Zoledronic acid-pharmex

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ZOLEDRONIC ACID-PHARMEX (ZOLEDRONICACID-PHARMEX)

Composition:

Active substance: zoledronic acid;

1 ml of concentrate contains 0.8 mg of zoledronic acid;

Excipients: mannite (E 421), sodium citrate, water for injections.

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical properties: clear, colorless liquid.

Pharmacotherapeutic group. Drugs affecting bone structure and mineralization. Bisphosphonates. ATC code M05BA08.

Pharmacological properties.

Pharmacodynamics.

Zoledronic acid belongs to a new class of bisphosphonates that specifically act on bone tissue. It is one of the most potent inhibitors of osteoclastic bone resorption known to date.

The selective action of bisphosphonates on bone is based on their high affinity for mineralized bone tissue; however, the molecular mechanism leading to inhibition of osteoclast activity has not yet been fully elucidated. Animal studies have shown that zoledronic acid inhibits bone resorption without negatively affecting bone formation, mineralization, or mechanical bone properties.

In addition to inhibiting osteoclast-mediated bone resorption, zoledronic acid exerts direct antitumor effects on cultured human myeloma and breast cancer cells by inhibiting cell proliferation and inducing apoptosis. This suggests that zoledronic acid may possess antimetastatic properties.

In vivo – inhibition of osteoblast-mediated bone resorption affecting the microcrystalline matrix structure of bone, thereby reducing tumor growth; antiangiogenic effects (effects on blood vessels leading to reduced tumor blood supply); and analgesic effects.

In vitro – inhibition of osteoblast proliferation, cytostatic effects, pro-apoptotic effects on tumor cells, synergistic cytostatic effects with other antineoplastic agents, anti-adhesive and anti-invasive effects.

Pharmacokinetics.

Pharmacokinetic data in patients with bone metastases were obtained after single and repeated 5- and 15-minute infusions of 2, 4, 8, and 16 mg of zoledronic acid administered to 64 patients. Pharmacokinetic parameters were independent of dose.

After the start of zoledronic acid infusion, plasma concentration rapidly increases, reaching peak levels at the end of the infusion. This is followed by a rapid decline to less than 10% of peak concentration within 4 hours and to less than 1% of peak concentration within 24 hours, with a subsequent prolonged period of low concentrations not exceeding 0.1% of peak levels until the next infusion on day 28. Zoledronic acid administered intravenously is eliminated by the kidneys in three phases: rapid biphasic elimination from systemic circulation with half-lives t½α = 0.24 hours and t½β = 1.87 hours, followed by a prolonged terminal phase with t½γ = 146 hours. No drug accumulation in plasma was observed with repeated dosing every 28 days. Zoledronic acid is not metabolized and is excreted unchanged by the kidneys. Within the first 24 hours, 39 ± 16% of the administered dose is recovered in urine. The remainder is primarily bound to bone tissue. Subsequently, zoledronic acid is slowly released back from bone into systemic circulation and eliminated renally. Total systemic clearance of the drug is 5.04 ± 2.5 L/h and is independent of dose, gender, age, race, and body weight. Increasing the infusion duration from 5 to 15 minutes reduces the zoledronic acid concentration at the end of infusion by 30%, but does not affect the plasma concentration-time curve (AUC).

Variability in pharmacokinetic parameters of zoledronic acid, as with other bisphosphonates, was high among different patients.

Pharmacokinetic data for zoledronic acid in patients with hypercalcemia and hepatic insufficiency are lacking. In vitro data indicate that zoledronic acid does not inhibit the human P450 enzyme system and is not subject to biotransformation. Animal experimental studies show that less than 3% of the administered dose is excreted in feces, suggesting that liver function does not significantly affect the pharmacokinetics of zoledronic acid.

Renal clearance of zoledronic acid correlates with creatinine clearance, with renal clearance averaging 5 ± 33% of creatinine clearance. In 64 oncology patients included in the study, mean creatinine clearance was 84 ± 29 mL/min (range 22–143 mL/min). Analysis of patient subgroups showed that in patients with creatinine clearance of 20 mL/min (severe renal impairment) and 50 mL/min (moderate renal impairment), relative zoledronic acid clearance was 37% and 72%, respectively. However, pharmacokinetic data in patients with severe renal impairment (creatinine clearance < 30 mL/min) are limited.

Zoledronic acid has been shown to have low affinity for blood cellular components. Plasma protein binding is low (approximately 56%) and independent of zoledronic acid concentration.

Special populations

Children

Limited pharmacokinetic data in children with severe forms of osteogenesis imperfecta suggest that the pharmacokinetics of zoledronic acid in children aged 3 to 17 years is similar to that in adults when administered at equivalent doses (mg/kg). Age, body weight, gender, and creatinine clearance were found not to influence systemic exposure to zoledronic acid.

Clinical characteristics.

Indications.

• Prevention of symptoms related to bone involvement (pathological fractures, spinal cord compression, complications following surgical procedures or radiation therapy, or hypercalcemia due to malignancy) in patients with advanced-stage malignant tumors.
• Treatment of hypercalcemia due to malignancy.

Contraindications.

Hypersensitivity to the active substance (zoledronic acid), other bisphosphonates, or any excipients contained in the medicinal product.

Pregnancy or breastfeeding.

Interaction with other medicinal products and other forms of interaction.

No clinically significant interactions have been observed when zoledronic acid was administered concomitantly with commonly used medicinal products such as anticancer agents, antibiotics, analgesics, and diuretics.

Zoledronic acid does not significantly bind to plasma proteins and, based on in vitro studies, does not inhibit human cytochrome P450 enzyme system. However, no specific clinical studies on drug interactions have been conducted.

Caution is recommended when bisphosphonates are used concomitantly with aminoglycosides, as they may have an additive effect, potentially leading to prolonged reduction in serum calcium levels. Caution is also advised when bisphosphonates are used concomitantly with loop diuretics, as additive effects may lead to hypocalcemia. Caution should be exercised when administering zoledronic acid with other potentially nephrotoxic medicinal products. The possibility of developing hypomagnesemia during treatment should also be considered.

In patients with multiple myeloma, no clinically significant interactions have been observed when bisphosphonates are administered intravenously in combination with thalidomide.

There are data on osteonecrosis of the jaw in patients receiving concomitant treatment with zoledronic acid and antiangiogenic medicinal products (which reduce tumor blood supply).

Special precautions for use

General

Before administering Zoledronic Acid-Pharmex, adequate hydration should be ensured in all patients, including those with mild to moderate renal impairment.

Hyperhydration should be avoided in patients at risk of developing heart failure.

Standard metabolic parameters associated with hypercalcaemia, such as levels of calcium, phosphates, and magnesium, should be carefully monitored after initiation of therapy with Zoledronic Acid-Pharmex. If hypocalcaemia, hypophosphataemia, or hypomagnesaemia occurs, short-term corrective therapy may be required.

Untreated patients with hypercalcaemia often have some degree of renal dysfunction; therefore, careful monitoring of renal function parameters is necessary.

Zoledronic Acid-Pharmex contains the active substance zoledronic acid. Patients receiving therapy with Zoledronic Acid-Pharmex should not simultaneously receive other medicinal products containing zoledronic acid.

Patients receiving therapy with Zoledronic Acid-Pharmex should also not simultaneously receive any other bisphosphonates.

Renal impairment

When considering the use of Zoledronic Acid-Pharmex in patients with malignancy-associated hypercalcaemia and concomitant renal impairment, the patient's condition should be evaluated and a decision made as to whether the potential benefit of treatment outweighs the possible risk.

When deciding on treatment of patients with bone metastases for prevention of skeletal-related events, it should be noted that the therapeutic effect becomes evident after 2–3 months.

Renal dysfunction has been reported with the use of bisphosphonates. Factors increasing the risk of renal impairment include dehydration, pre-existing renal dysfunction, multiple cycles of zoledronic acid or other bisphosphonates, concomitant use of nephrotoxic agents, or infusion over a shorter duration than recommended. Although the risk is reduced when zoledronic acid is administered at a dose of 4 mg over no less than 15 minutes, deterioration in renal function is still possible.

Elevations in serum creatinine levels have also been observed in some patients receiving the recommended doses for prevention of skeletal-related events, although this occurs infrequently.

Prior to each dose of Zoledronic Acid-Pharmex, serum creatinine levels should be assessed in patients. For patients with bone metastases and postmenopausal women with early-stage breast cancer receiving aromatase inhibitors (AIs) for prevention of bone mass loss and fractures, lower doses of Zoledronic Acid-Pharmex are recommended in cases of mild or moderate renal impairment (see table in section "Dosage and administration"). In patients who experience worsening of renal function during treatment, administration of the drug may be resumed only when serum creatinine returns to within 10% of the baseline value. Upon resumption of therapy, the same dose as prior to temporary discontinuation should be used.

Due to the potential effect of bisphosphonates, including Zoledronic Acid-Pharmex, on renal function and in view of the lack of comprehensive clinical safety data in patients with severe renal impairment (serum creatinine > 400 µmol/L, or > 4.5 mg/dL, for patients with tumour-induced hypercalcaemia; and serum creatinine > 265 µmol/L, or > 3 mg/dL, for patients with bone metastases and postmenopausal women with early-stage breast cancer receiving aromatase inhibitors (AIs) for prevention of bone mass loss and fractures, respectively) and the limited pharmacokinetic data available in patients with severe renal impairment (creatinine clearance < 30 mL/min), the use of Zoledronic Acid-Pharmex is not recommended in patients with severe renal impairment.

Hepatic impairment

No specific recommendations are available for patients with severe hepatic impairment due to limited clinical data.

Osteonecrosis of the jaw

Osteonecrosis of the jaw has been observed primarily in oncology patients receiving treatment regimens that include bisphosphonates, including zoledronic acid. Many of these patients were also receiving chemotherapy and corticosteroids. Most reported cases were associated with dental procedures such as tooth extraction. Many patients had signs of local infection, including osteomyelitis.

The following risk factors should be considered when assessing individual risk for developing osteonecrosis of the jaw:

• Potency of bisphosphonates (higher risk with more potent agents), route of administration (higher risk with parenteral administration), and cumulative dose;
• Cancer, chemotherapy, radiotherapy, corticosteroid therapy, smoking;
• Dental history, poor oral hygiene, periodontal disease, invasive dental procedures, and ill-fitting dentures.

An oral examination with appropriate dental preventive measures should be performed before initiating bisphosphonate therapy.

During therapy, invasive dental procedures should be avoided whenever possible in these patients. Dental surgery may worsen the condition in patients who develop osteonecrosis of the jaw during bisphosphonate therapy. There are no data available on patients requiring dental procedures to determine whether discontinuation of bisphosphonate therapy reduces the risk of osteonecrosis of the jaw. Treatment regimens for patients who develop osteonecrosis of the jaw should be developed in close collaboration between the treating physician and a dentist or oral surgeon experienced in managing patients with osteonecrosis of the jaw. Temporary discontinuation of zoledronic acid should be considered until the condition normalizes and risk factors are minimized as much as possible.

Osteonecrosis of the external auditory canal

Osteonecrosis of the external auditory canal has been reported with bisphosphonate use, primarily during long-term therapy. Possible risk factors for osteonecrosis of the external auditory canal include steroid use, chemotherapy, and/or local risk factors such as infections or trauma. Osteonecrosis of the external auditory canal should be considered in patients receiving bisphosphonates who present with symptoms related to the auditory organs, including chronic ear infections.

Musculoskeletal pain

There are reports of severe, sometimes incapacitating bone, joint, and/or muscle pain in patients taking bisphosphonates. This class of drugs includes zoledronic acid. However, such reports have been isolated. The time to onset of symptoms ranged from one day to several months after initiation of treatment. In most patients, symptoms improved after discontinuation of therapy. In this group of patients, symptoms recurred when treatment was resumed with the same or another bisphosphonate.

Atypical femoral fracture

Atypical subtrochanteric and diaphyseal femoral fractures have been reported during bisphosphonate therapy, particularly in patients receiving long-term treatment for osteoporosis. These transverse or short oblique fractures may occur anywhere along the femur from slightly below the lesser trochanter to slightly above the supracondylar region. These fractures occur after minimal or no trauma, and some patients experience thigh or groin pain, often associated with radiological signs of stress fracture, several weeks or months before a complete femoral fracture occurs. Fractures are often bilateral; therefore, the contralateral femur should be evaluated in patients receiving bisphosphonate therapy who have sustained a femoral fracture. Delayed healing of such fractures has also been reported. Based on individual assessment of benefit and risk, the decision to discontinue bisphosphonate therapy should be considered in patients suspected of having atypical femoral fractures.

During bisphosphonate therapy, patients should be advised to inform their physician about any pain in the hip, thigh, or groin. Any patient presenting with such symptoms should be evaluated for an incomplete femoral fracture.

Hypocalcaemia

Hypocalcaemia has been reported in patients receiving zoledronic acid. Cases of cardiac arrhythmias and neurological reactions (including seizures, numbness, and tetany) secondary to severe hypocalcaemia have been reported. Cases of severe hypocalcaemia requiring hospitalization have also been reported. In some cases, hypocalcaemia may be life-threatening.

Use during pregnancy or breastfeeding

The drug is contraindicated during pregnancy and breastfeeding.

Pregnancy

There are insufficient data on the use of zoledronic acid in pregnant women. Animal reproductive studies have shown reproductive toxicity. The potential risk to humans is unknown.

Breastfeeding

It is unknown whether zoledronic acid is excreted in human milk.

Ability to affect the speed of reactions while driving or operating machinery

Adverse reactions to the drug, such as dizziness and somnolence, may affect the ability to drive or operate machinery; therefore, caution should be exercised when driving or operating complex machinery during treatment with zoledronic acid.

Administration and Dosage

Zoledronic acid-Farmeks should only be administered by physicians experienced in intravenous administration of bisphosphonates.

Prior to administration, 4 mg of Zoledronic acid-Farmeks concentrate must be diluted in 100 mL of 0.9% sodium chloride solution or 5% glucose solution. The prepared Zoledronic acid-Farmeks solution for infusion should be administered as a single intravenous infusion over no less than 15 minutes.

The Zoledronic acid-Farmeks concentrate must not be mixed with infusion solutions containing calcium or other divalent cations, such as Ringer's lactate solution, and must be administered as a single intravenous infusion using a separate infusion system.

Prevention of skeletal-related events in patients with advanced malignancies involving bone

Adults, including elderly patients

The recommended dose of Zoledronic acid-Farmeks is 4 mg administered as an infusion every 3–4 weeks.

Patients should also receive daily oral calcium supplements (500 mg) and vitamin D (400 IU) per day.

When making treatment decisions for patients with bone metastases for the prevention of skeletal-related events, it should be considered that the onset of treatment effect occurs after 2–3 months.

Treatment of hypercalcemia of malignancy

Adults and elderly patients

For the treatment of hypercalcemia (serum calcium corrected for albumin ≥ 12 mg/dL, or ≥ 3 mmol/L), a single 4 mg dose of zoledronic acid is recommended.

Renal Impairment

Hypercalcemia of malignancy

Treatment of hypercalcemia of malignancy in patients with severe renal impairment may be considered only after careful assessment of the potential risks and expected benefits. There is no clinical experience with the use of the drug in patients with serum creatinine levels > 400 µmol/L, or > 4.5 mg/dL. Dose adjustment is not required in patients with hypercalcemia of malignancy who have serum creatinine levels < 400 µmol/L, or < 4.5 mg/dL.

Prevention of skeletal-related events in patients with advanced malignancies involving bone

Before initiating treatment with the drug in patients with multiple myeloma or bone metastases from solid tumors, serum creatinine levels and creatinine clearance should be determined. Creatinine clearance should be calculated using the Cockroft-Gault formula. Zoledronic acid-Farmeks is not recommended for patients with severe renal impairment prior to starting therapy (creatinine clearance < 30 mL/min). Clinical studies of Zoledronic acid-Farmeks have not been conducted in patients with serum creatinine levels ≥ 265 µmol/L, or ≥ 3 mg/dL.

For patients with bone metastases and mild to moderate renal impairment prior to starting therapy (creatinine clearance 30–60 mL/min), the following dosage recommendations apply:

Initial creatinine clearance level (ml/min)	Recommended dose of ZOLEDRONIC ACID-PHARMEKS (mg)*
>60	4 mg*
50–60	3.5 mg*
40–49	3.3 mg*
30–39	3 mg*

*Doses are calculated assuming an AUC value of 0.66 mg·h/L (creatinine clearance of 75 mL/min). For patients with impaired renal function, dosage reduction is recommended to achieve the same AUC as in patients with a creatinine clearance of 75 mL/min.

Serum creatinine levels should be measured before each dose of Zoledronic Acid-Farmex following initiation of therapy. If renal function impairment occurs, treatment should be discontinued. In clinical studies, renal function impairment was defined by the following criteria:

• For patients with normal baseline serum creatinine (<1.4 mg/dL or <124 µmol/L) – an increase of 0.5 mg/dL or 44 µmol/L;
• For patients with elevated baseline serum creatinine (>1.4 mg/dL or >124 µmol/L) – an increase of 1 mg/dL or 88 µmol/L.

During clinical trials, zoledronic acid therapy was resumed after serum creatinine levels returned to within 10% of the baseline value. Zoledronic Acid-Farmex therapy should be resumed at the same dose used prior to treatment interruption.

Pediatric populations

The safety and efficacy of zoledronic acid in children aged 1 to 17 years have not been established. There are no recommendations for use in pediatric patients.

Instructions for preparation of Zoledronic Acid-Farmex doses

Volumes of concentrate for infusion solution in milliliters corresponding to Zoledronic Acid-Farmex doses in milligrams:

• 4.4 mL corresponds to 3.5 mg;
• 4.1 mL corresponds to 3.3 mg;
• 3.8 mL corresponds to 3 mg.

The required volume of liquid concentrate should be diluted in 100 mL of sterile 0.9% sodium chloride solution or 5% glucose solution for intravenous infusion.

The contents of one vial (4 mg of zoledronic acid) should be diluted in 100 mL of 9 mg/mL sodium chloride solution or 50 mg/mL glucose solution. The prepared solution should ideally be used immediately after preparation. Unused solution may be stored in a refrigerator at 2–8°C for up to 24 hours.

Reduced doses of zoledronic acid are recommended for patients with mild to moderate renal impairment.

Adequate hydration should be ensured before and after administration of zoledronic acid.

Children

The safety and efficacy of zoledronic acid in children have not been established.

Overdose

Clinical experience with acute overdose of zoledronic acid is limited. Accidental administration of up to 48 mg of zoledronic acid has been reported. Patients who receive doses exceeding the recommended amount should be kept under continuous medical supervision, as renal function impairment (including renal failure) and changes in serum electrolyte levels (including calcium, phosphate, and magnesium) may occur. In cases of hypocalcemia, calcium gluconate infusion should be administered as clinically indicated. Treatment is symptomatic.

Adverse Reactions

Acute-phase reactions are usually reported within three days after administration of zoledronic acid, with symptoms including bone pain, fever, fatigue, arthralgia, myalgia, chills, and arthritis with joint swelling. These symptoms usually resolve within several days.

The most significant identified adverse reactions associated with the use of zoledronic acid include renal impairment, osteonecrosis of the jaw, acute-phase reactions, hypocalcemia, visual disturbances, atrial fibrillation, and anaphylaxis.

Adverse reactions associated with zoledronic acid are similar to those reported with other bisphosphonates and may occur in approximately one-third of all patients.

Blood and lymphatic system disorders: anemia, thrombocytopenia, leukopenia, pancytopenia.

Nervous system disorders: headache, paresthesia, dizziness, taste disturbances, hypoesthesia, hyperesthesia, tremor, somnolence, epileptic seizures, tetany and numbness (secondary to hypocalcemia).

Psychiatric disorders: sleep disorders, anxiety, confusion.

Eye disorders: conjunctivitis, blurred vision, scleritis and orbital inflammation, uveitis, episcleritis.

Gastrointestinal disorders: nausea, vomiting, anorexia, diarrhea, constipation, abdominal pain, dyspepsia, stomatitis, dry mouth.

Respiratory system disorders: dyspnea, cough, bronchoconstriction, interstitial lung disease.

Skin and subcutaneous tissue disorders: pruritus, rash (including erythematous and macular rash), increased sweating.

Musculoskeletal and connective tissue disorders: bone pain, myalgia, arthralgia, generalized pain, muscle cramps, osteonecrosis of the jaw.

Cardiac disorders: arterial hypertension, arterial hypotension, atrial fibrillation; arterial hypotension leading to syncope and circulatory collapse, bradycardia, cardiac arrhythmia (secondary to hypocalcemia).

Renal and urinary disorders: renal impairment, acute renal failure, hematuria, proteinuria, tubulointerstitial nephritis (with frequency "unknown" (cannot be estimated from available data)).

Immune system disorders: hypersensitivity reactions, angioneurotic edema.

General disorders and administration site conditions: fever, flu-like symptoms (including fatigue, chills, malaise, and hot flushes), injection site reactions (including pain, irritation, swelling, and induration), asthenia, peripheral edema, chest pain, weight gain, anaphylactic reactions/shock, urticaria, arthritis and joint swelling as symptoms of acute-phase reaction.

Laboratory abnormalities: hypophosphatemia, increased blood creatinine and urea levels, hypocalcemia, hypomagnesemia, hypokalemia, hyperkalemia, hypernatremia.

Renal function impairment

There is evidence that zoledronic acid may lead to deterioration in renal function. Factors that may increase the risk of renal impairment include dehydration, pre-existing renal dysfunction, multiple courses of treatment with zoledronic acid or other bisphosphonates, concomitant use of other nephrotoxic agents, or infusion duration shorter than recommended. Cases of worsening renal function, progression of renal failure, and the need for hemodialysis have been reported after the first or single 4 mg dose of zoledronic acid.

Osteonecrosis of the jaw

Cases of osteonecrosis (mainly of the jaw) have been reported primarily in cancer patients receiving zoledronic acid. Many of these patients had signs of local infection, including osteomyelitis. Most cases were associated with dental procedures, such as tooth extraction. Osteonecrosis of the jaw has several established risk factors, including malignancy, concomitant therapies (e.g., chemotherapy, radiation therapy, corticosteroids), and comorbid conditions (e.g., anemia, coagulopathies, infections, pre-existing oral diseases).

Although a causal relationship has not been established, patients should be advised to avoid invasive dental procedures.

Atrial fibrillation

In a clinical trial, the overall incidence of atrial fibrillation in postmenopausal women with osteoporosis was 2.5% in the group receiving 5 mg zoledronic acid and 1.9% in the placebo group. The reason for the increased incidence is unknown.

Acute-phase reactions

These adverse reactions include fever, myalgia, headache, limb pain, nausea, vomiting, diarrhea, and arthralgia, which may begin within the first 3 days after zoledronic acid infusion.

Atypical femoral fractures

There are data on acute subtrochanteric and diaphyseal fractures of the femur (an adverse reaction associated with bisphosphonates).

Adverse reactions due to hypocalcemia

Hypocalcemia is a significant identified risk with zoledronic acid use under approved indications. Clinical and post-marketing data indicate an association between zoledronic acid therapy, reports of hypocalcemia, and the development of secondary cardiac arrhythmias. Additionally, there is evidence linking hypocalcemia to secondary neurological reactions, including epileptic seizures, numbness, and tetany.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 ºC. Keep out of reach of children.

Incompatibilities.

The concentrate of Zoledronic Acid-Farmex must be diluted in sterile 0.9% sodium chloride solution or 5% glucose solution. The concentrate of Zoledronic Acid-Farmex must not be mixed with infusion solutions containing calcium or other divalent cations, such as Ringer's lactate solution, and must be administered as a single infusion using a separate infusion set.

Studies with glass vials and several types of infusion bags and infusion systems made of polyvinyl chloride, polyethylene, and polypropylene (pre-filled with 0.9% sodium chloride solution or 5% glucose solution) showed no incompatibility with the aforementioned packaging materials.

Packaging.

5 ml of concentrate in a vial. 1 vial in a blister pack, 1 blister pack in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

LLC "FARMEKS GROUP".

Manufacturer's address and location of business activity.

100 Shevchenka Street, Boryspil, Kyiv Oblast, 08301, Ukraine.

All cases of adverse reactions should be reported to the manufacturer:

LLC "Farmex Group", Ukraine, 08301, Kyiv Oblast, city of Boryspil, Shevchenka Street, 100, tel.: +38(044)391-19-19, fax: +38(044)391-19-18, or via the form on the website: http://www.pharmex.com.ua/kontakty/farmakonadzor*