1.1 Chronic Kidney Disease Stages 3 and 4

Paricalcitol Capsules are indicated in adults for the prevention and treatment of secondary hyperparathyroidism associated with Chronic Kidney Disease (CKD) Stages 3 and 4.

Pediatric use information for patients 10 to 16 years of age is approved for AbbVie Inc.’s Zemplar (Paricalcitol) capsules. However, due to AbbVie Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

1.2 Chronic Kidney Disease Stage 5
Paricalcitol Capsules are indicated in adults for the prevention and treatment of secondary hyperparathyroidism associated with CKD Stage 5 in patients on hemodialysis (HD) or peritoneal dialysis (PD).

Pediatric use information for patients 10 to 16 years of age is approved for AbbVie Inc.’s Zemplar (Paricalcitol) capsules. However, due to AbbVie Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

2.1 Chronic Kidney Disease Stages 3 and 4 in Adults

Administer Paricalcitol 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 Paricalcitol Capsules Starting Dose Based upon Baseline iPTH Level

Dose Titration

Table 2. Recommended Paricalcitol Capsules Dose Titration  Base upon  iPTH Level

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 Paricalcitol Capsules orally three times a week, no more frequently than every other day 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 Paricalcitol Capsules based on iPTH, serum calcium and phosphorus level. Titrate Paricalcitol Capsules dose based on 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.

Pediatric use information for patients 10 to 16 years of age is approved for AbbVie Inc.’s Zemplar (Paricalcitol) capsules. However, due to AbbVie Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

2.4 Monitoring  

Monitor serum calcium and phosphorus levels closely after initiation of Paricalcitol Capsules  during dose titration periods and during co-administration with strong CYP3A inhibitors [see Warnings and Precautions(5.3),  Drug Interactions (7), and  Clinical Pharmacology (12.3)].

If hypercalcemia is observed, the dose of Paricalcitol Capsules should be reduced or withheld until these parameters are normalized.

2.5 Administration

Paricalcitol Capsules may be taken without regard to food.

Paricalcitol Capsules are available as 1 mcg, 2 mcg, and 4 mcg soft gelatin capsules.

• 1 mcg-grey colour oval shaped soft gelatin capsules imprinted with "12" in black ink.
• 2 mcg-brown colour oval shaped soft gelatin capsules imprinted with "14" in black ink.
•  4 mcg-light yellow colour oval shaped soft gelatin capsules imprinted with "17" in black ink.

Paricalcitol Capsules should not be given to patients with evidence of

• hypercalcemia or
•  vitamin D toxicity [see  Warnings and Precautions (5.1)].

Excessive administration of vitamin D compounds. including Paricalcitol 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 diueretics with Paricalcitol may increase the risk of hypercalcemia. High intake of calcium and phosphate concomitant with vitamin D compounds may lead to serum abnormalities requiring more frequent patient monitoring and individualized dose titration. Patients also should be informed about the symptoms of elevated calcium, which include feeling tired, difficulty thinking clearly, loss of appetite, nausea, vomiting, constipation, increased thirst, increased urination and weight loss.
Prescription-based doses of vitamin D and its derivatives should be withheld during Paricalcitol treatment to avoid hypercalcemia.

5.2  Digitalis Toxicity

Digitalis toxicity is potentiated by hypercalcemia of any cause. Use caution when Paricalcitol 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, Paricalcitol 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 Paricalcitol, as increased blood levels of aluminum and aluminum bone toxicity may occur.

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 4

Adults

The safety of Paricalcitol Capsules has been evaluated in three 24-week (approximately six-month), double-blind, placebo-controlled, multicenter clinical studies involving 220 CKD Stages 3 and 4 patients. Six percent (6%) of Paricalcitol Capsules treated patients and 4% of placebo treated patients discontinued from clinical studies due to an adverse event. Adverse events occurring in the Paricalcitol Capsules group at a frequency of 2% or greater and more frequently than in the placebo group are presented in: Table 3.

Table 3. Adverse Reactions by Body System Occurring in ≥ 2% of Subjects in the Paricalcitol Capsules-Treated Group of Three, Double-Blind, Placebo-Controlled CKD Stages 3 and 4 Studies

Additional Adverse Reactions

The following additional adverse reactions , occurred in <2% of the Paricalcitol-treated adult 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 use information for patients 10 to 16 years of age is approved for AbbVie Inc.’s Zemplar (Paricalcitol) capsules. However, due to AbbVie Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

CKD Stage 5

Adults

The safety of Paricalcitol Capsules has been evaluated in one 12-week, double-blind, placebo controlled, multicenter clinical study involving 88 CKD Stage 5 patients. Sixty-one patients received Paricalcitol Capsules and 27 patients received placebo.

The proportion of patients who terminated prematurely from the study due to adverse events was 7% for Paricalcitol Capsules treated patients and 7% for placebo patients.

Adverse events occurring in the Paricalcitol Capsules group at a frequency of 2% or greater and more frequently than in the placebo group are as follows:

Table 4. Adverse Reactions by Body System Occurring in ≥ 2% of Subjects in the Paricalcitol Capsules-Treated Group, Double-Blind, Placebo-Controlled CKD Stage 5 Study

Additional Adverse Reactions

The following adverse reactions, occurred in <2% of the Paricalcitol Capsules- 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: Acne

Pediatric use information for patients 10 to 16 years of age is approved for AbbVie Inc.’s Zemplar (Paricalcitol) capsules. However, due to AbbVie Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

6.2 Postmarketing Experience

The following additional adverse reactions have been reported 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 casual relationship to drug exposure.



Immune System Disorders: Angioedema (including laryngeal edema)

Investigations: Blood creatinine increased

Table 5 shows the clinically significant drug interactions with Paricalcitol capsules.

Table 5: Clinically Significant Drug Interactions with Paricalcitol

Excessive administration of Paricalcitol 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 Paricalcitol 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.

Paricalcitol, USP, the active ingredient in Paricalcitol 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. Paricalcitol is available as soft gelatin capsules for oral administration containing 1 microgram, 2 micrograms, and 4 micrograms of paricalcitol. Each capsule also contains medium chain triglycerides, alcohol, and butylated hydroxytoluene. ..The capsule shell is composed of gelatin, glycerin, Noncrystallizing Sorbitol solution, titanium dioxide, iron oxide red (2 microgram capsules only), iron oxide yellow (2 microgram and 4 microgram capsules), iron oxide black (1 microgram capsules only) and water. The soft gelatin capsules are printed with black ink Opacode Black (S-1-17823) containing Isopropyl alcohol, Black iron oxide, N-Butyl alcohol, Propylene glycol, Ammonium hydroxide and Shellac.

Paricalcitol is a white, crystalline powder with the empirical formula of C 27H 44O 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:  

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 D 3 and from dietary intake as either vitamin D 2 or D 3. Both vitamin D 2 and D 3 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) 2D 3], 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) 2D 3 have been observed in early stages of chronic kidney disease. The decreased levels of 1,25(OH) 2D 3 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.

14.1 Chronic Kidney Disease Stages 3 and 4

Adults

The safety and efficacy of Paricalcitol 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 Paricalcitol 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 Paricalcitol Capsules was based on baseline iPTH. If iPTH was ≤ 500 pg/mL, Paricalcitol 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, Paricalcitol 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 Paricalcitol 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 Paricalcitol Capsules dose was decreased. Seventy-seven percent (77%) of the Paricalcitol 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 Paricalcitol Capsules treated patients and 13% of the placebo treated patients (p <0.001). The proportion of Paricalcitol 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 Paricalcitol Capsules treated patients was similar to placebo. There were no treatment related adverse events associated with hypercalcemia or hyperphosphatemia in the Paricalcitol Capsules group. No increases in urinary calcium or phosphorous were detected in Paricalcitol 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 Combined

The mean changes from baseline to final treatment visit in serum iPTH, calcium, phosphorus, calcium-phosphorus product (Ca x P), and bone-specific alkaline phosphatase are shown in Table 7.

Table 7. 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

Pediatric use information for patients 10 to 16 years of age is approved for AbbVie Inc.’s Zemplar (Paricalcitol) capsules. However, due to AbbVie Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

14.2 Chronic Kidney Disease Stage 5

Adults

The safety and efficacy of Paricalcitol 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 Paricalcitol 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 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 Paricalcitol 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. Paricalcitol 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 iPTH was 88% of Paricalcitol 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 > 10.5mg/dL) in patients treated with Paricalcitol Capsules was 6.6% as compared to 0% for patients given placebo. In PD patients the incidence of hypercalcemia in patients treated with Paricalcitol 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 Paricalcitol 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

Paricalcitol Capsules are available as 1 mcg, 2 mcg, and 4 mcg capsules.

The 1 mcg capsule is gray colour oval shaped soft gelatin capsule imprinted with ‘12’ in black ink and is available in the following package size.

Bottles of 30 (NDC 49483-687-03)

The 2 mcg capsule is brown colour oval shaped soft gelatin capsule imprinted with ‘14’ in black ink and is available in the following package size.

Bottles of 30 (NDC 49483-688-03)

The 4 mcg capsule is Light yellow colour oval shaped soft gelatin capsules imprinted with '17' in black ink and is available in the following package size.

Bottles of 30 (NDC 49483-699-03)

STORAGE

Store Paricalcitol Capsules at 20°C to 25°C (68°F to77°F). See USP Controlled Room Temperature.

Advise patients of the following:

· The most common adverse reactions with use of Paricalcitol Capsules, which include diarrhea, hypertension, nausea, nasopharyngitis dizziness and vomiting.

· Patients should adhere adhere to instructions regarding diet and phosphorus restriction.

· Patients should contact a health care provider if you 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 Paricalcitol capsules if a new medication is prescribed.

· Breastfeeding is not recommended during treatment with Paricalcitol capsules [see Use in Specific Populations (8.2)].

Manufactured For:

Time-Cap Labs, Inc.

7 Michael Avenue, Farmingdale

New York 11735, USA



Made in India

Rev. 11/22