Zolerix, 0.8 mg/ml, concentrate for solution for infusion, 5 ml, 1 pc.
Before infusion of Zolerix®, ensure that the patient is adequately hydrated. If necessary, it is recommended to administer a 0.9% sodium chloride solution before the infusion of Zolerix®. Overhydration of the patient should be avoided due to the risk of cardiovascular complications.
After administration of zoledronic acid, constant monitoring of the concentrations of calcium (adjusted for albumin), phosphorus, magnesium and creatinine in the blood plasma is necessary. 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 Zolerix® to reduce the risk of pathological fractures, spinal cord compression, tumor-related hypercalcemia, and reduce the need for radiation therapy or bone surgery, it should be taken into account that the therapeutic effect occurs 2–3 months after starting to use the drug.
Renal dysfunction
There are isolated reports of renal dysfunction associated with the use of bisphosphonates. Risk factors for such complications include dehydration, pre-existing renal impairment, repeated administration of zoledronic acid or other bisphosphonates, as well as the use of nephrotoxic drugs, and too rapid administration of the drug. Although the risk of the above-described complications is reduced when zoledronic acid is administered at a dose of 4 mg over at least 15 minutes, the possibility of renal dysfunction remains.
There have been cases of deterioration in renal function, progression of renal dysfunction up to the occurrence of renal failure and the need for hemodialysis with the first or single use of zoledronic acid.
Increases in plasma creatinine concentrations have also been observed in some patients with long-term use of zoledronic acid at recommended doses, although with less frequency.
The concentration of creatinine in the blood plasma should be determined before each administration of the drug. In patients with mild to moderate renal impairment, bone metastases from solid malignant tumors and multiple myeloma, a lower starting dose of the drug is recommended (see section "Dosage and Administration"). If signs of renal dysfunction are detected during therapy, treatment with Zolerix® should be resumed only after the creatinine concentration reaches values within ±10% of the initial value (see section “Dosage and Administration”). The use of Zolerix® in patients with severe renal impairment is contraindicated (see section “Contraindications”).
When deciding on the use of zoledronic acid in patients with hypercalcemia caused by a malignant tumor against the background of impaired renal function, it is necessary to assess the patient's condition and conclude whether the potential benefit of administering the drug outweighs the possible risk.
The physician should inform patients about the main manifestations of hypocalcemia and ensure regular monitoring of patients at risk.
To reduce the incidence of some adverse events observed within 3 days after drug administration, paracetamol or ibuprofen can be prescribed immediately after the zoledronic acid infusion.
Osteonecrosis
Cases of osteonecrosis of the jaw have been described, mainly in patients with cancer during treatment with bisphosphonates, including zoledronic acid. Many of these patients received concurrent corticosteroid therapy or chemotherapy. Many patients had signs of a local infectious and inflammatory process, including osteomyelitis.
In clinical practice, the development of osteonecrosis of the jaw was most often observed in patients with advanced breast cancer and multiple myeloma, as well as in the presence of dental diseases (after tooth extraction, periodontal diseases, unsatisfactory fixation of dentures). Known risk factors for the development of osteonecrosis of the jaw are cancer, concomitant treatment (chemotherapy, radiation therapy, antiangiogenic drugs, glucocorticosteroids), concomitant diseases (anemia, coagulopathy, infection, previous oral disease).
Before using bisphosphonates in patients with cancer, a dental examination and necessary preventive procedures should be performed, and strict oral hygiene should be recommended.
During treatment with bisphosphonates, dental surgery should be avoided if possible. In patients with osteonecrosis of the jaw resulting from bisphosphonate therapy, invasive dental intervention may worsen the condition. There is no evidence that interrupting bisphosphonate treatment before dental procedures reduces the risk of developing osteonecrosis of the jaw. The treatment plan for a particular patient should be based on an individual assessment of the risk/benefit ratio.
Cases of osteonecrosis of other localizations, including the pelvic bone, femur, and external auditory canal, have been described, mainly in adult patients receiving therapy with bisphosphonates, including zoledronic acid.
Cases of osteonecrosis of the external auditory canal have mostly been reported with long-term use of zoledronic acid. Risk factors for the development of osteonecrosis of the external auditory canal: simultaneous use with glucocorticosteroids, chemotherapy and/or local factors such as infection and trauma. The possibility of developing osteonecrosis of the external auditory canal should also be considered in patients with chronic ear infections taking bisphosphonates.
Atypical femur fractures.
Cases of atypical subtrochanteric and diaphyseal fractures of the femur have been described in patients receiving long-term treatment with bisphosphonates for osteoporosis. Transverse or short oblique fractures can be located anywhere along the femur from the lesser trochanter to the supracondylar fossa. The described fractures occur after minimal trauma or spontaneously.
Some patients experience hip or groin pain, often accompanied by visual signs of stress fractures, which occur weeks and months before the development of a complete femur fracture. Fractures often occur on both sides, so in patients receiving bisphosphonates who experience a fracture of one femur, the contralateral femur should be evaluated. Slow healing (healing) of these fractures has also been reported. The cause-and-effect relationship of such fractures with zoledronic acid therapy has not been established. The decision to discontinue zoledronic acid therapy in patients suspected of having an atypical femoral fracture should be based on an individualized risk/benefit assessment.
Patients receiving zoledronic acid therapy should be advised to inform medical personnel of any pain in the hip or groin area. Each patient complaining of such symptoms should be examined to identify a possible incomplete (incomplete) fracture of the femur.
Musculoskeletal pain
In clinical practice, rare cases of severe and in some cases disabling pain in bones, joints and muscles have been reported with the use of bisphosphonates, which include zoledronic acid. These symptoms developed over a period of one day to several months after the start of treatment. After cessation of treatment, most patients experienced resolution of symptoms. In several patients, symptoms recurred when therapy was restarted or another bisphosphonate was prescribed.
Hypocalcemia
In clinical practice, the development of hypocalcemia has been reported in patients receiving zoledronic acid. In the case of severe hypocalcemia, adverse events from the nervous system (convulsions, tetany and numbness), and cardiac arrhythmia may occur. In some cases, hypocalcemia can be life-threatening.
Caution should be exercised when using Zolerix® concomitantly with other drugs that can cause hypocalcemia, as this may lead to a synergistic interaction and the development of severe hypocalcemia. Before starting treatment, it is necessary to determine the concentration of calcium in the blood plasma and correct hypocalcemia.
If hypocalcemia is present, before starting the use of zoledronic acid, it is necessary to treat with adequate doses of calcium and vitamin D. Also, if possible, treatment should be carried out for other existing disorders of mineral metabolism (for example, occurring after surgery on the thyroid and parathyroid glands, with hypoparathyroidism or decreased absorption of calcium in intestines) and ensure regular monitoring of patients with hypocalcemia.
Use in children
The safety and effectiveness of zoledronic acid when used in children 1–17 years of age have not been established.
Other information
There have been isolated cases of bronchoconstriction in patients with a complete or incomplete combination of bronchial asthma, recurrent polyposis of the nose and paranasal sinuses, and intolerance to acetylsalicylic acid or other non-steroidal anti-inflammatory drugs (including a history) during the use of bisphosphonates. Although there were no such cases in clinical studies with zoledronic acid, it is recommended that the drug be used with caution in patients with aspirin-induced asthma.
Patients receiving Zolerix should not receive other bisphosphonate medications concomitantly.
In animal studies, zoledronic acid suppressed fertility at a dose of 0.1 mg/kg/day.
There are no data on the effects of zoledronic acid on fertility in humans.
Influence on the ability to drive vehicles and machinery.
The effect of zoledronic acid on the ability to drive vehicles and operate machinery has not been studied. In the event of adverse reactions from the nervous system, patients are advised to refrain from driving vehicles and other mechanisms, as well as engaging in activities that require concentration and strain on psychomotor functions.
Zolerix
Before infusion of Zolerix®, ensure that the patient is adequately hydrated.
If necessary, it is recommended to administer a 0.9% sodium chloride solution before the infusion of Zolerix®. Overhydration of the patient should be avoided due to the risk of cardiovascular complications. After administration of zoledronic acid, constant monitoring of the concentrations of calcium (adjusted for albumin), phosphorus, magnesium and creatinine in the blood plasma is necessary. 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 Zolerix® to reduce the risk of pathological fractures, spinal cord compression, tumor-related hypercalcemia, and reduce the need for radiation therapy or bone surgery, it should be taken into account that the therapeutic effect occurs 2-3 months after starting to use the drug.
Renal dysfunction
There are isolated reports of renal dysfunction associated with the use of bisphosphonates. Risk factors for such complications include dehydration, pre-existing renal impairment, repeated administration of zoledronic acid or other bisphosphonates, as well as the use of nephrotoxic drugs, and too rapid administration of the drug. Although the risk of the above-described complications is reduced when zoledronic acid is administered at a dose of 4 mg over at least 15 minutes, the possibility of renal dysfunction remains. There have been cases of deterioration in renal function, progression of renal dysfunction up to the occurrence of renal failure and the need for hemodialysis with the first or single use of zoledronic acid.
Increases in plasma creatinine concentrations have also been observed in some patients with long-term use of zoledronic acid at recommended doses, although with less frequency.
The concentration of creatinine in the blood plasma should be determined before each administration of the drug. In patients with mild to moderate renal impairment, bone metastases from solid malignant tumors and multiple myeloma, a lower starting dose of the drug is recommended (see section "Dosage and Administration"). If signs of renal dysfunction are detected during therapy, treatment with Zolerix® should be resumed only after the creatinine concentration reaches values within ±10% of the initial value (see section “Dosage and Administration”). The use of Zolerix® in patients with severe renal impairment is contraindicated (see section “Contraindications”).
When deciding on the use of zoledronic acid in patients with hypercalcemia caused by a malignant tumor against the background of impaired renal function, it is necessary to assess the patient's condition and conclude whether the potential benefit of administering the drug outweighs the possible risk. The physician should inform patients about the main manifestations of hypocalcemia and ensure regular monitoring of patients at risk.
To reduce the incidence of some adverse events observed within 3 days after drug administration, paracetamol or ibuprofen can be prescribed immediately after the zoledronic acid infusion.
Osteonecrosis
Cases of osteonecrosis of the jaw have been described, mainly in patients with cancer during treatment with bisphosphonates, including zoledronic acid. Many of these patients received concurrent corticosteroid therapy or chemotherapy. Many patients had signs of a local infectious and inflammatory process, including osteomyelitis.
In clinical practice, the development of osteonecrosis of the jaw was most often observed in patients with advanced breast cancer and multiple myeloma, as well as in the presence of dental diseases (after tooth extraction, periodontal diseases, unsatisfactory fixation of dentures). Known risk factors for the development of osteonecrosis of the jaw are cancer, concomitant treatment (chemotherapy, radiation therapy, antiangiogenic drugs, glucocorticosteroids), concomitant diseases (anemia, coagulopathy, infection, previous oral disease).
Before using bisphosphonates in patients with cancer, a dental examination and necessary preventive procedures should be performed, and strict oral hygiene should be recommended.
During treatment with bisphosphonates, dental surgery should be avoided if possible. In patients with osteonecrosis of the jaw resulting from bisphosphonate therapy, invasive dental intervention may worsen the condition. There is no evidence that interrupting bisphosphonate treatment before dental procedures reduces the risk of developing osteonecrosis of the jaw. The treatment plan for a particular patient should be based on an individual assessment of the risk/benefit ratio.
Cases of osteonecrosis of other localizations, including the pelvic bone, femur, and external auditory canal, have been described, mainly in adult patients receiving therapy with bisphosphonates, including zoledronic acid.
Cases of osteonecrosis of the external auditory canal have mostly been reported with long-term use of zoledronic acid. Risk factors for the development of osteonecrosis of the external auditory canal: simultaneous use with glucocorticosteroids, chemotherapy and/or local factors such as infection and trauma. The possibility of developing osteonecrosis of the external auditory canal should also be considered in patients with chronic ear infections taking bisphosphonates.
Atypical femur fractures.
Cases of atypical subtrochanteric and diaphyseal fractures of the femur have been described in patients receiving long-term treatment with bisphosphonates for osteoporosis. Transverse or short oblique fractures can be located anywhere along the femur from the lesser trochanter to the supracondylar fossa. The described fractures occur after minimal trauma or spontaneously. Some patients experience hip or groin pain, often accompanied by visual signs of stress fractures, which occur weeks and months before the development of a complete femur fracture. Fractures often occur on both sides, so in patients receiving bisphosphonates who experience a fracture of one femur, the contralateral femur should be evaluated. Slow healing (healing) of these fractures has also been reported. The cause-and-effect relationship of such fractures with zoledronic acid therapy has not been established. The decision to discontinue zoledronic acid therapy in patients suspected of having an atypical femoral fracture should be based on an individualized risk/benefit assessment.
Patients receiving zoledronic acid therapy should be advised to inform medical personnel of any pain in the hip or groin area. Each patient complaining of such symptoms should be examined to identify a possible incomplete (incomplete) fracture of the femur.
Musculoskeletal pain
In clinical practice, rare cases of severe and in some cases disabling pain in bones, joints and muscles have been reported with the use of bisphosphonates, which include zoledronic acid. These symptoms developed over a period of one day to several months after the start of treatment. After cessation of treatment, most patients experienced resolution of symptoms. In several patients, symptoms recurred when therapy was restarted or another bisphosphonate was prescribed.
Hypocalcemia
In clinical practice, the development of hypocalcemia has been reported in patients receiving zoledronic acid. In the case of severe hypocalcemia, adverse events from the nervous system (convulsions, tetany and numbness), and cardiac arrhythmia may occur. In some cases, hypocalcemia can be life-threatening.
Caution should be exercised when using Zolerix® concomitantly with other drugs that can cause hypocalcemia, as this may lead to a synergistic interaction and the development of severe hypocalcemia. Before starting treatment, it is necessary to determine the concentration of calcium in the blood plasma and correct hypocalcemia.
If hypocalcemia is present, before starting the use of zoledronic acid, it is necessary to treat with adequate doses of calcium and vitamin D. Also, if possible, treatment should be carried out for other existing disorders of mineral metabolism (for example, occurring after surgery on the thyroid and parathyroid glands, with hypoparathyroidism or decreased absorption of calcium in intestines) and ensure regular monitoring of patients with hypocalcemia.
Use in children
The safety and effectiveness of zoledronic acid when used in children 1-17 years of age have not been established.
Other information
There have been isolated cases of bronchoconstriction in patients with a complete or incomplete combination of bronchial asthma, recurrent polyposis of the nose and paranasal sinuses, and intolerance to acetylsalicylic acid or other non-steroidal anti-inflammatory drugs (including a history) during the use of bisphosphonates. Although there were no such cases in clinical studies with zoledronic acid, it is recommended that the drug be used with caution in patients with aspirin-induced asthma.
Patients receiving Zolerix should not receive other bisphosphonate medications concomitantly.
In animal studies, zoledronic acid suppressed fertility at a dose of 0.1 mg/kg/day.
There are no data on the effects of zoledronic acid on fertility in humans.
Solera
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); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10000, < 1/1000); very rare (< 1/10000), including isolated reports.
Disorders of the blood and lymphatic system: 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; very rarely - convulsions, hypoesthesia and tetany (developing as a result of hypocalcemia).
Visual disorders: often - conjunctivitis; infrequently - “blurred” vision; rarely - uveitis.
Disorders of the digestive system: 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).
Disorders of the musculoskeletal system and connective tissue: 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).
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 syncope or circulatory collapse, mainly in patients with risk factors.
Disorders of the respiratory system, thoracic and mediastinal organs: bronchospasm.
Skin and subcutaneous tissue disorders: urticaria.
Musculoskeletal 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, cases of osteonecrosis (mainly of the jaw, but also in other locations, including the pelvic bone, femur and external auditory canal) were observed, mainly in patients with cancer. 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 associated with 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 when administered at a dose of 4 mg once every 3-4 weeks in patients with cancer. The reason for the increased incidence of atrial fibrillation during zoledronic acid therapy in patients with postmenopausal osteoporosis was not established in another 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.
