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Diazepam

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Diazepam
Clinical data
Pregnancy
category
Routes of
administration		Oral, IM, IV, suppository
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability93%
MetabolismHepatic
Elimination half-life36-100 hours
ExcretionRenal
Identifiers
  • 7-chloro-1-methyl-
    5-phenyl-1,3-dihydro-2H-
    1,4-benzodiazepin-2-one
CAS Number
PubChem CID
DrugBank
CompTox Dashboard (EPA)
ECHA InfoCard100.006.476 Edit this at Wikidata
Chemical and physical data
FormulaTemplate:Carbon16Template:Hydrogen13Template:ChlorineTemplate:Nitrogen2Template:Oxygen
Molar mass284.7

Diazepam (marketed under brand names Valium®, Stesolid®, Seduxen® and Apozepam®)[2] is a drug which is a benzodiazepine derivative. It possesses anxiolytic, anticonvulsant, sedative, skeletal muscle relaxant and amnestic properties. This makes it a useful drug for treating anxiety, insomnia, muscle spasms and some forms of epilepsy. It is also used before certain medical procedures (such as endoscopies) to reduce tension and anxiety, and in some surgical procedures to induce amnesia.[3][4]

Diazepam is a core medicine in the World Health Organization's "Essential Drugs List", which is a list of minimum medical needs for a basic health care system.[5] Diazepam is used to treat a wide range of conditions and is one of the most frequently prescribed benzodiazepines.

History

Diazepam was the second benzodiazepine to be invented by Leo Sternbach, and was approved for use in 1963. It is five times more potent than its predecessor, chlordiazepoxide, which it quickly surpassed in terms of sales. After this initial success, other pharmaceutical companies began to introduce other benzodiazepine derivatives.[6]

The benzodiazepines gained popularity among medical professionals as an improvement upon barbiturates, which have a comparatively narrow therapeutic index, and are far more sedating at therapeutic doses. The benzodiazepines are also far less dangerous; death rarely results from diazepam overdose, except in cases where it is consumed with large amounts of other depressants (such as alcohol or other sedatives).[7]

Diazepam was the top-selling pharmaceutical in the United States from 1969 to 1982, with peak sales in 1978 of 2.3 billion pills.[6]

Over the years, physicians, psychiatrists and neurologists have discovered many new off-label uses for diazepam, such as treatment of spastic paresis and palliative treatment of stiff-person syndrome.[8]

Physical properties

Diazepam occurs as solid white or yellow crystals and has a melting point of 131.5 to 134.5°C. It is odorless, and has a slightly bitter taste. The British Pharmacopoeia lists diazepam as being very slightly soluble in water, soluble in alcohol and freely soluble in chloroform. The United States Pharmacopoeia lists diazepam as soluble 1 in 16 of ethyl alcohol, 1 in 2 of chloroform, 1 in 39 of ether, and practically insoluble in water. The pH of diazepam is neutral (i.e. 7). Diazepam has a shelf-life of 5 years for oral tablets and 3 years for IV/IM solution.[9]

Diazepam should be stored at room temperature (15°-30°C). The solution for parenteral injection should be protected from light and kept from freezing. The oral forms should be stored in air-tight containers and protected from light.[10]

Diazepam can absorb into plastic, and therefore diazepam solution is not stored in plastic bottles or syringes. It can absorb into plastic bags and tubing used for intervenous infusions. Absorption appears to be dependent on several factors such as temperature, concentration, flow rates and tube length. Diazepam should not be administered if a precipitate has formed and will not dissolve.[10]

Pharmacology

In animal models, diazepam appears to act on areas of the limbic system, thalamus and hypothalamus, inducing anxiolytic effects. Its actions are due to the enhancement of GABA activity.[3][11]

Diazepam binds to specific benzodiazepine sites on subunits of GABAA receptors, which are distinctly different than those which endogenous GABA molecules bind to.[11][12]

Due to the role of diazepam as a positive allosteric modulator of GABA, when it binds to benzodiazepine receptors it causes inhibitory effects. This arises from the hyperpolarization of the postsynaptic membrane, due to the control exerted over negative chloride ions by GABAA receptors.[11][13]

Pharmacokinetics

Diazepam can be administered orally, intravenously, intramuscularly, or as a suppository.[9]

When diazepam is administered orally, it is rapidly absorbed and has a fast onset of action. The onset of action is 1-5 minutes for IV administration and 15-30 minutes for IM administration. The duration of the diazepam's main pharmacological effects is 15 minutes to 1 hour for both routes of administration.[14]

Peak plasma levels are achieved 30 minutes to 2 hours after oral administration. When diazepam is administered as an intramuscular injection, absorption is slow, erratic and incomplete.[2][10]

Diazepam is highly lipid-soluble, and is widely distributed throughout the body after administration. It easily crosses both the blood-brain barrier and the placenta, and is excreted into breast milk. After absorption, diazepam is redistributed into muscle and adipose tissue. Continual daily doses of diazepam will quickly build up to a high concentration in the body (mainly in adipose tissue), which will be far in excess of the actual dose for any given day.[9][10]

Diazepam is metabolised in the liver via the cytochrome P450 enzyme system. It has a biphasic half-life of 1-2 and 2-5 days, and has several pharmacologically active metabolites. The main active metabolite of diazepam is desmethyldiazepam (also known as nordazepam or nordiazepam). Diazepam's other active metabolites include temazepam and oxazepam. These metabolites are conjugated with glucuronide, and are excreted primarily in the urine. Because of these active metabolites, the serum values of diazepam alone are not useful in predicting the effects of the drug.[2][10]

Diazepam has a half-life (t1/2α) of 20-50 hours, and desmethyldiazepam has a half-life of 30-200 hours.[10]

Most of the drug is metabolised; very little diazepam is excreted unchanged.[9]

In humans, the protein binding of diazepam is around 98.5%.[2]

Indications

Diazepam is mainly used to treat anxiety, insomnia, and symptoms of acute alcohol or opiate withdrawal. It is also used as a premedication for inducing sedation, anxiolysis or amnesia prior to certain medical procedures (e.g. endoscopy).[2]

Diazepam is rarely used as a primary drug for the long-term treatment of epilepsy. This is due to the fact that tolerance to the anticonvulsant effects of diazepam usually develops within 6 to 12 months of treatment, effectively rendering it useless for this purpose.[9]


Diazepam has a broad spectrum of indications (most of which are off-label), including:

  • Treatment of the symptoms of alcohol and opiate withdrawal[2]
  • Treatment of tetanus, together with other measures of intensive-treatment[15]
  • Adjunctive treatment of painful muscle conditions[8]
  • Adjunctive treatment of spastic muscular paresis (para-/tetraplegia) caused by cerebral or spinal cord conditions such as stroke, multiple sclerosis, spinal cord injury (long-term treatment is coupled with other rehabilitative measures)[8]
  • Pre-/postoperative sedation, anxiolysis and/or amnesia (e.g. before endoscopic or surgical procedures)[8]

Veterinary uses

Diazepam is very useful as short term sedative and anxiolytic for cats and dogs. It can also be used for preoperative sedation of cats and dogs and as an anticonvulsive suitable for short-term and long-term treatment, if sedation is tolerated. The anticonvulsant dosage is typically 0.25 milligram/pound administered intervenously or, for emergency treatment, rectally in suppository form.[17]

Dosage

Dosages should be determined on an individual basis, depending upon the condition to be treated, the severity of symptoms, the body weight of the patient, and any comorbid conditions the patient may have.[9]

Elderly patients and those with liver disorders experience decreased metabolism of diazepam; therefore the dosage for these patients should be reduced. General guidelines for this group of patients: initial doses of 2mg to 2.5mg, 1 or 2 times daily; increase gradually as required/tolerated.[13]


Adult dosage recommendations

  • Insomnia - Up to 30mg orally, as a single dose, at bedtime.[9]
  • Anxiety/panic attacks - Dosage differs depending upon severity of symptoms. For panic attacks, diazepam is taken "as needed".
    • Oral - 2mg to 10mg oral, 2 to 4 times daily.[13]
    • IV/IM - 2mg to 10mg. Repeat in 3 to 4 hours, if necessary.[8]
  • Pre-/postoperative sedation - If other premedications are used, they must be administered separately.[8]
    • Oral - Up to 20mg as a single dose.[9]
    • IV/IM - 2mg to 10mg, repeated at intervals of at least 5 to 10 minutes, until adequate sedation and/or anxiolysis is achieved.[9]
  • Status epilepticus
    • Oral - 2mg to 10mg, 2 to 4 times daily.[13]
    • IV/IM - 5mg to 10mg. May be repeated every 5 to 10 minutes until termination of seizures. Maximum dose of 40mg to 60mg can be used; if this dose is ineffective, other anticonvulsant drug therapy should be instituted.[9]
    • Rectal solution - 10mg as a single dose. May be repeated after 5 minutes, if necessary. The oral solution can also be administered rectally.[9]
  • Painful muscle conditions or muscle spasms
    • Oral - Up to 15mg daily, in divided doses. In severe spasticity associated with cerebral palsy, doses may be increased gradually up to 60mg daily.[9]
    • IV/IM - 5mg to 10mg initially, then 5mg to 10mg in 3 to 4 hours, if necessary.[8]
  • Tetanus - 100 to 300µg/kg intravenously, repeated every 1 to 4 hours.[9]
  • Spastic paresis - Usually starting with 3 times daily 2mg, increasing to up to 3 times 20mg in slow increments, taking care to avoid ataxia.[citation needed]
  • Alcohol/opioid withdrawal - For symptomatic relief of agitation, tremor, delirium tremens and hallucinosis.
    • Oral - 10mg, 3 or 4 times during the first 24 hours. Reduce to 5mg, 3 or 4 times a day, or as needed.[13]
    • IV/IM - 10mg initially, 5mg to 10mg in 3 to 4 hours, if necessary.[8]
  • Initial treatment of mania - 30 to 40mg daily oral or rectal, rarely more.[citation needed]
  • Overdosage with hallucinogens/CNS stimulants - Normally a single intravenous dose of 10 to 20mg is sufficient.[citation needed]
  • Adjunctive treatment of depression - Usually 10 to 30mg daily oral, the greater part of the dose given at bedtime. The doses should be decreased and the medication stopped as soon as the clinical situation allows.[citation needed]
  • Adjunctive treatment of extrapyramidal side-effects - Depends on the individual. Effective dose(s) unknown. Do not administer for more than 4 weeks.[citation needed]
  • Cardioversion - To relieve anxiety/tension and to reduce recall of procedure. 5mg to 15mg IV, 5 to 10 minutes prior to the procedure.[8]
  • Prophylactic treatment of oxygen toxicity during hyperbaric therapy - 5mg to 10mg.[16]

Pediatric dosage recommendations

  • Patients over 6 months of age:
    • Initiate therapy with the lowest effective dose.[13]
    • Oral: Initial dose of 40 to 200µg/kg of bodyweight. Can be repeated as tolerated, up to 4 times daily.[9]
    • Rectal suppository: 40 to 200µg/kg of bodyweight, which can be repeated as tolerated up to 4 times daily.[9]
      • Sedation or muscle relaxation[9]
        • IV/IM - 200µg/kg of bodyweight.
      • Status epilepticus[9]
        • IV/IM - 200 to 300µg/kg of bodyweight. May be repeated after 5 to 10 minutes, if required.
        • Rectal solution - 5mg (for patients 1 to 3 years of age); repeat after 5 to 10 minutes, if necessary.
      • Tetanus[8]
        • Patients 30 days to 5 years of age - 1mg to 2mg IV/IM, slowly; repeat every 3 to 4 hours, as necessary.
        • Patients 5 years of age or older - 5mg to 10mg IV/IM, slowly; repeat every 3 to 4 hours, as necessary.
      • Convulsive disorders[8]
        • Patients 30 days to 5 years of age - 0.2mg to 0.5mg IV/IM, slowly, every 2 to 5 minutes. Maximum dose of 5mg.
        • Patients 5 years of age or older - 1mg IV/IM, slowly, every 2 to 5 minutes. Maximum of dose of 10mg. Repeat in 2 to 4 hours, if necessary.
    • Patients under 6 months of age:
      • Diazepam should not be given to children under 6 months of age.[13]

Availability

Diazepam is supplied in the following forms:

  • For oral administration:
    • Tablets - 2mg, 5mg, 10mg[13]. Generic versions available.
    • Capsules, time-release - 15mg (marketed by Roche as Valrelease®)[10]
    • Liquid solution - 1mg/ml in 500ml containers and unit-dose (5mg & 10mg); 5mg/ml in 30 ml dropper bottle (marketed by Roxane as Diazepam Intensol®)[10]
  • For parenteral administration:
    • Solution for IV/IM injection - 5mg/ml. 2ml ampoules and syringes; 1ml, 2ml, 10ml vials; 2 ml Tel-E-Ject; also contains 40% propylene glycol, 10% ethyl alcohol, 5% sodium benzoate and benzoic acid as buffers, and 1.5% benzyl alcohol as a preservative.[18][10]
  • For rectal administration:

Side effects

Diazepam has a range of side effects which are common to most benzodiazepines. Most common side effects include:

Rare paradoxical side effects can include: nervousness, irritability, insomnia, muscle cramps, and in extreme cases, rage and violence.[citation needed] If these side effects are present, diazepam treatment should be immediately terminated.

Up to 30% of individuals treated on a long-term basis develop a form of dependence known as "low-dose-dependence". These patients do not develop a tolerance, and do not need increasingly large doses to experience the euphoric side effects of the drug.[citation needed]

Diazepam may impair the ability to drive vehicles or operate machinery. The impairment is worsened by consumption of alcohol, because both act as central nervous system depressants.[13]

During the course of therapy, tolerance to the sedative effects usually develops.[citation needed]

Patients with severe attacks of apnea during sleep may suffer respiratory depression (hypoventilation) leading to respiratory arrest and death.

Organic changes such as leukopenia and liver-damage of the cholostatic type with or without jaundice (icterus) have been observed in a few cases.[citation needed]

Interactions

If diazepam is to be administered concomitantly with other drugs, attention should be paid to the possible pharmacological interactions. Particular care should be taken with drugs that enhance the effects of diazepam, such as barbiturates, phenothiazines, narcotics and antidepressants.[13]

Diazepam does not increase or decrease hepatic enzyme activity, and does not alter the metabolism of other compounds. There is no evidence which would suggest that diazepam alters its own metabolism with chronic administration.[9]

Agents which have an effect on hepatic cytochrome P450 pathways or conjugation can alter the rate of diazepam metabolism. These interactions would be expected to be most significant with long-term diazepam therapy, and their clinical significance is variable.[9]


  • Oral contraceptives ("the pill") significantly decrease the elimination of desmethyldiazepam, a major metabolite of diazepam.[21]
  • Cisapride may enhance the absorption, and therefore the sedative activity, of diazepam.[22]
  • Diazepam may alter digoxin serum concentrations.[9]
  • Smoking tobacco can enhance the elimination of diazepam and decrease its action.[20]
  • Foods that acidify the urine can lead to faster absorption and elimination of diazepam, reducing drug levels and activity.[20]
  • Foods that alkalinize the urine can lead to slower absorption and elimination of diazepam, increasing drug levels and activity.[9]
  • There are conflicting reports as to whether food in general has any effects on the absorption and activity of orally administered diazepam.[20]

Contradications

Use of diazepam should be avoided, when possible, in individuals with the following conditions:

Special caution needed

  • Pediatric patients
    • Less than 18 years of age - Treatment usually not indicated, except treatment of epilepsy, and pre-/postoperative treatment. The smallest possible effective dose should be used for this group of patients.[21]
    • Under 6 months of age - Safety and effectiveness have not been established; diazepam should not be given to individuals in this age group.[13][21]
  • Elderly and very ill patients - Possibility that apnea and/or cardiac arrest may occur. Concomitant use of other central nervous system depressants increases this risk. The smallest possible effective dose should be used for this group of patients..[13][21][23]
  • I.V. or I.M. injections in hypotensive individuals or those in shock should be administered carefully and vital signs should be monitored.[23]

Patients at a high risk for abuse and dependence

Diazepam can lead to physiological tolerance, and psychological and/or physical dependence. At a particularly high risk for diazepam misuse, abuse, and dependence are:

Patients from the aforementioned groups should be monitored very closely during therapy for signs of abuse and development of dependence. Discontinue therapy if any of these signs are noted. Long-term therapy in these patients is not recommended.[13][24]

Withdrawal

Administration of therapeutic doses of diazepam for 6 weeks or longer can result in physical dependence, characterized by a withdrawal syndrome when the drug is discontinued. With larger doses, physical dependence develops more rapidly.[9]

After continued therapy in excess of a few weeks, diazepam should never be stopped abruptly. The dose should instead be lowered gradually, over a period of 2 to 4 weeks, in order to minimize withdrawal symptoms.[9][24]

Withdrawal symptoms are initially minimal, and increase in severity over the first 5 to 9 days after ingestion of the drug is stopped. Diazepam's long half-life and active metabolites delay the onset of such symptoms.[9]

The withdrawal symptoms for diazepam are similar to those of other CNS depressants (e.g. alcohol, barbiturates), and can include[9]:

  • Anxiety
  • Dysphoria
  • Irritability
  • Insomnia
  • REM Rebound
  • Confusion
  • Tremors
  • Muscle spasms
  • Abdominal and muscle cramps
  • Anorexia (i.e. lack of appetite)
  • Nausea/vomiting
  • Hyperthermia/sweating
  • Hypotension

In severe cases of diazepam withdrawal, symptoms can include:

  • Convulsions (i.e. seizures)
  • Death

The more severe side effects usually only develop for patients who were treated with excessive doses for extended periods of time. Usually only the milder symptoms develop in patients terminating therapeutic-level treatment after several months.[13]

Overdose

An individual who has consumed too much diazepam will display one or more of the following symptoms[13][25]:

  • Somnolence/difficulty staying awake
  • Mental confusion
  • Hypotension
  • Impaired motor functions
    • Impaired reflexes
    • Impaired coordination
    • Impaired balance
    • Dizziness
  • Coma

Although not usually fatal when taken alone, a diazepam overdose is considered a medical emergency and generally requires the immediate attention of medical personnel. The antidote for an overdose of diazepam (or any other benzodiazepine) is flumazenil (Anexate®). This drug is only used in cases with severe respiratory depression or cardiovascular complications. Because flumazenil is a short-acting drug and the effects of diazepam can last for days, several doses of flumazenil may be necessary. Artificial respiration and stabilization of cardiovascular functions may also be necessary. Although not routinely indicated, activated charcoal can be used for decontamination of the stomach following a diazepam overdose. Emesis is contraindicated. Dialysis is minimally effective. Hypotension may be treated with levarterenol or metaraminol.[9][7][13][25]

The oral LD50 (lethal dose in 50% of the population) of diazepam is 720mg/kg in mice and 1240mg/kg in rats.[13] A case where a patient took 300mg resulted only in prolonged sleep and consecutive drowsiness for the next days without serious impairment of cardiac or respiratory functions.[citation needed]

Overdoses of diazepam with alcohol and/or other depressants may be fatal.[7]

Recreational use

Generally, diazepam is not used as a recreational drug as frequently as alprazolam or flunitrazepam.

Diazepam is often found as an adulterant in heroin.[citation needed] This may be because diazepam greatly amplifies the effects of opioids.

Sometimes diazepam is used by stimulant abusers to 'come down' and sleep and also by users of LSD and other hallucinogens to help ease their trip without unpleasant after-effects.[citation needed]

Internationally, diazepam is a Schedule IV drug under the Convention on Psychotropic Substances.[26]

Trivia

  • Several plants, such as potato and wheat, contain trace amounts of naturally occurring diazepam and other benzodiazepines.[27]
  • In April 1975, a young New Jersey woman named Karen Ann Quinlan allegedly took a small dose of Valium along with alcohol, became unconscious and stopped breathing. She became comatose and was declared to be in a persistent vegetative state. Her right to die case ended up in the US Supreme Court. The life support system was not unplugged, however, and she was weaned from her respirator by doctors in 1976. She never woke up and died 9 years later.[citation needed]
  • Diazepam has had many high-profile users, including Andy Warhol and Elvis Presley.[6]
  • Valium is mentioned in the Sublime song "Don't Push," as well as Walk on the Wild Side by Lou Reed.

References

  • Fachinformationen (German) for Valium, provided by Roche Pharmaceuticals
  • Bandelow, Borwin et al. Handbuch der Arzneimitteltherapie, Bd.1, Psychopharmaka, 2nd edition. Enke, 2004. ISBN 3131130415.
  • Benkert, Otto et al. Kompendium der Psychiatrischen Pharmakotherapie, 5th edition. Springer, 2003. ISBN 3540218939.

Footnotes

  1. ^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 Oct 2023.
  2. ^ a b c d e f g h i Wishart, David (2006). "Diazepam". DrugBank. Retrieved 2006-03-10.
  3. ^ a b "Diazepam". PubChem. National Institute of Health: National Library of Medicine. 2006. Retrieved 2006-03-11.
  4. ^ "Diazepam". Medical Subject Headings (MeSH). National Library of Medicine. 2006. Retrieved 2006-03-10.
  5. ^ "WHO Model List of Essential Medicines" (PDF). World Health Organization. March 2005. Retrieved 2006-03-12.{{cite web}}: CS1 maint: year (link)
  6. ^ a b c Sample, Ian (Monday October 3, 2005). "Leo Sternbach's Obituary". The Guardian (Guardian Unlimited). Retrieved 2006-03-10. {{cite news}}: Check date values in: |date= (help)
  7. ^ a b c Barondes, Samuel H. (2003). Better Than Prozac. New York: Oxford University Press. pp. 47–59. ISBN 0195151305. {{cite book}}: Cite has empty unknown parameter: |month= (help)
  8. ^ a b c d e f g h i j k "Diazepam: indications". Rxlist.com. RxList Inc. January 24, 2005. Retrieved 2006-03-11.{{cite web}}: CS1 maint: year (link)
  9. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af Pere Munne/M. Ruse, Ed. (1990/1998 Ed.). "Diazepam". Inchem.org. Inchem.org. Retrieved 2006-03-11. {{cite web}}: Check date values in: |year= (help)CS1 maint: year (link)
  10. ^ a b c d e f g h i j Mikota, Susan K. and Plumb, Donald C. (2005). "Diazepam". The Elephant Formulary. Elephant Care International.{{cite web}}: CS1 maint: multiple names: authors list (link)
  11. ^ a b c Barondes, Samuel H. (1999). Molecules and Mental Illness. New York: Scientific American Library. pp. 190–194. ISBN 0716760339. {{cite book}}: Unknown parameter |month= ignored (help)
  12. ^ Sieghart, W. (1994). "Pharmacology of benzodiazepine receptors: an update". Journal of Psychiatry and Neuroscience. 19 (1): 24–29. PMID 8148363. Retrieved 2006-03-10. {{cite journal}}: Unknown parameter |month= ignored (help)
  13. ^ a b c d e f g h i j k l m n o p q r s Thomson Healthcare (Micromedex) (March 2000). "Diazepam". Prescription Drug Information. Drugs.com. Retrieved 2006-03-11.{{cite web}}: CS1 maint: year (link)
  14. ^ a b Langsam, Yedidyah. "DIAZEPAM (VALIUM AND OTHERS)". Brooklyn College (Eilat.sci.Brooklyn.CUNY.edu). Retrieved 2006-03-23.
  15. ^ Okoromah, C. N. (2004). "Diazepam for treating tetanus". Cochrane database of systematic reviews (Online) (1). PMID 14974046. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  16. ^ a b Hyperbaric Medicine Practice, Second Edition. Best Publishing Company. 1999. ISBN 0941332780. {{cite book}}: |first= missing |last= (help); Cite has empty unknown parameter: |month= (help)CS1 maint: multiple names: authors list (link)
  17. ^ Hines, Ron DVM PhD (January 14, 2006). "Epilepsy In Your Dog Or Cat". 2nd Chance Sanctuary Pet Health Center. Retrieved May 18. {{cite web}}: Check date values in: |accessdate= (help); Unknown parameter |accessyear= ignored (|access-date= suggested) (help)
  18. ^ "Diazepam: description". Rxlist.com. RxList Inc. January 24, 2005. Retrieved 2006-03-10.{{cite web}}: CS1 maint: year (link)
  19. ^ Kaewnopparat, N., Kaewnopparat, S., Rojanarat, W., Ingkatawornwong, S. (2004). "Enhanced Release of Diazepam From Hollow-Type Suppositories". International Journal of Pharmaceutical Compounding. Retrieved 2006-03-10. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  20. ^ a b c d e Holt, Gary A. (1998). Food and Drug Interactions: A Guide for Consumers. Chicago: Precept Press. pp. 90–91. ISBN 0944496598. {{cite book}}: Cite has empty unknown parameter: |month= (help)
  21. ^ a b c d e f g "Diazepam". PDRHealth.com. PDRHealth.com. 2006. Retrieved 2006-03-10.
  22. ^ Bateman, D.N. (1986). "The action of cisapride on gastric emptying and the pharmacodynamics and pharmacokinetics of oral diazepam". Eur J Clin Pharmacol. 30 (2): 205–8. PMID 3709647.
  23. ^ a b "Diazepam: precautions". Rxlist.com. RxList Inc. January 24, 2005. Retrieved 2006-03-10.{{cite web}}: CS1 maint: year (link)
  24. ^ a b c "Diazepam: abuse and dependence". Rxlist.com. RxList Inc. January 24, 2005. Retrieved 2006-03-10.{{cite web}}: CS1 maint: year (link)
  25. ^ a b "Diazepam: overdose". Rxlist.com. RxList Inc. January 24, 2005. Retrieved 2006-03-10.{{cite web}}: CS1 maint: year (link)
  26. ^ Wildmann J, Vetter W, Ranalder UB, Schmidt K, Maurer R, Mohler H (1988). "Occurrence of pharmacologically active benzodiazepines in trace amounts in wheat and potato". Biochem Pharmacol. 37 (19): 3549–59. PMID 3178869. {{cite journal}}: |access-date= requires |url= (help)CS1 maint: multiple names: authors list (link)

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