A synthetic vitamin D analogue called paricalcitol (Zemplar) is used to treat people with secondary hyperparathyroidism linked to chronic kidney disease.

 

Paricalcitol (Zemplar) Indications:

• Hyperparathyroidism:

  • IV:

    • It is intended for the prevention and treatment of secondary hyperparathyroidism in adults and children patients with chronic renal disease who are receiving hemodialysis. Patients must be 5 years of age or older.

  • Oral:

    • It is prescribed for stage 5 CKD patients on hemodialysis or peritoneal dialysis, as well as adults and paediatric patients 10 years of age and older with secondary hyperparathyroidism linked with those stages 3 and 4.

Paricalcitol Dose in Adults

Note:

• According to KDIGO recommendations, vitamin D analogues should only be used by patients with chronic kidney disease stages G4 or G5 and severe and progressive hyperparathyroidism, not by patients with chronic kidney disease stages G3 to G5 who are not on dialysis. To prevent hyperphosphatemia or hypercalcemia, caution is advised.

Dose in Secondary hyperparathyroidism in patients with chronic kidney disease on dialysis:

• IV:

  • At first, 0.04 to 0.1 mcg/kg (2.8 to 7 mcg) should be administered no more frequently than every other day at any point during dialysis.

  • Depending on serum intact PTH (iPTH), alter the dose as follows:

  • iPTH at target and stable:

    • Maintain paricalcitol dose

  • iPTH above target and increased:

    • Increase by 2 to 4 mcg every 2 to 4 weeks; maximum dose: 0.24 mcg/kg/day

  • iPTH above target and decreased by 30% to 60%:

    • Maintain paricalcitol dose

  • iPTH above target and decreased by <30%:

    • Increase by 2 to 4 mcg every 2 to 4 weeks;
    • maximum dose: 0.24 mcg/kg/day

  • iPTH above target and decreased by >60%:

    • Decrease paricalcitol dose based on the clinical judgment.

Note:

• In case of persistent and abnormally low iPTH or serum calcium persistently above normal, the dose should be suspended.
• It should be resumed with dose reduction once iPTH and/or serum calcium have normalized.

Oral:

• The 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: A more moderate starting and dose titration rate may be necessary when monitoring of iPTH, calcium, and phosphorus happens less frequently than once per week:

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.

Dose in Secondary hyperparathyroidism linked with stage 3 and 4 CKD:

• Adults: Oral:
  • Initial dose based on baseline serum iPTH:

  • iPTH >500 pg/mL:

    • 2 mcg once daily or 4 mcg 3 times/week

  • iPTH ≤500 pg/mL:

    • 1 mcg once daily or 2 mcg 3 times/week
• Dosage adjustment based on iPTH level relative to baseline, adjust dose at 2- to 4-week intervals:

  • iPTH decreased by >60%:

    • Decrease paricalcitol dose by 1 mcg once daily* or 2 mcg 3 times/week

  • iPTH same or increased:

    • Increase paricalcitol dose by 1 mcg once daily or 2 mcg 3 times/week

  • iPTH decreased by ≥30% and ≤60%:

    • Maintain paricalcitol dose

  • iPTH decreased by <30%:

    • Increase paricalcitol dose by 1 mcg once daily or 2 mcg 3 times/week

  • iPTH <60 pg/mL:

    • Decrease paricalcitol dose by 1 mcg once daily* or 2 mcg 3 times/week

*Decrease to 1 mcg three times per week if the patient is taking 1 mcg once daily and more dose reduction is required. If more therapy reduction is necessary, stop it and start it again at a reduced dose frequency.

Paricalcitol dose in children:

Note: According to KDIGO recommendations, vitamin D analogues may be taken into account in children to keep serum calcium levels in a normal range based on age.

Paricalcitol dose in secondary hyperparathyroidism associated with stage 5 chronic renal failure (CKD):

Oral:

• Children over or equal to 10 years and Adolescents ≤16 years:

  • Initial dose:

    • Use the equation below to calculate depending on intact parathyroid hormone (iPTH) serum levels.
    • Give the calculated dose three times a week, no more frequently than every other day, and round it down to the next whole number.

Initial dose (mcg) = baseline iPTH (pg/ml) divided by 120.

• Titration:

  • To keep iPTH within the intended range, titrate the dose every 4 weeks and/or increase it by 1 mcg/dose (e.g., go from 1 mcg 3 times/week to 2 mcg 3 times/week).
  • Each provided dose may be lowered by 2 mcg/dose at any time depending on the response and clinical markers (iPTH, serum Ca, and P).
  • If a dosage reduction is necessary while still receiving 1 or 2 mcg three times per week, stop therapy and resume as needed.

• Adolescents ≥17 years:

Note:

Start only when the baseline blood calcium has been corrected to less than 9.5 mg/dL to lower the risk of hypercalcemia. More conservative dose should be utilised in patients whose laboratory indicators are checked no more frequently than once per week.

• Initial dose:

  • Apply the following calculation to calculate based on iPTH serum levels, and then take the calculated dose three times each week, no more frequently than every other day.

Initial dose (mcg) = baseline iPTH (pg/mL) divided by 80.

• • Titration:

    • Administer calculated dose three times per week, but no more frequently than every other day, based on at least weekly test results (iPTH, Ca, and P).

iPTH level (pg/mL) based: Dose (mcg) = Most recent iPTH level (pg/mL) divided by 80.

• • For modest dosing adjustments:

    • A more moderate starting and dose titration rate may be necessary in cases when monitoring of iPTH, calcium, and phosphorus occurs less frequently than once per week.
    • Apply the following calculation to calculate based on iPTH serum levels, and then take the calculated dose three times each week, no more frequently than every other day.

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

  • Elevated serum calcium: Decrease dose by 2 to 4 mcg.

Parenteral:

• Children ≥5 years and Adolescents:

  • IV through HD access (not directly into a vein):

  • Initial:

    • Dose based on baseline serum iPTH; administer thrice weekly at any time during the dialysis session, and no more frequently than every other day
    • iPTH less than 500 pg per mL: 0.04 mcg per kg per dose
    • iPTH greater than or equal to 500 pg per mL: 0.08 mcg per kg per dose.

  • Dosing adjustment:

    • Prior to any paricalcitol dosing adjustments, ensure serum Ca is within normal limits. Based on the iPTH level in relation to the baseline and targets, the dose of paricalcitol should be modified as follows:

    • iPTH level greater than 150 pg per mL and decreased by greater than 30% to less than 60%:

      • Preserve current paricalcitol dosage.

    • Above target and iPTH level decreased by <30%:

      • Increase paricalcitol dose by 0.04 mcg/kg/dose every 2 to 4 weeks.

    • iPTH level less than 150 pg per mL or decreased by greater than 60%:

      • Reduce the dosage of paricalcitol by 0.04 mcg/kg every week, or by 50% if the dose is nil.

Paricalcitol dosage in stage 3 and stage 4 chronic kidney failure (CKD)-related secondary hyperparathyroidism:

• Children ≥10 years and Adolescents ≤16 years:

  • Oral:

    • To maintain iPTH within the desired range, the initial dose should be increased by 1 mcg (e.g., from 1 mcg 3 times/week to 2 mcg 3 times/week), with titrations possible every 4 weeks.
    • Each provided dose may be lowered by 1 mcg at any time based on the response and clinical markers (iPTH, serum Ca, and P).
    • If a dosage reduction is necessary while still receiving 1 mcg three times per week, stop therapy and resume it as needed.

• Adolescents ≥17 years:

Note: Doses should not be given more often than every other day if used three times a week:

• Initial: Dose based on baseline serum iPTH:
• Oral:

  • iPTH greater than 500 pg per mL:

    • 2 mcg once daily or 4 mcg thrice per week.

  • iPTH less than 500 pg per mL:

    • 1 mcg once daily or 2 mcg thrice per week.

• Titration and dosage adjustment:

  • iPTH decreased by greater than 30% and less than 60%:

    • Maintain paricalcitol dose.

  • iPTH decreased by greater than 60%:

    • Decrease paricalcitol dose by 1 mcg/day or 2 mcg 3 times/week (see Note).
  •  

  • May adjust at 2-4-week intervals based on iPTH level relative to baseline:

    • iPTH same or increased: Increase paricalcitol dose by 1 mcg once daily or 2 mcg 3 times/week.

  • iPTH decreased by less than 30%:

    • Increase paricalcitol dose by 1 mcg once daily or 2 mcg 3 times/week.

  • iPTH less than 60 pg/mL:

    • Decrease paricalcitol dose by 1 mcg/day or 2 mcg 3 times/week (see Note).

Pregnancy Risk Category: C

• Studies on animal reproduction have seen some unfavourable outcomes.

Paricalcitol use during breastfeeding:

• It is not known if breast milk secretes paricalcitol.
• The product's producer claims that the risks and advantages for the baby as well as the advantages for the mother should be taken into account while determining whether to continue breastfeeding or discontinue breastfeeding during therapy.
• Hypercalcemia symptoms should be monitored in breastfed infants.

Dose adjustment in renal impairment:

No dosage change is required.

Dose adjustment in liver illness:

• Extreme impairment:

  • The manufacturer's labelling does not mention dosage modifications.

• Mild to moderate impairment:

  • No dosage change is required.

Common Side Effects of Paricalcitol:

• Gastrointestinal:

  • Nausea
  • Diarrhea

• Infection:

  • Infection

• Respiratory:

  • Rhinitis

Rare Side Effects Of Paricalcitol:

• Cardiovascular:

  • Hypertension
  • Edema
  • Hypotension
  • Palpitations
  • Chest Pain
  • Peripheral Edema
  • Syncope
  • Atrial Flutter
  • Cardiac Arrhythmia
  • Cerebrovascular Accident
  • Chest Discomfort
  • Ischemic Bowel Disease

• Central Nervous System:

  • Dizziness
  • Chills
  • Insomnia
  • Vertigo
  • Headache
  • Anxiety
  • Depression
  • Fatigue
  • Malaise
  • Abnormal gait
  • Agitation
  • Confusion
  • Delirium
  • Hypoesthesia
  • Myoclonus
  • Nervousness
  • Paresthesia
  • Restlessness

• Dermatologic:

  • Skin Rash
  • Dermal Ulcer
  • Ecchymoses
  • Acne Vulgaris
  • Alopecia
  • Burning Sensation Of Skin
  • Extravasation Reactions
  • Night Sweats
  • Pruritus
  • Urticaria

• Endocrine & Metabolic:

  • Hypervolemia
  • Dehydration
  • Hypoglycemia
  • Hirsutism
  • Hypercalcemia
  • Hyperkalemia
  • Hyperparathyroidism
  • Hyperphosphatemia
  • Hypocalcemia
  • Hypoparathyroidism
  • Increased Thirst
  • Weight Loss

• Gastrointestinal:

  • Vomiting
  • Gastrointestinal Hemorrhage
  • Peritonitis
  • Constipation
  • Abdominal Pain
  • Dyspepsia
  • Xerostomia
  • Decreased Appetite
  • Dysgeusia
  • Dysphagia
  • Gastritis
  • Gastroesophageal Reflux Disease

• Genitourinary:

  • Urinary Urgency
  • Chronic Renal Failure
  • Uremia
  • Urinary Tract Infection
  • Erectile Dysfunction
  • Mastalgia
  • Vaginal Infection

• Hematologic & Oncologic:

  • Malignant Neoplasm Of Breast
  • Prolonged Bleeding Time
  • Rectal Hemorrhage
  • Anemia
  • Lymphadenopathy

• Hypersensitivity:

  • Hypersensitivity Reaction

• Local:

  • Pain At Injection Site

• Infection:

  • Influenza
  • Sepsis

• Ophthalmic:

  • Conjunctivitis
  • Glaucoma
  • Ocular Hyperemia

• Otic:

  • Otalgia

• Hepatic:

  • Abnormal Hepatic Function Tests
  • Increased Serum AST
•  

• Respiratory:

  • Bronchitis
  • Cough
  • Sinusitis
  • Dyspnea
  • Nasopharyngitis
  • Asthma
  • Pneumonia
  • Oropharyngeal Pain
  • Orthopnea
  • Pulmonary Edema
  • Upper Respiratory Tract Infection
  • Wheezing

• Neuromuscular & Skeletal:

  • Arthralgia
  • Arthritis
  • Weakness
  • Back Pain
  • Leg Cramps
  • Muscle Spasm
  • Joint Stiffness
  • Muscle Twitching
  • Myalgia

• Miscellaneous:

  • Fever
  • Laboratory Test Abnormality
  • Swelling

Contraindications to Paricalcitol:

• Intolerance to paricalcitol and all other formulation ingredients
• Hypercalcemia
• Vitamin D toxicity

Warnings and precautions

• Vitamin D excess:
  • Hyperphosphatemia, hypercalcemia, and hypercalciuria can result from overdosing on vitamin D.
• Hypercalcemia:
  • Vitamin D compounds, calcium-containing supplements, and drugs that raise serum calcium levels can all cause hypercalcemia (eg thiazide diuretics). It's crucial to regularly evaluate calcium levels.
  • Hypercalcemia increases the risk of seizures and cardiac arrhythmias.
  • Chronic hypercalcemia can cause soft-tissue calciumification. This can increase mortality among adults with chronic kidney disease.

Paricalcitol: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Risk Factor C (Monitor therapy)
Calcium Salts	May enhance the adverse/toxic effect of Vitamin D Analogs.
Cardiac Glycosides	Vitamin D Analogs may enhance the arrhythmogenic effect of Cardiac Glycosides.
CYP3A4 Inhibitors (Strong)	May increase the serum concentration of Paricalcitol.
Danazol	Could make vitamin D analogues' hypercalcemic impact stronger.
Digoxin	Digoxin may have a worse or more hazardous effect when taken with paricalcitol.
Thiazide and Thiazide-Like Diuretics	Could make vitamin D analogues' hypercalcemic impact stronger.
Risk Factor D (Consider therapy modification)
Bile Acid Sequestrants	May lower the level of vitamin D analogues in the serum. Bile acid sequestrants especially may hinder the absorption of vitamin D analogues. Avoid administering bile acid sequestrants and vitamin D analogues at the same time for management (eg, cholestyramine). To reduce the chance of interaction, administer these drugs several hours apart. track the levels of calcium in the plasma.
Erdafitinib	The therapeutic benefit of erfatinib may be diminished by serum phosphorus level-altering drugs. Management: Before the initial dose increase period depending on serum phosphate levels, avoid coadministering erdafitinib with medications that affect serum phosphate levels (Days 14 to 21).
Mineral Oil	May lower the level of vitamin D analogues in the serum. Mineral oil especially may prevent the absorption of Vitamin D analogues. Management: Prevent taking oral vitamin D analogues and mineral oil at the same time. To reduce the chance of interaction, think about giving these medications at different times. track the levels of calcium in the plasma.
Orlistat	May lower the level of paricalcitol in the serum. When using paricalcitol with orlistat, closely monitor the clinical reaction. When this combination is necessary, think about giving paricalcitol at least an hour before or four to six hours after giving orlistat.
Risk Factor X (Avoid combination)
Aluminum Hydroxide	Aluminum Hydroxide levels in the serum may rise while using vitamin D analogues. In particular, there may be an increase in aluminium absorption, which would raise serum aluminium contents.
Burosumab	Vitamin D analogues may intensify Burosumab's harmful or hazardous effects.
Multivitamins/Fluoride (with ADE)	Enhances the hazardous or harmful effects of vitamin D analogues.
Multivitamins/Minerals (with ADEK, Folate, Iron)	Enhances the hazardous or harmful effects of vitamin D analogues.
Sucralfate	The serum concentration of sucralfate may rise in response to vitamin D analogues. In particular, there may be an increase in the serum aluminium concentration as a result of enhanced aluminium absorption from sucralfate.
Vitamin D Analogs	Aluminum Hydroxide levels in the serum may rise while using vitamin D analogues. In particular, there may be an increase in aluminium absorption, which would raise serum aluminium contents. Possibly intensifies the hazardous or harmful effects of other vitamin D analogues.

Monitoring parameters:

• When taking an oral dose, the serum calcium and phosphorus levels should be checked at least every two weeks for the first three months or after a dose change, then monthly for three months, and finally every three months.
• Serum phosphorus and calcium (Serum calcium twice weekly for intravenous dose during the initial phase, then at least monthly).

Serum or plasma intact PTH:

• For intravenous doses administered during the initial phase or during dose modification, every 2 to 4 weeks.
• Signs and symptoms of hypercalcemia and vitamin D toxicity.
• Oral administration: baseline, at least every two weeks for three months; after a dose adjustment, monthly for three months; finally, every three months.

KDIGO guidelines (2017):

Serum calcium, phosphorus, and parathyroid hormone (PTH):

• The frequency of measurement depends on the rate of chronic renal disease progression, the therapies used to treat it, and any mineral and bone disorders.

CKD stage G3a to G3b:

• PTH:
  • Frequency-based on baseline level and progression of CKD
• Serum calcium and phosphate:
  • Every 6-12 months

CKD stage G4:

• PTH:
  • Every 6-12 months.
• Serum calcium and phosphate:
  • Every 3-6 months.

CKD stage G5 and G5D:

• PTH:
  • Every 3-6 months.
• Serum calcium and phosphate:
  • Every 1-3 months.

How to administer Paricalcitol (Zemplar)?

IV:

• Anytime while on dialysis, give a bolus dosage.
• It should be given on alternate days 3 times/week.
• May be delivered intravenously if a vascular access point for hemodialysis is not available.

Oral:

• It should be given orally 3 times/week with or without food.

Mechanism of action of Paricalcitol (Zamplar):

• Renal conversion may result from chronic renal failure. D vitamin It is distilled down to its main active metabolite (1,25-hydroxyvitamin E).
• As a result, the vitamin D receptor (VDR) becomes less activated, removing the inhibitory inhibition of parathyroid hormone release (PTH).
• Additionally, it elevates bone resorption, raises serum PTH, and decreases calcium excretion.
  A synthetic vitamin D analogue called paricalcitol lowers PTH levels, enhances calcium homeostasis, and engages the VDR in the parathyroid and renal glands.

Protein binding: >99%

Bioavailability:

• Oral: 72% to 86% in healthy subjects

Metabolism:

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

Time to peak, plasma:

• 3 hours: Delayed by food

Half-life elimination:

• CKD: Oral: 17 to 20 hours
• Stage 5 CKD (on HD or PD): Oral: 14 to 18 hours; IV: 14 to 15 hours
• Healthy subjects: Oral: 4 to 6 hours
• IV: 5 to 7 hours Stage 3 and 4

Excretion:

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

International Brands of Paricalcitol:

• Zemplar
• Paricalcistar
• Paricon
• Paritol
• Rextol
• Zemplar
• Zerecoz

Paricalcitol Brands in Pakistan:

No Brands Available in Pakistan.