Description: Diazepam is a long-acting oral and parenteral benzodiazepine. Diazepam is similar to chlordiazepoxide and clorazepate in that all three generate the same active metabolite. Diazepam is used orally for the short-term management of anxiety disorders and acute alcohol withdrawal, and as a skeletal muscle relaxant. Parenterally, it is indicated as an antianxiety agent, sedative, amnestic, anticonvulsant, skeletal muscle relaxant, anesthetic adjunct, and as a treatment for alcohol withdrawal. In addition to treating status epilepticus, diazepam has recently been shown effective in preventing recurrence of febrile seizures.I Although diazepam has been the benzodiazepine of choice for status epilepticus, recent evidence indicates that lorazepam may be more beneficial because it provides longer control of seizures and produces less cardiorespiratory depression. Diazepam was approved by the FDA in November 1963. Phase III data for a rectal formulation of diazepam in the treatment of acute repetitive seizures was completed April 1995. The NDA for the rectal formulation (Diastat) is expected to be filed in 1995. Diazepam is a schedule IV controlled substance.
Mechanism of Action: Benzodiazepines act at the level of the limbic, thalamic, and hypothalamic regions of the CNS, and can produce any level of CNS depression required including sedation, hypnosis, skeletal muscle relaxation, anticonvulsant activity, and coma. The action of these drugs is mediated through the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). Central benzodiazepine receptors interact allosterically with GABA receptors, potentiating the effects of GABA and increasing the inhibition of the ascending reticular activating system.
Evidence suggests that GABA receptors are heterogeneous with many different subtypes, which may account for the various effects of GABA receptor agonists and benzodiazepines. Midazolam, for example, has twice the affinity for benzodiazepine receptors than diazepam. The antianxiety action of benzodiazepines may be a result of their ability to block cortical and limbic arousal following stimulation of the reticular pathways while muscle relaxation properties are mediated by inhibiting both mono-and polysynaptic pathways. Benzodiazepine can also depress muscle and motor nerve function directly. Animal studies of the anticonvulsant actions suggest that benzodiazepines augment presynaptic inhibition of neurons, thereby limiting the spread of electrical activity, although they do not actually inhibit the abnormally discharging focus.
Benzodiazepines may also have other actions. For example, diazepam has been shown to counteract the cardiovascular toxicity of chloroquine. It is thought that diazepam increases the urinary clearance of chloroquine by improving electrocardiographic and hemodynamic function.
Pharmacokinetics: Diazepam is administered orally and parenterally. A viscous solution intended for rectal administration in undergoing investigation. Diazepam is the most rapidly absorbed benzodiazepine following an oral dose; however, absorption following an IM injection is slow and erratic. Anticonvulsant, skeletal muscle relaxant, and anxiolytic effects are usually evident after the first dose. The onset of action after an IV dose is 1-5 minutes. The duration for some clinical effects (e.g., sedation, anticonvulsant activity) is much shorter than would be expected considering the very long half-life for both diazepam and its metabolite, desmethyldiazepam.
Diazepam is widely distributed, with CSF levels similar to plasma levels. This benzodiazepine crosses the placenta and distributes into breast milk (see Contraindications). The disparity between elimination half-life and duration of action for some conditiona may be partially explained by rapid shifts in distribution of diazepam out of the CNS. Although diazepam is 99% protein-bound, interactions based on protein binding are not clinically significant. The half-life of diazepam is 30-60 hours. Oxidation in the liver produces the active metabolites desmethyldiazepam, temazepam, and oxazepam, with half-lives of 30-100 hours, 9.5-12 hours, and 5-15 hours, respectively. These metabolites are subsequently glucuronidated and excreted in the urine.
CONTRAINDICATIONS/PRECAUTIONS: Diazepam can cause physical and psychological dependence, and should be used with extreme caution in patients with known, suspected, or a history of substance abuse.
Abrupt discontinuation of diazepam after prolonged use can cause seizures in susceptible patients. Benzodiazepine withdrawal causes irritability, nervousness, and insomnia. Benzodiazepine withdrawal is more likely to occur following abrupt cessation after excessive or prolonged doses, but it can occur following the discontinuance of therapeutic doses administered for as few as 1-2 weeks. Benzodiazepine withdrawal is also more severe if the agent involved has a relative shorter duration of action. Abdominal cramps, confusion, depression, perceptual disturbances, sweating, nausea, vomiting, parasthesias, photophobia, hyperacusis, tachycardia, and trembling also occur during benzodiazepine withdrawal, but their incidence is less frequent. Convulsions, hallucinations, delirium, and paranoia also can occur. Benzodiazepines should be withdrawn cautiously and gradually, using a very gradual dosage-tapering schedule. Diazepam is usually chosen as the agent for controlled tapering in all cases of benzodiazepine withdrawal.
Diazepam should not be administered parenterally to patients with acute ethanol intoxication, shock, or coma because the drug can worsen CNS depression.
Diazepam should be used with extreme caution in patients with respiratory depression, pulmonary disease such as severe COPD (chronic obstructive pulmonary disease), or sleep apnea because the drug can exacerbate ventilatory failure.
Diazepam should be used with extreme caution in patients with myasthenia gravis because the drug can exacerbate this condition.
Diazepam is occasionally beneficial for patients with major depression or psychosis. It can, however, induce paradoxical effects in these patients and in those with suicidal ideation. The drug should be administered to such patients with careful monitoring.
Diazepam is classified as pregnancy category D because it can cause harm to the fetus when administered to pregnant women. Positive evidence of human fetal risk exists based on investigational, marketing, or human studies, but the potential benefit to the mother may outweigh the potential risks to the fetus. Diazepam is distributed into breast milk and can cause sedation, feeding difficulties, and weight loss in the nursing infant. The use of diazepam during breast-feeding is generally not recommended.
Diazepam should be administered cautiously to patients with severe hepatic disease because its elimination half-life can be prolonged, possibly resulting in toxicity. Diazepam is metabolized to an active metabolite, and patients with hepatic disease are more likely to experience adverse CNS reactions and should receive reduced initial dosages.
Patients with renal impairment should be carefully monitored during prolonged treatment with benzodiazepines to avoid the adverse reactions that occur from accumulation.
The clearance and/or elimination of many drugs are reduced in the elderly. Delayed elimination can either intensify or prolong the actions of adverse reactions of the drug. Benzodiazepines have been associated with falls in the elderly and the consumer advocate group, Public Citizen, has recommended these drugs not be used in the elderly.
DRUG INTERACTIONS: Diazepam is metabolized by oxidative metabolism and is susceptible to drugn interactions with drugs that inhibit this hepatic enzyme system. Cimetidine, disulfiram, erythromycin, or fluvoxamine can decrease the hepatic metabolism of diazepam if administered concomitantly. Patients should be monitored for signs of altered benzodiazepine response when cimetidine, disulfiram, erythromycin, or fluvoxamine are initiated or discontinued.
Patients receiving levodopa for Parkinson's disease experienced an exacerbation of parkinsonian symptoms when benzodiazepines were added to their regimen. Benzodiazepines should be administered cautiously to such patients.
Concomitant administration of diazepam with CNS-depressant drugs, including opiate agonists, phenothiazines, barbiturates, ethanol, HA-blockers, general anesthetics, or tricyclic antidepressants, can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent.
Omeprazole can increase the plasma concentrations and the elimination half-life of diazepam, presumably due to inhibition of the hepatic metabolism of diazepam. Although the pharmacodynamics of this interaction are not clear, it is recommended that patients receiving omeprazole and diazepam concomitantly should be monitored for enhanced diazepam response.
Long-term treatment with lansoprazole in conjunction with diazepam therapy has been studied. Plasma elimination half-life, clearance, and volume of distribution of diazepam were not affected by concurrent use of lansoprazole.D
Concurrent use of isoniazid, INH and diazepam can increase serum concentrations of diazepam due to alterations in the half-life and clearance of diazepam. Although patient response to diazepam has not been reported, patients should be observed for signs of altered diazepam effects if isoniazid therapy is initiated or discontinued.
Diazepam has reportedly decreased the elimination of digoxin in some patients. Digoxin toxicity has occurred in a patient receiving alprazolam and digoxin. The interaction between benzodiazepines and digoxin may be the result of increased protein binding of digoxin and/or an effect of benzodiazepines at the renal tubules, which decreases the elimination of digoxin. Pending further clarification of this interaction, patients receiving a benzodiazepine and digoxin concurrently should be monitored for increased serum digoxin levels.
Oral contraceptives can increase the effects of diazepam because they inhibit oxidative metabolism, thereby increasing serum concentrations of concomitantly administered benzodiazepines that undergo oxidation. Patients receiving oral contraceptive therapy should be observed for evidence of increased response to diazepam.
The administration of valproic acid to patients receiving diazepam can cause an increase in diazepam serum concentrations and a concurrent increase in absence seizures. This interaction appears to be the result of inhibited metabolism of diazepam during concurrent use. If absence seizures increase in patients receiving these medications, an alternative anticonvulsant should be instituted.
Rifampin is a potent hepatic enzyme inducer and can accelerate the hepatic metabolism of diazepam. Patients should be monitored closely for signs of reduced diazepam effects if given rifampin concomitantly.
Diazepam 2 mg/kg IV, in combination with epinephrine and mechanical ventilation, was used successfully in treating severe chloroquine poisoning. Ten patients receiving diazepam and epinephrine survived compared to one patient in a retrospective control group. Diazepam is reported to antagonize the toxic effects of chloroquine, although the mechanism is unclear. Further study is needed to confirm the usefulness of diazepam in chloroquine poisoning.
Flumazenil and benzodiazepines are pharmacological opposites. Flumazenil is specifically used to reverse the actions of benzodiazepines. Clinicians should note that the duration of action for some benzodiazepines may be much longer than that of flumazenil and repeat doses of flumazenil may be necessary.
ADVERSE REACTIONS: Most of the adverse effects associated with diazepam therapy are dose-dependent and CNS-related including headache, drowsiness, ataxia, dizziness, confusion, depression, syncope, fatigue, tremor, and vertigo. CNS stimulation occurs in as many as 10% of patients and is of particular significance in psychiatric patients and hyperactive children. This paradoxical effect is possibly due to release of previously inhibited responses. Symptoms of CNS stimulation include nightmares, talkativeness, excitement, mania, tremor, insomnia, anxiety, restlessness, euphoria, acute rage reactions, and hyperactivity. Benzodiazepine therapy usually should be discontinued if signs of CNS stimulation occur.
Apnea, hypotension, and cardiac arrest have been reported following parenteral administration of benzodiazepines to the elderly, severely ill patients, or patients with compromised respiratory function. Respiratory depression also has occurred in these patients during benzodiazepine therapy, occasionally resulting in death.
Abrupt discontinuation of diazepam after prolonged use can cause seizures in susceptible patients. Benzodiazepine withdrawal causes irritability, nervousness, and insomnia. Benzodiazepine withdrawal is more likely to occur following abrupt cessation after excessive or prolonged doses, but it can occur following the discontinuance of therapeutic doses administered for as few as 1-2 weeks. Benzodiazepine withdrawal is also more severe if the agent involved has a relative shorter duration of action. Abdominal cramps, confusion, depression, perceptual disturbances, sweating, nausea, vomiting, parasthesias, photophobia, hyperacusis, tachycardia, and trembling also occur during benzodiazepine withdrawal, but the incidence is less frequent. Convulsions, hallucinations, delirium, and paranoia can occur as well. Benzodiazepines should be withdrawn cautiously and gradually, using a very gradual dosage-tapering schedule. Diazepam is usually chosen as the agent for controlled tapering in all cases of benzodiazepine withdrawal.
Sexual dysfunction has been reported with diazepam. Libido decrease, impotence, ejaculation dysfunction (delayed ejaculation), and orgasm dysfunction (retarded or no orgasm).
A number of reports have documented diazepam causing interstitial nephritis, although this is considered a rare adverse effect.
What do diazepam tablets do?
Diazepam (ValiumTM ) is a benzodiazepine. Benzodiazepines belong to a group of medicines that slow down the central nervous system. Diazepam relieves anxiety and nervousness. It also can help patients cope with alcohol withdrawal, relax muscles, and treat certain types of seizures (convulsions). Federal law prohibits the transfer of diazepam to any person other than the patient for whom it was prescribed. Do not share this medicine with anyone else. Generic diazepam tablets are available.
What should my doctor or pharmacist know before I take diazepam?
They need to know if you have any of these conditions:
How should I take this medicine?
Take diazepam tablets by mouth. Follow the directions on the prescription label. Swallow the tablets with a drink of water. If diazepam upsets your stomach, take it with food or milk. Take your doses at regular intervals. Do not take your medicine more often than directed. Do not stop taking except on your doctor's advice.
Special precautions for use in children:
This medicine is not for children under 6 months old.
Elderly patients over 65 years old may have a stronger reaction to this medicine and need smaller doses.
What if I miss a dose?
If you miss a dose, take it as soon as you can. If it is almost time for your next dose, take only that dose. Do not take double or extra doses.
What other medicines can interact with diazepam?
Tell your doctor or pharmacist: about all other medicines you are taking, including non-prescription medicines; if you are a frequent user of drinks with caffeine or alcohol; if you smoke; or if you use illegal drugs. These may affect the way your medicine works. Check before stopping or starting any of your medicines.
What side effects may I notice from taking diazepam?
Serious side effects with diazepam include:
lightheadedness or fainting spells
mood changes, excitability or aggressive behavior
movement difficulty, staggering or jerky movements
problems passing urine
weakness or tiredness
Call your doctor as soon as you can if you get any of these side effects.
Minor side effects with diazepam include:
Let your doctor know about these side effects if they do not go away or if they annoy you.
What do I need to watch for while I take diazepam?
Visit your doctor for regular checks on your progress. Your body can become dependent on diazepam, ask your doctor if you still need to take it. However, if you have been taking diazepam regularly for some time, do not suddenly stop taking it. You must gradually reduce the dose or you may get severe side effects. Ask your doctor for advice. Even after you stop taking diazepam it can still affect your body for several days.
You may get drowsy or dizzy. Do not drive, use machinery, or do anything that needs mental alertness until you know how diazepam affects you. To reduce the risk of dizzy and fainting spells, do not stand or sit up quickly, especially if you are an older patient. Alcohol may increase dizziness and drowsiness. Avoid alcoholic drinks.
Do not treat yourself for coughs, colds or allergies without asking your doctor or pharmacist for advice. Some ingredients can increase possible side effects.
If you are going to have surgery, tell your doctor or dentist that you are taking diazepam.
Where can I keep my medicine?
Keep out of the reach of children in a container that small children cannot open.
Store at room temperature between 15 and 30C (59 and 86F). Protect from light. Keep container tightly closed. Throw away any unused medicine after the expiration date.