ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS. The necessity of discontinuing therapy because of undesirable effects has been rare. Drowsiness, ataxia and confusion have been reported in some patients -- particularly the elderly and debilitated. While these effects can be avoided in almost all instances by proper dosage adjustment, they have occasionally been observed at the lower dosage ranges. In few instances syncope has been reported.Other adverse reactions reported during therapy include isolated instances of skin eruptions, edema, minor menstrual irregularities, nausea and constipation, extrapyramidal symptoms, as well as increased and decreased libido. Such side effects have been infrequent, and are generally controlled with reduction of dosage. Changes in EEG patterns (low-voltage fast activity) have been observed in patients during and after chlordiazepoxide HCl treatment.Blood dyscrasias (including agranulocytosis), jaundice and hepatic dysfunction have occasionally been reported during therapy. When chlordiazepoxide HCl treatment is protracted, periodic blood counts and liver function tests are advisable.

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

Animal Pharmacology. The drug has been studied extensively in many species of animals and these studies are suggestive of action on the limbic system of the brain, which recent evidence indicates is involved in emotional responses.Hostile monkeys were made tame by oral drug doses which did not cause sedation. Chlordiazepoxide HCl revealed taming action with the elimination of fear and aggression. The taming effect of chlordiazepoxide HCl was further demonstrated in rats made vicious by lesions in the septal area of the brain. The drug dosage which effectively blocked the vicious reaction was well below the dose which caused sedation in these animals.The LD50 of parenterally administered chlordiazepoxide HCl was determined in mice (72 hours) and rats (5 days), and calculated according to the method of Miller and Tainter, with the following results: mice, IV, 123 +- 12 mg/kg; mice, IM, 366 +- mg/kg; rats, IV, 120 +- mg/kg; rats, IM, 160 mg/kg.

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. Chlordiazepoxide HCl has antianxiety, sedative, appetite-stimulating and weak analgesic actions. The precise mechanism of action is not known. The drug blocks EEG arousal from stimulation of the brain stem reticular formation. It takes several hours for peak blood levels to be reached and the half-life of the drug is between 24 and 48 hours. After the drug is discontinued plasma levels decline slowly over period of several days. Chlordiazepoxide is excreted in the urine, with 1% to 2% unchanged and 3% to 6% as conjugate.. Animal Pharmacology. The drug has been studied extensively in many species of animals and these studies are suggestive of action on the limbic system of the brain, which recent evidence indicates is involved in emotional responses.Hostile monkeys were made tame by oral drug doses which did not cause sedation. Chlordiazepoxide HCl revealed taming action with the elimination of fear and aggression. The taming effect of chlordiazepoxide HCl was further demonstrated in rats made vicious by lesions in the septal area of the brain. The drug dosage which effectively blocked the vicious reaction was well below the dose which caused sedation in these animals.The LD50 of parenterally administered chlordiazepoxide HCl was determined in mice (72 hours) and rats (5 days), and calculated according to the method of Miller and Tainter, with the following results: mice, IV, 123 +- 12 mg/kg; mice, IM, 366 +- mg/kg; rats, IV, 120 +- mg/kg; rats, IM, 160 mg/kg.. Effects on Reproduction. Reproduction studies in rats fed 10, 20 and 80 mg/kg daily and bred through one or two matings showed no congenital anomalies, nor were there adverse effects on lactation of the dams or growth of the newborn. However, in another study at 100 mg/kg daily there was noted significant decrease in the fertilization rate and marked decrease in the viability and body weight of off-spring which may be attributable to sedative activity, thus resulting in lack of interest in mating and lessened maternal nursing and care of the young. One neonate in each of the first and second matings in the rat reproduction study at the 100 mg/kg dose exhibited major skeletal defects. Further studies are in progress to determine the significance of these findings.

DESCRIPTION SECTION.

DESCRIPTION. Chlordiazepoxide hydrochloride is the prototype for the benzodiazepine compounds. It is versatile therapeutic agent of proven value for the relief of anxiety. Chlordiazepoxide hydrochloride is among the safer of the effective psychopharmacologic compounds available, as demonstrated by extensive clinical evidence.Chlordiazepoxide hydrochloride is 7-chloro-2- (methylamino)-5-phenyl-3H-1, 4-benzodiazepine 4-oxide hydrochloride. white to practically white crystalline substance, it is soluble in water. It is unstable in solution and the powder must be protected from light. The structural formula is: C16H14ClN3O HCl M.W. 336.22Each capsule, for oral administration, contains either mg, 10 mg or 25 mg of chlordiazepoxide hydrochloride USP and has the following inactive ingredients: anhydrous lactose, D&C yellow no. 10, FD&C blue no. 1, FD&C blue no. aluminum lake, gelatin, hydrogenated vegetable oil, microcrystalline cellulose, pharmaceutical glaze, and titanium dioxide. The mg and 25 mg also contains D&C yellow no. 10 aluminum lake, FD&C blue no. aluminum lake, FD&C red no. 40 aluminum lake, propylene glycol, and synthetic black iron oxide. In addition, the mg contains D&C red no. 33 and the 10 mg also contains butyl paraben, edetate calcium disodium, dimethyl polysiloxane, ethylene glycol monoethyl ether, FD&C red no. 40, methyl paraben, propyl paraben, sodium, sodium lauryl sulfate, sodium propionate, and soya lecithin.. Structural Formula.

DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION. Because of the wide range of clinical indications for chlordiazepoxide HCl, the optimum dosage varies with the diagnosis and response of the individual patient. The dosage, therefore, should be individualized for maximum beneficial effects.ADULTSUSUAL DAILY DOSERelief of Mild and Moderate Anxiety Disorders and Symptoms of Anxiety5 mg or 10 mg, or times dailyRelief of Severe Anxiety Disorders and Symptoms of Anxiety 20 mg or 25 mg, or times dailyGeriatric Patients, or in the presence of debilitating disease.5 mg, to times dailyPreoperative Apprehension and AnxietyOn days preceding surgery, to 10 mg orally, or times daily. If used as preoperative medication, 50 to 100 mg IM hour prior to surgery.PEDIATRIC PATIENTSUSUAL DAILY DOSEBecause of the varied response of pediatric patients to CNS-acting drugs, therapy should be initiated with the lowest dose and increased as required. Since clinical experience in pediatric patients under years of age is limited, the use of the drug in this age group is not recommended.5 mg, to times daily (may be increased in some pediatric patients to 10 mg, to times daily)For the relief of withdrawal symptoms of acute alcoholism, the parenteral form is usually used initially. If the drug is administered orally, the suggested initial dose is 50 to 100 mg, to be followed by repeated doses as needed until agitation is controlled -- up to 300 mg per day. Dosage should then be reduced to maintenance levels.See package insert for Injectable Chlordiazepoxide HCl.

DRUG ABUSE AND DEPENDENCE SECTION.

DRUG ABUSE AND DEPENDENCE. Chlordiazepoxide hydrochloride capsules are classified by the Drug Enforcement Administration as Schedule IV controlled substance.Withdrawal symptoms, similar in character to those noted with barbiturates and alcohol (convulsions, tremor, abdominal and muscle cramps, vomiting and sweating), have occurred following abrupt discontinuance of chlordiazepoxide. The more severe withdrawal symptoms have usually been limited to those patients who had received excessive doses over an extended period of time. Generally milder withdrawal symptoms (e.g., dysphoria and insomnia) have been reported following abrupt discontinuance of benzodiazepines taken continuously at therapeutic levels for several months. Consequently, after extended therapy, abrupt discontinuation should generally be avoided and gradual dosage tapering schedule followed. Addiction-prone individuals (such as drug addicts or alcoholics) should be under careful surveillance when receiving chlordiazepoxide or other psychotropic agents because of the predisposition of such patients to habituation and dependence.

HOW SUPPLIED SECTION.

HOW SUPPLIED. Chlordiazepoxide Hydrochoride Capsules USP, mg are available as two-piece hard gelatin capsule with an aqua green opaque cap and yellow opaque body filled with white powder, imprinted in black ink barr 158, packaged in Bottles of 30 NDC 54868-2463-1 Bottles of 100 NDC 54868-2463-0 Chlordiazepoxide Hydrochloride Capsules USP, 10 mg are available as two-piece hard gelatin capsule with black opaque cap and green opaque body filled with white powder, imprinted in white ink barr 033, packaged in Bottles of 20 NDC 54868-0070-2 Bottles of 30 NDC 54868-0070-0 Chlordiazepoxide Hydrochloride Capsules USP, 25 mg are available as two-piece hard gelatin capsule with an aqua green opaque cap and white opaque body filled with white powder, imprinted in black ink barr 159, available in Bottles of 20 NDC 54868-2361-3 Bottles of 30 NDC 54868-2361-4 Bottles of 100 NDC 54868-2361-0 Dispense in tight, light-resistant container as defined in the USP, with child-resistant closure (as required).Store at 20 to 25C (68 to 77F) [See USP Controlled Room Temperature] in dry place.KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.TEVA PHARMACEUTICALS USASellersville, PA 18960Rev. 8/2011Relabeling and Repackaging by:Physicians Total Care, Inc.Tulsa, Oklahoma 74146.

INDICATIONS & USAGE SECTION.

INDICATIONS AND USAGE. Chlordiazepoxide HCl capsules USP are indicated for the management of anxiety disorders or for the short term relief of symptoms of anxiety, withdrawal symptoms of acute alcoholism, and preoperative apprehension and anxiety. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic.The effectiveness of chlordiazepoxide HCl capsules USP in long term use, that is, more than months, has not been assessed by systematic clinical studies. The physician should periodically reassess the usefulness of the drug for the individual patient.

OVERDOSAGE SECTION.

OVERDOSAGE. Manifestations of chlordiazepoxide overdosage includes somnolence, confusion, coma and diminished reflexes. Respiration, pulse and blood pressure should be monitored, as in all cases of drug overdosage, although, in general, these effects have been minimal following chlordiazepoxide HCl overdosage. General supportive measures should be employed, along with immediate gastric lavage. Intravenous fluids should be administered and an adequate airway maintained. Hypotension may be combated by the use of norepinephrine or metaraminol. 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. Flumazenil, specific benzodiazepine-receptor antagonist, is indicated for the complete or partial reversal of the sedative effects of benzodiazepines and may be used in situations when an overdose with benzodiazepine is known or suspected. Prior to the administration of flumazenil, necessary measures should be instituted to secure airway, ventilation and intravenous access. Flumazenil is intended as an adjunct to, not as substitute for, proper management of benzodiazepine overdose. Patients treated with flumazenil should be monitored for resedation, respiratory depression and other residual benzodiazepine effects for an appropriate period after treatment. The prescriber should be aware of risk of seizure in association with flumazenil treatment, particularly in long term benzodiazepine users and in cyclic antidepressant overdose. The complete flumazenil package insert, including CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS, should be consulted prior to use.

PEDIATRIC USE SECTION.

Pediatric Use. Because of the varied response of pediatric patients to CNS-acting drugs, therapy should be initiated with the lowest dose and increased as required (see DOSAGE AND ADMINISTRATION). Since clinical experience with chlordiazepoxide HCl in pediatric patients under years of age is limited, use in this age group is not recommended. Hyperactive aggressive pediatric patients should be monitored for paradoxical reactions to chlordiazepoxide HCl (see PRECAUTIONS).

PRECAUTIONS SECTION.

PRECAUTIONS. 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 (10 mg or less per day initially, to be increased gradually as needed and tolerated). In general, the concomitant administration of chlordiazepoxide HCl 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 MAO inhibitors and phenothiazines are to be used. The usual precautions in treating patients with impaired renal or hepatic function should be observed.Paradoxical reactions, e.g., exctextent, stimulation and acute rage, have been reported in psychiatric patients and in hyperactive aggressive pediatric patients, and should be watched for during chlordiazepoxide HCl 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 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 HCl. In view of isolated reports associating chlordiazepoxide with exacerbation of porphyria, caution should be exercised in prescribing chlordiazepoxide to patients suffering from this disease.. Pediatric Use. Because of the varied response of pediatric patients to CNS-acting drugs, therapy should be initiated with the lowest dose and increased as required (see DOSAGE AND ADMINISTRATION). Since clinical experience with chlordiazepoxide HCl in pediatric patients under years of age is limited, use in this age group is not recommended. Hyperactive aggressive pediatric patients should be monitored for paradoxical reactions to chlordiazepoxide HCl (see PRECAUTIONS).. Information for Patients. To assure the safe and effective use of benzodiazepines, patients should be informed that, since benzodiazepines may produce psychological and physical dependence, it is advisable that they consult with their physician before either increasing the dose or abruptly discontinuing this drug.