Active ingredients: Diazepam
MICROPAM 5 mg / 2.5 ml Rectal solution
MICROPAM 10 mg / 2.5 ml Rectal solution
Why is Micropam used? What is it for?
PHARMACOTHERAPEUTIC CATEGORY
Anxiolytic, benzodiazepine derivative.
THERAPEUTIC INDICATIONS
As an antiepileptic: convulsions including febrile convulsions in children.
As a sedative: before exploratory examinations and treatments.
Contraindications When Micropam should not be used
Micropam is contraindicated in patients with:
- Hypersensitivity to the active substance, to benzodiazepines or to any of the excipients listed under "Composition"
- Myasthenia gravis.
- Sleep apnea syndrome.
- Severe hepatic insufficiency.
- Severe respiratory failure.
- Pregnancy.
- Feeding time.
Precautions for use What you need to know before taking Micropam
Concomitant use of alcohol / CNS depressants
The concomitant use of diazepam with alcohol and / or drugs with central nervous system depressant activity should be avoided. Concomitant use as it may increase the clinical effects of diazepam, including possible deep sedation and respiratory and / or cardiovascular depression clinically relevant (see "Interactions").
Medical history of alcohol or drug abuse
Diazepam should be used with extreme caution in patients with a history of drug or alcohol abuse. Tolerance After repeated use for a few weeks, there may be a reduction in the hypno-inducing effect of benzodiazepines.
Dependence
Treatment with diazepam can lead to the development of physical and psychological dependence. The risk increases with dose and duration of treatment; it is greater in patients with a history of drug or alcohol abuse or in patients with marked personality disorders. Regular monitoring is essential in these patients, routine repeat prescriptions should be avoided and treatment should be discontinued gradually.
Interruption
Once the physical dependence has developed, the abrupt termination of treatment will be accompanied by withdrawal symptoms. These can consist of headache, body aches, extreme anxiety, tension, restlessness, confusion and irritability. In severe cases, the following symptoms may occur: derealization, depersonalization, hyperacusis, numbness and tingling of the extremities, hypersensitivity to light, noise and physical contact, hallucinations or seizures.
Rebound insomnia and anxiety
Upon discontinuation of treatment, a transient syndrome may occur which consists of the accentuated reappearance of the symptoms that led to treatment with benzodiazepines. It may be accompanied by other reactions such as mood changes, anxiety or sleep disturbances and restlessness. Since the risk of withdrawal or rebound symptoms is more pronounced after an abrupt discontinuation of treatment, it is recommended to gradually decrease the dosage.
Abrupt discontinuation of diazepam treatment in patients with epilepsy or in patients with a history of seizures may lead to seizures or status epilepticus. Convulsions can also be observed following abrupt cessation in people with a history of alcohol or drug abuse. Discontinuation should be gradual in order to minimize the risk of withdrawal symptoms.
Duration of treatment
The duration of treatment should be as short as possible (see "Dose, method and time of administration") depending on the indication. The patient should be evaluated after a period of no more than four weeks and followed up on a regular basis in order to assess the need for continued treatment, especially if the patient is symptom-free. In general, treatment should not last more than 8-12 weeks, including the withdrawal process period. Extending therapy beyond these periods should not occur without reassessment of the clinical situation.
It may be helpful 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. It is also important that the patient is aware of the possibility of rebound phenomena, thus minimizing the anxiety about these symptoms that could occur upon discontinuation of the drug. There are elements to predict that in the case of benzodiazepines with a short duration of action, the Withdrawal symptoms may become manifest within the dosing interval between doses, particularly for high doses.
When using benzodiazepines with a long duration of action it is important to warn the patient against changing to a benzodiazepine with a short duration of action, as withdrawal symptoms may occur.
Like any psychiatric drug, the dosage of MICROPAM Rectal Solution must be established according to the tolerance which varies greatly from subject to subject in patients with cerebral organic changes (especially atherosclerotic) or with cardio-respiratory insufficiency. Since benzodiazepines can cause a slight fall in blood pressure or, in occasional circumstances, transient respiratory compromise, measures to support circulation or breathing should be available. In case of prolonged treatment it is advisable to check the haematological picture and liver function.
Amnesia
Anterograde amnesia can also occur when benzodiazepines are used within the normal dosage ranges, although this has been seen in particular with high doses. This occurs more often several hours after ingestion of the drug and, therefore, to reduce the risk it should be ensured that patients can have an uninterrupted sleep of 7-8 hours (see also "Undesirable effects"). Amnesic effects can be associated with inappropriate behavior.
Psychiatric and "paradoxical" reactions
Paradoxical reactions (restlessness, agitation, irritability, aggression, disappointment, anger, nightmares, hallucinations, psychosis, inappropriate behavior and other adverse behavioral effects) have been reported with the use of benzodiazepines. These reactions are possibly more frequent in children and adolescents. elderly and must lead to discontinuation of treatment.
Interactions Which drugs or foods can modify the effect of Micropam
Pharmacodynamic interactions
If diazepam is used with other centrally acting agents, the pharmacology of the agents used should be carefully considered, especially in the case of substances that can potentiate or are potentiated by the action of diazepam, such as neuroleptics, anxiolytics / sedatives, hypnotics, antidepressants, anticonvulsants, antihistamines with sedative effect, antipsychotics, anesthetics for general anesthesia and narcotic analgesics. Such concomitant use may increase the sedative effects and cause depression of respiratory and cardiovascular functions. The concomitant use of narcotic analgesics may promote psychic dependence due to of the enhancement of the euphoric effect.
Concomitant use not recommended
Alcohol
Alcohol should not be consumed during diazepam treatment due to additive CNS inhibition and increased sedation (see "Special Warnings"). This adversely affects the ability to drive or use machines.
Phenobarbital
Mechanism: additive inhibition of the CNS
Effect: increased risk of sedation and respiratory depression.
Clozapine
Mechanism: pharmacodynamic synergism
Effect: severe hypotension, respiratory depression, unconsciousness and life-threatening respiratory and / or cardiac arrest. Therefore concomitant use is not recommended and should be avoided.
Special caution for concomitant use
Theophylline
Mechanism: One hypothesis of mechanism is the competitive binding of theophylline to brain adenosine receptors.
Effect: inhibition of the pharmacodynamic effects of diazepam, e.g. reduction of sedation and psychomotor effects.
Muscle relaxants (suxamethionine, tubocurarine)
Mechanism: possible pharmacodynamic antagonism
Effect: intensity modification of neuromuscular block
Pharmacokinetic interactions
Diazepam is mainly metabolised to the pharmacologically active metabolites Ndesmethyldiazepam, temazepam and oxazepam. The oxidative metabolism of diazepam is mediated by CYP3A4 and CYP2C19 isoenzymes. Oxazepam and temazepam are further conjugated with glucuronic acid. CYP3A4 and / or CYP2C19 inhibitors can lead to increased diazepam concentrations while enzyme-induced drugs can lead to a substantial decrease in diazepam plasma concentrations.
Concomitant use not recommended
Inducers
Rifamycins (rifampicin)
Mechanism: Rifampicin is a potent inducer of CYP3A4 and substantially increases hepatic metabolism and clearance of diazepam. In a study with healthy subjects given 600 mg or 1.2 g of rifampicin / day for 7 days, diazepam clearance was increased approximately 4-fold. Co-administration with rifampicin leads to a substantial decrease in diazepam concentrations.
Effect: reduced effect of diazepam. The concomitant use of rifampicin and diazepam should be avoided.
Carbamazepine
Mechanism: Carbamazepine is a known inducer of CYP3A4 and increases the hepatic metabolism of diazepam. This can lead to up to three times higher plasma clearance and a shortened half-life of diazepam.
Effect: reduced effect of diazepam.
Phenytoin
Mechanism: effect on diazepam: phenytoin is a known inducer of CYP3A4 and increases the hepatic metabolism of diazepam.
Mechanism: - effect on phenytoin: the metabolism of phenytoin may be increased by diazepam or decreased or remained unchanged in an unpredictable manner.
Effect on diazepam: reduced effect of diazepam.
Effect on phenytoin: increase or decrease in the serum concentration of phenytoin. Phenytoin concentrations should be monitored more closely when diazepam is added or discontinued.
Phenobarbital
Mechanism: Phenobarbital is a known inducer of CYP3A4 and increases the hepatic metabolism of diazepam.
Effect: reduced effect of diazepam.
Inhibitors
Antiviral agents (atazanavir, ritonavir, delavirdine, efavirenz, indinavir, nelfinavir, saquinavir)
Mechanism: Antiviral agents may inhibit CYP3A4 in the metabolic pathway of diazepam.
Effect: increased risk of sedation and respiratory depression. Therefore concomitant use should be avoided.
Azoles (fluconazole, itraconazole, ketoconazole, voriconazole)
Mechanism: Increased plasma concentration of benzodiazepines, due to inhibition of CYP3A4 and / or CYP2C10 in the metabolic pathway.
Fluconazole: Concomitant administration with fluconazole 400 mg on day one and 200 mg on day two increased the AUC of a single oral 5 mg dose of diazepam 2.5 times and prolonged the half-life from 31 to 73 hours.
Voriconazole: A study with healthy subjects found that 400 mg voriconazole twice / day on the first day and 200 mg twice / day on the second day increased 2.2-fold the AUC of a single oral dose of 5 mg diazepam and prolonged the half-life from 31 to 61 hours.
Effect: Increased risk of benzodiazepine side effects and toxicity. Concomitant use should be avoided or the diazepam dose reduced.
Fluvoxamine
Mechanism: Fluvoxamine inhibits both CYP3A4 and CYP2C19 leading to inhibition of the oxidative metabolism of diazepam. Co-administration with fluvoxamine leads to an increase in the half-life and an approximately 190% increase in plasma concentrations (AUC) of diazepam.
Effect: drowsiness, reduced memory and psychomotor skills. It is preferable to replace with benzodiazepines which are metabolised non-oxidatively.
Special caution for concomitant use
Inducers
Corticosteroids
Mechanism: Chronic use of corticosteroids may lead to increased metabolism of diazepam due to induction of the cytochrome P450 isoenzyme CYP3A4, or enzymes responsible for glucuronidation.
Effect: reduced effect of diazepam.
Inhibitors
Cimetidine
Mechanism: Cimetidine inhibits the hepatic metabolism of diazepam, reducing its clearance and prolonging its half-life. In a study with cimetidine 300 mg four times / day for 2 weeks, the combined plasma level of diazepam and its metabolite desmethyldiazepam, had increased by 57% while the reaction times and other perceptual-motor tests remained unchanged.
Effect: Increased action of diazepam and increased risk of somnolence. Reduction of the diazepam dose may be necessary.
Omeprazole
Mechanism: Omeprazole inhibits the CYP2C19 metabolic pathway for diazepam. Omeprazole prolongs the elimination half-life of diazepam and increases its plasma concentration (AUC) by approximately 30% to 120%. The effect is visible in the extensive metabolisers of CYP2C19 but not poor metabolisers with low clearance of diazepam.
Effect: Increased action of diazepam. Reduction of the dose of diazepam may be necessary.
Esomeprazole
Mechanism: Esomeprazole inhibits the CYP2C19 metabolic pathway for diazepam. Co-administration with esomeprazole leads to a prolongation of the half-life and an increase in plasma concentration (AUC) of diazepam by approximately 80%.
Effect: Increased effect of diazepam. Reduction of the dose of diazepam may be necessary.
Isoniazid
Mechanism: Isoniazid inhibits the metabolic pathway of CYP2C19 and CYP3A4 for diazepam. Co-administration with 90 mg of isoniazid twice / day for 3 days resulted in a prolongation of the elimination half-life of diazepam and an increase of 35. % of the plasma concentration (AUC) of diazepam.
Effect: Increased effect of diazepam.
Itraconazole
Mechanism: Increased plasma concentration of diazepam due to inhibition of the CYP3A4 pathway. In a study with healthy subjects administered itroconazole 200 mg / day for 4 days, the AUC of a single oral 5 mg dose of diazepam increased by approximately 15%, but no clinically significant interaction was observed based on tests. of psychomotor skills.
Effect: Possible increased effect of diazepam.
Fluoxetine
Mechanism: Fluoxetine inhibits the metabolism of diazepam via CYP2C19 and other pathways leading to increased plasma concentration and decreased clearance of diazepam.
Effect: Increased effect of diazepam. Concomitant use should be closely monitored.
Disulfiram
Mechanism: Reduced metabolism of diazepam with prolonged half-life and increased plasma concentration of diazepam. Elimination of the N-desmethyl metabolites of diazepam is slowed and may lead to marked sedative effects.
Effect: Increased risk of CNS inhibition such as sedation.
Oral contraceptives
Mechanism - effect on diazepam: inhibition of the oxidative metabolism of diazepam.
Mechanism - effect on oral contraceptives: Concomitant administration of diazepam and oral contraceptives is known to cause breakthrough (contraceptive) bleeding. The mechanism of this reaction is unknown.
Effect on diazepam: Increased effects of diazepam
Effect on oral contraceptives: breakthrough bleeding (contraceptive) but no contraceptive failures have been reported.
Grapefruit juice
Mechanism: Grapefruit juice is thought to inhibit CYP3A4 and increase the plasma concentration of diazepam. The Cmax increases by 1.5 times and the AUC by 3.2 times.
Effect: Possible increased effect of diazepam.
Others
Cisapride
Mechanism: accelerated absorption of diazepam
Effect: Temporary increase in the sedative effects of orally administered diazepam.
Levodopa
Mechanism: unknown.
Effect: Concomitant use with diazepam leads to reduced effects of levodopa in a small number of cases.
Valproic acid
Mechanism: Valproate displaces diazepam from its binding sites to human albumin and inhibits its metabolism.
Effect: increased serum concentrations of diazepam.
Ketamine
Mechanism: Due to the similar oxidative processes, diazepam competitively inhibits the metabolism of ketamine. Premedication with diazepam leads to a prolongation of the half-life of ketamine with consequent enhancement of the effect.
Warnings It is important to know that:
Important information about some of the ingredients
The single-dose container contains benzyl alcohol (1 ml contains 15 mg of benzyl alcohol). The administration of benzyl alcohol in preterm infants at a dose of 100 mg / kg / day has caused severe and, in some cases, fatal poisoning with metabolic acidosis.
Particular groups of patients
Benzodiazepines should not be given to children without a careful assessment of the actual need; therefore the use of MICROPAM rectal solution should be limited to the indications previously described. In any case, the duration of the treatment should be as short as possible.
As safety and efficacy in children under 6 months have not been established, Micropam should be used with the utmost caution in this age group and only if no therapeutic alternatives are available. Elderly and debilitated patients should be given a reduced dose (see "Dose, method and time of administration"). Due to the muscle relaxant effect, there is a risk of falls and consequently of hip fractures in the elderly.
A lower dose is also recommended for patients with chronic respiratory failure, due to the risk of respiratory depression.
Benzodiazepines are not indicated for the treatment of patients with severe, acute or chronic hepatic insufficiency, as these drugs can precipitate encephalopathy. In patients with chronic liver disease it may be necessary to reduce the dosage.
The usual precautions should be observed when treating patients with impaired renal function. In the event of impaired renal function, the half-life of diazepam is not significantly changed and a dose adjustment is generally not necessary. Benzodiazepines are not recommended as the primary treatment of psychotic illness.
Benzodiazepines should not be used alone in the treatment of depression or anxiety associated with depression (the risk of suicide may increase in such patients). Individuals at potential suicide risk should not have access to high amounts of diazepam due to the risk of of overdose.
Babies under the age of three months should only be treated with diazepam in the hospital.
Pregnancy and breastfeeding
Women of childbearing age
Any woman intending to become pregnant or suspected of being pregnant should be advised to contact their doctor to discontinue treatment.
Pregnancy
There are limited data on the use of diazepam in pregnant women. If, for serious medical reasons, diazepam is administered during the last trimest of pregnancy, or during labor at high doses, effects on the newborn such as hypothermia, hypotonia may occur ( "Floppy Infant Syndrome"), irregular heart rate, poor sucking and moderate respiratory depression due to the drug's pharmacological action. In addition, infants born to mothers who have taken benzodiazepines regularly during late pregnancy may develop physical dependence and may present some risk of developing withdrawal symptoms in the postnatal period Animal studies have shown reproductive toxicity Diazepam should be used in pregnant women only for serious indications.
Feeding time
Diazepam is excreted in breast milk. Diazepam should not be used while breastfeeding.
Fertility
Animal studies have shown a decrease in pregnancy rate and a reduced number of surviving offspring in rats at high doses. No human data are available.
Effects on ability to drive and use machines
Diazepam significantly affects the ability to drive or use machines.
This is usually due to impaired motor skills, tremor, somnolence, amnesia, impaired concentration and tiredness (see "Undesirable effects" section 4.8).
The effect can be seen immediately after starting treatment and can last for several days after stopping due to the prolonged half-life of diazepam.
For those who carry out sporting activities, the use of medicines containing ethyl alcohol can determine positive doping tests in relation to the alcohol concentration limits indicated by some sports federations.
Dosage and method of use How to use Micropam: Dosage
Rectal use:
- children up to three years: 5 mg
- children over 3 years: 10 mg
- adults: 10 mg
- elderly and debilitated patients: 5 mg
If necessary, the dose could be repeated. In the case of repeated administration in children, respiration should be monitored. In children less than one year of age, diazepam could be used as an intermittent prophylaxis of febrile seizures. The usual dose is 0.5-1 mg / kg. In the treatment of elderly or debilitated patients, the doses used should not exceed half of those normally recommended. In patients with chronic pulmonary insufficiency and in patients with chronic renal and hepatic dysfunction, the posology needs to be reduced. The duration of treatment should be as short as possible.
METHOD OF USE
- Place the baby with the abdomen on your knees, with the buttocks raised.
- Remove the cap from the single-dose container and grease the spout.
- Insert the nozzle into the anus. In children under the age of 3 it is recommended to insert the nozzle into the anus up to half the length of the same, in older children and adults insert the nozzle into the anus for the entire length. .
- Important: to empty the single-dose container, the spout must be tilted downwards with respect to the ampoule of the single-dose container.
- When the single-dose container is empty, withdraw the spout while continuing to put pressure on the ampoule of the single-dose container.
- Hold the baby in the same position and squeeze his buttocks for a few minutes to prevent liquid from escaping.
Overdose What to do if you have taken too much Micropam
In all cases of overdose, consideration should be given to the possibility that other substances may have been taken at the same time, for example in the case of attempted suicide. Overdose symptoms are more pronounced in the presence of alcohol or drugs, which cause central nervous system depression.
Following an overdose of oral benzodiazepines, vomiting should be induced (within one "hour) if the patient is conscious or gastric lavage with respiratory protection undertaken if the patient is unconscious. If no improvement is observed. When the stomach is emptied, activated charcoal should be given to reduce absorption. Special attention should be paid to respiratory and cardiovascular functions in emergency therapy. Benzodiazepine overdose usually results in varying degrees of CNS depression ranging from clouding to coma. In mild cases, symptoms include drowsiness, mental confusion, and lethargy In severe cases, symptoms may include ataxia, hypotonia, hypotension, respiratory depression, rarely coma and very rarely death Flumazenil may be useful as an antidote.
Side Effects What are the side effects of Micropam
Somnolence, dulling of emotions, decreased alertness, confusion, fatigue, headache, dizziness, muscle weakness, ataxia or double vision occur mainly at the start of therapy but generally disappear with repeated administration. Confusional states may occur in elderly patients. high doses.
Falls and fractures. The risk of falls and fractures is increased in patients taking concomitant sedatives (including alcoholic beverages) and in elderly patients. Increased salivary and bronchial secretion has been reported, particularly in children.
Amnesia
Anterograde amnesia may occur at therapeutic doses, but the risk is greater with higher doses. Amnesic effects may be associated with inappropriate behavior (see "Special Warnings").
Dependence
Chronic use (even at therapeutic doses) can lead to the development of physical and psychological dependence: discontinuation of therapy can cause rebound or withdrawal phenomena (see section 4.4). Abuse of benzodiazepines has been reported.
The frequencies of adverse events are sorted according to the following criterion:
Very common (≥1 / 10)
Common (≥1 / 100 y
Uncommon (≥1 / 1,000 y
Rare (≥1 / 10,000 y
Very rare (
Not known (frequency cannot be estimated from the available data)
a Note when using benzodiazepines or benzodiazepine-like substances. These reactions can be very severe. They are more likely in children and the elderly. Diazepam should be discontinued if such symptoms occur (see "Special warnings").
b Pre-existing depression can be unmasked during benzodiazepine use.
c It can also occur at therapeutic dosages, the risk increases at higher dosages. Amnesic effects may be associated with inappropriate behavior (see "Special Warnings").
d The likelihood and severity of withdrawal symptoms depends on the duration of treatment, the dose and the degree of dependence.
Compliance with the instructions contained in the package leaflet reduces the risk of undesirable effects.
Reporting of side effects If you get any side effects, including any side effects not listed in this leaflet, contact your doctor or pharmacist. Undesirable effects can also be reported directly through the national reporting system at "https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse". By reporting side effects you can help provide more information on the safety of this medicine
Expiry and Retention
Expiry: See the expiry date printed on the package
The expiry date refers to the product in intact packaging, correctly stored
Warning: do not use the medicine after the expiry date shown on the package.
Store below 25 ° C.
After opening the aluminum foil, store at a temperature below 15 ° C.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Keep this medicine out of the sight and reach of children.
Composition and pharmaceutical form
COMPOSITION
MICROPAM 5 mg / 2.5 ml - 2.5 ml of rectal solution contain: 5.0 mg diazepam. Excipients: benzoic acid, purified water, benzyl alcohol, ethanol, propylene glycol, sodium benzoate.
MICROPAM 10 mg / 2.5 ml - 2.5 ml of rectal solution contain: diazepam 10.0 mg. Excipients: benzoic acid, purified water, benzyl alcohol, ethanol, propylene glycol, sodium benzoate.
PHARMACEUTICAL FORM AND CONTENT
5 mg / 2.5 ml rectal solution (2 mg / ml)
10 mg / 2.5 ml rectal solution (4 mg / ml)
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
MICRONOAN 5
MICRONOAN 10
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
MICRONOAN 5 Rectal solution
A 5 mg / 2.5 ml micro-enema contains:
Active principle:
Diazepam 5.0 mg
MICRONOAN 10 Rectal solution
A 10 mg / 2.5 ml micro-enema contains:
Active principle:
Diazepam 10.0 mg
03.0 PHARMACEUTICAL FORM
Rectal solution
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
As an antiepileptic: convulsions including febrile convulsions in children.
As a sedative: before exploratory examinations and treatments.
04.2 Posology and method of administration
Rectal use:
children up to three years: 5 mg
children over 3 years: 10 mg
adults: 10 mg
elderly and debilitated patients: 5 mg
If necessary, the dose could be repeated. In the case of repeated administration in children, respiration should be monitored.
In children less than one year of age, diazepam could be used as an intermittent prophylaxis of febrile seizures. The usual dose is 0.5-1 mg / kg.
In the treatment of elderly or debilitated patients, the doses used should not exceed half of those normally recommended.
In patients with chronic pulmonary insufficiency and in patients with chronic renal and hepatic dysfunction, the posology needs to be reduced.
The duration of treatment should be as short as possible.
04.3 Contraindications
Myasthenia gravis. Sleep apnea. Severe hepatic insufficiency. Acute respiratory depression. Hypersensitivity to the components or to other closely related substances from a chemical point of view.
Pregnancy.
Feeding time.
04.4 Special warnings and appropriate precautions for use
In case of insufficient sleep duration, the likelihood of a reduction in alertness may increase (see also section "Interactions with other medicines and other forms of interaction").
Tolerance
After repeated use for a few weeks, a reduction in the hypno-inducing effect of benzodiazepines may occur.
Rebound insomnia and anxiety
Upon discontinuation of treatment, a transient syndrome may occur which consists of the accentuated reappearance of the symptoms that led to treatment with benzodiazepines.
It may be accompanied by other reactions such as mood changes, anxiety or sleep disturbances and restlessness.
Since the risk of withdrawal phenomena (rebound phenomena) is more accentuated after an abrupt interruption of treatment, it is recommended to gradually decrease the dosage.
Like any psychotropic drug, the dosage of MICRONOAN Rectal Solution must be established according to the very variable tolerance from subject to subject in patients with cerebral organic changes (especially atherosclerotic) or with cardio-respiratory insufficiency.
Since benzodiazepines can cause a slight fall in blood pressure or, in occasional circumstances, transient respiratory compromise, measures to support circulation or breathing should be available.
In case of prolonged treatment it is advisable to check the haematological picture and liver function.
Amnesia
Benzodiazepines can cause antegrade amnesia. Most of the time this effect occurs several hours after taking the drug; to reduce this risk, patients should therefore be sure that they can have an uninterrupted sleep period of 7-8 hours (see also the section "Undesirable effects"). .
Particular groups of patients
Benzodiazepines should not be given to children without a careful assessment of the actual need; therefore the use of MICRONOAN rectal solution should be limited to the indications previously described. In any case, the duration of the treatment should be reduced to a minimum.
In elderly patients a reduced dose should be administered (see also section "Posology and method of administration").
A lower dose is also recommended for patients with chronic respiratory failure, due to the risk of depression of the breath.
Benzodiazepines are not indicated in patients with severe hepatic insufficiency, as these drugs can precipitate encephalopathy.
Benzodiazepines are not recommended as the primary treatment for psychotic illness.
Benzodiazepines should not be used alone in the treatment of depression or anxiety associated with depression (the risk of suicide may increase in such patients).
Benzodiazepines should be used with extreme caution in patients with a history of alcohol or drug abuse.
Abrupt discontinuation of diazepam administration, if continued over time, may cause withdrawal syndrome, which may appear up to 10 days later.
The micro-enema contains benzyl alcohol (1 ml contains 15 mg of benzyl alcohol). The administration of benzyl alcohol in premature babies at a dose of 100 mg / kg / day has caused severe and, in some cases, fatal poisoning with metabolic acidosis.
Babies under the age of three months should only be treated with diazepam in the hospital.
04.5 Interactions with other medicinal products and other forms of interaction
Cimetidine and omeprazole reduce the plasma clearance of diazepam, resulting in
enhancement of its effect.
Disulfiram blocks the metabolism of diazepam, resulting in increased serum concentrations of diazepam.
In the presence of diazepam the half-life of ketamine is lengthened with prolongation of its effect.
Rifampicin increases the plasma clearance of diazepam.
Theophylline counteracts the effect of diazepam.
The sedative action of diazepam is intensified by alcohol, hypnotics, neuroleptics, antihistamines, clonidine and opiates.
It is recommended to avoid the simultaneous intake of alcohol.
The sedative effect may be enhanced if the drug is taken concomitantly with alcohol. This adversely affects the ability to drive or use machines.
It is recommended to avoid the association with drugs having a depressing effect on the central nervous system.
In case of use in combination with antipsychotics (neuroleptics), hypnotics, anxiolytics / sedatives, antidepressants, narcotic analgesics, antiepileptic drugs, anesthetics and sedative antihistamines, a central increase in depressing effect may occur.
In the case of narcotic analgesics, an accentuation of euphoria may also occur, leading to an increase in psychic dependence.
Substances that inhibit some liver enzymes (particularly cytochrome P 450) may increase the activity of benzodiazepines. This latter effect also occurs, to a lesser extent, with benzodiazepines which are metabolised only by conjugation.
04.6 Pregnancy and lactation
Do not administer in the first trimester of pregnancy. In the further period, the drug must be administered only in case of real need and under the direct supervision of the doctor.
If for essential reasons the drug is administered during the last phase of pregnancy, or at high doses during labor, effects such as hypothermia, hypotonia and moderate respiratory depression, due to the mechanism of action of the drug, can be expected on the newborn.
Furthermore, babies born to mothers who took benzodiazepines chronically during the latter stages of pregnancy may have developed physical dependence and have some risk of postnatal danger.
Since benzodiazepines are found in breast milk, they should not be given to nursing mothers.
04.7 Effects on ability to drive and use machines
Vigilance, activity and operational dexterity may be impaired. Patients should not drive or operate machinery on the days the drug is administered.
04.8 Undesirable effects
Undesirable effects are dose-dependent and are generally moderate and rare; the most common is sleepiness.
More rarely, dizziness, difficulty concentrating, ataxia and diplopia appear. Elderly patients are particularly sensitive to these side effects.
In some cases, inhibition of respiratory function, attenuation of emotion, decreased alertness, confusion, asthenia, headache, muscle weakness has been reported.
Paradoxical reactions such as arousal, aggression and hallucinations have occurred very rarely.
These phenomena may occur mainly at the beginning of benzodiazepine therapy and usually disappear with continued treatment.
Confusional states may occur in elderly patients treated at high doses.
Other side effects have occasionally been reported such as: gastrointestinal disturbances, libido changes and skin reactions.
Amnesia
Anterograde amnesia may occur at therapeutic doses, but the risk is greater with higher doses. Amnesic effects may be associated with inappropriate behavior (see also section "Special warnings and precautions for" use ").
Depression
Pre-existing states of depression may occur during the use of benzodiazepines.
Psychiatric and "paradoxical" reactions
It is known that the following reactions may occur during the use of benzodiazepines: restlessness, agitation, irritability, aggression, delusions, fits of anger, nightmares, hallucinations, psychosis, inappropriate behavior and other behavioral side effects. Such reactions can be quite severe. These reactions are more likely to occur in children and the elderly.
Hypersensitivity reactions may occur in predisposed subjects.
Dependence
Prolonged use of benzodiazepines can lead to physical and mental dependence on these drugs.
The risk of addiction increases with dosage and duration of treatment.
It is also greater in patients with a history of alcohol or drug abuse.
In cases where physical dependence has developed, abrupt cessation of treatment will cause withdrawal symptoms which may include headache, muscle aches, extreme anxiety, tension, restlessness, confusion and irritability.
In severe cases the following symptoms may occur: derealization, depersonalization, hyperacusis, numbness and tingling in the extremities, hypersensitivity to light, noise and physical contact, hallucinations or seizures.
04.9 Overdose
Benzodiazepine overdose usually results in varying degrees of central nervous system depression ranging from somnolence to coma. In mild cases, symptoms include drowsiness, confusion and sedation, in severe cases symptoms may include ataxia, hypotonia, hypotension, respiratory depression, rarely coma and very rarely death.
Cardiovascular and respiratory functions must be closely monitored in intensive care units.
Flumazenil, a specific benzodiazepine antagonist, may be a useful antidote.
When treating overdose of any medicinal product, it should be borne in mind that more substances may have been taken.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Diazepam has anxiolytic, sedative, hypnotic, anticonvulsant and muscle relaxant activity.
05.2 "Pharmacokinetic properties
Absorption of the drug is rapid and complete.
The plasma peak of diazepam occurs approximately 10-20 minutes after rectal administration of the diazepam solution. It is metabolised in the liver and its major metabolite, desmethyldiazepam, is pharmacologically active. Diazepam spreads throughout the body and rapidly passes the blood-brain barrier. In the blood, 96-98% of diazepam binds to plasma proteins.
05.3 Preclinical safety data
No pathological effects were found at human therapeutic doses in animals. Given its low toxicity, diazepam has a favorable risk-benefit ratio.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Benzoic acid, purified water, benzyl alcohol, ethanol, propylene glycol, sodium benzoate.
06.2 Incompatibility
None
06.3 Period of validity
30 months, at a temperature below 25 ° C, with unopened packaging.
06.4 Special precautions for storage
After opening the aluminum foil, store at a temperature below 15 ° C
06.5 Nature of the immediate packaging and contents of the package
Carton containing 4 low density polyethylene microenemas, yellow, of 5 mg / 2.5 ml, individually packed in laminated aluminum pouches.
Carton containing 4 yellow low density polyethylene microenemas of 10 mg / 2.5 ml, individually packed in laminated aluminum pouches.
06.6 Instructions for use and handling
Rectal use
Place the baby with the abdomen on your knees, with the buttocks raised.
Remove the cap from the micro-enema and grease the nozzle.
Insert the nozzle into the anus. In children under the age of 3 it is recommended to insert the nozzle into the anus up to half the length of the same, in older children and adults insert the nozzle into the anus for the entire length. .
Important: to empty the microenema, the spout must be tilted downwards with respect to the microenema ampoule.
When the microenema is empty, withdraw the nozzle while continuing to put pressure on the microenema ampoule.
Hold the baby in the same position and squeeze his buttocks for a few minutes to prevent liquid from escaping.
07.0 MARKETING AUTHORIZATION HOLDER
DUMEX-ALPHARMA A / S - 11, Dalslandsgade - DK-2300 Copenhagen S
Sales representative in Italy:
ABBOTT S.p.A. - 04010 CAMPOVERDE (LT)
08.0 MARKETING AUTHORIZATION NUMBER
4 micro-enemas of 5 mg / 2.5 ml (2 mg / ml)
A.I.C. n. 029417019
4 micro-enemas of 10 mg / 2.5 ml (4 mg / ml)
A.I.C. n. 029417021
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
17.12.1998
10.0 DATE OF REVISION OF THE TEXT
November 2001
