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Paricalcitol Oral Formulation (Zemplar®▼) VERDICT & SUMMARY Paricalcitol oral formulation (Zemplar®▼) For the prevention and treatment of secondary hyperparathyroidism Committee’s Verdict: CATEGORY C (Q3) BNF: 9.6.4 Specialist opinion was that oral paricalcitol should be used only in patients with stage 5 chronic kidney disease (CKD) on dialysis, if treatment with alternative, less expensive, vitamin D analogues have failed. Patients with stage 5 CKD receiving dialysis are regularly treated and monitored in a secondary care setting. In the light of these pre-existing arrangements, and the monitoring requirements associated with use of paricalcitol, it is not suitable for prescribing in primary care. Category C: not suitable for prescribing in primary care Q rating: The evidence for the efficacy of oral paricalcitol was considered to be relatively strong (also taking into account the evidence Q2 Q1 for intravenous paricalcitol), based on double-blind randomised controlled higher place higher place weaker evidence stronger evidence trials, which found that paricalcitol reduced intact parathyroid hormone levels to a greater extent than placebo in patients with chronic kidney disease. The oral formulation of paricalcitol has not been compared directly with any other vitamin D analogue. It was considered to have a Q4 Q3 low place in therapy in primary care. lower place lower place weaker evidence stronger evidence The Q rating relates to the drug’s position on the effectiveness indicator grid. The strength of the evidence is determined by the quality and quantity of in primary carePlace therapy in studies that show significant efficacy of the drug compared with placebo or Strength of evidence for efficacy alternative therapy. Its place in therapy in primary care takes into account safety and practical aspects of using the drug in primary care, alternative options, relevant NICE guidance, and the need for secondary care input. MTRAC reviewed paricalcitol because it is a new product with potential for prescribing in primary care. Licensed indication alfacalcidol) and parathyroidectomy (surgical removal of the parathyroid glands). The oral formulation of paricalcitol is indicated for the prevention and treatment of secondary Paricalcitol is a synthetic vitamin D analogue which hyperparathyroidism in patients with CKD stages 3 selectively up-regulates the vitamin D receptor in the and 4 and in patients with CKD stage 5 on parathyroid glands, thereby suppressing PTH haemodialysis or peritoneal dialysis.1 synthesis and secretion.1 An intravenous formulation of paricalcitol is also Clinical efficacy available (see MTRAC Verdict Sheet 08/17). Three 24-week, multicentre, double-blind RCTs Background information compared oral paricalcitol (administered three times a week in two studies and once daily in the other) with Secondary hyperparathyroidism is a common placebo in patients (total n = 220) with CKD stages 3 consequence of chronic kidney disease (CKD). The 3 or 4. The initial dose of paricalcitol was based on disease is characterised by an elevation in parathyroid baseline serum intact parathyroid hormone (iPTH) hormone (PTH) associated with a decrease in 1,25- levels. If iPTH was ≤ 500 pg/mL at baseline, dihydroxyvitamin D (active vitamin D, also known as 3 paricalcitol was administered 1 mcg daily or 2 mcg calcitriol) and abnormal regulation of calcium and 2 three times a week (not more than every other day). If phosphorus homeostasis. Secondary iPTH was > 500 pg/mL, paricalcitol was administered hyperparathyroidism is associated with many 2 mcg daily or 4 mcg three times a week (not more complications including renal bone disease, soft tissue than every other day). Subsequent doses were and vascular calcification, cardiovascular disease and titrated by 2 mcg in the three-times-weekly studies increased mortality.2 and 1 mcg in the once-daily study, depending on Current therapy includes reducing phosphate in the serum calcium, phosphorus and iPTH levels. The diet, the use of phosphate binders, calcimimetic primary outcome measure in all three studies was the agents, hydroxylated vitamin D sterols (calcitriol and proportion of patients with at least two consecutive decreases in iPTH ≥ 30% from baseline. The main October 2008 Page 1 of 2 safety outcome was the incidence of “clinically calcium levels were observed during treatment in the meaningful” hypercalcaemia (defined as two paricalcitol group whereas small decreases in serum consecutive calcium values > 10.5 mg/dL). calcium levels were observed in the placebo group. The difference between the treatment groups in the In a pooled analysis of the three RCTs, the primary mean change in serum calcium from baseline to final outcome occurred significantly more frequently in the on-treatment visit was statistically significant (p < paricalcitol group than in the placebo group (91% vs. 0.05). Serum Ca x P also increased to a significantly 13%, p < 0.001). Outcomes relating to serum calcium greater extent with paricalcitol than with placebo (p < and phosphorus are discussed in the adverse events 0.05). section. For additional information on adverse events, refer to One multicentre, double-blind RCT (n = 88; duration 1 the Summary of Product Characteristics (SPC). 12 weeks) compared oral paricalcitol (three times a week) with placebo in patients with end-stage renal Additional information disease (CKD Stage 5) on haemodialysis or peritoneal dialysis.4 The initial dose of paricalcitol was the • In patients with CKD stages 3 or 4, paricalcitol microgram equivalent of baseline iPTH (pg/mL) capsules should be administered once daily or divided by 60. During the treatment period, dosage three times a week. When administered three adjustments depended on serum iPTH (measured times a week, the dose should be taken no more weekly), calcium, Ca x P and investigator judgment. frequently than every other day. The initial dose is The primary outcome was the proportion of patients 1 to 2 mcg daily or 2 to 4 mcg three times a week, achieving ≥ 30% reduction in iPTH from baseline on depending on baseline iPTH levels. Subsequent two consecutive occasions. The main safety outcome dosing is dependent on iPTH, and serum calcium was the incidence of “clinically meaningful” and phosphorus levels. Paricalcitol may be taken hypercalcaemia (defined as two consecutive calcium with or without food. For further details, see the 1 values > 11 mg/dL). SPC. The primary outcome occurred significantly more • In patients with CKD stage 5, paricalcitol capsules frequently in the paricalcitol group than in the placebo should be administered three times a week, every group (88% vs. 13%, p < 0.001), regardless of dialysis other day. The initial dose in microgram should be modality. Outcomes relating to serum calcium and based on baseline iPTH level (pg/mL) divided by phosphorus are discussed in the adverse events 60. Subsequent dosing is dependent on iPTH, section. serum calcium and phosphorus levels. For further details, see the SPC.1 The intravenous formulation of paricalcitol has been compared with placebo and calcitriol in RCTs and • At current prices, a year’s treatment with retrospective studies (see MTRAC Verdict Sheet paricalcitol capsules, 8 mcg three times a week 08/17). costs £3,095. Adverse events References In the three RCTs that compared oral paricalcitol with 1. Abbott Laboratories Limited. Zemplar soft capsules 1, 2 placebo in patients with CKD stages 3 or 4, the and 4 mcg. Electronic Medicines Compendium. 2008. www.emc.medicines.org.uk <accessed 10/2008> proportion of patients who experienced 2. National Institute for Health and Clinical Excellence. hypercalcaemia did not differ significantly between the 3 2007. Cinacalcet for the treatment of secondary groups (2% paricalcitol vs. 0% placebo, p > 0.05). hyperparathyroidism in patients with end-stage renal The proportion of patients who experienced two disease on maintenance dialysis therapy. Technology consecutive calcium-phosphorus product values > 55 appraisal guidance 117. mg2/dL2 also did not differ significantly between the http://www.nice.org.uk/nicemedia/pdf/word/TA117guidan groups. ceword.doc 3. Coyne D, Acharya M, Qiu P et al. Paricalcitol capsule In the study that compared oral paricalcitol with for the treatment of secondary hyperparathyroidism in placebo in patients with CKD stage 5 on stages 3 and 4 CKD. Am J Kidney Dis 2006;47:263-276. haemodialysis or peritoneal dialysis, the proportion of 4. Ross EA, Tian J, Abboud H et al. Oral paricalcitol for the patients who experienced hypercalcaemia did not treatment of secondary hyperparathyroidism in patients differ significantly between the groups (2% paricalcitol on hemodialysis or peritoneal dialysis. Am J Nephrol vs. 0% placebo, p > 0.05).4 Small increases in serum 2008;28:97-106. Launch date: April 2008 Manufacturer: Abbott Laboratories Limited PL 00037/0626-8 WARNING: This sheet should be read in conjunction with the Summary of Product Characteristics This guidance is based upon the published information available in English at the time the drug was considered. It remains open to review in the event of significant new evidence emerging. MTRAC can be contacted at the Dept. of Medicines Management, School of Pharmacy, Keele University, Keele, Staffs ST5 5BG Tel: 01782 584131 Fax: 01782 713586 Email: [email protected] Web: www.mtrac.co.uk NO GUIDANCE FROM NICE FOR PARICALCITOL WAS AVAILABLE AT THE TIME OF ISSUE OF THIS VERDICT Date: October 2008 ©Midlands Therapeutics Review & Advisory Committee VS08/18 .
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