days (total dose: 90 mg); administer each dose over 4 hours. Supplement with calcium and vitamin D if dietary intake inadequate. A clinician may consider retreatment if clinically indicated. For retreatment, the dose and duration of therapy are the same as for initial treatment. Pamidronate is associated with biochemical remissions lasting 1 to 3 years in most patients. A single dose of zoledronic acid is the drug of choice per treatment guidelines, due to higher potency, the rare need for retreatment within 5 years, and long-term data for reducing pain and lytic lesions and improving quality of life.

    For the treatment of osteogenesis imperfecta†.
    Intravenous dosage
    Adults

    1.5 mg/kg/dose (Max: 60 mg/dose) IV every 3 to 4 months.

    Children and Adolescents

    0.33 to 1 mg/kg/dose IV once daily for 2 to 3 consecutive days every 3 to 6 months. Usual dose range: 6 to 9 mg/kg/year.

    Infants

    0.5 mg/kg/dose IV once daily for 2 consecutive days at baseline, then 0.75 mg/kg/dose IV once daily for 2 consecutive days at week 7, then 1 mg/kg/dose IV once daily for 2 consecutive days at week 15, then 1 mg/kg/dose IV once daily for 2 consecutive days at week 24, then 1.25 mg/kg/dose IV once daily for 2 consecutive days at week 34, then 1.5 mg/kg/dose IV once daily for 2 consecutive days at week 46 (for a cumulative dose of 12 mg/kg/year).

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    90 mg/dose IV.

    Geriatric

    90 mg/dose IV.

    Adolescents

    Safety and efficacy have not been established; however, 1 mg/kg/day IV for a 2- to 3-day cycle up to a usual dose range of 6 to 9 mg/kg/year IV has been used for osteogenesis imperfecta.

    Children

    Safety and efficacy have not been established; however, 1 mg/kg/day IV for a 2- to 3-day cycle up to a usual dose range of 6 to 9 mg/kg/year IV has been used for osteogenesis imperfecta.

    Infants

    Safety and efficacy have not been established; however, doses up to 1.5 mg/kg/day IV for a 2-day cycle for a total yearly dose of 12 mg/kg/year IV have been used for osteogenesis imperfecta.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    No dosage adjustment necessary in patients with mild to moderate hepatic impairment; pamidronate has not been studied in patients with severe hepatic impairment.

    Renal Impairment

    No quantitative recommendations are available. Longer infusions (i.e., more than 2 hours), may decrease the risk for renal toxicity, especially in those patients with underlying renal impairment. Obtain a serum creatinine prior to each treatment.
     
    CrCl less than 30 mL/minute or Serum creatinine (SCr) greater than 3 mg/dL: Safety and efficacy have not been established in patients with severe renal impairment; there are limited data in patients with CrCl less than 30 mL/minute. If renal function deteriorates (e.g., SCr increase of 0.5 mg/dL in patients with normal baseline SCr or an increase of 1 mg/dL in patients with abnormal baseline SCr) during pamidronate treatment in patients with bone metastases, hold doses of pamidronate until renal function returns to baseline.

    ADMINISTRATION

    Hazardous Drugs Classification
    NIOSH 2016 List: Group 3
    NIOSH (Draft) 2020 List: Table 2
    Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
    Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system drug transfer device. Eye/face and respiratory protection may be needed during preparation and administration.

    Injectable Administration

    For intravenous infusion only.
    The patient's renal function (i.e., serum creatinine) and hydration status should be assessed prior to each treatment with pamidronate.
    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    Administer intravenously via slow IV infusion only. Dilute prior to administration.
     
    Reconstitution/Dilution:
    Reconstitute vial with 10 mL of sterile water for injection; the drug should be completely dissolved before solution is withdrawn. After reconstitution, store under refrigeration, 2 to 8 degrees C (36 to 46 degrees F) for up to 24 hours.
    Pamidronate can be diluted in 0.45% or 0.9% Sodium Chloride Injection or Dextrose 5% for injection. Do not dilute in calcium-containing solutions such as Ringer's solution.
    Hypercalcemia of malignancy: Dilute the recommended dose in 1000 mL of 0.45% or 0.9% Sodium Chloride Injection or Dextrose 5% for injection. The diluted solution is stable for up to 24 hours at room temperature.
    Paget's Disease: Dilute the recommended dose in 500 mL of 0.45% or 0.9% Sodium Chloride Injection or Dextrose 5% for injection.
    Osteolytic bone metastases of breast cancer: Dilute the recommended dose in 250 mL of 0.45% or 0.9% Sodium Chloride Injection or Dextrose 5% for injection.
    Osteolytic bone lesions of multiple myeloma: Dilute the recommended dose in 500 mL of 0.45% or 0.9% Sodium Chloride Injection or Dextrose 5% for injection.
    In children with osteogenesis imperfecta (off-label use): pamidronate has been diluted in 0.25% NS/D5W to a concentration of less than 0.12 mg/mL.
     
    Intravenous infusion:
    Due to risk of clinically significant renal toxicity, single doses should not exceed 90 mg and the duration of the IV infusion should be no less than 2 hours.
    Administer in an IV line separate from all other drugs.
    Hypercalcemia of malignancy: Infuse dose over 2 to 24 hours. A duration of infusion of more than 2 hours may decrease the risk for renal toxicity, especially in those patients with underlying renal impairment.
    Paget's Disease: Infuse dose over 4 hours.
    Osteolytic bone metastases of breast cancer: Infuse dose over 2 hours. A duration of infusion of more than 2 hours may decrease the risk for renal toxicity, especially in those patients with underlying renal impairment.
    Osteolytic bone lesions of multiple myeloma: Infuse dose over 4 hours.

    STORAGE

    Generic:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Aredia:
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Acute bronchospasm, asthma, phosphonate hypersensitivity

    Pamidronate should be used with caution in patients with phosphonate hypersensitivity. Treatment with bisphosphonates has been associated with acute bronchospasm in patients with aspirin-sensitive asthma or phosphonate hypersensitivity.

    Dehydration, hypovolemia

    Dehydration or hypovolemia should be corrected during treatment of hypercalcemia and prior to beginning pamidronate therapy; maintain adequate urine output during the treatment of hypercalcemia.

    Electrolyte imbalance, hypocalcemia, hypomagnesemia, hypoparathyroidism, hypophosphatemia

    Standard hypercalcemia-related metabolic parameters, such as serum levels of calcium, phosphate, and magnesium, as well as serum creatinine, should be carefully monitored during treatment with pamidronate. Pamidronate should not be used in patients with pre-existing hypocalcemia. Patients with a history of thyroid surgery may have a relative hypoparathyroidism, which may predispose patients to hypocalcemia. If electrolyte imbalance (i.e., hypocalcemia, hypomagnesemia, or hypophosphatemia) occurs during therapy, short-term supplementation may be necessary.

    Diabetes mellitus, hypertension, multiple myeloma, renal failure, renal impairment

    Pamidronate should be used with caution in patients with renal impairment; it is excreted intact primarily via the kidney. Pamidronate has been associated with acute deterioration in renal function, including acute renal failure; the risk of renal adverse effects may be greater in patients with impaired renal function. Single doses should not exceed 90 mg (see Dosage); further dosage adjustments may be necessary based on clinical response. Adverse effects on kidney function have been seen after the initial dose. Monitor renal function prior to each dose and throughout treatment, especially in patients with preexisting renal impairment. Longer infusions (i.e., > 2 hours) may decrease the risk for renal toxicity, especially in patients with underlying renal impairment. Other risk factors for renal deterioration are the presence of dehydration, multiple myeloma (see also osteonecrosis for other risks associated with zoledronic acid in patients with multiple myeloma), other advanced cancers (advanced neoplastic disease), diabetes mellitus, hypertension, and the use of additional nephrotoxic drugs (i.e., NSAIDs, radiopaque contrast media, thalidomide). Safety and efficacy have not been established in patients with severe renal impairment (i.e., SCr > 3 mg/dl or renal failure). Patients receiving pamidronate for bone metastases who show evidence of deterioration in renal function should have their next does withheld until renal function returns to within 10% of baseline; similar regimen adjustments may be required in patients receiving pamidronate for other indications, but no data are currently available.

    Pregnancy

    Pamidronate is classified as FDA pregnancy risk category D. Pamidronate may cause fetal harm when administered to a pregnant woman. No adequate and well-controlled studies have been conducted in pregnant women, although a few reports in the literature do exist. In one report, a single dose of 90 mg pamidronate was administered IV to a pregnant woman during gestation week 28; the infant was born at 29 weeks and required treatment for hypocalcemia. At 1 year of life, the infant was developing normally. The other 2 cases involve women with osteogenesis imperfecta who received pamidronate prior to conception. Both infants were born after 37 weeks gestation, and both acquired osteogenesis imperfecta. One of the infants required treatment for hypocalcemia, and the other had bilateral talipes, which may or may not be secondary to pamidronate administration. At 16 and 14 months of life, respectively, both patients were of normal weight and height. After a bisphosphonate is incorporated into bone matrix it is gradually released from the bone over a period of weeks to years. The extent of bisphosphonate incorporation into adult bone, and hence, the amount available for release back into systemic circulation, is directly related to the total dose and duration of bisphosphonate use. Therefore, there is a theoretical risk of fetal harm if a woman becomes pregnant during or after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration on this risk has not been established. Although these 3 reports demonstrate that administration of pamidronate during pregnancy may not be associated with a significant risk to the fetus or embryo, it is still recommended that pamidronate not be administered to pregnant women, if possible. If a 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. Furthermore, in those infants that are exposed to pamidronate in utero, serum calcium concentrations should be monitored for the first few days after birth.

    Breast-feeding

    According to the manufacturer, it is not known if pamidronate is excreted into breast milk. Based on pharmacokinetics, it is expected that pamidronate will be excreted in human breast milk; however, a woman breast-feeding her infant started receiving 30 mg pamidronate IV once monthly shortly after initiating breast-feeding. Expressed breast milk was discarded for 48 hours after each dose. Pamidronate (lower limit of detection 0.4 mcmol/L) was not detected in the breast milk in pooled samples taken 0—24 hours and 25—48 hours after the first dose. The low bioavailability most likely limits the amount excreted in breast milk. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Geriatric

    During clinical trials of pamidronate, approximately 20% of patients studied were 65 years and older and approximately 15% were 75 years and older. No overall differences in safety or effectiveness were observed between geriatric patients and younger patients, and other reported clinical experience has not identified differences in responses between these two populations. However, greater sensitivity of some elderly patients cannot be ruled out. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. There is an age-related decline in renal function in geriatric patients, which may increase the risk of adverse renal effects during administration of pamidronate. Cautious use and special care in renal monitoring are recommended in the elderly. The risk of adverse renal effects may be minimized by ensuring that patients are well-hydrated prior to therapy, avoiding concomitant use of nephrotoxic drugs in the post-infusion period, and not exceeding indication-specific administration guidelines and dosage limits. The federal Omnibus Budget Reconciliation Act (OBRA) regulates the use of medications in residents of long-term care facilities, including guidelines for the use of bisphosphonate agents; injectable bisphosphonates, such as pamidronate, are not generally used within a skilled care facility.

    Anemia, chemotherapy, coagulopathy, corticosteroid therapy, dental disease, dental work, infection

    Post-marketing surveillance has revealed reports of osteonecrosis, primarily of the jaw, in patients with cancer receiving treatment regimens which included bisphosphonates (most commonly pamidronate and zoledronic acid), but also occasionally in patients receiving chronic oral bisphosphonate therapy for osteoporosis. In patients with cancer receiving intravenous bisphosphonates, many patients were also receiving chemotherapy and corticosteroids. The majority of reported cases have been associated with dental procedures, such as tooth extraction, and many of these patients had signs of local infection including osteomyelitis; however cases have appeared spontaneously. Postmarketing experience and published literature suggest a greater incidence in patients with advanced breast cancer and multiple myeloma. It would be prudent for all patients including those with concomitant risk factors (e.g. anemia, cancer, chemotherapy, coagulopathy, corticosteroid therapy, dental disease, infection, poor oral hygiene) initiating bisphosphonate therapy to receive a dental examination with appropriate preventive dentistry and correction of dental complications prior to beginning treatment. Preventive measures such as these as well as continued regular follow-up with a dentist during bisphosphonate therapy are recommended by the American Academy of Oral Medicine as the best way to minimize the risk of osteonecrosis. Invasive dental procedures should be avoided, if possible, during treatment, but if they are necessary, should be performed by an experienced dentist with close patient follow-up. If osteonecrosis of the jaw does develop during bisphosphonate therapy, it should be noted that dental surgery may exacerbate the condition. For patients requiring dental work, no data are available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of osteonecrosis of the jaw. In addition, discontinuing the bisphosphonate once osteonecrosis develops is controversial as the estimated half-life of bisphosphonates in the bone is years. The Mayo Clinic has developed guidelines for the use of bisphosphonates in patients with multiple myeloma. Per their guidelines, pamidronate is preferred over zoledronic acid in this population because the incidence of osteonecrosis appears to be highest for zoledronic acid. Furthermore, they recommend discontinuing the bisphosphonate after 2 years of treatment if the patient has achieved a complete response or has reached a plateau; for other patients, prolonging the duration between doses to every 3 months is recommended, although clinical evidence supporting this recommendation is not available.

    Children, infants, neonates

    Safety and efficacy of use of pamidronate in pediatric patients (children, infants, neonates) have not been established. Bisphosphonates have been used successfully in pediatric patients for treatment of specific disease states (i.e., hypercalcemia of malignancy, idiopathic or glucocorticoid induced osteoporosis, osteogenesis imperfecta, Paget's disease). However, extreme caution must be used to ensure appropriate use in children; excessive doses of bisphosphonates may compromise skeletal quality during growth, despite concomitant increases in bone density. In a case report, inappropriate and excessive doses of pamidronate in a child resulted in osteopetrosis (abnormally dense and misshapen bone predisposed to fracture). Sclerotic lines at the metaphyseal end of long bones have been reported in children with nephropathy taking daily oral pamidronate for greater than 5 months. It is advisable to monitor biochemical markers of skeletal turnover when bisphosphonates are used in children. Periodic X-rays may also be prudent.

    ADVERSE REACTIONS

    Severe

    pleural effusion / Delayed / 10.7-10.7
    atrial fibrillation / Early / 6.0-6.0
    GI bleeding / Delayed / 0-6.0
    seizures / Delayed / 2.0-2.0
    uveitis / Delayed / 0-1.0
    angioedema / Rapid / 0-1.0
    anaphylactic shock / Rapid / 0-1.0
    heart failure / Delayed / 0-1.0
    atrial flutter / Early / 0-1.0
    hyperkalemia / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    nephrotic syndrome / Delayed / Incidence not known
    visual impairment / Early / Incidence not known
    osteonecrosis / Delayed / Incidence not known
    bone fractures / Delayed / Incidence not known
    acute respiratory distress syndrome (ARDS) / Early / Incidence not known

    Moderate

    anemia / Delayed / 6.0-42.5
    constipation / Delayed / 33.2-33.2
    dyspnea / Early / 30.4-30.4
    hypophosphatemia / Delayed / 1.7-18.0
    hypokalemia / Delayed / 4.0-18.0
    hypocalcemia / Delayed / 1.0-17.0
    hypomagnesemia / Delayed / 4.0-15.0
    thrombocytopenia / Delayed / 0-14.0
    sinus tachycardia / Rapid / 0-6.0
    candidiasis / Delayed / 0-6.0
    hypothyroidism / Delayed / 0-6.0
    leukopenia / Delayed / 4.0-4.0
    psychosis / Early / 0-4.0
    neutropenia / Delayed / 0-1.0
    stomatitis / Delayed / 0-1.0
    iritis / Delayed / 0-1.0
    edema / Delayed / 0-1.0
    hypotension / Rapid / 0-1.0
    bone pain / Delayed / 10.0
    hypertension / Early / 6.0
    lymphopenia / Delayed / Incidence not known
    erythema / Early / Incidence not known
    hypernatremia / Delayed / Incidence not known
    hematuria / Delayed / Incidence not known
    ocular inflammation / Early / Incidence not known
    conjunctivitis / Delayed / Incidence not known

    Mild

    musculoskeletal pain / Early / 66.8-66.8
    nausea / Early / 0-53.5
    fever / Early / 5.0-38.5
    fatigue / Early / 12.0-37.2
    vomiting / Early / 0-35.7
    diarrhea / Early / 0-28.5
    anorexia / Delayed / 0-26.0
    myalgia / Early / 0-26.0
    cough / Delayed / 25.7-25.7
    dyspepsia / Early / 0-22.6
    abdominal pain / Early / 0-22.6
    insomnia / Early / 0-22.2
    asthenia / Delayed / 22.2-22.2
    injection site reaction / Rapid / 4.0-18.0
    sinusitis / Delayed / 15.6-15.6
    anxiety / Delayed / 14.3-14.3
    arthralgia / Delayed / 13.6-13.6
    rhinitis / Early / 0-6.0
    syncope / Early / 0-6.0
    drowsiness / Early / 0-6.0
    back pain / Delayed / 5.0
    headache / Early / 10.0
    ocular pain / Early / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Monitor renal function during concomitant pamidronate and aspirin use due to risk for additive nephrotoxicity.
    Acetaminophen; Aspirin: (Moderate) Monitor renal function during concomitant pamidronate and aspirin use due to risk for additive nephrotoxicity.
    Acetaminophen; Aspirin; Diphenhydramine: (Moderate) Monitor renal function during concomitant pamidronate and aspirin use due to risk for additive nephrotoxicity.
    Amikacin: (Moderate) Coadministration of pamidronate with other nephrotoxic drugs, such as aminoglycosides, may increase the risk of developing nephrotoxicity following pamidronate administration, even in patients who have normal renal function.
    Aminoglycosides: (Moderate) Coadministration of pamidronate with other nephrotoxic drugs, such as aminoglycosides, may increase the risk of developing nephrotoxicity following pamidronate administration, even in patients who have normal renal function.
    Aprotinin: (Moderate) The manufacturer recommends using aprotinin cautiously in patients that are receiving drugs that can affect renal function, such as pamidronate, as the risk of renal impairment may be increased.
    Aspirin, ASA: (Moderate) Monitor renal function during concomitant pamidronate and aspirin use due to risk for additive nephrotoxicity.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Monitor renal function during concomitant pamidronate and aspirin use due to risk for additive nephrotoxicity.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Monitor renal function during concomitant pamidronate and aspirin use due to risk for additive nephrotoxicity.
    Aspirin, ASA; Caffeine: (Moderate) Monitor renal function during concomitant pamidronate and aspirin use due to risk for additive nephrotoxicity.
    Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Monitor renal function during concomitant pamidronate and aspirin use due to risk for additive nephrotoxicity.
    Aspirin, ASA; Carisoprodol: (Moderate) Monitor renal function during concomitant pamidronate and aspirin use due to risk for additive nephrotoxicity.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Monitor renal function during concomitant pamidronate and aspirin use due to risk for additive nephrotoxicity.
    Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Moderate) Monitor renal function during concomitant pamidronate and aspirin use due to risk for additive nephrotoxicity. (Moderate) Sodium bicarbonate can reduce the absorption of the oral bisphosphonates. Wait at least 30 minutes after oral alendronate, 1 hour after ibandronate, and 2 hours after oral etidronate, risedronate, or tiludronate before taking a sodium bicarbonatecontaining product.
    Aspirin, ASA; Dipyridamole: (Moderate) Monitor renal function during concomitant pamidronate and aspirin use due to risk for additive nephrotoxicity.
    Aspirin, ASA; Omeprazole: (Moderate) Monitor renal function during concomitant pamidronate and aspirin use due to risk for additive nephrotoxicity.
    Aspirin, ASA; Oxycodone: (Moderate) Monitor renal function during concomitant pamidronate and aspirin use due to risk for additive nephrotoxicity.
    Aspirin, ASA; Pravastatin: (Moderate) Monitor renal function during concomitant pamidronate and aspirin use due to risk for additive nephrotoxicity.
    Capreomycin: (Major) Since capreomycin is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including pamidronate, may increase serum concentrations of either drug. Theoretically, the chronic coadministration of these drugs may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Monitor patients for changes in renal function if these drugs are coadministered.
    Cidofovir: (Contraindicated) The administration of cidofovir with another potentially nephrotoxic agent, such as pamidronate, is contraindicated. Pamidronate should be discontinued at least 7 days prior to beginning cidofovir.
    Clindamycin: (Moderate) Concomitant use of pamidronate and clindamycin may result in additive nephrotoxicity. Monitor for renal toxicity if concomitant use is required.
    Colistimethate, Colistin, Polymyxin E: (Major) Theoretically, chronic coadministration may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Monitor patients for changes in renal function if these drugs are coadministered. Since colistimethate sodium is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including pamidronate, may increase serum concentrations of either drug.
    Colistin: (Major) Theoretically, chronic coadministration may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Monitor patients for changes in renal function if these drugs are coadministered. Since colistimethate sodium is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including pamidronate, may increase serum concentrations of either drug.
    Cyclosporine: (Moderate) Coadministration of pamidronate with other nephrotoxic drugs, including cyclosporine, may increase the risk of developing nephrotoxicity following pamidronate administration, even in patients who have normal renal function.
    Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as pamidronate. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus.
    Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as pamidronate. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as pamidronate. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as pamidronate. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus.
    Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as pamidronate. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus.
    Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as pamidronate. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus.
    Entecavir: (Moderate) Because entecavir is primarily eliminated by the kidneys and pamidronate can affect renal function, concurrent administration with pamidronate may increase the serum concentrations of entecavir and adverse events. The manufacturer of entecavir recommends monitoring for adverse effects when these drugs are coadministered.
    Gentamicin: (Moderate) Coadministration of pamidronate with other nephrotoxic drugs, such as aminoglycosides, may increase the risk of developing nephrotoxicity following pamidronate administration, even in patients who have normal renal function.
    Hyaluronidase, Recombinant; Immune Globulin: (Moderate) Immune Globulin (IG) products have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephrosis, and death. Patients predisposed to acute renal failure include patients receiving known nephrotoxic drugs like pamidronate. Coadminister IG products at the minimum concentration available and the minimum rate of infusion practicable. Also, closely monitor renal function.
    Immune Globulin IV, IVIG, IGIV: (Moderate) Immune Globulin (IG) products have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephrosis, and death. Patients predisposed to acute renal failure include patients receiving known nephrotoxic drugs like pamidronate. Coadminister IG products at the minimum concentration available and the minimum rate of infusion practicable. Also, closely monitor renal function.
    Inotersen: (Moderate) Use caution with concomitant use of inotersen and pamidronate due to the risk of glomerulonephritis and nephrotoxicity.
    Kanamycin: (Moderate) Coadministration of pamidronate with other nephrotoxic drugs, such as aminoglycosides, may increase the risk of developing nephrotoxicity following pamidronate administration, even in patients who have normal renal function.
    Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as pamidronate. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus.
    Lanthanum Carbonate: (Moderate) To limit absorption problems, the oral bisphosphonates should not be taken within 2 hours of dosing with lanthanum carbonate. Oral drugs known to interact with cationic antacids, like the oral bisphosphonates, may also be bound by lanthanum carbonate. Separating times of administration will maximize absorption and clinical benefit of the bisphosphonate. Separate the times of administration appropriately. Monitor the patient's clinical status and bone density as recommended to ensure the appropriate response to bisphosphonate therapy is obtained.
    Loop diuretics: (Moderate) Because both loop diuretics and intravenously administered bisphosphonates (i.e., alendronate, ibandronate, pamidronate, and zoledronic acid) can cause a decrease in serum calcium, caution is advised when used concomitantly in the treatment of hypercalcemia of malignancy in order to avoid hypocalcemia. In patients with hypercalcemia of malignancy, the initial treatment typically includes the use of loop diuretics, in combination with saline hydration, however, diuretic therapy should not be employed prior to correction of hypovolemia and dehydration.
    Mannitol: (Major) Avoid use of mannitol and pamidronate, if possible. Concomitant administration of nephrotoxic drugs, such as pamidronate, increases the risk of renal failure after administration of mannitol.
    Non-Ionic Contrast Media: (Moderate) Coadministration of pamidronate with other nephrotoxic drugs may increase the risk of developing nephrotoxicity following pamidronate administration, even in patients who have normal renal function.
    Nonsteroidal antiinflammatory drugs: (Moderate) Monitor renal function during concomitant pamidronate and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
    Omeprazole; Sodium Bicarbonate: (Moderate) Sodium bicarbonate can reduce the absorption of the oral bisphosphonates. Wait at least 30 minutes after oral alendronate, 1 hour after ibandronate, and 2 hours after oral etidronate, risedronate, or tiludronate before taking a sodium bicarbonatecontaining product.
    Paromomycin: (Moderate) Coadministration of pamidronate with other nephrotoxic drugs, such as aminoglycosides, may increase the risk of developing nephrotoxicity following pamidronate administration, even in patients who have normal renal function.
    Plazomicin: (Moderate) Coadministration of pamidronate with other nephrotoxic drugs, such as aminoglycosides, may increase the risk of developing nephrotoxicity following pamidronate administration, even in patients who have normal renal function.
    Sodium Bicarbonate: (Moderate) Sodium bicarbonate can reduce the absorption of the oral bisphosphonates. Wait at least 30 minutes after oral alendronate, 1 hour after ibandronate, and 2 hours after oral etidronate, risedronate, or tiludronate before taking a sodium bicarbonatecontaining product.
    Streptomycin: (Moderate) Coadministration of pamidronate with other nephrotoxic drugs, such as aminoglycosides, may increase the risk of developing nephrotoxicity following pamidronate administration, even in patients who have normal renal function.
    Tacrolimus: (Moderate) Coadministration of pamidronate with other nephrotoxic drugs may increase the risk of developing nephrotoxicity following pamidronate administration, even in patients who have normal renal function.
    Telavancin: (Moderate) Concurrent or sequential use of telavancin with other potentially nephrotoxic drugs such as pamidronate may lead to additive nephrotoxicity. Closely monitor renal function and adjust telavancin doses based on calculated creatinine clearance.
    Telbivudine: (Moderate) Drugs that alter renal function such as pamidronate may alter telbivudine plasma concentrations because telbivudine is eliminated primarily by renal excretion. Monitor renal function before and during telbivudine treatment.
    Tenofovir Alafenamide: (Moderate) Monitor for changes in renal function if tenofovir alafenamide is administered in combination with a nephrotoxic agent, such as pamidronate. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with a drug that reduces renal function or competes for active tubular secretion may increase concentrations of tenofovir and other renally eliminated drugs; thus, increasing the risk of developing renal-related adverse reactions.
    Tenofovir Disoproxil Fumarate: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as pamidronate. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus.
    Thalidomide: (Moderate) In patients with multiple myeloma, the risk of renal dysfunction may be higher in patients taking both pamidronate and thalidomide.
    Tobramycin: (Moderate) Coadministration of pamidronate with other nephrotoxic drugs, such as aminoglycosides, may increase the risk of developing nephrotoxicity following pamidronate administration, even in patients who have normal renal function.
    Vancomycin: (Moderate) Coadministration of pamidronate with other nephrotoxic drugs, like vancomycin, may increase the risk of developing nephrotoxicity following pamidronate administration, even in patients who have normal renal function.
    Voclosporin: (Moderate) Concomitant use of voclosporin and pamidronate may result in additive nephrotoxicity. Monitor for renal toxicity if concomitant use is required.

    PREGNANCY AND LACTATION

    Pregnancy

    Pamidronate is classified as FDA pregnancy risk category D. Pamidronate may cause fetal harm when administered to a pregnant woman. No adequate and well-controlled studies have been conducted in pregnant women, although a few reports in the literature do exist. In one report, a single dose of 90 mg pamidronate was administered IV to a pregnant woman during gestation week 28; the infant was born at 29 weeks and required treatment for hypocalcemia. At 1 year of life, the infant was developing normally. The other 2 cases involve women with osteogenesis imperfecta who received pamidronate prior to conception. Both infants were born after 37 weeks gestation, and both acquired osteogenesis imperfecta. One of the infants required treatment for hypocalcemia, and the other had bilateral talipes, which may or may not be secondary to pamidronate administration. At 16 and 14 months of life, respectively, both patients were of normal weight and height. After a bisphosphonate is incorporated into bone matrix it is gradually released from the bone over a period of weeks to years. The extent of bisphosphonate incorporation into adult bone, and hence, the amount available for release back into systemic circulation, is directly related to the total dose and duration of bisphosphonate use. Therefore, there is a theoretical risk of fetal harm if a woman becomes pregnant during or after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration on this risk has not been established. Although these 3 reports demonstrate that administration of pamidronate during pregnancy may not be associated with a significant risk to the fetus or embryo, it is still recommended that pamidronate not be administered to pregnant women, if possible. If a 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. Furthermore, in those infants that are exposed to pamidronate in utero, serum calcium concentrations should be monitored for the first few days after birth.

    According to the manufacturer, it is not known if pamidronate is excreted into breast milk. Based on pharmacokinetics, it is expected that pamidronate will be excreted in human breast milk; however, a woman breast-feeding her infant started receiving 30 mg pamidronate IV once monthly shortly after initiating breast-feeding. Expressed breast milk was discarded for 48 hours after each dose. Pamidronate (lower limit of detection 0.4 mcmol/L) was not detected in the breast milk in pooled samples taken 0—24 hours and 25—48 hours after the first dose. The low bioavailability most likely limits the amount excreted in breast milk. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    The principal pharmacologic action of pamidronate disodium, a first-generation bisphosphonate, is the 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.

    PHARMACOKINETICS

    Pamidronate is administered by intravenous infusion. Pamidronate distributes extensively to bone and less so to the liver, kidney, or spleen. Bone uptake occurs preferentially in areas of high bone turnover. It is not clear if it crosses the placenta or distributes into breast milk.
     
    Pamidronate is not metabolized and is excreted exclusively by the kidney. It has a half-life of 28 +/- 7 hours.  Within 120 hours, 46 +/- 14% of an intravenous dose is excreted unchanged in the urine and 54 +/- 14% is retained in the body. Cumulative urinary excretion is linearly dose-related. Eventually, nearly 100% of the dose is eliminated renally. The terminal phase elimination half-life in bone is estimated to be approximately 300 days.
     
    Studies in rats show that pamidronate is rapidly cleared from circulation and taken up by the bones, the liver, the spleen, teeth, and tracheal cartilage. Radioactivity is eliminated from most soft tissues within 1 to 4 days; however it is detectable in the liver for 1 month and the spleen for 3 months. High levels of radioactivity are detectable in the bones, trachea, and teeth for 6 months.

    Oral Route

    Pamidronate is poorly absorbed and poorly tolerated when administered orally.

    Intravenous Route

    After giving radiolabeled pamidronate IV to rats, approximately 50% to 60% is rapidly adsorbed by bone and slowly eliminated by the kidneys. In rats given 10 mg/kg IV, approximately 30% appears in the liver shortly after administration and redistributes to bone or is eliminated by the kidneys over the next 24 to 48 hours.