SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Pamidronate Disodium 9 mg/ ml Concentrate for solution for infusion.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml of concentrate for solution for infusion contains 11.90mg/ml of pamidronate disodium pentahydrate, which is equivalent to 9mg/ml of pamidronate disodium anhydrous

1 vial of 10 ml of Concentrate for solution for infusion contains 90 mg of pamidronate disodium.

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Concentrate for solution for infusion.

Pamidronate Disodium 9 mg/ ml is a clear colourless solution in flint glass vial.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Treatment of conditions associated with increased osteoclast activity:

•    The treatment of 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.

4.2 Posology and method of administration

Pamidronate disodium must never be given as a bolus injection (see section 4.4). The solution must be diluted before use (see below) and must be infused slowly.

For information concerning compatibility with infusion solutions, refer to section 6.6.

The infusion rate should never exceed 60 mg/hour (1 mg/min), and the concentration of pamidronate disodium in the infusion solution should not exceed 60 mg/250 ml. 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 20 mg/hour (see also “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

It is recommended that patients be rehydrated with 0.9% w/v sodium chloride solution before or during treatment.

The total dose of pamidronate disodium 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 or albumin in rehydrated patients.

Initial serum calcium		Recommended total dose
(mmol/litre)	(mg %)	(mg)
up to 3.0	up to 12.0	15-30
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

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

A significant decrease in serum calcium is generally observed 24-48 hours after administration of pamidronate disodium, 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 pamidronate disodium may become less effective as the number of treatments increases.

Osteolytic lesions and bone pain in multiple myeloma The recommended dose is 90 mg every 4 weeks.

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

The recommended dose is 90 mg 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 180 mg administered in unit doses of either 30 mg once a week for 6 consecutive weeks, or 60 mg every other week over 6 weeks. Experience to date suggests that any mild and transient unwanted effects (see section 4.8) tend to occur after the first dose. For this reason if unit doses of 60 mg are used it is recommended that treatment be started with an initial additional dose of 30 mg (i.e. total dose 210 mg). Each dose of 30 or 60 mg should be diluted in 125 or 250 ml 0.9 % w/v Sodium Chloride Intravenous Infusion BP respectively, and the infusion rate should not exceed 60 mg/hour (1 mg/min). This regimen or increased dose levels according to disease severity, up to a maximum total does of 360 mg (in divided doses of 60 mg) can be repeated every 6 months until remission of disease is achieved, and if relapse occurs.

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. 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 pamidronate disodium. In patients receiving pamidronate disodium for bone metastases or multiple myeloma 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 0.5mg/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 pamidronate disodium in children. Therefore until further experience is gained, pamidronate disodium is only recommended for use in adult patients.

4.3 Contraindications

Pamidronate disodium is contraindicated in:

•    patients with known    hypersensitivity to pamidronate or to other

bisphosphonates, or to any of the excipients of Aredia,

•    pregnancy,

•    breast feeding women.

4.4 Special warnings and precautions for use

Pamidronate 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 Pamidronate 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 Pamidronate. 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 Pamidronate, 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 Pamidronate. Deterioration of renal function (including renal failure) has also been reported following longterm treatment with Pamidronate in patients with multiple myeloma.

Pamidronate 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 Pamidronate 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 Pamidronate.

Patients treated with Pamidronate 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).

Pamidronate 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”). Pamidronate should not be given with other bisphosphonates because their combined effects have not been investigated.

There is very little experience of the use of Pamidronate 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 has been reported predominantly in cancer patients treated with bisphosphonates, including Pamidronate. 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 (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 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.

4.5 Interaction with other medicinal products and other forms of interaction

Pamidronate disodium has been administered concomitantly with commonly used anti-cancer agents without significant interactions.

Pamidronate 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 Pamidronate is used with other potentially nephrotoxic drugs.

In multiple myeloma patients, the risk of renal dysfunction may be increased when Pamidronate is used in combination with thalidomide.

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

4.6 Fertility, Pregnancy and lactation

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,Pamidronate should not be used during pregnancy (see Section 4.3 Contraindications).

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

4.7 Effects on ability to drive and use machines

Patients should be warned that in rare cases somnolence and/or dizziness may occur following pamidronate disodium 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.

4.8 Undesirable effects

Adverse reactions to pamidronate disodium 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.

One case of acute lymphoblastic leukaemia has been reported in a patient with Paget’s disease. The causal relationship to the treatment or the underlying disease is unknown.

\ Frequency Orga\ System\	Very Common (>1/10)	Common (>1/100 to <1/10)	Uncommon (>1/1,000 to <1/100)	Rare (>1/10,000 to <1/1,000)	Very rare (<1/10,000), not known (cannot be estimated from the available data)
Infection					reactivation of Herpes simplex, reactivation of Herpes zoster
Blood and lymphatic system disorders		Anaemia, thrombocyto penia, lymphocytop enia			leukopenia
Immune system disorders			Allergic reactions including anaphylactoi d reactions, bronchospas m/dyspnoea, Quincke's (angioneurot ic) oedema.		anaphylactic shock
Metabolism and nutrition disorders	hypocalcaem ia, hypophospha taemia	hypokalaemi a, hypomagnes aemia, increase in serum creatinine.	abnormal liver function tests, increase in serum urea.		hyperkalaem ia, hypernatrae mia
Nervous system disorders		symptomatic hypocalcaem ia (paraesthesia , tetany), headache, insomnia,	seizures, agitation, dizziness, lethargy		confusion, visual hallucinatio ns

		somnolence.
Eye disorders		conjunctivitis	uveitis (iritis, iridocyclitis).		scleritis, episcleritis, xanthopsia.
Cardiac disorders/ vascular disorders		hypertension	hypotension		left ventricular failure (dyspnoea, pulmonary oedema), congestive heart failure (oedema) due to fluid overload.
Gastrointesti nal disorders		nausea, vomiting, anorexia, abdominal pain, diarrhoea, constipation, gastritis.	dyspepsia
Skin and subcutaneous tissue disorders		rash	pruritus
Musculoskeletal and connective tissue disorders		transient bone pain, arthralgia, myalgia, generalised pain.	muscle cramps.
Renal and urinary disorders			acute renal failure.	focal segmental glomerulosc lerosis including the collapsing variant, nephrotic syndrome.	deterioration of preexisting renal disease, haematuria.
General disorders and administratio n site conditions	fever and influenzalike symptoms sometimes	reactions at the infusion site: pain, redness, swelling,

	accompanied by malaise, rigor, fatigue and_ flushes	induration, phlebitis, thrombophle bitis
Injury, poisoning and procedural complication s				Atypical subtrochant eric and diaphyseal femoral fractures

Postmarketing experience: Uncommonly, cases of osteonecrosis (primarily of the jaw) have been reported predominantly in cancer patients treated with bisphosphonates including Pamidronate. 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 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 special precautions for use).

4.9 Overdose

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.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Inhibitor of bone resorption

ATC code: M05BA03

Pamidronate disodium, 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 biphosphonate 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 pamidronate disodium 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, pamidronate disodium 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 pamidronate disodium 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 pamidronate disodium. 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.

5.2 Pharmacokinetic properties

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, and there is a tendency for the renal clearance to correlate with creatinine clearance.

Characteristics in patients

Hepatic and metabolic clearance of pamidronate are insignificant. Pamidronate disodium 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 Pamidronate 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 pamidronate is administered on a monthly basis, drug accumulation is not expected. No changes in pamidronate 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”).

5.3 Preclinical safety data

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.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Mannitol Phosphoric acid Water for Injections

6.2 Incompatibilities

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

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

6.3    Shelf life

2 years.

6.4    Special precautions for storage

Following dilution in 0.9% sodium chloride and 5% glucose infusion solutions, chemical and physical in-use stability has been demonstrated for 24 hours at temperatures not exceeding 25°C.

10 DATE OF REVISION OF THE TEXT

26/03/2013