ZEMPLAR Solution for injection Ref.[8397] Active ingredients: Paricalcitol

Over suppression of parathyroid hormone may result in elevations of serum calcium levels and may lead to metabolic bone disease. Patient monitoring and individualised dose titration is required to reach appropriate physiological endpoints.

If clinically significant hypercalcaemia develops, and the patient is receiving a calcium-based phosphate binder, the dose of the calcium-based phosphate binder should be reduced or interrupted.

Chronic hypercalcaemia may be associated with generalised vascular calcification and other soft-tissue calcification.

Phosphate or vitamin D-related medicinal products should not be taken concomitantly with paricalcitol due to an increased risk of hypercalcaemia and Ca x P product elevation (see section 4.5).

Digitalis toxicity is potentiated by hypercalcaemia of any cause, so caution should be applied when digitalis is prescribed concomitantly with paricalcitol (see section 4.5).

Caution should be exercised if co-administering paricalcitol with ketoconazole (see section 4.5).

Warning for excipients

A dose of 40 micrograms of this medicine administered to an adult weighing 70 kg would result in exposure to approximately 18 mg/kg of ethanol which may cause a rise in blood alcohol concentration (BAC) of about 3 mg/100 ml.

For comparison, for an adult drinking a glass of wine or 500 ml of beer, the BAC is likely to be about 50 mg/100 ml.

No interaction studies have been performed with paricalcitol injection. However, an interaction study between ketoconazole and paricalcitol has been performed with the capsule formulation.

Ketoconazole: Ketoconazole is known to be a non-specific inhibitor of several cytochrome P450 enzymes. The available in vivo and in vitro data suggest that ketoconazole may interact with enzymes that are responsible for the metabolism of paricalcitol and other vitamin D analogues. Caution should be taken while dosing paricalcitol with ketoconazole (see Section 4.4). The effect of multiple doses of ketaconazole administered as 200 mg, twice daily (BID) for 5 days on the pharmacokinetics of paricalcitol capsule has been studied in healthy subjects. The C_max of paricalcitol was minimally affected, but AUC_0-∞ approximately doubled in the presence of ketoconazole. The mean half-life of paricalcitol was 17.0 hours in the presence of ketoconazole as compared to 9.8 hours, when paricalcitol was administered alone. The results of this study indicate that following oral administration of paricalcitol the maximum amplification of the paricalcitol AUC_∞ from a drug interaction with ketoconazole is not likely to be greater than about two-fold.

Specific interaction studies were not performed. Digitalis toxicity is potentiated by hypercalcaemia of any cause, so caution should be applied when digitalis is prescribed concomitantly with paricalcitol (see section 4.4).

Phosphate or vitamin D-related medicinal products should not be taken concomitantly with paricalcitol, due to an increased risk of hypercalcaemia and Ca x P product elevation (see section 4.4).

High doses of calcium-containing preparations or thiazide diuretics may increase the risk of hypercalcaemia.

Magnesium-containing preparations (e.g. antacids) should not be taken concomitantly with vitamin D preparations, because hypermagnesemia may occur.

Aluminium-containing preparations (e.g. antacids, phosphate-binders) should not be administered chronically with Vitamin D medicinal products, as increased blood levels of aluminium and aluminium bone toxicity may occur.

Pregnancy

There are no or limited amount of data from the use of paricalcitol in pregnant women.

Studies in animals have shown reproductive toxicity (see section 5.3).

Zemplar is not recommended during pregnancy and in women of childbearing potential not using contraception.

Breast-feeding

It is unknown whether paricalcitol/metabolites are excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of paricalcitol/metabolites in milk (for details see 5.3).

A risk to the newborns/infants cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Zemplar therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Fertility

Animal studies have shown no effect of paricalcitol on fertility (see section 5.3).

Dizziness may occur following administration of paricalcitol, which may have a minor influence on the ability to drive and use machines (see section 4.8).

Summary of the safety profile

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

The most common adverse reaction associated with paricalcitol therapy was hypercalcaemia, occurring in 4.7% of patients. Hypercalcaemia is dependent on the level of PTH oversuppression and can be minimised by proper dose titration.

Tabulated list of adverse reactions

Adverse events at least possibly related to paricalcitol, both clinical and laboratory are displayed by MedDRA System Organ Class, Adverse Reaction and frequency. The following frequency groupings are used: Very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1,000, to <1/100); rare (≥1/10,000, <1/1,000); very rare (<1/10000), not known (cannot be estimated from the available data).

^* Frequencies for adverse reactions from postmarketing experience cannot be estimated and have been reported as "Not known."

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme: Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

Propylene glycol interacts with heparin and neutralises its effect. Zemplar solution for injection contains propylene glycol as an excipient and should be administered through a different injection port than heparin.