Resorba, lyophilizate 4 mg in kit

Pharmgroup: bone resorption inhibitor – bisphosphonate.
Pharmacological action: The drug Resorba belongs to a new class of highly effective bisphosphonates with selective action on bone tissue. It suppresses the activity of osteoclasts, has no undesirable effect on the formation, mineralization and mechanical properties of the 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 effectiveness in bone metastases.
In vitro it was found that zoledronic acid, by inhibiting cell proliferation and inducing apoptosis, has a direct antitumor effect on myeloma and breast cancer cells, reducing their risk of metastasis. Inhibition of osteoclast resorption of bone tissue, 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 the start of infusion, serum concentrations increase rapidly, reaching maximum concentration (Cmax) at the end of infusion, followed by a rapid decrease in concentration by 10% after 4 h and by less than 1% of Cmax after 24 h with a further long period of low concentrations not exceeding 0.1% of Cmax, before re-infusion on day 28.
Plasma protein binding is 56%. It is not metabolized.
It is excreted unchanged by the kidneys in 3 phases: Phase 1 and Phase 2 – rapid drug withdrawal from systemic blood flow, with half-life of 0.24 h and 1.87 h respectively, and Phase 3 – prolonged, with half-life of 146 h. No drug cumulation was noted with Resorb in repeated injections every 28 days. During the first 24 h, 23-55% of the drug is detected in the urine. The rest of the drug is bound to the bone tissue, after which it is slowly released back 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 infusion duration from 5 to 15 min leads to a 30% decrease in zoledronic acid concentration at the end of infusion, but does not affect AUC.
Renal clearance correlates positively with creatinine clearance (CK) and is 42-108% of CK, which is on average 55-113%. In patients with severe (CK 20 ml/min) and moderate renal impairment (CK 50 ml/min), zoledronic acid clearance is 37 and 72%, respectively, of the drug clearance values in patients with CK 84 ml/min.

Indications

• osteolytic, osteoblastic and mixed bone metastases of solid tumors;
• osteolytic foci in multiple myeloma;
• hypercalcemia caused by malignancy.

Active ingredient

Zoledronic acid

Composition

1fl:
– zoledronic acid monohydrate 4.26 mg, corresponding to zoledronic acid anhydrous 4 mg
Excipients: D-mannitol – 220 mg, sodium citrate 2-water – 27.
Solvent in ampoule: d/I water – 5 ml.
Solvent in container: 0.9% sodium chloride solution for infusion – 100 ml.

How to take, the dosage

Intravenously drip for at least 15 minutes.
For bone metastases and osteolytic foci in multiple myeloma, the recommended dose is 4 mg Resorba, every 3-4 weeks.
It is additionally recommended to administer calcium in a dose of 500 mg per day and vitamin D in a dose of 400 mg per day.
In hypercalcemia (calcium concentration with correction by albumin level ≥ 12 mg/dl or 3 mmol/l) due to malignant tumors the recommended dose is 4 mg, once. Rezorba infusion is carried out on condition of adequate hydration of the patient.
In postmenopausal and senile forms of primary osteoporosis to increase bone mineral density, to prevent fractures of vertebral bodies and other skeletal bones, the recommended dose is 4 mg, once a year.
If dietary intake of calcium and vitamin D is insufficient, patients with osteoporosis should be prescribed additional calcium and vitamin D preparations. The duration of preparation use is determined by a doctor individually depending on the condition of a patient (s) with postmenopausal or senile form of primary osteoporosis.
In secondary osteoporosis in order to increase bone mineral density, to prevent fractures of vertebral bodies and other skeleton bones the recommended dose is 4 mg of Resorba once a year.
If the intake of calcium and vitamin D with food is insufficient, patients with secondary osteoporosis should be additionally prescribed calcium and vitamin D preparations.
Patients with kidney function disorders:
Hypercalcemia associated with malignant tumors:
The decision to treat with zoledronic acid in patients with significant renal function disorders should be taken only after careful assessment of the risk/benefit ratio. With serum creatinine concentrations of < 400 μmol/L or < 4.5 mg/dL, no dosing adjustment is required.
Bone metastases of advanced malignancies and myeloma disease:
The dose of zoledronic acid depends on baseline creatinine clearance (CK) calculated by the Cockcroft-Gault formula. In severe renal impairment (CK < 30 ml/min) zoledronic acid is not recommended.

Interaction

When concomitant use with anticancer drugs, diuretics, antibiotics, analgesics no clinically significant interactions were observed.
Bisphosphonates and aminoglycosides have unidirectional influence on the calcium concentration in blood serum, therefore in concomitant use the risk of hypocalcaemia and hypomagnesaemia increases.
Caution is required when concomitant use of zoledronic acid with drugs with potentially nephrotoxic effects.
Patients with multiple myeloma may have increased risk of renal dysfunction when administering bisphosphonates in combination with thalidomide.
The drug should not be mixed with other medicinal products.

Special Instructions

Check for adequate hydration in the patient before infusion. If necessary, it is recommended to administer saline solution before, in parallel or after the infusion of zoledronic acid. Hyperhydration of the patient should be avoided due to the risk of cardiovascular complications.
After administration of the drug Resorb, continuous monitoring of serum calcium, magnesium, phosphorus and creatinine concentrations is necessary.
During therapy with zoledronic acid, renal function should be carefully monitored. Risk factors for renal dysfunction include dehydration, prior renal failure, repeated administration of zoledronic acid or other bisphosphonates, as well as the use of nephrotoxic drugs, and too rapid administration of the drug.
It should be noted that when prescribing other bisphosphonates to patients with bronchial asthma sensitive to acetylsalicylic acid, there have been cases of bronchospasm, but with zoledronic acid such cases have not yet been reported.

Contraindications

Hypersensitivity to zoledronic acid, other bisphosphonates or any other component of the drug.
Severe renal insufficiency (creatinine clearance < 30 ml/min).
Pregnancy and lactation.
Childhood and adolescence (safety and efficacy of use have not been established).
With caution: with impaired renal function, marked hepatic failure (no data on use), in patients with bronchial asthma, sensitive to acetylsalicylic acid.

Side effects

Unwanted reactions are listed below by organ and system with indication of their frequency of occurrence. Frequency criteria: very common (≥1/10), common (≥1/100). Blood organs: common – anemia, sometimes – thrombocytopenia, leukopenia; rarely – pancytopenia.
Nervous system: frequently – headache; sometimes – dizziness, paresthesia, taste disorders, hypoesthesia, hyperesthesia, tremor, anxiety, sleep disorders; rarely – confusion.
Organs of vision: often – conjunctivitis, sometimes – “blurred” vision, very rarely – uveitis, episcleritis.
Gastrointestinal tract: 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 erymatous and macular), increased sweating.
Musculoskeletal system: often – bone pain, myalgia, arthralgia, generalized pain; sometimes – muscle cramps.
Cardio-vascular system: sometimes – marked increase or decrease in blood pressure, rarely – bradycardia.
The urinary system: often – renal dysfunction, sometimes – acute renal failure, hematuria, proteinuria.
The immune system: sometimes – hypersensitivity reactions, rarely – angioedema.
Disorders of laboratory indexes: very common – hypophosphatemia, often – increased serum concentrations of creatinine and urea, hypocalcemia, sometimes – hypomagnesemia, hypokalemia, rarely – hyperkalemia, hypernatriemia.
Local reactions: pain, irritation, swelling, infiltrate formation at the site of drug administration.
Other: fever, flu-like syndrome (including general malaise, chills, malaise, fever), sometimes – asthenia, peripheral edema; pain in the chest, weight gain.
When treating patients with bisphosphonates, including zoledronic acid, sometimes there have been cases of osteonecrosis of the jaw (usually after tooth extraction or other dental interventions).
In very rare cases, decreased blood pressure during therapy with zoledronic acid has led to fainting or circulatory collapse.

Overdose

In case of accidental overdose of Resorba the patient should be under constant supervision.
In case of hypocalcemia accompanied by clinical manifestations calcium gluconate infusion is indicated.