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 2 μg;

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

Description:A clear, colorless solution.

Pharmacotherapeutic group:Calcium-phosphorus exchange regulator

ATX: & nbsp

H.05.B.X Other antiparatyroid drugs

H.05.B.X.02 Paricalcitol

Pharmacodynamics:

Parikaltsitol - a synthetic analogue of a biologically active vitamin D (calcitriol), a selective activator of vitamin A receptors D. Paricalcitol has a biological effect by interacting with the vitamin receptors D, which leads to a selective activation of the response mediated by this vitamin. Vitamin D and parikalcitol reduce the concentration of parathyroid hormone by inhibiting its synthesis and secretion. In the early stages of chronic kidney disease, a decrease in the concentration of calcitriol is observed.

Secondary hyperparathyroidism is characterized by an increase in the concentration of parathyroid hormone (PTH), which is associated with an inadequate concentration 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)₂ D3] is an endogenous hormone that activates 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 concentration of PTH, the development of secondary hyperparathyroidism and disruption of calcium and phosphorus homeostasis. Decreased concentrations of calcitriol and increased concentrations of PTH, which often precede changes in plasma concentrations of calcium and phosphorus, cause changes in the rate of bone metabolism and can lead to the development of renal osteodystrophy. In patients with chronic kidney disease, a decrease in PTH concentration has a beneficial effect onactivity of bone alkaline phosphatase, metabolic processes in bone tissue and bone tissue fibrosis. Therapy with an active vitamin D not only reduces the concentration 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 of 0.04 to 0.24 μg / kg, the concentration of paricalcitol rapidly decreases; but in the following the concentration of paricylcitol is reduced linearly, with an average half-life of about 15 hours. When repeated application of paricalcitol, there are no signs of cumulation.

Distribution

Para Kalcitol is actively associated with 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 (terminal renal failure - creatinine clearance less than 15 ml / min / 1.73 m² or the need for continuous dialysis) treated with hemodialysis or peritoneal dialysis, the volume of the distribution of paricylcitol at 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 paricylcytol are determined. Unchanged in urine parikalcitol Not found. Paricalcitol metabolized under the action of numerous hepatic and extrahepatic enzymes, including the mitochondrial isoenzyme CYP24, as well as isozymes CYP3A4 and UGT1A4. Identified metabolites include 24 (H) -hydroxylation products (low concentrations in plasma), as well as 24,26 and 24,28 dihydroxylation and direct glucuronation. Paricalcitol does not have an inhibitory effect on isozymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A in concentrations up to 50 nmol / l (21 ng / ml). At similar concentrations of paricalcitol, the activity of isoenzymes CYP2B6, CYP2C9 and CYP3A4 increases by less than 2 times.

Excretion

Paricalcitol is excreted by excretion with bile. In healthy people, approximately 63% of paricalcitol is excreted through the intestine and 19% by the kidneys. The half-life (T1/2) of paricalcitol in doses from 0.04 to 0.16 μg / kg in healthy volunteers averages 5-7 hours.

Impaired liver function

The pharmacokinetics of paricalcitol (0.24 μg / kg) were compared in patients with mild to moderate liver impairment (Child-Pugh class A and B classes) and healthy individuals. The pharmacokinetics of unbound paracyclotol was similar in these patient groups.

Correction of the dose in patients with mild or moderate impairment of liver function is not required. The pharmacokinetics of paricylcytol in patients with severe impairment of liver function have not been studied.

Impaired renal function

The pharmacokinetics of paricalcitol have been studied in patients with chronic kidney disease 5 stage treated with hemodialysis or peritoneal dialysis. 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 (Cl) and an increase T_1/2 parikiltsitola compared with healthy people.

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 application with preparations containing calcium and / or magnesium; Long-term use of aluminum preparations;

Hypercalcemia;

Hypersensitivity to any component of the drug;

Children under 18 years of age (effectiveness and safety not established);

Breastfeeding period.

Carefully:

Simultaneous use with cardiac glycosides.

Pregnancy and lactation:Studies in pregnant women have not been conducted. Information on the removal of paricalcitol with breast milk in women is not. Paricalcitol can be used in pregnancy only if the potential benefit to the mother justifies the possible risk to the fetus. If you need to use the drug during lactation, breastfeeding should be discontinued.

Dosing and Administration:

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. As with other solutions for parenteral use, the ampoule with Zemplar® preparation should be examined before administration for the presence offoreign particles and discoloration.

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 (in patients weighing about 100 kg).

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 initial dose taking into account the initial concentration of PTH

Patients with chronic renal failure (chronic kidney disease of stage 5) used the method of quantitative second-generation immunoassay for determining the concentration of biologically active intact PTH (determining intact PTH by N-the end fragment. C-terminal fragment and central fragment, in contrast to the method of the first generation, determining the concentration of PTH on the C-terminal fragment and the central fragment). 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 (μg) = Initial concentration of PTH (pg / ml) / 80

Dose titration

Conventional target concentrations of PTH in patients with chronic renal diseases of stage 5 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 concentrations, careful monitoring of PTH concentration and individual titration of the dose are necessary.

At any dose changes, serum calcium concentrations (adjusted for hypoalbuminemia) and phosphorus should be determined more often. If the adjusted calcium concentration is increased or the concentration of phosphorus is increased steadily, it is necessary to reduce the dose of the drug until these parameters are normalized. In the presence of hypercalcemia or persistent increase in the product of concentrations of calcium and phosphorus, Ca x P (more than 75), the dose of the drug should be reduced or the treatment should be interrupted until these parameters are normalized. Then you can resume therapy with paricalcitol in a smaller dose. If a patient receives a calcium-containing drug that binds phosphates, it is advisable to reduce his dose, temporarily cancel the drug or transfer the patient to a drug that does not contain calcium.As the concentrations of PTH decrease in response to treatment, a dose reduction of paricalcitol may be required. Thus, the dose should be selected individually.

If an adequate response is not obtained, the dose can be increased by 2-4 μg every 2-4 weeks. When the concentration of PTH <150 pg / ml is reduced, the dose of the drug should be reduced.

Recommended dose titration scheme

Concentration of PTH	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 preparation of 290 patients, Zemplar® was prepared. The most common adverse reaction associated with Zemplar® therapy was hypercalcaemia and developed in 4.1% of patients. Hypercalcemia depends on the level of excessive suppression of PTH and, with proper dose selection, can be minimized.

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

Class of organ systems	Adverse Reactions	Frequency
Infectious and parasitic diseases	Pneumonia, influenza, upper respiratory tract infection, nasopharyngitis.	Infrequently
Benign, Malignant and unspecified formations (including cysts and polyps)	Mammary cancer	Infrequently
From the side of the cardiovascular system	Anemia, atrial fibrillation, cardiac arrest, palpitations *, marked increase in blood pressure (BP), marked decrease in blood pressure.	Infrequently
From the endocrine system	Hypoparathyroidism	Infrequently
From the side of nutrition and metabolism	Hypercalcemia	Often
From the side of nutrition and metabolism	Hyperphosphatemia, hypocalcemia, decreased appetite.	Infrequently
From the nervous system	Dysgeusia, headache	Often
From the nervous system	Acute disorders of cerebral circulation, dizziness, hypoesthesia, myoclonia, paresthesia, fainting, agitation, confused consciousness, delirium, insomnia, nervousness, restlessness.	Infrequently
From the side of the organ of vision	Conjunctivitis	Infrequently
From the respiratory system	Cough, dyspnea, orthopnea, pulmonary edema	Infrequently
From the gastrointestinal tract	Gastrointestinal bleeding *, constipation, diarrhea	Often
From the gastrointestinal tract	Discomfort in the abdomen, dry mouth, intestinal ischemia, rectal bleeding, vomiting	Infrequently
From the skin and subcutaneous tissue	Alopecia, blisters, itching, itching rash, burning sensation on the skin	Infrequently
From the side of the musculoskeletal system	Arthralgia, joint stiffness, muscle twitching, myalgia	Infrequently
From the side reproductive system	Pain in the chest, erectile dysfunction	Infrequently
Other	Pain at the injection site, fever, chills *.	Often
Other	Asthenia, aggravation, fatigue, gait disturbance, malaise, swelling, increased activity aspartate aminotransferase (ACT), deviation of laboratory tests, weight loss	Infrequently

* Such adverse reactions as palpitations, gastrointestinal bleeding, and chills were observed in the study at a frequency greater than in patients taking placebo, the investigator did not establish a cause-and-effect relationship with taking the drug.

The following are side reactions, the frequency of which is not known.

Infections and parasitic diseases: sepsis, vaginal infection.

From the side of the cardiovascular system: lymphadenopathy, arrhythmia.

From the immune system: hypersensitivity, angioedema, edema of the larynx.

From the endocrine system: hyperparathyroidism.

From the side of nutrition and metabolism: hyperkalemia.

From the nervous system: lack of response to stimuli.

From the sense organs: glaucoma, hyperemia of the eyes, sensation of corkiness of the ears.

From the respiratory system: wheezing.

From the gastrointestinal tract: dysphagia, gastritis, nausea.

From the skin and subcutaneous tissue: hirsutism, night sweats, rash, hives.

Other: discomfort in the chest, chest pain, swelling, including peripheral, a feeling of malaise, extravasation at the injection site, pain in the limbs, thirst, increased bleeding time, heart rhythm disturbances.

Overdose:

Overdose of paricalcitol can lead to the development of hypercalcaemia, hypercalciuria, hyperphosphatemia and suppression of secretion of PTH.

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 is not significantly excreted in hemodialysis. Treatment of patients with clinically significant hypercalcemia includes immediate dose reduction or discontinuation of paricylcytol treatment, as well as a diet low in calcium, rejection of calcium supplements, patient mobilization, monitoring of electro-electrolyte balance, assessment of ECG abnormalities (especially important in patients taking cardiac glycosides) , as well as hemodialysis or peritoneal dialysis using dialysate without calcium salts (according to indications). When the serum calcium concentration is normalized, treatment with paricalcitol can begin at a lower dose. In the case of a persistent or pronounced increase in serum calcium concentration, several treatment options should be considered: phosphates, glucocorticosteroids, and diuresis stimulants.

Interaction:

The interaction of paricalcitol for injections with other drugs has not been specifically studied.

When studying the interaction of ketoconazole and paricalcitol in capsules, it was shown that ketoconazole increases AUCo-w (the area under the concentration-time curve) of paricalcitol is approximately two-fold. Paricalcitol partially metabolized by isoenzyme CYP3A, a ketoconazole is a potent inhibitor of isoenzyme CYP3A, therefore, care should be taken when combining the use of paricalcitol with ketoconazole and other potent inhibitors of the isoenzyme CYP3A.

Phosphates or drugs, which include a vitamin D, should not be taken with parikiltsitol in connection with an increased risk of hypercalcemia and an increase in the product of concentrations of calcium and phosphorus Ca x R

Simultaneous use of high doses of drugs containing calcium, or thiazide diuretics and parikiltsitol can increase the risk of hypercalcemia. Containing magnesium preparations (for example, antacids) should not be taken together with parikiltsitolom in connection with the possibility of hypermagnesemia.

Preparations containing aluminum (for example, antacids, phosphate binders) should not be used for a long time together with parikiltsitol in connection with the possibility of increasing the serum aluminum concentration and the development of toxicity of aluminum against bones.

According to the research data in vitro parikiltsitol should not inhibit C1 drugs that are metabolized by isoenzymes CYPIA2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A, or to induce the clearance of substances, biotransforms and isoenzymes CYP2B6, CYP2C9 or CYP3A.

Hypercalcemia of any nature aggravates intoxication with cardiac glycosides, therefore it is necessary to be careful when using them with parikiltsitol.

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 paricylcytol can be complicated by hypercalcemia, increased Ca x R, and calcification of soft tissues (metastatic calcification).

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

Concentrations of PTH in serum or plasma are recommended to be monitored every 3 months (see section "Method of administration and dose").

With a decrease in PTH concentration below the norm, it is possible to develop adynamic bone disease, a pathological state with low bone turnover.

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, 2 μg / ml.

Packaging:

1 ml into 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.

Storage conditions:

Store at a temperature of 15 to 25 ° C. The drug should be stored in places inaccessible to 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:LP-001078

Date of registration:28.10.2011

Expiration Date:28.10.2016

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

Manufacturer: & nbsp

HOSPIRA, S.p.A. Italy

Representation: & nbspABBOTT LABORATORIES LLC ABBOTT LABORATORIES LLC Russia

Information update date: & nbsp11.10.2017

Illustrated instructions

Instructions

Zemplar® (Zemplar®)