®Aredia Dry Powder 15mg

®Aredia Dry Powder 30mg

®Aredia Dry Powder 90mg

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

One vial contains 15mg, 30mg or 90mg of sterile, lyophilised pamidronate disodium. An ampoule containing 5mL sterile water for injections is supplied with each 15mg vial, and a 10mL ampoule with each 30mg or 90mg vial.

Powder and solvent for solution for infusion.

Treatment of conditions associated with increased osteoclast activity:

• Tumour-induced hypercalcaemia

• Osteolytic lesions and bone pain in patients with bone metastases associated with breast cancer or multiple myeloma

• Paget's disease of bone.

Aredia must never be given as a bolus injection (see Section 4.4 Special warnings and special precautions for use). The reconstituted solution of Aredia from powder in vials should be diluted in a calcium-free infusion solution (0.9 % w/v sodium chloride solution or 5% w/v glucose solution) and infused slowly.

The infusion rate should never exceed 60mg/hour (1mg/min), and the concentration of Aredia in the infusion solution should not exceed 60mg/250ml. In patients with established or suspected renal impairment (e.g. those with tumour-induced hypercalcaemia or multiple myeloma) it is recommended that the infusion rate does not exceed 20mg/h (see also Section 4.2 Posology and method of administration “Renal impairment”). In order to minimise local reactions at the infusion site, the cannula should be inserted carefully into a relatively large vein.

Tumour-induced hypercalcaemia

Patients must be adequately rehydrated, using 0.9% w/v sodium chloride solution, prior to and during administration of Aredia.

The total dose of Aredia to be used for a treatment course depends on the patient's initial serum calcium levels. The following guidelines are derived from clinical data on uncorrected calcium values. However, doses within the ranges given are also applicable for calcium values corrected for serum protein or albumin in rehydrated patients.

The total dose of Aredia may be administered either in a single infusion or in multiple infusions over 2 to 4 consecutive days. The maximum dose per treatment course is 90 mg for both initial and repeated courses.

A significant decrease in serum calcium is generally observed 24 to 48 hours after administration of Aredia, and normalisation is usually achieved within 3 to 7 days. If normocalcaemia is not achieved within this time, a further dose may be given. The duration of the response may vary from patient to patient, and treatment can be repeated whenever hypercalcaemia recurs. Clinical experience to date suggests that Aredia may become less effective as the number of treatments increases.

Osteolytic lesions and bone pain in multiple myeloma

The recommended dose is 90mg every 4 weeks.

Osteolytic lesions and bone pain in bone metastases associated with breast cancer

The recommended dose is 90mg every 4 weeks. This dose may also be administered at 3 weekly intervals to coincide with chemotherapy if desired.

Paget's disease of Bone

The recommended treatment course consists of a total dose of 180mg administered in unit doses of either 30mg once a week for 6 consecutive weeks, or 60mg every other week over 6 weeks. Experience to date suggests that any mild and transient unwanted effects (see Section 4.8 Undesirable effects) tend to occur after the first dose. For this reason if unit doses of 60mg are used it is recommended that treatment be started with an initial dose of 30mg followed by 60mg every other week (i.e. total dose 210mg). Each dose of 30 or 60mg should be diluted in 125 or 250 ml 0.9% w/v sodium chloride solution respectively, and the infusion rate should not exceed 60mg/hour (1mg/min). This regimen or increased dose levels according to disease severity, up to a maximum total dose of 360mg (in divided doses of 60mg) can be repeated every 6 months until remission of disease is achieved, and if relapse occurs.

Renal Impairment

Aredia should not be administered to patients with severe renal impairment (creatinine clearance < 30 mL/min) unless in cases of life-threatening tumour-induced hypercalcaemia where the benefit outweighs the potential risk. Because there is only limited clinical experience in patients with severe renal impairment no dose recommendations for this patient population can be made (see Section 4.4 “Special warnings and special precautions for use” and Section 5.2 “Pharmacokinetic properties”).

As with other i.v. bisphosphonates, renal monitoring is recommended, for instance, measurement of serum creatinine prior to each dose of Aredia. In patients receiving Aredia for bone metastases or multiple myeloma who show evidence of deterioration in renal function, Aredia treatment should be withheld until renal function returns to within 10% of the baseline value. This recommendation is based on a clinical study, in which renal deterioration was defined as follows:

• For patients with normal baseline creatinine, increase of 0.5mg/dL.

• For patients with abnormal baseline creatinine, increase of 1.0mg/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

Although patients with hepatic impairment exhibited higher mean AUC and Cmax values compared to patients with normal hepatic function, this is not perceived being clinically relevant. As pamidronate is still rapidly cleared from the plasma almost entirely into the bone and as is administered on a monthly basis for chronic treatment, drug accumulation is not expected. Therefore no dose adjustment is necessary in patients with mild to moderate abnormal hepatic function (see Section 5.2 Pharmacokinetic properties “Hepatic impairment”). Clinical data in patients with severe hepatic impairment is not available (see Section 4.4 Special warnings and special precautions for use). Pamidronate should be administered to this patient population with caution.

Children

There is no clinical experience with Aredia in children. Therefore until further experience is gained, Aredia is only recommended for use in adult patients.

Aredia is contraindicated

• in patients with known hypersensitivity to pamidronate or to other bisphosphonates, or to any of the excipients of Aredia,

• in pregnancy,

• in breast feeding women.

General

Aredia must never be given as a bolus injection, but should always be diluted and given as a slow intravenous infusion (see Section 4.2 Posology and method of administration).

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.

Standard hypercalcaemia-related metabolic parameters including serum, calcium and phosphate should be monitored following initiation of therapy with Aredia. Patients who have undergone thyroid surgery may be particularly susceptible to developing hypocalcaemia due to relative hypoparathyroidism.

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.

Convulsions have been precipitated in some patients with tumour-induced hypercalcaemia due to the electrolyte changes associated with this condition and its effective treatment.

Renal Insufficiency

Bisphosphonates, including Aredia, have been associated with renal toxicity manifested as deterioration of renal function and potential renal failure. Renal deterioration, progression to renal failure 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 is excreted intact primarily via the kidney (see Section 5.2 Pharmacokinetic properties), thus the risk of renal adverse reactions may be greater in patients with impaired renal function.

Due to the risk of clinically significant deterioration in renal function which may progress to renal failure, single doses of Aredia should not exceed 90mg, and the recommended infusion time should be observed (See Section 4.2. Posology and method of administration).

As with other i.v. bisphosphonates renal monitoring is recommended, for instance, measurement of serum creatinine prior to each dose of Aredia.

Patients treated with Aredia for bone metastases or multiple myeloma should have the dose withheld if renal function has deteriorated (see Section 4.2. Posology and method of administration).

Aredia should not be administered to patients with severe renal impairment (creatinine clearance < 30 mL/min) unless in cases of life-threatening tumour-induced hypercalcaemia where the benefit outweighs the potential risk. (See section 4.2 Posology and method of administration “Renal impairment”). Because there is only limited pharmacokinetic data with severe renal impairment no dose recommendations for this patient population can be made (See Section 4.2 “Posology and method of administration” and Section 5.2 “Pharmacokinetic properties”). Aredia should not be given with other bisphosphonates because their combined effects have not been investigated.

There is very little experience of the use of Aredia in patients receiving haemodialysis.

Hepatic Insufficiency

As there are no clinical data available in patients with severe hepatic insufficiency, no specific recommendations can be given for this patient population (see Sections 4.2 Posology and method of administration and 5.2 Pharmacokinetic properties).

Calcium and Vitamin D Supplementation

In the absence of hypercalcaemia, patients with predominantly lytic bone metastases or multiple myeloma, who are at risk of calcium or Vitamin D deficiency (e.g. through malabsorption or lack of exposure to sunlight) and patients with Paget's disease of the bone should take oral calcium and vitamin D supplementation in order to minimise the potential risk of hypocalcaemia.

Osteonecrosis of the jaw

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.

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).

A dental examination with appropriate preventive dentistry should be considered prior to treatment with bisphosphonates in patients with concomitant risk factors (e.g. cancer, chemotherapy, corticosteroids, poor oral hygiene).

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 judgement of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.

Musculoskeletal Pain

In post-marketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates. This category of drugs includes Aredia (pamidronate disodium for infusion). The time to onset of symptoms varied from one day to several months after starting the drug with the majority occurring within a few days. Most patients had relief or improvement of symptoms after stopping treatment. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate.

Atypical fractures of the femur

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 bisphosphonate-treated patients who have sustained a femoral shaft fracture. Poor healing of these fractures has also been reported. Discontinuation of bisphosphonate 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.

During bisphosphonate 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.

Aredia has been administered concomitantly with commonly used anticancer agents without interactions occurring.

Aredia has been used in combination with calcitonin in patients with severe hypercalcaemia, resulting in a synergistic effect producing 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 dysfunction may be increased when Aredia is used in combination with thalidomide.

Since pamidronate binds to bone, it could in theory interfere with bone scintigraphy examinations.

There are no adequate data from the use of pamidronate in pregnant women. Studies in animals have shown reproductive toxicity (see Section 5.3 Preclinical safety data). Dystocia was observed in the rats. Therefore, Aredia should not be used during pregnancy (see Section 4.3 Contraindications).

It is not known whether Aredia is excreted into human milk. A study in lactating rats has shown that pamidronate will pass into the milk. Mothers treated with Aredia should therefore not breast-feed their infants (see Section 4.3 Contraindications).

Patients should be warned that somnolence and/or dizziness may occur following Aredia infusion, in which case they should not drive, operate potentially dangerous machinery, or engage in other activities that may be hazardous because of decreased alertness.

Adverse reactions to Aredia are usually mild and transient. The most common adverse reactions are asymptomatic hypocalcaemia and fever (an increase in body temperature of 1-2°C), typically occurring within the first 48 hours of infusion. Fever usually resolves spontaneously and does not require treatment.

Frequency estimate: 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, not known (cannot be estimated from the available data).

When the effects of zoledronic acid (4 mg) and pamidronate (90 mg) were compared in one clinical trial, the number of atrial fibrillation adverse events was higher in the pamidronate group (12/556, 2.2%) than in the zoledronic acid group (3/563, 0.5%). Previously, it has been observed in a clinical trial, investigating patients with postmenopausal osteoporosis, that zoledronic acid treated patients (5 mg) had an increased risk of atrial fibrillation serious adverse events compared to placebo (1.3% compared to 0.6%). The mechanism behind the increased incidence of atrial fibrillation in association with zoledronic acid and pamidronate treatment is unknown.

Postmarketing experience:

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.

Cases of osteonecrosis (primarily of the jaw) have been reported predominantly in cancer patients treated with bisphosphonates including Aredia (uncommon). Many of these patients had signs of local infection including osteomyelitis andthe majority of the reports refer to cancer patients following tooth extractions or other dental surgeries. Osteonecrosis of the jaw 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 section 4.4 Special warnings and precautions for use). Data suggest a greater frequency of reports of ONJ based on tumour type (advanced breast cancer, multiple myeloma).

During post-marketing experience the following reactions have been reported (frequency rare): Atypical subtrochanteric and diaphyseal femoral fractures (bisphosphonate class adverse reaction).

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.

Pharmacotherapeutic group: Inhibitor of bone resorption (ATC code MO5B A 03).

Pamidronate disodium, the active substance of Aredia, is a potent inhibitor of osteoclastic bone resorption. It binds strongly to hydroxyapatite crystals and inhibits the formation and dissolution of these crystals in vitro. Inhibition of osteoclastic bone resorption in vivo may be at least partly due to binding of the drug to the bone mineral.

Pamidronate suppresses the accession of osteoclast precursors onto the bone. However, the local and direct antiresorptive effect of bone-bound bisphosphonate appears to be the predominant mode of action in vitro and in vivo.

Experimental studies have demonstrated that pamidronate inhibits tumour-induced osteolysis when given prior to or at the time of inoculation or transplantation with tumour cells. Biochemical changes reflecting the inhibitory effect of Aredia on tumour-induced hypercalcaemia, are characterised by a decrease in serum calcium and phosphate and secondarily by decreases in urinary excretion of calcium, phosphate, and hydroxyproline.

Hypercalcaemia can lead to a depletion in the volume of extracellular fluid and a reduction in the glomerular filtration rate (GFR). By controlling hypercalcaemia, Aredia improves GFR and lowers elevated serum creatinine levels in most patients.

Clinical trials in patients with breast cancer and predominantly lytic bone metastases or with multiple myeloma showed that Aredia prevented or delayed skeletal-related events (hypercalcaemia, fractures, radiation therapy, surgery to bone, spinal cord compression) and decreased bone pain

Paget's disease of bone, which is characterised by local areas of increased bone resorption and formation with qualitative changes in bone remodelling, 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.

General characteristics

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 site of "apparent elimination".

Absorption

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

Distribution

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 pamidronate concentrations of about 10 nmol/mL 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.

The percentage of circulating pamidronate bound to plasma proteins is relatively low (about 54%), and increases when calcium concentrations are pathologically elevated.

Elimination

Pamidronate does not appear to be eliminated by biotransformation and it is almost exclusively eliminated by renal excretion. 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). From the urinary elimination of pamidronate, two decay phases, with apparent half-lives of about 1.6 and 27 hours, can be observed. The apparent total plasma clearance is about 180mL/min and the apparent renal clearance is about 54 mL/min. There is a tendency for the renal clearance to correlate with creatinine clearance.

Characteristics in patients

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).

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 90mg dose of Aredia infused over 4 hours. There was a statistically significant difference in the pharmacokinetics between patients with normal and impaired hepatic function. Patients with hepatic impairment exhibited higher mean AUC (39.7%) and Cmax (28.6%) values. The difference was not considered clinically relevant. The mean ratio based on log transformed parameters of impaired versus normal patients was 1.38 (90% C.I. 1.12 – 1.70, P=0.02) for AUC and 1.23 (90% C.I. 0.89 – 1.70, P=0.27) for Cmax. Nevertheless, pamidronate was still rapidly cleared from the plasma. Drug levels were not detectable in patients by 12-36 hours after drug infusion. Because Aredia is administered on a monthly basis, drug accumulation is not expected. No changes in Aredia dosing regimen are recommended for patients with mild to moderate abnormal hepatic function (see Section 4.2 Posology and method of 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 <30mL/min), the AUC of pamidronate was approximately 3 times higher than in patients with normal renal function (creatinine clearance >90mL/min). Because there is only limited pharmacokinetic data with severe renal impairment no dose recommendations for this patient population can be made (See Section 4.2 “Posology and method of administration” and Section 4.4 “Special warnings and special precautions for use”).

The toxicity of pamidronate is characterised by direct (cytotoxic) effects on organs with a copious blood supply, particularly the kidneys following i.v. exposure. The compound is not mutagenic and does not appear to have carcinogenic potential.

Studies in rats and rabbits determined that pamidronate disodium produces maternal toxicity and embryo/foetal effects when administered at doses of 0.6 to 8.3 times the highest recommended human dose for a single intravenous infusion. The effects include protracted parturition leading to dystocia, and shortened long bones in the foetus. Animal data suggest that uptake of bisphosphonates into foetal bone is greater than into maternal bone.

Vials: Mannitol, phosphoric acid.

Solvent Ampoules: water for injections.

Studies with glass bottles, as well as infusion bags made from polyvinylchloride and polyethylene (prefilled with 0.9% w/v sodium chloride solution or 5% w/v glucose solution) showed no incompatibility with Aredia.

To avoid potential incompatibilities, Aredia reconstituted solution is to be diluted with 0.9% w/v sodium chloride solution or 5% w/v glucose solution.

Aredia reconstituted solution must not be mixed with calcium-containing solution such as Ringer's solution.

3 years

Protect vials from heat (store below 30°C). The reconstituted solution is chemically and physically stable for 24 hours at room temperature. However, from a microbiological point of view, it is preferable to use the product immediately after aseptic reconstitution and dilution.

If not used immediately, the duration and conditions of storage prior to use are the care provider's responsibility. The total time between reconstitution, dilution and storage in a refrigerator at 2 to 8ºC and end of administration must not exceed 24 hours.

Colourless glass vials of 10 mL, with closures made from a butyl rubber derivative.

The solvent is packaged in sealed glass ampoules.

Powder in vials should be first dissolved in sterile water for injection, i.e. 15mg in 5 mL. The sterile water for injection is available in ampoules which are supplied together with vials. The pH of the reconstituted solution is 6.0-7.0. The reconstituted solution should be further diluted with a calcium-free infusion solution (0.9% w/v sodium chloride or 5% w/v glucose solution) before administration. It is important that the powder be completely dissolved before the reconstituted solution is withdrawn for dilution.

Novartis Pharmaceuticals UK Limited,

trading as Ciba Laboratories.

Frimley Business Park

Frimley,

Camberley,

Surrey,

GU16 7SR

7 December 2011

POM