Prescription Drugs

CLINICAL PHARMACOLOGY The mechanism of action by which the Central Nervous System (CNS) is affected is not known. Chloral hydrate is readily absorbed from the gastrointestinal tract following oral administration; however, significant amounts of chloral hydrate have not been detected in the blood after oral administration. It is generally believed that the central depressant effects are due to the principal pharmacologically active metabolite trichloroethanol, which has a plasma half- life of 8 to 10 hours. A portion of the drug is oxidized to trichloroacetic acid (TCA) in the liver and kidneys; TCA is excreted in the urine and bile along with trichloroethanol in free or conjugated form. Hypnotic dosage produces mild cerebral depression and quiet, deep sleep with little or no ''hangover''; blood pressure and respiration are depressed only slightly more than in normal sleep and reflexes are not significantly depressed, so the patient can be awakened and completely aroused. Chloral hydrate's effect on rapid eye movement (REM) sleep is uncertain. Chloral hydrate has been detected in cerebrospinal fluid and human milk, and it crosses the placental barrier.

DESCRIPTION CHLORAL HYDRATE SYRUP, USP 500 mg (7½ gr) / 5 mL Chloral Hydrate Syrup, USP contains chloral hydrate, an effective sedative and hypnotic agent for oral administration. Each 5 mL (teaspoonful) contains: Chloral Hydrate, USP .................................................................................... 500 mg (7½ gr) (WARNING: May be habit forming) Alcohol .......................................................................................................... less than 0.4% In a clear, pink to orange colored, orange flavored syrup. INACTIVE INGREDIENTS: Citric Acid, USP; D&C Yellow No. 10; FD&C Red No. 40; Flavor; Glycerin, USP; Liquid Sugar; Methylparaben, NF; Propylene Glycol, USP; Purified Water, USP; Sodium Benzoate, NF and Sodium Citrate, USP. Chloral Hydrate is derived by combining a molecule of water with trichloroacetaldehyde (chloral). Chemically, chloral hydrate is 1,1-Ethanediol, 2,2,2-trichloro-; its molecular formula is CCl3CH(OH)2 and its molecular weight is 165.4. Chloral hydrate occurs as colorless or white, volatile, hygroscopic crystals very soluble in water and in olive oil and freely soluble in alcohol. It has an aromatic, pungent odor and a slightly bitter, caustic taste.

INDICATIONS Chloral hydrate is indicated for nocturnal sedation in all types of patients and especially for the ill, the young, and the elderly patient. In candidates for surgery, it is a satisfactory preoperative sedative that allays anxiety and induces sleep without depressing respiration or cough reflex. In postoperative care and control of pain, it is a valuable adjunct to opiates and analgesics. DOSAGE AND ADMINISTRATION The syrup may be administered in a half glass of water, fruit juice, or ginger ale. ADULTS The usual hypnotic dose is 500 mg to 1 g, taken 15 to 30 minutes before bedtime or ½ hour before surgery. The usual sedative dose is 250 mg three times daily after meals. Generally, single doses or daily dosage should not exceed 2 g. CHILDREN The usual daily hypnotic dose is 50 mg/ kg of body weight, with a maximum of 1 g per single dose. Daily dosage may be given in divided doses if indicated. The sedative dose is half of the hypnotic dosage. HOW SUPPLIED Chloral Hydrate Syrup, USP is supplied as a clear, pink to orange colored, orange flavored syrup containing 500 mg (7½ gr) in 5 mL (teaspoonful) in the following size: 16 fl oz (473 mL) Storage Store at controlled room temperature, 15°-30° C (59°-86° F). AVOID EXCESSIVE HEAT Dispense in tight, light- resistant containers as defined in the USP. CAUTION: Federal law prohibits dispensing without prescription.

PATIENT INFORMATION Chloral hydrate may cause gastrointestinal upset. The syrup should be diluted in half a glass of water or fruit juice. Chloral hydrate may cause drowsiness; therefore, patients should be instructed to use caution when driving, operating dangerous machinery, or performing any hazardous task. Patients should avoid alcohol and other CNS depressants. They should also be informed that chloral hydrate may be be habit-forming. Chloral hydrate and all drugs should be kept out of the reach of children. Patients should be warned against sudden discontinuation of chloral hydrate except under the advice of a Physician; they should also be informed of symptoms that would suggest potential adverse effects.

OVERDOSE The signs and symptoms of chloral hydrate overdosage resemble those of barbiturate overdosage and especially affect the CNS and cardiovascular system. They may include: hypothermia; pinpoint pupils; blood pressure falls; comatose state; slow, or rapid and shallow breathing. Gastric irritation may result in vomiting and even gastric necrosis. If the patient survives, icterus due to hepatic damage and albuminuria from renal irritation may appear. The toxic oral dose of chloral hydrate for adults is approximately 10 g; however, death has been reported from a dose of 4 g and some patients have survived after taking as much as 30 g. Accidental overdosage should be treated with gastric lavage or by inducing vomiting to empty the stomach. Supportive measures may be used. Hemodialysis is reported to be effective in promoting the clearance of trichloroethanol. CONTRAINDICATIONS Chloral hydrate is contraindicated in patients with marked hepatic or renal impairment and in patients with severe cardiac disease. Oral dosage forms of chloral hydrate are contraindicated in the presence of gastritis. Chloral hydrate is also contraindicated in patients who have previously exhibited an idiosyncrasy or hypersensitivity to the drug.

SIDE EFFECTS Central Nervous System Occasionally a patient becomes somnambulistic and he may be disoriented and incoherent and show paranoid behavior. Rarely, excitement, tolerance, addiction, delirium, drowsiness, staggering gait, ataxia, lightheadedness, vertigo, dizziness, nightmares, malaise, mental confusion and hallucinations have been reported. Hematelogical Leukopenia and eosinophilia have occasionally occurred. Dermatological Allergic skin rashes including hives, erythema, eczematoid dermatitis, urticaria, and scarlatiniform exanthems have occasionally been reported. Gastrointestinal Some patients experience gastric irritation and occasionally nausea and vomiting, flatulence, diarrhea, and unpleasant taste occur. Miscellaneous Rarely, headache, hangover, idiosyncratic syndrome, and ketonuria have been reported. DRUG ABUSE AND DEPENDENCE Controlled Substance Drug Enforcement Administration Schedule IV. Abuse Chloral hydrate may be habit- forming. Patients known to be addiction- prone and patients who actively solicit hypnotics in increasing doses are potential addicts. Many patients take higher doses of hypnotics than they admit, and slurring of speech, incoordination, tremulousness, and nystagmus should arouse suspicion. Drowsiness, lethargy, and hangover are frequently observed from excessive drug intake. Dependence Prolonged use of larger than usual therapeutic doses may result in psychic and physical dependence. Tolerance and psychologic dependence may develop by the second week of continued administration. Chloral hydrate addicts may take huge doses of the drug (i.e., up to 12 g nightly has been reported). This abuse is similar to alcohol addiction and sudden withdrawal may result in central nervous excitation, with tremor, anxiety, hallucination, or even delirium which may be fatal. In patients suffering from chronic chloral hydrate intoxication, gastritis is common and skin eruptions may develop. Parenchymatous renal injury may also occur. Withdrawal should be undertaken in a hospital and supportive treatment similar to that used during barbiturate withdrawal is recommended. DRUG INTERACTIONS Chloral hydrate may cause hypoprothrombinemic effects in patients taking oral anticoagulants (See WARNINGS). Administration of chloral hydrate followed by intravenous furosemide may result in sweating, hot flashes, and variable blood pressure including hypertension due to a hypermetabolic state caused by displacement of thyroid hormone from its bound state. Caution is recommended in combining chloral hydrate with other CNS depressants such as alcohol barbiturates and tranquilizers. Administration of chloral hydrate should be delayed in patients who have ingested significant amounts of alcohol in the preceding 12 to 24 hours. CNS depressants are additive in effect and the dosage should be reduced when such combinations are given concurrently.

WARNINGS Chloral hydrate may be habit-forming. Long-term use of larger than the usual therapeutic doses may result in psychic and physical dependence; therefore, caution must be exercised when administering the drug to patients susceptible to drug abuse. Sudden withdrawal may result in delirium. Chloral hydrate may increase the rate of metabolism of concomitantly administered coumarin or coumarinrelated anticoagulants, thus reducing their effectiveness. Upon withdrawal of chloral hydrate, the rate of metabolism of the anticoagulant drug may decrease with a concomitant rise in plasma levels and with the possibility of a gradual increase of anticoagulant effects (i.e., development of bleeding tendency and hemorrhage). Patients on oral anticoagulant therapy who are also taking chloral hydrate should have close observation of prothrombin times. PRECAUTIONS General Chloral hydrate has been reported to precipitate attacks of acute intermittent porphyria and should be used with caution in susceptible patients. Continued use of therapeutic doses of chloral hydrate has been shown to be without deleterious effect on the heart. Large doses of chloral hydrate, however, should not be used in patients with severe cardiac disease (See CONTRAINDICATIONS). Drug/ Laboratory Test Interactions Chloral hydrate may interfere with copper sulfate tests for glycosuria (suspected glycosuria should be confirmed by a glucose oxidase test when the patient is receiving chloral hydrate), fluorometric tests for urine catecholamines (it is recommended that the medication not be administered for 48 hours preceding the test), or urinary 17-hydroxycorticosteroid determinations (when using the Reddy, Jenkins, and Thorn procedure). Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals have not been performed. Pregnancy Category C Animal reproduction studies have not been conducted with chloral hydrate. Chloral hydrate crosses the placental barrier and chronic use during pregnancy may cause withdrawal symptoms in the neonate. It is not known whether chloral hydrate can affect reproduction capacity. Chloral hydrate should be given to a pregnant woman only if clearly needed. Nursing Mothers Chloral hydrate is excreted in human milk, use by nursing mothers may cause sedation in the infant.