4.1. Therapeutic indications

Zemplar is indicated in adult and paediatric patients 10 to 16 years of age for the prevention and treatment of secondary hyperparathyroidism associated with chronic kidney disease Stages 3 and 4.

Zemplar is indicated in adult patients for the prevention and treatment of secondary hyperparathyroidism associated with chronic kidney disease Stage 5 in patients who are on haemodialysis or peritoneal dialysis.

4.2. Posology and method of administration

Posology

Chronic Kidney Disease (CKD) Stages 3 and 4

Zemplar should be administered once a day, either daily or three times a week taken every other day.

Initial dose

The initial dose is based on baseline intact parathyroid hormone (iPTH) levels.

Table 1. Initial Dose

Baseline iPTH Level

Daily Dose

Three Times a Week Dose*

≤ 500 pg/ml (56 pmol/l)

1 microgram

2 micrograms

> 500 pg/ml (56 pmol/l)

2 micrograms

4 micrograms

*To be administered no more frequently than every other day

Dose titration

Dosing must be individualised based on serum or plasma iPTH levels, with monitoring of serum calcium and serum phosphorus. Table 2 presents a suggested approach for dose titration.

Table 2. Dose Titration

iPTH Level Relative to Baseline

Dose Adjustment at 2 to 4 Week Intervals

Daily Dose

Three Times a Week Dose1

The same or increased

Increase

1 microgram

Increase

2 micrograms

Decreased by < 30%

Decreased by ≥30%, ≤60%

Maintain

Maintain

Decreased > 60%

Decrease2

1 microgram

Decrease2

2 micrograms

iPTH < 60 pg/ml (7 pmol/l)

1 To be administered no more frequently than every other day.

2 If a patient is taking the lowest dose on the daily or three times a week regimen, and a dose reduction is needed, dosing frequency can be decreased.

Serum calcium levels should be closely monitored after initiation of the treatment and during dose titration periods. If hypercalcaemia or a persistently elevated calcium-phosphate product greater than 55 mg2/dl2 (4.4 mmol2/l2) is observed, the dose of calcium based phosphate binders should be reduced or withheld. Alternatively, the dose of Zemplar may be reduced or temporarily interrupted. If interrupted, the drug should be restarted at a lower dose, when serum calcium and calcium-phosphate product are in the target range.

Chronic Kidney Disease (CKD), Stage 5

Zemplar should be administered three times a week every other day.

Initial dose

The initial dose of Zemplar in micrograms is based on a baseline iPTH level (pg/ml)/60 [(pmol/l)/7], up to an initial maximum dose of 32 micrograms.

Dose titration

Subsequent dosing should be individualised and based on iPTH, serum calcium and phosphorus levels. A suggested dose titration of paricalcitol capsules is based on the following formula:

Serum calcium and phosphorus levels should be closely monitored after initiation, during dose titration periods, and with co-administration of strong P450 3A inhibitors. If an elevated serum calcium or elevated Ca x P is observed and the patient is on a calcium-based phosphate binder, the binder dose may be decreased or withheld, or the patient may be switched to a non-calcium-based phosphate binder.

If serum calcium > 11.0 mg/dl (2.8 mmol/l) or Ca x P > 70 mg2/dl2 (5.6 mmol2/l2) or iPTH ≤ 150 pg/ml, the dose should be decreased by 2 to 4 micrograms with respect to that calculated by the most recent iPTH/60 (pg/ml) [iPTH/7 (pmol/l)]. If further adjustment is required, the dose of paricalcitol capsules should be reduced or interrupted until these parameters are normalised.

As iPTH approaches the target range (150-300 pg/ml), small, individualised dose adjustments may be necessary in order to achieve a stable iPTH. In situations where monitoring of iPTH, Ca or P occurs less frequently than once per week, a more modest initial and dose titration ratio may be warranted.

Special populations

Hepatic impairment

No dose adjustment is required in patients with mild to moderate hepatic impairment.

There is no experience in patients with severe hepatic impairment (see section 5.2).

Renal transplant

Post-renal transplant patients with CKD Stages 3 and 4 and secondary hyperparathyroidism were not studied in phase 3 clinical trials. Based on the published literature, the initial dose and dose-titration algorithm for patients with post-transplant CKD Stages 3 and 4 and secondary hyperparathyroidism is the same as for patients with native CKD Stages 3 and 4 and secondary hyperparathyroidism. Serum calcium and phosphorus levels should be closely monitored after initiation, during dose titration periods, and with co-administration of strong cytochrome P450 3A inhibitors.

Paediatric population

The safety and efficacy of Zemplar capsules in children under the age of 10 years have not yet been established.

CKD Stages 3 and 4 (ages 10 to 16 years old)

Initial dose

The recommended starting dose of paricalcitol capsules is 1 microgram administered three times a week, no more frequently than every other day.

Dose titration

Subsequent dosing should be individualized and based on iPTH, serum calcium and phosphorus levels to maintain an iPTH level between 35 and 69 pg/ml (Stage 3) or 70 and 110 pg/ml (Stage 4).

Paricalcitol dose may be increased in 1 microgram increments every 4 weeks, maintaining the three times per week regimen. At any time, the dose may be decreased by 1 microgram or may be held if the patient is receiving a 1 microgram dose. Paricalcitol may be stopped if the patient requires reduction while receiving 1 microgram three times per week, resuming when appropriate. The maximum dose administered in the clinical study was 7 micrograms per dose.

CKD Stage 5

The efficacy of Zemplar in children with CKD Stage 5 has not been established.

Elderly

No overall differences in safety and effectiveness were observed between elderly patients (65-75 years) with regard to younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Method of administration

Zemplar can be taken with or without food.

4.3. Contraindications

Paricalcitol should not be given to patients with evidence of vitamin D toxicity, hypercalcaemia, or hypersensitivity to paricalcitol or any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

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 generalized 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

Each 1 microgram capsule contains 0.71 mg of alcohol (ethanol), and each 2 micrograms capsule contains 1.42 mg of alcohol (ethanol). The amount per capsule of this medicine is equivalent to less than 1 ml beer or wine.

4.5. Interaction with other medicinal products and other forms of interaction

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 analogs. 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 Cmax of paricalcitol was minimally affected, but AUC0-∞ 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 AUCINF 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.

4.6. Pregnancy and lactation

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 not be used unless clearly necessary.

Breast-feeding

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.

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

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 post-marketing 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

System Organ Class

Frequency*

Adverse Reaction

Infections and infestations

Uncommon

Pneumonia

Immune system disorders

Uncommon

Hypersensitivity

Not known*

Angioedema, laryngeal oedema

Endocrine Disorders

Uncommon

Hypoparathyroidism

Metabolism and nutrition disorders

Common

Hypercalcaemia, hyperphosphataemia

Uncommon

Decreased appetite, hypocalcaemia

Nervous system disorders

Uncommon

Dizziness, dysgeusia, headache

Cardiac disorders

Uncommon

Palpitations

Gastrointestinal disorders

Uncommon

Abdominal discomfort, abdominal pain upper, constipation, diarrhoea, dry mouth, gastroesophageal reflux disease, nausea, vomiting

Skin and subcutaneous tissue disorders

Uncommon

Acne, pruritus, rash, urticaria

Musculoskeletal and connective tissue disorders

Uncommon

Muscle spasms, myalgia

Reproductive system and breast disorders

Uncommon

Breast tenderness

General disorders and administration site conditions

Uncommon

Asthenia, malaise, oedema peripheral, pain

Investigations

Common

Calcium phosphate product increased

Uncommon

Blood creatinine increased†, hepatic enzyme abnormal

*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.

4.9. Overdose

Excessive administration of Zemplar capsules can cause hypercalcaemia, hypercalciuria, hyperphosphataemia, and over suppression of parathyroid hormone. High intake of calcium and phosphate concomitant with Zemplar capsules may lead to similar abnormalities.

Treatment of patients with clinically significant hypercalcaemia consists of immediate dose reduction or interruption of paricalcitol therapy and includes a low calcium diet, withdrawal of calcium supplements, patient mobilisation, attention to fluid and electrolyte imbalances, assessment of electrocardiographic abnormalities (critical in patients receiving digitalis), and haemodialysis or peritoneal dialysis against a calcium-free dialysate, as warranted.

Signs and symptoms of vitamin D intoxication associated with hypercalcaemia include:

Early: Weakness, headache, somnolence, nausea, vomiting, dry mouth, constipation, muscle pain, bone pain and metallic taste.

Late: Anorexia, weight loss, conjunctivitis (calcific), pancreatitis, photophobia, rhinorrhoea, pruritus, hyperthermia, decreased libido, elevated BUN, hypercholesterolaemia, elevated AST and ALT, ectopic calcification, hypertension, cardiac arrhythmias, somnolence, death and rarely, overt psychosis.

Serum calcium levels should be monitored frequently until normocalcaemia ensues.

Paricalcitol is not significantly removed by dialysis.