Source: Health Products and Food Branch (CA) Revision Year: 2023
LIBRAX is contraindicated in patients with:
Body Temperature: When clidinium is given to patients where the environmental temperature is high, there is risk of a rapid increase in body temperature because of suppression of sweat gland activity.
Concomitant use with opioids: Concomitant use of benzodiazepines, including LIBRAX, and opioids may result in profound sedation, respiratory depression, coma, and death. Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are not possible (see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX, Risks from Concomitant use with Opioids; 9.1 Serious Drug Interactions).
Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with benzodiazepines.
If a decision is made to prescribe LIBRAX concomitantly with opioids, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of LIBRAX than indicated, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking LIBRAX, prescribe a lower initial dose of the opioid analgesic and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation (see 5 OVERDOSAGE).
Advise both patients and caregivers about the risks of respiratory depression and sedation when LIBRAX is used with opioids.
Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the opioid have been determined.
Hypertension may be aggravated by clidinium bromide. Risk-benefit should be considered when prescribing LIBRAX to patients with hypertension.
Use of benzodiazepines, such as LIBRAX, can lead to abuse, misuse, addiction, physical dependence (including tolerance) and withdrawal reactions. Abuse and misuse can result in overdose or death, especially when benzodiazepines are combined with other medicines, such as opioids, alcohol, or illicit drugs.
The risk of dependence increases with higher doses and longer term use but can occur with shortterm use at recommended therapeutic doses. The risk of dependence is greater in patients with a history of psychiatric disorders and/or substance (including alcohol) use disorder.
Withdrawal: Benzodiazepines, such as LIBRAX, can produce withdrawal signs and symptoms, ranging from mild to severe and even life threatening, following abrupt discontinuation or rapid dose reduction. Other factors that may precipitate withdrawal are switching from a long-acting to a shortacting benzodiazepine, decreasing blood levels of the drug or administration of an antagonist. The risk of withdrawal is higher with higher dosages and/or prolonged use, but can occur with short-term use at recommended therapeutic doses.
The onset of withdrawal signs and symptoms can range from hours to weeks following drug cessation and occur even with tapered dosage. Some symptoms can persist for months. Since symptoms are often similar to those for which the patient is being treated, it may be difficult to distinguish from a relapse of the patient’s condition.
Severe or life-threatening signs and symptoms of withdrawal include catatonia, delirium tremens, depression, dissociative effects (e.g. hallucinations), mania, psychosis, seizures (including status epilepticus) and suicidal ideation and behaviour.
Other withdrawal signs and symptoms include abdominal cramps, cognitive impairment, diarrhea, dysphoria, extreme anxiety or panic attacks, headache, hypersensitivity to light, noise and physical contact, insomnia, irritability, muscle pain or stiffness, paresthesia, restlessness, sweating, tension, tremors and vomiting. There is also a possibility of rebound anxiety or rebound insomnia, a transient syndrome whereby the symptoms that led to treatment with a benzodiazepine recur in an enhanced form, on withdrawal of treatment.
(see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX, Addiction, Abuse and Misuse; Withdrawal; 4.1 Dosing Considerations)
Patients receiving LIBRAX should be cautioned against engaging in hazardous activities requiring complete mental alertness, judgement and physical coordination, such as operating machinery or a motor vehicle.
Risk-benefit should be considered when prescribing LIBRAX to a patient with hyperthyroidism characterized by tachycardia, which may be increased by clidinium bromide.
There have been reports of falls and fractures among benzodiazepine users due to adverse reactions such as sedation, dizziness and ataxia. The risk is increased in those taking concomitant sedatives (including alcoholic beverages), geriatricor debilitated patients.
Prolonged use of clidinium bromide may decrease or inhibit salivary flow, thus contributing to the development of caries, periodontal disease, oral candidiasis, and discomfort. Risk-benefit should be considered when prescribing LIBRAX to patients with xerostomia.
Severe Anaphylactic and Anaphylactoid Reactions: Rare cases of angioedema involving the tongue, glottis or larynx have been reported in patients after taking the first or subsequent doses of benzodiazepines, including LIBRAX. Some patients have had additional symptoms such as dyspnea, throat closing or nausea and vomiting that suggest anaphylaxis. Some patients have required medical therapy in the emergency department. If angioedema involves the throat, glottis or larynx, airway obstruction may occur and be fatal. Patients who develop angioedema after treatment with RESTORIL should not be rechallenged with the drug.
Periodic blood counts and liver function tests are recommended if the medication is administered over a protracted period of time.
Complex sleep-related behaviours: Complex sleep-related behaviours such as “sleep- driving” (i.e., driving while not fully awake after ingestion of a sedative-hypnotic, with amnesia for the event) have been reported in patients who have taken LIBRAX. Other potentially dangerous behaviours have been reported in patients who got out of bed after taking a sedative-hypnotic and were not fully awake, including preparing and eating food, making phone calls, leaving the house, etc. As with “sleepdriving”, patients usually do not remember these events. The use of alcohol and other CNSdepressants with LIBRAX appears to increase the risk of such behaviours, as does the use of LIBRAX at doses exceeding the maximum recommended dose. LIBRAX is not to be taken with alcohol. Caution is needed with concomitant use of other CNS depressant drugs. Due to the risk to the patient and the community, discontinuation of LIBRAX should be strongly considered for patients who report any such complex sleep-related behaviours.
Memory Disturbance: Anterograde amnesia may occur with therapeutic doses of benzodiazepines and may be associated with inappropriate behaviour. Anterograde amnesia is a dose-related phenomenon and geriatric patients may be at particular risk.
Glaucoma: LIBRAX is contraindicated in patients with angle-closure, or predisposition to glaucoma (see 2 CONTRAINDICATIONS).Clidinium bromide’s possible mydriatic effect may cause increase in intraocular pressure. This may precipitate an acute attack of angle-closure glaucoma.
Confusion: Benzodiazepines affect mental efficiency, e.g. concentration, attention and vigilance. The risk of confusion is greater in the elderly and in patients with cerebral impairment.
Mental and Emotional Disorders: Chlordiazepoxide hydrochloride may increase depression. Caution should be exercised if LIBRAX is prescribed to patients with signs or symptoms of depression that could be intensified by benzodiazepines. The potential for self-harm is high in patients with depression. Employ the usual precautions in treatment of anxiety states with evidence of impending depression; suicidal tendencies may be present and protective measures necessary.
Paradoxical Reactions: Paradoxical reactions such as restlessness, agitation, irritability, rage, aggressive or hostile behaviour, anxiety, delusion, anger, increased muscle spasticity, sleep disturbances, nightmares, hallucinations and other adverse behavioural effects may occur due to chlordiazepoxide rare instances and in a random fashion. Should these occur, use of the drug should be discontinued. They are more likely to occur in children and in the elderly.
Since excitement and other paradoxical reactions can result from the use of anxiolytic sedatives in psychotic patients, chlordiazepoxide should not be used in ambulatory patients suspected of having psychotic tendencies.
These reactions may be secondary to the relief of anxiety symptoms and should be watched for particularly in the early phase of medication.
Decreased excretion may increase risk of side effects in patients with renal function impairment. LIBRAX should be administered with caution to patients with a history of renal disease.
There are no adequate and well-controlled studies of LIBRAX in pregnant women. Animal studies with other anxiolytic-sedative agents have suggested increased risk of congenital malformations (see 7.1.1 Pregnant women; 16 NON-CLINICAL TOXICOLOGY, Reproductive and Developmental Toxicology).
Chronic use of chlordiazepoxide during pregnancy may cause physical dependence with resulting withdrawal symptoms in the neonate. Use of chlordiazepoxide just prior to or during labour may cause neonatal flaccidity. (see 7.1.1 Pregnant Women).
Severe Chronic Obstructive Pulmonary Disease:Anticholinergic effects may cause thickening of secretions and impair expectorations; ventilatory failure may be exacerbated with the use of chlordiazepoxide hydrochloride. Risk-benefit should be considered when prescribing LIBRAX to patients with severe chronic obstructive pulmonary disease.
Patients who are sensitive to other benzodiazepines or any of the belladonna alkaloids may be sensitive to LIBRAX as well.
The use of LIBRAX (anticholinergic and anxiolytic combination) in pregnancy is not recommended.
Chlordiazepoxide: Chlordiazepoxide crosses the placenta. Several studies have suggested an increased risk of congenital malformations (e.g. congenital malformations of the heart, cleft lip and/or palate) associated with the use of diazepam, chlordiazepoxide and meprobamate during the first trimester of pregnancy. Therefore, the administration of chlordiazepoxide is rarely justified in women of childbearing potential. If the drug is prescribed for a woman of childbearing potential, she should be warned to contact her physician regarding discontinuation of the drug if she intends to become, or suspects that she is pregnant. Because use of these drugs is rarely a matter of urgency, their use during this period should almost always be avoided.
Chronic use of chlordiazepoxide during pregnancy may cause physical dependence with resulting withdrawal symptoms in the neonate. Symptoms such as hypoactivity, hypotonia, hypothermia, respiratory depression, apnea, feeding problems, and impaired metabolic response to cold stress have been reported in neonates born of mothers who have received benzodiazepines during the late phase of pregnancy or at delivery. Use of chlordiazepoxide just prior to or during labour may cause neonatal flaccidity.
Clidinium: appropriate studies in humans have not been performed. However, reproduction studies in rats have not shown that clidinium has adverse effects on the foetus.
Chlordiazepoxide or its metabolites may be excreted in breast milk; use by breast-feeding mothers may cause sedation in the infant.
Clidinium may inhibit lactation.
LIBRAX should not be administered to breast-feeding women, unless the expected benefit to the mother outweighs the potential risk to the infant.
Pediatrics (<18 years of age): Health Canada has not authorized an indication for pediatric use.
No information is available on the relationship of age to the effect of chlordiazepoxide and clidinium in pediatric patients. However, it is known that infants and young children are especially susceptible to the toxic effects of atropine-like drugs, such as clidinium, and to the central nervous system effects of benzodiazepines, such as chlordiazepoxide.
Geriatrics (>65 years of age): Dosage should be limited to the smallest effective amount to preclude the development of ataxia, oversedation or confusion.
Geriatric patients may respond to usual doses of chlordiazepoxide and clidinium with excitement, agitation, drowsiness, or confusion.
Geriatric patients are especially susceptible to the anticholinergic side effects, such as constipation, dryness of mouth, and urinary retention (especially in males), of clidinium. If these side-effects occur and continue or are severe, medication should be discontinued.
Caution is also recommended when clidinium is given to geriatric patients, because of the danger of precipitating undiagnosed glaucoma.
Memory may become severely impaired in geriatric patients, especially those who already have memory problems, with the continued use of clidinium since this medication blocks the action of acetylcholine, which is responsible for many functions of the brain, including memory function.
Long-term use of LIBRAX should be avoided in geriatric or debilitated patients who may be more sensitive to benzodiazepines. There is an increased risk of cognitive impairment, delirium, falls, fractures, hospitalizations and motor vehicle accidents in these users. Enhanced monitoring is recommended in this population. (see 7 WARNINGS AND PRECAUTIONS, Falls and Fractures).
The following adverse reactions have been reported with the use of LIBRAX:
Blood and Lymphatic System Disorders: agranulocytosis; granulocytopenia; leukopenia
Eye Disorders: increased intraocular pressure (eye pain); blurred vision
Gastrointestinal Disorders: decreased peristalsis-possible paralytic ileus (constipation); bloated feeling; dryness of mouth; nausea; stomach cramps. Constipation has occurred more often when LIBRAX therapy has been combined with other spasmolytic agents and/or a low residue diet
General Disorders and Administration Site Conditions: edema, unusual tiredness or weakness
Hepatobiliary Disorders: hepatic dysfunction; jaundice
Musculoskeletal and Connective Tissue Disorders: muscle cramps
Nervous System Disorders: CNS depression (slow heartbeat, shortness of breath, or troubled breathing); dizziness; drowsiness; confusion; ataxia; headache; trembling; seizures; syncope; extrapyramidal symptoms; changes in EEG patterns (low-voltage fast activity) have been observed in patients during and after chlordiazepoxide hydrochloride treatment
Psychiatric Disorders: paradoxical reaction (trouble in sleeping; unusual excitement; nervousness, or irritability); decreased sexual ability
Renal and Urinary Disorders: urinary hesitancy
Reproductive System and Breast Disorders: increased and decreased libido; minor menstrual irregularities
Skin and Subcutaneous Tissue Disorders: skin rash or hives; decreased sweating
From the adverse reactions listed above, skin eruptions, edema, minor menstrual irregularities, nausea and constipation, extrapyramidal symptoms, as well as increased and decreased libido have been infrequent and are generally controlled with reduction of dosage.
There have been reports of falls and fractures in benzodiazepine users due to adverse reactions such as sedation, dizziness and ataxia. The risk is increased in those taking concomitant sedatives (including alcoholic beverages), the elderly and debilitated patients.
Development of physical dependence and withdrawal following discontinuation of therapy has been observed with benzodiazepines such as LIBRAX. Severe and life-threatening symptoms have been reported. (see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX, Addiction, Abuse and Misuse; 7 WARNINGS AND PRECAUTIONS, Dependence/Tolerance).
Concomitant use of LIBRAX and opioids may result in profound sedation, respiratory depression, coma and death.
Benzodiazepines, including LIBRAX, may produce additive CNS depressant effects when coadministered with alcohol, and medications, including opioids, which themselves can produce CNS depression.
The activity of benzodiazepines, including LIBRAX, may be enhanced by compounds which inhibit certain hepatic enzymes such as cytochrome P450 enzymes.
Benzodiazepines, including LIBRAX, may produce additive CNS depressant effects when coadministered with alcohol. Patients should be cautioned not to take alcohol because of the potentiation of effect that might occur.
CNS depressant drugs: Benzodiazepines, including LIBRAX,may produce additive CNS depressant effects when co-administered sedative antihistamines, narcotic analgesics, anticonvulsants, antipsychotics (neuroleptics), anesthetics, antidepressant agents or psychotropic medications which themselves can produce CNS depression.
Cytochrome P450: Compounds which inhibit certain hepatic enzymes (particularly cytochrome P450) may enhance the activity of benzodiazepines and benzodiazepine-like agents. Examples include cimetidine, erythromycin, ketoconazole, itroconazole, nefazodone and several HIV protease inhibitors.
Opioids: Due to additive CNS depressant effect, the concomitant use of benzodiazepines, including LIBRAX, and opioids increases the risk of profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations of concomitant use of benzodiazepines and opioids to the minimum required. Follow patients closely for respiratory depression and sedation (see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX, Risks from Concomitant use with Opioids; 7 WARNINGS AND PRECAUTIONS, General, Concomitant use with opioids).
Interactions with food have not been established.
Interactions with herbal products have not been established.
Interactions with laboratory tests have not been established.
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