Zoledrex^® (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Anstar, AG (Switzerland)

Manufactured By

Khandelwal Laboratories, Pvt. Ltd. (India)

Packaging and Quality Control Release

KHANDELWAL Laboratories, Pvt.Ltd. (India)

Or

N.N. Blokhin Russian Cancer Research Center of the Ministry of Health of Russia (Russia)

ATC Code

M05BA08 (Zoledronic acid)

Active Substance

Zoledronic acid (Swiss Ph. Swiss Pharmacopoeia)

Dosage Form

Zoledrex®

Lyophilisate for preparation of solution for infusion 4 mg: vial 1 pcs.

Dosage Form, Packaging, and Composition

Lyophilisate for preparation of solution for infusion as a white mass.

Excipients : mannitol – 220 mg, sodium citrate – 24 mg.

Glass vials (1) – cardboard packs.

Clinical-Pharmacological Group

Bone resorption inhibitor for bone metastases

Pharmacotherapeutic Group

Bone resorption inhibitor – bisphosphonate

Pharmacological Action

An 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, is localized mainly at sites 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 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.

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 exerts anti-angiogenic effects 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 infusion, the plasma concentration of zoledronic acid 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 eliminated 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 over no less than 15 minutes.

For tumor-induced hypercalcemia, use a maximum single dose of 4 mg.

Re-treat only after a minimum interval of one week and only after confirming persistent or recurrent hypercalcemia.

For bone metastases from solid tumors and multiple myeloma, administer a 4 mg dose every 3 to 4 weeks.

For Paget’s disease of bone, administer a single 5 mg infusion.

Re-evaluate patients with Paget’s disease after a minimum of 6 months based on biochemical markers.

For osteoporosis, administer a 5 mg dose once per year as a single intravenous infusion.

For glucocorticoid-induced osteoporosis, administer a 5 mg dose once per year.

Reconstitute the 4 mg lyophilisate with 5 mL of Sterile Water for Injection to yield a 4 mg/5 mL solution.

Further dilute the reconstituted solution in 100 mL of calcium-free infusion solution, such as 0.9% Sodium Chloride or 5% Dextrose.

After dilution, use the solution immediately.

If storage is necessary, hold the solution refrigerated at 2°C to 8°C for up to 24 hours.

Allow the refrigerated solution to reach room temperature before administration.

Assess renal function and serum creatinine before each dose.

Withhold the dose in patients with severe renal impairment (creatinine clearance less than 35 mL/min).

Ensure adequate patient hydration prior to administration.

Administer calcium and vitamin D supplements as necessary to prevent hypocalcemia.

Monitor serum levels of calcium, phosphorus, and magnesium following infusion.

Adverse Reactions

Blood and lymphatic system disorders: uncommon – anemia.

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

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

Psychiatric disorders: uncommon – insomnia, anxiety.

Eye disorders: uncommon – conjunctivitis, eye pain, vertigo; rare – uveitis, episcleritis, iritis.

Ear and labyrinth disorders: uncommon – vertigo.

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

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

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

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

Musculoskeletal and connective tissue disorders: common – arthralgia, myalgia, bone pain, back pain and limb pain; uncommon – 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: uncommon – increased blood creatinine, pollakiuria, proteinuria.

Infections and infestations: uncommon – influenza, nasopharyngitis.

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

General disorders and administration site conditions: very common – fever; common – flu-like syndrome, chills, increased fatigue, asthenia, pain, general malaise; uncommon – 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 in 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 data indicate worsening renal function, the risk and benefit of the ongoing therapy should be assessed.

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 low for longer than required, due to a possible additive effect on serum calcium concentration.

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

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.