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    Injectable Bisphosphonate Bone Calcium Regulators

    DEA CLASS

    Rx

    DESCRIPTION

    Parenteral bisphosphonate; used for hypercalcemia of malignancy, Paget's disease, and osteolytic bone lesions associated with multiple myeloma and breast cancer.

    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.
    NOTE: Vigorous saline hydration is an integral part of hypercalcemia treatment. Urine output should be maintained at approximately 2 L/day.
    For hypercalcemia associated with malignancy.
    Intravenous dosage in patients with an albumin-corrected serum calcium 12—13.5 mg/dL
    Adults

    60 mg or 90 mg IV infusion as a single dose; administer over 2—24 hours. To allow time for a full response after the initial dose, wait a minimum of 7 days before retreatment.

    Intravenous dosage in patients with an albumin-corrected serum calcium greater than 13.5 mg/dL
    Adults

    90 mg IV infusion as a single dose; administer over 2—24 hours. To allow time for a full response after the initial dose, wait a minimum of 7 days before retreatment.

    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—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—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 moderate to severe Paget's disease.
    NOTE: Patients should be given supplemental calcium and vitamin D to minimize the risk of hypocalcemia.
    Intravenous dosage
    Adults

    30 mg IV infusion once daily for 3 days (total dose: 90 mg); administer each dose over 4 hours. If clinically indicated, patient may be re-treated with the same dose.

    For the treatment of osteolytic bone metastases.
    NOTE: In the absence of hypercalcemia, patients deemed to be at risk for hypocalcemia should be given supplemental calcium and vitamin D.
    Patients with multiple myeloma.
    Intravenous dosage
    Adults

    90 mg IV infusion once a month; administer the dose over 4 hours. 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 carcinoma.
    Intravenous dosage
    Adults

    90 mg IV infused over 2 hours, given once every 3—4 weeks. 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 osteoporosis†.
    For corticosteroid-induced osteoporosis†.
    Intravenous dosage
    Adults

    Limited data are available. Seventeen patients who had been taking an average of 14 mg of oral prednisolone per day for an average of 14 years for steroid-dependent lung disease, were treated with pamidronate 30 mg IV once every 3 months for 1 year. After 1 year, a significant increase was seen in L2—4 density but no change was noted in density of the neck of the femur.

    Adolescents

    A case report describes a dose of 30 mg IV (0.45 mg/kg) over 3 hours once daily for 3 days in a female aged 16 years with end-stage renal disease; the patient had been previously diagnosed with vasculitis causing glomerulonephritis and required high-dose steroids and immunosuppressants. The patient presented with severe osteopenia (bone mineral density -2 SD) and avascular necrosis of both femoral heads and 1 of her shoulders. The patient underwent a renal transplant and was administered a second regimen of pamidronate 2 months posttransplant (6 months after the first dose). A subsequent bone scan demonstrated stable disease despite the continued need for steroids.

    For postmenopausal osteoporosis†.
    Intravenous dosage
    Adult females

    Data suggest that 45 mg IV infusion every 3 months, administered as a 15-mg IV infusion over 3 hours once daily for 3 days, or a single 30-mg IV infusion given over 3 hours every 3 months is effective in increasing bone mineral density (BMD). After 3 years of the 45 mg every 3 months regimen, BMD of the lumbar spine and femoral neck increased by 7.07% and 6.76%, respectively (p < 0.001 for both measurements). In this study, combination therapy with sodium fluoride caused an increase of the BMD of the lumbar spine and femoral neck by 12.74% and 3.89%, respectively (p < 0.001 for both measurements). Annual thoracic and lumbar spine radiographs revealed no asymptomatic fractures in either group. In the single 30 mg IV every 3 months regimen, after a mean of 22 months of treatment (range 6—36 months), pamidronate was associated with a significant increase in the lumbar spine BMD, but not the Ward's triangle BMD. Fractures were not evaluated.

    Oral dosage (not available in the US)†
    Adult females

    Limited data are available. Oral pamidronate has been used successfully in this condition, however, an oral dosage form is not currently available in the United States.

    For osteoporosis prophylaxis†.
    In patients with Crohn's disease†.
    Intravenous dosage
    Adults

    Limited data suggest that 30 mg IV infusion over 1 hour every 3 months for 1 year is effective in increasing bone mineral density (BMD) of the lumbar spine and hip in patients with Crohn's disease. In 1 study, 82.5% of patients were currently or had previously taken corticosteroids. After 12 months, BMD of the lumbar spine and hip increased by 2.6% (95% CI 1.4—3) and 1.6% (95% CI 0.6—2.5), respectively, in patients receiving pamidronate plus calcium/vitamin D (n = 37). Although BMD increased in patients taking calcium and vitamin D only, the increases were not statistically significant.

    In men with prostate cancer receiving androgen deprivation therapy†.
    Intravenous dosage
    Adult males

    Data suggest 60 mg IV infusion over 2 hours every 12 weeks for 48 weeks is effective in maintaining bone mineral density (BMD). Patients with locally advanced or recurrent prostate cancer receiving leuprolide and bicalutamide were randomized to receive pamidronate plus calcium and vitamin D or calcium and vitamin D only for 48 weeks. In patients receiving pamidronate, lumbar spine, trochanter, total hip, femoral neck, and trabecular BMD did not significantly change. In patients that were taking vitamin D and calcium only, BMD significantly decreased in three-fourths of the locations (3.3% lumbar spine, 1.8% total hip, and 2.1% trochanter). The differences between the 2 groups were statistically significant at these 3 locations.

    For steroid-induced osteoporosis prophylaxis† in children with nephropathy.
    Oral dosage (not available in the US)
    Children

    Preliminary data suggest 125 mg PO once daily for 3 months is effective in maintaining bone mineral density (BMD) in children with nephropathy receiving high-dose steroids. BMD decreased from 0.654 g/cm3 to 0.631 g/cm3 in the control group (oral calcium only, p = 0.0017), but did not change in the treatment group (oral calcium and pamidronate). Abdominal pain was reported as an adverse effect. Additionally, in 3 patients who continued to receive pamidronate for more than 5 months, sclerotic lines were visible at the metaphyseal ends of long bones on radiographs; sclerosis was not seen in patients who took pamidronate for 3 months (41 patients). Further study to determine the effects of long-term pamidronate therapy on bone damage and growth is warranted.

    For the treatment of osteogenesis imperfecta†.
    Intravenous dosage
    Children and Adolescents

    In an uncontrolled study, patients aged 3—16 years old were treated with pamidronate 1.5—3 mg/kg/cycle; each calculated cycle dose was then divided into 3 equivalent doses, which were administered via slow IV infusion over 4 hours once daily for 3 days. The treatment cycle was repeated every 6 months initially; however, the interval between cycles was shortened to every 4 months. During the treatment period of 1.3—5 years, bone mineral density (BMD) increased by 41.9 +/- 29% per year and the mean incidence of radiologically confirmed fractures decreased by 1.7 per year. In addition, mobility and ambulation improved in 16 children, and all children reported substantial relief of chronic pain and fatigue. During this trial, the children's calcium intake was evaluated regularly and maintained at 800—1000 mg/day; vitamin D intake was at least 400 units/day. A similarly designed study in patients aged 22 months to 14 years confirmed these findings; a dose of 1 mg/kg/day administered IV over 4 hours for 3 days given every 4 months on average (range 2—5 months) caused an increase in the BMD of the lumbar spine by 48% and the BMD z score by 1 (p < 0.03). Fracture rates did not decline, but all patients experienced improvements in functioning and mobility. No significant adverse effects were reported.

    For the treatment of ankylosing spondylitis†.
    NOTE: Guidelines developed by practicing rheumatologists indicate that insufficient data exist to support the use of pamidronate in ankylosing spondylitis (AS). The guidelines do recommend that any bisphosphonate can be used in patients with AS and osteoporosis.
    Intravenous dosage
    Adults

    Limited data show that 60 mg IV infusion over 4 hours (6-hour infusion for first dose) may be moderately effective in improving certain symptoms (e.g., axial pain and morning stiffness) in patients with NSAID-resistant disease. In a 6-month study, 84 patients were randomized to 60 mg IV monthly (n = 41) or 10 mg IV monthly (n = 43). The 10-mg dose was chosen rather than placebo to minimize the risk of unblinding due to arthralgias/myalgias that often occur after the initial dose of IV pamidronate; 10 mg is the lowest dose that has been shown to elicit such reactions. The primary outcome was change in the Bath AS Disease Activity Index (BASDAI). After 6 months of treatment, the reduction in BASDAI score was significantly greater in the patients receiving 60 mg (reduction of 2.22 points in the 60 mg group vs. 0.93 in the 10 mg group, p = 0.002). Transient arthralgias and myalgias after the initial infusion were commonly reported.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    90 mg/dose IV.

    Elderly

    90 mg/dose IV.

    Adolescents

    Although safety and efficacy have not been established, if used in this age group, the maximum adult dose (90 mg/dose IV) should not be exceeded.

    Children

    Although safety and efficacy have not been established, if used in this age group, the maximum adult dose (90 mg/dose IV) should not be exceeded.

    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

    Dosage should be modified depending on clinical response and degree of renal impairment, but no quantitative recommendations are available. Longer infusions (i.e., > 2 hours), may decrease the risk for renal toxicity, especially in those patients with underlying renal impairment. Safety and efficacy have not been established in severe renal impairment (e.g., serum creatinine > 3 mg/dl). If renal function has deteriorated during pamidronate treatment (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), further treatment may need to be withheld until SCr within 10% of baseline value. (Data are based on the treatment of patients with osteolytic metastases.)

    ADMINISTRATION

     
    NOTE: Serum creatinine should be assessed prior to each treatment with pamidronate.

    Injectable Administration

    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.
    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 [g/dl]).
     
    Reconstitution/Dilution:
    Reconstitute with 10 ml of sterile water for injection; the drug should be completely dissolved before solution is withdrawn. After reconstitution, store under refrigeration, 2—8 degrees C (36—46 degrees F) for up to 24 hours.
    Pamidronate can be diluted in 0.45% or 0.9% sodium chloride or D5W. 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 or D5W. 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 or D5W.
    Osteolytic bone metastases of breast cancer: Dilute the recommended dose in 250 ml of 0.45% or 0.9% sodium chloride or D5W.
    Osteolytic bone lesions of multiple myeloma: Dilute the recommended dose in 500 ml of 0.45% or 0.9% sodium chloride or D5W.
    In children with osteogenesis imperfecta, pamidronate was diluted in 0.25% NS/D5W to a concentration of < 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 > 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 > 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.

    Children

    Safe and effective use of pamidronate in children has not been established. Bisphosphonates have been used successfully in children 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 may be advisable to monitor biochemical markers of skeletal turnover when bisphosphonates are used in children to help assure clinicians that skeletal resorption is not excessively suppressed. Periodic X-rays may also be prudent.

    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.

    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) Aspirin, ASA use is associated with esophageal and/or gastric irritation, and GI ulceration. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. In clinical trials, aspirin use along with bisphosphonates increased the risk of GI events in some patients; however, some clinical trials of bisphosphonates have not reported increased rates of GI adverse events with aspirin co-use. Exercise caution when administering aspirin with a bisphosphonate. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, and monitor renal function during combined use.
    Aluminum Hydroxide: (Moderate) Separating times of administration of the oral bisphosphonate from aluminum-containing medications will maximize absorption and clinical benefit. Aluminum hydroxide will interfere with the absorption of the orally administered bisphosphonates alendronate, etidronate, ibandronate, risedronate, and tiludronate. At least 30 minutes should elapse after the oral administration of alendronate before taking any aluminum containing product. At least 1 hour should elapse after the oral administration of ibandronate before taking any aluminum containing product. At least 2 hours should elapse after the oral administration of etidronate, risedronate, or tiludronate before administering any aluminum containing product.
    Aluminum Hydroxide; Magnesium Carbonate: (Moderate) Separating times of administration of the oral bisphosphonate from aluminum-containing medications will maximize absorption and clinical benefit. Aluminum hydroxide will interfere with the absorption of the orally administered bisphosphonates alendronate, etidronate, ibandronate, risedronate, and tiludronate. At least 30 minutes should elapse after the oral administration of alendronate before taking any aluminum containing product. At least 1 hour should elapse after the oral administration of ibandronate before taking any aluminum containing product. At least 2 hours should elapse after the oral administration of etidronate, risedronate, or tiludronate before administering any aluminum containing product.
    Aluminum Hydroxide; Magnesium Hydroxide: (Moderate) Separating times of administration of the oral bisphosphonate from aluminum-containing medications will maximize absorption and clinical benefit. Aluminum hydroxide will interfere with the absorption of the orally administered bisphosphonates alendronate, etidronate, ibandronate, risedronate, and tiludronate. At least 30 minutes should elapse after the oral administration of alendronate before taking any aluminum containing product. At least 1 hour should elapse after the oral administration of ibandronate before taking any aluminum containing product. At least 2 hours should elapse after the oral administration of etidronate, risedronate, or tiludronate before administering any aluminum containing product.
    Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Moderate) Separating times of administration of the oral bisphosphonate from aluminum-containing medications will maximize absorption and clinical benefit. Aluminum hydroxide will interfere with the absorption of the orally administered bisphosphonates alendronate, etidronate, ibandronate, risedronate, and tiludronate. At least 30 minutes should elapse after the oral administration of alendronate before taking any aluminum containing product. At least 1 hour should elapse after the oral administration of ibandronate before taking any aluminum containing product. At least 2 hours should elapse after the oral administration of etidronate, risedronate, or tiludronate before administering any aluminum containing product.
    Aluminum Hydroxide; Magnesium Trisilicate: (Moderate) Separating times of administration of the oral bisphosphonate from aluminum-containing medications will maximize absorption and clinical benefit. Aluminum hydroxide will interfere with the absorption of the orally administered bisphosphonates alendronate, etidronate, ibandronate, risedronate, and tiludronate. At least 30 minutes should elapse after the oral administration of alendronate before taking any aluminum containing product. At least 1 hour should elapse after the oral administration of ibandronate before taking any aluminum containing product. At least 2 hours should elapse after the oral administration of etidronate, risedronate, or tiludronate before administering any aluminum containing product.
    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) Aspirin, ASA use is associated with esophageal and/or gastric irritation, and GI ulceration. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. In clinical trials, aspirin use along with bisphosphonates increased the risk of GI events in some patients; however, some clinical trials of bisphosphonates have not reported increased rates of GI adverse events with aspirin co-use. Exercise caution when administering aspirin with a bisphosphonate. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, and monitor renal function during combined use.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Aspirin, ASA use is associated with esophageal and/or gastric irritation, and GI ulceration. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. In clinical trials, aspirin use along with bisphosphonates increased the risk of GI events in some patients; however, some clinical trials of bisphosphonates have not reported increased rates of GI adverse events with aspirin co-use. Exercise caution when administering aspirin with a bisphosphonate. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, and monitor renal function during combined use.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Aspirin, ASA use is associated with esophageal and/or gastric irritation, and GI ulceration. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. In clinical trials, aspirin use along with bisphosphonates increased the risk of GI events in some patients; however, some clinical trials of bisphosphonates have not reported increased rates of GI adverse events with aspirin co-use. Exercise caution when administering aspirin with a bisphosphonate. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, and monitor renal function during combined use.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Aspirin, ASA use is associated with esophageal and/or gastric irritation, and GI ulceration. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. In clinical trials, aspirin use along with bisphosphonates increased the risk of GI events in some patients; however, some clinical trials of bisphosphonates have not reported increased rates of GI adverse events with aspirin co-use. Exercise caution when administering aspirin with a bisphosphonate. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, and monitor renal function during combined use.
    Aspirin, ASA; Carisoprodol: (Moderate) Aspirin, ASA use is associated with esophageal and/or gastric irritation, and GI ulceration. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. In clinical trials, aspirin use along with bisphosphonates increased the risk of GI events in some patients; however, some clinical trials of bisphosphonates have not reported increased rates of GI adverse events with aspirin co-use. Exercise caution when administering aspirin with a bisphosphonate. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, and monitor renal function during combined use.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Aspirin, ASA use is associated with esophageal and/or gastric irritation, and GI ulceration. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. In clinical trials, aspirin use along with bisphosphonates increased the risk of GI events in some patients; however, some clinical trials of bisphosphonates have not reported increased rates of GI adverse events with aspirin co-use. Exercise caution when administering aspirin with a bisphosphonate. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, and monitor renal function during combined use.
    Aspirin, ASA; Dipyridamole: (Moderate) Aspirin, ASA use is associated with esophageal and/or gastric irritation, and GI ulceration. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. In clinical trials, aspirin use along with bisphosphonates increased the risk of GI events in some patients; however, some clinical trials of bisphosphonates have not reported increased rates of GI adverse events with aspirin co-use. Exercise caution when administering aspirin with a bisphosphonate. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, and monitor renal function during combined use.
    Aspirin, ASA; Omeprazole: (Moderate) Aspirin, ASA use is associated with esophageal and/or gastric irritation, and GI ulceration. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. In clinical trials, aspirin use along with bisphosphonates increased the risk of GI events in some patients; however, some clinical trials of bisphosphonates have not reported increased rates of GI adverse events with aspirin co-use. Exercise caution when administering aspirin with a bisphosphonate. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, and monitor renal function during combined use.
    Aspirin, ASA; Oxycodone: (Moderate) Aspirin, ASA use is associated with esophageal and/or gastric irritation, and GI ulceration. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. In clinical trials, aspirin use along with bisphosphonates increased the risk of GI events in some patients; however, some clinical trials of bisphosphonates have not reported increased rates of GI adverse events with aspirin co-use. Exercise caution when administering aspirin with a bisphosphonate. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, and monitor renal function during combined use.
    Aspirin, ASA; Pravastatin: (Moderate) Aspirin, ASA use is associated with esophageal and/or gastric irritation, and GI ulceration. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. In clinical trials, aspirin use along with bisphosphonates increased the risk of GI events in some patients; however, some clinical trials of bisphosphonates have not reported increased rates of GI adverse events with aspirin co-use. Exercise caution when administering aspirin with a bisphosphonate. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, and monitor renal function during combined use.
    Calcium Carbonate: (Moderate) Separating times of administration of the oral bisphosphonate from calcium-containing supplements and medications will maximize absorption and clinical benefit. Calcium will interfere with the absorption of the orally administered bisphosphonates alendronate, etidronate, ibandronate, risedronate, and tiludronate. At least 30 minutes should elapse after the oral administration of alendronate before taking any calcium containing product. At least 1 hour should elapse after the oral administration of ibandronate before taking any calcium containing product. At least 2 hours should elapse after the oral administration of etidronate, risedronate, or tiludronate before administering any calcium containing product.
    Calcium Carbonate; Magnesium Hydroxide: (Moderate) Separating times of administration of the oral bisphosphonate from calcium-containing supplements and medications will maximize absorption and clinical benefit. Calcium will interfere with the absorption of the orally administered bisphosphonates alendronate, etidronate, ibandronate, risedronate, and tiludronate. At least 30 minutes should elapse after the oral administration of alendronate before taking any calcium containing product. At least 1 hour should elapse after the oral administration of ibandronate before taking any calcium containing product. At least 2 hours should elapse after the oral administration of etidronate, risedronate, or tiludronate before administering any calcium containing product.
    Calcium Carbonate; Risedronate: (Moderate) Separating times of administration of the oral bisphosphonate from calcium-containing supplements and medications will maximize absorption and clinical benefit. Calcium will interfere with the absorption of the orally administered bisphosphonates alendronate, etidronate, ibandronate, risedronate, and tiludronate. At least 30 minutes should elapse after the oral administration of alendronate before taking any calcium containing product. At least 1 hour should elapse after the oral administration of ibandronate before taking any calcium containing product. At least 2 hours should elapse after the oral administration of etidronate, risedronate, or tiludronate before administering any calcium containing product.
    Calcium Salts: (Moderate) Separating times of administration of the oral bisphosphonate from calcium-containing supplements and medications will maximize absorption and clinical benefit. Calcium will interfere with the absorption of the orally administered bisphosphonates alendronate, etidronate, ibandronate, risedronate, and tiludronate. At least 30 minutes should elapse after the oral administration of alendronate before taking any calcium containing product. At least 1 hour should elapse after the oral administration of ibandronate before taking any calcium containing product. At least 2 hours should elapse after the oral administration of etidronate, risedronate, or tiludronate before administering any calcium containing product.
    Calcium: (Moderate) Separating times of administration of the oral bisphosphonate from calcium-containing supplements and medications will maximize absorption and clinical benefit. Calcium will interfere with the absorption of the orally administered bisphosphonates alendronate, etidronate, ibandronate, risedronate, and tiludronate. At least 30 minutes should elapse after the oral administration of alendronate before taking any calcium containing product. At least 1 hour should elapse after the oral administration of ibandronate before taking any calcium containing product. At least 2 hours should elapse after the oral administration of etidronate, risedronate, or tiludronate before administering any calcium containing product.
    Calcium; Vitamin D: (Moderate) Separating times of administration of the oral bisphosphonate from calcium-containing supplements and medications will maximize absorption and clinical benefit. Calcium will interfere with the absorption of the orally administered bisphosphonates alendronate, etidronate, ibandronate, risedronate, and tiludronate. At least 30 minutes should elapse after the oral administration of alendronate before taking any calcium containing product. At least 1 hour should elapse after the oral administration of ibandronate before taking any calcium containing product. At least 2 hours should elapse after the oral administration of etidronate, risedronate, or tiludronate before administering any calcium containing product.
    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.
    Celecoxib: (Moderate) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    Chromium: (Moderate) Separating times of administration of the oral bisphosphonate from calcium-containing supplements and medications will maximize absorption and clinical benefit. Calcium will interfere with the absorption of the orally administered bisphosphonates alendronate, etidronate, ibandronate, risedronate, and tiludronate. At least 30 minutes should elapse after the oral administration of alendronate before taking any calcium containing product. At least 1 hour should elapse after the oral administration of ibandronate before taking any calcium containing product. At least 2 hours should elapse after the oral administration of etidronate, risedronate, or tiludronate before administering any calcium containing product.
    Cidofovir: (Severe) 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.
    Cobicistat; Elvitegravir; 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.
    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.
    Collagenase: (Moderate) Separating times of administration of the oral bisphosphonate from calcium-containing supplements and medications will maximize absorption and clinical benefit. Calcium will interfere with the absorption of the orally administered bisphosphonates alendronate, etidronate, ibandronate, risedronate, and tiludronate. At least 30 minutes should elapse after the oral administration of alendronate before taking any calcium containing product. At least 1 hour should elapse after the oral administration of ibandronate before taking any calcium containing product. At least 2 hours should elapse after the oral administration of etidronate, risedronate, or tiludronate before administering any calcium containing product.
    Cyanocobalamin, Vitamin B12: (Moderate) Separating times of administration of the oral bisphosphonate from calcium-containing supplements and medications will maximize absorption and clinical benefit. Calcium will interfere with the absorption of the orally administered bisphosphonates alendronate, etidronate, ibandronate, risedronate, and tiludronate. At least 30 minutes should elapse after the oral administration of alendronate before taking any calcium containing product. At least 1 hour should elapse after the oral administration of ibandronate before taking any calcium containing product. At least 2 hours should elapse after the oral administration of etidronate, risedronate, or tiludronate before administering any calcium containing product.
    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.
    Diclofenac: (Moderate) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    Diclofenac; Misoprostol: (Moderate) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    Diflunisal: (Moderate) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    Diphenhydramine; Ibuprofen: (Moderate) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    Diphenhydramine; Naproxen: (Moderate) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    Efavirenz; Emtricitabine; Tenofovir: (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.
    Esomeprazole; Naproxen: (Moderate) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Moderate) Separating times of administration of the oral bisphosphonate from iron-containing supplements and medications will maximize absorption and clinical benefit. Iron will interfere with the absorption of the orally administered bisphosphonates alendronate, etidronate, ibandronate, risedronate, and tiludronate. At least 30 minutes should elapse after the oral administration of alendronate before taking any iron containing product. At least 1 hour should elapse after the oral administration of ibandronate before taking any iron containing product. At least 2 hours should elapse after the oral administration of etidronate, risedronate, or tiludronate before administering any calcium containing product.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Moderate) Separating times of administration of the oral bisphosphonate from iron-containing supplements and medications will maximize absorption and clinical benefit. Iron will interfere with the absorption of the orally administered bisphosphonates alendronate, etidronate, ibandronate, risedronate, and tiludronate. At least 30 minutes should elapse after the oral administration of alendronate before taking any iron containing product. At least 1 hour should elapse after the oral administration of ibandronate before taking any iron containing product. At least 2 hours should elapse after the oral administration of etidronate, risedronate, or tiludronate before administering any calcium containing product.
    Etodolac: (Moderate) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    Famotidine; Ibuprofen: (Moderate) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    Fenoprofen: (Moderate) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    Flurbiprofen: (Moderate) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    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.
    Hetastarch; Dextrose; Electrolytes: (Moderate) Separating times of administration of the oral bisphosphonate from calcium-containing supplements and medications will maximize absorption and clinical benefit. Calcium will interfere with the absorption of the orally administered bisphosphonates alendronate, etidronate, ibandronate, risedronate, and tiludronate. At least 30 minutes should elapse after the oral administration of alendronate before taking any calcium containing product. At least 1 hour should elapse after the oral administration of ibandronate before taking any calcium containing product. At least 2 hours should elapse after the oral administration of etidronate, risedronate, or tiludronate before administering any calcium containing product.
    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.
    Hydrocodone; Ibuprofen: (Moderate) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    Ibuprofen: (Moderate) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    Ibuprofen; Oxycodone: (Moderate) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    Ibuprofen; Pseudoephedrine: (Moderate) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    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.
    Indomethacin: (Moderate) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    Iron Salts: (Moderate) Separating times of administration of the oral bisphosphonate from iron-containing supplements and medications will maximize absorption and clinical benefit. Iron will interfere with the absorption of the orally administered bisphosphonates alendronate, etidronate, ibandronate, risedronate, and tiludronate. At least 30 minutes should elapse after the oral administration of alendronate before taking any iron containing product. At least 1 hour should elapse after the oral administration of ibandronate before taking any iron containing product. At least 2 hours should elapse after the oral administration of etidronate, risedronate, or tiludronate before administering any calcium containing product.
    Iron: (Moderate) Separating times of administration of the oral bisphosphonate from iron-containing supplements and medications will maximize absorption and clinical benefit. Iron will interfere with the absorption of the orally administered bisphosphonates alendronate, etidronate, ibandronate, risedronate, and tiludronate. At least 30 minutes should elapse after the oral administration of alendronate before taking any iron containing product. At least 1 hour should elapse after the oral administration of ibandronate before taking any iron containing product. At least 2 hours should elapse after the oral administration of etidronate, risedronate, or tiludronate before administering any calcium containing product.
    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.
    Ketoprofen: (Moderate) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    Ketorolac: (Moderate) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    Lansoprazole; Naproxen: (Moderate) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    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.
    Meclofenamate Sodium: (Moderate) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    Mefenamic Acid: (Moderate) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    Meloxicam: (Moderate) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    Nabumetone: (Moderate) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    Naproxen: (Moderate) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    Naproxen; Pseudoephedrine: (Moderate) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    Naproxen; Sumatriptan: (Moderate) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    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) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    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.
    Oxaprozin: (Moderate) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    Pantothenic Acid, Vitamin B5: (Moderate) Separating times of administration of the oral bisphosphonate from calcium-containing supplements and medications will maximize absorption and clinical benefit. Calcium will interfere with the absorption of the orally administered bisphosphonates alendronate, etidronate, ibandronate, risedronate, and tiludronate. At least 30 minutes should elapse after the oral administration of alendronate before taking any calcium containing product. At least 1 hour should elapse after the oral administration of ibandronate before taking any calcium containing product. At least 2 hours should elapse after the oral administration of etidronate, risedronate, or tiludronate before administering any calcium containing 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.
    Piroxicam: (Moderate) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    Polymyxins: (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.
    Polysaccharide-Iron Complex: (Moderate) Separating times of administration of the oral bisphosphonate from iron-containing supplements and medications will maximize absorption and clinical benefit. Iron will interfere with the absorption of the orally administered bisphosphonates alendronate, etidronate, ibandronate, risedronate, and tiludronate. At least 30 minutes should elapse after the oral administration of alendronate before taking any iron containing product. At least 1 hour should elapse after the oral administration of ibandronate before taking any iron containing product. At least 2 hours should elapse after the oral administration of etidronate, risedronate, or tiludronate before administering any calcium containing product.
    Pyridoxine, Vitamin B6: (Moderate) Separating times of administration of the oral bisphosphonate from calcium-containing supplements and medications will maximize absorption and clinical benefit. Calcium will interfere with the absorption of the orally administered bisphosphonates alendronate, etidronate, ibandronate, risedronate, and tiludronate. At least 30 minutes should elapse after the oral administration of alendronate before taking any calcium containing product. At least 1 hour should elapse after the oral administration of ibandronate before taking any calcium containing product. At least 2 hours should elapse after the oral administration of etidronate, risedronate, or tiludronate before administering any calcium containing product.
    Rofecoxib: (Moderate) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    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.
    Sodium Ferric Gluconate Complex; ferric pyrophosphate citrate: (Moderate) Separating times of administration of the oral bisphosphonate from iron-containing supplements and medications will maximize absorption and clinical benefit. Iron will interfere with the absorption of the orally administered bisphosphonates alendronate, etidronate, ibandronate, risedronate, and tiludronate. At least 30 minutes should elapse after the oral administration of alendronate before taking any iron containing product. At least 1 hour should elapse after the oral administration of ibandronate before taking any iron containing product. At least 2 hours should elapse after the oral administration of etidronate, risedronate, or tiludronate before administering any calcium containing 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.
    Sulindac: (Moderate) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    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) 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 alafenamide 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, and urine glucose and protein.
    Tenofovir, PMPA: (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.
    Tolmetin: (Moderate) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    Valdecoxib: (Moderate) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    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.
    Zinc Salts: (Moderate) Separating times of administration of the oral bisphosphonate from calcium-containing supplements and medications will maximize absorption and clinical benefit. Calcium will interfere with the absorption of the orally administered bisphosphonates alendronate, etidronate, ibandronate, risedronate, and tiludronate. At least 30 minutes should elapse after the oral administration of alendronate before taking any calcium containing product. At least 1 hour should elapse after the oral administration of ibandronate before taking any calcium containing product. At least 2 hours should elapse after the oral administration of etidronate, risedronate, or tiludronate before administering any calcium containing product.

    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

    Mechanism of Action: Pamidronate has pharmacologic actions similar to those of pyrophosphate, which occurs naturally in the body and inhibits bone resorption. Bone resorption releases excessive amounts of calcium into the blood. The double phosphonate group common to all bisphosphonates allows them to bind to calcified bone matrix. Adsorption of pamidronate to hydroxyapatite crystals in the mineralized matrix reduces solubility of the matrix and therefore osteoclastic resorption. A stable bone matrix will also prevent signaling to osteoclasts to migrate to the site. Pamidronate blocks attachment of osteoclast precursors to mineralized matrix, preventing transformation into mature, functioning osteoclasts. Pamidronate reduces bone turnover and, when used in combination with adequate hydration to increase renal excretion of calcium, reduces serum calcium concentrations. Serum calcium concentrations, urinary calcium/creatinine ratio, and hydroxyproline/creatinine ratio usually return to within or below normal within the first week after treatment.The exact mechanism of pamidronate's therapeutic effect in patients with Paget's disease has not been clearly established. Paget's disease is a progressive, idiopathic disease of bone. Increasing numbers of unusually large osteoclasts are produced at affected sites. Increased bone resorption follows, which is compensated for by an increase in new bone formation. This new bone is inferior and often deformed, and can fracture easily. Pamidronate is believed to reduce the solubility of mineralized bone matrix by adsorption to hydroxyapatite crystals in the matrix. The matrix becomes less soluble and resistant to osteoclastic resorption. Pamidronate also can block the formation of mature osteoclasts by affecting the attachment of osteoclast precursors to the mineralized matrix. Osteolytic bone lesions refractory to combination therapy with etidronate and calcitonin are partially or completely healed with pamidronate.Pamidronate decreases the extent of accelerated bone resorption that results from osteoclast hyperactivity. Hypercalcemia is a common problem affecting cancer patients. Malignancy-associated hypercalcemia arises from accelerated bone resorption. Humoral hypercalcemia occurs when factors such as parathyroid hormone related protein stimulate osteoclasts; such proteins are elaborated by the tumor and circulate systemically. Humoral hypercalcemia occurs most commonly in squamous cell malignancies of the lung or head and neck or in genitourinary cancers. In multiple myeloma and breast cancer, the tumor metastasizes to the bone causing the release of soluble factors that activate osteoclasts to resorb bone. This action causes both periodic hypercalcemia as well as osteolytic skeletal destruction (bone pain and fractures). Pamidronate inhibits bone resorption without inhibiting bone formation or mineralization. It has no antineoplastic properties.In vitro studies have found that bisphosphonates have anti-inflammatory actions including inhibition of macrophage growth, migration, differentiation, and viability and inhibition of the function of monocyte antigen presenting cells. Additionally, pamidronate appears to suppress macrophage-generated proinflammatory cytokines in a dose-dependent manner. Serum concentrations required for cytokine suppression are > 5 X 10-5 M, which is not achieved by a 60 mg IV dose (dose studied). However, whether or not 60 mg IV is sufficient is not known as pamidronate is preferentially taken up by bone that is resorbing, which may increase the concentration of pamidronate locally.

    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.