Zemplar
Paricalcitol · Capsule, Liquid Filled · Oral, Intravenous
Uses
1 INDICATIONS AND USAGE ZEMPLAR is a vitamin D analog indicated in adults and pediatric patients 10 years and older for the prevention and treatment of secondary hyperparathyroidism associated with: Chronic kidney disease (CKD) Stages 3 and 4 ( 1.1 ). CKD Stage 5 in patients on hemodialysis or peritoneal dialysis ( 1.2 ). 1.1 Chronic Kidney Disease Stages 3 and 4 ZEMPLAR capsules are indicated in adults and pediatric patients 10 years of age and older for the prevention and treatment of secondary hyperparathyroidism associated with Chronic Kidney Disease (CKD) Stages 3 and 4. 1.2 Chronic Kidney Disease Stage 5 ZEMPLAR capsules are indicated in adults and pediatric patients 10 years of age and older for the prevention and treatment of secondary hyperparathyroidism associated with CKD Stage 5 in patients on hemodialysis (HD) or peritoneal dialysis (PD).
Dosage and administration
Initial Dosage: CKD Stages 3 and 4 ( 2.1 , 2.3 ) Adult: Baseline iPTH ≤ 500 pg/mL 1 mcg orally daily or 2 mcg three times a week* Adult: Baseline iPTH > 500 pg/mL 2 mcg orally daily or 4 mcg three times a week* Pediatric: Ages 10 to 16 years 1 mcg orally three times a week* Dose Titration: CKD Stages 3 and 4 ( 2.1 , 2.3 ) Adult: iPTH same, increased or decreased by < 30% relative to baseline Increase dose by 1 mcg daily or 2 mcg three times a week* Adult: iPTH decreased by ≥ 30% and ≤ 60% relative to baseline Maintain dose Adult: iPTH decreased by > 60% or iPTH < 60 pg/mL relative to baseline Decrease dose by 1 mcg daily or 2 mcg three times a week* Pediatric: Ages 10 to 16 years Increase each dose by 1 mcg three times a week every 4 weeks or decrease each dose by 1 mcg three times a week at any time based on iPTH, serum calcium and phosphorus levels.* * Not more frequently than every other day when dosing three times a week. Initial Dosage: CKD Stage 5 ( 2.2 , 2.3 ) Adult Dose (micrograms) = baseline iPTH (pg/mL) divided by 80. Administer dose orally three times a week.* Pediatric: Ages 10 to 16 years Dose (micrograms) = baseline iPTH (pg/mL) divided by 120. Administer dose orally three times a week.* Dose Titration: CKD Stage 5 ( 2.2 , 2.3 ) Adult Dose in micrograms is based on most recent iPTH (pg/mL) divided by 80 with adjustments based on serum calcium and phosphorous levels. Dose three times a week.* Pediatric: Ages 10 to 16 years Increase each dose by 1 mcg three times a week every 4 weeks or decrease each dose by 2 mcg three times a week at any time based on iPTH, serum calcium and phosphorus levels.* * Not more frequently than every other day. CKD Stage 5: To avoid hypercalcemia only treat patients after their baseline serum calcium has been reduced to 9.5 mg/dL or lower ( 2.2 ). 2.1 Chronic Kidney Disease Stages 3 and 4 in Adults Administer ZEMPLAR capsules orally once daily or three times a week [see Clinical Studies ( 14.1 )] . When dosing three times weekly, do not administer more frequently than every other day. Initial Dose Table 1. Recommended ZEMPLAR Starting Dose Based upon Baseline iPTH Level Baseline iPTH Level Daily Dose Three Times a Week Dose* Less than or equal to 500 pg/mL 1 mcg 2 mcg More than 500 pg/mL 2 mcg 4 mcg * To be administered not more often than every other day Dose Titration Table 2. Recommended ZEMPLAR Dose Titration Base upon iPTH Level 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 less than 30% Increase dose by 1 mcg 2 mcg Decreased by more than or equal to 30% and less than or equal to 60% Maintain dose - - Decreased by more than 60% or iPTH less than 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. 2.2 Chronic Kidney Disease Stage 5 in Adults Initial Dose Administer the dose of ZEMPLAR capsules orally three times a week, no more frequently than every other day based upon the following formula: Dose (micrograms) = baseline iPTH (pg/mL) divided by 80 Treat patients only after their baseline serum calcium has been adjusted to 9.5 mg/dL or lower to minimize the risk of hypercalcemia [see Clinical Pharmacology ( 12.2 ) and Clinical Studies ( 14.2 )] . Dose Titration Individualize the dose of ZEMPLAR based on iPTH, serum calcium and phosphorus levels. Titrate ZEMPLAR dose based on the following formula: Dose (micrograms) = most recent iPTH level (pg/ml) divided by 80 If serum calcium is elevated, the dose should be decreased by 2 to 4 micrograms. 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 divided by 100) may be warranted. 2.3 Pediatric Patients (Ages 10 to 16 Years) CKD Stages 3 and 4 Initial Dose Administer ZEMPLAR 1 mcg capsule orally three times a week, no more frequently than every other day. Dose Titration Individualize and titrate ZEMPLAR dose based on iPTH, serum calcium and phosphorus levels to maintain an iPTH level within target range. Every 4 weeks, each administered ZEMPLAR dose may be increased in 1 mcg increments, maintaining the three times per week regimen (e.g., increase from 1 mcg three times per week to 2 mcg three times per week). At any time, each administered dose may be decreased by 1 mcg. ZEMPLAR may be stopped if the patient requires reduction while receiving 1 mcg three times per week, resuming when appropriate. CKD Stage 5 Initial Dose Administer the dose of ZEMPLAR capsules orally three times a week, no more frequently than every other day based upon the following formula: Dose* (micrograms) = baseline iPTH (pg/mL) divided by 120 * Round down to the nearest whole number Dose Titration Subsequent dosing should be individualized and based on iPTH, serum calcium and phosphorus levels to maintain an iPTH level within target range. Every 4 weeks, each administered ZEMPLAR dose may be increased in 1 mcg increments, maintaining the three times per week regimen (e.g., increase from 1 mcg three times per week to 2 mcg three times per week). At any time, each administered dose may be decreased by 2 mcg. ZEMPLAR may be stopped if the patient requires reduction while receiving 2 mcg three times per week or 1 mcg three times per week, resuming when appropriate.
Dosage forms and strengths
3 DOSAGE FORMS AND STRENGTHS ZEMPLAR capsules are available as 1 mcg and 2 mcg soft gelatin capsules. 1 mcg: oval, gray capsule imprinted with “ZA” 1 mcg: oval, gray capsule imprinted with the “a” logo and “ZA” 2 mcg: oval, orange-brown capsule imprinted with “ZF” 2 mcg: oval, orange-brown capsule imprinted with the “a” logo and “ZF” Capsules: 1 mcg and 2 mcg ( 3 ).
Contraindications
4 CONTRAINDICATIONS ZEMPLAR capsules should not be given to patients with evidence of hypercalcemia or vitamin D toxicity [see Warnings and Precautions ( 5.1 )] . Evidence of hypercalcemia ( 4 ). Evidence of vitamin D toxicity ( 4 ).
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: Excessive administration of ZEMPLAR capsules can cause over suppression of PTH, hypercalcemia, hypercalciuria, hyperphosphatemia, and adynamic bone disease. Prescription-based doses of vitamin D and its derivatives should be withheld during ZEMPLAR treatment ( 5.1 ). Digitalis toxicity: Potentiated by hypercalcemia of any cause. Use caution when ZEMPLAR capsules are prescribed concomitantly with digitalis compounds ( 5.2 ). Laboratory tests: Monitor serum calcium, serum phosphorus, and serum or plasma iPTH during initial dosing or following any dose adjustment. ZEMPLAR capsules may increase serum creatinine and therefore decrease the estimated GFR (eGFR) ( 5.3 ). Aluminum overload and toxicity: Avoid excessive use of aluminum containing compounds ( 5.4 ). 5.1 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 diuretics 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. 5.2 Digitalis Toxicity Digitalis toxicity is potentiated by hypercalcemia of any cause. Use caution when ZEMPLAR capsules are prescribed concomitantly with digitalis compounds. 5.3 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, ZEMPLAR capsules may increase serum creatinine and therefore decrease the estimated GFR (eGFR). Similar effects have also been seen with calcitriol. 5.4 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.
Side effects
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. The most common adverse reactions (> 5% and more frequent than placebo) include diarrhea, nasopharyngitis, dizziness, vomiting, hypertension, hypersensitivity, nausea, and edema ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc. at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience CKD Stages 3 and 4 Adults 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 3: Table 3. Adverse Reactions by Body System Occurring in ≥ 2% of Subjects in the ZEMPLAR-Treated Group of Three, Double-Blind, Placebo-Controlled CKD Stages 3 and 4 Studies Number (%) of Subjects Adverse Event a ZEMPLAR Capsules (n = 107) Placebo (n = 113) Overall 88 (82%) 86 (76%) Ear and Labyrinth Disorders Vertigo 5 (5%) 0 (0%) Gastrointestinal Disorders Abdominal Discomfort 4 (4%) 1 (1%) Constipation 4 (4%) 4 (4%) Diarrhea 7 (7%) 5 (4%) Nausea 6 (6%) 4 (4%) Vomiting 5 (5%) 5 (4%) General Disorders and Administration Site Conditions Chest Pain 3 (3%) 1 (1%) Edema 6 (6%) 5 (4%) Pain 4 (4%) 4 (4%) Immune System Disorders Hypersensitivity 6 (6%) 2 (2%) Infections and Infestations Fungal Infection 3 (3%) 0 (0%) Gastroenteritis 3 (3%) 3 (3%) Infection 3 (3%) 3 (3%) Sinusitis 3 (3%) 1 (1%) Urinary Tract Infection 3 (3%) 1 (1%) Viral Infection 8 (7%) 8 (7%) Metabolism and Nutrition Disorders Dehydration 3 (3%) 1 (1%) Musculoskeletal and Connective Tissue Disorders Arthritis 5 (5%) 0 (0%) Back Pain 3 (3%) 1 (1%) Muscle Spasms 3 (3%) 0 (0%) Nervous System Disorders Dizziness 5 (5%) 5 (4%) Headache 5 (5%) 5 (4%) Syncope 3 (3%) 1 (1%) Psychiatric Disorders Depression 3 (3%) 0 (0%) Respiratory, Thoracic and Mediastinal Disorders Cough 3 (3%) 2 (2%) Oropharyngeal Pain 4 (4%) 0 (0%) Skin and Subcutaneous Tissue Disorders Pruritus 3 (3%) 3 (3%) Rash 4 (4%) 1 (1%) Skin Ulcer 3 (3%) 0 (0%) Vascular Disorders Hypertension 7 (7%) 4 (4%) Hypotension 5 (5%) 3 (3%) a. Includes only events more common in the ZEMPLAR treatment group. Additional Adverse Reactions The following additional adverse reactions occurred in <2% of the ZEMPLAR-treated patients in the above double-blind, placebo-controlled clinical trial. Gastrointestinal Disorders: Dry mouth Investigations: Hepatic enzyme abnormal Nervous System Disorders: Dysgeusia Skin and Subcutaneous Tissue Disorders: Urticaria Pediatric patients 10 to 16 years of age The safety of ZEMPLAR capsules has been evaluated in one multicenter clinical study involving CKD Stages 3 and 4 patients ages 10 to 16 years. A 12-week double-blind, placebo-controlled phase was followed by an open-label phase during which all patients received ZEMPLAR capsules. During the 12-week blinded phase, a total of 18 patients received ZEMPLAR capsules and 18 patients received placebo. Adverse events occurring more frequently in the ZEMPLAR capsules group than in the placebo group are presented in Table 4. Table 4. Adverse Reactions by Body System Occurring in the Double-Blind, Placebo-Controlled, CKD Stages 3 and 4 Study in Patients Ages 10 to 16 Years Number (%) of Subjects Adverse Event a ZEMPLAR Capsules (n = 18) Placebo (n = 18) Overall 7 (39%) 16 (89%) Gastrointestinal Disorders Nausea 1 (6%) 0 (0%) Infections and Infestations Conjunctivitis 1 (6%) 0 (0%) Rhinitis 3 (17%) 0 (0%) Renal and Urinary Disorders Micturition Urgency 1 (6%) 0 (0%) Respiratory, Thoracic and Mediastinal Disorders Asthma 1 (6%) 0 (0%) a. Includes only events more common in the ZEMPLAR treatment group. Additional Adverse Reactions The following adverse reactions have occurred in ZEMPLAR-treated patients: Gastrointestinal Disorders: Abdominal pain, constipation, vomiting Metabolism and Nutrition Disorders: Hypercalcemia and hyperphosphatemia Nervous System Disorders: Headache CKD Stage 5 Adults 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 5. Adverse Reactions by Body System Occurring in ≥ 2% of Subjects in the ZEMPLAR-Treated Group, Double-Blind, Placebo-Controlled CKD Stage 5 Study Number (%) of Subjects Adverse Events a ZEMPLAR Capsules (n=61) Placebo (n = 27) Overall 43 (70%) 19 (70%) Gastrointestinal Disorders Constipation 3 (5%) 0 (0%) Diarrhea 7 (11%) 3 (11%) Vomiting 4 (7%) 0 (0%) General Disorders and Administration Site Conditions Fatigue 2 (3%) 0 (0%) Edema Peripheral 2 (3%) 0 (0%) Infections and Infestations Nasopharyngitis 5 (8%) 2 (7%) Peritonitis 3 (5%) 0 (0%) Sinusitis 2 (3%) 0 (0%) Urinary Tract Infection 2 (3%) 0 (0%) Metabolism and Nutrition Disorders Fluid Overload 3 (5%) 0 (0%) Hypoglycemia 2 (3%) 0 (0%) Nervous System Disorders Dizziness 4 (7%) 0 (0%) Headache 2 (3%) 0 (0%) Psychiatric Disorders Anxiety 2 (3%) 0 (0%) Insomnia 3 (5%) 0 (0%) Renal and Urinary Disorders Renal Failure Chronic 2 (3%) 0 (0%) a.
Drug interactions
Table 6 shows the clinically significant drug interactions with ZEMPLAR 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 ZEMPLAR 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 ZEMPLAR 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 ZEMPLAR 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. Strong CYP3A inhibitors (e.g. ketoconazole) will increase the exposure of paricalcitol. Use with caution ( 7 ). Cholestyramine, Mineral Oil: Intestinal absorption of paricalcitol may be reduced if administered simultaneously with cholestyramine or mineral oil. Take ZEMPLAR Capsules at least 1 hour before or 4 to 6 hours after taking cholestyramine or mineral oil ( 7 ).
Use in specific populations
Lactation: Breastfeeding not recommended ( 8.2 ). 8.1 Pregnancy Risk Summary Limited data with ZEMPLAR 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/m 2 ). 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 ZEMPLAR. 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 ZEMPLAR 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 ZEMPLAR 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 ZEMPLAR capsules and with what has been reported in adult clinical studies [see Adverse Reactions ( 6.1 )] . Safety and effectiveness of ZEMPLAR 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 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.
Pregnancy
8.1 Pregnancy Risk Summary Limited data with ZEMPLAR 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/m 2 ). 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.
Pediatric use
8.4 Pediatric Use The safety and effectiveness of ZEMPLAR 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 ZEMPLAR 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 ZEMPLAR capsules and with what has been reported in adult clinical studies [see Adverse Reactions ( 6.1 )] . Safety and effectiveness of ZEMPLAR capsules in pediatric patients under the age of 10 years have not been established.
Geriatric use
8.5 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. Paricalcitol is not significantly removed by dialysis.
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 (D 2 ) and the A (19-nor) ring. ZEMPLAR is available as soft gelatin capsules for oral administration containing 1 microgram or 2 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 capsules only), iron oxide black (1 microgram capsules only), and water. Paricalcitol is a white, crystalline powder with the empirical formula of C 27 H 44 O 3 , which corresponds to a molecular weight of 416.64. Paricalcitol is chemically designated as 19-nor-1α,3β,25-trihydroxy-9,10-secoergosta-5(Z),7(E),22(E)-triene and has the following structural formula: the following structural formula: 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,3β,25-trihydroxy-9,10-secoergosta-5(Z),7(E),22(E).
Mechanism of action
12.1 Mechanism of Action Paricalcitol is a synthetic, biologically active vitamin D 2 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.
How supplied
16 HOW SUPPLIED/STORAGE AND HANDLING ZEMPLAR capsules are available as 1 mcg and 2 mcg capsules. The 1 mcg capsule is an oval, gray, soft gelatin capsule supplied and imprinted as follows: Bottles of 30 – NDC 0074-9036-30 (imprinted with “ZA”) Bottles of 30 – NDC 0074-4317-30 (imprinted with the “a” logo and “ZA”) The 2 mcg capsule is an oval, orange-brown, soft gelatin capsule supplied and imprinted as follows: Bottles of 30 – NDC 0074-9037-30 (imprinted with “ZF”) Bottles of 30 – NDC 0074-4314-30 (imprinted with the “a” logo and “ZF”) Storage Store ZEMPLAR capsules at 25°C (77°F). Excursions permitted between 15°- 30°C (59°- 86°F). See USP Controlled Room Temperature.
Patient information
Advise patients of the following: The most common adverse reactions with use of ZEMPLAR capsules include diarrhea, hypertension, nausea, nasopharyngitis, dizziness, and vomiting. Patients should adhere to instructions regarding diet and phosphorus restriction. Patients should contact a health care provider if they develop symptoms of elevated calcium, (e.g. feeling tired, difficulty thinking clearly, loss of appetite, nausea, vomiting, constipation, increased thirst, increased urination and weight loss). Patients should return to the physician's office for routine monitoring. More frequent monitoring is necessary during the initiation of therapy, following dose changes or when potentially interacting medications are started or discontinued. Patients should inform their physician of all medications, including prescription and nonprescription drugs, supplements, and herbal preparations they are taking and any change to their medical condition. Patients should also inform their physician that they are taking ZEMPLAR capsules if a new medication is prescribed. Breastfeeding is not recommended during treatment with ZEMPLAR capsules [see Use in Specific Populations ( 8.2 )] . © 2024 AbbVie. All rights reserved. ZEMPLAR and its design are trademarks of AbbVie Inc. Manufactured for AbbVie Inc. North Chicago, IL 60064, U.S.A. 131899 R1 August 2024
Label text from the FDA structured product label by AbbVie Inc. (revised Aug 7, 2024). Long sections are shortened; the complete label is on DailyMed.
Active ingredients
- Paricalcitol in 4 products
Zemplar NDC products (4)
| NDC | Strength & form | Labeler | Type |
|---|---|---|---|
| 0074-1658 | Paricalcitol 5 ug/mL Injection, Solution | AbbVie Inc. | NDA |
| 0074-4637 | Paricalcitol 2 ug/mL Injection, Solution | AbbVie Inc. | NDA |
| 0074-9036 | Paricalcitol 1 ug/1 Capsule, Liquid Filled | AbbVie Inc. | NDA |
| 0074-9037 | Paricalcitol 2 ug/1 Capsule, Liquid Filled | AbbVie Inc. | NDA |
Zemplar recalls
- D-0833-2016 Apr 27, 2016 · Class III · Terminated
Failed Content Uniformity Specifications - D-1388-2012 Jun 27, 2012 · Class II · Terminated
CGMP Deviations: There is potential that Abbott's third party manufacturer, Hospira, may have applied a foreign (incorrect) stopper to vials in a specific lot of Zemplar Injection.
Frequently asked questions
What is Zemplar used for?
1 INDICATIONS AND USAGE ZEMPLAR is a vitamin D analog indicated in adults and pediatric patients 10 years and older for the prevention and treatment of secondary hyperparathyroidism associated with: Chronic kidney disease (CKD) Stages 3 and 4 ( 1.1 ). CKD Stage 5 in patients on hemodialysis or peritoneal dialysis ( 1.2 ). 1.1 Chronic Kidney Disease Stages 3 and 4 ZEMPLAR capsules are indicated in…
What are the side effects of Zemplar?
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. The most common adverse reactions (> 5% and more frequent than placebo) include diarrhea, nasopharyngitis, dizziness, vomiting,… See the full label for the complete list.
Who makes Zemplar?
Zemplar is listed by 1 labeler in the FDA NDC directory, including AbbVie Inc..
Has Zemplar been recalled?
The FDA enforcement database lists 2 recalls for Zemplar, most recently D-0833-2016 (class iii): Failed Content Uniformity Specifications