Disodium Pamidronate 15mg/ ml Concentrate for Solution for Infusion

Main information

  • Trade name:
  • Disodium Pamidronate 15mg/ ml Concentrate for Solution for Infusion, 6ml
  • Dosage:
  • 15 milligram(s)/ millilitre
  • Pharmaceutical form:
  • Concentrate for solution for infusion
  • Prescription type:
  • Product subject to prescription which may not be renewed (A)
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • Disodium Pamidronate 15mg/ml Concentrate for Solution for Infusion, 6ml
    Ireland
  • Language:
  • English

Therapeutic information

  • Therapeutic area:
  • Bisphosphonates; pamidronic acid

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization status:
  • Marketed
  • Authorization number:
  • PA1339/007/004
  • Authorization date:
  • 26-08-2005
  • Last update:
  • 21-03-2019

Patient Information leaflet: composition, indications, side effects, dosage, interactions, adverse reactions, pregnancy, lactation

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 because it contains

important information for you.

- 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 only. Do not pass it on to others. It may harm

them, even if their signs of illness are the same as yours.

- If you get any side effects, talk to your doctor or nurse. This includes any possible side

effects not listed in this leaflet. See section 4.

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.

What is in this leaflet:

1. What Disodium Pamidronate is and what it is used for

2. What you need to know before you are given Disodium Pamidronate

3. How Disodium Pamidronate should be given

4. Possible side effects

5. How to store Disodium Pamidronate

6. Contents of the pack and other 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. What you need to know 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 of this medicine (listed in section 6. ‘Contents of the pack and other information’)

are pregnant

are breast feeding

Warnings and precautions

Talk to your doctor or nurse 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.

have or have had pain, swelling or numbness of the jaw, a feeling of heaviness in the jaw or

loosening of a tooth. Your doctor may recommend a dental examination before you start

treatment with Disodium Pamidronate.

are having dental treatment or are due to undergo dental surgery, tell your dentist that you

are being treated with Disodium Pamidronate and inform your doctor about your dental

treatment.

While being treated with Disodium Pamidronate , you should maintain good oral hygiene

(including regular teeth brushing) and receive routine dental check-ups.

Contact your doctor and dentist immediately if you experience any problems with your

mouth or teeth such as loose teeth, pain or swelling, non-healing of sores or discharge, as

these could be signs of a condition called osteonecrosis of the jaw.

Patients who are undergoing chemotherapy and/or radiotherapy, who are taking steroids, who

are undergoing dental surgery, who do not receive routine dental care, who have gum disease,

who are smokers, or who were previously treated with a bisphosphonate (used to treat or

prevent bone disorders) may have a higher risk of developing osteonecrosis of the jaw.

If any of the above statements apply to you, speak to your doctor or nurse before you

are given Disodium Pamidronate.

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.

Other medicines and Disodium Pamidronate

Tell your doctor or nurse if you are taking, have recently taken or might take any other

medicines. Taking another medicine while you are being given Disodium Pamidronate can

affect how it or the other medicine works.

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.

Disodium Pamidronate contains sodium

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 recommended 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 recommended 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 recommended 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.

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 all medicines, this medicine can cause side effects, 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: may affect more than 1 in 10 people

fever and flu-like symptoms, such as feeling unwell, shivering, tiredness and hot flushes

low calcium or low phosphate levels in the blood

Common: may affect up to 1 in 10 people

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: may affect up to 1 in 100 people

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: may affect up to 1 in 10,000 people

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.

Talk to your doctor if you have ear pain, discharge from the ear and/or an ear infection.

These could be signs of bone damage in the ear.

Not known: frequency cannot be estimated from the available data

- Pain in the mouth, teeth and/or jaw, swelling or non-healing sores inside the mouth or jaw,

discharge, numbness or a feeling of heaviness in the jaw, or loosening of a tooth. These could

be signs of bone damage in the jaw (osteonecrosis). Tell your doctor and dentist immediately

if you experience such symptoms while being treated with Disodium Pamidronate or after

stopping treatment.

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

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

Keep this medicine out of the sight and reach 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 their expiry 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.

Once the solution has been diluted the product should be used immediately.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist

how to throw away medicines you no longer use. These measures will help protect the

environment.

6. Contents of the pack and other 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 last revised in 12/2017.

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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:

Tumour-induced hypercalcaemia

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

cancer or multiple myeloma

Paget’s disease of bone.

4.2. Posology and method of administration

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.

Table 1

Initial serum calcium

Recommended total

(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

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.

Paget's disease of Bone

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 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.

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.

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.

Convulsions have been precipitated in some patients with tumour-induced hypercalcaemia

due to the electrolyte changes associated with this condition and its effective treatment.

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.

Osteonecrosis of the jaw

Osteonecrosis of the jaw (OJN) has been reported in clinical trials and in the post-marketing

setting in patients receiving 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).

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. While on

treatment, invasive dental procedures should be performed only after careful consideration

and be avoided in close proximity of pamidronate administration. For patients who develop

ONJ 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 ONJ.

The management plan for 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.

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.

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.

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 Insufficiency

Bisphosphonates, including disodium pamidronate, have been associated with renal toxicity

manifested as deterioration of renal function and potential renal failure. Renal deterioration,

progression to renal failure and dialysis have been reported in patients after the initial dose or

a single dose of disodium pamidronate. Deterioration of renal function (including renal

failure) has also been reported following long-term treatment with disodium pamidronate in

patients with multiple myeloma.

Disodium pamidronate is excreted intact primarily via the kidney (see section 5.2

Pharmacokinetic properties), thus the risk of renal adverse reactions may be greater in

patients with impaired renal function.

Due to the risk of clinically significant deterioration in renal function which may progress to

renal failure, single doses of disodium pamidronate should not exceed 90 mg, and the

recommended infusion time should be observed (see section 4.2 Posology and method of

administration).

As with other i.v. bisphosphonates renal monitoring is recommended, for instance,

measurement of serum creatinine prior to each dose of disodium pamidronate.

Patients receiving frequent infusions of disodium pamidronate over a prolonged period of

time, especially those with pre-existing renal disease or a predisposition to renal impairment

(e.g. patients with multiple myeloma and/or tumour-induced hypercalcaemia), should have

evaluations of standard laboratory and clinical parameters of renal function prior to each dose

of disodium pamidronate.

Patients treated with disodium 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).

Disodium pamidronate should not be given with other bisphosphonates because their

combined effects have not been investigated.

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.

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.

This medicinal product contains less than 1 mmol (23 mg) sodium per ampoule i.e.

essentially ‘sodium-free’.

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. 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.

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.

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.

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.

Very rare:

Osteonecrosis of the external auditory canal (bisphosphonate class adverse

reaction)

Unknown

Osteonecrosis of the jaw

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 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.

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 (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 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.

Pamidronate suppresses the accession of osteoclast precursors onto the bone. However, the

local and direct antiresorptive effect of bone-bound bisphosphonate appears to be the

predominant mode of action in vitro and in vivo.

Experimental studies have demonstrated that pamidronate inhibits tumour-induced osteolysis

when given prior to or at the time of inoculation or transplantation with tumour cells.

Biochemical changes reflecting the inhibitory effect of 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.

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.

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

6.2. Incompatibilities

Pamidronate will form complexes with divalent cations and should not be added to calcium-

containing intravenous solutions.

6.3. Shelf life

Three 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.

6.4. Special precautions for storage

Do not store above 25°C.

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

12/2017