Brand Names

 Valium

Description

• Diazepam is an intravenous and orally active benzodiazepine. The pharmacologic effects of benzodiazepines include anxiolysis, sedation, amnesia, anticonvulsant, muscle relation, and anesthesia. The amnestic effect may persist after sedation has worn off.

Dosing

Note:

• The solution should be injected slowly, taking at least 1 minute for each 5 mg (1 mL) given.
• Do not use small veins, such as those on the dorsum of the hand or wrist. Extreme care should be taken to avoid intra-arterial administration or extravasation.
• Do not mix or dilute diazepam with other solutions or drugs in syringe or infusion flask. If it is not feasible to administer diazepam directly IV, it may be injected slowly through the infusion tubing as close as possible to the vein insertion.
• Over 50% of the diazepam in the infusion solution may be adsorbed onto the walls of plastic containers. Therefore, only infusion solutions in glass containers can be administered.
• Adsorption onto plastic drip tubing causes an initial significant and variable reduction (up to 40% or more) of delivered diazepam concentration which then gradually rises over the next few hours. The drip rate should be frequently titrated against the patient's condition.

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Over Sedation

• Manifestations of diazepam overdosage include 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 overdosage.
• 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.
• Flumazenil is a specific benzodiazepine-receptor antagonist that is indicated for the complete or partial reversal of the sedative effects of benzodiazepines and may be used in situations when an overdose with a benzodiazepine is known or suspected.

Reversal Agents

 Flumazenil

Special Circumstances

• Use in Pregnancy: An increased risk of congenital malformations associated with the use of minor tranquilizers (diazepam, meprobamate and chlordiazepoxide) during the first trimester of pregnancy has been suggested in several studies. Because use of these drugs is rarely a matter of urgency, their 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 during therapy or intend to become pregnant they should communicate with their physicians about the desirability of discontinuing the drug.  
• Use in elderly and chronically ill patients: Initial dose should be small and gradually increased. Give with extreme care to elderly patients with limited pulmonary reserve.
• Use in impaired hepatic function: Observe caution to avoid accumulation of drug.
• Use in impaired renal function: Observe caution to avoid accumulation of drug. 
• Use in pediatric patients: Efficacy and safety of parenteral diazepam has not been established in the neonate (30 days or less of age). Prolonged central nervous system depression has been observed in neonates, apparently due to inability to biotransform diazepam into inactive metabolites. In pediatric use, in order to obtain maximal clinical effect with the minimum amount of drug and thus to reduce the risk of hazardous side effects, such as apnea or prolonged periods of somnolence, it is recommended that the drug be given slowly over a three-minute period in a dosage not to exceed 0.25 mg/kg. After an interval of 15 to 30 minutes the initial dosage can be safely repeated. If, however, relief of symptoms is not obtained after a third administration, adjunctive therapy appropriate to the condition being treated is recommended.

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Side Effects and Risks

• Drug Interactions:
  
  • Azole antifungal agents (eg, itraconazole, ketoconazole), diltiazem, fluvoxamine, isoniazid, macrolide antibiotics (eg, erythromycin), nefazodone, non-nucleoside reverse transcriptase inhibitors (eg, delavirdine, efavirenz), protease inhibitors (eg, indinavir): May increase diazepam plasma concentrations.
  • Cimetidine, oral contraceptives, disulfiram: May increase effects of diazepam with excessive sedation and impaired psychomotor function.
  • Digoxin: May increase serum digoxin concentrations.
  • Omeprazole: May increase diazepam levels and enhance effects.
  • Rifamycins: May decrease diazepam plasma concentrations.
  • Theophyllines: May antagonize sedative effects of diazepam.

• When diazepam is used with a narcotic analgesic, the dosage of the narcotic should be reduced by at least one-third and administered in small increments. In some cases the use of a narcotic may not be necessary.
• Diazepam should not be administered to patients in shock, coma or in acute alcoholic intoxication with depression of vital signs. As is true of most CNS-acting drugs, patients receiving diazepam should be cautioned against engaging in hazardous occupations requiring complete mental alertness, such as operating machinery or driving a motor vehicle.
• 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 diazepam. 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 (eg, dysphoria and insomnia) have been reported following abrupt discontinuance of benzodiazepines taken continuously at therapeutic levels for several months.
• Practitioners should assume that flumazenil administration may trigger dose-dependent withdrawal syndromes in patients with established physical dependence on benzodiazepines and may complicate the management of withdrawal syndromes for alcohol, barbiturates and cross-tolerant sedatives.
• Addiction-prone individuals (such as drug addicts or alcoholics) should be under careful surveillance when receiving diazepam or other psychotropic agents because of the predisposition of such patients to habituation and dependence.
• Since an increase in cough reflex and laryngospasm may occur with peroral endoscopic procedures, the use of a topical anesthetic agent and the availability of necessary countermeasures are recommended.

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Common Issues

• Side effects most commonly reported were drowsiness, fatigue and ataxia; venous thrombosis and phlebitis at the site of injection. Other adverse reactions less frequently reported include:
  • Central nervous system: confusion, depression, dysarthria, headache, hypoactivity, slurred speech, syncope, tremor, vertigo.
  • Gasterointestinal: constipation, nausea.
  • Gentiourinary: incontinence, changes in libido, urinary retention.
  • Cardiovascular: bradycardia, cardiovascular collapse, hypotension.
  • EENT: blurred vision, diplopia, nystagmus.
  • Skin: urticaria, skin rash.
  • Other: hiccups, changes in salivation, neutropenia, jaundice.
• Paradoxical reactions such as acute hyperexcited states, anxiety, hallucinations, increased muscle spasticity, insomnia, rage, sleep disturbances and stimulation have been reported; should these occur, use of the drug should be discontinued.
• Minor changes in EEG patterns, usually low-voltage fast activity, have been observed in patients during and after Valium therapy and are of no known significance.
• In peroral endoscopic procedures, coughing, depressed respiration, dyspnea, hyperventilation, laryngospasm and pain in throat or chest have been reported.
• Because of isolated reports of neutropenia and jaundice, periodic blood counts and liver function tests are advisable during long-term therapy.

 Warnings

• Withdrawal symptoms of the barbiturate type (e.g. dizziness, lightheadedness or faintness, anxiety or restlessness, hallucinations, vision problems, nausea and vomiting, seizures, weakness)  have occurred after the discontinuation of benzodiazepines.
• Rapid IV push may cause sudden respiratory depression, apnea, or hypotension.
• Diazepam is not of value in the treatment of psychotic patients and should not be employed in lieu of appropriate treatment.
• As is true of most preparations containing CNS-acting drugs, patients receiving diazepam should be cautioned against engaging in hazardous occupations requiring complete mental alertness such as operating machinery or driving a motor vehicle.
• As with other agents which have anticonvulsant activity, when diazepam is used as an adjunct in treating convulsive disorders, the possibility of an increase in the frequency and/or severity of grand mal seizures may require an increase in the dosage of standard anticonvulsant medication.
• Abrupt withdrawal of diazepam in such cases may also be associated with a temporary increase in the frequency and/or severity of seizures.
• Since diazepam has a central nervous system depressant effect, patients should be advised against the simultaneous ingestion of alcohol and other CNS-depressant drugs during diazepam therapy.

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Alternative Medications

 Midazolam

Contraindications

• Diazepam is contraindicated in patients with hypersensitivity to diazepam or any component of the formulation (cross-sensitivity with other benzodiazepines may exist).
• Diazepam is contraindicated in patients with acute narrow-angle glaucoma
• Diazepam is contraindicated in patients with myasthenia gravis.  
• Diazepam is contradicted in open angle glaucoma unless patients are receiving appropriate therapy.
• Diazepam is not for use in children less than 6 months of age.

Cohen LB, DeLegge MH, Aisenberg J, Brill JV, Inadomi JM, et al. AGA Institute review of endoscopic sedation. Gastroenterology. 2007 Aug;133(2):675-701.

Diazepam: A-Z drug facts for the professional. Drugs.com. Last updated March 12, 2008. http://www.drugs.com/ppa/diazepam.html  Accessed April 20, 2008.

Diazepam Injection [package insert], Baxter Healthcare Corporation. February 2006. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=1045  Accessed April 20, 2008.
Romazicon Injection (Roche). PDR Electronic Library [CD-ROM]. Vol. 2008:1.0. Thomson Healthcare. Montvale, NJ –2007.

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