Zemplar - instructions for use, doses, side effects, contraindications

Active substanceParicalcitolParicalcitol

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Zemplar®

solution in / in

Abbott Laboratories Limited United Kingdom

Zemplar®

solution in / in

Abbott Laboratories Limited United Kingdom

Zemplar®

capsules inwards

EbbVi Ltd. Russia

Dosage form: & nbspsolution for intravenous administration

Composition:

In 1 ml of solution contains:

Active substance: paricylcitol 5 μg;

Excipients: Ethanol (95%) - 20%, propylene glycol - 30%, water for injection up to 1 ml.

Description:A clear, colorless solution that does not contain any foreign particles visible to the naked eye.

Pharmacotherapeutic group:calcium-phosphorus exchange regulator.

ATX: & nbsp

H.05.B.X Other antiparatyroid drugs

H.05.B.X.02 Paricalcitol

Pharmacodynamics:

calcium-phosphorus exchange regulator.

Secondary hyperparathyroidism is characterized by an increase in the content of 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 subsequently hydroxylated in the liver and kidneys and is converted into an active form that interacts with the vitamin receptors D. Calcitriol [1.25 (OH) g D3] is an endogenous hormone that activates the vitamin receptors D in parathyroid glands, intestines,kidneys and bone tissue (due to this it supports the function of parathyroid glands 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. In diseases of the kidneys, vitamin activation is suppressed D, which leads to an increase in the level of PTH, the development of secondary hyperparathyroidism and 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 the level of PTH has a beneficial effect on the activity of bone alkaline phosphatase, metabolic processes in bone tissue and bone tissue fibrosis. Therapy with an active vitamin D not only reduces the level of PTH and improves metabolic processes in bone tissue, but also helps prevent or eliminate other consequences of vitamin deficiency D.

Pharmacokinetics:

Within two hours after the administration of paricalcitol intravenously in the form of a bolus in doses from 0.04 to 0.24 μg / kg, the drug concentration decreases rapidly; but in the subsequent concentration of the drug decreases linearly, with an average half-life of about 15 hours. When repeated application of paricalcitol, there are no signs of cumulation.

Distribution

Paricalcitol actively binds to plasma proteins (> 99%). In healthy people, the volume of distribution 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 volume of distribution of paricylcitol in a dose of 0.24 μg / 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. Unchanged in urine parikalcitol Not found. Paricalcitol metabolized under the action of numerous hepatic and non-hepatic enzymes, including mitochondrial CYP24, and CYP3A4 and UGT1A4. Identified metabolites include the products of 24 (11) -hydroxylation (in plasma is in low concentrations),as well as 24,26- and 24,28-dihydroxylation and direct glucuronation. Paricalcitol does not have an inhibitory effect on CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A in concentrations up to 50 nM (21 ng / ml). At similar concentrations of paricalcitol, activity CYP2B6, CYP2C9 and CYP3A4 increases by less than 2 times.

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. The half-life of paricalcitol in doses from 0.04 to 0.16 μg / kg in healthy volunteers averages 5-7 hours.

Special Groups Aged people

The pharmacokinetics of paricalcitol in people over the age of 65 years have not been studied.

Children

The pharmacokinetics of paricalcitol in children and adolescents less than 18 years of age have not been studied.

Floor

The pharmacokinetics of paricylcytol do not depend on sex.

Impaired liver function

The pharmacokinetics of paricalcitol (0.24 μg / kg) were compared in patients with mild to moderate liver function disorder (Child-Pugh classification) and healthy people. The pharmacokinetics of unbound paricalcitol 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.

Impaired renal function

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 in the half-life compared with healthy people were detected.

Indications:

Prevention and treatment of secondary hyperparathyroidism, which develops in chronic renal failure (chronic kidney disease of stage 5).

Contraindications:

- Hypervitaminosis D

- Simultaneous use with phosphates and / or derivatives of vitamin A D

- Simultaneous use with preparations containing magnesium

Simultaneous use with thiazide diuretics

- Long-term joint use with aluminum preparations

- Hypercalcemia

- Hypersensitivity to any component of the drug

- Children under 18 years of age (experience with children is limited)

Application in breastfeeding

Carefully:

Joint reception with cardiac glycosides.

Pregnancy and lactation:

Pregnancy

There is insufficient data on the use of paricalcitol in pregnant women. The data obtained in studies conducted on animals show that parikalcitol causes reproductive toxicity and is able to penetrate the hematoplacental barrier. Paricalcitol It should be used during pregnancy only if the potential benefit to the mother justifies the possible risk to the fetus.

Breastfeeding period

The data obtained in studies conducted on animals show that parikalcitol is excreted in breast milk in small amounts. Information on the removal of paricalcitol from pectoralThere is no milk for women.

If you need to use Zemplar ®, breastfeeding should be discontinued.

Dosing and Administration:

The drug Zemplar is usually administered intravenously via a hemodialysis catheter. If the patient does not have a hemodialysis catheter, the drug can be injected slowly intravenously for at least 30 seconds to minimize pain during infusion.Like other solutions for parenteral use, the ampoule with Zemplar preparation 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 μg.

The choice of the initial dose by body weight

The recommended initial dose of paricalcitol is 0.04-0.1 μg / kg (2.8-7 μg). It was administered as a bolus no more than a day later during dialysis.

The choice of the initial dose taking into account the initial level of PTH

Patients with chronic renal failure (chronic kidney disease of stage 5) used the second-generation method to analyze the level of biological active intact PTH. The initial dose was calculated according to the formula given below and administered intravenously in the form of a bolus no more often than every other day during dialysis:

Initial dose = baseline level of PTH (pg / ml ) / 80
(μg)

Dose titration

The generally accepted target levels of PTH in patients with terminal renal failure receiving dialysis treatment exceed the upper limit of the norm in patients without uremia (150-300 pg / ml) by 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 x P (more than 75), the dose of the drug should be reduced or the treatment should be interrupted until these parameters normalize. Then you can resume therapy with paricalcitol in a smaller dose. If the patient receives a calcium-containing drug that binds phosphates, it is advisable to reduce its 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. Therefore, the dose should be. select individually.

If an adequate response is not obtained, the dose can be increased by 2-4 μg every 2-4 weeks.With a decrease in PTH <150 pg / ml, the dose should be reduced.

Recommended dose titration scheme

PTH level	Dose of paricilcitol
The same or increases	Increase by 2-4 μg
Decreased by <30%	Increase by 2-4 μg
Decreased by> 30%, but <60%	Do not change the dose
Decreased by> 60%	Reduce by 2-4 μg
<150 pg / ml	Reduce by 2-4 μg
In 1,5-3 times above the upper limit of the norm (150-300 pg / ml)	Do not change the dose

Side effects:

In clinical studies of the 2-4 phase with placebo control or an active comparator, approximately 600 patients received Zemplar®. The overall incidence of adverse reactions was 6%.

The most common adverse reaction associated with Zemplar® therapy was hypercalcemia, which occurred in 4.7% of patients.

Hypercalcemia depends on the degree of excessive suppression of PTH synthesis and, with proper dose selection, can be minimized.

Adverse reactions, possibly associated with the use of paricalcitol, are reflected in the table below with the distribution of organ systems and frequency of occurrence: very often (> 1/10); often (> 1/100, <1/10); infrequently (> 1/1000, <1/100).

Class of organ system	Adverse Reactions	Frequency
Infections	Pneumonia, influenza, upper respiratory tract infection, nasopharyngitis, sepsis, vaginal infection.	Infrequently
Neoplasm	Mammary cancer.	Infrequently

On the part of the blood and lymphatic system	Anemia, leukopenia, lymphadenopathy.	Infrequently
From the immune system	Gensensitivity.	Infrequently
WE	Angioedema, edema	Unknown
	larynx, urticaria.	BUT
From the side of the cardio-	Atrial fibrillation,	Infrequently
cardiovascular system	heart palpitations, palpitations, increased blood pressure, lowering blood pressure, arrhythmia.
On the part of the endocrine system	Hypoparathyroidism.	Often
from the topic	Hyperparathyroidism.	Infrequently
From the side of metabolism	Hypercalcemia, hyperphosphatemia.	Often
	Hypocalcemia, anorexia, hyperkalemia.	Infrequently
From the nervous system	Dysgeusia, headache.	Often
	Acute disorders of cerebral circulation, dizziness, hypoesthesia, myoclonia, paresthesia, fainting, agitation, confused consciousness, delirium, insomnia, nervousness, motor anxiety, transient ischemic attack.	Infrequently

	Absence of a response to stimuli.	Unknown but
From the sense organs	Conjunctivitis, glaucoma, discomfort in the ears.	Infrequently
From the sense organs	Hyperemia of the eyes.	Unknown but
From the respiratory system	Cough, dyspnea, orthopnea, pulmonary edema, epistaxis.	Infrequently
From the respiratory system	Wheezing.	Unknown but
From the gastrointestinal tract	Gastrointestinal bleeding, constipation, diarrhea.	Often
From the gastrointestinal tract	Discomfort in the abdomen, dry mouth, intestinal ischemia, rectal bleeding, vomiting, colitis, dysphagia, gastritis, nausea.	Infrequently
From the skin and subcutaneous tissues	Itching.	Often
From the skin and subcutaneous tissues	Alopecia, blisters, hirsutism, night sweats, rash, itching rash, burning sensation on the skin.	Infrequently
From the musculoskeletal system	Arthralgia, joint stiffness, muscle twitching, myalgia.	Infrequently
From the side of the reproductive system	Pain in the mammary glands, erectile dysfunction.	Infrequently

Other	Pain at the injection site, fever, chills.	Often
	Asthenia, fatigue, malaise, gait disturbance, edema, including peripheral, chest discomfort, chest pain, feeling of malaise, bruising at the injection site, pain, thirst.	Infrequently
Laboratory indicators	Increase in activity of aspartate aminotransferase (ACT), deviation from the norm of laboratory indicators, weight loss, increased bleeding time.	Infrequently
	Heart rhythm disturbances.	Unknown
		BUT

Overdose:

Cases of an overdose of paricylcytol are not registered. Overdose of paricalcitol can lead to the development of hypercalcaemia, hypercalciuria, hyperphosphatemia and excessive suppression of PTH secretion.

When an overdose of paricalcitol should be monitored for signs and symptoms of hypercalcemia (the level of calcium in the blood). Leche

hypercalcemia should be initiated if necessary. The symptomatology of a paricalcitol overdose is generally similar to that of an overdose of vitamin A D: weakness, headache, drowsiness, nausea, vomiting, dry mouth, constipation, muscle pain, bone pain, metallic taste in the mouth, anorexia, abdominal pain, discomfort in the epigastric region. Paricalcitol little is eliminated in hemodialysis. Treatment of patients with clinically significant hypercalcemia includes immediate dose reduction or discontinuation of paricalcitol treatment, a diet low in calcium, discontinuation of calcium supplements, increased motor activity of the patient, control of electrolyte electrolyte balance, monitoring of ECG abnormalities (especially important in patients taking cardiac glycosides),as well as hemodialysis or peritoneal dialysis using dialysate, which does not contain calcium (according to indications).

When the serum calcium concentration is normalized, the treatment with paricylcytol can be resumed at a lower dose. In the case of a persistent or pronounced increase in serum calcium concentration, several treatment options should be considered, including the use of phosphates, glucocorticosteroids, and diuresis stimulants.

Zemplar®, an intravenous solution, contains propylene glycol (30% v / v) as an auxiliary. When propylene glycol was used in high doses, isolated cases of central nervous system, hemolysis and lactic acidosis. When using the preparation of the Earthplacer® in recommended doses, these side reactions are not expected to develop, since propylene glycol is excreted during dialysis; However, the risk of developing these adverse reactions should be taken into account in case of an overdose of Zemplar®.

Interaction:

The interaction of paricalcitol for injections with other drugs has not been studied separately.The interaction of paricalcitol with ketoconazole was studied in the dosage form of the "capsule".

When studying the interaction of ketoconazole and paricalcitol in capsules, it was shown that ketoconazole increases AUCo(the area under the concentration-time curve) of paricalcitol is approximately two-fold. The half-life of the paricalcitol was 17.0 hours when combined with ketoconazole compared to 9.8 hours when using paricalcitol in monotherapy. Paricalcitol partially metabolized by isoenzyme CYP3A, a ketoconazole is a potent inhibitor of isoenzyme CYP3A, therefore it is necessary to observe ostoValidity in the combined use of parikalcitol with ketoconazole and other potent inhibitors of isoenzyme CYP3A. Joint use of phosphates or drugs, which include a vitamin D, with paricalcitol is contraindicated in connection with an increased risk of hypercalcemia and an increase in the value of the product of Ca x R.

Simultaneous use of high doses of drugs containing calcium, or thiazide diuretics and parikiltsitol can increase the risk of hypercalcemia.The combined use of paricalcitol with thiazide diuretics is contraindicated.

Joint use of drugs containing magnesium (for example, antacids) with vitamin analogues D and parikiltsitolom contraindicated in connection with the possibility of hypermagnetism. Prolonged use of drugs containing aluminum (for example, some antacids and phosphate binders), in conjunction with vitamin analogues D and paricalcitol is contraindicated in connection with the possibility of increasing the serum concentration of aluminum and its toxic effects on the bones.

According to the research data in vitro parikiltsitol should not inhibit the clearance (C1) of drugs that are metabolized by isoenzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A, or induce the clearance of substances biotransforming under the action isoenzymes CYP2B6, CYP2C9 or CYP3A. Hypercalcemia of any nature exacerbates intoxication with cardiac glycosides, so care must be taken when they are used simultaneously with paricalcitol.

Special instructions:

During the period of dose selection, it is necessary to regularly monitor serum calcium and phosphorus concentrations.When the dose is matched, serum calcium and phosphorus concentrations should be measured at least once a month. Long-term therapy with paricalcitol may increase the risk of hypercalcaemia, an increase in the value of Ca x R, and soft tissue calcification (metastatic calcification).

Chronic hypercalcemia can lead to generalized calcification of blood vessels and other soft tissues.

With a decrease in PTH concentration below the norm, it is possible to develop adynamic bone disease, a pathological state with low bone turnover. To achieve the relevant physiological indicators, it is necessary to monitor the patient's condition and individually select the dose of Zemplar In the case of the development of clinically significant hypercalcemia in the patient receiving parikalcitol together with calcium-containing phosphate-binding drugs, the dose of the latter should be reduced, or the use of this drug should be temporarily canceled.

The toxicity of cardiac glycosides is enhanced by hypercalcemia. Cardiac glycosides should be used with caution when combined with paricalcitol.

Caution should be exercised in the combined use of paricalcitol with ketoconazole.

The drug Zemplar®, a solution for intravenous administration, as an auxiliary substance, contains ethanol (20% v / v). 1 ml of Zemplar ® contains about 1.3 g of ethanol. Ethanol can be potentially dangerous for patients with liver disease, alcoholism, epilepsy, pregnant women and children. Laboratory Tests

When titrating a dose of paricalcitol, more frequent laboratory testing may be required. When the dose is matched, serum calcium and phosphorus concentrations should be measured at least once a month. Concentrations of PTH in serum or plasma are recommended to be monitored every 3 months (see section "Method of administration and dose").

Use in children

The experience of using parikilcitol for injections in children and adolescents less than 18 years of age is limited.

Application in the elderly
He differences in efficacy or safety in patients older than 65 years were found.

Effect on the ability to drive transp. cf. and fur:Data on the effect of the drug on the ability to drive and work with mechanisms there.However, since it is possible the occurrence of such side effects as dizziness, fainting, etc., it is recommended during the therapy with Zemplar® to refrain from driving and doing other activities that require an increased concentration of attention and speed of psychomotor reactions.

Form release / dosage:

Solution for intravenous administration, 5 μg / ml.

1 ml or 2 ml in ampoules of colorless hydrolytically stable glass type I (Hev. Pharm.) with a break point. For 5 ampoules together with instructions for use in a cardboard bundle with partitions, or 5 ampoules in a plastic pallet, one plastic pallet together with instructions for use in a cardboard bundle.

Packaging:ampoules (5) - packs cardboard
ampoules (5) - pallets plastic-packs cardboard

Storage conditions:

Store at a temperature of 15 to 25 ° C. Do not freeze. The drug should be stored in places inaccessible to children.

Shelf life:2 of the year. Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LSR-004781/09

Date of registration:16.06.2009

The owner of the registration certificate:Abbott Laboratories LimitedAbbott Laboratories Limited United Kingdom

Manufacturer: & nbsp

HOSPIRA, S.p.A. Italy

Representation: & nbspEbbVi Ltd.EbbVi Ltd.Russia

Information update date: & nbsp19.08.2015

Illustrated instructions

Instructions

Zemplar® (Zemplar®)