Resorba, lyophilizate 4 mg 5 ml

The drug Resorba belongs to a new class of highly effective bisphosphonates with a selective effect on bone tissue. It suppresses the activity of osteoclasts and has no undesirable effect on the formation, mineralization and mechanical properties of bone tissue. The selective action of bisphosphonates on bone tissue is based on their high affinity for mineralized bone tissue, but the exact molecular mechanism providing inhibition of osteoclast activity is still unknown. It also has direct antitumor properties that provide efficacy in bone metastases.

In vitro it was found that zoledronic acid, by inhibiting cell proliferation and inducing cell apoptosis, has a direct antitumor effect on myeloma and breast cancer cells, reducing their risk of metastasis. Inhibition of osteoclastic bone resorption, which changes bone marrow microenvironment, leads to reduction of tumor cell growth; anti-angiogenic and anti-tumor activity is noted.

Zoledronic acid also inhibits proliferation of human endothelial cells. In tumor-induced hypercalcemia, it reduces serum calcium concentration.

Pharmacokinetics

Pharmacokinetic parameters are not dose dependent. After initiation of infusion, serum concentrations increase rapidly, reaching Cmax at the end of infusion, followed by a rapid decrease in concentration: by 10% after 4 h and to less than 1% of Cmax after 24 h with a further prolonged period of low concentrations, not exceeding 0.1% of Cmax, until repeat infusion on day 28.

The binding to plasma proteins is 56%. It is not metabolized.

It is excreted unchanged by the kidneys in 3 stages: 1st and 2nd stage – rapid elimination of the drug from systemic blood flow, with T1/2 – 0.24 h and 1.87 h, respectively, and the 3rd stage – prolonged, with T1/2 – 146 h. No drug cumulation was observed in repeated injections every 28 days. During the first 24 h, 23-55% is detectable in the urine.

The rest of the drug is bound to the bone tissue, after which it is slowly re-released into the systemic bloodstream and excreted by the kidneys; less than 3% is excreted with the feces. Total plasma clearance is 2.54-7.54 l/h. It does not depend on the drug dose, sex, age, race and body weight of the patient. Increasing the duration of infusion 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.

Renal clearance correlates positively with creatinine Cl and is 42-108% of Cl creatinine averaging 55-113%. In patients with severe (creatinine Cl ≤20 ml/min) and moderate renal insufficiency (creatinine Cl from 20 to 50 ml/min) clearance of zoledronic acid is 37 and 72%, respectively, from the drug clearance values in patients with creatinine Cl ≥84 ml/min.

Indications

Hypercalcemia (albumin-adjusted serum calcium concentration ≥12 mg/dL or 3 mmol/L) induced by malignancies; metastatic bone lesions in malignant solid tumors and myeloma disease (to reduce risk of pathological fractures, spinal cord compression, tumor-induced hypercalcemia and reduce the need for radiation therapy).

Active ingredient

Composition

Active substance:

zoledronic acid monohydrate;

Associates:

d-mannitol;

sodium citrate divalent;

Solvent in ampoule:

water for injection 5 ml;

Solvent in a polymer container:

Sodium chloride 9.0 g;

water for injection.

How to take, the dosage

Intravenously, drip, for at least 15 minutes.

Interaction

Calcium-containing solutions, in particular Ringer’s solution, should not be used as solvents.

In concomitant use with anticancer drugs, diuretics, antibiotics, analgesics no clinically significant interactions were noted.

Bisphosphonates and aminoglycosides have unidirectional influence on the calcium concentration in blood serum, therefore in concomitant usage the risk of hypocalcaemia and hypomagnesaemia increase. In case of hypocalcemia, hypophosphatemia or hypomagnesemia development there may be a need for short-term additional administration of appropriate substances. Patients with untreated hypercalcemia usually have impaired renal function, therefore careful monitoring of renal function is necessary in this category of patients. When deciding on treatment with zoledronic acid in patients with bone metastases, it should be taken into account that the therapeutic effect occurs 2-3 months after the start of treatment with zoledronic acid.

Caution is required when using zoledronic acid concomitantly with drugs with potential nephrotoxic effects. In patients with multiple myeloma, there may be an increased risk of renal dysfunction when bisphosphonates in combination with thalidomide are administered intravenously. Although the risk of the above described complications is reduced if zoledronic acid is administered at a dose of 4 mg for at least 15 minutes, the possibility of renal dysfunction remains. There have been cases of worsening of renal function, progression of renal failure and the need for hemodialysis during the first or single dose of zoledronic acid.

The drug should not be mixed with other drugs.

Special Instructions

People should ensure that the patient is adequately hydrated prior to infusion. If necessary, the administration of saline is recommended before, during or after the infusion of zoledronic acid. Hyperhydration of the patient should be avoided due to the risk of cardiovascular complications.

Permanent monitoring of serum calcium, magnesium, phosphorus and creatinine concentrations is required after administration.

With zoledronic acid therapy, renal function should be closely monitored. Risk factors for renal function impairment include dehydration, prior renal failure, repeated administration of zoledronic acid or other bisphosphonates, and use of nephrotoxic drugs and overdose of the drug.

Please note that other bisphosphonates have reported bronchospasm in patients with bronchial asthma sensitive to acetylsalicylic acid, but this has not yet been reported with zoledronic acid.

. During treatment with bisphosphonates, including zoledronic acid, cases of osteonecrosis of the jaw have been described in cancer patients, therefore before starting treatment with bisphosphonates it is necessary to provide for dental examination and in case of presence of risk factors (anemia, coagulopathy, infections, poor oral hygiene or diseases, concomitant chemo or radiation therapy, corticosteroid treatment) to perform appropriate preventive procedures. Patients with risk factors should avoid dental surgery if possible during treatment with zoledronic acid.

The effect on the ability to drive and operate motor vehicles and other mechanisms. Studies of the effect of the drug on the ability to drive vehicles and operate complex mechanisms have not been conducted. In case of CNS side effects it is recommended to avoid activities requiring increased attention and speed of mental and motor reactions.

Contraindications

With caution: impaired renal function; severe hepatic insufficiency (no data on use); patients with bronchial asthma sensitive to acetylsalicylic acid.

Side effects

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

Nervous system: 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.

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

Respiratory system: sometimes – shortness of breath, cough.

Skin and skin appendages: sometimes – itching, rash (including erythematous and macular), increased sweating.

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

System disorders: sometimes – marked increase or decrease of BP; rarely – bradycardia.

Perior urinary 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 zoledronic acid there may be renal dysfunction, including renal failure, changes in electrolyte composition, including the concentration of calcium, phosphate and magnesium in the blood plasma. In case of accidental overdose the patient should be under constant supervision.

Treatment: in case of hypocalcemia accompanied by clinical manifestations calcium gluconate infusion is indicated.

Pregnancy use

It is contraindicated in pregnancy. Breastfeeding should be stopped during treatment.