Diazepam

To assure the safe and effective use of benzodiazepines, patients should be informed that, since benzodiazepines may produce psychological and physical dependence, it is advisable that they consult with their physician before either increasing the dose or abruptly discontinuing this drug. The risk of dependence increases with duration of treatment; it is also greater in patients with a history of alcohol or drug abuse.

Patients should be advised against the simultaneous ingestion of alcohol and other CNS-depressant drugs during diazepam therapy. 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.

Diazepam is a prescription medication used to treat anxiety, muscle spasms, and seizures. It is also used to treat symptoms of alcohol withdrawal including agitation, tremor, and hallucinations. Diazepam belongs to a group of drugs called benzodiazepines which work by reducing the activity of nerves in the brain.

This medication comes in tablet, liquid (oral), injectable and rectal forms. Oral tablets and liquid may be taken 2 to 4 times daily, with or without food.

Common side effects include drowsiness, tiredness, and weakness. Do not drive or operate heavy machinery until you know how diazepam affects you.

Diazepam is a prescription medicine used to treat anxiety, muscle spasms, and seizures. It is also used to treat symptoms of alcohol withdrawal including agitation, tremor, and hallucinations.

This medicine may be prescribed for other uses. Ask your doctor or pharmacist for more information.

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

This medication falls into category D. Diazepam can cause harm or death to an unborn baby. Talk to your doctor about the risks of taking diazepam during pregnancy.

Oral diazepam (tablets and liquid) can be taken with our without food. Taking it with food may help if it bothers your stomach.

Diazepam concentrate (liquid) comes with a specially marked dropper for measuring the dose. Use only the calibrated dropper provided with this product. Draw into the dropper the amount prescribed for a single dose.

• Then squeeze the dropper contents into a liquid or semi-solid food. It is recommended that the dose be mixed with liquid or semi-solid food such as water, juices, soda or soda-like beverages, applesauce and puddings.
• Stir the liquid or food gently for a few seconds. The entire amount of the mixture, of drug and liquid or drug and food, should be consumed immediately. Do not store for future use.

If you miss a diazepam dose, do not take a double dose unless your doctor advises you to.

Do not abruptly stop taking diazepam without talking to your doctor. Your dosage may be gradually decreased to avoid withdrawal symptoms (anxiousness, sleeplessness, irritability).

Side effects most commonly reported were drowsiness, fatigue, muscle weakness, and ataxia. The following have also been reported:

Central Nervous System: confusion, depression, dysarthria, headache, slurred speech, tremor, vertigo

Gastrointestinal System: constipation, nausea, gastrointestinal disturbances

Special Senses : blurred vision, diplopia, dizziness

Cardiovascular System: hypotension

Psychiatric and Paradoxical Reactions : stimulation, restlessness, acute hyperexcited states, anxiety, agitation, aggressiveness, irritability, rage, hallucinations, psychoses, delusions, increased muscle spasticity, insomnia, sleep disturbances, and nightmares. Inappropriate behavior and other adverse behavioral effects have been reported when using benzodiazepines. Should these occur, use of the drug should be discontinued. They are more likely to occur in children and in the elderly.

Urogenital System: incontinence, changes in libido, urinary retention

Skin and Appendages : skin reactions

Laboratories : elevated transaminases and alkaline phosphatase

Other: changes in salivation, including dry mouth, hypersalivation

Antegrade amnesia may occur using therapeutic dosages, the risk increasing at higher dosages. Amnestic effects may be associated with inappropriate behavior.

Minor changes in EEG patterns, usually low-voltage fast activity, have been observed in patients during and after diazepam therapy and are of no known significance.

Because of isolated reports of neutropenia and jaundice, periodic blood counts and liver function tests are advisable during long-term therapy.

Postmarketing Experience

There have been reports of falls and fractures in benzodiazepine users. The risk is increased in those taking concomitant sedatives (including alcohol) and in the elderly.

Drug Abuse And Dependence

Diazepam is subject to Schedule IV control under the Controlled Substances Act of 1970. Abuse and dependence of benzodiazepines have been reported. 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. Once physical dependence to benzodiazepines has developed, termination of treatment will be accompanied by withdrawal symptoms. The risk is more pronounced in patients on long-term therapy.

Withdrawal symptoms, similar in character to those noted with barbiturates and alcohol have occurred following abrupt discontinuance of diazepam. These withdrawal symptoms may consist of tremor, abdominal and muscle cramps, vomiting, sweating, headache, muscle pain, extreme anxiety, tension, restlessness, confusion and irritability. In severe cases, the following symptoms may occur: derealization, depersonalization, hyperacusis, numbness and tingling of the extremities, hypersensitivity to light, noise and physical contact, hallucinations or epileptic seizures. 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 (e.g., dysphoria and insomnia) have been reported following abrupt discontinuance of benzodiazepines taken continuously at therapeutic levels for several months. Consequently, after extended therapy, abrupt discontinuation should generally be avoided and a gradual dosage tapering schedule followed.

Chronic use (even at therapeutic doses) may lead to the development of physical dependence: discontinuation of the therapy may result in withdrawal or rebound phenomena.

Rebound Anxiety

A transient syndrome whereby the symptoms that led to treatment with diazepam recur in an enhanced form. This may occur upon discontinuation of treatment. It may be accompanied by other reactions including mood changes, anxiety, and restlessness.

Since the risk of withdrawal phenomena and rebound phenomena is greater after abrupt discontinuation of treatment, it is recommended that the dosage be decreased gradually.

Read the entire FDA prescribing information for Diazepam (Diazepam Tablets)

General

• Use the smallest effective dosage to avoid oversedation.a b

• Consider long half-life of diazepam and its metabolites when making dosage adjustments (see Half-life under Pharmacokinetics).a b

• In patients who have received prolonged (e.g., for several months) therapy, avoid abrupt discontinuance, since manifestations of withdrawal can be precipitated; gradually taper dosage.a

Anxiety

• Periodically reassess usefulness for treatment of anxiety.a Administer for the shortest period of time; frequent dosage adjustments may be required.a

Seizure Disorders

• Do not discontinue diazepam abruptly in patients with a history of a seizure disorder, since seizures may be precipitated.a b

Administration

Administer orally,a by IM or IV injection,a c or rectally.c

Oral Administration

Initially, administer orally in 3 or 4 doses daily for the treatment of anxiety disorders or skeletal muscle spasticity.a b When dosage is stabilized, may administer orally in 1 or 2 doses daily, with all or most of the dosage given at bedtime to minimize daytime sedation.b

Dilute oral concentrate solution (e.g., with water, juice, carbonated beverages) or mix with semisolid foods (e.g., applesauce, pudding) just prior to administration.b

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

For IV injection, administer dose directly into a large vein; if this is not possible, inject the drug into the tubing of a flowing IV solution as close as possible to the vein insertion site.b c

Take care to avoid intra-arterial administration or extravasation.b c

Switch patient to oral therapy as soon as possible.b

Some clinicians recommend IV administration of a dilute solution to avoid extravasation; however, manufacturers do not recommend this method of administration, since precipitation may occur.b c

Adults: Inject dose slowly at rate of ≤5 mg per minute.b c

Children and infants ≥30 days of age: Administer dose slowly over 3 minutes.b c

IM Administration

May be administered as deep IM injection;a b c however, absorption may be slow and erratic.a b IM route is rarely justified.b

Rectal Administration

Administer rectally as the commercially available gel via the delivery device (a plastic applicator with a flexible molded tip) provided by the manufacturer. Consult the manufacturer’s labeling for specific instructions for administration of the rectal gel.

Alternatively, administer as the parenteral solution† via a syringe and rectally inserted tubing or via lubricated tuberculin syringe (without a needle) inserted 4–5 cm into the rectum.

Commercially available gel is provided in prefilled syringe applicators containing 2.5, 10, or 20 mg of diazepam.

Dose to be delivered by the AcuDial applicator is locked into the device prior to dispensing. If necessary, use 2 applicators to administer the prescribed dose.

The 2.5-mg unit-dose applicator also may be used as a partial replacement dose (supplemental dose) for patients who partially expel the recommended dose within 5 minutes after administration.

Prescription should indicate the appropriate dose to be locked into the applicator, the appropriate rectal tip size, and the number of packages (2 applicators per package) to be dispensed.

Pharmacist must dial in and lock the correct dose to be administered prior to dispensing Diastat AcuDial.

While holding the barrel of the applicator in one hand, turn the cap of the applicator to select the dose. After confirming that the dose visible in the display window is correct, lock the dose by grasping the locking ring and pushing upward to lock both sides of the ring. A green “ready” band becomes visible at the base of the applicator once the dose-locking ring is engaged.

Repeat the process for each applicator to be dispensed.

Prior to administering the dose, check the diazepam gel expiration date, verify that the green “ready” band on the Diastat AcuDial applicator is visible, and verify the dose displayed in the AcuDial display window.

Remove the protective cap from the syringe and ensure that the seal pin is removed with the cap.

Lubricate the rectal applicator tip with the water-soluble lubricant (jelly) provided by the manufacturer.

Turn the patient 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. Insert the lubricated applicator tip into the rectum until the rim of the syringe is snug against the rectal opening; slowly push the plunger (counting aloud slowly to 3) until it stops (i.e., until the entire dose of the applicator has been expelled into the rectum). Count aloud slowly to 3 before removing the syringe from the rectum; to prevent leakage of the administered dose from the rectum, hold the buttocks together while again counting aloud slowly to 3.

Leave the patient on their side facing the caregiver, note the time the dose was given, and observe the patient.

If bowel leakage occurs, a supplemental dose may be required. (See Rectal Administration under Dosage and Administration.)

Discard Diastat and Diastat AcuDial rectal delivery systems and all unused materials in the garbage in a safe place away from children; do not reuse.

Prior to discarding AcuDial applicator in the garbage, dispose of any gel remaining in the applicator. With the applicator tip pointed over the sink or toilet, pull back and remove the plunger from the barrel; then, replace the plunger in the barrel and gently depress the plunger until it stops, forcing gel from the applicator. Flush toilet or rinse sink with water until gel is no longer visible.

Formation of cracks at the base of the plastic tip of Diastat AcuDial applicators has been reported. (See Manufacturing Problem with Diazepam Rectal Gel [Diastat AcuDial] Applicators under Cautions.) Until the problem is resolved, Diastat AcuDial applicators should be inspected for cracks at the base of the applicator tip, without removal of the applicator cap, prior to dispensing and frequently (i.e., monthly) thereafter.

Obtain detailed instructions for inspecting syringe applicator from the manufacturer at 877-361-2719 or .

Instruct patients and/or their caregivers to return any cracked applicators to the pharmacy for immediate replacement.

Pharmacists should contact RxHope at 800-511-2120 or to obtain replacements for damaged products.

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Pediatric Patients

Children ≥6 months of age: Initially, 1–2.5 mg 3 or 4 times daily.b Alternatively, 0.12–0.8 mg/kg or 3.5–24 mg/m2 in 3 or 4 divided doses daily.b Increase dosage gradually as needed and tolerated.b

0.04–0.2 mg/kg; may repeat in 3–4 hours.b Total dose should not exceed 0.6 mg/kg in an 8-hour period.b

Children >2 years of age: 0.4 mg/kg has been administered 1–2 hours before surgery.b

6–15 mg daily (occasionally up to 30 mg daily) in divided doses has been used.b

Children 30 days to 5 years of age: Initially, 0.1–0.5 mg; may repeat every 2–5 minutes to a maximum total dose of 5–10 mg.b c May repeat dose in 2–4 hours.b

Children ≥5 years of age: Initially, 1 mg; may repeat every 2–5 minutes to a maximum total dose of 10 mg.b c May repeat dose in 2–4 hours.b

Children 2–5 years of age: Initially, 0.5 mg/kg as rectal gel, rounded up to the next available dose (i.e., the next multiple of 2.5 mg). If necessary, repeat initial dose in 4–12 hours. Administration of a third dose is not recommended by the manufacturer.

Children 6–11 years of age: Initially, 0.3 mg/kg as rectal gel, rounded up to the next available dose (i.e., the next multiple of 2.5 mg). If necessary, repeat initial dose in 4–12 hours. Administration of a third dose is not recommended by the manufacturer.

Children ≥12 years of age: Initially, 0.2 mg/kg as rectal gel, rounded up to the next available dose (i.e., the next multiple of 2.5 mg). If necessary, repeat initial dose in 4–12 hours. Administration of a third dose is not recommended by the manufacturer.

Usual dosage of parenteral solutions† administered rectally in children: 0.5 mg/kg (not to exceed 20 mg).

0.12–0.8 mg/kg in 3 or 4 divided doses daily.e

0.04–0.3 mg/kg has been administered every 2–4 hours, not to exceed 0.6 mg/kg in an 8-hour period.b

Children >30 days to 5 years of age: 1–2 mg.b c May repeat dose every 3–4 hours as needed.b c

Children >5 years of age: 5–10 mg.b c May repeat dose every 3–4 hours as needed.b c

Children >12 years of age: 0.03–0.1 mg/kg as an intermittent injection every 0.5–6 hours; more frequent administration may be required for the management of acutely agitated patients.

0.5–2 mg has been administered every 8 hours, followed by gradual dosage reduction.b

Adults

2–10 mg 2–4 times daily, depending on the severity of the symptoms.b

Initially, 2–5 mg for moderate or 5–10 mg for severe acute anxiety; may repeat in 3–4 hours.b

10 mg 1–2 hours before surgery;b c some clinicians recommend doses up to 20 mg.b

5–15 mg 5–10 minutes before the procedure.b c

Titrate dosage to obtain desired sedative response (e.g., slurring of speech).b c Initially, 10 mg, but up to 20 mg may be required, especially if opiates are not given concomitantly.b c

5–10 mg approximately 30 minutes prior to endoscopy.b c

10 mg 3 or 4 times during the first 24 hours, followed by 5 mg 3 or 4 times daily as needed.b

Initially, 10 mg (some clinicians recommend up to 20 mg), then 5–10 mg every hour if necessary, although an interval of 3–4 hours may be satisfactory.b c

Alternatively, some clinicians recommend 10 mg initially, followed by 10 mg at 20–30 minutes intervals until patient is calm.b

2–10 mg 2–4 times daily.b

Initially, 5–10 mg.b c May repeat at 10- to 15-minute intervals, to a maximum total dose of 30 mg.b c May repeat dose in 2–4 hours.b c

Initially, 0.2 mg/kg as rectal gel, rounded up to next available dose (i.e., the next multiple of 2.5 mg). If necessary, repeat initial dose in 4–12 hours. Administration of a third dose is not recommended by the manufacturer.

For rectal administration of parenteral solutions†, 0.5 mg/kg (not to exceed 20 mg).

2–10 mg 2–4 times daily.b

Initially, 5–10 mg; may repeat in 3–4 hours if necessary.b c

Doses up to 20 mg have been given every 2–8 hours.b

0.03–0.1 mg/kg as an intermittent injection every 0.5–6 hours; more frequent administration may be required for the management of acutely agitated patients.

Dosages of 5–20 mg at bedtime have been used.b

10–20 mg.b

Prescribing Limits

Pediatric Patients

Maximum 0.25 mg/kg as a single initial dose,b c repeated at 15- to 30-minute intervals to a maximum total dose of 0.75 mg/kg.b c

Maximum recommended frequency for administration by caregivers outside hospital is 1 treatment course every 5 days and 5 treatment courses per month.

Adults

Some clinicians recommend maximum dosage of 30 mg in an 8-hour period.b

Maximum recommended frequency for administration by caregivers outside hospital is 1 treatment course every 5 days and 5 treatment courses per month.

Special Populations

Hepatic Impairment

Reduce dosage;a use the smallest effective dose to avoid oversedation.a

Renal Impairment

Use the smallest effective dose to avoid oversedation.a

Geriatric Patients

Initially, 2–2.5 mg once or twice daily.b Increase dosage gradually as needed and tolerated.b c

Initially, 2–5 mg as a single dose.b c Increase dosage gradually as needed and tolerated.b c

Dosage to be administered should be adjusted downward for the commercially available prefilled applicators of rectal gel.

Other Populations

Use the smallest effective dosage in debilitated patient and patients with low serum albumin concentrations.b In debilitated patients, observe maximum geriatric dosages. (See Geriatric Patients under Dosage and Administration.)b

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Diazepam is subject to Schedule IV control under the Controlled Substances Act of 1970. Abuse and dependence of benzodiazepines have been reported. 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. Once physical dependence to benzodiazepines has developed, termination of treatment will be accompanied by withdrawal symptoms. The risk is more pronounced in patients on long-term therapy.

Withdrawal symptoms, similar in character to those noted with barbiturates and alcohol have occurred following abrupt discontinuance of Diazepam. These withdrawal symptoms may consist of tremor, abdominal and muscle cramps, vomiting, sweating, headache, muscle pain, extreme anxiety, tension, restlessness, confusion and irritability. In severe cases, the following symptoms may occur: derealization, depersonalization, hyperacusis, numbness and tingling of the extremities, hypersensitivity to light, noise and physical contact, hallucinations or epileptic seizures. 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 (e.g., dysphoria and insomnia) have been reported following abrupt discontinuance of benzodiazepines taken continuously at therapeutic levels for several months. Consequently, after extended therapy, abrupt discontinuation should generally be avoided and a gradual dosage tapering schedule followed.

Chronic use (even at therapeutic doses) may lead to the development of physical dependence: discontinuation of the therapy may result in withdrawal or rebound phenomena.

Rebound Anxiety: A transient syndrome whereby the symptoms that led to treatment with Diazepam recur in an enhanced form. This may occur upon discontinuation of treatment. It may be accompanied by other reactions including mood changes, anxiety, and restlessness.

Since the risk of withdrawal phenomena and rebound phenomena is greater after abrupt discontinuation of treatment, it is recommended that the dosage be decreased gradually.

• Anticonvulsant, Benzodiazepine
• Benzodiazepine

The half-life is prolonged and clearance is decreased.

There are no dosage adjustments provided in the manufacturer’s labeling; use with caution.

Hemodialysis: Not dialyzable (0% to 5%); supplemental dose is not necessary.

Injection: Store at 20°C to 25°C (68°F to 77°F). Protect from light. Do not refrigerate autoinjector.

Oral solution: Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from light. Discard opened bottle of concentrated oral solution after 90 days.

Rectal gel: Store at 25°C (77°F); excursion permitted to 15°C to 30°C (59°F to 86°F).

Tablet: Store at 15°C to 30°C (59°F to 86°F).

Frequency not defined. Adverse reactions may vary by route of administration.

Cardiovascular: Hypotension, localized phlebitis, vasodilatation

Central nervous system: Amnesia, ataxia, confusion, depression, drowsiness, dysarthria, fatigue, headache, slurred speech, vertigo

Dermatologic: Skin rash

Endocrine & metabolic: Change in libido

Gastrointestinal: Altered salivation (dry mouth or hypersalivation), constipation, diarrhea, nausea

Genitourinary: Urinary incontinence, urinary retention

Hepatic: Jaundice

Local: Pain at injection site

Neuromuscular & skeletal: Tremor, weakness

Ophthalmic: Blurred vision, diplopia

Respiratory: Apnea, asthma, bradypnea

Miscellaneous: Paradoxical reaction (eg, aggressiveness, agitation, anxiety, delusions, hallucinations, inappropriate behavior, increased muscle spasms, insomnia, irritability, psychoses, rage, restlessness, sleep disturbances, stimulation)

Heart rate, respiratory rate, blood pressure, and mental status; liver enzymes and CBC with long-term therapy; clinical signs of propylene glycol toxicity (for continuous high-dose and/or long duration intravenous use) including serum creatinine, BUN, serum lactate, osmol gap. Note: An osmol gap of ≥10 was predictive of elevated propylene glycol concentrations; values of ≥12 suggest propylene glycol toxicity (Barnes 2006; Yahwak 2008)

Critically-ill mechanically-ventilated patients: Monitor depth of sedation with either the Richmond Agitation-Sedation Scale (RASS) or Sedation-Agitation Scale (SAS) (Barr 2013)

You should not use this medicine if you are allergic to diazepam or similar medicines (Ativan, Klonopin, Restoril, Xanax, and others), or if you have myasthenia gravis, severe liver disease, narrow-angle glaucoma, a severe breathing problem, or sleep apnea.

Before you take diazepam, tell your doctor if you have glaucoma, asthma or other breathing problems, kidney or liver disease, seizures, or a history of drug or alcohol addiction, mental illness, depression, or suicidal thoughts.

Do not start or stop taking diazepam during pregnancy without your doctor's advice. Diazepam may cause harm to an unborn baby, but having a seizure during pregnancy could harm both the mother and the baby. Tell your doctor right away if you become pregnant while taking diazepam for seizures.

Diazepam may be habit-forming. Misuse of habit-forming medicine can cause addiction, overdose, or death.

Do not give this medication to a child younger than 6 months old.

This medication may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

Avoid drinking alcohol. Dangerous side effects could occur.

Grapefruit and grapefruit juice may interact with diazepam and lead to unwanted side effects. Discuss the use of grapefruit products with your doctor.

• May be used for the short-term relief of anxiety, to relieve symptoms associated with alcohol withdrawal, and to relieve muscle spasm.
• Can also be used in the treatment of prolonged seizures in conjunction with other anti-seizure medications.
• May also be used off-label, that is, prescribed for conditions that are not FDA-approved but may be well established.
• Generic diazepam is available.