Zometa, 4 mg/5 ml 5 ml

Zometa is a bone resorption inhibitor.

Pharmacodynamics

Zoledronic acid refers to highly effective bisphosphonates with a selective effect on bone. The drug suppresses bone resorption by acting on osteoclasts.

The selective action of bisphosphonates on bone tissue is based on the high affinity for mineralized bone tissue. The exact molecular mechanism providing inhibition of osteoclast activity is still unclear. Zoledronic acid has no undesirable effect on bone formation, mineralization and mechanical properties.

In addition to its inhibitory effect on bone resorption, zoledronic acid has antitumor properties that make the drug effective in bone metastases:

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

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

Zoledronic acid, by inhibiting proliferation and inducing apoptosis, has a direct antitumor effect against human myeloma cells and breast cancer cells, and also reduces penetration of breast cancer cells through the extracellular matrix, indicating that it has antimetastatic properties. In addition, zoledronic acid inhibits proliferation of human and animal endothelial cells and has anti-angiogenic effect.

In patients with breast cancer, prostate cancer and other solid tumors with metastatic bone involvement Zometa prevents development of pathological fractures, spinal cord compression, reduces the need for radiation therapy and surgical interventions, reduces tumor hypercalcemia.

The drug is able to inhibit the progression of pain syndrome. The therapeutic effect is less pronounced in patients with osteoblastic foci than in osteolytic ones. In patients with multiple myeloma and breast cancer with at least one bone focus the efficacy of Zometa at a dose of 4 mg is comparable with pamidronate at a dose of 90 mg.

In patients with tumor hypercalcemia the effect of Zometa is characterized by a decrease in serum calcium levels and urinary calcium excretion. The average time to normalization of calcium levels is about 4 days. By day 10, calcium concentrations normalize in 87-88% of patients.

The average time to relapse (albumin-corrected serum calcium level of at least 2.9 mmol/L) is 30-40 days. There are no significant differences between the efficacy of Zometa at doses of 4 and 8 mg in the treatment of hypercalcemia.

The studies show no significant differences in the frequency and severity of adverse events observed in patients treated with Zometa at doses of 4 or 8 mg, pamidronate at 90 mg, or placebo in both the treatment of bone metastases and hypercalcemia.

Pharmacokinetics

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

After initiation of Zometa infusion, serum concentrations increase rapidly, peaking at the end of the infusion, followed by a rapid 10% decrease in concentration after 4 h and less than 1% after 24 h with a consistently prolonged period of low concentrations not exceeding 0.1% of maximum until repeat infusion on day 28.

Zoledronic acid administered by IV is excreted by the kidneys in 3 phases: a rapid biphasic excretion of the drug from the systemic circulation with T_1/2 of 0.24 h and 1.87 h and a prolonged phase with a final T_1/2 of 146 h. No drug cumulation was noted with repeated injections every 28 days.

Zoledronic acid is not metabolized systemically and is excreted unchanged by the kidneys. During the first 24 hours (39±16)% of the administered dose is detected in the urine. The remaining amount of the drug is mainly bound to the bone tissue.

Then slowly zoledronic acid is re-released from the bone tissue into the systemic bloodstream and excreted by the kidneys. Total plasma clearance of the drug is (5.04±2.5) l/h and is independent of the drug dose, sex, age, race and body weight of the patient. Increasing the infusion time from 5 to 15 min leads to a 30% decrease in zoledronic acid concentration at the end of infusion, but does not affect the AUC.

Pharmacokinetic studies have not been performed in patients with hypercalcemia or impaired liver function. According to the data received in vitro, zoledronic acid does not inhibit human P450 enzyme and does not undergo biotransformation, which suggests that hepatic function status does not influence zoledronic acid pharmacokinetics in any significant way. Less than 3% of the drug dose is excreted with the feces.

The renal clearance of zoledronic acid correlates positively with creatinine clearance and is (75±33)% of Cl creatinine reaching an average (84±29)% (range, 22-143 ml/min) in 64 patients enrolled in the study.

Population analysis showed that patients with a creatinine Cl of 20 mL/min (severe renal failure) or 50 mL/min (moderate renal failure) had a calculated zoledronic acid clearance of 37 and 72%, respectively, of the zoledronate clearance value in patients with a creatinine Cl of 84 mL/min. Limited pharmacokinetic data were obtained for patients with severe renal insufficiency (creatinine Cl

Low affinity of zoledronic acid for blood components was shown. Binding to plasma proteins is low (about 50%) and is independent of Zometa concentration.

Indications

Bone metastases of advanced malignant tumors (prostate cancer, breast cancer) and myeloma disease, including to reduce the risk of pathological fractures, spinal cord compression, tumor-induced hypercalcemia, and reduce the need for radiation therapy or bone surgery; hypercalcemia caused by a malignant tumor.

Active ingredient

Composition

Active ingredient:

zoledronic acid monohydrate;

Excipients:

Mannitol,

Sodium citrate,

Injection water,

Nitrogen

How to take, the dosage

Intravenously, dropwise; infusion duration – at least 15 minutes. Frequency of administration – every 3-4 weeks. For bone metastases of advanced malignant tumors and myeloma in adults and elderly patients the recommended dose of the drug is 4 mg. Before administering the drug the concentrate (the content of 1 flask) should be diluted in 100 ml of calcium-free solution for infusion (0.9% sodium chloride solution or 5% dextrose solution).

Patients should also receive an additional oral calcium dose of 500 mg/day and an oral vitamin D dose of 400 IU/day.

In hypercalcemia due to malignancy (albumin-corrected calcium concentration ≥12 mg/dL or 3 mmol/L), the recommended dose of the drug is 4 mg in adults and elderly patients. In order to ensure adequate hydration of the patient it is recommended to administer saline solution before, in parallel or after infusion of Zometa.

The decision to treat malignant hypercalcemia with Zometa in patients with significant renal impairment should be made only after a careful assessment of the risk of the drug and the expected benefit of therapy. Patients with a serum creatinine concentration of

In bone metastases of advanced malignancies and myeloma, the dose of Zometa depends on the baseline creatinine clearance calculated using the Cockcroft-Gault formula. It is not recommended to use Zometa in patients with severe renal dysfunction (creatinine Cl values ≤30 ml/min).

Interaction

When concomitant use with Zometa of other commonly used drugs (anticancer agents, diuretics, antibiotics, analgesics) no clinically significant interactions have been noted.

According to the data received in in vitro studies, zoledronic acid has no significant binding to plasma proteins and does not inhibit enzymes of cytochrome P450 system. However, there have been no specific clinical studies to investigate drug interactions.

We recommend caution with concomitant use of bisphosphonates and aminoglycosides, because the concomitant action of these drugs has been shown to increase the duration of decrease in plasma calcium concentrations.

Caution is required when using Zometa concomitantly with drugs with potential nephrotoxic effects.

The possibility of hypomagnesemia should also be kept in mind.

In patients with multiple myeloma, there may be an increased risk of renal function impairment when bisphosphonates such as Zometa are administered IV in combination with thalidomide.

Pharmaceutical interactions

Diluted Zometa solution should not be mixed with infusion solutions containing calcium ions (e.g. Ringer’s solution).

When using glass vials, infusion systems and bags of different types made of PVC, polyethylene and polypropylene (pre-filled with 0.9% sodium chloride solution or 5% dextrose solution) for administration of Zometa, no evidence of incompatibility with Zometa has been found.

Special Instructions

The use in liver dysfunction. Since there are limited clinical data on the use of the drug in patients with severe hepatic impairment, it is not possible to give specific recommendations for this category of patients.

The use in impaired renal function. When deciding whether to use Zometa in patients with malignant hypercalcemia with impaired renal function, the patient’s condition must be evaluated to determine whether the potential benefit of administering the drug outweighs the possible risk.

Serum creatinine concentrations should be determined before each administration of Zometa. At the beginning of treatment with the drug in patients with bone metastases with mild to moderate renal dysfunction, it is recommended to use Zometa in lower doses.

In patients whose renal dysfunction has occurred during therapy with Zometa, therapy with the drug may be continued only after creatinine concentration has returned to values within 10% of the initial value.

Given the possibility of impaired renal function when using bisphosphonates, including Zometa. Zometa, and due to the lack of comprehensive data on the clinical safety of the drug in patients with severe renal dysfunction (serum creatinine concentration ≥400 µmol/L or ≥4.5 mg/dL – in patients with hypercalcemia due to malignancy and ≥265 µmol/L or ≥3,0 mg/dL – in patients with malignant tumors with bone metastases) and the presence of very limited pharmacokinetic data in patients with baseline severe renal dysfunction (creatinine Cl≤30 ml/min), the use of Zometa in this population of patients is not recommended.

Before infusion, ensure that the patient is adequately hydrated. If necessary, it is recommended to administer saline solution before, in parallel or after infusion of Zometa. Hyperhydration of the patient should be avoided due to the risk of cardiovascular complications.

After administration of Zometa, continuous monitoring of serum calcium, phosphorus, magnesium and creatinine concentrations is required. If hypocalcemia, hypophosphatemia or hypomagnesemia develops, short-term additional administration of the appropriate substances may be necessary. Patients with untreated hypercalcemia usually have impaired renal function, so close monitoring of renal function is necessary in this category of patients.

When deciding whether to treat patients with bone metastases with Zometa to decrease the risk of pathological fractures, spinal cord compression, and tumor-induced hypercalcemia and to decrease the need for radiation therapy or bone surgery, it should be considered that therapeutic effect occurs 2-3 months after starting treatment with Zometa.

There have been some reports of renal dysfunction with bisphosphonates. Risk factors for these complications include dehydration, prior renal insufficiency, repeated administration of Zometa or other bisphosphonates as well as the use of nephrotoxic drugs, and too rapid administration of the drug.

While the risk of the above complications is reduced if Zometa is administered at a dose of 4 mg for at least 15 minutes, the possibility of renal dysfunction persists.

There have been cases of impaired renal function, progression of renal failure, and the need for hemodialysis when Zometa is first or once administered.

Elevated serum creatinine concentrations have also been seen in some patients with long-term use of Zometa at the recommended doses, although less frequently.

As there are limited clinical data on the use of the drug in patients with severe hepatic impairment, it is not possible to give specific recommendations for this category of patients.

There have been cases of osteonecrosis of the jaw in cancer patients on antitumor treatment including bisphosphonates (including Zometa). Many patients had signs of local infectious inflammatory process, including osteomyelitis.

In clinical practice, the most frequent development of osteonecrosis of the jaw has been seen in patients with advanced breast cancer and myeloma, as well as in the presence of dental diseases (including after tooth extraction, periodontal disease, poor fixation of dentures).

Known risk factors for osteonecrosis of the jaw include: cancer, cancer-related treatment (including chemotherapy, radiation therapy, corticosteroids), comorbidities (including anemia, coagulopathy, infection, prior oral disease).

Bisphosphonates should be preceded by a dental workup and appropriate preventive procedures for patients with cancer, and strict oral hygiene should be recommended.

Dental surgery should be avoided if possible during treatment of these patients. There is no evidence that interrupting treatment with bisphosphonates prior to dental interventions reduces the risk of osteonecrosis of the jaw. The treatment plan for an individual patient should be based on an individual risk/benefit assessment.

In clinical practice, infrequent cases of severe and in some cases disabling bone, joint and muscle pain have been reported with bisphosphonates, which include zoledronic acid.

These symptoms developed over a period of 1 day to several months from the start of treatment. After discontinuation of treatment, most patients’ symptoms went away. In a few patients, symptoms recurred when therapy was resumed or another bisphosphonate was prescribed.

Zometa contains the same active ingredient as Aclasta, zoledronic acid. Patients treated with Zometa should not receive Aclasta at the same time.

Pediatric use. The efficacy and safety of Zometa in pediatric practice have not yet been established.

The effect on the ability to drive and operate machinery

The effect of Zometa on the ability to drive and operate machinery has not been studied.

Contraindications

Side effects

Blood organs: often – anemia, sometimes – thrombocytopenia, leukopenia; rarely – pancytopenia.

Peripheral nervous system and CNS: often – headache; sometimes – dizziness, paresthesia, taste disorders, hypoesthesia, hyperesthesia, tremor, anxiety, sleep disorders; rarely – confusion.

As for the organs of vision: often – conjunctivitis; sometimes – blurred vision; very rarely – uveitis, episcleritis.

The digestive system: frequently – nausea, vomiting, anorexia; sometimes – diarrhea, constipation, abdominal pain, dyspepsia, stomatitis, dry mouth.

Respiratory system: sometimes – shortness of breath, cough.

Dermatological reactions: sometimes – itching, rash (including erythematous and macular), increased sweating.

Muscular system disorders: often – bone pain, myalgia, arthralgia, generalized pain; sometimes – muscle cramps.

Cardiovascular system: sometimes – marked increase or decrease of BP; rarely – bradycardia.

Arenal system: often – renal dysfunction; sometimes – acute renal failure, hematuria, proteinuria.

The immune system: sometimes – hypersensitivity reactions; rarely – angioedema.

Laboratory disorders: very often – hypophosphatemia; often – increase of serum concentrations of creatinine and urea, hypocalcemia; sometimes – hypomagnesemia, hypokalemia; rarely – hyperkalemia, hypernatriemia.

Local reactions: pain, irritation, swelling, and formation of an infiltrate at the site of drug administration.

Others: often – fever, flu-like syndrome (including general malaise, chills, malaise, fever), sometimes – asthenia, peripheral edema; pain in the chest, weight gain.

Overdose

Symptoms: in acute overdose of the drug (limited data) renal dysfunction (including renal failure), changes in electrolyte composition (including plasma concentrations of calcium, phosphate and magnesium) have been reported.

Patients who have received more than the recommended dose should be monitored.

Treatment: In case of hypocalcemia with clinically significant manifestations calcium gluconate infusion is indicated.

Pregnancy use

The drug Zometa is contraindicated in pregnancy and during lactation (breastfeeding).