Zemplar solution for venous injection 5mcg/m 1ml ampoules, 5pcs

Composition

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1 ml of the solution contains:

Active ingredients:

paricalcitol 5 mcg.

Auxiliary substances:

ethanol 95%,

propylene glycol,

d/i water.

In an ampoule of 5 ml of the solution.

There are 5 ampoules in a cardboard box.

Pharmacological action

Pharmacodynamics

A drug that regulates the exchange of calcium and phosphorus. Paricalcitol is a synthetic analog of biologically active vitamin D (calcitriol). Paricalcitol has a biological effect by interacting with vitamin D receptors, which leads to selective activation of the response mediated by this vitamin. Vitamin D and paricalcitol reduce the level of parathyroid hormone by inhibiting its synthesis and secretion. In the early stages of chronic kidney disease, there is a decrease in the level of calcitriol.

Secondary hyperparathyroidism is characterized by an increase in parathyroid hormone (PTH), which is associated with inadequate levels of active vitamin D. This vitamin is synthesized in the skin and enters the body with food. Vitamin D consistently hydroxylases in the liver and kidneys and converted to its active form that interacts with the receptor of vitamin D.

Calcitriol [1,25(Oh)2 D3] is an endogenous hormone that activates the vitamin D receptor in the parathyroid glands, intestine, kidney and bone (due to this, it supports the function of the parathyroid gland and calcium homeostasis of calcium and phosphorus), as well as in many other tissues, including prostate, endothelium and immune cells. Activation of these receptors is essential for normal bone formation. In kidney diseases, vitamin D activation is suppressed, which leads to an increase in PTH levels, the development of secondary hyperparathyroidism, and impaired calcium and phosphorus homeostasis. Reduced calcitriol levels and increased PTH activity, 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 diseases, a decrease in PTH levels has a beneficial effect on the activity of bone alkaline phosphatase, metabolic processes in bone tissue, and bone fibrosis. Active vitamin D therapy not only reduces PTH levels and improves bone metabolism, but also helps prevent or eliminate other consequences of vitamin D deficiency

. Pharmacokinetics

Within two hours after intravenous bolus use of paricalcitol in doses ranging from 0.04 mcg / kg to 0.24 mcg/kg, the drug concentration decreases rapidly; however, subsequently, the drug concentration decreases linearly, with an average T_1/2 of about 15 hours. With repeated use of paricalcitol, there are no signs of accumulation.

Distribution

Paricalcitol actively binds to plasma proteins (more than 99%). In healthy people_{, the} steady-state VD is about 23.8 l. In patients with stage 5 chronic kidney disease treated with hemodialysis or peritoneal dialysis, the_{VD of} paricalcitol at a dose of 0.24 mcg / kg averages 31-35 l. The pharmacokinetics of paricalcitol were studied in patients with chronic renal failure treated with hemodialysis.

Metabolism

Several metabolites of the drug are detected in the urine and feces. No unchanged paricalcitol was detected in the urine. Paricalcitol is metabolized by hepatic and nonhepatic enzymes, including mitochondrial CYP24, as well as CYP3A4 and UGT1A4. The identified metabolites include products of 24(R)-hydroxylation (low plasma concentrations), as well as 24,26-and 24,28-dihydroxylation and direct glucuronidation. 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 paricalcitol, the activity of CYP2B6, CYP2C9 and CYP3A4 increases by less than 2 times.

Deduction

Paricalcitol is excreted by bile. In healthy people, approximately 63% of the drug is excreted through the intestines and 19% by the kidneys. T_1/2 of paricalcitol when used in doses from 0.04 to 0.16 mcg / kg in healthy volunteers is an average of 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 18 years of age have not been studied. The pharmacokinetics of paricalcitol are gender-independent.

The pharmacokinetics of paricalcitol (0.24 mcg / kg) were compared in patients with mild to moderate hepatic impairment (according to the Child-Pugh classification) and healthy people.

The pharmacokinetics of unbound paricalcitol were similar in these groups of patients. No dose adjustment is required in patients with mild to moderate hepatic impairment. The pharmacokinetics of paricalcitol in patients with severe hepatic impairment have not been studied.

The pharmacokinetics of paricalcitol were studied in patients with stage 5 chronic kidney disease treated with hemodialysis or peritoneal dialysis. Hemodialysis did not significantly affect the elimination of paricalcitol. However, patients with stage 5 chronic kidney disease showed a decrease in clearance and an increase in T_1/2 compared to healthy people.

Indications

• Prevention and treatment of secondary hyperparathyroidism that develops with chronic renal failure (stage 5 chronic kidney disease).

Contraindications

• Hypervitaminosis D;
• co-use with phosphates or vitamin D derivatives;
• hypercalcemia;
• children under 18 years of age (no clinical studies were conducted);
• breast-feeding period;
• hypersensitivity to the components of the drug.

With caution: the drug should be administered simultaneously with cardiac glycosides.

Side effects

Frequency of adverse events reported in Phase 2 and 3 clinical trials.

The table lists adverse events of any origin, the frequency of which in the paricalcitol group was 2% or more (patients who had the same reaction recorded repeatedly were counted 1 time).

Changes in the mean levels of calcium, phosphorus, and Ca × P products in an open-label 13-month study confirm the safety of long-term paricalcitol therapy in this group of patients.

Adverse events in phase 4 clinical trials

In one Phase 4 study, headache (2%) and taste distortion (2%) were frequently reported.

Adverse reactions reported in post-marketing observations

In clinical practice, the following adverse reactions were rarely reported when using injectable paricalcitol: :

Allergic reactions: urticaria, angioedema, laryngeal edema.

From the peripheral nervous system: perversion of taste (metallic taste).

Dermatological reactions: rash, pruritus.

Interaction

According to in vitro studies, paricalcitol should not inhibit the clearance of drugs that are metabolized by CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A isoenzymes, or induce the clearance of substances that are biotransformed by CYP2B6, CYP2C9 or CYP3A.

The interaction of paricalcitol for injection 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 the AUC of paricalcitol by about 2 times. Paricalcitol is partially metabolized by the CYP3A isoenzyme, and ketoconazole is a potent inhibitor of this isoenzyme, so caution should be exercised when using paricalcitol in combination with ketoconazole and other potent inhibitors of the CYP3A isoenzyme.

Hypercalcemia of any origin increases intoxication with cardiac glycosides, so caution should be exercised when using them in combination with paricalcitol.

How to take, course of use and dosage

Zemplar® is usually administered intravenously through a hemodialysis catheter. If the patient does not have a hemodialysis catheter, the drug can be administered slowly intravenously for at least 30 seconds to minimize pain during infusion. As with other solutions for parenteral use, the ampoule containing Zemplar® should be examined for foreign particles and discoloration before use. Unused solution residues should be emptied out.

Adults

Initial dose

There are two methods for selecting the initial dose of paricalcitol. In clinical trials, the maximum safe dose reached 40 mcg.

Selection of the initial dose by body weight

The recommended initial dose of paricalcitol is 0.04-0.1 mcg / kg (2.8-7 mcg). It is administered as a bolus no more often than every other day during dialysis. Selection of the initial dose taking into account the initial level of PTH In patients with chronic renal failure (stage 5 chronic kidney disease), the second-generation method is used to analyze the level of biologically active intact PTH. The initial dose is calculated according to the formula given below, and administered intravenously in the form of a bolus no more than every other day during dialysis:

Initial dose (mcg) = Initial PTH level (pg/ml) / 80.

Titration of the dose

Generally accepted target levels of PTH in patients with end-stage renal insufficiency treated with dialysis exceed the ULN in patients without uremia (150-300 pg / ml) by no more than 1.5-3 times. To achieve these levels, careful monitoring of PTH levels and individual dose titration are necessary.

With any dose changes, serum calcium (adjusted for hypoalbuminemia) and phosphorus levels should be measured more frequently. If the adjusted calcium level increases (> 11.2 mg / dl) or the phosphorus concentration is consistently increased (>6.5 mg/dl), the dose should be reduced until these values return to normal. In the presence of hypercalcemia or a persistent increase in the product of Ca × P (more than 75), the dose of the drug should be reduced or a break in treatment should be taken until these parameters normalize. Then you can resume therapy with paricalcitol at a lower dose. If the patient is receiving a calcium-containing phosphate-binding drug, it is advisable to reduce the dose, temporarily discontinue the drug, or transfer the patient to a calcium-free drug. As PTH levels decrease in response to treatment, it may be necessary to reduce the dose of paricalcitol. Thus, the dose should be selected individually.

If an adequate response is not achieved, the dose can be increased by 2-4 mcg every 2-4 weeks. When the PTH level decreases

Recommended dose titration scheme

Overdose

Symptoms: an overdose of paricalcitol can lead to the development of hypercalcemia, hypercalciuria, hyperphosphatemia and suppression of PTH secretion.

Acute overdose of paricalcitol can lead to the development of hypercalcemia and requires urgent care. Serum calcium and phosphorus levels should be monitored regularly during dose adjustment. Long-term therapy with paricalcitol may be complicated by hypercalcemia, an increase in the Ca × P product, and soft tissue calcification (metastatic calcification).

Treatment: In case of clinically significant hypercalcemia, the dose of paricalcitol should be reduced immediately or treatment should be discontinued. Recommended measures include a hypocalcium diet, discontinuation of calcium supplements, monitoring of water and electrolyte balance, assessment of ECG changes (critical for patients receiving cardiac glycosides), and hemodialysis or peritoneal dialysis using a calcium-free dialysate. Serum calcium levels should be monitored regularly until they return to normal. If PTH levels are suppressed below normal, adynamic bone disease, a pathological condition with low bone metabolism, may develop.

Special instructions

When titrating the dose of paricalcitol, more frequent laboratory tests may be required. When the dose is selected, serum calcium and phosphorus levels should be measured at least once a month. Serum or plasma PTH levels should be monitored every 3 months. For reliable analysis of biologically active PTH in patients with stage 5 chronic kidney disease, it is recommended to use the second or subsequent generation method.

There were no differences in the efficacy or safety of the drug in patients under 65 years of age and over 65 years of age.

Use in pediatrics

Experience with the use of paricalcitol for injection in children and adolescents under the age of 18 years is limited.

Form of production

Solution for intravenous use.

Storage conditions

At a temperature of 15-25 °C (do not freeze)

Shelf life

2 years

Active ingredient

Paricalcitol

Conditions of release from pharmacies

By prescription

Dosage form

infusion solution