PRODUCT MONOGRAPH

Prpms-PAMIDRONATE (Pamidronate disodium for injection, pms standard) 15mg/vial, 30 mg/vial, 60 mg/vial and 90 mg/vial For intravenous infusion only

Bone Metabolism Regulator

PHARMASCIENCE INC. Date of Preparation:

6111 Royalmount Ave., Suite 100 July 2, 2002 Montreal, Quebec H4P 2T4

Date of Revision:

www.pharmascience.com August 8, 2005

Control No. 097248

Table of Contents

PART I: HEALTH PROFESSIONAL INFORMATION

SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 4 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 7 DRUG INTERACTIONS 11 DOSAGE AND ADMINISTRATION 11 OVERDOSAGE 16 ACTION AND CLINICAL PHARMACOLOGY 16 STORAGE AND STABILITY 20 DOSAGE FORMS, COMPOSITION AND PACKAGING 20

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION 22 CLINICAL TRIALS 23 DETAILED PHARMACOLOGY 27 TOXICOLOGY 28 REFERENCES 32

PART III: CONSUMER INFORMATION

Prpms-PAMIDRONATE (Pamidronate disodium for injection, pms standard) 15mg/vial, 30 mg/vial, 60 mg/vial and 90 mg/vial For intravenous infusion only

Bone Metabolism Regulator PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

CONTRAINDICATIONS

Known or suspected hypersensitivity to pamidronate disodium, to any of the components of the drug product (For a complete listing, see the Dosage Forms, Composition and Packaging section of the product monograph), or to other bisphosphonates.

WARNINGS AND PRECAUTIONS

General

Pamidronate disodium MUST NEVER BE GIVEN AS A BOLUS INJECTION SINCE SEVERE LOCAL REACTIONS AND THROMBOPHLEBITIS MAY RESULT FROM HIGH LOCAL CONCENTRATIONS.

Pamidronate disodium SHOULD ALWAYS BE DILUTED AND ADMINISTERED AS A SLOW INTRAVENOUS INFUSION (see Dosage and Administration). REGARDLESS OF THE VOLUME OF SOLUTION IN WHICH Pamidronate disodium IS DILUTED, SLOW INTRAVENOUS INFUSION IS ABSOLUTELY NECESSARY FOR SAFETY.

Pamidronate disodium should not be given together with other bisphosphonates to treat hypercalcemia since the combined effects of these agents are unknown. Pamidronate disodium should not be mixed with calcium-containing intravenous infusions.

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.

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.

Renal

Biphosphonates, including Pamidronate disodium, 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 should not exceed 90 mg, and the recommended infusion time should be observed (see Dosage and Administration). As with other I.V. biphosphonates renal monitoring is recommended, for instance, measurement of serum creatinine prior to each dose of pamidronate disodium. Patients treated with pamidronate disodium for bone metatases should have the dose withheld if renal function has deteriorated (see Dosage and Administration). Pamidronate disodium is excreted intact primarily via the kidney, thus the risk of renal adverse reactions may be greater in patients with impaired renal function. 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. 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 :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 disodium should be used cautiously and renal function carefully monitored.

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/Biliary/Pancreatic

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

Osteonecrosis of the jaw (ONJ) has been reported in patients with cancer receiving treatment regimens including biphosphonates. 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 biphosphonates in patients with concomitant risk factors (e.g. 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 biphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of biphosphonate treatment reduces the risk of ONJ. Clinical judgement of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.

Patient Monitoring

Patients should have standard laboratory (serum creatinine and BUN) and clinical renal function parameters periodically evaluated, especially those receiving frequent pamidronate disodium 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). Fluid balance (urine output, daily weights) should also be followed carefully. If there is deterioration of renal function during pamidronate disodium therapy, the infusion must be stopped. Serum electrolytes, calcium and phosphate should be monitored following initiation of therapy with pamidronate disodium. 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. 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 x [40 - ALB]) where: cCa= adjusted calcium concentration (mmol/L) tCa= measured total calcium concentration (mmol/L) ALB= measured albumin concentration (g/L)

Special Populations: Use in Pregnancy:

There is no clinical evidence to support the use of pamidronate disodium in pregnant women. Therefore, pamidronate disodium 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 disodium 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 should therefore not breast feed their infants.

Pediatric Use

The safety and efficacy of pamidronate disodium in children has not been established. Until further experience is gained, pamidronate disodium is only recommended for use in adult patients.

DRUG INTERACTIONS

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 is used with other potentially nephrotoxic drugs In multiple myelomapatients, the risk of renal dysfunction may be increased when Pamidronate disodium is used in combination with thalidomide.

DOSAGE AND ADMINISTRATION

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.

Dosing Considerations

Patients with renal impairment Patients with hepatic impairment Patients with tumour-induced hypercalcemia Patients with bone metastases and multiple myeloma Patients with Paget's Disease of bone

Recommended Dose and Dosage Adjustment

pms-PAMIDRONATE (pamidronate disodium) must never be given as a bolus injection (see Warnings and Precautions).

pms-PAMIDRONATE should be administered in a compatible calcium-free intravenous solution (e.g., sterile normal saline or dextrose 5% in water). Regardless of the volume of solution in which pamidronate disodium is diluted, slow intravenous infusion is absolutely necessary for safety.

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 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).

Renal Impairment

Pamidronate disodium 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 pamidronate disodium. In patients receiving pamidronate disodium for bone metatases who show evidence of deterioration in renal function, pamidronate disodium 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).

Hepatic Impairment

A pharmacokinetic study indicates that no dose adjustment is necessary in patients with mild to moderate abnormal hepatic function (see Action & Clinical Pharmacology).

Tumour-Induced Hypercalcemia

The recommended total dose of pms-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 Warnings & 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 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 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 24-48 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 may be given, according to the dosing guidelines. The limited clinical experience available to date has suggested the possibility that pamidronate disodium may produce a weaker therapeutic response with repeat treatment in patients with advanced cancer.

Bone Metastases And Multiple Myeloma

The recommended dose of pms-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 disodium 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.

*for patients receiving chemotherapy every 3 weeks Paget's Disease of Bone The recommended total dose of pms-PAMIDRONATE 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).

Administration

Reconstitution

Each vial of sterile lyophilized powder should be reconstituted with sterile water for injection prior to dilution as givent in the following table:

Dilution of Reconstituted Solution for Intravenous Infusion

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 recontitution and dilution. If not used immediately, the duration and conditions of storage prior to use are the care providor'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.

Incompatibilities of the reconstituted solution

Pamidronate forms complexes with divalent cations. For this reason, pms-PAMIDRONATE reconstituted solution must not be mixed with calcium-containing intravenous solutions such as Ringer's solution. pms-PAMIDRONATE reconstituted solution should be diluted with 0.9% w/v sodium chloride solution or 5% w/v glucose solution. Studies with containers and infusion sets/devices for infusion made of glass, polyethylene and polyvinylchloride have been shown to be compatible with pms-PAMIDRONATE solution.

OVERDOSAGE

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 since plasma calcium levels fall progressively for several days after treatment.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Pamidronate disodium belongs to a class of bisphosphonates (previously termed diphosphonate), which inhibit bone resorption. The therapeutic activity of pamidronate disodium is attributable to its potent anti-osteoclastic activity on bone. Pamidronate disodium is a second-generation bisphosphonate. These agents are synthetic analogues of pyrophosphate and specifically inhibit bone resorption. First generation compounds such as 1-hydroxyethylidene-1, 1-biphosphonic acid (HEBP or etidronate disodium) block resorption but may also inhibit bone mineralization. Pamidronate disodium, a second generation bisphosphonate, inhibits bone resorption at doses that do not appear to affect the mineralization of newly-formed osteoid tissue and thus constitutes a rational treatment for pathological bone resorption. The predominant mode of action appears to be a local, direct effect; bisphosphonates complex tightly to, and inhibit the formation and dissolution of, hydroxyapatite crystals. 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.

Tumour-induced hypercalcemia

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 therapy is initiated, patients should be adequately rehydrated with isotonic saline (0.9%) (see Precautions). Normalization of plasma calcium levels by pamidronate disodium in adequately hydrated patients may also normalize plasma parathyroid hormone (PTH) which is suppressed by hypercalcemia. The duration of normocalcemia following pamidronate disodium 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 may be increased, or eventually, a combination drug therapy should be considered (see Warnings and Precautions).

Bone metastases and multiple myeloma

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 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

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. Repeated infusions of pamidronate disodium do not lead to reduced efficacy. In addition, patients resistant to etidronate and calcitonin respond well to pamidronate disodium 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.

Pharmakokinetics

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. 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. Pamidronate disodium is administered by intravenous infusion (direct exposure). 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 of distribution 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. Pamidronate does not appear to be metabolized. 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. As pamidronate has a strong affinity for calcified tissues, total elimination is not observed within the time frame of experimental studies. Urinary elimination is biphasic (t1/2"=1.6 h; t1/2$ = 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.

Special Populations and Conditions

Hepatic Impairment

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).

Renal Impairment

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).

STORAGE AND STABILITY

Protect vials from heat and store between 15degand 30degC. Reconstituted solutions should be used within 24 hours from initial entry (reconstitution) when stored at room temperature (15/ to 30/C).

DOSAGE FORMS, COMPOSITION AND PACKAGING

Availability of Dosage Forms

pms-PAMIDRONATE (pamidronate disodium) 15 mg vials for injection:

Each vial of white to practically white lyophilisate contains pamidronate disodium (15 mg). Available in cartons of 1 vial and 2 vials.

pms-PAMIDRONATE 30 mg vials for injection:

Each vial of white to practically white lyophilisate contains pamidronate disodium (30 mg). Available in cartons of 2 vials.

pms-PAMIDRONATE 60 mg vials for injection:

Each vial of white to practically white lyophilisate contains pamidronate disodium (60 mg). Available in cartons of 1 vial.

pms-PAMIDRONATE 90 mg vials for injection:

Each vial of white to practically white lyophilisate contains pamidronate disodium (90 mg). Available in cartons of 1 vial.

Composition

pms-PAMIDRONATE 15 mg/vial for injection:

Each vial of sterile lyophilized powder contains anhydrous pamidronate disodium (15 mg) and mannitol (235 mg). Phosphoric acid is employed to adjust the pH to 6.3.

pms-PAMIDRONATE 30 mg/vial for injection:

Each vial of sterile lyophilized powder contains anhydrous pamidronate disodium (30 mg) and mannitol (470 mg). Phosphoric acid is employed to adjust the pH to 6.3.

pms-PAMIDRONATE 60 mg/vial for injection:

Each vial of sterile lyophilized powder contains anhydrous pamidronate disodium (60 mg) and mannitol (400 mg). Phosphoric acid is employed to adjust the pH to 6.3.

pms-PAMIDRONATE 90 mg/vial for injection:

Each vial of sterile lyophilized powder contains anhydrous pamidronate disodium (90 mg) and mannitol (375 mg). Phosphoric acid is employed to adjust the pH to 6.3. These preparations contain NO preservatives.