Zoledronic acid concentrate for solution for infusion 4 mg/5 ml vial 5 ml

Instructions for use Zoledronic acid concentrate for solution for infusion 4 mg/5 ml vial 5 ml

Composition

active ingredient: zoledronic acid;

5 ml of concentrate contain 4 mg of zoledronic acid anhydrous, corresponding to 4.264 mg of zoledronic acid monohydrate;

1 ml of concentrate contains 0.8 mg of zoledronic acid anhydrous (in the form of zoledronic acid monohydrate);

excipients: mannitol (E 421), sodium citrate dihydrate, water for injections.

Dosage form

Concentrate for solution for infusion.

Main physicochemical properties: transparent colorless solution.

Pharmacotherapeutic group

Agents affecting bone structure and mineralization. Bisphosphonates. ATC code M05B A08.

Pharmacological properties

Pharmacodynamics

Zoledronic acid belongs to a new class of bisphosphonates that specifically target bone tissue. It is one of the most potent inhibitors of osteoclastic bone resorption known to date.

The selective action of bisphosphonates on bone is based on their high affinity for mineralized bone tissue, but the molecular mechanism leading to the inhibition of osteoclastic activity has not yet been elucidated. Animal studies have shown that zoledronic acid inhibits bone resorption without adversely affecting bone formation, mineralization, or mechanical properties.

In addition to inhibiting osteoclastic bone resorption, zoledronic acid has direct antitumor effects on cultured human myeloma and breast cancer cells by inhibiting cell proliferation and inducing apoptosis. This suggests that zoledronic acid may have antimetastatic properties. In preclinical studies, the following properties have been demonstrated:

In vivo - inhibition of osteoclastic bone resorption, which acts on the structure of the microcrystalline bone matrix, which reduces tumor growth, antiangiogenic effect (effect on blood vessels, which leads to a decrease in the blood supply to the tumor), analgesic effect. In vitro - inhibition of osteoblast proliferation, cytostatic effect, pro-apoptotic effect on tumor cells, synergistic cytostatic effect with other antitumor drugs, anti-adhesive and anti-invasive effect.

Pharmacokinetics

Pharmacokinetic data in bone metastases were obtained after single and repeated 5- and 15-minute infusions of 2 mg, 4 mg, 8 mg and 16 mg zoledronic acid in 64 patients. Pharmacokinetic parameters are independent of dose.

After the start of the zoledronic acid infusion, plasma drug concentrations increase rapidly, reaching a peak at the end of the infusion, followed by a rapid decrease in concentration by 10% of the peak value after 4 hours and by < 1% of the peak value after 24 hours with a successively prolonged period of low concentrations not exceeding 0.1% of the peak until the second infusion on day 28. Zoledronic acid administered intravenously is excreted by the kidneys in 3 phases: a rapid biphasic elimination of the drug from the systemic circulation with a half-life of t½α = 0.24 hours and t½β = 1.87 hours and a prolonged phase with a terminal half-life of t½γ = 146 hours. No accumulation of the drug in blood plasma was observed with repeated administration every 28 days. Zoledronic acid is not metabolized and is excreted unchanged by the kidneys. During the first 24 hours, 39 ± 16% of the administered dose is found in the urine. The rest of the drug is mainly bound to bone tissue. Then, zoledronic acid is slowly released back from bone tissue into the systemic circulation and excreted by the kidneys. The total clearance of the drug in the body 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 to 15 min leads to a 30% decrease in the concentration of zoledronic acid at the end of the infusion, but does not affect the plasma concentration-time curve (AUC). The variability of the pharmacokinetic parameters of zoledronic acid in different patients was high, as in other bisphosphonates.

There are no data on the pharmacokinetics of zoledronic acid in patients with hypercalcemia and hepatic insufficiency. According to in vitro data, zoledronic acid does not inhibit human P450 enzymes and is not biotransformed; according to experimental studies in animals, less than 3% of the administered dose is excreted in the feces, which suggests that the state of liver function does not affect the pharmacokinetics of zoledronic acid.

Renal clearance of zoledronic acid correlates with creatinine clearance, with renal clearance accounting for 75 ± 33% of creatinine clearance, reaching a mean of 84 ± 29 mL/min (range 22-143 mL/min) in 64 cancer patients enrolled in the study. Analysis of the patient population showed that patients with creatinine clearance of 20 mL/min (acute renal failure) and 50 mL/min (moderate renal failure) had relative clearances of 37% and 72%, respectively. However, pharmacokinetic data in patients with acute renal failure (< 30 mL/min) are limited.

Special populations.

Children.

Limited pharmacokinetic data in children with severe osteogenesis imperfecta suggest that the pharmacokinetics of zoledronic acid in children aged 3 to 17 years are similar to those in adults when administered at equivalent doses (mg/kg). Age, weight, gender and creatinine clearance did not appear to affect systemic exposure to zoledronic acid.

Indication

Prevention of symptoms associated with bone tissue damage (pathological fractures, spinal cord compression, complications after surgery and radiotherapy or hypercalcemia due to a malignant tumor) in patients with advanced malignant tumors.

Treatment of hypercalcemia caused by a malignant tumor.

Contraindication

Hypersensitivity to the active substance (zoledronic acid), other bisphosphonates or to any of the excipients of the medicinal product.

Pregnancy or breastfeeding.

Interaction with other medicinal products and other types of interactions

During clinical trials, other medicinal products such as antineoplastic agents, diuretics, antibiotics, and analgesics were frequently administered concomitantly with zoledronic acid. No clinically significant interactions were observed.

In vitro studies have shown that zoledronic acid is not significantly bound to plasma proteins and does not inhibit cytochrome P450 enzymes. However, no specific clinical drug interaction studies have been conducted. Caution is advised when bisphosphonates and aminoglycosides are used concomitantly, as they may have an additive effect, resulting in serum calcium levels remaining lower than necessary. Caution is advised when bisphosphonates and loop diuretics are used concomitantly, as they may have an additive effect, resulting in hypocalcemia. Caution should be exercised when prescribing this medicinal product with other potentially nephrotoxic medicinal products. The possibility of hypomagnesemia during treatment should be considered. In patients with multiple myeloma, the risk of renal failure is increased when bisphosphonates are administered intravenously in combination with thalidomide. Osteonecrosis of the jaw has been reported in patients receiving zoledronic acid and antiangiogenic (reducing blood supply to the tumor) medications.

Application features

General

Adequate hydration should be ensured in all patients, including those with mild to moderate renal impairment, before administration of Zoledronic Acid. Overhydration should be avoided in patients at risk of developing heart failure. Standard metabolic parameters associated with hypercalcaemia, such as calcium, phosphate and magnesium levels, should be carefully monitored after initiation of treatment. If hypocalcaemia, hypophosphataemia or hypomagnesaemia occurs, short-term corrective therapy may be necessary.

Untreated patients with hypercalcemia usually have some renal dysfunction, so careful monitoring of renal function is necessary.

Patients receiving Zoledronic Acid therapy should not take other medicinal products containing zoledronic acid concomitantly, nor should they take any other bisphosphonates.

Kidney dysfunction

When deciding whether to use the drug in patients with hypercalcemia caused by a malignant tumor and impaired renal function, the patient's condition should be assessed and a conclusion should be drawn as to whether the potential benefit of treatment outweighs the possible risk.

When deciding to treat patients with bone metastases to prevent symptoms associated with spinal diseases, it should be taken into account that the effect of the drug begins to appear after 2-3 months.

Elevations in serum creatinine have also been observed in some patients who have been taking Zoledronic acid at the recommended dose for the prevention of symptoms associated with spinal disorders, although this is rare. Patients should have their serum creatinine measured before each dose of Zoledronic acid. After initiation of treatment, lower doses of Zoledronic acid are recommended for patients with bone metastases and postmenopausal women with early breast cancer receiving aromatase inhibitors (AIs) to prevent bone loss and fractures in the presence of mild to moderate renal impairment (see table in section 4.2). Patients who experience renal impairment during treatment should not resume treatment until creatinine levels return to within 10% of baseline. When resuming therapy, Zoledronic acid is administered at the same dose as before temporary discontinuation.

Due to the potential impact of bisphosphonates, including Zoledronic Acid Teva, on renal function, due to the lack of extensive clinical safety data in patients with severe renal impairment (serum creatinine ≥ 400 μmol/L or ≥ 4.5 mg/dL for patients with tumour-induced hypercalcaemia and serum creatinine ≥ 265 μmol/L or ≥ 3 mg/dL for patients with bone metastases and in postmenopausal women with early breast cancer treated with aromatase inhibitors (AIs) to prevent bone loss and bone fractures, respectively) and only limited pharmacokinetic data in patients with severe renal impairment (creatinine clearance < 30 mL/min). The use of the medicinal product in patients with severe renal impairment is not recommended.

Liver dysfunction

There are no specific recommendations for patients with severe hepatic impairment as only limited clinical data are available.

Osteonecrosis of the jaw

Osteonecrosis of the jaw has been reported, predominantly in cancer patients receiving a regimen containing bisphosphonates, including zoledronic acid.

Many of these patients were also receiving chemotherapy and corticosteroids. Most of the reported cases were associated with dental procedures, such as tooth extractions. Many of the patients had evidence of local infection, including osteomyelitis.

The initiation of treatment or a new course of treatment should be postponed if patients have unhealed open soft tissue lesions in the oral cavity, except in medical emergencies. Before initiating bisphosphonate treatment, patients with concomitant risk factors are recommended to undergo a dental examination with appropriate preventive dental treatment and an individual benefit-risk assessment.

The following risk factors should be considered to assess individual risks of developing osteonecrosis of the jaw:

Bisphosphonate potency (higher risk for more active compounds), route of administration (higher risk for parenteral administration), and cumulative dose.

Cancer, comorbidities (e.g., anemia, coagulopathy, infection), smoking.

Concomitant treatment: chemotherapy, use of angiogenesis inhibitors, radiation therapy to the neck and head, corticosteroid therapy.

History of dental disease, poor oral hygiene, periodontal disease, invasive dental procedures, and ill-fitting dentures. An oral examination with appropriate dental prophylaxis should be performed before initiating bisphosphonate treatment.

All patients should be advised to maintain good oral hygiene, undergo routine dental examinations, and report symptoms such as tooth mobility, pain or swelling, and non-healing wounds while on bisphosphonate therapy. These patients should avoid invasive dental procedures whenever possible during therapy. Dental surgery may worsen the condition of patients who have developed osteonecrosis of the jaw while on bisphosphonate therapy. There are no data in patients who require dental procedures to determine whether the risk of osteonecrosis of the jaw is reduced when bisphosphonate therapy is discontinued. The physician should be guided by an individual patient management plan based on an individual benefit/risk assessment. The treatment regimen for patients who develop osteonecrosis of the jaw should be developed jointly by the treating physician and a dentist or dental surgeon experienced in the management of patients with osteonecrosis of the jaw. Temporary discontinuation of zoledronic acid should be considered until the condition normalizes and risk factors are minimized.

Osteonecrosis of the external auditory canal has been reported with bisphosphonates, mainly with long-term therapy. Possible risk factors for osteonecrosis of the external auditory canal include steroid use, chemotherapy, and/or local risk factors such as infection or trauma. The possibility of osteonecrosis of the external auditory canal should be considered in patients receiving bisphosphonates who present with auditory symptoms, including chronic ear infections. There have been sporadic reports of osteonecrosis of other bones, including the femur and pelvis, in adult cancer patients receiving bisphosphonate therapy.

Musculoskeletal pain.

During postmarketing surveillance, severe, sometimes disabling bone, joint, and/or muscle pain has been reported in patients receiving bisphosphonates. However, these reports have been isolated. This category of drugs includes zoledronic acid. The time to onset of symptoms ranged from one day to several months after initiation of treatment. In most patients, symptoms resolved after discontinuation of treatment. In this category of patients, symptoms have recurred when treatment with the same drug or another bisphosphonate was resumed.

Atypical femur fracture.

Atypical subtrochanteric and diaphyseal fractures of the femur have been reported with bisphosphonate therapy, primarily in patients receiving long-term treatment for osteoporosis. These transverse or short oblique fractures can occur anywhere along the femur from just below the lesser trochanter to just above the epicondyles. These fractures occur with or without minimal trauma, and some patients experience hip or groin pain, often associated with radiographic evidence of a stress fracture, weeks or months before a complete hip fracture occurs. Fractures are often bilateral, so the other femur should be examined in patients receiving bisphosphonate therapy who have sustained a femoral fracture. Poor healing of these fractures has also been reported. Based on an individual risk-benefit assessment, the decision to discontinue bisphosphonate therapy for patients with suspected atypical hip fractures should be made.

During treatment with bisphosphonates, the patient should report any pelvic, hip, or groin pain to the physician, and any patient with such symptoms should be evaluated for an incomplete femur fracture.

Hypocalcemia.

Hypocalcaemia has been reported in patients receiving zoledronic acid; cases of cardiac arrhythmias and neurological reactions (including seizures, hypoaesthesia, numbness and tetany) secondary to severe hypocalcaemia; cases of severe hypocalcaemia requiring hospitalisation. In some cases, hypocalcaemia may be life-threatening. Caution should be exercised when zoledronic acid is administered concomitantly with medicinal products that may cause hypocalcaemia, as they may have a synergistic effect leading to severe hypocalcaemia (see section 4.5). Serum calcium levels should be checked before initiating therapy and corrected if necessary. Treatment of such patients should be adequately supplemented with calcium and vitamin D.

Important information about excipients.

Sodium.

Zoledronic acid contains 24 mg/dose of sodium. Caution should be exercised when administering this medicine to patients on a controlled sodium diet.

Use during pregnancy or breastfeeding

The drug ZolendroVista is contraindicated during pregnancy or breastfeeding.

Pregnancy.

There are no adequate data from the use of zoledronic acid in pregnant women. Animal reproduction studies have shown reproductive toxicity. The potential risk for humans is unknown.

Breastfeeding period.

It is not known whether zoledronic acid passes into breast milk.

Fertility.

Zoledronic acid has been evaluated in rats for potential adverse effects on fertility. The results of the studies did not allow the effects of zoledronic acid on human fertility to be determined.

Ability to influence reaction speed when driving vehicles or other mechanisms

Adverse drug reactions, such as dizziness and drowsiness, may affect the ability to drive or operate other machinery, so caution should be exercised when driving or operating complex machinery while taking the drug.

Method of administration and doses

The drug should only be administered by a physician experienced in the intravenous administration of bisphosphonates.

Zoledronic acid concentrate must not be mixed with infusion solutions containing calcium or other divalent cations, such as lactated Ringer's solution, and must be administered as a single intravenous infusion using a separate infusion set.

Prevention of symptoms associated with bone damage in patients with advanced malignant neoplasms.

Adults and elderly patients.

The recommended dose of zoledronic acid is 4 mg as an infusion every 3-4 weeks.

Patients also need daily oral calcium supplements at a dose of 500 mg and 400 IU of vitamin D per day.

When considering the treatment of patients with metastatic bone lesions to prevent symptoms associated with bone lesions, it is important to consider that the onset of the effect of treatment occurs after 2-3 months.

Treatment of hypercalcemia caused by a malignant tumor.

Adults and elderly patients.

When using the drug in connection with hypercalcemia (albumin-corrected serum calcium ≥ 12.0 mg/dL or 3.0 mmol/L), a single administration of 4 mg zoledronic acid is recommended.

Kidney dysfunction.

Hypercalcemia caused by a malignant tumor.

Treatment of hypercalcemia due to malignant tumors in patients with severe renal impairment is possible after careful assessment of the risk of using the drug and the expected benefit. There is no clinical experience with the drug in patients with serum creatinine levels > 400 μmol/l or > 4.5 mg/dl. No dose adjustment is required for patients with hypercalcemia due to malignant tumors with serum creatinine levels < 400 μmol/l or < 4.5 mg/dl. Prevention of symptoms associated with bone lesions in patients with advanced malignant tumors.

At the beginning of treatment with zoledronic acid in patients with multiple myeloma or metastatic bone disease due to solid tumors, serum creatinine and creatinine clearance should be determined. Creatinine clearance is calculated using the Cockcroft-Gault formula for serum creatinine. Zoledronic acid is not recommended for patients with severe renal impairment prior to initiation of therapy (creatinine clearance < 30 mL/min). Clinical studies in patients with serum creatinine > 265 μmol/L or ≥ 3 mg/dL have not been conducted.

For patients with metastatic bone lesions and mild or moderate renal impairment prior to initiation of therapy (creatinine clearance 30-60 ml/min), the following doses of the drug are recommended:

*Doses are calculated assuming a given AUC of 0.66 mg•h/L (creatinine clearance of 75 mL/min). For patients with renal impairment, the dose is expected to be reduced to a level that achieves the same AUC as in patients with creatinine clearance of 75 mL/min.

After initiation of therapy, serum creatinine should be measured before each dose of the drug. In case of impaired renal function, treatment should be discontinued. In clinical trials, renal function impairment was defined as follows:

for patients with normal baseline serum creatinine levels (< 1.4 mg/dL or < 124 μmol/L) – an increase of 0.5 mg/dL or 44 μmol/L;

for patients with altered baseline serum creatinine levels (> 1.4 mg/dL, or > 124 μmol/L) – an increase of 1 mg/dL or 88 μmol/L.

In clinical trials, zoledronic acid therapy was resumed when creatinine returned to baseline within 10% of baseline. Zoledronic acid therapy should be resumed at the same dose as before treatment interruption.

Children

The safety and efficacy of zoledronic acid in children aged 1 to 17 years have not been established. There are no recommendations for use in children.

Instructions for preparing doses of zoledronic acid.

For intravenous administration.

5 ml of the concentrate containing 4 mg of zoledronic acid should be diluted in 100 ml of sterile 0.9% sodium chloride solution or 5% glucose for intravenous infusion.

Reduced doses of Zoledronic acid are recommended for patients with mild to moderate renal impairment.

Instructions for preparing reduced doses of the drug:

Withdraw the appropriate volume of concentrate as indicated below:

4.4 ml corresponds to 3.5 mg;

4.1 ml corresponds to 3.3 mg;

3.8 ml corresponds to 3 mg.

The required amount of liquid concentrate should be diluted in 100 ml of sterile 0.9% sodium chloride solution or 5% glucose for intravenous infusion.

Adequate hydration of the patient should be ensured before and after administration of Zoledronic Acid.

Children.

The safety and efficacy of zoledronic acid in children have not been established.

Overdose

Symptoms. Clinical experience in the treatment of acute overdose with zoledronic acid is limited. Misuse of zoledronic acid up to 48 mg has been reported. Treatment. Patients who have been given zoledronic acid in doses exceeding the recommended dose should be under constant medical supervision, as renal function impairment (including renal failure) and changes in serum electrolytes (including calcium, phosphate and magnesium concentrations) may occur. In the event of hypocalcemia, calcium gluconate infusion is indicated according to clinical indications. Treatment is symptomatic.

Side effects

Acute phase reactions have been reported within 3 days of zoledronic acid administration, with symptoms including bone pain, fever, malaise, arthralgia, myalgia, chills and arthritis with joint swelling. These symptoms usually resolve within a few days.

The following important adverse reactions have been reported with zoledronic acid: renal dysfunction, necrosis of the jaw, acute phase reactions, hypocalcemia, visual disturbances, atrial fibrillation, anaphylaxis, interstitial lung disease. The frequency of adverse reactions reported with zoledronic acid 4 mg is based primarily on data from long-term therapy. Adverse reactions associated with zoledronic acid are similar to those reported with other bisphosphonates and may occur in approximately one third of all patients.

Information on the adverse reactions listed below was collected during clinical trials, mainly after long-term treatment with zoledronic acid.

Adverse reactions are classified according to their frequency of occurrence: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10000, < 1/1000), very rare (< 1/10000), frequency unknown (cannot be estimated from the available data).

From the blood and lymphatic system:

often - anemia;

infrequently - thrombocytopenia, leukopenia;

rarely - pancytopenia.

From the nervous system:

often - headache;

infrequently - paresthesia, dizziness, taste disturbances, hypoesthesia, hyperesthesia, tremor, drowsiness;

very rarely - epileptic seizures, hypoesthesia, numbness and tetany (secondary to hypocalcemia).

From the psyche:

infrequently - anxiety, sleep disorders;

rarely - confusion.

On the part of the organs of vision:

often – conjunctivitis;

infrequently - blurred vision, scleritis and inflammation of the orbit;

rarely – uveitis;

very rarely - episcleritis.

From the gastrointestinal tract:

often - nausea, vomiting, anorexia;

infrequently - diarrhea, constipation, abdominal pain, dyspepsia, stomatitis, dry mouth.

On the part of the respiratory system:

infrequently - dyspnea, cough, bronchoconstriction;

rarely - interstitial lung disease.

Skin and subcutaneous tissue disorders:

infrequently - itching, rash (including erythematous and macular rashes), increased sweating.

From the musculoskeletal system, connective tissue:

often - bone pain, myalgia, arthralgia, generalized pain;

infrequently - muscle cramps, osteonecrosis of the jaw;

very rarely - osteonecrosis of the external auditory canal (adverse reactions typical of bisphosphonates) and other bones, including the femur and pelvic bones.

From the cardiovascular system:

infrequently - arterial hypertension, arterial hypotension, atrial fibrillation, arterial hypotension causing syncope and circulatory collapse;

rarely – bradycardia;

very rarely - cardiac arrhythmia (secondary to hypocalcemia).

From the kidneys and genitourinary system:

often - renal disorders;

infrequently - acute renal failure, hematuria, proteinuria;

rarely – acquired Fanconi syndrome.

On the part of the immune system:

infrequently - hypersensitivity reactions;

rarely - angioedema.

General disorders and administration site conditions:

often - fever, flu-like symptoms (including fatigue, chills, malaise and hot flashes);

infrequently - injection site reactions (including pain, irritation, swelling, induration), asthenia, peripheral edema, chest pain, weight gain, anaphylactic reactions/shock, urticaria;

rarely - arthritis and joint swelling as symptoms of an acute phase reaction.

Laboratory abnormalities:

very often – hypophosphatemia;

often - increased levels of creatinine and urea in the blood, hypocalcemia;

infrequently – hypomagnesemia, hypokalemia;

rarely - hyperkalemia, hypernatremia.

Renal impairment has been reported with zoledronic acid. Based on an analysis of safety data from the post-marketing studies of zoledronic acid for the prevention of bone-related adverse reactions, the incidence of renal impairment considered to be related to zoledronic acid in patients with advanced malignancies was 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 renal impairment include dehydration, pre-existing renal impairment, multiple courses of zoledronic acid or other bisphosphonates, and concomitant use of other nephrotoxic agents or reduction of the recommended infusion time. Cases of renal dysfunction, progression of renal failure and the need for hemodialysis have been reported with the first or single use of zoledronic acid at a dose of 4 mg.

Osteonecrosis of the jaw.

Cases of osteonecrosis (mainly of the jaw) have been reported primarily in cancer patients receiving zoledronic acid. Many of these patients had local infection, including osteomyelitis. Most cases were associated with dental procedures such as tooth extraction. Osteonecrosis of the jaw has many established risk factors, including diagnosed cancer, concomitant therapy (e.g. chemotherapy, radiotherapy, corticosteroids) and comorbidities (e.g. anemia, coagulopathy, infections, oral disease).

Although a causal relationship has not been proven, these patients are advised to avoid invasive dental procedures.

Atrial fibrillation.

The efficacy and safety of zoledronic acid in patients with postmenopausal osteoporosis have been documented, with an overall incidence of atrial fibrillation of 2.5% in the zoledronic acid 5 mg group and 1.9% in the placebo group. The reason for the increased incidence of atrial fibrillation is unknown. Acute phase reactions.

These adverse reactions include fever, myalgia, headache, pain in the extremities, nausea, vomiting, diarrhea, and arthralgia, as well as arthritis with associated joint swelling, which may occur within the first 3 days after drug infusion. This reaction is called "flu-like" syndrome or "post-drug syndrome".

Atypical fractures of the femur.

During post-marketing use, reactions such as acute subtrochanteric and diaphyseal femoral fractures (adverse reaction to bisphosphonates) have been reported rarely.

Adverse reactions due to hypocalcemia.

Hypocalcemia is an important identified risk when using the medicinal product in accordance with the registered indications. Clinical and post-marketing data suggest an association between zoledronic acid therapy, reports of hypocalcemia and the development of secondary cardiac arrhythmias. In addition, there is evidence of an association between hypocalcemia and secondary neurological reactions, including seizures, hypoesthesia, numbness and tetany.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after the marketing authorisation of a medicinal product is an important procedure. It allows for continued monitoring of the benefit-risk balance of the medicinal product in question. Healthcare professionals should report any suspected adverse reactions via the national reporting system.

Expiration date

3 years.

After dilution: from a microbiological point of view, the product should be used immediately.

If the medicinal product is not used immediately, it should be stored for 24 hours at 2-8ºC after opening.

The refrigerated solution should be brought to room temperature before administration.

Storage conditions

Does not require any special storage conditions. Keep out of the reach of children.

Incompatibility

The concentrate of the medicinal product must be diluted in sterile 0.9% sodium chloride solution or 5% glucose solution. The concentrate of the medicinal product must not be mixed with infusion solutions containing calcium or other divalent cations, such as lactated Ringer's solution, it must be administered as a single infusion using a separate infusion system.

Studies with glass vials, as well as several types of infusion bags and infusion systems made of polyvinyl chloride, polyethylene and polypropylene (pre-filled with 0.9% sodium chloride solution or 5% glucose solution), showed no incompatibility with the above-mentioned packaging materials.

Packaging

5 ml of concentrate for solution for infusion in a vial with a rubber stopper and aluminum cap. 1 vial in a cardboard box.

Vacation category

For re