Resorba lyophilisate for solution 4 mg vial №1 with solvent

Pharmacological group:

metabolism / correctors of bone and cartilage tissue metabolism.

Pharmachologic effect:

inhibitory bone resorption.

Pharmacological properties

The antiresorptive mechanism of action of zoledronic acid is not fully understood, but factors that contribute to this effect have been established. Zoledronic acid in vitro induces apoptosis and inhibits the activity of osteoclasts. Zoledronic acid blocks the resorption of osteoclasts of cartilage and mineralized bone tissue. Zoledronic acid inhibits the release of Calcium from the bone and an increase in the activity of osteoclasts under the action of stimulating factors that are released from tumor cells. In clinical experiments in patients who had hypercalcemia due to a malignant neoplasm, it was found that a single use of the drug was accompanied by a decrease in serum phosphorus and calcium levels and an increase in urine phosphorus and calcium excretion. The main pathophysiological mechanism of the onset of hypercalcemia in bone metastases and malignant tumors is the increased activation of osteoclasts, which leads to an increase in bone resorption.Increased intake of calcium in the blood due to bone resorption leads to a violation of the gastrointestinal tract and polyuria, which are accompanied by a decrease in filtration rate in the glomeruli of the kidneys and progressive dehydration. In turn, these processes lead to an increase in calcium reabsorption in the kidneys, which further aggravates systemic hypercalcemia and creates a pathological vicious circle. Maintaining adequate hydration and removal of excess bone resorption are essential points in the treatment of patients with hypercalcemia, which is caused by a malignant neoplasm. Patients with hypercalcemia in malignant neoplasms can be divided into two groups according to the main pathophysiological mechanism: patients with hypercalcemia due to tumor invasion of bone tissue and humoral hypercalcemia. In humoral hypercalcemia, stimulation of bone resorption and activation of osteoclasts is carried out by parathyroid hormone-bound protein, which is produced by tumor cells and enters the systemic circulation. Usually, humoral hypercalcemia develops in tumors of the urogenital system (for example, ovarian cancer, renal cell carcinoma) or squamous cell malignant neoplasms of the head, lung, and neck. In these patients, bone metastases may be minimal or absent.In case of a pronounced invasion of tumor cells into the bone, tumor cells are produced substances that act locally, which activate osteoclastic resorption, and this also leads to the appearance of hypercalcemia. Tumors that are usually accompanied by locally mediated hypercalcemia include multiple myeloma and breast cancer. The overall calcium content in the plasma of patients with hypercalcemia in malignant tumors may not reflect the full severity of hypercalcemia due to the presence of concomitant hypoalbuminemia. For detection and treatment of hypercalcemia, it is better to determine the content of ionized calcium, but in most clinical situations, this study is not performed quickly enough or is not available. Therefore, instead of determining ionized calcium, a common indicator of calcium content is often used, corrected for albumin (or corrected serum calcium), there are several nomograms for performing such calculations.
Standard biological studies evaluating the carcinogenicity of zoledronic acid were carried out in rats and mice. Rats were orally administered with 0.1; 0.5 or 2.0 mg / kg of the drug per day; there was no increase in the incidence of tumors at doses that are no more than 0.2 from an intravenous dose of 4 mg for a person (calculations are based on a comparison of the relative surface area of ​​the body).Mice were orally administered with 0.1; 0.5 or 2.0 mg / kg of the drug per day; in all groups, at doses that are not less than 0.002 from an intravenous dose of 4 mg for humans, the incidence of the adenoma of the harder glands in females and males increased.
The genotoxic properties of zoledronic acid in tests on ovarian cells of Chinese hamsters, on bacterial cultures, in micronucleus tests on rats in vivo, in the test of gene mutations on cells of Chinese hamsters in the presence or absence of metabolic activation, were not identified.
Evaluation of fertility disorders when using zoledronic acid. Female rats were injected subcutaneously with 0.01; 0.03 or 0.1 mg / kg of the drug daily, starting 15 days before mating, as well as throughout the gestation. In the group that received high doses of the drug (when calculated by AUC, the systemic dose is 1.2 times the systemic exposure in humans when administered intravenously with 4 mg of the drug), a decrease in the number of pregnant rats and inhibition of ovulation was observed. In the groups that received high doses and average doses (when calculating by AUC, correspond to 0.2 in humans with intravenous administration of 4 mg of the drug), there was a decrease in the number of live fetuses and implantations and an increase in preimplantation losses.
Evaluation of abnormalities during pregnancy. In female rats, which were injected subcutaneously with 0.01, 0.03, or 0.1 mg / kg of the drug per day, starting 15 days before mating and throughout the gestation, a decrease in the survival rate of the newborn and an increase in the number of stillbirths were observed in groups that received medium and high doses (when calculated by AUC is greater than 0.2 from systemic exposure in humans with an intravenous dose of 4 mg).In groups where systemic exposure for AUC calculations corresponded to more than 0.7 from systemic exposure in humans with an intravenous dose of 4 mg, toxicity was observed in the pregnant mother's body (delivery in labor and discoordination of labor activity) in pregnant rats during delivery. Perhaps maternal mortality was associated with a decrease in the mobilization of calcium from bone tissue under the influence of the drug, which led to the development of hypocalcemia during childbirth. This effect seems to be characteristic of all bisphosphonates. In pregnant rats, which received the drug subcutaneously in doses of 0.1; 0.2 or 0.4 mg / kg per day throughout gestation in the groups that received medium and high doses (when calculated by AUC, the system exposure was 2.4 and 4.8 times higher than the systemic exposure in humans when administered intravenously), an adverse effect on the fetus was noted: a decrease in the survival rate of the fetuses, an increase in post-and pre-implantation losses, external anomalies of fetal development, malformations of the internal organs and the skeleton. The effect on fetal bones in the group that received high doses was manifested by insufficient ossification or lack of ossification of the bones, curvature, thinning or shortening of the bones, shortening of the jaw, and wavy ribs. Other adverse reactions from the fetus in the group that received high doses included the rudimentary cerebellum, lens reduction, absence or reduction of the lobes of the lungs and / or liver, crevices of the upper palate, dilated vessels, edema.Variants of skeleton formation were also noted in the group that received low doses (when calculating by AUC, systemic exposure is 1.2 times greater than that in humans when 4 mg of the drug was administered intravenously). Manifestations of toxic effects on the mother's body, including a decrease in food intake and a decrease in body weight, were observed in the group that received high doses. When conducting research on pregnant rabbits, which received subcutaneously 0.01; 0.03 or 0.1 mg / kg of the drug per day during the entire gestation (based on a comparison of the relative surface area of ​​the body less than 0.5 from an intravenous dose of 4 mg for a person), no negative effect on the fetus was noted. Spontaneous miscarriages and maternal mortality were present in all groups that received doses that corresponded to less than 0.05 from an intravenous dose of 4 mg for a person when comparing the relative surface area of ​​the body). Manifestations of adverse effects on the mother's body were associated and, possibly, caused by drug hypocalcemia.
Use of the drug in pediatrics. Data on the safety and efficacy of the drug in children are not available. Due to the long-term deposition of the drug in bone tissue, the use of zoledronic acid in children is possible only when the expected benefit of treatment is greater than the possible risk.
The use of the drug in elderly patients. Significant differences in the development of side effects or the level of response were not observed when compared with patients of younger age.Since the possibility of lowering kidney function increases with age, it is worth paying special attention to monitoring the work of the kidneys when using the drug.
When administered intravenously by the end of the infusion, the maximum concentration is reached, then it decreases in three phases: a rapid two-phase decrease to

Indications

Multiple myeloma; Hypercalcemia in malignant neoplasms; confirmed metastases in the bones of a solid tumor (as an addition to standard antitumor treatment).

The method of use of zoledronic acid and dose

For bone metastases of solid tumors and multiple myeloma: The recommended dose is 4 mg in the form of a 15-minute intravenous infusion every 21–28 days, the duration of therapy in clinical studies was 1 year for breast cancer and multiple myeloma, 15 months for prostate cancer and 9 months for other solid tumors. Patients should also take orally calcium supplements at a dose of 500 mg per day and multivitamins containing vitamin D at the rate of 400 IU per day.
When hypercalcemia in malignant tumors: the feasibility of using the drug should be determined by taking into account the severity and manifestations of hypercalcemia in malignant tumors. For the treatment of asymptomatic mild forms of hypercalcemia, only the use of enhanced hydration — the introduction of saline solutions (with or without loop diuretics) may be sufficient.
The maximum recommended dose for hypercalcemia in malignant tumors (with corrected serum calcium ≥ 3.0 mmol / L or 12.0 mg / dL) is 4 mg, as a single intravenous infusion for at least 15 minutes. It is possible to introduce a repeated dose if deterioration occurs after a clear clinical effect or the calcium content is not normalized. The time interval before re-introduction should be not less than 1 week, which is necessary to realize the full clinical effect of the initial dose of the drug.
During the whole therapy, it is necessary to ensure adequate hydration, but it is necessary to avoid excessive hydration, especially in patients with circulatory failure. During the whole therapy, it is recommended to maintain a diuresis of about 2 liters per day. Only after correction of hypovolemia can diuretics be used.

A single dose of the drug should be no more than 4 mg and the duration of infusion should be not less than 15 minutes, since it is possible to develop a clinically significant deterioration of the functional state of the kidneys up to renal failure. Zoledronic acid can have a nephrotoxic effect, which is manifested by impaired kidney function and, probably, renal failure. In clinical experiments, the likelihood of impaired kidney function (defined as an increase in plasma creatinine) was significantly higher in patients who received an infusion for 5 minutes when compared with patients whose infusion with the same dose lasted 15 minutes.Also, the risk of renal impairment and the development of renal failure was significantly greater in the group of patients who received 8 mg of the drug, even with an infusion of 15 minutes. Despite the fact that the risk of developing kidney problems is reduced with the introduction of 4 mg of the drug over 15 minutes, a deterioration in the kidneys still remains likely. Risk factors for such disorders: initially high plasma creatinine, repeated cycles of biophosphonate therapy. Patients who take the drug, you need to control the content of creatinine in the blood plasma before each administration of the drug. With a deterioration in the functional state of the kidneys in patients with bone metastases, the introduction of a regular dose of the drug must be canceled. In identifying the symptoms of renal impairment in patients with hypercalcemia in malignant neoplasms, a thorough examination is necessary to resolve the question of the predominance of the possible benefits of using the drug over the possible risk. After the start of treatment, careful monitoring of plasma levels of phosphorus, calcium, creatinine and Magnesium , as well as hemoglobin and hematocrit is necessary. The appearance of hypophosphatemia, hypocalcemia, hypomagnesemia requires short-term corrective treatment. Before the introduction of each dose of the drug, it is necessary to control the content of creatinine in the blood plasma. Patients with hypercalcemia for malignant neoplasms prior to the start of therapy should be adequately rehydrated.Loop diuretics are used with caution with zoledronic acid (the risk of hypocalcemia increases) and only when a sufficient level of hydration is achieved.

Contraindications

Hypersensitivity (clinically significant), including to other bisphosphonates.

Restrictions on the use of

Aspirin-sensitive asthma, hepatic or / and renal failure.

Use during pregnancy and lactation

The use of zoledronic acid is contraindicated during pregnancy. Studies of the safety of the drug in pregnant women have not been conducted. If pregnancy occurs during drug therapy, the patient should be informed of the possible negative effects of the drug on the fetus; women of childbearing age are recommended to use reliable methods of contraception. At the time of therapy, zoledronic acid should stop breastfeeding (it is not known whether zoledronic acid is excreted in breast milk). Since most drugs are excreted in breast milk, and zoledronic acid is in the bones for a long time, the use of the drug in nursing women is contraindicated.

Side effects of zoledronic acid

When hypercalcemia in malignant tumors
Adverse reactions are usually transient and insignificant and are similar to adverse reactions that are noted with other bisphosphonates.Most often, intravenous administration is accompanied by fever. Sometimes patients develop flu-like syndrome, which includes chills, fever, pain in the bones and / or joints, muscle pain. Reactions from the digestive system (nausea and vomiting) are noted after intravenous administration. Local reactions in the injection area (swelling and redness) do not occur often. In many cases, non-specific therapy is needed and side effects subside within 1 to 2 days. There are rare reports of itching, rashes, and chest pains after the injection. As with other bisphosphonates, there are reports of the development of hypomagnesemia and conjunctivitis.
In two clinical experiments with hypercalcemia in malignant neoplasms, such deviations of laboratory parameters were noted: hypocalcemia, increased plasma creatinine, hypophosphatemia.
Below are the side reactions that were registered with a frequency of more than 10% during research.

Nervous system: insomnia, anxiety, confusion, agitation;
circulatory system and blood: anemia, hypotension;
respiratory system: shortness of breath, cough;
digestive system: nausea, constipation, diarrhea, abdominal pain, vomiting, anorexia;
metabolism: hypophosphatemia, hypomagnesemia, hypokalemia;
urinary system: urinary tract infections;
support and movement system: bone pain; other: fever, candidosis, progression of the tumor.

For bone metastases of solid tumors and multiple myeloma.

Nervous system: headache, dizziness, insomnia, paresthesia, depression, hypesthesia, anxiety;
blood and circulatory system: anemia, neutropenia;
respiratory system: shortness of breath, cough, upper respiratory tract infection;
digestive system: nausea, vomiting, constipation, diarrhea, abdominal pain, loss of appetite, anorexia;
support and movement system: bone pain, myalgia, arthralgia, back pain;
skin: alopecia, dermatitis; other: fatigue, fever, weakness, swelling of the lower extremities, chills, progression of malignant neoplasms, weight loss, dehydration, urinary tract infection;
laboratory values: increase in plasma creatinine, hypocalcemia, hypophosphatemia, hypermagnemia, hypomagnesemia.

In the post-marketing period, the following side effects have been reported.

Osteonecrosis: cases of osteonecrosis (mainly jaws) have been reported mainly in cancer patients with intravenous zoledronic acid. Most of these patients also received corticosteroids and Chemotherapy , which is also a risk factor for osteonecrosis of the jaw. The high frequency of reports of this side effect was observed in multiple myeloma and breast cancer.Many reported cases have been with cancer patients after invasive dental procedures (for example, tooth extraction). Therefore, if possible, during therapy, patients should avoid invasive dental procedures. Dental surgery can aggravate the condition in patients with developing osteonecrosis of the jaw during therapy with bisphosphonates.

Other post-marketing side effects: musculoskeletal pain (up to disability), pain in the joints, muscles, bones; uveitis, episcleritis, scleritis, conjunctivitis, iritis, and orbital inflammation, including orbital edema; allergic reactions, including bronchospasm, angioedema, Anaphylactic reactions / shock; taste disturbance, tremor, hyperesthesia; visual impairment; dry mouth; excessive sweating; muscle cramps; bronchospasm; proteinuria, hematuria; hypernatremia, hyperkalemia; weight gain, flu-like condition (asthenia, fever, malaise, or fatigue) that lasts more than 30 days; arterial hypertension, arterial hypotension (associated with vascular insufficiency or syncope, primarily in patients with concomitant risk factors), bradycardia.

The interaction of zoledronic acid with other substances

In vivo studies have not been conducted drug interactions. It has been established that the drug (in vitro) binds to plasma proteins by 56% and does not inhibit CYP450 microsomal enzymes, it has also been established (in vivo) that the drug is not metabolized and is excreted unchanged in the urine from the body.Additively aminoglycosides may enhance the hypocalcemic effect of bisphosphonates for an extended period, so caution is recommended when sharing. Zoledronic acid is used with caution along with loop diuretics (the risk of hypocalcemia increases) and other potentially nephrotoxic drugs. In patients with multiple myeloma, the likelihood of the development of a renal dysfunction with the use of thalidomide may increase. There is evidence of the pharmaceutical incompatibility of zoledronic acid with calcium-containing solutions.

Overdose

Cases of acute overdose zoledronic acid is not registered. Two patients received 32 mg of the drug as a 5-minute infusion, and no laboratory or clinical manifestations of toxic effects were noted. Symptoms: clinically significant hypophosphatemia, hypocalcemia, hypomagnesemia. Required symptomatic therapy: administration of intravenous Calcium gluconate , magnesium sulfate, sodium / potassium phosphate.