Buy sustanon 250
Receptors located on the main surface of parathyroid cells, are the main regulators of secretion of parathyroid hormone (PTH). Tsinakaltset has calcimimetic activity, reducing the concentration of PTH directly, increasing the sensitivity of the receptor to the extracellular calcium.
Reduction of PTH concentration buy sustanon 250 is accompanied by a decrease in calcium content in the blood serum. Reduction of PTH concentration correlates with the concentration tsinakaltseta. After reaching equilibrium state in serum calcium concentration remains at a constant level throughout the dosing interval of the drug.
Three clinical trials of six months (double-blind, placebo-controlled) included patients with end-stage renal disease on dialysis with uncontrolled form of secondary hyperparathyroidism (1136 patients). Patients taking tsinakaltset, there was a significant reduction in the concentration of intact PTH, calcium, phosphorus and serum calcium-phosphate product (Ca × R) compared to placebo in patients who received conventional therapy.
Reduced concentration iGTTG and Ca × P maintained throughout 12 months of therapy. Tsinakaltset reduced concentration iPTH, calcium and phosphorus and Ca × P, regardless of the initial concentrations iPTH or Ca × P dialysis mode (peritoneal dialysis as compared to hemodialysis), duration of dialysis, and whether or not the applied vitamin D.
Reducing the concentration of PTH associated with insignificant decrease bone turnover markers concentrations (bone specific alkaline phosphatase, N-telopeptides of bone turnover and bone fibrosis). A retrospective analysis of the data pool collected for the 6 and 12-month clinical trials, using buy sustanon 250 Kaplan-Meier method. parameters of bone fractures and parathyroidectomy were lower in the group tsinakaltseta comparison with the control group.
Preliminary studies in patients with chronic kidney disease (CKD) and secondary hyperparathyroidism. not on dialysis indicate that PTH concentration tsinakaltset reduced similarly as in patients diagnosed with end-stage renal failure (TSPN) and secondary hyperparathyroidism. on dialysis.
However, for patients with renal failure in the pre-dialysis step were not established the efficacy, safety, dosage and optimum therapy targets. These studies have shown that patients with CKD not on dialysis and receiving tsinakaltset, there is a greater risk of developing hypocalcemia compared to dialysis patients with end-stage renal disease receiving tsinakaltset that may be due to a lower initial concentration of calcium and / or residual renal function.
Mimpara after oral administration of the drug. the maximum concentration (C max ) tsinakaltseta plasma levels achieved after approximately 2-6 hours. Tsinakaltseta absolute bioavailability in the fasting state, established on the basis of comparing the results of different studies was approximately 20-25%. When taken with food tsinakaltseta, its bioavailability is increased by about 50-80%. Such an increase tsinakaltseta plasma concentration was observed regardless of the fat content in food. At dosages of 200 mg saturation absorption is observed, probably due to poor solubility.
There is a high volume of distribution (approximately 1000 liters), which indicates a broad distribution. Tsinakaltset approximately 97% bound to plasma proteins and is distributed at the minimum level in the erythrocytes.
After absorption, decreased tsinakaltseta concentration occurs in two steps with an initial half-life of about 6 hours and final half-life of 30 to 40 hours. The equilibrium state tsinakaltseta concentration is achieved within 7 days with minimal cumulation.
Pharmacokinetic parameters tsinakaltseta not change with time.
Tsinakaltset buy sustanon 250 metabolized by a group of clinical methods). The main circulating metabolites are inactive. According to studies in vitro, , tsinakaltset is a potent inhibitor of CYP2D6, but at concentrations reached in the clinical setting, tsinakaltset does not inhibit the activity of other enzymes CYP. including CYP1A2, CYP2C8, CYP2C9, CYP2C19, and CYP3A4, and also is not an inducer of CYP1A2, CYP2C19H, CYP3A4.
After the introduction of healthy volunteers 75 mg labeled dose radioisotope method tsinakaltset subjected to rapid and substantial oxidative metabolism, followed by conjugation. Excretion of radioactivity was mainly due to renal excretion of metabolites.
Approximately 80% of the injected dose detected in the urine and 15% in feces.
Linearity / non-linearity
Increasing the area under the curve “concentration-time» (AUC) and C max tsinakaltseta occurs almost linearly with dosage range 30-180 mg once a day.
Pharmacokinetic / pharmacodynamic interaction
Soon after the introduction of tsinakaltseta, PTH begins to decrease; wherein the maximum decrease occurs after about 2-6 hours after administration, which corresponds tsinakaltseta maximum concentration (C max ). Thereafter tsinakaltseta concentration starts to decrease and the concentration of PTH increases within 12 hours after dosing, and then PTH suppression remains approximately the same level until the end of the daily dosing regimen while the interval once a day. Concentration of PTH in clinical drug trials Mimpara measured at the end of the dosing interval.
Elderly: pharmacokinetics tsinakaltseta no clinically significant differences related to patient age.
pharmacokinetic profile tsinakaltseta in renal failure mild, moderate and severe, and hemodialysis or peritoneal dialysis is comparable to the pharmacokinetic profile of the drug in healthy volunteers.
– Hepatic impairment: pechenochnayanedostatochnost mild has no significant effect on the pharmacokinetics tsinakaltseta. Compared with the group with normal hepatic function tsinakaltseta average AUC were approximately twice as high in the group with moderate hepatic impairment, and approximately 4-fold higher with severe liver failure. The average half-life tsinakaltseta in patients with moderate and severe hepatic insufficiency, prolonged by 33% and 70%. Liver failure does not affect the binding of proteins tsinakaltseta. Since the selection of doses is carried out on the basis of the parameters of efficacy and safety in patients with hepatic impairment is not required to conduct additional dose adjustment (see. Sections “Dosage and administration”, “Special instructions and precautions”).
Gender: tsinakaltseta clearance may be lower in women than in men. Since the selection of doses are individually not required additional dose correction according to the sex of the patient.
Children: the pharmacokinetics tsinakaltseta has been studied in 12 children (6-17 years) with CKD who are on dialysis, after a single oral dose of 15 mg. The average values of AUC and C max (23.5 (range 7.22 to 77.2) ng * hr / mL and 7.26 (range 1.80 to 17.4) ng / mL, respectively) were within approximately 30 % mean values AUC and C max observed in one study in healthy adults after a single oral dose of 30 mg (33.6 (range 4.75 to 66.9) ng * h / mL and 5.42 (range 1.41 to 12.7) ng / ml, respectively). Due to limited data in children does not exclude potentially more severe exposure tsinakaltseta certain dose in young children, with less weight compared to older children, having more body weight. The pharmacokinetics of repeated doses in children has not been studied.
Smoking: tsinakaltseta clearance is higher in smokers than in metabolism, passing with the participation of CYP1A2. If a patient stops or starts smoking during therapy, tsinakaltseta concentration in plasma may change and may require dose adjustment.
Preclinical safety studies
Preclinical studies did not reveal any genotoxic. no carcinogenic potential tsinakaltseta. Safe range. According to toxicological studies it is quite narrow since in experiments on animals was dose-limiting factor gipokaltsiemnya. The development of cataracts and cataract were observed during the toxicological and carcinogenicity studies in rodents with repeated dosing. However, such phenomena have been observed in experiments on dogs or monkeys or in clinical trials where the monitoring was conducted in relation to cataract formation. It is known that rodents cataracts can occur as a result of hypocalcaemia.
Indications for use:
- Treatment of secondary hyperparathyroidism in patients with end-stage renal disease on dialysis. Mimpara may also be administered as part of combination therapy including agents that bind phosphate and / or vitamin D.
- Reduction of hypercalcemia in patients with parathyroid carcinoma.
- Hypersensitivity to the active component or any other components of the preparation.
- Children under 18 years old.
Use during pregnancy and breast-feeding
Clinical data on the use tsinakaltseta in pregnancy. As shown preclinical studies on rabbits, tsinakaltset crosses the placental barrier. In animal experiments found no direct negative impact on the course of pregnancy, childbirth or postnatal development. There was also revealed no embryotoxic or teratogenic effects in experiments on pregnant female rats and rabbits, except for the germ reduction in body weight in rats using toxic doses in pregnant females. In pregnancy, the drug Mimpara should be used only in cases where the potential benefit justifies the potential risk to the fetus.
is not explored tsinakaltseta excretion in breast milk Until now. Tsinakaltset appears in the breast milk of lactating rats, while there is a high concentration ratio of milk to plasma concentrations. After careful evaluation of risk / benefit ratio should decide to discontinue breastfeeding or receiving Mimpara preparation.
Dosage and administration:
For oral administration. The drug is recommended Mimpara be taken with food or shortly after ingestion of food, since during the study showed that increases bioavailability tsinakaltseta while taking the drug with meals (see., “Pharmacokinetic Properties”).
The tablets should be taken as a whole, without dividing them.
In the treatment of patients with hepatic impairment, the starting dose is not required to change. The drug Mimpara should be taken with caution to patients suffering from liver failure in the moderate and severe forms. It should be carefully monitored for treatment during dose titration and long-term therapy (see. “Special instructions and precautions”, “Pharmacokinetic properties”).
Adults and elderly (> 65 years)
The recommended starting dose for adults Mimpara drug is 30 mg once a day. Mimpara dose titration should be performed every 2-4 weeks to a maximum dose of 180 mg (once per day), in which in dialysis patients achieved the required level of PTH in the range of 150-300 pg / ml (15.9-31.8 pmol / L) defined the content of iPTH. PTH level analysis should be conducted no earlier than 12 hours after taking the drug Mimpara. In assessing the level of PTH should adhere to current guidelines.
Measurement of PTH levels should be performed 1-4 weeks after initiation of therapy and dose adjustment I Mimpara preparation When receiving a maintenance dose, monitoring ^ PTH levels should be carried out approximately every 1-3 months. For PTH level measurement, you can use the content of iPTH or biointaktnogo PTH (biPTG); therapy with Mimpara does not alter the relation between iPTH and biPTG. Information about famakokineticheskom / pharmacodynamic (PK / PD) profile tsinakaltseta see Pharmacodynamic properties.
During titration often necessary to carry out monitoring of the level of calcium in blood serum, including 1 week after initiating therapy or dose adjustments buy sustanon 250 drug. Upon reaching a maintenance dose, serum calcium levels should be measured about once a month. If serum calcium levels decrease below the normal range, appropriate steps should be taken (see. “Special instructions and precautions”).Concomitant therapy using drugs bind phosphate and / or Vitamin D, should be adjusted as needed.
Carcinoma of the parathyroid glands
Adults and elderly (> 65 years)
The recommended starting dose of Mimpara preparation for adults is 30 mg, the multiplicity of reception: twice a day. Mimpara dose titration should be performed every 2-4 weeks following sequence changes dosage: 30 mg twice daily, 60 mg twice daily, 90 mg twice daily and 90 mg three or four times daily as needed to reduce calcium concentration in the serum to an upper limit of the normal range or below this level. The maximum dose is used in clinical studies was 90 mg for the multiplicity of receiving four times a day. calcium levels in serum should be measured within 1 week after initiation of therapy and dose adjustment of Mimpara preparation. Upon reaching a maintenance dose, serum calcium levels should be measured every 2-3 months. After titration to the maximum dose of the drug dosage Mimpara, periodic monitoring of calcium levels in serum should be carried out; if you can not maintain a clinically significant reduction in the level of calcium in the blood serum, should decide on the termination of therapy with Mimpara ( “Pharmacodynamic properties” see.).
Metabolic disorders and eating
Disorders of the nervous system
Common: dizziness, paraesthesia.
Disorders of the gastrointestinal tract
Very common: nausea, vomiting.
Sometimes: dyspepsia, diarrhea.
Disorders of the skin and subcutaneous tissue disorders
Violations of the skeletal muscle, connective tissue and bone
General disorders and reactions to the drug
Common: hypocalcaemia (see section “Special instructions and precautions.”), Reduced testosterone levels (see section “Special instructions and precautions.”).
Carcinoma of the parathyroid glands
The safety profile of Mimpara in this patient population is generally consistent with the picture, ^ observed in patients suffering from chronic kidney disease. In this population of patients with the most common side effects were nausea and vomiting.
In patients with heart failure and receiving tsinakaltset during post-marketing studies, individual recorded idiosyncratic cases of hypotension and / or worsening heart failure.
Doses were titrated to a level of 300 mg (once a day), safe for patients who are on dialysis.
Overdose drug Mimpara may lead to hypocalcaemia. In case of overdose, patients should be monitored signs and symptoms of hypocalcemia. There should be symptomatic and supportive therapy. Since the degree of binding with proteins tsinakaltseta high, hemodialysis is not an effective therapeutic approach in overdose.
Interaction with other drugs
Effect of other drugs on tsinakaltset
Tsinakaltset partly metabolized by CYP3A4 enzyme. Simultaneous administration of ketoconazole 200 mg twice daily (expressed inhibitor of CYP3A4) resulted in increased levels tsinakaltseta about 2 times.You may need a dose adjustment drug Mimpara if the patient during therapy starts or stops taking a potent inhibitor (eg, ketoconazole, itraconazole, telithromycin, voriconazole, ritonavir) or inducer activity of this enzyme (eg rifampicin) (see. “Special instructions and precautions “)
The data obtained in the experiments in vitro suggest that tsinakaltset partially metabolized CYP1A2 enzyme.
Smoking stimuliruetaktivnost CYP1A2; it was noted that tsinakaltseta clearance at 36-38% higher in smokers than non-smokers. The effect of CYP1A2 inhibitors (fluvoxamine, ciprofloxacin) on tsinakaltseta levels has not been studied in plasma. You may need a dosage adjustment if during therapy with Mimpara patient starts or stops smoking or begins, or ceases to simultaneous reception of powerful SYP1A2 inhibitors.
Calcium carbonate: Concomitant use of calcium carbonate (1500 mg single dose) did not alter the pharmacokinetics of tsinakaltseta.
Sevelamer: Concomitant use of sevelamer (2400 mg three times daily) had no effect on the pharmacokinetics of tsinakaltseta.
Pantoprazole: Concomitant use of pantoprazole (80 mg once daily) did not alter the pharmacokinetics of tsinakaltseta.
tsinakaltseta effect on other drugs
Medicinal products metabolised by the enzyme P450 2D6 (CYP2D6): Tsinakaltset is a potent inhibitor of CYP2D6. You may need a dose adjustment of drugs while taking a drug Mimpara if such funds are predominantly metabolized of CYP2D6, have a narrow therapeutic index and require individual selection of doses (eg, flecainide, propafenone, metoprolol (appointed in heart failure), desipramine, nortriptyline, clomipramine ). (See. “Special instructions and precautions”)
Desipramine: Simultaneous administration dose of 90 mg tsinakaltseta once daily with 50 i desipramine, tricyclic antidepressants, predominantly metabolising CYP2D6, significantly increased the level of exposure to desipramine (3.6 times) (90% CI 3, 4.4) in patients with active metabolism of CYP2D6.
Warfarin: Multiple oral tsinakaltseta did not affect the pharmacokinetics or pharmacodynamics of warfarin (measured by prothrombin time and factor VII clotting).
Tsinakaltseta no effect on the pharmacokinetics of R- and S- warfarin and lack of autoinduction enzymes in patients following multiple dosing indicates that the inducer is not tsinakaltset CYP3A4, CYP1A2 or CYP2C9 in humans.
Special instructions and precautions
In clinical studies seizures were observed in 1.4% of patients receiving Mimpara preparation and in 0.7% of patients in the placebo group. Although the reasons for the reported difference in the appearance of seizures is unclear, the seizure threshold is lowered with a significant decrease in the concentration of calcium in the blood serum.
Hypotension and / or worsening heart failure
in patients with heart failure, taking tsinakaltset during postmarketing observations, recorded some idiosyncratic cases of hypotension and / or worsening of heart failure, in which a causal relationship to tsinakaltsetom can not be completely excluded and may be due to a decrease in calcium concentration in the serum. Data from clinical studies showed that hypotension occurred in 7% of patients treated with tsinakaltset and 12% of placebo-treated patients, and heart failure – in 2% of patients receiving placebo or tsinakaltset.
Treatment with Mimpara should not be carried out at a calcium concentration in serum (corrected for albumin) below the lower limit of the normal range. Since tsinakaltset lowers calcium concentration in the serum, you must be closely monitored with regard to the development of hypocalcemia (see. “Dosage and Administration” section). Patients diagnosed with CKD who are on dialysis, Mimpara when taking the drug. calcium concentration in the serum was 4% less than 7.5 mg / dL (1.875 mmol / L). In the case of hypocalcemia, increase of calcium concentration in the serum can be used fosfagevyazyvayuschie calcium-containing drugs, vitamin D and / or carry out the correction of calcium concentration in the dialysis solution.
When stable hypocalcemia should reduce the dose or stop taking Mimpara. Potential symptoms of hypocalcemia may be paresthesia, myalgia, cramps and tetany. Tsinakaltset not indicated for patients diagnosed with CKD not on dialysis.
Preliminary studies have shown that patients diagnosed with CKD not on dialysis increases the risk of hypocalcemia (concentration of serum calcium <8.4 mg / dL [2.1 mmol / L]) as compared with patients on dialysis, which can be due to the lower initial concentration of calcium and / or presence of residual renal function.
In chronic suppression of PTH concentration below the concentration of about 1.5 on the upper limit of normal for the results of the analysis of iPTH, adynamic bone disease. If PTH concentration falls below the recommended range, you should reduce the dose of Mimpara and / or of vitamin D, or to discontinue therapy.
testosterone concentration is often below the normal range in patients with end-stage renal failure. Data from clinical trials, which included patients with and those on TSPN diatize showed that free testosterone concentration was reduced by an average of 31.3% in patients taking the drug buy sustanon 250 and 16.3% of patients in the placebo group at 6 months after initiation of therapy. Open prolonged phase of this study showed no further decrease in the concentration of free and total testosterone in patients over a 3-year period of treatment with Mimpara. The clinical significance of reducing serum testosterone concentrations has not been established.
The drug should be used with caution in patients with hepatic insufficiency, moderate and severe (for the Child-Pugh classification). tsinakaltseta as plasma concentrations may be 2-4 times higher, should be closely monitored during treatment (see. sections “Dosage and administration”, “Pharmacokinetic properties”).
Clinical evidence tsinakaltseta exposure on fertility are not available. Animal experiments showed no effect on fertility.
Mimpara contains lactose as excipient (each tablet contains 30 mg of lactose 2.74 mg, each tablet contains 60 mg of lactose 5.47 mg, each tablet contains 90 mg 8.21 mg Lactose). Patients with rare hereditary galactose intolerance, Lapp lactase deficiency or malabsorption glyukogalaktozy should not take the drug.
Effects on ability to drive vehicles, machinery
Studies on the effect of the drug on the ability to drive or work not carried out with complex mechanisms. However, certain adverse reactions may affect the ability to drive or operate complex mechanisms (see. “Side effects” section).