Zemplar, 5 µg/ml 1 ml 5 pcs

Pharmacodynamics

The drug regulates calcium and phosphorus metabolism. Paricalcitol is a synthetic analogue of the biologically active vitamin D (calcitriol). Paricalcitol has a biological effect by interacting with vitamin D receptors, resulting in selective activation of the response mediated by this vitamin. Vitamin D and paricalcitol reduce parathyroid hormone levels by inhibiting its synthesis and secretion. In the early stages of chronic kidney disease there is a decrease in calcitriol levels.

Secondary hyperparathyroidism is characterized by increased levels of parathyroid hormone (PTH), which is associated with inadequate levels of active vitamin D. This vitamin is synthesized in the skin and is ingested with food. Vitamin D is sequentially hydroxylated in the liver and kidneys into the active form, which interacts with vitamin D receptors.

Calcitriol [1,25(OH)2 D3] is an endogenous hormone that activates vitamin D receptors in the parathyroid glands, intestines, kidneys and bones (thus supporting parathyroid function and calcium and phosphorus homeostasis) and in many other tissues, including the prostate, endothelium and immune cells. Receptor activation is necessary for normal bone formation. Kidney disease suppresses vitamin D activation, resulting in increased PTH levels, development of secondary hyperparathyroidism and impaired calcium and phosphorus homeostasis. Decreased calcitriol levels and increased PTH activity, which often precede changes in plasma levels of calcium and phosphorus, cause changes in the rate of bone metabolism and can lead to the development of renal osteodystrophy. In patients with chronic kidney disease, reducing PTH levels has a beneficial effect on bone ALP activity, bone metabolism, and bone fibrosis. Therapy with active vitamin D not only reduces PTH level and improves metabolic processes in bone tissue, but also allows to prevent or eliminate other consequences of insufficiency of vitamin D.

Pharmacokinetics

For two hours after an IV bolus injection of paricalcitol at doses of 0.04 µg/kg to 0.24 µg/kg, the drug concentration rapidly decreases; however, thereafter, the drug concentration decreases linearly, with a mean T_1/2 of approximately 15 h. There is no evidence of cumulation when paricalcitol is used repeatedly.

Distribution

Paricalcitol is actively bound to plasma proteins (more than 99%). In healthy individuals, the V_d in equilibrium is about 23.8 liters. In patients with stage 5 chronic kidney disease treated with hemodialysis or peritoneal dialysis, the V_d of paricalcitol at a dose of 0.24 µg/kg averages 31-35 L. The pharmacokinetics of paricalcitol were studied in patients with chronic renal failure treated with hemodialysis.

Metabolism

In urine and feces several metabolites of the drug are determined. Unchanged paricalcitol was not detected in the urine. Paricalcitol is metabolized by hepatic and nonhepatic enzymes, including mitochondrial CYP24 as well as CYP3A4 and UGT1A4. Identified metabolites include products of 24(R)-hydroxylation (found in low concentrations in plasma) as well as 24,26- and 24,28-dihydroxylation and direct glucuronidation. Paricalcitol has no inhibitory effect on CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A at concentrations below 50 nM (21 ng/mL). CYP2B6, CYP2C9, and CYP3A4 activity is increased less than 2-fold at similar concentrations of paricalcitol.

Paricalcitol is excreted by excretion with bile. In healthy subjects, approximately 63% of the drug is excreted through the intestine and 19% by the kidneys. T_1/2 paricalcitol at doses of 0.04 to 0.16 mcg/kg in healthy volunteers averages 5-7 hours.

Pharmacokinetics in Special Clinical Cases

Pharmacokinetics of paricalcitol in persons older than 65 years has not been studied.

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

The pharmacokinetics of paricalcitol (0.24 µg/kg) were compared in patients with mild to moderate hepatic impairment (Child-Pugh classification) and healthy subjects.

The pharmacokinetics of unbound paricalcitol were similar in these patient groups. No dose adjustment is required in patients with mild to moderate hepatic impairment. The pharmacokinetics of paricalcitol in patients with severe hepatic impairment have not been studied.

The pharmacokinetics of paricalcitol have been studied in patients with chronic kidney disease stage 5 treated with hemodialysis or peritoneal dialysis. Hemodialysis had no significant effect on paricalcitol excretion. However, patients with chronic kidney disease stage 5 showed decreased clearance and increased T_1/2 compared with healthy subjects.

Indications

Active ingredient

Composition

1 ml of the solution contains:

Active substances:

Paricalcitol 5 µg.

Associates:

Ethanol 95%,

Propylene glycol,

Water d/i.

There is 5 ml of solution in the ampoule.

There are 5 ampoules in the carton pack.

How to take, the dosage

Zemplar® is usually administered by IV through a hemodialysis catheter. If the patient does not have a hemodialysis catheter, the drug can be administered slowly by IV for at least 30 seconds to minimize pain during infusion. As with other parenteral solutions, the Zemplar® ampoule should be inspected for foreign particles and discoloration before administration. Unused residual solution should be discarded.

Adults

The starting dose

There are two methods for choosing the starting dose of paricalcitol. In clinical trials, the maximum safe dose has been as high as 40 mcg.

Choice of starting dose by body weight

The recommended starting dose of paricalcitol is 0.04-0.1 µg/kg (2.8-7 µg). It is given as a bolus no more often than every other day during dialysis. Selection of the initial dose taking into account the initial level of PTH In patients with chronic renal insufficiency (chronic kidney disease stage 5), the second generation method is used to analyze the level of biologically active intact PTH. The starting dose is calculated using the formula below and administered by IV bolus no more frequently than every other day during dialysis:

The starting dose (µg) = Baseline PTH level (pg/ml)/80.

Dose titration

Commonly accepted target levels of PTH in patients with terminal renal failure treated with dialysis are no more than 1.5 to 3 times higher than the IGN in patients without uremia (150-300 pg/ml). Careful monitoring of PTH levels and individual dose titration are necessary to achieve these levels.

For any dose changes, serum calcium (adjusted for hypoalbuminemia) and phosphorus levels should be determined more frequently. If corrected calcium levels ( > 11.2 mg/dL) or persistent elevated phosphorus concentrations ( > 6.5 mg/dL) increase, the dose should be reduced until these values return to normal. In presence of hypercalcemia or steady increase of Ca × P (more than 75) the drug dose should be reduced or treatment should be stopped until these parameters are normalized. Then therapy with paricalcitol can be resumed in lower dose. If the patient receives a calcium-containing phosphate-binding drug, it is advisable to reduce the dose, temporarily discontinue the drug, or transfer the patient to a calcium-free drug. As PTH levels decrease in response to treatment, the dose of paricalcitol may need to be reduced. Thus, the dose should be adjusted on an individual basis.

If an adequate response cannot be achieved, the dose may be increased by 2-4 mcg every 2-4 weeks. When PTH levels < 150 pg/mL decrease, the dose should be reduced.

The recommended dose titration schedule

PTH level

Paricalcitol dose

Same or increased

Increased by 2-4 µg

Decreased by < 30%

Increase by 2-4 µg

Decreased by > 30%, but < 60%

Do not change the dose

Reduced by > 60%

Reduce by 2-4 mcg

< 150 (1 pg/mL)

Reduce by 2-4 µg

At 1.5-3 times VGN (150-300 pg/mL)

Do not change the dose

Interaction

According to in vitro studies, paricalcitol should not inhibit the clearance of drugs that are metabolized by CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A isoenzymes or induce the clearance of CYP2B6, CYP2C9 or CYP3A biotransformed substances.

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

In studies of the interaction of ketoconazole and paricalcitol in capsules, it has been shown that ketoconazole causes an increase in the AUC of paricalcitol by about 2-fold. Paricalcitol is partially metabolized under the action of CYP3A isoenzyme, and ketoconazole is a potent inhibitor of this isoenzyme, so caution should be exercised when combining paricalcitol with ketoconazole and other potent inhibitors of CYP3A isoenzyme.

Hypercalcemia of any genesis increases intoxication by cardiac glycosides, so caution should be exercised when combining them with paricalcitol.

Special Instructions

In titrating the dose of paricalcitol, more frequent laboratory tests may be necessary. When the dose is adjusted, serum calcium and phosphorus levels should be measured at least once a month. Serum or plasma PTH levels should be monitored every 3 months. For reliable analysis of biologically active PTH in patients with stage 5 chronic kidney disease, a second or subsequent generation method is recommended.

There were no differences in efficacy or safety of the drug in patients younger than 65 years of age and older than 65 years of age.

Pediatric use

Paricalcitol for injection in children and adolescents less than 18 years of age has limited experience.

Contraindications

Cautions: The drug should be used concomitantly with cardiac glycosides.

Side effects

The incidence of adverse events reported in phase 2 and 3 clinical trials.

The table lists adverse events of any genesis that had a frequency of 2% or more in the paricalcitol group (patients who had the same reaction repeatedly were counted once).

The frequency of adverse events in all placebo-controlled trials

Adverse events

Paricalcitol (n=62)

Placebo (n=51)

General

Chills

5%

2%

Malaise

3%

0

Fever

5%

2%

Flu

5%

4%

Sepsis

5%

2%

Cardiovascular system disorders

Rapid heartbeat

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3%

0

Digestive system disorders

Dry mouth

3%

2%

Gastrointestinal bleeding

5%

2%

Nausea

13%

8%

Vomiting

8%

6%

CNS side

Headiness

5%

2%

Respiratory system side

Pneumonia

5%

0

Other

Oedema

7%

0

Changes in mean calcium, phosphorus, and Ca × P product levels in an open 13-month study confirm the safety of long-term paricalcitol therapy in this patient group.

An adverse event in phase 4 clinical trials

In one phase 4 study, headache (2%) and perversion of taste (2%) were frequently reported.

Indesirable reactions reported in post-marketing observations

In clinical practice, the following adverse reactions have rarely been reported with injectable paricalcitol:

Allergic reactions: urticaria, Quincke’s edema, laryngeal edema.

Peripheral nervous system disorders: perversion of taste (metallic taste).

Dermatological reactions: rash, itching.

Overdose

Symptoms: Paricalcitol overdose may lead to hypercalcemia, hypercalciuria, hyperphosphatemia and suppression of PTH secretion.

An acute paricalcitol overdose may result in hypercalcemia and requires emergency care. Serum calcium and phosphorus levels should be monitored regularly while the dose is being adjusted. Prolonged therapy with paricalcitol may be complicated by hypercalcemia, increased Ca × P and soft tissue calcification (metastatic calcinosis).

Treatment: If hypercalcemia is clinically significant, the dose of paricalcitol should be reduced immediately or treatment should be interrupted. Recommended measures include a hypocalcemic diet, withdrawal of calcium medications, monitoring of water-electrolyte balance, evaluation of ECG changes (critical in patients receiving cardiac glycosides) and hemodialysis or peritoneal dialysis using calcium-free dialysate. Serum calcium levels should be monitored regularly until they normalize. If PTH levels are suppressed below normal, adynamic bone disease, a pathological condition with low bone metabolism, may develop.