IBS symptoms intensify when anxiety and stress disrupt the GBA balance ^2-4

Physical symptoms of IBS are linked to neurotransmitters, causing abnormal gut motility and sensory dysfunctions. ²

Emotional states like anxiety and depression caused by stress increase the risk of hypersensitivity. ⁵

IBS is caused by a disruption in the gut-brain axis (GBA) ²

The GBA is comprised of the brain (central nervous system), neuroendocrine and neuroimmune systems, the autonomic nervous system, the enteric nervous system and the gut microbiome ⁶

Interaction between microbiota and GBA appears to be bidirectional, by means of neural, endocrine, immune, and humoral links ⁷

The symptoms of IBS are closely associated with neurotransmitters and encompass: ²

• Irregular gastrointestinal movement
• Anxiety & Depression
• Visceral & central sensory abnormalities resulting in pain

Changes in microbial composition affect neurotransmitters and impact the pathways controlling gut functions ²

These neurotransmitters not only impact blood circulation but also influence: ²

• Intestinal motility
• Nutrient absorption
• Gastrointestinal immune responses
• The composition of gut microbiota

Neurotransmitters play an important role in regulating the microbiota-gut-brain axis ²

Dysregulation of the ENS can lead to increased or reduced secretion of 5-HT, which can manifest as diarrhoea or constipation, respectively ⁶

• Psychological stress activates an inflammatory cascade that leads to increased production of inflammatory cytokines via the HPA axis ⁶

Stress can decrease the diversity and alter the composition of the gut microbiome ⁸

• Lower numbers of potentially beneficial Lactobacillus. Expression of pathogenic bacteria such as Pseudomonas aeruginosa and Campylobacter jejuni ^{6, 9}

Dysregulation of the gut microbiota plays a role in IBS ⁶

The gut microbiota plays a role in inflammation and immune dysfunction via the gut-brain axis, which may contribute to IBS pathophysiology ²

The gut microbiota communicate with the CNS, in order to maintain gut homeostasis ⁶

• They are involved in synthesis and regulation of neurotransmitters, immune function, maintaining the intestinal barrier, modulating the nociceptive sensory pathways implicated in visceral pain, intestinal permeability and gut motility ⁶

GABA is an inhibitory neurotransmitter with receptors in the CNS and GIT ¹¹

In IBS, the GABA signalling system is disrupted and there are decreased levels of GABA ²

IBS is often linked to anxiety and depression, with as many as 33 % of individuals with IBS experiencing these conditions ¹⁵

The only IBS treatment that combines the antispasmodic effects of Clidinium Bromide and the anti-anxiety action of Chlordiazepoxide ²

IBS: irritable bowel syndrome; GBA: gut-brain axis; GABA: gamma-aminobutyric acid; CRH: corticotropin-releasing hormone; ENS: enteric nervous system; 5-HT: 5-hydroxytryptamine; HPA: hypothalamic-pituitary-adrenal axis; ACTH: Adrenocorticotropic Hormone CNS: central nervous system; GIT: gastrointestinal tract

Find balance with Librax^®

Relief for the Stomach, Peace for the Mind ¹

The 2-in-1 treatment for stress- related IBS

As an adjunct in the short-term treatment of non-ulcerated irritable bowel syndrome (IBS) associated with anxiety, tension or apprehension in adults.

LIBRAX^® is only indicated when the disorder is severe, disabling or subjecting the individual to extreme stress.¹

The only IBS treatment that combines the antispasmodic effects of Clidinium Bromide and the anti-anxiety action of Chlordiazepoxide ¹

IBS: irritable bowel syndrome

Find balance with Librax^®

Relief for the Stomach, Peace for the Mind ¹

Potential for addiction and abuse with Librax is:

• Dose and duration dependent ( prolonged use and high doses) ¹
• Greater in patients with a history of alcohol or drug abuse ¹
• Increased when combined with other benzodiazepines ¹

Librax should not be used with concomitantly with opioids ¹

• Concomitant use of LIBRAX^® and opioids may lead to sedation, respiratory depression, coma and death ¹

Contra- Indications:
Due to the anticholinergic effects Librax is contra-indicated in:

• Myasthenia gravis, glaucoma, benign bladder, neck obstruction and paralytic ileus because, prostatic hypertrophy ¹

Other contra- indications:

• Pregnancy and lactation ¹
• Severe respiratory failure ¹
• Sleep apnoea syndrome ¹
• Severe hepatic impairment ¹

Caution should be exercised:

• In the elderly
• In patients suffering from impairment of renal or hepatic function ¹
• In patients suffering from anxiety accompanied by an underlying depressive disorder ¹
• In patients receiving barbiturates or other central nervous system depressants including alcohol ¹

LIBRAX^® is not recommended for the primary treatment of psychotic illness. ¹

LIBRAX^® should not be used alone to treat depression or anxiety with depression as suicide may be precipitated in such patients. ¹

Find balance with Librax^®

Relief for the Stomach, Peace for the Mind ¹

Dosage & Directions ¹

Adults

• 1 Tablet 3-4 times per day before meals and at bed time.

Elderly and debilitated patients

• 1 Tablet 2 times per day.

Posology

• Treatment should be started with the lowest recommended dose.
• The maximum dose should not be exceeded.
• Treatment should be as short as possible.
• The patient should be reassessed regularly and the need for continued treatment should be re-evaluated, especially in case the patient is symptom- free.
• The overall duration of treatment generally should not be more than 8 – 12 weeks, including a tapering off process.
• In certain cases, extension beyond the maximum treatment period may be necessary. If so, it should not take place without re-evaluation of the patient’s status.

Adults:

• Due to the varied individual response to tranquillisers and anticholinergics, the optimum dosage of LIBRAX^® varies with the diagnosis and response of the individual patient.
• The dosage, therefore, should be individualised for maximum beneficial effects however, a maximum daily dose of 8 tablets should not be exceeded.

Elderly and debilitated patients:

• The dosage can be adjusted as needed and tolerated.

Paediatric population

• The safety and efficacy of LIBRAX^® in children has not been established.

Method of administration

For oral use

The only IBS treatment that combines the antispasmodic effects of Clidinium Bromide and the anti-anxiety action of Chlordiazepoxide ¹

IBS: irritable bowel syndrome

Find balance with Librax^®

Relief for the Stomach, Peace for the Mind ¹

The 2-in-1 treatment for stress-related IBS

Dosage & Directions

Adults

• 1 Tablet 3-4 times per day before meals and at bed time.

Elderly and debilitated patients

• 1 Tablet 2 times per day.

Therapeutic indications

• As an adjunct in the short-term treatment of non-ulcerated irritable bowel syndrome (IBS) associated with anxiety, tension or apprehension in adults.
• LIBRAX^® is only indicated when the disorder is severe, disabling or subjecting the individual to extreme stress.

Contraindications

• Hypersensitivity to the active substances chlordiazepoxide, clidinium bromide, to other benzodiazepines, to any of the Belladonna alkaloids.
• Myasthenia gravis.
• LIBRAX^® is also contraindicated in the presence of glaucoma, benign bladder, neck obstruction and paralytic ileus because of its anticholinergic component.
• Pregnancy and lactation.
• Severe respiratory failure.
• Sleep apnoea syndrome.
• Severe hepatic impairment.
• Myasthenia gravis.
• Prostatic hypertrophy.

Special warnings and precautions for use

Alcohol and drug abuse:

• Patients receiving LIBRAX^® should be cautioned about possible combined effects with alcohol and other central nervous system (CNS) depressants.
• LIBRAX^® should be used with extreme caution in patients with a history of alcohol or drug abuse.
• LIBRAX^® is not recommended for the primary treatment of psychotic illness.
• LIBRAX^® should not be used alone to treat depression or anxiety with depression as suicide may be precipitated in such patients.

Duration of treatment:

• The duration of treatment should be as short as possible but should not exceed eight to twelve weeks in case of anxiety, including tapering off process.
• Extension beyond these periods should not take place without re-evaluation of the situation.
• It may be useful 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.
• Moreover, it is important that the patient should be aware of the possibility of rebound phenomena, thereby minimising anxiety over such symptoms, should they occur while the product is being discontinued.
• When benzodiazepines as contained in LIBRAX^® with a long duration of action are being used it is important to warn against changing to a benzodiazepine with a short duration of action, as withdrawal symptoms may develop.

Specific patient groups and risk of accumulation:

• Particular caution should be exercised with the elderly and debilitated- who are at particular risk of over-sedation, respiratory depression and ataxia. (The initial oral dosage should be reduced in these patients).
  Caution should be exercised in the following patients:
• Patients suffering from impairment of renal or hepatic function;
• Patients suffering from anxiety accompanied by an underlying depressive disorder;
• Patients receiving barbiturates or other central nervous system depressants. There is an additive risk of central nervous system depression when these medicines are taken together;
• Patients should be cautioned regarding the additive effect of alcohol (see sub-header ‘Alcohol and drug abuse’).
• In addition, LIBRAX^® should be used with caution in the elderly due to the danger of precipitating undiagnosed glaucoma.
• Due to the risk of sedation and/or myorelaxant effects, LIBRAX^® and similar medicines should be used with caution in elderly patients since they could lead to falls, frequently with serious sequelae in this patient population.

Tolerance:

Some loss of the hypnotic effects of LIBRAX^® may develop after repeated use for a few weeks.

Psychiatric and paradoxical reactions:

• In general, the concomitant administration of LIBRAX^® and other psychotrophic medicines is not recommended. If such combination therapy is indicated, careful consideration should be given to the pharmacology of the medicines to be employed – particularly when the known potentiating combinations such as monoamine oxide (MAO) inhibitors and phenothiazines are to be used.
• The usual precautions are indicated when LIBRAX^® is used in patients with associated anxiety states and where there is any evidence of impending depression.
• Paradoxical reactions such as acute hyper-excitability with rage may occur.
• In some patients, LIBRAX^® and similar medicines may cause various changes in the state of consciousness, as well as in behaviour and memory, such as: exacerbation of insomnia, nightmares, agitation, nervousness, confused state, delusions, confusion, psychotic symptoms, loss of inhibition with impulsive behaviour, euphoria, irritability, anterograde amnesia and suggestibility. This condition may be accompanied by potentially dangerous problems for the patient or others, such as inappropriate behaviour, aggressive behaviour against oneself or others, especially when friends and relatives try to prevent the patient’s activities, as well as automatic behaviour with post-event amnesia.
• These reactions are more common in elderly patients.
• Extreme caution must be exercised when prescribing LIBRAX^® to patients with personality disorders.
• If these occur, LIBRAX^® should be discontinued

Drug abuse and dependence:

• There is a potential for abuse and the development of physical and psychic dependence, especially with prolonged use and high doses.
• The risk of dependence is also greater in patients with a history of alcohol or drug abuse.
• Combining LIBRAX^® with several benzodiazepines, regardless of the indication, increases the risk of drug dependence. Cases of abuse have been reported.
• To minimise the risk of dependence, LIBRAX^® should be prescribed only after careful review of the indication and taken over the shortest possible duration. Checks must be performed periodically to determine whether it is necessary to continue treatment. Prolonged treatment is indicated only for certain patients (e.g. panic states).

Withdrawal symptoms:

• Once physical dependence has developed, abrupt termination of treatment will be accompanied by withdrawal symptoms. These may consist of insomnia, headaches, muscle pain, muscle tension, hyper reactivity, extreme anxiety, tension, restlessness, confusion and irritability.
• In severe cases the following symptoms may occur: derealisation, depersonalisation, hyperacusis, numbness and tingling of extremities, hypersensitivity to light, noise and physical contact, hallucinations or epileptic seizures.

Rebound effects:

• A transient syndrome whereby the symptoms that led to treatment with LIBRAX^® recur in an enhanced form may occur on withdrawal of treatment.
• It may be accompanied by other reactions including mood changes, anxiety and restlessness.
• Since the risk of withdrawal phenomena/rebound phenomena is greater after abrupt discontinuation of treatment, it is recommended that the dosage is decreased gradually.

Amnesia and changes in psychomotor function:

LIBRAX^® can cause anterograde amnesia. Amnesia along with psychomotor changes usually occur several hours after intake.

Risk due to concomitant use with opioids:

• Concomitant use of LIBRAX^® and opioids may lead to sedation, respiratory depression, coma and death. Due to these risks, concomitant prescription of opioids together with sedatives such as benzodiazepines, or related medicines such as LIBRAX^®, is indicated only for those patients for whom there are no alternative treatment options. Nevertheless, if concomitant prescription of LIBRAX^® together with opioids is deemed necessary, the lowest effective dose should be used and the duration of treatment should be as short as possible.
• Patients should be closely monitored for signs and symptoms of respiratory depression and sedation. In this regard, it is strongly recommended that patients and their caregivers (if applicable) be informed of these symptoms.

Other:

• Although clinical studies have not established a cause and effect relationship, medical practitioners should be aware that variable effects on blood coagulation have been reported infrequently in patients receiving oral anti-coagulants and chlordiazepoxide as contained in LIBRAX^®.
• Medical conditions which may be affected by the use of LIBRAX^® are :
• Cardiac disease, coronary insufficiency,
• Hiatus hernia with reflux oesophagitis,
• Intestinal atony, paralytic ileus, toxic megacolon,
• Obstruction in the gastro-intestinal or urinary tracts,
• Ulcerative colitis or urinary retention,
• Intestinal atony in elderly patients,
• Chronic bronchitis due to increased viscosity of bronchial mucus,
• Hyperthyroidism,
• Prostatic hypertrophy,
• Renal impairment or mild-to-moderate hepatic impairment.

Paediatric population:

LIBRAX^® is not recommended for children.

Lactose warning:

• LIBRAX^® contains lactose, which may have an effect on the glycaemic control of patients with diabetes mellitus.
• Patients with the rare hereditary conditions of galactose intolerance e.g. galactosaemia, Lapp lactase deficiency, glucose-galactose malabsorption intolerance should not take LIBRAX^®.

Sucrose warning:

• LIBRAX^® contains sucrose, which may have an effect on the glycaemic control of patients with diabetes mellitus.
• Patients with rare hereditary conditions such as fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take LIBRAX^®.

Interaction with other medicines and other forms of interaction Antacids or diarrhoea medicines containing kaolin or attapulgite:

• May reduce blood levels and therefore the effects of LIBRAX^®.
• These should therefore be taken at least 2-3 hours before or after LIBRAX^®.

Ketoconazole:

• LIBRAX^® may reduce the blood levels and therefore should be taken at least 2 hours - after ketoconazole.
• Diminished bowel motility with LIBRAX^® may increase the liability to superficial ulceration of the stomach or bowel with potassium chloride.

Interactions with chlordiazepoxide:

• Medicinal products with inhibitory activity on hepatic enzymes
• Chlordiazepoxide as contained in LIBRAX^® is hydroxylated by the isoenzyme CYP450 3A4. In principle, although no specific interaction studies are available, caution should be exercised when co-administering medicines that inhibit – or are metabolised by – this isoenzyme (such as macrolide antibiotics, azole- type antifungal agents, calcium antagonists, protease inhibitors, ergot alkaloids and antidepressants).
• The metabolism of chlordiazepoxide as contained in LIBRAX^® can be inhibited by ketoconazole, cimetidine or disulfiram. Concomitant ingestion of cimetidine leads to an increased risk of somnolence. The patient should be warned about this increased risk when driving or using machines.
• Caution should be exercised when combining LIBRAX^® with centrally acting medicines (such as neuroleptics, sedatives, hypnotics, analgesics, antitussives, sedating antihistamines, centrally acting antihypertensive agents, antiepileptic agents, opiates or baclofen), since the central depressant effect may be enhanced.
• Concomitant use of opioids together with sedatives such as benzodiazepines or related medicines such as LIBRAX^® increases the risk of sedation, respiratory depression, coma and death due to an additive central nervous system (CNS)-depressant effect. The dosage and duration of concomitant use should be restricted. Additionally, concomitant intake of opioids (narcotic analgesics) may lead to an increase in the euphoric effect and thus to accelerated development of psychological dependence.
• Muscle relaxants may potentiate the effect of chlordiazepoxide.
• Absorption of other medicines may be slowed by the effect on the gastrointestinal tract.
• Barbiturates, morphine derivatives
• There is an increased risk of respiratory depression in patients concomitantly taking barbiturates or morphine derivatives. This may be fatal in cases of overdose.
• Buprenorphine
• Concomitant intake with buprenorphine also leads to an increased risk of respiratory depression, which may be fatal. Inform the patient of the necessity of complying with the prescribed dose.

Interactions with clidinium bromide:

• The anticholinergic effect of clidinium is potentiated when LIBRAX^® is taken concomitantly with medicines with an anticholinergic (atropine-like) active component, for example amantadine, some antihistamines (H1 antagonists), butyrophenones, phenothiazines, tri- and tetracyclic antidepressants, antiparkinson agents, antiarrhythmic medicines (such as quinidine, disopyramide), pirenzepine, anticholinergic antispasmodic agents or asthma medicines. This may result in undesirable effects, e.g. urinary retention, progression of glaucoma, constipation, dry mouth, etc. Alcohol must not be consumed by persons under the influence of LIBRAX^® since the individual reaction in each case is unpredictable.

Find balance with Librax^®

Relief for the Stomach, Peace for the Mind ¹

The 2-in-1 treatment for stress-related IBS

• Librax^® is indicated as an adjunct in the short-term treatment of non-ulcerated irritable bowel syndrome (IBS) associated with anxiety, tension or apprehension in adults.¹
• Each LIBRAX^® TABLET contain two active substances:

5mg Chlordiazepoxide ¹ – a long acting benzodiazepine ²

• Efficacy based on the enhancement of GABA in the CNS ²
• Has muscle relaxant properties ³
• Contributes to patient well–being ³
• May facilitate the transition for pharmacotherapy to psychotherapy ³

2,5mg Clidinium bromide ¹ an antispasmodic

• Has an anti-cholinergic effect on the gastrointestinal tract ¹

The dose is one (1) tablet three (3) or four (4) times a day administered before meals and at bedtime. ¹

• Treatment should be started with the lowest recommended dose.¹
• The maximum dose should not be exceeded.¹
• Treatment should be as short as possible.¹
• The patient should be reassessed regularly and the need for continued treatment should be re-evaluated, especially in case the patient is symptom- free.¹
• The overall duration of treatment generally should not be more than 8 – 12 weeks, including a tapering off process.¹
• In certain cases, extension beyond the maximum treatment period may be necessary. If so, it should not take place without re-evaluation of the patient’s status.¹

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