Composition, form of production and packaging
The solution for intravenous administration is colorless, transparent.
1 ml
parikaltsitol 2 mcg
Excipients: ethanol 95% - 20 g, propylene glycol - 30%, water d / and - up to 1 ml.
1 ml ampoules of colorless glass (5) of hydrolytically stable type I (Hev.Pharm.) With a break point - packs of cardboard with partitions (1) or plastic pallets - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2012.
PHARMACHOLOGIC EFFECT
A drug that regulates the exchange of calcium and phosphorus. Parikaltsitol - a synthetic analogue of biologically active vitamin D (calcitriol). Paricalcitol has a biological effect by interacting with vitamin D receptors, which leads to a selective activation of the response mediated by this vitamin. Vitamin D and paricylcytol reduce the level of parathyroid hormone by inhibiting its synthesis and secretion. In the early stages of chronic kidney disease, a decrease in the level of calcitriol is observed.
Secondary hyperparathyroidism is characterized by an increase in parathyroid hormone (PTH), which is associated with an inadequate level of active vitamin D. This vitamin is synthesized in the skin and enters the body with food. Vitamin D is sequentially hydroxylated in the liver and kidneys and turns into an active form that interacts with vitamin D receptors.
Calcitriol [1,25 (OH) 2 D 3 ] is an endogenous hormone that activates vitamin D receptors in the parathyroid glands, intestines, kidneys and bone tissue (due to this it supports parathyroid function and homeostasis of calcium and phosphorus), as well as in many other tissues, including the prostate gland, endothelium and immune cells. Activation of receptors is necessary for the normal formation of bone tissue. With kidney diseases, vitamin D activation is suppressed, which leads to an increase in PTH levels, the development of secondary hyperparathyroidism, and the disruption of calcium and phosphorus homeostasis. Decreased calcitriol levels and increased activity of PTH, which often precede changes in plasma levels of calcium and phosphorus, cause changes in the rate of bone metabolism and can lead to the development of renal osteodystrophy. In patients with chronic kidney disease, a decrease in PTH levels has a beneficial effect on bone glandular activity, metabolic processes in bone tissue, and bone tissue fibrosis. Therapy with active vitamin D not only reduces PTH levels and improves metabolic processes in bone tissue, but also helps prevent or eliminate other consequences of vitamin D deficiency.
PHARMACOKINETICS
Within two hours after intravenous bolus administration of paricalcitol in doses from 0.04 Ојg / kg to 0.24 Ојg / kg, the drug concentration decreases rapidly; However, in the subsequent concentration of the drug is reduced linearly, with an average T 1/2 of about 15 hours. When repeated application of paricalcitol, there is no evidence of cumulation.
Distribution
Parikaltsitol actively binds to plasma proteins (more than 99%). In healthy people, V d in the equilibrium state is about 23.8 liters. In patients with chronic kidney disease of stage 5 who received hemodialysis or peritoneal dialysis treatment, the V d of the paricalcitol at a dose of 0.24 Ојg / kg averages 31-35 liters. The pharmacokinetics of paricalcitol were studied in patients with chronic renal insufficiency treated with hemodialysis.
Metabolism
In urine and feces several metabolites of the drug are determined. In the urine, unchanged paricalcitol is not detected. Paricalcitol is metabolized by hepatic and non-hepatic enzymes, including mitochondrial CYP24, as well as CYP3A4 and UGT1A4. Identified metabolites include 24 (R) -hydroxylation products (in plasma at low concentrations), as well as 24,26 and 24,28-dihydroxylation and direct glucuronation. Paricalcitol has no inhibitory effect on CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A at concentrations up to 50 nM (21 ng / ml). At similar concentrations of parikilcitol, the activity of CYP2B6, CYP2C9 and CYP3A4 increases less than 2-fold.
Excretion
Paricalcitol is excreted by excretion with bile. In healthy people, approximately 63% of the drug is excreted through the intestine and 19% by the kidneys. T 1/2 ofparicalcitol when administered at doses from 0.04 to 0.16 Ојg / kg in healthy volunteers averages 5-7 hours.
Pharmacokinetics in special clinical cases
The pharmacokinetics of paricalcitol in people over the age of 65 years have not been studied.
The pharmacokinetics of paricalcitol in children and adolescents under the age of 18 years have not been studied.
The pharmacokinetics of paricylcytol do not depend on sex.
The pharmacokinetics of paricalcitol (0.24 Ојg / kg) were compared in patients with mild to moderate liver function disorder (Child-Pugh classification) and healthy people. The pharmacokinetics of unbound paracyclotol was similar in these patient groups. Correction of the dose in patients with mild or moderate impairment of liver function is not required. The pharmacokinetics of paricalcitol in patients with severe impairment of liver function has not been studied.
The pharmacokinetics of paricalcitol were studied in patients with chronic kidney disease of stage 5 who received hemodialysis or peritoneal dialysis treatment.Hemodialysis did not have a significant effect on the excretion of paricalcitol. However, in patients with chronic kidney disease of stage 5, a decrease in clearance and an increase of T 1/2 in comparison with healthy people was detected.
INDICATIONS
- prevention and treatment of secondary hyperparathyroidism, which develops in chronic renal failure (chronic kidney disease of stage 5).
DOSING MODE
Zemplar В® is usually given intravenously via a hemodialysis catheter. If the patient does not have a hemodialysis catheter, then the drug can be injected slowly IV for at least 30 seconds to minimize pain during infusion. Like other solutions for parenteral use, the ampoule with Zemplar В® should be inspected for foreign particles and discoloration before administration. Dispose of unused solution residues.
Adults
Initial dose
There are two methods for choosing the initial dose of paricylcytol. In clinical trials, the maximum safe dose reached 40 Ојg.
The choice of the initial dose by body weight
The recommended initial dose of paricalcitol is 0.04-0.1 Ојg / kg (2.8-7 Ојg). It is administered in the form of a bolus no more often than every other day during dialysis.
The choice of the initial dose taking into account the initial level of PTH
In patients with chronic renal failure (chronic kidney disease of stage 5), the second-generation method is used to analyze the level of biological active intact PTH.The initial dose is calculated according to the formula given below and injected IV in the form of a bolus no more often than every other day during dialysis:
Initial dose (Ојg) = Initial PTH level (pg / ml) / 80
Dose titration
Conventional target levels of PTH in patients with terminal renal insufficiency receiving dialysis treatment exceed ILV in patients without uremia (150-300 pg / ml) no more than 1.5-3 times. To achieve these levels, careful monitoring of the level of PTH and individual titration of the dose are necessary.
At any dose changes, serum calcium levels (adjusted for hypoalbuminemia) and phosphorus should be more often determined. If the corrected calcium level (> 11.2 mg / dL) or a persistent increase in phosphorus concentration (> 6.5 mg / dl) is reached, the dose of the drug should be reduced until these parameters are normalized.In the presence of hypercalcemia or persistent increase in the product of Ca? P (more than 75) should reduce the dose of the drug or take a break in treatment, until these parameters are normalized. Then you can resume therapy with paricalcitol in a smaller dose. If a patient receives a calcium-containing drug that binds phosphates, it is advisable to reduce his dose, temporarily cancel the drug or transfer the patient to a drug that does not contain calcium. As the levels of PTH decrease in response to treatment, a reduction in the dose of paricalcitol may be required. Thus, the dose should be selected individually.
If an adequate response is not obtained, the dose can be increased by 2-4 Ојg every 2-4 weeks. With a decrease in PTH <150 pg / ml, the dose should be reduced.
Recommended dose titration scheme
The level of PTH The dose of paricylcitol
The same or increases Increase by 2-4 Ојg
Decreased by <30% Increase by 2-4 Ојg
Decreased by> 30%, but <60% Do not change the dose
Decreased by> 60% Reduce by 2-4 Ојg
<150 (1 pg / ml) Reduce by 2-4 Ојg
In 1.5-3 times higher than UGN (150-300 pg / ml) Do not change the dose
SIDE EFFECT
The incidence of adverse events reported in clinical trials 2 and 3
The table lists the undesirable events of any genesis, whose frequency in the paricalcitol group was 2% or more (patients who had the same reaction repeatedly were counted 1 time).
The incidence of adverse events in all placebo-controlled studies
Undesirable effects Paracalcitol (n = 62) Placebo (n = 51)
Are common
Chills 5% 2%
Malady 3% 0
Fever 5% 2%
Influenza 5% 4%
Sepsis 5% 2%
From the side of the cardiovascular system
Heart palpitations 3% 0
From the digestive system
Dry mouth 3% 2%
Gastrointestinal bleeding 5% 2%
Nausea 13% 8%
Vomiting 8% 6%
From the side of the central nervous system
Dizziness 5% 2%
From the respiratory system
Pneumonia 5% 0
Other
Edema 7% 0
Changes in the average levels of calcium, phosphorus, product of Ca? P in an open 13-month study confirm the safety of prolonged therapy with paricalcitol in this group of patients.
Adverse events in clinical trials of 4 phases
In one study, four phases often had headache (2%) and a taste distortion (2%).
Undesirable reactions recorded during post-marketing observations
In clinical practice, the following undesirable reactions were rarely recorded with the use of injection paricalcitol:
Allergic reactions: urticaria, Quincke's edema, laryngeal edema.
From the side of the peripheral nervous system: perversion of taste (metallic taste).
Dermatological reactions: rash, itching.
CONTRAINDICATIONS
- hypervitaminosis D;
- joint intake with phosphates or derivatives of vitamin D;
- hypercalcemia;
- Children under 18 years of age (no clinical studies have been performed);
- the period of breastfeeding;
- Hypersensitivity to the components of the drug.
Caution should be given to the drug simultaneously with cardiac glycosides.
PREGNANCY AND LACTATION
Studies in pregnant women have not been conducted. Information on the removal of paricalcitol with breast milk in women is not. Parikaltsitol can be used during pregnancy only if the potential benefit to the mother justifies the possible risk to the fetus. If you need to use the drug during lactation, breastfeeding should be discontinued.
APPLICATION FOR FUNCTIONS OF THE LIVER
It is used for the prevention and treatment of secondary hyperparathyroidism, which develops in chronic renal failure (chronic kidney disease of stage 5).
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
Correction of the dose in patients with mild or moderate impairment of liver function is not required. The pharmacokinetics of paricalcitol in patients with severe impairment of liver function has not been studied.
APPLICATION FOR CHILDREN
Contraindication: children under 18 years of age (no clinical studies have been performed).
SPECIAL INSTRUCTIONS
When titrating a dose of paricalcitol, more frequent laboratory testing may be required. When the dose is matched, serum calcium and phosphorus levels should be measured at least 1 time per month. PTH levels in serum or plasma are recommended to be monitored every 3 months. For reliable analysis of biologically active PTH in patients with chronic renal diseases, stage 5, it is recommended to use the method of the second or subsequent generation.
There was no difference in the efficacy or safety of the drug in patients younger than 65 years of age and over 65 years of age.
Use in Pediatrics
The experience of using parikilcitol for injections in children and adolescents under the age of 18 is limited.
OVERDOSE
Symptoms: an overdose of paricalcitol can lead to the development of hypercalcaemia, hypercalciuria, hyperphosphatemia and suppression of PTH secretion.
Acute overdose of paricalcitol can lead to the development of hypercalcemia and requires emergency care. During the period of dose selection, it is necessary to regularly monitor serum calcium and phosphorus levels. Long-term therapy with paricalcitol may be complicated by hypercalcemia, an increase in the product of Ca?P and calcification of soft tissues (metastatic calcification).
Treatment: with clinically significant hypercalcemia, it is necessary to immediately reduce the dose of paricylcytol or interrupt treatment. Recommended measures include a hypocalcemic diet, abolition of calcium preparations, monitoring of water-electrolyte balance, assessment of ECG changes (critical for patients receiving cardiac glycosides), and hemodialysis or peritoneal dialysis using dialysate that does not contain calcium. Serum calcium levels need to be monitored regularly before they normalize. When suppressing the level of PTH below the norm, it is possible to develop adynamic bone disease, a pathological state with low bone turnover.
DRUG INTERACTION
According to in vitro studies, paricalcitol should not inhibit the clearance of drugs that are metabolized by the isoenzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A, or induce clearance of substances biotransformed by CYP2B6, CYP2C9 or CYP3A.
The interaction of paricalcitol for injections with other drugs has not been specifically studied.
When studying the interaction of ketoconazole and paricalcitol in capsules, it was shown that ketoconazole causes an increase in AUC parikiltsitol approximately 2 times. Paricalcitol is partially metabolized by the isoenzyme CYP3A, and ketoconazole is a potent inhibitor of this isoenzyme, therefore caution should be exercised when combining paricalcitol with ketoconazole and other potent inhibitors of the CYP3A isoenzyme.
Hypercalcemia of any genesis increases intoxication with cardiac glycosides, therefore caution should be exercised when combined with paricalcitol.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug should be stored out of reach of children at a temperature of 15 В° to 25 В° C; Do not freeze. Shelf life - 2 years.
