Zemplar® (Zemplar®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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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: & nbspcapsules
    Composition:

    1 capsule of Zemplar® contains

    Dosage 1 μg

    Active substance: parikaltsitol - 1 mcg.

    Auxiliary matter: ethanol is 0.71 mg, Butyl hydroxytoluene 0.008 mg, medium chain triglycerides 70.28 mg, gelatin 52.1 mg, glycerol 23.1 mg, titanium dioxide 0.555 mg, iron ferric oxide black 0.042 mg, purified water - q.s., black ink Opacode® WB - traces (ethanol, propylene glycol, iron dye oxide black, polyvinyl acetate phthalate, water, isopropanol, macrogol 400, ammonium hydroxide (28%)).

    Dosage 2 μg

    Active substance: parikaltsitol - 2 mcg.

    Auxiliary matter: ethanol 1.42 mg, 0.016 mg, medium-chain triglycerides-140.56 mg, gelatin-75.34 mg, glycerol-33.41 mg, titanium dioxide-0.636 mg, iron-oxide red oxide-0.181 mg, iron oxide yellow oxide-0.542 mg, water purified - q.s., black ink Opacode® WB - traces (ethanol, propylene glycol, iron dye oxide black, polyvinyl acetate phthalate, water, isopropanol, macrogol 400, ammonium hydroxide (28%)).

    Description:

    Oval soft gelatin capsules.

    Dosage 1 μg: gray with printed symbol and "ZA".

    Dosage of 2 mcg: light brown with a printed symbol and "ZF".

    The contents of the capsules are a colorless or yellowish liquid, with no visible particles.

    Pharmacotherapeutic group:Calcium-phosphorus exchange regulator
    ATX: & nbsp

    H.05.B.X   Other antiparatyroid drugs

    H.05.B.X.02   Paricalcitol

    Pharmacodynamics:

    Mechanism of action

    Parikaltsitol - a synthetic analogue of a biologically active vitamin D (calcitriol), in the structure of which there are modifications of the side chain (D2) and the ring A (19-nor). Unlike calcitriol parikalcitol selectively activates vitamin receptors D (RVD) in the parathyroid glands without activation of the RVD in the intestine and less actively affects the resorption of bone tissue. Paricalcitol also activates calcium-sensitive receptors in the parathyroid glands, thereby reducing the concentration of parathyroid hormone (PTH) by inhibiting parathyroid proliferation and reducing the synthesis and secretion of PTH. Paricalcitol has minimal effect on the concentration of calcium and phosphorus, can directly affect bone cells, supporting the volume of bone tissue and improving the mineralization of bone tissue.Correction of the pathological content of PTH and normalization of the homeostasis of calcium and phosphorus can prevent and / or treat bone diseases associated with the disruption of its metabolism due to chronic kidney disease.

    Clinical efficacy

    Chronic kidney disease 3 and 4 stages

    The primary endpoint of efficacy, implying at least two consecutive decreases in the concentration of ipHP ≥30% compared with the baseline value of ipTG, was achieved in 91% of patients who received parikalcitol in capsules, and in 13% of patients in the placebo group (p <0.001). Activity of serum alkaline phosphatase of bone tissue, as well as osteocalcin concentration in serum significantly decreased (p <0.001) in patients receiving parikalcitol in capsules, in comparison with patients in the placebo group, which is associated with the correction of the accelerated process of bone tissue renewal due to secondary hyperparathyroidism. Deterioration of parameters of kidney function on the basis of the estimated glomerular filtration rate (according to the formula MDRD) and an increase in serum creatinine in patients who received parikalcitol in capsules, compared with patients in the placebo group was found. In a significantly larger number of patients who received parikalcitol in capsules, there was a decrease in the protein content in urine based on semiquantitative analysis, compared with patients in the placebo group.

    Chronic Kidney Disease Stage 5

    The primary endpoint of efficacy, implying at least two consecutive decreases in the concentration of ipHP ≥30% compared with the baseline value of ipTG, was achieved in 88% of patients who received parikalcitol in capsules, and in 13% of patients in the placebo group (p <0.001).

    Use in children

    Safety and efficacy of Zemplar® (in drug form, intravenous solution) were studied in a randomized, double-blind, placebo-controlled study of 12 weeks duration, which included 29 children aged 5-19 years with end-stage renal failure on hemodialysis. Six of the youngest patients in the study who received the drug

    Zemplar® (in the form of a drug - a solution for intravenous administration), were aged 5-12 years. Initial dose of Zemplar® (in the form of a solution for intravenous administration) was 0.04 μg / kg 3 times a week, based on the initial ipPT concentration of less than 500 pg / ml, or 0.08 μg / kg 3 times a week based on the initial concentration of ipHT ≥ 500 pg / ml, respectively. The dose of Zemplar® (in the form of a drug - a solution for intravenous administration) was adjusted to 0.04 μg / kg depending on the serum concentration of ipHP, calcium and the product of Ca x R 67% of patients treated with Zemplar® in a dosage form, a solution for intravenous administration), and 14% of patients in the placebo group completed the study. In 60% of patients in the group, receiving a drug Zemplar® (at drug form - solution for intravenous administration), 2 consecutive decreases in the concentration of IPPH were recorded by 30% compared with the initial value of ipTG compared with 21% of patients in the placebo group. 71% of patients in the placebo group discontinued the study due to an excessive increase in the concentration of ipH. None of the participants in the group, receiving a drug Zemplar® (at drug form - solution for intravenous administration), or the placebo group did not develop hypercalcemia. Data for patients under the age of 5 years is not obtained.

    Pharmacokinetics:

    Suction

    Parikaltsitol has good absorption from the gastrointestinal tract. In healthy volunteers with oral paricalcitol at a dose of 0.24 μg / kg, the absolute bioavailability of the drug averaged about 72%, the maximum concentration in the blood plasma (Cmax) - 0.63 ng / ml (1.512 pmol / ml), the time to reach Cmax - 3 hours, the area under the curve "concentration-time" (AUCo-∞) - 5.25 ng-hour / ml (12.6 pmol-hour / ml). The mean absolute bioavailability of paricalcitol in patients on hemodialysis (HD) and peritoneal dialysis (PD) is 79% and 86%, respectively, with an upper limit of 95% confidence interval of 93% and 112%, respectively. A study of the effect of food on the absorption of paricalcitol in healthy volunteers showed that Cmax and AUCo-∞ Do not change when using parikiltsitol with fatty foods compared to its use on an empty stomach. Thus, taking Zemplar® can be done regardless of the meal.

    In healthy volunteers, Cmax and AUCo-∞ parikaltsitola proportionally increase when it is used in doses from 0.06 μg / kg to 0.48 μg / kg. With repeated use every day or three times a week in healthy volunteers, the equilibrium concentration of paricylcytol was reached within seven days,not changing for a long time. Distribution

    Paricalcitol strongly binds to blood plasma proteins (> 99%). The ratio of the concentration of paricalcitol in the blood cells to the concentration of the paricalcitol in the plasma averaged 0.54 in the concentration range from 0.01 to 10 ng / ml (0.024 to 24 pmol / ml), indicating a very small degree of binding of the preparation to the blood cells. In healthy volunteers, after application of Zemplar® at a dose of 0.24 μg / kg, the volume of distribution was 34 liters.

    Metabolism

    Metabolism was studied using radiolabeled paricalcitol. Paricalcitol, after oral administration at a dose of 0.48 μg / kg, is metabolized to a large extent. Only 2% of the accepted dose is excreted through the intestine in unchanged form, in the urine parikalcitol is not found. Approximately 70% of metabolites are excreted through the intestine and 18% through the kidneys. Systemic exposure of the drug is mainly represented by paricalcitol. Two secondary metabolites of paricalcitol are detected in the plasma. One is defined as 24 (R) -hydroxyparacarcitol, while the other is not identified.24 (R) -hydroxyparacarcitol is less active than parikalcitol, regarding the suppression of PTH. The low activity of the active metabolite is determined in the preclinical model (in rats). Research data in vitro We can assume that parikalcitol metabolized by numerous hepatic and extrahepatic isoenzymes, including mitochondrial CYP24, and CYP3A4 and UGT1A4. Identified metabolites include the product 24 (H) -hydroxylation, as well as products of 24,26- and 24,28-dihydroxylation and direct glucuronation.

    Excretion

    Paricalcitol is excreted mainly through hepatobiliary excretion. In healthy volunteers, the average half-life of paricalcitol is between five and seven hours when Zemplar® is used at a dose of 0.06 μg / kg to 0.48 μg / kg.

    Special patient groups

    Age

    Elderly

    The pharmacokinetics of paricalcitol have not been studied in patients 65 years of age or older.

    Children

    The pharmacokinetics of paricyladitol have not been studied in patients under the age of 18 years.

    Floor

    The pharmacokinetics of paricalcitol in single use at a dose of 0.06 μg / kg to 0.48 μg / kg is independent of sex.

    Impaired liver function

    The distribution of paricalcitol (0.24 μg / kg) in patients with mild and moderately impaired liver function (Child-Pugh classification) was comparable to the distribution of paricalcitol in healthy volunteers.

    The pharmacokinetics of unbound paricalcitol were similar in patients with mild and moderately severe impairment of liver function. Correction of the dose in patients with mild and moderately expressed violations of the liver is not required. The pharmacokinetics of paricalcitol in patients with severe impairment of liver function has not been studied.

    Impaired renal function

    With repeated use of the drug Zemplar® once a day in patients with chronic kidney disease of the 4th stage, AUC was somewhat lower than after a single application of Zemplar®.

    The average volume of distribution of paricalcitol in patients with chronic kidney disease of the 3rd stage after the application of 4 μg of Zemplar® preparation and patients with chronic kidney disease of the 4th stage after application of 3 μg of Zemplar® preparation is 44-46 liters. Pharmacokinetic profile when using parikiltsitol (with oral use in capsules) in patients with chronic kidney disease of the 5th stage,of patients on hemodialysis or peritoneal dialysis is comparable to that in patients with chronic kidney disease of the 3rd and 4th stages. Therefore, no special dose adjustment other than that described in the "Method of administration and dose" section is required. The pharmacokinetics of paricalcitol (when administered orally in capsules) were studied in patients with chronic kidney disease of the 3rd and 4th stages (see Table 1). After applying 4 μg of paricalcitol (when administered orally in capsules), in patients with chronic kidney disease of the 3rd stage, the average half-life of the paricalcitol was 17 hours. The average half-life of paricalcitol in patients with chronic kidney disease of the 4th stage when administered at a dose of 3 μg (when administered orally in capsules) is 20 hours. The degree of cumulation of paricalcitol corresponded to the half-life and the frequency of application of Zemplar®. Conducting hemodialysis does not affect the rate of excretion of paricalcitol.

    Table 1. Pharmacokinetic parameters of paricalcitol in patients with chronic kidney disease of the 3rd and 4th stages.

    Pharmacokinetic parameter

    Healthy volunteers

    Chronic kidney disease of stage 3

    Chronic Kidney Disease Stage 4

    Chronic kidney disease of stage 3

    Patients on hemodialysis

    Patients on peritoneal dialysis

    Number of subjects in each group

    25

    15

    14

    14

    8

    Dose (μg / kg)

    0,240

    0,047

    0,036

    0,240

    0,240

    CL / F (l / h)

    3,6 ± 1,0

    1,77 ±0,50

    1,52 ±0,36

    1,8 ±0,8

    1,8 ±0,8

    T,/2 (h)

    5,9 ±2,8

    16,80 ±2,65

    19,70 ±7,2

    13,9 ±5,1

    17,7 ±9,6

    FROM (%)

    0,06 ±0,01

    0,06 ±0,01

    0,07 ± 0,02

    0,09 ± 0,04

    0,13 ±0,08

    * - measured at a concentration of paricalcitol 15 nmol.

    Indications:

    Prevention and treatment of secondary hyperparathyroidism developing in chronic kidney disease of the 3rd and 4th stage, as well as in patients with chronic kidney disease of the 5th stage who are on hemodialysis or peritoneal dialysis.

    Contraindications:

    - Hypersensitivity to paricalcitol or any excipients of Zemplar®.

    - Symptoms of vitamin intoxication D.

    - Hypercalcemia.

    - Combined use with phosphates or vitamin derivatives D.

    - Children under 18 years of age (no clinical studies have been performed).

    - Joint use with aluminum-containing preparations (for example, antacids, phosphate-binding drugs) on a permanent basis and magnesium-containing preparations (for example, antacids).

    Carefully:

    Joint use with cardiac glycosides, ketoconazole and other potent inhibitors CYP3A4.

    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 should be used during pregnancy only if necessary and in the event that 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 excreted in breast milk. Information on the removal of paricalcitol with breast milk in women is not.

    If you need to use Zemplar ®, breastfeeding should be discontinued. It is possible to continue breastfeeding with the refusal to take Zemplar®, taking into account the benefits of breastfeeding for the baby and the benefits of Zemplar® treatment for the mother.

    Dosing and Administration:
    Inside. The drug Zemplar® can be taken regardless of food intake.

    Chronic kidney disease 3 and 4 stages

    The drug Zemplar® is recommended to be taken once a day, daily or three times a week. When using Zemplar® three times a week, it should be taken no more often than once every two days. The average weekly doses with Zemplar® are not different every day and three times a week. Despite the fact that the clinical effect does not differ with different dosage regimens, the daily use of Zemplar® is recommended, as it contributes to a greater adherence of the patient to treatment and reduces the risk of accidental dysregulation.

    Starting dose

    The starting dose of Zemplar® is determined on the basis of the initial level of IPPH.

    Initial concentration

    Daily dose

    Dose when applied

    IPPG

    application of

    3 times a week*

    ≤500 pg / ml (56 pmol / L)

    1 μg

    2 μg

    > 500 pg / ml (56 pmol / L)

    2 μg

    4 μg

    * - take no more than once every two days.
    Dose selection

    The dose of Zemplar® should be selected individually based on the level of IPPH in plasma or serum, taking into account the serum concentrations of calcium and phosphorus. The approach to selection of a dose is offered below.

    Concentration

    IPPG

    compared with the original

    The dose of Zemplar® (in dosage form - capsules)

    Dose change at intervals of 2-4 weeks

    With daily use

    When applied 3 times a week1

    The same or increased

    Zoom in

    1 μg

    2 μg

    Decreased by <30%

    Decreased by ≥30%, but <60%

    Leave the same



    Decreased by> 60%

    2

    Decrease

    1 μg

    2 μg

    IPPG <60 pg / ml (7 pmol / L)

    1 - take no more than once every two days.

    2 - if a patient receives Zemplar® at a minimum dose daily or three times a week and needs a dose reduction, the frequency of Zemplar® can be reduced.

    Patients should carefully monitor serum concentrations of calcium and phosphorus after the start of Zemplar®, during the dose selection and when combined with potent inhibitors of the cytochrome P450 OA isoenzyme. If a patient develops hypercalcemia or a stable increase in the product of calcium and phosphorus when the Zemplar® drug is used, it is more than 55 mg2/ dL2 (4.4 mmol2/ l2), the dose of calcium-containing phosphate binding drugs should be reduced, or the withdrawal of such drugs should be necessary; if necessary, it is possible to reduce the dose of Zemplar® or to temporarily discontinue the use of Zemplar®.In case of temporary withdrawal of Zemplar®, resumption of its use should begin at a lower dose, when the values ​​of serum calcium concentrations and the products of calcium and phosphorus are in the target range.

    Chronic Kidney Disease Stage 5

    Zemplar® is recommended to be taken three times a week, no more often than once every two days.

    Starting dose

    Calculation of the starting dose of Zemplar® is carried out according to the following formula:

    Starting dose (μg) = The initial level of IPPH in pg/ ml / 60

    or

    Starting dose (μg) = .The initial level of ipHT in picomoles / l / 7

    Dose selection

    Subsequent doses of Zemplar® should be selected individually, depending on the initial level of ipHP, serum concentrations of calcium and phosphorus. Selection of the dose of Zemplar® is carried out according to the following formula:

    Titrated dose (μg) = The level of IPPG vpg / ml according to the last measurement / 60

    or

    Titrated dose (μg) = The level of ipTG in picomoles / l according to the last measurement / 7

    Serum calcium and phosphorus concentrations should be carefully monitored after initiation of treatment, during dose selection and when combined with powerful inhibitors of P450 OA.If the patient develops hypercalcemia or a stable increase in the product of calcium and phosphorus when using Zemplar®, the dose of calcium-containing phosphate binders should be reduced, or the withdrawal of such drugs should be necessary; or patients can be transferred to therapy with non-calcium phosphate binders.

    If the serum calcium concentration is> 11.0 mg / dL (2.8 mmol2 / l2 ) or a product of calcium and phosphorus> 70 mg 2 / dL 2 (5.6 mmol2 / l2), the dose of Zemplar should be reduced and should be 2-4 μg less than previously calculated according to the formula IPTG / 60 (or IPTG / 7). If an additional dose adjustment of Zemplar® is required, then, if necessary, it is possible to reduce the dose of Zemplar or temporarily stop using Zemplar® until the parameters described above are normalized.

    When the concentration of IPTE approaches the target range (150-300 pg / ml), a small individual dose adjustment of Zemplar® may be necessary to achieve a stable PTH level. In the event that control of the level of PTH and the concentration of calcium or phosphorus is less frequent,than once a week, it is recommended to use a smaller starting dose and a smaller dose change of Zemplar ® during its selection.

    The average dose of Zemplar® during its use three times a week in the first week of treatment in clinical trials was 11.2 μg. On average, the dose of Zemplar®, when used in clinical trials three times a week, was 6.3 μg. The maximum safe single dose of Zemplar ® in clinical trials was 32 μg.

    Special patient groups

    Impaired liver function

    Correction of the dose in patients with mild and moderately expressed violations of the liver is not required. The pharmacokinetics of paricalcitol in patients with severe impairment of liver function has not been studied.

    Use in children

    The efficacy and safety of Zemplar® (in capsule form) in children has not been studied.

    Application in the elderly

    There was no difference in efficacy or safety in patients aged 65-75 years and in younger patients, but the higher sensitivity of some elderly to the drug can not be ruled out.

    Side effects:

    Adverse reactions, both clinical and laboratory, whose relationship with the use of paricalcitol could be characterized, at least as possible, presented in accordance with the damage to organs and organ systems and the frequency of development. Adverse reactions are given below with frequency (very often ≥1 / 10; often ≥1 / 100, but <1/10; infrequently ≥ 1/1000, but <1/100; rarely ≥1 / 10000, but <1/1000 , very rarely <1/10000), including individual messages.

    Patients with chronic kidney disease 3 and 4 stages

    When using Zemplar®, the most frequent adverse reaction was a rash (in 2% of patients).

    The safety of paricalcitol was evaluated in three 24-week, double-blind, placebo-controlled, multicenter clinical trials involving 220 patients with chronic kidney disease at stages 3 and 4. In these studies, there were no statistically significant differences between the placebo group and the host group parikalcitol, in the frequency of occurrence of hypercalcemia (parikalcitol (2/106, 2%) compared with placebo (0/111; 0%)) or increased concentrations of calcium and phosphorus compoundsparikalcitol (13/106, 12%) compared with placebo (7/111, 6%)).

    The proportion of patients prematurely excluded from the study due to adverse reactions was 6% for the group receiving parikalcitol and 4% for the placebo group. This difference is not statistically significant.

    Adverse reactions in patients with chronic kidney disease 3 and 4 stages, described in clinical studies

    Organ or system

    Frequency of occurrence

    Adverse Reactions

    Immune system disorders

    Infrequently

    Hypersensitivity.

    Disturbances from the nervous system

    Infrequently

    Dizziness, dysgeusia.

    Disorders from the gastrointestinal tract

    Often

    Unpleasant sensations in the abdomen.

    tract

    Infrequently

    Constipation, dryness of the oral mucosa.

    Infringements from

    Often

    Rash.

    skin and subcutaneous tissue

    Infrequently

    Itching, hives.

    Disturbances from musculoskeletal and connective tissue

    Infrequently

    Muscle spasms.

    Laboratory and instrumental data

    Infrequently

    Deviation from the norm of activity of "liver" enzymes.

    Patients with chronic kidney disease of stage 5

    When using Zemplar ® clinical studies, there were no statistically significant or clinically significant differences in the types and incidence of adverse reactions between the group receiving parikalcitol and a placebo group.The proportion of patients who were excluded early due to adverse reactions was 7% for the group receiving parikalcitol and 7% for the placebo group. Adverse reactions in patients with chronic kidney disease of stage 5, described in clinical studies

    Organ or organ system

    Frequency of occurrence

    Adverse Reactions

    Infringements from

    Often

    Diarrhea,

    gastrointestinal

    gastroesophageal

    tract


    reflux disease.

    Disorders from the metabolism and nutrition

    Often

    Hypercalcemia, hypocalcemia, decreased appetite

    Disturbances from the nervous system

    Often

    Dizziness.

    Disturbances from the skin and subcutaneous tissues

    Often

    Acne.

    Violations of the genitals and mammary gland

    Often

    Soreness of mammary glands.
    Postmarketing data and clinical trial data when the drug is administered parenterally

    Organ or organ system

    Frequency of occurrence

    Adverse Reactions

    Laboratory and instrumental data

    Infrequently

    Increased bleeding time, an increase in the concentration of aspartate aminotransferase, a deviation from the norm of laboratory tests, weight loss,increased serum creatinine concentration *.

    Often

    The increase in the product

    Heart Disease

    Infrequently

    Cardiac arrest, arrhythmia, atrial flutter.

    Violations of the blood and lymphatic system

    Infrequently

    Anemia, leukopenia, lymphadenopathy.

    Disorders from the metabolism and nutrition

    Often

    Hypercalcemia, hyperphosphataemia.

    Infrequently

    Hyperkalemia, hypocalcemia, anorexia.

    Disturbances from the nervous system

    Often

    Headache, dysgeusia.

    Infrequently

    Coma, stroke, transient ischemic impairment of cerebral circulation, syncope, myoclonia, hypoesthesia, paresthesia, dizziness.

    Disturbances on the part of the organ of sight

    Infrequently

    Glaucoma, conjunctivitis.

    Hearing disorders and labyrinthine disorders

    Infrequently

    Violations from the organ of hearing.

    Disturbances from the respiratory system, chest and mediastinal organs

    Infrequently

    Pulmonary edema, asthma, shortness of breath, nosebleeds, cough.

    Disorders from the gastrointestinal tract

    Infrequently

    Rectal bleeding, colitis, diarrhea, gastritis, dyspepsia, dysphagia, abdominal pain, constipation, nausea, vomiting,dryness of the oral mucosa, disorders of the gastrointestinal tract.

    Unknown

    Bleeding from the gastrointestinal tract.

    Disturbances from the skin and subcutaneous tissues

    Often

    Itching.

    Infrequently

    Bullous dermatitis, alopecia, hirsutism, rash, hyperhidrosis.

    Disturbances from musculoskeletal and connective tissue

    Infrequently

    Arthralgia, joint stiffness, back pain, muscle cramps, muscle pain

    Infringements from

    Often

    Hypoparathyroidism.

    endocrine system

    Infrequently

    Hyperparathyroidism.

    Infectious and parasitic diseases

    Infrequently

    Sepsis, pneumonia, infection, pharyngitis, vaginal infections, influenza.

    Benign, malignant and unspecified neoplasms (including cysts and polyps)

    Infrequently

    Mammary cancer.

    Vascular disorders

    Infrequently

    Increase / decrease in blood pressure.

    General disorders and disorders at the site of administration

    Infrequently

    Violation of gait, swelling, peripheral edema, pain, pain at the injection site, fever, pain in the chest, exacerbation of the underlying disease, weakness, discomfort, thirst.

    Infringements from

    Infrequently

    Gensensitivity.

    immune system

    Unknown

    Laryngeal edema, Quincke's edema, hives.

    Violations of the genitals and mammary gland

    Infrequently

    Pain in the mammary glands, erectile dysfunction.

    Disorders from the psyche

    Infrequently

    Confusion, delirium, depersonalization, agitation, insomnia, increased excitability.

    * - these adverse reactions were observed in pre-dialysis patients.

    Adverse reactions are given below in accordance with the damage to organs and organ systems, the frequency of which is unknown.

    Immune system disorders: allergic reactions, hives, Quincke's edema and laryngeal edema.

    Disorders from the metabolism and nutrition: hypercalcemia.

    Laboratory and instrumental data: an increase in the value of the product of calcium and phosphorus (an increase is due to an increase in the concentration of Ca), an increase in the concentration of creatinine in the blood.

    Overdose:
    Overdose of the drug Zemplar® can cause hypercalcemia, hypercalciuria and hyperphosphatemia, as well as a marked decrease in PTH secretion. Consumption of large amounts of calcium and phosphorus simultaneously with the use of Zemplar® can lead to similar disturbances.

    Treatment of acute accidental overdose of Zemplar® requires urgent care. If the fact of overdose is detected in a relatively short time, you can induce vomiting or rinse the stomach, which will help prevent further absorption of paricalcitol. If it is assumed that the drug has already passed through the stomach, its rapid removal from the intestine can be facilitated by the intake of vaseline oil. It is necessary to monitor the serum concentration of electrolytes (especially calcium), the rate of excretion of calcium through the kidneys and to assess changes in the ECG, which may be associated with hypercalcemia. Such monitoring is very important in patients receiving cardiac glycosides. The cessation of consumption of dietary supplements containing calcium and compliance with a diet low in calcium is also indicated in case of accidental drug overdose. As parikalcitol has a relatively short duration of pharmacological action, the implementation of further actions, as a rule, is not required. For the treatment of severe hypercalcemia, the use of such drugs,as salts of phosphoric acids and glucocorticosteroids; it is also possible to carry out forced diuresis. Paricalcitol is not significantly eliminated during dialysis.

    Signs and symptoms of vitamin intoxication D, associated with hypercalcemia include:

    Early: weakness, headache, drowsiness, nausea, vomiting, dry mouth, constipation, muscle pain, bone pain and metallic taste in the mouth.

    Late: anorexia, weight loss, conjunctivitis (calcification), pancreatitis, photophobia, rhinorrhea, pruritus, hyperthermia, decreased libido, increased blood urea nitrogen concentration, hypercholesterolemia, increased concentration ACT and ALT, ectopic calcification, increased blood pressure, cardiac arrhythmia, drowsiness and rarely - psychosis. Cases of overdose with a lethal outcome have been reported.

    Interaction:

    It is known that ketoconazole is a nonspecific inhibitor of several cytochrome P450 isoenzymes. The available data obtained in the studies in vivo and in vitro, give grounds to believe that ketoconazole can interact with enzymes that are responsible for the metabolism of paricalcitol and other vitamin analogues D. Care should be taken when concomitantly administering paricalcitol with ketoconazole. The effect of repeated administration of ketoconazole when administered at a dose of 200 mg twice daily for 5 days on the pharmacokinetics of paricalcitol (in the form of a capsule) was studied in healthy volunteers. FROMmax parikiltsitola practically did not change, but AUCo-∞ with the appointment of ketoconazole increased approximately two-fold. The average half-life of paricalcitol in the administration of ketoconazole was 17.0 hours compared to 9.8 hours when a paricalcitol was administered without ketoconazole. The results of this study show that after oral or intravenous administration of paricalcitol, the maximum AUQinf parikaltsitol as a result of drug interaction with ketoconazole, probably increases no more than twice. Special studies of drug interactions have not been conducted. The toxicity of cardiac glycosides is enhanced with hypercalcemia (any etiology), therefore caution should be exercised while concomitant administration of cardiac glycosides with paricalcitol.

    Do not prescribe drugs associated with phosphorus or vitamin D, simultaneously with parikiltsitolom due to the increased risk of hypercalcemia and an increase in the product of Ca x R

    High doses of kalydium-containing drugs or thiazide diuretics may increase the risk of hypercalcemia.

    Do not prescribe magnesium-containing drugs (eg, antacids) concomitantly with preparations of the vitamin D, due to the risk of hypermagnesemia.

    Preparations containing aluminum (for example, antacids, drugs, phosphate binders) should not be prescribed for a long time at the same time as vitamin preparations D, due to a possible increase in the concentration of aluminum in the blood and the toxic effect of aluminum on bone tissue.

    Drugs that impair intestinal absorption of fat-soluble vitamins, such as colestramine, may interfere with the absorption of Zemplar® (in the form of a capsule).

    Special instructions:

    Excessive suppression of PTH secretion can lead to an increase in serum calcium concentration and a decrease in metabolic processes in bone tissue. To achieve the appropriate physiological parameters, monitoring of the patient's condition and individual selection of the dose of Zemplar® are necessary.

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

    In the case of the development of clinically significant hypercalcemia in the patient receiving parikalcitol together with calcium-containing phosphate binders, 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.

    Care should be exercised when using paricalcitol together with ketoconazole.

    The preparation Zemplar® capsules as an auxiliary substance contains ethanol (less than 100 mg per capsule (dosages of 1 μg, 2 μg and 4 μg). Ethanol can be potentially dangerous for patients with liver disease, alcoholism, epilepsy, pregnant women and children.

    Laboratory research

    With initial dose selection or any change in the dose, serum concentrations of calcium, phosphorus, serum or plasma concentrations of IPPH should be determined at least every 2 weeks for 3 months after starting treatment with Zemplar®or after changing the dose of Zemplar®, then every month for 3 months, then every 3 months.

    In patients at the pre-dialysis stage, parikalcitol, as well as other activators of the vitamin receptor D, can increase the concentration of serum creatinine (and, consequently, reduce the estimated rate of glomerular filtration (rSKF)) without changing the true glomerular filtration rate (GFR).

    Use in children

    The efficacy and safety of Zemplar® in children has not been studied.

    Application in the elderly

    There was no difference in efficacy or safety in patients aged 65 years and older.

    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 therapy with the drug Zemplar "to refrain from driving and doing other activities that require an increased concentration of attention and speed of psychomotor reactions.
    Form release / dosage:

    Capsules 1 μg, 2 μg.

    Packaging:7 capsules or 14 capsules in a blister of PVC / PVDC / polymer film and aluminum foil; 1, 2 or 4 blisters together with instructions for use in a cardboard bundle.
    Storage conditions:

    Store at temperatures between 15 ° C and 25 ° C. Do not freeze.

    Keep out of the reach of children.

    Shelf life:

    2 years. Do not use after the expiry date printed on the package.

    Terms of leave from pharmacies:On prescription
    Registration number:LSR-010759/09
    Date of registration:29.12.2009 / 23.07.2015
    Expiration Date:Unlimited
    The owner of the registration certificate:EbbVi Ltd.EbbVi Ltd. Russia
    Manufacturer: & nbsp
    Representation: & nbspEbbVi Ltd.EbbVi Ltd.Russia
    Information update date: & nbsp11.10.2017
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