Composition, form of production and packaging
Capsules soft gelatinous, oval, gray, with a printed logo of the company's logo and "ZA"; contents of capsules - colorless or yellowish liquid, without visible particles.
1 caps.
paricalcitol 1 Ојg
Auxiliaries: ethanol 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, ferric oxide black oxide 0.042 mg, purified water qs, black ink Opacode В® WB - traces (ethanol, propylene glycol, iron dye oxide black, polyvinyl acetate phthalate, water, isopropanol, macrogol 400, ammonium hydroxide (28%)).
7 pcs. - blisters (1) - packs of cardboard.
7 pcs. - blisters (2) - packs of cardboard.
7 pcs. - blisters (4) - packs of cardboard.
14 pcs. - blisters (1) - packs of cardboard.
14 pcs. - blisters (2) - packs of cardboard.
14 pcs. - blisters (4) - packs of cardboard.
Capsules soft gelatinous, oval, light brown, with a printed logo of the company's logo and "ZF"; contents of capsules - colorless or yellowish liquid without visible particles.
1 caps.
parikaltsitol 2 mcg
Auxiliary substances: ethanol 1.42 mg, butyl hydroxytoluene 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 , purified water - qs, black ink Opacode В® WB - traces (ethanol, propylene glycol, iron dye oxide black, polyvinyl acetate phthalate, water, isopropanol, macrogol 400, ammonium hydroxide (28%)).
7 pcs. - blisters (1) - packs of cardboard.
7 pcs. - blisters (2) - packs of cardboard.
7 pcs. - blisters (4) - packs of cardboard.
14 pcs. - blisters (1) - packs of cardboard.
14 pcs. - blisters (2) - packs of cardboard.
14 pcs. - blisters (4) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2016.
PHARMACHOLOGIC EFFECT
A drug that regulates the exchange of calcium and phosphorus. Parikaltsitol - a synthetic analogue of biologically active vitamin D (calcitriol), in the structure of which there are modifications of the side chain (D2) and ring A (19-nor). Unlike calcitriol, paricalcitol selectively activates vitamin D receptors in the parathyroid glands without increasing the activity of vitamin D receptors in the intestine and less actively affects the resorption of bone tissue. Paracalcitol also activates calcium-sensitive receptors in the parathyroid gland, thereby reducing the concentration of parathyroid hormone (PTH) by inhibiting parathyroid proliferation and decreasing the synthesis and secretion of PTH. Has minimal effect on the concentration of calcium and phosphorus, can directly affect the cells of bone tissue, supporting the volume of bone tissue and improving the mineralization of bone tissue. Correction of abnormal PTH content and normalization of homeostasis of calcium and phosphorus can prevent and / or treat bone diseases associated with impaired metabolism due to chronic kidney disease.
Clinical efficacy
Chronic kidney disease 3 and 4 stages
The primary endpoint of efficacy, implying at least two successive decreases in ipTG concentration, was 30% compared to the initial value of ipTG, was achieved in 91% of patients receiving paricylcytol in capsules and 13% of patients in the placebo group (p <0.001 ). The activity of bone alkaline phosphatase in the serum, as well as the concentration of osteocalcin in the blood serum, significantly decreased (p <0.001) in patients receiving paricylcytol in capsules, compared to 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 the parameters of kidney function on the basis of the calculated glomerular filtration rate (according to MDRD formula) and an increase in serum creatinine concentration in patients receiving paricylcytol in capsules was not found in comparison with patients in the placebo group. In a significantly larger number of patients receiving paricylcytol in capsules, a decrease in urinary protein was observed 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 IHPH concentration of ≥ 30% compared with the initial value of ipTG, was achieved in 88% of patients receiving paricylcytol in capsules and 13% of patients in the placebo group (p <0.001 ).
Use in children
The safety and efficacy of ZemplarВ® (an intravenous solution) were studied in a randomized, double-blind, placebo-controlled, 12-week study that included 29 children aged 5-19 years with end-stage renal failure on hemodialysis. The six youngest patients in the study who received the Zemplar В® preparation (solution for intravenous administration) were aged 5-12 years. The initial dose of the Zemplar В® preparation (IV solution) was 0.04 Ојg / kg 3 times a week, based on the initial ipPT concentration of less than 500 pg / ml, or 0.08 Ојg / kg 3 times a week based on the initial concentration of ipTG-500 pg / ml, respectively. The dose of Zemplar В®preparation (solution for intravenous administration) was adjusted to 0.04 Ојg / kg, depending on the serum concentration of ipPG, calcium and CaR product. 67% of patients treated with Zemplar В® (IV solution) and 14% of patients in the placebo group completed the study. In 60% of the patients treated with Zemplar В® (I / O solution), two consecutive decreases in ipHP were observed in 30% compared to the initial value of ipTG compared to 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 the preparation Zemplar В® (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 is well absorbed from the digestive tract. In healthy volunteers, the oral bioavailability of the drug at the dose of 0.24 Ојg / kg averaged about 72%, the Cmax in the blood plasma was 0.63 ng / ml (1.512 pmol / ml), the time to reach C max was 3 hours, AUC 0 -? - 5.25 ng h / ml (12.6 pmol / hr / ml). The mean absolute bioavailability of paricalcitol in patients on hemodialysis and peritoneal dialysis is 79% and 86%, respectively, with an upper 95% confidence limit of 93% and 112%, respectively. A study of the effect of food on the absorption of paricalcitol in healthy volunteers showed that C max and AUC 0-? Do not change when using parikiltsitol with fatty foods compared to its use on an empty stomach. Thus, Zemplar В® can be used regardless of food intake.
In healthy volunteers, C max and AUC 0-? parikiltsitola proportionally increase with the use of the drug in doses from 0.06 mkg / kg to 0.48 mkg / kg.
Distribution
The degree of binding of paricalcitol to plasma proteins is high (> 99%). The ratio of the concentration of paricalcitol in blood cells to the concentration of 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 low degree of binding of the drug to the blood cells. In healthy volunteers, after application of Zemplar В® in a dose of 0.24 Ојg / kg, V d was 34 liters.
Metabolism
Metabolism was studied with the help of radiolabeled paricalcitol. After oral administration at a dose of 0.48 Ојg / kg, paricalcitol is metabolized to a large extent.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 paricalcitol with respect to PTH suppression. The low activity of the active metabolite is determined in the preclinical model (in rats). In vitro studies suggest that paricalcitol is metabolized by numerous hepatic and extrahepatic isoenzymes, including mitochondrial CYP24, as well as CYP3A4 and UGT1A4. Identified metabolites include the product of 24 (R) -hydroxylation, as well as the products of 24,26- and 24,28-dihydroxylation and the direct product of glucuronation.
Excretion
Paricalcitol is excreted mainly through hepatobiliary excretion. In healthy volunteers, the mean T 1/2 of the paricalcitol is between 5 and 7 hours when Zemplar В® is usedat a dose of 0.06 Ојg / kg to 0.48 Ојg / kg.
Pharmacokinetics in specific patient groups
The pharmacokinetics of paricalcitol have not been studied in patients aged 65 years and older and in patients under the age of 18 years.
The pharmacokinetics of paricalcitol in single use at a dose of 0.06 Ојg / kg to 0.48 Ојg / kg is independent of sex.
The distribution of paricalcitol (0.24 Ојg / kg) in patients with mild to moderate liver function impairment (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 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.
With repeated use of the drug Zemplar В® 1 time / day in patients with chronic kidney disease, stage 4 AUC was slightly less than after a single application of ZemplarВ® . The average V d of the paricalcitol in patients with chronic kidney disease of the 3rd stage after application of the Zemplar В® preparation in a dose of 4 Ојg and in patients with chronic kidney disease of the 4th stage after application of the Zemplar В® preparation in a dose of 3 Ојg is 44-46 liters. The pharmacokinetic profile in the application of paricalcitol (when administered intravenously in the form of capsules) in patients with chronic kidney disease of stage 5, on hemodialysis or peritoneal dialysis, is comparable to that in patients with chronic kidney disease of stages 3 and 4. Thus, no special dose adjustment is required. The pharmacokinetics of paricalcitol (when administered intravenously in the form of capsules) was studied in patients with chronic kidney disease of stages 3 and 4 (see Table 1). After application of parikilcitol in a dose of 4 Ојg (in capsules) in patients with chronic kidney disease of the 3rd stage, the mean T 1/2 of the paricalcitol was 17 hours. The mean T 1/2 of the paricalcitol in patients with chronic kidney disease of stage 4 when the drug was administered at a dose of 3 Ојg (in capsules) is 20 hours. The degree of cumulation of paricalcitol corresponded to T 1/2 and the multiplicity of application of Zemplar В® . Conducting hemodialysis does not affect the rate of excretion of paricalcitol.
Table 1. Pharmacokinetic parameters of paricalcitol in patients with chronic kidney disease of stage 3 and 4
Pharmacokinetic parameter Healthy volunteers Chronic kidney disease Stage 3 Chronic kidney disease Stage 4 Chronic kidney disease Stage 3
Patients on hemodialysis Patients on peritoneal dialysis
Number of patients in each group 25 15 14 14 8
Dose (Ојg / kg) 0.240 0.047 0.036 0.240 0.240
CL / F (l / h) 3.6 В± 1.0 1.77 В± 0.50 1.52 В± 0.36 1.8 В± 0.8 1.8 В± 0.8
T 1/2 (h) 5.9 В± 2.8 16.80 В± 2.65 19.70 В± 7.2 13.9 В± 5.1 17.7 В± 9.6
f u * (%) 0.06 В± 0.01 0.06 В± 0.01 0.07 В± 0.02 0.09 В± 0.04 0.13 В± 0.08
* - measured at a concentration of paricalcitol 15 nmol.
INDICATIONS
- prevention and treatment of secondary hyperparathyroidism, developing in chronic kidney disease 3 and 4 stages, as well as in patients with chronic kidney disease of stage 5, who are on hemodialysis or peritoneal dialysis.
DOSING MODE
The drug is administered orally, regardless of food intake.
Chronic kidney disease 3 and 4 stages
The drug is prescribed 1 time / day, daily or 3 times a week. If Zemplar В® is used 3 times a week, it should be taken no more often than every other day. Average weekly doses with the drug every day and three times a week do not differ. Despite the fact that the clinical effect does not differ with different dosing regimens, daily use of Zemplar В® 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 В® is determined based on the initial concentration of IPPG.
Initial concentration of ipTG Dose at daily intake Dose at reception 3 times a week *
? 500 pg / ml (56 pmol / L) 1 Ојg 2 Ојg
> 500 pg / ml (56 pmol / L) 2 Ојg 4 Ојg
* Do not take more than a day
Dose titration
The dose of Zemplar В® should be selected individually, depending on the level of IPPH in plasma or serum, taking into account the serum concentrations of calcium and phosphorus.
The concentration of IPPH compared with baseline The dose of Zemplar В® (in caps.) Dose change with an interval of 2-4 weeks
With daily use When applied 3 times a week 1
The same or increased Increase 1 Ојg 2 Ојg
Decreased by <30%
Decreased by? 30%, but? 60% Leave the same - -
Decreased by> 60% Decreased 2 1 Ојg 2 Ојg
IPPG <60 pg / ml (7 pmol / L)
1 - take no more than a day. 2 - if the patient receives Zemplar В® in a minimal dose daily or 3 times a week, and a dose reduction is required, a decrease in the frequency of administration of Zemplar В® is possible.
Serum concentrations of calcium and phosphorus should be carefully monitored in patients after Zemplar В® is started, during the titration period and when combined with potent CYP3A inhibitors. If using the drug Zemplar В® the patient develops hypercalcemia or a stable increase in the product of Ca? P is more than 55 mg 2 / dl 2(4.4 mmol 2 / L 2 ), the dose of calcium-containing phosphate binders should be reduced or canceled. If necessary, it is possible to reduce the dose of Zemplar В® or temporarily discontinue it. In the case of temporary withdrawal of the drug Zemplar В® resume use of the drug should be from a lower dose, when serum calcium concentrations and the product of Ca? P will reach the target values.
Chronic Kidney Disease Stage 5
The drug Zemplar В® is prescribed 3 times a week, not more often than every other day.
Starting dose
Calculation of the starting dose of Zemplar В® is carried out according to the following formula:
Starting dose (Ојg) = Initial concentration of IPPG (pg / ml) / 60
or
Starting dose (Ојg) = Initial concentration of IPPH (pmol / l) / 7.
Dose titration
Subsequent doses of Zemplar В® are selected individually, depending on the initial concentration of IPPH, serum concentrations of calcium and phosphorus. Selection of the dose Zemplar В® is carried out according to the following formula:
Titrated dose (Ојg) = concentration of ipTG (pg / ml) according to the last measurement / 60
or
Titrated dose (Ојg) = concentration of IPPG (pmol / l) according to the last measurement / 7.
Serum calcium and phosphorus concentrations should be carefully monitored after initiation of treatment, during the titration period and with the concomitant use of potent inhibitors of CYP3A. If using the drug Zemplar В® the patient develops hypercalcemia or a stable increase in the product of Ca? P, the dose of calcium-containing phosphate binders should be reduced or eliminated. Patients can be transferred to therapy with noncalcium phosphate-binding drugs.
If the serum calcium concentration is> 11 mg / dL (2.8 mmol 2 / L 2 ) or the product of Ca? P> 70 mg 2 / dl 2 (5.6 mmol 2 / L 2 ), the dose of the drug should be reduced (it should be 2-4 Ојg less than previously calculated according to the formula IGTG / 60 (or IPTG / 7) .If additional correction of the dose of Zemplar В® , then, if necessary, it is possible to reduce the dose of Zemplar В® or temporarily cancel it, up to the normalization of the parameters described above.
When the concentration of IPPT approaches the target range (150-300 pg / ml), a small individual dose adjustment of Zemplar В® may be necessary to achieve a stable PTH level. In cases where PTH and calcium or phosphorus concentrations are monitored less than once a week, a lower starting dose and a smaller dose change of Zemplar В® are recommended when titrated.
The average dose of the drug Zemplar В® at its application 3 times a week in the first week of treatment in clinical studies was 11.2 Ојg. On average, the dose of Zemplar В®, when applied in clinical trials 3 times a week, was 6.3 Ојg. The maximum safe dose of Zemplar В® in clinical trials was 32 Ојg.
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.
The effectiveness and safety of Zemplar В® (in the capsule form) was not studied in children .
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 patients to the drug can not be ruled out.
SIDE EFFECT
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 indication: very often (? 1/10);often (? 1/100, but <1/10); infrequently (? 1/1000, but <1/100); rarely (? 1/10 000, but <1/1000); very rarely (<1/10 000, including individual messages).
Patients with chronic kidney disease 3 and 4 stages
In applying the drug Zemplar В® most common adverse event was rash (2% of patients).
paricalcitol Safety was evaluated in three 24-week double-blind, placebo-controlled, multi-center clinical study involving 220 patients with chronic kidney disease stages 3 and 4. In these studies was not observed any statistically significant differences between the placebo group and the group receiving paricalcitol, in the rate of hypercalcemia (paricalcitol (2/106; 2%) compared with placebo (0/111; 0%)) or increased concentration of calcium compounds and phosphorus (paricalcitol (13/106; 12%) compared with placebo (7/111; 6%)). The proportion of patients prematurely excluded from the study because of adverse reactions was 6% for the group receiving paricalcitol, and 4% - for the placebo group. This difference is not statistically significant.
Adverse reactions in patients with chronic kidney disease stages 3 and 4 described in clinical studies
Immune system: infrequently - hypersensitivity.
From the nervous system: rare - dizziness, dysgeusia.
On the part of the digestive tract: often - unpleasant sensations in the stomach; infrequently - constipation, dry mouth mucosa.
From the skin and subcutaneous tissues: often - a rash; rarely - itching, hives.
On the part of the musculoskeletal system: rarely - muscle spasms.
Laboratory and instrumental data: infrequently - abnormal liver enzymes.
Patients with chronic kidney disease stage 5
In applying the drug Zemplar В® in clinical trials was not statistically significant and clinically significant differences in the type and incidence of adverse reactions between the group receiving the placebo and paricalcitol. The proportion of patients prematurely excluded from the study due to adverse events was 7% for the group receiving paricalcitol and 7% for the placebo group.
Adverse reactions in patients with chronic kidney disease step 5 described in clinical studies
part of the intestine: often - diarrhea, gastroesophageal reflux disease, decreased appetite.
From a metabolism: often - hypercalcemia, hypocalcemia.
From the nervous system: often - dizziness.
Skin and subcutaneous tissue disorders: often - acne.
On the part of genitals and mammary gland: often - breast tenderness.
Post-marketing data and data from clinical trials of the drug when administered parenterally
Laboratory and instrumental data:Infrequent - increased bleeding time, an increase in AST activity, abnormal laboratory tests, weight loss, an increase in the concentration of creatinine in serum *.
Cardio-vascular system: seldom - heart failure, arrhythmia, atrial flutter, an increase / decrease in blood pressure.
From hemopoiesis system: rarely - anemia, leukopenia, lymphadenopathy.
From a metabolism: often - hypercalcemia, hyperphosphatemia; rarely - hyperkalemia, hypocalcemia, anorexia.
From the nervous system: often - headache, dysgeusia; infrequently - coma, stroke, transient ischemic cerebrovascular accident, syncope, myoclonus, hypoesthesia, paraesthesia, dizziness.
On the part of the mind: confusion, delirium, depersonalization, agitation, insomnia, irritability.
From a sight organ: seldom - glaucoma, conjunctivitis.
On the part of the ear and labyrinth disorders: rarely - a violation on the part of the organ of hearing.
The respiratory system: rarely - pulmonary edema, asthma, shortness of breath, nosebleeds, cough.
On the part of the digestive tract: rarely - rectal bleeding, colitis, diarrhea, gastritis, dyspepsia, dysphagia, abdominal pain, constipation, nausea, vomiting, dry mucous membranes of the mouth, disorders of the gastrointestinal tract; frequency is unknown - the bleeding from the gastrointestinal tract.
Skin and subcutaneous tissue disorders:often - itching; rare - bullous dermatitis, alopecia, hirsutism, rash, hyperhidrosis.
On the part of the musculoskeletal system: rarely - arthralgia, joint stiffness, back pain, muscle cramps, pain in the muscles.
From endocrine system: often - hypoparathyroidism; infrequently - hyperparathyroidism.
On the part of genitals and mammary glands: rarely - breast pain, erectile dysfunction.
Infectious and parasitic diseases: rare - sepsis, pneumonia, infection, pharyngitis, vaginal infection, influenza.
Benign, malignant neoplasms and unspecified (including cysts and polyps): infrequently - breast cancer.
Immune system:rarely - hypersensitivity; frequency is unknown - laryngeal edema, angioedema, urticaria.
Other: rarely - gait disturbance, edema, peripheral edema, pain, pain at the injection site, fever, pain in the chest, the aggravation of the underlying disease, weakness, discomfort, a feeling of thirst.
* - Data adverse reactions were observed in patients on predialysis stage.
Adverse reactions, frequency of which is unknown, given below in accordance with a lesion of organs and organ systems.
Immune system: allergic reactions, urticaria, angioedema and laryngeal edema.
From a metabolism: hypercalcaemia.
Laboratory and instrumental data:increasing the value of Ca? P (increase due to increased Ca concentration), increasing the concentration of creatinine in the blood.
CONTRAINDICATIONS
- vitamin D intoxication symptoms;
- hypercalcemia;
- combined use with phosphates or derivatives of vitamin D;
- combined use with aluminum-containing preparations (e.g., antacids, phosphate binders) on a permanent basis and magnesium-containing preparations (e.g., antacids);
- child and adolescence to 18 years (clinical studies have not been carried out);
- Hypersensitivity to any component of the drug.
With caution should be prescribed simultaneously with cardiac glycosides, ketoconazole and other potent inhibitors of CYP3A4.
PREGNANCY AND LACTATION
Insufficient data on the use of paricalcitol in pregnant women. The data obtained in studies on animals show that paricalcitol causes reproductive toxicity and is able to penetrate the placenta. Paricalcitol should be used during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus.
The data obtained in studies conducted in animals suggest that paricalcitol is excreted in breast milk. Information about breeding paricalcitol with breast milk in women there.
If necessary, use Zemplar В® breastfeeding should be discontinued. Possible continuation of breastfeeding in the case of cancellation of the drug Zemplar В®, Thus it is necessary to take into account the benefit of breast-feeding for the child and the benefit of therapy with Zemplar В® for the mother.
APPLICATION FOR FUNCTIONS OF THE LIVER
Use according to indications.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
No dose adjustment in patients with mild to moderate hepatic impairment is not required. The pharmacokinetics of paricalcitol in patients with severe hepatic impairment has not been studied.
APPLICATION FOR CHILDREN
Contraindications: Children under 18 years (clinical studies have not been performed).
APPLICATION IN ELDERLY PATIENTS
There were no differences in efficacy or safety in patients age 65 and older.
SPECIAL INSTRUCTIONS
Excessive suppression of PTH secretion can lead to increased serum calcium concentration and decrease of metabolic processes in the bone. To achieve the relevant physiological parameters of the patient are necessary control and individual drug dose selection Zemplar В® .
Chronic hypercalcemia can lead to generalized vascular calcification and other soft tissue calcification.
In the case of clinically significant hypercalcemia in patients receiving paricalcitol in conjunction with calcium-containing phosphate binders, the last dose should be reduced or temporarily discontinue use of the drug.
Cardiac glycosides toxicity increases with hypercalcemia. Cardiac glycosides should be used with caution when combined with paricalcitol.
Caution should be exercised when used together paricalcitol with ketoconazole.
Preparation Zemplar В® (in capsule form) as the excipient comprises ethanol (less than 100 mg per capsule (dosage 1 g, 2 g and 4 g). The ethanol can be potentially dangerous to patients with liver disease, alcoholism, epilepsy, pregnant women and children.
For the initial dose selection or any of its change should determine serum calcium, phosphorus, serum or plasma concentration of intact PTH, at least every 2 weeks for 3 months after initiation of treatment with Zemplar В® or after changing the dose of Zemplar preparation В® , then - each month for 3 months, then - every 3 months.
Patients in predialysis stage, paricalcitol, like other activators of receptors of vitamin D, may increase in serum creatinine concentration (and hence reduce the estimated glomerular filtration rate (eGFR)) without changing the true glomerular filtration rate (GFR).
Use in Pediatrics
The efficacy and safety of the drug Zemplar В® in children has not been studied.
Impact on the ability to drive vehicles and manage mechanisms
Data on the effect of the drug on the ability to drive a car and work with no mechanisms. However, since you may experience side effects such as dizziness, fainting, it is recommended during therapy with Zemplar В® refrain from driving and busy with other activities that require high concentration and psychomotor speed reactions.
OVERDOSE
Symptoms drug overdose Zemplar В® may cause hypercalcemia and hypercalciuria hyperphosphatemia and marked reduction of PTH secretion. Consumption of large amounts of calcium and phosphorus simultaneously with application of the drug Zemplar В® can cause similar disturbances.
Treatment of acute accidental overdosing Zemplar В®It requires emergency treatment. If overdose fact revealed in a relatively short period of time, can cause vomiting or gastric lavage conduct that will help prevent further absorption of paricalcitol. If it is assumed that the drug has passed through the stomach, its early removal of the intestines can contribute to the reception of vaseline oil. It is necessary to control the concentration of serum electrolytes (especially calcium), the rate of calcium excretion via the kidney and to assess changes in the ECG that might be associated with hypercalcemia. This monitoring is very important in patients receiving cardiac glycosides. Termination consumption of nutritional supplements containing calcium, and the adherence to a diet low in calcium at random as shown overdose.Because paricalcitol has a relatively short duration of the pharmacological action, proceeding, as a rule, is not required. For treatment of severe hypercalcemia possible to use drugs such as salts of phosphoric acids and corticosteroids; also possible to carry out forced diuresis. Paricalcitol significantly not displayed during dialysis.
Signs and symptoms of intoxication, vitamin D, associated with hypercalcemia include:
Early: weakness, headache, somnolence, nausea, vomiting, dry mucous membranes of the mouth, constipation, muscle pain, bone pain and metallic taste in the mouth.
late:anorexia, weight loss, conjunctivitis (calcined), pancreatitis, photophobia, rhinorrhea, itching, hyperthermia, decreased libido, increased concentration of blood urea nitrogen, hypercholesterolemia, elevated ACT concentration and ALT, ectopic calcification, increased blood pressure, cardiac arrhythmias, drowsiness, and rare - psychosis. cases of overdose have been reported with fatal consequences.
DRUG INTERACTION
It is known that ketoconazole is a nonspecific inhibitor of several cytochrome P450 isoenzymes. Available data from in vivo studies and in vitro, suggest that ketoconazole may interact with enzymes that are responsible for the metabolism of paricalcitol and other analogues of vitamin D. Use caution while appointing paricalcitol with ketoconazole. Effect of Repeated Administration of ketoconazole at a dose of 200 mg of 2 times / day for 5 days on the pharmacokinetics of paricalcitol (in capsule form) was studied in healthy volunteers. With max paricalcitol remained virtually unchanged, but the AUC 0-? when assigning ketoconazole increased approximately 2-fold. Average T 1/2paricalcitol when assigning ketoconazole was 17 hours compared to 9.8 hours at appointment paricalcitol without ketoconazole. The results of this study show that after oral or on / in the maximum drug AUC inf paricalcitol as a result of drug interaction with ketoconazole probably not increased by more than 2 times.
Special drug interaction studies have been conducted. Cardiac glycosides toxicity increases with hypercalcemia (of any etiology), so caution should be exercised while the use of cardiac glycosides to paricalcitol.
Do not use products containing phosphorus or vitamin D, along with paricalcitol due to an increased risk of hypercalcaemia and Ca increase in the product? R.
High doses of calcium-containing preparations or thiazide diuretics may increase the risk of hypercalcemia.
Do not apply magnesium-containing preparations (e.g., antacids) simultaneously with preparations of vitamin D, due to the risk of gipermagniemii.
Preparations containing aluminum (e.g., antacids, phosphate binders) should not be long-term use medications simultaneously with vitamin D, due to a possible increase in the aluminum concentration in blood and the toxic aluminum action on bone.
Drugs that impair the absorption of intestinal fat-soluble vitamins, such as cholestyramine, can interfere with the absorption of the drug Zemplar В® (in the form of capsules).
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug should be kept out of reach of children at a temperature of from 15 В° to
