Paricalcitol

H05B - Antiparathyroid agents ATC H05BX02 Small molecule approved 1998 Oral Parenteral Natural product

JFDA label: Zemplar

Mechanism of Action

Agonist of Vitamin D3 receptor — Vitamin D receptor agonist

Target	Action	Gene / class
Vitamin D3 receptor efficacy	AGONIST	VDR

Indications

Approved

IV
Oral

Contraindications

Source: Lexicomp

Hypersensitivity to paricalcitol or any component of the formulation Absolute
hypercalcemia Documentation of allergenic cross-reactivity for vitamin D analogues is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty Absolute
vitamin D toxicity Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (8)

Common atrial flutter, chills, insomnia, vertigo, headache, anxiety, depression, fatigue, malaise, abnormal gait, dermal ulcer, ecchymoses, acne vulgaris, dehydration, hypoglycemia, hirsutism, gastrointestin · chest pain · edema · Hypertension · hypotension · palpitations · peripheral edema · syncope

Gastrointestinal disorders (2)

Very Common diarrhea · Nausea

Infections and infestations (3)

Very Common Infection

Common Influenza · sepsis

General disorders and administration site conditions (1)

Common Pain at injection site, arthritis, weakness, back pain, leg cramps, muscle spasm, joint stiffness, asthma, pneumonia, oropharyngeal pain, bronchitis, cough, sinusitis, dyspnea, laboratory test abnorma

Respiratory, thoracic and mediastinal disorders (1)

Very Common Rhinitis

Dosing

Source: Lexicomp

Note: In stage 3 to 5 CKD maintain Ca x P 2/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 iPTH level decreased by >30% and 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 is calculated, in mcg, based on baseline iPTH level divided by 80 and 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 elevated serum calcium: Decrease dose by 2 to 4 mcg. Secondary hyperparathyroidism associated with stage 3 and 4 CKD: Adults: Oral: Initial dose based on baseline serum iPTH: iPTH ≤500 pg/mL: 1 mcg once daily or 2 mcg 3 times/week iPTH >500 pg/mL: 2 mcg once daily 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 once daily or 2 mcg 3 times/week iPTH decreased by iPTH decreased by ≥30% and ≤60%: Maintain paricalcitol dose iPTH decreased by >60%: Decrease paricalcitol dose by 1 mcg once daily* or 2 mcg 3 times/week iPTH *If patient is taking 1 mcg once daily and further dose reduction is needed, decrease to 1 mcg 3 times/week. If further dose reduction is required, withhold therapy as needed and restart at a lower dosing frequency.

(For additional information see "Paricalcitol: Pediatric drug information") Secondary hyperparathyroidism associated with chronic renal failure (stage 5 CKD): IV: Children ≥5 years and Adolescents: Refer to adult dosing. Oral: Children ≥10 to Adolescents ≤16 years: Initial dose is calculated, in mcg, based on baseline iPTH level divided by 120 (round down to the nearest whole number) and administered 3 times/week, no more frequently than every other day; every 4 weeks may increase each administered dose by 1 mcg (eg, increase from 1 mcg 3 times/week to 2 mcg 3 times/week) to maintain iPTH within target range. At any time, each administered dose may be decreased by 2 mcg. If dosage reduction is required while receiving 2 mcg 3 times/week or 1 mcg 3 times/week, discontinue therapy, resuming when appropriate. Secondary hyperparathyroidism associated with stage 3 and 4 CKD: Oral: Children ≥10 to Adolescents ≤16 years: Initial: 1 mcg 3 times/week, no more frequently than every other day; every 4 weeks may increase each administered dose by 1 mcg (eg, increase from 1 mcg 3 times/week to 2 mcg 3 times/week) to maintain iPTH within target range. At any time, each administered dose may be decreased by 1 mcg. If dosage reduction is required while receiving 1 mcg 3 times/week, discontinue therapy, resuming when appropriate.

Refer to adult dosing.

No dosage adjustment necessary.

Mild to moderate impairment: No dosage adjustment necessary. Severe impairment: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Warnings & Precautions

Source: Lexicomp

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:

Drug-drug interactions

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information

Pregnancy & Lactation

Pregnancy

FDA category C

Adverse events have been observed in some animal reproduction studies.

Lactation

Avoid

It is not known if paricalcitol is excreted in breast milk. Due to the potential for serious adverse reactions in the nursing infant, breast-feeding is not recommended by the manufacturer.

Monitoring

Clinical pearl	Signs and symptoms of vitamin D intoxication and hypercalcemia . Serum calcium and phosphorus: IV: Twice weekly during initial phase, then at least monthly once dose established Oral: Baseline, 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: : Baseline, at least every 2 weeks for 3 months or following dose adjustment, then monthly for 3 months, then every 3 months

Clinical pearl

Signs and symptoms of vitamin D intoxication and hypercalcemia . Serum calcium and phosphorus: IV: Twice weekly during initial phase, then at least monthly once dose established Oral: Baseline, 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: : Baseline, at least every 2 weeks for 3 months or following dose adjustment, then monthly for 3 months, then every 3 months

Chemistry & Properties

Formula	C27H44O3
Molecular weight	416.65 g/mol
IUPAC name	trans-(1R,3R)-5-[(2E)-2-[(1R,3aS,7aR)-1-[(E,2R,5S)-6-hydroxy-5,6-dimethylhept-3-en-2-yl]-7a-methyl-2,3,3a,5,6,7-hexahydro-1H-inden-4-ylidene]ethylidene]cyclohexane-1,3-diol
CAS	131918-61-1
PubChem CID	5281104
InChIKey	`BPKAHTKRCLCHEA-UBFJEZKGSA-N`
logP	5.56 (XLogP 5.0)
Polar surface area	60.69 Å²
H-bond acceptors / donors	3 / 3
Drug-likeness (QED)	0.51
Lipinski violations	1

SMILES

C[C@H](/C=C/[C@H](C)C(C)(C)O)[C@H]1CC[C@H]2/C(=C/C=C3C[C@@H](O)C[C@H](O)C3)CCC[C@]12C

Biology & Pharmacokinetics

Pharmacokinetics predicted

Bioavailability	70.0%
Half-life	1.431 h
Volume of distribution	0.505 L/kg
Protein binding	98.7%
BBB penetrant	No

Enzyme interactions

Enzyme	Role	Detail
CYP2B6	Inhibitor	—
CYP2C8	Inhibitor	—

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)MRP1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)P-gp (Inhibitor)P-gp (Substrate)

Drug–drug interactions (100+, DDInter)

Interacting drug	Severity	Management
Aluminum hydroxide	major
Burosumab	major
Calcifediol	major
Calcitriol	major
Cholecalciferol	major
Dihydrotachysterol	major
Doxercalciferol	major
Erdafitinib	major
Ergocalciferol	major
Sucralfate	major
Abametapir (topical)	moderate
Amobarbital	moderate
Amprenavir	moderate
Apalutamide	moderate
Atazanavir	moderate
Bendroflumethiazide	moderate
Benzthiazide	moderate
Berotralstat	moderate
Butabarbital	moderate
Butalbital	moderate
Calcipotriol (topical)	moderate
Calcitriol (topical)	moderate
Carbamazepine	moderate
Ceritinib	moderate
Chlorothiazide	moderate
Chlorthalidone	moderate
Cholestyramine	moderate
Clarithromycin	moderate
Cobicistat	moderate
Colesevelam	moderate
Colestipol	moderate
Dabrafenib	moderate
Delavirdine	moderate
Digitoxin	moderate
Digoxin	moderate
Duvelisib	moderate
Echinacea	moderate
Enzalutamide	moderate
Erythromycin	moderate
Fedratinib	moderate

Showing 40 of 100+.

Registered Products (1)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Zemplar	Ampoule 5 mcg/ml	5 amp	Abu Sheikha Drug Store	—