Paricalcitol (Zemplar)
paricalcitol — 19-nor-1,25-dihydroxyvitamin D2
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Secondary HPT in CKD Stages 3 and 4 (predialysis) | Adults and pediatric patients ≥10 years | Oral (daily or TIW) | FDA Approved |
| Secondary HPT in CKD Stage 5 on hemodialysis or peritoneal dialysis | Adults and pediatric patients ≥10 years | Oral (TIW) or IV (TIW via HD access) | FDA Approved |
Paricalcitol is a synthetic 19-nor-1,25-dihydroxyvitamin D2 analog that selectively activates the vitamin D receptor (VDR). Structurally modified at the A-ring (19-nor) and side chain (D2 configuration) compared to calcitriol, paricalcitol retains potent PTH-suppressing activity while producing less hypercalcemia and hyperphosphatemia at equivalent PTH-lowering doses. This selectivity profile makes paricalcitol a preferred vitamin D receptor agonist in CKD-MBD management, particularly where calcitriol-associated calcium and phosphorus elevations limit therapy. Paricalcitol is approved for both prevention and treatment of secondary hyperparathyroidism across CKD Stages 3 through 5, with iPTH-based dosing formulas that individualize therapy from the outset (FDA PI).
No well-established off-label indications exist for paricalcitol. Investigational interest has explored its potential anti-proteinuric and cardioprotective effects in CKD, but clinical trial data remain insufficient for routine clinical use outside the approved indications. Evidence quality: Low.
Dosing
Oral Dosing — CKD Stages 3 and 4 (Adults)
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Baseline iPTH ≤500 pg/mL | 1 mcg PO daily or 2 mcg PO TIW | Titrate per iPTH response | Individualized | Titrate q2–4 wk: increase by 1 mcg (daily) or 2 mcg (TIW) if iPTH unchanged or decreased <30%; maintain if decreased 30–60%; decrease if >60% or iPTH <60 pg/mL TIW = no more frequently than every other day |
| Baseline iPTH >500 pg/mL | 2 mcg PO daily or 4 mcg PO TIW | Titrate per iPTH response | Individualized | Same titration algorithm as above If on 1 mcg daily and needs further reduction: switch to 1 mcg TIW, then withhold if further reduction needed |
Oral Dosing — CKD Stage 5 on Dialysis (Adults)
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| CKD Stage 5 (HD or PD) — iPTH-based initiation | iPTH (pg/mL) ÷ 80 mcg PO TIW | Most recent iPTH ÷ 80 mcg TIW (adjusted for Ca) | Individualized | Baseline serum Ca must be ≤9.5 mg/dL before starting; if Ca elevated, decrease dose by 2–4 mcg; for less frequent monitoring, use iPTH ÷ 100 TIW = no more frequently than every other day |
IV Dosing — CKD Stage 5 on Hemodialysis (Adults)
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Baseline iPTH <500 pg/mL | 0.04 mcg/kg IV bolus TIW | Titrate by 2–4 mcg at 2–4 wk intervals | Individualized (up to 0.24 mcg/kg) | Administer as bolus dose no more frequently than QOD at any time during dialysis Typical adult initial dose: 2.8–7 mcg (0.04–0.1 mcg/kg) |
| Baseline iPTH ≥500 pg/mL | 0.08 mcg/kg IV bolus TIW | Titrate by 2–4 mcg at 2–4 wk intervals | Individualized | Same administration rules as above Mean dose in phase 3 studies: 7.5 mcg TIW (long-term) |
Pediatric Dosing (Ages 10–16 Years)
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| CKD Stages 3–4 (oral) | 1 mcg PO TIW | Increase by 1 mcg TIW q4wk per iPTH | Individualized | Decrease by 1 mcg at any time; stop if on 1 mcg TIW and further reduction needed Not established for <10 years |
| CKD Stage 5 (oral, HD/PD) | iPTH (pg/mL) ÷ 120 mcg PO TIW | Increase by 1 mcg TIW q4wk per iPTH | Individualized | Decrease by 2 mcg at any time; round initial dose down to nearest whole number Not established for <10 years |
Paricalcitol uses a unique iPTH-based dosing formula for CKD Stage 5 patients: Dose (mcg) = iPTH (pg/mL) ÷ 80 for adults (or ÷ 120 for pediatric patients). This approach individualizes the starting dose from the outset, proportional to disease severity. For patients monitored less frequently than weekly, the FDA PI suggests using a more conservative ratio of iPTH ÷ 100 to minimize hypercalcemia risk. Always confirm baseline serum calcium is ≤9.5 mg/dL before initiating therapy in CKD Stage 5 patients.
Pharmacology
Mechanism of Action
Paricalcitol is a synthetic vitamin D2 analog of calcitriol with two key structural modifications: removal of the C-19 methylene group (19-nor) and a D2 side chain. These modifications result in selective activation of vitamin D responsive pathways through VDR binding while producing less stimulation of intestinal calcium and phosphorus absorption compared to calcitriol. Paricalcitol suppresses PTH synthesis and secretion by activating VDR on parathyroid chief cells, reducing PTH gene transcription. In clinical studies, paricalcitol achieved a mean iPTH reduction of 30% within 6 weeks while maintaining a comparable incidence of hypercalcemia and hyperphosphatemia to placebo, reflecting its selectivity advantage over non-selective vitamin D receptor agonists.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Well absorbed orally; absolute bioavailability ~72% (healthy), 79% (HD), 86% (PD); Tmax ~3 h; food delays Tmax by ~2 h but does not affect AUC or Cmax; dose-proportional over 0.06–0.48 mcg/kg | Can be taken without regard to food; dose-proportional kinetics allow predictable titration |
| Distribution | ≥99.8% bound to plasma proteins; Vd ~23.8 L (healthy subjects, IV); crosses placenta in rats; present in rat milk | High protein binding limits free drug; relatively small Vd compared to calcitriol |
| Metabolism | Extensively metabolized (~98%) by multiple hepatic and non-hepatic enzymes: CYP24 (mitochondrial), CYP3A4, and UGT1A4; identified metabolites include 24(R)-hydroxy paricalcitol (less active), 24,26- and 24,28-dihydroxy products, and direct glucuronide conjugates; no accumulation with TIW dosing (IV) | CYP3A4 involvement means strong CYP3A inhibitors (ketoconazole) approximately double AUC and increase t½ from 9.8 h to 17 h; paricalcitol itself does not inhibit or induce CYP enzymes |
| Elimination | Primarily hepatobiliary excretion; oral: ~70% feces, ~18% urine; IV: ~63% feces, ~19% urine; t½ healthy: 4–6 h (oral), 5–7 h (IV); t½ CKD 3–5: 14–20 h (oral); t½ CKD 5: 13.9 h (HD, IV), 15.4 h (PD, IV); gender independent | Prolonged t½ in CKD means steady-state changes take longer; hemodialysis does not remove paricalcitol |
Side Effects
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Diarrhea | 7% | Vs 4% placebo; monitor hydration |
| Hypertension | 7% | Vs 4% placebo; common in CKD population; monitor blood pressure |
| Viral infection | 7% | Vs 7% placebo; no excess over placebo |
| Nausea | 6% | Vs 4% placebo; usually mild |
| Edema | 6% | Vs 4% placebo; assess volume status |
| Hypersensitivity | 6% | Vs 2% placebo; includes rash and urticaria |
| Vertigo | 5% | Vs 0% placebo; notable difference from placebo |
| Arthritis | 5% | Vs 0% placebo |
| Dizziness | 5% | Vs 4% placebo |
| Headache | 5% | Vs 4% placebo |
| Vomiting | 5% | Vs 4% placebo |
| Hypotension | 5% | Vs 3% placebo |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Diarrhea | 11% | Vs 11% placebo; no excess |
| Nasopharyngitis | 8% | Vs 7% placebo; minor excess |
| Dizziness | 7% | Vs 0% placebo; notable difference |
| Vomiting | 7% | Vs 0% placebo |
| Constipation | 5% | Vs 0% placebo |
| Insomnia | 5% | Vs 0% placebo |
| Fluid overload | 5% | Vs 0% placebo; common in dialysis population |
| Peritonitis | 5% | Vs 0% placebo; in PD patients |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Hypercalcemia | Dose-dependent; overall Ca >10.3 mg/dL in 7% (vs 7% placebo) in IV studies; 23% of pediatric CKD5 patients (2+ consecutive Ca >10.2) | Days to weeks after initiation or dose increase | Reduce or withhold paricalcitol; stop calcium supplements; lower dietary calcium; reinitiate at lower dose when calcium normalizes |
| Adynamic bone disease | Risk with chronic PTH over-suppression | Gradual; with sustained iPTH below target | Reduce or discontinue paricalcitol and/or vitamin D sterols; resume at lower dose when iPTH returns to target range |
| Cardiac arrhythmias (digitalis-treated patients) | Rare; mediated by hypercalcemia | Variable | Use paricalcitol cautiously with digitalis; monitor calcium frequently |
| Angioedema (including laryngeal edema) | Rare (postmarketing) | Any time | Discontinue permanently; emergency treatment as appropriate |
| Metastatic calcification | Rare; associated with chronic hypercalcemia and elevated Ca × P | Chronic exposure | Control Ca × P product; phosphate binders; discontinue if persistent elevation |
In the IV phase 3 studies, the overall incidence of serum calcium >10.3 mg/dL was 7% in both the paricalcitol and placebo groups, demonstrating that paricalcitol suppresses PTH effectively without the excess hypercalcemia typically seen with calcitriol at equivalent PTH-lowering doses. Nonetheless, monitoring remains essential, particularly in CKD Stage 5 patients where baseline calcium must be ≤9.5 mg/dL before initiation.
Drug Interactions
Paricalcitol is partially metabolized by CYP3A4 but does not itself inhibit or induce any CYP or UGT enzymes at clinically relevant concentrations. The primary interaction concern is with strong CYP3A inhibitors, which approximately double paricalcitol exposure. Pharmacodynamic interactions with calcium-raising or vitamin D compounds also warrant attention.
Monitoring
- Serum CalciumAt least q2wk × 3 months, then monthly × 3 months, then q3 months
RoutineReduce or withhold paricalcitol if hypercalcemia develops. In CKD Stage 5 patients, baseline Ca must be ≤9.5 mg/dL before initiating oral therapy. - Serum PhosphorusParallel to calcium monitoring schedule
RoutineParicalcitol may increase phosphorus absorption. Use phosphate binders as needed; avoid aluminum-containing compounds chronically (aluminum toxicity risk). - iPTHAt least q2wk × 3 months, then monthly × 3 months, then q3 months (predialysis); q2–4 wk during titration (IV)
RoutineDrives dose titration. Maintain within recommended KDIGO target range. If iPTH is chronically below target, reduce or stop paricalcitol to avoid adynamic bone disease. - Serum Creatinine / eGFRPeriodically in predialysis patients
RoutineParicalcitol may increase serum creatinine and decrease eGFR (also seen with calcitriol). This does not necessarily indicate true renal function decline. - Hypercalcemia SymptomsEach visit
Trigger-basedFatigue, difficulty thinking, appetite loss, nausea, vomiting, constipation, increased thirst, increased urination, weight loss. - CYP3A Inhibitor StatusAt each medication reconciliation
Trigger-basedInitiation or discontinuation of strong CYP3A inhibitors requires more frequent Ca and iPTH monitoring and potential paricalcitol dose adjustment.
Contraindications & Cautions
Absolute Contraindications
- Evidence of hypercalcemia — paricalcitol will worsen calcium elevation (FDA PI).
- Evidence of vitamin D toxicity — paricalcitol adds to existing vitamin D burden.
Relative Contraindications (Specialist Input Recommended)
- Concurrent pharmacologic vitamin D therapy — additive risk of hypercalcemia, hypercalciuria, hyperphosphatemia.
- Patients on digitalis — hypercalcemia potentiates arrhythmia risk.
- CKD Stage 5 with baseline Ca >9.5 mg/dL (oral route) — per FDA PI, reduce baseline Ca to ≤9.5 before initiating oral paricalcitol.
Use with Caution
- Concurrent strong CYP3A inhibitors — approximately double paricalcitol AUC.
- Chronic use of aluminum-containing compounds — risk of aluminum overload and bone toxicity (FDA PI Sec 5.4).
- Severe hepatic impairment — paricalcitol PK not studied in this population.
- Concomitant thiazides or high-dose calcium supplements — additive hypercalcemia risk.
Progressive hypercalcemia due to overdosage of vitamin D and its metabolites may be so severe as to require emergency attention. Acute hypercalcemia may exacerbate tendencies for cardiac arrhythmias and seizures and may potentiate the action of digitalis. Chronic hypercalcemia can lead to generalized vascular calcification and other soft-tissue calcification. Prescription-based doses of vitamin D and its derivatives should be withheld during paricalcitol treatment to avoid hypercalcemia.
Patient Counselling
Purpose of Therapy
Paricalcitol is a form of activated vitamin D that helps control overactive parathyroid glands in people with chronic kidney disease. By lowering parathyroid hormone levels, it protects bones and blood vessels from the damage caused by mineral imbalances.
How to Take
Paricalcitol capsules can be taken with or without food. If your doctor has prescribed it three times a week, take it every other day (for example, Monday, Wednesday, Friday) — never two days in a row. If you receive the intravenous form, it will be given during your dialysis session by your healthcare team.
Sources
- Zemplar (paricalcitol) Capsules — Full Prescribing Information. AbbVie Inc. Revised 08/2024. Drugs.comPrimary source for oral paricalcitol dosing, indications, adverse reactions, PK, and drug interactions across CKD Stages 3–5.
- Zemplar (paricalcitol) Injection — Full Prescribing Information. AbbVie Inc. DailyMedSource for IV paricalcitol dosing, PK parameters (t½ 13.9–15.4 h in HD/PD patients), and IV-specific safety data.
- Paricalcitol Injection — Full Prescribing Information. Accord Healthcare. FDAGeneric IV label confirming identical dosing, PK, and safety profile.
- Martin KJ, González EA, Gellens M, Brendt WJ, Lobaugh B, Lindberg JS. 19-Nor-1-alpha-25-dihydroxyvitamin D2 (paricalcitol) safely and effectively reduces the levels of intact parathyroid hormone in patients on hemodialysis. J Am Soc Nephrol. 1998;9(8):1427–1432. doi:10.1681/ASN.V981427Original phase 3 study demonstrating paricalcitol safety and efficacy with a 30% iPTH reduction within 6 weeks.
- Coyne D, Acharya M, Qiu P, et al. Paricalcitol capsule for the treatment of secondary hyperparathyroidism in stages 3 and 4 CKD. Am J Kidney Dis. 2006;47(2):263–276. doi:10.1053/j.ajkd.2005.10.007Pivotal placebo-controlled trial of oral paricalcitol in predialysis CKD patients; source of Table 3 adverse reaction data.
- Ross EA, Tian J, Abboud H, et al. Oral paricalcitol for the treatment of secondary hyperparathyroidism in patients on hemodialysis or peritoneal dialysis. Am J Nephrol. 2008;28(1):97–106. doi:10.1159/000109398CKD Stage 5 oral paricalcitol study with iPTH/80 dosing formula; source of Table 5 adverse reaction data.
- KDIGO 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of CKD-MBD. Kidney Int Suppl. 2017;7(1):1–59. doi:10.1016/j.kisu.2017.04.001International guideline recommending calcitriol, vitamin D analogs, or calcimimetics for CKD G5D patients requiring PTH-lowering therapy (Rec 4.2.4, 2B).
- Ketteler M, et al. Chronic kidney disease–mineral and bone disorder: conclusions from a KDIGO Controversies Conference. Kidney Int. 2025;107(3):405–423. doi:10.1016/j.kint.2024.11.013Most recent KDIGO CKD-MBD update discussing updated role of VDRAs in contemporary management of secondary HPT.
- Slatopolsky E, Finch J, Ritter C, et al. A new analog of calcitriol, 19-nor-1,25-(OH)2D2, suppresses parathyroid hormone secretion in uremic rats in the absence of hypercalcemia. Am J Kidney Dis. 1995;26(5):852–860. doi:10.1016/0272-6386(95)90456-5Foundational preclinical study establishing the selective VDR activation profile of paricalcitol with less calcemic activity than calcitriol.
- Brown AJ, Finch J, Slatopolsky E. Differential effects of 19-nor-1,25-dihydroxyvitamin D(2) and 1,25-dihydroxyvitamin D(3) on intestinal calcium and phosphate transport. J Lab Clin Med. 2002;139(5):279–284. doi:10.1067/mlc.2002.122819Mechanistic study demonstrating that the 19-nor modification reduces intestinal calcium and phosphorus absorption relative to calcitriol.
- Abboud H, Coyne D, Engelman C, et al. Pharmacokinetics and pharmacodynamics of paricalcitol capsules in CKD Stage 3 and 4 patients. Ren Fail. 2006;28(5):399–406. doi:10.1080/08860220600683698PK study establishing half-life (17–20 h), bioavailability, and dose-proportionality of oral paricalcitol in CKD patients.
- Paricalcitol monograph. In: AHFS Drug Information. American Society of Health-System Pharmacists. Drugs.comComprehensive AHFS monograph summarizing PK across special populations, including HD, PD, and hepatic impairment data.