ZEMPLAR Capsule, soft Ref.[8396] Active ingredients: Paricalcitol

Over suppression of parathyroid hormone may result in elevations of serum calcium levels and may lead to low-turnover 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).

In pre-dialysis patients, paricalcitol, like other vitamin D receptor activators, may increase serum creatinine (and therefore decrease the estimated GFR [eGFR]) without changing true glomerular filtration rate (GFR).

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

Warning for excipients

This medicinal product contains small amounts of ethanol (alcohol), less than 100 mg per 1 microgram and 2 microgram capsule which may be harmful to those suffering from alcoholism (refer to sections 2 and 4.2). To be taken into account in pregnant or breast-feeding women, children and high risk groups such as patients with liver disease or epilepsy.

Ketoconazole: 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 (see PRECAUTIONS section 4.4). 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.

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.

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 preparation 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.

Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar capsules.

Pregnancy

There are no adequate data on the use of paricalcitol in pregnant women. Animal studies have shown reproductive toxicity (see Section 5.3). Potential risk in human use is not known, therefore paricalcitol should be not be used unless clearly necessary.

Breastfeeding

It is not known whether paricalcitol is excreted in human milk. Animal studies have shown excretion of paricalcitol or its metabolites in breast milk, in small amounts. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with Zemplar should be made taking into account the benefit of breast-feeding to the child and the benefit of Zemplar therapy to the woman.

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

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 3 / 4 and Stage 5 clinical trials, the incidence of hypercalcaemia was Zemplar (3/167, 2%) vs placebo (0/137, 0%) and elevated calcium phosphate product was Zemplar (19/167, 11%) vs placebo (8/137, 6%).

Tabulated list of adverse reactions

All adverse reactions associated with Zemplar capsules are displayed in Table 3 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).

Table 3. Adverse Reactions Reported With Zemplar 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 (see also section 4.4).

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%).

Reporting of suspected adverse reactions

Reporting 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.

Not applicable.