Paricalcitol

There is no experience in patients with severe hepatic impairment.

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.

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

Ketoconazole is known to be a nonspecific 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.

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 either oral or intravenous administration of paricalcitol the maximum amplification of the paricalcitol AUC_INF from a drug interaction with ketoconazole is not likely to be greater than about two-fold.

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.

There are no or limited amount of data from the use of paricalcitol in pregnant women. Studies in animals have shown reproductive toxicity. Paricalcitol is not recommended during pregnancy and in women of childbearing potential not using contraception.

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.

A risk to the newborns/infants cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from paricalcitol 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.

Paricalcitol has negligible influence on ability to drive and use machines.

Oral administration

Summary of the safety profile

The safety of paricalcitol capsules has been evaluated in three 24-week, double-blind, placebo-controlled, multi-centre clinical trials involving 220 CKD Stage 3 and 4 adult patients and in one 12-week, double-blind, placebo-controlled, multi-centre clinical trial involving 88 CKD Stage 5 adult patients. In addition, there is postmarketing experience with paricalcitol capsules from three additional studies, and paediatric experience from two studies. The most commonly reported adverse reactions for paricalcitol treated patients were hypercalcaemia and calcium phosphate product increased.

In the Stage ¾ and Stage 5 clinical trials, the incidence of hypercalcaemia was paricalcitol (3/167, 2%) vs placebo (0/137, 0%) and elevated calcium phosphate product was paricalcitol (19/167, 11%) vs placebo (8/137, 6%).

Tabulated list of adverse reactions

All adverse reactions associated with paricalcitol capsules are displayed in the following table by MedDRA System Organ Class, Preferred Term and frequency. The following frequency groupings are used: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).

Adverse reactions reported with paricalcitol capsules in clinical trials and from post marketing experience:

^* Frequencies for adverse reactions from post marketing experience cannot be estimated and have been reported as "Not Known."
^† This adverse reaction has been observed in studies in predialysis patients.

Paediatric population

In children 10 years of age and older, the nature of the safety profile is similar to that seen in adults. Adverse reactions for paricalcitol treated patients were hypercalcaemia (4/47, 9%), hyperphosphataemia (2/47, 4%), headache (1/47, 2%), and nausea (1/47, 2%).

IV administration

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”.