Paricalcitol-vista

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PARICALCITOL-VISTA (PARICALCITOL-VISTA)

Composition:

Active ingredient: paricalitriol;

1 ml of injectable solution contains 5 mcg of paricalcitol;

Excipients: anhydrous ethanol, macrogol 15 hydroxystearate, water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear, colorless solution free from foreign particles.

Pharmacotherapeutic group. Anti-parathyroid agents. ATC code H05B X02.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

Paricalcitol is a synthetic biologically active vitamin D2 analog of calcitriol. Paricalcitol selectively increases the number of activated vitamin D receptors in the parathyroid gland, without causing a similar increase in the intestine and having a lesser effect on bone resorption. Paricalcitol also increases the number of activated calcium-sensitive receptors in the parathyroid gland. As a result, paricalcitol reduces parathyroid hormone (PTH) levels by inhibiting cell proliferation in the parathyroid gland and decreasing PTH synthesis and secretion, while exerting minimal effects on calcium and phosphorus levels. Additionally, paricalcitol may directly act on bone cells, maintaining bone tissue volume and improving surface mineralization.

Correction of PTH disturbances with normalization of calcium and phosphorus homeostasis may provide both preventive and therapeutic effects on bone metabolic disorders associated with chronic kidney disease.

Pharmacokinetics

Distribution

The pharmacokinetics of paricalcitol have been studied in patients with chronic kidney disease (CKD) (stage 5) requiring hemodialysis. Paricalcitol was administered as an intravenous bolus injection. Within two hours after administration of doses ranging from 0.04 to 0.24 mcg/kg, paricalcitol concentrations rapidly declined; thereafter, paricalcitol concentrations decreased logarithmically with a mean half-life of approximately 15 hours.

With repeated administration, accumulation of paricalcitol was not observed. In vitro, plasma protein binding of paricalcitol was extensive (>99.9%) and nonsaturable over a concentration range of 1 to 100 ng/mL.

Metabolism

Several metabolites have been identified in urine and feces. Unchanged paricalcitol was not detected in urine. Paricalcitol is metabolized by hepatic and non-hepatic enzymes, including mitochondrial CYP24, as well as CYP3A4 and UGT1A4.

Elimination.

A study in healthy volunteers receiving a single intravenous bolus dose of 0.16 mcg/kg of 3H-paricalcitol (n=4) showed that plasma radioactivity was attributed to the parent compound.

Paricalcitol is eliminated via biliary excretion. In healthy volunteers, approximately 63% of the drug is excreted through the intestine and 19% through the kidneys. The T1/2 of paricalcitol following doses of 0.04 to 0.16 mcg/kg in healthy volunteers averages 5–7 hours.

Special populations.

Sex, race, and age.

No pharmacokinetic differences related to age or sex were observed in the studied adult patients. Pharmacokinetic differences related to race have not been established.

Hepatic impairment

A study demonstrated that the pharmacokinetics of unbound paricalcitol were similar in patients with mild to moderate hepatic impairment and healthy volunteers. No dosage adjustment is necessary for patients with mild to moderate hepatic impairment. The effect of severe hepatic impairment on the pharmacokinetics of paricalcitol has not been evaluated.

Clinical characteristics.

Indications.

Paricalcitol is indicated for the prevention and treatment of secondary hyperparathyroidism in adult patients with stage 5 chronic kidney disease undergoing hemodialysis.

Contraindications.

• Hypersensitivity to paricalcitol or to any of the excipients of the medicinal product.
• Hypervitaminosis D.
• Hypercalcemia.

Interaction with other medicinal products and other forms of interaction.

Interaction studies with injectable paricalcitol have not been conducted. However, interaction studies between ketoconazole and paricalcitol administered in capsule form have been carried out.

Ketoconazole. Ketoconazole is known to be a non-specific inhibitor of several cytochrome P450 enzymes. *In vivo* and *in vitro* data indicate that ketoconazole may interact with enzymes responsible for the metabolism of paricalcitol and other vitamin D analogs. Paricalcitol should be used with caution when co-administered with ketoconazole (see section "Special warnings and precautions for use"). The effect of multiple doses of ketoconazole 200 mg twice daily for 5 days on the pharmacokinetics of paricalcitol capsule was studied in healthy volunteers. The Cmax of paricalcitol changed minimally, while the AUC 0–∞ doubled in the presence of ketoconazole. The mean elimination half-life of paricalcitol was 17 hours with ketoconazole, compared to 9.8 hours without ketoconazole. Drug interaction studies have demonstrated that ketoconazole nearly doubles the AUC 0–∞ of paricalcitol.

Interactions between paricalcitol in injectable solution form and other medicinal products have not been studied. Digitalis toxicity is potentiated by hypercalcemia regardless of its origin; therefore, cardiac glycosides should be used with caution when administered concomitantly with paricalcitol (see section "Special warnings and precautions for use").

Concurrent administration of phosphate preparations or medicinal products containing vitamin D with paricalcitol should be avoided due to increased risk of hypercalcemia and elevated Ca×P product (see section "Special warnings and precautions for use").

Concomitant use of high-dose calcium-containing medicinal products or thiazide diuretics with paricalcitol may increase the risk of hypercalcemia.

Medicinal products containing magnesium (e.g., antacids) should not be taken concurrently with vitamin D-containing products due to the risk of developing hypermagnesemia.

Long-term concurrent use of aluminum-containing medicinal products (e.g., antacids, phosphate binders) with vitamin D-containing products should be avoided due to the risk of increased serum aluminum levels and potential aluminum-related bone toxicity.

Special precautions for use.

Suppression of parathyroid hormone levels may lead to an increase in serum calcium levels and disturbances in bone metabolism. To achieve the required physiological level, patient monitoring and individual dose titration are necessary.

If clinically significant hypercalcemia develops and the patient is receiving a calcium-based phosphate binder, it is advisable to reduce the dose, temporarily discontinue, or switch to a non-calcium-containing phosphate binder. Chronic hypercalcemia may lead to generalized vascular calcification and soft tissue calcification. Concomitant use of phosphate preparations or medicinal products containing vitamin D with paricalcitol should be avoided due to increased risk of hypercalcemia and elevated Ca×P product (see section "Interaction with other medicinal products and other forms of interaction").

Digitalis toxicity is potentiated by hypercalcemia, regardless of its origin; therefore, digitalis preparations should be used with caution when administered together with paricalcitol (see section "Interaction with other medicinal products and other forms of interaction").

Paricalcitol should be administered with caution when used concomitantly with ketoconazole (see section "Interaction with other medicinal products and other forms of interaction").

Disposal of unused medicinal product or medicinal product past its expiry date.

Medicinal product should not be disposed of via wastewater or household waste. To minimize environmental contamination, unused medicinal products should be disposed of via a dedicated "waste collection system," if available.

Excipients.

A 40 mcg dose of Paricalcitol-Vista administered to an adult weighing 70 kg results in exposure to approximately 18 mg/kg ethanol, which may increase blood alcohol levels by approximately 3 mg/100 mL.

Use during pregnancy or breastfeeding.

Pregnancy.

Data on the use of paricalcitol during pregnancy are limited or lacking. Animal studies have shown reproductive toxicity. Paricalcitol-Vista should not be used in pregnant women or in women of childbearing potential who are not using effective contraception.

Breastfeeding.

It is unknown whether paricalcitol or its metabolites are excreted in human breast milk. Animal studies have shown that paricalcitol and its metabolites are excreted in breast milk. Risk to the newborn/infant cannot be excluded. A decision should be made whether to discontinue breastfeeding or to discontinue/abstain from treatment with Paricalcitol-Vista, taking into account the benefits of breastfeeding for the child and the benefits of therapy for the woman.

Fertility.

Animal studies did not show any effect of paricalcitol on fertility.

Ability to affect reaction speed when driving or operating machinery.

Dizziness may occur after administration of paricalcitol, which may have a minor influence on the ability to drive or operate machinery.

Administration and Dosage.

Initial Dose.

Adults.

The initial dose of paricalcitol is determined based on baseline levels of parathyroid hormone (PTH).

The initial dose of paricalcitol is calculated using the following formula:

and are administered intravenously as a bolus no more frequently than once daily at any time during dialysis.

The maximum safe dose used in clinical trials was 40 mcg per dose.

Dose titration:

Currently, the acceptable PTH level in dialysis patients with end-stage renal disease should not exceed the upper limit of normal in non-uremic patients by more than 1.5–3 times (150–300 pg/mL for iPTH). To achieve the required physiological level, careful monitoring of PTH levels and individual dose titration are necessary. In cases of hypercalcemia or a sustained increase in Ca×P product exceeding 5.2 mmol²/L² (65 mg²/dL²), the dose should be reduced or treatment temporarily interrupted until these parameters return to normal. Then, paricalcitol administration should be resumed at a lower dose. Over time, doses may be reduced as PTH levels decrease.

The table below outlines the recommended approach to dose titration:

After the dose has been established, calcium and phosphate levels in blood plasma should be monitored at least once a month. Plasma or serum PTH levels should be monitored once every 3 months. Laboratory tests should be performed more frequently during periods of dose adjustment.

Hepatic impairment.

The concentration of unbound paricalcitol in patients with mild to moderate hepatic impairment does not differ from that in healthy individuals; therefore, dose adjustment is not necessary in these patients. The use of the drug has not been studied in patients with severe hepatic impairment.

Elderly patients.

Experience with patients over 65 years of age receiving paricalcitol in phase III studies is limited. In these studies, no differences in efficacy and safety of the drug were observed between patients aged 65 years and older and younger patients.

Method of administration.

Paricalcitol-Vista as an injection solution is recommended to be administered via a hemodialysis catheter.

Children.

The safety and efficacy of paricalcitol in children under 18 years of age have not been established. The drug is not intended for use in children.

Overdose.

Cases of overdose have not been reported.

Symptoms. Overdose with paricalcitol may lead to hypercalcemia, hypercalciuria, hyperphosphatemia, and excessive suppression of PTH (see section "Special precautions for use"). In the event of overdose, signs and symptoms of hypercalcemia (serum calcium levels) should be monitored and a physician should be notified.

Treatment. Treatment should be initiated as clinically indicated. Paricalcitol is minimally removed by dialysis.

Management of patients with clinically significant hypercalcemia includes immediate dose reduction or discontinuation of paricalcitol therapy, a low-calcium diet, discontinuation of calcium-containing supplements, patient mobilization, attention to fluid and electrolyte imbalances, evaluation of electrocardiographic abnormalities (critical for patients receiving digitalis preparations), and hemodialysis or peritoneal dialysis using calcium-free dialysate as a preventive measure.

After serum calcium levels return to normal, paricalcitol therapy may be resumed, starting with a low dose.

If persistent and marked elevation of serum calcium levels persists, other therapeutic alternatives should be considered, including phosphates and corticosteroids, as well as induced diuresis.

Adverse reactions.

Summary of safety findings from paricalcitol clinical studies.

Approximately 600 patients received paricalcitol in Phase II/III/IV clinical trials. Overall, adverse reactions were reported in 6% of patients treated with paricalcitol.

The most commonly observed treatment-related adverse reaction was hypercalcemia, reported in 4.7% of patients.

The development of hypercalcemia is related to the degree of excessive PTH suppression and can be minimized through careful dose titration.

Adverse reactions listed in table format.

Adverse reactions associated with paricalcitol observed in clinical and laboratory studies are presented in the table below, classified by system organ class (MedDRA) and frequency. The following frequency categories are used: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1,000, <1/100); rare (≥1/10,000, <1/1,000); very rare (<1/10,000); frequency not known (cannot be estimated from available data).

*The frequency of adverse reactions reported during post-marketing use cannot be estimated; the frequency of such reactions is classified as "unknown".

Reporting of suspected adverse reactions.

Reporting of suspected adverse reactions after medicinal product authorization is an important procedure. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions through the national reporting system.

Shelf life. 2 years.

Storage conditions.

Store in the original packaging to protect from light at a temperature not exceeding 30 °C. Keep out of reach and sight of children.

Packaging. 1 ml or 2 ml in ampoules; 5 ampoules in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

FARMATEN S.A.

Manufacturer's address and location of activity.

Derwenakion 6, Pallini Attica, 15351, Greece.