Active ingredients: Amitriptyline (Amitriptyline hydrochloride), Chlordiazepoxide
Limbitryl 12.5 mg + 5 mg
Limbitryl package inserts are available for pack sizes:- Limbitryl 12.5 mg + 5 mg
- Limbitryl® 25 mg + 10 mg
Indications Why is Limbitryl used? What is it for?
Pharmacotherapeutic group
Limbitryl belongs to the therapeutic category of associated antidepressants.
Indications
Limbitryl is indicated in the treatment of all depressive states with an anxious component, including the frequent "masked" forms. Limbitryl indications therefore include the following functional disturbances, insofar as they are really depressive in origin. Psychic manifestations of the depressive syndrome: dysthymia, anxiety, agitation, tension, apathy, loss of interest. Gastrointestinal and cardiorespiratory disorders of depressive origin: anorexia, pharyngeal bolus sensation, abdominal spasms, epigastric pains, stabbing pains in the precordial region, pseudo-anginal disorders, air hunger. Depressive exhaustion syndrome in women: lumbar pain, irritability, fatigue, tremors, agitation. Genitourinary disorders of depressive origin. Headaches of depressive origin. Sleep disturbances of depressive origin.
Contraindications When Limbitryl should not be used
Known hypersensitivity to the product or to any of the excipients. Due to the anticholinergic action of amitriptyline, Limbitryl is contraindicated in glaucoma. It is also contraindicated in case of severe liver or kidney injury, in myasthenia gravis, in severe respiratory failure, in sleep apnea syndrome, in the post-infarct recovery period, during lactation, in pediatric age and in case of already known individual hypersensitivity. towards amitriptyline and / or chlordiazepoxide or towards other substances with a similar chemical structure.
Particular caution is advised in patients with prostatic hypertrophy.
Precautions for use What you need to know before taking Limbitryl
Tricyclic antidepressants and neuroleptics should be administered with caution, especially in the elderly, when heart failure is suspected or when rhythm and conduction disorders are present, in patients with a history of epilepsy, with urinary retention syndromes or of intestinal obstruction, and in hyperthyroid. The product should not be prescribed at the same time as MAO inhibitors; if a drug of this type has already been administered, a 2-week break should be interleaved before starting treatment with Limbitryl. simultaneously with thyroid-based medications, any changes in blood pressure and rhythm (which may, albeit rarely, also occur in other subjects) should be carefully monitored. In the case of simultaneous use of anticholinergic or sympathomimetic drugs, it is necessary strict medical supervision in order to arrive at an appropriateness ta dosage. Patients treated with Limbitryl or any other psychoactive substance should refrain from consuming alcoholic beverages for as long as they are under the effects of the drug, as individual reactions are not predictable. Even if no cases of dependence have been reported following the use of the product, the possibility that predisposed subjects, if treated with high doses and for prolonged periods, may present physical and mental dependence cannot be excluded due to the presence of chlordiazepoxide. The risk of addiction is greater in patients with a history of drug and alcohol abuse. 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 epileptic seizures. Rebound insomnia and anxiety: A transient syndrome may occur on discontinuation of treatment in which symptoms leading to treatment with benzodiazepines recur in an aggravated form. It may be accompanied by other reactions, including mood changes, anxiety, restlessness or sleep disturbances It is important that the patient is made aware of the possibility of rebound phenomena, thus minimizing anxiety about such symptoms should they occur upon discontinuation of Limbitryl. Since the risk of withdrawal or rebound symptoms is greater after abrupt discontinuation of treatment, a gradual decrease in dosage is suggested. Benzodiazepines can induce anterograde amnesia. This happens most 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 side effects).
When benzodiazepines are used it is known that reactions such as restlessness, agitation, irritability, aggression, disappointment, anger, nightmares, hallucinations, psychosis, behavioral changes can occur. Should this occur during treatment with Limbitryl, the use of the medicinal product should be discontinued. These reactions are more frequent in the elderly. The dosage in elderly patients should be appropriately reduced (see Dose, method and time of administration).
Likewise, a lower dose is suggested for patients with chronic respiratory failure due to the risk of respiratory depression. Benzodiazepines are not indicated in patients with severe hepatic insufficiency as they can precipitate encephalopathy. In patients with hepatic and / or renal insufficiency the dosage of Limbitryl must be suitably reduced to avoid the appearance of accentuated secondary reactions.
Use in children and adolescents under 18 years
Tricyclic antidepressants should not be used to treat children and adolescents under the age of 18. Studies conducted in depression in children of this age group have not shown efficacy for this class of drugs.
Studies with other antidepressants have highlighted the risk of suicide, self-harm and hostility related to these drugs. This risk can also occur with tricyclic antidepressants. Furthermore, tricyclic antidepressants are associated with a risk of adverse cardiovascular events in all age groups. It should be borne in mind that there are no long-term safety data available in children and adolescents regarding growth, maturation and cognitive and behavioral development.
Interactions Which drugs or foods can modify the effect of Limbitryl
Concomitant alcohol intake should be avoided. The sedative effect of Limbitryl may be enhanced when the medicinal product is taken in conjunction with alcohol. This adversely affects the ability to drive or use machines. When combined with centrally acting drugs such as antipsychotics (neuroleptics), hypnotics, anxiolytics / sedatives, antidepressants, narcotic analgesics, antiepileptics, anesthetics, and sedative antihistamines, Limbitryl may potentiate their sedative effect. Compounds that inhibit certain liver enzymes (especially cytochrome P 450) may increase the activity of benzodiazepines. To a lesser extent, this also applies to benzodiazepines which are metabolized only by conjugation. Based on experimental and clinical observations, amitriptyline may inhibit the effect of blocking antihypertensives on the adrenergic neuron, such as guanethidine, betanidine and debrisoquine.
Warnings It is important to know that:
Pregnancy and breastfeeding
If Limbitryl is prescribed to a woman of childbearing potential, she should be advised that, whether she intends to become pregnant or suspects she is pregnant, she should contact her doctor to consider stopping treatment. Do not administer the product 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 serious medical reasons, the product is administered during the last period of In pregnancy or during labor at high doses, effects on the newborn may occur, such as hypothermia, hypotonia and moderate respiratory depression due to the pharmacological action of the drug. In addition, newborns born to mothers who have taken benzodiazepines chronically during late pregnancy may develop physical dependence and may present some risk of developing withdrawal symptoms in the postnatal period.
Special warnings
To be used under direct medical supervision. The association with other psychotropic drugs requires particular caution and vigilance on the part of the physician to avoid unexpected undesirable effects from interaction. In case of need for surgery, treatment with the product must be interrupted several days before. In case of prolonged treatments, frequent treatments are recommended. checks of blood count and liver function. Tricyclic antidepressants and neuroleptics can cause electroencephalographic changes, particularly in predisposed subjects; in rare cases convulsions have been observed. Like other antidepressants, Limbitryl can cause, in the presence of paranoid or pre-delusional states, the appearance of manifestations of excitement. Based on the modalities of use, dose and individual sensitivity, sedation, amnesia, alteration of muscle concentration and function, which can be induced by the intake of Limbitryl, as by that of other drugs of the same type of action, may adversely affect the ability to drive or use machines.
If sleep duration has been insufficient, the likelihood of impaired alertness may be increased (see interactions).
SUICIDARY IDEATION / BEHAVIOR
Suicide / Suicidal ideation
Depression is associated with an increased risk of suicidal thoughts, self harm and suicide (suicide / related events). This risk persists until significant remission occurs. subsequent, patients should be carefully monitored until improvement occurs. It is clinical experience in general that the risk of suicide may increase in the early stages of improvement.
Other psychiatric conditions for which Limbitryl is prescribed may also be associated with an increased risk of suicidal behavior. In addition, these conditions may be associated with major depressive disorder.
Therefore, the same precautions followed when treating patients with other psychiatric disorders should be observed when treating patients with major depressive disorders.
Patients with a history of suicidal behavior or thoughts, or who exhibit a significant degree of suicidal ideation prior to initiation of treatment, are at increased risk of suicidal thoughts or suicidal thoughts, and should be closely monitored during treatment. of clinical trials conducted with antidepressant drugs in comparison with placebo in the treatment of psychiatric disorders, showed an increased risk of suicidal behavior in the age group "less than 25 years of patients treated with antidepressants compared to placebo.
Drug therapy with antidepressants should always be associated with close surveillance of patients, particularly those at high risk, especially in the initial stages of treatment and after dose changes. Patients (or caregivers) should be advised of the need to monitor and report immediately to their treating physician any clinical worsening, the onset of suicidal behavior or thoughts, or changes in behavior.
Dosage and method of use How to use Limbitryl: Dosage
The dosage of Limbitryl 12.5 / 5 is 2-6 capsules per day, according to the needs of individual cases. Start the treatment with one capsule in the morning and one in the evening.
Always give the main dose in the evening.
In the treatment of elderly patients, the posology must be carefully established by the doctor who will have to evaluate a possible reduction of the dosages indicated above. Since chlordiazepoxide is a long-acting benzodiazepine, the patient should be monitored regularly to decrease the dose or frequency of Limbitryl, if necessary, to prevent overdose of benzodiazepine due to accumulation.
Overdose What to do if you have taken too much Limbitryl
Symptoms of overdose are as follows: hypotension, tachycardia, arrhythmias, AV block, heart failure, respiratory depression, mental confusion, drowsiness, lethargy, ataxia, coma, mydriasis, hypotonia, convulsions, agitation.
Patients with signs of overdose should be hospitalized immediately.
When treating overdose of any medicinal product, it should be borne in mind that more substances may have been taken. In case of ingestion of an excessive dose of Limbitryl, vomiting should be induced if the patient is conscious or gastric lavage, with airway protection, should be carried out if the patient is unconscious. If stomach emptying is not beneficial, administration of activated charcoal, and possibly a reversible cholinesterase inhibitor, should be considered.
Cardiovascular and respiratory functions should be closely monitored in the intensive care unit. Any seizures should be treated with an inhalation anesthetic rather than barbiturates. Surveillance should last at least 48 hours.
Side Effects What are the side effects of Limbitryl
Some secondary effects may occur during treatment such as drowsiness, dulling of emotions, decreased alertness, confusion, fatigue, headache, dizziness, muscle weakness, ataxia, double vision or anticholinergic reactions (dry mouth, constipation, urination disturbances, moderate tachycardia , accommodation disturbances), which depend on the dose administered: these manifestations may disappear either spontaneously or upon dosage adjustment. Other less frequent disturbances include intense dreams, tremors, gastrointestinal disturbances and changes in libido. Granulocytopenia, jaundice and hepatic dysfunction of etiology uncertain have been rarely observed during treatment. Skin manifestations of an allergic nature and photosensitization may also occur. Anterograde amnesia can also occur at therapeutic dosages of benzodiazepines, the risk increases at higher dosages. Amnesic effects may also occur. re associated with behavioral changes (see precautions for use). Benzodiazepines can cause reactions such as: restlessness, agitation, irritability, aggression, disappointment, anger, nightmares, hallucinations, psychosis, behavioral changes. These reactions can be quite severe. They are more likely in the elderly. The use of benzodiazepines, even at therapeutic doses, can lead to the development of physical dependence: suspension of therapy can cause rebound or withdrawal phenomena (see precautions for use). Psychic dependence can occur. Even if not reported following the use of the product, the physician must keep in mind the possibility of onset of secondary reactions reported during therapy with the components of the combination administered alone. Hypersensitivity reactions may occur in predisposed subjects.
Rare: Suicidal ideation / behavior
(see section Special warnings).
It is advisable to consult your doctor or pharmacist in case of unwanted effects not mentioned in this leaflet.
Expiry and Retention
Warning: do not use the medicine after the expiry date indicated on the package.
Deadline "> Other information
Composition
One capsule contains:
Active ingredient amitriptyline hydrochloride 14.15 mg equal to amitriptyline base 12.5 mg, chlordiazepoxide 5 mg.
Excipients: ethylcellulose, starch, magnesium stearate, talc, lactose.
Packs
20 hard capsules
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 -
LIMBITRYL
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION -
One capsule contains:
Excipient with known effect: lactose
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM -
Hard capsules
04.0 CLINICAL INFORMATION -
04.1 Therapeutic indications -
Limbitryl is indicated in the treatment of all depressive states with an anxious component, including the frequent "masked" forms. Limbitryl indications therefore include the following functional disturbances, insofar as they are really depressive in origin.
Psychic manifestations of the depressive syndrome: dysthymia, anxiety, agitation, tension, apathy, loss of interest.
Gastro-intestinal and cardio-respiratory disorders of depressive origin: anorexia, pharyngeal bolus sensation, abdominal spasms, epigastric pains, stabbing pains in the precordial region, pseudo-anginal disorders, hunger for air.
Depressive exhaustion syndrome in women: lumbar pain, irritability, fatigue, tremors, agitation.
Genitourinary disorders of depressive origin.
Headaches of depressive origin.
Sleep disturbances of depressive origin.
04.2 Posology and method of administration -
Dosage
The dosage of Limbitryl 12.5 / 5 is 2-6 capsules per day, according to the needs of individual cases.
Start the treatment with one capsule in the morning and one in the evening. Always give the main dose in the evening.
The dosage of Limbitryl 25/10 varies according to the needs of individual cases. This posology will preferably be progressive. The average therapeutic dose is 3 capsules of Limbitryl 25/10 per day.
Senior citizens
In elderly patients, the administration of the lower dose form, i.e. Limbitryl 12.5 / 5, may be appropriate. Subsequently, the dosage can be progressively increased until the optimal dose is still well tolerated.
In the treatment of elderly and / or debilitated patients as well as patients with hepatic or renal insufficiency, the posology must be carefully established by the doctor who will have to evaluate a possible reduction of the dosages indicated above.
Since chlordiazepoxide is a long-acting benzodiazepine, the patient should be monitored regularly to decrease the dose or frequency of Limbitryl, if necessary, to prevent benzodiazepine overdose due to accumulation.
Children and adolescents:
Limbitryl is contraindicated in children below 18 years as the effects of this product have not been studied in this age group (see section 4.3).
Duration of treatment
The duration of treatment should be as short as possible. The overall duration of treatment should generally not exceed 8-12 weeks, including a period of tapering off. An "extension of the treatment beyond these periods must not take place without re-evaluating the patient's condition with specific expertise.
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 should be progressively decreased.
Furthermore, it is important that the patient is informed of the possibility of rebound phenomena, thus minimizing the anxiety about these symptoms should they appear after Limbitryl discontinuation.
Method of administration
Oral use. To be swallowed without chewing.
04.3 Contraindications -
Limbityl is contraindicated in patients with:
• hypersensitivity to the active substances (amitriptyline hydrochloride and chlordiazepoxide) or to any of the excipients listed in section 6.1
• Known individual hypersensitivity to benzodiazepines or tricyclic antidepressants
• untreated narrow-angle glaucoma (due to the anticholinergic action of amitriptyline)
• severe hepatic or renal impairment
• myasthenia gravis
• severe respiratory failure
• sleep apnea syndrome
• heart failure
• cardiac rhythm and conduction disturbances
• Prostatic hypertrophy, pyloric stenosis and other stenosing affections of the gastro-enteric and genito-urinary system
• acute intoxication with alcohol, barbiturates, narcotics or other CNS sedatives
• history of addiction (alcohol, drugs or drugs)
• states of acute delirium
• spinal or cerebral ataxia.
Limbitryl is also contraindicated:
• in the post-infarct recovery period
• during the first and third trimester of pregnancy (see section 4.6)
• during breastfeeding
• in the pediatric age
Finally, concomitant administration of tricyclic antidepressants with:
- monoamine oxidase (MAO) inhibitors. See sections 4.4 and 4.5;
04.4 Special warnings and appropriate precautions for use -
Benzodiazepines are only indicated when the disorder is severe, disabling, or makes the subject very uncomfortable.
The association with other psychotropic drugs requires particular caution and vigilance on the part of the physician to avoid unexpected undesirable effects from interaction.
In case of prolonged treatments, frequent checks of blood count and liver function are advisable.
In the case of simultaneous treatment with thyroid hormone-based medications, any changes in blood pressure and rhythm (which may, albeit rarely, also occur in other subjects) should be carefully monitored. Therefore, due to the risk of arrhythmia, Limbitryl should be administered with caution to hyperthyroid subjects or those being treated with thyroid hormones or thyreostatic preparations.
In case of simultaneous use of anticholinergic or sympathetic-mimetic drugs, close medical supervision is necessary in order to define an appropriate dosage.
Patients treated with Limbitryl or any other psychoactive substance should refrain from consuming alcoholic beverages for as long as they are under the effects of the drug, as individual reactions are not predictable.
Tricyclic antidepressants and neuroleptics can cause electroencephalographic changes, particularly in predisposed subjects; in rare cases convulsions have been observed. Therefore Limbitryl should be administered with caution to individuals with a history of epilepsy.
Like other antidepressants, Limbitryl can provoke arousal manifestations in the presence of paranoid or pre-delusional states.
MAO inhibitors
Serious, sometimes fatal, reactions have occurred in patients taking a tricyclic antidepressant concomitantly with a monoamine oxidase inhibitor, including the selective MAO-B inhibitor selegiline and the reversible MAO inhibitor moclobemide. Some patients have shown symptoms reminiscent of a hyperserotonergic state (serotonin syndrome).
Treatment with amitriptyline can only be started 14 days after therapy with irreversible non-selective MAO inhibitors has been stopped and not earlier than one day after treatment with moclobemide and / or selegiline has been stopped (see sections 4.3 and 4.5 ).
In rare cases, undesirable effects (including hypertension and dyskinesia) have been reported with the concomitant use of tricyclic antidepressants and levodopa products.
Caution is required in patients being treated with fentanyl. A serotonin syndrome may occur in patients taking fentanyl-containing medicines (see section 4.5).
Suicide / Suicidal ideation
Depression is associated with an increased risk of suicidal thoughts, self harm and suicide.
Treatment with antidepressants can also increase the development of suicidal ideation and suicidal behaviors. Analyzes of controlled studies have shown that patients are at higher risk at the start of treatment. Children and adolescents are particularly affected. This risk persists until significant remission occurs. As improvements may not occur during the first few weeks. treatment or improvement immediately occurred.It is clinical experience in general that the risk of suicide may increase in the early stages of improvement.
Other psychiatric conditions for which Limbitryl is prescribed may also be associated with an increased risk of suicidal behavior. Additionally, these conditions can be associated with major depressive disorder. Therefore, the same precautions followed when treating patients with other psychiatric disorders should be observed when treating patients with major depressive disorders.
Patients with a history of suicidal behavior or thoughts, or who exhibit a significant degree of suicidal ideation prior to initiation of treatment, are at increased risk of suicidal thoughts or suicidal thoughts, and should be closely monitored during treatment.
A meta-analysis of clinical trials conducted with antidepressant drugs compared with placebo in the therapy of psychiatric disorders showed an increased risk of suicidal behavior in the age group below 25 years of patients treated with antidepressants compared to placebo.
Patients treated with antidepressants should be closely monitored for any signs that their depression is worsening, especially for symptoms of suicidal behavior such as restlessness and / or psychomotor agitation. This is of particular importance in the initial stages of treatment and after dose changes. Patients (or caregivers) should be advised of the need to monitor and report immediately to their physician any clinical worsening, the onset of suicidal behavior or thoughts, or changes in behavior.
Even after cessation of therapy, patients should be monitored closely as these symptoms may manifest as drug withdrawal signs or early warning signs of relapse.
It is necessary to inform the patient's family (or caregiver) of this risk and educate them on how to deal with suspicious symptoms.
Antidepressant therapy is not suitable as a substitute for hospitalization indicated in the risk of self-harm.
In particular, when starting treatment, the smaller pack of this medicine should be prescribed to reduce the risk of self-harm.
Alongside depression, any other psychiatric diagnoses may also be associated with an increased risk of suicidal behavior and, therefore, the same precautions should be observed as described for the treatment of depression.
Exacerbation of schizophrenic symptoms
As with other antidepressant drugs, patients with schizophrenic or schizoaffective psychosis may experience exacerbation of schizophrenic symptoms when their depressive emotional response is treated with Limbitryl. Therefore, in these patients any previous long-term treatment with neuroleptic drugs should be continued, but cumulative anticholinergic effects should always be taken into account.
Tolerance
Some loss of efficacy to the hypnotic effects of chlordiazepoxide may develop after repeated use for a few weeks.
Dependence
The use of benzodiazepines can lead to psychological and physical dependence. The risk of dependence increases with dose and duration of treatment and is greater in patients with a history of drug or alcohol abuse as well as in predisposed patients.
Once physical dependence has established, abrupt discontinuation of treatment will be accompanied by withdrawal symptoms.These can consist of headache, body aches, tremor, sweating, extreme anxiety, tension, restlessness, sleep disorders, 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, delirium or epileptic seizures.
Depending on the duration of action of the substance in question, withdrawal phenomena can begin from a few hours to a week or more after the suspension of the treatment.
In order to minimize the risk of addiction, benzodiazepines should only be prescribed after careful consideration of the indication and taken for the shortest possible period (generally no more than four weeks when used as a hypnotic, for example). treatment should be reviewed periodically.
Discontinuation of therapy
Rebound insomnia and anxiety:
A transient syndrome in which symptoms leading to treatment with benzodiazepines recur in an aggravated form may occur upon discontinuation of treatment. It may be accompanied by other reactions, including mood changes, anxiety, restlessness or sleep disturbances.
Since the risk of withdrawal or rebound symptoms is greater after abrupt discontinuation of treatment, a gradual decrease in dosage is suggested.
In rare cases, hypomania or mania has been reported 2 to 7 days after discontinuation of long-term therapy with tricyclic antidepressants.
If withdrawal phenomena occur, close medical monitoring and patient support will be required.
Amnesia
Benzodiazepines can induce anterograde amnesia. This occurs most often several hours after ingestion of the drug and, therefore, to reduce the risk, it must be ensured that patients can have an uninterrupted sleep of 7-8 hours (see section 4.8).
Psychiatric and paradoxical reactions
Reactions such as restlessness, agitation, irritability, aggression, disappointment, anger, nightmares, hallucinations, psychosis, inappropriate behavior and other behavioral changes are known to occur when benzodiazepines are used. Should this occur during treatment with Limbitryl, the use of the medicine should be discontinued. These reactions are more likely to occur in children and the elderly.
Other - Neuroleptic Malignant Syndrome
A potentially life-threatening syndrome similar to neuroleptic malignant syndrome has been reported in connection with the intake of amitriptyline.
Special patient groups
Senior citizens
In elderly patients, tricyclic antidepressants and neuroleptics should be administered with caution.
The posology in elderly patients should be appropriately reduced (see section 4.2).
Also, a lower dose is recommended for patients with chronic respiratory failure due to the risk of respiratory depression.
Hepatic impairment
In patients with hepatic and / or renal insufficiency the dosage must be suitably reduced to avoid the appearance of accentuated secondary reactions.
Benzodiazepines are contraindicated in patients with severe hepatic impairment as they can precipitate encephalopathy (see section 4.3).
Renal impairment
In patients with impaired renal function, the dosage should be appropriately reduced in order to avoid the appearance of accentuated secondary reactions.
Benzodiazepines are contraindicated in patients with severe renal impairment (see section 4.3).
Benzodiazepines are not indicated for the primary treatment of psychotic illness.
Limbitryl should be used with particular caution:
- in patients with cardiovascular damage;
- in patients with a medical history of urinary retention;
- in patients in a paranoid or pre-delusional state.
Hyperpyrexia has been reported in case of concomitant treatment with tricyclic antidepressants and anticholinergic agents or neuroleptic agents, particularly during hot summer days.
Diabetes mellitus
When treating diabetic patients, attention should be paid to the fact that blood glucose levels may drop significantly due to Limbitryl.
Due to increased susceptibility, this product should be used with caution in elderly patients, in patients with organic brain damage, with hepatic or renal insufficiency or in poor general condition (see section 4.2). The lowest effective dose should be used and patients should be adequately monitored.
Due to the risk of respiratory depression, the use of a lower dose is recommended in the treatment of patients with chronic respiratory failure.
Patients with severe liver disease should not be treated with benzodiazepines as it may increase the risk of encephalopathy (see section 4.3).
It is recommended that blood counts and liver function be monitored regularly in patients receiving prolonged treatment with Limbitryl.
Tricyclic antidepressants - including amitriptyline - have been reported to cause changes in the ECG (prolongation of the QT interval), as well as arrhythmia (eg Torsades de pointes) and sinus tachycardia, particularly when given in high doses.
If surgery is required, treatment with the product should be stopped several days before.
Limbitryl contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Use in children and adolescents under 18 years
Tricyclic antidepressants should not be used to treat children and adolescents under the age of 18. Studies conducted in depression in children of this age group have not demonstrated efficacy for this class of drugs. Studies with other antidepressants have highlighted the risk of suicide, self-harm and hostility related to these drugs. This risk may also occur with these drugs. tricyclic antidepressants.
Furthermore, tricyclic antidepressants are associated with a risk of adverse cardiovascular events in all age groups. It should be borne in mind that there are no long-term safety data available in children and adolescents regarding growth, maturation and cognitive and behavioral development.
04.5 Interactions with other medicinal products and other forms of interaction -
Limbitryl may increase the sedative effect of other centrally acting medicinal products.
Concomitant alcohol intake should be avoided. The sedative effect of Limbitryl may be enhanced when the medicinal product is taken in conjunction with alcohol. This adversely affects the ability to drive or use machines (see section 4.7).
Concomitant administration of tricyclic antidepressants (such as amitriptyline) and the medicines listed below may have the following effects:
CYP 450 3A4 inhibitors
Chlordiazepoxide is hydroxylated by the CYP450 3A4 isoenzyme. Although no specific interaction studies are available, as a general rule, caution should be exercised when Limbitryl is administered in combination with medicinal products that inhibit or are metabolised by this enzyme (e.g. macrolide antibiotics, azole-like antifungals, calcium channel blockers, proteases, ergot alkaloids, antidepressant agents, and various herbal remedies).
Fentanyl
A serotonin syndrome may occur in patients taking fentanyl-containing medicines. Taking Limbitryl prior to fentanyl-containing medicines should be discussed with your doctor (see section 4.4).
04.6 Pregnancy and breastfeeding -
Pregnancy
If the product is prescribed to a woman of childbearing age, she should be advised that, whether she intends to become pregnant or suspects she is pregnant, she should contact her doctor to consider stopping treatment.
There are no adequate clinical data on the use of Limbitryl in pregnant women.
Do not administer the product in the first and last 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.
Animal studies have shown reproductive toxicity after administration of high doses of amitriptyline (see section 5.3). The potential risk for humans is unknown.
Withdrawal symptoms, including disturbances in heart and respiratory function, urination and defecation, as well as agitation have been reported in newborns after their mothers were given high doses of antidepressants.
Chlordiazepoxide crosses the placental barrier. Compared to the adult values, the half-life in newborns increased by about 20%.
If, for serious medical reasons, it is necessary to administer the product in high doses during the last period of pregnancy or during labor, effects on the newborn may occur, such as hypothermia, hypotonia and moderate respiratory depression due to the pharmacological action of the drug.
Additionally, infants born to mothers who have chronically taken benzodiazepines during late pregnancy may develop physical dependence and may be at some risk of developing withdrawal symptoms in the postnatal period.
Epidemiological data have suggested that the use of SSRIs during pregnancy, especially in the latter stage, may increase the risk of persistent pulmonary hypertension in the unborn child. The risk is approximately 5 cases per 1000 pregnancies. In the general population out of 100 pregnancies, one to two cases of persistent pulmonary hypertension in the unborn child are noted.
Feeding time
As benzodiazepines are excreted in breast milk they should not be given to breastfeeding mothers.
If taken for serious medical reasons, breastfeeding should be discontinued.
04.7 Effects on ability to drive and use machines -
Limbitryl can cause sedation, amnesia, impaired ability to concentrate and impaired muscle function. Therefore it can adversely affect the ability to drive and use machines, particularly when taken in combination with alcohol. If sleep duration has been insufficient, the likelihood of impaired alertness may be increased (see Section 4.5).
04.8 Undesirable effects -
Some secondary effects may occur during treatment such as drowsiness, dulling of emotions, reduced alertness, confusion, fatigue, headache, dizziness, muscle weakness, ataxia, double vision or anticholinergic reactions (dry mouth, constipation, urination disturbances, moderate tachycardia, accommodation disorders), which depend on the administered dose: these manifestations may disappear either spontaneously or upon dosage adjustment.
Some undesirable effects commonly occur at the start of treatment, such as transient fatigue and the aforementioned dose-related anticholinergic effects (dry mouth, moderate tachycardia and difficulty in accommodation). These effects often decrease if therapy is continued.
A pre-existing depressive state may be unmasked during the use of benzodiazepines.
The assessment of undesirable effects is based on the following frequency information:
Very common (≥ 1/10)
Common (≥ 1/100,
Uncommon (≥ 1/1 000,
Rare (≥ 1/10 000,
Very rare (
not known (frequency cannot be estimated from the available data).
Class effect:
Epidemiological studies conducted mainly in patients 50 years of age or older show an increased risk of bone fractures in those treated with SSRIs (serotonin reuptake inhibitors) and tricyclic antidepressants. The mechanism leading to this increased risk is unknown.
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address www.agenziadelfarmaco.gov.it/it/responsabili.
04.9 Overdose -
Limbitryl can cause intoxication symptoms induced by both of its active ingredients, benzodiazepine chlordiazepoxide and the tricyclic antidepressant amitriptyline. As for toxicity, the tricyclic antidepressant plays the main role.
Signs and symptoms
Symptoms can develop slowly and gradually or they can appear suddenly and unexpectedly.
During the first few hours, symptoms include drowsiness or excitement, restlessness and hallucinations, mydriasis, tachycardia, urinary retention, dry mucous membranes, impaired bowel motility, seizures and fever. Subsequently: sudden onset of CNS depression.
This may be followed by somnolence eventually culminating in a deep coma with respiratory depression.
Upon awakening, confusion, agitation, hallucinations, and ataxia may eventually return.
Cardiac symptoms include: arrhythmia (ventricular tachyarrhythmia, ventricular fibrillation); heart failure, drop in blood pressure, cardiogenic shock. Cardiac arrhythmia occurs in pathological ECG traces in the form of a large QRS complex. Other typical ECG changes include QT interval prolongation. Metabolic acidosis, hypokaliaemia.
Overdose with tricyclic antidepressants can lead to death. Overdose with benzodiazepines, in severe cases, can lead to ataxia, muscle atony, hypotonia, hypotension and respiratory depression, rarely coma and very rarely death.
Treatment
When treating overdose of any medicine, it should be borne in mind that more substances may have been taken.
In case of intoxication due to high doses, the use of activated charcoal or gastric lavage is indicated within the first hour after ingestion. Because of the increased risk of seizures, the use of activated charcoal should be preferred over gastric lavage.
In case of severe intoxication and / or reduced protective reflexes, the patient should be intubated early.
For the purpose of accelerated elimination (secondary decontamination), repeated oral administration of activated charcoal may prove effective in the case of some tricyclic antidepressants. Hemodialysis is of no value for secondary decontamination.
Particular attention must be given to the cardiovascular and respiratory systems.
Cardiac ECG monitoring should be started immediately. If arterial hypotension and / or ventricular arrhythmia are accompanied by a large QRS complex in the ECG (> 100 msec), sodium bicarbonate treatment is indicated [(adults: 50-100 mmol; children: 1-2 mmol / kg, given as an IV bolus injection (in less than 5 minutes) with close monitoring of AGBA)]. This can be repeated until blood pressure rises and ECG improves; however, only until a maximum arterial pH value of 7.50-7.55 is reached.
If needed, lidocaine can be given as an additional IV injection.
In patients with bradyarrhythmia, insertion of a temporary pacemaker is indicated.
In case of Torsades de pointes polymorphic ventricular tachycardia: administration of magnesium sulfate, 8 mmol by i.v. injection. slow; can be repeated after 10-15 minutes; if necessary followed by continuous infusion at a rate of 0.6-4.8 mmol / h.
In case of convulsions: IV administration of a benzodiazepine. Administration of the specific benzodiazepine antidote, flumazenil, is contraindicated with this combination containing a convulsive substance, as it would reduce the anticonvulsant effect of benzodiazepine.
In case of coma and / or respiratory failure: intubation and artificial ventilation.
Hyperventilation to increase arterial pH can only be used in the absence of concomitant bicarbonate administration (risk of strong alkalosis).
Due to their cardiac effects, pyridostigmine and physostigmine are contraindicated for the treatment of peripheral and central anticholinergic symptoms.
The surveillance must last at least 48 hours.
05.0 PHARMACOLOGICAL PROPERTIES -
05.1 "Pharmacodynamic properties -
Pharmacotherapeutic group: antidepressants in combination with psycholeptics.
ATC code: N06CA01.
The two active ingredients of Limbitryl act in a complementary way in the treatment of depressive states with a marked component of anxiety, regardless of the etiology of the depression (endogenous, neurotic, reactive, organic).
Amitriptyline, a tricyclic antidepressant, causes a liveliness of the mood and an improvement in other symptoms of depression, although usually only after several days of treatment.
The exact mechanism of action is not yet fully understood, but it is assumed that the antidepressant effect is mainly obtained by inhibiting the reuptake of the biogenic amines released in the involved endings (aminergic hypothesis).
Already at the moment of the first administration, chlordiazepoxide - a benzodiazepine - will exert its sedative, protective effect on the affective sphere, and anxiolytic. The characteristic mechanism of action of this class of substances is mainly based on an enhancement of neuronal inhibition mediated by gamma-amino butyric acid (GABA).
In this combination, chlordiazepoxide reduces anxiety, tension and agitation - symptoms which, particularly at the start of treatment, often play an important role for the patient experiencing a depressive syndrome.
05.2 "Pharmacokinetic properties -
Absorption
Amitriptyline is rapidly absorbed from the intestinal tract. The peak plasma concentration of the unchanged active substance occurs within approximately 6 hours. In the event of an overdose, absorption may be slowed due to inhibition of peristalsis. The bioavailability of amitriptyline reaches only 45%, this is attributed to an extensive first pass metabolism in the liver.
After oral administration of Limbitryl, chlordiazepoxide is well absorbed and almost completely systemically available. Normally, peak plasma levels are reached within approximately 2-4 hours.
Distribution
At steady state, the apparent volume of distribution reaches 14 l / kg for amitriptyline and 0.3-0.4 l / kg for chlordiazepoxide. Both amitriptyline and chlordiazepoxide are approximately 95% bound to plasma proteins. Amitriptyline and chlordiazepoxide as well as their metabolites pass the blood brain and placental barrier and to some extent arrive in breast milk.
Neither for amitriptyline nor for chlordiazepoxide and / or their active metabolites, a direct correlation has been established between their plasma concentration and clinical effect. After therapeutically satisfactory treatment with Limbitryl tablets for more than two weeks at mean daily doses of 50 -80 mg amitriptyline and 20-30 mg chlordiazepoxide, steady-state plasma concentrations of 10-70 ng / ml for amitriptyline and 200-1100 ng / ml for chlordiazepoxide were measured.
Biotransformation In the liver, both amitriptyline and chlordiazepoxide undergo significant demethylation and hydroxylation processes. In addition to 10-hydroxy nortriptyline and 10-hydroxyiamitriptyline, the main pharmacologically active metabolite of amitriptyline present in the blood is nortriptyline.
Chlordiazepoxide is mainly metabolised to its pharmacologically active metabolites: desmethylchlordiazepoxide, demoxepam and desmethyldiazepam.
Elimination
The elimination half-life of amitriptyline varies widely, averaging 15 hours. The mean elimination half-life of chlordiazepoxide is approximately 10 hours. Approximately 5% of a dose of amitriptyline is excreted unchanged in the urine, but mainly it is excreted in the form of its free or conjugated metabolites. Less than 1% of a dose of chlordiazepoxide is excreted as unchanged substance in the urine.
Kinetics in special populations
In elderly patients and in patients with hepatic or renal insufficiency, one or more pharmacokinetic and metabolic functions may be impaired. Depending on the conditions, the availability of active substances and active metabolites and / or the pharmacological effects of a given dose of Limbitryl may therefore be reduced or delayed or increased and / or prolonged.
05.3 Preclinical safety data -
In some studies, an increase in fetal mortality has been observed in both rats and mice, but to some extent this phenomenon was also attributed to maternal toxicity.
Amitriptyline
Mutagenic and carcinogenic potential
Amitriptyline has been adequately investigated for its mutagenic effects. Studies conducted to date do not indicate any mutagenic potential relevant to its use. Long-term studies have not been performed to determine carcinogenic potential.
Reproductive toxicity
After administration of very high doses - partly toxic to the mother - reproductive toxicity studies in hamsters and rabbits have shown foetotoxic and teratogenic effects. In the case of other antidepressants, animal experiments indicate behavioral disturbances in offspring exposed in the prenatal period. None of this information has been reported for amitriptyline.
Chlordiazepoxide
Mutagenic and carcinogenic potential
In vivo and in vitro studies with chlordiazepoxide clearly indicate a mutagenic effect, however negative results were also obtained in similar test systems. The relevance of the positive results is currently unclear.
Carcinogenicity studies showed a higher incidence of liver tumors in mice treated with high doses - and here mainly in male animals - while no such increase in the incidence rate of tumors was observed in the rat.
Reproductive toxicity
Available observations in humans did not lead to clear indications for a teratogenic effect; however, changes in the urogenital tract, pulmonary abnormalities and malformation of the skull (exencephaly, cleft palate), as well as behavioral disturbances in the offspring and neurochemical changes have been observed in experimental animal studies.
The risk of malformation with the administration of therapeutic doses of benzodiazepines in the first phase of pregnancy appears to be low, although some epidemiological studies have shown an increased risk of developing cleft palate and there are some cases of malformations and mental retardation in children exposed in the prenatal period after overdose and chlordiazepoxide poisoning.
Chlordiazepoxide crosses the placental barrier and is excreted in breast milk. Compared to adult values, the half-life time in newborns is approximately 20% greater.
06.0 PHARMACEUTICAL INFORMATION -
06.1 Excipients -
Each capsule contains: ethylcellulose, starch, magnesium stearate, talc, lactose.
Capsule components: gelatin, titanium dioxide, natural color E172
06.2 Incompatibility "-
No specific incompatibilities are known to date.
06.3 Period of validity "-
3 years: the expiry date refers to the intact product correctly stored.
06.4 Special precautions for storage -
No special precautions.
06.5 Nature of the immediate packaging and contents of the package -
Blisters in coupled aluminum and plastic material, enclosed in a cardboard box together with the package leaflet.
Limbitryl 12.5 mg / 5 mg 20 capsules
Limbitryl 25 mg / 10 mg 20 capsules
06.6 Instructions for use and handling -
No special instructions.
07.0 HOLDER OF THE "MARKETING AUTHORIZATION" -
Meda Pharma SpA
Via Felice Casati, 20
20124 Milan
08.0 MARKETING AUTHORIZATION NUMBER -
Limbitryl 12.5 mg / 5 mg 20 capsules AIC n. 021462066
Limbitryl 25 mg / 10 mg 20 capsules AIC n. 021462078
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION -
Renewal June 2010
10.0 DATE OF REVISION OF THE TEXT -
January 2017
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