Pamidronate is a parenteral, second-generation pyrophosphate bisphosphonate. Pamidronate is more potent than clodronate or etidronate and less potent than other bisphosphonates such as risedronate and zoledronic acid. Pamidronate is indicated for the treatment of moderate to severe Paget's disease, hypercalcemia associated with malignant neoplasms, and osteolytic metastases in patients with multiple myeloma or breast cancer. Generally, IV zoledronic acid and pamidronate are considered to be equally effective in treating hypercalcemia of malignancy and both are considered acceptable treatments; however, one pooled analysis found zoledronic acid to be more potent than pamidronate. Clinical practice guidelines support the use of bisphosphonates for the treatment of bone metastases in patients with multiple myeloma and breast cancer; IV pamidronate and zoledronic acid are generally considered equally effective in reducing skeletal-related adverse events. Pamidronate has also been used off-label for the treatment of hyperparathyroidism (primary or secondary) and ankylosing spondylitis. The newer, more potent bisphosphonates have more convenient dosing schedules (oral use, annual IV administration, etc.) and have largely replaced pamidronate in the treatment of Paget's disease in adults. In pediatric patients, pamidronate is very effective in treating children with osteogenesis imperfecta. Pamidronate was originally approved by the FDA in 1991.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Hazardous Drugs Classification
-NIOSH 2016 List: Group 3
-NIOSH (Draft) 2020 List: Table 2
-Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
-Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system drug transfer device. Eye/face and respiratory protection may be needed during preparation and administration.
Route-Specific Administration
Injectable Administration
-For intravenous infusion only.
-The patient's renal function (i.e., serum creatinine) and hydration status should be assessed prior to each treatment with pamidronate.
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
-Administer intravenously via slow IV infusion only. Dilute prior to administration.
Reconstitution/Dilution:
-Reconstitute vial with 10 mL of sterile water for injection; the drug should be completely dissolved before solution is withdrawn. After reconstitution, store under refrigeration, 2 to 8 degrees C (36 to 46 degrees F) for up to 24 hours.
-Pamidronate can be diluted in 0.45% or 0.9% Sodium Chloride Injection or Dextrose 5% for injection. Do not dilute in calcium-containing solutions such as Ringer's solution.
--Hypercalcemia of malignancy: Dilute the recommended dose in 1000 mL of 0.45% or 0.9% Sodium Chloride Injection or Dextrose 5% for injection. The diluted solution is stable for up to 24 hours at room temperature.
-Paget's Disease: Dilute the recommended dose in 500 mL of 0.45% or 0.9% Sodium Chloride Injection or Dextrose 5% for injection.
-Osteolytic bone metastases of breast cancer: Dilute the recommended dose in 250 mL of 0.45% or 0.9% Sodium Chloride Injection or Dextrose 5% for injection.
-Osteolytic bone lesions of multiple myeloma: Dilute the recommended dose in 500 mL of 0.45% or 0.9% Sodium Chloride Injection or Dextrose 5% for injection.
-In children with osteogenesis imperfecta (off-label use): pamidronate has been diluted in 0.25% NS/D5W to a concentration of less than 0.12 mg/mL.
Intravenous infusion:
-Due to risk of clinically significant renal toxicity, single doses should not exceed 90 mg and the duration of the IV infusion should be no less than 2 hours.
-Administer in an IV line separate from all other drugs.
--Hypercalcemia of malignancy: Infuse dose over 2 to 24 hours. A duration of infusion of more than 2 hours may decrease the risk for renal toxicity, especially in those patients with underlying renal impairment.
-Paget's Disease: Infuse dose over 4 hours.
-Osteolytic bone metastases of breast cancer: Infuse dose over 2 hours. A duration of infusion of more than 2 hours may decrease the risk for renal toxicity, especially in those patients with underlying renal impairment.
-Osteolytic bone lesions of multiple myeloma: Infuse dose over 4 hours.
Pamidronate is used to treat hypercalcemia of malignancy, Paget's disease, osteolytic bone metastases of breast cancer, and osteolytic lesions of multiple myeloma. Many of the adverse reactions reported may be associated with the underlying disease and not due to the drug. Adverse reactions are generally more common with the 90 mg dose. NOTE: Only small numbers of patients were enrolled in some trials.
In clinical trials for osteolytic bone metastases of breast cancer and osteolytic lesions of multiple myeloma, metastases were reported in 20.5% of pamidronate-treated patients compared to 17.5% of placebo-treated patients.
Conflicting data exists regarding the use of bisphosphonates (such as pamidronate) and an increased risk of serious atrial fibrillation. In the HORIZON Pivotal Fracture Trial, the incidence of serious atrial fibrillation (life-threatening or resulting in hospitalization or disability) was significantly higher in patients receiving zoledronic acid than placebo (50 patients or 1.3% versus 20 patients or 0.5%, p < 0.001), although the incidence of any atrial fibrillation (serious and non-serious) was not different between the 2 groups. Similarly, in a re-analysis of the Fracture Intervention Trial, patients taking alendronate also experienced a trend towards a higher incidence of serious atrial fibrillation versus those taking placebo (47 patients or 1.5% vs. 31 patients or 1%, HR 1.51, 95% CI 0.97-2.40, p=0.07). Similar to the HORIZON trial, any atrial fibrillation was not higher in patients taking alendronate. In controlled clinical trials of pamidronate, atrial fibrillation was reported at an incidence of 6% in patients receiving pamidronate 90 mg over 24 hours. There were no reports of atrial fibrillation in patients who received pamidronate 60 mg over 4 hours or over 24 hours. Post-marketing surveillance of reports of atrial fibrillation in patients receiving oral and intravenous bisphosphonates has not revealed a subset of patients at risk for the adverse effect. In the majority of cases in patients who received zoledronic acid, atrial fibrillation occurred more than 1 month after drug infusion. In order to review the potential risk of atrial fibrillation in patients receiving bisphosphonates, the FDA requested placebo-controlled clinical trial data from manufacturers. Information submitted to the FDA by the 4 manufacturers included data from 19,687 bisphosphonate-treated patients and 18,358 placebo-treated patients who were followed up for 6 months-3 years. After reviewing these data, the FDA concluded that most studies contained 2 or fewer events of atrial fibrillation. The absolute difference in event rates between each of the bisphosphonate and placebo arms varied from 0-3 per 1,000. No association between bisphosphonate exposure and the rate of serious or non-serious atrial fibrillation was found. In addition, an increase in dose or duration of bisphosphonate therapy did not correlate with an increased rate of atrial fibrillation. Because of the conflicting data in the literature, the FDA is exploring the feasibility of conducting additional epidemiologic studies to gather more data. The FDA continues to monitor post-marketing reports of atrial fibrillation in patients who have taken bisphosphonates. Currently, the FDA does not recommend a change in prescribing practices for this class of drugs; a causal relationship has not been identified.
Overall, fever was reported in 5-38.5% of all patients receiving pamidronate. It is the most common and prominent adverse effect of pamidronate. The fever develops within the first 3 days after a dose. The risk of developing fever increases as the dose increases. In patients with Paget's disease receiving a total of 90 mg, 21% experienced a transient, mild elevation of temperature (>1 degrees C above pretreatment baseline) within 48 hours. In patients with hypercalcemia of malignancy, 34% experienced a transient, mild elevation of temperature (> 1 degrees C above pretreatment baseline) within 48 hours compared to 18% of patients in the saline trial. Leukopenia and lymphopenia have been associated temporally with the fever but could occur independently as well. In clinical trials of patients with hypercalcemia of malignancy, leukopenia occurred in 4% of patients treated with pamidronate 60 mg administered over 4 hours, but was not reported in those receiving 60 or 90 mg over 24 hours or after saline hydration. Anemia has been reported in 6-42.5% of patients treated with pamidronate in clinical trials and was reported more frequently in trials for osteolytic metastases of breast cancer and osteolytic lesions of multiple myeloma than other indications. Neutropenia and thrombocytopenia were reported at an incidence of 0-1% in clinical trials of patients with hypercalcemia of malignancy. Thrombocytopenia (14% vs. 15% placebo) and granulocytopenia (19.8% vs. 18.8%) were reported in clinical trials of pamidronate for osteolytic bone metastases of breast cancer and osteolytic lesions of multiple myeloma at rates comparable to placebo.
An injection site reaction occurred in as many as 4-18% of patients receiving pamidronate. Local reactions include erythema, swelling or induration, and pain on palpation. These reactions were more common in patients receiving the 90 mg dose.
Pamidronate has been reported to cause laboratory abnormalities including hypocalcemia (1-17%), hypophosphatemia (1.7-18%), hypomagnesemia (4%-15%), and hypokalemia (4-18%). These reactions are usually asymptomatic. Hypophosphatemia is due to a decrease in phosphate release from bone and increased renal excretion as parathyroid hormone (PTH) concentrations return to normal. PTH is usually suppressed during hypercalcemia associated with malignant disease. Hypocalcemia is usually asymptomatic, but rare cases of symptoms, including tetany, have been documented. In one study of patient's with Paget's disease, 17% of patients that received pamidronate 90 mg experienced a serum calcium concentration < 8 mg/dl. Serum concentrations of calcium, phosphate, magnesium, and potassium should be monitored closely after initiation of treatment. During post-marketing surveillance, hyperkalemia and hypernatremia have also been reported.
GI adverse reactions have been reported with pamidronate therapy and are more common in patients being treated for osteolytic bone metastases of breast cancer and osteolytic lesion of multiple myeloma. GI adverse reactions include: anorexia (up to 26%), nausea (up to 53.5%), vomiting (up to 35.7%), constipation (up to 33.2%), diarrhea (up to 28.5%), abdominal pain (up to 22.6%), dyspepsia (up to 22.6%), GI bleeding (0-6%), and stomatitis (0-1%).
Fatigue was reported at an incidence of 12% in clinical trials of pamidronate for hypercalcemia of malignancy and more frequently (37.2%) in clinical trials for osteolytic bone metastases of breast cancer and osteolytic lesions of multiple myeloma.
Bone pain was reported with pamidronate during clinical trials in >= 10% of patients for Paget's disease and in >= 15% of patients for hypercalcemia of malignancy. Arthralgia (13.6%), arthrosis (>= 10%), musculoskeletal pain (66.8%), generalized pain (>= 15%), back pain (>= 5%), and myalgia (0-26%) have also been reported in clinical trials. In general, musculoskeletal adverse effects were reported more frequently in clinical trials of patients with osteolytic bone metastases of breast cancer and osteolytic lesions of multiple myeloma than in trials of pamidronate for other indications and may be related to the underlying disease state or cancer therapy. Rarely, arthralgia, bone pain, and myalgia, sometimes severe, have been reported in patients taking bisphosphonates during post-marketing surveillance. The bone, muscle, and/or joint pain can sometimes be severe and even incapacitating. The time to onset of symptoms varies from one day to years after drug initiation. Most patients have relief of symptoms after stopping the medication; a subset of patients have had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate. Risk factors for and the incidence of bone, muscle, and/or joint pain are not known. This reaction is different than the acute phase reaction of fever, chills, and bone, muscle, and/or joint pain that accompanies intermittent intravenous or weekly or monthly oral bisphosphonates. The acute phase reaction tends to resolve with continued use. Bisphosphonates should be considered as a cause for any patient who presents with severe musculoskeletal or joint pain; furthermore, if pamidronate is determined to be the cause, temporary or permanent discontinuation in drug therapy should be considered.
Nephrotoxicity including renal failure (unspecified) sometimes requiring dialysis has been reported during therapy with pamidronate; serum creatinine should be monitored during treatment. Focal segmental glomerulosclerosis (including the collapsing variant) with or without nephrotic syndrome has been reported, especially in patients with multiple myeloma and breast cancer. Improvements in renal function occurred in some patients after pamidronate was discontinued. Urinary tract infection was reported at an incidence of >= 15% in hypercalcemia of malignancy trials and in 18.5% of patients with osteolytic bone metastases of breast cancer and osteolytic lesions of multiple myeloma trials. Uremia was reported in 0-4% of pamidronate-treated patients in hypercalcemia of malignancy clinical trials. During post-marketing surveillance, hematuria has been reported.
Rarely, pamidronate has been reported to cause uveitis, iritis, episcleritis, or scleritis; these ocular reactions are expected to occur with other bisphosphonates as well. Nonspecific conjunctivitis has been reported but seldom requires treatment and usually decreases in intensity during subsequent exposure to a bisphosphonate. However, no reported case of unilateral or bilateral scleritis resolved until the bisphosphonate was discontinued. More than one ocular side effect can occur at the same time; for instance, episcleritis may occur in conjunction with uveitis. In some instances, the drug may need to be discontinued in order for the ocular inflammation to resolve; for scleritis to resolve the bisphosphonate must be discontinued. Patients with visual impairment or ocular pain should be referred to an ophthalmologist.
Post-marketing surveillance has revealed reports of osteonecrosis, primarily of the jaw, in patients receiving pamidronate. It is not possible to determine if the reported events are related to pamidronate or other bisphosphonates, to concomitant drugs or other therapies (e.g., chemotherapy, radiotherapy, corticosteroid), to a patient's underlying disease state, or to other comorbid risk factors (e.g., anemia, infection, preexisting oral disease). Typical signs and symptoms of osteonecrosis of the jaw include pain, swelling, infection, or poor healing of the gums, loosening of the teeth, numbness or a feeling of heaviness in the jaw, and drainage of exposed bone. 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. The majority of reported cases have occurred in cancer patients after invasive dental procedures, such as tooth extraction. The treating physician and dentist should use their best clinical judgment to guide the management plan of each patient based on individual benefit and risk assessments. Based on a review of the available literature, treatments that have been used include local debridement, bone resection or other surgery, antimicrobials, antiseptic mouthwash, and hyperbaric oxygen. While a consensus on the best treatment strategies does not exist, the American Academy of Oral Medicine recommends prevention. Preventive measure include evaluation by a dentist prior to intravenous bisphosphonate initiation and within 3 months of oral bisphosphonate initiation, correction of dental complications prior to drug initiation, and continued regular follow-up with a dentist. For the treatment of osteonecrosis, recommendations include superficial debridement, bone resection when indicated, systemic antimicrobial for infections with culture-directed therapy or penicillin, amoxicillin, or clindamycin empirically, or use of chlorhexidine mouthwash 3-4 times daily. Discontinuation of the bisphosphonate once osteonecrosis occurs is controversial as the half-life of bisphosphonates within the bone is estimated to be years.
Atypical subtrochanteric and diaphyseal femoral bone fractures have been reported in patients receiving bisphosphonate therapy, including pamidronate. These fractures occur after minimal or no trauma and can occur anywhere in the femoral shaft from just below the lesser trochanter to just above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution. Poor healing of these fractures has also been reported. Patients may experience thigh or groin pain weeks to months before presenting with a completed femoral fracture. The contralateral femur should be examined in patients who have sustained a femoral shaft fracture because fractures are often bilateral. Some reports noted that patients were also receiving treatment with glucocorticoids (such as prednisone or dexamethasone) at the time of fracture. Causality with bisphosphonate therapy has not been established. Any patient with a history of bisphosphonate exposure who presents with thigh or groin pain in the absence of trauma should be suspected of having an atypical fracture and should be evaluated. Discontinuation of pamidronate therapy in patients suspected to have an atypical femur fracture should be considered pending evaluation of the patient, based on an individual benefit risk assessment. It is unknown whether the risk of atypical femur fracture continues after therapy is discontinued.
During the four U.S. controlled hypercalcemia clinical studies, 5 of 231 patients (2%) who received pamidronate were reported to have had seizures, 2 of whom had preexisting seizure disorders. One patient (4%) in the saline arm had a seizure. Investigators did not consider the seizures to be drug-related; however, a possible relationship between the drug and the occurrence of seizures cannot be ruled out.
Fluid overload was reported in >= 15% of patients treated with pamidronate in a clinical trial of patients with hypercalcemia of malignancy. However, fluid overload was not reported in any patients treated with pamidronate during comparative, controlled trials. Edema was reported in 1% of patients treated with pamidronate 60 mg over 24 hours and in no patients treated with 60 mg over 4 hours or 90 mg over 24 hours in hypercalcemia trials.
Rarely, manifestations of allergic reaction have been reported, including hypotension, shortness of breath, or angioedema, and, very rarely, anaphylactic shock. Pamidronate is contraindicated in patients with clinically significant hypersensitivity to any bisphosphonate.
Respiratory-related adverse effects reported in clinical trials of pamidronate for hypercalcemia of malignancy included rales (0-6%) and rhinitis (0-6%). Respiratory-related adverse effects were also reported during clinical trials for osteolytic bone metastases of breast cancer and osteolytic lesions of multiple myeloma and included: cough (25.7%), dyspnea (30.4%), pleural effusion (10.7%), and sinusitis (15.6%). Upper respiratory tract infection was reported in clinical trials, but was reported more frequently during trials for osteolytic bone metastases of breast cancer and osteolytic lesions of multiple myeloma (24.1%) compared to trials for hypercalcemia of malignancy (0-3%). In clinical trials of multiple myeloma patients, there was one report of acute respiratory distress syndrome (ARDS) in a patient recovering from pneumonia and acute gangrenous cholecystitis. Acute respiratory distress syndrome (ARDS) and interstitial lung disease have also been reported during post-marketing use, although a causal relationship has not been established.
Hypertension was reported at an incidence of >= 15% in a clinical trial of pamidronate for hypercalcemia of malignancy and at an incidence of 0-6% during comparative clinical trials of pamidronate for hypercalcemia of malignancy. At least 10% of all pamidronate-treated patients with Paget's disease also experienced hypertension during clinical trials. Other cardiovascular-related adverse events reported during clinical trials include: atrial flutter (0-1%), heart failure (0-1%), syncope (0-6%), and sinus tachycardia (0-6%).
CNS-related adverse events reported during clinical trials of pamidronate for osteolytic bone metastases of breast cancer and osteolytic lesions of multiple myeloma included: asthenia (22.2%), anxiety (14.3%), headache (26.2%), and insomnia (22.2%). Headache was reported in >= 10% of patients treated with pamidronate in clinical trials of patients with Paget's disease. Insomnia was reported in clinical trials of patients with hypercalcemia of malignancy; however, the incidence was much less frequent (0-1%) than in trials of patients with osteolytic bone metastases of breast cancer and osteolytic lesions of multiple myeloma. Other CNS-related adverse events reported during hypercalcemia trials include psychosis (0-4%) and drowsiness (0-6%).
Candidiasis was reported in clinical trials of pamidronate for hypercalcemia of malignancy in 6% of patients administered pamidronate 90 mg over 24 hours and in no patients administered pamidronate 60 mg.
Hypothyroidism was reported in clinical trials of pamidronate for hypercalcemia if malignancy in 6% of patients administered pamidronate 90 mg over 24 hours and in no patients administered pamidronate 60 mg.
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 or hypovolemia should be corrected during treatment of hypercalcemia and prior to beginning pamidronate therapy; maintain adequate urine output during the treatment of hypercalcemia.
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.
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.
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.
No overall differences in safety or effectiveness were observed between geriatric adults and younger adults during controlled clinical trials, and other reported clinical experience has not identified differences in responses between these two populations. However, greater sensitivity of some geriatric adults cannot be ruled out. In general, dose selection for the geriatric 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 adults, which may increase the risk of adverse renal effects due to pamidronate. Close clinical and renal monitoring are recommended. 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.
Safety and efficacy of use of pamidronate in pediatric patients (children, infants, neonates) have not been established. Bisphosphonates have been used successfully in pediatric patients for treatment of specific disease states (i.e., hypercalcemia of malignancy, idiopathic or glucocorticoid induced osteoporosis, osteogenesis imperfecta, Paget's disease). However, extreme caution must be used to ensure appropriate use in children; excessive doses of bisphosphonates may compromise skeletal quality during growth, despite concomitant increases in bone density. In a case report, inappropriate and excessive doses of pamidronate in a child resulted in osteopetrosis (abnormally dense and misshapen bone predisposed to fracture). Sclerotic lines at the metaphyseal end of long bones have been reported in children with nephropathy taking daily oral pamidronate for greater than 5 months. It is advisable to monitor biochemical markers of skeletal turnover when bisphosphonates are used in children. Periodic X-rays may also be prudent.
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.
For the treatment of hypercalcemia:
-for hypercalcemia associated with malignancy:
Intravenous dosage:
Adults: IF ALBUMIN-CORRECTED SERUM CALCIUM IS 12 to 13.5 mg/dL: 60 mg or 90 mg IV infusion as a single dose; administer over 2 to 24 hours. IF ALBUMIN-CORRECTED SERUM CALCIUM IS MORE THAN 13.5 mg/dL: Give 90 mg IV infusion as a single dose; administer over 2 to 24 hours. RETREATMENT: To allow time for a full response after an initial dose, wait a minimum of 7 days before retreatment. CONCURRENT THERAPY: Vigorous saline hydration is an integral part of hypercalcemia treatment. Urine output should be maintained at approximately 2 L/day. DETERMINING WHICH DOSE TO USE: When treating hypercalcemia of malignancy, the serum calcium should be corrected based upon the serum albumin level to determine the appropriate dose. The following equation may be used: Albumin-corrected serum calcium (mg/dL) = serum calcium (mg/dL) + 0.8(4 - serum albumin [grams/dL]).
-for hypercalcemia associated with primary hyperparathyroidism*:
Intravenous dosage:
Adults: Limited data are available. In 1 report of 9 patients (median age 81 years) with moderate to severe hypercalcemia due to primary hyperparathyroidism, a single IV dose of 15 to 60 mg resulted in a therapeutic response in 8 patients with 6 achieving normocalcemia within 1 week. In a case report of a man with primary hyperparathyroidism, a dose of 90 mg IV infusion over 24 hours was effective in reducing his calcium concentration from 13.6 mg/dL to 9.4 mg/dL after 1 week; the patient required a second 60-mg dose approximately 2 months after the first dose and later died of a gastrointestinal hemorrhage. A second case reports the effectiveness of 60 mg IV followed by 60 mg IV 1 month later and 90 mg IV 2 weeks after the second dose in a patient with primary hyperparathyroidism. This patient eventually required surgery to treat the hyperparathyroidism.
-for hypercalcemia associated with end-stage renal failure* including patients with secondary hyperparathyroidism*:
Intravenous dosage:
Adults: Limited data are available. In 1 report, 10 patients with renal failure who developed symptomatic hypercalcemia secondary to use of calcium-based phosphate binders were given pamidronate. Doses ranged between 30 to 60 mg IV with a median dose of 60 mg IV. Serum calcium declined to within normal limits within 3 days in all 10 patients. In a 12-month study of 13 patients on hemodialysis with secondary hyperparathyroidism and mild hypercalcemia, 60 mg IV during hemodialysis every 2 months decreased serum calcium concentrations from a baseline of greater than 12 g/dL to approximately 10 g/dL and significantly decreased iPTH concentrations by 460 pg/mL (p < 0.001). Additionally, calcitriol dosages were increased from a mean dose of 1 mcg/week at baseline to 3 mcg/week after 6 months. Bone mineral density increased by 33% at the lumbar spine and femoral neck after 12 months of therapy (p < 0.01).
Adolescents: A case report describes a dose of 15 mg IV infusion (0.4 mg/kg) given over 2 hours in a boy aged 14 years with end-stage renal disease and secondary hyperparathyroidism; the serum calcium decreased from 12.5 mg/dL to 9.7 mg/dL. Although the serum calcium was controlled for 26 days and allowed for optimization of calcitriol treatment, surgical treatment was eventually required. The patient received acetaminophen prior to the infusion; no adverse reactions were reported.
For the treatment of osteolytic lesions of multiple myeloma or osteolytic bone metastases due to breast cancer:
-patients with multiple myeloma:
Intravenous dosage:
Adults: 90 mg IV infusion once a month; administer the dose over 4 hours. Supplement with calcium and vitamin D if intake inadequate and no hypercalcemia is present. Limited data are available in patients with a serum creatinine greater than 3 mg/dL. Withhold treatment if the renal function deteriorates. The optimal duration of therapy is not known; however data from a clinical study in myeloma patients indicate that treatment for 21 months is beneficial.
-patients with breast cancer and bone metastases:
Intravenous dosage:
Adults: 90 mg IV infusion once every 3 to 4 weeks, administered over 2 hours. Supplement with calcium and vitamin D if intake inadequate and no hypercalcemia is present. Withhold treatment if renal function deteriorates. The optimal duration of therapy is not known; however, data from a clinical study in breast cancer patients indicate that treatment for 24 months is beneficial.
For the treatment of moderate to severe Paget's disease:
Intravenous dosage:
Adults: 30 mg IV infusion once daily for 3 days (total dose: 90 mg); administer each dose over 4 hours. Supplement with calcium and vitamin D if dietary intake inadequate. A clinician may consider retreatment if clinically indicated. For retreatment, the dose and duration of therapy are the same as for initial treatment. Pamidronate is associated with biochemical remissions lasting 1 to 3 years in most patients. A single dose of zoledronic acid is the drug of choice per treatment guidelines, due to higher potency, the rare need for retreatment within 5 years, and long-term data for reducing pain and lytic lesions and improving quality of life.
For the treatment of osteogenesis imperfecta*:
Intravenous dosage:
Adults: 1.5 mg/kg/dose (Max: 60 mg/dose) IV every 3 to 4 months.
Children and Adolescents: 0.33 to 1 mg/kg/dose IV once daily for 2 to 3 consecutive days every 3 to 6 months. Usual dose range: 6 to 9 mg/kg/year.
Infants: 0.5 mg/kg/dose IV once daily for 2 consecutive days at baseline, then 0.75 mg/kg/dose IV once daily for 2 consecutive days at week 7, then 1 mg/kg/dose IV once daily for 2 consecutive days at week 15, then 1 mg/kg/dose IV once daily for 2 consecutive days at week 24, then 1.25 mg/kg/dose IV once daily for 2 consecutive days at week 34, then 1.5 mg/kg/dose IV once daily for 2 consecutive days at week 46 (for a cumulative dose of 12 mg/kg/year).
For the treatment of complex regional pain syndrome*:
Intravenous dosage:
Adults: 60 mg IV as a single dose.
Maximum Dosage Limits:
-Adults
90 mg/dose IV.
-Geriatric
90 mg/dose IV.
-Adolescents
Safety and efficacy have not been established; however, 1 mg/kg/day IV for a 2- to 3-day cycle up to a usual dose range of 6 to 9 mg/kg/year IV has been used for osteogenesis imperfecta.
-Children
Safety and efficacy have not been established; however, 1 mg/kg/day IV for a 2- to 3-day cycle up to a usual dose range of 6 to 9 mg/kg/year IV has been used for osteogenesis imperfecta.
-Infants
Safety and efficacy have not been established; however, doses up to 1.5 mg/kg/day IV for a 2-day cycle for a total yearly dose of 12 mg/kg/year IV have been used for osteogenesis imperfecta.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
No dosage adjustment necessary in patients with mild to moderate hepatic impairment; pamidronate has not been studied in patients with severe hepatic impairment.
Patients with Renal Impairment Dosing
No quantitative recommendations are available. Longer infusions (i.e., more than 2 hours), may decrease the risk for renal toxicity, especially in those patients with underlying renal impairment. Obtain a serum creatinine prior to each treatment.
CrCl less than 30 mL/minute or Serum creatinine (SCr) greater than 3 mg/dL: Safety and efficacy have not been established in patients with severe renal impairment; there are limited data in patients with CrCl less than 30 mL/minute. If renal function deteriorates (e.g., SCr increase of 0.5 mg/dL in patients with normal baseline SCr or an increase of 1 mg/dL in patients with abnormal baseline SCr) during pamidronate treatment in patients with bone metastases, hold doses of pamidronate until renal function returns to baseline.
*non-FDA-approved indication
Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Monitor renal function during concomitant pamidronate and aspirin use due to risk for additive nephrotoxicity.
Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Monitor renal function during concomitant pamidronate and aspirin use due to risk for additive nephrotoxicity.
Acetaminophen; Aspirin: (Moderate) Monitor renal function during concomitant pamidronate and aspirin use due to risk for additive nephrotoxicity.
Acetaminophen; Aspirin; Diphenhydramine: (Moderate) Monitor renal function during concomitant pamidronate and aspirin use due to risk for additive nephrotoxicity.
Acetaminophen; Ibuprofen: (Moderate) Monitor renal function during concomitant pamidronate and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Aldesleukin, IL-2: (Major) Avoid concomitant use of pamidronate and aldesleukin; coadministration may result in additive nephrotoxicity. Monitor for renal toxicity if concomitant use is required.
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.
Amlodipine; Celecoxib: (Moderate) Monitor renal function during concomitant pamidronate and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Aprotinin: (Moderate) The manufacturer recommends using aprotinin cautiously in patients that are receiving drugs that can affect renal function, such as pamidronate, as the risk of renal impairment may be increased.
Aspirin, ASA: (Moderate) Monitor renal function during concomitant pamidronate and aspirin use due to risk for additive nephrotoxicity.
Aspirin, ASA; Butalbital; Caffeine: (Moderate) Monitor renal function during concomitant pamidronate and aspirin use due to risk for additive nephrotoxicity.
Aspirin, ASA; Caffeine: (Moderate) Monitor renal function during concomitant pamidronate and aspirin use due to risk for additive nephrotoxicity.
Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Monitor renal function during concomitant pamidronate and aspirin use due to risk for additive nephrotoxicity.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Monitor renal function during concomitant pamidronate and aspirin use due to risk for additive nephrotoxicity.
Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Moderate) Monitor renal function during concomitant pamidronate and aspirin use due to risk for additive nephrotoxicity. (Moderate) Sodium bicarbonate can reduce the absorption of the oral bisphosphonates. Wait at least 30 minutes after oral alendronate, 1 hour after ibandronate, and 2 hours after oral etidronate, risedronate, or tiludronate before taking a sodium bicarbonatecontaining product.
Aspirin, ASA; Dipyridamole: (Moderate) Monitor renal function during concomitant pamidronate and aspirin use due to risk for additive nephrotoxicity.
Aspirin, ASA; Omeprazole: (Moderate) Monitor renal function during concomitant pamidronate and aspirin use due to risk for additive nephrotoxicity.
Aspirin, ASA; Oxycodone: (Moderate) Monitor renal function during concomitant pamidronate and aspirin use due to risk for additive nephrotoxicity.
Bictegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Monitor for changes in renal function if tenofovir alafenamide is administered in combination with a nephrotoxic agent, such as pamidronate. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with a drug that reduces renal function or competes for active tubular secretion may increase concentrations of tenofovir and other renally eliminated drugs; thus, increasing the risk of developing renal-related adverse reactions.
Bumetanide: (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.
Bupivacaine; Meloxicam: (Moderate) Monitor renal function during concomitant pamidronate and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Butalbital; Aspirin; Caffeine; Codeine: (Moderate) Monitor renal function during concomitant pamidronate and aspirin use due to risk for additive nephrotoxicity.
Capreomycin: (Major) Since capreomycin is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including pamidronate, may increase serum concentrations of either drug. Theoretically, the chronic coadministration of these drugs may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Monitor patients for changes in renal function if these drugs are coadministered.
Celecoxib: (Moderate) Monitor renal function during concomitant pamidronate and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Celecoxib; Tramadol: (Moderate) Monitor renal function during concomitant pamidronate and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) Monitor renal function during concomitant pamidronate and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Cidofovir: (Contraindicated) The administration of cidofovir with another potentially nephrotoxic agent, such as pamidronate, is contraindicated. Pamidronate should be discontinued at least 7 days prior to beginning cidofovir.
Clindamycin: (Moderate) Concomitant use of pamidronate and clindamycin may result in additive nephrotoxicity. Monitor for renal toxicity if concomitant use is required.
Colistimethate, Colistin, Polymyxin E: (Major) Theoretically, chronic coadministration may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Monitor patients for changes in renal function if these drugs are coadministered. Since colistimethate sodium is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including pamidronate, may increase serum concentrations of either drug.
Colistin: (Major) Theoretically, chronic coadministration may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Monitor patients for changes in renal function if these drugs are coadministered. Since colistimethate sodium is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including pamidronate, may increase serum concentrations of either drug.
Cyclosporine: (Moderate) Coadministration of pamidronate with other nephrotoxic drugs, including cyclosporine, may increase the risk of developing nephrotoxicity following pamidronate administration, even in patients who have normal renal function.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Monitor for changes in renal function if tenofovir alafenamide is administered in combination with a nephrotoxic agent, such as pamidronate. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with a drug that reduces renal function or competes for active tubular secretion may increase concentrations of tenofovir and other renally eliminated drugs; thus, increasing the risk of developing renal-related adverse reactions.
Diclofenac: (Moderate) Monitor renal function during concomitant pamidronate and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Diclofenac; Misoprostol: (Moderate) Monitor renal function during concomitant pamidronate and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Diflunisal: (Moderate) Monitor renal function during concomitant pamidronate and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Diphenhydramine; Ibuprofen: (Moderate) Monitor renal function during concomitant pamidronate and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Diphenhydramine; Naproxen: (Moderate) Monitor renal function during concomitant pamidronate and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as pamidronate. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as pamidronate. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as pamidronate. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Monitor for changes in renal function if tenofovir alafenamide is administered in combination with a nephrotoxic agent, such as pamidronate. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with a drug that reduces renal function or competes for active tubular secretion may increase concentrations of tenofovir and other renally eliminated drugs; thus, increasing the risk of developing renal-related adverse reactions.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as pamidronate. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Monitor for changes in renal function if tenofovir alafenamide is administered in combination with a nephrotoxic agent, such as pamidronate. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with a drug that reduces renal function or competes for active tubular secretion may increase concentrations of tenofovir and other renally eliminated drugs; thus, increasing the risk of developing renal-related adverse reactions.
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 alafenamide: (Moderate) Monitor for changes in renal function if tenofovir alafenamide is administered in combination with a nephrotoxic agent, such as pamidronate. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with a drug that reduces renal function or competes for active tubular secretion may increase concentrations of tenofovir and other renally eliminated drugs; thus, increasing the risk of developing renal-related adverse reactions.
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.
Ethacrynic Acid: (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.
Ethiodized Oil: (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.
Etodolac: (Moderate) Monitor renal function during concomitant pamidronate and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Fenoprofen: (Moderate) Monitor renal function during concomitant pamidronate and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Flurbiprofen: (Moderate) Monitor renal function during concomitant pamidronate and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Furosemide: (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.
Gentamicin: (Moderate) Coadministration of pamidronate with other nephrotoxic drugs, such as aminoglycosides, may increase the risk of developing nephrotoxicity following pamidronate administration, even in patients who have normal renal function.
Hyaluronidase, Recombinant; Immune Globulin: (Moderate) Immune Globulin (IG) products have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephrosis, and death. Patients predisposed to acute renal failure include patients receiving known nephrotoxic drugs like pamidronate. Coadminister IG products at the minimum concentration available and the minimum rate of infusion practicable. Also, closely monitor renal function.
Hydrocodone; Ibuprofen: (Moderate) Monitor renal function during concomitant pamidronate and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Ibuprofen: (Moderate) Monitor renal function during concomitant pamidronate and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Ibuprofen; Famotidine: (Moderate) Monitor renal function during concomitant pamidronate and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Ibuprofen; Oxycodone: (Moderate) Monitor renal function during concomitant pamidronate and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Ibuprofen; Pseudoephedrine: (Moderate) Monitor renal function during concomitant pamidronate and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
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) Monitor renal function during concomitant pamidronate and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Inotersen: (Moderate) Use caution with concomitant use of inotersen and pamidronate due to the risk of glomerulonephritis and nephrotoxicity.
Iodixanol: (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.
Iohexol: (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.
Iomeprol: (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.
Iopamidol: (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.
Iopromide: (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.
Ioversol: (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.
Isosulfan Blue: (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.
Ketoprofen: (Moderate) Monitor renal function during concomitant pamidronate and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Ketorolac: (Moderate) Monitor renal function during concomitant pamidronate and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as pamidronate. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus.
Lanthanum Carbonate: (Moderate) To limit absorption problems, the oral bisphosphonates should not be taken within 2 hours of dosing with lanthanum carbonate. Oral drugs known to interact with cationic antacids, like the oral bisphosphonates, may also be bound by lanthanum carbonate. Separating times of administration will maximize absorption and clinical benefit of the bisphosphonate. Separate the times of administration appropriately. Monitor the patient's clinical status and bone density as recommended to ensure the appropriate response to bisphosphonate therapy is obtained.
Loop diuretics: (Moderate) Because both loop diuretics and intravenously administered bisphosphonates (i.e., alendronate, ibandronate, pamidronate, and zoledronic acid) can cause a decrease in serum calcium, caution is advised when used concomitantly in the treatment of hypercalcemia of malignancy in order to avoid hypocalcemia. In patients with hypercalcemia of malignancy, the initial treatment typically includes the use of loop diuretics, in combination with saline hydration, however, diuretic therapy should not be employed prior to correction of hypovolemia and dehydration.
Mannitol: (Major) Avoid use of mannitol and pamidronate, if possible. Concomitant administration of nephrotoxic drugs, such as pamidronate, increases the risk of renal failure after administration of mannitol.
Meclofenamate Sodium: (Moderate) Monitor renal function during concomitant pamidronate and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Mefenamic Acid: (Moderate) Monitor renal function during concomitant pamidronate and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Meloxicam: (Moderate) Monitor renal function during concomitant pamidronate and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Nabumetone: (Moderate) Monitor renal function during concomitant pamidronate and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Naproxen: (Moderate) Monitor renal function during concomitant pamidronate and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Naproxen; Esomeprazole: (Moderate) Monitor renal function during concomitant pamidronate and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Naproxen; Pseudoephedrine: (Moderate) Monitor renal function during concomitant pamidronate and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Non-Ionic Contrast Media: (Moderate) Coadministration of pamidronate with other nephrotoxic drugs may increase the risk of developing nephrotoxicity following pamidronate administration, even in patients who have normal renal function.
Nonsteroidal antiinflammatory drugs: (Moderate) Monitor renal function during concomitant pamidronate and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Omeprazole; Sodium Bicarbonate: (Moderate) Sodium bicarbonate can reduce the absorption of the oral bisphosphonates. Wait at least 30 minutes after oral alendronate, 1 hour after ibandronate, and 2 hours after oral etidronate, risedronate, or tiludronate before taking a sodium bicarbonatecontaining product.
Oxaprozin: (Moderate) Monitor renal function during concomitant pamidronate and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
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) Monitor renal function during concomitant pamidronate and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Plazomicin: (Moderate) Coadministration of pamidronate with other nephrotoxic drugs, such as aminoglycosides, may increase the risk of developing nephrotoxicity following pamidronate administration, even in patients who have normal renal function.
Sodium Bicarbonate: (Moderate) Sodium bicarbonate can reduce the absorption of the oral bisphosphonates. Wait at least 30 minutes after oral alendronate, 1 hour after ibandronate, and 2 hours after oral etidronate, risedronate, or tiludronate before taking a sodium bicarbonatecontaining product.
Streptomycin: (Moderate) Coadministration of pamidronate with other nephrotoxic drugs, such as aminoglycosides, may increase the risk of developing nephrotoxicity following pamidronate administration, even in patients who have normal renal function.
Sulindac: (Moderate) Monitor renal function during concomitant pamidronate and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Sumatriptan; Naproxen: (Moderate) Monitor renal function during concomitant pamidronate and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
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.
Tenofovir Alafenamide: (Moderate) Monitor for changes in renal function if tenofovir alafenamide is administered in combination with a nephrotoxic agent, such as pamidronate. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with a drug that reduces renal function or competes for active tubular secretion may increase concentrations of tenofovir and other renally eliminated drugs; thus, increasing the risk of developing renal-related adverse reactions.
Tenofovir Alafenamide: (Moderate) Monitor for changes in renal function if tenofovir alafenamide is administered in combination with a nephrotoxic agent, such as pamidronate. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with a drug that reduces renal function or competes for active tubular secretion may increase concentrations of tenofovir and other renally eliminated drugs; thus, increasing the risk of developing renal-related adverse reactions.
Tenofovir Disoproxil Fumarate: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as pamidronate. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus.
Thalidomide: (Moderate) In patients with multiple myeloma, the risk of renal dysfunction may be higher in patients taking both pamidronate and thalidomide.
Tobramycin: (Moderate) Coadministration of pamidronate with other nephrotoxic drugs, such as aminoglycosides, may increase the risk of developing nephrotoxicity following pamidronate administration, even in patients who have normal renal function.
Tolmetin: (Moderate) Monitor renal function during concomitant pamidronate and nonsteroidal antiinflammatory drug use due to risk for additive nephrotoxicity.
Torsemide: (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.
Vancomycin: (Moderate) Coadministration of pamidronate with other nephrotoxic drugs, like vancomycin, may increase the risk of developing nephrotoxicity following pamidronate administration, even in patients who have normal renal function.
Voclosporin: (Moderate) Concomitant use of voclosporin and pamidronate may result in additive nephrotoxicity. Monitor for renal toxicity if concomitant use is required.
The principal pharmacologic action of pamidronate disodium, a first-generation bisphosphonate, is the inhibition of bone resorption. Although the mechanism of antiresorptive action is not completely understood, several factors are thought to contribute to this action. Pamidronate disodium adsorbs to calcium phosphate (hydroxyapatite) crystals in bone and may directly block dissolution of this mineral component of bone. In vitro studies also suggest that inhibition of osteoclast activity contributes to inhibition of bone resorption. In animal studies, at doses recommended for the treatment of hypercalcemia, pamidronate disodium inhibits bone resorption apparently without inhibiting bone formation and mineralization. Of relevance to the treatment of hypercalcemia of malignancy is the finding that pamidronate disodium inhibits the accelerated bone resorption that results from osteoclast hyperactivity induced by various tumors in animal studies.
Pharmacokinetics:
Pamidronate is administered by intravenous infusion. Pamidronate distributes extensively to bone and less so to the liver, kidney, or spleen. Bone uptake occurs preferentially in areas of high bone turnover. It is not clear if it crosses the placenta or distributes into breast milk.
Pamidronate is not metabolized and is excreted exclusively by the kidney. It has a half-life of 28 +/- 7 hours. Within 120 hours, 46 +/- 14% of an intravenous dose is excreted unchanged in the urine and 54 +/- 14% is retained in the body. Cumulative urinary excretion is linearly dose-related. Eventually, nearly 100% of the dose is eliminated renally. The terminal phase elimination half-life in bone is estimated to be approximately 300 days.
Studies in rats show that pamidronate is rapidly cleared from circulation and taken up by the bones, the liver, the spleen, teeth, and tracheal cartilage. Radioactivity is eliminated from most soft tissues within 1 to 4 days; however it is detectable in the liver for 1 month and the spleen for 3 months. High levels of radioactivity are detectable in the bones, trachea, and teeth for 6 months.
-Route-Specific Pharmacokinetics
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.
-Special Populations
Hepatic Impairment
In patients with mild to moderate hepatic impairment, the AUC and Cmax were 53% and 29% higher, respectively, when compared to patients with normal hepatic function; plasma clearance decreased by 33%, although these findings are not considered to be clinically relevant. Dose adjustment is not necessary in patients with mild to moderate hepatic impairment. Pamidronate has not been studied in patients with severe hepatic impairment.
Renal Impairment
The pharmacokinetics of pamidronate have been studied in patients with cancer and varying degrees of renal impairment. In patients receiving 90 mg IV infusion over 4 hours, the renal clearance was found to decrease as renal function decreased; a trend towards a lower percentage of drug excreted unchanged in the urine was observed. A dose adjustment is not necessary when administered on a monthly basis. If renal dysfunction occurs and is suspected to be secondary to pamidronate, pamidronate may need to be temporarily stopped (see Dosage).