Aklasta - instructions for use, doses, side effects, contraindications

100 ml of solution (1 bottle) contain: active substance - zoledronic acid monohydrate - 5.33 mg (equivalent to zoledronic acid anhydrous - 5.00 mg); Excipients: Mannitol - 4950.00 mg, sodium citrate dihydrate - 30.00 mg, water for injection up to 100 ml.

Description:

A clear, colorless solution.

Pharmacotherapeutic group:Inhibitor of bone resorption, bisphosphonate.

ATX: & nbsp

M.05.B.A.08 Zoledronic acid

Pharmacodynamics:

Zoledronic acid, a representative of the class of nitrogen-containing bisphosphonates, acts predominantly on bone tissue, suppresses the activity of osteoclasts and resorption of bone tissue.

Selective action of bisphosphonates on bone tissue is based on a high affinity for mineralized bone tissue. After intravenous administration zoledronic acid quickly redistributed in bone tissue and, like other bisphosphonates, is localized primarily in areas of bone tissue remodeling. The main molecular target of zoledronic acid in osteoclast is the enzyme farnesyl pyrophosphate synthetase (FPS); while the possibility of other mechanisms of action of the drug substance is not ruled out. The long period of action of the drug is determined by a high affinity for the active center of FBS and a pronounced affinity for the mineralized bone tissue.

Against the backdrop of using the drug Aklast, there is a rapid decrease in bone turnover from elevated postmenopausal values to the lowest acceptable level (by day 7 for bone resorption and by 12 weeks for bone formation).Subsequently, bone exchange rates stabilize within pre-menopausal values.

On experimental models of accelerated osteorheal resection with prolonged use of zoledronic acid, it was shown that zoledronic acid significantly inhibits bone resorption without undue influence on the formation, mineralization and mechanical properties of bone tissue, dose-dependently decreases the activity of osteoclasts and the frequency of activation of new foci of remodeling in both trabecular (spongy) and cortical (compact) bone tissue without causing the formation of fibrous bone tissue and aberrant accumulation of osteoid, as well as bone mineralization defects. With the exception of high antiresorptive action, the effect of zoledronic acid on bone tissue is similar to that of other bisphosphonates.

With the use of the drug Aklasta in patients with postmenopausal osteoporosis (values of T-criterion of bone mineral density of the femoral neck less than 2.5), a statistically significant reduction in the risk of vertebral fractures by 70% by the end of 3 years of treatment, as well as a reduction in the risk of developing one or more (new) / repeated fractures and vertebral fractures of medium / severe degree by 60-70%.In patients with osteoporosis at the age of 75 years and older, the risk of developing vertebral fractures was reduced by 61% when treated with the drug Aklast.

When treating the drug Aklast relative risk of developing fractures of the femur by the 3rd year of therapy was reduced by 40%. When treating drug Aklasta relative risk of all clinical fractures, nonvertebral fractures at any site (excluding fractures of the phalanges and the facial bones of the skull) was reduced by 33% and 25% respectively. In applying the drug within 3 years in patients with postmenopausal osteoporosis, an increase in bone mineral density (BMD) of the lumbar vertebrae and femur bones in general, in the neck of the femur and the distal radius by an average of 6.9%, 6 %, 5% and 3.2%, respectively.

The therapy drug Aklasta for 1 year in patients with postmenopausal osteoporosis observed decrease in activity of the bone isoenzyme of alkaline phosphatase, N-terminal propeptide of type I collagen (PINP), and P-C-terminal telopeptides of blood to premenopausal level. With repeated injections of the drug for 3 years, there was no further decrease in blood levels of markers of bone remodeling.

The use of the drug Aklasta for 3 years significantly reduced the rate of loss of growth in patients, and also increased physical activity in postmenopausal women with osteoporosis and vertebral fractures.

When the drug was administered to patients (men and women) with recent (within 90 days) fractures of the proximal femur (caused by minimal trauma and requiring surgical intervention), the incidence of subsequent osteoporotic fractures of any site was reduced by 35% compared with placebo (from of clinically significant vertebral fractures - by 46%, non-vertebral fractures - by 27%). When applying the drug Aklasta in this category of patients, the relative risk of deaths (regardless of their cause) decreased by 28%. In patients with fractures of the femur, using Aklasta for 2 years, the BMD of the femur in general and in the femoral neck area increased by 5.4% and 4.3%, respectively.

When applying the drug once a year in men with a primary (senile) or secondary (with hypogonadism) osteoporosis within 2 years, there was a marked increase in BMD of the lumbar vertebrae.

In patients with osteoporosis caused by the use of glucocorticosteroids, therapy with the drug Aklasta during the year also significantly increased BMD (lumbar vertebrae, cervix, trochanter, radius) without adversely affecting bone structure and mineralization.

When using the drug Aklasta for the prevention of postmenopausal osteoporosis, every 2 years in women with a postmenopausal period less than or more than 5 years, an increase in BMD of the lumbar vertebrae by 6.3% was noted. and 5.4% respectively. When the drug was administered once in 2 years, the BMD of the femur increased by 4.7% and 3.2% in women with a postmenopausal period of less than or more than 5 years, respectively.

In women with different duration of postmenopause, with the introduction of the drug Aklast, a decrease in the concentration of B-C-terminal telopeptides of blood by 44-46% (to the pre-menopausal level) and N-terminal propeptide of collagen type I (PINP) by 55-40 %.

When treating with drug Aklasta in patients with Paget's bone disease, there was a statistically significant, rapid and long-term therapeutic response, normalization of bone metabolism and alkaline phosphatase activity in blood plasma.

The drug is also highly effective in patients who received previous treatment with oral bisphosphonates. Therapeutic response with the use of the drug Aklasta persists longer than with the use of Residronic acid (7.7 years compared with 5.1 years).

The marked decrease in the pain syndrome at the 6th month after a single injection of the drug Aklast at a dose of 5 mg is comparable to the analgesic effect of risedron acid at a dose of 30 mg per day.

In patients with postmenopausal osteoporosis and bone disease Paget zoledronic acid does not affect the qualitative state of normal bone tissue, does not disrupt the processes of bone remodeling and mineralization and contributes to the preservation of normal architectonics of trabecular bone tissue.

Pharmacokinetics:

Data on pharmacokinetics 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.

After the start of the drug, the concentration of zoledronic acid in the blood plasma increases rapidly, reaching a maximum at the end of the infusion.

After the end of infusion, the concentration of zoledronic acid in the blood plasma decreases rapidly (to <10% of the peak value after 4 hours and to <1% of the peak after 24 hours), then a low concentration of the drug remains in the plasma for a long period of time (not exceeding 0.1% of the maximum).

Zoledronic acid is excreted by the kidneys in 3 stages: rapid two-phase elimination from the systemic blood stream with half-lives of 0.24 h (α-phase) and 1.87 hβ-phase) and a long phase with a terminal elimination half-life of 146 h (γ-phase ). Rapid reduction in the concentration of the drug (α and β phase) in blood plasma is probably due to the rapid distribution of zoledronic acid in the bone tissue and excretion of it by the kidneys. There was no cumulation of the drug with repeated administration every 28 days. Zoledronic acid It is not metabolized and 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 binds solely to bone tissue, after which a very slow release of zoledronic acid back from the bone tissue into the systemic circulation 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, sex, age, race and body weight of the patient. It was found that the variability of plasma clearance of zoledronic acid in the same patient and in different patients is 36% and 34%, respectively. Increasing the infusion time from 5 to 15 minutes 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). The binding of zoledronic acid with plasma proteins is low (23-40%) and does not depend on its concentration.

Pharmacokinetics in special clinical cases

Renal clearance of zoledronic acid correlates with creatinine clearance and is 75 ± 33% of creatinine clearance, the average of which is 84 ± 29 ml / min (range 22-143 ml / min) in 64 patients included in the pharmacokinetic study.

A slight increase in AUC_0-24(by 30-40%) with a mild and moderate renal dysfunction, as compared to the norm, and the absence of cumulation of the drug with repeated administration regardless of renal function, allow us to believe that there is no need to correct the dose of zoledronic acid in case of impaired renal function (creatinine clearance = 50-80 ml / min) and average (creatinine clearance = 30-50 ml / min) of severity.The use of the drug in patients with impaired renal function of severe severity (creatinine clearance <30 ml / min) is contraindicated because of the increased risk of renal failure.

Indications:

postmenopausal osteoporosis (to reduce the risk of fracture of the femur, vertebrae and extrinsic fractures, to increase bone mineral density);
prevention of subsequent (new) osteoporotic fractures in men and women with fractures of the proximal femur;
osteoporosis in men;
prevention and treatment of osteoporosis caused by the use of glucocorticosteroids;
prevention of postmenopausal osteoporosis (in patients with osteopenia);
Paget's bone disease.

Contraindications:

Hypersensitivity to zoledronic acid or to any other component of the drug or to any bisphosphonate.
Severe disorders of mineral metabolism, including hypocalcemia.
Pregnancy, the period of breastfeeding.
Age to 18 years (because safety and effectiveness of the drug Aklasta in this category of patients (children and adolescents) have not been studied).
Severe renal impairment (creatinine clearance <30 mL / min).

Carefully:

Care should be taken with the use of the drug Aklasta:

in patients with impaired renal function of mild and moderate severity;
in patients with severe dehydration;
in patients with concomitant oncological diseases and chemotherapy in the anamnesis;
in patients with complete or incomplete combination of bronchial asthma, recurrent nasal polyposis and paranasal sinuses and intolerance to acetylsalicylic acid or other non-steroidal anti-inflammatory drugs (including in the anamnesis);
with simultaneous use with drugs that can have a significant effect on kidney function (for example, with antibiotics-aminoglycosides or diuretics that cause dehydration).

If you have one of the listed diseases (conditions) before taking the drug necessarily consult a doctor.

Pregnancy and lactation:

The use of the drug Aklast during pregnancy is contraindicated.

The drug Aklasta 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, the risk of intrauterine malformations of the fetus (for example, anomalies in the development of the skeleton and other abnormalities of the intrauterine development) may occur. 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 specificity of the particular drug is unknown.

Patients of reproductive age should be warned about the need to apply reliable contraceptive methods during treatment with Aklasta. It is not known whether the zoledronic acid in breast milk. The use of the drug Aklast during breastfeeding is contraindicated.

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

Dosing and Administration:

The drug Aklasta, a solution for infusion, is administered intravenously infusion.The administration of the drug should be carried out with the help of a valvular infusion system, providing a constant infusion rate, for at least 15 minutes.

Before the introduction of the drug Aklast should provide adequate hydration of the body. This is especially important for elderly patients (> 65 years), as well as for patients receiving diuretic therapy.

For treatment postmenopausal osteoporosis in women and osteoporosis in men the recommended dose of the drug Aklasta is 5 mg (the contents of one vial of the drug - 100 ml of solution) intravenously once a year. If intake of calcium and vitamin D with food is not enough, patients should additionally prescribe calcium and vitamin D.

To prevent subsequent fractures in patients with fractures of the proximal femur the recommended dose of the drug Aklasta is 5 mg (the contents of one vial of the drug - 100 ml of solution) intravenously once a year. Patients with a recent (up to 90 days) fracture of the proximal femur are recommended to take single vitamin D at high doses (from 50,000 to 125,000 IU orally or intramuscularly) 2 weeks before the first infusion of the drug Aklast.With a single application of the drug Aklast, patients are recommended to take calcium supplements (1000 mg per day and vitamin D (800 IU per day) every 14 days before the infusion.) After the infusion of the drug Aklasta during the year, patients should also take calcium and vitamin D.

To prevent subsequent fractures in patients with fractures of the proximal femur, the first infusion of the drug should be performed 2 or more weeks after the operation.

For the treatment of osteoporosis caused by the use of glucocorticosteroids, the recommended dose of the drug Aklasta is 5 mg (the contents of one vial of the drug - 100 ml of solution) intravenously once a year. If the intake of calcium and vitamin D in the body is not enough, patients with osteoporosis should additionally be prescribed calcium and vitamin D.

For the prevention of postmenopausal osteoporosis the recommended dose of the drug Aklasta is 5 mg (the contents of one vial of the drug - 100 ml of solution) intravenously every 2 years.

An annual assessment of the risk of fracture and an evaluation of the clinical response to therapy should be conducted to determine whether a re-infusion is necessary.

For the prevention of postmenopausal osteoporosis, sufficient intake of calcium and vitamin D is very important. In case their intake with food is insufficient, an additional intake of calcium and vitamin D preparations is recommended.

For treatment bone disease Paget One-time administration of 5 mg of the drug Aklast intravenously is recommended.

Paget's bone disease is characterized by a high bone-exchange activity. Due to the rapid onset of the effect on bone metabolism, after the application of the drug Aklast, during the first 10 days after the infusion, transient hypocalcemia may develop. Against the backdrop of using the drug Aklast recommended sufficient intake of vitamin D. In addition, it is strongly recommended to take an adequate dose of calcium (at least 500 mg of elemental calcium 2 times a day) for at least the first 10 days after the introduction of the drug Aklasta.

Repeated treatment of Paget's bone disease with Aklast

After a single application of the drug Aklasta with bone disease Paget, patients had a long (about 7.7 years on average) remission.Since Paget's bone disease is a chronic disease, it is recommended to re-use the drug. Repeated use of the drug in Paget's disease is intravenously administered at a dose of 5 mg after one year or more from the start of treatment. The interval between the injections of the drug Aklast should be determined individually based on the effectiveness of treatment and the results of determining the concentration of alkaline phosphatase, which should be conducted every 6-12 months. In the absence of clinical signs of deterioration, such as bone pain and compression symptoms, and / or radiologic signs of disease progression, the next infusion of the drug Aklast can be performed no earlier than 12 months after the first.

Patients with impaired renal function

The use of the drug in patients with creatinine clearance <30 ml / min is contraindicated.

In patients with creatinine clearance> 35 ml / min, dose adjustment is not required.

Patients with hepatic impairment

Patients with impaired liver function do not need a dose adjustment.

Patients of advanced age (> 65 years)

Correction of the dose of the drug is not required, since the bioavailability, distribution and excretion of the drug in patients of different ages have a similar nature.

Instructions for use

When preparing and carrying out infusion, you should follow the rules of asepsis.

Before the introduction of the drug, Aklast should visually assess the quality and color of the solution. The drug can not be used when changing color or the appearance of undissolved visible particles.

The drug Aklast should not be mixed or injected with any other drugs. Do not allow the contact of the drug Aklast with any solutions containing calcium or any other divalent cations. To administer the drug, you should always use a separate system for infusion.

After the infusion of the drug Aklast, the unused solution remaining in the vial can not be used.

A solution of the drug Aklast should be used immediately after opening the vial. Unused immediately solution can be stored in the refrigerator at a temperature of +2 to +8 ° C not more than 24 hours. If the solution is cooled, it should be allowed to stand in the room before the room temperature is reached.

Side effects:

Treatment of various types of osteoporosis, Paget's bone disease and prevention of subsequent fractures in men and women with fractures of the proximal femur

With intravenous administration of 5 mg of the drug Aklasta once a year for the treatment of postmenopausal osteoporosis in women, osteoporosis in men, for the prevention of subsequent fractures in men and women with fractures of the proximal femur, for the prevention and treatment of osteoporosis caused by the use of glucocorticosteroids and for the treatment of bone Paget's disease most of the adverse events (AEs) were mild or moderately severe. After intravenous administration of the drug Aklast, the following AEs were most frequently observed in these patients: usually fever (18.1%), myalgia (9.4%), flu-like syndrome (7.8%), usually no more than 3 days ("postdose" symptoms) %), arthralgia (6.8%), headache (6.5%). Most of the above AEs that were noted within 3 days after the administration of the drug were mild or moderately severe. With the repeated administration of the drug, the frequency of AE data was significantly reduced.

Below are the AEs,(according to the attending physicians) with the use of the drug for the treatment of various types of osteoporosis, Paget's bone disease and for the prevention of new fractures in men and women with fractures of the proximal femur. The frequency of development of AE data was estimated as follows: very often (> 1/10); often (> 1/100, <1/10); infrequently (> 1/1 000, <1/100); rarely (> 1/10 000, <1/1 000); very rarely (<1/10 000); frequency is unknown (according to individual reports from clinical practice).

Impaired nervous system: often - headache, dizziness; infrequently - retardation *, paresthesia, drowsiness, tremor, fainting, dysgeusia. Disorders from the side of the organ of vision: often - sclera hyperemia; infrequently - conjunctivitis, pain in the eyes; rarely - uveitis *, episcleritis, iritis; frequency unknown - inflammation of the sclera and orbit.

Hearing disorders and labyrinthine disturbances: infrequently - vertigo. Disturbances from the respiratory system, chest and mediastinal organs: infrequently - shortness of breath *, cough.

Disorders from the digestive system: often - nausea, vomiting, diarrhea; infrequent - loss of appetite, dyspepsia *, abdominal pain *, dry mouth, esophagitis *, gastroesophageal reflux, pain in the upper abdomen, constipation,gastritis (in patients receiving glucocorticosteroids), toothache.

Disturbances from the skin and underarm tissues: infrequently - rash, hyperhidrosis *, itching, erythema.

Disturbances from the musculoskeletal and connective tissue: often - arthralgia *, myalgia *, bone pain, back and limb pain; infrequent pain in the neck, joint swelling *, muscle spasms, pain in the shoulder girdle, pain in the chest area * Musculoskeletal origin, muscle weakness, stiffness in the muscles * and joints *, arthritis, musculoskeletal pain; frequency unknown - osteonecrosis of the jaw.

Disorders from the kidneys and urinary tract: infrequently - increasing the concentration of creatinine in the blood, pollakiuria, proteinuria; frequency unknown - renal failure.

Violations from the blood and lymphatic system: infrequently - anemia.

Heart Disease: often - atrial fibrillation, infrequently - a feeling of palpitations.

Vascular disorders: infrequently - increased blood pressure, sudden redness of the face; frequency unknown - marked reduction in blood pressure (in patients with risk factors).

Disorders of the psyche: infrequently - insomnia.

Infectious and parasitic diseases: infrequently - flu, nasopharyngitis.

General disorders and disorders at the site of administration: very often - fever; often - flu-like syndrome, chills, fatigue *, asthenia, pain *, general malaise, reactions at the site of infusion; infrequent peripheral edema, thirst *, acute phase reactions *, chest pain (not associated with heart disease); frequency is unknown - dehydration (developing due to postinfusion phenomena such as fever, vomiting and diarrhea).

* - In some studies, the incidence of these adverse events increased as follows: Often - myalgia, arthralgia, increased fatigue, pain; often - retardation, dyspnea, dyspepsia, esophagitis, abdominal pain, hyperhidrosis, stiffness in muscles, swelling in the joint region, pain in the chest area of the musculoskeletal origin, joint stiffness, decreased appetite, thirst, acute phase reactions; infrequently - uveitis.

In individual studies, AEs were detected, the incidence of which was lower in the Aklasta group than in patients who did not receive the drug.

Heart Disease: atrial fibrillation, palpitation.

Disorders from the side of the organ of vision: redness of the eye.

Disorders from the digestive system: gastritis, toothache.

General disorders and disorders at the site of administration: reaction at the site of administration.

Laboratory and instrumental data: an increase in the C-reactive protein.

Disorders from the metabolism and nutrition: hypocalcemia.

Impaired nervous system: dysgeusia.

Prevention of postmenopausal osteoporosis

With the use of the drug Aklasta for the prevention of postmenopausal osteoporosis (MIP), the overall safety profile of the drug was comparable to that of MIP treatment, except for AEs that occurred within 3 days after the infusion: pain, fever, chills, myalgia, nausea, headache, increased fatigue, dizziness, arthralgia, whose frequency was higher in patients who received the drug for the prevention of MIP. Most of these AEs were of mild or moderate severity and passed within three days after manifestation. With the repeated administration of the drug, the severity of AE data was significantly reduced.

Below are the AEs,(in the opinion of the attending physicians): 1) AEs that were noted more than once with the introduction of the drug Aklast for the prevention of MI and not registered with the use of the drug Aklasta for the treatment of various types of osteoporosis, bone disease Paget and for the prevention of new fractures in men and women with fractures of the proximal femur; 2) AEs, the frequency of which was higher in women receiving the drug for the prevention of MI (in comparison with other categories of patients). The frequency of development of AE data was estimated as follows: very often (> 1/10); often (> 1/100, <1/10); infrequently (> 1/1 000, <1/100).

Disorders of the psyche: infrequently - anxiety.

Impaired nervous system: very often - headache; often - tremor, retardation; infrequently - hypoesthesia, dysgeusia.

Disorders from the side of the organ of vision: often - conjunctivitis, pain in the eyes, iritis; infrequently - indistinct vision.

Disorders from the digestive system: very often - nausea; often - decreased appetite, abdominal pain, pain in the upper abdomen, constipation.

Disturbances from the skin and subcutaneous tissue: often - increased sweating at night.

Disturbances from the musculoskeletal and connective tissue: very often - myalgia; often - muscle pain, muscle spasm, pain in the chest area of musculoskeletal origin, pain in the jaw, pain in the neck; infrequently - pain in the side.

General disorders and disorders at the site of administration: very often - pain, chills; often - peripheral edema, reactions at the injection site, non-cardiac pain in the thorax.

Change in the results of laboratory studies

In patients with postmenopausal osteoporosis, a decrease in calcium (<1.87 mmol / l) in the blood serum was observed in 0.2% of cases with the use of the drug Aklast, and no clinical signs of hypocalcemia were observed.

When using the drug in patients with fractures of the femur, with men's osteoporosis and osteoporosis caused by SCS, there were no patients who needed urgent therapy with a calcium concentration in the blood plasma <1.87 mmol / l. When using the drug in patients for the prevention of postmenopausal osteoporosis, one patient needed urgent therapy with a calcium concentration in the blood plasma <1.87 mmol / l.

In patients with Paget's disease, approximately 1% of cases showed transient hypocalcemia accompanied by clinical manifestations.

Renal impairment

With intravenous administration of bisphosphonates, including zoledronic acid, there were cases of impaired renal function with an increase in the concentration of creatinine in the blood, and in rare cases, with acute renal failure.

Impaired renal function after a single use of zoledronic acid has been observed in patients with a history of either renal disease or additional risk factors (eg, advanced age, concomitant use of nephrotoxic drugs, diuretics, oncological patients receiving chemotherapy, or severe dehydration) with a predominance of patients who received the drug at a dose of 4 mg every 3-4 weeks.

However, in patients with impaired renal function or any of the above risk factors, renal failure requiring hemodialysis or leading to death was rare. Care should be taken when using the drug Aklasta in patients with concomitant oncologicaldiseases and chemotherapy due to an increased risk of developing kidney failure.

With Aklast therapy for 3 years in patients with postmenopausal osteoporosis, the frequency of increase in creatinine concentration in the blood plasma and the development of renal failure did not differ from that with placebo. Patients treated with Aklast received a slightly more frequent increase in blood creatinine concentrations within 10 days after infusion compared with placebo (1.8% and 0.8%, respectively).

When using the drug Aklasta for 2 years in men with osteoporosis, the rate of change in creatinine clearance and the development of renal dysfunction was similar to that in the alendronic acid intake group.

In patients with osteoporosis caused by the use of GCS, against the background of therapy with the drug Aklast, the frequency of change in the creatinine clearance and the development of renal dysfunction was similar to that in the risedronic acid intake group.

When using the drug in patients with fractures of the femur, the frequency of changes in creatinine clearance and the development of renal dysfunction was similar to that in the placebo group.

When using the drug in patients for the prevention of postmenopausal osteoporosis, the frequency of change in creatinine clearance and the development of renal dysfunction was similar to that in the placebo group.

Reactions at the injection site

With the use of the drug Aklasta in patients with postmenopausal osteoporosis, redness, swelling and / or soreness in the injection site were noted in 0.7% of cases.

In patients with fractures of the femur, the incidence of local reactions was comparable to that in the placebo group.

In the treatment of osteoporosis in men, the incidence of reactions at the site of injection of the drug Aklast was 2.6% (compared with 1.4% in the alendronic acid intake group).

In patients with osteoporosis caused by the use of GCS, there were no reactions at the injection site.

When using the drug for the prevention of postmenopausal osteoporosis, the incidence of reactions at the place of injection of the drug Aklast was 1.1% (compared with 2.0% in the placebo group).

Osteonecrosis of the jaw

Cases of osteonecrosis (most often - osteonecrosis of the jaw) occurred mainly in cancer patients,receiving treatment with bisphosphonates (including zoledronic acid - infrequently), in most cases after extraction of the tooth or other dental manipulations. Most patients had symptoms of a local infectious-inflammatory process, including osteomyelitis.

In clinical studies in patients with osteoporosis, the case of osteonecrosis of the jaw occurred in 1 patient who took the drug Aklasta and 1 patient who took a placebo. In both cases, the resolution of the process was noted.

When applying the drug Aklasta in patients with fractures of the femur, with male osteoporosis and osteoporosis caused by the use of GCS, and also with the use of the drug for the prevention of postmenopausal osteoporosis, there were no cases of osteonecrosis of the jaw.

Atrial fibrillation

With the use of the drug Aklasta in patients with postmenopausal osteoporosis, the overall incidence of atrial fibrillation was 2.5% (96 patients out of 3,862) compared with 1.9% (75 of 3852 patients) in patients not treated with the drug (placebo group) . In 1.3% of patients (51 patients from 3862) who received the drug Aklasta and 0.6% (22 patients out of 3852) in the placebo group, this undesirable phenomenon was regarded as serious.The reason for the increase in the frequency of atrial fibrillation against the background of therapy with the drug Aklasta in this study is not established. An increase in the incidence of atrial fibrillation compared with placebo, noted in this study, was not found in other clinical studies of zoledronic acid.

Separate reports of undesirable events

Against the background of therapy with the drug Aklasta, the following undesirable phenomena were noted in clinical practice without indication of a cause-and-effect relationship with the use of the drug (frequency of AH not established): hypersensitivity reactions, including rare bronchoconstriction, hives, angioedema, and occasional reports on the development of anaphylactic reactions / shock.

In rare cases, with the use of the drug Aklast in clinical practice, patients had renal dysfunction, including renal insufficiency requiring hemodialysis, or death, especially in patients with a history of having a kidney disease, or additional risk factors (for example, old age , concomitant therapy with nephrotoxic drugs, diuretics or with severe dehydration).

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, inform the doctor about it.

Overdose:

Currently, there is not enough clinical data on cases of drug overdose. Patients who received a dose of the drug that exceeds recommended, should be under the supervision of a doctor.

In acute overdose of zoledronic acid (limited data), renal dysfunction was noted, including renal insufficiency, hypocalcemia, hypophosphatemia, hypomagnesemia. In case of an overdose of a drug accompanied by clinical symptoms (numbness, tingling sensation, especially in the mouth, muscle spasms, etc.), intravenous administration of solutions containing calcium, magnesium and phosphate ions is indicated. With the impossibility of intravenous administration of calcium preparations, their oral intake is possible.

Interaction:

Special studies to study the interaction of zoledronic acid with other drugs have not been conducted. Zoledronic acid is not subject to systemic metabolism and does not affect human cytochrome P450 isoenzymes in vitro.

Zoledronic acid has a relatively low degree of binding to plasma proteins (approximately 43-55%); drug interaction caused by the displacement of drugs with a high degree of binding to proteins from binding sites is unlikely.

Zoledronic acid is excreted by the kidneys. Caution should be exercised while using the drug Aklasta with drugs that can have a significant effect on kidney function (for example, with antibiotics-aminoglycosides or diuretics that cause dehydration).

In patients with impaired renal function with the drug Aklasta in conjunction with drugs that are excreted mainly by the kidneys, it is possible to increase the systemic effect of these drugs.

Pharmaceutical interaction and compatibility issues

The solution of the drug Aklast is incompatible with solutions containing calcium or other divalent cations (for example, in one system for intravenous drip).

Special instructions:

The physician should inform patients about the main manifestations of hypocalcemia and ensure regular monitoring of patients at risk.

Therapy with the drug Aklasta in patients with bone disease Paget should be conducted only by qualified doctors who have experience in the treatment of this disease.

The severity of post-infusion adverse events developing within 3 days after infusion can be reduced by the use of paracetamol or ibuprofen immediately after the infusion of the drug Aklast.

Zoledronic acid is an active substance of both the drug Aklasta and Zometa® (a drug for the treatment of cancer patients), but these medications are not interchangeable and should not be used simultaneously.

In the presence of hypocalcemia, before starting the use of the drug Aklast, adequate treatment with adequate doses of calcium and vitamin D should be performed. Other existing disorders of the mineral metabolism (for example, arising after operations on the thyroid and parathyroid glands, with hypoparathyroidism or a decrease in calcium absorption in the intestine) should be treated and Regular monitoring of patients with hypocalcemia.

Renal impairment

To reduce the risk of kidney disorders, the following guidelines should be observed:

The drug is contraindicated in patients with impaired renal function of severe severity (creatinine clearance <30 ml / min).
Before each injection of the drug, it is necessary to determine the clearance of creatinine (for example, according to the Cockcroft-Gault formula). Against the background of drug therapy in patients with a history of impaired renal function, a transient increase in serum creatinine concentration in plasma may be higher than in patients with normal renal function. When using the drug Aklasta in patients who have risk factors for kidney disorders, the determination of the concentration of creatinine in the blood plasma should be carried out regularly.
Caution should be exercised while using the drug Aklast with drugs that can have a significant effect on kidney function (see section "Interaction with other drugs"),
Before the introduction of the drug Aklast should provide adequate hydration of the body. This is especially important for patients aged> 65 years, as well as for patients receiving diuretic therapy.
The dose of drug in a single intravenous infusion should not exceed 5 mg, wherein the administration Aklasta preparation should be conducted for at least 15 min.

Osteonecrosis of the jaw

Risk factors for osteonecrosis are oncological diseases, concomitant therapy (e.g., chemotherapy, simultaneous application of inhibitors of angiogenesis drugs, radiation therapy, corticosteroids) and the presence of other concomitant disorders (e.g., anemia, bleeding disorders, infections, dental diseases in history).

Although causal relationship with the jaw osteonecrosis bisphosphonates is not installed, to avoid dental operations, since the recovery time after these operations may increase. Before the start of treatment with bisphosphonates, a dental examination should be performed and the necessary preventive procedures performed in advance in patients with risk factors (oncological diseases, chemotherapy, glucocorticosteroid treatment, and non-compliance with oral hygiene).

With the development of osteonecrosis of the jaw during therapy with bisphosphonates carrying out dental operations can worsen the condition of patients.There is no evidence that interruption of bisphosphonate treatment prior to dental interventions reduces the risk of osteonecrosis of the jaw. The tactics of treating a particular patient should be based on an individual assessment of the risk / benefit ratio.

There were isolated cases of bronchoconstriction in patients with complete or incomplete combination of bronchial asthma, recurrent nasal polyposis and paranasal sinuses and intolerance to acetylsalicylic acid or other non-steroidal anti-inflammatory drugs (including anamnesis) against bisphosphonate. Although no such cases have been noted in clinical trials involving Aklast, it is recommended to use the drug with caution in patients with complete or incomplete combination of bronchial asthma, recurrent nasal polyposis and paranasal sinuses and intolerance to acetylsalicylic acid or other non-steroidal anti-inflammatory drugs (incl. in the anamnesis).

Atypical fractures of the femur

There have been reports of cases of atypical susceptible and diaphyseal fractures of the femur in patients receiving long-term anti-osteoporotic therapy with bisphosphonates.These fractures, transverse or short oblique, are localized in any area from the small skewer to the epicondyles and arise, as a rule, spontaneously or after minor trauma. Before the detection of femoral fractures, patients may experience pain in the hip or groin for several weeks or months. Fractures are often bilateral, so when diagnosing a fracture of the femur in a patient receiving bisphosphonates, it is also necessary to examine the contralateral femur. There are reports that these fractures are accompanied by slow healing (fusion). The decision to discontinue bisphosphonate therapy in patients with suspected atypical fractures of the femur should be based on an individual assessment of the risk-benefit ratio. A clear causal relationship between the use of bisphosphonates and fractures of the femur was not established, since atypical fractures also occurred in patients with osteoporosis who did not receive bisphosphonate therapy. All patients receiving bisphosphonate therapy, including Aklast, should be informed of the need to report any pain in the hip or groin area,and any such patient should be examined for having a fracture of the femur.

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

Data on the effect of the drug Aklast on the ability to drive vehicles and work with mechanisms there. However, due to the fact that dizziness is one of the side effects of the drug Aklast, patients should be careful when carrying out potentially hazardous activities. When this undesirable phenomenon appears, one should refrain from these activities.

Form release / dosage:

Solution for infusions 5 mg / 100 ml.

Packaging:

To 100 ml of the drug in a colorless polyethylene bottle, sealed with a gray rubber stopper, coated with an aluminum cap with a "flip-off" device. The vial is attached to the bundle using a polymer tape. One bottle together with instructions for use in a cardboard tutu.

Storage conditions:

At a temperature of no higher than 25 ° C.

After opening the vial the solution is stable at a temperature of 2 to 8 ° C for 24 hours.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LS-002514

Date of registration:21.10.2011

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: & nbsp26.03.2015

Illustrated instructions

Instructions

Aklasta (Aclasta)