Consumer medicine information

APO-Calcitriol Capsules

Calcitriol

BRAND INFORMATION

Brand name

APO-Calcitriol

Active ingredient

Calcitriol

Schedule

What is in this leaflet

This leaflet answers some common questions about this medicine. 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 this medicine 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 this medicine is used for

The name of your medicine is APO-Calcitriol. It contains the active ingredient, calcitriol.

It is used to treat people with osteoporosis and to prevent osteoporosis in people taking oral corticosteroids.

It is also prescribed by doctors for the treatment of low blood calcium in patients with osteodystrophy (a form of bone disease), hypoparathyroidism (reduced function of the parathyroid glands) and rickets.

How it works

It works by improving absorption of calcium from the intestine and by stimulating growth of healthy bones.

Calcitriol occurs naturally in humans and is a biologically active form of vitamin D.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another purpose.

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

There is no evidence that this medicine is addictive.

Before you take this medicine

When you must not take it

Do not take this medicine if you have an allergy to:

calcitriol or any other medicine containing vitamin D compounds
any of the ingredients listed at the end of this leaflet

Symptoms of an allergic reaction may include:

cough, shortness of breath, wheezing or difficulty breathing
swelling of the face, lips, tongue, throat or other parts of the body
rash, itching or hives on the skin
fainting or hayfever-like symptoms

Do not take this medicine if have any of the following:

hypercalcaemia (high calcium levels in your blood)
vitamin D toxicity

Do not take this medicine if you are pregnant. It may affect your developing baby if you take it during pregnancy. Your doctor will discuss the risks and benefits of taking calcitriol when pregnant.

Do not breastfeed if you are taking this medicine. The active ingredient in this medicine passes into breast milk and there is a possibility that your baby may be affected.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any of the following medical conditions:

kidney problems
you are bedridden or in a wheelchair
vitamin D resistant rickets

Tell your doctor if you are pregnant or plan to become pregnant or are breastfeeding. Your doctor can discuss with you the risks and benefits involved.

If you have not told your doctor about any of the above, tell them before you start taking this medicine.

Taking other medicines

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

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

medicines, vitamin tablets or health supplements containing vitamin D or calcium
cholestyramine, used to lower cholesterol levels in the blood
antacids containing magnesium
sevelamer, used to lower phosphorous levels in your body
digoxin
thiazide diuretics
phenytoin
phenobarbital

These medicines may be affected by calcitriol 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 and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

How to take this medicine

How much to take

Your doctor will need to make regular measurements of the calcium level in your blood while you are taking this medicine.

Follow carefully all directions given to you by your doctor. Their instructions may be different to the information in this leaflet.

How to take it

Swallow capsules whole with a glass of water.

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

When to take it

Take your medicine at about the same time each day. Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

Calcitriol can be taken anytime of the day with or without food.

How long to take it for

Calcitriol is usually taken continuously for long term treatment.

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

Continue taking your medicine for as long as your doctor tells you.

If you forget to take it

If it is almost time to take your next dose, skip the dose you missed and take your next dose when you are meant to.

Otherwise, take it as soon as you remember and then go back to taking your medicine as you would normally.

Do not take a double dose to make up for the dose that you missed. This may increase the chance of you experiencing unwanted side effects.

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

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

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

While you are taking calcitriol

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking this medicine.

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine. It may affect other medicines used during surgery.

If you become pregnant or start to breastfeed while taking this medicine, tell your doctor immediately.

If you are about to have any blood tests, tell your doctor that you are taking this medicine. It may interfere with the results of some tests.

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.

Your doctor may occasionally do tests to make sure the medicine is working and to prevent side effects.

Go to your doctor regularly for a check-up.

CALCITRIOL & 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 experience weakness, feeling sick, vomiting, constipation, confusion and increased urination.

CALCITRIOL & 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 calcitriol. Your doctor will discuss your specific needs with you.

Things you must not do

Do not take this medicine to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Do not stop taking your medicine or lower the dosage without checking with your doctor.

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 calcitriol.

Side effects

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

All medicines can have side effects. Sometimes they are serious but most of the time they are not.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

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

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.

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. Other side effects not listed above may also occur in some patients and there may be some side effects not yet known.

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

Storage and disposal

Storage

Keep your medicine in its original packaging until it is time to take it. If you take your medicine out of its original packaging it may not keep well.

The capsule colour may change during storage. This does not affect the quality of the capsule.

Keep this medicine in a cool dry place where the temperature will stay below 25°C.

Do not store your medicine, or any other medicine, in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep this medicine where children cannot see or reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What APO- Calcitriol look like

APO-Calcitriol 0.25 microgram capsules are red coloured, oval soft gelatin capsules containing a clear oily liquid. AUST R 240872.

APO-Calcitriol is available in blisters of 100 capsules.

Ingredients

Each APO-Calcitriol capsule contains 0.25 micrograms of calcitriol as the active ingredient.

It also contains the following inactive ingredients:

butylated hydroxyanisole (320)
butylated hydroxytoluene (321)
coconut oil - fractionated
gelatin
glycerol
sorbitol and the colours iron oxide red and iron oxide yellow.

This medicine is gluten-free, lactose-free, sucrose-free, tartrazine-free and free of other azo dyes.

Sponsor

Apotex Pty Ltd
16 Giffnock Avenue
Macquarie Park NSW 2113
Australia

APO and APOTEX are registered trademarks of Apotex Inc.

This leaflet was last updated in July 2019.

Published by MIMS September 2019

BRAND INFORMATION

Brand name

APO-Calcitriol

Active ingredient

Calcitriol

Schedule

1 Name of Medicine

Calcitriol.

6.7 Physicochemical Properties

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

Chemical structure.

CAS number.

32222-06-3.

2 Qualitative and Quantitative Composition

Each APO-Calcitriol capsule contains 0.25 microgram of calcitriol as active ingredient.

Excipients with known effect.

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

3 Pharmaceutical Form

Red coloured, oval soft gelatin, capsules containing a clear oily liquid.

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 one of the most important active metabolites of vitamin D₃. It is normally formed in the kidney from its precursor 25-hydroxycholecalciferol (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 (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 α-hydroxylase (α-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.

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 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 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, 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.

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 picogram/mL at 4 hours, 50 ± 7.0 picogram/mL at 8 hours, 44 ± 4.6 picogram/mL at 12 hours and 41.5 ± 5.1 picogram/mL at 24 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 oxidized by CYP24A1.
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;
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 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 foetal circulation.

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. 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).

4 Clinical Particulars

4.1 Therapeutic Indications

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

4.3 Contraindications

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

4.4 Special Warnings and Precautions for Use

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 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 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 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.

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 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 calcitriol, serum calcium levels should be checked at least twice weekly (see Section 4.2 Dose and Method of 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 renal impairment.

Special care should be taken when administering calcitriol 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 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 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.

No data available.

Laboratory test results.

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

4.5 Interactions with Other Medicines and Other Forms of 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 APO-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 can reduce intestinal absorption of fat soluble vitamins; as such, it 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.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No data available.
(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 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.
Calcitriol 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 breastfeed while taking calcitriol.

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 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 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 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, polyuria, polydypsia, dehydration, apathy, growth retardation, anorexia, weight loss, 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 hyperphosphatemia of > 1.9 mmol/L calcinosis may occur; this can be seen radiographically.
The following adverse reactions have been reported in clinical trials involving calcitriol therapy.

Serious or life threatening reactions.

Severe dehydration.

More common reactions.

Metabolic.

Hypercalcaemia.

Central nervous system.

Drowsiness, weakness.

Gastrointestinal.

Nausea.

Less common reactions.

Dermatological.

Pruritus (associated with hypercalcaemia).

Gastrointestinal tract.

Diarrhoea, constipation.

Genitourinary.

Impairment of renal function.

Musculoskeletal.

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

Laboratory abnormalities.

In patients with normal renal function, chronic hypercalcaemia may be associated with an increase in serum creatinine.

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 http://www.tga.gov.au/reporting-problems and contact Apotex Medical Information Enquiries/Adverse Drug Reaction Reporting on 1800 195 055.

4.2 Dose and Method of Administration

APO-Calcitriol capsules are intended for oral administration.

Dosage.

General.

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.
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 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 calcitriol 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, 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.

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 oral prednisone.
Dietary calcium intake should not exceed 1000 mg/day (see Section 4.4 Special Warnings and Precautions for Use, Hypercalcaemia).

Other indications.

Uraemic 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 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 APO-Calcitriol may be needed.

Paediatric.

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

Geriatric.

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 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.

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.

4.9 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 calcitriol to patients in excess of their daily requirements can cause hypercalcaemia, hypercalciuria and hyperphosphatemia. 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 or 5.6 mmol²/L². In patients with uraemic osteodystrophy, high levels of calcium in the dialysate bath 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 calcitriol 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 APO-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, APO-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.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Butylated hydroxyanisole, butylated hydroxytoluene, gelatin, glycerol, sorbitol solution (70 percent) (noncrystallising), fractionated coconut oil, iron oxide red, iron oxide yellow.

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

Calcitriol 0.25 microgram capsules.

Bottles: HDPE bottles of 100 capsules. AUST R 128750.
Blisters: White opaque PVC/Al blisters of 100 capsules. AUST R 240872.
Not all pack types may be available.

6.6 Special Precautions for Disposal

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

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APO-Calcitriol 0.25 mcg Capsules