Zolendronik-Rus-4 (Lyophilisate) Instructions for Use

ATC Code

M05BA08 (Zoledronic acid)

Active Substance

Zoledronic acid (Swiss Ph. Swiss Pharmacopoeia)

Clinical-Pharmacological Group

Bone resorption inhibitor for bone metastases

Pharmacotherapeutic Group

Means for the treatment of bone diseases; agents affecting bone structure and mineralization; bisphosphonates

Pharmacological Action

Inhibitor of bone resorption, a nitrogen-containing bisphosphonate. It acts primarily on bone, suppressing osteoclast activity and bone resorption.

The selective action of bisphosphonates on bone tissue is based on their high affinity for mineralized bone. After intravenous administration, Zoledronic acid is rapidly redistributed to bone and, like other bisphosphonates, localizes mainly in areas of bone remodeling.

The main molecular target of zoledronic acid in the osteoclast is the enzyme farnesyl pyrophosphate synthase (FPPS), although the possibility of other mechanisms of action is not excluded. The prolonged duration of action is determined by its high affinity for the active site of FPPS and its pronounced affinity for mineralized bone tissue.

Except for its high anti-resorptive effect, the effect of zoledronic acid on bone tissue is similar to that of other bisphosphonates.

In addition to its inhibitory effect on bone resorption, Zoledronic acid has antitumor properties that provide therapeutic efficacy in bone metastases.

In vivo: inhibition of osteoclastic bone resorption, altering the bone marrow microenvironment, leading to reduced tumor cell growth; anti-angiogenic activity. Suppression of bone resorption is also clinically accompanied by a marked reduction in pain sensations.

In vitro: inhibition of osteoblast proliferation, direct cytotoxic and pro-apoptotic activity, synergistic cytostatic effect with antitumor drugs; anti-adhesive/invasive activity.

Zoledronic acid, by suppressing proliferation and inducing apoptosis, has a direct antitumor effect on human myeloma cells and breast cancer cells, and also reduces the penetration of breast cancer cells through the extracellular matrix, indicating its anti-metastatic properties. Furthermore, Zoledronic acid inhibits the proliferation of human endothelial cells and causes an anti-angiogenic effect in animals.

In patients with tumor-induced hypercalcemia, the action of zoledronic acid was shown to be characterized by a decrease in serum calcium concentration and a reduction in its urinary excretion.

Pharmacokinetics

After the start of the infusion, the concentration of zoledronic acid in plasma increases rapidly, reaching C_max at the end of the infusion, followed by a rapid decrease in concentration by 10% after 4 hours and to less than 1% after 24 hours, with a subsequent prolonged period of low concentrations not exceeding 0.1% of C_max until the next infusion on day 28.

Zoledronic acid, administered intravenously, is excreted by the kidneys in 3 phases: rapid biphasic elimination from the systemic circulation with T_1/2 of 0.24 hours and 1.87 hours, and a long terminal phase with a T_1/2 of 146 hours. No accumulation was noted with repeated administrations every 28 days.

Zoledronic acid does not undergo systemic metabolism and is excreted by the kidneys unchanged. Within the first 24 hours, 39±16% of the administered dose is found in the urine. The remainder is primarily bound to bone tissue. Then, zoledronic acid is slowly released back from bone tissue into the systemic circulation and excreted by the kidneys. Total plasma clearance is 5.04±2.5 L/h. Increasing the infusion time from 5 to 15 minutes results in a 30% decrease in zoledronic acid concentration at the end of the infusion but does not affect AUC.

Less than 3% is excreted in feces.

The renal clearance of zoledronic acid is positively correlated with creatinine clearance.

Zoledronic acid has been shown to have low affinity for blood components. Plasma protein binding is low (on average about 50%) and does not depend on the concentration of zoledronic acid.

Indications

Postmenopausal osteoporosis (to reduce the risk of hip, vertebral, and non-vertebral fractures, to increase bone mineral density); prevention of subsequent (new) osteoporotic fractures in men and women with fractures of the proximal femur; osteoporosis in men; prevention and treatment of glucocorticoid-induced osteoporosis; prevention of postmenopausal osteoporosis (in patients with osteopenia); Paget’s disease of bone.

Osteolytic, osteoblastic, and mixed bone metastases of solid tumors and osteolytic lesions in multiple myeloma, as part of combination therapy; tumor-induced hypercalcemia.

ICD codes

Dosage Regimen

Administer as a single intravenous infusion via a vented infusion line over no less than 15 minutes.

For tumor-induced hypercalcemia, use a maximum dose of 4 mg as a single infusion; retreatment may be considered only after a minimum 7-day interval following initial infusion, and only if hypercalcemia recurs.

For bone metastases from solid tumors and multiple myeloma, administer a 4 mg dose every 3 to 4 weeks; concurrently administer an oral calcium supplement of 500 mg and 400 IU of vitamin D daily.

For postmenopausal osteoporosis and osteoporosis in men, administer a 5 mg dose once per year as a single infusion; ensure adequate supplementation with calcium and vitamin D.

For Paget’s disease of bone, administer a single 5 mg infusion; re-treatment may be considered in patients who have relapsed, based on specific biochemical markers.

Reconstitute the lyophilisate only with 5 mL of Sterile Water for Injection to yield a solution containing 4 mg/5mL; ensure complete dissolution before further dilution.

Immediately after reconstitution, withdraw the required volume and dilute in 100 mL of either 0.9% Sodium Chloride or 5% Dextrose solution; do not mix with calcium-containing solutions.

Use the reconstituted and diluted solution immediately; if stored prior to infusion, hold at 2°C to 8°C for no more than 24 hours; after dilution, the solution is stable for 24 hours at 2°C to 8°C.

Prior to each dose, assess renal function by measuring serum creatinine; withhold the dose in patients with severe renal impairment.

Ensure patients are adequately hydrated prior to administration; monitor serum levels of calcium, phosphate, and magnesium following infusion.

Adverse Reactions

Blood and lymphatic system disorders: infrequently – anemia.

Metabolism and nutrition disorders: infrequently – decreased appetite; frequency unknown – dehydration (developing as a consequence of post-infusion phenomena such as fever, vomiting, and diarrhea), hypophosphatemia.

Nervous system disorders: frequently – headache, dizziness; infrequently – lethargy, paresthesia, somnolence, tremor, syncope, hypesthesia, dysgeusia.

Psychiatric disorders: infrequently – insomnia, anxiety.

Eye disorders: infrequently – conjunctivitis, eye pain, vertigo; rarely – uveitis, episcleritis, iritis.

Ear and labyrinth disorders: infrequently – vertigo.

Cardiac disorders: infrequently – increased blood pressure, sudden flushing; frequency unknown – marked decrease in blood pressure (in patients with risk factors).

Respiratory, thoracic and mediastinal disorders: infrequently – cough, dyspnea.

Skin and subcutaneous tissue disorders: infrequently – skin rash, hyperhidrosis, pruritus, erythema.

Gastrointestinal disorders: frequently – nausea, vomiting, diarrhea; infrequently – dyspepsia, upper abdominal pain, abdominal pain, gastroesophageal reflux, constipation, dry mouth, esophagitis.

Musculoskeletal and connective tissue disorders: frequently – arthralgia, myalgia, bone pain, back pain and limb pain; infrequently – neck pain, muscle stiffness, joint swelling, muscle spasms, musculoskeletal chest pain, musculoskeletal pain, joint stiffness, arthritis, muscle weakness; frequency unknown – osteonecrosis of the jaw.

Renal and urinary disorders: infrequently – increased blood creatinine, pollakiuria, proteinuria.

Infections and infestations: infrequently – influenza, nasopharyngitis.

Immune system disorders: hypersensitivity reactions, including anaphylactic reaction, anaphylactic shock, angioedema, bronchospasm, urticaria.

General disorders and administration site conditions: very frequently – fever; frequently – flu-like syndrome, chills, increased fatigue, asthenia, pain, general malaise; infrequently – peripheral edema, thirst, acute-phase reactions, non-cardiac chest pain.

Contraindications

Severe disorders of mineral metabolism, including hypocalcemia; severe renal impairment (creatinine clearance <35 ml/min); pregnancy; breastfeeding period; age under 18 years; hypersensitivity to zoledronic acid or to any bisphosphonates.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and breastfeeding.

Use in Renal Impairment

Not recommended for use in patients with severe renal impairment (serum creatinine concentration ≥400 µmol/L or ≥4.5 mg/dL) except when the expected benefit of therapy outweighs the potential risk.

There are isolated reports of renal function impairment during the use of bisphosphonates. Risk factors for the development of such complications include pre-existing renal failure and long-term use of zoledronic acid in high doses (8 mg), reduction of infusion time.

Pediatric Use

The efficacy and safety of zoledronic acid use in pediatric practice have not been established.

Special Precautions

The drug containing zoledronic acid should be used strictly according to the indications for the corresponding dosage form.

Use with caution in patients with mild to moderate renal impairment; in patients with a complete or incomplete combination of bronchial asthma, recurrent nasal and sinus polyposis and intolerance to acetylsalicylic acid or other NSAIDs (including history); with concurrent use of drugs that can significantly affect renal function (e.g., aminoglycoside antibiotics or diuretics causing dehydration).

With repeated use, serum creatinine concentration should be determined before each administration. If the obtained data indicate worsening renal function, it is necessary to assess the risk and benefit of the ongoing therapy.

Before infusion, the patient’s hydration status should be assessed and dehydration excluded. To ensure adequate hydration, administration of saline solution before, during, or after the infusion of zoledronic acid is recommended. Patient overhydration should be avoided due to the risk of cardiovascular complications.

After administration of zoledronic acid, constant monitoring of serum calcium, phosphorus, magnesium, and creatinine levels is necessary.

If hypocalcemia, hypophosphatemia, or hypomagnesemia develops, short-term maintenance therapy is required.

Effect on ability to drive vehicles and operate machinery

Since dizziness is one of the side effects of zoledronic acid, patients should exercise caution when engaging in potentially hazardous activities. If dizziness occurs, refrain from these activities.

Drug Interactions

With simultaneous use of bisphosphonates and aminoglycosides, serum calcium levels may remain lowered for a longer period than required, due to a possible additive effect on serum calcium concentration.

With simultaneous use with drugs potentially possessing nephrotoxic effects, the risk of worsening renal function increases.

Storage Conditions

Store at 15°C (59°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.