Composition, form of production and packaging
Concentrate for the preparation of a solution for infusions in the form of a transparent, colorless liquid.
1 ml of 1 fl.
disodium pamidronate 6 mg 60 mg
Auxiliary substances: mannitol, water d / and.
10 ml - bottles (1) - packs of cardboard.
Concentrate for the preparation of a solution for infusions in the form of a transparent, colorless liquid.
1 ml of 1 fl.
disodium pamidronate 9 mg 90 mg
Auxiliary substances: mannitol, water d / and.
10 ml - bottles (1) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
The product description was approved by the manufacturer for the 2009 print edition.
PHARMACHOLOGIC EFFECT
Pamidronic acid is an inhibitor of bone resorption mediated by osteoclasts. Pamidronic acid forms a stable compound with crystals of hydroxyapatite of bone tissue and inhibits the dissolution of these crystals in vitro. It is believed that in vivo inhibition of bone resorption can, at least in part, be explained by the binding of pamidronic acid to minerals. Pamidronic acid inhibits the entry of osteoclast precursors into bone tissue and their subsequent transformation into mature osteoclasts responsible for the resorption of this tissue.
In patients with malignant neoplasms, pamidronic acid suppresses osteolysis and in the presence of tumor-induced hypercalcemia, reduces serum levels of calcium and phosphorus and reduces their excretion, as well as the excretion of hydroxyproline in the urine.
The drug, reducing the severity of hypercalcemia, increases the rate of glomerular filtration, which in most patients is accompanied by a decrease in the initially elevated serum creatinine concentration.
PHARMACOKINETICS
Pamidronic acid has a high affinity for calcified tissues, which are considered the "place of apparent elimination" of pamidronic acid.
After the start of infusion, the concentration of pamidronic acid in the blood plasma increases rapidly, and at the end of the infusion, it also decreases rapidly. The apparent T 1/2 of the pamidronic acid in plasma is about 0.8 hours. Therefore, the equilibrium concentration of pamidronic acid is reached with an infusion time of more than 2-3 hours. Cumulation of pamidronic acid in bone tissue is not limited by the volume of this tissue, but depends solely on the total dose of the drug administered.
The binding of circulating pamidronic acid to plasma proteins is about 54% and increases when the upper limit of the normal value of the calcium concentration in the blood is exceeded.
It is believed that pamidronic acid does not undergo biotransformation and is excreted almost exclusively by the kidneys. After intravenous infusion, approximately 20-55% of the administered dose of pamidronic acid is detected in the urine for 72 hours unchanged. The remaining amount is retained in the body for an indefinitely long time. The excretion of pamidronic acid with urine biphasic, the apparent T 1/2 are 1.6 and 27 h, respectively,
When the liver function was abnormal, the mean AUC (39.7%) and C max (28.6%) were higher. Nevertheless, pamidronic acid was still as quickly removed from the plasma. After 12-36 h after the infusion, the drug was not detected in the plasma. Since the drug is used only 1 time / month, cumulation of pamidronic acid does not occur.
With significant violations of kidney function (QC <30 ml / min), the average value of AUC increases approximately 3-fold. Although the rate of excretion of pamidronic acid decreases as a function of CC, the total amount of pamidronic acid excreted by the kidneys does not change significantly.
INDICATIONS
- hypercalcemia caused by malignant tumors;
- diseases accompanied by increased activity of osteoclasts: bone metastases of malignant tumors (mainly osteolytic) and multiple myeloma;
- Paget's bone disease.
DOSING MODE
The drug is administered iv in the form of infusion with a rate of administration of not more than 1 mg / min.
In adults and elderly patients with hypercalcemia caused by malignant tumors, it is recommended to rehydrate the patient with a 0.9% solution of sodium chloride before starting Pomegra or during therapy. The total dose of Pomgana used during the course of treatment depends on the initial level of calcium in the patient's serum. Below in the table are recommendations on the choice of the required dose of pamidronic acid depending on the values ​​of calcium concentration in the blood serum.
Baseline calcium level in blood Recommended total dose of pamidronic acid (mg)
(mmol / L) (mg%)
not more than 3 not more than 12 15-30
3-3.5 12-14 30-60
3.5-4 14-16 60-90
more than 4 - 90
The total dose of Pomegra can be administered as one time or in the form of several infusions performed within 2-4 consecutive days. The maximum course dose of the drug (for both the first and subsequent courses of treatment) is 90 mg. A significant decrease in serum calcium concentration is usually observed 24-48 hours after the administration of pamidronic acid, the normalization of this indicator is within 3-7 days. If normalization of the level of calcium in the blood within the specified time is not achieved, additional administration of the drug is possible. The duration of the preservation of the effect in individual patients is different. With the resumption of hypercalcemia, repeated courses of therapy of pamidronic acid are carried out. With an increase in the number of courses of administration, the efficacy of pamidronic acid may decrease.
In bone metastases of malignant tumors (mainly osteolytic) and myeloma, the recommended dose is 90 mg, once every 4 weeks. In patients with bone metastases of malignant tumors receiving chemotherapy at 3-week intervals, Pmegara at a dose of 90 mg may also be administered at 3-week intervals.
In the case of Paget's bone disease, the recommended total dose of Pomegary during the course of treatment is 180-210 mg. The total dose of the drug, 180 mg, can be administered either as 6 infusions (30 mg once a week) or as 3 infusions (60 mg once every 2 weeks). If the total dose is supposed to be 210 mg, then a dose of 30 mg is recommended for the first dose. This dosing regimen (but already with the initial dose of 30 mg) can be repeated 6 months before remission of the disease or in case of an exacerbation.
Pamidronic acid is not recommended for patients with severe renal dysfunction (QC less than 30 ml / min) , except in cases of life-threatening hypercalcemia, if the potential benefit of the use exceeds the risk of possible complications. In patients with lungs (KK 61-90 ml / min) or moderately (KK 30-60 ml / min) severe renal dysfunction, correction of the dosing regimen is not required. The rate of infusion of pamidronic acid in such patients should not exceed 90 mg / 4 hours (approximately 20-22 mg / h). When there are symptoms of impaired renal function, therapy with pamidronic acid should be canceled until the kidney function is restored (exceeding the creatinine concentration by no more than 10% of the baseline level).
For patients with mild and moderate impairment of liver function, no correction of the dosage regimen is required.
Rules for the preparation of an infusion solution
The contents of the vial before administration should be further diluted with a solution for infusions that do not contain calcium (for example, 0.9% sodium chloride solution or 5% dextrose solution) to a concentration not exceeding 90 mg / 250 ml.
SIDE EFFECT
Adverse reactions with pamidronic acid are usually mild and temporary. The most frequent adverse reactions are asymptomatic hypocalcemia and fever (1-2 В° C body temperature increase), usually developing in the first 48 hours after the infusion of the drug. The fever usually passes independently and does not require treatment.
Criteria for assessing the incidence of adverse events: very often (? 10%), often (from? 1% to <10%), sometimes (from? 0.1% to <1%), rarely (from? 0.01% to <0.1%), very rarely (<0.001%), including individual messages.
From the hemopoietic system: often - anemia, thrombocytopenia, lymphocytopenia; very rarely - leukopenia.
Allergic reactions: sometimes - allergic reactions, including anaphylactoid reactions, bronchospasm, dyspnoea, Quincke's edema; very rarely - anaphylactic shock.
From the nervous system: often - paresthesia, tetany (as manifestations of hypocalcemia), headache, insomnia or increased drowsiness; sometimes - cramps, agitation, dizziness; very rarely - confusion, visual hallucinations.
From the sense organs: often - conjunctivitis; sometimes - uveitis (iritis, iridocyclitis); very rarely - scleritis, episcleritis, xanthopsia (vision of objects in yellow color).
From the cardiovascular system: often - marked increase in blood pressure; sometimes - a marked decrease in blood pressure; very rarely - dyspnea, pulmonary edema (as signs of left ventricular failure), edema (as a sign of congestive heart failure) due to overload of the injected fluid.
From the digestive system: often - nausea, vomiting, anorexia, abdominal pain, diarrhea, constipation, gastritis; sometimes - dyspepsia.
Dermatological reactions: often - a rash; sometimes itching.
From the musculoskeletal system: often - transient pain in the bones, pain in the joints, myalgia; sometimes - muscle spasms.
From the side of the urinary system: sometimes - acute renal failure; rarely - focal segmental glomerulosclerosis, including the collapoid variant, nephrotic syndrome; very rarely - exacerbation of concomitant kidney disease, hematuria.
Laboratory indicators: very often - hypocalcemia, hypophosphatemia; often hypokalemia, hypomagnesemia, increased serum creatinine concentration; sometimes - changes in functional liver samples, increased urea concentration in blood serum; very rarely - hyperkalemia, hypernatremia.
Infections: very rarely - reactivation of latent viral infections (Herpes simplex, Herpes zoster).
Local reactions: often - pain, redness, swelling, denseness, phlebitis, thrombophlebitis at the site of injection.
Other: very often - fever and flu-like symptoms, sometimes accompanied by malaise, chills, fatigue and tidal flare; very rarely - the development of osteonecrosis (mainly the jaw, usually after extraction of the tooth or other dental intervention). A clear causal relationship between the development of osteonecrosis is not established.
CONTRAINDICATIONS
- Pregnancy (except for cases of hypercalcemia, life threatening);
- the period of lactation (breastfeeding);
- Children's age (no experience with children);
- Hypersensitivity to pamidronic acid or other bisphosphonates, as well as to other ingredients that make up the drug.
With caution should prescribe the drug for violations of kidney function.
PREGNANCY AND LACTATION
Clinical experience of the use of pamidronic acid in pregnant women is absent. Do not use the drug in pregnancy, except for life-threatening hypercalcemia (experimental data have not shown the teratogenic effect of pamidronic acid, as well as negative effects on reproductive function and fertility).
APPLICATION FOR FUNCTIONS OF THE LIVER
With caution should prescribe the drug for violations of kidney function.
Pamidronic acid is not recommended for patients with severe renal dysfunction (QC less than 30 ml / min) , except in cases of life-threatening hypercalcemia, if the potential benefit of the use exceeds the risk of possible complications. In patients with lungs (KK 61-90 ml / min) or moderately (KK 30-60 ml / min) severe renal dysfunction, correction of the dosing regimen is not required. The rate of infusion of pamidronic acid in such patients should not exceed 90 mg / 4 hours (approximately 20-22 mg / h). When there are symptoms of impaired renal function, therapy with pamidronic acid should be canceled until the kidney function is restored (exceeding the creatinine concentration by no more than 10% of the baseline level).
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
When the liver function was abnormal, the mean AUC (39.7%) and C max (28.6%) were higher. Nevertheless, pamidronic acid was still as quickly removed from the plasma. After 12-36 hours after the infusion, the drug was not detected in the plasma. Since the drug is used only once a month, cumulation of pamidronic acid does not occur. For patients with mild and moderate impairment of liver function, no correction of the dosage regimen is required.
APPLICATION IN ELDERLY PATIENTS
The drug is prescribed to the elderly according to the indications.
SPECIAL INSTRUCTIONS
The use of bisphosphonates, including pamidronic acid, can lead to impaired renal function. Because of the risk of developing clinically significant renal dysfunction, a single dose should not exceed 90 mg, and the recommended rates of dilution and the rate of administration of the drug should also be observed. Usually pamidronic acid in a dose of 90 mg in 250 ml of the infusion solution is administered for 2 hours. In patients with myeloma and with hypercalcemia caused by malignant tumors, a dose of pamidronic acid of 90 mg is diluted in 500 ml of infusion solution and administered for more 4 hours
During the treatment, monitoring of renal function (determination of serum creatinine concentrations before each infusion of pamidronic acid), concentration of electrolytes, calcium and phosphorus in the blood serum is necessary.
The risk of hypocalcemia is elevated in patients who underwent surgical intervention on the thyroid gland, due to latent hypoparathyroidism.
In patients with 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. Fever (or flu-like syndrome) can also contribute to the development of this complication.
In order to reduce the risk of hypocalcemia, patients with Paget's bone disease who are at increased risk of developing calcium and vitamin D deficiency should be additionally prescribed.
Despite the fact that the causal relationship of the development of osteonecrosis with the use of bisphosphonates is not clearly established when using pamidronic acid, dental procedures should be avoided.
Pamidronic acid should not be used in conjunction with other bisphosphonates, since the effects of this combination treatment have not been studied.
Impact on the ability to drive vehicles and manage mechanisms
Some side effects of the drug, such as drowsiness and / or dizziness, can adversely affect the ability to drive and perform potentially dangerous activities requiring increased concentration and speed of psychomotor reactions.
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.
DRUG INTERACTION
The combined use of pamidronic acid with frequently used antineoplastic agents was not accompanied by any significant interactions.
When combined with calcitonin in patients with severe hypercalcemia synergism of action was noted, which led to a more rapid decrease in serum calcium concentration.
Caution is necessary when concomitant administration with other drugs that have a nephrotoxic effect.
In patients with myeloma disease, when combined with tolbutamide, the risk of renal impairment increases.
Pharmaceutical interaction
Pamidronic acid can form complexes with divalent cations and therefore should not be added to intravenous solutions containing calcium (for example, with Ringer's solution).
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug should be stored out of the reach of children. Shelf life - 2 years.
