Drug interaction studies with AREDIA in humans have not been conducted.
Caution is warranted when AREDIA is used with other potentially nephrotoxic drugs.
In multiple myeloma patients, the risk of renal dysfunction may be increased when AREDIA is used in combination with thalidomide.
AREDIA should not be used in combination with other bisphosphonates.
Reconstituted solutions that have been prepared with Sterile Water for Injection should be further diluted with either 0.9% w/v sodium chloride or 5% w/v glucose solution prior to intravenous infusion administration. The reconstituted solution is chemically and physically stable for 24 hours at room temperature. However, from a microbiological point of view, it is preferable to use the product immediately after aseptic reconstitution and dilution.
If not used immediately, the duration and conditions of storage prior to use are the care provider’s responsibility. The total time between reconstitution, dilution and end of administration must not exceed 24 hours.
All parenteral products should be visually inspected for particulate matter and discoloration prior to administration. Any solution found to have particulate matter or discoloration should be discarded.
Dosing recommendations differ for tumour-induced hypercalcemia, lytic bone metastases and multiple myeloma, and Paget's disease. For patients suffering from TIH and multiple myeloma, see the TIH dosage guidelines.
AREDIA (pamidronate disodium) must never be given as a bolus injection (see Warnings and Precautions). AREDIA should be administered in a compatible calcium-free intravenous solution (e.g., sterile normal saline or dextrose 5% in water). AREDIA should be infused slowly.
To minimize local reactions the cannula should be carefully inserted in a relatively large vein.
The infusion rate should never exceed 60 mg/h (1 mg/min) and the concentration of AREDIA in the infusion solution should not exceed 90 mg/250 mL. A dose of 90 mg should normally be administered as a 2-hour infusion in 250 mL infusion solution. However, in patients with multiple myeloma and in patients with tumour-induced hypercalcemia it is recommended not to exceed 90 mg in 500 mL over 4 hours (i.e., an infusion rate of 22.5 mg/h).
AREDIA should not be administered to patients with severe renal impairment (creatinine clearance <30 mL/min) unless in cases of life-threatening tumour-induced hypercalcaemia where the benefit outweighs the potential risk.
As with other i.v. bisphosphonates, renal monitoring is recommended, for instance, measurement of serum creatinine prior to each dose of AREDIA. In patients receiving AREDIA for bone metatases or multiple myeloma who show evidence of deterioration in renal function, AREDIA treatment should be withheld until renal function returns to within 10% of the baseline value. This recommendation is based on a clinical study, in which renal deterioration was defined as follows: For patients with normal baseline creatinine, increase of 0.5 mg/dL. For patients with abnormal baseline creatinine, increase of 1.0 mg/dL.
A pharmacokinetic study conducted in patients with cancer and normal or impaired renal function indicates that the dose adjustment is not necessary in mild (creatinine clearance 61-90 mL/min) to moderate renal impairment (creatinine clearance 30-60 mL/min). In such patients, the infusion rate should not exceed 90 mg/4h (approximately 20-22 mg/h).
hyperkalemia, hypernatremia, hematuria. Rare instances of allergic manifestations have been reported, including hypotension, dyspnea, or angioedema, and, very rarely, anaphylactic shock.
Bisphosphonates, including AREDIA, have been associated with renal toxicity manifested as deterioration of renal function and potential renal failure (see Warnings and Precautions). Since many patients with tumour-induced hypercalcemia have compromised renal function prior to receiving antihypercalcemia therapy (see Warnings and Precautions), it is difficult to estimate the role of individual bisphosphonates in subsequent changes in renal function. Deterioration of renal function (elevation of serum creatinine of >20% above baseline) which could not be readily explained in terms of pre-existing renal disease, prior nephrotoxic chemotherapies or compromised intravascular volume status has been noted in 7 cases of 404 patients treated with AREDIA where these data have been reported. As with other i.v. bisphosphonates, renal monitoring is recommended (see Warnings and Precautions, Monitoring and Laboratory Tests).
Common: symptomatic hypocalcemia (paresthesia, tetany), headache, insomnia, somnolence. Uncommon: seizures, agitation, dizziness, lethargy. Very rare: confusion, visual hallucinations.
Prior to treatment with AREDIA (pamidronate disodium), renal excretion of excess calcium should be promoted by restoring and maintaining adequate fluid balance and urine output.
Symptomatic Paget's disease of bone.
Overdosage
For management of a suspected drug overdose, CPhA recommends that you contact your regional Poison Control Centre. See the eCPS Directories section for a list of Poison Control Centres.
Patients who have received doses higher than those recommended should be carefully monitored. Clinically significant hypocalcemia with paresthesia, tetany and hypotension, may be reversed by an infusion of calcium gluconate. Acute hypocalcemia is not expected to occur with AREDIA (pamidronate disodium) since plasma calcium levels fall progressively for several days after treatment.
Dosage Forms, Composition and Packaging
Each vial of sterile, white to practically white lyophilized powder contains: pamidronate disodium (anhydrous) 30 mg and mannitol 470 mg. Phosphoric acid is employed to adjust the pH to 6.3. Preservative-free. Vials of 10 mL, cartons of 1.
Each vial of sterile, white to practically white lyophilized powder contains: pamidronate disodium (anhydrous) 90 mg and mannitol 375 mg. Phosphoric acid is employed to adjust the pH to 6.3. Preservative-free. Vials of 10 mL, cartons of 1.
Warnings and Precautions
Bisphosphonates, including AREDIA, have been associated with renal toxicity manifested as deterioration of renal function and potential renal failure. Renal deterioration, progression to renal failure (some with fatal outcome) have been reported very rarely in patients after the initial dose or a single dose of AREDIA. Deterioration of renal function (including renal failure) has also been reported following long-term treatment with AREDIA in patients with multiple myeloma.
Due to the risk of clinically significant deterioration in renal function which may progress to renal failure, single doses of AREDIA should not exceed 90 mg, and the recommended infusion time should be observed (see Dosage and Administration).
AREDIA is excreted intact primarily via the kidney (see Action and Clinical Pharmacology, Pharmacokinetics), thus the risk of adverse reactions may be greater in patients with impaired renal function.
As with other i.v. bisphophonates renal monitoring is recommended, for instance, measurement of serum creatinine prior to each dose of AREDIA. Experience with AREDIA in patients with severe renal impairment (serum creatinine >440 µmol/L in TIH patients; >180 µmol/L in multiple myeloma patients) is limited. If clinical judgment determines that the potential benefits outweigh the risk in such cases, AREDIA should be used cautiously and renal function carefully monitored. Patients treated with AREDIA for bone metastases or multiple myeloma should have their dose withheld if renal function has deteriorated (see Dosage and Administration, Renal Impairment).
There are no clinical data available in patients with severe hepatic insufficiency.
Somnolence and/or dizziness may occur following AREDIA infusion, in which case the patient should not drive, operate potentially dangerous machinery or engage in other activities that may be hazardous because of decreased alertness.
In post-marketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates. However, such reports occur rarely. This category of drugs includes AREDIA (pamidronate disodium for injection). The time to onset of symptoms varied from one day to several months after starting the drug. Most patients had relief of symptoms after stopping treatment. A subset of patients had recurrence of symptoms when re-challenged with the same drug or another bisphosphonate.
Osteonecrosis of the jaw (ONJ) has been reported in cancer patients treated with bisphosphonates, including AREDIA. Although no causal relationship has been established, there is an association between bisphosphonate use and the development of ONJ. Post-marketing experience suggests a greater frequency of reports of ONJ based on tumour type (advanced breast cancer, multiple myeloma) and dental status (dental extractions, periodontal disease and local trauma including poorly fitting dentures); these are associated with a greater risk of developing ONJ. Cancer patients also receive other treatments that may play a role in the development of ONJ, such as chemotherapy and glucocorticosteroids. Many patients had signs of local infection including osteomyelitis.
Presentation of ONJ may include altered local sensation (hyperaesthesia or numbness), maxillofacial pain, “toothaches”, denture sore spots, loose teeth, exposed bone in the oral cavity, impaired healing, recurrent or persistent soft tissue infection in the oral cavity and marked oral odour. The onset can be from months to years after commencing bisphosphonate therapy. Cancer patients should maintain good oral hygiene; it is recommended that advanced cancer patients be encouraged to have an oral examination of both hard and soft tissues, with preventive dentistry prior to treatment with bisphosphonates, and that such assessments continue at regularly scheduled intervals after bisphosphonate therapy is initiated. While on bisphosphonate treatment, these patients should avoid invasive dental procedures if possible. Biopsies are not recommended unless metastasis to the jaw is suspected. For patients who develop ONJ while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there is no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of ONJ. Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.
AREDIA (pamidronate disodium) must never be given as a bolus injection since severe local reactions and thrombophlebitis may result from high local concentrations.
AREDIA should always be diluted and administered as a slow intravenous infusion (see Dosage and Administration). Regardless of the volume of solution in which AREDIA is diluted, slow intravenous infusion is absolutely necessary for safety.
AREDIA should not be given together with other bisphosphonates to treat hypercalcemia since the combined effects of these agents are unknown.
AREDIA should not be mixed with calcium-containing intravenous infusions.
Patients must be assessed prior to and during administration of AREDIA to assure that they are appropriately hydrated. This is especially important for patients receiving diuretic therapy.
It is essential in the initial treatment of tumour-induced hypercalcemia that intravenous rehydration be instituted to restore urine output. Patients should be hydrated adequately throughout treatment but overhydration must be avoided.
Patients should have standard serum creatinine and clinical renal function parameters periodically evaluated. Patients receiving frequent AREDIA infusions over a prolonged period of time, and those with pre-existing renal disease or a predisposition to renal impairment (e.g., patients with multiple myeloma and/or tumour-induced hypercalcemia) should have evaluations of standard laboratory and clinical parameters of renal function prior to each dose of AREDIA. Fluid balance (urine output, daily weights) should also be followed carefully. If there is deterioration of renal function during AREDIA therapy, the infusion must be stopped (see Warnings and Precautions).
AREDIA is excreted intact primarily via the kidney, thus the risk of renal adverse reactions may be greater in patients with impaired renal function.
Serum electrolytes, calcium and phosphate should be monitored following initiation of therapy with AREDIA. Patients with anemia, leukopenia or thrombocytopenia should have regular hematology assessments. Occasional cases of mild, transient hypocalcemia, usually asymptomatic, have been reported. Symptomatic hypocalcemia occurs rarely and can be reversed with calcium gluconate. Patients who have undergone thyroid surgery may be particularly susceptible to develop hypocalcemia due to relative hypoparathyroidism.
In tumour-induced hypercalcemia, either ionized calcium or total serum calcium corrected (adjusted) for albumin should be monitored during treatment with AREDIA. Serum calcium levels in patients who have hypercalcemia of malignancy may not reflect the severity of hypercalcemia, since hypoalbuminemia is commonly present. Corrected serum calcium values should be calculated using established algorithms, such as:
cCa= tCa+(0.02×[40–ALB])
where:
cCa=adjusted calcium concentration (mmol/L)
tCa=measured total calcium concentration (mmol/L)
ALB=measured albumin concentration (g/L)
Although mild hypercalcemia may be asymptomatic, moderate to severe hypercalcemia usually associated with a variety of signs and symptoms, and can be life-threatening if not promptly recognized and treated. Individuals at risk and their caregivers should be made aware that signs and symptoms of hypercalcemia include: lethargy, fatigue, confusion, loss of appetite, nausea and vomiting, constipation, excessive thirst and urination. Measures such as maintaining mobility and ensuring adequate hydration could diminish the symptoms of hypercalcemia. However, when symptoms of hypercalcemia are detected, it is important to seek medical assistance promptly.
Pre-existing hypocalcemia must be treated by adequate intake of calcium and Vitamin D before initiating AREDIA. Other disturbances of mineral metabolism (e.g., parathyroidectomy resulting in partial or complete hypoparathyroidism) must also be effectively managed. It is recommended that patients with Paget’s disease of bone have their serum calcium levels assessed before and during treatment with AREDIA (e.g., as part of their annual examination). All patients should be counselled regarding the importance of calcium and vitamin D supplementation in maintaining serum calcium levels and on the symptoms of hypocalcemia.
In the absence of hypercalcemia, patients who are at risk of calcium or vitamin D deficiency, should be given oral calcium and Vitamin D supplementation in order to minimize the risk of hypocalcemia. In the event that hypercalcemia develops, calcium and Vitamin D supplements should be discontinued immediately.
The safety and efficacy of AREDIA in children has not been established. Until further experience is gained, AREDIA is only recommended for use in adult patients.
It has been shown that AREDIA can cross the placenta in rats and has produced marked maternal and embryo/fetal adverse effects in rats and rabbits.
There are no adequate and well-controlled studies in pregnant women and no clinical evidence to support the use of AREDIA in pregnant women. Therefore, AREDIA should not be used during pregnancy (see Contraindications).
Bisphosphonates are incorporated into the bone matrix, from where they are gradually released over periods of weeks to years. The extent of bisphosphonate incorporation into adult bone, and hence, the amount available for release back into the systemic circulation, is directly related to the total dose and duration of bisphosphonate use. Although there are very limited data on fetal risk in humans, bisphosphonates do cause fetal harm in animals, and animal data suggest that uptake of bisphosphonates into fetal bone is greater than into maternal bone. Therefore, there is a theoretical risk of fetal harm (e.g., skeletal and other abnormalities) if a woman becomes pregnant 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 (intravenous versus oral) on this risk has not been established.
There is no clinical experience with AREDIA in lactating women. A study in lactating rats has shown that pamidronate passes into the milk. Mothers treated with AREDIA should therefore not breast feed their infants.
In patients with cardiac disease, especially in the elderly, additional saline overload may precipitate cardiac failure (left ventricular failure or congestive heart failure). Fever (influenza-like symptoms) may also contribute to this deterioration.
Storage and Stability
Protect vials from heat (i.e., store below 30°C).
AREDIA must be kept out of the reach and sight of children and pets.
Action and Clinical Pharmacology
The pharmacokinetics of pamidronate were studied in male cancer patients at risk for bone metastases with normal hepatic function (n=6) and mild to moderate hepatic dysfunction (n=9). Each patient received a single 90 mg dose of AREDIA infused over 4 hours. Although there was a statistically significant difference in the pharmacokinetics between patients with normal and impaired hepatic function, the difference was not considered clinically relevant. Patients with hepatic impairment exhibited higher mean AUC (39.7%) and Cmax (28.6%) values. Nevertheless, pamidronate was still rapidly cleared from the plasma. Drug levels were not detectable in patients by 12 36 hours after drug infusion. Because AREDIA is administered on a monthly basis, drug accumulation is not expected. No changes in AREDIA dosing regimen are recommended for patients with mild to moderate abnormal hepatic function (see Dosage and Administration).
Hepatic and metabolic clearance of AREDIA are insignificant. AREDIA thus displays little potential for drug interactions at either the metabolic or protein binding level.
Plasma concentrations of pamidronate rise rapidly after infusion is started and fall rapidly when the infusion is stopped. The apparent plasma half-life is about 0.8 hours. Apparent steady state is therefore achieved with infusions of >2-3 hours’ duration. When infused i.v. at 60 mg over 1 hour, the peak plasma concentration is about 10 nmol/mL and the apparent total plasma clearance is about 180 mL/min.
As pamidronate has a strong affinity for calcified tissues, total elimination is not observed within the time frame of experimental studies.
After an i.v. infusion, about 20-55% of the dose is recovered in the urine within 72 hours as unchanged pamidronate, the majority being excreted within the first 24 hours. Pamidronate does not appear to be metabolized, and the remaining fraction of the dose is retained in the body (within the time frame of the studies). The percentage of the dose retained is independent of both the dose (range 15 180 mg) and the infusion rate (range 1.25-60 mg/h).
Retention is similar after each dose of pamidronate disodium. Thus, accumulation in bone is not capacity limited and is dependent solely on the cumulative dose.
Urinary elimination is biphasic (t½α=1.6 h; t½β=27.2 h). The apparent renal clearance is about 54 mL/min, and there is a tendency for renal clearance to correlate with creatinine clearance.
Pamidronate disodium binding to human serum proteins is relatively low (about 54%) but increases to approximately 5 mmol when exogenous 95% calcium is added to human plasma.
Paget's disease of bone, which is characterized by local areas of increased bone resorption and formation with qualitative changes in remodelling, responds well to treatment with AREDIA. Repeated infusions of pamidronate disodium do not lead to reduced efficacy. In addition, patients resistant to etidronate and calcitonin respond well to AREDIA infusions. In long-term follow-up to clinical trials, bone fracture rate does not appear to be increased following treatment with pamidronate disodium relative to the normally occurring rate in patients with Paget's disease.
Clinical and biochemical remission of Paget's disease has been demonstrated by bone scintigraphy, by decreases in urinary hydroxyproline and serum alkaline phosphatase, and by symptomatic improvement. Bone scans show that AREDIA reduces the number of bones and the percent of the skeleton affected and that bone scintigraphy significantly improves. Bone biopsies consistently show histological and histomorphometric improvement indicating the reversal of the disease process. Symptoms improve even in those with severe disease.
AREDIA (pamidronate disodium) belongs to a class of bisphosphonates (previously termed diphosphonate), which inhibit bone resorption. The therapeutic activity of AREDIA is attributable to its potent anti-osteoclastic activity on bone. In animal studies, at therapeutic doses, pamidronate disodium inhibits bone resorption apparently without inhibiting bone formation and mineralization.
The predominant means by which AREDIA reduces bone turnover both in vitro and in vivo appears to be through the local, direct antiresorptive effect of bone-bound bisphosphonate. Pamidronate disodium binds to calcium phosphate (hydroxyapatite) crystals and directly inhibits the formation and dissolution of this bone mineral component in vitro. In vitro studies indicate that pamidronate disodium is a potent inhibitor of osteoclastic bone resorption. Pamidronate disodium also suppresses the migration of osteoclast precursors onto the bone and their subsequent transformation into the mature resorbing osteoclast.
Lytic bone metastases in cancer patients are caused by increased osteoclast activity. Metastatic tumour cells secrete paracrine factors which stimulate neighboring osteoclasts to resorb bone. By inhibiting osteoclast function, bisphosphonates interrupt the cascade of events which lead to tumour-induced osteolysis. Lytic bone destruction causes significant complications and associated morbidity.
Clinical trials in patients with predominantly lytic bone metastases or multiple myeloma showed that AREDIA prevented or delayed skeletal-related events, (SREs: hypercalcemia, pathologic fractures, radiation therapy to bone, orthopedic surgery, spinal cord compression) and decreased bone pain. When used in combination with standard anticancer treatment, AREDIA led to a delay in progression of bone metastases. In addition, osteolytic bone metastases which have proved refractory to cytotoxic and hormonal therapy may show radiological evidence of disease stabilization or sclerosis.
A significant reduction in bone pain was also demonstrated, which in some patients led to decreased analgesic intake and increased mobility. Greater deteriorations in ECOG performance status and Spitzer quality of life scores were seen in the placebo patients compared to AREDIA-treated patients.
In tumour-induced hypercalcemia, AREDIA normalizes plasma calcium between 3 and 7 days following the initiation of treatment irrespective of the type of malignancy or presence of detectable metastases. This effect is dependent on initial calcium levels.
AREDIA improves symptoms associated with hypercalcemia, e.g. anorexia, nausea, vomiting and diminished mental status.
The kidneys play a prominent role in calcium homeostasis. In addition to skeletal osteolysis, renal dysfunction contributes to the pathogenesis of tumour-induced hypercalcemia. When diagnosed, most hypercalcemic patients are significantly dehydrated. Elevated plasma calcium antagonizes antidiuretic hormone-induced renal concentration, and thus results in polyuria and excessive fluid loss. Hydration status is further compromised by reduced fluid intake due to nausea, vomiting and diminished mental status. Furthermore, dehydration often leads to a fall in glomerular filtration rate (GFR).
Before AREDIA therapy is initiated, patients should be adequately rehydrated with isotonic saline (0.9%) (see Warnings and Precautions). Normalization of plasma calcium levels by AREDIA in adequately hydrated patients may also normalize plasma parathyroid hormone (PTH) which is suppressed by hypercalcemia.
The duration of normocalcemia following AREDIA treatment varies in patients with tumour-induced hypercalcemia because of early mortality, and the heterogeneity of diseases and cancer therapies. In general, recurrences tend to occur preferentially after treatment with lower doses: at doses of 30 mg or less, plasma calcium levels tend to increase after approximately 1 week, while at high doses (total treatment doses of 45 to 90 mg) plasma calcium levels remained normal for at least 2 weeks and up to several months. One study has shown a clear relationship between recurrence rates and AREDIA dose: in patients treated with single i.v. infusions of 30, 45, 60 and 90 mg AREDIA, recurrence rates were lower for the higher dose group 9 months after initial treatment. In patients in whom the underlying disease is well controlled by cancer therapy, the duration of response tends to be more prolonged.
Clinical experience with AREDIA in relapsed tumour-induced hypercalcemia is limited. In general, with re-treatment, the response is similar to that with the first AREDIA treatment, unless the cancer has progressed significantly. Therefore, AREDIA treatment appears effective for recurrent hypercalcemia at doses established for the initial treatment course (see Dosage and Administration). The mechanisms underlying possible decreased effects of repeat treatment with AREDIA in advanced cancer are unknown.
In severe forms of hypercalcemia the dose of AREDIA may be increased, or eventually, a combination drug therapy should be considered (see Warnings and Precautions).
A pharmacokinetic study conducted in patients with cancer showed no differences in plasma AUC of pamidronate between patients with normal renal function and patients with mild to moderate renal impairment. In patients with severe renal impairment (creatinine clearance <30 mL/min), the AUC of pamidronate was approximately 3 times higher than in patients with normal renal function (creatinine clearance >90 mL/min) (see Dosage and Administration).
Contraindications
AREDIA is contraindicated:
-
in patients with known or suspected hypersensitivity to AREDIA (pamidronate disodium), to any of its excipients (see Dosage Forms, Composition and Packaging), or to other bisphosphonates.
-
in pregnancy,
-
in breast-feeding women
