Paricalcitol (Page 3 of 6)

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of paricalcitol capsules. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune System Disorders: Angioedema (including laryngeal edema)

Investigations: Blood creatinine increased

7 DRUG INTERACTIONS

Table 6 shows the clinically significant drug interactions with paricalcitol capsules.

Table 6: Clinically Significant Drug Interactions with Paricalcitol

CYP3A Inhibitors
Clinical Impact	Paricalcitol is partially metabolized by CYP3A. Hence, exposure of paricalcitol will increase upon coadministration with strong CYP3A inhibitors such as but not limited to: boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole.
Intervention	Dose adjustment of paricalcitol capsules may be necessary. Monitor closely for iPTH and serum calcium concentrations, if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor.
Cholestyramine
Clinical Impact	Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of paricalcitol.
Intervention	Recommend to take paricalcitol capsules at least 1 hour before or 4 to 6 hours after taking cholestyramine (or at as great an interval as possible) to avoid impeding absorption of paricalcitol.
Mineral Oil
Clinical Impact	Mineral oil or other substances that may affect absorption of fat may influence the absorption of paricalcitol.
Intervention	Recommend to take paricalcitol capsules at least 1 hour before or 4 to 6 hours after taking mineral oil (or at as great an interval as possible) to avoid affecting absorption of paricalcitol.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Limited data with paricalcitol capsules in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. There are risks to the mother and fetus associated with chronic kidney disease in pregnancy [see Clinical Considerations].

In animal reproduction studies, slightly increased embryofetal loss was observed in pregnant rats and rabbits administered paricalcitol intravenously during the period of organogenesis at doses 2 and 0.5 times, respectively, the maximum recommended human dose (MRHD). Adverse reproductive outcomes were observed at doses that caused maternal toxicity [see Data].

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

Chronic kidney disease in pregnancy increases the maternal risk for hypertension, spontaneous abortion, preterm labor, and preeclampsia. Chronic kidney disease increases the fetal risk for intrauterine growth restriction (IUGR), prematurity, polyhydramnios, still birth, and low birth weight.

Data

Animal Data

Pregnant rats and rabbits were treated with paricalcitol by once-daily intravenous (IV) injection during the period of organogenesis (in rats, from gestation day (GD) 6 to 17; in rabbits, from GD 6 to 18). Rats were dosed at 0, 0.3, 1.0 or 3.0 mcg/kg/day and rabbits at 0, 0.03, 0.1 or 0.3 mcg/kg/day, representing up to 2 or 0.5 times, respectively, the maximum recommended human dose (MRHD) of 0.24 mcg/kg, based on body surface area (mcg/m²). Slightly decreased fetal viability was observed in both studies at the highest doses representing 2 and 0.5 times, respectively, the MRHD in the presence of maternal toxicity (decreased body weight and food consumption). Pregnant rats were administered paricalcitol by IV injection three times per week at doses of 0, 0.3, 3.0 or 20.0 mcg/kg/day throughout gestation, parturition and lactation (GD 6 to lactation day (LD) 20) representing exposures up to 13 times the MHRD. A small increase in stillbirths and pup deaths from parturition to LD 4 were observed at the high dose when compared to the control group (9.2% versus 3.3% in controls) at 13 times the MRHD, which occurred at a maternally toxic dose known to cause hypercalcemia in rats. Surviving pups were not adversely affected; body weight gains, developmental landmarks, reflex ontogeny, learning indices, and locomotor activity were all within normal parameters. F1 reproductive capacity was unaffected.

8.2 Lactation

Risk Summary

There is no information available on the presence of paricalcitol in human milk, the effects of the drug on the breastfed infant or the effects of the drug on milk production. Studies in rats have shown that paricalcitol and/or its metabolites are present in the milk of lactating rats; however, due to specifies-specific differences in lactation physiology, animal data may not reliably predict drug levels in human milk [see Data]. Because of the potential for serious adverse reactions, including hypercalcemia in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with paricalcitol.

Data

Following a single oral administration of 20 mcg/kg of radioactive [³ H] paricalcitol to lactating rats, the concentrations of total radioactivity was determined. Lower levels of total radioactivity were present in the milk compared to that in the plasma of the dams indicating that low levels of [³ H] paricalcitol and/or its metabolites are secreted into milk. Exposure of the pups to [³ H] paricalcitol through milk was confirmed by the presence of radioactive material in the pups’ stomachs.

8.4 Pediatric Use

The safety and effectiveness of paricalcitol capsules have been established in pediatric patients 10 to 16 years of age for the prevention and treatment of secondary hyperparathyroidism associated with Stage 3, 4, and 5 CKD.

Use of paricalcitol capsules in this age group is supported by evidence from adequate and well controlled studies in adults with CKD, a 12-week double-blind placebo-controlled randomized multicenter study in 36 pediatric patients 10 to 16 years of age with CKD Stages 3 and 4, and safety data from a 12-week open-label single-arm multicenter study in 13 pediatric patients 10 to 16 years of age with CKD Stage 5 receiving peritoneal dialysis or hemodialysis. The pharmacokinetics of paricalcitol in Stage 5 CKD pediatric patients appear to be similar to those observed in Stage 3 and 4 pediatric patients [see Clinical Pharmacology ( 12.3) and Clinical Studies ( 14.1)].

Adverse reactions reported in these pediatric studies are consistent with the known safety profile of paricalcitol capsules and with what has been reported in adult clinical studies [see Adverse Reactions ( 6.1)].

Safety and effectiveness of paricalcitol capsules in pediatric patients under the age of 10 years have not been established.

8.5 Geriatric Use

Of the total number (n = 220) of CKD Stages 3 and 4 patients in clinical studies of paricalcitol 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 paricalcitol 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.