For the use of a Registered Medical Practitioner only

1.0 GENERIC NAME AND BRAND NAME
Chlordiazepoxide & Clidinium Bromide Tablets
Librax®

2.0 QUALITATIVE AND QUANTITATIVE COMPOSITION :
Each film coated tablet contains:
Chlordiazepoxide I.P. 5 mg
Clidinium Bromide USP 2.5 mg
Excipients q.s.
Colours: Titanium Dioxide I.P., Ferric Oxide USP NF Yellow & Indigo Carmine Aluminum Lake

3.0 DOSAGE FORM AND STRENGTH
Refer section 1 & 2

4.0 CLINICAL PARTICULARS
4.1 THERAPEUTIC INDICATIO
Indicated for the treatment of organic manifestations of anxiety and tension in gastrointestinal and genitourinary tracts. The conditions may (but not limited to) include irritable bowel syndrome, dysmenorrhea, gastric & duodenal ulcer, gastro-duodenitis, intestinal spasms, ureteric spasm, biliary dyskinesia etc.

4.2 POSOLOGY AND METHOD OF ADMINISTRATION
Adults:
1–2 tablets 3–4 times daily. Elderly or debilitated: 1-2 tabs daily initially, then may increase gradually. In dysmenorrhoea, the drug should be taken three to four days prior to menstruation or as directed by the physician
Children: Not recommended
Elderly or debilitated patients and Special patient groups: In elderly patients, renal or hepatic insufficiency, dosage adjustment is required.
The tablets should be swallowed with water. They may be taken with meals, when going to bed or when experiencing pain. Treatment must be as brief as possible. The indication will be re-evaluated regularly, especially in the absence of symptoms. The total duration of treatment should not exceed 8 to 12 weeks for the majority of patients.

4.3 CONTRAINDICATIONS
Librax is contraindicated in

• hypersensitivity to the active substances or to any of the excipients
• Pathological subjects aged over 65 years, patients aged over 75 years and children under 6 years
• Risk of angle-closure glaucoma
• Risk of urinary retention associated with urethra-prostatic disorders
• Breastfeeding
• Severe respiratory insufficiency
• Sleep apnoea syndrome
• Severe, acute or chronic hepatic insufficiency (risk of occurrence of encephalopathy)
• Myasthenia gravis

4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE
Synergistic Effect
Benzodiazepines such as chlordiazepoxide can have a synergistic effect with other drugs especially sedatives and Clidinium may have synergistic effects with atropine or other anti-muscarinic drugs.
Duration of treatment
The duration of treatment including the tapering off process, should be as short as possible but should not exceed 8 to 12 weeks. Only after re-evaluation of the situation, extension beyond these periods may be done.
When benzodiazepines with a long duration of action are being used, change to a benzodiazepine with a short duration of action should not be done, as withdrawal symptoms may develop.
Alcohol and drug abuse
Caution is to be exercised before commencing therapy, if there is a history of alcoholism or other dependences, drug related or otherwise.
Major depressive episodes
Since they allow depression to develop separately with a persistent or increased risk of suicide, benzodiazepines should not be prescribed alone
Tolerance
After repeated use, loss of efficacy to the hypnotic effects of benzodiazepines may develop.
Dependence
Use of benzodiazepines (even at therapeutic doses) may lead to the development of physical and psychic dependence upon these products which is dose and time dependent. The risk of dependence increases with a history of alcohol or drug abuse. If the treatment is withdrawn abruptly, symptoms like insomnia, muscle tension, muscle pain, headaches, tension, restlessness, confusion, hyperreactivity, extreme anxiety, and irritability may develop. In severe cases the following symptoms may occur: derealisation, hypersensitivity to light, depersonalisation, hyperacusis, noise and physical contact, hallucinations, numbness and tingling of the extremities, or epileptic seizures.
Rebound reactions
Upon the withdrawal of therapy, a transient syndrome may occur whereby the symptoms that led to treatment with a benzodiazepine recur in an enhanced form which are accompanied by other reactions such as mood changes, anxiety or sleep disturbances and restlessness. The dosage is reduced gradually as risk of withdrawal/rebound phenomena is greater after abrupt discontinuation of treatment.
Amnesia and alteration in psychomotor function
Benzodiazepines may induce anterograde amnesia along with alterations in the psychomotor functions several hours after ingesting the drug.
Psychiatric and paradoxical reactions
Benzodiazepines may give rise to an alteration in the state of consciousness, behavioural and memory problems, the symptoms of which are aggravation of insomnia, nightmares, agitation, nervousness, loss of inhibitions with impulsiveness, psychotic type symptoms, anterograde amnesia, delirious thoughts, hallucinations, euphoria, irritability, confusional state, suggestibility. Discontinue treatment, if these symptoms occur. Extreme caution should be used prescribing benzodiazepines to patients with personality disorders.
Paradoxical reactions to chlordiazepoxide hydrochloride such as excitement, stimulation and acute rage, have been observed in psychiatric patients and the patient must be monitored for during Librax (chlordiazepoxide and clidinium) therapy.
Withdrawal symptoms
Withdrawal symptoms of the barbiturate type have occurred after the discontinuation of benzodiazepines.
Rebound reactions
Upon the discontinuation of treatment, a transient syndrome may occur whereby the
symptoms that led to treatment with a benzodiazepine recur in an enhanced form. It may be accompanied by other reactions including mood changes, anxiety or sleep disturbances and restlessness. Since the risk of withdrawal/rebound phenomena is greater after abrupt discontinuation of treatment, it is recommended that the dosage is decreased gradually.
Debilitated patients
In debilitated patients, the dose of Librax must be limited to the smallest effective amount to prevent the development of ataxia, over-sedation or confusion. It has been recommended that initially not more than 2 Librax (chlordiazepoxide and clidinium) tablets per day be given, and then the dose may be increased gradually as required depending on the tolerability of the patient. The concomitant administration of Librax and other psychotropic agents is not recommended. If such combination therapy is given, careful consideration must be given to the pharmacology of the drugs to be administered, particularly drugs such as the MAO inhibitors and phenothiazines.
Prostate hypertrophy
Caution should be exercised in prescribing Clidinium bromide to prostate hypertrophy patients.

Renal or hepatic Impairment
Caution should be exercised in prescribing Clidinium bromide to patients with renal and hepatic impairment.
Coronary insufficiency, heart rate problems, hyperthyroidism
Caution should be exercised in prescribing Clidinium bromide to these patients.
Carcinogenesis, Mutagenesis and effect of fertility
In in-vivo and in-vitro studies with chlordiazepoxide indicate a mutagenic effect. In carcinogenicity studies in mice an increase of liver tumor was seen at high doses, especially in males, whereas no increase of tumor incidence was seen in rats.
No clear evidence of a teratogenic effect of chlordiazepoxide have been seen in studies in humans.
Pediatric population.
The product is not recommended in children
Elderly
Elderly patients may be more prone to experience drowsiness, ataxia and confusion if receiving Librax (chlordiazepoxide and clidinium) . These effects can usually be avoided with the correct dosage adjustment. But a point to note is that, these adverse reactions have occasionally been observed even at the lower dosage ranges. Hence dosing in geriatric subjects must be initiated cautiously (no more than 2 tablets per day) and can be increased gradually if needed and tolerated.

4.5 DRUG INTERACTIONS

No	Drug	Drug Interactions	Remarks
1.	Centrally-acting drugs such as neuroleptics, tranquilisers, antidepressants, hypnotics, analgesics, anaesthetics, antitussives, sedative anti-histamines, central antihypertensives, and baclofen	If Chlordiazepoxide is combined with centrally-acting drugs, the central depressive effects are likely to be intensified.In the case of narcotic analgesics with Chlordiazepoxide, enhancement of the euphoria may also occur leading to an increase in psychic dependence.
2.	Barbiturates	Concomitant use of barbiturates and chlordiazepoxide leads to increased risk of respiratory depression, which may be fatal in the event of overdose.
3.	Buprenorphine	Concomitant use of buprenorphine with Chlordiazepoxide leads to increased risk of respiratory depression which may be fatal.	Risk-benefit ratio of this combination should be evaluated carefully.
4.	Cimetidine	Increased risk of drowsiness when chlordiazepoxide and cimetidine are co-administered.	Patients should be warned about the increased risk of drowsiness and the attendant difficulty in driving and using machinery and the subsequent risks involved
5.	Products derived from morphine	Increased risk of respiratory depression, when co-administered with chlordiazepoxide, which may be fatal in the event of overdose.
6.	Product which inhibit hepatic enzymes	Compounds which inhibit certain hepatic enzymes (particularly cytochrome P450) may enhance the activity of benzodiazepines.
7.	Atropine-like substances, substances having anticholinergic action belonging to the following therapeutic groups: antidepressants, antihistamine (H1 antagonists), antiparkinsonian agents, anticholinergics, other atropinic antispasmodics, disopyramide, phenothiazine neuroleptics, clozapine and amantadine	Atropine-like substances can increase the side effects and aggravate urinary retention, glaucoma, constipation, dry mouth, etc. when given concomitantly along with Clidinium bromide

4.6 USE IN SPECIAL POPULATION
Pregnancy
Librax is contraindicated in pregnancy. An increased risk of congenital malformations has been reported with the use of minor tranquilizers such as chlordiazepoxide during the first trimester of pregnancy. Patients should be advised that if they become pregnant during therapy or intend to become pregnant they should communicate with their physicians about the desirability of discontinuing the drug. The possibility that a woman of childbearing potential might be pregnant at the time of initiation of therapy must be considered.
Breast-feeding
Both Clidinium and chlordiazepoxide can appear in the breast milk Clidinium may decrease milk secretion and it may also pass into milk. This can result in atropinic
effects in the child. Therefore, the use of Librax is not recommended during breast feeding.

4.7 EFFECTS ON ABILITY TO DRIVE AND USE MACHINES
As there is risk of drowsiness, medication should not be used when driving or operating heavy machinery.

4.8 UNDESIRABLE EFFECTS
Most common adverse effects include sedation, ataxia, fatigue, somnolence, dizziness, and balance disorder. The elderly are particularly sensitive to the effects of centrally-depressant drugs and may experience confusion.

Organ Class	Effect
General disorders and administration site conditions	Dry mouth, fatigue
Blood and lymphatic system	Bone marrow depression (e.g. pancytopenia leucopenia, thrombocytopenia, agranulocytosis, acute thrombocytopenic purpura)
Psychiatric disorders	Depression, restlessness, agitation, irritability, paradoxical drug reaction (e.g. anxiety, sleep disorders, insomnia, suicide attempt, suicidal ideation), amnesia, emotional disturbances, depressed level of consciousness, aggression, delusion, dependence, hallucinations, nightmares, psychotic disorder, abnormal behaviour,
Nervous system disorders	Confusional state, vertigo, dizziness, dysarthria, sedation, headache, extrapyramidal disorder (e.g tremor, dyskinesia), somnolence, gait disturbance, ataxia, balance disorder,
Immune system disorders	Hypersensitivity
Cardiac disorders	Palpitations, tachycardia
Vascular disorders	Hypotension
Respiratory, thoracic and mediastinal disorders	Increased viscosity of bronchial secretion, respiratory depression
Gastrointestinal disorders	Constipation
Metabolism and nutrition disorders	Increased appetite
Hepato-biliary disorders	Raised bilirubin, alkaline phosphatise and transaminases, jaundice
Skin and subcutaneous tissues disorders	Skin reaction
Eye disorders	Diplopia, decreased lacrimation, visual impairment accommodation disorders
Musculoskeletal, connective tissue disorders	Asthenia, muscular weakness
Renal and urinary disorders	urinary retention
Reproductive system and breast disorders	Menstrual disorder, erectile dysfunction, dysmenorrhoea, libido disorder

4.9 OVERDOSE
Associated with chlordiazepoxide
Symptoms: Benzodiazepine overdosage can result in life threatening complications especially if the patient has taken other central nervous system depressants (including alcohol). The symptoms of overdose include drowsiness, mental confusion, drowsiness and lethargy. The more serious cases, symptoms may include hypotonia, ataxia, respiratory depression, rarely coma and very rarely death.
Treatment: In the conscious patient vomiting should be induced within one hour or gastric lavage can be undertaken with the airway protected if the patient is unconscious. Activated charcoal can be administered to reduce absorption. Monitor respiratory and cardiovascular functions. Flumazenil is a Benzodiazepine antagonist which may be useful in the diagnosis and/or treatment of overdose with benzodiazepines.
Associated with clidinium bromide
Symptoms: Patients with overdose of Clidinium bromide may present with anticholinergic effects such as dry mouth, urinary retention, tachycardia, redness of the skin, reduced gastrointestinal motility, mild drowsiness and transient disturbances of vision (including mydriasis, accommodation paralysis). The more serious disturbances include circulatory and respiratory alterations, tachycardia, delirium. Arousal state, agitation, confusion and hallucination, respiratory depression and coma.
Treatment: Symptomatic with cardiac and respiratory monitoring in a hospital environment.

5.0 PHARMACOLOGICAL PROPERTIES
5.1 Mechanism of action
Chlordiazepoxide is an anxiolytic belonging to the class of benzodiazepines.
Pharmacologically its properties are those of the class of benzodiazepines: anxiolytic,
sedative, hypnotic, anticonvulsant, myorelaxant and amnestic. These effects are associate with a specific agonist action on a central receptor forming part of the GABA-OMEGA macromolecular receptors complex (also known as BZ1 and BZ2) modulating the opening of the chlorine channel. Drug dependence may be observed in animals and in humans. Clidinium bromide is a synthetic anticholinergic that has a spasmolytic effect on smooth muscle and also inhibits secretions.

5.2 Pharmacodynamic Properties
Chlordiazepoxide is Benzodiazepine class drug. Chlordiazepoxide has sedative, anxiolytic, hypnotic, myorelaxant, anticonvulsant, and amnestic properties. These effects are attributed to specific agonist action on a central receptor forming part of the GABA-OMEGA macromolecular receptors complex (also known as BZ1 and BZ2) which affects the opening of the chlorine channel. Dependence of drug is observed in humans.
Clidinium bromide is a synthetic anticholinergic which has a spasmolytic effect on smooth muscle. It also inhibits various GI secretions.

5.3 Pharmacokinetic Properties

Parameters	Chlordiazepoxide	Clidinium bromide
Absorption	Well absorbed, with peak blood levels being achieved one or two hours after administration. Steady-state levels are usually reached within three days.	Incompletely absorbed from the GI tract since it is completely ionized
Bioavailability	Bioavailability after oral dose is close to 100%.
Distribution	The Foeto-placental crossover and passing into the mother’s milk have been demonstrated for benzodiazepines. Steady-state levels of active metabolites are reached after 10-15 days, with metabolite concentrations which are similar to those of the parent drug.	Does not readily penetrate the CNS or the eye. There is no data regarding the passage of clidinium bromide into the placenta or into milk
Metabolism	Metabolised into desmethyl-chlordiazepoxide. Also metabolised to a much lesser extent to the active metabolite demoxapam.The demoxepam is itself metabolised into an active metabolite, oxazepam, but in very small proportions	Metabolised into 3-hydroxy-1-methylquinuclidinium bromide, which is the principal form found in the urine of humans.
Excretion	Urinary elimination takes the form of demoxepam and oxazepam.	Clidinium bromide and its metabolites are found in faeces.
Half-life	Chlordiazepoxide half-life is 6-30 hours. Demoxepam and oxazepam half-life is 20 to 24 hours.	Biphasic; initial half-life was 2.4 hours and terminal half-life is about 20 hours

6.0 NON-CLINICAL PROPERTIES
6.1 ANIMAL TOXICOLOGY OR PHARMACOLOGY

Mutagenic and tumorigenic potential:
In in-vivo and in-vitro studies with chlordiazepoxide there are indications for a mutagenic effect. Nevertheless, in similar test systems results are negative. The relevance of the positive findings is currently unclear. In carcinogenicity studies in mice an increase of liver tumors was seen at high doses, especially in males, whereas no increase of tumor incidence was seen in rats.

Reproductive toxicity:
Observations in humans have shown no clear evidence of a teratogenic effect of chlordiazepoxide up to now, whereas in animal studies changes in the urogenital tract, lung anomalies and malformations of the skull (exencephaly, cleft palate), behavioral disorders and neurochemical changes have been observed in the offspring. The malformation risk with administration of therapeutic doses of benzodiazepines in early pregnancy appears to be low, although some epidemiological studies have found evidence of an increased risk for the occurrence of cleft palate and there are few case reports of malformations and mental retardation of prenatally exposed children after chlordiazepoxide overdose and poisoning.

7.0 DESCRIPTION
Light green to green coloured, circular biconvex film coated tablets plain on both sides.

8.0 PHARMACEUTICAL PARTICULARS
8.1 INCOMPATIBILITIES
Not applicable

8.2 SHELF LIFE
Refer Pack

8.3 PACKAGING INFORMATION
Strip of 20 tablets

8.4 STORAGE AND HANDLING INSTRUCTIONS
Store at a temperature not exceeding 25° C, protected from light.
Medicine: Keep out of reach of children.

9.0 PATIENT COUNSELING
a.Appropriate treatment
Each film-coated tablet contains: Chlordiazepoxide I.P. 5 mg and Clidinium Bromide USP 2.5 mg. this medicine is used for the treatment of organic manifestations of anxiety and tension in gastrointestinal and genitourinary tracts.
The posology should be adjusted according to the individual needs of the patient as directed by the physician. The tablets should be swallowed with water. They may be taken with meals, when going to bed or when experiencing pain.
Use of Librax is not recommended in children and pregnant and lactating mothers.
Caution should be exercised in prescribing Clidinium bromide to patients suffering from prostate hypertrophy, Renal or hepatic Impairment, Coronary insufficiency, heart rate problems, hyperthyroidism.

As there is risk of drowsiness, medication should not be used when driving or operating heavy machinery.

Advice the patient to reach out to the doctor if these symptoms do not improve after a while, if you develop new symptoms or you are concerned about your symptoms.

b.Drug Interaction
Concomitant intake of Librax with alcohol should be avoided. Librax if used along with drugs such as neuroleptics, antipsychotics, tranquillisers, antidepressants, hypnotics, analgesics, anaesthetics, barbiturates and sedative antihistamine may lead to enhancement of central depressive effects. The elderly may require special supervision.

Extra care in adjusting dosage in the initial stages of treatment when Librax is used concurrently with anti-epileptic drugs.

c.Warnings and Precautions
Treatment with Librax should be as brief as possible. Withdrawal symptoms of the barbiturate type have occurred after the discontinuation of benzodiazepines. Risk of withdrawal/rebound phenomena is greater after abrupt discontinuation of treatment; it is recommended that the dosage is decreased gradually. Dosing in geriatric subjects must be initiated cautiously and can be increased gradually if needed and tolerated. Caution should be exercised in prescribing Clidinium bromide to patients suffering from prostate hypertrophy, renal or hepatic impairment, coronary insufficiency, heart rate problems, hyperthyroidism.

10.0 DETAILS OF MANUFACTURER
MANUFACTURED BY
Abbott Healthcare Pvt. Ltd.,
Village Bhatauli Khurd, P.O Baddi- 173205,
Dist Solan, Himachal Pradesh,
India.

11.0 DETAILS OF REVISION OR LICENSE NUMBER WITH DATE
Mfg. License No. MNB/06/295, dated 02/12/2023.

12.0 DATE OF REVSION
Version: 1.0 dated 18/01/2024

® – Regd. Trademark of Abbott Healthcare Pvt. Ltd.

For Product Complaints/Adverse events or Queries please write to
webmasterindia@abbott.com