Drugs List

Therapeutic Indications

Uses

Acute alcohol withdrawal
Anxiety state (severe) - short term relief
Control of muscle spasm in tetanus
Epileptic convulsions
Febrile convulsions
Muscle spasms
Premedication for anaesthesia
Sedation for surgical and diagnostic procedures
Status epilepticus

Administration

Intravenous injection can be irritant and may cause venous thrombosis. The thrombosis may not become apparent until several days after the injection. Intravenous injection should be given slowly at a rate of 1ml per minute into a large vein (for example, the antecubital fossa) whilst the patient is in a supine position.

It is advisable to keep the patient supine for at least an hour after administration.

Emulsion injection:
Can be administered by intravenous injection or intravenous infusion or by injection into the tubing of an ongoing infusion of sodium chloride 0.9% or dextrose 5% or dextrose 10%. Other routes are contraindicated.

Solution injection:
The injection solution may be administered by intramuscular, intravenous injection or intravenous infusion.

As absorption is painful, slow and erratic, the intramuscular route should only be employed when alternative routes are not possible.

Contraindications

Acute respiratory impairment
Breastfeeding
Chronic psychosis
Myasthenia gravis
Obsessional states
Phobic states
Respiratory depression
Severe hepatic impairment
Severe respiratory impairment
Sleep apnoea

Precautions and Warnings

Children under 3 years
Debilitation
Elderly
Females of childbearing potential
Cardiorespiratory insufficiency
Cerebral arteriosclerosis
Chronic respiratory impairment
Coma
History of alcohol abuse
History of drug misuse
Mild hepatic impairment
Organic brain syndrome
Personality disorder
Pregnancy
Renal impairment

Reduce dose in patients with hepatic impairment
Reduce dose in patients with renal impairment
Advise patient ability to drive or operate machinery may be impaired
Advise patient not to drive until they know how the medicine affects them
Advise patient this medicine is subject to driving restrictions
Not all available brands are licensed for all age groups
Not all available brands are licensed for all routes of administration
Not suitable as sole treatment of depression or anxiety with depression
Some formulations contain egg phospholipids
Some formulations contain propylene glycol
Some presentations may contain benzyl alcohol
Some products may contain soya or soya derivative
Patient should remain under medical supervision for 1 hour after injection
Resuscitation facilities must be immediately available
Refer women considering pregnancy for specialist advice and monitoring
Tolerance and dependence may occur
Amnesia may occur
Potential for withdrawal symptoms
Psychological adjustment may be impaired in loss or bereavement
Withdraw gradually after long-term use
Discontinue if paradoxical reactions occur
Reduce dose in debilitated patients
Reduce dose in elderly
Avoid long term use
Advise patient not to take St John's wort concurrently
Advise patient to avoid alcohol during treatment
Advise patient grapefruit products may increase plasma level
Advise patient to ensure 7- 8 hours of uninterrupted sleep/rest post dose

Diazepam may induce anterograde amnesia which occurs most frequently several hours after a dose. To reduce the risk patients should ideally ensure they can have uninterrupted sleep for 7 to 8 hours after a dose.

Use with caution in patients with cardiorespiratory insufficiency, as the limits of tolerance may be very wide in this patient group and dosage adjustment should be considered.

Use with caution in patients with organic brain disease, particularly arteriosclerosis as the limits of tolerance may be very wide in this patient group and dosage adjustment should be considered.

Benzodiazepines should be used to treat insomnia only when it is severe, disabling, or subjecting the individual to extreme distress.

Emulsion formulation (Diazemuls) caution in children under 3.

Solution formulation is contraindicated in neonates, as some formulations contain benzyl alcohol.

Pregnancy and Lactation

Pregnancy

Caution is advised in the use of diazepam during pregnancy.

Both diazepam and its metabolites cross the placenta and accumulate in the foetus,

There may be a small increased risk of congenital malformation (such as oral cleft) if benzodiazepines are used during the first trimester of pregnancy.

Diazepam may alter thermogenesis, cause loss of beat-to-beat variability in the foetal heart rate and decrease foetal movements.

Animal studies indicate that low dosages may permanently modify downstream responses to benzodiazepine receptors so altering selected behaviours. This raises concerns that long lasting effects on the central nervous system could be possible.

If, for compelling reasons, diazepam is administered during the late phase of pregnancy or during labour at high doses, effects on the neonate such as hypothermia, hypotonia and moderate respiratory depression can be expected due to the pharmacological action of the drug.

Infants born to mothers who take benzodiazepines chronically during the latter stages of pregnancy may develop physical dependence and may be at some risk for developing withdrawal symptoms in the postnatal period. This may manifest as intrauterine growth retardation, irritability, restlessness, tremors, muscular hypertonia, vigorous sucking, vomiting, diarrhoea, and convulsions.
A 'floppy infant syndrome' has also been reported, with hypotonia, lethargy, disturbances of temperature regulation and weak suckling, sometimes lasting for several months.
A dose-response relationship is considered likely, as complications in the newborn are observed more frequently with higher doses or extended exposure. Exposed newborns should be monitored during the first days of life.

Schaefer concludes that exposure to benzodiazepines such as diazepam, is not an indication for termination of pregnancy, noting that in cases of long term abuse or high doses during organogenesis a detailed foetal ultrasound should be offered. In later pregnancy, monitoring of foetal motor patterns can be performed (Schaefer 2007).

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14 to 17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Lactation

Diazepam is not recommended for use during breastfeeding.

Diazepam, and its active metabolite nordiazepam are present in breast milk and accumulate in the serum of breastfed infants with repeated doses. Effects reported as seen in exposed infants include: weight loss, lethargy and a depressed EEG consistent with sedation, mild jaundice, sedation.

Both diazepam and nordiazepam have long half lives, therefore, timing of breastfeeding in relation to dosing will not usually reduce infant exposure.

Most authors conclude that single maternal doses (for example, for sedation before a procedure) should not affect an infant but advise caution and possible delay of resumption of breastfeeding by 6-8 hours.

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Side Effects

Accidental injury
Aggression
Agranulocytosis
Amnesia
Anaphylaxis
Anterograde amnesia
Anxiety
Apnoea
Ataxia
Behavioural disturbances
Blood dyscrasias
Bradycardia
Cardiac arrest
Changes in libido
Chest pain
Confusion
Dependence
Depression
Disinhibition
Dizziness
Drowsiness
Dry mouth
Dysarthria
Erythema at injection site
Euphoria
Excitation
Falls
Fatigue
Gastro-intestinal disturbances
Gynaecomastia
Hangover effects
Headache
Hypersensitivity reactions
Hypotension
Hypotonia
Incontinence
Increases in hepatic enzymes
Insomnia
Irritability
Jaundice
Leucopenia
Light-headedness
Muscle weakness
Myasthenia
Nausea
Numbed emotions
Pain
Paradoxical reactions
Reduced alertness
Reproductive disorders
Respiratory depression
Salivation changes
Sedation
Skin reactions
Sleep disturbances
Slurred speech
Thrombocytopenia
Thrombophlebitis
Tremor
Urinary retention
Urticaria
Venous thrombosis
Vertigo
Visual disturbances
Withdrawal symptoms

Presentation

Parenteral formulations of diazepam.

Drugs List

Therapeutic Indications

Uses

Acute alcohol withdrawal
Anxiety state (severe) - short term relief
Control of muscle spasm in tetanus
Epileptic convulsions
Febrile convulsions
Muscle spasms
Premedication for anaesthesia
Sedation for surgical and diagnostic procedures
Status epilepticus

Dosage

To reduce likelihood of adverse effects, administer intravenous injections slowly (1ml/minute). Keep the patient supine for an hour after administration.

During prolonged administration, the dose should be decreased after 6 to 7 days to reduce the likelihood of accumulation and prolonged central nervous system depression.

Doses may vary with age, weight and individual patient response.

Adults

Elderly

Children

Neonates

Patients with Renal Impairment

Administration

Intravenous injection can be irritant and may cause venous thrombosis. The thrombosis may not become apparent until several days after the injection. Intravenous injection should be given slowly at a rate of 1ml per minute into a large vein (for example, the antecubital fossa) whilst the patient is in a supine position.

It is advisable to keep the patient supine for at least an hour after administration.

Emulsion injection:
Can be administered by intravenous injection or intravenous infusion or by injection into the tubing of an ongoing infusion of sodium chloride 0.9% or dextrose 5% or dextrose 10%. Other routes are contraindicated.

Solution injection:
The injection solution may be administered by intramuscular, intravenous injection or intravenous infusion.

As absorption is painful, slow and erratic, the intramuscular route should only be employed when alternative routes are not possible.

Contraindications

Acute respiratory impairment
Breastfeeding
Chronic psychosis
Myasthenia gravis
Obsessional states
Phobic states
Respiratory depression
Severe hepatic impairment
Severe respiratory impairment
Sleep apnoea

Precautions and Warnings

Children under 3 years
Debilitation
Elderly
Females of childbearing potential
Cardiorespiratory insufficiency
Cerebral arteriosclerosis
Chronic respiratory impairment
Coma
History of alcohol abuse
History of drug misuse
Mild hepatic impairment
Organic brain syndrome
Personality disorder
Pregnancy
Renal impairment

Reduce dose in patients with hepatic impairment
Reduce dose in patients with renal impairment
Advise patient ability to drive or operate machinery may be impaired
Advise patient not to drive until they know how the medicine affects them
Advise patient this medicine is subject to driving restrictions
Not all available brands are licensed for all age groups
Not all available brands are licensed for all routes of administration
Not suitable as sole treatment of depression or anxiety with depression
Some formulations contain egg phospholipids
Some formulations contain propylene glycol
Some presentations may contain benzyl alcohol
Some products may contain soya or soya derivative
Patient should remain under medical supervision for 1 hour after injection
Resuscitation facilities must be immediately available
Refer women considering pregnancy for specialist advice and monitoring
Tolerance and dependence may occur
Amnesia may occur
Potential for withdrawal symptoms
Psychological adjustment may be impaired in loss or bereavement
Withdraw gradually after long-term use
Discontinue if paradoxical reactions occur
Reduce dose in debilitated patients
Reduce dose in elderly
Avoid long term use
Advise patient not to take St John's wort concurrently
Advise patient to avoid alcohol during treatment
Advise patient grapefruit products may increase plasma level
Advise patient to ensure 7- 8 hours of uninterrupted sleep/rest post dose

Diazepam may induce anterograde amnesia which occurs most frequently several hours after a dose. To reduce the risk patients should ideally ensure they can have uninterrupted sleep for 7 to 8 hours after a dose.

Use with caution in patients with cardiorespiratory insufficiency, as the limits of tolerance may be very wide in this patient group and dosage adjustment should be considered.

Use with caution in patients with organic brain disease, particularly arteriosclerosis as the limits of tolerance may be very wide in this patient group and dosage adjustment should be considered.

Benzodiazepines should be used to treat insomnia only when it is severe, disabling, or subjecting the individual to extreme distress.

Emulsion formulation (Diazemuls) caution in children under 3.

Solution formulation is contraindicated in neonates, as some formulations contain benzyl alcohol.

Pregnancy and Lactation

Pregnancy

Caution is advised in the use of diazepam during pregnancy.

Both diazepam and its metabolites cross the placenta and accumulate in the foetus,

There may be a small increased risk of congenital malformation (such as oral cleft) if benzodiazepines are used during the first trimester of pregnancy.

Diazepam may alter thermogenesis, cause loss of beat-to-beat variability in the foetal heart rate and decrease foetal movements.

Animal studies indicate that low dosages may permanently modify downstream responses to benzodiazepine receptors so altering selected behaviours. This raises concerns that long lasting effects on the central nervous system could be possible.

If, for compelling reasons, diazepam is administered during the late phase of pregnancy or during labour at high doses, effects on the neonate such as hypothermia, hypotonia and moderate respiratory depression can be expected due to the pharmacological action of the drug.

Infants born to mothers who take benzodiazepines chronically during the latter stages of pregnancy may develop physical dependence and may be at some risk for developing withdrawal symptoms in the postnatal period. This may manifest as intrauterine growth retardation, irritability, restlessness, tremors, muscular hypertonia, vigorous sucking, vomiting, diarrhoea, and convulsions.
A 'floppy infant syndrome' has also been reported, with hypotonia, lethargy, disturbances of temperature regulation and weak suckling, sometimes lasting for several months.
A dose-response relationship is considered likely, as complications in the newborn are observed more frequently with higher doses or extended exposure. Exposed newborns should be monitored during the first days of life.

Schaefer concludes that exposure to benzodiazepines such as diazepam, is not an indication for termination of pregnancy, noting that in cases of long term abuse or high doses during organogenesis a detailed foetal ultrasound should be offered. In later pregnancy, monitoring of foetal motor patterns can be performed (Schaefer 2007).

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14 to 17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Lactation

Diazepam is not recommended for use during breastfeeding.

Diazepam, and its active metabolite nordiazepam are present in breast milk and accumulate in the serum of breastfed infants with repeated doses. Effects reported as seen in exposed infants include: weight loss, lethargy and a depressed EEG consistent with sedation, mild jaundice, sedation.

Both diazepam and nordiazepam have long half lives, therefore, timing of breastfeeding in relation to dosing will not usually reduce infant exposure.

Most authors conclude that single maternal doses (for example, for sedation before a procedure) should not affect an infant but advise caution and possible delay of resumption of breastfeeding by 6-8 hours.

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Effects on Ability to Drive and Operate Machinery

This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988 (England and Wales). This medicine may be subject to police testing and has specified maximum blood levels for driving. When prescribing this medicine: Advise patient the medicine can affect cognitive function and is likely to affect ability to drive. Advise patient not to drive until they know how the medicine affects them. It is an offence to drive while under the influence of this medicine. However, a patient is not committing an offence (called 'statutory defence') if: 1.The medicine has been prescribed to treat a medical or dental problem and 2.The medicine has been taken according to the instructions given by the prescriber and/or in the information provided with the medicine and 3.The medicine was not affecting the ability to drive safely. For further guidance see https://www.gov.uk

Side Effects

Accidental injury
Aggression
Agranulocytosis
Amnesia
Anaphylaxis
Anterograde amnesia
Anxiety
Apnoea
Ataxia
Behavioural disturbances
Blood dyscrasias
Bradycardia
Cardiac arrest
Changes in libido
Chest pain
Confusion
Dependence
Depression
Disinhibition
Dizziness
Drowsiness
Dry mouth
Dysarthria
Erythema at injection site
Euphoria
Excitation
Falls
Fatigue
Gastro-intestinal disturbances
Gynaecomastia
Hangover effects
Headache
Hypersensitivity reactions
Hypotension
Hypotonia
Incontinence
Increases in hepatic enzymes
Insomnia
Irritability
Jaundice
Leucopenia
Light-headedness
Muscle weakness
Myasthenia
Nausea
Numbed emotions
Pain
Paradoxical reactions
Reduced alertness
Reproductive disorders
Respiratory depression
Salivation changes
Sedation
Skin reactions
Sleep disturbances
Slurred speech
Thrombocytopenia
Thrombophlebitis
Tremor
Urinary retention
Urticaria
Venous thrombosis
Vertigo
Visual disturbances
Withdrawal symptoms

Overdosage

It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.

The following number will direct the caller to the relevant local centre (0844) 892 0111

Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

The MHRA have produced 'generic' overdose sections for the top ten drugs for which the NPIS received the greatest number of queries about management of overdose in 2002. This information is attached below:

Signs and Symptoms

Benzodiazepines commonly cause drowsiness, ataxia, dysarthria and nystagmus. Coma, hypotension and respiratory depression occasionally occur but are seldom serious if these drugs are taken alone. Coma usually lasts only a few hours but in elderly people it may be more protracted and cyclical. Benzodiazepine respiratory depressant effects are more serious in patients with severe chronic respiratory disease.

Benzodiazepines potentiate the effects of other central nervous system depressants, including alcohol.

Treatment

Consider activated charcoal in adults or children who have taken more than 1 mg/kg within 1 hour, provided they are not too drowsy. Gastric lavage is unnecessary if these drugs have been taken alone. Patients who are asymptomatic at four hours are unlikely to develop symptoms. Institute supportive measures as indicated by the patient's clinical state.

If CNS depression is severe consider the use of flumazenil (Anexate), a benzodiazepine antagonist. This should rarely be required. It has a short half-life (about an hour) and should NOT TO BE USED IN MIXED OVERDOSE OR AS A "DIAGNOSTIC" TEST. It is contraindicated in the presence of drugs that reduce seizure threshold (e.g. tricyclic antidepressants).

Further Information

Last Full Review Date: September 2014

Reference Sources

Drugs During Pregnancy and Lactation: Treatment Options and Risk Assessment, 2nd edition (2007) ed. Schaefer, C., Peters, P. and Miller, R. Elsevier, London.

Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 9th edition (2011) ed. Briggs, G., Freeman, R. and Yaffe, S. Lippincott Williams & Wilkins, Philadelphia

Injectable Medicines Administration Guide, 3rd edition (2010) UCL NHS Foundation Trust. Wiley-Blackwell, Oxford.

Summary of Product Characteristics: Diazemuls. Actavis. Revised May 2017.

Summary of Product Characteristics: Diazepam injection. Wockhardt. Revised May 2017.

Summary of Product Characteristics: Diazepam injection. Hameln Pharmaceuticals. Revised December 2015.

The Renal Drug Handbook. 3rd edition. (2009) ed. Ashley, C and Currie, Radcliffe Publishing Ltd, Abingdon.

Drugs in Lactation Database, LactMed, diazepam record, Revised 27 December 2007.
Available at : https://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT
Accessed 4 September 2014.

European Porphyria Network
Available at: https://www.porphyria-europe.com/03-drugs/selecting-drugs.asp
Last accessed: September 4, 2014.

Gov.uk. Government departments. Department for Transport. Publications. Drug driving and medicine: advice for healthcare professionals. Drug driving: Guidance for healthcare professionals on drug driving. Available at: https://www.gov.uk Last accessed: 6 January 2015

MHRA (www.mhra.gov.uk) Generic Overdose sections based on Toxbase for Diazepam/Temazepam
Available at: https://www.mhra.gov.uk/home/idcplg?IdcService=SS_GET_PAGE&nodeId=786
Last updated 19 September 2005, accessed September 2014.

NICE - Evidence Services
Available at: www.nice.org.uk
Last accessed: 27 June 2017.

The Drug Data Base for Acute Porphyria
Available at: https://www.drugs-porphyria.org/languages/UnitedKingdom/s1.php?l=gbr
Diazepam last revised: March 21, 2012
Last accessed: 4 September, 2014.