NDC 0074-9037 Zemplar

Paricalcitol

NDC Product Code 0074-9037

NDC CODE: 0074-9037

Proprietary Name: Zemplar What is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

Non-Proprietary Name: Paricalcitol What is the Non-Proprietary Name?
The non-proprietary name is sometimes called the generic name. The generic name usually includes the active ingredient(s) of the product.

Drug Use Information

Drug Use Information
The drug use information is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate. This information is not individual medical advice and does not substitute for the advice of a health care professional. Always ask a health care professional for complete information about this product and your specific health needs.

  • Paricalcitol is a man-made active form of vitamin D, which is needed for building and keeping strong bones. Paricalcitol is used in patients with long-term kidney disease to treat or prevent high levels of a certain natural substance made by the body (parathyroid hormone). Too much parathyroid hormone can cause serious problems such as bone disorders. Most people get enough vitamin D from exposure to the sun and from fortified food products (e.g., dairy products, vitamins). Before regular vitamin D can be used by the body, it needs to be changed to the active form by the liver and kidneys. People with kidney disease cannot make enough of the active form of vitamin D. Vitamin D helps control parathyroid hormone and the levels of certain minerals (e.g., calcium, phosphorus) that are needed for building and keeping strong bones.

Product Characteristics

Color(s):
ORANGE (C48331 - ORANGE-BROWN)
GRAY (C48324)
Shape: CAPSULE (C48336)
Size(s):
10 MM
8 MM
Imprint(s):
A;ZF
A;ZA
ZA
ZF
Score: 1

NDC Code Structure

NDC 0074-9037-30

Package Description: 30 CAPSULE, LIQUID FILLED in 1 BOTTLE

NDC Product Information

Zemplar with NDC 0074-9037 is a a human prescription drug product labeled by Abbvie Inc.. The generic name of Zemplar is paricalcitol. The product's dosage form is capsule, liquid filled and is administered via oral form.

Labeler Name: Abbvie Inc.

Dosage Form: Capsule, Liquid Filled - A solid dosage form in which the drug is enclosed within a soluble, gelatin shell which is plasticized by the addition of a polyol, such as sorbitol or glycerin, and is therefore of a somewhat thicker consistency than that of a hard shell capsule; typically, the active ingredients are dissolved or suspended in a liquid vehicle.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Zemplar Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • PARICALCITOL 2 ug/1

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • GELATIN (UNII: 2G86QN327L)
  • GLYCERIN (UNII: PDC6A3C0OX)
  • TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
  • WATER (UNII: 059QF0KO0R)
  • FERRIC OXIDE RED (UNII: 1K09F3G675)
  • FERRIC OXIDE YELLOW (UNII: EX438O2MRT)
  • ALCOHOL (UNII: 3K9958V90M)
  • BUTYLATED HYDROXYTOLUENE (UNII: 1P9D0Z171K)
  • MEDIUM-CHAIN TRIGLYCERIDES (UNII: C9H2L21V7U)
  • ALCOHOL (UNII: 3K9958V90M)
  • GELATIN (UNII: 2G86QN327L)
  • GLYCERIN (UNII: PDC6A3C0OX)
  • TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
  • WATER (UNII: 059QF0KO0R)
  • FERROSOFERRIC OXIDE (UNII: XM0M87F357)
  • BUTYLATED HYDROXYTOLUENE (UNII: 1P9D0Z171K)
  • MEDIUM-CHAIN TRIGLYCERIDES (UNII: C9H2L21V7U)
  • ALCOHOL (UNII: 3K9958V90M)
  • GELATIN (UNII: 2G86QN327L)
  • GLYCERIN (UNII: PDC6A3C0OX)
  • TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
  • WATER (UNII: 059QF0KO0R)
  • FERROSOFERRIC OXIDE (UNII: XM0M87F357)
  • BUTYLATED HYDROXYTOLUENE (UNII: 1P9D0Z171K)
  • MEDIUM-CHAIN TRIGLYCERIDES (UNII: C9H2L21V7U)
  • GELATIN (UNII: 2G86QN327L)
  • GLYCERIN (UNII: PDC6A3C0OX)
  • TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
  • WATER (UNII: 059QF0KO0R)
  • FERRIC OXIDE RED (UNII: 1K09F3G675)
  • FERRIC OXIDE YELLOW (UNII: EX438O2MRT)
  • ALCOHOL (UNII: 3K9958V90M)
  • BUTYLATED HYDROXYTOLUENE (UNII: 1P9D0Z171K)
  • MEDIUM-CHAIN TRIGLYCERIDES (UNII: C9H2L21V7U)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Oral - Administration to or by way of the mouth.
  • Oral - Administration to or by way of the mouth.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Cholecalciferol - [CS]
  • Vitamin D3 Analog - [EPC] (Established Pharmacologic Class)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Abbvie Inc.
Labeler Code: 0074
FDA Application Number: NDA021606 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: NDA - A product marketed under an approved New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 04-20-2018 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2021 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA’s requests for correction to deficient or non-compliant submissions. Values = ‘Y’ or ‘N’.

* Please review the disclaimer below.

Zemplar Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

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).

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 DoseTable 1. Recommended ZEMPLAR Starting Dose Based upon Baseline iPTH LevelBaseline iPTH LevelDaily DoseThree Times a Week Dose*Less than or equal to 500 pg/mL1 mcg2 mcgMore than 500 pg/mL2 mcg4 mcg*   To be administered not more often than every other dayDose TitrationTable 2. Recommended ZEMPLAR Dose Titration Base upon iPTH Level  Dose Adjustment at 2 to 4 Week IntervalsiPTH Level Relative to BaselineZEMPLAR Capsule DoseDaily DosageThree Times a Week Dosage*The same, increased ordecreased by less than 30%Increase dose by1 mcg2 mcgDecreased by more than or equal to 30% and less than or equal to 60%Maintain dose--Decreased by more than 60% oriPTH less than 60 pg/mLDecrease dose by1 mcg2 mcg*   To be administered not more often than every other dayIf 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 DoseAdminister 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 TitrationIndividualize 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 80If 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 DoseAdminister ZEMPLAR 1 mcg capsule orally three times a week, no more frequently than every other day.Dose TitrationIndividualize 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 5Initial DoseAdminister 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 numberDose TitrationSubsequent 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.

2.4 Monitoring

Monitor serum calcium and phosphorus levels closely after initiation of ZEMPLAR, 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)].If hypercalcemia is observed, the dose of ZEMPLAR should be reduced or withheld until these parameters are normalized.

2.5 Administration

ZEMPLAR capsules may be taken without regard to food.

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”

4 Contraindications

  • ZEMPLAR capsules should not be given to patients with evidence ofhypercalcemia orvitamin D toxicity [see Warnings and Precautions (5.1)].

5 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.

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.

6 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.

6.1 Clinical Trials Experience

CKD Stages 3 and 4AdultsThe 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 SubjectsAdverse EventaZEMPLAR Capsules (n = 107)Placebo (n = 113)Overall88(82%)86(76%)Ear and Labyrinth Disorders        Vertigo5(5%)0(0%)Gastrointestinal Disorders        Abdominal Discomfort4(4%)1(1%)    Constipation4(4%)4(4%)    Diarrhea7(7%)5(4%)    Nausea6(6%)4(4%)    Vomiting5(5%)5(4%)General Disorders and Administration Site Conditions       Chest Pain3(3%)1(1%)   Edema6(6%)5(4%)   Pain4(4%)4(4%)Immune System Disorders        Hypersensitivity6(6%)2(2%)Infections and Infestations        Fungal Infection3(3%)0(0%)    Gastroenteritis3(3%)3(3%)    Infection3(3%)3(3%)    Sinusitis3(3%)1(1%)    Urinary Tract Infection3(3%)1(1%)    Viral Infection8(7%)8(7%)Metabolism and Nutrition Disorders         Dehydration3(3%)1(1%)Musculoskeletal and Connective Tissue Disorders        Arthritis5(5%)0(0%)    Back Pain3(3%)1(1%)    Muscle Spasms3(3%)0(0%)Nervous System Disorders        Dizziness5(5%)5(4%)    Headache5(5%)5(4%)    Syncope3(3%)1(1%)Psychiatric Disorders        Depression3(3%)0(0%)Respiratory, Thoracic and Mediastinal Disorders        Cough3(3%)2(2%)    Oropharyngeal Pain4(4%)0(0%)Skin and Subcutaneous Tissue Disorders        Pruritus3(3%)3(3%)    Rash4(4%)1(1%)    Skin Ulcer3(3%)0(0%)Vascular Disorders        Hypertension7(7%)4(4%)    Hypotension5(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: UrticariaPediatric patients 10 to 16 years of ageThe 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 SubjectsAdverse EventaZEMPLAR Capsules(n = 18)Placebo (n = 18)Overall7(39%) 16(89%)Gastrointestinal Disorders        Nausea1(6%)0(0%)Infections and Infestations        Conjunctivitis1(6%)0(0%)    Rhinitis3(17%)0(0%)Renal and Urinary Disorders        Micturition Urgency1(6%)0(0%)Respiratory, Thoracic and Mediastinal Disorders        Asthma1(6%)0(0%)a. Includes only events more common in the ZEMPLAR treatment group.Additional Adverse ReactionsThe following adverse reactions have occurred in ZEMPLAR-treated patients:Gastrointestinal Disorders: Abdominal pain, constipation, vomitingMetabolism and Nutrition Disorders: Hypercalcemia and hyperphosphatemiaNervous System Disorders: HeadacheCKD Stage 5AdultsThe 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 SubjectsAdverse EventsaZEMPLAR Capsules(n=61)Placebo(n = 27)Overall43(70%)19(70%)Gastrointestinal Disorders       Constipation3(5%)0(0%)   Diarrhea7(11%)3(11%)   Vomiting4(7%)0(0%)General Disorders and Administration Site Conditions        Fatigue2(3%)0(0%)    Edema Peripheral2(3%)0(0%)Infections and Infestations        Nasopharyngitis5(8%)2(7%)    Peritonitis3(5%)0(0%)    Sinusitis2(3%)0 (0%)    Urinary Tract Infection2(3%)0(0%)Metabolism and Nutrition Disorders         Fluid Overload3(5%)0(0%)    Hypoglycemia2(3%)0(0%)Nervous System Disorders        Dizziness4(7%)0(0%)    Headache2(3%)0(0%)Psychiatric Disorders        Anxiety2(3%)0(0%)    Insomnia3(5%)0(0%)Renal and Urinary Disorders        Renal Failure Chronic2(3%)0(0%)a.   Includes only events more common in the ZEMPLAR treatment group. Additional Adverse ReactionsThe following adverse reactions occurred in <2% of the ZEMPLAR-treated patients in the above double-blind, placebo-controlled clinical trial. 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: AcnePediatric patients 10 to 16 years of ageThe safety of ZEMPLAR capsules has been evaluated in one 12-week, open-label, single-arm, multicenter clinical studies involving 13 CKD Stage 5 patients ages 10 to 16 years of age receiving peritoneal dialysis or hemodialysis. The following adverse reactions were reported:Gastrointestinal Disorders: Abdominal pain, diarrhea, nausea, vomitingMetabolism and Nutrition Disorders: Hypercalcemia, hyperphosphatemiaThree of 13 patients (23%) had hypercalcemia defined as at least 2 consecutive serum calcium values >10.2 mg/dL (2.55 mmol/L).

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of ZEMPLAR 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 ZEMPLAR capsules.Table 6: Clinically Significant Drug Interactions with ParicalcitolCYP3A InhibitorsClinical ImpactParicalcitol 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.InterventionDose 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.CholestyramineClinical ImpactDrugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of paricalcitol.InterventionRecommend 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 OilClinical ImpactMineral oil or other substances that may affect absorption of fat may influence the absorption of paricalcitol.InterventionRecommend 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.

8.1 Pregnancy

Risk SummaryLimited 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 ConsiderationsDisease-associated maternal and/or embryo/fetal riskChronic 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. DataAnimal DataPregnant 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 (mg/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 SummaryThere 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. DataFollowing a single oral administration of 20 mcg/kg of radioactive [3H] 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 [3H] paricalcitol and/or its metabolites are secreted into milk. Exposure of the pups to [3H] 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.

10 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 OverdosageThe 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.

11 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 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 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)-triene and has the following structural formula:

12 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.

12.1 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.

12.2 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)].

12.3 Pharmacokinetics

AbsorptionThe mean absolute bioavailability of ZEMPLAR capsules under low-fat fed condition ranged from 72% to 86% in healthy adult volunteers, CKD Stage 5 patients on HD, and CKD Stage 5 patients on PD. A food effect study in healthy adult volunteers 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 adult volunteers.DistributionParicalcitol 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 adult volunteers 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.MetabolismAfter 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.EliminationParicalcitol 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 adult volunteers, 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 7. Paricalcitol Capsule Pharmacokinetic Parameters (mean ± SD) in CKD Stages 3, 4, and 5 Adult PatientsPharmacokinetic Parameters (units)CKD Stage 3n = 15*CKD Stage 4n = 14*CKD Stage 5 HD**n = 14CKD Stage 5 PD**n = 8Cmax (ng/mL)0.11 ± 0.040.06 ± 0.010.575 ± 0.170.413 ± 0.06AUC0-∞ (ng•h/mL)2.42 ± 0.612.13 ± 0.7311.67 ± 3.23 13.41 ± 5.48CL/F (L/h)1.77 ± 0.501.52 ± 0.361.82 ± 0.75 1.76 ± 0.77V/F (L)43.7 ± 14.446.4 ± 12.438 ± 16.4 48.7 ± 15.6t1/216.8 ± 2.6519.7 ± 7.213.9 ± 5.117.7 ± 9.6HD: hemodialysis; PD: peritoneal dialysis.* 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 PopulationsGeriatricThe pharmacokinetics of paricalcitol has not been investigated in geriatric patients greater than 65 years [see Use in Specific Populations (8.5)].PediatricParicalcitol Cmax, AUC, and t1/2 values were similar between Stage 3 and Stage 4 CKD pediatric patients 10 to 16 years of age. Population pharmacokinetic analysis shows that the pharmacokinetics of paricalcitol in Stage 5 CKD pediatric patients appear to be similar to those observed in Stage 3 and Stage 4 pediatric patients.Table 8. Paricalcitol Capsules Pharmacokinetic Parameters (mean ± SD) in CKD Stages 3 and 4 Patients 10 to 16 Years of AgePharmacokinetic Parameter (units)CKD Stage 3n = 6CKD Stage 4N = 5 Cmax (ng/mL)0.12 ± 0.06 0.13 ± 0.05 AUC∞ (ng•h/mL) 2.63 ± 0.763.2 ± 0.99CL/F (L/h)1.23 ± 0.381.02 ± 0.35 V/F (L) 27.78 ± 18.6024.36 ± 5.92t1/2 (h)15.0 ± 6.117.5 ± 5.9* Three 1 mcg paricalcitol capsules were given to CKD Stage 3 or 4 patients.GenderThe pharmacokinetics of paricalcitol following single doses over the 0.06 to 0.48 mcg/kg dose range was gender independent.Hepatic ImpairmentThe 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 ImpairmentFollowing 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 InteractionsAn 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. OmeprazoleThe 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.KetoconazoleThe 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)].

13.1 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, equivalent to 0.24 mcg/kg based on AUC). The incidence rate of uterine leiomyoma was significantly different than the control group at the highest dose of 10 mcg/kg. In a 104-week carcinogenicity study in rats, there was an increased incidence of benign adrenal pheochromocytoma at subcutaneous doses of 0.15, 0.5, 1.5 mcg/kg (< 1 to 7 times the exposure following a human dose of 14 mcg, equivalent to 0.24 mcg/kg based on AUC). The increased incidence of pheochromocytomas in rats may be related to the alteration of calcium homeostasis by paricalcitol. Paricalcitol did not exhibit genetic toxicity in vitro with or without metabolic activation in the microbial mutagenesis assay (Ames Assay), mouse lymphoma mutagenesis assay (L5178Y), or a human lymphocyte cell chromosomal aberration assay. There was also no evidence of genetic toxicity in an in vivo mouse micronucleus assay. Paricalcitol had no effect on fertility (male or female) in rats at intravenous doses up to 20 mcg/kg/dose (equivalent to 13 times a human dose of 14 mcg based on surface area, mcg/m2).

14.1 Chronic Kidney Disease Stages 3 And 4

AdultsThe safety and efficacy of ZEMPLAR capsules were evaluated in three, 24-week, double blind, placebo-controlled, randomized, multicenter, Phase 3 clinical studies in CKD Stages 3 and 4 patients. Two studies used an identical three times a week dosing design, and one study used a daily dosing design. A total of 107 patients received ZEMPLAR capsules and 113 patients received placebo. The mean age of the patients was 63 years, 68% were male, 71% were Caucasian, and 26% were African-American. The average baseline iPTH was 274 pg/mL (range: 145-856 pg/mL). The average duration of CKD prior to study entry was 5.7 years. At study entry 22% were receiving calcium based phosphate binders and/or calcium supplements. Baseline 25-hydroxyvitamin D levels were not measured.The initial dose of ZEMPLAR capsules was based on baseline iPTH. If iPTH was ≤ 500 pg/mL, ZEMPLAR capsules were administered 1 mcg daily or 2 mcg three times a week, not more than every other day. If iPTH was > 500 pg/mL, ZEMPLAR capsules were administered 2 mcg daily or 4 mcg three times a week, not more than every other day. The dose was increased by 1 mcg daily or 2 mcg three times a week every 2 to 4 weeks until iPTH levels were reduced by at least 30% from baseline. The overall average weekly dose of ZEMPLAR capsules was 9.6 mcg/week in the daily regimen and 9.5 mcg/week in the three times a week regimen.In the clinical studies, doses were titrated for any of the following reasons: if iPTH fell to < 60 pg/mL, or decreased > 60% from baseline, the dose was reduced or temporarily withheld; if iPTH decreased < 30% from baseline and serum calcium was ≤ 10.3 mg/dL and serum phosphorus was ≤ 5.5 mg/dL, the dose was increased; and if iPTH decreased between 30 to 60% from baseline and serum calcium and phosphorus were ≤ 10.3 mg/dL and ≤ 5.5 mg/dL, respectively, the dose was maintained. Additionally, if serum calcium was between 10.4 to 11.0 mg/dL, the dose was reduced irrespective of iPTH, and the dose was withheld if serum calcium was > 11.0 mg/dL. If serum phosphorus was > 5.5 mg/dL, dietary counseling was provided, and phosphate binders could have been initiated or increased. If the elevation persisted, the ZEMPLAR capsules dose was decreased. Seventy-seven percent (77%) of the ZEMPLAR capsules treated patients and 82% of the placebo treated patients completed the 24-week treatment. The primary efficacy endpoint of at least two consecutive ≥ 30% reductions from baseline iPTH was achieved by 91% of ZEMPLAR capsules treated patients and 13% of the placebo treated patients (p < 0.001). The proportion of ZEMPLAR capsules treated patients achieving two consecutive ≥ 30% reductions was similar between the daily and the three times a week regimens (daily: 30/33, 91%; three times a week: 62/68, 91%).The incidence of hypercalcemia (defined as two consecutive serum calcium values > 10.5 mg/dL), and hyperphosphatemia in ZEMPLAR capsules treated patients was similar to placebo. There were no treatment related adverse events associated with hypercalcemia or hyperphosphatemia in the ZEMPLAR capsules group. No increases in urinary calcium or phosphorous were detected in ZEMPLAR capsules treated patients compared to placebo.The pattern of change in the mean values for serum iPTH during the studies is shown in Figure 1.Figure 1. Mean Values for Serum iPTH Over Time in the Three Double-Blind, Placebo-Controlled, Phase 3, CKD Stages 3 and 4 Studies CombinedThe mean changes from baseline to final treatment visit in serum iPTH, calcium, phosphorus, and bone-specific alkaline phosphatase are shown in Table 9.Table 9. Mean Changes from Baseline to Final Treatment Visit in Serum iPTH, Bone Specific Alkaline Phosphatase, Calcium, Phosphorus, and Calcium x Phosphorus Product in Three Combined Double-Blind, Placebo-Controlled, Phase 3, CKD Stages 3 and 4 Studies  ZEMPLAR CapsulesPlaceboiPTH (pg/mL)n = 104n = 110    Mean Baseline Value266279    Mean Final Treatment Value162315    Mean Change from Baseline (SE)-104 (9.2)+35 (9.0)Bone Specific Alkaline Phosphatase (mcg/L)n = 101n = 107    Mean Baseline17.118.8    Mean Final Treatment Value9.217.4    Mean Change from Baseline (SE)-7.9 (0.76)-1.4 (0.74)Calcium (mg/dL)n = 104n = 110    Mean Baseline9.39.4    Mean Final Treatment Value9.59.3    Mean Change from Baseline (SE)+0.2 (0.04)-0.1 (0.04)Phosphorus (mg/dL)n = 104n = 110    Mean Baseline4.04.0    Mean Final Treatment Value4.34.3    Mean Change from Baseline (SE)+0.3 (0.08)+0.3 (0.08)Pediatric patients 10 to 16 years of age The safety and efficacy of ZEMPLAR capsules were evaluated in a 12-week, double-blind, placebo-controlled, randomized, multicenter study in pediatric patients ages 10 to 16 years with CKD Stages 3 and 4. A total of 18 patients received ZEMPLAR capsules and 18 patients received placebo during the blinded phase of the study. The mean age of the patients was 13.6 years, 69% were male, 86% were Caucasian, and 8% were Asian. The initial dose of ZEMPLAR capsules was 1 mcg three times a week. Serum iPTH, calcium, and phosphorus levels were monitored every 2-4 weeks with a goal to maintain levels within target ranges: iPTH 35 to 70pg/mL for CKD stage 3, iPTH 70 to 100pg/mL for CKD stage 4, calcium < 10.2mg/dL, phosphorous < 5.8mg/dL. Starting at Treatment Week 4 and every 4 weeks thereafter, doses may have been increased in 1 mcg increments three times a week (e.g., increase from 1 mcg three times per week to 2 mcg three times per week) based upon safety observations and blood chemistry evaluations. Each administered dose could be decreased in 1 mcg increments three times a week, or held if the patient was receiving a 1 mcg dose, as appropriate at any time. The average cumulative weekly dose of ZEMPLAR was 4mcg/week during the 12 week blinded treatment period.The primary efficacy endpoint, the proportion of Stage 3 and 4 patients achieving two consecutive ≥ 30% reductions from baseline in iPTH levels, was statistically significant during the 12-week blinded phase. Results are shown in Table 10.Table 10. Changes in iPTH from Baseline in the CKD Stages 3 and 4 Pediatric StudyPhase/TreatmentTwo Consecutive ≥ 30% Reductions From Baseline in iPTH LevelsaBlinded Phase  Placebo0/18 (0%) ZEMPLAR5/18 (28%)** p < 0.05 compared to placebo a. The analysis treats 3 patients on ZEMPLAR and 1 patient on placebo with unknown response status as non-responders.

14.2 Chronic Kidney Disease Stage 5

AdultsThe safety and efficacy of ZEMPLAR capsules were evaluated in a Phase 3, 12-week, double blind, placebo-controlled, randomized, multicenter study in patients with CKD Stage 5 on HD or PD. The study used a three times a week dosing design. A total of 61 patients received ZEMPLAR capsules and 27 patients received placebo. The mean age of the patients was 57 years, 67% were male, 50% were Caucasian, 45% were African- American, and 53% were diabetic. The average baseline serum iPTH was 701 pg/mL (range: 216-1933 pg/mL). The average time since first dialysis across all subjects was 3.3 years.The initial dose of ZEMPLAR capsules was based on baseline iPTH/60. Subsequent dose adjustments were based on iPTH/60 as well as primary chemistry results that were measured once a week. Starting at Treatment Week 2, study drug was maintained, increased or decreased weekly based on the results of the previous week’s calculation of iPTH/60. ZEMPLAR capsules were administered three times a week, not more than every other day.The proportion of patients achieving at least two consecutive weekly ≥ 30% reductions from baseline serum iPTH was 88% of ZEMPLAR capsules treated patients and 13% of the placebo treated patients. The proportion of patients achieving at least two consecutive weekly ≥ 30% reductions from baseline iPTH was similar for HD and PD patients.The incidence of hypercalcemia (defined as two consecutive serum calcium values > 10.5 mg/dL) in patients treated with ZEMPLAR capsules was 6.6% as compared to 0% for patients given placebo. In PD patients the incidence of hypercalcemia in patients treated with ZEMPLAR capsules was 21% as compared to 0% for patients given placebo. The patterns of change in the mean values for serum iPTH are shown in Figure 2. The rate of hypercalcemia with ZEMPLAR capsules may be reduced with a lower dosing regimen based on the iPTH/80 formula as shown by computer simulations. The hypercalcemia rate can be further predicted to decrease, if the treatment is initiated in only those with baseline serum calcium ≤ 9.5 mg/dL [see Clinical Pharmacology (12.2) and Dosage and Administration (2.2)].Figure 2. Mean Values for Serum iPTH Over Time in a Phase 3, Double-Blind, Placebo-Controlled CKD Stage 5 Study

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”)StorageStore ZEMPLAR capsules at 25°C (77°F). Excursions permitted between 15°- 30°C (59°- 86°F). See USP Controlled Room Temperature.

17 Patient Counseling 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)].

Other

© 2018 AbbVie Inc.Manufactured forAbbVie Inc.North Chicago, IL 60064, U.S.A.

03-B613 February 2018

* Please review the disclaimer below.