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PAMIDRONATE DISODIUM 9MG/ML STERILE CONCENTRATE

Active substance(s): PAMIDRONIC ACID

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Pamidronate Disodium 9 mg/ml Sterile Concentrate

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each ml of concentrate for solution for infusion contains 9 mg pamidronate disodium.
1 vial of 10 ml of sterile concentrate contains 90 mg of pamidronate disodium.
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Concentrate for solution for infusion.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
The treatment of tumour-induced hypercalcaemia
The prevention of skeletal related events (pathological fractures, spinal compression,
radiation or surgery to bone, hypercalcaemia and bone pain) in patients with breast
cancer with bone metastases, or multiple myeloma with bone lesions, in addition to
specific treatment of the tumour
Paget’s disease of bone

4.2

Posology and method of administration

Patients treated with pamidronate disodium should be given the package leaflet and
the patient reminder card.
For intravenous use as infusion only.
Pamidronate disodium must never be given as a bolus injection (see “Warnings”).
The solution must be diluted before use (see below) and must be infused slowly.
For information concerning compatibility with infusion solutions, see section 6.2.
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 90 mg/250 ml. In
patients with established or suspected renal impairment (e.g. those with tumourinduced hypercalcaemia or multiple myeloma) it is recommended that the infusion
rate does not exceed 22 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. A single dose of 90 mg should normally be administered as a 2
hour infusion in 250 ml of infusion solution. However in patients with established or
suspected renal impairment (e.g. those with tumour-induced hypercalcaemia or
multiple myeloma) it is recommended that no more than 90 mg in 500 ml is
administered over a 4 hour period.
Until further experience is gained, pamidronate disodium is only recommended for
use in adult patients. There is no clinical experience in the paediatric and adolescent
(<18 years old) population.
Tumour-induced hypercalcaemia:
It is recommended that patients be rehydrated with 0.9% w/v sodium chloride
solution before and 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 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 administered as a single infusion every 4 weeks.
Osteolytic lesions and bone pain in bone metastases associated with breast cancer:
The recommended dose is 90 mg administered as a single infusion 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 total dose of pamidronate disodium for a treatment course is 180
to 210 mg. This can be administered either in 6 unit doses of 30 mg once a week
(total dose 180 mg) or in 3 doses of 60 mg every other week . Experience to date
suggests that any mild and transient unwanted effects (see “Undesirable Effects”)
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
followed by 60 mg every other week (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 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:
Pharmacokinetic studies indicate that no dose adjustment is necessary in patients with
mild (creatinine clearance 61 to 90 mL/min) to moderate (creatinine clearance 30 to
60 mL/min) renal impairment (see 5.2 Pharmacokinetic properties). In such patients,
the infusion rate should not exceed 90 mg/4 h (approximately 22 mg/h).
Pamidronate disodium should not be administered to patients with severe renal
impairment (creatinine clearance < 30 ml/min) unless in case 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
4.4 Special warnings and precautions for use).

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 0.5 mg/dL.
• For patients with abnormal baseline creatinine, increase of 1.0 mg/dL.
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 as
being clinically relevant. As pamidronate is still rapidly cleared from the plasma
almost entirely into the bone and as it 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. Pamidronate
disodium has not been studied in patients with severe hepatic impairment, and
therefore it should be administered to this patient population with caution (see 4.4
Special warnings and precautions for use).

4.3

Contraindications
Known or suspected hypersensitivity to pamidronate, to any of the excipients, or to
other bisphosphonates.

4.4

Special warnings and precautions for use
Warnings:
Pamidronate should never be given as a bolus injection since severe local reactions
and thrombophlebitis may occur. It should always be diluted and then given as a
slow intravenous infusion (see “Posology and Method of Administration”).
Do not co-administer pamidronate with other bisphosphonates. If other calcium
lowering agents are used in conjunction with pamidronate, significant hypocalcaemia
may result.
Pamidronate is not recommended during pregnancy.
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.
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 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
develop 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.
The safety and efficacy of pamidronate in children has not been established. Until
further experience is gained, pamidronate is only recommended for use in adult
patients.
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 been reported following long-term treatment
with pamidronate 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.
Due to the risk of clinically significant deterioration in renal function which may
progress to renal failure, single doses of pamidronate should not exceed 90 mg, and
the recommended infusion time should be observed (see section 4.2 Posology and
method of administration).
Pamidronate disodium is excreted intact primarily via the kidney (see 5.2,
Pharmacokinetic properties), thus the risk of renal adverse reactions may be greater in
patients with impaired renal function.
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.

There is very little experience of the use of pamidronate disodium in patients
receiving haemodialysis.
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 given with other bisphosphonates because their combined
effects have not been investigated.
Hepatic insufficiency
Pamidronate disodium has not been studied in patients with severe hepatic
impairment, therefore no specific recommendations can be given for this patient
population (see 4.2 Posology and method of administration).
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 be given 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 in clinical trials and in the postmarketing 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 benefitrisk 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.

Osteonecrosis of the external auditory canal
Osteonecrosis of the external auditory canal has been reported with bisphosphonates,
mainly in association with long-term therapy. Possible risk factors for osteonecrosis
of the external auditory canal include steroid use and chemotherapy and/or local risk
factors such as infection or trauma. The possibility of osteonecrosis of the external
auditory canal should be considered in patients receiving bisphosphonates who
present with ear symptoms including chronic ear infections.
Musculoskeletal pain
In post-marketing experience, severe and occasionally incapacitating bone, joint,
and/or muscle pain has been reported in patients taking bisphosphonates. However,
such reports have been infrequent. This category of drugs includes pamidronate
disodium for infusion. The time to onset of symptoms varies 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 bisphosphate.
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 bisphosphonatetreated 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-tumour drugs (including aminoglutethimide, cisplatin, corticosteroids,
cyclophosphamide, cytarabine, doxorubicin, etoposide, fluorouracil, megestrol,
melphalan, methotrexate, mitoxantrone, paclitaxel, tamoxifen, vinblastine and
vincristine) without significant interactions.
Pamidronate should not be used concomitantly with other bisphosphonates.
In patients with severe hypercalcaemia, pamidronate has been sucessfully combined
with both calcitonin and mithramycin to accelerate and potentiate the calcium
lowering effect.
Since pamidronate binds to bone, it could in theory interfere with bone scintigraphy
examinations.
Caution is warranted when pamidronate is used with other potentially nephrotoxic
drugs.
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
In multiple myeloma patients, the risk of renal dysfunction may be increased when
pamidronate is used in combination with thalidomide.

4.6

Fertility, pregnancy and lactation
Pregnancy:
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 in pregnant women. It is not known if pamidronate
crosses the human placenta. The drug should not be given to pregnant women at any
stage unless life-threatening hypercalcaemia cannot be controlled by any other means.

Breast-feeding:
It is not known whether pamidronate is excreted into 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 will pass into the milk.
Moreover the oral bioavalibility is poor so the total absorption of pamidronate by a
breastfed infant is not likely. 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 which may last
up to 48 hours). 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.
When the effects of zoledronate (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 zoledronate group (3/563, 0.5%).
Previously, it has been observed in a clinical trial, investigating patients with
postmenopausal osteoporosis, that zoledronate treated patients (4 mg) had an
increased rate 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 zoledronate and pamidronate treatment is unknown.
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).The
following adverse drug reactions were reported from clinical studies and from postmarketing experience with pamidronate.
Infections and infestations:
Very rare: Reactivation of Herpes simplex and Herpes zoster

Blood and lymphatic system disorders:
Common: Anaemia, thrombocytopenia, lymphocytopenia
Very rare: Leukopenia
Immune system disorders:
Uncommon: Allergic reactions, anaphylactic reactions, bronchospasm (dyspnoea),
Quincke´s (angioneurotic) oedema
Very rare: Anaphylactic shock
Metabolism and nutrition disorders:
Very common: Hypocalcaemia, hypophosphataemia.
Common: Hypokalaemia, hypomagnesaemia
Very rare: Hyperkalaemia, hypernatraemia
Nervous system disorders:
Common: Symptomatic hypocalcaemia (paraesthesia, tetany), headache, insomnia,
somnolence
Uncommon: Seizures, agitation, dizziness, lethargy.
Very rare: Confusion, visual hallucinations.
Eye disorders:
Common: Conjunctivitis
Uncommon: Uveitis (iritis, iridocyclitis)
Very rare: Scleritis, episcleritis, xanthopsia.
Not known: Orbital inflammation
Ear and labyrinth disorders:
Very rare: Osteonecrosis of the external auditory canal (bisphosphonate class adverse
reaction)
Cardiac disorders:
Very rare: Left ventricular failure (dyspnoea, pulmonary oedema), congestive heart
failure (oedema) due to fluid overload
Not known: Atrial fibrilation
Vascular disorders:
Common: Hypertension
Uncommon: Hypotension
Respiratory thoracic and mediastinal disorders:
Uncommon: bronchospasm (dyspnoea)
Very rare: Adult respiratory distress syndrome, interstitial lung disease
Gastrointestinal disorders:
Common: Nausea, vomiting, anorexia, abdominal pain, diarrhoea, constipation,
gastritis
Uncommon: Dyspepsia
Hepato-bilary disorders:
Uncommon: Abnormal liver function tests
Skin and subcutaneous tissue disorders:
Common: Rash

Uncommon: Pruritus, Quincke´s oedema
Musculoskeletal and connective tissue disorders:
Common: Transient bone pain, arthralgia, myalgia, generalised pain.
Uncommon: Muscle cramps, Osteonecrosis
Not known: Osteonecrosis of the jaw
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.

Renal and urinary disorders:
Common: Increase in serum creatinine
Uncommon: Acute renal failure, increase in serum urea
Rare: deterioration of renal function (see 4.4 Special warning and precautions for
use). Focal segmental glomerulosclerosis including collapsing variant, nephrotic
syndrome. Reports of these events are generally associated with high dosage
(exceeding the recommended dosage or reduced dosing intervals) and/or long-term
use.
Very rare: Haematuria, deterioration of pre-existing renal disease, renal tubular
disorder, tubulointerstitial nephritis, glomerulonephropathy
General disorders and administration site conditions:
Very Common: Fever and influenza-like symptoms sometimes accompanied by
malaise, rigor, fatigue and flushes, generalised pain.
Common: Reactions at the infusion site (pain, redness, swelling, induration, phlebitis,
thrombophlebitis)

Many of these undesirable effects may have been related to the underlying disease.
Bisphosphonate class adverse reaction
Very rare: Atypical subtrochanteric and diaphyseal femoral fractures

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: Inhibitor of bone resorption, ATC code: MO5B A03
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, 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 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. 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 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. 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).
As pamidronic acid is administered on a monthly basis, drug accumulation is not
expected.

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 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.
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
Phosphoric acid
Sodium hydroxide
Water for Injections.

6.2

Incompatibilities
Pamidronate will form complexes with divalent cations and should not be added to
calcium-containing intravenous solutions such as Ringer’s solution.

6.3

Shelf life
As packaged for sale: 36 months.
In use: 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.
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.

6.4

Special precautions for storage
Prior to first use: Do not store above 25°C. Keep container in the outer carton.
For storage conditions after dilution of the medicinal product, see section 6.3

6.5

Nature and contents of container
15 mg/5 ml clear glass vials in pack of 5 vials.
30 mg/10 ml clear glass vial in packs of 1 vial.
Not all pack sizes may be marketed

6.6

Special precautions for disposal
Must be diluted prior to administration.
The concentration of pamidronate disodium in the infusion solution should not
exceed 90 mg/250 ml.

Do not use solution if particles are present.
Any unused medicinal product or waste material should be disposed of in accordance
with local requirements.

7

MARKETING AUTHORISATION HOLDER
Hospira UK Limited
Horizon
Honey Lane
Hurley
Maidenhead
SL6 6RJ
UK

8

MARKETING AUTHORISATION NUMBER(S)
PL 04515/0121

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
Date of first authorisation:
14 June 2001
Date of last renewal:
18 March 2009

10

DATE OF REVISION OF THE TEXT

15/06/2017

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Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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