BONDORMIN

Patient Leaflet According to the Pharmacists' Regulations (Preparations) -

1986

This medicine is sold with a doctor's prescription only

Bondormin

Tablets

Active ingredient:

Each tablet contains 0.25 mg brotizolam.

For a list of the other ingredients, please see section 6.

See also 'Important information about some of the medicine's ingredients' in section 2.

Read this entire leaflet carefully before using this medicine.

This leaflet contains concise information about the medicine. If you have any further

questions, please refer to your doctor or pharmacist.

This medicine has been prescribed for your treatment. Do not pass it on to others. It may

harm them, even if it seems to you that their medical condition is similar to yours.

Introduction to the Patient Leaflet for Benzodiazepines

This medicine belongs to the group of benzodiazepines, which has special properties

requiring the utmost caution while using it.

Close medical follow-up is very important while taking this medicine.

When taking this medicine, make sure to refer to your doctor after two weeks, since

treatment is intended for short periods of time only.

Prolonged use of this medicine may cause a reduction in its effect.

Prolonged use may cause a severe effect of dependence, making it difficult for the

patient to discontinue taking the medicine and therefore, discontinuation of the medicine

should be done gradually, according to the doctor's instructions.

Uncontrolled discontinuation of treatment is accompanied by withdrawal symptoms, such

as: tension, nervousness, confusion, tremor, insomnia, abdominal pains, vomiting,

nausea, sweating, spasms, cramps and muscle pain.

Sometimes prolonged use of the medicine may cause changes in behavioral patterns

and nagging thoughts.

Especially in the elderly, caution is recommended when walking, since the medicine

impairs alertness and sometimes coordination of body movements, thus raising concern

about stumbles or falls.

Taking this medicine along with medicines from the opioid group, other medicines

which depress the central nervous system (including drugs) or alcohol may cause a

feeling of profound drowsiness, difficulty breathing (respiratory depression), coma and

death.

1.

What is the medicine intended for?

Bondormin is a medicine which is intended for the treatment of insomnia.

Therapeutic group: benzodiazepines

2.

Before you take the medicine

Do not use this medicine if:

You are sensitive (allergic) to the active ingredient, to other benzodiazepines, or to any

of the other ingredients this medicine contains (for a list of the other ingredients, please

see section 6).

You are pregnant or breastfeeding.

You suffer from severe respiratory insufficiency, sleep apnea, severe liver insufficiency,

myasthenia gravis, or if you suffer or have suffered in the past from dependency on

medicines, drugs or alcohol.

You suffer from intoxication from alcohol, sleeping medicines (hypnotics), opioid

analgesics, or psychiatric medicines (such as antipsychotic medicines,

antidepressants, lithium).

Do not use this medicine in children and adolescents under the age of 18.

Special warnings regarding the use of this medicine

:

Prolonged use may cause dependence! The risk of dependency on this medicine is

increased when taking a high dosage and with a prolonged treatment period.

In addition,

the risk of developing dependence is higher in patients who have a history of

dependencies on medicines or alcohol. If a dependency on the medicine exists, sudden

discontinuation will be accompanied by withdrawal symptoms (see section 'If you stop

taking the medicine').

Do not use this medicine often or for prolonged periods without consulting your

doctor.

Taking the medicine daily for several weeks may cause a decrease in its

effectiveness.

Bondormin has a muscle-relaxing effect, which may increase the risks for falls.

Use with caution in the elderly.

Before treatment with Bondormin tell your doctor:

If you suffer or have suffered in the past from impaired function of the: respiratory

system, liver. In such cases, your doctor may recommend a reduced dosage.

If you suffer or have suffered in the past from depression or suicidal thoughts.

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

If you are taking or have recently taken any other medicines, including non-

prescription medicines and nutrition supplements, please tell your doctor or

pharmacist. Especially inform your doctor or pharmacist if you are taking the following

medicines (please note that the following list mentions the active ingredients of the

medicines. If you are unsure whether you are using any of these medicines, please

consult with your doctor or pharmacist):

Medicines which affect the central nervous system (such as: sedatives, sleeping

medicines, antidepressants or anti-anxiety, antipsychotics), medicines to treat

epilepsy, certain antihistamines, anaesthetics, narcotic analgesics).

Muscle relaxants, medicines for the treatment of diabetes and high blood pressure,

glycosides for the treatment of heart problems (such as digoxin), hormones.

The following medicines may cause an increase in the effectiveness of Bondormin:

azole antifungals (such itraconazole, ketoconazole), macrolide antibiotics (such as

clarithromycin, erythromycin), protease inhibitors (such as indinavir, nelfinavir,

ritonavir), cimetidine.

The following medicines may cause a decrease in the effectiveness of Bondormin:

carbamazepine, efavirenz, St. John's wort (hypericum), nevirapine, phenobarbital,

phenytoin, primidone, rifabutin, rifampicin.

Additional medicines that may affect the activity of Bondormin: immunosuppressants

(such as ciclosporin, sirolimus, tacromilus), calcium channel blockers, antimalarial

medicines such as mefloquine and halofantrine, midazolam, pimozide, sildenafil,

medicines for lowering cholesterol from the statins group (such as: atorvastatin,

lovastatin, simvastatin), steroids (such as ethinyl-estradiol), tamoxifen, terfenadine.

Use of the medicine and food:

Take the medicine on an empty stomach.

Do not drink grapefruit juice during treatment.

Use of the medicine and alcohol consumption: Do not drink wines or alcoholic

beverages during the treatment period with the medicine. Use of alcohol during

treatment with Bondormin may cause, among other things, sedation, drowsiness and

impair concentration.

Pregnancy and breastfeeding:

Do not use this medicine if you are pregnant or breastfeeding.

If you intend to become pregnant, or suspect you are pregnant, refer to the doctor.

Driving and use of machinery: The use of this medicine may impair alertness, ability to

concentrate, and muscle function (especially when the duration of sleep is insufficient or

in combination with medicines which affect the central nervous system). In the event that

you feel effects such as those detailed, do not drive or operate machinery. In any case,

caution must be exercised when driving a vehicle, operating dangerous machinery and

in any activity which requires alertness.

Use in children: This medicine is not intended for children and adolescents under the

age of 18.

Use in the elderly, debilitated patients, patients with liver function problems

or with respiratory insufficiency: this group may be more sensitive to the

effects of the medicine; therefore, it should be used with caution and with a

reduced dosage. Included among the effects of the medicine, especially in the

elderly, is an increase in the risk of falling as a result of muscle relaxation (see

'Introduction')

Important information about some of the medicine's ingredients:

Bondormin contains lactose. If you are sensitive to lactose, inform your doctor before

taking this medicine.

3.

How should this medicine be used?

Always use according to the doctor's instructions. Check with your doctor or pharmacist

if you are not sure.

The dosage and the manner of treatment will be determined by the doctor only.

The standard dosage is usually: 1/2-1 tablet (according to the doctor's decision),

before sleep.

Do not exceed the recommended dose under any circumstance.

There is no information regarding

crushing or chewing of the tablets.

Swallow the medicine with water or gradually dissolve under the tongue.

This medicine should be taken on an empty stomach.

This medicine can be halved using the score line.

Make sure to get at least 7 hours of sleep after taking the medicine, in order that you will

be able to function properly after waking up (see also section 'Driving and use of

machinery').

If you have accidentally taken a higher dosage: If you have taken an overdose, or if a

child has accidentally swallowed the medicine, refer immediately to a hospital

emergency room and bring the package of the medicine with you.

Symptoms of an overdose may include: drowsiness, confusion, fatigue. In severe cases,

impaired coordination, decrease in muscle tension, hypotension, respiratory depression,

coma (rare) and death (very rare) may also occur.

If you stop taking the medicine: Even if your state of health improves, do not stop

treatment with the medicine suddenly without consulting with your doctor. This

instruction is very important, especially with a medicine such as Bondormin (see

'Introduction').

Sometimes after discontinuation of the medicine, there may be a rebound or

worsening of insomnia, and also in rare cases, restlessness, mood changes, anxiety

and tension. The risk for this is higher with sudden treatment discontinuation or

sudden decrease in dosage.

In addition, there may be withdrawal symptoms after sudden discontinuation of the

medicine (especially if dependency on the medicine has developed) such as:

headaches, muscle pain, extreme anxiety, tension, insomnia, restlessness,

confusion, nervousness. In severe cases, there may be misinterpretation of reality,

personality changes, lack of sensation (numbness) and tingling in the hands and feet,

hypersensitivity to light, noise and touch; hallucinations, epileptic seizures. These

reactions may also occur several days after discontinuation of the medicine.

Do not take medicines in the dark! Check the label and the dose each time you take a

medicine. Wear glasses if you need them.

If you have any further questions regarding the use of this medicine, consult your doctor

or pharmacist.

4.

Side effects:

Like any medicine, the use of Bondormin may cause side effects in some users.

When side effects appear or if side effects persist or are bothersome or worsen, consult

with the doctor.

Do not be alarmed when reading the list of side effects, you may not suffer from any of

them.

Refer to a doctor immediately if the following side effects appear:

Paradoxical reactions such as: restlessness, agitation, nervousness, rage,

aggressiveness, increased insomnia, nightmares, hallucinations, psychoses, changes in

behavioral patterns including inappropriate behavior, confusion and delirium (uncommon

side-effects).

Additional side effects:

Common side effects (appear in 1-10 users out of 100): headache, feeling of dizziness

(light-headedness), disturbances of the digestive system.

Uncommon side effects (appear in 1-10 users out of 1,000): nightmares, depression,

changes in mood, anxiety, dependency on the medicine, emotional disturbances,

behavioural changes, agitation, changes in libido, dizziness, sedation, lack of

coordination and impairment of body movements coordination (ataxia), memory

disturbances, dementia, mental and psychomotor impairments, vision disturbances

(such as double-vision), liver disturbances (including jaundice and changes in liver

function test values), dry mouth, skin reactions, muscle weakness, withdrawal symptoms

and rebound or worsening of insomnia after discontinuation of the medicine, drowsiness

(during the day), nervousness, increased risk of accidents and falls.

Rare side effects, (appear in 1-10 users out of 10,000): confusion, restlessness,

decrease in alertness and preparedness.

If side effects appear, if one of the side effects worsens or when you suffer from side

effects not mentioned in this leaflet, consult with your doctor.

Side effects may be reported to the Ministry of Health by clicking on the link "Report on

side effects following medicinal treatment" on the homepage of the Ministry of Health

website (www.health.gov.il) which leads you to the online form for reporting side effects,

or by entering the link:

https://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectM

edic@moh.gov.il

5.

How to store the medicine?

Avoid poisoning! This medicine, and any other medicine, must be stored in a safe

place out of the reach of children and/or infants, to avoid poisoning. Do not induce

vomiting unless explicitly instructed to do so by a doctor.

Do not use the medicine after the expiry date (exp. date) stated on the package. The

expiry date refers to the last day of that month.

Storage conditions: Store below 25°C.

6.

Additional information

In addition to the active ingredient, the tablets also contain the following

ingredients:

Lactose, corn starch, cellulose-microcrystalline, sodium starch glycolate,

magnesium stearate.

Each tablet contains approximately 82 mg lactose.

What does the medicine look like and what does the package contain?

White round tablets with a score line, in blister packs of 10 or 20 tablets in a box. Not all

pack sizes may be marketed.

Registration holder: Rafa Laboratories Ltd., P.O.Box 405, Jerusalem 9100301.

Medicine

registration number in the National Drug Registry of the Ministry of Health:

120 37 26021 12

This leaflet was checked and approved by the Ministry of Health in April 2017.

009007

Page 1 of 10

Bondormin-DL-April 2017-01

Doctor leaflet

1.

NAME OF THE MEDICINAL PRODUCT

Bondormin

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each Bondormin tablet contains 0.25 mg brotizolam.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Tablets.

The tablet can be divided into 2 equal doses.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Treatment of Insomnia.

4.2

Posology and method of administration

Posology

Unless otherwise prescribed, the usual dose is ½ - 1 tablet a day (equivalent to 0.125 - 0.25 mg

brotizolam).

Treatment should be started with ½ a tablet a day (equivalent to 0.125 mg brotizolam). Depending on

individual response, ½ a tablet a day (equivalent to 0.125 mg brotizolam) may be sufficient. The

WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS

Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression,

coma, and death.

Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options

are inadequate.

Limit dosages and durations to the minimum required.

Follow patients for signs and symptoms of respiratory depression and sedation.

Page 2 of 10

maximum dose of 1 tablet a day (equivalent to 0.25 mg brotizolam) should not be exceeded because of

the increased risk of adverse CNS effects.

In isolated cases (e.g. pre-operative sleep disturbances) the dose may be increased to 2 tablets.

Special populations:

A reduction in dosage to ½ a tablet a day should be considered in the following populations (see

section 4.4):

- patients with impaired liver function (see section 4.3 and section 5.2)

- elderly and debilitated patients (see section 5.2)

- patients with chronic respiratory insufficiency with hypercapnia due to the risk of respiratory

depression, especially at night (see section 4.3)

The tablets can be divided into equal halves for this purpose.

No dosage adjustment is normally necessary in patients with impaired renal function (see 5.2).

Paediatric population

Bondormin is contraindicated in children aged up to 18 years (see section 4.3).

Method of administration

Bondormin should be taken with a little liquid just before going to bed. To avoid affecting the onset

and duration of action, Bondormin should not be taken on a full stomach.

Alternatively, the tablet may be allowed to dissolve under the tongue.

Sufficient time for sleep must be guaranteed to reduce the risk of affecting reactions (and hence the

ability to drive) the following morning. Patients should therefore ensure that they will be able to sleep

for 7 - 8 hours after taking a tablet.

Duration of treatment

Treatment should be as short as possible. Generally, the duration of treatment varies from a few days

to a maximum of two weeks. Treatment should be discontinued by gradual tapering, which should be

tailored to the individual (see section 4.4). It should be borne in mind that discontinuation may initially

cause rebound insomnia and that, in rare cases, restlessness, anxiety and tension may also occur.

In certain cases, extension beyond the maximum two-week treatment period may be necessary; if so, it

should not take place without re-evaluation of the patient's status.

4.3

Contraindications

Bondormin is contra-indicated in:

Patients with known hypersensitivity to brotizolam or other benzodiazepines or to any of the

excipients listed in section 6.1

Patients with myasthenia gravis.

Patients with severe respiratory insufficiency.

Patients with sleep apnoea syndrome.

Patients with severe hepatic insufficiency.

Patients with a history of dependence on alcohol, medicines or other drugs.

Patients acutely intoxicated with alcohol, hypnotics, opiate-type analgesics or psychotropics (anti-

psychotics, antidepressants, lithium).

Pregnant women.

Breast-feeding women.

Page 3 of 10

Children and adolescents up to 18 years of age, as safety and efficacy have not been investigated in

this age group.

Patients with any rare hereditary intolerance to any of the ingredients of the product (see 4.4).

4.4

Special warnings and precautions for use

Psychiatric conditions

Benzodiazepines should not be used alone for the treatment of psychotic illness.

Benzodiazepines alone are not suitable for the treatment of severe depression and should not be used

alone for the treatment of anxiety associated with severe depression (suicide may be precipitated in

such patients). Appropriate precautions must be taken when using benzodiazepines in severely

depressed and suicidal patients.

Pre-existing depression may be unmasked.

Psychiatric and paradoxical reactions can occur during benzodiazepine treatment, particularly in the

elderly. These reactions include restlessness, agitation, irritability, rages, nightmares, increased

insomnia, hallucinations, psychoses, inappropriate behaviour, delirium and other adverse behavioural

effects. Should this occur, use of the medicinal product should be discontinued.

Dependence

Chronic use of benzodiazepines may lead to the development of physical and psychic dependence.

The risk of dependence increases with dose and duration of treatment; it is also greater in patients with

a history of alcohol or drug abuse. Once physical dependence has developed, abrupt termination of

treatment will be accompanied by withdrawal symptoms. These may consist of headaches, muscle

pain, extreme anxiety, tension, insomnia, restlessness, confusion and irritability. In severe cases, the

following symptoms may occur: derealisation, depersonalisation, numbness and tingling of the

extremities, hypersensitivity to light, noise and physical contact, hallucinations or epileptic seizures.

Withdrawal symptoms may occur several days after discontinuation of treatment.

Use with alcohol

Concurrent use of brotizolam and alcohol can result in sedation, drowsiness and impaired

concentration (see section 4.5).

Tolerance

Some loss of efficacy to the hypnotic effect may develop after repeated use for a few weeks.

Rebound anxiety and tension

Withdrawal of brotizolam treatment can lead to the development of a transient syndrome whereby the

symptoms that led to treatment with a benzodiazepine recur in an enhanced form. The syndrome may

be accompanied by mood changes, sleep disturbances and restlessness. Since the risk of withdrawal

phenomena / rebound phenomena is greater after sudden dose reduction or abrupt discontinuation of

treatment, it is recommended that the dosage is decreased gradually.

Duration of treatment

The duration of treatment should be as short as possible (see 4.2). Extension beyond the

recommended maximum treatment period should not take place without re-evaluation of the situation.

It may be useful to inform the patient when treatment is started that it will be of limited duration and to

explain precisely how the dosage will be progressively decreased. Moreover, it is important that the

patient should be aware of the possibility of rebound phenomena, thereby minimising anxiety over

such symptoms should they occur while the medicinal product is being discontinued.

Page 4 of 10

Abrupt withdrawal of benzodiazepines can lead to the occurrence of paraesthesias, perceptual

disturbances and depersonalisation, which may last for a week or more. Convulsions have been

reported in a small number of cases.

Amnesia

In common with other benzodiazepines, brotizolam may induce anterograde amnesia. The condition

occurs most often several hours after ingesting the product.

Specific patient groups

Benzodiazepines have a muscle relaxant effect, which increases the risk of falls. Brotizolam should

therefore be used with caution in the elderly.

Benzodiazepines are not indicated to treat patients with severe hepatic insufficiency as they may

precipitate encephalopathy.

Benzodiazepines should be used with extreme caution in patients with a history of alcohol or drug

abuse.

Bondormin contains lactose

Bondormin tablets contain 82.75 mg lactose

monohydrate per tablet.

Patients with the rare

hereditary problems of galactose intolerance, lactase deficiency or glucose-galactose malabsorption

should not take Bondormin.

4.5

Interaction with other medicinal products and other forms of interaction

Alcohol should be avoided during treatment with brotizolam as it modifies and increases the effects of

brotizolam in an unpredictable manner (see 5.2).

Concurrent use of brotizolam and alcohol can result in sedation, drowsiness and impaired

concentration (see 5.2, under "Alcohol").

Co-administration of brotizolam with other CNS depressants (antipsychotics (neuroleptics),

antidepressants, hypnotics, anxiolytics/sedatives, narcotic analgesics, anaesthetics, anti-epileptics and

sedative antihistamines) can lead to mutual enhancement of the CNS depressant effect and therefore

requires very careful consideration.

Co-administration of brotizolam with narcotic analgesics can lead to enhancement of the euphoria and

accelerate the development of dependence.

The nature and extent of interactions between brotizolam and other medicinal products (antidiabetics,

antihypertensives, cardiac glycosides and hormones) varies unpredictably between individuals and

caution is therefore required when giving Bondormin to patients taking these products.

Co-administration of brotizolam with muscle relaxants can increase the muscle relaxant effect.

Brotizolam is metabolised chiefly by the cytochrome P450 isoenzyme CYP 3A4 in the liver. Agents

that compete with brotizolam for CYP 3A4 (competitive inhibition) and agents that inhibit CYP 3A4

can therefore increase the effect of brotizolam.

Known substrates for CYP 3A4 include astemizole, azole antifungals (such as itraconazole and

ketoconazole), immunosuppressants (such as ciclosporin A, sirolimus and tacrolimus), calcium

antagonists, macrolide antibiotics (such as clarithromycin and erythromycin), antimalarials (such as

halofantrine and mefloquine), midazolam, pimozide, protease inhibitors (such as indinavir, nelfinavir

and ritonavir), sildenafil, statins (such as atorvastatin, lovastatin and simvastatin), steroids (such as

ethinyl-estradiol), tamoxifen and terfenadine.

Inhibitors of CYP 3A4, which can increase the toxicity of brotizolam, include azole antifungals,

cimetidine, grapefruit juice, macrolide antibiotics and protease inhibitors.

Page 5 of 10

Inducers of CYP 3A4, which increase enzyme activity and can reduce the effect of brotizolam, include

carbamazepine, efavirenz, St. John's wort, nevirapine, phenobarbital, phenytoin, primidone, rifabutin

and rifampicin.

4.6

Fertility, pregnancy and lactation

Pregnancy

There are no systematic data from the use of brotizolam in pregnant or breast-feeding women.

onclinical studies

have shown reproductive toxicity (see 5.3). Brotizolam should not be used

during pregnancy or lactation.

Infants born to mothers who took benzodiazepines chronically during pregnancy may have developed

physical dependence and may be at some risk of developing withdrawal symptoms in the postnatal

period.

If, for compelling medical reasons, brotizolam is administered during the late phase of pregnancy or

during labour at high doses, effects on the neonate such as respiratory insufficiency, hypothermia,

hypotonia and feeding difficulties ("floppy infant syndrome") can be expected.

If brotizolam is prescribed to a woman of child-bearing potential, she should be warned to contact her

physician immediately if she intends to become or suspects that she is pregnant.

The risk of malformations following administration of therapeutic doses of benzodiazepines to women

in the early phase of pregnancy appears to be low, although evidence from some epidemiological

studies indicates an increased risk of cleft palate. There have been case reports of malformations and

mental retardation in prenatally exposed children following benzodiazepine overdose or intoxication.

Lactation

Brotizolam and its metabolites are excreted in breast milk. There is therefore a risk of accumulation in

the breast-feeding child. Accordingly, breast-feeding should be discontinued or interrupted on

repeated administration of brotizolam to the mother.

Fertility

There are no clinical data on the effects of brotizolam on fertility. N

onclinical studies

do not indicate

harmful effects with respect to fertility (see 5.3).

4.7

Effects on ability to drive and use machines

Even when used in accordance with the prescribing instructions, this product may affect reactions and

thus impair the ability to drive and operate machinery. Concurrent use of alcohol and/or medicinal

products with CNS depressant activity will potentiate this impairment.

No studies on the effects of Bondormin on the ability to drive and use machines have been performed.

However, patients should be advised that they may experience undesirable effects (see 4.8) such as

sedation, amnesia and impaired psychomotor skills during treatment with Bondormin. Psychomotor

impairment may increase the risk of falls and road traffic accidents.

Caution should therefore be recommended when driving a vehicle or operating machinery. If

insufficient sleep duration occurs, the likelihood of impaired alertness may be increased. If patients

experience any of the above-mentioned undesirable effects, they should avoid potentially hazardous

tasks such as driving a vehicle or operating machinery.

Page 6 of 10

4.8

Undesirable effects

Most of the undesirable effects observed to date are related to the product's pharmacological activity.

They occur predominantly at the start of therapy and usually decrease with continued administration.

The risk of dependence (in the form of e.g. a rebound effect, altered mood, anxiety and restlessness)

increases with the duration of Bondormin treatment, which should not exceed two weeks.

The following definitions of frequencies are used:

Very common (≥ 1/10)

Common (≥ 1/100 up to < 1/10)

Uncommon (≥ 1/1.000 up to < 1/100)

Rare (≥ 1/10.000 up to < 1/1.000)

Very rare (< 1/10.000)

Not known (frequency cannot be estimated from the available data)

Psychiatric disorders

Uncommon

Nightmares, depression, altered mood, anxiety,

drug dependence, emotional disorder,

behavioural changes, agitation, changes in libido

Rare

Confusion, restlessness

Nervous system disorders

Common

Light-headedness, headache

Uncommon

Dizziness, sedation, ataxia, anterograde amnesia,

dementia*, mental impairment*, impairment of

psychomotor skills*

Rare

Reduced alertness

Eye disorders

Uncommon

Diplopia

Gastrointestinal disorders

Common

Gastrointestinal disturbances

Uncommon

Dry mouth

Hepatobiliary disorders

Uncommon

Liver disorders, jaundice

Skin and subcutaneous tissue

disorders

Uncommon

Skin reactions

Musculoskeletal and

connective tissue disorders

Uncommon

Muscle weakness

General disorders and

administration site conditions

Uncommon

Withdrawal and rebound phenomena,

paradoxical reactions, irritability, drowsiness

Investigations

Uncommon

Changes in liver function values

Injury, poisoning and

procedural complications

Uncommon

Road traffic accidents*, falls*

*) Class effect of benzodiazepines

Brotizolam has a muscle relaxant effect and should therefore be used with caution in the elderly

because of the risk of falls.

Abuse of benzodiazepine has been reported.

Withdrawal symptoms

Withdrawal and rebound phenomena may indicate development of dependence.

Once physical dependence has developed, abrupt termination of treatment will be accompanied by

withdrawal symptoms such as headaches, muscle pain, extreme anxiety, tension, restlessness,

confusion and irritability.

Page 7 of 10

In severe cases, derealisation, depersonalisation, hyperacusis, numbness and tingling of the

extremities, hypersensitivity to light, noise and physical contact, hallucinations or epileptic seizures

may occur (see 4.4).

Psychiatric and paradoxical reactions

Reactions such as restlessness, agitation, irritability, aggressiveness, delusion, rages, vivid nightmares,

hallucinations, psychoses and behavioural changes are known to occur when using benzodiazepines

and benzodiazepine-like agents. They are more likely to occur in children and the elderly (see 4.4).

Should this occur, use of the medicinal product should be discontinued.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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.gov.il

4.9

Overdose

As with other benzodiazepines, overdose should not present a threat to life unless combined with other

CNS depressants (including alcohol).

In the management of overdose with any medicinal product, it should be borne in mind that multiple

agents may have been taken.

a) Symptoms

Overdose of benzodiazepines is usually manifested by various degrees of CNS depression. In mild

cases, symptoms include drowsiness, mental confusion and lethargy. In more serious cases, symptoms

may include ataxia, hypotonia, hypotension, respiratory depression, rarely coma and very rarely death.

b) Management

Symptomatic measures are the mainstay of treatment.

Following overdose with oral benzodiazepines, vomiting should be induced (within one hour) if the

patient is conscious or gastric lavage undertaken with the airway protected if the patient is

unconscious. If there is no advantage in emptying the stomach, activated charcoal should be given to

reduce absorption.

Special attention should be paid to respiratory and cardiovascular functions, in an intensive care

setting where appropriate.

If necessary, the specific benzodiazepine antagonist flumazenil may be used as an antidote. The

Summary of Product Characteristics for flumazenil should be consulted prior to use.

Forced diuresis and haemodialysis are likely to be of limited value in pure brotizolam poisoning in

view of the large volume of distribution of the substance and the fact that it is extensively bound to

plasma proteins.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Hypnotics and sedatives, benzodiazepines

ATC code: N05CD09

Page 8 of 10

Brotizolam is a thienotriazolo diazepine derivative (hetrazepine) which binds specifically and with

high affinity to benzodiazepine receptors in the CNS and which therefore exhibits the characteristic

pharmacological properties of benzodiazepines.

It shortens sleep onset time, reduces nocturnal awakenings and increases total sleep time.

At the

recommended doses, changes in sleep architecture measured by electroencephalographic

activity occurred: the mean duration and percentage of REM sleep were reduced during the

first 6 hours of sleep.

In addition to its hypnotic effects, brotizolam demonstrated anxiolytic, sedative and muscle relaxant

effects in animal studies.

5.2

Pharmacokinetic properties

Absorption

Following oral administration, brotizolam is rapidly absorbed from the gastro-intestinal tract. After a

single oral dose of 0.25 mg, a mean peak plasma concentration of 5.5 ± 0.7 ng/ml is achieved within

45 ± 12 min. Absorption is an apparent first-order process with a mean half-life of 14.9 ± 8.5 min.

Absolute bioavailability following oral administration is about 70%

Distribution

Brotizolam is 89 - 95% bound to human plasma proteins and has an apparent distribution half-life of

between 7 and 26 min.

The areas under the plasma concentration-time curve (AUC) range from 31.0 ± 5.7 ng∙h/ml to 56.6 ±

21.3 ng∙h/ml. Brotizolam is well distributed throughout the human body; the mean apparent volume

of distribution is about 0.66 l/kg. In animals, brotizolam crosses the placental barrier and is excreted

in the milk.

Biotransformation

Brotizolam is metabolised in the liver by CYP 3A4-mediated oxidative reactions; hydroxylation at

various sites on the molecule (the methyl group and the diazepine ring) is the preferred metabolic

pathway.

All the hydroxylated metabolites are virtually completely conjugated with glucuronic and/or sulphuric

acid. These metabolites are less active than the parent compounds and it is assumed that they do not

contribute to the clinical effect.

Elimination

Following oral administration of brotizolam, about two-thirds of a dose is excreted renally; the

remainder is excreted via the faeces. Less than 1% of the dose is excreted in the urine as the parent

compound. The major metabolites of brotizolam,

-hydroxybrotizolam and 6-hydroxybrotizolam, can

be detected in the urine at concentrations of 27% and 7% respectively. Other highly polar metabolites

whi-ch are presumed to have more than one hydroxyl group, as well as a substance which is less polar

than brotizolam, can also be detected in the urine.

The mean elimination half-life of brotizolam from plasma is short and varies between 3 and 8 h in

healthy subjects. Brotizolam has been classified as a short-acting benzodiazepine. The mean apparent

oral clearance values for brotizolam following an oral dose of 0.25 mg range from 128.36 to 188.37

ml/min. The differences observed can be attributed to the methods of determination used (RIA and

GLC). Repeated daily doses of 0.25 mg did not lead to accumulation or to any change in the

pharmacokinetics of brotizolam compared to administration of a single dose.

Specific patient groups:

Page 9 of 10

Elderly

Following oral administration of 0.25 mg, the mean time to peak plasma concentration was slightly

higher in elderly patients (mean age 82 years) than in younger subjects (mean age 23 years) (1.7 h vs.

1.1 h). The mean peak concentration in elderly patients after an oral dose of 0.25 mg is about

5.6 ng/ ml, which is no different from the concentrations found in studies in young healthy subjects.

The eli-mination half-life following oral administration is significantly longer in elderly patients than

in you-ng volunteers (9.1 h vs. 5.0 h; P < 0.02). The absolute bioavailability of brotizolam in elderly

patients is about 66%. Following continuous administration of a 0.25-mg dose of brotizolam over

three weeks, neither accumulation nor faster elimination was observed. The pharmacokinetics of

brotizolam are linear up to a dose of 1.5 mg.

Renal impairment

The pharmacokinetics of brotizolam are essentially the same for all patients with renal impairment

irrespective of their creatinine clearance values (< 15 ml/min, 15 - 45 ml/min or 45 - 80 ml/min). The

mean plasma elimination half-lives for patients with mild, moderate and severe renal insufficiency

were 8.15 h, 6.90 h and 7.6 h respectively.

Hepatic impairment

In patients with hepatic cirrhosis, the peak absorption time and peak concentration of brotizolam are

similar to those observed in healthy subjects, whilst the protein binding and clearance of unbound

brotizolam are lower; the mean elimination half-life in patients with hepatic cirrhosis is 12.8 h

(9.4 - 25 h).

Alcohol

Concurrent alcohol consumption significantly reduces the clearance of brotizolam (1.85 ml/min/kg vs.

2.19 ml/min/kg), increases peak plasma concentrations (5.3 ng/ml vs. 4.3 ng/ml) and prolongs the

terminal elimination half-life (5.2 h vs. 4.4 h).

5.3

Preclinical safety data

Preclinical data reveal no special hazard for humans based on conventional studies of safety

pharmacology and single- and repeated-dose toxicity.

Effects in preclinical studies were observed only at exposures considered sufficiently in excess of the

maximum human exposure, indicating little relevance to human use.

In embryotoxicity studies carried out in rats at doses up to 30 mg/kg/day and in rabbits at doses up to

9 mg/kg/day, brotizolam did not have any embryotoxic or teratogenic effects. In rats, embryotoxic

effects were seen at maternotoxic doses of 250 mg/kg/day and above. Fertility was not impaired at

dos-es up to 10 mg/kg/day. In a study on peri- and postnatal development in rats, sedation and

reduced weight gain were seen in the dams and increased mortality was observed in the pups at doses

2.5 mg/kg/day (equivalent to 80 times the MRHD calculated on a body surface area basis (mg/m

Results of in-vitro and in-vivo tests did not reveal any evidence of a mutagenic potential for

brotizolam. Brotizolam did not show any carcinogenic potential in mice at doses up to 200

mg/kg/day. In the rat study, the NOAEL was 10 mg/kg/day. At 200 mg/kg/day, hyperplastic and

neoplastic changes we-re seen in the thyroid, thymus and uterus but these were considered

species-specific and therefore not relevant to use of the substance in man.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Lactose monohydrate, Starch Corn, Cellulose microcrystalline, Sodium starch glycolate, Magnesium

stearate.

Page 10 of 10

6.2

Incompatibilities

Not applicable

6.3

Special precautions for storage

Store below 25°C.

6.4

Nature and contents of containers

Packs of 10 or 20 tablets in blisters.

Not all pack sizes may be marketed.

6.5

Special precautions for disposal

Any unused product or waste material should be disposed of in accordance with national requirements.

7.

REGISTRATION HOLDER

Rafa Laboratories Ltd., P.O.Box 405, Jerusalem 9100301

8.

REGISTRATION NUMBER

120 37 26021 12

The format of this leaflet was determined by the Ministry of Health and its content was checked and approved in April 2017.