Drug Class Description

Generic Name

Drug Description

Presentation

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.

Adult Dosage

Aredia must never be given as a bolus injection. The reconstituted solution of Aredia from powder in vials should be diluted in a calcium-free infusion solution (0.9 % w/v sodium chloride solution or 5% w/v glucose solution) and infused slowly.

The infusion rate should never exceed 60mg/hour (1mg/min), and the concentration of Aredia in the infusion solution should not exceed 60mg/250ml. 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. In order to minimise local reactions at the infusion site, the cannula should be inserted carefully into a relatively large vein.

Tumour-induced hypercalcaemia

Patients must be adequately rehydrated, using 0.9% w/v sodium chloride solution, prior to and during administration of Aredia.

The total dose of Aredia 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.

The total dose of Aredia 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 repeated courses.

A significant decrease in serum calcium is generally observed 24 to 48 hours after administration of Aredia, 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 Aredia may become less effective as the number of treatments increases.

Osteolytic lesions and bone pain in multiple myeloma

The recommended dose is 90mg every 4 weeks.

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

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

Paget's disease of Bone

The recommended treatment course consists of a total dose of 180mg administered in unit doses of either 30mg once a week for 6 consecutive weeks, or 60mg every other week over 6 weeks. Experience to date suggests that any mild and transient unwanted 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 dose of 30mg followed by 60mg every other week (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 solution 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 6 months until remission of disease is achieved, and if relapse occurs.

Renal Impairment

Aredia should not be administered to patients with severe renal impairment (creatinine clearance < 30 mL/min) unless in cases of life-threatening tumour-induced hypercalcaemia where the benefit outweighs the potential risk. Because there is only limited clinical experience in patients with severe renal impairment no dose recommendations for this patient population can be made.

As with other i.v. bisphosphonates, renal monitoring is recommended, for instance, measurement of serum creatinine prior to each dose of Aredia. In patients receiving Aredia for bone metastases or multiple myeloma who show evidence of deterioration in renal function, Aredia 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 0.5mg/dL.

• For patients with abnormal baseline creatinine, increase of 1.0mg/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 61-90 mL/min) to moderate renal impairment (creatinine clearance 30-60 mL/min). In such patients, the infusion rate should not exceed 90 mg/4h (approximately 20-22 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 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. Clinical data in patients with severe hepatic impairment is not available. Pamidronate should be administered to this patient population with caution.

Child Dosage

There is no clinical experience with Aredia in children. Therefore until further experience is gained, Aredia is only recommended for use in adult patients.

Contra Indications

Aredia is contraindicated

• in patients with known hypersensitivity to pamidronate or to other bisphosphonates, or to any of the excipients of Aredia,

• in pregnancy,

• in breast feeding women.

Special Precautions

General

Aredia must never be given as a bolus injection, but should always be diluted and given as a slow intravenous infusion.

Patients must be assessed prior to administration of Aredia to assure that they are appropriately hydrated. This is especially important for patients receiving diuretic therapy.

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

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.

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

Renal Insufficiency

Bisphosphonates, including Aredia, 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 Aredia. Deterioration of renal function (including renal failure) has also been reported following long-term treatment with Aredia in patients with multiple myeloma.

Aredia is excreted intact primarily via the kidney, 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 Aredia should not exceed 90mg, and the recommended infusion time should be observed.

As with other i.v. bisphosphonates renal monitoring is recommended, for instance, measurement of serum creatinine prior to each dose of Aredia.

Patients treated with Aredia for bone metastases or multiple myeloma should have the dose withheld if renal function has deteriorated.

Aredia should not be administered to patients with severe renal impairment (creatinine clearance < 30 mL/min) unless in cases of life-threatening tumour-induced hypercalcaemia where the benefit outweighs the potential risk. Because there is only limited pharmacokinetic data with severe renal impairment no dose recommendations for this patient population can be made. Aredia should not be given with other bisphosphonates because their combined effects have not been investigated.

There is very little experience of the use of Aredia in patients receiving haemodialysis.

Hepatic Insufficiency

As there are no clinical data available in patients with severe hepatic insufficiency, no specific recommendations can be given for this patient population.

Calcium and Vitamin D Supplementation

In the absence of hypercalcaemia, patients with predominantly lytic bone metastases or multiple myeloma, who are at risk of calcium or Vitamin D deficiency (e.g. through malabsorption or lack of exposure to sunlight) and patients with Paget's disease of the bone should take oral calcium and vitamin D supplementation in order to minimise the potential risk of hypocalcaemia.

Osteonecrosis of the jaw

Osteonecrosis of the jaw has been reported predominantly in cancer patients treated with bisphosphonates, including Aredia. 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 .

Musculoskeletal Pain

In post-marketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates. This category of drugs includes Aredia (pamidronate disodium for infusion). The time to onset of symptoms varied from one day to several months after starting the drug with the majority occurring within a few days. Most patients had relief or improvement of symptoms after stopping treatment. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate.

Interactions

Aredia has been administered concomitantly with commonly used anticancer agents without interactions occurring.

Aredia 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 Aredia is used with other potentially nephrotoxic drugs.

In multiple myeloma patients, the risk of renal dysfunction may be increased when Aredia is used in combination with thalidomide.

Since pamidronate binds to bone, it could in theory interfere with bone scintigraphy examinations

Adverse Reactions

Adverse reactions to Aredia 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.

Frequency estimate: very common (1/10), common (1/100, <1/10), uncommon (1/1,000, <1/100), rare (1/10,000, <1/1,000), very rare (<1/10,000) including isolated reports.

Postmarketing experience: Uncommonly, cases of osteonecrosis (primarily of the jaw) have been reported predominantly in cancer patients treated with bisphosphonates including Aredia. Many of these patients had signs of local infection including osteomyelitis andthe 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, coagulopathies, infection, pre-existing oral disease). Although causality has not been determined, it is prudent to avoid dental surgery as recovery may be prolonged.

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