1.

Denomination of the pharmaceutical specialty

SEDOXIL

2. Qualitative and quantitative composition

Mexazolam, 1 mg.

3. Pharmaceutical form
Uncoated tablets

4. Clinical information
4.1. Therapeutic indications
SEDOXIL is indicated for the treatment of anxiety associated or not with states
psychoneurotics.
Benzodiazepines are only indicated when these situations are severe, incapacitating, or
they create a marked state of suffering

4.2. Dosage and administration

The dose of SEDOXIL should be individualized according to the severity of the symptoms and the age of the
sick.
Adults: on average 1.0 to 3.0 mg per day, preferably divided into 3 doses.
Elderly: do not exceed a dose of 1.5 mg per day.
Children: SEDOXIL is not intended for pediatric use.
The treatment of anxiety should be as short as possible. The patient should be observed.
periodically, reassessing the need to continue treatment, especially if it is
assintomático. A duração total do tratamento não deve exceder oito a doze semanas incluindo o
discontinuation period. In some cases, it may be necessary to extend the period of
treatment beyond the maximum recommended time. If so, this should not happen without
a preliminary consultation by a specialist.
In all cases, treatment should start with the recommended minimum dose.
In case of missing one or more doses, do not take the dose if more than one hour has passed.
Never double the dose.
The patient should be regularly monitored at the beginning of treatment in order to reduce the dose or the
frequency of administration in case it is necessary to prevent an overdose
due to accumulation.
4.3. Contraindications
Myasthenia gravis, hypersensitivity to benzodiazepines, severe respiratory failure,
sleep apnea syndrome and severe liver failure.

4.4. Warnings and special precautions for use

Dependence
The use of benzodiazepines can lead to the development of psychic and physical dependence.
for these drugs. The risk of dependence increases with the dose and duration of treatment; it is
also greater in patients with a history of drug addiction or alcoholism.
Once the physical dependency is established, the abrupt interruption of treatment will be
accompanied by withdrawal symptoms. These may consist of headaches, muscle pain,
extreme anxiety, tension, restlessness, confusion, and irritability. In severe cases the
the following symptoms may occur: derealization, depersonalization, hyperacusis,
numbness and tingling in the extremities, hypersensitivity to light, noise, and contact
physical, hallucinations or epileptic seizure.
Anxiety rebound
A transient syndrome, in which the symptoms that led to treatment with a
benzodiazepines reappear in an aggravated form, can occur upon withdrawal of the
treatment. It may be accompanied by other reactions including mood changes,
anxiety or sleep disturbances and restlessness. Once the risk of the phenomena of
deprivation/rebound phenomena are greater after a sudden interruption of treatment, it is recommended
I know that the dose should be gradually decreased.
Duration of treatment
The duration of the treatment should be as short as possible (see dosage and method of ...
administration) depending on the indication, but should not exceed 8 to 12 weeks in the case of

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 anxiety, including the discontinuation period. The extension of treatment beyond
these periods should not be made without a reassessment of the situation. When one starts the
treatment can be helpful to inform the patient that it will have a limited duration, explaining to them
precisely how the gradual decrease of the dose will be carried out. It is also important that the
the patient should be informed about the possibility of the rebound phenomenon occurring, minimizing
thus anxiety occurs when such symptoms arise during the discontinuation of
drug.
When a long-acting benzodiazepine like mexazolam is used, one does not
must switch to a short-acting benzodiazepine, as such action could
lead to the appearance of withdrawal symptoms.
Amnesia
Benzodiazepines can induce anterograde amnesia. This happens more frequently
várias horas após ingerir o produto e assim, para diminuir o risco, os doentes devem assegurar a
possibility of having an uninterrupted sleep period of 7-8 hours (see also the effects)
undesirable)
Paradoxical and psychiatric reactions
When using benzodiazepines, restlessness, agitation, irritability may occur.
aggressiveness, illusions, fury, nightmares, hallucinations, psychoses, inappropriate behaviors and
other behavioral side effects. If this occurs, the medication should be discontinued. These
reactions are more likely to occur in children and the elderly. With mexazolam, there were
paradoxical reactions in schizophrenic patients.
Specific groups of patients
The elderly should receive a smaller dose (see dosage). A smaller dose is also
recommended for patients with chronic respiratory failure, due to the risk of depression
respiratory.
Benzodiazepines are not indicated in the treatment of patients with liver failure.
serious since they can precipitate encephalopathy.
Benzodiazepines are not recommended for the primary treatment of psychotic disorder.
Benzodiazepines should not be used alone to treat depression or anxiety.
associated with depression (can precipitate suicide in these patients).
Benzodiazepines should be used with extreme caution in patients with a history of
drug addiction or alcoholism.
Mexazolam should be used with great caution in patients with impaired functions.
cardiac, renal or hepatic, and in patients with organic brain injury.

4.5. Drug interactions and others

Not recommended: the concurrent intake of alcohol
The sedative effect may be enhanced when mexazolam is used in combination with the
alcohol, affecting the ability to drive or operate machinery.
Take precautions: in combination with CNS depressants
The worsening of the central depressant effect may occur when using SEDOXIL in
simultaneous with antipsychotics (neuroleptics), hypnotics, anxiolytics/sedatives, drugs
antidepressants, narcotic analgesics, antiepileptic drugs, anesthetics and anti-
sedative antihistamines.
In the case of narcotic analgesics, an exacerbation of euphoria can also occur.
leading to an increase in physical dependency.
In the experimental animals, the following interactions were observed:
Drugs that enhanced the effect of mexazolam: chlorpromazine, haloperidol, diazepam.
ciproheptadine, aminopyrine, phenobarbital, ethanol, sulpiride, trichlormethiazide, and alpha-methyl-dopa.
Drugs that antagonized the effect of mexazolam: imipramine, amitriptyline and
chlorpheniramine.
Drugs that showed no interaction with mexazolam: diphenylhydantoin,
scopolamine butylbromide, gerfanate, propranolol, and pindolol.

4.6. Use in case of pregnancy and lactation

Although animal experience does not suggest any harmful effect of mexazolam during the
Pregnancy, the safety during pregnancy in the human species is not established.
Benzodiazepines can cause congenital malformations when administered during
first trimester of pregnancy. If for medical reasons mexazolam is administered
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 late in pregnancy or during childbirth in high doses, can arise in the newborn
the following effects: hypothermia, hypotonia, and moderate respiratory depression.
The children of mothers who chronically took benzodiazepines during pregnancy
they may have developed physical dependence thus putting themselves at risk of experiencing
symptoms of deprivation in the postpartum period.
Since mexazolam can be found in breast milk, it should not be administered to
women breastfeeding.
Every woman of childbearing age should contact her doctor if she intends to or suspects she is.
pregnant.

4.7. Effects on the ability to drive and use machines

The sedation, amnesia, alteration of concentration and muscle function resulting from
administration of SEDOXIL may negatively affect the ability to drive and
use of machines. If the sleep period is insufficient, it increases the probability of
alert state is found to be altered (see also interactions).

4.8. Undesirable effects

The undesirable effects of benzodiazepines are almost always an extension of their
pharmacological actions and include daytime drowsiness, emotional blunting, reduction of state
alertness, confusion, fatigue, headaches, feeling of an empty head, muscle weakness, ataxia or
diplopia.
With mexazolam, changes in tongue movements occurred rarely (<0.1%).
hypotension, feeling of an empty head, nausea, vomiting, anorexia, gastric discomfort, pain
gastric, abdominal pain, diarrhea, hypersensitivity symptoms (e.g., rashes
cutaneous), decreased libido, increased alkaline phosphatase, anemia and leukopenia.
Infrequently (0.1 - 5%) there were drowsiness, dizziness, lightheadedness, headaches, ataxia, dry mouth
dryness, weakness, elevation of glutamic-oxaloacetic transaminases and glutamic-pyruvic transaminases and elevation
gamma-glutamyltranspeptidase.
Undesirable effects usually occur in the first few days of treatment and typically
they disappear with the continuation of the therapy.
Amnesia
Anterograde amnesia can occur when therapeutic doses of benzodiazepines are used.
increasing the risk when doses are raised. Amnesic effects may be associated
inappropriate behaviors (see warnings and special usage precautions).
Depression
A pre-existing depression may become evident during the use of benzodiazepines.
Psychiatric and paradoxical reactions
Reactions such as restlessness, agitation, irritability, aggression, delusions, fury, nightmares,
hallucinations, psychoses, inappropriate behavior and other adverse behavioral effects
they can occur and be particularly severe with benzodiazepines. These reactions are more
probability of occurring in children and the elderly.
Dependency
The use of SEDOXIL, even in therapeutic doses, can lead to the development of
physical dependence: the interruption of the therapy can result in withdrawal phenomena or
rebound (see warnings and special usage precautions). Dependence may occur.
psychic. There have been reports of abuse in the use of benzodiazepines.

4.9. Symptoms and treatment of overdose

As with other benzodiazepines, an overdose with SEDOXIL is not
life-threatening unless combined with other central nervous system depressants,
including alcohol.
In the treatment of overdose with any drug, one must be aware of the possibility of
several products have been ingested.
After an overdose of SEDOXIL taken orally, vomiting should be induced (within the
one hour period) if the patient is conscious or proceed with gastric lavage (with
prior placement of an endotracheal tube to prevent aspiration of vomit), if the patient
is unconscious. If there is no benefit in gastric emptying, it should be administered
activated charcoal to reduce the absorption of SEDOXIL. The respiratory and cardiovascular functions
They should be under special surveillance in an intensive care unit.

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 The overdose of benzodiazepines usually manifests as depression of the system
central nervous system in degrees ranging from drowsiness to coma. In mild cases, the symptoms
include drowsiness, mental confusion, and lethargy; in more severe cases, the symptoms may
include ataxia, hypotonia, hypotension, respiratory depression, rarely coma and very rarely
death.
Flumazenil (a specific antagonist for benzodiazepine receptors) can be helpful.
as an antidote.

5. Pharmacological Properties
5.1. Pharmacodynamic properties
Therapeutic drug category: II - 8-a - Anxiolytics, sedatives and hypnotics
ATC Classification: N05 BA
SEDOXIL is a benzodiazepine. As a rule, benzodiazepines act as depressants.
the central nervous system producing all levels of depression from mild sedation to
hypnosis and coma, depending on the dose.
The sites and mechanisms of action are not fully defined. It has been found that the
benzodiazepines influence neurotransmission mediated by gamma-aminobutyric acid
(GABA), through the stimulation of specific receptors. Binding to these receptors can
is modulated either by GABA or by the chloride ion.
Sedative effects - it has been demonstrated in mice, rats, hamsters, and monkeys that mexazolam
provokes a greater inhibition of conflict, violence, aggression, and excitement that
diazepam. Studies in cats and rabbits suggest that these sedative effects may
result of the drug's action on the limbic system, including the amygdala and the hypothalamus.
Anticonvulsant effects - it has been demonstrated in mice, rats, and monkeys that mexazolam
provokes a greater inhibitory effect on convulsions induced by megimide and pentetrazol than the
diazepam.
Muscle relaxing effects - mexazolam inhibited decerebrate rigidity and depressed the
activity of gamma motor neurons in cats.
Influence on motor function - it has been demonstrated in mice, rats, and dogs that the influence of
mexazolam on motor function (for example, inhibition of spontaneous motor activity, effect
muscle relaxant, inhibitory effect on the maintenance reflex in standing and ataxic effect), is limited.

5.2. Pharmacokinetic properties

After the administration of mexazolam by mouth, the unchanged drug is not detected in
blood. Only its active metabolites CND (chloronordazepam) and COX are found.
(cloroxazepam). It is assumed that in the liver, mexazolam will be hydroxylated and conjugated through
two metabolic pathways, one type benzodiazepine (active metabolites) and another type benzophenone
(inactive metabolites).
CND is the main plasma metabolite of mexazolam. With a single dose of mexazolam,
the maximum plasma concentration of the CND is reached after 1 to 2 hours. The apparent volume
the distribution is 150 L. The applicable pharmacokinetic model is of the bi-compartmental type. After
Repeated administration, the half-life of CND and COX is long (130 to 200 h).
The binding to proteins is > 90% for CND and COX.
Less than 10% of the dose of mexazolam administered orally is eliminated in the form of
metabolites in urine, with most of the drug being excreted in bile. The COX accounts for >
50% of the total metabolites excreted, mainly found in conjugated form.

5.3. Preclinical safety data

Studies were conducted with mexazolam in various animal species including the mouse.
rat, rabbit, dog, and monkey, which demonstrated a wide margin of safety and a
very low toxic capacity. In fact, the DL50for the oral route was 4.687 mg/kg in the mouse,
8100 mg/kg in Wistar-Imamichi rats and 1400 mg/kg in Fischer rats.
In subacute toxicity studies in rats (10, 30, 125, 250, 500, and 1500 mg/kg, orally, 5
(weeks) there was only mortality in the group that received 1500 mg/kg. The hypertrophy of hepatocytes.
occurred with doses equal to or greater than 250 mg/kg, but disappeared after discontinuation of the
drug. The administration of mexazolam, orally, for 26 weeks, in rats that
received daily doses of 2, 10, 50, or 125 mg/kg showed that the weight of the liver, kidneys and
adrenal glands increased in females of the group that received the highest dose.
However, the histological examination did not detect significant changes. No changes were observed.

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 changes in mating or fertility in male rats (2, 10 or 20 mg/kg for 9 weeks)
no lethal or teratogenic effects on the fetuses of female rats (2, 10, or 20 mg/kg, from day 14
days before copulation until the 7th day of gestation). The administration of mexazolam during the period of
organogenesis (mouse - 2, 10 or 20 mg/kg/day for 11 days; rabbit - 0.04, 0.2, 1 or 5 mg/kg/day
during 13 days) did not cause death or teratogenic effects in the embryos and fetuses.
administration of mexazolam during the perinatal period and breastfeeding period (rats - 2,
10 or 10 mg/kg/day for 4 weeks starting from the 17th day of gestation) did not cause changes
during labor, breastfeeding or offspring (external anomalies, postnatal differentiation time
and reproductive). Mexazolam did not show mutagenic potential in vitro, in the test
of reversion and noRec-assay. The antigenicity of mexazolam was investigated in guinea pigs and
rabbits having no evidence of exercising antigenic power.

6. Pharmaceutical information
6.1. List of excipients
Mannitol, corn starch, hydroxypropyl cellulose, sodium lauryl sulfate, and calcium stearate.

6.2. Incompatibilities
They are not known.

6.3. Expiration date

5 years.

6.4. Specific conservation precautions

The product must be kept away from light.

6.5. Nature and content of the container

The tablets are packaged in PVC and aluminum blisters with 10 tablets each.

6.6. Instructions for use and handling

No special usage or handling instructions are required.

7. Holder of the Market Introduction Authorization

MediBIAL – Medical and Pharmaceutical Products, S.A.
At Av. da Siderurgia Nacional
4745-457 S. Mamede do Coronado

8. Authorization Number for Market Introduction

9728220 - INFARMED

9. Date of Renewal of the Authorization for Market Introduction

1999.10.30

10. Date of the (partial) review of the text

2000.07.28