Calcitriol-AFT

New Zealand - English - Medsafe (Medicines Safety Authority)

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Active ingredient:
Calcitriol 0.25 µg;  
Available from:
AFT Pharmaceuticals Ltd
INN (International Name):
Calcitriol 0.25 µg
Dosage:
0.25 mcg
Pharmaceutical form:
Liquid filled capsule
Composition:
Active: Calcitriol 0.25 µg   Excipient: Ascorbyl palmitate Butylated hydroxyanisole Gelatin Glycerol Iron oxide red Medium-chain triglycerides Sodium ethyl hydroxybenzoate Sodium propyl hydroxybenzoate Sorbitol Titanium dioxide
Units in package:
Bottle, glass, Amber, 100 capsules, 100 capsules
Class:
Prescription
Prescription type:
Prescription
Manufactured by:
Cerbios-Pharma SA
Therapeutic indications:
- Established postmenopausal osteoporosis.
Product summary:
Package - Contents - Shelf Life: Bottle, glass, Amber, 100 capsules - 100 capsules - 24 months from date of manufacture stored at or below 25°C
Authorization number:
TT50-6976
Authorization date:
2002-09-26

Calcitriol-AFT

Calcitriol 0.25µg and 0.5µg soft gel capsules

What is in this leaflet

This leaflet answers some common questions about Calcitriol-AFT soft gel 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 your

taking Calcitriol-AFT 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 Calcitriol-AFT is used for

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

Calcitriol-AFT is used to treat people with postmenopausal osteoporosis (bone-

thinning) and to prevent osteoporosis in people taking oral corticosteroids. Calcitriol-

AFT is also for the treatment of low blood calcium in patients with renal

osteodystrophy

form

bone

disease

failure

kidneys),

hypoparathyroidism from various causes (reduced function of the parathyroid

glands), hyperparathyroidism (excessive levels of the parathyroid hormone in the

body) and rickets (Vitamin D deficiency).

Calcitriol-AFT works by improving absorption of calcium from the intestine and by

stimulating growth of healthy bones.

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

prescribed Calcitriol-AFT for another purpose.

Ask your doctor if you have any questions why Calcitriol-AFT has been

prescribed for you.

Before you take Calcitriol-AFT

When you must not take it

Do not take Calcitriol-AFT if:

you have had an allergic reaction to calcitriol or any other Vitamin D-like

substances, or any ingredients listed in the Ingredients section of this leaflet

you have high levels of calcium in your blood (called hypercalcaemia)

you have high levels of vitamin D in your blood

the package is torn or shows signs of tampering

the expiry date printed on the pack has passed

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

Before you start to take Calcitriol-AFT

You must tell your doctor if:

you are pregnant or plan to become pregnant.

It is not known whether Calcitriol-AFT is harmful to an unborn baby when taken

by a pregnant woman. If there is a need to take Calcitriol-AFT when you are

pregnant your doctor will discuss the risks and benefits to you and the unborn

baby.

you are breastfeeding or plan to breastfeed.

Mothers may breastfeed while taking Calcitriol-AFT provided that the blood

calcium levels of the mother and infant are monitored.

you have any other health problems, especially the following:

you are bedridden or in a wheelchair

kidney problems

Vitamin D resistant rickets (familial hypophosphataemia)

abnormal heartbeat

you are allergic to any other medicines, foods, dyes or preservatives

you are taking any other medicines including any that you have bought from a

pharmacy, supermarket or healthfood shop.

Some medicines may be affected by or interfere with how well Calcitriol-AFT works.

You may need to take different amounts of your medicine, or you may need to take

different medicines. Your doctor will advise you.

These medicines include:

medicines or vitamin tablets containing vitamin D or calcium

cholestyramine (Questran Light

if you are undergoing dialysis, antacids containing magnesium (e.g. Mylanta

Gastrogel

, Gaviscon

, Mucaine

digoxin (Lanoxin

thiazide diuretics (e.g. Chlotride

, Navidrex

, Neo-naclex

antihypertensives with thiazide diuretics (Accuretic

, Amizide

, Co-Renitec

Inhibace Plus

, Triamizide

phenytoin (Dilantin

phenobarbital (Gardenal

corticosteroids

taken

mouth

injection

prednisone,

prednisolone,

methylprednisolone, betamethasone, cortisone, dexamethasone, budesonide,

hydrocortisone, fludrocortisone.

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

How to use the Medicine

How much to take

Your doctor will tell you how much Calcitriol-AFT to take each day. Sometimes

Calcitriol-AFT does not need to be taken every day. This will vary depending on the

nature of your condition, the calcium level in your blood and your individual response

to the medicine.

Generally the daily dose for adults ranges from 0.25 to 1.00 micrograms

How to take it

Calcitriol-AFT capsules should be swallowed whole with a glass of water. Do not

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

When to take it

Calcitriol-AFT can be taken with or without food.

How long to take Calcitriol-AFT

Continue taking Calcitriol-AFT until your doctor tells you to stop.

If you forget to take Calcitriol-AFT

If it is almost time for 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 it as you

would normally.

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

If you have trouble remembering your dose, ask your pharmacist for some hints.

Things you must do

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

Calcitriol-AFT.

Tell your doctor if you become pregnant while taking Calcitriol-AFT.

Do not take any other medicines or dietary supplements whether they require a

prescription or not, without first telling your doctor. You must be especially

careful with medicines or dietary supplements that contain Vitamin D, calcium or

phosphate.

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 Calcitriol-AFT is not helping your condition.

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

be checked. Your doctor will need to make regular measurements of the calcium

level in your blood while you are taking Calcitriol-AFT.

Calcitriol-AFT 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 calcium containing foods, such as

dairy products, may lead to increased calcium in your blood. If this happens, you may

experience

weakness,

feeling

sick,

vomiting,

constipation,

confusion,

increased

urination, headache, loss of interest in everyday activities or loss of appetite.

Calcitriol-AFT and Laboratory Tests:

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

These are to check your blood calcium levels (and possibly some other blood factors)

while you are taking Calcitriol-AFT. Your doctor will discuss your specific needs with

you.

Things you must not do

Do not stop taking Calcitriol-AFT or change the dose without first checking

with your doctor.

Stopping suddenly can lead in a rapid fall in blood calcium levels.

Your doctor will tell you the best way to slowly reduce the amount of Calcitriol-AFT

you are taking before stopping completely.

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

Do not give Calcitriol-AFT to anyone else even if their symptoms seem similar to

yours.

Do not use Calcitriol-AFT to treat other complaints unless your doctor says to.

Things to be careful of

Be careful driving or operating machinery until you know how Calcitriol-AFT affects

you.

However, Calcitriol-AFT is not expected to affect your ability to drive a car or operate

machinery.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you

are taking Calcitriol-AFT.

Calcitriol-AFT helps most people but it may have unwanted side effects.

All medicines can have side effects. Sometimes they are serious. 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:

dehydration

rash, itchiness

nausea

loss of appetite

headache

stomach ache, constipation.

Tell you doctor immediately or go to your nearest Accident and Emergency centre if

you notice any of the following:

weakness, tiredness

vomiting

sight or hearing disturbances

confusion

fever and a dry mouth, thirst

frequent urination and/or pain on urination

loss of interest in everyday events

irregular heartbeat.

These are all symptoms of high levels of calcium in your blood. These may be

serious side effects and you may need urgent medical attention.

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.

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

if it is not on this list.

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

Overdose

Immediately telephone your doctor or National Poisons Information Centre

(telephone 0800 POISON or 0800 764 766) for advice or go to an Accident and

Emergency centre if you think that you or anyone else may have taken too

much Calcitriol-AFT, even if there are no signs of discomfort or poisoning. You

may need urgent medical attention.

The following are some symptoms, which may or may not occur:

loss of appetite

headache

vomiting

constipation

Keep telephone numbers for these places handy.

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

Storage

Keep your medicine in the original container until it is time to take it.

If you take the medicine out of the original container Calcitriol-AFT capsules may not

keep well.

Keep Calcitriol-AFT capsules in a cool dry place where the temperature stays

below 25°C.

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

them in the car or on window sills. Heat and moisture can destroy some medicines.

Keep Calcitriol-AFT 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.

Disposal

If your doctor tells you to stop taking Calcitriol-AFT, or it has passed its expiry date,

ask your pharmacist what to do with any medicine that is left over.

Other ingredients

capsule

shell

made

from

gelatin,

glycerol,

sorbitol,

sodium

ethyl-p-

hydroxybenzoate.

sodium

propyl-p-hydroxybenzoate

titanium

dioxide.

0.25µg strength capsule contains also contains red iron oxide as a colourant while

the 0.5µg strength capsule contains both red and yellow iron oxides as colourants.

Each

capsule

also

contains

butylated

hydroxyanisole

(BHA),

butylated

hydroxytoluene (BHT) and medium-chain triglycerides.

Distributor

New Zealand:

AFT Pharmaceuticals Ltd.,

Auckland

Date of Preparation:

19 November 2015

Page 1 of 8

NEW ZEALAND DATA SHEET

1.

CALCITRIOL – AFT

Calcitriol – AFT capsules 0.25 μg

Calcitriol – AFT capsules 0.5 μg

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Calcitrol – AFT 0.25 μg: Each capsule contains 0.25μg of synthetic calcitriol, a biologically active

form of vitamin D3.

Calcitrol – AFT 0.5 μg: Each capsule contains 0.25μg of synthetic calcitriol, a biologically active

form of vitamin D3.

Excipients with known effect:

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Capsule, liquid filled.

Calcitrol - AFT are oval, orange soft-gel capsules.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Established postmenopausal osteoporosis.

Renal osteodystrophy in patients with chronic renal failure, particularly those undergoing

haemodialysis.

Secondary hyperparathyroidism in patients with moderate to severe chronic renal failure (pre-

dialysis).

Postsurgical hypoparathyroidism.

Idiopathic hypoparathyroidism.

Pseudohypoparathyroidism.

Vitamin D-dependent rickets.

Hypophosphataemic vitamin D-resistant rickets.

Prevention of corticosteroid induced osteoporosis

4.2

Dose and method of administration

Standard dosage

The optimal daily dose of Calcitriol-AFT must be carefully determined for each patient on the basis

of the serum calcium level. Calcitriol-AFT therapy should always be started at the lowest possible

dose and should not be increased without careful monitoring of serum calcium (see Patient

monitoring).

Page 2 of 8

A prerequisite for optimal efficacy of Calcitriol-AFT is adequate but not excessive calcium intake

(in adults: approximately 800mg daily) at the beginning of therapy. Calcium supplements may be

necessary.

Because of improved calcium absorption from the gastrointestinal tract, some patients on Calcitriol-

AFT may be maintained on a lower calcium intake. Patients who tend to develop hypercalcaemia

may require only low doses of calcium or no supplementation at all.

The total daily calcium intake (i.e. from food, and, where applicable, from medicines) should

average approximately 800mg and should not exceed 1000mg.

Patient monitoring

During the stabilization phase of treatment with Calcitriol-AFT, serum calcium levels should be

checked at least twice weekly. When the optimal dosage of Calcitriol-AFT has been determined,

serum calcium levels should be checked every month (or as given below for individual indications).

Samples for serum calcium estimation should be taken without a tourniquet.

As soon as the serum calcium levels rise to 1 mg/100ml (250μmol/l) above normal (9 to 11mg/100

ml, or 2250-2750μmol/l), or serum creatinine rises to > 120μmol/l, treatment with Calcitriol-AFT

should be stopped immediately until normocalcaemia ensues.

During the periods of hypercalcaemia, serum calcium and phosphate levels must be determined

daily. When normal levels have been attained, the treatment with Calcitriol-AFT can be continued,

at a daily dose 0.25μg lower than that previously used. An estimate of daily dietary calcium intake

should be made and the intake adjusted when indicated.

Special dosage instructions

Postmenopausal osteoporosis

The recommended dosage for Calcitriol-AFT is 0.25μg twice daily.

Serum calcium and creatinine levels should be determined at 1, 3 and 6 months and at 6-month

intervals thereafter.

Renal osteodystrophy (dialysis patients)

The initial daily dose is 0.25μg. In patients with normal or only slightly reduced serum calcium

levels, doses of 0.25μg every other day are sufficient. If no satisfactory response in the biochemical

parameters and clinical manifestations of the disease is observed within 2 - 4 weeks, the daily

dosage may be increased by 0.25μg at two to

four-week intervals. During this period, serum calcium levels should be determined at least twice

weekly. Most patients respond to between 0.5μg and 1.0μg daily.

An oral Calcitriol-AFT pulse therapy with an initial dosage of 0.1μg/kg/week split into two or three

equal dosages given at night was found to be effective even in patients refractory to continuous

therapy. A maximum total cumulative dosage of 12μg per week should not be exceeded.

Secondary hyperparathyroidism (pre-dialysis patients)

recommended

initial

dosage

Calcitriol-AFT

treatment

secondary

hyperparathyroidism and resultant metabolic bone disease in patients with moderate to severe renal

failure i.e. creatinine clearance (Ccr) 15 to 55ml/min, is 0.25μg/day in adults and in paediatric

patients 3 years of age or older (corrected for a surface area of 1.73m2). This dosage may be

increased if necessary to 0.5μg/day.

Hypoparathyroidism, rickets

The recommended initial dose of Calcitriol-AFT is 0.25μg/day given in the morning. If a

satisfactory response in the biochemical parameters and clinical manifestations of the disease is not

observed, the dose may be increased at two to four-week intervals. During this period, serum

calcium levels should be determined at least twice weekly. If hypercalcaemia is noted, Calcitriol-

Page 3 of 8

AFT should be immediately discontinued until normocalcaemia ensues. Careful consideration

should also be given to lowering the dietary calcium intake.

Malabsorption is occasionally noted in patients with hypoparathyroidism; hence, larger doses of

Calcitriol-AFT may be needed.

If the physician decides to prescribe Calcitriol-AFT to a pregnant woman with hypoparathyroidism,

an increased dose may be required during the latter half of gestation, with dose reduction postpartum

or during lactation.

Prevention of corticosteroid induced osteoporosis

The recommended dosage range for the prevention of corticosteroid induced osteoporosis is 0.5-

0.75μg per day. Serum calcium and creatinine levels should be obtained at 2-4 weeks after initiating

treatment then at 3 and 6 months and every 6 months thereafter. If hypercalcaemia is noted, the

medicine should be immediately discontinued until normocalcemia ensues. While an adequate

dietary calcium intake is important, ordinarily it is more convenient to titrate medicine dosage

around the customary calcium intake of the patient.

Elderly patients

No specific dosage modifications are required in elderly patients. The general recommendations for

monitoring serum calcium and creatinine should be observed.

Infants and children

During the first 2 years of life, a daily dosage of 0.01-0.1μg/kg bodyweight is recommended as a

guideline.

4.3

Contraindications

Calcitriol-AFT is contraindicated in all diseases associated with hypercalcaemia.

Use of Calcitriol-AFT in patients with known hypersensitivity to calcitriol or medicines of the

same class and any of the constituent excipients is contraindicated.

Calcitriol-AFT is contraindicated if there is evidence of vitamin D toxicity.

4.4

Special warnings and precautions for use

There

close

correlation

between

treatment

with

calcitriol

development

hypercalcaemia. An abrupt increase in calcium intake as a result of changes in diet (e.g. increased

consumption of dairy products) or uncontrolled intake of calcium preparations may trigger

hypercalcaemia. Patients and their families should be advised that strict adherence to the prescribed

diet

mandatory

they

should

instructed

recognise

symptoms

hypercalcaemia. As soon as the serum calcium levels rise to 1mg/100 ml (250μmol/l) above normal

(9-11mg/100 ml, or 2250-2750μmol/l), or serum creatinine rises to >120μmol/l, treatment with

Calcitriol-AFT should be stopped immediately until normocalcaemia ensues (see Dosage and

Administration).

Immobilised patients, e.g. those who have undergone surgery, are particularly exposed to the risk

of hypercalcaemia.

Calcitriol increases inorganic phosphate levels in serum. While this is desirable in patients with

hypophosphatemia, caution is called for in patients with renal failure because of the danger of

ectopic calcification. In such cases, the plasma phosphate level should be maintained at the normal

level (2-5mg/100ml or 0.65-1.62mmol/l) by the oral administration of appropriate phosphate-

binding agents and low phosphate diet.

The serum calcium times phosphate (Ca x P) product should not be allowed to exceed 70mg2/dl2.

Patients with vitamin D-resistant rickets (familial hypophosphatemia) who are being treated with

Calcitriol-AFT must continue their oral phosphate therapy. However, possible stimulation of

Page 4 of 8

intestinal absorption of phosphate by Calcitriol-AFT should be taken into account since this effect

may modify the need for phosphate supplementation. The regular laboratory investigations that are

required

include

serum

determinations

calcium,

phosphorus,

magnesium

alkaline

phosphatase and of the calcium and phosphate content in 24-hour urine. During the stabilisation

phase of treatment with Calcitriol-AFT, serum calcium levels should be checked at least twice

weekly (see Dosage Administration).

Since calcitriol is the most effective vitamin D metabolite available, no other vitamin D preparation

should be prescribed during treatment with Calcitriol-AFT, thereby ensuring that the development

of hypervitaminosis D is avoided.

If the patient is switched from ergocalciferol (vitamin D2) to calcitriol, it may take several months

for the ergocalciferol level in the blood to return to the baseline value (see Overdosage).

Patients with normal renal function who are taking Calcitriol-AFT should avoid dehydration.

Adequate fluid intake should be maintained.

4.5

Interaction with other medicines and other forms of interaction

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-AFT to

avoid possible additive effects and hypercalcaemia.

Dietary instructions, especially concerning calcium supplements, should be strictly observed, and

uncontrolled intake of additional calcium-containing preparations avoided.

Concomitant treatment with a thiazide diuretic increases the risk of hypercalcaemia. Calcitriol

dosage

must

determined

with

care

patients

undergoing

treatment

with

digitalis,

hypercalcaemia

such

patients

precipitate

cardiac

arrhythmias

(see

Warnings

Precautions).

A relationship of functional antagonism exists between vitamin D analogues, which promote

calcium absorption, and corticosteroids, which inhibit it.

Magnesium-containing medicines (e.g. antacids) may cause hypermagnesemia and should therefore

not be taken during therapy with Calcitriol-AFT by patients on chronic renal dialysis.

Since Calcitriol-AFT 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 phosphate

concentration (normal values: 2-5mg/100ml, or 0.65-1.62mmol/l).

Patients with vitamin D-resistant rickets (familial hypophosphatemia) should continue their oral

phosphate therapy. However, possible stimulation of intestinal phosphate absorption by calcitriol

should be taken into account since this effect may modify the requirement for phosphate

supplements.

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 medicines are administered simultaneously.

Cholestyramine can reduce intestinal absorption of fat-soluble vitamins and therefore may impair

intestinal absorption of calcitriol.

4.6

Fertility, pregnancy and lactation

Category B3

Supravalvular aortic stenosis has been produced in foetuses by near-fatal oral doses of vitamin D

in pregnant rabbits. There is no evidence to suggest that vitamin D is teratogenic in humans even at

very high doses. Calcitriol-AFT should be used during pregnancy only if the benefits outweigh the

potential risk to the foetus.

It should be assumed that exogenous calcitriol passes into the breast milk. In view of the potential

for hypercalcaemia in the mother and for adverse reactions from Calcitriol-AFT in nursing infants,

mothers may breastfeed while taking Calcitriol-AFT, provided that the serum calcium levels of the

mother and infant are monitored.

Page 5 of 8

4.7

Effects on ability to drive and use machines

On the basis of the pharmacodynamic profile of reported adverse events, this product is presumed

to be safe or unlikely to adversely affect such activities.

4.8

Undesirable effects

Since calcitriol exerts vitamin D activity, adverse effects may occur which are similar to those found

when an excessive dose of vitamin D is taken, i.e. hypercalcaemia syndrome or calcium intoxication

(depending on the severity and duration of hypercalcaemia) (See Dosage and Administration and

Warnings and Precautions). Occasional acute symptoms include anorexia, headache, nausea,

vomiting, abdominal pain or stomach ache and constipation.

Because of the short biological half-life of calcitriol, pharmacokinetic investigations have shown

normalisation of elevated serum calcium within a few days of treatment withdrawal, i.e. much faster

than in treatment with vitamin D3 preparations.

Chronic effects may include dystrophy, sensory disturbances, fever with thirst, thirst/polydipsia,

polyuria, dehydration, apathy, arrested growth and urinary tract infections.

The number of adverse effects reported from clinical use of calcitriol over a period of 15 years in

all indications is very low with each individual effect, including hypercalcaemia, occurring at a rate

of 0.001% or less.

In concurrent hypercalcaemia and hyperphosphatemia of > 6mg/100ml or > 1.9mmol/l, soft-tissue

calcification may occur; this can be seen radiographically.

In patients with normal renal function, chronic hypercalcaemia may be associated with an increase

in serum creatinine.

Hypersensitivity reactions (pruritis, rash, urticaria, and very rarely severe erythematous skin

disorders) may occur in susceptible individuals.

4.9

Overdose

Treatment of asymptomatic hypercalcaemia: see Dosage and administration.

Since calcitriol is a derivative of vitamin D, the symptoms of overdose are the same as for an

overdose of vitamin D. Intake of high doses of calcium and phosphate together with Calcitriol-AFT

may give rise to similar symptoms. The serum calcium times phosphate (Ca x P) product should

not be allowed to exceed 70mg2/dl2. A high calcium level in the dialysate may contribute to the

development of hypercalcaemia.

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

Chronic symptoms: 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.

The following measures should be considered in treatment of accidental overdosage: immediate

gastric lavage or induction of vomiting to prevent further absorption. Administration of liquid

paraffin to promote faecal excretion. Repeated serum calcium determinations are advisable. If

elevated calcium levels persist in the serum, phosphates and corticosteroids may be administered

and measures instituted to bring about adequate diuresis.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

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 0.5-1.0μg and is somewhat higher during periods of increased bone synthesis (e.g.

growth or pregnancy). Calcitriol promotes intestinal absorption of calcium and regulates bone

mineralisation. The pharmacological effect of a single dose of calcitriol lasts about 3-5 days.

Page 6 of 8

The key role of calcitriol in the regulation of calcium homeostasis, which includes stimulating

effects on osteoblastic activity in the skeleton, provides a sound pharmacological basis for its

therapeutic effects in osteoporosis.

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, oral administration of Calcitriol-AFT normalises reduced

intestinal absorption of calcium, hypocalcaemia, increased serum alkaline phosphatase and serum

parathyroid hormone concentration. It alleviates bone and muscle pain and corrects the histological

alterations that occur in osteitis fibrosa and other mineralisation defects.

In patients with postsurgical hypoparathyroidism, idiopathic hypoparathyroidism, and pseudohypo-

parathyroidism, hypocalcaemia and its clinical manifestations are alleviated by Calcitriol-AFT

therapy.

In patients with vitamin D-dependent rickets, serum levels of calcitriol are low or absent. As the

endogenous production of calcitriol in the kidney is insufficient, Calcitriol-AFT is considered as a

replacement therapy.

In patients with vitamin D-resistant rickets and hypophosphatemia in whom plasma calcitriol levels

are reduced, treatment with Calcitriol-AFT reduces tubular elimination of phosphates and, in

conjunction with concurrent phosphate treatment, normalises bone development.

Patients with various other forms of rickets, e.g. in association with neonatal hepatitis, biliary

atresia, cystinosis and dietary calcium and vitamin D deficiency, have also benefited from

Calcitriol-AFT therapy.

The two known sites of action of calcitriol are intestine and bone.

A calcitriol receptor-binding protein appears to exist in the mucosa of human intestine. Additional

evidence suggests that calcitriol may also act on the kidney and the parathyroid glands. Calcitriol

is the most active known form of vitamin D3 in stimulating intestinal calcium transport. In acutely

uremic rats calcitriol has been shown to stimulate intestinal calcium absorption.

The kidneys of uremic patients cannot adequately synthesize calcitriol, the active hormone formed

from precursor Vitamin D. Resultant hypocalcaemia and secondary

hyperparathyroidism are a major cause of the metabolic bone disease of renal failure. However,

other bone-toxic substances which accumulate in uremia (e.g., aluminium) may also contribute.

The beneficial effect of Calcitriol-AFT in renal osteodystrophy appears to result from correction of

hypocalcaemia

secondary

hyperparathyroidism.

uncertain

whether

Calcitriol-AFT

produces other independent beneficial effects.

5.2

Pharmacokinetic properties

Absorption

Calcitriol is rapidly absorbed from the intestine. Peak serum concentrations following a single oral

dose

0.25-1.0μg

Calcitriol-AFT

were

found

within

hours.

Following

multiple

administration, serum calcitriol levels reached a steady state within 7 days, with a relationship to

the dose of calcitriol administered.

Distribution

After a single oral dose of 0.5μg Calcitriol-AFT, the average serum concentrations of calcitriol rose

from a baseline value of 40.0 ± 4.4pg/ml to 60.0 ± 4.4pg/ml after two hours, and then fell to 53.0 ±

6.9 after four hours, to 50.0 ± 7.0 after eight hours, to 44 ± 4.6 after twelve hours and to 41.5 ±

5.1pg/ml after 24 hours. During transport in the blood, calcitriol and other vitamin D metabolites

are bound to specific plasma proteins.

It can be assumed that exogenous calcitriol passes from the maternal blood into the foetal

bloodstream and breast milk.

Metabolism

Page 7 of 8

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-

trihydroxy-cholecalciferol,

1α,25R-dihydroxycholecalciferol-26,

23S-lactone,

1α,25S,26-

trihydroxycholecalciferol,

1α,25-dihydroxy-23-oxo-cholecalciferol,

1α,25R,26-trihydroxy-23-

oxo-cholecalciferol and 1α-hydroxy-23-carboxy-24,25,26,27-tetranorcholecalciferol.

Elimination

The elimination half-life of calcitriol in serum is 9 - 10 hours.

However, the pharmacological effect of a single dose of calcitriol lasts at least 7 days. Calcitriol is

excreted in the bile and is subject to enterohepatic circulation.

After i.v. administration of radioactive calcitriol in healthy subjects, about 27% of the radioactivity

is found in the faeces and about 7% in the urine within 24 hours.

After oral administration of 1μg radioactive calcitriol in healthy subjects, about 10% of the entire

radioactivity was found in the urine within 24 hours. On the sixth day after i.v. administration of

radioactive calcitriol, urine and faeces accounted for an average of 16% and 49% respectively of

the cumulative excretion of radioactivity.

Pharmacokinetics in special clinical situations

In patients with nephrotic syndrome or in those undergoing haemodialysis, serum levels of calcitriol

were reduced and time to peak levels was prolonged.

5.3

Preclinical safety data

Acute toxicity studies in mice and rats indicated that the oral approximate lethal dose of calcitriol

ranged from 1.35 to 3.9mg/kg. These values are several orders of magnitude higher than the

proposed clinical dose of 0.25μg twice daily (approximately 8 - 10ng/kg/day).

Subchronic toxicity studies in rats and dogs indicated that calcitriol at an oral dose of 20ng/kg/day

(twice the usual human dosage) for up to 6 months produced no or minimal adverse effects. A dose

of 80ng/kg/day (8 times the usual human dosage) for up to 6 months produced moderate adverse

effects; changes seen appeared to be primarily the result of prolonged hypercalcaemia.

Reproductive toxicity studies in rats indicated that oral doses up to 300ng/kg/day (30 times the

usual human dose) did not adversely affect reproduction. In rabbits, calcitriol produced some

maternal and foetotoxic effects at an oral dose of 300ng/kg/day, but did not show any adverse effect

at 20 or 80ng/kg/day (8 times the usual human dose).

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Capsule shell

Gelatin 69.45mg, glycerol 15.78mg, iron oxide red 0.368mg, sodium ethyl hydroxybenzoate

0.316mg, sodium propyl hydroxybenzoate 0.151mg, sorbitol 16.668mg (70% solution), titanium

dioxide 0.971 mg.

Other excipient

Acorbyl

palmitate

0.002mg,

butylated

hydroxyanisole

0.016mg,

medium-chain

triglycerides

160mg.

6.2

Incompatibilities

Not applicable.

Page 8 of 8

6.3

Shelf life

24 months.

6.4

Special precautions for storage

Do not store above 25°C. Store in the original container.

6.5

Nature and contents of container

Packs of 100 capsules.

6.6

Special precautions for disposal

No special requirements.

7.

MEDICINE SCHEDULE

Prescription medicine.

8.

SPONSOR

AFT Pharmaceuticals Ltd

PO Box 33-203

Takapuna

Auckland 0740

Phone: 0800 423 823

Email: customer.service@aftpharm.com

9.

DATE OF FIRST APPROVAL

12 January 2006

10.

DATE OF REVISION OF THE TEXT

25 February 2019

SUMMARY TABLE OF CHANGES

Date

Section(s)

Changed

Change (s)

February 2019

Reformat consistent with new Medsafe Data Sheet

Template.

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