MOGADON 5 mg Cpr séc Plq PVC/Alu/5

Scored tablet.

Nitrazepam ....................................................................................................................................5,0 mg

For a scored tablet.

Excipient with known effect: this medicine contains lactose (100,0 mg/scored tablet).

Excipients:

The indications are limited to severe sleep disorders in the following cases:

• occasional insomnia,
• transient insomnia.

Oral use.

RESERVED FOR ADULTS.

Dose

In all cases, treatment will be initiated at the lowest effective dose and the maximum dose of 1 tablet per day will not be exceeded.

The usual dose in adults is 5 mg per day (i.e. 1 tablet per day), to be taken immediately before bedtime.

Elderly subjects, patients with renal or hepatic impairment:

It is recommended to reduce the dose, by half for example.

Duration

Treatment should be as short as possible, from a few days to 4 weeks, including the period of dose reduction (see section Warnings and precautions).

The duration of treatment must be presented to the patient:

• 2 to 5 days in cases of occasional insomnia (such as during a trip),
• 2 to 3 weeks in cases of transient insomnia (such as when a serious event occurs).

In some cases, it may be necessary to extend treatment beyond the recommended periods. This requires precise and repeated assessments of the patient's condition.

This medicine must never be used in the following situations:

• hypersensitivity to the active substance or to any of the other constituents,
• severe respiratory failure,
• sleep apnea syndrome,
• severe hepatic insufficiency, acute or chronic (risk of occurrence of encephalopathy),
• myasthenia,
• patients under 15 years of age.

Warnings

This medicine contains lactose. Patients with galactose intolerance, total lactase deficiency or glucose-galactose malabsorption syndrome (rare hereditary diseases) must not take this medicine.

An underlying cause of insomnia must be investigated before deciding to use a benzodiazepine.

Benzodiazepines are not recommended as first-line treatment for phobic or obsessive states, chronic psychosis, or psychotic disease.

If the patient is awakened during the period of maximum activity of the drug, memory may be impaired.

PHARMACOLOGICAL TOLERANCE

The sedative or hypnotic effect of benzodiazepines and related drugs may gradually decrease despite the use of the same dose when administered over several weeks.

DEPENDENCE

Any treatment with benzodiazepines and related medicinal products, and particularly with prolonged use, may lead to a state of physical and psychological drug dependence.

Various factors appear to favour the occurrence of dependence:

• duration of treatment,
• dose,
• history of other drug or non-drug dependences, including alcohol dependence.

Drug dependence may occur at therapeutic doses and/or in patients without any individualised risk factor.

This state may lead to a withdrawal phenomenon upon discontinuation of treatment.

Certain symptoms are common and appear trivial: insomnia, headaches, significant anxiety, myalgia, muscle tension, irritability.

Other symptoms are rarer: agitation or even confusional episode, paraesthesia of the extremities, hyperreactivity to light, noise and physical contact, depersonalisation, derealisation, hallucinatory phenomena, convulsions.

Withdrawal symptoms may appear within the days following discontinuation of treatment. For short-acting benzodiazepines, and especially if given at high doses, symptoms may even appear in the interval between two doses.

The combination of several benzodiazepines risks, whatever the anxiolytic or hypnotic indication, increasing the risk of drug dependence.

Cases of abuse have also been reported.

REBOUND PHENOMENON

This transient syndrome may manifest as an exacerbation of the insomnia that had prompted treatment with benzodiazepines and related drugs.

AMNESIA AND IMPAIRMENT OF PSYCHOMOTOR FUNCTIONS

Anterograde amnesia as well as impairment of psychomotor functions may occur within hours after intake and may last up to several hours.

To reduce these risks, it is advised to take the medicine immediately before going to bed (see section Dosage and administration) and to set up the most favorable conditions for an uninterrupted sleep period of several hours.

BEHAVIOURAL DISORDERS

In certain subjects, benzodiazepines and related products may cause a syndrome associating, to varying degrees, an alteration of the state of consciousness and behavioural and memory disorders:

The following may be observed:

• worsening of insomnia, nightmares, agitation, nervousness,
• delusional ideas, hallucinations, confusional-dreamlike state, psychotic-type symptoms,
• disinhibition with impulsivity,
• euphoria, irritability,
• anterograde amnesia,
• suggestibility.

This syndrome may be accompanied by disorders that are potentially dangerous for the patient or for others, such as:

• behaviour unusual for the patient,
• self- or other-directed aggressive behaviour, particularly if the entourage attempts to hinder the patient's activity,
• automatic behaviour with post-event amnesia.

These manifestations require discontinuation of treatment.

RISK OF ACCUMULATION

Benzodiazepines and related drugs (like all medicines) persist in the body for a period of the order of 5 half-lives (see section Pharmacokinetics).

In elderly patients or those suffering from renal or hepatic impairment, the half-life may be considerably prolonged. On repeated administration, the medicine or its metabolites reach the steady-state plateau much later and at a much higher level. Only after a steady-state plateau has been reached is it possible to assess both the efficacy and the safety of the medicine.

A dose adjustment may be necessary (see section Dosage and administration).

ELDERLY SUBJECTS

Benzodiazepines and related products should be used with caution in elderly subjects, due to the risk of sedation and/or muscle-relaxant effect which may favour falls, with consequences often serious in this population.

Special precautions for use

The greatest caution is recommended in cases of a history of alcoholism or other dependencies, drug-related or not (see section Interactions).

Insomnia may reveal an underlying physical or psychiatric disorder. Persistence or worsening of insomnia after a short treatment period requires re-evaluation of the clinical diagnosis.

DURATION OF TREATMENT

It must be clearly explained to the patient, depending on the type of insomnia (see section Dosage and administration).

IN SUBJECTS WITH A MAJOR DEPRESSIVE EPISODE

Benzodiazepines and related drugs should not be prescribed alone, as they allow depression to progress on its own, with persistence or increase of suicidal risk.

TERMS OF PROGRESSIVE TREATMENT DISCONTINUATION

These must be stated to the patient precisely.

In addition to the need for gradual dose reduction, patients should be warned of the possibility of a rebound phenomenon, in order to minimise the insomnia that could result from symptoms related to this discontinuation, even if gradual.

The patient must be warned that this phase may be uncomfortable.

ELDERLY SUBJECTS, RENAL IMPAIRMENT AND HEPATIC IMPAIRMENT

The risk of accumulation leads to reducing the dosage, by half for example (cf. Warnings).

RESPIRATORY IMPAIRMENT

In patients with respiratory insufficiency, the depressant effect of benzodiazepines and related drugs should be taken into account by reducing the dosage accordingly, since anxiety and agitation may constitute warning signs of decompensation of respiratory function, which justifies transfer to an intensive care unit.

RISKS RELATED TO CONCOMITANT USE OF OPIOIDS:

Concomitant use of Mogadon and opioids may lead to sedation, respiratory depression, coma or even death. Because of these risks, concomitant prescription of sedative medicinal products such as benzodiazepines or related medicinal products such as Mogadon with opioids should be reserved for patients for whom other treatment options are not possible. If the decision to prescribe Mogadon in combination with opioids is made, the lowest effective dose should be used and the duration of treatment should be as short as possible (See section Dosage and administration).

Patients must be closely monitored in order to identify any signs and symptoms of respiratory depression and sedation. In this regard, it is strongly recommended to inform patients and caregivers (where applicable) to be attentive to these symptoms (see section Interactions).

+ Sedative medicinal product

It must be taken into account that many medicinal products or substances can add together their depressant effects on the central nervous system and contribute to reduced alertness. These include opiate derivatives (analgesics, antitussives and substitution treatments), neuroleptics, barbiturates, benzodiazepines, anxiolytics other than benzodiazepines (for example, meprobamate), hypnotics, sedative antidepressants (amitriptyline, doxepin, mianserin, mirtazapine, trimipramine), sedative H1 antihistamines, centrally acting antihypertensives, baclofen and thalidomide.

+ Hypnotics

The hypnotics currently prescribed are either benzodiazepines and related compounds (zolpidem, zopiclone) or H1 antihistamines. In addition to increased sedation when prescribed with other CNS depressant medicinal products, or in cases of alcohol consumption, for benzodiazepines the possibility of increased respiratory depressant effect when combined with morphinomimetics, other benzodiazepines, or phenobarbital must also be taken into account, particularly in elderly subjects.

Combinations not recommended

+ Alcohol (beverage or excipient)

Alcohol increases the sedative effect of these substances.

Impaired alertness may make driving vehicles and using machines dangerous.

Avoid taking alcoholic beverages and medicines containing alcohol.

+ Sodium oxybate

Increased central depression. Impaired alertness may make driving vehicles and using machines dangerous.

Associations to be taken into account

+ Other hypnotics

Increased central depression.

+ Other sedative medicines

Increased central depression.

Impaired alertness may make driving vehicles and using machines dangerous.

+ Barbiturates

Increased risk of respiratory depression, which may be fatal in the event of overdose.

+ Buprenorphine

With buprenorphine used as substitution treatment: increased risk of respiratory depression, which may be fatal.

Carefully evaluate the benefit/risk ratio of this combination. Inform the patient of the need to comply with the prescribed doses.

+ Clozapine

Increased risk of collapse with respiratory and/or cardiac arrest.

+ Morphinics

Increased risk of respiratory depression, which may be fatal in the event of overdose.

+ Opioids

Concomitant use of sedative medicinal products such as benzodiazepines or related medicinal products such as Mogadon with opioids increases the risk of sedation, respiratory depression, coma or even death due to an additional depressant effect on the central nervous system (CNS). The dose and duration of concomitant treatment must be limited (See section Warnings and precautions).

Pregnancy

Numerous data from cohort studies have not shown the occurrence of malformative effects during exposure to benzodiazepines during the 1° trimester of pregnancy. However, in some epidemiological case-control studies, an increase in the occurrence of cleft lip and palate was observed with benzodiazepines. According to these data, the incidence of cleft lip and palate in newborns would be less than 2/1000 after exposure to benzodiazepines during pregnancy, whereas the expected rate in the general population is 1/1000. 

In case of intake of benzodiazepines at high doses during the 2° and/or 3° trimesters of pregnancy, a decrease in active fetal movements and variability of the fetal heart rate have been described. Treatment with benzodiazepines at the end of pregnancy, even at low doses, may be responsible in the newborn for signs of impregnation such as axial hypotonia and feeding difficulties resulting in poor weight gain. These signs are reversible, but may last 1 to 3 weeks depending on the half-life of the prescribed benzodiazepine. At high doses, respiratory depression or apneas, and hypothermia may occur in the newborn. Furthermore, a neonatal withdrawal syndrome is possible, even in the absence of signs of impregnation. It is characterized in particular by hyperexcitability, agitation and tremors in the newborn occurring some time after delivery. The time of onset depends on the elimination half-life of the drug and may be considerable when this is long.

Given these data, as a precautionary measure, the use of nitrazepam is not recommended during pregnancy, regardless of the stage of term.

When nitrazepam is prescribed to a woman of childbearing potential, she should be warned of the need to contact her doctor if a pregnancy is planned or begun so that the benefit of the treatment can be reassessed.

At the end of pregnancy, if it proves truly necessary to initiate treatment with nitrazepam, avoid prescribing high doses and take into account, for monitoring the newborn, the effects described previously.

Breast-feeding

The use of this medicine during breastfeeding is not recommended.

Warn drivers of vehicles and users of machinery of the possible risk of drowsiness.

The combination with other sedative medicinal products or with alcohol should be not recommended when driving motor vehicles or operating machinery (see section Interactions).

If the duration of sleep is insufficient, the risk of impaired alertness is further increased.

Patients must further be informed that alcohol may intensify the disorders, and therefore should be avoided during treatment.

They are related to the dose ingested and the individual sensitivity of the patient.

Neuro-psychiatric undesirable effects (see section Warnings and precautions)

• anterograde amnesia, which may occur at therapeutic doses, the risk increasing proportionally with the dose,
• behavioural disorders, changes in consciousness, irritability, aggressiveness, agitation, paradoxical reaction,
• physical and psychological dependence, even at therapeutic doses, with withdrawal or rebound syndrome upon discontinuation of treatment,
• feelings of dizziness, headache, ataxia,
• confusion, reduced vigilance or even drowsiness (particularly in the elderly), insomnia, nightmares, tension,
• changes in libido,
• drug abuse,
• dysarthria.

Disorders ocular

• diplopia.

Gastrointestinal disorders

• abdominal discomfort, nausea.

Skin and subcutaneous tissue disorders

• Skin rashes, pruritic or not.

Musculoskeletal and systemic disorders

• Muscular hypotonia.

General disorders and administration site conditions

• Rebound effect,
• Fatigue;

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. Healthcare professionals are asked to report any suspected adverse reaction via the national reporting system: National Agency for the Safety of Medicines and Health Products (ANSM) and the network of Regional Centres of Pharmacovigilance - Website: https://signalement.social-sante.gouv.fr/.

The vital prognosis may be threatened, particularly in cases of polyintoxication involving other central nervous system depressants (including alcohol).

Symptoms of overdose

In case of massive ingestion, signs of overdose manifest mainly as depression of the central nervous system ranging from drowsiness to coma, depending on the amount ingested.

Mild cases manifest as signs of mental confusion, drowsiness, lethargy, dysarthria.

The most serious cases manifest as ataxia, hypotonia, hypotension, respiratory depression, rarely coma, exceptionally death.

Treatment of overdose

In case of acute benzodiazepine intoxication, monitoring of cardiorespiratory functions and level of consciousness must be instituted. The use of activated charcoal makes it possible to reduce absorption.

Administration of flumazenil may be useful for the diagnosis and/or treatment of an intentional or accidental benzodiazepine overdose.

Antagonism of the effect of benzodiazepines by flumazenil may promote the occurrence of neurological disorders (convulsions), particularly in epileptic patients.

Pharmacotherapeutic class: HYPNOTICS AND SEDATIVES, ATC code: N05CD02.

(N: central nervous system)

Nitrazepam belongs to the class of 1-4 benzodiazepines and has a pharmacodynamic activity qualitatively similar to that of the other compounds of this class:

• muscle relaxant,
• anxiolytic,
• sedative,
• hypnotic,
• anticonvulsant,
• amnesic.

These effects are related to a specific agonist action on a central receptor forming part of the "GABA-OMEGA macromolecular receptor" complex, also called BZ1 and BZ2, and modulating the opening of the chloride channel.

Nitrazepam binds to specific benzodiazepine receptors located on the neurons

GABAergic and potentiates the inhibitory actions of GABAergic neurons of the nervous system. After prolonged treatment with nitrazepam, the development of tolerance has been observed. Chronic intake of a benzodiazepine leads to compensatory changes in the central nervous system. Either the GABA receptorsA become less sensitive to the continuous acute effects of benzodiazepines, or there is an adaptation of the GABA receptorA itself, intracellular mechanisms, or changes in the functioning of neurotransmitters. Probably multiple adaptation mechanisms coexist simultaneously.

An increase in the intensity and incidence of central nervous system toxicity has been observed with age, particularly at high doses. Consequently, the dose of Mogadon must not exceed 5 mg in elderly patients (see section Dosage and administration).

Absorption

The medicine is well absorbed in the gastrointestinal tract and peak plasma concentration is reached within 2 hours after administration. The bioavailability after oral intake is approximately 80% with significant intra-individual variability (from 53% to 97%). Results concerning the influence of food on the absorption of nitrazepam are contradictory. Food may cause a decrease and delay in absorption (up to 30%).

Distribution

Protein binding is 85% to 88% in adults and children. In young patients, the volume of distribution is 2-2,5 L/kg; in elderly patients the volume of distribution is higher (4,8 L/kg).

The distribution half-life is approximately 15 minutes. Maximum serum concentrations of

35-40 ng/mL are reached after oral administration of 5 mg of nitrazepam.

The plasma elimination half-life of nitrazepam varies between individuals from approximately 16 to 48 hours.

The percentage ratio between the mean concentration in cerebrospinal fluid and in plasma increases from 8,0% at 2 hours to 15,6% at 36 hours. The concentration in cerebrospinal fluid therefore corresponds to the protein-unbound fraction of the active substance in plasma.

A concentration-effect relationship could not be established for this class of products, due to the intensity of their metabolism and the development of tolerance.

Benzodiazepines cross the blood-brain barrier as well as the placenta and breast milk.

The foeto-maternal ratio of plasma concentration is approximately 0,6 early in pregnancy and approximately 0,9 late in pregnancy.

Nitrazepam is found in breast milk. The milk/plasma ratio is approximately 0,3.

The pharmacokinetics of nitrazepam correspond to an open two-compartment model.

Metabolism and elimination

The liver plays a major role in the metabolism of benzodiazepines, which explains the negligible percentage (1%) of unchanged nitrazepam found in urine. The metabolites of nitrazepam are formed by nitroreduction, acetylation and hydroxylation and do not have any notable pharmacological activity. They are then glucuronide-conjugated, resulting in water-soluble substances eliminated in the urine. One fifth of the dose is found in the faeces.

The main metabolic pathway consists of reduction followed by acetylation of the 7-nitro group. The main metabolites are 7 aminonitrazepam (ANZ) and 7 - acetamidonitrazepam (AANZ), which are all 2 clinically inactive. The isoenzymes CYP3A4 and CYP2D6 are involved in the metabolism of nitrazepam. Nitrazepam is neither an inducer nor an inhibitor of enzymes.

Elimination

The plasma half-life of nitrazepam is 30 hours on average. In cerebrospinal fluid, the half-life is approximately 70 hours. Nitrazepam is mainly excreted as urinary metabolites, approximately 60% of which are conjugated.

Steady state is reached in 5 days. No clear correlation has been demonstrated between blood levels of Mogadon and its clinical effects.

At-risk population

Elderly subject : hepatic metabolism decreases, as does total clearance, with increased steady-state concentrations, free fraction and half-lives. In elderly patients, the plasma elimination half-life rises to 40 hours. Doses should therefore be reduced.

Reproduction and developmental toxicity studies were carried out in mice, rats and rabbits. A potential embryo-foetolethal effect was demonstrated in rats and rabbits. In rats, the frequency of external and skeletal malformations was increased at doses greater than or equal to 75 mg/kg/day (i.e. at least 120 times the maximum recommended daily dose).

Nitrazepam impairs spermatogenesis in male rats.

No carcinogenicity study has been conducted with nitrazepam.

5 years.

No special precautions for storage.

No special requirements.

List I
Prescription duration limited to 28 day(s).

Marketing authorisation (AMM)

CIP 3400930271261 (PVC/Alu/5 blister).

Not reimbursed by Social Security.
Collection.