Pamidronate Disodium 6mg/Ml Concentrate For Solution For Infusion

Informations for option: Pamidronate Disodium 6mg/Ml Concentrate For Solution For Infusion, show other option

Document: spc-doc_PL 11311-0219 change

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Pamidronate Disodium 6mg/ml Concentrate for Solution for Infusion

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

60mg pamidronate disodium :

Each ml of concentrate for solution for infusion contains 6mg pamidronate disodium.

1 vial of 10ml of sterile concentrate contains 60mg of pamidronate disodium.

For the full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Concentrate for solution for infusion.

The concentrate is a clear and colourless solution, free from visible particles.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

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 and 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 concentrate 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 60mg/hour (1mg/min), and the concentration of pamidronate disodium 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/hour (see also "Patients with renal impairment”). In order to minimise local reactions at the infusion site, the cannula should be inserted carefully into a relatively large vein.

Until further experience is gained, pamidronate disodium is only recommended for use in adult patients.

Tumour-induced hypercalcaemia:

Patient must be adequately 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 protein or albumin in rehydrated patients.

Initial serum calcium		Recommended total
(mm	(mg %)	dose (mg)
ol/L)
up to	up to 12.0	15 - 30
3.0	12.0 - 14.0	30 - 60
3.0 -3.5	14.0 - 16.0	60 - 90
3.5 -	> 16.0	90
4.0
> 4.0

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 90mg for both initial and repeated 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 treatment increases.

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.

Osteolytic lesions and bone pain in Multiple myeloma:

The recommended dose is 90mg every 4 weeks.

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) 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.

Patients with renal impairment:

Until further experience is gained a maximum infusion rate of 20mg/hour is recommended in renal impaired patients.

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 and Section 5.2).

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).

Patients with 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 “Hepatic impairment”).

Clinical data in patients with severe hepatic impairment is not available. Pamidronate disodium should be administered to this patient population with caution.

Paediatric _ population:

There is no clinical experience of pamidronate disodium in children. Therefore until further experience is gained, Pamidronate disodium is only recommended for use in adult patients.

Patients treated with pamidronate disodium should be given the package leaflet and the patient reminder card.

4.3 Contraindications

- hypersensitivity to the active substance or to other Bisphosphonates, or to any of the excipients listed in section 6.1.

- in pregnancy (see also section 4.6)

- in breast feeding women (see also section 4.6)

4.4 Special warnings and precautions for use General

Pamidronate disodium must never be given as a bolus injection, since severe local reactions and thrombophlebitis may occur but should always be diluted and given as a slow intravenous infusion (see Section 4.2).

Do not co-administer pamidronate with other bisphosphonates. If other calcium lowering agents are used in conjunction with pamidronate, significant hypocalcaemia may result.

Patients must be assessed prior to administration of Pamidronate disodium to assure that they are appropriately hydrated. This is especially important for patients receiving diuretic therapy.

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

Precautions:

General

Standard hypocalcaemia-related metabolic parameters including serum electrolyte, calcium and phosphate should be monitored following initiation of therapy with Pamidronate disodium. Patients who have undergone thyroid surgery may be particularly susceptible to developing hypocalcaemia due to relative hypoparathyroidism. The safety and efficacy of pamidronate in the treatment of hyperparathyroidism has not been established.

Patients with anaemia, leukopenia or thrombocytopenia should have regular haematology assessments.

It is essential in the initial treatment of tumour induced hypercalcaemia that intravenous rehydration be instituted to maintain urine output. Patients should be hydrated adequately throughout treatment but overhydration must be avoided.

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.

Pamidronate disodium should be given under the supervision of a physician with the facilities to monitor the clinical and biochemical effects.

Renal Insufficiency

Bisphosphonates, including Pamidronate disodium , 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 disodium . Deterioration of renal function (including renal failure) has also been reported following long-term treatment with Pamidronate disodium in patients with multiple myeloma however, underlying disease progression and/or concomitant complications were also present and therefore a causal relationship with pamidronate is unproven. If there is deterioration of renal function during pamidronate therapy, the infusion must be stopped.

Pamidronate disodium is excreted intact primarily via the kidney (see Section 5.2), 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 disodium should not exceed 90mg, and the recommended infusion time should be observed (See Section 4.2.).

Patients should have standard laboratory (serum creatinine and BUN) and clinical renal function parameters evaluated, prior to each dose of pamidronate, especially those receiving frequent pamidronate 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 hypercalcaemia). Fluid balance (urine output, daily weights) should also be followed carefully.

Experience with pamidronate in patients with severe renal impairment (serum creatinine: >440 micromol/litre, or 5 mg/dl in TIH patients; 180 micromol/litre, or 2 mg/dl in multiple myeloma patients) is limited. If clinical judgement determines that the potential benefits outweigh the risk in such cases, pamidronate should be used cautiously and renal function carefully monitored.

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

Patients treated with Pamidronate disodium for bone metastases or multiple myeloma should have the dose withheld if renal function has deteriorated (see Section 4.2.).

Pamidronate disodium 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 disodium in patients receiving haemodialysis.

Hepatic Insufficiency

As Pamidronate disodium has not been studied and no clinical data available in patients with severe hepatic impairment, therefore no specific recommendations can be given for this patient population (see Sections 4.2 and 5.2).

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) should take oral supplements of both during pamidronate disodium therapy to minimise the potential risk of hypocalcaemia.

Osteonecrosis of the jaw

Osteonecrosis of the jaw (ONJ) has been reported uncommonly in clinical trials and in the post-marketing setting in patients receiving pamidronate.

The start of treatment or of a new course of treatment should be delayed in patients with unhealed open soft tissue lesions in the mouth except in medical emergency situations.

A dental examination with appropriate preventive dentistry and an individual benefit-risk assessment is recommended prior to treatment with bisphosphonates in patients with concomitant risk factors.

The following risk factors should be considered when evaluating an individual’s risk of developing ONJ:

• Potency of the bisphosphonate (higher risk for highly potent compounds), route of administration (higher risk for parenteral administration) and cumulative dose of bisphosphonate

• Cancer, co-morbid conditions (e.g. anaemia, coagulopathies, infection), smoking

• Concomitant therapies: chemotherapy, angiogenesis inhibitors (see section 4.5), radiotherapy to neck and head, corticosteroids

• History of dental disease, poor oral hygiene, periodontal disease, invasive dental procedures (e.g. tooth extractions) and poorly fitting dentures

All patients should be encouraged to maintain good oral hygiene, undergo routine dental check-ups, and immediately report any oral symptoms such as dental mobility, pain or swelling, or non-healing of sores or discharge during treatment with pamidronate disodium. While on treatment, invasive dental procedures should be performed only after careful consideration and be avoided in close proximity to pamidronate administration.

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.

The management plan for the patients who develop ONJ should be set up in close collaboration between the treating physician and a dentist or oral surgeon with expertise in ONJ.

Temporary interruption of pamidronate treatment should be considered until the condition resolves and contributing risk factors are mitigated where possible.

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 (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

Other Bisphosphonates

Pamidronate disodium should not be co-administered with other bisphosphonates because their combined effects have not been investigated.

Anticancer agents

Pamidronate disodium has been administered concomitantly with commonly used anticancer agents (including aminoglutethimide, cisplatin, corticosteroids, cyclophosphamide, cytarabine, doxorubicin, etoposide, fluorouracil, megestrol, melphalan, methotrexate, mitoxantrone, paclitaxel, tamoxifen, vinblastine and vincristine) without significant interactions occurring.

Calcitonin and mithramycin

Pamidronate disodium has been used in combination with both calcitonin and mithramycin in patients with severe hypercalcaemia, resulting in a synergistic effect producing a more rapid fall in serum calcium.

Nephrotoxic drugs

Caution is warranted when Pamidronate disodium is used with other potentially nephrotoxic drugs.

Thalidomide

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

Bone scintigraphy examinations

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

Anti-angiogenic medicinal products

Caution is advised when pamidronate is administered with anti-angiogenic medicinal products, as an increase in the incidence of ONJ has been observed in patients treated concomitantly with these medicinal products.

4.6 Fertility, pregnancy and lactation

In animal experiments, pamidronate showed no teratogenic potential and did not affect general reproductive performance or fertility. Pamidronate may pose a risk to the foetus/newborn child through its pharmacological action on calcium homeostasis. When administered during the entire period of gestation in animals, pamidronate can cause bone mineralisation defects, especially in long bones, resulting in angular distortion.

The potential risk for humans is unknown, and there is insufficient clinical experience to support the use of pamidronate disodium in pregnant women. It is not known if pamidronate crosses the human placenta. Therefore, pamidronate disodium should not be administered during pregnancy at any stage except in cases of life-threatening hypercalcaemia cannot be controlled by any other means.

Brest-feeding:

It is not known whether pamidronate disodium is excreted in human milk. Very limited experience indicates maternal milk levels of pamidronate under the limit of detection. A study in lactating rats has shown that pamidronate disodium will pass into the milk. Moreover the oral bioavalibility is poor so the total absorption of pamidronate by a breastfed infant is not likely. Mothers treated with pamidronate disodium should therefore not breast-feed their infants. However due to extremely limited experience and the potential of pamidronate to have an important impact on bone mineralisation breastfeeding during the therapy is not recommended.

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. This effect rarely lasts more than 24 hours.

Outpatients who have received a pamidronate infusion should not drive themselves home.

4.8 Undesirable effects

Adverse reactions to pamidronate disodium are usually mild and transient. The most common adverse reactions are asymptomatic hypocalcaemia with influenza-like symptoms and mild fever (an increase in body temperature of > 1°C), typically occurring within the first 48 hours of infusion. Fever usually resolves spontaneously and does not require treatment. Acute “influenza-like” reactions usually occur only with the first pamidronate infusion. Symptomatic hypocalcaemia is uncommon. Local soft tissue inflammation at the infusion site also occurs, especially at the highest dose.

The frequency is defined using the following conventions: 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)

Not known (cannot be estimated from the available data).

The following adverse drug reactions were reported from clinical studies and from post-marketing experience with Pamidronate.

	VERY COMMON	COMMON	UNCOMMON	RARE	VERY RARE	NOT KNOWN
Infections and infestations					Reactivation of herpes simplex and herpes zoster
Blood and the lymphatic system disorders		Lymphocytopen ia, Thrombocytope nia, Anaemia			Leukopenia
Immune system disorders			Allergic reactions including anaphylactoid reactions, bronchospasm/ dyspnoea, Quincke’s (angioneurotic oedema)		Anaphylacti c shock

	VERY COMMON	COMMON	UNCOMMON	RARE	VERY RARE	NOT KNOWN
Metabolism and nutrition disorders	Hypocalcae mia, Hypophosp hataemia	Asymptomatic hypocalcaemia Anorexia, Hypomagnesae mia, Hypokalaemia			Hyperkalae mia, , Hypernatrae mia
Psychiatric disorders					Visual hallucination s, Confusion
Nervous system disorders		Symptomatic hypocalcaemia (paraesthesia, tetany), Headache, Insomnia, Somnolence	Agitation, Dizziness, Seizures, Lethargy
Eye disorders		Conjunctivitis	Uveitis (iritis, iridocyclitis)		Scleritis, Episcleritis, Xanthopsia	Orbital inflammation
Cardio Vascular disorders		Hypertension	Hypotension		Left ventricular failure (dyspnoea, pulmonary oedema), Congestive heart failure (oedema) due to fluid overload.	Atrial fibrilation
Respiratory thoracic and mediastinal disorders			Bronchospasm (dyspnoea)		Adult respiratory distress syndrome, Interstitial lung disease
Gastrointest inal disorders		Nausea, Vomiting, Abdominal pain, Diarrhoea, Constipation, Gastritis	Dyspepsia
Skin and subcutaneou s tissue disorders		Rash	Pruritus, Quincke's oedema

	VERY COMMON	COMMON	UNCOMMON	RARE	VERY RARE	NOT KNOWN
Musculoske letal, connective tissue and bone disorders		Transient bone pain, Arthralgia, Myalgia, Generalised pain	Muscle cramps, Osteonecrosis			Osteonecrosis of the jaw
Renal and urinary disorders			Acute renal failure	Deterioratio n of renal function (see 4.4), Focal segmental glomeruloscl erosis including the collapsing variant, nephrotic syndrome. Reports of these events are generally associated with high dosage (exceeding the recommende d dosage or reduced dosing intervals) and/or longterm use	Haematuria, Deterioratio n of preexisting renal disease, Renal tubular disorder, Tubulointers titial nephritis, Glomerulone phropathy
General disorders and administrati on site conditions	Fever and influenzalike symptoms, sometimes accompanie d by malaise, rigor, fatigue and flushes. Generalised pain	Reactions at the infusion site: pain, redness, swelling, induration, phlebitis, thrombophlebiti s.	Cases of Osteonecrosis*		Atypical subtrochante ric and diaphyseal femoral fractures (bisphospho nate class adverse reaction).

VERY

COMMON

UNCOMMON

RARE

VERY

RARE

NOT KNOWN

Investigatio

Increase in

serum

creatinine

Abnormal liver function tests, Increase in serum urea

Many of the adverse drug reactions may have been related to the underlying disease.

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 (4 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:

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.

During post-marketing experience the following reactions have been reported.*Uncommon cases of osteonecrosis (primarily of the jaw) have been reported predominantly in cancer patients treated with bisphosphonates including pamidronate disodium (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 jaw has multiple well documented risk factors including a diagnosis of cancer, concomitant therapies (e.g. chemotherapy, radiotherapy, corticosteroids) and comorbid 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).

Osteonecrosis of the jaw

Cases of osteonecrosis (of the jaw) have been reported, predominantly in cancer patients treated with medicinal products that inhibit bone resorption, such as pamidronate disodium (see section 4.4). Many of these patients were also receiving chemotherapy and corticosteroids and had signs of local infection including osteomyelitis. The majority of the reports refer to cancer patients following tooth extractions or other dental surgeries.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

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. Acute hypocalcaemia is not expected to occur with pamidronate since plasma calcium levels fall progressively for several days after treatment.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Bisphosphonates ATC code: M05B A03

Mechanism of action

The active substance 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 disodium 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 disodium 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 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

Pamidronate disodium has a strong affinity for calcified tissues, and total elimination of pamidronate disodium 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 disodium rise rapidly after the start of an infusion and fall rapidly when the infusion is stopped. The apparent halflife 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 disodium concentrations of about 10 nmol/ml are achieved after an intravenous infusion of 60mg given over 1 hour and the apparent plasma clearance is about 180 ml/min.

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 disodium in bone is not capacity-limited, and is dependent solely on the total cumulative dose administered.

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

Elimination. Pamidronate disodium 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 disodium. 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 1.25-60mg/h). From the urinary elimination of pamidronate disodium, two decay phases, with apparent halflife of about 1.6 and 27 hours, can be observed. 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 disodium is insignificant.

Hepatic Impairment:

Impairment of liver function is therefore not expected to influence the pharmacokinetics of pamidronate disodium. Pamidronate disodium thus displays little potential for drug-drug interactions both at the metabolic level and at the level of protein binding (see above). No changes in dosing are recommended for patients with mild to moderate hepatic dysfunction.

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 and Section 4.4).

5.3 Preclinical safety data

In pregnant rats, pamidronate has been shown to cross the placental barrier and accumulate in foetal 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). There was no unequivocal evidence for teratogenicity in studies with intravenous administration of pamidronate to pregnant rats, although high doses (12 and 15 mg/kg/day) were associated with maternal toxicity and foetal developmental abnormalities (foetal 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, but there was no evidence for teratogenicity.

The toxicity of pamidronate disodium is characterised by direct (cytotoxic) effects on organs with a copious blood supply, particularly the stomach, lungs and kidneys following i.v. exposure. The compound is not mutagenic and does not appear to have carcinogenic potential. In animal studies with intravenous administration, renal tubular lesions were the prominent and consistent untoward effects of treatment.

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.

Carcinogenesis and Mutagenesis:

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 pamidronate 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.Pamidronate by daily oral administration was not carcinogenic in an 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.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Mannitol, sodium hydroxide, phosphoric acid (for pH adjustment), water for injection.

6.2 Incompatibilities

Pamidronate disodium will form complexes with divalent cations and should not be added to calcium-containing intravenous solutions.

6.3 Shelf life 3 years

6.4 Special precautions for storage

Chemical and physical in-use stability in glucose 50mg/ml has been demonstrated for 24 hours at 2-8°C.

From a microbiological point of view, the product should be used immediately.

If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2-8°C, unless dilution has taken place in controlled and validated aseptic conditions.

6.5 Nature and contents of container

10ml vials made of clear, colourless glass (Type I glass, Ph.Eur.).

The vial closures are made from chlorobutyl rubber, with a PTFE coated surface. The vials are then sealed with tamper proof aluminium caps, and packaged in a carton.

Pack sizes:

1, 2, 4, 5, 6 and 10 vials

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

The concentrate should be further diluted with a calcium-free infusion solution (0.9% w/v Sodium Chloride Intravenous Infusion is recommended) before administration. Do not use if particles are present. Any portion of the contents remaining after use should be discarded

7 MARKETING AUTHORISATION HOLDER

Tillomed Laboratories Ltd 3 Howard Road Eaton Socon, St. Neots Cambs PE 19 8 ET United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 11311/0219

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

Date of first authorisation: 21/09/2011

10 DATE OF REVISION OF THE TEXT

01/06/2016