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Overview
Paricalcitol (capsule) is an endocrine metabolic agent that is FDA approved for the treatment of chronic kidney disease stages 3,4 and 5. Common adverse reactions include edema, hypertension, diarrhea, nausea, vomiting,dizziness, headache.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Indications
Chronic Kidney Disease Stages 3 and 4
Paricalcitol 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
Paricalcitol 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).
Dosage
Chronic Kidney Disease Stages 3 and 4
Paricalcitol 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.
Paricalcitol 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 paricalcitol capsules for CKD Stages 3 and 4 patients is based on baseline intact parathyroid hormone (iPTH) levels.
This image is provided by the National Library of Medicine.
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.
This image is provided by the National Library of Medicine.
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 paricalcitol should be reduced or withheld until these parameters are normalized.
Serum calcium and phosphorus levels should be closely monitored after initiation of paricalcitol capsules, during dose titration periods and during co-administration with strong CYP3A inhibitors.
Chronic Kidney Disease Stage 5
Paricalcitol capsules are to be administered three times a week, not more frequently than every other day.
Paricalcitol 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 paricalcitol 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.
Dose Titration
Subsequent dosing should be individualized and based on iPTH, serum calcium and phosphorus levels. A suggested dose titration of paricalcitol 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
Paricalcitol capsules are available as 1 mcg, 2 mcg, and 4 mcg soft gelatin capsules.
1 mcg: oval, gray capsule imprinted with "PA1"
2 mcg: oval, orange-brown capsule imprinted with "PA2"
4 mcg: oval, yellow capsule imprinted with "PA4"
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Paricalcitol (capsule) in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Paricalcitol (capsule) in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Paricalcitol (capsule) in pediatric patients.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Paricalcitol (capsule) in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Paricalcitol (capsule) in pediatric patients.
Contraindications
Paricalcitol capsules should not be given to patients with evidence of
Excessive administration of vitamin D compounds, including paricalcitol 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. 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 paricalcitol 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 paricalcitol treatment to avoid hypercalcemia.
Digitalis Toxicity
Digitalis toxicity is potentiated by hypercalcemia of any cause. Use caution when paricalcitol 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.
In pre-dialysis patients, paricalcitol capsules may increase serum creatinine and therefore decrease the estimated GFR (eGFR). Similar effects have also been seen with calcitriol.
Aluminum Overload and Toxicity
Aluminum-containing preparations (e.g., antacids, phosphate binders) should not be administered chronically with paricalcitol, as increased blood levels of aluminum and aluminum bone toxicity may occur.
Adverse Reactions
Clinical Trials Experience
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.
CKD Stages 3 and 4
The safety of paricalcitol 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 paricalcitol capsules treated patients and 4% of placebo treated patients discontinued from clinical studies due to an adverse event. Adverse events occurring in the paricalcitol capsules group at a frequency of 2% or greater and more frequently than in the placebo group are presented below:
This image is provided by the National Library of Medicine.
The following adverse reactions, with a causal relationship to paricalcitol, occurred in <2% of the paricalcitol treated patients in the above double-blind, placebo-controlled clinical trial data set.
The safety of paricalcitol 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 paricalcitol capsules and 27 patients received placebo.
The proportion of patients who terminated prematurely from the study due to adverse events was 7% for paricalcitol capsules treated patients and 7% for placebo patients.
Adverse events occurring in the paricalcitol capsules group at a frequency of 2% or greater and more frequently than in the placebo group are as follows:
This image is provided by the National Library of Medicine.
The following adverse reactions, with a causal relationship to paricalcitol, occurred in <2% of the paricalcitol treated patients in the above double-blind, placebo-controlled clinical trial data set.
The following additional adverse reactions have been reported during post-approval use and post-approval clinical trials with the active ingredient in paricalcitol capsules:
Immune System Disorders: angioedema (including laryngeal edema)
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 paricalcitol 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.
Cholestyramine
Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of paricalcitol capsules.
Mineral Oil
The use of mineral oil or other substances that may affect absorption of fat may influence the absorption of paricalcitol capsules.
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. Paricalcitol capsules should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.
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