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DISODIUM PAMIDRONATE 15 MG/ML CONCENTRATE FOR SOLUTION FOR INFUSION

Active substance(s): PAMIDRONIC ACID

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PACKAGE LEAFLET: INFORMATION FOR THE USER

Disodium Pamidronate 15mg/ml Concentrate for Solution for Infusion
Read all of this leaflet carefully before you start using this medicine.
- Keep this leaflet. You may need to read it again.
- If you have further questions, please ask your doctor or nurse.
- This medicine has been prescribed for you personally and you should not pass it on
to others. It may harm them, even if their symptoms are the same as yours.
- If any of the side effects get serious, or if you notice any side effects not listed in
this leaflet, please tell your doctor or nurse.
The name of your medicine is Disodium Pamidronate 15mg/ml Concentrate for Solution
for Infusion. In the rest of this leaflet it is called Disodium Pamidronate.
In this leaflet:
1. What Disodium Pamidronate is and what it is used for
2. Before you are given Disodium Pamidronate
3. How Disodium Pamidronate should be given
4. Possible side effects
5. How to store Disodium Pamidronate
6. Further information

1. WHAT DISODIUM PAMIDRONATE IS AND WHAT IT IS USED FOR
The active ingredient is called Disodium Pamidronate.
Disodium pamidronate belongs to a group of medicines called bisphosphonates, which
prevent bones from weakening and breaking.
Disodium Pamidronate is used to treat:
• high blood calcium levels (hypercalcaemia) due to tumours
• holes in the bone and bone pain due to the spread of breast cancer or bone marrow
cancer (myeloma)
• Paget’s disease of the bone (a chronic bone disorder)

2. BEFORE YOU ARE GIVEN DISODIUM PAMIDRONATE
You should not be given Disodium Pamidronate if you:
• are allergic to Disodium Pamidronate, any other bisphosphonate, or any of the other
ingredients listed in section 6. ‘FURTHER INFORMATION.’
• are pregnant
• are breast feeding
Speak to your doctor before being given Disodium Pamidronate if you:
• are receiving dental treatment or will be undergoing dental surgery such as a tooth
extraction (see information on osteonecrosis of the jaw below). Tell your dentist that
you are being treated with Disodium Pamidronate
• suffer from kidney disease or any other kidney problems
• have had an operation for thyroid problems
• suffer from liver disease or any other liver problems
• suffer from heart disease
• suffer from calcium or vitamin D deficiency which may have been caused by not
absorbing your food properly or by lack of exposure to the sun.
• are under 18 years of age.
If any of the above statements apply to you, speak to your doctor or nurse before you
are given Disodium Pamidronate.
Osteonecrosis of the jaw (a disease where bones die due to a lack of blood
supply) has been reported in patients treated with Disodium Pamidronate or other
bisphosphonates (see section 4 “POSSIBLE SIDE EFFECTS” for information on
recognising this condition). The majority of cases have been in cancer patients
following tooth extractions or other dental surgeries. A dental examination and
appropriate treatment is therefore recommended prior to starting treatment with
bisphosphonates.
If you have frequent infusions of Disodium Pamidronate over a prolonged period of time
your doctor may perform blood tests during your treatment to monitor calcium and
phosphate levels in the blood and to check your kidneys are working properly.
Your doctor will test your kidney function before each course of treatment.
Disodium Pamidronate may interfere with the results of bone scans. Please tell your
doctor or nurse if you are due to have a bone scan.
You should drink plenty of fluids during treatment so that you do not dehydrate.
SUMMARY OF PRODUCT CHARACTERISTICS
1. NAME OF THE MEDICINAL PRODUCT
Disodium pamidronate 15mg/ml concentrate for solution for infusion
2. QUALITATIVE AND QUANTITATIVE COMPOSTION
1ml of concentrate contains 15mg disodium pamidronate.
One ampoule of 1ml contains 15mg disodium pamidronate.
One ampoule of 2ml contains 30mg disodium pamidronate.
One ampoule of 4ml contains 60mg disodium pamidronate.
One ampoule of 6ml contains 90mg disodium pamidronate.
Excipient: Sodium.
For a full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Concentrate for solution for infusion.
Colourless solution, free from particles.
4. CLINICAL PARTICULARS
4.1. Therapeutic indications
Treatment of conditions associated with increased osteoclast activity:
CTumour-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
Disodium pamidronate concentrate must never be given as a bolus injection (see
“Warnings”). The concentrate of disodium pamidronate concentrate in ampoules should be
diluted in a calcium-free infusion solution (0.9 % Sodium Chloride Intravenous Infusion B.P. is
recommended) and infused slowly.
The infusion rate should never exceed 60mg/hour (1mg/min), and the concentration of
disodium pamidronate concentrate in the infusion solution should not exceed 90mg/250ml.
A dose of 90mg should normally be administered as a 2-hour infusion in 250mL infusion
solution. However, in patients with multiple myeloma and in patients with tumour-induced
hypercalcaemia, it is recommended not to exceed 90mg in 500mL over 4 hours. In
patients with established or suspected renal impairment (e.g. those with tumour-induced
hypercalcaemia or multiple myeloma) it is recommended that the infusion rate does not
exceed 20mg/h (see also “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, disodium pamidronate concentrate is only recommended
for use in adult patients. The optimal duration of bisphosphonate treatment for osteoporosis
has not been established. The need for continued treatment should be re-evaluated
periodically based on the benefits and potential risks of Disodium Pamidronate on an
individual patient basis, particularly after 5 or more years of use.
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 disodium pamidronate concentrate 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.
Recommended total

Initial serum calcium
(mmol/l)

(mg %)

dose (mg)

up to 3.0
3.0 – 3.5
3.5 – 4.0
> 4.0

up to 12.0
12.0 – 14.0
14.0 – 16.0
> 16.0

15 – 30
30 – 60
60 – 90
90

The total dose of disodium pamidronate concentrate 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 repeated courses.
A significant decrease in serum calcium is generally observed 24-48 hours after
administration of Disodium Pamidronate Injection, and normalisation is usually achieved
within three to seven 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
disodium pamidronate concentrate may become less effective as the number of treatments
increases.
Adults and Elderly
Predominantly lytic bone metastases and multiple myeloma
The recommended dose of disodium pamidronate for the treatment of predominantly lytic
bone metastases and multiple myeloma is 90mg administered as a single infusion every
4 weeks.
In patients with bone metastases who receive chemotherapy at 3-weekly intervals, disodium
pamidroante 90mg may also be given on a 3-weekly schedule.
Osteolytic lesions and bone pain in bone metastases associated with breast cancer
The recommended dose is 90mg every four weeks. This dose may also be administered at
three weekly intervals to coincide with chemotherapy if desired.
The recommended total dose of disodium pamidronate for a treatment course is 180 to
210mg. This can be administered either in 6 unit doses of 30mg once a week (total dose of
180mg), or in 3 unit doses of 60mg every other week. Experience to date suggests that any
mild and transient unwanted effects (see “Side-effects”) tend to occur after the first dose.
For this reason if unit doses of 60mg are used it is recommended that treatment be started
with an initial additional dose of 30mg (i.e. total dose 210mg). Each dose of 30 or 60mg

Taking other medicines
Taking another medicine while you are being given Disodium Pamidronate can affect
how it or the other medicine works. Please inform your doctor or nurse if you are taking
or have recently taken any other medicines, even those you may have bought yourself
without a prescription.
Please particularly check with your doctor if you are taking or need to take any of the
following:
• any other bisphosphonates
• calcitonin, used to control the levels of calcium in the blood
• aminoglycoside antibiotics such as gentamicin and amikacin
If you are suffering from Paget’s disease of the bone, you may be advised to take
calcium and vitamin D tablets while you are being treated with Disodium Pamidronate.
Pregnancy and breast-feeding
You should not be given Disodium Pamidronate during pregnancy except when your
calcium level is so high that it is life-threatening. You should let your doctor know
immediately if you are pregnant or trying for a baby, before this medicine is given to you.
You should not breast feed whilst receiving Disodium Pamidronate as the active
ingredient can enter breast milk. You should let your doctor know if you are breastfeeding or want to start breast-feeding while you are having treatment with Disodium
Pamidronate.
Driving and using machines
Sleepiness and dizziness may rarely occur with Disodium Pamidronate. If these side
effects are experienced whilst being given Disodium Pamidronate, you should not drive
or operate machinery.
Important information about the sodium content of Disodium Pamidronate
Disodium Pamidronate 1,2 and 4ml ampoules contain less than 1mmol (23 mg) sodium
per ampoule i.e. essentially ‘sodium-free’.
Disodium Pamidronate 6ml ampoules contain 1.04 mmol (or 23.9 mg) sodium per
ampoule. To be taken into consideration by patients on a controlled sodium diet.

3. HOW DISODIUM PAMIDRONATE SHOULD BE GIVEN
You will only be given Disodium Pamidronate under the supervision of a doctor and in
suitable premises. Your doctor or nurse will prepare your injection by diluting it with
a calcium free solution in a larger container (e.g. a salt solution). The mixture is given
by a slow injection into a vein (intravenous infusion).
Disodium Pamidronate must never be given as a single short injection.
The total dose of Disodium Pamidronate may be given either in a single infusion
or in several infusions over 2 to 4 consecutive days. The maximum dose per treatment
course is 90mg. The recommended infusion rate should not be greater than
60mg/hour (1mg/minute) and the amount of Disodium Pamidronate in the infusion
solution should not be greater than 60mg/250ml.
To treat high blood calcium levels due to tumours
The usual total dose for adults is 15 to 90mg, depending on your blood calcium levels.
To treat holes in the bones and bone pain due to cancer spread
The usual adult dose is 90mg every four weeks. For patients with breast cancer this
may be given at three week intervals to coincide with chemotherapy.
To treat Paget’s disease
The usual adult dose is 30mg once a week for six weeks (total 180mg), or 30mg once
and then 60mg every other week over 6 weeks (total 210mg). Treatment may be
repeated every six months.
If you have kidney disease
Although you will be given the same dose as described above, if you have kidney
disease your infusion will be given more slowly (the fastest infusion rate should
be 20mg/hour).
If you have liver disease
No changes in the doses described above are required.
Your doctor will decide the dose that is best for you. If you do not understand, or are in
any doubt, ask your doctor or nurse.
If you stop treatment with Disodium Pamidronate
Your doctor will decide when you can stop treatment with Disodium Pamidronate.

should be diluted in 125 or 250 ml 0.9% w/v Sodium Chloride Intravenous Infusion B.P.
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 six months until remission of disease is
achieved, and if relapse occurs.

Precautions
Serum electrolytes, calcium and phosphate should be monitored following initiation of
therapy with disodium pamidronate concentrate. Patients who have undergone thyroid
surgery may be particularly susceptible to developing hypocalcaemia due to relative
hypoparathyroidism.

Renal Impairment
Disodium pamidronate should not be administered to patients with severe renal impairment
(creatinine clearance < 30mL/min) unless in cases of life-threatening tumour-induced
hypercalcaemia when the benefit outweighs the potential risk.

Hepatic Insufficiency
Although there is no clinical data available in patients with severe hepatic impairment,
disodium pamidronate should be used with caution in this patient population.

As with other i.v. bisphosphonates, renal monitoring is recommended, for instance,
measurement of serum creatinine prior to each dose of disodium pamidronate.
In patients receiving disodium pamidronate for bone metastases or multiple myeloma
who show evidence of deterioration in renal function, disodium pamidronate 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.
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 to 90 mL/min) to moderate renal impairment (creatinine clearance 30 to 60 mL/min).
In such patients, the infusion rate should not exceed 90 mg/4h (approximately 20 to
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 as 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 Pharmacokinetic properties - Hepatic impairment). Clinical
data in patients with severe hepatic impairment is not available. Pamidronate should be
administered to this patient population with caution.
Children
There is no clinical experience of the use of disodium pamidronate in children.
4.3. Contraindications
Known hypersensitivity to disodium pamidronate or to other bisphosphonates or to any of the
excipients of disodium pamidronate.
Disodium Pamidronate is contraindicated in pregnancy and in breast feeding women.
4.4. Special warning and precautions for use
Warnings
Disodium pamidronate concentrate should be given under the supervision of a physician
with the facilities to monitor clinical and biochemical effects.
Disodium pamidronate concentrate should not 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”).
Disodium pamidronate concentrate should not be given with other bisphosphonates because
their combined effects have not been investigated.

There is very little experience of the use of disodium pamidronate concentrate in patients
receiving haemodialysis.
Patients should be adequately hydrated throughout treatment, this is especially important
for patients receiving diuretic therapy, but overhydration should 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. Patients with anaemia, leukopenia or
thrombocytopenia should have regular haematology.
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, and patients with
Paget’s disease of the bone, should be given oral calcium and vitamin D supplementation,
in order to minimise the risk of hypocalcaemia
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 varied from one day to several months after starting the drug.
Most patients had relief of symptoms after stopping treatment. A subset had recurrence of
symptoms when rechallenged with the same drug or another bisphosphonate.
Osteonecrosis of the jaw has been reported predominantly in patients with cancer receiving
treatment regimens involving bisphosphonates (including disodium 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.
Post-marketing experience and the literature suggest a greater frequency of reports of ONJ
based on tumour type (advanced breast cancer, multiple myeloma), and dental status (dental
extraction, periodontal disease, local trauma including poorly fitting dentures).
A dental examination with appropriate preventive dentistry should be considered prior to
treatment with bisphosphonates in patients with concomitant risk factors (e.g. cancer,
chemotherapy, corticosteroids, poor oral hygiene). While on treatment, these patients should
avoid invasive dental procedures if possible. For patients who develop osteonecrosis of
the jaw while on bisphosphonate therapy, dental surgery may exacerbate the condition.
For patients requiring dental procedures, there are no data available to suggest whether
discontinuation of bisphosphonate treatment reduces the risk of osteonecrosis of the jaw.
Clinical judgement of the treating physician should guide the management plan of each
patient based on individual benefit/risk assessment.
This medicinal product contains less than 1 mmol (23 mg) sodium per ampoule i.e.
essentially ‘sodium-free’.

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

4.5. Interaction with other medicinal products and other forms of interaction
Disodium pamidronate concentrate has been administered concomitantly with commonly
used anticancer agents without interactions occurring.

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

Disodium pamidronate concentrate 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.

Atypcal 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.
Osteonecrosis of the jaw has been reported in patients with cancer receiving treatment
regimens involving bisphosphonates (including disodium 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.

Caution is warranted when disodium pamidronate is used with other potentially nephrotoxic
drugs.
In multiple myeloma patients, the risk of renal dysfunction may be increased when disodium
pamidronate is used in combination with thalidomide.
Since pamidronate binds to bone, it could in theory interfere with bone scintigraphy
examinations.
Antibacterials: There may be an increased risk of hypocalcaemia when biphosphonates and
aminoglycosides are used concurrently or sequentially.
4.6. Pregnancy and lactation
Pregnancy
There are no adequate data for the use of pamidronate in pregnant women. There is no
unequivocal evidence for teratogenicity in animal studies. 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.
There is insufficient clinical experience to support the use of disodium pamidronate
concentrate in pregnant women. Therefore, disodium pamidronate concentrate should
not be administered during pregnancy except in cases of life-threatening hypercalcaemia.
Evidence is limited to a few cases but if used in the treatment of women with life threatening
hypercalcemia, infants should be monitored for hypocalcemia during the first few days
after birth.
Breastfeeding
Very limited experience indicates maternal milk levels of pamidronate under the limit of
detection. 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.

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Description

DISODIUM PAMIDRONATE CONCENTRATE FOR SOLUTION FOR INFUSION

Process Black

Item Code

104228/3

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As per uploaded pdf

Size

210 X 420mm

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Keylines

If you are given more Disodium Pamidronate than you should
A doctor or a nurse will give you this medicine. If you think you may have received too
much Disodium Pamidronate, please tell your doctor or nurse immediately. Signs that
you may have been given too much medicine include ‘pins and needles’, a locked jaw
and low blood pressure due to low calcium levels.
If you think you have missed a dose of Disodium Pamidronate
A doctor or a nurse will give you this medicine. If you think you have missed a dose,
please tell your doctor or nurse.

4. POSSIBLE SIDE EFFECTS
Like many medicines, Disodium Pamidronate may cause side effects in some patients,
although not everybody gets them.
Side effects of Disodium Pamidronate usually occur within the first 48 hours of
treatment and then go away again.
Allergic reactions occur uncommonly. If you experience difficulty breathing,
shortness of breath, swelling of the face, lips or eyes or anaphylactic shock
(allergic shock) with a sudden decrease in blood pressure, contact your doctor
immediately.
Other side effects include:
Very common (more than 1 in 10 patients)
• fever and flu-like symptoms, such as feeling unwell, shivering, tiredness and hot
flushes
• low calcium or low phosphate levels in the blood
Common (between 1 in 10 and 1 in 100 patients)
• reactions at the infusion site - pain, inflamed veins, swelling or redness
• bone pain, joint or muscle pain or general aches and pains
• nausea or vomiting
• headache
• reduction of lymphocytes (white cells) in the blood
• low magnesium levels in the blood
Uncommon (between 1 in 100 and 1 in 1000 patients)
The following are uncommon symptoms, but if you do get any you must tell your doctor
or nurse:
Muscle cramps, stomach pain, diarrhoea, constipation, loss of appetite, indigestion,
feeling agitated, confusion, dizziness, difficulty sleeping, sleepiness, feeling lethargic,
anaemia, a decrease of white blood cells, high or low blood pressure, rash, itching,
eye pain or irritation, a yellow tinge to your vision or changes in various salts
in the blood.
Very rare, including isolated cases (less than 1 in 10,000 patients)
Inflammation of the stomach, fits, hallucinations (seeing things that are not there),
a tendency to bruise or bleed easily, cold sores or shingles, blood in the urine,
worsening of kidney disease or changes in liver or kidney tests.
Unusual fracture of the thigh bone particularly in patients on long-term treatment for
osteoporosis may occur rarely. Contact your doctor if you experience pain, weakness
or discomfort in your thigh, hip or groin as this may be an early indication of a possible
fracture of the thigh bone.
Rarely osteonecrosis (a disease where bones die due to a lack of blood
supply), mainly of the jaw, has been reported in patients treated with Disodium
Pamidronate or other bisphosphonates. The symptoms of osteonecrosis of the
jaw include: pain, swelling or numbness of the jaw or a “heavy jaw feeling” or
loosening of a tooth. The majority of cases have been in cancer patients following
tooth extractions or other dental surgeries.
Irregular heart rhythm (atrial fibrillation) has been seen in patients receiving
pamidronate. It is currently unclear whether pamindronate causes this irregular heart
rhythm. You should tell your doctor if you experience irregular heart rhythm during
treatment with pamindronate.
Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any
possible side effects not listed in this leaflet. You can also report side effects directly via
the national reporting systems listed below.
United Kingdom
Yellow Card Scheme
www.mhra.gov.uk/yellowcard
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 disodium pamidronate 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 disodium pamidronate concentrate 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. Symptomatic
hypocalcaemia is rare.
Adverse reactions (Table 1) are ranked under headings of frequency, the most frequent
first,using the following convention:
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), 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.
Table 2
Infections and infestations
Very rare:

Reactivation of Herpes simplex, reactivation of
Herpes zoster.
Blood and lymphatic system disorders
Common:
Anaemia, thrombocytopenia, lymphocytopenia.
Very rare:
Leukopenia.
Immune system disorders
Uncommon:
Allergic reactions including anaphylactoid
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.
Cardiac disorders
Very rare:
Left ventricular failure (dyspnoea, pulmonary
oedema), congestive heart failure (oedema) due
to fluid overload.
Not known
Atrial fibrillation.
Vascular disorders
Common:
Hypertension.
Uncommon:
Hypotension.
Respiratory, thoracic and mediastinal disorders
Very rare:
Acute respiratory distress syndrome, interstitial
lung disease.
Gastrointestinal disorders
Common:
Nausea, vomiting, anorexia, abdominal pain,
diarrhoea, constipation, gastritis.
Uncommon:
Dyspepsia.
Skin and subcutaneous disorders
Common:
Rash.
Uncommon:
Pruritus.
Musculoskeletal and connective tissue disorders
Common:
Transient bone pain, arthralgia, myalgia,
generalised pain.
Uncommon:
Muscle cramps, Osteonecrosis.
Renal and urinary disorders
Uncommon:
Acute renal failure.
Rare:
Focal segmental glomerulosclerosis including the
collapsing variant, nephrotic syndrome.
Very rare:
Deterioration of pre-existing renal disease,
haematuria, renal tubular disorder,
tubulointerstitial nephritis, glomeruloephropathy.
General disorders and administration site conditions
Very Common:
Fever and influenza-like symptoms sometimes
accompanied by malaise, rigor, fatigue, and
flushes.
Common:
Reactions at the infusion site (pain, redness,
swelling, induration, phlebitis, thrombophlebitis).
Investigations
Common:
Increase in serum creatinine.
Uncommon:
Abnormal liver function tests, increase in
serum urea.
Atrial fibrillation: 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

Ireland
HPRA Pharmacovigilance
Earlsfort Terrace
IRL - Dublin 2
Tel: +353 1 6764971
Fax: +353 1 6762517
Website: www.hpra.ie
e-mail: medsafety@hpra.ie
By reporting side effects you can help provide more information on the safety of this
medicine.

5. HOW TO STORE DISODIUM PAMIDRONATE
Disodium Pamidronate must be kept out of the reach and sight of children.
• Disodium Pamidronate should not be used after the expiry date given on the
ampoule. The expiry date refers to the last day of that month.
• Your doctor, nurse or pharmacist will be responsible for storing and preparing
Disodium Pamidronate before use and for checking that the ampoules have not
passed theirexpiry date.
• The medicine should not be used if it shows any signs of deterioration such as going
cloudy.
• Disodium Pamidronate should not be stored above 25°C. The ampoules should be
kept in their outer carton, in order to protect from light.
• Once the solution has been diluted the product should be used immediately.
Medicines should not be disposed of via wastewater or household waste. Ask your
pharmacist how to dispose of medicines no longer required. These measures will help
to protect the environment.

6. FURTHER INFORMATION
What Disodium Pamidronate contains
Each 1ml of solution contains 15mg disodium pamidronate.
The other ingredients are sodium chloride, sodium hydroxide (E524), hydrochloric acid
(E507) and water for injections.
What Disodium Pamidronate looks like and contents of the pack
The injection is a clear, colourless solution.
1 ampoule of 1ml contains 15mg disodium pamidronate.
1 ampoule of 2ml contains 30mg disodium pamidronate.
1 ampoule of 4ml contains 60mg disodium pamidronate.
1 ampoule of 6ml contains 90mg disodium pamidronate.
Packs may contain 1, 2 or 4 ampoules. Not all pack sizes may be marketed.
Other formats
To listen to or request a copy of this leaflet in Braille, large print or audio please call,
free of charge: 0800 198 5000 (UK Only)
Please be ready to give the following information:
Product Name

Reference Number

Disodium Pamidronate 15mg/ml Concentrate for
Solution for Infusion (15mg in 1ml)

29831/0071

Disodium Pamidronate 15mg/ml Concentrate for
Solution for Infusion (30mg in 2ml)

29831/0072

Disodium Pamidronate 15mg/ml Concentrate for
Solution for Infusion (60mg in 4ml)

29831/0073

Disodium Pamidronate 15mg/ml Concentrate for
Solution for Infusion (90mg in 6ml)

29831/0074

This is a service provided by the Royal National Institute of Blind People.
For the Republic of Ireland please call +44 1978 669272.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder:
Wockhardt UK Ltd, Ash Road North, Wrexham, LL13 9UF, UK.
Manufacturer: CP Pharmaceuticals Ltd, Ash Road North,
Wrexham, LL13 9UF, UK.
This leaflet was revised in 08/2015.
104228/3

pamidronate group (12/556, 2.2%) than in the zoledronic acid group (3/563, 0.5%). Isolated
instances of higher incidence of atrial fibrillation have also been reported in a few studies
with other bisphosphonates. The mechanism of this increased incidence of atrial fibrillation in
isolated studies with some bisphosphonates, including disodium pamidronate, is unknown.
Post-marketing experience:
The following adverse reactions have been reported during post-approval use of disodium
pamidronate.
Cases of osteonecrosis (primarily of the jaws) have been reported predominantly in cancer
patients treated with bisphosphonates, including disodium pamidronate (uncommon).
Many of these patients had signs of local infection including osteomyelitis and the majority
of the reports refers to cancer patients following tooth extractions or other dental surgeries.
Osteonecrosis of the jaws has multiple well documented risk factors including a diagnosis
of cancer, concomitant therapies (e.g. chemotherapy, radiotherapy, corticosteroids) and
co-morbid conditions (e.g. anaemia, coagulopathies, infection, pre-existing oral disease).
Although causality has not been determined, it is prudent to avoid dental surgery as recovery
may be prolonged. Data suggest a greater frequency of reports of ONJ based on tumour type
(advanced breast cancer, multiple myeloma).
During post-marketing experience the following reactions have been reported (frequency rare):
Atypical subtrochanteric and diaphyseal femoral fractures (bisphosphonate class adverse
reaction)
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 national reporting system:
United Kingdom
Yellow Card Scheme
www.mhra.gov.uk/yellowcard
Ireland
HPRA Pharmacovigilance
Earlsfort Terrace
IRL - Dublin 2
Tel: +353 1 6764971
Fax: +353 1 6762517
Website: www.hpra.ie
e-mail: medsafety@hpra.ie
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
Pamidronate disodium, the active substance of disodium pamidronate concentrate,
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.

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 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. Disodium pamidronate
concentrate 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 disodium pamidronate concentrate 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 disodium pamidronate
concentrate is administered on a monthly basis, drug accumulation is not expected. No changes
in disodium pamidronate concentrate dosing regimen are recommended for patients with mild to
moderate abnormal hepatic function (see Posology and method of administration).
Renal impairment
The mean plasma AUC was approximately doubled in cancer patients at risk for bone
metastases with severe renal impairment (creatinine clearance <30ml/min, n=4).
Urinary excretion rate decreased with decreasing creatinine clearance, although the total
amount excreted in the urine was not greatly influenced by renal function. Body retention
of pamidronate was therefore similar in cancer patients with and without impaired
renal function, and dose adjustment is not necessary in these patients when using the
recommended dose schedule (see Posology and method of administration).
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.
6. PHARMACEUTICAL PARTICULARS
6.1. List of excipients
Sodium chloride, Sodium hydroxide, Hydrochloric acid, Water for Injections

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

6.2. Incompatibilities
Pamidronate will form complexes with divalent cations and should not be added to calciumcontaining intravenous solutions.

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 disodium pamidronate
concentrate 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.

6.3. Shelf life
3 years
Reconstituted solutions that have been further diluted with one of the recommended diluents
for intravenous infusion should be used immediately. Discard the unused portion.

Hypercalcaemia can lead to a depletion in the volume of extracellular fluid and a reduction
in the glomerular filtration rate (GFR). By controlling hypercalcaemia, disodium pamidronate
concentrate 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 disodium pamidronate concentrate 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
disodium pamidronate concentrate. 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 sites 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.

6.4. Special precautions for storage
Do not store above 25°C. Keep the ampoules in the outer carton. Chemical and physical
in-use stability has been demonstrated for 48 hours at 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 to 8 °C, unless dilution has taken place in controlled and validated
aseptic conditions.
Also refer to section 6.3.
6.5. Nature and contents of container
1ml, 2ml, 4ml or 6ml polyethylene ampoules in packs of 1, 2 or 4 ampoules.
Not all pack sizes may be marketed.
6.6. Special precautions for disposal
The concentrate should be diluted with a calcium-free infusion solution (0.9% w/v Sodium
Chloride Intravenous Infusion BP is recommended) before administration.
7. MARKETING AUTHORISATION HOLDER
Wockhardt UK Ltd, Ash Road North, Wrexham, LL13 9UF, UK.
8. MARKETING AUTHORISATION NUMBER(S)
15mg PL 29831/0071 PA 1339 / 7 / 1
30mg PL 29831/0072 PA 1339 / 7 / 2
60mg PL 29831/0073 PA 1339 / 7 / 3
90mg PL 29831/0074 PA 1339 / 7 / 4
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
UK. 2nd April 2008 Ireland. 6th June 2008
10. DATE OF REVISION OF THE TEXT
08/2015

104228/3

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the final responsibility must be taken by our client.
IF YOU SIGN THIS PROOF YOU ARE SIGNIFYING
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Customer

Wockhardt UK Limited

Colours Used

Description

DISODIUM PAMIDRONATE CONCENTRATE FOR SOLUTION FOR INFUSION

Process Black

Item Code

104228/3

Profile

As per uploaded pdf

Size

210 X 420mm

Min. Point Size

5pt (main body) / 6pt (variables)

Market

UK

Language

English

Proof By

elkie.bramall / tom.robertson

Proof No.

1

Date

11/08/2015

Artwork No.

589194

Pharma
Code

N/A

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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