INFORMATION FOR HEALTH PROFESSIONALS
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Chlordiazepoxide HCl in:
5mg Capsules: Opaque green cap and opaque yellow body size 4 capsules printed NOVO 5 and filled with a white powder.
10mg Capsules: Clear black cap and opaque green body size 4 capsules printed NOVO 10 and filled with a white powder.
Chlordiazepoxide HCl has antianxiety, sedative, appetite stimulating and weak analgesic activity. The medicine depresses the central nervous system at the levels of the cortex, limbic system and blocks EEG arousal due to stimulation of the brain stem reticular formation. It also depresses polysynaptic reflex arcs of the spinal cord but does not produce ganglionic blockade. Its skeletal muscle relaxant properties are similar to those of meprobamate. The effect of chlordiazepoxide on the limbic system has been shown in both rat and monkey experiments where a decrease in viciousness or a "taming" effect was found at non-sedating doses.
After oral administration, chlordiazepoxide appears in plasma after about 15 minutes, achieving a peak concentration at approximately 45 minutes. After administration of a 10mg dose, peak concentrations of approximately 500ng/mL are observed. Chlordiazepoxide distributes readily, however, studies have shown that the apparent volume of the central compartment and total distribution space are significantly larger in females. Chlordiazepoxide readily crosses the placenta but does not easily penetrate the CSF. The concentration in foetal blood circulation may approach or equal that of the maternal circulation. Plasma protein binding shows some variation in the range 90-97% and some red cell binding is also possible. The plasma half-life in humans is variable ranging from 6-30 hours.
Chlordiazepoxide is eliminated by metabolism in the liver, the major reaction being oxidation, giving rise to several metabolites, some of which are active, such as desmethylchlordiazepoxide, demoxepam, desmethyldiazepam and oxazepam. The metabolites are excreted as conjugates in the urine.
The presence of renal failure does not interfere with the pharmacokinetics of chlordiazepoxide.
Symptomatic relief of mild anxiety and tension and reduction of tension states that may accompany muscle spasm. As an adjunct in tension states associated with insomnia, pre- and post-operative apprehension, tension headache, premenstrual tension and stress, and functional, gastrointestinal, cardiovascular, gynaecological and dermatological disorders with an emotional overlay. May be useful in the alleviation of alcohol withdrawal syndromes although drug dependence may result, substituting for alcohol dependence. May also reduce anxiety associated with psychosis, but is not a specific management of psychosis.
Individual adjustment of dose is important, with strict use of the minimum effective dose.
Adults: Usually 15-40mg daily in divided doses. In severe cases, 25mg 3 or 4 times a day may be given.
Elderly or Debilitated Patients: 5mg 2-4 times daily.
Pre-Operative Apprehension: 50-100mg 8 hours prior to surgery.
Obstetrics: 25-50mg on admission.
Children: Initiate therapy with 5-10mg daily in divided doses, increasing if necessary to 30mg daily in divided doses.
Myasthenia gravis. Known hypersensitivity.
Chlordiazepoxide HCl may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a vehicle or operating machinery. Similarly, they may impair mental alertness in children. The concomitant use of alcohol or other central nervous system depressants may have an additive effect. Patients should be warned accordingly.
Physical and psychological dependence have been reported in persons taking recommended doses of chlordiazepoxide HCl. Caution must be exercised in administering chlordiazepoxide HCl to individuals known to be addiction-prone or those whose histories suggest they may increase the dosage on their own initiative. Withdrawal symptoms following abrupt discontinuation of chlordiazepoxide HCl have been reported in patients receiving excessive doses over extended periods of time.
These symptoms (including convulsions) are similar to those seen with barbiturates. Although infrequently seen, milder withdrawal symptoms have also been reported following abrupt discontinuance of benzodiazepines taken continuously, generally at higher therapeutic levels, for at least several months. Consequently, after extended therapy, abrupt discontinuation should generally be avoided and a gradual tapering in dosage followed.
In elderly and debilitated patients, it is recommended that the dosage be limited to the smallest effective amount to preclude the development of ataxia or oversedation (10mg or less per day initially, to be increased gradually as needed and tolerated).
In general, the concomitant administration of chlordiazepoxide and other psychotropic agents is not recommended. If such combination therapy seems indicated, careful consideration should be given to the pharmacology of the agents to be employed - particularly when the known potentiating compounds such as the MAO inhibitors and phenothiazines are to be used.
Paradoxical reactions, e.g. excitement, stimulation and acute rage, have been reported in psychiatric patients and in hyperactive aggressive children and should be watched for during therapy. The usual precautions are indicated when chlordiazepoxide HCl is used in the treatment of anxiety states where there is any evidence of impending depression; it should be borne in mind that suicidal tendencies may be present and protective measures may be necessary. Although clinical studies have not established a cause and effect relationship, physicians should be aware that variable effects on blood coagulation have been reported very rarely in patients receiving oral anticoagulants and chlordiazepoxide.
In view of isolated reports associating chlordiazepoxide HCl with exacerbation of porphyria, caution should be exercised in prescribing these agents to patients suffering from this disease.
Caution is also required in patients with a history of blood dyscrasias, hepatic or renal disease.The usual precautions in treating patients with impaired renal or hepatic function should be observed. Patients should also be warned against the ingestion of alcohol since tolerance may be decreased and effects enhanced. Periodic blood counts or liver function tests are recommended if the medication is administered over a long period.
An increased risk of congenital malformations has been associated with the use of minor tranquillizers such as chlordiazepoxide HCl. In one prospective study of 19044 live births an increased incidence of defects was noted in children of mothers exposed to chlordiazepoxide in the first 42 days of pregnancy. In a second study of 50282 children, 257 were found to have been exposed to chlordiazepoxide or other medicines during the first four months of pregnancy. No association between chlordiazepoxide exposure and any type of malformation could be detected. In a double-blind study in 166 women in early labour the effect of chlordiazepoxide was compared to that of placebo. Although chlordiazepoxide crossed the placenta, no foetal or neonatal depression occurred and no significant difference between the two treatments was detected.
Because use of chlordiazepoxide HCl is rarely a matter of urgency, its use during this period should almost always be avoided. The possibility that a woman of childbearing potential may be pregnant at the time of institution of therapy should be considered. Patients should be advised that if they become pregnant they should communicate with their physicians about the desirability of discontinuing the medicine.
Chlordiazepoxide is excreted in breast milk. It may cause sedation, feeding difficulties or weight loss in infants. If the mother requires NOVAPAM then an alternative infant feeding method is required.
Drowsiness, ataxia and confusion may occur, especially in the elderly and debilitated. These are reversible in most instances by proper dose adjustment, but are also occasionally observed at the lower dosage ranges. In a few instances syncope has been reported.
Also encountered are isolated instances of skin eruptions, oedema, minor menstrual irregularities, nausea and constipation, extrapyramidal symptoms, increased and decreased libido - all infrequent and generally controlled with dosage reduction; changes in EEG patterns may appear during and after treatment; blood dyscrasias (including leucopenia and rare cases of agranulocytosis), jaundice and hepatic dysfunction have been reported occasionally.
Paradoxical reactions such as excitement, stimulation, elevation of mood and rage, have been reported in psychotic patients and hyperactive aggressive children. These reactions may be secondary to the relief of anxiety symptoms and should be watched for, particularly in the early phase of medication.
Alcohol impairs the elimination of chlordiazepoxide HCl resulting in increased sedation when the two are taken together.
Concurrent administration of aluminium or magnesium hydroxide antacids may delay the absorption of chlordiazepoxide, however, they do not alter the completeness of absorption or rate of elimination.
Drowsiness as a side effect of chlordiazepoxide is less frequent in smokers than non-smokers. A possible explanation relates to hepatic enzyme induction by nicotine, however, this is disputed.
There are reports of the elimination of chlordiazepoxide being impaired by concurrent cimetidine administration. Concurrent administration of disulfiram also inhibits metabolism of chlordiazepoxide. The clearance of chlordiazepoxide is also impaired by concurrent administration of ketoconazole. Chlordiazepoxide diminishes the therapeutic effect of levodopa.
Symptoms: Drowsiness, ataxia, confusion. Depression of the cardiovascular and respiratory centres may occur.
Treatment: Gastric lavage or, in children, induce emesis and if there is no immediate response, use gastric lavage. General supportive measures. Monitor respiration, pulse and blood pressure. I.V. fluids should be administered and an adequate airway maintained. Hypotension may be overcome by the use of noradrenaline or metaraminol. Caffeine and sodium benzoate may be given to combat CNS-depressive effects. Dialysis is of limited value.
There have been occasional reports of excitation in patients following chlordiazepoxide HCl overdosage; if this occurs, barbiturates should not be used. As with the management of intentional overdosage with any drug, it should be borne in mind that multiple agents may have been ingested.
Store below 30°C. Protect from light and moisture. Keep out of reach of children.
Controlled Drug C5.
Bottles of 100 capsules.
Chlordiazepoxide HCl is 7-chloro-2-methyl amino-5-phenyl-3H,4-benzodiazepine-4-oxide hydrochloride. It is structurally related to diazepam and oxazepam. Its molecular formula and weight are C16H14ClN3O.HCl and 336.22 respectively.
Douglas Pharmaceuticals Ltd.,
P.O. Box 45-027,
AUCKLAND 8.
Ph: (09) 835-0660
Fax: (09) 835-0665
2 September 1999