Diazepam (Valium) is a benzodiazepine class of drug that has got anti-anxiety, sedative, muscle relaxant, amnestic, and anti-seizure properties.

Diazepam (Valium) Uses:

• Acute ethanol withdrawal (oral and injection):
  • Acute agitation, tremor, imminent or acute delirium, delirium tremens, and hallucinations can all be helped by it.
• Anxiety (oral and injection):
  • Additionally, it is employed in the treatment of anxiety disorders. It is used to temporarily relieve the signs and symptoms of anxiety.
• Muscle spasm (oral and injection):
  • It can be used in conjunction with other treatments to relieve skeletal muscle tonic spasm brought on by reflex spasm brought on by local pathology (eg, inflammation of muscles or joints, secondary to trauma).
  • Athetosis, stiff-man syndrome, tetanus, cerebral palsy, and paraplegia are among the spasticity conditions brought on by upper motor neuron lesions.
• Preoperative (injection):
  • Additionally, it is utilised to reduce stress and anxiety in patients undergoing surgical treatments.
  • When administered intravenously, it can be used to ease tension and anxiety before cardioversion and to reduce the patient's recollection.
  • Prior to endoscopic treatments, diazepam is used as an adjuvant to treat nervousness, anxiety, or acute stress reactions as well as to reduce the patient's ability to remember.
  • Midazolam is preferred over diazepam in individuals having cardioversion or endoscopic operations.
• Seizures:
  • It is used in the management of convulsive disorders in oral form as an adjunct.
  • When administered rectally, it can be used to treat a small number of patients with refractory epilepsy who are using stable antiepileptic treatment regimens and who occasionally need to take diazepam to control bouts of increasing seizure activity.
  • As an adjuvant, it is used in the treatment of severe recurring convulsive seizures.
• Status epilepticus (injection):
  • In an intravenous form, it is used in the management of Status epilepticus.
• Off Label Use of Diazepam in Adults:
  • In an off-label setting, it may be used for sedation in the ICU patient who is suffering from Status epilepticus via rectal formulation.

 

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Diazepam (Valium) Dose in Adults:

It is noteworthy that it has more smooth oral absorption than when given intramuscularly.

Diazepam (Valium) Dose in the Acute ethanol withdrawal:

• IV, IM: 10 mg is given in the initial phase. And can be administered as 5 to 10 mg 3 to 4 hours later, if indicated.
• Oral: 10 mg 3 to 4 times during the first 24 hours, then taper off to 5 mg 3 to 4 times daily as indicated.

Diazepam (Valium) Dose in the treatment of Anxiety:

• Orally it is given as 2 to 10 mg 2 to 4 times daily if indicated.
• IM, IV: In parenteral form, it is administered as 2 to 10 mg and can be repeated in 3 to 4 hours, if indicated.

Diazepam (Valium) Dose in the treatment of Muscle spasm:

• Orally it is given as 2 to 10 mg 3 or 4 times daily
• IV, IM: Initially it is given as 5 to 10 mg. Then 5 to 10 mg in 3 to 4 hours, if necessary. Patients with tetanus require larger doses.

Diazepam (Valium) Dose as Preoperative:

• Anxiety:
  • IM: It is given as IM prior to surgery.

Diazepam (Valium) Dose for Sedation in the ICU patient (off-label):

• IV:The maintenance dose is 0.03 to 0.1 mg/kg every 30 minutes to 6 hours, while the loading dose is 5 to 10 mg

Diazepam (Valium) Dose in the Seizures:

• Adjunctive maintenance therapy:
  • Oral: 2 to 10 mg 2 to 4 times daily.
• Intermittent management of seizures:
  • Rectal gel (Diastat): If necessary, it can be repeated in 4 to 12 hours at a dose of 0.2 mg/kg. More than five episodes each month or one episode every five days should not be used. The approximate daily round-off dose for an increase is 2.5 mg.

Diazepam (Valium) Dose in the treatment of Status epilepticus:

IV:

• American Epilepsy Society recommendations:
  • 0.15 to 0.2 mg/kg with a maximum dose of 10 mg. It can be repeated once.
• Neurocritical Care Society recommendations:
  • It is given as 0.15 mg/kg with a maximum dose of 10 mg which is given at a rate of less than 5 mg/minute. It can be repeated in 5 minutes.

Rectal (formulation not specified) (off-label):

It should be noted that IV formulation can be given rectally if required when the rectal formulation is not available.

• • American Epilepsy Society recommendations:
    • Its dose is 0.2 to 0.5 mg/kg with a maximum dose of 20 mg.
  • Premonitory/Out-of-hospital treatment:
    • It is given in a stat dose of 10 mg and can be repeated once.

Diazepam (Valium) Dose in the treatment of Skeletal muscle relaxant (adjunct therapy):

• Oral: 2 to 10 mg 3 to 4 times daily

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Diazepam (Valium) Dose in Childrens

Diazepam (Valium) Dose in the acute Seizures:

• Rectal gel formulation:
  • Infants and Children 6 months to 2 years: Rectal: Dose not established
  • Children 2 to 5 years: Rectal: 0.5 mg/kg
  • Children 6 to 11 years: Rectal: 0.3 mg/kg
  • Children ≥12 years and Adolescents: Rectal: 0.2 mg/kg

It should be noted that the dose should be rounded up to the next 2.5 mg increment, but not more than 20 mg each dose. If necessary, the dose may be given again in 4 to 12 hours. Use no more than five times per month or once every five days.

• Rectal: Undiluted 5 mg/mL parenteral formulation (filter if using ampule):
  • Infants, Children, and Adolescents:
    • It is given as 5 mg/kg/dose then 0.25 mg/kg/dose after 10 minutes if needed.
    • The maximum dose is 20 mg/dose.

Diazepam (Valium) Dose in the treatment of Status epilepticus:

• Weight-directed:
  • Infants >30 days, Children, and Adolescents:
    • In IV form it is administered as 0.1 to 0.3 mg/kg/dose given over 3 to 5 minutes, every 5 to 10 minutes.
    • The maximum dose is 10 mg/dose.
• Fixed dosing: Manufacturer's labeling:
  • Infants >30 days and Children <5 years:
    • In IV form, a maximum total dose of 5 mg is administered as 0.2 to 0.5 mg slowly every 2 to 5 minutes.
    • If necessary, it can be repeated in two to four hours.
  • Children ≥5 years and Adolescents:
    • It can be given as 1 mg slowly intravenously every 2 to 5 minutes up to a maximum of 10 mg.
    • It can be repeated in 2 to 4 hours if indicated.

Diazepam (Valium) Dose in the prophylaxis of Febrile seizure: Limited data available:

• Children:
  • The oral dose is 1 mg/kg/day divided every 8 hours.
  • Initiate the therapy at the first sign of fever and continue for 24 hours after fever resolves.

Diazepam (Valium) Dose in the treatment of Spasticity/ muscle spasms:

General dosing:

• Note: The lowest effective dose should be used to begin the therapy, and the dose should then be personalised and titrated to effect and tolerability.
• Manufacturer's labeling:
  • Infants ≥6 months, Children, and Adolescents:
    • At first, 1 to 2.5 mg are administered orally three to four times a day. As needed and tolerable, gradually increase the dosage.
• Alternate dosing: Oral:
  • Infants ≥6 months and Children <12 years:
    • It is administered as divided doses of 0.12 to 0.8 mg/kg/day every 6 to 8 hours, with a maximum dose of 10 mg/dose.
  • Children ≥12 years and Adolescents:
    • 2 to 10 mg 2 to 4 times a day.

Diazepam (Valium) Dose in the treatment of Cerebral palsy-associated spasticity:

In this scenario, the dose should vary from patient to patient and titrated up according to tolerability.

• Weight-based dosing:
  • Children:
    • It is given orally as 0.01 to 0.3 mg/kg/day divided into 2 or 4 doses each day.
• Low-dose fixed dosing:
  • Children <12 years: Oral:
    • <8.5 kg: 0.5 to 1 mg at bedtime
    • 5 to 15 kg: 1 to 2 mg at bedtime
• Fixed dosing:
  • Children ≥5 years and Adolescents:
    • Oral: Given initially at 1.25 mg three times daily, with a possible titration up to 5 mg four times daily.

Diazepam (Valium) Dose in the treatment of Tetanus-associated spasm:

• Manufacturer's labeling:
  • Infants >30 days and children <5 years:
    • IV or IM: According to the directions, it is given as 1 to 2 mg every 3 to 4 hours.
  • Children ≥5 years and Adolescents:
    • IV or IM: As recommended, it is administered as 5 to 10 mg every 3 to 4 hours.
• Alternate dosing:
  • Infants and Children:
    • IV: Every 2 to 6 hours at first, 0.1 to 0.2 mg/kg/dose is administered, and the dosage is increased as necessary.
  • Adolescents:
    • IV: The dosage is started out at 5 mg every 2 to 6 hours and increased as needed. Increased dosages may be a sign.

Diazepam (Valium) Dose for Muscle spasm/ spasticity associated with chronic/ terminal illness (eg, palliative care settings):

• Infants, Children, and Adolescents:
  • It is administered orally in doses of 0.12 to 0.8 mg/kg/day, spaced every 6 to 12 hours. 10 mg is the maximum dose.
  • IM or IV: A maximum cumulative total dose of 0.6 mg/kg is given in 8 hours and is administered as 0.05 to 0.2 mg/kg/dose every 6 to 12 hours.
  • In palliative situations, the usual initial dose for children of less than 5 years is 5 mg/dose and in children of more than 5 years and adolescents is 10 mg/dose.

Diazepam (Valium) Dose for Sedation, anxiety, and amnesia prior to procedure: 

Oral:

• Infants ≥6 months:
  • 0.2 to 0.3 mg/kg 45 to 60 minutes prior to the procedure.
  • The maximum dose is 10 mg/dose.
• Children:
  • 0.2 to 0.5 mg/kg 45 to 60 minutes before the procedure with a maximum dose of 10 mg/dose,
• Adolescents:
  • 0.2 to 0.3 mg/kg 45 to 60 minutes before procedure. The maximum dose is 10 mg.

IV:

• Infants and Children:
  • Initial: To get the desired effect, titrate up slowly to 0.05 to 0.1 mg/kg over 3 to 5 minutes (the maximum total dose is 0.25 mg/kg).
• Adolescents:
  • IV: 5 m. And it can be repeated with 2.5 mg if indicated.

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Diazepam (Valium) Pregnancy Risk Factor D

• Studies on animal reproduction have revealed negative results.
• Diazepam crosses the placenta (and its metabolites N-desmethyldiazepam, temazepam, and oxazepam in humans).
• Although diazepam has been shown to be teratogenic, more data are needed to confirm it.
• Low birth weights and premature births can increase when mothers use benzodiazepines. 
• Exposure late in pregnancy can lead to hypoglycemia or respiratory problems in the neonate.
• Neonatal withdrawal symptoms may occur as soon as a few days or weeks after birth.
• Some benzodiazepines, such as diazepam, can also cause "floppy infant syndrome", which includes withdrawal symptoms.
• The potential teratogenicity for anticonvulsant therapy is affected by a combination of factors.
• Monotherapy is the best option for treating epilepsy in women. Avoidance of medications with high teratogenic potential is advised.

Use of diazepam while breastfeeding

• The hormone diazepam is secreted, and the metabolites of it are found in breast milk.
• One study found that the relative infant dose (RID), of diazepam, is 8.9% compared to a maternal dose of 10mg/day.
• When the RID of medication for breastfeeding is less than 10%, it is generally acceptable. 
• Some sources state that breastfeeding should not be considered if psychotropic drugs have a RID of less than 5%.
• Calculating the RID of diazepam using 85 ng/mL milk concentration, gives an infant daily dose via breastmilk of 0.01275 mg/kg/day.
• This was the highest concentration of milk after maternal administration of diazepam 10mg once daily at bedtime to four women postpartum (this sample was taken after five maternal doses).
• There have been reports of higher milk concentrations. It was not reported that milk concentrations were related to maternal dose.
• Breast milk and urine from exposed infants also contained active metabolites of diazepam such as desmethyldiazepam and oxazepam.
• It has been reported that infants have received relative doses up to 11%.
• Some infants who were breastfed diazepam have experienced weight loss and sedation.
• The half-life of diazepam is long and can accumulate in breastfed infants, particularly preterm infants and those who have been exposed to high maternal doses.
• Even if the maternal dose was low, significant dose accumulation could occur.
• One maternal dose can be compatible (WHO 2002).
• It is preferable to use shorter-acting agents if benzodiazepine use is necessary for breastfeeding women.
• Monitor infants for signs of sedation, poor weight gain, and decreased feeding.

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Dose in Kidney Disease:

Caution is advised in kidney diseases, however, no renal adjustment is required.

• Hemodialysis: It is not dialyzable (0% to 5%).  Additional administration of doses is not recommended.

Dose in Liver disease:

The oral formulation is contraindicated in liver diseases. However, no dose adjustment is required.     

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Adverse reactions may bed different depending upon route of administration.

Common Side Effects of Diazepam (Valium):

• Central nervous system:
  • Drowsiness

Less Common Side Effects of Diazepam (Valium):

• Cardiovascular:
  • Hypotension
  • Vasodilation
• Central Nervous System:
  • Nervousness
  • Ataxia
  • Confusion
  • Euphoria
  • Agitation
  • Emotional Lability
  • Abnormality In Thinking
  • Pain
  • Dizziness
  • Speech Disturbance
  • Headache
• Dermatologic:
  • Skin Rash
• Gastrointestinal:
  • Abdominal Pain
  • Diarrhea
• Neuromuscular & Skeletal:
  • Asthenia
• Respiratory:
  • Rhinitis
  • Asthma

Frequency of side effects Not Defined:

• Cardiovascular:
  • Localized Phlebitis
  • Venous Thrombosis
  • ECG Changes
• Central Nervous System:
  • Slurred Speech
  • Fatigue
  • Central Nervous System Depression
  • Myasthenia
  • Drug Dependence
  • Dysarthria
  • Hypoactivity
  • Paradoxical Central Nervous System Stimulation
  • Depression
  • Psychiatric Signs And Symptoms
  • Drug Withdrawal
  • Vertigo
  • Anterograde Amnesia
• Endocrine & Metabolic:
  • Change In Libido
• Gastrointestinal:
  • Hiccups
  • Constipation
  • Nausea
  • Gastrointestinal Distress
  • Altered Salivation
• Genitourinary:
  • Urinary Retention
  • Urinary Incontinence
• Hematologic & Oncologic:
  • Neutropenia
• Hepatic:
  • Increased Serum Transaminases
  • Jaundice
  • Increased Serum Alkaline Phosphatase
• Neuromuscular & Skeletal:
  • Tremor
• Ophthalmic:
  • Diplopia
  • Blurred Vision

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Contraindications to Diazepam (Valium):

• An absolute contraindication is hypersensitivity to diazepam or any of the formulation's ingredients.
• Severe hepatic impairment.
• Infants younger than 6 months old
• Grave respiratory depression.
• Sleep apnea syndrome.
• Acute narrow-angle, untreated open angle glaucoma.
• Myasthenia gravis.

There is not much data on allergenic cross-reactivity of benzodiazepines. 

Cross-sensitivity is possible due to similarities in physiochemical properties.

Warnings and precautions

• Anterograde amnesia
  • Patients taking benzodiazepines can experience anterograde amnesia.
• Depression in the CNS:
  • They can cause CNS depression that may lead to mental or physical impairments. 
  • It is important to warn patients about tasks that require mental alertness, such as driving, operating machinery, or operating machinery.
• Paradoxical reactions
  • With benzodiazepines, there have been reports of paradoxical reactions including aggressive or hyperactive behavior.
  • Patients who have a history of alcoholism or other mental illnesses may be more susceptible.
• Activities that are sleep-related:
  • Dangerous sleep-related behaviours like eating, drinking, and making phone calls while you're asleep have been seen with benzodiazepines.
• Convulsive disorders
  • As an adjunct to the treatment of convulsive disorders it can cause an increase in the frequency and severity or tonic-clonic seizures.
  • This may require a dose adjustment.
  • An abrupt stopping can temporarily increase the severity and frequency of seizures.
• Depression
  • Suicidal risk is higher, so it is advisable to be cautious
• Use of drugs:
  • Patients with a history or severe alcoholism should be cautious. It can lead to drug addiction.
  • If you use for longer than 10 days, tolerance and physical dependence can occur.
• Glaucoma
  • This medication can be used for open-angle patients who have received appropriate therapy.
  • Patients with acute narrow-angle or untreated open-angle, however, should not use it.
• Hepatic impairment
  • Patients with severe hepatic impairment should exercise caution. 
  • Patients with severe hepatic impairment should not take the oral tablet.
• Renal impairment
  • Renal impairment patients need to exercise caution.
• Respiratory disease
  • If you have a chronic illness, lower doses of the medication are advised. It can worsen sleep apnea syndrome.

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Diazepam: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Risk Factor C (Monitor therapy).
Ajmaline	The toxic/adverse effects of Ajmaline may be exacerbated by DiazePAM. Particularly, there may be an increase in the risk of cholestasis.
Alcohol (Ethyl).	Alcohol's CNS depressing effects can be amplified by CNS depressants (Ethyl).
Alfentanil	Alfentanil's CNS depressing effects can be exacerbated by diazepam. Also possible is hypotension.
Alizapride	CNS Depressants may intensify the effects of CNS Depressants.
Aprepitant	High risk of Inhibitors causing an increase in serum CYP3A4 Substrates concentrations
Bosentan	Could decrease serum levels of CYP3A4 substrates (High Risk with Inducers).
Brexanolone	Brexanolone's CNS depressing effects can be intensified by CNS depressants.
Brimonidine	CNS Depressants may intensify the effects of CNS Depressants.
Bromopride	CNS Depressants may intensify the effects of CNS Depressants.
Cannabidiol	CNS Depressants may intensify the effects of CNS Depressants.
Cannabis	CNS Depressants may intensify the effects of CNS Depressants.
Chlorphenesin Carbamate	They may have a harmful/toxic effect that can be made worse by CNS Depressants.
Clofazimine	High risk of Inhibitors causing an increase in serum CYP3A4 Substrates concentrations
CNS Depressants	Can increase the toxic/adverse effects of CNS Depressants.
Cosyntropin	Might increase the hepatotoxic effects of DiazePAM.
Moderate CYP2C19 Inducers	Could reduce the level of CYP2C19 substrates in serum (High Risk with Inducers).
Moderate CYP2C19 inhibitors	May reduce CYP2C19 substrate metabolism (High Risk with Inhibitors).
Moderate CYP3A4 Inducers	Could reduce the level of CYP2C19 substrates in serum (High Risk with Inducers).
Moderate CYP3A4 inhibitors	May reduce CYP2C19 substrate metabolism (High Risk with Inhibitors).
Deferasirox	Could reduce the level of CYP2C19 substrates in serum (High Risk with Inducers).
Dimethindene (Topical).	CNS Depressants may intensify the effects of CNS Depressants.
Disulfiram	May raise serum levels of DiazePAM
Doxylamine	CNS Depressants may have a greater CNS depressant effect if taken with other CNS Depressants. Management: Diclegis (doxylamine/pyridoxine), which is intended for pregnancy, has specifically stated that it should not be used with any other CNS depressants.
Dronabinol	CNS Depressants may increase the CNS depressant effects.
Duvelisib	High risk of Inhibitors causing an increase in serum CYP3A4 Substrates concentrations
Erdafitinib	Could lower serum concentrations of CYP3A4 substrates (High Risk with Inducers).
Erdafitinib	High risk of Inhibitors causing an increase in serum CYP3A4 Substrates concentrations
Esketamine	CNS Depressants may intensify the effects of CNS Depressants.
Travirine	Could decrease serum DiazePAM concentration. The serum concentration of DiazePAM may be increased by Etravirine
Fosamprenavir	May increase serum DiazePAM concentrations
Fosaprepitant	High risk of Inhibitors causing an increase in serum CYP3A4 Substrates concentrations
Fosnetupitant	High risk of Inhibitors causing an increase in serum CYP3A4 Substrates concentrations
HydrOXYzine	CNS Depressants may intensify the effects of CNS Depressants.
Ivosidenib	Could lower serum concentrations of CYP3A4 substrates (High Risk with Inducers).
Kava Kava	CNS Depressants may have an adverse/toxic effect that can be exacerbated by them.
Larotrectinib	High risk of Inhibitors causing an increase in serum CYP3A4 Substrates concentrations
Lofexidine	CNS Depressants may have a greater depressant effect on the brain. Management: Separate drug interaction monographs are available for drugs listed as an exception to this monograph.
Magnesium Sulfate	CNS Depressants may intensify the effects of CNS Depressants.
Melatonin	May intensify benzodiazepine's sedative effects.
MetyroSINE	MetyroSINE may have a sedative effect that can be enhanced by CNS depressants.
Minocycline	CNS Depressants may increase the CNS depressant effects.
Mirtazapine	CNS Depressants can increase the CNS depressant effects of Mirtazapine.
Nabilone	CNS Depressants may increase the CNS depressant effects.
Netupitant	High risk of Inhibitors causing an increase in serum CYP3A4 Substrates concentrations
Ombitasvir and Paritaprevir are the three main ingredients in Ritonavir.	Could lower the serum level of DiazePAM.
Ombitasvir and Ritonavir are the three main components of Ombitasvir.	Could lower the serum level of DiazePAM.
Palbociclib	High risk of Inhibitors causing an increase in serum CYP3A4 Substrates concentrations
Piribedil	CNS Depressants could increase the CNS depressant effects of Piribedil.
Pramipexole	Pramipexole may have a greater sedative effect if it is combined with CNS depressants.
Ritonavir	Serum concentrations of DiazePAM might rise.
ROPINIRole	CNS depressants may intensify ROPINIRole's sedative effects.
Rotigotine	CNS depressants may intensify Rotigotine's sedative effects.
Rufinamide	CNS Depressants may have an adverse/toxic effect that can be exacerbated by this. Particularly, dizziness and sleepiness may be increased.
Saquinavir	May raise serum levels of DiazePAM
Sarilumab	Could decrease serum levels of CYP3A4 substrates (High Risk with Inducers).
Selective Serotonin Reuptake inhibitors	Selective serotonin reuptake inhibitors' toxic/unfavorable effects can be exacerbated by CNS depressants.
Siltuximab	Could decrease serum levels of CYP3A4 substrates (High Risk with Inducers).
Simeprevir	High likelihood that inhibitors will raise serum concentrations of CYP3A4 substrates
Teduglutide	May raise benzodiazepine serum concentrations.
Tetrahydrocannabinol	CNS Depressants may intensify the effects of CNS Depressants.
Tetrahydrocannabinol, and Cannabidiol	CNS Depressants may intensify the effects of CNS Depressants.
Tocilizumab	Could decrease serum levels of CYP3A4 substrates (High Risk with Inducers).
Trimeprazine	CNS Depressants may intensify the effects of CNS Depressants.
Yohimbine	Antianxiety agents may have a less therapeutic effect.
Risk Factor D (Consider therapy modifications)
Blonanserin	CNS Depressants can increase the CNS depressant effects of Blonanserin.
Buprenorphine	CNS Depressants can increase the CNS depressant effects of buprenorphine. Management: Reduced doses of CNS depressants should be considered and avoidance of such drugs for patients at high risk of buprenorphine self-injection/overuse. Buprenorphine patches (Butrans) should be initiated at 5 mg/hr for adults when taken with other CNS depression drugs.
Chlormethiazole	CNS Depressants may increase the CNS depressant effects. Monitoring: Look out for signs of CNS depression. If a combination of chlormethiazole and other drugs is required, a reduced dose should be used.
CloZAPine	CloZAPine's toxic/adverse effects may be exacerbated by benzodiazepines. Management: Before starting clozapine, reduce or discontinue your benzodiazepines.
Strong CYP2C19 Inducers	May accelerate CYP2C19 substrate metabolism (High Risk with Inducers). Management: You might think about switching out one of the interfering medications with another medication. Contraindications may apply to specific combinations. Observe the label on the product.
Strong CYP2C19 inhibitors	Might decrease metabolism of CYP2C19 substrates (High Risk with Inhibitors).
Strong CYP3A4 Inducers	May speed up CYP3A4 substrate metabolism (High Risk with Inducers). Management: You might think about switching out one of the interfering medications with another medication.Contraindications may apply to specific combinations. Observe the label on the product.
Strong CYP3A4 inhibitors	Could possibly reduce the metabolism of CYP3A4 substrates (High Risk with Inhibitors).
Dabrafenib	High chance that inducers will lower serum CYP3A4 substrate levels. Management: If at all possible, look for CYP3A4 substrate substitutes. It is best to avoid concurrent therapy wherever possible. Keep a close eye on the substrate's clinical effects (especially therapeutic effects).
Dabrafenib	High chance that inducers will lower serum CYP2C19 substrate levels. Management: If at all possible, look for CYP2C19 substitutes. It is best to avoid concurrent therapy wherever possible. Keep a close eye on the substrate's clinical effects (especially therapeutic effects).
Droperidol	CNS Depressants may increase the CNS depressant effects. Management: Droperidol and other CNS agents, such as opioids, may be reduced or used in combination with droperidol. Separate drug interaction monographs provide more detail on exceptions to this monograph.
Enzalutamide	High chance that inducers will lower serum levels of CYP3A4 substrates. Management: Steer clear of using enzalutamide and CYP3A4 substrates simultaneously. When utilising enzalutamide or any other CYP3A4 sub-substance, you should use caution.
Enzalutamide	High chance that inducers will lower serum levels of CYP2C19 substratesThe amounts of active metabolites may be higher for medications that are activated by CYP2C19.Management: Refrain from using enzalutamide and CYP2C19 substrates at the same time.When using enzalutamide or any other CYP2C19 substrate, you should use caution.
Flunitrazepam	CNS Depressants can increase the CNS depressant effects of Flunitrazepam.
HYDROcodone	CNS Depressants can increase the CNS depressant effects of HYDROcodone. When possible, avoid concomitant use with hydrocodone and other CNS depressants. Combining these agents is not recommended unless there are other options. Limit the amount and duration of each drug when combined.
Lorlatinib	High risk of Inducers causing a decrease in serum concentrations of CYP3A4 substrates. Management: Do not use lorlatinib concurrently with any CYP3A4 Substrates. Even a slight decrease in serum concentrations could cause therapeutic failure or serious clinical consequences.
Methadone	Methadone's CNS depressant effects may be exacerbated by benzodiazepines. Methadone and benzodiazepines should not be used in combination by doctors. Any such combination should be done with extreme caution.
Methotrimeprazine	Methotrimeprazine may have a higher CNS depressant activity than CNS Depressants. Methotrimeprazine can increase the CNS depressant effects of CNS Depressants. Management: Lower the adult dose of CNS Depressants by 50% and start concomitant methotrimeprazine treatment. After clinically proven efficacy of methotrimeprazine, further CNS depressant dose adjustments should only be made.
MiFEPRIStone	High chance that inhibitors will raise serum levels of CYP3A4 substrates. During and after mifepristone treatment, reduce CYP3A4 substrates and keep an eye out for toxicities or high amounts. Avoid ergotamine and dihydroergotamine.
Mitotane	High risk of Inducers causing a decrease in serum concentrations of CYP3A4 substrates. Treatment: Patients receiving mitotane may require significant adjustments in the dosage of CYP3A4 Substrates.
Opioid Agonists	CNS Depressants can increase the CNS depressant effects of Opioid Aggonists. Management: When possible, avoid concomitant use opioid agonists, benzodiazepines, or other CNS depressionants. Combining these agents is not recommended unless there are other options. Limit the amount and duration of each drug when combined.
OxyCODONE	CNS Depressants can increase OxyCODONE's CNS depressant effects. When possible, avoid the simultaneous use of oxycodone and other CNS depressants. Combining these agents is not recommended unless there are other options. Limit the amount and duration of each drug when combined.
Perampanel	CNS Depressants may have a greater CNS depressant effect. Perampanel and any other CNS depressant drug should be used in combination. Patients who take perampanel together with any other drug should not engage in complex or high-risk activities until they have had experience with the combination.
Pitolisant	High risk of Inducers causing a decrease in serum concentrations of CYP3A4 substrates Management: Avoid combining pitolisant and a CYP3A4 substrat with a low therapeutic index. Pitolisant should not be combined with other CYP3A4 sub-substances.
St John's Wort	High risk of Inducers causing a decrease in serum CYP3A4 Substrates. Management: You may consider a different drug to replace one of the interacting drugs. Some combinations might be contraindicated. Refer to the manufacturer's label.
Stiripentol	High chance that inhibitors will raise serum levels of CYP3A4 substrates. Treatment: Steer clear of using stiripentol with CYP3A4 substrates that have a limited therapeutic index. This is done to prevent negative consequences and toxicity. Any CYP3A4 substrate that is administered in conjunction with stiripentol should be strictly monitored.
Suvorexant	CNS Depressants can increase the CNS depressant effects of Suvorexant. Management: Suvorexant or any other CNS depressionant can be reduced in doses. Suvorexant should not be taken with alcohol. It is also not recommended to take suvorexant along with any other drugs for insomnia.
Tapentadol	CNS Depressants may increase the CNS depressant effects. Tapentadol, benzodiazepines and other CNS depressants should be avoided when possible. Combining these agents is not recommended unless there are other options. Limit the amount and duration of each drug when combined.
Theophylline Derivatives	This could lessen the therapeutic benefits of benzos.
Zolpidem	CNS Depressants can increase the CNS depressant effects of Zolpidem. Management: For men who also take CNS depressants, reduce the adult Intermezzo brand sublingual Zolpidem dose to 1.75mg. For women, no dose adjustment is advised. Avoid using CNS depressants at night; do not use alcohol.
Risk Factor X (Avoid Combination)
Azelastine - Nasal	Azelastine's CNS depressing effects may be exacerbated by other CNS depressants.
Benznidazole	Possibly makes items containing propylene glycol more poisonous or harmful.
Bromperidol	CNS Depressants may intensify the effects of CNS Depressants.
Conivaptan	High risk of Inhibitors causing an increase in serum CYP3A4 Substrates concentrations
Fusidic Acid (Systemic).	High risk of Inhibitors causing an increase in serum CYP3A4 Substrates concentrations
Idelalisib	High risk of Inhibitors causing an increase in serum CYP3A4 Substrates concentrations
MetroNIDAZOLE Systemic	Possibly makes items containing propylene glycol more poisonous or harmful. There is a chance of having a disulfiram-like reaction.
OLANZapine	May intensify the toxic/unfavorable effects of benzos. Management: Refrain from taking olanzapine intramuscularly or parenterally at the same time. Additional adverse effects, like cardiorespiratory depression, are possible. There are no recommendations for oral administration in the Olanzapine prescribing material.
Orphenadrine	Orphenadrine may be more effective against CNS depression than other drugs.
Oxomemazine	CNS Depressants may increase the CNS depressant effects.
Paraldehyde	Paraldehyde may be enhanced by CNS depressants.
Sodium Oxybate	Benzodiazepines can intensify sodium oxybate's CNS depressing effects.
Thalidomide	CNS Depressants can increase Thalidomide's CNS depressant effects.

Monitoring parameters:

• Including heart rate, breathing rate, blood pressure, and mental state.
• Liver enzymes
• CBC combined with long-term therapy
• There are many signs that propylene glycol poisoning can be seen, especially if intravenous drug use is continuous and high-dose.
• BUN, serum creatinine, serum lactate, and osmol gap.
• A higher concentration of propylene glycol was predicted by an osmol gap greater than 10. Propylene glycol toxicity is indicated by values greater than 12.
• Patients who are seriously ill or on mechanical ventilation should be assessed and adjusted according to the scoring system (Richmond Agitation–Sedation Scale, or Sedation–Agitation Scale).

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How to administer Diazepam (Valium)?

Oral:

• • Use with meals or beverages. Before using, combine the oral concentration with water, juice, or soda. Do not measure the dose using the calibrated dropper. 

IV:

• • Do not mix other medications or solutions with the undiluted IV push.
  • Rapid injections can cause hypotension or respiratory depression. Adults should infuse at a maximum rate of 5 mg/minute.
  • Do not put medication into a small vein, such as one on your hand or wrist. Avoid administering intravenously.
  • Because of the risk of IV fluid precipitation and drug absorption into the tubing and infusion bags, continuous infusion is not recommended.

NotificationTo avoid extravasation, dialyzepam can be used as a vesicant. Make sure you place the needle or catheter correctly before and during infusion.

Extravasation management

• • Extravasation can be prevented by stopping IV administration immediately. Use cold compresses to dry the area.

Rectal gel

• • Check that the prescribed dose is accurate and visible before giving it. Make sure you can see the green "ready" band as well.
  • The patient should be positioned side by side with their front leg bent slightly.
  • Gently insert the lubricated rectal tip into the rectum. Push the plunger gently for three seconds once the rim is firmly in place over the rectal entrance.
  • Continue to hold the syringe for 3 more seconds. To prevent leakage, hold the buttocks together and slowly count to 3.
  • Keep it on the patient's side, with the patient facing you. Continue to watch the patient.
  • All unused medications, syringes, and other materials should be thrown away. Reuse not

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Mechanism of action of Diazepam (Valium):

• Several locations in the central nervous system, including the limbic and reticular systems, are where this compound binds to stereospecific GABA neuron postsynaptic GABA receptors.
• Increased neuronal membrane permeability for chloride ions is possible by enhancing the inhibitory effect GABA has on neuronal excitability.
• The shift in the chloride ions causes hyperpolarization (a state that is less excitable) and stabilization. 
• The GABA-A receptors appear to be responsible for the effects and receptors of benzodiazepine. Benzodiazepines don't bind to GABAB receptors.

The onset of action:

• Sedation: Pediatric patients: IV: 4 to 5 minutes
• Status epilepticus:
  • IV: 1 to 3 minutes;
  • Rectal: 2 to 10 minutes

Duration of action:

• Sedation: Pediatric patients: 60 to 120 minutes
• Status epilepticus: 15 to 30 minutes

Absorption:

• Oral:
  • Good absorption (>90%). When taken with a moderate-fat meal, its absorption is slowed and reduced.
• Rectal:
  • Well absorbed

Protein binding:

• Oral:
  • Neonates: 84% to 86%;
  • Adults: 98%
• Rectal: 95% to 98%

Metabolism:

• It is metabolized in the liver.
• The active metabolite of benzodiazepines is N-demethylated by CYP3A4 and 2C19 into N-desmethyldiazepam, and it is hydroxylated by CYP3A4 into temazepam.
• The subsequent metabolism of temazepam and N-desmethyldiazepam results in oxazepam.
• Glucuronidation effectively eliminates temazepam and oxazepam.

Bioavailability:

• IM: >90%
• Oral: >90%
• Rectal: 90%

Half-life elimination:

Note: Diazepam accumulates upon multiple dosing and the terminal elimination half-life is slightly prolonged.

• IM:
  • Premature neonates (GA: 28 to 34 weeks): 54 hours
  • Infants: ~30 hours
  • Children 3 to 8 years: 18 hours
  • Adults: Parent: ~60 to 72 hours; Desmethyldiazepam: ~152 to 174 hours
• IV:
  • Parent: 33 to 45 hours;
  • Desmethyldiazepam: 87 hours.
• Oral:
  • Parent: 44 to 48 hours;
  • Desmethyldiazepam: 100 hours
• Rectal:
  • Parent: 45 to 46 hours;
  • Desmethyldiazepam: 71 to 99 hours

Time to peak:

• IM: Median: 1 hour (range: 0.25 to 2 hours)
• IV: ~1 minute
• Oral: 15 minutes to 2.5 hours (1.25 hours when fasting; 2.5 hours with food)
• Rectal: 1.5 hours

Excretion:

• In urine  as predominantly as glucuronide conjugates.

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International Brand Names of Diazepam:

• Diastat AcuDial
• Diastat Pediatric
• diazePAM Intensol
• Valium
• BIO-Diazepam
• Diastat
• Diazemuls
• Diazepam 10
• Diazepam 5
• NOVO-Dipam
• PMS-Diazepam
• Valium
• Aliseum
• Alsaval
• Anlin
• Ansiolin
• Antenex
• Anxicalm
• Apaurin
• Apo-diazepam
• Apozepam
• Assival
• Azepam
• Azepan
• Baogin
• Benzopin
• Calium
• Calmpose
• Calmvita
• Cercine
• Ceregulart
• Compaz
• Condition
• D-Pam
• Dialag
• Diapam
• Diapine
• Diapo
• Diazem
• Diazemuls
• Diazepam
• Diazepam Desitin
• Diazepam-Eurogenerics
• Diazepam-ratiopharm
• Diazepan
• Diazepeks
• Diazetop
• Dipezona
• Dizam
• Dizep
• Doval
• Dupin
• DZP
• Elcion CR
• Epival
• Euphorin
• Evalin
• Gewacalm
• Horizon
• Ifa Fonal
• Kratium
• Lembrol
• Melode
• Nercon
• Nivalen
• Nixtensyn
• Noan
• Normabel
• Orinil
• Ortopsique
• Paceum
• Pacitran
• Pamizep
• Paranten
• Pax
• Paxum
• Placidox 10
• Placidox 2
• Placidox 5
• Plidan
• Propam
• Prozepam
• Psychopax
• Radizepam
• Ranzepam
• Relanium
• Remedium
• Renborin
• Sedium
• Seduxen
• Serenzin
• Sibazon
• Sincronex
• Sipam
• Solina
• Stedon
• Stesolid
• Stesolid Rectal Tube
• Sunzepam
• Sunzepan
• Talema
• Tranquirit
• Valaxona
• Valdimex
• Valiquid
• Valisanbe
• Valium
• Valiuzam
• Valpam
• Valzepam
• Vanconin
• Vatran
• Vescopam
• Vexepam
• Vodin
• Zopam

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Diazepam Brand Names in Pakistan:

Diazepam Injection 5 Mg/Ml in Pakistan
Diazepam	Star Laboratories (Pvt) Ltd.
Diazepam	Ameer Pharma
Diazepam	Ameer Pharma
Dipam Injection	Medicraft Pharmaceuticals (Pvt) Ltd.
Dizalex	Multinational Buisness Link
Relaxowan	Swan Pharmaceuticals(Pvt) Ltd
Somnite	P.D.H. Pharmaceuticals (Pvt) Ltd.
Valium	Roche Pakistan Ltd.

 

Diazepam Injection 5 Mg/5ml in Pakistan
Dispim	Fynk Pharmaceuticals

 

Diazepam Solution 5 Mg/5ml in Pakistan
Xepam	Xenon Pharmaceuticals (Pvt) Ltd.
Xepam	Xenon Pharmaceuticals (Pvt) Ltd.
Xepam	Xenon Pharmaceuticals (Pvt) Ltd.

 

Diazepam Tablets 2 Mg in Pakistan
Anglopam	Euro Pharma International
Anxosal	Universal Pharmaceuticals (Pvt) Ltd
Apaurin	Krka-Pak Pharmaceutical & Chemical Works
Benzopine	Danas Pharmaceuticals (Pvt) Ltd
Diazemed	Medifine Laboratories
Diazepam	Ethical Laboratories (Pvt) Ltd.
Diazepam	Ethical Laboratories (Pvt) Ltd.
Diazepam	Shifa Laboratories.(Pvt) Ltd.
Diazepam	Harmann Pharmaceutical Laboratories (Pvt) Ltd.
Diazepam	Unexo Labs (Pvt) Ltd.
Diazepam	Lahore Chemical & Pharmaceutical Works (Pvt) Ltd
Diazepam	Efroze Chemical Industries (Pvt) Ltd.
Diazepam	Lahore Chemical & Pharmaceutical Works (Pvt) Ltd
Diazepam	Nawabsons Laboratories (Pvt) Ltd.
Diazepam	Lahore Chemical & Pharmaceutical Works (Pvt) Ltd
Diazepam	Unison Chemical Works
Diazepam	Ardin Pharmaceuticals
Diazepam	Lisko Pakistan (Pvt) Ltd
Diazepam	Wilsons Pharmaceuticals
Europam	Euro Pharma International
Neopam	Ferozsons Laboratoies Ltd.
Neopam	Ferozsons Laboratoies Ltd.
Somaid	Gray`S Pharmaceuticals
Valium	Roche Pakistan Ltd.
Vazepam	Valor Pharmaceuticals
Velipam	Karachi Pharmaceutical Laboratory
Xepam	Xenon Pharmaceuticals (Pvt) Ltd.

 

Diazepam Tablets 5 Mg in Pakistan
Anglopam	Euro Pharma International
Anglopam	Euro Pharma International
Anglopam	Euro Pharma International
Anxosal	Universal Pharmaceuticals (Pvt) Ltd
Apaurin	Krka-Pak Pharmaceutical & Chemical Works
Benzopine	Danas Pharmaceuticals (Pvt) Ltd
Dalium	Pliva Pakistan (Pvt) Limited
Daz	Safe Pharmaceutical (Pvt) Ltd.
Diazemed	Medifine Laboratories
Diazepam	Ideal Pharmaceutical Industries
Diazepam	Lahore Chemical & Pharmaceutical Works (Pvt) Ltd
Diazepam	Lahore Chemical & Pharmaceutical Works (Pvt) Ltd
Diazepam	Shifa Laboratories.(Pvt) Ltd.
Diazepam	Lisko Pakistan (Pvt) Ltd
Diazepam	Lahore Chemical & Pharmaceutical Works (Pvt) Ltd
Diazepam	Unipharma (Pvt) Ltd.
Diazepam	Unipharma (Pvt) Ltd.
Diazepam	Amros Pharmaceuticals.
Diazepam	Ideal Pharmaceutical Industries
Diazepam	Ethical Laboratories (Pvt) Ltd.
Diazepam	Popular Chemical Works (Pvt) Ltd.
Diazepam	Nawabsons Laboratories (Pvt) Ltd.
Diazepam	Tabros Pharma
Diazepam	Nawabsons Laboratories (Pvt) Ltd.
Diazepam	Efroze Chemical Industries (Pvt) Ltd.
Diazepam	Ardin Pharmaceuticals
Diazepam	Unexo Labs (Pvt) Ltd.
Diazepam	Star Laboratories (Pvt) Ltd.
Diazepam	Ethical Laboratories (Pvt) Ltd.
Diazepam	Harmann Pharmaceutical Laboratories (Pvt) Ltd.
Diazepam	Wilsons Pharmaceuticals
Diazepam	Efroze Chemical Industries (Pvt) Ltd.
Diazin	Polyfine Chempharma (Pvt) Ltd.
Diazip	Aries Pharmaceuticals (Pvt) Ltd
Diazomil	Mediate Pharmaceuticals (Pvt) Ltd
Dipam Tablet	Leads Pharma (Pvt) Ltd
Europam	Euro Pharma International
Europam	Euro Pharma International
Europam	Euro Pharma International
Kozypam	Lisko Pakistan (Pvt) Ltd
Kozypam	Lisko Pakistan (Pvt) Ltd
Neopam	Ferozsons Laboratoies Ltd.
Neopam	Ferozsons Laboratoies Ltd.
Relax	Wilshire Laboratories (Pvt) Ltd.
Relaxipam	Epla Laboratories (Pvt) Ltd.
Somaid	Gray`S Pharmaceuticals
Valium	Roche Pakistan Ltd.
Vazepam	Valor Pharmaceuticals
Velipam	Karachi Pharmaceutical Laboratory
Velipam	Karachi Pharmaceutical Laboratory
Xepam	Xenon Pharmaceuticals (Pvt) Ltd.
Xepam	Xenon Pharmaceuticals (Pvt) Ltd.

 

Diazepam Tablets 10 Mg in Pakistan
Benzopine	Danas Pharmaceuticals (Pvt) Ltd
Dalium	Pliva Pakistan (Pvt) Limited
Diazepam	Ardin Pharmaceuticals
Dipam Tablet	Leads Pharma (Pvt) Ltd
Relax	Wilshire Laboratories (Pvt) Ltd.
Somaid	Gray`S Pharmaceuticals
Valium	Roche Pakistan Ltd.