DISODIUM PAMIDRONATE

Method of administration Disodium pamidronate concentrate must never be given as a bolus injection (see "Warnings"). 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.

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.

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. 0 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 pamidronate 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. e. total dose 210mg). 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.

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.

5 mg/dL. 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 […]

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. 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. 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. g. 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. uk/yellowcard.

Warnings Disodium pamidronate concentrate should be given under the supervision of a physician with the facilities to monitor clinical and biochemical effects. 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 (ONJ) 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.

g. 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 […]

1. Disodium Pamidronate is contraindicated in pregnancy and in breast feeding women.