Consumer medicine information

Sical

Calcitriol

BRAND INFORMATION

Brand name

Sical

Active ingredient

Calcitriol

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Sical.

SUMMARY CMI

SICAL®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using SICAL?

SICAL contains the active ingredient calcitriol. SICAL is used to treat people with osteoporosis, a disease where the bones of the body weaken, and in the prevention of osteoporosis in people taking oral corticosteroids.

For more information, see Section 1. Why am I using SICAL? in the full CMI.

2. What should I know before I use SICAL?

Do not use if you have ever had an allergic reaction to SICAL or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use SICAL? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with SICAL and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use SICAL?

  • Your doctor will tell you how many SICAL capsules to take each day.
  • Generally the daily dose for adults is 0.25 micrograms (one capsule) taken twice daily.

More instructions can be found in Section 4. How do I use SICAL? in the full CMI.

5. What should I know while using SICAL?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using SICAL.
  • Do not take any other medicines whether they require a prescription or not without first telling your doctor.
  • Tell your doctor if you become pregnant while taking SICAL.
Things you should not do
  • Do not stop using this medicine suddenly or change the dose without first checking with your doctor.
  • Do not let yourself run out of SICAL over the weekend or on holidays.
  • Do not give SICAL to anyone else even if their symptoms seem similar to yours.
  • Do not use SICAL to treat other complaints unless your doctor says to.
Driving or using machines
  • Your ability to drive a car or operate machinery should not be affected by SICAL.
Looking after your medicine
  • Store below 25°C.
  • Do not leave SICAL in direct sunlight.

For more information, see Section 5. What should I know while using SICAL? in the full CMI.

6. Are there any side effects?

Possible side effects include loss of appetite, feeling sick, headache, feeling tired, sleepy or drowsy, fever, vomiting or stomach ache, constipation, weakness or muscle weakness, dry mouth or thirst, irregular and/or rapid heart beat, and urinary tract infection.

These are all symptoms of high levels of calcium in the blood.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

SICAL®

Active ingredient(s): calcitrol

Consumer Medicine Information (CMI)

This leaflet provides important information about using SICAL. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using SICAL.

Where to find information in this leaflet:

1. Why am I using SICAL?
2. What should I know before I use SICAL?
3. What if I am taking other medicines?
4. How do I use SICAL?
5. What should I know while using SICAL?
6. Are there any side effects?
7. Product details

1. Why am I using SICAL?

SICAL contains the active ingredient calcitriol, one of the naturally occurring and biologically active forms of Vitamin D. Calcitriol acts in the body in a similar manner to Vitamin D.

SICAL is used to used to treat people with osteoporosis, a disease where the bones of the body weaken, and in the prevention of osteoporosis in people taking oral corticosteroids.

2. What should I know before I use SICAL?

Warnings

Do not use SICAL if:

  • you are allergic to calcitrol, or any of the ingredients listed at the end of this leaflet.
  • Always check the ingredients to make sure you can use this medicine.
  • you have high levels of calcium in your blood (called hypercalcaemia)
  • you have vitamin D toxicity.

Check with your doctor if you:

  • have any other medical conditions particularly if you have kidney problems
  • take any medicines for any other condition
  • you are allergic to any other medicines, foods, dyes or preservatives.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

Do not take SICAL is you are breastfeeding or intend to breastfeed. SICAL may pass into the breastmilk and have unwanted effects in the baby.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may interfere with SICAL and affect how it works.

  • medicines or vitamin tablets containing vitamin D or calcium.
  • cholestyramine, medicine used to lower cholesterol levels in the blood.
  • sevelamer, a medicine used to lower phosphorus levels in your body.
  • antacids containing magnesium.
  • digoxin, medicine used to treat heart conditions.
  • thiazide diuretics, medicines used to treat hypertension (high blood pressure) and oedema (water retention).
  • phenytoin and phenobarbital. medicines used to control epilepsy and/or seizures.
  • Corticosteroids.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect SICAL.

4. How do I use SICAL?

How much to take

Your doctor will tell you how many SICAL capsules to take each day. This will vary depending on the nature of your illness, the level of calcium in your blood and your individual response to SICAL. Your doctor will need to make regular measurements of the calcium level in your blood while you are taking SICAL.

Osteoporosis Patients

  • Generally the daily dose for adults is 0.25 micrograms (one capsule) taken twice daily.

Osteodystrophy, hypoparathyroidism and rickets

  • Generally the initial daily dose for adults is 0.25 micrograms (one capsule) given in the morning. If calcium levels have not improved significantly after 2 to 4 weeks treatment with SICAL, your doctor may gradually increase the dose in 0.25 microgram steps until a satisfactory calcium level in your blood is achieved.

Paediatric Patients

  • The safety and efficacy of SICAL capsules in children has not been sufficiently investigated to enable dosing recommendations

How to take

  • Swallow whole capsules with a glass of water.
  • Do not open the capsules and do not take any capsules that are damaged.

When to take / use SICAL

SICAL can be taken at any time of day with or without food

If you forget to use SICAL

Do not take an extra dose. Wait until the next dose and take your normal dose then.

Do not try to make up for the dose that you missed by taking more than one dose at a time.

If you use too much SICAL

If you think that you have used too much SICAL, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (Australia telephone 13 11 26) for advice, or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using SICAL?

Things you should do

Tell all doctors, dentists and pharmacists who are treating you that you are taking SICAL.

Do not take any other medicines whether they require a prescription or not without first telling your doctor.

Tell your doctor if you become pregnant while taking SICAL.

Tell your doctor if, for any reason, you have not taken your medicine exactly as prescribed.

Otherwise, your doctor may think that it was not effective and change your treatment unnecessarily.

Tell your doctor if you feel the capsules are not helping your condition.

Be sure to keep all of your appointments with your doctor so that your progress can be checked.

Always discuss with your doctor any problems or difficulties during or after taking SICAL capsules.

SICAL and Diet

You should discuss your diet with your doctor and adhere strictly to your dietary recommendations.

Sudden changes in diet, particularly the amount of dairy products, may lead to increased calcium in your blood. If this happens, you may feel sick, vomit, be confused, experience weakness, be constipated and experience increased urination.

SICAL and Laboratory Tests

Make sure that you keep all blood test appointments with your doctor.

These are to check your blood calcium levels while you are taking SICAL. Your doctor will discuss your specific needs with you.

Call your doctor straight away if you:

  • Are not feeling hungry (loss of appetite)
  • feeling sick
  • headache
  • feeling tired, sleepy or drowsy
  • fever
  • vomiting or stomach ache
  • constipation
  • weakness or muscle weakness
  • dry mouth or thirst
  • irregular and/or rapid heart beat
  • urinary tract infection

Remind any doctor, dentist or pharmacist you visit that you are using SICAL.

Things you should not do

Do not suddenly stop taking SICAL or change the dose without first checking with your doctor. Your doctor will tell you the best way to slowly reduce the amount of SICAL you are taking before stopping completely.

Do not let yourself run out of medicine over the weekend or on holidays.

Do not give SICAL to anyone else even if their symptoms seem similar to yours.

Do not use SICAL to treat other complaints unless your doctor says to.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how SICAL affects you.

Looking after your medicine

  • Keep SICAL in a cool dry place where the temperature stays below 25°C.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
Skin related
  • rash, itching or hives on the skin
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Gastrointestinal related:
  • loss of appetite
  • feeling sick
  • vomiting or stomach ache
  • constipation
  • dry mouth or thirst
Neurological or brain related:
  • headache
  • feeling tired, sleepy or drowsy
Musculoskeletal or muscle related:
  • weakness or muscle weakness
Cardiovascular or heart related:
  • irregular and/or rapid heart beat
Urinary related:
  • urinary tract infection
Other side effects:
  • fever
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What SICAL contains

Active ingredient
(main ingredient)		calcitrol
Other ingredients
(inactive ingredients)
  • butylated hydroxyanisole
  • butylated hydroxytoluene
  • fractionated coconut oil
  • Gelatin
  • glycerol
  • iron oxide red
  • iron oxide yellow
  • purified water
  • sorbitol solution (70 per cent) (non-crystallising)
Potential allergenssulfites

Do not take this medicine if you are allergic to any of these ingredients.

What SICAL looks like

SICAL is a red coloured, oval shaped soft gelatin capsule containing clear oily fluid (AUST R 236776).

Who distributes SICAL

Alphapharm Pty Ltd trading as Viatris
Level 1, 30 The Bond
30-34 Hickson Road
Millers Point NSW 2000
www.viatris.com.au
Phone: 1800 274 276

This leaflet was prepared in November 2023.

SICAL® is a Viatris company trade mark

SICAL_cmi\Nov23/00

Published by MIMS January 2024

BRAND INFORMATION

Brand name

Sical

Active ingredient

Calcitriol

Schedule

S4

 

1 Name of Medicine

Calcitriol.

2 Qualitative and Quantitative Composition

Each soft gelatin capsule contains 0.25 microgram of calcitriol as the active ingredient.

Excipients with known effect.

Sulfites.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Sical is a red coloured, oval shaped soft gelatin capsule containing clear oily fluid.

4 Clinical Particulars

4.1 Therapeutic Indications

Sical is indicated for the treatment of established osteoporosis diagnosed by objective measuring techniques, such as densitometry, or by radiographic evidence of a traumatic fracture.
Sical is also indicated for the prevention of corticosteroid-induced osteoporosis in patients commencing oral steroid therapy in a dose and regimen expected to result in a significant bone loss.
Sical is indicated in the treatment of hypocalcaemia in patients with uraemic osteodystrophy, hypoparathyroidism and in hypophosphataemic rickets.

4.2 Dose and Method of Administration

General.

The optimal daily dose of Sical must be carefully determined for each patient and indication. Dosage optimisation should be accompanied by regular monitoring of serum calcium concentration.
When the optimal dosage of Sical has been determined, the serum calcium levels should be checked regularly. As soon as serum calcium nears hypercalcaemic levels (1 mg per 100 mL [0.25 mmol/L] above normal 9-11 mg per 100 mL [2.25-2.75 mmol/L] on average), the dosage of Sical should be substantially reduced or treatment stopped altogether until normocalcaemia ensues. If hypercalcaemia occurs, the drug should be immediately discontinued until normocalcaemia ensues. Withdrawal of additional doses of calcium can also be of benefit in bringing about rapid normalisation of serum calcium levels. Careful consideration should also be given to lowering the dietary calcium intake.
Should hypercalcaemia occur, Sical should be suspended immediately and serum calcium and phosphate levels must be determined daily. When normal levels have been attained, the treatment with Sical can be continued, at a daily dose of 0.25 microgram lower than that previously used.

Adults.

Osteoporosis.

Established osteoporosis.

The recommended dose of Sical is 0.25 microgram twice daily. If a satisfactory response is not obtained with this dose, it may be increased, with regular serum calcium monitoring, to a maximum of 0.5 microgram twice daily. This increased dose should rarely be necessary.

Corticosteroid-induced osteoporosis.

The recommended dose is 0.25 microgram twice daily for steroid doses equivalent to < 10 mg/day of oral prednisone increasing to 0.75 microgram/day for steroid doses > 10 mg/day oral prednisone.
Dietary calcium intake should not exceed 1,000 mg/day (see Section 4.4 Special Warnings and Precautions for Use).
Other indications.

Uraemic osteodystrophy.

The recommended initial dose of Sical is 0.25 microgram/day. If a satisfactory response in the biochemical parameters and clinical manifestations of the disease state is not observed, dosage may be increased by 0.25 microgram/day at intervals of two to four weeks. Patients with normal or only slightly reduced serum calcium levels may respond to Sical doses of 0.25 microgram every other day. Most patients undergoing haemodialysis respond to doses between 0.5 and 1 microgram daily.

Hypoparathyroidism and rickets.

The recommended initial dose of Sical is 0.25 microgram per day given in the morning. If a satisfactory response in the biochemical parameters and clinical manifestations of the disease are not observed, the dose may be increased at intervals of two to four weeks.
Malabsorption is occasionally noted in patients with hypoparathyroidism, therefore larger doses of Sical may be needed.

Paediatric use.

The safety and efficacy of Sical capsules in children have not been sufficiently investigated to enable dosing recommendations (see Section 4.4 Special Warnings and Precautions for Use, Paediatric use).

Use in the elderly.

No dosage adjustment is necessary in elderly patients. (See Section 4.4 Special Warnings and Precautions for Use, Use in the elderly.)

Information for the patient.

It is recommended that patients receive instruction in dietary management and that they be warned of the consequences and implications of not adhering strictly to the diet recommendations in relation to intake of calcium and vitamin D (see Section 4.4 Special Warnings and Precautions for Use, Hypercalcaemia). Patients should also be informed of the symptoms of hypercalcaemia, which include weakness, nausea and vomiting.

Laboratory monitoring.

For safety reasons, it is essential that regular monitoring of serum calcium concentration be performed during therapy with Sical. Blood samples should be taken without a tourniquet where possible to minimise local calcium effects.

Osteoporosis, including corticosteroid induced osteoporosis.

Patients should be monitored at the commencement of therapy, at 2 to 4 weeks and thereafter at 2 to 3 monthly intervals.

Hypocalcaemia/ uremic osteodystrophy/ hypoparathyroidism/ hypophosphataemic rickets.

Serum calcium, phosphorus, magnesium and alkaline phosphatase and 24 hour urinary calcium and phosphorus should be determined periodically. During the initial phase of the medication, serum calcium should be determined at least twice weekly. Subsequently, monitoring should also be undertaken at 2 to 4 weeks and at 2 to 3 monthly intervals thereafter.

4.3 Contraindications

Hypercalcaemia or vitamin D toxicity.
Hypersensitivity to calcitriol or any of the excipients in Sical.

4.4 Special Warnings and Precautions for Use

Concomitant therapy with other vitamin D compounds.

Since Sical is the most potent metabolite of vitamin D available, other vitamin D compounds should be withheld during treatment in order to avoid the development of hypervitaminosis D.
If patients are "changed over" from ergocalciferol to calcitriol it may take many months for blood levels of ergocalciferol to return to pretreatment values. Overdosage of any form of vitamin D is dangerous (also see Section 4.9 Overdose). Chronic hypercalcaemia can lead to generalised vascular calcification, nephrocalcinosis and other soft-tissue calcification.

Hypercalcaemia.

A strong relationship exists between calcitriol therapy and the development of hypercalcaemia. In some trials in uremic osteodystrophy, up to 40% of patients receiving calcitriol treatment became hypercalcaemic.
Sudden increases in calcium consumption due to dietary change (e.g. dairy products) or injudicious calcium supplements may precipitate hypercalcaemia. Patients and relatives should receive instruction in dietary management, be informed about the symptoms of hypercalcaemia, and be warned of the consequences of not adhering to dietary recommendations. Although an adequate dietary intake of calcium is important in patients with postmenopausal osteoporosis, calcitriol does increase calcium absorption in these patients and calcium supplements may lead to hypercalcaemia and are not recommended unless the dietary intake is clearly inadequate (see Section 4.2 Dose and Method of Administration, Information for the patient; Section 4.8 Adverse Effects (Undesirable Effects)).
In patients with normal renal function, chronic hypercalcaemia may be associated with an increase in serum creatinine.

Serum phosphate levels.

Sical raises serum inorganic phosphate levels. While this is a desirable effect in patients with hypophosphataemic states, caution must be taken in patients with renal failure. (See Section 4.4 Special Warnings and Precautions for Use, Ectopic calcification.)

Hypophosphataemic rickets.

Patients with hypophosphataemic rickets (familial hypophosphataemia) should pursue their oral phosphate therapy. However, the possible stimulation of intestinal phosphate absorption may modify the requirement for phosphate supplements. During the stabilisation phase of treatment with Sical, serum calcium levels should be checked at least twice weekly (see Section 4.2 Dose and Method of Administration, Laboratory monitoring).

Ectopic calcification.

Sical may increase plasma phosphate levels. While this effect is desirable in hypophosphataemic osteomalacia, it may cause ectopic calcification, especially in patients with renal failure. Plasma phosphate levels should be kept normal in such patients by the oral administration of phosphate binding agents.
Patients with normal renal function who are taking Sical should avoid dehydration. Adequate fluid intake should be maintained.

Immobilisation.

Patients immobilised after surgical procedures are more at risk of developing hypercalcaemia, therefore more frequent monitoring is recommended.

Use in renal impairment.

Special care should be taken when administering Sical to patients with renal dysfunction. More frequent monitoring in these patients is appropriate (see Section 4.2 Dose and Method of Administration).

Use in the elderly.

It is advised that in elderly patients suffering from ischemic heart disease, serum calcium levels should be carefully monitored. If hypercalcaemia is observed, calcitriol therapy should be suspended immediately. It should also be remembered that geriatric patients receive many other drugs and that their compliance may not be ideal.

Paediatric use.

Paediatric patients on long-term treatment with calcitriol are at risk of development of nephrocalcinosis. The younger the age at the commencement of therapy, and the higher the dose of calcitriol needed, the greater the risk. The drug should be used only if the benefits clearly outweigh the risks.

Effects on laboratory tests.

Sical affects serum calcium levels and serum phosphate levels (see Section 4.4 Special Warnings and Precautions for Use; Section 4.2 Dose and Method of Administration). It is essential that regular monitoring of serum calcium concentration be performed during therapy with Sical.

4.5 Interactions with Other Medicines and Other Forms of Interactions

In patients being treated for osteoporosis, calcium-containing preparations should be avoided unless required for specific dietary purposes.
Bile acid sequestrants including colestyramine and sevelamer can reduce intestinal absorption of fat soluble vitamins; and therefore may impair intestinal absorption of Sical.
A relationship of functional antagonism exists between vitamin D analogues, which promote calcium absorption, and corticosteroids, which inhibit it.
Magnesium containing antacids and Sical should not be used concomitantly, because such use may lead to the development of hypermagnesaemia.
Sical should be given cautiously to patients on digitalis because hypercalcaemia in such patients may precipitate cardiac arrhythmias.
The concomitant use of thiazide diuretics may precipitate hypercalcaemia.
Since Sical also has an effect on phosphate transport in the intestine, kidneys and bones, the dosage of phosphate-binding agents must be adjusted in accordance with the serum concentration (normal value: 0.6-1.6 mmol/L).
Administration of enzyme inducers such as phenytoin or phenobarbital (phenobarbitone) may lead to increased metabolism and hence reduced serum concentrations of calcitriol. Therefore, higher doses of calcitriol may be necessary if these drugs are administered simultaneously.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No data available.
(Category B3)
Category B3: drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human foetus having been observed. Studies in animals have shown evidence of an increased occurrence of fetal damage, the significance of which is considered uncertain in humans.
There are no adequate and well-controlled studies in pregnant women. Sical has been found to be teratogenic in rabbits when given at doses of 0.08 and 0.3 microgram/kg (approximately 1 and 5 times the maximum recommended dose based on mg/m2). All 15 foetuses in 3 litters at these doses showed external and skeletal abnormalities. However, none of the other 23 litters (156 foetuses) showed external and skeletal abnormalities compared to controls. Teratogenicity studies in rats up to 0.3 microgram/kg (approximately twice the maximum recommended dose based on mg/m2) showed no evidence of teratogenic potential.
Sical should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
 It should be assumed that exogenous calcitriol passes into the breast milk. In view of the possible adverse effects on the infant, mothers should not breast-feed while taking Sical.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

Clinical trials.

The adverse effects listed below reflect the experience from investigational studies of calcitriol, and the postmarketing experience.
The most commonly reported adverse reaction was hypercalcaemia. Patients may also experience hypercalciuria.
The adverse effects listed in Table 1 are presented by system organ class and frequency categories, defined using the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Since Sical exerts vitamin D activity in the body, adverse effects are, in general, similar to those encountered with excessive vitamin D intake.
Hypercalcaemia related to mechanism of action is the most important side effect and is manageable by dose modification. Hypercalcaemia has been demonstrated not to be an issue for calcitriol in the treatment of postmenopausal osteoporosis at the recommended dosage of 0.25 microgram twice daily.
However some women may require dose reductions (see Section 4.4 Special Warnings and Precautions for Use; Section 4.2 Dose and Method of Administration).
Acute hypercalcaemia may give rise to cardiac arrhythmia and/or arrest.
Signs and symptoms of vitamin D intoxication associated with hypercalcaemia include:

Acute.

Decreased appetite, weakness, headache, somnolence, nausea, vomiting, dry mouth, constipation, abdominal pain or abdominal pain upper, muscle pain, bone pain and metallic taste.

Chronic.

Muscular weakness, weight decreased, sensory disturbances, pyrexia, thirst polydipsia, polyuria, dehydration, apathy, growth retardation, nocturia, conjunctivitis (calcific), pancreatitis, photophobia, rhinorrhoea, hyperthermia, decreased libido, elevated BUN, albuminuria, hypercholesterolaemia, elevated AST and ALT, ectopic calcification, hypertension, cardiac arrhythmias, urinary tract infections and, rarely, overt psychosis.
Prolonged chronic hypercalcaemia or concurrent hypercalcaemia and hyperphosphataemia of > 1.9 mmol/L, calcinosis may occur; this can be seen radiographically.
Hypersensitivity reactions, including rash, pruritus, erythema and urticaria may occur in susceptible individuals.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

Since calcitriol is a derivative of vitamin D, the symptoms of overdose are the same as for an overdose of vitamin D. Administration of Sical to patients in excess of their daily requirements can cause hypercalcaemia, hypercalciuria and hyperphosphataemia. High intake of calcium and phosphate concomitant with Sical may lead to similar symptoms. The serum calcium times phosphate (Ca x P) product should not be allowed to exceed 70 mg2/dL2. In patients with uraemic osteodystrophy, high levels of calcium in the dialysate may contribute to the development of hypercalcaemia.

Symptoms.

Acute symptoms of vitamin D intoxication include anorexia, headache, vomiting and constipation.
Chronic symptoms include dystrophy (weakness, loss of weight), sensory disturbances, possibly fever with thirst, polyuria, dehydration, apathy, arrested growth and urinary tract infections. Hypercalcaemia ensues with metastatic calcification of the renal cortex, myocardium, lungs and pancreas.

Treatment.

Accidental overdosage.

The treatment of acute accidental overdosage of Sical should consist of general supportive measures. Serial serum electrolyte determinations (especially calcium), rate of urinary calcium excretion and assessment of electrocardiographic abnormalities due to hypercalcaemia should be obtained. Such monitoring is critical in patients receiving digitalis.
Discontinuation of supplemental calcium and a low calcium diet are also indicated in accidental overdosage.
Due to the relatively short duration of the pharmacological action of calcitriol, further measures are probably unnecessary. However, should persistent and markedly elevated serum levels occur, there are a variety of therapeutic alternatives that may be considered, depending on the patient's underlying condition. These include the use of drugs such as phosphates and corticosteroids as well as measures to induce an appropriate forced diuresis. The use of peritoneal dialysis against a calcium free dialysate has also been reported.

Hypercalcaemia and overdosage.

General treatment of hypercalcaemia (greater than 1 mg/100 mL (0.25 mmol/L) above the upper limit of the normal range) consists of immediate discontinuation of Sical therapy, institution of a low calcium diet and withdrawal of calcium supplements. Serum calcium levels should be determined daily until normocalcaemia ensues. Hypercalcaemia frequently resolves in two to seven days. When serum calcium levels have returned to within normal limits, Sical therapy may be reinstituted at a dose of 0.25 microgram/day less than prior therapy. Serum calcium levels should be obtained at least twice weekly after all dosage changes and subsequent dosage titration. Persistent or markedly elevated serum calcium levels in dialysis patients may be corrected by dialysis against a calcium-free dialysate.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

The biological effects of calcitriol are mediated by the vitamin D receptor, a nuclear hormone receptor expressed in most cell types and functioning as a ligand-activated transcription factor that binds to specific DNA sites to modify the expression of target genes.
Calcitriol is the most important active metabolite of vitamin D3. It is normally formed in the kidney from its precursor 25-hydroxycolecalciferol (25-HCC). Physiological daily production is normally 0.5-1.0 microgram and is somewhat higher during periods of increased bone synthesis (e.g. growth or pregnancy).
The natural supply of vitamin D in humans depends mainly on exposure to ultraviolet rays of the sun for conversion of 7-dehydrocholesterol in the skin to vitamin D3 (colecalciferol). Vitamin D3 must be metabolically activated in the liver and the kidney before it is fully active as a regulator of calcium and phosphorus metabolism at target tissues. The initial transformation of vitamin D3 is catalysed by a vitamin D3-25-hydroxylase enzyme (25-OHase) present in the liver, and the product of this reaction is 25-hydroxyvitamin D3 (25-(OH)D3). Hydroxylation of 25-(OH)D3 occurs in the mitochondria of kidney tissue, activated by the renal 25-hydroxyvitamin D3-1 alpha-hydroxylase (alpha-OHase), to produce 1,25-(OH)2D3 (calcitriol), the active form of vitamin D3.
Calcitriol binds to an intracellular receptor, a member of the steroid receptor superfamily. The calcitriol-receptor complex interacts with specific DNA sequences that regulate transcription and protein synthesis in a variety of cells including osteoblasts, mucosal cells of the intestine, renal tubular cells and parathyroid cells. The changes in protein synthesis induced in these cells by calcitriol are responsible for its profound physiological effects. A vitamin D-resistant state exists in uraemic patients because of the failure of the kidney to convert precursors to the active compound. The uraemic state may also inhibit the binding of the calcitriol receptor to its specific DNA responsive elements.
The key role of calcitriol in the regulation of bone and calcium homeostasis, which includes stimulating effects on osteoblastic activity in the skeleton, provides a sound pharmacological basis for its therapeutic effects in osteoporosis. Treatment of established osteoporosis with calcitriol is associated with an increase in bone density and a reduction in new vertebral fractures. Established osteoporosis is defined as the finding of: bone mineral density measurements of 2 or more standard deviations below the gender specific peak bone mass; or the presence or history of osteoporotic fracture. Calcitriol also reduces bone loss associated with corticosteroid therapy.
In patients with marked renal impairment, synthesis of endogenous calcitriol is correspondingly limited or may even cease altogether. This deficiency plays a key role in the development of renal osteodystrophy. In patients with renal osteodystrophy, administration of calcitriol normalises reduced intestinal absorption of calcium, hypocalcaemia, increased serum alkaline phosphatase and serum parathyroid hormone concentration.
In patients with hypophosphataemic rickets and hypophosphataemia, treatment with calcitriol reduces tubular elimination of phosphates and, in conjunction with concurrent phosphate treatment, corrects some skeletal abnormalities.

Clinical trials.

Females with osteoporosis. The pathophysiology of osteoporosis is essentially the same in females and males. There are few data on the safety and efficacy of calcitriol on fracture rates and bone mineral density in premenopausal women.
Postmenopausal osteoporosis.

Calcitriol versus calcium.

The pivotal evidence for the efficacy of calcitriol in postmenopausal osteoporosis is provided by a three year, open label, multicentre, randomised comparison of calcitriol versus calcium in 432 patients (calcitriol n = 213, calcium n = 219). Vertebral fracture rate was assessed by X-ray evidence. Treatment with calcitriol 0.25 microgram twice daily for three years resulted in a three-fold reduction in the rate of new vertebral fractures in women with postmenopausal osteoporosis compared with calcium supplementation of 1000 mg daily. There was a reduction in the number of patients with new fractures, the number of new fractures per se and the fracture rate expressed as fractures per 100 patient years in the calcitriol group when compared to the calcium group. The differences between calcitriol and calcium groups increased over the three year study period, reaching significance by the second year. Serum calcium and creatinine were monitored regularly and dosage was halved if levels became elevated. Hypercalcaemia was reported in two patients.

Calcitriol versus placebo.

A randomised, double blind, placebo-controlled trial was conducted in 40 patients (calcitriol n = 18, placebo n = 22). Calcitriol was increased from an initial dose of 0.25 microgram twice daily until hypercalcaemia developed, at which point the dosage was adjusted and calcium intake reduced to maintain stable serum and urinary calcium. Dietary calcium was maintained at 1000 mg per day and 400 IU vitamin D was administered to each patient. After two years, calcitriol treated patients had an increase in spine bone density of 1.94% measured by dual photon absorptiometry compared to a decrease of 3.92% in patients on placebo (p = 0.001). The sample size was too small to show positive data on fracture rate after two years.
Phase II studies of calcitriol in postmenopausal osteoporosis were undertaken in the USA and involved a total of 93 patients. The primary endpoint was effect on vertebral fracture rates. Dose titration resulted in a mean dose of 0.5 to 0.6 microgram/day. Two studies were very similar, with an initial two month placebo treatment for all patients, followed by a ten month double-blind comparison of calcitriol and placebo, with a subsequent extension of 12 to 30 months during which all patients received calcitriol. The third study compared calcitriol with placebo in an initial six month single-blind evaluation, with a subsequent open phase of up to 24 months calcitriol treatment. Dietary calcium was supplemented to 600 mg per day in the two double-blind trials. A highly significant reduction was noted in the fracture rate in patients treated with calcitriol in comparison with placebo in the three double blind studies. Overall, there was a statistically significant association between calcitriol treatment and the suppression of fractures. Calcium absorption was significantly increased in the calcitriol groups in all three studies.
Males with osteoporosis. There are few data on the safety and efficacy of calcitriol on fracture rates and bone mineral density in osteoporotic men.

Calcitriol versus calcium.

A randomised double-blind, placebo-controlled pilot trial assessed the efficacy of calcitriol 25 microgram twice daily versus calcium 500 mg twice daily for 24 months in men with osteoporosis. Twenty-one men were randomised to receive calcitriol and 20 to receive calcium. Due to the size of the study no valid conclusions were drawn regarding the efficacy in terms of bone mineral density (BMD) and vertebral fracture rates.
Corticosteroid induced osteoporosis. A randomised, double blind, placebo and comparator-controlled trial was conducted in 103 enrolled male and female patients with rheumatic, immunological or respiratory disease. The subjects enrolled within four weeks of starting long-term corticosteroid therapy. The three treatment groups were the placebo group (n = 29, calcium 1000 mg/day), calcitriol group (n = 34, oral calcium 1000 mg/day, calcitriol 0.5 - 1 microgram/day) and the calcitriol plus calcitonin group (n = 29, oral calcium 1000 mg/day, calcitriol 0.5-1 microgram/day, intranasal calcitonin 400 IU/day). Each treatment group received active treatment for 12 months and was followed up for a further 12 months.
The primary efficacy end-point was bone mineral density measured at the lumbar spine, femoral neck and distal radius by photon absorptiometry. Serum levels of parathyroid hormone, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D and osteocalcin and urinary levels of calcium, hydroxyproline and creatinine were also measured. The bone density measurements and biochemical analyses were made at baseline and then every four months for two years. Serum calcium was measured at one, three and five weeks and every two months thereafter.
After the first year both treatment groups showed a similar and statistically significant reduction in bone loss at the lumbar spine but not at the femoral neck or distal radius compared to the placebo group. In the second year, this reduction in bone loss was no longer apparent in the calcitriol group. However, this group did receive a higher cumulative dose of corticosteroids during the second year.
The study medications were generally well tolerated with few adverse effects. The most frequent events were hypercalcaemia and rhinorrhoea. Hypercalcaemia was seen in one placebo group patient, one calcitriol group patients and eight calcitriol plus calcitonin group patients. Other less frequently reported adverse events included rash, headache and gastrointestinal symptoms.

5.2 Pharmacokinetic Properties

Absorption.

Calcitriol is rapidly absorbed from the intestine. Peak serum concentrations (above basal values) were reached within 3 to 6 hours following oral administration of single doses of 0.25 to 1.0 microgram of calcitriol.
Peak plasma concentrations (above basal values) were reached within 2-6 hours following oral administration of a steady-state dose of 1 microgram per day.

Distribution.

Following a single oral dose of 0.5 microgram mean serum concentrations of calcitriol rose from a baseline value of 40.0 ± 4.4 (S.D.) picogram/mL to 60.0 ± 4.4 picogram/mL at 2 hours and declined to 53.0 ± 6.9 at 4 hours, 50 ± 7.0 at 8 hours, 44 ± 4.6 at 12 hours and 41.5 ± 5.1 at 24 hours.
Following a steady-state dose of 1 microgram per day the peak plasma concentrations of calcitriol rose from a baseline value of 47.9 ± 14.6 (SD) picogram/mL to 83.0 ± 17.2 (SD) picogram/mL after 4 hours.
Calcitriol and other vitamin D metabolites are transported approximately 99.9% bound to specific plasma proteins in the blood.

Metabolism.

Calcitriol is hydroxylated and oxidised by CYP24A1.
Several metabolites of calcitriol, each exerting different vitamin D activities, have been identified:
1α,25-dihydroxy-24-oxo-colecalciferol;
1α,23,25-trihydroxy-24-oxo-colecalciferol;
1α,24R,25-trihydroxycolecalciferol;
1α,25R-dihydroxycolecalciferol-26,23S-lactone;
1α,25S,26-trihydroxycolecalciferol;
1α,25-dihydroxy-23-oxo-colecalciferol;
1α,25R,26-trihydroxy-23-oxo-colecalciferol; and
1α-hydroxy-23-carboxy-24,25,26,27-tetranorcolecalciferol.
1α,25R-dihydroxycolecalciferol-26,23S-lactone is the major metabolite in humans.

Excretion.

The elimination half-life of calcitriol from serum was found to range from 3 to 6 hours. However, the pharmacological effect of a single dose of calcitriol lasts about three to five days. Enterohepatic recycling and biliary excretion occur. Following intravenous administration of radiolabelled calcitriol in normal subjects, approximately 27% and 7% of the radioactivity appeared in the faeces and urine, respectively, within 24 hours. When a 1 microgram oral dose of radiolabelled calcitriol was administered to normals, approximately 10% of the total radioactivity appeared in urine within 24 hours. Cumulative excretion of radioactivity on the sixth day following intravenous administration of radiolabelled calcitriol averaged 16% in urine and 49% in faeces.
There is evidence that maternal calcitriol may enter the fetal circulation.
A bioequivalence study comparing Sical capsules with Roche Rocaltrol capsules in a single 1 microgram dose is summarized in Tables 2 and 3.

5.3 Preclinical Safety Data

Genotoxicity.

No data available.

Carcinogenicity.

Long-term animal studies have not been conducted to evaluate the carcinogenic potential of calcitriol. Sical is not mutagenic in vitro in the Ames test. No significant effects of calcitriol on fertility and/or general reproductive performances were observed in a study in rats at oral doses of up to 0.3 microgram/kg (approximately 3 times the maximum recommended dose based on body surface area).

6 Pharmaceutical Particulars

6.1 List of Excipients

Butylated hydroxyanisole, butylated hydroxytoluene, fractionated coconut oil, gelatin, glycerol, sorbitol solution (70 percent, non-crystallising), iron oxide red, iron oxide yellow and purified water.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C. Protect from light.

6.5 Nature and Contents of Container

Container type: blister pack (PVC/Al).
Pack size: 100 capsules.

Australian register of therapeutic goods (ARTG).

AUSTR 236776 - Sical calcitriol 0.25 microgram capsule blister pack.
Some strengths, pack sizes and/or pack types may not be marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking it to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.

Structural formula:
Chemical name: (5Z,7E)-9,10-secocholesta-5,7,10(19)-triene-1α,3β,25-triol.
Molecular formula: C27H44O3. Molecular weight: 416.65.
Calcitriol is a white, crystalline compound, which occurs naturally in humans. It is soluble in organic solvents but practically insoluble in water.

CAS number.

32222-06-3.

7 Medicine Schedule (Poisons Standard)

S4 (Prescription Only Medicine).

Summary Table of Changes