Chlordiazepoxide and Clidinium (Systemic)


VA CLASSIFICATION
Primary: GA802

Commonly used brand name(s): Apo-Chlorax; Clindex; Clinoxide; Clipoxide; Corium; Librax; Lidox; Lidoxide; Zebrax.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Anticholinergic-sedative—

Indications

Accepted

Ulcer, peptic (treatment adjunct) or{01}
Bowel syndrome, irritable (treatment)—FDA has classified chlordiazepoxide and clidinium combination as possibly effective as adjunctive therapy in the treatment of peptic ulcer and irritable bowel syndrome. {01}

Note: The less-than-effective classifications require submission of adequate and well-controlled studies to provide substantial evidence of effectiveness. {01} FDA has notified manufacturers of the possible withdrawal from the market of products containing a combination of an anticholinergic and a sedative because their efficacy as fixed combinations has not been proven in adequately designed clinical trials. To date, no final action has been taken.


Unaccepted
Anticholinergic and sedative combinations have been used as adjuncts in the treatment of acute enterocolitis; however, their use for this condition is controversial since they cause a reduction in gastrointestinal motility, resulting in retention of the causative organism or toxin and the consequent prolongation of symptoms. {03}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    Chlordiazepoxide hydrochloride: 336.22
    Clidinium bromide: 432.36

Mechanism of action/Effect:

Chlordiazepoxide—In general, benzodiazepines, such as chlordiazepoxide, act as depressants of the central nervous system (CNS), producing all levels of CNS depression from mild sedation to hypnosis to coma depending on dose. {04}

Clidinium—Anticholinergics inhibit the muscarinic actions of acetylcholine on structures innervated by postganglionic cholinergic nerves as well as on smooth muscles that respond to acetylcholine but lack cholinergic innervation. These postganglionic receptor sites are present in the autonomic effector cells of the smooth muscle, cardiac muscle, sinoatrial and atrioventricular nodes, and exocrine glands. Depending on the dose, anticholinergics may reduce the motility and secretory activity of the gastrointestinal system. {05}

Absorption:

Chlordiazepoxide—Well absorbed from the gastrointestinal tract, usually within 1 to 2 hours.

Clidinium—Gastrointestinal absorption is poor and irregular.

Protein binding:

Chlordiazepoxide—Very high (96%).

Biotransformation:

Chlordiazepoxide—Hepatic.

Clidinium—Hepatic.

Half-life:

Chlordiazepoxide—5 to 30 hours.

Onset of action:

Clidinium—1 hour.

Duration of action:

Clidinium—Up to 3 hours.

Elimination:
    Chlordiazepoxide—Renal.
    Clidinium—Renal/fecal.


Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to other benzodiazepines or any of the belladonna alkaloids may be sensitive to this medication also.

Pregnancy/Reproduction

Pregnancy—
Use of anticholinergic and sedative combinations in pregnancy is generally not recommended. {01}

For chlordiazepoxide: Chlordiazepoxide crosses the placenta. Chronic use of chlordiazepoxide during pregnancy may cause physical dependence with resulting withdrawal symptoms in the neonate.

For clidinium: Appropriate studies in humans have not been performed. Reproduction studies in rats have not shown that clidinium has adverse effects on the fetus. {01}


First trimester

Chlordiazepoxide has been reported to increase the risk of congenital malformations when used during the first trimester of pregnancy. Its use during pregnancy, especially during the first trimester, should be avoided. {04}


Labor—

For chlordiazepoxide: Use of chlordiazepoxide just prior to or during labor may cause neonatal flaccidity. {04}

Breast-feeding

Chlordiazepoxide or its metabolites may be distributed into breast milk; use by nursing mothers may cause sedation in the infant. {01}

Clidinium may tend to inhibit lactation.

Pediatrics

No information is available on the relationship of age to the effects 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 (CNS) effects of benzodiazepines, such as chlordiazepoxide.


Geriatrics


Geriatric patients may respond to usual doses of chlordiazepoxide and clidinium with excitement, agitation, drowsiness, or confusion. {01}

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 probably be discontinued.

Caution is also recommended when clidinium is given to geriatric patients, because of the danger of precipitating undiagnosed glaucoma. {01}

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 functions. {01}


Dental

Prolonged use of clidinium may decrease or inhibit salivary flow, thus contributing to the development of caries, periodontal disease, oral candidiasis, and discomfort. {06}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Only specific interactions between chlordiazepoxide and clidinium combination and other oral medications have been identified in this monograph. However, because of clidinium's ability to decrease gastrointestinal motility and delay gastric emptying, absorption of other oral medications may be increased or reduced when they are used concurrently with clidinium. {14}
Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Antacids or
» Antidiarrheals, adsorbent    (concurrent administration may reduce therapeutic effects of clidinium because of particle adsorption; to avoid this occurrence, allow at least 2 or 3 hours between doses of the different medications {18} {19})


» Anticholinergics or other medications with anticholinergic activity (See Appendix II )    (concurrent use with clidinium may intensify anticholinergic effects {11})


» CNS depression–producing medications (See Appendix II )    (concurrent use with chlordiazepoxide may intensify sedative effects {01})


Contraceptives, estrogen-containing, oral    (concurrent long-term use with chlordiazepoxide may result in reduced contraceptive reliability and increased incidence of breakthrough bleeding {21} {22} {23})


» Ketoconazole    (clidinium may increase gastrointestinal pH; concurrent administration of ketoconazole with clidinium may result in a marked reduction in absorption of ketoconazole; patients should be advised to take clidinium at least 2 hours after ketoconazole {10})


Metoclopramide    (concurrent use with clidinium may antagonize the effects of metoclopramide on gastrointestinal motility {12} {13})


» Potassium chloride, especially wax-matrix preparations    (concurrent use with clidinium may increase severity of potassium chloride–induced gastrointestinal lesions {15} {16} {17})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
» Gastric acid secretion test    (clidinium may antagonize the effect of pentagastrin and histamine in the evaluation of gastric acid secretory function; administration of chlordiazepoxide and clidinium is not recommended during the 24 hours preceding the test {08})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
» Cardiovascular instability
Drug abuse or dependence, history of    (chlordiazepoxide may predispose to habituation and dependence {01})


» Glaucoma, angle-closure, or predisposition to    (clidinium's possible mydriatic effect resulting in increased intraocular pressure may precipitate an acute attack of angle-closure glaucoma)


Glaucoma, open-angle    (clidinium's possible mydriatic effect may cause a slight increase in intraocular pressure; glaucoma therapy may need to be adjusted {01})


» Hepatic function impairment    (decreased metabolism {01})


» Hiatal hernia with reflux esophagitis    (clidinium may aggravate condition)


Hypertension    (may be aggravated by clidinium)


Hyperthyroidism    (characterized by tachycardia, which may be increased by clidinium)


» Intestinal atony of the elderly or debilitated    (may result in obstruction due to clidinium's anticholinergic/antispasmodic effect)


» Intestinal obstruction    (may be exacerbated by clidinium)


Mental depression    (chlordiazepoxide may increase depression)


» Myasthenia gravis    (clidinium may aggravate condition because of inhibition of acetylcholine action)


Prostatic hypertrophy or{01}
» Urinary retention    (anticholinergic effects may precipitate or aggravate urinary retention {01})


Psychoses    (paradoxical reactions may occur due to chlordiazepoxide)


Pulmonary disease, severe, chronic obstructive    (anticholinergic ``drying'' effects may cause thickening of secretions and impair expectoration; ventilatory failure may be exacerbated with the use of chlordiazepoxide)


Renal function impairment    (decreased excretion may increase risk of side effects {01})


Sensitivity to chlordiazepoxide and/or clidinium{01}
» Ulcerative colitis, severe    (clidinium may suppress intestinal motility and cause paralytic ileus; also, use may precipitate or aggravate the serious complications of toxic megacolon)


Xerostomia    (prolonged use of clidinium may further reduce limited salivary flow {08})


Caution is also recommended in debilitated patients since they may show an increased susceptibility to this medication.

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Blood cell counts and
Hepatic function determinations{01}    (may be required at periodic intervals for patients on prolonged therapy)


Intraocular pressure determinations{01}    (recommended at periodic intervals, as clidinium may increase the intraocular pressure by producing mydriasis)




Side/Adverse Effects

Note: 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. {05}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence less frequent or rare
    
Agranulocytosis, granulocytopenia, or leukopenia (sore throat and fever)
    
CNS depression {01}(slow heartbeat, shortness of breath, or troubled breathing)
    
decreased peristalsis (constipation)—possible paralytic ileus{01}
    
hypersensitivity reaction (skin rash or hives){01}
    
increased intraocular pressure (eye pain){01}
    
jaundice (yellow eyes or skin){01}
    
paradoxical reaction (trouble in sleeping; unusual excitement, nervousness, or irritability)



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Bloated feeling
    
decreased sweating
    
dizziness
    
drowsiness
    
dryness of mouth
    
headache{01}

Incidence less frequent
    
Blurred vision
    
decreased sexual ability
    
loss of memory —especially in the elderly
    
nausea
    
unusual tiredness or weakness{01}



Those indicating possible withdrawal and the need for medical attention if they occur (usually within 2 weeks) after medication is discontinued
    
Muscle cramps
    
nausea or vomiting
    
seizures
    
stomach cramps
    
trembling{01}{04}




Overdose
For specific information on the agents used in the management of chlordiazepoxide and clidinium overdose, see:    • Pilocarpine (Systemic) monograph;
   • Norepinephrine bitartrate and Metaraminol in Sympathomimetic Agents—Cardiovascular Use (Parenteral-Systemic) monograph; and/or
   • Caffeine and Sodium Benzoate (Systemic) monograph.


For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptons in parentheses where appropriate)—not necessarily inclusive:
    
Confusion{01}
    
difficult urination{01}
    
drowsiness, severe
    
dryness of mouth, nose, or throat, severe
    
fast heartbeat
    
unusual warmth, dryness, and flushing of skin{01}


Treatment of overdose
To decrease absorption—Emesis or gastric lavage {01} with 4% tannic acid solution.

Specific treatment—Subcutaneous administration of 5 mg of pilocarpine, repeated as needed, until mouth is moist. Norepinephrine bitartrate or metaraminol infusions, to restore blood pressure. Caffeine and sodium benzoate, to treat CNS depression. {01} If excitation occurs, barbiturates should not be used since they may exacerbate excitation and/or prolong CNS depression. {01}

Supportive care—Artificial respiration, if needed, for respiratory depression. {01} Symptomatic treatment as necessary. {01} Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Chlordiazepoxide and Clidinium (Systemic).

In providing consultation, consider emphasizing the following selected information ( » = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to clidinium and chlordiazepoxide or to other benzodiazepines or any of the belladonna alkaloids

Pregnancy—Use is not recommended; chronic use of chlordiazepoxide may cause physical dependence and withdrawal symptoms in the neonate; chlordiazepoxide increases risk of congenital malformations in first trimester





Breast-feeding—Chlordiazepoxide distributed into breast milk; clidinium may cause inhibition of lactation





Use in children—Increased susceptibility to anticholinergic effects of clidinium and to CNS effects of chlordiazepoxide






Use in the elderly—Increased susceptibility to mental and other anticholinergic effects of clidinium and to CNS effects of chlordiazepoxide; danger of precipitating undiagnosed glaucoma; possible impairment of memory





Dental—Possible development of dental problems because of decreased salivary flow
Other medications, especially other anticholinergics, antacids, antidiarrheals, CNS depressants, ketoconazole, or potassium chloride
Other medical problems, especially cardiac disease, glaucoma, hepatic disease, hiatal hernia with reflux esophagitis, intestinal atony, myasthenia gravis, obstruction in gastrointestinal or urinary tract, ulcerative colitis, or urinary retention

Proper use of this medication
Taking dose 30 to 60 minutes before meals unless told otherwise by physician

» Taking medication only as directed

» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses

» Proper storage

Precautions while using this medication
Regular visits to physician to check progress of therapy if used for extended period of time

Avoiding medicine for diarrhea within 1 to 2 hours of taking this medication

» Caution if dizziness, lightheadedness, drowsiness, or blurred vision occurs

» Avoiding use of alcohol or other CNS depressants during and for a few days following therapy

» Caution during exercise and hot weather; overheating may result in heat stroke

Possible dryness of mouth, nose, and throat; using sugarless gum or candy, ice, or saliva substitute for relief; checking with dentist if mouth continues to feel dry for more than 2 weeks

» Checking with physician if constipation occurs

Checking with physician before discontinuing medication after prolonged use; gradual dosage reduction may be necessary to avoid the possibility of withdrawal symptoms


Side/adverse effects
Signs of potential side effects, especially agranulocytosis, granulocytopenia, or leukopenia; allergic reaction; CNS depression; increased intraocular pressure; jaundice; and paradoxical reaction


General Dosing Information
Dosage should be adjusted to meet the individual requirements of each patient since response varies according to the severity of the condition.

Geriatric and debilitated patients may respond to the usual doses with excitement, agitation, drowsiness, or confusion; lower doses may be required for such patients. {01}

Administration of this medication 30 to 60 minutes before meals is recommended to maximize absorption and, when used for reducing stomach acid formation, to allow its effect to coincide better with any antacid administration following the meal. {01}

Prolonged use of larger than usual therapeutic doses of chlordiazepoxide may result in psychic or physical dependence. {01}

Following prolonged administration, chlordiazepoxide should be withdrawn gradually in order to avoid the possibility of precipitating withdrawal symptoms.


Oral Dosage Forms

CHLORDIAZEPOXIDE HYDROCHLORIDE AND CLIDINIUM BROMIDE CAPSULES USP

Usual adult dose
Oral, 1 or 2 capsules one to four times a day, thirty to sixty minutes before meals or food, the dosage then being adjusted as needed and tolerated. {01}

Note: Debilitated patients—See Usual geriatric dose .


Usual adult prescribing limits
Up to a total of 8 capsules daily (40 mg of chlordiazepoxide hydrochloride and 20 mg of clidinium bromide). {01}

Usual pediatric dose
Dosage has not been established.

Usual geriatric dose
Oral, initially no more than 1 capsule two times a day, the dosage then being adjusted as needed and tolerated. {01}

Strength(s) usually available
U.S.—


5 mg of chlordiazepoxide hydrochloride and 2.5 mg of clidinium bromide per capsule (Rx) [Clindex] [Clinoxide] [Clipoxide] [Librax] [Lidox] [Lidoxide] [Zebrax][Generic]

Canada—


5 mg of chlordiazepoxide hydrochloride and 2.5 mg of clidinium bromide per capsule (Rx) [Apo-Chlorax] [Corium] [Librax]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from light.

Auxiliary labeling:
   • Take before meals.
   • Avoid alcoholic beverages.
   • May cause drowsiness.



Revised: 08/10/1994



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