Composition, form of production and packaging
Concentrate for the preparation of solution for infusions is transparent, colorless.
1 ml of 1 fl.
disodium pamidronate 3 mg 30 mg,
which corresponds to the content of pamidronic acid 2.527 mg 25.27 mg
Auxiliary substances: sodium hydroxide, hydrochloric acid, water d / u.
The bottle with the preparation is filled with nitrogen to create an inert atmosphere.
10 ml - bottles (1) - packs of cardboard.
Concentrate for the preparation of solution for infusions is transparent, colorless.
1 ml of 1 fl.
disodium pamidronate 3 mg 60 mg,
which corresponds to the content of pamidronic acid 2.527 mg 50.54 mg
Auxiliary substances: sodium hydroxide, hydrochloric acid, water d / u.
The bottle with the preparation is filled with nitrogen to create an inert atmosphere.
20 ml - bottles (1) - packs of cardboard.
Concentrate for the preparation of solution for infusions is transparent, colorless.
1 ml of 1 fl.
disodium pamidronate 3 mg 90 mg,
which corresponds to the content of pamidronic acid 2.527 mg 75.81 mg
Auxiliary substances: sodium hydroxide, hydrochloric acid, water d / u.
The bottle with the preparation is filled with nitrogen to create an inert atmosphere.
30 ml - bottles (1) - packs of cardboard.
Concentrate for the preparation of solution for infusions is transparent, colorless.
1 ml of 1 fl.
disodium pamidronate 3 mg 15 mg,
which corresponds to the content of pamidronic acid 2.527 mg 12.635 mg
Auxiliary substances: sodium hydroxide, hydrochloric acid, water d / u.
The bottle with the preparation is filled with nitrogen to create an inert atmosphere.
5 ml - bottles (1) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2012.
PHARMACHOLOGIC EFFECT
Pamidronic acid is an inhibitor of bone resorption mediated by osteoclasts. It strongly binds to calcium phosphate crystals (hydroxyapatite), preventing their dissolution in vitro. Blockage of bone resorption by osteoclasts in vivo may be incomplete, and, as a minimum, is a consequence of binding of the drug to bone mineral.
Pamidronic acid inhibits the migration of osteoclast precursors into bone tissue, disrupting their maturation. However, the local and direct antiresorptive effect of bisphosphonates, due to the affinity for the mineral components of the bone, is the prevailing mechanism of action in vivo and in vitro.
Biochemical changes that characterize the oppressive effect of pamidronic acid on tumor induced hypercalcemia are manifested by a decrease in calcium, phosphate and, second, by a decrease in the excretion of calcium, phosphate and hydroxyproline in the urine. A dose of 90 mg provides normocalcemia in more than 90% of patients.
Hypercalcemia can lead to a decrease in the volume of extracellular fluid and a decrease in the volume of glomerular filtration. By controlling hypercalcemia, pamidronic acid improves glomerular filtration and reduces elevated creatinine in most patients.
In patients with bone metastases (mostly osteolytic) of malignant tumors and myeloma, the drug prevents or slows the progression of skeletal changes and their consequences (hypercalcemia, fractures, the need for radiotherapy and surgical interventions, compression of the spinal cord), and also reduces bone pain.
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. T 1/2 from blood plasma is about 0.8 hours. Equilibrium concentration is reached for more than 2-3 hours. With intravenous infusion of 60 mg of the drug lasting more than 1 hour,Cmax of pamidronic acid in plasma 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 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 urine for 72 hours in unchanged form. 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 / min and 38-60 ml / min, respectively. On average, the plasma clearance is about 180 ml / min. The average renal clearance is 54 ml / min. Renal clearance of pamidronic acid correlates with creatinine clearance. Hepatic and metabolic clearance of pamidronic acid is negligible. In this regard, a violation of the liver does not affect the pharmacokinetics of disodium nitrite. 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 impairment of renal function (creatinine clearance 30 ml / min), the content of pamidronate was approximately three times higher than in patients with normal renal function (creatinine clearance> 90 ml / min).
INDICATIONS
Diseases accompanied by increased activity of osteoclasts:
- Bone metastases of malignant tumors (mainly osteolytic) and myeloma (multiple myeloma);
- hypercalcemia caused by malignant tumors.
DOSING MODE
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 of sodium 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.
Baseline calcium in Recommended Concentration
serum total dose of solution for
pamidron infusion
acids
mmol / l (mg /%) (mg / 100 ml) (mg) mg / ml
<3.0 <12.0 15-30 30/125
3.0-3.5 12.0-14.0 30-60 30/125 60/250
3.5-4.0 14.0-16.0 60-90 60/250 90/500
> 4.0> 16.0 90 90/500
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.
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).
For patients with mild and moderate impairment of liver function, no correction of the dosage regimen is 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 EFFECT
Side effects of pamidronic acid are usually mild and transient. The most common side effects are flu-like symptoms and low-grade fever (1-2 В° C increase in body temperature), usually developing in the first 48 hours after the infusion of the drug. Clinically pronounced hypocalcemia is very rare.
The frequency 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).
From the hemopoietic system: often - lymphocytopenia; infrequently - anemia, leukopenia; very rarely - thrombocytopenia.
On the part of the immune system: infrequently - hypersensitivity, including anaphylactic reactions, bronchospasm, dyspnea, angioedema; very rarely - anaphylactic shock, reactivation of viruses herpessimplex and herpeszoster.
From the nervous system: often - headache; infrequent - agitation, signs of confusion, dizziness, insomnia, increased drowsiness, retardation; very rarely - epileptic seizures, visual hallucinations, clinical manifestations of hypocalcemia (paresthesia, tetany, muscle spasm).
On the part of the organs of vision: infrequently - uveitis (iritis, iridocyclitis), scleritis, episcleritis, conjunctivitis; very rarely xanthopsy (vision in yellow color), orbital inflammation.
From the cardiovascular system: infrequently - increased blood pressure; very rarely - lowering blood pressure, exacerbation of heart disease (left ventricular failure / heart failure), accompanied by shortness of breath, swelling of the lungs due to the accumulation of excess fluid.
From the digestive tract: often - nausea, vomiting; infrequently - abdominal pain, anorexia, diarrhea, constipation, indigestion; very rarely - gastritis.
From the skin: rarely - rash, itching.
From the musculoskeletal system: often - transient pain in the bones, arthralgia, myalgia: infrequently - muscle spasms; rarely - osteonecrosis involving the bones of the jaw.
From the side of the urinary system: rarely - local segmental glomerulosclerosis, including the collaptoid variant, nephrotic syndrome, glomerulonephropathy, tubulointerstitial nephritis; very rarely - exacerbation of concomitant kidney disease, hematuria, acute renal failure.
Local reactions: often - pain, redness, swelling, denseness, phlebitis, thrombophlebitis at the site of injection.
From the laboratory indicators: very often - hypocalcemia, hypophosphatemia; often - hypomagnesemia, increased serum creatinine concentration; infrequently - hypokalemia, hyperkalemia, hypernatremia, changes in functional hepatic samples, increased urea concentration in blood serum; very rarely - hypernatremia with signs of confusion.
Other: very often - fever and flu-like symptoms, accompanied by malaise, chills, increased fatigue and hot flashes.
CONTRAINDICATIONS
- Hypersensitivity to pamidronic acid or other bisphosphonates, as well as to other ingredients that make up the drug;
- pregnancy and the period of breastfeeding;
- Children's age (experience with children is absent).
With caution: impaired renal function.
PREGNANCY AND LACTATION
Contraindicated in pregnancy and during lactation.
APPLICATION FOR FUNCTIONS OF THE LIVER
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).
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
For patients with mild and moderate impairment of liver function, no correction of the dosage regimen is required.
Data on the clinical use of pamidronic acid in patients with severe hepatic insufficiency are currently lacking.
APPLICATION FOR CHILDREN
Contraindicated in childhood (no experience in children).
APPLICATION IN ELDERLY PATIENTS
The application is possible according to the dosing regimen.
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 (determination of serum creatinine and urea concentrations) and serum electrolytes (calcium, phosphorus) is necessary.
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.
Impact on the ability to drive vehicles and manage mechanisms
Patients should be warned about the possibility of appearing during medication with Pamidronate medaka increased drowsiness and / or dizziness. If these symptoms occur, patients are advised to refrain from driving and practicing other potentially hazardous activities that require 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 symptoms of hypocalcemia (paresthesia, tetany, marked reduction of blood pressure) should hold infusion of calcium gluconate.
DRUG INTERACTION
The combined use of pamidronate with commonly used antitumor agents has not been accompanied by any significant interactions. Combined use with other bisphosphonates, antigiperkaltsiemicheskimi kaltsiotoninom drugs and can lead to severe hypocalcaemia with clinical manifestations (paresthesias, tetany, hypotension). Combination with pamidronate kaltsiotoninom mithramycin and in patients with severe hypercalcemia contributes to a more pronounced reduction of calcium. Care must be taken while applying a pamidronic acid other potentially nephrotoxic drugs.
In patients with multiple myeloma when used together with pamidronate tolbutamidom increases the risk of renal dysfunction.
Pharmaceutical incompatibility. Pamidronic acid forms complexes with divalent cations, and therefore it can not be added to the solutions containing calcium. The drug also can not be mixed with other drugs.
TERMS OF RELEASE FROM PHARMACY
On prescription.
TERMS AND CONDITIONS OF STORAGE
Store at a temperature not higher than 25 В° C in the reach of children in the original packaging. Do not freeze!
Shelf life - 3 years.
Do not use beyond the expiration date printed on the package.
