URSOLIT 100

The format of this leaflet was determined by the Ministry of

Health and its content was checked and approved

PATIENT LEAFLET IN ACCORDANCE WITH THE

PHARMACISTS’ REGULATIONS )PREPARATIONS( – 1986

The medicine is dispensed with a doctor’s

prescription only

Ursolit 100, 300 Tablets

The active ingredient:

Ursolit 100:

Ursodeoxycholic acid 100 mg.

Ursolit 300:

Ursodeoxycholic acid 300 mg

For inactive ingredients see section 6. See also section

2 “Important information about some ingredients of the

medicine”.

Read the entire leaflet carefully before using the

medicine. This leaflet contains concise information about

the medicine. If you have any other questions, refer to the

doctor or the pharmacist.

This medicine has been prescribed for treatment of your

illness. Do not pass it on to others. It may harm them

even if it seems to you that their medical condition is

similar.

1. What is the medicine intended for?

The medicine is intended for the dissolution or reduction

in size of gallstones composed of cholesterol, and for

treatment of certain chronic liver diseases.

Therapeutic class: Bile acids.

2. Before using the medicine:

Do not use this medicine if:

You are sensitive )allergic( to the active ingredient

)bile acids( or any of the additional components the

preparation contains )for a list of inactive ingredients,

see section 6(.

You are suffering from an inflammatory exacerbation

of the gallbladder and/or biliary tract.

You are suffering from biliary obstruction.

You are suffering from a severe liver disease )other

than primary biliary cirrhosis(.

You are suffering from a stomach ulcer.

You are suffering from calcified gallstones.

Your gallbladder is not contracting properly.

You are suffering from an inflammation of the

intestines.

You are suffering from biliary colic frequently )usually

characterized by pain in the upper right side of the

abdomen(.

Special warnings regarding the use of the medicine:

The medicine should be used under medical

supervision )see also “tests and follow-up” in section 3(.

If you have previously suffered from any of the

conditions mentioned in the “Do not use this medicine

if” section - inform your doctor.

In case you are suffering from diarrhea during the

treatment, inform the doctor immediately, since he

may decide to reduce the dosage or discontinue the

treatment.

In rare cases, some symptoms of biliary cirrhosis

)such as itching( may worsen in the beginning of the

treatment. In such a case, you should contact the

doctor, who may recommend to continue the treatment

with a lower daily dose )see also “Attention!” in

section 3(.

If you are sensitive to any type of food or medicine,

inform your doctor before starting treatment with this

medicine.

If you are taking or have recently taken other

medicines, including non-prescription medicines and

food supplements, tell the doctor or the pharmacist.

Especially if you are taking:

Colestyramine and colestipol )for lowering lipid blood

levels(, active charcoal and aluminum-containing

antacids. If you must take these medicines, take them

at least two hours before or two hours after taking

Ursolit.

Ciprofloxacin )antibiotics(, dapsone )antibiotics( and

nitrendipine )for lowering blood pressure( - Ursolit may

reduce the effect of these medicines. Their dosage may

need to be changed.

Ciclosporine )immunosuppressant( - Ursolit may affect

this medicine’s absorption. The doctor will test the

blood ciclosporine concentration and adjust the dosage

as needed.

Rosuvastatin )for lowering cholesterol levels( - Ursolit

may affect the medicine’s action.

Contraceptive pills, estrogen and certain medicines for

lowering blood cholesterol and lipids such as clofibrate.

In certain cases these medicines may affect Ursolit’s

action. Consult with the doctor about this.

Use of the medicine and food

The medicine should be taken with or after a meal.

A low-cholesterol diet may contribute to the treatment’s

success.

Pregnancy and breastfeeding

If you are planning pregnancy, are pregnant or

breastfeeding, consult a doctor before using the medicine.

Do not use the medicine during pregnancy unless the

doctor has decided that it is absolutely necessary.

Women who may become pregnant should use

contraceptives as will be recommended by the doctor.

Breastfeeding

A small amount of the medicine passes into breastmilk. If

you are breastfeeding, consult with your doctor.

Driving and operating machinery

Ursolit does not affect the ability to drive or operate

machinery.

Use in children

This medicine is not intended for babies and children.

Safety of use in children has not been established.

Important information about some ingredients of

the medicine

The preparation contains lactose and may cause an

allergic reaction in people who are sensitive to lactose.

Each tablet of Ursolit 100 contains 75 mg lactose

monohydrate.

Each tablet of Ursolit 300 contains 100 mg lactose

monohydrate.

3. How should you use the medicine?

Always use according to the doctor’s instructions.

Check with the doctor or pharmacist if you are uncertain.

The dosage and treatment regimen will be determined by

the doctor.

The doctor may recommend you to use Ursolit for up to

24 months, depending on the size of the gallstones. You

should continue treatment with Ursolit for 3 months after

the gallstones have been dissolved.

This medicine should be used at set intervals as

determined by the attending doctor.

The dosage will be determined by the doctor according to

your age and weight and disease severity.

The tablets may be halved or pulverized as necessary.

Do not exceed the recommended dose.

Attention! In rare cases, some symptoms of biliary

cirrhosis )such as itching( may worsen in the beginning

of the treatment. In such a case the treatment may

be continued at a lower daily dosage according to the

doctor’s orders. Afterwards, the doctor will increase the

dosage gradually )usually every week( up to the required

dosage.

Tests and follow-up

During the first three months of treatment liver functions

tests should be performed every 4 weeks. Afterwards, it is

recommended to perform the test every 3 months.

If you accidentally take a higher dosage, diarrhea is

possible. If you are suffering from prolonged diarrhea,

contact the doctor immediately.

If you have diarrhea, be sure to drink enough fluids in

order to restore your salt-fluid balance.

If you took an overdose or a child accidentally swallowed

this medicine, go to the doctor or the emergency room

of the hospital immediately and take the package of the

medicine with you.

If you forgot to take this medicine at the required time,

do not take a double dose. Take the next dose at the

scheduled time and consult a doctor.

Follow the treatment 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.

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

the dose every time you take the medicine. Wear glasses

if you need them.

If you have any other questions regarding use of the

medicine, consult the doctor or the pharmacist.

4. Side effects:

As with any medicine, using Ursolit may cause side

effects in some users. If the side effects do not go away,

if they are bothersome or if they worsen, consult your

doctor. Do not be alarmed when reading the list of side

effects. You may not experience any of them.

Common side effects )occurring in 1-10 out of 100

users(:

Soft stool and\or diarrhea )see also “Special warnings

regarding the use of the medicine” in section 2(.

Very rare side effects )occur in less than 1 out of

10,000 patients(:

Severe pain in the upper right side of the abdomen,

worsening of cirrhosis which partially improves upon

discontinuation of treatment.

Gallstones calcification.

Urticaria )hives(.

Side effects with unknown frequency )effects whose

frequency has not yet been determined(:

Nausea.

Vomiting.

Itching.

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

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

leaflet, consult your doctor.

Side effects may be reported to the Ministry of Health by

clicking on the link “report side effects due to medicinal

treatment” found on the Ministry of Health website

homepage )www.health.gov.il(, which will direct you to the

online form for reporting side effects, or by clicking on the

following link:

https://forms.gov.il/globaldata/getsequence/getsequence.

aspx?formType=AdversEffectMedic@moh.gov.il

5. How to store the medicine?

Avoid poisoning! This medicine and any other medicine

must be kept in a closed place out of the reach of

children and/or infants to avoid poisoning. Do not

induce vomiting without an explicit instruction from the

doctor.

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

date( appearing on the package. The expiry date refers

to the last day of that month.

Store at a temperature lower than 25°C.

6. Additional information:

In addition to the active ingredient the medicine also

contains:

Ursolit 100:

Lactose, Carboxymethyl-Cellulose Calcium, Maize

Starch, Povidone 25, Magnesium stearate

Ursolit 300:

Maize Starch, Lactose, Povidone 25, Magnesium

stearate, Colloidal Silicone Dioxide

What does the medicine look like and what are the

contents of the package?

Ursolit 100: Round, biconvex, scored, white tablets.

Blister pack of 60, 100, 500 and 1000.

Not all package sizes may be marketed.

Ursolit 300: Round, biconvex, scored, white tablets.

Blister pack of 30 tablets.

License holder/manufacturer and the address: CTS

Chemical Industries Ltd., Kiryat Malachi.

This leaflet was checked and approved by the Ministry

of Health in: September 2017

Registration number of the medicine in the National

Drug Registry of the Ministry of Health: Ursolit 100:

192520542, Ursolit 300: 586326923

؟ءاودلا لمعتست فيك .3 .بيبطلا تاميلعت قفو ا

مود لامعتسلاا بجي

دكأتم نكت مل اذإ يلديصلا وأ بيبطلا ةراشتسا كيلع .بيبطلا لب

ق نم جلاعلا ة

يفيكو ة

يئاودلا ةعرجلا ديدحت

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قفو ،ا

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دمل تيلوسروأب جلاعلا ةلصاوم كيلع بجي .ة

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ق نم ة

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بطلا تارا

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يبناج ضارعأ ثودح ىلإ تيلوسروأ لامعتسا ي

دؤي دق ،ءاود

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ي مل

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يسيئرلا ةحفصلا يف دوجوملا "

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يبناج ضارعأ نع غيلبتلا" ةرامتسلاا ىلإ ه

جوي يذلاو )www.health.gov.il( ة

حصلا ةرازو عقومل :طبارلا ىلإ لوخدلا قيرط نع وأ ،ة

يبناج ضارعأ نع غيلبتلل ةلص

تملا

https://forms.gov.il/globaldata/getsequence/getsequence.

aspx?formType=AdversEffectMedic@moh.gov.il

؟ءاودلا نيزخت بجي فيك .5

نع ا

ديعب قلغم ناكم يف رخآ ءاود يأو ءاودلا اذه ظفح بجي !ممستلا بنجت ؤيقتلا ببست لا .ممستلا ىدافتت كلذبو عضرلا لافطلأا وأ/و دلاولأا يديأ لوانتم .بيبطلا نم ةحيرص تاميلعت نودب

ودملا )Exp. Date( ةيحلاصلا ءاهتنا خيرات دعب ءاودلا لامعتسا زوجي لا .رهشلا سفن نم ريخلأا مويلا ىلإ ةيحلاصلا ءاهتنا خيرات ريشي .ة

وبعلا ىلع

يوئم ةجرد 25 نم

لقأ ةرارح ةجرد يف هن

زخ :ةيفاضإ تامولعم .6

:ىلع اضيأ ةلاعفلا ةداملل ةفاضلإاب ءاودلا يوتحي :100 تيلوسروأ

Lactose, Carboxymethyl-Cellulose Calcium, Maize

Starch, Povidone 25, Magnesium stearate

:300 تيلوسروأ

Maize Starch, Lactose, Povidone 25, Magnesium

stearate, Colloidal Silicone Dioxide

؟ة

وبعلا ىوتحم وه امو ءاودلا ودبي فيك

طخ عم نيبناجلا لاك نم ةب

دحمو ةريدتسم ،ءاضيب صارقلأا :100 تيلوسروأ .رطشلل .1000 و 500 ،100 ،60 صارقلأا نم اهيف تاحيول ةبلع .تا

وبعلا ماجحأ عيمج ق

وس

ت لا دق

طخ عم نيبناجلا لاك نم ةب

دحمو ةريدتسم ،ءاضيب صارقلأا :300 تيلوسروأ .رطشلل

صرق 30 اهيف تاحيول ةبلع

،.ض.م ة

يئايميكلا تاعانصلل ط ص ك :هناونعو ع

نصملا /زايتملاا بحاص .يخلام تايرق

ربمتپس /لوليأ :خيرات يف ة

حصلا ةرازو لب

ق نم ت

رق

أو تصح

ف ةرشنلا هذه

2017

:ةحصلا ةرازو يف

يموكحلا ةيودلأا

لجس يف ءاودلا

لجس مقر

586326923 :300 تيلوسروأ ,192520542 :100 تيلوسروأ

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

LFL 622 09/17

רשואו קדבנ ונכותו תואירבה דרשמ ידי לע עבקנ הז ןולע טמרופ

רבמטפס

2017

PRESCRIBING INFORMATION

1. TRADE NAME OF THE MEDICINAL PRODUCT

Ursolit 100 mg tablets

Ursolit 300 mg tablets

2. COMPOSITION

Each Ursolit 100 mg tablet contains: Ursodeoxycholic acid 100 mg

Each Ursolit 300 mg tablet contains: Ursodeoxycholic acid 300 mg

Ursolit 100mg also contains 75 mg Lactose monohydrate.

Ursolit 300mg also contains 100 mg Lactose monohydrate.

For full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Tablets for oral administration.

Appearance:

Ursolit 100: white round biconvex scored tablets.

Ursolit 300: white round biconvex scored tablets.

4. CLINICAL PARTICULARS.

4.1 Therapeutic Indications

Dissolution or reduction in size of radiolucent cholesterol in patient with a functioning

gallbladder.

Treatment of chronic liver diseases including primary billiary cirrhosis, primary sclerosing

cholangitis, cystic fibrosis associated liver disease, billiary atresia, chronic hepatitis, and

alcohol cirrhosis.

4.2 Posology and method of administration

Gallstone dissolution: 8 to 12 mg/kg/day given in 2 divided doses.

If doses are unequal the larger dose should be taken in late evening to counteract the rise in

biliary cholesterol saturation which occurs in the early morning. The late evening dose may

usefully be taken with food to help maintain bile flow overnight.

The time required for dissolution of gallstones is likely to range from 6 to 24 months

depending on stone size and composition. Follow-up cholecystograms or ultrasound

investigation may be useful at 6 month intervals until the gallstones have disappeared.

Treatment should be continued until 2 successive cholecystograms and/or ultrasound

investigations 4-12 weeks apart have failed to demonstrate gallstones. This is because these

techniques do not permit reliable visualisation of stones less than 2mm in diameter.

The efficiency of Ursolit in treating radio-opaque or partially radio opaque gallstones has not

been tested but these are generally thought to be less soluble than radiolucent stones.

Non-cholesterol stones account for 10-15% radiolucent stones and may not be dissolved by

bile acids.

Chronic liver diseases: 10 to 15 mg/kg/day administered in 2 to 4 divided doses with food.

The dose may be adjusted according to the patient's age and severity of symptoms.

4.3 Contra-indications:

Ursolit tablets should not be used in patients:

With hypersensitivity to bile acids or any of the excipients listed in section 6.1

With radio-opaque calcified gallstones

With occlusion of the biliary tract (occlusion of the common bile duct or cystic duct).

With acute inflammation of the gall bladder or biliary tract.

With frequent episodes of biliary colic

With impaired contractility of the gall bladder.

With chronic liver disease, peptic ulcers or in those with inflammatory diseases of the

small intestine and colon.

4.4 Special warnings and precautions for use:

Ursolit should be taken under medical supervision.

During the first 3 months of treatment, the liver function parameters AST (SGOT),

ALT (SGPT) and γ-GT should be monitored by the physician every 4 weeks,

thereafter every 3 months. Apart from allowing for identification of responders and

non-responders in patients being treated for primary biliary cirrhosis, this monitoring

would also enable early detection of potential hepatic deterioration, particularly in

patients with advanced stage primary biliary cirrhosis.

When used for the dissolution of cholesterol gallstones:

In order to assess therapeutic progress and for timely detection of any calcification of

the gallstones, depending on stone size, the gall bladder should be visualised (oral

cholecystography) with overview and occlusion views in standing and supine

positions (ultrasound control) 6-10 months after the beginning of treatment.

If the gall bladder cannot be visualised on X-ray images, or in cases of calcified

gallstones, impaired contractility of the gall bladder or frequent episodes of biliary

colic, Ursolit should not be used.

When used for treatment of advanced stage of primary biliary cirrhosis:

In very rare cases decompensation of hepatic cirrhosis has been observed, which

partially regressed after the treatment was discontinued.

If diarrhea occurs, the dose must be reduced and in cases of persistent diarrhea, the

therapy should be discontinued.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactose

deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction:

Ursodeoxycholic acid should not be administered concomitantly with charcoal,

colestyramine, colestipol or antacids containing aluminium hydroxide and/or smectite

(aluminium oxide), because these preparations bind ursodeoxycholic acid in the

intestine and thereby inhibit its absorption and efficacy. Should the use of a

preparation containing one of these substances be necessary, it must be taken at

least 2 hours before or after ursodeoxycholic acid.

Ursodeoxycholic acid can increase the absorption of ciclosporin from the intestine. In

patients receiving ciclosporin treatment, blood concentrations of this substance

should therefore be checked by the physician and the ciclosporin dose adjusted if

necessary.

In isolated cases ursodeoxycholic acid can reduce the absorption of ciprofloxacin.

Ursodeoxycholic acid has been shown to reduce the plasma peak concentrations

(Cmax) and the area under the curve (AUC) of the calcium antagonist nitrendipine.

An interaction with a reduction of the therapeutic effect of dapsone was also

reported.

These observations together with in vitro findings could indicate a potential for

ursodeoxycholic acid to induce cytochrome P450 3A enzymes. Controlled clinical

trials have shown, however, that ursodeoxycholic acid does not have a relevant

inductive effect on cytochrome P450 3A enzymes.

Oral contraceptives, oestrogenic hormones and blood cholesterol lowering agents

such as clofibrate may increase biliary lithiasis, which is a counter-effect to

ursodeoxycholic acid used for dissolution of gallstones.

4.6 Pregnancy and lactation

Animal studies did not show an influence of UDCA on fertility (see section 5.3). Human data

on fertility effects following treatment with UDCA are not available.

Pregnancy

There are no or limited amounts of data from the use of UDCA in pregnant women. Studies in

animals have shown reproductive toxicity during the early phase of gestation (see section

5.3). URSOLIT must not be used during pregnancy unless clearly necessary.

Women of childbearing potential:

Women of childbearing potential should be treated only if they use reliable contraception:

non-hormonal or low-oestrogen oral contraceptive measures are recommended. However, in

patients taking URSOLIT tablets for dissolution of gallstones, effective non-hormonal

contraception should be used, since hormonal oral contraceptives may increase biliary

lithiasis.

The possibility of a pregnancy must be excluded before beginning treatment.

Breastfeeding

According to few documented cases of breastfeeding women, milk levels of UDCA are very

low and probably no adverse reactions are to be expected in breastfed infants.

4.7 Effects on ability to drive and use machines

No effects on ability to drive and use machines have been observed.

4.8 Undesirable effects:

The evaluation of undesirable effects is based on the following frequency data:

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 / Not known (< 1/10,000 / cannot be estimated from available data)

Gastrointestinal disorders:

In clinical trials, reports of pasty stools or diarrhea during ursodeoxycholic acid therapy were

common.

Very rarely, severe right upper abdominal pain has occurred during the treatment of primary

biliary cirrhosis.

Ursodeoxycholic acid may give rise to nausea and vomiting. The frequency of these effects

are not known.

Hepatobiliary disorders:

During treatment with ursodeoxycholic acid, calcification of gallstones can occur in very rare

cases making them unable to be dissolved by bile acid therapy and resulting in surgery for

some patients.

During therapy of the advanced stages of primary biliary cirrhosis, in very rare cases

decompensation of hepatic cirrhosis has been observed, which partially regressed after the

treatment was discontinued.

Skin and subcutaneaous disorders:

Very rarely, urticaria can occur.

Ursodeoxycholic acid may give rise to pruritus. The frequency of this effect is not known.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is

important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

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

National Regulation by using an online form

(http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic

@moh.health.gov.il ).

4.9 Overdose:

Diarrhea may occur in cases of overdose. In general, other symptoms of overdose are

unlikely because the absorption of ursodeoxycholic acid decreases with increasing dose and

therefore more is excreted with the faeces.

No specific counter-measures are necessary and the consequences of diarrhoea should be

treated symptomatically with restoration of fluid and electrolyte balance.

5. PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Bile acid preparation

ATC code: A05AA02

5.1 Pharmacodynamics properties:

Ursolit is naturally occurring bile acid found in small quantities in normal human bile and in

larger quantities in the biles of certain species of bears. Ursolit suppresses hepatic synthesis

and cholesterol secretion and also inhibits intestinal absorption of cholesterol. It has little

inhibitory effect on synthesis and secretion into bile of endogenous bile acids and does not

appear to affect phospholipid secretion into bile.

Although insoluble in aqueous media, cholesterol may be solubilized in at least 2 ways in the

presence of dihydroxy bile acids. In addition to solubilizing cholesterol in micelles, Ursolit acts

by an apparently unique mechanism to cause dispersion of cholesterol as liquid crystals in

aqueous media. Thus even though administration of high doses (eg, 15 to 18 mg/kg/day)

does not result in concentration of ursodeoxycholic acid higher than 60% of the total bile acid

pool, ursodeoxycholic acid rich bile solubilizes cholesterol. The overall effect of Ursolit is to

increase the concentration level at which saturation of cholesterol occurs. The various actions

of Ursolit combine to change the bile of patients with gallstones from cholesterol –

precipitating to cholesterol – solubilizing.

5.2 Pharmacokinetic properties:

Absorption/Distribution - Ursodeoxycholic acid is absorbed in the small bowel after oral

administration. After absorption ursodeoxycholic acid enters the portal vein and undergoes

extraction from portal blood by the liver (ie, "first – pass" effect) where it is conjugated with

glycine or taurine and is then secreted into the hepatic bile ducts. In the bile it is concentrated

in the gallbladder and expelled into the duodenum in gallbladder via the cystic and common

ducts by gallbladder contractions provoked by physiologic responses to eating. With repeated

dosing, bile ursodeoxycholic acid concentrations reach steady state in about 3 weeks. After

ursodeoxycholic acid dosing is stopped, its concentration in bile falls exponentially, declining

to about 5% to 10% of its steady –state level in about 1 week.

Metabolism/Excretion – Small quantities of ursodeoxycholic acid appear in the systemic

circulation, and very small amounts are excreted into urine. A small portion of orally

administered drug undergoes bacterial degradation with each cycle of enterohepatic

circulation. Ursodeoxycholic acid can be oxidized and reduced, yielding 7-keto-lithocholic acid

or lithocholic acid respectively. Free ursodeoxycholic acid, 7-keto-lithocholic acid, and

lithocholic acid are relatively insoluble in aqueous media, and larger proportions of these

compounds are excreted via the feces. Reabsorbed free ursodeoxycholic acid is reconjugated

by the liver. Eighty present of lithocholic acid formed in the small bowel is excreted in the

feces, but the 20% that is adsorbed is sulfated in the liver to relatively insoluble lithocholyl

conjugates that are excreted into the bile and lost in feces. Absorbed 7-keto-lithocholic acid is

stereospecifically reduced in the liver to chenodiol.

6. PHARMACEUTICAL PARTICULARS

6.1 Ursolit 100 excipients: Lactose monohydrate, Carboxymethyl-Cellulose Calcium,

Maize Starch, Povidone , Magnesium Stearate

Ursolit 300 excipients: Lactose monohydrate, Maize Starch, Povidone,

Magnesium Stearate, Colloidal Silicone Dioxide

6.2 Special precautions for storage: Do not store above 25

7. MANUFACTURER/ MARKETING AUTHORIZATION HOLDER:

CTS Chemical Industries Ltd., 3 Hakidma St., Kiryat Malachi

8. MARKETING AUTHORIZATION NUMBER:

Ursolit 100: 0192520542

Ursolit 300: 0586326923

9. DATE OF REVISION OF THE TEXT:09.2017