ZEMPLAR 1 MICROGRAM

Israel - English - Ministry of Health

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Active ingredient:
PARICALCITOL
Available from:
ABBVIE BIOPHARMACEUTICALS LTD, ISRAEL
ATC code:
H05BX02
Pharmaceutical form:
CAPSULES
Composition:
PARICALCITOL 1 MCG
Administration route:
PER OS
Prescription type:
Required
Manufactured by:
ABBVIE LTD., UK
Therapeutic group:
PARICALCITOL
Therapeutic area:
PARICALCITOL
Therapeutic indications:
Zemplar is indicated for the prevention and treatment of secondary hyperparathyroidism associated with chronic renal insufficiency (chronic kidney disease stage 3 and 4 ) patients and chronic renal failure (chronic kidney disease stage 5) patients on haemodialysis or peritoneal dialysis.
Authorization number:
141 12 31816 00
Authorization date:
2014-06-30

Documents in other languages

Patient Information leaflet Patient Information leaflet - Arabic

22-01-2021

Patient Information leaflet Patient Information leaflet - Hebrew

11-08-2020

PATIENT PACKAGE INSERT IN ACCORDANCE

WITH THE PHARMACISTS’ REGULATIONS

)PREPARATIONS( – 1986

The medicine is dispensed with a doctor’s

prescription only

Zemplar 1 microgram

Soft capsules

The active ingredient and its quantity:

Each capsule of Zemplar 1 microgram )mcg( contains:

paricalcitol 1 microgram )mcg(

Inactive and allergenic ingredients – see section 6 “Further

information” in this leaflet.

Read the leaflet carefully in its entirety before using

the medicine. This leaflet contains concise information

about the medicine. If you have further questions, refer to

the doctor or pharmacist.

This medicine has been prescribed for the treatment of

your ailment/for you. Do not pass it on to others. It may harm

them, even if it seems to you that their ailment/medical

condition is similar.

1. WHAT IS THE MEDICINE INTENDED fOR?

The medicine is indicated for the prevention and treatment

of secondary hyperparathyroidism in patients who suffer

from chronic renal insufficiency )chronic kidney disease

at stage 3 or 4( or in patients suffering from renal failure

)chronic kidney disease stage 5( and undergoing

hemodialysis or peritoneal dialysis.

Therapeutic group: An anti-parathyroid agent.

This medicine is a synthetic form of active vitamin D.

Active vitamin D is required for the normal function of

many tissues in the body, including the parathyroid gland

and bones. In people who have normal kidney function,

this form of active vitamin D is produced naturally by the

kidneys, but in people with kidney failure, the production

of active vitamin D is markedly reduced.

Zemplar therefore provides a source of active vitamin D

when the body cannot produce enough active vitamin D,

and helps to prevent the consequences of low levels

of active vitamin D, namely, high levels of parathyroid

hormone, which may cause bone problems. Zemplar is

used in adult patients with chronic kidney disease )stages

3, 4 and 5(.

2. BEfORE USING THE MEDICINE

Do not use the medicine if:

you are sensitive )allergic( to the active ingredient

paricalcitol or to any of the additional ingredients

contained in the medicine )for a list of the inactive

ingredients, see section 6 “Further information”(.

you have very high levels of calcium or vitamin D in

your blood.

Your doctor can tell you if these conditions apply to you.

Special warnings regarding use of the medicine

Before treatment with Zemplar, it is important to limit

the amount of phosphorus in your diet.

Phosphate-binding medicines may be needed to control

phosphorus levels. If you are taking calcium-based

phosphate binders, the doctor may need to adjust the

dosage.

In some patients with chronic kidney disease stage 3

or 4, an increase in the blood levels of a substance called

creatinine has been observed. However, this increase

does not reflect a reduction in renal function.

Tests and follow-up

During the course of treatment with this medicine, blood

tests should be carried out in order to monitor your

treatment.

Children and adolescence

This medicine is not intended for children and adolescents

under 18 years of age.

Elderly patients

There is a limited amount of experience in using Zemplar

in patients aged 65 years or older. In general, no overall

differences in effectiveness or safety were seen between

patients aged 65 years or older and younger patients.

If you are taking, or have recently taken, other

medicines, including non-prescription medicines and

nutritional supplements, tell the doctor or pharmacist.

Some medicines can affect the activity of Zemplar or

increase the possibility of side effects.

It is particularly important to inform the doctor if you are

taking:

medicines used to treat fungal infections or oral thrush

)e.g., ketoconazole(

medicines used to treat high cholesterol levels

)e.g., cholestyramine(

medicines for treating heart problems or blood pressure

)e.g., digoxin and diuretics(

medicines containing a source of phosphate

)e.g., medicines to lower blood calcium levels(

medicines containing calcium or vitamin D, including

non-prescription

nutritional

supplements

multivitamins

medicines containing magnesium or aluminium

)e.g., certain types of medicines for indigestion )antacids(

and phosphate-binding medicines(

Use of the medicine and food

Zemplar can be taken with or without food.

Pregnancy and breastfeeding

If you are pregnant or breastfeeding, think you may be

pregnant or are planning to become pregnant, consult a

doctor or pharmacist before taking Zemplar.

There are no adequate data regarding use of paricalcitol

in pregnant women. The potential risk in of use in human

is not known. Therefore, paricalcitol should not be used

during pregnancy unless clearly necessary.

It is not known if paricalcitol passes into breast milk.

Consult the doctor before breastfeeding while taking

Zemplar.

Driving and operating machinery:

Zemplar should not affect your ability to drive or operate

machinery.

Important information about some of the ingredients

of Zemplar

The medicine contains a small amount of ethanol )alcohol(,

less than 100 mg per capsule. This amount may modify

or increase the effect of other medicines. This could

be harmful to people who suffer from liver disease,

alcoholism, epilepsy, brain injury or disease, to pregnant

or breastfeeding women and to children.

3. HOW SHOULD yOU USE THE MEDICINE?

Always use the preparation according to the doctor’s

instructions. Check with the doctor or pharmacist if

you are uncertain regarding the dosage and treatment

regimen of the preparation.

The dosage and treatment regimen will be determined

by the doctor only.

Gel capsules are soft and should therefore be swallowed

whole. Do not crush, pulverize or chew the capsules.

Do not exceed the recommended dose.

The doctor will use laboratory test results in order to

determine the dosage appropriate for you.

After starting treatment with Zemplar, the dosage

usually needs adjusting, depending on your response

to treatment.

Liver disease

If you have mild to moderate liver disease, there is no need

for dosage adjustment. However, there is no experience in

patients with severe liver disease.

If you accidentally take a higher dosage

Taking too high a dosage of Zemplar can cause an

abnormal increase in blood calcium levels; this condition

can be harmful.

If you took an overdose, or if a child has accidentally

swallowed the medicine, or if you experience one of

the side effects mentioned below, refer immediately to

a doctor, or proceed to a hospital emergency room and

bring the package of the medicine with you.

Symptoms which may occur immediately after taking

too high a dosage of Zemplar:

weakness and/or drowsiness

headache

nausea or vomiting

dry mouth

constipation

muscle or bone pain

metallic taste in the mouth

Symptoms which can develop over a longer period

of taking too much Zemplar include:

loss of appetite

drowsiness

weight loss

sore eyes

runny nose

itchy skin

feeling hot and feverish

loss of sex drive

severe abdominal pain )due to an inflamed pancreas(

kidney stones

changes in blood pressure

irregular heartbeat )palpitations(

blood and urine tests results can indicate high levels of

cholesterol, urea, nitrogen and liver enzymes

on rare occasions – mental changes, including: confusion,

drowsiness, insomnia or nervousness.

If you forget to take the medicine

Take a dose as soon as you remember. However, if it is

almost time for your next dose, skip the forgotten dose, and

take the next dose at the regular time. Do not take a double

dose to compensate for the forgotten dose.

Adhere to the treatment regimen as recommended by the

doctor. Even if there is an improvement in your health, do

not stop treatment with the medicine without consulting

the doctor or pharmacist.

If you stop taking the medicine

It is important to keep taking Zemplar as per the doctor’s

instructions, unless the doctor has instructed you to stop

treatment.

Do not take medicines in the dark! Check the label and

the dose each time you take medicine. Wear glasses

if you need them.

If you have further questions regarding use of the

medicine, consult the doctor or pharmacist.

4. SIDE EffECTS

As with any medicine, use of Zemplar may cause side

effects in some users. Do not be alarmed when reading

the list of side effects. You may not suffer from any of them.

Refer to the doctor immediately if you notice one of

the following side effects:

Allergic reactions )such as: shortness of breath, wheezing,

rash, itching, or swelling of the face or lips(.

∘ Common side effects )effects that occur in 1-10 in

100 users(:

increase in blood calcium levels

increase in blood calcium levels and, as a result,

increase in blood phosphate level )in patients with

advanced chronic kidney disease(

increase in blood phosphate levels

∘ Uncommon side effects )effects that occur in 1-10 in

1000 users(:

pneumonia )lung infection(

decreased levels of parathyroid hormone

decreased appetite

decreased levels of calcium

dizziness

unusual taste in the mouth

headache

irregular heartbeat

stomach discomfort or pain

constipation

diarrhea

nausea

dry mouth

heartburn )reflux or indigestion(

vomiting

acne

itchy skin

rash

allergic skin reactions )hives(

muscle cramps

muscle pain

breast tenderness

weakness

feeling tired, not feeling well

swelling in the legs

pain

increased levels of creatinine

changes in liver function tests

If a side effect occurs, if one of the side effects worsens

or if you suffer from a side effect not mentioned in the

leaflet, consult the doctor.

Reporting side effects

Side effects can be reported to the Ministry of Health

by clicking on the link “Report Side Effects of Drug

Treatment” found on the Ministry of Health homepage

)www.health.gov.il( that directs you to the online form for

reporting side effects, or by entering the link:

https://sideeffects.health.gov.il

5. HOW SHOULD THE MEDICINE BE STORED?

Avoid poisoning! This medicine, and any other medicine,

must be kept in a safe place out of the reach and sight

of children and/or infants to avoid poisoning. Do not

induce vomiting unless explicitly instructed to do so by

the doctor.

Do not use the medicine after the expiry date )exp. date(

that appears on the outer package and blister. The expiry

date refers to the last day of that month.

This medicine does not require special storage

conditions, but it is recommended to store it in a cool

and dry place.

Medicines that are no longer in use must not be disposed

via wastewater or household waste. Ask your pharmacist

how to dispose of medicines no longer required. These

measures will help to protect the environment.

6. fURTHER INfORMATION

In addition to the active ingredient, the medicine also

contains:

medium chain triglycerides, gelatin, glycerol anhydrous,

ethanol anhydrous, titanium dioxide, butylhydroxytoluene,

iron oxide black, purified water.

What the medicine looks like and the contents of the

package

The soft 1 mcg Zemplar capsules are oval and grey and

have ZA imprinted on them.

The soft capsules are packaged in a blister that contains 7

capsules. The blisters are packaged in a carton package.

There is a total of 7 or 28 capsules in one package.

License

holder

and

its

address:

AbbVie

Biopharmaceuticals Ltd., 4 Haharash St., Hod Hasharon,

Israel.

Manufacturer:

AbbVie Ltd., Vanwall Road, Maidenhead, Berkshire SL6

4UB, United Kingdom.

This leaflet was checked and approved by the Ministry

of Health in October 2015 and updated in accordance

with the Ministry of Health guidelines in March 2020.

Registration number of the medicine in the National

Drug Registry of the Ministry of Health:

141-12-31816

SH ZEM CAP APL MAR 2020

SH ZEM CAP APL MAR 2020

يئاود رادقم لوانت نم ةليوط ةرتف دعب روطتت دق يتلا ضارعلأا :رﻼﭙمز نم مزﻼلا نم ربكأ ماعطلل ةيهشلا ةلق ساعن نزولا ضافخنإ

نينيعلا يف ملاآ

حشر دلجلا يف ةكح ةعفترم ةنوخسو ةرارحب روعشلا

ةيسنجلا ةبغرلا نادقف )سايركنبلا باهتلإ ءارج( ةديدش ةينطب ملاآ

ىلكلا يف ىصح مدلا طغضب تاريغت )ناقفخ( ةمظتنم ريغ بلق تابرض ،لورتسلوكلا بسن يف عافترإ رهظ

ت نأ نكمي لوبلاو مدلا صوحف جئاتن دبكلا تاميزنإو نيجورتينلا ،ايرويلا .ةيبصع وأ قرأ ،ساعن ،كابترإ :لمشت ،ةيسفن تاريغت ـ ةردان تاقوأ يف ءاودلا لوانت تيسن اذإ لوانت دعوم برتقإ اذإ نكل ؛كركذت لاح ةيسنملا ةيئاودلا ةعرجلا لوانت بجي لوانتو ،ةيسنملا ةيئاودلا ةعرجلا تيوفت بجيف ،ةمداقلا ةيئاودلا ةعرجلا ةيئاود ةعرج لوانت زوجي لا .يدايتعلإا تقولا يف ةمداقلا ةيئاودلا ةعرجلا .ةيسنملا ةيئاودلا ةعرجلا نع ضيوعتلل ةفعاضم نع فقوتلا زوجي لا .بيبطلا هب ىصوأ امك جﻼعلا ىلع ةبظاوملا بجي نسحت أرط ولو ىتح ،يلديصلا وأ بيبطلا ةراشتسا نودب ءاودلاب جﻼعلا .ةيحصلا كتلاح ىلع ءاودلا لوانت نع تفقوت اذإ كاصوأ اذإ لاإ ،بيبطلا تاميلعت بسح رﻼﭙمز لوانت ىلع ةبظاوملا مهملا نم .جﻼعلا نع فقوتلاب بيبطلا دكأتلاو ءاودلا عباط صيخشت بجي

!

ةمتعلا

يف ةيودلأا

لوانت زوجي لا تاراظنلا عض . ءاود اهيف لوانتت ةرم لك يف يئاودلا رادقملا نم

. كلذ رملأا مزل اذإ ةيبطلا بيبطلا رشتسا ،ءاودلا لامعتسإ لوح ةيفاضإ ةلئسأ كيدل ترفوت اذإ .يلديصلا وأ ةيبناجلا ضارعلأا )4 ضعب دنع ةيبناج

اضارعأ ببسي دق رﻼﭙمز لامعتسإ نإ ،ءاود لكب امك يناعت لاأ زئاجلا نم .ةيبناجلا ضارعلأا ةمئاق نم شهدنت لا .نيلمعتسملا .اهنم

ايأ ضارعلأا ىدحإ روهظ ظحﻼت تنك اذإ بيبطلا ىلإ

ً

لااح هجوتلا بجي :ةيلاتلا ةيبناجلا خافتنإ وأ ةكح ،حفط ،ريفص ،سفنتلا يف قيض :لثم( ةيسسحت لعف دودر .)نيتفشلا يف وأ هجولا يف نيلمعتسم 1-10 ىدل رهظت ضارعأ( )common( ةعئاش ةيبناج ضارعأ

:)100 نيب نم مدلا يف مويسلاكلا بسن عافترإ

روفسوفلا ةبسن عافترإ كلذل ةجيتنو مدلا يف مويسلاكلا بسن عافترإ

)مدقتم نمزم يولك ضرم نم نوناعي نيذلا ىضرملا ىدل( مدلا يف مدلا يف روفسوفلا بسن عافترإ

1-10 ىدل رهظت ضارعأ( )uncommon( ةعئاش ريغ ةيبناج ضارعأ

:)1000 نيب نم نيلمعتسم نيتئرلا باهتلإ

ةيقردلا ةريظن ةدغ نومروه ةبسن يف ضافخنإ

ماعطلل ةيهشلا ةلق مويسلاكلا بسن يف ضافخنإ

راود مفلا يف فلتخم قاذم عادص بلقلا مظن ماظتنإ مدع نطبلا يف ملأ وأ نطبلا يف جاعزنإ

كاسمإ

لاهسإ

نايثغ مفلا يف فافج )مضه رسع وأ دادترإ( ناقرح تاؤيقت بابشلا بح دلجلا يف ةكح حفط )ىرش( يدلج يسسحت لعف در ةيلضع تاصلقت تﻼضعلا يف ملأ

نييدثلا يف ةيساسح فعض ديج ريغ ماع روعش ،قاهرإب روعشلا

نيلجرلا يف خافتنإ

ملأ

نينيتايريكلا بسن يف عافترإ

دبكلا فئاظو صحف يف تاريغت امدنع وأ ،ةيبناجلا ضارعلأا ىدحإ تمقافت اذإ ،يبناج ضرع رهظ اذإ ةراشتسإ كيلع ،ةرشنلا هذه يف ركذي مل يبناج ضرع نم يناعت .بيبطلا ةيبناج ضارعأ نع غيلبتلا ىلع طغضلا ةطساوب ةحصلا ةرازول ةيبناج ضارعأ نع غيلبتلا ناكملإاب ةحفصلا ىلع دوجوملا »يئاود جﻼع بقع ةيبناج ضارعأ نع غيلبت« طبارلا ىلإ كهجوي يذلا )www.health.gov.il( ةحصلا ةرازو عقومل ةيسيئرلا :طبارلا حفصت قيرط نع وأ ،ةيبناج ضارعأ نع غيلبتلل رشابملا جذومنلا

https://sideeffects.health.gov.il

؟ءاودلا نيزخت ةيفيك )5 قلغم ناكم يف رخآ ءاود لكو ءاودلا اذه ظفح بجي ! ممستلا بنجت

يدافتل كلذو

،عضرلا وأ/و لافطلأا ةيؤر لاجمو يديأ لوانتم نع

اديعب . بيبطلا نم ةحيرص تاميلعت نودب ؤيقتلا

ببست لا . ممستلاب مهتباصإ )exp. date( ةيحﻼصلا خيرات ءاضقنإ دعب ءاودلا لامعتسإ زوجي لا خيرات ريشي .)رتسيلب( ةحيوللاو ةيجراخلا ةبلعلا رهظ ىلع رهظي يذلا .رهشلا سفن نم ريخلأا مويلا ىلإ ةيحﻼصلا هنيزختب ىصوي كلذ عم ،نيزختلل ةصاخ طورش ىلإ جاتحي لا ءاودلا اذه .فاجو دراب ناكم يف .ةيتيبلا ةمامقلل وأ يراجملا ىلإ ةلمعتسملا ريغ ةيودلأا يمر زوجي لا اهل ةجاح لا ةيودأ نم صلختلا ةيفيك نع كب صاخلا يلديصلا لأسإ .ةئيبلا ىلع ظافحلا يف دعاست كلذب .دعب ةيفاضإ تامولعم )6 :ىلع

اضيأ ةلاعفلا ةداملل ةفاضلإاب ءاودلا يوتحي

medium chain triglycerides, gelatin, glycerol

anhydrous, ethanol anhydrous, titanium dioxide,

butylhydroxytoluene, iron oxide black, purified water.

ةبلعلا ىوتحم وه امو ءاودلا ودبي فيك

يدامر اهنول ،يوضيب اهلكش مارغوركيم 1 رﻼﭙمز نم ةنيللا تلاوسبكلا

.ZA اهيلع عوبطمو .تلاوسبك 7 يوحت )رتسيلب( ةحيول ةوبع نمض ةأبعم ةنيللا تلاوسبكلا

ةبلعب ةلوسبك 28 وأ 7

ايلامجإ .نوترك ةبلع نمض ةأبعم تاحيوللا .ةدحاو AbbVie Biopharmaceuticals :هناونعو زايتملإا بحاص .ليئارسإ ،نوراشه دوه ،4 شاراحاه عراش ،Ltd. :جتنملا مسإ

AbbVie Ltd., Vanwall Road, Maidenhead, Berkshire

SL6 4UB, United Kingdom.

نيرشت خيرات يف ةحصلا ةرازو لبق نم ت

رقأو ةرشنلا هذه تصح

ف خيرات يف ةحصلا ةرازو تاميلعت بجومب اهثيدحت متو 2015 لولأا .2020 راذآ :ةحصلا ةرازو يف يموكحلا ةيودلأا لجس يف ءاودلا لجس مقر

141-12-31816

.ركذملا ةغيصب ةرشنلا هذه ةغايص تمت ،ةءارقلا نيوهتو ةلوهس لجأ نم .نيسنجلا ﻼكل صصخم ءاودلا نإف ،كلذ نم مغرلا ىلع

Zem Cap_API_Mar_2020_CL

Zemplar 1 microgram

Soft Capsules

Prescribing Information

NAME OF THE MEDICINAL PRODUCT

Zemplar 1 microgram capsules, soft

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule of Zemplar 1 microgram contains 1 microgram of paricalcitol.

Excipient with known effect:

Each capsule of Zemplar 1 microgram contains 0.71 mg of ethanol.

For the full list of excipients, see section 6.1.

PHARMACEUTICAL FORM

Capsule, soft

1 microgram capsule: oval, grey soft capsule imprinted with ZA

CLINICAL PARTICULARS

Therapeutic indications

Zemplar is indicated for the prevention and treatment of secondary hyperparathyroidism

associated with chronic renal insufficiency (chronic kidney disease Stages 3 and 4) patients and

chronic renal failure (chronic kidney disease Stage 5) patients on haemodialysis or peritoneal

dialysis.

Posology and method of administration

Posology

Chronic Kidney Disease (CKD) Stages 3 and 4

Zemplar should be administered once a day, either daily or three times a week taken every other

day.

Initial dose

Zem Cap_API_Mar_2020_CL

The initial dose is based on baseline intact parathyroid hormone (iPTH) levels.

Table 1. Initial Dose

Baseline iPTH Level

Daily Dose

Three Times a Week Dose

≤ 500 pg/ml (56 pmol/l)

1 microgram

2 micrograms

> 500 pg/ml (56 pmol/l)

2 micrograms

4 micrograms

To be administered no more frequently than every other day

Dose titration

Dosing must be individualised based on serum or plasma iPTH levels, with monitoring of serum

calcium and serum phosphorus. Table 2 presents a suggested approach for dose titration.

Table 2. Dose Titration

iPTH Level Relative to Baseline

Dose Adjustment at 2 to 4 Week Intervals

Daily Dose

Three Times a Week Dose

The same or increased

Increase

1 microgram

Increase

2 micrograms

Decreased by < 30%

Decreased by ≥30%, ≤60%

Maintain

Maintain

Decreased > 60%

Decrease

1 microgram

Decrease

2 micrograms

iPTH < 60 pg/ml (7 pmol/l)

To be administered no more frequently than every other day.

If a patient is taking the lowest dose on the daily or three times a week regimen, and a dose

reduction is needed, dosing frequency can be decreased.

Serum calcium levels should be closely monitored after initiation of the treatment and during

dose titration periods. If hypercalcaemia or a persistently elevated calcium- phosphate product

greater than 55 mg

(4.4 mmol

) is observed, the dose of calcium based phosphate binders

should be reduced or withheld. Alternatively, the dose of Zemplar may be reduced or temporarily

interrupted. If interrupted, the drug should be restarted at a lower dose, when serum calcium and

calcium- phosphate product are in the target range.

Chronic Kidney Disease (CKD), Stage 5

Zemplar should be administered three times a week every other day.

Initial dose

The initial dose of Zemplar in micrograms is based on a baseline iPTH level (pg/ml)/60

[(pmol/l)/7], up to an initial maximum dose of 32 micrograms.

Dose titration

Zem Cap_API_Mar_2020_CL

Subsequent dosing should be individualised and based on iPTH, serum calcium and phosphorus

levels. A suggested dose titration of paricalcitol capsules is based on the following formula:

Serum calcium and phosphorus levels should be closely monitored after initiation, during dose

titration periods, and with co-administration of strong P450 3A inhibitors. If an elevated serum

calcium or elevated Ca x P is observed and the patient is on a calcium-based phosphate binder,

the binder dose may be decreased or withheld, or the patient may be switched to a non-calcium-

based phosphate binder.

If serum calcium > 11.0 mg/dl (2.8 mmol/l) or Ca x P > 70 mg

(5.6 mmol

) or iPTH

pg/ml, the dose should be decreased by 2 to 4 micrograms with respect to that calculated by the

most recent iPTH/60 (pg/ml) [iPTH/7 (pmol/l)]. If further adjustment is required, the dose of

paricalcitol capsules should be reduced or interrupted until these parameters are normalised.

As iPTH approaches the target range (150-300 pg/ml), small, individualised dose adjustments

may be necessary in order to achieve a stable iPTH. In situations where monitoring of iPTH, Ca

or P occurs less frequently than once per week, a more modest initial and dose titration ratio may

be warranted.

Special populations

Hepatic impairment

No dose adjustment is required in patients with mild to moderate hepatic impairment.

There is no experience in patients with severe hepatic impairment (see section 5.2).

Renal transplant

Post-renal transplant patients with CKD Stages 3 and 4 and secondary hyperparathyroidism were

not studied in phase 3 clinical trials. Based on the published literature, the initial dose and dose-

titration algorithm for patients with post-transplant CKD Stages 3 and 4 and secondary

hyperparathyroidism is the same as for patients with native CKD Stages 3 and 4 and secondary

hyperparathyroidism. Serum calcium and phosphorus levels should be closely monitored after

initiation, during dose titration periods, and with co-administration of strong cytochrome P450 3A

inhibitors.

Paediatric population

Zemplar is not indicated for children and adolescents below 18 years of age.

Elderly

Zem Cap_API_Mar_2020_CL

No overall differences in safety and effectiveness were observed between elderly patients (65-75

years) with regard to younger patients, but greater sensitivity of some older individuals cannot be

ruled out.

Method of administration

Zemplar can be taken with or without food.

Contraindications

Paricalcitol should not be given to patients with evidence of vitamin D toxicity, hypercalcaemia,

or hypersensitivity to paricalcitol or any of the excipients listed in section 6.1.

Special warnings and precautions for use

Over suppression of parathyroid hormone may result in elevations of serum calcium levels and

may lead to low-turnover bone disease. Patient monitoring and individualised dose titration is

required to reach appropriate physiological endpoints.

If clinically significant hypercalcaemia develops and the patient is receiving a calcium-based

phosphate binder, the dose of the calcium-based phosphate binder should be reduced or

interrupted.

Chronic hypercalcaemia may be associated with generalized vascular calcification and other soft

tissue calcification.

Phosphate or vitamin D-related medicinal products should not be taken concomitantly with

paricalcitol due to an increased risk of hypercalcaemia and Ca x P product elevation (see section

4.5).

Digitalis toxicity is potentiated by hypercalcaemia of any cause, so caution should be applied

when digitalis is prescribed concomitantly with paricalcitol (see section 4.5).

In pre-dialysis patients, paricalcitol, like other vitamin D receptor activators, may increase

serum creatinine (and therefore decrease the estimated GFR [eGFR]) without changing true

glomerular filtration rate (GFR).

Caution should be exercised if co-administering paricalcitol with ketoconazole (see section 4.5).

Warning for excipients

This medicinal product contains small amounts of ethanol (alcohol), less than 100 mg per 1

microgram, capsule which may be harmful to those suffering from alcoholism (refer to sections

2 and 4.2). To be taken into account in pregnant or breast-feeding women, children and high risk

groups such as patients with liver disease or epilepsy.

Interaction with other medicinal products and other forms of interaction

Ketoconazole

Zem Cap_API_Mar_2020_CL

Ketoconazole is known to be a nonspecific inhibitor of several cytochrome P450 enzymes. The

available in vivo and in vitro data suggest that ketoconazole may interact with enzymes that are

responsible for the metabolism of paricalcitol and other vitamin D analogs. Caution should be

taken while dosing paricalcitol with ketoconazole.The effect of multiple doses of ketaconazole

administered as 200 mg, twice daily (BID) for 5 days on the pharmacokinetics of paricalcitol

capsule has been studied in healthy subjects. The Cmax of paricalcitol was minimally affected,

but AUC0-

approximately doubled in the presence of ketoconazole. The mean half-life of

paricalcitol was 17.0 hours in the presence of ketoconazole as compared to 9.8 hours, when

paricalcitol was administered alone (see PRECAUTIONS section 4.4). The results of this study

indicate that following either oral or intravenous administration of paricalcitol the maximum

amplification of the paricalcitol AUCINF from a drug interaction with ketoconazole is not likely

to be greater than about two-fold.

Specific interaction studies were not performed. Digitalis toxicity is potentiated by

hypercalcaemia of any cause, so caution should be applied when digitalis is prescribed

concomitantly with paricalcitol.

Phosphate or vitamin D-related medicinal products should not be taken concomitantly with

paricalcitol due to an increased risk of hypercalcaemia and Ca x P product elevation (see section

4.4).

High doses of calcium-containing preparation or thiazide diuretics may increase the risk of

hypercalcaemia.

Magnesium-containing preparations (e.g. antacids) should not be taken concomitantly with

vitamin D preparations, because hypermagnesemia may occur.

Aluminium-containing preparations (e.g. antacids, phosphate-binders) should not be administered

chronically with Vitamin D medicinal products, as increased blood levels of aluminium and

aluminium bone toxicity may occur.

Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may

interfere with the absorption of Zemplar capsules.

Pregnancy and Lactation

Pregnancy

There are no adequate data on the use of paricalcitol in pregnant women. Animal studies have

shown reproductive toxicity (see section 5.3). Potential risk in human use is not known, therefore

paricalcitol should be not be used unless clearly necessary.

Breastfeeding

It is not known whether paricalcitol is excreted in human milk. Animal studies have shown

excretion of paricalcitol or its metabolites in breast milk, in small amounts. A decision on

whether to continue/discontinue breast-feeding or to continue/discontinue therapy with Zemplar

should be made taking into account the benefit of breast-feeding to the child and the benefit of

Zemplar therapy to the woman.

Effects on ability to drive and use machines

Zem Cap_API_Mar_2020_CL

Zemplar has negligible influence on ability to drive and use machines.

Undesirable effects

Summary of the safety profile

The safety of paricalcitol capsules has been evaluated in three 24-week, double-blind, placebo-

controlled, multi-centre clinical trials involving 220 CKD Stage 3 and 4 adult patients and in one

12-week, double-blind, placebo-controlled, multi-centre clinical trial involving 88 CKD Stage 5

adult patients. In addition, there is postmarketing experience with paricalcitol capsules from three

additional studies, and paediatric experience from two studies. The most commonly reported

adverse reactions for paricalcitol treated patients were hypercalcaemia and calcium phosphate

product increased.

In the Stage 3/4 and Stage 5 clinical trials, the incidence of hypercalcaemia was Zemplar (3/167,

2%) vs placebo (0/137, 0%) and elevated calcium phosphate product was Zemplar (19/167, 11%)

vs placebo (8/137, 6%).

Tabulated list of adverse reactions

All adverse reactions associated with Zemplar capsules are displayed in Table 3 by MedDRA

System Organ Class, Preferred Term and frequency. The following frequency groupings are used:

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).

Table 3: Adverse Reactions Reported With Zemplar Capsules in Clinical Trials and From Post

Marketing Experience

Zem Cap_API_Mar_2020_CL

System Organ Class

Frequency

Adverse Reaction

Infections and infestations

Uncommon

Pneumonia

Immune system disorders

Uncommon

Hypersensitivity

Not known

ngioedema, laryngeal oedema

Endocrine Disorders

Uncommon

Hypoparathyroidism

Metabolism and nutrition

disorders

Common

Hypercalcaemia,

hyperphosphataemia

Uncommon

Decreased appetite, hypocalcaemia

Nervous system disorders

Uncommon

Dizziness, dysgeusia, headache

Cardiac disorders

Uncommon

Palpitations

Gastrointestinal disorders

Uncommon

Abdominal discomfort, abdominal

pain upper, constipation, diarrhoea,

dry mouth, gastroesophageal reflux

disease, nausea, vomiting

Skin and subcutaneous tissue

disorders

Uncommon

Acne, pruritus, rash, urticaria

Musculoskeletal and connective

tissue disorders

Uncommon

Muscle spasms, myalgia

Reproductive system and breast

disorders

Uncommon

Breast tenderness

General disorders and

administration site conditions

Uncommon

sthenia, malaise, oedema

peripheral, pain

Investigations

Common

Calcium phosphate product

increased

Uncommon

Blood creatinine increased

, hepatic

enzyme abnormal

*Frequencies for adverse reactions from post marketing experience cannot be estimated and have

been reported as “Not Known.”

This adverse reaction has been observed in studies in predialysis patients (see also section 4.4).

Reporting of suspected adverse reactions

Any suspected adverse events should be reported to the Ministry of Health according to the

National Regulation by using an online form:

https://sideeffects.health.gov.il

Overdose

Excessive administration of Zemplar capsules can cause hypercalcaemia, hypercalciuria,

hyperphosphataemia, and over suppression of parathyroid hormone. High intake of calcium and

phosphate concomitant with Zemplar capsules may lead to similar abnormalities.

Zem Cap_API_Mar_2020_CL

Treatment of patients with clinically significant hypercalcaemia consists of immediate dose

reduction or interruption of paricalcitol therapy and includes a low calcium diet, withdrawal of

calcium supplements, patient mobilisation, attention to fluid and electrolyte imbalances,

assessment of electrocardiographic abnormalities (critical in patients receiving digitalis), and

haemodialysis or peritoneal dialysis against a calcium-free dialysate, as warranted.

Signs and symptoms of vitamin D intoxication associated with hypercalcaemia include:

Early: Weakness, headache, somnolence, nausea, vomiting, dry mouth, constipation, muscle pain,

bone pain and metallic taste.

Late: Anorexia, weight loss, conjunctivitis (calcific), pancreatitis, photophobia, rhinorrhoea,

pruritus, hyperthermia, decreased libido, elevated BUN, hypercholesterolaemia, elevated AST

and ALT, ectopic calcification, hypertension, cardiac arrhythmias, somnolence, death and rarely,

overt psychosis.

Serum calcium levels should be monitored frequently until normocalcaemia ensues.

Paricalcitol is not significantly removed by dialysis.

PHARMACOLOGICAL PROPERTIES

Pharmacodynamic properties

Pharmacotherapeutic group: Anti-parathyroid agents, ATC code: H05BX02.

Mechanism of Action

Paricalcitol is a synthetic, biologically active vitamin D analog of calcitriol with modifications to

the side chain (D

) and the A (19-nor) ring. Unlike calcitriol, paricalcitol is a selective vitamin D

receptor(VDR) activator. Paricalcitol selectively upregulates the VDR in the parathyroid glands

without

increasing VDR in the intestine and is less active on bone resorption

Paricalcitol also upregulates the calcium sensing receptor in the parathyroid glands. As a result,

paricalcitol reduces parathyroid hormone (PTH) levels by inhibiting parathyroid proliferation and

decreasing PTH synthesis and secretion, with minimal impact on calcium and phosphorus levels,

and can act directly on bone cells to maintain bone volume and improve mineralization surfaces.

Correcting abnormal PTH levels, with normalisation of calcium and phosphorus homeostasis,

may prevent or treat the metabolic bone disease associated with chronic kidney disease.

Clinical Efficacy

Chronic Kidney Disease, Stages 3-4

The primary efficacy endpoint of at least two consecutive

30 % reductions from baseline iPTH

was achieved by 91% of paricalcitol capsules-treated patients and 13% of the placebo patients

(p<0.001). Serum bone specific alkaline phosphatase like serum osteocalcin were significantly

reduced (p<0.001) in patients treated with paricalcitol capsules compared to placebo, which is

associated with a correction of the high bone turnover due to secondary hyperparathyroidism. No

Zem Cap_API_Mar_2020_CL

deterioration in the kidney function parameters of estimated glomerular filtration rate (via MDRD

formula) and serum creatinine was detected in paricalcitol capsules treated patients in comparison

to placebo treated patients. Significantly more of paricalcitol capsules treated patients

experienced a reduction in urinary protein, as measured by semi quantitative dipstick, compared

to placebo treated patients.

Chronic kidney disease, Stage 5

The primary efficacy endpoint of at least two consecutive

30 % reductions from baseline iPTH

was achieved by 88% of paricalcitol capsules treated patients and 13% of the placebo patients (p

< 0.001).

Pharmacokinetic properties

Absorption

Paricalcitol is well absorbed. In healthy adult subjects, following oral administration of

paricalcitol at 0.24 micrograms/kg, the mean absolute bioavailability was approximately 72%; the

maximum plasma concentration (C

) was 0.630 ng/ml (1.512 pmol/ml) at 3 hours and area

under the concentration time curve (AUC

) was 5.25 ngh/ml (12.60 pmolh/ml). The mean

absolute bioavailability of paricalcitol in haemodialysis (HD) and peritoneal dialysis (PD)

patients is 79% and 86%, respectively, with the upper bound of 95% confidence interval of 93%

and 112%, respectively. A food interaction study in healthy subjects indicated that the C

were unchanged when paricalcitol was administered with a high fat meal compared to

fasting. Therefore, Zemplar capsules may be taken without regard to food.

The C

and AUC

of paricalcitol increased proportionally over the dose range of 0.06 to 0.48

micrograms/kg in healthy subjects. Following multiple dosing, either as daily or three times a

week in healthy subjects, steady-state exposure was reached within seven days.

Distribution

Paricalcitol is extensively bound to plasma proteins (> 99%). The ratio of blood paricalcitol to

plasma paricalcitol concentration averaged 0.54 over the concentration range of 0.01 to 10 ng/ml

(0.024 to 24 pmol/ml) indicating that very little drug associated with blood cells. The mean

apparent volume of distribution following a 0.24 micrograms/kg dose of paricalcitol in healthy

adult subjects was 34 litres.

Biotransformation

After oral administration of a 0.48 micrograms/kg dose of

H-paricalcitol, parent drug was

extensively metabolised, with only about 2% of the dose eliminated unchanged in the faeces, and

no parent drug found in the urine. Approximately 70% of the radioactivity was eliminated in the

faeces and 18% was recovered in the urine. Most of the systemic exposure was from the parent

drug. Two minor metabolites, relative to paricalcitol, were detected in human plasma. One

metabolite was identified as 24(R)-hydroxy paricalcitol, while the other metabolite was

unidentified. The 24(R)-hydroxy paricalcitol is less active than paricalcitol in an in vivo rat model

of PTH suppression.

Zem Cap_API_Mar_2020_CL

In vitro data suggest that paricalcitol is metabolised by multiple hepatic and non-hepatic

enzymes, including mitochondrial CYP24, as well as CYP3A4 and UGT1A4. The identified

metabolites include the product of 24(R)-hydroxylation, as well as 24,26- and 24,28-

dihydroxylation and direct glucuronidation.

Elimination

Paricalcitol is eliminated primarily via hepatobiliary excretion.

In healthy subjects, the mean elimination half-life of paricalcitol is five to seven hours over the

studied dose range of 0.06 to 0.48 micrograms/kg. The degree of accumulation was consistent

with the half-life and dosing frequency. Haemodialysis procedure has essentially no effect on

paricalcitol elimination.

Special Populations

Elderly

The pharmacokinetics of paricalcitol have not been investigated in patients greater than 65 years.

Gender

The pharmacokinetics of paricalcitol following single doses over 0.06 to 0.48 micrograms/kg

dose range were gender independent.

Hepatic Impairment

In a study performed with Zemplar intravenous, the disposition of paricalcitol (0.24

micrograms/kg) was compared in patients with mild (n = 5) and moderate (n = 5) hepatic

impairment (in accordance with the Child-Pugh method) and subjects with normal hepatic

function (n = 10). The pharmacokinetics of unbound paricalcitol was similar across the range of

hepatic function evaluated in this study. No dosing adjustment is required in patients with mild to

moderate hepatic impairment. The influence of severe hepatic impairment on the

pharmacokinetics of paricalcitol has not been evaluated.

Renal Impairment

Paricalcitol pharmacokinetics following single dose administration were characterised in patients

with CKD Stage 3 or moderate renal impairment (n = 15, GFR = 36.9 to 59.1 ml/min/1.73 m

CKD Stage 4 or severe renal impairment (n = 14, GFR = 13.1 to 29.4 ml/min/1.73 m

), and CKD

5 or end-stage renal disease [n = 14 in haemodialysis (HD) and n = 8 in peritoneal dialysis (PD)].

Similar to endogenous 1,25(OH)

, the pharmacokinetics of paricalcitol following oral

administration were affected significantly by renal impairment, as shown in Table 4. Compared to

healthy subjects’ results obtained, CKD Stage 3, 4, and 5 patients showed decreased CL/F and

increased half-life.

Table 4 Comparison of Mean ± SD Pharmacokinetic Parameters in Different Stages of Renal

Impairment versus Healthy Subjects

העדוה העדוה

לע לע

הרמחה הרמחה

(

(

עדימ עדימ

ןולעב )תוחיטב ןולעב )תוחיטב

ל

ל

אפור אפור

ןכדועמ( ןכדועמ(

05.2013

05.2013

ךיראת

:

09

-

Sep-2015

םש

רישכת

תילגנאב

רפסמו

:םושירה

Zemplar 1 microgram, 141-12-31816-00

םש

לעב

םושירה

:

AbbVie Biopharmaceuticals Ltd

.

! דבלב תורמחהה טורפל דעוימ הז ספוט תורמחהה

תושקובמה קרפ

ןולעב טסקט

יחכונ טסקט

שדח

4. CLINICAL

PARTICULAR

S

4.8

Undesirable

effects

Chronic Kidney Disease, Stage 5

The following adverse reactions have been

seen in clinical trials and in post marketing

with Zemplar injection.

System

Organ

Class

Preferred

Term

Frequenc

y

Investiga

tions

Calcium-

phosphorus

product

(Ca×P)

increased

(increase

driven by

the calcium

component

of the Ca×P

Not Known

Chronic Kidney Disease, Stage 5

The following adverse reactions have

been seen in clinical trials with Zemplar

injection and in post marketing

experience, including post-approval

clinical trials with Zemplar Capsules.

System

Organ

Class

Preferred

Term

Frequenc

y

Investiga

tions

Calcium-

phosphate

product

increased

Common

ב"צמ

ובש ,ןולעה

נמוסמ תו

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שקובמה תו

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עקר

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.

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םוקימב .טסקטה רבעוה

ראודב

ינורטקלא

ךיראתב

:

09

-

Sep-2015

העדוה העדוה

לע לע

הרמחה הרמחה

(

(

עדימ עדימ

ןולעב )תוחיטב ןולעב )תוחיטב

ןכרצל ןכרצל

ןכדועמ( ןכדועמ(

05.2013

05.2013

ךיראת

:

09

-

Sep-2015

םש

רישכת

תילגנאב

רפסמו

:םושירה

Zemplar 1 microgram, 141-12-31816-00

םש

לעב

םושירה

:

AbbVie Biopharmaceuticals Ltd

.

דבלב תורמחהה טורפל דעוימ הז ספוט

תורמחהה

תושקובמה

קרפ

ןולעב טסקט

יחכונ טסקט

שדח דציכ שמתשת הפורתב תפסות הנשי יחכונה ןוכדעב ףסונ ןימסת לש לולעש

חתפתה הפוקת רחאל הובג ןונימ תליטנ לש תכשוממ רלפמז לש ידמ ל םילולעש םינימסת

חתפתה

תכשוממ הפוקת רחאל

רלפמז לש ידמ הובג ןונימ תליטנ לש

:

םוח תשוחת

םוח תיילעו

תועפות

:

יאוול תפסות הנשי יחכונה ןוכדעב תושדח יאוול תועפות לש תחאב ןיחבמ התא םא אפורל דימ תונפל שי :תואבה יאוולה תועפותמ םילבוסה םילפוטמב

מ בלשב תינורכ תוילכ תלחמ

3

וא

4

תוחפלב תועיפומש תועפות( תוחיכש יאוול תועפות ךותמ דחא שמתשמ

100

:)

.םדב ןדיסה תומרב היילע

ארקנה ףסונ רמוח לופכ ןדיסה תמרב היילע

תינורכ תוילכ תלחמב םילוחב) םדב טפסופ .(תמדקתמ ב"צמ

ובש ,ןולעה

נמוסמ תו

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תושקובמה

לע

עקר

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.טסקטה רבעוה

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:ךיראתב

09

-

Sep -2015

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