Aredia (Lyophilisate) Instructions for Use

ATC Code

M05BA03 (Pamidronic acid)

Active Substance

Pamidronic acid (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Bone resorption inhibitor for bone metastases

Pharmacotherapeutic Group

Bone resorption inhibitor – bisphosphonate

Pharmacological Action

A bone resorption inhibitor from the group of bisphosphonates. It reduces the loss of bone tissue and causes an increase in bone mass (density). This effect is explained by the inhibition of osteoclast activity, as well as by the influence on the differentiation of osteoclasts and their precursors.

Bisphosphonates exhibit a chemical affinity for the mineral of the main amorphous substance of bone – hydroxyapatite, therefore they can persist for a long time in areas of active bone formation. This apparently determines the long-term preservation of the effect after the cessation of treatment.

Pamidronic acid reduces osteolysis caused by malignant tumors and reduces hypercalcemia in cancer patients. In patients with bone metastases of malignant tumors and with multiple myeloma, Pamidronic acid prevents or slows the development of skeletal complications and their consequences (fractures, spinal cord compression, hypercalcemia), and alleviates pain caused by bone lesions.

Biochemical changes when using pamidronic acid in cancer patients are characterized by a decrease in the amount of calcium in the blood plasma and a decrease in the content of calcium and phosphorus in the urine. Pamidronic acid improves the filtration function of the kidneys and reduces the level of creatinine in the blood plasma.

Pharmacokinetics

Pamidronic acid has a pronounced tropism for calcified tissues, which are considered the “site of apparent elimination” of pamidronic acid.

Immediately after the start of the infusion, the concentration of pamidronic acid in the plasma increases rapidly, and after its completion, it decreases rapidly. The T_1/2 from plasma is about 0.8 hours. C_ss is achieved within more than 2-3 hours. With intravenous infusion of 60 mg of pamidronic acid lasting more than 1 hour, the C_max of pamidronic acid in plasma is about 10 nmol/ml.

Binding to plasma proteins is low (less than 50%).

Pamidronic acid is not believed to undergo biotransformation and is excreted almost exclusively by the kidneys. The excretion of pamidronic acid in the urine is biphasic, with apparent T_1/2 of 1.6 and 27 hours, respectively. Total plasma and renal clearance are 88-254 ml/min and 38-60 ml/min, respectively. On average, plasma clearance is about 180 ml/min. The average renal clearance is 54 ml/min. The renal clearance of pamidronic acid correlates with creatinine clearance.

The hepatic and metabolic clearance of pamidronic acid is insignificant.

Indications

Hypercalcemia caused by malignant tumors; bone metastases of malignant tumors (predominantly of osteolytic nature) and multiple myeloma; Paget’s disease of bone.

ICD codes

Dosage Regimen

Administer intravenously as a slow infusion. Do not administer as a bolus injection. The dosage regimen is set individually, depending on the indication and the patient’s renal function.

For tumor-induced hypercalcemia, the recommended single dose is 60-90 mg. The dose depends on the initial serum calcium level. For severe hypercalcemia (corrected serum calcium > 3.5 mmol/L), administer 90 mg as a single infusion. If necessary, a second infusion may be given after at least 7 days to achieve normocalcemia.

For osteolytic bone metastases and multiple myeloma, administer 90 mg every 3-4 weeks. Continue treatment as long as a clinical benefit is observed.

For Paget’s disease of bone, the recommended dose is 30 mg daily for 3 consecutive days, administered as a 4-hour infusion, for a total course dose of 90 mg. Retreatment may be considered if a relapse occurs, but no sooner than after 6 months.

Reconstitute the lyophilisate strictly according to the manufacturer’s instructions using sterile water for injection. After reconstitution, further dilute the solution in 0.9% sodium chloride or 5% glucose solution. The final concentration of the infusion solution should not exceed 90 mg in 500 mL.

Infuse the 60 mg dose over at least 2 hours. Infuse the 90 mg dose over at least 4 hours. Do not mix with solutions containing calcium, such as Ringer’s solution.

Monitor serum creatinine, calcium, phosphorus, and magnesium levels before each dose. Ensure patients are adequately hydrated prior to infusion. Withhold treatment for deterioration in renal function.

Adverse Reactions

From the hematopoietic system: often – anemia, thrombocytopenia, lymphocytopenia; very rarely – leukopenia.

From the immune system: sometimes – allergic reactions, including anaphylactoid reactions, bronchospasm/shortness of breath, angioedema; very rarely – anaphylactic shock.

From the nervous system: often – paresthesia, tetany (as manifestations of hypocalcemia), headache, insomnia or increased drowsiness; sometimes – convulsions, agitation, dizziness; very rarely – confusion, visual hallucinations.

From the organ of vision: often – conjunctivitis; sometimes – uveitis (iritis, iridocyclitis); very rarely – scleritis, episcleritis, xanthopsia.

From the cardiovascular system: often – marked increase in blood pressure; sometimes – marked decrease in blood pressure; very rarely – shortness of breath, pulmonary edema (as signs of left ventricular failure), edema (as a sign of congestive heart failure) due to fluid overload.

From the digestive system: often – nausea, vomiting, anorexia, abdominal pain, diarrhea, constipation, gastritis; sometimes – dyspepsia.

From the skin and subcutaneous tissues: often – rash; sometimes – itching.

From the musculoskeletal system: often – transient bone pain, joint pain, myalgia; sometimes – muscle spasms; very rarely – development of osteonecrosis (mainly of the jaw, usually after tooth extraction or other dental intervention).

From the respiratory system: very rarely – acute respiratory distress syndrome, interstitial lung disease.

From the urinary system: sometimes – acute renal failure; rarely – focal segmental glomerulosclerosis, including the collapsing variant, nephrotic syndrome; very rarely – exacerbation of concomitant kidney diseases, hematuria.

Infectious diseases: very rarely – reactivation of latent viral infections (Herpes simplex, Herpes Zoster).

From laboratory parameters: very often – hypocalcemia, hypophosphatemia; often – hypokalemia, hypomagnesemia, increased serum creatinine concentration; sometimes – changes in liver function tests, increased serum urea concentration; very rarely – hyperkalemia, hypernatremia.

Local reactions: often – pain, redness, swelling, induration, phlebitis, thrombophlebitis at the injection site.

Other: very often – fever and flu-like symptoms, sometimes accompanied by malaise, chills, feeling of tiredness, and flushing.

Contraindications

Hypersensitivity to pamidronic acid and other bisphosphonates; pregnancy (except for cases of life-threatening hypercalcemia), breastfeeding period; childhood.

With caution: impaired renal function.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy (except for cases of life-threatening hypercalcemia) and during lactation (breastfeeding).

Use in Renal Impairment

Use with caution in case of impaired renal function.

Pediatric Use

Contraindicated for use in children (there is no experience of use in children).

Special Precautions

Therapy with pamidronic acid should be carried out under the supervision of a specialist experienced in anticancer therapy.

During treatment with pamidronic acid, monitoring of renal function (determination of serum creatinine, urea concentrations) and serum electrolytes (calcium, phosphorus) is necessary before each infusion.

If renal function deteriorates during therapy with pamidronic acid, the use of the drug should be discontinued.

The risk of developing hypocalcemia is increased in patients who have undergone thyroid surgery due to concomitant hypoparathyroidism.

In patients with anemia, leukopenia, and thrombocytopenia, hematological parameters should be regularly monitored.

In patients with heart disease, especially elderly patients, the administration of additional amounts of saline may lead to the appearance or worsening of signs of heart failure (acute left ventricular or chronic). Fever (or flu-like syndrome) may also contribute to the development of this complication.

There are reports of the development of osteonecrosis of the jaw in cancer patients during anticancer treatment, including bisphosphonates. Risk factors for the development of jaw osteonecrosis are malignant tumors, concomitant therapy (e.g., chemotherapy, radiation therapy, corticosteroids) and concomitant conditions (e.g., anemia, coagulopathy, infections, predisposition to oral diseases).

Patients should be informed of the need to report any pain in the hip or groin area during therapy with pamidronic acid. If these symptoms are present, an examination should be performed to identify a possible violation of the integrity of the hip bone tissue.

Women of reproductive age receiving treatment with pamidronic acid should use highly effective methods of contraception.

Influence on the ability to drive vehicles and mechanisms

During the use of pamidronic acid, patients should exercise caution when driving vehicles and mechanisms, as well as when engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Drug Interactions

Concomitant use of pamidronic acid with other bisphosphonates, antihypercalcemic drugs and calcitonin may lead to the development of hypocalcemia with pronounced clinical manifestations (paresthesia, tetany, decreased blood pressure).

The combination of pamidronic acid with calcitonin in patients with severe hypercalcemia contributes to a more pronounced decrease in serum calcium concentration.

Caution should be exercised when using pamidronic acid concomitantly with other potentially nephrotoxic drugs.

In patients with multiple myeloma, concomitant use of pamidronic acid with thalidomide increases the risk of renal function impairment.

Pamidronic acid can form complexes with divalent cations, so it should not be added to intravenous solutions containing calcium (for example, Ringer’s solution). It should not be mixed with other medicines.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.