DORMICUM

Main information

  • Trade name:
  • DORMICUM 15 mg film-coated tablet
  • Dosage:
  • 15 mg
  • Pharmaceutical form:
  • film-coated tablet
  • Prescription type:
  • Prescription only
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • DORMICUM 15 mg film-coated tablet
    Finland
  • Language:
  • English

Therapeutic information

  • Therapeutic area:
  • Midazolam
  • Product summary:
  • Suitability for use in older adult patients Midazolami maleas Avoid using in older persons. Sedative. A short-acting. Significant adverse effects include drug addiction, rebound insomnia, cognitive disorder and risk for falls and traffic accidents. Paradoxically, may increase anxiety, restlessness and aggression. Take several interactions into account. Avoid consuming grapefruit juice during treatment.

Status

  • Source:
  • Fimea
  • Authorization status:
  • Marketing authorization granted
  • Authorization number:
  • 9054
  • Authorization date:
  • 20-03-2008
  • Last update:
  • 26-07-2018

Summary of Product characteristics: dosage, interactions, side effects

Dormicum

®

Midazolam

1.

DESCRIPTION

1.1.

Therapeutic/ Pharmacologic Class of Drug

Dormicum Tablet is a sleep-inducing agent belonging to the

benzodiazepines.

ATC code: N05CD08

1.2.

Type of Dosage Form

Tablets.

1.3.

Route of Administration

Oral use.

1.4.

Sterile / Radioactive Statement

Not applicable.

1.5.

Qualitative and Quantitative Composition

Active ingredient: midazolam as the maleate.

Tablets containing midazolam maleate equivalent to 7.5 mg

and 15 mg of midazolam.

Excipients: described as per local requirements (Dormicum

tablets

contain

anhydrous

lactose.

warning

related

lactose

monohydrate,

2.4.1

General

(Warnings

Precautions)).

2.

CLINICAL

PARTICULARS

2.1.

Therapeutic Indications

Short-term treatment of insomnia

Benzodiazepines are only indicated when the disorder is

severe, disabling or subjecting the individual to extreme

distress.

Sedation in premedication before surgical or diagnostic

procedures.

2.2.

Dosage and Administration

Duration

treatment

should

short

possible.

Generally the duration of treatment varies from a few days to

a maximum of 2 weeks. The tapering-off process should be

tailored to the individual. Treatment with Dormicum should

terminated

abruptly

(see

2.4.2

Drug

Abuse

Dependence).

In certain cases extension beyond the maximum treatment

period may be necessary; if so, it should not take place

without reevaluation of the patient’s status. Owing to the

rapid

onset

action

Dormicum

tablets

should

taken

immediately before going to sleep, and swallowed whole with

fluid. Dormicum can be taken any time of the day, provided

the patient is subsequently assured of at least 7 – 8 hours

undisturbed sleep.

Standard Dosage

Dosage range: 7.5 – 15 mg

Treatment should be started with the lowest recommended

dose. The maximum dose should not be exceeded because of

the increased risk of CNS adverse effects possibly including

clinically relevant respiratory and cardiovascular depression.

Premedication

In premedication, Dormicum should be given 30 – 60 minutes

before the procedure.

2.2.1.

Special Dosage Instructions

Elderly and/or debilitated patients

In elderly and/or debilitated patients the recommended dose is

7.5 mg.

Elderly patients showed a larger sedative effect, therefore

they may be at increased risk of cardio-respiratory depression

as well. Thus, Dormicum should be used very carefully in

elderly

patients,

needed,

lower

dose

should

considered.

Patients with hepatic impairment

In patients with impaired liver function, the recommended

dose is 7.5 mg. Dormicum should be used very carefully in

patients with hepatic impairment. If necessary a lower dose

should be considered (see 3.2.5 Pharmacokinetics in Special

Populations).

Patients with renal impairment

In patients with severe renal impairment, accumulation of the

major

midazolam

metabolite,

1’-hydroxymidazolam

glucuronide,

occur

resulting

more

apparent

prolonged

sedation

possibly

including

clinically

relevant

respiratory and cardiovascular depression. Dormicum should

therefore be dosed carefully in this patient population. The

recommended dose is 7.5 mg and when needed a lower dose

should be considered.

2.3.

Contraindications

Severe respiratory insufficiency;

Severe hepatic insufficiency;

Sleep apnea syndrome;

Children;

patients

with

known

hypersensitivity

benzodiazepines or to any component of the product;

Myasthenia gravis;

Concomitant

therapy

with

ketoconazole,

itraconazole, voriconazole, HIV protease inhibitors

including

ritonavir

boosted

protease

inhibitors

formulations

(see

2.4.4

Interactions

with

other

Medicinal Products and other Forms of Interaction).

2.4.

Warnings and Precautions

2.4.1.

General

Information should be given to the patients about following

warnings and precautions.

Tolerance

Some loss of efficacy to the hypnotic effects of short-acting

benzodiazepines may develop after repeated use for a few

weeks.

Duration of treatment

duration

treatment

with

benzodiazepine

hypnotics

should

short

possible

(see

Dosage

Administration),

should

exceed

weeks.

tapering-off

process

should

tailored

individual.

Extension beyond this period should not take place without

reevaluation of the situation.

Rebound insomnia

When discontinuing Dormicum therapy, insomnia may recur,

possibly with a higher severity than before starting treatment

(“rebound

insomnia”).

Rebound

insomnia,

transient

sundrome, may be accompanied by other reactions including

mood changes, anxiety and restlessness. The risk of rebound

phenomena

greater

after

abrupt

discontinuation

treatment. Therefore it is recommended that the dosage of

Dormicum is decreased gradually (see 2.4.2 Drug Abuse and

Dependence).

Amnesia

Dormicum

cause

anterograde

amnesia,

which

occurs

most frequently within the first few hours after ingesting the

product. In order to reduce the risk, patients should ensure

that they are able to have an uninterrupted sleep of 7 – 8 hours

(see 2.6 Undesirable effects).

Residual effects

Provided the oral dose of Dormicum is not larger than 15

mg/day and the patient is assured of at least 7 to 8 hours

undisturbed sleep, no residual effect is observed following

oral administration of Dormicum tablet in standard patients as

confirmed

clinical

observations

using

sensitive

pharmacological methods.

Psychiatric and ‘paradoxical’ reactions

Paradoxical

reactions

such

restlessness,

agitation,

irritability,

aggression,

more

rarely,

delusion,

anger,

nightmares,

hallucinations,

psychosis,

inappropriate

behaviour and other adverse behavioural effects are known to

occur when using benzodiazepines. Should this be so, use of

the drug should be discontinued.

These effects are more likely to occur in the elderly.

Specific patient groups

In elderly and/or debilitated patients, as well as in patients

with

respiratory

cardiovascular

impairment,

recommended dose is 7.5 mg. these patients may be more

sensitive to the clinical side effects of midazolam like cardio-

respiratory depression. Thus Dormicum should be used very

carefully in these patient populations and if needed a lower

dose

should

considered

(see

2.2.1

Special

Dosage

Instructions).

Dosage instructions for patients with hepatic and/or renal

impairment are described in section 2.2.1 Special Dosage

Instructions. Benzodiazepines are contraindicated in patients

with

severe

hepatic

insufficiency

they

precipitate

encephalopathy, see section 2.3 Contraindications.

Benzodiazepines

recommended

primary

treatment of psychotic illness. Benzodiazepines should not be

used alone to treat depression or anxiety associated

with

depression as suicide may occur in such patients.

Concomitant use of alcohol / CNS depressants

The concomitant use of Dormicum with alcohol or/and CNS

depressants should be avoided. Such concomitant use has the

potential to increase the clinical effects of Dormicum possibly

including

severe

sedation,

clinically

relevant

respiratory

and/or cardio-vascular depression (see 2.4.4 Interactions with

other Medicinal Products and other Forms of Interaction).

Medical history of alcohol or drug abuse

Dormicum

should

avoided

patients

with

medical

history of alcohol or drug abuse.

Co-medication with drugs that later CYP3A activity

Midazolam pharmacokinetics is altered in patients receiving

concomitantly

compounds

that

inhibit

induce

CYP3A.

consequently

clinical

adverse

effects

increased or decreased respectively (see 2.4.4 Interactions

with

other

Medicinal

Products

other

Forms

Interaction).

Lactose intolerance

Patients

with

rare

hereditary

problems

galactose

intolerance, the Lapp lactase deficiency or glucose-galactose

malabsoption should not take this medicine.

2.4.2.

Drug Abuse and Dependence

Dependence

Use of Dormicum 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 medical history of alcohol and/or drug abuse.

Withdrawal

Withdrawal

symptoms

consist

headaches,

muscle

pain, extreme anxiety, tension, restlessness, confusion and

irritability.

severe

cases

following

symptoms

occur:

derealization,

depersonalization,

hyperacusis,

numbness and tingling of the extermities, hypersensitivity to

light,

noise

physical

contact,

hallucinations

convulsions.

Since the risk of withdrawal phenomena/ rebound insomnia is

higher

after

abrupt

discontinuation

treatment,

recommended that the dosage be decreased gradually (see 2.2

Dosage and Administration and 2.4.1 General (Warnings and

Precautions).

2.4.3.

Ability to Drive and Use Machines

Sedation,

amnesia,

impaired

concentration

impaired

muscular function may adversely affect the ability to drive or

machines.

sleep

duration

insufficient,

likelihood of impaired alertness may be increased (see also

2.4.4 Interactions with Other Medicinal Products and other

Forms of Interaction).

2.4.4.

Interactions with other Medicinal Products

and other Forms of Interaction

Pharmacokinetic

Drug-Drug

Interaction

(DDI)

(See

2.3

Contraindications

and

2.4.1

General

(Warnings

and

Precautions))

Because

midazolam

almost

exclusively

metabolized

cytochrome P450 3 (CYP3A), modulators of CYP3A have the

potential to alter the plasma concentrations, and subsequently

the clinical effects of midazolam.

Increase

3-fold.

following

drugs

identified

strong/

moderate

inhibitors:

fluconazole,

clarithromycin,

telithromycin,

erythromycin,

diltiazem,

verapamil,

nefazodone,

aprepitant,

tabimoreline,

grapefruit juice.

Combination of midazolam with strong and moderate CYP3A

inhibitors

requires

a

careful

evaluation

of

the

patient

condition that could make the patient in particular sensitive to

the potential clinical side effects of midazolam (see 2.4.1

General (Warnings and Precautions)).

Weak inhibitors: Midazolam AUC increased by 1.25 to

< 2-fold or C

increased by 1.25 to < 2-fold. The

following drugs and gerbals are included in this category:

posaconazole,

roxithromycin,

cimetidine,

ranitidine,

fluvoxamine,

bicalutamide,

propiverine,

echinacea

purpurea, goldenseal.

Appropriate

clinical

monitoring

recommended

concomitant use with midazolam.

Drugs that induce CYP3A

Patients receiving a combination of midazolam with CYP3A

inducers may require a higher midazolam dose in particular if

midazolam is co0administered with strong CYP3A inducers.

Well

known

strong

CYP3A

inducers

include:

rifampicin,

carbamazepine,

phenytoin

while

moderate

CYP3A

inducers include efavirenz and St John’s wort.

Pharmacodynamic Drug-Drug Interactions (DDI)

co-administration

midazolam

with

other

sedative/

hypnotic

agents

likely

result

increased

sedative/hypnotic

effects.

Such

sedative/

hypnotic

agents

include

alcohol,

opiates/opioids

(when

they

used

analgesics,

antitussives

substitutive

treatments),

antipsychotics, other benzodiazepines used as anxiolytics or

hypnotics,

barbiturates,

propofol,

ketamine,

etomidate;

sedative antidepressants, antihistamines and centrally acting

antihypertensive drugs. Midazolam decreases the minimum

alveolar concentration (MAC) of inhalational anaesthetics.

Enhanced side effects such as sedation and cardiorespiratory

depression

also

occur

when

midazolam

administered with any centrally acting depressants including

alcohol. The combined influence of alcohol and midazolam

should

avoided

(see

2.4.1

General

(Warnings

Precautions)).

Please see section 2.7 Overdose for warning of other central

nervous system depressants, including alcohol.

2.5.

Use in Special Populations

2.5.1.

Pregnancy

Insufficient data are available on midazolam to assess its

safety during pregnancy. Benzodiazepines should be avoided

during pregnancy unless there is no safer alternative. If the

product is prescribed to a woman of childbearing potential,

should be

warned to contact her physician regarding

discontinuance of the product if she intends to become or

suspects that she is pregnant.

administration

midazolam

last

trimester

pregnancy or at high doses during labour has been reported to

produce irregularities in the foetal heart rate, hypotonia, poor

sucking and hypothermia and moderate respiratory depression

in the neonate.

Moreover, infants born to mothers who took benzodiazepines

chronically during the latter stages of pregnancy may have

developed physical dependence and may be at some risk of

developeing withdrawal symptoms in the postnatal period.

2.5.2.

Labor and Delivery

See 2.5.1 Pregnancy.

2.5.3.

Nursing Mothers

Since midazolam passes into breast milk, Dormicum should

not be administered to breast-feeding mothers.

2.5.4.

Pediatric Use

See 2.3 Contraindications.

2.5.5.

Geriatric Use

2.2.1

Special

Dosage

Instructions

2.4.1

General

(Warnings and Precautions).

2.5.6.

Renal Impairment

See 2.2.1 Special Dosage Instructions.

2.5.7.

Hepatic Impairment

See 2.2.1 Special Dosage Instructions.

2.6.

Undesirable Effects

2.6.1.

Post Marketing

Immune System Disorders: Hypersensitivity reactions may

occur in susceptible individuals.

Psychiatric Disorders: Confusional state, emotional disorder.

These phenomena occur predominantly at the start of therapy

and usually disappear with repeated administration. Libido

disorders have been reported occasionally.

Depression: pre-existing depression may be unmasked during

benzodiazepine use.

Paradoxical

reactions

such

restlessness,

agitation,

irritability,

aggression,

delusion,

anger,

nightmares,

hallucinations, psychosis, inappropriate behaviour and other

adverse

behavourial

effects

known

occur

with

benzodiazepines or benzodiazepine-like agents. Should this

be the case, the use of the drug should be discontinued. These

effects are more likely to occur in the elderly.

Dependence: Use (even at therapeutic doses) may lead to the

development of physical dependence: discontinuation of the

therapy

result

withdrawal

rebound

phenomena

including

rebound

insomnia,

mood

changes,

anxiety

restlessness (see 2.4.1 General (Warnings and Precautions).

Psychic drug dependence may occur. Abuse has been reported

in poly-drug abusers.

Nervous

System

Disorders:

Drowsiness

during

day,

headache,

dizziness,

decreased

alertness,

ataxia.

These

phenomena occur predominantly at the start of the therapy

and usually disappear with repeated administration.

When used as premedication, this product may contribute to

postoperative sedation.

Anterograde amnesia may occur with therapeutic doses, the

risk increasing at higher dosages. Amnestic effects may be

associated with inappropriate behaviour (see 2.4.1 General

(Warnings and Precautions)).

Eye

Disorders:

Diplopia,

this

phenomenon

occurs

predominantly at the start of therapy and usually disappears

with repeated administration.

Gastrointestinal

Disorders:

Gastrointestinal

disturbances,

have been reported occasionally.

Skin and Subcutaneous Tissue Disorders: Skin reactions have

been reported occasionally.

Musculoskeletal and Connective Tissue Disorders: Muscle

weakness, this phenomenon occurs predominantly at the start

therapy

usually

disappears

with

repeated

administration.

General

Disorders

and

Administration

Site

Conditions:

Fatigue, this phenomenon occurs predominantly at the start of

therapy and usually disappear with repeated administration.

Injury, Poisoning and Procedural Complications: There have

been reports of falls and fractures in benzodiazepine users.

The risk is increased in those taking concomitant sedatives

(including alcoholic beverages) and in the elderly.

Respiratory Disorders: Respiratory depression was reported.

Cardiac Disorders: Cardiac failure including cardiac arrest

was reported.

2.7.

Overdose

Symptoms

Benzodiazepines

commonly

cause

drowsiness,

ataxia,

dysarthria and nystagmus. Overdose of Dormicum is seldom

life-threatening, if the drug is taken alone, but may lead to

areflexia,

apnea,

hypotonia,

hypotension,

cardiorespiratory

depression and rare cases to coma. Coma, if it occurs, usually

lasts a few hours but it may be more protracted and cyclical,

particularly in elderly patients. Benzodiazepine respiratory

disease.

Benzodiazepines increase the effects of other central nervous

system depressants, including alcohol.

Treatment

Monitor

patient’s

vital

signs

institute

supportive

measures

indicated

patient’s

clinical

state.

particular, patients may require symptomatic treatment for

cardiorespiratory effects or central nervous system effects.

If taken orally further absorption should be prevented using

an appropriate method e.g. treatment within 1 – 2 hours with

activated

charcoal.

activated

charcoal

used

airway

protection is imperative for drowsy patients. In case of mixed

ingestion gastric lavage may be considered, however not as a

routine measure.

If CNS depression is severe consider the use of flumazenil

(Anexate

), a benzodiazepine antagonist. This should only be

administered under closely monitored conditions. It has a

short half-life (about an hour), therefore patients administered

flumazenil will require monitoring after its effects have worn

off. Flumazenil is to be used with extreme caution in the

presence of drugs that reduce seizure threshold (e.g. tricyclic

antidepressants).

Refer

prescribing

information

flumazenil (Anexate

), for further information on the correct

use of this drug.

3.

PHARMACOLOGICAL

PROPERTIES

AND

EFFECTS

3.1.

Pharmacodynamic Properties

3.1.1.

Mechanism of Action

Dormicum is a sleep-inducing agent characterized by a rapid

onset and short duration of action. It also exerts an anxiolytic,

hypnotic,

anticonvulsant

muscle-relaxant

effect.

Dormicum impairs psychomotor function after single and/or

multiple doses but causes minimal haemodynamic changes.

As for other benzodiazepines, it is believed that the effects of

Dormicum

mainly

mediated

agonistic

binding

gamma-aminobutyric acid receptors (GABA

) in the CNS.

hypothesis

that

benzodiazepines

directly

activate GABA

receptors, but require the endogenous ligand,

i.e. GABA, to exert the effects.

3.2.

Pharmacokinetics Properties

3.2.1.

Absorption

Midazolam

absorbed

rapidly

completely

after

oral

administration.

substantial

first-pass

effect,

absolute

bioavailability of oral midazolam ranges between is 30 –

50%. The pharmacokinetics of midazolam is linear in the 7.5

– 20 mg oral dose range.

After a dose of single administration of a Dormicum 15 mg

tablet, maximum plasma concentrations of 70 – 120 ng/ ml

are reached within one hour. Food prolongs the time to peak

plasma

concentration

around

hour,

pointing

reduced absorption rate of midazolam. The absorption half-

life is 5 – 20 minutes.

3.2.2.

Distribution

The tissue distribution of midazolam is very rapid and in most

cases a distribution phase is not apparent or is essentially

finished within 1 – 2 hours after oral administration. The

volume of distribution at steady state is 0.7 – 1.2 l / kg. 96 –

98% of midazolam is bound to plasma proteins. The major

fraction of plasma protein binding is due to albumin. There is

slow

insignificant

passage

midazolam

into

cerebrospinal fluid. In humans, midazolam has been shown to

cross the placenta slowly and to enter fetal circulation. Small

quantities of midazolam are found in human milk.

3.2.3.

Metabolism

Midazolam

almost

entirely

eliminated

biotransformation. Less than 1% of the dose is recovered in

urine

unchanged

drug.

Midazolam

hydroxylated

cytochrome

P450,

CYP3A

isozymes.

Both

isozymes,

CYP3A4

also

CYP3A5

actively

involved

hepatic oxidative metabolism of midazolam.

There

main

oxidized

metabolites

1’-

hydroxymidazolam (also named α-hydroxymidazolam) and 4-

hydroxymidazolam.

1’-hydroxymidazolam

major

urinary and plasma metabolite. 60 – 80% of the dose is

glucuronidated

excreted

urine

form

1’-

hydroxymidazolam conjugate. Plasma concentrations of 1’-

hydroxymidazolam may reach 30 – 50% those of the parent

compound. 1’-hydroxymidazolam is pharmacologically active

and contributes significantly (about 34%) to the effects of oral

midazolam.

Previous

investigation

show

clinically

relevant

genetic

polymorphism

oxidative

metabolism

midazolam.

3.2.4.

Elimination

young

healthy

volunteers,

elimination

half-life

midazolam ranges between 1.5 to 2.5 hours. Midazolam is a

non-accumulating

drug

when

given

once

daily.

Repeated

administrations

midazolam

induce

drug-

metabolizing enzymes.

elimination

half-life

1’-hydroxymidazolam

metabolite is shorter than 1 hour.

3.2.5.

Pharmacokinetics in Special Populations

Elderly

In elderly male subjects over 60 years of age, the elimination

half-life of midazolam was significantly prolonged by a factor

compared

with

younger

male

subjects.

Total

midazolam

clearance

significantly

reduced

male

elderly subjects and the bioavailability of the oral tablet was

significantly increased. However no significant differences

were

observed

elderly

female

compared

younger

subjects.

Patients with hepatic impairment

pharmacokinetics

midazolam

were

significantly

modified

patients

with

chronic

liver

disease

including

advanced liver cirrhosis. In particular, as a consequence of a

decreased

liver

clearance,

elimination

half-life

prolonged and the absolute bioavailability of oral midazolam

was significantly increased in cirrhotic patients compared to

control.

Patients with renal impairment

The pharmacokinetics of midazolam are not altered in patients

with chronic renal failure. However the major midazolam

metabolite,

1’-hydroxymidazolam

glucuronide,

which

excreted through the kidney, accumulates in patients with

severe chronic renal failure. This accumulation produces a

prolonged

sedation.

Oral

midazolam

should

therefore

administered carefully in patients with renal impairment.

Obese patients

In obese patients the volume of distribution of midazolam is

increased. As a consequence, the mean elimination half-life of

midazolam is longer in obese than in non-obese patients (5.9

hours vs 2.3 hours). The oral bioavailability of the midazolam

tablet was not different in obese patients compared to non-

obese patients.

4.

PHARMACEUTICAL

PARTICULARS

4.1.

Storage

Dormicum Film-Coated Tablets 15 mg: Keep container in

outer carton in order to protect from light.

This medicine should not be used after the expiry date (EXP)

shown on the pack.

5.

PACKS

Tablets 7.5 mg (white) 10

Tablets 15 mg (blue) 10, 20, 30, 100

Not all pack sizes are available for sale.

Medicine: keep out of reach of children

Current at Jul 2013

Made for F. Hoffmann-La Roche Ltd,

Basel, Switzerland

By Productos Roche S.A. de C.V.

Toluca, Mexico