Consumer medicine information

Kosteo

Calcitriol

BRAND INFORMATION

Brand name

Kosteo Capsules

Active ingredient

Calcitriol

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Kosteo.

What is in this leaflet

This leaflet answers some common questions about KOSTEO capsules. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking KOSTEO capsules against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine.

You may need to read it again.

What KOSTEO is used for

KOSTEO 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.

KOSTEO 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.

KOSTEO capsules are also prescribed for patients who have low blood calcium levels due to osteodystrophy (a type of bone disease), hypoparathyroidism (a condition where the parathyroid glands have decreased function) and rickets.

KOSTEO increases calcium absorption in the intestine and stimulates healthy bone growth.

There are many different types of medicines used to treat bone conditions. KOSTEO belongs to a group of medicines known as vitamin D compounds.

Your doctor may have prescribed this medicine for another purpose.

Ask your doctor if you have any questions why KOSTEO has been prescribed for you.

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

KOSTEO is not addictive.

Before you take KOSTEO

When you must not take it

Do not take KOSTEO if:

  • you have had an allergic reaction to KOSTEO, calcitriol or any ingredients listed in the Ingredients section of this leaflet
  • you have high blood calcium levels (hypercalcaemia)
  • you have vitamin D toxicity
  • you are breastfeeding or wish to breastfeed.
    KOSTEO may pass into the breastmilk and have unwanted effects in the baby.

Do not take KOSTEO if the package shows signs of tampering or if the capsules do not look quite right.

Do not take it if the expiry date (EXP) printed on the bottle has passed.

If you take this medicine after the expiry date has passed, it may not work as well.

If you are not sure if you should be taking KOSTEO, talk to your doctor.

Before you start to take it

You must tell your doctor if you are allergic to any other medicines, foods, dyes or preservatives

You must tell your doctor if you have any other health problems including:

  • kidney problems.
  • you are bedridden or in a wheelchair
  • Vitamin D resistant rickets
  • an abnormal heartbeat

You must tell your doctor if you are pregnant or intend to become pregnant.

Your doctor will discuss the risks and benefits of taking KOSTEO when pregnant.

If you have not told your doctor about any of the above, tell them before you take any KOSTEO.

Taking other medicines

Tell your doctor if you are taking any other medicines including any that you have bought from a pharmacy, supermarket or health food shop.

Some medicines and KOSTEO may interfere with each other. These include:

  • medicines, vitamin tablets or health supplements containing vitamin D or calcium
  • cholestyramine
  • antacids containing magnesium
  • digoxin
  • thiazide diuretics
  • phenytoin
  • phenobarbital
  • corticosteroids

These medicines may be affected by KOSTEO, or may affect how well it works. You may need to take different amounts of your medicine, or you may need to take different medicines. Your doctor will advise you.

Your doctor and pharmacist have a complete list of medicines to be careful with or avoid while taking KOSTEO.

Ask your doctor or pharmacist if you are not sure about this list of medicines.

Use in children

When children are taking KOSTEO for a long time, the dose should be well controlled and blood levels of calcium should be monitored so that kidney stones don’t develop.

How to take KOSTEO

How much to take

Your doctor will tell you how many KOSTEO 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 KOSTEO. Your doctor will need to make regular measurements of the calcium level in your blood while you are taking KOSTEO.

Capsules should be swallowed whole with a glass of water.

Do not open the capsules and do not take any capsules that are damaged.

When to take it

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

How long to take it for

KOSTEO is usually taken continuously for long term treatment.

Always tell your doctor if you want to stop taking KOSTEO, as stopping suddenly can lead to a rapid fall in calcium levels.

If you forget to take it

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 take too much (overdose)

Immediately telephone your doctor or Poisons Information Centre (telephone 13 11 26) for advice or go to Accident and Emergency at your nearest hospital if you think that you or anyone else may have taken too much KOSTEO, even if there are no signs of discomfort or poisoning.

You may need urgent medical attention. Signs of overdosage include loss of appetite, headache, excessive thirst, feeling sick, vomiting and constipation.

Keep telephone numbers for these places handy.

If you are not sure what to do, contact your doctor or pharmacist.

While you are taking it

Things you must do

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

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 KOSTEO.

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 KOSTEO capsules.

KOSTEO 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.

KOSTEO 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 KOSTEO. Your doctor will discuss your specific needs with you.

Things you must not do

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

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

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

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

Things to be careful of

Your ability to drive a car or operate machinery may be affected by medicines.

Normally, your ability to drive a car or operate machinery will not be affected by KOSTEO.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking KOSTEO.

KOSTEO helps most people but it may have unwanted side effects in a few. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Tell your doctor if you notice any of the following and they worry you:

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

These are all symptoms of high levels of calcium in your blood. If you experience any of these, tell your doctor immediately.

This is not a complete list of all possible side effects. Others may occur in some people and there may be some side effects not yet known.

Other side effects not listed above may also occur in some patients.

Tell your doctor if you notice anything else that is making you feel unwell.

Ask your doctor or pharmacist if you do not understand anything in this list.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

After using it

Disposal

Keep your capsules in the bottle until it is time to take them.

If you take the capsules out of the bottle they may not keep well.

Storage

Keep your medicine in a cool dry place where the temperature stays below 25°C.

Do not store it, or any other medicine, in a bathroom or near a sink.

Do not leave it in the car or on window sills.

Heat and dampness can destroy some medicines.

Keep KOSTEO where young children cannot reach it.

A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

If your doctor tells you to stop taking KOSTEO, or the capsules have passed their expiry date, ask your pharmacist what to do with any capsules that are left over.

Product description

What it looks like

KOSTEO 0.25 microgram capsules are oval and red in colour.

KOSTEO does not contain sucrose, gluten, tartrazine or any other azo dyes.

Ingredients

Active ingredient - calcitriol
Each KOSTEO capsule contains 0.25 micrograms of calcitriol.

Inactive ingredients -
The capsules also contain:

  • butylated hydroxyanisole (320)
  • butylated hydroxytoluene (321)
  • fractionated coconut oil
  • gelatin
  • glycerol
  • sorbitol and the colours titanium dioxide (C177891), iron oxide red (C177491) and iron oxide yellow (C177492).

KOSTEO is available in blister packs of 100 capsules.

Supplier

Arrow Pharma Pty Ltd
15 – 17 Chapel Street
Cremorne VIC 3121

Australian registration numbers:
AUST R 234863 (blister pack)

Date of revision: March 2017

BRAND INFORMATION

Brand name

Kosteo Capsules

Active ingredient

Calcitriol

Schedule

S4

 

Name of the medicine

Calcitriol.

Excipients.

Butylated hydroxyanisole, butylated hydroxytoluene, medium chain triglyceride, gelatin, glycerol, sorbitol (70%, noncrystallising), iron oxide red CI77491 and iron oxide yellow CI77492.

Description

Chemical name: 1,25-dihydroxycholecalciferol. Molecular formula: C27H44O3. MW: 416.65. CAS: 32222-06-3. Calcitriol is a white, crystalline compound, which occurs naturally in humans. It is soluble in organic solvents but practically insoluble in water.
Kosteo is available as soft gelatin capsules containing 0.25 microgram of calcitriol.

Pharmacology

Pharmacodynamics.

Calcitriol is the most important active metabolite of vitamin D3. It is normally formed in the kidney from its precursor 25-hydroxycholecalciferol (25-HCC). Physiological daily production is normally 0.5 to 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 (cholecalciferol). 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)2 D3 (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.

Pharmacokinetics.

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 calcitriol 0.25 to 1.0 microgram.
Peak plasma concentrations (above basal values) were reached within 2-6 hours following oral administration of a steady-state dose of 1 microgram/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 (SD) 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/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.

Several metabolites of calcitriol, each exerting different vitamin D activities, have been identified: 1α,25-dihydroxy-24-oxo-cholecalciferol, 1α,23,25-trihydroxy-24-oxo-cholecalciferol, 1α,24R,25-trihydroxycholecalciferol, 1α,25R-dihydroxycholecalciferol-26,23S-lactone, 1α,25S,26-trihydroxycholecalciferol, 1α25-dihydroxy-23-oxo-cholecalciferol, 1α25R,26-trihydroxy-23-oxo-cholecalciferol and 1α-hydroxy-23-carboxy-24,25,26,27-tetranorcholecalciferol. 1α,25R-dihydroxycholecalciferol-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 the 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 Kosteo capsules with Roche Rocaltrol capsules in a single 1 microgram dose is summarised in Tables 1 and 2.

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 threefold 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/day and vitamin D 400 IU 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 of calcitriol treatment. Dietary calcium was supplemented to 600 mg/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 0.25 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 to 1 microgram/day) and the calcitriol plus calcitonin group (n = 29, oral calcium 1000 mg/day, calcitriol 0.5 to 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 endpoint was bone mineral density measured at the lumbar spine, femoral neck and distal radius by photon absorptiometry. Serum levels of parathyroid hormone, 25hydroxyvitamin 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 rhinorrhea. Hypercalcaemia was seen in one placebo group patient, one calcitriol group patient and eight calcitriol plus calcitonin group patients. Other less frequently reported adverse events included rash, headache and gastrointestinal symptoms.

Indications

Kosteo is indicated for the treatment of established osteoporosis diagnosed by objective measuring techniques, such as densitometry, or by radiographic evidence of atraumatic fracture.
Kosteo 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.
Kosteo is indicated in the treatment of hypocalcaemia in patients with uraemic osteodystrophy, hypoparathyroidism and in hypophosphataemic rickets.

Contraindications

Hypercalcaemia or vitamin D toxicity.
Hypersensitivity to calcitriol or drugs of the same class, or any of the excipients in Kosteo.

Precautions

Concomitant therapy with other vitamin D compounds.

Since calcitriol 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 (see also Overdosage). 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 uraemic 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 Dosage and Administration, Information for the patient and Adverse Effects.)
In patients with normal renal function, chronic hypercalcaemia may be associated with an increase in serum creatinine.

Serum phosphate levels.

Calcitriol 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 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 calcitriol, serum calcium levels should be checked at least twice weekly (see Dosage and Administration, Laboratory monitoring).

Ectopic calcification.

Calcitriol 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 calcitriol 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 patients with impaired renal function.

Special care should be taken when administering calcitriol to patients with renal dysfunction. More frequent monitoring in these patients is appropriate (see Dosage and Administration).

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.

Use in elderly.

It is advised that in elderly patients suffering from ischaemic 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 elderly patients receive many other drugs and that their compliance may not be ideal.

Carcinogenicity/ mutagenicity.

Long-term animal studies have not been conducted to evaluate the carcinogenic potential of calcitriol. Calcitriol 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).

Use in pregnancy.

(Category B3)
There are no adequate and well controlled studies in pregnant women. Calcitriol 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 fetuses in 3 litters at these doses showed external and skeletal abnormalities. However, none of the other 23 litters (156 fetuses) 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.
Calcitriol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Australian categorisation definition of 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 fetus 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.

Use in lactation.

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 breastfeed while taking calcitriol.

Interactions

Since calcitriol is one of the most important active metabolites of vitamin D3, pharmacological doses of vitamin D and its derivatives should be withheld during treatment with calcitriol to avoid possible additive effects and hypercalcaemia.
In patients being treated for osteoporosis, calcium containing preparations should be avoided unless required for specific dietary purposes.
Bile acid sequestrants, including cholestyramine and sevelamer, have been reported to reduce intestinal absorption of fat soluble vitamins; as such, they may impair intestinal absorption of calcitriol.
A relationship of functional antagonism exists between vitamin D analogues, which promote calcium absorption, and corticosteroids, which inhibit it.
Magnesium containing antacids and calcitriol should not be used concomitantly, because such use may lead to the development of hypermagnesaemia.
Calcitriol 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 calcitriol 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 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.

Effect on laboratory tests.

Calcitriol affects serum calcium levels and serum phosphate levels (see Precautions, Hypercalcaemia and Serum phosphate levels and Dosage and Administration, Laboratory monitoring). It is essential that regular monitoring of serum calcium concentration be performed during therapy with calcitriol.

Adverse Effects

Since calcitriol exerts vitamin D activity in the body, adverse effects are, in general, similar to those encountered with excessive vitamin D intake.
Hypercalcaemia related to the 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 Precautions and Dosage and Administration).
Acute hypercalcaemia may give rise to cardiac arrhythmia and/or arrest.
Signs and symptoms of vitamin D intoxication associated with hypercalcaemia include the following.

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, sensory disturbances, pyrexia, thirst, dehydration, apathy, growth retardation, urinary tract infections, polyuria, polydipsia, anorexia, weight loss, nocturia, conjunctivitis (calcific), pancreatitis, photophobia, rhinorrhea, hyperthermia, decreased libido, elevated BUN, albuminuria, hypercholesterolaemia, elevated AST and ALT, ectopic calcification, hypertension, cardiac arrhythmias and, rarely, overt psychosis.
Prolonged chronic hypercalcaemia or concurrent hypercalcaemia and hyperphosphataemia of > 1.9 mmol/L can result in metastatic calcification of soft tissues; this can be seen radiographically.

Laboratory abnormalities.

In patients with normal renal function, chronic hypercalcaemia may be associated with an increase in serum creatinine.
The following adverse reactions have been reported in clinical trials involving calcitriol therapy.
The most commonly reported adverse reaction was hypercalcaemia. Patients may also experience hypercalciuria.

Serious or life threatening reactions.

Severe dehydration.

More common reactions.

Metabolic.

Hypercalcaemia.

Central nervous system.

Drowsiness, weakness, headache.

Gastrointestinal.

Nausea, abdominal pain.

Dermatological.

Rash.

Genitourinary.

Urinary tract infection.

Less common reactions.

Dermatological.

Pruritus (associated with hypercalcaemia).

Gastrointestinal tract.

Diarrhoea, constipation.

Genitourinary.

Impairment of renal function, vomiting, decreased appetite.

Musculoskeletal.

Metastatic or ectopic calcification.
Hypersensitivity reactions including rash, pruritus, erythema and urticaria may occur in susceptible individuals.

Uncommon.

Investigations.

Blood creatinine increased.

Post-marketing experience.

Frequency not known: hypersensitivity, urticaria, dehydration, polydipsia, apathy, muscular weakness, sensory disturbance, drowsiness, constipation, abdominal pain upper, diarrhoea, erythema, pruritus, growth retardation, polyuria, calcinosis, pyrexia, thirst, and weight decreased.

Dosage and Administration

The optimal daily dose of calcitriol must be carefully determined for each patient and indication. Dosage optimisation should be accompanied by regular monitoring of serum calcium concentration. If hypercalcaemia occurs, the drug should be immediately discontinued until normocalcaemia ensues.

Adults.

Osteoporosis.

Established osteoporosis.

The recommended dose of calcitriol 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 of oral prednisone.
Dietary calcium intake should not exceed 1000 mg/day (see Precautions, Hypercalcaemia).

Other indications.

Uremic osteodystrophy.

The recommended initial dose of calcitriol 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 calcitriol 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 calcitriol is 0.25 microgram/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 calcitriol may be needed.

Paediatric.

The safety and efficacy of calcitriol capsules in children have not been sufficiently investigated to enable dosing recommendations (see Precautions, Paediatric Use).

Geriatric.

No dosage adjustment is necessary in elderly patients. (See Precautions, 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 Precautions, Hypercalcaemia). Patients should also be informed of the symptoms of hypercalcaemia, which include weakness, nausea and vomiting.

Generally.

When the optimal dosage of calcitriol has been determined, the serum calcium levels should be checked regularly. As soon as serum calcium nears hypercalcaemic levels (1 mg/100 mL (0.25 mmol/L) above normal 9 to 11 mg/100 mL (2.25 to 2.75 mmol/L) on average), the dosage of calcitriol should be substantially reduced or treatment stopped altogether 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, calcitriol should be suspended immediately and serum calcium and phosphate levels must be determined daily. When normal levels have been attained, the treatment with calcitriol can be continued, at a daily dose 0.25 microgram lower than that previously used.

Laboratory monitoring.

For safety reasons, it is essential that regular monitoring of serum calcium concentration be performed during therapy with calcitriol. 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, uraemic 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.

Overdosage

Since calcitriol is a derivative of vitamin D, the symptoms of overdose are the same as for an overdose of vitamin D. Administration of calcitriol to patients in excess of their daily requirements can cause hypercalcaemia, hypercalciuria and hyperphosphataemia. High intake of calcium and phosphate concomitant with calcitriol may lead to similar abnormalities. 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 bath may contribute to the hypercalcaemia.

Symptoms.

Acute symptoms.

Acute symptoms of vitamin D intoxication include anorexia, headache, vomiting and constipation.

Chronic symptoms.

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 calcitriol should consist of general supportive measures. If drug ingestion is discovered within a relatively short time, induction of emesis or gastric lavage may be of benefit in preventing further absorption. 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 calcitriol 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, calcitriol 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.

Presentation

Kosteo is supplied as red coloured, soft gelatin capsules of 0.25 microgram in HDPE bottles* or PVC/Al blister packs of 100 capsules.
*Presentation not marketed.

Storage

Bottles.

Store below 25°C. Protect from light.

Blisters.

Store below 25°C. Protect from light.

Poison Schedule

S4.