Package leaflet: Information for the patient

Medac Disodium Pamidronate 3 mg/ml, sterile concentrate

Pamidronate disodium

Read all of this leaflet carefully before you are given this medicine because it contains important information for you.

•    Keep this leaflet. You may need to read it again.

•    If you have any further questions, ask your doctor or pharmacist.

•    If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

1.    What Medac Disodium Pamidronate 3 mg/ml is and what it is used for

2.    What you need to know before Medac Disodium Pamidronate 3 mg/ml is administered to you

3.    How Medac Disodium Pamidronate 3 mg/ml is administered to you

4.    Possible side effects

5.    How to store Medac Disodium Pamidronate 3 mg/ml

6.    Contents of the pack and further information

1. What Medac Disodium Pamidronate 3 mg/ml is and what it is used for

Medac Disodium Pamidronate 3 mg/ml is a medicine which affects the formation and destruction of bone in the form of a solution which can be given as a slow injection via a drip.

Medac Disodium Pamidronate 3 mg/ml is used in three ways: • It reduces high levels of calcium in the blood caused by cancers.

•    It inhibits bone destruction in patients with spread of breast cancer to the bones.

•    It is used in patients with advanced multiple myeloma (a tumour of bone marrow cells).

2. What you need to know before Medac Disodium Pamidronate 3 mg/ml is administered to you

Medac Disodium Pamidronate 3 mg/ml will not be used

•    if you are allergic to pamidronate disodium, other bisphosphonate medicines or to any of the other ingredients of this medicine (listed in section 6).

•    if you are breast-feeding.

Warnings and precautions

Talk to your doctor or pharmacist before you are given Medac Disodium Pamidronate 3 mg/ml

•    if you are pregnant.

•    if you are on a controlled sodium diet.

•    if you have low levels of blood cells (red blood cells, white blood cells or platelets).

•    if you have undergone thyroid surgery.

•    if you have heart problems.

•    if you have liver problems.

•    if you suffer from kidney disease.

•    if you are taking other medicines that can affect the kidneys.

•    if you are taking other similar medicines that reduce the calcium level in blood.

•    if you undergo dental surgery.

Your doctor will monitor serum electrolytes, calcium and phosphate following the initiation of your therapy with Medac Disodium Pamidronate 3 mg/ml and he will ensure that you are well liydrated.

Bone damage in the jaw (osteonecrosis) has been reported predominantly in cancer patients treated with bisphosphonates, including Medac Disodium Pamidronate 3 mg/ml. Many of these patients were also receiving chemotherapy and corticosteroids. The majority of reported cases occurred in relation to dental treatments such as tooth extractions. Many of these patients had signs of local infection, including inflammation of the bone marrow (osteomyelitis).

You should consider visiting your dentist and seek advice on preventive measures before starting treatment with Medac Disodium Pamidronate 3 mg/ml If you suffer from cancer, are receiving chemotherapy, taking corticosteroids or have poor dental hygiene.

You should avoid invasive dental procedures such as surgery during treatment with Medac Disodium Pamidronate 3 mg/ml.

If you suffered bone damage (osteonecrosis) in your jaw during treatment with Medac Disodium Pamidronate 3 mg/ml dental surgery may make the condition worse.

Because treatment with Medac Disodium Pamidronate 3 mg/ml may affect your jaw bone (osteonecrosis, severe bone damage), you must make sure that your dentist knows that you are having Medac Disodium Pamidronate 3 mg/ml before you have any dental treatment or surgery. The dentist should avoid invasive dental procedures during treatment with Medac Disodium Pamidronate 3 mg/ml.

Make sure you are careful with your dental hygiene and go to the dentist regularly throughout your Medac Disodium Pamidronate 3 mg/ml treatment.

Tell your physician or dentist if there is pain or swelling of the gums and/or jaw, numbness of the jaw, if the jaw feels heavy, or you have lost a tooth since these are the signs of osteonecrosis of the jaw.

Pamidronate should not be prescribed to you if you are pregnant unless absolutely necessary.

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Other medicines and Medac Disodium Pamidronate 3 mg/ml

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

Some medicines can interfere with your treatment. Please inform your doctor or pharmacist if you are taking any of the following:

•    Other medicines for high calcium levels such as calcitonin.

•    Other bisphosphonates.

•    Other medicines that may affect the kidneys (your doctor or pharmacist will know which medicines these are).

•    Thalidomide (used to treat some cancers).

Pregnancy, breast-feeding and fertility

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

Pregnancy

If you are pregnant or likely to become pregnant, you should inform your doctor before you take pamidronate disodium.

Breast-feeding

If you are breast-feeding you must not take pamidronate disodium.

Driving and using machines

Do not drive or use machines

•    if you feel sleepy or dizzy following Medac Disodium Pamidronate 3 mg/ml infusion.

•    if you experience any effect tliat may impair your ability to drive or use machines.

3. How Medac Disodium Pamidronate 3 mg/ml is administered to you

Method and routes of administration

Medac Disodium Pamidronate 3 mg/ml is a solution which must be diluted and is then given to you as a slow injection via a drip. Medac Disodium Pamidronate 3 mg/ml is administered to you

in a prepared solution given very slowly into the vein via the drip (intravenous infusion). Your doctor will only use freshly prepared and clear dilutions and will not use the solution if particles are present.

Pamidronate disodium is given only to adults of 18 years and above under the supervision of a physician with the facilities to monitor its effects.

Dosage

The dose of medicine given to you will depend upon your medical condition, the levels of calcium in your blood and how well your kidneys are working. The usual dose per treatment course is between 15 mg and 90 mg. Your doctor will decide how many infusions you need, how often they will be given and how long the therapy will be continued.

During treatment you will have blood tests and may be asked to provide urine samples.

If you have received more Medac Disodium Pamidronate 3 mg/ml than you should

As this medicine will be given to you whilst you are in hospital it is unlikely that you will be given too little or too much.

If you experience paraesthesia (pins and needles), tetany (muscle spasm particularly of the jaw or limbs) and hypotension (feeling light-headed) during treatment with Medac Disodium Pamidronate 3 mg/ml, you should inform the medical staff who will give you calcium into the vein to reverse the symptoms. It is unlikely that these symptoms would occur however during the infusion.

If nevertheless you have received doses higher than those recommended you will be carefully monitored by your doctor.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. Many of the following side effects may have been related to your underlying disease.

• Very common (may affect more than 1 in 10 people) side effects are flu-like symptoms and a mild fever (increase in body temperature of 1 - 2 °C) which occur within the first 48 hours and usually last no longer than 24 hours. Acute “influenza-like” reactions usually occur only with the first Medac Disodium Pamidronate 3 mg/ml infusion given to you.

If these effects happen to you they will usually disappear after you have received Medac Disodium Pamidronate 3 mg/ml for a while, so you should be able to continue the therapy. Tell your doctor if any effect becomes troublesome or lasts a long time.

Cases of bone damage (osteonecrosis) - primarily of the

jaw - have been reported uncommonly predominantly in cancer patients treated with bisphosphonates including Medac Disodium Pamidronate 3 mg/ml. Many of these patients had signs of local infection including bone marrow inflammation (osteomyelitis) and the majority of the reports refer to cancer patients following tooth extractions or other dental surgeries. Osteonecrosis of the jaw has multiple well-documented risk factors including a diagnosis of cancer, concomitant therapies (e.g. chemotherapy, radiotherapy, corticosteroids) and co-morbid conditions (e.g. anaemia, blood-cloning disorders (coagulopathies), infection, pre-existing oral disease). You should avoid dental surgery while you are treated with Medac Disodium Pamidronate 3 mg/ml.

If you have developed osteonecrosis of jaw the dental surgery may exacerbate the condition. It is unknown whether the discontinuation of bisphosphonate treatment reduces the risk of osteonecrosis of jaw in patients requiring dental procedure.

If you develop symptoms such as sudden Itcliy rash, swelling of the hands, feet, ankles, face, lips, mouth or throat, difficulty in swallowing or breathing, this can be a severe allergic reaction.

If any of this happens, tell your doctor immediately.

Pamidronate disodium may affect your blood. Your doctor will monitor for this with blood tests.

The following information is intended for medical or healthcare professionals only:

Method of administration

Medac Disodium Pamidronate 3 mg/ml is a concentrate for solution for infusion and must therefore always be diluted in a calcium-free infusion solution (0.9 % sodium chloride or 5 % glucose) before use. The resulting solution must be infused slowly.

Tumour-induced hypercalcaemia

Patients must be adequately reiiydrated with 0.9 % w/v sodium chloride solution before or and during administration of pamidronate disodium.

The total dose of pamidronate disodium to be used for a treatment course depends on the patient’s initial serum calcium levels. The following guidelines are derived from clinical data on uncorrected calcium values. However, doses within the ranges given are also applicable for calcium values corrected for serum protein or albumin in reiiydrated patients.

Table 1

Initial plasma calcium level		Recommended total dose of pamidronate disodium	Concentration of solution for infusion	Maximum infusion rate
(mmol/l)	(mg %) (mg/100ml)	(mg)	mg/ml	mg/h
<3.0	<12.0	15-30	30/125	22.5
3.0-3.5	12.0-14.0	30-60	30/125 60/250	22.5
3.5-4.0	14.0-16.0	60-90	60/250 90/500	22.5
>4.0	>16.0	90	90/500	22.5

Tiie total dose of pamidronate disodium may be administered either in a single infusion or in multiple infusions over 2 to 4 consecutive days. The maximum dose per treatment course is 90 mg for both initial and repeat courses. Higher doses did not improve clinical response.

A significant decrease in serum calcium is generally observed 24 to 48 hours after administration of pamidronate disodium, and normalisation is usually achieved within 3 to 7 days. If normocalcaemia is not achieved within this time, a further dose may be given. The duration of the response may vary from patient to patient, and treatment can be repeated whenever hypercalcaemia recurs. Clinical experience to date suggests that pamidronate disodium may become less effective as the number of treatments increases.

Osteolytic lesions in multiple myeloma

Tiie recommended dose is 90 mg every 4 weeks.

Osteolytic lesions in bone metastases associated with breast cancer

Tiie recommended dose is 90 mg every 4 weeks. This dose may also be administered at 3 weekly intervals to coincide with chemotherapy if desired.

Treatment should be continued until there is evidence of a substantial decrease in a patient’s general performance status.

Renal impairment

Medac Disodium Pamidronate 3 mg/ml should not be administered to patients with severe renal impairment (creatinine clearance < 30 ml/min) unless in case of life-threatening tumour-induced fiypercalcaemia where tiie benefit outweighs tiie potential risk.

As with other intravenous bisphosphonates, monitoring of renal function is recommended, for instance, measurements of serum creatinine prior to each dose of pamidronate disodium. In patients receiving pamidronate disodium for bone metastases or multiple myeloma who show evidence of deterioration in renal function, treatment with pamidronate disodium 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, tiie infusion rate should not exceed 90 mg/4h (approximately 20 to 22 mg/li).

Hepatic impairment

A pharmacokinetic study indicates that no dose adjustment is necessary in patients with mild to moderate abnormal hepatic function. Pamidronate disodium has not been studied in patients with severe hepatic impairement. Therefore no specific recommendations can be given for pamidronate disodium in such patients.

Paediatric population

The safety and efficacy of pamidronate disodium in children and adolescents aged < 18 years have not been established.