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.

Librax has an anticholinergic/spasmolytic action and anxiolytic effect. It contains 5mg Chlordiazepoxide and 2,5mg Clidinium Bromide.

Chlordiazepoxide Hydrochloride is a versatile, therapeutic agent of proven value for the relief of anxiety and tension.¹ It is indicated when anxiety, tension or apprehension are significant components of the clinical profile.¹

Clidinium Bromide is a synthetic anticholinergic agent which has been shown in experimental and clinical studies to have a pronounced antispasmodic and antisecretory effect on the gastro-intestinal tract.¹

• Chlordiazepoxide Structural Formula

• Clidinium Bromide Structural Formula

Librax improves not only patient outlook and attitudes but also effectively relieves both the physiologic and psychic manifestations of common functional gastrointestinal disorders such as IBS.¹

67.5 % of patients showed improvement of symptoms when treated with Librax.¹

Evaluation of the effect of chlordiazepoxide and clidinium bromide on target symptoms revealed the greatest effect on anxiety-tension, insomnia, abdominal pain and nausea, thus reflecting the combined tranquilizing-anticholinergic action of the medication.¹

The advantage of such a combination over anticholinergic therapy alone is obvious for the treatment of tense, anxious and emotional patients with functional gastrointestinal disorders.¹

Librax is widely used to alleviate abdominal spasms and cramps associated with IBS as well as deceases GI motility and hypersensitivity.³

In patients with irritable-bowel syndrome Clidinium decreased the spike and motor response from 30 to 80 minutes after a meal.² After Clidinium the duration of the colonic spike and motor response to a meal became like that in the normal subjects. ² Studies indicate that anticholinergic therapy shortens the duration and reduces the magnitude of the abnormal colonic myoelectric and motor responses to a meal in patients with the irritable bowel syndrome. ²

IBS patients with comorbidities of anxiety and/or depression may benefit from a benzodiazepine.⁴

3.9.4.1 Safety profile of Librax

Chlordiazepoxide ranks among the safer of the effective psychopharmacologic benzodiazepine compounds.¹

They have a favourable side-effect profile.² Benzodiazepine misuse rarely occurs in patients with anxiety disorders who do not have current or past substance misuse problems.²

3.9.4.2 General tolerability profile of Librax

With regards to tolerance to benzodiazepines, the vast majority of patients with anxiety disorders do not show a tendency to increase the dose and do not exhibit loss of the therapeutic benefit² They are generally well tolerated and there is no evidence that they cause organ toxicity.² Tolerance to anxiolytic and hypnotic effects of benzodiazepines occurs less often and over a longer period of time, than tolerance to anticonvulsant and sedative effects³

Withdrawal symptoms may occur in the course of benzodiazepine taper and are very likely to occur on abrupt discontinuation, but they are rarely dangerous.

The risk of withdrawal should be minimised through a gradual and individualised taper²

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 evaluated, especially if 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.

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.

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 usual dose is 1 tablet, 3 or 4 times a day administered before meals and at bedtime.

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:

Initially 1 tablet twice a day. The dosage can be adjusted as needed and tolerated.

Treatment Guidelines

3.9.6.1 World Gastroenterology Organisation Global Guidelines for Irritable Bowel Syndrome¹

With this guideline, the World Gastroenterology Organisation (WGO) is aiming to guide health providers in the best management of irritable bowel disease (IBS) through a concise document with recommendations based on the latest evidence and resulting from global expert consensus process based on best current practice.¹

Definition: Irritable bowel syndrome (IBS) is a functional bowel disorder in which abdominal pain or discomfort is associated with defecation and/or a change in bowel habit. Sensations of discomfort (bloating), distension, and disordered defecation are commonly associated features. In some languages, the words “bloating” and “distension” may be represented by the same term.¹

To distinguish IBS from transient gut symptoms, experts have underscored the chronic and relapsing nature of IBS and have proposed diagnostic criteria based on the occurrence rate of symptoms and their duration.¹

According to the Rome III criteria, IBS may be subtyped or subclassified on the basis of the patient’s stool characteristics, as defined by the Bristol Stool Scale:¹

• IBS with diarrhea (IBS-D):

— Loose stools > 25% of the time and hard stools < 25% of the time

— Up to one-third of cases

— More common in men

• IBS with constipation (IBS-C):

— Hard stools > 25% of the time and loose stools < 25% of the time

— Up to one-third of cases

— More common in women

• IBS with mixed bowel habits or cyclic pattern (IBS-M):

— Both hard and soft stools > 25% of the time

— One-third to one-half of cases

• Un-subtyped IBS

— Insufficient abnormality of stool consistency to meet criteria IBS-C or M

Rome III criteria for diagnosing IBS¹

1. Onset of symptoms at least 6 months before diagnosis
2. Recurrent abdominal pain or discomfort for > 3 days per month during the previous 3 months
3. At least two of the following features:

—Improvement with defecation
—Association with a change in stool frequency
—Association with a change in stool form

In the majority of cases of IBS, no additional tests or investigations are required. An effort to keep investigations to a minimum is recommended in straightforward cases of IBS, and especially in younger individuals.

Additional tests or investigations should be considered if warning signs (“red flags”) are present:¹

• Onset of symptoms after 50 years of age

• Short history of symptoms

• Change in the bowel habit pattern

• Unintended weight loss

• Nocturnal symptoms

• Family history of colon cancer, celiac disease, inflammatory bowel disease

• Anemia

• Rectal bleeding

• Recent antibiotic use

• Abdominal/rectal masses

• Raised inflammatory markers

• Fever

The following tests (although commonly performed) are indicated only if supported by the clinical history and where locally relevant:

• Full blood counts

• Serum biochemistry

• Thyroid function tests

• Stool testing for occult blood and ova and parasites

Additional tests or investigations may also be considered if:

• The patient has persistent symptoms or is anxious despite treatment.

• A major qualitative change in chronic symptoms has occurred.

• A new coexisting condition should be considered.

Management of patients with symptoms of irritable bowel syndrome.¹

Overall symptoms—first-line therapy¹

• Certain antispasmodics (otilonium, hyoscine, cimetropium, pinaverium, dicyclomine and mebeverine) provide symptomatic short-term relief in IBS.
• Peppermint oil

Overall symptoms—second-line therapy¹

• Laxatives.
• Antidiarrheals.
• Tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs)

Overall symptoms—other therapeutic options¹

• Rifaximin
• Alosetron
• Lubiprostone
• Linaclotide
• There is insufficient evidence to recommend loperamide for use in IBS.
• Ondansetron was found to improve urgency, diarrhoea, and bloating in IBS-D, but did not provide any benefits in relation to pain.

3.9.6.2 American College of Gastroentorology (ACG) Clinical Guideline: Management of Irritable Bowel Syndrome²

Although bloating is a commonly reported symptom, its presence is not mandatory to accurately diagnose IBS.²

Recommendations:

• Serologic testing to be performed to rule out celiac disease (CD) in patients with IBS and diarrhoea symptoms.²
• Suggest that either faecal calprotectin1 or faecal lactoferrin2 and C-reactive protein1 be checked in patients without alarm features and with suspected IBS and diarrhoea symptoms to rule out inflammatory bowel disease²
• No routine stool testing for enteric pathogens in all patients with IBS.²
• No routine colonoscopy in patients with IBS symptoms younger than 45 years without warning signs.²
• Suggest a positive diagnostic strategy as compared to a diagnostic strategy of exclusion for patients with symptoms of IBS to improve time to initiate appropriate therapy.²
• A positive diagnostic strategy as compared to a diagnostic strategy of exclusion for patients with symptoms of IBS to improve cost-effectiveness^.2
• Suggest that categorizing patients based on an accurate IBS subtype improves patient therapy^.2
• No routine testing for food allergies and food sensitivities in all patients with IBS unless there are reproducible symptoms concerning for a food allergy.²
• Suggest that anorectal physiology testing be performed in patients with IBS and symptoms suggestive of a pelvic floor disorder and/or refractory constipation not responsive to standard medical therapy.²
• Recommend a limited trial of a low FODMAP diet in patients with IBS to improve global symptoms.²
• Suggests that soluble, but not insoluble, fiber be used to treat global IBS symptoms.²
• Against the use of antispasmodics currently available in the United States to treat global IBS symptoms.²
• Suggests the use of peppermint to provide relief of global IBS symptoms.²
• Suggests against probiotics for the treatment of global IBS symptoms.²
• Suggests against the use of PEG products to relieve global IBS symptoms in those with IBS-C.²
• Recommends the use of chloride channel activators to treat global IBS-C symptoms^.2
• Recommends the use of guanylate cyclase activators to treat global IBS-C symptoms. ²
• Suggest that the 5-HT4 agonist tegaserod be used to treat IBS-C symptoms in women younger than 65 years with <1 cardiovascular risk factor who have not adequately responded to secretagogues. ²
• We do not suggest the use of bile acid sequestrants to treat global IBS-D symptoms. ²
• We recommend the use of rifaximin to treat global IBS-D symptoms. ²
• We recommend that alosetron be used to relieve global IBS-D symptoms in women with severe symptoms who have failed conventional therapy.²
• Suggests that mixed opioid agonists/antagonists be used to treat global IBS-D symptoms. ²
• Recommends that TCAs be used to treat global symptoms of IBS.²
• We suggest that gut-directed psychotherapies be used to treat global IBS symptoms.²
• Faecal transplant for the treatment of global IBS symptoms, is not recommended.²

3.9.6.3 British Society of Gastroenterology guidelines on the management of irritable bowel syndrome³

• There is no role for colonoscopy in IBS, other than in those with alarm symptoms or signs, or those with symptoms suggestive of IBS with diarrhoea who have atypical features and/or relevant risk factors that increase the likelihood of them having microscopic colitis (female sex, age ≥50 years, coexistent autoimmune disease, nocturnal or severe, watery, diarrhoea, duration of diarrhoea <12 months, weight loss or use of potential precipitating drugs including non-steroidal anti-inflammatory drugs, proton pump inhibitors, etc) (recommendation: strong, quality of evidence: moderate).³
• In those with symptoms suggestive of IBS with diarrhoea, but with atypical features such as nocturnal diarrhoea, or a prior cholecystectomy, 23-seleno-25-homotaurocholic acid scanning or serum 7α-hydroxy-4-cholesten-3-one should be considered to exclude bile acid diarrhoea (recommendation: strong, quality of evidence: low). ³
• In patients with IBS and coexisting symptoms suggestive of a defecatory disorder or faecal incontinence, anorectal physiology tests can be considered, where available, to select those who might benefit from biofeedback (recommendation: weak, quality of evidence: low). ³
• There is no role for testing for exocrine pancreatic insufficiency, or for hydrogen breath testing to rule out small intestinal bacterial overgrowth or carbohydrate intolerance, in patients with typical IBS symptoms (recommendation: strong, quality of evidence: weak). ³
• The diagnosis of IBS, its underlying pathophysiology and the natural history of the condition, including common symptom triggers, should be explained to the patient. This should introduce the concept of IBS as a disorder of gut-brain interaction, together with a simple account of the gut-brain axis and how this is impacted by diet, stress, cognitive, behavioural and emotional responses to symptoms, and post infective changes (recommendation: strong, quality of evidence: weak). ³

Treatment algorithm for IBS.³

Title:¹

A Tranquilizer-Anticholinergic Preparation in Functional Gastrointestinal Disorders: A Double-Blind Evaluation

Abstract:¹

Chlordiazepoxide plus clidinium bromide (Librax^®) was evaluated and compared with a placebo by means of a random sample, double-blind crossover technique in 42 patients presenting ordinary functional gastrointestinal disorders.

Background:¹

Emotions exert a distinct and widely recognized effect on somatic activity. Over 50 % of the varied digestive tract complaints seen by physicians are quite clearly functional, mainly resulting from disturbed motility.

The variety of complaints induced by these spasms is indeed impressive, ranging from functional indigestion to "irritable colon syndrome."
Common clinical symptoms are: abdominal pain of varying degree, constipation, gaseous distension of the proximal colon, flatus, diarrhea, nausea and, occasionally, vomiting.
The knowledge that onset and recurrences of this syndrome usually coincide with periods of stress or conflict and disappear spontaneously with their abatement is fundamental to differential diagnosis.

Objectives:¹
It was therefore decided to undertake a controlled study of the effects of this combination and an identically appearing placebo, using a standard double-blind crossover technique.

Methods: ¹

Patient selection was based on the chronicity and duration of illness to rule out the possibility that symptoms of brief duration might subside spontaneously and be falsely attributed to the medication.

Forty-two patients were selected, all of whom had had gastrointestinal disorders ranging from six months to many years.

The test drug was supplied in capsule form, each containing 2.5 mg of clidinium bromide and 5 mg of chlordiazepoxide, in sufficient quantity to permit varying the dosage from one capsule daily to one four times daily for a minimum four-week period.

Identical placebo capsules were provided in similar amounts, and both were sealed in separate envelopes coded for future identification and random order of administration.

Initially the patients were instructed to take one capsule four times daily and to return after two weeks for evaluation. At the end of the four-week period (or sooner if the patient complained strongly of lack of response) the alternate crossover envelope was supplied.

Upon completion of the study and breaking of the code numbers, patients were divided by order of drug administration into Group I (receiving the active medication initially) and Group II (receiving the placebo first).

At the completion of both trial periods, follow-up treatment with the active drug was continued if the patient so requested.

Results:¹

• 73.9 percent excellent-to-good response to the active drug in patients receiving it before they received the placebo, compared with 44.5 percent in those who did not receive it until after the placebo period.
• 58.9 percent excellent-to-good response to the active drug in patients who received it after the placebo period, as compared with 31.8 percent in those receiving the placebo last.
• Overall clinical response 67.5 percent excellent-to-good with the active drug as compared with 37.5 percent with the placebo.
• Excellent-to-good results in 12 follow-up patients receiving the known active drug.
• Statistically significant symptomatic response in four of eight target symptoms.

The tranquilizer-anticholinergic preparation used appeared to improve not only patient outlook and attitudes but to effectively relieve both the physiologic and psychic manifestations of common functional gastrointestinal disorders.

Conclusions:¹

The tranquilizer-anticholinergic preparation used appeared to improve not only patient outlook and attitudes but to effectively relieve both the physiologic and psychic manifestations of common functional gastrointestinal disorders.¹

Title:²

Colonic myoelectrical activity in irritable-bowel syndrome

Abstract:²

To determine the effect of a standard meal on colonic myoelectrical and motor activity in the irritable-bowel syndrome and to determine the effect of a single dose of an oral anticholinergic drug (clidinium bromide) on this response, we studied 10 patients.

These patients showed a prolonged increase in both colonic spike (P<0.05) and motor activity (P<0.05) after eating as compared to normal subjects. Clidinium did not affect the frequency of colonic slow waves or the basal colonic spike and motor activity. However, the anticholinergic reduced the prolonged postprandial colonic spike and motor response in the patients and also reduced the postprandial increase in colonic contractions at 3 cycles per minute (P<0.05). These studies indicate that patients with the irritable· bowel syndrome show an abnormally prolonged postprandial increase in colonic spike and motor activity. An anticholinergic drug reduces the duration and the magnitude of this abnormal colonic response.

Background:²

Although the irritable-bowel syndrome is a common clinical gastrointestinal disorder, there is limited objective information concerning the colonic response to therapeutic agents in this disorder.

Previous studies have shown an abnormal colonic contractile response after emotional stress, feeding, cholinergic drugs or rectal distention in patients with the syndrome.

In recent studies, we have reported that patients with the syndrome have an underlying difference in the frequency of colonic slow waves as compared to normal subjects.

Patients with the irritable-bowel syndrome have an increase in slow-wave activity at 3 cycles per minute that leads to increased motor activity at the same frequency during periods of colonic stimulation.

Most recently, we have demonstrated a marked increase in colonic motility in normal subjects in response to a standardized meal.

Objectives:²

The purposes of the present study were to compare colonic myoelectrical and motor activity in response to a meal in patients with the irritable-bowel syndrome and in normal subjects and, secondly, to determine, in a double-blind fashion, the effect of oral anticholinergic therapy on the colonic myoelectrical response to eating in patients with the syndrome.

Methods:²

Using the following diagnostic criteria, we selected 10 patients with the irritable-bowel syndrome: diarrhoea, constipation or a combination of both symptoms lasting for more than three months; unexplained abdominal pain either related or unrelated to meals; normal sigmoidoscopic examination, barium-enema and upper-gastrointestinal radiographic study; absence of ova or parasites and pathogenic bacteria on stool examination and culture; and a negative history of lactose intolerance.

Each patient was studied twice, two to 14 days apart, in a double-blind crossover manner, which compared 5.0 mg of an oral anticholinergic, clidinium bromide, to a placebo. Each patient took both the placebo and clidinium, which were in identical-appearing capsules. The order in which the patients took each capsule was assigned randomly before the study was begun. Neither the patient nor the investigators knew the composition ofthe capsules until the data had been completed and analyzed for all 10 patients. Two bipolar silver-silver chloride wire electrodes were attached to the colonic mucosa.

Two investigators evaluated each myoelectrical recording for slow waves and spike activity. We analysed the recordings for the percentage of total recording time during which slow-wave activity was present. We evaluated pressure by determining the number of contractions during each 10-minute period and calculating a motility index (i.e., product of the mean amplitude of the pressure waves multiplied by the sum of duration of each pressure wave) for each 10-minute period.

Results:²

The results suggest not only that patients with the syndrome show both a qualitative and quantitative difference in the colonic myoelectric and motor response to a meal but also that anticholinergic therapy shortens the duration and reduces the magnitude of this abnormal colonic activity after a meal.

Conclusions:²

These studies indicate that anticholinergic myoelectric therapy shortens the duration and reduces the magnitude of the abnormal colonic myoelectric and motor responses to a meal in patients with the irritable bowel syndrome.

 

IBS patient information booklet

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