Ibandronic acid Sandoz® (Ibandronic Acid Sandoz)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceIbandronic acidIbandronic acid
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  • Ibandronic acid Sandoz®
    concentrate d / infusion 
    Sandoz d.     Slovenia
    • Dosage form: & nbspconcentrate for solution for infusion
    Composition:
    Per 1 ml of the preparation:
    active substance: ibandronate sodium monohydrate - 1.125 mg (corresponding to ibandronic acid - 1 mg); Excipients: citric acid monohydrate 2.1 mg; sodium chloride - 8.6 mg; sodium hydroxide - q.s., hydrochloric acid - q.s., water for injection - up to 1.0 ml.
    For 1 ampoule or a vial containing 2 ml of the drug:
    active substance: ibandronate sodium monohydrate - 2.25 mg (corresponding to ibandronic acid - 2 mg); Excipients: citric acid monohydrate 4.2 mg; sodium chloride - 17.2 mg; sodium hydroxide * - q.s., hydrochloric acid ** - q.s., water for injection - up to 2.0 ml.
    On 1 bottle containing 6 ml of the drug:
    active substance: ibandronate sodium monohydrate - 6.75 mg (corresponding to ibandronic acid - 6 mg); Excipients: citric acid monohydrate - 12.6 mg; sodium chloride - 51.6 mg; sodium hydroxide * - q.s., hydrochloric acid ** - q.s., water for injection - up to 6.0 ml.
    * added to adjust the pH as a 5 M solution; ** is added to adjust the pH as a 1 M solution.

    Description:clear colorless liquid
    Pharmacotherapeutic group:bone resorption inhibitor-bisphosphonate.
    ATX: & nbsp

    M.05.B.A.06   Ibandronic acid

    Pharmacodynamics:
    Inhibitor of bone resorption, bisphosphonate. It has a specific selective effect on bone tissue due to its high affinity for the mineral components of the bone. Suppresses the activity of osteoclasts, reduces the frequency of skeletal complications in malignant diseases. Reduces osteoclast-associated release of tumor growth factors, inhibits the spread and invasion of tumor cells. Ibandronic acid shows a synergistic effect with taxanes in vitro. Prevents bone destruction caused by blockade of the function of the gonads, retinoids, tumor processes or the introduction of extracts of tumor tissue in vivo. Does not affect the mineralization of bone tissue.
    With hypercalcemia, the inhibitory effect on tumor induced osteolysis and, in particular, on the concomitant hypercalcaemia of the tumor process, is accompanied by a decrease in Ca2 + concentration in the blood serum and its excretion by the kidneys.Concentration of Ca2 + normalizes usually within 4-7 days after drug administration. The mean time to re-increase of serum albumin-corrected Ca2 + above 3 mmol / L is 18-26 days.
    Ibandronic acid prevents the development of new ones and reduces the growth of already existing metastases, which leads to a reduction in the frequency of skeletal complications, the intensity of the pain syndrome, the need for radiotherapy and surgical interventions for the metastatic process in the bones, thereby leading to a significant improvement in the quality of life of patients.
    Dose-dependent inhibition of tumor osteolysis, which is determined with the help of markers of bone resorption (pyridinoline and deoxypyridinoline).

    Pharmacokinetics:
    After infusion of 2, 4 or 6 mg of ibandronic acid, the pharmacokinetic parameters depend on the dose.
    Distribution
    After entering the systemic circulation, about 40-50% of ibandronic acid binds to bone tissue. The apparent final volume of the distribution is 90 liters.
    Communication with plasma proteins at therapeutic concentrations is 87%.
    Metabolism
    Data that ibandronic acid metabolized (both in humans and animals), no.
    Excretion
    The concentration of the drug in the blood decreases rapidly and is 10% of the maximum concentration (Cmax) 3 hours after intravenous administration. Part of the drug, not bound by bone tissue, is excreted unchanged by the kidneys. With iv introduction of ibandronic acid once every 4 weeks for 48 weeks in patients with metastatic lesion of systemic cumulation bones was not observed. The total clearance of ibandronic acid is low with an average of 84-160 ml / min.
    Kidney clearance (60 ml / min in healthy women in menopause) is 50-60% of the total clearance and depends on the clearance of creatinine. The difference between general and renal clearance reflects the capture of matter in bone tissue. The pharmacokinetics and bioavailability of ibandronic acid does not depend on sex.

    Pharmacokinetics in specific patient groups
    Patients with impaired renal function
    With a decrease in creatinine clearance (CK), the area under the concentration-time curve AUC0-24 and Cmax increases.
    In patients with impaired renal function of medium and severe degree, dose adjustment is necessary.
    The drug is excreted during hemodialysis (37% within 4 hours).
    Patients with hepatic impairment
    Ibandronic acid is not metabolized in the liver, and if the liver function is not corrected, dose adjustment is not required.
    Elderly age
    The studied pharmacokinetic parameters do not depend on age.
    It should be taken into account the possible decrease in kidney function in elderly patients.
    Indications:
    - metastatic bone damage in order to reduce the risk of hypercalcemia, pathological fractures, reduce pain, reduce the need for radiotherapy for pain syndrome and the threat of fractures;
    - hypercalcemia in malignant neoplasms.

    Contraindications:
    - increased sensitivity to ibandronic acid or other components of the drug;
    - children's age till 18 years;
    - hypocalcemia;
    - pregnancy;
    - lactation period.

    Carefully:
    - hypersensitivity to other bisphosphonates;
    - Creatinine clearance (CK) is less than 50 ml / min.

    Pregnancy and lactation:You should not use ibandronic acid during pregnancy and the period of breastfeeding.
    Dosing and Administration:

    The drug should be administered only intravenously. Avoid accidental intra-arterial administration of the drug or exposure to surrounding tissues,which can lead to their damage.

    Concentrate for the preparation of solution for infusion should be used once.

    It is usually used in a hospital.

    Use only a transparent freshly prepared solution without foreign particles. From a microbiological point of view, the infusion solution for intravenous administration should be used immediately after preparation. If the drug is not used immediately, then the time and storage conditions of the prepared solution are the responsibility of the health worker.

    Store the prepared solution for a maximum of 24 hours at a temperature of 2 to 8 ° C if dilution is carried out under controlled and validated aseptic conditions.

    Do not mix with solutions containing calcium. Dispose of unused solution.

    The contact with the waste products of the medicinal product in the environment should be minimized. Do not dispose of with sewage or with household waste.

    It is necessary to use established systems for the disposal of medicinal products.

    Standard dosing regimen

    Metastatic bone damage

    6 mg IV in the drip for at least 15 minutes, once every 3 to 4 weeks. Concentrate for the preparation of solution for infusion should be diluted in 100 ml of 0.9% solution of sodium chloride or 5% solution of dextrose.

    Hypercalcemia in malignant neoplasms

    Drug therapy Ibandronic acid Sandoz® is started after adequate rehydration with 0.9% sodium chloride solution. The drug is used only in the form of 1-2 hour intravenous infusion. Concentrate for the preparation of solution for infusion is diluted in 500 ml of 0.9% solution of sodium chloride or in 500 ml of a 5% solution of dextrose.

    The dose of the drug depends on the severity of hypercalcemia, as well as on the type of malignant neoplasm. As a rule, patients with osteolytic metastases require smaller doses of the drug than patients with a humoral type of hypercalcemia. In most cases, patients with severe hypercalcemia (serum albumin> 3 mmol / L or> 12 mg / dl) receive 4 mg once. Patients with moderate hypercalcemia (serum albumin-corrected serum <3 mmol / L or <12 mg / dL) - 2 mg. The maximum single dose used in clinical trials, 6 mg, does not lead to an enhanced effect.

    In most cases, the elevated serum calcium concentration returns to normal values ​​within 7 days. The mean time of recurrence of hypercalcemia (repeated increase in the concentration of albumin-corrected serum calcium more than 3 mmol / L) was 18-19 days at doses of 2 and 4 mg. The average time of recurrence with 6 mg of the drug was 26 days.

    A limited number of patients (n = 50) received a second infusion to treat hypercalcemia. With insufficient effectiveness or relapse of hypercalcemia, a re-introduction is possible.

    The concentration of albumin-corrected calcium in the serum (mmol / l) is calculated by the formula:

    serum calcium (mmol / l) - [0.02 x albumin (g / l)] + 0.8.

    The concentration of albumin-corrected calcium in serum in mg / dL is calculated by the formula:

    serum calcium (mg / dL) + 0.8 x [4-albumin (g / dL)].

    To translate the values ​​of albumin-corrected calcium in the serum, expressed in mmol / l, in mg / dl, multiply by 4.

    Dosing in special patient groups

    Impaired liver function: correction of the dose is not required.

    Impaired renal function

    Metastatic bone damage

    With mild renal impairment (> 50 and <80 mL / min), dose adjustment is not required.

    Patients with an average degree of severity (CK> 30 and <50 mL / min) or severe renal impairment (CC <30 mL / min) with metastatic bone lesions due to breast cancer should be treated against bone complications, taking into account the recommendations presented in Table 1. Table 1:

    Creatinine clearance (ml / min)

    Dosage / duration of infusion 1

    Infusion volume 2

    > 50 and <80

    6 mg / 15 min

    100 ml

    > 30 and <50

    4 mg / 1 hour

    500 ml

    <30

    2 mg / 1 hour

    500 ml

    administration every 3-4 weeks; 2 0.9% solution of sodium chloride or 5% solution of dextrose.

    In patients with SC <50 ml / min, the efficacy and safety of 15-min infusion has not been studied.

    Elderly age: correction of the dose is not required.
    Side effects:
    According to the World Health Organization (WHO), unwanted effects are classified according to their frequency of development as follows: very often (> 1/10), often (> 1/100, <1/10), infrequently (> 1/1000, < 1/100), rarely (> 1/10000, <1/1000) and very rarely (<1/10000); frequency is unknown (the frequency of occurrence of phenomena can not be determined on the basis of available data).
    Infectious and parasitic diseases
    often: infections;
    infrequently: cystitis, vaginitis, candidiasis of the oral cavity.
    Benign, malignant and unspecified formations (including cysts and polyps)
    infrequently: Benign neoplasm of the skin.
    On the part of the blood and lymphatic system
    infrequently: anemia, violation of hemostasis.
    From the endocrine system
    often: violation of parathyroid glands.
    From the side of metabolism and nutrition
    often: hypocalcemia;
    infrequently: hypophosphatemia.
    Disorders of the psyche
    infrequently: sleep disturbance, anxiety, emotional lability.
    From the nervous system
    often: headache, dizziness, dysgeusia (a violation of taste perception);
    infrequently: cerebrovascular disorders, radicular syndrome, amnesia, migraine, neuralgia, passing paresthesia and hyperesthesia, parosmia (impaired perception of odors).
    From the side of the organ of vision
    often: cataract.
    From the side of the hearing organ and labyrinthine disorders
    infrequently: hearing loss.
    From the side of the cardiovascular system
    often: blockade of the bundle of the bundle;
    infrequently: myocardial ischemia, cardiovascular disorders, heart palpitations.
    From the respiratory system
    often: pharyngitis;
    infrequently: pulmonary edema, stridor.
    From the gastrointestinal tract
    often: diarrhea, vomiting, dyspepsia, abdominal pain, dental lesions;
    infrequently: gastroenteritis, dysphagia, gastritis, ulceration of the mouth, cheilitis (inflammation of the lips, accompanied by reddening and the appearance of cracks in the corners of the mouth).
    From the side of the liver and bile ducts
    infrequently: cholelithiasis.
    From the skin and subcutaneous tissues
    often: skin lesion, ecchymosis;
    infrequently: skin rash, alopecia.
    From the side of musculoskeletal and connective tissue
    often: osteoarthritis, myalgia, arthralgia, dysfunction of the joints, pain in the
    bones;
    rarely: podatazluzhnye and diaphyseal fractures of the femur (side effects observed in the treatment of bisphosphonates);
    rarely: osteonecrosis of the jaw (an adverse event observed with bisphosphonate treatment).
    From the side of the kidneys and urinary tract
    infrequently: urinary retention, kidney cysts.
    From the genitals and breast
    infrequently: pain in the pelvis.
    General disorders and disorders at the site of administration
    often: fever, peripheral edema, asthenia, thirst, flu-like syndrome;
    infrequently: decrease in body temperature.
    Laboratory indicators
    often: increased activity of gamma-glutamyltransferase, creatinine;
    infrequently: increased alkaline phosphatase activity in the blood, weight loss.
    Trauma, intoxication and complications of manipulation
    infrequently: damage, pain in the injection site.
    Postmarketing observations
    From the side of the organ of vision:
    In the treatment of bisphosphonates, including ibandronic acid, inflammatory diseases of the eyes, such as episcleritis, scleritis and uveitis have been reported. In some cases, despite ongoing treatment, the recovery came only after the removal of bisphosphonates.
    From the immune system
    very rarely: hypersensitivity reactions, angioedema; with the treatment of ibandronic acid, cases of anaphylactic reactions / shock, including fatal, have been reported; allergic reactions, in particular, exacerbation of bronchial asthma.
    From the respiratory system, chest and mediastinum:
    bronchospasm.
    Overdose:
    To date, no data have been obtained on acute poisoning with ibandronic acid.
    Symptoms: indigestion, heartburn, esophagitis, gastritis or ulcer.
    Treatment: Because preclinical studies using high doses have shown that the drug has toxic effects on the kidneys and liver, it is necessary to monitor kidney and liver function. Clinically significant hypocalcemia can be corrected by intravenous calcium gluconate. Conducting standard procedures of hemodialysis leads to a significant decrease in the concentration of ibandronic acid in the blood plasma.

    Interaction:
    Clinically important drug interactions are unlikely. Ibandronic acid is excreted from the body only by the kidneys and is not subjected to biotransformation. The route of excretion of ibandronic acid does not include any transport systems involved in the excretion of other drugs.
    Ibandronic acid does not inhibit or induce the basic isoenzymes of the cytochrome P450 system. When used in therapeutic concentrations, binding to blood plasma proteins is low, so the possibility of drug interaction due to the displacement of drugs from the binding sites with proteins is small.With the simultaneous use of melphalan / prednisolone in patients with multiple myeloma, there was no evidence of inter-drug interaction.
    There was no interaction of ibandronic acid with tamoxifen or hormone replacement therapy (estrogen) in postmenopausal women. Care should be taken when using bisphosphonates and aminoglycosides at the same time, as both these drugs can reduce the concentration of calcium in the serum for a long time. It is necessary to consider the possibility of simultaneous development of hypomagnesemia.
    There was no clinically significant interaction of ibandronic acid with various antitumor drugs, diuretics, antibiotics and analgesics.
    Chemically incompatible with calcium (Ca2 +) - containing solutions.
    Special instructions:
    Before the beginning of therapy with the drug, it is necessary to correct hypocalcemia and other disorders of bone tissue metabolism and electrolyte balance.
    Patients should consume sufficient amounts of calcium and vitamin D. If the patient does not receive calcium and vitamin D with food, then they should additionally be taken as food supplements. Possible development of hypocalcemia.In this case, patients should make appropriate correction of calcium concentration in the blood serum.
    The drug for parenteral administration is administered only intravenously. Avoid accidental intra-arterial administration of the drug or exposure to surrounding tissues, which can lead to their damage. In clinical placebo-controlled randomized trials involving patients with metastatic bone lesions, in breast cancer, there is no evidence of renal impairment with prolonged administration of ibandronic acid. Despite this, according to the clinical evaluation of each patient, kidney function, serum calcium, phosphorus and magnesium levels should be monitored during treatment.
    For patients with severe impairment of liver function, due to the lack of clinical data, no recommendations for dosing are given. To prevent the development of heart failure, rehydration should be avoided for patients.
    Hyperhydration should be avoided in patients at risk of developing heart failure.
    In patients treated with ibandronic acid for intravenous administration,cases of anaphylactic reactions / shock, including fatal outcome, have been reported.
    During intravenous administration of the drug should be monitored the patient's condition, as well as ensure the availability of appropriate medical care. When anaphylactic or other severe hypersensitivity / allergic reaction is detected, it is necessary to immediately stop the infusion and begin the appropriate treatment.
    In the appointment of bisphosphonates, there were very few cases of osteonecrosis of the jaw. Most cases have been reported in cancer patients during dental procedures, several cases in patients with postmenopausal osteoporosis or other diseases.
    Risk factors for osteonecrosis of the jaw include established diagnosis of cancer, concomitant therapy (chemotherapy, radiation therapy, corticosteroids), non-compliance with oral hygiene. Surgical dental intervention on the background of therapy can strengthen the manifestations of osteonecrosis of the jaw. It is unknown whether the risk of osteonecrosis reduces the elimination of bisphosphonates in patients with the need for dental procedures.The decision to conduct treatment should be taken for each patient individually after assessing the risk / benefit ratio. In the treatment of bisphosphonates, cases of atypical subacute and diaphyseal fractures of the femur were seldom observed, in particular, with prolonged treatment of osteoporosis.
    Transverse and short oblique fractures can be localized along the entire length of the femur from a small spit to an epicondylitis elevation. The occurrence of atypical fractures occurs spontaneously or as a result of minor injuries.
    In the weeks or months before the hip fracture, some patients experienced pain in the thigh or in the groin, which is often accompanied by radiographic signs of a stress fracture. Fractures are often bilateral, so it is necessary to examine patients for fractures on the opposite side of the femur. Patients receiving bisphosphonate therapy should be immediately notified to the treating physician of the appearance of pain in the groin, femur or neck of the thigh and examined for appropriate fractures.
    If a suspected atypical fracture is suspected and the results of the survey are obtained, consideration should be given to discontinuing bisphosphonate therapy, based on the benefit / risk ratio in each individual case.
    Effect on the ability to drive transp. cf. and fur:Studies to study the effect of the drug on the ability to drive a car and work with mechanisms were not conducted. Patients should be informed that after the infusion of the drug, fatigue and dizziness may occur. In this regard, they should not sit behind the wheel, work with potentially dangerous machinery and vehicles.
    Form release / dosage:
    Concentrate for solution for infusion, 2 mg / 2 ml, 6 mg / 6 ml.
    Packaging:
    2 ml each in ampoules of clear, colorless glass with a blue breaking ring or in clear glass bottles, sealed with bromobutyl rubber stoppers, crimped aluminum caps with a protective polypropylene cover.
    To 6 ml in bottles of transparent colorless glass, ukuporennye brombutilovymi rubber stoppers, crimped aluminum caps with protective polypropylene lid.
    For 1, 3, 5 or 10 ampoules or vials with instructions for use
    placed in a cardboard box.
    Storage conditions:
    At a temperature of no higher than 25 ° C.
    Keep out of the reach of children.
    Special precautions when destroying an unused preparation
    Dispose of unused solution.
    The contact with the waste products of medicines in the environment should be minimized.
    Shelf life:
    3 years.
    Ready to use drug in a solution of sodium chloride or dextrose stored for no more than 24 hours at a temperature of 2 to 8 ° C.
    Do not use the drug after the expiration date.
    Terms of leave from pharmacies:On prescription
    Registration number:LP-002469
    Date of registration:20.05.2014
    The owner of the registration certificate:Sandoz d.Sandoz d. Slovenia
    Manufacturer: & nbsp
    Representation: & nbspSANDOZ SANDOZ Switzerland
    Information update date: & nbsp20.05.2014
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