Pamidronate medak (Pamidronate medac)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substancePamidronic acidPamidronic acid
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  • Pamidronate medak
    concentrate d / infusion 
    medac GmbH     Germany
  • Pomegara
    concentrate d / infusion 
    Genfa Medica S.A.     Switzerland
    • Dosage form: & nbspconcentrate for solution for infusion
    Composition:

    1 ml of the preparation contains:

    active substance: disodium pamidronate 3 mg (corresponding to 2.527 mg of pamidronic acid)

    Excipients: sodium hydroxide, hydrochloric acid, water for injection.

    The bottle with the preparation is filled with nitrogen to create an inert atmosphere.

    Description:

    Transparent colorless liquid.

    Pharmacotherapeutic group:inhibitor of bone resorption, bisphosphonate
    ATX: & nbsp

    M.05.B.A   Bisphosphonates

    M.05.B.A.03   Pamidronic acid

    Pharmacodynamics:

    Pamidronic acid is an inhibitor of bone resorption mediated by osteoclasts. It strongly binds to calcium phosphate crystals (hydroxyapatite), preventing their dissolution in vitro. Blocking bone resorption of osteoclasts in vivo may be incomplete, and, as a minimum, is a consequence of the binding of the drug to the minerals of bone tissue.

    Pamidronic acid inhibits the migration of osteoclast initiators into bone tissue, disrupting their maturation.However, the local and direct antiresorptive effect bisfosfonagov caused by affinity to the mineral component of bone, is the most prevalent mechanism of action in vivo and in vitro.

    Biochemical changes characterizing pamidronic acid inhibitory effect on tumor-induced hypercalcemia, manifested decrease in calcium indicators and phosphates, secondary, lower urinary calcium, phosphate and hydroxyproline excretion. A dose of 90 mg provides normocalcemia in more than 90% of patients.

    Hypercalcemia may reduce the volume of extracellular fluid, and reduction of glomerular filtration capacity. By controlling hypercalcemia, pamidronic acid improves glomerular filtration and reduces elevated creatinine levels in most patients.

    In patients with bone metastases (primarily osteologic nature), malignancy, and multiple myeloma drug prevents or slows the progression of skeletal changes and their effects (hypercalcemia, fractures, need for radiation therapy and surgery, spinal cord compression) and also reduces pain in the bones.
    Pharmacokinetics:

    Pamidronic acid has a pronounced tropism in relation to calcified tissues, which are considered to be the "place of apparent elimination" of pamidronic acid.

    The concentration of pamidronic acid in plasma rapidly increases immediately after the onset of infusion and rapidly decreases after its termination. The half-life of plasma is about 0.8 hours. The equilibrium concentration is reached for more than 2-3 hours. With intravenous infusion of 60 mg of the drug lasting more than 1 hour, the maximum concentration of pamidronic acid in plasma (Cmax) is about 10 nmol / ml.

    A similar percentage (approximately 50%) of pamidronic acid is distributed in the body after the administration of different doses (30-90 mg), regardless of the duration of the infusion (4 or 24 hours). Thus, the accumulation of pamidronic acid in the bones is unlimited in quantitative terms and depends solely on the total cumulative dose. The amount of circulating pamidronic acid associated with plasma proteins is relatively low (less than 50%) and may increase with a pathological increase in the calcium concentration.

    It is believed that pamidronic acid It does not undergo biotransformation and is excreted almost exclusively by the kidneys. After intravenous administration, about 20-55% of the administered dose is detected in the urine for 72 hours unchanged. Residual fractions from the administered dose can be detected in the body. The excretion of pamidronic acid with urine is biphasic, the apparent half-lives are 1.6 and 27 hours, respectively. The total plasma and renal clearance is 88-254 ml / minute and 38-60 ml / minute, respectively. The average plasma clearance is about 180 ml / minute. The average renal clearance is 54 ml / minute. Renal clearance of pamidronic acid correlates with creatinine clearance.

    Hepatic and metabolic clearance of pamidronic acid is negligible. In connection with this, a violation of liver function does not affect the pharmacokinetics of disodium antisodium. The differences between the content of pamidronic acid in plasma in patients with normal renal function and in patients with mild or moderate renal dysfunction do not exist. In patients with severe impaired renal function (creatinine clearance 30 ml / minute), the content of pamidronate was approximately three times higher than in patients with normal renal function (creatinine clearance> 90 ml / minute).

    Indications:

    Diseases accompanied by increased activity of osteoclasts:

    - bone metastases of malignant tumors (mainly osteolytic) and myeloma (multiple myeloma);

    - hypercalcemia due to malignant tumors.

    Contraindications:

    - Hypersensitivity to pamidronic acid or other bisphosphonates, as well as to other ingredients that make up the drug.

    - Pregnancy and lactation.

    - Child age (no experience with children)

    Carefully:Impaired renal function.
    Pregnancy and lactation:

    Pregnancy

    There is insufficient data on the use of pamidronic acid during pregnancy. Clear evidence of teratogenicity in animal experiments has not been identified. Pamidronic acid may pose a risk to the fetus / newborn child due to the pharmacological effect on the exchange calcium. In studies on animals, data have been obtained that when using pamidronic acid during pregnancy, development of mineralization defects, especially of long bones, is possible, which leads to their angular deformation.

    Potential risk to humans is not established. Do not prescribe pamidronic acid during pregnancy for except for life-threatening hypercalcemia.

    Breast-feeding
    According to very limited experience of application, the concentration of pamidronic acid in human milk is below the detection limit. Moreover, due to low bioavailability of the drug for oral administration, significant absorption of pamidronic acid during breastfeeding is unlikely. Nevertheless, due to the extremely limited experience of application and the potential ability of pamidronic acid to have a significant effect on the mineralization of bones during the treatment period breastfeeding is not recommended.
    Dosing and Administration:

    Intravenously in the form of infusion. The infusion rate should not exceed 60 mg / h (1 mg / min). Avoid extravasation.

    Use in adults and elderly patients:

    Bone metastases of malignant tumors (mainly osteolytic) and myeloma. The recommended dose of Pamidronate Medac is 90 mg, once every 4 weeks.This dose can also be administered at a 3-week interval if there is a need for synchronization with chemotherapy. With bone metastases of malignant tumors, the drug is administered as a 2-hour infusion. In osteolytic bone lesions with multiple myeloma, the drug is injected into 500 ml of the solution as a 4 hour infusion.

    Hypercalcemia caused by malignant tumors. Before starting the use of pamidronate medaka or during therapy, it is recommended to rehydrate the patient with a 0.9% solution Mr.atria of chloride. The total exchange dose of Pamidronate Medac depends on the initial level of calcium in the patient's serum. The following guidelines are designed for uncorrected concentrations of calcium in the blood serum.

    The baseline level of calcium inRecommendedConcentration
    blood serumtotal dosesolution for
    pamidronicinfusion
    acids
    mmol / l(mg /%) (mg / 100 ml)(mg)mg / ml
    <3,0<12,015-3030/125
    3.0-3,512,0-14,030-6030/125 60/250
    3,5-4,014,0-16,060-9060/250 90/500
    >4.0>16,09090/500

    The total dose of Pamidronate Medac can be prescribed both as a single infusion, and as a few infusions for 2-4 consecutive days. The maximum exchange rate is 90 mg, for both primary therapy and repeated courses. Higher doses do not improve the clinical response to therapy.An especially noticeable decrease in the serum calcium level is observed 24-48 hours after the administration of Pamidronate medaka. Normalization occurs on the 3rd-7th day. In the event that the normal level of calcium in the blood is not reached during this period, it is possible to re-administer the drug. The duration of the clinical response may vary in different patients. With the resumption of hypercalcemia, repeated courses of therapy with pamidronate medak are performed. With an increase in the number of courses of therapy with pamidronate medak, the effectiveness of the drug may decrease.

    Use in patients with impaired renal function

    Pamidronate medac should not be given to patients with severe renal insufficiency (creatinine clearance less than 30 ml / min.), Except in cases of life-threatening hypercalcemia, if the potential benefit of therapy exceeds the risk of possible complications.

    At weakly expressed (creatinine clearance of 61-90 ml / min.) And moderately expressed (creatinine clearance of 30-60 ml / min.) Renal failure correction of the dose is not required. The speed of the drug administered in these cases should not exceed 90 mg / 4 hours (approximately 20-22 mg / h).

    When there are signs of impaired renal function,The appointment of pamidronate medaka should be reversed until the kidney function is restored (exceeding the creatinine concentration by no more than 10% of the baseline level).

    Use in patients with impaired liver function

    For patients with mild and moderate impairment of the function of liver correction, the dosage regimen of the drug is not required.

    Data on the clinical use of pamidronic acid in patients with severe hepatic insufficiency are currently lacking.

    Rules of preparation of infusion solution.

    Before use, the contents of the vial should be diluted with a solution that does not contain calcium (5% dextrose solution or 0.9% sodium chloride solution). The concentration of pamidronate medac in the infusion solution should not exceed 90 mg / 250 ml.

    Before use, the prepared solution must be thoroughly inspected for the absence of foreign particles and suspensions.

    Side effects:

    Side effects of pamidronic acid are usually mild and transient. The most common side effects are asymptomatic hypocalcemia, influenza-like symptoms and low-grade fever (1-2 ° C increase in body temperature), usually developing in the first 48 hours after the infusion of the drug.Subfebrile temperature is transient and does not require special treatment.

    Usually influenza-like reactions are observed only with the first application of pamidronic acid. Reactions at the site of administration are frequent (≥ 1/100, <1/10), especially when infusing the maximum doses of the drug. The incidence of side effects: 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), the frequency can not be estimated (the frequency can not be determined based on the data already available).

    On the part of the hematopoiesis system: often - anemia, thrombocytopenia, lymphocytopenia; it is very rare that it is lenient.

    From the immune system: infrequently - reactions of hypersensitivity, including anaphylactic reactions, bronchospasm, dyspnea, Quincke's edema (angioedema); very rarely - anaphylactic shock, reactivation of viruses herpes simplex and herpes zoster.

    From the nervous system: often - clinical manifestations of gipocalcemia (paresthesia, tetany, muscle spasm), headache; insomnia, increased drowsiness; infrequently - epileptic seizures, anxiety, dizziness, retardation; very rarely - signs of confusion, visual hallucinations.

    From the side of the organ of vision: often - conjunctivitis, infrequently - uveitis (iritis, iridocyclitis); very rarely - scleritis, episcleritis, xantopsy (vision in yellow color); frequency can not be evaluated - inflammation of the orbit.

    From the respiratory system: very rarely - acute respiratory distress syndrome, interstitial lung disease.

    From the cardiovascular system: often - increased arterial pressure; infrequently - lowering blood pressure; very rarely left ventricular failure (dyspnea, pulmonary edema), congestive heart failure (peripheral edema) due to accumulation of excess fluid; frequency can not be assessed - atrial fibrillation.

    From the gastrointestinal tract: often - nausea, vomiting, anorexia, abdominal pain, diarrhea, constipation, gastritis; infrequently - dyspepsia.

    From the skin: often - a rash; infrequently itching.

    From the musculoskeletal system: often - transient pain in the bones, muscles and joints; infrequently - muscle spasms, osteonecrosis (mainly the lower jaw); rarely - atypical susceptible and diaphyseal fractures of the femur.

    From the urinary system: infrequent acute renal failure; rarely - focal segmental glomerulosclerosis, including collapse, nephrotic syndrome, very rarely - exacerbation of concomitant renal diseases, hematuria, renal tubular dysfunction, tubulointerstitial nephritis, glomerulonephropathy.

    Local reactions: often - pain, redness, swelling, denseness, phlebitis, thrombophlebitis at the injection site.

    From the laboratory indicators: very often hypocalcemia, hypophosphatemia; often hypokalemia, hypomagnesemia, increased serum creatinine concentration; infrequent changes in functional hepatic samples, increased urea concentration in serum; very rarely - hyperkalemia, hypernatremia.

    Other: very often - fever and flu-like symptoms accompanied by malaise, chills, increased fatigue and "hot flashes"; often - generalized pain.

    Many of the side effects listed in this section may be caused by a major medical condition.

    Overdose:

    When exceeding the recommended doses of the drug, careful monitoring of the patient's condition is necessary. The antidote is not known.With the development of clinical signs of hypocalcemia (paresthesia, tetany, pronounced decrease in blood pressure) should be an infusion of calcium gluconate.

    Interaction:

    Joint use of pamidron acids with frequently usednot with the help ofwas led by some significant interactions.

    Joint use with other bisphosphonates, antihypercalcemic drugs and calcitonin can lead to the development of hypocalcemia with pronounced clinical manifestations (paresthesia, tetany, lowering blood pressure).

    The combination of pamidronic acid with calcitonin in patients with severe hypercalcemia contributes to a more pronounced decrease in serum calcium concentration. Care should be taken when using pamidronic acid with other potentially nephrotoxic drugs.

    In patients with myeloma, combined use of pamidronic acid with thalidomide increases the risk of renal dysfunction.

    Pharmaceutical incompatibility.

    Pamidronic acid forms complexes with divalent cations,in connection with which it can not be added to solutions containing calcium. The drug should also not be mixed with other drugs.

    Special instructions:

    Therapy Pamidronate medak should be performed under the supervision of a specialist who has experience in the use of antitumor therapy.

    Pamidronate medak can not be injected intravenously, it should be administered only after preliminary dilution, by slow intravenous infusion.

    Because of the risk of developing clinically significant renal dysfunction, a single dose of Pamidronate Medac should not exceed 90 mg, and the recommended rates of dilution and the rate of administration of the drug should also be observed. Usually pamidronate medac in a dose of 90 mg in 250 ml of infusion solution is administered for 2 hours. In patients with myeloma and with hypercalcemia due to malignant tumors, the dose of Pamidronate medaca of 90 mg is diluted in 500 ml of infusion solution and administered for 4 h and more.

    In the process of treatment with pamidronate medak (before each infusion), monitoring of renal function (serum creatinine, urea) and electrolytes of serum (calcium,phosphorus).

    With worsening of renal function against the background of therapy with pamidronate medac, administration of the drug should be discontinued.

    The risk of hypocalcemia is elevated in patients who underwent surgical intervention on the thyroid gland due to concomitant hypoparathyroidism.

    In patients with anemia, leukopenia and thrombocytopenia, haematological parameters should be regularly evaluated.

    In patients suffering from heart disease, especially in elderly patients, the introduction of additional amounts of saline can lead to the appearance or strengthening of signs of heart failure (acute left ventricular or chronic). Fever (or flu-like syndrome) can also contribute to the development of this complication.

    Cases of osteonecrosis of the jaw are described in cancer patients on the background of antitumor treatment, including bisphosphonates. Risk factors for osteonecrosis of the jaw are malignant tumors, concomitant therapy (for example: chemotherapy, radiation, corticosteroids) and concomitant conditions (for example: anemia, coagulopathy, infection, predisposition to oral diseases).

    Most of the cases described were directly related to dental procedures, such as tooth extraction. Many of these patients received polychemotherapy or corticosteroids and had evidence of a local infectious inflammatory process, including osteomyelitis.

    Therapy Pamidronate medak should be preceded by an examination of the oral cavity. During treatment, these patients should, if possible, avoid invasive dental procedures. With the development of osteonecrosis of the jaw on the background of therapy with pamidronate medac, surgical treatment can provoke a worsening of the condition. Patients in need of dental treatment are offered a discontinuous course of Pamidronate medication that reduces the risk of osteonecrosis of the jaw. The treatment plan for a particular patient should be based on an individual risk / benefit ratio.

    Pamidronate medak contains sodium (0.65 mmol for 90 mg of the drug), which must be taken into account when prescribing the drug to patients on a low-salt diet.

    Women of reproductive age should apply high efficiencycontraceptive methods. Reported atypical exposuresand diaphyseal fractures of the femur on therapy bisphosphonates, predominantly patients who received long-term therapy of osteoporosis. Cross and short oblique fractures can be are localized along the entire length of the femoral bones, from a small spit to nadmaclick elevation. Occurrenceatypical fractures occurspontaneously or as a result notlarge injuries. Some patients experienced pain in the thigh or in the groinoften accompanied byX-ray signs stress fracture, weeks or months before it occurs. As fractures are often bilateralin patients with diaphysialbreakage of the femur receiving treatment with bisphosphonates, it is necessary to monitor the condition of the bone tissue of the contralateral limb. Reported a poor healing of thefractures. If you suspect the presence of atypical fractures and to obtain results of the survey should consider discontinuing bisphosphonate therapy on the basis of an estimate of the anticipated benefits of treatment to the possible risks in each individual case. Patients should be informed of the need to report any pain in the thigh or in the groin during the therapy with pamidronate medaka. If these symptoms are present, examination to identify possible damage to the integrity of bone tissue of the hip.

    Reported on the occurrence of intermittent pain in the bones, joints and / or muscles in patients receiving bisphosphonate therapy. However, such reports were infrequent. The time of onset of symptoms varied from one day to several months after the start of the drug. In most patients It was possible to reduce the severity of symptoms after discontinuation of treatment. Some patients experienced a relapse of symptoms after the resumption of the same drug or other bisphosphonate.

    Effect on the ability to drive transp. cf. and fur:During treatment it is recommended to refrain from driving vehicles and controlling mechanisms due to the risk of developing adverse reactions (dizziness and / or drowsiness) affecting the ability to concentrate attention and the speed of psychomotor reactions
    Form release / dosage:

    Concentrate for the preparation of a solution for infusions of 3 mg / ml.

    Packaging:

    For 15mg / 5ml, 30mg / 10ml, 60mg / 20ml or 90mg / 30ml in colorless glass bottles, closed with a cork made of bromobutyl rubber with aluminum rolling and plastic protective cover.

    1 bottle with instructions for use in a cardboard box.

    Storage conditions:

    At a temperature of no higher than 25 ° C in the original packaging.

    Do not freeze!

    Keep out of the reach of children!

    Shelf life:4 years.
    Terms of leave from pharmacies:On prescription
    Registration number:LSR-006190/08
    Date of registration:04.08.2008
    The owner of the registration certificate:medac GmbHmedac GmbH Germany
    Manufacturer: & nbsp
    Representation: & nbspTIRUFARM, LLCTIRUFARM, LLCRussia
    Information update date: & nbsp11.08.2015
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