Paricalcitol (injection)

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# Overview
Paricalcitol (injection) is a synthetically manufactured analog of calcitriol that is FDA approved for the treatment of secondary hyperparathyroidism associated with chronic kidney disease Stage 5.   Common adverse reactions include edema, hypertension, diarrhea, nausea, vomiting, dizziness, headache.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
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:

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Paricalcitol (injection) in adult patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Paricalcitol (injection) in adult patients.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
Zemplar is indicated for the prevention and treatment of secondary hyperparathyroidism associated with chronic kidney disease Stage 5 (5 years of age and older).
- 0.04 mcg/kg/dose IV 3 times per week for baseline intact parathyroid hormone (iPTH) of less than 500 picograms (pg)/mL;
- 0.08 mcg/kg IV 3 times per week for baseline iPTH of 500 pg/mL or greater;
- Dose was adjusted in 0.04 mcg/kg increments based on the levels of serum iPTH, calcium, and the product of calcium x phosphorus in a clinical trial

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Paricalcitol (injection) in pediatric patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Paricalcitol (injection) in pediatric patients.

# Contraindications
Zemplar should not be given to patients with evidence of vitamin D toxicity, hypercalcemia, or hypersensitivity to any ingredient in this product

# Warnings
Acute overdose of Zemplar may cause hypercalcemia, and require emergency attention. 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.

### Precautions
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.

# Adverse Reactions

## Clinical Trials Experience
Zemplar has been evaluated for safety in clinical studies in 609 CKD Stage 5 patients. In four, placebo-controlled, 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, 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:
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.

### Other Adverse Reactions Observed During Clinical Evaluation of Zemplar Injection
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, 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

## Postmarketing Experience
Allergic reactions, such as rash, urticaria, and angioedema (including laryngeal edema) have been reported.

# Drug Interactions
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-. 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.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): C
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.
Pregnancy Category (AUS): 
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Paricalcitol (injection) in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Paricalcitol (injection) during labor and delivery.

### 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.

### Pediatric Use
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.

### Geriatic Use
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.

### Gender
There is no FDA guidance on the use of Paricalcitol (injection) with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Paricalcitol (injection) with respect to specific racial populations.

### Renal Impairment
There is no FDA guidance on the use of Paricalcitol (injection) in patients with renal impairment.

### Hepatic Impairment
There is no FDA guidance on the use of Paricalcitol (injection) in patients with hepatic impairment.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Paricalcitol (injection) in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Paricalcitol (injection) in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- Intravenous

### Monitoring
There is limited information regarding Monitoring of Paricalcitol (injection) in the drug label.

# IV Compatibility
There is limited information regarding the compatibility of Paricalcitol (injection) and IV administrations.

# Overdosage
Overdosage of Zemplar may lead to hypercalcemia, hypercalciuria, hyperphosphatemia, and over suppression of PTH.

### Treatment of Overdosage and Hypercalcemia
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.

# Pharmacology

## 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.

## Structure
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-1,3,25-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.

## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Paricalcitol (injection) in the drug label.

## Pharmacokinetics
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.
Distribution
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 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.
Elimination
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).
No accumulation of paricalcitol was observed with three times a week dosing which is consistent with the observed half-life.

## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Paricalcitol (injection) in the drug label.

# Clinical Studies
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:
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).

# How Supplied
Zemplar Injection is available as 2 mcg/mL (NDC 0074-4637-01) and 5 mcg/mL (NDC 0074-1658-01 and NDC 0074165805) in trays of 25 vials.

## Storage
Store at 25C (77F). Excursions permitted between 15 - 30C (59 - 86F).

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
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. Patients should also be carefully informed about the symptoms of elevated calcium.

# Precautions with Alcohol
- Alcohol-Paricalcitol (injection) interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
- ZEMPLAR

# Look-Alike Drug Names
There is limited information regarding Paricalcitol (injection) Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price