Zolendronic acid, freeze-dried powder for preparing a solution for infusions 4 mg

 

International non-proprietary name

Zolendronic acid

 

Synonyms

Aclasta, Zometa, Rezorba

 

Pharmacotherapeutic group

Preparations for treating diseases of bones. Bisphosphonates.

 

Composition

1 bottle contains: active substance: zolendronic acid – 4 mg.

 

ATX Code: M05BA08.

 

Pharmaceutical action

It is new class of high-efficient bisphosphonates having a selective action on the osseous tissue. The selective action is pre-conditioned by a high affinity with the mineralized osseous tissue however the exact molecular mechanism providing the osteoclastic activity inhibition is still not clear. Zolendronic acid inhibits the osseous tissue resorption having no undesirable impact on the bone formation, mineralization, and mechanic characteristics. The osseous tissue osteoclastic resorption inhibition changing the bone marrow micromedium results in the tumor cells growth retardation, anti-angiogenic and analgetic activities are observed. Zolendronic acid suppresses the human endothelial cells proliferation, too. In case of hypercalcemia caused by a tumor the serum Ca2+ concentration is reduced.

 

Indications

-          the solid tumors osteolytic, osteosclerotic, and mixed bone metastases;

-          osteolytic foci under multiple myeloma (as a part of the combined therapy);

-          hypercalcemia caused by a malignant tumor.

 

Mode of administration and dosage

Intravenous by drops during 15 minutes.

In case of bone metastases and osteolytic foci the recommended dose within the combined therapy is 4 mg every 3 – 4 weeks.

In case of hypercalcemia caused by a tumor: when the Ca2+ concentration is 1.2 mg/ml or the albumin concentration is 3 mmol/l it is recommended to administer 4 mg of the drug. When the patient hydration is adequate infusions may be performed. The drug re-infusion is indicated when the patient’s state worsened after an evident effect has been achieved (when the Ca2+ blood concentration became 2.7 mmol/l or lower) or when the patient has been refractory to the first infusion. The re-infusion dose is 8 mg for 15 min. the interval between the first infusion and the re-infusion should be not less than 1 week necessary for the effect evaluation.

Usually the blood Ca2+ reduction achieved continues for 30 days after 4 mg has been infused and for 40 days after 8 mg has been infused.

The dosage correcting is not required for persons with a mild or moderate renal insufficiency. When re-infusions are necessary the serum creatinine concentration should be determined before every infusion.

Preparation of the solution for injections: the solution is prepared under aseptic conditions – 4 mg is dissolved in 5 ml of water for injections (8 mg – in 10 ml, respectively) mixing carefully until the powder has dissolved completely. A single dose of the solution made is diluted by 50 ml of NaCl 0.9% solution or by dextrose 5% solution.

Solutions containing Ca2+ cannot be used. The drug solution should be used immediately after it has been made.

 

Special warnings

Only fresh made solutions may be used. Solutions containing Ca2+ including Ringer’s solution cannot be used as solvents.

As the renal function can worsen clinically resulting even in the renal failure the single dose should not exceed 4 mg and the infusion duration should be not less than 15 min.

Zolendronic acid should not be mixed with other medicinal agents in the same syringe.

 

Side effects

Water-electrolyte exchange: hypophoshatemia, hypocalcemia, hypomagnesemia, K+ metabolism disturbances (both hypercaliemia and hypocaliemia), hypernatriemia.

Haemopoietic organs: thrombocytopenia, anemia, leucopenia, pancytopenia.

Digestive system: nausea, vomiting, dysorexia, constipations or diarrhea, abdominal pain, dyspepsia, dry mouth.

Nervous system: headache, asthenia, paresthesia, hypesthesia, hyperesthesia, tremor, anxiety, sleep disorders, mental confusion.

Sense organs: taste perversion, conjunctivitis, “clouded” vision.

Urogenital system: renal function impairment (serum creatinine and urea concentrations increase), acute renal insufficiency, hematuria, proteinuria.

Respiratory system: dyspnea, cough.

Skin integument: itching, eruptions (including the erythematous and macular eruptions), hyperhidrosis.

Locomotor apparatus: bone pains, myalgia, arthralgia, muscular convulsions.

Allergic reactions: very rare skin eruptions, itching, angioneurotic edema.

Local reactions: pain, irritability, slight swelling, infiltrate formation in the area of infusion.

Others: fever, influenza-like syndrome (fever, shiver, bone and/or muscular pain (; asthenia, peripheral edemas, body mass gain, chest pain, bradycardia.

 

Contraindications

Hypersensitivity (including that to bicphosphonates), pregnancy, period of lactation, childish and adolescent age.

Cautiously. Severe renal (the creatinine serum concentration not less than 400 µmol/l or 4.5 mg/dl) or hepatic insufficiency, “aspirin” bronchial asthma.

 

Measures of precaution

To be administered in hospital only.

Before infusing the doctor should evaluate the patient hydration degree. Hyperhydration should be avoided because of a risk of cardiovascular complications development. After the drug has been infused the serum Ca2+, Mg2+, phosphorus, and creatinine levels should be monitored permanently. When the patient is infused zolendronic acid the serum creatinine level should be determined before every infusion. In case the renal function of patients with bone metastasis has worsened the drug should be cancelled. When signs of the renal function worsening appear in patients having malignant hypercalcemia they should be examined thoroughly for making a conclusion whether the potential risk associated with the zolendronic acid administration dominates over a possible risk.

Patients suffering from bronchial asthma, sensitive to acetyl salicylic acid can have bronchospasms. The lower jaw osteonecrosis can develop when the patient having a malignant neoplasm is infused the drug. Malignant neoplasma, chemotherapy, glucocorticoid administration, insufficient oral hygiene can be risk factors.

 

Interaction with other medicinal agents

When administered simultaneously with anti-tumor medicinal agents, antibiotics, analgesics no clinically significant interaction has been observed.thr drug is prescribed cautiously in combination with loop diuretics (the risk of hypocalcemia increases), with other potentially nephrotoxic medicinal preparation. Aminoglycosides have a unidirectional action on the serum Ca2+ concentration, therefore being prescribed simultaneously they increase the risk of hypocalcemia and hypomagnesemia. Patients having multiple myeloma can be at a higher risk of the renal function impairment when infused the drug simultaneously with the Thalidomide administration.

 

Overdosing

Symptoms: hypocalcemia symptoms aggravation, hypophsphatemia, hypomagnesemia.

Treatment: calcium gluconate, sodium/potassium phosphate, magnesium sulfate intravenous infusions.

 

Release form

Freeze-dried powder for preparing a solution for infusions 4 mg in bottles in packs No. 1, No. 40.