Zemplar

2024 Author: Rachel Wainwright | [email protected]. Last modified: 2023-12-15 07:39

Zemplar: instructions for use and reviews

1. Release form and composition
2. Pharmacological properties
3. Indications for use
4. Contraindications
5. Method of application and dosage
6. Side effects
7. Overdose
8. Special instructions
9. Application during pregnancy and lactation
10. Use in childhood
11. In case of impaired renal function
12. For violations of liver function
13. Use in the elderly
14. Drug interactions
15. Analogs
16. Terms and conditions of storage
17. Terms of dispensing from pharmacies
18. Reviews
19. Price in pharmacies

Latin name: Zemplar

ATX code: H05BX02

Active ingredient: Paricalcitol (Paricalcitol)

Producer: AbbVi LLC (Russia)

Description and photo update: 10.07.2018

Prices in pharmacies: from 5300 rubles.

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Zemplar is a drug that regulates calcium-phosphorus metabolism.

Release form and composition

capsules: soft gelatinous, oval, filled with colorless or yellowish liquid without visible inclusions; at a dosage of 1 mcg - gray, with ZA imprinting and the manufacturer's logo; at a dosage of 2 μg - light brown, with ZF imprinting and the manufacturer's logo; in a dosage of 4 mcg - light yellow, with ZK overprinting and the manufacturer's logo (7 or 14 pcs. in blisters, in a cardboard box 1, 2 or 4 blisters);
solution for intravenous (i / v) administration: a clear, colorless liquid without visible inclusions (at a dosage of 5 μg, 1 or 2 ml, at a dosage of 2 μg, 1 ml each in colorless glass ampoules with a break point; 5 ampoules in a plastic tray, 1 pallet in a cardboard box, or 5 ampoules in a cardboard box with partitions).

Composition of 1 capsule:

active substance: paricalcitol - 1, 2 or 4 mcg;
auxiliary ingredients: gelatin, butylhydroxytoluene, glycerol, ethanol, titanium dioxide, medium-chain triglycerides, purified water; for a dosage of 1 mcg - iron oxide black oxide; for a dosage of 2 μg - iron dye yellow oxide, iron dye red oxide; for a dosage of 4 mcg - iron oxide yellow oxide;
black ink Opakod WB: isopropanol, polyvinyl acetate phthalate, propylene glycol, macrogol 400, iron dye black oxide, ammonium hydroxide (28%), ethanol, water.

Composition of 1 ml solution:

active substance: paricalcitol - 2 or 5 mcg;
auxiliary ingredients: ethanol (95%), propylene glycol, water for injection.

Pharmacological properties

Pharmacodynamics

Paricalcitol is a synthetic analogue of calcitriol (biologically active vitamin D). Its structure contains modifications of the ring A (19-nor) and side chain (D2), which determine the tissue and organ selectivity of paricalcitol. Due to this, paricalcitol selectively activates vitamin D receptors (PBD) in the parathyroid glands without increasing their activity in the intestine and has a weaker effect on bone resorption.

By activating receptors in the parathyroid glands that are sensitive to calcium, paricalcitol reduces the level of parathyroid hormone (PTH), inhibiting parathyroid proliferation and inhibiting the synthesis and secretion of PTH. The drug has a minimal effect on the levels of phosphorus and calcium, it can act directly on bone cells. Correction of pathological levels of PTH and normalization of phosphorus and calcium homeostasis due to the use of paricalcitol contributes to the therapy and prevention of bone tissue diseases associated with metabolic disorders due to chronic kidney disease (CKD).

Secondary hyperparathyroidism is characterized by an increase in the PTH content due to an inadequate increase in the level of active vitamin D synthesized in the skin, as well as entering the body with food. Vitamin D, through sequential hydroxylation in the liver and kidneys, is transformed into an active form that interacts with vitamin D receptors. Vitamin D in an active form stimulates the work of vitamin D receptors in the intestines, parathyroid glands, kidneys, bone tissue (thereby maintaining the function of the parathyroid glands and phosphorus homeostasis and calcium), in many other tissues, including in immune cells, prostate and endothelium. Receptor activation is required for adequate osteogenesis. In the case of renal failure, vitamin D activation is suppressed, leading to an increase in PTH levels,the development of secondary hyperparathyroidism and impaired homeostasis of phosphorus and calcium. Decreases in the active form of vitamin D seen in the early stages of CKD, combined with an increase in PTH activity, often preceding changes in serum phosphorus and calcium levels, can cause changes in the rate of bone turnover with subsequent development of renal osteodystrophy.

Decreased PTH levels in CKD have a positive effect on bone metabolism, bone alkaline phosphatase (ALP) activity, and bone fibrosis. Concomitant use of active vitamin D can increase phosphorus and calcium levels. Due to its selective action on vitamin D receptors, paricalcitol effectively reduces the level of PTH, normalizes metabolism in bone tissue, prevents and eliminates the consequences of deficiency in the activation of vitamin D receptors, without significantly affecting the level of phosphorus and calcium.

Pharmacokinetics

Zemplar capsules are well absorbed in the digestive tract. When taken orally at a dose of 0.24 μg / kg in healthy volunteers, the absolute bioavailability of paricalcitol is ~ 72%, the maximum plasma concentration (C _max) is 0.63 ng / ml, the time to reach the maximum concentration (T _max) is 3 hours, the area under the pharmacokinetic curve "concentration-time" AUC (0 → ∞) - 5.25 ng × h / ml. In patients undergoing hemodialysis and peritoneal dialysis, the mean absolute bioavailability of paricalcitol is 79 and 86%, respectively. According to the research results, it was determined that the indicators C _max and AUC (0 → ∞) when taking paricalcitol with fatty foods in comparison with taking it on an empty stomach do not change, therefore Zemplar capsules can be taken regardless of the diet.

C _max and AUC (0 → ∞) in healthy volunteers proportionally increase if the drug is used in doses from 0.06 to 0.48 μg / kg. Repeated intake of Zemplar daily or 3 times a week for 7 days, a constant concentration of paricalcitol is achieved and does not change in the future. With repeated daily administration of paricalcitol in patients with stage 4 CKD, the AUC level (0 → ∞) was also slightly lower than after a single dose of it.

Within 2 hours after intravenous administration of Zemplar solution in the form of a bolus in doses from 0.04 to 0.24 μg / kg, the concentration of the active substance decreases rapidly, further its decrease occurs linearly, with an average half-life (T½) ~ 15 hours. In the case of repeated infusions, there are no signs of accumulation of paricalcitol.

The main pharmacokinetic characteristics of the drug Zemplar:

distribution:> 99% of paricalcitol binds to plasma proteins. The average volume of distribution of paricalcitol when taken orally: at a dose of 0.24 μg / kg in healthy volunteers - 34 liters; after taking 4 mcg in patients with stage 3 CKD and 3 mcg in patients with stage 4 CKD ~ 44–46 liters. The volume of distribution of paricalcitol with intravenous bolus administration of the solution in an equilibrium state in healthy people is ~ 23.8 liters. In patients with stage 5 CKD who are on hemodialysis or peritoneal dialysis, the volume of distribution of paricalcitol at a dose of 0.24 mcg / kg averages 31–35 liters;
metabolism: when taken orally (dose 0.48 μg / kg), paricalcitol is largely metabolized, only 2% of the dose taken is excreted unchanged through the intestine, the presence of the original drug in the urine is not determined. When administered intravenously, paricalcitol is metabolized under the influence of various hepatic and extrahepatic enzymes; several metabolites of the original drug are found in urine and feces; unchanged paricalcitol is not detected in urine;
excretion: paricalcitol is excreted mainly due to hepatobiliary excretion, T½ in healthy volunteers is on average 5-7 hours; oral administration - up to 70% of metabolites are excreted in the feces and 18% in the urine; bolus intravenous injection - ~ 63% of the drug is excreted in the feces and 19% in the urine.

Indications for use

capsules: prevention and therapy of secondary hyperparathyroidism that develops in stage 3–4 CKD, as well as in patients with stage 5 CKD who are on hemodialysis or peritoneal dialysis;
solution for intravenous administration: prevention and therapy of secondary hyperparathyroidism that develops in stage 5 CKD.

Contraindications

Absolute:

hypercalcemia;
hypervitaminosis D;
complex use with derivatives of vitamin D and / or phosphates;
period of breastfeeding (lactation);
children and adolescents up to 18 years old;
increased individual sensitivity to any of the components.

With caution, Zemplar is recommended to be used in conjunction with cardiac glycosides.

Instructions for use of Zemplar: method and dosage

Capsules

Zemplar is taken orally, the drug intake does not depend on the diet.

For the treatment of stage 3-4 CKD, paricalcitol capsules are taken once a day, daily or 3 times a week (no more than every other day). At the same time, the average weekly doses for both regimens of therapy are the same. Despite similar dosing regimens, daily administration of the drug is preferable, since it reduces the risk of unintentional disruption of the drug regimen and promotes greater patient adherence to therapy.

The initial dose of Zemplar at the level of the initial concentration of PTH:

≤ 500 pg / ml (56 pmol / l): with daily intake - 1 μg, with intake 3 times a week - 2 μg;
> 500 pg / ml (56 pmol / l): when taken daily - 2 mcg, when taken 3 times a week - 4 mcg.

Dose titration is performed on an individual basis and depends on the baseline plasma / serum PTH concentration and monitoring data for serum phosphorus and calcium levels.

Serum levels of phosphorus and calcium should be monitored carefully during the period after the start of taking paricalcitol capsules, during dose titration and in the case of co-administration with potent inhibitors of P450 3A. If hypercalcemia is detected or in the case of a stable increase in the product of Ca (calcium) × P (phosphorus), it is necessary to reduce the dose of calcium-containing phosphate-binding drugs or stop taking them. Alternatively, a reduction in the dose of paricalcitol in capsules or a temporary interruption of the course of therapy is allowed. At the end of the break, the drug is resumed at a lower dose, after reaching the target serum levels of phosphorus and calcium, as well as the product of Ca × P.

With CKD stage 5, Zemplar capsules are taken 3 times a week, but not more often than after 1 day. The starting dose of paricalcitol in capsules is determined by the formula: paricalcitol (μg) = IPTH (baseline parathyroid hormone level) (pg / ml) / 60 or IPTH (pmol / L) / 7.

The titration of the dose of paricalcitol in capsules is performed individually and depends on the level of iPTH, as well as serum levels of phosphorus and calcium. It is recommended to select the dose according to the following formula: titrated dose (μg) = IPTH according to the last measurement (pg / ml) / 60.

Serum levels of phosphorus and calcium must be carefully monitored after initiation of therapy, during dose titration, and in the case of coadministration with potent P450 3A inhibitors. With an increase in the serum calcium level or the product of Ca × P while receiving calcium-containing phosphate binders, the dose of the latter must be reduced or discontinued. The use of phosphate-binding drugs that do not contain calcium is allowed. If the serum calcium level is> 11 mg / dl or the product of Ca × P> 70 mg / dl, the dose of the drug should be reduced by 2–4 μg from the last time calculated using the IPTH / 60 formula. If additional dose adjustment of paricalcitol in capsules is necessary, it is allowed to reduce it or stop taking the drug for the period of normalization of indicators. As the PTH level approaches the required level, a small individual dose adjustment may be required to achieve a stable PTH level. If PTH, phosphorus, or calcium levels are monitored less than once a week, a lower starting dose and a smaller dose change during titration is acceptable.

According to clinical studies, when using Zemplar 3 times a week, the average dose was: in the 1st week - 11.2 μg; average exchange rate - 6.3 mcg; maximum safe - 32 mcg.

Solution

Zemplar solution is usually injected into a vein through a hemodialysis catheter. If the patient does not have a hemodialysis catheter, the solution can be injected intravenously, slowly (at least 30 seconds) to minimize pain from the infusion.

Before the introduction of the ampoule with the drug Zemplar should be inspected for foreign inclusions and discoloration. You can only use a clear, colorless solution without visible impurities. The unused residue of the drug must be disposed of.

Initial dose, calculation options (administered as a bolus during dialysis, but not more often than once every 2 days):

by body weight: 0.04–0.1 μg / kg, corresponding to the value of a single dose in the range of 2.8–7 μg;
according to iPTH (the second generation method is used in patients with stage 5 CKD): according to the formula - iPTG (pg / ml) / 80.

The maximum safe dose according to clinical studies reached 40 μg.

The generally accepted target values for PTH in dialysis patients with end-stage renal failure exceed the upper limit of normal (ULN) in patients without uremia by no more than 1.5–3 times (150–300 pg / ml). To achieve such indicators, it is necessary to carefully monitor the PTH levels and titrate the doses individually.

Any dose changes require frequent determination of serum phosphorus and calcium concentrations (corrected for hypoalbuminemia). In the case of a persistent increase in the concentration of phosphorus (> 6.5 mg / dl) or an increase in the adjusted level of calcium (> 11.2 mg / dl), the dose of the drug should be reduced until these indicators are normalized. In the presence of a persistent increase in Ca × P (> 75) or hypercalcemia, the dose of the drug should be reduced or discontinued until the indicated parameters are normalized; it is recommended to resume treatment with paricalcitol with a lower dose. If the patient receives calcium-containing drugs that bind phosphates, it is advisable to reduce their dose, temporarily cancel or switch to analogs that do not contain calcium. As PTH levels decline in response to therapy, a dose reduction of paricalcitol may be required.

When it is not possible to achieve an adequate response, the dose of Zemplar can be increased every 2-4 weeks by 2-4 micrograms. If the PTH level decreases <150 pg / ml, a dose reduction is required.

Side effects

The scale of the frequency of occurrence of adverse reactions: very often - ≥ 0.1; often - 0.01-0.1; infrequently - 0.001–0.01; rarely - 0.0001-0.001; extremely rare - <0.00001, including individual messages.

Capsules

Adverse reactions from organs and systems in patients with CKD stage 3-4 according to clinical studies:

immune system: infrequently - hypersensitivity;
nervous system: infrequently - dizziness, taste distortion (dysgeusia);
gastrointestinal tract (GIT): often - discomfort in the epigastric region; infrequently - dryness of the oral mucosa, constipation;
skin and subcutaneous tissue: often - rash; infrequently - urticaria, itchy skin;
musculoskeletal system: infrequently - muscle spasm;
data from laboratory and instrumental studies: infrequently - deviation from the norm of indicators of the activity of liver enzymes.

Adverse reactions from organs and systems in patients with stage 5 CKD according to clinical studies:

metabolism: often - hypocalcemia, hypercalcemia;
nervous system: often - dizziness;
Gastrointestinal tract: often - decreased appetite, GERD (gastroesophageal reflux disease), diarrhea;
skin and subcutaneous tissue: often - acne;
mammary gland and genitals: often - breast tenderness.

Solution

Adverse reactions from organs and systems, possibly associated with the use of Zemplar solution:

infections: infrequently - nasopharyngitis, influenza, pneumonia, upper respiratory tract infections, vaginal infections, sepsis;
hematopoietic system: infrequently - anemia, lymphadenopathy, leukopenia;
immune system: infrequently - hypersensitivity reactions; frequency unknown - urticaria, laryngeal edema, angioedema;
cardiovascular system: infrequently - a feeling of palpitations, atrial fibrillation, increase / decrease in blood pressure, arrhythmia, cardiac arrest;
endocrine system: often - hypoparathyroidism; infrequently - hyperparathyroidism;
metabolism: often - hyperphosphatemia, hypercalcemia; infrequently - hyperkalemia, hypocalcemia;
neoplasms: infrequently - breast cancer;
nervous system: often - headache, taste distortion (dysgeusia); infrequently - dizziness, acute disturbances of cerebral circulation, hypesthesia, paresthesia, myoclonus, fainting, confusion, agitation, nervousness, restlessness, insomnia, transient ischemic attack, delirium; frequency unknown - lack of responses to stimuli;
sense organs: infrequently - discomfort in the ears, glaucoma, conjunctivitis; frequency unknown - redness of the eyes;
Gastrointestinal tract: often - constipation, diarrhea, gastrointestinal bleeding; infrequently - dry mouth, nausea / vomiting, colitis, epigastric discomfort, gastritis, intestinal ischemia, dysphagia, rectal bleeding;
skin and subcutaneous tissue: often - itching; infrequently - rash, blisters, hirsutism, alopecia, night sweats, itchy rash, burning sensation of the skin;
musculoskeletal system: infrequently - joint stiffness, myalgia, arthralgia, muscle twitching;
mammary gland and genitals: infrequently - erectile dysfunction, breast tenderness;
laboratory data: infrequently - an increase in the activity of alanine aminotransferase (ACT), a deviation of laboratory parameters from the norm, an increase in bleeding time, a decrease in body weight;
other reactions: often - pain at the injection site, chills, fever; infrequently - fatigue, asthenia, feeling unwell, thirst, edema (including peripheral), gait disturbance, chest discomfort / pain, bruising at the injection site, pain.

Overdose

No cases of overdose of paricalcitol with parenteral administration have been reported.

Symptoms of a paricalcitol overdose when taken orally (capsules) are: hypercalcemia, hypercalciuria, hyperphosphatemia, and excessive suppression of PTH secretion. Symptoms appear as a whole similar to those of a vitamin D overdose: weakness, headache, drowsiness, nausea / vomiting, dry mouth, constipation, muscle pain, bone and abdominal pain, metallic taste in the mouth, anorexia, epigastric discomfort.

In case of overdose, it is required to monitor the manifestation of signs and symptoms of hypercalcemia by monitoring the level of calcium concentration in the blood. And only when necessary, with clinically significant hypercalcemia, should treatment be started.

For the treatment of the condition, it is recommended immediately:

reduce the dose or stop taking paricalcitol;
follow a diet low in calcium;
stop taking dietary supplements that include calcium;
increase physical activity;
monitor the water and electrolyte balance and electrocardiogram (ECG), which is especially important for patients taking cardiac glycosides;
to carry out hemodialysis or peritoneal dialysis using dialysate without calcium content (according to indications). Little paricalcitol is excreted during hemodialysis.

After the normalization of serum calcium concentration, therapy with Zemplar in capsules can be resumed, but at a lower dose. For persistent or severe elevations in serum calcium, several alternative treatment options are recommended, including phosphates, glucocorticosteroids (GCS), and diuresis stimulants.

According to the instructions, Zemplar in the form of a solution for intravenous administration contains an auxiliary substance - propylene glycol (30% vol.). With the introduction of the solution in high doses, isolated cases of depression of the central nervous system, lactic acidosis and hemolysis were observed. The development of these side effects, subject to the dosing regimen, is not expected, since during the dialysis process, propylene glycol is excreted, but the risk of developing such adverse reactions must be taken into account in case of overdose of Zemplar solution.

special instructions

Excessive inhibition of PTH secretion can cause an increase in serum calcium levels and a decrease in the rate of metabolic processes in bone tissue. Therefore, in order to achieve physiological indicators, it is necessary to constantly monitor the patient's condition and individually select and titrate doses.

If a patient develops clinically significant hypercalcemia due to the intake of calcium-containing phosphate-binding drugs, the dose of the latter should be reduced or interrupted.

For the initial selection of the dose of Zemplar in capsules, as well as for any change in it, it is necessary to determine the serum level of phosphorus, calcium, serum or plasma levels of iPTH at least once every 2 weeks for 3 months from the start of therapy. Further, such control is carried out monthly for another 3 months. If further treatment is needed, laboratory parameters are monitored every 3 months.

Laboratory tests in the case of using Zemplar in the form of a solution for intravenous administration during titration of the dose of paricalcitol may need to be performed more often. Once the dose is adjusted, serum calcium and phosphorus levels are recommended to be measured at least monthly, and serum / plasma PTH levels should be monitored every 3 months.

To obtain more reliable data on the analysis of biologically active PTH in patients with stage 5 CKD, it is preferable to use the method of the second or subsequent generations.

Influence on the ability to drive vehicles and complex mechanisms

The study of the effect of paricalcitol on the ability of patients to drive a car and work with complex mechanisms has not been conducted. But, given the possibility of such side effects as dizziness and fainting, during therapy with Zemplar it is recommended to refrain from engaging in activities that require increased concentration of attention and speed of psychomotor reactions.

Application during pregnancy and lactation

Due to the fact that studies of the effect of paricalcitol have not been carried out in pregnant women, Zemplar is recommended to be used only according to indications, provided that the potential benefits to the mother exceed the possible risks to the fetus.

There is no information on the elimination of paricalcitol in breast milk during lactation. If it is necessary to use the drug during lactation, breastfeeding must be discontinued.

Pediatric use

In childhood and adolescence (up to 18 years), the use of Zemplar is contraindicated, since clinical studies on the effectiveness and safety of drug therapy in this age group have not been conducted.

With impaired renal function

In case of impaired renal function, Zemplar is used according to indications.

For violations of liver function

For patients with mild to moderate hepatic impairment (according to Child-Pugh classification), dose adjustment is not required.

Since the pharmacokinetics of paricalcitol have not been studied in patients with severely impaired liver function, the use of Zemplar is contraindicated for them.

Use in the elderly

There were no differences in the efficacy and safety of paricalcitol use in older people over the age of 65 compared with younger patients.

Drug interactions

Separately, the interaction of Zemplar in the form of a solution for injection with other drugs has not been specifically studied.

Paricalcitol drug interactions:

ketoconazole: causes an increase in AUC (0 → ∞) of paricalcitol with oral administration of the latter approximately 2 times, T½ of paricalcitol increases from 9.8 to 17 hours; since paricalcitol is partially metabolized by the CYP3A isoenzyme, and ketoconazole is a potent inhibitor of this isoenzyme, caution should be exercised when using paricalcitol and ketoconazole, as well as other potent CYP3A inhibitors;
phosphates or drugs containing vitamin D: their use with paricalcitol is contraindicated due to the increased risk of hypercalcemia and an increase in the value of the Ca × P product;
calcium-containing drugs in high doses, thiazide diuretics: the risk of hypercalcemia may increase; the combined use of Zemplar with thiazide diuretics is contraindicated;
preparations containing magnesium (antacids): use with paricalcitol and vitamin D analogues is contraindicated due to the risk of hypermagnesemia;
preparations containing aluminum (some antacids and phosphate-binding drugs): long-term combined use with paricalcitol and vitamin D analogues is contraindicated due to the risk of increased serum aluminum concentration and its toxic effect on bones;
medicinal substances metabolized by isoenzymes CYP1A2, CYP2A6, CYP2C19, CYP2B6, CYP2C8, CYP2C9, CYP2D6, CYP2E1, CYP3A: paricalcitol should not inhibit their clearance (data from in vitro studies);
medicinal substances biotransformed under the action of isoenzymes CYP2B6, CYP2C9, CYP3A: paricalcitol should not induce their clearance (data from in vitro studies);
cardiac glycosides: since hypercalcemia of any etiology aggravates intoxication, caution must be exercised when using them with paricalcitol.

Analogs

Zemplar has no structural analogs, the drug Mimpara has a similar effect.

Terms and conditions of storage

Store at 15–25 ° C, do not freeze. Keep out of the reach of children.

Shelf life is 2 years.

Terms of dispensing from pharmacies

Dispensed by prescription.

Reviews about Zemplar

According to a few reviews, Zemplar is an effective drug, although it is quite expensive, especially provided that in some forms of the disease it should be taken for life.

Price for Zemplar in pharmacies

Zemplar price:

solution for intravenous administration (5 μg / ml, 1 ml in ampoules, 5 ampoules in a cardboard box) ~ 8000 rubles;
capsules (1 μg, 7 pcs in a package, 4 packages in a cardboard box) ~ 6500 rubles

Zemplar: prices in online pharmacies

Drug name

Price

Pharmacy

Zemplar 5 μg / ml solution for intravenous administration 1 ml 5 pcs.

RUB 5300

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Anna Kozlova Medical journalist About the author

Education: Rostov State Medical University, specialty "General Medicine".

Information about the drug is generalized, provided for informational purposes only and does not replace the official instructions. Self-medication is hazardous to health!