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ZEMPLAR®
(paricalcitol) Capsules
DESCRIPTION
Paricalcitol, USP, the active ingredient in Zemplar Capsules, is a synthetically manufactured analog of calcitriol, the metabolically active form of vitamin D indicated for the prevention and treatment of secondary hyperparathyroidism in chronic kidney disease. Zemplar is available as soft gelatin capsules for oral administration containing 1 microgram, 2 micrograms or 4 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 and 4 microgram capsules), 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:
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 and from dietary intake. Vitamin D requires 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)2 D3], 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.1 Decreased levels of 1,25(OH)2D3 have been observed in early stages of chronic kidney disease. The decreased levels of 1,25(OH)2 D3 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.
Mechanism of Action
Paricalcitol is a synthetic, biologically active vitamin D analog of calcitriol with modifications to the side chain (D2) and the A (19-nor) ring. 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.
Pharmacokinetics
Special Populations
Drug Interactions
An in vitro study indicates that paricalcitol is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A at concentrations up to 50 nM (21 ng/mL) (approximately 20-fold greater than that obtained after highest tested dose). In fresh primary cultured hepatocytes, the induction observed at paricalcitol concentrations up to 50 nM was less than two-fold for CYP2B6, CYP2C9 or CYP3A, where the positive controls rendered a six- to nineteen-fold induction. Hence, paricalcitol is not expected to inhibit or induce the clearance of drugs metabolized by these enzymes.
CLINICAL STUDIES
The safety and efficacy of Zemplar Capsules were evaluated in three, 24-week, double blind, placebo-controlled, randomized, multicenter, Phase 3 clinical studies in CKD Stage 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 titrated 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 incidences of hypercalcemia (defined as two consecutive serum calcium values > 10.5 mg/dL), hyperphosphatemia and elevated Ca x P product 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 are shown in Figure 1.
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 2.
| Zemplar Capsules | Placebo | |
| iPTH (pg/mL) | n = 104 | n = 110 |
| Mean Baseline Value | 266 | 279 |
| Mean Final Treatment Value | 162 | 315 |
| Mean Change from Baseline (SE) | -104 (9.2) | +35 (9.0) |
| Bone Specific Alkaline Phosphatase (mcg/L) | n = 101 | n = 107 |
| Mean Baseline | 17.1 | 18.8 |
| Mean Final Treatment Value | 9.2 | 17.4 |
| Mean Change from Baseline (SE) | -7.9 (0.76) | -1.4 (0.74) |
| Calcium (mg/dL) | n = 104 | n = 110 |
| Mean Baseline | 9.3 | 9.4 |
| Mean Final Treatment Value | 9.5 | 9.3 |
| Mean Change from Baseline (SE) | +0.2 (0.04) | -0.1 (0.04) |
| Phosphorus (mg/dL) | n = 104 | n = 110 |
| Mean Baseline | 4.0 | 4.0 |
| Mean Final Treatment Value | 4.3 | 4.3 |
| Mean Change from Baseline (SE) | +0.3 (0.08) | +0.3 (0.08) |
| Calcium x Phosphorus Product (mg2/dL2) | n = 104 | n = 110 |
| Mean Baseline | 36.7 | 36.9 |
| Mean Final Treatment Value | 40.7 | 39.7 |
| Mean Change from Baseline (SE) | +4.0 (0.74) | +2.9 (0.72) |
INDICATIONS AND USAGE
Zemplar Capsules are indicated for the prevention and treatment of secondary hyperparathyroidism associated with chronic kidney disease (CKD) Stage 3 and 4.
CONTRAINDICATIONS
Zemplar Capsules should not be given to patients with evidence of vitamin D toxicity, hypercalcemia, or hypersensitivity to any ingredient in this product (see WARNINGS).
WARNINGS
Excessive administration of vitamin D compounds, including Zemplar Capsules, can cause over suppression of PTH, hypercalcemia, hypercalciuria, hyperphosphatemia, and adynamic bone disease. Progressive hypercalcemia due to overdosage of vitamin D and its metabolites may be so severe as to require emergency attention. Acute hypercalcemia may exacerbate tendencies for cardiac arrhythmias and seizures and may potentiate the action of digitalis. Chronic hypercalcemia can lead to generalized vascular calcification and other soft-tissue calcification. High intake of calcium and phosphate concomitant with vitamin D compounds may lead to similar abnormalities and patient monitoring and individualized dose titration is required.
Pharmacologic doses of vitamin D and its derivatives should be withheld during Zemplar treatment to avoid hypercalcemia.
PRECAUTIONS
General
Digitalis toxicity is potentiated by hypercalcemia of any cause, so caution should be applied when digitalis compounds are prescribed concomitantly with Zemplar Capsules.
Information for Patients
The patient or guardian should be informed about compliance with dosage instructions, adherence to instructions about diet and phosphorus restriction, and avoidance of the use of unapproved nonprescription drugs. Phosphate-binding agents may be needed to control serum phosphorus levels in patients, but excessive use of aluminum containing compounds should be avoided. Patients also should be informed about the symptoms of elevated calcium (see ADVERSE REACTIONS).
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 after initiation of Zemplar therapy or following dose-adjustments in Zemplar therapy, then monthly for 3 months, and every 3 months thereafter.
Drug Interactions
Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A.
A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0-∞ (see CLINICAL PHARMACOLOGY). Since paricalcitol is partially metabolized by CYP3A and ketoconazole is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole.
Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules.
Carcinogenesis, Mutagenesis, 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).
Pregnancy
Nursing Mothers
Studies in rats have shown that paricalcitol is present in the milk. It is not known whether paricalcitol is excreted in human milk. In the nursing patient, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Geriatric Use
Of the total number (n = 220) of patients in clinical studies of Zemplar Capsules, 49% were 65 and over, while 17% were 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.
Pediatric Use
Safety and efficacy of Zemplar Capsules in pediatric patients have not been established.
ADVERSE REACTIONS
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 Stage 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. All reported adverse events occurring in at least 2% in either treatment group are presented in Table 3.
| Number (%) of Subjects | ||||
| Body Systema COSTART V Term | Zemplar
Capsules (n = 107) | Placebo (n = 113) | ||
a. Includes all patients with events in that body system. | ||||
| Overall | 88 | (82%) | 86 | (76%) |
| Body as a Whole | 49 | (46%) | 40 | (35%) |
| Accidental Injury | 10 | (9%) | 8 | (7%) |
| Pain | 8 | (7%) | 7 | (6%) |
| Viral Infection | 8 | (7%) | 8 | (7%) |
| Allergic Reaction | 6 | (6%) | 2 | (2%) |
| Headache | 5 | (5%) | 5 | (4%) |
| Abdominal Pain | 4 | (4%) | 2 | (2%) |
| Back Pain | 4 | (4%) | 1 | (1%) |
| Infection | 4 | (4%) | 4 | (4%) |
| Asthena | 3 | (3%) | 2 | (2%) |
| Chest Pain | 3 | (3%) | 1 | (1%) |
| Fever | 3 | (3%) | 1 | (1%) |
| Infection Fungal | 3 | (3%) | 0 | (0%) |
| Cyst | 2 | (2%) | 0 | (0%) |
| Flu Syndrome | 2 | (2%) | 1 | (1%) |
| Infection Bacterial | 2 | (2%) | 1 | (1%) |
| Cardiovascular | 27 | (25%) | 19 | (17%) |
| Hypertension | 7 | (7%) | 4 | (4%) |
| Hypotension | 5 | (5%) | 3 | (3%) |
| Syncope | 3 | (3%) | 1 | (1%) |
| Cardiomyopathy | 2 | (2%) | 0 | (0%) |
| Congestive Heart Failure | 2 | (2%) | 5 | (4%) |
| Myocardial Infarct | 2 | (2%) | 0 | (0%) |
| Postural Hypotension | 2 | (2%) | 0 | (0%) |
| Digestive | 29 | (27%) | 31 | (27%) |
| Diarrhea | 7 | (7%) | 5 | (4%) |
| Nausea | 6 | (6%) | 4 | (4%) |
| Vomiting | 6 | (6%) | 5 | (4%) |
| Constipation | 4 | (4%) | 4 | (4%) |
| Gastroenteritis | 3 | (3%) | 3 | (3%) |
| Dyspepsia | 2 | (2%) | 2 | (2%) |
| Gastritis | 2 | (2%) | 4 | (4%) |
| Rectal Disorder | 2 | (2%) | 0 | (0%) |
| Hemic and Lymphatic System | 4 | (4%) | 10 | (9%) |
| Hypervolemia | 2 | (2%) | 4 | (4%) |
| Ecchymosis | 2 | (2%) | 4 | (4%) |
| Metabolic and Nutritional Disorders | 24 | (22%) | 34 | (30%) |
| Edema | 7 | (7%) | 5 | (4%) |
| Uremia | 7 | (7%) | 9 | (8%) |
| Gout | 4 | (4%) | 6 | (5%) |
| Dehydration | 3 | (3%) | 1 | (1%) |
| Acidosis | 2 | (2%) | 1 | (1%) |
| Hyperkalemia | 2 | (2%) | 3 | (3%) |
| Hyperphosphatemia | 2 | (2%) | 4 | (4%) |
| Hypoglycemia | 2 | (2%) | 4 | (4%) |
| Hypokalemia | 2 | (2%) | 1 | (1%) |
| Musculoskeletal | 12 | (11%) | 9 | (8%) |
| Arthritis | 5 | (5%) | 1 | (1%) |
| Leg Cramps | 3 | (3%) | 0 | (0%) |
| Myalgia | 2 | (2%) | 5 | (4%) |
| Nervous | 18 | (17%) | 12 | (11%) |
| Dizziness | 5 | (5%) | 5 | (4%) |
| Vertigo | 5 | (5%) | 0 | (0%) |
| Depression | 3 | (3%) | 0 | (0%) |
| Insomnia | 2 | (2%) | 2 | (2%) |
| Neuropathy | 2 | (2%) | 1 | (1%) |
| Respiratory | 26 | (24%) | 25 | (22%) |
| Pharyngitis | 11 | (10%) | 12 | (11%) |
| Rhinitis | 5 | (5%) | 4 | (4%) |
| Bronchitis | 3 | (3%) | 1 | (1%) |
| Cough Increased | 3 | (3%) | 2 | (2%) |
| Sinusitis | 3 | (3%) | 1 | (1%) |
| Epistaxis | 2 | (2%) | 1 | (1%) |
| Pneumonia | 2 | (2%) | 0 | (0%) |
| Skin and Appendages | 17 | (16%) | 10 | (9%) |
| Rash | 6 | (6%) | 3 | (3%) |
| Pruritus | 3 | (3%) | 3 | (3%) |
| Skin Ulcer | 3 | (3%) | 0 | (0%) |
| Skin Hypertrophy | 2 | (2%) | 0 | (0%) |
| Vesiculobullous Rash | 2 | (2%) | 1 | (1%) |
| Special Senses | 9 | (8%) | 11 | (10%) |
| Amblyopia | 2 | (2%) | 0 | (0%) |
| Retinal Disorder | 2 | (2%) | 0 | (0%) |
| Urogenital System | 10 | (9%) | 10 | (9%) |
| Urinary Tract Infection | 3 | (3%) | 1 | (1%) |
| Kidney Function Abnormal | 2 | (2%) | 1 | (1%) |
Potential adverse effects of Zemplar Capsules are, in general, similar to those encountered with excessive vitamin D intake. The early and late signs and symptoms of hypercalcemia associated with vitamin D overdoses include:
Early
Weakness, headache, somnolence, nausea, vomiting, dry mouth, constipation, muscle pain, bone pain, and metallic taste.
Late
Anorexia, weight loss, conjunctivitis (calcific), pancreatitis, photophobia, rhinorrhea, pruritus, hyperthermia, decreased libido, elevated BUN, hypercholesterolemia, elevated AST and ALT, ectopic calcification, hypertension, cardiac arrhythmias, somnolence, death, and, rarely, overt psychosis.
OVERDOSAGE
Excessive administration of Zemplar Capsules can cause hypercalcemia, hypercalciuria, and hyperphosphatemia, and over suppression of PTH (see WARNINGS).
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.
DOSAGE AND ADMINISTRATION
Zemplar Capsules may be administered daily or three times a week. When dosing three times weekly, the dose should be administered no more frequently than every other day. The average weekly doses for both daily and three times a week dosage regimens are similar (see CLINICAL STUDIES).
Zemplar Capsules may be taken without regard to food. No dosing adjustment is required in patients with mild and moderate hepatic impairment.
Initial Dose
The initial dose of Zemplar Capsules is based on baseline intact parathyroid hormone (iPTH) levels.
| Baseline iPTH Level | Daily Dose | Three Times a Week Dose* |
* To be administered not more often than every other day | ||
| ≤ 500 pg/mL | 1 mcg | 2 mcg |
| > 500 pg/mL | 2 mcg | 4 mcg |
Dose Titration
Dosing must be individualized and based on serum or plasma iPTH levels, with monitoring of serum calcium and serum phosphorus. The following is a suggested approach in titration.
| Dose Adjustment at 2 to 4 Week Intervals | |||
| iPTH Level Relative to Baseline | Zemplar Capsule Dose | Daily Dosage | Three Times a Week Dosage* |
* To be administered not more often than every other day | |||
| The same or increased Decreased by < 30% | Increase | 1 mcg | 2 mcg |
| Decreased by ≥ 30%, ≤ 60% | Maintain | ||
| Decreased > 60% iPTH < 60 pg/mL | Decrease | 1 mcg | 2 mcg |
If a patient is taking the lowest dose 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 can be restarted at a lower dose. If a patient is on a calcium-based phosphate binder, the binder dose may be decreased or withheld, or the patient may be switched to a non-calcium-based phosphate binder. If hypercalcemia or an elevated Ca x P is observed, the dose of Zemplar should be reduced or interrupted until these parameters are normalized.
Serum calcium and phosphorus levels should be closely monitored after initiation of Zemplar Capsules and during dose titration periods and coadministration with strong P450 3A inhibitors (see CLINICAL PHARMACOLOGY and PRECAUTIONS).
HOW SUPPLIED
Zemplar Capsules are available as 1 mcg, 2 mcg, and 4 mcg capsules.
The 1 mcg capsule is an oval, gray, soft gelatin capsule imprinted with Abbott“A” logo and ZA, and is available in the following package size:
Bottles of 30 (NDC 0074-4317-30)
The 2 mcg capsule is an oval, orange-brown, soft gelatin capsule imprinted with Abbott “A” logo and ZF, and is available in the following package size:
Bottles of 30 (NDC 0074-4314-30)
The 4 mcg capsule is an oval, gold soft gelatin capsule imprinted with Abbott“A” logo and ZK, and is available in the following package size:
Bottles of 30 (NDC 0074-4315-30)
Storage
Store Zemplar Capsules at 25°C (77°F). Excursions permitted between 15°- 30°C (59°- 86°F). See USP Controlled Room Temperature.
U.S. patents: 5,246,925; 5,587,497
REFERENCES
- K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease. Am J Kidney Dis 2003; Volume 42(4): Supplement 3.
Abbott Laboratories
North Chicago, IL 60064, U.S.A.