PrPAMIDRONATE DISODIUM FOR INJECTION Pamidronate Disodium for Injection 3 mg, 6 mg, & 9 mg pamidronate disodium per mL Solution for Intravenous Injection (slow infusion only) Bone Metabolism Regulator Pharmaceutical Partners of Canada Inc. Date of Preparation: 45 Vogell Road, Suite 200 January 15, 2008 Richmond Hill, ON L4B 3P6 Submission Control No: 119282
Table of Contents
SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 3 WARNINGS AND PRECAUTIONS 3 ADVERSE REACTIONS 6 DRUG INTERACTIONS 10 DOSAGE AND ADMINISTRATION 10 OVERDOSAGE 13 ACTION AND CLINICAL PHARMACOLOGY 14 STORAGE AND STABILITY 17 DOSAGE FORMS, COMPOSITION AND PACKAGING 17
PHARMACEUTICAL INFORMATION 18 CLINICAL TRIALS 18 DETAILED PHARMACOLOGY 22 TOXICOLOGY 23 REFERENCES 25
PrPAMIDRONATE DISODIUM FOR INJECTION PART I: HEALTH PROFESSIONAL INFORMATION
| Route of Administration | Dosage Form/Strength | Clinically Relevant Nonmedicinal Ingredients |
| Intravenous (slow infusion only) | Solution/3 mg, 6 mg, & 9 mg pamidronate disodium per mL | Mannitol, USP Phosphoric Acid, NF Sodium Hydroxide, NF Water for Injection, USP For a complete listing see Dosage Forms, Composition, and Packaging section. |
Pamidronate Disodium for Injection is indicated for:
Tumour-induced hypercalcemia following adequate saline rehydration.
Prior to treatment with Pamidronate Disodium for Injection, 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. Pediatric
The safety and efficacy of Pamidronate Disodium for Injection in children has not been established. Until further experience is gained, Pamidronate Disodium for Injection is only recommended for use in adult patients.
Known or suspected hypersensitivity to Pamidronate Disodium for Injection (pamidronate disodium), to any of its components (see DOSAGE FORMS, COMPOSITION AND PACKAGING), or to other bisphosphonates.
General
Pamidronate Disodium for Injection should not be given together with other bisphosphonates to treat hypercalcemia since the combined effects of these agents are unknown. Pamidronate Disodium for Injection should not be mixed with calcium-containing intravenous infusions. 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 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.
Cardiovascular
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.
Hepatic
As there are no clinical data available in patients with severe hepatic insufficiency, no specific recommendations can be given for this patient population.
Osteonecrosis of the Jaw (ONJ)
Osteonecrosis of the jaw (ONJ) has been reported in patients with cancer receiving treatment regimens including bisphosphonates. Many of these patients were also receiving chemotherapy and corticosteroids. The majority of reported cases have been associated with dental procedures such as tooth extraction. Many had signs of local infection including osteomyelitis. A dental examination with appropriate preventive dentistry should be considered prior to treatment with bisphosphonates in patients with concomitant risk factors such as cancer, chemotherapy, head and neck radiotherapy, corticosteroids, poor oral hygiene. While on treatment, these patients should avoid invasive dental procedures if possible. For patients who develop ONJ while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are 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.
Renal
Bisphosphonates, including Pamidronate Disodium for Injection, have been associated with renal toxicity manifested as deterioration of renal function and potential renal failure. Due to the risk of clinically significant deterioration in renal function which may progress to renal failure, single doses of Pamidronate Disodium for Injection should not exceed 90 mg, and the recommended infusion time should be observed (see DOSAGE AND ADMINISTRATION). As with other i.v. bisphophonates, renal monitoring is recommended; for instance, measurement of serum creatinine prior to each dose of Pamidronate Disodium for Injection. Patients treated with Pamidronate Disodium for Injection for bone metastases should have the dose withheld if renal function has deteriorated (see DOSAGE AND ADMINISTRATION). Although pamidronate disodium is excreted unchanged by the kidney (see ACTIONS AND CLINICAL 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 disodium in patients with severe renal impairment (serum creatinine > 440 mmol/L or 5 mg/dL in TIH patients; > 180 mmol/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 Disodium for Injection should be used cautiously and renal function carefully monitored.
Special Populations
There is no clinical evidence to support the use of Pamidronate Disodium for Injection in pregnant women. Therefore, Pamidronate Disodium for Injection 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.
There is no clinical experience with Pamidronate Disodium for Injection in lactating women and it is not known whether pamidronate disodium passes into breast milk. A study in lactating rats has shown that pamidronate passes into the milk. Mothers treated with Pamidronate Disodium for Injection should therefore not breast-feed their infants.
The safety and efficacy of Pamidronate Disodium for Injection in children has not been established. Until further experience is gained, Pamidronate Disodium for Injection is only recommended for use in adult patients.
Effects on Ability to Drive or Use Machines
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.
Monitoring and Laboratory Tests
Patients should have standard laboratory (serum creatinine and BUN) and clinical renal function parameters periodically evaluated. Patients receiving frequent Pamidronate Disodium for Injection 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 Pamidronate Disodium for Injection. Fluid balance (urine output, daily weights) should also be followed carefully. If there is deterioration of renal function during Pamidronate Disodium for Injection therapy, the infusion must be stopped (see WARNINGS AND PRECAUTIONS, Renal). Pamidronate Disodium for Injection 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 Pamidronate Disodium for Injection. 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 Pamidronate Disodium for Injection. 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:
where:
cCa = tCa + (0.02 x [40 - ALB])
cCa = adjusted calcium concentration (mmol/L)
tCa = measured total calcium concentration (mmol/L) ALB = measured albumin concentration (g/L)
Adverse Drug Reaction Overview
Adverse reactions with Pamidronate Disodium for Injection are usually mild and transient. The most common adverse reactions are influenza-like symptoms and mild fever (an increase in body temperature of > 1degC, 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 disodium infusion.
Clinical Trial Adverse Drug Reactions
The tables below show the incidence of the more commonly observed adverse effects overall and by indication.
Adverse Experiences by Body System
Frequency estimate: very common > 10%; common 1-10%; uncommon 0.001-1%; rare 0.0001%-0.001%; very rare < 0.0001%, including isolated reports.
Body as a Whole:
Very common:fever and influenza-like symptoms sometimes accompanied by malaise, rigor, fatigue, and flushes
Local Reactions:
Common:reactions at the infusion site (pain, redness, swelling, induration, phlebitis, thrombophlebitis)
Musculoskeletal System:
Common:transient bone pain, arthralgia, myalgia, generalized pain Uncommon:muscle cramps
Gastrointestinal Tract:
Common:nausea, vomiting, anorexia, abdominal pain, diarrhea, constipation, gastritis Uncommon:dyspepsia
Central Nervous System:
Common:symptomatic hypocalcemia (paresthesia, tetany), headache, insomnia, somnolence Uncommon:seizures, agitation, dizziness, lethargy Very rare:confusion, visual hallucinations
Blood:
Common:anemia, thrombocytopenia, lymphocytopenia Very rare:leukopenia 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 System:
Common:hypertension Uncommon:hypotension
Very rare:left ventricular failure (dyspnea, pulmonary edema), congestive heart failure (edema) due to fluid overload
Respiratory System:
Rare:adult respiratory distress syndrome, interstitial pneumonitis
Renal System:
Uncommon:acute renal failure Rare:focal segmental glomerulosclerosis including the collapsing variant, nephrotic syndrome Very rare:hematuria, deterioration of pre-existing renal disease
Skin:
Common:rash Uncommon:pruritus Special Senses: Common:conjunctivitis Uncommon:uveitis (iritis, iridocyclitis) Very rare:scleritis, episcleritis, xanthopsia
Infection:
Very rare:reactivation of Herpes simplex and Herpes zoster
Immune System:
Uncommon:allergic reactions including anaphylactoid reactions, bronchospasm, dyspnoea, Quincke's (angioneurotic) edema Very rare:anaphylactic shock
Biochemical Changes:
Very common:hypocalcemia, hypophosphatemia Common:hypokalemia, hypomagnesemia, increase in serum creatinine Uncommon:abnormal liver function tests, increase in serum urea Very rare:hyperkalemia, hypernatremia
Many of these adverse events may have been related to the underlying disease.
Tumour-Induced Hypercalcemia and Paget's Disease
Adverse experiences considered to be related to pamidronate disodium occurring in >= 1% patients in the specified indication:
| Adverse Experiences | Tumour-Induced Hypercalcemia | Paget's Disease |
| no. of patients | n = 910 | n = 395 |
| Fever | (%) | (%) |
| 6.9 | 8.9 | |
| Headache | 0.0 | 4.8 |
| Hypocalcemia | 3.2 | 0.8 |
| Influenza-like symptoms | 0.0 | 11.9 |
| Infusion site reaction | 1.7 | 1.8 |
| Malaise | 0.0 | 5.8 |
| Myalgia | 0.0 | 2.0 |
| Nausea | 0.9 | 2.0 |
| Pain (bone) | 0.0 | 8.9 |
| Pain (unspecified) | 0.0 | 7.9 |
| Rigors | 0.0 | 2.8 |
Bisphosphonates, including pamidronate disodium, 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 pamidronate disodium where these data have been reported. As with other i.v. bisphosphonates, renal monitoring is recommended (see WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests).
Bone Metastases and Multiple Myeloma
The most commonly reported adverse experiences regardless of relationship to therapy are shown in the table below. Deterioration of renal function (including renal failure) has been associated with bisphosphonates including pamidronate disodium. Renal monitoring is recommended (see WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests).
| Commonly Reported Adverse Experiences in Three Controlled Trials (regardless of causality) | ||
| Bone Metastases and Multiple Myeloma Patients | ||
| Adverse Event | Pamidronate Disodium 90 mg | Placebo |
| n = 572 | n = 573 | |
| General | ||
| Asthenia | 16.4 | 15.4 |
| Fatigue | 30.4 | 35.5 |
| Fever | 35.5 | 30.5 |
| Metastases | 14.0 | 13.6 |
| Digestive System | ||
| Anorexia | 20.8 | 18.0 |
| Constipation | 27.6 | 30.9 |
| Diarrhea | 24.3 | 26.2 |
| Dyspepsia | 13.6 | 12.4 |
| Nausea | 48.4 | 46.4 |
| Pain (Abdominal) | 17.3 | 14.0 |
| Vomiting | 30.9 | 28.1 |
| Hemic and Lymphatic Systems | ||
| Anemia | 35.1 | 32.6 |
| Granulocytopenia | 16.8 | 17.3 |
| Thrombocytopenia | 11.0 | 13.1 |
| Musculoskeletal System | ||
| Myalgias | 22.6 | 16.9 |
| Skeletal Pain | 59.4 | 69.1 |
| CNS | ||
| Headache | 24.0 | 19.7 |
| Insomnia | 18.2 | 17.3 |
| Respiratory System | ||
| Coughing | 21.2 | 18.8 |
| Dyspnea | 23.3 | 18.7 |
| Commonly Reported Adverse Experiences in Three Controlled Trials (regardless of causality) | ||
| Bone Metastases and Multiple Myeloma Patients | ||
| Adverse Event | Pamidronate Disodium 90 mg | Placebo |
| Upper Respiratory Infection | 19.8 | 20.9 |
| Urogenital System | ||
| Urinary Tract Infection | 14.5 | 10.8 |
Postmarket Adverse Drug Reactions
A number of cases of osteonecrosis (primarily of the jaws) have been reported in association with pamidronate disodium since market introduction. Osteonecrosis of the jaws has other well documented multiple risk factors. It is not possible to determine if these events are related to pamidronate disodium or other bisphosphonates, to concomitant drugs or other therapies (e.g., chemotherapy, head and neck radiotherapy, corticosteroid), to patient's underlying disease, or to other co-morbid risk factors (e.g., anemia, infection, pre-existing oral disease).
Drug-Drug Interactions
Pamidronate disodium has been used concomitantly with the following medications without evidence of significant adverse interactions (see ACTIONS AND CLINICAL 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. Caution is warranted when Pamidronate Disodium for Injection is used with other potentially nephrotoxic drugs. In multiple myeloma patients, the risk of renal dysfunction may be increased when Pamidronate Disodium for Injection is used in combination with thalidomide.
Drug-Food Interactions
Interactions with food have not been established.
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.
Pamidronate Disodium for Injection should be administered in a compatible calcium-free intravenous solution (e.g., sterile normal saline or dextrose 5% in water). Pamidronate Disodium for Injection 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 Disodium for Injection 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).
Dilution of Pamidronate Disodium for Injection for I.V. Infusion
Pamidronate Disodium for Injection should be further diluted with either 0.9% w/v sodium chloride or 5% w/v dextrose injection prior to intravenous infusion administration. Diluted solutions prepared in this manner should be used within 24 hours from dilution when stored at room temperature (15-30degC) due to the possibility of microbial contamination during preparation. Discard the unused portion. As with all parenteral drug products, intravenous admixtures should be inspected visually for clarity, particulate matter, precipitate, discolouration and leakage prior to administration, whenever solution and container permit. Solutions showing haziness, particulate matter, precipitate, discolouration or leakage should not be used. Discard unused portions.
Pamidronate Disodium for Injection must not be mixed with calcium-containing infusion solutions, such as Ringer's solution.
Renal Impairment
Pamidronate Disodium for Injection should not be administered to patients with severe renal impairment (creatinine clearance < 30 mL/min) unless in cases of life-threatening tumour- induced hypercalcemia 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 Pamidronate Disodium for Injection. In patients receiving Pamidronate Disodium for Injection for bone metastases who show evidence of deterioration in renal function, Pamidronate Disodium for Injection 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/4 h (approximately 20 - 22 mg/h).
Hepatic Impairment
A pharmacokinetic study indicates that no dose adjustment is necessary in patients with mild to moderate abnormal hepatic function (see
).
Dosing Guidelines for Tumour-Induced Hypercalcemia
The recommended total dose of Pamidronate Disodium for Injection 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 WARNINGS AND PRECAUTIONS). A dose of 90 mg should be administered in 500 mL of infusion solution. The infusion rate should not exceed 22.5 mg/hour. The total dose for a treatment course may be given as a single infusion, or in multiple infusions spread over 2-4 consecutive days. The maximum dose of Pamidronate Disodium for Injection per treatment course is 90 mg whether for initial or repeat treatment courses. Higher doses have not been associated with increased clinical effect. The following table presents dosing guidelines for Pamidronate Disodium for Injection derived from clinical data on uncorrected calcium values. These dose ranges also apply for calcium corrected for serum protein.
| Tumour-Induced Hypercalcemia | ||||
| Initial Serum Calcium | Total Dose (mg) | Concentration of Infusate (mg/mL) | Maximum Infusion Rate (mg/h) | |
| (mmol/L) | (mg %) | |||
| Up to 3.0 | Up to 12.0 | 30 | 30 mg/125 mL | 22.5 mg/h |
| 3.0-3.5 | 12.0-14.0 | 30 or 60 | 30 mg/125 mL 60 mg/250 mL | 22.5 mg/h 22.5 mg/h |
| 3.5-4.0 | 14.0-16.0 | 60 or 90 | 60 mg/250 mL 90 mg/500 mL | 22.5 mg/h 22.5 mg/h |
| > 4.0 | > 16.0 | 90 | 90 mg/500 mL | 22.5 mg/h |
Decreases in serum calcium levels are generally observed within 24-48 hours after drug administration, with maximum lowering occurring by 3-7 days. If hypercalcemia recurs, or if plasma calcium does not decrease within 2 days, repeat infusions of Pamidronate Disodium for Injection may be given, according to the dosing guidelines. The limited clinical experience available to date has suggested the possibility that Pamidronate Disodium for Injection 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 Disodium for Injection 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 Disodium for Injection 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.
| Bone Metastases | ||
| Disease State | Dosing Schedule | Concentration of Infusate (mg/mL) |
| Bone metastases | 90 mg/2 hours every 3 *- 4 weeks | 90 mg/250 mL |
| Multiple myeloma | 90 mg/4 hours every 4 weeks | 90 mg/500 mL |
* for patients receiving chemotherapy every 3 weeks
Dosing Guidelines for Paget's Disease of Bone
The recommended total dose of Pamidronate Disodium for Injection for a treatment course is 180-210 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 mg or 60 mg should be diluted in at least 250 mL or 500 mL, respectively, of normal saline or D5W. An infusion rate of 15 mg per hour is recommended. This regimen, omitting the initial dose, can be repeated after 6 months until remission of disease is achieved, and when relapse occurs (see table below).
| Paget's Disease | |||
| Recommended total dose/treatment course : 180-210 mg | |||
| Regimen | Dosing Schedule | Concentration of Infusate (mg/mL) | Infusion Rate (mg/h) |
| Regimen 1 Total dose 180 mg | 30 mg once weekly for 6 weeks | 30 mg in >= 250-500 mL | 15 mg/h |
| Regimen 2 Total dose 210 mg | Infusions administered every 2 weeks; initial dose (week 1) = 30 mg; subsequent doses (weeks 3, 5 & 7) = 60 mg | 30/60 mg in >= 250-500 mL | 15 mg/h |
| Retreatment Regimen Total dose 180 mg | 60 mg every 2 weeks for a total of 3 infusions. | 60 mg in 500 mL | 15 mg/h |
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 Disodium for Injection since plasma calcium levels fall progressively for several days after treatment.
Mechanism of Action
Pamidronate disodium belongs to a class of bisphosphonates (previously termed diphosphonates), which inhibit bone resorption. The therapeutic activity of Pamidronate Disodium for Injection 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 pamidronate disodium 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.
In tumour-induced hypercalcemia, pamidronate disodium 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 disodium 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 Pamidronate Disodium for Injection therapy is initiated, patients should be adequately rehydrated with isotonic saline (0.9%) (see WARNINGS AND PRECAUTIONS). Normalization of plasma calcium levels by Pamidronate Disodium for Injection in adequately hydrated patients may also normalize plasma parathyroid hormone (PTH) which is suppressed by hypercalcemia. The duration of normocalcemia following Pamidronate Disodium for Injection 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 - 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 disodium dose: in patients treated with single i.v. infusions of 30, 45, 60, and 90 mg pamidronate disodium, 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 pamidronate disodium in relapsed tumour-induced hypercalcemia is limited. In general, with retreatment, the response is similar to that with the first pamidronate disodium treatment, unless the cancer has progressed significantly. Therefore, pamidronate disodium 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 pamidronate disodium in advanced cancer are unknown. In severe forms of hypercalcemia, the dose of Pamidronate Disodium for Injection may be increased, or eventually, a combination drug therapy should be considered (see WARNINGS AND PRECAUTIONS).
Lytic bone metastases in cancer patients are caused by increased osteoclast activity. Metastatic tumour cells secrete paracrine factors which stimulate neighbouring 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 pamidronate disodium 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 disodium 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 disodium-treated patients.
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 Disodium for Injection. Repeated infusions of pamidronate disodium do not lead to reduced efficacy. In addition, patients resistant to etidronate and calcitonin respond well to Pamidronate Disodium for Injection 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 pamidronate disodium 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.
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 hour. 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 (t1/2a = 1.6 h; t1/2b = 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.
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 pamidronate disodium 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 pamidronate disodium is administered on a monthly basis, drug accumulation is not expected. No changes in pamidronate disodium dosing regimen are recommended for patients with mild to moderate abnormal hepatic function (see DOSAGE AND ADMINISTRATION). Hepatic and metabolic clearance of pamidronate disodium are insignificant. Pamidronate disodium thus displays little potential for drug interactions at either the metabolic or protein binding level.
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).
Protect vials from heat. Store at room temperature (15-30degC).
Composition
Each vial contains 3 mg/mL Pamidronate disodium (formed from 2.53 mg pamidronic acid and 0.86 mg sodium hydroxide); Mannitol, USP, 47 mg/mL; Water for Injection, USP; and for pH adjustment Phosphoric Acid, NF.
Each vial contains 6 mg/mL Pamidronate disodium (formed from 5.05 mg pamidronic acid and 1.72 mg sodium hydroxide); Mannitol, USP, 40 mg/mL; Water for Injection, USP; and for pH adjustment Phosphoric Acid, NF.
Each vial contains 9 mg/mL Pamidronate disodium (formed from 7.58 mg pamidronic acid and 2.58 mg sodium hydroxide); Mannitol, USP, 37.50 mg/mL; Water for Injection, USP; and for pH adjustment Phosphoric Acid, NF.
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452000 10 mL plastic single-dose vials packaged individually
:
452005 10 mL plastic single-dose vials packaged individually
:
452010 10 mL plastic single-dose vials packaged individually Discard the unused portion. Vial stoppers do not contain natural rubber latex.