The active ingredient is disodium-3-amino-1-hydroxypropylidene-1,1-bisphosphonate pentahydrate.

DESCRIPTION

Disodium pamidronate is a white crystalline powder that is soluble in water or 2N sodium hydroxide, poorly soluble in 0.1N hydrochloric acid and 0.1N acetic acid and virtually insoluble in organic solvents. The pH of a 1% solution in water is approximately 8.2. Molecular formula: C3H9NO7P2Na2.5H2O

Aredia is a lyophilised powder for injection containing 15 mg, 30 mg, 60 mg or 90 mg disodium pamidronate (calculated as the anhydrous form), mannitol and phosphoric acid. This powder, after reconstitution and appropriate dilution, is for slow intravenous infusion.

PHARMACOLOGY

Disodium pamidronate is a potent inhibitor of osteoclastic bone resorption. This anti- resorptive activity is responsible for its therapeutic effect. Disodium pamidronate inhibits the formation and dissolution of calcium apatite crystals in vitro. The physico-chemical interaction of disodium pamidronate with apatite crystals accounts for its avid binding to bone, but the mechanism for the anti-osteoclastic activity at the cellular level is unknown at present. Pamidronate suppresses the accession of osteoclast precursors onto the bone and their subsequent transformation into the mature, resorbing osteoclasts. However, the local and direct antiresorptive effect of bone-bound bisphosphonate appears to be the predominant mode of action in vitro and in vivo. Changes in biochemical parameters, which reflect a decrease in bone resorption and improvements secondary to normalisation of plasma calcium, include: decreased urinary hydroxyproline, urinary calcium and serum phosphate. Hypercalcaemia can lead to haemoconcentration by inhibition of tubular reabsorption of water and to decreased GFR, both of which lead to increased plasma creatinine concentration. A direct consequence of treatment with Aredia is improvement in GFR and decreased creatinine levels in most patients. Paget's disease of bone, which is characterised by local areas of increased bone resorption and formation with qualitative changes in bone remodeling, responds well to treatment with Aredia. Clinical and biochemical remission of the disease has been demonstrated by bone scintigraphy, decreases in urinary hydroxyproline and serum alkaline phosphatase, and by symptomatic improvement.

Pamidronate has a strong affinity for calcified tissues, and total elimination of pamidronate from the body is not observed within the time-frame of experimental studies. Calcified tissues are therefore regarded as the site of "apparent elimination".

Pamidronate disodium is given by intravenous infusion. By definition, absorption is complete at the end of the infusion.

Plasma concentrations of pamidronate rise rapidly after the start of an infusion and fall rapidly when the infusion is stopped. The apparent half-life in plasma is about 0.8 hours. Apparent steady-state concentrations are therefore achieved with infusions of more than about 2 - 3 hours duration. Peak plasma concentrations of about 10 nmol/mL pamidronate are achieved after an intravenous infusion of 60 mg given over 1 hour. In animals and in man, a similar percentage of the dose is retained in the body after each dose of pamidronate disodium. Thus the accumulation of pamidronate in bone is not capacity- limited and is dependent solely on the total cumulative dose administered. Clinicians should be aware that some 50% of the infused material will remain in the patient's skeleton for years. The percentage of circulating pamidronate bound to plasma proteins is relatively low (about 54%), and increases when calcium concentrations are pathologically elevated.

Pamidronate does not appear to be eliminated by biotransformation. After an intravenous infusion, about 20 - 55% of the dose is recovered in the urine within 72 hours as unchanged pamidronate. Within the time-frame of experimental studies the remaining fraction of the dose is retained in the body. The percentage of the dose retained in the body is independent of both the dose (range 15 - 180 mg) and the infusion rate (range 1.25 - 60 mg/h). The elimination of pamidronate in the urine is biexponential, with apparent half-lives of about 1.6 and 27 hours. The apparent renal clearance is about 54 mL/min, and there is a tendency for the renal clearance to correlate with creatinine clearance.

Hepatic and metabolic clearance of pamidronate are insignificant. Aredia thus displays little potential for drug-drug interactions both at the metabolic level and at the level of protein binding (see above).

A pharmacokinetic study conducted in 19 patients with cancer showed no differences in plasma AUC of pamidronate between patients with normal renal function and patients with mild (creatinine clearance 61-90 mL/min) to moderate (creatinine clearance 30-60 mL/min) renal impairment, following administration of a single 90 mg intravenous dose. 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 "PRECAUTIONS" and "DOSAGE AND ADMINISTRATION"].

A single 90 mg dose of Aredia was infused intravenously over 4 hours in male cancer patients at risk of bone metastases (n = 14), some of whom (n= 8) had mild to moderate hepatic impairment (AST 86 u/L and/or ALT 60 u/L). There was an average 60% increase in AUC 0-36h and C max and the drug was cleared more slowly from plasma (within 36 hours versus within 12 hours) in patients with hepatic impairment compared with other patients. The increase in AUC was statistically significant (p = 0.02). It was not determined if the percentage of the dose retained in the body is increased in hepatic impairment. Patients with hepatic impairment did not experience an increased incidence of adverse events over the limited observation period of the study (6 days). If Aredia is administered monthly, the pharmacokinetic changes in mild to moderate hepatic impairment are unlikely to be clinically relevant (see "DOSAGE AND ADMINISTRATION").

CLINICAL TRIALS

Clinical trials in patients with advanced multiple myeloma or predominantly lytic bone metastases from breast cancer:

Three randomised, double-blind, placebo-controlled trials investigated the effects of Aredia on the occurrence of skeletal-related events (SREs: pathological fractures, radiation therapy or surgery to bone, spinal cord compression) and pain score in patients with multiple myeloma and in breast cancer patients with predominantly lytic bone metastases. In the first trial, patients with advanced multiple myeloma received 90 mg of Aredia or placebo as a monthly 4-hour intravenous infusion for 9 months, in addition to antimyeloma therapy. Patients had received appropriate chemotherapy for a minimum 2 months prior to entry into the trial. A total of 196 Aredia patients and 181 placebo patients were evaluable for efficacy. Compared with placebo, significantly fewer patients in the Aredia group had any SRE (24% vs 41%, P<0.001) and the mean skeletal morbidity rate was lower (1.1 vs 2.1 SREs/year, P<0.02). The times to first SRE, pathological fracture and radiation therapy to bone were significantly longer in the Aredia group (P=0.001, 0.006, and 0.046, respectively). Fewer Aredia patients suffered any pathological fracture (17% vs 30%, P=0.004) or needed radiation therapy to bone (14% vs 22%, P=0.049). In patients with pain at baseline, pain scores at the last assessment were significantly reduced with Aredia treatment (P<0.05) but not with placebo. Patients completing the first part of the trial continued to receive 4-weekly infusions of Aredia or placebo for a further 11 infusions during the maintenance phase of the trial (observation period). After 21 months, the proportion of patients with any SRE was significantly less in the Aredia group than in the placebo group (P=0.015), the mean skeletal morbidity rate was lower (P=0.008) and the time to first SRE was longer (P=0.016). There was an increased incidence of renal toxicity observed in patients receiving Aredia during the observation period of the trial, although this was not statistically significantly different from the placebo group (see "DOSAGE AND ADMINISTRATION"). In the second and third trials, breast cancer patients with at least one predominantly osteolytic bone metastasis received 90 mg of Aredia or placebo as a 2-hour intravenous infusion every 3 or 4 weeks for 12 months. Breast cancer patients in the second trial were treated with cytotoxic chemotherapy. A total of 185 Aredia patients and 195 placebo patients were evaluable for efficacy. Compared with placebo, significantly fewer patients in the Aredia group had any SRE (43% vs 56%, P<0.01), the mean skeletal morbidity rate was lower (2.5 vs 3.3 SREs/year, P<0.01) and the time to first SRE was longer (median 13.1 vs 7.0 months, P<0.01). Fewer patients in the Aredia group than the placebo group needed radiation therapy to bone, the mean skeletal morbidity rate for radiation therapy to bone was lower and the time to first radiation therapy was longer (P<0.01 for each). The complete plus partial response rate for bone lesions was 33% in Aredia patients and 18% in placebo patients (P=0.001). Breast cancer patients in the third trial were treated with hormonal therapy at trial entry. A total of 182 Aredia patients and 189 placebo patients were evaluable for efficacy. The mean skeletal morbidity rate for radiation therapy to bone was lower with Aredia treatment than with placebo (0.6 vs 1.1 SREs/year, P<0.01) and the time to first radiation therapy was longer (P<0.01; median time not reached during the trial). The proportion of patients having any radiation to bone was lower with Aredia treatment than with placebo (21% vs 33% at 12 months, p<0.01). There was no statistically significant difference in the proportion of patients with any SRE, in the skeletal morbidity rate for any SRE, in the time to first SRE and in the bone lesion response rate. In both trials, pain scores (mean change from baseline at last measurement) showed that breast cancer patients treated with Aredia had significantly less pain than patients treated with placebo (P<0.05 for chemotherapy patients, P<0.01 for hormonal therapy patients).

CONTRAINDICATIONS

Aredia is contraindicated: in patients with known hypersensitivity to pamidronate or other bisphosphonates, or to any of the other ingredients in the formulation of Aredia in pregnancy in breastfeeding.

PRECAUTIONS

The safety and efficacy of Aredia in the treatment of hyperparathyroidism has not been established. Patients must be assessed prior to administration of Aredia to assure that they are appropriately hydrated. This is especially important for patients receiving diuretic therapy. The onset of action of Aredia is not immediate. Therefore, Aredia should be considered as only one component of the acute clinical management of tumour-induced hypercalcaemia.

Bisphosphonates, including Aredia, have been associated with renal toxicity manifested as deterioration of renal function and potential renal failure. Aredia is excreted intact primarily via the kidney and, therefore, the risk of renal adverse reactions may be greater in patients with impaired renal function. Renal deterioration, progression to renal failure and dialysis have been reported 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. Aredia should not be administered to patients with severe renal impairment (creatinine clearance < 30 mL/min) except in cases of life-threatening tumour-induced hypercalcaemia where the benefit outweighs the potential risk. Although a pharmacokinetic study conducted in patients with cancer and normal or impaired renal function (see "Pharmacokinetics - Renal impairment") indicates that a dose reduction may not be necessary in patients with mild (creatinine clearance 61-90 mL/min) to moderate (creatinine clearance 30-60 mL/min) renal impairment, there are insufficient clinical data on the use of Aredia in such patients to support this recommendation (see "DOSAGE AND ADMINISTRATION").

As there are no clinical data available in patients with severe hepatic impairment, no specific recommendations can be given for this patient population but caution should be exercised when Aredia is given to these patients (see Dosage and administration and Pharmacokinetics properties).

Osteonecrosis of the jaw (ONJ) has been reported predominantly in cancer patients treated with bisphosphonates, including Aredia. Many of these patients were also receiving chemotherapy and corticosteroids. Many had signs of local infection including osteomyelitis. Presentation may include jaw pain, toothache, exposed bone, altered sensation and local infection, including osteomyelitis. The condition may result in chronic pain, may be resistant to treatment, and in serious cases may result in disfigurement. Post-marketing experience and the literature suggest a greater frequency of reports of ONJ based on tumour type (advanced breast cancer, multiple myeloma), and dental status (dental extraction, periodontal disease, local trauma including poorly fitting dentures). Cancer patients should maintain good oral hygiene and should have a dental examination with preventive dentistry prior to treatment with bisphosphonates. Patients and their dentists should be advised of the reports of osteonecrosis of the jaw so that dental symptoms developing during treatment can be fully assessed before commencing dental procedures. While on treatment, these patients should avoid invasive dental procedures if possible. For patients who develop osteonecrosis of the jaw 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 osteonecrosis of the jaw. Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.

Atypical subtrochanteric and diaphyseal femoral fractures have been reported with bisphosphonate therapy, primarily in patients receiving long-term treatment for osteoporosis. These transverse or short oblique fractures can occur anywhere along the femur from just below the lesser trochanter to just above the supracondylar flare. These fractures occur after minimal or no trauma and some patients experience thigh or groin pain, often associated with imaging features of stress fractures, weeks to months before presenting with a completed femoral fracture. Fractures are often bilateral; therefore the contralateral femur should be examined in Aredia-treated patients, who have sustained a femoral shaft fracture. Poor healing of these fractures has also been reported. Discontinuation of Aredia therapy in patients suspected to have an atypical femur fracture should be considered pending evaluation of the patient, based on an individual benefit risk assessment. Reports of atypical femoral fracture have been received in patients treated with Aredia. During Aredia treatment patients should be advised to report any thigh, hip or groin pain and any patient presenting with such symptoms should be evaluated for an incomplete femur fracture.

In post-marketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates including Aredia. 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 had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate.

Patients should be warned that 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. This effect rarely lasts more than 24 hours. Outpatients who have received a pamidronate infusion should not drive themselves home.

The toxicity of pamidronate is characterised by direct (cytotoxic) effects on organs with a copious blood supply, such as the stomach, lungs and kidneys. In animal studies with intravenous administration, renal tubular lesions were the prominent and consistent untoward effects of treatment.

There is a lack of long term toxicology data from animal studies, with intravenous administration. In a 104-week carcinogenicity study of daily oral administration to rats, there was a positive dose-response relationship for benign phaeochromocytoma in male animals. Although this condition was also observed in female animals, the incidence was not statistically significant. When the dosage calculations were adjusted to account for the limited oral bioavailability of Aredia in rats, the lowest daily dose associated with adrenal phaeochromocytoma was similar to the intended clinical dose in humans. In a second rat carcinogenicity study, adrenal phaeochromocytomas were not reported at doses similar to the intended clinical dose in humans. Aredia by daily oral administration was not carcinogenic in either a 80-week or a 104-week study in mice. Pamidronate showed no genotoxic activity in a standard battery of assays for gene mutations and chromosomal damage. Fertility and general reproductive performance were not affected by oral pamidronate doses (to 150 mg/kg/day), although prolonged and abnormal parturition was seen; there were no such studies with intravenous administration.

Pamidronate has been shown to cross the placenta and has produced marked maternal and non-teratogenic embryo/fetal effects in rats and rabbits. It accumulates in fetal bone in a manner similar to that observed in adult animals. Pamidronate has been shown to increase the length of gestation and parturition in rats resulting in an increasing pup mortality when given orally at daily doses of 60 mg/kg and above (0.7 times the highest recommended human dose for a single intravenous infusion). In pregnant rats, high doses of intravenous pamidronate (12 and 15 mg/kg/day) were associated with maternal toxicity and fetal developmental abnormalities (fetal oedema and shortened bones) and doses of 6 mg/kg and above with reduced ossification. Lower intravenous pamidronate doses (1-6 mg/kg/day) interfered (pre- partum distress and fetotoxicity) with normal parturition in the rat, and this may be associated with maternal hypocalcaemia. Only low intravenous doses have been investigated in pregnant rabbits, because of maternal toxicity, and the highest dose used (1.5 mg/kg/day) was associated with an increased resorption rate and reduced ossification. It is not known if Aredia crosses the human placenta. Pamidronate may pose a risk to the fetus/newborn child through its pharmacological action on calcium homeostasis. There are no adequate data for the use of Aredia in pregnant women. The potential risk for humans is unknown. Therefore, Aredia should not be used during pregnancy(see "CONTRAINDICATIONS"). Women of child-bearing potential must use highly effective contraception during treatment. 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. 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 in lactating women and it is unknown if disodium pamidronate and/or its metabolites pass into human milk. A study in lactating rats has shown that pamidronate will pass into the milk. Therefore, mothers taking Aredia should not breastfeed (see "CONTRAINDICATIONS").

There are limited data on efficacy and safety of Aredia in pediatric patients. Aredia should not be given to children unless other measures have either failed to control life-threatening hypercalcaemia or are deemed inappropriate. Until further experience is gained, Aredia is only recommended for use in adult patients.

Aredia has been used concomitantly with commonly used anti-tumour drugs without interactions. Aredia should not be used concomitantly with other bisphosphonates. Aredia has been used in combination with calcitonin in patients with severe hypercalcaemia, resulting in a synergistic effect with a more rapid fall in serum calcium. Caution is warranted when Aredia is used with other potentially nephrotoxic drugs. In multiple myeloma patients, the risk of renal deterioration may be increased when Aredia is used in combination with thalidomide.

Since Aredia binds to bone it can interfere with bone scintigraphy examinations.

ADVERSE REACTIONS

Adverse reactions to Aredia are usually not sufficient to require intervention. The most common adverse reactions are asymptomatic hypocalcaemia and pyrexia (an increase in body temperature > 1C, which may last for 48 hours). Pyrexia usually resolves spontaneously and does not require treatment. Symptomatic hypocalcaemia is uncommon. Local soft-tissue inflammation at the infusion site also occurs, especially at the highest dose (90 mg). The frequency estimate for the adverse reactions below is as follows: very common (>1/10), common (>1/100, <1/10), uncommon (>1/1,000, <1/100), rare (>1/10,000, <1/1,000), very rare (<1/10,000), including isolated reports.

Metabolism and nutrition disorders:

Very common:hypocalcaemia, hypophosphataemia Common:hypokalaemia, hypomagnesaemia, Very rare:hyperkalaemia, hypernatraemia

Investigations:

Common:increase in serum creatinine Uncommon:abnormal liver function tests, increase in serum urea

Blood and lymphatic system disorders:

Common:anaemia, thrombocytopenia, lymphocytopenia Very rare:leukopenia

Cardiac disorders:

Common:Atrial fibrillation Very rare:left ventricular failure (dyspnoea, pulmonary oedema), congestive heart failure (oedema) due to fluid overload

Vascular disorders:

Common:hypertension Uncommon:hypotension

Nervous system disorders:

Common:symptomatic hypocalcemia (tetany, paraesthesia), headache, insomnia, somnolence Uncommon:seizures, lethargy, agitation, dizziness Very rare:confusion, visual hallucinations

Gastrointestinal disorders:

Common:nausea, vomiting, anorexia, abdominal pain, diarrhoea, constipation, gastritis Uncommon:dyspepsia

General disorders and administration site conditions:

Very common:fever and influenza-like symptoms sometimes accompanied by malaise, rigor, fatigue and flushes Common:reactions at the infusion site (pain, redness, swelling, induration, phlebitis, thrombophlebitis)

Immune system disorders:

Uncommon:allergic reactions including anaphylactoid reactions, bronchospasm/dyspnoea, Quincke's (angioneurotic) oedema Very rare:anaphylactic shock

Infections and infestations:

Very rare:reactivation of Herpes simplex, reactivation of Herpes zoster

Musculoskeletal and connective tissue disorders:

Common:transient bone pain, arthralgia, myalgia, generalised pain Uncommon:muscle cramps

Renal and urinary disorders:

Uncommon:acute renal failure Rare:focal segmental glomerulosclerosis including the collapsing variant, nephrotic syndrome Very rare:deterioration of pre-existing renal disease, haematuria

Skin and subcutaneous disorders:

Common:rash Uncommon:pruritus

Eye disorders:

Common:conjunctivitis Uncommon:uveitis (iritis, iridocyclitis) Very rare:scleritis, episcleritis, xanthopsia Many of these adverse reactions may have been related to the underlying disease. ADVERSE DRUG REACTIONS FROM SPONTANEOUS REPORTS AND LITERATURE CASES The following adverse reactions have been reported during post-approval use of Aredia. Because these reports are from a population of uncertain size and are subject to confounding factors, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Frequency not known

Respiratory, thoracic and mediastinal disorders

: adult respiratory distress syndrome (ARDS), interstitial lung disease (ILD).

Musculoskeletal and connective tissue disorders:

severe and occasionally incapacitating bone, joint, and/or muscle pain (infrequent cases reported). Cases of atypical subtrochanteric and diaphyseal femoral fractures have been reported with bisphosphonates (class adverse reaction), including Aredia.

Renal and urinary disorders:

renal tubular disorders (RTD), tubulointerstitial nephritis, and glomerulonephropathies.

Frequency rare

Orbital inflammation:

Very rare cases of orbital inflammation events have been reported.

Description of selected ADRs (class label)

Atrial fibrillation

: Isolated instances of higher incidence of atrial fibrillation have been reported in a few studies with some bisphosphonates, including Aredia. The mechanism of this increased incidence of atrial fibrillation in isolated studies with these bisphosphonates, is unknown.

Osteonecrosis of the jaw

: Cases of osteonecrosis (primarily of the jaws) have been reported predominantly in cancer patients treated with bisphosphonates, including Aredia (uncommon). Many of these patients had signs of local infection including osteomyelitis and the majority of the reports refer to cancer patients following tooth extractions or other dental surgeries. Osteonecrosis of the jaws has multiple well documented risk factors including a diagnosis of cancer, concomitant therapies (e.g. chemotherapy, radiotherapy, corticosteroids) and co-morbid conditions (e.g. anaemia, coagulopathies, infection, pre-existing oral disease). Although causality has not been determined, it is prudent to avoid dental surgery as recovery may be prolonged (see "PRECAUTIONS"). Data suggest a greater frequency of reports of ONJ based on tumour type (advanced breast cancer, multiple myeloma).

DOSAGE AND ADMINISTRATION

Aredia powder for injection should be first reconstituted in 5 mL (15 mg vial) or 10 mL (30, 60 and 90 mg vials) sterile water for injection. It is important that the powder be completely dissolved before the reconstituted solution is withdrawn for dilution. Aredia must never be given as a bolus injection since severe local reactions and thrombophlebitis may occur as a result of high local concentrations. Aredia should always be diluted and administered by slow intravenous infusion in sodium chloride 0.9% or dextrose 5%. Do not co-administer with other bisphosphonates. If other calcium lowering agents are used in conjunction with pamidronate, significant hypocalcaemia may result. Aredia should not be added to intravenous infusion fluids containing calcium or other divalent cation-containing solutions such as Ringer's solution, and should be administered as a single intravenous solution in a line separate from all other drugs. Aredia powder for injection contains no antimicrobial agent. Once reconstituted, the solution should preferably be used immediately and any residue remaining discarded. If the reconstituted or diluted product cannot be used immediately or as soon as practicable after preparation, store at 2 - 8 C for not more than 24 hours. In order to minimise local reactions at the infusion site, the cannula should be inserted carefully into a relatively large vein.

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.

Predominantly lytic bone metastases from breast cancer and advanced multiple myeloma:

The recommended dose of Aredia for the treatment of predominantly lytic bone metastases from breast cancer and advanced 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, Aredia 90 mg may also be given on a 3-weekly schedule. The infusion rate should not exceed 60 mg/h (1 mg/min) and the concentration of Aredia in the infusion solution should not exceed 90 mg/250 mL. In breast cancer patients, 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, it is recommended not to exceed a concentration of 90 mg in 500 mL administered over 4 hours.

: The total dose for a treatment course can be given as a single infusion. It can also be divided into 2 or 3 consecutive daily doses. The infusion rate should not exceed 60 mg/h (1 mg/min) and the concentration of Aredia in the infusion solution should not exceed 90 mg/250 mL. However, it is recommended not to exceed 90 mg in 500 mL over 4 hours.

The recommended total doses for each treatment course with Aredia are related to initial plasma calcium levels. A dosing guideline is shown in the table.

: If hypercalcaemia recurs, or if plasma calcium does not decrease within 2 days, further infusions of Aredia may be given, according to the guidelines for initial treatment.

Clinical experience to date has revealed a possibility of a weaker therapeutic response in patients with advanced malignant disease and/or with increased number of treatments. The maximum dose per treatment course of Aredia is 90 mg whether for initial or repeat treatment. Higher doses bring no greater clinical benefit.

The recommended dose of Aredia in patients with symptomatic Paget's disease is a single infusion of 60 mg. The infusion rate should not exceed 15 - 30 mg/2 hours and the concentration of Aredia should not exceed 90 mg/L.

When clinically indicated, patients should be retreated at the dose of initial therapy.

Aredia is not recommended for patients with severe renal impairment (see "PRECAUTIONS"). In mild to moderate renal impairment, the maximum recommended Aredia infusion rate is 90 mg over 4 hours (approximately 20 - 22 mg/h).

Dose reduction does not appear necessary in patients with mild to moderate hepatic impairment; however, the data are limited (see "Pharmacokinetics"). There are no data in patients with severe hepatic impairment. Until further experience is gained, a maximum infusion rate of 20 mg/h is recommended in patients with mild to moderate hepatic impairment. Aredia has not been studied in patients with severe hepatic impairment. Therefore, caution should be exercised when Aredia is given to patients with severe hepatic impairment. No specific recommendation can be given for patients with severe hepatic impairment.

Serum creatinine should be measured prior to each dose of Aredia. In patients receiving Aredia for bone metastases, multiple myeloma or for tumour-induced hypercalcaemia who have a deterioration in renal function defined as: for patients with normal baseline serum creatinine, an increase of > 45 micromol/L and for patients with abnormal baseline serum creatinine, an increase of > 90 micromol/L, Aredia should be withheld until serum creatinine returns to within 10% of the baseline value, unless treatment is required immediately for life-threatening hypercalcaemia. Standard hypercalcaemia-related metabolic parameters including serum electrolytes, calcium, phosphate, magnesium and potassium should be monitored after commencing Aredia therapy. Patients who have undergone thyroid surgery may be particularly susceptible to develop hypocalcaemia due to relative hypoparathyroidism. Patients receiving frequent infusions of Aredia over a prolonged period of time, especially those with pre-existing renal disease or a predisposition to renal impairment (e.g. patients with multiple myeloma and/or tumour-induced hypercalcaemia) should have evaluations of standard clinical and laboratory parameters of renal function prior to each dose. In patients with cardiac disease, especially in the elderly, additional saline overload may precipitate cardiac failure (left ventricular failure or congestive heart failure). Therefore, overhydration should be avoided especially in patients at risk of cardiac failure. Fever (influenza-like symptoms) may also contribute to this deterioration. Patients with anaemia, leukopenia or thrombocytopenia should have regular haematology assessments. 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 in order to minimise the risk of hypocalcaemia. Individual data revealed significant decreases in white cell and platelet counts in several patients. Haematological testing should be carried out if clinically indicated.

OVERDOSAGE

Patients who have received doses higher than those recommended should be carefully monitored. In the event of clinically significant hypocalcaemia with paraesthesia, tetany and hypotension, reversal may be achieved with an infusion of calcium gluconate.

PRESENTATION

15 mg vials: containing 15 mg sterile lyophilised disodium pamidronate, 235 mg mannitol, phosphoric acid; packs of 4 vials and 4 ampoules water for injection 5 mL. 30 mg vials: containing 30 mg sterile lyophilised disodium pamidronate, 470 mg mannitol, phosphoric acid; packs of 2 vials and 2 ampoules water for injection 10 mL. 60 mg vials: containing 60 mg sterile lyophilised disodium pamidronate, 400 mg mannitol, phosphoric acid; packs of 1 vial and 1 ampoule water for injection 10 mL. 90 mg vials: containing 90 mg sterile lyophilised disodium pamidronate, 375 mg mannitol, phosphoric acid; packs of 1 vial and 1 ampoule water for injection 10 mL. Store below 30C.

SPONSOR

NOVARTIS Pharmaceuticals Australia Pty Limited ABN 18 004 244 160 54 Waterloo Road North Ryde NSW 2113

Initial Serum Calcium *		Total Dose
(mmol/L)	(mg%)	(mg)
Up to 3.0	Up to 12.0	30
3.0-3.5	12.0-14.0	30-60
3.5-4.0	14.0-16.0	60-90
> 4.0	> 16.0	90

NAME OF THE DRUG