Bone Metabolism Regulator
Action And Clinical Pharmacology: Pamidronate belongs to a class of bisphosphonates (previously termed diphosphonate), which inhibit bone resorption. The therapeutic activity of pamidronate is attributable to its potent anti-osteoclastic activity on bone. In animal studies, at therapeutic doses, pamidronate inhibits bone resorption apparently without inhibiting bone formation and mineralization.
The predominant means by which pamidronate reduces bone turnover both in vitro and in vivo appears to be through the local, direct antiresorptive effect of bone-bound bisphosphonate. Pamidronate 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 is a potent inhibitor of osteoclastic bone resorption. Pamidronate also suppresses the migration of osteoclast precursors onto the bone and their subsequent transformation into the mature resorbing osteoclast.
Tumor-induced Hypercalcemia: In tumor-induced hypercalcemia, pamidronate 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.
Pamidronate 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 tumor-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 pamidronate therapy is initiated, patients should be adequately rehydrated with isotonic saline (0.9%) (see Precautions). Normalization of plasma calcium levels by pamidronate in adequately hydrated patients may also normalize plasma parathyroid hormone (PTH) which is suppressed by hypercalcemia.
The duration of normocalcemia following pamidronate treatment varies in patients with tumor-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 pamidronate dose: in patients treated with single i.v. infusions of 30, 45, 60 and 90 mg pamidronate, recurrence rates were lower for the higher dose group 9 months after initial treatment. The duration of response tends to be more prolonged in patients in whom the underlying disease is well controlled by cancer therapy.
Clinical experience with pamidronate in relapsed tumor-induced hypercalcemia is limited. In general, with retreatment, the response is similar to that with the first pamidronate treatment, unless the cancer has progressed significantly. Therefore, pamidronate treatment appears effective for recurrent hypercalcemia at doses established for the initial treatment course (see Dosage). The mechanisms underlying possible decreased effects of repeat treatment with pamidronate in advanced cancer are unknown.
In severe forms of hypercalcemia the dose of pamidronate may be increased, or eventually, a combination drug therapy should be considered (see Warnings).
Bone Metastases and Multiple Myeloma: Lytic bone metastases in cancer patients are caused by increased osteoclast activity. Metastatic tumor cells secrete paracrine factors which stimulate neighboring osteoclasts to resorb bone. By inhibiting osteoclast function, bisphosphonates interrupt the cascade of events which lead to tumor-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 pamidronate 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, pamidronate 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 pamidronate-treated patients.
Paget’s Disease: Paget’s Disease of bone, which is characterized by local areas of increased bone resorption and formation with qualitative changes in remodeling, responds well to treatment with pamidronate. Repeated infusions of pamidronate do not lead to reduced efficacy. In addition, patients resistant to etidronate and calcitonin respond well to pamidronate infusions. In long-term follow-up to clinical trials, bone fracture rate does not appear to be increased following treatment with pamidronate 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 pamidronate reduces the number of bones and the percentage 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.
Pharmacokinetics: 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 to 3 hours’ duration. When infused i.v. at 60 mg/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 to 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 to 180 mg) and the infusion rate (range 1.25 to 60 mg/hour).
Retention is similar after each dose of pamidronate. Thus, accumulation in bone is not capacity limited and is dependent solely on the cumulative dose.
Urinary elimination is biphasic (t1/2=1.6 hours; t1/2=27.2 hours). The apparent renal clearance is about 54 mL/min and there is a tendency for renal clearance to correlate with creatinine clearance.
Pamidronate 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.
Hepatic Impairment: Impaired liver function is not expected to influence pamidronate pharmacokinetics as hepatic and metabolic clearance of pamidronate are insignificant. Pamidronate thus displays little potential for drug interactions at either the metabolic or protein binding level.
Indications And Clinical Uses: Tumor-induced hypercalcemia following adequate saline rehydration. Prior to treatment with pamidronate, renal excretion of excess calcium should be promoted by restoring and maintaining adequate fluid balance and urine output.
Conditions associated with increased osteoclast activity: predominantly lytic bone metastases and multiple myeloma.
Symptomatic Paget’s disease of bone.
Contra-Indications: Known or suspected hypersensitivity to pamidronate, to any of its components (see Supplied), or to other bisphosphonates.
Manufacturers’ Warnings In Clinical States: Pamidronate must never be given as a bolus injection since severe local reactions and thrombophlebitis may result from high local concentrations.
Pamidronate should always be diluted and administered as a slow i.v. infusion (see Dosage). Regardless of the volume of solution in which pamidronate is diluted, slow i.v. infusion is absolutely necessary for safety.
Pamidronate should not be given together with other bisphosphonates to treat hypercalcemia since the combined effects of these agents are unknown.
Pamidronate should not be mixed with calcium-containing i.v. infusions.
Precautions: It is essential in the initial treatment of tumor-induced hypercalcemia that i.v. rehydration be instituted to restore urine output. Patients should be hydrated adequately throughout treatment but overhydration must be avoided.
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.
Although pamidronate is excreted unchanged by the kidney (see Pharmacology), the drug has been used without apparent increase in adverse effects in patients with significantly elevated plasma creatinine levels (including patients undergoing renal replacement therapy with both hemodialysis and peritoneal dialysis). However, experience with pamidronate in patients with severe renal impairment (serum creatinine >440 mol/L, or 5 mg/dL in TIH patients; >180 mol/L, or 2 mg/dL in multiple myeloma patients) is limited. If clinical judgment determines that the potential benefits outweigh the risk in such cases, pamidronate should be used cautiously and renal function carefully monitored.
Patients with Paget’s disease of the bone, who are at risk of calcium or vitamin D deficiency, should be given oral calcium supplements and vitamin D to minimize the risk of hypocalcemia.
Patient Monitoring: Patients should have standard laboratory (serum creatinine and BUN) and clinical renal function parameters periodically evaluated, especially those receiving frequent pamidronate 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 tumor-induced hypercalcemia). Fluid balance (urine output, daily weights) should also be followed carefully. If there is deterioration of renal function during pamidronate therapy, the infusion must be stopped.
Serum electrolytes, calcium and phosphate should be monitored following initiation of therapy with pamidronate. 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 tumor-induced hypercalcemia, either ionized calcium or total serum calcium corrected (adjusted) for albumin should be monitored during treatment with pamidronate. 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.
Drug Interactions: Pamidronate has been used concomitantly with the following medications without evidence of significant adverse interactions (see Pharmacology): aminoglutethimide, cisplatin, corticosteroids, cyclophosphamide, cytarabine, doxorubicin, etoposide, fluouracil, loop diuretics, megestrol, melphalan, methotrexate, mitoxantrone, paclitaxel, tamoxifen, vinblastine, vincristine, and, in patients with severe hypercalcemia, calcitonin or mithramycin.
Pregnancy: There is no clinical evidence to support the use of pamidronate in pregnant women. Therefore, pamidronate should not be administered during pregnancy except for life-threatening hypercalcemia.
In animal experiments, pamidronate was not teratogenic and did not affect general reproductive performance or fertility. In rats, prolonged parturition and reduced pup survival were probably caused by a decrease in maternal serum calcium levels. The fertility of the pups was also reduced. Pamidronate crosses the placental barrier and accumulates in fetal bone.
Lactation: There is no clinical experience with pamidronate in lactating women and it is not known whether pamidronate passes into breast milk. A study in lactating rats has shown that pamidronate passes into the milk. Mothers treated with pamidronate should therefore not breast-feed their infants.
Children: The safety and efficacy of pamidronate in children have not been established. Until further experience is gained, pamidronate is only recommended for use in adult patients.
Occupational Hazards: In rare cases, somnolence and/or dizziness may occur, in which case the patient should not drive, operate potentially dangerous machinery or engage in other activities that may be hazardous.
Adverse Reactions: Adverse reactions with pamidronate are usually mild and transient. The most common adverse reactions are influenza-like symptoms and mild fever (an increase in body temperature of>1°C, which may last up to 48 hours). Fever usually resolves spontaneously and does not require treatment. Acute “influenza-like” reactions usually occur only with the first pamidronate infusion.
Adverse experiences by body system (Frequency estimate: Frequent: >10%; Occasional: >1% to 10%; Rare: >0.001% to 1%; Isolated cases:
Body as a Whole: Frequent: fever and influenza-like symptoms sometimes accompanied by malaise, rigor, fatigue and flushes.
Isolated cases: allergic reaction (swollen and itchy eyes, runny nose and scratchy throat).
Local Reactions: Occasional: reactions at the infusion site: pain, redness, swelling, induration, phlebitis, thrombophlebitis.
Musculoskeletal: Occasional: transient bone pain, arthralgia, myalgia, generalized pain, skeletal pain. Rare: muscle cramps.
Gastrointestinal: Occasional: nausea, vomiting. Rare: anorexia, abdominal pain, diarrhea, constipation, dyspepsia. Isolated cases: gastritis.
CNS: Occasional: headache. Rare: symptomatic hypocalcemia (paresthesia, tetany), agitation, confusion, dizziness, insomnia, somnolence, lethargy. Isolated cases: seizures, visual hallucinations in one case.
Blood: Occasional: lymphocytopenia. Rare: anemia, leukopenia. Isolated cases: thrombocytopenia. One case of acute lymphoblastic leukemia has been reported in a patient with Paget’s disease. The causal relationship to the treatment or the underlying disease is unknown.
Cardiovascular: Rare: hypotension, hypertension. Isolated cases: left ventricular failure (dyspnea, pulmonary edema), congestive heart failure (edema) due to fluid overload.
Respiratory: Isolated cases: adult respiratory distress syndrome, interstitial pneumonitis.
Renal: Isolated cases: hematuria, acute renal failure, deterioration of pre-existing renal disease.
Skin: Rare: rash, pruritus.
Special Senses: Isolated cases: conjunctivitis, uveitis (iritis, iridocyclitis), scleritis, episcleritis, xanthopsia.
Others: Isolated cases: reactivation of herpes simplex and herpes zoster.
Biochemical Changes: Frequent: hypocalcemia, hypophosphatasemia. Occasional: hypomagnesemia. Rare: hyperkalemia, hypokalemia, hypernatremia, symptomatic hypocal- cemia. Isolated cases: abnormal liver function test results, increase in serum creatinine and urea.
Many of these adverse events may have been related to the underlying disease.
Other adverse reactions reported rarely in postmarketing use include: allergic reaction, anaphylactic shock (very rare), anaphylactic reactions, bronchospasm (dyspnea) and Quincke’s edema.
Tumor-induced Hypercalcemia and Paget’s Disease: Adverse experiences considered to be related to pamidronate occurring in Â³1% patients in the specified indication.
Deterioration of renal function has been noted in patients treated with bisphosphonates. Since many patients with tumor-induced hypercalcemia have compromised renal function prior to receiving antihypercalcemia therapy (see 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 pamidronate where these data have been reported. The role of pamidronate in these changes in renal function is unclear, but merits cautious observation.
Deterioration of renal function (including renal failure) has been reported following long-term treatment with pamidronate in patients with multiple myeloma. However, underlying disease progression and/or concomitant complications were also present and therefore a causal relationship with pamidronate is unproven.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: 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 pamidronate since plasma calcium levels fall progressively for several days after treatment.
Dosage And Administration: Dosing recommendations differ for tumor-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.
Pamidronate must never be given as a bolus injection (see Warnings). Pamidronate should be administered in a compatible calcium-free i.v. solution (e.g., sterile normal saline or dextrose 5% in water). Pamidronate 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 pamidronate 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 tumor-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).
Renal Impairment: Pharmacokinetic studies indicate that no dose adjustment is necessary in patients with any degree of renal impairment when pamidronate is administered as recommended. However, until further experience is gained a maximum infusion rate of 22.5 mg/h is recommended in renally impaired patients (see Pharmacology and Precautions).
Dosing Guidelines for Tumor-induced Hypercalcemia: The recommended total dose of pamidronate for a treatment course depends upon initial plasma calcium levels. Doses should be adapted to the degree of severity of hypercalcemia to ensure normalization of plasma calcium and to optimize the duration of response. Rehydration with normal saline before treatment is recommended (see Precautions). A dose of 90 mg should be administered in 500 mL of infusion solution. The infusion rate should not exceed 22.5 mg/h.
The total dose for a treatment course may be given as a single infusion, or in multiple infusions spread over 2 to 4 consecutive days. The maximum dose of pamidronate per treatment course is 90 mg whether for initial or repeat treatment courses. Higher doses have not been associated with increased clinical effect.
Table III presents dosing guidelines for pamidronate derived from clinical data on uncorrected calcium values. These dose ranges also apply for calcium corrected for serum protein.
Decreases in serum calcium levels are generally observed within 24 to 48 hours after drug administration, with maximum lowering occurring by 3 to 7 days. If hypercalcemia recurs, or if plasma calcium does not decrease within 2 days, repeat infusions of pamidronate may be given, according to the dosing guidelines. The limited clinical experience available to date has suggested the possibility that pamidronate may produce a weaker therapeutic response with repeat treatment in patients with advanced cancer.
Dosing Guidelines for Bone Metastases and Multiple Myeloma: The recommended dose of pamidronate for the treatment of predominantly lytic bone metastases and multiple myeloma is 90 mg administered as a single infusion every 4 weeks. In patients with bone metastases who receive chemotherapy at 3-weekly intervals, pamidronate 90 mg may also be given every 3 weeks. A dose of 90 mg should normally be administered as a 2-hour infusion in 250 mL of infusion solution. However, in patients with multiple myeloma it is recommended not to exceed 90 mg in 500 mL over 4 hours.
Radiotherapy is the treatment of choice for patients with solitary lesions in weight bearing bones.
Dosing Guidelines for Paget’s Disease of Bone: The recommended total dose of pamidronate for a treatment course is 180 to 210 mg. This may be administered either as 6 doses of 30 mg once a week (total dose 180 mg). Alternatively, 3 doses of 60 mg may be administered every second week, but treatment should be initiated with a 30 mg dose (total dose 210 mg) as influenza-like reactions are common only with the first infusion. Each dose of 30 or 60 mg should be diluted in at least 250 or 500 mL, respectively, or normal saline or D5W. An infusion rate of 15 mg/h is recommended. This regimen, omitting the initial dose, can be repeated after 6 months until remission of disease is achieved, and when relapse occurs.
Reconstitution of Lyophilized Vials: Each vial of sterile lyophilized powder should be reconstituted with sterile water for injection prior to dilution.
Dilution of Reconstituted Solution for I.V. Infusion: Reconstituted solutions that have been prepared with sterile water for injection should be further diluted with either 0.9% sodium chloride or 5% dextrose injection prior to i.v. infusion administration. Diluted solutions prepared in this manner should be used within 24 hours from the time of initial entry (reconstitution) when stored at room temperature (15 to 30°C) due to the possibility of microbial contamination during preparation. Discard the unused portion.
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.
Incompatibilities: Pamidronate must not be mixed with calcium-containing infusion solutions, such as Ringer’s solution.
Availability And Storage: 30 mg: 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 2.
60 mg: Each vial of sterile, white to practically white lyophilized powder contains: pamidronate disodium (anhydrous) 60 mg and mannitol 400 mg. Phosphoric acid is employed to adjust the pH to 6.3. Preservative-free. Vials of 10 mL, cartons of 1.
90 mg: 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.
Protect vials from heat (store below 30°C).
AREDIA® Novartis Pharmaceuticals Pamidronate Disodium Bone Metabolism Regulator