Zometa - instructions for use, dose, side effects, contraindications

Zoledronic acid is a highly effective bisphosphonate that acts selectively on bone tissue. The drug suppresses the resorption of bone tissue, affecting the osteoclasts. Selective action of bisphosphonates on bone tissue is based on a high affinity for mineralized bone tissue. The exact molecular mechanism providing inhibition of osteoclast activity is still unclear.

Zoledronic acid does not have undesirable effects on the formation, mineralization and mechanical properties of bone.

In addition to the inhibitory effect on bone resorption, zoledronic acid has antitumor properties that ensure the effectiveness of the drug with metastases in the bones. In vivo: inhibits bone resorption by osteoclasts, changes the microenvironment of the bone marrow, reduces the growth of tumor cells; shows antiangiogenic activity. Suppression of bone resorption is clinically accompanied, in particular, by a marked decrease in pain.

In vitro: inhibits the proliferation of osteoblasts, exhibits direct cytostatic and pro-apoptotic activity, a synergistic cytotoxic effect with antitumor drugs; anti-adhesive and anti-invasive activity.

Zoledronic acid, suppressing proliferation and inducing 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 that it has antimetastatic properties. Besides, zoledronic acid inhibits the proliferation of endothelial cells in humans and animals and has an anti-angiogenic effect.

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

In patients with multiple myeloma and breast cancer with at least one bone focus, 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 serum calcium and calcium excretion by the kidneys. The average time to normalize the calcium content is about 4 days. By the 10th day, the calcium content is normalized in 87-88% of patients. The average time to relapse (adjusted for albumin serum calcium content is not less than 2.9 mmol / l) is 30-40 days. Significant differences between the efficacy of zoledronic acid in doses of 4 and 8 mg in the treatment of hypercalcemia is not observed. The studies do not reveal significant differences in the incidence and severity of adverse events observed in patients treated with zoledronic acid at doses of 4 mg, 8 mg, pamidronic acid at a dose of 90 mg or placebo in both bone metastases and hypercalcemia.

Pharmacokinetics:

Data on the pharmacokinetics for bone metastases were obtained after a 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.

After starting the infusion of the drug, the serum concentrations increase rapidly, reaching a peak at the end of the infusion, followed by a rapid decrease in the concentration by 10% after 4 hours and by less than 1% of the peak after 24 hours with a successively prolonged period of low concentrations not exceeding 0.1% infusion for 28 days.

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-life periods of 0.24 h and 1.87 h and a long phase with a terminal elimination half-life of 146 h. No cumulation of the drug was observed with repeated injections every 28 days. Zoledronic acid is not metabolized and is excreted by the kidneys unchanged. During the first 24 hours, 39 ± 16% of the administered dose is detected in the urine. The rest of the drug is mainly associated with bone tissue.Then slowly the reverse release of zoledronic acid from the bone tissue into the systemic blood flow and its excretion 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, sex, age, race and body weight of the patient. Increasing the infusion time from 5 minutes to 15 leads to a 30% decrease in zoledronic acid at the end of the infusion, but does not affect the area under the concentration-time curve (AUC). Pharmacokinetic studies in patients with hypercalcemia or liver dysfunction were not performed. According to the data obtained in vitro, zoledronic acid does not inhibit the isoenzymes of the human cytochrome P450 system and does not undergo biotransformation, which suggests that the liver function state does not significantly affect the pharmacokinetics of zoledronic acid. Less than 3% of the dose is excreted through the intestine. Renal clearance of zoledronic acid positively correlates with creatinine clearance and is 75 ± 33% of creatinine clearance, averaging 84 ± 29% (range 22-143 ml / min) in 64 patients included in the study.Analysis of the population showed that in patients with impaired renal function of moderate severity (creatinine clearance 50 ml / min) the calculated clearance of zoledronic acid is 72% of the zoledronate clearance value in patients with creatinine clearance> 84 ml / min. Limited pharmacokinetic data were obtained for patients with impaired renal function of severe degree (creatinine clearance less than 30 ml / min).

The low affinity of zoledronic acid for the cellular components of the blood is shown, the average ratio of the concentration in whole blood to the plasma concentration is 0.59 in the concentration range from 30 ng / ml to 5000 ng / ml. Binding to plasma proteins is low, the fraction of unbound fraction is 60-77% and slightly depends on the drug concentration (from 2 to 2000 ng / ml).

Indications:

Metastases in the bone with malignant solid tumors (prostate cancer, breast cancer and others) and multiple myeloma, including to reduce the risk of pathological fractures, spinal cord compression, tumor-induced hypercalcemia and reduce the need for radiotherapy or surgical interventions on the bone.
Hypercalcemia due to malignant tumors

Contraindications:

Hypersensitivity to zoledronic acid, other bisphosphonates or any other components that make up the drug.
Severe renal insufficiency (creatinine clearance less than 30 ml / min).
Pregnancy and lactation.
Children and adolescence (efficacy and safety not established).

Carefully:

If you have any of the listed diseases before taking the drug, be sure to consult a doctor.

When deciding on the use of Zometa in patients with hypercalcemia due to a malignant tumor, against a background of impaired renal function, it is necessary to assess the patient's condition and to conclude whether the potential benefit from the drug's administration is greater than the potential risk.

Before each injection of Zometa ®, the serum creatinine concentration should be determined. At the beginning of drug treatment in all patients with mild and moderate renal dysfunction, in addition to patients with hypercalcemia caused by a malignant tumor, it is recommended to use the drug in reduced doses.Patients with renal dysfunction appeared during the application of Zometa® can continue therapy with the drug only after the creatinine concentration has returned to values that are within ± 10% of the baseline value.

Given the potential for renal dysfunction in the use of bisphosphonates, including Zometa®, and in the absence of comprehensive data on the clinical safety of the drug in patients with severe renal dysfunction (serum creatinine concentration> 400 μmol / l or> 4.5 mg / dl y patients with hypercalcemia due to a malignant tumor and> 265 μmol / L or> 3.0 mg / dl in all other patients) and the presence of very limited pharmacokinetic data in patients with initial severe impairment of renal function <30 ml / min), the use of Zometa® in this patient population is not recommended.

It is used with caution in patients with hepatic insufficiency, bronchial asthma induced by acetylsalicylic acid.

Pregnancy and lactation:

The use of Zometa® during pregnancy is contraindicated.

The drug Zometa® can have an adverse effect on the fetus. In studies in animals, toxic effects on reproductive function have been identified. There is no data on the use of the drug during pregnancy in humans.

When pregnancy occurs during therapy with bisphosphonates, there may be a risk of intrauterine malformations of the fetus (for example, skeletal anomalies and other anomalies). The dependence of risk on the magnitude of the time interval between cessation of bisphosphonate therapy and the moment of conception, the route of administration and the specific features of the particular drug is unknown. Women of reproductive age should be warned about the need to apply reliable contraceptive methods during treatment with Zometa®.

It is not known whether the zoledronic acid in breast milk. The use of Zometa ® during breastfeeding is contraindicated.

In animal studies zoledronic acid suppressed fertility in a dose of 0.1 mg / kg / day. There is no evidence of the effect of zoledronic acid on fertility in humans.

Dosing and Administration:

The Zometa® drug should be administered to patients by qualified medical personnel who have experience of intravenous bisphosphonate administration.

The Zometa® preparation is not recommended for mixing with solutions containing calcium or other divalent ions (eg Ringer's solution). The drug Zometa ® should be administered intravenously drip, for at least 15 minutes, without mixing with other drugs. It is necessary to correct the dehydration in patients (if any) before the administration of Zometa®.

Metastases in the bone of solid malignant tumors and multiple myeloma in adults and elderly patients:

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

Patients should also be prescribed calcium inwards at a dose of 500 mg per day and vitamin D inside at a dose of 400 IU per day.

Hypercalcemia due to malignant tumors in adults and elderly patients:

In hypercalcemia (concentration of albumin corrected for serum calcium> 12 mg / dL or 3 mmol / L), the recommended single dose of the drug is 4 mg. To ensure adequate hydration of the patient, it is recommended that the physiological solution be administered before, simultaneously or after the infusion of the Zometa® preparation.

Patients with impaired renal function

Hypercalcemia due to malignant tumors:

The decision to treat Zometa with patients with severe renal dysfunction should only be taken after a thorough assessment of the risk of the drug and the expected benefit of the therapy. Patients who have a creatinine serum concentration of <400 μmol / L or <4.5 mg / dl do not need a dosage adjustment.

Metastases in the bone of solid malignant tumors and multiple myeloma:

The dose of Zometa® depends on the initial creatinine clearance calculated by the Cockcroft-Gault formula. Do not recommend the use of the drug in patients with severe renal dysfunction (creatinine clearance <30 ml / min).

Recommended doses in patients with mild or moderate severity of impaired renal function (creatinine clearance values of 30-60 ml / min) are given below.

The baseline creatinine clearance (ml / min)	The recommended dose of Zometa®
>60	4.0 mg (5 ml of concentrate)
50-60	3.5 mg (4.4 ml of concentrate)
40-49	3.3 mg (4.1 ml of concentrate)
30-39	3.0 mg (3.8 ml of concentrate)

After initiation of therapy, serum creatinine concentration should be determined before each dose of the drug is administered.In the detection of violations of kidney function, another injection of Zometa ® should be postponed. Impaired renal function is determined by the following parameters:

For patients with normal baseline creatinine values (<1.4 mg / dL), an increase of 0.5 mg / dl.
For patients with baseline creatinine abnormalities (> 1.4 mg / dl), an increase of 1 mg / dl.

Therapy with Zometa® is resumed only after concentration creatinine reaches values within ± 10% of the baseline, at the same dose that was used before the interruption of treatment.

Instructions for preparing a solution for infusions

Before the infusion, additionally dissolve the preparation Zometa concentrate 4 mg / 5 ml in 100 ml of 0.9% sodium chloride solution or 5% dextrose solution. The solution should be prepared under aseptic conditions. The finished product should be entered immediately after its preparation. Unused solution can be stored in the refrigerator at a temperature of + 2-8 ° C for no more than 24 hours. Before administration, the solution should be kept indoors until the room temperature is reached. The total time between the dilution of the concentrate, storage of the prepared solution in the refrigerator at a temperature of + 2-8 ° C and the end of the drug administration should not exceed 24 hours.

Solution Zometa® should not be mixed with any other medicines. The Zometa® preparation should not be mixed with any solutions containing calcium or other divalent ions, such as Ringer's lactate solution. The prepared zoledronic acid solution must be administered using a separate system for intravenous infusion.

Side effects:

The most serious adverse reactions (HP) in patients receiving the Zometa® product according to the recorded indications were: anaphylactic reaction, undesirable eyes, osteonecrosis of the lower jaw, atypical femur fracture, atrial fibrillation, renal dysfunction, acute phase reaction and hypocalcemia . The information on the incidence of undesired reactions (HP) when using Zometa® in a dose of 4 mg is mainly based on data obtained during long-term therapy. Undesirable reactions associated with the use of Zometa®, usually mild and transient; are similar to those reported in the use of other bisphosphonates.These HP can be observed in about a third of patients receiving Zometa®. Symptoms of acute phase reactions usually developed 3 days after the application of Zometa®: general malaise, bone pain, fever, chills, flu-like syndrome and arthritis followed by swelling of the joints; usually the symptoms were resolved within a few days. Also, such HP as arthralgia and myalgia were often noted. Very often, a decrease in renal calcium excretion was accompanied by a sharp decrease in the phosphorus content, which was asymptomatic and did not require treatment. The frequent decrease in serum calcium in the presence of hypocalcaemia was accompanied by a lack of clinical manifestations.

There are reports of reactions from the gastrointestinal tract, such as nausea and vomiting, after intravenous infusion of the Zometa® preparation.

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

Anorexia was often observed in patients who received the drug Zometa® at a dose of 4 mg. Cases of rash or itching were rare. As with other bisphosphonates, there are frequent cases of conjunctivitis.

Based on a summary analysis of controlled trials, the occurrence of severe severe anemia (hemoglobin <8.0 g / dL) in 5.2% of patients receiving a 4 mg dose of Zometa compared with 4.2% receiving placebo was reported.

Undesirable reactions are listed below for organs and systems, indicating the frequency of their occurrence. Frequency criteria: very often (≥1 / 10), often (≥1 / 100, <1/10), infrequently (≥1 / 1000, <1/100), rarely - (≥1 / 10000 <1/1000) , very rarely (<1/10000), including individual messages.

Violations from the blood and lymphatic system: often - anemia, infrequently - thrombocytopenia, leukopenia; rarely - pancytopenia.

Disorders of the psyche: often - sleep disturbance; infrequent feeling of anxiety; rarely confusion.

Impaired nervous system: often - headache, paresthesia; infrequently - dizziness, dysgeusia, hypoesthesia, hyperesthesia, tremor; very rarely - convulsions, hypesthesia and tetany (developing due to hypocalcemia).

Disorders from the side of the organ of vision: often - conjunctivitis; infrequently blurred vision; rarely - uveitis. Disorders from the digestive system: often - nausea, vomiting, decreased appetite, constipation; infrequently - diarrhea, abdominal pain, dyspepsia, stomatitis, dry mouth.

Disturbances from the respiratory system, chest and mediastinal organs: infrequently - shortness of breath, cough; rarely - interstitial lung disease.

Disturbances from the skin and subcutaneous tissues: often - increased sweating; infrequently - itching, rash (including erythematous and macular).

Disturbances from the musculoskeletal system and connective tissue: often - pain in the bones, myalgia, arthralgia, generalized pain, joint stiffness; infrequently - necrosis of the lower jaw, muscle cramps.

Heart Disease: rarely - bradycardia, arrhythmia (developing due to hypocalcemia).

Vascular disorders: often - increased blood pressure; infrequently - lowering blood pressure.

Disorders from the kidneys and urinary tract: often - impaired renal function; infrequently - acute renal failure, hematuria, proteinuria. Disorders from the immune system: infrequently - reactions of increased sensitivity; rarely angioedema.

Laboratory and instrumental data: very often - hypophosphatemia; often - increased serum creatinine and urea concentrations, hypocalcemia; infrequently - hypomagnesemia, hypokalemia; rarely - hyperkalemia, hypernatremia.

General disorders and disorders at the site of administration: often - acute phase reaction, fever, flu-like syndrome (including general malaise, chills, sickness, fever), peripheral edema, asthenia; infrequently - the reaction at the injection site (pain, irritation, swelling, tightness, redness), chest pain, weight gain; rarely arthritis and swelling of the joints as a symptom of the reaction of the acute phase.

It should be borne in mind that when using other bisphosphonates in patients with bronchial asthma sensitive to acetylsalicylic acid, there have been cases of bronchospasm, but no application of Zometa® has been observed.

Atrial fibrillation

In one clinical trial with 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 persons out of 3862) compared with 1.9% (75 of 3852) in the placebo group. The incidence of atrial fibrillation accompanied by severe hemodynamic disturbances was 1.3% (51 of 3862) and 0.6% (22 of 3852) for zoledronic acid and placebo, respectively.The reason for the increase in the incidence of atrial fibrillation with zoledronic acid therapy in patients with postmenopausal osteoporosis has not been established.

In clinical studies using zoledronic acid (at a dose of 4 mg every 3-4 weeks) in patients with oncological diseases, an increase in the frequency of atrial fibrillation was not observed.

In the treatment of patients with bisphosphonates, including the Zometa® preparation, there were occasional cases of osteonecrosis of the jaw (usually after extraction of the tooth or other dental intervention).

Undesirable reactions according to spontaneous reports and literary reports (frequency unknown):

Impaired immune system: anaphylactic reaction / shock.

Disturbances from the nervous system: drowsiness.

Disorders from the side of the organ of vision: episcleritis, scleritis and inflammatory diseases of the orbit.

Heart disorders: atrial fibrillation.

Violations from the vessels: a decrease in blood pressure, leading to fainting or circulatory collapse, mainly in patients with risk factors.

Disturbances from the respiratory system, chest and mediastinal organs: bronchospasm.

Disturbances from the skin and subcutaneous tissues: urticaria.

Violations by skeletnomyshechnoy and connective tissue disorders: sudden pronounced limited mobility of the joints and / or severe and sometimes disabling pain in the bones, joints and / or muscles, atypical subtrochanteric and diaphyseal femoral fractures.

Acute phase reaction

This unwanted reaction is a complex of symptoms: fever, general weakness, bone pain, chills, flu-like syndrome. Usually begins in the interval <3 days after the infusion of the Zometa® preparation. The reaction is also referred to using the terms "influenza-like" or "postdose" symptoms. Symptoms usually resolve after a few days.

If any of the side effects listed in the manual are aggravated, or if you notice any other side effects not listed in the instructions, tell your doctor.

Overdose:

In acute drug overdose (limited data) had impaired renal function, including renal failure, changes in the electrolyte composition, including reducing the concentration of calcium, phosphate and magnesium in the blood plasma.

The patient who received a dose of the drug that exceeds the recommended dose should be under constant supervision. In the case of hypocalcemia, accompanied by clinical manifestations, an infusion of calcium gluconate is indicated.

Interaction:

It is advisable to use caution when using bisphosphonates, aminoglycosides, calcitonin and loop diuretics, because the simultaneous action of these drugs is manifested by an increase in the duration of calcium in the blood plasma.

Caution is necessary when using Zometa with drugs potentially having a nephrotoxic effect.

Care must be taken when using angiogenesis inhibitors in conjunction with an increased incidence of mandibular necrosis.

When other commonly used medications are used simultaneously with the Zometa® drug (antitumor agents, diuretics [except for loop ones], antibiotics, analgesics), no clinically relevant interactions were noted.

Combined use of Zometa® with thalidomide does not require correction of zoledronic acid dose, except for patients with mild and moderate renal dysfunction. The combined use of thalidomide (100 mg or 200 mg once daily) and Zometa® (4 mg) in patients with multiple myeloma does not significantly affect the pharmacokinetics of zoledronic acid and creatinine clearance.

Pharmaceutical interaction and compatibility issues

A diluted solution of Zometa should not be mixed with infusion solutions containing calcium ions, for example, Ringer's solution.

When using glass bottles, infusion systems and bags of different types made of polyvinyl chloride, polyethylene and polypropylene (pre-filled with 0.9% sodium chloride solution or 5% dextrose solution) for the introduction of Zometa® preparation, no signs of incompatibility with the drug were found.

Special instructions:

Before infusion, ensure adequate hydration of the patient. If necessary, the introduction of 0.9% sodium chloride solution before, parallel or after infusion of the Zometa® preparation is recommended.Avoid hyperhydration of the patient due to the risk of complications from the cardiovascular system.

After the administration of the Zometa preparation, a constant control of the calcium, phosphorus, magnesium and creatinine in the blood serum is necessary. With the development of hypocalcemia, hypophosphatemia, or hypomagnesemia, there may be a need for short-term additional relevant substances. In patients with untreated hypercalcemia, there is usually a violation of kidney function, so careful monitoring of kidney function in this category of patients is necessary.

When deciding whether to treat patients with metastases in the bone with the aim of reducing the risk of pathological fractures, spinal cord compression, tumor-induced hypercalcemia and reducing the need for radiotherapy or bone surgery, it should be taken into account that the therapeutic effect occurs 2-3 months after the start of treatment with the drug.

There are some reports of a violation of kidney function against the background of bisphosphonates. The risk factors for such complications include dehydration,previous renal failure, repeated administration of Zometa® or other bisphosphonates, as well as the use of nephrotoxic drugs, and too rapid administration of the drug. Despite the fact that the risk of the complications described above decreases with the administration of the drug at a dose of 4 mg for at least 15 minutes, the possibility of renal dysfunction remains. There have been cases of impaired renal function, progression of renal failure and the need for hemodialysis in the first or one-time use of Zometa®.

An increase in serum creatinine concentrations is also observed in some patients with prolonged use of the drug at recommended doses, although at a lower frequency.

Cases of osteonecrosis of the jaw in cancer patients are described on the background of treatment with bisphosphonates, including the Zometa drug. Many patients had signs of a local infectious inflammatory process, including osteomyelitis.

In clinical practice, the most common development of osteonecrosis of the jaw was observed in patients with advanced breast cancer and myeloma,as well as in the presence of dental diseases (after tooth extraction, with periodontal disease, unsatisfactory fixation of dentures). Known risk factors for osteonecrosis of the jaw are cancer, concomitant medication (chemotherapy, radiation therapy, corticosteroids), concomitant diseases (anemia, coagulopathy, infection, previous oral disease).

Before using bisphosphonates in patients with cancer, you should conduct a dental examination and perform the necessary preventive procedures, as well as recommend strict observance of oral hygiene.

When treating these patients, dental operations should be avoided whenever possible. There is no evidence that discontinuing bisphosphonate treatment before dental interventions reduces the risk of osteonecrosis of the jaw. The treatment plan for a particular patient should be based on an individual risk / benefit ratio.

Cases of occurrence of atypical susceptible and diaphyseal fractures of the femur are described in patients who have been receiving bisphosphonates for a long time for osteoporosis.Transverse or short oblique fractures can be localized anywhere along the femur from a small spit to the supracondylar fossa. The described fractures appear after minimal trauma or spontaneously. Some patients experience pain in the thigh or groin, often accompanied by visual signs of stress fractures that occur weeks and months before the development of a full (completed) fracture of the femur. Fractures often occur on both sides, therefore, in patients receiving bisphosphonates, which have a fracture of one femur, the contralateral femur should be examined. It was also reported about the slow healing (fusion) of these fractures. Reports of atypical femoral fractures in patients treated with Zometa® have been reported, but the cause-and-effect relationship of these fractures to zoledronic acid therapy has not been established. The decision to discontinue therapy with Zometa® in patients who are expected to have an atypical femur fracture should be based on an individual risk / benefit ratio.

Patients receiving Zometa® therapy should be warned of the need to inform medical personnel of any pain in the thigh or inguinal region; Each patient who complains of such symptoms should be examined to identify a possible incomplete fracture of the femur.

In clinical practice, infrequent cases of development of strong and in some cases disabling pain in bones, joints and muscles against the background of bisphosphonate administration, including zoledronic acid.

These symptoms developed during the period from one day to several months after the start of treatment. After discontinuation of treatment in most patients, the symptoms passed. In several patients, the symptoms recurred when the therapy was resumed or another bisphosphonate was used.

Clinical practice reported the development of hypocalcemia in patients receiving Zometa®. In the case of severe hypocalcemia, development of undesirable phenomena from the side of the nervous system (convulsions, tetany and numbness), cardiac arrhythmia was noted. In some cases, hypocalcemia may pose a threat to life.

Care should be taken when using Zometa® concomitantly with other drugs that can cause hypocalcemia), as this can lead to synergistic interaction and the development of severe hypocalcemia. Before starting therapy with Zometa ®, you should determine the level of calcium in the blood serum and correct hypocalcemia).

Patients should receive adequate supplementation with calcium and vitamin D.

Patients receiving therapy with Zometa should not simultaneously receive the drug Aklasta, as well as other bisphosphonates.

The effectiveness and safety of Zometa® in pediatric practice have not been established to date.

Effect on the ability to drive transp. cf. and fur:

Studies of the effect of the Zometa drug on the ability to drive vehicles and work with mechanisms have not been conducted. In case of adverse reactions from the nervous system, patients are advised to refrain from driving and other mechanisms, as well as activities that require concentration of attention, stresses of psychomotor functions.

Form release / dosage:

Concentrate for the preparation of a solution for infusions of 4 mg / 5 ml.

Packaging:

The colorless plastic bottle, sealed with gray rubber stopper, run-aluminum cap with a plastic lid snaps. 1 bottle with instructions for use in a cardboard box.

Storage conditions:

At a temperature not exceeding 30 ° C.

The drug should be stored out of the reach of children.

Shelf life:

3 years

The drug should not be used after the expiry date indicated on the package.

Terms of leave from pharmacies:On prescription

Registration number:LS-001356

Date of registration:26.09.2011

The owner of the registration certificate:Novartis Pharma AGNovartis Pharma AG Switzerland

Manufacturer: & nbsp

NOVARTIS PHARMA STEIN, AG Switzerland

Representation: & nbspNOVARTIS PHARMA LLCNOVARTIS PHARMA LLC

Information update date: & nbsp07.10.2015

Illustrated instructions

Instructions

Zometa® (Zometa®)