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Calcitriol - Activated Vitamin D for Hypocalcemia

The activated form of vitamin D is called calcitriol. It boosts intestinal calcium absorption, stops calcium and phosphorus from leaking out of the renal tubules, and inhibits parathyroid hormone production. It is used in the treatment of the following conditions:

Management of hypocalcemia in patients with Hypoparathyroidism and pseudohypoparathyroidism.
Management of Secondary hyperparathyroidism in patients with chronic kidney disease
- According to the manufacturer's labeling, it may be used in mild to moderate kidney disease for the treatment of hypocalcemia, experts recommend its use in severe and progressive hyperparathyroidism.
Off Label Use Of Calcitriol in Adults include:
- Hypophosphatemia
- X-linked Vitamin D resistant to rickets
- Vitamin D-dependent rickets type I or pseudovitamin D deficiency rickets (PDDR)

Calcitriol Dose in Adults

Calcitriol use for treating Hypocalcemia in hypoparathyroidism and pseudohypoparathyroidism:

0.25 mcg orally once a day.
The dose may be adjusted at 2 - 4-week intervals to achieve the target calcium levels.
The usual dose ranges from 0.5 to 2 mcg per day.

Dose in the treatment of Hypophosphatemia and X-linked vitamin D-resistant rickets:

0.5 - 0.75 mcg/day orally in 2 divided doses
The dose may be adjusted by 0.25 mcg/day every 3 or 4 weeks to achieve the target calcium and parathyroid hormone levels.
Therapy may be discontinued if no clinical is observed after 9 - 12 months.

Dose for treating Secondary hyperparathyroidism in patients with chronic kidney disease:

Calcitriol is recommended for use by most experts only in stage 4 or 5 CKD and in patients with severe and progressive hyperparathyroidism.

Patients with chronic renal failure and on dialysis:
- 0.25 mcg one time a day orally
- The dose may be increased by 0.25 mcg/day at 4 to 8-week intervals t the usual dose of 0.5 - 1 mcg/day.
- Higher doses and intravenous formulations may be used in advanced disease.
- The dose should be adjusted by 0.5 - 1 mcg intravenous at 2 - 4-week intervals to the usual dosing range of 0.5 - 4 mcg 3 times a week.
Patients with moderate to severe CKD not yet on dialysis:
- The manufacturer recommends an initial dose of 0.25 mcg/day orally, although lower doses of 0.25 mcg 3 - 4 times a week may be used.
- The usual dose is 0.25 - 0.5 mcg/day.

Off label use in the treatment of Vitamin D-dependent rickets type 1 or pseudovitamin D deficiency rickets (PDDR):

0.5 mcg orally twice a day.
In order to maintain normal serum calcium and PTH levels, subsequent dose should be changed.

Discontinuation of therapy for hypercalcemia:

If hypercalcemia occurs, therapy should be discontinued.
As soon as the calcium levels are back to normal, it could be continued at a lower dose.

Calcitriol Dose in Childrens

Use in the treatment of Hypocalcemia with chronic kidney disease (CKD) or Metabolic bone disease:

Treatment with calcitriol is indicated:
- When the serum 25(OH)D levels are below 30 ng/mL
- For the stage of renal disease, serum levels of intact parathyroid hormone (iPTH) are above the therapeutic range.
- Less than 9.5–10 mg/dL of adjusted total calcium is seen in serum.
- Children's serum phosphorus levels are below the upper limits of normal for their age group.
Children and Adolescents with CKD Stages 2 - 4:
- less than 10 kg:
  - 0.05 mcg orally every other day
- 10 - 20 kg:
  - 0.1 - 0.15 mcg orally once a day.
- more than 20 kgs:
  - 0.25 mcg orally once a day.
Adjustment of calcitriol dose:
- If the intact PTH levels fall to less than 30% after three months of therapy and the serum calcium and phosphate levels are within the normal range, the dose should be raised by 50%.
- Hold off on starting calcitriol therapy if the intact PTH levels fall below the target range for the stage of chronic kidney disease (CKD) you have, and then start it again at half the prior dose when they do.
- .Hold off on starting calcitriol medication until serum calcium levels are below 9.8 mg/dL (2.37 mmol/L) if they are higher than 10.2 mg/dL (2.37 mmol/L).
- Hold calcitriol medication, start treatment with a phosphate binder, then resume calcitriol at half the regular dose if the serum phosphorus levels rise above the age-appropriate upper limits.

CKD Stage 5 on dialysis:
- Therapy with calcitriol should be initiated with the following points in mind:
  - For babies and children under the age of 12, the serum calcium and phosphorus (Ca x P) product should not exceed 65 mg/dL, and for teenagers, it should not exceed 55 mg/dL.
  - The desired range for serum phosphorus should be reached.
  - A healthy level of serum calcium is less than 10 mg/dL (2.37 mmol/L).
  - The serum calcium level should be less than 10.5 mg/dl if the iPTH level is higher than 1,000 pg/mL.
- iPTH 300 - 500 pg/mL:
  - 0.0075 mcg/kg 3 times a week to a maximum dose of 0.25 mcg/dose
- iPTH more than 500 - 1,000 pg/mL:
  - 0.015 mcg/kg 3 times a week to a maximum dose of 0.5 mcg/dose
- iPTH of more than 1,000 pg/mL:
  - 0.025 mcg/kg 3 times a week to a maximum dose of 1 mcg/dose
Dosage adjustment:
- If the iPTH decline is less than 30% after three months of therapy and blood calcium and phosphorus levels are within the target ranges, the dose should be raised by 50%.

Use for treating Hypoparathyroidism and pseudo-hypoparathyroidism:

Infants:
- 0.02 - 0.06 mcg/kg orally once a day
Children 1 - 5 years:
- 0.25 to 0.75 mcg orally once a day.
Children older than 6 years and Adolescents:
- 0.5 - 2 mcg orally once a day.

Use for treating of Secondary hyperparathyroidism with moderate to severe CKD in patients not on dialysis:

Children less than 3 years of age:
- 0.01 - 0.015 mcg/kg/dose one time a day orally.
Children older than 3 years and Adolescents:
- 0.25 mcg orally once a day.
- The dose may be increased to 0.5 mcg/day if necessary.

Use for treating Vitamin D-dependent rickets:

Infants, Children, and Adolescents:
- 0.25 - 2 mcg orally once a day.
- Adjust dose based on the clinical response.

Pregnancy Risk Factor C

Studies on animals have shown adverse outcomes for fetuses.
Mild hypercalcemia may develop in the newborn due to maternal consumption of calcitriol during pregnancy.
If the patient is being treated with hypoparathyroidism, it is important to adjust the dose of Calcitriol during pregnancy.
Monitor the levels of Vitamin D, calcium and other nutrients to keep them within normal limits.

Calcitriol use during breastfeeding:

You can use it in lactating women, as small amounts are excreted from breastmilk.

Calcitriol Dose in Renal Disease:

Dose adjustment has not been recommended by the manufacturer in patients with renal disease.

Calcitriol Dose in Liver Disease:

Dose adjustment has not been recommended by the manufacturer in patients with liver disease.

Common Side Effects Of Calcitriol Include:

Endocrine & metabolic:
- Hypercalcemia

Side Effects Of Calcitriol Include that are less common:

Central nervous system:
- Headache
Dermatologic:
- Skin rash
Endocrine & metabolic:
- Polydipsia
Gastrointestinal:
- Nausea
- Abdominal pain
Genitourinary:
- Urinary tract infection

Frequency not defined:

Cardiovascular:
- Hypertension
- Cardiac arrhythmia
Central nervous system:
- Drowsiness
- Apathy
- Hyperthermia
- Psychosis
- Metallic taste
- Sensory disturbance
Dermatologic:
- Erythema multiforme
- Urticaria
- Pruritus
- Erythema
Endocrine & metabolic:
- Weight loss
- Calcinosis
- Decreased libido
- Dehydration
- Albuminuria
- Hypercholesterolemia
- Growth suppression
Gastrointestinal:
- Constipation
- Xerostomia
- Pancreatitis
- Vomiting
- Stomach pain
- Anorexia
Genitourinary:
- Nocturia
- Hypercalciuria
Hepatic:
- Increased serum AST
- Increased serum ALT
Hypersensitivity:
- Hypersensitivity reaction
Local:
- Pain at the injection site.
Neuromuscular & skeletal:
- Myalgia
- Weakness
- Ostealgia
- Dystrophy
Ophthalmic:
- Photophobia
- Conjunctivitis
Renal:
- Increased blood urea nitrogen
- Polyuria
- Increased serum creatinine
- Calcium nephrolithiasis
Respiratory:
- Rhinorrhea

Contraindication to Calcitriol include:

Hypercalcemia
Allergy reactions to calcitriol or other vitamin D analogs or any component of this formulation
Vitamin D toxicity

Warnings and Precautions

Vitamin D excess:
- People who consume too much vitamin D can develop hypercalcemia and hyperphosphatemia as well as renal stones.
- They may also experience suppression of the parathyroid hormone, which could lead to a dynamic bone disease.
- It may take several months for patients who switch from ergocalciferol or calcitriol to return to baseline.
Hypercalcemia:
- A high level of vitamin D may lead to acute and progressive hypercalcemia, which can increase the risk of seizures and cardiac arrhythmias.
- A chronic elevation in calcium levels can lead to generalized vascular or soft-tissuecalcification, which may eventually lead to nephrolithiasis.
- Patients with chronic renal disease who have hypercalcemia have a higher mortality rate.
- Concomitant medications like thiazide diuretics may increase the risk of hypercalcemia.
Malabsorption syndrome:
- Oral calcitriol may not be effective in malabsorption patients. This is why caution should be taken when using oral calcitriol.
Renal impairment
- Patients who are not compliant or have deteriorating kidney function should not receive calcitriol as treatment for secondary hyperparathyroidism.
- Patients with renal insufficiency may experience hyperphosphatemia, which can cause vascular calcification.
- Patients who are undergoing dialysis need to be informed that non-aluminum containing Phosphate-binders is not recommended.

Calcitriol (systemic): Drug Interaction

Risk Factor C (Monitor therapy)
Aprepitant	May elevate CYP3A4 substrates' serum concentration (High risk with Inhibitors).
Bosentan	May lower the serum level of CYP3A4 substrates (High risk with Inducers).
Calcium Salts	Enhances the hazardous or harmful effects of vitamin D analogues.
Cardiac Glycosides	Cardiac Glycosides' arrhythmogenic impact may be increased by vitamin D analogues.
Clofazimine	May elevate CYP3A4 substrates' serum concentration (High risk with Inhibitors).
Corticosteroids (Systemic)	May reduce Calcitriol's therapeutic impact (Systemic).
CYP3A4 Inducers (Moderate)	May lower the serum level of CYP3A4 substrates (High risk with Inducers).
CYP3A4 Inhibitors (Moderate)	May slow down CYP3A4 substrate metabolism (High risk with Inhibitors).
Danazol	Could make vitamin D analogues' hypercalcemic impact stronger.
Deferasirox	May lower the serum level of CYP3A4 substrates (High risk with Inducers).
Duvelisib	May elevate CYP3A4 substrates' serum concentration (High risk with Inhibitors).
Fosaprepitant	May elevate CYP3A4 substrates' serum concentration (High risk with Inhibitors).
Fosnetupitant	May elevate CYP3A4 substrates' serum concentration (High risk with Inhibitors).
Ivosidenib	May lower the serum level of CYP3A4 substrates (High risk with Inducers).
Larotrectinib	May elevate CYP3A4 substrates' serum concentration (High risk with Inhibitors).
Netupitant	May elevate CYP3A4 substrates' serum concentration (High risk with Inhibitors).
Palbociclib	May elevate CYP3A4 substrates' serum concentration (High risk with Inhibitors).
Sarilumab	May lower the serum level of CYP3A4 substrates (High risk with Inducers).
Sevelamer	May lower the level of calcitriol in the serum (Systemic).
Siltuximab	May lower the serum level of CYP3A4 substrates (High risk with Inducers).
Simeprevir	May elevate CYP3A4 substrates' serum concentration (High risk with Inhibitors).
Thiazide and Thiazide-Like Diuretics	Could make vitamin D analogues' hypercalcemic impact stronger.
Tocilizumab	May lower the serum level of CYP3A4 substrates (High risk with Inducers).
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 an interaction, administer these drugs several hours apart. Track the levels of calcium in the plasma.
CYP3A4 Inducers (Strong)	May speed up CYP3A4 substrate metabolism (High risk with Inducers). Management: Take into account a substitute for one of the interfering medications. Specific contraindications may apply to some combinations. The relevant manufacturer's label.
CYP3A4 Inhibitors (Strong)	May slow down CYP3A4 substrate metabolism (High risk with Inhibitors).
Dabrafenib	May lower the serum level of CYP3A4 substrates (High risk with Inducers). Management: When possible, look for substitutes for the CYP3A4 substrate. If concurrent therapy cannot be avoided, pay special attention to the substrate's clinical consequences (particularly therapeutic effects).
Enzalutamide	May lower the serum level of CYP3A4 substrates (High risk with Inducers). Treatment: Enzalutamide should not be used concurrently with CYP3A4 substrates that have a limited therapeutic index. Enzalutamide use, like with the use of any other CYP3A4 substrate, should be done cautiously and under close observation.
Lorlatinib	May lower the serum level of CYP3A4 substrates (High risk with Inducers). Management: Avoid taking lorlatinib at the same time as any CYP3A4 substrates for which even a small drop in serum levels of the substrate could result in therapeutic failure and negative clinical outcomes.
Magnesium Salts	The serum content of magnesium salts may rise when calcitriol is administered systemically. Treatment: If a patient is also taking calcitriol, consider using a non-magnesium antacid or phosphate-binding medication. Serum magnesium concentrations should be carefully watched if magnesium-containing products must be used with calcitriol.
MiFEPRIStone	May elevate CYP3A4 substrates' serum concentration (High risk with Inhibitors). Management: During and two weeks after mifepristone treatment, reduce doses of CYP3A4 substrates and keep an eye out for elevated amounts or toxicity. Fentanyl, pimozide, quinidine, sirolimus, and tacrolimus should all be avoided. Cyclosporine should also be avoided.
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 an interaction, think about giving these medications at different times. Track the levels of calcium in the plasma.
Mitotane	May lower the serum level of CYP3A4 substrates (High risk with Inducers). Treatment: When administered in individuals receiving mitotane, doses of CYP3A4 substrates may need to be significantly modified.
Orlistat	May lower the level of vitamin D analogues in the serum. Orlistat may specifically hinder the absorption of vitamin D analogues. If administered with orlistat, closely monitor the clinical response (including serum calcium) to oral vitamin D analogues. Consider administering the vitamin D analogue at least two hours before or after the orlistat if this combination is required.
Pitolisant	May lower the serum level of CYP3A4 substrates (High risk with Inducers). Management: Pitolisant should not be used in conjunction with a CYP3A4 substrate that has a limited therapeutic index. When administered with pitolisant, other CYP3A4 substrates need to be checked more carefully.
St John's Wort	May lower the serum level of CYP3A4 substrates (High risk with Inducers). Management: Take into account a substitute for one of the interfering medications. Specific contraindications may apply to some combinations. The relevant manufacturer's label.
Stiripentol	May elevate CYP3A4 substrates' serum concentration (High risk with Inhibitors). Management: Due to the increased potential for side effects and toxicity, stiripentol should not be used with CYP3A4 substrates that are thought to have a narrow therapeutic index. Use of stiripentol with any CYP3A4 substrate necessitates closer observation.
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.
Conivaptan	May elevate CYP3A4 substrates' serum concentration (High risk with Inhibitors).
Fusidic Acid (Systemic)	May elevate CYP3A4 substrates' serum concentration (High risk with Inhibitors).
Idelalisib	May elevate CYP3A4 substrates' serum concentration (High risk with Inhibitors).
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	Enhances the hazardous or harmful effects of vitamin D analogues. 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	May enhance the adverse/toxic effect of other Vitamin D Analogs.

Monitoring parameters:

Secondary hyperparathyroidism (CKD patients):
- During therapy initiation and dosage adjustments:
  - Monitor serum calcium and phosphate levels at least twice weekly.
- KDIGO guidelines (2017):
  - CKD stage G3a to G3b:
    - Serum calcium and phosphate:
      - Monitor every 6 - 12 months
    - PTH
    - Alkaline phosphatase
  - CKD stage G4:
    - Serum calcium and phosphate:
      - Monitor every 3 - 6 months
    - PTH
      - Monitor every 6 - 12 months
    - Alkaline phosphatase every 12 months with elevated PTH
  - CKD stage G5 and G5D:
    - Serum calcium and phosphate:
      - Monitor every 1 -3 months;
    - PTH:
      - Monitor every 3 - 6 months;
    - Alkaline phosphatase every 12 months or frequently in the presence of elevated PTH
Hypoparathyroidism:

Note: Frequency depends on the baseline characteristics. Observance required frequently or yearly.

Monitor:
- phosphate
- Serum calcium
- renal function (BUN, CrCl)
- magnesium
- In asymptomatic patients with a history of renal stones or nephrocalcinosis, renal imaging should be performed every five years.
- 24-hour urinary calcium and creatinine,
- Ophthalmologic exam
- CNS imaging for basal ganglia calcification
- BMD as indicated

Hypophosphatemia, X-linked:
- Monitor:
  - Serum calcium
  - phosphorous
  - PTH
  - alkaline phosphatase (ALP)
  - Creatinine
  - 24-hour urinary calcium and creatinine 4 - 6 weeks after initiation of therapy. If a biochemical response is noted monitoring should be continued at 6 - 8 weeks, and then every 3 - 4 months for the first year and every 6 - 9 months thereafter.

How to administer Calcitriol?

It may be taken orally without regard to meals, however, administration with meals may reduce the gastrointestinal side effects.
It can also be given as an intravenous bolus injection through an intravenous line or a catheter.

Mechanism of action of Calcitriol:

The activated form of vitamin D is called calcitriol, often known as 1,25-hydroxyvitamin D.
It activates vitamin D receptors through binding to vitamin D receptors in kidney, parathyroid, bone, and intestine.
In addition to renal tubular calcium and phosphate absorption, it causes intestinal calcium absorption.
Chronic renal failure causes vitamin D to stop activating, which results in its inhibition of the parathyroid hormone.
Secondary hyperparathyroidism results in bone loss, which can lead to renal osteodystrophy.

It has beenStart of actionThe maximum effect can be seen within 10 hours. After intravenous or oral intake, the duration of action takes between 3 and 5 days. It is growing rapidlyabsorbedAfter oral intake, it is almost completely bound to albumin.

Thehalf-life eliminationChildren can live from 1.8 to 16 years old, while those who are undergoing peritoneal dialysis last 27.4 hours. Half-life in healthy adults is between 5 and 8 hours, while it is 16 to 22 hours for patients on hemodialysis. TheTimed to achieve peak plasma concentrationAfter oral intake, it takes 3 - 6 hours. It is mostly excreted through Feces.

Calcitriol International Brands: