Experience with the use of zoledronic acid (Rezorba) for the treatment of patients with bone metastases

Zoledronic acid

The most serious adverse reactions (APs) in patients receiving zoledronic acid for registered indications were: anaphylactic reaction, ocular adverse events, osteonecrosis of the jaw, atypical femoral fracture, atrial fibrillation, renal dysfunction, acute phase reaction, and hypocalcemia.

Information on the incidence of HP with zoledronic acid 4 mg is based primarily on data obtained during long-term therapy. HP associated with zoledronic acid use is usually mild and transient, similar to those reported with other bisphosphonates. These HP may occur in approximately one third of patients treated with zoledronic acid.

Symptoms of the acute phase reaction typically developed 3 days after use of zoledronic acid: general malaise, bone pain, fever, chills, flu-like syndrome, and arthritis followed by joint swelling; Symptoms usually resolved within a few days. HPs such as arthralgia and myalgia were also frequently reported. Very often, a decrease in renal calcium excretion was accompanied by a sharp decrease in phosphorus levels, which was asymptomatic and did not require treatment. Often, a decrease in calcium levels in the blood serum up to the development of hypocalcemia may be accompanied by the absence of clinical manifestations.

There have been reports of frequent gastrointestinal reactions, such as nausea and vomiting, following intravenous infusion of zoledronic acid.

Local reactions at the infusion site, such as redness or swelling and/or pain, were observed infrequently.

Anorexia has been frequently observed in patients receiving zoledronic acid 4 mg. Cases of rash or itching were reported infrequently. As with other bisphosphonates, frequent cases of conjunctivitis have been reported.

Based on a pooled analysis of controlled studies, severe anemia (hemoglobin concentration <8.0 g/dL) was reported to occur frequently in patients receiving zoledronic acid 4 mg.

HP are grouped in accordance with the MedDRA classification of organs and organ systems, within each group they are listed in order of decreasing frequency of occurrence, within each subgroup - in decreasing order of importance.

Criteria for assessing the frequency of occurrence: very often (≥1/10), often (≥1/100, <1/10), infrequently (≥1/1000, <1/100), rarely (≥1/10000, <1/ 1000), very rare (<1/10000), including isolated reports.

Blood and lymphatic system disorders

: often - anemia; uncommon - thrombocytopenia, leukopenia; rarely - pancytopenia.

Mental disorders:

often - sleep disturbance; infrequently - feeling of anxiety; rarely - confusion.

Nervous system disorders

: often - headache, paresthesia; infrequently - dizziness, dysgeusia, hypoesthesia, hyperesthesia, tremor; very rarely - convulsions, hypoesthesia and tetany (developing as a result of hypocalcemia).

Visual disorders:

often - conjunctivitis; infrequently - “blurred” vision; rarely - uveitis.

Digestive system disorders

: often - nausea, vomiting, loss of appetite, constipation; uncommon - diarrhea, abdominal pain, dyspepsia, stomatitis, dry mouth.

Disorders of the respiratory system, chest and mediastinal organs:

infrequently - shortness of breath, cough; rarely - interstitial lung disease.

Disorders of the skin and subcutaneous tissues:

often - increased sweating; Uncommon: itching, rash (including erythematous and macular).

Musculoskeletal and connective tissue disorders:

often - bone pain, myalgia, arthralgia, generalized pain, joint stiffness; infrequently - necrosis of the jaw, muscle cramps.

Cardiac disorders:

rarely - bradycardia, arrhythmia (developing as a result of hypocalcemia).

Vascular disorders:

often - increased blood pressure; infrequently - decreased blood pressure.

Renal and urinary tract disorders:

often - renal dysfunction; uncommon - acute renal failure, hematuria, proteinuria; rarely - acquired Fanconi syndrome.

Immune system disorders:

uncommon - hypersensitivity reactions; rarely angioedema.

Laboratory and instrumental data:

very often - hypophosphatemia; often - increased concentrations of creatinine and urea in the blood serum, hypocalcemia; uncommon: hypomagnesemia, hypokalemia; rarely - hyperkalemia, hypernatremia.

General disorders and disorders at the injection site:

often - acute phase reaction, increased body temperature, flu-like syndrome (including general malaise, chills, feeling of malaise, “hot flashes”), peripheral edema, asthenia; uncommon - reaction at the injection site (pain, irritation, swelling, induration, redness), chest pain, weight gain; rarely - arthritis and swelling of the joints as a symptom of an acute phase reaction.

It should be borne in mind that when using other bisphosphonates in patients with bronchial asthma who are sensitive to acetylsalicylic acid, cases of bronchospasm were observed, but this phenomenon was not observed when using zoledronic acid.

Adverse reactions based on spontaneous reports and literature reports (frequency unknown)

Immune system disorders

: anaphylactic reaction/shock.

Nervous system disorders

: drowsiness.

Visual disorders:

episcleritis, scleritis and inflammatory diseases of the orbit.

Cardiac disorders:

atrial fibrillation.

Vascular disorders:

decreased blood pressure leading to fainting or circulatory collapse, mainly in patients with risk factors.

Respiratory, thoracic and mediastinal disorders

: bronchospasm.

Disorders of the skin and subcutaneous tissues:

hives.

Musculoskeletal and connective tissue disorders:

sudden severe limitation of joint mobility and/or severe and in some cases life-limiting pain in bones, joints and/or muscles, atypical subtrochanteric and diaphyseal fractures of the femur.

Description of selected adverse reactions

Renal dysfunction

The use of zoledronic acid has been associated with the development of renal dysfunction. When zoledronic acid was used in clinical trials for the prevention of skeletal complications in patients with advanced bone malignancies, the incidence of renal dysfunction associated with zoledronic acid was distributed as follows: multiple myeloma (3.2%), prostate cancer (3.1%), breast cancer (4.3%), lung cancer and other solid tumors (3.2%).

Factors that may increase the risk of deterioration of renal function include: dehydration, pre-existing renal impairment, multiple courses of treatment with zoledronic acid or other bisphosphonates, concomitant use of nephrotoxic drugs, or administration of the drug for less than the recommended period of time. There was a deterioration in renal function, progression of renal dysfunction up to renal failure and the need for hemodialysis after administration of a starting or single dose of zoledronic acid.

Osteonecrosis

When treated with bisphosphonates, including zoledronic acid, mainly in patients with cancer, cases of osteonecrosis were observed (mainly in the jaw, but also in other locations, including the pelvic bone, femur and external auditory canal). Many patients with osteonecrosis of the jaw showed signs of a local infectious process, incl. osteomyelitis; Most of these cases were observed in patients with cancer after tooth extraction or after dental surgery.

There are widely recognized multiple risk factors that predispose to the development of osteonecrosis of the jaw, such as malignancies, concurrent therapies (eg, chemotherapy, antiangiogenic drugs, radiation therapy, glucocorticosteroids), and concomitant conditions (eg, anemia, coagulopathies, infections, pre-existing oral disease) . Although a cause-and-effect relationship has not been established, it is advisable to avoid dental surgery due to the possibility of delayed recovery. Based on the available data, the incidence of osteonecrosis of the jaw is related to the nature of the tumor (advanced breast cancer, multiple myeloma).

Acute phase reaction

This adverse reaction is a complex of symptoms: fever, general weakness, bone pain, chills, flu-like syndrome. Typically begins ≤ 3 days after zoledronic acid infusion. The reaction is also referred to using the terms "flu-like" or "post-dose" symptoms. Symptoms usually resolve within a few days.

Atrial fibrillation

In one clinical study, using zoledronic acid for 3 years in patients with postmenopausal osteoporosis (at a dose of 5 mg once a year), the overall incidence of atrial fibrillation was 2.5% (96 of 3862 people) compared with 1.9 % (75 of 3852) in the placebo group. The incidence of atrial fibrillation associated with severe hemodynamic compromise was 1.3% (51 of 3862) and 0.6% (22 of 3852) for zoledronic acid and placebo, respectively.

A similar imbalance has not been observed in other clinical studies of zoledronic acid, including the use of zoledronic acid 4 mg once every 3-4 weeks in patients with cancer. The reason for the increased incidence of atrial fibrillation during therapy with zoledronic acid in patients with postmenopausal osteoporosis was not established in this study.

If any of the side effects indicated in the instructions get worse, or you notice any other side effects not listed in the instructions, tell your doctor.

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– Pharm-Sintez Zoledronic acid

Types of tumors » Medicines in this group »

Instructions for use

Registration number:

No. LS-002724.
Trade name:
Rezorba.
International nonproprietary name:
zoledronic acid.
Dosage form:
Lyophilisate for the preparation of solution for infusion.

Compound

One bottle contains:

active substance:

• zoledronic acid monohydrate – 4.26 mg (corresponding to zoledronic acid anhydrous – 4.0 mg)

Excipients:

• D-mannitol – 220 mg
• Sodium citrate dihydrate – 27.34 mg, in terms of anhydrous – 24.0 mg

Solvent in ampoule:

• Water for injections – 5 ml

Solvent in a polymer container:

• Sodium chloride – 9.0 g
• Water for injections – up to 1 l

Description

Lyophilisate is a lyophilized powder or porous mass of white or almost white color. Solvent is a transparent, colorless, odorless liquid. The solvent in a polymer container is a transparent, colorless, odorless liquid.

Pharmacotherapeutic group

: bone resorption inhibitor – bisphosphonate.
ATX code
: M05BA08.

Pharmacological properties

Pharmacodynamics

Zoledronic acid is a highly effective bisphosphonate that selectively acts on bone tissue. The drug inhibits bone resorption by acting on osteoclasts. The selective effect of bisphosphonates on bone tissue is based on their high affinity for mineralized bone tissue. The exact molecular mechanism responsible for the inhibition of osteoclast activity still remains unclear.

Zoledronic acid does not have undesirable effects on bone formation, mineralization, or mechanical properties.

In addition to its inhibitory effect on bone resorption, zoledronic acid has antitumor properties that ensure the effectiveness of the drug against bone metastases.

In vivo

: inhibits bone resorption by osteoclasts, changes the microenvironment of the bone marrow, leads to a decrease in the growth of tumor cells; exhibits anti-angiogenic activity. Suppression of bone resorption is clinically accompanied, among other things, by a pronounced decrease in pain.

In vitro

: inhibits the proliferation of osteoblasts, exhibits direct cytostatic and proapoptotic activity, a synergistic cytostatic effect with antitumor drugs; anti-adhesive and anti-invasive activity. Zoledronic acid, due to its synergistic effect, in combination with hormonal therapy or chemotherapy, suppresses proliferation and induces apoptosis, has a direct antitumor effect against human myeloma cells and breast cancer, and also reduces the penetration of human breast cancer cells through the extracellular matrix, which indicates the presence of antimetastatic properties. In addition, zoledronic acid inhibits the proliferation of human and animal endothelial cells and has an antiangiogenic effect.

In patients with breast cancer, prostate cancer and other solid tumors with metastatic bone lesions, zoledronic acid prevents the development of pathological fractures, spinal cord compression, reduces the need for radiation therapy and surgical interventions, and reduces tumor hypercalcemia. The drug is able to inhibit the progression of pain. The therapeutic effect is less pronounced in patients with osteoblastic lesions than in patients with osteolytic lesions.

In patients with multiple myeloma and breast cancer with at least one bone lesion, the effectiveness of zoledronic acid at a dose of 4 mg is comparable to pamidronic acid at a dose of 90 mg.

In patients with tumor hypercalcemia, the effect of the drug is characterized by a decrease in the level of calcium in the blood serum and calcium excretion by the kidneys. The average time for calcium levels to normalize is about 4 days. By the 10th day, calcium concentration is normalized 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 effectiveness of zoledronic acid at doses of 4 and 8 mg in the treatment of hypercalcemia.

Studies have shown no significant differences in the incidence or severity of adverse events observed in patients receiving zoledronic acid 4 mg, 8 mg, pamidronic acid 90 mg, or placebo for either bone metastases or 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 do not depend on the dose of the drug. Once the infusion is started, serum concentrations increase rapidly, reaching a peak at the end of the infusion, followed by a rapid decrease in concentrations of 10% after 4 hours and less than 1% of the peak after 24 hours, with a successively prolonged period of low concentrations not exceeding 0.1% of the maximum to repeated infusion on day 28.

Zoledronic acid administered intravenously is excreted by the kidneys in three stages: a rapid two-phase elimination of the drug from the systemic circulation with half-lives of 0.24 hours and 1.87 hours and a long phase with a final half-life of 146 hours. No accumulation of the drug was observed with repeated administrations every 28 days. Zoledronic acid is not metabolized and is excreted unchanged by the kidneys.

Zoledronic acid does not inhibit isoenzymes of the cytochrome P450 system in humans. During the first 24 hours, 39±16% of the administered dose is found in the urine. The remaining amount of the drug is mainly associated with bone tissue. Zoledronic acid is then slowly released back from bone tissue into the systemic circulation and excreted by the kidneys. The total plasma clearance of the drug is 5.04 ± 2.5 l/h and does not depend on the dose of the drug, gender, age, race and body weight of the patient. Increasing the infusion time from 5 minutes to 15 minutes resulted in a 30% decrease in zoledronic acid concentration at the end of the infusion but did not affect the area under the concentration-time curve (AUC).

Pharmacokinetic studies have not been conducted in patients with hypercalcemia or liver failure.

in vitro data

zoledronic acid does not inhibit human cytochrome P450 isoenzymes and does not undergo biotransformation, suggesting that the state of liver function does not significantly affect the pharmacokinetics of zoledronic acid. Less than 3% of the drug dose is excreted through the intestines.

Renal clearance of zoledronic acid correlates positively with creatinine clearance and accounts for 75±33% of the creatinine clearance averaging 84±29% (range 22-143 mL/min) in the 64 patients included in the study.

A population analysis showed that in patients with severe renal impairment (creatinine clearance ≤20 ml/min.) or moderate renal impairment (creatinine clearance 20-50 ml/min.), the calculated clearance of zoledronic acid was 37% and 72%, respectively, of the clearance values ​​of zoledronate in patients with creatinine clearance ≥84 ml/min. Limited pharmacokinetic data have been obtained for patients with severe renal impairment (creatinine clearance less than 30 ml/min).

Zoledronic acid has been shown to have a low affinity for blood components, binding to plasma proteins is low (about 56%) and does not depend on the concentration of the drug.

Indications for use

• Hypercalcemia (albumin-corrected serum calcium concentration ≥12 mg/dL or 3 mmol/L) induced by malignancies
• Metastatic bone disease from malignant solid tumors and multiple myeloma (to reduce the risk of pathological fractures, spinal cord compression, tumor-related hypercalcemia, and reduce the need for radiation therapy)

Contraindications

• Hypersensitivity to zoledronic acid, other bisphosphonates or any other components of the drug
• Severe renal failure (creatinine clearance less than 30 ml/min.)
• Pregnancy and lactation period
• Children and adolescents (safety and effectiveness have not been established)

Carefully

: in case of impaired renal function, severe liver failure (no data on use), in patients with bronchial asthma who are sensitive to acetylsalicylic acid.

Directions for use and doses

Intravenous drip over at least 15 minutes.

For bone metastases and osteolytic lesions in multiple myeloma

The recommended dose is 4 mg, every 3-4 weeks.

Additionally, it is recommended to prescribe oral calcium at a dose of 500 mg per day and vitamin D at a dose of 400 IU per day.

For hypercalcemia

(albumin-corrected calcium concentration ≥12 mg/dL or 3 mmol/L) due to malignancy, the recommended dose is 4 mg, once. The infusion is carried out provided that the patient is adequately hydrated.

Precautions for use in patients with impaired renal function

Hypercalcemia due to malignant tumors

The decision to treat patients with severe renal impairment with zoledronic acid should only be made after a careful assessment of the risk/benefit ratio. If the serum creatinine concentration is <400 µmol/L or <4.5 mg/dL, no dosage adjustment is required.

Bone metastases of common malignant tumors and multiple myeloma

The dose of zoledronic acid depends on the initial level of creatinine clearance (CC), calculated using the Cockcroft-Gault formula. In case of severe renal impairment (creatinine clearance <30 ml/min.), the use of zoledronic acid is not recommended.

Recommended doses for mild or moderate renal impairment (creatinine clearance values ​​30-60 ml/min) are given below.

Serum creatinine concentrations should be determined before each dose of the drug. If renal dysfunction is detected, the next administration of zoledronic acid should be postponed. Renal dysfunction is determined by the following parameters:

• For patients with normal baseline creatinine values ​​(<1.4 mg/dL), an increase in serum creatinine by 0.5 mg/dL.
• For patients with abnormal baseline creatinine levels (>1.4 mg/dL), an increase in serum creatinine by 1 mg/dL.

Therapy with zoledronic acid is resumed only after the creatinine level reaches values ​​exceeding the initial value by no more than 10%, at the same dose that was used before interruption of treatment.

Instructions for preparing a solution for infusion:

The solution is prepared under aseptic conditions; 4 mg is dissolved in 5 ml of water for injection, shake gently until completely dissolved. The resulting solution with the required dose is diluted in 100 ml of 0.9% sodium chloride solution or 5% dextrose solution. Do not use solutions containing calcium. It is advisable to use the prepared solution immediately after preparation. Unused solution can be stored in the refrigerator at a temperature of +2-8°C for no more than 24 hours. The solution stored in the refrigerator should be warmed to room temperature before administration.

Possible side effects

Adverse reactions are listed below by organ and system, indicating the frequency of their occurrence. Frequency criteria: very often (≥1/10), often (≥1/100, <1/10), sometimes (≥1/1,000, <1/100), rarely (≥1/10,000, <1/1,000) , very rare (<1/10,000), including isolated reports.

From the hematopoietic organs

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

From the nervous system

: often – headache; sometimes - dizziness, paresthesia, taste disturbances, hypoesthesia, hyperesthesia, tremor, anxiety, sleep disorders; rarely – confusion.

From the organs of vision

: often – conjunctivitis; sometimes – “blurred” vision; very rarely - uveitis, episcleritis.

From the gastrointestinal tract

: often – nausea, vomiting, anorexia; sometimes - diarrhea, constipation, abdominal pain, dyspepsia, stomatitis, dry mouth.

From the respiratory system

: sometimes – shortness of breath, cough.

From the skin and skin appendages

: sometimes – itching, rash (including erymatous and macular), increased sweating.

From the musculoskeletal system

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

From the cardiovascular system

: sometimes – a pronounced increase or decrease in blood pressure; rarely – bradycardia.

From the excretory system

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

From the immune system

: sometimes – hypersensitivity reactions; rarely – angioedema.

Laboratory abnormalities

: very often – hypophosphatemia; often - increased serum concentrations of creatinine and urea, hypocalcemia; sometimes – hypomagnesemia, hypokalemia; rarely – hyperkalemia, hypernatremia.

Local reactions

: pain, irritation, swelling, formation of infiltrate at the site of drug administration.

Others

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

When treating patients with bisphosphonates, including zoledronic acid, cases of osteonecrosis of the jaw have sometimes been reported (usually after tooth extraction or other dental surgery).

In very rare cases, a decrease in blood pressure during therapy with zoledronic acid has led to fainting or circulatory collapse.

Overdose

In case of acute overdose of zoledronic acid, renal dysfunction may occur, 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. In case of hypocalcemia accompanied by clinical manifestations, an infusion of calcium gluconate is indicated.

Interaction with other drugs

Solutions containing calcium, in particular Ringer's solution, should not be used as solvents.

When used simultaneously with antitumor drugs, diuretics, antibiotics, analgesics, no clinically significant interactions were observed.

Bisphosphonates and aminoglycosides have a unidirectional effect on the concentration of calcium in the blood serum, therefore, when administered simultaneously, the risk of developing hypocalcemia and hypomagnesemia increases. If hypocalcemia, hypophosphatemia or hypomagnesemia develops, short-term additional administration of the corresponding substances may be necessary. Patients with untreated hypercalcemia usually have impaired renal function, so careful monitoring of renal function in this category of patients is necessary. When deciding whether to treat patients with bone metastases with zoledronic acid, it should be taken into account that the therapeutic effect occurs 2-3 months after the start of treatment with zoledronic acid.

Caution is necessary when using zoledronic acid concomitantly with drugs that have a potential nephrotoxic effect.

In patients with multiple myeloma, there may be an increased risk of developing renal dysfunction when administered intravenously with bisphosphonates in combination with thalidomide.

Although the risk of the above-described complications is reduced when 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 deterioration in renal function, progression of renal failure and the need for hemodialysis with the first or single use of zoledronic acid.

The drug should not be mixed with other drugs.

special instructions

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

After administration of the drug, constant monitoring of the concentration of calcium, magnesium, phosphorus and creatinine in the blood serum is necessary.

Renal function should be closely monitored during zoledronic acid therapy. Risk factors for renal dysfunction include dehydration, previous 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 borne in mind that cases of bronchospasm have been reported when prescribing other bisphosphonates to patients with bronchial asthma sensitive to acetylsalicylic acid, but such cases have not yet been reported with the use of zoledronic acid.

During treatment with bisphosphonates, including zoledronic acid, cases of osteonecrosis of the jaw have been described in cancer patients, and therefore, before starting treatment with bisphosphonates, it is necessary to provide a dental examination and in the presence of risk factors (anemia, coagulopathies, infections, poor hygiene or oral diseases, concomitant chemotherapy or radiation therapy, treatment with corticosteroids) carry out appropriate preventive procedures. During treatment with zoledronic acid, patients with risk factors should, if possible, avoid dental surgery.

Features of the medical use of the drug by pregnant women, women during breastfeeding, children

Use is contraindicated during pregnancy and breastfeeding.

The use of the drug in childhood and adolescence is contraindicated, since the safety and effectiveness of use have not been established.

Impact on the ability to drive a car and other mechanisms

No studies have been conducted on the effect of the drug on the ability to drive vehicles and operate complex machinery. In case of side effects from the central nervous system, it is recommended to avoid activities that require increased attention and speed of mental and motor reactions.

Release form

Lyophilisate containing 4.0 mg of zoledronic acid (calculated as an anhydrous substance), in 10 ml dark neutral glass bottles, hermetically sealed with rubber stoppers and closed with aluminum-plastic caps.

5 ml of solvent (“Water for injection”) in neutral glass ampoules with a tension ring for opening, either with or without a breaking point. 100 solvents each (“Sodium chloride solution for infusion 0.9%”) in polyvinyl chloride containers for single-use infusion solutions KPIR with two sterile ports. One container is placed in a bag made of polyethylene or polyethylene-polyamide film. 1 bottle with the drug and 1 ampoule with the solvent (“Water for injection”) in a blister pack. 1 blister pack together with a knife for opening ampoules or an ampoule scarifier and instructions for use in a cardboard box. 1 blister pack together with a knife for opening ampoules or an ampoule scarifier, 1 container in a bag with a solvent (“Sodium chloride solution for infusion 0.9%”) and instructions for use in a cardboard box. When packaging a solvent (“Water for injection”), a knife or ampoule scarifier is not inserted into imported ampoules that have a tension ring for opening, or into ampoules with a breaking point.

Storage conditions

In a dry place, protected from light, at a temperature not exceeding 25°C. Reconstituted solution: at temperatures from 5 to 25°C. Keep out of the reach of children.

Best before date

Lyophilisate – 3 years. Reconstituted solution – 24 hours. Solvent (“Water for injection”) – 5 years. Solvent (“Sodium chloride solution for infusion 0.9%”) – 3 years. The shelf life of the kit is determined by the component with the shortest shelf life. Do not use after the expiration date stated on the packaging.

Conditions for dispensing from pharmacies:

on prescription.

Lyophilisate manufacturer:

1. JSC "Pharm-Sintez" Legal address: 111024, Russia, Moscow, Kabelnaya 2nd street, 2, building 9 Address: 121357 Moscow, Vereyskaya, 29, building 134, Business Center "Vereyskaya Plaza - 3" Tel., fax E-mail: or
2. LLC Legal address: 129344, Russia, Moscow, st. Yeniseiskaya, 3, building 4 Production address: 171130, Tver region, Vyshnevolotsky district, Zelenogorsky village, st. Sovetskaya, 6A or
3. Diamed LLC Legal address: 123182, Russia, Moscow, st. Zhivopisnaya, 46, building 8 Production address: 123182, Russia, Moscow, st. Zhivopisnaya, 46, building 8

Manufacturer of solvent (water for injection):

1. JSC "Pharm-Sintez" Legal address: 111024, Russia, Moscow, Kabelnaya 2nd street, 2, building 9 Address: 121357 Moscow, Vereyskaya, 29, building 134, Business Center "Vereyskaya Plaza - 3" Tel., fax E-mail: or
2. LLC Legal address: 129344, Russia, Moscow, st. Yeniseiskaya, 3, building 4 Production address: 171130, Russia, Tver region, Vyshnevolotsky district, Zelenogorsky village, st. Sovetskaya, 6A or
3. Altair LLC Legal address: 142100, Russia, Moscow region, Podolsk, st. Komsomolskaya, 1 Production address: 142279, Russia, Moscow region, Serpukhov district, pos. Obolensk, building 31

Manufacturer of solvent (sodium chloride solution for infusion 0.9%):

1. LLC "Plant Medsintez" Address: 620144, Russia, Ekaterinburg, st. March 8, 90a Production address: 624130, Russia, Sverdlovsk region, Novouralsk, st. Trading, p.15

Organization accepting complaints:

JSC "Pharm-Sintez" Legal address: 111024, Russia, Moscow, Kabelnaya 2nd street, 2, building 9 Address: 121357 Moscow, Vereyskaya, 29, building 134, Business Center "Vereyskaya Plaza - 3" Tel., fax E-mail: www.pharm-sintez.ru

Efficacy and safety of zoledronic acid in older women with osteoporosis

85% of elderly patients living in specialized institutions have osteoporosis, as well as an 8-9 times increased risk of developing fractures, compared with people of the same age, but living at home. Despite this, they are rarely included in osteoporosis studies.

Target.

To evaluate the effectiveness and safety of zoledronic acid in the treatment of osteoporosis in elderly frail women undergoing long-term treatment in specialized medical institutions.

design .

The two-year, randomized, placebo-controlled, double-blind study, conducted from December 2007 to March 2012, enrolled 181 women aged 65 years or older with osteoporosis, including those with cognitive impairment, immobility, and several comorbidities. All patients lived in nursing homes or specialized medical institutions. Participants were prescribed 5 mg zoledronic acid or placebo intravenously once daily and calcium and vitamin D supplements. Endpoints included hip and spine mineral density at 12 and 24 months after initiation of therapy and the number of adverse drug events. .

Results.

There were no differences in the baseline characteristics of the included patients in terms of age (mean 85.4 years), functional status, or cognitive status. Moreover, in the group of patients where zoledronic acid was prescribed, there were more weakened individuals, women with a history of falls, diabetes mellitus, and the use of anticonvulsants. The mean change in femoral bone mineral density was greater in the zoledronic acid group, 3.2% at 12 months and 3.9% at 24 months (P<0.01 for both comparisons), and 1.8% and 3.6% for the spine (P<0.01). 0.01). Fractures occurred in 16% of patients receiving placebo and 20% of those receiving zoledronic acid (OR, 1.30; 95% CI, 0.61-2.78); death occurred in 13% and 16%, respectively (OR, 1.24; 95% CI, 0.54–2.86). There was no difference in the incidence of single falls (28% in the study group vs 24% in the control group; OR, 1.24; 95% CI, 0.64-2.42; P = 0.52), however, multiple falls were more common in patients receiving zoledronic acid ( 49% vs 35%; OR, 1.83; 95% CI, 1.01-3.33; P = 0.047). After controlling for baseline characteristics, the difference between groups did not reach statistical significance.

Conclusion.

Administration of zoledronic acid to elderly patients with osteoporosis is associated with an increase in bone mineral density over 2 years. The clinical significance of the statistically nonsignificant increase in fracture risk and mortality should be examined in future studies.

Source:
Susan L. Greenspan, MD;
Subashan Perera, PhD; Mary Anne Ferchak, BSN; David A. Nace, MD; Neil M. Resnick, MD. Efficacy and Safety of Single-Dose Zoledronic Acid for Osteoporosis in Frail Elderly Women A Randomized Clinical Trial JAMA Intern Med. 2015;175(6):913-921. Prepared by:

Evsyutina Yu.V.