Diazepam

Introduction

• Diazepam is a benzodiazepine.

Uses

Diazepam shares the actions of other benzodiazepines. The drug is used preoperatively to relieve anxiety and provide sedation, light anesthesia, and anterograde amnesia; as an adjunct during endoscopy to relieve anxiety and provide sedation, light anesthesia, and anterograde amnesia; for the management of agitation associated with acutealcohol withdrawal; as an adjunct for the relief of acute, painful musculoskeletal conditions; to manage skeletal muscle spasticity such as reflex spasm secondary to local pathology (e.g., trauma, inflammation), spasticity caused by upper motor neuron disorders (e.g., cerebral palsy, paraplegia), athetosis, stiff-man syndrome, or tetanus; and for the management of anxiety disorders or for the short-term relief of symptoms of anxiety. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic. The efficacy of diazepam for long-term use (i.e., longer than 4 months) as an anxiolytic has not been evaluated.

Diazepam is also used IV or rectally as an anticonvulsant, and IV diazepam or lorazepam generally are considered the drugs of choice for termination of status epilepticus. Diazepam has been administered rectally either as a commercially available gel (Diastat®) or using parenteral formulations. Although IV administration of benzodiazepines generally is preferred for the management of status epilepticus, rectal administration also may be useful for the treatment of status attacks, particularly forout-of-hospital management (e.g., at home or school, during transport to an emergency room). Rectal diazepam also may be particularly useful for the management of acute repetitive seizures (also referred to as serial, cyclic, cluster, breakthrough, or crescendo seizures), especially for out-of-hospital management. Acute repetitive seizures are exacerbations of an underlying seizure disorder that exhibit a pattern distinct from the patient's usual seizure pattern; the repetitive, periodic episodes often are predictable by the patient and caregivers according to a prodrome/aura, time of day when they originate, particular seizure type, and/or accompanying patient behavioral changes. Patients typically experience recovery between the repetitions; however, if untreated, acute repetitive seizures can evolve into more serious problems, including status epilepticus. The distinguishing features of these seizures are their predictability and pattern that differs from the underlying disorder rather than the actual seizure type; thus, while the pattern of presentation and patient and caregiver recognition are common features of the diagnosis, the actual seizure type can be different albeit definable for each individual patient.

In the 2 clinical studies establishing efficacy of rectal diazepam for the management of acute repetitive seizures in adults and children 2 years of age and older, the drug was more effective than placebo in reducing seizure frequency and improving global assessment of treatment outcome by caregivers (e.g., frequency and severity of

seizures and patient tolerance of therapy). In these studies in adult and pediatric patients, the time to next seizure was prolonged in diazepam-treated patients relative to placebo, and about 55-62% of patients were seizure-free during the 12-hour observation period versus 20-34% for placebo recipients. In these studies, patients with a history of acute repetitive seizures that typically progressed to status epilepticus were excluded from study entry. Similar efficacy has been reported in other placebo-controlled andopen-label studies. Although formal economic analyses have not been performed to date, patients treated with rectal diazepam out of the hospital required emergency medical treatment less commonly than did placebo recipients.

Diazepam has been used orally to prevent night terrors. Although not recommended by the manufacturer, parenteral diazepam is used to reduce the requirements for opiate analgesics and produce anterograde amnesia during labor and delivery. The drug has been used parenterally to manage neonatal opiate withdrawal.

Dosage and Administration

Diazepam is administered orally, by IV or IM injection, or rectally.

• AdministrationOral AdministrationDiazepam usually is administered orally as conventional tablets or oral solution in 3 or 4 doses daily. After dosage has been stabilized, most clinicians believe that the drug maybe administered orally as conventional tablets or oral solution in 1 or 2 doses daily.

When diazepam oral concentrate solution is used, the dose should be diluted (e.g., with water, juice, carbonated beverages) or mixed with semisolid foods (e.g., applesauce, pudding) just prior to administration.

Parenteral AdministrationWhen oral therapy is not feasible or when a rapid therapeutic effect is necessary, diazepam may be administered slowly IV at a rate not exceeding 5 mg/minute in adultsand over a 3-minute period in children. When given IV, diazepam should beadministered directly into a large vein to avoid thrombosis; if this is not feasible, the drug should be given into the tubing of a flowing IV solution as close as possible to the veininsertion. Small veins such as those of the wrist or the dorsum of the hand should not be used. Care should be taken to avoid intra-arterial administration or extravasation.Alternatively, some clinicians have suggested IV administration of dilute solutions of thedrug to avoid extravasation; however, the drug may precipitate when diluted and the manufacturers do not recommend this method of administration. (See Chemistry andStability: Stability.)

Although diazepam may also be given by deep IM injection, this route of administration of the drug is rarely justified because absorption is slow and erratic.

Therapy with oral diazepam should replace parenteral administration as soon as possible.

Rectal Administration

When diazepam is administered rectally, the drug has been given as a commercially available rectal gel via the delivery device (a plastic applicator with a flexible molded tip) provided by the manufacturer or as the parenteral solution via a syringe and rectally inserted tubing or via a lubricated tuberculin syringe (without a needle) inserted 4-5 cm into the rectum.

Caregivers should be instructed carefully in the use of diazepam rectal gel and should be given a copy of the administration instructions provided by the manufacturer. As soon as an episode of acute repetitive seizures is recognized, the caregiver should place the patient on their side so they won't fall and administer the prescribed dose of rectal diazepam. Before administering the prescribed dose, the appropriate applicator labeled as containing 2.5., 5, 10, 15, or 20 mg of diazepam should be checked for the expiration date and, if in date, prepared for use by removing the protective cap from the syringe and the seal pin from the applicator tip. Diazepam rectal gel is commercially available in prefilled syringe applicators with either a pediatric or universal plastic applicator tip that is 4.4 cm in length or an adult plastic applicator tip that is 6 cm in length. The rectal applicator tip should be lubricated with the water-soluble lubricant (jelly) provided by the manufacturer and the patient should be turned so that they are resting on their side facing the caregiver; the patient's upper leg should be bent forward and the buttocks separated to expose the rectum. The lubricated applicator tip should then be inserted rectally until the rim of the syringe is snug against the rectal opening; once inserted, the plunger should be pushed slowly (counting aloud slowly to 3) until itstops (i.e., until the entire dose of the applicator has been expelled into the rectum). The caregiver should again count aloud slowly to 3 before removing the syringe from the rectum; to prevent leakage of the administered dose from the rectum, the buttocks should then be held together while again counting aloud slowly to 3. The patient should be left on their side facing the caregiver, the time the dose was given noted, and the patient observed.

Although dosage of diazepam rectal gel is calculated on a mg/kg basis by age, the actual dose administered is approximate, being determined by rounding upward to the next commercially available prefilled dose. In some cases, it may be necessary to administer the prescribed dose using 2 applicators (e.g., to administer a 15-mg dose in a child, one 5-mg and one 10-mg pediatric applicator would be used). The rectal delivery system and all unused materials should be discarded in the garbage and not reused. Such disposal should be in a safe place away from children. If bowel leakage occurs during rectal administration, it may be necessary to administer a supplemental dose. (See Dosage: Rectal Dosage, in Dosage and Administration.)

• DosageDosage of diazepam must be individualized, and the smallest effective dosage shouldbe used (especially in geriatric or debilitated patients or in those with liver disease or low serum albumin) to avoid oversedation. The doses recommended by the manufacturers for IM and IV administration are identical. When parenteral diazepam is used with anopiate analgesic, the dosage of the opiate should be reduced by at least one-third andadministered in small increments. Because of the unpredictable response of children toCNS drugs, diazepam therapy should be initiated with the lowest dosage and increased as required. Since diazepam and its metabolites have long elimination half-lives, time toreach steady-state plasma concentrations should be considered when dosage

adjustments are made.

In patients who have received prolonged (e.g., for several months) diazepam therapy, abrupt discontinuance of the drug should be avoided since manifestations of withdrawal can be precipitated; if the drug is to be discontinued in such patients, it is recommended that dosage be gradually tapered. It is particularly important that the drugs not be discontinued abruptly in patients with a history of a seizure disorder since seizures may be precipitated.

Oral DosageAdult DosageFor the symptomatic treatment of anxiety, as an adjunct to other anticonvulsants in the prophylaxis of epileptic seizures, and as an adjunct in the relief of acute, painfulmusculoskeletal conditions and spasticity, the usual adult oral dosage of diazepam as conventional tablets or oral solution is 2-10 mg 2-4 times daily.

For the management of agitation associated with acute alcohol withdrawal, the usual adult oral dosage of diazepam as conventional tablets or oral solution is 10 mg 3 or 4 times daily during the first 24 hours, followed by 5 mg 3 or 4 times daily as needed. In adults with night terrors, 5-20 mg of diazepam has been administered orally as conventional tablets or oral solution at bedtime.

The initial oral dosage of diazepam as conventional tablets or oral solution for geriatric or debilitated patients should be 2-2.5 mg once or twice daily. Dosage is adjusted gradually according to response and tolerance.

Pediatric DosageChildren 6 months of age or older may receive an initial oral dosage of 1-2.5 mg 3 or 4 times daily as conventional tablets or oral solution. Alternatively, some cliniciansrecommend 0.12-0.8 mg/kg or 3.5-24 mg/m2 orally in 3 or 4 divided doses daily asconventional tablets. Dosage is adjusted gradually according to response and tolerance.

As an adjunct in the management of epilepsy in children, 6-15 mg daily (and occasionally up to 30 mg daily) in divided doses as conventional tablets or oral solution has been used by some clinicians.

Parenteral DosageAdult DosageThe adult IV dose of diazepam for moderate or severe, acute anxiety is 2-5 mg or 5-10 mg, respectively. In acute conditions, the manufacturers state that diazepam may beadministered hourly if necessary, although an interval of 3-4 hours is usuallysatisfactory. Some clinicians recommend that the adult dosage not exceed 30 mg within an 8-hour period.

For the management of agitation associated with acute alcohol withdrawal in adults, 10 mg may be administered IV initially; however, some clinicians recommend an initial dose of up to 20 mg. The manufacturers state that, if necessary, additional doses of5-10 mg may be administered every hour, although an interval of 3-4 hours is usually satisfactory. For acute alcohol withdrawal, some clinicians recommend 10 mg of

diazepam IV initially, followed by 10 mg at 20- to 30-minute intervals until the patient is calm.

To provide light anesthesia and anterograde amnesia in adults prior to electrical cardioversion, 5-15 mg of diazepam is given IV within 5-10 minutes prior to the procedure.

To reduce anxiety prior to endoscopy, diazepam is administered slowly IV immediately before the procedure; dosage is titrated to obtain the desired sedative response, such as slurring of speech. Generally, IV administration of up to 10 mg is adequate, but up to20 mg may be required especially if opiates are not given concomitantly. If IV administration is not feasible, 5-10 mg of diazepam may be given IM approximately 30 minutes prior to endoscopy in adults.

For preoperative sedation in adults, 10 mg of diazepam may be administered parenterally 1-2 hours prior to surgery. Some clinicians have recommended a dose of up to 20 mg preoperatively.

To reduce the requirements for opiate analgesics and produce anterograde amnesia during labor and delivery, the usual parenteral dosage of diazepam is 10-20 mg.

For painful musculoskeletal conditions and spasticity in adults, 5-10 mg may be administered IV initially and 3-4 hours later if necessary. For tetanus in adults, larger doses may be required and up to 20 mg has been given every 2-8 hours.

The usual initial IV anticonvulsant dose of diazepam in adults is 5-10 mg. Since diazepam may have a short duration of action after IV administration, it may be necessary to readminister the drug. The inital dose may be repeated at 10- to 15-minute intervals until a maximum total of 30 mg has been given. After seizures are terminated, appropriate maintenance anticonvulsant therapy should be instituted. If necessary, the initial dose of diazepam may be repeated in 2-4 hours. Diazepam may be given IM if seizures make IV administration impossible.

In geriatric or debilitated patients or in patients receiving other sedative drugs, single parenteral doses of 2-5 mg of diazepam should be used, and dosage should be slowly increased if needed.

Pediatric DosageIn children, IV diazepam should be given slowly over a 3-minute period. The manufacturers recommend that the initial dose not exceed 0.25 mg/kg; the dose may berepeated at 15- to 30-minute intervals to a maximum total of 0.75 mg/kg.

For the management of seizures (e.g., status epilepticus) in children 30 days to 5 years of age, the usual initial IV dose of diazepam is 0.1-0.5 mg; this dose may be repeated every 2-5 minutes until a maximum total of 5-10 mg has been given. In children 5 years of age or older, the initial IV dose for the management of seizures is 1 mg; this dose may be repeated every 2-5 minutes until a maximum total of 10 mg has been given. Diazepam may have a short duration of action after IV administration, and it may benecessary to readminister the drug. For this reason, some clinicians prefer IV lorazepam

because of its more prolonged duration of effect. If seizures continue with either diazepam or lorazepam, an additional long-acting anticonvulsant (e.g., IV phenytoin or fosphenytoin) generally is initiated.

After seizures are terminated, appropriate maintenance anticonvulsant therapy should be instituted. If necessary, the initial dose may be repeated in 2-4 hours. Diazepam may be given IM if seizures make IV administration impossible.

For tetanus in children, the manufacturers recommend 1-2 mg of diazepam for infants older than 30 days to 5 years of age and 5-10 mg for children older than 5 years of age administered slowly IV. This dose may be repeated every 3-4 hours as needed.

In painful musculoskeletal conditions and spasticity including tetanus in children, some clinicians recommend diazepam 0.04-0.3 mg/kg IV every 2-4 hours; however, dosage generally should not exceed 0.6 mg/kg in an 8-hour period.

Although the manufacturers have not established pediatric dosage recommendations for preoperative sedation, some clinicians have recommended IM administration of 0.4 mg/kg of diazepam in children older than 2 years of age 1-2 hours prior to surgery.

For acute anxiety reactions in children, some clinicians recommend 0.04-0.2 mg/kg of diazepam IV; this dose may be repeated in 3-4 hours, but dosage should not exceed 0.6 mg/kg in an 8-hour period.

Although the safety and efficacy of parenteral diazepam in infants 30 days of age or younger have not been established, neonates with agitation due to opiate withdrawal have received 0.5-2 mg IM every 8 hours followed by gradual reduction in dosage.

Rectal DosageWhen parenteral solutions of diazepam are administered rectally for the management of status epilepticus, the usual dosage in adults and children is 0.5 mg/kg (not to exceed20 mg).

When diazepam is administered rectally as the commercially available gel for the management of acute repetitive seizures, the dose should be individualized for maximum benefit. Children 2-5 years of age should receive 0.5 mg/kg and those 6-11 years of age should receive 0.3 mg/kg; adults and children 12 years of age and older should receive 0.2 mg/kg. These age-adjusted doses were based on the observation that diazepam clearance in children declines with age until about 12 years of age, at which time adult values are reached. Because diazepam gel is provided in standard, fixed, unit doses of 5, 10, 15, and 20 mg, the actual dose to be administered is determined by rounding up to the nearest commercially available fixed dose. Using this method of rounded dosing, patients will receive 90-180% of the dose calculated on a weight and age basis. The safety of this dosing method has been established in clinical studies in adults and children 2 years of age and older. For geriatric or debilitated patients, the dose of the rectal gel should be adjusted downward to reduce the likelihood of ataxia and oversedation. The 2.5-mg unit-dose applicator may be used at the discretion of the clinician for more precise dose titration than can be achieved with the standard 5- to 20-mg applicators. The 2.5-mg applicator also may be used to

provide a partial replacement dose (supplemental dose) for patients who partially expel the recommended dose within 5 minutes after administration.

If necessary for adequate seizure control, the usual age- and weight-adjusted dose of diazepam rectal gel may be repeated 4-12 hours after the initial dose. Although the usual dose was repeated a third time 8 hours after the second dose in adults in one clinical study, the additional dose resulted in increased sedation and appeared to negatively affect global caregiver assessment of treatment outcome; therefore, a third dose currently is not recommended by the manufacturer. Dosage should be adjusted periodically by the clinician to reflect changes in the patient's age and/or weight; the manufacturer recommends dosage reevaluation at 6-month intervals.

The manufacturer states that diazepam rectal gel is intended for use solely on an intermittent basis and therefore should be administered by caregivers outside the hospital no more frequently than one treatment course every 5 days nor more frequently than 5 treatment courses per month. In addition, chronic daily use of the rectal gel is not recommended because of the potential for development of tolerance to diazepam; chronic daily use may increase the frequency and/or severity of tonic-clonic seizures, requiring an increase in the dosage of concomitant chronic anticonvulsant therapy. In such cases, abrupt withdrawal of chronic diazepam also may be associated with a temporary increase in the frequency and/or severity of seizures.

Because caregivers will be responsible for recognizing seizure episodes suitable for treatment, making the decision to initiate treatment, administering the drug, monitoring the patient, and assessing the adequacy of response, a major component of the prescribing process is the careful instruction of these individuals. The clinician and caregiver must share a common explicit understanding of what constitutes a seizure episode (and/or the events, which may be nonconvulsive, presumed to herald their onset) that is appropriate for treatment, the timing of administration in relation to the onset of the episode, the mechanics of competently administering the drug, how and what to observe following administration, when to repeat a dose, and what would constitute an outcome requiring immediate and direct medical attention.

The caregiver should be instructed to contact the patient's clinician or seek other medical assistance if the seizure episode persists for longer than 15 minutes after administering the rectal gel (or as otherwise instructed), if the seizure behavior differs from other episodes, if the seizure frequency or severity or patient color or breathing is alarming, or if the patient is experiencing unusual or serious problems.

The patient's underlying seizure disorder should be stabilized with a standard chronic anticonvulsant drug regimen, and rectal diazepam should be used only as an adjunct to this regimen for characteristic breakthrough bouts of repetitive seizures.

Cautions

• Precautions and ContraindicationsDiazepam shares the toxic potentials of the benzodiazepines, and the usual precautions of benzodiazepine administration should be observed. (See Cautions in the Benzodiazepines General Statement 28:24.08.)

Parenterally administered diazepam may cause hypotension and/or respiratory depression, particularly if the drug is administered too rapidly IV. The drug should be administered slowly IV at a rate not exceeding 5 mg/minute in adults and over a3-minute period in children; facilities and equipment for respiratory or cardiovascular assistance should be readily available.

The possibility that respiratory depression could occur with rectal administration of diazepam also should be considered, although the risk of its development probably is less than that with IV administration. The drug should be used with caution in patients with compromised respiratory function secondary to an underlying disease (e.g., asthma, pneumonia) or neurologic damage.Repeated rectal therapy at relatively short intervals by out-of-hospital caregivers should be avoided because of the possibility of life-threatening respiratory depression; the manufacturer recommends thatout-of-hospital rectal diazepam therapy be repeated no more frequently than once during a 5-day period or 5 times monthly and that dosing be limited to 2 doses per treatment course. (See Dosage: Rectal Dosage, in Dosage and Administration.)

Diazepam is contraindicated in patients with known hypersensitivity to the drug. The manufacturers state that the drug is contraindicated in patients with acute angle-closure glaucoma but may be used with caution in patients with open-angle glaucoma who are receiving appropriate therapy. However, the clinical rationale for this contraindication has been questioned.

• Pediatric PrecautionsSafety and efficacy of oral diazepam in infants younger than 6 months of age have not been established. Safety and efficacy of parenteral diazepam in infants 30 days of age or younger have not been established. Safety and efficacy of rectal diazepam have not been established via clinical studies in children younger than 2 years of age, and the manufacturer states that the gel is not recommended for use in infants younger than 6 months of age.

Chemistry and Stability

• Chemistry

Diazepam is a benzodiazepine. Diazepam occurs as an off-white to yellow, practically odorless, crystalline powder. The drug is sparingly soluble in propylene glycol and has solubilities of approximately 3 mg/mL in water and 62.5 mg/mL in alcohol at 25°C. Diazepam has a pKa of 3.4. Sodium benzoate and benzoic acid are added to the

Solution, 5 mg/mL Diazepam Intensol ®, ((concentrate with alcohol 19%) Roxane

commercially available injection to adjust the pH to 6.2-6.9.

Diazepam rectal gel is commercially available as a nonsterile viscous gel formulated in an aqueous base that contains propylene glycol, alcohol (10%), hydroxypropyl methylcellulose, sodium benzoate, benzyl alcohol (1.5%), and benzoic acid. The rectal gel is clear to slightly yellow and has a pH of 6.5-7.2.

• StabilityDiazepam injection should be protected from light and stored at 15-30°C; freezing should be avoided. Diazepam tablets and extended-release capsules should be stored in tight, light-resistant containers at 15-30°C. Diazepam oral solution and oral concentrate solution should be stored at 15-30°C.

The manufacturers state that diazepam injection should not be mixed with other drugs or IV fluids. Although some studies indicate that diazepam injection may be compatible with various drugs and IV fluids (e.g., diluted to a concentration of 5 mg/50 mL to 5 mg/100 mL with 0.9% sodium chloride, 5% dextrose, Ringer's, or lactated Ringer's injection), compatibility may depend on several factors (e.g., the concentration of the drugs, resulting pH, temperature). Specialized references should be consulted for more specific compatibility information. The addition of diazepam injection to an IV infusion solution or plastic syringes may result in adsorption of diazepam to the plastic container and tubing.

Diazepam rectal gel should be stored at a controlled room temperature of 15-30°C.

For further information on chemistry, pharmacology, pharmacokinetics, uses, cautions, chronic toxicity, acute toxicity, drug interactions, laboratory test interferences, and dosage and administration of diazepam, see the Benzodiazepines General Statement28:24.08.

Preparations

Diazepam is subject to control under the Federal Controlled Substances Act of 1970 as a schedule IV (C-IV) drug.

Diazepam

Oral

Solution 5 mg/5 mL Diazepam Solution, ((C-IV)) Roxane

C-IV);

Tablets 2 mg Valium®, ((C-IV); scored)

Roche

5 mg Valium ®, ((C-IV); scored) Roche

10 mg Valium ®, ((C-IV); scored) Roche

Parenteral

Injection 5 mg/mL Diazepam ® Injection, ((C-IV)) Baxter Hospira Wyeth

Valium ®, ((C-IV); with alcohol10%, benzyl alcohol 1.5%, and propylene glycol 40%) Roche

Rectal

Gel 5 mg/mL (2.5, 5, 10, 15, and Diastat® Rectal Delivery20 mg) System, ((C-IV); with benzyl

alcohol 1.5%, alcohol 10%, andpropylene glycol in prefilledapplicators with pediatric universal or adult applicatortips) Xcel

References

For references used in the monograph on diazepam, see References in theBenzodiazepines General Statement 28:24.08.

Location In Book:

AHFS DRUG INFORMATION® (2004)28:00 Central Nervous System Agents

28:24 Anxiolytics, Sedatives, and Hypnotics28:24.08 Benzodiazepines

Diazepam