NOTE: Diazepam is a schedule C-IV controlled substance. 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.[4] 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 originally approved by the FDA in November 1963. A rectal gel formulation of diazepam (Diastat) was approved for the treatment of acute repetitive seizures July 31, 1997 and is designed for in-home use. 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, and anticonvulsant activity. Recent evidence indicates that benzodiazepines exert their effects through enhancement of the gamma-aminobutyric acid (GABA)-benzodiazepine receptor complex. GABA is an inhibitory neurotransmitter that exerts its effects at specific receptor subtypes designated GABA-A and GABA-B. GABA-A is the primary receptor subtype in the CNS and is thought to be involved in the actions of anxiolytics and sedatives. Specific benzodiazepine receptor subtypes are thought to be coupled to GABA-A receptors. Three types of BNZ receptors are located in the CNS and other tissues; the BNZ1 receptors are located in the cerebellum and cerebral cortex, the BNZ2 receptors in the cerebral cortex and spinal cord, and the BNZ3 receptors in peripheral tissues. Activation of the BNZ1 receptor is thought to mediate sleep while the BNZ2 receptor affects muscle relaxation, anticonvulsant activity, motor coordination, and memory. Benzodiazepines bind nonspecifically to BNZ1 and BNZ2 which ultimately enhances the effects of GABA. Unlike barbiturates which augment GABA responses by increasing the length of time that chloride channels are open, benzodiazepines enhance the effects of GABA by increasing GABA affinity for the GABA receptor. Binding of GABA to the site opens the chloride channel resulting in a hyperpolarized cell membrane that prevents further excitation of the cell. 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 alleviate insomnia by decreasing the latency to sleep and increasing sleep continuity and total sleep time through their effects on GABA. Benzodiazepines may also have other actions. For example, diazepam has been shown to counteract the cardiovascular toxicity of chloroquine.[260] It is thought that diazepam increases the urinary clearance of chloroquine by improving electrocardiographic and hemodynamic function.

Pharmacokinetics: Diazepam is administered orally, rectally, and parenterally. Diazepam is the most rapidly absorbed benzodiazepine following an oral dose; however, absorption following an IM injection is slow and erratic. Diazepam administered rectally is well absorbed with an absolute bioavailability of about 90% relative to Valium� injection. 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 conditions 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. Metabolism of diazepam is primarily hepatic and involves demethylation (involving primarily CYP2C19 and CYP3A4) and 3-hydroxylation (involving primarily CYP3A4). Diazepam is extensively metabolized to one major active metabolite desmethyldiazepam and two minor active metabolites temazepam (3-hydroxydiazepam) and oxazepam (3-hydroxy-N-diazepam), with half-lives of 30�100 hours, 9.5�12 hours, and 5�15 hours, respectively. At therapeutic doses, desmethyldiazepam is found in plasma at concentrations equivalent to those of diazepam. Oxazepam and temazepam plasma concentrations are usually undetectable. The half-life of diazepam is 30�60 hours. These metabolites are subsequently glucuronidated and excreted in the urine.

Indications...Dosage For the treatment of anxiety: Oral dosage (oral solution or regular tablets): Adults and adolescents: 2�10 mg PO two to three times per day. Elderly: 2�2.5 mg PO one to two times per day, increasing the dose according to response and patient tolerability. Children and infants >= 6 months: 1�2.5 mg PO three to four times per day. The dose may be increased as needed and tolerated. Alternatively, a dose of 0.12�0.8 mg/kg/day PO in divided doses every 6�8 hours may be used. Oral dosage (extended-release capsules): Adults and adolescents: 15 or 30 mg PO once daily. Parenteral dosage: Adults and adolescents: 2�10 mg IM or IV, depending on severity of anxiety. The dose may be repeated in 3�4 hours. For use preoperatively as an anxiolytic, 5�10 mg is recommended. Children and infants >= 6 months: 0.04�0.3 mg/kg/dose IM or IV every 2�4 hours to a maximum of 0.6 mg/kg within an 8-hour period if needed. For the treatment of acute ethanol withdrawal: Intravenous dosage: Adults: Until it is known how the patient will respond, a dose of 10 mg IV initially, followed by 5�10 mg IV every 3�4 hours as needed. Doses of 5�10 mg IV may be given every hour if required. Some patients may require massive doses of benzodiazepines during the acute phase of ethanol withdrawal. Intravenous doses of 270 mg over 45 minutes and 2335 mg over a period of 4 days have been reported.[924] For the treatment of benzodiazepine withdrawal�: Oral dosage: Adults: Because benzodiazepine withdrawal is more pronounced with shorter-acting agents,[925] diazepam has been proposed as the benzodiazepine of choice for managing withdrawal. Diazepam-equivalent doses have been established for some other benzodiazepines.[645] Diazepam should be tapered off in increments of 0.5�2 mg per week over a period of 4�16 weeks.[645] For the treatment of muscle spasm due to local pathology such as muscle or joint inflammation or trauma; athetosis; stiff-man syndrome; tetanus; or spasticity due to upper motor neuron diseases such as cerebral palsy: Oral dosage (oral solution or regular tablets): Adults and adolescents: 2�10 mg PO three to four times per day. Elderly: 2�2.5 mg PO one to two times per day, increasing the dose according to response and patient tolerability. Children and infants >= 6 months: 1�2.5 mg PO three to four times per day. The dose may be increased as needed and tolerated. Alternatively, a dose of 0.12�0.8 mg/kg/day PO in divided doses every 6�8 hours may be used. Parenteral dosage: Adults and adolescents: 5�10 mg IM or IV initially, repeated every 3�4 hours as needed. For tetanus, larger doses may be required. Children >= 5 years: 5�10 mg IM or IVevery 3�4 hours as needed. Children and infants 1 month�5 years: 1�2 mg IM or IV 3�4 hours as needed. For the treatment of status epilepticus or for treatment of drug-induced seizures: NOTE: Many clinicians now prefer IV lorazepam over IV diazepam for the acute treatment of seizures. Intravenous dosage: Adults and adolescents: 5�10 mg IV initially, repeated at 10�15 minute intervals to a maximum dosage of 30 mg. The dosage may be repeated in 2�4 hours if needed. Children >= 5 years: 1 mg IV every 2�5 minutes to a maximum of 10 mg. The dose may be repeated in 2�4 hours. Alternatively, 0.05�0.3 mg/kg IV over 3�5 minutes, given every 15�30 minutes to a maximum total dose of 10 mg. Children and infants 1 month�5 years: 0.2�0.5 mg IV every 2�5 minutes to a maximum dose of 5 mg. Repeat in 2�4 hours as needed. Alternatively, 0.05�0.3 mg/kg IV over 3�5 minutes, given every 15�30 minutes to a maximum total dose of 5 mg. Neonates: 0.1�0.3 mg/kg IV over 3�5 minutes, given every 15�30 minutes to a maximum total dose of 2 mg. NOTE: Not recommended as a first-line agent due to sodium benzoate and benzoic acid in the injection (see Precautions). For adjunctive treatment of seizures other than status epilepticus in selected, refractory patients with partial seizures or generalized tonic-clonic seizures who require intermittent use of diazepam to control bouts of increased seizure activity: Oral dosage (oral solution or regular tablets): Adults and adolescents: 2�10 mg PO two to four times per day. The manufacturer, however, notes that diazepam is not useful as sole therapy and may not be effective as adjunctive therapy for longer than 4 months. Elderly: 2�2.5 mg PO one to two times per day, increasing the dose according to response and patient tolerability. Children and infants >= 6 months: 1�2.5 mg PO three to four times per day. The dose may be increased as needed and tolerated. Rectal dosage: NOTE: It is recommended that rectal diazepam be used to treat no more than five episodes per month and no more than one episode every five days. Adults and adolescents: 0.2 mg/kg PR. Doses should be rounded upward to the next available dosage strength. The second dose may be given 4�12 hours after the first dose. Elderly and debilitated patients: 0.2 mg/kg PR. Doses should be rounded downward to reduce the likelihood of ataxia or oversedation. The second dose may be given 4�12 hours after the first dose. Children: 0.5 mg/kg PR, then 0.25 mg/kg PR in 10 minutes if needed. For febrile seizure prophylaxis�: Oral dosage: Children and infants 6 months�5 years: Children ranging in age from 6 months to 5 years and who had had at least one febrile seizure were randomized to receive oral diazepam 0.33 mg/kg PO every 8 hours during each episode of fever until the child was afebrile for at least 24 hours or placebo. An 82% reduction in the rate of recurrent febrile seizures was observed in the diazepam group.[4] For amnesia induction or for preprocedure sedation induction: Intravenous dosage: Adults (prior to cardioversion): 5�15 mg IV five to ten minutes before the procedure. Adults (prior to endoscopy): Dose may be titrated up to 20 mg IV, depending on response and patient tolerability. Adolescents: 5 mg IV five to ten minutes before the procedure. Repeat with 2.5 mg IV if needed. Oral dosage: Adults and adolescents: 10 mg PO 45�60 minutes prior to procedure. Children (for procedures or conscious sedation): 0.2�0.3 mg/kg PO 45�60 minutes prior to procedure. Maximum dose is 10 mg PO. For the treatment of agitation� in intensive care unit patients: Intravenous or oral dosage: Adults: Single doses of 2�5 mg IV or PO have been recommended.[644] Repeat doses should be based on clinical response. For the treatment of acute chloroquine overdose� in combination with epinephrine: Intravenous dosage: Adults: Eleven cases of acute chloroquine overdose (total ingested dose ranged 5�12 g) were treated with diazepam 2 mg/kg IV over 30 minutes in combination with IV epinephrine, general anesthesia with thiopental, and FiO2 40%. Diazepam was continued at a dose of 1�2 mg/kg/day IV for 2�4 additional days. Other vasopressors and/or inotropic agents were used as necessary. Ten of 11 patients were discharged alive from the hospital. The one patient who died had ingested the largest total dose (15 g) of chloroquine.[260] Patients with renal impairment: Dosage should be modified depending on clinical response and degree of renal impairment, but no quantitative recommendations are available. �non-FDA-approved indication

Administration Oral Administration �The dose of the oral concentrate solution should be added to 30 ml or more of liquid (e.g., water, juices, carbonated, soda-like beverages) or to semi-solid foods (e.g., applesauce, pudding) prior to administration. Parenteral Administration �Strict aseptic technique must always be maintained during handling of parenteral products. Diazepam injectable emulsion (Dizac�) contains no antimicrobial preservatives and can support rapid growth of microorganisms. �Following parenteral administration, patients should be kept under observation for a period of 3 to 8 hours or longer, based on the patient's clinical response and rate of recovery. �Replace parenteral therapy with oral therapy as soon as possible. �Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Diazepam injection solution: �No dilution necessary. Dilution may cause precipitation. Diazepam emulsified injection: �For intravenous administration only. Diazepam emulsified injection should be prepared for single patient use only. �Diazepam emulsified injection should be prepared for use just prior to initiation of each individual treatment procedure. �The injection emulsion should be drawn into sterile syringes immediately after ampules are opened. The syringe(s) should be labeled with appropriate information including the date and time the ampule was opened. �Administration should commence promptly and be completed within 6 hours after the ampules have been opened. �Any unused portion of diazepam emulsified injection reservoirs, dedicated administration tubing and/or solutions containing diazepam emulsified injection must be discarded after the end of parenteral treatment or at 6 hours, whichever occurs sooner. �The IV line should be flushed every 6 hours and at the end of treatment procedure to remove residual diazepam emulsified injection. Do not use if there is evidence of separation of the phases of the emulsion. Intramuscular injection (Diazepam injection solution only): �This route is usually not recommended due to slow and erratic absorption. �Inject deeply into a large muscle mass. Aspirate prior to injection to avoid injection into a blood vessel. Intravenous injection: �Do not administer rapidly because respiratory depression or hypotension may develop. Monitor heart rate, respiratory rate, and blood pressure during IV use. �A large vein should be used to avoid thrombosis. If a large vein is not available, inject into the tubing of a flowing IV solution as close as possible to the vein insertion. �Do not add diazepam emulsified injection to infusion sets containing PVC. Do not administer diazepam emulsified injection through filters with a pore size less than 5 microns because this could restrict the flow of the emulsion and/or cause the breakdown of the emulsion. �Adults: inject IV slowly at a rate not exceeding 5 mg/minute. �Infants and children: inject IV slowly at a rate not exceeding 1�2 mg/minute. Rectal Administration �Patients/Caregivers should thoroughly read and understand the administration steps for diazepam rectal gel. Administration steps: �Put person on their side where they can not fall. �Get the medicine and the syringe. To remove protective cover from syringe, push up with thumb and pull. �Lubricate rectal tip with lubricating jelly. �Turn person on side facing you and bend upper leg forward to expose rectum. Separate buttocks to expose rectum. �Gently insert syringe tip into rectum (rim should be snug against rectal opening) and slowly count to 3 while gently pushing the plunger in until it stops. Slowly count to 3 before removing the syringe from the rectum. �Slowly count to 3 while holding the buttocks together to prevent leakage. �Keep person on the side facing you, note time given and continue to observe.

Contraindications 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. 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 and other benzodiazepines should be administered cautiously in patients with CNS depression. There is a potential for synergistic CNS-depressant effects if benzodiazepines are administered concomitantly with alcohol or other CNS depressants. Diazepam should not be administered parenterally to patients with acute ethanol intoxication, shock, or coma because the drug can worsen CNS depression. Additionally, prolonged CNS depression has been observed in neonates treated with diazepam, therefore, diazepam is not recommended for use in children under 6 months of age. Further, the response of children to benzodiazepine therapy can be unpredictable. In general the pediatric population is more sensitive to the effects of the benzodiazepines. Initially, children should receive the lowest dose of diazepam, with increases made according to response. Diazepam is contraindicated in patients with closed-angle glaucoma. Diazepam may be used in patients with open-angle glaucoma who are receiving appropriate therapy. 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. The drug should be administered cautiously to patients with suicidal ideation. 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. Patients with late stage Parkinson's disease may experience worsening of their psychosis or impaired cognition with administration of benzodiazepines. Benzodiazepines may also cause incoordination or paradoxical reactions that may worsen symptoms of Parkinson's disease. 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. The impairment of cognitive and motor function may be more marked in this patient group and lower initial dosage is recommended together with close monitoring (see Dosage).

Interactions Diazepam is metabolized by oxidative metabolism, specifically, the hepatic isozymes CYP2C19 and CYP3A4. As a result, diazepam is susceptible to interactions with drugs that inhibit these hepatic enzymes. Clinicians should note that while diazepam clearance may be inhibited, diazepam pharmacodynamics are not always affected. Fluoxetine inhibits both metabolic pathways for diazepam, however the effect on diazepam pharmacodynamics is unclear. Studies of the impact of fluoxetine on diazepam may have been compromised by not continuing fluoxetine long enough to acheive steady-state with norfluoxetine. Other drugs that have been shown to inhibit diazepam clearance include cimetidine, dalfopristin; quinupristin, disulfiram, erythromycin, fluvoxamine, or itraconazole can decrease the hepatic metabolism of diazepam if administered concomitantly. Itraconazole affected diazepam pharmacokinetics, but not diazepam pharmacodynamics. Ciprofloxacin also inhibits diazepam clearance although diazepam pharmacodynamics were not affected. Probenecid should also inhibit the hepatic metabolism of diazepam although this interaction has been documented with other benzodiazepines and not diazepam per se. Patients receiving benzodiazepines should be monitored for signs of an exaggerated response if any of the above drugs are used concomitantly. Omeprazole inhibits both CYP2C19 and CYP3A4 metabolic pathways for diazepam, however, the effect on diazepam pharmacodynamics is unclear. Rabeprazole has no effect on diazepam pharmacokinetics in poor and extensive S-mephenytoin 4'-hydroxylase (CYP2C19) metabolizers; the AUC of desmethyldiazepam is increased during concurrent rabeprazole and diazepam administration in poor metabolizers, but this change is not clinically significant. Therefore, rabeprazole as a substrate is metabolized less by CYP2C19 isoenzymes and has less potential to interact with diazepam compared with omeprazole.[2557] Concomitant administration of diazepam with CNS-depressant drugs, including opiate agonists, butorphanol, nalbuphine, pentazocine, phenothiazines, barbiturates, ethanol, some H1-blockers (e.g., brompheniramine, carbinoxamine, cetirizine, chlorpheniramine, clemastine, cyproheptadine, dimenhydrinate, diphenhydramine, doxylamine, methdilazine, promethazine, trimeprazine), entacapone, general anesthetics, tramadol, tricyclic antidepressants, or other anxiolytics, sedatives, and hypnotics 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.[762] 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. An interaction between digoxin, when administered concommitantly with either alprazolam or diazepam, has been reported. Digoxin toxicity has occurred in a patient receiving alprazolam and digoxin. This interaction may be the result of increased plasma protein binding of digoxin and/or an effect of the benzodiazepine at the renal tubules that results in decreased digoxin elimination. Pending further clarification of this interaction, patients receiving alprazolam or diazepam 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. Pioglitazone may increase the clearance of diazepam by inducing CYP3A4. However, this interaction has not been studied. Rifampin is a potent inducer of the hepatic isoenzyme CYP3A4, one of the pathways responsible for the hepatic metabolism of diazepam. Patients receiving rifampin may require higher doses of diazepam to achieve the desired clinical effect. In addition, patients should be monitored closely for signs of reduced diazepam effects if rifampin is added. Rifabutin may exert similar effects on diazepam clearance, although not to the degree that rifampin does. Diazepam 2 mg/kg IV, in combination with epinephrine and mechanical ventilation, was used successfully in treating severe chloroquine poisoning.[260] 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. It appears prudent to recommend caution when diazepam is prescribed in conjunction with melatonin. In animal studies, melatonin has been shown to increase benzodiazepine binding to receptor sites, and this may result in clinically significant drug interactions. Case reports exist of concomitant benzodiazepine and melatonin use in humans; the cases resulted in lethargy, short-term amnestic responses, or prolonged benzodiazepine activity. These apparent interactions could have been the result of a pharmacokinetic or pharmacodynamic enhancement of benzodiazepine activity by melatonin. An interaction of kava kava, Piper methysticum with benzodiazepines has been reported in the medical literature. A single case report is noted of an acute, lethargic and disoriented state in a 54-year old male following the ingestion of alprazolam and kava kava for 3 consecutive days. After several hours, he gradually became more alert. The gentleman denied taking more than his normal prescribed dose of alprazolam or excessive doses of kava kava.[1839] The possibility of interactions at normal prescription dosages signals the need for patients who are on diazepam therapy to avoid concomitant administration of kava kava. Any substances that act on the CNS, including barbiturates and psychopharmacologic agents, may interact with valerian, Valeriana officinalis. These interactions are probably pharmacodynamic in nature, or result from additive mechanisms of action. The possibility of pharmacodynamic interactions at normal prescription dosages of anxiolytics, sedatives, and hypnotics signals the need for patients who are on these therapies to avoid concomitant administration of valerian. Prior to general anesthesia, carbidopa; levodopa may be continued as long as the patient is permitted to take oral medication. If levodopa-based therapy is interrupted temporarily, the patient should be observed for signs of neuroleptic malignant syndrome, and the usual dosage should be administered as soon as the patient is able to take oral medication.

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. Tolerance may develop to these effects. 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.

Diazepam Diastat�, Dizac�, Valium�, Diazepam by Schein, Diazepam by Zenith, Diazepam IM/IV by Elkins-Sinn | Valic

924. Woo E, Greenblatt DJ. Massive benzodiazepine requirements during acute alcohol withdrawal. Am J Psychiatry 1979;136:821�3.

645. Higgitt AC, Lader MH, Fonagy P. Clinical management of benzodiazepine dependence. Br Med J 1985;291:688�90.

925. Bond WS, Berwish NJ, Swift B. Severe withdrawal syndrome after substitution of a short-acting benzodiazepine for a long-acting benzodiazepine. Drug Intel Clin Pharm 1985;19:742�4.

644. Tesar GE, Stern TA. Rapid tranquilization of the agitated intensive care unit patient. J Intensive Care Med 1988;3:195�201.

260. Riou B, Barriot P, Rimailho A et al. Treatment of severe chloroquine poisoning. N Engl J Med 1988;318:1�6.

762. Lefebvre RA, Flouvat B, Karolac-Tamisier S, et al. Influence of lansoprazole treatment on diazepam plasma concentrations. Clin Pharmacol Ther 1992;52:458�63.