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Paricalcitol, USP, the active ingredient in Zemplar Injection, is a synthetically manufactured analog of calcitriol, the metabolically active form of vitamin D indicated for the prevention and treatment of secondary hyperparathyroidism associated with chronic kidney disease(CKD) Stage 5. Zemplar is available as a sterile, clear, colorless, aqueous solution for intravenous injection. Each mL contains paricalcitol, 2 mcg or 5 mcg and the following inactive ingredients: alcohol, 20% (v/v) and propylene glycol, 30% (v/v).
Paricalcitol is a white powder 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:
 |
Molecular formula is C27H44O3.
Molecular weight is 416.64.
Zemplar is indicated for the prevention and treatment of secondary hyperparathyroidism associated with chronic kidney disease Stage 5.
The currently accepted target range for iPTH levels in CKD Stage 5 patients is no more than 1.5 to 3 times the non-uremic upper limit of normal.
The recommended initial dose of Zemplar is 0.04 mcg/kg to 0.1 mcg/kg (2.8 – 7 mcg) administered as a bolus dose no more frequently than every other day at any time during dialysis.
If a satisfactory response is not observed, the dose may be increased by 2 to 4 mcg at 2- to 4-week intervals. During any dose adjustment period, serum calcium and phosphorus levels should be monitored more frequently, and if an elevated calcium level or a Ca × P product greater than 75 is noted, the drug dosage should be immediately reduced or interrupted until these parameters are normalized. Then, Zemplar should be reinitiated at a lower dose. If a patient is on a calcium-based phosphate binder, the dose may be decreased or withheld, or the patient may be switched to a non-calcium-based phosphate binder. Zemplar doses may need to be decreased as the PTH levels decrease in response to therapy. Thus, incremental dosing must be individualized.
The following table is a suggested approach in dose titration:
Suggested Dosing Guidelines
| PTH Level | Zemplar Dose |
| the same or increasing | increase |
| decreasing by < 30% | increase |
| decreasing by > 30%, < 60% | maintain |
| decreasing by > 60% | decrease |
| one and one-half to three times upper limit of normal | maintain |
The influence of mild to moderately impaired hepatic function on paricalcitol pharmacokinetics is sufficiently small that no dosing adjustment is required.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.
After initial vial use, the contents of the multi-dose vial remain stable up to seven days when stored at controlled room temperature (see HOW SUPPLIED). Discard unused portion of the single-dose vial.
Zemplar Injection is available as 2 mcg/mL (NDC 0074-4637-01) and 5 mcg/mL (NDC 0074-1658-01 and NDC 0074–1658–05) in trays of 25 vials.
| List No. | Volume/Container | Concentration | Total Content | Vial T ype |
| 4637-01 | 1 mL/Fliptop Vial | 2 mcg/mL | 2 mcg | Single-dose |
| 1658-01 | 1 mL/Fliptop Vial | 5 mcg/mL | 5 mcg | Single-dose |
| 1658-05 | 2 mL/Fliptop Vial | 5 mcg/mL | 10 mcg | Multi-dose |
Store at 25°C (77°F). Excursions permitted between 15° - 30°C (59° - 86°F).
Manufactured for: AbbVie Inc., North Chicago, IL 60064, U.S.A. Revised: July, 2013.
ZEMPLAR is indicated for the prevention and treatment of secondary hyperparathyroidism in patients 5 years of age and older with chronic kidney disease (CKD) on dialysis.
Table 1: Recommended ZEMPLAR Adult Dose Titration Based Upon intact PTH
| Intact PTH Level At Follow-up Visit | Dosage Adjustment |
| Above target and intact PTH increased | Increase* by 2 mcg to 4 mcg every 2 to 4 weeks |
| Above target and intact PTH decreased by less than 30% | Increase* by 2 mcg to 4 mcg every 2 to 4 weeks |
| Above target and intact PTH decreased by 30% to 60% | No Change |
| Above target and intact PTH decreased by more than 60% | Decrease per clinical judgement |
| At target and intact PTH stable | No Change |
| * The maximum daily adult dose is 0.24 mcg/kg | |
Table 2: Recommended ZEMPLAR Pediatric Dose Titration Based Upon intact PTH – Patients 5 years of age and older
| Intact PTH Level At Follow-up Visit | Dosage Adjustment |
| Above target and intact PTH decreased by less than 30% | Increase by 0.04 mcg/kg every 2 to 4 weeks |
| Intact PTH 150 pg/mL or greater and decreased by 30% to 60% | No Change |
| Intact PTH less than 150 pg/mL or decreased by more than 60% | Decrease by 0.04 mcg/kg weekly, or by 50% if decreased dose equals zero |
Injection: clear, colorless solution available as follows:
ZEMPLAR injection is a clear, colorless solution available in cartons of 25 vials as follows:
Table 7: ZEMPLAR Presentations
| Total Strength per Total Volume | Strength per mL | Total Vial Volume and Vial Type | NDC No. |
| 2 mcg/mL | 2 mcg/mL | 1 mL single-dose vial | 0074-4637-01 |
| 5 mcg/mL | 5 mcg/mL | 1 mL single-dose vial | 0074-1658-01 |
| 10 mcg/2 mL | 5 mcg/mL | 2 mL multiple-dose vial | 0074-1658-05 |
Store at 25°C (77°F). Excursions permitted between 15° to 30°C (59° to 86°F).
Discard any unused portion of the single-dose vial after use.
The contents of the multiple-dose vial remain stable up to seven days after initial use when stored at controlled room temperature.
Manufactured for: AbbVie Inc.,North Chicago, IL 60064, U.S.A. Revised: May 2021
Zemplar has been evaluated for safety in clinical studies in 609 CKD Stage 5 patients. In four, placebocontrolled, double-blind, multicenter studies, discontinuation of therapy due to any adverse event occurred in 6.5% of 62 patients treated with Zemplar (dosage titrated as tolerated, see Clinical Studies) and 2.0% of 51 patients treated with placebo for 1 to 3 months. Adverse events occurring in the Zemplar group at a frequency of 2% or greater and with an incidence greater than that in the placebo group, regardless of causality, are presented in the following table:
Adverse Event Incidence Rates for All Treated Patients
In All Placebo-Controlled Studies
| Adverse Event | Zemplar (n = 62) % |
Placebo (n = 51) % |
| Overall | 71 | 78 |
| Cardiac Disorders | ||
| Palpitations | 3.2 | 0.0 |
| Gastrointestinal Disorders | ||
| Dry Mouth | 3.2 | 2.0 |
| Gastrointestinal Hemorrhage | 4.8 | 2.0 |
| Nausea | 12.9 | 7.8 |
| Vomiting | 8.1 | 5.9 |
| General Disorders and Administration Site Conditions | ||
| Chills | 4.8 | 2.0 |
| Edema | 6.5 | 0.0 |
| Malaise | 3.2 | 0.0 |
| Pyrexia | 4.8 | 2.0 |
| Infections and Infestations | ||
| Influenza | 4.8 | 3.9 |
| Pneumonia | 4.8 | 0.0 |
| Sepsis | 4.8 | 2.0 |
| Musculoskeletal and Connective Tissue Disorders | ||
| Arthralgia | 4.8 | 3.9 |
A patient who reported the same medical term more than once was counted only once for that medical term.
Safety parameters (changes in mean Ca, P, Ca × P) in an open-label safety study up to 13 months in duration support the long-term safety of Zemplar in this patient population (see Clinical Studies).
The following adverse reactions, with a causal relationship to Zemplar, occurred in < 2% of the Zemplar treated patients in the above double-blind, placebo-controlled clinical trial data set. In addition,the following also includes adverse reactions reported in Zemplar-treated patients who participated in other studies (non placebo-controlled), including double-blind, active-controlled and open-label studies:
Blood and Lymphatic System Disorders:
Anemia, lymphadenopathy
Cardiac Disorders:
Arrhythmia, atrial flutter, cardiac arrest
Ear and Labyrinth Disorders:
Ear discomfort
Endocrine Disorders:
Hyperparathyroidism, hypoparathyroidism
Eye Disorders:
Conjunctivitis, glaucoma, ocular hyperemia
Gastrointestinal Disorders:
Abdominal discomfort, constipation, diarrhea, dysphagia, gastritis, intestinal ischemia, rectal hemorrhage
General Disorders and Administration Site Conditions:
Asthenia, chest discomfort, chest pain, condition aggravated, edema peripheral, fatigue, feeling abnormal, gait disturbance, injection site extravasation, injection site pain, pain, swelling, thirst
Infections and Infestations:
Nasopharyngitis, upper respiratory tract infection, vaginal infection
Investigations:
Aspartate aminotransferase increased, bleeding time prolonged, heart rate irregular, laboratory test abnormal, weight decreased
Metabolism and Nutrition Disorders:
Decreased appetite, hypercalcemia, hyperkalemia, hyperphosphatemia, hypocalcemia
Musculoskeletal and Connective Tissue Disorders:
Joint stiffness, muscle twitching, myalgia
Neoplasms Benign, Malignant and Unspecified:
Breast cancer
Nervous System Disorders:
Cerebrovascular accident, dizziness, dysgeusia, headache, hypoesthesia, myoclonus, paresthesia, syncope, unresponsive to stimuli
Psychiatric Disorders:
Agitation, confusional state, delirium, insomnia, nervousness, restlessness
Reproductive System and Breast Disorders:
Breast pain, erectile dysfunction
Respiratory, Thoracic and Mediastinal Disorders:
Cough, dyspnea, orthopnea, pulmonary edema, wheezing
Skin and Subcutaneous Tissue Disorders:
Alopecia, blister, hirsutism, night sweats, rash pruritic, pruritus, skin burning sensation
Vascular Disorders:
Hypertension, hypotension
Allergic reactions, such as rash, urticaria, and angioedema (including laryngeal edema) have been reported.
Specific interaction studies were not performed with Zemplar Injection. 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 drug metabolized by CYP2B6, CYP2C9 or CYP3A.
A multiple dose drug-drug interaction study with ketoconazole and paricalcitol capsule 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 paricalcitol is co-administered with ketoconazole and other strong P450 3A inhibitors including the following drugs but not limited to: atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole.
Digitalis toxicity is potentiated by hypercalcemia of any cause, so caution should be applied when digitalis compounds are prescribed concomitantly with Zemplar.
The following serious adverse reactions are described below and elsewhere in the labeling:
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.
Four placebo-controlled, double-blind, multicenter studies were conducted in 113 patients (51% male, 10% Caucasian, 81% African-American and 9% Hispanic, ranging in age from 18 to 90 years). Sixty-two patients were exposed to ZEMPLAR and the average dose at the end of treatment was 0.12 mcg/kg/dose with a mean number of 55 days of dosing across the studies. Discontinuation of therapy due to any adverse reaction occurred in 6.5% of patients treated with ZEMPLAR and 2.0% of patients treated with placebo. Adverse reactions occurring with greater frequency in the ZEMPLAR group and at a frequency of 2% or greater are presented in Table 3.
Table 3: Adverse Reactions Occurring at a Rate of 2% or Greater in Patients with CKD on Dialysis in Four Placebo-Controlled Studies
| Adverse Reaction | Placebo (n = 51) % |
ZEMPLAR (n = 62) % |
| Nausea | 8 | 13 |
| Vomiting | 6 | 8 |
| Edema | 0 | 7 |
| Gastrointestinal Hemorrhage | 2 | 5 |
| Chills | 2 | 5 |
| Pyrexia | 2 | 5 |
| Pneumonia | 0 | 5 |
| Sepsis | 2 | 5 |
| Influenza | 4 | 5 |
| Arthralgia | 4 | 5 |
| Palpitations | 0 | 3 |
| Dry Mouth | 2 | 3 |
| Malaise | 0 | 3 |
The following adverse reactions occurred in less than 2% of the ZEMPLAR treated patients in the above mentioned studies and in additional double-blind, active-controlled and open-label studies:
Blood and Lymphatic System Disorders: Anemia, lymphadenopathy
Cardiac Disorders: Arrhythmia, atrial flutter, irregular heart rate, cardiac arrest, chest discomfort, chest pain, edema peripheral
Ear and Labyrinth Disorders: Ear discomfort
Endocrine Disorders: Hypoparathyroidism
Eye Disorders: Conjunctivitis, glaucoma, ocular hyperemia
Gastrointestinal Disorders: Abdominal discomfort, constipation, diarrhea, dysphagia, gastritis, intestinal ischemia, rectal hemorrhage
General Disorders: Asthenia, condition aggravated, fatigue, feeling abnormal, pain, swelling
Infections: Nasopharyngitis, upper respiratory tract infection, vaginal infection
Injection site reactions: Injection site extravasation, injection site pain
Laboratory abnormalities: Hypercalcemia, hyperkalemia, hyperphosphatemia, hypocalcemia, increased aspartate aminotransferase, prolonged bleeding time
Metabolism and Nutrition Disorders: Decreased appetite, thirst, decreased weight
Musculoskeletal and Connective Tissue Disorders: Joint stiffness, muscle twitching, myalgia
Neoplasms Benign, Malignant and Unspecified: Breast cancer
Nervous System Disorders: Cerebrovascular accident, dizziness, dysgeusia, headache, hypoesthesia, myoclonus, paresthesia, syncope, unresponsive to stimuli, gait disturbance
Psychiatric Disorders: Agitation, confusional state, delirium, insomnia, nervousness, restlessness
Reproductive System and Breast Disorders: Breast pain, erectile dysfunction
Respiratory, Thoracic and Mediastinal Disorders: Cough, dyspnea, orthopnea, pulmonary edema, wheezing
Skin and Subcutaneous Tissue Disorders: Alopecia, blister, hirsutism, night sweats, rash pruritic, pruritus, skin burning sensation
Vascular Disorders: Hypertension, hypotension
The following adverse reactions have been identified during post-approval use of ZEMPLAR. 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.
Allergic reactions, such as rash, urticaria, and angioedema (including laryngeal edema) have been reported.
Table 4 includes clinically significant drug interactions with ZEMPLAR.
Table 4: Clinically Significant Drug Interactions with ZEMPLAR
| Drugs that May Increase the risk of Hypercalcemia | |
| Clinical Impact | Concomitant administration of high doses of calcium-containing preparations or other vitamin D compounds may increase the risk of hypercalcemia. Thiazide diuretics are known to induce hypercalcemia by reducing excretion of calcium in the urine. |
| Examples | Calcium-containing products, other vitamin D compounds or thiazide diuretics |
| Intervention | Monitor calcium more frequently and adjust ZEMPLAR dose as needed [see WARNINGS AND PRECAUTIONS]. |
| Digitalis Compounds | |
| Clinical Impact | ZEMPLAR can cause hypercalcemia which can potentiate the risk of digitalis toxicity. |
| Intervention | Monitor patients for signs and symptoms of digitalis toxicity and increase frequency of serum calcium monitoring when initiating or adjusting the dose of ZEMPLAR in patients receiving digitalis compounds [see WARNINGS AND PRECAUTIONS]. |
| Strong CYP3A Inhibitors | |
| Clinical Impact | ZEMPLAR is partially metabolized by CYP3A. Exposure of ZEMPLAR will increase upon coadministration with strong CYP3A inhibitors [see CLINICAL PHARMACOLOGY]. |
| Examples | Boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telithromycin, and voriconazole |
| Intervention | If a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor, dose adjustment of ZEMPLAR may be necessary. Monitor intact PTH and serum calcium concentrations closely. |
Acute overdose of Zemplar may cause hypercalcemia, and require emergency attention (see OVERDOSAGE). During dose adjustment, serum calcium and phosphorus levels should be monitored closely (e.g., twice weekly). If clinically significant hypercalcemia develops, the dose should be reduced or interrupted. Chronic administration of Zemplar may place patients at risk of hypercalcemia, elevated Ca × P product, and metastatic calcification. 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 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.
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.
Digitalis toxicity is potentiated by hypercalcemia of any cause, so caution should be applied when digitalis compounds are prescribed concomitantly with Zemplar. Adynamic bone lesions may develop if PTH levels are suppressed to abnormal levels.
During the initial phase of medication, serum calcium and phosphorus should be determined frequently (e.g., twice weekly). Once dosage has been established, serum calcium and phosphorus should be measured at least monthly. Measurements of serum or plasma PTH are recommended every 3 months. During dose adjustment of Zemplar, laboratory tests may be required more frequently.
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 (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. Zemplar had no effect on fertility (male or female) in rats at intravenous doses up to 20 mcg/kg/dose [equivalent to 13 times the highest recommended human dose (0.24 mcg/kg) based on surface area, mg/m²].
Paricalcitol has been shown to cause minimal decreases in fetal viability (5%) when administered daily to rabbits at a dose 0.5 times the 0.24 mcg/kg human dose (based on surface area, mg/m²) and when administered to rats at a dose 2 times the 0.24 mcg/kg human dose (based on plasma levels of exposure). At the highest dose tested (20 mcg/kg 3 times per week in rats, 13 times the 0.24 mcg/kg human dose based on surface area), there was a significant increase of the mortality of newborn rats at doses that were maternally toxic (hypercalcemia). No other effects on offspring development were observed. Paricalcitol was not teratogenic at the doses tested.
There are no adequate and well-controlled studies in pregnant women. Zemplar should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.
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.
The safety and effectiveness of Zemplar were examined in a 12-week randomized, double-blind, placebo-controlled study of 29 pediatric patients, aged 5-19 years, with end-stage renal disease on hemodialysis and nearly all had received some form of vitamin D prior to the study. Seventy-six percent of the patients were male, 52% were Caucasian and 45% were African-American. The initial dose of Zemplar was 0.04 mcg/kg 3 times per week based on baseline iPTH level of less than 500 pg/mL, or 0.08 mcg/kg 3 times a week, based on baseline iPTH level of ≥ 500 pg/mL, respectively. The dose of Zemplar was adjusted in 0.04 mcg/kg increments based on the levels of serum iPTH, calcium and Ca x P. The mean baseline levels of iPTH were 841 pg/mL for the 15 Zemplar-treated patients and 740 pg/mL for the 14 placebo-treated subjects. The mean dose of Zemplar administered was 4.6 mcg (range: 0.8 mcg – 9.6 mcg). Ten of the 15 (67%) Zemplar-treated patients and 2 of the 14 (14%) placebo-treated patients completed the trial. Ten of the placebo patients (71%) were discontinued due to excessive elevations in iPTH levels as defined by 2 consecutive iPTH levels > 700 pg/mL and greater than baseline after 4 weeks of treatment.
In the primary efficacy analysis, 9 of 15 (60%) subjects in the Zemplar group had 2 consecutive 30% decreases from baseline iPTH compared with 3 of 14 (21%) patients in the placebo group (95% CI for the difference between groups –1%, 63%). Twenty-three percent of Zemplar vs. 31% of placebo patients had at least one serum calcium level > 10.3 mg/dL, and 40% vs. 14% of Zemplar vs. placebo subjects had at least one Ca x P ion product > 72 (mg/dL)2. The overall percentage of serum calcium measurements > 10.3 mg/dL was 7% in the Zemplar group and 7% in the placebo group; the overall percentage of patients with Ca x P product > 72 (mg/dL)2 was 8% in the Zemplar group and 7% in the placebo group. No subjects in either the Zemplar group or placebo group developed hypercalcemia (defined as at least one calcium value > 11.2 mg/dL) during the study.
Of the 40 patients receiving Zemplar in the three phase 3 placebo-controlled CKD Stage 5 studies, 10 patients were 65 years or over. In these studies, no overall differences in efficacy or safety were observed between patients 65 years or older and younger patients.
Included as part of the PRECAUTIONS section.
Hypercalcemia may occur during ZEMPLAR treatment. Acute hypercalcemia may increase the risk of cardiac arrhythmias and seizures and may potentiate the effect of digitalis on the heart [see WARNINGS AND PRECAUTIONS]. Chronic hypercalcemia can lead to generalized vascular calcification and other soft-tissue calcification. Severe hypercalcemia may require emergency attention.
Hypercalcemia may be exacerbated by concomitant administration of high doses of calciumcontaining preparations, thiazide diuretics, or other vitamin D compounds [see DRUG INTERACTIONS]. In addition, high intake of calcium and phosphate concomitantly with vitamin D compounds may lead to hypercalciuria and hyperphosphatemia. Patients with a history of hypercalcemia prior to initiating therapy may be at increased risk for development of hypercalcemia with ZEMPLAR. In these circumstances, frequent serum calcium monitoring and ZEMPLAR dose adjustments may be required.
When initiating ZEMPLAR or adjusting ZEMPLAR dose, measure serum calcium frequently (e.g., twice weekly). Once a maintenance dose has been established, measure serum calcium at least monthly. If hypercalcemia occurs, reduce the dose or discontinue ZEMPLAR until serum calcium is normal [see DOSAGE AND ADMINISTRATION].
Inform patients about the symptoms of elevated calcium (feeling tired, difficulty thinking clearly, loss of appetite, nausea, vomiting, constipation, increased thirst, increased urination and weight loss) and instruct them to report new or worsening symptoms when they occur.
ZEMPLAR can cause hypercalcemia [see WARNINGS AND PRECAUTIONS] which increases the risk of digitalis toxicity. In patients using ZEMPLAR concomitantly with digitalis compounds, monitor serum calcium and patients for signs and symptoms of digitalis toxicity. Increase the frequency of monitoring when initiating or adjusting the dose of ZEMPLAR [see DRUG INTERACTIONS].
Adynamic bone disease with subsequent increased risk of fractures may develop if intact PTH levels are suppressed by ZEMPLAR to abnormally low levels. Monitor intact PTH levels to avoid over suppression and adjust ZEMPLAR dose, if needed [see DOSAGE AND ADMINISTRATION].
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 administered 3 times per week (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 10mcg/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 administered 3 times per week (at less than clinical exposure 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 (13 times a human dose of 14 mcg, equivalent to 0.24 mcg/kg based on surface area, mg/m²).
Limited data with ZEMPLAR 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, a human dose of 14 mcg (equivalent to 0.24 mcg/kg), based on body surface area (mg/m²). 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. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Disease-Associated Maternal And/Or Embryo/Fetal Risk
Chronic kidney disease in pregnancy increases the risk for maternal hypertension and preeclampsia, miscarriage, preterm delivery, polyhydramnios, still birth, and low birth weight infants.
Animal Data
Pregnant rats and rabbits were treated with paricalcitol by once-daily intravenous 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 or 3 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, a human dose 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, a human dose of 0.24 mcg/kg, in the presence of maternal toxicity (decreased body weight and food consumption). Pregnant rats were administered paricalcitol by intravenous injection three times per week at doses of 0, 0.3, 3 or 20 mcg/kg/day throughout gestation, parturition and lactation (GD 6 to lactation day (LD) 20) representing exposures up to 13 times a human dose of 0.24 mcg/kg. 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 a human dose of 0.24 mcg/kg, 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.
There is no information available on the presence of paricalcitol in human milk, the effects of the drug on the breastfed infant or the effects of the drug on milk production. Studies in rats have shown that paricalcitol and/or its metabolites are present in the milk of lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk (see Data). Infants exposed to ZEMPLAR through breast milk should be monitored for signs and symptoms of hypercalcemia (see Clinical Considerations). The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ZEMPLAR and any potential adverse effects on the breast-fed child from ZEMPLAR or from the underlying maternal condition.
Infants exposed to ZEMPLAR through breast milk should be monitored for signs and symptoms of hypercalcemia, including seizures, vomiting, constipation and weight loss. Monitoring of serum calcium in the infant should be considered.
Following 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.
The safety and efficacy of ZEMPLAR for the prevention and treatment of secondary hyperparathyroidism associated with CKD have been established in pediatric patients 5 years of age and older with CKD on dialysis. Use of ZEMPLAR in pediatric patients 5 years of age and older is supported by evidence from an adequate and well-controlled study in 29 patients, 5 to 19 years of age, with CKD on hemodialysis [see Clinical Studies].
The safety and efficacy of ZEMPLAR have not been established in pediatric patients less than 5 years old.
Clinical studies of ZEMPLAR did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic or cardiac function, and of concomitant disease or other drug therapy.
The pharmacokinetics of ZEMPLAR were studied in patients with mild and moderate hepatic impairment and were similar to that of patients with normal hepatic function. No dose adjustment is required in patients with mild or moderate hepatic function.
ZEMPLAR has not been studied in patients with severe hepatic impairment.
Overdosage of Zemplar may lead to hypercalcemia, hypercalciuria, hyperphosphatemia, and over suppression of PTH. (see WARNINGS).
The treatment of acute overdosage should consist of general supportive measures. 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 acute overdosage.
General treatment of hypercalcemia due to overdosage consists of immediate dose reduction or suspension of Zemplar therapy, institution of a low calcium diet, withdrawal of calcium supplements, patient mobilization, and attention to fluid and electrolyte imbalances. Serum calcium levels should be determined at least weekly until normocalcemia ensues. When serum calcium levels have returned to within normal limits, Zemplar may be reinitiated at a lower dose. If persistent and markedly elevated serum calcium levels occur, there are a variety of therapeutic alternatives that may be considered. These include the use of drugs such as phosphates and corticosteroids as well as measures to induce diuresis. Also, one may consider dialysis against a calcium-free dialysate.
Zemplar is not significantly removed by dialysis.
Zemplar should not be given to patients with evidence of vitamin D toxicity, hypercalcemia, or hypersensitivity to any ingredient in this product (see WARNINGS).
Overdosage of ZEMPLAR may lead to hypercalcemia, hypercalciuria, and hyperphosphatemia. [see WARNINGS AND PRECAUTIONS].
The treatment of acute overdosage should consist of supportive measures and discontinuation of drug administration. Serum calcium levels should be measured until normal.
Paricalcitol is not significantly removed by dialysis.
ZEMPLAR is contraindicated in patients with:
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)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. 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.
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.
Within two hours after administering Zemplar intravenous doses ranging from 0.04 to 0.24 mcg/kg, concentrations of paricalcitol decreased rapidly; thereafter, concentrations of paricalcitol declined loglinearly. No accumulation of paricalcitol was observed with three times a week dosing.
Paricalcitol is extensively bound to plasma proteins ( ≥ 99.8%). In healthy subjects, the steady state volume of distribution is approximately 23.8 L. The mean volume of distribution following a 0.24 mcg/kg dose of paricalcitol in CKD Stage 5 subjects requiring hemodialysis (HD) and peritoneal dialysis (PD) is between 31 and 35 L.
After IV 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 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 (present at low levels in plasma), as well as 24,26- and 24,28- dihydroxylation and direct glucuronidation.
Paricalcitol is excreted primarily by hepatobiliary excretion. Approximately 63% of the radioactivity was eliminated in the feces and 19% was recovered in the urine in healthy subjects. In healthy subjects, the mean elimination half-life of paricalcitol is about five to seven hours over the studied dose range of 0.04 to 0.16 mcg/kg. The pharmacokinetics of paricalcitol has been studied in CKD Stage 5 subjects requiring hemodialysis (HD) and peritoneal dialysis (PD). The mean elimination half-life of paricalcitol after administration of 0.24 mcg/kg paricalcitol IV bolus dose in CKD Stage 5 HD and PD patients is 13.9 and 15.4 hours, respectively (Table 1).
Table 1 : Mean ± SD Paricalcitol Pharmacokinetic
Parameters in CKD Stage 5 Subjects Following Single 0.24 mcg/kg IV Bolus Dose
| CKD Stage 5-HD (n=14) |
CKD Stage 5-PD (n=8) |
|
| Cmax (ng/mL) | 1.680 ± 0.511 | 1.832 ± 0.315 |
| AUC0-∞ (ng•h/mL) | 14.51 ± 4.12 | 16.01 ± 5.98 |
| β(1/h) | 0.050 ± 0.023 | 0.045 ± 0.026 |
| t½ (h) † | 13.9 ± 7.3 | 15.4 ± 10.5 |
| CL (L/h) | 1.49 ± 0.60 | 1.54 ± 0.95 |
| Vdβ (L) | 30.8 ± 7.5 | 34.9 ± 9.5 |
| † harmonic mean ± pseudo standard deviation, HD: hemodialysis, PD: peritoneal dialysis | ||
No accumulation of paricalcitol was observed with three times a week dosing which is consistent with the observed half-life.
The pharmacokinetics of paricalcitol have not been investigated in geriatric patients greater than 65 years.
The pharmacokinetics of paricalcitol have not been investigated in patients less than 18 years of age.
The pharmacokinetics of paricalcitol were gender independent.
The 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 were 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.
The pharmacokinetics of paricalcitol have been studied in CKD Stage 5 subjects requiring hemodialysis (HD) and peritoneal dialysis (PD). Hemodialysis procedure has essentially no effect on paricalcitol elimination. However, compared to healthy subjects, CKD Stage 5 subjects showed a decreased CL and increased half-life (see Pharmacokinetics -Elimination).
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.
Drug interactions with paricalcitol injection have not been studied.
The pharmacokinetic interaction between paricalcitol capsule (16 mcg) and omeprazole (40 mg; oral), a strong inhibitor of CYP2C19, was investigated in a single dose, crossover study in healthy subjects. The pharmacokinetics of paricalcitol were unaffected when omeprazole was administrated approximately 2 hours prior to the paricalcitol dose.
Although no data are available for the drug interaction between paricalcitol injection and ketoconazole, a strong inhibitor of CYP3A, the effect of multiple doses of ketoconazole administered as 200 mg BID for 5 days on the pharmacokinetics of paricalcitol 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 PRECAUTIONS).
In three 12-week, placebo-controlled, phase 3 studies in chronic kidney disease Stage 5 patients on dialysis, the dose of Zemplar was started at 0.04 mcg/kg 3 times per week. The dose was increased by 0.04 mcg/kg every 2 weeks until intact parathyroid hormone (iPTH) levels were decreased at least 30% from baseline or a fifth escalation brought the dose to 0.24 mcg/kg, or iPTH fell to less than 100 pg/mL, or the Ca × P product was greater than 75 within any 2 week period, or serum calcium became greater than 11.5 mg/dL at any time.
Patients treated with Zemplar achieved a mean iPTH reduction of 30% within 6 weeks. In these studies, there was no significant difference in the incidence of hypercalcemia or hyperphosphatemia between Zemplar and placebo-treated patients. The results from these studies are as follows:
| Group (No. of Pts.) | Baseline Mean (Range) | Mean (SE) Change From Baseline to Final Evaluation | |
| PTH (pg/mL) | Zemplar (n = 40) | 783 (291 – 2076) | -379 (43.7) |
| placebo (n = 38) | 745 (320 -1671) | -69.6 (44.8) | |
| Alkaline | Zemplar (n = 31) | 150 (40 - 600) | -41.5 (10.6) |
| Phosphatase (U/L) | placebo (n = 34) | 169 (56 - 911) | +2.6 (10.1) |
| Calcium (mg/dL) | Zemplar (n = 40) | 9.3 (7.2 - 10.4) | +0.47 (0.1) |
| placebo (n = 38) | 9.1 (7.8 - 10.7) | +0.02 (0.1) | |
| Phosphorus (mg/dL) | Zemplar (n = 40) | 5.8 (3.7 - 10.2) | +0.47 (0.3) |
| placebo (n = 38) | 6.0 (2.8 - 8.8) | -0.47 (0.3) | |
| Calcium x | Zemplar (n = 40) | 54 (32 - 106) | +7.9 (2.2) |
| Phosphorus Product | placebo (n = 38) | 54 (26 - 77) | -3.9 (2.3) |
A long-term, open-label safety study of 164 CKD Stage 5 patients (mean dose of 7.5 mcg three times per week), demonstrated that mean serum Ca, P, and Ca × P remained within clinically appropriate ranges with PTH reduction (mean decrease of 319 pg/mL at 13 months).
 |
Paricalcitol is a synthetic, biologically active vitamin D2 analog. Preclinical and in vitro studies have demonstrated that paricalcitol's biological actions are mediated through binding of the vitamin D receptor (VDR), which results in the selective activation of vitamin D responsive pathways. Vitamin D and paricalcitol have been shown to reduce PTH levels by inhibiting PTH synthesis and secretion.
Within two hours after administering ZEMPLAR intravenous doses ranging from 0.04 to 0.24 mcg/kg, concentrations of paricalcitol decreased rapidly; thereafter, concentrations of paricalcitol declined log-linearly. No accumulation of paricalcitol was observed with three times a week dosing.
Paricalcitol is extensively bound to plasma proteins (≥99.8%). In healthy subjects, the steady state volume of distribution is approximately 23.8 L. The mean volume of distribution following a 0.24 mcg/kg dose of paricalcitol in CKD Stage 5 subjects requiring hemodialysis (HD) and peritoneal dialysis (PD) is between 31 and 35 L.
Metabolism
After intravenous 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 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 (present at low levels in plasma), as well as 24,26- and 24,28-dihydroxylation and direct glucuronidation.
Excretion
Paricalcitol is excreted primarily by hepatobiliary excretion. Approximately 63% of the radioactivity was eliminated in the feces and 19% was recovered in the urine in healthy subjects. In healthy subjects, the mean elimination half-life of paricalcitol is about five to seven hours over the studied dose range of 0.04 to 0.16 mcg/kg. The pharmacokinetics of paricalcitol has been studied in CKD patients requiring hemodialysis (HD) and peritoneal dialysis (PD). The mean elimination half-life of paricalcitol after administration of 0.24 mcg/kg paricalcitol IV bolus dose in CKD HD and PD patients is 13.9 and 15.4 hours, respectively (Table 5).
Table 5: Mean ± SD Paricalcitol Pharmacokinetic Parameters in CKD Patients on Dialysis Following Single 0.24 mcg/kg Intravenous Bolus Dose
| CKD -HD (n=14) |
CKD -PD (n=8) |
|
| Cmax (ng/mL) | 1.680 ± 0.511 | 1.832 ± 0.315 |
| AUC0-∞ (ng•h/mL) | 14.51 ± 4.12 | 16.01 ± 5.98 |
| β (1/h) | 0.050 ± 0.023 | 0.045 ± 0.026 |
| t½ (h)* | 13.9 ± 7.3 | 15.4 ± 10.5 |
| CL (L/h) | 1.49 ± 0.60 | 1.54 ± 0.95 |
| Vdβ (L) | 30.8 ± 7.5 | 34.9 ± 9.5 |
| * harmonic mean ± pseudo standard deviation, HD: hemodialysis, PD: peritoneal dialysis. The degree of accumulation was consistent with the half-life and dosing frequency. | ||
The pharmacokinetics of paricalcitol has not been investigated in geriatric and pediatric patients.
The pharmacokinetics of paricalcitol were gender independent.
The 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 were similar across the range of hepatic function evaluated in this study. The influence of severe hepatic impairment on the pharmacokinetics of paricalcitol has not been evaluated.
The pharmacokinetics of paricalcitol have been studied in CKD patients requiring hemodialysis (HD) and peritoneal dialysis (PD). Hemodialysis procedure has essentially no effect on paricalcitol elimination. However, compared to healthy subjects, CKD patients on dialysis showed a decreased CL and increased half-life.
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.
Drug interactions with paricalcitol injection have not been studied. The following studies have been performed with oral paricalcitol capsules.
The pharmacokinetic interaction between paricalcitol capsule (16 mcg) and omeprazole (40 mg; oral), a strong inhibitor of CYP2C19, was investigated in a single dose, crossover study in healthy subjects. The pharmacokinetics of paricalcitol were unaffected when omeprazole was administrated approximately 2 hours prior to the paricalcitol dose.
Ketoconazole
The effect of multiple doses of ketoconazole, a strong inhibitor of CYP3A administered as 200 mg BID for 5 days, on the pharmacokinetics of paricalcitol 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].
Three 12-week, placebo-controlled studies were conducted in 78 patients with CKD on hemodialysis. In these studies, patients ranged in age from 22 to 90 years, 51% were males, 13% were Caucasian, 79% were African-American, and 8% were Hispanic. The most common causes of renal failure were hypertension and diabetes. The dose of ZEMPLAR was started at 0.04 mcg/kg 3 times per week intravenously. The dose was increased by 0.04 mcg/kg every 2 weeks until intact PTH levels were decreased at least 30% from baseline or a fifth escalation brought the dose to 0.24 mcg/kg, or intact PTH fell to less than 100 pg/mL, or the Ca × P product was greater than 75 within any 2 week period, or serum calcium became greater than 11.5 mg/dL at any time.
Patients treated with ZEMPLAR achieved a mean intact PTH reduction of 30% within 6 weeks. The results from these studies are as follows:
Table 6: Mean Changes from Baseline to Final Evaluation in intact PTH, Alkaline Phosphatase, Phosphorus and Calcium × Phosphorus Product in Adult Patients with CKD on Dialysis in Three 12-Week Placebo-Controlled Studies
| Group (No. of Pts.) | Baseline Mean (Range) | Mean (SE) Change From Baseline to Final Evaluation | |
| intact PTH (pg/mL) | ZEMPLAR (n = 40) |
783 (291 - 2076) |
-379 (43.7) |
| placebo (n = 38) |
745 (320 - 1671) |
-69.6 (44.8) |
|
| Alkaline Phosphatase (U/L) | ZEMPLAR (n = 31) |
150 (40 - 600) |
-41.5 (10.6) |
| placebo (n = 34) |
169 (56 - 911) |
+2.6 (10.1) |
|
| Phosphorus (mg/dL) | ZEMPLAR (n = 40) |
5.8 (3.7 - 10.2) |
+0.47 (0.3) |
| placebo (n = 38) |
6.0 (2.8 - 8.8) |
-0.47 (0.3) |
|
| Calcium x Phosphorus Product | ZEMPLAR (n = 40) |
54 (32 - 106) |
+7.9 (2.2) |
| placebo (n = 38) |
54 (26 - 77) |
-3.9 (2.3) |
ZEMPLAR was evaluated in a 12-week randomized, double-blind, placebo-controlled study of 29 pediatric patients, aged 5 to 19 years, with CKD on hemodialysis; nearly all had received some form of vitamin D prior to the study. Of the 29 patients, 76% were male, 52% were Caucasian and 45% were African-American. The initial dose of ZEMPLAR was 0.04 mcg/kg 3 times per week, based on baseline intact PTH level of less than 500 pg/mL, or 0.08 mcg/kg 3 times per week, based on baseline intact PTH level of 500 pg/mL or greater. The dose of ZEMPLAR was adjusted in 0.04 mcg/kg increments based on the levels of serum intact PTH, calcium and Ca × P. The mean baseline levels of intact PTH were 841 pg/mL for the 15 ZEMPLAR-treated patients and 740 pg/mL for the 14 placebo-treated patients. The mean dose of ZEMPLAR administered was 4.6 mcg (range: 0.8 mcg to 9.6 mcg). Sixty-seven percent of the ZEMPLAR-treated patients and 14% of the placebo-treated patients completed the trial. Seventyone percent of the placebo-treated patients discontinued due to excessive elevations in intact PTH levels, as defined by 2 consecutive intact PTH levels greater than 700 pg/mL and greater than baseline after 4 weeks of treatment.
The primary efficacy analysis demonstrated that 60% of ZEMPLAR-treated patients and 21% of placebo-treated patients achieved two consecutive greater than or equal to 30% reductions from baseline in intact PTH.
The patient should be instructed that, to ensure effectiveness of Zemplar therapy, it is important to adhere to a dietary regimen of calcium supplementation and phosphorus restriction. Appropriate types of phosphate-binding compounds may be needed to control serum phosphorus levels in patients with chronic kidney disease (CKD) Stage 5, but excessive use of aluminum containing compounds should be avoided (see WARNINGS). Patients should also be carefully informed about the symptoms of elevated calcium (see WARNINGS).
Advise patients to 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) [see WARNINGS AND PRECAUTIONS].
Inform patients that they will need routine monitoring of laboratory parameters such as calcium and intact PTH while receiving ZEMPLAR. Inform patients that more frequent monitoring is necessary during the initiation of therapy, following dose changes or when potentially interacting medications are started or discontinued [see DOSAGE AND ADMINISTRATION, DRUG INTERACTIONS].
Advise patients to inform their physician of all medications, including prescription and nonprescription drugs, and supplements they are taking. Advise patients to also inform their physician that they are receiving ZEMPLAR if a new medication is prescribed [see DRUG INTERACTIONS].
