Chronic Kidney Disease Stages 3 and 4
Zemplar Capsules are indicated for the prevention and treatment of secondary hyperparathyroidism associated with Chronic Kidney Disease (CKD) Stages 3 and 4.
Chronic Kidney Disease Stage 5
Zemplar Capsules are indicated for the prevention and treatment of secondary hyperparathyroidism associated with CKD Stage 5 in patients on hemodialysis (HD) or peritoneal dialysis (PD).
Zemplar Dosage and Administration
Chronic Kidney Disease Stages 3 and 4
Zemplar Capsules may be administered daily or three times a week. When dosing three times weekly, the dose should be administered not more frequently than every other day. The total weekly doses for both daily and three times a week dosage regimens are similar [see Clinical Studies (14.1)].
Zemplar Capsules may be taken without regard to food. No dosing adjustment is required in patients with mild and moderate hepatic impairment.
Initial Dose
The initial dose of Zemplar Capsules for CKD Stages 3 and 4 patients is based on baseline intact parathyroid hormone (iPTH) levels.
| Baseline iPTH Level |
Daily Dose |
Three Times a Week Dose* |
| ≤ 500 pg/mL |
1 mcg |
2 mcg |
| > 500 pg/mL |
2 mcg |
4 mcg |
| * To be administered not more often than every other day |
Dose Titration
Dosing must be individualized and based on serum or plasma iPTH levels, with monitoring of serum calcium and serum phosphorus. The following is a suggested approach to dose titration.
| |
|
Dose Adjustment at 2 to 4 Week Intervals |
| iPTH Level Relative to Baseline |
Zemplar Capsule Dose |
Daily Dosage |
Three Times a Week Dosage* |
The same, increased or
decreased by < 30% |
Increase dose by |
1 mcg |
2 mcg |
| Decreased by ≥ 30% and ≤ 60% |
Maintain dose |
- |
- |
Decreased by > 60% or
iPTH < 60 pg/mL |
Decrease dose by |
1 mcg |
2 mcg |
| * To be administered not more often than every other day |
If a patient is taking the lowest dose, 1 mcg, on the daily regimen and a dose reduction is needed, the dose can be decreased to 1 mcg three times a week. If a further dose reduction is required, the drug should be withheld as needed and restarted at a lower dosing frequency. If a patient is on a calcium-based phosphate binder, the phosphate-binder dose may be decreased or withheld, or the patient may be switched to a non-calcium-based phosphate binder. If hypercalcemia or an elevated Ca x P is observed, the dose of Zemplar should be reduced or withheld until these parameters are normalized.
Serum calcium and phosphorus levels should be closely monitored after initiation of Zemplar Capsules, during dose titration periods and during co-administration with strong CYP3A inhibitors [see Warnings and Precautions (5.3), Drug Interactions (7) and Clinical Pharmacology (12.3)].
Chronic Kidney Disease Stage 5
Zemplar Capsules are to be administered three times a week, not more frequently than every other day.
Zemplar Capsules may be taken without regard to food. No dosing adjustment is required in patients with mild and moderate hepatic impairment.
Initial Dose
The initial dose of Zemplar Capsules in micrograms is based on a baseline iPTH level (pg/mL)/80. To minimize the risk of hypercalcemia patients should be treated only after their baseline serum calcium has been adjusted to 9.5 mg/dL or lower [see Clinical Pharmacology (12.2) and Clinical Studies (14.2)].
Dose Titration
Subsequent dosing should be individualized and based on iPTH, serum calcium and phosphorus levels. A suggested dose titration of Zemplar Capsules is based on the following formula:
Titration dose (micrograms) = most recent iPTH level (pg/ml)/80
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 or Ca x P are elevated, the dose should be decreased by 2 to 4 micrograms lower than that calculated by the most recent iPTH/80. If further adjustment is required, the dose of paricalcitol capsules should be reduced or withheld until these parameters are normalized.
As iPTH approaches the target range, small, individualized 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 (e.g., iPTH/100) may be warranted.
Dosage Forms and Strengths
Zemplar Capsules are available as 1 mcg, 2 mcg, and 4 mcg soft gelatin capsules.
- 1 mcg: oval, gray capsule imprinted with Abbott “A” logo and “ZA”
- 2 mcg: oval, orange-brown capsule imprinted with Abbott “A” logo and “ZF”
- 4 mcg: oval, gold capsule imprinted with Abbott “A” logo and “ZK”
Contraindications
Zemplar Capsules should not be given to patients with evidence of
- hypercalcemia or
- vitamin D toxicity [see Warnings and Precautions (5.1)].
Warnings and Precautions
Excessive administration of vitamin D compounds, including Zemplar Capsules, can cause over suppression of PTH, hypercalcemia, hypercalciuria, hyperphosphatemia, and adynamic bone disease.
Hypercalcemia
Progressive hypercalcemia due to overdosage of vitamin D and its metabolites may be so severe as to require emergency attention [see Overdosage (10)]. 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. Concomitant administration of high doses of calcium-containing preparations or thiazide diueretics with Zemplar may increase the risk of hypercalcemia. High intake of calcium and phosphate concomitant with vitamin D compounds may lead to serum abnormalities requiring more frequent patient monitoring and individualized dose titration. Patients also should be informed about the symptoms of elevated calcium, which include feeling tired, difficulty thinking clearly, loss of appetite, nausea, vomiting, constipation, increased thirst, increased urination and weight loss.
Prescription-based doses of vitamin D and its derivatives should be withheld during Zemplar treatment to avoid hypercalcemia.
Digitalis Toxicity
Digitalis toxicity is potentiated by hypercalcemia of any cause. Use caution when Zemplar Capsules are prescribed concomitantly with digitalis compounds.
Laboratory Tests
During the initial dosing or following any dose adjustment of medication, serum calcium, serum phosphorus, and serum or plasma iPTH should be monitored at least every two weeks for 3 months, then monthly for 3 months, and every 3 months thereafter.
Aluminum Overload and Toxicity
Aluminum-containing preparations (e.g., antacids, phosphate binders) should not be administered chronically with Zemplar, as increased blood levels of aluminum and aluminum bone toxicity may occur.
Adverse Reactions
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.
Clinical Trials Experience
CKD Stages 3 and 4
The safety of Zemplar Capsules has been evaluated in three 24-week (approximately six-month), double-blind, placebo-controlled, multicenter clinical studies involving 220 CKD Stages 3 and 4 patients. Six percent (6%) of Zemplar Capsules treated patients and 4% of placebo treated patients discontinued from clinical studies due to an adverse event. Adverse events occurring in the Zemplar Capsules group at a frequency of 2% or greater and more frequently than in the placebo group are presented in Table 1:
Table 1. Treatment-Emergent Adverse Events by Body System Occurring in ≥ 2% of Subjects in the Zemplar-Treated Group of Three, Double-Blind, Placebo-Controlled, Phase 3, CKD Stages 3 and 4 Studies; All Treated Patients
| |
Number (%) of Subjects |
Adverse Eventa
|
Zemplar Capsules
(n = 107) |
Placebo
(n = 113) |
| Overall |
88 |
(82%) |
86 |
(76%) |
| Ear and Labyrinth Disorders |
|
|
|
|
| Vertigo |
5 |
(4.7%) |
0 |
(0.0%) |
| Gastrointestinal Disorders |
|
|
|
|
| Abdominal Discomfort |
4 |
(3.7%) |
1 |
(0.9%) |
| Constipation |
4 |
(3.7%) |
4 |
(3.5%) |
| Diarrhea |
7 |
(6.5%) |
5 |
(4.4%) |
| Nausea |
6 |
(5.6%) |
4 |
(3.5%) |
| Vomiting |
5 |
(4.7%) |
5 |
(4.4%) |
| General Disorders and Administration Site Conditions |
|
|
|
|
| Chest Pain |
3 |
(2.8%) |
1 |
(0.9%) |
| Edema |
6 |
(5.6%) |
5 |
(4.4%) |
| Pain |
4 |
(3.7%) |
4 |
(3.5%) |
| Immune System Disorders |
|
|
|
|
| Hypersensitivity |
6 |
(5.6%) |
2 |
(1.8%) |
| Infections and Infestations |
|
|
|
|
| Fungal Infection |
3 |
(2.8%) |
0 |
(0.0%) |
| Gastroenteritis |
3 |
(2.8%) |
3 |
(2.7%) |
| Infection |
3 |
(2.8%) |
3 |
(2.7%) |
| Sinusitis |
3 |
(2.8%) |
1 |
(0.9%) |
| Urinary Tract Infection |
3 |
(2.8%) |
1 |
(0.9%) |
| Viral Infection |
8 |
(7.5%) |
8 |
(7.1%) |
| Metabolism and Nutrition Disorders |
|
|
|
|
| Dehydration |
3 |
(2.8%) |
1 |
(0.9%) |
| Musculoskeletal and Connective Tissue Disorders |
|
|
|
|
| Arthritis |
5 |
(4.7%) |
0 |
(0.0%) |
| Back Pain |
3 |
(2.8%) |
1 |
(0.9%) |
| Muscle Spasms |
3 |
(2.8%) |
0 |
(0.0%) |
| Nervous System Disorders |
|
|
|
|
| Dizziness |
5 |
(4.7%) |
5 |
(4.4%) |
| Headache |
5 |
(4.7%) |
5 |
(4.4%) |
| Syncope |
3 |
(2.8%) |
1 |
(0.9%) |
| Psychiatric Disorders |
|
|
|
|
| Depression |
3 |
(2.8%) |
0 |
(0.0%) |
| Respiratory, Thoracic and Mediastinal Disorders |
|
|
|
|
| Cough |
3 |
(2.8%) |
2 |
(1.8%) |
| Oropharyngeal Pain |
4 |
(3.7%) |
0 |
(0.0%) |
| Skin and Subcutaneous Tissue Disorders |
|
|
|
|
| Pruritus |
3 |
(2.8%) |
3 |
(2.7%) |
| Rash |
4 |
(3.7%) |
1 |
(0.9%) |
| Skin Ulcer |
3 |
(2.8%) |
0 |
(0.0%) |
| Vascular Disorders |
|
|
|
|
| Hypertension |
7 |
(6.5%) |
4 |
(3.5%) |
| Hypotension |
5 |
(4.7%) |
3 |
(2.7%) |
| a. Includes only events more common in the Zemplar treatment group. |
The following adverse reactions, with a causal relationship to Zemplar, occurred in <2% of the Zemplar treated patients in the above double-blind, placebo-controlled clinical trial data set.
Gastrointestinal Disorders: Dry mouth
Investigations: Hepatic enzyme abnormal
Nervous System Disorders: Dysgeusia
Skin and Subcutaneous Tissue Disorders: Urticaria
CKD Stage 5
The safety of Zemplar Capsules has been evaluated in one 12-week, double-blind, placebo-controlled, multicenter clinical study involving 88 CKD Stage 5 patients. Sixty-one patients received Zemplar Capsules and 27 patients received placebo.
The proportion of patients who terminated prematurely from the study due to adverse events was 7% for Zemplar Capsules treated patients and 7% for placebo patients.
Adverse events occurring in the Zemplar Capsules group at a frequency of 2% or greater and more frequently than in the placebo group are as follows:
Table 2. Treatment-Emergent Adverse Events by Body System Occurring in ≥ 2% of Subjects in the Zemplar-Treated Group, Double-Blind, Placebo-Controlled, Phase 3, CKD Stage 5 Study; All Treated Patients
| |
Number (%) of Subjects |
| Adverse Eventsa |
Zemplar Capsules
(n=61) |
Placebo
(n = 27) |
| Overall |
43 |
(70%) |
19 |
(70%) |
| Gastrointestinal Disorders |
|
|
|
|
| Constipation |
3 |
(4.9%) |
0 |
(0.0%) |
| Diarrhea |
7 |
(11.5%) |
3 |
(11.1%) |
| Vomiting |
4 |
(6.6%) |
0 |
(0.0%) |
| General Disorders and Administration Site Conditions |
|
|
|
|
| Fatigue |
2 |
(3.3%) |
0 |
(0.0%) |
| Edema Peripheral |
2 |
(3.3%) |
0 |
(0.0%) |
| Infections and Infestations |
|
|
|
|
| Nasopharyngitis |
5 |
(8.2%) |
2 |
(7.4%) |
| Peritonitis |
3 |
(4.9%) |
0 |
(0.0%) |
| Sinusitis |
2 |
(3.3%) |
0 |
(0.0%) |
| Urinary Tract Infection |
2 |
(3.3%) |
0 |
(0.0%) |
| Metabolism and Nutrition Disorders |
|
|
|
|
| Fluid Overload |
3 |
(4.9%) |
0 |
(0.0%) |
| Hypoglycemia |
2 |
(3.3%) |
0 |
(0.0%) |
| Nervous System Disorders |
|
|
|
|
| Dizziness |
4 |
(6.6%) |
0 |
(0.0%) |
| Headache |
2 |
(3.3%) |
0 |
(0.0%) |
| Psychiatric Disorders |
|
|
|
|
| Anxiety |
2 |
(3.3%) |
0 |
(0.0%) |
| Insomnia |
3 |
(4.9%) |
0 |
(0.0%) |
| Renal and Urinary Disorders |
|
|
|
|
| Renal Failure Chronic |
2 |
(3.3%) |
0 |
(0.0%) |
| a. Includes only events more common in the Zemplar treatment group. |
The following adverse reactions, with a causal relationship to Zemplar, occurred in <2% of the Zemplar treated patients in the above double-blind, placebo-controlled clinical trial data set.
Gastrointestinal Disorders: Gastroesophageal reflux disease
Metabolism and Nutrition Disorders: Decreased appetite, hypercalcemia, hypocalcemia
Reproductive System and Breast Disorders: Breast tenderness
Skin and Subcutaneous Tissue Disorders: Acne
Postmarketing Experience
The following additional adverse reactions have been reported during post-approval use with the active ingredient in Zemplar capsules: angioedema (including laryngeal edema).
Drug Interactions
CYP3A Inhibitors
Since paricalcitol is partially metabolized by CYP3A, exposure of paricalcitol will be increased while paricalcitol is co-administered with strong CYP3A inhibitors including the following drugs but not limited to: ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor [see Clinical Pharmacology (12.3)].
Cholestyramine
Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules.
Mineral Oil
The use of mineral oil or other substances that may affect absorption of fat may influence the absorption of Zemplar Capsules.
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category C.
Paricalcitol has been shown to cause minimal decreases in fetal viability (5%) when administered daily to rabbits at a dose 0.5 times a human dose of 14 mcg or 0.24 mcg/kg (based on body surface area, mcg/m2), and when administered to rats at a dose two times the 0.24 mcg/kg human dose (based on body surface area, mcg/m2). At the highest dose tested, 20 mcg/kg administered three times per week in rats (13 times the 14 mcg human dose based on surface area, mcg/m2), there was a significant increase in the mortality of newborn rats at doses that were maternally toxic and are known to produce hypercalcemia in rats. No other effects on offspring development were observed.
Paricalcitol was not teratogenic at the doses tested.
Paricalcitol (20 mcg/kg) has been shown to cross the placental barrier in rats. There are no adequate and well-controlled clinical studies in pregnant women. Zemplar Capsules should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.
Nursing Mothers
Studies in rats have shown that paricalcitol is present in the milk. It is not known whether paricalcitol is excreted in human milk. In the nursing patient, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use
Safety and efficacy of Zemplar Capsules in pediatric patients have not been established.
Geriatric Use
Of the total number (n = 220) of CKD Stages 3 and 4 patients in clinical studies of Zemplar Capsules, 49% were age 65 and over, while 17% were age 75 and over. Of the total number (n = 88) of CKD Stage 5 patients in the pivotal study of Zemplar Capsules, 28% were age 65 and over, while 6% were age 75 and over. No overall differences in safety and effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Overdosage
Excessive administration of Zemplar Capsules can cause hypercalcemia, hypercalciuria, and hyperphosphatemia, and over suppression of PTH [see Warnings and Precautions (5.1)].
Treatment of Overdosage
The treatment of acute overdosage of Zemplar Capsules should consist of general supportive measures. If drug ingestion is discovered within a relatively short time, induction of emesis or gastric lavage may be of benefit in preventing further absorption. If the drug has passed through the stomach, the administration of mineral oil may promote its fecal elimination. Serial serum electrolyte determinations (especially calcium), rate of urinary calcium excretion, and assessment of electrocardiographic abnormalities due to hypercalcemia should be obtained. Such monitoring is critical in patients receiving digitalis. Discontinuation of supplemental calcium and institution of a low-calcium diet are also indicated in accidental overdosage. Due to the relatively short duration of the pharmacological action of paricalcitol, further measures are probably unnecessary. If persistent and markedly elevated serum calcium levels occur, there are a variety of therapeutic alternatives that may be considered depending on the patient's underlying condition. These include the use of drugs such as phosphates and corticosteroids, as well as measures to induce an appropriate forced diuresis.
Zemplar is not significantly removed by dialysis.
Zemplar Description
Paricalcitol, USP, the active ingredient in Zemplar Capsules, is a synthetically manufactured, metabolically active vitamin D analog of calcitriol with modifications to the side chain (D2) and the A (19-nor) ring. Zemplar is indicated for the prevention and treatment of secondary hyperparathyroidism in chronic kidney disease. Zemplar is available as soft gelatin capsules for oral administration containing 1 microgram, 2 micrograms or 4 micrograms of paricalcitol. Each capsule also contains medium chain triglycerides, alcohol, and butylated hydroxytoluene. The medium chain triglycerides are fractionated from coconut oil or palm kernel oil. The capsule shell is composed of gelatin, glycerin, titanium dioxide, iron oxide red (2 microgram capsules only), iron oxide yellow (2 microgram and 4 microgram capsules), iron oxide black (1 microgram capsules only), and water.
Paricalcitol is a white, crystalline powder with the empirical formula of C27H44O3, which corresponds to a molecular weight of 416.64. Paricalcitol is chemically designated as 19-nor-1α,3ÎČ,25-trihydroxy-9,10-secoergosta-5(Z),7(E),22(E)-triene and has the following structural formula:
Zemplar - Clinical Pharmacology
Secondary hyperparathyroidism is characterized by an elevation in parathyroid hormone (PTH) associated with inadequate levels of active vitamin D hormone. The source of vitamin D in the body is from synthesis in the skin as vitamin D3 and from dietary intake as either vitamin D2 or D3. Both vitamin D2 and D3 require two sequential hydroxylations in the liver and the kidney to bind to and to activate the vitamin D receptor (VDR). The endogenous VDR activator, calcitriol [1,25(OH)2D3], is a hormone that binds to VDRs that are present in the parathyroid gland, intestine, kidney, and bone to maintain parathyroid function and calcium and phosphorus homeostasis, and to VDRs found in many other tissues, including prostate, endothelium and immune cells. VDR activation is essential for the proper formation and maintenance of normal bone. In the diseased kidney, the activation of vitamin D is diminished, resulting in a rise of PTH, subsequently leading to secondary hyperparathyroidism and disturbances in the calcium and phosphorus homeostasis. Decreased levels of 1,25(OH)2D3 have been observed in early stages of chronic kidney disease. The decreased levels of 1,25(OH)2D3 and resultant elevated PTH levels, both of which often precede abnormalities in serum calcium and phosphorus, affect bone turnover rate and may result in renal osteodystrophy.
Mechanism of Action
Paricalcitol is a synthetic, biologically active vitamin D2 analog of calcitriol. Preclinical and in vitro studies have demonstrated that paricalcitol's biological actions are mediated through binding of the VDR, which results in the selective activation of vitamin D responsive pathways. Vitamin D and paricalcitol have been shown to reduce parathyroid hormone levels by inhibiting PTH synthesis and secretion.
Pharmacodynamics
Paricalcitol decreases serum intact parathyroid hormone (iPTH) and increases serum calcium and serum phosphorous in both HD and PD patients. This observed relationship was quantified using a mathematical model for HD and PD patient populations separately. Computer-based simulations of 100 trials in HD or PD patients (N = 100) using these relationships predict slightly lower efficacy (at least two consecutive ≥ 30% reductions from baseline iPTH) with lower hypercalcemia rates (at least two consecutive serum calcium ≥ 10.5 mg/dL) for lower iPTH-based dosing regimens. Further lowering of hypercalcemia rates was predicted if the treatment with paricalcitol is initiated in patients with lower serum calcium levels at screening.
Based on these simulations, a dosing regimen of iPTH/80 with a screening serum calcium ≤ 9.5 mg/dL, approximately 76.5% (95% CI: 75.6% – 77.3%) of HD patients are predicted to achieve at least two consecutive weekly ≥ 30% reductions from baseline iPTH over a duration of 12 weeks. The predicted incidence of hypercalcemia is 0.8% (95% CI: 0.7% – 1.0%). In PD patients, with this dosing regimen, approximately 83.3% (95% CI: 82.6% – 84.0%) of patients are predicted to achieve at least two consecutive weekly ≥ 30% reductions from baseline iPTH. The predicted incidence of hypercalcemia is 12.4% (95% CI: 11.7% - 13.0%) [see Clinical Studies (14.2) and Dosage and Administration (2.2)].
Pharmacokinetics
Absorption
The mean absolute bioavailability of Zemplar Capsules under low-fat fed condition ranged from 72% to 86% in healthy subjects, CKD Stage 5 patients on HD, and CKD Stage 5 patients on PD. A food effect study in healthy subjects indicated that the Cmax and AUC0-∞ were unchanged when paricalcitol was administered with a high fat meal compared to fasting. Food delayed Tmax by about 2 hours. The AUC0-∞ of paricalcitol increased proportionally over the dose range of 0.06 to 0.48 mcg/kg in healthy subjects.
Distribution
Paricalcitol is extensively bound to plasma proteins (≥ 99.8%). The mean apparent volume of distribution following a 0.24 mcg/kg dose of paricalcitol in healthy subjects was 34 L. The mean apparent volume of distribution following a 4 mcg dose of paricalcitol in CKD Stage 3 and a 3 mcg dose in CKD Stage 4 patients is between 44 and 46 L.
Metabolism
After oral administration of a 0.48 mcg/kg dose of 3H-paricalcitol, parent drug was extensively metabolized, with only about 2% of the dose eliminated unchanged in the feces, and no parent drug was found in the urine. Several metabolites were detected in both the urine and feces. Most of the systemic exposure was from the parent drug. Two minor metabolites, relative to paricalcitol, were detected in human plasma. One metabolite was identified as 24(R)-hydroxy paricalcitol, while the other metabolite was unidentified. The 24(R)-hydroxy paricalcitol is less active than paricalcitol in an in vivo rat model of PTH suppression.
In vitro data suggest that paricalcitol is metabolized by multiple hepatic and non-hepatic enzymes, including mitochondrial CYP24, as well as CYP3A4 and UGT1A4. The identified metabolites include the product of 24(R)-hydroxylation, 24,26- and 24,28-dihydroxylation and direct glucuronidation.
Elimination
Paricalcitol is eliminated primarily via hepatobiliary excretion; approximately 70% of the radiolabeled dose is recovered in the feces and 18% is recovered in the urine. While the mean elimination half-life of paricalcitol is 4 to 6 hours in healthy subjects, the mean elimination half-life of paricalcitol in CKD Stages 3, 4, and 5 (on HD and PD) patients ranged from 14 to 20 hours.
Table 3. Paricalcitol Capsule Pharmacokinetic Characteristics in CKD Stages 3, 4, and 5 Patients
| Pharmacokinetic Parameters |
CKD Stage 3
n = 15* |
CKD Stage 4
n = 14* |
CKD Stage 5 HD**
n = 14 |
CKD Stage 5 PD**
n = 8 |
| Cmax (ng/mL) |
0.11 ± 0.04 |
0.06 ± 0.01 |
0.575 ± 0.17 |
0.413 ± 0.06 |
| AUC0-∞ (ng•h/mL) |
2.42 ± 0.61 |
2.13 ± 0.73 |
11.67 ± 3.23 |
13.41 ± 5.48 |
| CL/F (L/h) |
1.77 ± 0.50 |
1.52 ± 0.36 |
1.82 ± 0.75 |
1.76 ± 0.77 |
| V/F (L) |
43.7 ± 14.4 |
46.4 ± 12.4 |
38 ± 16.4 |
48.7 ± 15.6 |
| t1/2 |
16.8 ± 2.65 |
19.7 ± 7.2 |
13.9 ± 5.1 |
17.7 ± 9.6 |
* Four mcg paricalcitol capsules were given to CKD Stage 3 patients; three mcg paricalcitol capsules were given to CKD Stage 4 patients.
** CKD Stage 5 HD and PD patients received a 0.24 mcg/kg dose of paricalcitol as capsules. |
Specific Populations
Geriatric
The pharmacokinetics of paricalcitol has not been investigated in geriatric patients greater than 65 years [see Use in Specific Populations (8.5)].
Pediatric
The pharmacokinetics of paricalcitol has not been investigated in patients less than 18 years of age.
Gender
The pharmacokinetics of paricalcitol following single doses over the 0.06 to 0.48 mcg/kg dose range was gender independent.
Hepatic Impairment
The disposition of paricalcitol (0.24 mcg/kg) was compared in patients with mild (n = 5) and moderate (n = 5) hepatic impairment (as indicated by the Child-Pugh method) and subjects with normal hepatic function (n = 10). The pharmacokinetics of unbound paricalcitol was similar across the range of hepatic function evaluated in this study. No dose adjustment is required in patients with mild and moderate hepatic impairment. The influence of severe hepatic impairment on the pharmacokinetics of paricalcitol has not been evaluated.
Renal Impairment
Following administration of Zemplar Capsules, the pharmacokinetic profile of paricalcitol for CKD Stage 5 on HD or PD was comparable to that in CKD 3 or 4 patients. Therefore, no special dose adjustments are required other than those recommended in the Dosage and Administration section [see Dosage and Administration (2)].
Drug Interactions
An in vitro study indicates that paricalcitol is neither an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A nor an inducer of CYP2B6, CYP2C9 or CYP3A. Hence, paricalcitol is neither expected to inhibit nor induce the clearance of drugs metabolized by these enzymes.
Omeprazole
The effect of omeprazole (40 mg capsule), a strong inhibitor of CYP2C19, on paricalcitol (four 4 mcg capsules) pharmacokinetics was investigated in a single dose, crossover study in healthy subjects. The pharmacokinetics of paricalcitol was not affected when omeprazole was administered approximately 2 hours prior to the paricalcitol dose.
Ketoconazole
The effect of multiple doses of ketoconazole, a strong inhibitor of CYP3A, administered as 200 mg BID for 5 days on the pharmacokinetics of paricalcitol (4 mcg 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 Drug Interactions (7)].
Nonclinical Toxicology
Carcinogenesis, Mutagenesis and Impairment of Fertility
In a 104-week carcinogenicity study in CD-1 mice, an increased incidence of uterine leiomyoma and leiomyosarcoma was observed at subcutaneous doses of 1, 3, 10 mcg/kg given three times weekly (2 to 15 times the AUC at a human dose of 14 mcg, e
