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Paricalcitol

Pronunciation

(pah ri KAL si tole)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral:

Zemplar: 1 mcg, 2 mcg, 4 mcg [contains alcohol, usp]

Generic: 1 mcg, 2 mcg, 4 mcg

Solution, Intravenous:

Zemplar: 2 mcg/mL (1 mL); 5 mcg/mL (1 mL, 2 mL) [contains alcohol, usp, propylene glycol]

Generic: 2 mcg/mL (1 mL); 5 mcg/mL (1 mL, 2 mL)

Brand Names: U.S.

  • Zemplar

Pharmacologic Category

  • Vitamin D Analog

Pharmacology

Decreased renal conversion of vitamin D to its primary active metabolite (1,25-hydroxyvitamin D) in chronic renal failure leads to reduced activation of vitamin D receptor (VDR), which subsequently removes inhibitory suppression of parathyroid hormone (PTH) release; increased serum PTH (secondary hyperparathyroidism) reduces calcium excretion and enhances bone resorption. Paricalcitol is a synthetic vitamin D analog which binds to and activates the VDR in kidney, parathyroid gland, intestine and bone, thus reducing PTH levels and improving calcium and phosphate homeostasis.

Distribution

Vd:

Healthy subjects: Oral: 34 L; IV: 24 L

Stage 3 and 4 CKD: Oral: 44 to 46 L

Stage 5 CKD: Oral: 38 to 49 L; IV: 31 to 35 L

Metabolism

Hydroxylation and glucuronidation via hepatic and nonhepatic enzymes, including CYP24, CYP3A4, UGT1A4; forms metabolites (at least one active)

Excretion

Healthy subjects: Feces (oral: 70%; IV: 63%); urine (oral: 18%, IV: 19%); 51% to 59% as metabolites

Time to Peak

Plasma: 3 hours: Delayed by food

Half-Life Elimination

Healthy subjects: Oral: 4 to 6 hours; IV: 5 to 7 hours

Stage 3 and 4 CKD: Oral: 17 to 20 hours

Stage 5 CKD (on HD or PD): Oral: 14 to 18 hours; IV: 14 to 15 hours

Protein Binding

>99%

Special Populations: Renal Function Impairment

Hemodialysis and peritoneal dialysis have essentially no effect on paricalcitol elimination. However, compared with healthy subjects, stage 5 chronic kidney disease subjects showed a decreased Cl and increased half-life.

Special Populations: Hepatic Function Impairment

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.

Special Populations: Elderly

The pharmacokinetics of paricalcitol have not been investigated in patients older than 65 y.

Special Populations: Children

The pharmacokinetics of paricalcitol have not been investigated in patients younger than 18 y.

Special Populations: Gender

The pharmacokinetics of paricalcitol were gender independent.

Use: Labeled Indications

IV: Prevention and treatment of secondary hyperparathyroidism associated with stage 5 chronic kidney disease (CKD)

Oral: Prevention and treatment of secondary hyperparathyroidism associated with stage 3 and 4 CKD and stage 5 CKD patients on hemodialysis or peritoneal dialysis

Contraindications

Hypersensitivity to paricalcitol or any component of the formulation; patients with evidence of vitamin D toxicity; hypercalcemia

Dosing: Adult

Note: In stage 3 to 5 CKD maintain Ca x P <55 mg2/dL2, reduce or interrupt dosing if recommended calcium phosphorus product (Ca x P) is exceeded or hypercalcemia is observed (K/DOQI Clinical Practice Guidelines, 2003).

Secondary hyperparathyroidism associated with chronic renal failure (stage 5 CKD):

IV: 0.04 to 0.1 mcg/kg (2.8 to 7 mcg) given as a bolus dose no more frequently than every other day at any time during dialysis; dose may be increased by 2 to 4 mcg every 2 to 4 weeks; doses as high as 0.24 mcg/kg (16.8 mcg) have been administered safely; the dose of paricalcitol should be adjusted based on serum intact PTH (iPTH) levels, as follows:

Same or increasing iPTH level: Increase paricalcitol dose

iPTH level decreased by <30%: Increase paricalcitol dose

iPTH level decreased by >30% and <60%: Maintain paricalcitol dose

iPTH level decrease by >60%: Decrease paricalcitol dose

iPTH level 1.5 to 3 times upper limit of normal: Maintain paricalcitol dose

Oral: Initial dose, in mcg, based on baseline iPTH level divided by 80. Administered 3 times weekly, no more frequently than every other day. Note: To reduce the risk of hypercalcemia initiate only after baseline serum calcium has been adjusted to ≤9.5 mg/dL.

Dose titration:

Titration dose (mcg) = Most recent iPTH level (pg/mL) divided by 80

Note: In situations where monitoring of iPTH, calcium, and phosphorus occurs less frequently than once per week, a more modest initial and dose titration rate may be warranted:

Modest titration dose (mcg) = Most recent iPTH level (pg/mL) divided by 100

Dosage adjustment for hypercalcemia or elevated Ca x P: Decrease calculated dose by 2 to 4 mcg. If further adjustment is required, dose should be reduced or interrupted until these parameters are normalized. If applicable, phosphate binder dosing may also be adjusted or withheld, or switched to a noncalcium-based phosphate binder

Secondary hyperparathyroidism associated with stage 3 and 4 CKD: Adults: Oral: Initial dose based on baseline serum iPTH:

iPTH ≤500 pg/mL: 1 mcg/day or 2 mcg 3 times/week

iPTH >500 pg/mL: 2 mcg/day or 4 mcg 3 times/week

Dosage adjustment based on iPTH level relative to baseline, adjust dose at 2- to 4-week intervals:

iPTH same or increased: Increase paricalcitol dose by 1 mcg/day or 2 mcg 3 times/week

iPTH decreased by <30%: Increase paricalcitol dose by 1 mcg/day or 2 mcg 3 times/week

iPTH decreased by ≥30% and ≤60%: Maintain paricalcitol dose

iPTH decreased by >60%: Decrease paricalcitol dose by 1 mcg/day* or 2 mcg 3 times/week

iPTH <60 pg/mL: Decrease paricalcitol dose by 1 mcg/day* or 2 mcg 3 times/week

*If patient is taking the lowest dose on a once-daily regimen, but further dose reduction is needed, decrease dose to 1 mcg 3 times/week. If further dose reduction is required, withhold drug as needed and restart at a lower dose and frequency. If applicable, calcium-phosphate binder dosing may also be adjusted or withheld, or switched to noncalcium-based binder.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Secondary hyperparathyroidism associated with chronic renal failure (stage 5 CKD): IV: Children ≥5 years: Refer to adult dosing.

Dosing: Renal Impairment

No dosage adjustment necessary.

Dosing: Hepatic Impairment

Mild to moderate impairment: No dosage adjustment necessary.

Severe impairment: No dosage adjustment provided in manufacturer’s labeling (has not been studied).

Administration

Oral: May be administered with or without food. With the 3 times/week dosing schedule, doses should not be given more frequently than every other day.

IV: Administered as a bolus dose at anytime during dialysis. Doses should not be administered more often than every other day.

Dietary Considerations

May be taken with or without food. Some products may contain coconut or palm kernel oil.

Storage

Store at 25°C (77°F); excursions permitted between 15°C to 30°C (59°F to 86°F).

Drug Interactions

Aluminum Hydroxide: Vitamin D Analogs may increase the serum concentration of Aluminum Hydroxide. Specifically, the absorption of aluminum may be increased, leading to increased serum aluminum concentrations. Avoid combination

Bile Acid Sequestrants: May decrease the serum concentration of Vitamin D Analogs. More specifically, bile acid sequestrants may impair absorption of Vitamin D Analogs. Management: Avoid concomitant administration of vitamin D analogs and bile acid sequestrants (e.g., cholestyramine). Separate administration of these agents by several hours to minimize the potential risk of interaction. Monitor plasma calcium concentrations. Consider therapy modification

Calcium Salts: May enhance the adverse/toxic effect of Vitamin D Analogs. Monitor therapy

Cardiac Glycosides: Vitamin D Analogs may enhance the arrhythmogenic effect of Cardiac Glycosides. Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Paricalcitol. Monitor therapy

Danazol: May enhance the hypercalcemic effect of Vitamin D Analogs. Monitor therapy

Digoxin: Paricalcitol may enhance the adverse/toxic effect of Digoxin. Monitor therapy

Mineral Oil: May decrease the serum concentration of Vitamin D Analogs. More specifically, mineral oil may interfere with the absorption of Vitamin D Analogs. Management: Avoid concomitant, oral administration of mineral oil and vitamin D analogs. Consider separating the administration of these agents by several hours to minimize the risk of interaction. Monitor plasma calcium concentrations. Consider therapy modification

Multivitamins/Fluoride (with ADE): May enhance the adverse/toxic effect of Vitamin D Analogs. Avoid combination

Multivitamins/Minerals (with ADEK, Folate, Iron): May enhance the adverse/toxic effect of Vitamin D Analogs. Avoid combination

Orlistat: May decrease the serum concentration of Paricalcitol. Management: Monitor clinical response to paricalcitol closely when used with orlistat. When this combination must be used, consider administering paricalcitol at least 2 hours before or after the administration of orlistat. Consider therapy modification

Sucralfate: Vitamin D Analogs may increase the serum concentration of Sucralfate. Specifically, the absorption of aluminum from sucralfate may be increased, leading to an increase in the serum aluminum concentration. Avoid combination

Thiazide and Thiazide-Like Diuretics: May enhance the hypercalcemic effect of Vitamin D Analogs. Monitor therapy

Vitamin D Analogs: May enhance the adverse/toxic effect of other Vitamin D Analogs. Avoid combination

Test Interactions

In predialysis patients, paricalcitol may increase serum creatinine and therefore decrease the estimated GFR (eGFR).

Adverse Reactions

>10%:

Gastrointestinal: Nausea (5% to 13%), diarrhea (7% to 12%)

Infection: Infection (bacterial, fungal, viral: 3% to 15%)

2% to 10%:

Cardiovascular: Hypertension (7%), edema (6% to 7%), hypotension (5%), palpitations (3%), chest pain (3%), peripheral edema (3%), syncope (3%)

Central nervous system: Pain (4% to 8%), dizziness (5% to 7%), chills (5%), insomnia (5%), vertigo (5%), headache (3% to 5%), anxiety (3%), depression (3%), fatigue (3%), malaise (3%)

Dermatologic: Skin rash (4% to 6%), dermal ulcer (3%), ecchymoses (3%)

Endocrine & metabolic: Hypervolemia (5%), dehydration (3%), hypoglycemia (3%)

Gastrointestinal: Vomiting (5% to 8%), gastrointestinal hemorrhage (5%), peritonitis (5%), constipation (4% to 5%), abdominal pain (4%), dyspepsia (3%), xerostomia (3%)

Genitourinary: Uremia (3%), urinary tract infection (3%)

Hypersensitivity: Hypersensitivity reaction (6%)

Infection: Influenza (5%), sepsis (5%)

Neuromuscular & skeletal: Arthralgia (5%), arthritis (5%), weakness (3% to 5%), back pain (3% to 4%), leg cramps (3%), muscle spasm (3%)

Respiratory: Nasopharyngitis (8%), pneumonia (5%), rhinitis (5%), oropharyngeal pain (4%), bronchitis (3%), cough (3%), sinusitis (3%)

Miscellaneous: Fever (3% to 5%)

<2% (Limited to important or life-threatening): Abnormal gait, abnormal hepatic function tests, anemia, angioedema (including laryngeal edema), atrial flutter, burning sensation of skin, cardiac arrest, cardiac arrhythmia, cerebrovascular accident, confusion, conjunctivitis, delirium, dysphagia, erectile dysfunction, extravasation reactions, gastritis, gastroesophageal reflux disease, glaucoma, hirsutism, hypercalciuria, hypercalcemia, hyperparathyroidism, hyperkalemia, hyperphosphatemia, hypocalcemia, hypoparathyroidism, increased serum creatinine, ischemic bowel disease, lymphadenopathy, malignant neoplasm of breast, myalgia, myoclonus, night sweats, ocular hyperemia, orthopnea, paresthesia, prolonged bleeding time, pruritus, pulmonary edema, rectal hemorrhage, upper respiratory tract infection, urticaria, vaginal infection, weight loss, wheezing

Warnings/Precautions

Concerns related to adverse effects:

• Excessive vitamin D: Excessive vitamin D administration may lead to over suppression of PTH, progressive or acute hypercalcemia, hypercalciuria, hyperphosphatemia and adynamic bone disease.

• Hypercalcemia: Progressive and/or acute hypercalcemia may increase risk of cardiac arrhythmias and seizures; chronic hypercalcemia may lead to generalized vascular and other soft-tissue calcification. Phosphate and vitamin D (and its derivatives) should be withheld during therapy to avoid hypercalcemia. Risk of hypercalcemia may be increased by concomitant use of calcium-containing supplements and/or medications that increase serum calcium (eg, thiazide diuretics).

Concurrent drug therapy issues:

• Aluminum: Avoid regular administration of aluminum-containing preparations (eg, antacids, phosphate binders) to prevent aluminum overload and bone toxicity. Dialysate concentration of aluminum should be maintained at <10 mcg/L.

• Cardiac glycosides: Use with caution in patients taking cardiac glycosides; digitalis toxicity is potentiated by hypercalcemia.

Monitoring Parameters

Signs and symptoms of vitamin D intoxication; signs and symptoms of hypercalcemia (eg, feeling tired, difficulty thinking clearly, loss of appetite, nausea, vomiting, constipation, increased thirst, increased urination, weight loss).

Serum calcium and phosphorus (closely monitor levels during dosage titration and after initiation of a strong CYP3A4 inhibitor):

IV: Twice weekly during initial phase, then at least monthly once dose established

Oral: At least every 2 weeks for initial 3 months or following dose adjustment, then monthly for 3 months, then every 3 months

Serum or plasma intact PTH (iPTH):

IV: Every 2 to 4 weeks, then every 3 months once dose established

Oral: At least every 2 weeks for 3 months or following dose adjustment, then monthly for 3 months, then every 3 months

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events were observed in some animal reproduction studies.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience dizziness, nausea, or diarrhea. Have patient report immediately to prescriber signs of fluid and electrolyte imbalance, signs of hypercalcemia, polyuria, weight loss, severe headache, melena, muscle cramps, muscle spasms, dyspepsia, or edema of extremities (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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